9	30613437	Ultimately, the diagnosis is based on two out of the three following criteria: the presence of biochemical cholestasis (an elevated ALP), presence of ant-mitochondrial antibodies (AMA), and classic histological findings of PBC on a liver biopsy (destructive cholangitis affecting the interlobular bile ducts).	('presence', 'Var', (138, 146))	('ALP', 'Gene', (132, 135))	('interlobular bile ducts', 'Phenotype', 'HP:0025344', (284, 307))	('PBC', 'Phenotype', 'HP:0002613', (223, 226))	('cholangitis', 'Disease', 'MESH:D002761', (258, 269))	('cholestasis', 'Phenotype', 'HP:0001396', (107, 118))	('PBC', 'Gene', (223, 226))	('ALP', 'Gene', '250', (132, 135))	('cholangitis', 'Disease', (258, 269))	('PBC', 'Gene', '1737', (223, 226))	('cholangitis', 'Phenotype', 'HP:0030151', (258, 269))	('ant-mitochondrial antibodies', 'Protein', (150, 178))	('cholestasis', 'Disease', 'MESH:D002779', (107, 118))	('elevated ALP', 'Phenotype', 'HP:0003155', (123, 135))	('cholestasis', 'Disease', (107, 118))
46	30613437	In addition, US-MSC was shown to improve quality of life in PBC patients as it alleviated pruritus and fatigue.	('quality', 'MPA', (41, 48))	('improve', 'PosReg', (33, 40))	('fatigue', 'Disease', 'MESH:D005221', (103, 110))	('PBC', 'Phenotype', 'HP:0002613', (60, 63))	('patients', 'Species', '9606', (64, 72))	('fatigue', 'Disease', (103, 110))	('fatigue', 'Phenotype', 'HP:0012378', (103, 110))	('pruritus', 'Phenotype', 'HP:0000989', (90, 98))	('pruritus', 'Disease', (90, 98))	('alleviated', 'NegReg', (79, 89))	('PBC', 'Gene', '1737', (60, 63))	('pruritus', 'Disease', 'MESH:D011537', (90, 98))	('PBC', 'Gene', (60, 63))	('US-MSC', 'Var', (13, 19))
107	30613437	Targeted therapy towards this protein and other inducers of cellular senescence could have significant utility in the treatment of PSC.	('Targeted', 'Var', (0, 8))	('PSC', 'Gene', (131, 134))	('PSC', 'Gene', '100653366', (131, 134))
114	30613437	As it is primarily secreted in the unchanged glucuronidated form, 24-norUDCA increases hydrophilicity of biliary bile acids stimulating bile flow.	('bile acids', 'Chemical', 'MESH:D001647', (113, 123))	('bile flow', 'MPA', (136, 145))	('24-norUDCA', 'Var', (66, 76))	('increases', 'PosReg', (77, 86))	('hydrophilicity of biliary bile acids', 'MPA', (87, 123))
120	30613437	Damage in the livers of mice with the Mdr2 knocked out (Mdr2-/-) have been shown to mimic PSC-associated damage.	('mice', 'Species', '10090', (24, 28))	('PSC', 'Gene', '100653366', (90, 93))	('Mdr2', 'Gene', (38, 42))	('knocked out', 'Var', (43, 54))	('PSC', 'Gene', (90, 93))
171	30613437	A recent article published in Human Pathology studied 54 intrahepatic tumors and found that 7.4% of cases were found to have mutated KRAS genes and a mutually exclusive 7.4% were found to have mutated BRAF genes.	('Human', 'Species', '9606', (30, 35))	('intrahepatic tumors', 'Disease', (57, 76))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('intrahepatic tumors', 'Disease', 'MESH:D002780', (57, 76))	('BRAF', 'Gene', '673', (201, 205))	('mutated', 'Var', (125, 132))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('KRAS', 'Gene', (133, 137))	('KRAS', 'Gene', '3845', (133, 137))	('BRAF', 'Gene', (201, 205))
173	30613437	S100 calcium-binding protein A7, which is implicated in the progression of CCA, was found to be a downregulated by microRNA-26b-5p.	('downregulated', 'NegReg', (98, 111))	('S100 calcium-binding protein A7', 'Gene', '6278', (0, 31))	('S100 calcium-binding protein A7', 'Gene', (0, 31))	('CCA', 'Disease', (75, 78))	('microRNA-26b-5p', 'Var', (115, 130))	('CCA', 'Phenotype', 'HP:0030153', (75, 78))
183	30613437	It was found that activation of epidermal growth factor receptor (EGFR), fibroblast growth factor (FGFR), and platelet-derived growth factor receptor (PDGFR) via phosphorylation leads to activation of STAT3, and a subsequent increase of the cell cycle.	('platelet-derived growth factor receptor', 'Gene', (110, 149))	('epidermal growth factor receptor', 'Gene', '1956', (32, 64))	('STAT3', 'Gene', '6774', (201, 206))	('phosphorylation', 'Var', (162, 177))	('activation', 'PosReg', (187, 197))	('EGFR', 'Gene', (66, 70))	('increase', 'PosReg', (225, 233))	('cell cycle', 'CPA', (241, 251))	('EGFR', 'Gene', '1956', (66, 70))	('STAT3', 'Gene', (201, 206))	('epidermal growth factor receptor', 'Gene', (32, 64))	('platelet-derived growth factor receptor', 'Gene', '5159', (110, 149))	('PDGFR', 'Gene', (151, 156))	('activation', 'PosReg', (18, 28))	('PDGFR', 'Gene', '5159', (151, 156))
205	28199974	We employed transient transfection experiments, clonogenic assays and cell cycle profiling to evaluate the biological consequences of miR-204 perturbation.	('miR-204', 'Gene', '406987', (134, 141))	('perturbation', 'Var', (142, 154))	('miR-204', 'Gene', (134, 141))
228	28199974	We showed that manipulating the levels of miR-204 (by means of agonist molecules) in representative GC and CC cell lines, led to a reversal of the identified gene target signature.	('miR-204', 'Gene', '406987', (42, 49))	('miR-204', 'Gene', (42, 49))	('manipulating', 'Var', (15, 27))
275	28199974	Next, we assessed whether manipulating the levels of the miR-204 gene targets in the GTL-16 and HUCCT1 cells, by means of transfecting mimic-204, could affect some of their protumorigenic properties.	('transfecting', 'Var', (122, 134))	('GTL-16', 'Chemical', '-', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('miR-204', 'Gene', (57, 64))	('tumor', 'Disease', (176, 181))	('manipulating', 'Var', (26, 38))	('affect', 'Reg', (152, 158))	('miR-204', 'Gene', '406987', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
281	28199974	In detail, silencing of SHCBP1 in HUCCT1 cells strongly increased the Sub-G1 cells (Figure 6A).	('Sub-G1 cells', 'CPA', (70, 82))	('silencing', 'Var', (11, 20))	('increased', 'PosReg', (56, 65))	('SHCBP1', 'Gene', '79801', (24, 30))	('SHCBP1', 'Gene', (24, 30))
283	28199974	Silencing of the mentioned genes affected very similarly both the GTL-16 and HUCCT1 cells, with the exception of FOXM1 in the GTL-16 cells (Figure 6B).	('affected', 'Reg', (33, 41))	('GTL-16', 'Chemical', '-', (126, 132))	('FOXM1', 'Gene', '2305', (113, 118))	('FOXM1', 'Gene', (113, 118))	('GTL-16', 'Chemical', '-', (66, 72))	('Silencing', 'Var', (0, 9))
284	28199974	Clonogenic assays revealed that silencing of each of the target caused a reduction in colony formation, thus fully matching what observed when ectopically expressing the miR-204 (Figure 6C-6D).	('miR-204', 'Gene', (170, 177))	('silencing', 'Var', (32, 41))	('miR-204', 'Gene', '406987', (170, 177))	('colon', 'Disease', (86, 91))	('reduction', 'NegReg', (73, 82))	('colon', 'Disease', 'MESH:D015179', (86, 91))
285	28199974	Interestingly, silencing of KIF15 did not affect and rather increased the colony forming ability of both the transfected cell lines, despite silencing of the latter elicited increased sub-G1 cells in both cell lines (Figure 6C-6D).	('silencing', 'NegReg', (141, 150))	('sub-G1 cells', 'CPA', (184, 196))	('colon', 'Disease', 'MESH:D015179', (74, 79))	('silencing', 'Var', (15, 24))	('KIF15', 'Gene', '56992', (28, 33))	('colon', 'Disease', (74, 79))	('KIF15', 'Gene', (28, 33))	('increased', 'PosReg', (174, 183))	('increased', 'PosReg', (60, 69))
306	28199974	More in detail, while silencing of SHCBP1, RAD51, NOTCH1 and FOXM1 significantly increased the cells in the sub-G1 phase, all of the tested miR-204 targets (except for KIF15) affected the clonogenicity of the transfected cell lines.	('NOTCH1', 'Gene', '4851', (50, 56))	('miR-204', 'Gene', '406987', (140, 147))	('clonogenicity of the transfected cell lines', 'CPA', (188, 231))	('SHCBP1', 'Gene', (35, 41))	('increased', 'PosReg', (81, 90))	('NOTCH1', 'Gene', (50, 56))	('affected', 'Reg', (175, 183))	('miR-204', 'Gene', (140, 147))	('KIF15', 'Gene', '56992', (168, 173))	('FOXM1', 'Gene', (61, 66))	('silencing', 'Var', (22, 31))	('FOXM1', 'Gene', '2305', (61, 66))	('RAD51', 'Gene', (43, 48))	('cells in the sub-G1 phase', 'CPA', (95, 120))	('KIF15', 'Gene', (168, 173))	('RAD51', 'Gene', '5888', (43, 48))	('SHCBP1', 'Gene', '79801', (35, 41))
310	28199974	With regard to this, we also observed different kinetics between the two cell lines analyzed (GTL-16 and HUCCT1, respectively, with the GTL-16 exhibiting a earlier modulation of the targets when transfected with the mimic-204 (as compared with the HUCCT1 cells, transfected in very similar conditions).	('GTL-16', 'Chemical', '-', (136, 142))	('GTL-16', 'Gene', (136, 142))	('GTL-16', 'Chemical', '-', (94, 100))	('mimic-204', 'Var', (216, 225))
325	28199974	Human gastric cancer cell lineGTL-16 was grown in DMEM medium (Invitrogen) supplemented with 10% fetal bovine serum (FBS), penicillin (100 U/ml) and streptomycin (100ug/ml) at 37 C in a balanced air humidified incubator with 5% CO2.	('Human', 'Species', '9606', (0, 5))	('GTL-16', 'Chemical', '-', (30, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (6, 20))	('CO2', 'Chemical', '-', (228, 231))	('bovine', 'Species', '9913', (103, 109))	('FBS', 'Disease', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('penicillin', 'Chemical', 'MESH:D010406', (123, 133))	('streptomycin', 'Chemical', 'MESH:D013307', (149, 161))	('FBS', 'Disease', 'MESH:D005198', (117, 120))	('DMEM medium', 'Chemical', '-', (50, 61))	('gastric cancer', 'Disease', (6, 20))	('gastric cancer', 'Disease', 'MESH:D013274', (6, 20))	('100ug/ml', 'Var', (163, 171))
326	28199974	The cholangiocarcinoma cell line HUCCT1 was grown in RPMI medium (Invitrogen) supplemented with 10% fetal bovine serum (FBS), penicillin (100 U/ml) and streptomycin (100ug/ml) at 37 C in a balanced air humidified incubator with 5% CO2.	('bovine', 'Species', '9913', (106, 112))	('CO2', 'Chemical', '-', (231, 234))	('streptomycin', 'Chemical', 'MESH:D013307', (152, 164))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (4, 22))	('FBS', 'Disease', 'MESH:D005198', (120, 123))	('penicillin', 'Chemical', 'MESH:D010406', (126, 136))	('100ug/ml', 'Var', (166, 174))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (4, 22))	('RPMI medium', 'Chemical', '-', (53, 64))	('100 U/ml', 'Var', (138, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('FBS', 'Disease', (120, 123))	('cholangiocarcinoma', 'Disease', (4, 22))
376	26842558	2-NBDLG and 2-TRLG were provided by Peptide Institute Inc. Carbenoxolone (100 muM, C4790, Sigma) was routinely added to block hemichannel/gap junction.	('C4790', 'Var', (83, 88))	('2-TRLG', 'Chemical', '-', (12, 18))	('Carbenoxolone', 'Chemical', 'MESH:D002229', (59, 72))	('2-NBDLG', 'Chemical', '-', (0, 7))	('hemichannel/gap', 'Protein', (126, 141))
439	26842558	However, careful investigation should be required for the comparison, since 2-NBDLG is taken up into tumor cells, whereas fluorescein is not taken up into cells.	('2-NBDLG', 'Chemical', '-', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('2-NBDLG', 'Var', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('fluorescein', 'Chemical', 'MESH:D019793', (122, 133))
457	26842558	A highly disorganized fluorescence pattern obtained from CDDB/BOP group was very different from that in normal group.	('CDDB/BOP', 'Var', (57, 65))	('CDDB/BOP', 'Chemical', '-', (57, 65))	('fluorescence pattern', 'MPA', (22, 42))
489	31341363	For example, aberrant overexpression of cyclins D1 and E, two members of the cyclin family, contributes to carcinogenesis and malignant progression due to the dysfunction of the cell cycle.	('contributes', 'Reg', (92, 103))	('cell cycle', 'CPA', (178, 188))	('overexpression', 'PosReg', (22, 36))	('malignant progression', 'CPA', (126, 147))	('cyclins D1 and E', 'Gene', '595', (40, 56))	('carcinogenesis', 'Disease', 'MESH:D063646', (107, 121))	('carcinogenesis', 'Disease', (107, 121))	('dysfunction', 'CPA', (159, 170))	('aberrant', 'Var', (13, 21))
490	31341363	Wee1 is essential for G2 cell cycle checkpoint in response to DNA damage and repair and overexpressed Wee1 has been linked to a number of cancers, such as carcinoma and glioblastoma.	('Wee1', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('Wee1', 'Gene', '7465', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (169, 181))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('overexpressed', 'Var', (88, 101))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('linked to', 'Reg', (116, 125))	('carcinoma and glioblastoma', 'Disease', 'MESH:D005909', (155, 181))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancers', 'Disease', (138, 145))	('Wee1', 'Gene', '7465', (102, 106))	('Wee1', 'Gene', (102, 106))
552	31341363	In conclusion, our results suggest that RA treatment causes increased apoptosis and impaired cell functions in cholangiocarcinoma cell lines via a Wee1-dependent mechanism and that RA is an enhancer of 5-Fu in bile duct cancer through activating multiple cell cycle and apoptosis-related factors, such as Cox-2, Bax, Bcl-2, and cyclins E/D1.	('Bcl-2', 'Gene', '596', (317, 322))	('Bax', 'Gene', (312, 315))	('impaired', 'NegReg', (84, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cholangiocarcinoma cell lines', 'Disease', (111, 140))	('apoptosis', 'CPA', (70, 79))	('Bax', 'Gene', '581', (312, 315))	('Wee1', 'Gene', '7465', (147, 151))	('E/D1', 'Var', (336, 340))	('Cox-2', 'Gene', '5743', (305, 310))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))	('bile duct cancer', 'Phenotype', 'HP:0030153', (210, 226))	('cell functions', 'CPA', (93, 107))	('bile duct cancer', 'Disease', (210, 226))	('RA', 'Chemical', 'MESH:C584473', (40, 42))	('cholangiocarcinoma cell lines', 'Disease', 'MESH:D018281', (111, 140))	('bile duct cancer', 'Disease', 'MESH:D001650', (210, 226))	('activating', 'PosReg', (235, 245))	('E/D1', 'SUBSTITUTION', 'None', (336, 340))	('Bcl-2', 'Gene', (317, 322))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('RA', 'Chemical', 'MESH:C584473', (181, 183))	('Cox-2', 'Gene', (305, 310))	('5-Fu', 'Chemical', 'MESH:D005472', (202, 206))	('Wee1', 'Gene', (147, 151))
664	26911896	In addition, benign biliary strictures can cause jaundice, pain, pruritus, hepatocellular dysfunction, biliary cirrhosis, and cholangitis.	('hepatocellular dysfunction', 'Phenotype', 'HP:0001404', (75, 101))	('hepatocellular dysfunction', 'Disease', (75, 101))	('cirrhosis', 'Phenotype', 'HP:0001394', (111, 120))	('pain', 'Disease', 'MESH:D010146', (59, 63))	('biliary cirrhosis', 'Disease', 'MESH:D008105', (103, 120))	('jaundice', 'Phenotype', 'HP:0000952', (49, 57))	('cholangitis', 'Disease', 'MESH:D002761', (126, 137))	('hepatocellular dysfunction', 'Disease', 'MESH:D006528', (75, 101))	('cholangitis', 'Disease', (126, 137))	('biliary cirrhosis', 'Phenotype', 'HP:0002613', (103, 120))	('jaundice', 'Disease', (49, 57))	('pain', 'Disease', (59, 63))	('pruritus', 'Phenotype', 'HP:0000989', (65, 73))	('biliary cirrhosis', 'Disease', (103, 120))	('cause', 'Reg', (43, 48))	('cholangitis', 'Phenotype', 'HP:0030151', (126, 137))	('jaundice', 'Disease', 'MESH:D007565', (49, 57))	('pruritus', 'Disease', (65, 73))	('benign', 'Var', (13, 19))	('pruritus', 'Disease', 'MESH:D011537', (65, 73))	('pain', 'Phenotype', 'HP:0012531', (59, 63))
677	26911896	However, CSEMS can increase the risk of stent migration, and pancreatitis is a well-known complication.	('pancreatitis', 'Disease', (61, 73))	('stent migration', 'CPA', (40, 55))	('pancreatitis', 'Phenotype', 'HP:0001733', (61, 73))	('CSEMS', 'Var', (9, 14))	('pancreatitis', 'Disease', 'MESH:D010195', (61, 73))
689	26911896	If expected survival is more than 4 months; however, a recent meta-analysis reported that, compared with a plastic stent, SEMS in the management of malignant biliary obstruction is associated with significantly longer stent patency, fewer ERCPs, and longer patient survival.	('ERCPs', 'Disease', (239, 244))	('stent', 'MPA', (218, 223))	('longer', 'PosReg', (211, 217))	('patient', 'Species', '9606', (257, 264))	('malignant biliary obstruction', 'Disease', 'MESH:D009369', (148, 177))	('SEMS', 'Var', (122, 126))	('malignant biliary obstruction', 'Disease', (148, 177))	('biliary obstruction', 'Phenotype', 'HP:0005230', (158, 177))
719	25032189	ICC with DPM pattern is histologically characterized by irregular and tortuous glandular structures with bridge formation, biliary cell projections into the lumens, and intraluminal tumor cells.	('intraluminal tumor', 'Disease', 'MESH:D009369', (169, 187))	('intraluminal tumor', 'Disease', (169, 187))	('ICC', 'Disease', (0, 3))	('biliary cell projections', 'CPA', (123, 147))	('DPM pattern', 'Var', (9, 20))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
749	25032189	It is therefore possible that ICC with DPM patterns may also fall under the category of combined hepatocellular and cholangiocarcinoma with stem cell features, along with CCC.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (116, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('DPM patterns', 'Var', (39, 51))	('fall', 'Phenotype', 'HP:0002527', (61, 65))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))	('ICC', 'Disease', (30, 33))	('hepatocellular', 'Disease', (97, 111))	('cholangiocarcinoma', 'Disease', (116, 134))	('combined hepatocellular', 'Disease', (88, 111))
787	24043969	However, only one case showed the detailed imaging findings of MALT lymphoma of the CBD as thickened CBD wall with homogeneous enhancement on CT, slight hyperintensity on T2-weighted MR images, and hypointensity on T1-weighted MR images.	('MALT lymphoma', 'Disease', 'MESH:D018442', (63, 76))	('hypointensity', 'Var', (198, 211))	('hyperintensity', 'MPA', (153, 167))	('MALT lymphoma', 'Disease', (63, 76))	('lymphoma', 'Phenotype', 'HP:0002665', (68, 76))	('enhancement', 'PosReg', (127, 138))
828	33212880	In the MOSCATO trial, 68% of patients with biliary tract cancer (n = 43) were identified to have potentially actionable mutations, 33% of which had an objective response.	('patients', 'Species', '9606', (29, 37))	('biliary tract cancer', 'Disease', 'MESH:D001661', (43, 63))	('biliary tract cancer', 'Disease', (43, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (120, 129))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (43, 63))	('nab', 'Chemical', '-', (114, 117))
829	33212880	The fibroblast growth factor (FGF) pathway upregulates the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase-A (PI3KA) pathways; FGF receptor 2 (FGFR2) gene alterations are particularly involved in the pathogenesis of cholangiocarcinoma (CCA) and harbored by about 9-16% of patients.	('fibroblast', 'Pathway', (4, 14))	('alterations', 'Var', (181, 192))	('FGF receptor 2', 'Gene', '2263', (153, 167))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (242, 260))	('mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase-A (PI3KA) pathways', 'Pathway', (59, 151))	('involved', 'Reg', (210, 218))	('patients', 'Species', '9606', (298, 306))	('upregulates', 'PosReg', (43, 54))	('CCA', 'Phenotype', 'HP:0030153', (262, 265))	('FGFR2', 'Gene', (169, 174))	('FGFR2', 'Gene', '2263', (169, 174))	('cholangiocarcinoma', 'Disease', (242, 260))	('FGF receptor 2', 'Gene', (153, 167))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (242, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))
830	33212880	In the FIGHT-202 trial, pemigatinib (selective, oral inhibitor of FGFR1, 2 and 3) was found to achieve high response rates (36%, including three complete responses) and disease control rates (80%) in patients with FGFR2 fusions or rearrangements as compared to those who had no FGF/FGFR alterations, with a duration of disease control of about 7.5 months.	('FGFR', 'Gene', (214, 218))	('FGFR', 'Gene', '2263', (66, 70))	('patients', 'Species', '9606', (200, 208))	('FGFR', 'Gene', '2263', (282, 286))	('FGFR', 'Gene', (282, 286))	('FGFR2', 'Gene', (214, 219))	('FGFR', 'Gene', (66, 70))	('FGFR2', 'Gene', '2263', (214, 219))	('disease control', 'CPA', (169, 184))	('FGFR', 'Gene', '2263', (214, 218))	('pemigatinib', 'Chemical', '-', (24, 35))	('fusions', 'Var', (220, 227))	('rearrangements', 'Var', (231, 245))
831	33212880	A phase III trial comparing pemigatinib to gemcitabine-cisplatin in the first-line setting for patients with advanced BTC with FGFR2 alterations is also underway.	('FGFR2', 'Gene', '2263', (127, 132))	('patients', 'Species', '9606', (95, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('BTC', 'Phenotype', 'HP:0100574', (118, 121))	('alterations', 'Var', (133, 144))	('pemigatinib', 'Chemical', '-', (28, 39))	('FGFR2', 'Gene', (127, 132))	('gemcitabine', 'Chemical', 'MESH:C056507', (43, 54))
832	33212880	Isocitrate dehydrogenase 1 (IDH1) is a key enzyme involved in the citric acid cycle, and mutations in this enzyme have been linked to oncogenesis.	('linked to', 'Reg', (124, 133))	('IDH1', 'Gene', '3417', (28, 32))	('Isocitrate dehydrogenase 1', 'Gene', '3417', (0, 26))	('Isocitrate dehydrogenase 1', 'Gene', (0, 26))	('oncogenesis', 'Disease', (134, 145))	('mutations', 'Var', (89, 98))	('citric acid', 'Chemical', 'MESH:D019343', (66, 77))	('IDH1', 'Gene', (28, 32))
833	33212880	IDH1 mutations are present in 25% and IDH2 mutations in 3% of BTC patients, particularly in intrahepatic cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (105, 123))	('mutations', 'Var', (5, 14))	('BTC', 'Phenotype', 'HP:0100574', (62, 65))	('IDH2', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (92, 123))	('IDH1', 'Gene', (0, 4))	('IDH2', 'Gene', '3418', (38, 42))	('intrahepatic cholangiocarcinoma', 'Disease', (92, 123))	('patients', 'Species', '9606', (66, 74))	('IDH1', 'Gene', '3417', (0, 4))
835	33212880	Neurotrophic tyrosine receptor kinase (NTRK) rearrangements are rare in incidence in BTC (<5%), but could still be a potential drug target.	('NTRK', 'Gene', '4914', (39, 43))	('NTRK', 'Gene', (39, 43))	('BTC', 'Phenotype', 'HP:0100574', (85, 88))	('rearrangements', 'Var', (45, 59))
838	33212880	BTCs usually do not have high mutational burden; in a report of 239 BTC tumors, where whole exome sequencing (WES) was performed, the median numbers of mutations across the IHCC, EHCC and gallbladder cancer subtypes were 39, 35 and 64, respectively, with only 5 patients showing a deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) genotype.	('dMMR', 'Chemical', '-', (308, 312))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('IHCC', 'Disease', (173, 177))	('mutations', 'Var', (152, 161))	('patients', 'Species', '9606', (262, 270))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('BTC', 'Phenotype', 'HP:0100574', (68, 71))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('microsatellite instability-high', 'MPA', (317, 348))	('BTC', 'Phenotype', 'HP:0100574', (0, 3))	('gallbladder cancer', 'Disease', (188, 206))	('gallbladder cancer', 'Disease', 'MESH:D005706', (188, 206))	('EHCC', 'Disease', (179, 183))
839	33212880	The MSI-H or dMMR status confers a higher neoantigen load and tumor mutational burden (TMB), leading to a potential increase in responsiveness to immune checkpoint inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('MSI-H', 'Var', (4, 9))	('dMMR', 'Chemical', '-', (13, 17))	('neoantigen load', 'MPA', (42, 57))	('tumor', 'Disease', (62, 67))	('TMB', 'Chemical', '-', (87, 90))	('dMMR status', 'Var', (13, 24))	('responsiveness to', 'MPA', (128, 145))	('increase', 'PosReg', (116, 124))	('higher', 'PosReg', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
840	33212880	The KEYNOTE 158 study highlighted how MSI-H BTC patients had response rates as high as 40% with duration of responses more than 2 years, and that patients with high TMB also correlated with greater benefit from immunotherapy.	('immunotherapy', 'CPA', (211, 224))	('high', 'Var', (160, 164))	('BTC', 'Phenotype', 'HP:0100574', (44, 47))	('TMB', 'Chemical', '-', (165, 168))	('patients', 'Species', '9606', (48, 56))	('patients', 'Species', '9606', (146, 154))	('greater benefit', 'PosReg', (190, 205))
847	33212880	One study suggested that chronic inflammation may lead to biliary tract cancers through aberrant activation-induced cytidine deaminase (AID) expression, resulting in the generation of somatic mutations in key cancer genes including TP53, c-MYC and promotor region of INK4A/p16.	('biliary tract cancer', 'Phenotype', 'HP:0100574', (58, 78))	('biliary tract cancers', 'Disease', 'MESH:D001661', (58, 79))	('INK4A', 'Gene', (267, 272))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('TP53', 'Gene', '7157', (232, 236))	('aberrant', 'Var', (88, 96))	('mutations', 'Var', (192, 201))	('AID', 'Gene', (136, 139))	('cancer', 'Disease', (72, 78))	('activation-induced cytidine deaminase', 'Gene', '57379', (97, 134))	('p16', 'Gene', (273, 276))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('p16', 'Gene', '1029', (273, 276))	('activation-induced cytidine deaminase', 'Gene', (97, 134))	('c-MYC', 'Gene', '4609', (238, 243))	('lead to', 'Reg', (50, 57))	('biliary tract cancers', 'Disease', (58, 79))	('c-MYC', 'Gene', (238, 243))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('TP53', 'Gene', (232, 236))	('INK4A', 'Gene', '1029', (267, 272))	('chronic inflammation', 'Disease', (25, 45))	('cancer', 'Disease', (209, 215))	('chronic inflammation', 'Disease', 'MESH:D007249', (25, 45))	('AID', 'Gene', '57379', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
855	33212880	Furthermore, transcriptomic results from 10 IHCC tumors found high vascular endothelial growth factor (VEGF) expression, which is thought to induce remodeling of the tumor microenvironment (TME) and limit T-cell infiltration, therefore leading to lower responsiveness to immunotherapy.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('T-cell infiltration', 'CPA', (205, 224))	('VEGF', 'Gene', (103, 107))	('high vascular endothelial growth factor', 'Phenotype', 'HP:0031052', (62, 101))	('limit', 'NegReg', (199, 204))	('vascular endothelial growth factor', 'Gene', '7422', (67, 101))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('lower', 'NegReg', (247, 252))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', (166, 171))	('VEGF', 'Gene', '7422', (103, 107))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('high', 'Var', (62, 66))	('vascular endothelial growth factor', 'Gene', (67, 101))
864	33212880	Subsequently, Rosenberg's team in National Institute of Health (NIH) reported in 2014, a case of a metastatic cholangiocarcinoma patient, who received TIL infusion that had been co-cultured with antigen-presenting cells (APCs) transfected with somatic non-synonymous mutations identified in the tumor, resulted in tumor regression for 7 months.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (110, 128))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('tumor', 'Disease', (314, 319))	('cholangiocarcinoma', 'Disease', (110, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('non-synonymous mutations', 'Var', (252, 276))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (110, 128))	('tumor', 'Disease', (295, 300))	('patient', 'Species', '9606', (129, 136))
871	33212880	WT1 mutations were found in about 80% of BTC, while MUC1 was reported to be overexpressed in 90% of BTC.	('WT1', 'Gene', '7490', (0, 3))	('WT1', 'Gene', (0, 3))	('BTC', 'Phenotype', 'HP:0100574', (41, 44))	('BTC', 'Phenotype', 'HP:0100574', (100, 103))	('mutations', 'Var', (4, 13))	('MUC1', 'Gene', (52, 56))	('MUC1', 'Gene', '4582', (52, 56))
897	33212880	Preclinical organoid or cell line models may be able to reveal key mutations and mediators that influence TIL infiltration or response to immunotherapy, and can potentially aid in future cell therapy development.	('aid', 'Gene', '57379', (173, 176))	('mutations', 'Var', (67, 76))	('TIL infiltration', 'CPA', (106, 122))	('aid', 'Gene', (173, 176))	('influence', 'Reg', (96, 105))
898	33212880	For example, a recent large study on GBC uncovered significantly mutated genes related to ERBB2, ERBB3, KRAS, PIK3CA and BRAF, and neoantigens from several mutated GBC genes including ELF3, ERBB2 and TP53 that were proven to activate T cells, therefore being potential candidate antigens for a therapeutic cancer vaccine.	('BRAF', 'Gene', (121, 125))	('ELF3', 'Gene', '1999', (184, 188))	('TP53', 'Gene', '7157', (200, 204))	('ERBB3', 'Gene', (97, 102))	('ERBB2', 'Gene', '2064', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('ERBB2', 'Gene', (190, 195))	('KRAS', 'Gene', '3845', (104, 108))	('ELF3', 'Gene', (184, 188))	('GBC', 'Gene', (164, 167))	('mutated', 'Var', (156, 163))	('activate', 'PosReg', (225, 233))	('ERBB2', 'Gene', '2064', (190, 195))	('KRAS', 'Gene', (104, 108))	('PIK3CA', 'Gene', '5290', (110, 116))	('TP53', 'Gene', (200, 204))	('ERBB3', 'Gene', '2065', (97, 102))	('T cells', 'CPA', (234, 241))	('cancer', 'Disease', (306, 312))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('PIK3CA', 'Gene', (110, 116))	('BRAF', 'Gene', '673', (121, 125))	('ERBB2', 'Gene', (90, 95))
899	33212880	In particular, frame shift mutations in ELF3 led to the identification of several immunogenic cancer neoantigens.	('ELF3', 'Gene', (40, 44))	('ELF3', 'Gene', '1999', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('frame shift mutations', 'Var', (15, 36))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
906	33212880	He started treatment with DC+Bev in December 2014 and achieved a dramatic reduction in Carbohydrate Antigen (CA) 19-9 and neutrophil-to-lymphocyte (NLR) ratio (Figure 1) after three cycles of treatment.	('Carbohydrate Antigen', 'Chemical', '-', (87, 107))	('reduction', 'NegReg', (74, 83))	('Bev', 'Chemical', '-', (29, 32))	('DC+Bev', 'Var', (26, 32))
908	33212880	Following this, the patient received anti-programmed death 1 (PD1) immunotherapy (nivolumab) at a private oncology clinic with rapid disease progression.	('nivolumab', 'Chemical', 'MESH:D000077594', (82, 91))	('anti-programmed', 'Var', (37, 52))	('oncology', 'Phenotype', 'HP:0002664', (106, 114))	('patient', 'Species', '9606', (20, 27))	('PD1', 'Gene', (62, 65))
911	33212880	A multiplex gene sequencing analysis (ACT Genomics, Singapore) found the cancer to contain KRAS and ABL1 mutations.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('ABL1', 'Gene', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (105, 114))	('KRAS', 'Gene', (91, 95))	('ABL1', 'Gene', '25', (100, 104))	('KRAS', 'Gene', '3845', (91, 95))
951	32846862	IgG4-related sclerosing cholangitis (IgG4-RSC) occurs when IgG4-RD invades the biliary tract and can be confused with other benign or malignant diseases such as primary sclerosing cholangitis (PSC) or cholangiocarcinoma.	('IgG4-RD', 'Var', (59, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (201, 219))	('cholangitis', 'Disease', 'MESH:D002761', (180, 191))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (13, 35))	('malignant diseases', 'Disease', 'MESH:D009369', (134, 152))	('cholangitis', 'Disease', (24, 35))	('primary sclerosing cholangitis', 'Disease', 'MESH:D015209', (161, 191))	('cholangitis', 'Disease', 'MESH:D002761', (24, 35))	('cholangitis', 'Phenotype', 'HP:0030151', (24, 35))	('cholangiocarcinoma', 'Disease', (201, 219))	('malignant diseases', 'Disease', (134, 152))	('cholangitis', 'Disease', (180, 191))	('primary sclerosing cholangitis', 'Disease', (161, 191))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (169, 191))	('cholangitis', 'Phenotype', 'HP:0030151', (180, 191))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (201, 219))
955	32846862	Although several studies suggest that IgG4-RD may be a risk factor for malignancy, the mechanism has not been revealed.	('malignancy', 'Disease', (71, 81))	('IgG4-RD', 'Var', (38, 45))	('malignancy', 'Disease', 'MESH:D009369', (71, 81))
983	32846862	But, several recent studies have suggested that IgG4-RSC may be a risk factor for cholangiocarcinoma.	('IgG4-RSC', 'Var', (48, 56))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (82, 100))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (82, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('cholangiocarcinoma', 'Disease', (82, 100))
993	32846862	Second, the immunological environments associated with IgG4-RD can interfere with immune responses that inhibit cancer development.	('immune responses', 'CPA', (82, 98))	('IgG4-RD', 'Var', (55, 62))	('cancer', 'Disease', (112, 118))	('interfere', 'NegReg', (67, 76))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('inhibit', 'NegReg', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
997	32846862	Treg cells which are activated in IgG4-RD suppress immune responses and interleukin-10 is a regulatory cytokine that broadly functions as an immune inhibitory cytokine to support tumor growth.	('IgG4-RD', 'Var', (34, 41))	('suppress', 'NegReg', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('immune responses', 'CPA', (51, 67))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('interleukin-10', 'Gene', '3586', (72, 86))	('suppress immune responses', 'Phenotype', 'HP:0002721', (42, 67))	('interleukin-10', 'Gene', (72, 86))	('tumor', 'Disease', (179, 184))
1002	32846862	Based on these findings, it is thought that IgG4-RSC may promote the development of cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('promote', 'PosReg', (57, 64))	('cholangiocarcinoma', 'Disease', (84, 102))	('IgG4-RSC', 'Var', (44, 52))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
1010	31605774	The combination of BET and PARP inhibitors is synergistic in models of cholangiocarcinoma Our previous finding that the BET inhibitor (BETi) JQ1 increases levels of the DNA damage marker gammaH2AX suggested that JQ1 might enhance the sensitivity of tumor cells to PARP inhibitors (PARPi), which are selectively toxic to cells that harbor relatively high levels of DNA damage.	('sensitivity', 'MPA', (234, 245))	('BET', 'Gene', '92737', (120, 123))	('tumor', 'Disease', (249, 254))	('PARP', 'Gene', '142', (27, 31))	('gammaH2AX', 'MPA', (187, 196))	('enhance', 'PosReg', (222, 229))	('JQ1', 'Var', (141, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('BET', 'Gene', '92737', (135, 138))	('levels of the DNA damage', 'MPA', (155, 179))	('PARP', 'Gene', (27, 31))	('BETi', 'Chemical', '-', (135, 139))	('increases', 'PosReg', (145, 154))	('BET', 'Gene', (19, 22))	('PARP', 'Gene', '142', (281, 285))	('JQ1', 'Var', (212, 215))	('PARP', 'Gene', '142', (264, 268))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (71, 89))	('PARP', 'Gene', (281, 285))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('PARP', 'Gene', (264, 268))	('cholangiocarcinoma', 'Disease', (71, 89))	('BET', 'Gene', (120, 123))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (71, 89))	('BET', 'Gene', '92737', (19, 22))	('BET', 'Gene', (135, 138))	('gammaH2AX', 'Chemical', '-', (187, 196))
1025	31605774	Further, we made the novel observation that JQ1 increased levels of the DNA damage marker gammaH2AX and induced apoptosis as reflected by increases in cleaved caspase-3 and cleaved PARP.	('increased', 'PosReg', (48, 57))	('caspase-3', 'Gene', (159, 168))	('apoptosis', 'CPA', (112, 121))	('PARP', 'Gene', (181, 185))	('levels of the DNA', 'MPA', (58, 75))	('increases', 'PosReg', (138, 147))	('induced', 'Reg', (104, 111))	('JQ1', 'Var', (44, 47))	('caspase-3', 'Gene', '836', (159, 168))	('PARP', 'Gene', '142', (181, 185))	('gammaH2AX', 'Protein', (90, 99))	('gammaH2AX', 'Chemical', '-', (90, 99))
1027	31605774	The current study evaluates the potency of the BETi (JQ1 or I-BET762) with the PARPi (olaparib or veliparib) in CCA cell lines and efficacy of JQ1 + olaparib in a xenograft model of CCA.	('veliparib', 'Chemical', 'MESH:C521013', (98, 107))	('PARP', 'Gene', (79, 83))	('CCA', 'Disease', (112, 115))	('olaparib', 'Chemical', 'MESH:C531550', (86, 94))	('olaparib', 'Chemical', 'MESH:C531550', (149, 157))	('JQ1', 'Var', (143, 146))	('BETi', 'Chemical', '-', (47, 51))	('I-BET762', 'Chemical', 'MESH:C554645', (60, 68))	('PARP', 'Gene', '142', (79, 83))
1033	31605774	Serial dilutions of BET inhibitors (JQ1 or I-BET762) and/or PARPi (olaparib or veliparib) were added to the culture medium for 96 hours.	('BET', 'Gene', (45, 48))	('BET', 'Gene', (20, 23))	('JQ1', 'Var', (36, 39))	('PARP', 'Gene', '142', (60, 64))	('BET', 'Gene', '92737', (20, 23))	('veliparib', 'Chemical', 'MESH:C521013', (79, 88))	('BET', 'Gene', '92737', (45, 48))	('olaparib', 'Chemical', 'MESH:C531550', (67, 75))	('I-BET762', 'Chemical', 'MESH:C554645', (43, 51))	('PARP', 'Gene', (60, 64))
1040	31605774	Primary antibodies used were: c-Myc (5606S, Cell Signaling, 1:1,000), GAPDH (2118S, Cell Signaling, 1:1,000), vinculin (v4505, MilliporeSigma, 1:10,000), Chk1 (A300-298AT, Bethyl, 1:5,000), BRD2 (5848, Cell Signaling, 1:1,000), BRD4 (13440, Cell Signaling, 1:1,000), cleaved PARP (5625, Cell Signaling, 1:1,000) and gammaH2AX (9718S, Cell Signaling, 1:1,000).	('GAPDH', 'Gene', '2597', (70, 75))	('9718S', 'CellLine', 'CVCL:Z231', (327, 332))	('BRD4', 'Gene', (228, 232))	('Chk1', 'Gene', '1111', (154, 158))	('Chk1', 'Gene', (154, 158))	('vinculin', 'Gene', '7414', (110, 118))	('9718S', 'Var', (327, 332))	('GAPDH', 'Gene', (70, 75))	('PARP', 'Gene', (275, 279))	('c-Myc', 'Gene', '4609', (30, 35))	('5606S', 'CellLine', 'CVCL:Z231', (37, 42))	('vinculin', 'Gene', (110, 118))	('BRD4', 'Gene', '23476', (228, 232))	('gammaH2AX', 'Chemical', '-', (316, 325))	('BRD2', 'Gene', '6046', (190, 194))	('BRD2', 'Gene', (190, 194))	('PARP', 'Gene', '142', (275, 279))	('c-Myc', 'Gene', (30, 35))
1065	31605774	Neither KKU-055 nor KKU-100 cells harbored mutations in six previously characterized hot spots for BRCA1 mutations or in four hotspots for BRCA2 mutations (Fig.1a, Fig.S1).	('BRCA1', 'Gene', (99, 104))	('BRCA2', 'Gene', (139, 144))	('mutations', 'Var', (105, 114))	('BRCA2', 'Gene', '675', (139, 144))	('BRCA1', 'Gene', '672', (99, 104))
1069	31605774	Further, because Chk1 expression was downregulated by JQ1 in an in vivo model of CCA and is regulated by c-Myc, we assessed the effect of JQ1 on Chk1 expression, as a measure of c-Myc function.	('downregulated', 'NegReg', (37, 50))	('Chk1', 'Gene', '1111', (145, 149))	('c-Myc', 'Gene', (178, 183))	('Chk1', 'Gene', (17, 21))	('JQ1', 'Var', (54, 57))	('CCA', 'Disease', (81, 84))	('c-Myc', 'Gene', '4609', (105, 110))	('Chk1', 'Gene', '1111', (17, 21))	('expression', 'MPA', (22, 32))	('c-Myc', 'Gene', '4609', (178, 183))	('Chk1', 'Gene', (145, 149))	('c-Myc', 'Gene', (105, 110))
1071	31605774	JQ1 decreased expression of the c-Myc transcriptional target CHEK1 mRNA up to ~60% (P<0.05) and by >80% (P<0.001) in KKU-055 and KKU-100 cells, respectively (Figs.	('decreased', 'NegReg', (4, 13))	('CHEK1', 'Gene', (61, 66))	('c-Myc', 'Gene', '4609', (32, 37))	('expression', 'MPA', (14, 24))	('c-Myc', 'Gene', (32, 37))	('JQ1', 'Var', (0, 3))	('CHEK1', 'Gene', '1111', (61, 66))
1076	31605774	Based on our previous finding that JQ1 also increases levels of the DNA damage marker gammaH2AX in pancreatic cancer models and a PDX model of CCA, we next assessed the effect of JQ1 on levels of this DNA damage marker, using assay conditions similar to those under which we observed decreases in c-Myc and Chk1.	('JQ1', 'Var', (35, 38))	('pancreatic cancer', 'Disease', (99, 116))	('gammaH2AX', 'Chemical', '-', (86, 95))	('Chk1', 'Gene', '1111', (307, 311))	('c-Myc', 'Gene', '4609', (297, 302))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (99, 116))	('c-Myc', 'Gene', (297, 302))	('Chk1', 'Gene', (307, 311))	('levels of', 'MPA', (54, 63))	('increases', 'PosReg', (44, 53))	('pancreatic cancer', 'Disease', 'MESH:D010190', (99, 116))
1078	31605774	JQ1 increased the levels of gammaH2AX in a dose-dependent manner (Figs.	('gammaH2AX', 'Protein', (28, 37))	('increased', 'PosReg', (4, 13))	('JQ1', 'Var', (0, 3))	('gammaH2AX', 'Chemical', '-', (28, 37))
1079	31605774	In light of reports in the literature documenting that DNA repair deficiency or relatively high levels of DNA damage sensitize tumor cells to PARP inhibitors, we next assessed the potency of BET inhibitors in combination with PARP inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('sensitize', 'Reg', (117, 126))	('PARP', 'Gene', '142', (142, 146))	('tumor', 'Disease', (127, 132))	('PARP', 'Gene', (226, 230))	('BET', 'Gene', '92737', (191, 194))	('BET', 'Gene', (191, 194))	('DNA repair', 'Gene', (55, 65))	('deficiency', 'Var', (66, 76))	('PARP', 'Gene', (142, 146))	('PARP', 'Gene', '142', (226, 230))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
1083	31605774	Using clonogenic assays, we observed that the combination of JQ1 + olaparib was more effective than either drug alone in both CCA cell lines (Figs.	('JQ1 +', 'Var', (61, 66))	('CCA', 'Disease', (126, 129))	('olaparib', 'Chemical', 'MESH:C531550', (67, 75))
1084	31605774	Further, we evaluated the impact of JQ1 +- olaparib or veliparib on levels of protein markers for DNA damage (gammaH2AX) and apoptosis (cleaved PARP).	('PARP', 'Gene', (144, 148))	('JQ1 +- olaparib', 'Var', (36, 51))	('PARP', 'Gene', '142', (144, 148))	('veliparib', 'Chemical', 'MESH:C521013', (55, 64))	('olaparib', 'Chemical', 'MESH:C531550', (43, 51))	('gammaH2AX', 'Chemical', '-', (110, 119))
1085	31605774	As shown in Fig.S3, the combinations increased the levels of cleaved PARP >100-fold compared to DMSO controls.	('PARP', 'Gene', '142', (69, 73))	('levels of cleaved', 'MPA', (51, 68))	('combinations', 'Var', (24, 36))	('DMSO', 'Chemical', 'MESH:D004121', (96, 100))	('PARP', 'Gene', (69, 73))	('increased', 'PosReg', (37, 46))
1086	31605774	We also performed cell cycle analysis using JQ1 +- olaparib or veliparib (Fig.S4).	('olaparib', 'Chemical', 'MESH:C531550', (51, 59))	('JQ1 +- olaparib', 'Var', (44, 59))	('veliparib', 'Chemical', 'MESH:C521013', (63, 72))	('cell cycle', 'CPA', (18, 28))
1088	31605774	Interestingly, the combination of JQ1 + olaparib arrests cells in G2- similar to olaparib as a single agent and in contrast to JQ1 as a single agent.	('olaparib', 'Chemical', 'MESH:C531550', (81, 89))	('G2-', 'Gene', (66, 69))	('cells in', 'CPA', (57, 65))	('JQ1', 'Var', (34, 37))	('olaparib', 'Chemical', 'MESH:C531550', (40, 48))	('arrests', 'NegReg', (49, 56))
1102	31605774	We interpret the data to indicate that cells with low level BET protein expression are more sensitive to BET inhibitors than cells with high level BET expression.	('sensitive', 'MPA', (92, 101))	('BET', 'Gene', '92737', (105, 108))	('BET', 'Gene', '92737', (60, 63))	('BET', 'Gene', (60, 63))	('BET', 'Gene', (105, 108))	('low level', 'Var', (50, 59))	('BET', 'Gene', '92737', (147, 150))	('BET', 'Gene', (147, 150))
1103	31605774	We also observed that shBRD2 transfectants showed less than 3-fold increase in sensitivity to olaparib and veliparib, and shBRD4 transfectants less than 1.5-fold increase in sensitivity to these PARPi (Figs.	('sensitivity to olaparib', 'MPA', (79, 102))	('sensitivity', 'MPA', (174, 185))	('BRD2', 'Gene', '6046', (24, 28))	('BRD2', 'Gene', (24, 28))	('PARP', 'Gene', (195, 199))	('BRD4', 'Gene', '23476', (124, 128))	('veliparib', 'Chemical', 'MESH:C521013', (107, 116))	('transfectants', 'Var', (29, 42))	('increase', 'PosReg', (67, 75))	('PARP', 'Gene', '142', (195, 199))	('BRD4', 'Gene', (124, 128))	('veliparib', 'MPA', (107, 116))	('olaparib', 'Chemical', 'MESH:C531550', (94, 102))	('transfectants', 'Var', (129, 142))
1109	31605774	Data assessing the effect of JQ1 + olaparib, JQ1 + veliparib, I-BET762 + olaparib and I-BET762 + veliparib on cell viability in shBRD2 (Fig.	('BRD2', 'Gene', (130, 134))	('olaparib', 'Chemical', 'MESH:C531550', (35, 43))	('I-BET762', 'Chemical', 'MESH:C554645', (62, 70))	('olaparib', 'Chemical', 'MESH:C531550', (73, 81))	('I-BET762', 'Var', (62, 70))	('BRD2', 'Gene', '6046', (130, 134))	('I-BET762', 'Chemical', 'MESH:C554645', (86, 94))	('veliparib', 'Chemical', 'MESH:C521013', (97, 106))	('veliparib', 'Chemical', 'MESH:C521013', (51, 60))	('JQ1', 'Var', (45, 48))	('I-BET762 +', 'Var', (86, 96))
1112	31605774	The data show that in both shBRD4 and shBRD2 transfected cells, JQ1 increased the levels of the apoptosis marker cleaved PARP.	('BRD4', 'Gene', (29, 33))	('transfected', 'Var', (45, 56))	('PARP', 'Gene', '142', (121, 125))	('BRD4', 'Gene', '23476', (29, 33))	('increased', 'PosReg', (68, 77))	('BRD2', 'Gene', '6046', (40, 44))	('BRD2', 'Gene', (40, 44))	('JQ1', 'Gene', (64, 67))	('PARP', 'Gene', (121, 125))
1113	31605774	Further, JQ1 + olaparib or veliparib increased levels of this apoptotic marker more than JQ1 as a single agent.	('JQ1 +', 'Var', (9, 14))	('veliparib', 'Chemical', 'MESH:C521013', (27, 36))	('increased', 'PosReg', (37, 46))	('olaparib', 'Chemical', 'MESH:C531550', (15, 23))	('levels of this apoptotic marker', 'MPA', (47, 78))
1119	31605774	We also verified that, consistent with in vitro data, JQ1 and the combination of JQ1 + olaparib decreased MYC expression compared to VC (P<0.0001) (Fig.	('MYC', 'Gene', (106, 109))	('decreased', 'NegReg', (96, 105))	('JQ1', 'Var', (81, 84))	('JQ1', 'Var', (54, 57))	('olaparib', 'Chemical', 'MESH:C531550', (87, 95))	('MYC', 'Gene', '4609', (106, 109))
1126	31605774	Mechanistically, JQ1 reduced expression of c-Myc and Chk1 in dose and time dependent manners in vitro.	('reduced', 'NegReg', (21, 28))	('Chk1', 'Gene', (53, 57))	('Chk1', 'Gene', '1111', (53, 57))	('c-Myc', 'Gene', '4609', (43, 48))	('JQ1', 'Var', (17, 20))	('expression', 'MPA', (29, 39))	('c-Myc', 'Gene', (43, 48))
1127	31605774	The data demonstrate that BRD2 and BRD4 contribute to the regulation of c-Myc expression in CCA cells, a novel finding in CCA tumor models, and that JQ1 + olaparib have efficacy in preclinical models of this tumor type.	('BRD2', 'Gene', (26, 30))	('CCA tumor', 'Disease', (122, 131))	('c-Myc', 'Gene', '4609', (72, 77))	('CCA tumor', 'Disease', 'MESH:C536211', (122, 131))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('c-Myc', 'Gene', (72, 77))	('olaparib', 'Chemical', 'MESH:C531550', (155, 163))	('BRD4', 'Gene', '23476', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('JQ1 +', 'Var', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('regulation', 'MPA', (58, 68))	('BRD2', 'Gene', '6046', (26, 30))	('BRD4', 'Gene', (35, 39))	('tumor', 'Disease', (126, 131))
1128	31605774	The likely mechanism by which JQ1 decreases c-Myc expression has been postulated to involve competitive inhibition of the K-Ac binding function of the BET protein BRD4.	('decreases', 'NegReg', (34, 43))	('JQ1', 'Var', (30, 33))	('c-Myc', 'Gene', '4609', (44, 49))	('K-Ac', 'Chemical', '-', (122, 126))	('BET', 'Gene', '92737', (151, 154))	('BET', 'Gene', (151, 154))	('BRD4', 'Gene', '23476', (163, 167))	('K-Ac binding', 'Interaction', (122, 134))	('BRD4', 'Gene', (163, 167))	('c-Myc', 'Gene', (44, 49))
1131	31605774	Our data demonstrate that JQ1 decreased c-Myc expression, and we propose that BETi may have utility for treatment of this tumor type.	('JQ1', 'Var', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('BETi', 'Chemical', '-', (78, 82))	('c-Myc', 'Gene', '4609', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('c-Myc', 'Gene', (40, 45))	('tumor', 'Disease', (122, 127))	('decreased', 'NegReg', (30, 39))
1134	31605774	Notably, JQ1 and I-BET762 inhibit all four BET protein family members (BRD2, BRD3, BRD4, BRDT), with varying binding affinities.	('BRDT', 'Gene', '676', (89, 93))	('BRD4', 'Gene', '23476', (83, 87))	('I-BET762', 'Chemical', 'MESH:C554645', (17, 25))	('BRD3', 'Gene', (77, 81))	('JQ1', 'Var', (9, 12))	('BET', 'Gene', '92737', (19, 22))	('BRD3', 'Gene', '8019', (77, 81))	('BRDT', 'Gene', (89, 93))	('inhibit', 'NegReg', (26, 33))	('BET', 'Gene', '92737', (43, 46))	('BET', 'Gene', (19, 22))	('BET', 'Gene', (43, 46))	('BRD4', 'Gene', (83, 87))	('BRD2', 'Gene', '6046', (71, 75))	('BRD2', 'Gene', (71, 75))
1139	31605774	Our data demonstrate that JQ1 decreased c-Myc and increased the levels of DNA damage and apoptosis, and that BETi JQ1 sensitized CCA tumor cells to PARPi olaparib.	('PARP', 'Gene', '142', (148, 152))	('CCA tumor', 'Disease', 'MESH:C536211', (129, 138))	('olaparib', 'Chemical', 'MESH:C531550', (154, 162))	('apoptosis', 'CPA', (89, 98))	('JQ1', 'Var', (26, 29))	('levels of DNA damage', 'MPA', (64, 84))	('increased', 'PosReg', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('BETi JQ1', 'Var', (109, 117))	('sensitized', 'Reg', (118, 128))	('c-Myc', 'Gene', '4609', (40, 45))	('BETi', 'Chemical', '-', (109, 113))	('PARP', 'Gene', (148, 152))	('CCA tumor', 'Disease', (129, 138))	('c-Myc', 'Gene', (40, 45))	('decreased', 'NegReg', (30, 39))
1140	31605774	Further, in addition to inhibiting expression of c-Myc and Chk1, BETi also decreases levels of multiple genes including Ku80, RAD51, BRCA1, WEE1, CDC25B or TOPBP1, that contribute to the DNA damage repair and response.	('TOPBP1', 'Gene', '11073', (156, 162))	('BETi', 'Chemical', '-', (65, 69))	('Ku80', 'Gene', '7520', (120, 124))	('expression', 'MPA', (35, 45))	('CDC25B', 'Gene', '994', (146, 152))	('TOPBP1', 'Gene', (156, 162))	('WEE1', 'Gene', (140, 144))	('CDC25B', 'Gene', (146, 152))	('c-Myc', 'Gene', (49, 54))	('Chk1', 'Gene', (59, 63))	('levels', 'MPA', (85, 91))	('Ku80', 'Gene', (120, 124))	('Chk1', 'Gene', '1111', (59, 63))	('decreases', 'NegReg', (75, 84))	('RAD51', 'Gene', (126, 131))	('c-Myc', 'Gene', '4609', (49, 54))	('RAD51', 'Gene', '5888', (126, 131))	('inhibiting', 'NegReg', (24, 34))	('BRCA1', 'Gene', '672', (133, 138))	('WEE1', 'Gene', '7465', (140, 144))	('BRCA1', 'Gene', (133, 138))	('BETi', 'Var', (65, 69))
1144	31605774	JQ1 + olaparib inhibits growth of cholangiocarcinoma tumors in a preclinical model.	('cholangiocarcinoma tumors', 'Disease', (34, 59))	('olaparib', 'Chemical', 'MESH:C531550', (6, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (34, 52))	('growth', 'MPA', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cholangiocarcinoma tumors', 'Disease', 'MESH:D018281', (34, 59))	('inhibits', 'NegReg', (15, 23))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('JQ1 +', 'Var', (0, 5))
1228	25038797	Levels of ANXA1 expression was increased in AGS and N87 cells induced ANXA1/pcDNA3.1 transfection (Figure 5A, B).	('ANXA1', 'Gene', (10, 15))	('ANXA1/pcDNA3.1', 'Gene', (70, 84))	('AGS', 'Gene', '182', (44, 47))	('transfection', 'Var', (85, 97))	('N87', 'CellLine', 'CVCL:1603', (52, 55))	('expression', 'Species', '29278', (16, 26))	('AGS', 'Gene', (44, 47))	('expression', 'MPA', (16, 26))
1231	25038797	However, silencing of ANXA1 by ANXA1-shRNA promoted cell viability in N87 cells (Figure 6A).	('promoted', 'PosReg', (43, 51))	('silencing', 'Var', (9, 18))	('cell viability', 'CPA', (52, 66))	('N87', 'CellLine', 'CVCL:1603', (70, 73))	('ANXA1', 'Gene', (22, 27))
1233	25038797	Western blotting analysis revealed that silencing of ANXA1 leaded to up-regulation of COX-2 (Figure 6B), while forced expression of ANXA1 decreased COX-2 production (Figure 6C).	('up-regulation', 'PosReg', (69, 82))	('COX-2 production', 'MPA', (148, 164))	('COX-2', 'Enzyme', (86, 91))	('decreased', 'NegReg', (138, 147))	('ANXA1', 'Gene', (53, 58))	('expression', 'Species', '29278', (118, 128))	('silencing', 'Var', (40, 49))
1265	25038797	In line with our previous study, loss of ANXA1 is a frequent event in gastric carcinogenesis.	('gastric carcinogenesis', 'Disease', (70, 92))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (70, 92))	('ANXA1', 'Gene', (41, 46))	('loss', 'Var', (33, 37))
1274	25038797	Notably, knockdown ANXA1 expression with ANXA1-specific shRNA leads to an increase of COX-2 expression, suggesting ANXA1 mediating many diverse cellular functions, such as inflammation and proliferation.	('inflammation', 'Disease', 'MESH:D007249', (172, 184))	('expression', 'Species', '29278', (25, 35))	('knockdown', 'Var', (9, 18))	('proliferation', 'CPA', (189, 202))	('inflammation', 'Disease', (172, 184))	('increase', 'PosReg', (74, 82))	('ANXA1', 'Gene', (19, 24))	('COX-2', 'Protein', (86, 91))	('expression', 'Species', '29278', (92, 102))	('expression', 'MPA', (92, 102))
1276	25038797	This notion is supported by a previous study showing that IL-1beta increased the expression of COX-2 and concomittantly decreased the expression of lipocortin 1 (ANXA1) on the surface of A549 cells.	('decreased', 'NegReg', (120, 129))	('expression', 'MPA', (134, 144))	('IL-1beta', 'Var', (58, 66))	('A549', 'CellLine', 'CVCL:0023', (187, 191))	('lipocortin 1', 'Gene', (148, 160))	('COX-2', 'Gene', (95, 100))	('increased', 'PosReg', (67, 76))	('expression', 'Species', '29278', (81, 91))	('expression', 'MPA', (81, 91))	('expression', 'Species', '29278', (134, 144))
1390	21808282	In FISH analysis, three subsets of chromosomal amplification can occur: trisomy 7; tetra-somy or duplication of all chromosomes labeled; and polysomy or amplification of at least two chromosomes beyond tetrasomy.	('polysomy', 'Var', (141, 149))	('tetra-somy', 'Disease', (83, 93))	('trisomy', 'Disease', (72, 79))	('tetra-somy', 'Disease', 'MESH:C536498', (83, 93))	('amplification', 'CPA', (153, 166))	('duplication', 'Var', (97, 108))
1394	21808282	These include a dominant stricture in the perihilar biliary tree with either the presence of adenocarcinoma cells revealed by conventional cytology and/or polysomy on FISH analysis of cytologic specimens.	('adenocarcinoma', 'Disease', 'MESH:D000230', (93, 107))	('polysomy', 'Var', (155, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('adenocarcinoma', 'Disease', (93, 107))	('stricture', 'Disease', (25, 34))
1407	21808282	In summary, the diagnosis of distal extrahepatic cholangiocarcinoma requires the presence of a dominant stricture and a positive cytology for adenocarcinoma cells and/or polysomy on FISH.	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (36, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('extrahepatic cholangiocarcinoma', 'Disease', (36, 67))	('polysomy', 'Var', (170, 178))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (49, 67))	('adenocarcinoma', 'Disease', (142, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('adenocarcinoma', 'Disease', 'MESH:D000230', (142, 156))
1414	21808282	Inaccurate staging can result in inappropriate selection of a treatment option that either deprives patients of a potentially curative procedure or exposes them to unnecessary morbidity and mortality.	('patients', 'Species', '9606', (100, 108))	('deprives', 'NegReg', (91, 99))	('Inaccurate', 'Var', (0, 10))
1437	21808282	The corresponding stages were defined as stage I (sT1N0M0), stage II (sT2N0M0), stage III (sT3N0M0 or N1M0 with any sT) and stage IV (M1 with any sT and N).	('sT2', 'Gene', '6761', (70, 73))	('sT1', 'Gene', '6386', (50, 53))	('sT3', 'Gene', (91, 94))	('sT1', 'Gene', (50, 53))	('sT3', 'Gene', '6762', (91, 94))	('N1M0', 'Var', (102, 106))	('sT2', 'Gene', (70, 73))
1487	30302867	Inhibiting FBXW7 enhances the malignant potential of several cancers.	('Inhibiting', 'Var', (0, 10))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('enhances', 'PosReg', (17, 25))	('cancers', 'Disease', (61, 68))	('FBXW7', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
1491	30302867	Depletion of FBXW7 resulted in NOTCH1 accumulation and increased cholangiocarcinoma cell migration and self-renewal.	('accumulation', 'PosReg', (38, 50))	('cholangiocarcinoma', 'Disease', (65, 83))	('increased', 'PosReg', (55, 64))	('FBXW7', 'Gene', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('Depletion', 'Var', (0, 9))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (65, 83))	('NOTCH1', 'Gene', '4851', (31, 37))	('NOTCH1', 'Gene', (31, 37))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))
1536	30302867	We evaluated patient survival using Kaplan-Meier survival analysis to compare the postoperative prognosis of patients with high vs low FBXW7 expression.	('patient', 'Species', '9606', (109, 116))	('patients', 'Species', '9606', (109, 117))	('patient', 'Species', '9606', (13, 20))	('high', 'Var', (123, 127))	('low', 'NegReg', (131, 134))	('FBXW7', 'Gene', (135, 140))
1538	30302867	Both DFS and OS rates were lower in patients with low FBXW7 expression than in those with high FBXW7 expression, with 5-year survival rates of 38.6% and 89.7%, respectively.	('DFS', 'Chemical', 'MESH:C045207', (5, 8))	('DFS', 'MPA', (5, 8))	('patients', 'Species', '9606', (36, 44))	('low', 'Var', (50, 53))	('FBXW7', 'Gene', (54, 59))	('OS rates', 'MPA', (13, 21))	('lower', 'NegReg', (27, 32))	('OS', 'Chemical', 'MESH:D009992', (13, 15))
1549	30302867	FBXW7 knockdown resulted in the accumulation of NOTCH1, as determined by immunoblotting (Figures 2H, S2D); however, qRT-PCR analysis revealed that the NOTCH1 mRNA level was unaltered (Figure 2I).	('FBXW7', 'Gene', (0, 5))	('NOTCH1', 'Gene', '4851', (48, 54))	('NOTCH1', 'Gene', '4851', (151, 157))	('accumulation', 'PosReg', (32, 44))	('NOTCH1', 'Gene', (151, 157))	('knockdown', 'Var', (6, 15))	('NOTCH1', 'Gene', (48, 54))
1552	30302867	To determine whether these effects were attributable to NOTCH1 activation, we knocked down NOTCH1 in FBXW7-depleted CC cells (Figures 3D, S3).	('NOTCH1', 'Gene', '4851', (91, 97))	('NOTCH1', 'Gene', (91, 97))	('knocked', 'Var', (78, 85))	('NOTCH1', 'Gene', '4851', (56, 62))	('NOTCH1', 'Gene', (56, 62))
1553	30302867	Loss of NOTCH1 attenuated the migratory capacity of CC cells, restoring control levels (Figure 3E,F).	('control levels', 'MPA', (72, 86))	('migratory capacity of CC cells', 'CPA', (30, 60))	('NOTCH1', 'Gene', '4851', (8, 14))	('restoring', 'PosReg', (62, 71))	('NOTCH1', 'Gene', (8, 14))	('attenuated', 'NegReg', (15, 25))	('Loss', 'Var', (0, 4))
1556	30302867	In cells without CDDP treatment, the rate of apoptosis was unaffected by FBXW7 knockdown (Figure 4A).	('knockdown', 'Var', (79, 88))	('CDDP', 'Chemical', 'MESH:D002945', (17, 21))	('FBXW7', 'Gene', (73, 78))
1566	30302867	Loss of FBXW7 has been linked to tumor progression and poor prognosis in intrahepatic CC44; however, in this prior study, downregulation of FBXW7 was not identified as an independent prognostic factor for DFS or OS, most likely because of the small number of patients included.	('FBXW7', 'Gene', (8, 13))	('patients', 'Species', '9606', (259, 267))	('intrahepatic CC', 'Disease', (73, 88))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('FBXW7', 'Gene', (140, 145))	('downregulation', 'NegReg', (122, 136))	('CC4', 'Chemical', '-', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('DFS', 'Chemical', 'MESH:C045207', (205, 208))	('intrahepatic CC', 'Disease', 'MESH:D002780', (73, 88))	('OS', 'Chemical', 'MESH:D009992', (212, 214))	('Loss', 'Var', (0, 4))	('DFS', 'Disease', (205, 208))
1569	30302867	Moreover, FBXW7 knockdown induced CC cell migration by an increase in NOTCH1, which could promote malignant potential and metastasis in CC.	('increase', 'PosReg', (58, 66))	('knockdown', 'Var', (16, 25))	('FBXW7', 'Gene', (10, 15))	('CC cell migration', 'CPA', (34, 51))	('promote', 'PosReg', (90, 97))	('NOTCH1', 'Gene', '4851', (70, 76))	('NOTCH1', 'Gene', (70, 76))
1578	30302867	In tumor tissue samples from CC patients who received or did not receive CDDP, however, FBXW7 expression was not an independent prognostic factor for OS, likely because of the small number of high-FBXW7 patients who were treated with CDDP, which is a limitation of this retrospective analysis.	('CDDP', 'Chemical', 'MESH:D002945', (234, 238))	('patients', 'Species', '9606', (32, 40))	('tumor', 'Disease', (3, 8))	('high-FBXW7', 'Var', (192, 202))	('FBXW7', 'Gene', (88, 93))	('CDDP', 'Chemical', 'MESH:D002945', (73, 77))	('patients', 'Species', '9606', (203, 211))	('OS', 'Chemical', 'MESH:D009992', (150, 152))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
1594	30302867	FBXW7 was found to regulate the migration and self-renewal of CC cells through modulation of NOTCH1 as well as CDDP-induced apoptosis by MCL1 accumulation in CC cells.	('NOTCH1', 'Gene', (93, 99))	('regulate', 'Reg', (19, 27))	('MCL1', 'Gene', '4170', (137, 141))	('MCL1', 'Gene', (137, 141))	('CDDP', 'Chemical', 'MESH:D002945', (111, 115))	('FBXW7', 'Gene', (0, 5))	('NOTCH1', 'Gene', '4851', (93, 99))	('migration', 'CPA', (32, 41))	('self-renewal', 'CPA', (46, 58))	('modulation', 'Var', (79, 89))
1641	28854772	The diagnostic sensitivity among all patients with INF a (alpha) or INF b (beta) was 87.5% (21/24); among patients with biliary lesions, the sensitivity was 100.0% (14/14), and among those with extrabiliary lesions, the sensitivity was 70.0% (7/10) (Table 7).	('patients', 'Species', '9606', (37, 45))	('INF', 'Var', (51, 54))	('biliary lesions', 'Disease', (120, 135))	('biliary lesions', 'Disease', (199, 214))	('patients', 'Species', '9606', (106, 114))	('biliary lesions', 'Disease', 'MESH:D001660', (199, 214))	('biliary lesions', 'Disease', 'MESH:D001660', (120, 135))	('INF', 'Var', (68, 71))
1643	28854772	The sensitivity for inf c (gamma) (53.3%) tumors was significantly lower than that for INF a (alpha) and INF b (beta) (87.5%) tumors.	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('sensitivity', 'MPA', (4, 15))	('inf', 'Var', (20, 23))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('lower', 'NegReg', (67, 72))
1723	27343073	With acquisition of additional mutations, however, the tumor becomes antigen-independent and capable of systemic spread.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('mutations', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))
1764	25992300	A FLR <30% has been shown to be a predictor of postoperative hepatic dysfunction and death.	('postoperative hepatic dysfunction', 'Disease', (47, 80))	('death', 'Disease', 'MESH:D003643', (85, 90))	('death', 'Disease', (85, 90))	('hepatic dysfunction', 'Phenotype', 'HP:0001410', (61, 80))	('<30%', 'Var', (6, 10))	('postoperative hepatic dysfunction', 'Disease', 'MESH:D000079690', (47, 80))
1845	32843607	In a Chinese study that included 78 patients with partial resection of the CC, the patients developed associated symptoms, including new cysts, calculus of the bile duct (65.4%), and carcinogenesis (14.1%) in the residual intrapancreatic bile duct.	('pancreatic', 'Disease', (227, 237))	('CC', 'Phenotype', 'HP:0100890', (75, 77))	('calculus of the bile duct', 'Disease', 'MESH:D001650', (144, 169))	('carcinogenesis', 'Disease', (183, 197))	('patients', 'Species', '9606', (36, 44))	('partial resection', 'Var', (50, 67))	('calculus of the bile duct', 'Disease', (144, 169))	('carcinogenesis', 'Disease', 'MESH:D063646', (183, 197))	('patients', 'Species', '9606', (83, 91))	('pancreatic', 'Disease', 'MESH:D010195', (227, 237))
1851	32843607	Second, the existence of stenosis at the anastomosis or in the intrahepatic bile duct may induce carcinogenesis.	('carcinogenesis', 'Disease', (97, 111))	('anastomosis', 'Disease', (41, 52))	('induce', 'Reg', (90, 96))	('anastomosis', 'Disease', 'MESH:C563598', (41, 52))	('stenosis', 'Var', (25, 33))	('carcinogenesis', 'Disease', 'MESH:D063646', (97, 111))
1889	26269932	The risk of death with poor differentiation was 1.356 times that of medium differentiation, while the latter is 1.356 times that of high differentiation.	('poor differentiation', 'Var', (23, 43))	('death', 'Disease', 'MESH:D003643', (12, 17))	('death', 'Disease', (12, 17))
1904	26269932	Prognoses are poorer on low-differentiated tumors than on high-differentiated ones.	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('low-differentiated', 'Var', (24, 42))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
1923	26269932	The exact mechanism by which intraoperative blood transfusion effects prognosis is still not clear, but research shows that blood transfusion could cause immune system adjustment by inhibiting the immune function of recipients and causing a drop in antibody level.	('antibody level', 'MPA', (249, 263))	('drop', 'NegReg', (241, 245))	('immune system adjustment', 'MPA', (154, 178))	('inhibiting', 'NegReg', (182, 192))	('immune function', 'CPA', (197, 212))	('blood transfusion', 'Var', (124, 141))	('cause', 'Reg', (148, 153))	('drop in antibody level', 'Phenotype', 'HP:0004313', (241, 263))	('men', 'Species', '9606', (174, 177))
2110	32713914	A biopsy targeting at the wall of the cystic tumor posed a high risk of bleeding and peritoneal dissemination.	('bleeding', 'Disease', (72, 80))	('peritoneal dissemination', 'CPA', (85, 109))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cystic tumor', 'Disease', (38, 50))	('biopsy', 'Var', (2, 8))	('cystic tumor', 'Disease', 'MESH:D052177', (38, 50))	('bleeding', 'Disease', 'MESH:D006470', (72, 80))
2177	25957621	This defect impairs biliary bicarbonate secretion, a process important in preventing bile salt toxicity to cholangiocytes; malfunction of this mechanism likely contributes to the pathogenesis of the disease.	('bile salt', 'Chemical', 'MESH:D001647', (85, 94))	('defect', 'Var', (5, 11))	('biliary bicarbonate secretion', 'MPA', (20, 49))	('bicarbonate', 'Chemical', 'MESH:D001639', (28, 39))	('salt toxicity', 'Phenotype', 'HP:0000127', (90, 103))	('malfunction', 'Var', (123, 134))	('impairs', 'NegReg', (12, 19))	('toxicity', 'Disease', 'MESH:D064420', (95, 103))	('toxicity', 'Disease', (95, 103))
2213	25957621	Cystic fibrosis (CF) is a systemic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene.	('CF transmembrane conductance regulator', 'Gene', (70, 108))	('Cystic fibrosis', 'Disease', 'MESH:D003550', (0, 15))	('CFTR', 'Gene', '1080', (110, 114))	('systemic disease', 'Disease', (26, 42))	('CF transmembrane conductance regulator', 'Gene', '1080', (70, 108))	('caused by', 'Reg', (43, 52))	('CFTR', 'Gene', (110, 114))	('mutations', 'Var', (53, 62))	('Cystic fibrosis', 'Disease', (0, 15))	('systemic disease', 'Disease', 'MESH:D034721', (26, 42))
2217	25957621	Mutations of CFTR result in alterations of Cl- and Na+ transport across epithelia that, in turn, cause water efflux abnormalities responsible for increasing the density of secretions in different tissues.	('alterations', 'Reg', (28, 39))	('increasing', 'PosReg', (146, 156))	('CFTR', 'Gene', (13, 17))	('density of secretions in different', 'MPA', (161, 195))	('water efflux abnormalities', 'Disease', (103, 129))	('water efflux abnormalities', 'Disease', 'MESH:D000069578', (103, 129))	('Mutations', 'Var', (0, 9))	('CFTR', 'Gene', '1080', (13, 17))	('cause', 'Reg', (97, 102))
2232	25957621	To date, there is no direct correlation between specific CFTR mutations and development of liver disease.	('liver disease', 'Disease', 'MESH:D008107', (91, 104))	('CFTR', 'Gene', (57, 61))	('CFTR', 'Gene', '1080', (57, 61))	('liver disease', 'Phenotype', 'HP:0001392', (91, 104))	('liver disease', 'Disease', (91, 104))	('mutations', 'Var', (62, 71))
2241	25957621	A validated genome-wide association study of patients with biliary atresia from China revealed a strong association with a single nucleotide polymorphism on chromosome 10q24.	('biliary atresia', 'Phenotype', 'HP:0005912', (59, 74))	('single nucleotide polymorphism', 'Var', (123, 153))	('patients', 'Species', '9606', (45, 53))	('biliary atresia', 'Disease', (59, 74))	('biliary atresia', 'Disease', 'MESH:D001656', (59, 74))
2244	25957621	Genetic defects of XPNPEP1 could result in dysregulation of the inflammatory response in these patients, and mutation in ADD3 could lead to excessive deposition of actin and myosin, contributing to biliary fibrosis.	('ADD3', 'Gene', (121, 125))	('XPNPEP1', 'Gene', '7511', (19, 26))	('ADD3', 'Gene', '120', (121, 125))	('myosin', 'Gene', (174, 180))	('patients', 'Species', '9606', (95, 103))	('result in', 'Reg', (33, 42))	('fibrosis', 'Disease', (206, 214))	('Genetic defects', 'Var', (0, 15))	('fibrosis', 'Disease', 'MESH:D005355', (206, 214))	('myosin', 'Gene', '79784', (174, 180))	('dysregulation', 'MPA', (43, 56))	('contributing to', 'Reg', (182, 197))	('XPNPEP1', 'Gene', (19, 26))	('lead to', 'Reg', (132, 139))	('excessive', 'PosReg', (140, 149))	('mutation', 'Var', (109, 117))
2252	25957621	Autosomal dominant polycystic liver disease has a prevalence of approximately 1 per 100,000 people and is due to a mutation of PRKCSH or Sec63 genes, both of which are expressed in cholangiocytes.	('Autosomal dominant polycystic liver disease', 'Disease', (0, 43))	('Autosomal dominant polycystic liver disease', 'Disease', 'MESH:C536330', (0, 43))	('Sec63', 'Gene', (137, 142))	('Sec63', 'Gene', '11231', (137, 142))	('due to', 'Reg', (106, 112))	('cystic liver disease', 'Phenotype', 'HP:0006706', (23, 43))	('PRKCSH', 'Gene', (127, 133))	('people', 'Species', '9606', (92, 98))	('liver disease', 'Phenotype', 'HP:0001392', (30, 43))	('polycystic liver disease', 'Phenotype', 'HP:0006557', (19, 43))	('mutation', 'Var', (115, 123))	('PRKCSH', 'Gene', '5589', (127, 133))
2253	25957621	Autosomal dominant polycystic kidney disease, most often due to mutations in polycystin 1 or 2, is the most common inherited renal cystic disease; it affects the liver in approximately 85% of patients.	('kidney disease', 'Phenotype', 'HP:0000112', (30, 44))	('inherited renal cystic disease', 'Disease', (115, 145))	('inherited renal cystic disease', 'Disease', 'MESH:D052177', (115, 145))	('due', 'Reg', (57, 60))	('patients', 'Species', '9606', (192, 200))	('Autosomal dominant polycystic kidney disease', 'Disease', 'MESH:D007690', (0, 44))	('polycystin 1', 'Gene', '5310', (77, 89))	('Autosomal dominant polycystic kidney disease', 'Disease', (0, 44))	('renal cystic disease', 'Phenotype', 'HP:0000107', (125, 145))	('mutations', 'Var', (64, 73))	('polycystic kidney', 'Phenotype', 'HP:0000113', (19, 36))	('polycystin 1', 'Gene', (77, 89))
2254	25957621	Autosomal recessive polycystic kidney disease is due to mutations of PKHD1, which encodes for fibrocystin/polyductin, and is characterized by bile duct dysgenesis, intrahepatic bile duct dilatation, and congenital hepatic fibrosis.	('intrahepatic bile duct dilatation', 'Disease', 'MESH:C531647', (164, 197))	('fibrocystin', 'Gene', '5314', (94, 105))	('bile duct dysgenesis', 'Disease', 'MESH:D001649', (142, 162))	('congenital hepatic fibrosis', 'Disease', 'MESH:C562378', (203, 230))	('intrahepatic bile duct dilatation', 'Disease', (164, 197))	('kidney disease', 'Phenotype', 'HP:0000112', (31, 45))	('intrahepatic bile duct dilatation', 'Phenotype', 'HP:0005209', (164, 197))	('Autosomal recessive polycystic kidney disease', 'Disease', 'MESH:D007690', (0, 45))	('bile duct dilatation', 'Phenotype', 'HP:0006560', (177, 197))	('bile duct dysgenesis', 'Disease', (142, 162))	('mutations', 'Var', (56, 65))	('Autosomal recessive polycystic kidney disease', 'Disease', (0, 45))	('dilatation', 'Phenotype', 'HP:0002617', (187, 197))	('fibrocystin', 'Gene', (94, 105))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (214, 230))	('polyductin', 'Gene', '5314', (106, 116))	('polycystic kidney', 'Phenotype', 'HP:0000113', (20, 37))	('PKHD1', 'Gene', (69, 74))	('PKHD1', 'Gene', '5314', (69, 74))	('congenital hepatic fibrosis', 'Disease', (203, 230))	('polyductin', 'Gene', (106, 116))	('congenital hepatic fibrosis', 'Phenotype', 'HP:0002612', (203, 230))	('due', 'Reg', (49, 52))
2282	25799509	During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancer', 'Disease', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('silenced', 'NegReg', (77, 85))	('tumor', 'Disease', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('aberrant DNA methylation', 'Var', (89, 113))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
2286	25799509	Zebularine treatment decreased the concentrations of DNA methyltransferase (DNMT) proteins, and DNMT1 knockdown led to apoptotic cell death in the CCA cell lines TFK-1 and HuCCT1.	('DNMT', 'Gene', '1786', (76, 80))	('CCA', 'Phenotype', 'HP:0030153', (147, 150))	('DNMT1', 'Gene', '1786', (96, 101))	('decreased', 'NegReg', (21, 30))	('DNA methyltransferase', 'Gene', (53, 74))	('DNMT', 'Gene', (76, 80))	('apoptotic cell death', 'CPA', (119, 139))	('DNA methyltransferase', 'Gene', '1786', (53, 74))	('knockdown', 'Var', (102, 111))	('led to', 'Reg', (112, 118))	('Zebularine', 'Chemical', 'MESH:C009131', (0, 10))	('HuCCT1', 'CellLine', 'CVCL:0324', (172, 178))	('DNMT', 'Gene', '1786', (96, 100))	('DNMT1', 'Gene', (96, 101))	('DNMT', 'Gene', (96, 100))
2294	25799509	In recent years, much has been learned about epigenetic change, which has been confirmed as an important mechanism in multiple tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('multiple tumors', 'Disease', (118, 133))	('multiple tumors', 'Disease', 'MESH:D009369', (118, 133))	('epigenetic change', 'Var', (45, 62))
2296	25799509	Aberrant promoter methylation is initiated at about 1% of all CpG islands, and as many as 10% of all CpG islands become methylated during the multistep process of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('promoter methylation', 'MPA', (9, 29))	('tumor', 'Disease', (163, 168))
2297	25799509	The hypermethylation of promoter CpG islands can result in gene silencing, an alternative mechanism of gene inactivation that contributes to the formation of tumors including CCA.	('result in', 'Reg', (49, 58))	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('CCA', 'Phenotype', 'HP:0030153', (175, 178))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('CCA', 'Disease', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('gene', 'MPA', (59, 63))	('hypermethylation', 'Var', (4, 20))
2298	25799509	Given that aberrant methylation is a major event in the early and late stages of tumorigenesis, this process may represent a critical target for cancer risk assessment, treatment, and chemoprevention.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('aberrant methylation', 'Var', (11, 31))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Disease', (81, 86))
2301	25799509	Overexpression of DNMT has been reported to be involved in tumorigenesis and has been suggested as a prognostic factor in diffuse large B-cell lymphomas.	('tumor', 'Disease', (59, 64))	('lymphomas', 'Phenotype', 'HP:0002665', (143, 152))	('involved', 'Reg', (47, 55))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (136, 152))	('lymphomas', 'Disease', 'MESH:D008223', (143, 152))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('DNMT', 'Gene', '1786', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('lymphomas', 'Disease', (143, 152))	('DNMT', 'Gene', (18, 22))
2308	25799509	Furthermore, decitabine and 5'-azacitidine have been demonstrated to cause both DNA hypomethylation and DNA damage, albeit at lower concentrations.	('DNA damage', 'MPA', (104, 114))	("5'-azacitidine", 'Chemical', 'MESH:D001374', (28, 42))	('decitabine', 'Gene', (13, 23))	('cause', 'Reg', (69, 74))	("5'-azacitidine", 'Var', (28, 42))	('DNA hypomethylation', 'MPA', (80, 99))	('decitabine', 'Chemical', 'MESH:D000077209', (13, 23))
2317	25799509	Zebularine altered DNA methylation status and demethylated many CpG sites including "hemophilic cell adhesion", "regulation of transcription, DNA-dependent" and "Wnt signaling pathway" genes.	('Wnt', 'Gene', '89780', (162, 165))	('altered', 'Reg', (11, 18))	('Zebularine', 'Chemical', 'MESH:C009131', (0, 10))	('demethylated', 'Var', (46, 58))	('DNA methylation status', 'MPA', (19, 41))	('Wnt', 'Gene', (162, 165))
2329	25799509	The electrophoretically separated proteins were transferred to polyvinylidene fluoride (PVDF) membranes, blocked, and immunoblotted with anti-DNMT1 (D63A6, #5032, Cell Signaling Technology Japan, Tokyo, Japan), DNMT3a (sc-20703), DNMT3b (sc-81252), beta-catenin (sc-1496) (Santa Cruz Biotechnology, Santa Cruz, CA, USA), or glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (#MAB374, Millipore, Temecula, CA, USA) antibodies (each 1:1000 dilution), and then with peroxidase-conjugated secondary antibodies (NA931 or NA940, each 1:10000 dilution, GE Healthcare Japan, Tokyo, Japan, or sc-2020, 1:5000 dilution, Santa Cruz Biotechnology).	('DNMT1', 'Gene', (142, 147))	('GAPDH', 'Gene', (366, 371))	('DNMT1', 'Gene', '1786', (142, 147))	('DNMT3b', 'Gene', '1789', (230, 236))	('DNMT3a', 'Gene', '1788', (211, 217))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (324, 364))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (324, 364))	('DNMT3b', 'Gene', (230, 236))	('beta-catenin', 'Gene', (249, 261))	('beta-catenin', 'Gene', '1499', (249, 261))	('GAPDH', 'Gene', '2597', (366, 371))	('DNMT3a', 'Gene', (211, 217))	('NA940', 'Var', (515, 520))
2348	25799509	They were then incubated for 1 h at room temperature with an anti-DNMT1 (10 mug/ml, ab19905, abcam, Tokyo, Japan).	('DNMT1', 'Gene', (66, 71))	('10 mug/ml', 'Var', (73, 82))	('DNMT1', 'Gene', '1786', (66, 71))
2363	25799509	An apoptotic/necrotic/healthy cell detection assay revealed that, in TFK-1 cells exposed to zebularine for 72 h, zebularine did not induce necrotic cell death (data not shown); rather, it induced apoptotic cell death in a dose-dependent manner (Fig.	('necrotic', 'Disease', 'MESH:D009336', (13, 21))	('zebularine', 'Chemical', 'MESH:C009131', (92, 102))	('induced', 'Reg', (188, 195))	('apoptotic cell death', 'CPA', (196, 216))	('necrotic cell death', 'Disease', 'MESH:D003643', (139, 158))	('necrotic', 'Disease', (139, 147))	('zebularine', 'Chemical', 'MESH:C009131', (113, 123))	('necrotic', 'Disease', (13, 21))	('zebularine', 'Var', (113, 123))	('necrotic', 'Disease', 'MESH:D009336', (139, 147))	('necrotic cell death', 'Disease', (139, 158))
2368	25799509	Furthermore, DNMT1 knock-down increased apoptotic cell death in TFK-1 cells (Fig.	('apoptotic cell death', 'CPA', (40, 60))	('DNMT1', 'Gene', (13, 18))	('increased', 'PosReg', (30, 39))	('DNMT1', 'Gene', '1786', (13, 18))	('knock-down', 'Var', (19, 29))
2373	25799509	Furthermore, DNMT1 knock-down increased apoptotic cell death in HuCCT1 cells (Fig.	('apoptotic cell death', 'CPA', (40, 60))	('HuCCT1', 'CellLine', 'CVCL:0324', (64, 70))	('DNMT1', 'Gene', (13, 18))	('increased', 'PosReg', (30, 39))	('DNMT1', 'Gene', '1786', (13, 18))	('knock-down', 'Var', (19, 29))
2393	25799509	It has been reported that global alterations of DNA methylation in CCA target the Wnt signaling pathway, and that promoter silencing of Wnt signaling-related genes such as SOX17, WNT3A, DKK2, SFRP1, SFRP2, and SFRP4 is reversed upon treatment of CCA cell lines with 5-aza-2' deoxycytidine.	('target', 'Reg', (71, 77))	('SFRP1', 'Gene', (192, 197))	('CCA', 'Phenotype', 'HP:0030153', (246, 249))	('Wnt', 'Gene', '89780', (136, 139))	('WNT3A', 'Gene', '89780', (179, 184))	('DKK2', 'Gene', (186, 190))	('SOX17', 'Gene', '64321', (172, 177))	('DKK2', 'Gene', '27123', (186, 190))	('SFRP1', 'Gene', '6422', (192, 197))	('SFRP4', 'Gene', '6424', (210, 215))	('SFRP2', 'Gene', '6423', (199, 204))	('Wnt', 'Gene', (82, 85))	('DNA', 'Gene', (48, 51))	('alterations', 'Var', (33, 44))	('CCA', 'Phenotype', 'HP:0030153', (67, 70))	('WNT3A', 'Gene', (179, 184))	('methylation', 'Var', (52, 63))	("5-aza-2' deoxycytidine", 'Chemical', 'MESH:D000077209', (266, 288))	('SFRP4', 'Gene', (210, 215))	('SFRP2', 'Gene', (199, 204))	('SOX17', 'Gene', (172, 177))	('Wnt', 'Gene', (136, 139))	('Wnt', 'Gene', '89780', (82, 85))
2397	25799509	Therefore, treatment of these CCA cell lines with zebularine is likely to partially reactivate any genes that were silenced during the carcinogenesis processes by demethylating their promoter regions, which may cause cancerous cells to commit to apoptotic cell death.	('apoptotic cell death', 'CPA', (246, 266))	('genes', 'Gene', (99, 104))	('cancerous', 'Disease', 'MESH:D009369', (217, 226))	('reactivate', 'NegReg', (84, 94))	('CCA', 'Phenotype', 'HP:0030153', (30, 33))	('zebularine', 'Chemical', 'MESH:C009131', (50, 60))	('demethylating', 'Var', (163, 176))	('promoter regions', 'MPA', (183, 199))	('commit', 'CPA', (236, 242))	('cancerous', 'Disease', (217, 226))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cause', 'Reg', (211, 216))
2411	25799509	9), suggesting that upregulation of DNMT1 results in the development of CCA and that inhibition of DNMT1 is effective therapy against it.	('CCA', 'Disease', (72, 75))	('inhibition', 'Var', (85, 95))	('DNMT1', 'Gene', (36, 41))	('CCA', 'Phenotype', 'HP:0030153', (72, 75))	('DNMT1', 'Gene', (99, 104))	('DNMT1', 'Gene', '1786', (36, 41))	('upregulation', 'PosReg', (20, 32))	('DNMT1', 'Gene', '1786', (99, 104))
2425	25799509	The role of altered expression of DNMTs in DNA hypomethylation and hypermethylation in cancer is uncertain and may involve changes in mRNA or protein expression.	('cancer', 'Disease', (87, 93))	('changes', 'Reg', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('hypermethylation', 'Var', (67, 83))	('mRNA or protein expression', 'MPA', (134, 160))	('DNMT', 'Gene', '1786', (34, 38))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('DNMT', 'Gene', (34, 38))
2433	25799509	In this study, we also demonstrated that zebularine treatment decreased DNMT levels and that DNMT1 knockdown led to decreased cell viability in TFK-1 and HuCCT1 cells.	('cell viability', 'CPA', (126, 140))	('DNMT', 'Gene', '1786', (93, 97))	('DNMT', 'Gene', '1786', (72, 76))	('DNMT', 'Gene', (93, 97))	('DNMT1', 'Gene', '1786', (93, 98))	('decreased', 'NegReg', (62, 71))	('DNMT', 'Gene', (72, 76))	('HuCCT1', 'CellLine', 'CVCL:0324', (154, 160))	('knockdown', 'Var', (99, 108))	('zebularine', 'Chemical', 'MESH:C009131', (41, 51))	('decreased', 'NegReg', (116, 125))	('DNMT1', 'Gene', (93, 98))
2450	25799509	Aberrant activation of the Wnt signaling pathway is known to be closely related to one subtype of CCA.	('CCA', 'Phenotype', 'HP:0030153', (98, 101))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('Wnt', 'Gene', (27, 30))	('CCA', 'Disease', (98, 101))	('Wnt', 'Gene', '89780', (27, 30))
2451	25799509	beta-catenin gene mutations have also been detected in a few patients with CCA, suggesting that tyrosine phosphorylation-dependent beta-catenin activation or Wnt/Frizzled dysfunction may contribute to the genesis of CCA.	('contribute', 'Reg', (187, 197))	('Frizzled dysfunction', 'Disease', (162, 182))	('Frizzled dysfunction', 'Disease', 'MESH:D006331', (162, 182))	('beta-catenin', 'Gene', '1499', (0, 12))	('beta-catenin', 'Gene', (131, 143))	('Wnt', 'Gene', (158, 161))	('tyrosine', 'Chemical', 'MESH:D014443', (96, 104))	('patients', 'Species', '9606', (61, 69))	('CCA', 'Phenotype', 'HP:0030153', (216, 219))	('Wnt', 'Gene', '89780', (158, 161))	('beta-catenin', 'Gene', '1499', (131, 143))	('CCA', 'Phenotype', 'HP:0030153', (75, 78))	('CCA', 'Disease', (216, 219))	('beta-catenin', 'Gene', (0, 12))	('mutations', 'Var', (18, 27))
2452	25799509	A previous study demonstrated that the Wnt signaling pathway is activated in CCA cell lines and that blocking the Wnt signaling pathway enhances cell apoptosis and suppresses cell proliferation.	('Wnt', 'Gene', '89780', (114, 117))	('cell proliferation', 'CPA', (175, 193))	('Wnt', 'Gene', (39, 42))	('enhances', 'PosReg', (136, 144))	('suppresses', 'NegReg', (164, 174))	('Wnt', 'Gene', '89780', (39, 42))	('activated', 'PosReg', (64, 73))	('Wnt', 'Gene', (114, 117))	('cell apoptosis', 'CPA', (145, 159))	('blocking', 'Var', (101, 109))	('CCA', 'Phenotype', 'HP:0030153', (77, 80))
2465	25799509	Its effects are dependent on DNMT1 depletion and DNA demethylation, which induces the activation of certain genes including protocadherin, transcriptional regulators, and Wnt signaling-related genes.	('DNMT1', 'Gene', (29, 34))	('DNMT1', 'Gene', '1786', (29, 34))	('Wnt', 'Gene', (171, 174))	('Wnt', 'Gene', '89780', (171, 174))	('activation', 'PosReg', (86, 96))	('depletion', 'Var', (35, 44))
2476	21871105	In the in vivo study, there was a 43% reduction in weight of tumors derived from CypA-silenced CCA cell lines compared with control vector CCA tumors in mice; these tumors with stable CypA silencing showed a reduced cell proliferation.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('CCA tumors', 'Disease', 'MESH:C536211', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('CCA', 'Phenotype', 'HP:0030153', (95, 98))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Disease', (143, 149))	('weight', 'CPA', (51, 57))	('CCA tumors', 'Disease', (139, 149))	('cell proliferation', 'CPA', (216, 234))	('reduced', 'NegReg', (208, 215))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('CCA', 'Phenotype', 'HP:0030153', (139, 142))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('mice', 'Species', '10090', (153, 157))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('CypA', 'Var', (184, 188))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('reduction', 'NegReg', (38, 47))
2557	21871105	Tumors from mice injected with M139-shCypA cells were smaller in size and weight compared with those from mice treated with M139-shV cells; there was a 43% reduction in weight in the M139-shCypA tumors (0.138 +- 0.107 g vs 0.240 +- 0.187 g, Figure 7A).	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('mice', 'Species', '10090', (106, 110))	('M139-shCypA', 'Var', (183, 194))	('weight', 'MPA', (169, 175))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('reduction', 'NegReg', (156, 165))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mice', 'Species', '10090', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
2559	21871105	We also determined that tumors from M139-shCypA injected mice demonstrated reduced cell proliferation, as indicated by fewer Ki-67 positive staining nuclei than observed in vector control tumors (P < 0.05; Figure 7C and 7D).	('mice', 'Species', '10090', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('cell proliferation', 'CPA', (83, 101))	('Ki-67', 'Gene', (125, 130))	('M139-shCypA', 'Var', (36, 47))	('reduced', 'NegReg', (75, 82))	('fewer', 'NegReg', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('Ki-67', 'Gene', '17345', (125, 130))
2561	21871105	There are numerous studies suggesting a role for CypA in tumorigenesis and progression of human cancer, and overexpression of CypA in various tumor tissues has been shown to both confer growth advantage and correlate with poor clinical outcomes.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('growth advantage', 'CPA', (186, 202))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('overexpression', 'Var', (108, 122))	('human', 'Species', '9606', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Disease', (57, 62))	('cancer', 'Disease', (96, 102))
2572	21871105	On the other hand, it seems that CypA does not play significant role in controlling cell proliferation of a non-tumor cholangiocyte cells as manipulating CypA levels by gene knockdown and overexpression experiments had no effects on MMNK1 cell proliferation.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('MMNK1 cell proliferation', 'CPA', (233, 257))	('manipulating', 'Var', (141, 153))
2577	21871105	We demonstrated that CypA is upregulated in human CCA samples; CypA expression correlates with a malignant cell growth phenotype in CCA cell lines; inhibiting CypA expression reduces CCA cell proliferation and migration in vitro, with the effects on proliferation likely mediated by reduced enzymatic activity and that the ERK1/2 pathway may be involved; overexpression of CypA enhances cell proliferation; and, finally, that suppression of CypA reduces tumor size and cell proliferation in vivo.	('human', 'Species', '9606', (44, 49))	('reduces', 'NegReg', (175, 182))	('cell proliferation', 'CPA', (469, 487))	('reduces', 'NegReg', (446, 453))	('CypA', 'Gene', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (454, 459))	('CypA', 'Gene', (441, 445))	('tumor', 'Disease', (454, 459))	('cell proliferation', 'CPA', (387, 405))	('CCA cell proliferation', 'CPA', (183, 205))	('CCA', 'Phenotype', 'HP:0030153', (183, 186))	('inhibiting', 'Var', (148, 158))	('suppression', 'Var', (426, 437))	('enhances', 'PosReg', (378, 386))	('CCA', 'Phenotype', 'HP:0030153', (132, 135))	('CCA', 'Phenotype', 'HP:0030153', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (454, 459))
2584	21871105	Presently, we are engaged in an ongoing project focused on the roles of extracellular CypA and its trans-membrane receptor CD147 as well as the subsequent downstream signaling pathway; we hope to gain new insight into the molecular mechanisms by which CypA promotes CCA cell proliferation.	('promotes', 'PosReg', (257, 265))	('CD147', 'Gene', '682', (123, 128))	('CCA', 'Disease', (266, 269))	('CypA', 'Var', (252, 256))	('CD147', 'Gene', (123, 128))	('CCA', 'Phenotype', 'HP:0030153', (266, 269))
2586	21871105	Finally, treatment with non-immunosuppressive CsA derivatives, novel CypA inhibitors and/or inhibitors of CypA-mediated signaling may lead to better treatment outcomes for CCA patients with high CypA expression.	('patients', 'Species', '9606', (176, 184))	('CsA', 'Gene', '1161', (46, 49))	('CCA', 'Phenotype', 'HP:0030153', (172, 175))	('CCA', 'Disease', (172, 175))	('CsA', 'Gene', (46, 49))	('CypA', 'Enzyme', (69, 73))	('high CypA expression', 'Var', (190, 210))
2608	17436128	CD24 has apoptotic activity, and its cross-linking induces the sustained activation of p38 MAPK (mitogen-activated protein kinases):the magnitude of which may determine the survival or death of pre-B cells.	('activation', 'PosReg', (73, 83))	('apoptotic activity', 'CPA', (9, 27))	('cross-linking', 'Var', (37, 50))	('CD24', 'Gene', '100133941', (0, 4))	('CD24', 'Gene', (0, 4))	('determine', 'Reg', (159, 168))	('p38', 'Enzyme', (87, 90))
2637	17436128	Overexpression of CD24 continued to affect survival adversely despite the overall improvement noted with the addition of radiation therapy.	('affect', 'Reg', (36, 42))	('Overexpression', 'Var', (0, 14))	('CD24', 'Gene', '100133941', (18, 22))	('improvement', 'PosReg', (82, 93))	('CD24', 'Gene', (18, 22))
2648	17436128	Median survival for patients with overexpression of CD24 was significantly shorter, and the addition of chemotherapy improved survival.	('overexpression', 'Var', (34, 48))	('improved', 'PosReg', (117, 125))	('Median survival', 'MPA', (0, 15))	('patients', 'Species', '9606', (20, 28))	('shorter', 'NegReg', (75, 82))	('CD24', 'Gene', '100133941', (52, 56))	('survival', 'MPA', (126, 134))	('CD24', 'Gene', (52, 56))
2650	17436128	The use of radiation therapy in patients with low expression of CD24 was also associated with an improved survival than with overexpression of CD24 although the data did not attain statistical significance possibly due to the small number of patients in this series.	('patients', 'Species', '9606', (32, 40))	('CD24', 'Gene', '100133941', (64, 68))	('improved', 'PosReg', (97, 105))	('CD24', 'Gene', (64, 68))	('CD24', 'Gene', '100133941', (143, 147))	('CD24', 'Gene', (143, 147))	('survival', 'MPA', (106, 114))	('low expression', 'Var', (46, 60))	('patients', 'Species', '9606', (242, 250))
2651	17436128	that the cross-linking of CD24 induces apoptosis in Burkitt's lymphoma enhanced by a B-cell antigen receptor (BCR)-mediated signal.	('cross-linking', 'Var', (9, 22))	('apoptosis', 'CPA', (39, 48))	('BCR', 'Gene', (110, 113))	('BCR', 'Gene', '613', (110, 113))	('CD24', 'Gene', '100133941', (26, 30))	('B-cell antigen receptor', 'Gene', '613', (85, 108))	('lymphoma', 'Phenotype', 'HP:0002665', (62, 70))	('CD24', 'Gene', (26, 30))	('B-cell antigen receptor', 'Gene', (85, 108))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (52, 70))	("Burkitt's lymphoma", 'Disease', (52, 70))
2652	17436128	They observed that simultaneous cross-linking of pre-BCR clearly inhibited CD24-mediated apoptosis in pre-B cells.	('cross-linking', 'Var', (32, 45))	('CD24', 'Gene', '100133941', (75, 79))	('CD24', 'Gene', (75, 79))	('BCR', 'Gene', (53, 56))	('inhibited', 'NegReg', (65, 74))	('BCR', 'Gene', '613', (53, 56))
2653	17436128	CD24 cross-linking also induces the sustained activation of p38 MAPK, and whether pre-B cells survive or die may be determined by the magnitude of MAPK activation.	('activation', 'PosReg', (46, 56))	('CD24', 'Gene', '100133941', (0, 4))	('CD24', 'Gene', (0, 4))	('p38', 'Protein', (60, 63))	('cross-linking', 'Var', (5, 18))
2655	17436128	Our data indicate that high expression of CD24 remains an adverse prognosticator despite the use of additional therapy.	('CD24', 'Gene', '100133941', (42, 46))	('CD24', 'Gene', (42, 46))	('high', 'Var', (23, 27))
2656	17436128	Chemotherapy and radiation were noted to provide maximal survival benefit to low expressors of CD24 although the data for the use of radiation was statistically insignificant probably due to the small number of patients in this study.	('patients', 'Species', '9606', (211, 219))	('CD24', 'Gene', '100133941', (95, 99))	('CD24', 'Gene', (95, 99))	('low expressors', 'Var', (77, 91))	('survival', 'CPA', (57, 65))
2666	17436128	This finding that shows that patients with low expression of CD24 may benefit from chemotherapy or radiation is of importance because it has been previously reported that adjuvant or palliative radiation had no effect on survival in patients with cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (247, 265))	('patients', 'Species', '9606', (29, 37))	('benefit', 'PosReg', (70, 77))	('CD24', 'Gene', '100133941', (61, 65))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (247, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (247, 265))	('CD24', 'Gene', (61, 65))	('patients', 'Species', '9606', (233, 241))	('low expression', 'Var', (43, 57))
2688	31433515	There is evidence that TP53 mutation in proliferating epithelium leads to high-grade dysplasia, while SMAD4 mutation precedes the development of invasive carcinoma.	('invasive carcinoma', 'Disease', 'MESH:D009361', (145, 163))	('SMAD4', 'Gene', '4089', (102, 107))	('leads to', 'Reg', (65, 73))	('SMAD4', 'Gene', (102, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('invasive carcinoma', 'Disease', (145, 163))	('dysplasia', 'Disease', 'MESH:D015792', (85, 94))	('mutation', 'Var', (28, 36))	('dysplasia', 'Disease', (85, 94))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))
2698	31433515	For some rare tumours, distinctive driver mutations have been identified; for example, the characteristic MALAT1-GLI1 fusion gene in gastroblastoma and EWSR1 fusions in gastrointestinal clear cell sarcoma and malignant gastrointestinal neuroectodermal tumour.	('neuroectodermal tumour', 'Phenotype', 'HP:0030061', (236, 258))	('MALAT1', 'Gene', (106, 112))	('rare tumours', 'Disease', (9, 21))	('malignant gastrointestinal neuroectodermal tumour', 'Disease', 'MESH:D005770', (209, 258))	('EWSR1', 'Gene', '2130', (152, 157))	('gastroblastoma', 'Disease', 'None', (133, 147))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('gastrointestinal clear cell sarcoma', 'Disease', 'MESH:D018227', (169, 204))	('MALAT1', 'Gene', '378938', (106, 112))	('GLI1', 'Gene', '2735', (113, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('EWSR1', 'Gene', (152, 157))	('malignant gastrointestinal neuroectodermal tumour', 'Disease', (209, 258))	('rare tumours', 'Disease', 'MESH:D035583', (9, 21))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('GLI1', 'Gene', (113, 117))	('fusions', 'Var', (158, 165))	('gastrointestinal clear cell sarcoma', 'Disease', (169, 204))	('tumour', 'Phenotype', 'HP:0002664', (252, 258))	('gastroblastoma', 'Disease', (133, 147))
2702	31433515	Colorectal cancers, in which it will make a difference to patient treatment, should undergo molecular testing for microsatellite instability and extended RAS testing for mutations in KRAS, NRAS and BRAF.	('microsatellite instability', 'Disease', (114, 140))	('NRAS', 'Gene', '4893', (189, 193))	('BRAF', 'Gene', '673', (198, 202))	('KRAS', 'Gene', (183, 187))	('Colorectal cancers', 'Disease', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('mutations', 'Var', (170, 179))	('patient', 'Species', '9606', (58, 65))	('KRAS', 'Gene', '3845', (183, 187))	('BRAF', 'Gene', (198, 202))	('Colorectal cancers', 'Disease', 'MESH:D015179', (0, 18))	('microsatellite instability', 'Disease', 'MESH:D053842', (114, 140))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('NRAS', 'Gene', (189, 193))
2712	31433515	Mutations in MEN1, DAXX and ATRX are entity-defining for well-differentiated NETs, whereas NECs usually have TP53 or RB1 mutations.	('NETs', 'Disease', (77, 81))	('NECs', 'Disease', 'MESH:D018278', (91, 95))	('MEN1', 'Gene', '4221', (13, 17))	('RB1', 'Gene', (117, 120))	('DAXX', 'Gene', '1616', (19, 23))	('ATRX', 'Gene', (28, 32))	('NECs', 'Disease', (91, 95))	('NETs', 'Disease', 'MESH:D018358', (77, 81))	('TP53', 'Gene', '7157', (109, 113))	('Mutations', 'Var', (0, 9))	('RB1', 'Gene', '5925', (117, 120))	('NECs', 'Phenotype', 'HP:0100634', (91, 95))	('TP53', 'Gene', (109, 113))	('DAXX', 'Gene', (19, 23))	('ATRX', 'Gene', '546', (28, 32))	('MEN1', 'Gene', (13, 17))
2789	30258932	For example, in breast cancer, overexpression of NEAT1 promotes EMT and invasion in vitro as well as dissemination and metastasis in vivo.	('breast cancer', 'Disease', (16, 29))	('overexpression', 'Var', (31, 45))	('promotes', 'PosReg', (55, 63))	('NEAT1', 'Gene', '283131', (49, 54))	('NEAT1', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('dissemination', 'CPA', (101, 114))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
2790	30258932	Exogenous modulation of NEAT1 modulates gemcitabine sensitivity in cholangiocarcinoma.	('modulates', 'Reg', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('modulation', 'Var', (10, 20))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('gemcitabine sensitivity', 'MPA', (40, 63))	('NEAT1', 'Gene', '283131', (24, 29))	('NEAT1', 'Gene', (24, 29))	('cholangiocarcinoma', 'Disease', (67, 85))	('gemcitabine', 'Chemical', 'MESH:C056507', (40, 51))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))
2792	30258932	Moreover, in breast cancer, hepatocellular carcinoma, and papillary kidney cancer, whole-genome analysis indicates NEAT1 carries specific mutations that affect their expression levels.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (28, 52))	('kidney cancer', 'Phenotype', 'HP:0009726', (68, 81))	('hepatocellular carcinoma', 'Disease', (28, 52))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('papillary kidney cancer', 'Disease', (58, 81))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (28, 52))	('affect', 'Reg', (153, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('expression levels', 'MPA', (166, 183))	('breast cancer', 'Disease', (13, 26))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('papillary kidney cancer', 'Phenotype', 'HP:0006766', (58, 81))	('NEAT1', 'Gene', (115, 120))	('NEAT1', 'Gene', '283131', (115, 120))	('papillary kidney cancer', 'Disease', 'MESH:D007681', (58, 81))	('mutations', 'Var', (138, 147))
2793	30258932	rs512715 of NEAT1 is also associated with an increased risk of cervical cancer.	('rs512715', 'Mutation', 'rs512715', (0, 8))	('NEAT1', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cervical cancer', 'Disease', 'MESH:D002583', (63, 78))	('rs512715', 'Var', (0, 8))	('cervical cancer', 'Disease', (63, 78))	('NEAT1', 'Gene', '283131', (12, 17))	('associated', 'Reg', (26, 36))
2816	30258932	However, a recent study indicated that in breast invasive cancer, from TCGA datasets, NEAT1 was focally deleted in ~8% of breast cancers and its promoters carried various mutations, and three out of the four mutations they validated reproducibly decreased NEAT1 expression compared with the wild type sequence.	('NEAT1', 'Gene', '283131', (256, 261))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancers', 'Disease', 'MESH:D001943', (122, 136))	('breast cancers', 'Disease', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('NEAT1', 'Gene', (256, 261))	('deleted', 'NegReg', (104, 111))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('expression', 'MPA', (262, 272))	('breast invasive cancer', 'Disease', (42, 64))	('mutations', 'Var', (208, 217))	('breast invasive cancer', 'Disease', 'MESH:D001943', (42, 64))	('NEAT1', 'Gene', '283131', (86, 91))	('NEAT1', 'Gene', (86, 91))	('breast cancers', 'Phenotype', 'HP:0003002', (122, 136))	('mutations', 'Var', (171, 180))	('decreased', 'NegReg', (246, 255))
2829	30258932	In lung cancer, NEAT1 is up-regulated by the direct binding of Oct4, since knockdown of NEAT1 abolishes Oct4-mediated lung cancer cell growth and motility.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('Oct4', 'Gene', '5460', (63, 67))	('lung cancer', 'Disease', (118, 129))	('abolishes', 'NegReg', (94, 103))	('NEAT1', 'Gene', (88, 93))	('Oct4', 'Gene', (104, 108))	('knockdown', 'Var', (75, 84))	('binding', 'Interaction', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('NEAT1', 'Gene', (16, 21))	('lung cancer', 'Disease', (3, 14))	('Oct4', 'Gene', (63, 67))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('NEAT1', 'Gene', '283131', (88, 93))	('up-regulated', 'PosReg', (25, 37))	('motility', 'CPA', (146, 154))	('NEAT1', 'Gene', '283131', (16, 21))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('Oct4', 'Gene', '5460', (104, 108))
2841	30258932	The aberrant expression of NEAT1 in certain types of cancer may be resulted from the cooperation and antagonism between different transcription factors.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('expression', 'MPA', (13, 23))	('aberrant', 'Var', (4, 12))	('NEAT1', 'Gene', '283131', (27, 32))	('NEAT1', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('resulted from', 'Reg', (67, 80))
2848	30258932	In laryngeal squamous cell cancer, high expression of NEAT1 decreases miR-107 expression, thus regulating CDK6 level and exerting an oncogenic effect.	('decreases', 'NegReg', (60, 69))	('regulating', 'Reg', (95, 105))	('laryngeal squamous cell cancer', 'Disease', (3, 33))	('NEAT1', 'Gene', (54, 59))	('expression', 'MPA', (78, 88))	('NEAT1', 'Gene', '283131', (54, 59))	('laryngeal squamous cell cancer', 'Disease', 'MESH:D002294', (3, 33))	('CDK6', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('CDK6', 'Gene', '1021', (106, 110))	('oncogenic effect', 'CPA', (133, 149))	('high expression', 'Var', (35, 50))	('miR-107', 'Gene', '406901', (70, 77))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (13, 33))	('miR-107', 'Gene', (70, 77))
2867	30258932	Recently, several studies have revealed the mutations and polymorphisms of NEAT1 are also closely correlated with the prognosis of cancers, which has added complexity to NEAT1-associated signaling and function.	('NEAT1', 'Gene', '283131', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('NEAT1', 'Gene', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('polymorphisms', 'Var', (58, 71))	('correlated', 'Reg', (98, 108))	('mutations', 'Var', (44, 53))	('NEAT1', 'Gene', '283131', (170, 175))	('NEAT1', 'Gene', (170, 175))
2868	30258932	Moreover, since the two major isoforms of NEAT1 produced from alternative transcription have been reported to have different cellular location and tumor regulation properties, it is necessary to distinguish the exact expression and function of these two isoforms.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('NEAT1', 'Gene', '283131', (42, 47))	('alternative transcription', 'Var', (62, 87))	('NEAT1', 'Gene', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
2888	29620225	Recently, regarding the multivariate and multi-stage processes of cancer, interfering with or inhibiting one or several factors leading to these processes is an effective method of preventing, or providing therapy for cancer.	('interfering', 'Var', (74, 85))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('inhibiting', 'NegReg', (94, 104))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
2924	29620225	C84E11; 1:1,000), IKKalpha (cat no.	('IKKalpha', 'Gene', (18, 26))	('C84E11', 'Var', (0, 6))	('IKKalpha', 'Gene', '1147', (18, 26))
2981	29620225	ROS are the principal stimulator of cytotoxicity and an important factor causing oxidative damage.	('ROS', 'Var', (0, 3))	('cytotoxicity', 'Disease', 'MESH:D064420', (36, 48))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('cytotoxicity', 'Disease', (36, 48))
3020	29765232	Older age, depth of tumor invasion, positive surgical margin, lower hemoglobin, and higher lactic dehydrogenase (LDH) were associated with significantly worse OS using multivariate analysis.	('higher', 'PosReg', (84, 90))	('OS', 'Chemical', '-', (159, 161))	('hemoglobin', 'MPA', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('lower', 'NegReg', (62, 67))	('lower hemoglobin', 'Phenotype', 'HP:0001903', (62, 78))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('positive', 'Var', (36, 44))	('lactic dehydrogenase', 'MPA', (91, 111))	('tumor', 'Disease', (20, 25))
3021	29765232	In the entire cohort, the estimate of median OS in patients with LDH <271 U/L was 36.291 months (95% CI; 30.989-41.594 months), and 30.736 months (95% CI; 19.154-42.318 months) in patients with LDH >=271 U/L (adjusted HR-1.505, 95% CI; 1.009-2.245, P = 0.045).	('OS', 'Chemical', '-', (45, 47))	('LDH', 'Gene', (65, 68))	('patients', 'Species', '9606', (51, 59))	('<271 U/L', 'Var', (69, 77))	('patients', 'Species', '9606', (180, 188))
3062	29765232	The median serum levels of CEA, CA19-9, and LDH of the entire cohort were 3.40 ng/mL (IQR 2.11-5.27 ng/mL), 83.2 U/mL (IQR 24.8-417.2 U/mL), and 215 U/L (IQR 184-273 U/L), respectively.	('serum levels', 'MPA', (11, 23))	('CA19-9', 'Var', (32, 38))	('CA19-9', 'Chemical', 'MESH:C086528', (32, 38))	('LDH', 'Gene', (44, 47))	('CEA', 'Gene', (27, 30))	('CEA', 'Gene', '1084', (27, 30))
3070	29765232	For all patients included in the analysis, the estimate of median OS in patients with LDH <271 U/L was 36.291 months (95% CI; 30.989-41.594 months) and 30.736 months (95% CI; 19.154-42.318 months) in patients with LDH >=271 U/L (log-rank P = 0.028) (Figure 2E).	('OS', 'Chemical', '-', (66, 68))	('patients', 'Species', '9606', (200, 208))	('patients', 'Species', '9606', (72, 80))	('LDH', 'Gene', (86, 89))	('<271 U/L', 'Var', (90, 98))	('patients', 'Species', '9606', (8, 16))
3074	29765232	The data showed a nonsignificant improvement in survival with LDH <271 U/L compared with LDH >=271 U/L in multivariate model in individual subgroups: GBC (Table S1) or hilar cancer (Table S2).	('improvement', 'PosReg', (33, 44))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('GBC', 'Disease', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('LDH <271 U/L', 'Var', (62, 74))
3090	29765232	Lee et al suggested that CA19-9 but not CEA served as a predictor of better survival in patients with advanced cholangiocarcinoma on gemcitabine-based chemotherapy.	('gemcitabine', 'Chemical', 'MESH:C056507', (133, 144))	('CA19-9', 'Chemical', 'MESH:C086528', (25, 31))	('CA19-9', 'Var', (25, 31))	('cholangiocarcinoma', 'Disease', (111, 129))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 129))	('patients', 'Species', '9606', (88, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('CEA', 'Gene', (40, 43))	('better', 'PosReg', (69, 75))	('CEA', 'Gene', '1084', (40, 43))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))
3092	29765232	Our study showed a nonsignificant trend for better survival of patients with a low level of CA19-9 or CEA.	('better', 'PosReg', (44, 50))	('CA19-9', 'Gene', (92, 98))	('low level', 'Var', (79, 88))	('CA19-9', 'Chemical', 'MESH:C086528', (92, 98))	('CEA', 'Gene', (102, 105))	('patients', 'Species', '9606', (63, 71))	('CEA', 'Gene', '1084', (102, 105))
3141	26022776	However, chronic inflammation and stasis of bile flow are felt to be the key contributors to genetic alterations in biliary cells leading to malignancy.	('genetic alterations', 'Var', (93, 112))	('alterations', 'Var', (101, 112))	('malignancy', 'Disease', 'MESH:D009369', (141, 151))	('leading to', 'Reg', (130, 140))	('stasis of bile', 'Phenotype', 'HP:0001396', (34, 48))	('malignancy', 'Disease', (141, 151))	('inflammation', 'Disease', 'MESH:D007249', (17, 29))	('stasis', 'MPA', (34, 40))	('inflammation', 'Disease', (17, 29))
3144	26022776	Other studies have reported mutations in the K-ras gene in up to 60 % of patients, similar to those found in other gastrointestinal cancers; K-ras mutations were noted to be particularly common in hilar tumors larger than 3 cm.	('K-ras', 'Gene', (141, 146))	('mutations', 'Var', (147, 156))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (115, 139))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('K-ras', 'Gene', (45, 50))	('K-ras', 'Gene', '3845', (45, 50))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('K-ras', 'Gene', '3845', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('common', 'Reg', (187, 193))	('patients', 'Species', '9606', (73, 81))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('gastrointestinal cancers', 'Disease', (115, 139))
3145	26022776	K-ras mutations have also been noted to be found more frequent in patients with lymph node metastases than those without, and are associated with poor survival.	('metastases', 'Disease', (91, 101))	('K-ras', 'Gene', (0, 5))	('metastases', 'Disease', 'MESH:D009362', (91, 101))	('K-ras', 'Gene', '3845', (0, 5))	('mutations', 'Var', (6, 15))	('patients', 'Species', '9606', (66, 74))	('associated', 'Reg', (130, 140))
3191	26022776	Cholangiocarcinomas can often be identified due to thickening and irregularity of the bile duct walls with upstream dilatation of the intrahepatic bile ducts.	('intrahepatic', 'Disease', 'MESH:D002780', (134, 146))	('irregularity', 'Var', (66, 78))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (0, 18))	('Cholangiocarcinomas', 'Disease', (0, 19))	('Cholangiocarcinomas', 'Disease', 'MESH:D018281', (0, 19))	('intrahepatic', 'Disease', (134, 146))	('dilatation', 'Phenotype', 'HP:0002617', (116, 126))
3206	26022776	PVE has been shown to increase FLR volumes in those patients with normal liver parenchyma prior to major hepatic resection for hepatic malignancy, although a majority of patients with chronic liver disease have also been shown to obtain significant benefit.	('patients', 'Species', '9606', (170, 178))	('PVE', 'Phenotype', 'HP:0030242', (0, 3))	('FLR volumes', 'MPA', (31, 42))	('hepatic malignancy', 'Disease', 'MESH:D056486', (127, 145))	('chronic liver disease', 'Disease', (184, 205))	('PVE', 'Var', (0, 3))	('increase', 'PosReg', (22, 30))	('PVE', 'Chemical', '-', (0, 3))	('hepatic malignancy', 'Phenotype', 'HP:0002896', (127, 145))	('chronic liver disease', 'Disease', 'MESH:D058625', (184, 205))	('hepatic malignancy', 'Disease', (127, 145))	('liver disease', 'Phenotype', 'HP:0001392', (192, 205))	('patients', 'Species', '9606', (52, 60))
3270	24746211	Lastly, we found that pharmacological inhibition of the YAP complex in both cholangiocyte and cholangiocarcinoma cell lines blocked compensatory bile duct proliferation, an early marker of BA that requires nuclear YAP expression, in a time- and dose-dependent manner.	('BA', 'Phenotype', 'HP:0005912', (189, 191))	('compensatory bile duct proliferation', 'CPA', (132, 168))	('cholangiocarcinoma', 'Disease', (94, 112))	('inhibition', 'Var', (38, 48))	('bile duct proliferation', 'Phenotype', 'HP:0001408', (145, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('blocked', 'NegReg', (124, 131))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (94, 112))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (94, 112))
3326	24746211	Here, we are the first to show YAP as a useful diagnostic marker in non-neoplastic, human hepatobiliary disease; we show that YAP highlights proliferating bile ducts, a hallmark of BA.	('proliferating bile ducts', 'CPA', (141, 165))	('hepatobiliary disease', 'Disease', 'MESH:D004066', (90, 111))	('hepatobiliary disease', 'Disease', (90, 111))	('BA', 'Phenotype', 'HP:0005912', (181, 183))	('human', 'Species', '9606', (84, 89))	('YAP', 'Var', (126, 129))
3329	24746211	Deletion of YAP in the developing murine liver results in ductopenia, while deletion in the adult liver yields no phenotype unless the liver is challenged with bile duct ligation.	('ductopenia', 'Disease', 'None', (58, 68))	('murine', 'Species', '10090', (34, 40))	('YAP', 'Gene', (12, 15))	('ductopenia', 'Disease', (58, 68))	('Deletion', 'Var', (0, 8))
3341	24746211	As a parallel finding, inhibition of YAP in H69 cholangiocytes and HuCCT1, a cholangiocarcinoma cell line, significantly reduces proliferation.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (77, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('inhibition', 'Var', (23, 33))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (77, 95))	('reduces', 'NegReg', (121, 128))	('proliferation', 'CPA', (129, 142))	('YAP', 'Gene', (37, 40))	('cholangiocarcinoma', 'Disease', (77, 95))
3349	21620848	Mnt seems to inhibit cell-cycle entry, because the lack of Mnt in cells accelerates the G0 to S-phase transition.	('cell-cycle entry', 'CPA', (21, 37))	('G0 to S-phase transition', 'CPA', (88, 112))	('lack', 'Var', (51, 55))	('accelerates', 'PosReg', (72, 83))	('inhibit', 'NegReg', (13, 20))	('Mnt', 'Gene', (59, 62))	('Mnt', 'Gene', (0, 3))	('Mnt', 'Gene', '17428', (0, 3))	('Mnt', 'Gene', '17428', (59, 62))
3351	21620848	Correspondingly, Mnt overexpression suppresses cell-cycle entry and cell proliferation, suggesting that the relative ratio of c-Myc-Max to Mnt-Max is critical for cell-cycle entry.	('overexpression', 'Var', (21, 35))	('Myc', 'Gene', '17869', (128, 131))	('Mnt', 'Gene', (139, 142))	('cell proliferation', 'CPA', (68, 86))	('suppresses', 'NegReg', (36, 46))	('Mnt', 'Gene', '17428', (139, 142))	('Mnt', 'Gene', (17, 20))	('Mnt', 'Gene', '17428', (17, 20))	('Myc', 'Gene', (128, 131))	('cell-cycle entry', 'CPA', (47, 63))
3352	21620848	These results demonstrate that Mnt-Myc antagonism plays a fundamental role in regulating cell-cycle entry and proliferation.	('antagonism', 'Var', (39, 49))	('proliferation', 'CPA', (110, 123))	('Myc', 'Gene', (35, 38))	('Mnt', 'Gene', (31, 34))	('Myc', 'Gene', '17869', (35, 38))	('Mnt', 'Gene', '17428', (31, 34))	('cell-cycle entry', 'CPA', (89, 105))
3356	21620848	LMBDL induced a marked increase in c-Myc expression in the first 8 weeks after surgery, whereas IP and oral treatment with DEN (DD) without bile duct ligation resulted in increased c-Myc at later time points between 12 and 28 weeks.	('DEN', 'Chemical', 'MESH:D004052', (123, 126))	('LMBDL', 'Chemical', '-', (0, 5))	('Myc', 'Gene', (37, 40))	('LMBDL', 'Var', (0, 5))	('Myc', 'Gene', '17869', (37, 40))	('increase', 'PosReg', (23, 31))	('Myc', 'Gene', (183, 186))	('Myc', 'Gene', '17869', (183, 186))
3365	21620848	miR-210 expression was also increased by combined DLD, but with a time course that correlated better with HIF-2alpha than with HIF-1alpha expression.	('increased', 'PosReg', (28, 37))	('HIF-1alpha', 'Gene', '15251', (127, 137))	('miR-210', 'Gene', '387206', (0, 7))	('HIF-2alpha', 'Gene', '13819', (106, 116))	('miR-210', 'Gene', (0, 7))	('expression', 'MPA', (8, 18))	('combined DLD', 'Var', (41, 53))	('DLD', 'Var', (50, 53))	('HIF-1alpha', 'Gene', (127, 137))	('HIF-2alpha', 'Gene', (106, 116))
3467	24475740	Recent study suggested that aberrant expression of p53 and mdm-2 correlated with the high histological grade of the tumor and were associated with tumor behavior and local recurrence.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('p53', 'Gene', (51, 54))	('tumor', 'Disease', (147, 152))	('p53', 'Gene', '7157', (51, 54))	('mdm-2', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('aberrant', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('associated with', 'Reg', (131, 146))	('mdm-2', 'Gene', '4193', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('local recurrence', 'CPA', (166, 182))	('expression', 'MPA', (37, 47))	('tumor', 'Disease', (116, 121))	('correlated', 'Reg', (65, 75))
3473	24475740	However, the overexpression or gene amplification of HER2 in intrahepatic mucoepidermoid carcinoma has not been clarified yet, although it could be detected in up to one-third of patients with mucoepidermoid carcinoma in the salivary glands.	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('carcinoma in the salivary', 'Phenotype', 'HP:0100684', (208, 233))	('gene amplification', 'Var', (31, 49))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (193, 217))	('HER2', 'Gene', (53, 57))	('intrahepatic mucoepidermoid carcinoma', 'Disease', (61, 98))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (74, 98))	('HER2', 'Gene', '2064', (53, 57))	('patients', 'Species', '9606', (179, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('intrahepatic mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (61, 98))	('mucoepidermoid carcinoma', 'Disease', (193, 217))
3521	23921971	Preoperative biliary drainage is only indicated in patients with cholangitis, longstanding jaundice, or poor nutrition and in those in whom the insufficient liver volume is <40% of the total liver volume.	('jaundice', 'Disease', (91, 99))	('jaundice', 'Phenotype', 'HP:0000952', (91, 99))	('poor nutrition', 'Var', (104, 118))	('insufficient liver', 'Disease', 'MESH:D048550', (144, 162))	('cholangitis', 'Disease', (65, 76))	('cholangitis', 'Phenotype', 'HP:0030151', (65, 76))	('patients', 'Species', '9606', (51, 59))	('jaundice', 'Disease', 'MESH:D007565', (91, 99))	('insufficient liver', 'Disease', (144, 162))	('cholangitis', 'Disease', 'MESH:D002761', (65, 76))
3704	33362392	After surgery, EN can effectively stimulate the immune system, rapidly increase the ratios of CD3+T, CD4+T, CD8+T cells, and CD4+T/CD8+T cells in peripheral blood, and increase the plasma immunoglobulin level.	('increase', 'PosReg', (168, 176))	('CD4', 'Gene', '920', (101, 104))	('stimulate', 'PosReg', (34, 43))	('CD4', 'Gene', (101, 104))	('ratios', 'MPA', (84, 90))	('immune system', 'CPA', (48, 61))	('CD4', 'Gene', (125, 128))	('increase', 'PosReg', (71, 79))	('plasma immunoglobulin level', 'MPA', (181, 208))	('CD8', 'Gene', (108, 111))	('CD4', 'Gene', '920', (125, 128))	('CD8', 'Gene', '925', (108, 111))	('CD8', 'Gene', (131, 134))	('CD3+T', 'Var', (94, 99))	('CD8', 'Gene', '925', (131, 134))
3716	33362392	In a study on postoperative abdominal surgery, PN with postoperative EEN not only improved the nutritional status of patients with tumors but also reduced the incidence of postoperative complications.	('nutritional status', 'MPA', (95, 113))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('EEN', 'Chemical', '-', (69, 72))	('PN', 'Gene', '79650', (47, 49))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('EEN', 'Var', (69, 72))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('patients', 'Species', '9606', (117, 125))	('reduced', 'NegReg', (147, 154))	('improved', 'PosReg', (82, 90))
3734	33182517	To this end, the therapeutic exploitation of IDH mutations is the first successful example of precision medicine in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (116, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('IDH', 'Gene', (45, 48))	('mutations', 'Var', (49, 58))	('IDH', 'Gene', '3417', (45, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))	('cholangiocarcinoma', 'Disease', (116, 134))
3738	33182517	Recently, mutations in isocitrate dehydrogenase genes (IDH1/2) and fusions of the fibroblast growth factor receptor have emerged as the most amenable to molecularly targeted inhibition, with several compounds actively investigated in advanced-phase clinical trials.	('isocitrate dehydrogenase', 'Gene', '3417', (23, 47))	('mutations', 'Var', (10, 19))	('isocitrate dehydrogenase', 'Gene', (23, 47))	('IDH1/2', 'Gene', (55, 61))
3739	33182517	Specifically, the IDH1 inhibitor ivosidenib has been the first targeted agent to show a survival benefit in a randomized phase III trial of cholangiocarcinoma patients harboring IDH1 mutations.	('IDH', 'Gene', '3417', (178, 181))	('mutations', 'Var', (183, 192))	('IDH', 'Gene', (18, 21))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (140, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('IDH', 'Gene', '3417', (18, 21))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (140, 158))	('ivosidenib', 'Chemical', 'MESH:C000627630', (33, 43))	('patients', 'Species', '9606', (159, 167))	('IDH', 'Gene', (178, 181))	('cholangiocarcinoma', 'Disease', (140, 158))
3748	33182517	Regarding later lines treatment, determining a role for chemotherapy is a recent achievement, with the results of the ABC-06 trial showing an advantage for the mFOLFOX6 regimen compared to active symptoms control, while beyond second-line, no high-level evidence currently supports the use of systemic treatment in clinical practice.	('ABC-06', 'Gene', (118, 124))	('mFOLFOX6', 'Var', (160, 168))	('mFOLFOX6', 'Chemical', '-', (160, 168))	('advantage', 'PosReg', (142, 151))
3750	33182517	Specifically, tumor profiling studies have reported that nearly 40% of BTCs harbor potentially actionable aberrations, among which are isocitrate dehydrogenase (IDH) 1/2 mutations (10%), fibroblast growth factor receptor (FGFR) fusions (10%), HER2 amplifications/mutations (10-15%), BRAFV600E mutation (3%), BRCA2 mutations (3%), and microsatellite instability (1%).	('FGFR', 'Gene', (222, 226))	('tumor', 'Disease', (14, 19))	('fusions', 'Var', (228, 235))	('mutations', 'Var', (314, 323))	('mutations', 'Var', (170, 179))	('BTC', 'Gene', (71, 74))	('BRCA2', 'Gene', (308, 313))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('BRCA2', 'Gene', '675', (308, 313))	('HER2', 'Gene', (243, 247))	('microsatellite', 'MPA', (334, 348))	('HER2', 'Gene', '2064', (243, 247))	('BRAFV600E', 'Mutation', 'rs113488022', (283, 292))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('isocitrate dehydrogenase (IDH) 1/2', 'Gene', '3417;3418', (135, 169))	('BRAFV600E', 'Gene', (283, 292))	('BTC', 'Gene', '685', (71, 74))
3751	33182517	To this end, IDH 1/2 mutations and FGFR 2 fusions are being clinically exploited as the most relevant therapeutic targets so far, with several targeted agents showing unprecedented results in refractory disease settings.	('IDH 1/2', 'Gene', (13, 20))	('FGFR 2', 'Gene', '2263', (35, 41))	('FGFR 2', 'Gene', (35, 41))	('IDH 1/2', 'Gene', '3417;3418', (13, 20))	('fusions', 'Var', (42, 49))	('mutations', 'Var', (21, 30))
3754	33182517	To this end, IDH1/2 mutations (4.9-36%), FGFR 1-3 fusions, mutations and amplifications (11-45%), as well as BAP-1 mutations (13%) have been reported to occur more frequently in iCCA, whereas KRAS mutations (8.3-42%), SMAD4 mutations (21%), and ERBB2/3 amplifications (11-17%) have been observed more commonly in eCCA.	('SMAD4', 'Gene', '4089', (218, 223))	('mutations', 'Var', (115, 124))	('SMAD4', 'Gene', (218, 223))	('BAP-1', 'Gene', '8314', (109, 114))	('iCCA', 'Disease', (178, 182))	('fusions', 'Var', (50, 57))	('FGFR 1-3', 'Gene', '2260;2263;2261', (41, 49))	('eCCA', 'Disease', (313, 317))	('IDH1/2', 'Gene', (13, 19))	('KRAS', 'Gene', (192, 196))	('FGFR 1-3', 'Gene', (41, 49))	('BAP-1', 'Gene', (109, 114))	('mutations', 'Var', (59, 68))	('ERBB2/3', 'Gene', (245, 252))	('mutations', 'Var', (20, 29))	('ERBB2/3', 'Gene', '2064;2065', (245, 252))	('KRAS', 'Gene', '3845', (192, 196))
3755	33182517	Moreover, Nakamura and colleagues described how eCCA was more specifically associated with previously unknown aberrations, such as ATP1B-PRKACA and ATP1B-PRKACB fusions, along with mutations in ELF3 and ARID1B genes.	('ATP1B', 'Gene', (148, 153))	('PRKACB', 'Gene', '5567', (154, 160))	('PRKACB', 'Gene', (154, 160))	('PRKACA', 'Gene', (137, 143))	('ATP1B', 'Gene', (131, 136))	('ATP1B', 'Gene', '481', (148, 153))	('ARID1B', 'Gene', '57492', (203, 209))	('PRKACA', 'Gene', '5566', (137, 143))	('ELF3', 'Gene', (194, 198))	('ELF3', 'Gene', '1999', (194, 198))	('eCCA', 'Disease', (48, 52))	('fusions', 'Var', (161, 168))	('associated', 'Reg', (75, 85))	('ARID1B', 'Gene', (203, 209))	('ATP1B', 'Gene', '481', (131, 136))
3756	33182517	In addition, cholangiocarcinoma also displays genomic diversity according to aetiological risk factor as demonstrated by the higher mutational burden found in liver fluke-driven tumors (median 4700 vs 3143 somatic mutations/tumor) and the enrichment for ERBB2 amplification and TP53 mutations.	('cholangiocarcinoma', 'Disease', (13, 31))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (13, 31))	('amplification', 'Var', (260, 273))	('ERBB2', 'Gene', (254, 259))	('higher', 'PosReg', (125, 131))	('mutational burden', 'MPA', (132, 149))	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('mutations', 'Var', (283, 292))	('tumor', 'Disease', (224, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('tumors', 'Disease', (178, 184))	('TP53', 'Gene', (278, 282))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (13, 31))	('liver fluke', 'Species', '6192', (159, 170))	('liver fluke-driven', 'Disease', (159, 177))
3757	33182517	In contrast, non-liver fluke-associated cholangiocarcinoma has been shown to harbor high copy-number aberrations, PD-1/PD-L1 expression, epigenetic mutations involving IDH1/2 and BAP-1, and FGFR/PRKA-related gene rearrangement.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (40, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('liver fluke', 'Species', '6192', (17, 28))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (40, 58))	('PD-1/PD-L1', 'Gene', (114, 124))	('BAP-1', 'Gene', '8314', (179, 184))	('BAP-1', 'Gene', (179, 184))	('epigenetic mutations', 'Var', (137, 157))	('IDH1/2', 'Gene', (168, 174))	('cholangiocarcinoma', 'Disease', (40, 58))	('high copy-number aberrations', 'Var', (84, 112))	('FGFR/PRKA-related gene', 'Gene', (190, 212))
3761	33182517	Another study by The Cancer Genome Atlas employed an integrative approach looking at somatic mutations, DNA methylation patterns, copy number alterations, and RNA expressions in a series of iCCA-predominant tumors.	('Cancer', 'Disease', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('Cancer', 'Disease', 'MESH:D009369', (21, 27))	('Cancer', 'Phenotype', 'HP:0002664', (21, 27))	('iCCA-predominant tumors', 'Disease', (190, 213))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('copy number alterations', 'Var', (130, 153))	('iCCA-predominant tumors', 'Disease', 'MESH:D006689', (190, 213))
3766	33182517	Recurrent somatic mutations usually occur at a single amino acid residue of both IDH1 (arginine 132) and IDH2 (arginine 172 or arginine 140).	('IDH', 'Gene', '3417', (105, 108))	('arginine', 'Chemical', 'MESH:D001120', (127, 135))	('arginine 172', 'Var', (111, 123))	('arginine', 'Chemical', 'MESH:D001120', (87, 95))	('IDH', 'Gene', (105, 108))	('arginine', 'Chemical', 'MESH:D001120', (111, 119))	('IDH', 'Gene', (81, 84))	('arginine 140', 'Var', (127, 139))	('arginine 132', 'Var', (87, 99))	('occur', 'Reg', (36, 41))	('IDH', 'Gene', '3417', (81, 84))
3767	33182517	IDH mutations are considered gain-of-function and lead to the disruption of the normal catalytic activity of IDH1/2, ultimately resulting in increased conversion of alpha-KG to D-2-hydroxyglutarate (D-2HG), which acts as an oncometabolite, promoting tumor proliferation and metastasis development through several pathways, such as DNA methylation and activation of VEGFR (Figure 2).	('VEGFR', 'Gene', (365, 370))	('increased', 'PosReg', (141, 150))	('D-2HG', 'Chemical', 'MESH:C019417', (199, 204))	('DNA', 'CPA', (331, 334))	('tumor', 'Disease', (250, 255))	('activation', 'PosReg', (351, 361))	('IDH', 'Gene', (0, 3))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (177, 197))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('catalytic activity', 'MPA', (87, 105))	('IDH', 'Gene', (109, 112))	('promoting', 'PosReg', (240, 249))	('IDH', 'Gene', '3417', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('mutations', 'Var', (4, 13))	('IDH', 'Gene', '3417', (109, 112))	('conversion', 'MPA', (151, 161))	('disruption', 'NegReg', (62, 72))	('metastasis development', 'CPA', (274, 296))	('VEGFR', 'Gene', '3791', (365, 370))	('alpha-KG', 'Chemical', 'MESH:D007656', (165, 173))
3769	33182517	Furthermore, the D-2HG-induced dysregulation of histone and DNA methylation inhibited normal cellular differentiation, promoting malignant transformation.	('DNA methylation', 'Protein', (60, 75))	('normal cellular differentiation', 'CPA', (86, 117))	('dysregulation', 'Var', (31, 44))	('malignant transformation', 'CPA', (129, 153))	('D-2HG', 'Chemical', 'MESH:C019417', (17, 22))	('inhibited', 'NegReg', (76, 85))	('histone', 'Protein', (48, 55))	('promoting', 'PosReg', (119, 128))	('D-2HG-induced', 'Var', (17, 30))
3773	33182517	IDH mutations are prevalent in several rare malignancies, such as iCCA, glioma, acute myeloid leukemia, chondrosarcoma, thyroid carcinoma, angioimmunoblastic T-cell lymphoma, and other cancers.	('acute myeloid leukemia', 'Disease', (80, 102))	('chondrosarcoma', 'Disease', 'MESH:D002813', (104, 118))	('chondrosarcoma', 'Disease', (104, 118))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (86, 102))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancers', 'Disease', (185, 192))	('IDH', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (80, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (158, 173))	('iCCA', 'Disease', (66, 70))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (104, 118))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (80, 102))	('leukemia', 'Phenotype', 'HP:0001909', (94, 102))	('glioma', 'Disease', (72, 78))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('lymphoma', 'Phenotype', 'HP:0002665', (165, 173))	('thyroid carcinoma, angioimmunoblastic T-cell lymphoma', 'Disease', 'MESH:D016399', (120, 173))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('mutations', 'Var', (4, 13))	('malignancies', 'Disease', 'MESH:D009369', (44, 56))	('cell lymphoma', 'Phenotype', 'HP:0012191', (160, 173))	('malignancies', 'Disease', (44, 56))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (120, 137))	('prevalent', 'Reg', (18, 27))
3788	33182517	The first IDH2 inhibitor developed was AGI-6780, which induced thex differentiation of IDH2 mutated erythroleukemia and primary human AML cells.	('IDH', 'Gene', (10, 13))	('erythroleukemia', 'Disease', (100, 115))	('IDH', 'Gene', '3417', (10, 13))	('IDH', 'Gene', (87, 90))	('erythroleukemia', 'Disease', 'MESH:D004915', (100, 115))	('AML', 'Disease', 'MESH:D015470', (134, 137))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('IDH', 'Gene', '3417', (87, 90))	('AGI-6780', 'Chemical', 'MESH:C581155', (39, 47))	('human', 'Species', '9606', (128, 133))	('mutated', 'Var', (92, 99))	('AML', 'Disease', (134, 137))	('AML', 'Phenotype', 'HP:0004808', (134, 137))	('thex differentiation', 'CPA', (63, 83))
3801	33182517	In a first report, two patients with IDH2-mutant AML developed resistance to the mutant IDH2 inhibitor enasidenib as a result of the emergence of second-site IDH2 mutations in trans (Q316E, I319M) in the wild-type allele.	('AML', 'Disease', (49, 52))	('IDH', 'Gene', '3417', (158, 161))	('mutations', 'Var', (163, 172))	('enasidenib', 'Chemical', 'MESH:C000605269', (103, 113))	('patients', 'Species', '9606', (23, 31))	('AML', 'Disease', 'MESH:D015470', (49, 52))	('AML', 'Phenotype', 'HP:0004808', (49, 52))	('I319M', 'Mutation', 'rs1471392809', (190, 195))	('resistance to the', 'MPA', (63, 80))	('I319M', 'Var', (190, 195))	('IDH', 'Gene', (88, 91))	('Q316E', 'Mutation', 'rs766676533', (183, 188))	('IDH', 'Gene', (37, 40))	('IDH', 'Gene', '3417', (88, 91))	('IDH', 'Gene', (158, 161))	('developed', 'Reg', (53, 62))	('IDH', 'Gene', '3417', (37, 40))
3802	33182517	This cooperated with the gain-of-function mutation (R140Q) on the other allele in inducing resistance either by breaking up the hydrogen bond between the IDH2 dimer and enasidenib or by hindrance of binding of the IDH2 dimer to enasidenib.	('inducing', 'Reg', (82, 90))	('hindrance', 'NegReg', (186, 195))	('R140Q', 'Var', (52, 57))	('breaking up', 'NegReg', (112, 123))	('binding', 'Interaction', (199, 206))	('resistance', 'MPA', (91, 101))	('gain-of-function', 'PosReg', (25, 41))	('hydrogen bond', 'MPA', (128, 141))	('enasidenib', 'Chemical', 'MESH:C000605269', (169, 179))	('enasidenib', 'Chemical', 'MESH:C000605269', (228, 238))	('breaking up', 'Phenotype', 'HP:0001061', (112, 123))	('IDH', 'Gene', (214, 217))	('IDH', 'Gene', (154, 157))	('R140Q', 'Mutation', 'rs121913502', (52, 57))	('hydrogen', 'Chemical', 'MESH:D006859', (128, 136))	('IDH', 'Gene', '3417', (214, 217))	('IDH', 'Gene', '3417', (154, 157))
3804	33182517	Receptor tyrosine kinase (RTK) pathway mutations have been associated with primary resistance to this drug, while multiple mechanisms contributed to acquired resistance, such as the development of RTK pathway mutations and 2-HG restoring mutations.	('primary resistance to this drug', 'MPA', (75, 106))	('acquired resistance', 'MPA', (149, 168))	('2-HG', 'Chemical', 'MESH:C019417', (223, 227))	('mutations', 'Var', (238, 247))	('RTK', 'Gene', (197, 200))	('mutations', 'Var', (39, 48))	('RTK', 'Gene', (26, 29))	('associated', 'Reg', (59, 69))	('2-HG restoring', 'Gene', (223, 237))	('contributed', 'Reg', (134, 145))	('mutations', 'Var', (209, 218))	('Receptor tyrosine kinase', 'Gene', (0, 24))	('RTK', 'Gene', '5979', (197, 200))	('Receptor tyrosine kinase', 'Gene', '5979', (0, 24))	('RTK', 'Gene', '5979', (26, 29))
3806	33182517	The discovery of mutations in IDH isoforms (IDH1 and IDH2) has been a major breakthrough in the translational research of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (122, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('IDH', 'Gene', '3417', (30, 33))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (122, 140))	('IDH', 'Gene', (30, 33))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', (53, 56))	('IDH', 'Gene', '3417', (44, 47))	('cholangiocarcinoma', 'Disease', (122, 140))	('mutations', 'Var', (17, 26))	('IDH', 'Gene', '3417', (53, 56))
3807	33182517	IDH1 mutations are more common than mutations of IDH2, with IDH1 hotspots located in the arginine 132 residue, IDH1-R132C (44%), and IDH1-R132G (14%).	('R132C', 'Mutation', 'rs121913499', (116, 121))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (133, 136))	('IDH', 'Gene', (49, 52))	('arginine', 'Chemical', 'MESH:D001120', (89, 97))	('R132G', 'Mutation', 'rs121913499', (138, 143))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (5, 14))	('IDH', 'Gene', (111, 114))	('IDH', 'Gene', '3417', (49, 52))	('IDH', 'Gene', (60, 63))	('IDH', 'Gene', '3417', (111, 114))	('common', 'Reg', (24, 30))	('IDH', 'Gene', '3417', (60, 63))	('IDH', 'Gene', (133, 136))
3808	33182517	The prognostic value of IDH mutations in cholangiocarcinoma remains controversial.	('IDH', 'Gene', (24, 27))	('cholangiocarcinoma', 'Disease', (41, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('IDH', 'Gene', '3417', (24, 27))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (41, 59))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (41, 59))	('mutations', 'Var', (28, 37))
3809	33182517	As previously mentioned, these mutations cause elevated levels of the oncometabolite 2-hydroxyglutarate (2-HG), which can be detected in tissue and blood as a surrogate biomarker for IDH-mutant iCCA.	('mutations', 'Var', (31, 40))	('elevated', 'PosReg', (47, 55))	('IDH', 'Gene', (183, 186))	('levels of the oncometabolite 2-hydroxyglutarate', 'MPA', (56, 103))	('IDH', 'Gene', '3417', (183, 186))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (85, 103))	('iCCA', 'Disease', (194, 198))	('2-HG', 'Chemical', 'MESH:C019417', (105, 109))
3811	33182517	Moreover, IDH mutations cause alterations in the hypoxia signaling, collagen processing, and activation of EMT via increased expression of ZEB1 and decreased levels of miR-200.	('IDH', 'Gene', (10, 13))	('activation', 'PosReg', (93, 103))	('ZEB1', 'Gene', '6935', (139, 143))	('IDH', 'Gene', '3417', (10, 13))	('increased', 'PosReg', (115, 124))	('EMT', 'CPA', (107, 110))	('ZEB1', 'Gene', (139, 143))	('collagen', 'CPA', (68, 76))	('decreased', 'NegReg', (148, 157))	('expression', 'MPA', (125, 135))	('hypoxia', 'Disease', 'MESH:D000860', (49, 56))	('alterations', 'Reg', (30, 41))	('hypoxia', 'Disease', (49, 56))	('levels of miR-200', 'MPA', (158, 175))	('mutations', 'Var', (14, 23))
3813	33182517	IDH1 and IDH2 mutations are mutually exclusive with NRAS/KRAS and FGFR mutations and may co-exist with BAP1 mutations.	('NRAS', 'Gene', (52, 56))	('BAP1', 'Gene', '8314', (103, 107))	('IDH', 'Gene', (0, 3))	('NRAS', 'Gene', '4893', (52, 56))	('IDH', 'Gene', '3417', (0, 3))	('BAP1', 'Gene', (103, 107))	('IDH', 'Gene', (9, 12))	('KRAS', 'Gene', (57, 61))	('FGFR', 'Gene', (66, 70))	('KRAS', 'Gene', '3845', (57, 61))	('IDH', 'Gene', '3417', (9, 12))	('mutations', 'Var', (14, 23))
3815	33182517	IDH1 mutations were found in 19.1% of cases.	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (0, 3))	('mutations', 'Var', (5, 14))
3820	33182517	A cohort of 168 patients with IDH-1 mutated cholangiocarcinoma, chondrosarcoma, and glioma were treated with ivosidenib in order to evaluate pharmacokinetic and pharmacodynamics profiles.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (64, 78))	('glioma', 'Disease', (84, 90))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (44, 62))	('patients', 'Species', '9606', (16, 24))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (44, 62))	('mutated', 'Var', (36, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('IDH', 'Gene', (30, 33))	('chondrosarcoma', 'Disease', 'MESH:D002813', (64, 78))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('cholangiocarcinoma', 'Disease', (44, 62))	('IDH', 'Gene', '3417', (30, 33))	('chondrosarcoma', 'Disease', (64, 78))	('ivosidenib', 'Chemical', 'MESH:C000627630', (109, 119))
3822	33182517	In a phase I dose-escalation and expansion trial, 73 patients with IDH-1 mutations received AG-120.	('patients', 'Species', '9606', (53, 61))	('pan', 'Gene', (35, 38))	('pan', 'Gene', '51816', (35, 38))	('IDH', 'Gene', (67, 70))	('IDH', 'Gene', '3417', (67, 70))	('AG-120', 'Chemical', 'MESH:C000627630', (92, 98))	('mutations', 'Var', (73, 82))
3827	33182517	The recent phase III ClarIDHy trial randomized 230 patients with advanced pretreated IDH-1 mutated cholangiocarcinoma to ivosidenib or a placebo (2:1).	('IDH', 'Gene', '3417', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (99, 117))	('mutated', 'Var', (91, 98))	('patients', 'Species', '9606', (51, 59))	('cholangiocarcinoma to ivosidenib', 'Disease', (99, 131))	('IDH', 'Gene', (85, 88))	('cholangiocarcinoma to ivosidenib', 'Disease', 'MESH:D018281', (99, 131))
3841	33182517	Indeed, SRC is a target of dasatinib, and IDH mutated iCCA cells are critically dependent on SRC activity for survival and proliferation.	('SRC', 'Gene', (8, 11))	('SRC', 'Gene', '6714', (8, 11))	('IDH', 'Gene', (42, 45))	('IDH', 'Gene', '3417', (42, 45))	('mutated', 'Var', (46, 53))	('dasatinib', 'Chemical', 'MESH:D000069439', (27, 36))	('SRC', 'Gene', '6714', (93, 96))	('SRC', 'Gene', (93, 96))
3851	32536040	The variable association between expression and methylation of estrogen receptors and the survival of patients with different tumors Estrogen receptor (ER) is essential in reproductive development and is also the primary driver of breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (231, 245))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('breast cancers', 'Disease', (231, 245))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('patients', 'Species', '9606', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('ER', 'Gene', '2099', (152, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (231, 244))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('breast cancers', 'Phenotype', 'HP:0003002', (231, 245))	('methylation', 'Var', (48, 59))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))
3852	32536040	Deregulation of ER may also be involved in tumorigenesis of other organs.	('Deregulation', 'Var', (0, 12))	('involved', 'Reg', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('ER', 'Gene', '2099', (16, 18))	('tumor', 'Disease', (43, 48))
3861	32536040	Deregulation of ERs are involved in tumorigenesis of different organs.	('Deregulation', 'Var', (0, 12))	('involved', 'Reg', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('ER', 'Gene', '2099', (16, 18))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
3863	32536040	The expression/methylation of ESR1/2 were associated with survival of patients.	('ESR1/2', 'Gene', (30, 36))	('patients', 'Species', '9606', (70, 78))	('associated', 'Reg', (42, 52))	('expression/methylation', 'MPA', (4, 26))	('expression/methylation', 'Var', (4, 26))	('ESR1/2', 'Gene', '2099;2100', (30, 36))
3875	32536040	16  ESR1 mutations are frequently detected in ER+ metastatic breast cancer and may be associated with endocrine therapy resistance.	('detected', 'Reg', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('ESR1', 'Gene', (4, 8))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('mutations', 'Var', (9, 18))	('associated', 'Reg', (86, 96))	('ER', 'Gene', '2099', (46, 48))	('ESR1', 'Gene', '2099', (4, 8))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
3892	32536040	We downloaded eight microarrays set from four different cancers, including GSE63514 and GSE63678 of cervical cancer; GSE73360 and GSE74602 of colorectal cancer; GSE76297 of cholangiocarcinoma; GSE87630, GSE112790, and GSE121248 of hepatocellular cancer.	('hepatocellular cancer', 'Disease', (231, 252))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (231, 252))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (56, 62))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (231, 252))	('colorectal cancer', 'Disease', 'MESH:D015179', (142, 159))	('GSE74602', 'Var', (130, 138))	('cancer', 'Disease', (246, 252))	('GSE63678', 'Var', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('colorectal cancer', 'Disease', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('GSE76297', 'Var', (161, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancers', 'Disease', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (109, 115))	('GSE121248', 'Var', (218, 227))	('GSE112790', 'Var', (203, 212))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (173, 191))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('GSE73360', 'Var', (117, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('GSE63514', 'Var', (75, 83))	('GSE87630', 'Var', (193, 201))	('cholangiocarcinoma', 'Disease', (173, 191))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (173, 191))
3902	32536040	Methylation is a crucial epigenetic regulation mechanism; the DNA methylation in promoter regions is strongly associated with gene expression and could be a predictor of patients' prognosis.	('patients', 'Species', '9606', (170, 178))	('methylation', 'Var', (66, 77))	('associated', 'Reg', (110, 120))	('gene expression', 'MPA', (126, 141))	('DNA methylation', 'Var', (62, 77))
3921	32536040	We compared the expression of estrogen receptor gene in eight microarray expression datasets of four tumors (Cervical cancer: GSE63514 and GSE63678; Colorectal cancer: GSE73360 and GSE74602; Cholangiocarcinoma: GSE76297; Hepatocellular cancer: GSE87630, GSE112790 and GSE121248).	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('GSE63678', 'Var', (139, 147))	('GSE76297', 'Var', (211, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('Hepatocellular cancer', 'Disease', 'MESH:D006528', (221, 242))	('GSE112790', 'Var', (254, 263))	('GSE121248', 'Var', (268, 277))	('cancer', 'Disease', (160, 166))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (149, 166))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('GSE63514', 'Var', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('GSE73360', 'Var', (168, 176))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', (236, 242))	('GSE87630', 'Var', (244, 252))	('Colorectal cancer', 'Disease', 'MESH:D015179', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (191, 209))	('Hepatocellular cancer', 'Disease', (221, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('tumors', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('Colorectal cancer', 'Disease', (149, 166))	('GSE74602', 'Var', (181, 189))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (191, 209))	('Cholangiocarcinoma', 'Disease', (191, 209))	('Hepatocellular cancer', 'Phenotype', 'HP:0001402', (221, 242))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
3931	32536040	We also noticed that IDH-mutant or IDH-like LIHC and PRAD samples belonged to subtypes with low ESR1 expression, while high ESR1 subtype was exclusively IDH-wild-type in glioma (GBM and LGG), and the expression of ESR1 was lower in IDH1 mutated samples (Figure S6).	('IDH1', 'Gene', (232, 236))	('ESR1', 'Gene', (124, 128))	('IDH', 'Gene', '3417', (35, 38))	('IDH', 'Gene', (153, 156))	('IDH', 'Gene', '3417', (232, 235))	('glioma', 'Disease', (170, 176))	('IDH1', 'Gene', '3417', (232, 236))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('ESR1', 'Gene', '2099', (96, 100))	('IDH', 'Gene', '3417', (153, 156))	('IDH', 'Gene', (21, 24))	('ESR1', 'Gene', (96, 100))	('lower', 'NegReg', (223, 228))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('IDH', 'Gene', (35, 38))	('IDH', 'Gene', '3417', (21, 24))	('low', 'NegReg', (92, 95))	('ESR1', 'Gene', '2099', (214, 218))	('IDH', 'Gene', (232, 235))	('expression', 'MPA', (101, 111))	('ESR1', 'Gene', (214, 218))	('mutated', 'Var', (237, 244))	('ESR1', 'Gene', '2099', (124, 128))
3938	32536040	Besides, compared with low ESR2 mRNA level, high mRNA level ESR2 was ascertained worse prognosis in KIRC and STAD (Figure 7C,D).	('high', 'Var', (44, 48))	('ESR2', 'Gene', '2100', (27, 31))	('ESR2', 'Gene', (60, 64))	('STAD', 'Disease', (109, 113))	('KIRC', 'Disease', (100, 104))	('ESR2', 'Gene', (27, 31))	('ESR2', 'Gene', '2100', (60, 64))
3941	32536040	Survival differences between high- and low-methylation of ESR1/2 group patients were compared.	('patients', 'Species', '9606', (71, 79))	('low-methylation', 'Var', (39, 54))	('ESR1/2', 'Gene', '2099;2100', (58, 64))	('ESR1/2', 'Gene', (58, 64))
3942	32536040	Moreover, we found that the overall and progression-free survival was longer in the high ESR1 methylation group in BLCA, BRCA, LAML, LGG, and STAD, but shorter in KIRC and KIRP (Figure S9A-G).	('ESR1', 'Gene', (89, 93))	('high', 'Var', (84, 88))	('BRCA', 'Gene', '672', (121, 125))	('BRCA', 'Gene', (121, 125))	('longer', 'PosReg', (70, 76))	('shorter', 'NegReg', (152, 159))	('progression-free survival', 'CPA', (40, 65))	('ESR1', 'Gene', '2099', (89, 93))	('methylation', 'Var', (94, 105))
3943	32536040	In the ESR2 high-methylation group, the overall and progression-free survival was significantly longer in LGG and STAD (Figure S9H,I).	('LGG', 'Disease', (106, 109))	('ESR2', 'Gene', '2100', (7, 11))	('progression-free survival', 'CPA', (52, 77))	('STAD', 'Disease', (114, 118))	('high-methylation', 'Var', (12, 28))	('longer', 'PosReg', (96, 102))	('ESR2', 'Gene', (7, 11))
3948	32536040	Overall, these data demonstrated that higher expression of ERalpha or over-phosphorylation of ERalpha in the S118 site should protect and prolong tumor patient life, except for a little particular type.	('over-phosphorylation', 'Var', (70, 90))	('prolong', 'PosReg', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('ERalpha', 'Gene', (59, 66))	('tumor', 'Disease', (146, 151))	('ERalpha', 'Gene', '2099', (59, 66))	('ERalpha', 'Gene', '2099', (94, 101))	('expression', 'MPA', (45, 55))	('ERalpha', 'Gene', (94, 101))	('higher', 'PosReg', (38, 44))	('patient', 'Species', '9606', (152, 159))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
3961	32536040	The cellular biological processes suggest a negative correlation between DNA methylation and mRNA expression, a positive correlation between mRNA and protein expression, as we observed in most cancers.	('mRNA expression', 'MPA', (93, 108))	('methylation', 'Var', (77, 88))	('cancers', 'Disease', 'MESH:D009369', (193, 200))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('cancers', 'Disease', (193, 200))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('DNA', 'MPA', (73, 76))	('negative', 'NegReg', (44, 52))
3965	32536040	Recent studies have verified tissues ESR1 mutations in most tumor patients, especially with metastatic breast cancer, and some of them to activate the estrogen-independent receptor, 18 ,  39 ,  40  whereas ESR1 and ESR2 expression not only express in breast cancer but also have been shown in other cancer types.	('ESR2', 'Gene', (215, 219))	('ESR1', 'Gene', '2099', (37, 41))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('breast cancer', 'Disease', (103, 116))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('ESR1', 'Gene', (37, 41))	('tumor', 'Disease', (60, 65))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('activate', 'PosReg', (138, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (251, 264))	('cancer', 'Disease', (110, 116))	('estrogen-independent receptor', 'MPA', (151, 180))	('breast cancer', 'Disease', 'MESH:D001943', (251, 264))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (251, 264))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ESR1', 'Gene', '2099', (206, 210))	('cancer', 'Disease', (258, 264))	('cancer', 'Disease', (299, 305))	('patients', 'Species', '9606', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('ESR1', 'Gene', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('ESR2', 'Gene', '2100', (215, 219))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
3973	32536040	6 ,  7  Moreover, the low ESR1 expression subtypes enriched IDH1 mutations in glioma, liver cancer, and prostate adenocarcinoma.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('prostate adenocarcinoma', 'Disease', (104, 127))	('IDH1', 'Gene', (60, 64))	('glioma', 'Disease', 'MESH:D005910', (78, 84))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (104, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('liver cancer', 'Disease', 'MESH:D006528', (86, 98))	('liver cancer', 'Phenotype', 'HP:0002896', (86, 98))	('ESR1', 'Gene', '2099', (26, 30))	('liver cancer', 'Disease', (86, 98))	('glioma', 'Disease', (78, 84))	('IDH1', 'Gene', '3417', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutations', 'Var', (65, 74))	('ESR1', 'Gene', (26, 30))
3976	32536040	ER methylation has previously been reported to be associated with the progression and prognosis of female tumors.	('ER', 'Gene', '2099', (0, 2))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumors', 'Disease', (106, 112))	('methylation', 'Var', (3, 14))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('associated', 'Reg', (50, 60))
3977	32536040	Promoter methylation of ESR1 in breast cancer was related to worse overall survival and associated with a lack of response to endocrine treatment.	('breast cancer', 'Disease', (32, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('ESR1', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Promoter methylation', 'Var', (0, 20))	('overall', 'MPA', (67, 74))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('ESR1', 'Gene', '2099', (24, 28))	('worse', 'NegReg', (61, 66))
3978	32536040	26 ,  33  Both primary tumors and paired ctDNA detected methylated ESR1 and the presence of ESR1 methylation correlated with better clinical outcome in ovarian cancer.	('tumors', 'Disease', (23, 29))	('ovarian cancer', 'Disease', (152, 166))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('ovarian cancer', 'Disease', 'MESH:D010051', (152, 166))	('methylated', 'Var', (56, 66))	('presence', 'Var', (80, 88))	('better', 'PosReg', (125, 131))	('ESR1', 'Gene', '2099', (92, 96))	('ESR1', 'Gene', '2099', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ovarian cancer', 'Phenotype', 'HP:0100615', (152, 166))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('ESR1', 'Gene', (92, 96))	('ESR1', 'Gene', (67, 71))	('methylation', 'Var', (97, 108))
3979	32536040	14  Methylation of the ESR1 promoter correlated with tumor grade, while unmethylated ESR1 predicted for chemoradiation resistance in cervical carcinoma.	('ESR1', 'Gene', (85, 89))	('Methylation', 'Var', (4, 15))	('cervical carcinoma', 'Disease', (133, 151))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('ESR1', 'Gene', '2099', (23, 27))	('correlated', 'Reg', (37, 47))	('unmethylated', 'Var', (72, 84))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('predicted', 'Reg', (90, 99))	('ESR1', 'Gene', '2099', (85, 89))	('cervical carcinoma', 'Disease', 'MESH:D002583', (133, 151))	('tumor', 'Disease', (53, 58))	('chemoradiation', 'MPA', (104, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('ESR1', 'Gene', (23, 27))
3980	32536040	21 ,  36  Our study showed the ESR1 methylation difference and its association with survival in BLCA, BRCA, and KIRC.	('methylation difference', 'Var', (36, 58))	('BRCA', 'Gene', (102, 106))	('ESR1', 'Gene', (31, 35))	('BLCA', 'Disease', (96, 100))	('association', 'Interaction', (67, 78))	('ESR1', 'Gene', '2099', (31, 35))	('BRCA', 'Gene', '672', (102, 106))
3981	32536040	Both ESR1 and ESR2 showed the correlation between promoter methylation and survival in LGG and STAD.	('STAD', 'Disease', (95, 99))	('survival', 'CPA', (75, 83))	('ESR1', 'Gene', '2099', (5, 9))	('promoter methylation', 'Var', (50, 70))	('ESR2', 'Gene', '2100', (14, 18))	('LGG', 'Disease', (87, 90))	('correlation', 'Reg', (30, 41))	('ESR1', 'Gene', (5, 9))	('ESR2', 'Gene', (14, 18))
3983	32536040	3  The phosphorylation of ERalpha further activates the hormone signal pathway and then unique coactivator complexes to specific genes.	('ERalpha', 'Gene', '2099', (26, 33))	('activates', 'PosReg', (42, 51))	('phosphorylation', 'Var', (7, 22))	('hormone signal pathway', 'Pathway', (56, 78))	('ERalpha', 'Gene', (26, 33))
3985	32536040	Shrivastav et al showed that the p-S118, p-S167, and p-S282 of the ERalpha were positively correlated with breast cancer.	('ERalpha', 'Gene', '2099', (67, 74))	('p-S118', 'Var', (33, 39))	('correlated', 'Reg', (91, 101))	('p-S167', 'Var', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('p-S282', 'Var', (53, 59))	('ERalpha', 'Gene', (67, 74))
3995	32536040	As the prognostic significance of ESR1 in an eight genes assessment model in liver cancer, and ER-beta expression in colorectal cancer and ESR2 polymorphisms in advanced gastric cancer.	('liver cancer', 'Disease', 'MESH:D006528', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (170, 184))	('liver cancer', 'Phenotype', 'HP:0002896', (77, 89))	('liver cancer', 'Disease', (77, 89))	('polymorphisms', 'Var', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ESR1', 'Gene', '2099', (34, 38))	('gastric cancer', 'Disease', (170, 184))	('colorectal cancer', 'Disease', 'MESH:D015179', (117, 134))	('ESR1', 'Gene', (34, 38))	('ER-beta', 'Gene', (95, 102))	('colorectal cancer', 'Disease', (117, 134))	('ESR2', 'Gene', '2100', (139, 143))	('gastric cancer', 'Disease', 'MESH:D013274', (170, 184))	('ER-beta', 'Gene', '2099', (95, 102))	('ESR2', 'Gene', (139, 143))
4000	32536040	32  Estrogen receptor knockout enhanced immune cell infiltration and liver tumorigenesis in the mouse tumor model.	('enhanced', 'PosReg', (31, 39))	('mouse', 'Species', '10090', (96, 101))	('immune cell infiltration', 'CPA', (40, 64))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('knockout', 'Var', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('liver tumorigenesis', 'Disease', (69, 88))	('liver tumorigenesis', 'Disease', 'MESH:D063646', (69, 88))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
4001	32536040	41  While our study found the correlation between estrogen receptors and immune cell differentiation, immune cell signaling, and inflammation pathways in multiple tumors, target estrogen receptor in combination with immunotherapy may potentially benefit patients.	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('target', 'Var', (171, 177))	('inflammation', 'Disease', (129, 141))	('inflammation', 'Disease', 'MESH:D007249', (129, 141))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('benefit', 'PosReg', (246, 253))	('patients', 'Species', '9606', (254, 262))
4002	32536040	Overall, our findings revealed DNA methylation and mRNA expression of ESR1 and ESR2, proteins expression of ESR1 in different tumor tissues, and ESR1 and ESR2 participated in some critical cancer development and progression as they associated with tumor subtypes, pathological features, and patients' survival.	('ESR1', 'Gene', '2099', (108, 112))	('ESR1', 'Gene', '2099', (70, 74))	('ESR2', 'Gene', '2100', (79, 83))	('ESR1', 'Gene', (108, 112))	('ESR1', 'Gene', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('mRNA expression', 'MPA', (51, 66))	('ESR2', 'Gene', (79, 83))	('tumor', 'Disease', (248, 253))	('participated', 'Reg', (159, 171))	('patients', 'Species', '9606', (291, 299))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('ESR1', 'Gene', '2099', (145, 149))	('methylation', 'Var', (35, 46))	('ESR1', 'Gene', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('cancer', 'Disease', (189, 195))	('tumor', 'Disease', (126, 131))	('ESR2', 'Gene', '2100', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('ESR2', 'Gene', (154, 158))	('associated', 'Reg', (232, 242))
4003	32536040	This pan-cancer analysis work showed that the expression and methylation of ESR genes are significantly associated with overall survival or progression-free survival of some tumor types, which may suggest that ESR genes are potential prognosis markers of these tumors.	('tumor', 'Disease', (174, 179))	('progression-free survival', 'CPA', (140, 165))	('expression', 'MPA', (46, 56))	('cancer', 'Disease', (9, 15))	('methylation', 'Var', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('tumors', 'Disease', (261, 267))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('associated', 'Reg', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('overall survival', 'CPA', (120, 136))	('ESR genes', 'Gene', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (261, 266))
4036	16479083	To treat the pulmonary thromboemboli, anticoagulation therapy using low-molecular-weight-heparin (LMWH) in therapeutic dose of 10 IU/kg every 12 hr was given subcutaneously.	('low-molecular-weight-heparin', 'Var', (68, 96))	('heparin', 'Chemical', 'MESH:D006493', (89, 96))	('pulmonary thromboemboli', 'Disease', 'MESH:D008171', (13, 36))	('pulmonary thromboemboli', 'Disease', (13, 36))	('LMWH', 'Chemical', 'MESH:D006495', (98, 102))
4072	16479083	A recent experimental study demonstrated the advantage of LMWH over unfractionated heparin for cancer-related thromboembolism.	('LMWH', 'Var', (58, 62))	('thromboembolism', 'Disease', 'MESH:D013923', (110, 125))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('LMWH', 'Chemical', 'MESH:D006495', (58, 62))	('thromboembolism', 'Phenotype', 'HP:0001907', (110, 125))	('cancer', 'Disease', (95, 101))	('thromboembolism', 'Disease', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('heparin', 'Chemical', 'MESH:D006493', (83, 90))
4084	32845921	Combination Kaplan-Meier models showed that HCC stage III or IV and both the content of alpha-2-HS-glycoprotein and apolipoprotein CIII <0.2% exhibited the poorest post-surgical recurrence-free and overall survivals.	('HCC', 'Gene', (44, 47))	('alpha-2-HS-glycoprotein', 'Gene', (88, 111))	('post-surgical recurrence-free', 'CPA', (164, 193))	('alpha-2-HS-glycoprotein', 'Gene', '197', (88, 111))	('HCC', 'Gene', '619501', (44, 47))	('apolipoprotein CIII', 'Gene', '345', (116, 135))	('overall survivals', 'CPA', (198, 215))	('HCC', 'Phenotype', 'HP:0001402', (44, 47))	('poorest', 'NegReg', (156, 163))	('apolipoprotein CIII', 'Gene', (116, 135))	('<0.2%', 'Var', (136, 141))
4170	32845921	Although detecting enhanced levels of these biomarkers resulting from the growth of a solitary tumor from stage I to II with affordable liver functions is plausible, when transitioning to stage III, liver functions might be severely impaired because of expansions of multiple large tumors, thereby contributing to a detrimental effect of protein synthesis.	('levels', 'MPA', (28, 34))	('protein synthesis', 'MPA', (338, 355))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('enhanced', 'PosReg', (19, 27))	('tumors', 'Disease', (282, 288))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('tumor', 'Disease', (282, 287))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('liver functions', 'MPA', (199, 214))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('impaired', 'NegReg', (233, 241))	('tumor', 'Disease', (95, 100))	('expansions', 'Var', (253, 263))
4215	32169416	Fa2p deletion is involved with delay at the G2-M transition in Chlamydomonas.	('Fa2p', 'Gene', (0, 4))	('deletion', 'Var', (5, 13))	('Fa2p', 'Gene', '2187', (0, 4))	('delay', 'NegReg', (31, 36))	('G2-M', 'MPA', (44, 48))
4235	32169416	The zinc finger transcription factors Gli1, Gli2 and Gli3 binds to the inhibitor SuFu during the inactivated state, facilitating their proteasomal degradation and the generation of the Gli3 repressor through partial proteolysis of Gli3.	('partial', 'Var', (208, 215))	('Gli1', 'Gene', '2735', (38, 42))	('Gli3', 'Gene', '2737', (231, 235))	('Gli3', 'Gene', (185, 189))	('Gli3', 'Gene', '2737', (53, 57))	('proteasomal degradation', 'MPA', (135, 158))	('Gli3', 'Gene', (231, 235))	('facilitating', 'PosReg', (116, 128))	('SuFu', 'Gene', '51684', (81, 85))	('SuFu', 'Gene', (81, 85))	('Gli3', 'Gene', '2737', (185, 189))	('Gli3', 'Gene', (53, 57))	('Gli1', 'Gene', (38, 42))
4247	32169416	It has been stated that the progression of tumors associated with defects in cilia are linked to a constitutive activation of the Wnt/beta-catenin pathway.	('defects', 'Var', (66, 73))	('beta-catenin', 'Gene', '1499', (134, 146))	('activation', 'PosReg', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('cilia', 'Protein', (77, 82))	('beta-catenin', 'Gene', (134, 146))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
4272	32169416	p53, BRCA1 and PARP1 are linked to centrosome physiology since p53 and PARP1 deficiencies, and BRCA1 mutations leads to centrosome amplification that may also lead to aberrant number of primary cilia.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('BRCA1', 'Gene', (95, 100))	('deficiencies', 'NegReg', (77, 89))	('mutations', 'Var', (101, 110))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('leads to', 'Reg', (111, 119))	('PARP1', 'Gene', '142', (15, 20))	('PARP1', 'Gene', (71, 76))	('PARP1', 'Gene', (15, 20))	('lead to', 'Reg', (159, 166))	('BRCA1', 'Gene', '672', (5, 10))	('PARP1', 'Gene', '142', (71, 76))	('centrosome amplification', 'MPA', (120, 144))	('BRCA1', 'Gene', '672', (95, 100))	('BRCA1', 'Gene', (5, 10))
4276	32169416	It is caused by mutations in PKD1 involved in encoding the protein PC-1, a likely membrane mechano-sensor ciliary receptor, and PKD2, involved in encoding the ciliary protein PC-2, a non-selective cationic channel permeable to calcium.	('PC-1', 'Gene', '5310', (67, 71))	('PKD1', 'Gene', '5310', (29, 33))	('PC-2', 'Gene', (175, 179))	('mutations', 'Var', (16, 25))	('PC-2', 'Gene', '5311', (175, 179))	('caused by', 'Reg', (6, 15))	('PKD1', 'Gene', (29, 33))	('PC-1', 'Gene', (67, 71))	('calcium', 'Chemical', 'MESH:D002118', (227, 234))
4277	32169416	The recessive form of this ciliopathy is caused by the mutation of PKHD1 that encodes the integral transmembrane protein fibrocystin that is found on primary cilia.	('PKHD1', 'Gene', '5314', (67, 72))	('fibrocystin', 'Gene', '5314', (121, 132))	('fibrocystin', 'Gene', (121, 132))	('ciliopathy', 'Disease', (27, 37))	('mutation', 'Var', (55, 63))	('caused by', 'Reg', (41, 50))	('PKHD1', 'Gene', (67, 72))
4278	32169416	Half of the neonates carrying this mutation die due to pulmonary hypoplasia.	('pulmonary hypoplasia', 'Disease', 'MESH:C562992', (55, 75))	('pulmonary hypoplasia', 'Disease', (55, 75))	('mutation', 'Var', (35, 43))	('pulmonary hypoplasia', 'Phenotype', 'HP:0002089', (55, 75))
4280	32169416	Polycystic liver disease (PLD) is a manifestation of PKD in the liver that can also exist alone as a result of mutations of the genes PRKCSH, SEC63, LRP5, ALG8, SEC61B, GANAB and PKHD1, PKD1 and PKD2 which products are ciliary proteins.	('PKD', 'Disease', 'MESH:C537180', (186, 189))	('PKHD1', 'Gene', (179, 184))	('Polycystic liver disease', 'Phenotype', 'HP:0006557', (0, 24))	('GANAB', 'Gene', '23193', (169, 174))	('ALG8', 'Gene', '79053', (155, 159))	('mutations', 'Var', (111, 120))	('PKD1', 'Gene', '5310', (186, 190))	('LRP5', 'Gene', (149, 153))	('SEC61B', 'Gene', '10952', (161, 167))	('liver disease', 'Phenotype', 'HP:0001392', (11, 24))	('PRKCSH', 'Gene', '5589', (134, 140))	('PLD', 'Disease', 'None', (26, 29))	('Polycystic liver disease', 'Disease', 'MESH:C536330', (0, 24))	('PKD', 'Disease', 'MESH:C537180', (53, 56))	('SEC63', 'Gene', (142, 147))	('PKD', 'Disease', (53, 56))	('PRKCSH', 'Gene', (134, 140))	('LRP5', 'Gene', '4041', (149, 153))	('PLD', 'Disease', (26, 29))	('SEC63', 'Gene', '11231', (142, 147))	('ALG8', 'Gene', (155, 159))	('PKD', 'Disease', (195, 198))	('PKD', 'Disease', 'MESH:C537180', (195, 198))	('GANAB', 'Gene', (169, 174))	('Polycystic liver disease', 'Disease', (0, 24))	('PKD1', 'Gene', (186, 190))	('PKD', 'Disease', (186, 189))	('SEC61B', 'Gene', (161, 167))	('PKHD1', 'Gene', '5314', (179, 184))
4297	32169416	It is an inherited autosomal recessive disorder caused by mutations in more than 20 different genes which includes, BBS1, BBS2, ARL6 (BBS3), BBS4, BBS5, MKKS (BBS6), BBS7, TTC8 (BBS8), BBS9, BBS10, TRIM32 (BBS11), BBS12, MKS1 (BBS13), CEP290 (BBS14), WDPCP (BBS15), SDCCAG8 (BBS16), LZTFL1 (BBS17), BBIP1 (BBS18), IFT27 (BBS19), IFT72 (BBS20), and C8ORF37 (BBS21).	('inherited autosomal recessive disorder', 'Disease', (9, 47))	('BBS16', 'Gene', (275, 280))	('BBS1', 'Gene', '582', (258, 262))	('BBS3', 'Gene', '84100', (134, 138))	('BBS1', 'Gene', (258, 262))	('BBS4', 'Gene', (141, 145))	('BBS20', 'Gene', '80173', (336, 341))	('BBS2', 'Gene', '583', (122, 126))	('MKS1', 'Gene', '54903', (221, 225))	('BBS2', 'Gene', '583', (357, 361))	('ARL6', 'Gene', (128, 132))	('BBS1', 'Gene', (191, 195))	('BBS5', 'Gene', (147, 151))	('BBS5', 'Gene', '129880', (147, 151))	('BBS1', 'Gene', '582', (206, 210))	('BBS1', 'Gene', (206, 210))	('BBS14', 'Gene', '80184', (243, 248))	('MKS1', 'Gene', (221, 225))	('C8ORF37', 'Gene', (348, 355))	('SDCCAG8', 'Gene', (266, 273))	('BBS4', 'Gene', '585', (141, 145))	('IFT27', 'Gene', (314, 319))	('LZTFL1', 'Gene', '54585', (283, 289))	('ARL6', 'Gene', '84100', (128, 132))	('BBS19', 'Gene', (321, 326))	('BBS7', 'Gene', '55212', (166, 170))	('BBS1', 'Gene', (116, 120))	('BBS14', 'Gene', (243, 248))	('BBS1', 'Gene', '582', (306, 310))	('BBS1', 'Gene', (306, 310))	('WDPCP', 'Gene', (251, 256))	('BBS8', 'Gene', '123016', (178, 182))	('BBS9', 'Gene', '27241', (185, 189))	('LZTFL1', 'Gene', (283, 289))	('BBS18', 'Gene', (306, 311))	('TRIM32', 'Gene', (198, 204))	('BBS1', 'Gene', '582', (191, 195))	('BBS6', 'Gene', (159, 163))	('BBS2', 'Gene', (122, 126))	('CEP290', 'Gene', '80184', (235, 241))	('BBS21', 'Gene', '157657', (357, 362))	('MKKS', 'Gene', '8195', (153, 157))	('BBS13', 'Gene', '54903', (227, 232))	('BBS2', 'Gene', (357, 361))	('BBS1', 'Gene', (275, 279))	('CEP290', 'Gene', (235, 241))	('BBS15', 'Gene', (258, 263))	('BBS6', 'Gene', '8195', (159, 163))	('TRIM32', 'Gene', '22954', (198, 204))	('BBS1', 'Gene', (243, 247))	('BBS1', 'Gene', '582', (116, 120))	('BBS17', 'Gene', (291, 296))	('BBS13', 'Gene', (227, 232))	('BBS1', 'Gene', '582', (227, 231))	('BBS1', 'Gene', (227, 231))	('WDPCP', 'Gene', '51057', (251, 256))	('BBS2', 'Gene', '583', (336, 340))	('caused by', 'Reg', (48, 57))	('BBS10', 'Gene', '79738', (191, 196))	('BBIP1', 'Gene', '92482', (299, 304))	('BBS19', 'Gene', '11020', (321, 326))	('BBS20', 'Gene', (336, 341))	('BBS21', 'Gene', (357, 362))	('MKKS', 'Gene', (153, 157))	('BBS11', 'Gene', (206, 211))	('mutations', 'Var', (58, 67))	('BBS12', 'Gene', (214, 219))	('BBS1', 'Gene', '582', (275, 279))	('inherited autosomal recessive disorder', 'Disease', 'MESH:D030342', (9, 47))	('TTC8', 'Gene', '123016', (172, 176))	('BBS1', 'Gene', '582', (243, 247))	('BBS1', 'Gene', '582', (291, 295))	('C8ORF37', 'Gene', '157657', (348, 355))	('BBS1', 'Gene', (291, 295))	('BBS17', 'Gene', '54585', (291, 296))	('BBS15', 'Gene', '51057', (258, 263))	('BBS7', 'Gene', (166, 170))	('BBS11', 'Gene', '22954', (206, 211))	('TTC8', 'Gene', (172, 176))	('BBS10', 'Gene', (191, 196))	('BBS1', 'Gene', '582', (321, 325))	('BBS1', 'Gene', (321, 325))	('BBS18', 'Gene', '92482', (306, 311))	('IFT27', 'Gene', '11020', (314, 319))	('BBS9', 'Gene', (185, 189))	('BBIP1', 'Gene', (299, 304))	('BBS2', 'Gene', (336, 340))	('BBS8', 'Gene', (178, 182))	('BBS16', 'Gene', '10806', (275, 280))	('BBS12', 'Gene', '166379', (214, 219))	('BBS1', 'Gene', '582', (214, 218))	('BBS1', 'Gene', (214, 218))	('SDCCAG8', 'Gene', '10806', (266, 273))	('BBS3', 'Gene', (134, 138))
4306	32169416	It was reported that the ARL3 mutation is implicated in Joubert Syndrome by ciliary disruption.	('mutation', 'Var', (30, 38))	('ARL3', 'Gene', '403', (25, 29))	('ciliary disruption', 'Disease', (76, 94))	('Joubert Syndrome', 'Disease', 'MESH:C536293', (56, 72))	('Joubert Syndrome', 'Disease', (56, 72))	('implicated', 'Reg', (42, 52))	('ARL3', 'Gene', (25, 29))
4309	32169416	Mutations of this gene are also responsible for Joubert Syndrome.	('Joubert Syndrome', 'Disease', 'MESH:C536293', (48, 64))	('Mutations', 'Var', (0, 9))	('Joubert Syndrome', 'Disease', (48, 64))	('responsible', 'Reg', (32, 43))
4314	32169416	A study also reported that mutation in B9D1 and B9D2 genes are responsible for Meckel syndrome.	('Meckel syndrome', 'Disease', 'MESH:C536133', (79, 94))	('B9D1', 'Gene', (39, 43))	('B9D2', 'Gene', '80776', (48, 52))	('mutation', 'Var', (27, 35))	('responsible', 'Reg', (63, 74))	('B9D1', 'Gene', '27077', (39, 43))	('Meckel syndrome', 'Disease', (79, 94))	('B9D2', 'Gene', (48, 52))
4315	32169416	Mutations in TZ proteins like MKS6 results in cilia dysfunction  Interestingly, there are points of contact between ciliopathies and tumor cells, such as the loss of response to extracellular signals, increased cell proliferation, cell polarity alteration, and abnormal extracellular matrix control leading to fibrosis.	('results in', 'Reg', (35, 45))	('leading to', 'Reg', (299, 309))	('increased', 'PosReg', (201, 210))	('MKS6', 'Gene', '57545', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cell polarity alteration', 'CPA', (231, 255))	('extracellular matrix control', 'CPA', (270, 298))	('MKS6', 'Gene', (30, 34))	('Mutations', 'Var', (0, 9))	('cilia dysfunction', 'Disease', 'MESH:C536287', (46, 63))	('response to extracellular signals', 'MPA', (166, 199))	('tumor', 'Disease', (133, 138))	('cilia dysfunction', 'Disease', (46, 63))	('fibrosis', 'Disease', 'MESH:D005355', (310, 318))	('fibrosis', 'Disease', (310, 318))	('loss', 'NegReg', (158, 162))	('cell proliferation', 'CPA', (211, 229))
4322	32169416	The knockout of ciliary proteins such as Kif3a, blocked tumor formation on a medulloblastoma mouse model that has only one Ptch allele.	('medulloblastoma', 'Phenotype', 'HP:0002885', (77, 92))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Kif3a', 'Gene', (41, 46))	('mouse', 'Species', '10090', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('Ptch', 'Gene', '19206', (123, 127))	('tumor', 'Disease', (56, 61))	('medulloblastoma', 'Disease', (77, 92))	('knockout', 'Var', (4, 12))	('Ptch', 'Gene', (123, 127))	('medulloblastoma', 'Disease', 'MESH:D008527', (77, 92))	('blocked', 'NegReg', (48, 55))
4338	32169416	Mutations of the tumor suppressor gene FLCN, that its protein has shown to be localized in the primary cilia and basal body, are linked with Birt-Hogg-Dube syndrome that manifest with renal cysts and predisposes to an increased risk for kidney tumor development.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('renal cysts', 'Phenotype', 'HP:0000107', (184, 195))	('Birt-Hogg-Dube syndrome', 'Disease', 'MESH:D058249', (141, 164))	('tumor', 'Disease', (17, 22))	('FLCN', 'Gene', '201163', (39, 43))	('kidney tumor', 'Disease', (237, 249))	('tumor', 'Disease', (244, 249))	('renal cysts', 'Disease', 'MESH:D007674', (184, 195))	('Mutations', 'Var', (0, 9))	('renal cysts', 'Disease', (184, 195))	('FLCN', 'Gene', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('kidney tumor', 'Disease', 'MESH:D007680', (237, 249))	('linked', 'Reg', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('Birt-Hogg-Dube syndrome', 'Disease', (141, 164))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('kidney tumor', 'Phenotype', 'HP:0009726', (237, 249))
4339	32169416	Tuberous sclerosis complex is caused by the mutation of the tumor suppressor genes TSC1 or TSC2, and it can lead to renal manifestations such as renal cell carcinoma and renal cystic disease.	('TSC2', 'Gene', (91, 95))	('Tuberous sclerosis', 'Disease', 'MESH:D014402', (0, 18))	('Tuberous sclerosis', 'Disease', (0, 18))	('mutation', 'Var', (44, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (145, 165))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('caused by', 'Reg', (30, 39))	('renal cystic disease', 'Phenotype', 'HP:0000107', (170, 190))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('TSC1', 'Gene', '7248', (83, 87))	('lead to', 'Reg', (108, 115))	('TSC2', 'Gene', '7249', (91, 95))	('tumor', 'Disease', (60, 65))	('TSC1', 'Gene', (83, 87))	('renal cell carcinoma and renal cystic disease', 'Disease', 'MESH:C538614', (145, 190))
4343	32169416	In this particular cancer it has been demonstrated that HDAC2 is responsible for promotion of ciliary loss, and the inhibition of HDAC2 decreases the expression of Aurora A that is needed for ciliary disassembly, and thus promotes ciliary restoration.	('promotes', 'PosReg', (222, 230))	('expression', 'MPA', (150, 160))	('Aurora A', 'Gene', '6790', (164, 172))	('inhibition', 'Var', (116, 126))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('HDAC2', 'Gene', '3066', (130, 135))	('ciliary restoration', 'CPA', (231, 250))	('HDAC2', 'Gene', (130, 135))	('cancer', 'Disease', (19, 25))	('ciliary loss', 'CPA', (94, 106))	('HDAC2', 'Gene', (56, 61))	('Aurora A', 'Gene', (164, 172))	('HDAC2', 'Gene', '3066', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('decreases', 'NegReg', (136, 145))
4344	32169416	On the other hand a study shows that the presence of primary cilia correlates with poor prognosis and lymph node metastasis in pancreatic ductal adenocarcinoma.	('pancreatic ductal adenocarcinoma', 'Disease', (127, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('lymph node metastasis', 'CPA', (102, 123))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (127, 159))	('primary', 'Protein', (53, 60))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (127, 159))	('presence', 'Var', (41, 49))
4345	32169416	Mice that lack primary cilia on the thyroids due to a thyroid follicular epithelial cell-specific deletion of IFT88 showed follicular cells with malignant phenotype and developed papillary solid proliferative thyroid follicles with malignant features.	('IFT88', 'Gene', (110, 115))	('papillary solid proliferative thyroid follicles', 'CPA', (179, 226))	('deletion', 'Var', (98, 106))	('developed', 'PosReg', (169, 178))	('Mice', 'Species', '10090', (0, 4))	('IFT88', 'Gene', '8100', (110, 115))
4348	32169416	The deciliation of normal cholangiocyte cells using drugs such as chloral hydrate or using gene-silencing techniques on ciliary proteins such as IFT88 induces proliferation, anchorage-independent growth, and invasion.	('invasion', 'CPA', (208, 216))	('chloral hydrate', 'Chemical', 'MESH:D002697', (66, 81))	('IFT88', 'Gene', (145, 150))	('induces', 'PosReg', (151, 158))	('anchorage-independent growth', 'CPA', (174, 202))	('proliferation', 'CPA', (159, 172))	('IFT88', 'Gene', '8100', (145, 150))	('gene-silencing', 'Var', (91, 105))
4354	32169416	HDAC6 inhibition with pharmacological or genetic approaches induces partial cilia restoration and reverses the malignant phenotype in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (134, 152))	('HDAC6', 'Gene', (0, 5))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (134, 152))	('inhibition', 'Var', (6, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('partial', 'NegReg', (68, 75))	('cholangiocarcinoma', 'Disease', (134, 152))
4355	32169416	HDAC6 is overexpressed in cholangiocarcinoma, and its targeting restores ciliary expression, decrease proliferation and anchorage independent growth, and down regulates Hedgehog and MAPK pathways.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (26, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('ciliary expression', 'MPA', (73, 91))	('HDAC6', 'Gene', (0, 5))	('anchorage independent growth', 'CPA', (120, 148))	('restores', 'PosReg', (64, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (26, 44))	('down regulates', 'NegReg', (154, 168))	('decrease', 'NegReg', (93, 101))	('proliferation', 'CPA', (102, 115))	('cholangiocarcinoma', 'Disease', (26, 44))	('targeting', 'Var', (54, 63))
4357	32169416	In vivo experiments in a model of cholangiocarcinoma showed that the inhibition of HDAC6 reduces tumor growth and induces partial restoration of cilia (Figure 3).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('inhibition', 'Var', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (34, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (34, 52))	('tumor', 'Disease', (97, 102))	('HDAC6', 'Gene', (83, 88))	('cilia', 'CPA', (145, 150))	('reduces', 'NegReg', (89, 96))	('cholangiocarcinoma', 'Disease', (34, 52))
4358	32169416	Additionally, HDAC6 inhibition also decreases proliferation and invasion capacity of chondrosarcoma tumor cells and restores the expression of primary cilia.	('invasion capacity', 'CPA', (64, 81))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('primary cilia', 'MPA', (143, 156))	('expression', 'MPA', (129, 139))	('inhibition', 'Var', (20, 30))	('restores', 'PosReg', (116, 124))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (85, 99))	('HDAC6', 'Gene', (14, 19))	('proliferation', 'CPA', (46, 59))	('chondrosarcoma tumor', 'Disease', 'MESH:D002813', (85, 105))	('chondrosarcoma tumor', 'Disease', (85, 105))	('decreases', 'NegReg', (36, 45))
4363	32169416	It is reported that the silencing of HDAC2 restores primary cilia in pancreatic ductal adenocarcinoma cells  Nevertheless, several non-selective HDAC inhibitors have already been approved by the US Food and Drug Administration (FDA) for cancer treatment including vorinostat, romidepsin, and panobinostat, but they show toxicity to normal tissues during cancer therapy.	('vorinostat', 'Chemical', 'MESH:D000077337', (264, 274))	('romidepsin', 'Chemical', 'MESH:C087123', (276, 286))	('panobinostat', 'Chemical', 'MESH:D000077767', (292, 304))	('HDAC', 'Gene', '9734', (145, 149))	('toxicity', 'Disease', (320, 328))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (69, 101))	('cancer', 'Disease', 'MESH:D009369', (354, 360))	('HDAC2', 'Gene', (37, 42))	('primary cilia', 'CPA', (52, 65))	('HDAC2', 'Gene', '3066', (37, 42))	('restores', 'PosReg', (43, 51))	('HDAC', 'Gene', (145, 149))	('pancreatic ductal adenocarcinoma', 'Disease', (69, 101))	('cancer', 'Disease', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('HDAC', 'Gene', '9734', (37, 41))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (69, 101))	('cancer', 'Disease', (354, 360))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('HDAC', 'Gene', (37, 41))	('toxicity', 'Disease', 'MESH:D064420', (320, 328))	('silencing', 'Var', (24, 33))
4364	32169416	In contrast with specific HDAC6 targeting, the use of pan-HDAC inhibitors have profound non-desirable effects due to the global epigenetic modification of gene expression.	('HDAC', 'Gene', (58, 62))	('HDAC', 'Gene', '9734', (58, 62))	('HDAC', 'Gene', (26, 30))	('epigenetic modification', 'Var', (128, 151))	('HDAC', 'Gene', '9734', (26, 30))
4365	32169416	Tubacin, tubastatin A, CAY10603 and ACY1215 are among the HDAC6 selective inhibitors that have a protective effect on primary cilia.	('HDAC6', 'Gene', (58, 63))	('ACY1215', 'Chemical', 'MESH:C572255', (36, 43))	('primary cilia', 'CPA', (118, 131))	('CAY10603', 'Var', (23, 31))	('ACY1215', 'Var', (36, 43))	('tubastatin A', 'Chemical', 'MESH:C553587', (9, 21))	('CAY10603', 'Chemical', '-', (23, 31))	('Tubacin', 'Chemical', 'MESH:C474316', (0, 7))
4367	32169416	The therapeutic use of Tubastatin-A, Tubacin, or ACY1215, specific HDAC6 inhibitors, reduced cell proliferation and cyst growth in vitro, and ACY-1215 reduced liver cysts and fibrosis in an animal model of PKD in vivo.	('ACY-1215', 'Chemical', 'MESH:C572255', (142, 150))	('reduced', 'NegReg', (151, 158))	('fibrosis', 'Disease', 'MESH:D005355', (175, 183))	('fibrosis', 'Disease', (175, 183))	('ACY-1215', 'Var', (142, 150))	('PKD', 'Disease', (206, 209))	('liver cysts', 'Disease', 'MESH:D017093', (159, 170))	('liver cysts', 'Phenotype', 'HP:0001407', (159, 170))	('liver cysts', 'Disease', (159, 170))	('PKD', 'Disease', 'MESH:C537180', (206, 209))	('cell proliferation', 'CPA', (93, 111))	('Tubacin', 'Chemical', 'MESH:C474316', (37, 44))	('Tubastatin-A', 'Chemical', 'MESH:C553587', (23, 35))	('reduced', 'NegReg', (85, 92))	('cyst growth', 'CPA', (116, 127))	('ACY1215', 'Chemical', 'MESH:C572255', (49, 56))	('ACY1215', 'Var', (49, 56))
4369	32169416	Additionally, on a PKD murine model, the use of the drug fenoldopam, that is a known ciliary DR5 dopaminergic agonist, increased ciliary length and serum nitric oxide (NO) levels, reducing blood pressure.	('PKD', 'Disease', 'MESH:C537180', (19, 22))	('PKD', 'Disease', (19, 22))	('DR5', 'Gene', (93, 96))	('DR5', 'Gene', '21933', (93, 96))	('reducing blood pressure', 'Phenotype', 'HP:0002615', (180, 203))	('murine', 'Species', '10090', (23, 29))	('reducing', 'NegReg', (180, 188))	('fenoldopam', 'Var', (57, 67))	('blood pressure', 'MPA', (189, 203))	('fenoldopam', 'Chemical', 'MESH:D018818', (57, 67))	('ciliary length', 'CPA', (129, 143))	('nitric oxide', 'Chemical', 'MESH:D009569', (154, 166))	('increased', 'PosReg', (119, 128))
4446	30653586	Similarly, levels of circulating miR-122, miR-192, miR-29b and miR-155 were unaltered between patients with different T-status (T1-4, S1E-S1H Fig), nodal negative and positive (N0 vs. N1, S1I-S1L Fig) as well as non-metastasized and metastasized disease (M0 vs. M1, S1M-S1P Fig).	('patients', 'Species', '9606', (94, 102))	('miR-155', 'Gene', '406947', (63, 70))	('miR-29b', 'Gene', '407024', (51, 58))	('N0 vs. N1', 'Var', (177, 186))	('miR-192', 'Gene', (42, 49))	('non-metastasized', 'Disease', (212, 228))	('miR-192', 'Gene', '406967', (42, 49))	('miR-122', 'Gene', '406906', (33, 40))	('miR-122', 'Gene', (33, 40))	('miR-29b', 'Gene', (51, 58))	('miR-155', 'Gene', (63, 70))
4486	30653586	Silencing of miR-122 has been associated with steatohepatitis, fibrosis and carcinogenesis.	('associated', 'Reg', (30, 40))	('hepatitis', 'Phenotype', 'HP:0012115', (52, 61))	('fibrosis', 'Disease', 'MESH:D005355', (63, 71))	('fibrosis', 'Disease', (63, 71))	('steatohepatitis', 'Disease', (46, 61))	('carcinogenesis', 'Disease', 'MESH:D063646', (76, 90))	('steatohepatitis', 'Disease', 'MESH:D005234', (46, 61))	('miR-122', 'Gene', '406906', (13, 20))	('miR-122', 'Gene', (13, 20))	('Silencing', 'Var', (0, 9))	('carcinogenesis', 'Disease', (76, 90))
4511	30653586	Furthermore, patients with high levels of miR-192 post-operatively showed a significantly shorter median survival compared to patients with low levels.	('high levels', 'Var', (27, 38))	('median survival', 'MPA', (98, 113))	('shorter', 'NegReg', (90, 97))	('patients', 'Species', '9606', (13, 21))	('miR-192', 'Gene', (42, 49))	('miR-192', 'Gene', '406967', (42, 49))	('patients', 'Species', '9606', (126, 134))
4531	30038723	In conclusion, high circulating IL-6 was associated with short OS in most studies in GI cancer patients.	('high', 'Var', (15, 19))	('GI cancer', 'Disease', (85, 94))	('associated', 'Reg', (41, 51))	('OS', 'Chemical', '-', (63, 65))	('patients', 'Species', '9606', (95, 103))	('high circulating IL-6', 'Phenotype', 'HP:0030783', (15, 36))	('GI cancer', 'Disease', 'MESH:D009369', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('GI cancer', 'Phenotype', 'HP:0007378', (85, 94))	('GI', 'Phenotype', 'HP:0007378', (85, 87))	('short OS', 'Disease', (57, 65))
4532	30038723	Whether inhibition of IL-6 would decrease GI cancer symptoms and increase quality of life is unknown.	('increase', 'PosReg', (65, 73))	('GI cancer', 'Phenotype', 'HP:0007378', (42, 51))	('decrease', 'NegReg', (33, 41))	('GI cancer symptoms', 'Disease', 'MESH:D051271', (42, 60))	('GI', 'Phenotype', 'HP:0007378', (42, 44))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('IL-6', 'Gene', (22, 26))	('quality', 'MPA', (74, 81))	('GI cancer symptoms', 'Disease', (42, 60))	('inhibition', 'Var', (8, 18))
4570	30038723	Various factors increase such as growth factors in the microenvironment (IL-1beta, NF-kappaB, PGE2, low O2) and/or their active receptors, and the lack of STAT3 inhibitors increase the secretion of IL-6.	('NF-kappaB', 'Protein', (83, 92))	('increase', 'PosReg', (172, 180))	('men', 'Species', '9606', (67, 70))	('O2', 'Chemical', '-', (104, 106))	('increase', 'PosReg', (16, 24))	('secretion of IL-6', 'MPA', (185, 202))	('lack', 'Var', (147, 151))	('IL-1beta', 'Gene', '3553', (73, 81))	('PGE2', 'Chemical', 'MESH:D015232', (94, 98))	('PGE2', 'Gene', (94, 98))	('IL-1beta', 'Gene', (73, 81))
4578	30038723	A high IL-6 level is generally associated with a poorer outcome, particularly regarding renal cell, ovarian and prostate cancer, and correlated to more severe symptoms in regards to cancer as well as the development of anti-cancer drug resistance.	('renal cell', 'Disease', (88, 98))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('high IL-6 level', 'Phenotype', 'HP:0030783', (2, 17))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('high', 'Var', (2, 6))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('ovarian and prostate cancer', 'Disease', 'MESH:D010051', (100, 127))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('men', 'Species', '9606', (211, 214))	('drug resistance', 'Phenotype', 'HP:0020174', (231, 246))	('cancer', 'Disease', (121, 127))	('IL-6', 'Gene', (7, 11))	('cancer', 'Disease', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (224, 230))
4584	30038723	In a study by Chung et al., the treatment of gastric cancer cells with Helicobacter pylori was shown to regulate miRNA, particularly enhancing the expression of miR-195 and miR-488, which plays an important role in controlling IL-6.	('miRNA', 'MPA', (113, 118))	('gastric cancer', 'Phenotype', 'HP:0012126', (45, 59))	('expression', 'MPA', (147, 157))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('miR-488', 'Gene', (173, 180))	('men', 'Species', '9606', (37, 40))	('Helicobacter pylori', 'Species', '210', (71, 90))	('gastric cancer', 'Disease', (45, 59))	('regulate', 'Reg', (104, 112))	('gastric cancer', 'Disease', 'MESH:D013274', (45, 59))	('miR-195', 'Var', (161, 168))	('enhancing', 'PosReg', (133, 142))
4585	30038723	showed that CDX2 is suppressed by the activation of the IL-6/STAT3 signal pathway via miR181b in vitro.	('miR181b', 'Var', (86, 93))	('CDX2', 'Gene', (12, 16))	('suppressed', 'NegReg', (20, 30))	('CDX2', 'Gene', '1045', (12, 16))	('activation', 'PosReg', (38, 48))	('IL-6/STAT3 signal pathway', 'Pathway', (56, 81))
4605	30038723	In a murine study that combined anti-IL-6 and anti-programmed death-1-ligand in treating pancreatic cancer, a decrease in tumor weight was observed compared to the control group and mice treated with either drug alone, and the OS improved by 35% compared to the control group.	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('anti-programmed', 'Var', (46, 61))	('OS', 'Chemical', '-', (227, 229))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('murine', 'Species', '10090', (5, 11))	('mice', 'Species', '10090', (182, 186))	('anti-IL-6', 'Var', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('death', 'Disease', 'MESH:D003643', (62, 67))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('decrease', 'NegReg', (110, 118))	('death', 'Disease', (62, 67))	('tumor', 'Disease', (122, 127))	('pancreatic cancer', 'Disease', (89, 106))
4608	30038723	IL-6's activation of STAT3 appears to protect the epithelium of the GI tract from apoptosis and stimulates regeneration, and high IL-6 levels have been associated with increased colorectal cancer tumor risk.	('regeneration', 'CPA', (107, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (178, 195))	('colorectal cancer tumor', 'Disease', (178, 201))	('high IL-6 levels', 'Phenotype', 'HP:0030783', (125, 141))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('colorectal cancer tumor', 'Disease', 'MESH:D015179', (178, 201))	('stimulates', 'PosReg', (96, 106))	('associated with', 'Reg', (152, 167))	('high IL-6 level', 'Phenotype', 'HP:0030783', (125, 140))	('GI', 'Phenotype', 'HP:0007378', (68, 70))	('high', 'Var', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
4609	30038723	showed that IL-6 plays a pivotal role in the development of cancer stem cells in colorectal cancer and that anti-IL-6-antibody significantly increased chemo sensibility, and Cross-Knorr et al.	('colorectal cancer', 'Disease', (81, 98))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('men', 'Species', '9606', (52, 55))	('increased', 'PosReg', (141, 150))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))	('cancer', 'Disease', (60, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('chemo sensibility', 'CPA', (151, 168))	('anti-IL-6-antibody', 'Var', (108, 126))
4643	30038723	The area under the curve (AUC) for the diagnosis of pancreatic cancer was higher for CA 19.9 (AUC 0.94) compared to IL-6 (AUC 0.87).	('higher', 'PosReg', (74, 80))	('pancreatic cancer', 'Disease', (52, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (52, 69))	('CA 19.9', 'Var', (85, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (52, 69))
4655	30038723	Although the number of studies of patients with gastric cancer was small, all studies found a significant association between high serum IL-6 and short OS, suggesting a prognostic value in gastric cancer (Table 1).	('gastric cancer', 'Phenotype', 'HP:0012126', (189, 203))	('gastric cancer', 'Phenotype', 'HP:0012126', (48, 62))	('OS', 'Chemical', '-', (152, 154))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('short OS', 'Disease', (146, 154))	('high', 'Var', (126, 130))	('patients', 'Species', '9606', (34, 42))	('gastric cancer', 'Disease', (189, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('gastric cancer', 'Disease', (48, 62))	('gastric cancer', 'Disease', 'MESH:D013274', (189, 203))	('gastric cancer', 'Disease', 'MESH:D013274', (48, 62))
4657	30038723	found that OS was significantly longer in the low IL-6 level group than in the high IL-6 level group for both advanced gastric cancer and patients with lymphatic invasion.	('OS', 'Chemical', '-', (11, 13))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('gastric cancer', 'Disease', (119, 133))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('low IL-6 level', 'Var', (46, 60))	('high IL-6 level', 'Phenotype', 'HP:0030783', (79, 94))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('patients', 'Species', '9606', (138, 146))
4658	30038723	After 1 year, 69% of the gastric cancer patients with high IL-6 levels were alive compared to 94% of the gastric cancer patients with low serum IL-6, and after 3 years, the survival rates were 43% and 87%, respectively.	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('high', 'Var', (54, 58))	('high IL-6 level', 'Phenotype', 'HP:0030783', (54, 69))	('patients', 'Species', '9606', (40, 48))	('gastric cancer', 'Phenotype', 'HP:0012126', (25, 39))	('high IL-6 levels', 'Phenotype', 'HP:0030783', (54, 70))	('gastric cancer', 'Disease', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (105, 119))	('patients', 'Species', '9606', (120, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (25, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (105, 119))	('gastric cancer', 'Disease', (25, 39))
4659	30038723	found a significant relation between high IL-6 and shorter OS (HR 1.77, 95% CI 1.07-2.92).	('shorter OS', 'Disease', (51, 61))	('OS', 'Chemical', '-', (59, 61))	('high', 'Var', (37, 41))
4660	30038723	The gastric cancer patients with stage II/III and high IL-6 levels had a median survival of 618 days in contrast to 1418 days in patients with stage II/III and low IL-6 levels.	('high', 'Var', (50, 54))	('patients', 'Species', '9606', (19, 27))	('high IL-6 level', 'Phenotype', 'HP:0030783', (50, 65))	('gastric cancer', 'Phenotype', 'HP:0012126', (4, 18))	('patients', 'Species', '9606', (129, 137))	('high IL-6 levels', 'Phenotype', 'HP:0030783', (50, 66))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('gastric cancer', 'Disease', (4, 18))	('gastric cancer', 'Disease', 'MESH:D013274', (4, 18))
4662	30038723	studied serum IL-6 and CRP in 115 gastric cancer patients undergoing gastrectomy, and found that high IL-6 was associated to short PFS and OS.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('OS', 'Chemical', '-', (139, 141))	('CRP', 'Gene', (23, 26))	('associated', 'Reg', (111, 121))	('IL-6', 'Gene', (102, 106))	('gastric cancer', 'Disease', (34, 48))	('short PFS', 'Disease', (125, 134))	('CRP', 'Gene', '1401', (23, 26))	('gastric cancer', 'Disease', 'MESH:D013274', (34, 48))	('patients', 'Species', '9606', (49, 57))	('high', 'Var', (97, 101))	('gastric cancer', 'Phenotype', 'HP:0012126', (34, 48))
4668	30038723	found that high IL-6 in pancreatic cancer patients was associated with short OS, and in multivariate analyses, the HR was 1.71 (95% CI 1.33-2.20) for high serum IL-6 and 1.54 (95% CI 1.06-2.24) for high serum CA 19.9 in patients with locally advanced or metastatic pancreatic cancer.	('pancreatic cancer', 'Disease', (24, 41))	('pancreatic cancer', 'Disease', 'MESH:D010190', (24, 41))	('high serum CA', 'Phenotype', 'HP:0003072', (198, 211))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (265, 282))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (24, 41))	('pancreatic cancer', 'Disease', (265, 282))	('pancreatic cancer', 'Disease', 'MESH:D010190', (265, 282))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('patients', 'Species', '9606', (220, 228))	('OS', 'Chemical', '-', (77, 79))	('high', 'Var', (11, 15))	('patients', 'Species', '9606', (42, 50))	('short OS', 'Disease', (71, 79))
4670	30038723	The combination of high CA 19.9 and high IL-6 identified pancreatic cancer patients with a very short median survival of only 7.5 months compared to 34.4 months for pancreatic cancer patients with normal levels of CA 19.9 and IL-6.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('high', 'Var', (19, 23))	('pancreatic cancer', 'Disease', 'MESH:D010190', (165, 182))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (57, 74))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('patients', 'Species', '9606', (183, 191))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('IL-6', 'Gene', (41, 45))	('pancreatic cancer', 'Disease', (57, 74))	('high', 'Var', (36, 40))	('pancreatic cancer', 'Disease', 'MESH:D010190', (57, 74))	('pancreatic cancer', 'Disease', (165, 182))
4672	30038723	assessed the prognostic value of IL-6 and IL-1beta in patients with pancreatic cancer receiving gemcitabine, and using multivariate analysis they found that high IL-6/high IL-1beta levels were an independent prognostic factor for poor OS (HR = 2.10) and short PFS (HR = 2.32).	('poor OS', 'Disease', (230, 237))	('short PFS', 'Disease', (254, 263))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (54, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('gemcitabine', 'Chemical', 'MESH:C056507', (96, 107))	('high', 'Var', (157, 161))	('IL-1beta', 'Gene', (42, 50))	('OS', 'Chemical', '-', (235, 237))	('IL-1beta', 'Gene', (172, 180))	('IL-1beta', 'Gene', '3553', (172, 180))	('pancreatic cancer', 'Disease', (68, 85))	('IL-1beta', 'Gene', '3553', (42, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))
4687	30038723	They found that the pooled HR was 1.76 (95% CI 1.42-2.19), indicating that high serum IL-6 in colorectal cancer patients is a predictor of short OS.	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('high', 'Var', (75, 79))	('OS', 'Chemical', '-', (145, 147))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Disease', (94, 111))	('short OS', 'Disease', (139, 147))
4688	30038723	Using a cut-off level of 10 pg/ml, the OS of patients with serum IL-6 >10 pg/ml was significantly shorter after 3 years (HR 0.40, 95% CI 0.18-0.88), 5 years (HR 0.37, 95% CI 0.20-0.70) and 10 years (HR 0.42, 95% CI 0.25-0.73).	('>10 pg/ml', 'Var', (70, 79))	('OS', 'Chemical', '-', (39, 41))	('serum IL-6', 'Gene', (59, 69))	('patients', 'Species', '9606', (45, 53))	('shorter', 'NegReg', (98, 105))
4709	30038723	Using the cut-off value 4.3 pg/ml, patients with high IL-6 had significantly shorter 3-year OS than those with low IL-6 levels (21% vs. 71%).	('IL-6', 'Gene', (54, 58))	('high', 'Var', (49, 53))	('OS', 'Chemical', '-', (92, 94))	('patients', 'Species', '9606', (35, 43))	('shorter', 'NegReg', (77, 84))	('3-year', 'CPA', (85, 91))
4721	30038723	Regarding the results of this review, some studies find equivocal results when investigating tumor depth invasion or lymph node metastases, but the overall picture seems to indicate that high levels of IL-6 are associated with severe clinical features of patients with GI cancer.	('metastases', 'Disease', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('GI cancer', 'Phenotype', 'HP:0007378', (269, 278))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('GI cancer', 'Disease', 'MESH:D009369', (269, 278))	('GI', 'Phenotype', 'HP:0007378', (269, 271))	('IL-6', 'Protein', (202, 206))	('tumor', 'Disease', (93, 98))	('metastases', 'Disease', 'MESH:D009362', (128, 138))	('patients', 'Species', '9606', (255, 263))	('GI cancer', 'Disease', (269, 278))	('associated', 'Reg', (211, 221))	('high', 'Var', (187, 191))
4739	30038723	For pancreatic cancer, the results of the studies assessed were unanimous showing a significant association between high circulating IL-6 and short OS, which was confirmed in the meta-analysis.	('pancreatic cancer', 'Disease', (4, 21))	('pancreatic cancer', 'Disease', 'MESH:D010190', (4, 21))	('high', 'Var', (116, 120))	('OS', 'Chemical', '-', (148, 150))	('short OS', 'Disease', (142, 150))	('high circulating IL-6', 'Phenotype', 'HP:0030783', (116, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (4, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
4744	30038723	found that IL-6 appears to be a better prognostic biomarker than CA 19.9 in non-operable pancreatic cancer patients, but CA 19.9 is a better prognostic biomarker for pancreatic cancer patients who undergo surgery.	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('non-operable', 'Disease', (76, 88))	('patients', 'Species', '9606', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (166, 183))	('CA 19.9', 'Var', (121, 128))	('pancreatic cancer', 'Disease', (166, 183))	('pancreatic cancer', 'Disease', 'MESH:D010190', (166, 183))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('patients', 'Species', '9606', (107, 115))	('pancreatic cancer', 'Disease', (89, 106))
4762	30038723	by the anti-IL6R monoclonal antibody Tocilizumab, is known to down-regulate the immune suppression caused by tumor cells, and inhibition of IL-6 signaling may be a therapeutic for patients with cancer when IL-6 is over-expressed.	('IL6R', 'Gene', (12, 16))	('cancer', 'Disease', (194, 200))	('Tocilizumab', 'Chemical', 'MESH:C502936', (37, 48))	('inhibition', 'Var', (126, 136))	('immune suppression', 'MPA', (80, 98))	('IL6R', 'Gene', '3570', (12, 16))	('down-regulate', 'NegReg', (62, 75))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('patients', 'Species', '9606', (180, 188))	('tumor', 'Disease', (109, 114))
4770	30038723	The use of IL-6 as a therapeutic target is currently being investigated for pancreatic cancer, but trials should be done for the three other cancers types, especially since inhibition of anti-IL-6R with Tocilizumab seems to be well tolerated.	('IL-6R', 'Gene', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('IL-6R', 'Gene', '3570', (192, 197))	('pancreatic cancer', 'Disease', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('Tocilizumab', 'Chemical', 'MESH:C502936', (203, 214))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (76, 93))	('pancreatic cancer', 'Disease', 'MESH:D010190', (76, 93))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('inhibition', 'Var', (173, 183))	('cancers', 'Disease', (141, 148))
4790	30038723	They found that high IL-6 was associated with impairments in general activity and working ability.	('working ability', 'CPA', (82, 97))	('men', 'Species', '9606', (52, 55))	('high', 'Var', (16, 20))	('general activity', 'CPA', (61, 77))
4806	29290774	Recently, accumulating evidences have demonstrated that deregulated expression of non-coding RNAs (ncRNAs) is closely associated with the etiopathogenesis of CCA.	('deregulated', 'Var', (56, 67))	('expression', 'MPA', (68, 78))	('ncRNA', 'Gene', (99, 104))	('ncRNA', 'Gene', '220202', (99, 104))	('CCA', 'Disease', (158, 161))	('associated', 'Reg', (118, 128))	('rat', 'Species', '10116', (45, 48))
4835	29290774	The dual luciferase reporter assay showed that RhoC was a direct target of miR-138.	('miR-138', 'Var', (75, 82))	('RhoC', 'Gene', '389', (47, 51))	('RhoC', 'Gene', (47, 51))	('miR-138', 'Chemical', '-', (75, 82))
4845	29290774	Knockout of miR-21 decreased the metastatic potential of CCA cells through the regulation of PDCD4 and TIMP3.	('regulation', 'Reg', (79, 89))	('metastatic potential of', 'CPA', (33, 56))	('miR-21', 'Gene', '406991', (12, 18))	('PDCD4', 'Gene', (93, 98))	('Knockout', 'Var', (0, 8))	('PDCD4', 'Gene', '27250', (93, 98))	('decreased', 'NegReg', (19, 28))	('TIMP3', 'Gene', '7078', (103, 108))	('miR-21', 'Gene', (12, 18))	('TIMP3', 'Gene', (103, 108))
4880	29290774	Their dates suggested that miR-101 reduced VEGF and COX-2 levels, resulting in decreasing vascular density.	('miR-101', 'Chemical', '-', (27, 34))	('miR-101', 'Var', (27, 34))	('COX-2', 'Gene', (52, 57))	('reduced', 'NegReg', (35, 42))	('decreasing', 'NegReg', (79, 89))	('VEGF', 'Gene', (43, 47))	('vascular density', 'CPA', (90, 106))	('COX-2', 'Gene', '4513', (52, 57))	('VEGF', 'Gene', '7422', (43, 47))
4889	29290774	In this regard, Meng et al predicted that miRNA-141 which was overexpressed in iCCA targets CLOCK gene directly by bioinformatics technology.	('CLOCK', 'Gene', '9575', (92, 97))	('CLOCK', 'Gene', (92, 97))	('miRNA-141', 'Var', (42, 51))
4893	29290774	Overexpressed miRNA-21 and miRNA-200b were contribute to the gemcitabine chemoresistance of CCA.	('contribute', 'Reg', (43, 53))	('miRNA-21', 'Gene', (14, 22))	('miRNA-200b', 'Var', (27, 37))	('CCA', 'Disease', (92, 95))	('gemcitabine', 'MPA', (61, 72))	('miRNA-21', 'Gene', '406991', (14, 22))	('gemcitabine', 'Chemical', 'MESH:C056507', (61, 72))
4898	29290774	Meng et al found that miRNA-let7a could increase gemcitabine toxicity by targeting NF2 in vivo and vitro.	('toxicity', 'Disease', 'MESH:D064420', (61, 69))	('toxicity', 'Disease', (61, 69))	('NF2', 'Gene', (83, 86))	('increase', 'PosReg', (40, 48))	('gemcitabine', 'Chemical', 'MESH:C056507', (49, 60))	('targeting', 'Reg', (73, 82))	('NF2', 'Gene', '4771', (83, 86))	('miRNA-let7a', 'Var', (22, 33))
4917	29290774	Using bioinformatics, they built 4 lncRNA -mRNA pairs in ICC: RNA43085 and SULF1, RNA47504 and KDM8, RNA58630 and PCSK6, and RNA40057 and CYP2D6.	('RNA47504', 'Var', (82, 90))	('ncRNA', 'Gene', (36, 41))	('RNA40057', 'Var', (125, 133))	('KDM8', 'Gene', (95, 99))	('RNA58630', 'Var', (101, 109))	('CYP2D6', 'Gene', '1565', (138, 144))	('ncRNA', 'Gene', '220202', (36, 41))	('CYP2D6', 'Gene', (138, 144))	('SULF1', 'Gene', '23213', (75, 80))	('SULF1', 'Gene', (75, 80))	('PCSK6', 'Gene', (114, 119))	('PCSK6', 'Gene', '5046', (114, 119))	('KDM8', 'Gene', '79831', (95, 99))
4923	29290774	Inhibition of those two lncRNAs in CCA cells suppressed their migration and invasion potential, whereas increased expression had the opposite effect.	('migration', 'CPA', (62, 71))	('ncRNA', 'Gene', '220202', (25, 30))	('suppressed', 'NegReg', (45, 55))	('invasion potential', 'CPA', (76, 94))	('Inhibition', 'Var', (0, 10))	('expression', 'MPA', (114, 124))	('ncRNA', 'Gene', (25, 30))	('rat', 'Species', '10116', (65, 68))
4924	29290774	By ponging let-7a/let-7b and miR-372/miR-373, H19 and HULC activate the IL-6, CXCR4 pathway may be responsible for this procedure.	('miR-372', 'Gene', (29, 36))	('CXCR4', 'Gene', '7852', (78, 83))	('IL-6', 'Gene', '3569', (72, 76))	('HULC', 'Gene', (54, 58))	('ponging', 'Var', (3, 10))	('activate', 'PosReg', (59, 67))	('miR-373', 'Gene', '442918', (37, 44))	('miR-372', 'Gene', '442917', (29, 36))	('miR-373', 'Gene', (37, 44))	('H19', 'Gene', '283120', (46, 49))	('CXCR4', 'Gene', (78, 83))	('H19', 'Gene', (46, 49))	('let-7b', 'Gene', '406884', (18, 24))	('HULC', 'Gene', '728655', (54, 58))	('let-7b', 'Gene', (18, 24))	('IL-6', 'Gene', (72, 76))
4925	29290774	Mutations of BRCA-1 associated protein-1 (BAP1) was frequent in ICC.	('BRCA-1 associated protein-1', 'Gene', '8314', (13, 40))	('BAP1', 'Gene', '8314', (42, 46))	('BAP1', 'Gene', (42, 46))	('ICC', 'Disease', (64, 67))	('BRCA-1 associated protein-1', 'Gene', (13, 40))	('Mutations', 'Var', (0, 9))	('frequent', 'Reg', (52, 60))
4926	29290774	Parasramka et al found high level of BAP1 could make CCA cell resistance to gemcitabine.	('gemcitabine', 'Chemical', 'MESH:C056507', (76, 87))	('resistance to gemcitabine', 'MPA', (62, 87))	('BAP1', 'Gene', '8314', (37, 41))	('CCA', 'Disease', (53, 56))	('high level', 'Var', (23, 33))	('make', 'Reg', (48, 52))	('BAP1', 'Gene', (37, 41))
4928	29290774	NEAT-1 interruption significantly restored cell response to gemcitabine, which means it could be a potential sensitizer.	('gemcitabine', 'Chemical', 'MESH:C056507', (60, 71))	('restored', 'PosReg', (34, 42))	('interruption', 'Var', (7, 19))	('cell response to gemcitabine', 'MPA', (43, 71))	('NEAT-1', 'Gene', (0, 6))	('NEAT-1', 'Gene', '283131', (0, 6))
4930	29290774	AFAP1-AS1 knockdown inhibited G0/G1 cell cycle arrest and S-G2/M transition, by increasing AFAP1 and interrupting cell stress filament formation.	('S-G2/M transition', 'CPA', (58, 75))	('AFAP1', 'Gene', (91, 96))	('AFAP1', 'Gene', '60312', (91, 96))	('cell stress filament formation', 'CPA', (114, 144))	('G0/G1 cell cycle arrest', 'CPA', (30, 53))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (0, 9))	('interrupting', 'NegReg', (101, 113))	('AFAP1', 'Gene', (0, 5))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (36, 53))	('AFAP1', 'Gene', '60312', (0, 5))	('inhibited', 'NegReg', (20, 29))	('AFAP1-AS1', 'Gene', (0, 9))	('knockdown', 'Var', (10, 19))	('increasing', 'PosReg', (80, 90))
4938	29290774	Moreover, Obstruction of PANDAR or TUG1 induced cell apoptosis and erased EMT progress.	('TUG1', 'Gene', '55000', (35, 39))	('PANDAR', 'Gene', '101154753', (25, 31))	('PANDAR', 'Gene', (25, 31))	('EMT progress', 'CPA', (74, 86))	('TUG1', 'Gene', (35, 39))	('Obstruction', 'Var', (10, 21))	('cell apoptosis', 'CPA', (48, 62))	('erased', 'NegReg', (67, 73))
4939	29290774	Silencing of H19 inhibited cell proliferation and promoted cell apoptosis.	('promoted', 'PosReg', (50, 58))	('cell proliferation', 'CPA', (27, 45))	('rat', 'Species', '10116', (39, 42))	('H19', 'Gene', '283120', (13, 16))	('inhibited', 'NegReg', (17, 26))	('cell apoptosis', 'CPA', (59, 73))	('Silencing', 'Var', (0, 9))	('H19', 'Gene', (13, 16))
4948	29290774	CCA carcinogenesis is result from disorders of numerous oncogenes, tumor-suppressor genes and the related molecules.	('disorders', 'Var', (34, 43))	('oncogenes', 'Protein', (56, 65))	('result from', 'Reg', (22, 33))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('CCA carcinogenesis', 'Disease', (0, 18))	('carcinogenesis', 'Disease', (4, 18))
4984	27412505	The secretion of HCO3- creates an AE2-dependent bicarbonate-rich umbrella and serves as a protective mechanism against the cytotoxicity of hydrophobic bile salts.	('bile salts', 'Chemical', 'MESH:D001647', (151, 161))	('HCO3-', 'Var', (17, 22))	('AE2', 'Gene', '24780', (34, 37))	('cytotoxicity', 'Disease', (123, 135))	('AE2', 'Gene', (34, 37))	('cytotoxicity', 'Disease', 'MESH:D064420', (123, 135))	('HCO3', 'Chemical', 'MESH:D001639', (17, 21))	('bicarbonate', 'Chemical', 'MESH:D001639', (48, 59))
4989	27412505	Ablation of this pathway using specific inhibitors resulted in decreased cholangiocyte proliferation.	('rat', 'Species', '10116', (94, 97))	('Ablation', 'Var', (0, 8))	('cholangiocyte proliferation', 'CPA', (73, 100))	('decreased', 'NegReg', (63, 72))
4992	27412505	The Janus kinase/signal transducer activator of transcription (JAK/STAT) pathway has also been implicated in cholangiocarcinoma growth, and inhibition of this pathway with sorafenib has been shown to accelerate dephosphorylation of STAT3.	('sorafenib', 'Chemical', 'MESH:D000077157', (172, 181))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('inhibition', 'Var', (140, 150))	('cholangiocarcinoma growth', 'Disease', (109, 134))	('implicated', 'Reg', (95, 105))	('STAT3', 'Gene', (232, 237))	('dephosphorylation', 'MPA', (211, 228))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (109, 134))	('rat', 'Species', '10116', (206, 209))	('accelerate', 'PosReg', (200, 210))	('Janus kinase/signal transducer', 'Pathway', (4, 34))	('STAT3', 'Gene', '25125', (232, 237))
4995	27412505	Inhibition of CFTR did not change flow-stimulated currents in their studies, suggesting a different mechanism of Cl- transport when cholangiocytes are exposed to shear forces.	('Cl- transport', 'MPA', (113, 126))	('CFTR', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('CFTR', 'Gene', '24255', (14, 18))
5002	27412505	These mice serve as an animal model of sclerosing cholangitis because their loss of Mdr2 (a flippase) significantly reduces biliary phospholipid secretion and increases levels of nonmicellar bile acids that subsequently cause biliary injury with proliferation, pericholangitis, and fibrosis.	('reduces', 'NegReg', (116, 123))	('biliary phospholipid secretion', 'MPA', (124, 154))	('mice', 'Species', '10090', (6, 10))	('mice', 'Species', '10090', (182, 186))	('fibrosis', 'Disease', (282, 290))	('cholangitis', 'Phenotype', 'HP:0030151', (265, 276))	('proliferation', 'CPA', (246, 259))	('fibrosis', 'Disease', 'MESH:D005355', (282, 290))	('phospholipid', 'Chemical', 'MESH:D010743', (132, 144))	('cholangitis', 'Phenotype', 'HP:0030151', (50, 61))	('rat', 'Species', '10116', (253, 256))	('bile acids', 'Chemical', 'MESH:D001647', (191, 201))	('levels of nonmicellar bile acids', 'MPA', (169, 201))	('pericholangitis', 'Disease', 'None', (261, 276))	('increases', 'PosReg', (159, 168))	('loss', 'Var', (76, 80))	('biliary injury', 'Disease', 'MESH:D001658', (226, 240))	('pericholangitis', 'Disease', (261, 276))	('Mdr2', 'Gene', '18670', (84, 88))	('cause', 'Reg', (220, 225))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (39, 61))	('Mdr2', 'Gene', (84, 88))	('cholangitis', 'Disease', 'MESH:D002761', (265, 276))	('cholangitis', 'Disease', (265, 276))	('cholangitis', 'Disease', 'MESH:D002761', (50, 61))	('biliary injury', 'Disease', (226, 240))	('cholangitis', 'Disease', (50, 61))
5011	27412505	demonstrated that knockout of the SR significantly reduced large intrahepatic bile duct mass in mice following BDL.	('BDL', 'Chemical', '-', (111, 114))	('reduced', 'NegReg', (51, 58))	('mice', 'Species', '10090', (96, 100))	('intrahepatic bile duct mass', 'Disease', 'MESH:D002780', (65, 92))	('intrahepatic bile duct mass', 'Phenotype', 'HP:0005209', (65, 92))	('reduced large intrahepatic bile', 'Phenotype', 'HP:0006571', (51, 82))	('intrahepatic bile duct mass', 'Disease', (65, 92))	('rat', 'Species', '10116', (7, 10))	('knockout', 'Var', (18, 26))
5046	27412505	They further demonstrated that secretion of VEGF-A and VEGF-C, and expression of their corresponding receptors are upregulated following BDL.	('VEGF-C', 'Gene', '114111', (55, 61))	('VEGF-A', 'Gene', (44, 50))	('VEGF-C', 'Gene', (55, 61))	('BDL', 'Chemical', '-', (137, 140))	('secretion', 'MPA', (31, 40))	('VEGF-A', 'Gene', '83785', (44, 50))	('expression', 'MPA', (67, 77))	('rat', 'Species', '10116', (20, 23))	('BDL', 'Var', (137, 140))	('upregulated', 'PosReg', (115, 126))
5060	27412505	Knockout of hepatic VEGF with oligonucleotides inhibited proliferation and recruitment of BM SPCs to the liver parenchyma.	('liver parenchyma', 'Disease', (105, 121))	('inhibited', 'NegReg', (47, 56))	('recruitment', 'CPA', (75, 86))	('rat', 'Species', '10116', (64, 67))	('oligonucleotides', 'Chemical', 'MESH:D009841', (30, 46))	('proliferation', 'CPA', (57, 70))	('oligonucleotides', 'Var', (30, 46))	('liver parenchyma', 'Disease', 'MESH:D010195', (105, 121))
5080	27412505	Furthermore, vagotomy impairs cholangiocyte proliferation, enhances apoptosis, and limits ductular reaction following BDL in rats.	('rat', 'Species', '10116', (125, 128))	('cholangiocyte proliferation', 'CPA', (30, 57))	('limits', 'NegReg', (83, 89))	('rat', 'Species', '10116', (51, 54))	('apoptosis', 'CPA', (68, 77))	('rats', 'Species', '10116', (125, 129))	('ductular reaction', 'CPA', (90, 107))	('enhances', 'PosReg', (59, 67))	('vagotomy', 'Var', (13, 21))	('BDL', 'Chemical', '-', (118, 121))	('impairs', 'NegReg', (22, 29))
5100	27412505	The same study also demonstrated that serotonin stimulates myofibroblast production of TGF-beta1, which decreases tryptophan hydroxylase-2 (TPH2) expression and subsequently decreases serotonin levels and its effects on cholangiocyte proliferation.	('serotonin levels', 'MPA', (184, 200))	('tryptophan hydroxylase-2', 'Gene', (114, 138))	('expression', 'MPA', (146, 156))	('TGF-beta1', 'Gene', (87, 96))	('cholangiocyte proliferation', 'CPA', (220, 247))	('stimulates', 'PosReg', (48, 58))	('TGF-beta1', 'Gene', '59086', (87, 96))	('decreases serotonin', 'Phenotype', 'HP:0003144', (174, 193))	('serotonin', 'Chemical', 'MESH:D012701', (184, 193))	('myofibroblast', 'CPA', (59, 72))	('tryptophan hydroxylase-2', 'Gene', '317675', (114, 138))	('decreases tryptophan', 'Phenotype', 'HP:0500135', (104, 124))	('rat', 'Species', '10116', (27, 30))	('serotonin', 'Var', (38, 47))	('rat', 'Species', '10116', (241, 244))	('TPH2', 'Gene', '317675', (140, 144))	('decreases', 'NegReg', (104, 113))	('TPH2', 'Gene', (140, 144))	('serotonin', 'Chemical', 'MESH:D012701', (38, 47))	('decreases', 'NegReg', (174, 183))
5106	27412505	Furthermore, performing BDL in histidine decarboxylase knockout mice (HDC-/-) demonstrated that inhibiting the pathway for histamine production decreased cholangiocyte proliferation and VEGF/HIF-1alpha expression via decreasing PKA/ERK1/2 activation.	('inhibiting', 'Var', (96, 106))	('histidine decarboxylase', 'Gene', '15186', (31, 54))	('expression', 'MPA', (202, 212))	('rat', 'Species', '10116', (175, 178))	('BDL', 'Chemical', '-', (24, 27))	('histidine decarboxylase', 'Gene', (31, 54))	('decreased', 'NegReg', (144, 153))	('histamine', 'Chemical', 'MESH:D006632', (123, 132))	('rat', 'Species', '10116', (85, 88))	('decreasing', 'NegReg', (217, 227))	('HDC-/-)', 'Gene', '15186', (70, 77))	('cholangiocyte proliferation', 'CPA', (154, 181))	('HIF-1alpha', 'Gene', '15251', (191, 201))	('mice', 'Species', '10090', (64, 68))	('PKA', 'Gene', (228, 231))	('HIF-1alpha', 'Gene', (191, 201))	('PKA', 'Gene', '25636', (228, 231))	('HDC-/-', 'Gene', (70, 76))	('activation', 'MPA', (239, 249))
5121	27412505	demonstrated that loss of the NK-1R receptor was associated with increased biliary apoptosis, decreased serum transaminases, and decreased expression of fibrotic genes following BDL.	('increased', 'PosReg', (65, 74))	('fibrotic genes', 'Gene', (153, 167))	('loss', 'Var', (18, 22))	('decreased', 'NegReg', (129, 138))	('NK-1R', 'Gene', (30, 35))	('BDL', 'Chemical', '-', (178, 181))	('decreased serum transaminases', 'Phenotype', 'HP:0001410', (94, 123))	('serum transaminases', 'MPA', (104, 123))	('decreased', 'NegReg', (94, 103))	('rat', 'Species', '10116', (7, 10))	('expression of', 'MPA', (139, 152))	('biliary apoptosis', 'CPA', (75, 92))
5125	27412505	NGF stimulated cholangiocyte proliferation in vitro through AKT and ERK1/2 pathways, whereas neutralizing NGF following BDL decreased biliary proliferation.	('AKT', 'Gene', '24185', (60, 63))	('cholangiocyte proliferation', 'CPA', (15, 42))	('rat', 'Species', '10116', (149, 152))	('neutralizing', 'Var', (93, 105))	('rat', 'Species', '10116', (36, 39))	('BDL', 'Chemical', '-', (120, 123))	('decreased', 'NegReg', (124, 133))	('NGF', 'Gene', (106, 109))	('NGF', 'Gene', '310738', (0, 3))	('NGF', 'Gene', (0, 3))	('AKT', 'Gene', (60, 63))	('stimulated', 'PosReg', (4, 14))	('NGF', 'Gene', '310738', (106, 109))	('ERK1/2 pathways', 'Pathway', (68, 83))	('biliary proliferation', 'CPA', (134, 155))	('BDL decreased', 'Phenotype', 'HP:0003563', (120, 133))
5142	27412505	Immunoreactivity and receptor expression of the ER-beta subtypes were significantly upregulated in BDL rats, more so than the ER-alpha subtype.	('upregulated', 'PosReg', (84, 95))	('BDL', 'Chemical', '-', (99, 102))	('rats', 'Species', '10116', (103, 107))	('receptor expression', 'MPA', (21, 40))	('ER-alpha', 'Gene', '24890', (126, 134))	('ER-alpha', 'Gene', (126, 134))	('BDL', 'Var', (99, 102))	('Immunoreactivity', 'MPA', (0, 16))	('ER-beta', 'Gene', (48, 55))	('ER-beta', 'Gene', '25149', (48, 55))
5156	27412505	Administration of anti-FSH antibodies to BDL rats significantly reduced bile duct mass, cholangiocyte proliferation, secretin-induced cAMP levels, and ERK1/2 and Elk-1 phosphorylation.	('Elk-1', 'Gene', '314436', (162, 167))	('rat', 'Species', '10116', (8, 11))	('rats', 'Species', '10116', (45, 49))	('Elk-1', 'Gene', (162, 167))	('antibodies', 'Var', (27, 37))	('secretin-induced cAMP levels', 'MPA', (117, 145))	('rat', 'Species', '10116', (109, 112))	('BDL', 'Chemical', '-', (41, 44))	('cAMP', 'Chemical', 'MESH:D000242', (134, 138))	('reduced bile duct mass', 'Phenotype', 'HP:0006571', (64, 86))	('reduced', 'NegReg', (64, 71))	('bile duct mass', 'CPA', (72, 86))	('ERK1/2', 'Protein', (151, 157))	('cholangiocyte proliferation', 'CPA', (88, 115))	('rat', 'Species', '10116', (45, 48))
5161	27412505	Disruption of the GnRH/GnRHR interaction decreased cholangiocyte proliferation, bile duct mass, and liver fibrosis following BDL.	('BDL', 'Chemical', '-', (125, 128))	('GnRH', 'Gene', (23, 27))	('liver fibrosis', 'Disease', 'MESH:D008103', (100, 114))	('bile duct mass', 'CPA', (80, 94))	('rat', 'Species', '10116', (72, 75))	('decreased', 'NegReg', (41, 50))	('liver fibrosis', 'Phenotype', 'HP:0001395', (100, 114))	('GnRH', 'Gene', '25194', (18, 22))	('GnRH', 'Gene', (18, 22))	('cholangiocyte proliferation', 'CPA', (51, 78))	('GnRHR', 'Gene', '81668', (23, 28))	('interaction', 'Interaction', (29, 40))	('liver fibrosis', 'Disease', (100, 114))	('GnRHR', 'Gene', (23, 28))	('GnRH', 'Gene', '25194', (23, 27))	('Disruption', 'Var', (0, 10))
5203	27412505	Inhibition of Wnt signaling with Dickkopf-1, a Wnt coreceptor antagonist, restores stellate cells to a quiescent state in vitro and ameliorates liver fibrosis in vivo.	('rat', 'Species', '10116', (138, 141))	('restores', 'PosReg', (74, 82))	('Wnt', 'Pathway', (14, 17))	('liver fibrosis', 'Disease', (144, 158))	('Inhibition', 'Var', (0, 10))	('liver fibrosis', 'Disease', 'MESH:D008103', (144, 158))	('ameliorates', 'PosReg', (132, 143))	('Dickkopf-1', 'Gene', (33, 43))	('liver fibrosis', 'Phenotype', 'HP:0001395', (144, 158))
5204	27412505	Furthermore, Wnt signaling has been shown to regulate proliferation of cholangiocarcinoma, a malignancy of the biliary epithelium, and antagonizing this pathway decreases cholangiocarcinoma proliferation and tumor growth.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (71, 89))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (71, 89))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (171, 189))	('rat', 'Species', '10116', (197, 200))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (171, 189))	('malignancy', 'Disease', 'MESH:D009369', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('rat', 'Species', '10116', (61, 64))	('decreases cholangiocarcinoma proliferation and tumor', 'Disease', 'MESH:D018281', (161, 213))	('malignancy', 'Disease', (93, 103))	('proliferation', 'MPA', (54, 67))	('cholangiocarcinoma', 'Disease', (71, 89))	('antagonizing', 'Var', (135, 147))	('cholangiocarcinoma', 'Disease', (171, 189))
5213	27412505	demonstrated that inhibition of Notch signaling with a gamma-secretase inhibitor significantly attenuated CCl4-induced liver fibrosis by decreasing stellate cell activation, inhibiting M1 inflammatory macrophages, and increasing M2-suppressive macrophages.	('increasing', 'PosReg', (218, 228))	('CCl4', 'Gene', '116637', (106, 110))	('M1 inflammatory macrophages', 'CPA', (185, 212))	('inhibiting', 'NegReg', (174, 184))	('stellate cell activation', 'CPA', (148, 172))	('liver fibrosis', 'Disease', (119, 133))	('M2-suppressive macrophages', 'CPA', (229, 255))	('decreasing', 'NegReg', (137, 147))	('rat', 'Species', '10116', (7, 10))	('liver fibrosis', 'Disease', 'MESH:D008103', (119, 133))	('inhibition', 'Var', (18, 28))	('attenuated', 'NegReg', (95, 105))	('CCl4', 'Gene', (106, 110))	('liver fibrosis', 'Phenotype', 'HP:0001395', (119, 133))
5230	19291182	Modulation of VEGF-A and VEGF-C (by ET-1) may be important for managing cholangiocarcinoma growth.	('VEGF-C', 'Gene', (25, 31))	('Modulation', 'Var', (0, 10))	('cholangiocarcinoma growth', 'Disease', (72, 97))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (72, 97))	('VEGF-A', 'Gene', (14, 20))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))
5269	19291182	Then, cells were stimulated with (i) 0.2% BSA (basal), (ii) ET-1 (10 nM) for 6 h in the absence or presence of BQ610 and BQ788 (100 nM) or (iii) BQ610 or BQ788 (100 nM).	('BQ788', 'Var', (121, 126))	('BQ610', 'Var', (145, 150))	('BQ788', 'Chemical', 'MESH:C086539', (154, 159))	('BQ610', 'Var', (111, 116))	('BQ788', 'Chemical', 'MESH:C086539', (121, 126))
5295	19291182	By real-time PCR, ETA and ETB receptor mRNA levels were significantly higher in Mz-ChA-1 cells compared with H69 cells (Fig.	('ETB receptor', 'Gene', (26, 38))	('H69', 'CellLine', 'CVCL:8121', (109, 112))	('ETB receptor', 'Gene', '50672', (26, 38))	('Mz-ChA-1', 'Var', (80, 88))	('higher', 'PosReg', (70, 76))
5299	19291182	The inhibitory effect of ET-1 (10 nM for 48 h) on Mz-ChA-1 growth was blocked by both BQ-610 and BQ-788 (Fig.	('growth', 'CPA', (59, 65))	('BQ-788', 'Chemical', 'MESH:C086539', (97, 103))	('blocked', 'NegReg', (70, 77))	('BQ-610', 'Var', (86, 92))	('BQ-788', 'Var', (97, 103))	('Mz-ChA-1', 'Gene', (50, 58))	('BQ-610', 'Chemical', 'MESH:C087220', (86, 92))
5303	19291182	Consistent with the concept that both ETA and ETB receptors regulate the effects of ET-1 on cholangiocarcinoma growth, ET-1 inhibition of VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 expression was blocked by BQ610 (an ETA receptor inhibitor) and BQ788 (an ETB receptor inhibitor) (Fig.	('BQ788', 'Chemical', 'MESH:C086539', (238, 243))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (92, 110))	('inhibition', 'NegReg', (124, 134))	('ETB receptor', 'Gene', '50672', (46, 58))	('VEGFR-2', 'Gene', (154, 161))	('expression', 'MPA', (174, 184))	('ETB receptor', 'Gene', (248, 260))	('VEGF-C', 'Gene', (146, 152))	('ET-1', 'Gene', (119, 123))	('cholangiocarcinoma growth', 'Disease', (92, 117))	('BQ610', 'Var', (200, 205))	('VEGFR-3', 'Gene', (166, 173))	('VEGF-A', 'Gene', (138, 144))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (92, 117))	('ETB receptor', 'Gene', (46, 58))	('ETB receptor', 'Gene', '50672', (248, 260))
5304	19291182	At 73 days (the time when mice were sacrificed), a significant difference in tumour size was found in ET-1-treated mice compared with mice injected with vehicle only (431.47 +- 55.45mm3, ET-1-treated mice vs. 904.08 +- 194mm3, vehicle-treated mice; P < 0.02) (Fig.	('mice', 'Species', '10090', (134, 138))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', (77, 83))	('mice', 'Species', '10090', (26, 30))	('mice', 'Species', '10090', (200, 204))	('ET-1-treated', 'Var', (102, 114))	('mice', 'Species', '10090', (115, 119))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('mice', 'Species', '10090', (243, 247))
5311	19291182	6) showed a more expressed fibrotic tissue in ET-1-treated mice compared with vehicle-treated mice (Fig.	('ET-1-treated', 'Var', (46, 58))	('fibrotic tissue', 'CPA', (27, 42))	('mice', 'Species', '10090', (59, 63))	('mice', 'Species', '10090', (94, 98))
5312	19291182	We have shown that (i) normal and malignant cholangiocyte cell lines and normal and cholangiocarcinoma human tissue of biopsy samples express ETA and ETB receptors, (ii) ETA and ETB expression is higher in cholangiocarcinoma cells compared with normal cholangiocytes and (iii) ET-1 decreases the growth of the cholangiocarcinoma cell line, Mz-ChA-1 cells.	('ETB', 'Gene', (178, 181))	('ETB', 'Gene', '1910', (178, 181))	('human', 'Species', '9606', (103, 108))	('decreases', 'NegReg', (282, 291))	('ETB receptor', 'Gene', '50672', (150, 162))	('higher', 'PosReg', (196, 202))	('growth', 'MPA', (296, 302))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (310, 328))	('ETB', 'Gene', (150, 153))	('ETB receptor', 'Gene', (150, 162))	('ETB', 'Gene', '1910', (150, 153))	('expression', 'MPA', (182, 192))	('cholangiocarcinoma', 'Disease', (310, 328))	('cholangiocarcinoma cells', 'Disease', 'MESH:D018281', (206, 230))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (310, 328))	('cholangiocarcinoma cells', 'Disease', (206, 230))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (206, 224))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('cholangiocarcinoma', 'Disease', (206, 224))	('ET-1', 'Var', (277, 281))	('cholangiocarcinoma', 'Disease', (84, 102))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (206, 224))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
5324	19291182	Furthermore, a study has shown that transfected cholecystokinin receptors mediate growth inhibition of human pancreatic cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cholecystokinin', 'Gene', (48, 63))	('human', 'Species', '9606', (103, 108))	('growth inhibition', 'CPA', (82, 99))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (109, 126))	('cholecystokinin', 'Gene', '885', (48, 63))	('pancreatic cancer', 'Disease', 'MESH:D010190', (109, 126))	('transfected', 'Var', (36, 47))	('pancreatic cancer', 'Disease', (109, 126))
5351	32231683	During this entirely evolutionary process, certain somatic mutations could give tumor cells survival advantage and subpopulation carrying these genomic alterations expanded, while subclones with mutations reducing survival capacity diminished.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('alterations', 'Var', (152, 163))	('tumor', 'Disease', (80, 85))	('mutations', 'Var', (59, 68))	('survival advantage', 'CPA', (92, 110))
5360	32231683	Somatic single nucleotide variants (SNV) and copy number alterations (CNA) were detected for the whole exome sequencing data of tumor tissue samples using the corresponding peritumor as control.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('single nucleotide variants', 'Var', (8, 34))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('copy number', 'Var', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', (177, 182))
5361	32231683	The identified SNVs were further filtered with such criteria to rule out possible false discovery: (1) read depth >= 50 in both tumor and peritumor tissues; (2) variant allele frequency >= 10% in tumor tissue; (3) variant allele frequency < 10% in normal peritumor tissues.	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('variant', 'Var', (161, 168))	('tumor', 'Disease', (259, 264))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
5378	32231683	Annotation of acquired SNVs revealed a number of common mutated genes across tumor samples, containing several known cancer-related genes (Figure 1B).	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('mutated', 'Var', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cancer', 'Disease', (117, 123))	('tumor', 'Disease', (77, 82))
5391	32231683	For 7 of the included patients (CCA-1218, CCA-1431, CCA-1461, CCA-950, CCA-1429, CCA-1590, and CCA-1600), no subclonal mutations were identified since all mutations within each sample could be clustered into one single cluster according to their allele frequencies.	('CCA', 'Phenotype', 'HP:0030153', (62, 65))	('patients', 'Species', '9606', (22, 30))	('CCA', 'Phenotype', 'HP:0030153', (42, 45))	('CCA', 'Phenotype', 'HP:0030153', (52, 55))	('CCA-1429', 'Var', (71, 79))	('CCA', 'Phenotype', 'HP:0030153', (32, 35))	('CCA-950', 'Var', (62, 69))	('CCA', 'Phenotype', 'HP:0030153', (71, 74))
5392	32231683	These results showed that during the tumor clonal evolution of these patients, the randomly accumulated mutations might not create subclones with significant survival advantage.	('mutations', 'Var', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('patients', 'Species', '9606', (69, 77))
5398	32231683	One possible explanation is that in this kind of patients, some critical mutations that might greatly benefit tumors' growth took place in the later period of tumor development (which explained the expanding tumor subclones), while other tumor acquired these genetic alterations in the early stage, and thus resulted in the differences in patients' prognosis.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('resulted in', 'Reg', (308, 319))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('patients', 'Species', '9606', (339, 347))	('tumors', 'Disease', (110, 116))	('tumor', 'Disease', (208, 213))	('differences', 'Reg', (324, 335))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Disease', (159, 164))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumor', 'Disease', (238, 243))	('patients', 'Species', '9606', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('benefit', 'PosReg', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('growth', 'MPA', (118, 124))	('mutations', 'Var', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
5399	32231683	Evaluation of known immune signature based on gene expression further revealed that CCA-1141 and CCA-1174 could be categorized into cold tumor with relatively low level of cells correlated with immune response (Figure 2B).	('CCA', 'Phenotype', 'HP:0030153', (84, 87))	('tumor', 'Disease', (137, 142))	('CCA-1141', 'Var', (84, 92))	('CCA', 'Phenotype', 'HP:0030153', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('CCA-1174', 'Var', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
5401	32231683	To better understand how tumor clonal evolution affected different biological pathways/processes in tumor cells, we first divided patients' somatic mutations into clonal mutations and subclonal mutations, and then HotNet2 algorithm was used to scan gene interaction networks for altered subnetworks affected by different categories of mutations.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (25, 30))	('patients', 'Species', '9606', (130, 138))	('mutations', 'Var', (335, 344))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
5403	32231683	These two genes were both related to gene transcription and their dysregulation has been reported to promote tumorigenesis in various cancer.	('promote', 'PosReg', (101, 108))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('dysregulation', 'Var', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', (109, 114))
5416	32231683	GO-term enrichment analysis revealed that the up-regulated genes (Figure 4C) were mostly enriched in the regulation of biological process (GO:0048519, GO:0048522 and GO:0048523), while down-regulated genes (Figure 4D) were mostly enriched in metabolism related biological processes including carboxylic acid metabolic process (GO:0019752) and oxoacid metabolic process (GO:0043436).	('GO:0043436', 'Var', (370, 380))	('GO:0048519', 'Var', (139, 149))	('carboxylic acid metabolic process', 'MPA', (292, 325))	('regulation of biological process', 'MPA', (105, 137))	('carboxylic acid', 'Chemical', 'MESH:D002264', (292, 307))	('GO:0019752', 'Var', (327, 337))	('oxoacid metabolic process', 'MPA', (343, 368))	('up-regulated', 'PosReg', (46, 58))	('GO:0048523', 'Var', (166, 176))	('GO:0048522', 'Var', (151, 161))
5419	32231683	Meanwhile, Gene Ontology enrichment analysis revealed that subnetworks altered by transcriptome change were dominantly enriched in biological processes related to cell division and cell cycle (Figure 4E), including cell division (GO:0051301), cell cycle (GO:0004857), protein localization (GO:0008104) and cellular component organization (GO:0016043), indicating notable change of proliferation capacity happened during tumor clonal evolution.	('cell cycle', 'CPA', (243, 253))	('tumor', 'Disease', 'MESH:D009369', (420, 425))	('cell division', 'CPA', (163, 176))	('tumor', 'Phenotype', 'HP:0002664', (420, 425))	('GO:0008104', 'Var', (290, 300))	('tumor', 'Disease', (420, 425))	('cell division', 'CPA', (215, 228))	('GO:0051301', 'Var', (230, 240))	('GO:0004857', 'Var', (255, 265))	('GO:0016043', 'Var', (339, 349))
5426	32231683	All these results suggested that the alteration of tumor genome and transcriptome were closely related, and the influence of driver gene mutations might spread to faraway downstream.	('mutations', 'Var', (137, 146))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
5432	32231683	Meanwhile, identification of subnetworks affected by CCA clonal/subclonal mutations revealed that clonal mutations' influence spread across a number of different biological pathways, while subclonal mutations influence mainly focused on pathways that benefiting tumor metastasis.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('influence', 'Reg', (116, 125))	('tumor', 'Disease', (262, 267))	('mutations', 'Var', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('CCA', 'Phenotype', 'HP:0030153', (53, 56))
5433	32231683	This result indicated that most mutations with survival advantage were acquired during early stage of CCA development and acquisition of mutations on key regulator genes could affect how tumor evolved.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('CCA', 'Phenotype', 'HP:0030153', (102, 105))	('affect', 'Reg', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (187, 192))	('mutations', 'Var', (32, 41))	('CCA', 'Disease', (102, 105))
5434	32231683	Although a lot of studies have been conducted on every single omics level, discovering a variety of patterns and mechanism for how these alterations contribute to tumorigenesis, one major question still remained largely unanswered: how the alteration on multiple biological levels interact?	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('alterations', 'Var', (137, 148))	('contribute', 'Reg', (149, 159))
5502	31182960	The rates of grade 3 or higher acute toxicity were higher with RFA (11%) than with SBRT (5%).	('toxicity', 'Disease', (37, 45))	('RFA', 'Var', (63, 66))	('toxicity', 'Disease', 'MESH:D064420', (37, 45))
5506	31182960	While no OS differences were noted, 2-year LC rates were higher with SBRT than with TACE (91% versus 23%).	('higher', 'PosReg', (57, 63))	('LC rates', 'CPA', (43, 51))	('OS', 'Chemical', '-', (9, 11))	('SBRT', 'Var', (69, 73))	('TACE', 'Chemical', '-', (84, 88))
5519	31182960	Many ongoing studies are currently evaluating the combination of TACE with SBRT [NCT01918683, NCT02507765, NCT02513199, and NCT02794337] and comparing SBRT to TACE [NCT02182687 and NCT02470533].	('NCT02794337]', 'Var', (124, 136))	('NCT02507765', 'Var', (94, 105))	('TACE', 'Chemical', '-', (65, 69))	('TACE', 'Chemical', '-', (159, 163))	('NCT02513199', 'Var', (107, 118))
5577	31182960	A phase II trial evaluated whether testing for mismatch-repair (MMR) deficiencies in treatment-refractory cases of IHC might be of help in identifying those who might benefit from PD-1 pathway blockade.	('men', 'Species', '9606', (90, 93))	('IHC', 'Disease', (115, 118))	('PD-1 pathway', 'Pathway', (180, 192))	('deficiencies', 'Var', (69, 81))
5590	31182960	The addition of anti-PD-1 antibodies to RT is therefore expected to promote the proimmunogenic tumor microenvironment.	('anti-PD-1 antibodies', 'Var', (16, 36))	('antibodies', 'Var', (26, 36))	('promote', 'PosReg', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('men', 'Species', '9606', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
5592	31182960	In a study by Yoshimoto et al., mice exposed to the combination of RT and anti-CTLA-4 antibody had improved antitumor immunity and prolonged tumor growth delay (from 13.1 to 19.5 days) when compared to those exposed to RT alone.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('anti-CTLA-4', 'Var', (74, 85))	('improved', 'PosReg', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('growth delay', 'Phenotype', 'HP:0001510', (147, 159))	('prolonged tumor growth delay', 'Disease', 'MESH:D006130', (131, 159))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mice', 'Species', '10090', (32, 36))	('prolonged tumor growth delay', 'Disease', (131, 159))	('tumor', 'Disease', (112, 117))	('combination', 'Interaction', (52, 63))
5632	31182960	Gene expression analysis of cells from the irradiated tumors revealed an IFN type I gene signature following exposure to 8Gy in 3 fractions but not following a single dose of 20 or 30Gy.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('8Gy', 'Var', (121, 124))	('IFN', 'Gene', '3439', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('IFN', 'Gene', (73, 76))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
5770	28566890	Furthermore, there was a tendency of downstaging in the NACCRT group compared to the non-NACCRT group.	('NACCRT', 'Var', (56, 62))	('NACCRT', 'Chemical', '-', (56, 62))	('downstaging', 'NegReg', (37, 48))	('NACCRT', 'Chemical', '-', (89, 95))
5781	28566890	In addition, there is a conclusion that CA19-9 is the independent risk factor for recurrence after curative resection in biliary tract cancer as well as the staging system including preoperative CA19-9.	('recurrence', 'Disease', (82, 92))	('CA19-9', 'Var', (40, 46))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (121, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('biliary tract cancer', 'Disease', 'MESH:D001661', (121, 141))	('biliary tract cancer', 'Disease', (121, 141))
5782	28566890	These results including our study suggest that CA19-9 is sufficient marker for predicting prognosis as well as marker for tracking cancer recurrence.	('cancer', 'Disease', (131, 137))	('CA19-9', 'Var', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))
5785	28566890	In addition, CA19-9 >= 300 was analyzed as an independent risk factor for DFS and OS in multivariate analysis including the effect of bilirubin >= 3.	('bilirubin', 'Chemical', 'MESH:D001663', (134, 143))	('DFS', 'Disease', (74, 77))	('CA19-9', 'Var', (13, 19))
5814	28445951	The number of PD-L1 positive inflammatory cell aggregates was higher in tumors with high PD-1 expression (p < 0.0001).	('PD-L1', 'Protein', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('high', 'Var', (84, 88))	('PD-1', 'Gene', (89, 93))	('PD-1', 'Gene', '5133', (89, 93))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('higher', 'PosReg', (62, 68))	('expression', 'MPA', (94, 104))
5840	28445951	Adjacent non tumoral liver fibrosis could be analyzed in all but one case and was graded as follows: F0-F1 in 45% (n = 44), F2-F3 in 47% (n = 46) and F4 in 8% (n = 8) of cases.	('liver fibrosis', 'Phenotype', 'HP:0001395', (21, 35))	('tumoral liver fibrosis', 'Disease', 'MESH:D008103', (13, 35))	('tumoral liver fibrosis', 'Disease', (13, 35))	('tumoral liver fibrosis', 'Phenotype', 'HP:0002612', (13, 35))	('F0-F1', 'Var', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('F2-F3', 'Var', (124, 129))
5844	28445951	An almost significant relationship with poor differentiation and high PD-1 expression was observed (p = 0.06 and 0.05, respectively) (Table 2 and Figure 1).	('poor differentiation', 'CPA', (40, 60))	('high', 'Var', (65, 69))	('PD-1', 'Gene', (70, 74))	('PD-1', 'Gene', '5133', (70, 74))	('expression', 'MPA', (75, 85))
5846	28445951	The number of PD-L1 positive aggregates of inflammatory cells was also higher in tumors with high PD-1 expression (p < 0.0001) (Figure 2).	('PD-L1', 'Protein', (14, 19))	('higher', 'PosReg', (71, 77))	('PD-1', 'Gene', (98, 102))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('PD-1', 'Gene', '5133', (98, 102))	('expression', 'MPA', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('high', 'Var', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
5855	28445951	showed that clinical trials using a 5% positivity cut-off for PD-L1 expression in tumor cells correlated with objective response, but the relationship was lost when a 1% positivity cut-off was used.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('objective response', 'CPA', (110, 128))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('positivity', 'Var', (39, 49))	('PD-L1', 'Gene', (62, 67))	('tumor', 'Disease', (82, 87))
5872	28445951	Tumors with less than 10 HPFs comprising at least 100 CD3+ TILs were scored "low" and those with 10 or more were scored "high" for intratumoral lymphocytic infiltration density.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD3+ TILs', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
5884	24968753	The aim of this study was to demonstrate the role of fused-in-glioblastoma-c-ros-oncogene1 (FIG-ROS) fusion gene in ICC.	('fusion', 'Var', (101, 107))	('fused-in-glioblastoma', 'Gene', '57120', (53, 74))	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('ROS', 'Chemical', '-', (96, 99))	('fused-in-glioblastoma', 'Gene', (53, 74))	('ICC', 'Disease', (116, 119))	('FIG-ROS', 'Gene', (92, 99))	('c-ros-oncogene1', 'Gene', (75, 90))	('c-ros-oncogene1', 'Gene', '6098', (75, 90))
5888	24968753	Moreover, the co-inhibition of ROS- and FIG-specific shRNA exhibited stronger effects on HUCCT1 cell proliferation, apoptosis, colony formation, cell cycle progression, migration and invasion, when compared to single inhibition of ROS and FIG.	('HUCCT1 cell proliferation', 'CPA', (89, 114))	('shRNA', 'Gene', (53, 58))	('ROS', 'Chemical', '-', (31, 34))	('apoptosis', 'CPA', (116, 125))	('migration', 'CPA', (169, 178))	('stronger effects', 'PosReg', (69, 85))	('cell cycle progression', 'CPA', (145, 167))	('ROS', 'Chemical', '-', (231, 234))	('colony formation', 'CPA', (127, 143))	('HUCCT1', 'CellLine', 'CVCL:0324', (89, 95))	('co-inhibition', 'Var', (14, 27))	('invasion', 'CPA', (183, 191))
5898	24968753	In various types of cancer, dysregulated RTK activation was found in the process of initiation and progression.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('RTK', 'Protein', (41, 44))	('dysregulated', 'Var', (28, 40))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('activation', 'PosReg', (45, 55))
5957	24968753	2B, the expression of FIG protein was significantly downregulated in HUCCT1 cells transfected with plasmids expressing FIG-363, FIG-475, and FIG-504 shRNAs, respectively, compared to the control HUCCT1 cells without any transfection.	('FIG-363', 'Var', (119, 126))	('HUCCT1', 'CellLine', 'CVCL:0324', (69, 75))	('FIG-475', 'Var', (128, 135))	('downregulated', 'NegReg', (52, 65))	('HUCCT1', 'CellLine', 'CVCL:0324', (195, 201))	('FIG-504', 'Var', (141, 148))	('expression', 'MPA', (8, 18))	('FIG protein', 'Protein', (22, 33))
5962	24968753	Moreover, our findings showed that co-downregulation of ROS and FIG had an improved inhibitory effect on HUCCT1 cell proliferation, compared to the single downregulation of ROS (Fig.	('improved', 'PosReg', (75, 83))	('FIG', 'Gene', (64, 67))	('inhibitory effect', 'MPA', (84, 101))	('HUCCT1 cell proliferation', 'CPA', (105, 130))	('ROS', 'Chemical', '-', (56, 59))	('HUCCT1', 'CellLine', 'CVCL:0324', (105, 111))	('ROS', 'Chemical', '-', (173, 176))	('ROS', 'Gene', (56, 59))	('co-downregulation', 'Var', (35, 52))
5965	24968753	However, single downregulation of ROS or co-inhibition of ROS and FIG induced HUCCT1 cell apoptosis.	('downregulation', 'NegReg', (16, 30))	('ROS', 'Chemical', '-', (58, 61))	('ROS', 'Chemical', '-', (34, 37))	('ROS', 'Protein', (34, 37))	('ROS', 'Gene', (58, 61))	('HUCCT1', 'CellLine', 'CVCL:0324', (78, 84))	('co-inhibition', 'Var', (41, 54))	('HUCCT1 cell apoptosis', 'CPA', (78, 99))
5970	24968753	By contrast, HUCCT1 cells transfected with ROS1-6290 shRNA plasmid or co-transfected with ROS1-6290 and FIG-363 shRNA plasmids showed a different cell cycle distribution compared to the control group, indicating that the inhibition of ROS or ROS-FIG suppressed HUCCT1 cell proliferation partially at least by inducing an abnormal cell cycle progression (Fig.	('suppressed', 'NegReg', (250, 260))	('ROS-FIG', 'Gene', (242, 249))	('inhibition', 'Var', (221, 231))	('ROS1', 'Gene', (43, 47))	('ROS', 'Gene', (235, 238))	('ROS1', 'Gene', '6098', (43, 47))	('cell cycle progression', 'CPA', (330, 352))	('inducing', 'Reg', (309, 317))	('ROS', 'Chemical', '-', (235, 238))	('ROS', 'Chemical', '-', (90, 93))	('ROS', 'Chemical', '-', (242, 245))	('ROS1', 'Gene', (90, 94))	('HUCCT1', 'CellLine', 'CVCL:0324', (13, 19))	('ROS', 'Chemical', '-', (43, 46))	('ROS1', 'Gene', '6098', (90, 94))	('HUCCT1', 'CellLine', 'CVCL:0324', (261, 267))	('HUCCT1 cell proliferation', 'CPA', (261, 286))
5975	24968753	Single inhibition of ROS or co-inhibition of ROS and FIG notably downregulated HUCCT1 cell migration, while single inhibition of FIG had no effect on cell migration (Fig.	('HUCCT1', 'CellLine', 'CVCL:0324', (79, 85))	('ROS', 'Chemical', '-', (21, 24))	('HUCCT1 cell migration', 'CPA', (79, 100))	('ROS', 'Chemical', '-', (45, 48))	('ROS', 'Protein', (21, 24))	('ROS', 'Protein', (45, 48))	('downregulated', 'NegReg', (65, 78))	('co-inhibition', 'Var', (28, 41))
5984	24968753	ROS fusions were identified originally in glioblastoma and non-small cell lung cancer (NSCLC) to promote their progression.	('NSCLC', 'Disease', (87, 92))	('ROS', 'Chemical', '-', (0, 3))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (59, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (59, 85))	('ROS', 'Gene', (0, 3))	('glioblastoma', 'Disease', (42, 54))	('glioblastoma', 'Disease', 'MESH:D005909', (42, 54))	('non-small cell lung cancer', 'Disease', (59, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('progression', 'MPA', (111, 122))	('fusions', 'Var', (4, 11))	('promote', 'PosReg', (97, 104))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (63, 85))
5987	24968753	Dysregulated ROS1 may occur in different types, including ROS1 gene fusion, overexpression, or mutations.	('ROS1', 'Gene', (13, 17))	('ROS1', 'Gene', '6098', (13, 17))	('ROS1', 'Gene', (58, 62))	('gene fusion', 'Var', (63, 74))	('ROS1', 'Gene', '6098', (58, 62))	('mutations', 'Var', (95, 104))	('occur', 'Reg', (22, 27))	('overexpression', 'PosReg', (76, 90))
5988	24968753	In many cases, the ROS1 pathway was activated by interchromosomal translocation or intrachromosomal deletion, which resulted in N-terminal ROS1 fusion genes.	('resulted in', 'Reg', (116, 127))	('N-terminal', 'MPA', (128, 138))	('interchromosomal translocation', 'Var', (49, 79))	('activated', 'PosReg', (36, 45))	('intrachromosomal deletion', 'Var', (83, 108))	('ROS1', 'Gene', (19, 23))	('ROS1', 'Gene', (139, 143))	('ROS1', 'Gene', '6098', (19, 23))	('ROS1', 'Gene', '6098', (139, 143))
5989	24968753	Increasing evidence has shown that ROS1 fusions as a distinct subgroup within various types of cancer promoted the development of ROS1-directed therapeutic strategies.	('ROS1', 'Gene', (130, 134))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('fusions', 'Var', (40, 47))	('ROS1', 'Gene', '6098', (130, 134))	('cancer', 'Disease', (95, 101))	('ROS1', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ROS1', 'Gene', '6098', (35, 39))
5995	24968753	In malignant gliomas, the demethylation of ROS promoter enhanced the elevated expression of ROS kinase.	('ROS', 'Protein', (92, 95))	('expression', 'MPA', (78, 88))	('malignant gliomas', 'Disease', (3, 20))	('ROS promoter', 'Protein', (43, 55))	('demethylation', 'Var', (26, 39))	('malignant gliomas', 'Disease', 'MESH:D005910', (3, 20))	('enhanced', 'PosReg', (56, 64))	('elevated', 'PosReg', (69, 77))	('ROS', 'Chemical', '-', (43, 46))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))	('ROS', 'Chemical', '-', (92, 95))
5999	24968753	Thus, specific ROS inhibitors, such as crizotinib and foretinib, may provide approaches for the treatment of patients with liver cancer harboring ROS fusions.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('crizotinib', 'Chemical', 'MESH:D000077547', (39, 49))	('liver cancer', 'Disease', 'MESH:D006528', (123, 135))	('patients', 'Species', '9606', (109, 117))	('liver cancer', 'Disease', (123, 135))	('fusions', 'Var', (150, 157))	('ROS', 'Chemical', '-', (146, 149))	('foretinib', 'Chemical', 'MESH:C544831', (54, 63))	('ROS', 'Chemical', '-', (15, 18))	('liver cancer', 'Phenotype', 'HP:0002896', (123, 135))
6016	24968753	Aberrant ROS1 kinase activity resulted in the activated downstream signaling of several oncogenic pathways, including AKT/mTOR, RAS-MAPK/ERK, and Src-homology 2 domain-containing phosphatase (SHP)-1 and -2 pathways.	('ROS1', 'Gene', '6098', (9, 13))	('activated', 'PosReg', (46, 55))	('AKT', 'Gene', '207', (118, 121))	('Aberrant', 'Var', (0, 8))	('AKT', 'Gene', (118, 121))	('downstream signaling', 'MPA', (56, 76))	('activity', 'MPA', (21, 29))	('ERK', 'Gene', '5594', (137, 140))	('ERK', 'Gene', (137, 140))	('mTOR', 'Gene', (122, 126))	('mTOR', 'Gene', '2475', (122, 126))	('Src-homology 2 domain-containing phosphatase (SHP)-1 and -2', 'Gene', '5777;5781', (146, 205))	('ROS1', 'Gene', (9, 13))	('oncogenic pathways', 'Pathway', (88, 106))
6054	20395200	The gene expression compendium of HCC (HCCcomp) was constructed by collecting six different data sets including data from LEC (i.e., data from Laboratory of Experimental Carcinogenesis, National Cancer Institute, GSE1898 and GSE4024), GSE5975, E-TABM-36, GSE9843, SNU (data from Seoul National University, GSE15765), and a new platform data for formalin-fixed, paraffin-embedded (FFPE) tumors (GSE10186).	('GSE9843', 'Chemical', '-', (255, 262))	('Cancer', 'Disease', (195, 201))	('formalin', 'Chemical', 'MESH:D005557', (345, 353))	('GSE4024', 'Var', (225, 232))	('Carcinogenesis', 'Disease', 'MESH:D063646', (170, 184))	('Carcinogenesis', 'Disease', (170, 184))	('GSE1898', 'Chemical', '-', (213, 220))	('Cancer', 'Disease', 'MESH:D009369', (195, 201))	('paraffin', 'Chemical', 'MESH:D010232', (361, 369))	('GSE5975', 'Chemical', '-', (235, 242))	('tumors', 'Disease', 'MESH:D009369', (386, 392))	('HCC', 'Phenotype', 'HP:0001402', (39, 42))	('tumors', 'Phenotype', 'HP:0002664', (386, 392))	('CC', 'Phenotype', 'HP:0030153', (35, 37))	('tumor', 'Phenotype', 'HP:0002664', (386, 391))	('rat', 'Species', '10116', (147, 150))	('tumors', 'Disease', (386, 392))	('GSE4024', 'Chemical', '-', (225, 232))	('GSE1898', 'Var', (213, 220))	('Cancer', 'Phenotype', 'HP:0002664', (195, 201))	('CC', 'Phenotype', 'HP:0030153', (40, 42))	('GSE10186', 'Var', (394, 402))	('HCC', 'Phenotype', 'HP:0001402', (34, 37))
6076	20395200	Supervised clustering of the tumors with these genes revealed that a fraction of HCC (14 out of 70) was clustered together with CC samples.	('genes', 'Var', (47, 52))	('CC', 'Phenotype', 'HP:0030153', (128, 130))	('HCC', 'Disease', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('HCC', 'Phenotype', 'HP:0001402', (81, 84))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('CC', 'Phenotype', 'HP:0030153', (82, 84))	('tumors', 'Disease', (29, 35))
6085	20395200	In addition, univariate and multivariate analyses in the validation data set (n=139, Table 1) and test data set (n=70, Supplementary Table S4) also demonstrated that the C1-C2 classification is significant in predicting RFS as well as OS.	('rat', 'Species', '10116', (155, 158))	('RFS', 'Disease', (220, 223))	('C1-C2', 'Var', (170, 175))
6106	20395200	When we re-classified the 209 tumors (LEC and SNU) which survival data are available into four classes based on the expression of CC and ES signatures (i.e., CC+ES+, CC+ES-, CC-ES+, and CC-ES-), the CC+ES+ tumors showed the worst prognosis for both RFS (hazard ratio, HR=2.84; 95% CI =1.51-5.34; P=7.42 x 10-4) and OS (HR=2.98; 95% CI=1.79-4.98; P=1.2 x 10-5) compared with the CC-ES- showing the best prognosis (Fig.	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('CC', 'Phenotype', 'HP:0030153', (166, 168))	('ES', 'Chemical', '-', (381, 383))	('rat', 'Species', '10116', (261, 264))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('CC', 'Phenotype', 'HP:0030153', (186, 188))	('tumors', 'Disease', (206, 212))	('ES', 'Chemical', '-', (189, 191))	('CC', 'Phenotype', 'HP:0030153', (130, 132))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumors', 'Disease', (30, 36))	('ES', 'Chemical', '-', (202, 204))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('ES', 'Chemical', '-', (169, 171))	('ES', 'Chemical', '-', (177, 179))	('RFS', 'Disease', (249, 252))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('ES', 'Chemical', '-', (137, 139))	('ES', 'Chemical', '-', (161, 163))	('CC', 'Phenotype', 'HP:0030153', (174, 176))	('CC', 'Phenotype', 'HP:0030153', (158, 160))	('CC+ES+', 'Var', (199, 205))
6119	20395200	The association of TP53 mutation with poor prognosis is well known in many cancer types (reviewed in 31).	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('mutation', 'Var', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
6295	30898798	The crude analysis using simple logistic regression found the variable with the strongest association to BDD to be PDF3 compared with non-PDF (OR=6.35, 95% CI 5.40 to 7.46, p<0.001).	('PDF3', 'Var', (115, 119))	('to 7', 'Species', '1214577', (164, 168))	('BDD', 'Chemical', '-', (105, 108))	('BDD', 'Disease', (105, 108))	('PDF', 'Chemical', '-', (138, 141))	('BDD', 'Phenotype', 'HP:0006560', (105, 108))	('PDF', 'Chemical', '-', (115, 118))
6411	28683174	In a cellular model of HCV, NS3/4A (HCV viral protease) and NS5B (RNA-dependent RNA polymerase) impeded DNA repair via interaction with the ATM-driven response pathway.	('interaction', 'Interaction', (119, 130))	('ATM-driven response pathway', 'Pathway', (140, 167))	('HCV', 'Species', '11103', (36, 39))	('impeded', 'NegReg', (96, 103))	('NS5B', 'Var', (60, 64))	('DNA repair', 'MPA', (104, 114))	('NS3/4A', 'Var', (28, 34))	('HCV', 'Species', '11103', (23, 26))
6412	28683174	Selected genotypes of HCV also might be associated with risk of development of HCC: greater carcinogenic potential has been reported for some variants, mostly genotypes 1 [1b] and 3, although definitive studies are lacking.	('carcinogenic', 'Disease', 'MESH:D063646', (92, 104))	('carcinogenic', 'Disease', (92, 104))	('variants', 'Var', (142, 150))	('HCV', 'Gene', (22, 25))	('HCV', 'Species', '11103', (22, 25))	('HCC', 'Gene', (79, 82))	('HCC', 'Phenotype', 'HP:0001402', (79, 82))	('HCC', 'Gene', '619501', (79, 82))
6414	28683174	Most cases of HCC arise from hepatocytes or liver stem cells in cirrhotic nodules that have accumulated enough mutations to re-enter the cell cycle, reactivate telomerase, and progress through cancer checkpoints.	('mutations', 'Var', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('HCC', 'Gene', (14, 17))	('progress', 'PosReg', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('telomerase', 'Protein', (160, 170))	('HCC', 'Gene', '619501', (14, 17))	('reactivate', 'Reg', (149, 159))	('HCC', 'Phenotype', 'HP:0001402', (14, 17))
6418	28683174	Genetic studies suggest that mutations accumulate in the premalignant stage of HCC and that mutation of the TERT promoter is an early genetic event.	('mutation', 'Var', (92, 100))	('mutations', 'Var', (29, 38))	('HCC', 'Gene', (79, 82))	('TERT', 'Gene', (108, 112))	('TERT', 'Gene', '7015', (108, 112))	('HCC', 'Phenotype', 'HP:0001402', (79, 82))	('HCC', 'Gene', '619501', (79, 82))
6419	28683174	The other genes most commonly mutated in HCC are TP53 and CTNNB1.	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('HCC', 'Gene', (41, 44))	('CTNNB1', 'Gene', (58, 64))	('mutated', 'Var', (30, 37))	('HCC', 'Gene', '619501', (41, 44))	('HCC', 'Phenotype', 'HP:0001402', (41, 44))	('CTNNB1', 'Gene', '1499', (58, 64))
6420	28683174	Recurrent mutations in epigenetic modifier genes ARID1A and ARID2 are also often present.	('ARID2', 'Gene', '196528', (60, 65))	('ARID1A', 'Gene', '8289', (49, 55))	('ARID1A', 'Gene', (49, 55))	('ARID2', 'Gene', (60, 65))	('mutations', 'Var', (10, 19))
6494	28683174	For instance, viral eradication may normalize transaminases, allowing access to chemotherapeutic agents that would otherwise be contraindicated, eliminate the risk of developing HCV reactivation that can lead to discontinuation of chemotherapy, prevent liver disease progression, or the development of HCC or NHL as a secondary cancer, and allow access to multiple clinical trials of cancer chemotherapies (see more details in section Potential benefits of antiviral therapy).	('cancer', 'Disease', (328, 334))	('liver disease', 'Disease', (253, 266))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('HCC', 'Gene', '619501', (302, 305))	('transaminases', 'MPA', (46, 59))	('prevent', 'NegReg', (245, 252))	('normalize', 'Reg', (36, 45))	('HCC', 'Phenotype', 'HP:0001402', (302, 305))	('eliminate', 'NegReg', (145, 154))	('cancer', 'Disease', 'MESH:D009369', (384, 390))	('discontinuation', 'MPA', (212, 227))	('HCC', 'Gene', (302, 305))	('HCV', 'Species', '11103', (178, 181))	('viral', 'Var', (14, 19))	('NHL', 'Disease', (309, 312))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('NHL', 'Phenotype', 'HP:0012539', (309, 312))	('HCV reactivation', 'MPA', (178, 194))	('liver disease', 'Phenotype', 'HP:0001392', (253, 266))	('cancer', 'Disease', (384, 390))	('liver disease', 'Disease', 'MESH:D008107', (253, 266))	('cancer', 'Phenotype', 'HP:0002664', (384, 390))
6500	28683174	Previous studies have established that the prevalence of seronegative HCV infection in HIV-infected patients is as high as 6.9%, but no similar data exist for cancer patients.	('cancer', 'Disease', (159, 165))	('HCV infection', 'Disease', (70, 83))	('HCV infection', 'Disease', 'MESH:D006526', (70, 83))	('HIV-infected', 'Disease', (87, 99))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('patients', 'Species', '9606', (100, 108))	('HIV-infected', 'Disease', 'MESH:D015658', (87, 99))	('seronegative', 'Var', (57, 69))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('patients', 'Species', '9606', (166, 174))
6659	20934397	Ongoing research is determining that regulation of the endocannabinoid system may be effective in the treatment of pain, glaucoma, and neurodegenerative disorders such as Parkinson's disease and multiple sclerosis.	('regulation', 'Var', (37, 47))	('pain', 'Phenotype', 'HP:0012531', (115, 119))	('men', 'Species', '9606', (107, 110))	('coma', 'Phenotype', 'HP:0001259', (125, 129))	('glaucoma', 'Disease', (121, 129))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (135, 162))	("Parkinson's disease", 'Disease', (171, 190))	('multiple sclerosis', 'Disease', (195, 213))	('pain', 'Disease', (115, 119))	('pain', 'Disease', 'MESH:D010146', (115, 119))	('neurodegenerative disorders', 'Disease', (135, 162))	('multiple sclerosis', 'Disease', 'MESH:D009103', (195, 213))	('glaucoma', 'Disease', 'MESH:D005901', (121, 129))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (135, 162))	('endocannabinoid', 'Chemical', 'MESH:D063388', (55, 70))	("Parkinson's disease", 'Disease', 'MESH:D010300', (171, 190))	('glaucoma', 'Phenotype', 'HP:0000501', (121, 129))
6689	20934397	Modulation of the endocannabinoid system has been suggested as a potential strategy for treating liver fibrosis.	('Modulation', 'Var', (0, 10))	('liver fibrosis', 'Disease', 'MESH:D008103', (97, 111))	('liver fibrosis', 'Phenotype', 'HP:0001395', (97, 111))	('endocannabinoid', 'Chemical', 'MESH:D063388', (18, 33))	('liver fibrosis', 'Disease', (97, 111))
6690	20934397	Inhibition of Cb1 activity has been shown to have antifibrogenic effects in a number of experimental models of fibrosis.	('activity', 'MPA', (18, 26))	('men', 'Species', '9606', (94, 97))	('Cb1', 'Gene', (14, 17))	('fibrosis', 'Disease', 'MESH:D005355', (111, 119))	('Inhibition', 'Var', (0, 10))	('fibrosis', 'Disease', (111, 119))	('antifibrogenic effects', 'CPA', (50, 72))
6729	20934397	Modulation of both cannabinoid receptors by the synthetic cannabinoid WIN 55,212-2 (WIN) induces apoptosis in a hepatocellular carcinoma cell line.	('Modulation', 'Var', (0, 10))	('N', 'Chemical', 'MESH:D009584', (86, 87))	('cannabinoid', 'Chemical', 'MESH:D002186', (58, 69))	('induces', 'Reg', (89, 96))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (112, 136))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (112, 136))	('N', 'Chemical', 'MESH:D009584', (72, 73))	('cannabinoid', 'Chemical', 'MESH:D002186', (19, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('hepatocellular carcinoma', 'Disease', (112, 136))	('apoptosis', 'CPA', (97, 106))
6733	20934397	Taken together, these data suggest that cannabinoid receptor expression may be useful as prognostic markers for hepatocellular carcinoma, and that the modulation of cannabinoid receptor activity may be an important therapeutic target for the treatment of hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (255, 279))	('modulation', 'Var', (151, 161))	('hepatocellular carcinoma', 'Disease', (255, 279))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (255, 279))	('men', 'Species', '9606', (247, 250))	('cannabinoid', 'Chemical', 'MESH:D002186', (165, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (112, 136))	('cannabinoid', 'Chemical', 'MESH:D002186', (40, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('hepatocellular carcinoma', 'Disease', (112, 136))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (112, 136))
6750	20934397	Indeed, activation of Notch 1 has been shown to upregulate the expression of Wnt5a in a number of cell models.	('Notch 1', 'Gene', '4851', (22, 29))	('Wnt5a', 'Gene', (77, 82))	('Wnt5a', 'Gene', '7474', (77, 82))	('expression', 'MPA', (63, 73))	('Notch 1', 'Gene', (22, 29))	('activation', 'Var', (8, 18))	('upregulate', 'PosReg', (48, 58))
6752	20934397	Modulation of endocannabinoid signaling seems to be a promising target for the treatment of not only the type of liver disease in question (eg cholestatic liver diseases) but may also alleviate the symptoms arising from the complications of acute and chronic liver diseases (eg hepatic encephalopathy).	('Modulation', 'Var', (0, 10))	('encephalopathy', 'Phenotype', 'HP:0001298', (286, 300))	('liver disease', 'Phenotype', 'HP:0001392', (259, 272))	('liver diseases', 'Disease', 'MESH:D008107', (155, 169))	('liver disease', 'Disease', (113, 126))	('liver disease', 'Disease', 'MESH:D008107', (259, 272))	('liver diseases', 'Disease', (259, 273))	('alleviate', 'NegReg', (184, 193))	('liver disease', 'Phenotype', 'HP:0001392', (155, 168))	('cholestatic liver diseases', 'Phenotype', 'HP:0002611', (143, 169))	('cholestatic liver diseases', 'Disease', (143, 169))	('endocannabinoid', 'Chemical', 'MESH:D063388', (14, 29))	('liver disease', 'Disease', 'MESH:D008107', (155, 168))	('cholestatic liver diseases', 'Disease', 'MESH:D008107', (143, 169))	('liver diseases', 'Phenotype', 'HP:0001392', (259, 273))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (278, 300))	('hepatic encephalopathy', 'Disease', (278, 300))	('liver disease', 'Phenotype', 'HP:0001392', (113, 126))	('liver disease', 'Disease', 'MESH:D008107', (113, 126))	('cholestatic liver disease', 'Phenotype', 'HP:0002611', (143, 168))	('men', 'Species', '9606', (84, 87))	('liver diseases', 'Phenotype', 'HP:0001392', (155, 169))	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (278, 300))	('liver diseases', 'Disease', 'MESH:D008107', (259, 273))	('symptoms', 'MPA', (198, 206))
6764	33688345	Moreover, elevated levels of CA19-9 can also be found in patients with benign diseases and affected by jaundice and biliary tract inflammation.	('CA19-9', 'Var', (29, 35))	('affected', 'Reg', (91, 99))	('elevated', 'PosReg', (10, 18))	('elevated levels of CA19-', 'Phenotype', 'HP:0031030', (10, 34))	('inflammation', 'Disease', 'MESH:D007249', (130, 142))	('levels', 'MPA', (19, 25))	('jaundice', 'Disease', 'MESH:D007565', (103, 111))	('benign diseases', 'Disease', (71, 86))	('inflammation', 'Disease', (130, 142))	('benign diseases', 'Disease', 'MESH:D009369', (71, 86))	('jaundice', 'Disease', (103, 111))	('jaundice', 'Phenotype', 'HP:0000952', (103, 111))
6773	32252311	ROS amount was partly lowered by the combination in Mz-ChA-1 cells, while increased in H69 cells.	('lowered', 'NegReg', (22, 29))	('Mz-ChA-1', 'Chemical', '-', (52, 60))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('ROS amount', 'MPA', (0, 10))	('increased', 'PosReg', (74, 83))	('combination', 'Var', (37, 48))
6803	32252311	In support, modulators of cell cycle checkpoints, alone or in combination with standard anticancer drugs, have been proposed as possible new strategies against cancer.	('modulators', 'Var', (12, 22))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
6826	32252311	Intracellular ROS proportionally reduced DCFH-DA to the fluorophore DCF, whose fluorescence was measured at an excitation wavelength of 485 nm and emission wavelength of 528 nm by a BD Accuri  C6 flow cytometer (BD Biosciences, Milan, Italy).	('DCF', 'Chemical', 'MESH:D015649', (41, 44))	('ROS', 'Var', (14, 17))	('ROS', 'Chemical', 'MESH:D017382', (14, 17))	('DCFH-DA', 'Chemical', 'MESH:C029569', (41, 48))	('reduced', 'NegReg', (33, 40))	('DCF', 'Chemical', 'MESH:D015649', (68, 71))
6860	32252311	The concentration-response curves were obtained by nonlinear regression, using the "Hill equation": E = Emax/ [1 + (10LogEC50/A)HillSlope], where E is the effect at a given concentration of the substance, Emax is the maximum activity, IC50 is the concentration that produces a 50% of the inhibitory response, A is the substance concentration, HillSlope is the curve slope.	('mum', 'Gene', '56925', (221, 224))	('mum', 'Gene', (221, 224))	('inhibitory response', 'MPA', (288, 307))	('IC50', 'Var', (235, 239))
6873	32252311	Applying the metronomic schedule, wherein the anticancer drug was administered as a short and/or double repeated treatment of 2 h followed by an extended cell recovery time, doxorubicin showed a cytotoxic profile in Mz-ChA-1 cells similar to that found after 24 h exposure (Figure 3B).	('cytotoxic', 'MPA', (195, 204))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('doxorubicin', 'Chemical', 'MESH:D004317', (174, 185))	('Mz-ChA-1', 'Chemical', '-', (216, 224))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('doxorubicin', 'Var', (174, 185))
6949	32252311	Likewise, the anticancer drug enhanced by almost 6 and 10-fold the basal expression of phospho(Tyr705)-STAT3 in H69 cholangiocytes after 2 h and 24 h, respectively (Figure 12B).	('enhanced', 'PosReg', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('expression', 'MPA', (73, 83))	('phospho', 'Var', (87, 94))	('Tyr705', 'Chemical', '-', (95, 101))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
6959	32252311	Under our experimental conditions, the cytotoxic effect of doxorubicin was slightly increased by beta-caryophyllene, although no statistical difference was found in the IC50 values (48.4, C.L.	('cytotoxic effect', 'CPA', (39, 55))	('doxorubicin', 'Chemical', 'MESH:D004317', (59, 70))	('increased', 'PosReg', (84, 93))	('beta-caryophyllene', 'Chemical', 'MESH:C024714', (97, 115))	('beta-caryophyllene', 'Var', (97, 115))
6976	32252311	In regard to the mechanisms of action, doxorubicin is known to possess a powerful cancer-killing potential, mediated by multiple cytotoxic mechanisms, involving increased intracellular oxidative stress, inhibition of topoisomerase IIalpha, DNA-damage and blocking of cancer cell growth, which in turn lead to destruction of cell structures and cell death.	('DNA-damage', 'MPA', (240, 250))	('destruction of cell structures', 'CPA', (309, 339))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('doxorubicin', 'Chemical', 'MESH:D004317', (39, 50))	('oxidative stress', 'Phenotype', 'HP:0025464', (185, 201))	('topoisomerase IIalpha', 'Enzyme', (217, 238))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('increased', 'PosReg', (161, 170))	('doxorubicin', 'Var', (39, 50))	('inhibition', 'NegReg', (203, 213))	('cell death', 'CPA', (344, 354))	('intracellular oxidative stress', 'MPA', (171, 201))
6997	32252311	The increased ROS levels by doxorubicin are also associated with DNA-damage, although other genotoxic mechanisms, such as a direct DNA-intercalation through the planar aromatic aglycone and a topoisomerase IIalpha inhibition, which result in the accumulation of double-strand DNA breaks, have been reported.	('topoisomerase IIalpha', 'Enzyme', (192, 213))	('doxorubicin', 'Var', (28, 39))	('ROS levels', 'MPA', (14, 24))	('inhibition', 'NegReg', (214, 224))	('ROS', 'Chemical', 'MESH:D017382', (14, 17))	('accumulation', 'PosReg', (246, 258))	('DNA-damage', 'Disease', (65, 75))	('doxorubicin', 'Chemical', 'MESH:D004317', (28, 39))	('double-strand DNA breaks', 'MPA', (262, 286))	('increased', 'PosReg', (4, 13))	('increased ROS levels', 'Phenotype', 'HP:0025464', (4, 24))
6998	32252311	Double-strand DNA breaks by doxorubicin are usually correlated with a G2-phase cell cycle block, while a S-phase accumulation is associated to DNA adducts.	('G2-phase cell cycle block', 'CPA', (70, 95))	('correlated', 'Reg', (52, 62))	('doxorubicin', 'Chemical', 'MESH:D004317', (28, 39))	('Double-strand', 'Var', (0, 13))
7003	32252311	Furthermore, in both cell lines, along with a cell cycle arrest in S-phase induced by doxorubicin, beta-caryophyllene significantly increased the cell percentage in G2/M phase: this point was of particular interest in H69 cholangiocytes, wherein this phase was almost lacking (Figure 14A,B).	('cell cycle arrest', 'Phenotype', 'HP:0011018', (46, 63))	('cell percentage in G2/M phase', 'CPA', (146, 175))	('beta-caryophyllene', 'Var', (99, 117))	('beta-caryophyllene', 'Chemical', 'MESH:C024714', (99, 117))	('arrest', 'Disease', 'MESH:D006323', (57, 63))	('increased', 'PosReg', (132, 141))	('doxorubicin', 'Chemical', 'MESH:D004317', (86, 97))	('arrest', 'Disease', (57, 63))
7007	32252311	Phosphorylation of H2AX at the serine residue (S139) represents one of the earliest events upon DNA double-strand breaks and is involved in DDR induction, delayed cell cycle progression and DNA repair, thus leading to cells recovering or death if damage is unrepairable.	('DDR', 'Chemical', '-', (140, 143))	('leading to', 'Reg', (207, 217))	('S139', 'Var', (47, 51))	('H2AX', 'Gene', '3014', (19, 23))	('serine', 'Chemical', 'MESH:D012694', (31, 37))	('cell cycle progression', 'CPA', (163, 185))	('Phosphorylation', 'MPA', (0, 15))	('H2AX', 'Gene', (19, 23))	('cells recovering', 'CPA', (218, 234))	('DDR', 'Disease', (140, 143))	('involved', 'Reg', (128, 136))
7008	32252311	In line with this evidence, the stimulation by beta-caryophyllene of G2/M checkpoint in response to the increased gamma-H2AX by doxorubicin can be considered as a cytoprotective mechanism aimed at blocking cell cycle and repairing DNA-damage.	('stimulation', 'PosReg', (32, 43))	('gamma-H2AX', 'Var', (114, 124))	('beta-caryophyllene', 'Chemical', 'MESH:C024714', (47, 65))	('G2/M', 'Gene', (69, 73))	('cell cycle', 'CPA', (206, 216))	('blocking', 'NegReg', (197, 205))	('gamma-H2AX', 'Chemical', '-', (114, 124))	('doxorubicin', 'Chemical', 'MESH:D004317', (128, 139))
7018	32252311	In numerous malignancies, apoptosis has been found downregulated by STAT3, a latent cytosolic transcription factor, activated by phosphorylation at tyrosine 705 (Tyr705) or serine 727 (Ser727) in response to different endogenous and exogenous stimuli and aberrantly phosphorylated in cancer cells, likely to facilitate their transformation.	('apoptosis', 'CPA', (26, 35))	('tyrosine', 'Chemical', 'MESH:D014443', (148, 156))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('activated', 'PosReg', (116, 125))	('Tyr705', 'Var', (162, 168))	('cancer', 'Disease', (284, 290))	('phosphorylation', 'Var', (129, 144))	('Ser727', 'Var', (185, 191))	('serine', 'Chemical', 'MESH:D012694', (173, 179))	('Ser727', 'Chemical', '-', (185, 191))	('serine 727 (Ser727', 'Var', (173, 191))	('downregulated', 'NegReg', (51, 64))	('Tyr705', 'Chemical', '-', (162, 168))	('malignancies', 'Disease', 'MESH:D009369', (12, 24))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('facilitate', 'PosReg', (308, 318))	('malignancies', 'Disease', (12, 24))	('STAT3', 'Gene', (68, 73))
7022	32252311	Accordingly, under our experimental conditions, we found that phosphorylation of STAT3 at tyrosine 705 was promoted by doxorubicin in both cancer and noncancerous cells, being markedly overexpressed in Mz-ChA-1 cells (about a 10-fold higher expression with respect H69 cholangiocytes), whereas the combination with beta-caryophyllene hindered its activation especially in H69 cells, achieving the normal expression in the control (Figure 14A,B).	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('overexpressed', 'PosReg', (185, 198))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('beta-caryophyllene', 'Chemical', 'MESH:C024714', (315, 333))	('cancer', 'Disease', (153, 159))	('tyrosine', 'Chemical', 'MESH:D014443', (90, 98))	('doxorubicin', 'Var', (119, 130))	('phosphorylation', 'MPA', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('expression', 'MPA', (241, 251))	('doxorubicin', 'Chemical', 'MESH:D004317', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('STAT3', 'Gene', (81, 86))	('Mz-ChA-1', 'Chemical', '-', (202, 210))	('higher', 'PosReg', (234, 240))	('promoted', 'PosReg', (107, 115))	('cancer', 'Disease', (139, 145))
7057	30305026	It has been shown that noncoding RNAs could serve as ideal diagnostic biomarkers and potential therapeutic targets for cancers.	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('noncoding', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('RNAs', 'Protein', (33, 37))
7095	30305026	Subsequently, using the discriminant analysis, we revealed the optimal combination of H19, C3P1, AC005550.3, PVT1, and LPAL2 to distinguish the CCA tissue from the normal ones.	('H19', 'Gene', '283120', (86, 89))	('PVT1', 'Gene', '5820', (109, 113))	('H19', 'Gene', (86, 89))	('LPAL2', 'Gene', '80350', (119, 124))	('AC005550.3', 'Var', (97, 107))	('CCA', 'Phenotype', 'HP:0030153', (144, 147))	('C3P1', 'Gene', (91, 95))	('C3P1', 'Gene', '388503', (91, 95))	('LPAL2', 'Gene', (119, 124))	('CCA', 'Disease', (144, 147))	('PVT1', 'Gene', (109, 113))
7108	30305026	TLR3 is pivotal gene in the Toll-like receptor signaling pathway that controls the activation of inflammatory pathways, and another gene KLKB1 encodes a serine protease named kallikrein, which induces inflammatory reactions by producing pro-inflammatory peptides.	('TLR3', 'Gene', (0, 4))	('TLR3', 'Gene', '7098', (0, 4))	('kallikrein', 'Gene', '9622', (175, 185))	('kallikrein', 'Gene', (175, 185))	('gene', 'Var', (132, 136))	('KLKB1', 'Gene', '3818', (137, 142))	('induces', 'Reg', (193, 200))	('KLKB1', 'Gene', (137, 142))	('inflammatory', 'MPA', (201, 213))
7109	30305026	We found that two lncRNAs, XLOC_003821 and NR_033900, were located near the respective gene locus of TLR3 and KLKB1, suggesting that they might share similar functions.	('XLOC_003821', 'Var', (27, 38))	('NR_033900', 'Var', (43, 52))	('TLR3', 'Gene', (101, 105))	('KLKB1', 'Gene', (110, 115))	('TLR3', 'Gene', '7098', (101, 105))	('KLKB1', 'Gene', '3818', (110, 115))
7122	30305026	The IL6 levels displayed a considerable change upon knockdown of APOC1P1, LPAL2, and PVT1, indicating that these lncRNAs could affect the CAA progression by regulating IL6 level (Fig.5b and Additional file 12: Figure S6d).	('IL6', 'Gene', '3569', (168, 171))	('LPAL2', 'Gene', '80350', (74, 79))	('change', 'Reg', (40, 46))	('LPAL2', 'Gene', (74, 79))	('PVT1', 'Gene', (85, 89))	('CAA progression', 'CPA', (138, 153))	('APOC1P1', 'Gene', (65, 72))	('APOC1P1', 'Gene', '342', (65, 72))	('IL6', 'Gene', (4, 7))	('IL6', 'Gene', (168, 171))	('IL6', 'Gene', '3569', (4, 7))	('regulating', 'Reg', (157, 167))	('PVT1', 'Gene', '5820', (85, 89))	('knockdown', 'Var', (52, 61))	('affect', 'Reg', (127, 133))
7124	30305026	We designed and synthetized two siRNAs to knock down these selected lncRNAs APOC1P1 and LPAL2, respectively.	('LPAL2', 'Gene', '80350', (88, 93))	('LPAL2', 'Gene', (88, 93))	('APOC1P1', 'Gene', (76, 83))	('APOC1P1', 'Gene', '342', (76, 83))	('knock', 'Var', (42, 47))
7125	30305026	6b, knocking down APOC1P1 and LPAL2 could significantly enhanced the ability of migration in RBE cells.	('knocking down', 'Var', (4, 17))	('LPAL2', 'Gene', '80350', (30, 35))	('LPAL2', 'Gene', (30, 35))	('APOC1P1', 'Gene', (18, 25))	('APOC1P1', 'Gene', '342', (18, 25))	('enhanced', 'PosReg', (56, 64))
7129	30305026	On the other hand, when knocking down the PVT1, a lncRNA with a higher expression level in CCA (Fig.	('knocking down', 'Var', (24, 37))	('higher', 'PosReg', (64, 70))	('PVT1', 'Gene', (42, 46))	('expression level', 'MPA', (71, 87))	('CCA', 'Phenotype', 'HP:0030153', (91, 94))	('PVT1', 'Gene', '5820', (42, 46))
7152	30305026	However, aberrant epigenetic modifications of certain genomic sites are also major causes of carcinoma genesis, such as the aberrant DNA methylation level of chr13q14.3.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('carcinoma genesis', 'Disease', (93, 110))	('carcinoma genesis', 'Disease', 'MESH:D002277', (93, 110))	('aberrant epigenetic modifications', 'Var', (9, 42))	('aberrant', 'Var', (124, 132))	('causes', 'Reg', (83, 89))	('DNA methylation level', 'MPA', (133, 154))
7153	30305026	in chronic lymphocytic leukemia and the abnormal H3K79 histone methylation in chr7p15.2 in MLL-rearranged leukemia, and the observation that these lncRNAs act in cis in genome sites with inflammatory genes and dysregulate lncRNAs might provide new insight for suppressing or activating these genomic locations by imprinting modifications or transcriptional factor binding adjustments in CCA treatment.	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (3, 31))	('CCA', 'Phenotype', 'HP:0030153', (387, 390))	('leukemia', 'Phenotype', 'HP:0001909', (106, 114))	('MLL-rearranged leukemia', 'Disease', 'MESH:D007938', (91, 114))	('chronic lymphocytic leukemia', 'Disease', (3, 31))	('activating', 'PosReg', (275, 285))	('MLL-rearranged leukemia', 'Disease', (91, 114))	('CCA', 'Disease', (387, 390))	('leukemia', 'Phenotype', 'HP:0001909', (23, 31))	('H3K79', 'Var', (49, 54))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (3, 31))
7168	30305026	Based on the expression pattern analysis of the adjacent genes and co-expressed genes of lncRNAs, we identified a set of dysregulated lncRNAs correlated with inflammation, which may play key roles in the pathogenesis of CCA.	('CCA', 'Phenotype', 'HP:0030153', (220, 223))	('dysregulated', 'Var', (121, 133))	('correlated', 'Reg', (142, 152))	('lncRNAs', 'Gene', (134, 141))	('CCA', 'Disease', (220, 223))	('inflammation', 'Disease', 'MESH:D007249', (158, 170))	('inflammation', 'Disease', (158, 170))
7169	30305026	We finally confirmed the optimal combination of H19, C3P1, AC005550.3, PVT1, and LPAL2 to differentiate the CCA tissue from the normal ones, suggesting that specific lncRNAs may have potential for detecting CCA.	('H19', 'Gene', '283120', (48, 51))	('PVT1', 'Gene', (71, 75))	('CCA', 'Disease', (207, 210))	('LPAL2', 'Gene', '80350', (81, 86))	('C3P1', 'Gene', (53, 57))	('H19', 'Gene', (48, 51))	('LPAL2', 'Gene', (81, 86))	('C3P1', 'Gene', '388503', (53, 57))	('PVT1', 'Gene', '5820', (71, 75))	('CCA', 'Phenotype', 'HP:0030153', (108, 111))	('CCA', 'Phenotype', 'HP:0030153', (207, 210))	('CCA', 'Disease', (108, 111))	('AC005550.3', 'Var', (59, 69))
7175	29340115	The particularly high rate of somatic mutation in these tumors correlates with the generation of neo-antigens capable of eliciting an immune response.	('somatic mutation', 'Var', (30, 46))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('neo-antigens', 'MPA', (97, 109))
7176	29340115	Identification of hypermutated tumors is therefore clinically valuable for selecting patients suitable for immunotherapy treatment.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('hypermutated', 'Var', (18, 30))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('patients', 'Species', '9606', (85, 93))
7178	29340115	In gastrointestinal cancers, one of the leading causes of hypermutation is a defect in DNA mismatch repair, which results in microsatellite instability (MSI).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('results in', 'Reg', (114, 124))	('microsatellite instability', 'MPA', (125, 151))	('DNA', 'Gene', (87, 90))	('gastrointestinal cancers', 'Disease', (3, 27))	('defect', 'Var', (77, 83))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (3, 27))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (3, 26))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))
7188	29340115	Recent progress in genomic analysis using next-generation sequencing (NGS) technology has enabled comprehensive detection of mutations and mutation burden in cancer tissues.	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('mutations', 'Var', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
7193	29340115	Ultraviolet (UV) light is the cause of many mutations in melanoma, while tobacco smoke causes the mutations that accumulate in non-small cell lung cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (131, 153))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (127, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cause', 'Reg', (30, 35))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (127, 153))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('mutations', 'Var', (44, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('non-small cell lung cancer', 'Disease', (127, 153))	('tobacco', 'Species', '4097', (73, 80))
7194	29340115	A leading cause of the mutations found in several gastrointestinal cancers, such as colorectal, gastric, and hepato-pancreato-biliary cancer, is dysfunction in the mismatch repair (MMR) system.	('hepato-pancreato-biliary cancer', 'Disease', (109, 140))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('colorectal', 'Disease', (84, 94))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (50, 74))	('gastrointestinal cancers', 'Disease', (50, 74))	('cause', 'Reg', (10, 15))	('gastric', 'Disease', (96, 103))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (50, 73))	('dysfunction', 'Var', (145, 156))	('mutations', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('hepato-pancreato-biliary cancer', 'Disease', 'MESH:D001661', (109, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('colorectal', 'Disease', 'MESH:D015179', (84, 94))
7196	29340115	This highlights the clinical significance of identifying hypermutated tumors for immunotherapy treatment.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('hypermutated', 'Var', (57, 69))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))
7197	29340115	In this article, we review the current understanding of hypermutation and MMR deficiency in gastrointestinal cancer from the perspective of surgical oncology.	('deficiency in gastrointestinal cancer', 'Disease', (78, 115))	('MMR deficiency', 'Disease', (74, 88))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (92, 115))	('MMR deficiency', 'Disease', 'MESH:C536143', (74, 88))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('oncology', 'Phenotype', 'HP:0002664', (149, 157))	('deficiency in gastrointestinal cancer', 'Disease', 'MESH:D004067', (78, 115))	('hypermutation', 'Var', (56, 69))
7199	29340115	Mutations in oncogenes and tumor suppressor genes are the main mechanisms for cancer development.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('Mutations', 'Var', (0, 9))	('oncogenes', 'Gene', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
7201	29340115	Importantly, hypermutated cancer cells are believed to create numerous neo-antigens, which promote infiltration of cytotoxic (CD8+) T-lymphocytes and activated Th1 cells to the tumor microenvironment (Figure 1).	('promote', 'PosReg', (91, 98))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('infiltration', 'CPA', (99, 111))	('hypermutated', 'Var', (13, 25))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('CD', 'Chemical', 'MESH:D002104', (126, 128))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', (177, 182))
7202	29340115	Furthermore, studies have indicated an association between elevated mutation burden and response to checkpoint blockade immunotherapy in certain solid cancers.	('mutation burden', 'Var', (68, 83))	('solid cancers', 'Disease', 'MESH:D009369', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('solid cancers', 'Disease', (145, 158))
7203	29340115	Hypermutation in cancer can be caused by a variety of mechanisms, including exogenous mutagens and endogenous processes.	('caused', 'Reg', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('Hypermutation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
7204	29340115	Exposure to exogenous mutagens, such as UV light in melanoma or tobacco smoke in lung cancer, can cause an accumulation of mutations in affected cells.	('lung cancer', 'Disease', (81, 92))	('cause', 'Reg', (98, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('melanoma', 'Disease', (52, 60))	('tobacco', 'Species', '4097', (64, 71))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('mutations', 'Var', (123, 132))
7208	29340115	In sporadic CRCs, MMR deficiency most commonly occurs through epigenetic inactivation from hypermethylation of the MLH1 gene.	('MMR deficiency', 'Disease', 'MESH:C536143', (18, 32))	('occurs', 'Reg', (47, 53))	('epigenetic inactivation', 'Var', (62, 85))	('CRC', 'Phenotype', 'HP:0003003', (12, 15))	('CRCs', 'Disease', (12, 16))	('hypermethylation', 'Var', (91, 107))	('MLH1', 'Gene', '4292', (115, 119))	('MMR deficiency', 'Disease', (18, 32))	('MLH1', 'Gene', (115, 119))
7209	29340115	A germline mutation inactivating one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) may lead to a hereditary form, termed hereditary non-polyposis colon cancer (HNPCC).	('germline mutation inactivating', 'Var', (2, 32))	('HNPCC', 'Phenotype', 'HP:0006716', (160, 165))	('MLH1', 'Gene', '4292', (55, 59))	('hereditary non-polyposis colon cancer', 'Phenotype', 'HP:0006716', (121, 158))	('PMS2', 'Gene', (77, 81))	('MMR', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('non-polyposis colon cancer', 'Disease', 'MESH:D015179', (132, 158))	('MSH2', 'Gene', (61, 65))	('MSH6', 'Gene', (67, 71))	('MSH6', 'Gene', '2956', (67, 71))	('HNPCC', 'Gene', '4292', (160, 165))	('non-polyposis colon cancer', 'Disease', (132, 158))	('PMS2', 'Gene', '5395', (77, 81))	('MSH2', 'Gene', '4436', (61, 65))	('MLH1', 'Gene', (55, 59))	('lead to', 'Reg', (87, 94))	('colon cancer', 'Phenotype', 'HP:0003003', (146, 158))	('HNPCC', 'Gene', (160, 165))
7211	29340115	The National Cancer Institute (NCI) recommends a microsatellite panel (NCI panel) consisting of two mononucleotide repeats (BAT25 and BAT26) and three dinucleotide repeats (D5S346, D2S123, and D17S250).	('D17S250', 'Var', (193, 200))	('D5S346', 'Var', (173, 179))	('BAT25', 'Var', (124, 129))	('Cancer', 'Disease', (13, 19))	('Cancer', 'Disease', 'MESH:D009369', (13, 19))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mononucleotide', 'Chemical', '-', (100, 114))	('D2S123', 'Var', (181, 187))	('BAT26', 'Var', (134, 139))
7218	29340115	One of the most frequent genetic alterations in CRCs with MSI is the oncogenic BRAF V600E mutation.	('V600E', 'Mutation', 'rs113488022', (84, 89))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('V600E', 'Var', (84, 89))	('BRAF', 'Gene', '673', (79, 83))	('BRAF', 'Gene', (79, 83))
7219	29340115	The TCGA study has also revealed that hypermutated CRCs had fewer APC, KRAS, and TP53 mutations compared with the non-hypermutated CRCs.	('mutations', 'Var', (86, 95))	('CRC', 'Phenotype', 'HP:0003003', (51, 54))	('APC', 'Disease', 'MESH:D011125', (66, 69))	('CRC', 'Phenotype', 'HP:0003003', (131, 134))	('APC', 'Disease', (66, 69))	('hypermutated', 'Var', (38, 50))	('KRAS', 'Gene', (71, 75))	('KRAS', 'Gene', '3845', (71, 75))	('fewer', 'NegReg', (60, 65))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
7220	29340115	In contrast, mutations in transforming growth factor (TGF)-beta signaling genes and BRAF were dramatically elevated in the hypermutated tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('mutations', 'Var', (13, 22))	('elevated', 'PosReg', (107, 115))
7224	29340115	It has been reported that CRCs with MSI-H, especially tumors with BRAF mutations, show increased proliferative activities.	('increased', 'PosReg', (87, 96))	('MSI-H, especially tumors', 'Disease', 'MESH:D009369', (36, 60))	('proliferative activities', 'CPA', (97, 121))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mutations', 'Var', (71, 80))	('BRAF', 'Gene', '673', (66, 70))	('CRC', 'Phenotype', 'HP:0003003', (26, 29))	('BRAF', 'Gene', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
7234	29340115	Recently, it has been reported that CRC patients with MSI showed significantly better progression-free and overall survival than patients without MSI.	('CRC', 'Disease', (36, 39))	('overall survival', 'CPA', (107, 123))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (40, 48))	('MSI', 'Var', (54, 57))	('better', 'PosReg', (79, 85))	('CRC', 'Phenotype', 'HP:0003003', (36, 39))	('progression-free', 'CPA', (86, 102))
7235	29340115	In addition to dysfunction in the MMR system, mutations in DNA polymerase D1 (POLD1) and DNA polymerase E (POLE) genes have been described as another cause of hypermutated CRC.	('CRC', 'Phenotype', 'HP:0003003', (172, 175))	('mutations', 'Var', (46, 55))	('cause', 'Reg', (150, 155))	('POLD1', 'Gene', '5424', (78, 83))	('polymerase D1', 'Gene', '5424', (63, 76))	('POLD1', 'Gene', (78, 83))	('hypermutated CRC', 'Disease', (159, 175))	('polymerase D1', 'Gene', (63, 76))
7237	29340115	CRC with mutations in the exonuclease domain of POLE1 is associated with a high number of mutations, multiple tumor neo-epitopes, and extensive T lymphocyte infiltration.	('CRC', 'Phenotype', 'HP:0003003', (0, 3))	('mutations', 'Var', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('POLE1', 'Gene', '5426', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('POLE1', 'Gene', (48, 53))	('CRC', 'Disease', (0, 3))	('associated', 'Reg', (57, 67))	('mutations in the', 'Var', (9, 25))
7239	29340115	The MSI-H phenotype in gastric cancer is predominantly caused by epigenetic hypermethylation of MLH1 rather than germline mutations in an MMR gene.	('caused by', 'Reg', (55, 64))	('gastric cancer', 'Disease', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('gastric cancer', 'Disease', 'MESH:D013274', (23, 37))	('MSI-H', 'Disease', (4, 9))	('MLH1', 'Gene', '4292', (96, 100))	('MLH1', 'Gene', (96, 100))	('gastric cancer', 'Phenotype', 'HP:0012126', (23, 37))	('MSI-H', 'Disease', 'MESH:D000848', (4, 9))	('epigenetic hypermethylation', 'Var', (65, 92))
7245	29340115	Although reports are inconsistent, MSI in gastric cancer may be considered a favorable prognostic indicator for both early and advanced stages.	('MSI', 'Var', (35, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (42, 56))	('gastric cancer', 'Disease', 'MESH:D013274', (42, 56))	('gastric cancer', 'Disease', (42, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
7248	29340115	However, a more recent study found disease-free survival was improved in the MSI-Low/MSS group treated with 5-FU-based chemotherapy.	('improved', 'PosReg', (61, 69))	('5-FU', 'Chemical', 'MESH:D005472', (108, 112))	('MSS', 'Chemical', '-', (85, 88))	('disease-free survival', 'CPA', (35, 56))	('MSI-Low/MSS', 'Var', (77, 88))
7252	29340115	Indeed, TGFBR2, ACVR2A, SMAD4, and ELF3 are frequently mutated, suggesting an important role in gastric cancer biology.	('TGFBR2', 'Gene', '7048', (8, 14))	('SMAD4', 'Gene', '4089', (24, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('ACVR2A', 'Gene', (16, 22))	('mutated', 'Var', (55, 62))	('ELF3', 'Gene', (35, 39))	('ELF3', 'Gene', '1999', (35, 39))	('TGFBR2', 'Gene', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ACVR2A', 'Gene', '92', (16, 22))	('SMAD4', 'Gene', (24, 29))	('gastric cancer', 'Disease', (96, 110))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))
7273	29340115	The number of single-nucleotide variants in cholangiocarcinoma resected from printing workers exposed to organic solvents was significantly higher than in control common cholangiocarcinoma tissues, with somatic mutations at an average of 44.8/Mb.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (44, 62))	('higher', 'PosReg', (140, 146))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (44, 62))	('cholangiocarcinoma', 'Disease', (170, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('single-nucleotide variants', 'Var', (14, 40))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (170, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (170, 188))	('cholangiocarcinoma', 'Disease', (44, 62))
7287	29340115	This review has outlined how hypermutation may play a pivotal role as a cancer biomarker able to identify cancer subtypes most likely to respond to treatment, and therefore predict the clinical benefit of immunotherapy, especially in advanced cancers where surgery is usually not indicated.	('hypermutation', 'Var', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancers', 'Disease', 'MESH:D009369', (243, 250))	('cancer', 'Disease', (106, 112))	('cancers', 'Disease', (243, 250))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Disease', (72, 78))
7289	29340115	Detection of hypermutation in cancers may not only predict the clinical benefit of immune checkpoint inhibitors, but has the potential to also provide better surgical strategies for the patients with hypermutated tumors.	('tumors', 'Disease', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancers', 'Disease', (30, 37))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('hypermutation', 'Var', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('patients', 'Species', '9606', (186, 194))
7291	29340115	Hypermutated tumors tend to show expansive growth in a localized region and have less metastasis.	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('Hypermutated', 'Var', (0, 12))	('expansive growth', 'CPA', (33, 49))	('metastasis', 'CPA', (86, 96))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
7297	31576243	Furthermore, the co-expressed networks of dysregulated RBPs with transcriptional factors and lncRNAs also require further investigation.	('ncRNA', 'Gene', '220202', (94, 99))	('ncRNA', 'Gene', (94, 99))	('RBP', 'Gene', (55, 58))	('RBP', 'Gene', '57794', (55, 58))	('dysregulated', 'Var', (42, 54))
7308	31576243	Furthermore, dysregulated expression of some RBPs can lead to disease, including neurological disorders and cancers.	('disease', 'Disease', (62, 69))	('expression', 'MPA', (26, 36))	('lead to', 'Reg', (54, 61))	('neurological disorders', 'Disease', 'MESH:D009422', (81, 103))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('RBP', 'Gene', (45, 48))	('RBP', 'Gene', '57794', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('neurological disorders', 'Disease', (81, 103))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('dysregulated', 'Var', (13, 25))	('cancers', 'Disease', (108, 115))
7314	31576243	Silencing RPL34 plays a blocking role in cell proliferation and metastasis, but promoting cell apoptosis of oral squamous cell carcinomas (OSCCs).	('metastasis', 'CPA', (64, 74))	('RPL34', 'Gene', '6164', (10, 15))	('OSCCs', 'Disease', (139, 144))	('OSCCs', 'Disease', 'MESH:D002294', (139, 144))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (113, 137))	('promoting', 'PosReg', (80, 89))	('Silencing', 'Var', (0, 9))	('RPL34', 'Gene', (10, 15))	('cell apoptosis', 'CPA', (90, 104))	('oral squamous cell carcinomas', 'Disease', (108, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (108, 137))
7318	31576243	In addition, the silencing of SRSF7 affects the expression of osteopontin splice variants and decreases the proliferation rate of renal cancer cells.	('renal cancer', 'Disease', (130, 142))	('affects', 'Reg', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('SRSF7', 'Gene', (30, 35))	('renal cancer', 'Phenotype', 'HP:0009726', (130, 142))	('SRSF7', 'Gene', '6432', (30, 35))	('expression', 'MPA', (48, 58))	('renal cancer', 'Disease', 'MESH:D007680', (130, 142))	('decreases', 'NegReg', (94, 103))	('silencing', 'Var', (17, 26))	('osteopontin', 'Gene', '6696', (62, 73))	('osteopontin', 'Gene', (62, 73))
7330	31576243	An accumulating genome-wide association study (GWAS) shows that the mutations of TFs or TF-binding sites are closely related to many human cancers (reviewed in), such as gastric cancer, liver cancer, prostate cancer, colorectal cancer and breast cancer.	('breast cancer', 'Disease', (239, 252))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('prostate cancer', 'Disease', 'MESH:D011471', (200, 215))	('gastric cancer', 'Phenotype', 'HP:0012126', (170, 184))	('cancers', 'Disease', (139, 146))	('prostate cancer', 'Phenotype', 'HP:0012125', (200, 215))	('colorectal cancer', 'Disease', (217, 234))	('liver cancer', 'Disease', 'MESH:D006528', (186, 198))	('related', 'Reg', (117, 124))	('prostate cancer', 'Disease', (200, 215))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('liver cancer', 'Phenotype', 'HP:0002896', (186, 198))	('human', 'Species', '9606', (133, 138))	('liver cancer', 'Disease', (186, 198))	('TFs', 'Gene', (81, 84))	('gastric cancer', 'Disease', (170, 184))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('colorectal cancer', 'Phenotype', 'HP:0003003', (217, 234))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('gastric cancer', 'Disease', 'MESH:D013274', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('mutations', 'Var', (68, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (217, 234))	('breast cancer', 'Disease', 'MESH:D001943', (239, 252))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
7368	31576243	Generally, in the TNM system, 'T' refers to a primary tumor, 'T1 ~ T4' represents the severity of primary cancer according to the increase in tumor volume and the extent of involvement of adjacent tissues, and 'T0' indicates no primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('TNM', 'Disease', 'MESH:D009362', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Disease', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Disease', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('increase', 'PosReg', (130, 138))	('tumor', 'Disease', (54, 59))	("'T1 ~ T4'", 'Var', (61, 70))	('TNM', 'Disease', (18, 21))
7429	31576243	These results suggest that dysregulated RBPs play a key role in the regulation of the development of the CHOL and KICH M-stage, which may provide a new perspective for potential prognostic biomarkers and therapeutic targets for patients with cancers at M stages in two cancer types CHOL and KICH.	('cancers', 'Disease', 'MESH:D009369', (242, 249))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('cancer', 'Disease', (242, 248))	('cancers', 'Disease', (242, 249))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('patients', 'Species', '9606', (228, 236))	('cancer', 'Disease', (269, 275))	('CHOL', 'Phenotype', 'HP:0030153', (282, 286))	('RBP', 'Gene', '57794', (40, 43))	('CHOL', 'Phenotype', 'HP:0030153', (105, 109))	('RBP', 'Gene', (40, 43))	('dysregulated', 'Var', (27, 39))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
7434	31576243	Functional enrichment analyzing demonstrated that cluster 1 and cluster 3 had similar functions and mainly enriched in functional categories involved in gene silencing and negative regulation of translation, such as post transcriptional gene silencing, negative regulation of translation and cellular amide metabolic process, cellular response to dsRNA, miRNA metabolic process.	('negative regulation', 'NegReg', (253, 272))	('translation', 'MPA', (276, 287))	('negative regulation', 'NegReg', (172, 191))	('amide', 'Chemical', 'MESH:D000577', (301, 306))	('miRNA', 'CPA', (354, 359))	('cellular', 'CPA', (326, 334))	('gene silencing', 'Var', (237, 251))	('translation', 'MPA', (195, 206))	('cellular amide metabolic process', 'MPA', (292, 324))	('involved', 'Reg', (141, 149))	('gene silencing', 'Var', (153, 167))
7445	31576243	First, we found the five largest transcription factor families, they are C2H2-ZF, Homeodomain, Nuclear receptor, bHLH and bZIP, and the corresponding proportion is 37%, 17%, 9%, 9% and 9% (Figs.	('C2H2-ZF', 'Var', (73, 80))	('C2H2', 'Chemical', 'MESH:C543495', (73, 77))	('bHLH', 'Gene', (113, 117))
7533	30871788	Specifically, patients with microscopic residual disease (35.1% vs 14.8%) or macroscopic residual disease (2.0% vs 0.8%) were more likely than patients with negative margins to receive AT (p<0.001).	('microscopic', 'Var', (28, 39))	('patients', 'Species', '9606', (143, 151))	('macroscopic', 'Var', (77, 88))	('patients', 'Species', '9606', (14, 22))
7548	30871788	However, when examining the 'high-risk' patient population alone, the Kaplan-Meier curves of those who did or did not receive AT did not intersect, and demonstrated a significant association between improved OS and receipt of AT (p<0.001) (Figure 3).	('patient', 'Species', '9606', (40, 47))	('improved', 'PosReg', (199, 207))	('receipt of AT', 'Var', (215, 228))
7559	30871788	A systematic review and meta-analysis of biliary tract cancers, including ICC, found no significant association between OS and receipt of AT, although the authors did note a survival benefit in patients with node-positive disease or R1 disease who received AT.	('R1 disease', 'Var', (233, 243))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (41, 61))	('patients', 'Species', '9606', (194, 202))	('biliary tract cancers', 'Disease', 'MESH:D001661', (41, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('ICC', 'Disease', (74, 77))	('biliary tract cancers', 'Disease', (41, 62))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))
7566	30871788	However, in per-protocol analysis, adjuvant capecitabine was associated with significantly improved OS compared to observation (53 vs 36 months, HR 0.75, 95% CI 0.58-0.97, p=0.028).	('improved', 'PosReg', (91, 99))	('capecitabine', 'Chemical', 'MESH:D000069287', (44, 56))	('adjuvant', 'Var', (35, 43))	('capecitabine', 'Gene', (44, 56))
7591	30871788	This study of a large nationwide cohort of patients with resected ICC demonstrates that adjuvant therapy is associated with significant improvements in OS in patients with 'high-risk' tumors (positive margins, positive lymph nodes, and clinical stage III or IVa).	('positive', 'Var', (192, 200))	('patients', 'Species', '9606', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('IVa', 'Disease', (258, 261))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('improvements', 'PosReg', (136, 148))	('patients', 'Species', '9606', (158, 166))
7661	25706257	Cilia were once considered vestigial organelles with no physiologically relevant functions, but during the last 20 years it has been observed that mutations in genes required for the assembly and/or responsible for the sensory properties of cilia result in diverse human disorders, now referred as ciliopathies.	('mutations', 'Var', (147, 156))	('Cilia', 'Disease', (0, 5))	('human disorders', 'Disease', (265, 280))	('human', 'Species', '9606', (265, 270))	('Cilia', 'Disease', 'MESH:C536287', (0, 5))	('result in', 'Reg', (247, 256))
7678	25706257	The knockdown of AURA partially induced ciliary restoration.	('AURA', 'Gene', '6790', (17, 21))	('ciliary restoration', 'CPA', (40, 59))	('AURA', 'Gene', (17, 21))	('knockdown', 'Var', (4, 13))	('induced', 'Reg', (32, 39))
7682	25706257	VHL binds and stabilizes microtubules, and its inactivation induces Hef1 and AuroraA by a mechanism involving beta-catenin, leading to activation of HDAC6, once more suggesting an important role of HDAC6 in ciliary loss in tumors of different origins.	('inactivation', 'Var', (47, 59))	('AuroraA', 'Gene', (77, 84))	('induces', 'Reg', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('activation', 'PosReg', (135, 145))	('beta-catenin', 'Gene', (110, 122))	('tumors', 'Disease', (223, 229))	('Hef1', 'Gene', '4739', (68, 72))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('beta-catenin', 'Gene', '1499', (110, 122))	('stabilizes', 'MPA', (14, 24))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('VHL', 'Gene', (0, 3))	('AuroraA', 'Gene', '6790', (77, 84))	('microtubules', 'Protein', (25, 37))	('VHL', 'Gene', '7428', (0, 3))	('Hef1', 'Gene', (68, 72))	('HDAC6', 'Gene', (149, 154))
7686	25706257	The absence of TTLL3, a tubulin glycine ligase, leads to a reduced number of cilia in colon epithelium, increased cell proliferation, and amplification of tumor development in mice.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('reduced', 'NegReg', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('increased', 'PosReg', (104, 113))	('amplification', 'PosReg', (138, 151))	('TTLL3', 'Gene', (15, 20))	('tumor', 'Disease', (155, 160))	('mice', 'Species', '10090', (176, 180))	('absence', 'Var', (4, 11))	('cell proliferation', 'CPA', (114, 132))
7709	25706257	Since the loss of primary cilia induces a malignant-like phenotype in normal cholangiocytes, the restoration of cilia in tumor cells may represent a potential therapeutic approach.	('loss', 'Var', (10, 14))	('primary cilia', 'Protein', (18, 31))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('malignant-like phenotype', 'MPA', (42, 66))	('tumor', 'Disease', (121, 126))	('induces', 'Reg', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
7718	25706257	showed both, in vitro and in vivo that fenoldopam increases ciliary length in vascular endothelial cells, which have been shown to have abnormal sensory functions in PKD.	('fenoldopam', 'Chemical', 'MESH:D018818', (39, 49))	('fenoldopam', 'Var', (39, 49))	('ciliary length in vascular', 'CPA', (60, 86))	('abnormal sensory functions', 'Phenotype', 'HP:0011730', (136, 162))	('increases', 'PosReg', (50, 59))
7798	25685318	There was no significant difference in OS (p = 0.13) or PFS (p = 0.08), however, in regards to RR, it was marginally higher in 5-FU + gemcitabine regimens (median 30.0%) compared with gemcitabine alone regimens (median 17.5%) with p = 0.047.	('5-FU + gemcitabine', 'Var', (127, 145))	('5-FU', 'Chemical', 'MESH:D005472', (127, 131))	('gemcitabine', 'Chemical', 'MESH:C056507', (184, 195))	('higher', 'PosReg', (117, 123))	('gemcitabine', 'Chemical', 'MESH:C056507', (134, 145))
7875	24362053	Hepatobiliary cancers were identified using linked cancer registry data, based on International Classification of Disease for Oncology (ICD-O-3) topography codes C22 (primary liver cancer), C23.9 (gallbladder cancer), and C24 (other biliary tract cancers), with further refinements described in Supplemental Table 1.	('biliary tract cancers', 'Disease', 'MESH:D001661', (233, 254))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (247, 253))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('gallbladder cancer', 'Disease', 'MESH:D005706', (197, 215))	('Hepatobiliary cancers', 'Disease', 'MESH:D004066', (0, 21))	('Oncology', 'Phenotype', 'HP:0002664', (126, 134))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('Hepatobiliary cancers', 'Disease', (0, 21))	('primary liver cancer', 'Disease', (167, 187))	('C23', 'Gene', (190, 193))	('biliary tract cancers', 'Disease', (233, 254))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('C23', 'Gene', '4691', (190, 193))	('cancer', 'Disease', (181, 187))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (233, 253))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('primary liver cancer', 'Disease', 'MESH:D006528', (167, 187))	('cancer', 'Disease', (14, 20))	('liver cancer', 'Phenotype', 'HP:0002896', (175, 187))	('C24', 'Var', (222, 225))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('gallbladder cancer', 'Disease', (197, 215))	('cancer', 'Disease', (209, 215))	('cancer', 'Disease', (51, 57))	('C22', 'Var', (162, 165))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
7887	24362053	Because the dataset included children (ages 2-19 years) and adults (ages >=20 years), BMI was defined as follows (adults, children): underweight (15-18.4 kg/m2, <5th percentile) normal (18.5-24.9 kg/m2, 5th-85th percentile) overweight (25.0-29.9 kg/m2, 85-95th percentile) obese (>=30.0 kg/m2, >=95th percentile).	('obese', 'Disease', 'MESH:D009765', (273, 278))	('children', 'Species', '9606', (29, 37))	('overweight', 'Phenotype', 'HP:0025502', (224, 234))	('15-18.4', 'Var', (146, 153))	('obese', 'Disease', (273, 278))	('children', 'Species', '9606', (122, 130))
7909	24362053	No immunosuppressive medications were associated with HCC (Table 4), but azathioprine was associated with increased cholangiocarcinoma risk (RR,2.0; 95%CI,1.1-3.7) with similar results after adjusting or stratifying by year of transplant (RR,2.1; 95%CI,0.9-4.6; Supplemental Table 3).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (116, 134))	('azathioprine', 'Var', (73, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('HCC', 'Gene', '619501', (54, 57))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))	('azathioprine', 'Chemical', 'MESH:D001379', (73, 85))	('increased cholangiocarcinoma risk', 'Phenotype', 'HP:0001402', (106, 139))	('cholangiocarcinoma', 'Disease', (116, 134))	('HCC', 'Gene', (54, 57))
7960	24362053	Given evidence that azathioprine is hepatotoxic in humans, it seems plausible that azathioprine may increase risk of cholangiocarcinoma in solid organ transplant recipients.	('azathioprine', 'Chemical', 'MESH:D001379', (83, 95))	('hepatotoxic', 'Disease', 'MESH:D056486', (36, 47))	('azathioprine', 'Var', (83, 95))	('increase risk of cholangiocarcinoma', 'Phenotype', 'HP:0001402', (100, 135))	('cholangiocarcinoma', 'Disease', (117, 135))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (117, 135))	('azathioprine', 'Chemical', 'MESH:D001379', (20, 32))	('hepatotoxic', 'Disease', (36, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (117, 135))	('humans', 'Species', '9606', (51, 57))
8048	22700119	The uptake of Gd-EOB-DTPA by functioning hepatocytes in the delayed phase provides additional information that further improves detection and characterisation of many hepatic lesions.	('improves', 'PosReg', (119, 127))	('hepatic lesions', 'Disease', 'MESH:D056486', (167, 182))	('hepatic lesions', 'Disease', (167, 182))	('detection', 'MPA', (128, 137))	('Gd-EOB-DTPA', 'Chemical', '-', (14, 25))	('Gd-EOB-DTPA', 'Var', (14, 25))
8051	22700119	Gd-EOB-DTPA has greater hepatocellular uptake and biliary excretion than Gd-BOTPA and is the focus of this review.	('biliary excretion', 'MPA', (50, 67))	('Gd-BOTPA', 'Chemical', '-', (73, 81))	('hepatocellular uptake', 'MPA', (24, 45))	('greater', 'PosReg', (16, 23))	('Gd-EOB-DTPA', 'Chemical', '-', (0, 11))	('Gd-EOB-DTPA', 'Var', (0, 11))
8053	22700119	Due to the presence of the lipophilic EOB group, Gd-EOB-DTPA is actively transported from the sinusoidal space into hepatocytes via organic anion transporting polypeptides (OATPs).	('Gd-EOB-DTPA', 'Chemical', '-', (49, 60))	('Gd-EOB-DTPA', 'Var', (49, 60))	('OATP', 'Gene', '6579', (173, 177))	('OATP', 'Gene', (173, 177))
8058	22700119	Arterial phase enhancement of vessels and lesions with Gd-EOB-DTPA tends to be less intense than with extracellular agents due to the following factors.	('Arterial phase', 'MPA', (0, 14))	('Gd-EOB-DTPA', 'Var', (55, 66))	('enhancement', 'PosReg', (15, 26))	('Gd-EOB-DTPA', 'Chemical', '-', (55, 66))
8112	22700119	Most of these hyperintense HCCs are well or moderately differentiated, with bile-producing or bile-containing capacity maintained.	('bile-containing', 'MPA', (94, 109))	('HCC', 'Gene', (27, 30))	('HCCs', 'Phenotype', 'HP:0001402', (27, 31))	('hyperintense', 'Var', (14, 26))	('HCC', 'Gene', '619501', (27, 30))	('bile-producing', 'MPA', (76, 90))
8121	22700119	In hepatocellular phase some viable areas of the tumour may show some uptake of Gd-EOB-DTPA.	('Gd-EOB-DTPA', 'Var', (80, 91))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('uptake', 'MPA', (70, 76))	('Gd-EOB-DTPA', 'Chemical', '-', (80, 91))	('tumour', 'Disease', (49, 55))
8152	22700119	Usually no enhancement of hepatic adenoma is seen in the hepatocellular phase because of absent or strongly reduced hepatocellular uptake of Gd-EOB-DTPA (Fig.	('hepatocellular uptake', 'MPA', (116, 137))	('Gd-EOB-DTPA', 'Var', (141, 152))	('reduced', 'NegReg', (108, 115))	('hepatic adenoma', 'Disease', 'MESH:C564190', (26, 41))	('hepatic adenoma', 'Disease', (26, 41))	('Gd-EOB-DTPA', 'Chemical', '-', (141, 152))	('hepatic adenoma', 'Phenotype', 'HP:0012028', (26, 41))
8168	22700119	Contrary to delayed enhancement of fibrosis on gadolinium-enhanced MRI, confluent hepatic fibrosis demonstrates hypointense areas due to decreased or absent hepatocellular uptake of Gd-EOB-DTPA.	('hypointense areas', 'MPA', (112, 129))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (82, 98))	('fibrosis', 'Disease', 'MESH:D005355', (35, 43))	('fibrosis', 'Disease', (35, 43))	('Gd-EOB-DTPA', 'Chemical', '-', (182, 193))	('fibrosis', 'Disease', (90, 98))	('fibrosis', 'Disease', 'MESH:D005355', (90, 98))	('absent', 'NegReg', (150, 156))	('Gd-EOB-DTPA', 'Var', (182, 193))	('gadolinium', 'Chemical', 'MESH:D005682', (47, 57))	('hepatocellular uptake', 'MPA', (157, 178))
8252	33925189	In this work, we address these questions, adding clinical evidence and in vitro mechanistic explanations in support of the view that CAF infiltration indeed causes CCA progression through impairing the autophagy flux in cancer cells, thus resulting in reduced chemoresponsiveness.	('chemoresponsiveness', 'Disease', 'None', (260, 279))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('CCA', 'Phenotype', 'HP:0030153', (164, 167))	('chemoresponsiveness', 'Disease', (260, 279))	('infiltration', 'Var', (137, 149))	('CAF', 'Gene', (133, 136))	('CAF', 'Gene', '8850', (133, 136))	('causes', 'Reg', (157, 163))	('reduced', 'NegReg', (252, 259))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('CCA', 'Disease', (164, 167))	('impairing', 'NegReg', (188, 197))	('cancer', 'Disease', (220, 226))	('si', 'Chemical', 'MESH:D012825', (175, 177))	('si', 'Chemical', 'MESH:D012825', (271, 273))
8271	33925189	Further, and most importantly, survival analysis demonstrated that high IL-6 in CAF-containing fibrotic areas was significantly associated with a shorter overall survival time in univariate (Figure 1C; I = 0.024) and multivariate analyses (Table 2; HR = 2.004; CI = 1.138-3.527; p = 0.016).	('high', 'Var', (67, 71))	('si', 'Chemical', 'MESH:D012825', (114, 116))	('CAF', 'Gene', '8850', (80, 83))	('IL-6', 'Gene', '3569', (72, 76))	('IL-6', 'Gene', (72, 76))	('shorter', 'NegReg', (146, 153))	('overall survival', 'MPA', (154, 170))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('CAF', 'Gene', (80, 83))
8273	33925189	The high IHC score of LC3 (Figure 2A) showed a positive association with longer overall survival of CCA patients in univariate (Figure 2B; green line; p = 0.001) and multivariate analysis (Table 2; HR = 0.401; CI = 0.236-0.681; p = 0.001).	('si', 'Chemical', 'MESH:D012825', (184, 186))	('CCA', 'Phenotype', 'HP:0030153', (100, 103))	('overall', 'MPA', (80, 87))	('high', 'Var', (4, 8))	('LC3', 'Gene', '84557', (22, 25))	('LC3', 'Gene', (22, 25))	('longer', 'PosReg', (73, 79))	('patients', 'Species', '9606', (104, 112))	('CCA', 'Disease', (100, 103))	('si', 'Chemical', 'MESH:D012825', (49, 51))
8275	33925189	Consistently, the prognosis was better in patients bearing a CCA with high expression of LC3 along with low (green line) or high (violet line) p62 expression compared with patients bearing a CCA with low expression of LC3 (Figure 2D).	('p62', 'Gene', '8878', (143, 146))	('si', 'Chemical', 'MESH:D012825', (153, 155))	('p62', 'Gene', (143, 146))	('expression', 'MPA', (147, 157))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('CCA', 'Phenotype', 'HP:0030153', (191, 194))	('LC3', 'Gene', '84557', (89, 92))	('LC3', 'Gene', '84557', (218, 221))	('patients', 'Species', '9606', (172, 180))	('high', 'Var', (70, 74))	('si', 'Chemical', 'MESH:D012825', (24, 26))	('better', 'Reg', (32, 38))	('patients', 'Species', '9606', (42, 50))	('LC3', 'Gene', (89, 92))	('LC3', 'Gene', (218, 221))	('CCA', 'Phenotype', 'HP:0030153', (61, 64))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('si', 'Chemical', 'MESH:D012825', (210, 212))	('expression', 'MPA', (75, 85))
8277	33925189	The pattern of high LC3 but low p62 showed a positive correlation in CCA tissues (Figure 2E; rho = 0.518; p = 0.000), supporting the view that high LC3 was reflecting effective autophagy degradation of the cargo.	('LC3', 'Gene', '84557', (20, 23))	('autophagy degradation', 'CPA', (177, 198))	('LC3', 'Gene', (20, 23))	('CCA', 'Phenotype', 'HP:0030153', (69, 72))	('high', 'Var', (143, 147))	('LC3', 'Gene', '84557', (148, 151))	('LC3', 'Gene', (148, 151))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('p62', 'Gene', '8878', (32, 35))	('p62', 'Gene', (32, 35))	('CCA', 'Disease', (69, 72))
8284	33925189	It was found that the pattern of L/H/L, representing a low inflammatory stroma (low IL-6 staining) and an efficient autophagy flux in cancer cells (high LC3 and low p62), was significantly associated with the best prognostic clinical outcome (Figure 3, green line; p = 0.007).	('IL-6', 'Gene', (84, 88))	('p62', 'Gene', '8878', (165, 168))	('autophagy flux', 'CPA', (116, 130))	('L/H/L', 'Var', (33, 38))	('p62', 'Gene', (165, 168))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('IL-6', 'Gene', '3569', (84, 88))	('LC3', 'Gene', '84557', (153, 156))	('si', 'Chemical', 'MESH:D012825', (175, 177))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('LC3', 'Gene', (153, 156))
8287	33925189	The pattern with low IL-6 in the stroma and high LC3/high p62 in cancer cells (violet line; L/H/H; HR: 1.659, 95% CI: 0.813-3.384) also showed a good prognosis when compared with the other patterns having high IL-6 and/or low LC3 expression.	('IL-6', 'Gene', '3569', (210, 214))	('LC3', 'Gene', '84557', (226, 229))	('p62', 'Gene', (58, 61))	('LC3', 'Gene', (226, 229))	('p62', 'Gene', '8878', (58, 61))	('si', 'Chemical', 'MESH:D012825', (156, 158))	('LC3', 'Gene', '84557', (49, 52))	('si', 'Chemical', 'MESH:D012825', (236, 238))	('LC3', 'Gene', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('IL-6', 'Gene', (210, 214))	('IL-6', 'Gene', (21, 25))	('low', 'Var', (17, 20))	('IL-6', 'Gene', '3569', (21, 25))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
8290	33925189	In an attempt to clarify the respective role of chemotherapy versus CCA inflammation/autophagy status in the clinical outcome, we estimated the overall survival in those patients with a favorable status (based on the above analysis), i.e., with low IL-6, high LC3, and low p62, that were subjected or not to chemotherapy (see Figure S1).	('LC3', 'Gene', (260, 263))	('patients', 'Species', '9606', (170, 178))	('CCA', 'Phenotype', 'HP:0030153', (68, 71))	('low', 'NegReg', (245, 248))	('si', 'Chemical', 'MESH:D012825', (228, 230))	('inflammation', 'Disease', (72, 84))	('IL-6', 'Gene', (249, 253))	('IL-6', 'Gene', '3569', (249, 253))	('inflammation', 'Disease', 'MESH:D007249', (72, 84))	('high', 'Var', (255, 259))	('LC3', 'Gene', '84557', (260, 263))	('p62', 'Gene', '8878', (273, 276))	('p62', 'Gene', (273, 276))
8295	33925189	The multivariate analysis indicated that the status of drug-treated plus low IL-6 plus high LC3 plus low p62 was an independent factor associated with longer overall survival.	('low', 'Var', (73, 76))	('IL-6', 'Gene', (77, 81))	('longer', 'PosReg', (151, 157))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('IL-6', 'Gene', '3569', (77, 81))	('p62', 'Gene', '8878', (105, 108))	('LC3', 'Gene', '84557', (92, 95))	('overall survival', 'MPA', (158, 174))	('p62', 'Gene', (105, 108))	('LC3', 'Gene', (92, 95))
8296	33925189	Overall, we found a positive correlation between drug-treated and low IL-6 (in fibroblasts) plus high LC3 plus low p62 in cancer cells (Table 3; Pearson r = 0.898, p < 0.01).	('low', 'Var', (111, 114))	('LC3', 'Gene', (102, 105))	('IL-6', 'Gene', (70, 74))	('IL-6', 'Gene', '3569', (70, 74))	('cancer', 'Disease', (122, 128))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('low', 'NegReg', (66, 69))	('p62', 'Gene', '8878', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('p62', 'Gene', (115, 118))	('high', 'Var', (97, 101))	('LC3', 'Gene', '84557', (102, 105))
8297	33925189	Based on the previous observations, we assumed that high expression of LC3 could impact the chemoresponsivity regardless of the level of p62 expression.	('p62', 'Gene', '8878', (137, 140))	('p62', 'Gene', (137, 140))	('impact', 'NegReg', (81, 87))	('chemoresponsivity', 'CPA', (92, 109))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('LC3', 'Gene', '84557', (71, 74))	('si', 'Chemical', 'MESH:D012825', (147, 149))	('high expression', 'Var', (52, 67))	('LC3', 'Gene', (71, 74))	('si', 'Chemical', 'MESH:D012825', (63, 65))
8308	33925189	Consistently, a better prognosis was observed in patients bearing a CCA with MAP-LC3B gene amplification (n = 5) compared with patients bearing a CCA with diploid CNV (n = 22) or with shallow (monoallelic) deletion (n = 6) (not shown).	('LC3B', 'Gene', (81, 85))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('CCA', 'Phenotype', 'HP:0030153', (68, 71))	('gene amplification', 'Var', (86, 104))	('patients', 'Species', '9606', (127, 135))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('LC3B', 'Gene', '81631', (81, 85))	('CCA', 'Phenotype', 'HP:0030153', (146, 149))	('patients', 'Species', '9606', (49, 57))	('better', 'PosReg', (16, 22))
8310	33925189	Quite surprisingly, the 29 patients bearing a CCA expressing a low level of BECN1 showed a better OS (not significant; p = 0.23) than the 5 patients bearing a CCA expressing a high level of BECN1 (Figure S2C).	('BECN1', 'Gene', (190, 195))	('low level', 'Var', (63, 72))	('si', 'Chemical', 'MESH:D012825', (169, 171))	('si', 'Chemical', 'MESH:D012825', (12, 14))	('CCA', 'Phenotype', 'HP:0030153', (159, 162))	('BECN1', 'Gene', '8678', (190, 195))	('BECN1', 'Gene', '8678', (76, 81))	('patients', 'Species', '9606', (27, 35))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('patients', 'Species', '9606', (140, 148))	('CCA', 'Phenotype', 'HP:0030153', (46, 49))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('BECN1', 'Gene', (76, 81))
8315	33925189	Though not statistically significant (p = 0.99) because of the small numbers, we found that 29 patients bearing a CCA with a low level of p62 (only eight underwent chemotherapy) showed a much better prognosis than the four patients bearing a CCA with a high level of p62 (no one underwent chemotherapy) (Figure S3).	('patients', 'Species', '9606', (95, 103))	('better', 'PosReg', (192, 198))	('p62', 'Gene', '8878', (138, 141))	('si', 'Chemical', 'MESH:D012825', (205, 207))	('low level', 'Var', (125, 134))	('p62', 'Gene', (138, 141))	('CCA', 'Phenotype', 'HP:0030153', (242, 245))	('CCA', 'Phenotype', 'HP:0030153', (114, 117))	('p62', 'Gene', '8878', (267, 270))	('si', 'Chemical', 'MESH:D012825', (25, 27))	('patients', 'Species', '9606', (223, 231))	('p62', 'Gene', (267, 270))
8320	33925189	To this end, we have specifically inhibited the production of IL-6 by transfecting the CAFs with an appropriate si-RNA.	('CAF', 'Gene', '8850', (87, 90))	('transfecting', 'Var', (70, 82))	('inhibited', 'NegReg', (34, 43))	('production', 'MPA', (48, 58))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('IL-6', 'Gene', (62, 66))	('CAF', 'Gene', (87, 90))	('IL-6', 'Gene', '3569', (62, 66))
8321	33925189	The data shown in Figure 6 prove that the si-RNA transfection effectively downregulated the expression and secretion in the medium of IL-6 by CAFs without altering their myofibroblast-like phenotype (as monitored by alpha-SMA expression).	('CAF', 'Gene', '8850', (142, 145))	('si', 'Chemical', 'MESH:D012825', (232, 234))	('alpha-SMA', 'Gene', '58', (216, 225))	('alpha-SMA', 'Gene', (216, 225))	('IL-6', 'Gene', (134, 138))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('IL-6', 'Gene', '3569', (134, 138))	('secretion in the', 'MPA', (107, 123))	('CAF', 'Gene', (142, 145))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('downregulated', 'NegReg', (74, 87))	('si-RNA transfection', 'Var', (42, 61))
8322	33925189	Next, we tested whether and how the conditioned media from control or si-RNA-transfected CAFs would affect the autophagy regulation and the chemosensitivity of CCA cells.	('si', 'Chemical', 'MESH:D012825', (70, 72))	('chemosensitivity', 'CPA', (140, 156))	('affect', 'Reg', (100, 106))	('CAF', 'Gene', (89, 92))	('si', 'Chemical', 'MESH:D012825', (148, 150))	('CCA', 'Phenotype', 'HP:0030153', (160, 163))	('CAF', 'Gene', '8850', (89, 92))	('autophagy regulation', 'CPA', (111, 131))	('si-RNA-transfected', 'Var', (70, 88))	('tested', 'Reg', (9, 15))
8327	33925189	More importantly, the growth was greatly inhibited by 5-FU, and even more when the treatment was performed in the cells incubated with the CAF-conditioned medium lacking IL-6 (Figure 7A).	('growth', 'MPA', (22, 28))	('CAF', 'Gene', (139, 142))	('IL-6', 'Gene', '3569', (170, 174))	('CAF', 'Gene', '8850', (139, 142))	('inhibited', 'NegReg', (41, 50))	('5-FU', 'Var', (54, 58))	('5-FU', 'Chemical', 'MESH:D005472', (54, 58))	('IL-6', 'Gene', (170, 174))
8338	33925189	On treatment with 5-FU, autophagy was stimulated along with increased expression of BAX in the cells cultivated in standard medium, consistent with the induction of a toxic stress-response and the onset of apoptosis (Figure 8A,B).	('BAX', 'Gene', '581', (84, 87))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('si', 'Chemical', 'MESH:D012825', (135, 137))	('5-FU', 'Var', (18, 22))	('5-FU', 'Chemical', 'MESH:D005472', (18, 22))	('increased', 'PosReg', (60, 69))	('expression', 'MPA', (70, 80))	('stimulated', 'PosReg', (38, 48))	('si', 'Chemical', 'MESH:D012825', (212, 214))	('BAX', 'Gene', (84, 87))	('autophagy', 'CPA', (24, 33))
8342	33925189	The images in Figure 8C show that 5-FU can induce BAX-mediated apoptosis only in the cells cultivated in standard medium or in IL-6-deficient CAF medium, while it is not effective in cells cultivated in IL-6-rich CAF medium.	('5-FU', 'Var', (34, 38))	('CAF', 'Gene', '8850', (142, 145))	('CAF', 'Gene', (213, 216))	('5-FU', 'Chemical', 'MESH:D005472', (34, 38))	('IL-6', 'Gene', (127, 131))	('CAF', 'Gene', '8850', (213, 216))	('IL-6', 'Gene', '3569', (127, 131))	('induce', 'Reg', (43, 49))	('IL-6', 'Gene', (203, 207))	('CAF', 'Gene', (142, 145))	('BAX', 'Gene', (50, 53))	('IL-6', 'Gene', '3569', (203, 207))	('si', 'Chemical', 'MESH:D012825', (69, 71))	('BAX', 'Gene', '581', (50, 53))
8345	33925189	The data confirm that apoptosis associated with autophagy occurs in 5-FU-treated cells, and this event is more pronounced when the cells are incubated in IL6-deprived CAF CM.	('si', 'Chemical', 'MESH:D012825', (28, 30))	('5-FU', 'Chemical', 'MESH:D005472', (68, 72))	('IL6', 'Gene', (154, 157))	('autophagy', 'CPA', (48, 57))	('apoptosis', 'CPA', (22, 31))	('5-FU-treated', 'Var', (68, 80))	('CAF', 'Gene', (167, 170))	('CAF', 'Gene', '8850', (167, 170))	('IL6', 'Gene', '3569', (154, 157))
8366	33925189	For instance, in vitro experiments with CCA cells showed that disruption of BECLIN-1-dependent autophagy could either sensitize to or abrogate cytotoxicity by chemotherapeutic drugs.	('sensitize', 'NegReg', (118, 127))	('cytotoxicity', 'Disease', (143, 155))	('BECLIN-1', 'Gene', (76, 84))	('cytotoxicity', 'Disease', 'MESH:D064420', (143, 155))	('disruption', 'Var', (62, 72))	('abrogate', 'NegReg', (134, 142))	('BECLIN-1', 'Gene', '8678', (76, 84))	('CCA', 'Phenotype', 'HP:0030153', (40, 43))	('si', 'Chemical', 'MESH:D012825', (121, 123))
8374	33925189	In addition, many CCAs with high BECN1 mRNA indeed expressed a low level of LC3 mRNA, indicating that autophagy in those samples was not active.	('BECN1', 'Gene', (33, 38))	('LC3', 'Gene', '84557', (76, 79))	('CCA', 'Phenotype', 'HP:0030153', (18, 21))	('BECN1', 'Gene', '8678', (33, 38))	('LC3', 'Gene', (76, 79))	('high', 'Var', (28, 32))
8384	33925189	Primary CAFs were isolated from human CCA and genetically impaired to produce IL-6 through specific siRNA transfection.	('CAF', 'Gene', '8850', (8, 11))	('CCA', 'Phenotype', 'HP:0030153', (38, 41))	('transfection', 'Var', (106, 118))	('IL-6', 'Gene', (78, 82))	('IL-6', 'Gene', '3569', (78, 82))	('human', 'Species', '9606', (32, 37))	('CAF', 'Gene', (8, 11))	('si', 'Chemical', 'MESH:D012825', (100, 102))
8406	33925189	The primary antibodies used for immunohistochemistry (IHC), immunofluorescence (IF), and Western blotting (WB) were purchased from Abcam (Cambridge, MA, USA), anti-LC3 (ab51520, IHC 1:500; WB 1:1000; IF 1:100), anti-p62 (ab91526, IHC 1:500; WB 1:500; IF 1:100), anti-IL-6 (ab6672, IHC 1:1000; WB 1:1000; IF 1:100), anti-BAX (ab3191,WB 1:2000; IF 1:100), and anti-BCL-2 (ab196495, WB 1:1000; IF 1:100).	('LC3', 'Gene', '84557', (164, 167))	('LC3', 'Gene', (164, 167))	('BCL-2', 'Gene', (363, 368))	('p62', 'Gene', '8878', (216, 219))	('p62', 'Gene', (216, 219))	('IL-6', 'Gene', (267, 271))	('BAX', 'Gene', (320, 323))	('IL-6', 'Gene', '3569', (267, 271))	('ab3191', 'Var', (325, 331))	('ab51520', 'Var', (169, 176))	('ab6672', 'Var', (273, 279))	('BAX', 'Gene', '581', (320, 323))	('ab91526', 'Var', (221, 228))	('BCL-2', 'Gene', '596', (363, 368))
8703	29765958	Excess ROS and RNS can also increase endogenous nitrosation reactions to yield carcinogenic N-nitrosamines such as NDMA that alkylate DNA bases.	('ROS', 'Chemical', '-', (7, 10))	('ROS', 'Var', (7, 10))	('N-nitrosamines', 'Chemical', '-', (92, 106))	('endogenous nitrosation reactions', 'MPA', (37, 69))	('NDMA', 'Disease', (115, 119))	('RNS', 'Chemical', 'MESH:D011886', (15, 18))	('increase', 'PosReg', (28, 36))	('NDMA', 'Chemical', '-', (115, 119))
8849	26785809	Thus, L1CAM could serve as a therapeutic target and anti-L1CAM antibodies may have potential as anticancer agents.	('cancer', 'Disease', (100, 106))	('anti-L1CAM', 'Var', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
8852	26785809	First, we selected an antibody (Ab4) that binds human and mouse L1CAM from the human naive Fab library using phage display, then increased its affinity 45-fold through mutation of 3 residues in the complementarity-determining regions (CDRs) to generate Ab4M.	('Ab4', 'Gene', (253, 256))	('Ab4', 'Gene', '636752', (253, 256))	('Fab', 'Gene', '2187', (91, 94))	('human', 'Species', '9606', (79, 84))	('mouse', 'Species', '10090', (58, 63))	('human', 'Species', '9606', (48, 53))	('Fab', 'Gene', (91, 94))	('increased', 'PosReg', (129, 138))	('affinity', 'MPA', (143, 151))	('mutation', 'Var', (168, 176))	('Ab4', 'Gene', (32, 35))	('Ab4', 'Gene', '636752', (32, 35))	('rat', 'Species', '10116', (248, 251))
8865	26785809	L1CAM has been shown to enhance the proliferation, survival, motility, and apoptosis resistance of tumor cells in several types of cancers.	('tumor', 'Disease', (99, 104))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('proliferation', 'CPA', (36, 49))	('enhance', 'PosReg', (24, 31))	('rat', 'Species', '10116', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('L1CAM', 'Var', (0, 5))	('survival', 'CPA', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('motility', 'CPA', (61, 69))	('apoptosis resistance', 'CPA', (75, 95))
8868	26785809	In studies with anti-L1CAM mAbs, a murine mAb significantly reduced tumor growth in pancreatic and ovarian carcinoma xenograft models, whereas a chimeric antibody reduced tumor growth in a cholangiocarcinoma xenograft model.	('tumor', 'Disease', (68, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('anti-L1CAM', 'Var', (16, 26))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('pancreatic and ovarian carcinoma', 'Disease', 'MESH:D010051', (84, 116))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('reduced', 'NegReg', (60, 67))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (189, 207))	('cholangiocarcinoma xenograft', 'Disease', 'MESH:D018281', (189, 217))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (99, 116))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('cholangiocarcinoma xenograft', 'Disease', (189, 217))	('murine', 'Species', '10090', (35, 41))
8869	26785809	The results suggest that these anti-L1CAM mAbs have potential as anticancer agents for the treatment of cancer.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (104, 110))	('anti-L1CAM', 'Var', (31, 41))	('cancer', 'Disease', (69, 75))
8882	26785809	Here, we isolated a human anti-L1CAM mAb that binds to human and mouse L1CAM from a human naive Fab library using phage display and developed an affinity-matured antibody (Ab417) through site-directed mutagenesis of complementarity-determining regions (CDR) residues and yeast display of scFvs containing randomly mutated light chain CDR3.	('human', 'Species', '9606', (20, 25))	('mouse', 'Species', '10090', (65, 70))	('human', 'Species', '9606', (55, 60))	('Fab', 'Gene', '2187', (96, 99))	('mutagenesis', 'Var', (201, 212))	('mutated', 'Var', (314, 321))	('CDR3', 'Gene', (334, 338))	('human', 'Species', '9606', (84, 89))	('Fab', 'Gene', (96, 99))	('yeast', 'Species', '4932', (271, 276))	('scFv', 'Gene', '652070', (288, 292))	('Ab417', 'Chemical', '-', (172, 177))	('scFv', 'Gene', (288, 292))
8890	26785809	1A, alanine mutation (H97A) of His97 in HCDR3 increased the antigen-binding activity for human and mouse L1CAM, whereas the mutation of other residues in HCDR1, HCDR2, and HCDR3 significantly decreased the binding activity for human L1CAM.	('antigen-binding activity', 'MPA', (60, 84))	('HCDR', 'Chemical', '-', (154, 158))	('mouse', 'Species', '10090', (99, 104))	('human', 'Species', '9606', (89, 94))	('His97', 'Chemical', '-', (31, 36))	('decreased', 'NegReg', (192, 201))	('binding', 'Interaction', (206, 213))	('alanine mutation', 'Var', (4, 20))	('increased', 'PosReg', (46, 55))	('HCDR3', 'Gene', (40, 45))	('H97A', 'Var', (22, 26))	('alanine', 'Chemical', 'MESH:D000409', (4, 11))	('HCDR', 'Chemical', '-', (172, 176))	('human', 'Species', '9606', (227, 232))	('HCDR', 'Chemical', '-', (40, 44))	('H97A', 'SUBSTITUTION', 'None', (22, 26))	('HCDR1', 'Gene', (154, 159))	('HCDR', 'Chemical', '-', (161, 165))
8891	26785809	In the case of LCDR3, alanine mutation (D93A) of Asp93 increased the activity, but the mutation of other residues did not (Fig.	('alanine mutation (D93A', 'Var', (22, 44))	('activity', 'MPA', (69, 77))	('increased', 'PosReg', (55, 64))	('Asp93', 'Chemical', '-', (49, 54))	('alanine', 'Chemical', 'MESH:D000409', (22, 29))	('D93A', 'Mutation', 'rs750335671', (40, 44))	('Asp93', 'Gene', (49, 54))
8892	26785809	We also mutated Val50 in HCDR2 to glutamate, phenylalanine, tyrosine, arginine, or threonine.	('threonine', 'Chemical', 'MESH:D013912', (83, 92))	('tyrosine', 'MPA', (60, 68))	('Val50', 'Gene', (16, 21))	('phenylalanine', 'Chemical', 'MESH:D010649', (45, 58))	('glutamate', 'Chemical', 'MESH:D018698', (34, 43))	('mutated', 'Var', (8, 15))	('Val50', 'Chemical', '-', (16, 21))	('tyrosine', 'Chemical', 'MESH:D014443', (60, 68))	('glutamate', 'MPA', (34, 43))	('arginine', 'Chemical', 'MESH:D001120', (70, 78))	('HCDR', 'Chemical', '-', (25, 29))	('arginine', 'MPA', (70, 78))
8893	26785809	Because alanine mutation (V50A) of Val50 moderately decreased the activity, the valine residue was speculated to be involved in antigen binding, but to not be optimal for antigen binding.	('valine', 'Chemical', 'MESH:D014633', (80, 86))	('decreased', 'NegReg', (52, 61))	('activity', 'MPA', (66, 74))	('alanine mutation (V50A', 'Var', (8, 30))	('rat', 'Species', '10116', (45, 48))	('alanine', 'Chemical', 'MESH:D000409', (8, 15))	('V50A', 'Mutation', 'p.V50A', (26, 30))	('Val50', 'Gene', (35, 40))	('Val50', 'Chemical', '-', (35, 40))
8894	26785809	Substitution of glutamate or phenylalanine for valine increased the binding activity for human L1CAM (Fig.	('Substitution', 'Var', (0, 12))	('human', 'Species', '9606', (89, 94))	('phenylalanine', 'Var', (29, 42))	('binding', 'Interaction', (68, 75))	('phenylalanine', 'Chemical', 'MESH:D010649', (29, 42))	('valine', 'Chemical', 'MESH:D014633', (47, 53))	('human L1CAM', 'Protein', (89, 100))	('increased', 'PosReg', (54, 63))	('valine increased', 'Phenotype', 'HP:0010910', (47, 63))	('glutamate', 'Chemical', 'MESH:D018698', (16, 25))
8895	26785809	Consequently, we constructed a variant (Ab4M) of Ab4 that contains 3 mutations (V50F in HCDR2, H97A in HCDR3, and D93A in LCDR3) and compared its affinity to that of Ab4 by competitive ELISA.	('V50F', 'Mutation', 'p.V50F', (80, 84))	('Ab4', 'Gene', (49, 52))	('H97A', 'Var', (95, 99))	('Ab4', 'Gene', '636752', (40, 43))	('HCDR', 'Chemical', '-', (103, 107))	('Ab4', 'Gene', '636752', (49, 52))	('D93A', 'Mutation', 'rs750335671', (114, 118))	('Ab4', 'Gene', '636752', (166, 169))	('HCDR', 'Chemical', '-', (88, 92))	('V50F', 'Var', (80, 84))	('Ab4', 'Gene', (166, 169))	('D93A', 'Var', (114, 118))	('HCDR2', 'Gene', (88, 93))	('Ab4', 'Gene', (40, 43))	('H97A', 'SUBSTITUTION', 'None', (95, 99))
8896	26785809	The affinities (KD) of Ab4 and Ab4M for human L1CAM were 130 nM and 2.9 nM, respectively, whereas those of the mutants carrying D93A, H97A, or V50F and H97A were 28 nM, 23 nM, or 16 nM, respectively (Fig.	('H97A', 'SUBSTITUTION', 'None', (134, 138))	('V50F', 'Var', (143, 147))	('Ab4', 'Gene', '636752', (23, 26))	('Ab4', 'Gene', '636752', (31, 34))	('H97A', 'Var', (134, 138))	('H97A', 'Var', (152, 156))	('Ab4', 'Gene', (31, 34))	('V50F', 'Mutation', 'p.V50F', (143, 147))	('D93A', 'Var', (128, 132))	('D93A', 'Mutation', 'rs750335671', (128, 132))	('H97A', 'SUBSTITUTION', 'None', (152, 156))	('affinities', 'MPA', (4, 14))	('Ab4', 'Gene', (23, 26))	('human', 'Species', '9606', (40, 45))
8897	26785809	The results indicate that the affinity of Ab4M for human L1CAM was increased 44-fold compared to that of Ab4 due to the synergistic effect of the 3 critical mutations.	('L1CAM', 'Protein', (57, 62))	('Ab4', 'Gene', '636752', (105, 108))	('Ab4', 'Gene', (42, 45))	('Ab4', 'Gene', '636752', (42, 45))	('human', 'Species', '9606', (51, 56))	('mutations', 'Var', (157, 166))	('affinity', 'Interaction', (30, 38))	('increased', 'PosReg', (67, 76))	('Ab4', 'Gene', (105, 108))
8917	26785809	Because the affinities of Ab417 for human and mouse L1CAM are high enough to characterize in vivo profiles, we considered Ab417 as the final candidate for preclinical study.	('affinities', 'MPA', (12, 22))	('mouse', 'Species', '10090', (46, 51))	('Ab417', 'Var', (122, 127))	('Ab417', 'Chemical', '-', (26, 31))	('Ab417', 'Chemical', '-', (122, 127))	('human', 'Species', '9606', (36, 41))
8941	26785809	The Ab417-treated groups had a mean tumor volume of 320 mm3 (p < 0.01) and tumor weight of 0.219 g (p < 0.05), whereas cA10-A3-treated groups had a mean tumor volume of 722 mm3 and tumor weight of 0.649 g (p < 0.05) (Fig.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (181, 186))	('Ab417-treated', 'Var', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('cA10', 'Gene', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('cA10', 'Gene', '56934', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Ab417', 'Chemical', '-', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', (75, 80))
8942	26785809	Based on tumor weight, Ab417 resulted in 68.6% tumor growth inhibition compared to hFc without affecting body weight, whereas cA10-A3 resulted in 22.5% tumor growth inhibition.	('cA10', 'Gene', '56934', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('Ab417', 'Var', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('Ab417', 'Chemical', '-', (23, 28))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('hFc', 'Chemical', '-', (83, 86))	('tumor', 'Disease', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('cA10', 'Gene', (126, 130))
8943	26785809	No general toxicities were observed in the control or treated mice, and the mice treated with Ab417 had increased weight compared to those treated with cA10-A3 (Fig.	('cA10', 'Gene', (152, 156))	('increased', 'PosReg', (104, 113))	('Ab417', 'Chemical', '-', (94, 99))	('mice', 'Species', '10090', (62, 66))	('toxicities', 'Disease', 'MESH:D064420', (11, 21))	('cA10', 'Gene', '56934', (152, 156))	('weight', 'CPA', (114, 120))	('mice', 'Species', '10090', (76, 80))	('increased weight', 'Phenotype', 'HP:0004324', (104, 120))	('toxicities', 'Disease', (11, 21))	('Ab417', 'Var', (94, 99))
8944	26785809	Thus, the results clearly demonstrate that Ab417 has higher antitumor activity than cA10-A3.	('tumor', 'Disease', (64, 69))	('higher', 'PosReg', (53, 59))	('Ab417', 'Var', (43, 48))	('rat', 'Species', '10116', (33, 36))	('cA10', 'Gene', (84, 88))	('cA10', 'Gene', '56934', (84, 88))	('Ab417', 'Chemical', '-', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
8951	26785809	In addition, Ab417 has advantages over previous anti-L1CAM mAbs due to high affinity, better therapeutic efficacy, and cross-reactivity with rodent L1CAM, which may facilitate its preclinical and clinical development.	('facilitate', 'PosReg', (165, 175))	('advantages', 'PosReg', (23, 33))	('Ab417', 'Var', (13, 18))	('Ab417', 'Chemical', '-', (13, 18))	('therapeutic efficacy', 'CPA', (93, 113))
8959	26785809	Ab417 did not inhibit the proliferation of tumor cells in vitro, but it exhibited excellent tumor growth inhibition in vivo.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('rat', 'Species', '10116', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Ab417', 'Var', (0, 5))	('Ab417', 'Chemical', '-', (0, 5))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (43, 48))
8962	26785809	L1CAM expression in the peripheral nerves and kidney tubules raises concerns that anti-L1CAM mAb may induce toxicity.	('toxicity', 'Disease', (108, 116))	('L1CAM', 'Gene', (0, 5))	('anti-L1CAM', 'Var', (82, 92))	('toxicity', 'Disease', 'MESH:D064420', (108, 116))
8969	26785809	Therefore, Ab417 may have potential as a therapeutic agent for the treatment of cholangiocarcinoma and other types of L1CAM-positive cancers.	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cholangiocarcinoma', 'Disease', (80, 98))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (80, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (80, 98))	('Ab417', 'Var', (11, 16))	('Ab417', 'Chemical', '-', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
8974	26785809	Also, the ECD (mL1-ECD-S1) of mouse L1CAM fused to the preS1 tag at its C-terminus was expressed and purified by affinity chromatography on a sepharose column conjugated with anti-preS1 mAb, KR127, as described previously.	('preS1', 'Gene', (180, 185))	('sepharose', 'Chemical', 'MESH:D012685', (142, 151))	('preS1', 'Gene', '944569', (180, 185))	('preS1', 'Gene', '944569', (55, 60))	('L1', 'Gene', '3897', (16, 18))	('L1', 'Gene', '3897', (36, 38))	('KR127', 'Chemical', '-', (191, 196))	('mouse', 'Species', '10090', (30, 35))	('preS1', 'Gene', (55, 60))	('fused', 'Var', (42, 47))
9032	22983262	In the present study, we aimed at identifying novel epigenetic biomarkers with the potential to improve the diagnostic accuracy of cholangiocarcinoma.	('improve', 'PosReg', (96, 103))	('cholangiocarcinoma', 'Disease', (131, 149))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (131, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))	('epigenetic biomarkers', 'Var', (52, 73))
9033	22983262	Microarray data analyses of cholangiocarcinoma cell lines treated with epigenetic drugs and their untreated counterparts were compared with previously published gene expression profiles of primary tumors and with non-malignant controls.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('cholangiocarcinoma', 'Disease', (28, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (28, 46))	('epigenetic drugs', 'Var', (71, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (28, 46))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))
9034	22983262	Genes responding to the epigenetic treatment that were simultaneously downregulated in primary cholangiocarcinoma compared with controls (n = 43) were investigated for their promoter methylation status in cancer cell lines from the gastrointestinal tract.	('gastrointestinal tract', 'Disease', (232, 254))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (95, 113))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (95, 113))	('cancer', 'Disease', (205, 211))	('epigenetic treatment', 'Var', (24, 44))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (232, 254))	('downregulated', 'NegReg', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cholangiocarcinoma', 'Disease', (95, 113))
9047	22983262	Tumor-specific molecular alterations, including both genetic and epigenetic aberrations, have been shown to play important roles in cancer development.	('cancer', 'Disease', (132, 138))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('epigenetic aberrations', 'Var', (65, 87))	('genetic', 'Var', (53, 60))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
9048	22983262	Impaired epigenetic regulation, including aberrant DNA methylation, is frequently reported in cancers.	('Impaired', 'NegReg', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('aberrant', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('DNA methylation', 'MPA', (51, 66))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('epigenetic regulation', 'MPA', (9, 30))	('cancers', 'Disease', (94, 101))
9051	22983262	Since aberrant DNA methylation also has been shown to be an early event in tumorigenesis, such targets may represent attractive biomarkers for early detection.	('aberrant', 'Var', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('DNA', 'Protein', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
9055	22983262	The identification of suitable epigenetic CCA biomarkers with high sensitivity and specificity may facilitate cancer diagnostics at an early stage, perhaps performed upon biliary brush specimens, and thus contribute to increase survival of this patient cohort which presently carries such a poor prognosis.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('survival', 'CPA', (228, 236))	('cancer', 'Disease', (110, 116))	('CCA', 'Phenotype', 'HP:0030153', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('facilitate', 'PosReg', (99, 109))	('increase', 'PosReg', (219, 227))	('patient', 'Species', '9606', (245, 252))	('epigenetic', 'Var', (31, 41))
9057	22983262	Genes in group I (n = 12) were frequently methylated (>= 5/6; SFRP1, TCF4, NAP1L2, DCLK1, CDO1, ZSCAN18 (NM_023926), ZNF331 (NM_018555), GREM1, BEX4, TPM2, LHX6 and FAM3B.	('BEX4', 'Gene', '56271', (144, 148))	('FAM3B', 'Gene', (165, 170))	('ZNF331', 'Gene', '55422', (117, 123))	('ZNF331', 'Gene', (117, 123))	('NM_023926', 'Var', (105, 114))	('TCF4', 'Gene', '6925', (69, 73))	('GREM1', 'Gene', '26585', (137, 142))	('CDO1', 'Gene', (90, 94))	('GREM1', 'Gene', (137, 142))	('SFRP1', 'Gene', (62, 67))	('LHX6', 'Gene', '26468', (156, 160))	('NAP1L2', 'Gene', (75, 81))	('NM_018555', 'Var', (125, 134))	('TCF4', 'Gene', (69, 73))	('TPM2', 'Gene', (150, 154))	('TPM2', 'Gene', '7169', (150, 154))	('ZSCAN18', 'Gene', '65982', (96, 103))	('CDO1', 'Gene', '1036', (90, 94))	('BEX4', 'Gene', (144, 148))	('NAP1L2', 'Gene', '4674', (75, 81))	('FAM3B', 'Gene', '54097', (165, 170))	('SFRP1', 'Gene', '6422', (62, 67))	('methylated', 'Var', (42, 52))	('LHX6', 'Gene', (156, 160))	('DCLK1', 'Gene', (83, 88))	('DCLK1', 'Gene', '9201', (83, 88))	('ZSCAN18', 'Gene', (96, 103))
9060	22983262	Genes/transcript variants CXCL14, DPYSL3, EGR2 (NM_001136178), STXBP1, ZNF331 (NM_001079906), ZNF331 (NM_001079907) and ZSCAN18 (NR_027135), were excluded from analysis based on the presence of a weak band in one of the following control reactions; the methylated reaction using normal blood, the unmethylated reaction using completely methylated DNA, or the methylated reaction using non-bisulfite treated DNA.	('ZNF331', 'Gene', '55422', (94, 100))	('ZNF331', 'Gene', (94, 100))	('CXCL14', 'Gene', (26, 32))	('EGR2', 'Gene', '1959', (42, 46))	('EGR2', 'Gene', (42, 46))	('NM_001136178', 'Var', (48, 60))	('ZNF331', 'Gene', '55422', (71, 77))	('ZNF331', 'Gene', (71, 77))	('CXCL14', 'Gene', '9547', (26, 32))	('STXBP1', 'Gene', (63, 69))	('ZSCAN18', 'Gene', '65982', (120, 127))	('STXBP1', 'Gene', '6812', (63, 69))	('NM_001079907', 'Var', (102, 114))	('NM_001079906', 'Var', (79, 91))	('DPYSL3', 'Gene', '1809', (34, 40))	('DPYSL3', 'Gene', (34, 40))	('ZSCAN18', 'Gene', (120, 127))	('bisulfite', 'Chemical', 'MESH:C042345', (389, 398))
9072	22983262	By combining all four genes and scoring samples with methylation in minimum one out of the four genes as positive, 100% of the tumors and 0% of the non-malignant samples were methylation positive.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('methylation', 'Var', (53, 64))
9074	22983262	The combined panel in archival tissue was methylation positive in 81% of the tumors.	('tumors', 'Disease', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('methylation', 'Var', (42, 53))
9076	22983262	In the present study, we have identified CDO1, DCLK1 and ZSCAN18 as novel frequently methylated genes in cholangiocarcinoma, and confirmed frequent methylation of the SFRP1 gene.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (105, 123))	('DCLK1', 'Gene', (47, 52))	('SFRP1', 'Gene', (167, 172))	('CDO1', 'Gene', (41, 45))	('CDO1', 'Gene', '1036', (41, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (105, 123))	('DCLK1', 'Gene', '9201', (47, 52))	('ZSCAN18', 'Gene', (57, 64))	('ZSCAN18', 'Gene', '65982', (57, 64))	('SFRP1', 'Gene', '6422', (167, 172))	('methylation', 'Var', (148, 159))	('cholangiocarcinoma', 'Disease', (105, 123))
9086	22983262	Using a similar approach, we recently identified promising epigenetic markers for early detection of bladder and colorectal cancer.	('colorectal cancer', 'Disease', (113, 130))	('bladder', 'Disease', (101, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('epigenetic', 'Var', (59, 69))
9093	22983262	Such a clinical proof-of-principle was recently published, demonstrating that epigenetic biomarkers with high sensitivity and specificity could be detected in the bile of cholangiocarcinoma patients.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (171, 189))	('clinical', 'Species', '191496', (7, 15))	('patients', 'Species', '9606', (190, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (171, 189))	('epigenetic', 'Var', (78, 88))	('detected', 'Reg', (147, 155))	('cholangiocarcinoma', 'Disease', (171, 189))
9095	22983262	Secreted frizzled-related protein (SFRP) family members act as modulators of the Wnt-pathway, and methylation of these promoter regions can lead to deregulation of this pathway and subsequent cancer development.	('Wnt-pathway', 'Pathway', (81, 92))	('deregulation', 'MPA', (148, 160))	('SFRP', 'Gene', (35, 39))	('lead to', 'Reg', (140, 147))	('methylation', 'Var', (98, 109))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
9099	22983262	Methylation of the CDO1 promoter was recently shown to be a strong marker for distant metastasis in lymph node positive, estrogen receptor positive breast cancer patients.	('patients', 'Species', '9606', (162, 170))	('estrogen receptor', 'Gene', (121, 138))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('estrogen receptor', 'Gene', '2099', (121, 138))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('breast cancer', 'Disease', (148, 161))	('distant metastasis', 'CPA', (78, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('CDO1', 'Gene', '1036', (19, 23))	('CDO1', 'Gene', (19, 23))
9100	22983262	In addition, CDO1 has been indicated to be epigenetically deregulated in colorectal cancer, lung cancer and Wilms tumor.	('lung cancer', 'Disease', (92, 103))	('epigenetically deregulated', 'Var', (43, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('Wilms tumor', 'Disease', (108, 119))	('CDO1', 'Gene', '1036', (13, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('Wilms tumor', 'Phenotype', 'HP:0002667', (108, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', (73, 90))	('Wilms tumor', 'Disease', 'MESH:D009396', (108, 119))	('CDO1', 'Gene', (13, 17))
9107	22983262	In the present study we showed that ZSCAN18 is slightly more frequently methylated in cholangiocarcinomas compared with renal cancer (32%).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('ZSCAN18', 'Gene', '65982', (36, 43))	('renal cancer', 'Disease', 'MESH:D007680', (120, 132))	('renal cancer', 'Phenotype', 'HP:0009726', (120, 132))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (86, 104))	('methylated', 'Var', (72, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (86, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('ZSCAN18', 'Gene', (36, 43))	('more', 'PosReg', (56, 60))	('renal cancer', 'Disease', (120, 132))	('cholangiocarcinomas', 'Disease', (86, 105))
9112	22983262	Responding and simultaneously downregulated genes harboring a CpG island in the promoter region were subjected to qualitative methylation analysis in cancer cell lines.	('CpG island', 'Var', (62, 72))	('downregulated', 'NegReg', (30, 43))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
9142	31802940	This study reveals that preoperative LMR is an independent predictor of OS in ICC patients after hepatectomy, and the IPS can be applied as a novel prognostic indicator in these patients.	('patients', 'Species', '9606', (82, 90))	('patients', 'Species', '9606', (178, 186))	('ICC', 'Disease', (78, 81))	('LMR', 'Var', (37, 40))	('ICC', 'Disease', 'MESH:C535533', (78, 81))
9169	31802940	Higher levels of GPS, mGPS, NLR, PLR, LMR, PNI and pTNM were associated with reduced OS, although PI displayed marginal significance for predicting survival (P=0.055).	('mGPS', 'Var', (22, 26))	('NLR', 'Var', (28, 31))	('PNI ', 'Gene', '30833', (43, 47))	('PNI ', 'Gene', (43, 47))	('pTNM', 'Gene', (51, 55))	('reduced', 'NegReg', (77, 84))	('PLR', 'Var', (33, 36))	('GPS', 'Var', (17, 20))
9174	31802940	It turned out that patients with higher ALP, CEA, microscopic vascular invasion, elevated GPS and modified GPS were more likely to have advanced stages of IPS.	('patients', 'Species', '9606', (19, 27))	('ALP', 'Gene', (40, 43))	('CEA', 'Gene', '1048', (45, 48))	('ALP', 'Gene', '250', (40, 43))	('GPS', 'MPA', (90, 93))	('CEA', 'Gene', (45, 48))	('microscopic', 'Var', (50, 61))
9182	31802940	Lin et al from Sun Yat-sen University Cancer Center demonstrated a significant association between high levels of serum CRP and adverse cancer-specific survival (P=0.001) and recurrence-free survival (P<0.001) in ICC.	('high levels of serum CRP', 'Phenotype', 'HP:0011227', (99, 123))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('high', 'Var', (99, 103))	('recurrence-free survival', 'CPA', (175, 199))	('CRP', 'Gene', (120, 123))	('ICC', 'Disease', (213, 216))	('cancer', 'Disease', (136, 142))	('ICC', 'Disease', 'MESH:C535533', (213, 216))	('CRP', 'Gene', '1401', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
9192	31802940	In our study, we demonstrated for the first time that patients with increased pretreatment LMR (>=3.62) exhibited longer overall survival after hepatectomy for ICC.	('overall survival', 'MPA', (121, 137))	('patients', 'Species', '9606', (54, 62))	('ICC', 'Disease', (160, 163))	('ICC', 'Disease', 'MESH:C535533', (160, 163))	('LMR', 'Var', (91, 94))	('longer', 'PosReg', (114, 120))
9232	29713629	Besides, they detail the carcinogenic process for cholangiocarcinoma and squamous cell carcinoma highlighting the oncogenes activation, suppressor genes inactivation, and somatic mutations as key factors in the initiation and promotion of malignancy.	('malignancy', 'Disease', (239, 249))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('activation', 'PosReg', (124, 134))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (50, 68))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (50, 68))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 96))	('squamous cell carcinoma', 'Disease', (73, 96))	('carcinogenic', 'Disease', 'MESH:D063646', (25, 37))	('carcinogenic', 'Disease', (25, 37))	('cholangiocarcinoma', 'Disease', (50, 68))	('malignancy', 'Disease', 'MESH:D009369', (239, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('inactivation', 'Var', (153, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
9233	29713629	Complementarily and challenged by the questioning of Brindley and colleagues, other studies proposed a new hypothesis: reactive metabolites of oxysterol-like and estrogen-like precursors of helminth origin represent genotoxins that mutate genes of epithelial cells lining the biliary tract and urinary bladder and initiate biliary duct cancer and squamous cell carcinoma of the bladder during opisthorchiasis and urogenital schistosomiasis.	('squamous cell carcinoma of the bladder', 'Disease', (347, 385))	('carcinoma', 'Phenotype', 'HP:0030731', (361, 370))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('opisthorchiasis', 'Disease', (393, 408))	('genes', 'Gene', (239, 244))	('urogenital schistosomiasis', 'Disease', (413, 439))	('urogenital schistosomiasis', 'Disease', 'MESH:D012553', (413, 439))	('initiate', 'Reg', (314, 322))	('biliary duct cancer', 'Disease', 'MESH:D001661', (323, 342))	('squamous cell carcinoma of the bladder', 'Disease', 'MESH:D002294', (347, 385))	('biliary duct cancer', 'Disease', (323, 342))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (347, 370))	('mutate', 'Var', (232, 238))
9235	29713629	Thus, Plieskatt and colleagues demonstrated that infection with O. viverrini led to changes in the microbial communities of the gastrointestinal tract, including the emergence of microbes in the biliary system, enlarging inflammatory and fibrotic responses originated during opisthorchiasis.	('enlarging', 'PosReg', (211, 220))	('gastrointestinal tract', 'Disease', (128, 150))	('changes', 'Reg', (84, 91))	('microbial communities', 'CPA', (99, 120))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (128, 150))	('O. viverrini', 'Species', '6198', (64, 76))	('infection', 'Var', (49, 58))	('rat', 'Species', '10116', (38, 41))	('opisthorchiasis', 'Disease', (275, 290))
9236	29713629	Subsequently, Sripa and colleagues hypothesized that co-infection with Helicobacter species induces epithelial and adenomatous hyperplasias in the biliary tract.	('induces', 'Reg', (92, 99))	('Helicobacter', 'Species', '210', (71, 83))	('co-infection', 'Var', (53, 65))	('adenomatous hyperplasias', 'Phenotype', 'HP:0040261', (115, 139))	('epithelial', 'Disease', (100, 110))	('Helicobacter', 'Gene', (71, 83))	('adenomatous hyperplasias', 'Disease', 'MESH:D011125', (115, 139))	('adenomatous hyperplasias', 'Disease', (115, 139))
9246	29713629	Besides causing public health issues through parasitism with consequences to human populations, C. sinensis and O. viverrini can also lead to cholangiocarcinoma development (bile duct cancer), while S. haematobium has been related to squamous cell carcinoma of the urinary bladder [reviewed in Ref.	('bile duct cancer', 'Disease', 'MESH:D001650', (174, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('C. sinensis', 'Species', '79923', (96, 107))	('squamous cell carcinoma of the urinary bladder', 'Disease', (234, 280))	('parasitism', 'Disease', (45, 55))	('related', 'Reg', (223, 230))	('O. viverrini', 'Species', '6198', (112, 124))	('squamous cell carcinoma of the urinary bladder', 'Disease', 'MESH:D001749', (234, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('S. haematobium', 'Species', '6185', (199, 213))	('human', 'Species', '9606', (77, 82))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (142, 160))	('parasitism', 'Disease', 'MESH:D010272', (45, 55))	('C. sinensis', 'Var', (96, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (234, 257))	('lead to', 'Reg', (134, 141))	('cholangiocarcinoma', 'Disease', (142, 160))	('bile duct cancer', 'Phenotype', 'HP:0030153', (174, 190))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (142, 160))	('bile duct cancer', 'Disease', (174, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
9298	29486735	Positive expression of MK predicts poor prognosis in patients with resectable CHCC-CC.	('CC', 'Phenotype', 'HP:0030153', (83, 85))	('CC', 'Phenotype', 'HP:0030153', (80, 82))	('patients', 'Species', '9606', (53, 61))	('CHCC-CC', 'Disease', (78, 85))	('Positive', 'Var', (0, 8))	('MK', 'Gene', '4192', (23, 25))	('HCC', 'Phenotype', 'HP:0001402', (79, 82))
9350	29486735	There was, however, a significant association between high expression of MK protein and clinically advanced T stage (T3/T4 vs T1/T2; p = 0.007) (Table 1).	('T stage', 'Disease', (108, 115))	('MK', 'Gene', '4192', (73, 75))	('high', 'Var', (54, 58))
9370	29486735	Univariate analysis of our patients' data found LVI, T stage III-IV, AJCC tumor stage III-IV and positive midkine expression to be associated with poorer disease free and overall survival.	('LVI', 'Disease', (48, 51))	('AJCC tumor', 'Disease', 'MESH:D009369', (69, 79))	('CC', 'Phenotype', 'HP:0030153', (71, 73))	('poorer', 'NegReg', (147, 153))	('disease free', 'CPA', (154, 166))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('AJCC tumor', 'Disease', (69, 79))	('midkine', 'Gene', '4192', (106, 113))	('patients', 'Species', '9606', (27, 35))	('positive', 'Var', (97, 105))	('overall survival', 'CPA', (171, 187))	('midkine', 'Gene', (106, 113))
9372	29486735	In this study, positive expression of MK in tumors was associated with poor prognosis and reduced survival in CHCC-CC patients, suggesting that MK could potentially be used as an independent post-surgical prognostic biomarker for CHCC-CC.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('survival', 'CPA', (98, 106))	('CHCC-CC', 'Disease', (110, 117))	('reduced', 'NegReg', (90, 97))	('MK', 'Gene', '4192', (144, 146))	('expression', 'MPA', (24, 34))	('CC', 'Phenotype', 'HP:0030153', (115, 117))	('CC', 'Phenotype', 'HP:0030153', (232, 234))	('HCC', 'Phenotype', 'HP:0001402', (231, 234))	('HCC', 'Phenotype', 'HP:0001402', (111, 114))	('CC', 'Phenotype', 'HP:0030153', (112, 114))	('CC', 'Phenotype', 'HP:0030153', (235, 237))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('MK', 'Gene', '4192', (38, 40))	('positive', 'Var', (15, 23))	('patients', 'Species', '9606', (118, 126))
9389	29486735	Our study showed the patients with CHCC-CC who had a positive expression of MK to be at much higher risk of early recurrence and poor survival.	('positive expression', 'Var', (53, 72))	('MK', 'Gene', '4192', (76, 78))	('HCC', 'Phenotype', 'HP:0001402', (36, 39))	('CC', 'Phenotype', 'HP:0030153', (40, 42))	('CC', 'Phenotype', 'HP:0030153', (37, 39))	('patients', 'Species', '9606', (21, 29))	('CHCC-CC', 'Disease', (35, 42))
9443	29367874	A recent RCT (n = 20) comparing chemotherapy with EBS versus chemotherapy with EBS and PDT found longer median progression-free survival (PFS) in the group having PDT.	('EBS', 'Chemical', '-', (79, 82))	('longer', 'PosReg', (97, 103))	('EBS', 'Chemical', '-', (50, 53))	('PDT', 'Var', (163, 166))	('progression-free', 'CPA', (111, 127))
9478	29367874	A recent retrospective study (n = 37) found that although there was no difference in OS, patients having percutaneous PDT for unresectable perihilar cholangiocarcinoma had longer hospital admissions than those having endoscopic PDT (37 vs 63 days).	('cholangiocarcinoma', 'Disease', (149, 167))	('patients', 'Species', '9606', (89, 97))	('percutaneous PDT', 'Var', (105, 121))	('OS', 'Chemical', '-', (85, 87))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (149, 167))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (149, 167))
9497	29367874	In the two SEER analyses, one found adjuvant radiotherapy to increase OS in intrahepatic cholangiocarcinoma (median OS 6 vs 11 months, p = 0.014, n = 1234) whereas the other found no effect in extrahepatic cholangiocarcinoma (18 vs 18 months, p = 0.8, n = 1491).	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (193, 224))	('OS', 'Chemical', '-', (70, 72))	('extrahepatic cholangiocarcinoma', 'Disease', (193, 224))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (76, 107))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (89, 107))	('intrahepatic cholangiocarcinoma', 'Disease', (76, 107))	('OS', 'Chemical', '-', (116, 118))	('adjuvant', 'Var', (36, 44))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (206, 224))
9634	25100243	The occurrence of the aberrant NPP7 from the 1.2 kb mRNA in the majority of the bile samples is not a finding we expected, but interesting.	('aberrant', 'Var', (22, 30))	('NPP7', 'Gene', (31, 35))	('NPP7', 'Gene', '339221', (31, 35))
9644	25100243	However, further studies to characterize sugar moiety of the two products in human bile is still necessary, as abnormal glycosylation has great impact on carcinogenesis.	('impact', 'Reg', (144, 150))	('sugar', 'Chemical', 'MESH:D000073893', (41, 46))	('abnormal glycosylation', 'Phenotype', 'HP:0012345', (111, 133))	('abnormal', 'Var', (111, 119))	('glycosylation', 'MPA', (120, 133))	('carcinogenesis', 'CPA', (154, 168))	('human', 'Species', '9606', (77, 82))
9695	23090140	The regenerated epithelium gradually produces a variant accompanied by cellular atypical changes, as well as mutations of the K-ras and p53 genes.	('cellular', 'CPA', (71, 79))	('p53', 'Gene', (136, 139))	('mutations', 'Var', (109, 118))	('K-ras', 'Gene', (126, 131))	('K-ras', 'Gene', '3845', (126, 131))	('p53', 'Gene', '7157', (136, 139))
9766	33247676	Only those curves are presented herein which showed significant differences in overall survival (p<0.05) of patients with high cut-off values compared to those with low cut-off values.	('patients', 'Species', '9606', (108, 116))	('high cut-off values', 'Var', (122, 141))	('differences', 'Reg', (64, 75))
9776	33247676	For mutation, it provides mutation ID, details of genetic change, protein change, type of mutation and its VEP impact across all available TCGA tumour data sets.	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('tumour', 'Disease', (144, 150))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('mutation', 'Var', (26, 34))
9812	33247676	TC2N mutation profile in pan-cancer  Our analyses show several frequent somatic mutations in TC2N gene in various cancers.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancer', 'Disease', (29, 35))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('mutations', 'Var', (80, 89))	('TC2N', 'Gene', '123036', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('TC2N', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('TC2N', 'Gene', '123036', (93, 97))	('TC2N', 'Gene', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', (114, 120))
9813	33247676	A total of 142 mutations were identified across 145 cases in a total of 18 TCGA tumour types.	('tumour', 'Disease', (80, 86))	('mutations', 'Var', (15, 24))	('TCGA', 'Disease', (75, 79))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('identified', 'Reg', (30, 40))
9814	33247676	Highest pathogenic mutation rates of TC2N were present in SKCM, UCEC, COAD, BLCA and BRCA (Table 3).	('BLCA', 'Disease', (76, 80))	('COAD', 'Disease', 'MESH:D029424', (70, 74))	('BRCA', 'Gene', (85, 89))	('mutation', 'Var', (19, 27))	('pathogenic', 'Reg', (8, 18))	('TC2N', 'Gene', (37, 41))	('BRCA', 'Gene', '672;675', (85, 89))	('UCEC', 'Disease', (64, 68))	('COAD', 'Disease', (70, 74))	('TC2N', 'Gene', '123036', (37, 41))	('SKCM', 'Disease', (58, 62))
9825	33247676	Promoter hypermethylation is a key feature for transcriptional silencing of several genes in cancer (Park, 2010).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Promoter hypermethylation', 'Var', (0, 25))
9826	33247676	In particular, tumour suppressor genes are silenced via hypermethylation in several caners (Nag and Yu, 2015).	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('tumour', 'Disease', (15, 21))	('hypermethylation', 'Var', (56, 72))	('Nag', 'Gene', (92, 95))	('silenced', 'NegReg', (43, 51))	('Nag', 'Gene', '51594', (92, 95))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))
9827	33247676	We also found TC2N promoter hypomethylation in HNSC and KIRC.	('TC2N', 'Gene', (14, 18))	('hypomethylation', 'Var', (28, 43))	('TC2N', 'Gene', '123036', (14, 18))
9828	33247676	There are evidence that hypomethylation may lead to increased genomic stability that may contribute towards carcinogenesis (Pfeifer, 2018).	('increased', 'PosReg', (52, 61))	('genomic stability', 'CPA', (62, 79))	('contribute', 'Reg', (89, 99))	('hypomethylation', 'Var', (24, 39))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('carcinogenesis', 'Disease', (108, 122))
9829	33247676	Moreover, DNA hypomethylation also leads to overexpression of proinvasive, antiapoptotic and angiogenic factors in prostate cancer (Vestergaar et al., 2010).	('prostate cancer', 'Disease', (115, 130))	('hypomethylation', 'Var', (14, 29))	('overexpression', 'PosReg', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (115, 130))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))	('DNA', 'Var', (10, 13))
9830	33247676	In summary, TC2N promoter hyper and hypo-methylation are important findings of this study demanding further exploration.	('TC2N', 'Gene', '123036', (12, 16))	('hyper', 'Var', (26, 31))	('hypo-methylation', 'Var', (36, 52))	('TC2N', 'Gene', (12, 16))
9839	33247676	In a recent study that recruited 28 highly-aggregated-extended-highrisk-familial-lung-cancer (HRFLC) families, highest cluster of genetic variants associated with lung cancer were identified within CATSPERB gene (14q32) (Musolf et al., 2019).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('associated', 'Reg', (147, 157))	('familial-lung-cancer', 'Disease', (72, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CATSPERB', 'Gene', (198, 206))	('variants', 'Var', (138, 146))	('familial-lung-cancer', 'Disease', 'MESH:D008175', (72, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', (163, 174))	('CATSPERB', 'Gene', '79820', (198, 206))
9843	33247676	We identified a range of genetic alterations in the TC2N gene in several cancers.	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TC2N', 'Gene', '123036', (52, 56))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('TC2N', 'Gene', (52, 56))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('genetic alterations', 'Var', (25, 44))
9844	33247676	The highest pathogenic non-synonymous mutation rates were observed in SKCM, UCEC, COAD, BLCA and BRCA.	('COAD', 'Disease', (82, 86))	('UCEC', 'Disease', (76, 80))	('BLCA', 'Disease', (88, 92))	('SKCM', 'Disease', (70, 74))	('pathogenic', 'Reg', (12, 22))	('non-synonymous mutation', 'Var', (23, 46))	('COAD', 'Disease', 'MESH:D029424', (82, 86))	('BRCA', 'Gene', (97, 101))	('BRCA', 'Gene', '672;675', (97, 101))
9845	33247676	Whether these genetic mutations are causative or a sequel of cancer processes needs to be investigated.	('genetic mutations', 'Var', (14, 31))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
9846	33247676	It is important to note that cancer cells are susceptible to accumulate several mutations for multiple reasons such as increased cellular turnover, inflammatory tumour microenvironment, altered metabolic wiring, increased reactive oxygen species, increased susceptibility to DNA damage and decreased capacity of DNA damage repair amongst others (Loeb and Loeb, 2000; Hanahan and Weinberg, 2011; Fouad and Anani, 2017).	('decreased', 'NegReg', (290, 299))	('oxygen', 'Chemical', 'MESH:D010100', (231, 237))	('cancer', 'Disease', (29, 35))	('susceptibility', 'MPA', (257, 271))	('mutations', 'Var', (80, 89))	('increased reactive oxygen species', 'Phenotype', 'HP:0025464', (212, 245))	('metabolic wiring', 'CPA', (194, 210))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('altered', 'Reg', (186, 193))	('tumour', 'Disease', (161, 167))	('increased', 'PosReg', (212, 221))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('reactive oxygen species', 'MPA', (222, 245))	('increased', 'PosReg', (119, 128))	('cellular turnover', 'CPA', (129, 146))
9861	32692591	High expression of GM2 was associated with vascular invasion in tissue from patients with cholangiocarcinoma.	('GM2', 'Chemical', '-', (19, 22))	('patients', 'Species', '9606', (76, 84))	('High', 'Var', (0, 4))	('cholangiocarcinoma', 'Disease', (90, 108))	('associated with', 'Reg', (27, 42))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (90, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('vascular invasion', 'CPA', (43, 60))	('GM2', 'Gene', (19, 22))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))
9872	32692591	These studies have shown that tissue expression levels of sialyl Lewis A and serum levels of the carbohydrate marker S121 are related to cholangiocarcinoma prognosis; in an animal model, S121 was expressed in the cytoplasm and at the apical surface of biliary cells at the early stage of tumor development, then increased with tumor progression.	('tumor', 'Disease', (288, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('S121', 'Var', (187, 191))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (137, 155))	('tumor', 'Disease', (327, 332))	('carbohydrate', 'Chemical', 'MESH:D002241', (97, 109))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (137, 155))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('increased', 'PosReg', (312, 321))	('men', 'Species', '9606', (301, 304))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('cholangiocarcinoma', 'Disease', (137, 155))	('tumor', 'Disease', 'MESH:D009369', (327, 332))
9927	32692591	High expression levels of GM3 have been observed in various tumor tissues; moreover, serum GM3 was proposed as a biomarker for kidney cancer and a risk factor for metabolic syndrome.	('kidney cancer', 'Disease', 'MESH:D007680', (127, 140))	('kidney cancer', 'Phenotype', 'HP:0009726', (127, 140))	('metabolic syndrome', 'Disease', (163, 181))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('kidney cancer', 'Disease', (127, 140))	('serum GM3', 'Var', (85, 94))	('GM3', 'Chemical', '-', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('metabolic syndrome', 'Disease', 'MESH:D024821', (163, 181))	('GM3', 'Chemical', '-', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', (60, 65))
9949	32694937	Identification of prognostic factors for intrahepatic cholangiocarcinoma using long non-coding RNAs-associated ceRNA network Accumulating amount of evidence has highlighted the important roles of long non-coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) in tumor pathogenesis.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (41, 72))	('tumor', 'Disease', (275, 280))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('intrahepatic cholangiocarcinoma', 'Disease', (41, 72))	('long non-coding RNAs', 'Var', (196, 216))	('tumor', 'Disease', 'MESH:D009369', (275, 280))
9960	32694937	The methylation of DLEC1 cilia and flagella associated protein is engaged in a favorable clinical outcome and prognosis in patients with small duct ICC.	('patients', 'Species', '9606', (123, 131))	('methylation', 'Var', (4, 15))	('DLEC1', 'Gene', (19, 24))	('DLEC1', 'Gene', '9940', (19, 24))	('small duct ICC', 'Disease', (137, 151))
10000	32694937	The inhibition of the TGF-beta signaling pathway can induce the anti-proliferation properties of cholangiocarcinoma cells.	('anti-proliferation properties', 'CPA', (64, 93))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (97, 115))	('TGF-beta', 'Gene', '7039', (22, 30))	('inhibition', 'Var', (4, 14))	('cholangiocarcinoma', 'Disease', (97, 115))	('TGF-beta', 'Gene', (22, 30))	('induce', 'PosReg', (53, 59))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))
10001	32694937	Additionally, it was also documented that the inhibition of the hedgehog signaling pathway, a potential therapeutic target for human cholangiocarcinoma, attenuated the progression of carcinogenesis in vitro and subsequently increased the necrosis rate of cholangiocarcinoma.	('hedgehog signaling pathway', 'Pathway', (64, 90))	('cholangiocarcinoma', 'Disease', (133, 151))	('inhibition', 'Var', (46, 56))	('carcinogenesis', 'Disease', (183, 197))	('cholangiocarcinoma', 'Disease', (255, 273))	('human', 'Species', '9606', (127, 132))	('necrosis', 'Disease', (238, 246))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (133, 151))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (255, 273))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (133, 151))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (255, 273))	('attenuated', 'NegReg', (153, 163))	('carcinogenesis', 'Disease', 'MESH:D063646', (183, 197))	('necrosis', 'Disease', 'MESH:D009336', (238, 246))	('increased', 'PosReg', (224, 233))
10016	32694937	Interestingly, IGF2 has been reported to be methylated in ICC compared to extrahepatic cholangiocarcinoma.	('methylated', 'Var', (44, 54))	('IGF2', 'Gene', '3481', (15, 19))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (74, 105))	('IGF2', 'Gene', (15, 19))	('extrahepatic cholangiocarcinoma', 'Disease', (74, 105))	('ICC', 'Disease', (58, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))
10020	32694937	The inhibition of IR/IGF1R reduced the epithelial-mesenchymal transition and cancer stem cell-like traits in 'resistant cells' of cholangiocarcinoma.	('reduced', 'NegReg', (27, 34))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (130, 148))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (130, 148))	('inhibition', 'Var', (4, 14))	('IGF1R', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cholangiocarcinoma', 'Disease', (130, 148))	('IGF1R', 'Gene', '3480', (21, 26))	('epithelial-mesenchymal transition', 'CPA', (39, 72))
10058	31956102	Similarly, some studies also suggest that aberrantly expressed miRNAs can be used as diagnostic and prognostic markers for CCA that are closely associated with the pathogenesis, progression and metastasis of CCA.	('CCA', 'Disease', 'MESH:D018281', (208, 211))	('associated', 'Reg', (144, 154))	('CCA', 'Disease', 'MESH:D018281', (123, 126))	('CCA', 'Disease', (208, 211))	('CCA', 'Disease', (123, 126))	('miRNAs', 'Protein', (63, 69))	('aberrantly expressed', 'Var', (42, 62))
10066	31956102	identified nine key lncRNAs in the overall ceRNET by constructing lncRNA-related ceRNETs (HCG18, AC021078.1, ENT-PD1-AS1, MCM3AP-AS1, GMDS-AS1, AC019080.1, AC245452.1, LINC00630 and AP000766.1).	('ENT-PD1-AS1', 'Gene', (109, 120))	('MCM3AP-AS1', 'Gene', (122, 132))	('ENT-PD1-AS1', 'Gene', '728558', (109, 120))	('GMDS-AS1', 'Gene', '100508120', (134, 142))	('LINC00630', 'Gene', (168, 177))	('GMDS-AS1', 'Gene', (134, 142))	('HCG18', 'Gene', '414777', (90, 95))	('MCM3AP-AS1', 'Gene', '114044', (122, 132))	('AC019080.1', 'Var', (144, 154))	('LINC00630', 'Gene', '100287765', (168, 177))	('HCG18', 'Gene', (90, 95))
10086	31956102	The expression level of lncRNA RP11-328K4.1 in the peripheral plasma of 10 ICC patients and 10 healthy subjects is shown in Figure 13.	('RP11', 'Gene', (31, 35))	('ICC', 'Disease', (75, 78))	('RP11', 'Gene', '26121', (31, 35))	('ICC', 'Disease', 'MESH:C535533', (75, 78))	('patients', 'Species', '9606', (79, 87))	('lncRNA', 'Var', (24, 30))
10105	31956102	The areas under the ROC curve (AUCs) of RP11-328K4.1 were 1.000, 0.802, and 1.000 in GSE61850, GSE103909, and TCGA, respectively.	('GSE103909', 'Var', (95, 104))	('GSE61850', 'Var', (85, 93))	('RP11', 'Gene', (40, 44))	('RP11', 'Gene', '26121', (40, 44))
10106	31956102	The AUCs of hsa-miR-27a-3p were 0.965, 0.814, 0.748 and 1.000 in GSE53870, GSE53992, GSE57555, and TCGA, respectively.	('GSE57555', 'Var', (85, 93))	('miR-27a', 'Gene', (16, 23))	('0.748', 'Var', (46, 51))	('miR-27a', 'Gene', '407018', (16, 23))	('GSE53992', 'Var', (75, 83))	('GSE53870', 'Var', (65, 73))	('0.814', 'Var', (39, 44))
10113	31956102	Accumulated evidence suggests that the dysregulation of ceRNA interactions and ceRNETs is involved in the pathogenesis, progression and prognosis of a variety of cancers, including HCC and CCA.	('dysregulation', 'Var', (39, 52))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('cancers', 'Disease', (162, 169))	('HCC', 'Disease', 'MESH:D006528', (181, 184))	('CCA', 'Disease', 'MESH:D018281', (189, 192))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('HCC', 'Disease', (181, 184))	('involved', 'Reg', (90, 98))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('CCA', 'Disease', (189, 192))
10143	31956102	The abnormal expression of miR-27-3p, one of two isoforms of mature miR-27a (the other isoform is miR-27-5p), has been found to play a role in various types of tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('play', 'Reg', (128, 132))	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('miR-27a', 'Gene', (68, 75))	('role', 'Reg', (135, 139))	('miR-27', 'Gene', '407018', (98, 104))	('miR-27', 'Gene', (98, 104))	('miR-27', 'Gene', '407018', (68, 74))	('miR-27', 'Gene', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('miR-27', 'Gene', '407018', (27, 33))	('miR-27', 'Gene', (27, 33))	('miR-27a', 'Gene', '407018', (68, 75))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
10169	31956102	showed that the expression of PROS1 was significantly increased in pleomorphic glioblastoma and that silencing the expression of PROS1 could effectively reduce the activity of pleomorphic malignant glioblastoma cells, inhibiting their proliferation, migration, and invasion and inducing apoptosis.	('glioblastoma', 'Disease', (198, 210))	('glioblastoma', 'Phenotype', 'HP:0012174', (198, 210))	('pleomorphic glioblastoma', 'Disease', 'MESH:D005909', (67, 91))	('invasion', 'CPA', (265, 273))	('inhibiting', 'NegReg', (218, 228))	('inducing', 'Reg', (278, 286))	('silencing', 'Var', (101, 110))	('proliferation', 'CPA', (235, 248))	('PROS1', 'Gene', (30, 35))	('expression', 'MPA', (16, 26))	('pleomorphic glioblastoma', 'Disease', (67, 91))	('PROS1', 'Gene', (129, 134))	('migration', 'CPA', (250, 259))	('glioblastoma', 'Disease', 'MESH:D005909', (79, 91))	('reduce', 'NegReg', (153, 159))	('apoptosis', 'CPA', (287, 296))	('activity', 'MPA', (164, 172))	('glioblastoma', 'Disease', 'MESH:D005909', (198, 210))	('increased', 'PosReg', (54, 63))	('glioblastoma', 'Disease', (79, 91))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))
10171	31956102	showed that the addition of the purified human PROS1 gene significantly increased the migration capacity of these cells, which is inconsistent with our findings.	('increased', 'PosReg', (72, 81))	('human', 'Species', '9606', (41, 46))	('migration capacity of these cells', 'CPA', (86, 119))	('addition', 'Var', (16, 24))	('PROS1 gene', 'Gene', (47, 57))
10174	31956102	A lack of PS can cause anticoagulant mechanism disorder, leading to the formation of thrombosis.	('anticoagulant mechanism disorder', 'MPA', (23, 55))	('thrombosis', 'Disease', 'MESH:D013927', (85, 95))	('lack', 'Var', (2, 6))	('leading to', 'Reg', (57, 67))	('cause', 'Reg', (17, 22))	('thrombosis', 'Disease', (85, 95))
10199	31956102	Upregulated expression of lncRNA RP11-328K4.1 can eliminate the suppression of PROS1 mRNA expression caused by oncogenic miRNA hsa- miR-27a through sponge adsorption, and this thereby illustrates the protective effect of lncRNA RP11-328K4.1 in ICC inhibition.	('ICC', 'Disease', (244, 247))	('miR-27a', 'Gene', (132, 139))	('ICC', 'Disease', 'MESH:C535533', (244, 247))	('suppression', 'MPA', (64, 75))	('eliminate', 'NegReg', (50, 59))	('RP11', 'Gene', (228, 232))	('RP11', 'Gene', (33, 37))	('lncRNA', 'Var', (26, 32))	('miR-27a', 'Gene', '407018', (132, 139))	('PROS1 mRNA expression', 'MPA', (79, 100))	('RP11', 'Gene', '26121', (228, 232))	('RP11', 'Gene', '26121', (33, 37))	('Upregulated', 'PosReg', (0, 11))
10204	31956102	The lncRNA expression profile data were obtained from GSE61850 (five pairs of ICC tumor tissue and matched adjacent nontumor tissue) and GSE103909 (nine pairs of CCA tumor including ICC and adjacent nontumor tissue sample) datasets.	('CCA', 'Disease', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('ICC', 'Disease', (182, 185))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('lncRNA expression profile', 'MPA', (4, 29))	('GSE61850', 'Var', (54, 62))	('tumor', 'Disease', (166, 171))	('ICC', 'Disease', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('ICC', 'Disease', 'MESH:C535533', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('CCA', 'Disease', 'MESH:D018281', (162, 165))	('ICC', 'Disease', 'MESH:C535533', (78, 81))
10205	31956102	miRNA expression profiling data were obtained from GSE53992 (14 pairs of ICC tumor tissues and matched adjacent nontumor tissues), GSE53870 (63 ICC tumor tissues and nine matched adjacent nontumor tissues) and GSE57555 (11 pairs of ICC tumor tissues and matched adjacent nontumor tissues) datasets.	('GSE57555', 'Var', (210, 218))	('ICC', 'Disease', (232, 235))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (274, 279))	('GSE53992', 'Var', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('ICC', 'Disease', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('ICC', 'Disease', 'MESH:C535533', (232, 235))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('ICC', 'Disease', (144, 147))	('GSE53870', 'Var', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('ICC', 'Disease', 'MESH:C535533', (73, 76))	('miRNA expression', 'MPA', (0, 16))	('tumor', 'Disease', (191, 196))	('ICC', 'Disease', 'MESH:C535533', (144, 147))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
10206	31956102	mRNA expression profile data were obtained from GSE61850 (five pairs of ICC tumor tissue and matched adjacent nontumor tissue), GSE103909 (nine pairs of CCA tumor including ICC and matched adjacent nontumor tissues) and GSE57555 (11 pairs of ICC tumor tissue and matched adjacent nontumor tissues) datasets.	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('tumor', 'Disease', (76, 81))	('ICC', 'Disease', 'MESH:C535533', (242, 245))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('CCA', 'Disease', 'MESH:D018281', (153, 156))	('CCA', 'Disease', (153, 156))	('GSE103909', 'Var', (128, 137))	('tumor', 'Disease', (201, 206))	('GSE61850', 'Var', (48, 56))	('ICC', 'Disease', (72, 75))	('tumor', 'Disease', (113, 118))	('ICC', 'Disease', (173, 176))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', (246, 251))	('tumor', 'Disease', (157, 162))	('GSE57555', 'Var', (220, 228))	('ICC', 'Disease', (242, 245))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('ICC', 'Disease', 'MESH:C535533', (72, 75))	('ICC', 'Disease', 'MESH:C535533', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (283, 288))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mRNA expression profile', 'MPA', (0, 23))
10242	31022996	The interruption of such a function can cause cholangiopathies.	('cholangiopathies', 'Disease', 'None', (46, 62))	('cause', 'Reg', (40, 45))	('cholangiopathies', 'Disease', (46, 62))	('interruption', 'Var', (4, 16))
10258	31022996	Disruptions in these signals during bile duct formation or biliary differentiation can cause duct malformation, the most common being Alagille's syndrome, which is caused by mutations in Jag-1 or Notch2.	('Jag-1', 'Gene', (187, 192))	('duct malformation', 'Disease', (93, 110))	('Disruptions', 'Var', (0, 11))	("Alagille's syndrome", 'Disease', (134, 153))	('Notch2', 'Gene', (196, 202))	('cause', 'Reg', (87, 92))	("Alagille's syndrome", 'Disease', 'MESH:D016738', (134, 153))	('caused by', 'Reg', (164, 173))	('Jag-1', 'Gene', '182', (187, 192))	('mutations', 'Var', (174, 183))
10277	31022996	Inactivation of the transcription factor HNF1beta causes similar symptoms; however, unlike HNF6, the gallbladder is present, but clear abnormalities in this organ can be seen through the presence of severe jaundice as well as the intrahepatic bile duct.	('jaundice', 'Disease', 'MESH:D007565', (206, 214))	('HNF1beta', 'Gene', '6928', (41, 49))	('jaundice', 'Disease', (206, 214))	('HNF1beta', 'Gene', (41, 49))	('jaundice', 'Phenotype', 'HP:0000952', (206, 214))	('Inactivation', 'Var', (0, 12))
10283	31022996	Another study performed with the knockout of the RBP-Jkappa gene, which is controlled by the canonical Notch pathway, shows a decline in the number of cells ready to commit to a biliary fate, further highlighting the importance of the Notch pathway.	('RBP-Jkappa', 'Gene', '3516', (49, 59))	('knockout', 'Var', (33, 41))	('RBP-Jkappa', 'Gene', (49, 59))	('Notch', 'Gene', (103, 108))	('Notch', 'Gene', '4851;18128;4853;18129;4854', (103, 108))	('Notch', 'Gene', '4851;18128;4853;18129;4854', (235, 240))	('Notch', 'Gene', (235, 240))	('decline', 'NegReg', (126, 133))
10287	31022996	In chicks, the pro-proliferative action of Wnt signaling was shown, which was further proven in the mice model through the deletion of the CTNNB1 where liver hypoplasia was observed.	('liver hypoplasia', 'Disease', 'MESH:D008107', (152, 168))	('pro-proliferative action', 'MPA', (15, 39))	('mice', 'Species', '10090', (100, 104))	('liver hypoplasia', 'Disease', (152, 168))	('deletion', 'Var', (123, 131))	('rat', 'Species', '10116', (26, 29))	('chick', 'Species', '9031', (3, 8))	('CTNNB1', 'Gene', (139, 145))
10288	31022996	Not only do they play an important role in regulating the normal developmental stages of the liver, but studies also show that the Wnt/beta-catenin pathway also promotes biliary differentiation where a disruption in this pathway has led to the inhibition of this process.	('promotes', 'PosReg', (161, 169))	('beta-catenin', 'Gene', (135, 147))	('disruption', 'Var', (202, 212))	('beta-catenin', 'Gene', '1499', (135, 147))	('biliary', 'Disease', (170, 177))
10292	31022996	Studies done on mice models that are heterozygous for the SMAD2/3 (signaling mediators) show that mutations or disruptions can cause liver hypoplasia.	('disruptions', 'Var', (111, 122))	('SMAD2/3', 'Gene', '17126;17127', (58, 65))	('cause', 'Reg', (127, 132))	('liver hypoplasia', 'Disease', 'MESH:D008107', (133, 149))	('mice', 'Species', '10090', (16, 20))	('mutations', 'Var', (98, 107))	('liver hypoplasia', 'Disease', (133, 149))	('SMAD2/3', 'Gene', (58, 65))
10293	31022996	However, the distal mediator called Yap1 can provide some evidence where the deletion of this gene can cause bile duct formation to fall through and the levels of serum bilirubin to increase.	('increase', 'PosReg', (182, 190))	('bile duct formation', 'MPA', (109, 128))	('Yap1', 'Gene', (36, 40))	('fall', 'NegReg', (132, 136))	('deletion', 'Var', (77, 85))	('fall', 'Phenotype', 'HP:0002527', (132, 136))	('bilirubin', 'Chemical', 'MESH:D001663', (169, 178))	('levels of serum bilirubin', 'MPA', (153, 178))	('Yap1', 'Gene', '10413', (36, 40))
10299	31022996	In the mouse model, mutations in the Jagged 1 ligand and notch2 receptor cause Alagille syndrome (AGS).	('Alagille syndrome', 'Disease', (79, 96))	('Jagged 1', 'Gene', '16449', (37, 45))	('mouse', 'Species', '10090', (7, 12))	('AGS', 'Disease', (98, 101))	('Alagille syndrome', 'Disease', 'MESH:D016738', (79, 96))	('Jagged 1', 'Gene', (37, 45))	('notch2', 'Gene', (57, 63))	('AGS', 'Disease', 'MESH:C535607', (98, 101))	('notch2', 'Gene', '18129', (57, 63))	('cause', 'Reg', (73, 78))	('mutations', 'Var', (20, 29))
10305	31022996	Among hepatobiliary flues, infections with Opisthorchis viverrini as well as Clonorchis sinensis are known to cause CCA due to their ability to cause inflammation through infections.	('inflammation through infections', 'Disease', (150, 181))	('CCA', 'Phenotype', 'HP:0030153', (116, 119))	('Clonorchis sinensis', 'Var', (77, 96))	('hepatobiliary flues, infections', 'Disease', 'MESH:D004066', (6, 37))	('cause', 'Reg', (144, 149))	('Clonorchis sinensis', 'Species', '79923', (77, 96))	('CCA', 'Disease', (116, 119))	('Opisthorchis viverrini', 'Species', '6198', (43, 65))	('cause', 'Reg', (110, 115))	('inflammation through infections', 'Disease', 'MESH:D007249', (150, 181))	('Opisthorchis', 'Gene', (43, 55))
10322	31022996	DPM is also associated with autosomal dominant polycystic disease (ADPKD) and is thought to be a result of PKD1 as well as PKD2 mutations.	('PKD2', 'Gene', (123, 127))	('ADPKD', 'Disease', 'MESH:D007690', (67, 72))	('mutations', 'Var', (128, 137))	('autosomal dominant polycystic disease', 'Disease', 'MESH:C536324', (28, 65))	('DPM', 'Disease', (0, 3))	('PKD2', 'Gene', '5311', (123, 127))	('PKD1', 'Gene', (107, 111))	('associated', 'Reg', (12, 22))	('autosomal dominant polycystic disease', 'Disease', (28, 65))	('ADPKD', 'Disease', (67, 72))	('PKD1', 'Gene', '5310', (107, 111))
10326	31022996	Cystic fibrosis is the result of an accumulation of mutations in the CFTR gene that affects cholangiocytes and is therefore called 'cystic fibrosis-associated cholangiopathy'.	('mutations', 'Var', (52, 61))	('Cystic fibrosis', 'Disease', 'MESH:D003550', (0, 15))	('CFTR', 'Gene', '1080', (69, 73))	('cholangiopathy', 'Disease', (159, 173))	('result', 'Reg', (23, 29))	('CFTR', 'Gene', (69, 73))	('Cystic fibrosis', 'Disease', (0, 15))	('cystic fibrosis', 'Disease', 'MESH:D003550', (132, 147))	('cholangiopathy', 'Disease', 'None', (159, 173))	('cystic fibrosis', 'Disease', (132, 147))
10333	31022996	Furthermore, there is insufficient data showing that UDCA can increase the survival time of patients suffering with cholangiopathies.	('survival time', 'CPA', (75, 88))	('UDCA', 'Var', (53, 57))	('cholangiopathies', 'Disease', 'None', (116, 132))	('patients', 'Species', '9606', (92, 100))	('cholangiopathies', 'Disease', (116, 132))	('increase', 'PosReg', (62, 70))
10343	31022996	Their first step was from hIPSC to definitive endoderm by the addition of Activin A, FGF2, BMP4, Ly294001 and conditioned differentiation media.	('Ly294001', 'Var', (97, 105))	('FGF2', 'Gene', (85, 89))	('BMP4', 'Gene', (91, 95))	('BMP4', 'Gene', '652', (91, 95))	('FGF2', 'Gene', '2247', (85, 89))	('Activin', 'Gene', (74, 81))
10415	28808285	Differentiating peripheral cholangiocarcinoma in stages T1N0M0 and T2N0M0 from hepatic hypovascular nodules using dynamic contrast-enhanced MRI Because cholangiocarcinoma shows no specific clinical signs or symptoms and presents with non-specific biological and tumor markers in the early stages, MRI findings often lack typical features before this lesion becomes symptomatic and might be mistaken for other liver lesions.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (152, 170))	('hepatic hypovascular', 'Disease', 'MESH:D056486', (79, 99))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (152, 170))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('cholangiocarcinoma', 'Disease', (27, 45))	('liver lesions', 'Disease', 'MESH:D017093', (409, 422))	('tumor', 'Disease', (262, 267))	('liver lesions', 'Disease', (409, 422))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (27, 45))	('T2N0M0', 'Var', (67, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('cholangiocarcinoma', 'Disease', (152, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (27, 45))	('hepatic hypovascular', 'Disease', (79, 99))	('tumor', 'Disease', 'MESH:D009369', (262, 267))
10416	28808285	An evaluation of relevant radiological findings in nodular cholangiocarcinoma (<=3 cm) in stages T1N0M0 and T2N0M0 is urgently needed.	('nodular cholangiocarcinoma', 'Disease', (51, 77))	('T2N0M0', 'Var', (108, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('nodular cholangiocarcinoma', 'Disease', 'MESH:D020518', (51, 77))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (59, 77))
10434	28808285	TNM staging of PCC (UICC/AJCC, 5th Edition of TNM Staging) defined T1N0M0 in 10 lesions and T2N0M0 in 16.	('TNM', 'Gene', (46, 49))	('TNM', 'Gene', '10178', (0, 3))	('T1N0M0', 'Var', (67, 73))	('PCC', 'Gene', '1421', (15, 18))	('TNM', 'Gene', (0, 3))	('TNM', 'Gene', '10178', (46, 49))	('T2N0M0', 'Var', (92, 98))	('PCC', 'Gene', (15, 18))
10463	28808285	Although early stage PCCs showed almost no such performance, most SNNs in our cases had iso- or hypointensity on T2WI, which is thought to be related to a low level of hydration, vascularity, and cellularity and to the presence of coagulative necrosis.	('necrosis', 'Disease', 'MESH:D009336', (243, 251))	('PCC', 'Gene', (21, 24))	('iso-', 'MPA', (88, 92))	('coagulative necrosis', 'Phenotype', 'HP:0010885', (231, 251))	('necrosis', 'Disease', (243, 251))	('hypointensity', 'Var', (96, 109))	('PCC', 'Gene', '1421', (21, 24))
10494	28036280	We thus assume that the destruction of a coordinated regulatory network might result in tumorigenesis and tumor progression.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('result in', 'Reg', (78, 87))	('destruction', 'Var', (24, 35))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (106, 111))
10498	28036280	They proposed that perturbation of these conserved genes was associated with embryonic lethality and cancer.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('perturbation', 'Var', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('associated', 'Reg', (61, 71))	('embryonic lethality', 'Disease', 'MESH:D020964', (77, 96))	('embryonic lethality', 'Disease', (77, 96))
10537	28036280	Meanwhile, gene ontology (GO) analysis of DEGs (244 genes) in at least 12 cancers revealed that they were mainly enriched in the cell cycle (FDR corrected P-value 1.6260E-40, 77 genes), organelle organization (FDR corrected P-value 5.6591E-18, 68 genes), mitosis (FDR corrected P-value 1.3085E-35, 45 genes), etc., which were all closely related to tumor characteristics (Figures 4B, , and 4D).	('mitosis', 'Disease', 'None', (255, 262))	('cell cycle', 'CPA', (129, 139))	('FDR', 'Var', (210, 213))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('FDR', 'Var', (264, 267))	('organelle organization', 'CPA', (186, 208))	('mitosis', 'Disease', (255, 262))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('related', 'Reg', (338, 345))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (349, 354))
10541	28036280	Additionally, they can be significantly separated into two groups (Supplementary Figure 3, logrank test, P < 0.05) based on 3~25 survival-related DEGs in each cancer (Supplementary Table 3).	('cancer', 'Disease', (159, 165))	('DEGs', 'Var', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
10555	28036280	Further identification of shared DEGs between normal and tumor tissues uncovers dysregulation of cell cycle processes, which is one of the hallmarks in cancer.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('dysregulation of cell cycle', 'Phenotype', 'HP:0011018', (80, 107))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cell cycle processes', 'CPA', (97, 117))	('dysregulation', 'Var', (80, 93))	('tumor', 'Disease', (57, 62))
10561	28036280	It encodes thyroid peroxidase enzyme, which is a thyroid-specific glycosylated hemoprotein, and aberrant regulation of TPO can result in thyroid dyshormonogenesis.	('TPO', 'Gene', (119, 122))	('aberrant regulation', 'Var', (96, 115))	('thyroid dyshormonogenesis', 'Disease', (137, 162))	('result in', 'Reg', (127, 136))	('thyroid dyshormonogenesis', 'Disease', 'MESH:C564766', (137, 162))	('TPO', 'Gene', '7173', (119, 122))
10624	26937426	Additionally, inactivation of tumor suppressor genes like TP53, and activation of oncogenes like CTNNB1/beta-catenin (and the Wnt pathway) has been implicated in the etiopathogenesis of HCC.	('tumor suppressor', 'Gene', '7248', (30, 46))	('HCC', 'Gene', '619501', (186, 189))	('beta-catenin', 'Gene', (104, 116))	('CC', 'Phenotype', 'HP:0030153', (187, 189))	('implicated', 'Reg', (148, 158))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('beta-catenin', 'Gene', '1499', (104, 116))	('HCC', 'Phenotype', 'HP:0001402', (186, 189))	('CTNNB1', 'Gene', '1499', (97, 103))	('inactivation', 'Var', (14, 26))	('activation', 'PosReg', (68, 78))	('tumor suppressor', 'Gene', (30, 46))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('HCC', 'Gene', (186, 189))	('CTNNB1', 'Gene', (97, 103))
10625	26937426	On the other hand, a microsatellite instability (MSI-H) phenotype, TP53 and KRAS2 mutations have been described in CC.	('MSI-H', 'Disease', 'MESH:D000848', (49, 54))	('microsatellite instability', 'MPA', (21, 47))	('KRAS2', 'Gene', '3845', (76, 81))	('CC', 'Phenotype', 'HP:0030153', (115, 117))	('mutations', 'Var', (82, 91))	('TP53', 'Gene', '7157', (67, 71))	('KRAS2', 'Gene', (76, 81))	('TP53', 'Gene', (67, 71))	('MSI-H', 'Disease', (49, 54))	('described', 'Reg', (102, 111))
10627	26937426	Genome-wide typing has demonstrated higher incidences of LOH at chromosomes 3p and 14q in cHCC-CC and CC and can be taken as specific to these tumors.	('LOH', 'Var', (57, 60))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('HCC', 'Gene', '619501', (91, 94))	('HCC', 'Phenotype', 'HP:0001402', (91, 94))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('rat', 'Species', '10116', (30, 33))	('CC', 'Phenotype', 'HP:0030153', (92, 94))	('CC', 'Phenotype', 'HP:0030153', (95, 97))	('CC', 'Phenotype', 'HP:0030153', (102, 104))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('HCC', 'Gene', (91, 94))
10631	26937426	Mutation of tumor suppressor gene TP53 cannot be correlated with tumor differentiation in primary hepatic tumors, as it is seen in 11% of CC, 27% of cHCC-CC, and 26% of HCC.	('hepatic tumors', 'Disease', (98, 112))	('HCC', 'Gene', '619501', (150, 153))	('HCC', 'Phenotype', 'HP:0001402', (150, 153))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', (106, 111))	('HCC', 'Gene', (150, 153))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('CC', 'Phenotype', 'HP:0030153', (154, 156))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('CC', 'Phenotype', 'HP:0030153', (138, 140))	('tumor suppressor', 'Gene', (12, 28))	('TP53', 'Gene', (34, 38))	('hepatic tumor', 'Phenotype', 'HP:0002896', (98, 111))	('CC', 'Phenotype', 'HP:0030153', (170, 172))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('HCC', 'Gene', '619501', (169, 172))	('HCC', 'Phenotype', 'HP:0001402', (169, 172))	('tumor suppressor', 'Gene', '7248', (12, 28))	('Mutation', 'Var', (0, 8))	('HCC', 'Gene', (169, 172))	('hepatic tumors', 'Disease', 'MESH:D056486', (98, 112))	('CC', 'Phenotype', 'HP:0030153', (151, 153))	('TP53', 'Gene', '7157', (34, 38))
10638	26937426	This demonstration of common allelic losses in each element of the lesion strongly supports the hypothesis that these cancers are of monoclonal origin with bidirectional phenotypic differentiation.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('rat', 'Species', '10116', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('allelic losses', 'Var', (29, 43))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
10708	21440549	Chronic cholestasis was induced by DLD and accelerated progression of cholangiocarcinoma, compared with mice given only DEN.	('rat', 'Species', '10116', (49, 52))	('DEN', 'Chemical', 'MESH:D004052', (120, 123))	('cholangiocarcinoma', 'Disease', (70, 88))	('Chronic cholestasis', 'Disease', (0, 19))	('mice', 'Species', '10090', (104, 108))	('DLD', 'Var', (35, 38))	('accelerated', 'PosReg', (43, 54))	('cholestasis', 'Phenotype', 'HP:0001396', (8, 19))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (70, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('induced', 'Reg', (24, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))	('Chronic cholestasis', 'Disease', 'MESH:D002779', (0, 19))
10716	21440549	DLD induction of chronic cholestasis accelerated progression of cholangiocarcinoma, which is mediated by downregulation of miR-34a, upregulation miR-210, and replacement of Mnt by c-Myc in binding to cyclin D1.	('Myc', 'Gene', (182, 185))	('cyclin D1', 'Gene', (200, 209))	('binding', 'Interaction', (189, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('miR-34a', 'Gene', '723848', (123, 130))	('miR-34a', 'Gene', (123, 130))	('Mnt', 'Gene', (173, 176))	('cholestasis', 'Phenotype', 'HP:0001396', (25, 36))	('Myc', 'Gene', '17869', (182, 185))	('miR-210', 'Gene', (145, 152))	('chronic cholestasis', 'Disease', 'MESH:D002779', (17, 36))	('upregulation', 'PosReg', (132, 144))	('chronic cholestasis', 'Disease', (17, 36))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('cholangiocarcinoma', 'Disease', (64, 82))	('replacement', 'Var', (158, 169))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (64, 82))	('downregulation', 'NegReg', (105, 119))	('rat', 'Species', '10116', (43, 46))	('cyclin D1', 'Gene', '12443', (200, 209))	('miR-210', 'Gene', '387206', (145, 152))	('Mnt', 'Gene', '17428', (173, 176))
10732	21440549	c-Myc target gene cyclin D1 is a CCA molecular biomarker and aberrant expression of cyclin D1 contributes to dedifferentiation and cell proliferation in CCA.	('aberrant expression', 'Var', (61, 80))	('cyclin D1', 'Gene', '12443', (84, 93))	('cyclin D1', 'Gene', (18, 27))	('dedifferentiation', 'CPA', (109, 126))	('CCA', 'Disease', (153, 156))	('cyclin D1', 'Gene', (84, 93))	('cyclin D1', 'Gene', '12443', (18, 27))	('contributes', 'Reg', (94, 105))	('cell proliferation', 'CPA', (131, 149))	('rat', 'Species', '10116', (143, 146))	('CCA', 'Phenotype', 'HP:0030153', (153, 156))	('Myc', 'Gene', (2, 5))	('Myc', 'Gene', '17869', (2, 5))	('CCA', 'Phenotype', 'HP:0030153', (33, 36))
10761	21440549	In order to maintain a high level of c-Myc or Mnt knockdown for 16 weeks, repeated tail vein injections were done at week 1, 2, 4, 6, 8, 10, 12 and 14.	('Myc', 'Gene', (39, 42))	('Myc', 'Gene', '17869', (39, 42))	('Mnt', 'Gene', (46, 49))	('Mnt', 'Gene', '17428', (46, 49))	('knockdown', 'Var', (50, 59))
10774	21440549	Mice with LMBDL surgery displayed reduced activity during the first week but regained normal activity after 2 weeks.	('reduced', 'NegReg', (34, 41))	('activity', 'MPA', (42, 50))	('LMBDL', 'Chemical', '-', (10, 15))	('activity', 'MPA', (93, 101))	('surgery', 'Var', (16, 23))	('Mice', 'Species', '10090', (0, 4))	('LMBDL', 'Gene', (10, 15))
10781	21440549	Our results showed that LMBDL alone caused cholangiofibrosis and bile duct proliferation in the ligated lobes (Supplementary Fig.	('cholangiofibrosis', 'Disease', (43, 60))	('LMBDL', 'Chemical', '-', (24, 29))	('bile duct proliferation', 'Phenotype', 'HP:0001408', (65, 88))	('LMBDL', 'Var', (24, 29))	('rat', 'Species', '10116', (82, 85))	('caused', 'Reg', (36, 42))	('bile duct proliferation', 'CPA', (65, 88))	('cholangiofibrosis', 'Disease', 'None', (43, 60))
10787	21440549	At week 28, the ALT levels in the LMBDL, DL and DLD groups were 6.2, 10.7 and 13.4 fold higher compared to the control group, respectively.	('higher', 'PosReg', (88, 94))	('LMBDL', 'Chemical', '-', (34, 39))	('DLD', 'Var', (48, 51))	('ALT', 'Gene', '76282', (16, 19))	('LMBDL', 'Var', (34, 39))	('ALT', 'Gene', (16, 19))
10797	21440549	We found PCNA-positive cholangiocytes peaked at week 1 and declined steadily from week 2 on in the LMBDL group, whereas it kept rising for the DL and DLD groups.	('LMBDL', 'Var', (99, 104))	('PCNA', 'Gene', '18538', (9, 13))	('declined', 'NegReg', (59, 67))	('PCNA', 'Gene', (9, 13))	('LMBDL', 'Chemical', '-', (99, 104))
10798	21440549	The number of PCNA positive cholangiocytes in the LMBDL, DL and DLD groups was 1.6, 6.8 and 10.1 fold higher compared to that of the DD group at week 28, respectively (Fig.	('PCNA', 'Gene', '18538', (14, 18))	('DLD', 'Var', (64, 67))	('DD', 'Chemical', 'MESH:C007792', (133, 135))	('higher', 'PosReg', (102, 108))	('PCNA', 'Gene', (14, 18))	('LMBDL', 'Chemical', '-', (50, 55))
10801	21440549	1A-B), we speculate that LMBDL would accelerate DEN-initiated liver cancer formation.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('liver cancer', 'Phenotype', 'HP:0002896', (62, 74))	('rat', 'Species', '10116', (43, 46))	('DEN', 'Chemical', 'MESH:D004052', (48, 51))	('LMBDL', 'Chemical', '-', (25, 30))	('liver cancer', 'Disease', 'MESH:D006528', (62, 74))	('LMBDL', 'Var', (25, 30))	('liver cancer', 'Disease', (62, 74))	('accelerate', 'PosReg', (37, 47))
10808	21440549	Cholangiomas which consisted of densely packed proliferating tubular ducts was observed in the DL and DLD groups (Fig.	('DLD', 'Var', (102, 105))	('Cholangiomas', 'Disease', (0, 12))	('Cholangiomas', 'Disease', 'MESH:D002759', (0, 12))	('rat', 'Species', '10116', (54, 57))
10814	21440549	Previously, we showed that c-Myc expression was upregulated during acute liver injury induced by LHBDL and CBDL.	('Myc', 'Gene', '17869', (29, 32))	('LHBDL', 'Chemical', '-', (97, 102))	('liver injury', 'Disease', 'MESH:D056486', (73, 85))	('CBDL', 'Chemical', '-', (107, 111))	('LHBDL', 'Var', (97, 102))	('expression', 'MPA', (33, 43))	('upregulated', 'PosReg', (48, 59))	('CBDL', 'Var', (107, 111))	('liver injury', 'Disease', (73, 85))	('Myc', 'Gene', (29, 32))
10833	21440549	We previously showed that Mnt expression was downregulated during acute liver injury induced by LHBDL and CBDL.	('liver injury', 'Disease', (72, 84))	('liver injury', 'Disease', 'MESH:D056486', (72, 84))	('LHBDL', 'Chemical', '-', (96, 101))	('CBDL', 'Chemical', '-', (106, 110))	('Mnt', 'Gene', '17428', (26, 29))	('Mnt', 'Gene', (26, 29))	('LHBDL', 'Var', (96, 101))	('downregulated', 'NegReg', (45, 58))
10866	21440549	Mnt siRNA knockdown in DLD mice increased cholangiofibrosis, CA and proliferation of the ductular cells compared to DLD+scrambled siRNA (Fig.	('cholangiofibrosis', 'Disease', 'None', (42, 59))	('mice', 'Species', '10090', (27, 31))	('rat', 'Species', '10116', (75, 78))	('cholangiofibrosis', 'Disease', (42, 59))	('Mnt', 'Gene', (0, 3))	('increased', 'PosReg', (32, 41))	('Mnt', 'Gene', '17428', (0, 3))	('knockdown', 'Var', (10, 19))	('proliferation of the', 'CPA', (68, 88))
10868	21440549	c-Myc siRNA knockdown in DLD led to a 2.1 fold fall in c-Myc mRNA, a 1.7 fold increase in Mnt and a 1.9 fold fall in cyclin D1 compared to DLD+scrambled siRNA.	('fall', 'Phenotype', 'HP:0002527', (47, 51))	('cyclin D1', 'Gene', (117, 126))	('Myc', 'Gene', (57, 60))	('fall', 'Phenotype', 'HP:0002527', (109, 113))	('Myc', 'Gene', '17869', (57, 60))	('knockdown', 'Var', (12, 21))	('increase', 'PosReg', (78, 86))	('fall', 'NegReg', (109, 113))	('cyclin D1', 'Gene', '12443', (117, 126))	('fall', 'NegReg', (47, 51))	('Mnt', 'Gene', '17428', (90, 93))	('Myc', 'Gene', (2, 5))	('Myc', 'Gene', '17869', (2, 5))	('Mnt', 'Gene', (90, 93))
10869	21440549	Mnt siRNA in DLD led to a 2.6 fold fall in Mnt, a 1.5 fold increase in c-Myc, and a 1.8 fold increase in cyclin D1 compared to scrambled siRNA (Fig.	('cyclin D1', 'Gene', '12443', (105, 114))	('increase', 'PosReg', (93, 101))	('fall', 'NegReg', (35, 39))	('Mnt', 'Gene', (43, 46))	('Mnt', 'Gene', '17428', (43, 46))	('siRNA', 'Var', (4, 9))	('Mnt', 'Gene', '17428', (0, 3))	('Mnt', 'Gene', (0, 3))	('cyclin D1', 'Gene', (105, 114))	('Myc', 'Gene', (73, 76))	('Myc', 'Gene', '17869', (73, 76))	('fall', 'Phenotype', 'HP:0002527', (35, 39))	('increase', 'PosReg', (59, 67))
10870	21440549	c-Myc or Mnt siRNA knockdown in DLD had a similar effect on c-Myc, Mnt and cyclin D1 protein expression (Fig.	('Mnt', 'Gene', (67, 70))	('Mnt', 'Gene', (9, 12))	('Mnt', 'Gene', '17428', (67, 70))	('cyclin D1', 'Gene', '12443', (75, 84))	('Mnt', 'Gene', '17428', (9, 12))	('knockdown', 'Var', (19, 28))	('Myc', 'Gene', (62, 65))	('Myc', 'Gene', '17869', (62, 65))	('cyclin D1', 'Gene', (75, 84))	('Myc', 'Gene', (2, 5))	('Myc', 'Gene', '17869', (2, 5))
10886	21440549	Our results confirm that c-Myc induction and Mnt reduction are required for the upregulation of cyclin D1 in vivo since c-Myc knockdown prevented the switch from Mnt to c-Myc E-box binding (Fig.	('cyclin D1', 'Gene', (96, 105))	('Mnt', 'Gene', (162, 165))	('Myc', 'Gene', (171, 174))	('prevented', 'NegReg', (136, 145))	('Mnt', 'Gene', '17428', (45, 48))	('Myc', 'Gene', (122, 125))	('Myc', 'Gene', (27, 30))	('cyclin D1', 'Gene', '12443', (96, 105))	('Myc', 'Gene', '17869', (171, 174))	('Myc', 'Gene', '17869', (27, 30))	('Myc', 'Gene', '17869', (122, 125))	('Mnt', 'Gene', (45, 48))	('knockdown', 'Var', (126, 135))	('Mnt', 'Gene', '17428', (162, 165))
10887	21440549	Mnt siRNA knockdown also led to increased c-Myc binding and expression of cyclin D1 (Fig.	('expression', 'MPA', (60, 70))	('Myc', 'Gene', (44, 47))	('Myc', 'Gene', '17869', (44, 47))	('binding', 'Interaction', (48, 55))	('cyclin D1', 'Gene', (74, 83))	('Mnt', 'Gene', (0, 3))	('increased', 'PosReg', (32, 41))	('Mnt', 'Gene', '17428', (0, 3))	('knockdown', 'Var', (10, 19))	('cyclin D1', 'Gene', '12443', (74, 83))
10888	21440549	In addition, c-Myc knockdown significantly reduced both cholangiofibrosis and CA in the DLD mice, but not completely blocked its formation.	('Myc', 'Gene', '17869', (15, 18))	('knockdown', 'Var', (19, 28))	('cholangiofibrosis', 'Disease', 'None', (56, 73))	('cholangiofibrosis', 'Disease', (56, 73))	('reduced', 'NegReg', (43, 50))	('mice', 'Species', '10090', (92, 96))	('Myc', 'Gene', (15, 18))
10891	21440549	It is possible that the CCA in the unligated lobes of a few DLD mice maybe the result of signaling pathways that work in a paracrine manner that is activated under the conditions of DLD and not with other treatments.	('DLD', 'Var', (182, 185))	('signaling pathways', 'Pathway', (89, 107))	('CCA', 'Phenotype', 'HP:0030153', (24, 27))	('activated', 'PosReg', (148, 157))	('CCA', 'Disease', (24, 27))	('mice', 'Species', '10090', (64, 68))
10932	31044430	The SEER-Medicare database was queried for patients with cholangiocarcinoma as defined by the International Classification of Diseases for Oncology Third Edition [ICD-O-3] topography codes (C22.1 or C24.0) between the years 1991 and 2013.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (57, 75))	('Oncology', 'Phenotype', 'HP:0002664', (139, 147))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('C22.1', 'Var', (190, 195))	('patients', 'Species', '9606', (43, 51))	('cholangiocarcinoma', 'Disease', (57, 75))
10986	31044430	Obstruction is common in this patient population and surgical resection in the setting of unrelieved obstruction has been associated with elevated rates of postoperative mortality (3-18%) resulting from liver failure.	('obstruction', 'Disease', 'MESH:D000402', (101, 112))	('patient', 'Species', '9606', (30, 37))	('mortality', 'Disease', (170, 179))	('obstruction', 'Disease', (101, 112))	('surgical', 'Var', (53, 61))	('mortality', 'Disease', 'MESH:D003643', (170, 179))	('liver failure', 'Phenotype', 'HP:0001399', (203, 216))	('liver failure', 'Disease', 'MESH:D017093', (203, 216))	('liver failure', 'Disease', (203, 216))
11016	27357089	These findings from a large prospective cohort provide evidence that suboptimal Se status in Europeans may be associated with an appreciably increased risk of HCC development.	('HCC', 'Gene', (159, 162))	('Se', 'Chemical', 'MESH:D012643', (80, 82))	('men', 'Species', '9606', (170, 173))	('HCC', 'Gene', '619501', (159, 162))	('suboptimal', 'Var', (69, 79))	('HCC', 'Phenotype', 'HP:0001402', (159, 162))
11022	27357089	A growing body of experimental and observational evidence suggests that suboptimal intakes of the micronutrient selenium (Se) contribute to the development of several cancers.	('men', 'Species', '9606', (151, 154))	('men', 'Species', '9606', (24, 27))	('Se', 'Chemical', 'MESH:D012643', (122, 124))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('selenium', 'Chemical', 'MESH:D012643', (112, 120))	('cancers', 'Disease', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('suboptimal', 'Var', (72, 82))
11031	27357089	Interestingly, low Se intake is thought to increase vulnerability to viral infections, which may be particularly important due to the marked link between hepatitis virus infection and liver cancer development.	('hepatitis', 'Phenotype', 'HP:0012115', (154, 163))	('low', 'Var', (15, 18))	('hepatitis virus infection', 'Disease', 'MESH:D006525', (154, 179))	('viral infections', 'Disease', (69, 85))	('hepatitis virus infection', 'Disease', (154, 179))	('men', 'Species', '9606', (204, 207))	('liver cancer', 'Disease', 'MESH:D006528', (184, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('liver cancer', 'Phenotype', 'HP:0002896', (184, 196))	('viral infections', 'Disease', 'MESH:D001102', (69, 85))	('liver cancer', 'Disease', (184, 196))	('Se', 'Chemical', 'MESH:D012643', (19, 21))
11043	27357089	First incident HCC and IHBC were defined as C22.0 and C22.1, respectively, as per the 10th Revision of the International Statistical Classification of Diseases, Injury and Causes of Death (ICD-10) and the 2nd edition of the International Classification of Diseases for Oncology (ICD-O-2).	('Oncology', 'Phenotype', 'HP:0002664', (269, 277))	('HCC', 'Phenotype', 'HP:0001402', (15, 18))	('HCC', 'Gene', '619501', (15, 18))	('IHBC', 'Disease', (23, 27))	('C22.1', 'Var', (54, 59))	('HCC', 'Gene', (15, 18))
11044	27357089	Gallbladder and biliary tract cancers (GBTC) included tumours in the gallbladder (C23.9), extrahepatic bile ducts (C24.0), Ampulla of Vater (C24.1), and biliary tract (C24.8 and C24.9) with morphology code ICD-O-2 "8162/3".	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('GBTC', 'Chemical', '-', (39, 43))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('tumours', 'Disease', (54, 61))	('C24.8', 'Var', (168, 173))	('extrahepatic', 'Disease', (90, 102))	('C24.9', 'Var', (178, 183))	('biliary tract cancers', 'Disease', 'MESH:D001661', (16, 37))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('biliary tract cancers', 'Disease', (16, 37))
11071	27357089	Additional analyses were performed including adjustment for an ad hoc liver function score (range from 0 to 6; categorized as 0=no liver injury, 1-2=possible minor injury, >=3=possible injury), which summarizes the number of abnormal values for six liver function tests (ALT>55 U/L, AST>34 U/L, GGT men>64 U/L, GGT women>36 U/L, AP>150 U/L, albumin<35 g/L, total bilirubin>20.5 mumol/L; cut-points were provided by the laboratory and were based on assay specifications).	('men', 'Species', '9606', (51, 54))	('GGT', 'Gene', (295, 298))	('total bilirubin', 'MPA', (357, 372))	('bilirubin', 'Chemical', 'MESH:D001663', (363, 372))	('ALT>55 U/L', 'Var', (271, 281))	('GGT', 'Gene', '728226', (311, 314))	('minor injury', 'Disease', 'MESH:D006259', (158, 170))	('liver injury', 'Disease', (131, 143))	('AST', 'Gene', '26503', (283, 286))	('men', 'Species', '9606', (317, 320))	('women', 'Species', '9606', (315, 320))	('GGT', 'Gene', '728226', (295, 298))	('GGT', 'Gene', (311, 314))	('albumin', 'MPA', (341, 348))	('men', 'Species', '9606', (299, 302))	('liver injury', 'Disease', 'MESH:D056486', (131, 143))	('minor injury', 'Disease', (158, 170))	('AST', 'Gene', (283, 286))	('rat', 'Species', '10116', (423, 426))
11100	27357089	In this study, the correlation between Se and SePP levels was relatively high (r=0.62; P=<0.001), reflecting that most subjects had suboptimal Se levels to fully saturate SePP (and GPX3), and very similar to our previous analysis of the same Se status markers in a separate study on colorectal cancer, also nested within EPIC.	('Se a', 'Chemical', '-', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('GPX3', 'Gene', '2878', (181, 185))	('suboptimal', 'Var', (132, 142))	('Se', 'Chemical', 'MESH:D012643', (143, 145))	('GPX3', 'Gene', (181, 185))	('Se', 'Chemical', 'MESH:D012643', (171, 173))	('colorectal cancer', 'Disease', 'MESH:D015179', (283, 300))	('rat', 'Species', '10116', (166, 169))	('colorectal cancer', 'Phenotype', 'HP:0003003', (283, 300))	('Se', 'Chemical', 'MESH:D012643', (242, 244))	('Se', 'Chemical', 'MESH:D012643', (39, 41))	('rat', 'Species', '10116', (269, 272))	('Se', 'Chemical', 'MESH:D012643', (46, 48))	('colorectal cancer', 'Disease', (283, 300))	('SePP', 'MPA', (171, 175))
11102	27357089	Attenuated expression of SePP and dysregulation of the expression of other selenoproteins resulting from suboptimal Se availability affects responses to important carcinogenic processes like oxidative stress and this may underline the association of these Se status markers with liver cancer.	('affects', 'Reg', (132, 139))	('Se a', 'Chemical', '-', (116, 120))	('Se', 'Chemical', 'MESH:D012643', (116, 118))	('liver cancer', 'Phenotype', 'HP:0002896', (279, 291))	('Attenuated', 'NegReg', (0, 10))	('dysregulation', 'Var', (34, 47))	('suboptimal', 'Var', (105, 115))	('expression', 'MPA', (11, 21))	('Se', 'Chemical', 'MESH:D012643', (25, 27))	('liver cancer', 'Disease', 'MESH:D006528', (279, 291))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('expression', 'MPA', (55, 65))	('liver cancer', 'Disease', (279, 291))	('carcinogenic', 'Disease', 'MESH:D063646', (163, 175))	('carcinogenic', 'Disease', (163, 175))	('SePP', 'Gene', (25, 29))	('oxidative stress', 'Phenotype', 'HP:0025464', (191, 207))	('Se', 'Chemical', 'MESH:D012643', (256, 258))
11108	27357089	Together, these studies indicate that even a minor dysfunction of hepatocytes may reduce serum Se and SePP concentrations (through lower circulating SePP levels).	('rat', 'Species', '10116', (114, 117))	('serum Se', 'MPA', (89, 97))	('SePP concentrations', 'MPA', (102, 121))	('dysfunction', 'Var', (51, 62))	('reduce', 'NegReg', (82, 88))	('circulating SePP levels', 'MPA', (137, 160))	('lower', 'NegReg', (131, 136))	('Se a', 'Chemical', '-', (95, 99))
11109	27357089	This suggests a potential mechanism of liver carcinogenesis whereby the dysregulation of SePP expression and secretion due to impaired Se organification (i.e., weakened conversion of dietary Se into selenoproteins such as SePP by sub-functional or de-differentiated hepatocytes) contributes to oxidative stress damage in hepatocytes.	('stress damage', 'Disease', (304, 317))	('secretion', 'MPA', (109, 118))	('Se', 'Chemical', 'MESH:D012643', (89, 91))	('weakened', 'NegReg', (160, 168))	('liver carcinogenesis', 'Disease', 'MESH:D063646', (39, 59))	('conversion', 'MPA', (169, 179))	('oxidative stress', 'Phenotype', 'HP:0025464', (294, 310))	('contributes', 'Reg', (279, 290))	('liver carcinogenesis', 'Disease', (39, 59))	('expression', 'MPA', (94, 104))	('Se', 'Chemical', 'MESH:D012643', (135, 137))	('SePP', 'Gene', (89, 93))	('Se organification', 'MPA', (135, 152))	('dysregulation', 'Var', (72, 85))	('Se', 'Chemical', 'MESH:D012643', (191, 193))	('Se', 'Chemical', 'MESH:D012643', (222, 224))	('stress damage', 'Disease', 'MESH:D004194', (304, 317))
11134	27357089	In conclusion, the present study provides significant prospective data indicating a strong association between high Se status and a lower risk of HCC.	('high Se status', 'Var', (111, 125))	('HCC', 'Gene', '619501', (146, 149))	('Se', 'Chemical', 'MESH:D012643', (116, 118))	('high Se status', 'Phenotype', 'HP:0500138', (111, 125))	('HCC', 'Phenotype', 'HP:0001402', (146, 149))	('HCC', 'Gene', (146, 149))
11151	27764785	Besides, overexpressed ZNF703 could even induce the gene expression of lymphoid enhancer-binding factor 1 (LEF1), transcription factor 12 (TCF12), wingless-type MMTV integration site family, member 4 (WNT4) and achaete-scute complex-like 1 (ASCL1) that related to the WNT or NOTCH signaling pathways, to regulate the activity of breast cancer stem cells.	('LEF1', 'Gene', (107, 111))	('TCF12', 'Gene', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('regulate', 'Reg', (304, 312))	('activity', 'MPA', (317, 325))	('breast cancer', 'Disease', 'MESH:D001943', (329, 342))	('wingless-type MMTV integration site family, member 4', 'Gene', '54361', (147, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (329, 342))	('breast cancer', 'Disease', (329, 342))	('overexpressed', 'Var', (9, 22))	('induce', 'PosReg', (41, 47))	('ZNF703', 'Var', (23, 29))	('NOTCH', 'Gene', '4855', (275, 280))	('gene expression', 'MPA', (52, 67))	('NOTCH', 'Gene', (275, 280))
11167	27764785	Necropsy were conducted after 4 weeks and results revealed a significant increase of metastatic nodules in ZNF703 overexpressed mice, while the number of metastatic nodules was reduced in ZNF703 inhibited mice, compared to the control group.	('metastatic nodules', 'CPA', (85, 103))	('ZNF703', 'Gene', (107, 113))	('increase', 'PosReg', (73, 81))	('overexpressed', 'Var', (114, 127))	('mice', 'Species', '10090', (128, 132))	('mice', 'Species', '10090', (205, 209))
11169	27764785	Usually genes altered by amplification and concomitant overexpression are considered candidate oncogenes, but amplicons often include several candidates making it difficult to notarize the accurate oncogenes of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (211, 229))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (211, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('cholangiocarcinoma', 'Disease', (211, 229))	('amplification', 'Var', (25, 38))
11178	27764785	Consistent with previous data in which ZNF703 was overexpressed not only in breast but gastric and colorectal cancer and high ZNF703 expression contributed to tumor aggressiveness, our investigations reached much similar conclusions in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (236, 254))	('colorectal cancer', 'Disease', (99, 116))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('overexpressed', 'PosReg', (50, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('breast', 'Disease', (76, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))	('tumor aggressiveness', 'Disease', (159, 179))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gastric', 'Disease', (87, 94))	('contributed', 'Reg', (144, 155))	('expression', 'MPA', (133, 143))	('cholangiocarcinoma', 'Disease', (236, 254))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (236, 254))	('aggressiveness', 'Phenotype', 'HP:0000718', (165, 179))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('high', 'Var', (121, 125))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (159, 179))	('ZNF703', 'Gene', (126, 132))
11180	27764785	Researchers had identified ZNF703 as a cofactor of a nuclear complex covering DCAF7, PHB2 and NCOR2 through mass spectrometry and pointed out that ZNF703 expression could result in the activation of stem cell-related gene expression leading to an increase in cancer stem cells.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('DCAF7', 'Gene', (78, 83))	('stem cell-related gene', 'Gene', (199, 221))	('PHB2', 'Gene', '11331', (85, 89))	('NCOR2', 'Gene', '9612', (94, 99))	('expression', 'MPA', (222, 232))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('ZNF703', 'Var', (147, 153))	('NCOR2', 'Gene', (94, 99))	('activation', 'PosReg', (185, 195))	('PHB2', 'Gene', (85, 89))	('DCAF7', 'Gene', '10238', (78, 83))	('increase', 'PosReg', (247, 255))	('cancer', 'Disease', (259, 265))
11227	27396933	The most common genetic alterations are FGFR2-PPHLN1 fusions, which are present in ~45% of tumors, and IDH1 or IDH2 mutations, which are in ~20% of cholangiocarcinomas.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (148, 166))	('IDH1', 'Gene', '3417', (103, 107))	('fusions', 'Var', (53, 60))	('PPHLN1', 'Gene', (46, 52))	('IDH2', 'Gene', '3418', (111, 115))	('mutations', 'Var', (116, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('FGFR2', 'Gene', (40, 45))	('FGFR2', 'Gene', '2263', (40, 45))	('PPHLN1', 'Gene', '51535', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('IDH2', 'Gene', (111, 115))	('IDH1', 'Gene', (103, 107))
11228	27396933	Although the presence of these and other mutations may be specific for cholangiocarcinoma, over other intrahepatic malignancies, and may provide relevant guidance for therapeutic intervention, these tests are not sufficiently sensitive to differentiate between benign and malignant biliary lesions and are not readily available in many laboratories.	('malignant biliary lesions', 'Disease', (272, 297))	('mutations', 'Var', (41, 50))	('intrahepatic malignancies', 'Disease', (102, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('intrahepatic malignancies', 'Disease', 'MESH:D002780', (102, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (71, 89))	('malignant biliary lesions', 'Disease', 'MESH:D009369', (272, 297))	('cholangiocarcinoma', 'Disease', (71, 89))
11235	27396933	Mutations in TP53 have been reported in ~30% of intrahepatic cholangiocarcinomas.	('intrahepatic cholangiocarcinomas', 'Disease', (48, 80))	('TP53', 'Gene', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('reported', 'Reg', (28, 36))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (13, 17))
11304	22568985	Any factors interfering with one or several phases of this highly regulated process can cause impaired (chronic wounds) or overly (fibrosis and hypertrophic scarring) wound healing.	('factors', 'Var', (4, 11))	('scar', 'Phenotype', 'HP:0100699', (157, 161))	('scarring', 'Phenotype', 'HP:0100699', (157, 165))	('impaired', 'NegReg', (94, 102))	('hypertrophic', 'Disease', (144, 156))	('fibrosis', 'Disease', 'MESH:D005355', (131, 139))	('fibrosis', 'Disease', (131, 139))	('hypertrophic', 'Disease', 'MESH:D006984', (144, 156))
11309	22568985	It is the incorporation of alpha-SMA into stress fibers that renders myofibroblasts highly contractile (Fig.	('incorporation', 'Var', (10, 23))	('renders', 'Reg', (61, 68))	('highly', 'PosReg', (84, 90))	('alpha-SMA', 'Chemical', '-', (27, 36))	('rat', 'Species', '10116', (17, 20))
11312	22568985	Neo-expression of alpha-SMA is the most widely used criterion to identify tissue myofibroblasts and to diagnose myofibroblast-related diseases.	('alpha-SMA', 'Chemical', '-', (18, 27))	('alpha-SMA', 'Protein', (18, 27))	('myofibroblast-related diseases', 'Disease', (112, 142))	('Neo-expression', 'Var', (0, 14))
11363	22568985	Deletion or inhibition of beta6 integrin in vivo efficiently protects from the development of experimentally induced lung fibrosis with no apparent side effects.	('beta6 integrin', 'Protein', (26, 40))	('inhibition', 'NegReg', (12, 22))	('lung fibrosis', 'Disease', (117, 130))	('lung fibrosis', 'Phenotype', 'HP:0002206', (117, 130))	('protects', 'Reg', (61, 69))	('lung fibrosis', 'Disease', 'MESH:D005355', (117, 130))	('Deletion', 'Var', (0, 8))
11366	22568985	However, inhibition of the "pro-angiogenic" integrins alphavbeta3 and alphavbeta5 has already entered clinical trials as one strategy to interfere with tumor angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('alphavbeta5', 'Protein', (70, 81))	('interfere', 'NegReg', (137, 146))	('tumor', 'Disease', (152, 157))	('rat', 'Species', '10116', (127, 130))	('alphavbeta3', 'Protein', (54, 65))	('inhibition', 'Var', (9, 19))
11372	22568985	Small changes in tissue stiffness occur during the inflammatory response in fibrosis and tumor development and seem to be induced by cross-linking of collagen by lysyl oxidases (LOX) and LOX-like enzymes; inhibition of these enzymes has tumor-suppressing effects.	('tissue stiffness', 'MPA', (17, 33))	('tumor', 'Disease', (237, 242))	('LOX', 'Gene', (178, 181))	('lysyl oxidases', 'Gene', '4015', (162, 176))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('LOX', 'Gene', '4015', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('induced', 'Reg', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('LOX', 'Gene', '4015', (178, 181))	('LOX', 'Gene', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('fibrosis', 'Disease', 'MESH:D005355', (76, 84))	('fibrosis', 'Disease', (76, 84))	('lysyl oxidases', 'Gene', (162, 176))	('tumor', 'Disease', (89, 94))	('inhibition', 'Var', (205, 215))
11467	22568985	Inhibiting the amplification loop operated by TGFbeta1 on tumor cells leads to a decrease of tumor neovascularization and in the end to limit the tumor metastasis impairing with the dissemination of cells by the blood tract and acting directly on the cells.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('limit', 'NegReg', (136, 141))	('tumor', 'Disease', (58, 63))	('Inhibiting', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('decrease', 'NegReg', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('rat', 'Species', '10116', (37, 40))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (146, 151))	('dissemination', 'CPA', (182, 195))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('TGFbeta1', 'Gene', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
11522	32457264	2), and positivity for CK7, and CK19 (markers of cholangiocarcinoma in absence of thyroid-specific markers).	('CK19', 'Gene', (32, 36))	('CK7', 'Gene', (23, 26))	('cholangiocarcinoma', 'Disease', (49, 67))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (49, 67))	('CK19', 'Gene', '3880', (32, 36))	('positivity', 'Var', (8, 18))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (49, 67))	('CK7', 'Gene', '3855', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
11539	30001234	SD was the most common (84%; 24% SD1 and 60% SD2) with lower proportions of LD (8%), and indeterminate (8%).	('SD1', 'Gene', '57306', (33, 36))	('SD1', 'Gene', (33, 36))	('SD2', 'Var', (45, 48))
11542	30001234	LD was associated with mucin production (P<.001), perineural invasion (P=.002), CA19-9 staining (P<.001), CK7+, CK19+, CD56- immunophenotype (P=.005), and negative albumin RNA in situ hybridization (P<.001).	('mucin', 'Gene', (23, 28))	('CK19+', 'Var', (112, 117))	('CA19-9 staining', 'Var', (80, 95))	('perineural invasion', 'CPA', (50, 69))	('CK7+', 'Var', (106, 110))	('mucin', 'Gene', '100508689', (23, 28))	('CD56- immunophenotype', 'Var', (119, 140))
11555	30001234	Hepatocellular progenitor cells label with CD56 (NCAM), CK7, SALL4, Okt4, CRP, and CK19 and neoplasms with bile ductular-like growth patterns stain similarly.	('neoplasms', 'Disease', 'MESH:D009369', (92, 101))	('neoplasms', 'Phenotype', 'HP:0002664', (92, 101))	('SALL4', 'Gene', '57167', (61, 66))	('SALL4', 'Gene', (61, 66))	('NCAM', 'Gene', (49, 53))	('CRP', 'Gene', (74, 77))	('CRP', 'Gene', '1401', (74, 77))	('neoplasms', 'Disease', (92, 101))	('NCAM', 'Gene', '4684', (49, 53))	('bile ductular-like growth', 'Phenotype', 'HP:0001408', (107, 132))	('CD56', 'Var', (43, 47))	('neoplasm', 'Phenotype', 'HP:0002664', (92, 100))
11590	30001234	Immunohistochemistry for antibody (clone, manufacturer, dilution) were as follows: HepPar1 (OCH1E5, Dako, 1:2000), Arginase-1 (Cell Marque, 1:1000), Glypican-3 (Santa Cruz, 1:100); S100P (Dako 1:5000); CD56 (MRQ42, Cell Marque, 1:50); CK19 (RCK108, Dako, 1:400); CA19.9 (Ventana); and CK7 (OV-TL12130, Dako, 1:1000) were performed using standard immunoperoxidase methods and manufacturer instructions.	('S100P', 'SUBSTITUTION', 'None', (181, 186))	('Arginase-1', 'Gene', '11846', (115, 125))	('Arginase-1', 'Gene', (115, 125))	('S100P', 'Var', (181, 186))
11629	30001234	The higher rate of albumin expression in SD2 (78% positive) compared with SD1 (53% positive) was statistically significant (P=0.018).	('higher', 'PosReg', (4, 10))	('albumin', 'Protein', (19, 26))	('SD1', 'Gene', (74, 77))	('SD2', 'Var', (41, 44))	('SD1', 'Gene', '57306', (74, 77))
11633	30001234	Comparing SD1 and SD2, there was no difference in expression of CA19-9, the CK7+, CK19+, CD56- phenotype, CD56, and S100P (P>.05).	('CD56-', 'Var', (89, 94))	('CK19+', 'Var', (82, 87))	('CK7+', 'Var', (76, 80))	('SD1', 'Gene', (10, 13))	('S100P', 'SUBSTITUTION', 'None', (116, 121))	('CA19-9', 'Var', (64, 70))	('CD56', 'Var', (106, 110))	('SD1', 'Gene', '57306', (10, 13))	('S100P', 'Var', (116, 121))
11634	30001234	S100P was rarely positive in SD (SD1 4% and SD2 8%).	('SD1', 'Gene', '57306', (33, 36))	('SD1', 'Gene', (33, 36))	('S100P', 'SUBSTITUTION', 'None', (0, 5))	('S100P', 'Var', (0, 5))
11635	30001234	The CK7+/CK19+/CD56- phenotype, CD56, and S100P expression did not show an association with periductal infiltration, >10% cholangiocellular carcinoma pattern, or grade.	('S100P', 'Var', (42, 47))	('cholangiocellular carcinoma pattern', 'Disease', 'MESH:D018281', (122, 157))	('periductal infiltration', 'Disease', (92, 115))	('S100P', 'SUBSTITUTION', 'None', (42, 47))	('cholangiocellular carcinoma pattern', 'Disease', (122, 157))	('CK7+/CK19+/CD56-', 'Var', (4, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cholangiocellular carcinoma', 'Phenotype', 'HP:0030153', (122, 149))
11642	30001234	Other authors have shown differences between LD and SD including a unique LD immunophenotype (S100P, TFF1, galectin-3, and AGR2 expression, absent N-cadherin) and a higher prevalence of KRAS mutation. )	('KRAS', 'Gene', (186, 190))	('S100P', 'SUBSTITUTION', 'None', (94, 99))	('galectin-3', 'Gene', '3958', (107, 117))	('N-cadherin', 'Gene', (147, 157))	('AGR2', 'Gene', (123, 127))	('S100P', 'Var', (94, 99))	('KRAS', 'Gene', '3845', (186, 190))	('N-cadherin', 'Gene', '1000', (147, 157))	('TFF1', 'Gene', '7031', (101, 105))	('AGR2', 'Gene', '10551', (123, 127))	('galectin-3', 'Gene', (107, 117))	('expression', 'MPA', (128, 138))	('absent', 'NegReg', (140, 146))	('TFF1', 'Gene', (101, 105))
11644	30001234	We did not reproduce a previously reported association between S100P expression and LD type but showed a high proportion of the "mature cholangiocyte" CK7+, CK19+, CD56- phenotype.	('S100P', 'Var', (63, 68))	('CK19+', 'Var', (157, 162))	('S100P', 'SUBSTITUTION', 'None', (63, 68))	('CD56- phenotype', 'Var', (164, 179))	('CK7+', 'Var', (151, 155))
11651	30001234	Other authors have used S100P to increase recognition of LD.	('increase', 'PosReg', (33, 41))	('S100P', 'Var', (24, 29))	('S100P', 'SUBSTITUTION', 'None', (24, 29))
11652	30001234	We did not apply S100P results to classification but it would be unlikely to have reclassified many SD cases because only 8 (7%) non-large duct cases (1 SD1 cases, 6 SD2 cases) expressed S100P.	('S100P', 'Var', (17, 22))	('S100P', 'SUBSTITUTION', 'None', (17, 22))	('S100P', 'Var', (187, 192))	('non-large', 'Disease', (129, 138))	('SD1', 'Gene', '57306', (153, 156))	('SD1', 'Gene', (153, 156))	('S100P', 'SUBSTITUTION', 'None', (187, 192))
11653	30001234	We tested for S100P on a TMA but that is not a major limitation because S100P positive cholangiocarcinomas tend to have diffuse reactivity.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('S100P', 'Var', (14, 19))	('cholangiocarcinomas', 'Disease', (87, 106))	('S100P', 'Var', (72, 77))	('reactivity', 'MPA', (128, 138))	('diffuse', 'MPA', (120, 127))	('S100P', 'SUBSTITUTION', 'None', (14, 19))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (87, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('S100P', 'SUBSTITUTION', 'None', (72, 77))
11728	27144432	CA19-9 has been widely used as a diagnostic or prognostic marker for various types of cancers, including pCCA, colorectal cancer, and gastric cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('colorectal cancer', 'Disease', (111, 128))	('gastric cancer', 'Disease', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('CA19-9', 'Var', (0, 6))	('pCCA', 'Disease', (105, 109))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (86, 93))
11729	27144432	pCCA patients with preoperative CA19-9 levels < 150 U/ml showed better OS than those with higher CA19-9 levels.	('OS', 'Chemical', '-', (71, 73))	('better', 'PosReg', (64, 70))	('patients', 'Species', '9606', (5, 13))	('CA19-9', 'Var', (32, 38))
11734	27144432	The prognostic effects of perineural invasion for patients with extrahepatic cholangiocarcinoma have been determined, showing that patients with perinerual invasion had worse prognoses relative to those who were negative in univariate but not multivariate analyses.	('patients', 'Species', '9606', (131, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('patients', 'Species', '9606', (50, 58))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (64, 95))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (77, 95))	('perinerual', 'Var', (145, 155))	('extrahepatic cholangiocarcinoma', 'Disease', (64, 95))
11740	27144432	However, invasion of the main portal vein was independently associated with treatment outcomes (R0 or R1/2, data not shown) and with worse OS compared to those without main portal vein invasion.	('OS', 'Chemical', '-', (139, 141))	('treatment outcomes', 'CPA', (76, 94))	('associated', 'Reg', (60, 70))	('invasion', 'Var', (9, 17))
11992	29264586	PVE can accelerate unwanted growth of metastastic tumors at the FRL, thus not being indicated.	('metastastic tumors', 'Disease', 'MESH:D009369', (38, 56))	('PVE', 'Phenotype', 'HP:0030242', (0, 3))	('metastastic tumors', 'Disease', (38, 56))	('PVE', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('accelerate', 'PosReg', (8, 18))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('unwanted growth', 'CPA', (19, 34))
12022	27588228	In particular, cytokeratin-7 (CK-7) positivity is consistent with biliary tract origin.	('cytokeratin-7', 'Gene', '3855', (15, 28))	('biliary tract origin', 'Disease', (66, 86))	('CK-7', 'Gene', '3855', (30, 34))	('CK-7', 'Gene', (30, 34))	('positivity', 'Var', (36, 46))	('cytokeratin-7', 'Gene', (15, 28))
12102	26131439	The magnifying power for CK7 and CK19 was x100 and that of other cancer stem cells (CSCs) markers was x400.	('x400', 'Var', (102, 106))	('CK7', 'Gene', '3855', (25, 28))	('CK19', 'Gene', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('CK7', 'Gene', (25, 28))	('CK19', 'Gene', '3880', (33, 37))	('x100', 'Var', (42, 46))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
12124	26131439	However, recurrence-free survival analysis of the expression of each cancer stem cell marker revealed that the CD44 positive group showed earlier recurrence than the CD44 negative group (P = 0.040) (Fig.	('recurrence', 'CPA', (146, 156))	('CD44', 'Gene', (111, 115))	('positive', 'Var', (116, 124))	('CD44', 'Gene', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('earlier', 'PosReg', (138, 145))	('CD44', 'Gene', '960', (111, 115))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('CD44', 'Gene', '960', (166, 170))	('cancer', 'Disease', (69, 75))
12125	26131439	The recurrence-free survival time of the CD44 positive group was 4.4 +- 1.3 (mean +- standard deviation) months, whereas that of the CD44 negative group was 41.8 +- 14.4 months.	('recurrence-free survival time', 'CPA', (4, 33))	('CD44', 'Gene', '960', (133, 137))	('CD44', 'Gene', '960', (41, 45))	('CD44', 'Gene', (133, 137))	('CD44', 'Gene', (41, 45))	('positive', 'Var', (46, 54))
12153	26131439	CD44 expression is associated with the Wnt signaling pathway in the intestinal epithelium and is regulated by microRNAs such as microRNA-21 and microRNA-373-520c.	('associated', 'Reg', (19, 29))	('CD44', 'Gene', '960', (0, 4))	('CD44', 'Gene', (0, 4))	('microRNA-373-520c', 'Var', (144, 161))	('regulated', 'Reg', (97, 106))	('Wnt signaling pathway', 'Pathway', (39, 60))
12155	26131439	And the cooperation between CD44 and receptor tyrosine kinases induced antiapoptosis.	('cooperation', 'Var', (8, 19))	('CD44', 'Gene', '960', (28, 32))	('CD44', 'Gene', (28, 32))	('antiapoptosis', 'CPA', (71, 84))
12188	25385169	Hepatitis B virus-related antigen and antibody were negative with the exception of hepatitis B surface antibody (578.200 IU/l) and hepatitis B core antibody.	('Hepatitis', 'Phenotype', 'HP:0012115', (0, 9))	('hepatitis', 'Phenotype', 'HP:0012115', (83, 92))	('hepatitis B', 'Disease', (131, 142))	('578.200 IU/l', 'Var', (113, 125))	('hepatitis B surface antibody', 'Phenotype', 'HP:0410369', (83, 111))	('hepatitis', 'Phenotype', 'HP:0012115', (131, 140))	('Hepatitis B virus', 'Species', '10407', (0, 17))	('hepatitis B', 'Disease', 'MESH:D006509', (83, 94))	('negative', 'NegReg', (52, 60))	('hepatitis B', 'Disease', 'MESH:D006509', (131, 142))	('hepatitis B', 'Disease', (83, 94))
12234	22484120	Human cholangiocarcinoma tissues and cell lines had increased levels of miR-26a compared with the noncancerous biliary epithelial cells.	('levels', 'MPA', (62, 68))	('Human', 'Species', '9606', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cholangiocarcinoma', 'Disease', (6, 24))	('increased', 'PosReg', (52, 61))	('miR-26a', 'Var', (72, 79))	('cancer', 'Disease', (101, 107))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (6, 24))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (6, 24))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
12276	22484120	miR-26a overexpression was also found to increase colony-formation efficiency in the CCLP1 and SG231 cells (Figure 2C).	('SG231', 'CellLine', 'CVCL:0519', (95, 100))	('miR-26a', 'Gene', (0, 7))	('overexpression', 'Var', (8, 22))	('increase', 'PosReg', (41, 49))	('colony-formation efficiency', 'CPA', (50, 77))
12277	22484120	Accordingly, CCLP1 and SG231 cells with miR-26a depletion showed decreased cell growth and colony-formation capacity (Figure 2D).	('miR-26a', 'Gene', (40, 47))	('SG231', 'CellLine', 'CVCL:0519', (23, 28))	('decreased', 'NegReg', (65, 74))	('cell growth', 'CPA', (75, 86))	('colony-formation capacity', 'CPA', (91, 116))	('depletion', 'Var', (48, 57))
12278	22484120	These data indicate that miR-26a is able to enhance the growth and colonogenic potential in CCLP1 and SG231 cells.	('SG231', 'CellLine', 'CVCL:0519', (102, 107))	('miR-26a', 'Var', (25, 32))	('growth', 'CPA', (56, 62))	('enhance', 'PosReg', (44, 51))	('colonogenic potential', 'CPA', (67, 88))
12284	22484120	As shown in Figure 3B and C, miR-26a:overexpressed HuCCT1 cells exhibit significantly increased proliferation and colony-forming capacity after COX-2 knockdown or PGE2 degradation by 15-PGDH.	('increased', 'PosReg', (86, 95))	('15-PGDH', 'Gene', '3248', (183, 190))	('proliferation', 'CPA', (96, 109))	('knockdown', 'Var', (150, 159))	('PGE2', 'Chemical', 'MESH:D015232', (163, 167))	('COX-2', 'Gene', (144, 149))	('15-PGDH', 'Gene', (183, 190))	('colony-forming capacity', 'CPA', (114, 137))	('COX-2', 'Gene', '5743', (144, 149))	('HuCCT1', 'CellLine', 'CVCL:0324', (51, 57))
12294	22484120	Treatment with specific miR-26a inhibitor prevented miR-26a-induced reduction of GSK-3beta mRNA and protein (Figure 4C).	('GSK-3beta', 'Gene', '2932', (81, 90))	('GSK-3beta', 'Gene', (81, 90))	('miR-26a-induced', 'Var', (52, 67))	('reduction', 'NegReg', (68, 77))
12295	22484120	miR-26a overexpression decreased the GSK-3beta 3'UTR luciferase reporter activity; this effect was abolished when the 3 nucleotides in the miR-26a seed binding site of the GSK-3beta 3'UTR were mutated (Figure 4D).	('GSK-3beta', 'Gene', '2932', (172, 181))	('GSK-3beta', 'Gene', (172, 181))	('activity', 'MPA', (73, 81))	('mutated', 'Var', (193, 200))	('GSK-3beta', 'Gene', '2932', (37, 46))	('GSK-3beta', 'Gene', (37, 46))	('decreased', 'NegReg', (23, 32))
12296	22484120	Consistent with these observations, alteration of GSK-3beta level or activity impaired the pro-proliferation function of miR-26a.	('activity', 'MPA', (69, 77))	('alteration', 'Var', (36, 46))	('GSK-3beta', 'Gene', '2932', (50, 59))	('GSK-3beta', 'Gene', (50, 59))	('impaired', 'NegReg', (78, 86))	('miR-26a', 'Gene', (121, 128))	('pro-proliferation function', 'CPA', (91, 117))
12300	22484120	As shown in Figure 4B, miR-26a-mediated reduction of GSK-3beta is associated with decreased phospho-beta-catenin (Ser33/37/Thr41) and accumulation of total beta-catenin.	('miR-26a-mediated', 'Var', (23, 39))	('beta-catenin', 'Gene', (100, 112))	('accumulation', 'PosReg', (134, 146))	('beta-catenin', 'Gene', '1499', (100, 112))	('reduction', 'NegReg', (40, 49))	('beta-catenin', 'Gene', (156, 168))	('GSK-3beta', 'Gene', '2932', (53, 62))	('GSK-3beta', 'Gene', (53, 62))	('beta-catenin', 'Gene', '1499', (156, 168))	('Thr41', 'Chemical', '-', (123, 128))	('Ser33', 'Chemical', '-', (114, 119))	('decreased', 'NegReg', (82, 91))
12306	22484120	The importance of beta-catenin in miR-26a-induced tumor cell growth is further supported by the observation that siRNA depletion of beta-catenin prevented miR-26a-induced cell proliferation and colony-formation capacity (Figure 5D).	('cell proliferation', 'CPA', (171, 189))	('colony-formation capacity', 'CPA', (194, 219))	('beta-catenin', 'Gene', (18, 30))	('beta-catenin', 'Gene', '1499', (18, 30))	('beta-catenin', 'Gene', (132, 144))	('depletion', 'Var', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('beta-catenin', 'Gene', '1499', (132, 144))	('miR-26a-induced', 'Gene', (155, 170))	('prevented', 'NegReg', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
12314	22484120	As a parallel approach, we established SG231 and CCLP1 cell lines with stable knockdown of miR-26a; these cells were then injected subcutaneously into the flank of SCID mice and the animals were monitored for tumor growth.	('tumor', 'Disease', (209, 214))	('knockdown', 'Var', (78, 87))	('SCID', 'Disease', 'MESH:D053632', (164, 168))	('SCID', 'Disease', (164, 168))	('mice', 'Species', '10090', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('miR-26a', 'Gene', (91, 98))	('SG231', 'CellLine', 'CVCL:0519', (39, 44))
12315	22484120	As shown in Supplementary Figure 5, the miR-26a knockdown tumors were smaller in size and weight compared to the scramble control tumors.	('tumors', 'Disease', (130, 136))	('miR-26a', 'Gene', (40, 47))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('smaller', 'NegReg', (70, 77))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('knockdown', 'Var', (48, 57))
12316	22484120	An approximately 2- to 3-fold decrease of tumor weight was observed in miR-26a knockdown tumors compared to the controls (0.32 +- 0.15 g vs 0.62 +- 0.18 g; P < .05 for SG231 and 0.18 +- 0.06 g vs 0.57 +- 0.12 g; P < .001 for CCLP1).	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('decrease', 'NegReg', (30, 38))	('SG231', 'CellLine', 'CVCL:0519', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('knockdown', 'Var', (79, 88))	('miR-26a', 'Gene', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
12319	22484120	As shown in Figure 7A, the levels of these molecules were all increased in CCLP1 and SG231 cells stably overexpressing miR-26a, in vitro.	('increased', 'PosReg', (62, 71))	('levels', 'MPA', (27, 33))	('miR-26a', 'Var', (119, 126))	('SG231', 'CellLine', 'CVCL:0519', (85, 90))
12321	22484120	These findings demonstrate that miR-26a induces the expression of (beta-catenin downstream genes in human cholangiocarcinoma cells.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (106, 124))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (106, 124))	('human', 'Species', '9606', (100, 105))	('miR-26a', 'Var', (32, 39))	('expression', 'MPA', (52, 62))	('induces', 'PosReg', (40, 47))	('beta-catenin', 'Gene', (67, 79))	('beta-catenin', 'Gene', '1499', (67, 79))	('cholangiocarcinoma', 'Disease', (106, 124))
12327	22484120	We have found that GSK-3beta is a direct target of miR-26a in cholangiocarcinoma cells, and this conclusion is supported by the following observations: complementary sequence of miR-26a is identified in the 3'UTR of GSK-3beta mRNA; miR-26a overexpression reduced GSK-3beta mRNA and protein and this effect was attenuated by miR-26a inhibitor; miR-26a1 overexpression decreased GSK-3beta 3'UTR luciferase report activity and this effect was abolished by mutation of the miR-26a seed binding site.	('miR-26a1', 'Gene', (343, 351))	('miR-26a', 'Gene', (469, 476))	('activity', 'MPA', (411, 419))	('GSK-3beta', 'Gene', (377, 386))	('cholangiocarcinoma', 'Disease', (62, 80))	('GSK-3beta', 'Gene', '2932', (377, 386))	('GSK-3beta', 'Gene', '2932', (263, 272))	('GSK-3beta', 'Gene', (263, 272))	('miR-26a1', 'Gene', '407015', (343, 351))	('GSK-3beta', 'Gene', '2932', (19, 28))	('GSK-3beta', 'Gene', (19, 28))	('GSK-3beta', 'Gene', (216, 225))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (62, 80))	('mutation', 'Var', (453, 461))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (62, 80))	('GSK-3beta', 'Gene', '2932', (216, 225))	('decreased', 'NegReg', (367, 376))
12328	22484120	The role of GSK-3beta in miR-26a-mediated cholangiocarcinoma growth is further supported by the observations that alteration of GSK-3beta level or activity by overexpression, siRNA, or lithium chloride impairs miR-26a-induced cholangiocarcinoma cell proliferation.	('overexpression', 'PosReg', (159, 173))	('cholangiocarcinoma', 'Disease', (42, 60))	('cholangiocarcinoma growth', 'Disease', (42, 67))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (226, 244))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (226, 244))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (42, 67))	('GSK-3beta', 'Gene', '2932', (128, 137))	('GSK-3beta', 'Gene', (128, 137))	('GSK-3beta', 'Gene', '2932', (12, 21))	('GSK-3beta', 'Gene', (12, 21))	('impairs', 'NegReg', (202, 209))	('miR-26a-induced', 'Gene', (210, 225))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (42, 60))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (42, 60))	('alteration', 'Var', (114, 124))	('lithium chloride', 'Chemical', 'MESH:D018021', (185, 201))	('cholangiocarcinoma', 'Disease', (226, 244))	('activity', 'MPA', (147, 155))
12331	22484120	The importance of beta-catenin in miR-26a-in-duced tumor cell growth is also supported by the observation that siRNA depletion of beta-catenin prevented miR-26a-induced cholangiocarcinoma proliferation and colony-formation capacity.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('beta-catenin', 'Gene', (18, 30))	('beta-catenin', 'Gene', '1499', (130, 142))	('prevented', 'NegReg', (143, 152))	('cholangiocarcinoma proliferation', 'Disease', 'MESH:D018281', (169, 201))	('beta-catenin', 'Gene', '1499', (18, 30))	('tumor', 'Disease', (51, 56))	('miR-26a-induced', 'Var', (153, 168))	('colony-formation capacity', 'CPA', (206, 231))	('beta-catenin', 'Gene', (130, 142))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (169, 187))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('cholangiocarcinoma proliferation', 'Disease', (169, 201))
12336	22484120	Our findings in this study demonstrate a key role of miR-26a for beta-catenin activation in human cholangiocarcinoma cells.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (98, 116))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (98, 116))	('beta-catenin', 'Gene', '1499', (65, 77))	('miR-26a', 'Var', (53, 60))	('activation', 'PosReg', (78, 88))	('cholangiocarcinoma', 'Disease', (98, 116))	('human', 'Species', '9606', (92, 97))	('beta-catenin', 'Gene', (65, 77))
12342	22484120	Many human or mouse miRNAs are located near cancer susceptibility loci and miRNA alterations are involved in all stages of tumor development, including initiation, progression, and metasta-sis.	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', (75, 78))	('tumor', 'Disease', (123, 128))	('mouse', 'Species', '10090', (14, 19))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', (20, 23))	('alterations', 'Var', (81, 92))	('involved', 'Reg', (97, 105))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('human', 'Species', '9606', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
12349	22484120	In summary, this study provides novel evidence that miR-26a enhances cholangiocarcinoma progression by targeting the GSK-3beta and beta-catenin pathway.	('GSK-3beta', 'Gene', '2932', (117, 126))	('GSK-3beta', 'Gene', (117, 126))	('enhances', 'PosReg', (60, 68))	('beta-catenin', 'Gene', (131, 143))	('miR-26a', 'Var', (52, 59))	('cholangiocarcinoma', 'Disease', (69, 87))	('targeting', 'Reg', (103, 112))	('beta-catenin', 'Gene', '1499', (131, 143))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (69, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (69, 87))
12367	21748296	Tannapfel and colleagues demonstrated that BRAF gene mutations were detected in 15 out of 69 (22%) human biliary carcinoma specimens.	('biliary carcinoma', 'Disease', 'MESH:D001661', (105, 122))	('BRAF', 'Gene', '673', (43, 47))	('BRAF', 'Gene', (43, 47))	('mutations', 'Var', (53, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('detected', 'Reg', (68, 76))	('biliary carcinoma', 'Disease', (105, 122))	('human', 'Species', '9606', (99, 104))
12368	21748296	All cholangiocarcinomas with a BRAF mutation exhibited stronger immunostaining of the MAPK protein, with a median of 69% positive tumor cells.	('cholangiocarcinomas', 'Disease', (4, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('MAPK', 'Gene', '5594', (86, 90))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (4, 23))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (4, 22))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('stronger', 'PosReg', (55, 63))	('MAPK', 'Gene', (86, 90))	('immunostaining', 'MPA', (64, 78))	('BRAF', 'Gene', '673', (31, 35))	('tumor', 'Disease', (130, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (13, 23))	('mutation', 'Var', (36, 44))	('BRAF', 'Gene', (31, 35))
12369	21748296	Yoon and associates showed that Raf-1 inhibitors rendered cholangiocarcinoma cells more susceptible to apoptosis by blocking the increase in Mcl-1, an anti-apoptotic protein.	('cholangiocarcinoma', 'Disease', (58, 76))	('Raf-1', 'Gene', (32, 37))	('Mcl-1', 'Gene', '4170', (141, 146))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 76))	('inhibitors', 'Var', (38, 48))	('Raf-1', 'Gene', '5894', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('blocking', 'NegReg', (116, 124))	('Mcl-1', 'Gene', (141, 146))
12375	21748296	This phase II study was designed to test the hypothesis that inhibition of the Ras-Raf pathway as well as the VEGF axis in patients with biliary cancers would result in significant tumor responses and improved progression free survival.	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('inhibition', 'Var', (61, 71))	('Raf', 'Gene', '22882', (83, 86))	('progression free survival', 'CPA', (210, 235))	('biliary cancers', 'Disease', 'MESH:D001661', (137, 152))	('VEGF', 'Gene', '7422', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('improved', 'PosReg', (201, 209))	('patients', 'Species', '9606', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('Raf', 'Gene', (83, 86))	('biliary cancers', 'Disease', (137, 152))	('VEGF', 'Gene', (110, 114))
12470	20565817	The mutation status of the KRAS gene affects the response of cetuximab.	('affects', 'Reg', (37, 44))	('mutation', 'Var', (4, 12))	('cetuximab', 'Chemical', 'MESH:D000068818', (61, 70))	('response', 'MPA', (49, 57))	('KRAS', 'Gene', (27, 31))
12471	20565817	Patients with a colorectal tumor bearing mutated KRAS did not benefit from cetuximab, whereas patients with a tumor bearing wild-type KRAS did.	('KRAS', 'Var', (49, 53))	('not', 'NegReg', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('patients', 'Species', '9606', (94, 102))	('colorectal tumor', 'Disease', (16, 32))	('tumor', 'Disease', (27, 32))	('mutated KRAS', 'Var', (41, 53))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('Patients', 'Species', '9606', (0, 8))	('colorectal tumor', 'Disease', 'MESH:D015179', (16, 32))	('cetuximab', 'Chemical', 'MESH:D000068818', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
12496	20565817	Mouse IgG (#M5284, Sigma), mouse IgM (#X0942) and goat serum (#X0907, DakoCytomation, Hamburg, Germany) were used as isotype controls.	('goat', 'Species', '9925', (50, 54))	('mouse', 'Species', '10090', (27, 32))	('#X0907', 'Var', (62, 68))	('IgM', 'Gene', '641025', (33, 36))	('Mouse', 'Species', '10090', (0, 5))	('IgM', 'Gene', (33, 36))
12532	20565817	As Ras activation is likely to promote tumor cell proliferation to assess whether successful inhibition of the EGFR signaling pathway is associated with KRAS mutations cell lines were examined for KRAS gene mutations.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('mutations', 'Var', (207, 216))	('rat', 'Species', '10116', (57, 60))	('promote', 'PosReg', (31, 38))	('tumor', 'Disease', (39, 44))
12533	20565817	In EGI-1 a heterozygous mutation was found in codon 12 (c.35G>A; p.G12D).	('p.G12D', 'Var', (65, 71))	('c.35G>A; p.G12D', 'Var', (56, 71))	('c.35G>A', 'Mutation', 'rs121913529', (56, 63))	('p.G12D', 'Mutation', 'rs121913529', (65, 71))	('EGI-1', 'Gene', (3, 8))
12534	20565817	Codon 12 mutations usually lead to KRAS activation in colorectal cancer cell lines, but the activation status was not formally tested in EGI-1.	('mutations', 'Var', (9, 18))	('colorectal cancer', 'Disease', 'MESH:D015179', (54, 71))	('KRAS', 'CPA', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('activation', 'PosReg', (40, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (54, 71))	('lead to', 'Reg', (27, 34))	('colorectal cancer', 'Disease', (54, 71))
12535	20565817	Two cell lines carrying either wild-type or mutated KRAS were chosen to test the effect of cetuximab on cell growth and apoptosis.	('test', 'Reg', (72, 76))	('cetuximab', 'Chemical', 'MESH:D000068818', (91, 100))	('mutated', 'Var', (44, 51))
12551	20565817	EGFR expression was found to be correlated with frequency of lymph node metastases, aberrant p53 expression, proliferative activity and differentiation of the carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (159, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('EGFR', 'Gene', (0, 4))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('correlated', 'Reg', (32, 42))	('proliferative activity', 'CPA', (109, 131))	('lymph node metastases', 'Disease', 'MESH:D009362', (61, 82))	('lymph node metastases', 'Disease', (61, 82))	('carcinoma', 'Disease', (159, 168))	('rat', 'Species', '10116', (116, 119))	('differentiation', 'CPA', (136, 151))	('aberrant', 'Var', (84, 92))	('expression', 'MPA', (97, 107))
12576	20565817	As it was reported that cetuximab can induce apoptosis in tumor cells in vitro and in vivo , we tested the effect of cetuximab on cell survival.	('cetuximab', 'Chemical', 'MESH:D000068818', (24, 33))	('tumor', 'Disease', (58, 63))	('cetuximab', 'Chemical', 'MESH:D000068818', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cetuximab', 'Var', (24, 33))	('tested', 'Reg', (96, 102))	('apoptosis', 'CPA', (45, 54))
12577	20565817	As we wanted to compare cell lines with activating KRAS mutation and without with respect to their response to cetuximab the cell lines EGI-1 (with activating KRAS mutations) and TFK-1 (without KRAS mutations) were chosen for growth inhibition experiments to further compare the two different KRAS genotypes.	('KRAS', 'Gene', (159, 163))	('cetuximab', 'Chemical', 'MESH:D000068818', (111, 120))	('activating', 'PosReg', (148, 158))	('mutations', 'Var', (164, 173))
12578	20565817	Cetuximab did not significantly inhibit cell growth in EGI-1 cells (containing the activating KRAS mutation), but had a dose-dependent effect on growth of TFK-1 cells.	('growth', 'MPA', (145, 151))	('Cetuximab', 'Chemical', 'MESH:D000068818', (0, 9))	('KRAS', 'Gene', (94, 98))	('mutation', 'Var', (99, 107))
12592	20565817	Antagonizing the binding of HGF to HGFR also inhibited invasion in HuCC-T1, a human CC cell line, in vitro and in vivo suggesting that blockade of HGFR might be a therapeutic strategy which should be the focus of further studies.	('CC', 'Phenotype', 'HP:0030153', (69, 71))	('Antagonizing', 'Var', (0, 12))	('binding', 'Interaction', (17, 24))	('HGF', 'Gene', (147, 150))	('rat', 'Species', '10116', (177, 180))	('CC', 'Phenotype', 'HP:0030153', (84, 86))	('HGF', 'Gene', (35, 38))	('HGF', 'Gene', '3082', (147, 150))	('HGF', 'Gene', (28, 31))	('invasion in HuCC-T1', 'CPA', (55, 74))	('HGF', 'Gene', '3082', (35, 38))	('HGF', 'Gene', '3082', (28, 31))	('HuCC-T1', 'CellLine', 'CVCL:0324', (67, 74))	('inhibited', 'NegReg', (45, 54))	('blockade', 'Var', (135, 143))	('human', 'Species', '9606', (78, 83))
12594	20565817	IGF1R antagonists can inhibit proliferation of CC cell lines after serum deprivation and re-administration.	('antagonists', 'Var', (6, 17))	('inhibit', 'NegReg', (22, 29))	('rat', 'Species', '10116', (37, 40))	('IGF1R', 'Gene', (0, 5))	('CC', 'Phenotype', 'HP:0030153', (47, 49))	('rat', 'Species', '10116', (100, 103))	('proliferation', 'CPA', (30, 43))
12595	20565817	In addition, IGF1R antisense oligonucleotides diminished cell growth in HuH-28 cells.	('oligonucleotides', 'Chemical', 'MESH:D009841', (29, 45))	('IGF1R', 'Gene', (13, 18))	('antisense oligonucleotides', 'Var', (19, 45))	('cell growth in HuH-28 cells', 'CPA', (57, 84))	('diminished', 'NegReg', (46, 56))	('HuH-28', 'CellLine', 'CVCL:2955', (72, 78))
12602	20565817	Cetuximab did not significantly inhibit cell growth in EGI-1 cells carrying a heterozygous KRAS mutation, but had a dose-dependent effect on growth of TFK-1 cells displaying the KRAS wild-type.	('KRAS', 'Gene', (91, 95))	('Cetuximab', 'Chemical', 'MESH:D000068818', (0, 9))	('growth', 'MPA', (141, 147))	('mutation', 'Var', (96, 104))
12621	31221103	Since the main cause of postoperative complications is unsatisfactory bilioenteric anastomosis, the risk is even higher in patients with Bismuth types IV HCCA.	('Bismuth', 'Chemical', 'MESH:D001729', (137, 144))	('unsatisfactory', 'Var', (55, 69))	('Bismuth', 'Var', (137, 144))	('patients', 'Species', '9606', (123, 131))	('bilioenteric anastomosis', 'Disease', (70, 94))
12630	31221103	According to the Memorial Sloan-Kettering Cancer Center Classification, the criteria for unresectability were as follows: bilateral involvement up to the secondary biliary stumps; encasement of the main portal vein proximal to its bifurcation; atrophy of one hepatic lobe with encasement of the contralateral portal vein branch or with contralateral involvement of secondary biliary radicals; and distant metastases.	('atrophy of one hepatic lobe', 'Disease', (244, 271))	('atrophy of one hepatic lobe', 'Disease', 'MESH:D056486', (244, 271))	('Cancer', 'Disease', 'MESH:D009369', (42, 48))	('metastases', 'Disease', (405, 415))	('Cancer', 'Disease', (42, 48))	('Cancer', 'Phenotype', 'HP:0002664', (42, 48))	('encasement', 'Var', (180, 190))	('vein branch', 'Disease', (316, 327))	('vein branch', 'Disease', 'MESH:D012170', (316, 327))	('metastases', 'Disease', 'MESH:D009362', (405, 415))
12658	31221103	As a consequence of resection segment 4(or plus resection segment 1) for radical resection of hilar cholangiocarcinoma, all of the patients had abundant bile stumps, ranging in number from 4 to 8 (Table 2).	('patients', 'Species', '9606', (131, 139))	('resection', 'Var', (20, 29))	('cholangiocarcinoma', 'Disease', (100, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (100, 118))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))
12696	31192125	Genome instability syndromes are a group of inherited conditions caused by germline mutations in genes encoding DNA repair proteins involved in diverse DNA damage response (DDR) pathways, resulting in defects in genome maintenance, sensitivity toward various genotoxic agents, and early-onset cancer susceptibility.	('cancer', 'Disease', (293, 299))	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('defects', 'NegReg', (201, 208))	('germline mutations', 'Var', (75, 93))	('caused', 'Reg', (65, 71))	('genome maintenance', 'CPA', (212, 230))	('Genome instability syndromes', 'Disease', (0, 28))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('sensitivity', 'MPA', (232, 243))
12699	31192125	Known genome instability syndromes are, for example, caused by mutations in genes encoding DNA helicases like WRN in Werner Syndrome and BLM in Bloom syndrome, mutations in genes involved in nucleotide excision repair like XPA-HPV in Xeroderma pigmentosum and CSA and CSB in Cockayne syndrome, mutations in genes involved in DDR in response to the DNA double-strand breaks like ATM in Ataxia-telangiectasia and NBS1 in Nijmegen breakage syndrome, mutations in genes involved in protein-DNA crosslink repair like SPRTN in Ruijs-Aalfs syndrome, and mutations in genes involved in interstrand DNA crosslink repair like FANCA-FANCU in Fanconi anemia.	('WRN', 'Gene', '7486', (110, 113))	('FA', 'Phenotype', 'HP:0001994', (622, 624))	('mutations', 'Var', (160, 169))	('WRN', 'Gene', (110, 113))	('SPRTN', 'Gene', (512, 517))	('Xeroderma pigmentosum', 'Disease', (234, 255))	('FANCA', 'Gene', (616, 621))	('NBS1 in Nijmegen breakage syndrome', 'Disease', 'MESH:D049932', (411, 445))	('FANCU in Fanconi anemia', 'Phenotype', 'HP:0001994', (622, 645))	('XPA', 'Gene', (223, 226))	('mutations', 'Var', (547, 556))	('SPRTN', 'Gene', '83932', (512, 517))	('XPA', 'Gene', '7507', (223, 226))	('Ataxia-telangiectasia', 'Disease', 'MESH:D001260', (385, 406))	('Fanconi anemia', 'Disease', (631, 645))	('BLM', 'Disease', 'MESH:D001816', (137, 140))	('mutations', 'Var', (294, 303))	('Fanconi anemia', 'Disease', 'MESH:D005199', (631, 645))	('Werner Syndrome', 'Disease', 'MESH:D014898', (117, 132))	('Werner Syndrome', 'Disease', (117, 132))	('ATM', 'Gene', '472', (378, 381))	('Ruijs-Aalfs syndrome', 'Disease', 'OMIM:616200', (521, 541))	('Cockayne syndrome', 'Disease', (275, 292))	('Ruijs-Aalfs syndrome', 'Disease', (521, 541))	('NBS1 in Nijmegen breakage syndrome', 'Disease', (411, 445))	('Cockayne syndrome', 'Disease', 'MESH:D003057', (275, 292))	('Ataxia-telangiectasia', 'Disease', (385, 406))	('Bloom syndrome', 'Disease', 'MESH:D001816', (144, 158))	('telangiectasia', 'Phenotype', 'HP:0001009', (392, 406))	('anemia', 'Phenotype', 'HP:0001903', (639, 645))	('FANCA', 'Gene', '2175', (616, 621))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (631, 645))	('BLM', 'Disease', (137, 140))	('Bloom syndrome', 'Disease', (144, 158))	('FA', 'Phenotype', 'HP:0001994', (616, 618))	('ATM', 'Gene', (378, 381))	('mutations', 'Var', (447, 456))	('Ataxia', 'Phenotype', 'HP:0001251', (385, 391))	('Xeroderma pigmentosum', 'Disease', 'MESH:D014983', (234, 255))
12705	31192125	Namely, mutations affecting the FANCB, located on the X-chromosome, are inherited in an X-linked manner, therefore the female carriers do not develop FA-associated clinical signs and symptoms.	('FA-associated', 'Disease', (150, 163))	('FA', 'Phenotype', 'HP:0001994', (150, 152))	('mutations', 'Var', (8, 17))	('develop', 'PosReg', (142, 149))	('FA', 'Phenotype', 'HP:0001994', (32, 34))	('man', 'Species', '9606', (97, 100))	('FANCB', 'Gene', (32, 37))	('FANCB', 'Gene', '2187', (32, 37))
12706	31192125	In addition, heterozygous de novo mutations in RAD51 have also been connected to FA, representing an autosomal-dominant mode of inheritance.	('connected', 'Reg', (68, 77))	('RAD51', 'Gene', (47, 52))	('RAD51', 'Gene', '5888', (47, 52))	('mutations', 'Var', (34, 43))	('FA', 'Phenotype', 'HP:0001994', (81, 83))
12710	31192125	The patient's history revealed, that he was on day 11 of his first cycle of a standard chemotherapeutic regime of gemcitabine (500 mg/m2; dose reduction of 50% due to bilirubinemia prior to treatment initiation) and cisplatin (25 mg/m2) for advanced cholangiocarcinoma, which he had received in an outpatient setting on days 1 and 8.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (250, 268))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (250, 268))	('outpatient', 'Species', '9606', (298, 308))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('bilirubinemia', 'Disease', (167, 180))	('patient', 'Species', '9606', (4, 11))	('gemcitabine', 'Chemical', 'MESH:C056507', (114, 125))	('patient', 'Species', '9606', (301, 308))	('25 mg/m2', 'Var', (227, 235))	('bilirubinemia', 'Disease', 'MESH:D006932', (167, 180))	('cholangiocarcinoma', 'Disease', (250, 268))	('cisplatin', 'Chemical', 'MESH:D002945', (216, 225))	('men', 'Species', '9606', (195, 198))
12737	31192125	Namely, a missense variant c.3391A>G, (p.Thr1131Ala), that had already been associated with FA, and a novel variant within the splice acceptor site of intron 7, c.710-3A>G.	('FA', 'Phenotype', 'HP:0001994', (92, 94))	('c.710-3A>G', 'Mutation', 'c.710-3A>G', (161, 171))	('c.710-3A>G', 'Var', (161, 171))	('p.Thr1131Ala', 'Mutation', 'rs574034197', (39, 51))	('c.3391A>G', 'Mutation', 'rs574034197', (27, 36))	('associated', 'Reg', (76, 86))	('c.3391A>G', 'Var', (27, 36))
12738	31192125	Notably, a disrupting variant of the same splice acceptor (c.710-5T>C) had been previously described in a FA patient and was shown to induce an aberrant FANCA isoform by skipping of exon 8.	('induce', 'Reg', (134, 140))	('FANCA', 'Gene', '2175', (153, 158))	('patient', 'Species', '9606', (109, 116))	('FA', 'Phenotype', 'HP:0001994', (106, 108))	('c.710-5T>C', 'Mutation', 'c.710-5T>C', (59, 69))	('FANCA', 'Gene', (153, 158))	('skipping', 'Var', (170, 178))	('FA', 'Phenotype', 'HP:0001994', (153, 155))	('c.710-5T>C', 'Var', (59, 69))
12739	31192125	Segregation analysis with DNA samples of both healthy parents and his brother revealed the missense variant to be paternally inherited, whereas both the mother and his brother only bear the c.710-3A>G variant (Figure 2A), confirming the compound heterozygosity and an autosomal recessive inheritance.	('c.710-3A>G', 'Mutation', 'c.710-3A>G', (190, 200))	('missense', 'Var', (91, 99))	('c.710-3A>G', 'Var', (190, 200))
12740	31192125	Further, RT-PCR analysis performed with RNA isolated from lymphocytes of the healthy brother as previously described revealed that the c.710-3A>G variant causes skipping of exon 8 (Figure 2B), thus confirming its pathogenicity and allowing the post mortem diagnosis of FA in the index patient.	('skipping', 'MPA', (161, 169))	('c.710-3A>G', 'Var', (135, 145))	('allowing', 'Reg', (231, 239))	('c.710-3A>G', 'Mutation', 'c.710-3A>G', (135, 145))	('FA', 'Phenotype', 'HP:0001994', (269, 271))	('patient', 'Species', '9606', (285, 292))
12741	31192125	Notably, primary dermal fibroblasts from a FA patient harboring the c.710-5T>C variant of FANCA (in compound heterozygosity with c.3558insG; FA-52 cells), that also causes skipping of exon 8, demonstrated chromosomal instability after exposure to diepoxybutane.	('chromosomal instability after exposure to diepoxybutane', 'Phenotype', 'HP:0003221', (205, 260))	('patient', 'Species', '9606', (46, 53))	('chromosomal instability', 'MPA', (205, 228))	('FANCA', 'Gene', (90, 95))	('diepoxybutane', 'Chemical', 'MESH:C007366', (247, 260))	('FA', 'Phenotype', 'HP:0001994', (141, 143))	('c.710-5T>C', 'Var', (68, 78))	('FA', 'Phenotype', 'HP:0001994', (90, 92))	('c.3558insG', 'Mutation', 'c.3558insG', (129, 139))	('FA', 'Phenotype', 'HP:0001994', (43, 45))	('chromosomal instability', 'Phenotype', 'HP:0040012', (205, 228))	('FANCA', 'Gene', '2175', (90, 95))	('c.710-5T>C', 'Mutation', 'c.710-5T>C', (68, 78))
12742	31192125	Furthermore, a previous study has shown that the c.3391A>G variant in FANCA significantly decreases FANCD2 monoubiquitination and the number of FANCD2 foci before and after mitomyocin C treatment, which is the critical event in the Fanconi/BRCA pathway for initiation of DNA repair.	('BRCA', 'Gene', '672', (240, 244))	('FANCA', 'Gene', (70, 75))	('FANCD2', 'Gene', '2177', (100, 106))	('BRCA', 'Gene', (240, 244))	('FANCD2', 'Gene', (100, 106))	('decreases', 'NegReg', (90, 99))	('FA', 'Phenotype', 'HP:0001994', (100, 102))	('FA', 'Phenotype', 'HP:0001994', (70, 72))	('men', 'Species', '9606', (191, 194))	('c.3391A>G', 'Mutation', 'rs574034197', (49, 58))	('FANCA', 'Gene', '2175', (70, 75))	('FANCD2', 'Gene', '2177', (144, 150))	('FANCD2', 'Gene', (144, 150))	('c.3391A>G', 'Var', (49, 58))	('FA', 'Phenotype', 'HP:0001994', (144, 146))
12743	31192125	Taken together, the herein performed genetic analyses identified compound heterozygosity for two clearly pathogenic FANCA mutations thereby allowing the post-mortem clinical diagnosis of FA according to the published guidelines.	('FANCA', 'Gene', '2175', (116, 121))	('pathogenic', 'Reg', (105, 115))	('FANCA', 'Gene', (116, 121))	('mutations', 'Var', (122, 131))	('compound heterozygosity', 'Var', (65, 88))	('FA', 'Phenotype', 'HP:0001994', (187, 189))	('FA', 'Phenotype', 'HP:0001994', (116, 118))
12775	31192125	It is further worth noting that NGS-based testing of the tumor sample first, would have also likely identified two heterozygous FANCA mutations.	('FANCA', 'Gene', '2175', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('FANCA', 'Gene', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('FA', 'Phenotype', 'HP:0001994', (128, 130))	('mutations', 'Var', (134, 143))	('tumor', 'Disease', (57, 62))
12776	31192125	Misinterpretation of this finding, which is not completely excluded without pairing to normal tissue, could have potentially led to misinterpretation with even recommending a cisplatin-based therapy in this patient as the onset of somatic Fanconi/BRCA pathway defects is a feature of some cisplatin-sensitive tumors.	('men', 'Species', '9606', (165, 168))	('led', 'Reg', (125, 128))	('BRCA', 'Gene', (247, 251))	('cisplatin', 'Chemical', 'MESH:D002945', (289, 298))	('tumors', 'Disease', (309, 315))	('tumors', 'Disease', 'MESH:D009369', (309, 315))	('tumors', 'Phenotype', 'HP:0002664', (309, 315))	('defects', 'Var', (260, 267))	('somatic Fanconi', 'Phenotype', 'HP:0001994', (231, 246))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('patient', 'Species', '9606', (207, 214))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('BRCA', 'Gene', '672', (247, 251))
12777	31192125	Indeed, the vast majority of early-onset cancer patients, which are either non-syndromic patients or have a negative family history, receive genetic analyses of normal tissue only after a mutation in a gene known to be associated with germline cancer predisposition is first identified in the tumor sample.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('mutation', 'Var', (188, 196))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('non-syndromic', 'Disease', 'MESH:C580335', (75, 88))	('non-syndromic', 'Disease', (75, 88))	('tumor', 'Disease', (293, 298))	('patients', 'Species', '9606', (89, 97))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('patients', 'Species', '9606', (48, 56))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
12780	31192125	One major aspect of precision medicine in oncology is the identification of patients with germline cancer predisposing mutations, in order to optimize the initial therapy.	('patients', 'Species', '9606', (76, 84))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('oncology', 'Phenotype', 'HP:0002664', (42, 50))	('mutations', 'Var', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
12871	30969381	In addition, a previous study of cirrhosis and thrombocytopenia reported that eltrombopag increased the risk of portal vein thrombosis (4%; 6/143).	('cirrhosis', 'Phenotype', 'HP:0001394', (33, 42))	('cirrhosis', 'Disease', 'MESH:D005355', (33, 42))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (47, 63))	('thrombocytopenia', 'Disease', (47, 63))	('eltrombopag', 'Var', (78, 89))	('portal vein thrombosis', 'Phenotype', 'HP:0030242', (112, 134))	('thrombocytopenia', 'Disease', 'MESH:D013921', (47, 63))	('cirrhosis', 'Disease', (33, 42))	('vein thrombosis', 'Disease', 'MESH:D020246', (119, 134))	('vein thrombosis', 'Disease', (119, 134))	('eltrombopag', 'Chemical', 'MESH:C520809', (78, 89))	('vein thrombosis', 'Phenotype', 'HP:0004936', (119, 134))
12933	28858292	By Kaplan-Meier analysis, there was no statistical difference in median survival of all patients with malignant hilar strictures who were treated with MFPS vs. SEMS (195+-131.9 days vs. 259+-145.5 days, P=0.88, Figure 3a), or in the subgroups with cholangiocarcinoma compared to those with strictures secondary to hilar metastasis (Figure 3b).	('patients', 'Species', '9606', (88, 96))	('MFPS', 'Var', (151, 155))	('cholangiocarcinoma', 'Disease', (248, 266))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (248, 266))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (248, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
12940	28858292	In subgroup analysis, MFPS compared to SEMS also had shorter stent patency both in patients with cholangiocarcinoma (27+-4.1 days in MFPS group vs. 149+-65.9 days in SEMS group, P=0.002) and in patients with local invasion or distant metastasis to the hepatic hilum (27+-7.2 days for MFPS vs. 56+-27.1 days for SEMS, P=0.01).	('MFPS', 'Var', (22, 26))	('patients', 'Species', '9606', (194, 202))	('stent', 'MPA', (61, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('cholangiocarcinoma', 'Disease', (97, 115))	('shorter', 'NegReg', (53, 60))	('patients', 'Species', '9606', (83, 91))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (97, 115))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))
12961	28858292	Cox proportional regression analysis showed that patients with lower Karnofsky score and higher serum total bilirubin level, particularly >=10 mg/dl at presentation had significantly worse survival.	('lower', 'NegReg', (63, 68))	('>=10', 'Var', (138, 142))	('bilirubin', 'Chemical', 'MESH:D001663', (108, 117))	('Karnofsky score', 'MPA', (69, 84))	('higher serum total bilirubin', 'Phenotype', 'HP:0003573', (89, 117))	('higher', 'PosReg', (89, 95))	('serum total bilirubin level', 'MPA', (96, 123))	('worse', 'NegReg', (183, 188))	('patients', 'Species', '9606', (49, 57))	('higher serum total bilirubin level', 'Phenotype', 'HP:0002904', (89, 123))
12974	27999621	The purpose of this study was to evaluate the diagnostic and prognostic value of promoter hypermethylation of the SHOX2 and SEPT9 gene loci in BTC.	('SEPT9', 'Gene', (124, 129))	('promoter hypermethylation', 'Var', (81, 106))	('SEPT9', 'Gene', '10801', (124, 129))	('BTC', 'Disease', (143, 146))	('SHOX2', 'Gene', (114, 119))
12977	27999621	SEPT9 hypermethylation was significantly more frequent in gallbladder carcinomas compared to cholangiocarcinomas (p = 0.01) and was associated with large primary tumors (p = 0.01) as well as age (p = 0.03).	('primary tumors', 'Disease', (154, 168))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('hypermethylation', 'Var', (6, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('cholangiocarcinomas', 'Disease', (93, 112))	('gallbladder carcinomas', 'Disease', (58, 80))	('SEPT9', 'Gene', '10801', (0, 5))	('primary tumors', 'Disease', 'MESH:D009369', (154, 168))	('SEPT9', 'Gene', (0, 5))	('gallbladder carcinomas', 'Disease', 'MESH:D005706', (58, 80))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (93, 112))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('associated', 'Reg', (132, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('frequent', 'Reg', (46, 54))
12978	27999621	Cox proportional hazard analysis confirmed microscopic residual tumor at the surgical margin (R1-resection) as an independent prognostic factor, while SHOX2 and SEPT9 methylation showed no correlation with overall survival.	('SEPT9', 'Gene', '10801', (161, 166))	('tumor', 'Disease', (64, 69))	('Cox', 'Gene', '1351', (0, 3))	('SEPT9', 'Gene', (161, 166))	('Cox', 'Gene', (0, 3))	('microscopic', 'Var', (43, 54))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
12980	27999621	SHOX2 and SEPT9 methylation as a marker panel achieved a sensitivity of 45% and a specificity of 99% in differentiating between samples from patients with and without cholangiocarcinoma (AUC = 0.752; 95% CI 0.631-0.873).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (167, 185))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (167, 185))	('SHOX2', 'Gene', (0, 5))	('patients', 'Species', '9606', (141, 149))	('SEPT9', 'Gene', '10801', (10, 15))	('SEPT9', 'Gene', (10, 15))	('cholangiocarcinoma', 'Disease', (167, 185))	('methylation', 'Var', (16, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
12981	27999621	SHOX2 and SEPT9 are frequently methylated in biliary tract cancers.	('biliary tract cancers', 'Disease', 'MESH:D001661', (45, 66))	('biliary tract cancers', 'Disease', (45, 66))	('SHOX2', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('SEPT9', 'Gene', '10801', (10, 15))	('methylated', 'Var', (31, 41))	('SEPT9', 'Gene', (10, 15))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))
12982	27999621	Promoter hypermethylation of SHOX2 and SEPT9 may therefore serve as a minimally invasive biomarker supporting diagnosis finding and therapy monitoring in clinical specimens.	('SHOX2', 'Gene', (29, 34))	('SEPT9', 'Gene', (39, 44))	('clinical', 'Species', '191496', (154, 162))	('SEPT9', 'Gene', '10801', (39, 44))	('Promoter hypermethylation', 'Var', (0, 25))
12991	27999621	There is emerging evidence that genetic and epigenetic alterations play a pivotal role during human carcinogenesis.	('human', 'Species', '9606', (94, 99))	('epigenetic alterations', 'Var', (44, 66))	('genetic', 'Var', (32, 39))
12992	27999621	Accordingly, aberrant methylation of CpG dinucleotides has been evidenced as a hallmark epigenetic alteration in numerous malignant diseases.	('numerous malignant diseases', 'Disease', 'MESH:D009369', (113, 140))	('CpG', 'Gene', (37, 40))	('methylation', 'MPA', (22, 33))	('numerous malignant diseases', 'Disease', (113, 140))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (37, 54))	('aberrant', 'Var', (13, 21))
12993	27999621	Promoter hypermethylation, in particular, has been linked to transcriptional silencing of tumor suppressor genes, thus enabling neoplastic cells to proliferate without restriction.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('transcriptional', 'MPA', (61, 76))	('enabling', 'PosReg', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('Promoter hypermethylation', 'Var', (0, 25))
12994	27999621	In BTC and its precursor lesions, these epigenetic alterations can be detected with possible valuable clinical implications.	('epigenetic alterations', 'Var', (40, 62))	('BTC', 'Disease', (3, 6))	('clinical', 'Species', '191496', (102, 110))
12995	27999621	Aberrant DNA methylation of SHOX2 has been extensively characterized as a biomarker for the diagnosis of lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('SHOX2', 'Gene', (28, 33))	('lung cancer', 'Disease', (105, 116))	('DNA', 'MPA', (9, 12))
13002	27999621	Hypermethylation of SEPT9 was also present in colon adenomas, thus indicating that this epigenetic alteration is an early event in the adenoma-carcinoma sequence.	('SEPT9', 'Gene', '10801', (20, 25))	('colon adenomas', 'Disease', 'MESH:D000236', (46, 60))	('Hypermethylation', 'Var', (0, 16))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (135, 152))	('SEPT9', 'Gene', (20, 25))	('colon adenomas', 'Disease', (46, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('adenoma-carcinoma', 'Disease', (135, 152))
13003	27999621	Methylated SEPT9 has also been detected in plasma samples from colorectal cancer patients, and several studies have proposed its biomarker application for early diagnosis of CRC.	('detected', 'Reg', (31, 39))	('CRC', 'Phenotype', 'HP:0003003', (174, 177))	('SEPT9', 'Gene', (11, 16))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('patients', 'Species', '9606', (81, 89))	('colorectal cancer', 'Disease', (63, 80))	('SEPT9', 'Gene', '10801', (11, 16))	('CRC', 'Disease', (174, 177))	('Methylated', 'Var', (0, 10))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
13004	27999621	Furthermore, SEPT9 was found to be frequently methylated in the head and neck and esophageal squamous cell carcinoma, as well as prostate cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('esophageal squamous cell carcinoma', 'Disease', (82, 116))	('SEPT9', 'Gene', '10801', (13, 18))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('prostate cancer', 'Disease', (129, 144))	('SEPT9', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (82, 116))	('prostate cancer', 'Disease', 'MESH:D011471', (129, 144))	('prostate cancer', 'Phenotype', 'HP:0012125', (129, 144))	('methylated', 'Var', (46, 56))
13007	27999621	Due to the encouraging results found in other cancer entities, we hypothesize that these epigenetic alterations can serve as biomarkers in cancers arising from the biliary tract.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('cancers arising from the biliary tract', 'Phenotype', 'HP:0100574', (139, 177))	('epigenetic alterations', 'Var', (89, 111))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (139, 145))
13041	27999621	Sixteen BTC samples showed SEPT9 positivity, providing a sensitivity and specificity of 29 and 100%, respectively.	('SEPT9', 'Gene', (27, 32))	('positivity', 'Var', (33, 43))	('SEPT9', 'Gene', '10801', (27, 32))
13050	27999621	PMR values >100% have been previously reported for SHOX2 in lung cancer, when ACTB was used as a reference, and were attributed to amplification of the SHOX2 locus or deletion of the ACTB locus.	('ACTB', 'Gene', (183, 187))	('PMR', 'MPA', (0, 3))	('amplification', 'Var', (131, 144))	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('ACTB', 'Gene', (78, 82))	('ACTB', 'Gene', '60', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('deletion', 'Var', (167, 175))	('SHOX2', 'Gene', (152, 157))	('ACTB', 'Gene', '60', (183, 187))
13051	27999621	Therefore, we presume that deletion of the ACTB locus or amplification of the SHOX2 and SEPT9 locus, respectively, may have also led to PMR values >100% in these five BTC samples.	('SEPT9', 'Gene', '10801', (88, 93))	('SHOX2', 'Gene', (78, 83))	('SEPT9', 'Gene', (88, 93))	('ACTB', 'Gene', (43, 47))	('led', 'Reg', (129, 132))	('amplification', 'Var', (57, 70))	('ACTB', 'Gene', '60', (43, 47))	('deletion', 'Var', (27, 35))	('PMR values', 'MPA', (136, 146))
13053	27999621	However, no significant association was found between SHOX2 or SEPT9 methylation and the remaining clinicopathological parameters.	('SEPT9', 'Gene', '10801', (63, 68))	('SEPT9', 'Gene', (63, 68))	('SHOX2', 'Gene', (54, 59))	('methylation', 'Var', (69, 80))
13057	27999621	On multivariate analysis merely microscopic residual carcinoma at the final surgical margin (R1) proved to be an independent prognostic factor associated with a dismal outcome (p = 0.026, HR = 3.8).	('carcinoma', 'Disease', (53, 62))	('microscopic', 'Var', (32, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinoma', 'Disease', 'MESH:D002277', (53, 62))
13067	27999621	4   Epigenetic alterations such as aberrant DNA methylation patterns have been extensively studied across multiple human cancer types, with BTC being no exception.	('DNA', 'MPA', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('aberrant', 'Var', (35, 43))	('human', 'Species', '9606', (115, 120))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
13068	27999621	published global methylation data for intrahepatic and extrahepatic CC and identified numerous aberrantly methylated genes involved in cholangiocarcinogenesis, including components of the Wnt signaling pathway.	('intrahepatic', 'Disease', (38, 50))	('cholangiocarcinogenesis', 'Disease', (135, 158))	('intrahepatic', 'Disease', 'MESH:D002780', (38, 50))	('aberrantly methylated', 'Var', (95, 116))	('CC', 'Phenotype', 'HP:0030153', (68, 70))
13072	27999621	Merely 36% of papillary thyroid carcinomas were found to be methylated at the SHOX2 locus.	('papillary thyroid carcinomas', 'Disease', (14, 42))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (14, 42))	('SHOX2', 'Gene', (78, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (14, 42))	('carcinomas', 'Phenotype', 'HP:0030731', (32, 42))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (24, 42))	('methylated', 'Var', (60, 70))
13078	27999621	In our study, we demonstrated that the DNA methylation of SHOX2 and SEPT9 can accurately differentiate between tumor tissue from BTC patients and normal adjacent tissue with high specificity.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('SEPT9', 'Gene', '10801', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('patients', 'Species', '9606', (133, 141))	('SEPT9', 'Gene', (68, 73))	('SHOX2', 'Gene', (58, 63))	('tumor', 'Disease', (111, 116))	('DNA methylation', 'Var', (39, 54))	('differentiate', 'Reg', (89, 102))
13080	27999621	The results confirm our hypothesis that epigenetic alterations of SHOX2 and SEPT9 may serve as biomarkers to support the detection of BTC in tissue specimens due to its high specificity, and a use as biomarkers for response prediction can be discussed.	('SEPT9', 'Gene', (76, 81))	('epigenetic alterations', 'Var', (40, 62))	('SHOX2', 'Gene', (66, 71))	('SEPT9', 'Gene', '10801', (76, 81))
13087	27999621	Half a century after Mendel and Metais discovered the presence of cell-free nucleic acids in human blood, it has become generally acknowledged that extracellular DNA from cancer patients also harbors tumor-related epigenetic alterations.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('human', 'Species', '9606', (93, 98))	('patients', 'Species', '9606', (178, 186))	('epigenetic alterations', 'Var', (214, 236))	('tumor', 'Disease', (200, 205))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
13088	27999621	Accordingly, aberrant methylation of circulating cell-free DNA has been extensively studied as a biomarker in human cancer.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('human', 'Species', '9606', (110, 115))	('methylation', 'MPA', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('aberrant', 'Var', (13, 21))
13091	27999621	However, methylation analysis of SHOX2 and SEPT9 in plasma, naturally containing circulating DNA from any site of the body, bears some disadvantages for diagnostic purposes in BTC.	('methylation', 'Var', (9, 20))	('SEPT9', 'Gene', '10801', (43, 48))	('SEPT9', 'Gene', (43, 48))
13093	27999621	In our tissue study, SHOX2 methylation proved to be superior to SEPT9 in terms of sensitivity to correctly identify BTC specimens.	('methylation', 'Var', (27, 38))	('SEPT9', 'Gene', (64, 69))	('SEPT9', 'Gene', '10801', (64, 69))
13097	27999621	Methylation status of SHOX2 and SEPT9 showed no relation to overall survival in our cohort.	('SEPT9', 'Gene', '10801', (32, 37))	('SHOX2', 'Gene', (22, 27))	('Methylation status', 'Var', (0, 18))	('SEPT9', 'Gene', (32, 37))
13098	27999621	Nevertheless, a prognostic value of methylated SHOX2 and SEPT9 has been reported in the literature, although the findings were partially ambiguous.	('SEPT9', 'Gene', '10801', (57, 62))	('methylated', 'Var', (36, 46))	('SHOX2', 'Gene', (47, 52))	('SEPT9', 'Gene', (57, 62))
13099	27999621	For instance, low SHOX2 DNA methylation values predicted a shorter progression-free survival following resection in non-small cell lung cancer, whereas hypermethylation of SHOX2 in pleural effusions was associated with an adverse outcome.	('pleural effusions', 'Disease', (181, 198))	('shorter', 'NegReg', (59, 66))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (116, 142))	('hypermethylation', 'Var', (152, 168))	('SHOX2', 'Gene', (18, 23))	('pleural effusions', 'Disease', 'MESH:D010996', (181, 198))	('non-small cell lung cancer', 'Disease', (116, 142))	('pleural effusions', 'Phenotype', 'HP:0002202', (181, 198))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (120, 142))	('low', 'NegReg', (14, 17))	('progression-free survival', 'CPA', (67, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (116, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
13102	27999621	Likewise, colorectal cancer patients with high SEPT9 serum methylation levels at 1-year follow-up were found to be at high risk of disease recurrence.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('SEPT9', 'Gene', '10801', (47, 52))	('colorectal cancer', 'Phenotype', 'HP:0003003', (10, 27))	('SEPT9', 'Gene', (47, 52))	('colorectal cancer', 'Disease', (10, 27))	('high', 'Var', (42, 46))	('patients', 'Species', '9606', (28, 36))	('serum methylation levels', 'MPA', (53, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (10, 27))
13103	27999621	Although these promising findings in other cancer entities suggested that aberrant SHOX2 and SEPT9 methylation may also correlate with prognosis in BTC, our results did not confirm this hypothesis.	('methylation', 'Var', (99, 110))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('correlate', 'Reg', (120, 129))	('SHOX2', 'Gene', (83, 88))	('SEPT9', 'Gene', '10801', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('SEPT9', 'Gene', (93, 98))	('aberrant', 'Var', (74, 82))	('BTC', 'Disease', (148, 151))
13106	27999621	Thus, a larger study cohort, possibly based on a multicenter approach in a prospective fashion, is needed to more precisely assess the potential of SHOX2 and SEPT9 methylation as a biomarker for all four subgroups of biliary tract cancer.	('SEPT9', 'Gene', '10801', (158, 163))	('methylation', 'Var', (164, 175))	('SEPT9', 'Gene', (158, 163))	('biliary tract cancer', 'Disease', 'MESH:D001661', (217, 237))	('biliary tract cancer', 'Disease', (217, 237))	('SHOX2', 'Gene', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
13109	27999621	already demonstrated that hypermethylation of SEPT9 in adenoma and CRC specimens is limited to one of the several CpG islands.	('adenoma', 'Disease', 'MESH:D000236', (55, 62))	('CRC', 'Phenotype', 'HP:0003003', (67, 70))	('hypermethylation', 'Var', (26, 42))	('SEPT9', 'Gene', '10801', (46, 51))	('adenoma', 'Disease', (55, 62))	('SEPT9', 'Gene', (46, 51))
13112	27999621	Epigenetic alterations are promising for the development of biomarkers in human cancer.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('human', 'Species', '9606', (74, 79))	('cancer', 'Disease', (80, 86))
13113	27999621	In addition, our results confirmed the presence of aberrant methylation of the SEPT9 locus in BTC.	('aberrant', 'Var', (51, 59))	('SEPT9', 'Gene', '10801', (79, 84))	('SEPT9', 'Gene', (79, 84))	('methylation', 'MPA', (60, 71))	('BTC', 'Disease', (94, 97))
13114	27999621	Furthermore, we demonstrated that methylated SHOX2 and SEPT9 DNA can be detected in plasma from BTC patients highlighting a use in clinical samples for minimally invasive diagnostic applications and therapy monitoring.	('methylated', 'Var', (34, 44))	('clinical samples', 'Species', '191496', (131, 147))	('SHOX2', 'Gene', (45, 50))	('patients', 'Species', '9606', (100, 108))	('SEPT9', 'Gene', '10801', (55, 60))	('SEPT9', 'Gene', (55, 60))
13155	25355800	The ability to obtain a cholangiogram without injection of contrast into the biliary tree is significant, since the injection of contrast medium can result in hard-to-treat cholangitis in patients in whom adequate biliary drainage cannot be achieved during ERCP.	('result in', 'Reg', (149, 158))	('cholangitis', 'Disease', 'MESH:D002761', (173, 184))	('patients', 'Species', '9606', (188, 196))	('injection', 'Var', (116, 125))	('cholangitis', 'Disease', (173, 184))	('cholangitis', 'Phenotype', 'HP:0030151', (173, 184))
13156	25355800	A meta-analysis of 67 studies, including 4711 patients with suspected biliary obstruction, found a sensitivity and specificity of 98% for MRCP in determining the level of obstruction, while the corresponding numbers were 88% and 95% for diagnosing malignancy, which can be further improved with the use of diffusion-weighted imaging (DWI).	('patients', 'Species', '9606', (46, 54))	('biliary obstruction', 'Disease', 'MESH:D001658', (70, 89))	('biliary obstruction', 'Phenotype', 'HP:0005230', (70, 89))	('malignancy', 'Disease', 'MESH:D009369', (248, 258))	('malignancy', 'Disease', (248, 258))	('biliary obstruction', 'Disease', (70, 89))	('MRCP', 'Var', (138, 142))
13178	25355800	The fluid aspirate from the bile duct can also be analysed for Kras and p53 mutations, to increase the diagnostic yield for malignancy if truly present.	('mutations', 'Var', (76, 85))	('increase', 'PosReg', (90, 98))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('malignancy', 'Disease', 'MESH:D009369', (124, 134))	('malignancy', 'Disease', (124, 134))	('Kras', 'Gene', (63, 67))
13179	25355800	Other studies have also shown the possible value of bile aspirate spectroscopy in diagnosing cholangiocarcinoma and presence of S100A9 protein as marker of PSC severity.	('PSC', 'Disease', (156, 159))	('cholangiocarcinoma', 'Disease', (93, 111))	('S100A9', 'Gene', '6280', (128, 134))	('presence', 'Var', (116, 124))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('protein', 'Protein', (135, 142))	('S100A9', 'Gene', (128, 134))
13185	25355800	Even though the presence of previously placed stents can cause some acoustic shadowing and/or interfere with the passage of the FNA needle into the area of interest, studies have not shown any significant decrease in diagnostic yield; however, the presence of a biliary stent for several weeks prior to EUS examination can induce inflammatory changes, with accompanying reactive cellular atypia, which can confound the cytological diagnosis and potentially lower the sensitivity and specificity of EUS-FNA in these patients.	('inflammatory changes', 'CPA', (330, 350))	('presence', 'Var', (248, 256))	('sensitivity', 'MPA', (467, 478))	('lower', 'NegReg', (457, 462))	('induce', 'Reg', (323, 329))	('patients', 'Species', '9606', (515, 523))
13192	25355800	showed no difference in overall- or progression-free survival in patients who underwent EUS-FNA for cholangiocarcinoma than in those who did not undergo FNA.	('cholangiocarcinoma', 'Disease', (100, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('EUS-FNA', 'Var', (88, 95))	('patients', 'Species', '9606', (65, 73))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (100, 118))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))
13231	25355800	The addition of FISH, Kras/p53 mutation analysis, intra-ductal biopsies and pCLE may help improve the diagnostic yield but more prospective data are needed.	('mutation analysis', 'Var', (31, 48))	('p53', 'Gene', '7157', (27, 30))	('p53', 'Gene', (27, 30))
13233	25355800	Despite limited data, concern remains over needle tract seeding resulting from EUS-FNA, especially if more centers are going to offer transplant as an option for cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (162, 180))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (162, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (162, 180))	('EUS-FNA', 'Var', (79, 86))
13264	32140709	The data from the study of 37 biliary tract specimens obtained from biliary tract patients have shown mutations in the beta-catenin gene suggesting the role of this gene in the poor prognosis in these cancer patients.	('beta-catenin', 'Gene', '1499', (119, 131))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('patients', 'Species', '9606', (208, 216))	('cancer', 'Disease', (201, 207))	('patients', 'Species', '9606', (82, 90))	('mutations', 'Var', (102, 111))	('beta-catenin', 'Gene', (119, 131))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))
13265	32140709	Another study has shown the mutations in the beta-catenin genes in the 24 surgically resected samples of intrahepatic CCA.	('beta-catenin', 'Gene', '1499', (45, 57))	('CCA', 'Phenotype', 'HP:0030153', (118, 121))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (105, 121))	('mutations', 'Var', (28, 37))	('beta-catenin', 'Gene', (45, 57))	('intrahepatic CCA', 'Disease', (105, 121))
13283	32140709	In QBC939 cells, knockout of endogenous Fascin expression by short hairpin RNA (shRNA) inhibited EMT, cellular proliferation and invasion, and tumor volume.	('Fascin', 'Gene', (40, 46))	('tumor', 'Disease', (143, 148))	('QBC939', 'CellLine', 'CVCL:6942', (3, 9))	('EMT', 'CPA', (97, 100))	('knockout', 'Var', (17, 25))	('inhibited', 'NegReg', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('Fascin', 'Gene', '6624', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
13284	32140709	Moreover, knockdown of Fascin up-regulated the expression of beta-catenin on the plasma membrane fraction (a relative increase) and down-regulated the nuclear localization of beta-catenin in the QBC939 cells.	('beta-catenin', 'Gene', '1499', (61, 73))	('Fascin', 'Gene', (23, 29))	('beta-catenin', 'Gene', '1499', (175, 187))	('Fascin', 'Gene', '6624', (23, 29))	('beta-catenin', 'Gene', (61, 73))	('beta-catenin', 'Gene', (175, 187))	('down-regulated', 'NegReg', (132, 146))	('up-regulated', 'PosReg', (30, 42))	('knockdown', 'Var', (10, 19))	('QBC939', 'CellLine', 'CVCL:6942', (195, 201))	('expression', 'MPA', (47, 57))	('nuclear localization', 'MPA', (151, 171))
13292	32140709	described the inhibition of Wnt2 and beta-catenin by transfection of siRNAs targeting Wnt2 and beta-catenin induced cell apoptosis and suppressed cell proliferation in CCA cells (FRH0201 cells).	('CCA', 'Phenotype', 'HP:0030153', (168, 171))	('Wnt2', 'Gene', (86, 90))	('transfection', 'Var', (53, 65))	('cell apoptosis', 'CPA', (116, 130))	('Wnt2', 'Gene', '7472', (28, 32))	('beta-catenin', 'Gene', (95, 107))	('beta-catenin', 'Gene', (37, 49))	('beta-catenin', 'Gene', '1499', (37, 49))	('CCA', 'Disease', (168, 171))	('Wnt2', 'Gene', '7472', (86, 90))	('beta-catenin', 'Gene', '1499', (95, 107))	('siRNAs', 'Gene', (69, 75))	('suppressed', 'NegReg', (135, 145))	('cell proliferation', 'CPA', (146, 164))	('Wnt2', 'Gene', (28, 32))	('inhibition', 'NegReg', (14, 24))
13296	32140709	It was shown that there is overexpression of T-UCR uc.158- in CCA cells with nuclear localization of beta-catenin.	('C', 'Chemical', 'MESH:D002244', (48, 49))	('C', 'Chemical', 'MESH:D002244', (62, 63))	('CCA', 'Phenotype', 'HP:0030153', (62, 65))	('beta-catenin', 'Gene', (101, 113))	('T-UCR', 'Var', (45, 50))	('beta-catenin', 'Gene', '1499', (101, 113))	('overexpression', 'PosReg', (27, 41))	('C', 'Chemical', 'MESH:D002244', (63, 64))
13304	32140709	The role of Wnt signaling was further affirmed by the observations showing that specific inhibitors of Wnt pathway, i.e., ICG-001 and C-59 reduced the number and area of tumor in experimental models.	('C', 'Chemical', 'MESH:D002244', (134, 135))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('ICG', 'Chemical', 'MESH:D007208', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('C-59', 'Var', (134, 138))	('tumor', 'Disease', (170, 175))	('Wnt pathway', 'Pathway', (103, 114))	('reduced', 'NegReg', (139, 146))	('C', 'Chemical', 'MESH:D002244', (123, 124))	('ICG-001', 'Var', (122, 129))
13307	32140709	It has been identified that hypermethylation in the promoter region of the Wnt inhibitory factor 1 (WIF-1) promoter region is crucial in the progression of cholecystitis to gallbladder cancer.	('cholecystitis', 'Phenotype', 'HP:0001082', (156, 169))	('hypermethylation', 'Var', (28, 44))	('WIF-1', 'Gene', '11197', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('WIF-1', 'Gene', (100, 105))	('cholecystitis to gallbladder cancer', 'Disease', 'MESH:D005706', (156, 191))	('Wnt inhibitory factor 1', 'Gene', '11197', (75, 98))	('crucial', 'Reg', (126, 133))	('cholecystitis to gallbladder cancer', 'Disease', (156, 191))	('Wnt inhibitory factor 1', 'Gene', (75, 98))
13309	32140709	A previous study also documented the increase in the nuclear translocation of beta-catenin in intrahepatic CCA patients is not a result of mutations in the exon portion of beta-catenin.	('beta-catenin', 'Gene', (172, 184))	('mutations', 'Var', (139, 148))	('beta-catenin', 'Gene', '1499', (172, 184))	('CCA', 'Phenotype', 'HP:0030153', (107, 110))	('increase', 'PosReg', (37, 45))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (94, 110))	('beta-catenin', 'Gene', (78, 90))	('intrahepatic CCA', 'Disease', (94, 110))	('nuclear translocation', 'MPA', (53, 74))	('beta-catenin', 'Gene', '1499', (78, 90))	('patients', 'Species', '9606', (111, 119))
13310	32140709	Accordingly, it may be proposed that a decrease in the SFRP1 protein expression and hypermethylation in the WIF-1 promoter region may increase the expression of Wnt ligands to enhance Wnt/ beta-catenin in CCA.	('beta-catenin', 'Gene', (189, 201))	('SFRP1', 'Gene', '6422', (55, 60))	('decrease', 'NegReg', (39, 47))	('CCA', 'Disease', (205, 208))	('expression', 'MPA', (147, 157))	('beta-catenin', 'Gene', '1499', (189, 201))	('expression', 'MPA', (69, 79))	('enhance', 'PosReg', (176, 183))	('WIF-1', 'Gene', (108, 113))	('SFRP1', 'Gene', (55, 60))	('hypermethylation', 'Var', (84, 100))	('increase', 'PosReg', (134, 142))	('CCA', 'Phenotype', 'HP:0030153', (205, 208))	('protein', 'Protein', (61, 68))	('WIF-1', 'Gene', '11197', (108, 113))
13323	32140709	Inhibition of miR26a attenuated the growth rate of the tumor and prevented the activation of beta-catenin.	('attenuated', 'NegReg', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('miR26a', 'Gene', '407015', (14, 20))	('beta-catenin', 'Gene', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('miR26a', 'Gene', (14, 20))	('activation', 'MPA', (79, 89))	('prevented', 'NegReg', (65, 74))	('tumor', 'Disease', (55, 60))	('beta-catenin', 'Gene', '1499', (93, 105))	('Inhibition', 'Var', (0, 10))
13333	32140709	The knockdown of miR-191 was shown to trigger apoptosis and prevent tumor progression.	('prevent', 'NegReg', (60, 67))	('apoptosis', 'CPA', (46, 55))	('tumor', 'Disease', (68, 73))	('miR-191', 'Gene', (17, 24))	('trigger', 'PosReg', (38, 45))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('knockdown', 'Var', (4, 13))	('miR-191', 'Gene', '406966', (17, 24))
13340	32140709	Based on the in vitro and in vivo studies, it was reported that overexpression of miRNA Let-7c inhibits the tumorigenic properties of CCA by modulating beta-catenin signaling pathway (Figure 2).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('CCA', 'Phenotype', 'HP:0030153', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Let-7c', 'Gene', (88, 94))	('beta-catenin', 'Gene', (152, 164))	('overexpression', 'PosReg', (64, 78))	('miRNA', 'Var', (82, 87))	('tumor', 'Disease', (108, 113))	('modulating', 'Reg', (141, 151))	('beta-catenin', 'Gene', '1499', (152, 164))	('CCA', 'Disease', (134, 137))	('inhibits', 'NegReg', (95, 103))	('Let-7c', 'Gene', '406885', (88, 94))
13342	32140709	However, aberrant activation of this signaling cascade induces deleterious effects including the development of cancers, including CCA.	('CCA', 'Disease', (131, 134))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('aberrant', 'Var', (9, 17))	('CCA', 'Phenotype', 'HP:0030153', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('activation', 'PosReg', (18, 28))
13359	32140709	Studies have shown that the aberrant expression of RARgamma is associated with the development of cancers including hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (116, 140))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('associated', 'Reg', (63, 73))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('aberrant expression', 'Var', (28, 47))	('cancers', 'Disease', (98, 105))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (116, 140))	('RARgamma', 'Gene', (51, 59))	('RARgamma', 'Gene', '5916', (51, 59))	('hepatocellular carcinoma', 'Disease', (116, 140))
13382	32140709	It was shown that the silencing of PRKAR1A and inhibition of PKA leads to inhibition of Wnt/beta-catenin signaling, attenuates the growth and induces apoptosis in the CCA cells.	('PRKAR1A', 'Gene', '5573', (35, 42))	('CCA', 'Phenotype', 'HP:0030153', (167, 170))	('apoptosis', 'CPA', (150, 159))	('PKA', 'Gene', (61, 64))	('inhibition', 'NegReg', (47, 57))	('growth', 'CPA', (131, 137))	('inhibition', 'NegReg', (74, 84))	('PRKAR1A', 'Gene', (35, 42))	('silencing', 'Var', (22, 31))	('beta-catenin', 'Gene', (92, 104))	('induces', 'Reg', (142, 149))	('beta-catenin', 'Gene', '1499', (92, 104))	('attenuates', 'NegReg', (116, 126))
13387	32140709	Moreover, an increase in the CXCR4 expression is shown to significantly lower the survival rate and CXCR4 knockdown is associated with the down-regulation of Wnt target genes and inhibition of progression of malignant tumor of the biliary tract.	('Wnt target genes', 'Gene', (158, 174))	('CXCR4', 'Gene', '7852', (29, 34))	('CXCR4', 'Gene', (100, 105))	('tumor of the biliary', 'Phenotype', 'HP:0100574', (218, 238))	('down-regulation', 'NegReg', (139, 154))	('CXCR4', 'Gene', (29, 34))	('lower', 'NegReg', (72, 77))	('malignant tumor', 'Disease', (208, 223))	('knockdown', 'Var', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('inhibition', 'NegReg', (179, 189))	('increase', 'PosReg', (13, 21))	('malignant tumor', 'Disease', 'MESH:D009369', (208, 223))	('CXCR4', 'Gene', '7852', (100, 105))	('progression', 'CPA', (193, 204))	('survival rate', 'CPA', (82, 95))
13425	26587304	Hemorrhage is said to be an uncommon complication in PRES (5% to 17%] of patients), based on older sequences such as FLAIR and T2*, but it is antiquated relative to SWI (susceptibility-weighted imaging) and other newer and postprocessed sequences.	('Hemorrhage', 'Disease', 'MESH:D006470', (0, 10))	('T2*', 'Var', (127, 130))	('patients', 'Species', '9606', (73, 81))	('Hemorrhage', 'Disease', (0, 10))
13442	24987359	We found that tissue factor and mucin tumor marker (CA19-9, CA15-3 and CA-125) expression in cancer cells may be involved in the pathogenesis of thromboembolism.	('CA15-3', 'Gene', '4582', (60, 66))	('tissue factor', 'Gene', (14, 27))	('thromboembolism', 'Disease', (145, 160))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('CA15-3', 'Gene', (60, 66))	('CA-125', 'Gene', (71, 77))	('CA19-9', 'Var', (52, 58))	('mucin', 'Gene', (32, 37))	('thromboembolism', 'Disease', 'MESH:D013923', (145, 160))	('thromboembolism', 'Phenotype', 'HP:0001907', (145, 160))	('mucin', 'Gene', '100508689', (32, 37))	('tissue factor', 'Gene', '2152', (14, 27))	('tumor', 'Disease', (38, 43))	('cancer', 'Disease', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('CA-125', 'Gene', '94025', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('involved', 'Reg', (113, 121))
13461	24987359	Cerebral magnetic resonance imaging showed multi-regional hypointense areas in the hemisphere of her right cortex, which were compatible with acute cerebral infarction.	('hypointense areas', 'Var', (58, 75))	('acute cerebral infarction', 'Disease', (142, 167))	('acute cerebral infarction', 'Disease', 'MESH:D002544', (142, 167))
13492	24987359	In pancreatic cancer, patients with high TF expression had about a five times higher rate of thromboembolism as compared to patients with low expression.	('pancreatic cancer', 'Disease', (3, 20))	('patients', 'Species', '9606', (124, 132))	('thromboembolism', 'Disease', 'MESH:D013923', (93, 108))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('higher', 'PosReg', (78, 84))	('patients', 'Species', '9606', (22, 30))	('thromboembolism', 'Phenotype', 'HP:0001907', (93, 108))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('thromboembolism', 'Disease', (93, 108))	('TF', 'Gene', '2152', (41, 43))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('high', 'Var', (36, 40))
13500	24987359	In our case, in addition to CA15-3 and CA-125, elevated CA19-9 may also be involved in the formation of thromboembolism.	('involved', 'Reg', (75, 83))	('thromboembolism', 'Disease', 'MESH:D013923', (104, 119))	('thromboembolism', 'Phenotype', 'HP:0001907', (104, 119))	('CA-125', 'Gene', '94025', (39, 45))	('CA15-3', 'Gene', '4582', (28, 34))	('CA15-3', 'Gene', (28, 34))	('CA-125', 'Gene', (39, 45))	('thromboembolism', 'Disease', (104, 119))	('CA19-9', 'Var', (56, 62))
13511	24987359	Screening for coagulation time and TF are regarded as important factors for hypercoagulability in cancer patients, and mucin production by cancer cells should be speculated by elevation of mucin tumor markers such as CA19-9, CA-125 and CA15-3.	('tumor', 'Disease', (195, 200))	('CA15-3', 'Gene', (236, 242))	('hypercoagulability', 'Disease', 'MESH:D019851', (76, 94))	('CA-125', 'Gene', (225, 231))	('TF', 'Gene', '2152', (35, 37))	('cancer', 'Disease', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('hypercoagulability', 'Disease', (76, 94))	('hypercoagulability', 'Phenotype', 'HP:0100724', (76, 94))	('elevation', 'PosReg', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('patients', 'Species', '9606', (105, 113))	('mucin', 'Gene', (119, 124))	('mucin', 'Gene', (189, 194))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('CA19-9', 'Var', (217, 223))	('CA-125', 'Gene', '94025', (225, 231))	('mucin', 'Gene', '100508689', (119, 124))	('mucin', 'Gene', '100508689', (189, 194))	('cancer', 'Disease', (139, 145))	('CA15-3', 'Gene', '4582', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))
13518	23055147	Metformin is purportedly associated with a reduced risk for various cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('Metformin', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('reduced', 'NegReg', (43, 50))
13526	23055147	A novel finding was that treatment with metformin was significantly associated with a 60% reduction in ICC risk in diabetic patients.	('diabetic', 'Disease', (115, 123))	('reduction', 'NegReg', (90, 99))	('ICC', 'Disease', (103, 106))	('metformin', 'Chemical', 'MESH:D008687', (40, 49))	('men', 'Species', '9606', (30, 33))	('diabetic', 'Disease', 'MESH:D003920', (115, 123))	('patients', 'Species', '9606', (124, 132))	('metformin', 'Var', (40, 49))
13534	23055147	Recent epidemiologic studies have shown that metformin use by patients with type 2 DM, but not use of other glucose lowering agents, is associated with a decreased risk for a number of cancers, including hepatocellular carcinoma (HCC).	('decreased', 'NegReg', (154, 163))	('glucose', 'Chemical', 'MESH:D005947', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('HCC', 'Gene', (230, 233))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('metformin', 'Var', (45, 54))	('DM', 'Disease', 'MESH:D009223', (83, 85))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (204, 228))	('HCC', 'Gene', '619501', (230, 233))	('hepatocellular carcinoma', 'Disease', (204, 228))	('metformin', 'Chemical', 'MESH:D008687', (45, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('patients', 'Species', '9606', (62, 70))	('cancers', 'Disease', (185, 192))
13557	23055147	Metabolic syndrome was defined according to the American Heart Association/National Cholesterol Education Program Adult Treatment Panel III (AHA/NCEP ATP III) criteria (at least three of the following 5 criteria: triglyceride level >= 150 mg/dL, high-density lipoprotein cholesterol <40 mg/dL in men or <50 mg/dL in women, systolic blood pressure >= 130 mmHg or diastolic pressure >= 85 mmHg, fasting plasma glucose >= 110 mg/dL and waist circumference >102 cm in men or >88 cm in women).	('men', 'Species', '9606', (296, 299))	('women', 'Species', '9606', (481, 486))	('men', 'Species', '9606', (464, 467))	('>= 150 mg/dL', 'Var', (232, 244))	('high-density lipoprotein', 'MPA', (246, 270))	('Metabolic syndrome', 'Disease', 'MESH:D008659', (0, 18))	('men', 'Species', '9606', (125, 128))	('Metabolic syndrome', 'Disease', (0, 18))	('men', 'Species', '9606', (483, 486))	('glucose', 'Chemical', 'MESH:D005947', (408, 415))	('diastolic pressure', 'MPA', (362, 380))	('AHA', 'Disease', (141, 144))	('AHA', 'Disease', 'None', (141, 144))	('men', 'Species', '9606', (318, 321))	('triglyceride level', 'MPA', (213, 231))	('women', 'Species', '9606', (316, 321))	('>102', 'Var', (453, 457))	('systolic blood pressure >', 'MPA', (323, 348))
13610	23055147	Our data showed that metformin use is associated with a 60% reduction in ICC risk in diabetic patients, a magnitude comparable to that of shown in other cancers (50-85% risk reduction) including HCC, pancreatic, colorectal, breast and lung cancer.	('cancers', 'Disease', (153, 160))	('metformin', 'Var', (21, 30))	('colorectal', 'Disease', 'MESH:D015179', (212, 222))	('metformin', 'Chemical', 'MESH:D008687', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('pancreatic', 'Disease', 'MESH:D010195', (200, 210))	('ICC', 'Disease', (73, 76))	('patients', 'Species', '9606', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('breast and lung cancer', 'Disease', 'MESH:D001943', (224, 246))	('reduction', 'NegReg', (60, 69))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('pancreatic', 'Disease', (200, 210))	('colorectal', 'Disease', (212, 222))	('HCC', 'Gene', '619501', (195, 198))	('diabetic', 'Disease', 'MESH:D003920', (85, 93))	('HCC', 'Gene', (195, 198))	('diabetic', 'Disease', (85, 93))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (235, 246))
13650	25435926	A meta-analysis by Li et al revealed that HBV is associated with an increased risk of CCA, particularly for ICC.	('ICC', 'Disease', (108, 111))	('CCA', 'Phenotype', 'HP:0030153', (86, 89))	('HBV', 'Species', '10407', (42, 45))	('HBV', 'Var', (42, 45))	('CCA', 'Disease', (86, 89))
13658	25435926	CA19-9 is a serum tumor marker for pancreatic cancer, CCA and other malignancies with a suboptimal sensitivity and specificity.	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('tumor', 'Disease', (18, 23))	('malignancies', 'Disease', (68, 80))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (35, 52))	('pancreatic cancer', 'Disease', 'MESH:D010190', (35, 52))	('CCA', 'Disease', (54, 57))	('pancreatic cancer', 'Disease', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('CA19-9', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('CCA', 'Phenotype', 'HP:0030153', (54, 57))	('malignancies', 'Disease', 'MESH:D009369', (68, 80))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
13660	25435926	Leelawat et al considered the sensitivity and specificity of serum CA19-9 as a serum marker, with a cut-off value of 100 units/ml, to be 68 and 87%, respectively.	('CA19-9', 'Chemical', 'MESH:C086528', (67, 73))	('CA19-9', 'Gene', (67, 73))	('serum', 'Var', (61, 66))
13665	25435926	These results may indicate that CA19-9 is associated with biliary obstruction, but a large-scale clinic investigation is required to verify the findings.	('CA19-9', 'Var', (32, 38))	('associated', 'Reg', (42, 52))	('CA19-9', 'Chemical', 'MESH:C086528', (32, 38))	('biliary obstruction', 'Disease', (58, 77))	('biliary obstruction', 'Disease', 'MESH:D001658', (58, 77))	('biliary obstruction', 'Phenotype', 'HP:0005230', (58, 77))
13667	25435926	For example, allelic variants of fucosyltransferase (FUT)2 and 3 affect the serum levels of CA19-9.	('affect', 'Reg', (65, 71))	('CA19-9', 'Chemical', 'MESH:C086528', (92, 98))	('FUT)2 and 3', 'Gene', '2524;2525', (53, 64))	('serum levels of CA19-9', 'MPA', (76, 98))	('allelic variants', 'Var', (13, 29))
13678	25435926	Silsirivanit et al established a novel monoclonal antibody (MoAb) using pooled CCA tissue, they obtained an S121 immunoglobulin M MoAb that recognized a novel glycan epitope.	('glycan', 'Protein', (159, 165))	('CCA', 'Phenotype', 'HP:0030153', (79, 82))	('S121', 'Var', (108, 112))	('glycan', 'Chemical', 'MESH:D011134', (159, 165))
13679	25435926	Their findings demonstrated that mucin 5AC (MUC5AC) is a core glycoprotein for the S121 epitope.	('MUC5AC', 'Gene', '4586', (44, 50))	('mucin 5AC', 'Gene', '4586', (33, 42))	('mucin 5AC', 'Gene', (33, 42))	('MUC5AC', 'Gene', (44, 50))	('S121', 'Var', (83, 87))
13680	25435926	The serum S121 level was able to differentiate CCA patients from healthy individuals, active OV-infected individuals and patients with various gastrointestinal cancers, hepatoma and benign hepatobiliary diseases with high sensitivity (87.63%), specificity (89.58%), positive predictive value (80.95%) and negative predictive value (93.47%).	('benign hepatobiliary diseases', 'Disease', (182, 211))	('benign hepatobiliary diseases', 'Disease', 'MESH:D004066', (182, 211))	('OV-infected', 'Disease', (93, 104))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('CCA', 'Phenotype', 'HP:0030153', (47, 50))	('hepatoma', 'Disease', (169, 177))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (143, 167))	('CCA', 'Disease', (47, 50))	('OV-infected', 'Disease', 'MESH:D007239', (93, 104))	('gastrointestinal cancers', 'Disease', (143, 167))	('hepatoma', 'Disease', 'MESH:D006528', (169, 177))	('patients', 'Species', '9606', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('patients', 'Species', '9606', (121, 129))	('S121', 'Var', (10, 14))	('biliary disease', 'Phenotype', 'HP:0001080', (195, 210))
13685	25435926	Also, patients with high serum CA-S27 exhibited a significantly shorter survival time compared with those possessing a low serum CA-S27 level, regardless of the serum MUC5AC levels.	('MUC5AC', 'Gene', '4586', (167, 173))	('low serum CA', 'Phenotype', 'HP:0002901', (119, 131))	('CA-S27', 'Var', (31, 37))	('high serum CA-S27', 'Phenotype', 'HP:0031414', (20, 37))	('high', 'Var', (20, 24))	('survival time', 'CPA', (72, 85))	('MUC5AC', 'Gene', (167, 173))	('patients', 'Species', '9606', (6, 14))	('high serum CA', 'Phenotype', 'HP:0003072', (20, 33))	('shorter', 'NegReg', (64, 71))
13687	25435926	CA242 is a sialiated carbohydrate antigen that has been used as a tumor marker in several tumors.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('carbohydrate antigen', 'Chemical', '-', (21, 41))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('CA242', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('CA242', 'Chemical', '-', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
13736	25435926	M2-PK is a novel tumor metabolic marker that plays a key role in tumor metabolism and energy production by channeling glucose carbons, either into synthetic processes or toward glycolytic energy production.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('carbons', 'Chemical', 'MESH:D002244', (126, 133))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', (65, 70))	('glucose', 'Chemical', 'MESH:D005947', (118, 125))	('channeling glucose carbons', 'MPA', (107, 133))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('M2-PK', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
13737	25435926	Increased aerobic glycolysis is one of the most common metabolic phenomenons in tumor cells, which particularly express M2-PK.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('Increased', 'PosReg', (0, 9))	('M2-PK', 'Var', (120, 125))	('aerobic glycolysis', 'MPA', (10, 28))
13796	25368755	The cytological results were indicated as one of the following: 1) benign, 2) atypia (reactive), 3) atypia (indeterminate), 4) atypia (suspicious for malignancy), and 5) positive for malignancy.	('malignancy', 'Disease', (150, 160))	('malignancy', 'Disease', 'MESH:D009369', (183, 193))	('malignancy', 'Disease', (183, 193))	('atypia', 'Var', (127, 133))	('malignancy', 'Disease', 'MESH:D009369', (150, 160))	('atypia', 'Disease', (78, 84))
13826	25368755	Our results demonstrated that the overall sensitivity of TTS was higher than that of DTS.	('sensitivity', 'MPA', (42, 53))	('rat', 'Species', '10116', (19, 22))	('DTS', 'Chemical', '-', (85, 88))	('TTS', 'Chemical', '-', (57, 60))	('TTS', 'Var', (57, 60))	('higher', 'PosReg', (65, 71))
13934	22736272	HCC is of special concern in individuals who are living with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) because of frequent HBV and HCV coinfection and accelerated progression of viral hepatitis to chronic liver disease and cirrhosis.	('human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome', 'Disease', 'MESH:D015658', (61, 133))	('coinfection', 'Var', (173, 184))	('liver disease', 'Phenotype', 'HP:0001392', (243, 256))	('viral hepatitis', 'Phenotype', 'HP:0006562', (216, 231))	('HCC', 'Phenotype', 'HP:0001402', (0, 3))	('HCC', 'Gene', '619501', (0, 3))	('cirrhosis', 'Disease', 'MESH:D005355', (261, 270))	('AIDS', 'Disease', (135, 139))	('immunodeficiency', 'Phenotype', 'HP:0002721', (108, 124))	('HCC', 'Gene', (0, 3))	('immunodeficiency', 'Phenotype', 'HP:0002721', (67, 83))	('viral hepatitis to chronic liver disease', 'Disease', 'MESH:D056486', (216, 256))	('cirrhosis', 'Phenotype', 'HP:0001394', (261, 270))	('hepatitis', 'Phenotype', 'HP:0012115', (222, 231))	('accelerated', 'PosReg', (189, 200))	('HBV', 'Gene', (161, 164))	('cirrhosis', 'Disease', (261, 270))	('HCV', 'Species', '11103', (169, 172))	('HBV', 'Species', '10407', (161, 164))	('AIDS', 'Disease', 'MESH:D000163', (135, 139))	('HCV', 'Gene', (169, 172))	('viral hepatitis to chronic liver disease', 'Disease', (216, 256))
13999	22736272	Among HCV-infected individuals, coinfection with HIV is associated with increased risk of chronic liver disease and HCC.	('HCV-infected', 'Disease', (6, 18))	('HIV', 'Species', '12721', (49, 52))	('HCC', 'Gene', (116, 119))	('chronic liver disease', 'Disease', (90, 111))	('coinfection', 'Var', (32, 43))	('HCC', 'Gene', '619501', (116, 119))	('chronic liver disease', 'Disease', 'MESH:D058625', (90, 111))	('liver disease', 'Phenotype', 'HP:0001392', (98, 111))	('HCC', 'Phenotype', 'HP:0001402', (116, 119))	('HCV-infected', 'Disease', 'MESH:D006526', (6, 18))
14039	21702920	In these resected patients, improved survival rates have been related to negative margin status.	('negative margin status', 'Var', (73, 95))	('survival rates', 'CPA', (37, 51))	('patients', 'Species', '9606', (18, 26))	('improved', 'PosReg', (28, 36))
14117	21711594	The clonal evolution model demonstrates a multi-step process of tumor development from precancerous lesions to metastatic carcinoma, arising from the accumulation of genetic and epigenetic changes in a cell in the setting of chronic inflammation.	('chronic inflammation', 'Disease', (225, 245))	('tumor', 'Disease', (64, 69))	('chronic inflammation', 'Disease', 'MESH:D007249', (225, 245))	('arising from', 'Reg', (133, 145))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('precancerous lesions to metastatic carcinoma', 'Disease', (87, 131))	('epigenetic changes', 'Var', (178, 196))	('precancerous lesions to metastatic carcinoma', 'Disease', 'MESH:D011230', (87, 131))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('genetic', 'Var', (166, 173))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
14144	21711594	Large-scale quantitative comparisons of HCC tumors to non-tumors by the use of comparative genomic hybridization (CGH) arrays and loss of heterozygosity (LOH) has revealed the occurrence of chromosomal and microsatellite instability in HCC.	('microsatellite instability', 'Var', (206, 232))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('HCC tumors to non-tumors', 'Disease', 'MESH:D009369', (40, 64))	('HCC', 'Gene', '619501', (236, 239))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('HCC', 'Gene', '619501', (40, 43))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('HCC', 'Phenotype', 'HP:0001402', (236, 239))	('HCC', 'Phenotype', 'HP:0001402', (40, 43))	('chromosomal', 'MPA', (190, 201))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('HCC', 'Gene', (236, 239))	('HCC tumors to non-tumors', 'Disease', (40, 64))	('HCC', 'Gene', (40, 43))
14147	21711594	The frequent loss of chromosome regions observed by LOH and SNP arrays has revealed the concomitant loss or mutation of tumor suppressor genes such as TP53 (p53), retinoblastoma RB1 (Rb), CDKN2A (p16INK4A) and insulin-like growth factor-2 receptor IGF-2R , which are strongly associated with carcinogenetic signaling pathways.	('IGF-2R', 'Gene', '3482', (248, 254))	('CDKN2A', 'Gene', '1029', (188, 194))	('TP53', 'Gene', '7157', (151, 155))	('IGF-2R', 'Gene', (248, 254))	('retinoblastoma', 'Gene', '5925', (163, 177))	('RB1', 'Gene', (178, 181))	('retinoblastoma', 'Phenotype', 'HP:0009919', (163, 177))	('p53', 'Gene', '7157', (157, 160))	('Rb', 'Gene', '5925', (183, 185))	('tumor', 'Disease', (120, 125))	('p16INK4A', 'Gene', (196, 204))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('p16INK4A', 'Gene', '1029', (196, 204))	('p53', 'Gene', (157, 160))	('TP53', 'Gene', (151, 155))	('RB1', 'Gene', '5925', (178, 181))	('retinoblastoma', 'Gene', (163, 177))	('CDKN2A', 'Gene', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('mutation', 'Var', (108, 116))	('loss', 'NegReg', (100, 104))
14148	21711594	Gain of function mutations have also been observed in HCC, for example mutations in CTNNBI (beta-catenin), which results in the deregulation of similar signaling pathways in HCC.	('deregulation', 'MPA', (128, 140))	('HCC', 'Gene', (174, 177))	('HCC', 'Gene', (54, 57))	('HCC', 'Gene', '619501', (54, 57))	('HCC', 'Gene', '619501', (174, 177))	('HCC', 'Phenotype', 'HP:0001402', (54, 57))	('mutations', 'Var', (71, 80))	('similar signaling pathways', 'Pathway', (144, 170))	('beta-catenin', 'Gene', (92, 104))	('HCC', 'Phenotype', 'HP:0001402', (174, 177))	('beta-catenin', 'Gene', '1499', (92, 104))	('Gain of function', 'PosReg', (0, 16))	('CTNNBI', 'Gene', (84, 90))
14150	21711594	Therefore, it is not surprising that TP53 loss of function mutations or allelic deletions in chromosome 17p are commonly associated with human carcinogenesis, and depending on the extent of damage, p53 can either regulate the production of anti-oxidant genes to initiate DNA repair, or induce apoptosis through the activation of pro-oxidant genes.	('human', 'Species', '9606', (137, 142))	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('production', 'MPA', (226, 236))	('activation', 'PosReg', (315, 325))	('induce', 'PosReg', (286, 292))	('DNA repair', 'MPA', (271, 281))	('TP53', 'Gene', '7157', (37, 41))	('regulate', 'Reg', (213, 221))	('loss of function', 'NegReg', (42, 58))	('p53', 'Gene', (198, 201))	('mutations', 'Var', (59, 68))	('allelic', 'Var', (72, 79))	('carcinogenesis', 'Disease', (143, 157))	('TP53', 'Gene', (37, 41))	('p53', 'Gene', '7157', (198, 201))	('apoptosis', 'CPA', (293, 302))
14151	21711594	AFB1 is a particular mutagen of TP53, causing G:C to T:A transversions at the third base in codon 249 (converting arginine to serine), and the rate of TP53 R249S mutation may be accelerated in the presence of viral infection.	('serine', 'Chemical', 'MESH:D012694', (126, 132))	('AFB', 'Chemical', 'MESH:D016604', (0, 3))	('TP53', 'Gene', (151, 155))	('causing', 'Reg', (38, 45))	('viral infection', 'Disease', (209, 224))	('TP53', 'Gene', '7157', (32, 36))	('R249S', 'Mutation', 'rs28934571', (156, 161))	('accelerated', 'PosReg', (178, 189))	('R249S', 'Var', (156, 161))	('TP53', 'Gene', (32, 36))	('arginine', 'Chemical', 'MESH:D001120', (114, 122))	('transversions', 'MPA', (57, 70))	('viral infection', 'Disease', 'MESH:D001102', (209, 224))	('TP53', 'Gene', '7157', (151, 155))
14154	21711594	A recent study has linked this p53 hotspot mutation to HCC with aggressive tumors, poor prognosis and an acquisition of stem cell-like traits, which is not unexpected since a separate study has shown that TP53 mutations have the ability to reprogram terminally differentiated cells into pluripotent stem cells.	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('mutations', 'Var', (210, 219))	('mutation', 'Var', (43, 51))	('HCC', 'Phenotype', 'HP:0001402', (55, 58))	('HCC', 'Gene', (55, 58))	('aggressive tumors', 'Disease', 'MESH:D001523', (64, 81))	('TP53', 'Gene', (205, 209))	('TP53', 'Gene', '7157', (205, 209))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('aggressive tumors', 'Disease', (64, 81))	('reprogram terminally differentiated cells', 'CPA', (240, 281))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('HCC', 'Gene', '619501', (55, 58))
14155	21711594	Structural genomic mutations and epigenetic changes may lead to altered gene expression patterns that significantly affect the signal transduction pathways in HCC and the variability in pathway expressed may allude to the cellular origin of HCC.	('gene expression patterns', 'MPA', (72, 96))	('HCC', 'Gene', (241, 244))	('signal transduction pathways', 'Pathway', (127, 155))	('HCC', 'Gene', (159, 162))	('affect', 'Reg', (116, 122))	('HCC', 'Gene', '619501', (241, 244))	('HCC', 'Phenotype', 'HP:0001402', (159, 162))	('HCC', 'Gene', '619501', (159, 162))	('altered', 'Reg', (64, 71))	('HCC', 'Phenotype', 'HP:0001402', (241, 244))	('Structural genomic mutations', 'Var', (0, 28))	('epigenetic changes', 'Var', (33, 51))
14159	21711594	Inflammation and subsequent genomic mutations in IGF-2R result in IGF-2 over-expression and a reduction in the inhibitory effects of TGF-beta signaling, a feature commonly observed early in the development of HCC.	('IGF-2R', 'Gene', (49, 55))	('HCC', 'Gene', (209, 212))	('IGF-2', 'Gene', (66, 71))	('reduction', 'NegReg', (94, 103))	('over-expression', 'PosReg', (72, 87))	('IGF-2', 'Gene', (49, 54))	('TGF-beta', 'Gene', '7040', (133, 141))	('IGF-2', 'Gene', '3481', (49, 54))	('mutations', 'Var', (36, 45))	('IGF-2', 'Gene', '3481', (66, 71))	('HCC', 'Gene', '619501', (209, 212))	('HCC', 'Phenotype', 'HP:0001402', (209, 212))	('TGF-beta', 'Gene', (133, 141))	('IGF-2R', 'Gene', '3482', (49, 55))
14161	21711594	This indicates a link between IL-6, a major stem cell signaling pathway and the disruption of TGF-beta signaling, resulting in CSC driven HCC.	('HCC', 'Phenotype', 'HP:0001402', (138, 141))	('TGF-beta', 'Gene', '7040', (94, 102))	('resulting in', 'Reg', (114, 126))	('HCC', 'Gene', (138, 141))	('TGF-beta', 'Gene', (94, 102))	('IL-6', 'Gene', (30, 34))	('IL-6', 'Gene', '3569', (30, 34))	('disruption', 'Var', (80, 90))	('HCC', 'Gene', '619501', (138, 141))
14163	21711594	Recent studies indicate that gain of function mutations of glycoprotein-130 (gp130), a co-receptor of IL-6, is associated with a marked activation of IL-6 in inflammatory hepatocellular adenomas.	('hepatocellular adenomas', 'Disease', (171, 194))	('gain of function', 'PosReg', (29, 45))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (171, 194))	('mutations', 'Var', (46, 55))	('hepatocellular adenoma', 'Phenotype', 'HP:0012028', (171, 193))	('gp130', 'Gene', (77, 82))	('IL-6', 'Gene', (102, 106))	('IL-6', 'Gene', (150, 154))	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (171, 194))	('activation', 'PosReg', (136, 146))	('glycoprotein-130', 'Gene', '3572', (59, 75))	('IL-6', 'Gene', '3569', (102, 106))	('gp130', 'Gene', '3572', (77, 82))	('IL-6', 'Gene', '3569', (150, 154))	('glycoprotein-130', 'Gene', (59, 75))
14164	21711594	Noticeably, rare gp130 alterations are always accompanied by beta-catenin activating mutations in HCC, suggesting that these two signaling pathways are converged to contribute to hepatocarcinogenesis.	('activating', 'PosReg', (74, 84))	('HCC', 'Gene', (98, 101))	('beta-catenin', 'Gene', '1499', (61, 73))	('gp130', 'Gene', '3572', (17, 22))	('HCC', 'Gene', '619501', (98, 101))	('hepatocarcinogenesis', 'Disease', (179, 199))	('mutations', 'Var', (85, 94))	('HCC', 'Phenotype', 'HP:0001402', (98, 101))	('contribute', 'Reg', (165, 175))	('alterations', 'Var', (23, 34))	('beta-catenin', 'Gene', (61, 73))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (179, 199))	('gp130', 'Gene', (17, 22))
14169	21711594	In the event that Wnt signaling receptors are engaged, conformational changes in the Axin complex cause the release of beta-catenin, which then localizes to the nucleus and activates the transcription of Myc, cyclin D1 and COX2 amongst others.	('beta-catenin', 'Gene', '1499', (119, 131))	('Axin', 'Gene', (85, 89))	('activates', 'PosReg', (173, 182))	('conformational changes', 'Var', (55, 77))	('COX2', 'Gene', (223, 227))	('cyclin D1', 'Gene', '595', (209, 218))	('beta-catenin', 'Gene', (119, 131))	('Myc', 'Gene', '4609', (204, 207))	('COX2', 'Gene', '4513', (223, 227))	('transcription', 'MPA', (187, 200))	('Axin', 'Gene', '8312', (85, 89))	('localizes', 'MPA', (144, 153))	('cyclin D1', 'Gene', (209, 218))	('release', 'MPA', (108, 115))	('Myc', 'Gene', (204, 207))
14170	21711594	In HCC, our studies and a number of other transcriptomic and proteomic studies have indicated an increase in Wnt signaling, possibly as a result of an accumulation of Axin1 mutations at sites that bind beta-catenin and/or CTNNB1 mutations along sites marked for phosphorylation by GSK-3beta.	('Wnt signaling', 'MPA', (109, 122))	('CTNNB1', 'Gene', (222, 228))	('Axin1', 'Gene', (167, 172))	('increase', 'PosReg', (97, 105))	('beta-catenin', 'Gene', (202, 214))	('beta-catenin', 'Gene', '1499', (202, 214))	('HCC', 'Gene', (3, 6))	('mutations', 'Var', (229, 238))	('bind', 'Interaction', (197, 201))	('mutations', 'Var', (173, 182))	('HCC', 'Gene', '619501', (3, 6))	('CTNNB1', 'Gene', '1499', (222, 228))	('Axin1', 'Gene', '8312', (167, 172))	('HCC', 'Phenotype', 'HP:0001402', (3, 6))	('GSK-3beta', 'Gene', '2932', (281, 290))	('GSK-3beta', 'Gene', (281, 290))
14174	21711594	Moreover, the up-regulation of Myc in a variety of tumors has also been associated with deregulated microRNA (miRNA) expression in many human malignancies, which as discussed in the next section, have a significant impact on tumorigenesis and progression.	('human', 'Species', '9606', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('up-regulation', 'PosReg', (14, 27))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('impact', 'Reg', (215, 221))	('deregulated', 'Var', (88, 99))	('progression', 'CPA', (243, 254))	('Myc', 'Gene', '4609', (31, 34))	('tumor', 'Disease', (51, 56))	('malignancies', 'Disease', 'MESH:D009369', (142, 154))	('tumor', 'Disease', (225, 230))	('Myc', 'Gene', (31, 34))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('malignancies', 'Disease', (142, 154))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
14175	21711594	On the other hand, the inactivation of Myc in HCC causes a subpopulation of cells to differentiate while the rest remain dormant, giving rise to a phenotypically diverse tumor population and possibly the origin of CSCs.	('HCC', 'Gene', '619501', (46, 49))	('Myc', 'Gene', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('HCC', 'Phenotype', 'HP:0001402', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('HCC', 'Gene', (46, 49))	('giving rise to', 'Reg', (130, 144))	('Myc', 'Gene', '4609', (39, 42))	('inactivation', 'Var', (23, 35))	('causes', 'Reg', (50, 56))
14177	21711594	The activation of the Akt pathway is mediated by either an activated tyrosine kinase receptor, or more rarely the constitutive activation of PI3K or the loss of phosphatase and tensin homolog (PTEN).	('tyrosine', 'Protein', (69, 77))	('PTEN', 'Gene', (193, 197))	('PTEN', 'Gene', '5728', (193, 197))	('Akt', 'Gene', (22, 25))	('loss', 'Var', (153, 157))	('Akt', 'Gene', '207', (22, 25))	('activated tyrosine', 'Protein', (59, 77))	('activation', 'PosReg', (4, 14))
14182	21711594	In recent years, the aberrant expression of miRNAs has been implicated in a wide variety of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('aberrant expression', 'Var', (21, 40))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('miRNAs', 'Gene', (44, 50))	('implicated', 'Reg', (60, 70))	('cancers', 'Disease', (98, 105))	('human', 'Species', '9606', (92, 97))
14186	21711594	miR-26 expression has been found to be associated with HCC gender disparity and silencing of miR-26 in tumor cells is linked to a subtype of HCC with an activated inflammatory pathway and a favorable response to interferon therapy.	('HCC', 'Gene', '619501', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('silencing', 'Var', (80, 89))	('tumor', 'Disease', (103, 108))	('HCC', 'Phenotype', 'HP:0001402', (55, 58))	('HCC', 'Gene', (55, 58))	('linked', 'Reg', (118, 124))	('HCC', 'Phenotype', 'HP:0001402', (141, 144))	('HCC', 'Gene', (141, 144))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('miR-26', 'Gene', (0, 6))	('associated', 'Reg', (39, 49))	('inflammatory pathway', 'Pathway', (163, 183))	('HCC', 'Gene', '619501', (141, 144))	('miR-26', 'Gene', (93, 99))
14187	21711594	In addition, increased expression of miR-21 has been associated with loss of heterozygosity at the PTEN locus, consequently activating the Akt pathway and promoting tumorigenesis.	('Akt', 'Gene', '207', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('promoting', 'PosReg', (155, 164))	('miR-21', 'Gene', '406991', (37, 43))	('Akt', 'Gene', (139, 142))	('expression', 'MPA', (23, 33))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('loss of heterozygosity', 'Var', (69, 91))	('activating', 'PosReg', (124, 134))	('miR-21', 'Gene', (37, 43))	('PTEN', 'Gene', (99, 103))	('PTEN', 'Gene', '5728', (99, 103))	('increased', 'PosReg', (13, 22))	('tumor', 'Disease', (165, 170))
14191	21711594	In the last decade there has been increasing evidence to support the occurrence of aberrant DNA methylation patterns in human HCC.	('human', 'Species', '9606', (120, 125))	('HCC', 'Gene', (126, 129))	('DNA methylation', 'MPA', (92, 107))	('aberrant', 'Var', (83, 91))	('HCC', 'Gene', '619501', (126, 129))	('HCC', 'Phenotype', 'HP:0001402', (126, 129))
14193	21711594	Though methylation is imperative for normal development and differentiation, aberrant hypomethylation in HCC and many human cancers can lead to the expression of oncogenes, or, similarly, hypermethylation can lead to the silencing of tumor-suppressor genes.	('aberrant hypomethylation', 'Var', (77, 101))	('tumor', 'Disease', (234, 239))	('HCC', 'Gene', (105, 108))	('lead to', 'Reg', (136, 143))	('lead to', 'Reg', (209, 216))	('HCC', 'Gene', '619501', (105, 108))	('HCC', 'Phenotype', 'HP:0001402', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('oncogenes', 'MPA', (162, 171))	('silencing', 'MPA', (221, 230))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('human', 'Species', '9606', (118, 123))	('expression', 'MPA', (148, 158))	('hypermethylation', 'Var', (188, 204))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
14195	21711594	The frequency of aberrant DNA methylation increases from precancerous lesions to dysplastic nodules and finally HCC, signifying their important role in tumor progression.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('aberrant', 'Var', (17, 25))	('HCC', 'Gene', (112, 115))	('precancerous lesions to dysplastic nodules', 'Disease', 'MESH:D011230', (57, 99))	('increases', 'PosReg', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('HCC', 'Gene', '619501', (112, 115))	('tumor', 'Disease', (152, 157))	('HCC', 'Phenotype', 'HP:0001402', (112, 115))	('DNA', 'Protein', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('precancerous lesions to dysplastic nodules', 'Disease', (57, 99))
14196	21711594	For instance, the tumor suppressor genes: RB1  and CDKN2A  have been shown to be hypermethylated in HCC, leading to uncontrolled cell proliferation.	('CDKN2A', 'Gene', '1029', (51, 57))	('RB1', 'Gene', (42, 45))	('tumor', 'Disease', (18, 23))	('hypermethylated', 'Var', (81, 96))	('leading to', 'Reg', (105, 115))	('HCC', 'Gene', (100, 103))	('RB1', 'Gene', '5925', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('HCC', 'Gene', '619501', (100, 103))	('uncontrolled cell proliferation', 'CPA', (116, 147))	('CDKN2A', 'Gene', (51, 57))	('HCC', 'Phenotype', 'HP:0001402', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
14198	21711594	Epigenetic changes in HCC have also been reported at the miRNA level.	('HCC', 'Gene', (22, 25))	('HCC', 'Phenotype', 'HP:0001402', (22, 25))	('Epigenetic changes', 'Var', (0, 18))	('HCC', 'Gene', '619501', (22, 25))
14199	21711594	For example, the deregulation of miR-1 due to hypermethylation in HCC was reversed with 5-azacytidine, resulting in decreased cell proliferation and increased apoptosis.	('cell proliferation', 'CPA', (126, 144))	('increased', 'PosReg', (149, 158))	('miR-1', 'Gene', '79187', (33, 38))	('HCC', 'Gene', (66, 69))	('miR-1', 'Gene', (33, 38))	('hypermethylation', 'Var', (46, 62))	('HCC', 'Phenotype', 'HP:0001402', (66, 69))	('HCC', 'Gene', '619501', (66, 69))	('5-azacytidine', 'Chemical', 'MESH:D001374', (88, 101))	('decreased', 'NegReg', (116, 125))	('apoptosis', 'CPA', (159, 168))
14202	21711594	Apart from their potential as a diagnostic platform though, further understanding of methylation patterns in HCC may provide them useful in determining recurrence and survival, as well.	('methylation', 'Var', (85, 96))	('HCC', 'Phenotype', 'HP:0001402', (109, 112))	('HCC', 'Gene', '619501', (109, 112))	('HCC', 'Gene', (109, 112))
14209	21711594	The first group was linked to low copy number HBV infection, particularly in Africa, increased Axin 1 mutations, absence of TP53 mutations and possessed an over expression of imprinted genes.	('TP53', 'Gene', '7157', (124, 128))	('absence', 'NegReg', (113, 120))	('mutations', 'Var', (129, 138))	('TP53', 'Gene', (124, 128))	('Axin 1', 'Gene', '8312', (95, 101))	('low copy number HBV infection', 'Disease', 'MESH:D006509', (30, 59))	('mutations', 'Var', (102, 111))	('increased', 'PosReg', (85, 94))	('over expression', 'PosReg', (156, 171))	('Axin 1', 'Gene', (95, 101))	('low copy number HBV infection', 'Disease', (30, 59))
14210	21711594	The second group was linked to high copy number HBV infection, many regions of LOH, and TP53 and Axin1 gene mutations.	('linked', 'Reg', (21, 27))	('mutations', 'Var', (108, 117))	('Axin1', 'Gene', '8312', (97, 102))	('TP53', 'Gene', '7157', (88, 92))	('HBV infection', 'Disease', (48, 61))	('Axin1', 'Gene', (97, 102))	('HBV infection', 'Disease', 'MESH:D006509', (48, 61))	('high copy number', 'Var', (31, 47))	('TP53', 'Gene', (88, 92))
14212	21711594	Groups 5 and 6 were also substantially different since they were easily classified based on the abundance of CTNNB1 mutations (near 100%) and the high level of Wnt pathway activation.	('CTNNB1', 'Gene', (109, 115))	('mutations', 'Var', (116, 125))	('CTNNB1', 'Gene', '1499', (109, 115))	('Wnt pathway', 'Pathway', (160, 171))
14220	21711594	Furthermore, clinical data revealed that those patients with low miR-26 expression had a better response to adjuvant interferon therapy with interferon alpha than those with high miR-26 expression.	('patients', 'Species', '9606', (47, 55))	('low', 'Var', (61, 64))	('miR-26', 'Gene', (65, 71))	('response', 'MPA', (96, 104))
14225	21711594	The stepwise progression from altered hepatocytes to dysplastic nodules, or precancerous lesion, occurs as a consequence of chronic inflammation and genomic alterations, which commonly precede HCC.	('HCC', 'Gene', '619501', (193, 196))	('dysplastic nodules', 'Disease', (53, 71))	('precancerous lesion', 'Disease', 'MESH:D011230', (76, 95))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('HCC', 'Phenotype', 'HP:0001402', (193, 196))	('genomic alterations', 'Var', (149, 168))	('dysplastic nodules', 'Disease', 'MESH:D004416', (53, 71))	('HCC', 'Gene', (193, 196))	('chronic inflammation', 'Disease', (124, 144))	('chronic inflammation', 'Disease', 'MESH:D007249', (124, 144))	('precancerous lesion', 'Disease', (76, 95))
14234	21711594	Depending on the extent of genetic alterations, the tumor cells may remain benign or develop and metastasize.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('metastasize', 'CPA', (97, 108))	('tumor', 'Disease', (52, 57))	('develop', 'CPA', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('genetic alterations', 'Var', (27, 46))
14244	21711594	In the stepwise model, an accumulation of inflammatory-mediated genetic and epigenetic alterations has been proposed to lead to the successive development of ICC from biliary epithelial cells to biliary dysplastic lesions and eventually cancer.	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('dysplastic lesions', 'Disease', 'MESH:D021782', (203, 221))	('lead to', 'Reg', (120, 127))	('dysplastic lesions', 'Disease', (203, 221))	('ICC', 'Disease', (158, 161))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (237, 243))	('epigenetic alterations', 'Var', (76, 98))
14250	21711594	Short segments of chromosomes 1p, 3p, 6q and 9q are commonly deleted in ICC, with a frequency of at least 55%, whereas the frequency of such events in HCC are usually less than 40%.	('ICC', 'Disease', (72, 75))	('HCC', 'Gene', (151, 154))	('HCC', 'Gene', '619501', (151, 154))	('HCC', 'Phenotype', 'HP:0001402', (151, 154))	('deleted', 'Var', (61, 68))
14252	21711594	Further studies to detect the loss of tumor suppressor genes during a consistent LOH have indicated a high rate of allelic losses at 5q and 17p.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('allelic losses', 'Var', (115, 129))
14254	21711594	Persistent structural genomic changes in these cells have been associated with a variety of mutations, conferring a loss in tumor suppression and the amplification of oncongenic pathways.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('associated', 'Reg', (63, 73))	('tumor', 'Disease', (124, 129))	('mutations', 'Var', (92, 101))	('amplification', 'Reg', (150, 163))	('oncongenic pathways', 'Pathway', (167, 186))	('loss', 'NegReg', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
14255	21711594	TP53 mutations in ICC are common and their frequency ranges from 20-80% depending on the geographic region.	('TP53', 'Gene', '7157', (0, 4))	('ICC', 'Gene', (18, 21))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
14257	21711594	This renders the p53 regulatory pathway non-functional and supports the notion that either TP53 mutations or an alteration to the p53 pathway may be critical to the development of ICC.	('TP53', 'Gene', (91, 95))	('ICC', 'Disease', (180, 183))	('p53', 'Gene', '7157', (130, 133))	('non-functional', 'MPA', (40, 54))	('alteration', 'Reg', (112, 122))	('p53', 'Gene', (130, 133))	('TP53', 'Gene', '7157', (91, 95))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))	('mutations', 'Var', (96, 105))
14259	21711594	The CDK4:cyclin D complex is also influenced by the p16INK4A inhibitory protein, which coincidentally is altered by LOH and/or promoter hypermethylation in 25%-83% of resected cholangiocarcinoma specimens.	('LOH', 'Var', (116, 119))	('p16INK4A', 'Gene', '1029', (52, 60))	('cholangiocarcinoma', 'Disease', (176, 194))	('CDK4', 'Gene', (4, 8))	('influenced', 'Reg', (34, 44))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (176, 194))	('promoter hypermethylation', 'Var', (127, 152))	('CDK4', 'Gene', '1019', (4, 8))	('altered', 'Reg', (105, 112))	('p16INK4A', 'Gene', (52, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (176, 194))
14260	21711594	K-ras mutations occurring at codon 12 are often observed in ICC, involving either a glycine to aspartic acid or a glycine to cystine transition.	('aspartic acid', 'Chemical', 'MESH:D001224', (95, 108))	('involving', 'Reg', (65, 74))	('ICC', 'Disease', (60, 63))	('cystine', 'Chemical', 'MESH:D003553', (125, 132))	('glycine', 'Chemical', 'MESH:D005998', (114, 121))	('glycine to aspartic acid', 'MPA', (84, 108))	('K-ras', 'Gene', (0, 5))	('glycine', 'Chemical', 'MESH:D005998', (84, 91))	('K-ras', 'Gene', '3845', (0, 5))	('glycine to cystine transition', 'MPA', (114, 143))	('mutations', 'Var', (6, 15))
14261	21711594	K-ras mutations corresponding to over expression are observed early in carcinogenesis, which suggests an important role in ICC development.	('carcinogenesis', 'Disease', (71, 85))	('K-ras', 'Gene', (0, 5))	('K-ras', 'Gene', '3845', (0, 5))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))	('mutations', 'Var', (6, 15))
14263	21711594	The inactivation of tumor suppressor genes and the concordant amplification of proto-oncogenes, such as TP53 and K-ras, respectively, play a significant role in altering the signaling network and promoting tumorigenesis.	('altering', 'Reg', (161, 169))	('promoting', 'PosReg', (196, 205))	('inactivation', 'Var', (4, 16))	('TP53', 'Gene', '7157', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('TP53', 'Gene', (104, 108))	('tumor', 'Disease', (206, 211))	('signaling network', 'Pathway', (174, 191))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('K-ras', 'Gene', (113, 118))	('K-ras', 'Gene', '3845', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('amplification', 'Var', (62, 75))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', (20, 25))
14266	21711594	Just as in HCC, the altered expression of miRNAs in ICC has been reported to contribute to tumor growth.	('altered', 'Var', (20, 27))	('HCC', 'Gene', (11, 14))	('contribute', 'Reg', (77, 87))	('expression', 'MPA', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('HCC', 'Gene', '619501', (11, 14))	('miRNAs', 'Protein', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('HCC', 'Phenotype', 'HP:0001402', (11, 14))	('tumor', 'Disease', (91, 96))
14342	32012241	Mutations in ATM, MITF and NBN, moderate-penetrance cancer susceptibility genes, were identified in 1 patient each.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('patient', 'Species', '9606', (102, 109))	('ATM', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('MITF', 'Gene', '4286', (18, 22))	('cancer', 'Disease', (52, 58))	('MITF', 'Gene', (18, 22))	('ATM', 'Gene', '472', (13, 16))	('NBN', 'Gene', '4683', (27, 30))	('NBN', 'Gene', (27, 30))
14357	32012241	The most commonly mutated genes are CDKN2A, TP53, and KRAS with estimated incidence at over 20% of patients with biliary tract tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('biliary tract tumors', 'Disease', (113, 133))	('CDKN2A', 'Gene', (36, 42))	('biliary tract tumors', 'Disease', 'MESH:D001661', (113, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('mutated', 'Var', (18, 25))	('CDKN2A', 'Gene', '1029', (36, 42))	('patients', 'Species', '9606', (99, 107))	('KRAS', 'Gene', (54, 58))	('TP53', 'Gene', '7157', (44, 48))	('KRAS', 'Gene', '3845', (54, 58))	('biliary tract tumors', 'Phenotype', 'HP:0100574', (113, 133))	('TP53', 'Gene', (44, 48))
14358	32012241	CDKN2A mutations have been associated with poor progression-free survival and TP53 and KRAS mutations have been linked to poor overall survial among patients with intrahepatic cholangiocarcinoa.	('CDKN2A', 'Gene', '1029', (0, 6))	('KRAS', 'Gene', (87, 91))	('patients', 'Species', '9606', (149, 157))	('progression-free survival', 'CPA', (48, 73))	('KRAS', 'Gene', '3845', (87, 91))	('poor', 'NegReg', (43, 47))	('intrahepatic cholangiocarcinoa', 'Disease', 'MESH:D002780', (163, 193))	('mutations', 'Var', (92, 101))	('poor', 'NegReg', (122, 126))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('intrahepatic cholangiocarcinoa', 'Disease', (163, 193))	('CDKN2A', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
14359	32012241	Our group and others have shown that within intrahepatic cholangiocarcinoma, the most prevalent biliary tract cancer, IDH1/2, ARID1A and BAP1 mutations have been commonly observed.	('BAP1', 'Gene', (137, 141))	('intrahepatic cholangiocarcinoma', 'Disease', (44, 75))	('mutations', 'Var', (142, 151))	('IDH1/2', 'Gene', (118, 124))	('cancer', 'Disease', (110, 116))	('ARID1A', 'Gene', '8289', (126, 132))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (96, 116))	('ARID1A', 'Gene', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('BAP1', 'Gene', '8314', (137, 141))	('IDH1/2', 'Gene', '3417;3418', (118, 124))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (44, 75))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
14360	32012241	IDH1 and IDH2 mutations, found almost exclusively in intrahepatic cholangiocarcinomas, represent an important example of a potentially actionable mutation for which there are several ongoing clinical trials.	('IDH2', 'Gene', (9, 13))	('intrahepatic cholangiocarcinomas', 'Disease', (53, 85))	('IDH2', 'Gene', '3418', (9, 13))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (53, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (66, 84))	('IDH1', 'Gene', '3417', (0, 4))
14361	32012241	In addition, FGFR2 rearrangements and HER2 mutations are potentially actionable mutations found in patients with cholangiocarcinoma for which there are with available targeted therapies.	('cholangiocarcinoma', 'Disease', (113, 131))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (113, 131))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (113, 131))	('HER2', 'Gene', '2064', (38, 42))	('patients', 'Species', '9606', (99, 107))	('mutations', 'Var', (43, 52))	('FGFR2', 'Gene', '2263', (13, 18))	('rearrangements', 'Var', (19, 33))	('HER2', 'Gene', (38, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('FGFR2', 'Gene', (13, 18))
14365	32012241	Germline mutations in BRCA1/2 mutations have been identified in a small subset of cholangiocarcinoma cases, which influence the choice of targeted therapy for these tumors.	('Germline mutations', 'Var', (0, 18))	('influence', 'Reg', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('BRCA1/2', 'Gene', (22, 29))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (82, 100))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (82, 100))	('mutations', 'Var', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('BRCA1/2', 'Gene', '672;675', (22, 29))	('identified', 'Reg', (50, 60))	('cholangiocarcinoma', 'Disease', (82, 100))
14366	32012241	Here, we aimed to define the prevelance of pathogenic germline mutations in an unselected group of patients with biliary tract cancers with and without a personal or family history of cancer to better understand the frequency and spectrum of pathogenic germline mutations in known cancer susceptibility genes.	('cancer', 'Disease', (184, 190))	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('cancer', 'Disease', (281, 287))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (113, 133))	('patients', 'Species', '9606', (99, 107))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancer', 'Disease', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('biliary tract cancers', 'Disease', 'MESH:D001661', (113, 134))	('biliary tract cancers', 'Disease', (113, 134))
14384	32012241	The high-penetrance cancer susceptibility genes most commonly mutated were found in patients with BRCA2 (N=5) and BRCA1 (N=2).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('patients', 'Species', '9606', (84, 92))	('BRCA1', 'Gene', '672', (114, 119))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('BRCA2', 'Gene', (98, 103))	('cancer', 'Disease', (20, 26))	('BRCA1', 'Gene', (114, 119))	('BRCA2', 'Gene', '675', (98, 103))	('mutated', 'Var', (62, 69))
14391	32012241	Assessment of the matched tumors revealed loss of heterozygosity in 2 patients with BRCA1 mutations, 1 with a BRCA2 mutation, and 1 with a mutation in the BAP1 gene providing further evidence of the likely role of these germline mutations in cancer development.	('patients', 'Species', '9606', (70, 78))	('mutations', 'Var', (90, 99))	('BRCA2', 'Gene', (110, 115))	('cancer', 'Disease', (242, 248))	('BAP1', 'Gene', '8314', (155, 159))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('mutation', 'Var', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('BRCA1', 'Gene', '672', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('BAP1', 'Gene', (155, 159))	('BRCA2', 'Gene', '675', (110, 115))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('BRCA1', 'Gene', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('tumors', 'Disease', (26, 32))
14392	32012241	Notably, the patient with a PMS2 germline mutation had a microsatellite stable tumor, suggesting that the PMS2 mutation may not have been causative of the cancer.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('patient', 'Species', '9606', (13, 20))	('PMS2', 'Gene', '5395', (106, 110))	('PMS2', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('PMS2', 'Gene', '5395', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cancer', 'Disease', (155, 161))	('PMS2', 'Gene', (106, 110))	('germline', 'Var', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
14393	32012241	Among the moderate-penetrance genes, mutations were identified in ATM, MITF, and NBN with one each in 3 patients with intrahepatic cholangiocarcinoma (Table 3).	('ATM', 'Gene', '472', (66, 69))	('MITF', 'Gene', '4286', (71, 75))	('MITF', 'Gene', (71, 75))	('NBN', 'Gene', '4683', (81, 84))	('mutations', 'Var', (37, 46))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (118, 149))	('NBN', 'Gene', (81, 84))	('ATM', 'Gene', (66, 69))	('intrahepatic cholangiocarcinoma', 'Disease', (118, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))	('patients', 'Species', '9606', (104, 112))
14394	32012241	Loss of heterozygosity was noted in the tumor of the patient harboring an ATM mutation.	('mutation', 'Var', (78, 86))	('ATM', 'Gene', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('ATM', 'Gene', '472', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('patient', 'Species', '9606', (53, 60))
14396	32012241	Although mutations in FH are generally associated with the autosomal dominant Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), in our cohort, two patients were found to harbor the c.1431_1433dupAAA small duplication which does not cause HLRCC, but rather represents carrier status for the autosomal recessive condition, fumarate hydratase deficiency.	('hydratase deficiency', 'Disease', (337, 357))	('c.1431_1433dupAAA', 'Var', (188, 205))	('c.1431_1433dupAAA', 'Mutation', 'rs367543046', (188, 205))	('mutations', 'Var', (9, 18))	('patients', 'Species', '9606', (154, 162))	('Cancer', 'Phenotype', 'HP:0002664', (119, 125))	('autosomal dominant Hereditary Leiomyomatosis and Renal Cell Cancer', 'Disease', 'MESH:C535516', (59, 125))	('hydratase deficiency', 'Disease', 'MESH:C538191', (337, 357))	('Renal Cell Cancer', 'Phenotype', 'HP:0005584', (108, 125))	('fumarate hydratase deficiency', 'Phenotype', 'HP:0003536', (328, 357))	('associated', 'Reg', (39, 49))
14400	32012241	A detailed look at the spectrum of mutations found in intrahepatic cholangiocarcinoma, the largest cohort patients in this study, can be seen in Table 3.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('patients', 'Species', '9606', (106, 114))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (54, 85))	('intrahepatic cholangiocarcinoma', 'Disease', (54, 85))	('mutations', 'Var', (35, 44))
14401	32012241	The median age of diagnosis for patients with a germline mutation and intrahepatic cholangiocarcinoma was 51 years of age, as compared to the median age of the patients without a mutation, which was 59 years.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (70, 101))	('patients', 'Species', '9606', (160, 168))	('patients', 'Species', '9606', (32, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('intrahepatic cholangiocarcinoma', 'Disease', (70, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('germline mutation', 'Var', (48, 65))
14402	32012241	Three of the pateints with intrahepatic cholangiocarcinoma and a PGA had a personal history of another primary cancer, including both patients with BRCA2 mutations.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (27, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('BRCA2', 'Gene', (148, 153))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (40, 58))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('intrahepatic cholangiocarcinoma', 'Disease', (27, 58))	('BRCA2', 'Gene', '675', (148, 153))	('patients', 'Species', '9606', (134, 142))	('mutations', 'Var', (154, 163))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('PGA', 'Chemical', '-', (65, 68))
14410	32012241	The median age of diagnosis for patients with a mutation and extrahepatic cholangiocarcinoma was 65 years of age, as compared to the median age for germline wildtype patients with extrahepatic cholangiocarcinoma, which was 62.	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 92))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (193, 211))	('patients', 'Species', '9606', (32, 40))	('extrahepatic cholangiocarcinoma', 'Disease', (180, 211))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (74, 92))	('extrahepatic cholangiocarcinoma', 'Disease', (61, 92))	('mutation', 'Var', (48, 56))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (180, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('patients', 'Species', '9606', (166, 174))
14411	32012241	None of the patients with underlying mutations had a personal history of another primary cancer, however all four patients had at least one first degree relative with a history of cancer.	('patients', 'Species', '9606', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('patients', 'Species', '9606', (114, 122))	('cancer', 'Disease', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
14414	32012241	Three patients had a germline BRCA2 mutation.	('patients', 'Species', '9606', (6, 14))	('BRCA2', 'Gene', (30, 35))	('mutation', 'Var', (36, 44))	('BRCA2', 'Gene', '675', (30, 35))
14416	32012241	Table 5 has information on the five patients with pathogenic germline alterations and gallbladder adenocarcinoma.	('patients', 'Species', '9606', (36, 44))	('gallbladder adenocarcinoma', 'Disease', (86, 112))	('gallbladder adenocarcinoma', 'Disease', 'MESH:D000230', (86, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('germline alterations', 'Var', (61, 81))
14422	32012241	Of the 131 patients in the study, 7 had non-oncogenic, and 15 oncogenic somatic mutations in BRCA1, BRCA2, BAP1, ATM, and PALB2.	('BRCA2', 'Gene', (100, 105))	('BAP1', 'Gene', '8314', (107, 111))	('mutations', 'Var', (80, 89))	('ATM', 'Gene', (113, 116))	('BRCA1', 'Gene', '672', (93, 98))	('PALB2', 'Gene', '79728', (122, 127))	('BRCA2', 'Gene', '675', (100, 105))	('BAP1', 'Gene', (107, 111))	('PALB2', 'Gene', (122, 127))	('BRCA1', 'Gene', (93, 98))	('ATM', 'Gene', '472', (113, 116))	('patients', 'Species', '9606', (11, 19))
14432	32012241	Very little has been reported on the topic of germline mutations in biliary tract cancers.	('biliary tract cancers', 'Disease', 'MESH:D001661', (68, 89))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('biliary tract cancers', 'Disease', (68, 89))	('germline mutations', 'Var', (46, 64))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (68, 88))
14433	32012241	BRCA2 mutations and Lynch Syndrome have previously been associated with biliary tract carcinoma.	('BRCA2', 'Gene', '675', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('Lynch Syndrome', 'Disease', (20, 34))	('associated', 'Reg', (56, 66))	('biliary tract carcinoma', 'Disease', (72, 95))	('BRCA2', 'Gene', (0, 5))	('biliary tract carcinoma', 'Disease', 'MESH:D001661', (72, 95))	('mutations', 'Var', (6, 15))
14434	32012241	Our data is comparable with these few studies as pathogenic BRCA1 or BRCA2 mutations were identified in seven patients, with 43% of these patients demonstrating evidence of biallelic inactivation with loss of heterozygosity in the tumor corresponding to the BRCA1 or BRCA2 regions supporting a role of the BRCA germline mutation in tumor etiology.	('BRCA1', 'Gene', '672', (258, 263))	('BRCA', 'Gene', '672', (69, 73))	('BRCA1', 'Gene', (258, 263))	('BRCA', 'Gene', '672', (60, 64))	('BRCA1', 'Gene', '672', (60, 65))	('BRCA', 'Gene', '672', (267, 271))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('biallelic', 'MPA', (173, 182))	('BRCA1', 'Gene', (60, 65))	('BRCA', 'Gene', '672', (258, 262))	('loss', 'NegReg', (201, 205))	('BRCA', 'Gene', (69, 73))	('BRCA', 'Gene', '672', (306, 310))	('tumor', 'Disease', (231, 236))	('BRCA2', 'Gene', (69, 74))	('patients', 'Species', '9606', (138, 146))	('BRCA', 'Gene', (60, 64))	('BRCA', 'Gene', (267, 271))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('BRCA2', 'Gene', (267, 272))	('BRCA', 'Gene', (258, 262))	('BRCA', 'Gene', (306, 310))	('tumor', 'Disease', (332, 337))	('BRCA2', 'Gene', '675', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('BRCA2', 'Gene', '675', (267, 272))	('mutations', 'Var', (75, 84))	('patients', 'Species', '9606', (110, 118))
14437	32012241	Notably, germline mutations in two additional genes of interest, namely germline mutations in ATM and BAP1, were identified in our cohort.	('BAP1', 'Gene', (102, 106))	('ATM', 'Gene', '472', (94, 97))	('mutations', 'Var', (81, 90))	('BAP1', 'Gene', '8314', (102, 106))	('ATM', 'Gene', (94, 97))
14438	32012241	Although ATM has long been recognized as a moderate-penetrance breast cancer susceptibility gene, more recently, germline mutations in ATM have also been found in individuals with pancreatic cancer.	('ATM', 'Gene', (135, 138))	('ATM', 'Gene', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('pancreatic cancer', 'Disease', 'MESH:D010190', (180, 197))	('ATM', 'Gene', '472', (9, 12))	('germline mutations', 'Var', (113, 131))	('pancreatic cancer', 'Disease', (180, 197))	('breast cancer', 'Disease', (63, 76))	('found', 'Reg', (154, 159))	('ATM', 'Gene', '472', (135, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (180, 197))
14445	32012241	In our cohort, we identified a 51 year-old patient with intrahepatic cholangiocarcinoma, with a prior diagnosis of oral cancer, who harbored a likely pathogenic BAP1 mutation with interrogation of the tumor revealing loss of heterozygosity involving the BAP1 gene locus.	('oral cancer', 'Disease', (115, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('BAP1', 'Gene', (161, 165))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (69, 87))	('BAP1', 'Gene', (254, 258))	('patient', 'Species', '9606', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (56, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('intrahepatic cholangiocarcinoma', 'Disease', (56, 87))	('oral cancer', 'Disease', 'MESH:D009369', (115, 126))	('pathogenic', 'Reg', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))	('BAP1', 'Gene', '8314', (161, 165))	('BAP1', 'Gene', '8314', (254, 258))	('mutation', 'Var', (166, 174))
14446	32012241	Notably, a prior case report also noted cholangiocarcinoma in a germline BAP1 mutation carrier, suggesting that cholangiocarcinoma may be among the expanding spectrum of cancers associated with mutations in this tumor suppressor gene.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cancers', 'Disease', (170, 177))	('BAP1', 'Gene', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('cholangiocarcinoma', 'Disease', (112, 130))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 130))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (40, 58))	('cholangiocarcinoma', 'Disease', (40, 58))	('tumor', 'Disease', (212, 217))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (40, 58))	('BAP1', 'Gene', '8314', (73, 77))	('mutation', 'Var', (78, 86))	('mutations', 'Var', (194, 203))	('tumor', 'Disease', 'MESH:D009369', (212, 217))
14448	32012241	Additionally, we also identified one patient with a mutations in the PMS2 gene, consistent with a diagnosis of Lynch syndrome.	('mutations', 'Var', (52, 61))	('patient', 'Species', '9606', (37, 44))	('Lynch syndrome', 'Disease', (111, 125))	('PMS2', 'Gene', (69, 73))	('Lynch syndrome', 'Disease', 'MESH:D003123', (111, 125))	('PMS2', 'Gene', '5395', (69, 73))
14449	32012241	However, somatic analysis indicated be a microsatellite stable tumor, without evidence of PMS2 LOH or a second somatic mutation, suggesting that the PGA in PMS2 was likely not a driver of this patients biliary tract cancer.	('biliary tract cancer', 'Phenotype', 'HP:0100574', (202, 222))	('tumor', 'Disease', (63, 68))	('patients', 'Species', '9606', (193, 201))	('microsatellite', 'Var', (41, 55))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('PGA', 'Var', (149, 152))	('PMS2', 'Gene', (156, 160))	('PMS2', 'Gene', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('cancer', 'Disease', (216, 222))	('PMS2', 'Gene', '5395', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('PGA', 'Chemical', '-', (149, 152))	('PMS2', 'Gene', '5395', (156, 160))
14451	32012241	Monoallelic MUTYH mutations have not been linked to cancer predisposition, aside from a modest increased risk for colorectal cancer.	('MUTYH', 'Gene', '4595', (12, 17))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('Monoallelic', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('colorectal cancer', 'Disease', (114, 131))	('MUTYH', 'Gene', (12, 17))
14452	32012241	On the contrary, biallelic mutations in MUTYH are diagnostic of MUTYH-associated polyposis (MAP), a syndrome characterized by a large burden of colonic polyps and predisposition to colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (181, 198))	('polyposis', 'Disease', (81, 90))	('MUTYH', 'Gene', (40, 45))	('MUTYH', 'Gene', '4595', (40, 45))	('polyposis', 'Disease', 'MESH:D044483', (81, 90))	('MUTYH', 'Gene', (64, 69))	('MUTYH', 'Gene', '4595', (64, 69))	('colorectal cancer', 'Disease', (181, 198))	('biallelic mutations', 'Var', (17, 36))	('colonic polyps', 'Disease', (144, 158))	('colorectal cancer', 'Disease', 'MESH:D015179', (181, 198))	('colonic polyps', 'Disease', 'MESH:D003111', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
14456	32012241	While many patients did have a second primary cancer or a first-degree family member with a history of cancer, this information alone was not sufficient to identify those likely to harbor a germline mutation in a cancer susceptibility gene.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('germline mutation', 'Var', (190, 207))	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (213, 219))	('patients', 'Species', '9606', (11, 19))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
14458	32012241	These results indicate that many patients who carry PGA alterations may not meet current clinical criteria for germline testing.	('PGA', 'Chemical', '-', (52, 55))	('PGA', 'Gene', (52, 55))	('patients', 'Species', '9606', (33, 41))	('alterations', 'Var', (56, 67))
14463	32012241	In addition, although germline mutations were identified in 11 different genes among patients with biliary tract cancers, it is unclear whether these are causative of the malignancy, although our integrated tumor analysis did identify biallelic inactivation in 42% of patients with high/moderate-penetrance germline mutations.	('biliary tract cancers', 'Disease', 'MESH:D001661', (99, 120))	('biliary tract cancers', 'Disease', (99, 120))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('patients', 'Species', '9606', (85, 93))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (99, 119))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))	('malignancy', 'Disease', 'MESH:D009369', (171, 181))	('patients', 'Species', '9606', (268, 276))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('biallelic inactivation', 'Var', (235, 257))	('malignancy', 'Disease', (171, 181))
14466	32012241	In summary, our results show that 16% of patients with biliary tract cancers to have a pathogenic or likely pathogenic germline mutations.	('pathogenic', 'Reg', (87, 97))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (55, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('germline mutations', 'Var', (119, 137))	('patients', 'Species', '9606', (41, 49))	('biliary tract cancers', 'Disease', 'MESH:D001661', (55, 76))	('biliary tract cancers', 'Disease', (55, 76))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))
14469	32012241	In the interim, germline testing for all patients with biliary tract carcinoma patients, is warranted, particularly, for patients up to their 50's at diagnosis, with tumor mutations known to be potentially germline, and with family history.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('mutations', 'Var', (172, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('patients', 'Species', '9606', (41, 49))	('patients', 'Species', '9606', (79, 87))	('biliary tract carcinoma', 'Disease', 'MESH:D001661', (55, 78))	('biliary tract carcinoma', 'Disease', (55, 78))	('patients', 'Species', '9606', (121, 129))
14635	32375822	The pathogenesis of HCC comprises a multistep process that involves genetic and epigenetic events of multiple genes.	('HCC', 'Gene', (20, 23))	('HCC', 'Gene', '619501', (20, 23))	('epigenetic', 'Var', (80, 90))
14671	31011252	It was suggested that for a tumor with specific morphologic variation to qualify for a subtype, the following criteria should be met: the tumor should have reproducible microscopic pattern, immuno-histochemical and molecular tests that help in the subcategorization of the tumor should be available, and there should be a particular clinical correlate regarding the proposed subtype.	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', (138, 143))	('variation', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (273, 278))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
14691	31011252	In their cohort, the aberrant CDX2 expression was common in poorly differentiated HCC.	('HCC', 'Gene', (82, 85))	('aberrant', 'Var', (21, 29))	('common', 'Reg', (50, 56))	('expression', 'MPA', (35, 45))	('HCC', 'Gene', '619501', (82, 85))	('CDX2', 'Gene', (30, 34))	('HCC', 'Phenotype', 'HP:0001402', (82, 85))	('CDX2', 'Gene', '1045', (30, 34))
14692	31011252	Also, aberrant CK20 expression has been described in 14% of HCCs.	('HCCs', 'Gene', (60, 64))	('expression', 'MPA', (20, 30))	('aberrant', 'Var', (6, 14))	('HCCs', 'Gene', '3052', (60, 64))	('CK20', 'Gene', (15, 19))	('HCC', 'Phenotype', 'HP:0001402', (60, 63))	('CK20', 'Gene', '54474', (15, 19))	('described', 'Reg', (40, 49))
14705	31011252	For example, scirrhous subtype, one of the histologic subtypes that were recognized in 2010 WHO, is associated with TSC1/TSC2 mutations.	('scirrhous subtype', 'Disease', (13, 30))	('TSC1', 'Gene', '7248', (116, 120))	('TSC2', 'Gene', '7249', (121, 125))	('TSC2', 'Gene', (121, 125))	('associated', 'Reg', (100, 110))	('TSC1', 'Gene', (116, 120))	('mutations', 'Var', (126, 135))
14706	31011252	Also, the authors recognized new morphological subtype, "macrotrabecular-massive" subtype, associated with TP53 mutations, FGF19 amplifications and with poor survival and high serum alpha-fetoprotein (AFP) level.	('alpha-fetoprotein', 'Gene', '174', (182, 199))	('AFP', 'Gene', '174', (201, 204))	('amplifications', 'Var', (129, 143))	('FGF19', 'Gene', (123, 128))	('alpha-fetoprotein', 'Gene', (182, 199))	('FGF19', 'Gene', '9965', (123, 128))	('TP53', 'Gene', (107, 111))	('TP53', 'Gene', '7157', (107, 111))	('mutations', 'Var', (112, 121))	('high', 'PosReg', (171, 175))	('high serum alpha-fetoprotein', 'Phenotype', 'HP:0006254', (171, 199))	('AFP', 'Gene', (201, 204))	('associated', 'Reg', (91, 101))
14725	31011252	Subsequently the same group established a correlation between the steatohepatitic variant HCC and an underlying steatohepatitis or metabolic risk factors, and suggested a role of steatohepatitis in human hepatocarcinogenesis.	('steatohepatitis', 'Disease', 'MESH:D005234', (112, 127))	('HCC', 'Phenotype', 'HP:0001402', (90, 93))	('hepatitis', 'Phenotype', 'HP:0012115', (185, 194))	('steatohepatitis', 'Disease', 'MESH:D005234', (179, 194))	('steatohepatitis', 'Disease', (179, 194))	('hepatitis', 'Phenotype', 'HP:0012115', (118, 127))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (204, 224))	('HCC', 'Gene', (90, 93))	('variant', 'Var', (82, 89))	('human', 'Species', '9606', (198, 203))	('hepatocarcinogenesis', 'Disease', (204, 224))	('HCC', 'Gene', '619501', (90, 93))	('steatohepatitis', 'Disease', (112, 127))
14730	31011252	For example, CTNNB1 mutation (beta catenin pathway alterations) are less frequent in steatohepatitic HCC compared to conventional HCC.	('HCC', 'Gene', (130, 133))	('HCC', 'Gene', '619501', (101, 104))	('HCC', 'Phenotype', 'HP:0001402', (101, 104))	('steatohepatitic HCC', 'Disease', 'MESH:D006528', (85, 104))	('mutation', 'Var', (20, 28))	('CTNNB1', 'Gene', (13, 19))	('HCC', 'Gene', '619501', (130, 133))	('steatohepatitic HCC', 'Disease', (85, 104))	('HCC', 'Gene', (101, 104))	('CTNNB1', 'Gene', '1499', (13, 19))	('HCC', 'Phenotype', 'HP:0001402', (130, 133))
14744	31011252	Interestingly, Lee et al reported the presence of IDH1 mutation in 25% of clear cell HCC.	('IDH1', 'Gene', (50, 54))	('presence', 'Reg', (38, 46))	('IDH1', 'Gene', '3417', (50, 54))	('HCC', 'Gene', '619501', (85, 88))	('HCC', 'Phenotype', 'HP:0001402', (85, 88))	('mutation', 'Var', (55, 63))	('HCC', 'Gene', (85, 88))
14745	31011252	These IDH1 mutated clear cell HCCs showed a statistically significant worse prognosis compared to IDH1 wild-type clear cell HCCs.	('IDH1', 'Gene', '3417', (6, 10))	('HCC', 'Phenotype', 'HP:0001402', (124, 127))	('HCCs', 'Gene', (30, 34))	('HCCs', 'Gene', '3052', (124, 128))	('HCCs', 'Gene', '3052', (30, 34))	('IDH1', 'Gene', (98, 102))	('HCC', 'Phenotype', 'HP:0001402', (30, 33))	('HCCs', 'Gene', (124, 128))	('IDH1', 'Gene', (6, 10))	('IDH1', 'Gene', '3417', (98, 102))	('mutated', 'Var', (11, 18))
14746	31011252	Of note, IDH1 mutations are not uncommon in intrahepatic cholangiocarcinoma, a tumor with a significantly worse prognosis than HCC.	('intrahepatic cholangiocarcinoma', 'Disease', (44, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('HCC', 'Gene', (127, 130))	('tumor', 'Disease', (79, 84))	('IDH1', 'Gene', (9, 13))	('IDH1', 'Gene', '3417', (9, 13))	('HCC', 'Gene', '619501', (127, 130))	('HCC', 'Phenotype', 'HP:0001402', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (44, 75))	('mutations', 'Var', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
14775	31011252	On the other hand, TSC1/TSC2 mutations and the overexpression of TGF-beta signaling have been identified in S-HCC.	('TSC1', 'Gene', '7248', (19, 23))	('HCC', 'Phenotype', 'HP:0001402', (110, 113))	('TSC2', 'Gene', '7249', (24, 28))	('TSC2', 'Gene', (24, 28))	('overexpression', 'PosReg', (47, 61))	('TSC1', 'Gene', (19, 23))	('mutations', 'Var', (29, 38))	('identified', 'Reg', (94, 104))	('HCC', 'Gene', (110, 113))	('HCC', 'Gene', '619501', (110, 113))
14837	30459814	In patients with postoperative albumin levels <30 g/dl, a trend was observed towards an increase in serious complications with the need for intervention or re-operation and a prolonged hospital stay (median: 60 postoperative days vs. 37 postoperative days; p = 0.18).	('<30 g/dl', 'Var', (46, 54))	('albumin', 'Gene', (31, 38))	('patients', 'Species', '9606', (3, 11))	('albumin', 'Gene', '213', (31, 38))
14995	24123296	Together, these findings provide a "proof-of-principle" for CAF deletion as a novel anticancer strategy for cholangiocarcinoma, which is also germane to other desmoplastic tumor types.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('desmoplastic tumor', 'Disease', (159, 177))	('cancer', 'Disease', (88, 94))	('CAF', 'Gene', (60, 63))	('rat', 'Species', '10116', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('desmoplastic tumor', 'Phenotype', 'HP:0100245', (159, 177))	('deletion', 'Var', (64, 72))	('cholangiocarcinoma', 'Disease', (108, 126))	('desmoplastic tumor', 'Disease', 'MESH:D058405', (159, 177))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (108, 126))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (108, 126))
14999	24123296	Targeting human KMCH-1cholangiocarcinoma cells, expressing PDGFR-beta receptor, but not c-Kit, with imatinib mesylate or linifanib, as well as by PDGFR-beta shRNA silencing has also been found to significantly decrease TRAIL-induced cholangiocarcinoma cell apoptosis in vitro.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (22, 40))	('human', 'Species', '9606', (10, 15))	('TRAIL', 'Gene', (219, 224))	('linifanib', 'Chemical', 'MESH:C513486', (121, 130))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (233, 251))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (100, 117))	('cholangiocarcinoma', 'Disease', (233, 251))	('KMCH-1cholangiocarcinoma', 'Disease', 'None', (16, 40))	('decrease', 'NegReg', (210, 218))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (233, 251))	('PDGFR-beta', 'Gene', (59, 69))	('PDGFR-beta', 'Gene', (146, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('c-Kit', 'Gene', '3815', (88, 93))	('silencing', 'Var', (163, 172))	('KMCH-1cholangiocarcinoma', 'Disease', (16, 40))	('TRAIL', 'Gene', '8743', (219, 224))	('c-Kit', 'Gene', (88, 93))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (22, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('PDGFR-beta', 'Gene', '5159', (59, 69))	('cholangiocarcinoma', 'Disease', (22, 40))	('PDGFR-beta', 'Gene', '5159', (146, 156))
15006	24123296	Most notable are the paradigm-shifting experiments of Tuveson and his colleagues, in which IPI-926, a semisynthetic derivative of the Smoothened antagonist cyclopamine, was shown to significantly reduce collagen type I deposition and alpha-SMA+CAF levels in the tumor microenvironment in the KPC mouse model of desmoplastic pancreatic adenocarcinoma.	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (324, 349))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('Smoothened', 'Gene', (134, 144))	('mouse', 'Species', '10090', (296, 301))	('desmoplastic pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (311, 349))	('carcinoma', 'Phenotype', 'HP:0030731', (340, 349))	('alpha-SMA+CAF levels', 'MPA', (234, 254))	('collagen type I deposition', 'MPA', (203, 229))	('tumor', 'Disease', (262, 267))	('IPI-926', 'Var', (91, 98))	('reduce', 'NegReg', (196, 202))	('Smoothened', 'Gene', '319757', (134, 144))	('reduce collagen type I', 'Phenotype', 'HP:0030095', (196, 218))	('IPI-926', 'Chemical', 'MESH:C541444', (91, 98))	('desmoplastic pancreatic adenocarcinoma', 'Disease', (311, 349))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('cyclopamine', 'Chemical', 'MESH:C000541', (156, 167))
15021	28389139	Promising candidates for targeted, personalized therapy have emerged including potential driver FGFR gene fusions and somatic mutations in IDH 1/2 in iCCA, PRKACA or PRKACB gene fusions in pCCA, and ELF3 mutations in dCCA/ampullary carcinoma.	('PRKACB', 'Gene', (166, 172))	('IDH 1', 'Gene', (139, 144))	('ELF3', 'Gene', (199, 203))	('ampullary carcinoma', 'Disease', 'MESH:D002277', (222, 241))	('mutations', 'Var', (204, 213))	('gene fusions', 'Var', (101, 113))	('ampullary carcinoma', 'Disease', (222, 241))	('IDH 1', 'Gene', '3417', (139, 144))	('fusions', 'Var', (106, 113))	('FGF', 'Gene', (96, 99))	('PRKACB', 'Gene', '5567', (166, 172))	('PRKACA', 'Gene', (156, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('ELF3', 'Gene', '1999', (199, 203))	('FGF', 'Gene', '2252;2255', (96, 99))	('PRKACA', 'Gene', '5566', (156, 162))
15036	28389139	Opisthorchis viverrini (O. viverrini)-related tumors had 206 somatic mutations which included mutations in known cancer-related genes, such as tumor protein 53 (TP53) which was mutated in 44.4% of cases, Kristen ras sarcoma viral oncogene homolog (KRAS) and SMAD4, both mutated in 16.7% of cases.	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancer', 'Disease', (113, 119))	('ras sarcoma viral', 'Disease', (212, 229))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('Opisthorchis viverrini', 'Species', '6198', (0, 22))	('KRAS', 'Gene', '3845', (248, 252))	('tumors', 'Disease', (46, 52))	('O. viverrini', 'Species', '6198', (24, 36))	('mutations', 'Var', (69, 78))	('KRAS', 'Gene', (248, 252))	('TP53', 'Gene', (161, 165))	('mutations', 'Var', (94, 103))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Disease', (46, 51))	('ras sarcoma viral', 'Disease', 'MESH:D001102', (212, 229))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('TP53', 'Gene', '7157', (161, 165))
15037	28389139	KRAS mutations were associated with a poor overall survival.	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('KRAS', 'Gene', '3845', (0, 4))
15038	28389139	Genes involved in genomic stability and G-protein signaling which had somatic mutations included GNAS, ROBO2, RNF43, PEG3, XIRP2, RADIL, NDC80, PCDHA13 and LAMA2.	('PEG3', 'Gene', (117, 121))	('NDC80', 'Gene', (137, 142))	('LAMA2', 'Gene', (156, 161))	('GNAS', 'Gene', '2778', (97, 101))	('RADIL', 'Gene', '55698', (130, 135))	('PEG3', 'Gene', '5178', (117, 121))	('ROBO2', 'Gene', (103, 108))	('RNF43', 'Gene', '54894', (110, 115))	('XIRP2', 'Gene', '129446', (123, 128))	('PCDHA13', 'Gene', '56136', (144, 151))	('mutations', 'Var', (78, 87))	('RNF43', 'Gene', (110, 115))	('PCDHA13', 'Gene', (144, 151))	('NDC80', 'Gene', '10403', (137, 142))	('XIRP2', 'Gene', (123, 128))	('RADIL', 'Gene', (130, 135))	('ROBO2', 'Gene', '6092', (103, 108))	('LAMA2', 'Gene', '3908', (156, 161))	('GNAS', 'Gene', (97, 101))
15039	28389139	Inactivating mutations in MLL3, which has a role in histone modification, were also identified.	('MLL3', 'Gene', '58508', (26, 30))	('MLL3', 'Gene', (26, 30))	('Inactivating mutations', 'Var', (0, 22))
15045	28389139	A subsequent whole-exome sequencing of 32 intrahepatic CCAs also identified inactivating mutations in multiple chromatin-remodeling genes including BAP1, ARID1A and PBRM1.	('ARID1A', 'Gene', '8289', (154, 160))	('ARID1A', 'Gene', (154, 160))	('BAP1', 'Gene', '8314', (148, 152))	('intrahepatic CCAs', 'Disease', 'MESH:D002780', (42, 59))	('inactivating mutations', 'Var', (76, 98))	('PBRM1', 'Gene', (165, 170))	('PBRM1', 'Gene', '55193', (165, 170))	('BAP1', 'Gene', (148, 152))	('intrahepatic CCAs', 'Disease', (42, 59))
15048	28389139	Deregulation of FGF signaling with consequent carcinogenesis has been implicated in various malignancies including CCA.	('FGF', 'Gene', (16, 19))	('malignancies', 'Disease', (92, 104))	('CCA', 'Disease', (115, 118))	('Deregulation', 'Var', (0, 12))	('FGF', 'Gene', '2252;2255', (16, 19))	('implicated', 'Reg', (70, 80))	('malignancies', 'Disease', 'MESH:D009369', (92, 104))
15049	28389139	FGFR2 gene fusions have been detected in iCCA in several recent studies.	('iCCA', 'Disease', (41, 45))	('detected', 'Reg', (29, 37))	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (11, 18))	('FGFR2', 'Gene', '2263', (0, 5))
15051	28389139	A higher frequency of FGFR gene fusions was noted by Sia et al.	('fusions', 'Var', (32, 39))	('FGF', 'Gene', (22, 25))	('FGF', 'Gene', '2252;2255', (22, 25))
15053	28389139	FGFR2 gene fusions are rare in pCCA/dCCA.	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (11, 18))	('FGFR2', 'Gene', '2263', (0, 5))	('pCCA/dCCA', 'Disease', (31, 40))
15054	28389139	Mechanistic studies indicate that the FGFR binding partners mediate oligomerization and resultant activation of the respective FGFR kinase in tumors harboring FGFR translocations.	('FGF', 'Gene', '2252;2255', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('FGF', 'Gene', '2252;2255', (38, 41))	('FGF', 'Gene', '2252;2255', (127, 130))	('activation', 'PosReg', (98, 108))	('oligomerization', 'MPA', (68, 83))	('FGF', 'Gene', (127, 130))	('tumors', 'Disease', (142, 148))	('FGF', 'Gene', (38, 41))	('translocations', 'Var', (164, 178))	('FGF', 'Gene', (159, 162))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))
15055	28389139	Moreover, FGFR2 fusion proteins activate FGFR signaling with mitogen-activated protein kinase (MAPK) activation and confer anchorage-independent growth.	('FGF', 'Gene', '2252;2255', (10, 13))	('FGFR2', 'Gene', '2263', (10, 15))	('activation', 'PosReg', (101, 111))	('anchorage-independent growth', 'CPA', (123, 151))	('FGF', 'Gene', (41, 44))	('activate', 'PosReg', (32, 40))	('confer', 'Reg', (116, 122))	('FGF', 'Gene', (10, 13))	('fusion', 'Var', (16, 22))	('FGFR2', 'Gene', (10, 15))	('FGF', 'Gene', '2252;2255', (41, 44))
15057	28389139	Intrahepatic cholangiocarcinomas harboring FGFR2 gene fusions appear to have distinct clinical and pathologic features.	('Intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (0, 32))	('fusions', 'Var', (54, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (13, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('Intrahepatic cholangiocarcinomas', 'Disease', (0, 32))	('FGFR2', 'Gene', '2263', (43, 48))	('FGFR2', 'Gene', (43, 48))
15059	28389139	Immunohistochemically, iCCAs with FGFR2 gene fusions have strong cytokeratin (CK)-7 positivity but only weak and patchy expression of CK-19.	('FGFR2', 'Gene', (34, 39))	('FGFR2', 'Gene', '2263', (34, 39))	('positivity', 'MPA', (84, 94))	('CK-19', 'Gene', '3880', (134, 139))	('CK-19', 'Gene', (134, 139))	('fusions', 'Var', (45, 52))	('cytokeratin', 'Protein', (65, 76))
15062	28389139	However, in an Asian cohort the presence of FGFR2 gene fusions in iCCA did not appear to have an impact on overall survival, clinical stage or tumor differentiation.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (143, 148))	('presence', 'Var', (32, 40))	('FGFR2', 'Gene', '2263', (44, 49))	('FGFR2', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
15067	28389139	Evaluation of BGJ398 in a phase I trial single-agent dose escalation and dose-expansion study in 132 patients with advanced solid organ malignancies harboring FGFR gene aberrations demonstrated antitumor activity in several tumor types as well as a manageable safety profile.	('FGF', 'Gene', '2252;2255', (159, 162))	('patients', 'Species', '9606', (101, 109))	('FGF', 'Gene', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('malignancies', 'Disease', 'MESH:D009369', (136, 148))	('BGJ398', 'Chemical', 'MESH:C568950', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('malignancies', 'Disease', (136, 148))	('aberrations', 'Var', (169, 180))	('tumor', 'Disease', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
15068	28389139	Interim analysis from a phase II, multi-center study of BGJ398 in patients with advanced CCA with FGFR2 gene fusions or other FGFR genetic alterations who have failed platinum-based chemotherapy (NCT02150967) demonstrated an impressive disease control rate of 82%.	('gene fusions', 'Var', (104, 116))	('BGJ398', 'Chemical', 'MESH:C568950', (56, 62))	('FGF', 'Gene', (98, 101))	('alterations', 'Var', (139, 150))	('CCA', 'Disease', (89, 92))	('BGJ398', 'Gene', (56, 62))	('FGF', 'Gene', (126, 129))	('FGFR2', 'Gene', (98, 103))	('FGFR2', 'Gene', '2263', (98, 103))	('FGF', 'Gene', '2252;2255', (98, 101))	('platinum', 'Chemical', 'MESH:D010984', (167, 175))	('FGF', 'Gene', '2252;2255', (126, 129))	('patients', 'Species', '9606', (66, 74))
15070	28389139	Results of a phase I dose-escalation study of JNJ-42756493 in patients with advanced solid tumors and FGFR pathway aberrations indicated 4 confirmed responses, one unconfirmed partial response and disease stability in 16 patients.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('patients', 'Species', '9606', (221, 229))	('solid tumors', 'Disease', (85, 97))	('FGF', 'Gene', (102, 105))	('aberrations', 'Var', (115, 126))	('JNJ-42756493', 'Gene', (46, 58))	('solid tumors', 'Disease', 'MESH:D009369', (85, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('FGF', 'Gene', '2252;2255', (102, 105))	('patients', 'Species', '9606', (62, 70))
15072	28389139	ARQ 087 is an ATP-competitive SMKI with anti-proliferative activity in cell lines driven by FGFR aberrations including amplifications, fusions, and mutations.	('amplifications', 'Var', (119, 133))	('mutations', 'Var', (148, 157))	('fusions', 'Var', (135, 142))	('FGF', 'Gene', (92, 95))	('ARQ 087', 'Chemical', 'MESH:C000621805', (0, 7))	('aberrations', 'Var', (97, 108))	('ATP', 'Chemical', 'MESH:D000255', (14, 17))	('FGF', 'Gene', '2252;2255', (92, 95))	('anti-proliferative activity', 'MPA', (40, 67))
15074	28389139	Other FGFR SMKIs which have demonstrated efficacy against FGFR-driven malignancies in preclinical studies and are currently being assessed in early phase clinical trials include TAS-120, AZD4547, and CH5183284/Debio 1347 (NCT02052778, NCT01948297).	('CH5183284', 'Chemical', 'MESH:C000602562', (200, 209))	('TAS-120', 'Chemical', '-', (178, 185))	('malignancies', 'Disease', 'MESH:D009369', (70, 82))	('CH5183284/Debio', 'Var', (200, 215))	('FGF', 'Gene', (58, 61))	('FGF', 'Gene', (6, 9))	('AZD4547', 'Chemical', 'MESH:C572463', (187, 194))	('FGF', 'Gene', '2252;2255', (6, 9))	('FGF', 'Gene', '2252;2255', (58, 61))	('malignancies', 'Disease', (70, 82))
15075	28389139	demonstrated early evidence of efficacy of the non-selective FGFR inhibitors ponatinib and pazopanib in advanced iCCA patients harboring FGFR2 gene fusions.	('FGFR2', 'Gene', (137, 142))	('FGFR2', 'Gene', '2263', (137, 142))	('pazopanib', 'Chemical', 'MESH:C516667', (91, 100))	('FGF', 'Gene', (61, 64))	('ponatinib', 'Chemical', 'MESH:C545373', (77, 86))	('FGF', 'Gene', (137, 140))	('FGF', 'Gene', '2252;2255', (137, 140))	('FGF', 'Gene', '2252;2255', (61, 64))	('gene fusions', 'Var', (143, 155))	('patients', 'Species', '9606', (118, 126))	('iCCA', 'Disease', (113, 117))
15077	28389139	In a patient with metastatic iCCA and FGFR2-TACC3 fusion, partial response to pazopanib was noted.	('patient', 'Species', '9606', (5, 12))	('FGFR2', 'Gene', '2263', (38, 43))	('FGFR2', 'Gene', (38, 43))	('iCCA', 'Disease', (29, 33))	('TACC3', 'Gene', '10460', (44, 49))	('pazopanib', 'Chemical', 'MESH:C516667', (78, 87))	('fusion', 'Var', (50, 56))	('TACC3', 'Gene', (44, 49))
15078	28389139	Ponatinib is currently being assessed in an active phase II clinical trial in patients with advanced biliary tract cancer harboring FGFR2 gene fusions detected by next generation sequencing or FISH break-apart assay (NCT02265341).	('biliary tract cancer', 'Disease', 'MESH:D001661', (101, 121))	('biliary tract cancer', 'Disease', (101, 121))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('FGFR2', 'Gene', '2263', (132, 137))	('FGFR2', 'Gene', (132, 137))	('Ponatinib', 'Chemical', 'MESH:C545373', (0, 9))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (101, 121))	('fusions', 'Var', (143, 150))
15080	28389139	Deregulation of the Raf/MEK/ERK pathway is a well-established occurrence in CCA and the MEK inhibitor Selumetinib has been shown to have some benefit in advanced biliary tract cancer.	('ERK', 'Gene', (28, 31))	('biliary tract cancer', 'Disease', (162, 182))	('MEK', 'Gene', '5609', (88, 91))	('Selumetinib', 'Chemical', 'MESH:C517975', (102, 113))	('Raf', 'Gene', '22882', (20, 23))	('CCA', 'Disease', (76, 79))	('Deregulation', 'Var', (0, 12))	('MEK', 'Gene', (24, 27))	('benefit', 'PosReg', (142, 149))	('MEK', 'Gene', '5609', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('biliary tract cancer', 'Disease', 'MESH:D001661', (162, 182))	('Raf', 'Gene', (20, 23))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (162, 182))	('ERK', 'Gene', '5594', (28, 31))	('MEK', 'Gene', (88, 91))
15083	28389139	identified different FGFR2 mutations in individual resistant clones in patients with acquired resistance to BGJ398.	('mutations', 'Var', (27, 36))	('FGFR2', 'Gene', (21, 26))	('FGFR2', 'Gene', '2263', (21, 26))	('patients', 'Species', '9606', (71, 79))	('BGJ398', 'Chemical', 'MESH:C568950', (108, 114))
15084	28389139	Preclinical studies have indicated that mutations in the FGFR gatekeeper residue can confer resistance to FGFR inhibitors.	('resistance', 'MPA', (92, 102))	('FGF', 'Gene', (57, 60))	('mutations', 'Var', (40, 49))	('FGF', 'Gene', (106, 109))	('FGF', 'Gene', '2252;2255', (57, 60))	('gatekeeper', 'Species', '111938', (62, 72))	('FGF', 'Gene', '2252;2255', (106, 109))	('confer', 'Reg', (85, 91))
15085	28389139	described novel, next-generation covalent FGFR inhibitors, FGFR irreversible inhibitors 2 and 3, which can overcome the gatekeeper residue mutation and potently inhibit tumor cells dependent upon FGFR1 and FGFR2 gatekeeper mutants.	('FGF', 'Gene', '2252;2255', (206, 209))	('FGFR2', 'Gene', '2263', (206, 211))	('FGF', 'Gene', (206, 209))	('FGFR1', 'Gene', '2260', (196, 201))	('gatekeeper', 'Species', '111938', (212, 222))	('FGF', 'Gene', '2252;2255', (196, 199))	('mutation', 'Var', (139, 147))	('FGF', 'Gene', (196, 199))	('tumor', 'Disease', (169, 174))	('FGF', 'Gene', '2252;2255', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('overcome', 'PosReg', (107, 115))	('FGFR1', 'Gene', (196, 201))	('gatekeeper', 'Species', '111938', (120, 130))	('FGF', 'Gene', (59, 62))	('FGF', 'Gene', '2252;2255', (42, 45))	('FGFR2', 'Gene', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('inhibit', 'NegReg', (161, 168))	('FGF', 'Gene', (42, 45))
15087	28389139	detected the FGFR-IIIb isoform in all of the identified FGFR2 gene fusions in their study.	('fusions', 'Var', (67, 74))	('FGF', 'Gene', (13, 16))	('FGFR2', 'Gene', '2263', (56, 61))	('FGFR2', 'Gene', (56, 61))	('FGF', 'Gene', '2252;2255', (56, 59))	('FGF', 'Gene', '2252;2255', (13, 16))	('FGF', 'Gene', (56, 59))
15089	28389139	Monoclonal antibodies directed against specific isoforms would theoretically be an attractive therapeutic option in advanced iCCA cases harboring FGFR gene aberrations as they would avoid the off-target effects of SMKIs.	('FGF', 'Gene', '2252;2255', (146, 149))	('FGF', 'Gene', (146, 149))	('aberrations', 'Var', (156, 167))
15090	28389139	FPA144, a humanized monoclonal antibody directed against the FGFR2b isoform with demonstrated efficacy in preclinical tumor models of gastric cancer, is being evaluated in a phase I clinical trial in patients with advanced solid tumors with FGFR2b overexpression or amplification (NCT02318329).	('human', 'Species', '9606', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('gastric cancer', 'Disease', (134, 148))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('FGFR2', 'Gene', '2263', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('solid tumors', 'Disease', 'MESH:D009369', (223, 235))	('FGFR2', 'Gene', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('amplification', 'Var', (266, 279))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('FGFR2', 'Gene', '2263', (241, 246))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', (229, 234))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('overexpression', 'PosReg', (248, 262))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('patients', 'Species', '9606', (200, 208))	('solid tumors', 'Disease', (223, 235))	('FGFR2', 'Gene', (61, 66))	('tumor', 'Disease', (118, 123))
15108	28389139	Epigenetic silencing of suppressor of cytokine signaling 3 (SOCS-3) mediates sustained IL-6/STAT-3 signaling and enhanced Mcl-1 expression in CCA.	('SOCS-3', 'Gene', (60, 66))	('STAT-3', 'Gene', (92, 98))	('Mcl-1', 'Gene', (122, 127))	('suppressor of cytokine signaling 3', 'Gene', (24, 58))	('suppressor of cytokine signaling 3', 'Gene', '9021', (24, 58))	('Epigenetic silencing', 'Var', (0, 20))	('SOCS-3', 'Gene', '9021', (60, 66))	('Mcl-1', 'Gene', '4170', (122, 127))	('enhanced', 'PosReg', (113, 121))	('CCA', 'Disease', (142, 145))	('STAT-3', 'Gene', '6774', (92, 98))
15110	28389139	Mcl-1 amplification is a critical event in many cancers as cancer cells with Mcl-1 amplification are dependent on this potent anti-apoptotic protein for survival.	('cancers', 'Disease', (48, 55))	('Mcl-1', 'Gene', (77, 82))	('Mcl-1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('Mcl-1', 'Gene', '4170', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (48, 54))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('Mcl-1', 'Gene', '4170', (77, 82))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('amplification', 'Var', (83, 96))
15113	28389139	Mechanistic studies have also demonstrated that S63845, a small molecule inhibitor of Mc-1 which binds with high affinity to the BH3-binding groove of Mcl-1, potently induces cell death in various solid cancer-derived cell lines.	('cell death', 'CPA', (175, 185))	('induces', 'Reg', (167, 174))	('BH3', 'Chemical', 'MESH:C006008', (129, 132))	('S63845', 'Var', (48, 54))	('Mcl-1', 'Gene', '4170', (151, 156))	('Mc-1', 'Chemical', '-', (86, 90))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('Mcl-1', 'Gene', (151, 156))	('Mc-1', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
15116	28389139	IDH mutations are heterozygous point mutations in catalytic amino acid residues and these alteration occur in Arginine 132 of IDH1 and Arginine 140 or Arginine 172 of IDH2.	('IDH1', 'Gene', '3417', (126, 130))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (167, 170))	('IDH', 'Gene', '3417', (126, 129))	('Arginine', 'Chemical', 'MESH:D001120', (151, 159))	('IDH', 'Gene', '3417', (0, 3))	('IDH2', 'Gene', (167, 171))	('Arginine', 'Chemical', 'MESH:D001120', (110, 118))	('occur', 'Reg', (101, 106))	('IDH1', 'Gene', (126, 130))	('IDH', 'Gene', (167, 170))	('Arginine 172', 'Var', (151, 163))	('Arginine 132', 'Var', (110, 122))	('Arginine', 'Chemical', 'MESH:D001120', (135, 143))	('Arginine 140', 'Var', (135, 147))	('IDH', 'Gene', (126, 129))	('IDH2', 'Gene', '3418', (167, 171))
15117	28389139	IDH1/IDH2 mutations results in elevated levels of 2-hydroxyglutarate, an oncometabolite which induces widespread epigenetic changes.	('IDH2', 'Gene', (5, 9))	('IDH2', 'Gene', '3418', (5, 9))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (50, 68))	('elevated', 'PosReg', (31, 39))	('levels of 2-hydroxyglutarate', 'MPA', (40, 68))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (10, 19))	('IDH1', 'Gene', '3417', (0, 4))
15118	28389139	Consequently, IDH mutations have pleiotropic effect on differentiation, growth factor dependence, collagen processing and hypoxia signaling.	('IDH', 'Gene', (14, 17))	('differentiation', 'CPA', (55, 70))	('IDH', 'Gene', '3417', (14, 17))	('hypoxia', 'Disease', (122, 129))	('hypoxia', 'Disease', 'MESH:D000860', (122, 129))	('growth factor dependence', 'MPA', (72, 96))	('collagen', 'MPA', (98, 106))	('mutations', 'Var', (18, 27))
15119	28389139	IDH1/IDH2 mutations, albeit a relatively common occurrence in gliomas, were previously thought to be rare in other solid organ tumors.	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('solid organ tumors', 'Disease', (115, 133))	('IDH2', 'Gene', (5, 9))	('solid organ tumors', 'Disease', 'MESH:D009369', (115, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('IDH2', 'Gene', '3418', (5, 9))	('mutations', 'Var', (10, 19))	('IDH1', 'Gene', (0, 4))	('gliomas', 'Disease', (62, 69))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('IDH1', 'Gene', '3417', (0, 4))
15120	28389139	However, several recent mutational profiling studies have demonstrated that IDH mutations are a relatively frequent genetic aberration in CCA.	('CCA', 'Disease', (138, 141))	('IDH', 'Gene', '3417', (76, 79))	('IDH', 'Gene', (76, 79))	('mutations', 'Var', (80, 89))
15121	28389139	IDH mutations are more frequently observed in intrahepatic cholangiocarcinomas than pCCAs and dCCAs (23-28% versus 0-7%).	('IDH', 'Gene', (0, 3))	('dCCAs', 'Chemical', '-', (94, 99))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (46, 78))	('intrahepatic cholangiocarcinomas', 'Disease', (46, 78))	('IDH', 'Gene', '3417', (0, 3))	('pCCAs', 'Chemical', 'MESH:C075943', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('observed', 'Reg', (34, 42))	('mutations', 'Var', (4, 13))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (59, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))
15122	28389139	Histopathologic analysis of 94 surgically resected primary cholangiocarcinomas demonstrated that IDH mutations are associated with clear cell change and poorly differentiated histology.	('cholangiocarcinomas', 'Disease', (59, 78))	('mutations', 'Var', (101, 110))	('IDH', 'Gene', (97, 100))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (59, 78))	('IDH', 'Gene', '3417', (97, 100))	('associated', 'Reg', (115, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (59, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))	('clear cell change', 'Disease', (131, 148))
15123	28389139	In this study, patients with IDH1/2 gene mutations also appeared to have a better overall survival a year after surgical resection compared to patients without the presence of IDH mutations.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (15, 23))	('better', 'PosReg', (75, 81))	('IDH1/2', 'Gene', (29, 35))	('IDH', 'Gene', (176, 179))	('patients', 'Species', '9606', (143, 151))	('IDH1/2', 'Gene', '3417;3418', (29, 35))	('IDH', 'Gene', '3417', (176, 179))	('IDH', 'Gene', (29, 32))	('overall survival', 'MPA', (82, 98))	('IDH', 'Gene', '3417', (29, 32))
15124	28389139	A positive prognostic association with IDH mutations was also observed in a study of 326 iCCAs which demonstrated that IDH mutations were associated with longer overall survival and longer time to tumor recurrence after iCCA resection.	('IDH', 'Gene', '3417', (119, 122))	('longer', 'PosReg', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('IDH', 'Gene', '3417', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('IDH', 'Gene', (39, 42))	('overall survival', 'MPA', (161, 177))	('IDH', 'Gene', (119, 122))	('tumor', 'Disease', (197, 202))	('mutations', 'Var', (123, 132))
15126	28389139	demonstrated that patients with IDH mutations had a 3-year survival of 33% compared to 81% for those with wild-type IDH genes, although patients with IDH mutations were somewhat older and had a higher tumor stage.	('IDH', 'Gene', (116, 119))	('IDH', 'Gene', '3417', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('patients', 'Species', '9606', (136, 144))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('IDH', 'Gene', (150, 153))	('patients', 'Species', '9606', (18, 26))	('tumor', 'Disease', (201, 206))	('IDH', 'Gene', '3417', (150, 153))
15129	28389139	assessed the correlation of IDH mutations with prognosis in 104 patients with unresectable or advanced iCCA.	('IDH', 'Gene', (28, 31))	('patients', 'Species', '9606', (64, 72))	('IDH', 'Gene', '3417', (28, 31))	('iCCA', 'Disease', (103, 107))	('mutations', 'Var', (32, 41))
15131	28389139	The finding that IDH mutations are a relatively frequent occurrence in several human malignancies logically lead to speculation whether inhibition of mutant IDH activity may have therapeutic benefits.	('human', 'Species', '9606', (79, 84))	('IDH', 'Gene', '3417', (17, 20))	('malignancies', 'Disease', 'MESH:D009369', (85, 97))	('IDH', 'Gene', '3417', (157, 160))	('malignancies', 'Disease', (85, 97))	('mutant', 'Var', (150, 156))	('IDH', 'Gene', (17, 20))	('IDH', 'Gene', (157, 160))
15132	28389139	Small molecule inhibitors of mutant IDH were assessed in two proof of concept preclinical studies.	('mutant', 'Var', (29, 35))	('IDH', 'Gene', '3417', (36, 39))	('IDH', 'Gene', (36, 39))
15135	28389139	AG-120 is a first-in-class, orally bioavailable inhibitor of mutant IDH1.	('IDH1', 'Gene', '3417', (68, 72))	('AG-120', 'Chemical', 'MESH:C000627630', (0, 6))	('mutant', 'Var', (61, 67))	('IDH1', 'Gene', (68, 72))
15136	28389139	Phase 1 results of AG-120 in solid organ malignancies (NCT02073994) including iCCA presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in 2015 demonstrated that AG-120: i) is well-tolerated in the solid tumor patient population, ii) had encouraging evidence of clinical activity, iii) reduced intra-tumoral 2-HG levels.	('malignancies', 'Disease', 'MESH:D009369', (41, 53))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('reduced', 'NegReg', (335, 342))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('malignancies', 'Disease', (41, 53))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('Cancer', 'Phenotype', 'HP:0002664', (165, 171))	('intra-tumoral', 'Disease', 'MESH:D009369', (343, 356))	('tumor', 'Disease', (253, 258))	('AG-120', 'Chemical', 'MESH:C000627630', (211, 217))	('intra-tumoral', 'Disease', (343, 356))	('AG-120', 'Var', (211, 217))	('patient', 'Species', '9606', (259, 266))	('AG-120', 'Chemical', 'MESH:C000627630', (19, 25))	('tumor', 'Disease', (349, 354))
15137	28389139	On the basis of these preliminary results, an advanced phase multi-center, randomized, double-blind, placebo-controlled study of AG-120 in previously treated subjects with unresectable or metastatic cholangiocarcinoma with an IDH1 mutation is planned (NCT02989857).	('AG-120', 'Chemical', 'MESH:C000627630', (129, 135))	('AG-120', 'Gene', (129, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (199, 217))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (199, 217))	('IDH1', 'Gene', (226, 230))	('IDH1', 'Gene', '3417', (226, 230))	('mutation', 'Var', (231, 239))	('cholangiocarcinoma', 'Disease', (199, 217))
15138	28389139	AG-221, an orally available, selective inhibitor of mutant IDH2, has received fast-track designation from the Food and Drug Administration (FDA) and is currently being evaluated in multiple clinical trials including a Phase 1/2, multi-center study in subjects with advanced solid tumors including iCCA who harbor an IDH2 mutation (NCT02273739).	('mutant', 'Var', (52, 58))	('IDH2', 'Gene', '3418', (316, 320))	('NCT02273739', 'Var', (331, 342))	('solid tumors', 'Disease', 'MESH:D009369', (274, 286))	('IDH2', 'Gene', (59, 63))	('iCCA', 'Disease', (297, 301))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumors', 'Phenotype', 'HP:0002664', (280, 286))	('solid tumors', 'Disease', (274, 286))	('IDH2', 'Gene', (316, 320))	('AG-221', 'Chemical', 'MESH:C000605269', (0, 6))	('IDH2', 'Gene', '3418', (59, 63))
15139	28389139	recently demonstrated that iCCA cells with mutant IDH have a unique dependency on SRC kinase.	('dependency', 'MPA', (68, 78))	('SRC', 'Gene', '6714', (82, 85))	('SRC', 'Gene', (82, 85))	('mutant', 'Var', (43, 49))	('IDH', 'Gene', (50, 53))	('IDH', 'Gene', '3417', (50, 53))
15140	28389139	Consequently, the SRC inhibitor, dasatinib, had a significant anti-tumor effect in mutant IDH xenografts, signifying a potential new therapeutic strategy against mutant IDH iCCA  Members of the protein tyrosine phosphatase (PTP) are enzymes which remove phosphate from tyrosine residues in proteins.	('mutant', 'Var', (83, 89))	('IDH', 'Gene', '3417', (90, 93))	('mutant', 'Var', (162, 168))	('IDH', 'Gene', '3417', (169, 172))	('tumor', 'Disease', (67, 72))	('phosphate', 'Chemical', 'MESH:D010710', (254, 263))	('SRC', 'Gene', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tyrosine', 'Chemical', 'MESH:D014443', (269, 277))	('tyrosine', 'Chemical', 'MESH:D014443', (202, 210))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('PTP', 'Gene', (224, 227))	('IDH', 'Gene', (90, 93))	('protein tyrosine phosphatase', 'Gene', '26191', (194, 222))	('protein tyrosine phosphatase', 'Gene', (194, 222))	('IDH', 'Gene', (169, 172))	('dasatinib', 'Chemical', 'MESH:D000069439', (33, 42))	('PTP', 'Gene', '26191', (224, 227))	('SRC', 'Gene', '6714', (18, 21))
15141	28389139	Genetic aberrations of PTPs can result in disequilibrium of protein tyrosine-kinase phosphatase activity with consequent oncogenic potential.	('disequilibrium', 'MPA', (42, 56))	('result in', 'Reg', (32, 41))	('PTP', 'Gene', (23, 26))	('oncogenic potential', 'CPA', (121, 140))	('PTP', 'Gene', '26191', (23, 26))	('protein tyrosine-kinase phosphatase activity', 'MPA', (60, 104))	('Genetic aberrations', 'Var', (0, 19))	('tyrosine', 'Chemical', 'MESH:D014443', (68, 76))
15142	28389139	A prevalence screen of 124 pairs of iCCAs and nontumor samples demonstrated that 41.4% of iCCAs had gain of function mutations in PTPN3.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('mutations', 'Var', (117, 126))	('PTPN3', 'Gene', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('gain of function', 'PosReg', (100, 116))	('PTPN3', 'Gene', '5774', (130, 135))
15143	28389139	Presence of these mutations conferred markedly enhanced pro-tumor activity and significantly increased postoperative tumor recurrence.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('enhanced', 'PosReg', (47, 55))	('increased', 'PosReg', (93, 102))	('tumor', 'Disease', (117, 122))	('postoperative tumor', 'Disease', (103, 122))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('postoperative tumor', 'Disease', 'MESH:D010149', (103, 122))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('mutations', 'Var', (18, 27))
15144	28389139	This study has important therapeutic implications as it is well-known that gain of function mutations are potential therapeutic targets in various malignancies.	('malignancies', 'Disease', (147, 159))	('gain of function', 'PosReg', (75, 91))	('malignancies', 'Disease', 'MESH:D009369', (147, 159))	('mutations', 'Var', (92, 101))
15145	28389139	Inactivating mutations were frequently identified in BAP1, ARID1A and PBRM1.	('Inactivating mutations', 'Var', (0, 22))	('ARID1A', 'Gene', '8289', (59, 65))	('PBRM1', 'Gene', (70, 75))	('BAP1', 'Gene', '8314', (53, 57))	('ARID1A', 'Gene', (59, 65))	('PBRM1', 'Gene', '55193', (70, 75))	('BAP1', 'Gene', (53, 57))
15148	28389139	ARID1A mutations appear to be more frequent in iCCA than pCCA/dCCA as indicated by a recent mutational profiling which identified ARID1A aberrations in 20% of iCCAs compared to 5% of pCCA/dCCAs.	('ARID1A', 'Gene', '8289', (130, 136))	('ARID1A', 'Gene', (130, 136))	('mutations', 'Var', (7, 16))	('iCCAs', 'Disease', (159, 164))	('ARID1A', 'Gene', '8289', (0, 6))	('ARID1A', 'Gene', (0, 6))	('dCCAs', 'Chemical', '-', (188, 193))	('frequent', 'Reg', (35, 43))	('aberrations', 'Var', (137, 148))	('iCCA', 'Disease', (47, 51))
15149	28389139	BAP1 and PBRM1 alterations were identified in 9% and 11% of iCCAs, respectively.	('BAP1', 'Gene', (0, 4))	('BAP1', 'Gene', '8314', (0, 4))	('alterations', 'Var', (15, 26))	('PBRM1', 'Gene', (9, 14))	('PBRM1', 'Gene', '55193', (9, 14))
15150	28389139	BAP1 mutations were also detected in 10% of pCCA/dCCA cases, and in these patients the presence of BAP1 mutation was significantly associated with reduced progression-free survival (median 3 months vs. 8.8 months) and reduced overall survival (median 8.9 vs. 19.9 months).	('BAP1', 'Gene', (99, 103))	('overall', 'MPA', (226, 233))	('BAP1', 'Gene', (0, 4))	('presence', 'Var', (87, 95))	('pCCA/dCCA', 'Disease', (44, 53))	('patients', 'Species', '9606', (74, 82))	('mutations', 'Var', (5, 14))	('progression-free survival', 'CPA', (155, 180))	('mutation', 'Var', (104, 112))	('BAP1', 'Gene', '8314', (99, 103))	('reduced', 'NegReg', (218, 225))	('BAP1', 'Gene', '8314', (0, 4))	('reduced', 'NegReg', (147, 154))
15151	28389139	Overall, in all cases harboring BAP1 mutations in this study, progression after first-line chemotherapy was observed within 4 months.	('mutations', 'Var', (37, 46))	('BAP1', 'Gene', '8314', (32, 36))	('BAP1', 'Gene', (32, 36))
15153	28389139	Aberrant expression and signaling of the epidermal growth factor receptor (ERBB) family of receptor tyrosine kinases has been reported in cholangiocarcinoma.	('Aberrant', 'Var', (0, 8))	('tyrosine kinase', 'Gene', '7294', (100, 115))	('epidermal growth factor receptor', 'Gene', (41, 73))	('cholangiocarcinoma', 'Disease', (138, 156))	('ERBB', 'Gene', (75, 79))	('signaling', 'MPA', (24, 33))	('epidermal growth factor receptor', 'Gene', '1956', (41, 73))	('expression', 'MPA', (9, 19))	('tyrosine kinase', 'Gene', (100, 115))	('ERBB', 'Gene', '1956', (75, 79))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (138, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (138, 156))	('reported', 'Reg', (126, 134))
15156	28389139	A recent mutation profiling of 75 CCA specimens identified ERBB2 genetic aberrations in 20% of pCCAs/dCCAs and in only 1.8% of iCCAs.	('pCCAs/dCCAs', 'Disease', (95, 106))	('genetic aberrations', 'Var', (65, 84))	('dCCAs', 'Chemical', '-', (101, 106))	('ERBB2', 'Gene', (59, 64))	('ERBB2', 'Gene', '2064', (59, 64))	('pCCAs', 'Chemical', 'MESH:C075943', (95, 100))
15157	28389139	The pCCA/dCCA ERBB2 alterations included one amplification and four mutations, the latter being a novel finding, as mutations had previously not been reported in CCA.	('mutations', 'Var', (68, 77))	('alterations', 'Var', (20, 31))	('ERBB2', 'Gene', (14, 19))	('ERBB2', 'Gene', '2064', (14, 19))
15159	28389139	The V777L mutation is an activating mutation with some demonstrated resistance to lapatinib, a reversible, dual inhibitor of EGFR and HER2.	('EGFR', 'Gene', '1956', (125, 129))	('V777L', 'Mutation', 'rs121913471', (4, 9))	('EGFR', 'Gene', (125, 129))	('HER2', 'Gene', (134, 138))	('lapatinib', 'Chemical', 'MESH:D000077341', (82, 91))	('HER2', 'Gene', '2064', (134, 138))	('V777L', 'Var', (4, 9))
15160	28389139	However, the V777L mutation was sensitive to nertatinib, an irreversible, dual inhibitor of EGFR and HER2.	('HER2', 'Gene', (101, 105))	('HER2', 'Gene', '2064', (101, 105))	('V777L', 'Mutation', 'rs121913471', (13, 18))	('nertatinib', 'Chemical', '-', (45, 55))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('V777L', 'Var', (13, 18))
15166	28389139	These fusions stimulated significantly enhanced expression of the PRKACA and PRKACB genes with consequent downstream MAPK signaling activation.	('activation', 'PosReg', (132, 142))	('PRKACB', 'Gene', (77, 83))	('expression', 'MPA', (48, 58))	('PRKACA', 'Gene', (66, 72))	('PRKACA', 'Gene', '5566', (66, 72))	('fusions', 'Var', (6, 13))	('PRKACB', 'Gene', '5567', (77, 83))	('enhanced', 'PosReg', (39, 47))
15167	28389139	Interestingly, fusion of the same exon of the PRKACA gene to DNAJB1 has been demonstrated in fibrolamellar hepatocellular carcinoma.	('fusion', 'Var', (15, 21))	('PRKACA', 'Gene', '5566', (46, 52))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (107, 131))	('DNAJB1', 'Gene', '3337', (61, 67))	('fibrolamellar hepatocellular carcinoma', 'Disease', (93, 131))	('fibrolamellar hepatocellular carcinoma', 'Disease', 'MESH:C537258', (93, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('DNAJB1', 'Gene', (61, 67))	('PRKACA', 'Gene', (46, 52))
15169	28389139	PRKAR1A expression is enhanced in CCA, and PRKAR1A knockdown induces growth inhibition and apoptosis of CCA cells with resultant decrease in MAPK, phosphatidylinositol 3-kinase (PI3K)/Akt, JAT/STAT, and Wnt/beta-catenin pathway signaling.	('PRKAR1A', 'Gene', (43, 50))	('beta-catenin', 'Gene', (207, 219))	('PI3', 'Gene', (178, 181))	('growth inhibition', 'CPA', (69, 86))	('beta-catenin', 'Gene', '1499', (207, 219))	('PRKAR1A', 'Gene', (0, 7))	('PRKAR1A', 'Gene', '5573', (43, 50))	('JAT', 'Disease', 'None', (189, 192))	('knockdown', 'Var', (51, 60))	('phosphatidylinositol 3-kinase', 'Gene', '5295', (147, 176))	('decrease', 'NegReg', (129, 137))	('apoptosis', 'CPA', (91, 100))	('MAPK', 'MPA', (141, 145))	('JAT', 'Disease', (189, 192))	('phosphatidylinositol 3-kinase', 'Gene', (147, 176))	('PRKAR1A', 'Gene', '5573', (0, 7))	('enhanced', 'PosReg', (22, 30))	('PI3', 'Gene', '5266', (178, 181))	('Akt', 'Gene', (184, 187))	('Akt', 'Gene', '207', (184, 187))
15177	28389139	Two recent genomic analyses detected inactivating mutations of ELF3 in ampullary carcinoma/dCCA.	('ampullary carcinoma', 'Disease', 'MESH:D002277', (71, 90))	('ELF3', 'Gene', (63, 67))	('ampullary carcinoma', 'Disease', (71, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('inactivating mutations', 'Var', (37, 59))	('ELF3', 'Gene', '1999', (63, 67))
15179	28389139	identified inactivating frameshift or nonsense mutations in 10.6% of periampullary tumors.	('nonsense mutations', 'Var', (38, 56))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('inactivating frameshift', 'Var', (11, 34))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
15180	28389139	Similarly, ELF3 mutations had been reported in 9.5% of extrahepatic CCAs (pCCA/dCCA) in a molecular characterization of biliary tract cancers.	('ELF3', 'Gene', (11, 15))	('ELF3', 'Gene', '1999', (11, 15))	('biliary tract cancers', 'Disease', 'MESH:D001661', (120, 141))	('biliary tract cancers', 'Disease', (120, 141))	('reported', 'Reg', (35, 43))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('extrahepatic CCAs', 'Disease', (55, 72))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (120, 140))
15181	28389139	In a cohort of 172 ampullary carcinomas, driver mutations in ELF3 were also identified in 13.3% of cases.	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('carcinomas', 'Phenotype', 'HP:0030731', (29, 39))	('ampullary carcinomas', 'Disease', 'MESH:D002277', (19, 39))	('ELF3', 'Gene', (61, 65))	('ampullary carcinomas', 'Disease', (19, 39))	('ELF3', 'Gene', '1999', (61, 65))	('mutations', 'Var', (48, 57))
15182	28389139	ELF3 mutations were present at high allele frequencies, indicating that ELF3 mutation may represent a founder or driver mutation in ampullary carcinoma.	('ELF3', 'Gene', '1999', (72, 76))	('ampullary carcinoma', 'Disease', (132, 151))	('mutation', 'Var', (77, 85))	('ELF3', 'Gene', (72, 76))	('ELF3', 'Gene', '1999', (0, 4))	('ampullary carcinoma', 'Disease', 'MESH:D002277', (132, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('ELF3', 'Gene', (0, 4))
15183	28389139	Functional studies were subsequently carried out and demonstrated that ELF3 knockdown promotes motility and invasion in epithelial cells.	('knockdown', 'Var', (76, 85))	('invasion in epithelial cells', 'CPA', (108, 136))	('ELF3', 'Gene', '1999', (71, 75))	('motility', 'CPA', (95, 103))	('ELF3', 'Gene', (71, 75))	('promotes', 'PosReg', (86, 94))
15184	28389139	Molecular alterations in the ERBB family are well-described in pCCA (please see above) and have recently been reported in dCCA/ampullary carcinoma.	('ERBB', 'Gene', (29, 33))	('well-described', 'Reg', (45, 59))	('pCCA', 'Disease', (63, 67))	('reported', 'Reg', (110, 118))	('ERBB', 'Gene', '1956', (29, 33))	('ampullary carcinoma', 'Disease', 'MESH:D002277', (127, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('ampullary carcinoma', 'Disease', (127, 146))	('Molecular alterations', 'Var', (0, 21))
15185	28389139	ERBB3 mutations were identified in 14% of pancreatobiliary-type ampullary carcinomas and ERBB2 mutations were identified in 11.6% of ampullary carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('identified', 'Reg', (21, 31))	('ERBB3', 'Gene', (0, 5))	('ERBB3', 'Gene', '2065', (0, 5))	('ERBB2', 'Gene', (89, 94))	('ERBB2', 'Gene', '2064', (89, 94))	('ampullary carcinomas', 'Disease', 'MESH:D002277', (133, 153))	('pancreatobiliary-type ampullary carcinomas', 'Disease', 'MESH:D002277', (42, 84))	('ampullary carcinomas', 'Disease', 'MESH:D002277', (64, 84))	('pancreatobiliary-type ampullary carcinomas', 'Disease', (42, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('mutations', 'Var', (6, 15))	('ampullary carcinomas', 'Disease', (133, 153))
15187	28389139	KRAS mutations and the activation of the PI3K-AKT-mTOR pathway are amongst the most prevalent aberrations noted in a number of malignancies and have a significant role in carcinogenesis.	('malignancies', 'Disease', 'MESH:D009369', (127, 139))	('malignancies', 'Disease', (127, 139))	('mTOR', 'Gene', (50, 54))	('mTOR', 'Gene', '2475', (50, 54))	('PI3', 'Gene', '5266', (41, 44))	('mutations', 'Var', (5, 14))	('PI3', 'Gene', (41, 44))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
15188	28389139	Activating mutations of the proto-oncogene KRAS are one of the most frequently encountered genetic mutations in CCA.	('Activating mutations', 'Var', (0, 20))	('KRAS', 'Gene', (43, 47))	('CCA', 'Disease', (112, 115))	('mutations', 'Var', (99, 108))	('KRAS', 'Gene', '3845', (43, 47))
15189	28389139	The rate of KRAS mutations appear to be higher in pCCA/dCCA (40%) compared to iCCA (9%-24%).	('KRAS', 'Gene', (12, 16))	('higher', 'Reg', (40, 46))	('KRAS', 'Gene', '3845', (12, 16))	('pCCA/dCCA', 'Disease', (50, 59))	('mutations', 'Var', (17, 26))
15190	28389139	The presence of these mutations has prognostic utility as patients harboring KRAS mutations have worse progression-free and overall survival.	('overall survival', 'CPA', (124, 140))	('worse', 'NegReg', (97, 102))	('KRAS', 'Gene', (77, 81))	('mutations', 'Var', (82, 91))	('KRAS', 'Gene', '3845', (77, 81))	('progression-free', 'CPA', (103, 119))	('patients', 'Species', '9606', (58, 66))
15193	28389139	Presently, there are no effective direct inhibitors of KRAS and therefore the therapeutic approach for KRAS mutant tumors is inhibition of the downstream pathways.	('KRAS', 'Gene', (55, 59))	('KRAS', 'Gene', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('KRAS', 'Gene', '3845', (103, 107))	('KRAS', 'Gene', '3845', (55, 59))	('mutant', 'Var', (108, 114))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))
15201	28389139	Exome sequencing has identified mutations in multiple family members of the PI3K pathway including inactivating mutations of PIK3R1 and activating mutations of PIK3CA, PIK3C2A, PIK3C2G.	('activating', 'PosReg', (136, 146))	('PI3', 'Gene', (76, 79))	('PIK3C2G', 'Gene', '5288', (177, 184))	('PIK3CA', 'Gene', '5290', (160, 166))	('PIK3R1', 'Gene', '5295', (125, 131))	('PIK3R1', 'Gene', (125, 131))	('PIK3C2A', 'Gene', (168, 175))	('mutations', 'Var', (32, 41))	('PIK3C2A', 'Gene', '5286', (168, 175))	('PIK3C2G', 'Gene', (177, 184))	('inactivating mutations', 'Var', (99, 121))	('PI3', 'Gene', '5266', (76, 79))	('PIK3CA', 'Gene', (160, 166))
15205	28389139	However, preclinical data suggests that AKT inhibition can potentiate the anti-tumor efficacy of mTOR inhibition.	('mTOR', 'Gene', '2475', (97, 101))	('inhibition', 'Var', (44, 54))	('tumor', 'Disease', (79, 84))	('mTOR', 'Gene', (97, 101))	('AKT', 'Protein', (40, 43))	('potentiate', 'PosReg', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
15216	28389139	Consequently, a mouse xenograft model treated with low-dose paclitaxel had reduced lung metastasis, albeit no significant effect on local tumor growth.	('tumor', 'Disease', (138, 143))	('low-dose', 'Var', (51, 59))	('reduced', 'NegReg', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('paclitaxel', 'Chemical', 'MESH:D017239', (60, 70))	('mouse', 'Species', '10090', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('lung metastasis', 'Disease', (83, 98))	('lung metastasis', 'Disease', 'MESH:D009362', (83, 98))
15219	28389139	Preclinical studies have demonstrated that hedgehog signaling inhibition with cyclopamine hinders CCA cell proliferation, migration, and invasion and promotes tumor suppression in vivo.	('cyclopamine', 'Var', (78, 89))	('promotes', 'PosReg', (150, 158))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('invasion', 'CPA', (137, 145))	('cyclopamine', 'Chemical', 'MESH:C000541', (78, 89))	('tumor', 'Disease', (159, 164))	('CCA', 'Disease', (98, 101))	('migration', 'CPA', (122, 131))	('inhibition', 'NegReg', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('hinders', 'NegReg', (90, 97))	('hedgehog', 'Protein', (43, 51))
15237	28389139	The finding of the critical role of cytotoxic t-lymphocyte associated protein 4 (CTLA-4) in T-cell downregulation was paradigm shifting and spurred the notion that coinhibitory signals block anti-tumor T-cell responses and removal of these signals would have an anti-tumor effect.	('cytotoxic t-lymphocyte associated protein 4', 'Gene', '1493', (36, 79))	('tumor', 'Disease', (196, 201))	('CTLA-4', 'Gene', '1493', (81, 87))	('downregulation', 'NegReg', (99, 113))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', (267, 272))	('coinhibitory', 'Var', (164, 176))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('CTLA-4', 'Gene', (81, 87))	('cytotoxic t-lymphocyte associated protein 4', 'Gene', (36, 79))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('block', 'NegReg', (185, 190))
15245	28389139	In another series of iCCA cases, a favorable clinical course was noted in cases with positive HLA class 1 antigen expression and negative PD-L1 expression, indicating that HLA expression defects in combination with PD-L1 expression may provide an immune escape mechanism for iCCAs.	('iCCAs', 'Disease', (275, 280))	('HLA expression', 'Protein', (172, 186))	('defects', 'Var', (187, 194))	('PD-L1', 'Gene', (215, 220))	('PD-L1', 'Gene', '29126', (215, 220))	('PD-L1', 'Gene', (138, 143))	('PD-L1', 'Gene', '29126', (138, 143))
15259	28389139	In the future, one can envision a portfolio of therapies to treat this disease guided by genetic biomarkers (e.g., FGFR2 directed therapy for a CCA with FGFR2 fusion aberrations) coupled to a checkpoint inhibitor (if the CCA also expresses checkpoint modulators such as PD-L1), or a CAF-directed therapy (if the CCA is highly desmoplastic).	('CAF', 'Gene', (283, 286))	('fusion aberrations', 'Var', (159, 177))	('FGFR2', 'Gene', (115, 120))	('PD-L1', 'Gene', (270, 275))	('FGFR2', 'Gene', '2263', (115, 120))	('FGFR2', 'Gene', (153, 158))	('CAF', 'Gene', '8850', (283, 286))	('FGFR2', 'Gene', '2263', (153, 158))	('PD-L1', 'Gene', '29126', (270, 275))
15264	26189129	In this study, we identified and compared somatic mutations in ICC and ECC patients using next generation sequencing (NGS) (Ampliseq Cancer Hotspot Panel v2 and Ion Torrent 318v2 chips).	('ECC', 'Disease', (71, 74))	('Cancer', 'Phenotype', 'HP:0002664', (133, 139))	('mutations', 'Var', (50, 59))	('patients', 'Species', '9606', (75, 83))	('rat', 'Species', '10116', (99, 102))	('ICC', 'Disease', (63, 66))
15265	26189129	ICC cases (n = 3) showed IDH1 (33.3%) and NRAS (33.3%) mutations.	('NRAS', 'Gene', '4893', (42, 46))	('mutations', 'Var', (55, 64))	('ICC', 'Disease', (0, 3))	('IDH1', 'Gene', (25, 29))	('NRAS', 'Gene', (42, 46))	('IDH1', 'Gene', '3417', (25, 29))
15266	26189129	Meanwhile, TP53 (75%), KRAS (50%), and BRAF (12.5%) mutations were identified in ECC cases (n = 8).	('mutations', 'Var', (52, 61))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('BRAF', 'Gene', (39, 43))	('ECC', 'Disease', (81, 84))	('KRAS', 'Gene', (23, 27))
15286	26189129	The long-term objective of these studies is to find actionable genes which may improve the management and outcome of ICC and ECC patients.	('ICC', 'Disease', (117, 120))	('ECC', 'Disease', (125, 128))	('patients', 'Species', '9606', (129, 137))	('genes', 'Var', (63, 68))	('improve', 'PosReg', (79, 86))
15288	26189129	In the era of personalized medicine, NGS plays an important role in identifying mutations which may predict the prognosis or alter the management for cancer patients.	('predict', 'Reg', (100, 107))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('patients', 'Species', '9606', (157, 165))	('cancer', 'Disease', (150, 156))	('alter', 'Reg', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
15329	26189129	A series of studies using traditional and advanced technologies have described a variety of gene mutations and genomic alterations in cholangiocarcinoma, particularly ICC, to further explore the disease mechanism and to develop potential targeted therapies.	('mutations', 'Var', (97, 106))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (134, 152))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (134, 152))	('rat', 'Species', '10116', (123, 126))	('ICC', 'Disease', (167, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('cholangiocarcinoma', 'Disease', (134, 152))
15332	26189129	Using a 50-gene panel, we identified IDH1 and NRAS gene alterations in patients with ICC and mutated KRAS, TP53, and BRAF genes in ECC cases.	('NRAS', 'Gene', (46, 50))	('mutated', 'Var', (93, 100))	('alterations', 'Var', (56, 67))	('patients', 'Species', '9606', (71, 79))	('TP53', 'Gene', '7157', (107, 111))	('NRAS', 'Gene', '4893', (46, 50))	('IDH1', 'Gene', (37, 41))	('TP53', 'Gene', (107, 111))	('rat', 'Species', '10116', (60, 63))	('BRAF', 'Gene', (117, 121))	('ICC', 'Disease', (85, 88))	('IDH1', 'Gene', '3417', (37, 41))	('KRAS', 'Disease', (101, 105))
15335	26189129	reported that altered IDH1/2 alteration was identified in 36% of the cases, similar prevalence to AT rich interactive domain 1 A (ARID1A) (36%), TP53 (36%), and myeloid cell leukemia 1 (MCL1) (21%) alterations.	('ARID1A', 'Gene', '8289', (130, 136))	('ARID1A', 'Gene', (130, 136))	('myeloid cell leukemia 1', 'Gene', '4170', (161, 184))	('leukemia', 'Phenotype', 'HP:0001909', (174, 182))	('AT rich interactive domain 1 A', 'Gene', (98, 128))	('myeloid cell leukemia 1', 'Gene', (161, 184))	('rat', 'Species', '10116', (33, 36))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('IDH1', 'Gene', (22, 26))	('AT rich interactive domain 1 A', 'Gene', '8289', (98, 128))	('IDH1', 'Gene', '3417', (22, 26))	('rat', 'Species', '10116', (202, 205))	('MCL1', 'Gene', (186, 190))	('MCL1', 'Gene', '4170', (186, 190))	('alteration', 'Var', (29, 39))
15336	26189129	Similar to one of our ICC patients, the majority (99%) of somatic mutations in IDH1 is found at codon R132, which is functionally conserved and aligns with R172 of IDH2.	('mutations', 'Var', (66, 75))	('IDH1', 'Gene', '3417', (79, 83))	('patients', 'Species', '9606', (26, 34))	('IDH2', 'Gene', (164, 168))	('IDH1', 'Gene', (79, 83))	('IDH2', 'Gene', '3418', (164, 168))
15338	26189129	The mutant enzyme induces the reduction of a-ketoglutarate to 2-hydroxyglutarate, with the conversion of NADPH to NADP+.	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (62, 80))	('mutant', 'Var', (4, 10))	('a-ketoglutarate', 'Chemical', '-', (43, 58))	('reduction', 'NegReg', (30, 39))	('NADP+', 'Chemical', 'MESH:D009249', (114, 119))	('NADPH', 'Chemical', 'MESH:D009249', (105, 110))	('a-ketoglutarate to 2-hydroxyglutarate', 'MPA', (43, 80))
15341	26189129	IDH1 mutations are associated with poorly differentiated tumors with clear cell changes histologically.	('associated', 'Reg', (19, 29))	('clear cell changes', 'Disease', (69, 87))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('IDH1', 'Gene', '3417', (0, 4))
15344	26189129	In gliomas, AG1-5198, a selective IDH1 inhibitor, blocks the 2-hydroxyglutarate production in a dose-dependent manner and stunted the growth of IDH-1 mutant tumor cells sparing the IDH1 wild-type cells.	('IDH-1', 'Gene', (144, 149))	('AG1', 'Gene', '51060', (12, 15))	('gliomas', 'Disease', (3, 10))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('AG1', 'Gene', (12, 15))	('IDH1', 'Gene', '3417', (34, 38))	('stunted', 'NegReg', (122, 129))	('IDH1', 'Gene', (181, 185))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('mutant', 'Var', (150, 156))	('blocks', 'NegReg', (50, 56))	('IDH-1', 'Gene', '3417', (144, 149))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('2-hydroxyglutarate production', 'MPA', (61, 90))	('IDH1', 'Gene', '3417', (181, 185))	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('growth', 'MPA', (134, 140))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (61, 79))	('IDH1', 'Gene', (34, 38))
15349	26189129	Due to the low frequency, no information on clinicopathological correlation is available for tumors with this particular gene mutation and thus it would be considered a variant of unknown clinical significance in this tumor type.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('mutation', 'Var', (126, 134))	('tumor', 'Disease', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Disease', (93, 99))	('tumor', 'Disease', (218, 223))	('clinical', 'Species', '191496', (188, 196))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
15350	26189129	Mutation of KRAS and loss-of-function mutations of TP53 are frequently seen in both ICC and ECC.	('TP53', 'Gene', (51, 55))	('ICC', 'Disease', (84, 87))	('loss-of-function', 'NegReg', (21, 37))	('ECC', 'Disease', (92, 95))	('KRAS', 'Gene', (12, 16))	('mutations', 'Var', (38, 47))	('TP53', 'Gene', '7157', (51, 55))
15351	26189129	TP53 mutations were reported in 21% of cholangiocarcinoma cases in a review of studies with 229 patients.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (39, 57))	('mutations', 'Var', (5, 14))	('cholangiocarcinoma', 'Disease', (39, 57))	('patients', 'Species', '9606', (96, 104))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (39, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
15352	26189129	A direct DNA sequencing analysis of 69 cholangiocarcinomas identified KRAS and BRAF mutations in 22% and 45% of the tumors.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (39, 58))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (39, 57))	('KRAS', 'Gene', (70, 74))	('mutations', 'Var', (84, 93))	('cholangiocarcinomas', 'Disease', (39, 58))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('BRAF', 'Gene', (79, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
15359	26189129	reported 1,259 somatic mutations in 1128 genes; Frequent inactivating mutations in multiple chromatin-remodeling genes (BRCA-associated protein 1 (BAP1), ARID1A, and polybromo-1 (PBRM1)), and mutation in one of these genes occurred in 47% of the carcinomas sequenced.	('BRCA-associated protein 1', 'Gene', '8314', (120, 145))	('occurred', 'Reg', (223, 231))	('BAP1', 'Gene', (147, 151))	('ARID1A', 'Gene', '8289', (154, 160))	('PBRM1', 'Gene', (179, 184))	('ARID1A', 'Gene', (154, 160))	('BRCA-associated protein 1', 'Gene', (120, 145))	('mutation', 'Var', (192, 200))	('inactivating', 'NegReg', (57, 69))	('polybromo-1', 'Gene', '55193', (166, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('PBRM1', 'Gene', '55193', (179, 184))	('mutations', 'Var', (23, 32))	('carcinomas', 'Disease', 'MESH:D002277', (246, 256))	('carcinomas', 'Phenotype', 'HP:0030731', (246, 256))	('carcinomas', 'Disease', (246, 256))	('polybromo-1', 'Gene', (166, 177))	('BAP1', 'Gene', '8314', (147, 151))
15360	26189129	A novel recurrent oncogenic fusion, fibroblast growth factor receptor 2 (FGFR2) : periphilin1 (PPHLN1), gene and damaging mutations in the V-raf murine sarcoma 3611 viral oncogene homolog (ARAF) gene were recently described in 16% and 11% of 122 ICC cases.	('fibroblast growth factor receptor 2', 'Gene', (36, 71))	('sarcoma', 'Disease', 'MESH:D012509', (152, 159))	('ARAF', 'Gene', '11836', (189, 193))	('periphilin1', 'Gene', '223828', (82, 93))	('ICC', 'Disease', (246, 249))	('murine', 'Species', '10090', (145, 151))	('fibroblast growth factor receptor 2', 'Gene', '14183', (36, 71))	('sarcoma', 'Disease', (152, 159))	('PPHLN1', 'Gene', (95, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('mutations', 'Var', (122, 131))	('ARAF', 'Gene', (189, 193))	('periphilin1', 'Gene', (82, 93))
15362	26189129	In the study, phosphatidylinositol-4,5 biphosponate 3-kinase, catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), cyclin-dependent kinase inhibitor 2A (CDKN2A), and TP53 mutations were harbored exclusively in ICCs with normal background liver.	('phosphatidylinositol-4,5 biphosponate', 'Chemical', '-', (14, 51))	('PIK3CA', 'Gene', '5290', (87, 93))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (135, 171))	('CDKN2A', 'Gene', (173, 179))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (135, 171))	('PTEN', 'Gene', (128, 132))	('PTEN', 'Gene', '5728', (128, 132))	('mutations', 'Var', (191, 200))	('CDKN2A', 'Gene', '1029', (173, 179))	('TP53', 'Gene', '7157', (186, 190))	('TP53', 'Gene', (186, 190))	('PIK3CA', 'Gene', (87, 93))
15363	26189129	Meanwhile, epidermal growth factor receptor (EGFR) mutation was seen more frequently in ICCs with chronic liver disease.	('liver disease', 'Disease', 'MESH:D008107', (106, 119))	('epidermal growth factor receptor', 'Gene', (11, 43))	('ICCs', 'Disease', (88, 92))	('EGFR', 'Gene', (45, 49))	('liver disease', 'Disease', (106, 119))	('mutation', 'Var', (51, 59))	('epidermal growth factor receptor', 'Gene', '1956', (11, 43))	('liver disease', 'Phenotype', 'HP:0001392', (106, 119))	('seen', 'Reg', (64, 68))	('EGFR', 'Gene', '1956', (45, 49))
15364	26189129	Most of these EGFR mutations were located at exon 19, identical to deletions identified in non-small cell lung carcinomas.	('EGFR', 'Gene', '1956', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('EGFR', 'Gene', (14, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('non-small cell lung carcinomas', 'Disease', 'MESH:D002289', (91, 121))	('non-small cell lung carcinomas', 'Disease', (91, 121))	('mutations', 'Var', (19, 28))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (95, 121))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (91, 121))
15366	26189129	A study from showed that ERBB2 mutations were seen in the kinase domain (V777L) and extracellular domain (S310F).	('S310F', 'Var', (106, 111))	('V777L', 'Mutation', 'rs121913471', (73, 78))	('V777L', 'Var', (73, 78))	('S310F', 'Mutation', 'rs1057519816', (106, 111))	('ERBB2', 'Gene', '2064', (25, 30))	('ERBB2', 'Gene', (25, 30))
15380	25605008	We explored that the expression of six miRNAs (mir124, 182, 27b, let7b, 221 and 181a), which could directly target cell-cycle-regulatory genes, was altered by metformin in vitro and in vivo.	('let7b', 'Gene', (65, 70))	('mir124', 'Var', (47, 53))	('altered', 'Reg', (148, 155))	('expression', 'MPA', (21, 31))	('metformin', 'Chemical', 'MESH:D008687', (159, 168))	('let7b', 'Gene', '406884', (65, 70))
15392	25605008	In addition, several reports also outlined the decreased cancer incidence and cancer related mortality in the tumor patients who received metformin.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (57, 63))	('patients', 'Species', '9606', (116, 124))	('decreased cancer', 'Disease', (47, 63))	('cancer', 'Disease', (78, 84))	('metformin', 'Var', (138, 147))	('tumor', 'Disease', (110, 115))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('decreased cancer', 'Disease', 'MESH:D009369', (47, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('metformin', 'Chemical', 'MESH:D008687', (138, 147))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
15393	25605008	Further investigations found that metformin inhibited the proliferation of various human cancer cell types including prostate, esophageal, renal and glioma tumor cells.	('glioma tumor', 'Disease', (149, 161))	('proliferation', 'CPA', (58, 71))	('renal', 'CPA', (139, 144))	('inhibited', 'NegReg', (44, 53))	('metformin', 'Var', (34, 43))	('esophageal', 'Disease', (127, 137))	('glioma tumor', 'Disease', 'MESH:D005910', (149, 161))	('human', 'Species', '9606', (83, 88))	('metformin', 'Chemical', 'MESH:D008687', (34, 43))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancer', 'Disease', (89, 95))	('prostate', 'Disease', (117, 125))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
15395	25605008	Numerous researches have demonstrated that aberrant expression of miRNAs are involved in the development, invasion, metastasis and prognosis of various cancers.	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('involved', 'Reg', (77, 85))	('aberrant expression', 'Var', (43, 62))	('invasion', 'CPA', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('metastasis', 'CPA', (116, 126))	('miRNAs', 'Gene', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
15402	25605008	The results showed that metformin treatment was closely associated with a decrease in the tumor size and volume of CCA patients, and the improved postoperative survival.	('decrease', 'NegReg', (74, 82))	('CCA', 'Disease', (115, 118))	('metformin', 'Var', (24, 33))	('volume', 'CPA', (105, 111))	('postoperative', 'CPA', (146, 159))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('metformin', 'Chemical', 'MESH:D008687', (24, 33))	('CCA', 'Phenotype', 'HP:0030153', (115, 118))	('improved', 'PosReg', (137, 145))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
15406	25605008	These data indicated that metformin could also reduce tumor volume and growth rate of CCA cells in vivo.	('reduce', 'NegReg', (47, 53))	('metformin', 'Chemical', 'MESH:D008687', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('CCA', 'Phenotype', 'HP:0030153', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('growth rate', 'CPA', (71, 82))	('tumor', 'Disease', (54, 59))	('CCA', 'Disease', (86, 89))	('metformin', 'Var', (26, 35))
15419	25605008	Among these fourteen candidates, six miRNAs (hsa-mir-124-3p, hsa-mir-182-5p, hsa-mir-27b-3p, hsa-mir-let7b-5p, hsa-mir-221-3p and hsa-mir-181a-3p), which might target cell-cycle-regulatory genes according to bioinformatic algorithms, were selected for further study.	('mir-221', 'Gene', '407006', (115, 122))	('hsa-mir-27b-3p', 'Var', (77, 91))	('let7b', 'Gene', (101, 106))	('let7b', 'Gene', '406884', (101, 106))	('mir-221', 'Gene', (115, 122))	('mir-182', 'Gene', (65, 72))	('mir-182', 'Gene', '406958', (65, 72))
15426	25605008	Upregulation of mir124, 182, 27b and let7b could inhibit the CCA cells proliferation and arrest the cell cycle in G0/G1 phase, however, the proliferation and cell cycle were both promoted through upregulating mir221 or mir181a expression (Fig.	('mir124', 'Var', (16, 22))	('proliferation', 'CPA', (140, 153))	('cell cycle', 'CPA', (158, 168))	('CCA', 'Phenotype', 'HP:0030153', (61, 64))	('mir221', 'Gene', '407006', (209, 215))	('upregulating', 'PosReg', (196, 208))	('CCA cells proliferation', 'CPA', (61, 84))	('mir221', 'Gene', (209, 215))	('expression', 'MPA', (227, 237))	('let7b', 'Gene', (37, 42))	('let7b', 'Gene', '406884', (37, 42))	('promoted', 'PosReg', (179, 187))	('arrest', 'NegReg', (89, 95))	('cell cycle in G0/G1 phase', 'CPA', (100, 125))	('mir181a', 'Gene', (219, 226))	('inhibit', 'NegReg', (49, 56))
15428	25605008	The results further confirmed that these dysregulated miRNAs, including downregulated mir124, 182, 27b, let7b and upregulated mir221, 181a, were involved in the CCA genesis and promoted this process.	('promoted', 'PosReg', (177, 185))	('mir124', 'Gene', (86, 92))	('CCA', 'Phenotype', 'HP:0030153', (161, 164))	('mir221', 'Gene', '407006', (126, 132))	('let7b', 'Gene', (104, 109))	('let7b', 'Gene', '406884', (104, 109))	('mir221', 'Gene', (126, 132))	('involved', 'Reg', (145, 153))	('CCA', 'Disease', (161, 164))	('downregulated', 'NegReg', (72, 85))	('182', 'Var', (94, 97))	('upregulated', 'PosReg', (114, 125))
15433	25605008	In summary, the cell-cycle-regulatory genes CDK2, CDK4, CyclinD1 and CyclinE1 were targeted by mir124, CDK2 and CyclinD1 were targeted by mir182 and mir27b, CyclinD1 was targeted by mirlet7b, P27 was targeted by mir221 and mir181a.	('targeted', 'Reg', (83, 91))	('CyclinE1', 'Gene', (69, 77))	('mirlet7b', 'Gene', '406884', (182, 190))	('mir124', 'Var', (95, 101))	('P27', 'Gene', (192, 195))	('mir182', 'Gene', '406958', (138, 144))	('mir221', 'Gene', '407006', (212, 218))	('mir181a', 'Var', (223, 230))	('mir182', 'Gene', (138, 144))	('CDK4', 'Gene', (50, 54))	('mir221', 'Gene', (212, 218))	('CyclinD1', 'Gene', '595', (112, 120))	('CDK2', 'Gene', '1017', (103, 107))	('mir27b', 'Gene', '407019', (149, 155))	('mirlet7b', 'Gene', (182, 190))	('mir27b', 'Gene', (149, 155))	('CyclinE1', 'Gene', '898', (69, 77))	('CDK4', 'Gene', '1019', (50, 54))	('CDK2', 'Gene', (103, 107))	('CyclinD1', 'Gene', (112, 120))	('CyclinD1', 'Gene', '595', (56, 64))	('CyclinD1', 'Gene', (56, 64))	('CyclinD1', 'Gene', '595', (157, 165))	('targeted', 'Reg', (126, 134))	('CDK2', 'Gene', '1017', (44, 48))	('P27', 'Gene', '3429', (192, 195))	('CyclinD1', 'Gene', (157, 165))	('CDK2', 'Gene', (44, 48))
15436	25605008	6B showed that the expression change of mir124, 27b, let7b and 181a was also closely associated with postoperative survival of G2 patients (R<=-0.45 or >=0.45).	('expression', 'MPA', (19, 29))	('mir124', 'Var', (40, 46))	('let7b', 'Gene', '406884', (53, 58))	('patients', 'Species', '9606', (130, 138))	('181a', 'Gene', (63, 67))	('let7b', 'Gene', (53, 58))	('associated', 'Reg', (85, 95))
15440	25605008	The postoperative survival of Low and High mir patients was listed in Supplementary Table 3 and there were significant differences of postoperative survival between Low and High mir patients of mir124, 27b, let7, 221 and 181a (Fig.	('mir124', 'Var', (194, 200))	('let7', 'Var', (207, 211))	('patients', 'Species', '9606', (47, 55))	('patients', 'Species', '9606', (182, 190))
15441	25605008	In one patient, the expression change of mir124, 182, 27b or let7b was less than its cutoff value and this single miRNA expression of the patient scored one; the expression change of mir221 or 181a was greater than its cutoff value and this single miRNA expression of the patient also scored one.	('expression', 'MPA', (20, 30))	('patient', 'Species', '9606', (7, 14))	('expression', 'MPA', (162, 172))	('mir124', 'Var', (41, 47))	('let7b', 'Gene', (61, 66))	('patient', 'Species', '9606', (138, 145))	('patient', 'Species', '9606', (272, 279))	('let7b', 'Gene', '406884', (61, 66))	('182', 'Var', (49, 52))	('mir221', 'Gene', (183, 189))	('mir221', 'Gene', '407006', (183, 189))
15449	25605008	6I showed that the tumor size and volume of Low mirs patients were less than those of High mirs patients and there were the most significant differences of tumor volume and postoperative survival between Low and High mirs patients.	('patients', 'Species', '9606', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('volume', 'CPA', (34, 40))	('patients', 'Species', '9606', (222, 230))	('less', 'NegReg', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', (156, 161))	('Low', 'Var', (44, 47))	('patients', 'Species', '9606', (96, 104))
15450	25605008	These data showed that the associations with tumor volume and postoperative survival were stronger for mirs-expression than for single miRNA expression, and the differences of tumor volume and postoperative survival between Low and High mirs patients were more significant than those between single Low and High mir patients.	('mirs-expression', 'Var', (103, 118))	('associations', 'Interaction', (27, 39))	('Low', 'Var', (224, 227))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('High mirs', 'Var', (232, 241))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', (45, 50))	('stronger', 'PosReg', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('patients', 'Species', '9606', (316, 324))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('patients', 'Species', '9606', (242, 250))
15456	25605008	7F showed the expression changes of mature and pri-miRNAs after Drosha siRNA transfection by using qRT-PCR.	('transfection', 'Var', (77, 89))	('Drosha', 'Gene', (64, 70))	('changes', 'Reg', (25, 32))	('expression', 'MPA', (14, 24))	('Drosha', 'Gene', '29102', (64, 70))
15458	25605008	Further we found that downregulated Drosha could lessen the miRNAs expression changes induced by metformin (Fig.	('lessen', 'NegReg', (49, 55))	('miRNAs expression changes', 'MPA', (60, 85))	('Drosha', 'Gene', (36, 42))	('downregulated', 'Var', (22, 35))	('Drosha', 'Gene', '29102', (36, 42))	('metformin', 'Chemical', 'MESH:D008687', (97, 106))
15472	25605008	Using siRNA to knock down Drosha/DGCR8 in vitro, the proliferation and cell cycle of CCA cells were both promoted (Fig.	('promoted', 'PosReg', (105, 113))	('DGCR8', 'Gene', (33, 38))	('knock down', 'Var', (15, 25))	('Drosha', 'Gene', (26, 32))	('DGCR8', 'Gene', '54487', (33, 38))	('proliferation', 'CPA', (53, 66))	('CCA', 'Phenotype', 'HP:0030153', (85, 88))	('Drosha', 'Gene', '29102', (26, 32))	('cell cycle', 'CPA', (71, 81))
15473	25605008	9B showed the mRNA and protein expression changes of cell-cycle-regulatory genes after Drosha/DGCR8 siRNA transfection.	('DGCR8', 'Gene', (94, 99))	('cell-cycle-regulatory genes', 'Gene', (53, 80))	('Drosha', 'Gene', (87, 93))	('transfection', 'Var', (106, 118))	('DGCR8', 'Gene', '54487', (94, 99))	('Drosha', 'Gene', '29102', (87, 93))	('changes', 'Reg', (42, 49))	('mRNA', 'MPA', (14, 18))
15477	25605008	Previous studies have pointed out that metformin was associated with reduced risk and improved prognosis of many cancers and had an excellent safety record in diabetic patients; metformin also inhibited various tumor cells proliferation both in vitro and in vivo.	('inhibited', 'NegReg', (193, 202))	('reduced', 'NegReg', (69, 76))	('metformin', 'Var', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('improved', 'PosReg', (86, 94))	('metformin', 'Chemical', 'MESH:D008687', (178, 187))	('metformin', 'Chemical', 'MESH:D008687', (39, 48))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('diabetic', 'Disease', 'MESH:D003920', (159, 167))	('prognosis', 'CPA', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('patients', 'Species', '9606', (168, 176))	('diabetic', 'Disease', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
15483	25605008	To investigate whether miRNAs were involved in the anticancer effect of metformin, we identified six miRNAs which were altered by metformin in vitro and in vivo, and the targets of these miRNAs were all cell-cycle-regulatory genes.	('metformin', 'Var', (130, 139))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('metformin', 'Chemical', 'MESH:D008687', (130, 139))	('miRNAs', 'MPA', (101, 107))	('altered', 'Reg', (119, 126))	('metformin', 'Chemical', 'MESH:D008687', (72, 81))	('cancer', 'Disease', (55, 61))
15484	25605008	It was found that there were obvious differences of these miRNAs expression in tumor tissues compared with adjacent normal tissues and the dysregulation of these miRNAs could promote the cell cycle and enhance the CCA cells proliferation.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('enhance', 'PosReg', (202, 209))	('tumor', 'Disease', (79, 84))	('CCA', 'Disease', (214, 217))	('promote', 'PosReg', (175, 182))	('cell cycle', 'CPA', (187, 197))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('dysregulation', 'Var', (139, 152))	('CCA', 'Phenotype', 'HP:0030153', (214, 217))
15486	25605008	The miRNAs expression changes induced by metformin were opposite to the expression changes of these dysregulated miRNAs in human tumor tissues and metformin could lessen dysregulated expression changes of these miRNAs.	('lessen', 'NegReg', (163, 169))	('miRNAs', 'MPA', (4, 10))	('metformin', 'Chemical', 'MESH:D008687', (41, 50))	('human', 'Species', '9606', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('metformin', 'Var', (147, 156))	('dysregulated expression changes', 'MPA', (170, 201))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('metformin', 'Chemical', 'MESH:D008687', (147, 156))	('tumor', 'Disease', (129, 134))
15491	25605008	Based on the cutoff value of each miRNA expression change, G2 patients were divided into High and Low mir patients, and High mir patients of mir124, 182, 27b, let7b and Low mir patients of mir221, 181a had smaller tumor volume and longer postoperative survival.	('postoperative survival', 'CPA', (238, 260))	('longer', 'PosReg', (231, 237))	('let7b', 'Gene', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('let7b', 'Gene', '406884', (159, 164))	('patients', 'Species', '9606', (177, 185))	('smaller', 'NegReg', (206, 213))	('patients', 'Species', '9606', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('mir221', 'Gene', '407006', (189, 195))	('patients', 'Species', '9606', (106, 114))	('mir221', 'Gene', (189, 195))	('tumor', 'Disease', (214, 219))	('mir124', 'Var', (141, 147))	('patients', 'Species', '9606', (62, 70))
15493	25605008	The results proved that the associations with tumor volume and postoperative survival were stronger for composite six miRNAs assessment than for single miRNA evaluation; and the differences of tumor volume and postoperative survival between High and Low mirs patients were more significant than those between single High and Low mir patients.	('associations', 'Interaction', (28, 40))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('patients', 'Species', '9606', (259, 267))	('Low mirs', 'Var', (250, 258))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', (46, 51))	('patients', 'Species', '9606', (333, 341))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
15494	25605008	In addition, Low mirs patients had the smallest tumor volume and the longest postoperative survival.	('tumor', 'Disease', (48, 53))	('smallest', 'NegReg', (39, 47))	('patients', 'Species', '9606', (22, 30))	('Low mirs', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
15499	25605008	The miRNAs expression changes induced by regulating Drosha were consistent with the miRNAs expression changes after metformin treatment, and downregulating Drosha could lessen the miRNAs expression changes induced by metformin.	('downregulating', 'Var', (141, 155))	('Drosha', 'Gene', '29102', (52, 58))	('Drosha', 'Gene', (156, 162))	('lessen', 'NegReg', (169, 175))	('miRNAs expression', 'MPA', (4, 21))	('metformin', 'Chemical', 'MESH:D008687', (116, 125))	('metformin', 'Chemical', 'MESH:D008687', (217, 226))	('Drosha', 'Gene', '29102', (156, 162))	('Drosha', 'Gene', (52, 58))	('miRNAs expression', 'MPA', (84, 101))	('miRNAs expression changes', 'MPA', (180, 205))
15500	25605008	Compared with regulating single miRNA, downregulated Drosha could suppress antiproliferative and cell cycle arrest effect of relative high concentration metformin.	('metformin', 'Chemical', 'MESH:D008687', (153, 162))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (97, 114))	('downregulated', 'Var', (39, 52))	('suppress', 'NegReg', (66, 74))	('Drosha', 'Gene', (53, 59))	('Drosha', 'Gene', '29102', (53, 59))	('cell cycle arrest effect', 'CPA', (97, 121))
15593	23613672	No prognostic significance was found in EHC in Korean data, however, in a meta-analysis, Chinese researchers suggested that high expression of p53 may be a prognostic factor in EHC.	('high expression', 'Var', (124, 139))	('p53', 'Gene', (143, 146))	('p53', 'Gene', '7157', (143, 146))	('EHC', 'Disease', (177, 180))
15603	23613672	According to one report, which included a small number of patients, nuclear survivin expression can also predict a poor survival outcome for patients with cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (155, 173))	('nuclear', 'Var', (68, 75))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (155, 173))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (141, 149))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (155, 173))
15614	22514698	The sensitizing effect of ZnPP was associated with increased ROS formation and loss of mitochondrial transmembrane potential, while Gem alone did not show any effects.	('ZnPP', 'Chemical', 'MESH:C017803', (26, 30))	('loss', 'NegReg', (79, 83))	('increased', 'PosReg', (51, 60))	('Gem', 'Chemical', 'MESH:C056507', (132, 135))	('ZnPP', 'Var', (26, 30))	('mitochondrial transmembrane potential', 'MPA', (87, 124))	('ROS formation', 'MPA', (61, 74))	('ROS', 'Chemical', 'MESH:D017382', (61, 64))
15618	22514698	Targeted inhibition of HO-1 may be a strategy to overcome drug resistance in chemotherapy of bile duct cancer.	('bile duct cancer', 'Phenotype', 'HP:0030153', (93, 109))	('drug resistance', 'Phenotype', 'HP:0020174', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('bile duct cancer', 'Disease', (93, 109))	('Targeted inhibition', 'Var', (0, 19))	('HO-1', 'Gene', (23, 27))	('bile duct cancer', 'Disease', 'MESH:D001650', (93, 109))	('HO-1', 'Gene', '3162', (23, 27))
15634	22514698	Thus, some studies revealed that suppression of HO-1 activity or HO-1 knockdown by siRNA increased the chemosensitivity of AML cells, pancreatic and lung cancer cells, but was not effective in other cancer cells.	('knockdown', 'Var', (70, 79))	('chemosensitivity', 'CPA', (103, 119))	('HO-1', 'Gene', '3162', (65, 69))	('suppression', 'NegReg', (33, 44))	('cancer', 'Disease', (199, 205))	('HO-1', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('HO-1', 'Gene', '3162', (48, 52))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('HO-1', 'Gene', (48, 52))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('activity', 'MPA', (53, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('increased', 'PosReg', (89, 98))	('AML', 'Disease', 'MESH:D015470', (123, 126))	('cancer', 'Disease', (154, 160))	('pancreatic and lung cancer', 'Disease', 'MESH:D010190', (134, 160))	('AML', 'Disease', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
15638	22514698	Mitochondria may be a primary target of HO-1 inhibition, as ZnPP and triiodothyronine induced the opening of the mitochondrial permeability transition (MPT) pore leading to liver injury.	('opening', 'Disease', 'MESH:D005597', (98, 105))	('opening', 'Disease', (98, 105))	('MPT', 'Chemical', '-', (152, 155))	('liver injury', 'Disease', (173, 185))	('triiodothyronine', 'Var', (69, 85))	('HO-1', 'Gene', (40, 44))	('liver injury', 'Disease', 'MESH:D056486', (173, 185))	('triiodothyronine', 'Chemical', 'MESH:D014284', (69, 85))	('HO-1', 'Gene', '3162', (40, 44))	('ZnPP', 'Var', (60, 64))	('ZnPP', 'Chemical', 'MESH:C017803', (60, 64))
15640	22514698	The results show that inhibition of HO-1 induced the sensitization of CCA cells to gemcitabine (Gem) and doxorubicin (Dox).	('inhibition', 'Var', (22, 32))	('doxorubicin', 'Chemical', 'MESH:D004317', (105, 116))	('Gem', 'Chemical', 'MESH:C056507', (96, 99))	('HO-1', 'Gene', (36, 40))	('Dox', 'Chemical', 'MESH:D004317', (118, 121))	('sensitization', 'MPA', (53, 66))	('gemcitabine', 'Chemical', 'MESH:C056507', (83, 94))	('HO-1', 'Gene', '3162', (36, 40))	('CCA', 'Phenotype', 'HP:0030153', (70, 73))
15641	22514698	Inhibition of HO-1 could be a strategy to enhance the response of CCA to chemotherapeutic drugs.	('HO-1', 'Gene', '3162', (14, 18))	('enhance', 'PosReg', (42, 49))	('response', 'MPA', (54, 62))	('CCA', 'Phenotype', 'HP:0030153', (66, 69))	('Inhibition', 'Var', (0, 10))	('CCA', 'Disease', (66, 69))	('HO-1', 'Gene', (14, 18))
15649	22514698	The numbers of viable, apoptotic and necrotic cells which were stained with green fluorescence, bright orange fluorescence and green fluorescence with appearance of cell shrinkage, condensation and fragmentation of the nuclei, respectively, were enumerated.	('necrotic', 'Disease', 'MESH:D009336', (37, 45))	('green fluorescence', 'Var', (127, 145))	('necrotic', 'Disease', (37, 45))	('fragmentation', 'CPA', (198, 211))	('condensation', 'CPA', (181, 193))
15667	22514698	The PVDF membrane was incubated overnight at 4 C with primary antibodies of rabbit polyclonal anti-human HO-1 (1:1000) (ADI-SPA-895: Enzo Life Sciences, Switzerland), rabbit monoclonal anti-human p21Cip/WAF1 (1:500) (#2947: Cell Signaling Technology, MA, USA), mouse monoclonal anti-human cytochrome c (1:1000) (sc-13560) and horseradish peroxidase (HRP)-goat polyclonal anti-human beta-actin (1:2500) (sc-1616 HRP) in TBS.	('rabbit', 'Species', '9986', (76, 82))	('PVDF', 'Chemical', 'MESH:C024865', (4, 8))	('HO-1', 'Gene', (105, 109))	('TBS', 'Chemical', '-', (419, 422))	('beta-actin', 'Gene', '728378', (382, 392))	('cytochrome c', 'Gene', (289, 301))	('mouse', 'Species', '10090', (261, 266))	('rabbit', 'Species', '9986', (167, 173))	('human', 'Species', '9606', (190, 195))	('p21', 'Gene', (196, 199))	('horseradish', 'Species', '3704', (326, 337))	('human', 'Species', '9606', (283, 288))	('goat', 'Species', '9925', (355, 359))	('beta-actin', 'Gene', (382, 392))	('WAF1', 'Gene', '1026', (203, 207))	('sc-1616', 'Var', (403, 410))	('cytochrome c', 'Gene', '54205', (289, 301))	('human', 'Species', '9606', (376, 381))	('WAF1', 'Gene', (203, 207))	('HO-1', 'Gene', '3162', (105, 109))	('p21', 'Gene', '1026', (196, 199))	('human', 'Species', '9606', (99, 104))
15668	22514698	After washing with TBS the blots were incubated for 1 h at room temperature with the HRP-conjugated secondary antibodies (anti-rabbit IgG-HRP sc-2004, anti-mouse IgG-HRP sc-2005, anti-goat IgG-HRP sc-2354).	('anti-mouse', 'Var', (151, 161))	('TBS', 'Chemical', '-', (19, 22))	('rabbit', 'Species', '9986', (127, 133))	('mouse', 'Species', '10090', (156, 161))	('goat', 'Species', '9925', (184, 188))	('anti-rabbit', 'Var', (122, 133))
15679	22514698	3A and 3B, ZnPP rendered both CCA cells to be highly susceptible to cytotoxic effect of Gem, which can be seen as the downward shift of the dose-response curves of Gem in the presence of ZnPP.	('ZnPP', 'Var', (11, 15))	('CCA', 'Phenotype', 'HP:0030153', (30, 33))	('ZnPP', 'Chemical', 'MESH:C017803', (11, 15))	('ZnPP', 'Chemical', 'MESH:C017803', (187, 191))	('Gem', 'Chemical', 'MESH:C056507', (88, 91))	('cytotoxic effect', 'CPA', (68, 84))	('Gem', 'Chemical', 'MESH:C056507', (164, 167))
15681	22514698	The presence of ZnPP augmented significantly Gem- or Dox-induced cell growth inhibition and induction of apoptotic cell death in both cell lines (Fig.	('Gem- or Dox-induced cell growth inhibition', 'CPA', (45, 87))	('ZnPP', 'Gene', (16, 20))	('apoptotic cell death', 'CPA', (105, 125))	('Gem', 'Chemical', 'MESH:C056507', (45, 48))	('augmented', 'PosReg', (21, 30))	('Dox', 'Chemical', 'MESH:D004317', (53, 56))	('presence', 'Var', (4, 12))	('ZnPP', 'Chemical', 'MESH:C017803', (16, 20))
15686	22514698	KKU-100 and KKU-M214 cells were treated with Gem (0.1 microM) or Dox (0.5 microM) with or without SnCl2 for 24 h. Induction of HO-1 was associated with increased cell viability more than 2 fold after treatment with Gem or Dox (Fig.	('Dox', 'Chemical', 'MESH:D004317', (65, 68))	('Gem', 'Chemical', 'MESH:C056507', (45, 48))	('increased', 'PosReg', (152, 161))	('cell viability', 'CPA', (162, 176))	('Induction', 'Var', (114, 123))	('Dox', 'Chemical', 'MESH:D004317', (222, 225))	('Gem', 'Chemical', 'MESH:C056507', (215, 218))	('HO-1', 'Gene', (127, 131))	('KKU-100 and KKU-M214', 'Disease', 'OMIM:300114', (0, 20))	('HO-1', 'Gene', '3162', (127, 131))
15730	22514698	Our results showed that ZnPP caused marked increase in ROS levels in KKU-100 cells, whereas Gem treatment alone did not induce ROS.	('ROS', 'Chemical', 'MESH:D017382', (127, 130))	('ZnPP', 'Var', (24, 28))	('ROS levels', 'MPA', (55, 65))	('ZnPP', 'Chemical', 'MESH:C017803', (24, 28))	('ROS', 'Chemical', 'MESH:D017382', (55, 58))	('increase', 'PosReg', (43, 51))	('Gem', 'Chemical', 'MESH:C056507', (92, 95))
15733	22514698	Moreover, these results imply that inhibition of HO-1 increases the oxidative stress, where ROS may be derived from the metabolism of the cells themselves.	('ROS', 'Chemical', 'MESH:D017382', (92, 95))	('HO-1', 'Gene', (49, 53))	('oxidative stress', 'Phenotype', 'HP:0025464', (68, 84))	('HO-1', 'Gene', '3162', (49, 53))	('oxidative stress', 'MPA', (68, 84))	('increases', 'PosReg', (54, 63))	('inhibition', 'Var', (35, 45))
15734	22514698	The loss of Deltapsim is regarded as an early event of mitochondrial dysfunction.	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (55, 80))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (55, 80))	('mitochondrial dysfunction', 'Disease', (55, 80))	('loss', 'Var', (4, 8))	('Deltapsim', 'Protein', (12, 21))
15735	22514698	It is apparent that a small change in mitochondrial permeability transition (MPT) could depolarize the mitochondria, whilst increasing number of MPT leads to necrosis and apoptosis.	('necrosis', 'Disease', (158, 166))	('MPT', 'Chemical', '-', (145, 148))	('mitochondrial permeability transition', 'MPA', (38, 75))	('MPT', 'Var', (145, 148))	('apoptosis', 'CPA', (171, 180))	('necrosis', 'Disease', 'MESH:D009336', (158, 166))	('MPT', 'Chemical', '-', (77, 80))	('depolarize', 'NegReg', (88, 98))	('mitochondria', 'MPA', (103, 115))	('leads to', 'Reg', (149, 157))	('increasing', 'PosReg', (124, 134))
15741	22514698	Alternatively, inhibition of HO-1 activity results in an increase accumulation of protoporphyrin in mitochondria and this lead to depolarization of Deltapsim and sensitize MPT to cytotoxic agents.	('Deltapsim', 'MPA', (148, 157))	('protoporphyrin', 'Chemical', 'MESH:C028025', (82, 96))	('HO-1', 'Gene', (29, 33))	('MPT', 'MPA', (172, 175))	('increase accumulation', 'PosReg', (57, 78))	('depolarization', 'NegReg', (130, 144))	('MPT', 'Chemical', '-', (172, 175))	('HO-1', 'Gene', '3162', (29, 33))	('sensitize', 'Reg', (162, 171))	('inhibition', 'Var', (15, 25))
15744	22514698	Our study is in agreement with recent reports, ZnPP alone shows no effect on MPT, however ZnPP in combination with triiodothyronine induced oxidative stress, MPT opening and apoptotic cell death.	('apoptotic cell death', 'CPA', (174, 194))	('oxidative stress', 'Phenotype', 'HP:0025464', (140, 156))	('ZnPP', 'Var', (90, 94))	('MPT', 'Chemical', '-', (77, 80))	('MPT opening', 'Disease', 'MESH:D005597', (158, 169))	('ZnPP', 'Chemical', 'MESH:C017803', (90, 94))	('MPT', 'Chemical', '-', (158, 161))	('MPT opening', 'Disease', (158, 169))	('triiodothyronine', 'Chemical', 'MESH:D014284', (115, 131))	('oxidative stress', 'MPA', (140, 156))	('ZnPP', 'Chemical', 'MESH:C017803', (47, 51))	('MPT', 'MPA', (77, 80))	('induced', 'Reg', (132, 139))
15751	22514698	In summary, HO-1 plays an important role in cytoprotection in both low and high HO-1 expressing CCA cells.	('HO-1', 'Gene', (80, 84))	('CCA', 'Phenotype', 'HP:0030153', (96, 99))	('high', 'Var', (75, 79))	('HO-1', 'Gene', (12, 16))	('HO-1', 'Gene', '3162', (80, 84))	('HO-1', 'Gene', '3162', (12, 16))	('CCA', 'Disease', (96, 99))
15752	22514698	Inhibition of HO-1 induced ROS formation, which may initiate the loss of Deltapsim and sensitizes CCA cells to a cytotoxic effect of anticancer agents.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('loss', 'NegReg', (65, 69))	('sensitizes', 'Reg', (87, 97))	('CCA', 'Phenotype', 'HP:0030153', (98, 101))	('ROS', 'Chemical', 'MESH:D017382', (27, 30))	('HO-1', 'Gene', '3162', (14, 18))	('ROS formation', 'MPA', (27, 40))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('CCA', 'Disease', (98, 101))	('Deltapsim', 'Protein', (73, 82))	('cancer', 'Disease', (137, 143))	('Inhibition', 'Var', (0, 10))	('HO-1', 'Gene', (14, 18))
15753	22514698	Thus, targeted suppression of HO-1 may be a strategy to overcome drug resistance in cholangiocarcinoma chemotherapy.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('targeted', 'Var', (6, 14))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))	('drug resistance', 'Phenotype', 'HP:0020174', (65, 80))	('cholangiocarcinoma', 'Disease', (84, 102))	('suppression', 'NegReg', (15, 26))	('HO-1', 'Gene', (30, 34))	('HO-1', 'Gene', '3162', (30, 34))
15780	32039389	The hazard ratio (HR) of HCC recurrence for patients with total tumour volume (TTV) <=115 cm3 and serum AFP <<400 ng/ml was 2.0 (95% CI 1.7-2.4), when compared to patients with TTV >>115 cm3 and serum AFP >>400 ng/ml.	('<=115 cm3', 'Var', (84, 93))	('patients', 'Species', '9606', (163, 171))	('patients', 'Species', '9606', (44, 52))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', (64, 70))	('HCC', 'Disease', 'MESH:D006528', (25, 28))	('HCC', 'Disease', (25, 28))	('HCC', 'Phenotype', 'HP:0001402', (25, 28))	('serum AFP', 'Var', (98, 107))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
15854	32039389	In the LT group, 70 patients were listed and 46 (66%) underwent LT. Transplantation was associated with improved OS compared to LR (64% vs. 18% 5-year OS, p <<0.001).	('improved', 'PosReg', (104, 112))	('patients', 'Species', '9606', (20, 28))	('Transplantation', 'Var', (68, 83))
15889	32039389	Mutations in KRAS, BAP1 and CDKN2A are related to a higher probability of recurrence, while mutations in FGFR2 are related to more indolent phenotype.	('BAP1', 'Gene', '8314', (19, 23))	('mutations', 'Var', (92, 101))	('CDKN2A', 'Gene', (28, 34))	('Mutations', 'Var', (0, 9))	('FGFR2', 'Gene', (105, 110))	('CDKN2A', 'Gene', '1029', (28, 34))	('KRAS', 'Gene', (13, 17))	('BAP1', 'Gene', (19, 23))	('KRAS', 'Gene', '3845', (13, 17))	('FGFR2', 'Gene', '2263', (105, 110))
15890	32039389	In hCCA, mutations in P53, BRCA1, BRCA2 and PIK3CA are related to a worse prognosis.	('PIK3CA', 'Gene', (44, 50))	('BRCA2', 'Gene', '675', (34, 39))	('BRCA1', 'Gene', '672', (27, 32))	('hCCA', 'Gene', (3, 7))	('CCA', 'Phenotype', 'HP:0030153', (4, 7))	('P53', 'Gene', '7157', (22, 25))	('mutations', 'Var', (9, 18))	('PIK3CA', 'Gene', '5290', (44, 50))	('BRCA1', 'Gene', (27, 32))	('hCCA', 'Gene', '2201', (3, 7))	('BRCA2', 'Gene', (34, 39))	('related', 'Reg', (55, 62))	('P53', 'Gene', (22, 25))
15922	32039389	Low CEA levels were also confirmed as a good prognostic factor by another study from an international consortium.	('CEA', 'Gene', (4, 7))	('CEA', 'Gene', '1084', (4, 7))	('Low', 'Var', (0, 3))
15927	32039389	The TRANSMET study contemplates additional criteria such as BRAF mutations, in order to exclude patients with aggressive tumour biology.	('aggressive tumour', 'Disease', 'MESH:D001523', (110, 127))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('aggressive tumour', 'Disease', (110, 127))	('patients', 'Species', '9606', (96, 104))	('mutations', 'Var', (65, 74))
15954	32039389	Risk factors for worse outcomes were primary tumour arising from the pancreas, resection of the primary tumour during the LT, presence of hepatomegaly, hepatic involvement >>50%, tumour bulk, poor differentiation, margin-positive and presence of lymph node involvement.	('hepatomegaly', 'Disease', (138, 150))	('margin-positive', 'Var', (214, 229))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('hepatomegaly', 'Phenotype', 'HP:0002240', (138, 150))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (179, 185))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('poor differentiation', 'CPA', (192, 212))	('hepatic involvement', 'Disease', 'MESH:D056486', (152, 171))	('hepatic involvement', 'Disease', (152, 171))	('tumour', 'Disease', (179, 185))	('tumour', 'Disease', (45, 51))	('tumour', 'Disease', (104, 110))	('hepatomegaly', 'Disease', 'MESH:D006529', (138, 150))
15987	31818290	With the current data, we concluded that HGD/CIS would increase the risk of local recurrence compared with R0, although it did not affect the prognosis of patients with extrahepatic cholangiocarcinoma regardless of TNM stage.	('TNM', 'Gene', (215, 218))	('CIS', 'Phenotype', 'HP:0030075', (45, 48))	('local', 'Disease', (76, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (182, 200))	('patients', 'Species', '9606', (155, 163))	('TNM', 'Gene', '10178', (215, 218))	('HGD/CIS', 'Var', (41, 48))	('extrahepatic cholangiocarcinoma regardless', 'Disease', 'MESH:D018281', (169, 211))	('extrahepatic cholangiocarcinoma regardless', 'Disease', (169, 211))
16015	31818290	Reasons are as follows: (1) the extent of cholangiocarcinoma infiltration is hard to diagnose preoperatively; (2) complex anatomy of extrahepatic bile duct often increases the risk of surgery in technique; (3) negative false incidence of intraoperative frozen section remains high.	('complex', 'Var', (114, 121))	('cholangiocarcinoma', 'Disease', (42, 60))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (42, 60))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (42, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
16017	31818290	Some argued that HGD/CIS affected the prognosis of patients with pN0M0, partly because the prognosis of patients at early stage might be more likely to be affected by the margin status than those at advanced stage.	('affected', 'Reg', (25, 33))	('CIS', 'Phenotype', 'HP:0030075', (21, 24))	('patients', 'Species', '9606', (51, 59))	('affected', 'Reg', (155, 163))	('patients', 'Species', '9606', (104, 112))	('pN0M0', 'Var', (65, 70))
16076	30215043	In contrast, hepatic artery resection and reconstruction was generally associated with higher morbidity and mortality without any additional survival advantage, which highlights the importance of preoperative identification of vascular involvement and allows surgeons to identify patients who are candidates for potentially curative resection.	('resection', 'Var', (28, 37))	('patients', 'Species', '9606', (280, 288))	('hepatic artery', 'Disease', (13, 27))
16279	21209818	Nowadays MRCP replaces the role of ERCP in the diagnosis of PSC because it is noninvasive with high sensitivity and specificity (both are greater than 80%) whereas ERCP can lead to potential serious complications such as pancreatitis and bacterial cholangitis.	('pancreatitis', 'Phenotype', 'HP:0001733', (221, 233))	('ERCP', 'Var', (164, 168))	('PSC', 'Gene', (60, 63))	('pancreatitis', 'Disease', 'MESH:D010195', (221, 233))	('bacterial cholangitis', 'Disease', (238, 259))	('cholangitis', 'Phenotype', 'HP:0030151', (248, 259))	('pancreatitis', 'Disease', (221, 233))	('bacterial cholangitis', 'Disease', 'MESH:D002761', (238, 259))	('PSC', 'Gene', '100653366', (60, 63))	('lead to', 'Reg', (173, 180))
16349	32703191	The protocol permitted dose modifications and cycle interruptions were as follows: white blood cells < 2000/mm3, neutrophils < 1000/mm3, platelet < 75,000/mm3, hemoglobin < 8.0 g/dL, adequate liver function (AST > 150 IU/L, ALT > 150 IU/L), serum total bilirubin > 3.0 mg/dL, serum creatinine > 1.5 mg/dL, and adverse events associated with gastrointestinal symptom >= Grade 3.	('AST', 'Gene', '26503', (208, 211))	('liver function', 'CPA', (192, 206))	('gastrointestinal symptom', 'Disease', (341, 365))	('adequate liver function', 'Phenotype', 'HP:0001410', (183, 206))	('serum creatinine', 'MPA', (276, 292))	('ALT', 'MPA', (224, 227))	('creatinine', 'Chemical', 'MESH:D003404', (282, 292))	('AST', 'Gene', (208, 211))	('< 2000/mm3', 'Var', (101, 111))	('< 1000/mm3', 'Var', (125, 135))	('bilirubin', 'Chemical', 'MESH:D001663', (253, 262))
16426	30255697	Intriguingly, eruption of these alterations reflects the genetic susceptibility to cholangiocarcinoma (CCA) which is a fetal sequel of this chronic disease (Sripa et al., 2012).	('cholangiocarcinoma', 'Disease', (83, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('alterations', 'Var', (32, 43))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))
16481	30255697	In addition, differences in PCNA expression were apparent in the in time series for the DMN (p<0.001) and OVDMN (p=0.002) groups but not in the control group (p=0.897).	('DMN', 'Chemical', '-', (88, 91))	('DMN', 'Var', (88, 91))	('expression', 'MPA', (33, 43))	('PCNA', 'Gene', (28, 32))	('DMN', 'Chemical', '-', (108, 111))
16489	30255697	At week 4, the relative mRNA level in the DMN and OVDMN groups was not different from that in the tissue from the normal and OV groups.	('mRNA level', 'MPA', (24, 34))	('OV', 'Species', '6198', (50, 52))	('DMN', 'Chemical', '-', (42, 45))	('DMN', 'Chemical', '-', (52, 55))	('DMN', 'Var', (42, 45))	('OV', 'Species', '6198', (125, 127))
16516	30255697	The lack of granulin can cause neurological diseases and susceptible to metabolic diseases (Nguyen et al., 2013).	('neurological diseases', 'Disease', 'MESH:D019636', (31, 52))	('metabolic diseases', 'Disease', (72, 90))	('granulin', 'Gene', (12, 20))	('cause', 'Reg', (25, 30))	('lack', 'Var', (4, 8))	('neurological diseases', 'Disease', (31, 52))	('metabolic diseases', 'Disease', 'MESH:D008659', (72, 90))	('granulin', 'Gene', '2896', (12, 20))
16517	30255697	By contrast, abnormal expression of granulin could lead to cancer development.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lead to', 'Reg', (51, 58))	('granulin', 'Gene', (36, 44))	('abnormal', 'Var', (13, 21))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('granulin', 'Gene', '2896', (36, 44))	('expression', 'MPA', (22, 32))
16523	30255697	So far, granulin is believed to involve in cancers at least in three alternatives: 1) increase in various cancers, 2) excessive granulin could stimulate cancer formation and growth, and 3) granulin inhibitors such as antibody or grn antisense could stop granulin formation and decrease cancer development (Cheung et al., 2004; Jone et al., 2003; Ong and Bateman, 2003).	('cancer', 'Disease', (153, 159))	('stop', 'NegReg', (249, 253))	('decrease', 'NegReg', (277, 285))	('granulin', 'Gene', (128, 136))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('granulin', 'Gene', (8, 16))	('cancers', 'Disease', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (106, 112))	('cancers', 'Disease', (106, 113))	('cancer', 'Disease', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('increase', 'PosReg', (86, 94))	('granulin', 'Gene', (254, 262))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('stimulate', 'PosReg', (143, 152))	('granulin', 'Gene', '2896', (128, 136))	('antisense', 'Var', (233, 242))	('granulin', 'Gene', '2896', (8, 16))	('growth', 'CPA', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('granulin', 'Gene', (189, 197))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('grn', 'Gene', (229, 232))	('granulin', 'Gene', '2896', (254, 262))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('cancer', 'Disease', (43, 49))	('grn', 'Gene', '2896', (229, 232))	('granulin', 'Gene', '2896', (189, 197))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
16567	24603802	Together, these data suggest that targeting XIAP in cholangiocarcinoma cells increases sensitivity to apoptosis.	('cholangiocarcinoma', 'Disease', (52, 70))	('sensitivity to apoptosis', 'CPA', (87, 111))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (52, 70))	('targeting', 'Var', (34, 43))	('XIAP', 'Gene', (44, 48))	('increases', 'PosReg', (77, 86))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (52, 70))	('XIAP', 'Gene', '331', (44, 48))
16607	24603802	Embelin treatment resulted in nuclear changes in the presence or absence of Z-VAD-fmk (Fig.	('Z-VAD-fmk', 'Var', (76, 85))	('absence', 'NegReg', (65, 72))	('Z-VAD-fmk', 'Chemical', 'MESH:C096713', (76, 85))	('resulted', 'Reg', (18, 26))	('nuclear changes', 'CPA', (30, 45))
16626	24603802	In a pancreatic cancer cell line, combined treatment with an antisense oligonucleotide to cFLIP, embelin, and TRAIL decreased cell viability compared to cFLIP antisense and TRAIL alone in a tetrazolium-based assay.	('cell viability', 'CPA', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (5, 22))	('tetrazolium', 'Chemical', 'MESH:D013778', (190, 201))	('embelin', 'Chemical', 'MESH:C010945', (97, 104))	('TRAIL', 'Gene', '8743', (110, 115))	('TRAIL', 'Gene', '8743', (173, 178))	('antisense oligonucleotide', 'Var', (61, 86))	('pancreatic cancer', 'Disease', (5, 22))	('TRAIL', 'Gene', (110, 115))	('oligonucleotide', 'Chemical', 'MESH:D009841', (71, 86))	('cFLIP', 'Gene', (90, 95))	('TRAIL', 'Gene', (173, 178))	('decreased', 'NegReg', (116, 125))	('pancreatic cancer', 'Disease', 'MESH:D010190', (5, 22))
16627	24603802	Because XIAP has a strong effect in cholangiocarcinoma cell lines to protect against cell death, we tested the effect of embelin on XIAP protein levels in human cholangiocarcinoma cell lines and found that embelin caused a reduction in XIAP in Mz-ChA-1 and KMCH cells.	('XIAP', 'Gene', '331', (236, 240))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (36, 54))	('cholangiocarcinoma cell lines', 'Disease', (161, 190))	('embelin', 'Chemical', 'MESH:C010945', (121, 128))	('XIAP', 'Gene', (132, 136))	('human', 'Species', '9606', (155, 160))	('XIAP', 'Gene', '331', (132, 136))	('cholangiocarcinoma cell lines', 'Disease', 'MESH:D018281', (36, 65))	('embelin', 'Chemical', 'MESH:C010945', (206, 213))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (161, 179))	('cholangiocarcinoma cell lines', 'Disease', (36, 65))	('XIAP', 'Gene', (8, 12))	('XIAP', 'Gene', '331', (8, 12))	('XIAP', 'Gene', (236, 240))	('reduction', 'NegReg', (223, 232))	('cholangiocarcinoma cell lines', 'Disease', 'MESH:D018281', (161, 190))	('embelin', 'Var', (206, 213))
16684	24603802	Mouse anti-XIAP antibody (#610717) was from BD Biosciences, and anti-actin antiserum was from SantaCruz.	('XIAP', 'Gene', (11, 15))	('#610717', 'Var', (26, 33))	('Mouse', 'Species', '10090', (0, 5))	('XIAP', 'Gene', '331', (11, 15))
16788	21789263	Furthermore, 80% of patients with microinvasion and/or satellitosis suffer recurrence within the first 2 years of followup after surgery.	('microinvasion', 'Var', (34, 47))	('suffer', 'Reg', (68, 74))	('patients', 'Species', '9606', (20, 28))	('satellitosis', 'Disease', (55, 67))	('satellitosis', 'Disease', 'None', (55, 67))
16800	21789263	Small cell change ("small cell dysplasia") is defined as hepatocytes exhibiting decreased cytoplasmic volume, cytoplasmic basophilia, mild nuclear pleomorphism, hyperchromasia, and increased nuclear-cytoplasmic ratio, giving an impression of nuclear crowding/increased cellular density.	('hyperchromasia', 'Disease', 'None', (161, 175))	('mild nuclear pleomorphism', 'Var', (134, 159))	('nuclear-cytoplasmic ratio', 'CPA', (191, 216))	('cell dysplasia', 'Disease', (26, 40))	('basophilia', 'Phenotype', 'HP:0031807', (122, 132))	('hyperchromasia', 'Disease', (161, 175))	('Small cell change', 'Disease', (0, 17))	('decreased', 'NegReg', (80, 89))	('cell dysplasia', 'Disease', 'MESH:C567703', (26, 40))	('increased', 'PosReg', (181, 190))
16826	21789263	Well known for its heterogeneity, HCC has variants and mixed lesions that may mimic other tumors.	('HCC', 'Gene', (34, 37))	('variants', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('HCC', 'Gene', '619501', (34, 37))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('HCC', 'Phenotype', 'HP:0001402', (34, 37))
16883	21789263	HCCs may exhibit focal CK19 positivity:this may imply poorer prognosis.	('HCC', 'Gene', (0, 3))	('positivity', 'Var', (28, 38))	('CK19', 'Gene', (23, 27))	('HCCs', 'Phenotype', 'HP:0001402', (0, 4))	('HCC', 'Phenotype', 'HP:0001402', (0, 3))	('HCC', 'Gene', '619501', (0, 3))	('CK19', 'Gene', '3880', (23, 27))
16922	21789263	The demonstration of AFP positivity points towards a malignant tumor of hepatocellular origin provided nonseminomatous germ cell tumors and extrahepatic AFP-producing carcinomas have been excluded.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('nonseminomatous germ cell tumors', 'Disease', (103, 135))	('AFP', 'Gene', (153, 156))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('positivity', 'Var', (25, 35))	('AFP', 'Gene', '174', (153, 156))	('nonseminomatous germ cell tumors', 'Disease', 'MESH:C537844', (103, 135))	('AFP', 'Gene', (21, 24))	('malignant tumor', 'Disease', 'MESH:D018198', (53, 68))	('malignant tumor', 'Disease', (53, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('AFP', 'Gene', '174', (21, 24))	('hepatocellular origin', 'Disease', (72, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('carcinomas', 'Disease', (167, 177))	('carcinomas', 'Disease', 'MESH:D002277', (167, 177))
16944	33017884	CASC15 knockout in ICC xenografts suppressed tumor development in vivo, decreased the expression of PRDX2 and Ki67 and inhibited PI3K/AKT pathway.	('AKT', 'Gene', (134, 137))	('PRDX2', 'Gene', '7001', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('suppressed', 'NegReg', (34, 44))	('decreased', 'NegReg', (72, 81))	('PRDX2', 'Gene', (100, 105))	('tumor', 'Disease', (45, 50))	('inhibited', 'NegReg', (119, 128))	('expression', 'MPA', (86, 96))	('AKT', 'Gene', '207', (134, 137))	('knockout', 'Var', (7, 15))	('CASC15', 'Gene', (0, 6))	('CASC15', 'Gene', '401237', (0, 6))	('Ki67', 'Gene', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
16952	33017884	For example, lncRNA-HOX transcript antisense RNA promotes prostate cancer, lncRNA-retinoic acid receptor-related orphan receptor (ROR) predicts poor prognosis in pancreatic cancer.	('antisense RNA', 'Var', (35, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (58, 73))	('pancreatic cancer', 'Disease', (162, 179))	('promotes', 'PosReg', (49, 57))	('pancreatic cancer', 'Disease', 'MESH:D010190', (162, 179))	('prostate cancer', 'Disease', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (162, 179))	('prostate cancer', 'Disease', 'MESH:D011471', (58, 73))
16974	33017884	The antibodies used were GAPDH (ab9485, Abcam, Cambridge, UK), caspase-8 (ab32397, Abcam), poly(adenosine diphosphate-ribose) polymerase (PARP) (ab32064, Abcam), BAX (ab32503, Abcam), cyclin E1 (ab33911, Abcam), cyclin D1 (ab134175, Abcam), cyclin B1 (ab32053, Abcam), CDK4 (ab108357, Abcam), CDK6 (ab124821, Abcam), p21 (ab109520, Abcam), N-cadherin (ab18203, Abcam), E-cadherin (ab15148, Abcam), PI3 kinase p110alpha (4255S, Cell Signaling Technology, Danvers, MA), AKT (9272S, CST), phospho-AKT (Ser473) (4060S, Cell Signaling Technology), c-Myc (9402S, Cell Signaling Technology), phospho-c-Myc (Ser62) (13748S, Cell Signaling Technology), and PRDX2 (10545-2-AP, Proteintech, Rocky Hill, NJ).	('CDK4', 'Gene', (269, 273))	('AKT', 'Gene', (468, 471))	('N-cadherin', 'Gene', (340, 350))	('caspase-8', 'Gene', '841', (63, 72))	('PRDX2', 'Gene', '7001', (648, 653))	('AKT', 'Gene', '207', (494, 497))	('N-cadherin', 'Gene', '1000', (340, 350))	('CDK6', 'Gene', '1021', (293, 297))	('PARP', 'Gene', '142', (138, 142))	('E-cadherin', 'Gene', (369, 379))	('E-cadherin', 'Gene', '999', (369, 379))	('CDK4', 'Gene', '1019', (269, 273))	('cyclin E1', 'Gene', (184, 193))	('p21', 'Gene', (317, 320))	('GAPDH', 'Gene', '2597', (25, 30))	('PARP', 'Gene', (138, 142))	('p110alpha', 'Gene', (409, 418))	('p21', 'Gene', '644914', (317, 320))	('p110alpha', 'Gene', '5290', (409, 418))	('c-Myc', 'Gene', (593, 598))	('cyclin D1', 'Gene', (212, 221))	('AKT', 'Gene', '207', (468, 471))	('CDK6', 'Gene', (293, 297))	('adenosine', 'Chemical', 'MESH:D000241', (96, 105))	('caspase-8', 'Gene', (63, 72))	('cyclin B1', 'Gene', (241, 250))	('cyclin B1', 'Gene', '891', (241, 250))	('c-Myc', 'Gene', '4609', (543, 548))	('GAPDH', 'Gene', (25, 30))	('CST', 'Gene', '106478911', (480, 483))	('c-Myc', 'Gene', '4609', (593, 598))	('cyclin D1', 'Gene', '595', (212, 221))	('AKT', 'Gene', (494, 497))	('10545-2-AP', 'Var', (655, 665))	('c-Myc', 'Gene', (543, 548))	('phosphate', 'Chemical', 'MESH:D010710', (108, 117))	('BAX', 'Gene', (162, 165))	('PRDX2', 'Gene', (648, 653))	('cyclin E1', 'Gene', '898', (184, 193))	('BAX', 'Gene', '581', (162, 165))	('CST', 'Gene', (480, 483))
17010	33017884	High expression of CASC15 indicated a poor prognosis, and the results were significant (Fig.	('CASC15', 'Gene', (19, 25))	('CASC15', 'Gene', '401237', (19, 25))	('High', 'Var', (0, 4))
17017	33017884	We used siRNA-CASC15 to knock down the expression of CASC15 in HuCCT1 and RBE.	('CASC15', 'Gene', (14, 20))	('CASC15', 'Gene', '401237', (14, 20))	('CASC15', 'Gene', (53, 59))	('CASC15', 'Gene', '401237', (53, 59))	('knock', 'Var', (24, 29))	('expression', 'MPA', (39, 49))
17018	33017884	In the Transwell assay, the migration and invasion of HuCCT1 and RBE cells considerably decreased when CASC15 was knocked down (Fig.	('knocked down', 'Var', (114, 126))	('CASC15', 'Gene', (103, 109))	('CASC15', 'Gene', '401237', (103, 109))	('decreased', 'NegReg', (88, 97))
17020	33017884	In HuCCT1 and RBE cells, the EdU-stained cell proportion was significantly decreased in the knockdown group compared to in the control group (Fig.	('EdU', 'Chemical', 'MESH:C031086', (29, 32))	('knockdown', 'Var', (92, 101))	('EdU-stained cell proportion', 'CPA', (29, 56))	('decreased', 'NegReg', (75, 84))
17021	33017884	The CCK-8 test showed that cell viability was decreased in the knockdown group at 24, 48, 72, and 96 hours (Fig.	('cell viability', 'CPA', (27, 41))	('knockdown', 'Var', (63, 72))	('decreased', 'NegReg', (46, 55))	('CCK-8', 'Chemical', '-', (4, 9))
17023	33017884	Western blotting showed that the expression of proteins relating to apoptosis such as BAX, cleaved PARP, and cleaved caspase-8 were increased in the knockdown group (Fig.	('PARP', 'Gene', (99, 103))	('cleaved', 'MPA', (91, 98))	('knockdown', 'Var', (149, 158))	('caspase-8', 'Gene', (117, 126))	('BAX', 'Gene', (86, 89))	('increased', 'PosReg', (132, 141))	('caspase-8', 'Gene', '841', (117, 126))	('expression of proteins', 'MPA', (33, 55))	('PARP', 'Gene', '142', (99, 103))	('BAX', 'Gene', '581', (86, 89))
17024	33017884	Knocking down the expression of CASC15 promoted the apoptosis of ICC cells.	('promoted', 'PosReg', (39, 47))	('Knocking down', 'Var', (0, 13))	('CASC15', 'Gene', (32, 38))	('CASC15', 'Gene', '401237', (32, 38))	('expression', 'MPA', (18, 28))	('apoptosis', 'CPA', (52, 61))
17025	33017884	After knocking down the expression of CASC15, G1/S transition was blocked (Fig.	('expression', 'MPA', (24, 34))	('G1/S transition', 'CPA', (46, 61))	('blocked', 'NegReg', (66, 73))	('CASC15', 'Gene', (38, 44))	('CASC15', 'Gene', '401237', (38, 44))	('knocking down', 'Var', (6, 19))
17031	33017884	TCGA revealed that the expression of PRDX2 was associated with disease-free survival of ICC (Fig.	('ICC', 'Disease', (88, 91))	('disease-free survival', 'CPA', (63, 84))	('expression', 'Var', (23, 33))	('PRDX2', 'Gene', '7001', (37, 42))	('PRDX2', 'Gene', (37, 42))	('associated', 'Reg', (47, 57))
17037	33017884	After knocking down PRDX2 expression, the proportion of cells in G1 phase increased, but the proportion of cells in S phase decreased, and western blotting revealed that the expression of cyclin B1 and cyclin D1 was reduced in the knockdown group (Fig.	('PRDX2', 'Gene', (20, 25))	('reduced', 'NegReg', (216, 223))	('cyclin B1', 'Gene', (188, 197))	('cyclin D1', 'Gene', (202, 211))	('cyclin B1', 'Gene', '891', (188, 197))	('expression', 'MPA', (174, 184))	('G1 phase', 'CPA', (65, 73))	('increased', 'PosReg', (74, 83))	('PRDX2', 'Gene', '7001', (20, 25))	('cyclin D1', 'Gene', '595', (202, 211))	('knocking down', 'Var', (6, 19))
17039	33017884	In the Transwell invasion experiment, knockdown of PRDX2 expression decreased the number of cells that passed through the Transwell (Fig.	('PRDX2', 'Gene', '7001', (51, 56))	('decreased', 'NegReg', (68, 77))	('knockdown', 'Var', (38, 47))	('PRDX2', 'Gene', (51, 56))
17041	33017884	When PRDX2 expression was knocked down in ICC cells, the IC50 of 5-FU was greatly decreased (S4B Fig.).	('knocked down', 'Var', (26, 38))	('IC50 of 5-FU', 'MPA', (57, 69))	('5-FU', 'Chemical', 'MESH:D005472', (65, 69))	('PRDX2', 'Gene', '7001', (5, 10))	('PRDX2', 'Gene', (5, 10))	('decreased', 'NegReg', (82, 91))
17042	33017884	Compared to the control group, apoptosis in the knockdown group was significantly increased in the presence of 10 ng/mL 5-FU (Fig.	('apoptosis', 'CPA', (31, 40))	('5-FU', 'Var', (120, 124))	('5-FU', 'Chemical', 'MESH:D005472', (120, 124))	('increased', 'PosReg', (82, 91))
17044	33017884	After knocking down the expression of PRDX2 in RBE and HUCCT1 cells, western blot analysis showed that the PI3K/AKT/c-Myc pathway was blocked.	('knocking', 'Var', (6, 14))	('PRDX2', 'Gene', '7001', (38, 43))	('PRDX2', 'Gene', (38, 43))	('expression', 'MPA', (24, 34))	('blocked', 'NegReg', (134, 141))	('AKT', 'Gene', '207', (112, 115))	('c-Myc', 'Gene', '4609', (116, 121))	('AKT', 'Gene', (112, 115))	('c-Myc', 'Gene', (116, 121))
17045	33017884	Additionally, the protein p21, which regulates the cell cycle, and downstream proteins of the PI3K/AKT pathway were decreased in the knockdown group (Fig.	('AKT', 'Gene', '207', (99, 102))	('cell cycle', 'CPA', (51, 61))	('knockdown', 'Var', (133, 142))	('AKT', 'Gene', (99, 102))	('p21', 'Gene', (26, 29))	('decreased', 'NegReg', (116, 125))	('p21', 'Gene', '644914', (26, 29))
17046	33017884	Western blot analysis showed that PI3K/AKT/c-Myc pathway was blocked in the CASC15 knockdown group (Fig.	('c-Myc', 'Gene', (43, 48))	('knockdown', 'Var', (83, 92))	('AKT', 'Gene', '207', (39, 42))	('c-Myc', 'Gene', '4609', (43, 48))	('blocked', 'NegReg', (61, 68))	('AKT', 'Gene', (39, 42))	('CASC15', 'Gene', (76, 82))	('CASC15', 'Gene', '401237', (76, 82))
17048	33017884	Additionally, overexpressed PRDX2 rescued the block of G1/S transition under knockdown of CASC15 (S5 Fig.).	('PRDX2', 'Gene', (28, 33))	('knockdown', 'Var', (77, 86))	('G1/S transition', 'CPA', (55, 70))	('CASC15', 'Gene', (90, 96))	('CASC15', 'Gene', '401237', (90, 96))	('PRDX2', 'Gene', '7001', (28, 33))
17051	33017884	Western blotting showed that the expression of PRDX2 was decreased in the CASC15 knockdown group (Fig.	('CASC15', 'Gene', (74, 80))	('knockdown', 'Var', (81, 90))	('CASC15', 'Gene', '401237', (74, 80))	('expression', 'MPA', (33, 43))	('PRDX2', 'Gene', '7001', (47, 52))	('decreased', 'NegReg', (57, 66))	('PRDX2', 'Gene', (47, 52))
17053	33017884	The decrease in PRDX2 and block of the PI3K/AKT pathway in the CASC15 knockdown group was rescued by adding MG132 (20 mug/mL for 2 hours) (Fig.	('knockdown', 'Var', (70, 79))	('AKT', 'Gene', '207', (44, 47))	('decrease', 'NegReg', (4, 12))	('MG132', 'Chemical', 'MESH:C072553', (108, 113))	('PRDX2', 'Gene', '7001', (16, 21))	('PRDX2', 'Gene', (16, 21))	('AKT', 'Gene', (44, 47))	('CASC15', 'Gene', (63, 69))	('CASC15', 'Gene', '401237', (63, 69))
17056	33017884	Knockdown of CASC15 decreased the growth of ICC in vivo (Fig.	('Knockdown', 'Var', (0, 9))	('decreased', 'NegReg', (20, 29))	('growth', 'MPA', (34, 40))	('ICC', 'Disease', (44, 47))	('CASC15', 'Gene', (13, 19))	('CASC15', 'Gene', '401237', (13, 19))
17057	33017884	IHC showed that the expression of PRDX2 decreased in the knockdown group compared to in the control group, which matched the result in cell lines.	('expression', 'MPA', (20, 30))	('PRDX2', 'Gene', (34, 39))	('knockdown', 'Var', (57, 66))	('decreased', 'NegReg', (40, 49))	('PRDX2', 'Gene', '7001', (34, 39))
17058	33017884	IHC also showed that PI3K/AKT signaling pathway was inhibited in the knockdown group.	('AKT', 'Gene', (26, 29))	('AKT', 'Gene', '207', (26, 29))	('knockdown', 'Var', (69, 78))	('inhibited', 'NegReg', (52, 61))
17063	33017884	In cell functional experiments and animal experiments, we found that knockdown of CASC15 inhibited the proliferation, mitosis, tumor formation, migration, and invasion of ICC cells, while it increased the apoptosis of ICC cells.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('apoptosis', 'CPA', (205, 214))	('mitosis', 'CPA', (118, 125))	('tumor', 'Disease', (127, 132))	('inhibited', 'NegReg', (89, 98))	('CASC15', 'Gene', (82, 88))	('increased', 'PosReg', (191, 200))	('CASC15', 'Gene', '401237', (82, 88))	('invasion', 'CPA', (159, 167))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('knockdown', 'Var', (69, 78))	('migration', 'CPA', (144, 153))
17066	33017884	Knockdown of CASC15 increased the expression of BAX, cleaved PARP, and cleaved caspase-8.	('increased', 'PosReg', (20, 29))	('cleaved', 'MPA', (53, 60))	('expression', 'MPA', (34, 44))	('caspase-8', 'Gene', (79, 88))	('PARP', 'Gene', (61, 65))	('caspase-8', 'Gene', '841', (79, 88))	('cleaved', 'Var', (71, 78))	('BAX', 'Gene', (48, 51))	('CASC15', 'Gene', (13, 19))	('CASC15', 'Gene', '401237', (13, 19))	('BAX', 'Gene', '581', (48, 51))	('PARP', 'Gene', '142', (61, 65))
17069	33017884	In the present study, knockdown of CASC15 decreased the expression of N-cadherin and migration and invasion of ICC cells.	('decreased', 'NegReg', (42, 51))	('N-cadherin', 'Gene', (70, 80))	('knockdown', 'Var', (22, 31))	('expression', 'MPA', (56, 66))	('N-cadherin', 'Gene', '1000', (70, 80))	('CASC15', 'Gene', (35, 41))	('CASC15', 'Gene', '401237', (35, 41))
17070	33017884	Thus, knockdown of CASC15 inhibited the migration and invasion of ICC cells.	('knockdown', 'Var', (6, 15))	('CASC15', 'Gene', (19, 25))	('CASC15', 'Gene', '401237', (19, 25))	('inhibited', 'NegReg', (26, 35))
17074	33017884	In our study, we showed that knockdown of PRDX2 inhibited the invasion of ICC cells, resulting in the block of G1/S transition and increasing the sensitivity to 5-FU.	('5-FU', 'Chemical', 'MESH:D005472', (161, 165))	('invasion of ICC cells', 'CPA', (62, 83))	('PRDX2', 'Gene', (42, 47))	('knockdown', 'Var', (29, 38))	('block', 'NegReg', (102, 107))	('G1/S transition', 'CPA', (111, 126))	('inhibited', 'NegReg', (48, 57))	('increasing', 'PosReg', (131, 141))	('sensitivity to 5-FU', 'MPA', (146, 165))	('PRDX2', 'Gene', '7001', (42, 47))
17087	33017884	We found that knockdown of CASC15 decreased the expression of PRDX2 and it was rescued by inhibiting proteasome formation, but we did not evaluate the mechanism or how it bound to the proteasome.	('PRDX2', 'Gene', '7001', (62, 67))	('PRDX2', 'Gene', (62, 67))	('decreased', 'NegReg', (34, 43))	('CASC15', 'Gene', '401237', (27, 33))	('expression', 'MPA', (48, 58))	('inhibiting', 'NegReg', (90, 100))	('knockdown', 'Var', (14, 23))	('CASC15', 'Gene', (27, 33))	('proteasome formation', 'MPA', (101, 121))
17187	27549595	The cure fraction for patients with a CA 19.9 < 50 U/ml and no lymph nodes metastases were 39.0 % versus only 5.1 % among patients with a CA 19.9 >= 50 who also had lymph node metastasis.	('patients', 'Species', '9606', (22, 30))	('metastases', 'Disease', (75, 85))	('patients', 'Species', '9606', (122, 130))	('CA 19.9 < 50 U/ml', 'Var', (38, 55))	('metastases', 'Disease', 'MESH:D009362', (75, 85))
17249	27549595	For example, while patients with a preoperative CA 19.9 <50 U/ml and no lymph nodes metastases had a cure fraction of 39 % and a time to cure of 4.1 years, patients who had a CA 19.9 > 50 U/ml and lymph nodes metastases had only a cure fraction of 5.1 % and a time to cure of 6.8 years.	('patients', 'Species', '9606', (156, 164))	('metastases', 'Disease', 'MESH:D009362', (209, 219))	('patients', 'Species', '9606', (19, 27))	('metastases', 'Disease', (84, 94))	('metastases', 'Disease', 'MESH:D009362', (84, 94))	('metastases', 'Disease', (209, 219))	('CA 19.9 <50 U/ml', 'Var', (48, 64))
17275	26410576	Furthermore, vorinostat-NPs have similar effectiveness in the suppression or expression of histone deacetylase, mutant type p53, p21, and PARP/cleaved caspase-3.	('vorinostat', 'Chemical', 'MESH:D000077337', (13, 23))	('expression', 'MPA', (77, 87))	('p53', 'Gene', (124, 127))	('histone deacetylase', 'Gene', (91, 110))	('caspase-3', 'Gene', '836', (151, 160))	('p53', 'Gene', '7157', (124, 127))	('mutant type', 'Var', (112, 123))	('suppression', 'MPA', (62, 73))	('PARP', 'Gene', '142', (138, 142))	('PARP', 'Gene', (138, 142))	('p21', 'Gene', (129, 132))	('histone deacetylase', 'Gene', '9734', (91, 110))	('p21', 'Gene', '644914', (129, 132))	('caspase-3', 'Gene', (151, 160))
17276	26410576	However, vorinostat-NPs showed improved antitumor activity against HuCC-T1 cancer cell-bearing mice compared to vorinostat, whereas empty nanoparticles had no effect on tumor growth.	('improved', 'PosReg', (31, 39))	('vorinostat-NPs', 'Var', (9, 23))	('mice', 'Species', '10090', (95, 99))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('cancer', 'Disease', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('vorinostat', 'Chemical', 'MESH:D000077337', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (169, 174))	('HuCC-T1', 'CellLine', 'CVCL:0324', (67, 74))	('vorinostat', 'Chemical', 'MESH:D000077337', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Disease', (44, 49))
17287	26410576	Accumulation of acetylated histones and acetylated proteins has correlation with p21WAF1 gene expression, apoptotic signals such as mutant-type p53 and active-type caspase expression, cell differentiation and cell death.	('p53', 'Gene', '7157', (144, 147))	('mutant-type', 'Var', (132, 143))	('acetylated', 'MPA', (16, 26))	('cell differentiation', 'CPA', (184, 204))	('expression', 'MPA', (94, 104))	('p21', 'Gene', (81, 84))	('p21', 'Gene', '644914', (81, 84))	('p53', 'Gene', (144, 147))
17332	26410576	In particular, vorinostat-NPs has higher cytotoxicity than vorinostat alone even though empty nanoparticles have small effect on the viability of cells.	('vorinostat-NPs', 'Var', (15, 29))	('vorinostat', 'Chemical', 'MESH:D000077337', (59, 69))	('higher', 'PosReg', (34, 40))	('cytotoxicity', 'Disease', (41, 53))	('vorinostat', 'Chemical', 'MESH:D000077337', (15, 25))	('cytotoxicity', 'Disease', 'MESH:D064420', (41, 53))
17339	26410576	3a, acetylated histone H3 was evidently increased upon treatment with 5 mug/ml vorinostat and vorinostat-NPs, whereas empty-NPs have no effect on this signal.	('vorinostat-NPs', 'Var', (94, 108))	('vorinostat', 'Chemical', 'MESH:D000077337', (79, 89))	('vorinostat', 'Chemical', 'MESH:D000077337', (94, 104))	('H3', 'Chemical', 'MESH:C012616', (23, 25))	('increased', 'PosReg', (40, 49))	('acetylated', 'MPA', (4, 14))
17345	26410576	One possible explanation of these results is that high concentrations of empty-NPs show some cytotoxic effects in the in vitro cell culture environment, even though LGE block copolymer has already been approved as a biocompatible polymer and approved for human use by the US FDA.	('cytotoxic effects', 'CPA', (93, 110))	('human', 'Species', '9606', (255, 260))	('polymer', 'Chemical', 'MESH:D011108', (230, 237))	('LGE', 'Chemical', '-', (165, 168))	('polymer', 'Chemical', 'MESH:D011108', (177, 184))	('empty-NPs', 'Var', (73, 82))	('copolymer', 'Chemical', '-', (175, 184))
17346	26410576	Figure 4A shows that the level of mutant p53 was significantly decreased both by vorinostat and vorinostat-NPs, whereas that of wild-type p53 was not significantly changed.	('p53', 'Gene', '7157', (41, 44))	('p53', 'Gene', (138, 141))	('vorinostat', 'Chemical', 'MESH:D000077337', (81, 91))	('decreased', 'NegReg', (63, 72))	('p53', 'Gene', '7157', (138, 141))	('vorinostat', 'Chemical', 'MESH:D000077337', (96, 106))	('vorinostat-NPs', 'Var', (96, 110))	('mutant', 'Var', (34, 40))	('p53', 'Gene', (41, 44))
17348	26410576	Upon immunocytochemical staining of HuCC-T1 cells, a decrease in mutant-type p53 and an increase in p21 were also observed.	('p21', 'Gene', (100, 103))	('mutant-type', 'Var', (65, 76))	('decrease', 'NegReg', (53, 61))	('p21', 'Gene', '644914', (100, 103))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('HuCC-T1', 'CellLine', 'CVCL:0324', (36, 43))
17353	26410576	Including the result of Bax expression, these results indicated that vorinostat-NPs induced apoptosis and affected the expression of apoptotic molecular signals to the same extent as did vorinostat.	('vorinostat-NPs', 'Var', (69, 83))	('apoptosis', 'CPA', (92, 101))	('Bax', 'Gene', '581', (24, 27))	('affected', 'Reg', (106, 114))	('vorinostat', 'Chemical', 'MESH:D000077337', (69, 79))	('expression of apoptotic molecular signals', 'MPA', (119, 160))	('vorinostat', 'Chemical', 'MESH:D000077337', (187, 197))	('Bax', 'Gene', (24, 27))
17354	26410576	On treatment with vorinostat or vorinostat-NPs, actin was disrupted in HuCC-T1 cells as shown in Fig.	('vorinostat', 'Chemical', 'MESH:D000077337', (32, 42))	('vorinostat-NPs', 'Var', (32, 46))	('vorinostat', 'Chemical', 'MESH:D000077337', (18, 28))	('vorinostat', 'Var', (18, 28))	('actin', 'MPA', (48, 53))	('disrupted', 'NegReg', (58, 67))	('HuCC-T1', 'CellLine', 'CVCL:0324', (71, 78))
17360	26410576	Interestingly, vorinostat-NPs showed higher efficacy of tumor growth inhibition: tumor volume following treatment of vorinostat-NPs was almost 50 % smaller than following treatment of vorinostat.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('vorinostat', 'Chemical', 'MESH:D000077337', (117, 127))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('vorinostat', 'Chemical', 'MESH:D000077337', (184, 194))	('vorinostat', 'Chemical', 'MESH:D000077337', (15, 25))	('smaller', 'NegReg', (148, 155))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('vorinostat-NPs', 'Var', (117, 131))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (81, 86))
17363	26410576	Interestingly, the expression of ac-histone H3 in tumor tissue was significantly increased upon treatment with vorinostat-NPs compared to empty-NPs and vorinostat as shown in Fig.	('expression', 'MPA', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('vorinostat', 'Chemical', 'MESH:D000077337', (111, 121))	('H3', 'Chemical', 'MESH:C012616', (44, 46))	('vorinostat-NPs', 'Var', (111, 125))	('ac-histone H3', 'Protein', (33, 46))	('ac-histone', 'Chemical', '-', (33, 43))	('vorinostat', 'Chemical', 'MESH:D000077337', (152, 162))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('increased', 'PosReg', (81, 90))	('tumor', 'Disease', (50, 55))
17364	26410576	Furthermore, the expression levels of HDAC 1, 2, 3 and 4/5/7 were relatively decreased upon treatment of vorinostat and vorinostat-NPs, compared to treatment of empty-NPs.	('expression levels', 'MPA', (17, 34))	('decreased', 'NegReg', (77, 86))	('vorinostat-NPs', 'Var', (120, 134))	('vorinostat', 'Chemical', 'MESH:D000077337', (105, 115))	('vorinostat', 'Chemical', 'MESH:D000077337', (120, 130))	('HDAC 1, 2, 3 and 4/5/7', 'Gene', '3065;3066;8841;9759;10014;51564', (38, 60))
17370	26410576	In particular, the strongest fluorescence intensity was observed at the center of the solid tumor at 1 day after treatment with NIR-NPs, whereas intact NIR-dye revealed the strongest fluorescence intensity in the region surrounding the solid tumor.	('solid tumor', 'Disease', (236, 247))	('solid tumor', 'Disease', 'MESH:D009369', (236, 247))	('NIR-NPs', 'Var', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('solid tumor', 'Disease', (86, 97))	('fluorescence intensity', 'MPA', (29, 51))	('solid tumor', 'Disease', 'MESH:D009369', (86, 97))
17378	26410576	Inhibition of the molecular action of HDAC using HDAC inhibitors is a promising candidate for cancer chemotherapy.	('HDAC', 'Gene', '9734', (38, 42))	('HDAC', 'Gene', (49, 53))	('HDAC', 'Gene', '9734', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Inhibition', 'Var', (0, 10))	('HDAC', 'Gene', (38, 42))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
17388	26410576	Vorinostat-NPs as well as vorinostat properly inhibited the growth of HuCC-T1 cells in vitro and the growth of tumor volume in vivo through inhibition of HDAC expression in the HuCC-T1 cells and tumor tissues, as shown in Figs.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', (195, 200))	('vorinostat', 'Var', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('HuCC-T1', 'CellLine', 'CVCL:0324', (70, 77))	('tumor', 'Disease', (111, 116))	('expression', 'MPA', (159, 169))	('inhibition', 'NegReg', (140, 150))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('growth', 'CPA', (60, 66))	('vorinostat', 'Chemical', 'MESH:D000077337', (26, 36))	('Vorinostat', 'Chemical', 'MESH:D000077337', (0, 10))	('HuCC-T1', 'CellLine', 'CVCL:0324', (177, 184))	('HDAC', 'Gene', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('inhibited', 'NegReg', (46, 55))	('HDAC', 'Gene', '9734', (154, 158))
17390	26410576	The apoptotic signals of HuCC-T1 cells were also significantly altered upon treatment with vorinostat or vorinostat-NPs in vitro and in vivo as shown in Figs.	('HuCC-T1', 'CellLine', 'CVCL:0324', (25, 32))	('altered', 'Reg', (63, 70))	('vorinostat-NPs', 'Var', (105, 119))	('vorinostat', 'Chemical', 'MESH:D000077337', (91, 101))	('vorinostat', 'Chemical', 'MESH:D000077337', (105, 115))	('apoptotic signals', 'CPA', (4, 21))
17391	26410576	4, levels of mutant p53 were significantly decreased with little change in wild-type p53 and this suppression is correlated with the expression of PARP/cleaved caspase-3.	('mutant', 'Var', (13, 19))	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('PARP', 'Gene', (147, 151))	('caspase-3', 'Gene', (160, 169))	('p53', 'Gene', '7157', (85, 88))	('caspase-3', 'Gene', '836', (160, 169))	('p53', 'Gene', (85, 88))	('levels', 'MPA', (3, 9))	('PARP', 'Gene', '142', (147, 151))	('decreased', 'NegReg', (43, 52))
17392	26410576	Other researchers have reported that the expression of mutant p53 was significantly decreased in a dose- and time-dependent manner.	('expression', 'MPA', (41, 51))	('mutant', 'Var', (55, 61))	('decreased', 'NegReg', (84, 93))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
17393	26410576	found that disruption of HDAC8 expression significantly inhibits proliferation of cancer cells having mutant-type p53 irrespective of wild-type p53.	('proliferation', 'CPA', (65, 78))	('HDAC8', 'Gene', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('p53', 'Gene', '7157', (144, 147))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('inhibits', 'NegReg', (56, 64))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('disruption', 'Var', (11, 21))	('HDAC8', 'Gene', '55869', (25, 30))	('mutant-type', 'Var', (102, 113))	('p53', 'Gene', (144, 147))
17394	26410576	In their results, colony formation of mutant-type p53 cell lines SW480 was remarkably decreased by treatment of vorinostat while wild-type p53 cell lines HCT116 showed little changes.	('HCT116', 'CellLine', 'CVCL:0291', (154, 160))	('SW480', 'CellLine', 'CVCL:0546', (65, 70))	('decreased', 'NegReg', (86, 95))	('p53', 'Gene', (139, 142))	('p53', 'Gene', (50, 53))	('mutant-type', 'Var', (38, 49))	('p53', 'Gene', '7157', (139, 142))	('vorinostat', 'Chemical', 'MESH:D000077337', (112, 122))	('p53', 'Gene', '7157', (50, 53))	('colony formation', 'CPA', (18, 34))
17395	26410576	Furthermore, both vorinostat-NPs and vorinostat were able to arrest cell growth and induced apoptosis as shown in Figs.	('induced', 'Reg', (84, 91))	('apoptosis', 'CPA', (92, 101))	('arrest cell growth', 'CPA', (61, 79))	('vorinostat', 'Chemical', 'MESH:D000077337', (18, 28))	('vorinostat', 'Chemical', 'MESH:D000077337', (37, 47))	('vorinostat-NPs', 'Var', (18, 32))
17398	26410576	Our results showed that vorinostat-incorporated nanoparticles as well as vorinostat itself also affects in induction of apoptotic signals, suppression of mutant-type p53, up-regulation of p21 and disruption of actin in HuCC-T1 cells.	('disruption', 'Reg', (196, 206))	('induction', 'MPA', (107, 116))	('p21', 'Gene', '644914', (188, 191))	('vorinostat', 'Chemical', 'MESH:D000077337', (24, 34))	('HuCC-T1', 'CellLine', 'CVCL:0324', (219, 226))	('actin', 'Protein', (210, 215))	('apoptotic signals', 'MPA', (120, 137))	('p53', 'Gene', (166, 169))	('p53', 'Gene', '7157', (166, 169))	('vorinostat', 'Chemical', 'MESH:D000077337', (73, 83))	('mutant-type', 'Var', (154, 165))	('suppression', 'NegReg', (139, 150))	('affects', 'Reg', (96, 103))	('up-regulation', 'PosReg', (171, 184))	('p21', 'Gene', (188, 191))
17575	25989801	In the ABC-02 trial, gemcitabine-cisplatin significantly improved overall survival (OS), progression-free survival (PFS), and tumor control rates compared with gemcitabine monotherapy.	('ABC', 'Gene', (7, 10))	('progression-free survival', 'CPA', (89, 114))	('overall', 'MPA', (66, 73))	('gemcitabine', 'Chemical', 'MESH:C056507', (21, 32))	('ABC', 'Gene', '10058', (7, 10))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('improved', 'PosReg', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('gemcitabine-cisplatin', 'Var', (21, 42))	('gemcitabine', 'Chemical', 'MESH:C056507', (160, 171))	('tumor', 'Disease', (126, 131))
17611	25989801	In the ABC-02 trial, significantly greater OS, PFS, and disease control rate were observed (p < 0.001 for OS and PFS; p=0.049 for disease control rate) in the gemcitabinecisplatin group compared with the gemcitabine only group.	('ABC', 'Gene', (7, 10))	('greater', 'PosReg', (35, 42))	('PFS', 'CPA', (47, 50))	('ABC', 'Gene', '10058', (7, 10))	('gemcitabine', 'Chemical', 'MESH:C056507', (159, 170))	('gemcitabine', 'Chemical', 'MESH:C056507', (204, 215))	('gemcitabinecisplatin', 'Chemical', '-', (159, 179))	('gemcitabinecisplatin', 'Var', (159, 179))	('disease control rate', 'CPA', (56, 76))
17614	25989801	However, in a meta-analysis of these two RCTs, significantly greater OS and PFS were observed (p < 0.001) in the gemcitabinecisplatin group than in the gemcitabine only group.	('gemcitabine', 'Chemical', 'MESH:C056507', (113, 124))	('greater', 'PosReg', (61, 68))	('gemcitabinecisplatin', 'Chemical', '-', (113, 133))	('gemcitabinecisplatin', 'Var', (113, 133))	('gemcitabine', 'Chemical', 'MESH:C056507', (152, 163))	('PFS', 'CPA', (76, 79))
17651	25989801	Compared with gemcitabine monotherapy, gemcitabine-cisplatin was associated with longer survival (OS and/or PFS) and greater response and disease control rates.	('longer', 'PosReg', (81, 87))	('gemcitabine-cisplatin', 'Var', (39, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('gemcitabine', 'Chemical', 'MESH:C056507', (14, 25))	('disease control', 'CPA', (138, 153))	('greater', 'PosReg', (117, 124))	('survival', 'MPA', (88, 96))	('gemcitabine', 'Chemical', 'MESH:C056507', (39, 50))	('response', 'CPA', (125, 133))
17676	25989801	This observation is supported by comparison of the British ABC-02 and Japanese BT 22 RCTs, which reported similar median OS (11.7 and 11.2 months) and treatment effects of gemcitabine-cisplatin compared with gemcitabine monotherapy (OS hazard ratios of 0.64 [95% CI, 0.52 to 0.80] and 0.69 [0.42 to 1.13]).	('ABC', 'Gene', (59, 62))	('gemcitabine', 'Chemical', 'MESH:C056507', (172, 183))	('gemcitabine', 'Chemical', 'MESH:C056507', (208, 219))	('cisplatin', 'Chemical', 'MESH:D002945', (184, 193))	('ABC', 'Gene', '10058', (59, 62))	('gemcitabine-cisplatin', 'Var', (172, 193))
17696	25369307	Therapeutic efforts in development are directed at several key pathways due to genetic aberrations including receptor tyrosine kinase pathways, mutant IDH enzymes, the PI3K-AKT-mTOR pathway, and chromatin remodeling networks.	('AKT', 'Gene', '207', (173, 176))	('mutant', 'Var', (144, 150))	('IDH', 'Gene', '3417', (151, 154))	('mTOR', 'Gene', (177, 181))	('AKT', 'Gene', (173, 176))	('mTOR', 'Gene', '2475', (177, 181))	('receptor tyrosine kinase', 'Gene', (109, 133))	('receptor tyrosine kinase', 'Gene', '5979', (109, 133))	('IDH', 'Gene', (151, 154))
17722	25369307	Consequently, iNOS activation results in inhibition of DNA repair proteins, and single-stranded, double-stranded, and oxidative DNA lesions.	('iNOS', 'Gene', '4843', (14, 18))	('iNOS', 'Gene', (14, 18))	('activation', 'PosReg', (19, 29))	('single-stranded', 'Var', (80, 95))	('DNA', 'MPA', (55, 58))	('double-stranded', 'Var', (97, 112))	('inhibition', 'NegReg', (41, 51))	('oxidative DNA lesions', 'MPA', (118, 139))
17732	25369307	A recent whole-exome sequencing analysis of eight liver O. viverrini-related tumors and matched normal tissue identified 206 somatic mutations in 187 genes.	('tumors', 'Disease', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutations', 'Var', (133, 142))	('O. viverrini', 'Species', '6198', (56, 68))
17734	25369307	Somatic mutations were identified in genes with a known association with malignancy, such as tumor protein 53 (TP53) found to be mutated in 44.4% of cases, Kristen ras sarcoma viral oncogene homolog (KRAS) mutated in 16.7% of cases, and SMAD4 that was mutated in 16.7% of cases.	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('KRAS', 'Gene', (200, 204))	('TP53', 'Gene', '7157', (111, 115))	('tumor protein 53', 'Gene', (93, 109))	('SMAD4', 'Gene', '4089', (237, 242))	('malignancy', 'Disease', 'MESH:D009369', (73, 83))	('TP53', 'Gene', (111, 115))	('malignancy', 'Disease', (73, 83))	('mutated', 'Var', (129, 136))	('KRAS', 'Gene', '3845', (200, 204))	('SMAD4', 'Gene', (237, 242))	('ras sarcoma viral', 'Disease', 'MESH:D001102', (164, 181))	('tumor protein 53', 'Gene', '7157', (93, 109))	('ras sarcoma viral', 'Disease', (164, 181))	('mutated', 'Var', (206, 213))
17735	25369307	In addition, mutations were found in several newly implicated oncogenes including MLL3 (mutated in 14.8% of cases), ROBO2 (9.3%), RNF43 (9.3%), PEG3 (5.6%), and GNAS (9.3%).	('ROBO2', 'Gene', '6092', (116, 121))	('RNF43', 'Gene', (130, 135))	('GNAS', 'Gene', (161, 165))	('MLL3', 'Gene', (82, 86))	('RNF43', 'Gene', '54894', (130, 135))	('PEG3', 'Gene', '5178', (144, 148))	('ROBO2', 'Gene', (116, 121))	('PEG3', 'Gene', (144, 148))	('mutations', 'Var', (13, 22))	('MLL3', 'Gene', '58508', (82, 86))	('GNAS', 'Gene', '2778', (161, 165))
17736	25369307	KRAS mutations were associated with a poor survival in this cohort of patients.	('patients', 'Species', '9606', (70, 78))	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('KRAS', 'Gene', '3845', (0, 4))
17740	25369307	BAP1 and isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) were noted to be mutated more frequently in nonliver-fluke-related CCAs, and TP53 mutations occurred with increased frequency in liver-fluke-related tumors.	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('mutated', 'Var', (72, 79))	('IDH2', 'Gene', '3418', (49, 53))	('nonliver-fluke-related CCAs', 'Disease', (99, 126))	('BAP1', 'Gene', (0, 4))	('CCA', 'Phenotype', 'HP:0030153', (122, 125))	('liver-fluke', 'Species', '6192', (102, 113))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('IDH1', 'Gene', (43, 47))	('isocitrate', 'Chemical', 'MESH:C034219', (9, 19))	('IDH1', 'Gene', '3417', (43, 47))	('tumors', 'Disease', (204, 210))	('IDH2', 'Gene', (49, 53))	('BAP1', 'Gene', '8314', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('liver-fluke', 'Species', '6192', (184, 195))
17741	25369307	Inactivating mutations of chromatin-remodeling genes such as BAP1, ARID1A, and PBRM1 were also identified in exome sequencing of 32 iCCAs.	('BAP1', 'Gene', (61, 65))	('PBRM1', 'Gene', (79, 84))	('Inactivating mutations', 'Var', (0, 22))	('PBRM1', 'Gene', '55193', (79, 84))	('BAP1', 'Gene', '8314', (61, 65))	('ARID1A', 'Gene', '8289', (67, 73))	('CCA', 'Phenotype', 'HP:0030153', (133, 136))	('ARID1A', 'Gene', (67, 73))
17742	25369307	Mutations in genes encoding protein tyrosine phosphatases, particularly PTPN3, have been recently reported in iCCA.	('iCCA', 'Disease', (110, 114))	('PTPN3', 'Gene', '5774', (72, 77))	('Mutations', 'Var', (0, 9))	('PTPN3', 'Gene', (72, 77))	('CCA', 'Phenotype', 'HP:0030153', (111, 114))	('ros', 'Chemical', '-', (38, 41))	('reported', 'Reg', (98, 106))
17743	25369307	Whole-exome sequencing of seven pairs of iCCA tumors and the surrounding nontumor tissue identified mutations in nine genes encoding protein tyrosine phosphatases.	('mutations', 'Var', (100, 109))	('CCA tumors', 'Disease', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (46, 51))	('CCA', 'Phenotype', 'HP:0030153', (42, 45))	('CCA tumors', 'Disease', 'MESH:C536211', (42, 52))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('ros', 'Chemical', '-', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
17744	25369307	A prevalence screen of 124 paired samples was then conducted and identified somatic mutations in at least one of these nine protein tyrosine phosphatase genes in 51.6% of iCCAs, including PTPN3 mutations in 41.1% of iCCAs.	('PTPN3', 'Gene', (188, 193))	('CCA', 'Phenotype', 'HP:0030153', (172, 175))	('mutations', 'Var', (194, 203))	('CCA', 'Phenotype', 'HP:0030153', (217, 220))	('mutations', 'Var', (84, 93))	('ros', 'Chemical', '-', (134, 137))	('PTPN3', 'Gene', '5774', (188, 193))
17748	25369307	Features of the proliferation class, consisting of 62% of the analyzed iCCAs, included activation of oncogenic signaling pathways (such as RAS, mitogen-activated protein kinase, and MET), KRAS and BRAF mutations, DNA amplifications at 11q13.2, and deletions at 14q22.1.	('RAS', 'Protein', (139, 142))	('activation', 'PosReg', (87, 97))	('BRAF', 'Gene', (197, 201))	('BRAF', 'Gene', '673', (197, 201))	('oncogenic signaling pathways', 'Pathway', (101, 129))	('MET', 'Pathway', (182, 185))	('KRAS', 'Gene', (188, 192))	('deletions', 'Var', (248, 257))	('CCA', 'Phenotype', 'HP:0030153', (72, 75))	('DNA amplifications', 'Var', (213, 231))	('KRAS', 'Gene', '3845', (188, 192))	('mitogen-activated protein kinase', 'Pathway', (144, 176))	('mutations', 'Var', (202, 211))
17749	25369307	In a recent integrated genomic analyses of 104 iCCAs and 59 matched controls, unique subclasses of patients were identified on the basis of KRAS mutations, early recurrence, and overall survival time.	('KRAS', 'Gene', '3845', (140, 144))	('mutations', 'Var', (145, 154))	('CCA', 'Phenotype', 'HP:0030153', (48, 51))	('patients', 'Species', '9606', (99, 107))	('KRAS', 'Gene', (140, 144))
17751	25369307	Activating mutations of KRAS and loss-of-function mutations of TP53 are a common occurrence in CCA.	('KRAS', 'Gene', '3845', (24, 28))	('TP53', 'Gene', '7157', (63, 67))	('mutations', 'Var', (50, 59))	('TP53', 'Gene', (63, 67))	('CCA', 'Disease', (95, 98))	('CCA', 'Phenotype', 'HP:0030153', (95, 98))	('loss-of-function', 'NegReg', (33, 49))	('KRAS', 'Gene', (24, 28))
17752	25369307	TP53 mutations were reported in 21% of CCAs in a review of studies with an aggregate of 229 CCA patients.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('CCA', 'Phenotype', 'HP:0030153', (92, 95))	('patients', 'Species', '9606', (96, 104))	('CCAs', 'Disease', (39, 43))	('CCA', 'Phenotype', 'HP:0030153', (39, 42))
17753	25369307	Direct DNA sequencing analysis of 69 CCAs identified KRAS and BRAF mutations in 22% and 45% of tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('mutations', 'Var', (67, 76))	('KRAS', 'Gene', '3845', (53, 57))	('CCAs', 'Disease', (37, 41))	('KRAS', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('CCA', 'Phenotype', 'HP:0030153', (37, 40))	('tumors', 'Disease', (95, 101))
17754	25369307	Mutations have also been reported in other genes, albeit less frequently, including EGFR, PIK3CA, NRAS, and APC.	('APC', 'Disease', 'MESH:D011125', (108, 111))	('NRAS', 'Gene', (98, 102))	('PIK3CA', 'Gene', (90, 96))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', '4893', (98, 102))	('APC', 'Disease', (108, 111))	('EGFR', 'Gene', (84, 88))	('PIK3CA', 'Gene', '5290', (90, 96))
17762	25369307	Consequently, IL-6 inhibition reduces Mcl-1 expression and enhances TRAIL-mediated apoptosis.	('TRAIL', 'Gene', '8743', (68, 73))	('inhibition', 'Var', (19, 29))	('TRAIL', 'Gene', (68, 73))	('Mcl-1', 'Gene', (38, 43))	('enhances', 'PosReg', (59, 67))	('IL-6', 'Gene', (14, 18))	('reduces', 'NegReg', (30, 37))	('IL-6', 'Gene', '3569', (14, 18))	('Mcl-1', 'Gene', '4170', (38, 43))
17764	25369307	A suppressor of cytokine signaling 3 (SOCS) regulates the IL-6/STAT-3 signaling pathway in a feedback manner, and epigenetic silencing of SOCS-3 facilitates sustained IL-6/STAT-3 signaling with resultant enhanced Mcl-1 expression.	('SOCS-3', 'Gene', '9021', (138, 144))	('SOCS-3', 'Gene', (138, 144))	('SOCS', 'Gene', '1154', (138, 142))	('SOCS', 'Gene', (138, 142))	('Mcl-1', 'Gene', (213, 218))	('regulates', 'Reg', (44, 53))	('facilitates', 'PosReg', (145, 156))	('STAT-3', 'Gene', (63, 69))	('IL-6', 'Gene', '3569', (58, 62))	('epigenetic silencing', 'Var', (114, 134))	('STAT-3', 'Gene', (172, 178))	('IL-6', 'Gene', '3569', (167, 171))	('IL-6', 'Gene', (58, 62))	('STAT-3', 'Gene', '6774', (63, 69))	('enhanced', 'PosReg', (204, 212))	('expression', 'MPA', (219, 229))	('IL-6', 'Gene', (167, 171))	('SOCS', 'Gene', '1154', (38, 42))	('STAT-3', 'Gene', '6774', (172, 178))	('SOCS', 'Gene', (38, 42))	('Mcl-1', 'Gene', '4170', (213, 218))
17765	25369307	For example, neutralizing antibodies to IL-6 are in human clinical trials and may be therapeutic in CCA.	('IL-6', 'Gene', (40, 44))	('CCA', 'Phenotype', 'HP:0030153', (100, 103))	('human', 'Species', '9606', (52, 57))	('neutralizing antibodies', 'Var', (13, 36))	('IL-6', 'Gene', '3569', (40, 44))	('CCA', 'Disease', (100, 103))
17776	25369307	Moreover, ERBB2 amplification was recently described in a cohort of 100 CCA patients, with a reported prevalence of 3%.	('patients', 'Species', '9606', (76, 84))	('CCA', 'Disease', (72, 75))	('amplification', 'Var', (16, 29))	('ERBB2', 'Gene', (10, 15))	('CCA', 'Phenotype', 'HP:0030153', (72, 75))
17782	25369307	Loss of function mutation in ERRFI1, an endogenous inhibitor of EGFR, ERBB2, ERBB3, and ERBB4, was detected in a patient with metastatic, treatment refractory iCCA.	('ERBB3', 'Gene', (77, 82))	('patient', 'Species', '9606', (113, 120))	('ERBB4', 'Gene', (88, 93))	('mutation', 'Var', (17, 25))	('CCA', 'Phenotype', 'HP:0030153', (160, 163))	('Loss of function', 'NegReg', (0, 16))	('iCCA', 'Disease', (159, 163))	('ERBB4', 'Gene', '2066', (88, 93))	('ERBB3', 'Gene', '2065', (77, 82))	('ERRFI1', 'Gene', '54206', (29, 35))	('ERRFI1', 'Gene', (29, 35))
17788	25369307	MET amplification has been described in malignancies including gastric, esophageal, ovarian, and nonsmall cell lung cancer, and is associated with a poor clinical outcome.	('esophageal', 'Disease', 'MESH:D004941', (72, 82))	('malignancies', 'Disease', (40, 52))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (100, 122))	('MET amplification', 'Var', (0, 17))	('described', 'Reg', (27, 36))	('nonsmall cell lung cancer', 'Disease', (97, 122))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (97, 122))	('gastric', 'Disease', (63, 70))	('esophageal', 'Disease', (72, 82))	('associated', 'Reg', (131, 141))	('ovarian', 'Disease', (84, 91))	('malignancies', 'Disease', 'MESH:D009369', (40, 52))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))
17791	25369307	Crizotinib, cabozantinib, and tivozanib have therapeutic potential in targeted cancer chemotherapy of CCA tumors with MET amplification (Fig.	('CCA tumors', 'Disease', (102, 112))	('tivozanib', 'Chemical', 'MESH:C553176', (30, 39))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('CCA', 'Phenotype', 'HP:0030153', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cabozantinib', 'Chemical', 'MESH:C558660', (12, 24))	('CCA tumors', 'Disease', 'MESH:C536211', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Disease', (79, 85))	('MET amplification', 'Var', (118, 135))
17796	25369307	In tumors harboring Kras and p53 mutations, FIG-ROS inactivation led to the inhibition of tumor growth.	('FIG-ROS', 'Protein', (44, 51))	('inhibition', 'NegReg', (76, 86))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Disease', (3, 8))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('ROS', 'Chemical', '-', (48, 51))	('mutations', 'Var', (33, 42))	('p53', 'Gene', (29, 32))	('inactivation', 'NegReg', (52, 64))	('Kras', 'Gene', (20, 24))	('p53', 'Gene', '7157', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('Kras', 'Gene', '3845', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
17797	25369307	Accordingly, ROS1 inhibitors have potential as targeted therapy in a subset of patients harboring ROS1 fusion proteins.	('ROS1', 'Gene', (98, 102))	('ROS1', 'Gene', (13, 17))	('ROS1', 'Gene', '6098', (98, 102))	('ROS1', 'Gene', '6098', (13, 17))	('fusion', 'Var', (103, 109))	('patients', 'Species', '9606', (79, 87))
17802	25369307	Fusions of the FGFR gene have been reported in solid cancers.	('Fusions', 'Var', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('reported', 'Reg', (35, 43))	('solid cancers', 'Disease', (47, 60))	('solid cancers', 'Disease', 'MESH:D009369', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('FGFR', 'Gene', (15, 19))
17803	25369307	Gene fusions are a class of driver mutations with an essential role in certain cancers, such as the BCR-ABL gene in chronic myeloid leukemia.	('cancers', 'Disease', (79, 86))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (116, 140))	('myeloid leukemia', 'Disease', (124, 140))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Gene fusions', 'Var', (0, 12))	('BCR-ABL', 'Gene', '25', (100, 107))	('myeloid leukemia', 'Disease', 'MESH:D007951', (124, 140))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (124, 140))	('BCR-ABL', 'Gene', (100, 107))	('leukemia', 'Phenotype', 'HP:0001909', (132, 140))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
17807	25369307	In addition to detecting several cases with FGFR2-BICC1 fusions, a single case of a novel FGFR gene fusion, FGFR2-AHCYL1, was also identified in this cohort.	('fusions', 'Var', (56, 63))	('AHCYL1', 'Gene', '10768', (114, 120))	('BICC1', 'Gene', (50, 55))	('FGFR2', 'Gene', (108, 113))	('FGFR2', 'Gene', '2263', (108, 113))	('BICC1', 'Gene', '80114', (50, 55))	('FGFR2', 'Gene', '2263', (44, 49))	('FGFR2', 'Gene', (44, 49))	('AHCYL1', 'Gene', (114, 120))
17808	25369307	More recently, single cases of FGFR2-MGEA5 and FGFR2-TACC3 gene fusions have been described in iCCA.	('iCCA', 'Disease', (95, 99))	('MGEA5', 'Gene', '10724', (37, 42))	('FGFR2', 'Gene', (31, 36))	('FGFR2', 'Gene', '2263', (31, 36))	('CCA', 'Phenotype', 'HP:0030153', (96, 99))	('MGEA5', 'Gene', (37, 42))	('fusions', 'Var', (64, 71))	('TACC3', 'Gene', '10460', (53, 58))	('FGFR2', 'Gene', (47, 52))	('TACC3', 'Gene', (53, 58))	('FGFR2', 'Gene', '2263', (47, 52))
17809	25369307	Overexpression of FGFR2-BICC1 is associated with enhanced cell proliferation and altered cell morphology.	('FGFR2', 'Gene', (18, 23))	('cell morphology', 'CPA', (89, 104))	('FGFR2', 'Gene', '2263', (18, 23))	('enhanced', 'PosReg', (49, 57))	('BICC1', 'Gene', '80114', (24, 29))	('cell proliferation', 'CPA', (58, 76))	('BICC1', 'Gene', (24, 29))	('Overexpression', 'Var', (0, 14))	('altered', 'Reg', (81, 88))
17810	25369307	Based on mechanistic studies, Wu et al proposed that FGFR fusion partners mediate oligomerizations, which initiates activation of the respective FGFR kinase in tumors harboring these mutations.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('mediate', 'Reg', (74, 81))	('FGFR', 'Gene', (145, 149))	('mutations', 'Var', (183, 192))	('activation', 'PosReg', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('oligomerizations', 'MPA', (82, 98))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
17812	25369307	Indeed, FGFR genetic alterations have been reported to be the most significant predictor for sensitivity to the pan-FGFR inhibitor BGJ398.	('sensitivity', 'MPA', (93, 104))	('FGFR', 'Gene', (8, 12))	('genetic alterations', 'Var', (13, 32))	('BGJ398', 'Chemical', 'MESH:C568950', (131, 137))
17814	25369307	Clinical efficacy of BGJ398 is currently being investigated in a phase I study in adult patients with advanced solid tumors harboring FGFR1/FGFR2 amplification or FGFR3 mutation (ClinicalTrials.gov identifier: NCT01004224).	('amplification', 'Var', (146, 159))	('FGFR2', 'Gene', '2263', (140, 145))	('solid tumors', 'Disease', 'MESH:D009369', (111, 123))	('mutation', 'Var', (169, 177))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('BGJ398', 'Chemical', 'MESH:C568950', (21, 27))	('FGFR1', 'Gene', (134, 139))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('patients', 'Species', '9606', (88, 96))	('FGFR1', 'Gene', '2260', (134, 139))	('FGFR3', 'Gene', '2261', (163, 168))	('FGFR3', 'Gene', (163, 168))	('solid tumors', 'Disease', (111, 123))	('FGFR2', 'Gene', (140, 145))
17815	25369307	Targeted therapy with ponatinib, another pan-FGFR inhibitor, in an iCCA patient with the FGFR2-MGEA5 fusion resulted in a decrease in tumor necrosis and levels of the tumor marker, CA 19-9.	('fusion', 'Var', (101, 107))	('FGFR2', 'Gene', '2263', (89, 94))	('CCA', 'Phenotype', 'HP:0030153', (68, 71))	('tumor necrosis', 'Disease', (134, 148))	('decrease', 'NegReg', (122, 130))	('ponatinib', 'Chemical', 'MESH:C545373', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor necrosis', 'Disease', 'MESH:D009336', (134, 148))	('patient', 'Species', '9606', (72, 79))	('MGEA5', 'Gene', '10724', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('MGEA5', 'Gene', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('FGFR2', 'Gene', (89, 94))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', (134, 139))
17816	25369307	Ponatinib also demonstrated preliminary antitumor activity with tumor-size reduction in an iCCA patient harboring the FGFR2-TACC3 fusion.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('fusion', 'Var', (130, 136))	('tumor', 'Disease', (64, 69))	('TACC3', 'Gene', '10460', (124, 129))	('patient', 'Species', '9606', (96, 103))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('FGFR2', 'Gene', (118, 123))	('FGFR2', 'Gene', '2263', (118, 123))	('Ponatinib', 'Chemical', 'MESH:C545373', (0, 9))	('reduction', 'NegReg', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('TACC3', 'Gene', (124, 129))	('tumor', 'Disease', (44, 49))	('CCA', 'Phenotype', 'HP:0030153', (92, 95))
17819	25369307	IDH1 and IDH2 mutations have been reported in 10% to 28% of cholangiocarcinomas, occurring primarily in iCCA.	('IDH2', 'Gene', (9, 13))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (60, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (60, 78))	('IDH2', 'Gene', '3418', (9, 13))	('cholangiocarcinomas', 'Disease', (60, 79))	('CCA', 'Phenotype', 'HP:0030153', (105, 108))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('IDH1', 'Gene', '3417', (0, 4))
17820	25369307	In a cohort of 94 CCA cases, the prevalence of IDH1 and IDH2 mutations was 15% and 7%, respectively.	('CCA', 'Disease', (18, 21))	('IDH2', 'Gene', '3418', (56, 60))	('IDH1', 'Gene', (47, 51))	('mutations', 'Var', (61, 70))	('CCA', 'Phenotype', 'HP:0030153', (18, 21))	('IDH1', 'Gene', '3417', (47, 51))	('IDH2', 'Gene', (56, 60))
17821	25369307	IDH mutations were associated with clear cell change, poorly differentiated histology, and longer overall survival.	('associated', 'Reg', (19, 29))	('poorly differentiated histology', 'CPA', (54, 85))	('longer', 'PosReg', (91, 97))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('clear', 'Disease', (35, 40))	('mutations', 'Var', (4, 13))
17822	25369307	Similarly, in a separate cohort of 326 iCCA patients, IDH mutations had a prevalence of 10% and were associated with longer overall survival and longer time to recurrence.	('overall survival', 'MPA', (124, 140))	('mutations', 'Var', (58, 67))	('patients', 'Species', '9606', (44, 52))	('longer', 'PosReg', (117, 123))	('IDH', 'Gene', (54, 57))	('IDH', 'Gene', '3417', (54, 57))	('CCA', 'Phenotype', 'HP:0030153', (40, 43))
17824	25369307	IDH2 mutations are observed less frequently in iCCA with a prevalence of 27% compared with 73% prevalence of IDH1 mutations.	('IDH1', 'Gene', (109, 113))	('CCA', 'Phenotype', 'HP:0030153', (48, 51))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', '3417', (109, 113))	('IDH2', 'Gene', (0, 4))	('IDH2', 'Gene', '3418', (0, 4))
17825	25369307	A range of IDH1/2 mutations exists and varies according to the IDH amino acid residues mutated.	('IDH', 'Gene', (11, 14))	('IDH', 'Gene', '3417', (11, 14))	('IDH1/2', 'Gene', '3417;3418', (11, 17))	('IDH', 'Gene', (63, 66))	('IDH', 'Gene', '3417', (63, 66))	('IDH1/2', 'Gene', (11, 17))	('mutations', 'Var', (18, 27))
17826	25369307	Arginine 132 (R132), IDH1 R132C, is mutated in 44% of iCCA cases whereas IDH1 R132G alteration is seen in 14% iCCAs containing mutated samples.	('R132', 'Var', (14, 18))	('R132C', 'Mutation', 'rs121913499', (26, 31))	('R132G', 'Mutation', 'rs121913499', (78, 83))	('IDH1', 'Gene', '3417', (73, 77))	('CCA', 'Phenotype', 'HP:0030153', (55, 58))	('Arginine', 'Chemical', 'MESH:D001120', (0, 8))	('IDH1', 'Gene', (21, 25))	('CCA', 'Phenotype', 'HP:0030153', (111, 114))	('IDH1', 'Gene', (73, 77))	('iCCA', 'Disease', (54, 58))	('IDH1', 'Gene', '3417', (21, 25))
17827	25369307	The mutated IDH enzymes convert alpha-ketoglutarate to 2-hydroxyglutarate (2-HG) rather than isocitrate, resulting in an approximate100-fold increase in levels of this oncometabolite in IDH-mutant tumors.	('mutated', 'Var', (4, 11))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('2-HG', 'Chemical', 'MESH:C019417', (75, 79))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (32, 51))	('increase', 'PosReg', (141, 149))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (55, 73))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('isocitrate', 'Chemical', 'MESH:C034219', (93, 103))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('IDH', 'Gene', (186, 189))	('IDH', 'Gene', '3417', (186, 189))	('tumors', 'Disease', (197, 203))	('levels of', 'MPA', (153, 162))
17828	25369307	As 2-HG is present in negligible amounts in normal cells, it has utility as a biomarker in patients with IDH mutations who may be candidates for therapy with IDH inhibitors.	('IDH', 'Gene', '3417', (105, 108))	('IDH', 'Gene', '3417', (158, 161))	('patients', 'Species', '9606', (91, 99))	('2-HG', 'Chemical', 'MESH:C019417', (3, 7))	('IDH', 'Gene', (105, 108))	('mutations', 'Var', (109, 118))	('IDH', 'Gene', (158, 161))
17840	25369307	Deregulation of the PI3K-AKT-mTOR pathway fosters tumor development, cell proliferation and survival, tumor invasion, and angiogenesis.	('AKT', 'Gene', (25, 28))	('Deregulation', 'Var', (0, 12))	('mTOR', 'Gene', (29, 33))	('fosters', 'PosReg', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('mTOR', 'Gene', '2475', (29, 33))	('cell proliferation', 'CPA', (69, 87))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('AKT', 'Gene', '207', (25, 28))	('angiogenesis', 'CPA', (122, 134))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', (50, 55))
17841	25369307	PIK3CA mutations were identified in 5 of 94 resected CCA specimens using MassARRAY technology.	('mutations', 'Var', (7, 16))	('PIK3CA', 'Gene', (0, 6))	('CCA', 'Disease', (53, 56))	('PIK3CA', 'Gene', '5290', (0, 6))	('CCA', 'Phenotype', 'HP:0030153', (53, 56))
17842	25369307	In a cohort of Chinese CCA patients, PIK3CA mutations were identified in 34.2% of cases.	('PIK3CA', 'Gene', '5290', (37, 43))	('CCA', 'Disease', (23, 26))	('patients', 'Species', '9606', (27, 35))	('mutations', 'Var', (44, 53))	('CCA', 'Phenotype', 'HP:0030153', (23, 26))	('PIK3CA', 'Gene', (37, 43))
17847	25369307	GDC-0980, an orally bioavailable potent inhibitor of class I PI3K and mTOR kinase, and BAY 80-6946, a highly selective and potent pan-class PI3K inhibitor, are entering clinical studies.	('mTOR', 'Gene', (70, 74))	('mTOR', 'Gene', '2475', (70, 74))	('BAY 80-6946', 'Var', (87, 98))	('GDC-0980', 'Gene', (0, 8))	('BAY 80-6946', 'Chemical', 'MESH:C000589253', (87, 98))	('PI3K', 'Enzyme', (61, 65))	('GDC-0980', 'Chemical', 'MESH:C569670', (0, 8))
17849	25369307	Mutations in KRAS have been frequently described in CCA, along with other mutations in NRAS, BRAF, and downstream MAPK effector pathways.	('BRAF', 'Gene', (93, 97))	('CCA', 'Disease', (52, 55))	('NRAS', 'Gene', '4893', (87, 91))	('KRAS', 'Gene', '3845', (13, 17))	('CCA', 'Phenotype', 'HP:0030153', (52, 55))	('Mutations', 'Var', (0, 9))	('MAPK', 'Gene', '5594', (114, 118))	('described', 'Reg', (39, 48))	('KRAS', 'Gene', (13, 17))	('BRAF', 'Gene', '673', (93, 97))	('MAPK', 'Gene', (114, 118))	('NRAS', 'Gene', (87, 91))
17851	25369307	Strategies to therapeutically target tumors with KRAS mutations have focused on targeting downstream effector pathways of KRAS such as Raf/MEK/ERK and PI3K/AKT.	('Raf', 'Gene', (135, 138))	('AKT', 'Gene', '207', (156, 159))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('KRAS', 'Gene', '3845', (49, 53))	('KRAS', 'Gene', '3845', (122, 126))	('mutations', 'Var', (54, 63))	('AKT', 'Gene', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('Raf', 'Gene', '22882', (135, 138))	('ERK', 'Gene', '5594', (143, 146))	('tumors', 'Disease', (37, 43))	('KRAS', 'Gene', (122, 126))	('MEK', 'Gene', (139, 142))	('ERK', 'Gene', (143, 146))	('MEK', 'Gene', '5609', (139, 142))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('KRAS', 'Gene', (49, 53))
17857	25369307	In a cohort of 32 iCCA cases, the prevalence of inactivating mutations in BAP1 was 25%.	('inactivating mutations', 'Var', (48, 70))	('iCCA', 'Disease', (18, 22))	('BAP1', 'Gene', '8314', (74, 78))	('BAP1', 'Gene', (74, 78))	('CCA', 'Phenotype', 'HP:0030153', (19, 22))
17858	25369307	Patients with these mutations had a trend, albeit not statistically significant, toward shorter survival times.	('shorter', 'NegReg', (88, 95))	('Patients', 'Species', '9606', (0, 8))	('survival times', 'CPA', (96, 110))	('mutations', 'Var', (20, 29))
17859	25369307	In a separate cohort of 209 CCAs, BAP1 mutations were detected in 10.5% of non-liver-fluke-related CCAs, compared with 2.8% of liver- fluke-related CCAs.	('BAP1', 'Gene', (34, 38))	('liver- fluke', 'Species', '6192', (127, 139))	('CCA', 'Phenotype', 'HP:0030153', (28, 31))	('detected', 'Reg', (54, 62))	('mutations', 'Var', (39, 48))	('CCA', 'Phenotype', 'HP:0030153', (148, 151))	('liver-fluke', 'Species', '6192', (79, 90))	('non-liver-fluke-related CCAs', 'Disease', (75, 103))	('BAP1', 'Gene', '8314', (34, 38))	('CCA', 'Phenotype', 'HP:0030153', (99, 102))
17866	25369307	Preclinical studies have demonstrated a reduction in fibrosis and carcinogenesis in CCA with 1D11, a transforming growth factor beta (TGF-beta) antagonist, as well as curcumin, a nutraceutical agent.	('TGF-beta', 'Gene', (134, 142))	('fibrosis', 'Disease', 'MESH:D005355', (53, 61))	('transforming growth factor beta', 'Gene', (101, 132))	('CCA', 'Disease', (84, 87))	('curcumin', 'Chemical', 'MESH:D003474', (167, 175))	('reduction', 'NegReg', (40, 49))	('carcinogenesis', 'Disease', 'MESH:D063646', (66, 80))	('transforming growth factor beta', 'Gene', '7040', (101, 132))	('TGF-beta', 'Gene', '7040', (134, 142))	('carcinogenesis', 'Disease', (66, 80))	('CCA', 'Phenotype', 'HP:0030153', (84, 87))	('fibrosis', 'Disease', (53, 61))	('1D11', 'Var', (93, 97))
17876	25369307	Inhibition of the PDGF receptor, PDGFR-beta, with imatinib induced CCA cell apoptosis.	('CCA', 'Disease', (67, 70))	('imatinib', 'Chemical', 'MESH:D000068877', (50, 58))	('CCA', 'Phenotype', 'HP:0030153', (67, 70))	('PDGFR-beta', 'Gene', '5159', (33, 43))	('Inhibition', 'Var', (0, 10))	('PDGFR-beta', 'Gene', (33, 43))
17883	25369307	Inhibition of immune receptors such as programmed cell death 1 has shown promise in certain malignancies.	('programmed cell death 1', 'Gene', (39, 62))	('malignancies', 'Disease', 'MESH:D009369', (92, 104))	('Inhibition', 'Var', (0, 10))	('malignancies', 'Disease', (92, 104))
17885	25369307	Preclinical studies have demonstrated tumor regression and enhanced survival with selective deletion of CAF from the CCA tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('survival', 'CPA', (68, 76))	('deletion', 'Var', (92, 100))	('enhanced', 'PosReg', (59, 67))	('tumor', 'Disease', (121, 126))	('CAF', 'Gene', '8850', (104, 107))	('CCA', 'Phenotype', 'HP:0030153', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('CAF', 'Gene', (104, 107))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
17910	25806130	Immunohistochemical staining showed the neoplastic cells were positive for cluster of differentiation 20 (CD20), cluster of differentiation 10 (CD10), and B cell lymphoma 6 (BCL6) markers [Figure 3c and d].	('BCL6', 'Gene', (174, 178))	('lymphoma', 'Phenotype', 'HP:0002665', (162, 170))	('CD20', 'Gene', (106, 110))	('CD20', 'Gene', '931', (106, 110))	('B cell lymphoma 6', 'Gene', '604', (155, 172))	('BCL6', 'Gene', '604', (174, 178))	('cluster of differentiation 20', 'Gene', (75, 104))	('cluster of differentiation', 'Var', (113, 139))	('cluster of differentiation 20', 'Gene', '931', (75, 104))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (155, 170))	('B cell lymphoma 6', 'Gene', (155, 172))
17924	25806130	Homogenous intensity in both pre- and post-contrast study at the stenotic site of bile duct is another suggestive feature of lymphoma.	('lymphoma', 'Disease', (125, 133))	('lymphoma', 'Disease', 'MESH:D008223', (125, 133))	('Homogenous', 'Var', (0, 10))	('lymphoma', 'Phenotype', 'HP:0002665', (125, 133))
18095	33390787	A recent systematic review showed that sorafenib was not superior to hepatic arterial infusion chemotherapy in advanced HCC patients, because that sorafenib was associated with diarrhea and hand-foot syndrome.	('sorafenib', 'Var', (147, 156))	('hand-foot syndrome', 'Disease', (190, 208))	('diarrhea', 'Disease', 'MESH:D003967', (177, 185))	('sorafenib', 'Chemical', 'MESH:D000077157', (147, 156))	('associated with', 'Reg', (161, 176))	('patients', 'Species', '9606', (124, 132))	('hand-foot syndrome', 'Disease', 'MESH:D060831', (190, 208))	('HCC', 'Gene', (120, 123))	('HCC', 'Gene', '619501', (120, 123))	('sorafenib', 'Chemical', 'MESH:D000077157', (39, 48))	('diarrhea', 'Phenotype', 'HP:0002014', (177, 185))	('diarrhea', 'Disease', (177, 185))
18115	32460791	This study suggests FAM83H and ZNF16 are associated with the progression of gallbladder carcinoma, and the expressions of FAM83H and ZNF16 might be novel prognostic indicators of gallbladder carcinoma patients.	('patients', 'Species', '9606', (201, 209))	('expressions', 'Var', (107, 118))	('ZNF16', 'Gene', (133, 138))	('associated', 'Reg', (41, 51))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (179, 200))	('FAM83H', 'Gene', '286077', (122, 128))	('FAM83H', 'Gene', '286077', (20, 26))	('ZNF16', 'Gene', '7564', (133, 138))	('ZNF16', 'Gene', (31, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('gallbladder carcinoma', 'Disease', (179, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (76, 97))	('FAM83H', 'Gene', (122, 128))	('FAM83H', 'Gene', (20, 26))	('gallbladder carcinoma', 'Disease', (76, 97))	('ZNF16', 'Gene', '7564', (31, 36))
18116	32460791	FAM83H is primarily known for its importance in tooth development because mutation in FAM83H causes amelogenesis imperfecta.	('mutation', 'Var', (74, 82))	('FAM83H', 'Gene', (86, 92))	('FAM83H', 'Gene', (0, 6))	('FAM83H', 'Gene', '286077', (0, 6))	('amelogenesis imperfecta', 'Disease', 'MESH:D000567', (100, 123))	('FAM83H', 'Gene', '286077', (86, 92))	('amelogenesis imperfecta', 'Disease', (100, 123))	('amelogenesis imperfecta', 'Phenotype', 'HP:0000705', (100, 123))	('causes', 'Reg', (93, 99))
18120	32460791	Disruption of the actin filament network by deregulated FAM83H expression is thought to induce epithelial-to-mesenchymal transition (EMT).	('FAM83H', 'Gene', (56, 62))	('deregulated', 'Var', (44, 55))	('FAM83H', 'Gene', '286077', (56, 62))	('epithelial-to-mesenchymal transition', 'CPA', (95, 131))	('induce', 'PosReg', (88, 94))
18137	32460791	Gallbladder cancer is commonly correlated to inflammation, and inflammation-associated accumulation of genetic alteration is one of the main causes of gallbladder cancer development.	('gallbladder cancer', 'Disease', 'MESH:D005706', (151, 169))	('inflammation', 'Disease', (45, 57))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('causes', 'Reg', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('genetic alteration', 'Var', (103, 121))	('inflammation', 'Disease', 'MESH:D007249', (63, 75))	('inflammation', 'Disease', 'MESH:D007249', (45, 57))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('inflammation', 'Disease', (63, 75))	('gallbladder cancer', 'Disease', (151, 169))
18173	32460791	Positivity for nuclear ZNF16 was significantly associated with tumor stage (p = 0.028), T category of the tumor stage (p = 0.014), histologic grade (p <  0.001), and the cytoplasmic expression of ZNF16 (p <  0.001) (Table 1).	('tumor', 'Disease', (63, 68))	('ZNF16', 'Gene', (23, 28))	('ZNF16', 'Gene', '7564', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cytoplasmic expression', 'MPA', (170, 192))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('ZNF16', 'Gene', (196, 201))	('Positivity', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('associated', 'Reg', (47, 57))	('ZNF16', 'Gene', '7564', (196, 201))	('tumor', 'Disease', (106, 111))
18177	32460791	Cytoplasmic FAM83H positivity predicted a 2.292-fold (95% CI; 1.413-3.720) greater risk of death and a 2.201-fold (95% CI; 1.360-3.564) greater risk of relapse or death of gallbladder carcinoma patients.	('patients', 'Species', '9606', (194, 202))	('death', 'Disease', 'MESH:D003643', (91, 96))	('death', 'Disease', (91, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('Cytoplasmic', 'Var', (0, 11))	('death of gallbladder carcinoma', 'Disease', 'MESH:D005706', (163, 193))	('relapse', 'Disease', (152, 159))	('FAM83H', 'Gene', (12, 18))	('death of gallbladder carcinoma', 'Disease', (163, 193))	('FAM83H', 'Gene', '286077', (12, 18))	('death', 'Disease', 'MESH:D003643', (163, 168))	('death', 'Disease', (163, 168))
18178	32460791	Patients with nuclear ZNF16 positive carcinomas had a 3.287-fold (95% CI; 1.888-5.722) greater risk of death and a 3.038-fold (95% CI; 1.765-5.229) greater risk of relapse or death from gallbladder carcinoma.	('ZNF16', 'Gene', (22, 27))	('ZNF16', 'Gene', '7564', (22, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('death', 'Disease', 'MESH:D003643', (175, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('death', 'Disease', (175, 180))	('carcinomas', 'Disease', 'MESH:D009369', (37, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('Patients', 'Species', '9606', (0, 8))	('death', 'Disease', 'MESH:D003643', (103, 108))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (186, 207))	('death', 'Disease', (103, 108))	('nuclear', 'Var', (14, 21))	('carcinomas', 'Disease', (37, 47))	('gallbladder carcinoma', 'Disease', (186, 207))
18179	32460791	Patients with cytoplasmic ZNF16 positive carcinomas had a 1.675-fold (95% CI; 1.038-2.703) greater risk of death from gallbladder carcinoma (Table 3).	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('gallbladder carcinoma', 'Disease', (118, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('carcinomas', 'Disease', (41, 51))	('ZNF16', 'Gene', (26, 31))	('ZNF16', 'Gene', '7564', (26, 31))	('death', 'Disease', 'MESH:D003643', (107, 112))	('Patients', 'Species', '9606', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinomas', 'Disease', 'MESH:D009369', (41, 51))	('death', 'Disease', (107, 112))	('cytoplasmic', 'Var', (14, 25))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (118, 139))
18185	32460791	Moreover, the expression of nuclear FAM83H, cytoplasmic FAM83H, nuclear ZNF16, and cytoplasmic ZNF16 were associated with the survival of gallbladder carcinoma patients.	('cytoplasmic', 'Var', (83, 94))	('FAM83H', 'Gene', '286077', (36, 42))	('patients', 'Species', '9606', (160, 168))	('associated with', 'Reg', (106, 121))	('FAM83H', 'Gene', (56, 62))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (138, 159))	('ZNF16', 'Gene', (95, 100))	('FAM83H', 'Gene', '286077', (56, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('FAM83H', 'Gene', (36, 42))	('ZNF16', 'Gene', '7564', (95, 100))	('gallbladder carcinoma', 'Disease', (138, 159))	('ZNF16', 'Gene', (72, 77))	('ZNF16', 'Gene', '7564', (72, 77))
18192	32460791	In univariate Cox regression analysis, the poor prognostic subgroup with co-expression of nFAM83H/nZNF16 predicted a 5.463-fold (95% CI; 2.598-11.487, p <  0.001) higher risk of death and a 4.796-fold (95% CI; 2.367-9.717, p <  0.001) higher risk of relapse or death of patients (Table 6).	('patients', 'Species', '9606', (270, 278))	('relapse', 'CPA', (250, 257))	('ZNF16', 'Gene', (99, 104))	('nFAM83H', 'Chemical', '-', (90, 97))	('death', 'Disease', 'MESH:D003643', (178, 183))	('death', 'Disease', (178, 183))	('ZNF16', 'Gene', '7564', (99, 104))	('co-expression', 'Var', (73, 86))	('death', 'Disease', 'MESH:D003643', (261, 266))	('higher', 'PosReg', (163, 169))	('death', 'Disease', (261, 266))
18193	32460791	In multivariate analysis, the co-expression of nFAM83H/nZNF16 was also an independent indicator of poor prognosis of gallbladder carcinoma patients (Table 6).	('patients', 'Species', '9606', (139, 147))	('co-expression', 'Var', (30, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (117, 138))	('gallbladder carcinoma', 'Disease', (117, 138))	('ZNF16', 'Gene', (56, 61))	('nFAM83H', 'Chemical', '-', (47, 54))	('ZNF16', 'Gene', '7564', (56, 61))
18210	32460791	Therefore, although the prognostic significance of FAM83H expression varied according to its subcellular localization with different cancer type, it has been suggested that the overall expression of FAM83H in the cell could be vital in the progression of cancers because knock-down of FAM83H suppressed cancer progression and overexpression of FAM83H stimulated cancer progression.	('FAM83H', 'Gene', (51, 57))	('FAM83H', 'Gene', '286077', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('FAM83H', 'Gene', (344, 350))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('cancer', 'Disease', (255, 261))	('FAM83H', 'Gene', (199, 205))	('cancers', 'Disease', (255, 262))	('cancer', 'Disease', 'MESH:D009369', (362, 368))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer', 'Disease', (303, 309))	('suppressed', 'NegReg', (292, 302))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('FAM83H', 'Gene', '286077', (285, 291))	('stimulated', 'PosReg', (351, 361))	('FAM83H', 'Gene', (285, 291))	('cancer', 'Disease', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('cancers', 'Disease', 'MESH:D009369', (255, 262))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (303, 309))	('cancer', 'Disease', (362, 368))	('knock-down', 'Var', (271, 281))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('FAM83H', 'Gene', '286077', (51, 57))	('FAM83H', 'Gene', '286077', (344, 350))
18232	32460791	In SNU-308 gallbladder carcinoma cells, knock-down of FAM83H decreased ZNF16 expression and overexpression of FAM83H increased expression of ZNF16.	('expression', 'MPA', (77, 87))	('knock-down', 'Var', (40, 50))	('FAM83H', 'Gene', '286077', (54, 60))	('ZNF16', 'Gene', '7564', (141, 146))	('increased', 'PosReg', (117, 126))	('expression', 'MPA', (127, 137))	('ZNF16', 'Gene', (71, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('ZNF16', 'Gene', '7564', (71, 76))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (11, 32))	('FAM83H', 'Gene', (110, 116))	('SNU', 'Chemical', '-', (3, 6))	('FAM83H', 'Gene', (54, 60))	('FAM83H', 'Gene', '286077', (110, 116))	('decreased', 'NegReg', (61, 70))	('gallbladder carcinoma', 'Disease', (11, 32))	('ZNF16', 'Gene', (141, 146))
18294	32130786	The first method is to specifically target the specific signaling pathways in tumors by altering the key adenovirus replication genes.12 This design is primarily achieved by deleting either the E1A or E1B genes.	('tumors', 'Disease', (78, 84))	('E1A', 'Gene', (194, 197))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('deleting', 'Var', (174, 182))	('adenovirus', 'Species', '10508', (105, 115))	('E1B', 'Gene', '100306944', (201, 204))	('E1B', 'Gene', (201, 204))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))
18302	32130786	LoAd703 is an Ad5/35 expressing human CD40L and 4-1BBL.	('Ad5/35', 'Gene', (14, 20))	('CD40L and 4-1BBL', 'Gene', '959', (38, 54))	('LoAd703', 'Var', (0, 7))	('human', 'Species', '9606', (32, 37))	('Ad5/35', 'Gene', '8081', (14, 20))
18303	32130786	CD40L can induce the adaptive immune response and CD40-mediated tumor cell apoptosis, whereas 4-1BBL enhances immunological memory and expands T and NK cells, modulating the pancreatic cancer stroma to support the antitumor response.41 LoAd703 can efficiently lyse pancreatic cancer cell lines in vitro and reduce the established tumors in xenograft models in vivo.41 A Phase I/II clinical trial is currently underway to actively recruit patients to assess the efficacy and safety of an intratumoral injection of LOAd703 combined with gemcitabine and nab-paclitaxel as a treatment for pancreatic cancer.	('tumor', 'Phenotype', 'HP:0002664', (492, 497))	('pancreatic cancer', 'Disease', 'MESH:D010190', (174, 191))	('tumor', 'Disease', (330, 335))	('CD40', 'Gene', (50, 54))	('pancreatic cancer', 'Disease', 'MESH:D010190', (585, 602))	('tumor', 'Disease', (218, 223))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (265, 282))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('LOAd703', 'Var', (513, 520))	('CD40', 'Gene', '958', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('rat', 'Species', '10116', (490, 493))	('pancreatic cancer', 'Disease', (585, 602))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('4-1BBL', 'Gene', '8744', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (330, 336))	('cancer', 'Phenotype', 'HP:0002664', (596, 602))	('CD40L', 'Gene', (0, 5))	('CD40', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('tumor', 'Disease', (492, 497))	('pancreatic cancer stroma', 'Disease', 'MESH:D010190', (174, 198))	('tumors', 'Disease', (330, 336))	('pancreatic cancer', 'Disease', 'MESH:D010190', (265, 282))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (174, 191))	('tumor', 'Disease', 'MESH:D009369', (492, 497))	('CD40', 'Gene', '958', (0, 4))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (585, 602))	('tumor', 'Disease', (64, 69))	('patients', 'Species', '9606', (438, 446))	('pancreatic cancer', 'Disease', (265, 282))	('4-1BBL', 'Gene', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (330, 336))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('CD40L', 'Gene', '959', (0, 5))	('pancreatic cancer stroma', 'Disease', (174, 198))	('gemcitabine', 'Chemical', 'MESH:C056507', (535, 546))
18312	32130786	GLV-1h68 (GL-ONC1) is a replication-competent virus containing the marker genes ruc-gfp and mutations in the F14.5L, J2R, and A56R loci, which disrupts TK and hemagglutinin.	('hemagglutinin', 'Protein', (159, 172))	('GLV-1h68', 'Species', '502057', (0, 8))	('disrupts', 'NegReg', (143, 151))	('mutations', 'Var', (92, 101))	('F14.5L', 'Gene', (109, 115))	('A56R', 'Mutation', 'p.A56R', (126, 130))	('ruc-gfp', 'Gene', (80, 87))	('A56R', 'Var', (126, 130))	('J2R', 'Gene', (117, 120))
18318	32130786	The genome of HSV-1 is approximately 150 kb, including many non-essential genes that have no significant effect on viral replication and can be modified without losing the oncolytic effect of the virus.73 In the HSV-1 OV, LCSOV, expression of the viral glycoprotein H gene is driven by the liver-specific apolipoprotein E (apoE)-AAT promoter and contains additional miRNA complementary sequences of miR-122a, miR-124a, and let-7 inserted into the same 3' UTR region of the modified gH gene.74 miR-122a is a liver-specific miRNA that is expressed at low levels only in HCC, whereas miR-124a and let-7 are down-regulated or lacking in malignant cancer cells enabling translational control of gH expression in LCSOV infected normal cells.74, 75 LCSOV also displays high selectivity and effective killing in HCC xenografts and cell lines, and significantly reduces tumor volume with minimal toxicity.74 G47Delta is a third-generation oncolytic HSV with mutations in the gamma34.5, ICP6, and ICP47 genes.	('tumor', 'Disease', (861, 866))	('infected', 'Disease', (713, 721))	('apolipoprotein E', 'Gene', '348', (305, 321))	('gamma34.5', 'Gene', (966, 975))	('miR-124a', 'Gene', '406907', (409, 417))	('malignant cancer', 'Disease', 'MESH:D009369', (633, 649))	('tumor', 'Disease', 'MESH:D009369', (861, 866))	('toxicity', 'Disease', 'MESH:D064420', (887, 895))	('miR-122a', 'Gene', '406906', (399, 407))	('miR-122a', 'Gene', '406906', (493, 501))	('miR-124a', 'Gene', (581, 589))	('miR-124a', 'Gene', '406907', (581, 589))	('cancer', 'Phenotype', 'HP:0002664', (643, 649))	('apoE', 'Gene', (323, 327))	('malignant cancer', 'Disease', (633, 649))	('apoE', 'Gene', '348', (323, 327))	('toxicity', 'Disease', (887, 895))	('tumor', 'Phenotype', 'HP:0002664', (861, 866))	('HCC', 'Gene', '619501', (568, 571))	('HCC', 'Phenotype', 'HP:0001402', (568, 571))	('HCC', 'Gene', (568, 571))	('HSV-1', 'Species', '10298', (212, 217))	('apolipoprotein E', 'Gene', (305, 321))	('ICP6', 'Gene', (977, 981))	('HSV-1', 'Species', '10298', (14, 19))	('HCC', 'Gene', '619501', (804, 807))	('HCC', 'Phenotype', 'HP:0001402', (804, 807))	('mutations', 'Var', (949, 958))	('ICP47', 'Gene', (987, 992))	('rat', 'Species', '10116', (923, 926))	('miR-122a', 'Gene', (493, 501))	('HCC', 'Gene', (804, 807))	('miR-122a', 'Gene', (399, 407))	('infected', 'Disease', 'MESH:D007239', (713, 721))	('miR-124a', 'Gene', (409, 417))
18319	32130786	The gamma34.5 gene production can prevent the host cell from stopping translation due to viral infection, allowing viral proteins to be continuously synthesized.	('gamma34.5 gene', 'Var', (4, 18))	('viral infection', 'Disease', (89, 104))	('viral infection', 'Disease', 'MESH:D001102', (89, 104))	('stopping translation', 'MPA', (61, 81))
18320	32130786	Since tumor cells often lack control over translation and the antiviral response, HSV with the gamma34.5 gene mutation can replicate in tumor cells.73, 76 The ICP6 gene product is required for the replication of viruses in noncycling cells, so mutations in the ICP6 gene enable HSV to selectively replicate in constantly dividing cells (eg, tumor cells).77 Moreover, an ICP47 gene mutation can amplify the targeting of tumor cells caused by a gamma34.5 gene mutation and stimulate T cells to enhance the immune response and antitumor immunity to virus-infected tumor cells.73, 78 G47Delta requires only a very low MOI to effectively kill a variety of different HCC cell lines and inhibit tumor growth in HCC xenografts with no significant toxicity.78 HSV-1-T-01 is similar to G47Delta, in which the gamma34.5 and ICP6 genes were deleted and the ICP6 gene was replaced with the LacZ gene.	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('tumor', 'Disease', 'MESH:D009369', (688, 693))	('toxicity', 'Disease', (739, 747))	('deleted', 'Var', (829, 836))	('gamma34.5', 'Gene', (799, 808))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (419, 424))	('ICP6', 'Gene', (813, 817))	('tumor', 'Disease', (528, 533))	('virus-infected tumor', 'Disease', (546, 566))	('virus-infected tumor', 'Disease', 'MESH:D014412', (546, 566))	('tumor', 'Disease', 'MESH:D009369', (528, 533))	('tumor', 'Disease', (136, 141))	('HCC', 'Gene', '619501', (704, 707))	('HCC', 'Phenotype', 'HP:0001402', (704, 707))	('HCC', 'Gene', (704, 707))	('tumor', 'Disease', (341, 346))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (528, 533))	('tumor', 'Disease', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (341, 346))	('tumor', 'Disease', (419, 424))	('HCC', 'Gene', '619501', (661, 664))	('toxicity', 'Disease', 'MESH:D064420', (739, 747))	('tumor', 'Disease', (561, 566))	('HSV-1-T-01', 'CellLine', 'CVCL:G033', (751, 761))	('HCC', 'Phenotype', 'HP:0001402', (661, 664))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (688, 693))	('tumor', 'Disease', 'MESH:D009369', (419, 424))	('HCC', 'Gene', (661, 664))	('tumor', 'Disease', 'MESH:D009369', (561, 566))
18322	32130786	G207 is a typical engineered HSV-1 with deletions in both copies of gamma34.5 and genetic inactivation of ICP6, which replicated in and lysed human pancreatic cancer cells in vitro.80 Another engineered HSV-1, NV1020, had a deletion in only one copy of gamma34.5 also displayed effective viral replication and cell lysis in human pancreatic cancer cells in vitro, as well as a higher production of viral progeny.81 Both the injection of G207 and NV1020 into athymic mice xenografts induced complete pancreatic tumor eradication in 25% and 40% of mice, respectively.81 FusOn-H2 is an HSV-2 construct with a deletion in the PK domain which encodes serine/threonine protein kinase activity and replicates in cells with an activated Ras signaling pathway.	('pancreatic cancer', 'Disease', 'MESH:D010190', (148, 165))	('mice', 'Species', '10090', (546, 550))	('pancreatic tumor', 'Disease', (499, 515))	('mice', 'Species', '10090', (466, 470))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('pancreatic cancer', 'Disease', 'MESH:D010190', (330, 347))	('pancreatic cancer', 'Disease', (148, 165))	('pancreatic tumor', 'Disease', 'MESH:D010190', (499, 515))	('serine', 'Chemical', 'MESH:D012694', (646, 652))	('human', 'Species', '9606', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('pancreatic cancer', 'Disease', (330, 347))	('human', 'Species', '9606', (324, 329))	('HSV-2', 'Species', '10310', (583, 588))	('deletion in', 'Var', (606, 617))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (148, 165))	('HSV-1', 'Species', '10298', (29, 34))	('FusOn-H2', 'Chemical', '-', (568, 576))	('tumor', 'Phenotype', 'HP:0002664', (510, 515))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (499, 515))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (330, 347))	('HSV-1', 'Species', '10298', (203, 208))
18324	32130786	No adverse effects were observed and HF10 infection stimulated the host antitumor immune responses and increased the number of NK cells, CD4+ cells, CD8+ cells, and macrophages after virus injection; four of the six patients showed clinical efficacy with longer survival.83 Additionally, talimogene laherparepvec (T-VEC), a modified HSV-1 with deletions in gamma34.5 and ICP47, and also expressing GM-CSF, has been approved by the FDA as the first oncolytic virus therapy for the treatment of melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (493, 501))	('infection', 'Disease', (42, 51))	('tumor', 'Disease', (76, 81))	('melanoma', 'Disease', (493, 501))	('GM-CSF', 'Gene', '1437', (398, 404))	('infection', 'Disease', 'MESH:D007239', (42, 51))	('CD8', 'Gene', '925', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('ICP47', 'Gene', (371, 376))	('HF10', 'Gene', '7584', (37, 41))	('HF10', 'Gene', (37, 41))	('deletions', 'Var', (344, 353))	('CD4', 'Gene', '920', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('patients', 'Species', '9606', (216, 224))	('melanoma', 'Disease', 'MESH:D008545', (493, 501))	('CD8', 'Gene', (149, 152))	('HSV-1', 'Species', '10298', (333, 338))	('CD4', 'Gene', (137, 140))	('GM-CSF', 'Gene', (398, 404))	('gamma34.5', 'Gene', (357, 366))
18327	32130786	NV1203 is an attenuated HSV with a UL56 deletion, a single copy of ICP0, ICP4, and gamma34.5, as well as the insertion of the Escherichia coli lacZ marker gene into the ICP47 locus.	('UL56', 'Gene', '2703428', (35, 39))	('Escherichia coli', 'Species', '562', (126, 142))	('NV1203', 'Var', (0, 6))	('UL56', 'Gene', (35, 39))
18374	32244128	Furthermore, experimental infection of hamsters with the gene-edited liver flukes resulted in markedly reduced disease even though gene-edited parasites colonized the biliary tract and developed into the adult developmental stage of the liver fluke.	('infection', 'Disease', (26, 35))	('infection', 'Disease', 'MESH:D007239', (26, 35))	('reduced', 'NegReg', (103, 110))	('disease', 'Disease', (111, 118))	('gene-edited', 'Var', (57, 68))	('liver fluke', 'Species', '6192', (237, 248))	('liver flukes', 'Species', '6192', (69, 81))	('liver fluke', 'Species', '6192', (69, 80))
18381	32244128	To mutate and disrupt the human progranulin gene, huPGRN, with the aim of minimizing or eliminating endogenous granulin in H69 cells that might obfuscate interpretation of the effect of liver fluke granulin, we employed a pre-designed lentiviral CRISPR/Cas9 vector, 'All in One CRISPR/Cas9 vector system (Sigma-Aldrich).	('granulin', 'Gene', '2896', (198, 206))	('liver fluke', 'Species', '6192', (186, 197))	('granulin', 'Gene', (35, 43))	('mutate', 'Var', (3, 9))	('PGRN', 'Gene', '2896', (52, 56))	('granulin', 'Gene', (111, 119))	('H69', 'Chemical', '-', (123, 126))	('progranulin', 'Gene', '2896', (32, 43))	('granulin', 'Gene', '2896', (35, 43))	('granulin', 'Gene', (198, 206))	('PGRN', 'Gene', (52, 56))	('progranulin', 'Gene', (32, 43))	('granulin', 'Gene', '2896', (111, 119))	('human', 'Species', '9606', (26, 31))
18465	32244128	The rate of H69 and DeltahuPGRN cell growth was monitored for 48 h and differences compared every 8 h. Both the wild type and the daughter mutant DeltahuPGRN cholangiocytes proliferated at a similar rate for 48 h, suggesting that the programmed knockout of huPGRN was not detrimental to normal cell growth.	('PGRN', 'Gene', (153, 157))	('PGRN', 'Gene', (259, 263))	('H69', 'Chemical', '-', (12, 15))	('PGRN', 'Gene', '2896', (27, 31))	('mutant', 'Var', (139, 145))	('PGRN', 'Gene', (27, 31))	('PGRN', 'Gene', '2896', (153, 157))	('PGRN', 'Gene', '2896', (259, 263))
18466	32244128	Next, the wild type and mutant H69 cell lines were exposed to liver fluke granulin at 100 nM.	('mutant', 'Var', (24, 30))	('granulin', 'Gene', '2896', (74, 82))	('liver fluke', 'Species', '6192', (62, 73))	('granulin', 'Gene', (74, 82))	('H69', 'Chemical', '-', (31, 34))
18477	32244128	The programmed mutation induced INDELs at exon 2 of the huPGRN locus lead to reduced levels of progranulin within the protein complement of the EVs.	('mutation', 'Var', (15, 23))	('PGRN', 'Gene', '2896', (58, 62))	('INDELs', 'Var', (32, 38))	('reduced', 'NegReg', (77, 84))	('PGRN', 'Gene', (58, 62))	('progranulin', 'Gene', '2896', (95, 106))	('progranulin', 'Gene', (95, 106))
18482	32244128	To investigate if liver fluke granulin stimulated H69 cells shed EVs containing CCA-related transcripts, the huPGRN gene was mutated by CRISPR/Cas9 knockout (above).	('granulin', 'Gene', (30, 38))	('H69', 'Chemical', '-', (50, 53))	('mutated', 'Var', (125, 132))	('PGRN', 'Gene', '2896', (111, 115))	('granulin', 'Gene', '2896', (30, 38))	('liver fluke', 'Species', '6192', (18, 29))	('CCA', 'Phenotype', 'HP:0030153', (80, 83))	('PGRN', 'Gene', (111, 115))
18521	32244128	Mutations in the human progranulin gene, huPGRN, are associated with a spectrum on neurological disorders.	('progranulin', 'Gene', (23, 34))	('human', 'Species', '9606', (17, 22))	('PGRN', 'Gene', (43, 47))	('Mutations', 'Var', (0, 9))	('neurological disorders', 'Disease', 'MESH:D009422', (83, 105))	('associated with', 'Reg', (53, 68))	('progranulin', 'Gene', '2896', (23, 34))	('neurological disorders', 'Disease', (83, 105))	('PGRN', 'Gene', '2896', (43, 47))
18523	32244128	We have exploited this link infection to explore the role of the secreted liver fluke granulin in pre-malignant lesions by undertaking programmed CRISPR/Cas9 knockout of the Ov-grn-1 gene from the genome of O. viverrini.	('liver fluke', 'Species', '6192', (74, 85))	('O. viverrini', 'Species', '6198', (207, 219))	('Ov-grn-1', 'Gene', (174, 182))	('infection', 'Disease', (28, 37))	('infection', 'Disease', 'MESH:D007239', (28, 37))	('granulin', 'Gene', (86, 94))	('knockout', 'Var', (158, 166))	('granulin', 'Gene', '2896', (86, 94))
18528	32244128	Cholangiocytes of the resulting mutant DeltahuPGRN-H69 lines shown the proliferate rate as same as parental H69 cells (Fig.	('mutant', 'Var', (32, 38))	('proliferate', 'CPA', (71, 82))	('PGRN', 'Gene', '2896', (46, 50))	('H69', 'Chemical', '-', (51, 54))	('H69', 'Chemical', '-', (108, 111))	('PGRN', 'Gene', (46, 50))
18541	32244128	Progranulin affects the activation of the MAPK signaling pathway, highlighted by the upregulation of huPRGN activity during hepatocellular carcinoma and as the gene target of microRNA-140-3p (miR-140-3p).	('miR-140-3p', 'Chemical', '-', (192, 202))	('microRNA-140-3p', 'Var', (175, 190))	('MAPK signaling pathway', 'Pathway', (42, 64))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (124, 148))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (124, 148))	('huPRGN activity', 'MPA', (101, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('hepatocellular carcinoma', 'Disease', (124, 148))	('Progranulin', 'Gene', '2896', (0, 11))	('Progranulin', 'Gene', (0, 11))	('upregulation', 'PosReg', (85, 97))
18542	32244128	Overexpression of miR-140-3p disrupts the stimulation in the MAPK signaling pathway by inhibition of expression of progranulin, leading to phosphorylation of ERK and p38.	('inhibition', 'NegReg', (87, 97))	('phosphorylation', 'MPA', (139, 154))	('stimulation', 'MPA', (42, 53))	('miR-140-3p', 'Var', (18, 28))	('ERK', 'Pathway', (158, 161))	('p38', 'Gene', (166, 169))	('miR-140-3p', 'Chemical', '-', (18, 28))	('MAPK signaling pathway', 'Pathway', (61, 83))	('progranulin', 'Gene', '2896', (115, 126))	('progranulin', 'Gene', (115, 126))	('expression', 'MPA', (101, 111))	('disrupts', 'NegReg', (29, 37))	('p38', 'Gene', '1432', (166, 169))
18577	31565837	Furthermore, knockdown of lncRNA ZFAS1 could inhibit breast cancer cell proliferation and metabolic activity, which indicated lncRNA ZFAS1 a tumour suppressor.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('lncRNA ZFAS1', 'Gene', (26, 38))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('metabolic activity', 'CPA', (90, 108))	('tumour', 'Disease', (141, 147))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('inhibit', 'NegReg', (45, 52))	('knockdown', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))
18610	31565837	In that case, CCK-8 and colony formation assays were performed and the results indicated that compared with siRNA of negative control (si-NC), silence of ZFAS1 significantly suppressed cell growth (Figure 2C), and the tumour cell colonies formed troublesomely for the very inhibition of ZFAS1 (Figure 2D).	('tumour', 'Disease', (218, 224))	('suppressed', 'NegReg', (174, 184))	('ZFAS1', 'Gene', (154, 159))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('silence', 'Var', (143, 150))	('cell growth', 'CPA', (185, 196))	('tumour', 'Disease', 'MESH:D009369', (218, 224))
18611	31565837	Interestingly, the activities of caspase-3 and caspase-9 were both higher in the ZFAS1 silence group than the negative control (Figure 2E) and the Hoechst 33342 staining outcomes also presented severer apoptosis of cells resulted from ZFAS1 inhibition (Figure 2F).	('caspase-9', 'Gene', '842', (47, 56))	('higher', 'PosReg', (67, 73))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (147, 160))	('silence', 'Var', (87, 94))	('caspase-3', 'Gene', (33, 42))	('ZFAS1', 'Gene', (235, 240))	('caspase-9', 'Gene', (47, 56))	('caspase-3', 'Gene', '836', (33, 42))	('apoptosis', 'CPA', (202, 211))	('ZFAS1', 'Gene', (81, 86))	('activities', 'MPA', (19, 29))	('inhibition', 'NegReg', (241, 251))
18617	31565837	After transfected with si-ZFAS1-1, si-ZFAS1-2 or si-NC, we found E-cadherin and Bax were increased but the expression levels of others were decreased (Figure 3C).	('decreased', 'NegReg', (140, 149))	('si-ZFAS1-1', 'Var', (23, 33))	('Bax', 'Gene', (80, 83))	('expression levels', 'MPA', (107, 124))	('si-ZFAS1-2', 'Gene', '441951', (35, 45))	('increased', 'PosReg', (89, 98))	('si-NC', 'Var', (49, 54))	('Bax', 'Gene', '581', (80, 83))	('si-ZFAS1-2', 'Gene', (35, 45))	('E-cadherin', 'Gene', (65, 75))	('E-cadherin', 'Gene', '999', (65, 75))
18618	31565837	Wild and mutant ZFAS1 sequences were inserted into pmirGLO reporter, and the luciferase activity in CCLP-1 and RBE cells were cotransfected with miR-296-5p mimics or miR-NC and pmirGLO-ZFAS1-WT or pmirGLO-ZFAS1-Mut.	('miR-296', 'Gene', '407022', (145, 152))	('miR-296', 'Gene', (145, 152))	('mutant', 'Var', (9, 15))	('luciferase', 'Enzyme', (77, 87))	('ZFAS1', 'Gene', (16, 21))	('activity', 'MPA', (88, 96))	('miR', 'Gene', '220972', (145, 148))	('miR', 'Gene', (145, 148))	('miR', 'Gene', '220972', (166, 169))	('miR', 'Gene', (166, 169))
18620	31565837	And the inhibition of miR-296-5p could promote cell growth which was tested by CCK-8 (Figure 4D).	('promote', 'PosReg', (39, 46))	('miR-296', 'Gene', '407022', (22, 29))	('cell growth', 'CPA', (47, 58))	('miR-296', 'Gene', (22, 29))	('inhibition', 'Var', (8, 18))
18626	31565837	So that, knockdown of ZFAS1 decreased miR-296-5p but increased USF1, and either of ZFAS1 and miR-296-5p or miR-296-5p and USF1 3'UTR could bind directly.	('miR-296', 'Gene', '407022', (93, 100))	('miR-296', 'Gene', '407022', (107, 114))	('USF1', 'Gene', '7391', (122, 126))	('knockdown', 'Var', (9, 18))	('decreased', 'NegReg', (28, 37))	('miR-296', 'Gene', (38, 45))	('bind', 'Interaction', (139, 143))	('USF1', 'Gene', '7391', (63, 67))	('miR-296', 'Gene', (93, 100))	('ZFAS1', 'Gene', (22, 27))	('miR-296', 'Gene', (107, 114))	('USF1', 'Gene', (122, 126))	('increased', 'PosReg', (53, 62))	('miR-296', 'Gene', '407022', (38, 45))	('USF1', 'Gene', (63, 67))
18631	31565837	The cell immunofluorescence results displayed that the expression of vimentin turned down after transfection with siRNA.	('vimentin', 'Gene', '7431', (69, 77))	('transfection', 'Var', (96, 108))	('vimentin', 'Gene', (69, 77))	('expression', 'MPA', (55, 65))
18636	31565837	In the present study, we predicted that the potential transcription factor USF1 could bind to ZFAS1 promoter region at two binding sites E1 (-1878 to -1872) and E2 (-1530 to -1524) with relative high scores by using JASPAR database (Figure 6).	('USF1', 'Gene', '7391', (75, 79))	('-1878 to -1872', 'Var', (141, 155))	('bind', 'Interaction', (86, 90))	('USF1', 'Gene', (75, 79))	('-1530 to -1524', 'Var', (165, 179))
18650	31565837	We found that ZFAS1 was up-regulated in most of our preserved CCA cells, and after ZFAS1 silencing in CCLP-1 and RBE cells, the CCK-8 assay, colony formation, migration and invasion abilities all significantly glided downside but apoptosis by Hoechst 33342 and caspase-3.	('colony formation', 'CPA', (141, 157))	('ZFAS1', 'Gene', (83, 88))	('glided downside', 'NegReg', (210, 225))	('caspase-3', 'Gene', (261, 270))	('CCA', 'Phenotype', 'HP:0030153', (62, 65))	('caspase-3', 'Gene', '836', (261, 270))	('migration', 'CPA', (159, 168))	('ZFAS1', 'Gene', (14, 19))	('CCA', 'Disease', 'MESH:D018281', (62, 65))	('invasion abilities', 'CPA', (173, 191))	('CCA', 'Disease', (62, 65))	('silencing', 'Var', (89, 98))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (243, 256))	('up-regulated', 'PosReg', (24, 36))
18708	31432273	in their study reported that adjuvant therapy was associated with a survival benefit in patients with advanced T stage (T2/3/4) (5-year OS: 37% vs. 30%; p = 0.006), periductal growth type (PI), or PI + MF subtype (5-year OS: 37% vs. 8%; p < 0.001) and lymph node metastasis (5-year OS: 18.3% vs. 12%; p = 0.050).	('OS', 'Chemical', '-', (282, 284))	('survival', 'CPA', (68, 76))	('patients', 'Species', '9606', (88, 96))	('lymph node metastasis', 'CPA', (252, 273))	('OS', 'Chemical', '-', (221, 223))	('OS', 'Chemical', '-', (136, 138))	('benefit', 'PosReg', (77, 84))	('PI + MF', 'Var', (197, 204))
18731	29246010	GEM and GEM+FU were associated with a higher risk of neutropenia and thrombocytopenia compared to FU, FU+PLA and GEM+PLA.	('thrombocytopenia', 'Disease', 'MESH:D013921', (69, 85))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (69, 85))	('GEM', 'Chemical', 'MESH:C056507', (8, 11))	('neutropenia', 'Disease', (53, 64))	('neutropenia', 'Phenotype', 'HP:0001875', (53, 64))	('thrombocytopenia', 'Disease', (69, 85))	('GEM+FU', 'Chemical', '-', (8, 14))	('GEM', 'Chemical', 'MESH:C056507', (113, 116))	('neutropenia', 'Disease', 'MESH:D009503', (53, 64))	('GEM', 'Chemical', 'MESH:C056507', (0, 3))	('GEM+FU', 'Var', (8, 14))
18757	29246010	In terms of overall response rate (ORR) (Table 2 and Figure 4), most treatments, including FU+PLA, GEM+FU, GEM+PLA and GEM+PLA+TAR were significantly better than BSC (OR=27.66, 95%CrI=3.25-572.49; OR=14.88, 95%CrI=1.73-214.86; OR=20.29, 95%CrI=2.64-361.41; OR=40.85, 95%CrI=4.85-780.55).	('GEM', 'Chemical', 'MESH:C056507', (107, 110))	('BSC', 'Gene', (162, 165))	('BSC', 'Gene', '6558', (162, 165))	('GEM', 'Chemical', 'MESH:C056507', (99, 102))	('GEM', 'Chemical', 'MESH:C056507', (119, 122))	('FU+PLA', 'Var', (91, 97))	('GEM+FU', 'Chemical', '-', (99, 105))
18769	29246010	reported that all survival outcomes were significantly more favorable for patients treated with GEM+PLA than those with GEM alone, while another systematic review conducted by Park suggested that the adverse events associated with GEM+PLA were generally more acceptable and manageable.	('GEM', 'Chemical', 'MESH:C056507', (96, 99))	('patients', 'Species', '9606', (74, 82))	('GEM', 'Chemical', 'MESH:C056507', (231, 234))	('survival', 'CPA', (18, 26))	('GEM+PLA', 'Var', (96, 103))	('GEM', 'Chemical', 'MESH:C056507', (120, 123))
18805	27894959	Inhibition of the apelin/APLNR axis decreases tumor growth in our xenograft model.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('axis decreases tumor', 'Disease', 'MESH:C566610', (31, 51))	('Inhibition', 'Var', (0, 10))	('axis decreases tumor', 'Disease', (31, 51))	('apelin/APLNR', 'Protein', (18, 30))
18858	27894959	Cells were incubated at 37  C in 5% albumin media and treated with 10 muM of ML221 or left untreated as a control.	('muM', 'Gene', (70, 73))	('ML221', 'Chemical', 'MESH:C578927', (77, 82))	('ML221', 'Var', (77, 82))	('muM', 'Gene', '56925', (70, 73))
18886	27894959	VEGF-C expression was increased in Mz-ChA-1 cells following ML221 treatment, but these results were not statistically significant.	('VEGF-C', 'Gene', (0, 6))	('ML221', 'Gene', (60, 65))	('ML221', 'Chemical', 'MESH:C578927', (60, 65))	('expression', 'MPA', (7, 17))	('VEGF-C', 'Gene', '7424', (0, 6))	('increased', 'PosReg', (22, 31))	('treatment', 'Var', (66, 75))
18888	27894959	Results of the wound-healing assay in control and ML221 treated Mz-ChA-1 cells is shown in Fig.	('wound-healing assay', 'CPA', (15, 34))	('ML221', 'Chemical', 'MESH:C578927', (50, 55))	('ML221', 'Var', (50, 55))
18891	27894959	Treatment of Mz-ChA-1 cells with ML221 did not significantly change cell invasion compared to untreated controls (Fig.	('cell invasion', 'CPA', (68, 81))	('ML221', 'Chemical', 'MESH:C578927', (33, 38))	('ML221', 'Var', (33, 38))
18893	27894959	In H69 cells, ML221 significantly decreased wound-healing over 24 h, but statistical significance was lost at 48 h (Supplementary Fig.	('wound-healing', 'CPA', (44, 57))	('ML221', 'Var', (14, 19))	('ML221', 'Chemical', 'MESH:C578927', (14, 19))	('decreased', 'NegReg', (34, 43))
18894	27894959	In HuccT cells, ML221 significantly inhibited wound-healing over 48 h compared to untreated cells (Supplementary Fig.	('inhibited', 'NegReg', (36, 45))	('ML221', 'Chemical', 'MESH:C578927', (16, 21))	('wound-healing over 48 h', 'CPA', (46, 69))	('HuccT', 'CellLine', 'CVCL:3174', (3, 8))	('ML221', 'Var', (16, 21))
18897	27894959	HuH28 cells treated with ML221 showed significantly decreased expression of Ki-67, as well as VEGF-A, VEGF-C, Ang-1 and Ang-2 (Fig.	('Ang-2', 'Gene', (120, 125))	('Ang-1', 'Gene', (110, 115))	('Ang-1', 'Gene', '284', (110, 115))	('HuH28', 'CellLine', 'CVCL:2955', (0, 5))	('decreased', 'NegReg', (52, 61))	('ML221', 'Var', (25, 30))	('expression', 'MPA', (62, 72))	('VEGF-A', 'Gene', '7422', (94, 100))	('Ki-67', 'Gene', (76, 81))	('VEGF-C', 'Gene', '7424', (102, 108))	('VEGF-A', 'Gene', (94, 100))	('Ang-2', 'Gene', '285', (120, 125))	('ML221', 'Chemical', 'MESH:C578927', (25, 30))	('VEGF-C', 'Gene', (102, 108))
18901	27894959	Tumors in mice treated with ML221 were significantly smaller compared to the tumors in the untreated control mice.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('mice', 'Species', '10090', (10, 14))	('ML221', 'Var', (28, 33))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('ML221', 'Chemical', 'MESH:C578927', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mice', 'Species', '10090', (109, 113))	('smaller', 'NegReg', (53, 60))
18905	27894959	Immunoblots were performed on protein isolated form control and ML221 treated Mz-ChA-1 tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ML221', 'Var', (64, 69))	('ML221', 'Chemical', 'MESH:C578927', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('Mz-ChA-1', 'Disease', (78, 86))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
18909	27894959	RtPCR confirmed decreased gene expression of proliferative markers (PCNA, Ki-67), angiogenic factors (VEGF-A, VEGF-C, Ang-1, Ang-2), and markers of tumor progression (Vimentin, MMP-9, MMP-3) in tumors treated with ML221 compare to untreated controls (Fig.	('proliferative', 'CPA', (45, 58))	('MMP-3', 'Gene', '4314', (184, 189))	('Vimentin', 'Gene', '7431', (167, 175))	('VEGF-C', 'Gene', (110, 116))	('Ang-2', 'Gene', '285', (125, 130))	('PCNA', 'Gene', '5111', (68, 72))	('tumor', 'Disease', (194, 199))	('Vimentin', 'Gene', (167, 175))	('VEGF-C', 'Gene', '7424', (110, 116))	('VEGF-A', 'Gene', '7422', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('decreased', 'NegReg', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('Ang-2', 'Gene', (125, 130))	('MMP-9', 'Gene', (177, 182))	('MMP-9', 'Gene', '4318', (177, 182))	('tumors', 'Disease', (194, 200))	('MMP-3', 'Gene', (184, 189))	('PCNA', 'Gene', (68, 72))	('gene expression', 'MPA', (26, 41))	('Ang-1', 'Gene', (118, 123))	('VEGF-A', 'Gene', (102, 108))	('ML221', 'Chemical', 'MESH:C578927', (214, 219))	('tumor', 'Disease', (148, 153))	('Ang-1', 'Gene', '284', (118, 123))	('angiogenic', 'CPA', (82, 92))	('ML221', 'Var', (214, 219))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
18939	27894959	APLNR signaling has also been shown to induce nitric oxide synthase in endothelial cells and decrease intracellular reactive oxygen species, however, it is unclear if these signaling properties also help regulate cell proliferation.	('APLNR', 'Var', (0, 5))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (116, 139))	('intracellular reactive oxygen species', 'MPA', (102, 139))	('nitric oxide synthase', 'MPA', (46, 67))	('decrease', 'NegReg', (93, 101))	('induce', 'PosReg', (39, 45))
18945	27894959	Not only do we show decreased proliferation and angiogenesis in ML221 treated tumors, but we also demonstrate decreased expression of vimentin, MMP-9 and MMP-3.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('MMP-9', 'Gene', (144, 149))	('expression', 'MPA', (120, 130))	('ML221', 'Var', (64, 69))	('decreased', 'NegReg', (20, 29))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('ML221', 'Chemical', 'MESH:C578927', (64, 69))	('decreased', 'NegReg', (110, 119))	('MMP-3', 'Gene', '4314', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MMP-3', 'Gene', (154, 159))	('vimentin', 'Gene', '7431', (134, 142))	('vimentin', 'Gene', (134, 142))	('MMP-9', 'Gene', '4318', (144, 149))	('angiogenesis', 'CPA', (48, 60))	('proliferation', 'CPA', (30, 43))
18961	27894959	An APLNR antagonist may serve as a novel, tumor-directed, treatment strategy to limit tumor neo-vascularization and subsequent disease progression, however, additional studies are needed to determine its therapeutic potential.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (42, 47))	('APLNR', 'Gene', (3, 8))	('tumor', 'Disease', (86, 91))	('limit', 'NegReg', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('antagonist', 'Var', (9, 19))
19010	21994885	Large bile ducts affected by IgG4-SC show transmural inflammation with storiform fibrosis and obliterative phlebitis (Figure 1), whereas inflammation is more extensive on the luminal side with erosion or xanthogranulomatous changes in PSC.	('storiform', 'Disease', (71, 80))	('fibrosis', 'Disease', 'MESH:D005355', (81, 89))	('PSC', 'Gene', (235, 238))	('fibrosis', 'Disease', (81, 89))	('obliterative phlebitis', 'Disease', 'MESH:D010689', (94, 116))	('inflammation', 'Disease', 'MESH:D007249', (53, 65))	('inflammation', 'Disease', 'MESH:D007249', (137, 149))	('Large bile ducts', 'Phenotype', 'HP:0006560', (0, 16))	('obliterative phlebitis', 'Disease', (94, 116))	('inflammation', 'Disease', (53, 65))	('inflammation', 'Disease', (137, 149))	('IgG4-SC', 'Var', (29, 36))	('PSC', 'Gene', '100653366', (235, 238))
19013	21994885	Positivity for ANCA is suggestive of PSC.	('PSC', 'Gene', (37, 40))	('ANCA', 'Disease', (15, 19))	('PSC', 'Gene', '100653366', (37, 40))	('Positivity', 'Var', (0, 10))
19052	32903763	CCND1 Amplification Contributes to Immunosuppression and Is Associated With a Poor Prognosis to Immune Checkpoint Inhibitors in Solid Tumors Cyclin D1 (CCND1) amplification relevant to malignant biological behavior exists in solid tumors.	('Immunosuppression', 'MPA', (35, 52))	('Tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Cyclin D1', 'Gene', (141, 150))	('amplification', 'Var', (159, 172))	('Tumors', 'Disease', (134, 140))	('Tumors', 'Disease', 'MESH:D009369', (134, 140))	('Tumors', 'Phenotype', 'HP:0002664', (134, 140))	('solid tumors', 'Disease', 'MESH:D009369', (225, 237))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('Amplification', 'Var', (6, 19))	('Contributes', 'Reg', (20, 31))	('CCND1', 'Gene', '595', (0, 5))	('CCND1', 'Gene', '595', (152, 157))	('CCND1', 'Gene', (0, 5))	('solid tumors', 'Disease', (225, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('Cyclin D1', 'Gene', '595', (141, 150))	('CCND1', 'Gene', (152, 157))
19053	32903763	The prevalence and utility of CCND1 amplification as a biomarker for the clinical response to treatment with immune checkpoint inhibitors (ICIs) are unknown.	('amplification', 'Var', (36, 49))	('CCND1', 'Gene', (30, 35))	('CCND1', 'Gene', '595', (30, 35))
19054	32903763	Our study is a preliminary investigation mainly focused on the predictive function of CCND1 amplification in the tumor microenvironment (TME) in the aspect of genome and transcriptome.	('CCND1', 'Gene', (86, 91))	('tumor', 'Disease', (113, 118))	('CCND1', 'Gene', '595', (86, 91))	('amplification', 'Var', (92, 105))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
19056	32903763	Comprehensive profiling was performed to determine the prevalence of CCND1 amplification and the correlation with the prognosis and the response to ICIs.	('amplification', 'Var', (75, 88))	('CCND1', 'Gene', (69, 74))	('CCND1', 'Gene', '595', (69, 74))
19057	32903763	A CCND1 amplification occurs in many cancer types and correlates with shorter overall survival and inferior outcomes with ICI therapy.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('amplification', 'Var', (8, 21))	('shorter', 'NegReg', (70, 77))	('CCND1', 'Gene', (2, 7))	('overall survival', 'MPA', (78, 94))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('CCND1', 'Gene', '595', (2, 7))
19059	32903763	The gene set enrichment analysis suggested that CCND1 amplification correlates with multiple aggressive, immunosuppressive hallmarks including epithelial-mesenchymal transition, transforming growth factor (TGF)-beta signaling, KRAS signaling, phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling, p53 pathway, and hypoxia signaling in solid tumors.	('hypoxia', 'Disease', (345, 352))	('tumor', 'Phenotype', 'HP:0002664', (372, 377))	('KRAS', 'Gene', '3845', (227, 231))	('transforming growth factor (TGF)-beta', 'Gene', '7039', (178, 215))	('AKT', 'Gene', (276, 279))	('solid tumors', 'Disease', 'MESH:D009369', (366, 378))	('tumors', 'Phenotype', 'HP:0002664', (372, 378))	('p53', 'Gene', (328, 331))	('hypoxia', 'Disease', 'MESH:D000860', (345, 352))	('phosphoinositide 3-kinase', 'Gene', (243, 268))	('KRAS', 'Gene', (227, 231))	('CCND1', 'Gene', '595', (48, 53))	('correlates', 'Reg', (68, 78))	('mTOR', 'Gene', (311, 315))	('CCND1', 'Gene', (48, 53))	('mammalian target of rapamycin', 'Gene', '2475', (280, 309))	('epithelial-mesenchymal transition', 'CPA', (143, 176))	('AKT', 'Gene', '207', (276, 279))	('mTOR', 'Gene', '2475', (311, 315))	('mammalian target of rapamycin', 'Gene', (280, 309))	('amplification', 'Var', (54, 67))	('solid tumors', 'Disease', (366, 378))	('p53', 'Gene', '7157', (328, 331))	('phosphoinositide 3-kinase', 'Gene', '5295', (243, 268))
19060	32903763	These findings indicate that CCND1 amplification may be a key point related to immunosuppression in TME and multiple malignancy hallmarks, and it hinders not only the natural host immune responses but also the efficacy of ICIs.	('amplification', 'Var', (35, 48))	('hinders', 'NegReg', (146, 153))	('CCND1', 'Gene', (29, 34))	('ICIs', 'CPA', (222, 226))	('malignancy hallmarks', 'Disease', (117, 137))	('malignancy hallmarks', 'Disease', 'MESH:D009369', (117, 137))	('CCND1', 'Gene', '595', (29, 34))
19067	32903763	Recently, several studies revealed that CCND1 amplification associates with a negative response to ICIs.	('negative', 'NegReg', (78, 86))	('response to ICIs', 'MPA', (87, 103))	('amplification', 'Var', (46, 59))	('CCND1', 'Gene', (40, 45))	('CCND1', 'Gene', '595', (40, 45))
19072	32903763	We hypothesized that CCND1 amplification may be associated with poor clinical benefits of ICI therapy through suppressing the antitumor immunity in TME.	('tumor', 'Disease', (130, 135))	('CCND1', 'Gene', '595', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('suppressing', 'NegReg', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('CCND1', 'Gene', (21, 26))	('amplification', 'Var', (27, 40))
19073	32903763	We mainly focused on the predictive function of CCND1 amplification in the TME in the aspect of genome and transcriptome.	('CCND1', 'Gene', (48, 53))	('amplification', 'Var', (54, 67))	('CCND1', 'Gene', '595', (48, 53))
19075	32903763	Importantly, we aimed to explore whether CCND1 amplification correlates with a poor response to ICIs in solid tumors, for which the potential mechanism may be correlated with events within the TME.	('CCND1', 'Gene', '595', (41, 46))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('solid tumors', 'Disease', (104, 116))	('amplification', 'Var', (47, 60))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('CCND1', 'Gene', (41, 46))
19083	32903763	Survival information and RSEM-normalized gene-level data from cancers with CCND1 amplification frequency ranked first to 10th were further downloaded.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('amplification frequency', 'Var', (81, 104))	('CCND1', 'Gene', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('CCND1', 'Gene', '595', (75, 80))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
19085	32903763	Patients with CCND1 amplification or neutral phenotypes were further analyzed.	('amplification', 'Var', (20, 33))	('Patients', 'Species', '9606', (0, 8))	('CCND1', 'Gene', (14, 19))	('CCND1', 'Gene', '595', (14, 19))
19089	32903763	Survival information from cancers with CCND1 amplification frequency ranked first to 10th was further downloaded.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('CCND1', 'Gene', (39, 44))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('amplification frequency', 'Var', (45, 68))	('CCND1', 'Gene', '595', (39, 44))
19092	32903763	To explore the association between CCND1 amplification and the clinical outcomes of ICIs, we included CNA and clinical data from four clinical cohorts treated with ICIs.	('amplification', 'Var', (41, 54))	('CCND1', 'Gene', (35, 40))	('CCND1', 'Gene', '595', (35, 40))
19100	32903763	Based on the hallmark gene sets, Gene Set Enrichment Analysis (GSEA) software version 3.0 (Broad Institute) was used to identify the different regulated pathways between the CCND1 amplification and neutral groups in the TCGA pan-cancer cohort ( NES  > 1, NOM P-value <0.10, FDR q-value <0.25).	('GSEA', 'Chemical', '-', (63, 67))	('amplification', 'Var', (180, 193))	('CCND1', 'Gene', '595', (174, 179))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('CCND1', 'Gene', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
19106	32903763	Gene expression analysis from the TCGA database showed that CCND1 amplification was significantly related to the upregulation of mRNA expression of CCND1 across the top nine cancer types (TCGA pan-cancer: cancers with CCND1 amplification frequency ranked first to 10th; CHOL was excluded because of the limited number of samples) (Figure 1B).	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('CCND1', 'Gene', (218, 223))	('CCND1', 'Gene', (60, 65))	('CHOL', 'Disease', (270, 274))	('mRNA expression', 'MPA', (129, 144))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('amplification', 'Var', (66, 79))	('cancers', 'Disease', (205, 212))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', (197, 203))	('CCND1', 'Gene', '595', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('CCND1', 'Gene', (148, 153))	('upregulation', 'PosReg', (113, 125))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('CHOL', 'Disease', 'None', (270, 274))	('CCND1', 'Gene', '595', (218, 223))	('CCND1', 'Gene', '595', (60, 65))
19107	32903763	Next, we examined the association of CCND1 amplification with clinical outcome for pan-cancer in the TCGA and MSKCC databases.	('cancer', 'Disease', (87, 93))	('CCND1', 'Gene', (37, 42))	('amplification', 'Var', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CCND1', 'Gene', '595', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
19108	32903763	Kaplan-Meier survival analysis showed that CCND1 amplification was not associated with median OS for pan-cancer in the TCGA database.	('amplification', 'Var', (49, 62))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('CCND1', 'Gene', (43, 48))	('median OS', 'Disease', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('CCND1', 'Gene', '595', (43, 48))
19109	32903763	The median OS for the CCND1 amplification and CCND1 neutral groups was 1,838.0 and 2,133.0 days, respectively [P = 0.1305, HR 1.13 (95% CI 0.96-1.32); Figure 1C].	('CCND1', 'Gene', (46, 51))	('CCND1', 'Gene', (22, 27))	('CCND1', 'Gene', '595', (46, 51))	('CCND1', 'Gene', '595', (22, 27))	('amplification', 'Var', (28, 41))
19112	32903763	The median OS for the CCND1 amplification and CCND1 neutral groups was 1,079.0 and 2,002.0 days, respectively [P = 0.0125, HR 1.51 (95% CI 1.07-2.11); Figure S1A].	('CCND1', 'Gene', (46, 51))	('CCND1', 'Gene', (22, 27))	('CCND1', 'Gene', '595', (46, 51))	('CCND1', 'Gene', '595', (22, 27))	('amplification', 'Var', (28, 41))
19113	32903763	For melanoma in the MSKCC database, the median OS for the CCND1 amplification and CCND1 neutral groups was 13.5 months and not reached [P = 0.0139, HR 2.56 (95% CI 0.79-8.29); Figure S1B].	('CCND1', 'Gene', '595', (58, 63))	('amplification', 'Var', (64, 77))	('CCND1', 'Gene', (82, 87))	('CCND1', 'Gene', (58, 63))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('CCND1', 'Gene', '595', (82, 87))	('melanoma', 'Disease', (4, 12))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))
19119	32903763	Based on the impact of CCND1 amplification as a negative prognostic factor for efficacy of ICIs in melanoma, we further investigated its role in patients with a solid tumor.	('patients', 'Species', '9606', (145, 153))	('amplification', 'Var', (29, 42))	('CCND1', 'Gene', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('negative', 'NegReg', (48, 56))	('CCND1', 'Gene', '595', (23, 28))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('tumor', 'Disease', (167, 172))
19120	32903763	To validate CCND1 amplification as a clinical factor associated with poor prognosis in patients with solid tumors treated with ICIs, we performed three analyses.	('solid tumors', 'Disease', 'MESH:D009369', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('CCND1', 'Gene', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('CCND1', 'Gene', '595', (12, 17))	('solid tumors', 'Disease', (101, 113))	('amplification', 'Var', (18, 31))	('patients', 'Species', '9606', (87, 95))
19122	32903763	Fifty-two patients with CCND1 amplification were identified comprising of 14 melanomas, 11 head and neck carcinomas (HNCs), 11 bladder carcinomas, eight non-small-cell lung carcinomas, five breast carcinomas, three esophagogastric carcinomas, and one glioma (Table S3).	('melanomas', 'Disease', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('glioma', 'Disease', 'MESH:D005910', (251, 257))	('amplification', 'Var', (30, 43))	('carcinomas', 'Disease', 'MESH:D009369', (105, 115))	('lung carcinomas', 'Disease', 'MESH:D008175', (168, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Disease', (173, 183))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('carcinomas', 'Disease', (197, 207))	('lung carcinomas', 'Disease', (168, 183))	('carcinomas', 'Disease', 'MESH:D009369', (135, 145))	('CCND1', 'Gene', '595', (24, 29))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('neck carcinomas', 'Disease', 'MESH:D006258', (100, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('head and neck carcinomas', 'Phenotype', 'HP:0012288', (91, 115))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('HNCs', 'Phenotype', 'HP:0012288', (117, 121))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('carcinomas', 'Disease', 'MESH:D009369', (231, 241))	('carcinomas', 'Phenotype', 'HP:0030731', (231, 241))	('breast carcinomas', 'Disease', 'MESH:D001943', (190, 207))	('CCND1', 'Gene', (24, 29))	('breast carcinomas', 'Disease', (190, 207))	('neck carcinomas', 'Disease', (100, 115))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (127, 144))	('carcinomas', 'Disease', 'MESH:D009369', (173, 183))	('esophagogastric', 'Disease', (215, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('carcinomas', 'Disease', 'MESH:D009369', (197, 207))	('carcinomas', 'Phenotype', 'HP:0030731', (197, 207))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (127, 145))	('patients', 'Species', '9606', (10, 18))	('carcinomas', 'Disease', (105, 115))	('breast carcinomas', 'Phenotype', 'HP:0003002', (190, 207))	('bladder carcinomas', 'Disease', 'MESH:D001749', (127, 145))	('breast carcinoma', 'Phenotype', 'HP:0003002', (190, 206))	('small-cell lung carcinomas', 'Phenotype', 'HP:0030357', (157, 183))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('carcinomas', 'Disease', (135, 145))	('non-small-cell lung carcinomas', 'Phenotype', 'HP:0030358', (153, 183))	('carcinomas', 'Disease', (231, 241))	('glioma', 'Disease', (251, 257))	('bladder carcinomas', 'Disease', (127, 145))
19123	32903763	Across the entire cohort, CCND1 amplification was associated with a decreased OS.	('CCND1', 'Gene', (26, 31))	('decreased', 'NegReg', (68, 77))	('amplification', 'Var', (32, 45))	('CCND1', 'Gene', '595', (26, 31))
19124	32903763	The median OS for the CCND1 amplification and CCND1 neutral groups was 11.0 and 18.0 months, respectively [P = 0.0024, HR 1.63 (95% CI 1.09-2.43); Figure 2B].	('CCND1', 'Gene', (46, 51))	('CCND1', 'Gene', (22, 27))	('CCND1', 'Gene', '595', (46, 51))	('CCND1', 'Gene', '595', (22, 27))	('amplification', 'Var', (28, 41))
19125	32903763	We performed a stratified analysis with the melanoma (n = 231) and bladder carcinoma patients (n = 111) and observed a similar association between CCND1 amplification with a shorter OS.	('CCND1', 'Gene', '595', (147, 152))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('amplification', 'Var', (153, 166))	('melanoma', 'Disease', (44, 52))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (67, 84))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('patients', 'Species', '9606', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('bladder carcinoma', 'Disease', 'MESH:D001749', (67, 84))	('CCND1', 'Gene', (147, 152))	('bladder carcinoma', 'Disease', (67, 84))
19126	32903763	In melanoma (n = 231), the median OS for the CCND1 amplification and CCND1 neutral groups was 22.0 and 42.0 months [P = 0.0029, HR 2.48 (95% CI 0.99-6.23); Figure S1D].	('CCND1', 'Gene', (45, 50))	('CCND1', 'Gene', '595', (69, 74))	('CCND1', 'Gene', '595', (45, 50))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('CCND1', 'Gene', (69, 74))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('amplification', 'Var', (51, 64))
19127	32903763	In bladder carcinoma (n = 111), the median OS for the CCND1 amplification and CCND1 neutral groups was 8.0 and 16.0 months, respectively [P = 0.0244, HR 2.17 (95% CI 0.83-5.66); Figure S1E].	('bladder carcinoma', 'Phenotype', 'HP:0002862', (3, 20))	('amplification', 'Var', (60, 73))	('bladder carcinoma', 'Disease', (3, 20))	('bladder carcinoma', 'Disease', 'MESH:D001749', (3, 20))	('CCND1', 'Gene', (78, 83))	('CCND1', 'Gene', (54, 59))	('CCND1', 'Gene', '595', (78, 83))	('CCND1', 'Gene', '595', (54, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
19128	32903763	Recent studies have shown that a high level of TMB associates with improved survival in patients receiving ICIs across a wide variety of cancer types.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('TMB', 'Chemical', '-', (47, 50))	('high', 'Var', (33, 37))	('survival', 'MPA', (76, 84))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('TMB', 'MPA', (47, 50))	('improved', 'PosReg', (67, 75))
19131	32903763	The median TMB for the CCND1 amplification and CCND1 neutral groups was 6.79 vs. 5.90 (P = 0.46; Figure S2).	('amplification', 'Var', (29, 42))	('TMB', 'Chemical', '-', (11, 14))	('CCND1', 'Gene', (23, 28))	('CCND1', 'Gene', (47, 52))	('CCND1', 'Gene', '595', (23, 28))	('CCND1', 'Gene', '595', (47, 52))	('TMB', 'MPA', (11, 14))
19134	32903763	Of note, according to a study by Robert M. Samstein et al., in patients treated with ICIs, there is a significant association between a high level of TMB and a better OS.	('high', 'Var', (136, 140))	('better', 'Disease', (160, 166))	('TMB', 'MPA', (150, 153))	('patients', 'Species', '9606', (63, 71))	('TMB', 'Chemical', '-', (150, 153))
19135	32903763	But in our stratified analysis, in spite of a high level of TMB, patients with CCND1 amplification have a significantly decreased median OS [10.0 vs. 41.0 months, HR 2.82 (95% CI 1.11-7.20), P = 0.0003; Figure 2D].	('decreased', 'NegReg', (120, 129))	('CCND1', 'Gene', '595', (79, 84))	('median OS', 'MPA', (130, 139))	('amplification', 'Var', (85, 98))	('patients', 'Species', '9606', (65, 73))	('CCND1', 'Gene', (79, 84))	('TMB', 'Chemical', '-', (60, 63))
19136	32903763	Finally, a multivariable analysis using Cox proportional-hazards regression demonstrated that CCND1 amplification was significantly associated with a shorter median OS [HR 1.60 (95% CI 1.16-2.21), P = 0.0040], with adjustment for TMB, cancer type, age, drug class of ICI, and the year of ICI start (Table S4).	('amplification', 'Var', (100, 113))	('TMB', 'Chemical', '-', (230, 233))	('CCND1', 'Gene', (94, 99))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('median OS [', 'MPA', (158, 169))	('CCND1', 'Gene', '595', (94, 99))	('shorter', 'NegReg', (150, 157))
19138	32903763	reported 319 patients with CCND1 amplification and 46 cases received ICIs.	('CCND1', 'Gene', (27, 32))	('amplification', 'Var', (33, 46))	('patients', 'Species', '9606', (13, 21))	('CCND1', 'Gene', '595', (27, 32))
19149	32903763	For example, the median values of B cells (-0.1870 vs. -0.1691, P < 0.001), T cells (-0.2160 vs. -0.1935, P = 0.0090), CD8+ T cells (0.0914 vs. 0.1009, P < 0.001), and DC cells (-0.1810 vs. -0.1465, P = 0.0170) were significantly attenuated in the CCND1 amplification group in breast cancer, while Th2 cells (0.05419 vs. 0.0148, P < 0.001) and MDSCs (0.0051 vs. -0.0198, P = 0.0094) appear upregulated (Figure S4).	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('-0.1870', 'Var', (43, 50))	('CCND1', 'Gene', '595', (248, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('CD8', 'Gene', (119, 122))	('breast cancer', 'Disease', (277, 290))	('attenuated', 'NegReg', (230, 240))	('CD8', 'Gene', '925', (119, 122))	('0.0051 vs. -0.0198', 'Var', (351, 369))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('0.05419', 'Var', (309, 316))	('CCND1', 'Gene', (248, 253))	('upregulated', 'PosReg', (390, 401))	('-0.2160', 'Var', (85, 92))
19150	32903763	The signature of immune cell subsets in HNSCC showed a dramatic decrease in median values of cytotoxic cells (-0.1418 vs. -0.0970, P = 0.0030), T cells (-0.2357 vs. -0.2056, P = 0.0010), CD8+ T cells (0.0730 vs. 0.0761, P = 0.1310), DC cells (-0.2267 vs. -0.1796, P < 0.001), and B cells (-0.1676 vs. -0.1373, P < 0.001), while MDSCs (0.0250 vs. -0.0058, P < 0.001) (Figure S4).	('decrease', 'NegReg', (64, 72))	('-0.1676', 'Var', (289, 296))	('-0.1418', 'Var', (110, 117))	('-0.2357', 'Var', (153, 160))	('B cells', 'CPA', (280, 287))	('DC cells', 'CPA', (233, 241))	('CD8', 'Gene', (187, 190))	('HNSCC', 'Phenotype', 'HP:0012288', (40, 45))	('CD8', 'Gene', '925', (187, 190))	('T cells', 'CPA', (144, 151))	('0.0730 vs. 0.0761', 'Var', (201, 218))
19151	32903763	To investigate signaling pathways activated for CCND1 amplification tumors, we performed GSEA comparing the CCND1 amplification group and the CCND1 neutral group in the TCGA pan-cancer cohort.	('CCND1', 'Gene', (142, 147))	('amplification', 'Var', (114, 127))	('tumors', 'Disease', (68, 74))	('CCND1', 'Gene', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('CCND1', 'Gene', '595', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('CCND1', 'Gene', '595', (142, 147))	('GSEA', 'Chemical', '-', (89, 93))	('CCND1', 'Gene', '595', (108, 113))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CCND1', 'Gene', (48, 53))
19158	32903763	Another study showed that cyclin D1 (encoded by CCND1) may play a key role in the maintenance of VEGFs, and antisense to cyclin D1 could be useful for targeting both cancer cells and blood vessels in tumors.	('cyclin D1', 'Gene', (121, 130))	('antisense', 'Var', (108, 117))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('CCND1', 'Gene', '595', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('cyclin D1', 'Gene', '595', (26, 35))	('cyclin D1', 'Gene', (26, 35))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cyclin D1', 'Gene', '595', (121, 130))	('CCND1', 'Gene', (48, 53))
19161	32903763	We found that CCND1 amplification can hinder not only the natural host immune response but also the efficacy of ICIs.	('CCND1', 'Gene', '595', (14, 19))	('hinder', 'NegReg', (38, 44))	('ICIs', 'CPA', (112, 116))	('amplification', 'Var', (20, 33))	('CCND1', 'Gene', (14, 19))
19162	32903763	A CCND1 amplification may potentially identify a patient population that will not benefit from ICIs irrespective of TMB status.	('TMB', 'Chemical', '-', (116, 119))	('amplification', 'Var', (8, 21))	('CCND1', 'Gene', (2, 7))	('patient', 'Species', '9606', (49, 56))	('CCND1', 'Gene', '595', (2, 7))
19164	32903763	To our knowledge, our results are the first to reveal that a CCND1 amplification may significantly correlate with tumorigenesis and attenuation of various types of effector immune cells in the TME, including cytotoxic cells, T cells, CD8+ T cells, DC cells, and B cells, and upregulation of Treg cells and MDSCs.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('upregulation', 'PosReg', (275, 287))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('amplification', 'Var', (67, 80))	('CCND1', 'Gene', (61, 66))	('Treg cells', 'CPA', (291, 301))	('CD8', 'Gene', (234, 237))	('tumor', 'Disease', (114, 119))	('CD8', 'Gene', '925', (234, 237))	('CCND1', 'Gene', '595', (61, 66))	('attenuation', 'NegReg', (132, 143))
19167	32903763	In our analysis of the TCGA pan-cancer cohort, CCND1 amplification showed a statistically significant correlation with high mRNA expression of TGFB1.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('amplification', 'Var', (53, 66))	('CCND1', 'Gene', (47, 52))	('TGFB1', 'Gene', (143, 148))	('high mRNA expression', 'MPA', (119, 139))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('CCND1', 'Gene', '595', (47, 52))	('TGFB1', 'Gene', '7040', (143, 148))
19168	32903763	More importantly, further study showed significant upregulation of mRNA expression of VEGFA, another known factor inducing tumor immune escape and immunotherapy resistance, associated with the CCND1 amplification phenotype.	('upregulation', 'PosReg', (51, 63))	('tumor', 'Disease', (123, 128))	('CCND1', 'Gene', (193, 198))	('amplification phenotype', 'Var', (199, 222))	('VEGFA', 'Gene', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('VEGFA', 'Gene', '7422', (86, 91))	('CCND1', 'Gene', '595', (193, 198))	('mRNA expression', 'MPA', (67, 82))
19169	32903763	From the survival analysis in TCGA and MSKCC public databases, we found no significant correlation between CCND1 amplification with prognosis in the pan-cancer group.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('CCND1', 'Gene', '595', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('amplification', 'Var', (113, 126))	('CCND1', 'Gene', (107, 112))
19174	32903763	Meanwhile, the analysis of the transcriptome showed that the amplification of CCND1 was strongly correlated with higher expression level of mRNA.	('expression level of mRNA', 'MPA', (120, 144))	('higher', 'PosReg', (113, 119))	('CCND1', 'Gene', (78, 83))	('amplification', 'Var', (61, 74))	('CCND1', 'Gene', '595', (78, 83))
19175	32903763	Thirdly, according to our investigation, activations of a variety of oncogenes and deactivations of tumor suppressor genes were observed along with the amplification of CCND1 in different cancer types.	('amplification', 'Var', (152, 165))	('deactivations', 'MPA', (83, 96))	('activations', 'PosReg', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('CCND1', 'Gene', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('CCND1', 'Gene', '595', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('oncogenes', 'Gene', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
19177	32903763	Nevertheless, the CCND1 amplification is a potential predictive biomarker for the use of ICIs in patients with solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('CCND1', 'Gene', '595', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('amplification', 'Var', (24, 37))	('CCND1', 'Gene', (18, 23))	('solid tumors', 'Disease', (111, 123))	('patients', 'Species', '9606', (97, 105))
19178	32903763	In the melanoma pooled cohort, the median OS was shorter in the CCND1 amplification subgroup.	('melanoma', 'Disease', 'MESH:D008545', (7, 15))	('shorter', 'NegReg', (49, 56))	('median OS', 'MPA', (35, 44))	('CCND1', 'Gene', (64, 69))	('CCND1', 'Gene', '595', (64, 69))	('melanoma', 'Phenotype', 'HP:0002861', (7, 15))	('melanoma', 'Disease', (7, 15))	('amplification', 'Var', (70, 83))
19179	32903763	The survival analysis in the MSKCC-IO cohort further verified the negative impact of CCND1 amplification on the efficacy of ICIs.	('ICIs', 'CPA', (124, 128))	('CCND1', 'Gene', '595', (85, 90))	('amplification', 'Var', (91, 104))	('CCND1', 'Gene', (85, 90))	('negative', 'NegReg', (66, 74))
19180	32903763	Strikingly, by comparing CCND1 amplification with TMB in patients with solid tumors from the MSKCC-IO cohort, we found that the association between CCND1 amplification and a worse clinical outcome was more distinct in TMB-high patients.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('CCND1', 'Gene', (25, 30))	('CCND1', 'Gene', (148, 153))	('solid tumors', 'Disease', (71, 83))	('patients', 'Species', '9606', (57, 65))	('TMB', 'Chemical', '-', (218, 221))	('CCND1', 'Gene', '595', (25, 30))	('CCND1', 'Gene', '595', (148, 153))	('amplification', 'Var', (154, 167))	('solid tumors', 'Disease', 'MESH:D009369', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('TMB', 'Chemical', '-', (50, 53))	('patients', 'Species', '9606', (227, 235))	('TMB-high', 'Disease', (218, 226))
19181	32903763	This indicates that ICIs may not be useful, and even harmful, to patients with CCND1 amplification.	('CCND1', 'Gene', '595', (79, 84))	('amplification', 'Var', (85, 98))	('patients', 'Species', '9606', (65, 73))	('CCND1', 'Gene', (79, 84))
19182	32903763	First, various types of effector immune cell exclusion and immunosuppression in the TME were found in tumors with CCND1 amplification.	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('CCND1', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('CCND1', 'Gene', '595', (114, 119))	('amplification', 'Var', (120, 133))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
19183	32903763	Second, CCND1 amplification results in high mRNA expression of TGFB1, VEGFA, and HIF1A; these molecules have direct or indirect negative effects on components of the immune system.	('TGFB1', 'Gene', '7040', (63, 68))	('VEGFA', 'Gene', (70, 75))	('HIF1A', 'Gene', (81, 86))	('CCND1', 'Gene', (8, 13))	('HIF1A', 'Gene', '3091', (81, 86))	('mRNA expression', 'MPA', (44, 59))	('TGFB1', 'Gene', (63, 68))	('negative', 'NegReg', (128, 136))	('VEGFA', 'Gene', '7422', (70, 75))	('CCND1', 'Gene', '595', (8, 13))	('amplification', 'Var', (14, 27))
19184	32903763	Finally, some oncogene pathways are activated in CCND1 amplification tumor that may lead to acceleration of tumor growth.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('amplification', 'Var', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CCND1', 'Gene', '595', (49, 54))	('tumor', 'Disease', (69, 74))	('oncogene pathways', 'Pathway', (14, 31))	('activated', 'PosReg', (36, 45))	('tumor', 'Disease', (108, 113))	('acceleration', 'PosReg', (92, 104))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('CCND1', 'Gene', (49, 54))
19185	32903763	Recently, a study reported on five patients experiencing hyper-progression who had NGS performed on pretreatment tumor tissue, and it confirmed CNAs in MDM2/MDM4, epidermal growth factor receptor (EGFR), and several genes located on 11q13 associated with hyper-progression.	('associated', 'Reg', (239, 249))	('tumor', 'Disease', (113, 118))	('MDM4', 'Gene', (157, 161))	('MDM4', 'Gene', '4194', (157, 161))	('epidermal growth factor receptor', 'Gene', '1956', (163, 195))	('epidermal growth factor receptor', 'Gene', (163, 195))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('EGFR', 'Gene', '1956', (197, 201))	('patients', 'Species', '9606', (35, 43))	('CNAs', 'Var', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('MDM2', 'Gene', '4193', (152, 156))	('EGFR', 'Gene', (197, 201))	('MDM2', 'Gene', (152, 156))
19187	32903763	Considering the immunosuppression in the TME and overexpression of various oncogenes caused by CCND1 amplification, patients with such features should avoid ICI monotherapy.	('patients', 'Species', '9606', (116, 124))	('CCND1', 'Gene', (95, 100))	('amplification', 'Var', (101, 114))	('CCND1', 'Gene', '595', (95, 100))
19190	32903763	The small number of CCND1 amplification tumors and the rarity of the event suggest that further additional data are warranted.	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('amplification', 'Var', (26, 39))	('CCND1', 'Gene', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('CCND1', 'Gene', '595', (20, 25))
19191	32903763	Our study is a preliminary investigation mainly focused on the predictive function of CCND1 amplification in the tumor microenvironment in the aspect of genome and transcriptome.	('CCND1', 'Gene', (86, 91))	('tumor', 'Disease', (113, 118))	('CCND1', 'Gene', '595', (86, 91))	('amplification', 'Var', (92, 105))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
19194	32903763	These findings indicate that CCND1 amplification may be a key point related to immunosuppression in the TME and multiple malignancy hallmark; it may be a common mechanism of resistance to ICIs.	('malignancy hallmark', 'Disease', (121, 140))	('amplification', 'Var', (35, 48))	('malignancy hallmark', 'Disease', 'MESH:D009369', (121, 140))	('CCND1', 'Gene', (29, 34))	('related', 'Reg', (68, 75))	('CCND1', 'Gene', '595', (29, 34))
19238	30760718	Here we comprehensively analyze the genomic alterations of the genes encoding histone acetylation modulator proteins (HAMPs) in the Cancer Genome Atlas cohort and observe that HAMPs have a high frequency of focal copy number alterations and recurrent mutations, whereas transcript fusions of HAMPs are relatively rare genomic events in common adult cancers.	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('mutations', 'Var', (251, 260))	('Cancer Genome Atlas cohort', 'Disease', 'MESH:D009369', (132, 158))	('cancers', 'Phenotype', 'HP:0002664', (349, 356))	('Cancer Genome Atlas cohort', 'Disease', (132, 158))	('focal', 'MPA', (207, 212))	('adult cancers', 'Disease', (343, 356))	('HAMP', 'Gene', '57817', (292, 296))	('adult cancers', 'Disease', 'MESH:C535836', (343, 356))	('HAMP', 'Gene', (292, 296))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('HAMP', 'Gene', '57817', (176, 180))	('HAMP', 'Gene', '57817', (118, 122))	('HAMP', 'Gene', (176, 180))	('HAMP', 'Gene', (118, 122))
19240	30760718	For example, the recurrent focal amplification of BRD9 is observed in 9 cancer types and genetic depletion of BRD9 inhibits tumor growth.	('genetic depletion', 'Var', (89, 106))	('BRD9', 'Gene', '65980', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('BRD9', 'Gene', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', (124, 129))	('BRD9', 'Gene', (50, 54))	('inhibits', 'NegReg', (115, 123))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('BRD9', 'Gene', '65980', (110, 114))	('cancer', 'Disease', (72, 78))
19288	30760718	BRD9, BRD4, KAT6A, ATAD2, CLOCK, ASH1L, and BPTF showed high overall G-scores for copy number gain, whereas HDAC4, BRD1, SIRT3, HDAC10, SP100, SP140L, SP110, and PBRM1 had high overall G-scores for copy number loss (overall G-score > 0.9; Fig.	('BRD4', 'Gene', '23476', (6, 10))	('BPTF', 'Gene', (44, 48))	('SP140L', 'Gene', (143, 149))	('SP110', 'Gene', '3431', (151, 156))	('ATAD2', 'Gene', (19, 24))	('KAT6A', 'Gene', '7994', (12, 17))	('HDAC10', 'Gene', '83933', (128, 134))	('SIRT3', 'Gene', (121, 126))	('ASH1L', 'Gene', (33, 38))	('SIRT3', 'Gene', '23410', (121, 126))	('BRD9', 'Gene', '65980', (0, 4))	('copy number gain', 'Disease', 'MESH:D015430', (82, 98))	('CLOCK', 'Gene', '9575', (26, 31))	('CLOCK', 'Gene', (26, 31))	('BRD1', 'Gene', (115, 119))	('HDAC4', 'Gene', '9759', (108, 113))	('copy number', 'Var', (198, 209))	('ASH1L', 'Gene', '55870', (33, 38))	('copy number gain', 'Disease', (82, 98))	('KAT6A', 'Gene', (12, 17))	('SP110', 'Gene', (151, 156))	('SP100', 'Gene', '6672', (136, 141))	('BRD4', 'Gene', (6, 10))	('SP140L', 'Gene', '93349', (143, 149))	('BRD9', 'Gene', (0, 4))	('PBRM1', 'Gene', '55193', (162, 167))	('ATAD2', 'Gene', '29028', (19, 24))	('BRD1', 'Gene', '23774', (115, 119))	('HDAC10', 'Gene', (128, 134))	('HDAC4', 'Gene', (108, 113))	('BPTF', 'Gene', '2186', (44, 48))	('PBRM1', 'Gene', (162, 167))	('SP100', 'Gene', (136, 141))
19290	30760718	3b); in contrast, high-level alterations (GISTIC status = - 2) were markedly less frequent in HAMPs with copy number loss (0.8-9.4%; Fig.	('HAMP', 'Gene', (94, 98))	('HAMP', 'Gene', '57817', (94, 98))	('copy number loss', 'Var', (105, 121))
19294	30760718	The mutation call set was generated via an ensemble calling strategy by the MC3 (Multi-Center Mutation Calling in Multiple Cancers) project, then we integrated five complementary methods to identify the genes with mutations that have significant signs of positive selection during tumor evolution (Fig.	('Multiple Cancers', 'Disease', (114, 130))	('MC3', 'Gene', (76, 79))	('Multiple Cancers', 'Disease', 'MESH:D009369', (114, 130))	('MC3', 'Gene', '4159', (76, 79))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Cancers', 'Phenotype', 'HP:0002664', (123, 130))	('mutations', 'Var', (214, 223))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumor', 'Disease', (281, 286))
19295	30760718	Collectively, across 33 cancer types, we identified 34 HAMPs that have recurrent mutations in at least one cancer type (Fig.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('HAMP', 'Gene', '57817', (55, 59))	('HAMP', 'Gene', (55, 59))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
19297	30760718	3b), the recurrent mutations of HAMPs were largely cancer type-specific (Fig.	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', (51, 57))	('HAMP', 'Gene', '57817', (32, 36))	('HAMP', 'Gene', (32, 36))
19298	30760718	4b): 17 of 34 (50%) HAMPs with recurrent mutations were only observed in one cancer type and no recurrent mutation of HAMPs was found in more than 7 cancer types.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('HAMP', 'Gene', '57817', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('HAMP', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('HAMP', 'Gene', '57817', (118, 122))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('HAMP', 'Gene', (118, 122))
19300	30760718	UCEC (n = 20), SKCM (n = 8), BLCA (n = 6), cervical squamous cell carcinoma, and endocervical adenocarcinoma (CESC; n = 6), and HNSC (n = 6) had the largest numbers of recurrent mutations in HAMPs, whereas ACC, DLBC, ESCA, KICH, LAML, LGG, mesothelioma (MESO), OV, PAAD, PCPG, READ, SARC, TGCT, THCA, THYM, UCS, and UVM had none (Fig.	('READ', 'Disease', 'None', (277, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('KICH', 'Disease', (223, 227))	('PAAD', 'Phenotype', 'HP:0006725', (265, 269))	('cervical squamous cell carcinoma', 'Disease', (43, 75))	('UCS', 'Phenotype', 'HP:0002891', (307, 310))	('OV', 'Phenotype', 'HP:0012887', (261, 263))	('mesothelioma', 'Disease', (240, 252))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (81, 108))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 75))	('HAMP', 'Gene', '57817', (191, 195))	('mesothelioma', 'Disease', 'MESH:D008654', (240, 252))	('ACC', 'Phenotype', 'HP:0006744', (206, 209))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))	('ESCA', 'Phenotype', 'HP:0011459', (217, 221))	('READ', 'Disease', (277, 281))	('KICH', 'Disease', 'None', (223, 227))	('HAMP', 'Gene', (191, 195))	('THYM', 'Phenotype', 'HP:0100522', (301, 305))	('THCA', 'Phenotype', 'HP:0002890', (295, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('mutations', 'Var', (178, 187))	('endocervical adenocarcinoma', 'Disease', (81, 108))
19301	30760718	Among the three types of HAMPs, BRD proteins and HATs had the highest frequencies of recurrent mutations and HDACs had few recurrent events (Fig.	('HAMP', 'Gene', '57817', (25, 29))	('HDAC', 'Gene', (109, 113))	('HAMP', 'Gene', (25, 29))	('HDAC', 'Gene', '9734', (109, 113))	('mutations', 'Var', (95, 104))
19303	30760718	Among eight HAMPs with M-scores > 0.4, EP300, PBRM1, and CREBBP had the largest overall M-scores across the 33 cancer types (Fig.	('CREBBP', 'Gene', (57, 63))	('HAMP', 'Gene', '57817', (12, 16))	('HAMP', 'Gene', (12, 16))	('M-scores', 'MPA', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('CREBBP', 'Gene', '1387', (57, 63))	('PBRM1', 'Gene', (46, 51))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('EP300', 'Gene', (39, 44))	('EP300', 'Gene', '2033', (39, 44))	('PBRM1', 'Gene', '55193', (46, 51))	('M-scores > 0.4', 'Var', (23, 37))
19305	30760718	At a pan-cancer level, except for PBRM1, the most common mutation category of HAMPs was missense mutation (53.0-77.5%; Fig.	('cancer', 'Disease', (9, 15))	('HAMP', 'Gene', (78, 82))	('PBRM1', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('PBRM1', 'Gene', '55193', (34, 39))	('missense mutation', 'Var', (88, 105))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('HAMP', 'Gene', '57817', (78, 82))
19306	30760718	In contrast, PBRM1 was most commonly affected by truncating mutations (49.1%; Fig.	('truncating mutations', 'Var', (49, 69))	('PBRM1', 'Gene', (13, 18))	('PBRM1', 'Gene', '55193', (13, 18))	('affected', 'Reg', (37, 45))
19307	30760718	Using the ABSOLUTE algorithm, we also determined the timing of the mutational processes and the clonal statuses of the mutations in HAMPs.	('HAMP', 'Gene', (132, 136))	('mutations', 'Var', (119, 128))	('HAMP', 'Gene', '57817', (132, 136))
19308	30760718	More than 50% of mutations in HAMPs were early genomic events (Fig.	('HAMP', 'Gene', '57817', (30, 34))	('mutations', 'Var', (17, 26))	('HAMP', 'Gene', (30, 34))
19309	30760718	5d and Supplementary Data 15) and more than 65% of mutations in HAMPs were clonal mutations (Fig.	('HAMP', 'Gene', (64, 68))	('mutations', 'Var', (51, 60))	('HAMP', 'Gene', '57817', (64, 68))
19311	30760718	We also analyzed the distributions of the mutations across the gene bodies and found that mutations in HAMPs were widely spatially distributed along the entire coding sequences, not concentrated within a specific local region (Fig.	('HAMP', 'Gene', '57817', (103, 107))	('mutations', 'Var', (90, 99))	('HAMP', 'Gene', (103, 107))
19314	30760718	Notably, we observed that PBRM1 mutations showed a unique pattern in KIRC and cholangiocarcinoma (CHOL).	('CHOL', 'Phenotype', 'HP:0030153', (98, 102))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 96))	('PBRM1', 'Gene', (26, 31))	('PBRM1', 'Gene', '55193', (26, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (78, 96))	('mutations', 'Var', (32, 41))	('KIRC', 'Disease', (69, 73))	('cholangiocarcinoma', 'Disease', (78, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
19315	30760718	Compared with other cancer types, KIRC and CHOL showed higher frequencies of PBRM1 mutations (40.1% in KIRC and 19.4% in CHOL vs. an average of 2.3% among other cancer types).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (83, 92))	('PBRM1', 'Gene', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('PBRM1', 'Gene', '55193', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('CHOL', 'Phenotype', 'HP:0030153', (121, 125))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', (161, 167))	('CHOL', 'Phenotype', 'HP:0030153', (43, 47))
19316	30760718	Importantly, the dominant PBRM1 mutation category and type in KIRC and CHOL were truncating (83.9% and 85.7%, respectively) and homozygous (85.2% and 71.4%, respectively) mutations, which were remarkably higher than the averages in other cancer types (30.3% and 19.4%, respectively).	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('PBRM1', 'Gene', (26, 31))	('PBRM1', 'Gene', '55193', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('truncating', 'MPA', (81, 91))	('mutation', 'Var', (32, 40))	('CHOL', 'Phenotype', 'HP:0030153', (71, 75))
19317	30760718	Interestingly, we observed that, in both the CREBBP and EP300 genes, the most frequent mutations were located within the catalytic domain, although the mutations were not statistically significant hotspot mutations at the individual gene level based on OncodriveCLUST analysis (Fig.	('CREBBP', 'Gene', '1387', (45, 51))	('EP300', 'Gene', (56, 61))	('EP300', 'Gene', '2033', (56, 61))	('CREBBP', 'Gene', (45, 51))	('mutations', 'Var', (87, 96))
19324	30760718	6a and Supplementary Data 18), which suggests that transcript fusion is a rare genetic alteration compared with SCNAs and mutations in HAMPs in common adult cancers.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('adult cancers', 'Disease', 'MESH:C535836', (151, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('adult cancers', 'Disease', (151, 164))	('transcript fusion', 'Var', (51, 68))	('HAMP', 'Gene', '57817', (135, 139))	('HAMP', 'Gene', (135, 139))
19328	30760718	KAT6B-ADK (n = 6), BPTF-PITPNC1 (n = 5), and NCOA3-EYA2 (n = 5) were the most frequent fusions among the common cancer types examined in our study (Fig.	('fusions', 'Var', (87, 94))	('PITPNC1', 'Gene', '26207', (24, 31))	('cancer', 'Disease', (112, 118))	('BPTF', 'Gene', (19, 23))	('PITPNC1', 'Gene', (24, 31))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('NCOA3', 'Gene', '8202', (45, 50))	('EYA2', 'Gene', '2139', (51, 55))	('BPTF', 'Gene', '2186', (19, 23))	('EYA2', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('NCOA3', 'Gene', (45, 50))
19332	30760718	Taken together, these results suggest that, although certain HAMP transcript fusions may be actionable for clinical cancer care, transcript fusion is a rare genomic alteration compared with SCNAs and mutations of HAMPs in common cancers.	('HAMP', 'Gene', '57817', (61, 65))	('cancer', 'Disease', (229, 235))	('HAMP', 'Gene', (61, 65))	('transcript fusion', 'Var', (129, 146))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancers', 'Disease', (229, 236))	('HAMP', 'Gene', '57817', (213, 217))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('HAMP', 'Gene', (213, 217))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
19336	30760718	Across the different lineages of cancers, three types of alterations were observed: (1) consistent, putative gain-of-function (such as for KAT6A and CLOCK, which were focally amplified in six and five cancer types, respectively); (2) consistent, putative loss-of-function (such as for PBRM1, which is mutated in four and focally deleted in five cancer types, and for CREBBP, which is mutated in four and focally deleted in two cancer types); and (3) diverse alterations (such as for ATAD2, which is mutated in three and focally amplified in five cancer types, and for BPTF, which is mutated in three and focally amplified in five cancer types).	('gain-of-function', 'PosReg', (109, 125))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', (630, 636))	('cancer', 'Disease', 'MESH:D009369', (427, 433))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (345, 351))	('KAT6A', 'Gene', '7994', (139, 144))	('ATAD2', 'Gene', '29028', (483, 488))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('loss-of-function', 'NegReg', (255, 271))	('cancers', 'Disease', (33, 40))	('CREBBP', 'Gene', (367, 373))	('cancer', 'Disease', (546, 552))	('PBRM1', 'Gene', '55193', (285, 290))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (630, 636))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Disease', (427, 433))	('KAT6A', 'Gene', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (546, 552))	('ATAD2', 'Gene', (483, 488))	('PBRM1', 'Gene', (285, 290))	('cancer', 'Phenotype', 'HP:0002664', (427, 433))	('BPTF', 'Gene', '2186', (568, 572))	('CREBBP', 'Gene', '1387', (367, 373))	('cancer', 'Disease', (345, 351))	('CLOCK', 'Gene', '9575', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('CLOCK', 'Gene', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (546, 552))	('BPTF', 'Gene', (568, 572))	('deleted', 'Var', (329, 336))
19337	30760718	This suggests that a large fraction of HAMP alterations may be commonly shared by multiple cancer types, whereas others may be tumor-lineage dependent.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('HAMP', 'Gene', (39, 43))	('HAMP', 'Gene', '57817', (39, 43))	('multiple cancer', 'Disease', (82, 97))	('tumor', 'Disease', (127, 132))	('alterations', 'Var', (44, 55))	('multiple cancer', 'Disease', 'MESH:D009369', (82, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
19366	30760718	Consistent with the GBA prediction, knocking down BRD9 expression dramatically inhibited cancer cell growth in vitro (Fig.	('BRD9', 'Gene', '65980', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('BRD9', 'Gene', (50, 54))	('expression', 'MPA', (55, 65))	('cancer', 'Disease', (89, 95))	('inhibited', 'NegReg', (79, 88))	('knocking down', 'Var', (36, 49))	('GBA', 'Chemical', '-', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
19367	30760718	Finally, we demonstrated that the expression of BRD9 shRNAs significantly suppressed the growth of subcutaneous tumors formed by MDA-MB-231 or OVCAR8 cells in nude mice (Fig.	('subcutaneous tumors', 'Disease', (99, 118))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (129, 139))	('BRD9', 'Gene', (48, 52))	('nude mice', 'Species', '10090', (159, 168))	('OV', 'Phenotype', 'HP:0012887', (143, 145))	('suppressed', 'NegReg', (74, 84))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (99, 118))	('expression', 'Var', (34, 44))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (99, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('growth', 'CPA', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('BRD9', 'Gene', '65980', (48, 52))
19368	30760718	Collectively, our results demonstrate that genetic depletion of BDR9 expression significantly represses tumor cell growth in vitro and in vivo, suggesting that small molecular compounds targeting BRD9 may have strong clinical application potentials.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('BDR9', 'Gene', (64, 68))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('represses', 'NegReg', (94, 103))	('BRD9', 'Gene', '65980', (196, 200))	('BRD9', 'Gene', (196, 200))	('genetic depletion', 'Var', (43, 60))
19376	30760718	A HAMP with a high score indicates its recurrent alterations are common genomic events across multiple adult cancer types.	('HAMP', 'Gene', '57817', (2, 6))	('alterations', 'Var', (49, 60))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('HAMP', 'Gene', (2, 6))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
19389	30760718	Furthermore, genetic depletion of HDACs in tumor cells leads to cell cycle arrest, apoptosis, and senescence, suggesting that HDACs are required for the survival and growth of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('genetic depletion', 'Var', (13, 30))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('senescence', 'CPA', (98, 108))	('HDAC', 'Gene', (126, 130))	('HDAC', 'Gene', '9734', (34, 38))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (64, 81))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('apoptosis', 'CPA', (83, 92))	('tumor', 'Disease', (43, 48))	('HDAC', 'Gene', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('cell cycle arrest', 'CPA', (64, 81))	('HDAC', 'Gene', '9734', (126, 130))
19393	30760718	In contrast, PBRM1 showed high-frequency, cancer type-specific mutations in KIRC (40.1%).	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('PBRM1', 'Gene', (13, 18))	('PBRM1', 'Gene', '55193', (13, 18))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
19399	30760718	Collectively, our comprehensive genomic analysis identified 63 putative cancer-causing HAMPs driven by SCNAs and/or mutations (recurrent score >= 1).	('SCNAs', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (116, 125))	('HAMP', 'Gene', '57817', (87, 91))	('HAMP', 'Gene', (87, 91))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
19402	30760718	For example, the breast and ovarian cancer patients with BRD4 amplifications may be potential candidates for treatment with BET inhibitors that have been successfully developed to the preclinical stage.	('BET', 'Gene', '92737', (124, 127))	('BET', 'Gene', (124, 127))	('ovarian cancer', 'Phenotype', 'HP:0100615', (28, 42))	('patients', 'Species', '9606', (43, 51))	('BRD4', 'Gene', (57, 61))	('amplifications', 'Var', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('BRD4', 'Gene', '23476', (57, 61))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (17, 42))
19403	30760718	In addition, eight HAMPs focally lost copy numbers (overall G-score > 0.9) and eight HAMPs showed high frequencies of mutations (overall M-score > 0.4), which indicates that their functions may be reduced and/or deficient due to partial loss of wild-type alleles during cancer development.	('HAMP', 'Gene', (19, 23))	('deficient', 'NegReg', (212, 221))	('copy', 'MPA', (38, 42))	('HAMP', 'Gene', '57817', (85, 89))	('functions', 'MPA', (180, 189))	('mutations', 'Var', (118, 127))	('HAMP', 'Gene', (85, 89))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('lost', 'NegReg', (33, 37))	('HAMP', 'Gene', '57817', (19, 23))
19405	30760718	For example, mutations of the BRD-containing protein SMARCA4 in tumor cells results in a unique functional dependence on SMARCA2.	('tumor', 'Disease', (64, 69))	('functional dependence', 'MPA', (96, 117))	('SMARCA4', 'Gene', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mutations', 'Var', (13, 22))	('SMARCA2', 'Gene', (121, 128))	('SMARCA2', 'Gene', '6595', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('results in', 'Reg', (76, 86))	('SMARCA4', 'Gene', '6597', (53, 60))
19407	30760718	Notably, very few homozygous deletions or mutations of HAMPs (except for PBRM1) were observed in cancer, suggesting that HAMPs may be essential for tumor growth, and that complete loss may be lethal.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', (148, 153))	('mutations', 'Var', (42, 51))	('HAMP', 'Gene', '57817', (55, 59))	('PBRM1', 'Gene', '55193', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('HAMP', 'Gene', (55, 59))	('HAMP', 'Gene', '57817', (121, 125))	('HAMP', 'Gene', (121, 125))	('deletions', 'Var', (29, 38))	('PBRM1', 'Gene', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
19421	30760718	Our genomic and functional studies demonstrated that: (1) BRD9 is recurrently and focally amplified in nine cancer types with the highest recurrent score; (2) the expression of BRD9 is significantly increased in cancer specimens compared with that in corresponding normal tissues; (3) computational prediction suggests that BRD9 expression is associated with cell cycle, DNA damage repair, and RNA metabolic pathways in cancer; and (4) genetic depletion of BRD9 by shRNAs reduced cancer cell growth in vitro and in vivo.	('associated', 'Reg', (343, 353))	('genetic depletion', 'Var', (436, 453))	('BRD9', 'Gene', (324, 328))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (480, 486))	('cancer', 'Disease', (420, 426))	('BRD9', 'Gene', '65980', (324, 328))	('BRD9', 'Gene', (457, 461))	('cancer', 'Phenotype', 'HP:0002664', (420, 426))	('BRD9', 'Gene', '65980', (457, 461))	('BRD9', 'Gene', (58, 62))	('BRD9', 'Gene', (177, 181))	('cancer', 'Disease', (212, 218))	('BRD9', 'Gene', '65980', (58, 62))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (420, 426))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Disease', (480, 486))	('reduced', 'NegReg', (472, 479))	('BRD9', 'Gene', '65980', (177, 181))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (480, 486))
19427	30760718	Taken together, our functional studies on BRD9 are the proof-of-concept for the HAMP candidates identified in our study and strongly suggest the clinical potential of targeting BRD9 in common adult solid cancers.	('BRD9', 'Gene', (42, 46))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('targeting', 'Var', (167, 176))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('BRD9', 'Gene', '65980', (177, 181))	('BRD9', 'Gene', (177, 181))	('HAMP', 'Gene', '57817', (80, 84))	('HAMP', 'Gene', (80, 84))	('BRD9', 'Gene', '65980', (42, 46))
19432	30760718	The gene expression data of 2012 cancer cell lines were downloaded through the Expression Atlas (https://www.ebi.ac.uk/gxa/download.html) under the accessions E-MTAB-2770, E-MTAB-3983, and E-MTAB-2706.	('E-MTAB-2770', 'Var', (159, 170))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('MTAB-2706', 'CellLine', 'CVCL:A552', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('E-MTAB-2706', 'Var', (189, 200))
19456	30760718	ABSOLUTE calculated the purity, ploidy, and absolute DNA copy numbers from the segmented copy number alterations and mutation profiles of tumor samples.	('alterations', 'Var', (101, 112))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', (138, 143))
19459	30760718	The cancer cell fraction of each somatic single-nucleotide variant was extracted from the output.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('single-nucleotide variant', 'Var', (41, 66))
19508	26089873	NAFLD can lead to nonalcoholic steatohepatitis (NASH), eventual cirrhosis, and HCC.	('cirrhosis', 'Phenotype', 'HP:0001394', (64, 73))	('cirrhosis', 'Disease', 'MESH:D005355', (64, 73))	('NAFLD', 'Var', (0, 5))	('nonalcoholic steatohepatitis', 'Disease', (18, 46))	('hepatitis', 'Phenotype', 'HP:0012115', (37, 46))	('lead to', 'Reg', (10, 17))	('HCC', 'Disease', (79, 82))	('HCC', 'Phenotype', 'HP:0001402', (79, 82))	('nonalcoholic steatohepatitis', 'Disease', 'MESH:D065626', (18, 46))	('cirrhosis', 'Disease', (64, 73))
19529	26089873	While the prognostic value of these tumor markers is not well defined, a small report from the Mayo Clinic evaluating 50 patients found that serum CA19-9 >100 U/mL was associated with a sensitivity of 53% for the diagnosis of cholangiocarcinoma and a specificity of 75-90%.	('serum CA19-9 >100 U/mL', 'Var', (141, 163))	('CA19-9', 'Chemical', 'MESH:C086528', (147, 153))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (226, 244))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (226, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Mayo', 'Species', '162683', (95, 99))	('tumor', 'Disease', (36, 41))	('patients', 'Species', '9606', (121, 129))	('cholangiocarcinoma', 'Disease', (226, 244))
19532	26089873	Reports of more specific serum marks such as CYFRA21-1, claudin-4, insulin-like growth factor binding protein 5 (IGFBP-5), and biglycan exist; however, none of these are routinely clinically used.	('claudin-4', 'Gene', '1364', (56, 65))	('insulin-like growth factor binding protein 5', 'Gene', (67, 111))	('IGFBP-5', 'Gene', (113, 120))	('claudin-4', 'Gene', (56, 65))	('CYFRA21-1', 'Var', (45, 54))	('insulin-like growth factor binding protein 5', 'Gene', '3488', (67, 111))	('IGFBP-5', 'Gene', '3488', (113, 120))
19584	26089873	In a small study of 90 patients which included pancreatic (53 patients) as well as biliary tract cancers (37 patients), 5-FU, leucovorin, and etoposide therapy showed a significantly longer overall survival time versus best supportive care (median 6 versus 2.5 months; P < 0.01).	('etoposide', 'Chemical', 'MESH:D005047', (142, 151))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('leucovorin', 'Chemical', 'MESH:D002955', (126, 136))	('5-FU', 'Chemical', 'MESH:D005472', (120, 124))	('pancreatic', 'Disease', 'MESH:D010195', (47, 57))	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (23, 31))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (83, 103))	('overall survival', 'MPA', (190, 206))	('biliary tract cancers', 'Disease', (83, 104))	('pancreatic', 'Disease', (47, 57))	('biliary tract cancers', 'Disease', 'MESH:D001661', (83, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('longer', 'PosReg', (183, 189))	('patients', 'Species', '9606', (62, 70))	('5-FU', 'Var', (120, 124))
19643	24753059	identified a panel of five microRNAs (191, 486-3p, 1274b, 16 and 484) with potential clinical utility as an accurate biomarker for cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (131, 149))	('191', 'Var', (38, 41))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (131, 149))
19654	24753059	Proteomic analysis has identified several biomarkers within bile, including proteins such as CA19-9, Neutrophil gelatinase-associated lipocalin, carcinoembryonic cell adhesion molecule 6, S100 and RNU2-1f.	('CA19-9', 'Var', (93, 99))	('S100', 'Gene', (188, 192))	('Neutrophil gelatinase-associated lipocalin', 'Gene', (101, 143))	('Neutrophil gelatinase-associated lipocalin', 'Gene', '3934', (101, 143))	('S100', 'Gene', '6271', (188, 192))	('carcinoembryonic', 'Disease', (145, 161))	('carcinoembryonic', 'Disease', 'None', (145, 161))
19661	24753059	Deregulated expression of microRNA in cholangiocarcinoma has now been shown in several studies and justifies further study of the contribution of their transfer via extracellular vesicles on disease pathogenesis and spread.	('cholangiocarcinoma', 'Disease', (38, 56))	('microRNA', 'Protein', (26, 34))	('Deregulated', 'Var', (0, 11))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (38, 56))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (38, 56))	('expression', 'MPA', (12, 22))
19667	24753059	Further studies to examine other tumor-associated markers such as gene mutations in IDH1 and 2, BAP1 or FGFR2 fusions within extracellular vesicles may allow us to further improve sensitivity for early diagnosis of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (215, 233))	('FGFR2', 'Gene', (104, 109))	('BAP1', 'Gene', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('FGFR2', 'Gene', '2263', (104, 109))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (215, 233))	('improve', 'PosReg', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('cholangiocarcinoma', 'Disease', (215, 233))	('BAP1', 'Gene', '8314', (96, 100))	('IDH1 and 2', 'Gene', '3417;3418', (84, 94))	('fusions', 'Var', (110, 117))
19708	32221351	Here by analyzing miRNA expression data from 40 human healthy tissues and those from human body fluids, including plasma, serum, urine, bile, and feces, we revealed a positive correlation between BF-miRNAs and T-miRNAs.	('human', 'Species', '9606', (48, 53))	('T-miRNAs', 'MPA', (210, 218))	('BF', 'Chemical', 'MESH:C006703', (196, 198))	('BF-miRNAs', 'Var', (196, 205))	('human', 'Species', '9606', (85, 90))
19714	32221351	Therefore, the dysfunctions of miRNAs could be associated with a wide range of diseases, including cancer and cardiovascular disease.	('dysfunctions', 'Var', (15, 27))	('cardiovascular disease', 'Disease', (110, 132))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('miRNAs', 'Protein', (31, 37))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (110, 132))	('associated', 'Reg', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cardiovascular disease', 'Disease', 'MESH:D002318', (110, 132))
19783	30202637	In turn, Pazopanib in combination with another TKI drug Trametinib showed a trend to increase 4-month progression-free survival as compared with the prespecified null hypothesized 4-month PFS of 25%.	('Trametinib', 'Chemical', 'MESH:C560077', (56, 66))	('Pazopanib', 'Var', (9, 18))	('increase', 'PosReg', (85, 93))	('progression-free survival', 'CPA', (102, 127))	('Pazopanib', 'Chemical', 'MESH:C516667', (9, 18))
19842	24504124	Possibly, alterations in Wnt, transforming growth factor-beta, Notch and hypoxia pathways in these LPCs can cause them to give rise to cancer stem cells, capable of driving tumourigenesis.	('tumour', 'Disease', (173, 179))	('cancer', 'Disease', (135, 141))	('alterations', 'Var', (10, 21))	('Wnt', 'Pathway', (25, 28))	('give rise to', 'Reg', (122, 134))	('transforming growth factor-beta', 'Gene', '7040', (30, 61))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('LPC', 'Chemical', '-', (99, 102))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('hypoxia', 'Disease', 'MESH:D000860', (73, 80))	('transforming growth factor-beta', 'Gene', (30, 61))	('cause', 'Reg', (108, 113))	('Notch', 'Pathway', (63, 68))	('hypoxia', 'Disease', (73, 80))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
19870	24504124	Firstly, the clonal evolution model, which presumes that a single cell acquires random mutations and gives rise to a group of identical tumour cells, each with equal potential to generate a tumour.	('tumour', 'Disease', (190, 196))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('tumour', 'Disease', (136, 142))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('mutations', 'Var', (87, 96))	('tumour', 'Disease', 'MESH:D009369', (190, 196))
19899	24504124	In HCC cells, inhibition of TGF-beta has been reported to upregulate epithelial-cadherin (E-cadherin) and thereby lower migration and invasion potential.	('TGF-beta', 'Gene', (28, 36))	('epithelial-cadherin', 'Gene', '12550', (69, 88))	('epithelial-cadherin', 'Gene', (69, 88))	('upregulate', 'PosReg', (58, 68))	('lower', 'NegReg', (114, 119))	('HCC', 'Phenotype', 'HP:0001402', (3, 6))	('inhibition', 'Var', (14, 24))	('E-cadherin', 'Gene', (90, 100))	('E-cadherin', 'Gene', '12550', (90, 100))
19903	24504124	Furthermore, in patients, high nuclear beta-catenin accumulation is correlated with higher vascular invasion grades and increased recurrence after transplantation.	('nuclear beta-catenin accumulation', 'MPA', (31, 64))	('high', 'Var', (26, 30))	('vascular invasion grades', 'CPA', (91, 115))	('recurrence', 'CPA', (130, 140))	('patients', 'Species', '9606', (16, 24))	('higher', 'PosReg', (84, 90))
19908	24504124	Like the Wnt and TGF-beta pathway, aberrant Notch signalling is well described in many different kinds of cancer, such as breast, lung, colorectal, pancreatic and hepatic cancer.	('Notch signalling', 'MPA', (44, 60))	('pancreatic and hepatic cancer', 'Disease', 'MESH:D010190', (148, 177))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('aberrant', 'Var', (35, 43))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('hepatic cancer', 'Phenotype', 'HP:0002896', (163, 177))	('cancer', 'Disease', (171, 177))	('colorectal', 'Disease', (136, 146))	('cancer', 'Disease', (106, 112))	('lung', 'Disease', (130, 134))	('breast', 'Disease', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
19909	24504124	However, deregulation of the Notch pathway has been described as both oncogenic and tumour suppressive, depending on tissue type and circumstances.	('tumour', 'Disease', (84, 90))	('Notch pathway', 'Pathway', (29, 42))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('deregulation', 'Var', (9, 21))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
19910	24504124	For example, the effect of Notch signalling on hepatocarcinogenesis can be determined by its effect on several players in cell cycle control such as p53, cyclin-A, -D1 and -E. Induction of p53 in HepG2 cells, leads to an increased expression of NICD and downregulation of the cells proliferative capacity, but not the other way around.	('hepatocarcinogenesis', 'Disease', (47, 67))	('increased', 'PosReg', (221, 230))	('cyclin-A, -D1 and -E', 'Gene', '12428;12443', (154, 174))	('downregulation', 'NegReg', (254, 268))	('Induction', 'Var', (176, 185))	('cells proliferative capacity', 'CPA', (276, 304))	('HepG2', 'CellLine', 'CVCL:0027', (196, 201))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (47, 67))	('NICD', 'MPA', (245, 249))	('expression', 'MPA', (231, 241))	('p53', 'Gene', (189, 192))
19913	24504124	In accordance, Notch pathway inhibition by DAPT (gamma-secretase inhibitor) in adult mice after conditional deletion of retinoblastoma protein family genes in the liver, which causes proliferation of the progenitor compartment, resulted in an increased number of HCC nodules.	('mice', 'Species', '10090', (85, 89))	('DAPT', 'Chemical', '-', (43, 47))	('retinoblastoma', 'Phenotype', 'HP:0009919', (120, 134))	('Notch pathway', 'Pathway', (15, 28))	('inhibition', 'NegReg', (29, 39))	('HCC nodules', 'CPA', (263, 274))	('HCC', 'Phenotype', 'HP:0001402', (263, 266))	('retinoblastoma', 'Disease', 'MESH:D012175', (120, 134))	('increased', 'PosReg', (243, 252))	('retinoblastoma', 'Disease', (120, 134))	('deletion', 'Var', (108, 116))
19929	24504124	Also, administration of EF24, could synergistically enhance the antitumour effects of sorafenib, reduce metastasis and overcome sorafenib resistance through inhibiting HIF-1alpha by sequestering it in the cytoplasm and promoting degradation by upregulating the Von Hippel-Lindau tumour suppressor in five different cell lines and in both xenograft and orthotopic mouse models for HCC.	('metastasis', 'CPA', (104, 114))	('sorafenib', 'Chemical', 'MESH:D000077157', (86, 95))	('inhibiting', 'NegReg', (157, 167))	('degradation', 'MPA', (229, 240))	('HCC', 'Phenotype', 'HP:0001402', (380, 383))	('reduce', 'NegReg', (97, 103))	('mouse', 'Species', '10090', (363, 368))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('promoting', 'PosReg', (219, 228))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('tumour', 'Disease', (68, 74))	('HIF-1alpha', 'Gene', '15251', (168, 178))	('Von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (261, 285))	('tumour', 'Phenotype', 'HP:0002664', (279, 285))	('EF24', 'Var', (24, 28))	('sequestering', 'NegReg', (182, 194))	('enhance', 'PosReg', (52, 59))	('tumour', 'Disease', 'MESH:D009369', (279, 285))	('HIF-1alpha', 'Gene', (168, 178))	('tumour', 'Disease', (279, 285))	('sorafenib', 'Chemical', 'MESH:D000077157', (128, 137))	('upregulating', 'PosReg', (244, 256))	('Von Hippel-Lindau tumour', 'Disease', (261, 285))
19945	24504124	As discussed here, the major target of altered signalling could be the EMT, a major process in malignant conversion, provoking hepatocytes to exhibit more stem/progenitor-like features and thus increasing the pool of cancer cells with an LPC signature.	('provoking', 'PosReg', (117, 126))	('LPC', 'Chemical', '-', (238, 241))	('hepatocytes', 'MPA', (127, 138))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('altered', 'Var', (39, 46))	('increasing', 'PosReg', (194, 204))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('stem/progenitor-like features', 'CPA', (155, 184))
19972	23593604	The very rare cause of serious adverse events associated with the use of SonoVue is an anaphylactoid reaction, but the incidence of this phenomenon has been lower than those when using other imaging contrast agents for X-ray imaging and CT. Also, UCAs can be used in patients with iodine allergy or renal dysfunction.	('anaphylactoid reaction', 'Phenotype', 'HP:0100845', (87, 109))	('renal dysfunction', 'Phenotype', 'HP:0000083', (299, 316))	('SonoVue', 'Var', (73, 80))	('renal dysfunction', 'Disease', (299, 316))	('patients', 'Species', '9606', (267, 275))	('iodine allergy', 'Phenotype', 'HP:0012394', (281, 295))	('allergy', 'Disease', (288, 295))	('renal dysfunction', 'Disease', 'MESH:D007674', (299, 316))	('UCA', 'Chemical', '-', (247, 250))	('allergy', 'Phenotype', 'HP:0012393', (288, 295))	('allergy', 'Disease', 'MESH:D004342', (288, 295))	('iodine', 'Chemical', 'MESH:D007455', (281, 287))
19975	23593604	For example, 0.06 is selected as an optimal MI for SonoVue according to manufacturer's recommendations when using the iU22 ultrasound system, and 0.2 is recommended for Sonazoid when using the Logiq 7 device (Table 2).	('Sonazoid', 'Chemical', 'MESH:C069727', (169, 177))	('0.06', 'Var', (13, 17))	('SonoVue', 'MPA', (51, 58))
20098	33660222	In PC, adjuvant treatment with mFOLFIRINOX has improved overall survival (OS) and in BTC adjuvant treatment with capecitabine seems to improve OS and relapse-free survival.	('improved', 'PosReg', (47, 55))	('overall survival', 'MPA', (56, 72))	('BTC', 'Phenotype', 'HP:0100574', (85, 88))	('relapse-free survival', 'CPA', (150, 171))	('OS', 'Gene', '17451', (143, 145))	('capecitabine', 'Chemical', 'MESH:D000069287', (113, 125))	('PC', 'Phenotype', 'HP:0002894', (3, 5))	('mFOLFIRINOX', 'Chemical', '-', (31, 42))	('mFOLFIRINOX', 'Var', (31, 42))	('OS', 'Gene', '17451', (74, 76))	('improve', 'PosReg', (135, 142))
20121	33660222	KRAS mutations make the pancreatic ductal cells as well as these ADM cells to remain ductal, upregulate EGFR signaling, and progress to PanIN1.	('EGFR', 'Gene', '1956', (104, 108))	('PanIN1', 'Disease', (136, 142))	('EGFR', 'Gene', (104, 108))	('mutations', 'Var', (5, 14))	('progress', 'PosReg', (124, 132))	('KRAS', 'Gene', (0, 4))	('upregulate', 'PosReg', (93, 103))	('KRAS', 'Gene', '3845', (0, 4))
20122	33660222	The evolution to PanIN2 needs additional mutations in tumor suppressor genes like CDKN2A.	('mutations', 'Var', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('CDKN2A', 'Gene', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('CDKN2A', 'Gene', '1029', (82, 88))	('tumor', 'Disease', (54, 59))
20123	33660222	Inactivation of other suppressor genes like SMAD4, BRCA2, TP53, etc.	('BRCA2', 'Gene', (51, 56))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('SMAD4', 'Gene', (44, 49))	('BRCA2', 'Gene', '675', (51, 56))	('SMAD4', 'Gene', '4089', (44, 49))	('Inactivation', 'Var', (0, 12))
20125	33660222	After BRG1 inactivation, KRAS mutated duct cells may also progress to IPMN and some of them to invasive IPMN or PDAC through consecutive gene alterations.	('BRG1', 'Gene', '6597', (6, 10))	('IPMN', 'Disease', (70, 74))	('inactivation', 'Var', (11, 23))	('PDAC', 'Phenotype', 'HP:0006725', (112, 116))	('progress', 'PosReg', (58, 66))	('BRG1', 'Gene', (6, 10))	('KRAS', 'Gene', (25, 29))	('PDAC', 'Chemical', '-', (112, 116))	('KRAS', 'Gene', '3845', (25, 29))
20181	33660222	Napoli trial demonstrated a superior OS, PFS, and RR in patients treated with 5-fluorouracil and nal-IRI compared with patients treated with 5-Fluorouracil alone.	('patients', 'Species', '9606', (56, 64))	('PFS', 'MPA', (41, 44))	('patients', 'Species', '9606', (119, 127))	('5-Fluorouracil', 'Chemical', 'MESH:D005472', (141, 155))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (78, 92))	('nal-IRI', 'Chemical', 'MESH:C584112', (97, 104))	('OS', 'Gene', '17451', (37, 39))	('5-fluorouracil', 'Var', (78, 92))
20185	33660222	Pancreatic cancer patients with mutations in BRCA1 or BRCA2 with a prevalence between 6 and 7% would be especially sensitive to platinum-based chemotherapy.	('Pancreatic cancer', 'Disease', (0, 17))	('platinum', 'Chemical', 'MESH:D010984', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('BRCA1', 'Gene', '672', (45, 50))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('BRCA1', 'Gene', (45, 50))	('mutations', 'Var', (32, 41))	('BRCA2', 'Gene', (54, 59))	('sensitive', 'Reg', (115, 124))	('patients', 'Species', '9606', (18, 26))	('BRCA2', 'Gene', '675', (54, 59))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))
20187	33660222	The POLO trial evaluated Olaparib as maintenance therapy for individuals with germline BRCA1/2 mutations and mPDAC that was stable or responded after at least 4 months of platinum-based chemotherapy.	('BRCA1/2', 'Gene', (87, 94))	('PDAC', 'Chemical', '-', (110, 114))	('BRCA1/2', 'Gene', '672;675', (87, 94))	('Olaparib', 'Chemical', 'MESH:C531550', (25, 33))	('platinum', 'Chemical', 'MESH:D010984', (171, 179))	('PDAC', 'Phenotype', 'HP:0006725', (110, 114))	('mutations', 'Var', (95, 104))
20195	33660222	Current data favor an approach of frontline platinum-based chemotherapy followed by maintenance with Olaparib with mPDAC with germline BRCA 1 and BRCA2 mutations (I, A).	('mutations', 'Var', (152, 161))	('BRCA2', 'Gene', '675', (146, 151))	('PDAC', 'Phenotype', 'HP:0006725', (116, 120))	('BRCA 1', 'Gene', '672', (135, 141))	('BRCA 1', 'Gene', (135, 141))	('platinum', 'Chemical', 'MESH:D010984', (44, 52))	('PDAC', 'Chemical', '-', (116, 120))	('Olaparib', 'Chemical', 'MESH:C531550', (101, 109))	('BRCA2', 'Gene', (146, 151))
20242	33660222	Potentially targetable genetic alterations occur in around 40-60% of BTC patients.	('BTC', 'Phenotype', 'HP:0100574', (69, 72))	('genetic alterations', 'Var', (23, 42))	('patients', 'Species', '9606', (73, 81))	('BTC', 'Disease', (69, 72))
20243	33660222	Interestingly, these aberrations distribution is according to the anatomic location: in ICC are found mostly mutations in IDH1/2, BAP1, and ARID1A and FGFR rearrangements, while in ECC are more frequently found novel fusions in PRKACA/PRKACB and mutations in ARID1B (see Fig.	('BAP1', 'Gene', (130, 134))	('ARID1A', 'Gene', '8289', (140, 146))	('PRKACB', 'Gene', (235, 241))	('ARID1A', 'Gene', (140, 146))	('FGFR', 'Gene', (151, 155))	('ARID1B', 'Gene', (259, 265))	('IDH1/2', 'Gene', (122, 128))	('mutations', 'Var', (246, 255))	('fusions', 'Var', (217, 224))	('mutations', 'Var', (109, 118))	('PRKACA', 'Gene', (228, 234))	('BAP1', 'Gene', '8314', (130, 134))	('rearrangements', 'Var', (156, 170))	('PRKACB', 'Gene', '5567', (235, 241))	('ARID1B', 'Gene', '57492', (259, 265))	('PRKACA', 'Gene', '5566', (228, 234))	('IDH1/2', 'Gene', '3417;3418', (122, 128))
20244	33660222	Alterations in DNA repair genes (MSH6, BAP1, ATM, MLH1, MSH2, BRCA1 and BRCA2) are relatively frequent: up to 16% of ICC and 45% of ECC display mutations in these genes.	('MLH1', 'Gene', '4292', (50, 54))	('BRCA2', 'Gene', (72, 77))	('ICC', 'Disease', (117, 120))	('MLH1', 'Gene', (50, 54))	('MSH2', 'Gene', '4436', (56, 60))	('ATM', 'Gene', '472', (45, 48))	('BRCA1', 'Gene', '672', (62, 67))	('Alterations', 'Var', (0, 11))	('BRCA2', 'Gene', '675', (72, 77))	('MSH6', 'Gene', (33, 37))	('BRCA1', 'Gene', (62, 67))	('BAP1', 'Gene', '8314', (39, 43))	('MSH2', 'Gene', (56, 60))	('ATM', 'Gene', (45, 48))	('mutations', 'Var', (144, 153))	('MSH6', 'Gene', '2956', (33, 37))	('BAP1', 'Gene', (39, 43))
20246	33660222	The most frequent actionable alterations are IDH1/2 gain of function mutations and FGFR2 fusions/rearrangements, found in around 5-36% and 8-25%, respectively, of CC cases, mostly ICC.	('mutations', 'Var', (69, 78))	('FGFR2', 'Gene', (83, 88))	('ICC', 'Disease', (180, 183))	('IDH1/2', 'Gene', '3417;3418', (45, 51))	('FGFR2', 'Gene', '2263', (83, 88))	('nab', 'Chemical', '-', (23, 26))	('fusions/rearrangements', 'Var', (89, 111))	('IDH1/2', 'Gene', (45, 51))	('gain of function', 'PosReg', (52, 68))
20247	33660222	Amplification of HER2 (3-19%) is more frequent in GBC and ECC than in ICC.	('Amplification', 'Var', (0, 13))	('HER2', 'Gene', (17, 21))	('GBC', 'Disease', (50, 53))	('HER2', 'Gene', '2064', (17, 21))	('ECC', 'Disease', (58, 61))
20248	33660222	BRAF (~ 5%) and BRCA2 mutations (~ 5%), fusion genes involving the genes NTRK1/2/3 (4%), ROS (8-9%), ALK (3%) and mismatch repair deficiency (dMMR) and/or high microsatellite instability (MSI-H) (3% in ICC, 2% ECC and 6% in GBC) are quite rare in BTC.	('ALK', 'Gene', (101, 104))	('ICC', 'Disease', (202, 205))	('OS', 'Gene', '17451', (90, 92))	('BRCA2', 'Gene', '675', (16, 21))	('BRCA2', 'Gene', (16, 21))	('ALK', 'Gene', '238', (101, 104))	('NTRK1/2/3', 'Gene', (73, 82))	('MSI', 'Gene', (188, 191))	('MSI', 'Gene', '5928', (188, 191))	('NTRK1/2/3', 'Gene', '4914;4915;4916', (73, 82))	('mutations', 'Var', (22, 31))	('BRAF', 'Gene', '673', (0, 4))	('BTC', 'Phenotype', 'HP:0100574', (247, 250))	('BRAF', 'Gene', (0, 4))	('ECC', 'Disease', (210, 213))	('high', 'Var', (155, 159))
20249	33660222	The main targetable genetic aberrations (IDH1 and BRAF mutations, FGFR fusions, HER2 amplification) can be identified in circulating tumour DNA (ctDNA) in around 20% of BTC patients.	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('BRAF', 'Gene', (50, 54))	('HER2', 'Gene', '2064', (80, 84))	('HER2', 'Gene', (80, 84))	('patients', 'Species', '9606', (173, 181))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('fusions', 'Var', (71, 78))	('tumour', 'Disease', (133, 139))	('FGFR', 'Gene', (66, 70))	('IDH1', 'Gene', (41, 45))	('BRAF', 'Gene', '673', (50, 54))	('IDH1', 'Gene', '3417', (41, 45))	('BTC', 'Phenotype', 'HP:0100574', (169, 172))
20250	33660222	Recommendations For patients with MMR/MSI-H tumors and BRCA 1/2 mutations consider referral to genetic counseling and germline testing (III, B).	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('MSI-H tumors', 'Disease', (38, 50))	('MSI-H tumors', 'Disease', 'MESH:D009369', (38, 50))	('BRCA 1/2', 'Gene', '672;675', (55, 63))	('patients', 'Species', '9606', (20, 28))	('mutations', 'Var', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('BRCA 1/2', 'Gene', (55, 63))
20284	33660222	This decision was based on results from a single-arm, phase 2 study (FIGHT-202) that enrolled 146 patients, 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, and 18 with no FGF/FGFR alterations.	('rearrangements', 'Var', (134, 148))	('FGFR2', 'Gene', (117, 122))	('FGFR2', 'Gene', '2263', (117, 122))	('patients', 'Species', '9606', (98, 106))	('fusions', 'Var', (123, 130))
20285	33660222	An objective response was observed in 38 patients with FGFR2 fusions or rearrangements (33%), including 3 complete responses.	('rearrangements', 'Var', (72, 86))	('FGFR2', 'Gene', '2263', (55, 60))	('FGFR2', 'Gene', (55, 60))	('patients', 'Species', '9606', (41, 49))	('fusions', 'Var', (61, 68))
20287	33660222	Several FGFR2 inhibitors (infigratinib, TAS120, pemigatinib) are currently being evaluated in several ongoing randomized trials in advanced cholangiocarcinoma with FGFR rearrangements, versus cisplatin-gemcitabine in the first-line setting.	('infigratinib', 'Chemical', 'MESH:C568950', (26, 38))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (140, 158))	('gemcitabine', 'Chemical', 'MESH:C056507', (202, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (140, 158))	('rearrangements', 'Var', (169, 183))	('TAS120', 'Chemical', '-', (40, 46))	('FGFR2', 'Gene', (8, 13))	('FGFR2', 'Gene', '2263', (8, 13))	('pemigatinib', 'Chemical', '-', (48, 59))	('cholangiocarcinoma', 'Disease', (140, 158))	('cisplatin', 'Chemical', 'MESH:D002945', (192, 201))
20288	33660222	BRAF mutations are encountered in 1-22% of intrahepatic cholangiocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('mutations', 'Var', (5, 14))	('encountered', 'Reg', (19, 30))	('intrahepatic cholangiocarcinomas', 'Disease', (43, 75))	('BRAF', 'Gene', '673', (0, 4))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (43, 75))	('BRAF', 'Gene', (0, 4))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (56, 74))
20292	33660222	Other potential targets currently being explored include Her2 amplification that is not uncommon in gallbladder cancer, but only case reports are available to date.	('gallbladder cancer', 'Disease', (100, 118))	('gallbladder cancer', 'Disease', 'MESH:D005706', (100, 118))	('Her2', 'Gene', (57, 61))	('Her2', 'Gene', '2064', (57, 61))	('amplification', 'Var', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
20294	33660222	Such is the case for pembrolizumab for tumors with microsatellite instability (< 1% of cholangiocarcinomas) or high tumor mutational burden (TMB > 10 mutations/Mb), or TRK-inhibitors (larotrectinib or entrectinib) for tumors with NTRK rearrangements (< 5% of cholangiocarcinomas).	('microsatellite instability', 'MPA', (51, 77))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (87, 106))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (259, 278))	('tumor', 'Disease', (218, 223))	('tumors', 'Disease', (39, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('entrectinib', 'Chemical', 'MESH:C000607349', (201, 212))	('cholangiocarcinomas', 'Disease', (259, 278))	('cholangiocarcinomas', 'Disease', (87, 106))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('TRK', 'Gene', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('TRK', 'Gene', (231, 234))	('TRK', 'Gene', '4914', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (39, 44))	('larotrectinib', 'Chemical', 'MESH:C000609083', (184, 197))	('rearrangements', 'Var', (235, 249))	('tumors', 'Disease', (218, 224))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (259, 277))	('pembrolizumab', 'Chemical', 'MESH:C582435', (21, 34))	('TRK', 'Gene', '4914', (231, 234))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
20302	33660222	A comprehensive tumor molecular characterization shall be pursued where available in patients with advanced BTCs, as certain genetic alterations, such as IDH1 mutations (I,A), FGFR2 fusions (II, B), BRAF mutations (II, B), microsatellite instability (II, B), high-TMB (II, B), and NTRK rearrangements (II, B), among others, may benefit from specific targeted therapies.	('rearrangements', 'Var', (286, 300))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('BRAF', 'Gene', (199, 203))	('BRAF', 'Gene', '673', (199, 203))	('IDH1', 'Gene', '3417', (154, 158))	('benefit', 'PosReg', (328, 335))	('TRK', 'Gene', (282, 285))	('microsatellite instability', 'MPA', (223, 249))	('high-TMB', 'Var', (259, 267))	('FGFR2', 'Gene', (176, 181))	('mutations', 'Var', (159, 168))	('patients', 'Species', '9606', (85, 93))	('TRK', 'Gene', '4914', (282, 285))	('FGFR2', 'Gene', '2263', (176, 181))	('mutations', 'Var', (204, 213))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('IDH1', 'Gene', (154, 158))	('fusions', 'Var', (182, 189))	('BTC', 'Phenotype', 'HP:0100574', (108, 111))
20314	33660222	Funded by grants to JM from Catalan Agency for Management of University and Research Grants (AGAUR) (2014-SGR-474 and 2017-SGR-1174), Fundacio la Marato de TV3 (201330.10), Instituto de Salud Carlos III (PI13/01728 and PI19/00740) and Fundacion Olga Torres (Modalitat A.	('age', 'Gene', (50, 53))	('PI19/00740', 'Var', (219, 229))	('age', 'Gene', '5973', (50, 53))	('Age', 'Gene', (36, 39))	('Age', 'Gene', '5973', (36, 39))	('PI13/01728', 'Var', (204, 214))
20321	33037585	Difficulty in differentiating between IgG4-related hepatic inflammatory pseudotumor and intrahepatic cholangiocarcinoma A 71-year-old man on prednisolone for immunoglobulin (Ig) G4-related renal disease showed increased carbohydrate antigen (CA) 19-9 level; abdominal enhanced computed tomography (CT) showed a lesion in the left lateral segment and dilatation of the peripheral biliary duct.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('carbohydrate antigen', 'Chemical', '-', (220, 240))	('hepatic inflammatory pseudotumor', 'Disease', (51, 83))	('dilatation', 'Phenotype', 'HP:0002617', (350, 360))	('increased', 'PosReg', (210, 219))	('dilatation', 'CPA', (350, 360))	('prednisolone', 'Chemical', 'MESH:D011239', (141, 153))	('carbohydrate antigen', 'MPA', (220, 240))	('renal disease', 'Disease', (189, 202))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('renal disease', 'Disease', 'MESH:D007674', (189, 202))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 119))	('renal disease', 'Phenotype', 'HP:0000112', (189, 202))	('hepatic inflammatory pseudotumor', 'Disease', 'MESH:D006104', (51, 83))	('intrahepatic cholangiocarcinoma', 'Disease', (88, 119))	('lesion', 'Var', (311, 317))
20338	33037585	Although he was asymptomatic, his carbohydrate antigen (CA) 19-9 level increased (from 32.4 U/ml to 304.9 U/ml), and abdominal enhanced computed tomography (CT) showed a lesion in the left lateral segment and dilatation of the peripheral biliary duct.	('carbohydrate antigen', 'Chemical', '-', (34, 54))	('dilatation', 'CPA', (209, 219))	('increased', 'PosReg', (71, 80))	('lesion', 'Var', (170, 176))	('dilatation', 'Phenotype', 'HP:0002617', (209, 219))
20368	31568700	Meanwhile, the high level of MIR155HG was associated with poorer OS in glioblastoma multiforme (GBM), kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), and uveal melanoma (UVM).	('glioblastoma multiforme', 'Disease', (71, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (180, 194))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (71, 94))	('GBM', 'Disease', (96, 99))	('GBM', 'Disease', 'MESH:D005909', (96, 99))	('glioma', 'Disease', (162, 168))	('KIRC', 'Disease', (137, 141))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (102, 135))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('UVM', 'Disease', 'MESH:C536494', (196, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('KIRC', 'Disease', 'MESH:D002292', (137, 141))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('UVM', 'Disease', (196, 199))	('kidney renal clear cell carcinoma', 'Disease', (102, 135))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('uveal melanoma', 'Disease', (180, 194))	('uveal melanoma', 'Disease', 'MESH:C536494', (180, 194))	('MIR155HG', 'Var', (29, 37))
20369	31568700	(b) The expression of MIR155HG was significantly correlated with infiltrating levels of immune cells and immune molecules, especially with immune checkpoint molecules such as programmed cell death protein 1 (PD-1), PD-1 ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) in most kinds of cancers.	('CTLA4', 'Gene', (287, 292))	('MIR155HG', 'Var', (22, 30))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', (242, 285))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', '1493', (242, 285))	('PD-L1', 'Gene', (230, 235))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('cancers', 'Disease', (311, 318))	('PD-L1', 'Gene', '29126', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('PD-1', 'Gene', (215, 219))	('PD-1', 'Gene', '5133', (215, 219))	('PD-1', 'Gene', (208, 212))	('correlated', 'Reg', (49, 59))	('PD-1', 'Gene', '5133', (208, 212))	('PD-1 ligand 1', 'Gene', (215, 228))	('programmed cell death protein 1', 'Gene', (175, 206))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('infiltrating levels of immune cells', 'MPA', (65, 100))	('CTLA4', 'Gene', '1493', (287, 292))	('PD-1 ligand 1', 'Gene', '29126', (215, 228))	('programmed cell death protein 1', 'Gene', '5133', (175, 206))
20370	31568700	(c) Detection of clinical CHOL and liver hepatocellular carcinoma tissues confirmed that there was a strong positive correlation between MIR155HG expression and the levels of CTLA4 and PD-L1.	('CTLA4', 'Gene', '1493', (175, 180))	('MIR155HG', 'Var', (137, 145))	('CHOL', 'Disease', (26, 30))	('CTLA4', 'Gene', (175, 180))	('CHOL', 'Disease', 'MESH:D018281', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('PD-L1', 'Gene', '29126', (185, 190))	('liver hepatocellular carcinoma', 'Disease', (35, 65))	('PD-L1', 'Gene', (185, 190))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (35, 65))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (41, 65))	('clinical', 'Species', '191496', (17, 25))
20380	31568700	At the same time, MIR155HG is also thought to be involved in the human immune response.	('involved', 'Reg', (49, 57))	('human', 'Species', '9606', (65, 70))	('MIR155HG', 'Var', (18, 26))
20382	31568700	We also analyzed the association of MIR155HG with tumor-infiltrating immune cells and immune molecules in tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (50, 55))	('MIR155HG', 'Var', (36, 44))	('tumor', 'Disease', (106, 111))
20383	31568700	The results indicated that the expression of MIR155HG in these tumors is closely related to the immunological checkpoint molecules PD-1, PD-L1, CTLA4, LAG3, and TIM3.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('CTLA4', 'Gene', (144, 149))	('PD-L1', 'Gene', (137, 142))	('MIR155HG', 'Var', (45, 53))	('tumors', 'Disease', (63, 69))	('LAG3', 'Gene', (151, 155))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('LAG3', 'Gene', '3902', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('TIM3', 'Gene', (161, 165))	('PD-1', 'Gene', (131, 135))	('PD-L1', 'Gene', '29126', (137, 142))	('TIM3', 'Gene', '84868', (161, 165))	('PD-1', 'Gene', '5133', (131, 135))	('CTLA4', 'Gene', '1493', (144, 149))
20385	31568700	Therefore, we believe that MIR155HG can be used as a predictor for assessing the prognosis of cancer patients and the effectiveness of immunotherapy with checkpoint blockade.	('patients', 'Species', '9606', (101, 109))	('MIR155HG', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
20387	31568700	The gene pattern was used to analyze the correlation of MIR155HG with immune cell infiltration in various tumors, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells (DCs).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('MIR155HG', 'Var', (56, 64))
20389	31568700	The gene expression profiling interactive analysis (GEPIA) database integrates tens of thousands of tumor and non-tumor samples from TCGA and GTEx gene expression data to analyze gene expression, differential gene expression, survival, correlation, and co-expression of genes online.21 We analyzed the expression of MIR155HG in various tumors and corresponding normal tissues by GEPIA quick start tab.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (336, 342))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumors', 'Disease', (336, 342))	('tumors', 'Disease', 'MESH:D009369', (336, 342))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('tumor', 'Disease', (114, 119))	('MIR155HG', 'Var', (316, 324))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumor', 'Disease', (336, 341))
20394	31568700	The TIMER online database was used to analyze the differential expression of MIR155HG in 17 types of tumors and adjacent tissues in TCGA, and the differential expression was evaluated by Wilcoxon test.	('MIR155HG', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
20395	31568700	The results showed that, compared to the paracancerous control, MIR155HG was highly expressed in breast invasive carcinoma, HNSC, KIRC, kidney renal papillary cell carcinoma, LUAD, stomach adenocarcinoma and uterine corpus endometrial carcinoma, lower expression in kidney chromophobe (KICH), rectum adenocarcinoma (P < .05) (Figure 1A).	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (97, 122))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (223, 244))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('stomach adenocarcinoma', 'Disease', (181, 203))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D002292', (136, 173))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (143, 173))	('KIRC', 'Disease', (130, 134))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (97, 122))	('kidney chromophobe', 'Disease', (266, 284))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (293, 314))	('LUAD', 'Disease', (175, 179))	('MIR155HG', 'Var', (64, 72))	('KIRC', 'Disease', 'MESH:D002292', (130, 134))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (181, 203))	('endometrial carcinoma', 'Disease', (223, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('kidney renal papillary cell carcinoma', 'Disease', (136, 173))	('expression', 'MPA', (252, 262))	('cancer', 'Disease', (45, 51))	('lower', 'NegReg', (246, 251))	('LUAD', 'Disease', 'MESH:C538231', (175, 179))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('breast invasive carcinoma', 'Disease', (97, 122))	('rectum adenocarcinoma', 'Disease', (293, 314))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (223, 244))
20396	31568700	The GEPIA database analyzes the expression of MIR155HG in various tumors and matched normal tissues (match TCGA normal and GTEx data), and the results showed that MIR155HG was higher than the matched normal tissue in the lymphoid neoplasm DLBC lymphoma, GBM, KIRC, acute myeloid leukemia, thymoma (cutoff criteria:  log2fold change  > 1.0 and P < .05) (Figure 1B).	('KIRC', 'Disease', (259, 263))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (265, 287))	('lymphoma', 'Disease', (244, 252))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('lymphoma', 'Disease', 'MESH:D008223', (244, 252))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (265, 287))	('thymoma', 'Disease', (289, 296))	('MIR155HG', 'Var', (163, 171))	('thymoma', 'Phenotype', 'HP:0100522', (289, 296))	('KIRC', 'Disease', 'MESH:D002292', (259, 263))	('GBM', 'Disease', (254, 257))	('lymphoid neoplasm', 'Phenotype', 'HP:0002665', (221, 238))	('GBM', 'Disease', 'MESH:D005909', (254, 257))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('lymphoma', 'Phenotype', 'HP:0002665', (244, 252))	('higher', 'PosReg', (176, 182))	('MIR155HG', 'Var', (46, 54))	('acute myeloid leukemia', 'Disease', (265, 287))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('neoplasm', 'Phenotype', 'HP:0002664', (230, 238))	('leukemia', 'Phenotype', 'HP:0001909', (279, 287))	('tumors', 'Disease', (66, 72))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (271, 287))	('thymoma', 'Disease', 'MESH:D013945', (289, 296))
20397	31568700	We used GEPIA to analyze the relation of MIR155HG and clinical features in 33 kinds of tumors and found that MIR155HG was correlated with OS, DFS, and staging in multiple tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('multiple tumors', 'Disease', (162, 177))	('DFS', 'Disease', (142, 145))	('multiple tumors', 'Disease', 'MESH:D009369', (162, 177))	('correlated', 'Reg', (122, 132))	('tumors', 'Disease', (87, 93))	('clinical', 'Species', '191496', (54, 62))	('tumors', 'Disease', (171, 177))	('MIR155HG', 'Var', (109, 117))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
20398	31568700	The MIR155HG higher expression has better OS and DFS in CHOL and prophase SKCM.	('SKCM', 'Disease', 'MESH:C562393', (74, 78))	('SKCM', 'Disease', (74, 78))	('DFS', 'MPA', (49, 52))	('MIR155HG higher expression', 'Var', (4, 30))	('better', 'PosReg', (35, 41))	('CHOL', 'Disease', (56, 60))	('CHOL', 'Disease', 'MESH:D018281', (56, 60))
20399	31568700	In LUAD and early stage of HNSC, patients with high levels of MIR155HG have better OS than patients with low expression of MIR155HG.	('LUAD', 'Disease', (3, 7))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (33, 41))	('LUAD', 'Disease', 'MESH:C538231', (3, 7))	('MIR155HG', 'Var', (62, 70))	('better', 'PosReg', (76, 82))
20400	31568700	While high levels of MIR155HG was associated with poor OS in GBM, KIRC, LGG, and UVM, and poor DFS in LGG early stage and UVM MIR155HG was closely related to tumor stage in KICH, KIRC, LUAD, SKCM, Thyroid carcinoma (THCA) (Figure 2; Table S2).	('SKCM', 'Disease', (191, 195))	('GBM', 'Disease', 'MESH:D005909', (61, 64))	('KIRC', 'Disease', (179, 183))	('UVM', 'Disease', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('THCA', 'Disease', 'MESH:D013964', (216, 220))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (197, 214))	('UVM', 'Disease', (122, 125))	('LUAD', 'Disease', (185, 189))	('KIRC', 'Disease', 'MESH:D002292', (179, 183))	('related', 'Reg', (147, 154))	('THCA', 'Disease', (216, 220))	('SKCM', 'Disease', 'MESH:C562393', (191, 195))	('KIRC', 'Disease', (66, 70))	('LUAD', 'Disease', 'MESH:C538231', (185, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('KIRC', 'Disease', 'MESH:D002292', (66, 70))	('tumor', 'Disease', (158, 163))	('MIR155HG', 'Var', (21, 29))	('UVM', 'Disease', 'MESH:C536494', (81, 84))	('MIR155HG', 'Var', (126, 134))	('Thyroid carcinoma', 'Disease', (197, 214))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('UVM', 'Disease', 'MESH:C536494', (122, 125))	('Thyroid carcinoma', 'Disease', 'MESH:D013964', (197, 214))	('GBM', 'Disease', (61, 64))
20401	31568700	According to the correlation between MIR155HG and OS or DFS in eight types of tumors (CHOL, HNSC, GBM, KIRC, LGG, LUAD, SKCM, UVM), the gene pathway enrichment and functional enrichment were further analyzed.	('CHOL', 'Disease', 'MESH:D018281', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('SKCM', 'Disease', (120, 124))	('GBM', 'Disease', (98, 101))	('GBM', 'Disease', 'MESH:D005909', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('LUAD', 'Disease', (114, 118))	('LGG', 'Disease', (109, 112))	('UVM', 'Disease', 'MESH:C536494', (126, 129))	('tumors', 'Disease', (78, 84))	('SKCM', 'Disease', 'MESH:C562393', (120, 124))	('KIRC', 'Disease', (103, 107))	('CHOL', 'Disease', (86, 90))	('LUAD', 'Disease', 'MESH:C538231', (114, 118))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('UVM', 'Disease', (126, 129))	('HNSC', 'Disease', (92, 96))	('KIRC', 'Disease', 'MESH:D002292', (103, 107))	('MIR155HG', 'Var', (37, 45))
20402	31568700	The top 80 mRNAs co-expressed with MIR155HG in various tumors were obtained by GEPIA's similar genes model.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('MIR155HG', 'Var', (35, 43))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))
20406	31568700	To investigate the correlation between MIR155HG and tumor immune cells, we used the TIMER to analyze the correlation of MIR155HG with tumor purity, lymphocytes, macrophages, neutrophils, DCs, NK cells, Treg cells, mast cells, Th1, Th2, Th17, Tfh cells, MDSC in the above eight tumors.	('Th1', 'Gene', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Th1', 'Gene', '51497', (236, 239))	('tumor', 'Disease', (52, 57))	('MIR155HG', 'Var', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('Th1', 'Gene', (236, 239))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('Th1', 'Gene', '51497', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('tumor', 'Disease', (277, 282))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (134, 139))	('tumors', 'Disease', (277, 283))
20407	31568700	The results showed that the expression of MIR155HG in CHOL, HNSC, KIRC, LGG, LUAD, and SKCM was significantly correlated with tumor purity and the infiltration level of immune cells such as B lymphocytes, CD8+ T cells, CD4+ T cells and DCs.	('CHOL', 'Disease', (54, 58))	('SKCM', 'Disease', (87, 91))	('CHOL', 'Disease', 'MESH:D018281', (54, 58))	('correlated', 'Reg', (110, 120))	('infiltration level', 'MPA', (147, 165))	('MIR155HG', 'Var', (42, 50))	('SKCM', 'Disease', 'MESH:C562393', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('KIRC', 'Disease', 'MESH:D002292', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('KIRC', 'Disease', (66, 70))	('LUAD', 'Disease', (77, 81))	('LUAD', 'Disease', 'MESH:C538231', (77, 81))	('tumor', 'Disease', (126, 131))
20409	31568700	MIR155 host gene was highly correlated with NK cells, Treg cells, macrophages, Th1, Tfh cells and M-MDSC in CHOL, HNSC, KIRC, LUAD, and SKCM, and have a certain correlation with MDSC in GBM MIR155HG was related to the infiltration of macrophages, Th1 and DMSC in a certain degree in LGG, and has moderate correlated with Treg cells, Th1 and Tfh cells in UVM (Table S3).	('LUAD', 'Disease', 'MESH:C538231', (126, 130))	('Th1', 'Gene', (79, 82))	('Th1', 'Gene', '51497', (333, 336))	('SKCM', 'Disease', (136, 140))	('GBM', 'Disease', (186, 189))	('Th1', 'Gene', '51497', (79, 82))	('GBM', 'Disease', 'MESH:D005909', (186, 189))	('MIR155', 'Gene', (0, 6))	('UVM', 'Disease', 'MESH:C536494', (354, 357))	('SKCM', 'Disease', 'MESH:C562393', (136, 140))	('KIRC', 'Disease', (120, 124))	('CHOL', 'Disease', (108, 112))	('MIR155HG', 'Var', (190, 198))	('Th1', 'Gene', (247, 250))	('LUAD', 'Disease', (126, 130))	('KIRC', 'Disease', 'MESH:D002292', (120, 124))	('UVM', 'Disease', (354, 357))	('Th1', 'Gene', '51497', (247, 250))	('CHOL', 'Disease', 'MESH:D018281', (108, 112))	('Th1', 'Gene', (333, 336))
20411	31568700	To evaluate the efficacy of MIR155HG in predicting cancer patient response to checkpoint inhibitor, we used the TIMER database to analyze the relevance of MIR155HG and the currently available blocking molecules with superior therapeutic effects PD-1, PD-L1, CTLA4, LAG3, TIM3.	('LAG3', 'Gene', '3902', (265, 269))	('TIM3', 'Gene', '84868', (271, 275))	('PD-L1', 'Gene', '29126', (251, 256))	('CTLA4', 'Gene', '1493', (258, 263))	('PD-1', 'Gene', '5133', (245, 249))	('patient', 'Species', '9606', (58, 65))	('CTLA4', 'Gene', (258, 263))	('MIR155HG', 'Var', (155, 163))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('PD-L1', 'Gene', (251, 256))	('PD-1', 'Gene', (245, 249))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('LAG3', 'Gene', (265, 269))	('TIM3', 'Gene', (271, 275))
20412	31568700	A significant strong positive correlation (cor > 0.5) was found between MIR155HG with PD-1 (PDCD1), PD-L1 (CD274), CTLA4, LAG3, and TIM3 (HAVCR2) molecules in LUAD and SKCM, and with a median or higher correlation in CHOL and UVM patients (cor > 0.3), a significant correlation in HNSC, LGG (P < .0001).	('TIM3', 'Gene', (132, 136))	('UVM', 'Disease', (226, 229))	('TIM3', 'Gene', '84868', (132, 136))	('HAVCR2', 'Gene', '84868', (138, 144))	('CD274', 'Gene', '29126', (107, 112))	('CHOL', 'Disease', (217, 221))	('HNSC', 'Disease', (281, 285))	('SKCM', 'Disease', (168, 172))	('LGG', 'Disease', (287, 290))	('PDCD1', 'Gene', '5133', (92, 97))	('PDCD1', 'Gene', (92, 97))	('CTLA4', 'Gene', '1493', (115, 120))	('LAG3', 'Gene', '3902', (122, 126))	('CHOL', 'Disease', 'MESH:D018281', (217, 221))	('CD274', 'Gene', (107, 112))	('HAVCR2', 'Gene', (138, 144))	('SKCM', 'Disease', 'MESH:C562393', (168, 172))	('LAG3', 'Gene', (122, 126))	('LUAD', 'Disease', (159, 163))	('MIR155HG', 'Var', (72, 80))	('CTLA4', 'Gene', (115, 120))	('UVM', 'Disease', 'MESH:C536494', (226, 229))	('PD-L1', 'Gene', (100, 105))	('PD-L1', 'Gene', '29126', (100, 105))	('patients', 'Species', '9606', (230, 238))	('LUAD', 'Disease', 'MESH:C538231', (159, 163))	('PD-1', 'Gene', (86, 90))	('PD-1', 'Gene', '5133', (86, 90))
20414	31568700	The relationship between MIR155HG and immunity was relatively close in the eight types of prognostic-related tumor mentioned above, and what is the relationship with other types of tumors that unrelated to prognosis?	('tumor', 'Disease', (181, 186))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('MIR155HG', 'Var', (25, 33))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', (109, 114))
20416	31568700	The results showed that MIR155HG was significantly negative associated with tumor purity, positive correlated with B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and DCs.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('negative', 'NegReg', (51, 59))	('tumor', 'Disease', (76, 81))	('MIR155HG', 'Var', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
20417	31568700	In LIHC, MIR155HG has a high correlation with immunological checkpoint molecules PD-1, CTLA4, LAG3, and TIM3 (cor > 0.5), and also has a significant correlation with PD-L1.	('LAG3', 'Gene', (94, 98))	('LIHC', 'Disease', 'MESH:D006528', (3, 7))	('PD-L1', 'Gene', '29126', (166, 171))	('TIM3', 'Gene', '84868', (104, 108))	('PD-1', 'Gene', (81, 85))	('LIHC', 'Disease', (3, 7))	('CTLA4', 'Gene', '1493', (87, 92))	('PD-1', 'Gene', '5133', (81, 85))	('CTLA4', 'Gene', (87, 92))	('correlation', 'Interaction', (149, 160))	('LAG3', 'Gene', '3902', (94, 98))	('MIR155HG', 'Var', (9, 17))	('PD-L1', 'Gene', (166, 171))	('correlation', 'Interaction', (29, 40))	('TIM3', 'Gene', (104, 108))
20419	31568700	We also analyzed the relationship between MIR155HG and immune in other tumors, and found that MIR155HG is closely related to immune cells and molecules in most kind of tumors (Figures S2 and S3).	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('MIR155HG', 'Var', (94, 102))	('related', 'Reg', (114, 121))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
20420	31568700	Since the great value of MIR155HG predicting the immune checkpoint molecular expression level in tumor, we selected the prognostic-related tumor type CHOL and the prognostic-unrelated tumor type LIHC to detect the correlation.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CHOL', 'Disease', (150, 154))	('MIR155HG', 'Var', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('immune checkpoint molecular expression level', 'MPA', (49, 93))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (184, 189))	('CHOL', 'Disease', 'MESH:D018281', (150, 154))	('LIHC', 'Disease', (195, 199))	('LIHC', 'Disease', 'MESH:D006528', (195, 199))
20421	31568700	The relationship of MIR155HG and the immunological checkpoint molecules PD-L1 and CTLA4 were verified by qRT-PCR.	('PD-L1', 'Gene', '29126', (72, 77))	('MIR155HG', 'Var', (20, 28))	('CTLA4', 'Gene', '1493', (82, 87))	('PD-L1', 'Gene', (72, 77))	('CTLA4', 'Gene', (82, 87))
20422	31568700	The results showed that MIR155HG showed a striking positive correlation with both PD-L1 and CTLA4 in CHOL and LIHC (Figure 7).	('CTLA4', 'Gene', (92, 97))	('LIHC', 'Disease', 'MESH:D006528', (110, 114))	('PD-L1', 'Gene', (82, 87))	('MIR155HG', 'Var', (24, 32))	('PD-L1', 'Gene', '29126', (82, 87))	('positive', 'PosReg', (51, 59))	('CHOL', 'Disease', (101, 105))	('LIHC', 'Disease', (110, 114))	('CTLA4', 'Gene', '1493', (92, 97))	('CHOL', 'Disease', 'MESH:D018281', (101, 105))	('correlation', 'Interaction', (60, 71))
20423	31568700	In this report, we analyzed the expression of MIR155HG in various cancers and paracancer or normal tissues, and analyzed the relationship between MIR155HG expression and OS, DFS and staging, consistent with Wu's finding that MIR155HG was associated with poor tumor prognosis in glioma.10 As reported, the expression of MIR155HG was significantly higher in cancer than paracancer in KIRC,26 and MIR155HG was associated with poor OS.27 GO and KEGG analysis in these types of tumors showed that mRNAs co-expressed with MIR155HG were mostly enriched in immune-related functions and immune-related pathways, which indicated that MIR155HG may be related to immunity.	('tumors', 'Disease', 'MESH:D009369', (473, 479))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', (473, 478))	('tumor', 'Disease', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('immune-related functions', 'CPA', (549, 573))	('cancer', 'Disease', (356, 362))	('tumor', 'Disease', 'MESH:D009369', (473, 478))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('glioma', 'Disease', (278, 284))	('enriched', 'Reg', (537, 545))	('KIRC', 'Disease', (382, 386))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('tumors', 'Phenotype', 'HP:0002664', (473, 479))	('cancer', 'Disease', (372, 378))	('glioma', 'Disease', 'MESH:D005910', (278, 284))	('immune-related pathways', 'Pathway', (578, 601))	('cancer', 'Phenotype', 'HP:0002664', (372, 378))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('MIR155HG', 'Var', (516, 524))	('tumor', 'Phenotype', 'HP:0002664', (473, 478))	('KIRC', 'Disease', 'MESH:D002292', (382, 386))	('tumors', 'Disease', (473, 479))	('cancer', 'Disease', 'MESH:D009369', (356, 362))	('glioma', 'Phenotype', 'HP:0009733', (278, 284))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancer', 'Disease', 'MESH:D009369', (372, 378))	('cancer', 'Disease', (66, 72))
20426	31568700	In this study, we examined the association of MIR155HG with immune cells attempting to reveal the immune status in cancer patients by understanding the expression of MIR155HG.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('patients', 'Species', '9606', (122, 130))	('MIR155HG', 'Var', (166, 174))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
20427	31568700	The results showed that MIR155HG was significantly negatively correlated with tumor purity and significantly positively correlated with B cells, CD8+ T cells, CD4+ T cells, and DCs in most kinds of cancers.	('positively correlated', 'Reg', (109, 130))	('negatively', 'NegReg', (51, 61))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cancers', 'Disease', (198, 205))	('MIR155HG', 'Var', (24, 32))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', (78, 83))
20428	31568700	Moreover, to fully demonstrate the relationship between MIR155HG and immunity, we also analyzed the association of MIR155HG with immunosuppressive molecules and immunostimulatory molecules in the above described cancer types.	('association', 'Interaction', (100, 111))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('MIR155HG', 'Var', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
20432	31568700	We found that MIR155HG was significantly associated with immunological checkpoint blocking molecules PD-1, PD-L1, CTLA4, LAG3, and TIM3 in many tumors, and some of those types of tumor have better reactivity against immunological checkpoint blockade.	('tumors', 'Disease', (144, 150))	('associated', 'Reg', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('reactivity', 'MPA', (197, 207))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('TIM3', 'Gene', (131, 135))	('TIM3', 'Gene', '84868', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('LAG3', 'Gene', '3902', (121, 125))	('tumor', 'Disease', (144, 149))	('CTLA4', 'Gene', '1493', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('LAG3', 'Gene', (121, 125))	('PD-L1', 'Gene', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('PD-L1', 'Gene', '29126', (107, 112))	('MIR155HG', 'Var', (14, 22))	('PD-1', 'Gene', (101, 105))	('PD-1', 'Gene', '5133', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('CTLA4', 'Gene', (114, 119))	('tumor', 'Disease', (179, 184))
20436	31568700	They found that the expression of LAYN was associated with increased levels of immune permeation of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in colon and gastric cancer.41 Compared with the results of Pan et al, MIR155HG has a wider range of tumor applicability and was more closely related to immune cells and immune molecules.	('LAYN', 'Gene', '143903', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('MIR155HG', 'Var', (233, 241))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', (263, 268))	('LAYN', 'Gene', (34, 38))	('colon and gastric cancer', 'Disease', 'MESH:D013274', (165, 189))	('gastric cancer', 'Phenotype', 'HP:0012126', (175, 189))
20437	31568700	The previous research reported that MIR155HG participate the regulator of innate immunity17 and macrophage polarization,16 and associated with acute rejection, T-cell-mediated acute rejection and graft loss.42 MIR-155 regulates the expression of many immune-specific transcripts, such as regulate polarization of macrophages, DCs maturation, T-cell differentiation, controls B cell proliferation and antibody production.43, 44 Consider that MIR155 is derived from MIR155HG and that MIR155HG play a critical role by interaction with MIR155,9, 10 we speculated that MIR155HG may affect the immune process through its interaction with MIR155 or other mechanisms.	('affect', 'Reg', (577, 583))	('graft loss', 'Disease', 'MESH:D055589', (196, 206))	('interaction', 'Interaction', (615, 626))	('graft loss', 'Disease', (196, 206))	('MIR-155', 'Gene', '406947', (210, 217))	('MIR155HG', 'Var', (564, 572))	('MIR-155', 'Gene', (210, 217))	('immune process', 'CPA', (588, 602))
20438	31568700	To preliminarily verify the relationship between MIR155HG and immune infiltration in an individual patient, we verified the correlation between MIR155HG and immune checkpoint molecules PD-L1 and CTLA4 by realtime quantitative reverse transcription polymerase chain reaction (qRT-PCR) in frozen tissue specimens of patients with CHOL and LIHC.	('patient', 'Species', '9606', (99, 106))	('CTLA4', 'Gene', '1493', (195, 200))	('LIHC', 'Disease', (337, 341))	('patients', 'Species', '9606', (314, 322))	('LIHC', 'Disease', 'MESH:D006528', (337, 341))	('CTLA4', 'Gene', (195, 200))	('CHOL', 'Disease', (328, 332))	('MIR155HG', 'Var', (144, 152))	('CHOL', 'Disease', 'MESH:D018281', (328, 332))	('PD-L1', 'Gene', (185, 190))	('patient', 'Species', '9606', (314, 321))	('PD-L1', 'Gene', '29126', (185, 190))
20439	31568700	There was a significant positive correlation between the expression of MIR155HG and PD-L1, CTLA4 in clinical specimens.	('expression', 'MPA', (57, 67))	('clinical', 'Species', '191496', (100, 108))	('PD-L1', 'Gene', (84, 89))	('MIR155HG', 'Var', (71, 79))	('PD-L1', 'Gene', '29126', (84, 89))	('CTLA4', 'Gene', '1493', (91, 96))	('CTLA4', 'Gene', (91, 96))
20441	31568700	In conclusion, the above results indicate that MIR155HG expression might help to predict the prognosis and understanding immune status in cancer.	('MIR155HG', 'Var', (47, 55))	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('help', 'Reg', (73, 77))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
20442	31568700	In this study, we found that MIR155HG can be used as a biomarker of prognosis in CHOL, GBM, HNSC, KIRC, LGG, LUAD, SKCM, and UVM through bioinformatics analysis.	('UVM', 'Disease', 'MESH:C536494', (125, 128))	('SKCM', 'Disease', (115, 119))	('GBM', 'Disease', (87, 90))	('KIRC', 'Disease', (98, 102))	('CHOL', 'Disease', (81, 85))	('KIRC', 'Disease', 'MESH:D002292', (98, 102))	('CHOL', 'Disease', 'MESH:D018281', (81, 85))	('UVM', 'Disease', (125, 128))	('LUAD', 'Disease', 'MESH:C538231', (109, 113))	('GBM', 'Disease', 'MESH:D005909', (87, 90))	('HNSC', 'Disease', (92, 96))	('SKCM', 'Disease', 'MESH:C562393', (115, 119))	('LUAD', 'Disease', (109, 113))	('MIR155HG', 'Var', (29, 37))
20443	31568700	And the expression level of MIR155HG has a certain correlation with immune molecules in various types of tumors, especially in HNSC, LUAD, KIRC, SKCM, and LIHC, which are suitable for predicting the curative effect of immune checkpoint blockade therapy.	('LIHC', 'Disease', (155, 159))	('tumors', 'Disease', (105, 111))	('KIRC', 'Disease', (139, 143))	('correlation', 'Reg', (51, 62))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('SKCM', 'Disease', (145, 149))	('LIHC', 'Disease', 'MESH:D006528', (155, 159))	('MIR155HG', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('expression', 'MPA', (8, 18))	('SKCM', 'Disease', 'MESH:C562393', (145, 149))	('HNSC', 'Disease', (127, 131))	('LUAD', 'Disease', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('LUAD', 'Disease', 'MESH:C538231', (133, 137))	('KIRC', 'Disease', 'MESH:D002292', (139, 143))
20503	28316853	This variation of Ki-67 index within individual NETs or within their metastasis is common, and the higher Ki-67 index value decides the tumor grade.	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('decides', 'Reg', (124, 131))	('NETs', 'Phenotype', 'HP:0100634', (48, 52))	('tumor', 'Disease', (136, 141))	('variation', 'Var', (5, 14))
20556	25889352	Although FDG PET/CT provides less sensitivity than MRI, FDG PET/CT provides the advantage of allowing an assessment of extramedullary disease status.	('FDG', 'Chemical', 'MESH:D019788', (56, 59))	('extramedullary disease', 'Disease', (119, 141))	('FDG', 'Chemical', 'MESH:D019788', (9, 12))	('FDG PET/CT', 'Var', (56, 66))
20732	29627364	However, this approach is not sufficient to investigate the myriad of biologic process occurring in tumors including cell survival, inflammation, angiogenesis, and mutations.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('inflammation', 'Disease', 'MESH:D007249', (132, 144))	('inflammation', 'Disease', (132, 144))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('mutations', 'Var', (164, 173))
20743	29627364	DMN promotes alkylation of DNA structure and generation of reactive oxygen species known to induce protein, lipid and DNA damage.	('DNA structure', 'Protein', (27, 40))	('DMN', 'Chemical', 'MESH:D004128', (0, 3))	('oxygen', 'Chemical', 'MESH:D010100', (68, 74))	('lipid', 'Chemical', 'MESH:D008055', (108, 113))	('alkylation', 'MPA', (13, 23))	('rat', 'Species', '10116', (49, 52))	('DMN', 'Var', (0, 3))
20744	29627364	Consequently, DMN induces not only CCA but also other gastrointestinal tumors, as well as skin, lung and hematopoietic tumors.	('hematopoietic tumors', 'Disease', (105, 125))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('skin', 'Disease', (90, 94))	('lung', 'Disease', (96, 100))	('gastrointestinal tumors', 'Disease', (54, 77))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (54, 77))	('DMN', 'Chemical', 'MESH:D004128', (14, 17))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (54, 77))	('CCA', 'Phenotype', 'HP:0030153', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('hematopoietic tumors', 'Disease', 'MESH:D019337', (105, 125))	('induces', 'Reg', (18, 25))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('DMN', 'Var', (14, 17))	('CCA', 'Disease', (35, 38))
20756	29627364	In mice with liver-specific deletion of cylindromatosis (CYLD), a tumor suppressor gene which is mutated in familial cylindromatosis, DEN single intraperitoneal injection combined with phenobarbital in drinking water results in CCA development.	('cylindromatosis', 'Gene', '74256', (40, 55))	('familial cylindromatosis', 'Disease', (108, 132))	('water', 'Chemical', 'MESH:D014867', (211, 216))	('CYLD', 'Gene', '74256', (57, 61))	('CCA development', 'CPA', (228, 243))	('results in', 'Reg', (217, 227))	('cylindromatosis', 'Gene', '74256', (117, 132))	('CYLD', 'Gene', (57, 61))	('tumor', 'Disease', (66, 71))	('familial cylindromatosis', 'Disease', 'MESH:C536611', (108, 132))	('CCA', 'Phenotype', 'HP:0030153', (228, 231))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('DEN', 'Chemical', 'MESH:D004052', (134, 137))	('mice', 'Species', '10090', (3, 7))	('cylindromatosis', 'Gene', (40, 55))	('phenobarbital', 'Chemical', 'MESH:D010634', (185, 198))	('cylindromatosis', 'Gene', (117, 132))	('deletion', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))
20768	29627364	Hence, TAA treated fa/fa Zucker rats which have faulty leptin receptors, had reduced tumor burden compared to TAA-treated lean Zucker rats.	('tumor', 'Disease', (85, 90))	('TAA', 'Chemical', 'MESH:D013853', (110, 113))	('fa/fa', 'Disease', (19, 24))	('faulty', 'Var', (48, 54))	('rats', 'Species', '10116', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('reduced', 'NegReg', (77, 84))	('rats', 'Species', '10116', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('leptin receptors', 'Protein', (55, 71))	('TAA', 'Chemical', 'MESH:D013853', (7, 10))
20786	29627364	However, furan can induce other malignancies as well including malignant mesothelioma and mononuclear cell leukemia.	('malignant mesothelioma', 'Disease', (63, 85))	('furan', 'Chemical', 'MESH:C039281', (9, 14))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (63, 85))	('leukemia', 'Disease', 'MESH:D007938', (107, 115))	('leukemia', 'Disease', (107, 115))	('malignancies', 'Disease', 'MESH:D009369', (32, 44))	('induce', 'Reg', (19, 25))	('furan', 'Var', (9, 14))	('malignancies', 'Disease', (32, 44))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (63, 85))
20789	29627364	Chronic cholestasis promotes CCA carcinogenesis by inducing genetic aberrations and pro-survival signaling pathways.	('inducing', 'PosReg', (51, 59))	('rat', 'Species', '10116', (72, 75))	('pro-survival signaling pathways', 'Pathway', (84, 115))	('cholestasis', 'Phenotype', 'HP:0001396', (8, 19))	('genetic aberrations', 'Var', (60, 79))	('Chronic cholestasis promotes CCA carcinogenesis', 'Disease', (0, 47))	('Chronic cholestasis promotes CCA carcinogenesis', 'Disease', 'MESH:C536211', (0, 47))	('CCA', 'Phenotype', 'HP:0030153', (29, 32))
20793	29627364	The combination of DMN and LMBDL resulted in CCA formation in approximately 40% of the mice after 40 weeks of treatment.	('LMBDL', 'Chemical', '-', (27, 32))	('mice', 'Species', '10090', (87, 91))	('DMN', 'Var', (19, 22))	('CCA', 'Phenotype', 'HP:0030153', (45, 48))	('LMBDL', 'Var', (27, 32))	('DMN', 'Chemical', 'MESH:D004128', (19, 22))	('CCA formation', 'CPA', (45, 58))
20806	29627364	Such weaknesses include the potential loss of tumor heterogeneity due to selective pressures, loss of tumor representation due to culture specific mutations and gene silencing, and the lack of interaction with the tumor microenvironment and the immune system.	('mutations', 'Var', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('loss', 'NegReg', (94, 98))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('gene silencing', 'Var', (161, 175))	('tumor', 'Disease', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('loss', 'NegReg', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
20823	29627364	Another study using this model demonstrated a reduction in CCA metastases with JP1584, a second mitochondria-derived activator of caspase mimetic, treatment.	('second mitochondria-derived activator of caspase', 'Gene', (89, 137))	('reduction', 'NegReg', (46, 55))	('CCA', 'Phenotype', 'HP:0030153', (59, 62))	('CCA metastases', 'Disease', 'MESH:D009362', (59, 73))	('JP1584', 'Chemical', '-', (79, 85))	('CCA metastases', 'Disease', (59, 73))	('second mitochondria-derived activator of caspase', 'Gene', '66593', (89, 137))	('JP1584', 'Var', (79, 85))	('rat', 'Species', '10116', (38, 41))
20838	29627364	Indeed, the possibility to generate animal models which have the potential to recapitulate specific genetic mutation as well as the biochemical, proteomic and phenotypic features observed in human CCA has enabled important progress in the understanding of CCA cancer.	('CCA', 'Phenotype', 'HP:0030153', (256, 259))	('CCA', 'Disease', (197, 200))	('CCA cancer', 'Disease', (256, 266))	('CCA', 'Phenotype', 'HP:0030153', (197, 200))	('CCA cancer', 'Disease', 'MESH:C536211', (256, 266))	('mutation', 'Var', (108, 116))	('human', 'Species', '9606', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('rat', 'Species', '10116', (31, 34))
20845	29627364	Therefore, to study the impact of Smad4 deletion, the investigators utilized a mouse strain carrying a conditional allele of Smad4 (Smad4Co/Co) and a tissue specific Cre expression system using albumin to induce liver-specific Smad4 deletion.	('mouse', 'Species', '10090', (79, 84))	('Smad4', 'Gene', (227, 232))	('Smad4Co/Co', 'Gene', (132, 142))	('Smad4Co/Co', 'Gene', '17128', (132, 142))	('deletion', 'Var', (233, 241))
20846	29627364	Pten deletion induces constitutive activation of the PI3K/AKT pathway and extracellular signal regulated protein kinases 1/2 (ERK1/2) hyperphosphorylation, which has an essential role in cell proliferation and survival.	('deletion', 'Var', (5, 13))	('hyperphosphorylation', 'MPA', (134, 154))	('Pten', 'Chemical', '-', (0, 4))	('ERK1/2', 'Gene', '26417;26413', (126, 132))	('PI3', 'Gene', (53, 56))	('Pten', 'Gene', (0, 4))	('extracellular', 'MPA', (74, 87))	('rat', 'Species', '10116', (199, 202))	('ERK1/2', 'Gene', (126, 132))	('PI3', 'Gene', '20702', (53, 56))	('activation', 'PosReg', (35, 45))
20849	29627364	Smad4 and Pten deletions were observed in both hepatocytes and cholangiocytes of the Smad4Co/Co/PtenCo/Co Alb-Cre phenotype.	('deletions', 'Var', (15, 24))	('Pten', 'Chemical', '-', (96, 100))	('Pten', 'Chemical', '-', (10, 14))	('Pten', 'Gene', (10, 14))	('Smad4Co/Co', 'Gene', (85, 95))	('Smad4', 'Gene', (0, 5))	('Smad4Co/Co', 'Gene', '17128', (85, 95))
20850	29627364	Consistently, Smad4 and Pten deletion resulted in bile duct hyperplasia at 2 months of age in these mice, and all animals had tumor development by 4-7 months of age.	('deletion', 'Var', (29, 37))	('Smad4', 'Gene', (14, 19))	('bile duct hyperplasia', 'Disease', 'MESH:D001650', (50, 71))	('mice', 'Species', '10090', (100, 104))	('resulted in', 'Reg', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('Pten', 'Chemical', '-', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('Pten', 'Gene', (24, 28))	('bile duct hyperplasia', 'Disease', (50, 71))	('bile duct hyperplasia', 'Phenotype', 'HP:0006560', (50, 71))	('tumor', 'Disease', (126, 131))
20855	29627364	However, the authors did note that this might not be a pure CCA model as an earlier study had demonstrated that liver-specific disruption of Pten results in HCC in the majority of mice at 74-78 weeks of age.	('Pten', 'Gene', (141, 145))	('rat', 'Species', '10116', (101, 104))	('results in', 'Reg', (146, 156))	('HCC', 'Disease', (157, 160))	('disruption', 'Var', (127, 137))	('mice', 'Species', '10090', (180, 184))	('Pten', 'Chemical', '-', (141, 145))	('HCC', 'Phenotype', 'HP:0001402', (157, 160))	('CCA', 'Phenotype', 'HP:0030153', (60, 63))
20859	29627364	Mutations activating the proto-oncogene KRAS are some of the most frequent occurrences in human malignancies, including distal CCA; KRAS mutations are less frequent in iCCA.	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('KRAS', 'Gene', (132, 136))	('CCA', 'Phenotype', 'HP:0030153', (127, 130))	('KRAS', 'Gene', '3845', (132, 136))	('distal CCA', 'Disease', (120, 130))	('KRAS', 'Gene', (40, 44))	('activating', 'PosReg', (10, 20))	('malignancies', 'Disease', (96, 108))	('human', 'Species', '9606', (90, 95))	('CCA', 'Phenotype', 'HP:0030153', (169, 172))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', '3845', (40, 44))
20861	29627364	Accordingly, liver-specific Kras activation and Pten deletion promotes iCCA in mice.	('mice', 'Species', '10090', (79, 83))	('deletion', 'Var', (53, 61))	('promotes', 'PosReg', (62, 70))	('CCA', 'Phenotype', 'HP:0030153', (72, 75))	('Pten', 'Chemical', '-', (48, 52))	('Pten', 'Gene', (48, 52))	('iCCA', 'Disease', (71, 75))
20862	29627364	introduced an activating mutation of Kras (LSL-KrasG12D) plus deletion of Pten (Ptenflox) specifically in hepatocytes and hepatoblasts by crossing mice carrying a LSL-KrasG12D allele and/or a Ptenflox with Alb-Cre+ mice.	('mice', 'Species', '10090', (147, 151))	('Pten', 'Chemical', '-', (74, 78))	('Pten', 'Gene', (74, 78))	('Kras', 'Gene', (37, 41))	('LSL-KrasG12D', 'Gene', (163, 175))	('LSL-KrasG12D', 'Gene', '16653', (163, 175))	('Pten', 'Chemical', '-', (192, 196))	('activating', 'PosReg', (14, 24))	('LSL-KrasG12D', 'Gene', (43, 55))	('mice', 'Species', '10090', (215, 219))	('deletion', 'Var', (62, 70))	('LSL-KrasG12D', 'Gene', '16653', (43, 55))	('Pten', 'Chemical', '-', (80, 84))
20867	29627364	Immunohistochemical analyses demonstrated that AKPP mice develop iCCA exclusively whereas Alb-Cre+/LSL-KrasG12D/+/Ptenflox/+ mice which had deletion of only one Pten allele developed hepatocellular dysplasia in the majority of nodules with some nodules resembling iCCA.	('hepatocellular dysplasia', 'Disease', 'MESH:D006528', (183, 207))	('rat', 'Species', '10116', (36, 39))	('Pten', 'Chemical', '-', (161, 165))	('CCA', 'Phenotype', 'HP:0030153', (66, 69))	('CCA', 'Phenotype', 'HP:0030153', (265, 268))	('Pten', 'Gene', (161, 165))	('iCCA', 'Disease', (65, 69))	('mice', 'Species', '10090', (52, 56))	('mice', 'Species', '10090', (125, 129))	('LSL-KrasG12D', 'Gene', (99, 111))	('deletion', 'Var', (140, 148))	('LSL-KrasG12D', 'Gene', '16653', (99, 111))	('Pten', 'Chemical', '-', (114, 118))	('AKPP', 'Chemical', '-', (47, 51))	('hepatocellular dysplasia', 'Disease', (183, 207))	('AKPP', 'Var', (47, 51))	('developed', 'Reg', (173, 182))
20869	29627364	Mice without Pten deletion developed hepatocellular dysplasia but no features of CCA, suggesting that Pten may play a role in fate determination of hepatotumorigenesis.	('hepatocellular dysplasia', 'Disease', (37, 61))	('hepatocellular dysplasia', 'Disease', 'MESH:D006528', (37, 61))	('Pten', 'Chemical', '-', (13, 17))	('Pten', 'Chemical', '-', (102, 106))	('Pten', 'Gene', (13, 17))	('developed', 'Reg', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('CCA', 'Phenotype', 'HP:0030153', (81, 84))	('deletion', 'Var', (18, 26))	('tumor', 'Disease', (154, 159))
20870	29627364	As activating Kras gene mutations and PI3K pathway alterations are frequently observed in human iCCA, this model recapitulates a subset of human iCCAs.	('PI3', 'Gene', (38, 41))	('alterations', 'Reg', (51, 62))	('iCCA', 'Disease', (96, 100))	('activating', 'PosReg', (3, 13))	('PI3', 'Gene', '20702', (38, 41))	('human', 'Species', '9606', (90, 95))	('CCA', 'Phenotype', 'HP:0030153', (97, 100))	('human', 'Species', '9606', (139, 144))	('CCA', 'Phenotype', 'HP:0030153', (146, 149))	('mutations', 'Var', (24, 33))	('rat', 'Species', '10116', (55, 58))	('Kras gene', 'Gene', (14, 23))
20873	29627364	Gain of function mutations of IDH1 and IDH2 occur in approximately 25% of iCCAs.	('IDH2', 'Gene', (39, 43))	('iCCAs', 'Disease', (74, 79))	('IDH1', 'Gene', (30, 34))	('IDH2', 'Gene', '269951', (39, 43))	('CCA', 'Phenotype', 'HP:0030153', (75, 78))	('IDH1', 'Gene', '15926', (30, 34))	('mutations', 'Var', (17, 26))	('Gain of function', 'PosReg', (0, 16))
20874	29627364	Mutant IDH blocks hepatocyte differentiation from progenitor cells via suppression of hepatocyte nuclear factor-4alpha, a transcriptional regulator of hepatocyte differentiation.	('IDH', 'Gene', (7, 10))	('hepatocyte differentiation', 'CPA', (18, 44))	('hepatocyte nuclear factor-4alpha', 'Gene', (86, 118))	('suppression', 'NegReg', (71, 82))	('blocks', 'NegReg', (11, 17))	('hepatocyte nuclear factor-4alpha', 'Gene', '15378', (86, 118))	('Mutant', 'Var', (0, 6))
20875	29627364	Intercrossing of mutant Idh2 (LSL-IDH2R172K), mice with activating Kras mutations, (LSL-KrasG12), and Alb-Cre+ mice resulted in palpable liver tumors in six out of six IDH2R172K/KrasG12D mice at 33-58 weeks of age.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('Kras', 'Gene', (67, 71))	('liver tumors', 'Disease', (137, 149))	('activating', 'PosReg', (56, 66))	('mice', 'Species', '10090', (187, 191))	('Idh2', 'Gene', '269951', (24, 28))	('mutant', 'Var', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('IDH2', 'Gene', '269951', (168, 172))	('mutations', 'Var', (72, 81))	('Idh2', 'Gene', (24, 28))	('LSL-IDH2R172K', 'Gene', '269951', (30, 43))	('IDH2', 'Gene', (34, 38))	('liver tumors', 'Disease', 'MESH:D008113', (137, 149))	('liver tumors', 'Phenotype', 'HP:0002896', (137, 149))	('mice', 'Species', '10090', (111, 115))	('LSL-IDH2R172K', 'Gene', (30, 43))	('mice', 'Species', '10090', (46, 50))	('IDH2', 'Gene', (168, 172))	('IDH2', 'Gene', '269951', (34, 38))
20879	29627364	As KRAS and IDH mutations occur frequently in human CCA, this genetically engineered model recapitulates a subset of human iCCAs.	('CCA', 'Disease', (52, 55))	('KRAS', 'Gene', '3845', (3, 7))	('human', 'Species', '9606', (117, 122))	('mutations', 'Var', (16, 25))	('CCA', 'Phenotype', 'HP:0030153', (124, 127))	('CCA', 'Phenotype', 'HP:0030153', (52, 55))	('human', 'Species', '9606', (46, 51))	('IDH', 'Gene', (12, 15))	('KRAS', 'Gene', (3, 7))
20881	29627364	This model was established by intercrossing Alb-Cre mutants with KrasG12D mice with or without deletion of tumor protein 53 (TP53), a tumor suppressor gene frequently mutated in human cancer.	('cancer', 'Disease', (184, 190))	('mice', 'Species', '10090', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('deletion', 'Var', (95, 103))	('tumor protein 53', 'Gene', '22059', (107, 123))	('TP53', 'Gene', '22059', (125, 129))	('tumor protein 53', 'Gene', (107, 123))	('human', 'Species', '9606', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutants', 'Var', (52, 59))	('TP53', 'Gene', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Disease', (134, 139))
20884	29627364	Mice with homozygous p53 deletion (Alb-Cre/KrasG12D/p53L/L) developed tumors at 9 weeks of age and had a mean survival of 19 weeks.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('deletion', 'Var', (25, 33))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('Mice', 'Species', '10090', (0, 4))	('p53', 'Gene', (21, 24))
20888	29627364	Characterization of the molecular features demonstrated that the Alb-Cre/KrasG12D/p53L/L mice have activation of the MAPK/MEK and PI3K/AKT pathways, similar to a subset of human CCAs.	('CCA', 'Phenotype', 'HP:0030153', (178, 181))	('MEK', 'Gene', (122, 125))	('PI3', 'Gene', '20702', (130, 133))	('mice', 'Species', '10090', (89, 93))	('rat', 'Species', '10116', (50, 53))	('human', 'Species', '9606', (172, 177))	('activation', 'PosReg', (99, 109))	('PI3', 'Gene', (130, 133))	('Alb-Cre/KrasG12D/p53L/L', 'Var', (65, 88))	('MEK', 'Gene', '17242', (122, 125))
20894	29627364	treated mice harboring a p53 deletion with CCL4.	('p53', 'Gene', (25, 28))	('deletion', 'Var', (29, 37))	('mice', 'Species', '10090', (8, 12))
20898	29627364	However, cholangiocyte apoptosis was observed only in the mice without a p53 deletion (p53+/+) and mice with deletion of only one p53 allele (p53+/-).	('mice', 'Species', '10090', (99, 103))	('p53', 'Gene', (73, 76))	('cholangiocyte apoptosis', 'CPA', (9, 32))	('mice', 'Species', '10090', (58, 62))	('deletion', 'Var', (77, 85))
20901	29627364	CCA was detected in 54% of mice with homozygous p53 deletion and only 18% of mice with heterozygous p53 deletion, with a shorter tumor latency being observed in the p53-/- (29 weeks) compared with p53+/- mice (52 weeks).	('p53', 'Gene', (48, 51))	('mice', 'Species', '10090', (77, 81))	('CCA', 'Phenotype', 'HP:0030153', (0, 3))	('mice', 'Species', '10090', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('CCA', 'Disease', (0, 3))	('mice', 'Species', '10090', (204, 208))	('tumor', 'Disease', (129, 134))	('deletion', 'Var', (52, 60))
20911	29627364	Analyses of the transgene expression showed that both the gallbladder adenocarcinoma and CCA expressed the transgene.	('gallbladder adenocarcinoma', 'Disease', (58, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('CCA', 'Disease', (89, 92))	('gallbladder adenocarcinoma', 'Disease', 'MESH:D000230', (58, 84))	('transgene', 'Var', (107, 116))	('CCA', 'Phenotype', 'HP:0030153', (89, 92))
20912	29627364	The BK-ErbB-2A mice had increased COX-2 levels and MAPK pathway activation, similar to human CCA.	('MAPK pathway', 'Pathway', (51, 63))	('human', 'Species', '9606', (87, 92))	('CCA', 'Phenotype', 'HP:0030153', (93, 96))	('activation', 'PosReg', (64, 74))	('BK-ErbB-2A', 'Var', (4, 14))	('COX-2 levels', 'MPA', (34, 46))	('mice', 'Species', '10090', (15, 19))	('increased', 'PosReg', (24, 33))
20917	29627364	Accordingly, aberrations in the pathway are associated with CCA carcinogenesis.	('associated', 'Reg', (44, 54))	('CCA carcinogenesis', 'Disease', 'MESH:C536211', (60, 78))	('CCA carcinogenesis', 'Disease', (60, 78))	('rat', 'Species', '10116', (17, 20))	('aberrations', 'Var', (13, 24))	('CCA', 'Phenotype', 'HP:0030153', (60, 63))
20924	29627364	The investigators also demonstrated that Notch induces cyclin E promoter activation leading to cyclin E expression and DNA instability, features found in human CCA.	('Notch', 'Var', (41, 46))	('human', 'Species', '9606', (154, 159))	('cyclin E promoter activation', 'MPA', (55, 83))	('rat', 'Species', '10116', (30, 33))	('cyclin E expression', 'MPA', (95, 114))	('DNA instability', 'MPA', (119, 134))	('CCA', 'Phenotype', 'HP:0030153', (160, 163))
20938	29627364	Ten weeks following the surgery, tumors were noted in 72% of mice which received transduction of both oncogenes and systemic IL-33 administration.	('mice', 'Species', '10090', (61, 65))	('transduction', 'Var', (81, 93))	('rat', 'Species', '10116', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))
21017	29353872	However, they suggested the following requirements to accurately diagnose EC: 1) thickening of the biliary wall or narrowing of the biliary tree; 2) eosinophilic infiltration on histopathology; and 3) regression of the stricture or resolution of other biliary abnormalities in the absence of treatment or subsequent steroid therapy.	('men', 'Species', '9606', (45, 48))	('biliary abnormalities', 'Disease', 'MESH:D001657', (252, 273))	('men', 'Species', '9606', (297, 300))	('steroid', 'Chemical', 'MESH:D013256', (316, 323))	('eosinophilic', 'Var', (149, 161))	('biliary abnormalities', 'Disease', (252, 273))	('biliary abnormalities', 'Phenotype', 'HP:0001080', (252, 273))	('EC', 'Chemical', '-', (74, 76))
21035	25889726	For all 154 patients, the resection rate of J-B T1 was 68.6% (48/70), higher than that of J-B T2 (44.8%, P = 0.007).	('higher', 'PosReg', (70, 76))	('patients', 'Species', '9606', (12, 20))	('resection', 'CPA', (26, 35))	('J-B T1', 'Var', (44, 50))
21091	25889726	Poor differentiation, J-B T2 stage, and R1 resection are labels of advance stage of tumor and predict poor survival.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('Poor differentiation', 'CPA', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('R1 resection', 'Var', (40, 52))	('tumor', 'Disease', (84, 89))
21092	25889726	So, the patients with one of the following risk factors, J-B T2 stage, poor differentiation, or R1 resection, have a poor survival and they were considered as stage II in the current staging system.	('poor', 'NegReg', (117, 121))	('poor', 'Var', (71, 75))	('J-B T2 stage', 'Var', (57, 69))	('R1 resection', 'Var', (96, 108))	('patients', 'Species', '9606', (8, 16))
21111	25608662	The entire biliary tree, including the gallbladder is lined with a simple columnar epithelium and malignant transformation of this epithelium gives rise to predominantly adenocarcinomas.	('malignant', 'Var', (98, 107))	('adenocarcinomas', 'Disease', 'MESH:D000230', (170, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (175, 185))	('adenocarcinomas', 'Disease', (170, 185))
21141	25608662	In addition, a genetic predisposition is suggested with a mutation in the p53 tumor suppressor and k-ras genes seen in intrahepatic and extrahepatic CCA respectively.	('seen in', 'Reg', (111, 118))	('k-ras', 'Gene', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutation', 'Var', (58, 66))	('p53', 'Gene', (74, 77))	('extrahepatic CCA', 'Disease', (136, 152))	('tumor', 'Disease', (78, 83))	('p53', 'Gene', '7157', (74, 77))	('k-ras', 'Gene', '3845', (99, 104))
21171	25608662	iCCA are typically hypo- or iso-attenuating relative to normal hepatic parenchyma on unenhanced CT with most remaining hypoattenuating during the arterial and portal venous phases with enhancement only in the delayed phase (Figures 3, 4, 5 and 6).	('hepatic parenchyma', 'Disease', (63, 81))	('hepatic parenchyma', 'Disease', 'MESH:D010195', (63, 81))	('men', 'Species', '9606', (192, 195))	('hypoattenuating', 'Var', (119, 134))
21227	25608662	In patients with PSC, CA19-9 has sensitivity and specificity of 79%and 98% respectively at serum concentration >129U/ml.	('PSC', 'Gene', '100653366', (17, 20))	('CA19-9', 'Var', (22, 28))	('PSC', 'Gene', (17, 20))	('patients', 'Species', '9606', (3, 11))	('serum concentration >129U/ml', 'MPA', (91, 119))
21228	25608662	In patients without PSC, a CA19-9 > 100U/ml has sensitivity of 76% and a negative predictive value of 92% compared to those with benign strictures.	('CA19-9 > 100U/ml', 'Var', (27, 43))	('patients', 'Species', '9606', (3, 11))	('PSC', 'Gene', (20, 23))	('PSC', 'Gene', '100653366', (20, 23))
21336	25608662	Any focal or eccentric stenosis, irregularity of the lumen or abrupt amputation is suggestive of invasion.	('eccentric stenosis', 'Disease', (13, 31))	('men', 'Species', '9606', (55, 58))	('focal', 'Disease', (4, 9))	('eccentric stenosis', 'Disease', 'MESH:D003251', (13, 31))	('irregularity', 'Var', (33, 45))
21417	21757981	Two (0.13%) of the 1,549 patients who underwent PEI, 4 (0.12%) of the 3,391 who underwent FNAB, and one (0.66%) of the 152 patients who underwent PTBD for HCC experienced needle-track seeding during the study period.	('PEI', 'Var', (48, 51))	('HCC', 'Phenotype', 'HP:0001402', (155, 158))	('patients', 'Species', '9606', (123, 131))	('needle-track seeding', 'CPA', (171, 191))	('HCC', 'Gene', (155, 158))	('patients', 'Species', '9606', (25, 33))	('PEI', 'Chemical', '-', (48, 51))	('HCC', 'Gene', '619501', (155, 158))
21448	21757981	In the current study, two (0.13%) of the 1,549 patients who underwent PEI, four (0.12%) of the 3,391 patients who underwent FNAB, and one (0.66%) of the 152 patients who underwent PTBD for HCC experienced needle-track seeding.	('patients', 'Species', '9606', (101, 109))	('needle-track seeding', 'CPA', (205, 225))	('PEI', 'Var', (70, 73))	('patients', 'Species', '9606', (47, 55))	('HCC', 'Gene', (189, 192))	('patients', 'Species', '9606', (157, 165))	('HCC', 'Gene', '619501', (189, 192))	('PEI', 'Chemical', '-', (70, 73))	('HCC', 'Phenotype', 'HP:0001402', (189, 192))
21459	21757981	Furthermore, our findings show that PTBD, like PEI and FNAB, can cause needle-track seeding.	('cause', 'Reg', (65, 70))	('needle-track seeding', 'CPA', (71, 91))	('PEI', 'Chemical', '-', (47, 50))	('PTBD', 'Var', (36, 40))
21476	19435499	This study investigates changes in gene expression and copy number in biliary cancers and correlates these changes with anatomical site of origin, histopathology and outcome.	('biliary cancers', 'Disease', (70, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('biliary cancers', 'Disease', 'MESH:D001661', (70, 85))	('changes', 'Reg', (24, 31))	('copy number', 'Var', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
21489	19435499	Studies have shown that biliary carcinogenesis may be related in-part to loss of heterozygosity at the loci of chromosomes 1p, 6q, 9p, 16q, and 17p, and point mutations at the K-ras oncogene and the p-53 tumor suppressor gene.	('loss', 'NegReg', (73, 77))	('biliary carcinogenesis', 'Disease', (24, 46))	('K-ras', 'Gene', (176, 181))	('p-53 tumor suppressor', 'Gene', '7157', (199, 220))	('K-ras', 'Gene', '3845', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('p-53 tumor suppressor', 'Gene', (199, 220))	('biliary carcinogenesis', 'Disease', 'MESH:D063646', (24, 46))	('point mutations', 'Var', (153, 168))
21500	19435499	1 ug of total RNA was reverse-transcribed using the Thermoscript RT-PCR system (Invitrogen) at 52 C for 1 h. 20 ng of resultant cDNA was used in a Q-PCR reaction using an iCycler (Biorad, Hercules, California, USA) and pre-designed TaqMan ABI Gene expression Assays (Hs00270424_m1 for CCNB2, Hs00938777_m1 for CDC2, Hs00175938_m1 for CDKN1C, Hs01665258_m1 for DLC1, Hs01547109_m1 for FOSB, Hs99999032_m1 for IL6, s01118813_m1 for NR4A2, Hs00971643_g1 for SRD5A1, Hs01014001_m1 for STAT1, Hs00426591_m1 for TYMS, Hs00197374_m1 for UBD).	('Hs01547109_m1', 'Var', (366, 379))	('CCNB2', 'Gene', '9133', (285, 290))	('CDKN1C', 'Gene', '1028', (334, 340))	('IL6', 'Gene', (408, 411))	('Hs01014001_m1', 'Var', (463, 476))	('STAT1', 'Gene', '6772', (481, 486))	('DLC1', 'Gene', '10395', (360, 364))	('Hs00971643_g1', 'Var', (437, 450))	('DLC1', 'Gene', (360, 364))	('CCNB2', 'Gene', (285, 290))	('NR4A2', 'Gene', '4929', (430, 435))	('FOSB', 'Gene', '2354', (384, 388))	('CDKN1C', 'Gene', (334, 340))	('TYMS', 'Gene', '7298', (506, 510))	('Hs01665258_m1', 'Var', (342, 355))	('FOSB', 'Gene', (384, 388))	('SRD5A1', 'Gene', (455, 461))	('IL6', 'Gene', '3569', (408, 411))	('Hs00426591_m1', 'Var', (488, 501))	('SRD5A1', 'Gene', '6715', (455, 461))	('NR4A2', 'Gene', (430, 435))	('STAT1', 'Gene', (481, 486))	('Hs99999032_m1', 'Var', (390, 403))	('s01118813_m1', 'Var', (413, 425))	('TYMS', 'Gene', (506, 510))	('CDC2', 'Gene', (310, 314))	('CDC2', 'Gene', '983', (310, 314))
21521	19435499	To better understand the molecular pathogenesis of biliary tract cancers we used an array based CGH analysis to detect chromosomal areas of DNA copy number gain (DNA copy number of 3 or greater) and loss (DNA copy number of 0 or 1) in the GBC, IHC, and EHC specimens.	('DNA', 'Gene', (140, 143))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (51, 71))	('IHC', 'Disease', (244, 247))	('EHC', 'Disease', (253, 256))	('biliary tract cancers', 'Disease', (51, 72))	('copy number', 'Var', (144, 155))	('biliary tract cancers', 'Disease', 'MESH:D001661', (51, 72))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('gain', 'PosReg', (156, 160))	('GBC', 'Disease', (239, 242))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('loss', 'NegReg', (199, 203))
21526	19435499	Patients with IHC had an average of 49.2 alterations (range 11-101) in DNA copy number with slightly more deletions (mean 26.9, range 8-80) than amplifications (mean 22.2, range 2-47).	('IHC', 'Disease', (14, 17))	('deletions', 'Var', (106, 115))	('Patients', 'Species', '9606', (0, 8))	('DNA copy number', 'Gene', (71, 86))	('alterations', 'Reg', (41, 52))
21528	19435499	For example, a number of patients within each cancer subtype had mutations in nearly every chromosomal arm while other patients with the same tumor type had minimal structural changes in their entire genome (Figure 2a).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('tumor', 'Disease', (142, 147))	('patients', 'Species', '9606', (119, 127))	('chromosomal', 'Gene', (91, 102))	('patients', 'Species', '9606', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('mutations', 'Var', (65, 74))
21530	19435499	For example, a short segment of chromosome 1p was deleted in greater than 75% of patients with GBC and IHC and nearly 50% of patients with EHC.	('IHC', 'Disease', (103, 106))	('patients', 'Species', '9606', (81, 89))	('GBC', 'Disease', (95, 98))	('deleted', 'Var', (50, 57))	('patients', 'Species', '9606', (125, 133))
21538	19435499	These included genes which were overexpressed in EHC (SRDA21, STAT1, UBD, TYMS), underexpressed in EHC (FOSB, CDKN1C, IL6), overexpressed in IHC (SRDA21, STAT1, UBD, TYMS), underexpressed in IHC (DLC1, NR4A2, IL6), and overexpressed in GBC (UBD, TYMS, CDC2, CCNB2).	('IL6', 'Gene', (209, 212))	('NR4A2', 'Gene', '4929', (202, 207))	('CCNB2', 'Gene', '9133', (258, 263))	('TYMS', 'Gene', (74, 78))	('CDC2', 'Gene', '983', (252, 256))	('TYMS', 'Gene', '7298', (166, 170))	('CDC2', 'Gene', (252, 256))	('STAT1', 'Gene', '6772', (154, 159))	('TYMS', 'Gene', '7298', (246, 250))	('CDKN1C', 'Gene', '1028', (110, 116))	('IL6', 'Gene', '3569', (118, 121))	('FOSB', 'Gene', '2354', (104, 108))	('STAT1', 'Gene', (62, 67))	('SRDA21', 'Var', (146, 152))	('NR4A2', 'Gene', (202, 207))	('TYMS', 'Gene', (166, 170))	('CCNB2', 'Gene', (258, 263))	('IL6', 'Gene', (118, 121))	('TYMS', 'Gene', (246, 250))	('overexpressed', 'PosReg', (32, 45))	('FOSB', 'Gene', (104, 108))	('IL6', 'Gene', '3569', (209, 212))	('DLC1', 'Gene', '10395', (196, 200))	('CDKN1C', 'Gene', (110, 116))	('TYMS', 'Gene', '7298', (74, 78))	('DLC1', 'Gene', (196, 200))	('overexpressed', 'PosReg', (124, 137))	('STAT1', 'Gene', '6772', (62, 67))	('STAT1', 'Gene', (154, 159))
21545	19435499	Our current findings also show mutated expression of a large number of cell cycle regulators including UBD, BCL2L2, CDC2, MCM2, and CDKN1C in all subtypes.	('CDC2', 'Gene', (116, 120))	('UBD', 'Disease', (103, 106))	('CDKN1C', 'Gene', (132, 138))	('BCL2L2', 'Gene', '599', (108, 114))	('CDKN1C', 'Gene', '1028', (132, 138))	('MCM2', 'Gene', '4171', (122, 126))	('MCM2', 'Gene', (122, 126))	('BCL2L2', 'Gene', (108, 114))	('expression', 'MPA', (39, 49))	('CDC2', 'Gene', '983', (116, 120))	('mutated', 'Var', (31, 38))
21548	19435499	reported that the mutation of the p53, p16, and K-ras genes occurred at rates of 36%, 31% and 20%, respectively, in GBC.	('p53', 'Gene', (34, 37))	('K-ras', 'Gene', '3845', (48, 53))	('p53', 'Gene', '7157', (34, 37))	('p16', 'Gene', (39, 42))	('occurred', 'Reg', (60, 68))	('p16', 'Gene', '1029', (39, 42))	('mutation', 'Var', (18, 26))	('GBC', 'Disease', (116, 119))	('K-ras', 'Gene', (48, 53))
21550	19435499	studied loss of heterozygosity in 32 cases of GBC and 11 cases of dysplasia.	('dysplasia', 'Disease', (66, 75))	('GBC', 'Disease', (46, 49))	('loss', 'Var', (8, 12))	('dysplasia', 'Disease', 'MESH:D004476', (66, 75))
21557	19435499	Overexpression of EGFR was found in 8% of tumors and was also associated with a high frequency of gene amplification (77%).	('EGFR', 'Gene', '1956', (18, 22))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('EGFR', 'Gene', (18, 22))	('gene amplification', 'MPA', (98, 116))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
21559	19435499	They found evidence of microsatellite instability in equal proportions in early and late cancers, and it was also found in premalignant lesions, indicating that inactivation of mismatch repair genes occurs early in gallbladder carcinogenesis.	('late cancers', 'Disease', 'MESH:D009369', (84, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('late cancers', 'Disease', (84, 96))	('microsatellite', 'Var', (23, 37))	('gallbladder carcinogenesis', 'Disease', (215, 241))	('gallbladder carcinogenesis', 'Disease', 'MESH:D063646', (215, 241))	('mismatch repair genes', 'Gene', (177, 198))
21567	19435499	There is accumulating evidence that deregulation of this pathway as a result of mutations or altered expression of ubiquitylating or de-ubiquitylating enzymes as well as of Ub-binding proteins affect crucial mediators of these functions and are underlie the pathogenesis of several human malignancies.	('ubiquitylating', 'Protein', (115, 129))	('mediators', 'MPA', (208, 217))	('mutations', 'Var', (80, 89))	('altered', 'Reg', (93, 100))	('malignancies', 'Disease', (288, 300))	('human', 'Species', '9606', (282, 287))	('affect', 'Reg', (193, 199))	('deregulation', 'PosReg', (36, 48))	('expression', 'MPA', (101, 111))	('malignancies', 'Disease', 'MESH:D009369', (288, 300))
21570	19435499	The transcription factors of this family are activated by the Janus Kinase JAK and dysregulation of this pathway has been observed in primary tumors and leads to increased angiogenesis, metastases, enhanced survival of tumors, and immunosuppression.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('JAK', 'Gene', (75, 78))	('tumors', 'Disease', (219, 225))	('increased', 'PosReg', (162, 171))	('metastases', 'Disease', (186, 196))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('metastases', 'Disease', 'MESH:D009362', (186, 196))	('dysregulation', 'Var', (83, 96))	('JAK', 'Gene', '3717', (75, 78))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('survival', 'CPA', (207, 215))	('enhanced', 'PosReg', (198, 206))	('activated', 'PosReg', (45, 54))	('angiogenesis', 'CPA', (172, 184))
21591	32234665	It is also important to point out that there are prognostic model and scoring system that can identify patients who will unlikely benefit from second-line therapy such as peritoneal disease, poor baseline ECOG status or elevated CA 19/9.	('CA 19/9', 'Gene', '768', (229, 236))	('peritoneal disease', 'Disease', 'MESH:D010532', (171, 189))	('CA 19/9', 'Gene', (229, 236))	('peritoneal disease', 'Disease', (171, 189))	('patients', 'Species', '9606', (103, 111))	('poor', 'Var', (191, 195))	('ECOG status', 'MPA', (205, 216))
21595	32234665	Comprehensive genomic profiling of biliary tract cancers revealed that the KRAS mutation can be as high as 42% in EHCCA compared to 22% in intrahepatic cholangiocarcinoma and 11% in gallbladder cancer.	('gallbladder cancer', 'Disease', (182, 200))	('gallbladder cancer', 'Disease', 'MESH:D005706', (182, 200))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (152, 170))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (139, 170))	('biliary tract cancers', 'Disease', 'MESH:D001661', (35, 56))	('biliary tract cancers', 'Disease', (35, 56))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('KRAS', 'Gene', (75, 79))	('intrahepatic cholangiocarcinoma', 'Disease', (139, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('EHCCA', 'Disease', (114, 119))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('mutation', 'Var', (80, 88))	('KRAS', 'Gene', '3845', (75, 79))
21596	32234665	On the other hand, BRAF mutation can be found in 5% of the intrahepatic cholangiocarcinoma compared to 3% in EHCCA and 1% in gallbladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('gallbladder cancer', 'Disease', (125, 143))	('gallbladder cancer', 'Disease', 'MESH:D005706', (125, 143))	('BRAF', 'Gene', '673', (19, 23))	('BRAF', 'Gene', (19, 23))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (59, 90))	('intrahepatic cholangiocarcinoma', 'Disease', (59, 90))	('found', 'Reg', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('mutation', 'Var', (24, 32))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))
21639	32234665	The observed hazard rates for mortality and disease progression were higher for patients who received trametinib versus those who received chemotherapy (Figs.1 and 2).	('patients', 'Species', '9606', (80, 88))	('trametinib', 'Chemical', 'MESH:C560077', (102, 112))	('trametinib', 'Var', (102, 112))	('mortality', 'Disease', 'MESH:D003643', (30, 39))	('disease progression', 'CPA', (44, 63))	('mortality', 'Disease', (30, 39))	('higher', 'PosReg', (69, 75))
21659	32234665	This study was based on the hypothesis that targeting the RAS/RAF/MAPK (MEK)/extracellular signal-related kinase (ERK) pathway would result in superior survival and anti-tumour activity given the reported presence of MAPK alterations in BC.	('RAF', 'Gene', (62, 65))	('ERK', 'Gene', (114, 117))	('MAPK', 'Gene', (217, 221))	('tumour', 'Disease', (170, 176))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('MEK', 'Gene', (72, 75))	('superior', 'PosReg', (143, 151))	('MEK', 'Gene', '5609', (72, 75))	('alterations', 'Var', (222, 233))	('survival', 'CPA', (152, 160))	('RAF', 'Gene', '22882', (62, 65))	('ERK', 'Gene', '5594', (114, 117))	('tumour', 'Disease', 'MESH:D009369', (170, 176))
21672	32234665	One hypothesis is that the patients who responded may have harboured MEK mutations, which have no correlations with RAF or RAS mutations.	('MEK', 'Gene', (69, 72))	('MEK', 'Gene', '5609', (69, 72))	('patients', 'Species', '9606', (27, 35))	('RAF', 'Gene', (116, 119))	('mutations', 'Var', (73, 82))	('RAF', 'Gene', '22882', (116, 119))
21679	32234665	In this study, the patients with aberrations in the RAS/RAF/MEK/ERK pathway showed longer PFS and OS than those without such aberrations.	('MEK', 'Gene', '5609', (60, 63))	('patients', 'Species', '9606', (19, 27))	('RAF', 'Gene', '22882', (56, 59))	('ERK', 'Gene', '5594', (64, 67))	('RAF', 'Gene', (56, 59))	('aberrations', 'Var', (33, 44))	('PFS', 'CPA', (90, 93))	('ERK', 'Gene', (64, 67))	('longer', 'PosReg', (83, 89))	('MEK', 'Gene', (60, 63))
21683	32234665	In advanced colon cancer, single-agent RAF or MEK inhibitors have failed to demonstrate activity in KRAS or BRAF mutant tumours.	('KRAS', 'Gene', (100, 104))	('MEK', 'Gene', (46, 49))	('mutant', 'Var', (113, 119))	('colon cancer', 'Disease', (12, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('RAF', 'Gene', '22882', (39, 42))	('RAF', 'Gene', '22882', (109, 112))	('tumours', 'Disease', (120, 127))	('BRAF', 'Gene', '673', (108, 112))	('BRAF', 'Gene', (108, 112))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('RAF', 'Gene', (39, 42))	('RAF', 'Gene', (109, 112))	('colon cancer', 'Phenotype', 'HP:0003003', (12, 24))	('KRAS', 'Gene', '3845', (100, 104))	('MEK', 'Gene', '5609', (46, 49))	('colon cancer', 'Disease', 'MESH:D015179', (12, 24))
21688	32234665	Based on molecular profiling, 53% of patients in the study were found to have actionable mutations such as fibroblast growth factor receptor (FGFR) fusions, IDH 1 mutations and ERBB amplifications and derived clinical benefit.	('fusions', 'Var', (148, 155))	('ERBB', 'Gene', (177, 181))	('mutations', 'Var', (163, 172))	('patients', 'Species', '9606', (37, 45))	('IDH 1', 'Gene', (157, 162))	('FGFR', 'Gene', (142, 146))	('ERBB', 'Gene', '1956', (177, 181))	('IDH 1', 'Gene', '3417', (157, 162))
21689	32234665	Recently, encouraging results have been observed in tyrosine kinase inhibitors targeting FGFR receptors in patients who harbour FGFR fusions including RR up to 25%.	('FGFR', 'Gene', (89, 93))	('fusions', 'Var', (133, 140))	('patients', 'Species', '9606', (107, 115))	('FGFR', 'Gene', (128, 132))
21696	32379819	However, additional resection of pCCA typically increased the risk of perioperative morbidity and mortality.	('resection', 'Var', (20, 29))	('mortality', 'Disease', (98, 107))	('pCCA', 'Gene', (33, 37))	('mortality', 'Disease', 'MESH:D003643', (98, 107))
21726	32379819	In our newly published meta-analysis, no significant differences were observed in the 1-, 2-, and 3-year survival rates between groups of R0 and R-cis (all P>0.05), both of which were significantly higher than those in the group of R-inv (all P<0.05), which indicated that additional resection would be not necessary for patients with initial R-cis.	('patients', 'Species', '9606', (321, 329))	('R-cis', 'Var', (145, 150))	('higher', 'PosReg', (198, 204))
21739	32307602	Her serum levels of CA19-9 were trending down to 9029.2 and 2659.8 U/mL at 1 and 3 weeks after surgery, respectively.	('9029.2', 'Var', (49, 55))	('2659.8', 'Var', (60, 66))	('mL at 1 and 3', 'Gene', '20539;72401', (69, 82))	('serum levels', 'MPA', (4, 16))	('CA19-9', 'Chemical', 'MESH:C086528', (20, 26))
21767	32307602	Although the preoperative serum levels of CA19-9 and CEA were extremely high, the preoperative D-dimer, fibrin degradation product (FDP), and fibrinogen levels were slightly higher than the normal limits (Table 1).	('fibrinogen', 'Gene', '2244', (142, 152))	('fibrinogen', 'Gene', (142, 152))	('higher', 'PosReg', (174, 180))	('CEA', 'Gene', (53, 56))	('CA19-9', 'Var', (42, 48))	('fibrin degradation product', 'MPA', (104, 130))	('serum levels', 'MPA', (26, 38))	('CEA', 'Gene', '1084', (53, 56))	('CA19-9', 'Chemical', 'MESH:C086528', (42, 48))	('D-dimer', 'MPA', (95, 102))
21801	32307602	However, the elevated tumor maker levels such as CA19-9, CEA, CA125, CA15-3, and Sialyl Lewis X (SLX) in the present patient might have been triggers for the observed thrombotic events (Table 1), as reported in a previous study.	('CA125', 'Gene', (62, 67))	('thrombotic', 'Disease', 'MESH:D013927', (167, 177))	('thrombotic', 'Disease', (167, 177))	('CA19-9', 'Chemical', 'MESH:C086528', (49, 55))	('patient', 'Species', '9606', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('CA125', 'Gene', '94025', (62, 67))	('CEA', 'Gene', (57, 60))	('elevated tumor', 'Disease', 'MESH:D006973', (13, 27))	('CA15-3', 'Gene', '4582', (69, 75))	('thrombotic event', 'Phenotype', 'HP:0001907', (167, 183))	('elevated tumor', 'Disease', (13, 27))	('CEA', 'Gene', '1084', (57, 60))	('thrombotic events', 'Phenotype', 'HP:0001907', (167, 184))	('CA19-9', 'Var', (49, 55))	('CA15-3', 'Gene', (69, 75))
21814	32307602	As illustrated in the present case, an extremely high level of CA19-9 might trigger Trousseau's syndrome in patients with cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (122, 140))	("Trousseau's syndrome", 'Disease', (84, 104))	('CA19-9', 'Chemical', 'MESH:C086528', (63, 69))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (122, 140))	('patients', 'Species', '9606', (108, 116))	('cholangiocarcinoma', 'Disease', (122, 140))	('CA19-9', 'Var', (63, 69))	('trigger', 'Reg', (76, 83))
21815	32307602	CT Computed tomography MRI Magnetic resonance imaging CA19-9 Carbohydrate antigen 19-9 CEA Carcinoembryonic antigen RS, YO, SH, SM, and ON were the attending physicians.	('CEA', 'Gene', (87, 90))	('Carcinoembryonic', 'Disease', (91, 107))	('CA19-9', 'Var', (54, 60))	('CEA', 'Gene', '1084', (87, 90))	('Carcinoembryonic', 'Disease', 'None', (91, 107))	('CA19-9', 'Chemical', 'MESH:C086528', (54, 60))	('Carbohydrate antigen', 'Chemical', '-', (61, 81))
21863	30478801	In radiological images, low-density mass with enhancement by contrast medium on CT, hypointensity on T1WI, and hyperintensity on T2WI are reported to be key sarcomatous ICC features.	('hyperintensity', 'Var', (111, 125))	('hypointensity', 'Var', (84, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('enhancement', 'PosReg', (46, 57))	('sarcomatous ICC', 'Disease', (157, 172))	('low-density mass', 'MPA', (24, 40))	('sarcomatous ICC', 'Disease', 'MESH:C566123', (157, 172))
22016	25204668	In the ICC models with misclassified and reclassified Klatskin tumors, older age (>=50 years), Asian race, and male sex were associated with an increased risk for ICC, while Black race was associated with a lower risk for ICC (Table 4).	('CC', 'Phenotype', 'HP:0030153', (223, 225))	('Klatskin tumors', 'Disease', 'MESH:D018285', (54, 69))	('CC', 'Phenotype', 'HP:0030153', (8, 10))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('Asian race', 'Var', (95, 105))	('CC', 'Phenotype', 'HP:0030153', (164, 166))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('skin tumors', 'Phenotype', 'HP:0008069', (58, 69))	('Klatskin tumors', 'Disease', (54, 69))	('ICC', 'Disease', (163, 166))
22032	26686459	QBC939 and RBE cells lines were chosen and divided into five groups: miR-122 mimic group, anti-miR-122 group, negative control (NC) group, mock group and blank group.	('anti-miR-122', 'Var', (90, 102))	('QBC939', 'CellLine', 'CVCL:6942', (0, 6))	('miR-122', 'Gene', (69, 76))
22036	26686459	In both QBC939 and RBE cells lines, miR-122 expression was higher in miR-122 mimic group than that in NC group, mock group and blank group; opposite results were found in anti-miR-122 group.	('expression', 'MPA', (44, 54))	('miR-122', 'Gene', (69, 76))	('QBC939', 'CellLine', 'CVCL:6942', (8, 14))	('miR-122', 'Gene', (36, 43))	('higher', 'PosReg', (59, 65))	('mimic group', 'Var', (77, 88))
22045	26686459	The liver homoeostasis is considered to be closely associated with miR-122 expression level; low expression of miR-122 may cause cirrhosis and advanced HCC.	('liver homoeostasis', 'Disease', (4, 22))	('advanced HCC', 'Disease', (143, 155))	('cirrhosis', 'Phenotype', 'HP:0001394', (129, 138))	('cirrhosis', 'Disease', 'MESH:D005355', (129, 138))	('CC', 'Phenotype', 'HP:0030153', (153, 155))	('liver homoeostasis', 'Disease', 'MESH:D017093', (4, 22))	('HCC', 'Phenotype', 'HP:0001402', (152, 155))	('miR-122', 'Gene', (111, 118))	('cause', 'Reg', (123, 128))	('cirrhosis', 'Disease', (129, 138))	('low expression', 'Var', (93, 107))
22047	26686459	The function of miR-122 as tumor suppressor may inhibit the development of CC by binding to target genes related with tumor cell proliferation, apoptosis, invasion and angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', (27, 32))	('CC', 'Phenotype', 'HP:0030153', (75, 77))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('miR-122', 'Gene', (16, 23))	('development of', 'CPA', (60, 74))	('tumor', 'Disease', (118, 123))	('invasion', 'CPA', (155, 163))	('binding', 'Interaction', (81, 88))	('function', 'Var', (4, 12))	('inhibit', 'NegReg', (48, 55))
22080	26686459	The relative expressions of miR-122 in HCCC-9810, RBE and QBC939 were (1.582 +- 0.088), (1.534 +- 0.047), and (0.968 +- 0.012), respectively.	('miR-122', 'Gene', (28, 35))	('QBC939', 'CellLine', 'CVCL:6942', (58, 64))	('CC', 'Phenotype', 'HP:0030153', (40, 42))	('HCC', 'Phenotype', 'HP:0001402', (39, 42))	('HCCC-9810', 'CellLine', 'CVCL:6908', (39, 48))	('0.968', 'Var', (111, 116))
22081	26686459	Furthermore, the expression level of miR-122 in QBC939 was significantly lower than those of the first two cell lines (both P < 0.05), while there was no significant difference in the expression levels of miR-122 between HCCC-9810 and RBE (P > 0.05) (Fig.	('QBC939', 'Var', (48, 54))	('expression level', 'MPA', (17, 33))	('QBC939', 'CellLine', 'CVCL:6942', (48, 54))	('HCC', 'Phenotype', 'HP:0001402', (221, 224))	('CC', 'Phenotype', 'HP:0030153', (222, 224))	('lower', 'NegReg', (73, 78))	('HCCC-9810', 'CellLine', 'CVCL:6908', (221, 230))
22085	26686459	The transfection efficiency of GFP was observed by fluorescence microscope for many times for this kind of transient transfection assay, and results indicated that the transfection efficiency of liposome miR-122mimics/inhibitor and Lip2000 in QBC939 and RBE cells were both better than those in the other cells, with the transfection efficiency reached to 70%-80% (Fig.	('QBC939', 'CellLine', 'CVCL:6942', (243, 249))	('Lip2000', 'Var', (232, 239))	('man', 'Species', '9606', (79, 82))	('transfection efficiency', 'CPA', (168, 191))	('better', 'PosReg', (274, 280))
22089	26686459	However, compared to the NC group, Mock group and Blank group, QBC939 and RBE cell proliferations were both significantly inhibited in the miR-122 mimic group at the time points of 48 h and 72 h after the transfection (P < 0.05), while the cell proliferation was remarkably promoted in the anti-miR-122 group (Tables 3-4 and Fig.	('cell proliferation', 'CPA', (240, 258))	('promoted', 'PosReg', (274, 282))	('inhibited', 'NegReg', (122, 131))	('miR-122', 'Gene', (139, 146))	('QBC939', 'CellLine', 'CVCL:6942', (63, 69))	('anti-miR-122', 'Var', (290, 302))	('RBE cell proliferations', 'CPA', (74, 97))
22094	26686459	However, the number of invasive QBC939 cells into Matrigel in anti-miR-122 group was (101.02 +- 5.92), significantly greater than those in the NC group, the Mock group and the Blank group (all P < 0.05).	('anti-miR-122', 'Var', (62, 74))	('QBC939', 'CellLine', 'CVCL:6942', (32, 38))	('invasive QBC939 cells into Matrigel', 'CPA', (23, 58))	('greater', 'PosReg', (117, 124))
22097	26686459	The design of the experiment constituted a knockout mouse model modeling the loss of miRNA in hepatocytes, and finally liver disruptions including steatosis, inflammation and hepatocyte apoptosis were identified, suggesting that miRNAs played a key role in the liver function and that miR-122 may be associated with hepatocarcinogenesis by influencing hepatocyte survival and tumor progression.	('liver disruptions', 'Disease', 'MESH:D019958', (119, 136))	('tumor', 'Phenotype', 'HP:0002664', (376, 381))	('steatosis', 'Phenotype', 'HP:0001397', (147, 156))	('steatosis', 'Disease', 'MESH:D005234', (147, 156))	('influencing', 'Reg', (340, 351))	('mouse', 'Species', '10090', (52, 57))	('liver disruptions', 'Disease', (119, 136))	('tumor', 'Disease', (376, 381))	('associated', 'Reg', (300, 310))	('steatosis', 'Disease', (147, 156))	('hepatocarcinogenesis', 'Disease', (316, 336))	('hepatocyte survival', 'CPA', (352, 371))	('inflammation', 'Disease', 'MESH:D007249', (158, 170))	('tumor', 'Disease', 'MESH:D009369', (376, 381))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (316, 336))	('miR-122', 'Var', (285, 292))	('inflammation', 'Disease', (158, 170))
22098	26686459	MiR-122 deficiency in CC patients may contribute to the dysregulation of mitochondrial functions related with liver function, so its loss of expression may lead to increased morbidity and mortality and may predict poor prognosis of CC patients.	('lead to', 'Reg', (156, 163))	('CC', 'Phenotype', 'HP:0030153', (232, 234))	('patients', 'Species', '9606', (235, 243))	('CC', 'Phenotype', 'HP:0030153', (22, 24))	('patients', 'Species', '9606', (25, 33))	('MiR-122', 'Gene', (0, 7))	('MiR-122', 'Gene', '406906', (0, 7))	('mitochondrial functions', 'MPA', (73, 96))	('deficiency', 'Var', (8, 18))	('increased', 'PosReg', (164, 173))	('morbidity', 'CPA', (174, 183))	('dysregulation', 'MPA', (56, 69))	('loss of', 'NegReg', (133, 140))
22101	26686459	Previous evidence have shown that compared with adjacent benign liver, miR-122 appears to be down regulated in deficient liver, suggesting the potential of miR-122 as a novel biomarker for liver injury.	('miR-122', 'Var', (156, 163))	('liver injury', 'Disease', 'MESH:D056486', (189, 201))	('deficient liver', 'Disease', (111, 126))	('miR-122', 'Gene', (71, 78))	('down regulated', 'NegReg', (93, 107))	('deficient liver', 'Disease', 'MESH:D017093', (111, 126))	('deficient liver', 'Phenotype', 'HP:0001410', (111, 126))	('liver injury', 'Disease', (189, 201))
22105	26686459	In addition, we identified that the expression level of miR-122 in QBC939 was significantly lower than those of HCCC-9810 and RBE cells, while there was no significant difference between HCCC-9810 and RBE.	('HCCC-9810', 'CellLine', 'CVCL:6908', (112, 121))	('HCC', 'Phenotype', 'HP:0001402', (187, 190))	('QBC939', 'Var', (67, 73))	('CC', 'Phenotype', 'HP:0030153', (113, 115))	('expression level', 'MPA', (36, 52))	('HCC', 'Phenotype', 'HP:0001402', (112, 115))	('HCCC-9810', 'CellLine', 'CVCL:6908', (187, 196))	('CC', 'Phenotype', 'HP:0030153', (188, 190))	('miR-122', 'Var', (56, 63))	('QBC939', 'CellLine', 'CVCL:6942', (67, 73))	('lower', 'NegReg', (92, 97))
22106	26686459	These results supported that QBC939 cells were promising for further in vitro experiment; the reason might be that QBC939 cells widely exist in metastatic foci in liver of extrahepatic bile duct carcinoma, while HCCC-9810 and RBE cells mainly exist in the primary foci in the liver, so QBC939 had a higher degree of malignancy.	('HCCC-9810', 'CellLine', 'CVCL:6908', (212, 221))	('liver of extrahepatic bile duct carcinoma', 'Disease', 'MESH:D001651', (163, 204))	('malignancy', 'Disease', 'MESH:D009369', (316, 326))	('bile duct carcinoma', 'Phenotype', 'HP:0030153', (185, 204))	('QBC939', 'Var', (115, 121))	('malignancy', 'Disease', (316, 326))	('QBC939', 'CellLine', 'CVCL:6942', (286, 292))	('liver of extrahepatic bile duct carcinoma', 'Disease', (163, 204))	('QBC939', 'CellLine', 'CVCL:6942', (29, 35))	('QBC939', 'CellLine', 'CVCL:6942', (115, 121))	('CC', 'Phenotype', 'HP:0030153', (213, 215))	('HCC', 'Phenotype', 'HP:0001402', (212, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))
22112	26686459	The imbalance between miR-122 and CCNG1 may help to inhibit the tumor cell proliferation of CC through triggering p53 tumor suppressor gene.	('inhibit', 'NegReg', (52, 59))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('miR-122', 'Gene', (22, 29))	('CC', 'Phenotype', 'HP:0030153', (92, 94))	('imbalance', 'Var', (4, 13))	('tumor', 'Disease', (118, 123))	('triggering', 'Reg', (103, 113))	('CCNG1', 'Gene', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('CC', 'Phenotype', 'HP:0030153', (34, 36))	('CCNG1', 'Gene', '900', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
22113	26686459	A previous study demonstrated that the abnormal expression of miR-122 was responsible for hepatocarcinogenesis; the loss of miR-122 led to the down-regulation of tumor cell apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('miR-122', 'Gene', (124, 131))	('tumor', 'Disease', (162, 167))	('hepatocarcinogenesis', 'Disease', (90, 110))	('down-regulation', 'NegReg', (143, 158))	('loss', 'Var', (116, 120))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (90, 110))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
22225	19085911	In brief, those identified as infected had diagnosis codes specifying HCV infection (070.41, 070.44, 070.51, 070.54, and V02.62) on two visits, including one outpatient visit.	('HCV infection', 'Disease', (70, 83))	('HCV infection', 'Disease', 'MESH:D006526', (70, 83))	('070.41', 'Var', (85, 91))	('outpatient', 'Species', '9606', (158, 168))	('V02.62', 'Var', (121, 127))	('070.51', 'Var', (101, 107))
22229	19085911	Outcomes of interest, identified by ICD-9 code and recorded in the hospitalization or outpatient files, were ECC (156.1, 156.2, 156.8, 156.9), pancreatic adenocarcinoma (157.0, 157.1, 157.2, 157.3, 157.8, 157.9), ICC (155.1), and HCC (155.0).	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (143, 168))	('pancreatic adenocarcinoma', 'Disease', (143, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('ECC', 'Disease', (109, 112))	('HCC', 'Gene', (230, 233))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (143, 168))	('ICC', 'Disease', (213, 216))	('157.0', 'Var', (170, 175))	('HCC', 'Gene', '619501', (230, 233))	('155.1', 'Var', (218, 223))	('outpatient', 'Species', '9606', (86, 96))
22238	19085911	These included hepatitis B infection (070.22, 070.23, 070.32, 070.33, V02.61), alcoholic liver disease (571.0-571.3), cirrhosis (571.2, 571.5, 571.6), alcoholism (291, 303.0, 303.9, 305.0, V0401:V0405); acute pancreatitis (577.0), chronic pancreatitis (577.1), inflammatory bowel disease (555, 556), cholelithiasis (574.0, 574.1), choledocholithiasis (574.5), choledochal cyst (751.69), or record of a cholecystectomy (51.22, 51.23).	('choledocholithiasis', 'Disease', 'MESH:D042883', (331, 350))	('pancreatitis', 'Disease', (209, 221))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (261, 287))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (261, 287))	('pancreatitis', 'Disease', 'MESH:D010195', (239, 251))	('inflammatory bowel disease', 'Disease', (261, 287))	('hepatitis B infection', 'Phenotype', 'HP:0410369', (15, 36))	('pancreatitis', 'Disease', (239, 251))	('hepatitis B infection', 'Disease', (15, 36))	('cholelithiasis', 'Disease', (300, 314))	('cirrhosis', 'Disease', 'MESH:D005355', (118, 127))	('hepatitis', 'Phenotype', 'HP:0012115', (15, 24))	('choledochal cyst', 'Phenotype', 'HP:0100890', (360, 376))	('cirrhosis', 'Phenotype', 'HP:0001394', (118, 127))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (231, 251))	('hepatitis B infection', 'Disease', 'MESH:D006509', (15, 36))	('cirrhosis', 'Disease', (118, 127))	('alcoholism', 'Phenotype', 'HP:0030955', (151, 161))	('pancreatitis', 'Phenotype', 'HP:0001733', (209, 221))	('alcoholic liver disease', 'Disease', 'MESH:D008108', (79, 102))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (203, 221))	('cholelithiasis', 'Phenotype', 'HP:0001081', (300, 314))	('574.5', 'Var', (352, 357))	('liver disease', 'Phenotype', 'HP:0001392', (89, 102))	('alcoholism', 'Disease', (151, 161))	('cholelithiasis', 'Disease', 'MESH:D002769', (300, 314))	('alcoholism', 'Disease', 'MESH:D000437', (151, 161))	('pancreatitis', 'Phenotype', 'HP:0001733', (239, 251))	('choledocholithiasis', 'Disease', (331, 350))	('pancreatitis', 'Disease', 'MESH:D010195', (209, 221))	('choledochal cyst', 'Disease', (360, 376))	('alcoholic liver disease', 'Disease', (79, 102))
22277	19085911	HCV is a strong risk factor for HCC, and hepatocytes and cholangiocytes have the same progenitor cell; therefore, it could be postulated that HCV could induce carcinogenesis in both cell types by the same mechanism.	('carcinogenesis', 'Disease', (159, 173))	('HCV', 'Var', (142, 145))	('HCC', 'Gene', '619501', (32, 35))	('HCV', 'Species', '11103', (0, 3))	('HCV', 'Species', '11103', (142, 145))	('induce', 'Reg', (152, 158))	('HCC', 'Gene', (32, 35))	('carcinogenesis', 'Disease', 'MESH:D063646', (159, 173))
22280	19085911	It may be that effects are indirect as well, with HCV damaging the liver, causing cirrhosis, and thereby increasing ICC risk.	('increasing', 'PosReg', (105, 115))	('cirrhosis', 'Phenotype', 'HP:0001394', (82, 91))	('cirrhosis', 'Disease', 'MESH:D005355', (82, 91))	('HCV', 'Var', (50, 53))	('ICC', 'Disease', (116, 119))	('liver', 'MPA', (67, 72))	('HCV', 'Species', '11103', (50, 53))	('cirrhosis', 'Disease', (82, 91))	('causing', 'Reg', (74, 81))
22299	19085911	These are consistent with findings of a published meta-analysis, where the pooled odds ratio from 32 case-control studies was 17.3 (95% CI, 13.9-21.6) for anti-HCV/HCV RNA positivity in the setting of HBsAg negativity, and confer internal validity to the study.	('positivity', 'Var', (172, 182))	('anti-HCV/HCV', 'Var', (155, 167))	('HCV', 'Species', '11103', (160, 163))	('HBsAg', 'Disease', (201, 206))	('HCV', 'Species', '11103', (164, 167))
22324	29064885	Among patients who underwent resection for tumors <3cm with lymph-node negative disease, and excluding PSC patients, transplant was still associated with improved OS (3-yr: 54vs44%; 5-yr: 54vs29%; p=0.03).	('improved', 'PosReg', (154, 162))	('PSC', 'Gene', '100653366', (103, 106))	('OS', 'Chemical', '-', (163, 165))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PSC', 'Gene', (103, 106))	('patients', 'Species', '9606', (6, 14))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('patients', 'Species', '9606', (107, 115))	('transplant', 'Var', (117, 127))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
22325	29064885	Transplant remained associated with improved survival on intention-to-treat analysis, even after accounting for tumor size, LN status, and PSC (p=0.049).	('PSC', 'Gene', (139, 142))	('Transplant', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('improved', 'PosReg', (36, 44))	('tumor', 'Disease', (112, 117))	('PSC', 'Gene', '100653366', (139, 142))	('survival', 'MPA', (45, 53))
22360	29064885	Transplantation was also associated with a lower incidence of any postoperative complication compared to resection (49% vs 68%; p=0.03), but there was no difference between groups in major complications (34% vs 45%; p=0.30), postoperative liver failure (10% vs 7%; p=0.50), 90-day mortality (5% vs 12%; p=0.27).	('postoperative liver failure', 'Disease', (225, 252))	('Transplantation', 'Var', (0, 15))	('liver failure', 'Phenotype', 'HP:0001399', (239, 252))	('postoperative liver failure', 'Disease', 'MESH:D017093', (225, 252))
22365	29064885	Comparing all transplant patients with pathologically-confirmed H-CCA (n=41) to those who underwent curative-intent resection (n=191), transplantation was associated with improved OS (MNR vs 21.0 months, 95% CI 16.5-25.5; p<0.001; Figure 2a).	('improved', 'PosReg', (171, 179))	('OS', 'Chemical', '-', (180, 182))	('patients', 'Species', '9606', (25, 33))	('H-CCA', 'Disease', (64, 69))	('transplantation', 'Var', (135, 150))
22367	29064885	Comparing these same transplant patients with pathologically-confirmed H-CCA to those who underwent curative-intent resection but had tumors <3cm in size and no lymph node disease (N0) on pathologic examination (n=57), still transplantation was associated with improved OS (MNR vs 27.4 months, 95% CI 6.0-48.8; p<0.001; Figure 2b).	('lymph node disease', 'Disease', 'MESH:D000072717', (161, 179))	('tumors', 'Disease', (134, 140))	('patients', 'Species', '9606', (32, 40))	('lymph node disease', 'Disease', (161, 179))	('improved', 'PosReg', (261, 269))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('OS', 'Chemical', '-', (270, 272))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('lymph node disease', 'Phenotype', 'HP:0002733', (161, 179))	('transplantation', 'Var', (225, 240))
22376	29064885	Transplantation was associated with improved OS (median 77.4 months, 95% CI not reported) compared to resection (median 17.1 months, 95% CI 17.8-26.3; p<0.001).	('Transplantation', 'Var', (0, 15))	('improved', 'PosReg', (36, 44))	('OS', 'Chemical', '-', (45, 47))
22378	29064885	Transplantation was still associated with improved OS, even when comparing all attempted resections for <3cm/N0 patients with all patients enrolled in a transplant protocol (p=0.002; Figure 4a), as well as with all non-PSC patients enrolled in a transplant protocol (p=0.049; Figure 4b).	('OS', 'Chemical', '-', (51, 53))	('improved', 'PosReg', (42, 50))	('PSC', 'Gene', '100653366', (219, 222))	('patients', 'Species', '9606', (112, 120))	('PSC', 'Gene', (219, 222))	('patients', 'Species', '9606', (130, 138))	('Transplantation', 'Var', (0, 15))	('patients', 'Species', '9606', (223, 231))
22384	29064885	We found that, among patients undergoing curative-intent surgery, neoadjuvant therapy/transplantation was associated with improved OS, even when compared to resection for tumors <3cm and N0 disease, and with negative margins, as well as when excluding patients with a PSC diagnosis.	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('patients', 'Species', '9606', (252, 260))	('OS', 'Chemical', '-', (131, 133))	('PSC', 'Gene', '100653366', (268, 271))	('patients', 'Species', '9606', (21, 29))	('PSC', 'Gene', (268, 271))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('neoadjuvant therapy/transplantation', 'Var', (66, 101))	('tumors', 'Disease', (171, 177))	('improved', 'PosReg', (122, 130))
22385	29064885	On intention-to-treat analysis, neoadjuvant therapy/transplantation was still associated with improved OS, even when compared to resection for tumors <3cm and N0 disease, and when excluding patients with PSC.	('PSC', 'Gene', (204, 207))	('OS', 'Chemical', '-', (103, 105))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('patients', 'Species', '9606', (190, 198))	('tumors', 'Disease', (143, 149))	('neoadjuvant therapy/transplantation', 'Var', (32, 67))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('improved', 'PosReg', (94, 102))	('PSC', 'Gene', '100653366', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
22397	29064885	The authors found improved 1-, 3-, and 5-year survivals among patients who underwent transplant (92%, 82%, and 82%, respectively) compared to those who underwent curative-intent resection (82%, 48%, and 21%, respectively), which persisted even among patients without PSC.	('improved', 'PosReg', (18, 26))	('patients', 'Species', '9606', (250, 258))	('transplant', 'Var', (85, 95))	('PSC', 'Gene', '100653366', (267, 270))	('patients', 'Species', '9606', (62, 70))	('PSC', 'Gene', (267, 270))
22415	29064885	Among all patients who underwent curative-intent surgery for pathologically-diagnosed H-CCA, transplantation was associated with improved survival over resection (5-yr OS: 64% vs 18%).	('survival', 'MPA', (138, 146))	('H-CCA', 'Disease', (86, 91))	('patients', 'Species', '9606', (10, 18))	('improved', 'PosReg', (129, 137))	('transplantation', 'Var', (93, 108))	('OS', 'Chemical', '-', (168, 170))
22420	29064885	Still, transplantation was associated with improved survival over resection (5-yr OS: 54% vs 29%).	('transplantation', 'Var', (7, 22))	('OS', 'Chemical', '-', (82, 84))	('survival', 'MPA', (52, 60))	('improved', 'PosReg', (43, 51))
22439	29573058	In contrast, five core driver genes (TP53,ARID1A,KRAS,SMAD4, and BAP1) with characteristic molecular alterations including fusion transcripts involving fibroblast growth factor receptor 2 and the protein kinase A pathway, and IDH1/2 mutation constituted the biliary tract cancer genomes.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('ARID1A', 'Gene', (42, 48))	('BAP1', 'Gene', (65, 69))	('TP53', 'Gene', (37, 41))	('fibroblast growth factor receptor 2', 'Gene', '2263', (152, 187))	('fibroblast growth factor receptor 2', 'Gene', (152, 187))	('KRAS', 'Gene', '3845', (49, 53))	('SMAD4', 'Gene', (54, 59))	('ARID1A', 'Gene', '8289', (42, 48))	('mutation', 'Var', (233, 241))	('biliary tract cancer', 'Disease', (258, 278))	('KRAS', 'Gene', (49, 53))	('fusion transcripts', 'Var', (123, 141))	('IDH1/2', 'Gene', (226, 232))	('TP53', 'Gene', '7157', (37, 41))	('SMAD4', 'Gene', '4089', (54, 59))	('protein kinase A pathway', 'Pathway', (196, 220))	('BAP1', 'Gene', '8314', (65, 69))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (258, 278))	('biliary tract cancer', 'Disease', 'MESH:D001661', (258, 278))
22443	29573058	1,2-DCP 1,2-dichloropropane AA aristolochic acid AAV2 adeno-associated virus type 2 ARID AT-rich interaction domain BTC biliary tract cancer CCA cholangiocarcinoma CDKN2A cyclin-dependent kinase inhibitor 2A COSMIC Catalogue of Somatic Mutations in Cancer CTNNB1 catenin beta1 ECC extrahepatic cholangiocarcinoma GB gallbladder cancer HBV hepatitis B virus HCC hepatocellular carcinoma HCV hepatitis C virus ICC intrahepatic cholangiocarcinoma TCGA The Cancer Genome Atlas TERT telomerase reverse transcriptase TPM  TERT promoter mutation WES whole exome sequencing WGS whole genome sequencing Hepatocellular and biliary tract cancers are both dismal tumors.	('cholangiocarcinoma', 'Disease', (425, 443))	('AAV2', 'Species', '10804', (49, 53))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (425, 443))	('hepatitis', 'Phenotype', 'HP:0012115', (390, 399))	('CTNNB1', 'Gene', '1499', (256, 262))	('tumor', 'Phenotype', 'HP:0002664', (651, 656))	('extrahepatic cholangiocarcinoma', 'Disease', (281, 312))	('HCC', 'Gene', '619501', (357, 360))	('HCC', 'Phenotype', 'HP:0001402', (357, 360))	('CDKN2A', 'Gene', '1029', (164, 170))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (613, 633))	('biliary tract cancers', 'Disease', 'MESH:D001661', (613, 634))	('tumors', 'Disease', (651, 657))	('cancers', 'Phenotype', 'HP:0002664', (627, 634))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (145, 163))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (120, 140))	('biliary tract cancer', 'Disease', 'MESH:D001661', (613, 633))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('TERT', 'Gene', (473, 477))	('Cancer', 'Phenotype', 'HP:0002664', (249, 255))	('hepatitis B', 'Disease', 'MESH:D006509', (339, 350))	('gallbladder cancer', 'Disease', 'MESH:D005706', (316, 334))	('HCC', 'Gene', (357, 360))	('TERT', 'Gene', '7015', (473, 477))	('biliary tract cancer', 'Disease', 'MESH:D001661', (120, 140))	('1,2-DCP', 'Chemical', '-', (0, 7))	('1,2-dichloropropane', 'Chemical', 'MESH:C004765', (8, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (361, 385))	('cholangiocarcinoma', 'Disease', (145, 163))	('cancer', 'Phenotype', 'HP:0002664', (627, 633))	('Cancer', 'Phenotype', 'HP:0002664', (453, 459))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (145, 163))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (651, 657))	('CTNNB1', 'Gene', (256, 262))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (281, 312))	('ARID', 'Disease', 'None', (84, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (434, 443))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (294, 312))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (361, 385))	('aristolochic acid', 'Chemical', 'MESH:C000228', (31, 48))	('hepatitis C', 'Disease', (390, 401))	('biliary tract cancers', 'Disease', (613, 634))	('hepatitis', 'Phenotype', 'HP:0012115', (339, 348))	('cholangiocarcinoma', 'Disease', (294, 312))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (412, 443))	('carcinoma', 'Phenotype', 'HP:0030731', (376, 385))	('gallbladder cancer', 'Disease', (316, 334))	('intrahepatic cholangiocarcinoma', 'Disease', (412, 443))	('hepatitis C', 'Disease', 'MESH:D006526', (390, 401))	('Mutations', 'Var', (236, 245))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (294, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('hepatitis B', 'Disease', (339, 350))	('CDKN2A', 'Gene', (164, 170))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (425, 443))	('hepatocellular carcinoma', 'Disease', (361, 385))	('biliary tract cancer', 'Disease', (120, 140))	('TERT', 'Gene', (516, 520))	('TERT', 'Gene', '7015', (516, 520))	('tumors', 'Phenotype', 'HP:0002664', (651, 657))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('ARID', 'Disease', (84, 88))	('Hepatocellular', 'Disease', (594, 608))
22450	29573058	Using the largest HCC cohort ever reported, we attempted to identify driver genes that could evaluate the most precise frequencies of mutations in HCC.	('HCC', 'Phenotype', 'HP:0001402', (18, 21))	('HCC', 'Gene', (147, 150))	('HCC', 'Gene', '619501', (147, 150))	('HCC', 'Gene', (18, 21))	('mutations', 'Var', (134, 143))	('HCC', 'Phenotype', 'HP:0001402', (147, 150))	('HCC', 'Gene', '619501', (18, 21))
22459	29573058	Both ARID1A and ARID2 encode components of SWI/SNF chromatin remodeling machinery, and their genetic alterations are also reported in other tumor types.13 Because SWI/SNF machinery regulates chromatin conformation in an ATP-dependent manner, their alterations are supposed to affect epigenetic changes in cancer cells; however, the biological roles of ARID1A/ARID2 mutations in HCC remain to be clarified.	('ARID2', 'Gene', '196528', (359, 364))	('epigenetic changes', 'MPA', (283, 301))	('ARID1A', 'Gene', (5, 11))	('ATP', 'Chemical', 'MESH:D000255', (220, 223))	('affect', 'Reg', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('ARID1A', 'Gene', (352, 358))	('ARID1A', 'Gene', '8289', (5, 11))	('ARID2', 'Gene', (359, 364))	('ARID2', 'Gene', '196528', (16, 21))	('chromatin conformation', 'MPA', (191, 213))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('ARID1A', 'Gene', '8289', (352, 358))	('alterations', 'Var', (248, 259))	('ARID2', 'Gene', (16, 21))	('HCC', 'Gene', '619501', (378, 381))	('HCC', 'Phenotype', 'HP:0001402', (378, 381))	('cancer', 'Disease', (305, 311))	('HCC', 'Gene', (378, 381))	('regulates', 'Reg', (181, 190))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('tumor', 'Disease', (140, 145))
22462	29573058	Therefore, its inactivation is largely complimentary to CTNNB1 activating mutations for WNT signal activation in HCC.15 In contract to these well-characterized tumor suppressor genes, the biological roles of highly frequent mutations of ALB and APOB in HCC are uncertain.	('HCC', 'Gene', (253, 256))	('CTNNB1', 'Gene', '1499', (56, 62))	('ALB', 'Gene', (237, 240))	('HCC', 'Gene', '619501', (253, 256))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('HCC', 'Gene', '619501', (113, 116))	('HCC', 'Phenotype', 'HP:0001402', (113, 116))	('HCC', 'Phenotype', 'HP:0001402', (253, 256))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('CTNNB1', 'Gene', (56, 62))	('mutations', 'Var', (224, 233))	('tumor', 'Disease', (160, 165))	('APOB', 'Gene', '338', (245, 249))	('ALB', 'Gene', '213', (237, 240))	('APOB', 'Gene', (245, 249))	('HCC', 'Gene', (113, 116))
22463	29573058	Because both ALB and APOB mutations were strongly enriched in indels, these indels could be caused by replication slippage errors and may result from conflicts between the replication and transcription machineries.16  The remaining top driver genes were mutated in a fraction of cases (<5%) with various biological functions (Figure 2A).	('mutated', 'Var', (254, 261))	('APOB', 'Gene', '338', (21, 25))	('APOB', 'Gene', (21, 25))	('ALB', 'Gene', '213', (13, 16))	('ALB', 'Gene', (13, 16))
22472	29573058	Integration of AAV2 was reported to be rarer (~1%) in Japanese (3/300) and Korean (2/289) cohorts.7, 21  Endogenous and exogenous mutational processes induced by various factors, such as defects in DNA repair or exposure to smoking-associated carcinogens, leave unique nucleotide changes (substitutions, insertion, or deletions) within characteristic sequence contexts (Figure 3).	('defects', 'Var', (187, 194))	('substitutions', 'Var', (289, 302))	('nucleotide changes', 'MPA', (269, 287))	('AAV2', 'Species', '10804', (15, 19))	('insertion', 'Var', (304, 313))	('deletions', 'Var', (318, 327))
22477	29573058	COSMIC signature 4 (C>A substitution) was associated with smoking status, patient age, clinical history of double cancer, and the presence of TP53 mutation.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('patient', 'Species', '9606', (74, 81))	('clinical', 'Species', '191496', (87, 95))	('associated', 'Reg', (42, 52))	('TP53', 'Gene', '7157', (142, 146))	('TP53', 'Gene', (142, 146))	('mutation', 'Var', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('C>A substitution', 'Var', (20, 36))	('cancer', 'Disease', (114, 120))
22478	29573058	COSMIC signature 16 was associated with alcohol consumption and the presence of TPM and CTNNB1 mutation, and also male gender and older age.	('TPM', 'Gene', (80, 83))	('alcohol consumption', 'Disease', (40, 59))	('alcohol', 'Chemical', 'MESH:D000438', (40, 47))	('associated', 'Reg', (24, 34))	('CTNNB1', 'Gene', (88, 94))	('CTNNB1', 'Gene', '1499', (88, 94))	('presence', 'Var', (68, 76))	('mutation', 'Var', (95, 103))
22480	29573058	COSMIC signature 24 was found to be an aflatoxin B1-associated signature, and was more frequent in African cases with significant enrichment of a somatic TP53 p. Arg249Ser mutation, which is a typical mutation of aflatoxin B1-exposed HCC.	('Arg249Ser', 'Var', (162, 171))	('aflatoxin B1', 'Chemical', 'MESH:D016604', (39, 51))	('TP53', 'Gene', (154, 158))	('HCC', 'Gene', (234, 237))	('aflatoxin B1', 'Chemical', 'MESH:D016604', (213, 225))	('HCC', 'Gene', '619501', (234, 237))	('HCC', 'Phenotype', 'HP:0001402', (234, 237))	('TP53', 'Gene', '7157', (154, 158))	('Arg249Ser', 'SUBSTITUTION', 'None', (162, 171))
22483	29573058	They also reproduced the significant association between the presence of CTNNB1 mutation and the frequency of COSMIC signature 16.	('CTNNB1', 'Gene', '1499', (73, 79))	('presence', 'Var', (61, 69))	('mutation', 'Var', (80, 88))	('CTNNB1', 'Gene', (73, 79))
22491	29573058	TERT promoter mutations were detected in 21% of GB cases, whereas only one ICC case had these mutations.	('TERT', 'Gene', '7015', (0, 4))	('mutations', 'Var', (14, 23))	('TERT', 'Gene', (0, 4))
22494	29573058	By contrast, characteristically, alterations in WNT signaling and TERT were infrequent and IDH1 mutations (3%) were unique in BTC.	('WNT signaling', 'MPA', (48, 61))	('IDH1', 'Gene', (91, 95))	('TERT', 'Gene', (66, 70))	('TERT', 'Gene', '7015', (66, 70))	('IDH1', 'Gene', '3417', (91, 95))	('mutations', 'Var', (96, 105))
22495	29573058	For example, IDH1 and BAP1 mutations were ICC-specific, whereas ELF3 and ARID1B mutations were more common in ECC.	('ECC', 'Disease', (110, 113))	('common', 'Reg', (100, 106))	('mutations', 'Var', (27, 36))	('ARID1B', 'Gene', (73, 79))	('IDH1', 'Gene', (13, 17))	('ELF3', 'Gene', (64, 68))	('ELF3', 'Gene', '1999', (64, 68))	('BAP1', 'Gene', '8314', (22, 26))	('IDH1', 'Gene', '3417', (13, 17))	('ARID1B', 'Gene', '57492', (73, 79))	('BAP1', 'Gene', (22, 26))	('ICC-specific', 'Disease', (42, 54))
22496	29573058	EGFR, ERBB2, PTEN, and ARID2 mutations with TPMs occurred more frequently in GB cases.	('EGFR', 'Gene', (0, 4))	('ERBB2', 'Gene', '2064', (6, 11))	('mutations', 'Var', (29, 38))	('ARID2', 'Gene', '196528', (23, 28))	('ERBB2', 'Gene', (6, 11))	('ARID2', 'Gene', (23, 28))	('PTEN', 'Gene', (13, 17))	('PTEN', 'Gene', '5728', (13, 17))	('EGFR', 'Gene', '1956', (0, 4))	('occurred', 'Reg', (49, 57))
22499	29573058	Whole genome sequencing of liver cancer displaying biliary phenotypes revealed a mixture genetic profiles of HCC and ICC, suggesting that this category could be a marginal mixture of two tumor types.26 Activation or inactivation of some driver genes might exert cytotoxicity or a differentiation switch in specific lineages of liver and bile duct cancer, as reported in the case of IDH1 mutations.27  The Cancer Genome Atlas CCA project analyzed 34 CCA samples that were fluke-negative and HBV/HCV-negative.28 Due to the limited size of the cohort, frequencies of driver genes were variable compared to other large-scale studies; however, notably, this cohort represented a higher frequency of IDH1 (13%) and IDH2 (5%) mutations compared to Asian cohorts.	('IDH1', 'Gene', (382, 386))	('IDH1', 'Gene', '3417', (694, 698))	('liver cancer', 'Disease', 'MESH:D006528', (27, 39))	('tumor', 'Disease', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('liver cancer', 'Phenotype', 'HP:0002896', (27, 39))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('Cancer', 'Phenotype', 'HP:0002664', (405, 411))	('liver cancer', 'Disease', (27, 39))	('IDH1', 'Gene', '3417', (382, 386))	('HCC', 'Gene', '619501', (109, 112))	('HCC', 'Phenotype', 'HP:0001402', (109, 112))	('cytotoxicity', 'Disease', (262, 274))	('bile duct cancer', 'Phenotype', 'HP:0030153', (337, 353))	('HCC', 'Gene', (109, 112))	('IDH2', 'Gene', (709, 713))	('cytotoxicity', 'Disease', 'MESH:D064420', (262, 274))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('bile duct cancer', 'Disease', (337, 353))	('IDH2', 'Gene', '3418', (709, 713))	('bile duct cancer', 'Disease', 'MESH:D001650', (337, 353))	('IDH1', 'Gene', (694, 698))	('mutations', 'Var', (719, 728))
22504	29573058	They found that KRAS, FBXW7, and PTEN mutations and ERBB2 amplification were significantly more frequent in fluke-positive cholangiocarcinoma, whereas IDH1, PBRM1, and ACVR2A mutations occurred more frequently in fluke-negative cases.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (123, 141))	('frequent', 'Reg', (96, 104))	('IDH1', 'Gene', (151, 155))	('cholangiocarcinoma', 'Disease', (123, 141))	('PBRM1', 'Gene', '55193', (157, 162))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (123, 141))	('mutations', 'Var', (38, 47))	('IDH1', 'Gene', '3417', (151, 155))	('amplification', 'Var', (58, 71))	('FBXW7', 'Gene', (22, 27))	('PBRM1', 'Gene', (157, 162))	('PTEN', 'Gene', (33, 37))	('KRAS', 'Gene', '3845', (16, 20))	('ERBB2', 'Gene', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('ACVR2A', 'Gene', '92', (168, 174))	('PTEN', 'Gene', '5728', (33, 37))	('ERBB2', 'Gene', '2064', (52, 57))	('KRAS', 'Gene', (16, 20))	('ACVR2A', 'Gene', (168, 174))	('FBXW7', 'Gene', '55294', (22, 27))
22505	29573058	Mutations of TP53, ARID1A, and SMAD4, three of the top five driver genes, were common in both types.	('TP53', 'Gene', (13, 17))	('common', 'Reg', (79, 85))	('SMAD4', 'Gene', '4089', (31, 36))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (13, 17))	('ARID1A', 'Gene', '8289', (19, 25))	('SMAD4', 'Gene', (31, 36))	('ARID1A', 'Gene', (19, 25))
22512	29573058	They showed that cases with 3'-UTR-truncated FGFR2 exhibited higher expression levels compared with those of wild-type FGFR2 transcript.	('FGFR2', 'Gene', '2263', (119, 124))	('FGFR2', 'Gene', (45, 50))	('expression levels', 'MPA', (68, 85))	('FGFR2', 'Gene', '2263', (45, 50))	('higher', 'PosReg', (61, 67))	("3'-UTR-truncated", 'Var', (28, 44))	('FGFR2', 'Gene', (119, 124))
22517	29573058	Jusakul et al31 analyzed WGS data of 71 CCA cases and extracted 10 mutational signatures comprising COSMIC signatures 1, 5, 8, 16, and 17, APOBEC signatures (C>T and C>G substitutions), mismatch-repair deficiency-associated signatures (COSMIC signatures 6 and 20), and AA-exposure signature 22.	('C>T', 'Var', (158, 161))	('CCA', 'Disease', (40, 43))	('C>G substitutions', 'Var', (166, 183))	('mismatch-repair deficiency-associated', 'Disease', (186, 223))	('APOB', 'Gene', '338', (139, 143))	('APOB', 'Gene', (139, 143))
22524	29573058	These clusters partly overlapped with the gene expression-based subtypes (S1-3) reported by Hoshida et al.43 Tumors in iClust 1 tended to have lower frequency of CTNNB1 mutation, TPMs, and CDKN2A silencing, whereas iClust3 was characterized by a higher degree of chromosomal instability with high frequency of TP53 mutation and CpG hypomethylation.	('mutation', 'Var', (169, 177))	('Tumors', 'Disease', (109, 115))	('CpG', 'Var', (328, 331))	('Tumors', 'Disease', 'MESH:D009369', (109, 115))	('TP53', 'Gene', '7157', (310, 314))	('lower', 'NegReg', (143, 148))	('CTNNB1', 'Gene', '1499', (162, 168))	('TPMs', 'Gene', (179, 183))	('CDKN2A', 'Gene', '1029', (189, 195))	('TP53', 'Gene', (310, 314))	('chromosomal instability', 'Phenotype', 'HP:0040012', (263, 286))	('silencing', 'NegReg', (196, 205))	('CTNNB1', 'Gene', (162, 168))	('CDKN2A', 'Gene', (189, 195))	('Tumors', 'Phenotype', 'HP:0002664', (109, 115))
22530	29573058	Transcriptome sequencing and WES of 160 Japanese BTC identified four BTC subtypes (Nakamura clusters 1-4), that were associated with prognosis and specific driver gene profiles.25 Nakamura cluster 3 was enriched with IDH1, BAP1, and NRAS mutations and FGFR2 fusion genes, but rarely harbored TP53, KRAS, and SMAD4 mutations.	('NRAS', 'Gene', '4893', (233, 237))	('BAP1', 'Gene', '8314', (223, 227))	('TP53', 'Gene', '7157', (292, 296))	('TP53', 'Gene', (292, 296))	('fusion genes', 'Var', (258, 270))	('SMAD4', 'Gene', (308, 313))	('BAP1', 'Gene', (223, 227))	('mutations', 'Var', (238, 247))	('KRAS', 'Gene', '3845', (298, 302))	('KRAS', 'Gene', (298, 302))	('FGFR2', 'Gene', (252, 257))	('IDH1', 'Gene', (217, 221))	('FGFR2', 'Gene', '2263', (252, 257))	('NRAS', 'Gene', (233, 237))	('SMAD4', 'Gene', '4089', (308, 313))	('IDH1', 'Gene', '3417', (217, 221))
22531	29573058	This cluster partly overlaps to the UM subtype identified in the above study,44 which was enriched in IDH1 and BAP1 mutations.	('BAP1', 'Gene', '8314', (111, 115))	('IDH1', 'Gene', (102, 106))	('BAP1', 'Gene', (111, 115))	('mutations', 'Var', (116, 125))	('IDH1', 'Gene', '3417', (102, 106))
22533	29573058	Cholangiocarcinoma cluster 4 was enriched with liver fluke-negative cases and BAP1 and IDH1/2 mutations and FGFR alterations, which are similar to Nakamura cluster 3.	('IDH1/2', 'Gene', (87, 93))	('liver fluke', 'Species', '6192', (47, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('mutations', 'Var', (94, 103))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (0, 18))	('Cholangiocarcinoma cluster', 'Disease', 'MESH:D018281', (0, 26))	('Cholangiocarcinoma cluster', 'Disease', (0, 26))	('FGFR', 'Gene', (108, 112))	('BAP1', 'Gene', '8314', (78, 82))	('alterations', 'Var', (113, 124))	('BAP1', 'Gene', (78, 82))
22534	29573058	Cases in CCA cluster 4 also showed CpG shore hypermethylation, partly due to IDH1 mutations, and better prognosis.	('CCA', 'Disease', (9, 12))	('IDH1', 'Gene', (77, 81))	('mutations', 'Var', (82, 91))	('CpG shore hypermethylation', 'Var', (35, 61))	('IDH1', 'Gene', '3417', (77, 81))
22536	29573058	They proposed that chronic inflammation by liver fluke infection might continuously induce CpG island methylation, which resulted in accumulation of COSMIC signature 1-associated mutations and tumor heterogeneity in CCA cluster 1 cases, whereas tumors in CCA cluster 4 acquired strong driver mutations with rapid growth.	('COSMIC signature', 'Gene', (149, 165))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('inflammation', 'Disease', 'MESH:D007249', (27, 39))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('CCA', 'Disease', (216, 219))	('liver fluke infection', 'Disease', (43, 64))	('methylation', 'Var', (102, 113))	('CpG island', 'Gene', (91, 101))	('inflammation', 'Disease', (27, 39))	('tumor', 'Disease', (193, 198))	('tumors', 'Disease', (245, 251))	('liver fluke infection', 'Disease', 'MESH:D017093', (43, 64))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('induce', 'Reg', (84, 90))	('mutations', 'Var', (179, 188))	('tumor', 'Disease', (245, 250))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('accumulation', 'PosReg', (133, 145))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))
22537	29573058	The Cancer Genome Atlas CCA group more clearly isolated a subtype enriched with IDH1/2-mutated tumors, which showed a unique methylation pattern and upregulation of mitochondrial gene expression signatures.28 Their data could separate IDH1/2 mutated cases from BAP1/FGFR2 altered cases based on methylation signature.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('BAP1', 'Gene', '8314', (261, 265))	('mutated', 'Var', (242, 249))	('IDH1/2', 'Gene', (235, 241))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('BAP1', 'Gene', (261, 265))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('FGFR2', 'Gene', (266, 271))	('FGFR2', 'Gene', '2263', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
22546	29755690	HCC cases with hypomethylated LINE-1 had significantly shorter relapse-free survival (RFS) (log-rank, p = 0.008); however, this was not observed for the cHCC-CC or ICC cases.	('HCC', 'Gene', (154, 157))	('HCC', 'Gene', (0, 3))	('hypomethylated', 'Var', (15, 29))	('HCC', 'Gene', '619501', (154, 157))	('shorter', 'NegReg', (55, 62))	('CC', 'Phenotype', 'HP:0030153', (1, 3))	('HCC', 'Phenotype', 'HP:0001402', (154, 157))	('LINE-1', 'Gene', (30, 36))	('HCC', 'Phenotype', 'HP:0001402', (0, 3))	('CC', 'Phenotype', 'HP:0030153', (158, 160))	('HCC', 'Gene', '619501', (0, 3))	('CC', 'Phenotype', 'HP:0030153', (165, 167))	('relapse-free survival', 'CPA', (63, 84))	('CC', 'Phenotype', 'HP:0030153', (155, 157))
22547	29755690	Multivariate Cox regression analysis revealed a significantly higher HCC recurrence rate in the group with hypomethylated LINE-1 (hazard ratio, 1.62; 95% confidence interval, 1.06-2.58; p = 0.025).	('CC', 'Phenotype', 'HP:0030153', (70, 72))	('C', 'Chemical', 'MESH:D003596', (13, 14))	('hypomethylated', 'Var', (107, 121))	('HCC', 'Phenotype', 'HP:0001402', (69, 72))	('C', 'Chemical', 'MESH:D003596', (70, 71))	('HCC', 'Gene', (69, 72))	('higher', 'PosReg', (62, 68))	('C', 'Chemical', 'MESH:D003596', (71, 72))	('HCC', 'Gene', '619501', (69, 72))
22558	29755690	Cancer initiation and progression are caused by concurrent changes in multiple genes via genetic and epigenetic alterations leading to the activation of oncogenes or the suppression of tumor suppressor genes.	('tumor', 'Disease', (185, 190))	('epigenetic alterations', 'Var', (101, 123))	('activation', 'PosReg', (139, 149))	('suppression', 'NegReg', (170, 181))	('oncogenes', 'Protein', (153, 162))	('Cancer initiation', 'Disease', 'MESH:D009369', (0, 17))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('changes', 'Reg', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('Cancer initiation', 'Disease', (0, 17))
22559	29755690	Along with genetic mutations, epigenetic changes such as DNA methylation and histone acetylation are important for carcinogenesis and tumor development.	('DNA', 'MPA', (57, 60))	('histone acetylation', 'MPA', (77, 96))	('epigenetic', 'Var', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('carcinogenesis', 'Disease', 'MESH:D063646', (115, 129))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('carcinogenesis', 'Disease', (115, 129))	('tumor', 'Disease', (134, 139))
22561	29755690	Global DNA hypomethylation plays an important role in genomic instability, and site-specific promoter hypermethylation can silence tumor suppressor genes, leading to cancer development.	('promoter hypermethylation', 'Var', (93, 118))	('cancer', 'Disease', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('silence', 'NegReg', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('leading to', 'Reg', (155, 165))
22563	29755690	LINE-1 hypomethylation is associated with poor prognosis in esophageal, gastric, colorectal, pancreas and breast cancer, and it can be measured in a cost-effective manner via high-throughput pyrosequencing techniques.	('colorectal', 'Disease', 'MESH:D015179', (81, 91))	('esophageal', 'Disease', (60, 70))	('gastric', 'Disease', (72, 79))	('hypomethylation', 'Var', (7, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('colorectal', 'Disease', (81, 91))	('pancreas and breast cancer', 'Disease', 'MESH:D010190', (93, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('LINE-1', 'Gene', (0, 6))
22564	29755690	We previously reported that LINE-1 hypomethylation was associated with poor prognosis in 208 patients with HCC; However, there are no reports that comprehensively analyzed LINE-1 methylation levels in PLCs including ICC and cHCC-CC.	('C', 'Chemical', 'MESH:D003596', (217, 218))	('CC', 'Phenotype', 'HP:0030153', (229, 231))	('ICC', 'Disease', (216, 219))	('patients', 'Species', '9606', (93, 101))	('C', 'Chemical', 'MESH:D003596', (230, 231))	('CC', 'Phenotype', 'HP:0030153', (108, 110))	('associated', 'Reg', (55, 65))	('hypomethylation', 'Var', (35, 50))	('HCC', 'Gene', (225, 228))	('C', 'Chemical', 'MESH:D003596', (229, 230))	('CC', 'Phenotype', 'HP:0030153', (217, 219))	('CC', 'Phenotype', 'HP:0030153', (226, 228))	('C', 'Chemical', 'MESH:D003596', (109, 110))	('C', 'Chemical', 'MESH:D003596', (226, 227))	('HCC', 'Gene', '619501', (107, 110))	('HCC', 'Phenotype', 'HP:0001402', (107, 110))	('C', 'Chemical', 'MESH:D003596', (203, 204))	('HCC', 'Gene', '619501', (225, 228))	('C', 'Chemical', 'MESH:D003596', (227, 228))	('HCC', 'Phenotype', 'HP:0001402', (225, 228))	('C', 'Chemical', 'MESH:D003596', (108, 109))	('HCC', 'Gene', (107, 110))	('C', 'Chemical', 'MESH:D003596', (218, 219))
22589	29755690	Multivariate Cox regression analysis also revealed that LINE-1 hypomethylation was an independent prognostic factor for HCC (HR; 1.62, 95% CI; 1.06-2.58, p = 0.025) (Table 2).	('C', 'Chemical', 'MESH:D003596', (13, 14))	('C', 'Chemical', 'MESH:D003596', (121, 122))	('HCC', 'Gene', (120, 123))	('hypomethylation', 'Var', (63, 78))	('C', 'Chemical', 'MESH:D003596', (139, 140))	('HCC', 'Gene', '619501', (120, 123))	('HCC', 'Phenotype', 'HP:0001402', (120, 123))	('CC', 'Phenotype', 'HP:0030153', (121, 123))	('C', 'Chemical', 'MESH:D003596', (122, 123))
22592	29755690	On the other hand, in univariate and multivariate Cox regression analyses for ICC, LINE-1 hypomethylation was not an independent prognostic factor (p = 0.372), while vascular invasion (p = 0.007) and lymph node metastasis (p = 0.019) were independent prognostic factors (Table 2).	('CC', 'Phenotype', 'HP:0030153', (79, 81))	('C', 'Chemical', 'MESH:D003596', (79, 80))	('hypomethylation', 'Var', (90, 105))	('C', 'Chemical', 'MESH:D003596', (80, 81))	('ICC', 'Disease', (78, 81))	('C', 'Chemical', 'MESH:D003596', (50, 51))
22595	29755690	There were no significant differences between the hyper- and hypomethylation groups in any subtype of PLC (Supplementary Figure 2).	('C', 'Chemical', 'MESH:D003596', (104, 105))	('hypomethylation', 'Var', (61, 76))	('hyper-', 'Var', (50, 56))
22596	29755690	Thus, LINE-1 hypomethylation was associated with poor RFS in HCC patients only.	('LINE-1', 'Gene', (6, 12))	('hypomethylation', 'Var', (13, 28))	('HCC', 'Gene', (61, 64))	('RFS', 'MPA', (54, 57))	('HCC', 'Gene', '619501', (61, 64))	('HCC', 'Phenotype', 'HP:0001402', (61, 64))	('patients', 'Species', '9606', (65, 73))	('CC', 'Phenotype', 'HP:0030153', (62, 64))
22600	29755690	In addition, LINE-1 hypomethylation was associated with unfavorable clinical outcomes in patients with HCC only.	('CC', 'Phenotype', 'HP:0030153', (104, 106))	('HCC', 'Phenotype', 'HP:0001402', (103, 106))	('hypomethylation', 'Var', (20, 35))	('patients', 'Species', '9606', (89, 97))	('HCC', 'Gene', (103, 106))	('LINE-1', 'Gene', (13, 19))	('clinical', 'Species', '191496', (68, 76))	('HCC', 'Gene', '619501', (103, 106))
22601	29755690	Thus, the current study demonstrated differences in epigenetic status among PLC subtypes and the association between LINE-1 methylation and prognosis in PLC patients.	('differences', 'Reg', (37, 48))	('C', 'Chemical', 'MESH:D003596', (155, 156))	('patients', 'Species', '9606', (157, 165))	('association', 'Interaction', (97, 108))	('epigenetic', 'MPA', (52, 62))	('C', 'Chemical', 'MESH:D003596', (78, 79))	('methylation', 'Var', (124, 135))	('LINE-1', 'Gene', (117, 123))
22602	29755690	Our results suggested that global DNA hypomethylation, which leads to chromosome instability and fragility, is correlated with cancer initiation and progression in HCC and cHCC-CC but not in ICC.	('CC', 'Phenotype', 'HP:0030153', (165, 167))	('cancer initiation', 'Disease', (127, 144))	('HCC', 'Gene', '619501', (173, 176))	('chromosome instability', 'CPA', (70, 92))	('HCC', 'Phenotype', 'HP:0001402', (173, 176))	('HCC', 'Gene', '619501', (164, 167))	('fragility', 'Disease', (97, 106))	('HCC', 'Gene', (173, 176))	('cancer initiation', 'Disease', 'MESH:D009369', (127, 144))	('HCC', 'Phenotype', 'HP:0001402', (164, 167))	('correlated', 'Reg', (111, 121))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('HCC', 'Gene', (164, 167))	('CC', 'Phenotype', 'HP:0030153', (177, 179))	('CC', 'Phenotype', 'HP:0030153', (192, 194))	('leads to', 'Reg', (61, 69))	('chromosome instability', 'Phenotype', 'HP:0040012', (70, 92))	('CC', 'Phenotype', 'HP:0030153', (174, 176))	('global DNA hypomethylation', 'Var', (27, 53))
22605	29755690	One of the reasons behind the differences may be the presence of isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations in ICC.	('IDH1', 'Gene', (93, 97))	('IDH2', 'Gene', '3418', (103, 107))	('mutations', 'Var', (108, 117))	('IDH1', 'Gene', '3417', (93, 97))	('CC', 'Phenotype', 'HP:0030153', (122, 124))	('isocitrate dehydrogenase 1', 'Gene', (65, 91))	('isocitrate dehydrogenase 1', 'Gene', '3417', (65, 91))	('IDH2', 'Gene', (103, 107))
22607	29755690	IDH1/2 mutations are observed in 15 to 20% of ICC cases and result in the production of the 2-hydroxyglutarate (2-HG), which inhibits the , 2-HG contributes to maintaining (TET) proteins.	('ICC', 'Disease', (46, 49))	('mutations', 'Var', (7, 16))	('TET', 'Chemical', 'MESH:C010349', (173, 176))	('CC', 'Phenotype', 'HP:0030153', (47, 49))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (92, 110))	('result in', 'Reg', (60, 69))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
22610	29755690	Therefore, IDH1/2 mutations lead to DNA hypermethylation in ICC, leading LINE-1 hypermethylation.	('IDH1', 'Gene', '3417', (11, 15))	('CC', 'Phenotype', 'HP:0030153', (61, 63))	('ICC', 'Disease', (60, 63))	('lead to', 'Reg', (28, 35))	('DNA hypermethylation', 'MPA', (36, 56))	('IDH1', 'Gene', (11, 15))	('mutations', 'Var', (18, 27))
22611	29755690	However, IDH 1/2 mutations only partly account for the differences in the methylation patterns in ICC, and there may be other mechanisms underlying the hypermethylation of DNA in ICC compared to that in the other PLC subtypes.	('C', 'Chemical', 'MESH:D003596', (99, 100))	('CC', 'Phenotype', 'HP:0030153', (180, 182))	('C', 'Chemical', 'MESH:D003596', (100, 101))	('C', 'Chemical', 'MESH:D003596', (215, 216))	('C', 'Chemical', 'MESH:D003596', (180, 181))	('CC', 'Phenotype', 'HP:0030153', (99, 101))	('ICC', 'Disease', (98, 101))	('IDH 1/2', 'Gene', '3417;3418', (9, 16))	('IDH 1/2', 'Gene', (9, 16))	('methylation', 'MPA', (74, 85))	('mutations', 'Var', (17, 26))	('C', 'Chemical', 'MESH:D003596', (181, 182))
22612	29755690	In addition, there was only one patient with neoadjuvant chemotherapy in ICC using FOLFOX (leucovorin and fluorouracil and oxaliplatin): the presence of preoperative chemotherapy would affect the LINE-1 methylation level in cancerous or noncancerous tissues of ICC; however, we cannot refer this issue because of the lack of samples to evaluate.	('affect', 'Reg', (185, 191))	('patient', 'Species', '9606', (32, 39))	('cancerous', 'Disease', 'MESH:D009369', (240, 249))	('cancerous', 'Disease', 'MESH:D009369', (224, 233))	('CC', 'Phenotype', 'HP:0030153', (262, 264))	('presence', 'Var', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('FOLFOX', 'Chemical', '-', (83, 89))	('CC', 'Phenotype', 'HP:0030153', (74, 76))	('LINE-1 methylation level', 'MPA', (196, 220))	('leucovorin', 'Chemical', 'MESH:D002955', (91, 101))	('fluorouracil', 'Chemical', 'MESH:D005472', (106, 118))	('cancerous', 'Disease', (240, 249))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (123, 134))	('cancerous', 'Disease', (224, 233))
22614	29755690	LINE-1 hypomethylation is associated with poor prognosis in several cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('hypomethylation', 'Var', (7, 22))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('LINE-1', 'Gene', (0, 6))
22615	29755690	The underlying mechanisms may be as follows: First, global DNA hypomethylation contributes to cancer development by inducing genomic instability.	('inducing', 'Reg', (116, 124))	('global DNA hypomethylation', 'Var', (52, 78))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('genomic instability', 'MPA', (125, 144))	('contributes', 'PosReg', (79, 90))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
22616	29755690	Third, LINE-1 hypomethylation activates oncogenes (e.g., c-MET) and cell cycle-related genes (e.g., CDK6), which are associated with cancer progression.	('c-MET', 'Gene', '4233', (57, 62))	('associated', 'Reg', (117, 127))	('hypomethylation', 'Var', (14, 29))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('oncogenes', 'Gene', (40, 49))	('c-MET', 'Gene', (57, 62))	('cancer', 'Disease', (133, 139))	('CDK6', 'Gene', (100, 104))	('cell cycle-related genes', 'Gene', (68, 92))	('activates', 'PosReg', (30, 39))	('CDK6', 'Gene', '1021', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
22617	29755690	Therefore, LINE-1 hypomethylation may also be associated with cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('hypomethylation', 'Var', (18, 33))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('associated', 'Reg', (46, 56))	('LINE-1', 'Gene', (11, 17))
22619	29755690	The present study showed that LINE-1 hypomethylation is related to short RFS in HCC patients only.	('HCC', 'Gene', '619501', (80, 83))	('short RFS', 'Disease', (67, 76))	('patients', 'Species', '9606', (84, 92))	('HCC', 'Phenotype', 'HP:0001402', (80, 83))	('CC', 'Phenotype', 'HP:0030153', (81, 83))	('short RFS', 'Disease', 'MESH:D005198', (67, 76))	('HCC', 'Gene', (80, 83))	('related', 'Reg', (56, 63))	('hypomethylation', 'Var', (37, 52))
22621	29755690	Therefore, although the RFS for HCC was short in the LINE-1 hypomethylation group, OS was not.	('HCC', 'Gene', '619501', (32, 35))	('CC', 'Phenotype', 'HP:0030153', (33, 35))	('OS', 'Chemical', '-', (83, 85))	('HCC', 'Phenotype', 'HP:0001402', (32, 35))	('HCC', 'Gene', (32, 35))	('hypomethylation', 'Var', (60, 75))
22623	29755690	However, we could observe a trend toward poorer RFS and OS in the LINE-1 hypomethylation group than those in the LINE-1 hypermethylation group for cHCC-CC.	('RFS', 'MPA', (48, 51))	('CC', 'Phenotype', 'HP:0030153', (149, 151))	('OS', 'Chemical', '-', (56, 58))	('HCC', 'Phenotype', 'HP:0001402', (148, 151))	('poorer', 'NegReg', (41, 47))	('CC', 'Phenotype', 'HP:0030153', (152, 154))	('LINE-1 hypomethylation', 'Var', (66, 88))	('hypomethylation', 'Var', (73, 88))	('HCC', 'Gene', (148, 151))	('HCC', 'Gene', '619501', (148, 151))
22624	29755690	Therefore, we need additional studies with larger sample sizes to determine whether LINE-1 hypomethylation is indicative of poor prognosis in cHCC-CC.	('LINE-1', 'Gene', (84, 90))	('HCC', 'Gene', (143, 146))	('HCC', 'Gene', '619501', (143, 146))	('HCC', 'Phenotype', 'HP:0001402', (143, 146))	('CC', 'Phenotype', 'HP:0030153', (144, 146))	('hypomethylation', 'Var', (91, 106))	('CC', 'Phenotype', 'HP:0030153', (147, 149))
22631	29755690	Therefore, especially in patients without hepatitis virus infection, LINE-1 hypomethylation may be an effective biomarker of HCC recurrence.	('LINE-1', 'Gene', (69, 75))	('HCC', 'Gene', '619501', (125, 128))	('hepatitis', 'Phenotype', 'HP:0012115', (42, 51))	('HCC', 'Phenotype', 'HP:0001402', (125, 128))	('hypomethylation', 'Var', (76, 91))	('hepatitis virus infection', 'Disease', 'MESH:D006525', (42, 67))	('patients', 'Species', '9606', (25, 33))	('CC', 'Phenotype', 'HP:0030153', (126, 128))	('hepatitis virus infection', 'Disease', (42, 67))	('HCC', 'Gene', (125, 128))
22645	29755690	First, we could confirm prognostic significance of LINE-1 hypomethylation in HCC by using a greater number of cases.	('LINE-1', 'Gene', (51, 57))	('hypomethylation', 'Var', (58, 73))	('HCC', 'Gene', '619501', (77, 80))	('HCC', 'Phenotype', 'HP:0001402', (77, 80))	('CC', 'Phenotype', 'HP:0030153', (78, 80))	('HCC', 'Gene', (77, 80))
22646	29755690	Second, LINE-1 hypomethylation was found to be not associated with poor prognosis in ICC and cHCC-CC patients.	('patients', 'Species', '9606', (101, 109))	('HCC', 'Phenotype', 'HP:0001402', (94, 97))	('ICC', 'Disease', (85, 88))	('HCC', 'Gene', (94, 97))	('CC', 'Phenotype', 'HP:0030153', (98, 100))	('CC', 'Phenotype', 'HP:0030153', (95, 97))	('hypomethylation', 'Var', (15, 30))	('HCC', 'Gene', '619501', (94, 97))	('CC', 'Phenotype', 'HP:0030153', (86, 88))
22648	29755690	The mechanisms of epigenetic regulation in PLC and its relationship with cancer initiation and progression should be explored.	('epigenetic regulation', 'Var', (18, 39))	('C', 'Chemical', 'MESH:D003596', (45, 46))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer initiation', 'Disease', 'MESH:D009369', (73, 90))	('cancer initiation', 'Disease', (73, 90))
22682	26633034	UMIN-CTR in (JPRN) UMIN000005109  Biliary tract cancer (BTC) is one of the most lethal malignancies, and surgery is the only potentially curative treatment.	('Biliary tract cancer', 'Disease', 'MESH:D001661', (34, 54))	('UMIN000005109', 'Var', (19, 32))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('malignancies', 'Disease', 'MESH:D009369', (87, 99))	('Biliary tract cancer', 'Disease', (34, 54))	('CTR', 'Gene', '799', (5, 8))	('Biliary tract cancer', 'Phenotype', 'HP:0100574', (34, 54))	('CTR', 'Gene', (5, 8))	('malignancies', 'Disease', (87, 99))	('BTC', 'Phenotype', 'HP:0100574', (56, 59))
22724	26633034	Six (50%) patients was treated with the standard dose of gemcitabine (1000 mg/m2 on days 1, 8, and 15 every 4 weeks or 1000 mg/m2 on days 1 and 8 every 3 weeks) for treating advanced solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (183, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('solid tumors', 'Disease', (183, 195))	('patients', 'Species', '9606', (10, 18))	('gemcitabine', 'Chemical', 'MESH:C056507', (57, 68))	('1000 mg/m2', 'Var', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
22743	26633034	The study in rats demonstrated that in the early period after operation, gemcitabine concentration was affected by liver resection, but was less affected after the completion of liver regeneration.	('rats', 'Species', '10116', (13, 17))	('gemcitabine concentration', 'MPA', (73, 98))	('gemcitabine', 'Chemical', 'MESH:C056507', (73, 84))	('affected', 'Reg', (103, 111))	('liver resection', 'Var', (115, 130))
22872	24145988	Moreover, these genes could predict outcomes in HCC and other tumors.	('predict', 'Reg', (28, 35))	('genes', 'Var', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('HCC', 'Disease', (48, 51))
22875	24145988	Recent data from whole transcriptome sequencing has identified the presence of gene fusions that are associated with iCCA such as FGFR2-BICC and FIG-ROS.	('gene fusions', 'Var', (79, 91))	('BICC', 'Gene', '80114', (136, 140))	('iCCA', 'Disease', (117, 121))	('associated', 'Reg', (101, 111))	('FGFR2', 'Gene', (130, 135))	('FGFR2', 'Gene', '2263', (130, 135))	('BICC', 'Gene', (136, 140))
22877	24145988	Notch in involved in biliary tract differentiation, and disrupted Notch signaling results in congenital hypoplasia of the biliary tract.	('congenital hypoplasia', 'Disease', (93, 114))	('Notch signaling', 'Gene', (66, 81))	('congenital hypoplasia', 'Disease', 'MESH:D000013', (93, 114))	('results in', 'Reg', (82, 92))	('congenital hypoplasia', 'Phenotype', 'HP:0011451', (93, 114))	('disrupted', 'Var', (56, 65))
22896	24145988	Amongst the most frequent genetic mutations are activating mutations of KRAS particularly in hotspots located at codon 12.	('KRAS', 'Gene', '3845', (72, 76))	('activating', 'PosReg', (48, 58))	('mutations', 'Var', (34, 43))	('KRAS', 'Gene', (72, 76))
22897	24145988	KRAS mutations may predict worse survival after hepatectomy although these data need to be validated in independent cohorts of samples.	('KRAS', 'Gene', (0, 4))	('worse', 'NegReg', (27, 32))	('mutations', 'Var', (5, 14))	('KRAS', 'Gene', '3845', (0, 4))
22898	24145988	BRAF and EGFR mutations have also been reported but are less common.	('BRAF', 'Gene', '673', (0, 4))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))
22899	24145988	On the other hand, NRAS or PI3K mutations are rather rare in iCCA.	('NRAS', 'Gene', (19, 23))	('PI3K mutations', 'Var', (27, 41))	('NRAS', 'Gene', '4893', (19, 23))	('iCCA', 'Disease', (61, 65))
22900	24145988	A large number of TP53 loss-of-function mutations have been reported in iCCA and this tumor suppressor has been linked to iCCA in experimental animal models.	('loss-of-function', 'NegReg', (23, 39))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('iCCA', 'Disease', (122, 126))	('TP53', 'Gene', '7157', (18, 22))	('tumor', 'Disease', (86, 91))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (40, 49))	('iCCA', 'Disease', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
22902	24145988	Aberrant methylation of several genes including the tumor suppressor genes such as p16, RASSF1A and APC has been examined in iCCA.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('p16', 'Gene', '1029', (83, 86))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', (52, 57))	('RASSF1A', 'Gene', '11186', (88, 95))	('APC', 'Disease', 'MESH:D011125', (100, 103))	('APC', 'Disease', (100, 103))	('p16', 'Gene', (83, 86))	('RASSF1A', 'Gene', (88, 95))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
22913	24145988	The over-expression of IL-6 observed in cholangiocarcinoma may result from epigenetic silencing of SOCS-3.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (40, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('SOCS-3', 'Gene', (99, 105))	('over-expression', 'PosReg', (4, 19))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (40, 58))	('IL-6', 'Gene', (23, 27))	('IL-6', 'Gene', '3569', (23, 27))	('SOCS-3', 'Gene', '9021', (99, 105))	('epigenetic silencing', 'Var', (75, 95))	('result from', 'Reg', (63, 74))	('cholangiocarcinoma', 'Disease', (40, 58))
22914	24145988	Targeting IL-6 dependent phenotype defined by genetic changes has been used to identify potential new therapeutics.	('IL-6', 'Gene', '3569', (10, 14))	('changes', 'Var', (54, 61))	('IL-6', 'Gene', (10, 14))
22916	24145988	Although mutations in EGFR family members are infrequent, overexpression of receptors occurs in 10-32%.	('mutations', 'Var', (9, 18))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', (22, 26))	('overexpression', 'MPA', (58, 72))
22917	24145988	Aberrant phosphorylation of EGFR receptors activates MAPK/ERK and p38, which can increase COX-2 and inhibits apoptosis as well as promote tumor growth.	('promote', 'PosReg', (130, 137))	('EGFR', 'Gene', '1956', (28, 32))	('inhibits', 'NegReg', (100, 108))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', (138, 143))	('COX-2', 'Gene', (90, 95))	('COX-2', 'Gene', '4513', (90, 95))	('apoptosis', 'CPA', (109, 118))	('EGFR', 'Gene', (28, 32))	('activates', 'PosReg', (43, 52))	('p38', 'Gene', '1432', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('increase', 'PosReg', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('MAPK/ERK', 'Pathway', (53, 61))	('phosphorylation', 'MPA', (9, 24))	('p38', 'Gene', (66, 69))
22918	24145988	In vitro, blocking EGFR with erlotinib can decrease cholangiocarcinoma cell proliferation.	('decrease', 'NegReg', (43, 51))	('erlotinib', 'Chemical', 'MESH:D000069347', (29, 38))	('cholangiocarcinoma', 'Disease', (52, 70))	('blocking', 'Var', (10, 18))	('EGFR', 'Gene', '1956', (19, 23))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (52, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('EGFR', 'Gene', (19, 23))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (52, 70))
22924	24145988	Alterations in VEGF occur in almost 50% of iCCA and correlate with a poor prognosis.	('VEGF', 'Gene', '7422', (15, 19))	('Alterations', 'Var', (0, 11))	('VEGF', 'Gene', (15, 19))	('iCCA', 'Disease', (43, 47))
22927	24145988	Other pathways such as Wnt/-beta catenin pathways may be of importance, although genetic mutations in beta-catenin, axin 1 and APC are rare, and few studies have shown aberrant nuclear localization of beta catenin in iCCA.	('axin 1', 'Gene', '8312', (116, 122))	('beta-catenin', 'Gene', '1499', (102, 114))	('APC', 'Disease', 'MESH:D011125', (127, 130))	('iCCA', 'Disease', (217, 221))	('axin 1', 'Gene', (116, 122))	('beta catenin', 'Gene', '1499', (28, 40))	('APC', 'Disease', (127, 130))	('beta catenin', 'Gene', '1499', (201, 213))	('mutations', 'Var', (89, 98))	('beta catenin', 'Gene', (28, 40))	('beta-catenin', 'Gene', (102, 114))	('beta catenin', 'Gene', (201, 213))
23038	31689237	Loss of FoxA2 accelerates neoplastic changes in the intrahepatic bile duct partly via the MAPK signaling pathway Background: Intrahepatic cholangiocarcinoma (ICC) is characterized by a highly aggressive nature and a dismal outcome.	('intrahepatic bile duct', 'Disease', 'MESH:D002780', (52, 74))	('neoplastic changes', 'Phenotype', 'HP:0002664', (26, 44))	('Intrahepatic cholangiocarcinoma', 'Disease', (125, 156))	('FoxA2', 'Gene', (8, 13))	('FoxA2', 'Gene', '15376', (8, 13))	('neoplastic changes', 'CPA', (26, 44))	('Intrahepatic cholangiocarcinoma', 'Disease', 'MESH:C535533', (125, 156))	('ICC', 'Disease', (158, 161))	('accelerates', 'PosReg', (14, 25))	('ICC', 'Disease', 'MESH:C535533', (158, 161))	('Loss', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (138, 156))	('intrahepatic bile duct', 'Disease', (52, 74))
23042	31689237	RNA sequencing analysis showed that the expression of genes in the MAPK signaling pathway was significantly higher in FoxA2-/- mice.	('expression', 'MPA', (40, 50))	('mice', 'Species', '10090', (127, 131))	('FoxA2-/-', 'Var', (118, 126))	('MAPK signaling pathway', 'Pathway', (67, 89))	('higher', 'PosReg', (108, 114))
23043	31689237	IHC and Western blot results showed that p-ERK1/2, CREB1 and RAS were highly expressed in FoxA2-/- mice.	('mice', 'Species', '10090', (99, 103))	('ERK1/2', 'Gene', '26417;26413', (43, 49))	('CREB1', 'Gene', (51, 56))	('FoxA2-/-', 'Var', (90, 98))	('ERK1/2', 'Gene', (43, 49))	('RAS', 'Gene', (61, 64))
23047	31689237	Loss of FoxA2 expression could promote intrahepatic bile duct neoplasia partly via activation of the MAPK signaling pathway.	('neoplasia', 'Phenotype', 'HP:0002664', (62, 71))	('FoxA2', 'Gene', (8, 13))	('intrahepatic bile duct neoplasia', 'Disease', 'MESH:D002780', (39, 71))	('intrahepatic bile duct neoplasia', 'Disease', (39, 71))	('MAPK signaling pathway', 'Pathway', (101, 123))	('promote', 'PosReg', (31, 38))	('bile duct neoplasia', 'Phenotype', 'HP:0030153', (52, 71))	('Loss', 'Var', (0, 4))
23056	31689237	Liver-specific knockdown of FOX family members can affect the transcription of the bile acid transporter gene, which leads to intrahepatic cholestasis.	('intrahepatic cholestasis', 'Phenotype', 'HP:0001406', (126, 150))	('bile acid', 'Chemical', 'MESH:D001647', (83, 92))	('knockdown', 'Var', (15, 24))	('affect', 'Reg', (51, 57))	('bile acid transporter gene', 'Gene', (83, 109))	('transcription', 'MPA', (62, 75))	('intrahepatic cholestasis', 'Disease', (126, 150))	('leads to', 'Reg', (117, 125))	('intrahepatic cholestasis', 'Disease', 'MESH:D002780', (126, 150))	('cholestasis', 'Phenotype', 'HP:0001396', (139, 150))
23059	31689237	Notably, previous studies reported that the dysfunction of FOXA2 is related to the prognosis of several cancers.	('FOXA2', 'Gene', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('related', 'Reg', (68, 75))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('dysfunction', 'Var', (44, 55))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
23072	31689237	The survival analysis (Figure 1D) showed that the tumor-free survival rates at 1 year and 3 years in the high FOXA2 expression group were 68.6% and 32.9%, respectively, and were 34.0% and 9.9%, respectively in the low FOXA2 expression group (p < 0.001).	('high', 'Var', (105, 109))	('FOXA2', 'Gene', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
23076	31689237	Western blot showed that FoxA2 expression in FoxA2 knockout mice was significantly decreased (Figure 2C and 2D).	('decreased', 'NegReg', (83, 92))	('expression', 'MPA', (31, 41))	('knockout', 'Var', (51, 59))	('mice', 'Species', '10090', (60, 64))	('FoxA2', 'Gene', (25, 30))	('FoxA2', 'Gene', (45, 50))
23082	31689237	The serum albumin level was observed to be similar in both groups, and ALP and AST levels were elevated in FoxA2-/- mice (Figure 2F).	('mice', 'Species', '10090', (116, 120))	('AST', 'Gene', (79, 82))	('AST', 'Gene', '235504', (79, 82))	('elevated', 'PosReg', (95, 103))	('serum albumin level', 'MPA', (4, 23))	('FoxA2-/-', 'Var', (107, 115))	('ALP', 'MPA', (71, 74))
23084	31689237	Interestingly, at 20 weeks after TAA administration, H&E (hematoxylin and eosin) staining revealed that the loss of FoxA2 resulted in early and profound dysplastic changes in the biliary epithelium, which subsequently progressed to biliary cytokeratin (CK19)-expressing invasive ICC.	('the', 'Var', (104, 107))	('ICC', 'Disease', 'MESH:C535533', (279, 282))	('FoxA2', 'Reg', (116, 121))	('profound dysplastic', 'CPA', (144, 163))	('eosin', 'Chemical', 'MESH:D004801', (74, 79))	('-expressing invasive', 'Disease', (258, 278))	('hematoxylin', 'Chemical', 'MESH:D006416', (58, 69))	('CK19', 'Gene', '16669', (253, 257))	('TAA', 'Chemical', 'MESH:D013853', (33, 36))	('CK19', 'Gene', (253, 257))	('subsequently', 'PosReg', (205, 217))	('ICC', 'Disease', (279, 282))
23091	31689237	As shown in Figure 3E, depletion of FoxA2 led to the activation of the MAPK signaling pathway in the bile duct in FoxA2-/- mice treated with TAA for 20 weeks.	('TAA', 'Chemical', 'MESH:D013853', (141, 144))	('depletion', 'Var', (23, 32))	('activation', 'PosReg', (53, 63))	('FoxA2-/-', 'Gene', (114, 122))	('FoxA2', 'Gene', (36, 41))	('MAPK signaling pathway', 'Pathway', (71, 93))	('mice', 'Species', '10090', (123, 127))
23093	31689237	Notably, the phosphorylation of ERK1/2 and CREB1 was also markedly increased in the dysplastic bile ducts of FoxA2-/- mice (Figure 4A and 4B).	('phosphorylation', 'MPA', (13, 28))	('ERK1/2', 'Gene', '26417;26413', (32, 38))	('increased', 'PosReg', (67, 76))	('FoxA2-/-', 'Var', (109, 117))	('dysplastic', 'Disease', (84, 94))	('ERK1/2', 'Gene', (32, 38))	('mice', 'Species', '10090', (118, 122))	('CREB1', 'Gene', (43, 48))
23100	31689237	As shown in Figure 5B, the number of ICC cells that incorporated EdU in the siFoxA2 group was higher than that in the control group.	('siFoxA2', 'Var', (76, 83))	('ICC', 'Disease', (37, 40))	('EdU', 'Chemical', 'MESH:C031086', (65, 68))	('ICC', 'Disease', 'MESH:C535533', (37, 40))	('higher', 'PosReg', (94, 100))
23103	31689237	Taken together, these results implied that the loss of FoxA2 might promote the malignant phenotype of ICC via activation of the MAPK signaling pathway.	('FoxA2', 'Gene', (55, 60))	('activation', 'PosReg', (110, 120))	('MAPK signaling pathway', 'Pathway', (128, 150))	('malignant phenotype', 'CPA', (79, 98))	('ICC', 'Disease', (102, 105))	('loss', 'Var', (47, 51))	('ICC', 'Disease', 'MESH:C535533', (102, 105))	('promote', 'PosReg', (67, 74))
23108	31689237	Interestingly, the 3-year recurrence-free survival and overall survival rates in patients with high FOXA2 expression were significantly better than rates in patients with low FOXA2 expression (RFS: 32.9% vs. 9.9%; OS: 44.8% vs. 13.6%).	('better', 'PosReg', (136, 142))	('overall survival', 'CPA', (55, 71))	('recurrence-free survival', 'CPA', (26, 50))	('FOXA2', 'Gene', (100, 105))	('high', 'Var', (95, 99))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (157, 165))	('expression', 'Var', (106, 116))
23118	31689237	To study whether the loss of FoxA2 promotes the early-stage development of ICC, we primarily focused on the difference between both groups at 20 weeks.	('loss', 'Var', (21, 25))	('ICC', 'Disease', (75, 78))	('early-stage development', 'CPA', (48, 71))	('FoxA2', 'Gene', (29, 34))	('promotes', 'PosReg', (35, 43))	('ICC', 'Disease', 'MESH:C535533', (75, 78))
23120	31689237	Biliary cytokeratin (CK19) expression within the intrahepatic portal area was also evident but was much higher in the FoxA2-/- mice.	('mice', 'Species', '10090', (127, 131))	('FoxA2-/-', 'Var', (118, 126))	('expression', 'MPA', (27, 37))	('CK19', 'Gene', '16669', (21, 25))	('CK19', 'Gene', (21, 25))	('higher', 'PosReg', (104, 110))
23122	31689237	These findings indicated that the loss of FoxA2 expression might promote cholangiocyte proliferation under hepatotoxicant injury.	('loss', 'Var', (34, 38))	('expression', 'MPA', (48, 58))	('hepatotoxicant injury', 'Disease', 'MESH:D014947', (107, 128))	('cholangiocyte proliferation', 'CPA', (73, 100))	('promote', 'PosReg', (65, 72))	('hepatotoxicant injury', 'Disease', (107, 128))	('FoxA2', 'Gene', (42, 47))
23124	31689237	We also found that the liver/body weight ratio was higher in FoxA2-/- mice, which suggested severe liver injury and regeneration.	('FoxA2-/-', 'Var', (61, 69))	('liver injury', 'Disease', (99, 111))	('mice', 'Species', '10090', (70, 74))	('liver injury', 'Disease', 'MESH:D056486', (99, 111))	('regeneration', 'CPA', (116, 128))	('liver/body', 'MPA', (23, 33))	('higher', 'PosReg', (51, 57))
23125	31689237	The level of ALP, which is an indicator of inflamed bile ducts, was much higher in FoxA2-/- mice.	('mice', 'Species', '10090', (92, 96))	('ALP', 'MPA', (13, 16))	('FoxA2-/-', 'Var', (83, 91))	('higher', 'PosReg', (73, 79))
23126	31689237	This indicated that loss of FoxA2 in bile duct cells might contribute to intrahepatic bile duct inflammation in TAA-induced chronic hepatocellular injury.	('chronic hepatocellular injury', 'Disease', (124, 153))	('loss', 'Var', (20, 24))	('chronic hepatocellular injury', 'Disease', 'MESH:D056487', (124, 153))	('intrahepatic bile duct inflammation', 'Disease', 'MESH:D002780', (73, 108))	('intrahepatic bile duct inflammation', 'Disease', (73, 108))	('bile duct inflammation', 'Phenotype', 'HP:0030151', (86, 108))	('TAA', 'Chemical', 'MESH:D013853', (112, 115))	('TAA-induced', 'Disease', (112, 123))	('contribute', 'Reg', (59, 69))	('FoxA2', 'Gene', (28, 33))
23128	31689237	Stable FoxA2 expression might protect cells from hepatotoxins and carcinogens and thus may prevent carcinogenesis.	('prevent', 'NegReg', (91, 98))	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('carcinogenesis', 'Disease', (99, 113))	('expression', 'Var', (13, 23))	('FoxA2', 'Gene', (7, 12))	('hepatotoxins and carcinogens', 'Disease', 'MESH:D063646', (49, 77))
23146	31689237	The loss of FoxA2 accelerated ICC development partly via the MAPK signaling pathway.	('FoxA2', 'Gene', (12, 17))	('ICC', 'Disease', (30, 33))	('ICC', 'Disease', 'MESH:C535533', (30, 33))	('accelerated', 'PosReg', (18, 29))	('loss', 'Var', (4, 8))
23194	27933122	SOCS-3 epigenetic silencing is responsible for sustained IL-6/STAT-3 signalling in cholangiocarcinoma.	('epigenetic silencing', 'Var', (7, 27))	('IL-6', 'Gene', (57, 61))	('cholangiocarcinoma', 'Disease', (83, 101))	('SOCS-3', 'Gene', (0, 6))	('STAT-3', 'Gene', '6774', (62, 68))	('sustained', 'PosReg', (47, 56))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('STAT-3', 'Gene', (62, 68))	('IL-6', 'Gene', '3569', (57, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('SOCS-3', 'Gene', '9021', (0, 6))
23195	27933122	Recent reports suggest SOCS-3 may be silenced by epigenetic phenomenon in human cancers, namely methylation of CpG islands.	('SOCS-3', 'Gene', (23, 29))	('CpG', 'Protein', (111, 114))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('methylation', 'Var', (96, 107))	('human', 'Species', '9606', (74, 79))	('SOCS-3', 'Gene', '9021', (23, 29))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
23209	27933122	Methylation of multiple tumor suppressor genes is seen in cholangiocarcinoma.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cholangiocarcinoma', 'Disease', (58, 76))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', (24, 29))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 76))	('seen', 'Reg', (50, 54))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
23210	27933122	The methylation profile of multiple genes in cholangiocarcinoma may facilitate the distinction of cholangiocarcinoma from benign biliary epithelium in clinical settings.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (98, 116))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (98, 116))	('cholangiocarcinoma', 'Disease', (45, 63))	('methylation', 'Var', (4, 15))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (45, 63))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (45, 63))	('cholangiocarcinoma', 'Disease', (98, 116))
23211	27933122	Hypermethylation of regulatory regions called CpG islands in some tumor suppressor genes induce their inactivation.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('Hypermethylation', 'Var', (0, 16))	('inactivation', 'MPA', (102, 114))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
23213	27933122	Disruption of the G1/S and G2/M check points leads to uncontrolled cell growth, resulting in the development and progression of cancers (Fig.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('leads to', 'Reg', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('uncontrolled', 'MPA', (54, 66))	('resulting in', 'Reg', (80, 92))	('Disruption', 'Var', (0, 10))
23222	27933122	Inactivation of p53 caused by missens mutations or interaction with oncogenic viral proteins allows progression through the cell cycle without a physiological checkpoint and resulting from a selective growth advantage for cancer cells.	('growth advantage', 'CPA', (201, 217))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('progression through the cell cycle', 'CPA', (100, 134))	('interaction', 'Interaction', (51, 62))	('cancer', 'Disease', (222, 228))	('p53', 'Gene', (16, 19))	('p53', 'Gene', '7157', (16, 19))	('missens mutations', 'Var', (30, 47))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('Inactivation', 'NegReg', (0, 12))
23223	27933122	Alteration of p53 gene plays a key role in late-stage events of tumor pathogenesis and is associated with poor prognosis of CC, but the others show no association of protein over-expression with outcomes, however the role of p53 remains controversial.	('CC', 'Phenotype', 'HP:0030153', (124, 126))	('tumor', 'Disease', (64, 69))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('Alteration', 'Var', (0, 10))	('p53', 'Gene', (225, 228))	('associated', 'Reg', (90, 100))	('p53', 'Gene', '7157', (225, 228))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
23224	27933122	Alterations in p53 and p16INK4a are frequently detected in CC and are likely contributing to oncogenesis in the biliary tract.	('p16INK4a', 'Gene', (23, 31))	('Alterations', 'Var', (0, 11))	('p53', 'Gene', (15, 18))	('p16INK4a', 'Gene', '1029', (23, 31))	('p53', 'Gene', '7157', (15, 18))	('CC', 'Phenotype', 'HP:0030153', (59, 61))	('contributing', 'Reg', (77, 89))
23225	27933122	Point mutations in the promoter region of p16INK4a seem to represent an apparent early event associated CC.	('Point mutations', 'Var', (0, 15))	('p16INK4a', 'Gene', (42, 50))	('p16INK4a', 'Gene', '1029', (42, 50))	('CC', 'Phenotype', 'HP:0030153', (104, 106))
23229	27933122	Mutational inactivation of DCP4/Smad4, has been found to occur more commonly in distal bile duct cancers (55-60%) than in proximal bile duct and intrahepatic tumors but there was no correlation with survival.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('bile duct cancer', 'Phenotype', 'HP:0030153', (87, 103))	('bile duct cancers', 'Disease', 'MESH:D001650', (87, 104))	('Mutational inactivation', 'Var', (0, 23))	('bile duct cancers', 'Disease', (87, 104))	('Smad4', 'Gene', (32, 37))	('intrahepatic tumors', 'Disease', (145, 164))	('Smad4', 'Gene', '4089', (32, 37))	('bile duct cancers', 'Phenotype', 'HP:0030153', (87, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('intrahepatic tumors', 'Disease', 'MESH:D002780', (145, 164))
23231	27933122	The abnormal expression of RECK gene might be one of the molecular mechanisms of hilar cholangiocarcinoma metastasis.	('abnormal', 'Var', (4, 12))	('hilar cholangiocarcinoma metastasis', 'Disease', (81, 116))	('expression', 'MPA', (13, 23))	('RECK', 'Gene', (27, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('RECK', 'Gene', '8434', (27, 31))	('hilar cholangiocarcinoma metastasis', 'Disease', 'MESH:D018285', (81, 116))
23232	27933122	Others tumor suppressor gene whose expression is modified in CC are p16, p27, p57, SMAD4, p16INK4a, p21WAF1.	('p16', 'Gene', (68, 71))	('p16INK4a', 'Gene', '1029', (90, 98))	('CC', 'Phenotype', 'HP:0030153', (61, 63))	('expression', 'MPA', (35, 45))	('p16', 'Gene', (90, 93))	('p16', 'Gene', '1029', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('p16', 'Gene', '1029', (90, 93))	('modified', 'Reg', (49, 57))	('SMAD4', 'Gene', (83, 88))	('p21WAF1', 'Var', (100, 107))	('p57', 'Gene', (78, 81))	('p16INK4a', 'Gene', (90, 98))	('tumor', 'Disease', (7, 12))	('SMAD4', 'Gene', '4089', (83, 88))	('p27', 'Gene', '3429', (73, 76))	('p27', 'Gene', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('p57', 'Gene', '1028', (78, 81))
23234	27933122	RTK appear to be considered as important protooncogenes for cholangiocarcinogenesis, being used as pharmaceutically targeted.	('carcinogenesis', 'Disease', 'MESH:D063646', (69, 83))	('RTK', 'Var', (0, 3))	('carcinogenesis', 'Disease', (69, 83))
23237	27933122	Inhibition of EGFR signaling has been shown to significantly suppress cholangiocarcinoma cell growth.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('cholangiocarcinoma', 'Disease', (70, 88))	('suppress', 'NegReg', (61, 69))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (70, 88))	('Inhibition', 'Var', (0, 10))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))
23244	27933122	While it now seems apparent that aberrant EGFR and/or ErbB2 expression and signaling is associated with the molecular pathogenesis of intrahepatic cholangiocarcinoma, there is still a significant gap in our knowledge as how to best exploit such alterations in terms of targeted therapies that can then be successfully translated into positive clinical outcomes.	('expression', 'MPA', (60, 70))	('ErbB2', 'Gene', (54, 59))	('signaling', 'MPA', (75, 84))	('intrahepatic cholangiocarcinoma', 'Disease', (134, 165))	('EGFR', 'Gene', '1956', (42, 46))	('EGFR', 'Gene', (42, 46))	('ErbB2', 'Gene', '2064', (54, 59))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (147, 165))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (134, 165))	('associated', 'Reg', (88, 98))	('aberrant', 'Var', (33, 41))
23255	27933122	Mutations of k-ras gene activate cellular proliferation and promote cellular growth.	('promote', 'PosReg', (60, 67))	('k-ras', 'Gene', (13, 18))	('cellular proliferation', 'CPA', (33, 55))	('cellular growth', 'CPA', (68, 83))	('activate', 'PosReg', (24, 32))	('Mutations', 'Var', (0, 9))	('k-ras', 'Gene', '3845', (13, 18))
23256	27933122	K-ras mutations, typically at codon 12, have been reported to be less frequently detected in peripheral CC than in hilar CC.	('peripheral CC', 'Disease', (93, 106))	('CC', 'Phenotype', 'HP:0030153', (104, 106))	('K-ras', 'Gene', (0, 5))	('K-ras', 'Gene', '3845', (0, 5))	('CC', 'Phenotype', 'HP:0030153', (121, 123))	('mutations', 'Var', (6, 15))
23257	27933122	The incidence of K-ras mutations has been reported to be higher in CC patients with lymph node metastasis than in those without lymph node metastasis but no significant correlation with survival has found.	('K-ras', 'Gene', '3845', (17, 22))	('patients', 'Species', '9606', (70, 78))	('higher', 'Reg', (57, 63))	('CC', 'Phenotype', 'HP:0030153', (67, 69))	('mutations', 'Var', (23, 32))	('lymph node metastasis', 'Disease', (84, 105))	('K-ras', 'Gene', (17, 22))
23278	27933122	High concentrations of Bcl-2 or Bcl-xL affect the susceptibility of a cell to the induction of apoptosis by altering the ratio of death promoters to suppressors, providing tumour cells with a survival advantage, and permitting expansion of transformed cells harbouring mutations within their genome.	('ratio of death promoters', 'MPA', (121, 145))	('survival advantage', 'CPA', (192, 210))	('Bcl-xL', 'Gene', (32, 38))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('mutations', 'Var', (269, 278))	('affect', 'Reg', (39, 45))	('altering', 'Reg', (108, 116))	('Bcl-2', 'Gene', (23, 28))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('Bcl-2', 'Gene', '596', (23, 28))	('tumour', 'Disease', (172, 178))	('susceptibility', 'MPA', (50, 64))	('providing', 'PosReg', (162, 171))	('Bcl-xL', 'Gene', '598', (32, 38))
23321	25376337	The survival rates for patients who had received R1 or R2 resection were significantly better than those with unresectable tumors.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('patients', 'Species', '9606', (23, 31))	('survival', 'CPA', (4, 12))	('R2 resection', 'Var', (55, 67))	('better', 'PosReg', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
23329	25376337	Patients with R1 margin or R2 margin have a dismal survival.	('Patients', 'Species', '9606', (0, 8))	('R1 margin', 'Var', (14, 23))	('R2 margin', 'Var', (27, 36))
23402	25376337	Limited central liver resection means excision of liver segments/subsegments around the liver hilum, such as segment 1 resection, segment 1 and 4 (4b) resection, segment 1, 4 (4b), and 5 resection, or mesohepatectomy (segment 1, 4 (4b), 5, and 8 resection).	('resection', 'Var', (151, 160))	('Lim', 'Gene', '10611', (0, 3))	('Lim', 'Gene', (0, 3))
23407	25376337	Second, although there are some concerns that minor central liver resection may decrease the rate of curative surgical resection, the Japanese surgeons have shown clearly that surgical curability and postoperative survival rates in selected patients with minor central hepatic resection were not compromised and surgical morbidity/mortality rate was significantly lower than that in the combined major liver resection group .	('surgical curability', 'CPA', (176, 195))	('lower', 'NegReg', (364, 369))	('decrease', 'NegReg', (80, 88))	('patients', 'Species', '9606', (241, 249))	('postoperative survival', 'CPA', (200, 222))	('minor', 'Var', (46, 51))
23526	17067385	Estimates of the survival probability were calculated using the Kaplan-Meier method, and the logrank test was employed to test the null hypothesis of equality in overall survival among patients with Maspin above or below the cutpoint.	('Maspin', 'Gene', (199, 205))	('Maspin', 'Gene', '5268', (199, 205))	('above', 'Var', (206, 211))	('patients', 'Species', '9606', (185, 193))
23567	17067385	Student's t-test revealed that only the simultaneous expression of Maspin and Bax was associated with a significant (P-value = 0.015) reduction in tumor mass, while the sole presence of Maspin was not associated with any significant reduction (P-value = 0.250).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('Maspin', 'Gene', '5268', (67, 73))	('expression', 'Var', (53, 63))	('simultaneous expression', 'Var', (40, 63))	('Bax', 'Gene', (78, 81))	('reduction', 'NegReg', (134, 143))	('Maspin', 'Gene', (186, 192))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('Maspin', 'Gene', (67, 73))	('Maspin', 'Gene', '5268', (186, 192))	('Bax', 'Gene', '581', (78, 81))
23597	17067385	In contrast, it has been shown in metastatic breast adenocarcinoma, that the expression of Bax protein is associated with increased overall survival and better response to chemotherapy.	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (45, 66))	('overall survival', 'CPA', (132, 148))	('Bax', 'Gene', (91, 94))	('expression', 'Var', (77, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('protein', 'Protein', (95, 102))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (45, 66))	('Bax', 'Gene', '581', (91, 94))	('increased', 'PosReg', (122, 131))	('breast adenocarcinoma', 'Disease', (45, 66))
23607	17067385	Interestingly, it has been shown that tumor neo-vessels become leaky after Maspin treatment, whereas normal mature vessels are not affected by Maspin treatment.	('leaky', 'CPA', (63, 68))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('treatment', 'Var', (82, 91))	('Maspin', 'Gene', (143, 149))	('Maspin', 'Gene', '5268', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('Maspin', 'Gene', (75, 81))	('Maspin', 'Gene', '5268', (143, 149))
23624	17067385	Our results (not shown) suggest that immunohistochemical negativity for Maspin clearly indicates a neoplasm with a clinically aggressive course.	('neoplasm', 'Phenotype', 'HP:0002664', (99, 107))	('negativity', 'Var', (57, 67))	('neoplasm', 'Disease', 'MESH:D009369', (99, 107))	('Maspin', 'Gene', (72, 78))	('neoplasm', 'Disease', (99, 107))	('Maspin', 'Gene', '5268', (72, 78))
23782	33852640	3 (prostate vs. non-prostate), prostate cancer was distinguished from the other tumors by the overexpression of miR-133a and miR-133b (Fig 2).	('overexpression', 'PosReg', (94, 108))	('prostate cancer', 'Disease', 'MESH:D011471', (31, 46))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (31, 46))	('miR-133a', 'Var', (112, 120))	('miR-133b', 'Gene', '442890', (125, 133))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('miR-133b', 'Gene', (125, 133))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('prostate cancer', 'Disease', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
23798	33852640	This finding is consistent with a report that miR-30a knockdown in zebrafish larvae results in defective biliary morphogenesis.	('biliary morphogenesis', 'CPA', (105, 126))	('knockdown', 'Var', (54, 63))	('defective', 'NegReg', (95, 104))	('zebrafish', 'Species', '7955', (67, 76))	('miR-30a', 'Gene', (46, 53))
23806	33852640	As previously reported, miR-194 and miR-192 were relatively abundant in both colorectal and gastric cancers compared to non-gastrointestinal tumors.	('miR-192', 'Gene', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('gastric cancers', 'Phenotype', 'HP:0012126', (92, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('miR-194', 'Var', (24, 31))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('abundant', 'Reg', (60, 68))	('non-gastrointestinal tumors', 'Phenotype', 'HP:0006719', (120, 147))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (124, 147))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('miR-192', 'Gene', '406967', (36, 43))	('colorectal and gastric cancers', 'Disease', 'MESH:D013274', (77, 107))
23807	33852640	12 (breast vs. non-breast), miR-196a was abundant in breast cancers, whereas miR-449a and miR-449b were relatively abundant in endometrial and ovarian cancers (Fig 2).	('miR-449a', 'Gene', (77, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('miR-449a', 'Gene', '554213', (77, 85))	('miR-449b', 'Gene', '693123', (90, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (143, 157))	('ovarian cancers', 'Phenotype', 'HP:0100615', (143, 158))	('breast cancers', 'Phenotype', 'HP:0003002', (53, 67))	('miR-196a', 'Var', (28, 36))	('miR-449b', 'Gene', (90, 98))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('endometrial and ovarian cancers', 'Disease', 'MESH:D004714', (127, 158))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancers', 'Disease', 'MESH:D001943', (53, 67))	('breast cancers', 'Disease', (53, 67))
23830	33852640	While miR-30a plays an oncogenic role in biliary epithelium, miR-30a acts as a tumor suppressor in prostate and gastric tissue.	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('miR-30a', 'Var', (61, 68))	('tumor', 'Disease', (79, 84))
23840	33852640	Using a large number of frozen tissue samples, the current study clearly demonstrates that gastrointestinal cancer can be differentiated from cholangiocarcinomas by the 4-microRNA cholangiocarcinoma signature using miR-30a, miR-200c, miR-141, and miR-425.	('miR-141', 'Gene', '406933', (234, 241))	('miR-141', 'Gene', (234, 241))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (142, 161))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('cholangiocarcinomas', 'Disease', (142, 161))	('miR-425', 'Gene', '494337', (247, 254))	('miR-200c', 'Gene', '406985', (224, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('carcinomas', 'Phenotype', 'HP:0030731', (151, 161))	('miR-200c', 'Gene', (224, 232))	('miR-425', 'Gene', (247, 254))	('cancer', 'Disease', (108, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (180, 198))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (142, 160))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (91, 114))	('cholangiocarcinoma', 'Disease', (180, 198))	('cholangiocarcinoma', 'Disease', (142, 160))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (180, 198))	('miR-30a', 'Var', (215, 222))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (142, 160))
23850	33655035	ERCP procedures were performed under deep sedation with intravenous infusion of propofol (Diprivan, Zeneca, Germany), using Pentax duodenoscopes (ED3470TK, ED34i10 T), by expert endoscopists who had performed over 200 procedures per year.	('ED3470TK', 'Var', (146, 154))	('propofol', 'Chemical', 'MESH:D015742', (80, 88))	('ED34i10 T', 'Var', (156, 165))	('Diprivan', 'Chemical', 'MESH:D015742', (90, 98))
23902	29742707	Though Park et al has reported that F-18 FDG PET/CT showed high sensitivity for lymphoepithelioma -like gastric carcinoma, and high specificity for both lymph node and distant metastasis.	('lymphoepithelioma', 'Disease', 'None', (80, 97))	('F-18 FDG', 'Var', (36, 44))	('lymphoepithelioma', 'Disease', (80, 97))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (104, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('gastric carcinoma', 'Disease', 'MESH:D013274', (104, 121))	('distant metastasis', 'CPA', (168, 186))	('gastric carcinoma', 'Disease', (104, 121))
23929	29465585	On immunohistochemistry, the tumor cells showed positive staining for AE1/AE3, CK19, CK7, and Ki-67, where staining for p53 was negative.	('CK19', 'Gene', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('CK19', 'Gene', '3880', (79, 83))	('p53', 'Gene', '7157', (120, 123))	('AE3', 'Gene', '6508', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('CK7', 'Gene', (85, 88))	('Ki-67', 'Var', (94, 99))	('AE1', 'Gene', (70, 73))	('AE1', 'Gene', '6521', (70, 73))	('tumor', 'Disease', (29, 34))	('AE3', 'Gene', (74, 77))	('p53', 'Gene', (120, 123))	('CK7', 'Gene', '3855', (85, 88))
24011	26357636	Also, there were fewer episodes of fever in patients with antireflux stents, suggesting a reduction in cholangitis.	('fewer', 'NegReg', (17, 22))	('cholangitis', 'Disease', 'MESH:D002761', (103, 114))	('reduction', 'NegReg', (90, 99))	('patients', 'Species', '9606', (44, 52))	('antireflux', 'Var', (58, 68))	('episodes of fever', 'Phenotype', 'HP:0001954', (23, 40))	('cholangitis', 'Disease', (103, 114))	('fever', 'Disease', 'MESH:D005334', (35, 40))	('cholangitis', 'Phenotype', 'HP:0030151', (103, 114))	('fever', 'Disease', (35, 40))	('fever', 'Phenotype', 'HP:0001945', (35, 40))
24112	26357636	The number of complications (6 vs 30, respectively p=0.001), including acute cholangitis (p=0.004), were more common in the stent group compared to balloon dilation group.	('cholangitis', 'Phenotype', 'HP:0030151', (77, 88))	('stent', 'Var', (124, 129))	('cholangitis', 'Disease', 'MESH:D002761', (77, 88))	('cholangitis', 'Disease', (77, 88))
24146	26357636	In this study, cSEMS are less prone to migration but are associated with ulcerations, choledocholithaisis, and strictures.	('strictures', 'Disease', (111, 121))	('cSEMS', 'Var', (15, 20))	('ulcerations', 'Disease', (73, 84))	('choledocholithaisis', 'Disease', (86, 105))	('ulcerations', 'Disease', 'MESH:D014456', (73, 84))	('cSEMS', 'Chemical', '-', (15, 20))	('associated', 'Reg', (57, 67))
24148	26357636	To further assist in dissolution of biliary stone, ursodeoxycholic acid with terpene has been shown to increase dissolution of the stone when a stent is in place.	('dissolution', 'MPA', (112, 123))	('increase', 'PosReg', (103, 111))	('ursodeoxycholic acid', 'Var', (51, 71))	('biliary stone', 'Disease', (36, 49))	('ursodeoxycholic acid', 'Chemical', 'MESH:D014580', (51, 71))	('terpene', 'Chemical', 'MESH:D013729', (77, 84))	('biliary stone', 'Phenotype', 'HP:0000787', (36, 49))
24162	26357636	Risk factors for cholecystitis are neoplastic involvement of the cystic duct and gallbladder stones.	('neoplastic', 'Var', (35, 45))	('cholecystitis', 'Disease', (17, 30))	('cholecystitis', 'Phenotype', 'HP:0001082', (17, 30))	('gallbladder stones', 'Disease', (81, 99))	('cholecystitis', 'Disease', 'MESH:D002764', (17, 30))
24192	26257778	The abnormal communication predisposes to reflux of pancreatic juice into bile duct, leading to ineffective bile flow which in turn results in increased intraductal pressure, chronic inflammation, and its associated carcinogenic effect.	('increased', 'PosReg', (143, 152))	('abnormal', 'Var', (4, 12))	('reflux of pancreatic juice into bile duct', 'MPA', (42, 83))	('carcinogenic', 'Disease', 'MESH:D063646', (216, 228))	('carcinogenic', 'Disease', (216, 228))	('intraductal pressure', 'MPA', (153, 173))	('ineffective bile flow', 'MPA', (96, 117))
24198	26257778	Mutations in the polycystic kidney and hepatic disease gene 1 (PKHD1) are responsible for this condition.	('PKHD1', 'Gene', '5314', (63, 68))	('hepatic disease', 'Phenotype', 'HP:0001392', (39, 54))	('responsible', 'Reg', (74, 85))	('PKHD1', 'Gene', (63, 68))	('polycystic kidney', 'Disease', 'MESH:D007690', (17, 34))	('polycystic kidney', 'Phenotype', 'HP:0000113', (17, 34))	('polycystic kidney', 'Disease', (17, 34))	('Mutations', 'Var', (0, 9))
24212	26257778	Hepatolithiasis is most often noted in type IV-A CCD and may be related to the presence of membranous or septal stenosis or segmental bile duct near main biliary convergence.	('type IV-A', 'Var', (39, 48))	('related', 'Reg', (64, 71))	('Hepatolithiasis', 'Disease', (0, 15))	('septal stenosis', 'Disease', (105, 120))	('Hepatolithiasis', 'Disease', 'None', (0, 15))	('septal stenosis', 'Disease', 'MESH:D003251', (105, 120))
24254	25471741	The overall survival of patients with high CXCR4 expression was significantly lower than that of patients with low CXCR4 expression.	('expression', 'Species', '29278', (121, 131))	('expression', 'Species', '29278', (49, 59))	('patients', 'Species', '9606', (97, 105))	('patients', 'Species', '9606', (24, 32))	('lower', 'NegReg', (78, 83))	('high CXCR4 expression', 'Var', (38, 59))
24255	25471741	Furthermore, we showed that the abrogation of CXCR4 had significantly negative influence on the IHCC cell phenotype, including in vitro cell proliferation, cell cycle, colony formation, cell invasion, and in vivo tumorigenicity.	('tumor', 'Disease', (213, 218))	('abrogation', 'Var', (32, 42))	('cell invasion', 'CPA', (186, 199))	('IHCC', 'Disease', (96, 100))	('negative', 'NegReg', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('cell cycle', 'CPA', (156, 166))	('colony formation', 'CPA', (168, 184))
24270	25471741	found that CD24 could induce CXCR4 expression in cholangiocarcimoma cells, which may assist invasion of the cancer cells.	('assist', 'PosReg', (85, 91))	('expression', 'Species', '29278', (35, 45))	('invasion', 'CPA', (92, 100))	('cholangiocarcimoma', 'Disease', 'None', (49, 67))	('cholangiocarcimoma', 'Disease', (49, 67))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('CD24', 'Var', (11, 15))	('CXCR4 expression', 'MPA', (29, 45))	('induce', 'PosReg', (22, 28))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
24271	25471741	When treated by AMD3100, the motility and invasiveness of CD24 (+) cells were decreased, implying the importance of CXCR4 in cholangiocarcinoma cell invasion.	('invasiveness', 'CPA', (42, 54))	('cholangiocarcinoma', 'Disease', (125, 143))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (125, 143))	('decreased', 'NegReg', (78, 87))	('motility', 'CPA', (29, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (125, 143))	('CD24', 'Gene', (58, 62))	('AMD3100', 'Var', (16, 23))
24280	25471741	Control cells or cells stably transfected with sh-CXCR4 or negative control were seeded into 96-well plates at 2000 cells per well and incubated overnight with or without CXCL12 (R&D, MN, USA) at 100 ng/ml.	('CXCL12', 'Gene', (171, 177))	('MN', 'CellLine', 'CVCL:U508', (184, 186))	('CXCL12', 'Gene', '6387', (171, 177))	('sh-CXCR4', 'Var', (47, 55))
24282	25471741	A quantity of 500 cells transfected with either shCXCR4 or negative control were cultured in 6-well plates with or without CXCL12 for 2 weeks in regular culture medium.	('CXCL12', 'Gene', '6387', (123, 129))	('shCXCR4', 'Var', (48, 55))	('CXCL12', 'Gene', (123, 129))
24292	25471741	The cell lysates were separated by electrophoresis in 10% SDS-polyacrylamide gels, transferred to nitrocellulose membranes, blocked in 5% nonfat milk, and incubated with primary antibodies against CXCR4 (1:1000 dilution, Abcam), phospho-CXCR4 (1:1000 dilution, Abcam), beta-catenin (1:1000 dilution, Abcam), Vimentin (1:1000 dilution, Abcam), MMP-9 (1:1000 dilution, Abcam), and beta-actin (1:5000 dilution; Abcam) at 4 C overnight.	('1:1000 dilution', 'Var', (318, 333))	('MMP-9', 'Gene', '4318', (343, 348))	('MMP-9', 'Gene', (343, 348))
24317	25471741	As shown in Figure 3D, shCXCR4-3 inhibited the tumor formation of IHCC cells in vivo.	('inhibited', 'NegReg', (33, 42))	('shCXCR4-3', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
24328	25471741	Preclinical cancer models have revealed that directed metastasis of cancer cells is mediated by CXCR4 activation and migration of cancer cells is towards CXCL12 expressing organs while targeting CXCR4 impairs the spread of cancer cells and development of metastasis.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('directed metastasis', 'CPA', (45, 64))	('targeting', 'Var', (185, 194))	('cancer', 'Disease', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('CXCL12', 'Gene', '6387', (154, 160))	('migration', 'CPA', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('CXCL12', 'Gene', (154, 160))	('impairs', 'NegReg', (201, 208))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('CXCR4', 'MPA', (96, 101))	('development of metastasis', 'CPA', (240, 265))	('cancer', 'Disease', (12, 18))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
24333	25471741	In this study, we demonstrated that the overall survival rate of IHCC patients with high CXCR4 expression is significantly lower than those with low CXCR4 expression.	('patients', 'Species', '9606', (70, 78))	('expression', 'Species', '29278', (155, 165))	('lower', 'NegReg', (123, 128))	('high CXCR4 expression', 'Var', (84, 105))	('IHCC', 'Disease', (65, 69))	('expression', 'Species', '29278', (95, 105))
24336	25471741	We also found that CXCR4 shRNA not only significantly reduced the expression of CXCR4, but also notably decreased phosphorylation of CXCR4 at serine 339.	('CXCR4 shRNA', 'Var', (19, 30))	('CXCR4', 'Gene', (80, 85))	('phosphorylation of CXCR4 at serine 339', 'MPA', (114, 152))	('expression', 'Species', '29278', (66, 76))	('decreased', 'NegReg', (104, 113))	('expression', 'MPA', (66, 76))	('reduced', 'NegReg', (54, 61))	('serine', 'Chemical', 'MESH:D012694', (142, 148))
24337	25471741	Considering the findings that the phosphorylation of CXCR4 at serine 339 may be a way to activate CXCR4 on the cells, our data further confirmed that CXCR4 shRNA could effectively inhibit CXCR4 function in IHCC cancers.	('CXCR4', 'MPA', (98, 103))	('IHCC cancers', 'Disease', (206, 218))	('CXCR4 shRNA', 'Var', (150, 161))	('inhibit', 'NegReg', (180, 187))	('serine', 'Chemical', 'MESH:D012694', (62, 68))	('IHCC cancers', 'Disease', 'MESH:D009369', (206, 218))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('CXCR4 function', 'MPA', (188, 202))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))
24339	25471741	In this study, we have demonstrated that the blockade of CXCR4 can decrease IHCC cancer cell growth and cell cycle by prolonging the G0-G1 cycle and reducing the G2 and S phases, and inhibit tumorigenesis both in vitro and in vivo.	('inhibit', 'NegReg', (183, 190))	('IHCC cancer', 'Disease', (76, 87))	('decrease', 'NegReg', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('IHCC cancer', 'Disease', 'MESH:D009369', (76, 87))	('CXCR4', 'Gene', (57, 62))	('cell cycle', 'CPA', (104, 114))	('prolonging', 'PosReg', (118, 128))	('blockade', 'Var', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('G0-G1', 'MPA', (133, 138))	('reducing', 'NegReg', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
24341	25471741	Dysregulation of beta-catenin and other Wnt components leads to activation of Wnt target genes, including c-myc, cyclin D1, and MMP-9, and the enhancement of tumor formation.	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('Dysregulation', 'Var', (0, 13))	('MMP-9', 'Gene', '4318', (128, 133))	('cyclin D1', 'MPA', (113, 122))	('MMP-9', 'Gene', (128, 133))	('activation', 'PosReg', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('c-myc', 'MPA', (106, 111))	('enhancement', 'PosReg', (143, 154))	('beta-catenin', 'Protein', (17, 29))
24343	25471741	Moreover, the expression of Wnt target genes, including beta-catenin, c-myc, and MMP-9, was markedly decreased, suggesting that the TCF-binding activity could be effectively inhibited by CXCR4 knockdown, which may suppress theWnt/beta-catenin signaling and Wnt target genes expression.	('expression', 'MPA', (274, 284))	('theWnt/beta-catenin', 'MPA', (223, 242))	('beta-catenin', 'Protein', (56, 68))	('suppress', 'NegReg', (214, 222))	('knockdown', 'Var', (193, 202))	('expression', 'Species', '29278', (14, 24))	('decreased', 'NegReg', (101, 110))	('inhibited', 'NegReg', (174, 183))	('expression', 'MPA', (14, 24))	('c-myc', 'Gene', (70, 75))	('MMP-9', 'Gene', '4318', (81, 86))	('MMP-9', 'Gene', (81, 86))	('expression', 'Species', '29278', (274, 284))	('TCF-binding activity', 'Protein', (132, 152))
24349	25471741	Furthermore, in a recent phase I study of another CXCR4 inhibitor LY2510924 for advanced cancer, the circulating tumor cell (CTC) counts were included as one of the study endpoints in addition to safety, pharmacokinetics, efficacy, and pharmacodynamics.	('tumor', 'Disease', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('LY2510924', 'Var', (66, 75))	('cancer', 'Disease', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('LY2510924', 'Chemical', 'MESH:C000595455', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
24352	25471741	In conclusion, the present study has shown that high CXCR4 expression is associated with metastasis and a poor clinical outcome of IHCC.	('high', 'Var', (48, 52))	('expression', 'Species', '29278', (59, 69))	('CXCR4 expression', 'MPA', (53, 69))	('associated', 'Reg', (73, 83))	('metastasis', 'CPA', (89, 99))	('IHCC', 'Disease', (131, 135))
24353	25471741	Future in vivo studies will be conducted with clinical available CXCR4 inhibitors like AMD3100 or LY2510924, and data from these experiments could result in faster changes of treatment for patients with IHCC.	('LY2510924', 'Var', (98, 107))	('patients', 'Species', '9606', (189, 197))	('LY2510924', 'Chemical', 'MESH:C000595455', (98, 107))	('IHCC', 'Disease', (203, 207))
24359	33672838	In this review, we summarize molecular and cellular evidence linking liver fluke-associated cholangiocarcinoma with mis-regulation of epithelial-mesenchymal transition (EMT), a multicellular morphogenetic process known to be involved in many normal and pathological settings, including cancer.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (92, 110))	('mis-regulation', 'Var', (116, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('liver fluke', 'Species', '6192', (69, 80))	('cancer', 'Disease', (286, 292))	('cholangiocarcinoma', 'Disease', (92, 110))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (92, 110))
24383	33672838	An exome sequencing-based analysis of O. viverrini-associated CCAs revealed 206 somatic mutations in 187 genes as potential CCA-associated genetic alternations, most of which (about 90%) being missense or nonsense mutations.	('CCAs', 'Disease', (62, 66))	('CCA', 'Phenotype', 'HP:0030153', (62, 65))	('mutations', 'Var', (88, 97))	('CCA', 'Phenotype', 'HP:0030153', (124, 127))	('missense', 'Var', (193, 201))	('CCA-associated', 'Disease', (124, 138))	('O. viverrini', 'Species', '6198', (38, 50))
24384	33672838	They further validated 15 of those genes in additional CCA samples, and the top three of those mutations were in the TP53 (44%), KRAS (17%), and SMAD4 (17%) genes.	('SMAD4', 'Gene', (145, 150))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('CCA', 'Phenotype', 'HP:0030153', (55, 58))	('mutations', 'Var', (95, 104))	('CCA', 'Disease', (55, 58))
24386	33672838	In a recent study of genomic and epigenetic analyses of 489 patients with CCA, fluke-positive CCA specimens showed significant enrichment in genetic mutations of the TP53, ARID1A, and BRCA1/2 genes, in contrast to fluke-negative CCA showing mutations in the IDH1/2 and BAP1 epigenetic modifier genes, suggesting a bias towards selection of specific cancer mutations during fluke-associated CCA progression.	('ARID1A', 'Gene', '8289', (172, 178))	('CCA', 'Disease', (74, 77))	('CCA', 'Phenotype', 'HP:0030153', (390, 393))	('IDH1/2', 'Gene', '3417;3418', (258, 264))	('BRCA1/2', 'Gene', (184, 191))	('patients', 'Species', '9606', (60, 68))	('BAP1', 'Gene', '8314', (269, 273))	('TP53', 'Gene', '7157', (166, 170))	('cancer', 'Disease', (349, 355))	('CCA', 'Phenotype', 'HP:0030153', (94, 97))	('IDH1/2', 'Gene', (258, 264))	('CCA', 'Phenotype', 'HP:0030153', (229, 232))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('mutations', 'Var', (149, 158))	('BAP1', 'Gene', (269, 273))	('BRCA1/2', 'Gene', '672;675', (184, 191))	('ARID1A', 'Gene', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (349, 355))	('TP53', 'Gene', (166, 170))	('CCA', 'Phenotype', 'HP:0030153', (74, 77))
24387	33672838	Promoter hyper-methylation silences gene expression and has been implicated in tumor initiation and malignant transformation.	('malignant transformation', 'CPA', (100, 124))	('silences', 'NegReg', (27, 35))	('gene expression', 'MPA', (36, 51))	('tumor', 'Disease', (79, 84))	('Promoter hyper-methylation', 'Var', (0, 26))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('implicated', 'Reg', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
24389	33672838	Cancer cells have been shown to promote DNA hyper-methylation in promoter regions of bivalent genes marked by MLL-mediated H3K4me3 and PRC2-mediated H3K27me3, which are known to be activated upon the differentiation of ES cells, suggesting that PRC2 fine-tunes the level of promoter DNA methylation in normal cells, and that functional impairment of PRC2 may promote DNA hyper-methylation and subsequent methylation-mediated mutations to drive the development of cancer.	('drive', 'PosReg', (438, 443))	('functional impairment', 'Var', (325, 346))	('cancer', 'Phenotype', 'HP:0002664', (463, 469))	('methylation-mediated mutations', 'Var', (404, 434))	('cancer', 'Disease', 'MESH:D009369', (463, 469))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', (463, 469))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (425, 434))	('DNA hyper-methylation', 'MPA', (367, 388))	('PRC2', 'Gene', (350, 354))	('promote', 'PosReg', (359, 366))
24396	33672838	In addition, cytokine signaling commonly associated with EMT regulation has also been shown to participate in CCA progression, including TGFbeta1, 2, and 3 and TGFbeta receptors 1 and 2 (expressed in both CCA tumor cells and surrounding stroma cells), chromatic regulator Hmgb1 (a positive regulator of TGFbeta-induced EMT), BMP7 (a negative regulator of TGFbeta-induced EMT), TNFalpha (a positive regulator of E-cadherin and CK19 and negative regulator of S100A4, Snail, and Zeb2), IL-6 (expressed by CCA tumor cells and surrounding cells, and inhibiting epithelial and promoting mesenchymal characteristics), SOCS3 (inhibitor of IL-6 induced EMT), SMAD4 (converging point of IL-6- and TGFbeta1-induced EMT), EGFR (promoting cytoplasmic localization of E-cadherin), EphA2 (inhibiting epithelial junctions and promoting mesenchymal markers), H4HR (inhibiting fibronectin, vimentin, and S100A4 expression and promoting CK7, CK8, and CK19 expression), CXCR4 (promoting Slug, vimentin, and MMP-9 expression and cell migration), Notch1 (upregulating Snail, Sox9, alphaSMA, and vimentin levels and downregulating E-cadherin levels), Hedgehog signaling (downregulating E-cadherin), and several EMT-related microRNAs (miR-221, miR-200c, miR-204, miR-214, miR-34a, and miR-21).	('E-cadherin', 'MPA', (1163, 1173))	('downregulating', 'NegReg', (1093, 1107))	('CCA', 'Phenotype', 'HP:0030153', (502, 505))	('promoting', 'PosReg', (957, 966))	('miR-204', 'Var', (1230, 1237))	('EGFR', 'Gene', (710, 714))	('miR-200c', 'Var', (1220, 1228))	('tumor', 'Phenotype', 'HP:0002664', (506, 511))	('Slug', 'Gene', (967, 971))	('downregulating', 'NegReg', (1148, 1162))	('vimentin', 'Gene', '7431', (1073, 1081))	('miR-34a', 'Var', (1248, 1255))	('CCA', 'Phenotype', 'HP:0030153', (110, 113))	('Hedgehog signaling', 'MPA', (1128, 1146))	('CCA tumor', 'Disease', (502, 511))	('vimentin', 'Gene', (1073, 1081))	('CCA', 'Phenotype', 'HP:0030153', (205, 208))	('CCA tumor', 'Disease', 'MESH:C536211', (205, 214))	('miR-221', 'Var', (1211, 1218))	('upregulating', 'PosReg', (1033, 1045))	('miR-214', 'Var', (1239, 1246))	('EGFR', 'Gene', '1956', (710, 714))	('alphaSMA', 'MPA', (1059, 1067))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('Slug', 'Gene', '6591', (967, 971))	('Sox9', 'MPA', (1053, 1057))	('vimentin', 'Gene', '7431', (872, 880))	('vimentin', 'Gene', '7431', (973, 981))	('inhibiting', 'NegReg', (848, 858))	('vimentin', 'Gene', (872, 880))	('vimentin', 'Gene', (973, 981))	('Snail', 'MPA', (1046, 1051))	('miR-21', 'Var', (1261, 1267))	('CCA tumor', 'Disease', 'MESH:C536211', (502, 511))	('CCA tumor', 'Disease', (205, 214))
24405	33672838	In the aforementioned exome sequencing of liver fluke-associated CCAs; four of the genetic mutations uncovered in that analysis are known to be associated with EMT regulation (SMAD4, MLL3, ROBO2, and RNF43).	('associated', 'Reg', (144, 154))	('liver fluke-associated CCAs', 'Disease', (42, 69))	('EMT regulation', 'Disease', (160, 174))	('CCA', 'Phenotype', 'HP:0030153', (65, 68))	('liver fluke', 'Species', '6192', (42, 53))	('mutations', 'Var', (91, 100))
24406	33672838	Two separate studies using the hamster model of fluke-induced CCAs showed high levels of expression of terminal fucose in CCAs and that inhibition of fucosyltransferase 1 activity in liver fluke-associated CCA cell lines reduced mesenchymal marker (Slug, vimentin, and S100A4) expression and increased epithelial marker (E-cadherin and Claudin1) expression.	('CCA', 'Phenotype', 'HP:0030153', (122, 125))	('increased', 'PosReg', (292, 301))	('vimentin', 'Gene', '7431', (255, 263))	('Slug', 'Gene', '6591', (249, 253))	('S100A4', 'Gene', (269, 275))	('vimentin', 'Gene', (255, 263))	('CCA', 'Phenotype', 'HP:0030153', (206, 209))	('inhibition', 'Var', (136, 146))	('CCA', 'Phenotype', 'HP:0030153', (62, 65))	('mesenchymal marker', 'CPA', (229, 247))	('expression', 'MPA', (277, 287))	('fucose', 'Chemical', 'MESH:D005643', (112, 118))	('epithelial marker', 'MPA', (302, 319))	('reduced', 'NegReg', (221, 228))	('Slug', 'Gene', (249, 253))	('expression', 'MPA', (346, 356))	('Claudin1', 'Protein', (336, 344))	('E-cadherin', 'Protein', (321, 331))	('liver fluke', 'Species', '6192', (183, 194))	('hamster', 'Species', '10034', (31, 38))
24412	33672838	In another study, a stress-response gene, Gadd45b, was shown to be highly expressed in clinical CCA samples and that in a liver fluke-associated CCA cell line, Gadd45b knockdown led to a reduction in mesenchymal and an increase in epithelial marker expression.	('epithelial marker expression', 'MPA', (231, 259))	('mesenchymal', 'CPA', (200, 211))	('reduction', 'NegReg', (187, 196))	('CCA', 'Phenotype', 'HP:0030153', (96, 99))	('liver fluke', 'Species', '6192', (122, 133))	('CCA', 'Phenotype', 'HP:0030153', (145, 148))	('Gadd45b', 'Gene', (42, 49))	('knockdown', 'Var', (168, 177))	('increase', 'PosReg', (219, 227))	('Gadd45b', 'Gene', (160, 167))
24417	33672838	Cancer arises through genetic and/or epigenetic-based malfunction of normal tissue homeostasis, including failure in controlling cellular proliferation and differentiation, and in maintaining tissue-level cell-cell and cell-matrix organizations.	('epigenetic-based', 'Var', (37, 53))	('differentiation', 'CPA', (156, 171))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('failure', 'NegReg', (106, 113))
24423	33672838	Genetic and epigenetic alternations leading to cancer malignancy can be categorized as either spontaneous or induced.	('epigenetic alternations', 'Var', (12, 35))	('cancer malignancy', 'Disease', 'MESH:D009369', (47, 64))	('cancer malignancy', 'Disease', (47, 64))	('leading to', 'Reg', (36, 46))	('Genetic', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
24458	30205418	A questionnaire-based study revealed that a history of "blue-collar" work was noted in 88% of patients with IgG4-SC and/or AIP in the Amsterdam cohort, and in 61% of patients with IgG4-SC and/or AIP in the Oxford cohort, both of which were much higher than the rate observed in patients with PSC.	('PSC', 'Gene', '100653366', (292, 295))	('patients', 'Species', '9606', (94, 102))	('SC', 'Phenotype', 'HP:0030991', (185, 187))	('PSC', 'Gene', (292, 295))	('SC', 'Phenotype', 'HP:0030991', (293, 295))	('IgG4-SC', 'Disease', (108, 115))	('AIP', 'Var', (123, 126))	('patients', 'Species', '9606', (278, 286))	('patients', 'Species', '9606', (166, 174))	('SC', 'Phenotype', 'HP:0030991', (113, 115))
24555	31097929	Liver function and other organ functions were rapidly improved (BUN 17 mg/dL, creatinine 0.9 mg/dL, total bilirubin 0.7 mg/dL, and alkaline phosphatase 1,694 IU/L), and the scheduled left hepatectomy with caudate and extrahepatic duct resection was successfully performed (operating time 9 h 32 min, blood loss 1,190 mL).	('Liver', 'MPA', (0, 5))	('BUN', 'Var', (64, 67))	('total bilirubin', 'MPA', (100, 115))	('improved', 'PosReg', (54, 62))	('alkaline phosphatase', 'MPA', (131, 151))	('creatinine', 'MPA', (78, 88))	('organ functions', 'CPA', (25, 40))	('bilirubin', 'Chemical', 'MESH:D001663', (106, 115))	('creatinine', 'Chemical', 'MESH:D003404', (78, 88))
24649	30519546	The histological counterpart to this change is the presence inside the lesion of unpaired arteries associated with modifications of the endothelium lining the sinusoids, which looses its fenestration and expresses markers usually expressed by nonsinusoidal endothelium (eg, CD34).	('CD34', 'Gene', '947', (274, 278))	('expresses', 'Reg', (204, 213))	('modifications', 'Var', (115, 128))	('CD34', 'Gene', (274, 278))	('looses', 'NegReg', (176, 182))	('fenestration', 'CPA', (187, 199))
24688	30519546	One type consisted of large well-differentiated cholestatic tumors in the pseudo-glandular and microtrabecular patterns, showing mutations in CTNNB1, the gene encoding for beta-catenin.	('CTNNB1', 'Gene', '1499', (142, 148))	('cholestatic tumors', 'Disease', (48, 66))	('beta-catenin', 'Gene', (172, 184))	('mutations', 'Var', (129, 138))	('beta-catenin', 'Gene', '1499', (172, 184))	('cholestatic tumors', 'Disease', 'MESH:D002779', (48, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('CTNNB1', 'Gene', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
24689	30519546	The other type consisted of poorly differentiated tumors, displaying a compact growth pattern, with frequent vascular invasion, and showing mutation in TP53.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('TP53', 'Gene', '7157', (152, 156))	('mutation', 'Var', (140, 148))	('vascular invasion', 'CPA', (109, 126))	('TP53', 'Gene', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
24690	30519546	A novel subtype defined as "macrotrabecular massive" due to the particular growth pattern showed vascular invasion, high serum AFP, mutation in TP53 and FGF19 amplifications, and poor survival.	('TP53', 'Gene', '7157', (144, 148))	('mutation in', 'Var', (132, 143))	('TP53', 'Gene', (144, 148))	('vascular invasion', 'CPA', (97, 114))	('AFP', 'Gene', (127, 130))	('AFP', 'Gene', '174', (127, 130))	('FGF19', 'Gene', '9965', (153, 158))	('FGF19', 'Gene', (153, 158))
24714	30519546	In some instances, however, the glutamine synthetase staining is patchy and may not correlate well with mutations in CTNNB1.	('CTNNB1', 'Gene', '1499', (117, 123))	('mutations', 'Var', (104, 113))	('CTNNB1', 'Gene', (117, 123))	('glutamine synthetase', 'Gene', (32, 52))	('glutamine synthetase', 'Gene', '2752', (32, 52))
24718	30519546	About 10% of inflammatory hepatocellular adenoma, for example, harbor mutation in the CTNNB1 and are also at risk of malignant transformation (Figure 3).	('inflammatory hepatocellular adenoma', 'Disease', (13, 48))	('hepatocellular adenoma', 'Phenotype', 'HP:0012028', (26, 48))	('inflammatory hepatocellular adenoma', 'Disease', 'MESH:D018248', (13, 48))	('CTNNB1', 'Gene', (86, 92))	('mutation', 'Var', (70, 78))	('harbor', 'Reg', (63, 69))	('CTNNB1', 'Gene', '1499', (86, 92))
24721	30519546	An indolent looking steatotic hepatocellular adenoma with features of an HNF-1-mutated variant in a young healthy woman taking oral contraceptives and with an entirely normal background liver is probably at very low risk of progression and may regress once hormonal stimulation is withdrawn.	('hepatocellular adenoma', 'Phenotype', 'HP:0012028', (30, 52))	('steatotic hepatocellular adenoma', 'Disease', 'MESH:D018248', (20, 52))	('steatotic hepatocellular adenoma', 'Disease', (20, 52))	('variant', 'Var', (87, 94))	('woman', 'Species', '9606', (114, 119))	('HNF-1', 'Gene', (73, 78))	('HNF-1', 'Gene', '6927', (73, 78))
24736	29163820	This study shows the increase in the expression of specific drug transporters exerted by cisplatin treatment thereby enhancing their transport activity.	('cisplatin', 'Var', (89, 98))	('transport activity', 'MPA', (133, 151))	('enhancing', 'PosReg', (117, 126))	('expression', 'MPA', (37, 47))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('increase', 'PosReg', (21, 29))
24935	26441331	In addition, restoration of HDAC4 attenuated miR-29a-mediated inhibition of cell proliferation and metastasis.	('restoration', 'Var', (13, 24))	('miR-29a', 'Gene', (45, 52))	('miR-29a', 'Gene', '407021', (45, 52))	('inhibition', 'NegReg', (62, 72))	('HDAC4', 'Gene', (28, 33))	('attenuated', 'NegReg', (34, 44))
24942	26441331	Increasing evidence demonstrates that dysregulation of TGF-beta1 has been identified in several cancers, including cholangiocarcinoma.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('TGF-beta1', 'Gene', '7040', (55, 64))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (115, 133))	('TGF-beta1', 'Gene', (55, 64))	('dysregulation', 'Var', (38, 51))	('cholangiocarcinoma', 'Disease', (115, 133))	('identified', 'Reg', (74, 84))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (115, 133))	('cancers', 'Disease', (96, 103))
24946	26441331	Aberrant miRNAs expression are involved in cholangiocarcinoma development, such as miR-21, miR-370, miR-373 and miR-200.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (43, 61))	('miR', 'Gene', (100, 103))	('miR', 'Gene', '220972', (83, 86))	('cholangiocarcinoma', 'Disease', (43, 61))	('miR-21', 'Gene', '406991', (83, 89))	('miR', 'Gene', (91, 94))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (43, 61))	('Aberrant', 'Var', (0, 8))	('involved', 'Reg', (31, 39))	('miR-370', 'Gene', (91, 98))	('miR', 'Gene', (83, 86))	('miR-373', 'Gene', (100, 107))	('miR', 'Gene', '220972', (9, 12))	('miR-370', 'Gene', '442915', (91, 98))	('miR', 'Gene', '220972', (112, 115))	('miR-21', 'Gene', (83, 89))	('miR-373', 'Gene', '442918', (100, 107))	('miR', 'Gene', (9, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('miR', 'Gene', (112, 115))	('miR', 'Gene', '220972', (100, 103))	('miR', 'Gene', '220972', (91, 94))
24965	26441331	To regulate miR-29a expression, both mimics (50 nM) and inhibitors (100 nM) of miR-29a were transfected.	('50 nM', 'Var', (45, 50))	('expression', 'MPA', (20, 30))	('miR-29a', 'Gene', '407021', (79, 86))	('100', 'Var', (68, 71))	('miR-29a', 'Gene', (79, 86))	('regulate', 'Reg', (3, 11))	('miR-29a', 'Gene', (12, 19))	('miR-29a', 'Gene', '407021', (12, 19))
24973	26441331	To construct plasmid pmirGLO-mHDAC4 (containing a mutant HDAC4 3'-UTR), a mutation identified using Targetscan (http://www.TargetScan.org/) was induced using a Site-Directed Mutagenesis kit (SBSGenetech, China), following the manufacturer's instructions.	('mHDAC4', 'Gene', (29, 35))	('HDAC4', 'Gene', (57, 62))	('mHDAC4', 'Gene', '208727', (29, 35))	('mutant', 'Var', (50, 56))
24979	26441331	These data suggest that dysregulation of miR-29a might contribute to the tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('miR-29a', 'Gene', '407021', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('dysregulation', 'Var', (24, 37))	('miR-29a', 'Gene', (41, 48))	('tumor', 'Disease', (73, 78))	('contribute', 'Reg', (55, 65))
24980	26441331	Overexpression of TGF-beta1 are associated with tumor progression and metastasis in cholangiocarcinoma.	('metastasis', 'CPA', (70, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('tumor', 'Disease', (48, 53))	('TGF-beta1', 'Gene', '7040', (18, 27))	('TGF-beta1', 'Gene', (18, 27))	('cholangiocarcinoma', 'Disease', (84, 102))	('Overexpression', 'Var', (0, 14))	('associated', 'Reg', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
24997	26441331	To confirm that HDAC4 was indeed a direct target of miR-29a in human cells, we used luciferase reporter constructs containing wild-type and mutant HDAC4-3'-UTRs, both with the putative binding site of miR-29a (Fig 6A).	("HDAC4-3'-UTRs", 'Gene', (147, 160))	('human', 'Species', '9606', (63, 68))	('miR-29a', 'Gene', (52, 59))	('miR-29a', 'Gene', '407021', (52, 59))	('miR-29a', 'Gene', (201, 208))	('miR-29a', 'Gene', '407021', (201, 208))	('mutant', 'Var', (140, 146))
25012	26441331	Since aberrant miRNA expression contributes to tumor initiation and progression, thus the mechanisms inducing dysregulation of miR-29a expression in cholangiocarcinoma are of significant interest.	('contributes', 'Reg', (32, 43))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (149, 167))	('miR-29a', 'Gene', (127, 134))	('miR-29a', 'Gene', '407021', (127, 134))	('aberrant', 'Var', (6, 14))	('progression', 'CPA', (68, 79))	('cholangiocarcinoma', 'Disease', (149, 167))	('miR', 'Gene', '220972', (127, 130))	('miR', 'Gene', (127, 130))	('miR', 'Gene', '220972', (15, 18))	('tumor initiation', 'Disease', 'MESH:D009369', (47, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (149, 167))	('tumor initiation', 'Disease', (47, 63))	('miR', 'Gene', (15, 18))
25014	26441331	It has been confirmed that mutations in components of the TGF-beta1 signaling pathway promote the malignant phenotype of a given tissue in pancreatic cancer and colon carcinoma.	('mutations', 'Var', (27, 36))	('TGF-beta1', 'Gene', '7040', (58, 67))	('TGF-beta1', 'Gene', (58, 67))	('colon carcinoma', 'Disease', 'MESH:D015179', (161, 176))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (139, 156))	('colon carcinoma', 'Disease', (161, 176))	('malignant phenotype of a given tissue', 'CPA', (98, 135))	('pancreatic cancer', 'Disease', (139, 156))	('promote', 'PosReg', (86, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('pancreatic cancer', 'Disease', 'MESH:D010190', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
25018	26441331	In addition, upregulation of miR-29a suppresses tumor cells proliferation, migration and invasion, whereas silencing of miR-29a promotes TGF-beta1-induced tumor progression.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('TGF-beta1', 'Gene', '7040', (137, 146))	('miR-29a', 'Gene', '407021', (120, 127))	('silencing', 'Var', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('suppresses', 'NegReg', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('miR-29a', 'Gene', (120, 127))	('tumor', 'Disease', (155, 160))	('invasion', 'CPA', (89, 97))	('upregulation', 'PosReg', (13, 25))	('promotes', 'PosReg', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('miR-29a', 'Gene', '407021', (29, 36))	('migration', 'CPA', (75, 84))	('TGF-beta1', 'Gene', (137, 146))	('miR-29a', 'Gene', (29, 36))
25030	26441331	Aberrant HDAC expression is associated with carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (44, 58))	('Aberrant', 'Var', (0, 8))	('associated', 'Reg', (28, 38))	('HDAC', 'Protein', (9, 13))	('carcinogenesis', 'Disease', (44, 58))
25035	26441331	Our observation suggest that the aberrant TGF-beta1 expression in cholangiocarcinoma may led to reduced miR-29a level, which in turn affects the histone acetylation level and thereby facilitates carcinogenesis and tumor progression.	('TGF-beta1', 'Gene', '7040', (42, 51))	('TGF-beta1', 'Gene', (42, 51))	('cholangiocarcinoma', 'Disease', (66, 84))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('miR-29a', 'Gene', '407021', (104, 111))	('carcinogenesis', 'Disease', 'MESH:D063646', (195, 209))	('carcinogenesis', 'Disease', (195, 209))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('affects', 'Reg', (133, 140))	('miR-29a', 'Gene', (104, 111))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (66, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('facilitates', 'PosReg', (183, 194))	('tumor', 'Disease', (214, 219))	('histone acetylation level', 'MPA', (145, 170))	('aberrant', 'Var', (33, 41))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (66, 84))	('reduced', 'NegReg', (96, 103))
25047	25889600	CSH-DTX resulted in higher apoptosis of cancer cells with ~30% and ~50 of cells in early apoptosis quadrant when treated with 100 and 1000 ng/ml of equivalent drug.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('higher', 'PosReg', (20, 26))	('cancer', 'Disease', (40, 46))	('CSH-DTX', 'Var', (0, 7))	('apoptosis', 'CPA', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('CSH-DTX', 'Chemical', '-', (0, 7))
25049	25889600	Immunohistochemical analysis of tumor sections showed that fewer number of Ki-67 cells were present in CSH-DTX treated group comparing to that of free DTX treated group.	('CSH-DTX', 'Chemical', '-', (103, 110))	('DTX', 'Chemical', 'MESH:D000077143', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('Ki-67 cells', 'CPA', (75, 86))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('CSH-DTX', 'Var', (103, 110))	('tumor', 'Disease', (32, 37))	('fewer', 'NegReg', (59, 64))	('DTX', 'Chemical', 'MESH:D000077143', (151, 154))
25050	25889600	Our data suggests that nanoformulation of DTX could potentially improve the chemotherapy treatment in cholangiocarcinoma as well as in other malignancies.	('improve', 'PosReg', (64, 71))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (102, 120))	('DTX', 'Chemical', 'MESH:D000077143', (42, 45))	('nanoformulation', 'Var', (23, 38))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (102, 120))	('malignancies', 'Disease', 'MESH:D009369', (141, 153))	('cholangiocarcinoma', 'Disease', (102, 120))	('malignancies', 'Disease', (141, 153))	('chemotherapy treatment', 'CPA', (76, 98))
25103	25889600	At lower pH, when the histidine was protonated, imbalance of hydrophilic and hydrophobic force destabilizes the micelles structure and the drug diffuses in higher rate.	('rat', 'Species', '10116', (163, 166))	('imbalance', 'Phenotype', 'HP:0002172', (48, 57))	('micelles', 'MPA', (112, 120))	('destabilizes', 'NegReg', (95, 107))	('histidine', 'Chemical', 'MESH:D006639', (22, 31))	('diffuses', 'MPA', (144, 152))	('higher rate', 'PosReg', (156, 167))	('mice', 'Species', '10090', (112, 116))	('imbalance', 'Var', (48, 57))
25112	25889600	It has to be noted that cytotoxicity of CSH-DTX was more pronounced than that of free drug in all the time points.	('CSH-DTX', 'Var', (40, 47))	('CSH-DTX', 'Chemical', '-', (40, 47))	('cytotoxicity', 'Disease', 'MESH:D064420', (24, 36))	('cytotoxicity', 'Disease', (24, 36))
25122	25889600	Notably, CSH-DTX remarkably induced the apoptosis in cancer cells with typical features of cell death such as chromatic condensation, membrane blebbing and apoptotic bodies were visible.	('CSH-DTX', 'Var', (9, 16))	('cancer', 'Disease', (53, 59))	('membrane blebbing', 'CPA', (134, 151))	('induced', 'PosReg', (28, 35))	('apoptosis', 'CPA', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('CSH-DTX', 'Chemical', '-', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('chromatic condensation', 'Phenotype', 'HP:0011516', (110, 132))	('chromatic condensation', 'CPA', (110, 132))
25127	25889600	As expected, CSH-DTX resulted in higher apoptosis of cancer cells with ~30% and ~50 of cells in early apoptosis quadrant for the same concentrations, respectively.	('higher', 'PosReg', (33, 39))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('apoptosis', 'CPA', (40, 49))	('CSH-DTX', 'Var', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('CSH-DTX', 'Chemical', '-', (13, 20))	('rat', 'Species', '10116', (141, 144))
25133	25889600	As shown in Figure 7a, CSH-DTX significantly slowed down the growth of tumor in mice models comparing to that of free DTX and saline treated mice groups.	('saline', 'Chemical', 'MESH:D012965', (126, 132))	('DTX', 'Chemical', 'MESH:D000077143', (27, 30))	('CSH-DTX', 'Var', (23, 30))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('DTX', 'Chemical', 'MESH:D000077143', (118, 121))	('slowed down', 'NegReg', (45, 56))	('CSH-DTX', 'Chemical', '-', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mice', 'Species', '10090', (141, 145))	('mice', 'Species', '10090', (80, 84))	('tumor', 'Disease', (71, 76))
25149	25889600	As seen (Figure 8b), fewer number of Ki-67 cells were present in CSH-DTX treated cells comparing to that of free DTX treated group.	('DTX', 'Chemical', 'MESH:D000077143', (69, 72))	('CSH-DTX', 'Chemical', '-', (65, 72))	('DTX', 'Chemical', 'MESH:D000077143', (113, 116))	('Ki-67 cells', 'CPA', (37, 48))	('fewer', 'NegReg', (21, 26))	('CSH-DTX treated', 'Var', (65, 80))
25159	25889600	Immunohistochemical analysis of tumor sections showed that fewer number of Ki-67 cells were present in CSH-DTX treated cells comparing to that of free DTX treated group.	('CSH-DTX', 'Chemical', '-', (103, 110))	('DTX', 'Chemical', 'MESH:D000077143', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('Ki-67 cells', 'CPA', (75, 86))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('CSH-DTX', 'Var', (103, 110))	('tumor', 'Disease', (32, 37))	('fewer', 'NegReg', (59, 64))	('DTX', 'Chemical', 'MESH:D000077143', (151, 154))
25209	22591401	Upon stimulation with EGF, ligand-induced EGFR degradation was impaired and the expression of phospho-tyrosine 1068 and phospho-p44/42 MAPK was sustained in RBE cells as compared with MMNK-1 cells.	('MMNK-1', 'CellLine', 'CVCL:M266', (184, 190))	('EGFR', 'Gene', '1956', (42, 46))	('EGF', 'Gene', '1950', (22, 25))	('EGFR', 'Gene', (42, 46))	('EGF', 'Gene', (42, 45))	('expression', 'MPA', (80, 90))	('phospho-p44/42 MAPK', 'Var', (120, 139))	('tyrosine', 'Chemical', 'MESH:D014443', (102, 110))	('degradation', 'MPA', (47, 58))	('phospho-tyrosine 1068', 'Var', (94, 115))	('impaired', 'NegReg', (63, 71))	('EGF', 'Gene', (22, 25))	('EGF', 'Gene', '1950', (42, 45))
25211	22591401	A disrupted association between EGFR and the E3 ubiquitin ligase c-Cbl, as well as hypo-phosphorylation of EGFR at tyrosine 1045 (Tyr1045), were also observed in RBE cells.	('Tyr1045', 'Var', (130, 137))	('EGFR', 'Gene', '1956', (107, 111))	('hypo-phosphorylation', 'MPA', (83, 103))	('c-Cbl', 'Gene', (65, 70))	('c-Cbl', 'Gene', '867', (65, 70))	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'Gene', (107, 111))	('tyrosine', 'Chemical', 'MESH:D014443', (115, 123))	('Tyr1045', 'Chemical', '-', (130, 137))	('association', 'Interaction', (12, 23))	('EGFR', 'Gene', (32, 36))
25212	22591401	In RBE cells, up-regulation of EGFR Tyr1045 phosphorylation is a potentially useful molecular alteration in EGFR-targeted therapy.	('EGFR', 'Gene', '1956', (31, 35))	('up-regulation', 'PosReg', (14, 27))	('Tyr1045', 'Var', (36, 43))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('EGFR', 'Gene', (31, 35))	('Tyr1045', 'Chemical', '-', (36, 43))
25216	22591401	Molecular-targeted treatment is superior to traditional chemotherapy through its ability to selectively suppress cancer cells.	('suppress', 'NegReg', (104, 112))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('Molecular-targeted', 'Var', (0, 18))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
25217	22591401	Overexpression, gene amplification, and mutation of epidermal growth factor receptor (EGFR) have all been associated with the tumorigenesis and progression of cholangiocarcinoma, and thus EGFR and its molecular transducers are thought to be ideal therapeutic targets for cholangiocarcinoma treatment.	('progression', 'CPA', (144, 155))	('tumorigenesis', 'CPA', (126, 139))	('EGFR', 'Gene', '1956', (188, 192))	('gene amplification', 'Var', (16, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('associated with', 'Reg', (106, 121))	('EGFR', 'Gene', '1956', (86, 90))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (271, 289))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (159, 177))	('mutation', 'Var', (40, 48))	('cholangiocarcinoma', 'Disease', (271, 289))	('cholangiocarcinoma', 'Disease', (159, 177))	('epidermal growth factor receptor', 'Gene', (52, 84))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (271, 289))	('epidermal growth factor receptor', 'Gene', '1956', (52, 84))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (159, 177))	('EGFR', 'Gene', (188, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('EGFR', 'Gene', (86, 90))
25221	22591401	Aberrant EGFR activity has been shown to play a key role in the development and growth of various types of cancer cells.	('activity', 'MPA', (14, 22))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('development', 'CPA', (64, 75))	('growth', 'CPA', (80, 86))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
25222	22591401	To date, several mechanisms involving abnormal activation of EGFR have been reported, including increased production of ligands, increased levels of EGFR protein, EGFR mutations giving rise to constitutively active variants, defective down-regulation of EGFR, and cross-talk with heterologous receptor systems.	('increased', 'PosReg', (96, 105))	('levels', 'MPA', (139, 145))	('EGFR', 'Gene', (254, 258))	('EGFR', 'Gene', '1956', (163, 167))	('activation', 'PosReg', (47, 57))	('increased', 'PosReg', (129, 138))	('down-regulation', 'NegReg', (235, 250))	('production of ligands', 'MPA', (106, 127))	('EGFR', 'Gene', '1956', (149, 153))	('cross-talk', 'Reg', (264, 274))	('EGFR', 'Gene', (163, 167))	('EGFR', 'Gene', (149, 153))	('mutations', 'Var', (168, 177))	('variants', 'Var', (215, 223))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', '1956', (254, 258))	('EGFR', 'Gene', (61, 65))
25226	22591401	In a related report, Cbl mutation and reduced EGFR ubiquitination inhibited early endosome fusion and EGFR degradation in HEK 293 cells.	('Cbl', 'Gene', '867', (21, 24))	('reduced', 'NegReg', (38, 45))	('EGFR', 'Gene', '1956', (102, 106))	('early endosome fusion', 'MPA', (76, 97))	('mutation', 'Var', (25, 33))	('EGFR', 'Gene', '1956', (46, 50))	('EGFR', 'Gene', (46, 50))	('inhibited', 'NegReg', (66, 75))	('Cbl', 'Gene', (21, 24))	('EGFR', 'Gene', (102, 106))	('HEK 293', 'CellLine', 'CVCL:0045', (122, 129))
25228	22591401	Since hypo-phosphorylation of Tyr1045 and a diminished association of c-Cbl and EGFR were considered as the responsible mechanisms, upregulation of Tyr1045 phosphorylation might be a useful alteration in EGFR-targeted therapy.	('Tyr1045', 'Var', (30, 37))	('upregulation', 'PosReg', (132, 144))	('diminished', 'NegReg', (44, 54))	('Tyr1045', 'Chemical', '-', (148, 155))	('EGFR', 'Gene', '1956', (80, 84))	('c-Cbl', 'Gene', (70, 75))	('association', 'Interaction', (55, 66))	('EGFR', 'Gene', (80, 84))	('c-Cbl', 'Gene', '867', (70, 75))	('Tyr1045', 'Chemical', '-', (30, 37))	('hypo-phosphorylation', 'Var', (6, 26))	('EGFR', 'Gene', '1956', (204, 208))	('EGFR', 'Gene', (204, 208))	('Tyr1045', 'Var', (148, 155))
25261	22591401	To investigate the impact of impaired degradation of EGFR on EGFR-signaled pathways, we studied the expression of phosphorylated EGFR (pY1068) and downstream phosphorylated p44/42 MAPK (p-p44/42 MAPK) (Figure 2A).	('pY1068', 'Var', (135, 141))	('EGFR', 'Gene', '1956', (129, 133))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('EGFR', 'Gene', (129, 133))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
25262	22591401	The expression of pY1068 persisted in RBE cells while a marked decrease of pEGFR was witnessed in MMNK-1 cells following 2 hr of EGF stimulation (7.2 +- 0.3 vs. 2.6 +- 0.4 folds of pY1068/total EGFR of RBE cells before EGF stimulation)(p < 0.05, n = 3, Figure 2B).	('EGF', 'Gene', (194, 197))	('pY1068', 'Var', (18, 24))	('EGF', 'Gene', (129, 132))	('EGF', 'Gene', '1950', (76, 79))	('EGFR', 'Gene', '1956', (76, 80))	('EGF', 'Gene', (219, 222))	('decrease', 'NegReg', (63, 71))	('EGF', 'Gene', '1950', (194, 197))	('EGFR', 'Gene', (76, 80))	('EGF', 'Gene', '1950', (129, 132))	('EGFR', 'Gene', (194, 198))	('pY1068/total', 'Var', (181, 193))	('EGFR', 'Gene', '1956', (194, 198))	('EGF', 'Gene', (76, 79))	('EGF', 'Gene', '1950', (219, 222))	('MMNK-1', 'CellLine', 'CVCL:M266', (98, 104))
25281	22591401	Immunofluorescent staining of EGFR and EEA-1 or LAMP-1 demonstrated that Rab11a depletion could suppress cell surface EGFR expression and maintain more EGFR in the early endosome of RBE cells (Figure 4C, lower panel, upper right).	('EGFR', 'Gene', (30, 34))	('expression', 'MPA', (123, 133))	('cell surface', 'MPA', (105, 117))	('LAMP-1', 'Gene', '3916', (48, 54))	('more', 'PosReg', (147, 151))	('EGFR', 'Gene', '1956', (152, 156))	('LAMP-1', 'Gene', (48, 54))	('depletion', 'Var', (80, 89))	('EEA-1', 'Gene', (39, 44))	('Rab11a', 'Gene', '8766', (73, 79))	('EEA-1', 'Gene', '8411', (39, 44))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('EGFR', 'Gene', '1956', (30, 34))	('EGFR', 'Gene', (152, 156))	('maintain', 'Reg', (138, 146))	('suppress', 'NegReg', (96, 104))	('Rab11a', 'Gene', (73, 79))
25282	22591401	Rab11a depletion could not promote EGFR sorting into late endosome/lysosome in RBE cells (Figure 4C, lower panel, lower right), hence EGFR degradation was not enhanced by this treatment (data not shown).	('EGFR', 'Gene', (134, 138))	('Rab11a', 'Gene', '8766', (0, 6))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('Rab11a', 'Gene', (0, 6))	('depletion', 'Var', (7, 16))	('EGFR', 'Gene', '1956', (134, 138))
25288	22591401	When we studied the expression of phosphorylated Tyr1045 (pY1045) and total c-Cbl after 3, 10 and 15 min of EGF stimulation in both cell lines, we uncovered that phosphorylation of Tyr1045 was impaired in RBE cells but intact in MMNK-1 cells (Figure 5C).	('Tyr1045', 'Chemical', '-', (181, 188))	('EGF', 'Gene', '1950', (108, 111))	('Tyr1045', 'Chemical', '-', (49, 56))	('EGF', 'Gene', (108, 111))	('c-Cbl', 'Gene', '867', (76, 81))	('MMNK-1', 'CellLine', 'CVCL:M266', (229, 235))	('Tyr1045', 'Var', (181, 188))	('phosphorylation', 'MPA', (162, 177))	('c-Cbl', 'Gene', (76, 81))
25292	22591401	Clathrin-coated vesicles containing EGF-EGFR complexes release their coat and fuse with early endosomes quickly following endocytosis.	('EGF', 'Gene', (40, 43))	('coat', 'MPA', (69, 73))	('release', 'PosReg', (55, 62))	('complexes', 'Var', (45, 54))	('EGF', 'Gene', '1950', (36, 39))	('EGF', 'Gene', '1950', (40, 43))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('EGF', 'Gene', (36, 39))
25300	22591401	Reduced Cbl association and/or impaired EGFR ubiquitination could be linked with a Cbl mutation in the RING Finger domain, especially cysteine 381 (C381), which is the first cysteine of the C3HC4 zinc finger motif, or at the RING finger C-terminal flank, especially valine 431 (V431) and phenylalanine 434 (F434).	('mutation in', 'Var', (87, 98))	('Cbl', 'Gene', (8, 11))	('Cbl', 'Gene', (83, 86))	('V431', 'CellLine', 'CVCL:0037', (278, 282))	('valine', 'Chemical', 'MESH:D014633', (266, 272))	('Reduced', 'NegReg', (0, 7))	('Cbl', 'Gene', '867', (8, 11))	('Cbl', 'Gene', '867', (83, 86))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('association', 'Interaction', (12, 23))	('phenylalanine', 'Chemical', 'MESH:D010649', (288, 301))	('cysteine', 'Chemical', 'MESH:D003545', (134, 142))	('impaired', 'NegReg', (31, 39))	('cysteine', 'Chemical', 'MESH:D003545', (174, 182))	('C3HC4', 'Chemical', '-', (190, 195))
25301	22591401	Apart from mutations in c-Cbl, the loss of the Cbl docking site on EGFR (pY1068 and pY1045) for numerous reasons, such as EGFR mutations in the tyrosine kinase domain or mutations at ubiquitination sites of EGFR, could also lead to reduced Cbl association and/or impaired EGFR ubiquitination.	('Cbl', 'Gene', '867', (240, 243))	('c-Cbl', 'Gene', (24, 29))	('reduced', 'NegReg', (232, 239))	('Cbl', 'Gene', (47, 50))	('EGFR', 'Gene', (67, 71))	('EGFR', 'Gene', (122, 126))	('EGFR', 'Gene', (272, 276))	('association', 'Interaction', (244, 255))	('EGFR', 'Gene', (207, 211))	('ubiquitination', 'MPA', (277, 291))	('Cbl', 'Gene', '867', (47, 50))	('impaired', 'NegReg', (263, 271))	('Cbl', 'Gene', (26, 29))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', '1956', (272, 276))	('Cbl', 'Gene', (240, 243))	('mutations', 'Var', (170, 179))	('EGFR', 'Gene', '1956', (207, 211))	('c-Cbl', 'Gene', '867', (24, 29))	('mutations in', 'Var', (127, 139))	('Cbl', 'Gene', '867', (26, 29))	('tyrosine', 'Chemical', 'MESH:D014443', (144, 152))
25302	22591401	In RBE cells, no mutations at C381, V431 or F434 of Cbl, the tyrosine kinase domain or Tyr1068 or 1045 residues of EGFR, or of the extracellular domain that binds to ligands (exon 2 ~ 16) were identified.	('Cbl', 'Gene', (52, 55))	('EGFR', 'Gene', '1956', (115, 119))	('F434', 'Var', (44, 48))	('Tyr1068', 'Var', (87, 94))	('EGFR', 'Gene', (115, 119))	('V431', 'Var', (36, 40))	('Cbl', 'Gene', '867', (52, 55))	('binds', 'Interaction', (157, 162))	('tyrosine', 'Chemical', 'MESH:D014443', (61, 69))	('V431', 'CellLine', 'CVCL:0037', (36, 40))	('Tyr1068', 'Chemical', '-', (87, 94))
25305	22591401	However, unlike Tyr1068 that could be phosphorylated normally, Tyr1045 could not be phosphorylated following EGF stimulation.	('Tyr1068', 'Chemical', '-', (16, 23))	('Tyr1045', 'Chemical', '-', (63, 70))	('EGF', 'Gene', (109, 112))	('EGF', 'Gene', '1950', (109, 112))	('Tyr1045', 'Var', (63, 70))
25306	22591401	Combining this with the data from Grovdal et al., who described that a direct association of c-Cbl with EGFR pY1045 was important for MVB sorting of EGFR, we surmised that aberrant EGFR sorting into lysosomes in RBE cells was caused by an impaired association between c-Cbl and EGFR through pY1045.	('pY1045', 'Var', (291, 297))	('EGFR', 'Gene', '1956', (278, 282))	('EGFR', 'Gene', (181, 185))	('EGFR', 'Gene', (104, 108))	('EGFR', 'Gene', (278, 282))	('impaired', 'NegReg', (239, 247))	('EGFR', 'Gene', '1956', (149, 153))	('c-Cbl', 'Gene', (268, 273))	('c-Cbl', 'Gene', (93, 98))	('association', 'Interaction', (248, 259))	('c-Cbl', 'Gene', '867', (268, 273))	('EGFR', 'Gene', (149, 153))	('c-Cbl', 'Gene', '867', (93, 98))	('EGFR', 'Gene', '1956', (181, 185))	('EGFR', 'Gene', '1956', (104, 108))
25307	22591401	Hypophosphorylation of Tyr1045 has been reported in non-small cell lung cancers (NSCLCs) bearing EGFR mutations in the tyrosine kinase domain and in an EGFRvIII variant bearing an internal in-frame deletion in the extracellular domain.	('EGFR', 'Gene', '1956', (97, 101))	('Tyr1045', 'Var', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (52, 79))	('cell lung cancers', 'Disease', 'MESH:D008175', (62, 79))	('EGFR', 'Gene', '1956', (152, 156))	('lung cancers', 'Phenotype', 'HP:0100526', (67, 79))	('EGFR', 'Gene', (97, 101))	('Hypophosphorylation', 'MPA', (0, 19))	('mutations', 'Var', (102, 111))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('EGFR', 'Gene', (152, 156))	('tyrosine', 'Chemical', 'MESH:D014443', (119, 127))	('Tyr1045', 'Chemical', '-', (23, 30))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (56, 79))	('cell lung cancers', 'Disease', (62, 79))	('NSCLCs', 'Phenotype', 'HP:0030358', (81, 87))
25308	22591401	However, no EGFR mutation was identified in our RBE cells, nor was Tyr1045 of the transfected wtEGFR seen to be phosphorylated (data not shown).	('Tyr1045', 'Var', (67, 74))	('EGFR', 'Gene', (96, 100))	('Tyr1045', 'Chemical', '-', (67, 74))	('EGFR', 'Gene', '1956', (12, 16))	('EGFR', 'Gene', (12, 16))	('EGFR', 'Gene', '1956', (96, 100))
25310	22591401	In their study, AR activation of EGFR resulted in increased steady-state levels of the receptor that accumulated at the cell surface as a result of decreased phosphorylation of Tyr1045 on EGFR (wild type) and a resultant failure to ubiquitinate.	('phosphorylation', 'MPA', (158, 173))	('AR', 'Gene', '374', (16, 18))	('activation', 'PosReg', (19, 29))	('increased', 'PosReg', (50, 59))	('decreased', 'NegReg', (148, 157))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', '1956', (188, 192))	('Tyr1045', 'Chemical', '-', (177, 184))	('EGFR', 'Gene', (33, 37))	('ubiquitinate', 'MPA', (232, 244))	('EGFR', 'Gene', (188, 192))	('Tyr1045', 'Var', (177, 184))
25313	22591401	Uncovering the mechanism of Tyr1045 hypophosphorylation is of great importance in restoring EGFR degradation and negatively controlling EGFR over-activation in RBE cells.	('Tyr1045', 'Chemical', '-', (28, 35))	('restoring', 'PosReg', (82, 91))	('Tyr1045', 'Var', (28, 35))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))
25318	22591401	Recent strategies examining EGFR-targeted therapy of cholangiocarcinoma have focused on EGFR tyrosine kinases related to the signaling of mutated and over-expressed EGFR.	('EGFR', 'Gene', (165, 169))	('EGFR', 'Gene', '1956', (28, 32))	('mutated', 'Var', (138, 145))	('tyrosine', 'Chemical', 'MESH:D014443', (93, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (53, 71))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (53, 71))	('EGFR', 'Gene', (28, 32))	('EGFR', 'Gene', '1956', (88, 92))	('cholangiocarcinoma', 'Disease', (53, 71))	('over-expressed', 'PosReg', (150, 164))	('EGFR', 'Gene', (88, 92))	('EGFR', 'Gene', '1956', (165, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
25320	22591401	In cholangiocarcinoma cell types resembling RBE, up-regulation of EGFR Tyr1045 phosphorylation may be a potentially useful molecular alteration in EGFR-targeted therapy.	('cholangiocarcinoma', 'Disease', (3, 21))	('Tyr1045', 'Var', (71, 78))	('EGFR', 'Gene', (147, 151))	('up-regulation', 'PosReg', (49, 62))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('Tyr1045', 'Chemical', '-', (71, 78))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('EGFR', 'Gene', '1956', (147, 151))
25323	32629723	An unusual complication of pyloric ring obstruction caused by flange of lumen apposing metal stent in endoscopic ultrasound-guided gallbladder drainage Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) is an alternative treatment option for patients with acute cholecystitis, especially for those who are unsuitable for cholecystectomy.	('flange', 'Var', (62, 68))	('obstruction', 'Disease', 'MESH:D000402', (40, 51))	('acute cholecystitis', 'Disease', 'MESH:D041881', (265, 284))	('cholecystitis', 'Phenotype', 'HP:0001082', (271, 284))	('obstruction', 'Disease', (40, 51))	('patients', 'Species', '9606', (251, 259))	('acute cholecystitis', 'Disease', (265, 284))
25329	32629723	Intrahepatic cholangiocarcinoma with multiple lung and intrahepatic metastasis, acute cholecystitis, and pyloric ring obstruction caused by flange of LAMS in EUS-GBD.	('acute cholecystitis', 'Disease', (80, 99))	('flange', 'Var', (140, 146))	('Intrahepatic cholangiocarcinoma', 'Disease', (0, 31))	('obstruction', 'Disease', 'MESH:D000402', (118, 129))	('Intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 31))	('cholecystitis', 'Phenotype', 'HP:0001082', (86, 99))	('obstruction', 'Disease', (118, 129))	('caused by', 'Reg', (130, 139))	('acute cholecystitis', 'Disease', 'MESH:D041881', (80, 99))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (13, 31))	('LAMS', 'Chemical', '-', (150, 154))	('intrahepatic metastasis', 'Disease', (55, 78))	('intrahepatic metastasis', 'Disease', 'MESH:D009362', (55, 78))
25362	32629723	A complete gastric outlet obstruction by the flange of LAMS was noted on EGD (Fig.	('gastric outlet obstruction', 'Disease', (11, 37))	('gastric outlet obstruction', 'Disease', 'MESH:D017219', (11, 37))	('flange', 'Var', (45, 51))	('LAMS', 'Chemical', '-', (55, 59))
25373	32629723	Also, PTGBD can cause postoperative pain in about 12% of patients and multiple additional interventions might be needed for catheter obstruction or migration.	('postoperative pain', 'Disease', (22, 40))	('patients', 'Species', '9606', (57, 65))	('obstruction', 'Disease', 'MESH:D000402', (133, 144))	('pain', 'Phenotype', 'HP:0012531', (36, 40))	('postoperative pain', 'Disease', 'MESH:D010149', (22, 40))	('PTGBD', 'Var', (6, 11))	('obstruction', 'Disease', (133, 144))	('cause', 'Reg', (16, 21))
25387	32629723	However, after complete deployment of stent, esophagogastroduodenoscopy showed complete gastric outlet obstruction by flange of LAMS.	('LAMS', 'Chemical', '-', (128, 132))	('gastric outlet obstruction', 'Disease', (88, 114))	('flange', 'Var', (118, 124))	('gastric outlet obstruction', 'Disease', 'MESH:D017219', (88, 114))
25393	32629723	The strong shortening of the bilateral flange also made it less likely for food to pass by the LAMS flange.	('LAMS', 'Chemical', '-', (95, 99))	('less likely', 'NegReg', (59, 70))	('shortening', 'Var', (11, 21))
25419	25655565	In addition, while biliary excretion of Gd-EOB-DTPA is known to provide positive T1-weighted intrabiliary contrast imaging, only a few studies have evaluated MR cholangiography with Gd-EOB-DTPA.	('biliary excretion', 'MPA', (19, 36))	('Gd-EOB-DTPA', 'Chemical', 'MESH:C073590', (40, 51))	('Gd-EOB-DTPA', 'Var', (40, 51))	('Gd-EOB-DTPA', 'Chemical', 'MESH:C073590', (182, 193))	('T1-weighted intrabiliary contrast imaging', 'MPA', (81, 122))
25447	25655565	On T2WI, the tumors were hyperintense relative to normal livers (Figure 1a, and Figure 2a, b) in 15 of 25 (60%) patients, hypointense in three patients (12%) (Figure 3a), and had mixed intensity in seven patients (28%).	('patients', 'Species', '9606', (204, 212))	('hypointense', 'Var', (122, 133))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('patients', 'Species', '9606', (112, 120))	('patients', 'Species', '9606', (143, 151))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
25460	25655565	Its characteristics include hypointensity on T1-weighted images, hyperintensity on T2-weighted images, the presence or absence of a central scar, ductal dilatation, satellite nodules, portal vein invasion, and lobar atrophy.	('portal vein invasion', 'CPA', (184, 204))	('hyperintensity', 'MPA', (65, 79))	('dilatation', 'Phenotype', 'HP:0002617', (153, 163))	('satellite nodules', 'CPA', (165, 182))	('atrophy', 'Disease', 'MESH:D001284', (216, 223))	('ductal dilatation', 'CPA', (146, 163))	('hypointensity', 'Var', (28, 41))	('atrophy', 'Disease', (216, 223))	('scar', 'Phenotype', 'HP:0100699', (140, 144))
25512	33233485	Fox and coworkers were the first to speculate that H. pylori also can cause hepatobiliary diseases in humans.	('hepatobiliary diseases', 'Disease', (76, 98))	('cause', 'Reg', (70, 75))	('H. pylori', 'Species', '210', (51, 60))	('humans', 'Species', '9606', (102, 108))	('H. pylori', 'Var', (51, 60))
25515	33233485	Among these, in vitro studies revealed that H. pylori induces multiple effects in CCA cell lines, including inflammation (IL-8 production), cell proliferation, and apoptosis.	('cell proliferation', 'CPA', (140, 158))	('CCA', 'Phenotype', 'HP:0030153', (82, 85))	('inflammation', 'Disease', (108, 120))	('H. pylori', 'Species', '210', (44, 53))	('IL-8', 'Gene', '3576', (122, 126))	('IL-8', 'Gene', (122, 126))	('apoptosis', 'CPA', (164, 173))	('H. pylori', 'Var', (44, 53))	('inflammation', 'Disease', 'MESH:D007249', (108, 120))
25521	33233485	Here, we investigated interactions between the NCTC 11637 strain of H. pylori, the related species H. bilis, and the human cholangiocyte.	('NCTC 11637', 'Var', (47, 57))	('interactions', 'Interaction', (22, 34))	('human', 'Species', '9606', (117, 122))	('H. pylori', 'Species', '210', (68, 77))	('H. bilis', 'Species', '37372', (99, 107))	('investigated', 'Reg', (9, 21))
25530	33233485	The regulatory transcriptional factor, Snail was markedly up-regulated with the highest level of fold difference, namely, 88-, 656-, and 5309-fold at an MOI of 10, 50, and 100, respectively, followed by MMP7, with 15-, 21-, and 44-fold at an MOI of 10, 50, and 100, respectively.	('Snail', 'Gene', (39, 44))	('up-regulated', 'PosReg', (58, 70))	('MOI', 'Var', (153, 156))	('MMP7', 'Gene', (203, 207))	('MMP7', 'Gene', '4316', (203, 207))	('Snail', 'Gene', '6615', (39, 44))
25536	33233485	At an MOI of 1, 10, and 50, H. pylori stimulated significantly more migration of CC-LP-1 cells from 20 to 40 h after starting the assay (Figure 3B).	('CC-LP-1', 'Gene', (81, 88))	('H. pylori', 'Species', '210', (28, 37))	('CC-LP-1', 'Gene', '8495', (81, 88))	('more', 'PosReg', (63, 67))	('H. pylori', 'Var', (28, 37))	('migration', 'CPA', (68, 77))
25538	33233485	In addition, scratch assays revealed two-dimensional migration of H69 cells over 24 h. Wound closure by H69 cells increased significantly to 19.47% at MOI of 10 (p <= 0.05) although an effect at an MOI of 100 was not apparent in comparison with the control group (Figure 4).	('Wound closure', 'CPA', (87, 100))	('increased', 'PosReg', (114, 123))	('MOI of 10', 'Var', (151, 160))	('H69', 'Gene', (104, 107))	('H69', 'Chemical', '-', (66, 69))	('H69', 'Chemical', '-', (104, 107))
25541	33233485	The size of colonies also increased in all groups exposed to H. pylori, although this was statistically significant only at an MOI of 50 (Figure S2; p <= 0.05).	('H. pylori', 'Species', '210', (61, 70))	('colonies', 'CPA', (12, 20))	('increased', 'PosReg', (26, 35))	('H. pylori', 'Var', (61, 70))
25556	33233485	Here, H69 cells exposed to H. pylori exhibited an up-regulation of the expression of Snail, Slug, vimentin, JAM1, and MMP7 in a dose-dependent fashion, changes that strongly supported the EMT of this informative cholangiocyte cell line.	('MMP7', 'Gene', (118, 122))	('H. pylori', 'Var', (27, 36))	('expression', 'MPA', (71, 81))	('Slug', 'Gene', (92, 96))	('JAM1', 'Gene', '50848', (108, 112))	('MMP7', 'Gene', '4316', (118, 122))	('up-regulation', 'PosReg', (50, 63))	('Snail', 'Gene', (85, 90))	('Snail', 'Gene', '6615', (85, 90))	('H. pylori', 'Species', '210', (27, 36))	('vimentin', 'Gene', '7431', (98, 106))	('Slug', 'Gene', '6591', (92, 96))	('H69', 'Chemical', '-', (6, 9))	('vimentin', 'Gene', (98, 106))	('JAM1', 'Gene', (108, 112))
25567	33233485	Overall, the pro-carcinogenic changes induced by H. pylori but not by H. bilis were not unexpected, given that H. pylori is a biological carcinogen, even though H. bilis colonized the intestines and hepatobiliary tract, and has been associated with hepatobiliary disease including multifocal chronic hepatitis and biliary tract malignancies.	('H. pylori', 'Var', (111, 120))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (292, 309))	('H. bilis', 'Species', '37372', (161, 169))	('hepatitis', 'Phenotype', 'HP:0012115', (300, 309))	('associated with', 'Reg', (233, 248))	('H. pylori', 'Species', '210', (111, 120))	('multifocal chronic hepatitis and biliary tract malignancies', 'Disease', 'MESH:D001661', (281, 340))	('hepatobiliary disease', 'Disease', (249, 270))	('H. bilis', 'Species', '37372', (70, 78))	('H. pylori', 'Species', '210', (49, 58))	('H. bilis', 'Var', (161, 169))
25590	33233485	Moreover, to confirm that the CagA virulence factor of H. pylori strain NCTC 11637 induced the elongate, hummingbird-like appearance of the H69 cholangiocyte, a demonstration that H69 cells could also be infected by another CagA positive H. pylori, and that the cagPAI cag pathogenicity island encoded type IV secretory system was functional and active during the infection, as established by detection of phosphorylated CagA, would be required.	('infected', 'Disease', (204, 212))	('infection', 'Disease', (364, 373))	('CagA', 'Gene', (30, 34))	('infected', 'Disease', 'MESH:D007239', (204, 212))	('infection', 'Disease', 'MESH:D007239', (364, 373))	('CagA', 'Gene', (224, 228))	('CagA', 'Gene', '6279', (30, 34))	('elongate', 'CPA', (95, 103))	('NCTC 11637', 'Var', (72, 82))	('CagA', 'Gene', '6279', (224, 228))	('H69', 'Chemical', '-', (140, 143))	('CagA', 'Gene', (421, 425))	('H. pylori', 'Species', '210', (55, 64))	('CagA', 'Gene', '6279', (421, 425))	('H. pylori', 'Species', '210', (238, 247))	('H. pylori strain NCT', 'Species', '102618', (55, 75))	('H69', 'Chemical', '-', (180, 183))
25689	33194090	Interestingly, exosome-derived miR-205 from human CCA cell lines was found to be overexpressed, and knockdown of miR-205-5p expression repressed migration and invasion in CCA cell lines.	('human', 'Species', '9606', (44, 49))	('knockdown', 'Var', (100, 109))	('rat', 'Species', '10116', (148, 151))	('repressed', 'NegReg', (135, 144))	('miR-205', 'Gene', (113, 120))	('miR-205', 'Gene', '406988', (113, 120))	('invasion', 'CPA', (159, 167))	('miR-205', 'Gene', (31, 38))	('miR-205', 'Gene', '406988', (31, 38))
25692	33194090	Furthermore, a panel of five miRNAs (miR-191, miR-486-3p, miR-1274b, miR-16 and miR-484) were upregulated in bile EVs from CCA patients vs a control group of patients suffering from PSC, biliary obstruction and bile leak.	('miR-191', 'Gene', (37, 44))	('miR-1274b', 'Var', (58, 67))	('biliary obstruction', 'Disease', (187, 206))	('miR-484', 'Gene', (80, 87))	('miR-486-3p', 'Var', (46, 56))	('miR-16', 'Gene', (69, 75))	('miR-16', 'Gene', '51573', (69, 75))	('CCA', 'Disease', (123, 126))	('bile EV', 'Chemical', '-', (109, 116))	('upregulated', 'PosReg', (94, 105))	('patients', 'Species', '9606', (127, 135))	('PSC', 'Disease', (182, 185))	('miR-484', 'Gene', '619553', (80, 87))	('patients', 'Species', '9606', (158, 166))	('biliary obstruction', 'Phenotype', 'HP:0005230', (187, 206))	('miR-191', 'Gene', '406966', (37, 44))	('biliary obstruction', 'Disease', 'MESH:D001657', (187, 206))
25699	33194090	It is worth noting that miR-551b-3p expression in cancer varies in the literature.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('rat', 'Species', '10116', (75, 78))	('miR-551b-3p', 'Var', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('miR-551b-3p', 'Chemical', '-', (24, 35))
25700	33194090	For instance, miR-551b-3p upregulation has been reported in papillary thyroid carcinoma and ovarian cancer, whereas gastric cancer has been associated with miR-551b-3p downregulation.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (70, 87))	('miR-551b-3p', 'Chemical', '-', (14, 25))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (60, 87))	('miR-551b-3p', 'Chemical', '-', (156, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('miR-551b-3p', 'Var', (14, 25))	('gastric cancer', 'Disease', (116, 130))	('papillary thyroid carcinoma and ovarian cancer', 'Disease', 'MESH:D010051', (60, 106))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('gastric cancer', 'Disease', 'MESH:D013274', (116, 130))	('upregulation', 'PosReg', (26, 38))	('ovarian cancer', 'Phenotype', 'HP:0100615', (92, 106))	('miR-551b-3p', 'Var', (156, 167))	('gastric cancer', 'Phenotype', 'HP:0012126', (116, 130))
25701	33194090	Therefore, further research may be required in order to investigate the expression and functional roles of miR-551b-3p in CCA.	('miR-551b-3p', 'Chemical', '-', (107, 118))	('miR-551b-3p', 'Var', (107, 118))	('CCA', 'Disease', (122, 125))
25702	33194090	Recently, four miRNAs (miR-96-5p, miR-151a-5p, miR-191-5p and miR-4732-3p) were found to be significantly overexpressed in blood-derived exosomes of CCA patients, and exosomal miR-9-5p was proposed as a potential prognostic biomarker for intrahepatic cholangiocarcinoma.	('CCA', 'Disease', (149, 152))	('miR-4732-3p', 'Var', (62, 73))	('miR-191', 'Gene', (47, 54))	('patients', 'Species', '9606', (153, 161))	('miR-96', 'Gene', '407053', (23, 29))	('miR-96', 'Gene', (23, 29))	('miR-151a', 'Gene', '442893', (34, 42))	('miR-151a', 'Gene', (34, 42))	('miR-9-5p', 'Gene', (176, 184))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (238, 269))	('miR-9-5p', 'Gene', '407052', (176, 184))	('intrahepatic cholangiocarcinoma', 'Disease', (238, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (251, 269))	('miR-191', 'Gene', '406966', (47, 54))	('overexpressed', 'PosReg', (106, 119))
25711	33194090	Ge et al, reported that two lncRNAs (ENST00000588480.1 and ENST00000517758.1) were significantly upregulated in exosomes isolated from bile samples of CCA and benign biliary obstruction patients.	('ENST00000517758.1', 'Var', (59, 76))	('ncRNA', 'Gene', (29, 34))	('ncRNA', 'Gene', '54719', (29, 34))	('benign biliary obstruction', 'Disease', 'MESH:D001657', (159, 185))	('biliary obstruction', 'Phenotype', 'HP:0005230', (166, 185))	('CCA', 'Disease', (151, 154))	('upregulated', 'PosReg', (97, 108))	('benign biliary obstruction', 'Disease', (159, 185))	('patients', 'Species', '9606', (186, 194))
25714	33194090	More specifically, the expression of three lncRNAs (MALAT-1, LOC643955 and LOC100190986) was significantly altered in serum EVs from CCA patients compared to patients with PSC.	('MALAT-1', 'Gene', (52, 59))	('LOC100190986', 'Var', (75, 87))	('ncRNA', 'Gene', (44, 49))	('patients', 'Species', '9606', (137, 145))	('CCA', 'Disease', (133, 136))	('altered', 'Reg', (107, 114))	('ncRNA', 'Gene', '54719', (44, 49))	('MALAT-1', 'Gene', '378938', (52, 59))	('patients', 'Species', '9606', (158, 166))	('LOC643955', 'Var', (61, 70))	('expression', 'MPA', (23, 33))
25717	33194090	Furthermore, Shi et al reported the aberrant expression of three lncRNAs (including MALAT-1) in plasma samples from hilar cholangiocarcinoma patients, suggesting that they may serve as candidate biomarkers for the early detection of hilar cholangiocarcinoma.	('MALAT-1', 'Gene', '378938', (84, 91))	('ncRNA', 'Gene', '54719', (66, 71))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (122, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('cholangiocarcinoma', 'Disease', (239, 257))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (239, 257))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (239, 257))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (122, 140))	('MALAT-1', 'Gene', (84, 91))	('expression', 'MPA', (45, 55))	('aberrant', 'Var', (36, 44))	('ncRNA', 'Gene', (66, 71))	('cholangiocarcinoma', 'Disease', (122, 140))	('patients', 'Species', '9606', (141, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
25718	33194090	Similarly, three lncRNAs (LOC100134868, HLA complex group 4 and LOC100134713) were differentially expressed in urine EVs from CCA patients compared to patients with PSC.	('ncRNA', 'Gene', '54719', (18, 23))	('LOC100134868', 'Var', (26, 38))	('patients', 'Species', '9606', (151, 159))	('patients', 'Species', '9606', (130, 138))	('ncRNA', 'Gene', (18, 23))	('CCA', 'Disease', (126, 129))	('LOC100134713', 'Var', (64, 76))
25729	33194090	The authors also supported that high Cdr1as expression was associated with poor overall survival, highlighting the potential role of this circRNA as a prognostic biomarker.	('high', 'Var', (32, 36))	('expression', 'MPA', (44, 54))	('overall survival', 'MPA', (80, 96))	('Cdr1', 'Gene', '1038', (37, 41))	('poor', 'NegReg', (75, 79))	('Cdr1', 'Gene', (37, 41))
25730	33194090	Another study found that hsa_circ_0001649 was downregulated in CCA tissues, and it was associated with tumor size and grade.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('associated', 'Reg', (87, 97))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('downregulated', 'NegReg', (46, 59))	('CCA', 'Disease', (63, 66))	('hsa_circ_0001649', 'Var', (25, 41))
25734	33194090	Finally, Xu et al proposed that circ_0005230 inhibited cell apoptosis and promoted cell proliferation and metastasis in CCA cells.	('promoted', 'PosReg', (74, 82))	('inhibited', 'NegReg', (45, 54))	('rat', 'Species', '10116', (95, 98))	('cell proliferation', 'CPA', (83, 101))	('CCA', 'Disease', (120, 123))	('circ_0005230', 'Var', (32, 44))	('cell apoptosis', 'CPA', (55, 69))
25736	33194090	According to Wang et al, circRNA 0000284 was found to be significantly upregulated in CCA cell lines, tumor tissues and plasma exosomes.	('circRNA 0000284', 'Var', (25, 40))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('CCA', 'Disease', (86, 89))	('upregulated', 'PosReg', (71, 82))
25744	33194090	More importantly, the authors suggested that piR-10506469 was significantly overexpressed in plasma-derived exosomes from CCA patients and that piR-10506469 and piR-20548188 were significantly downregulated after surgery, suggesting that these piRNAs may serve as potential diagnostic and prognostic biomarkers.	('downregulated', 'NegReg', (193, 206))	('overexpressed', 'PosReg', (76, 89))	('piR-10506469', 'Var', (45, 57))	('piR-10506469', 'Var', (144, 156))	('patients', 'Species', '9606', (126, 134))	('CCA', 'Disease', (122, 125))	('piR-20548188', 'Var', (161, 173))
25745	33194090	For instance, epigenetic silencing of tumor suppressor miR-370 in human CCA has been linked to hypermethylation of its promoter by IL-6-dependent overexpression of DNA methyltransferases.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('CCA', 'Disease', (72, 75))	('miR-370', 'Gene', (55, 62))	('IL-6', 'Gene', (131, 135))	('hypermethylation', 'MPA', (95, 111))	('epigenetic silencing', 'Var', (14, 34))	('IL-6', 'Gene', '3569', (131, 135))	('human', 'Species', '9606', (66, 71))	('promoter', 'MPA', (119, 127))	('tumor suppressor', 'Gene', (38, 54))	('linked', 'Reg', (85, 91))	('miR-370', 'Gene', '442915', (55, 62))	('tumor suppressor', 'Gene', '7248', (38, 54))
25747	33194090	Furthermore, CpG island hypermethylation of miR-373 resulted in miR-373 downregulation in hilar cholangiocarcinoma.	('hypermethylation', 'Var', (24, 40))	('miR-373', 'Gene', '442918', (44, 51))	('miR-373', 'Gene', '442918', (64, 71))	('cholangiocarcinoma', 'Disease', (96, 114))	('miR-373', 'Gene', (44, 51))	('miR-373', 'Gene', (64, 71))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))	('downregulation', 'NegReg', (72, 86))
25755	33194090	The hypomethylated status of the miR-429 promoter has been correlated with increased miR-429 expression in CCA.	('CCA', 'Disease', (107, 110))	('miR-429', 'Gene', (33, 40))	('miR-429', 'Gene', (85, 92))	('hypomethylated status', 'Var', (4, 25))	('expression', 'MPA', (93, 103))	('miR-429', 'Gene', '554210', (33, 40))	('increased', 'PosReg', (75, 84))	('miR-429', 'Gene', '554210', (85, 92))
25756	33194090	Goeppert et al demonstrated that epigenetically dysregulated miR-429 directly targeted cadherin-6 and promoted tumor growth.	('miR-429', 'Gene', '554210', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('promoted', 'PosReg', (102, 110))	('rat', 'Species', '10116', (22, 25))	('miR-429', 'Gene', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('cadherin-6', 'Gene', (87, 97))	('cadherin-6', 'Gene', '1004', (87, 97))	('targeted', 'Reg', (78, 86))	('epigenetically dysregulated', 'Var', (33, 60))
25758	33194090	LncRNA SMARCC2 acts as a "sponge" RNA promoting the aberrant miR-551b-3p expression in gastric cancer.	('promoting', 'PosReg', (38, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('SMARCC2', 'Gene', (7, 14))	('SMARCC2', 'Gene', '6601', (7, 14))	('ncRNA', 'Gene', '54719', (1, 6))	('miR-551b-3p', 'Chemical', '-', (61, 72))	('miR-551b-3p', 'Gene', (61, 72))	('aberrant', 'Var', (52, 60))	('gastric cancer', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ncRNA', 'Gene', (1, 6))
25759	33194090	On the other hand, Chang et al demonstrated that miR-551b-3p directly targeted and decreased CCND1 expression, inhibiting CCA cell cycle progression and proliferation.	('expression', 'MPA', (99, 109))	('rat', 'Species', '10116', (160, 163))	('CCND1', 'Gene', '595', (93, 98))	('decreased', 'NegReg', (83, 92))	('miR-551b-3p', 'Var', (49, 60))	('proliferation', 'CPA', (153, 166))	('inhibiting', 'NegReg', (111, 121))	('CCA', 'Disease', (122, 125))	('rat', 'Species', '10116', (38, 41))	('CCND1', 'Gene', (93, 98))	('miR-551b-3p', 'Chemical', '-', (49, 60))
25760	33194090	miR-551b downregulation in breast cancer patients was associated with hypermethylation of its promoter.	('downregulation', 'NegReg', (9, 23))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('miR-551b', 'Gene', (0, 8))	('miR-551b', 'Gene', '693136', (0, 8))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('hypermethylation', 'Var', (70, 86))	('breast cancer', 'Disease', (27, 40))	('patients', 'Species', '9606', (41, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))
25768	33194090	KEGG pathway analysis revealed that several CCA-associated, exosomal miRNA (miR-96-5p, miR-151a-5p, miR-191-5p and miR-4732-3p) target genes were enriched in the MAPK signaling pathway, suggesting their role in the process of neurogenesis.	('CCA-associated', 'Disease', (44, 58))	('miR-191', 'Gene', '406966', (100, 107))	('MAPK', 'Gene', '5594', (162, 166))	('miR-96', 'Gene', '407053', (76, 82))	('MAPK', 'Gene', (162, 166))	('miR-4732-3p', 'Var', (115, 126))	('miR-191', 'Gene', (100, 107))	('miR-151a', 'Gene', '442893', (87, 95))	('miR-151a', 'Gene', (87, 95))	('miR-96', 'Gene', (76, 82))
25781	33194090	The lncRNAs, ENST00000588480.1 and ENST00000517758.1 have been associated with promoting CCA development via the p53 signaling pathway.	('promoting', 'PosReg', (79, 88))	('ncRNA', 'Gene', (5, 10))	('ENST00000517758.1', 'Var', (35, 52))	('ncRNA', 'Gene', '54719', (5, 10))	('CCA', 'Disease', (89, 92))	('p53', 'Gene', '7157', (113, 116))	('p53', 'Gene', (113, 116))	('ENST00000588480.1', 'Var', (13, 30))
25783	33194090	The oncogenic role of circ_0005230 in CCA was first described by Xu et al, who proposed its role as a ceRNA by sponging miR-1238 and miR-1299.	('miR-1238', 'Gene', (120, 128))	('miR-1299', 'Gene', (133, 141))	('miR-1238', 'Gene', '100302226', (120, 128))	('circ_0005230', 'Var', (22, 34))	('miR-1299', 'Gene', '100302167', (133, 141))	('CCA', 'Disease', (38, 41))
25784	33194090	Circ_0005230 was previously associated with an unfavorable prognosis of breast cancer patients; reportedly, it can act as a miR-618 sponge and thus enhance CBX8 expression.	('CBX8', 'Gene', (156, 160))	('miR-618', 'Gene', '693203', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('expression', 'MPA', (161, 171))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('miR-618', 'Gene', (124, 131))	('Circ_0005230', 'Var', (0, 12))	('enhance', 'PosReg', (148, 155))	('breast cancer', 'Disease', (72, 85))	('CBX8', 'Gene', '57332', (156, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('patients', 'Species', '9606', (86, 94))
25785	33194090	Increasing evidence supports the role of hsa_circ_0001649 as a tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor suppressor', 'Gene', (63, 79))	('hsa_circ_0001649', 'Var', (41, 57))	('tumor suppressor', 'Gene', '7248', (63, 79))
25788	33194090	Matrix metalloproteinase-9 was significantly regulated by hsa_circ_0001649 expression in CCA cells.	('Matrix metalloproteinase-9', 'Gene', (0, 26))	('regulated', 'Reg', (45, 54))	('Matrix metalloproteinase-9', 'Gene', '4318', (0, 26))	('hsa_circ_0001649 expression', 'Var', (58, 85))
25789	33194090	Concerning exosomal circRNAs in CCA, circ-0000284 was identified as a ceRNA, directly binding to miRNA-637 and thus stimulating LY6E expression.	('LY6E', 'Gene', (128, 132))	('LY6E', 'Gene', '4061', (128, 132))	('stimulating', 'PosReg', (116, 127))	('binding', 'Interaction', (86, 93))	('circ-0000284', 'Var', (37, 49))
25791	33194090	YY1 is a transcription factor and gene target of miR-514a-5p.	('YY1', 'Gene', '7528', (0, 3))	('miR-514a-5p', 'Var', (49, 60))	('YY1', 'Gene', (0, 3))
25825	33194090	Indeed, an increasing number of studies have proposed EV modification towards enhancing targeted drug delivery and anticancer efficacy.	('enhancing', 'PosReg', (78, 87))	('modification', 'Var', (57, 69))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('targeted drug delivery', 'MPA', (88, 110))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
25836	32293336	Distinct clinical and prognostic implication of IDH1/2 mutation and other most frequent mutations in large duct and small duct subtypes of intrahepatic cholangiocarcinoma Isocitrate dehydrogenase 1/2 (IDH1/2), BAP1, ARID1A and PBRM1 have been reported as the most frequent mutant genes in intrahepatic cholangiocarcinoma (ICC), and their relationships with clinicopathological features and prognosis were researched in this study.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (139, 170))	('intrahepatic cholangiocarcinoma', 'Disease', (139, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (311, 320))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (289, 320))	('ARID1A', 'Gene', (216, 222))	('intrahepatic cholangiocarcinoma', 'Disease', (289, 320))	('BAP1', 'Gene', '8314', (210, 214))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (302, 320))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (152, 170))	('ARID1A', 'Gene', '8289', (216, 222))	('IDH1/2', 'Gene', '3417;3418', (201, 207))	('mutation', 'Var', (55, 63))	('PBRM1', 'Gene', '55193', (227, 232))	('IDH1/2', 'Gene', (201, 207))	('BAP1', 'Gene', (210, 214))	('IDH1/2', 'Gene', '3417;3418', (48, 54))	('PBRM1', 'Gene', (227, 232))	('IDH1/2', 'Gene', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))
25838	32293336	The IDH1/2 mutation and loss of BAP1, ARID1A and PBRM1 expressions were detected by DNA sequencing or immunohistochemical methods, and histological subtype of ICCs was determined by hematoxylin-eosin, Alcian blue and S100P staining.	('S100P', 'Gene', (217, 222))	('ARID1A', 'Gene', '8289', (38, 44))	('ARID1A', 'Gene', (38, 44))	('hematoxylin', 'Chemical', 'MESH:D006416', (182, 193))	('Alcian blue', 'Chemical', 'MESH:D000423', (201, 212))	('BAP1', 'Gene', '8314', (32, 36))	('eosin', 'Chemical', 'MESH:D004801', (194, 199))	('IDH1/2', 'Gene', '3417;3418', (4, 10))	('BAP1', 'Gene', (32, 36))	('PBRM1', 'Gene', (49, 54))	('IDH1/2', 'Gene', (4, 10))	('mutation', 'Var', (11, 19))	('PBRM1', 'Gene', '55193', (49, 54))	('S100P', 'Gene', '6286', (217, 222))	('loss', 'NegReg', (24, 28))
25839	32293336	IDH1/2 mutation was related to decreased preoperative serum total bilirubin (P = 0.039), ferritin (P = 0.000) and higher histological differentiation (P = 0.024), and was associated with prolonged disease-free survival (P = 0.009) and a trend toward increased overall survival (P = 0.126) in small duct type of ICCs.	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('bilirubin', 'Chemical', 'MESH:D001663', (66, 75))	('small duct type of ICCs', 'Disease', (292, 315))	('ferritin', 'MPA', (89, 97))	('serum total bilirubin', 'MPA', (54, 75))	('decreased', 'NegReg', (31, 40))	('mutation', 'Var', (7, 15))	('histological differentiation', 'CPA', (121, 149))	('disease-free', 'CPA', (197, 209))	('increased', 'PosReg', (250, 259))	('prolonged', 'PosReg', (187, 196))	('IDH1/2', 'Gene', (0, 6))	('higher', 'PosReg', (114, 120))
25840	32293336	Immunohistochemical staining results of MsMab-1 were generally consistent with DNA sequencing for IDH1/2 mutant in ICCs (kappa = 0.691).	('IDH1/2', 'Gene', '3417;3418', (98, 104))	('mutant', 'Var', (105, 111))	('IDH1/2', 'Gene', (98, 104))
25842	32293336	IDH1/2 mutation is a favorable predictor and may be related to iron metabolism in small duct type of ICCs.	('iron', 'Chemical', 'MESH:D007501', (63, 67))	('small duct type of ICCs', 'Disease', (82, 105))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('mutation', 'Var', (7, 15))	('IDH1/2', 'Gene', (0, 6))	('related', 'Reg', (52, 59))
25843	32293336	Furthermore, we suggest that the detection of IDH1/2 mutation is indispensable to determine targeted therapy in small duct type ICCs, while it is not necessary in large duct of ICCs.	('IDH1/2', 'Gene', (46, 52))	('mutation', 'Var', (53, 61))	('IDH1/2', 'Gene', '3417;3418', (46, 52))	('small duct type ICCs', 'Disease', (112, 132))
25844	32293336	MsMab-1 is a relatively effective multi-specific antibody against IDH1/2 mutant in ICCs.	('IDH1/2', 'Gene', (66, 72))	('mutant', 'Var', (73, 79))	('IDH1/2', 'Gene', '3417;3418', (66, 72))	('ICCs', 'Disease', (83, 87))
25848	32293336	With the application of next-generation sequencing technology, many frequent genetic mutations have been discovered in ICCs, such as isocitrate dehydrogenase 1/2 (IDH1/2), KRAS, BAP1, ARID1A, PBRM1 and FGFR2-fusion.	('KRAS', 'Gene', (172, 176))	('BAP1', 'Gene', '8314', (178, 182))	('FGFR2', 'Gene', (202, 207))	('KRAS', 'Gene', '3845', (172, 176))	('FGFR2', 'Gene', '2263', (202, 207))	('PBRM1', 'Gene', (192, 197))	('BAP1', 'Gene', (178, 182))	('ARID1A', 'Gene', '8289', (184, 190))	('IDH1/2', 'Gene', '3417;3418', (163, 169))	('mutations', 'Var', (85, 94))	('ARID1A', 'Gene', (184, 190))	('PBRM1', 'Gene', '55193', (192, 197))	('IDH1/2', 'Gene', (163, 169))	('isocitrate', 'Chemical', 'MESH:C034219', (133, 143))
25850	32293336	For example, large duct type ICC representatively lacks IDH1/2 mutation and FGFR2-fusion, characteristics exclusively seen in small duct ICC.	('lacks', 'NegReg', (50, 55))	('FGFR2', 'Gene', (76, 81))	('IDH1/2', 'Gene', '3417;3418', (56, 62))	('mutation', 'Var', (63, 71))	('FGFR2', 'Gene', '2263', (76, 81))	('large duct type ICC', 'Disease', (13, 32))	('IDH1/2', 'Gene', (56, 62))
25853	32293336	IDH1/2 mutations have been detected in many human cancers, including glioma, chondrosarcoma, acute myeloid leukemia, and cholangiocarcinoma.	('glioma', 'Disease', (69, 75))	('human', 'Species', '9606', (44, 49))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))	('acute myeloid leukemia', 'Disease', (93, 115))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('IDH1/2', 'Gene', (0, 6))	('detected', 'Reg', (27, 35))	('cholangiocarcinoma', 'Disease', (121, 139))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (121, 139))	('chondrosarcoma', 'Disease', (77, 91))	('chondrosarcoma', 'Disease', 'MESH:D002813', (77, 91))	('mutations', 'Var', (7, 16))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (93, 115))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (99, 115))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (93, 115))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (77, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))
25855	32293336	2-HG accumulation may inhibit specific alpha-KG dependent dioxygenases and participate in tumorigenesis involving cell signaling, extracellular matrix maturation, and epigenetic regulation.	('alpha-KG', 'Chemical', 'MESH:D007656', (39, 47))	('2-HG', 'Chemical', 'MESH:C019417', (0, 4))	('inhibit', 'NegReg', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('participate', 'Reg', (75, 86))	('epigenetic', 'Var', (167, 177))	('alpha-KG dependent dioxygenases', 'Enzyme', (39, 70))	('cell signaling', 'MPA', (114, 128))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
25858	32293336	Due to the diversity of mutational hot-spots and the large scales of these genes, detection of these mutations is relatively difficult compared with IDH or KRAS.	('mutations', 'Var', (101, 110))	('IDH', 'Gene', (149, 152))	('KRAS', 'Gene', (156, 160))	('IDH', 'Gene', '3417', (149, 152))	('KRAS', 'Gene', '3845', (156, 160))
25881	32293336	IDH1/2 mutant exhibited cytoplasmic and mild nuclear expression, while only nuclear staining was interpreted as immunopositive in the evaluation of BAP1, ARID1A, and PBRM1 expression (Figs.	('exhibited', 'Reg', (14, 23))	('ARID1A', 'Gene', '8289', (154, 160))	('mutant', 'Var', (7, 13))	('ARID1A', 'Gene', (154, 160))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('BAP1', 'Gene', '8314', (148, 152))	('BAP1', 'Gene', (148, 152))	('PBRM1', 'Gene', (166, 171))	('PBRM1', 'Gene', '55193', (166, 171))	('IDH1/2', 'Gene', (0, 6))
25882	32293336	Two pairs of primers were designed for hotspot mutations of IDH1/2.	('IDH1/2', 'Gene', (60, 66))	('IDH1/2', 'Gene', '3417;3418', (60, 66))	('mutations', 'Var', (47, 56))
25884	32293336	The target DNA sequences were amplified by polymerase chain reaction using the primers above, and were further sequenced and analyzed for IDH1/2 mutation.	('IDH1/2', 'Gene', '3417;3418', (138, 144))	('IDH1/2', 'Gene', (138, 144))	('mutation', 'Var', (145, 153))
25891	32293336	The large duct type was more likely to have higher level of CA19-9 (P = 0.002), higher frequencies of lymphadenectomy (P = 0.002), nerve invasion (P = 0.025), satellite lesions (P = 0.009), smaller size of tumor (P = 0.021) and more aggressive tumor stage of pT (P = 0.041), pM (P = 0.019), and TNM classification (P = 0.04) than small duct type (Supplementary Table S3).	('aggressive tumor', 'Disease', 'MESH:D001523', (233, 249))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('satellite lesions', 'CPA', (159, 176))	('tumor', 'Disease', (244, 249))	('CA19-9', 'Var', (60, 66))	('tumor', 'Disease', (206, 211))	('higher', 'PosReg', (44, 50))	('nerve invasion', 'CPA', (131, 145))	('aggressive tumor', 'Disease', (233, 249))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('TNM', 'Gene', (295, 298))	('CA19-9', 'Chemical', 'MESH:C086528', (60, 66))	('TNM', 'Gene', '10178', (295, 298))	('lymphadenectomy', 'CPA', (102, 117))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('higher', 'PosReg', (80, 86))
25896	32293336	IHC analysis verified the specificity of MsMab-1 according to results detected by DNA sequencing, and showed that sensitivity and specificity of MsMab-1 to detect specific types of IDH1/2 mutation were 81.8% (9 of 11) and 95.8% (114 of 119), respectively.	('mutation', 'Var', (188, 196))	('MsMab-1', 'Gene', (145, 152))	('IDH1/2', 'Gene', (181, 187))	('IDH1/2', 'Gene', '3417;3418', (181, 187))
25897	32293336	Accordingly, MsMab-1 was a relatively effective multi-specific antibody against IDH1/2 mutant in ICCs (kappa = 0.691).	('mutant', 'Var', (87, 93))	('ICCs', 'Disease', (97, 101))	('IDH1/2', 'Gene', '3417;3418', (80, 86))	('IDH1/2', 'Gene', (80, 86))
25898	32293336	IDH1/2 mutation was detected in 3.7% (1/27) of cases with large duct type and 19.4% (20/103) of patients with small duct type, respectively.	('detected', 'Reg', (20, 28))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('large duct type', 'Disease', (58, 73))	('mutation', 'Var', (7, 15))	('patients', 'Species', '9606', (96, 104))	('IDH1/2', 'Gene', (0, 6))
25899	32293336	Patients with IDH1/2 mutation had decreased TBIL (total bilirubin) (P = 0.039), Fe (ferritin) (P = 0.000) and higher histological differentiation (P = 0.024) in small duct type (Table 3).	('TBIL', 'Chemical', 'MESH:D001663', (44, 48))	('decreased', 'NegReg', (34, 43))	('bilirubin', 'Chemical', 'MESH:D001663', (56, 65))	('IDH1/2', 'Gene', '3417;3418', (14, 20))	('mutation', 'Var', (21, 29))	('Patients', 'Species', '9606', (0, 8))	('histological differentiation', 'CPA', (117, 145))	('higher', 'PosReg', (110, 116))	('IDH1/2', 'Gene', (14, 20))	('small duct type', 'Disease', (161, 176))
25900	32293336	Univariate and multivariate analyses exhibited that cases with IDH1/2 mutation had significantly improved prognosis than those without IDH1/2mutation in terms of DFS (P = 0.006) and OS (P = 0.031) in total cohort of ICCs (Fig.	('IDH1/2', 'Gene', '3417;3418', (63, 69))	('ICCs', 'Disease', (216, 220))	('improved', 'PosReg', (97, 105))	('IDH1/2', 'Gene', '3417;3418', (135, 141))	('mutation', 'Var', (70, 78))	('DFS', 'MPA', (162, 165))	('prognosis', 'MPA', (106, 115))	('IDH1/2', 'Gene', (135, 141))	('IDH1/2', 'Gene', (63, 69))
25901	32293336	And more notably, Kaplan-Meier analysis showed IDH1/2 mutation was associated with prolonged DFS (P = 0.009) and a trend toward increased OS (P = 0.126) in small duct type of ICCs.	('IDH1/2', 'Gene', '3417;3418', (47, 53))	('mutation', 'Var', (54, 62))	('increased', 'PosReg', (128, 137))	('IDH1/2', 'Gene', (47, 53))	('small duct type of ICCs', 'Disease', (156, 179))	('DFS', 'MPA', (93, 96))
25902	32293336	Further multivariate analysis confirmed IDH1/2 mutation was a favorable independent predictor of DFS (P = 0.022, HR = 3.452, 95% CI = 1.191-10.004), and was not significantly related to OS (P = 0.114, HR = 2.686, 95%CI = 0.789-9.144) in patients with small duct type (Fig.	('IDH1/2', 'Gene', (40, 46))	('mutation', 'Var', (47, 55))	('DFS', 'Disease', (97, 100))	('IDH1/2', 'Gene', '3417;3418', (40, 46))	('small duct type', 'Disease', (251, 266))	('patients', 'Species', '9606', (237, 245))
25922	32293336	As reported in previous studies, IDH1/2 mutations were detected in 10.2-28.8% of ICCs, and exclusively in small duct type of ICCs.	('detected', 'Reg', (55, 63))	('IDH1/2', 'Gene', (33, 39))	('ICCs', 'Disease', (81, 85))	('mutations', 'Var', (40, 49))	('IDH1/2', 'Gene', '3417;3418', (33, 39))
25923	32293336	In the present study, we found that 16.1% of patients with ICC harbored IDH1/2 mutation.	('IDH1/2', 'Gene', '3417;3418', (72, 78))	('harbored', 'Reg', (63, 71))	('mutation', 'Var', (79, 87))	('patients', 'Species', '9606', (45, 53))	('IDH1/2', 'Gene', (72, 78))	('ICC', 'Disease', (59, 62))
25924	32293336	Meanwhile, the incidence of IDH1/2 mutation in large duct and small duct type of ICCs was 3.7 and 19.4%, respectively.	('large duct', 'Disease', (47, 57))	('IDH1/2', 'Gene', '3417;3418', (28, 34))	('IDH1/2', 'Gene', (28, 34))	('mutation', 'Var', (35, 43))	('small duct type', 'Disease', (62, 77))
25925	32293336	Consequently, the clinical features and prognostic value of IDH1/2 mutations should be investigated in small duct type, rather than in large duct type.	('small duct type', 'Disease', (103, 118))	('IDH1/2', 'Gene', (60, 66))	('IDH1/2', 'Gene', '3417;3418', (60, 66))	('mutations', 'Var', (67, 76))
25927	32293336	identified that ICC patients with IDH1/2 mutation had 3-year overall survival of 33% compared to 81% for patients with IDH1/2 wild-type (P = 0.0034), but Pu Wang, et al.	('IDH1/2', 'Gene', '3417;3418', (34, 40))	('patients', 'Species', '9606', (105, 113))	('IDH1/2', 'Gene', '3417;3418', (119, 125))	('ICC', 'Disease', (16, 19))	('IDH1/2', 'Gene', (34, 40))	('mutation', 'Var', (41, 49))	('IDH1/2', 'Gene', (119, 125))	('patients', 'Species', '9606', (20, 28))
25928	32293336	showed IDH1/2 mutation was significantly associated with improved prognosis in ICCs (4-years tumor recurrence rate was 45.3% vs. 71.5%; P = 0.046).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('IDH1/2', 'Gene', '3417;3418', (7, 13))	('tumor', 'Disease', (93, 98))	('mutation', 'Var', (14, 22))	('improved', 'PosReg', (57, 65))	('IDH1/2', 'Gene', (7, 13))	('ICCs', 'Disease', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
25929	32293336	At the same time, one study on advanced stage ICCs from Massachusetts General Hospital Cancer Center found that there were no significant differences in DFS and OS between patients with IDH mutation and patients with IDH wild-type.	('mutation', 'Var', (190, 198))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))	('IDH', 'Gene', (217, 220))	('IDH', 'Gene', '3417', (217, 220))	('patients', 'Species', '9606', (203, 211))	('IDH', 'Gene', (186, 189))	('IDH', 'Gene', '3417', (186, 189))	('patients', 'Species', '9606', (172, 180))	('Cancer', 'Disease', (87, 93))	('Cancer', 'Disease', 'MESH:D009369', (87, 93))
25930	32293336	In the present study, univariate and multivariate analyses showed patients with IDH1/2 mutation had significant prolonged DFS and a trend toward increased OS in small duct type of ICCs.	('prolonged', 'PosReg', (112, 121))	('small duct type of ICCs', 'Disease', (161, 184))	('DFS', 'MPA', (122, 125))	('IDH1/2', 'Gene', '3417;3418', (80, 86))	('increased', 'PosReg', (145, 154))	('mutation', 'Var', (87, 95))	('patients', 'Species', '9606', (66, 74))	('IDH1/2', 'Gene', (80, 86))
25931	32293336	Furthermore, IDH1/2 mutations were associated with higher histological differentiation, but not tumor stage.	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('histological differentiation', 'CPA', (58, 86))	('tumor', 'Disease', (96, 101))	('IDH1/2', 'Gene', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('higher', 'PosReg', (51, 57))	('mutations', 'Var', (20, 29))
25932	32293336	Therefore, these findings suggest that IDH1/2 mutation is a favorable predictor for small duct type ICCs.	('IDH1/2', 'Gene', '3417;3418', (39, 45))	('mutation', 'Var', (46, 54))	('small duct type ICCs', 'Disease', (84, 104))	('IDH1/2', 'Gene', (39, 45))
25933	32293336	Due to worse prognosis of large duct type ICCs, cases with IDH1/2 mutation had significantly better DFS and OS than those with IDH1/2 wild-type in total cohort of ICCs.	('IDH1/2', 'Gene', '3417;3418', (127, 133))	('IDH1/2', 'Gene', '3417;3418', (59, 65))	('IDH1/2', 'Gene', (127, 133))	('DFS', 'MPA', (100, 103))	('mutation', 'Var', (66, 74))	('better', 'PosReg', (93, 99))	('IDH1/2', 'Gene', (59, 65))
25934	32293336	Our results may be account for the conflicting predictive values of IDH1/2 mutation in ICCs described above.	('IDH1/2', 'Gene', (68, 74))	('IDH1/2', 'Gene', '3417;3418', (68, 74))	('mutation', 'Var', (75, 83))	('ICCs', 'Disease', (87, 91))
25935	32293336	In small duct type of ICCs, IDH1/2 mutations were correlated to a trend toward improved OS though the differences were not statistically significant.	('small duct type of ICCs', 'Disease', (3, 26))	('IDH1/2', 'Gene', '3417;3418', (28, 34))	('improved', 'PosReg', (79, 87))	('IDH1/2', 'Gene', (28, 34))	('mutations', 'Var', (35, 44))
25938	32293336	Coincidentally, a total of 9 patients underwent reoperation or radiofrequency ablation (RFA), all of which were classified as IDH wild-type.	('radiofrequency', 'Var', (63, 77))	('patients', 'Species', '9606', (29, 37))	('IDH', 'Gene', '3417', (126, 129))	('IDH', 'Gene', (126, 129))
25940	32293336	Moreover, the typical case described in methods who reached long-term (20 months) SD after treated with dasatinib also proved that ICC patient with IDH1/2 mutation had a better prognosis, even if the tumor is of advanced stage.	('IDH1/2', 'Gene', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('patient', 'Species', '9606', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('IDH1/2', 'Gene', '3417;3418', (148, 154))	('dasatinib', 'Chemical', 'MESH:D000069439', (104, 113))	('mutation', 'Var', (155, 163))	('SD', 'Disease', 'MESH:D029461', (82, 84))
25941	32293336	In summary, IDH1/2 mutation may be a favorable predictor of small duct type ICCs, and have higher prognostic value for DFS than for OS.	('mutation', 'Var', (19, 27))	('DFS', 'Disease', (119, 122))	('IDH1/2', 'Gene', (12, 18))	('IDH1/2', 'Gene', '3417;3418', (12, 18))	('small duct type ICCs', 'Disease', (60, 80))
25942	32293336	Some investigators have found that IDH1/2 mutation was correlated to several clinical characteristics in ICCs, such as lower level of CA19-9, lower incidence of lymph node metastasis and smaller size of tumors.	('ICCs', 'Disease', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('lower', 'NegReg', (119, 124))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('lower', 'NegReg', (142, 147))	('IDH1/2', 'Gene', '3417;3418', (35, 41))	('mutation', 'Var', (42, 50))	('CA19-9', 'Chemical', 'MESH:C086528', (134, 140))	('lymph node metastasis', 'CPA', (161, 182))	('IDH1/2', 'Gene', (35, 41))
25943	32293336	Since IDH1/2 mutations were typically detected in small duct type of ICCs, we considered these factors (CA19-9, lymph node metastasis and size of tumor) might be associated with small duct type, rather than IDH1/2 mutation.	('IDH1/2', 'Gene', (207, 213))	('detected', 'Reg', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('CA19-9', 'Chemical', 'MESH:C086528', (104, 110))	('small duct', 'Disease', (50, 60))	('tumor', 'Disease', (146, 151))	('IDH1/2', 'Gene', '3417;3418', (6, 12))	('IDH1/2', 'Gene', '3417;3418', (207, 213))	('mutations', 'Var', (13, 22))	('IDH1/2', 'Gene', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
25944	32293336	We firstly found that IDH1/2 mutation was strongly associated with decreased preoperative Fe and total bilirubin in small duct type of ICCs.	('mutation', 'Var', (29, 37))	('total bilirubin', 'MPA', (97, 112))	('small duct', 'Disease', (116, 126))	('IDH1/2', 'Gene', (22, 28))	('bilirubin', 'Chemical', 'MESH:D001663', (103, 112))	('IDH1/2', 'Gene', '3417;3418', (22, 28))	('decreased', 'NegReg', (67, 76))
25945	32293336	Although the association of IDH1/2 mutation with iron and bilirubin metabolism has not been reported, previous studies have showed that in tricarboxylic acid cycle, iron homeostasis is regulated by haem and citric acid, both of which are closely related to the activity of IDH.	('citric acid', 'Chemical', 'MESH:D019343', (207, 218))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (139, 157))	('iron', 'Chemical', 'MESH:D007501', (165, 169))	('IDH', 'Gene', (28, 31))	('iron', 'Chemical', 'MESH:D007501', (49, 53))	('IDH1/2', 'Gene', '3417;3418', (28, 34))	('bilirubin', 'Chemical', 'MESH:D001663', (58, 67))	('IDH', 'Gene', '3417', (28, 31))	('haem', 'MPA', (198, 202))	('tricarboxylic acid cycle', 'MPA', (139, 163))	('IDH1/2', 'Gene', (28, 34))	('citric acid', 'MPA', (207, 218))	('mutation', 'Var', (35, 43))	('IDH', 'Gene', (273, 276))	('regulated', 'Reg', (185, 194))	('IDH', 'Gene', '3417', (273, 276))	('iron homeostasis', 'MPA', (165, 181))
25946	32293336	Accordingly, the association between IDH1/2 mutation and iron metabolism may provide a new direction for the function study of IDH1/2 mutation in ICCs.	('IDH1/2', 'Gene', (37, 43))	('mutation', 'Var', (44, 52))	('IDH1/2', 'Gene', '3417;3418', (127, 133))	('association', 'Interaction', (17, 28))	('iron metabolism', 'MPA', (57, 72))	('IDH1/2', 'Gene', (127, 133))	('IDH1/2', 'Gene', '3417;3418', (37, 43))	('iron', 'Chemical', 'MESH:D007501', (57, 61))
25947	32293336	Meanwhile, ICCs with IDH1/2 mutation, often categorized as small duct type, localized at the periphery of bile duct, rarely resulting in biliary obstruction in contralateral bile duct, which can explain the relationship between IDH1/2 mutation and lower level of serum total bilirubin.	('biliary obstruction', 'Phenotype', 'HP:0005230', (137, 156))	('bilirubin', 'Chemical', 'MESH:D001663', (275, 284))	('lower', 'NegReg', (248, 253))	('IDH1/2', 'Gene', '3417;3418', (21, 27))	('biliary obstruction', 'Disease', 'MESH:D001657', (137, 156))	('resulting in', 'Reg', (124, 136))	('mutation', 'Var', (28, 36))	('IDH1/2', 'Gene', '3417;3418', (228, 234))	('biliary obstruction', 'Disease', (137, 156))	('IDH1/2', 'Gene', (21, 27))	('IDH1/2', 'Gene', (228, 234))
25948	32293336	It should be noted that IDH1/2 mutation is the most frequent mutant type of gliomas and can be detected by either DNA sequencing or IHC methods.	('IDH1/2', 'Gene', '3417;3418', (24, 30))	('gliomas', 'Disease', (76, 83))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('mutation', 'Var', (31, 39))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('IDH1/2', 'Gene', (24, 30))
25949	32293336	Although DNA sequencing is regarded as gold standard, IHC seems to be more accurate, easier to perform and cheaper for detecting IDH1/2 mutation in glioma patients.	('IDH1/2', 'Gene', '3417;3418', (129, 135))	('glioma', 'Disease', (148, 154))	('mutation', 'Var', (136, 144))	('IDH1/2', 'Gene', (129, 135))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('patients', 'Species', '9606', (155, 163))
25950	32293336	We firstly used MsMab-1 for detecting IDH1/2 mutation in ICCs by IHC method, and found that the results were basically consistent with those obtained by DNA sequencing.	('IDH1/2', 'Gene', (38, 44))	('mutation', 'Var', (45, 53))	('IDH1/2', 'Gene', '3417;3418', (38, 44))
25952	32293336	Therefore, multi-specific antibodies against hotspot mutations of IDH1/2 in ICCs need to be constructed and validated effectively in future.	('IDH1/2', 'Gene', (66, 72))	('IDH1/2', 'Gene', '3417;3418', (66, 72))	('mutations', 'Var', (53, 62))
25955	32293336	Because of the low incidence of IDH1/2 mutations (3.7%), postoperative chemotherapy is recommended for ICC patients with large duct type without the need for gene sequencing.	('ICC', 'Disease', (103, 106))	('IDH1/2', 'Gene', (32, 38))	('mutations', 'Var', (39, 48))	('IDH1/2', 'Gene', '3417;3418', (32, 38))	('patients', 'Species', '9606', (107, 115))
25956	32293336	In contrast, due to the high incidence of IDH1/2 mutations (19.4%) in small bile duct type of ICCs, DNA sequencing should be recommend to detect IDH1/2 mutation and choose appropriate adjuvant therapies.	('IDH1/2', 'Gene', (145, 151))	('mutations', 'Var', (49, 58))	('IDH1/2', 'Gene', '3417;3418', (42, 48))	('IDH1/2', 'Gene', '3417;3418', (145, 151))	('small bile', 'Phenotype', 'HP:0030985', (70, 80))	('IDH1/2', 'Gene', (42, 48))	('small bile duct type of ICCs', 'Disease', (70, 98))
25958	32293336	With the development of specific antibodies against mutant IDH1/2, IHC will be an easy and cheap way to detect IDH1/2 mutation.	('mutant', 'Var', (52, 58))	('IDH1/2', 'Gene', '3417;3418', (111, 117))	('IDH1/2', 'Gene', '3417;3418', (59, 65))	('mutation', 'Var', (118, 126))	('IDH1/2', 'Gene', (111, 117))	('IDH1/2', 'Gene', (59, 65))
25973	32293336	The typical ICC patient with IDH1 mutation provided informed written consent to the use of clinical data and MR images for publication.	('ICC', 'Disease', (12, 15))	('IDH1', 'Gene', (29, 33))	('mutation', 'Var', (34, 42))	('IDH1', 'Gene', '3417', (29, 33))	('patient', 'Species', '9606', (16, 23))
26149	30544406	Those primary targeted agents are monoclonal antibodies and tyrosine kinase inhibitors against epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF).	('epidermal growth factor receptor', 'Gene', '1956', (95, 127))	('VEGF', 'Gene', '7422', (175, 179))	('monoclonal', 'Var', (34, 44))	('EGFR', 'Gene', '1956', (129, 133))	('VEGF', 'Gene', (175, 179))	('tyrosine', 'Var', (60, 68))	('epidermal growth factor receptor', 'Gene', (95, 127))	('EGFR', 'Gene', (129, 133))	('vascular endothelial growth factor', 'Gene', (139, 173))	('vascular endothelial growth factor', 'Gene', '7422', (139, 173))
26206	30544406	The study showed the antineoplastic potential of MLN0128, suggesting that it might be superior to gemcitabine/oxaliplatin-based chemotherapy for treating ICC, especially in tumors exhibiting an activated AKT/mTOR cascade.	('MLN0128', 'Var', (49, 56))	('gemcitabine', 'Chemical', 'MESH:C056507', (98, 109))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (110, 121))	('AKT', 'Gene', '207', (204, 207))	('MLN0128', 'Chemical', 'MESH:C572449', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('ICC', 'Disease', (154, 157))	('AKT', 'Gene', (204, 207))	('tumors', 'Disease', (173, 179))	('antineoplastic potential', 'CPA', (21, 45))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))
26208	30544406	They found that pazopanib and ponatinib showed antitumor activity in patients with FGFR 2 fusion.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('patients', 'Species', '9606', (69, 77))	('FGFR 2', 'Gene', '2263', (83, 89))	('ponatinib', 'Chemical', 'MESH:C545373', (30, 39))	('fusion', 'Var', (90, 96))	('FGFR 2', 'Gene', (83, 89))	('pazopanib', 'Chemical', 'MESH:C516667', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
26210	30544406	Another study showed that FIG-ROS inactivation in carcinomas harboring mutant Kirsten rat sarcoma (Kras) viral oncogene homolog, and P53 mutations could potently inhibit tumor growth, thereby validating ROS as a therapeutic target in ICC.	('Kras', 'Gene', (99, 103))	('tumor', 'Disease', (170, 175))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('carcinomas', 'Disease', 'MESH:D002277', (50, 60))	('ROS', 'Chemical', '-', (30, 33))	('rat', 'Species', '10116', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('inactivation', 'NegReg', (34, 46))	('P53', 'Gene', (133, 136))	('Kras', 'Gene', '24525', (99, 103))	('FIG-ROS', 'Protein', (26, 33))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))	('ROS', 'Chemical', '-', (203, 206))	('sarcoma', 'Disease', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('carcinomas', 'Disease', (50, 60))	('P53', 'Gene', '301300', (133, 136))	('inhibit', 'NegReg', (162, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('mutations', 'Var', (137, 146))
26261	29088737	Our previous work had also demonstrated that MSCs could effectively induce metastatic growth and chemoresistance of CCA via activation of Wnt/beta-catenin signaling pathway.	('chemoresistance', 'CPA', (97, 112))	('CCA', 'Phenotype', 'HP:0030153', (116, 119))	('activation', 'PosReg', (124, 134))	('induce', 'PosReg', (68, 74))	('beta-catenin', 'Gene', (142, 154))	('beta-catenin', 'Gene', '1499', (142, 154))	('CCA', 'Disease', (116, 119))	('metastatic growth', 'CPA', (75, 92))	('MSCs', 'Var', (45, 49))
26262	29088737	On the contrary, studies also showed that MSCs can inhibit the growth and migration of glioma cells via down-regulating the PI3K/Akt pathway.	('down-regulating', 'NegReg', (104, 119))	('glioma', 'Disease', (87, 93))	('Akt', 'Gene', '207', (129, 132))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('Akt', 'Gene', (129, 132))	('inhibit', 'NegReg', (51, 58))	('MSCs', 'Var', (42, 46))
26283	29088737	To confirm the above in vitro cell lines results in in vivo mice studies, we established an xenograft model in which QBC939 (2 x 106 cell/mice), QBC939 mixed with MSCs (3:1) and QBC939 mixed with MSCs (pretreated with TNF-alpha and IFN-gamma) injected subcutaneously into immunocompromised mice.	('QBC939', 'Var', (117, 123))	('QBC939', 'Var', (145, 151))	('mice', 'Species', '10090', (138, 142))	('mice', 'Species', '10090', (60, 64))	('mice', 'Species', '10090', (290, 294))
26291	29088737	These data suggest that MSCs enhance in vivo tumor growth and liver metastases, and inflammatory cytokines treated MSCs could increase CCA cells migration and metastases to a greater degree than untreated MSCs.	('metastases', 'Disease', (159, 169))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('MSCs', 'Var', (115, 119))	('CCA', 'Disease', (135, 138))	('liver metastases', 'Disease', (62, 78))	('tumor', 'Disease', (45, 50))	('metastases', 'Disease', 'MESH:D009362', (159, 169))	('liver metastases', 'Disease', 'MESH:D009362', (62, 78))	('CCA', 'Phenotype', 'HP:0030153', (135, 138))	('enhance', 'PosReg', (29, 36))	('metastases', 'Disease', (68, 78))	('increase', 'PosReg', (126, 134))	('metastases', 'Disease', 'MESH:D009362', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
26292	29088737	As shown in Figure 3A, MSC(TI)-CM increased the phosphorylation of p65 at ser536 and phosphorylation of Akt at ser473 (Figure 3A).	('Akt', 'Gene', (104, 107))	('Akt', 'Gene', '207', (104, 107))	('phosphorylation', 'MPA', (85, 100))	('ser536', 'Chemical', '-', (74, 80))	('p65', 'Gene', '5970', (67, 70))	('ser473', 'Chemical', '-', (111, 117))	('phosphorylation', 'MPA', (48, 63))	('MSC', 'Var', (23, 26))	('ser536', 'Var', (74, 80))	('increased', 'PosReg', (34, 43))	('p65', 'Gene', (67, 70))
26296	29088737	As shown in figure 3D and 3E, MSC-CM induced the transcription of Vimentin, slug, ZEB1, ZEB2 in QBC939, while had no obvious effects on Mz-chA-1.	('ZEB2', 'Gene', (88, 92))	('Vimentin', 'Gene', (66, 74))	('slug', 'Gene', '6591', (76, 80))	('ZEB2', 'Gene', '9839', (88, 92))	('ZEB1', 'Gene', '6935', (82, 86))	('Vimentin', 'Gene', '7431', (66, 74))	('ZEB1', 'Gene', (82, 86))	('transcription', 'MPA', (49, 62))	('MSC-CM', 'Var', (30, 36))	('induced', 'PosReg', (37, 44))	('slug', 'Gene', (76, 80))
26307	29088737	Then a migration assay was performed to investigate whether MSCs promoting cholangiocarcinoma cell migration and invasion was associated with high expression level of CCL5.	('promoting', 'PosReg', (65, 74))	('cholangiocarcinoma cell migration', 'Disease', 'MESH:D018281', (75, 108))	('CCL5', 'Gene', '6352', (167, 171))	('invasion', 'CPA', (113, 121))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (75, 93))	('high expression level', 'Var', (142, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('cholangiocarcinoma cell migration', 'Disease', (75, 108))	('CCL5', 'Gene', (167, 171))
26308	29088737	The results were presented in Figure 4E and 4F, when treated with MSC(TI)-CM, the number of cancer cells migrating through the membrane increased significantly compared with the control group or MSC-CM group.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('increased', 'PosReg', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('MSC', 'Var', (66, 69))
26319	29088737	MK-2206, an inhibitor of Akt, can effectively inhibit the phosphorylation of Akt in MSC(TI)-CM cultured cancer cells.	('Akt', 'Gene', '207', (77, 80))	('MK-2206', 'Chemical', 'MESH:C548887', (0, 7))	('inhibit', 'NegReg', (46, 53))	('phosphorylation', 'MPA', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Akt', 'Gene', (77, 80))	('Akt', 'Gene', '207', (25, 28))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('Akt', 'Gene', (25, 28))	('MK-2206', 'Var', (0, 7))
26320	29088737	After treated with MK-2206 (10 microM), the phosphorylation of P65 also decreased in Mz-chA-1 cells.	('phosphorylation', 'MPA', (44, 59))	('P65', 'Gene', '5970', (63, 66))	('decreased', 'NegReg', (72, 81))	('P65', 'Gene', (63, 66))	('MK-2206', 'Chemical', 'MESH:C548887', (19, 26))	('MK-2206', 'Var', (19, 26))
26516	28632730	Other eligibility criteria included a Zubrod performance status of 0-1; adequate bone marrow function indicated by a leukocyte count >=3000 per mul, absolute neutrophil count >=1000 per mul, and platelet count >=75,000 per mul; adequate hepatic function with a total bilirubin up to 2.5 x the institutional upper limit of normal; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels <=2.5 the upper limit of normal.	('alanine aminotransferase', 'Gene', (367, 391))	('aspartate aminotransferase', 'Gene', (330, 356))	('AST', 'Gene', (358, 361))	('alanine aminotransferase', 'Gene', '2875', (367, 391))	('AST', 'Gene', '26503', (358, 361))	('bilirubin', 'Chemical', 'MESH:D001663', (267, 276))	('bone marrow function', 'CPA', (81, 101))	('>=3000', 'Var', (133, 139))	('hepatic function', 'MPA', (237, 253))	('aspartate aminotransferase', 'Gene', '26503', (330, 356))
26644	33692336	Typing FGFR2 translocation determines the response to targeted therapy of intrahepatic cholangiocarcinomas Chromosomal translocations involving fibroblast growth factor receptor 2 (FGFR2) gene at the breakpoints are common genetic lesions in intrahepatic cholangiocarcinoma (ICC) and the resultant fusion protein products have emerged as promising druggable targets.	('FGFR2', 'Gene', (181, 186))	('FGFR2', 'Gene', '2263', (181, 186))	('FGFR2', 'Gene', (7, 12))	('FGFR2', 'Gene', '2263', (7, 12))	('fibroblast growth factor receptor 2', 'Gene', (144, 179))	('intrahepatic cholangiocarcinomas', 'Disease', (74, 106))	('fibroblast growth factor receptor 2', 'Gene', '2263', (144, 179))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (74, 106))	('Chromosomal translocations', 'Var', (107, 133))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (242, 273))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (255, 273))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (74, 105))	('intrahepatic cholangiocarcinoma', 'Disease', (242, 273))
26645	33692336	Here, we report identification of nine FGFR2 translocations out of 173 (5.2%) ICC tumors.	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('ICC tumors', 'Disease', (78, 88))	('ICC tumors', 'Disease', 'MESH:C566123', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('FGFR2', 'Gene', (39, 44))	('translocations', 'Var', (45, 59))
26646	33692336	Although clinicopathologically these FGFR2 translocation bearing ICC tumors are indistinguishable from the rest of the cohort, they are invariably of the mass-forming type originated from the small bile duct.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('small bile', 'Phenotype', 'HP:0030985', (192, 202))	('ICC tumors', 'Disease', (65, 75))	('FGFR2', 'Gene', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('ICC tumors', 'Disease', 'MESH:C566123', (65, 75))	('translocation', 'Var', (43, 56))
26647	33692336	We show that the protein products of FGFR2 fusions can be classified into three subtypes based on the breaking positions of the fusion partners: the classical fusions that retain the tyrosine kinase (TK) and the Immunoglobulin (Ig)-like domains (n = 6); the sub-classical fusions that retain only the TK domain without the Ig-like domain (n = 1); and the non-classical fusions that lack both the TK and Ig-like domains (n = 2).	('breaking positions', 'Phenotype', 'HP:0001061', (102, 120))	('tyrosine', 'Chemical', 'MESH:D014443', (183, 191))	('FGFR2', 'Gene', (37, 42))	('fusions', 'Var', (43, 50))	('tyrosine kinase', 'MPA', (183, 198))
26655	33692336	Recently, many groups have shown that chromosomal translocations with breakpoints at fibroblast growth factor receptor 2 (FGFR2) frequently occur in ICC but not PHCC and DCC.	('fibroblast growth factor receptor 2', 'Gene', '2263', (85, 120))	('fibroblast growth factor receptor 2', 'Gene', (85, 120))	('occur', 'Reg', (140, 145))	('breakpoints', 'Var', (70, 81))	('FGFR2', 'Gene', (122, 127))	('chromosomal translocations', 'Var', (38, 64))	('ICC', 'Disease', (149, 152))
26657	33692336	Numerous studies have demonstrated that FGFR2 fusions promote tumorigenesis due to their inappropriately activated kinase activity.	('promote', 'PosReg', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('kinase activity', 'MPA', (115, 130))	('fusions', 'Var', (46, 53))	('tumor', 'Disease', (62, 67))	('FGFR2', 'Gene', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
26659	33692336	Different partners of FGFR2 gene fusions have also been demonstrated in recent studies of ICC patients.	('FGFR2', 'Gene', (22, 27))	('gene fusions', 'Var', (28, 40))	('ICC', 'Disease', (90, 93))	('patients', 'Species', '9606', (94, 102))
26663	33692336	Also, another FGFR inhibitor Pemigatinib was granted accelerated approval by the Food and Drug Administration for cholangiocarcinoma with an FGFR2 fusion or rearrangement in the United States.	('rearrangement', 'Var', (157, 170))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (114, 132))	('fusion', 'Var', (147, 153))	('FGFR2', 'Gene', (141, 146))	('cholangiocarcinoma', 'Disease', (114, 132))	('Pemigatinib', 'Chemical', '-', (29, 40))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (114, 132))
26666	33692336	In a previous study, we found that the incidence of FGFR2 translocation in a cohort of Chinese ICC patients was much lower than that in other countries, and no prognostic utility and gender trends were observed.	('patients', 'Species', '9606', (99, 107))	('FGFR2', 'Gene', (52, 57))	('translocation', 'Var', (58, 71))	('lower', 'NegReg', (117, 122))
26667	33692336	When we enlarged the number of patients, we found that the incidence of FGFR2 translocation was even lower, and the fusion partners and breakpoints were different from reported studies.	('lower', 'NegReg', (101, 106))	('translocation', 'Var', (78, 91))	('patients', 'Species', '9606', (31, 39))	('FGFR2', 'Gene', (72, 77))
26668	33692336	In the present study, we identified FGFR2 translocation in a group of 173 patients with ICC.	('FGFR2', 'Gene', (36, 41))	('patients', 'Species', '9606', (74, 82))	('ICC', 'Disease', (88, 91))	('translocation', 'Var', (42, 55))
26687	33692336	The kinase-dead mutant was constructed by replacing tyrosine with phenylalanine at amino acid 564 of FGFR2 in the fusion gene BF494 (abbreviation to BICC1(exon 1-3)-FGFR2(exon10-18) fusion) using a site-directed mutagenesis kit (Takara Bio).	('BICC1', 'Gene', '80114', (149, 154))	('FGFR2', 'Gene', (101, 106))	('tyrosine with phenylalanine at amino acid 564', 'Mutation', 'p.Y564F', (52, 97))	('replacing', 'Var', (42, 51))	('BICC1', 'Gene', (149, 154))	('BF494', 'Chemical', '-', (126, 131))
26691	33692336	Mouse NIH3T3 fibroblast cells were transfected with indicated FGFR2 fusion chimeras using Fugene HD (Promega).	('FGFR2', 'Gene', (62, 67))	('fusion chimeras', 'Var', (68, 83))	('HD', 'Disease', 'MESH:D006816', (97, 99))	('NIH3T3', 'CellLine', 'CVCL:0594', (6, 12))	('Mouse', 'Species', '10090', (0, 5))
26693	33692336	RBE and HCCC-9810 grown in 6-well plates were transfected with FGFR2 fusion chimeras or their mutants.	('mutants', 'Var', (94, 101))	('HCCC-9810', 'CellLine', 'CVCL:6908', (8, 17))	('fusion chimeras', 'Var', (69, 84))	('FGFR2', 'Gene', (63, 68))
26695	33692336	RBE and HCCC-9810 were infected with recombinant lentiviruses expressing FGFR2 fusion chimeras or their mutants, then were distributed into 96-well plates with indicated concentrations of BGJ398 (#T1975, TargetMol, USA) or AZD4547 (#T1948, TargetMol, USA).	('mutants', 'Var', (104, 111))	('infected', 'Disease', (23, 31))	('AZD4547', 'Chemical', 'MESH:C572463', (223, 230))	('FGFR2', 'Gene', (73, 78))	('fusion chimeras', 'Var', (79, 94))	('#T1948', 'Var', (232, 238))	('infected', 'Disease', 'MESH:D007239', (23, 31))	('#T1975', 'Var', (196, 202))	('HCCC-9810', 'CellLine', 'CVCL:6908', (8, 17))	('BGJ398', 'Chemical', 'MESH:C568950', (188, 194))
26697	33692336	The primary antibodies were antibodies against FLAG tag (#F1804, Sigma, USA), Phospho-FRS2-alpha (Tyr196) (#3864, Cell Signaling Technology), ERK (#4695, Cell Signaling Technology), phospho-p44/42 ERK(Thr202/Tyr204) (#9106, Cell Signaling Technology), AKT1 (#2967, Cell Signaling Technology), and phospho-AKT (Ser473) (#4051, Cell Signaling Technology).	('AKT1', 'Gene', '207', (252, 256))	('AKT1', 'Gene', (252, 256))	('Tyr196', 'Chemical', '-', (98, 104))	('Ser473', 'Chemical', '-', (310, 316))	('#F1804', 'Var', (57, 63))	('FRS2-alpha', 'Gene', (86, 96))	('phospho-p44/42', 'Var', (182, 196))	('Tyr204', 'Chemical', '-', (208, 214))	('Thr202', 'Chemical', '-', (201, 207))	('FRS2-alpha', 'Gene', '10818', (86, 96))
26700	33692336	Through FISH testing, FGFR2 translocations were identified in nine (5.2%) tumor specimens (Fig.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('FGFR2', 'Gene', (22, 27))	('tumor', 'Disease', (74, 79))	('translocations', 'Var', (28, 42))
26702	33692336	Same as in the North American study, we found that FGFR2 translocations presented in younger patients (p = 0.054), and the ICC harboring the translocations were histologically classified as pancreaticobiliary type (p = 0.052).	('FGFR2', 'Gene', (51, 56))	('pancreaticobiliary type', 'Disease', (190, 213))	('patients', 'Species', '9606', (93, 101))	('translocations', 'Var', (57, 71))
26703	33692336	In our study, all of the tumors with FGFR2 translocations showed MF pattern (p = 0.038).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('FGFR2', 'Gene', (37, 42))	('translocations', 'Var', (43, 57))	('tumors', 'Disease', 'MESH:D009369', (25, 31))
26704	33692336	Radiological, gross anatomical, and histopathologic (magnification 20x and 200x) images of three representative patients whose tumors possessed an FGFR2 translocation are shown in Fig.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('patients', 'Species', '9606', (112, 120))	('translocation', 'Var', (153, 166))	('FGFR2', 'Gene', (147, 152))
26721	33692336	We also introduced these fusions into ICC cell lines RBE and HCCC-9810 for assaying their ability to induce cell migration.	('HCCC-9810', 'CellLine', 'CVCL:6908', (61, 70))	('fusions', 'Var', (25, 32))	('cell migration', 'CPA', (108, 122))
26723	33692336	Taken together, these data indicate that the FGFR2 fusions we identified have the propensity to promote tumorigenesis and metastasis of ICC.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('FGFR2', 'Gene', (45, 50))	('tumor', 'Disease', (104, 109))	('promote', 'PosReg', (96, 103))	('ICC', 'Disease', (136, 139))	('metastasis', 'CPA', (122, 132))	('fusions', 'Var', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
26726	33692336	This manipulation of endogenous FGFR2 did not change the viability of RBE cells in response to either BGJ398 or AZD4547 treatment (Fig.	('AZD4547', 'Chemical', 'MESH:C572463', (112, 119))	('BGJ398', 'Gene', (102, 108))	('FGFR2', 'Gene', (32, 37))	('AZD4547', 'Var', (112, 119))	('BGJ398', 'Chemical', 'MESH:C568950', (102, 108))
26727	33692336	We then infected RBE with lentiviruses expressing FGFR2 fusions corresponding to FB949, BF494, and BF846 representing classical, sub-classical, and non-classical FGFR2 fusion, respectively.	('BF846', 'Var', (99, 104))	('BF494', 'Var', (88, 93))	('infected', 'Disease', 'MESH:D007239', (8, 16))	('BF494', 'Chemical', '-', (88, 93))	('FB949', 'Var', (81, 86))	('infected', 'Disease', (8, 16))	('FGFR2', 'Gene', (50, 55))
26729	33692336	Cells expressing FB949 and BF494 were highly sensitive to BGJ398 (Fig.	('BGJ398', 'Chemical', 'MESH:C568950', (58, 64))	('FB949', 'Var', (17, 22))	('BF494', 'Chemical', '-', (27, 32))	('sensitive', 'Reg', (45, 54))	('BF494', 'Var', (27, 32))
26732	33692336	The RBE cells expressing FB949 were highly sensitive (IC50 70.8 nM to BGJ398 and IC50 113.3 nM to AZD4547), ones expressing BF494 were also sensitive (IC50 69.5 nM to BGJ398 and IC50 130.2 nM to AZD4547), whereas ones expressing BF846 were resistant (IC50 > 1 muM) (Fig.	('AZD4547', 'Chemical', 'MESH:C572463', (98, 105))	('FB949', 'Var', (25, 30))	('AZD4547', 'Chemical', 'MESH:C572463', (195, 202))	('BGJ398', 'Chemical', 'MESH:C568950', (70, 76))	('sensitive', 'MPA', (43, 52))	('BF494', 'Chemical', '-', (124, 129))	('BGJ398', 'Chemical', 'MESH:C568950', (167, 173))
26733	33692336	BGJ389 and AZD4547 treatment in HCCC-9810 cells expressing representative FGFR2 fusions showed the similar results (Supplementary Fig.	('BGJ389', 'Chemical', '-', (0, 6))	('AZD4547', 'Chemical', 'MESH:C572463', (11, 18))	('fusions', 'Var', (80, 87))	('FGFR2', 'Gene', (74, 79))	('HCCC-9810', 'CellLine', 'CVCL:6908', (32, 41))
26741	33692336	Besides, our data also showed that the cells expressing V564F mutant of BF494 had reduced cell proliferation, compared to ones expressing wild type and truncated BF494.	('BF494', 'Gene', (72, 77))	('BF494', 'Chemical', '-', (72, 77))	('BF494', 'Chemical', '-', (162, 167))	('cell proliferation', 'CPA', (90, 108))	('V564F', 'Var', (56, 61))	('reduced', 'NegReg', (82, 89))	('V564F', 'Mutation', 'p.V564F', (56, 61))
26742	33692336	We speculate that the gatekeeper mutation changes the conformation of BF494, thereby inducing a spatial conflict with BGJ398 in its FGFR2-binding pocket and reducing kinase activity as well.	('BF494', 'Gene', (70, 75))	('spatial', 'MPA', (96, 103))	('mutation', 'Var', (33, 41))	('reducing', 'NegReg', (157, 165))	('inducing', 'Reg', (85, 93))	('kinase activity', 'MPA', (166, 181))	('gatekeeper', 'Species', '111938', (22, 32))	('BF494', 'Chemical', '-', (70, 75))	('conformation', 'MPA', (54, 66))	('BGJ398', 'Chemical', 'MESH:C568950', (118, 124))	('BGJ398', 'Gene', (118, 124))	('changes', 'Reg', (42, 49))
26744	33692336	Truncated BF494 showed the phosphorylation of ERK, and MAPK that was suppressed by BGJ398 and AZD4547, whereas kinase-dead mutation could not activate MAPK/ERK and PI3K/AKT pathways (Fig.	('BF494', 'Chemical', '-', (10, 15))	('AZD4547', 'Var', (94, 101))	('BGJ398', 'Chemical', 'MESH:C568950', (83, 89))	('AZD4547', 'Chemical', 'MESH:C572463', (94, 101))	('MAPK', 'Gene', (55, 59))	('phosphorylation', 'MPA', (27, 42))	('ERK', 'Protein', (46, 49))	('suppressed', 'NegReg', (69, 79))	('BF494', 'Gene', (10, 15))
26745	33692336	FGFR2 translocations, which are present in 5-38% of ICCs, represent driver mutations and predict tumor sensitivity to specific FGFR inhibitors in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (146, 164))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (146, 164))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('cholangiocarcinoma', 'Disease', (146, 164))	('predict', 'Reg', (89, 96))	('FGFR2', 'Gene', (0, 5))	('ICCs', 'Disease', (52, 56))	('translocations', 'Var', (6, 20))
26746	33692336	Our studies based on a cohort of Chinese patients showed that FGFR2 fusions have many partners and breakpoints that were not reported previously and FGFR2 translocation was only found in 9 of 173 patients with 5.2% incidence rate.	('fusions', 'Var', (68, 75))	('FGFR2', 'Gene', (62, 67))	('patients', 'Species', '9606', (41, 49))	('patients', 'Species', '9606', (196, 204))
26747	33692336	In North American study, FGFR2 translocation was associated with enhanced survival, younger cohort, and female preponderant, whereas in Japanese cohort, no survival or gender differences were noted but associated with hepatitis B and C virus infection.	('survival', 'CPA', (74, 82))	('FGFR2', 'Gene', (25, 30))	('virus infection', 'Disease', 'MESH:D001102', (236, 251))	('hepatitis B', 'Disease', 'MESH:D006509', (218, 229))	('associated', 'Reg', (202, 212))	('hepatitis B', 'Disease', (218, 229))	('virus infection', 'Disease', (236, 251))	('enhanced', 'PosReg', (65, 73))	('translocation', 'Var', (31, 44))	('hepatitis', 'Phenotype', 'HP:0012115', (218, 227))
26748	33692336	Nevertheless, in our study, we found that tumors carrying FGFR2 translocation were all of MF type (p = 0.038) gross classification.	('translocation', 'Var', (64, 77))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('MF type', 'Disease', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('FGFR2', 'Gene', (58, 63))
26751	33692336	Thus, it is beneficial for selecting FGFR2 translocation patients before molecular target treatment based on its macroscopic appearance.	('patients', 'Species', '9606', (57, 65))	('FGFR2', 'Gene', (37, 42))	('translocation', 'Var', (43, 56))
26759	33692336	BGJ398 and AZD4547 are both orally bioavailable, selective, ATP-competitive selective FGFR kinase inhibitors showing vigorous suppressing activity against tumor models harboring FGFR alterations.	('AZD4547', 'Var', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('ATP', 'Chemical', 'MESH:D000255', (60, 63))	('BGJ398', 'Chemical', 'MESH:C568950', (0, 6))	('AZD4547', 'Chemical', 'MESH:C572463', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('alterations', 'Var', (183, 194))	('tumor', 'Disease', (155, 160))	('suppressing', 'NegReg', (126, 137))	('FGFR', 'Gene', (86, 90))
26761	33692336	Consistent with other studies, our results showed that BGJ398 and AZD4547 had strong efficiency in FGFR2 classical and sub-classical fusions but not in non-classical fusions.	('sub-classical', 'Var', (119, 132))	('efficiency', 'PosReg', (85, 95))	('AZD4547', 'Gene', (66, 73))	('AZD4547', 'Chemical', 'MESH:C572463', (66, 73))	('classical', 'Var', (105, 114))	('BGJ398', 'Chemical', 'MESH:C568950', (55, 61))	('BGJ398', 'Gene', (55, 61))	('FGFR2', 'Gene', (99, 104))
26841	33478536	As demonstrated by pharmacological researches, YCHD can modulate inflammatory as well as immune response, ameliorate liver function, and regulate multiple pathways in cancer.	('inflammatory', 'CPA', (65, 77))	('modulate', 'Reg', (56, 64))	('liver function', 'MPA', (117, 131))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('regulate', 'Reg', (137, 145))	('immune response', 'CPA', (89, 104))	('cancer', 'Disease', (167, 173))	('ameliorate', 'PosReg', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('YCHD', 'Var', (47, 51))
26858	33478536	The RNA polymerase II binding to the tumor suppressor CDC73 contributed to transcriptional repression of oncogenes, conversely, oncogene overexpression could down-regulate CDC73 in tumors and lead to cell proliferation.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('down-regulate', 'NegReg', (158, 171))	('cell proliferation', 'CPA', (200, 218))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('transcriptional repression', 'MPA', (75, 101))	('CDC73', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('CDC73', 'Gene', '79577', (54, 59))	('CDC73', 'Gene', (172, 177))	('overexpression', 'Var', (137, 151))	('CDC73', 'Gene', '79577', (172, 177))	('tumors', 'Disease', (181, 187))	('lead to', 'Reg', (192, 199))	('tumor', 'Disease', (181, 186))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('binding', 'Interaction', (22, 29))
26861	33478536	A previous research has confirmed that cholangiocarcinoma cell apoptosis was induced by THZ1 inhibiting the synthesis of antiapoptotic protein, and THZ1 could down-regulate the transcriprion of RNA polymerase II promoter in cancer cells and produce anti-tumour effects.	('transcriprion', 'MPA', (177, 190))	('induced', 'Reg', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (39, 57))	('tumour', 'Disease', 'MESH:D009369', (254, 260))	('tumour', 'Disease', (254, 260))	('THZ1', 'Gene', (88, 92))	('down-regulate', 'NegReg', (159, 172))	('cholangiocarcinoma', 'Disease', (39, 57))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('synthesis of antiapoptotic protein', 'MPA', (108, 142))	('inhibiting', 'NegReg', (93, 103))	('cancer', 'Disease', (224, 230))	('THZ1', 'Var', (148, 152))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (39, 57))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))
26873	33478536	Existing research has elucidated that theinhibitory of transcription factor 21 mediated by PI3K-Akt signaling pathway could inhibit the progression of cholangiocarcinoma .	('cholangiocarcinoma', 'Disease', (151, 169))	('progression', 'CPA', (136, 147))	('theinhibitory', 'Var', (38, 51))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (151, 169))	('Akt', 'Gene', '207', (96, 99))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (151, 169))	('inhibit', 'NegReg', (124, 131))	('Akt', 'Gene', (96, 99))
26875	33478536	According to one previous research, microRNA-329 had an inhibitory effect on the expression of PTTG1 and inactivated the MAPK signaling pathway to inhibit the cholangiocarcinoma cell proliferation, induce cell cycle arrest as well as promote cell apoptosis, thus prevented the progression of cholangiocarcinoma.	('cell apoptosis', 'CPA', (242, 256))	('inactivated', 'NegReg', (105, 116))	('arrest', 'Disease', 'MESH:D006323', (216, 222))	('PTTG1', 'Gene', '9232', (95, 100))	('MAPK', 'Gene', (121, 125))	('induce', 'PosReg', (198, 204))	('MAPK', 'Gene', 'None', (121, 125))	('microRNA-329', 'Var', (36, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (159, 177))	('cholangiocarcinoma', 'Disease', (159, 177))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (292, 310))	('inhibit', 'NegReg', (147, 154))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (159, 177))	('cholangiocarcinoma', 'Disease', (292, 310))	('arrest', 'Disease', (216, 222))	('PTTG1', 'Gene', (95, 100))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (292, 310))	('promote', 'PosReg', (234, 241))	('prevented', 'NegReg', (263, 272))
26905	33432491	Compared to gadobenate dimeglumine, gadoxetate disodium is administered at a lower dose (0.1 mmol/kg vs 0.025 mmol/kg of body weights), has greater uptake (50% vs. 3-5%) and has earlier onset uptake by the hepatocytes (starting from 40 min vs. 60-90 s after contrast injection), which results in differences in the enhancement of hepatic parenchyma and vessels on portal venous, delayed and hepatobiliary phase (HBP), as well as earlier acquisition of HBP.	('hepatic parenchyma', 'Disease', 'MESH:D056486', (330, 348))	('greater', 'PosReg', (140, 147))	('uptake', 'MPA', (148, 154))	('gadoxetate', 'Var', (36, 46))	('hepatic parenchyma', 'Disease', (330, 348))	('enhancement', 'PosReg', (315, 326))	('gadoxetate disodium', 'Chemical', 'MESH:C073590', (36, 55))	('men', 'Species', '9606', (322, 325))	('gadobenate dimeglumine', 'Chemical', 'MESH:C064572', (12, 34))	('hepatobiliary phase', 'MPA', (391, 410))	('onset uptake', 'MPA', (186, 198))
26915	33432491	FNHs show iso- or hyperintensity in the HBP relatively to liver parenchyma in the vast majority (97%) of cases (Fig.	('iso-', 'Var', (10, 14))	('hyperintensity', 'Var', (18, 32))	('FNHs', 'Disease', 'None', (0, 4))	('FNHs', 'Disease', (0, 4))
26918	33432491	classified all FNHs in only 3 patterns (i.e., uniform uptake, iso- or hyperintense to liver, hyperintense rim with core that is hypointense relative to liver, or hyperintense rim with core that is iso- or hyperintense to liver) while a more recent paper identified two patterns for FNH in the HBP, including an homogenous or a doughnut-like pattern.	('doughnut-like', 'MPA', (327, 340))	('FNHs', 'Disease', 'None', (15, 19))	('FNHs', 'Disease', (15, 19))	('hyperintense', 'Var', (162, 174))	('homogenous', 'MPA', (311, 321))
26936	33432491	The causative mechanism of focal fatty sparing is usually related to abnormal vascular inflow, due to aberrant small veins, arterial perfusion abnormalities or reduced portal flow and increased arterial flow in case of fatty sparing surrounding focal liver lesions.	('vascular inflow', 'MPA', (78, 93))	('portal flow', 'MPA', (168, 179))	('arterial flow', 'MPA', (194, 207))	('liver lesions', 'Disease', 'MESH:D017093', (251, 264))	('increased', 'PosReg', (184, 193))	('reduced', 'NegReg', (160, 167))	('liver lesions', 'Disease', (251, 264))	('arterial perfusion abnormalities', 'Disease', (124, 156))	('arterial perfusion abnormalities', 'Disease', 'MESH:D020765', (124, 156))	('aberrant', 'Var', (102, 110))
26952	33432491	Iso-hyperintensity on HBP in a lesion detected in oncologic patients usually indicates benignity.	('patients', 'Species', '9606', (60, 68))	('Iso-hyperintensity', 'Var', (0, 18))	('benignity', 'Disease', (87, 96))
26966	33432491	Another possible theory is the presence of aberrant expression of OATP1B3 in liver metastases as possible explanation of the hepatobiliary uptake; however, while Park et al.	('hepatobiliary uptake', 'MPA', (125, 145))	('liver metastases', 'Disease', 'MESH:D009362', (77, 93))	('OATP1B3', 'Gene', '28234', (66, 73))	('liver metastases', 'Disease', (77, 93))	('OATP1B3', 'Gene', (66, 73))	('aberrant', 'Var', (43, 51))
26967	33432491	showed an increased expression of aberrant OATP1B3 (i.e., the protein involved in hepatocyte contrast uptake), Wlcek et al.	('expression', 'MPA', (20, 30))	('aberrant', 'Var', (34, 42))	('OATP1B3', 'Gene', '28234', (43, 50))	('OATP1B3', 'Gene', (43, 50))	('increased', 'PosReg', (10, 19))
26977	33432491	Hyperintensity on HBP in a cirrhotic liver usually indicates benignity, but well-differentiated HCC in cirrhotic patients may also show hyperintensity on HBP.	('indicates', 'Reg', (51, 60))	('HCC', 'Gene', (96, 99))	('benignity', 'MPA', (61, 70))	('patients', 'Species', '9606', (113, 121))	('hyperintensity', 'MPA', (136, 150))	('HCC', 'Gene', '619501', (96, 99))	('cirrhotic liver', 'Phenotype', 'HP:0001394', (27, 42))	('Hyperintensity', 'Var', (0, 14))
27044	25598674	A cumulative body of evidence suggests that these liver cancers can originate from CSCs which themselves may be derived from hepatic stem/progenitor cells (HPCs) upon genetic deregulation of stem cell self-renewal pathway.	('CSCs', 'Disease', (83, 87))	('liver cancers', 'Disease', (50, 63))	('originate', 'Reg', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('liver cancers', 'Phenotype', 'HP:0002896', (50, 63))	('liver cancer', 'Phenotype', 'HP:0002896', (50, 62))	('liver cancers', 'Disease', 'MESH:D006528', (50, 63))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('genetic deregulation', 'Var', (167, 187))
27062	25598674	Repeated rounds of inflammation and regeneration in chronic liver disease result in various genetic and epigenetic changes to both parenchymal cells and HPCs, activating various signaling pathways due to the stromal microenvironment.	('epigenetic', 'Var', (104, 114))	('chronic liver disease', 'Disease', (52, 73))	('genetic', 'MPA', (92, 99))	('inflammation', 'Disease', 'MESH:D007249', (19, 31))	('chronic liver disease', 'Disease', 'MESH:D058625', (52, 73))	('signaling pathways', 'Pathway', (178, 196))	('liver disease', 'Phenotype', 'HP:0001392', (60, 73))	('activating', 'PosReg', (159, 169))	('inflammation', 'Disease', (19, 31))	('changes', 'Reg', (115, 122))
27169	25598674	reported that the incidence of chronic liver disease was higher in the atypical enhancement group of intrahepatic CCs (arterial enhancement on dynamic contrast-enhanced CT in > 50% of the lesion volume) than in the typical enhancement group.	('chronic liver disease', 'Disease', (31, 52))	('chronic liver disease', 'Disease', 'MESH:D058625', (31, 52))	('atypical enhancement', 'Var', (71, 91))	('liver disease', 'Phenotype', 'HP:0001392', (39, 52))	('intrahepatic CCs', 'Disease', (101, 117))	('intrahepatic CCs', 'Disease', 'MESH:D002780', (101, 117))
27288	32468445	The majority of tumour specimens showed positivity for CD31 and CD105 to varying degrees (Fig.	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('tumour', 'Disease', (16, 22))	('CD105', 'Gene', '13805', (64, 69))	('CD105', 'Gene', (64, 69))	('CD31', 'Protein', (55, 59))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('positivity', 'Var', (40, 50))
27295	32468445	Neither CD31 nor CD105 MVD was significantly associated with DFS.	('DFS', 'Disease', (61, 64))	('CD105', 'Gene', (17, 22))	('associated', 'Reg', (45, 55))	('CD105', 'Gene', '13805', (17, 22))	('CD31', 'Var', (8, 12))
27303	32468445	Neovascularization enhances both local aggressiveness and metastatic potential in tumour tissue by increasing nutrient and oxygen delivery to cancer cells.	('aggressiveness', 'Disease', (39, 53))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('aggressiveness', 'Phenotype', 'HP:0000718', (39, 53))	('Neovascularization', 'Var', (0, 18))	('increasing', 'PosReg', (99, 109))	('enhances', 'PosReg', (19, 27))	('oxygen', 'Chemical', 'MESH:D010100', (123, 129))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumour', 'Disease', (82, 88))	('aggressiveness', 'Disease', 'MESH:D001523', (39, 53))	('metastatic potential', 'CPA', (58, 78))	('cancer', 'Disease', (142, 148))
27306	32468445	In a series of 60 pCCA patients who underwent resection, tumours with high CD31 MVD (based on a cut-off value of 20) were found to be significantly linked to higher risk of nodal involvement and local recurrence, whilst upon Cox regression analysis high MVD was found to be an independent predictor of adverse OS.	('local recurrence', 'CPA', (195, 211))	('patients', 'Species', '9606', (23, 31))	('linked', 'Reg', (148, 154))	('nodal involvement', 'CPA', (173, 190))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('CD31', 'Gene', (75, 79))	('tumours', 'Disease', (57, 64))	('high', 'Var', (70, 74))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('MVD', 'Var', (80, 83))	('CCA', 'Phenotype', 'HP:0030153', (19, 22))
27308	32468445	Our work scrutinizes the expression and prognostic impact of CD105 MVD in pCCA, and although this bore no significant statistical association with any patient features, we were able to show that a MVD > 31 was associated with a significantly poorer OS.	('MVD > 31', 'Var', (197, 205))	('CD105', 'Gene', '13805', (61, 66))	('CD105', 'Gene', (61, 66))	('patient', 'Species', '9606', (151, 158))	('poorer', 'NegReg', (242, 248))	('pCCA', 'Disease', (74, 78))	('CCA', 'Phenotype', 'HP:0030153', (75, 78))
27320	32468445	Accordingly, our immunofluorescence experiments confirmed CD105 positivity on the surface of murine SVR endothelial cells.	('CD105', 'Gene', (58, 63))	('murine', 'Species', '10090', (93, 99))	('positivity', 'Var', (64, 74))	('CD105', 'Gene', '13805', (58, 63))
27481	30756133	Glyphosate levels were below the limit of detection in the 50% control, 11% NK603, 50% NK603, 11% NK603 + Roundup and 50% NK603 + Roundup diets, while glyphosate was detected in the 33% control and 33% NK603 + Roundup diets used for the 90-day feeding trial with the GM maize NK603 at an inclusion rate of up to 50% (Table 4, Electronic Supplementary Material).	('NK603 +', 'Var', (98, 105))	('maize', 'Species', '4577', (270, 275))	('NK603', 'Chemical', '-', (98, 103))	('glyphosate', 'Chemical', 'MESH:C010974', (151, 161))	('NK603', 'Chemical', '-', (122, 127))	('Glyphosate', 'Chemical', 'MESH:C010974', (0, 10))	('Glyphosate levels', 'MPA', (0, 17))	('rat', 'Species', '10116', (298, 301))	('GM', 'Chemical', '-', (267, 269))	('NK603', 'Chemical', '-', (87, 92))	('NK603', 'Chemical', '-', (202, 207))	('NK603', 'Chemical', '-', (276, 281))	('NK603', 'Chemical', '-', (76, 81))
27488	30756133	There was one unscheduled death: a male rat fed the 33% NK603 diet was sacrificed moribund on day 51 due to a malignant lymphoma, which was considered not to be treatment-related, since it was only observed in 1 out of 16 young animals having been fed the diet for less than 2 months.	('malignant lymphoma', 'Disease', (110, 128))	('death', 'Disease', 'MESH:D003643', (26, 31))	('death', 'Disease', (26, 31))	('rat', 'Species', '10116', (40, 43))	('lymphoma', 'Phenotype', 'HP:0002665', (120, 128))	('malignant lymphoma', 'Disease', 'MESH:D008223', (110, 128))	('NK603', 'Var', (56, 61))	('NK603', 'Chemical', '-', (56, 61))
27493	30756133	The MCHC was significantly lower in male rats fed the 11% NK603 diet and the 11% NK603 + Roundup (with a Roundup application during cultivation) diet when compared to the control value based on the 95% confidence interval.	('NK603', 'Chemical', '-', (81, 86))	('rats', 'Species', '10116', (41, 45))	('lower', 'NegReg', (27, 32))	('NK603', 'Var', (58, 63))	('NK603', 'Chemical', '-', (58, 63))	('MCHC', 'MPA', (4, 8))
27494	30756133	The percentage lymphocytes (determined in the differential leukocyte analysis) was significantly lower and the percentage neutrophils significantly higher in male rats fed the 33% NK603 diet.	('NK603', 'Var', (180, 185))	('lower', 'NegReg', (97, 102))	('rats', 'Species', '10116', (163, 167))	('NK603', 'Chemical', '-', (180, 185))	('higher', 'PosReg', (148, 154))
27500	30756133	In male rats, K levels were significantly higher in animals fed the 33% NK603 diet, ALT activity was significantly lower and ALB, TP, CREA and K levels were significantly higher in animals fed the 11% NK603 + Roundup diet and ALP activity was significantly higher in animals fed the 33% NK603 + Roundup diet when compared to the corresponding control diets.	('K levels', 'MPA', (14, 22))	('rats', 'Species', '10116', (8, 12))	('NK603', 'Chemical', '-', (287, 292))	('NK603', 'Chemical', '-', (201, 206))	('CREA', 'Chemical', 'MESH:D003404', (134, 138))	('higher', 'PosReg', (171, 177))	('ALB', 'Gene', (125, 128))	('higher', 'PosReg', (42, 48))	('lower', 'NegReg', (115, 120))	('ALP activity', 'MPA', (226, 238))	('NK603', 'Var', (72, 77))	('higher', 'PosReg', (257, 263))	('TP', 'Chemical', '-', (130, 132))	('NK603', 'Chemical', '-', (72, 77))	('K levels', 'MPA', (143, 151))	('ALT activity', 'MPA', (84, 96))	('ALB', 'Gene', '24186', (125, 128))
27504	30756133	The testosterone and T3 levels in the four groups fed the NK603 diet were not significantly different from those in the corresponding control group, whereas the T4 level was significantly lower in the group fed the 33% NK603 diet if compared to the control group.	('T3 levels', 'MPA', (21, 30))	('lower', 'NegReg', (188, 193))	('testosterone', 'MPA', (4, 16))	('testosterone', 'Chemical', 'MESH:D013739', (4, 16))	('NK603', 'Var', (58, 63))	('T4 level', 'MPA', (161, 169))	('T3', 'Chemical', 'MESH:D014284', (21, 23))	('NK603', 'Chemical', '-', (58, 63))	('NK603', 'Chemical', '-', (219, 224))
27506	30756133	The 17beta-estradiol levels in the four groups fed the NK603 diet were significantly lower than that in the control group.	('17beta-estradiol', 'Chemical', 'MESH:D004958', (4, 20))	('lower', 'NegReg', (85, 90))	('NK603', 'Chemical', '-', (55, 60))	('NK603', 'Var', (55, 60))	('17beta-estradiol levels', 'MPA', (4, 27))
27507	30756133	The T3 levels in the four groups fed the NK603 diet were not significantly different from that in the control group, while the T4 level was significantly lower in the 33% NK603 + Roundup group than in the control group.	('lower', 'NegReg', (154, 159))	('NK603', 'Chemical', '-', (171, 176))	('NK603 + Roundup', 'Var', (171, 186))	('NK603', 'Var', (41, 46))	('T4 level', 'MPA', (127, 135))	('T3', 'Chemical', 'MESH:D014284', (4, 6))	('NK603', 'Chemical', '-', (41, 46))
27508	30756133	The urine pH was significantly lower in male rats fed the 33% NK603 and 33% NK603 + Roundup diets than in the control group, while the ketone level was significantly lower in female rats fed the 33% NK603 + Roundup diet than in the control group.	('33% NK603', 'Var', (58, 67))	('urine pH', 'MPA', (4, 12))	('rats', 'Species', '10116', (45, 49))	('ketone level', 'MPA', (135, 147))	('NK603', 'Chemical', '-', (199, 204))	('rats', 'Species', '10116', (182, 186))	('lower', 'NegReg', (31, 36))	('ketone', 'Chemical', 'MESH:D007659', (135, 141))	('lower', 'NegReg', (166, 171))	('NK603', 'Chemical', '-', (62, 67))	('NK603', 'Chemical', '-', (76, 81))
27511	30756133	The relative thymus weight in male rats fed the 11% NK603 + Roundup diet was significantly higher than that in the control group.	('NK603 +', 'Var', (52, 59))	('higher', 'PosReg', (91, 97))	('NK603', 'Chemical', '-', (52, 57))	('rats', 'Species', '10116', (35, 39))
27512	30756133	In female rats, the relative adrenal gland weight in the groups fed the 11% NK603, 33% NK603 and the 11% NK603 + Roundup diets, the relative ovary weight in the animals fed the 11% NK603 and the 33% NK603 + Roundup diets, as well as the relative spleen weight in rats fed the 11% NK603 + Roundup diet were significantly lower when compared to the corresponding control groups.	('NK603', 'Chemical', '-', (280, 285))	('NK603', 'Chemical', '-', (105, 110))	('rats', 'Species', '10116', (10, 14))	('NK603', 'Chemical', '-', (181, 186))	('NK603', 'Chemical', '-', (199, 204))	('NK603', 'Chemical', '-', (87, 92))	('lower', 'NegReg', (320, 325))	('NK603', 'Var', (76, 81))	('NK603', 'Chemical', '-', (76, 81))	('rats', 'Species', '10116', (263, 267))
27517	30756133	There were no treatment-related necropsy findings following the feeding of NK603 or NK603 + Roundup to rats for 90 days.	('NK603', 'Var', (75, 80))	('NK603 +', 'Var', (84, 91))	('NK603', 'Chemical', '-', (75, 80))	('rats', 'Species', '10116', (103, 107))	('NK603', 'Chemical', '-', (84, 89))
27519	30756133	There were no treatment-related histopathological findings following the feeding of NK603 or NK603 + Roundup to rats for 90 days.	('rats', 'Species', '10116', (112, 116))	('NK603', 'Chemical', '-', (93, 98))	('NK603 +', 'Var', (93, 100))	('NK603', 'Var', (84, 89))	('NK603', 'Chemical', '-', (84, 89))
27521	30756133	The body weight as well as the feed consumption during the 90-day feeding period was significantly decreased for male rats fed NK603 at the 50% inclusion rate relative to the 50% control diet.	('feed consumption', 'CPA', (31, 47))	('decreased', 'NegReg', (99, 108))	('rat', 'Species', '10116', (118, 121))	('rat', 'Species', '10116', (154, 157))	('NK603', 'Var', (127, 132))	('body weight', 'CPA', (4, 15))	('NK603', 'Chemical', '-', (127, 132))	('rats', 'Species', '10116', (118, 122))
27522	30756133	The body weight as well as the feed consumption of female rats during the 90-day feeding period was significantly increased for female rats fed NK603 + Roundup at an inclusion rate of 11% compared to the control group with an inclusion rate of 50%.	('feed consumption', 'CPA', (31, 47))	('rat', 'Species', '10116', (176, 179))	('rat', 'Species', '10116', (135, 138))	('NK603 + Roundup', 'Var', (144, 159))	('rat', 'Species', '10116', (236, 239))	('rats', 'Species', '10116', (58, 62))	('increased', 'PosReg', (114, 123))	('body weight', 'CPA', (4, 15))	('NK603', 'Chemical', '-', (144, 149))	('rat', 'Species', '10116', (58, 61))	('rats', 'Species', '10116', (135, 139))
27523	30756133	The growth rate was significantly increased for female rats fed NK603 at an inclusion rate of 50%.	('NK603', 'Var', (64, 69))	('rats', 'Species', '10116', (55, 59))	('NK603', 'Chemical', '-', (64, 69))	('growth', 'MPA', (4, 10))	('rat', 'Species', '10116', (11, 14))	('increased', 'PosReg', (34, 43))	('rat', 'Species', '10116', (55, 58))	('rat', 'Species', '10116', (86, 89))
27526	30756133	In male rats, HGB in the group fed the 11% NK603 and the 11% NK603 + Roundup diets, PLT in the group fed the 50% NK603 and the 50% NK603 + Roundup diets and HCT in the group fed the 11% NK603 + Roundup diet were significantly higher than in the 50% control group, MCV and MCH were significantly lower in the group fed the 33% NK603 + Roundup than in the 33% control group and MCV and MCH were significantly higher in the group fed the 50% NK603 + Roundup diet than in the group fed the 33% NK603 + Roundup diet.	('NK603', 'Var', (43, 48))	('NK603 +', 'Var', (61, 68))	('NK603', 'Chemical', '-', (326, 331))	('HCT', 'CPA', (157, 160))	('NK603', 'Chemical', '-', (113, 118))	('MCV', 'CPA', (264, 267))	('lower', 'NegReg', (295, 300))	('NK603', 'Chemical', '-', (61, 66))	('NK603', 'Chemical', '-', (490, 495))	('higher', 'PosReg', (226, 232))	('rats', 'Species', '10116', (8, 12))	('NK603', 'Chemical', '-', (131, 136))	('MCH', 'CPA', (272, 275))	('NK603', 'Chemical', '-', (186, 191))	('higher', 'PosReg', (407, 413))	('NK603', 'Chemical', '-', (43, 48))	('NK603', 'Chemical', '-', (439, 444))	('PLT', 'CPA', (84, 87))	('HGB', 'CPA', (14, 17))
27528	30756133	The percentage neutrophils was significantly lower in male rats fed the 50% NK603 diet than in the groups fed the 50% control diet or the 33% NK603 diet.	('rats', 'Species', '10116', (59, 63))	('lower', 'NegReg', (45, 50))	('NK603', 'Var', (76, 81))	('NK603', 'Chemical', '-', (142, 147))	('percentage neutrophils', 'CPA', (4, 26))	('NK603', 'Chemical', '-', (76, 81))
27529	30756133	In female rats, RBC was significantly higher and MCV significantly lower in the group fed the 33% NK603 + Roundup diet than in the group fed the 33% control diet, while PLT was significantly lower in the group fed the 50% NK603 diet + Roundup than in the group fed the 33% NK603 + Roundup diet.	('NK603', 'Chemical', '-', (222, 227))	('PLT', 'MPA', (169, 172))	('NK603', 'Chemical', '-', (273, 278))	('NK603', 'Chemical', '-', (98, 103))	('NK603 + Roundup', 'Var', (98, 113))	('RBC', 'MPA', (16, 19))	('rats', 'Species', '10116', (10, 14))	('MCV', 'MPA', (49, 52))	('higher', 'PosReg', (38, 44))	('lower', 'NegReg', (191, 196))	('lower', 'NegReg', (67, 72))
27534	30756133	In female rats, ALT was significantly higher in the group fed the 50% NK603 + Roundup diet than in the group fed the 33% NK603 + Roundup diet, whereas it was significantly lower in the group fed the 33% NK603 + Roundup diet than in the 33% control group.	('rats', 'Species', '10116', (10, 14))	('lower', 'NegReg', (172, 177))	('NK603', 'Chemical', '-', (203, 208))	('ALT', 'MPA', (16, 19))	('higher', 'PosReg', (38, 44))	('NK603 + Roundup', 'Var', (70, 85))	('NK603', 'Chemical', '-', (70, 75))	('NK603', 'Chemical', '-', (121, 126))
27535	30756133	ALB was significantly lower in the group fed the 50% NK603 + Roundup diet than in the group fed the 33% NK603 + Roundup diet.	('ALB', 'Gene', (0, 3))	('NK603 + Roundup', 'Var', (53, 68))	('NK603', 'Chemical', '-', (53, 58))	('ALB', 'Gene', '24186', (0, 3))	('NK603', 'Chemical', '-', (104, 109))	('lower', 'NegReg', (22, 27))
27536	30756133	CHOL was significantly lower in the 50% NK603 group than in the 33% NK603 group and the 33% NK603 + Roundup group; moreover, CHOL was significantly lower in the 50% NK603 + Roundup group than in the 50% control group.	('NK603', 'Var', (40, 45))	('NK603', 'Chemical', '-', (92, 97))	('CHOL', 'Disease', 'None', (0, 4))	('NK603', 'Chemical', '-', (40, 45))	('NK603', 'Chemical', '-', (165, 170))	('NK603', 'Chemical', '-', (68, 73))	('lower', 'NegReg', (148, 153))	('NK603 + Roundup', 'Var', (165, 180))	('CHOL', 'Disease', (0, 4))	('CHOL', 'Disease', 'None', (125, 129))	('CHOL', 'Disease', (125, 129))	('lower', 'NegReg', (23, 28))
27537	30756133	TAG levels were significantly lower in the group fed the 50% NK603 + Roundup diet than in the group fed the 50% control diet and the 33% NK603 + Roundup diet.	('TAG levels', 'MPA', (0, 10))	('lower', 'NegReg', (30, 35))	('NK603 + Roundup', 'Var', (61, 76))	('NK603', 'Chemical', '-', (61, 66))	('NK603', 'Chemical', '-', (137, 142))
27538	30756133	CREA was significantly lower in the group fed the 50% NK603 + Roundup diet than in the group fed the 33% NK603 + Roundup diet.	('CREA', 'MPA', (0, 4))	('NK603 + Roundup', 'Var', (54, 69))	('NK603', 'Chemical', '-', (54, 59))	('NK603', 'Chemical', '-', (105, 110))	('CREA', 'Chemical', 'MESH:D003404', (0, 4))	('lower', 'NegReg', (23, 28))
27542	30756133	The urine pH was significantly lower in male rats fed the 50% NK603 + Roundup diet than in the group fed the 33% NK603 + Roundup diet.	('urine pH', 'MPA', (4, 12))	('rats', 'Species', '10116', (45, 49))	('NK603', 'Chemical', '-', (113, 118))	('lower', 'NegReg', (31, 36))	('NK603 + Roundup', 'Var', (62, 77))	('NK603', 'Chemical', '-', (62, 67))	('Roundup', 'Var', (70, 77))
27543	30756133	In female rats, the urine volume and pH were significantly lower in the group fed the 50% NK603 diet than in the group fed the 33% NK603 diet, while the urine volume/body weight was significantly higher in the group fed the 33% NK603 diet than in the group fed the 33% control diet and the urine osmolarity was significantly lower in the group fed the 33% NK603 diet than in the group fed the 33% control diet.	('lower', 'NegReg', (325, 330))	('NK603', 'Chemical', '-', (228, 233))	('50% NK603 diet', 'Var', (86, 100))	('urine osmolarity', 'MPA', (290, 306))	('lower', 'NegReg', (59, 64))	('rats', 'Species', '10116', (10, 14))	('NK603', 'Chemical', '-', (356, 361))	('urine volume/body weight', 'MPA', (153, 177))	('higher', 'PosReg', (196, 202))	('urine volume', 'MPA', (20, 32))	('NK603', 'Chemical', '-', (131, 136))	('NK603', 'Chemical', '-', (90, 95))
27545	30756133	In male rats fed the 50% NK603 diet, the relative brain and testis weights were significantly higher than those in the 50% control group and the relative heart weight and thymus weight were significantly higher than that in the 33% NK603 group.	('NK603', 'Chemical', '-', (232, 237))	('thymus weight', 'CPA', (171, 184))	('NK603', 'Chemical', '-', (25, 30))	('NK603', 'Var', (25, 30))	('rats', 'Species', '10116', (8, 12))	('higher', 'PosReg', (94, 100))	('higher', 'PosReg', (204, 210))
27546	30756133	The relative heart weight in the 33% NK603 group was significantly lower than in the 33% control group.	('NK603', 'Chemical', '-', (37, 42))	('lower', 'NegReg', (67, 72))	('NK603', 'Var', (37, 42))
27547	30756133	In female rats fed the 50% NK603 + Roundup diet, the relative kidney and ovary weights were significantly higher than those in the 50% control group and the relative heart and ovary weights were significantly higher than those in the 33% NK603 + Roundup group.	('NK603', 'Chemical', '-', (238, 243))	('rats', 'Species', '10116', (10, 14))	('higher', 'PosReg', (106, 112))	('higher', 'PosReg', (209, 215))	('NK603', 'Chemical', '-', (27, 32))	('50% NK603 + Roundup', 'Var', (23, 42))
27548	30756133	The relative thymus weight in the 11% NK603 + Roundup group was significantly lower than in the 50% control group.	('lower', 'NegReg', (78, 83))	('NK603 + Roundup', 'Var', (38, 53))	('NK603', 'Chemical', '-', (38, 43))
27552	30756133	There were no treatment-related necropsy and histopathological findings following the feeding of NK603 or NK603 + Roundup to rats up to 50% inclusion rate for 90 days.	('rat', 'Species', '10116', (125, 128))	('NK603', 'Chemical', '-', (106, 111))	('rat', 'Species', '10116', (150, 153))	('NK603 + Roundup', 'Var', (106, 121))	('rats', 'Species', '10116', (125, 129))	('NK603', 'Var', (97, 102))	('NK603', 'Chemical', '-', (97, 102))
27554	30756133	The mortality rate of the male rats fed the 33% NK603 + Roundup diet was significantly higher than that of the corresponding control group (p = 0.03 in a one-sided test).	('mortality', 'Disease', 'MESH:D003643', (4, 13))	('NK603', 'Chemical', '-', (48, 53))	('rats', 'Species', '10116', (31, 35))	('mortality', 'Disease', (4, 13))	('NK603 +', 'Var', (48, 55))	('rat', 'Species', '10116', (14, 17))	('rat', 'Species', '10116', (31, 34))	('higher', 'PosReg', (87, 93))
27555	30756133	In contrast, the female rats fed the 33% NK603 + Roundup diet showed a lower, though not significantly lower mortality rate than the corresponding control group (p = 0.07 if the test would have been performed for decreased rather than increased mortality).	('mortality', 'Disease', (245, 254))	('mortality', 'Disease', 'MESH:D003643', (109, 118))	('rats', 'Species', '10116', (24, 28))	('NK603 +', 'Var', (41, 48))	('rat', 'Species', '10116', (119, 122))	('lower', 'NegReg', (103, 108))	('mortality', 'Disease', (109, 118))	('NK603', 'Chemical', '-', (41, 46))	('rat', 'Species', '10116', (24, 27))	('rat', 'Species', '10116', (223, 226))	('mortality', 'Disease', 'MESH:D003643', (245, 254))
27557	30756133	The male rats fed the NK603 + Roundup diet at an inclusion rate of 33% showed a significantly higher body weight when compared to the corresponding control group in the second half of the experimental period, while the body weight of the female rats was similar in all five experimental groups (Fig.	('NK603 +', 'Var', (22, 29))	('NK603', 'Chemical', '-', (22, 27))	('rat', 'Species', '10116', (9, 12))	('rat', 'Species', '10116', (245, 248))	('rat', 'Species', '10116', (59, 62))	('rats', 'Species', '10116', (245, 249))	('body weight', 'CPA', (101, 112))	('rats', 'Species', '10116', (9, 13))	('higher', 'PosReg', (94, 100))
27561	30756133	At t = 3 months, WBC were significantly higher in the group fed the 33% NK603 diet than in the control group.	('WBC', 'MPA', (17, 20))	('NK603', 'Var', (72, 77))	('higher', 'PosReg', (40, 46))	('NK603', 'Chemical', '-', (72, 77))
27562	30756133	At t = 6 months, WBC and LYMA were significantly higher in the groups fed the 33% NK603 and 11% NK603 + Roundup diets than in the control group, while the percentage monocytes was significantly lower in the group fed the 11% NK603 diet than in the control group.	('NK603', 'Chemical', '-', (82, 87))	('NK603', 'Chemical', '-', (96, 101))	('higher', 'PosReg', (49, 55))	('NK603', 'Chemical', '-', (225, 230))	('NK603', 'Var', (82, 87))
27563	30756133	At t = 12 months, HCT was significantly higher and MCHC was significantly lower in the group fed the 11% NK603 + Roundup diet than in the control group, while PLT was significantly higher in the groups fed the 33% NK603 and the 33% NK603 + Roundup diets than in the control group.	('PLT', 'MPA', (159, 162))	('NK603', 'Chemical', '-', (214, 219))	('higher', 'PosReg', (40, 46))	('NK603', 'Chemical', '-', (232, 237))	('NK603', 'Chemical', '-', (105, 110))	('higher', 'PosReg', (181, 187))	('HCT', 'MPA', (18, 21))	('MCHC', 'CPA', (51, 55))	('lower', 'NegReg', (74, 79))	('NK603 +', 'Var', (105, 112))
27565	30756133	At t = 6 months, PLT was significantly higher in the group fed the 11% NK603 + Roundup diet than in the control group, whereas the percentage monocytes was significantly lower in the group fed the 33% NK603 + Roundup diet than in the control group.	('higher', 'PosReg', (39, 45))	('NK603', 'Chemical', '-', (201, 206))	('NK603 + Roundup', 'Var', (71, 86))	('NK603', 'Chemical', '-', (71, 76))	('lower', 'NegReg', (170, 175))	('PLT', 'CPA', (17, 20))
27566	30756133	At t = 12 months, MCH was significantly lower in the groups fed the 11% NK603 + Roundup and the 33% NK603 + Roundup diets and MCHC was significantly lower in the group fed the 11% NK603 + Roundup diet than in the control group.	('NK603 + Roundup', 'Var', (72, 87))	('NK603', 'Chemical', '-', (100, 105))	('NK603', 'Chemical', '-', (72, 77))	('MCH', 'CPA', (18, 21))	('lower', 'NegReg', (149, 154))	('NK603', 'Chemical', '-', (180, 185))	('lower', 'NegReg', (40, 45))
27568	30756133	At t = 24 months, the percentage eosinophils was significantly higher in the group fed the 33% NK603 diet than in the control group.	('NK603', 'Var', (95, 100))	('higher', 'PosReg', (63, 69))	('NK603', 'Chemical', '-', (95, 100))	('eosin', 'Chemical', 'MESH:D004801', (33, 38))
27573	30756133	The TAG levels were significantly higher in the groups fed the 11% NK603 + Roundup diet than in the control group at t = 6 and 12 months, while UREA was significantly higher in the group fed the 11% NK603 diet than in the control group at t = 24 months.	('higher', 'PosReg', (167, 173))	('TAG levels', 'MPA', (4, 14))	('NK603', 'Chemical', '-', (67, 72))	('higher', 'PosReg', (34, 40))	('11% NK603 +', 'Var', (63, 74))	('NK603', 'Chemical', '-', (199, 204))	('UREA', 'MPA', (144, 148))	('UREA', 'Chemical', 'MESH:D014508', (144, 148))
27574	30756133	Cl was significantly lower in the groups fed the 33% NK603, 11% NK603 + Roundup and 33% NK603 + Roundup diets than in the control group at t = 12 months, whereas K was significantly higher in the group fed the 11% NK603 + Roundup diet than in the control group at t = 24 months and P was significantly lower in the group fed the 11% NK603 diet than in the control group at t = 12 months.	('NK603', 'Chemical', '-', (88, 93))	('NK603', 'Chemical', '-', (214, 219))	('NK603', 'Chemical', '-', (53, 58))	('NK603 + Roundup', 'Var', (64, 79))	('NK603', 'Chemical', '-', (64, 69))	('lower', 'NegReg', (21, 26))	('NK603', 'Chemical', '-', (333, 338))	('higher', 'PosReg', (182, 188))	('NK603', 'Var', (53, 58))
27576	30756133	ALT was significantly lower in the group fed the 11% NK603 + Roundup diet than in the control group after 12 months and AST was significantly higher in the group fed the 33% NK603 + Roundup diet than in the control group at t = 6 months.	('AST', 'Gene', (120, 123))	('ALT', 'MPA', (0, 3))	('NK603', 'Chemical', '-', (53, 58))	('NK603', 'Chemical', '-', (174, 179))	('11% NK603 + Roundup', 'Var', (49, 68))	('lower', 'NegReg', (22, 27))	('higher', 'PosReg', (142, 148))	('AST', 'Gene', '25721', (120, 123))
27577	30756133	TAG was significantly lower in the group fed the 11% NK603 + Roundup diet than in the control group at t = 6 months.	('TAG', 'MPA', (0, 3))	('NK603 +', 'Var', (53, 60))	('lower', 'NegReg', (22, 27))	('NK603', 'Chemical', '-', (53, 58))
27578	30756133	CREA was significantly higher in the group fed the 11% NK603 diet than in the control group at t = 12 months and was significantly higher in the groups fed the 33% NK603, 11% NK603 + Roundup and 33% NK603 + Roundup diets than in the control group at t = 24 months.	('CREA', 'MPA', (0, 4))	('NK603', 'Chemical', '-', (175, 180))	('higher', 'PosReg', (23, 29))	('CREA', 'Chemical', 'MESH:D003404', (0, 4))	('NK603', 'Chemical', '-', (199, 204))	('NK603', 'Chemical', '-', (164, 169))	('NK603 + Roundup', 'Var', (199, 214))	('NK603', 'Chemical', '-', (55, 60))	('higher', 'PosReg', (131, 137))
27579	30756133	UREA was significantly higher in all four groups fed the NK603 containing diets than in the control group at t = 12 months.	('NK603', 'Chemical', '-', (57, 62))	('higher', 'PosReg', (23, 29))	('UREA', 'MPA', (0, 4))	('NK603 containing', 'Var', (57, 73))	('UREA', 'Chemical', 'MESH:D014508', (0, 4))
27583	30756133	P was significantly higher in the group fed the 33% NK603 diet than in the control group at t = 3 months.	('higher', 'PosReg', (20, 26))	('NK603', 'Chemical', '-', (52, 57))	('NK603', 'Var', (52, 57))
27585	30756133	Likewise, the equivalence tests at t = 3 and t = 6 months showed "equivalence" for 225 comparisons involving the 15 clinical biochemical parameters, and "equivalence more likely than not" for 15 comparisons: one or both ELSD confidence limits were outside the interval [- 1, + 1] for CHOL in female rats fed the 33% NK603, the 11% NK603 + Roundup or the 33% NK603 + Roundup diet at t = 3 months, or fed any NK603 diet at t = 6 months, and P levels in female rats fed the 33% NK603 diet at t = 3 months.	('NK603', 'Chemical', '-', (358, 363))	('CHOL', 'Disease', (284, 288))	('NK603', 'Chemical', '-', (407, 412))	('rats', 'Species', '10116', (299, 303))	('33% NK603 + Roundup', 'Var', (354, 373))	('NK603', 'Chemical', '-', (475, 480))	('NK603', 'Chemical', '-', (316, 321))	('CHOL', 'Disease', 'None', (284, 288))	('rats', 'Species', '10116', (458, 462))	('NK603', 'Chemical', '-', (331, 336))
27586	30756133	In male rats, at t = 3 months, the urine volume was significantly lower and the urine leukocyte number as well as the urine ketone level were significantly higher in the group fed the 33% NK603 diet than in the control group.	('higher', 'PosReg', (156, 162))	('urine leukocyte', 'MPA', (80, 95))	('33% NK603', 'Var', (184, 193))	('urine ketone level', 'MPA', (118, 136))	('lower', 'NegReg', (66, 71))	('NK603', 'Chemical', '-', (188, 193))	('urine ketone', 'Phenotype', 'HP:0002919', (118, 130))	('ketone', 'Chemical', 'MESH:D007659', (124, 130))	('rats', 'Species', '10116', (8, 12))	('urine volume', 'MPA', (35, 47))
27587	30756133	At t = 6 months, the urine volume was significantly lower in the group fed the 33% NK603 diet than in the control group.	('urine volume', 'MPA', (21, 33))	('NK603', 'Var', (83, 88))	('lower', 'NegReg', (52, 57))	('NK603', 'Chemical', '-', (83, 88))
27588	30756133	At t = 12 months, the urine volume and the urine volume/body weight were significantly lower and the urine osmolarity and the urine ketone level were significantly higher in the group fed the 33% NK603 diet than in the control group, while the urine volume, urine volume/body weight and urine leukocyte number were significantly lower in the group fed the 11% NK603 diet than in the control group.	('urine osmolarity', 'MPA', (101, 117))	('lower', 'NegReg', (329, 334))	('lower', 'NegReg', (87, 92))	('NK603', 'Chemical', '-', (360, 365))	('higher', 'PosReg', (164, 170))	('ketone', 'Chemical', 'MESH:D007659', (132, 138))	('urine leukocyte number', 'CPA', (287, 309))	('urine volume/body weight', 'CPA', (258, 282))	('urine volume', 'MPA', (22, 34))	('urine volume/body weight', 'MPA', (43, 67))	('urine ketone level', 'MPA', (126, 144))	('NK603', 'Chemical', '-', (196, 201))	('33% NK603', 'Var', (192, 201))	('urine ketone', 'Phenotype', 'HP:0002919', (126, 138))	('urine volume', 'CPA', (244, 256))
27589	30756133	At t = 24 months, the urine ketone level was significantly higher in the group fed the 33% NK603 + Roundup diet than in the control group.	('ketone', 'Chemical', 'MESH:D007659', (28, 34))	('NK603', 'Chemical', '-', (91, 96))	('urine ketone level', 'MPA', (22, 40))	('urine ketone', 'Phenotype', 'HP:0002919', (22, 34))	('higher', 'PosReg', (59, 65))	('NK603 +', 'Var', (91, 98))
27590	30756133	In female rats, at t = 3 months, the urine ketone level was higher in the group fed the 11% NK603 + Roundup diet than in the control group, while the urine volume/bodyweight was lower in the group fed the 33% NK603 + Roundup diet than in the control group.	('NK603', 'Chemical', '-', (92, 97))	('higher', 'PosReg', (60, 66))	('lower', 'NegReg', (178, 183))	('NK603 + Roundup', 'Var', (92, 107))	('rats', 'Species', '10116', (10, 14))	('NK603', 'Chemical', '-', (209, 214))	('urine volume/bodyweight', 'MPA', (150, 173))	('urine ketone level', 'MPA', (37, 55))	('urine ketone', 'Phenotype', 'HP:0002919', (37, 49))	('ketone', 'Chemical', 'MESH:D007659', (43, 49))
27591	30756133	At t = 24 months, the urine pH was higher in the group fed the 33% NK603 diet than in the control group.	('urine pH', 'MPA', (22, 30))	('NK603', 'Var', (67, 72))	('higher', 'PosReg', (35, 41))	('NK603', 'Chemical', '-', (67, 72))
27592	30756133	Apart from these 13 cases of significance, the other 243 comparisons involving 8 urinalysis parameters in male and female rats over 4 points in time and 4 NK603 groups showed no significant differences between the NK603-fed groups and the group fed the control diet.	('NK603', 'Chemical', '-', (214, 219))	('rats', 'Species', '10116', (122, 126))	('urinalysis', 'MPA', (81, 91))	('NK603-fed', 'Var', (214, 223))	('NK603', 'Chemical', '-', (155, 160))
27594	30756133	In male rats fed the 11% NK603 diet, the relative epididymides weight was significantly higher than that in the control group.	('rats', 'Species', '10116', (8, 12))	('higher', 'PosReg', (88, 94))	('NK603', 'Chemical', '-', (25, 30))	('NK603', 'Var', (25, 30))
27595	30756133	In female rats, the relative brain weight was significantly higher in the four groups fed the NK603 diets, whereas the relative kidney weight was significantly higher in the groups fed the 11% NK603 + Roundup and the 33% NK603 + Roundup diets than in the control group.	('higher', 'PosReg', (160, 166))	('NK603', 'Chemical', '-', (94, 99))	('higher', 'PosReg', (60, 66))	('rats', 'Species', '10116', (10, 14))	('NK603', 'Chemical', '-', (193, 198))	('NK603', 'Var', (94, 99))	('NK603', 'Chemical', '-', (221, 226))	('relative brain weight', 'CPA', (20, 41))
27597	30756133	As previously mentioned, the mortality rate of the male rats fed the 33% NK603 + Roundup diet was significantly higher than that of the corresponding control group.	('NK603', 'Chemical', '-', (73, 78))	('rat', 'Species', '10116', (56, 59))	('higher', 'PosReg', (112, 118))	('mortality', 'Disease', (29, 38))	('rat', 'Species', '10116', (39, 42))	('rats', 'Species', '10116', (56, 60))	('NK603 +', 'Var', (73, 80))	('mortality', 'Disease', 'MESH:D003643', (29, 38))
27612	30756133	All neoplastic microscopic findings observed in the rats fed the 33% control, 33% NK603 and 33% NK603 + Roundup diets in the carcinogenicity phase are listed in Table 24.	('NK603', 'Chemical', '-', (82, 87))	('NK603 +', 'Var', (96, 103))	('rats', 'Species', '10116', (52, 56))	('NK603', 'Chemical', '-', (96, 101))	('NK603', 'Var', (82, 87))
27614	30756133	The observed increase in the number of benign thymomas in the female group fed NK603 + Roundup at an inclusion rate of 33% was not statistically significant when compared to the control group, or when benign and malignant thymomas were analyzed in combination.	('malignant thymomas', 'Disease', 'MESH:D013945', (212, 230))	('rat', 'Species', '10116', (111, 114))	('benign thymomas', 'Disease', 'MESH:D013945', (39, 54))	('thymoma', 'Phenotype', 'HP:0100522', (46, 53))	('malignant thymomas', 'Phenotype', 'HP:0100697', (212, 230))	('malignant thymomas', 'Disease', (212, 230))	('NK603', 'Chemical', '-', (79, 84))	('thymoma', 'Phenotype', 'HP:0100522', (222, 229))	('increase', 'PosReg', (13, 21))	('NK603 + Roundup', 'Var', (79, 94))	('benign thymomas', 'Disease', (39, 54))
27631	30756133	Therefore, the Wistar Han RCC rat strain used in the present study was a suitable choice to test if the GM maize NK603 had the ability to stimulate mammary gland carcinogenesis.	('maize NK603', 'Var', (107, 118))	('Wistar Han RCC', 'Disease', (15, 29))	('NK603', 'Chemical', '-', (113, 118))	('mammary gland carcinogenesis', 'CPA', (148, 176))	('rat', 'Species', '10116', (30, 33))	('GM', 'Chemical', '-', (104, 106))	('Wistar Han RCC', 'Disease', 'MESH:C538614', (15, 29))	('maize', 'Species', '4577', (107, 112))	('stimulate', 'PosReg', (138, 147))
27635	30756133	The T4 level was significantly lower in the sera of male rats fed the 33% NK603 diet and in the sera of female rats fed the 33% NK603 + Roundup diet if compared to the corresponding control groups, but there were no histopathological changes in the thyroid gland, so that these changes in the T4 levels are considered not to be adverse.	('NK603', 'Chemical', '-', (74, 79))	('lower', 'NegReg', (31, 36))	('T4 level', 'MPA', (4, 12))	('rats', 'Species', '10116', (111, 115))	('rats', 'Species', '10116', (57, 61))	('NK603', 'Chemical', '-', (128, 133))	('NK603', 'Var', (74, 79))
27636	30756133	The 17beta-estradiol levels in the four groups of female rats fed the GM maize NK603 were significantly lower than that in the control group.	('17beta-estradiol', 'Chemical', 'MESH:D004958', (4, 20))	('NK603', 'Chemical', '-', (79, 84))	('GM', 'Chemical', '-', (70, 72))	('lower', 'NegReg', (104, 109))	('maize', 'Species', '4577', (73, 78))	('rats', 'Species', '10116', (57, 61))	('17beta-estradiol levels', 'MPA', (4, 27))	('maize NK603', 'Var', (73, 84))
27643	30756133	Mortality was significantly increased in male rats fed the 33% NK603 + Roundup diet when compared to the control group and was related to the increased number of deaths from pituitary neoplasia (12 male rats fed the control diet versus 17 male rats fed the 33% NK603 + Roundup diet), the most common cause of death in all groups including controls.	('rats', 'Species', '10116', (203, 207))	('death', 'Disease', (309, 314))	('NK603', 'Chemical', '-', (63, 68))	('death', 'Disease', 'MESH:D003643', (162, 167))	('pituitary neoplasia', 'Phenotype', 'HP:0040277', (174, 193))	('pituitary neoplasia', 'Disease', 'MESH:D009369', (174, 193))	('increased', 'PosReg', (28, 37))	('neoplasia', 'Phenotype', 'HP:0002664', (184, 193))	('NK603', 'Chemical', '-', (261, 266))	('Mortality', 'Disease', (0, 9))	('deaths', 'Disease', (162, 168))	('death', 'Disease', 'MESH:D003643', (309, 314))	('NK603 +', 'Var', (63, 70))	('death', 'Disease', (162, 167))	('rats', 'Species', '10116', (46, 50))	('rats', 'Species', '10116', (244, 248))	('deaths', 'Disease', 'MESH:D003643', (162, 168))	('Mortality', 'Disease', 'MESH:D003643', (0, 9))	('pituitary neoplasia', 'Disease', (174, 193))
27644	30756133	However, it is important to mention that there was no effect of the 33% NK603 + Roundup diet on the overall incidence of pituitary neoplasia, i.e.	('pituitary neoplasia', 'Phenotype', 'HP:0040277', (121, 140))	('pituitary neoplasia', 'Disease', (121, 140))	('neoplasia', 'Phenotype', 'HP:0002664', (131, 140))	('NK603 +', 'Var', (72, 79))	('NK603', 'Chemical', '-', (72, 77))	('pituitary neoplasia', 'Disease', 'MESH:D009369', (121, 140))
27645	30756133	the incidence of pituitary pars anterior adenomas in male rats fed the control and the 33% NK603 + Roundup diets was 62 and 58%, respectively.	('pituitary pars anterior adenomas', 'Disease', 'MESH:D010911', (17, 49))	('NK603', 'Chemical', '-', (91, 96))	('rats', 'Species', '10116', (58, 62))	('pituitary pars anterior adenomas', 'Disease', (17, 49))	('NK603 +', 'Var', (91, 98))
27646	30756133	The increased mortality observed between the 12th and 24th month of the feeding trial in male rats fed the 33% NK603 + Roundup diet coincided with a strong increase in the body weight of these rats in this period of time.	('mortality', 'Disease', (14, 23))	('body weight', 'CPA', (172, 183))	('increase', 'PosReg', (156, 164))	('mortality', 'Disease', 'MESH:D003643', (14, 23))	('rats', 'Species', '10116', (193, 197))	('NK603', 'Chemical', '-', (111, 116))	('rats', 'Species', '10116', (94, 98))	('NK603 +', 'Var', (111, 118))
27649	30756133	Therefore, it is concluded that the increased mortality associated with a higher body weight and an increased incidence of pituitary neoplasms in male rats fed the 33% NK603 + Roundup diet is not specifically related to the feeding of this diet (Keenan et al.	('pituitary neoplasms', 'Disease', (123, 142))	('pituitary neoplasm', 'Phenotype', 'HP:0040277', (123, 141))	('higher', 'PosReg', (74, 80))	('rats', 'Species', '10116', (151, 155))	('mortality', 'Disease', (46, 55))	('NK603 +', 'Var', (168, 175))	('neoplasms', 'Phenotype', 'HP:0002664', (133, 142))	('NK603', 'Chemical', '-', (168, 173))	('pituitary neoplasms', 'Disease', 'MESH:D010911', (123, 142))	('mortality', 'Disease', 'MESH:D003643', (46, 55))	('neoplasm', 'Phenotype', 'HP:0002664', (133, 141))	('body weight', 'CPA', (81, 92))
27650	30756133	In female rats fed the 33% NK603 + Roundup diet, the mortality rate was decreased when compared to the control female rats, but this difference was not statistically significant (p = 0.07).	('rat', 'Species', '10116', (118, 121))	('rats', 'Species', '10116', (10, 14))	('decreased', 'NegReg', (72, 81))	('NK603 +', 'Var', (27, 34))	('mortality', 'Disease', (53, 62))	('rat', 'Species', '10116', (10, 13))	('NK603', 'Chemical', '-', (27, 32))	('rat', 'Species', '10116', (63, 66))	('rats', 'Species', '10116', (118, 122))	('mortality', 'Disease', 'MESH:D003643', (53, 62))
27656	30756133	Based on the results obtained in the three feeding trials performed in the course of the G-TwYST project, it is concluded that there were no adverse findings related to the feeding with the NK603 or NK603 + Roundup diets to rats for up to 2 years.	('NK603', 'Chemical', '-', (190, 195))	('NK603 +', 'Var', (199, 206))	('rats', 'Species', '10116', (224, 228))	('NK603', 'Chemical', '-', (199, 204))	('NK603', 'Var', (190, 195))
27658	30756133	indicated that the diets containing the untreated GM maize NK603 and the Roundup-treated GM maize NK603 contained significantly lower levels of the phenolic acids caffeic acid and ferulic acid than the control diet and hypothesised that this decrease could explain the higher tumor incidence observed in the GM maize NK603-fed rats due to less protection afforded by these compounds.	('GM', 'Chemical', '-', (89, 91))	('GM', 'Chemical', '-', (50, 52))	('ferulic acid', 'Chemical', 'MESH:C004999', (180, 192))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('levels', 'MPA', (134, 140))	('phenolic acids', 'Chemical', 'MESH:C017616', (148, 162))	('NK603', 'Chemical', '-', (317, 322))	('maize', 'Species', '4577', (311, 316))	('ferulic acid', 'MPA', (180, 192))	('rats', 'Species', '10116', (327, 331))	('GM', 'Chemical', '-', (308, 310))	('tumor', 'Disease', (276, 281))	('NK603', 'Chemical', '-', (59, 64))	('lower', 'NegReg', (128, 133))	('maize', 'Species', '4577', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('maize', 'Species', '4577', (92, 97))	('NK603', 'Chemical', '-', (98, 103))	('NK603', 'Var', (59, 64))	('caffeic acid', 'Chemical', 'MESH:C040048', (163, 175))	('phenolic acids caffeic acid', 'MPA', (148, 175))
27749	31019860	Overall, the role of immunotherapy in gastrointestinal tumors is limited, with the exception of mismatch repair deficient (dMMR) or microsatellite instability high (MSI-H) tumors.	('MSI-H) tumors', 'Disease', 'MESH:D009369', (165, 178))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('dMMR', 'Chemical', '-', (123, 127))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (38, 61))	('gastrointestinal tumors', 'Disease', (38, 61))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('microsatellite instability', 'Var', (132, 158))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (38, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('mismatch', 'MPA', (96, 104))
27766	30158952	In general, the majority of recurrent genetic alterations identified in ICC are enriched in known tumor suppressor genes and oncogenes, such as mutations in TP53, KRAS, BAP1, ARID1A, IDH1, IDH2, and novel FGFR2 fusion genes.	('TP53', 'Gene', (157, 161))	('ICC', 'Disease', (72, 75))	('ARID1A', 'Gene', '8289', (175, 181))	('IDH1', 'Gene', '3417', (183, 187))	('ARID1A', 'Gene', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('KRAS', 'Gene', (163, 167))	('BAP1', 'Gene', '8314', (169, 173))	('FGFR2', 'Gene', (205, 210))	('FGFR2', 'Gene', '2263', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('IDH2', 'Gene', (189, 193))	('BAP1', 'Gene', (169, 173))	('tumor', 'Disease', (98, 103))	('mutations', 'Var', (144, 153))	('IDH1', 'Gene', (183, 187))	('IDH2', 'Gene', '3418', (189, 193))	('TP53', 'Gene', '7157', (157, 161))
27768	30158952	Interestingly, recent studies utilized multi-omics data to classify ICC into two main subgroups, one with immune response genes as the main driving factor, while another is enriched with driver mutations in the genes associated with epigenetic regulations, such as IDH1 and IDH2.	('IDH2', 'Gene', (274, 278))	('mutations', 'Var', (194, 203))	('IDH1', 'Gene', '3417', (265, 269))	('ICC', 'Disease', (68, 71))	('IDH2', 'Gene', '3418', (274, 278))	('IDH1', 'Gene', (265, 269))
27821	30158952	Even though most transcriptomic studies on ICC and relating cancers have been focused on mRNA (Jinawath et al.,), dysfunction of non-coding RNAs, particularly microRNA (miRNA) and long non-coding (lncRNA), have recently been found to play roles in ICC as well (Wang et al.,; Yang et al.,; Zheng et al.,).	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('dysfunction', 'Var', (114, 125))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('play roles', 'Reg', (234, 244))	('ICC', 'Disease', (248, 251))
27822	30158952	Transcriptional levels significantly depend on epigenetic configuration of regulatory elements targeting the oncogenes and tumor suppressor genes.	('epigenetic configuration', 'Var', (47, 71))	('depend', 'Reg', (37, 43))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('Transcriptional levels', 'MPA', (0, 22))
27824	30158952	Aberrant proteins secreted by cancer cells and released into various kinds of body fluids, such as blood, urine and saliva, provide good non-invasive biomarkers for early detection of cancer and the recurrent disease.	('cancer', 'Disease', (184, 190))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
27833	30158952	The M class tumors show primarily genomic mutations and epigenetic alterations, such as DNA hypermethylation.	('DNA hypermethylation', 'Disease', (88, 108))	('genomic mutations', 'Var', (34, 51))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('epigenetic alterations', 'Var', (56, 78))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
27836	30158952	More recently, an integrated analysis of genetic alterations focusing on the 10 canonical signaling pathways in the 9,125 TCGA-profiled tumors from 33 cancer types including CCA has underlined significant representation of individual and co-occurring actionable alterations among these pathways, which suggests targeted and combination therapy opportunities (Sanchez-Vega et al.,).	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('alterations', 'Var', (49, 60))	('CCA', 'Phenotype', 'HP:0030153', (174, 177))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('TCGA-profiled', 'Gene', (122, 135))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
27845	30158952	By ablation of genes in Hippo signaling pathways (Lee et al.,; Lu et al.,) or knocking out neurofibromatosis type 2 (Nf2) gene (Benhamouche et al.,) in mouse, the authors proposed that ICC and HCC may share the same progenitor cells since all surviving mice eventually developed both CCA and HCC.	('Nf2', 'Gene', '18016', (117, 120))	('HCC', 'Gene', '619501', (193, 196))	('HCC', 'Phenotype', 'HP:0001402', (193, 196))	('CCA', 'Disease', (284, 287))	('HCC', 'Gene', '619501', (292, 295))	('HCC', 'Gene', (292, 295))	('Hippo', 'Gene', (24, 29))	('mouse', 'Species', '10090', (152, 157))	('neurofibromatosis type 2', 'Gene', '18016', (91, 115))	('HCC', 'Gene', (193, 196))	('Nf2', 'Gene', (117, 120))	('neurofibromatosis type 2', 'Gene', (91, 115))	('knocking', 'Var', (78, 86))	('CCA', 'Phenotype', 'HP:0030153', (284, 287))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (91, 108))	('mice', 'Species', '10090', (253, 257))	('ablation', 'Var', (3, 11))	('HCC', 'Phenotype', 'HP:0001402', (292, 295))
27847	30158952	Regardless of the hepatic lineage hierarchy, transduced cells were able to give rise to a continuous spectrum of liver cancers from HCC to CCA suggesting that any hepatic lineage cell can be cell-of-origin of primary liver cancer (Holczbauer et al.,).	('HCC', 'Gene', '619501', (132, 135))	('liver cancers', 'Phenotype', 'HP:0002896', (113, 126))	('liver cancers', 'Disease', 'MESH:D006528', (113, 126))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('liver cancer', 'Phenotype', 'HP:0002896', (217, 229))	('liver cancer', 'Disease', 'MESH:D006528', (217, 229))	('HCC', 'Phenotype', 'HP:0001402', (132, 135))	('CCA', 'Disease', (139, 142))	('liver cancers', 'Disease', (113, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('give rise', 'Reg', (75, 84))	('liver cancer', 'Disease', (217, 229))	('transduced', 'Var', (45, 55))	('liver cancer', 'Phenotype', 'HP:0002896', (113, 125))	('HCC', 'Gene', (132, 135))	('CCA', 'Phenotype', 'HP:0030153', (139, 142))	('liver cancer', 'Disease', 'MESH:D006528', (113, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
27854	30158952	Aberrant activation of NOTCH signaling and gain-of-function mutations in the genes encoding isocitrate dehydrogenases (IDH1 and IDH2) are required for ICC development, and thus are significantly more common in ICC than in HCC (Sekiya and Suzuki,; Moeini et al.,).	('activation', 'PosReg', (9, 19))	('IDH2', 'Gene', '3418', (128, 132))	('NOTCH signaling', 'Pathway', (23, 38))	('gain-of-function', 'PosReg', (43, 59))	('IDH1', 'Gene', (119, 123))	('HCC', 'Gene', '619501', (222, 225))	('HCC', 'Phenotype', 'HP:0001402', (222, 225))	('IDH1', 'Gene', '3417', (119, 123))	('ICC', 'Disease', (210, 213))	('mutations', 'Var', (60, 69))	('IDH2', 'Gene', (128, 132))	('HCC', 'Gene', (222, 225))
27855	30158952	In addition, activation of KRAS and deletion of PTEN in the mouse model will only generate ICC (Ikenoue et al.,).	('PTEN', 'Gene', (48, 52))	('deletion', 'Var', (36, 44))	('ICC', 'Disease', (91, 94))	('activation', 'PosReg', (13, 23))	('KRAS', 'Protein', (27, 31))	('mouse', 'Species', '10090', (60, 65))
27859	30158952	They identified a distinct subtype of ICC enriched for IDH mutants, and found that HCC can be characterized by CTNNB1 and TERT promoter mutations, which are absent in ICC (Farshidfar et al.,).	('mutants', 'Var', (59, 66))	('HCC', 'Phenotype', 'HP:0001402', (83, 86))	('TERT', 'Gene', (122, 126))	('IDH', 'Gene', (55, 58))	('TERT', 'Gene', '7015', (122, 126))	('IDH', 'Gene', '3417', (55, 58))	('HCC', 'Gene', (83, 86))	('mutations', 'Var', (136, 145))	('CTNNB1', 'Gene', (111, 117))	('HCC', 'Gene', '619501', (83, 86))	('CTNNB1', 'Gene', '1499', (111, 117))
27869	30158952	Another WES study further showed that TP53 mutations are more enriched in OV-related ICCs, while mutations in BAP1, IDH1, and IDH2 genes are more common in non-OV-related tumors (Chan-On et al.,).	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('OV-related ICCs', 'Disease', (74, 89))	('BAP1', 'Gene', '8314', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('TP53', 'Gene', (38, 42))	('OV', 'Species', '6198', (160, 162))	('IDH2', 'Gene', (126, 130))	('BAP1', 'Gene', (110, 114))	('IDH1', 'Gene', (116, 120))	('mutations', 'Var', (43, 52))	('OV', 'Species', '6198', (74, 76))	('IDH1', 'Gene', '3417', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('IDH2', 'Gene', '3418', (126, 130))	('tumors', 'Disease', (171, 177))	('TP53', 'Gene', '7157', (38, 42))
27872	30158952	From this study, clusters 1 and 2, which are liver fluke positive, are enriched for recurrent mutations in TP53, ARID1A and BRCA1/2, and ERBB2 amplifications.	('BRCA1/2', 'Gene', (124, 131))	('mutations', 'Var', (94, 103))	('ARID1A', 'Gene', (113, 119))	('TP53', 'Gene', '7157', (107, 111))	('liver fluke', 'Species', '6192', (45, 56))	('ERBB2', 'Gene', (137, 142))	('TP53', 'Gene', (107, 111))	('ARID1A', 'Gene', '8289', (113, 119))
27873	30158952	In contrast, clusters 3 and 4, which comprise mostly non-liver fluke-associated tumors, are enriched for recurrent mutations in epigenetic-related genes, i.e., BAP1 and IDH1/2, as well as FGFR rearrangements, and have high PD-1/PD-L2 expression.	('mutations', 'Var', (115, 124))	('IDH1/2', 'Gene', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PD-L2', 'Gene', (228, 233))	('expression', 'MPA', (234, 244))	('PD-L2', 'Gene', '80380', (228, 233))	('BAP1', 'Gene', '8314', (160, 164))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', (80, 86))	('BAP1', 'Gene', (160, 164))	('rearrangements', 'Var', (193, 207))	('epigenetic-related genes', 'Gene', (128, 152))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('liver fluke', 'Species', '6192', (57, 68))	('FGFR', 'Gene', (188, 192))
27879	30158952	N-cadherin IHC positivity is also strongly associated with cholangiolar morphology, lack of CEA, high MUC2 expression, and low KRAS mutation frequency (Yu et al.,).	('MUC2', 'Gene', (102, 106))	('MUC2', 'Gene', '4583', (102, 106))	('cholangiolar', 'Disease', (59, 71))	('N-cadherin', 'Gene', (0, 10))	('CEA', 'Gene', '1048', (92, 95))	('positivity', 'Var', (15, 25))	('N-cadherin', 'Gene', '1000', (0, 10))	('CEA', 'Gene', (92, 95))	('associated', 'Reg', (43, 53))	('high', 'MPA', (97, 101))
27883	30158952	The PF subtype is more common and can be characterized by activation of oncogenic signaling pathways, DNA amplifications of 11q13.2 (including CCND1 and FGF19 gene loci), deletions of 14q22.1 (including SAV1 gene locus), mutations in KRAS and BRAF, and is associated with a poor prognosis.	('mutations', 'Var', (221, 230))	('14q22.1', 'Gene', (184, 191))	('BRAF', 'Gene', '673', (243, 247))	('deletions', 'Var', (171, 180))	('oncogenic signaling pathways', 'Pathway', (72, 100))	('CCND1', 'Gene', '595', (143, 148))	('BRAF', 'Gene', (243, 247))	('SAV1', 'Gene', '60485', (203, 207))	('DNA amplifications', 'Var', (102, 120))	('CCND1', 'Gene', (143, 148))	('FGF19', 'Gene', '9965', (153, 158))	('SAV1', 'Gene', (203, 207))	('activation', 'PosReg', (58, 68))	('KRAS', 'Gene', (234, 238))	('FGF19', 'Gene', (153, 158))
27885	30158952	classified ICC patients into two subgroups based on 5-year survival rate, time to recurrence, and the absence or presence of KRAS mutations.	('patients', 'Species', '9606', (15, 23))	('mutations', 'Var', (130, 139))	('ICC', 'Disease', (11, 14))	('KRAS', 'Gene', (125, 129))
27886	30158952	Similarly, KRAS mutations are associated with poor clinical outcomes (Andersen et al.,).	('KRAS', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('clinical', 'Species', '191496', (51, 59))
27887	30158952	ICC of C class harbors recurrent focal CNAs including deletions involving CDKN2A, ROBO1, ROBO2, RUNX3, and SMAD4, while those of M class harbor recurrent mutations in the genes frequently mutated in ICC, i.e., TP53, KRAS, and IDH1, as well as epigenetic regulators and genes in TGFbeta signaling pathway.	('ROBO1', 'Gene', (82, 87))	('ROBO1', 'Gene', '6091', (82, 87))	('TGFbeta signaling pathway', 'Pathway', (278, 303))	('TP53', 'Gene', (210, 214))	('RUNX3', 'Gene', '864', (96, 101))	('RUNX3', 'Gene', (96, 101))	('SMAD4', 'Gene', '4089', (107, 112))	('CDKN2A', 'Gene', (74, 80))	('CDKN2A', 'Gene', '1029', (74, 80))	('ROBO2', 'Gene', '6092', (89, 94))	('IDH1', 'Gene', (226, 230))	('ROBO2', 'Gene', (89, 94))	('IDH1', 'Gene', '3417', (226, 230))	('deletions', 'Var', (54, 63))	('SMAD4', 'Gene', (107, 112))	('TP53', 'Gene', '7157', (210, 214))
27888	30158952	Focusing on the genomic findings from all ICC studies discussed above, recurrent mutations of ICC are enriched in tumor suppressor genes, i.e., ARID1A, ARID1B, BAP1, PBRM1, TP53, STK11, and PTEN, and oncogenes, i.e., IDH1, IDH2, KRAS, BRAF, and PIK3CA.	('PIK3CA', 'Gene', (245, 251))	('STK11', 'Gene', (179, 184))	('ARID1B', 'Gene', (152, 158))	('BAP1', 'Gene', (160, 164))	('mutations', 'Var', (81, 90))	('TP53', 'Gene', (173, 177))	('PBRM1', 'Gene', '55193', (166, 171))	('IDH1', 'Gene', '3417', (217, 221))	('ARID1B', 'Gene', '57492', (152, 158))	('ARID1A', 'Gene', (144, 150))	('tumor', 'Disease', (114, 119))	('STK11', 'Gene', '6794', (179, 184))	('PBRM1', 'Gene', (166, 171))	('ARID1A', 'Gene', '8289', (144, 150))	('BRAF', 'Gene', '673', (235, 239))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('PIK3CA', 'Gene', '5290', (245, 251))	('BRAF', 'Gene', (235, 239))	('ICC', 'Gene', (94, 97))	('TP53', 'Gene', '7157', (173, 177))	('PTEN', 'Gene', (190, 194))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('BAP1', 'Gene', '8314', (160, 164))	('IDH2', 'Gene', (223, 227))	('IDH1', 'Gene', (217, 221))	('IDH2', 'Gene', '3418', (223, 227))
27889	30158952	The majority of these genes are associated with genome instability and epigenetic alterations, which are the common underlying mechanisms of cancer.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('epigenetic alterations', 'Var', (71, 93))	('associated', 'Reg', (32, 42))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('genome', 'MPA', (48, 54))
27890	30158952	Recurrent mutations of BRCA2, MLL3, APC, NF1, and ELF3 tumor-suppressor genes have also been reported in ICC (Farshidfar et al.,).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('BRCA2', 'Gene', (23, 28))	('ELF3', 'Gene', '1999', (50, 54))	('ICC', 'Disease', (105, 108))	('MLL3', 'Gene', (30, 34))	('tumor', 'Disease', (55, 60))	('reported', 'Reg', (93, 101))	('MLL3', 'Gene', '58508', (30, 34))	('ELF3', 'Gene', (50, 54))	('NF1', 'Gene', (41, 44))	('BRCA2', 'Gene', '675', (23, 28))	('mutations', 'Var', (10, 19))	('NF1', 'Gene', '4763', (41, 44))	('APC', 'Disease', 'MESH:D011125', (36, 39))	('APC', 'Disease', (36, 39))
27906	30158952	After subcutaneous injection, it retains in vivo tumorigenicity and expresses CEA and CA19-9; KRAS G12D mutation is also maintained in this cell line.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('KRAS G12D', 'Var', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('CEA', 'Gene', '1048', (78, 81))	('CEA', 'Gene', (78, 81))	('G12D', 'Mutation', 'rs121913529', (99, 103))
27916	30158952	Other than PDX, a genetically engineered mouse model of ICC has been generated by inducing oncogenic Kras mutation and homozygous Pten deletion in the liver.	('inducing', 'Reg', (82, 90))	('deletion', 'Var', (135, 143))	('mouse', 'Species', '10090', (41, 46))	('mutation', 'Var', (106, 114))	('Pten', 'Gene', (130, 134))	('Kras', 'Gene', '16653', (101, 105))	('Kras', 'Gene', (101, 105))
27918	30158952	This mouse line is suited for the development of new therapies for ICCs with an oncogenic KRAS mutation and the activated PI3K pathway (Ikenoue et al.,) (Figure 2C).	('mouse', 'Species', '10090', (5, 10))	('KRAS', 'Gene', (90, 94))	('mutation', 'Var', (95, 103))
27920	30158952	introduced mutations in a set of tumor suppressor genes often altered in human ICC/HCC such as Arid1a, Pten, Smad4, Trp53, Apc, Cdkn2a, and in a few rarely mutated genes including Tet2, Brca1/2, in mice by conducting multiplex CRISPR/Cas9 gene editing.	('Cdkn2a', 'Gene', (128, 134))	('mutations', 'Var', (11, 20))	('Brca1/2', 'Gene', (186, 193))	('Cdkn2a', 'Gene', '1029', (128, 134))	('Brca1/2', 'Gene', '672;675', (186, 193))	('Tet2', 'Gene', '54790', (180, 184))	('Apc', 'Gene', (123, 126))	('Smad4', 'Gene', (109, 114))	('altered', 'Reg', (62, 69))	('Apc', 'Gene', '324', (123, 126))	('human', 'Species', '9606', (73, 78))	('Arid1a', 'Gene', (95, 101))	('tumor', 'Disease', (33, 38))	('Trp53', 'Gene', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('Trp53', 'Gene', '7157', (116, 121))	('Smad4', 'Gene', '4089', (109, 114))	('Pten', 'Gene', (103, 107))	('HCC', 'Gene', '619501', (83, 86))	('Tet2', 'Gene', (180, 184))	('HCC', 'Phenotype', 'HP:0001402', (83, 86))	('Arid1a', 'Gene', '8289', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('HCC', 'Gene', (83, 86))	('mice', 'Species', '10090', (198, 202))
27922	30158952	However, the authors unexpectedly observed a high mutation frequency of Tet2, which has never been observed in human ICCs.	('Tet2', 'Gene', '54790', (72, 76))	('human', 'Species', '9606', (111, 116))	('Tet2', 'Gene', (72, 76))	('mutation', 'Var', (50, 58))
27948	30158952	Among the 22 evaluable metastatic patients harboring FGFR2 fusions or other alterations, three patients achieved partial response (PR) and 15 patients had stable disease (SD).	('patients', 'Species', '9606', (95, 103))	('FGFR2', 'Gene', (53, 58))	('patients', 'Species', '9606', (34, 42))	('partial response', 'MPA', (113, 129))	('FGFR2', 'Gene', '2263', (53, 58))	('patients', 'Species', '9606', (142, 150))	('fusions', 'Var', (59, 66))
27949	30158952	A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor, in patients harboring FGFR2 fusions demonstrated two patients with a confirmed PR and one with durable SD at >=16 weeks (Papadopoulos et al.,).	('patients', 'Species', '9606', (109, 117))	('fusions', 'Var', (84, 91))	('FGFR2', 'Gene', '2263', (78, 83))	('FGFR2', 'Gene', (78, 83))	('patients', 'Species', '9606', (59, 67))	('ARQ 087', 'Chemical', 'MESH:C000621805', (19, 26))
27950	30158952	A phase 3 study of ARQ 087 is ongoing and recruiting more patients with FGFR2 fusions as well as inoperable or advanced ICC (NCT03230318).	('FGFR2', 'Gene', '2263', (72, 77))	('FGFR2', 'Gene', (72, 77))	('fusions', 'Var', (78, 85))	('patients', 'Species', '9606', (58, 66))	('ARQ 087', 'Chemical', 'MESH:C000621805', (19, 26))
27951	30158952	Other novel drugs targeting FGFR fusions such as INCB054828, H3B-6527, erdafitinib, and INCB062079 are in early phases of clinical development (Table 3).	('INCB054828', 'Var', (49, 59))	('fusions', 'Var', (33, 40))	('FGFR', 'Gene', (28, 32))	('H3B-6527', 'Gene', (61, 69))	('erdafitinib', 'Chemical', 'MESH:C000604580', (71, 82))	('clinical', 'Species', '191496', (122, 130))
27952	30158952	Mutations of IDH1 were reported in up to 25% of CCA (Lowery et al.,).	('CCA', 'Phenotype', 'HP:0030153', (48, 51))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('reported', 'Reg', (23, 31))	('CCA', 'Disease', (48, 51))
27953	30158952	AG-120, a highly selective small molecule inhibitor of mutant IDH1 protein, demonstrated a preliminary efficacy in refractory CCA patients with IDH1 mutations.	('mutations', 'Var', (149, 158))	('IDH1', 'Gene', '3417', (62, 66))	('CCA', 'Phenotype', 'HP:0030153', (126, 129))	('AG-120', 'Chemical', 'MESH:C000627630', (0, 6))	('mutant', 'Var', (55, 61))	('patients', 'Species', '9606', (130, 138))	('protein', 'Protein', (67, 74))	('IDH1', 'Gene', (144, 148))	('IDH1', 'Gene', (62, 66))	('refractory CCA', 'Disease', (115, 129))	('IDH1', 'Gene', '3417', (144, 148))
27958	30158952	A phase 2 non-randomized study of pembrolizumab, an anti-PD1 antibody, in 41 patients with progressive metastatic carcinoma demonstrated an immune-related objective response rate of 40, 71, and 0% for the patients who have colorectal cancer with dMMR, CCA and other cancers with dMMR, and colorectal cancer with mismatch-repair proficiency (pMMR), respectively (Le et al.,).	('patients', 'Species', '9606', (205, 213))	('dMMR', 'Chemical', '-', (246, 250))	('colorectal cancer', 'Disease', 'MESH:D015179', (289, 306))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinoma', 'Disease', (114, 123))	('colorectal cancer', 'Disease', 'MESH:D015179', (223, 240))	('colorectal cancer', 'Disease', (289, 306))	('cancers', 'Disease', 'MESH:D009369', (266, 273))	('patients', 'Species', '9606', (77, 85))	('colorectal cancer', 'Disease', (223, 240))	('mismatch-repair', 'Var', (312, 327))	('CCA', 'Phenotype', 'HP:0030153', (252, 255))	('PD1', 'Gene', '5133', (57, 60))	('CCA', 'Disease', (252, 255))	('carcinoma', 'Disease', 'MESH:D002277', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('dMMR', 'Chemical', '-', (279, 283))	('colorectal cancer', 'Phenotype', 'HP:0003003', (289, 306))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('cancers', 'Disease', (266, 273))	('colorectal cancer', 'Phenotype', 'HP:0003003', (223, 240))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('pembrolizumab', 'Chemical', 'MESH:C582435', (34, 47))	('PD1', 'Gene', (57, 60))
27987	28959141	Smad2/3 knock-down suppressed TGF-beta1 ability to induce ERK1/2 phosphorylation, Slug expression and cell invasion, whereas Slug knock-down suppressed cell invasion and vimentin expression but marginally affected ERK1/2 activation and MMP-9 secretion.	('Slug expression', 'MPA', (82, 97))	('knock-down', 'Var', (130, 140))	('vimentin', 'Protein', (170, 178))	('suppressed', 'NegReg', (19, 29))	('TGF-beta1', 'Gene', (30, 39))	('cell invasion', 'CPA', (152, 165))	('induce', 'PosReg', (51, 57))	('Smad2/3', 'Gene', (0, 7))	('suppressed', 'NegReg', (141, 151))	('activation', 'MPA', (221, 231))	('phosphorylation', 'MPA', (65, 80))	('MMP-9', 'Gene', '4318', (236, 241))	('ERK1/2', 'Protein', (58, 64))	('Slug', 'Gene', (125, 129))	('TGF-beta1', 'Gene', '7040', (30, 39))	('cell invasion', 'CPA', (102, 115))	('Smad2/3', 'Gene', '4087;4088', (0, 7))	('MMP-9', 'Gene', (236, 241))
27989	28959141	Inhibiting ERK1/2 activation attenuates TGF-beta1 tumor promoting effect (invasion) but retains its tumor suppressing role, thereby highlighting the importance of ERK1/2 in resolving the TGF-beta paradox switch.	('ERK1/2', 'Protein', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Inhibiting', 'Var', (0, 10))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('attenuates', 'NegReg', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('TGF-beta1', 'Gene', '7040', (40, 49))	('TGF-beta1', 'Gene', (40, 49))	('tumor', 'Disease', (50, 55))
28002	28959141	However, during cancer development, cells frequently lose their response to TGF-beta growth inhibitory activity, either through mutations in TGF-beta signaling mediators, such as TGF-beta receptor type II (TbetaRII), Smad2 and Smad4, or through alterations in cell cycle regulatory proteins, viz., down-regulation of p53, p21 and pRb or up-regulation of Myc, Akt, Ras/ERK1/2 (extracellular signal regulated kinase 1/2).	('pRb', 'Gene', (330, 333))	('alterations', 'Reg', (245, 256))	('extracellular signal regulated kinase 1/2', 'Gene', '5595', (376, 417))	('p21', 'Gene', '1026', (322, 325))	('Smad2', 'Gene', (217, 222))	('extracellular signal regulated kinase 1/2', 'Gene', (376, 417))	('pRb', 'Gene', '5925', (330, 333))	('Smad4', 'Gene', (227, 232))	('p53', 'Gene', '7157', (317, 320))	('TGF-beta receptor type II', 'Gene', '7048', (179, 204))	('mutations', 'Var', (128, 137))	('cancer', 'Disease', (16, 22))	('response', 'MPA', (64, 72))	('TbetaRII', 'Gene', '7048', (206, 214))	('Myc', 'Gene', (354, 357))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('TGF-beta receptor type II', 'Gene', (179, 204))	('p53', 'Gene', (317, 320))	('TGF-beta signaling mediators', 'Gene', (141, 169))	('down-regulation', 'NegReg', (298, 313))	('p21', 'Gene', (322, 325))	('up-regulation', 'PosReg', (337, 350))	('Smad4', 'Gene', '4089', (227, 232))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('Akt', 'Gene', (359, 362))	('lose', 'NegReg', (53, 57))	('rat', 'Species', '10116', (249, 252))	('Myc', 'Gene', '4609', (354, 357))	('Smad2', 'Gene', '4087', (217, 222))	('TbetaRII', 'Gene', (206, 214))	('Akt', 'Gene', '207', (359, 362))
28006	28959141	Overexpression of cyclin D and loss of Smad4 contribute to ICC ability to escape from TGF-beta growth inhibitory activity during the initial stages of tumorigenesis.	('escape', 'MPA', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('loss', 'Var', (31, 35))	('tumor', 'Disease', (151, 156))	('Smad4', 'Gene', (39, 44))	('Smad4', 'Gene', '4089', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
28008	28959141	ERK and its upstream regulators, namely, Ras, B-Raf and growth factor receptors, frequently are mutated and participate in cancer progression.	('mutated', 'Var', (96, 103))	('participate', 'Reg', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Ras', 'Protein', (41, 44))	('Raf', 'Gene', '22882', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('ERK', 'Gene', '5594', (0, 3))	('Raf', 'Gene', (48, 51))	('ERK', 'Gene', (0, 3))
28056	28959141	Silencing MMP-9 gene expression by siMMP-9 reduced TGF-beta1-induced MMP-9 secretion by approximately 60% (Fig.	('secretion', 'MPA', (75, 84))	('MMP-9', 'Gene', (10, 15))	('MMP-9', 'Gene', '4318', (69, 74))	('MMP-9', 'Gene', '4318', (10, 15))	('MMP-9', 'Gene', (69, 74))	('TGF-beta1', 'Gene', '7040', (51, 60))	('MMP-9', 'Gene', '4318', (37, 42))	('TGF-beta1', 'Gene', (51, 60))	('MMP-9', 'Gene', (37, 42))	('reduced', 'NegReg', (43, 50))	('Silencing', 'Var', (0, 9))
28063	28959141	In addition, U0126 attenuated TGF-beta ability to reduce E-cadherin membrane localization (Fig.	('reduce', 'NegReg', (50, 56))	('TGF-beta', 'Protein', (30, 38))	('E-cadherin', 'Gene', (57, 67))	('E-cadherin', 'Gene', '999', (57, 67))	('U0126', 'Var', (13, 18))	('attenuated', 'NegReg', (19, 29))	('U0126', 'Chemical', 'MESH:C113580', (13, 18))
28067	28959141	Interestingly in the absence of h-TGF-beta1, invasiveness of both cell lines was also attenuated by U0126, indicating that ERK1/2 pathway was involved also in ICC cell basal invasiveness.	('TGF-beta1', 'Gene', (34, 43))	('U0126', 'Chemical', 'MESH:C113580', (100, 105))	('attenuated', 'NegReg', (86, 96))	('ICC', 'Disease', (159, 162))	('involved', 'Reg', (142, 150))	('U0126', 'Var', (100, 105))	('invasiveness', 'CPA', (45, 57))	('TGF-beta1', 'Gene', '7040', (34, 43))
28069	28959141	Thus, we examined their roles in ERK1/2 activation and invasiveness of h-TGF-beta1-induced KKU-M213 cell by knocking down Smad2/3 and Slug expression levels by means of siRNA.	('Slug expression levels', 'MPA', (134, 156))	('TGF-beta1', 'Gene', '7040', (73, 82))	('TGF-beta1', 'Gene', (73, 82))	('knocking', 'Var', (108, 116))	('Smad2/3', 'Gene', (122, 129))	('Smad2/3', 'Gene', '4087;4088', (122, 129))
28071	28959141	Smad2/3 silencing also suppressed Slug (30 +- 10%) and vimentin (50 +- 10%) expression levels (Fig.	('suppressed', 'NegReg', (23, 33))	('silencing', 'Var', (8, 17))	('expression levels', 'MPA', (76, 93))	('Smad2/3', 'Gene', (0, 7))	('Slug', 'MPA', (34, 38))	('Smad2/3', 'Gene', '4087;4088', (0, 7))	('vimentin', 'Protein', (55, 63))
28074	28959141	Similarly, Slug silencing inhibited h-TGF-beta1-induced KKU-M213 cell migration (40 +- 6%), cell invasion (39 +- 3%), vimentin expression (75 +- 15%) and Smad phosphorylation (26 +- 5%) (Fig.	('TGF-beta1', 'Gene', '7040', (38, 47))	('TGF-beta1', 'Gene', (38, 47))	('vimentin', 'Protein', (118, 126))	('inhibited', 'NegReg', (26, 35))	('KKU-M213 cell migration', 'CPA', (56, 79))	('cell invasion', 'CPA', (92, 105))	('silencing', 'Var', (16, 25))	('Slug', 'Gene', (11, 15))	('rat', 'Species', '10116', (73, 76))	('Smad phosphorylation', 'CPA', (154, 174))
28080	28959141	U0126 (1 microM) also possessed similar anti-proliferative effect and h-TGF-beta1 in combination with inhibitor does not significantly enhance the effect of either one alone (Fig.	('rat', 'Species', '10116', (52, 55))	('TGF-beta1', 'Gene', '7040', (72, 81))	('TGF-beta1', 'Gene', (72, 81))	('anti-proliferative', 'MPA', (40, 58))	('U0126', 'Var', (0, 5))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))
28089	28959141	Inhibiting ERK1/2 signaling blocks TGF-beta-induced EMT in normal murine mammary glands (NMuMG) cells and NSCLC cells.	('ERK1/2', 'Protein', (11, 17))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('Inhibiting', 'Var', (0, 10))	('TGF-beta-induced', 'Gene', (35, 51))	('EMT', 'CPA', (52, 55))	('blocks', 'NegReg', (28, 34))	('murine', 'Species', '10090', (66, 72))	('NSCLC', 'Disease', (106, 111))	('NMuMG', 'CellLine', 'CVCL:0075', (89, 94))
28090	28959141	Overexpression of TGF-beta1 and aberrant expressions of EMT-related proteins, namely E-cadherin, vimentin and Slug, in CCA patients are correlated with metastasis and short survival time.	('vimentin', 'Protein', (97, 105))	('TGF-beta1', 'Gene', '7040', (18, 27))	('TGF-beta1', 'Gene', (18, 27))	('metastasis', 'CPA', (152, 162))	('patients', 'Species', '9606', (123, 131))	('expressions', 'MPA', (41, 52))	('CCA', 'Disease', (119, 122))	('Slug', 'Gene', (110, 114))	('E-cadherin', 'Gene', (85, 95))	('E-cadherin', 'Gene', '999', (85, 95))	('correlated', 'Reg', (136, 146))	('aberrant', 'Var', (32, 40))	('CCA', 'Phenotype', 'HP:0030153', (119, 122))
28091	28959141	In addition, mutations in MAPK/ERK pathway components, especially KRas, are relatively common in ICC and are associated with reduction in progression-free survival and overall survival of ICC patients.	('reduction', 'NegReg', (125, 134))	('ICC', 'Disease', (97, 100))	('ERK', 'Gene', (31, 34))	('overall survival', 'CPA', (168, 184))	('progression-free survival', 'CPA', (138, 163))	('common', 'Reg', (87, 93))	('patients', 'Species', '9606', (192, 200))	('KRas', 'Gene', '3845', (66, 70))	('KRas', 'Gene', (66, 70))	('ERK', 'Gene', '5594', (31, 34))	('mutations', 'Var', (13, 22))
28092	28959141	Using two human ICC cell lines, KKU-M213 and HuCCA-1, we demonstrate that h-TGF-beta1 promotes cell invasion and that inhibition of ERK1/2 pathway suppresses this effect in both ICC cell lines with KKU-M213 being more sensitive to ERK1/2 inhibition.	('human', 'Species', '9606', (10, 15))	('CCA', 'Phenotype', 'HP:0030153', (47, 50))	('TGF-beta1', 'Gene', '7040', (76, 85))	('ERK1/2 pathway', 'Pathway', (132, 146))	('TGF-beta1', 'Gene', (76, 85))	('rat', 'Species', '10116', (64, 67))	('promotes', 'PosReg', (86, 94))	('suppresses', 'NegReg', (147, 157))	('inhibition', 'Var', (118, 128))	('cell invasion', 'CPA', (95, 108))
28104	28959141	However, in Madin-Darby canine kidney cells prolonging hyperactivation of Raf, a positive regulator of ERK, down-regulates Smad3, causing resistance to TGF-beta-induced growth arrest.	('hyperactivation', 'Var', (55, 70))	('growth arrest', 'Disease', 'MESH:D006323', (169, 182))	('growth arrest', 'Disease', (169, 182))	('ERK', 'Gene', (103, 106))	('Raf', 'Gene', (74, 77))	('growth arrest', 'Phenotype', 'HP:0001510', (169, 182))	('causing', 'Reg', (130, 137))	('Smad3', 'Gene', (123, 128))	('down-regulates', 'NegReg', (108, 122))	('canine', 'Species', '9615', (24, 30))	('resistance to TGF-beta-induced', 'MPA', (138, 168))	('Raf', 'Gene', '22882', (74, 77))	('ERK', 'Gene', '5594', (103, 106))	('Smad3', 'Gene', '610902', (123, 128))
28202	22888427	The AUC for the combination of the 4204 Da peptide and CA19-9 was significantly greater than that for CEA and CA19-9 (P < 0.01).	('CEA', 'Gene', '1084', (102, 105))	('peptide', 'Chemical', 'MESH:D010455', (43, 50))	('CEA', 'Gene', (102, 105))	('greater', 'PosReg', (80, 87))	('AUC', 'MPA', (4, 7))	('CA19-9', 'Var', (55, 61))
28213	22888427	conducted proteomic profiling of sera from cases of cholangiocarcinoma using SELDI-TOF MS and found that a serum peptide corresponding to a 4463 m/z peak had superior discriminatory ability to CA19-9 and CEA, but did not identify the peak.	('cholangiocarcinoma', 'Disease', (52, 70))	('peptide', 'Chemical', 'MESH:D010455', (113, 120))	('CEA', 'Gene', (204, 207))	('discriminatory', 'MPA', (167, 181))	('4463 m/z', 'Var', (140, 148))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (52, 70))	('CEA', 'Gene', '1084', (204, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (52, 70))
28217	22888427	It was of note that the sensitivity of 4204 Da in stages I and II patients was far greater than those of the conventional markers and that serum 4204 Da peptide levels were elevated in 79% of cases in which both CA19-9 and CEA were within their reference intervals.	('serum 4204 Da peptide levels', 'MPA', (139, 167))	('CEA', 'Gene', (223, 226))	('peptide', 'Chemical', 'MESH:D010455', (153, 160))	('elevated', 'PosReg', (173, 181))	('CEA', 'Gene', '1084', (223, 226))	('sensitivity', 'MPA', (24, 35))	('4204 Da', 'Var', (39, 46))	('patients', 'Species', '9606', (66, 74))
28219	22888427	This is supported by the greater AUC with the combination of CEA, CA19-9, and the 4204 Da peptide, compared to individual AUCs.	('peptide', 'Chemical', 'MESH:D010455', (90, 97))	('AUC', 'MPA', (33, 36))	('CA19-9', 'Var', (66, 72))	('CEA', 'Gene', (61, 64))	('CEA', 'Gene', '1084', (61, 64))
28353	22136171	In Hes1-/- mice, biliary epithelia differentiate into endocrine and exocrine cells and form acini and islet-like structures in the mutant bile ducts.	('biliary epithelia', 'Disease', (17, 34))	('mutant', 'Var', (131, 137))	('biliary epithelia', 'Disease', 'MESH:D001658', (17, 34))	('mice', 'Species', '10090', (11, 15))	('Hes1', 'Gene', (3, 7))	('Hes1', 'Gene', '15205', (3, 7))
28377	22136171	The cancer cell of origin has great importance in tumor cell fate and pathology; the activation of the same genetic/epigenetic mutation in different cellular compartment of a given organ may have profound implication in malignant potential.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('malignant potential', 'CPA', (220, 239))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('activation', 'PosReg', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('tumor', 'Disease', (50, 55))	('genetic/epigenetic mutation', 'Var', (108, 135))
28383	33669326	Tumor Type Agnostic Therapy Carrying BRAF Mutation: Case Reports and Review of Literature Background: Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('patient', 'Species', '9606', (157, 164))	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', (37, 41))	('Mutation', 'Var', (42, 50))
28384	33669326	BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types.	('Cancer', 'Disease', (46, 52))	('mutations', 'Var', (86, 95))	('Cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('BRAF', 'Gene', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutation', 'Var', (5, 13))	('Cancer', 'Phenotype', 'HP:0002664', (46, 52))
28385	33669326	Tumor type agnostic therapy is based on targeting genomic alterations, regardless of tumor origin.	('tumor', 'Disease', (85, 90))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('genomic alterations', 'Var', (50, 69))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
28387	33669326	Case presentation, Case 1: The first case is chemotherapy-refractory, BRAF V600E mutated intrahepaticcholangiocarcinoma treated with vemurafenib and cobimetinib as third line therapy.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('cobimetinib', 'Chemical', 'MESH:C574276', (149, 160))	('intrahepaticcholangiocarcinoma', 'Disease', (89, 119))	('V600E', 'Mutation', 'rs113488022', (75, 80))	('BRAF V600E mutated', 'Var', (70, 88))	('intrahepaticcholangiocarcinoma', 'Disease', 'None', (89, 119))	('vemurafenib', 'Chemical', 'MESH:D000077484', (133, 144))
28388	33669326	In this setting the dual BRAF and MEK inhibition resulted in improved progression-free survival and quality of life; Case 2: The second case shows aBRAF G466A mutated Bellini duct carcinoma (BDC), treated with dabrafenib and trametinib in second line therapy.	('G466A', 'Mutation', 'rs121913351', (153, 158))	('trametinib', 'Chemical', 'MESH:C560077', (225, 235))	('mutated', 'Var', (159, 166))	('Bellini duct carcinoma', 'Disease', (167, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('MEK', 'Gene', (34, 37))	('MEK', 'Gene', '5609', (34, 37))	('Bellini duct carcinoma', 'Disease', 'MESH:D021441', (167, 189))	('dabrafenib', 'Chemical', 'MESH:C561627', (210, 220))	('G466A mutated', 'Var', (153, 166))
28389	33669326	Discussion: In the literature there is strong evidence that melanoma, colorectal cancer, non small cell lung cancer and anaplastic thyroid cancer with BRAF mutations are good targets for BRAF/MEK pathway inhibitors.	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('non small cell lung cancer', 'Disease', (89, 115))	('BRAF', 'Gene', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('anaplastic thyroid cancer', 'Disease', 'MESH:D065646', (120, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('non small cell lung cancer', 'Phenotype', 'HP:0030358', (89, 115))	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('MEK', 'Gene', '5609', (192, 195))	('thyroid cancer', 'Phenotype', 'HP:0002890', (131, 145))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (120, 145))	('mutations', 'Var', (156, 165))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('colorectal cancer', 'Disease', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (93, 115))	('MEK', 'Gene', (192, 195))	('non small cell lung cancer', 'Disease', 'MESH:D002289', (89, 115))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('anaplastic thyroid cancer', 'Disease', (120, 145))
28397	33669326	The BRAF mutant is an oncogenic driver, since BRAF inactivation slows down systemic tumor growth and induces cancer cell toxicity.	('BRAF', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('inactivation', 'Var', (51, 63))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Disease', (109, 115))	('tumor', 'Disease', (84, 89))	('toxicity', 'Disease', 'MESH:D064420', (121, 129))	('toxicity', 'Disease', (121, 129))	('slows down', 'NegReg', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('induces', 'Reg', (101, 108))
28399	33669326	The Cancer Genome Atlas (TCGA) has identified BRAF mutations in many different cancer types: 60% of melanomas, 60% of thyroid cancers, 15% of colorectal cancers, and 5-8% of non-small cell lung cancers.	('melanomas', 'Disease', 'MESH:D008545', (100, 109))	('mutations', 'Var', (51, 60))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('cancer', 'Disease', (153, 159))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (174, 201))	('melanomas', 'Disease', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('colorectal cancers', 'Disease', (142, 160))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (178, 200))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('BRAF', 'Gene', (46, 50))	('thyroid cancer', 'Phenotype', 'HP:0002890', (118, 132))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (178, 201))	('cancer', 'Disease', (126, 132))	('thyroid cancers', 'Disease', (118, 133))	('Cancer', 'Disease', (4, 10))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('cancer', 'Disease', (79, 85))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('colorectal cancers', 'Disease', 'MESH:D015179', (142, 160))	('lung cancers', 'Disease', 'MESH:D008175', (189, 201))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (194, 200))	('lung cancers', 'Disease', (189, 201))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('thyroid cancers', 'Disease', 'MESH:D013964', (118, 133))	('lung cancers', 'Phenotype', 'HP:0100526', (189, 201))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
28400	33669326	Moreover, mutations in this gene are present in diffuse gliomas, cholangiocarcinoma, hairy cell leukemia, multiple myeloma, Langerhans cell histiocytosis and Erdheim-Chester disease.	('multiple myeloma', 'Disease', (106, 122))	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('histiocytosis', 'Phenotype', 'HP:0100727', (140, 153))	('Erdheim-Chester disease', 'Disease', 'MESH:D031249', (158, 181))	('hairy cell leukemia', 'Disease', 'MESH:D007943', (85, 104))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('Langerhans cell histiocytosis', 'Disease', (124, 153))	('Erdheim-Chester disease', 'Disease', (158, 181))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))	('multiple myeloma', 'Phenotype', 'HP:0006775', (106, 122))	('cholangiocarcinoma', 'Disease', (65, 83))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (65, 83))	('present', 'Reg', (37, 44))	('multiple myeloma', 'Disease', 'MESH:D009101', (106, 122))	('hairy cell leukemia', 'Disease', (85, 104))	('gliomas', 'Disease', (56, 63))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('mutations', 'Var', (10, 19))
28401	33669326	Around 200 BRAF mutant alleles and 30 mutations of BRAF have been identified and characterized and V600E is the most common mutation.	('V600E', 'Mutation', 'rs113488022', (99, 104))	('BRAF', 'Gene', (51, 55))	('V600E', 'Var', (99, 104))	('BRAF', 'Gene', (11, 15))
28403	33669326	The first case study is that of a 59-year-old Caucasian man with BRAF V600E mutated intrahepatic cholangiocarcinoma (ICC).	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('BRAF V600E mutated', 'Var', (65, 83))	('intrahepatic cholangiocarcinoma', 'Disease', (84, 115))	('V600E', 'Mutation', 'rs113488022', (70, 75))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))
28405	33669326	One of its targetable alterations is a v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation.	('mutation', 'Var', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('alterations', 'Var', (22, 33))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', '673', (39, 84))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', (39, 84))	('BRAF', 'Gene', (86, 90))
28406	33669326	While BRAF mutations are rare in pancreato-biliary cancers, they are reported with higher frequency, about 5% of all cases, in ICC.	('mutations', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('ICC', 'Disease', (127, 130))	('pancreato-biliary cancers', 'Disease', 'MESH:D009369', (33, 58))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('BRAF', 'Gene', (6, 10))	('pancreato-biliary cancers', 'Disease', (33, 58))
28407	33669326	The majority of mutations occur at the V600 position, with V600E observed in 5% of cholangiocarcinoma (CCA).	('cholangiocarcinoma', 'Disease', (83, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('CCA', 'Phenotype', 'HP:0030153', (103, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('V600E', 'Mutation', 'rs113488022', (59, 64))	('V600E', 'Var', (59, 64))
28408	33669326	The second case study is that of a 50-year-old, Caucasian woman, with BRAF G466A mutated Bellini duct carcinoma (BDC).	('G466A', 'Mutation', 'rs121913351', (75, 80))	('Bellini duct carcinoma', 'Disease', (89, 111))	('mutated', 'Var', (81, 88))	('Bellini duct carcinoma', 'Disease', 'MESH:D021441', (89, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('woman', 'Species', '9606', (58, 63))	('BRAF G466A mutated', 'Var', (70, 88))
28412	33669326	These clinical cases may represent a proof of concept of how identifying and targeting potential molecular drivers, such as BRAF mutations, independently of tissue origin, could provide represent therapeutic opportunities, especially for rare cancers.	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('mutations', 'Var', (129, 138))	('cancers', 'Disease', 'MESH:D009369', (243, 250))	('cancers', 'Disease', (243, 250))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('BRAF', 'Gene', (124, 128))
28421	33669326	In light of tumor resistance to second line chemotherapy, primary tumor next generation sequencing was performed in January 2019, which showed the presence of a BRAF V600E mutation.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('V600E', 'Var', (166, 171))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('BRAF', 'Gene', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('V600E', 'Mutation', 'rs113488022', (166, 171))
28448	33669326	In 2011, the Food and Drug Administration approved the BRAF inhibitor vemurafenib for the treatment of BRAF V600E mutant metastatic melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('V600E mutant', 'Var', (108, 120))	('vemurafenib', 'Chemical', 'MESH:D000077484', (70, 81))	('V600E', 'Mutation', 'rs113488022', (108, 113))	('BRAF', 'Gene', (103, 107))
28450	33669326	demonstrated that the combination of vemurafenib with the MEK inhibitor cobimetinib resulted in significant progression-free survival (PFS) improvement among patients with BRAF V600E mutated metastatic melanoma in comparison to the combination of vemurafenib with placebo.	('vemurafenib', 'Chemical', 'MESH:D000077484', (247, 258))	('cobimetinib', 'Chemical', 'MESH:C574276', (72, 83))	('MEK', 'Gene', (58, 61))	('MEK', 'Gene', '5609', (58, 61))	('BRAF V600E mutated', 'Var', (172, 190))	('V600E', 'Mutation', 'rs113488022', (177, 182))	('progression-free survival', 'CPA', (108, 133))	('patients', 'Species', '9606', (158, 166))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', (202, 210))	('improvement', 'PosReg', (140, 151))	('vemurafenib', 'Chemical', 'MESH:D000077484', (37, 48))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))
28456	33669326	Beside melanoma, thyroid cancers and colon cancers, the prevalence of a BRAF V600E mutation in other cancers is less than 5%.	('melanoma', 'Disease', 'MESH:D008545', (7, 15))	('thyroid cancers', 'Disease', (17, 32))	('colon cancers', 'Disease', (37, 50))	('V600E', 'Mutation', 'rs113488022', (77, 82))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', (43, 50))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('BRAF', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('V600E', 'Var', (77, 82))	('melanoma', 'Phenotype', 'HP:0002861', (7, 15))	('melanoma', 'Disease', (7, 15))	('thyroid cancers', 'Disease', 'MESH:D013964', (17, 32))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('colon cancers', 'Phenotype', 'HP:0003003', (37, 50))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('colon cancer', 'Phenotype', 'HP:0003003', (37, 49))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('colon cancers', 'Disease', 'MESH:D015179', (37, 50))	('thyroid cancer', 'Phenotype', 'HP:0002890', (17, 31))
28459	33669326	To address such paradoxes, basket trials have come to the rescue, putting together tumors with different histology, on the basis of their molecular landscapes and, more specifically, the presence of a BRAF V600E mutation.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('V600E', 'Var', (206, 211))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('V600E', 'Mutation', 'rs113488022', (206, 211))	('BRAF', 'Gene', (201, 205))
28467	33669326	The contribution of mutated BRAF seems to change amongst tumor types, as suggested by the very heterogeneous results in terms of clinical benefit of BRAF inhibition in different cancers.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('BRAF', 'Gene', (28, 32))	('tumor', 'Disease', (57, 62))	('mutated', 'Var', (20, 27))
28468	33669326	For instance, this mutation alone may not sufficient to drive tumor progression in certain tumor types, such as colon cancer.	('mutation', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('colon cancer', 'Phenotype', 'HP:0003003', (112, 124))	('colon cancer', 'Disease', 'MESH:D015179', (112, 124))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('drive', 'Reg', (56, 61))	('colon cancer', 'Disease', (112, 124))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
28474	33669326	The ClarIDHy study showed that ivosidenub significantly improved PFS, with a trend towards favorable overall survival, in comparison to placebo in patients with advanced cholangiocarcinoma carrying an IDH1 mutation.	('ivosidenub', 'Chemical', '-', (31, 41))	('PFS', 'MPA', (65, 68))	('IDH1', 'Gene', '3417', (201, 205))	('improved', 'PosReg', (56, 64))	('cholangiocarcinoma', 'Disease', (170, 188))	('mutation', 'Var', (206, 214))	('patients', 'Species', '9606', (147, 155))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (170, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (170, 188))	('IDH1', 'Gene', (201, 205))
28476	33669326	reported that BRAF V600E occurs with the highest frequency in ICC (1.5%) and is associated with poor prognosis.	('BRAF V600E', 'Var', (14, 24))	('V600E', 'Mutation', 'rs113488022', (19, 24))	('ICC', 'Disease', (62, 65))
28477	33669326	Focusing on biliary tract cancer, preliminary data from the ROAR basket trial demonstrated promising activity of dabrafenib plus trametinib with a favorable safety profile in patients with BRAF V600E (ROAR trial; NCT 02034110).	('V600E', 'Mutation', 'rs113488022', (194, 199))	('trametinib', 'Chemical', 'MESH:C560077', (129, 139))	('BRAF V600E', 'Var', (189, 199))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('activity', 'MPA', (101, 109))	('V600E', 'Var', (194, 199))	('patients', 'Species', '9606', (175, 183))	('dabrafenib', 'Chemical', 'MESH:C561627', (113, 123))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (12, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('biliary', 'Disease', (12, 19))
28478	33669326	Based on all these results, we decided to administer a combination of MEK and BRAF inhibitors in a patient with BRAF mutant, chemotherapy-refractory ICC and obtained results in line with the few cases reported in literature.	('patient', 'Species', '9606', (99, 106))	('mutant', 'Var', (117, 123))	('BRAF', 'Gene', (78, 82))	('BRAF', 'Gene', (112, 116))	('MEK', 'Gene', (70, 73))	('MEK', 'Gene', '5609', (70, 73))	('ICC', 'Disease', (149, 152))
28490	33669326	For this reason and on the basis of the genomic sequencing results, with the presence of a BRAF G466A mutation, we decided to use the combination of anti-BRAF and anti-MEK treatment.	('MEK', 'Gene', (168, 171))	('MEK', 'Gene', '5609', (168, 171))	('BRAF', 'Gene', (91, 95))	('G466A', 'Mutation', 'rs121913351', (96, 101))	('G466A', 'Var', (96, 101))
28491	33669326	G466A belongs to Class 3 BRAF mutations depending on RAS signaling: thus, blocking RAS signaling would appear to be a potential therapeutic strategy for class 3 BRAF-mutant tumors, but to date there are no specific inhibitors available.	('G466A', 'Mutation', 'rs121913351', (0, 5))	('G466A', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('tumors', 'Disease', (173, 179))
28494	33669326	In the literature, there is strong evidence that different tumors with BRAF mutations are good targets for BRAF/MEK pathway inhibitors and our work adds to this evidence.	('MEK', 'Gene', (112, 115))	('mutations', 'Var', (76, 85))	('MEK', 'Gene', '5609', (112, 115))	('BRAF', 'Gene', (71, 75))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
28503	32039729	The expression of 6 putative CSC markers, cluster of differentiation 44 (CD44), CD44 variant 6 (CD44v6), CD44 variants 8-10 (CD44v8-10), cluster of differentiation 133 (CD133), epithelial cell adhesion molecule (EpCAM), and aldehyde dehydrogenase 1A1 (ALDH1A1), was investigated in 178 CCA tissue samples using immunohistochemistry (IHC) and analyzed with respect to clinicopathological data and patient outcome including recurrence-free survival (RFS) and overall survival (OS).	('ALDH1A1', 'Gene', '216', (252, 259))	('CCA', 'Disease', (286, 289))	('epithelial cell adhesion molecule', 'Gene', '4072', (177, 210))	('CD44', 'Gene', (105, 109))	('EpCAM', 'Gene', '4072', (212, 217))	('aldehyde dehydrogenase 1A1', 'Gene', (224, 250))	('recurrence-free survival', 'CPA', (422, 446))	('variants', 'Var', (110, 118))	('CCA', 'Phenotype', 'HP:0030153', (286, 289))	('ALDH1A1', 'Gene', (252, 259))	('EpCAM', 'Gene', (212, 217))	('aldehyde dehydrogenase 1A1', 'Gene', '216', (224, 250))	('patient', 'Species', '9606', (396, 403))	('epithelial cell adhesion molecule', 'Gene', (177, 210))	('CCA', 'Disease', 'MESH:D018281', (286, 289))	('overall', 'CPA', (457, 464))
28505	32039729	Elevated protein level of CD44 and positive expression of CD44v6 and CD44v8-10 were significantly associated with short RFS and OS, while high levels of ALDH1A1 were correlated with a favorable prognosis patient.	('short RFS', 'Disease', (114, 123))	('expression', 'MPA', (44, 54))	('ALDH1A1', 'Gene', (153, 160))	('CD44v6', 'Var', (58, 64))	('Elevated', 'PosReg', (0, 8))	('protein level', 'MPA', (9, 22))	('positive', 'PosReg', (35, 43))	('CD44v8-10', 'Var', (69, 78))	('ALDH1A1', 'Gene', '216', (153, 160))	('CD44', 'MPA', (26, 30))	('associated', 'Reg', (98, 108))	('patient', 'Species', '9606', (204, 211))
28507	32039729	Furthermore, soluble CD44, CD44v6, CD44v8-10 and EpCAM were significantly increased in the recurrence group for early stage CCA; they also correlated with high levels of the tumor marker CA19-9.	('tumor', 'Disease', (174, 179))	('CCA', 'Disease', (124, 127))	('EpCAM', 'Gene', (49, 54))	('high levels', 'MPA', (155, 166))	('CA19-9', 'MPA', (187, 193))	('soluble CD44', 'MPA', (13, 25))	('EpCAM', 'Gene', '4072', (49, 54))	('increased', 'PosReg', (74, 83))	('CCA', 'Phenotype', 'HP:0030153', (124, 127))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('CCA', 'Disease', 'MESH:D018281', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('CD44v6', 'MPA', (27, 33))	('CD44v8-10', 'Var', (35, 44))
28508	32039729	Elevated levels of CD44, CD44v6, CD44v8-10 or EpCAM alone or in combination has the potential to predict CCA recurrence.	('CD44v8-10', 'Var', (33, 42))	('CCA', 'Disease', 'MESH:D018281', (105, 108))	('EpCAM', 'Gene', (46, 51))	('CCA', 'Disease', (105, 108))	('CD44', 'MPA', (19, 23))	('EpCAM', 'Gene', '4072', (46, 51))	('CCA', 'Phenotype', 'HP:0030153', (105, 108))	('CD44v6', 'Var', (25, 31))
28509	32039729	The overexpression of CD44, CD44v6, CD44v8-10 and EpCAM increases predictability of post-operative CCA recurrence.	('CD44', 'Var', (22, 26))	('increases', 'PosReg', (56, 65))	('CD44v8-10', 'Var', (36, 45))	('CCA', 'Disease', 'MESH:D018281', (99, 102))	('CCA', 'Disease', (99, 102))	('EpCAM', 'Gene', (50, 55))	('CD44v6', 'Var', (28, 34))	('overexpression', 'PosReg', (4, 18))	('CCA', 'Phenotype', 'HP:0030153', (99, 102))	('EpCAM', 'Gene', '4072', (50, 55))
28527	32039729	High expression of CD133 was reported to be significantly associated with more aggressive tumors and correlated with a worse outcome for cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('more', 'PosReg', (74, 78))	('associated', 'Reg', (58, 68))	('High', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('correlated', 'Reg', (101, 111))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('CD133', 'Gene', (19, 24))	('patients', 'Species', '9606', (144, 152))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', (137, 143))	('aggressive tumors', 'Disease', 'MESH:D001523', (79, 96))	('aggressive tumors', 'Disease', (79, 96))
28533	32039729	The overexpression of ALDH1A1 is mostly involved in poor cancer prognosis, however, numerous studies suggest that high expression of ALDH1A1 is also associated with a better prognosis of the patients.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('ALDH1A1', 'Gene', '216', (22, 29))	('patients', 'Species', '9606', (191, 199))	('cancer', 'Disease', (57, 63))	('ALDH1A1', 'Gene', '216', (133, 140))	('ALDH1A1', 'Gene', (133, 140))	('ALDH1A1', 'Gene', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('high expression', 'Var', (114, 129))
28534	32039729	Although many studies have reported that the expression of CD44, CD44v, CD133, EpCAM and ALDH1A1 is associated with tumor progression and can be used to predict patient's outcome, their prognostic significance in the recurrence of CCA in patients has not been elucidated.	('CD133', 'Gene', (72, 77))	('ALDH1A1', 'Gene', '216', (89, 96))	('EpCAM', 'Gene', '4072', (79, 84))	('CD44', 'Var', (59, 63))	('CCA', 'Disease', (231, 234))	('patient', 'Species', '9606', (161, 168))	('associated', 'Reg', (100, 110))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('CD44v', 'Var', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('ALDH1A1', 'Gene', (89, 96))	('CCA', 'Phenotype', 'HP:0030153', (231, 234))	('patient', 'Species', '9606', (238, 245))	('tumor', 'Disease', (116, 121))	('patients', 'Species', '9606', (238, 246))	('EpCAM', 'Gene', (79, 84))	('CCA', 'Disease', 'MESH:D018281', (231, 234))
28550	32039729	Tissue sections was incubated with primary antibodies (CD44; #ab51037; dilution 1:50, CD44v6; #ab78960; dilution 1:50, CD133; #ab19898; dilution 1:100, EpCAM; #ab71916; dilution 1:100, ALDH1A1; #ab52492; dilution 1:100) (Abcam, UK), and (CD44v8-10; #LKG-M001; dilution 1:50) (Cosmo Bio, JP) for 1 h at room temperature followed by 4  C overnight.	('EpCAM', 'Gene', (152, 157))	('ALDH1A1', 'Gene', '216', (185, 192))	('EpCAM', 'Gene', '4072', (152, 157))	('CD44v8-10; #LKG-M001;', 'Var', (238, 259))	('dilution 1:100', 'Var', (204, 218))	('ALDH1A1', 'Gene', (185, 192))
28579	32039729	Univariate analysis showed that the patients with a high expression of CD44, positive expression of CD44v6 and CD44v8-10 had a shorter RFS compared with other patients (p = 0.007, p = 0.001 and p = 0.007, respectively).	('shorter', 'NegReg', (127, 134))	('patients', 'Species', '9606', (36, 44))	('CD44v6', 'Gene', (100, 106))	('RFS', 'MPA', (135, 138))	('CD44', 'Gene', (71, 75))	('patients', 'Species', '9606', (159, 167))	('CD44v8-10', 'Var', (111, 120))
28580	32039729	In addition, a high expression of CD44 and ALDH1A1, positive expression of CD44v6 and CD44v8-10 was associated with a shorter OS compared with the other group of patients (p = 0.001, p = 0.022, p = 0.006 and p < 0.001, respectively) (Table 2).	('patients', 'Species', '9606', (162, 170))	('ALDH1A1', 'Gene', '216', (43, 50))	('CD44v8-10', 'Var', (86, 95))	('shorter', 'Disease', (118, 125))	('CD44v6', 'Gene', (75, 81))	('CD44', 'Gene', (34, 38))	('ALDH1A1', 'Gene', (43, 50))	('positive', 'PosReg', (52, 60))
28582	32039729	The result from intrahepatic CCA showed that a high expression of CD44 or the positive expression of CD44v6, and CD44v8-10 was significantly correlated with a shorter RFS compared with samples showing a low expression (p = 0.007, p = 0.017 and p < 0.001, respectively), while a high expression of EpCAM and ALDH1A1 was significantly correlated with a favorable prognosis in patients (p = 0.028 and p = 0.008) (Fig.	('CD44', 'Gene', (66, 70))	('ALDH1A1', 'Gene', (307, 314))	('CD44v6', 'Var', (101, 107))	('CD44v8-10', 'Var', (113, 122))	('shorter', 'NegReg', (159, 166))	('EpCAM', 'Gene', (297, 302))	('patients', 'Species', '9606', (374, 382))	('ALDH1A1', 'Gene', '216', (307, 314))	('RFS', 'MPA', (167, 170))	('CCA', 'Phenotype', 'HP:0030153', (29, 32))	('EpCAM', 'Gene', '4072', (297, 302))	('intrahepatic CCA', 'Disease', 'MESH:C535533', (16, 32))	('intrahepatic CCA', 'Disease', (16, 32))
28586	32039729	The expression of CD44, CD44v6, and CD44v8-10 seems to increase at higher stages compared with stage I tumor (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('increase', 'PosReg', (55, 63))	('CD44v8-10', 'Var', (36, 45))	('stage I tumor', 'Disease', 'MESH:D007676', (95, 108))	('expression', 'MPA', (4, 14))	('stage I tumor', 'Disease', (95, 108))	('CD44v6', 'Var', (24, 30))	('CD44', 'Gene', (18, 22))
28589	32039729	CD44, CD44v6, CD44v8-10 and ALDH1A1 showed prognostic significance for CCA patients.	('CCA', 'Disease', 'MESH:D018281', (71, 74))	('ALDH1A1', 'Gene', (28, 35))	('CCA', 'Disease', (71, 74))	('patients', 'Species', '9606', (75, 83))	('CD44', 'Var', (0, 4))	('CD44v8-10', 'Var', (14, 23))	('ALDH1A1', 'Gene', '216', (28, 35))	('CCA', 'Phenotype', 'HP:0030153', (71, 74))	('CD44v6', 'Var', (6, 12))
28590	32039729	The correlation between these markers was therefore further analyzed and significant positive correlations between CD44, CD44v6, and CD44v8-10 were observed, while there was no significant correlation between ALDH1A1 with the other markers (Table 5).	('ALDH1A1', 'Gene', '216', (209, 216))	('CD44v8-10', 'Var', (133, 142))	('positive', 'PosReg', (85, 93))	('ALDH1A1', 'Gene', (209, 216))	('CD44', 'Var', (115, 119))	('CD44v6', 'Var', (121, 127))
28591	32039729	The combination of high expression of CD44 with positive expression of CD44v6 and CD44v8-10 was significantly associated with RFS (p = 0.001 and p = 0.002) and OS (p = 0.001 and p < 0.001) in intrahepatic CCA.	('intrahepatic CCA', 'Disease', (192, 208))	('CD44v8-10', 'Var', (82, 91))	('high', 'PosReg', (19, 23))	('RFS', 'Disease', (126, 129))	('intrahepatic CCA', 'Disease', 'MESH:C535533', (192, 208))	('associated', 'Reg', (110, 120))	('positive', 'PosReg', (48, 56))	('CD44v6', 'Gene', (71, 77))	('CCA', 'Phenotype', 'HP:0030153', (205, 208))	('CD44', 'Gene', (38, 42))
28593	32039729	In order to identify soluble CSC markers that can be used to predict cancer relapse, soluble CD44, CD44v6, and CD44v8-10 were further determined in CCA sera.	('CCA', 'Disease', 'MESH:D018281', (148, 151))	('CCA', 'Disease', (148, 151))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('CCA', 'Phenotype', 'HP:0030153', (148, 151))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('CD44v6', 'Gene', (99, 105))	('CD44v8-10', 'Var', (111, 120))	('cancer', 'Disease', (69, 75))
28596	32039729	Therefore, the different of soluble CSC markers, CD44, CD44v6, CD44v8-10 and EpCAM on patients with and without recurrence was analyzed according to tumor staging in order to avoid the effect of T, N and TNM stage on recurrence.	('CD44v6', 'Var', (55, 61))	('N', 'Chemical', 'MESH:D009584', (198, 199))	('N', 'Chemical', 'MESH:D009584', (205, 206))	('TNM', 'Gene', (204, 207))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('EpCAM', 'Gene', (77, 82))	('CD44v8-10', 'Var', (63, 72))	('tumor', 'Disease', (149, 154))	('TNM', 'Gene', '10178', (204, 207))	('EpCAM', 'Gene', '4072', (77, 82))	('patients', 'Species', '9606', (86, 94))
28600	32039729	The results from the early stage group show that high levels of CD44, CD44v8-10 and EpCAM were significantly correlated with high levels of CA19-9 (p = 0.006, p = 0.011 and p < 0.001, respectively) (Table 6).	('CD44', 'Var', (64, 68))	('EpCAM', 'Gene', (84, 89))	('correlated', 'Reg', (109, 119))	('CA19-9', 'MPA', (140, 146))	('EpCAM', 'Gene', '4072', (84, 89))	('CD44v8-10', 'Var', (70, 79))
28602	32039729	In addition, the results from the late stage group show that a high level of CD44v6 was significantly associated with elevated total bilirubin, direct bilirubin, AST and ALP (p = 0.037, p = 0.029, p = 0.037 and p = 0.049, respectively) (Table 7).	('ALP', 'Gene', (170, 173))	('bilirubin', 'Chemical', 'MESH:D001663', (151, 160))	('AST', 'Gene', (162, 165))	('total bilirubin', 'MPA', (127, 142))	('direct bilirubin', 'MPA', (144, 160))	('high', 'Var', (63, 67))	('AST', 'Gene', '26503', (162, 165))	('CD44v6', 'Gene', (77, 83))	('bilirubin', 'Chemical', 'MESH:D001663', (133, 142))	('elevated', 'PosReg', (118, 126))	('ALP', 'Gene', '470', (170, 173))
28603	32039729	Moreover, CD44v8-10 and EpCAM were also associated with elevated of ALP (p = 0.024 and p = 0.006) (Table 7).	('elevated', 'PosReg', (56, 64))	('ALP', 'Gene', '470', (68, 71))	('EpCAM', 'Gene', '4072', (24, 29))	('ALP', 'Gene', (68, 71))	('CD44v8-10', 'Var', (10, 19))	('EpCAM', 'Gene', (24, 29))
28605	32039729	The cut-off values for soluble CD44, CD44v6, CD44v8-10 and EpCAM suitable for the discrimination between recurrence and non-recurrence in the patients with early stage CCA were 0.505 (area under curve; AUC = 0.670, p = 0.029), 0.814 (AUC = 0.670, p = 0.029), 0.713 (AUC = 0.702, p = 0.010), and 0.506 (AUC = 0.739, p = 0.002), respectively (Additional file 2: Fig.	('CCA', 'Phenotype', 'HP:0030153', (168, 171))	('EpCAM', 'Gene', '4072', (59, 64))	('0.506', 'Var', (295, 300))	('CD44v6', 'Var', (37, 43))	('0.814', 'Var', (227, 232))	('CCA', 'Disease', 'MESH:D018281', (168, 171))	('CCA', 'Disease', (168, 171))	('CD44v8-10', 'Var', (45, 54))	('patients', 'Species', '9606', (142, 150))	('EpCAM', 'Gene', (59, 64))	('0.713', 'Var', (259, 264))
28606	32039729	The positive predictive value (PPV) and negative predictive value (NPV) were 51.7 and 77.4 for CD44, 55.6 and 78.8 for CD44v6, 59.3 and 81.8 for CD44v8-10 and 62.5 and 80.6 for EpCAM.	('N', 'Chemical', 'MESH:D009584', (67, 68))	('CD44', 'Var', (95, 99))	('EpCAM', 'Gene', (177, 182))	('CD44v6', 'Var', (119, 125))	('EpCAM', 'Gene', '4072', (177, 182))	('CD44v8-10', 'Var', (145, 154))
28607	32039729	By using the cut-off derived from the ROC curve, the predictive ability of CD44, CD44v6, CD44v8-10 and EpCAM on post-operative recurrence was explored.	('CD44v8-10', 'Var', (89, 98))	('EpCAM', 'Gene', (103, 108))	('EpCAM', 'Gene', '4072', (103, 108))
28608	32039729	The crude and adjusted odds ratio (OR) of CD44, CD44v6, CD44v8-10 and EpCAM were 3.67 (p = 0.022), 4.64 (p = 008), 6.55 (p = 0.002), 6.91 (p = 0.001) and 3.62 (p = 0.031), 4.98 (p = 0.009), 5.92 (p = 0.004), 6.23 (p = 0.003) (Table 9).	('EpCAM', 'Gene', (70, 75))	('EpCAM', 'Gene', '4072', (70, 75))	('CD44', 'Var', (42, 46))	('CD44v6', 'Var', (48, 54))	('CD44v8-10', 'Var', (56, 65))
28610	32039729	Soluble CD44, CD44v6, CD44v8-10 and EpCAM are promising factors for predicting cancer recurrence.	('CD44v6', 'Var', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('CD44v8-10', 'Var', (22, 31))	('EpCAM', 'Gene', (36, 41))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('EpCAM', 'Gene', '4072', (36, 41))
28612	32039729	Interestingly, a combination of high levels of CD44, CD44v6, CD44v8-10 and EpCAM could increase the risk for recurrence with a high value of crude OR (crude OR = 7.08, p = 0.004) and adjusted OR (adjusted OR = 7.39, p = 0.006).	('CD44', 'Var', (47, 51))	('increase', 'PosReg', (87, 95))	('CD44v8-10', 'Var', (61, 70))	('CD44v6', 'Var', (53, 59))	('recurrence', 'CPA', (109, 119))	('high levels', 'Var', (32, 43))	('EpCAM', 'Gene', (75, 80))	('EpCAM', 'Gene', '4072', (75, 80))
28613	32039729	The survival analysis was also evaluated in patients with high levels of CD44, CD44v6, CD44v8-10 and EpCAM combined with an elevated CA19-9 level compared with other groups of patients.	('patients', 'Species', '9606', (176, 184))	('patients', 'Species', '9606', (44, 52))	('EpCAM', 'Gene', (101, 106))	('CD44', 'Var', (73, 77))	('CA19-9 level', 'MPA', (133, 145))	('EpCAM', 'Gene', '4072', (101, 106))	('CD44v8-10', 'Var', (87, 96))	('CD44v6', 'Var', (79, 85))	('elevated', 'PosReg', (124, 132))
28614	32039729	Patients with high levels of CD44, CD44v6, CD44v8-10 and EpCAM combined with elevated CA19-9 had a lower RFS when compared with other groups (p = 0.004) (Fig.	('CD44v6', 'Var', (35, 41))	('CD44v8-10', 'Var', (43, 52))	('lower', 'NegReg', (99, 104))	('EpCAM', 'Gene', (57, 62))	('RFS', 'MPA', (105, 108))	('Patients', 'Species', '9606', (0, 8))	('EpCAM', 'Gene', '4072', (57, 62))	('CD44', 'Var', (29, 33))	('CA19-9', 'MPA', (86, 92))
28620	32039729	Moreover, the presence of such markers is likely to be useful for targeted therapy in order to prevent cancer progression and recurrence.	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('presence', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))
28622	32039729	demonstrated the existent of CSC in biliary tract cancer (BTC) and suggest that the isolated BTC cells that express CD24, CD44 or EpCAM had a higher potential of tumorigenesis than the negative groups.	('biliary tract cancer', 'Disease', 'MESH:D001661', (36, 56))	('BTC', 'Disease', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('EpCAM', 'Gene', '4072', (130, 135))	('BTC', 'Disease', 'MESH:D001661', (93, 96))	('biliary tract cancer', 'Disease', (36, 56))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('CD44', 'Var', (122, 126))	('CD24', 'Gene', '100133941', (116, 120))	('tumor', 'Disease', (162, 167))	('BTC', 'Disease', (58, 61))	('CD24', 'Gene', (116, 120))	('EpCAM', 'Gene', (130, 135))	('BTC', 'Disease', 'MESH:D001661', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('higher', 'PosReg', (142, 148))
28625	32039729	To answer this hypothesis, we performed immunohistochemical staining to evaluate the expression of 6 putative CSC markers, CD44, CD44v6, CD44v8-10, CD133, EpCAM and ALDH1A1 in CCA tissue.	('CCA', 'Disease', (176, 179))	('EpCAM', 'Gene', (155, 160))	('CD133', 'Gene', (148, 153))	('ALDH1A1', 'Gene', (165, 172))	('CD44v8-10', 'Var', (137, 146))	('ALDH1A1', 'Gene', '216', (165, 172))	('EpCAM', 'Gene', '4072', (155, 160))	('CD44', 'Gene', (123, 127))	('CCA', 'Phenotype', 'HP:0030153', (176, 179))	('CCA', 'Disease', 'MESH:D018281', (176, 179))	('CD44v6', 'Gene', (129, 135))
28626	32039729	The results show that among the 6 CSC markers investigated, the expression of CD44 and its variant isoforms (CD44v6 and CD44v8-10), and also ALDH1A1, were associated with tumor progression and poor outcome of CCA patients, including short RFS and OS.	('ALDH1A1', 'Gene', (141, 148))	('CD44', 'Gene', (78, 82))	('CD44v8-10', 'Var', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('CCA', 'Disease', 'MESH:D018281', (209, 212))	('CD44v6', 'Var', (109, 115))	('short RFS', 'Disease', (233, 242))	('CCA', 'Disease', (209, 212))	('associated with', 'Reg', (155, 170))	('ALDH1A1', 'Gene', '216', (141, 148))	('patients', 'Species', '9606', (213, 221))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('CCA', 'Phenotype', 'HP:0030153', (209, 212))
28628	32039729	There is considerable evidence suggesting that a high expression of CD44 is associated with tumor progression and recurrence, which is similar to the other two variant isoforms that have also been reported to be involved in cancer progression and recurrence.	('expression', 'MPA', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('CD44', 'Gene', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('associated', 'Reg', (76, 86))	('high', 'Var', (49, 53))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('tumor', 'Disease', (92, 97))	('cancer', 'Disease', (224, 230))	('recurrence', 'CPA', (114, 124))
28629	32039729	This is consistent with our finding for CCA which shows that patients with a high expression of CD44, CD44v6, and CD44v8-10 had a shorter RFS and OS compared with the low expression group.	('CCA', 'Disease', 'MESH:D018281', (40, 43))	('CD44v8-10', 'Var', (114, 123))	('RFS', 'MPA', (138, 141))	('patients', 'Species', '9606', (61, 69))	('CCA', 'Disease', (40, 43))	('CD44v6', 'Var', (102, 108))	('CD44', 'Gene', (96, 100))	('shorter', 'NegReg', (130, 137))	('CCA', 'Phenotype', 'HP:0030153', (40, 43))
28633	32039729	In the present study, we found that a high expression of ALDH1A1 was also associated with a favorable prognosis for CCA patients.	('CCA', 'Phenotype', 'HP:0030153', (116, 119))	('ALDH1A1', 'Gene', '216', (57, 64))	('high expression', 'Var', (38, 53))	('CCA', 'Disease', 'MESH:D018281', (116, 119))	('patients', 'Species', '9606', (120, 128))	('CCA', 'Disease', (116, 119))	('ALDH1A1', 'Gene', (57, 64))	('associated', 'Reg', (74, 84))
28635	32039729	A significant positive correlation was found in CD44, CD44v6 and CD44v8-10, with the combination of high expression in two or three markers being more useful in dividing patients into the different prognostic groups.	('CD44', 'Var', (48, 52))	('CD44v6', 'Var', (54, 60))	('CD44v8-10', 'Var', (65, 74))	('patients', 'Species', '9606', (170, 178))
28637	32039729	The panel of protein expression markers (CD44, CD44v6, and CD44v8-10) shows more efficacy in discriminating patients into different prognostic groups than the individual markers.	('patients', 'Species', '9606', (108, 116))	('CD44v8-10', 'Var', (59, 68))	('CD44', 'Var', (41, 45))	('CD44v6', 'Var', (47, 53))
28639	32039729	As many studies suggest that soluble EpCAM is associated with an aggressive tumor phenotype, soluble EpCAM was also considered to be a marker for CCA recurrence.	('CCA', 'Disease', (146, 149))	('EpCAM', 'Gene', (101, 106))	('aggressive tumor', 'Disease', 'MESH:D001523', (65, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('EpCAM', 'Gene', (37, 42))	('aggressive tumor', 'Disease', (65, 81))	('soluble', 'Var', (29, 36))	('EpCAM', 'Gene', '4072', (101, 106))	('CCA', 'Phenotype', 'HP:0030153', (146, 149))	('associated', 'Reg', (46, 56))	('EpCAM', 'Gene', '4072', (37, 42))	('CCA', 'Disease', 'MESH:D018281', (146, 149))
28641	32039729	Therefore, in order to determine the effect of staging on cancer recurrence, the different levels of soluble CD44, CD44v6, CD44v8-10 and EpCAM in patients with and without recurrence were examined according to staging.	('CD44v6', 'MPA', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('EpCAM', 'Gene', '4072', (137, 142))	('CD44v8-10', 'Var', (123, 132))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('patients', 'Species', '9606', (146, 154))	('EpCAM', 'Gene', (137, 142))
28646	32039729	CD44 is known as a surface marker associated with CSC in various cancer types, and several CD44 variant isoforms are generated by alternative splicing processes.	('associated', 'Reg', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('CSC', 'Disease', (50, 53))	('CD44', 'Gene', (91, 95))	('variant', 'Var', (96, 103))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
28651	32039729	Thus, the CSC markers, CD44, CD44v6, CD44v8-10, and EpCAM have the potential to predict cancer recurrence including CCA.	('cancer', 'Disease', (88, 94))	('CD44', 'Var', (23, 27))	('CD44v6', 'Var', (29, 35))	('CD44v8-10', 'Var', (37, 46))	('EpCAM', 'Gene', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('CCA', 'Phenotype', 'HP:0030153', (116, 119))	('predict', 'Reg', (80, 87))	('CCA', 'Disease', 'MESH:D018281', (116, 119))	('EpCAM', 'Gene', '4072', (52, 57))	('CCA', 'Disease', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
28653	32039729	In this study, we also found that high levels of soluble CD44, CD44v6, CD44v8-10 and EpCAM were correlated with elevated levels of CA19-9, suggesting that their expression is involved in tumor progression.	('CD44v6', 'Var', (63, 69))	('levels', 'MPA', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('EpCAM', 'Gene', '4072', (85, 90))	('CD44v8-10', 'Var', (71, 80))	('CA19-9', 'MPA', (131, 137))	('involved', 'Reg', (175, 183))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('elevated', 'PosReg', (112, 120))	('tumor', 'Disease', (187, 192))	('EpCAM', 'Gene', (85, 90))
28654	32039729	However, in late stage disease, there was no difference in the levels of soluble CD44, CD44v6, CD44v8-10 and EpCAM in patients with and without recurrence, even though some of them showed an association with poor results for the liver function test.	('CD44v6', 'Var', (87, 93))	('CD44v8-10', 'Var', (95, 104))	('EpCAM', 'Gene', (109, 114))	('patients', 'Species', '9606', (118, 126))	('EpCAM', 'Gene', '4072', (109, 114))
28655	32039729	Therefore, our further analysis focused on early stage disease in CCA patient with the aim of examining the predictive value of soluble CD44, CD44v6, CD44v8-10 and EpCAM on post-operative CCA recurrence.	('CD44v6', 'Var', (142, 148))	('CCA', 'Phenotype', 'HP:0030153', (188, 191))	('CD44v8-10', 'Var', (150, 159))	('CCA', 'Disease', 'MESH:D018281', (188, 191))	('CCA', 'Phenotype', 'HP:0030153', (66, 69))	('patient', 'Species', '9606', (70, 77))	('EpCAM', 'Gene', '4072', (164, 169))	('CCA', 'Disease', 'MESH:D018281', (66, 69))	('CCA', 'Disease', (188, 191))	('EpCAM', 'Gene', (164, 169))	('CCA', 'Disease', (66, 69))
28656	32039729	Interestingly, we found that either high levels of soluble CD44, CD44v6, CD44v8-10 and EpCAM alone or a combination of these markers provides more precise predictive potential of CCA recurrence.	('EpCAM', 'Gene', (87, 92))	('CCA', 'Phenotype', 'HP:0030153', (179, 182))	('EpCAM', 'Gene', '4072', (87, 92))	('CCA', 'Disease', 'MESH:D018281', (179, 182))	('CD44v8-10', 'Var', (73, 82))	('CCA', 'Disease', (179, 182))	('CD44v6', 'Var', (65, 71))
28657	32039729	Furthermore, there are studies that suggest that elevated serum levels of CA19-9 are also associated with CCA recurrence, a result corroborated by our study with soluble CD44, CD44v6, CD44v8-10, EpCAM and CA19-9.	('EpCAM', 'Gene', '4072', (195, 200))	('CCA', 'Phenotype', 'HP:0030153', (106, 109))	('CA19-9', 'Var', (74, 80))	('CD44v6', 'Var', (176, 182))	('CCA', 'Disease', 'MESH:D018281', (106, 109))	('CCA', 'Disease', (106, 109))	('associated', 'Reg', (90, 100))	('elevated', 'PosReg', (49, 57))	('EpCAM', 'Gene', (195, 200))	('CD44v8-10', 'Var', (184, 193))	('serum levels', 'MPA', (58, 70))
28660	32039729	The elevated of CD44, CD44v6, CD44v8-10 and EpCAM increases predictability of post-operative CCA recurrence.	('CCA', 'Disease', (93, 96))	('CD44', 'Protein', (16, 20))	('CD44v6', 'Var', (22, 28))	('CCA', 'Phenotype', 'HP:0030153', (93, 96))	('CD44v8-10', 'Var', (30, 39))	('increases', 'PosReg', (50, 59))	('EpCAM', 'Gene', (44, 49))	('elevated', 'PosReg', (4, 12))	('CCA', 'Disease', 'MESH:D018281', (93, 96))	('EpCAM', 'Gene', '4072', (44, 49))
28689	19669700	However, epothilones bypass the multi drug resistance (MDR) protein and tubulin mutation modes of resistance, which play significant roles in taxane resistance.	('drug resistance', 'Phenotype', 'HP:0020174', (38, 53))	('epothilones', 'Chemical', 'MESH:D034261', (9, 20))	('taxane', 'Chemical', 'MESH:C080625', (142, 148))	('as', 'Chemical', 'MESH:D001151', (24, 26))	('tubulin', 'Protein', (72, 79))	('multi', 'Protein', (32, 37))	('mutation', 'Var', (80, 88))
28690	19669700	Aza-epothilone B (ixabepilone; BMS-247550), a semisynthetic analog of the natural product epothilone B, has shown a broad spectrum of activity in vitro and in vivo against cancer models that are inherently insensitive to the taxanes or have developed resistance to them.	('as', 'Chemical', 'MESH:D001151', (105, 107))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('epothilone B', 'Chemical', 'MESH:C093788', (4, 16))	('taxanes', 'Chemical', 'MESH:D043823', (225, 232))	('epothilone B', 'Chemical', 'MESH:C093788', (90, 102))	('Aza-epothilone', 'Var', (0, 14))	('Aza-epothilone B', 'Chemical', 'MESH:C430592', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('activity', 'MPA', (134, 142))	('ixabepilone', 'Chemical', 'MESH:C430592', (18, 29))
28782	24715669	NOTCH pathway activation induces SOX9 expression, which is the most specific and earliest marker of biliary cells in developing liver and controls bile duct morphogenesis.	('SOX9', 'Gene', '6662', (33, 37))	('expression', 'MPA', (38, 48))	('induces', 'Reg', (25, 32))	('activation', 'Var', (14, 24))	('NOTCH', 'Gene', (0, 5))	('SOX9', 'Gene', (33, 37))
28851	24715669	Finally, since cholangiocytes proliferate in response to VEGF (vascular endothelial growth factor), we stimulated HepaRG-Chol with VEGF, which induced a significant 2-fold increase in the number of cells in G2/M phases (Supporting Fig.	('increase', 'PosReg', (172, 180))	('vascular endothelial growth factor', 'Gene', (63, 97))	('VEGF', 'Gene', (131, 135))	('rat', 'Species', '10116', (37, 40))	('vascular endothelial growth factor', 'Gene', '7422', (63, 97))	('HepaRG-Chol', 'Chemical', '-', (114, 125))	('VEGF', 'Gene', (57, 61))	('VEGF', 'Gene', '7422', (131, 135))	('HepaRG-Chol', 'Var', (114, 125))	('VEGF', 'Gene', '7422', (57, 61))
28884	24715669	When cysts were incubated with cholyl-lysyl-fluorescein (CLF), fluorescence accumulation was detected inside the central lumen (Fig.	('CLF', 'Disease', (57, 60))	('cholyl-lysyl-fluorescein', 'Var', (31, 55))	('cholyl-lysyl-fluorescein', 'Chemical', 'MESH:C072313', (31, 55))	('CLF', 'Disease', 'OMIM:604595', (57, 60))	('fluorescence accumulation', 'MPA', (63, 88))
28907	24715669	Of note CFTR, ASBT, and EpCAM are mutated in HepaRG (Dubois-Pot-Schneider, pers.	('mutated', 'Var', (34, 41))	('EpCAM', 'Gene', '4072', (24, 29))	('CFTR', 'Gene', '1080', (8, 12))	('ASBT', 'Gene', (14, 18))	('ASBT', 'Gene', '6555', (14, 18))	('CFTR', 'Gene', (8, 12))	('EpCAM', 'Gene', (24, 29))
28934	33535621	Herein, we provide an overview on the current knowledge regarding the predictive biomarkers of the response to ICIs in advanced BTCs, especially focusing on the role of programmed death-ligand 1 (PD-L1) expression, tumor mutational burden (TMB), mismatch repair deficiency (dMMR), high microsatellite instability (MSI-H), and DNA damage repair (DDR) gene mutations in this setting.	('deficiency', 'Disease', (262, 272))	('DNA', 'Gene', (326, 329))	('PD-L1', 'Gene', '29126', (196, 201))	('mutations', 'Var', (355, 364))	('deficiency', 'Disease', 'MESH:D007153', (262, 272))	('dMMR', 'Chemical', '-', (274, 278))	('TMB', 'Chemical', '-', (240, 243))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('MSI-H', 'Chemical', '-', (314, 319))	('programmed death-ligand 1', 'Gene', (169, 194))	('programmed death-ligand 1', 'Gene', '29126', (169, 194))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))	('PD-L1', 'Gene', (196, 201))	('BTC', 'Phenotype', 'HP:0100574', (128, 131))
28935	33535621	We performed research using PubMed/Medline, Cochrane Library, and Scopus with the keywords "biliary tract cancer" OR "cholangiocarcinoma" OR "intrahepatic cholangiocarcinoma" OR "extrahepatic cholangiocarcinoma" OR "gallbladder cancer" AND "immunotherapy" OR "immune checkpoint inhibitors" AND "PD-L1" OR "tumor mutational burden" OR "TMB" OR "MSI" OR "DDR" OR "DNA damage repair" OR "tumor microenvironment."	('gallbladder cancer', 'Disease', 'MESH:D005706', (216, 234))	('cholangiocarcinoma', 'Disease', (155, 173))	('PD-L1', 'Gene', (295, 300))	('tumor', 'Disease', (306, 311))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (155, 173))	('PD-L1', 'Gene', '29126', (295, 300))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (179, 210))	('tumor', 'Disease', (385, 390))	('biliary tract cancer', 'Disease', (92, 112))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (192, 210))	('mutational', 'Var', (312, 322))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('TMB', 'Chemical', '-', (335, 338))	('tumor', 'Disease', 'MESH:D009369', (385, 390))	('gallbladder cancer', 'Disease', (216, 234))	('cholangiocarcinoma', 'Disease', (192, 210))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (192, 210))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (92, 112))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (118, 136))	('biliary tract cancer', 'Disease', 'MESH:D001661', (92, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('tumor', 'Phenotype', 'HP:0002664', (385, 390))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (142, 173))	('cholangiocarcinoma', 'Disease', (118, 136))	('intrahepatic cholangiocarcinoma', 'Disease', (142, 173))	('extrahepatic cholangiocarcinoma', 'Disease', (179, 210))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (118, 136))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (155, 173))
28955	33535621	TMB is commonly defined as the overall number of somatic nonsynonymous mutations per megabase (Mut/Mb), including frame-shift mutations, insertions, point mutations, and deletions.	('insertions', 'Var', (137, 147))	('TMB', 'Chemical', '-', (0, 3))	('frame-shift mutations', 'Var', (114, 135))	('deletions', 'Var', (170, 179))	('point mutations', 'Var', (149, 164))
28956	33535621	The onset of these mutations is involved in the synthesis of abnormal proteins, which can act as neoantigens, activating antitumor responses (Figure 1).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('proteins', 'Protein', (70, 78))	('mutations', 'Var', (19, 28))	('tumor', 'Disease', (125, 130))	('activating', 'PosReg', (110, 120))
28965	33535621	More specifically, MSI results in the accumulation of mutations, leading to the formation of neoantigens and the activation of antitumor immune responses.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('neoantigens', 'MPA', (93, 104))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('mutations', 'Var', (54, 63))	('MSI', 'Var', (19, 22))	('activation', 'PosReg', (113, 123))	('tumor', 'Disease', (131, 136))	('formation', 'MPA', (80, 89))
28973	33535621	In addition, the previously discussed KEYNOTE-158 and KEYNOTE-028 trials exploring the role of pembrolizumab in pretreated patients with advanced BTC reported an interesting finding: in fact, all responders to the ICI were microsatellite stable, adding further confusion on the putative role of MSI.	('microsatellite stable', 'Var', (223, 244))	('patients', 'Species', '9606', (123, 131))	('pembrolizumab', 'Chemical', 'MESH:C582435', (95, 108))	('confusion', 'Phenotype', 'HP:0001289', (261, 270))	('responders', 'MPA', (196, 206))	('BTC', 'Phenotype', 'HP:0100574', (146, 149))
28979	33535621	First, the proportion of DDR gene mutations in BTC has been reported to occur in approximately 30% of patients, while Breast Related Cancer Antigens (BRCA) mutations seem to fluctuate between 1% and 7%, according to previous reports.	('Breast Related Cancer', 'Disease', (118, 139))	('BRCA', 'Gene', (150, 154))	('Cancer', 'Phenotype', 'HP:0002664', (133, 139))	('Breast Related Cancer', 'Disease', 'MESH:D001943', (118, 139))	('patients', 'Species', '9606', (102, 110))	('BTC', 'Phenotype', 'HP:0100574', (47, 50))	('BTC', 'Disease', (47, 50))	('DDR gene', 'Gene', (25, 33))	('mutations', 'Var', (34, 43))	('BRCA', 'Gene', '672', (150, 154))
28981	33535621	Of note, BRCA mutations were observed in 3.6% of tumor samples, without showing significant differences according to tumor site; in addition, an important finding of this report is the association between BRCA mutations, MSI/dMMR, and TMB-H, something that supports the evaluation of ICIs in a specific subgroup of BTC patients, with DDR gene mutations potentially representing biomarkers predictive of the response to immunotherapy.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('dMMR', 'Chemical', '-', (225, 229))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutations', 'Var', (210, 219))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('BTC', 'Phenotype', 'HP:0100574', (315, 318))	('BRCA', 'Gene', '672', (205, 209))	('tumor', 'Disease', (117, 122))	('BRCA', 'Gene', '672', (9, 13))	('tumor', 'Disease', (49, 54))	('association', 'Interaction', (185, 196))	('BRCA', 'Gene', (205, 209))	('DDR', 'Gene', (334, 337))	('patients', 'Species', '9606', (319, 327))	('TMB-H', 'Chemical', '-', (235, 240))	('BRCA', 'Gene', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
28982	33535621	Lastly, none of the recent studies investigating ICIs as a monotherapy or in combination with other anticancer agents in metastatic BTC have reported the number of patients harboring DDR aberrations; further studies are warranted in this direction to shed light on this promising:and still barely known:landscape.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('aberrations', 'Var', (187, 198))	('patients', 'Species', '9606', (164, 172))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('BTC', 'Phenotype', 'HP:0100574', (132, 135))
29077	31919404	Six- and 12-months OS rates were significantly longer in the modified FOLFOX arm (50.6% and 25.9%) than in the ASC arm (35.5% and 11.4%).	('modified FOLFOX', 'Var', (61, 76))	('longer', 'PosReg', (47, 53))	('OS rates', 'CPA', (19, 27))	('FOLFOX', 'Chemical', '-', (70, 76))
29079	31919404	Median OS and PFS of modified FOLFIRINOX in our study were longer compared to those in the ABC-06 trial.	('PFS', 'MPA', (14, 17))	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (30, 40))	('modified', 'Var', (21, 29))
29082	31919404	An ongoing phase 3 trial (NCT02989857) is evaluating the efficacy of ivosidenib versus placebo in cholangiocarcinoma with IDH1 mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (98, 116))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (98, 116))	('mutation', 'Var', (127, 135))	('IDH1', 'Gene', (122, 126))	('ivosidenib', 'Chemical', 'MESH:C000627630', (69, 79))	('IDH1', 'Gene', '3417', (122, 126))	('cholangiocarcinoma', 'Disease', (98, 116))
29083	31919404	Two phase 2 trials studied the efficacy of fibroblast growth factor receptor (FGFR) inhibitors in intrahepatic cholangiocarcinoma with FGFR2 aberrations and found a median PFS of 5.8 months and an ORR of 14.8-21.0%.	('FGFR', 'Gene', (78, 82))	('intrahepatic cholangiocarcinoma', 'Disease', (98, 129))	('aberrations', 'Var', (141, 152))	('FGFR2', 'Gene', (135, 140))	('FGFR2', 'Gene', '2263', (135, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (98, 129))
29084	31919404	Dabrafenib, a BRAF inhibitor, combined with trametinib, a MEK inhibitor, showed an ORR of 41%, a median PFS of 7.2 months and a median OS of 11.3 months in patients with BRAF V600E-mutated BTC previously treated in the first line.	('patients', 'Species', '9606', (156, 164))	('trametinib', 'Chemical', 'MESH:C560077', (44, 54))	('BRAF', 'Gene', (170, 174))	('MEK', 'Gene', (58, 61))	('MEK', 'Gene', '5609', (58, 61))	('V600E-mutated', 'Var', (175, 188))	('BRAF', 'Gene', '673', (14, 18))	('V600E', 'Mutation', 'rs113488022', (175, 180))	('BTC', 'Phenotype', 'HP:0100574', (189, 192))	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('BRAF', 'Gene', (14, 18))	('BTC', 'Gene', (189, 192))	('BRAF', 'Gene', '673', (170, 174))
29157	30813178	Hypoechoic tumor in ultrasound, low-density mass with enhancement in the periphery by contrast medium in CT, hypointensity in T1-weighted MRI, and hyperintensity on T2-weighted MRI were reported as dominant features of SIC.	('Hypoechoic tumor', 'Disease', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('hypointensity', 'Var', (109, 122))	('low-density mass', 'CPA', (32, 48))	('SIC', 'Disease', (219, 222))	('enhancement', 'PosReg', (54, 65))	('Hypoechoic tumor', 'Disease', 'MESH:D009369', (0, 16))	('SIC', 'Disease', 'None', (219, 222))	('hyperintensity', 'Var', (147, 161))
29200	29805739	The ligation of PD-1 and PD-L1 inhibits T cell proliferation and activation and induces apoptosis of tumor antigen-specific T cells to inhibit antitumor immunity and escape immune surveillance.	('apoptosis', 'CPA', (88, 97))	('tumor', 'Disease', (147, 152))	('PD-1', 'Gene', '5133', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('inhibit', 'NegReg', (135, 142))	('T cell proliferation', 'CPA', (40, 60))	('PD-L1', 'Gene', (25, 30))	('inhibits', 'NegReg', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('ligation', 'Var', (4, 12))	('induces', 'Reg', (80, 87))	('activation', 'CPA', (65, 75))	('PD-1', 'Gene', (16, 20))
29203	29805739	Recent clinical data have demonstrated that presence of CD8 tumor infiltrating lymphocytes (TILs) and PD-L1 expression in tumor microenvironment have not only prognostic implication but also predict clinical response to PD-1 blockade immunotherapy in a number of malignant tumors.	('tumor', 'Disease', (273, 278))	('CD8', 'Gene', '925', (56, 59))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (122, 127))	('TIL', 'Gene', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('PD-L1', 'Gene', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('malignant tumors', 'Disease', 'MESH:D018198', (263, 279))	('predict', 'Reg', (191, 198))	('presence', 'Var', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('CD8', 'Gene', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('malignant tumors', 'Disease', (263, 279))	('PD-1', 'Gene', '5133', (220, 224))	('PD-1', 'Gene', (220, 224))	('TIL', 'Gene', '7096', (92, 95))
29235	29805739	While the presence of TILs and PD-L1 expression have been identified in cholangiocarcinoma, their clinical associations have not been fully elucidated due to the rarity of the disease.	('identified', 'Reg', (58, 68))	('cholangiocarcinoma', 'Disease', (72, 90))	('TIL', 'Gene', '7096', (22, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 90))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))	('presence', 'Var', (10, 18))	('PD-L1', 'Gene', (31, 36))	('TIL', 'Gene', (22, 25))
29324	28943929	All the IMCC with cirrhosis were either hypointense (14, 93.3%) or isointense (1, 6.7%) on T1WI with a presence of homogeneous or heterogeneous hyperintense on T2WI.	('cirrhosis', 'Disease', (18, 27))	('heterogeneous hyperintense', 'MPA', (130, 156))	('cirrhosis', 'Phenotype', 'HP:0001394', (18, 27))	('cirrhosis', 'Disease', 'MESH:D005355', (18, 27))	('homogeneous', 'MPA', (115, 126))	('hypointense', 'Var', (40, 51))	('IMCC', 'Chemical', '-', (8, 12))
29328	28943929	As for HCC with cirrhosis, three (14.3%) tumors appeared high-low mixed signals owing to hemorrhage and the remaining (18, 85.7%) were hypointense on T1WI.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('hemorrhage', 'Disease', 'MESH:D006470', (89, 99))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('cirrhosis', 'Disease', 'MESH:D005355', (16, 25))	('cirrhosis', 'Phenotype', 'HP:0001394', (16, 25))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('HCC', 'Disease', (7, 10))	('hypointense', 'Var', (135, 146))	('cirrhosis', 'Disease', (16, 25))	('hemorrhage', 'Disease', (89, 99))
29333	28943929	The average +- SD numbers of CA199, AFP and CEA were 1497.53+-3626.50 U/ml, 517.92+-2047.69 and 58.04+-225.09 respectively in IMCC group.	('AFP', 'Gene', (36, 39))	('517.92+-2047.69', 'Var', (76, 91))	('AFP', 'Gene', '174', (36, 39))	('IMCC', 'Chemical', '-', (126, 130))	('CEA', 'Gene', (44, 47))	('CEA', 'Gene', '1084', (44, 47))
29334	28943929	While, the average +- SD numbers of CA199, AFP and CEA were 25.26+-30.29 U/ml, 5460.10+-17028.11 and 2.94+-1.65 ng/ml, respectively in HCC group.	('CEA', 'Gene', '1084', (51, 54))	('AFP', 'Gene', (43, 46))	('CA199', 'Var', (36, 41))	('AFP', 'Gene', '174', (43, 46))	('5460.10+-17028.11', 'Var', (79, 96))	('CEA', 'Gene', (51, 54))
29349	28943929	According to this enhancement pattern, radiologists could differentiate IMCC from HCC in patients with cirrhosis, which appeared peripheral hyperdensity/hyperintensity at hepatic arterial phase (HAP) or partial hyperdensity/hyperintensity with gradual and centripetal enhancement during later phases.	('men', 'Species', '9606', (275, 278))	('cirrhosis', 'Disease', (103, 112))	('HCC', 'Disease', (82, 85))	('men', 'Species', '9606', (25, 28))	('IMCC', 'Disease', (72, 76))	('patients', 'Species', '9606', (89, 97))	('cirrhosis', 'Phenotype', 'HP:0001394', (103, 112))	('cirrhosis', 'Disease', 'MESH:D005355', (103, 112))	('IMCC', 'Chemical', '-', (72, 76))	('peripheral', 'Disease', (129, 139))	('partial hyperdensity/hyperintensity', 'Var', (203, 238))
29377	28943929	It should be seriously considered the diagnosis of IMCC in cirrhotic patients that progressive and/or peripheral rim-like enhancement on CEMP CT and MRI, hyperintense at delayed phase on CEMP MRI with capsule retraction, portal vein invasion, bile duct dilation, abdominal lymphadenectasis and CA199 elevated.	('abdominal lymphadenectasis', 'CPA', (263, 289))	('portal vein invasion', 'CPA', (221, 241))	('hyperintense', 'Var', (154, 166))	('IMCC', 'Chemical', '-', (51, 55))	('men', 'Species', '9606', (129, 132))	('enhancement', 'PosReg', (122, 133))	('CEMP CT', 'Chemical', '-', (137, 144))	('patients', 'Species', '9606', (69, 77))	('bile', 'Disease', (243, 247))
29380	28484084	In univariate analysis, increased preoperative and postoperative CA19-9 levels in the light of different cut-off points (37, 100, 150, 200, 400, 1000 U/ml) were significantly associated with poor survival outcomes, of which the cut-off point of 150 U/ml showed the strongest predictive value (both P < 0.001).	('poor', 'NegReg', (191, 195))	('CA19-9', 'Chemical', 'MESH:C086528', (65, 71))	('CA19-9 levels', 'MPA', (65, 78))	('37', 'Var', (121, 123))	('survival outcomes', 'CPA', (196, 213))	('increased', 'PosReg', (24, 33))
29411	28484084	Differences in survival outcome were statistically significant between groups divided in the light of the six preoperative CA19-9 cut-off points (37, 100, 150, 200, 400, 1000 U/ml, the corresponding P values of which were 0.035, 0.028, < 0.001, 0.026, 0.010 and 0.010 respectively; Table 2).	('CA19-9', 'Chemical', 'MESH:C086528', (123, 129))	('CA19-9', 'Gene', (123, 129))	('37', 'Var', (146, 148))	('significant', 'Reg', (51, 62))
29413	28484084	And then, statistical differences in postoperative CA19-9 levels divided on the basis of the six cut-off points were also confirmed (cut-off points: 37, 100, 150, 200, 400, 1000 U/ml, the corresponding P values were 0.004, 0.013, < 0.001, 0.006, < 0.001 and < 0.001 respectively; Table 2).	('CA19-9', 'MPA', (51, 57))	('CA19-9', 'Chemical', 'MESH:C086528', (51, 57))	('0.013', 'Var', (223, 228))
29417	28484084	Finally, in the last group with CA19-9 decreased > 50%, a relatively better median survival time of 38.1 months was expected (Figure 3, P < 0.001).	('decreased', 'NegReg', (39, 48))	('CA19-9', 'Chemical', 'MESH:C086528', (32, 38))	('better', 'PosReg', (69, 75))	('CA19-9', 'Var', (32, 38))
29423	28484084	Patients with preoperative CA19-9 > 150 U/ml are easy to suffer vascular invasion (OR = 3.643, 95% CI 0.955-13.897; P = 0.058), however, it did not reach statistical significance.	('CA19-9', 'Chemical', 'MESH:C086528', (27, 33))	('Patients', 'Species', '9606', (0, 8))	('vascular invasion', 'CPA', (64, 81))	('CA19-9', 'Gene', (27, 33))	('> 150 U/ml', 'Var', (34, 44))
29426	28484084	Furthermore, the predictive value of preoperative to postoperative CA19-9 alterations on survival has also not been well defined.	('CA19-9', 'Chemical', 'MESH:C086528', (67, 73))	('CA19-9', 'Gene', (67, 73))	('alterations', 'Var', (74, 85))
29438	28484084	CA19-9 alterations could indirectly predict the disease evolution and increased postoperative CA19-9 is a reflection of tumor recurrence.	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('increased', 'PosReg', (70, 79))	('CA19-9', 'Chemical', 'MESH:C086528', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('CA19-9', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('CA19-9', 'Gene', (94, 100))	('alterations', 'Var', (7, 18))	('tumor', 'Disease', (120, 125))
29439	28484084	Our results demonstrated that patients with increased postoperative CA19-9 tend to have poor survival outcome.	('CA19-9', 'Var', (68, 74))	('survival', 'CPA', (93, 101))	('patients', 'Species', '9606', (30, 38))	('increased', 'PosReg', (44, 53))	('CA19-9', 'Chemical', 'MESH:C086528', (68, 74))
29440	28484084	Thus, attentions should also be paid on the preoperative to postoperative CA19-9 alterations so as to better predict the survival and tumor recurrence after surgery.	('CA19-9', 'Gene', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('CA19-9', 'Chemical', 'MESH:C086528', (74, 80))	('alterations', 'Var', (81, 92))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
29451	28484084	On the other hand, CA19-9 levels can impact lymph node metastasis, vascular invasion, early recurrence, and then indirectly affect survival.	('impact', 'Reg', (37, 43))	('affect', 'Reg', (124, 130))	('lymph node metastasis', 'CPA', (44, 65))	('vascular invasion', 'CPA', (67, 84))	('early recurrence', 'CPA', (86, 102))	('CA19-9', 'Chemical', 'MESH:C086528', (19, 25))	('survival', 'CPA', (131, 139))	('CA19-9 levels', 'Var', (19, 32))
29472	23558953	Identification of Targetable FGFR Gene Fusions in Diverse Cancers Through a prospective clinical sequencing program for advanced cancers, four index cases were identified which harbor gene rearrangements of FGFR2 including patients with cholangiocarcinoma, breast cancer, and prostate cancer.	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Cancers', 'Disease', 'MESH:D009369', (58, 65))	('clinical', 'Species', '191496', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('FGFR', 'Gene', (29, 33))	('Cancers', 'Disease', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('Cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('prostate cancer', 'Disease', 'MESH:D011471', (276, 291))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (237, 255))	('FGFR2', 'Gene', (207, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (257, 270))	('prostate cancer', 'Phenotype', 'HP:0012125', (276, 291))	('prostate cancer', 'Disease', (276, 291))	('cholangiocarcinoma', 'Disease', (237, 255))	('breast cancer', 'Disease', 'MESH:D001943', (257, 270))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (237, 255))	('breast cancer', 'Disease', (257, 270))	('FGFR2', 'Gene', '2263', (207, 212))	('patients', 'Species', '9606', (223, 231))	('gene rearrangements', 'Var', (184, 203))
29473	23558953	After extending our assessment of FGFR rearrangements across multiple tumor cohorts, we identified additional FGFR gene fusions with intact kinase domains in lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (185, 199))	('FGFR', 'Gene', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('head and neck squamous cell cancer', 'Phenotype', 'HP:0012288', (248, 282))	('oral cancer', 'Disease', 'MESH:D009062', (217, 228))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('neck squamous cell cancer', 'Disease', 'MESH:D002294', (257, 282))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (262, 282))	('lung squamous cell cancer', 'Phenotype', 'HP:0030359', (158, 183))	('oral cancer', 'Disease', (217, 228))	('thyroid cancer', 'Disease', (201, 215))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (163, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (230, 242))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('thyroid cancer', 'Disease', 'MESH:D013964', (201, 215))	('lung squamous cell cancer', 'Disease', 'MESH:D002294', (158, 183))	('neck squamous cell cancer', 'Disease', (257, 282))	('thyroid cancer', 'Phenotype', 'HP:0002890', (201, 215))	('tumor', 'Disease', (70, 75))	('lung squamous cell cancer', 'Disease', (158, 183))	('glioblastoma', 'Disease', (230, 242))	('bladder cancer', 'Disease', 'MESH:D001749', (185, 199))	('bladder cancer', 'Disease', (185, 199))	('fusions', 'Var', (120, 127))	('glioblastoma', 'Phenotype', 'HP:0012174', (230, 242))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
29474	23558953	Two bladder cancer cell lines that harbor FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo.	('bladder cancer', 'Disease', (4, 18))	('proteins', 'Protein', (55, 63))	('FGFR3', 'Gene', '2261', (42, 47))	('fusion', 'Var', (48, 54))	('bladder cancer', 'Phenotype', 'HP:0009725', (4, 18))	('susceptibility to pharmacologic inhibition', 'MPA', (83, 125))	('FGFR3', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('bladder cancer', 'Disease', 'MESH:D001749', (4, 18))	('enhanced', 'PosReg', (74, 82))
29475	23558953	Due to the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts which incorporate transcriptome analysis for gene fusions are poised to identify rare, targetable FGFR fusions across diverse cancer types.	('clinical', 'Species', '191496', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('fusions', 'Var', (234, 241))	('cancer', 'Disease', (257, 263))	('FGFR', 'Gene', (229, 233))
29479	23558953	In addition to the potential of identifying "actionable" therapeutic targets in cancer patients, these clinical sequencing efforts may lead to the identification of novel "driver" mutations that may be rare in a common cancer type or be newly revealed in relatively rare cancer types.	('clinical', 'Species', '191496', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('mutations', 'Var', (180, 189))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('patients', 'Species', '9606', (87, 95))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Disease', (219, 225))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (271, 277))	('cancer', 'Disease', (80, 86))
29482	23558953	In 2005, it was discovered that over 50% of prostate cancers harbor recurrent gene fusions of the androgen-regulated gene TMPRSS2 with ETS transcription factors, suggesting that gene fusions/translocations may play a significant role in common epithelial tumors similar to hematologic malignancies and sarcomas.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('prostate cancers', 'Phenotype', 'HP:0012125', (44, 60))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('prostate cancers', 'Disease', (44, 60))	('sarcomas', 'Disease', 'MESH:D012509', (302, 310))	('TMPRSS2', 'Gene', (122, 129))	('hematologic malignancies', 'Disease', 'MESH:D019337', (273, 297))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('sarcomas', 'Phenotype', 'HP:0100242', (302, 310))	('sarcomas', 'Disease', (302, 310))	('epithelial tumors', 'Disease', (244, 261))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('hematologic malignancies', 'Disease', (273, 297))	('prostate cancers', 'Disease', 'MESH:D011471', (44, 60))	('TMPRSS2', 'Gene', '7113', (122, 129))	('gene fusions', 'Var', (78, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (44, 59))	('epithelial tumors', 'Disease', 'MESH:D002277', (244, 261))
29485	23558953	Recently, FGFR1 and FGFR3 fusions with TACC1 and TACC3, respectively, have been identified in approximately 3% of the tumor glioblastoma multiforme (GBM) and FGFR3-TACC3 fusions were identified in a subset of bladder carcinomas.	('TACC3', 'Gene', '10460', (164, 169))	('TACC3', 'Gene', (164, 169))	('tumor glioblastoma multiforme', 'Disease', 'MESH:D005909', (118, 147))	('FGFR3', 'Gene', (158, 163))	('TACC1', 'Gene', '6867', (39, 44))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (209, 227))	('tumor glioblastoma multiforme', 'Disease', (118, 147))	('tumor glioblastoma multiforme', 'Phenotype', 'HP:0012174', (118, 147))	('FGFR3', 'Gene', '2261', (158, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))	('bladder carcinomas', 'Disease', 'MESH:D001749', (209, 227))	('identified', 'Reg', (80, 90))	('FGFR3', 'Gene', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('FGFR1', 'Gene', '2260', (10, 15))	('FGFR3', 'Gene', '2261', (20, 25))	('bladder carcinomas', 'Disease', (209, 227))	('fusions', 'Var', (26, 33))	('TACC3', 'Gene', '10460', (49, 54))	('TACC3', 'Gene', (49, 54))	('TACC1', 'Gene', (39, 44))	('FGFR1', 'Gene', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('carcinomas', 'Phenotype', 'HP:0030731', (217, 227))
29491	23558953	In this study, four MI-ONCOSEQ patients were prospectively identified that harbored gene fusions of FGFR2 by transcriptome sequencing (Fig.	('FGFR2', 'Gene', (100, 105))	('FGFR2', 'Gene', '2263', (100, 105))	('gene fusions', 'Var', (84, 96))	('patients', 'Species', '9606', (31, 39))	('MI-ONCOSEQ', 'Disease', (20, 30))
29494	23558953	The most interesting of these in terms of tumor biology was the inactivation of the SWI/SNF chromatin remodeling complex through mutation of ARID1A (Q1573*) and PBRM1 (C736*).	('PBRM1', 'Gene', (161, 166))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('ARID1A', 'Gene', '8289', (141, 147))	('Q1573*', 'Var', (149, 155))	('PBRM1', 'Gene', '55193', (161, 166))	('ARID1A', 'Gene', (141, 147))	('C736*', 'SUBSTITUTION', 'None', (168, 173))	('SWI/SNF', 'Gene', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('Q1573*', 'SUBSTITUTION', 'None', (149, 155))	('C736*', 'Var', (168, 173))	('inactivation', 'NegReg', (64, 76))
29495	23558953	The SWI/SNF complex has been implicated as a tumor suppressor and inactivating somatic mutations of ARID1A and PBRM1 have been identified in renal cell carcinoma, breast, and ovarian cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('renal cell carcinoma', 'Disease', (141, 161))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (141, 161))	('tumor', 'Disease', (45, 50))	('ARID1A', 'Gene', '8289', (100, 106))	('PBRM1', 'Gene', '55193', (111, 116))	('mutations', 'Var', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('inactivating', 'Var', (66, 78))	('ovarian cancer', 'Disease', 'MESH:D010051', (175, 189))	('breast', 'Disease', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('PBRM1', 'Gene', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('identified', 'Reg', (127, 137))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (141, 161))	('ovarian cancer', 'Disease', (175, 189))	('ovarian cancer', 'Phenotype', 'HP:0100615', (175, 189))	('ARID1A', 'Gene', (100, 106))
29496	23558953	Interestingly, by paired-end RNA sequencing we detected an intrachromosomal fusion which resulted in the in frame fusion of the FGFR2 kinase to BICC1 (Fig.	('FGFR2', 'Gene', (128, 133))	('BICC1', 'Gene', (144, 149))	('FGFR2', 'Gene', '2263', (128, 133))	('fusion', 'Var', (114, 120))	('BICC1', 'Gene', '80114', (144, 149))
29502	23558953	By contrast, however, this cholangiocarcinoma case exhibited 27 nonsynonymous somatic point mutations including an inactivating mutation of TP53 (R267W, Supplementary Table S5) and a distinct copy number landscape (Fig.	('R267W', 'Var', (146, 151))	('TP53', 'Gene', (140, 144))	('cholangiocarcinoma', 'Disease', (27, 45))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (27, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('R267W', 'Mutation', 'rs55832599', (146, 151))	('inactivating mutation', 'Var', (115, 136))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (27, 45))	('TP53', 'Gene', '7157', (140, 144))
29504	23558953	The third patient with an FGFR2 fusion identified was a 31 year old woman with metastatic breast cancer (MO_1051).	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('woman', 'Species', '9606', (68, 73))	('patient', 'Species', '9606', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('FGFR2', 'Gene', (26, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('fusion', 'Var', (32, 38))	('FGFR2', 'Gene', '2263', (26, 31))
29507	23558953	This breast cancer case also harbored 204 nonsynonymous point mutations including mutation of TP53 (G199E) and a known activating mutation of PIK3CA (H1047R) (Supplementary Table S8).	('PIK3CA', 'Gene', '5290', (142, 148))	('H1047R', 'Mutation', 'rs121913279', (150, 156))	('activating', 'PosReg', (119, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (5, 18))	('H1047R', 'Var', (150, 156))	('G199E', 'Mutation', 'p.G199E', (100, 105))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('G199E', 'Var', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('PIK3CA', 'Gene', (142, 148))	('breast cancer', 'Disease', 'MESH:D001943', (5, 18))	('breast cancer', 'Disease', (5, 18))
29508	23558953	While this breast cancer case exhibited a number of amplifications and deletions (Supplementary Table S9), as expected (based on past clinical pathology data) this patient was negative for the ERBB2 amplification.	('deletions', 'Var', (71, 80))	('ERBB2', 'Gene', '2064', (193, 198))	('ERBB2', 'Gene', (193, 198))	('patient', 'Species', '9606', (164, 171))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('amplifications', 'Var', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancer', 'Disease', (11, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('clinical', 'Species', '191496', (134, 142))
29511	23558953	Since SLC45A3 is a prostate-specific, androgen-regulated gene, the SLC45A3-FGFR2 fusion is predicted to drive overexpression of wild type FGFR2.	('SLC45A3', 'Gene', '85414', (6, 13))	('FGFR2', 'Gene', (138, 143))	('FGFR2', 'Gene', '2263', (138, 143))	('fusion', 'Var', (81, 87))	('SLC45A3', 'Gene', (67, 74))	('FGFR2', 'Gene', (75, 80))	('SLC45A3', 'Gene', '85414', (67, 74))	('FGFR2', 'Gene', '2263', (75, 80))	('overexpression', 'PosReg', (110, 124))	('SLC45A3', 'Gene', (6, 13))
29514	23558953	As we had identified novel FGFR2 gene fusions in cholangiocarcinoma, breast cancer and prostate cancer, we next asked whether FGFR family fusions are present across carcinomas of different histologies.	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('fusions', 'Var', (38, 45))	('FGFR2', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('carcinomas', 'Disease', (165, 175))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('breast cancer', 'Disease', (69, 82))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (49, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('FGFR2', 'Gene', '2263', (27, 32))	('prostate cancer', 'Disease', 'MESH:D011471', (87, 102))	('cholangiocarcinoma', 'Disease', (49, 67))	('prostate cancer', 'Phenotype', 'HP:0012125', (87, 102))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (49, 67))	('prostate cancer', 'Disease', (87, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('carcinomas', 'Disease', 'MESH:D002277', (165, 175))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
29516	23558953	Including the initial 4 index cases, we identified 24 tumors or cell lines with FGFR1, 2, and 3 fusions (Fig.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('FGFR1, 2, and 3', 'Gene', '2260;2263;2261', (80, 95))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('fusions', 'Var', (96, 103))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
29518	23558953	Cancer types harboring FGFR fusions were quite diverse and included cholangiocarcinoma (n=2), breast cancer (n=4), prostate cancer (n=1), thyroid cancer (n=1), lung squamous cell carcinoma (n=6), bladder cancer (n=5), oral cancer (n=1), head and neck squamous cell carcinoma (n=2), and glioblastoma (n=2).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (68, 86))	('prostate cancer', 'Disease', 'MESH:D011471', (115, 130))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))	('neck squamous cell carcinoma', 'Disease', (246, 274))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (246, 274))	('cholangiocarcinoma', 'Disease', (68, 86))	('prostate cancer', 'Disease', (115, 130))	('thyroid cancer', 'Disease', (138, 152))	('FGFR', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (68, 86))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('fusions', 'Var', (28, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (251, 274))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (160, 188))	('oral cancer', 'Disease', 'MESH:D009062', (218, 229))	('breast cancer', 'Disease', (94, 107))	('lung squamous cell carcinoma', 'Disease', (160, 188))	('oral cancer', 'Disease', (218, 229))	('thyroid cancer', 'Disease', 'MESH:D013964', (138, 152))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('bladder cancer', 'Disease', 'MESH:D001749', (196, 210))	('bladder cancer', 'Disease', (196, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('glioblastoma', 'Disease', 'MESH:D005909', (286, 298))	('thyroid cancer', 'Phenotype', 'HP:0002890', (138, 152))	('bladder cancer', 'Phenotype', 'HP:0009725', (196, 210))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Cancer', 'Disease', (0, 6))	('glioblastoma', 'Disease', (286, 298))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('glioblastoma', 'Phenotype', 'HP:0012174', (286, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))
29521	23558953	Thus, we expressed selected epitope tagged versions of the FGFR fusions in HEK 293T cells and looked for protein oligomerization by co-immunoprecipitation.	('FGFR', 'Gene', (59, 63))	('fusions', 'Var', (64, 71))	('looked', 'Reg', (94, 100))	('HEK 293T', 'CellLine', 'CVCL:0063', (75, 83))
29526	23558953	To further demonstrate that FGFR fusion kinases are biologically active, we stably expressed FGFR fusions in benign immortalized TERT-HME cell lines.	('FGFR', 'Gene', (93, 97))	('TERT-HME', 'CellLine', 'CVCL:3383', (129, 137))	('fusions', 'Var', (98, 105))
29527	23558953	Stable lines harboring the FGFR3-BAIAP2L1, FGFR3-TACC3, and FGFR2-CCDC6 fusions showed expression of active FGFR fusion kinases (as demonstrated by tyrosine phosphorylation of the fusion kinases) and enhanced proliferation of the cells (Fig.	('FGFR3', 'Gene', '2261', (27, 32))	('tyrosine', 'Chemical', 'MESH:D014443', (148, 156))	('FGFR3', 'Gene', (43, 48))	('proliferation of the cells', 'CPA', (209, 235))	('TACC3', 'Gene', '10460', (49, 54))	('FGFR3', 'Gene', (27, 32))	('TACC3', 'Gene', (49, 54))	('BAIAP2L1', 'Gene', (33, 41))	('FGFR', 'Gene', (108, 112))	('FGFR3', 'Gene', '2261', (43, 48))	('FGFR2', 'Gene', (60, 65))	('enhanced', 'PosReg', (200, 208))	('CCDC6', 'Gene', (66, 71))	('fusions', 'Var', (72, 79))	('FGFR2', 'Gene', '2263', (60, 65))	('BAIAP2L1', 'Gene', '55971', (33, 41))	('CCDC6', 'Gene', '8030', (66, 71))
29529	23558953	Additionally, the ERLIN2-FGFR1 fusion also produces an active FGFR kinase, as shown by tyrosine phosphorylation of the expressed fusion construct (Supplementary Fig.	('FGFR kinase', 'Enzyme', (62, 73))	('ERLIN2', 'Gene', (18, 24))	('tyrosine', 'Chemical', 'MESH:D014443', (87, 95))	('active', 'MPA', (55, 61))	('tyrosine phosphorylation', 'MPA', (87, 111))	('ERLIN2', 'Gene', '11160', (18, 24))	('fusion', 'Var', (31, 37))	('FGFR1', 'Gene', (25, 30))	('FGFR1', 'Gene', '2260', (25, 30))
29532	23558953	S7A), while J82 and HT-1197 cells harbor activating point mutations of FGFR3 (K652E and S249C respectively, COSMIC).	('S249C', 'Mutation', 'rs121913483', (88, 93))	('FGFR3', 'Gene', (71, 76))	('K652E', 'Mutation', 'rs78311289', (78, 83))	('activating', 'PosReg', (41, 51))	('HT-1197', 'CellLine', 'CVCL:1291', (20, 27))	('FGFR3', 'Gene', '2261', (71, 76))	('S249C', 'Var', (88, 93))	('K652E', 'Var', (78, 83))
29533	23558953	Importantly, while the FGFR fusion cell line SW780 was sensitive to nanomolar concentrations of PD173074, the FGFR3 mutant cell lines used here were not (Fig.	('PD173074', 'Var', (96, 104))	('SW780', 'CellLine', 'CVCL:1728', (45, 50))	('PD173074', 'Chemical', 'MESH:C115711', (96, 104))	('FGFR3', 'Gene', '2261', (110, 115))	('FGFR3', 'Gene', (110, 115))
29535	23558953	PD173074 exerted a cell cycle arrest effect on fusion positive SW780 cells, but not fusion-negative HT-1197 cells (Supplementary Fig.	('PD173074', 'Var', (0, 8))	('SW780', 'CellLine', 'CVCL:1728', (63, 68))	('PD173074', 'Chemical', 'MESH:C115711', (0, 8))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (19, 36))	('cell cycle arrest', 'CPA', (19, 36))	('HT-1197', 'CellLine', 'CVCL:1291', (100, 107))
29536	23558953	SW780 xenografts exhibited decreased tumor growth with increasing doses of PD173074 while J82 xenografts did not (Fig.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('PD173074', 'Chemical', 'MESH:C115711', (75, 83))	('SW780', 'CellLine', 'CVCL:1728', (0, 5))	('PD173074', 'Var', (75, 83))	('decreased', 'NegReg', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))
29539	23558953	The RT4 urothelial carcinoma line harboring a FGFR3-TACC3 fusion also exhibited sensitivity to FGFR inhibition in a xenograft model (Fig.	('urothelial carcinoma', 'Disease', (8, 28))	('TACC3', 'Gene', '10460', (52, 57))	('fusion', 'Var', (58, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('FGFR3', 'Gene', '2261', (46, 51))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (8, 28))	('TACC3', 'Gene', (52, 57))	('FGFR3', 'Gene', (46, 51))
29540	23558953	Toxicity of PD173074 was monitored by assessment of mouse body weight (Supplementary Fig.	('mouse', 'Species', '10090', (52, 57))	('Toxicity', 'Disease', (0, 8))	('Toxicity', 'Disease', 'MESH:D064420', (0, 8))	('PD173074', 'Var', (12, 20))	('PD173074', 'Chemical', 'MESH:C115711', (12, 20))
29541	23558953	Further experiments utilizing siRNA knockdown demonstrate the central role of FGFR3-BAIAP2L1 fusion in SW780 cell proliferation.	('FGFR3', 'Gene', (78, 83))	('SW780', 'CellLine', 'CVCL:1728', (103, 108))	('BAIAP2L1', 'Gene', '55971', (84, 92))	('BAIAP2L1', 'Gene', (84, 92))	('FGFR3', 'Gene', '2261', (78, 83))	('fusion', 'Var', (93, 99))
29546	23558953	The first cholangiocarcinoma patient MO_1036, who harbored the FGFR2-BICC1 fusion, underwent a conventional chemotherapy regimen in which her cancer progressed and chose not to pursue FGFR directed therapy and died 3 months after enrollment on this protocol.	('cholangiocarcinoma', 'Disease', (10, 28))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('patient', 'Species', '9606', (29, 36))	('BICC1', 'Gene', '80114', (69, 74))	('fusion', 'Var', (75, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (10, 28))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (10, 28))	('BICC1', 'Gene', (69, 74))	('FGFR2', 'Gene', '2263', (63, 68))	('progressed', 'PosReg', (149, 159))	('FGFR2', 'Gene', (63, 68))	('cancer', 'Disease', (142, 148))
29547	23558953	The second cholangiocarcinoma patient, MO_1039, also harboring an FGFR2-BICC1 fusion underwent conventional chemotherapy but did not show tumor shrinkage and was enrolled on an FGFR inhibitor clinical trial.	('BICC1', 'Gene', '80114', (72, 77))	('fusion', 'Var', (78, 84))	('FGFR2', 'Gene', (66, 71))	('FGFR2', 'Gene', '2263', (66, 71))	('tumor', 'Disease', (138, 143))	('patient', 'Species', '9606', (30, 37))	('cholangiocarcinoma', 'Disease', (11, 29))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (11, 29))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (11, 29))	('clinical', 'Species', '191496', (192, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('BICC1', 'Gene', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
29548	23558953	The metastatic breast cancer patient, MO_1051, harboring the FGFR2-AFF3 fusion, died of end-stage disease before the sequencing results were available, while the metastatic prostate cancer patient underwent irradiation of the brain (after brain metastasis resection) and continues to be maintained on hormonal treatment.	('patient', 'Species', '9606', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('AFF3', 'Gene', '3899', (67, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (173, 188))	('fusion', 'Var', (72, 78))	('patient', 'Species', '9606', (189, 196))	('FGFR2', 'Gene', (61, 66))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (173, 188))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('FGFR2', 'Gene', '2263', (61, 66))	('breast cancer', 'Disease', (15, 28))	('AFF3', 'Gene', (67, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))	('prostate cancer', 'Disease', (173, 188))
29550	23558953	Activating point mutations of FGFR1, FGFR2, FGFR3 or FGFR4 have been identified in a variety of cancers including gliomas, bladder cancer, multiple myeloma, and rhabdomyosarcomas.	('rhabdomyosarcomas', 'Disease', (161, 178))	('Activating', 'PosReg', (0, 10))	('bladder cancer', 'Phenotype', 'HP:0009725', (123, 137))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (161, 178))	('FGFR1', 'Gene', '2260', (30, 35))	('FGFR2', 'Gene', '2263', (37, 42))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancers', 'Disease', (96, 103))	('gliomas', 'Disease', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('multiple myeloma', 'Phenotype', 'HP:0006775', (139, 155))	('point mutations', 'Var', (11, 26))	('FGFR1', 'Gene', (30, 35))	('gliomas', 'Disease', 'MESH:D005910', (114, 121))	('FGFR3', 'Gene', (44, 49))	('sarcomas', 'Phenotype', 'HP:0100242', (170, 178))	('multiple myeloma', 'Disease', 'MESH:D009101', (139, 155))	('FGFR4', 'Gene', '2264', (53, 58))	('FGFR3', 'Gene', '2261', (44, 49))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('identified', 'Reg', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('FGFR2', 'Gene', (37, 42))	('bladder cancer', 'Disease', 'MESH:D001749', (123, 137))	('FGFR4', 'Gene', (53, 58))	('multiple myeloma', 'Disease', (139, 155))	('bladder cancer', 'Disease', (123, 137))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (161, 178))
29551	23558953	Studies of hematological diseases led to the identification of 3' gene fusions of FGFR1 in myeloproliferative disorder and 3' FGFR3 fusions in peripheral T-cell lymphoma and multiple myeloma.	('myeloproliferative disorder', 'Phenotype', 'HP:0005547', (91, 118))	('peripheral T-cell lymphoma', 'Disease', 'MESH:D016411', (143, 169))	('FGFR1', 'Gene', (82, 87))	('fusions', 'Var', (132, 139))	('peripheral T-cell lymphoma', 'Disease', (143, 169))	('FGFR3', 'Gene', (126, 131))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (154, 169))	('FGFR1', 'Gene', '2260', (82, 87))	('hematological diseases', 'Disease', (11, 33))	('myeloproliferative disorder', 'Disease', (91, 118))	('myeloproliferative disorder', 'Disease', 'MESH:D009196', (91, 118))	('cell lymphoma', 'Phenotype', 'HP:0012191', (156, 169))	('lymphoma', 'Phenotype', 'HP:0002665', (161, 169))	('multiple myeloma', 'Phenotype', 'HP:0006775', (174, 190))	('FGFR3', 'Gene', '2261', (126, 131))	('multiple myeloma', 'Disease', 'MESH:D009101', (174, 190))	('multiple myeloma', 'Disease', (174, 190))	('hematological diseases', 'Disease', 'MESH:D006402', (11, 33))
29553	23558953	Here, we identify potentially actionable 5' and 3' FGFR rearrangements across a diverse array of both common and rare solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('solid tumors', 'Disease', 'MESH:D009369', (118, 130))	('FGFR', 'Gene', (51, 55))	('rearrangements', 'Var', (56, 70))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('solid tumors', 'Disease', (118, 130))
29559	23558953	The SLC45A3-FGFR2 gene fusion identified in the index prostate cancer is quite interesting as its pathogenic role is likely through a mechanism that is distinct from fusion protein oligomerization (shared by the other gene fusions tested).	('SLC45A3', 'Gene', '85414', (4, 11))	('fusion', 'Var', (23, 29))	('prostate cancer', 'Disease', (54, 69))	('SLC45A3', 'Gene', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('FGFR2', 'Gene', (12, 17))	('prostate cancer', 'Disease', 'MESH:D011471', (54, 69))	('FGFR2', 'Gene', '2263', (12, 17))	('prostate cancer', 'Phenotype', 'HP:0012125', (54, 69))
29561	23558953	The SLC45A3-FGFR2 fusion is analogous to the previously characterized TMPRSS2-ETS gene fusions characterized in over 50% of prostate cancers.	('SLC45A3', 'Gene', '85414', (4, 11))	('prostate cancers', 'Disease', 'MESH:D011471', (124, 140))	('SLC45A3', 'Gene', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('TMPRSS2', 'Gene', (70, 77))	('FGFR2', 'Gene', (12, 17))	('prostate cancer', 'Phenotype', 'HP:0012125', (124, 139))	('fusion', 'Var', (18, 24))	('FGFR2', 'Gene', '2263', (12, 17))	('prostate cancers', 'Phenotype', 'HP:0012125', (124, 140))	('prostate cancers', 'Disease', (124, 140))	('TMPRSS2', 'Gene', '7113', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
29563	23558953	Another interesting observation in this study is the enhanced sensitivity to the FGFR inhibitor PD173074 of cell lines harboring an FGFR3 fusion relative to those that have an activating point mutation of FGFR3.	('FGFR3', 'Gene', (132, 137))	('FGFR3', 'Gene', (205, 210))	('PD173074', 'Chemical', 'MESH:C115711', (96, 104))	('sensitivity to the FGFR inhibitor', 'MPA', (62, 95))	('fusion', 'Var', (138, 144))	('FGFR3', 'Gene', '2261', (132, 137))	('FGFR3', 'Gene', '2261', (205, 210))	('enhanced', 'PosReg', (53, 61))
29565	23558953	It will be important to enrich these early stage clinical trials with patients harboring FGFR gene fusions similar to the successful development of the small molecule kinase inhibitor crizotonib in lung cancer patients harboring the EML4-ALK gene fusion.	('lung cancer', 'Disease', (198, 209))	('patients', 'Species', '9606', (70, 78))	('clinical', 'Species', '191496', (49, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('FGFR', 'Gene', (89, 93))	('ALK', 'Gene', '238', (238, 241))	('EML4', 'Gene', (233, 237))	('gene fusions', 'Var', (94, 106))	('fusions', 'Var', (99, 106))	('lung cancer', 'Disease', 'MESH:D008175', (198, 209))	('EML4', 'Gene', '27436', (233, 237))	('crizotonib', 'Chemical', '-', (184, 194))	('patients', 'Species', '9606', (210, 218))	('ALK', 'Gene', (238, 241))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
29566	23558953	The wide range of cancers in which FGFR rearrangements were detected in this study, suggest that development of FGFR rearrangements are lineage independent and emphasizes the importance of developing mutation enriched clinical trials rather than trials based on tissue of origin.	('cancers', 'Disease', (18, 25))	('FGFR', 'Gene', (112, 116))	('rearrangements', 'Var', (117, 131))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('clinical', 'Species', '191496', (218, 226))	('cancers', 'Disease', 'MESH:D009369', (18, 25))
29569	23558953	Combining these index patients with an analysis of transcriptome data from our internal tumor cohorts as well as the TCGA identified FGFR fusions in a wide array of cancers including cholangiocarcinoma, GBM, squamous lung cancer, bladder cancer, breast cancer, thyroid cancer, oral cancer, head and neck squamous cell carcinoma, and prostate cancer.	('squamous lung cancer', 'Disease', (208, 228))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('GBM', 'Disease', (203, 206))	('oral cancer', 'Disease', (277, 288))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (318, 327))	('bladder cancer', 'Disease', 'MESH:D001749', (230, 244))	('thyroid cancer', 'Disease', 'MESH:D013964', (261, 275))	('bladder cancer', 'Disease', (230, 244))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('squamous lung cancer', 'Disease', 'MESH:D008175', (208, 228))	('breast cancer', 'Disease', (246, 259))	('FGFR', 'Gene', (133, 137))	('bladder cancer', 'Phenotype', 'HP:0009725', (230, 244))	('thyroid cancer', 'Phenotype', 'HP:0002890', (261, 275))	('patients', 'Species', '9606', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('prostate cancer', 'Disease', 'MESH:D011471', (333, 348))	('tumor', 'Disease', (88, 93))	('fusions', 'Var', (138, 145))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (183, 201))	('prostate cancer', 'Phenotype', 'HP:0012125', (333, 348))	('squamous lung cancer', 'Phenotype', 'HP:0030359', (208, 228))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('neck squamous cell carcinoma', 'Disease', (299, 327))	('prostate cancer', 'Disease', (333, 348))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (299, 327))	('cholangiocarcinoma', 'Disease', (183, 201))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (183, 201))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('thyroid cancer', 'Disease', (261, 275))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (304, 327))	('oral cancer', 'Disease', 'MESH:D009062', (277, 288))
29571	23558953	We also suggest a common mechanism of activation of these fusion proteins and show that FGFR gene fusion positive cancers have enhanced susceptibility to FGFR inhibitors over activating point mutations of FGFR.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('activating', 'PosReg', (175, 185))	('enhanced', 'PosReg', (127, 135))	('cancers', 'Disease', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('FGFR', 'Gene', (205, 209))	('point mutations', 'Var', (186, 201))	('susceptibility', 'MPA', (136, 150))	('FGFR', 'Gene', (88, 92))
29594	23558953	The set of candidates used for estimation consisted of coding variants that (1) exhibited at least 3 variant fragments in the tumor sample, (2) exhibited zero variant fragments in the matched benign sample with at least 16 fragments of coverage, (3) were not present in dbSNP, (4) were within a targeted exon or within 100 base pairs of a targeted exon, (5) were not in homopolymer runs of four or more bases, and (6) exhibited no evidence of amplification or deletion.	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('variants', 'Var', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
29622	23558953	The siRNAs used were as follows: ON-TARGETplus FGFR3 L-003133-00-0005, ON-TARGETplus BAIAP2L1 L-018664-00-0005, and ON-TARGETplus Non-targeting pool.	('BAIAP2L1', 'Gene', '55971', (85, 93))	('FGFR3', 'Gene', (47, 52))	('L-003133-00-0005', 'Var', (53, 69))	('FGFR3', 'Gene', '2261', (47, 52))	('BAIAP2L1', 'Gene', (85, 93))
29629	23558953	Xenografted mice with palpable tumors were treated with a FGFR inhibitor PD173074 (Selleck Chemicals) dissolved in 5% ethanol in corn oil (intraperitoneal).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('ethanol', 'Chemical', 'MESH:D000431', (118, 125))	('tumors', 'Disease', (31, 37))	('mice', 'Species', '10090', (12, 16))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('FGFR', 'Gene', (58, 62))	('corn', 'Species', '4577', (129, 133))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('PD173074', 'Chemical', 'MESH:C115711', (73, 81))	('PD173074', 'Var', (73, 81))
29636	23558953	Here through integrative sequencing efforts, we identified a variety of FGFR gene fusions in a spectrum of human cancers.	('human', 'Species', '9606', (107, 112))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('FGFR', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('gene fusions', 'Var', (77, 89))
29637	23558953	Cells harboring FGFR fusions showed enhanced sensitivity to the FGFR inhibitors PD173074 and pazopanib, suggesting cancer patients with FGFR fusions may benefit from targeted FGFR kinase inhibition.	('cancer', 'Disease', (115, 121))	('PD173074', 'Chemical', 'MESH:C115711', (80, 88))	('sensitivity', 'MPA', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('patients', 'Species', '9606', (122, 130))	('pazopanib', 'Chemical', 'MESH:C516667', (93, 102))	('fusions', 'Var', (21, 28))	('enhanced', 'PosReg', (36, 44))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('fusions', 'Var', (141, 148))
29767	33073719	Both CEA and CA19-9 were significantly higher in CC than in other tumors, whereas AFP was significantly higher in HCC, classical ChC, and SC-INT; PIVKA-II was significantly higher in HCC.	('HCC', 'Phenotype', 'HP:0001402', (183, 186))	('higher', 'PosReg', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('CEA', 'Gene', (5, 8))	('ChC', 'Chemical', '-', (129, 132))	('AFP', 'Gene', (82, 85))	('AFP', 'Gene', '174', (82, 85))	('CA19-9', 'Var', (13, 19))	('ChC', 'Phenotype', 'HP:0030153', (129, 132))	('CEA', 'Gene', '1084', (5, 8))	('CC', 'Phenotype', 'HP:0030153', (184, 186))	('CC', 'Phenotype', 'HP:0030153', (115, 117))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('HCC', 'Disease', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('CC', 'Phenotype', 'HP:0030153', (49, 51))	('HCC', 'Phenotype', 'HP:0001402', (114, 117))	('tumors', 'Disease', (66, 72))	('classical ChC', 'Disease', (119, 132))
29810	33073719	They found that AT-rich interactive domain-containing protein 1A (ARID1A), which is involved in remodeling of chromatin mutations, was significantly associated with CLC-subtype predominance (p < 0.05), whereas telomerase reverse transcriptase (TERT) promoter mutations correlated with classical and SC-INT subtype-predominant histology, higher clinical stage, and a higher N-factor (p < 0.05).	('CLC', 'Chemical', '-', (165, 168))	('CLC', 'Phenotype', 'HP:0030153', (165, 168))	('CLC-subtype predominance', 'Disease', (165, 189))	('mutations', 'Var', (259, 268))	('TERT', 'Gene', (244, 248))	('N-factor', 'Species', '556193', (373, 381))	('associated', 'Reg', (149, 159))
29811	33073719	Mutational analysis revealed that ChC had diverse mutations, and that mutations in the TERT promoter and ARID1A may reflect the etiology, histological subtype, histogenesis, and tumor aggressiveness.	('aggressiveness', 'Phenotype', 'HP:0000718', (184, 198))	('ARID1A', 'Gene', (105, 111))	('mutations', 'Var', (70, 79))	('reflect', 'Reg', (116, 123))	('ChC', 'Phenotype', 'HP:0030153', (34, 37))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (178, 198))	('TERT promoter', 'Gene', (87, 100))	('ChC', 'Chemical', '-', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor aggressiveness', 'Disease', (178, 198))
29860	32021453	CA19-9/BR was classified as elevated compared with normal based on the upper serum normal values of CA19-9 (37 U/mL) and bilirubin (1.5 mg/dL), which gives a cut-off at 25 U/mL/mg/dL.	('CA19-9/BR', 'Var', (0, 9))	('CA19-9', 'Gene', (100, 106))	('bilirubin', 'MPA', (121, 130))	('bilirubin', 'Chemical', 'MESH:D001663', (121, 130))
29861	32021453	Univariate analysis showed that the overall survival of patients with a high CA19-9/BR ratio was significantly worse compared with patients with a low CA19-9/BR ratio (Hazard Ratio [HR] 2.149; 95% Confidence Interval [95% CI] 1.027-4.495; P=0.042).	('patients', 'Species', '9606', (131, 139))	('patients', 'Species', '9606', (56, 64))	('high CA19-9/BR ratio', 'Var', (72, 92))	('worse', 'NegReg', (111, 116))	('overall survival', 'CPA', (36, 52))
29901	32021453	OS of the patients with high CA19-9/BR ratio was significantly worse compared with patients with low CA19-9/BR ratio (Hazard Ratio [HR] 2.149; 95% Confidence Interval [95% CI] 1.027-4.495; P=0.042).	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (10, 18))	('worse', 'NegReg', (63, 68))	('high CA19-9/BR ratio', 'Var', (24, 44))
29904	32021453	In addition to prognostic factors that are associated with ECC that were shown in several studies, some studies identified CA19-9 as a predicting prognosis factor for cancer.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('CA19-9', 'Var', (123, 129))	('cancer', 'Disease', (167, 173))	('ECC', 'Disease', 'MESH:D018281', (59, 62))	('ECC', 'Disease', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
29905	32021453	CA19-9 was initially widely studied as having prognostic value in tumors, such as in pancreatic cancer.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('pancreatic cancer', 'Disease', (85, 102))	('pancreatic cancer', 'Disease', 'MESH:D010190', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('CA19-9', 'Var', (0, 6))
29907	32021453	Kondo et al identified preoperative CA19-9 >=200 IU/mL as an independent prognostic factor for poor OS in resectable cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (117, 135))	('CA19-9 >=200 IU/mL', 'Var', (36, 54))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (117, 135))	('poor OS', 'Disease', (95, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (117, 135))
29908	32021453	Kato et al and Yamashita et al found that non-normalization of CA19-9 after biliary tract cancer surgery was associated with poor OS.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (76, 96))	('non-normalization', 'Var', (42, 59))	('CA19-9', 'Gene', (63, 69))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
29910	32021453	Bolm et al identified preoperative bilirubin-adjusted CA19-9 as a good predictive factor for distal cholangiocarcinoma in Western patients.	('CA19-9', 'Var', (54, 60))	('cholangiocarcinoma', 'Disease', (100, 118))	('bilirubin', 'Chemical', 'MESH:D001663', (35, 44))	('patients', 'Species', '9606', (130, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (100, 118))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))
29915	32021453	CA19-9 is a tumor-associated antigen which is produced by bile duct epithelium.	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('CA19-9', 'Var', (0, 6))
29937	32021453	This is the first study in China that investigated the CA19-9/BR in ECC patients and we showed its predictive value.	('CA19-9/BR', 'Var', (55, 64))	('ECC', 'Disease', (68, 71))	('ECC', 'Disease', 'MESH:D018281', (68, 71))	('patients', 'Species', '9606', (72, 80))
29950	31361379	By knockdown of CXCL12, we could significantly suppress the invasive and migratory capabilities of 2 human cholangiocarcinoma cell lines.	('cholangiocarcinoma', 'Disease', (107, 125))	('CXCL12', 'Gene', (16, 22))	('human', 'Species', '9606', (101, 106))	('suppress', 'NegReg', (47, 55))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (107, 125))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (107, 125))	('knockdown', 'Var', (3, 12))	('CXCL12', 'Gene', '6387', (16, 22))
29989	31361379	In patients' characteristics, CA19-9 was significantly higher (P = .004) in the high CXCL12 group than in the low group.	('CA19-9', 'MPA', (30, 36))	('CXCL12', 'Gene', (85, 91))	('patients', 'Species', '9606', (3, 11))	('higher', 'PosReg', (55, 61))	('high', 'Var', (80, 84))	('CXCL12', 'Gene', '6387', (85, 91))
29990	31361379	In addition, in tumor-related factors, there were more patients with vascular invasion (P = .02), lymph node metastasis (P = .047), and adjuvant chemotherapy (P = .02) in the high CXCL12 group (Table 1).	('CXCL12', 'Gene', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('lymph node metastasis', 'CPA', (98, 119))	('high', 'Var', (175, 179))	('CXCL12', 'Gene', '6387', (180, 186))	('tumor', 'Disease', (16, 21))	('patients', 'Species', '9606', (55, 63))	('vascular invasion', 'CPA', (69, 86))
29994	31361379	In the invasion assay, we confirmed that knockdown of CXCL12 (Figure 4A), and it significantly inhibited the invasive capabilities of SSP-25 and HuH-28 cell lines (Figure 4B).	('inhibited', 'NegReg', (95, 104))	('CXCL12', 'Gene', (54, 60))	('invasive capabilities of SSP-25', 'CPA', (109, 140))	('knockdown', 'Var', (41, 50))	('CXCL12', 'Gene', '6387', (54, 60))
29995	31361379	In addition, in the migration assay, we also confirmed that knockdown of CXCL12 significantly inhibited their migratory capabilities (Figure 4C).	('CXCL12', 'Gene', (73, 79))	('migratory capabilities', 'CPA', (110, 132))	('knockdown', 'Var', (60, 69))	('CXCL12', 'Gene', '6387', (73, 79))	('inhibited', 'NegReg', (94, 103))
29996	31361379	On the other hand, by knockdown of CXCL12, neither morphological change nor inhibitory effect on cell proliferation could be observed (data not shown).	('knockdown', 'Var', (22, 31))	('CXCL12', 'Gene', '6387', (35, 41))	('CXCL12', 'Gene', (35, 41))
29999	31361379	We also found that patients with high expression of CXCL12 in primary lesions had a higher incidence of LM and poor prognosis.	('CXCL12', 'Gene', (52, 58))	('patients', 'Species', '9606', (19, 27))	('high expression', 'Var', (33, 48))	('CXCL12', 'Gene', '6387', (52, 58))	('LM', 'Disease', 'MESH:D009362', (104, 106))
30206	30152073	There was no significant difference in OS or FFLP between patients who received EDR to portions of the GTV and patients who did not.	('FFLP', 'MPA', (45, 49))	('EDR to', 'Var', (80, 86))	('patients', 'Species', '9606', (58, 66))	('GTV', 'Chemical', '-', (103, 106))	('patients', 'Species', '9606', (111, 119))
30279	30152073	Elevated baseline peripheral NLR indicates systemic inflammation and has been reported to be associated with worse prognosis in several types of cancers.23 Our data demonstrate that high baseline NLR (>5.3) is associated with shorter FFLP and OS.	('cancers', 'Disease', (145, 152))	('inflammation', 'Disease', (52, 64))	('NLR', 'Gene', (196, 199))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('FFLP', 'Disease', (234, 238))	('high', 'Var', (182, 186))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('inflammation', 'Disease', 'MESH:D007249', (52, 64))
30302	29601088	H1/H2HR antagonists decreased tumor growth, serum HA, angiogenesis and EMT.	('angiogenesis', 'CPA', (54, 66))	('decreased', 'NegReg', (20, 29))	('serum HA', 'MPA', (44, 52))	('antagonists', 'Var', (8, 19))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('H1/H2HR', 'Protein', (0, 7))	('EMT', 'CPA', (71, 74))	('HA', 'Chemical', 'MESH:D006632', (50, 52))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
30304	29601088	Inhibition of H1/H2HR reverses PSC-associated damage and decreases CCA growth, angiogenesis and EMT.	('EMT', 'CPA', (96, 99))	('CCA', 'Disease', (67, 70))	('PSC', 'Disease', 'MESH:D015209', (31, 34))	('Inhibition', 'Var', (0, 10))	('H1/H2HR', 'Protein', (14, 21))	('angiogenesis', 'CPA', (79, 91))	('decreases', 'NegReg', (57, 66))	('PSC', 'Disease', (31, 34))	('CCA', 'Disease', 'MESH:D018281', (67, 70))
30358	29601088	To determine if hHSCs express the H1HR or H2HR we performed reverse-transcription PCR and real-time PCR, and compared expression levels to cultured mast cells and cholangiocytes, which express H1HR and H2HR.	('H1HR', 'Var', (193, 197))	('hHSC', 'Gene', '2523', (16, 20))	('chol', 'Chemical', 'MESH:C038777', (163, 167))	('H2HR', 'Var', (202, 206))	('hHSC', 'Gene', (16, 20))
30368	29601088	H2HR expression was absent in small cholangiocytes and slightly present in large cholangiocytes in WT mice; however, Mdr2-/- mice showed a significant increase in H2HR expression in large cholangiocytes, but not small cholangiocytes (Figure 1A).	('mice', 'Species', '10090', (102, 106))	('expression', 'MPA', (168, 178))	('H2HR', 'Protein', (163, 167))	('chol', 'Chemical', 'MESH:C038777', (36, 40))	('Mdr2-/-', 'Var', (117, 124))	('chol', 'Chemical', 'MESH:C038777', (218, 222))	('chol', 'Chemical', 'MESH:C038777', (188, 192))	('mice', 'Species', '10090', (125, 129))	('chol', 'Chemical', 'MESH:C038777', (81, 85))	('increase', 'PosReg', (151, 159))
30370	29601088	We found that mast cell activation is decreased in Mdr2-/- mice (shown by mMCP-1 staining) and nu/nu mice (shown by toluidine blue staining) treated with H1HR or H2HR antagonists (Figures 2A and 2B).	('decreased', 'NegReg', (38, 47))	('mice', 'Species', '10090', (59, 63))	('Mdr2-/-', 'Var', (51, 58))	('H1HR', 'Protein', (154, 158))	('toluidine blue', 'Chemical', 'MESH:D014048', (116, 130))	('H2HR antagonists', 'Protein', (162, 178))	('mice', 'Species', '10090', (101, 105))	('mast cell activation', 'CPA', (14, 34))	('mMCP-1', 'Gene', (74, 80))	('mMCP-1', 'Gene', '17224', (74, 80))
30371	29601088	Further, mast cell markers were significantly decreased in Mdr2-/- mice and tumors from nu/nu mice treated with either H1HR or H2HR antagonists (Figures 2C and 2D).	('H1HR', 'Protein', (119, 123))	('Mdr2-/-', 'Var', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('H2HR', 'Protein', (127, 131))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('mice', 'Species', '10090', (94, 98))	('decreased', 'NegReg', (46, 55))	('mast', 'MPA', (9, 13))	('mice', 'Species', '10090', (67, 71))
30373	29601088	We have previously demonstrated that histamine levels increase in PSC and here we found that histamine serum levels were decreased in both Mdr2-/- mice (Figure 3D) and nu/nu mice (Figure 3E) treated with either H1HR or H2HR blockers compared to saline treatment.	('PSC', 'Disease', 'MESH:D015209', (66, 69))	('histamine levels', 'MPA', (37, 53))	('mice', 'Species', '10090', (147, 151))	('mice', 'Species', '10090', (174, 178))	('histamine', 'Chemical', 'MESH:D006632', (93, 102))	('increase', 'PosReg', (54, 62))	('histamine serum levels', 'MPA', (93, 115))	('decreased', 'NegReg', (121, 130))	('histamine', 'Chemical', 'MESH:D006632', (37, 46))	('PSC', 'Disease', (66, 69))	('Mdr2-/-', 'Var', (139, 146))	('H2HR', 'Protein', (219, 223))	('H1HR', 'Protein', (211, 215))
30380	29601088	WT mice treated with either H1HR or H2HR blockers had no visible change in collagen deposition as shown in Figure 5A.	('H1HR', 'Var', (28, 32))	('mice', 'Species', '10090', (3, 7))	('collagen deposition', 'CPA', (75, 94))
30381	29601088	The expression of fibronectin and collagen type-1a is significantly reduced in Mdr2-/- mice treated with either H1HR or H2HR antagonists, or combined H1HR/H2HR antagonist treatment when compared to saline (Supplemental Figure 3B and 3C).	('fibronectin', 'Gene', (18, 29))	('mice', 'Species', '10090', (87, 91))	('H1HR', 'Var', (112, 116))	('expression', 'MPA', (4, 14))	('collagen', 'Protein', (34, 42))	('Mdr2-/-', 'Gene', (79, 86))	('H2HR', 'Gene', (120, 124))	('reduced', 'NegReg', (68, 75))	('fibronectin', 'Gene', '14268', (18, 29))
30385	29601088	We conclude that H1HR or H2HR antagonism directly modulates biliary proliferation and activation, which in turn, mediates HSC activation and subsequent liver fibrosis.	('activation', 'CPA', (86, 96))	('liver fibrosis', 'Disease', (152, 166))	('H1HR', 'Protein', (17, 21))	('antagonism', 'Var', (30, 40))	('HSC', 'Gene', (122, 125))	('liver fibrosis', 'Disease', 'MESH:D008103', (152, 166))	('modulates', 'Reg', (50, 59))	('liver fibrosis', 'Phenotype', 'HP:0001395', (152, 166))	('HSC', 'Gene', '2523', (122, 125))	('mediates', 'Reg', (113, 121))	('H2HR', 'Protein', (25, 29))	('biliary proliferation', 'CPA', (60, 81))
30386	29601088	Tumor volume significantly increased over time when nu/nu mice were treated with saline, whereas treatment with either H1HR or H2HR blunted tumor growth beginning at day 13 and continuing throughout the treatment (Figure 6A).	('blunted', 'NegReg', (132, 139))	('Tumor volume', 'CPA', (0, 12))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('increased', 'PosReg', (27, 36))	('mice', 'Species', '10090', (58, 62))	('H1HR', 'Var', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('H2HR', 'Var', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
30396	29601088	Similar to our previous work, inhibition of H1HR decreased histamine-stimulated IP3 levels in small cholangiocytes (Supplemental Figure 9A), but did not alter large cholangiocyte IP3 levels (not shown).	('H1HR', 'Protein', (44, 48))	('histamine', 'Chemical', 'MESH:D006632', (59, 68))	('inhibition', 'Var', (30, 40))	('decreased', 'NegReg', (49, 58))	('histamine-stimulated IP3 levels', 'MPA', (59, 90))	('chol', 'Chemical', 'MESH:C038777', (165, 169))	('chol', 'Chemical', 'MESH:C038777', (100, 104))
30398	29601088	Inhibition of H2HR had no significant effect on small cholangiocyte intracellular cAMP levels (not shown).	('small cholangiocyte intracellular cAMP levels', 'MPA', (48, 93))	('cAMP', 'Chemical', 'MESH:D000242', (82, 86))	('chol', 'Chemical', 'MESH:C038777', (54, 58))	('Inhibition', 'Var', (0, 10))	('H2HR', 'Protein', (14, 18))
30403	29601088	Our novel findings show that inhibition of histamine signaling via receptor antagonism alleviates features of both PSC and CCA.	('PSC', 'Disease', 'MESH:D015209', (115, 118))	('CCA', 'Disease', 'MESH:D018281', (123, 126))	('PSC', 'Disease', (115, 118))	('histamine', 'Protein', (43, 52))	('CCA', 'Disease', (123, 126))	('receptor', 'Protein', (67, 75))	('antagonism', 'Var', (76, 86))	('histamine', 'Chemical', 'MESH:D006632', (43, 52))	('inhibition', 'Var', (29, 39))	('alleviates', 'NegReg', (87, 97))
30414	29601088	Our previous work shows that inhibition of HDC using alpha-methyl-dl-histidine decreases BDL-induced damage and CCA progression.	('HDC', 'Gene', '15186', (43, 46))	('decreases', 'NegReg', (79, 88))	('BDL-induced damage', 'MPA', (89, 107))	('CCA', 'Disease', 'MESH:D018281', (112, 115))	('decreases BDL', 'Phenotype', 'HP:0003563', (79, 92))	('histidine decreases', 'Phenotype', 'HP:0500145', (69, 88))	('HDC', 'Gene', (43, 46))	('CCA', 'Disease', (112, 115))	('alpha-methyl-dl-histidine', 'Chemical', 'MESH:C115717', (53, 78))	('inhibition', 'Var', (29, 39))
30418	29601088	Thus, we propose that histamine indirectly effects HSC activation, even though HSCs express both the H1HR and H2HR.	('H2HR', 'Var', (110, 114))	('HSC', 'Gene', '2523', (51, 54))	('HSC', 'Gene', (79, 82))	('HSC', 'Gene', (51, 54))	('H1HR', 'Protein', (101, 105))	('histamine', 'Chemical', 'MESH:D006632', (22, 31))	('HSC', 'Gene', '2523', (79, 82))
30428	29601088	Our study reveals that inhibition of HRs decreases mast cell activation leading to decreased tumor growth and angiogenesis along with a reversal of EMT.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('mast cell', 'CPA', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('decreases', 'NegReg', (41, 50))	('inhibition', 'Var', (23, 33))	('decreased', 'NegReg', (83, 92))	('tumor', 'Disease', (93, 98))	('angiogenesis', 'CPA', (110, 122))	('HRs', 'Protein', (37, 40))
30438	29601088	In support of our current findings, it has been shown that blocking H1HR inhibits colony growth in pancreatic cancer cells, in vitro and blocking H2HR may inhibit cell proliferation, migration and induce apoptosis in colorectal cancer.	('blocking', 'Var', (137, 145))	('pancreatic cancer', 'Disease', (99, 116))	('H1HR', 'Protein', (68, 72))	('H2HR', 'Gene', (146, 150))	('colorectal cancer', 'Phenotype', 'HP:0003003', (217, 234))	('colony growth in', 'CPA', (82, 98))	('blocking', 'Var', (59, 67))	('inhibits', 'NegReg', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('colorectal cancer', 'Disease', (217, 234))	('cell proliferation', 'CPA', (163, 181))	('induce', 'Reg', (197, 203))	('colorectal cancer', 'Disease', 'MESH:D015179', (217, 234))	('inhibit', 'NegReg', (155, 162))	('pancreatic cancer', 'Disease', 'MESH:D010190', (99, 116))	('apoptosis', 'CPA', (204, 213))
30439	29601088	Our data demonstrate that intracellular signaling mediates histamine-regulated biliary proliferation as shown by our in vitro studies demonstrating that blocking H1HR decreases small cholangiocyte IP3 levels, whereas H2HR inhibition reduces large cholangiocyte cAMP signaling.	('reduces', 'NegReg', (233, 240))	('large cholangiocyte cAMP signaling', 'MPA', (241, 275))	('chol', 'Chemical', 'MESH:C038777', (183, 187))	('histamine', 'Chemical', 'MESH:D006632', (59, 68))	('small cholangiocyte IP3 levels', 'MPA', (177, 207))	('chol', 'Chemical', 'MESH:C038777', (247, 251))	('H1HR', 'Protein', (162, 166))	('decreases', 'NegReg', (167, 176))	('cAMP', 'Chemical', 'MESH:D000242', (261, 265))	('blocking', 'Var', (153, 161))
30443	29601088	recently demonstrated that Notch 1, 2 and 3 are important components in CCA proliferation and it's been demonstrated that inhibition of Notch 2 reduces tumor burden in both CCA and hepatocellular carcinoma.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('hepatocellular carcinoma', 'Disease', (181, 205))	('Notch 1', 'Gene', (27, 34))	('CCA', 'Disease', (72, 75))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (181, 205))	('CCA', 'Disease', (173, 176))	('inhibition', 'Var', (122, 132))	('reduces', 'NegReg', (144, 151))	('Notch 2', 'Gene', '18129', (136, 143))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('Notch 2', 'Gene', (136, 143))	('Notch 1', 'Gene', '18128', (27, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('CCA', 'Disease', 'MESH:D018281', (173, 176))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (181, 205))	('CCA', 'Disease', 'MESH:D018281', (72, 75))
30452	28574171	Mutations in the pathway frequently lead to developmental defects and cancer.	('developmental defects', 'Disease', 'MESH:D003147', (44, 65))	('lead to', 'Reg', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('developmental defects', 'Disease', (44, 65))
30460	28574171	Mutations in beta-catenin-dependent Wnt signalling components occur frequently in cancer and result in constitutive beta-catenin accumulation and signalling (Polakis, 2012; Zhan et al., 2017).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('signalling', 'MPA', (146, 156))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('Mutations', 'Var', (0, 9))	('result in', 'Reg', (93, 102))
30461	28574171	For example, loss-of-function APC mutations are prevalent in colorectal cancer, and CTNNB1 (beta-catenin) stabilizing mutations have been identified in colorectal cancer and a high percentage of liver and endometrioid tumours (Kwong and Dove, 2009; McConechy et al., 2014; Zucman-Rossi et al., 2015).	('liver and endometrioid tumours', 'Disease', 'MESH:D016889', (195, 225))	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('colorectal cancer', 'Disease', (152, 169))	('APC', 'Phenotype', 'HP:0005227', (30, 33))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('colorectal cancer', 'Phenotype', 'HP:0003003', (61, 78))	('APC', 'Disease', 'MESH:D011125', (30, 33))	('tumours', 'Phenotype', 'HP:0002664', (218, 225))	('APC', 'Disease', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('CTNNB1', 'Gene', '1499', (84, 90))	('mutations', 'Var', (118, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('colorectal cancer', 'Disease', 'MESH:D015179', (61, 78))	('loss-of-function', 'NegReg', (13, 29))	('colorectal cancer', 'Disease', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('CTNNB1', 'Gene', (84, 90))	('mutations', 'Var', (34, 43))
30462	28574171	Additionally, loss-of-function alterations in zinc and ring finger 3 (ZNRF3)/ring finger protein 43 (RNF43), which are ubiquitin ligases promoting FZD degradation, or translocations involving R-spondin proteins, which are secreted Wnt agonists by inhibiting ZNRF3/RNF43, are also found in colorectal cancer and other malignancies (Seshagiri et al., 2012; Assie et al., 2014; Giannakis et al., 2014; Hao et al., 2016).	('ring finger protein 43', 'Gene', '54894', (77, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (289, 306))	('zinc and ring finger 3', 'Gene', '84133', (46, 68))	('translocations', 'Var', (167, 181))	('colorectal cancer', 'Disease', (289, 306))	('RNF43', 'Gene', '54894', (101, 106))	('malignancies', 'Disease', 'MESH:D009369', (317, 329))	('ZNRF3', 'Gene', '84133', (70, 75))	('malignancies', 'Disease', (317, 329))	('ZNRF3', 'Gene', (70, 75))	('RNF43', 'Gene', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('ZNRF3', 'Gene', '84133', (258, 263))	('inhibiting', 'NegReg', (247, 257))	('colorectal cancer', 'Phenotype', 'HP:0003003', (289, 306))	('ring finger protein 43', 'Gene', (77, 99))	('ZNRF3', 'Gene', (258, 263))	('RNF43', 'Gene', '54894', (264, 269))	('alterations', 'Var', (31, 42))	('loss-of-function', 'NegReg', (14, 30))	('RNF43', 'Gene', (264, 269))
30481	28574171	Furthermore, DKK1 binding to LRP6 can induce a conformational change that may allosterically impede Wnt binding (Matoba et al., 2017).	('induce', 'Reg', (38, 44))	('DKK1', 'Var', (13, 17))	('impede', 'NegReg', (93, 99))	('Wnt binding', 'Interaction', (100, 111))	('binding', 'Interaction', (18, 25))	('LRP6', 'Gene', '4040', (29, 33))	('LRP6', 'Gene', (29, 33))	('conformational change', 'MPA', (47, 68))
30484	28574171	Based on the ability of DKK1 to inhibit beta-catenin-dependent Wnt signalling, a pathway that is frequently overactivated in cancer, it is not surprising that DKK1 was initially characterized as a tumour suppressor.	('tumour', 'Disease', 'MESH:D009369', (197, 203))	('beta-catenin-dependent Wnt signalling', 'Pathway', (40, 77))	('inhibit', 'NegReg', (32, 39))	('DKK1', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumour', 'Disease', (197, 203))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('DKK1', 'Var', (159, 163))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))
30486	28574171	Additional studies indicated DKK1 could suppress tumours by inducing apoptosis and inhibiting tumour growth, proliferation, invasion and angiogenesis (Lee et al., 2004; Maehata et al., 2008; Mikheev et al., 2008; Qiao et al., 2008; Hirata et al., 2011; Kim et al., 2012; Menezes et al., 2012; Qi et al., 2012).	('tumours', 'Disease', (49, 56))	('tumour growth', 'Disease', 'MESH:D006130', (94, 107))	('suppress', 'NegReg', (40, 48))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour growth', 'Disease', (94, 107))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('inducing', 'NegReg', (60, 68))	('inhibiting', 'NegReg', (83, 93))	('apoptosis', 'CPA', (69, 78))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('DKK1', 'Var', (29, 33))
30490	28574171	For example, DKK1 staining has been detected in a high percentage of oesophageal and cholangiocarcinoma tumours and this correlated with a decrease in overall survival (Yamabuki et al., 2007; Shi et al., 2013).	('staining', 'Var', (18, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('DKK1 staining', 'Var', (13, 26))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('detected', 'Reg', (36, 44))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('overall survival', 'MPA', (151, 167))	('oesophageal and cholangiocarcinoma tumours', 'Disease', 'MESH:D018281', (69, 111))	('decrease', 'NegReg', (139, 147))
30492	28574171	In support of this, DKK1 positivity has been associated with lymph node metastasis in cancers (Kemik et al., 2011; Li et al., 2013; Shi et al., 2013; Shi et al., 2014; 2016).	('positivity', 'Var', (25, 35))	('lymph node metastasis in cancers', 'Disease', (61, 93))	('lymph node metastasis in cancers', 'Disease', 'MESH:D009362', (61, 93))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('associated', 'Reg', (45, 55))	('DKK1', 'Gene', (20, 24))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))
30495	28574171	In tumours that stain for beta-catenin and DKK1, the negative feedback may have been disrupted by, for example, stabilizing mutations in beta-catenin that would render the inhibitory activity of DKK1 inoperative.	('inhibitory activity', 'MPA', (172, 191))	('mutations', 'Var', (124, 133))	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('tumours', 'Disease', (3, 10))	('beta-catenin', 'Gene', (137, 149))
30499	28574171	For some of these cancer cell lines, this may have occurred through DKK1 regulation of MMP expression, a family of proteases with well characterized roles in cancer cell migration (Kessenbrock et al., 2010; Chen et al., 2013; Shi et al., 2013; Shi et al., 2016).	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('DKK1', 'Var', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('MMP', 'Gene', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
30500	28574171	Furthermore, DKK1 knockdown reduced the expression of VEGF-C, a protein associated with promoting metastasis to lymph nodes, in cholangiocarcinoma (Park et al., 2006; Shi et al., 2013).	('expression', 'MPA', (40, 50))	('knockdown', 'Var', (18, 27))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (128, 146))	('reduced', 'NegReg', (28, 35))	('DKK1', 'Gene', (13, 17))	('VEGF-C', 'Gene', '7424', (54, 60))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (128, 146))	('cholangiocarcinoma', 'Disease', (128, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('promoting', 'PosReg', (88, 97))	('VEGF-C', 'Gene', (54, 60))	('metastasis to lymph nodes', 'CPA', (98, 123))
30508	28574171	In multiple myeloma, treatment with anti-DKK1 antibodies reduced disease burden and improved bone health in mouse models (Yaccoby et al., 2007; Fulciniti et al., 2009; Pozzi et al., 2013).	('antibodies', 'Var', (46, 56))	('multiple myeloma', 'Disease', (3, 19))	('bone health', 'CPA', (93, 104))	('disease', 'MPA', (65, 72))	('anti-DKK1 antibodies', 'Var', (36, 56))	('mouse', 'Species', '10090', (108, 113))	('improved', 'PosReg', (84, 92))	('reduced', 'NegReg', (57, 64))	('multiple myeloma', 'Phenotype', 'HP:0006775', (3, 19))	('multiple myeloma', 'Disease', 'MESH:D009101', (3, 19))
30509	28574171	Lung cancer, melanoma, osteosarcoma and prostate cancer also responded to anti-DKK1 antibody treatment in vivo (Hall et al., 2010; Sato et al., 2010; D'Amico et al., 2016; Goldstein et al., 2016).	('responded', 'Reg', (61, 70))	('anti-DKK1', 'Var', (74, 83))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (5, 11))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('prostate cancer', 'Phenotype', 'HP:0012125', (40, 55))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanoma', 'Disease', (13, 21))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('osteosarcoma', 'Phenotype', 'HP:0002669', (23, 35))	('cancer', 'Disease', (49, 55))	('osteosarcoma and prostate cancer', 'Disease', 'MESH:D011471', (23, 55))
30510	28574171	In both breast cancer and hepatocellular carcinoma xenograft models, DKK1 increased tumour growth and promoted angiogenesis, suggesting that DKK1 has pro-angiogenic activity (Smadja et al., 2010; Tung et al., 2011).	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('tumour growth', 'Disease', 'MESH:D006130', (84, 97))	('angiogenesis', 'CPA', (111, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('promoted', 'PosReg', (102, 110))	('pro-angiogenic', 'MPA', (150, 164))	('increased', 'PosReg', (74, 83))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (26, 50))	('DKK1', 'Gene', (69, 73))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumour growth', 'Disease', (84, 97))	('hepatocellular carcinoma', 'Disease', (26, 50))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (26, 50))	('DKK1', 'Var', (141, 145))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Disease', (8, 21))
30511	28574171	In support of this, knockdown of DKK1 decreased tumour growth and angiogenesis in hepatocellular carcinoma (Huang et al., 2014).	('DKK1', 'Gene', (33, 37))	('decreased tumour growth', 'Disease', 'MESH:D006130', (38, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('decreased tumour growth', 'Disease', (38, 61))	('knockdown', 'Var', (20, 29))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (82, 106))	('angiogenesis', 'CPA', (66, 78))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (82, 106))	('hepatocellular carcinoma', 'Disease', (82, 106))
30512	28574171	In addition to affecting primary tumour growth, DKK1 has also been linked to the development of metastasis in bone, breast, liver, lung and prostate cancer models, possibly related to the prominent role of DKK1 in stimulating migration and invasion observed in vitro (Thudi et al., 2011; Tao et al., 2013; Huang et al., 2014; Goldstein et al., 2016; Malladi et al., 2016; Pang et al., 2017).	('affecting', 'Reg', (15, 24))	('metastasis', 'CPA', (96, 106))	('stimulating', 'PosReg', (214, 225))	('prostate cancer', 'Disease', (140, 155))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('invasion', 'CPA', (240, 248))	('linked', 'Reg', (67, 73))	('DKK1', 'Var', (48, 52))	('prostate cancer', 'Disease', 'MESH:D011471', (140, 155))	('migration', 'CPA', (226, 235))	('prostate cancer', 'Phenotype', 'HP:0012125', (140, 155))	('tumour growth', 'Disease', (33, 46))	('tumour growth', 'Disease', 'MESH:D006130', (33, 46))
30516	28574171	Impeding DKK1 expression re-sensitized these LCC cells to beta-catenin-dependent Wnt signalling and up-regulated the expression of activating ligands for natural killer (NK) cells, leading to NK cell-mediated clearance of the LCC cells and reduced metastasis.	('up-regulated', 'PosReg', (100, 112))	('Impeding', 'Var', (0, 8))	('reduced', 'NegReg', (240, 247))	('metastasis', 'CPA', (248, 258))	('expression', 'MPA', (117, 127))	('LCC', 'Chemical', '-', (226, 229))	('LCC', 'Chemical', '-', (45, 48))	('NK cell-mediated clearance', 'CPA', (192, 218))	('DKK1', 'Gene', (9, 13))
30517	28574171	These results suggest the intriguing possibility that the reactivation of beta-catenin-dependent Wnt signalling could be an effective way to eliminate tumour-initiating cells with metastatic potential through immune surveillance.	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('reactivation', 'Var', (58, 70))	('tumour', 'Disease', (151, 157))
30518	28574171	However, caution and further studies are warranted, since the reactivation of beta-catenin-dependent Wnt signalling may also induce proliferation of LCC cells and in principle increase tumour growth.	('reactivation', 'Var', (62, 74))	('increase tumour growth', 'Disease', 'MESH:D006130', (176, 198))	('increase tumour growth', 'Disease', (176, 198))	('beta-catenin-dependent', 'Protein', (78, 100))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('induce', 'PosReg', (125, 131))	('proliferation', 'CPA', (132, 145))	('LCC', 'Chemical', '-', (149, 152))
30520	28574171	For certain cancer cells, inhibition of beta-catenin-dependent Wnt signalling by DKK1 can favour the formation of an undifferentiated phenotype, which in general is more malignant.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('favour', 'PosReg', (90, 96))	('DKK1', 'Gene', (81, 85))	('cancer', 'Disease', (12, 18))	('inhibition', 'Var', (26, 36))	('undifferentiated phenotype', 'MPA', (117, 143))	('formation', 'MPA', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('beta-catenin-dependent Wnt signalling', 'MPA', (40, 77))
30522	28574171	Treatment with an anti-DKK1 antibody reduced tumour growth in patient-derived xenograft models, increased nuclear beta-catenin staining and increased the expression of osteopontin, a bone differentiation marker.	('increased', 'PosReg', (96, 105))	('patient', 'Species', '9606', (62, 69))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour growth', 'Disease', (45, 58))	('expression', 'MPA', (154, 164))	('nuclear beta-catenin staining', 'MPA', (106, 135))	('tumour growth', 'Disease', 'MESH:D006130', (45, 58))	('osteopontin', 'Gene', '6696', (168, 179))	('anti-DKK1', 'Var', (18, 27))	('reduced', 'NegReg', (37, 44))	('increased', 'PosReg', (140, 149))	('osteopontin', 'Gene', (168, 179))
30525	28574171	In liver cancer cells, knockdown of DKK1 decreased metastasis and reduced the levels of phosphorylated JNK, a downstream mediator of the Wnt/PCP pathway, suggesting that signalling was occurring through beta-catenin-independent Wnt pathways (Tao et al., 2013).	('metastasis', 'CPA', (51, 61))	('reduced', 'NegReg', (66, 73))	('liver cancer', 'Phenotype', 'HP:0002896', (3, 15))	('liver cancer', 'Disease', 'MESH:D006528', (3, 15))	('decreased', 'NegReg', (41, 50))	('PCP', 'Chemical', '-', (141, 144))	('knockdown', 'Var', (23, 32))	('JNK', 'Gene', '5599', (103, 106))	('liver cancer', 'Disease', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('DKK1', 'Gene', (36, 40))	('JNK', 'Gene', (103, 106))
30527	28574171	A similar result has been observed in ovarian cancer cells where DKK1 promoted cell invasion and increased phosphorylated JNK without affecting beta-catenin levels (Wang and Zhang, 2011).	('JNK', 'Gene', (122, 125))	('JNK', 'Gene', '5599', (122, 125))	('ovarian cancer', 'Phenotype', 'HP:0100615', (38, 52))	('increased', 'PosReg', (97, 106))	('cell invasion', 'CPA', (79, 92))	('ovarian cancer', 'Disease', 'MESH:D010051', (38, 52))	('DKK1', 'Var', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('promoted', 'PosReg', (70, 78))	('ovarian cancer', 'Disease', (38, 52))
30530	28574171	Taken together, these results implicate DKK1 activation of beta-catenin-independent Wnt signalling in cancer cells as a potential driver of tumour growth and metastasis.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('tumour growth', 'Disease', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumour growth', 'Disease', 'MESH:D006130', (140, 153))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('activation', 'PosReg', (45, 55))	('beta-catenin-independent Wnt signalling', 'Pathway', (59, 98))	('DKK1', 'Var', (40, 44))
30534	28574171	For instance, even though DKK1 showed a clear phenotypic response in lung, pancreatic and prostate cancer cell lines in culture, attempts to detect measurable changes in either beta-catenin-dependent or independent Wnt signalling pathways were largely unsuccessful, leading the authors to speculate that the effects of DKK1 occurred through an undefined signalling pathway (Hall et al., 2010; Sato et al., 2010; Takahashi et al., 2010).	('DKK1', 'Var', (26, 30))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('DKK1', 'Gene', (319, 323))	('pancreatic and prostate cancer', 'Disease', 'MESH:D010190', (75, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
30544	28574171	An anti-DKK1 antibody resulted in tumour regression and a shift in the tumour micro-environment from anti-inflammatory to pro-inflammatory, suggesting that the anti-DKK1 antibody was having immune modulatory activity.	('tumour regression', 'Disease', 'MESH:D009365', (34, 51))	('tumour', 'Disease', (71, 77))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour', 'Disease', (34, 40))	('shift', 'Reg', (58, 63))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('antibody', 'Var', (13, 21))	('anti-DKK1 antibody', 'Var', (3, 21))	('tumour regression', 'Disease', (34, 51))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
30547	28574171	Mechanistically, this study gives a clear example of DKK1 signalling to immune cells and the benefit of blocking DKK1 in order to promote an anti-tumour immune response.	('promote', 'PosReg', (130, 137))	('tumour', 'Disease', (146, 152))	('blocking', 'Var', (104, 112))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('DKK1', 'Gene', (113, 117))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
30549	28574171	Even though this study was not conducted in a cancer model, DKK1 antagonized T-helper 1 polarization and suppressed the secretion of the pro-inflammatory cytokine interferon gamma, which are both cellular events that are usually not favourable for an anti-tumour immune response (Fridman et al., 2012).	('suppressed', 'NegReg', (105, 115))	('tumour', 'Disease', 'MESH:D009369', (256, 262))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('antagonized', 'NegReg', (65, 76))	('DKK1', 'Var', (60, 64))	('tumour', 'Disease', (256, 262))	('cancer', 'Disease', (46, 52))	('T-helper 1 polarization', 'CPA', (77, 100))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))
30554	28574171	In addition, DKK1 regulation of Wnt signalling and PI3K/Akt signalling in cancer cells contributes to tumour growth and immune evasion and may favour a cancer stem cell phenotype.	('Wnt signalling', 'Pathway', (32, 46))	('Akt', 'Gene', '207', (56, 59))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumour growth', 'Disease', 'MESH:D006130', (102, 115))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('Akt', 'Gene', (56, 59))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('DKK1 regulation', 'Var', (13, 28))	('contributes', 'PosReg', (87, 98))	('immune evasion', 'MPA', (120, 134))	('favour', 'PosReg', (143, 149))	('tumour growth', 'Disease', (102, 115))
30555	28574171	Even though DKK1 can clearly promote tumour growth, it has also been hypothesized to function as a tumour suppressor by inhibiting beta-catenin-dependent Wnt signalling in cancer cells.	('promote', 'PosReg', (29, 36))	('tumour growth', 'Disease', 'MESH:D006130', (37, 50))	('inhibiting', 'NegReg', (120, 130))	('DKK1', 'Var', (12, 16))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumour', 'Disease', (37, 43))	('tumour', 'Disease', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', (172, 178))	('beta-catenin-dependent Wnt signalling', 'MPA', (131, 168))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('tumour growth', 'Disease', (37, 50))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
30558	28574171	(i) Depending on the Wnt signalling wiring in a cancer cell, inhibition of beta-catenin-dependent Wnt signalling is not necessarily tumour suppressive.	('tumour', 'Disease', (132, 138))	('inhibition', 'Var', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))
30559	28574171	As discussed earlier, DKK1 and its inhibition of beta-catenin-dependent Wnt signalling favoured an undifferentiated phenotype in osteosarcoma and the tumour-initiating ability of LCC cells.	('favoured', 'PosReg', (87, 95))	('undifferentiated phenotype', 'MPA', (99, 125))	('DKK1', 'Var', (22, 26))	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('tumour', 'Disease', (150, 156))	('LCC', 'Chemical', '-', (179, 182))	('osteosarcoma', 'Phenotype', 'HP:0002669', (129, 141))	('inhibition', 'NegReg', (35, 45))	('osteosarcoma', 'Disease', (129, 141))	('osteosarcoma', 'Disease', 'MESH:D012516', (129, 141))
30561	28574171	For example, DKK1 activation of beta-catenin-independent Wnt signalling and/or PI3K/Akt signalling in cancer cells or DKK1 signalling to immune cells may outweigh any tumour-suppressive activity of DKK1 inhibition of beta-catenin-dependent Wnt signalling in cancer cells.	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('Akt', 'Gene', '207', (84, 87))	('DKK1', 'Var', (13, 17))	('tumour', 'Disease', (167, 173))	('Akt', 'Gene', (84, 87))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (258, 264))	('beta-catenin-independent', 'MPA', (32, 56))	('activation', 'PosReg', (18, 28))
30563	28574171	In this context, it can be hypothesized that DKK1 is unable to inhibit beta-catenin-dependent Wnt signalling, thereby eradicating its potential tumour suppressor activity.	('beta-catenin-dependent Wnt signalling', 'MPA', (71, 108))	('eradicating', 'NegReg', (118, 129))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('DKK1', 'Var', (45, 49))	('tumour', 'Disease', (144, 150))
30565	28574171	BHQ880, an antibody developed by Novartis Pharmaceuticals, has completed phase 1B trials in multiple myeloma (NCT00741377, NCT01337752 and NCT01302886).	('NCT01337752', 'Var', (123, 134))	('multiple myeloma', 'Phenotype', 'HP:0006775', (92, 108))	('multiple myeloma', 'Disease', 'MESH:D009101', (92, 108))	('NCT00741377', 'Var', (110, 121))	('BHQ880', 'Chemical', 'MESH:C557618', (0, 6))	('multiple myeloma', 'Disease', (92, 108))	('NCT01302886', 'Var', (139, 150))
30574	28574171	Therefore, a DKK1-neutralizing therapy could have the benefit of both a direct anti-tumour effect and the stimulation of a pro-inflammatory anti-tumour response.	('tumour', 'Disease', (145, 151))	('tumour', 'Disease', (84, 90))	('stimulation', 'PosReg', (106, 117))	('DKK1-neutralizing', 'Var', (13, 30))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
30579	28619747	Successful immune checkpoint blockade in a patient with advanced stage microsatellite-unstable biliary tract cancer Cancers acquire multiple somatic mutations that can lead to the generation of immunogenic mutation-induced neoantigens.	('microsatellite-unstable', 'Var', (71, 94))	('Cancers', 'Disease', (116, 123))	('mutations', 'Var', (149, 158))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('patient', 'Species', '9606', (43, 50))	('Cancers', 'Phenotype', 'HP:0002664', (116, 123))	('immunogenic mutation-induced neoantigens', 'MPA', (194, 234))	('cancer', 'Disease', (109, 115))	('Cancers', 'Disease', 'MESH:D009369', (116, 123))	('lead to', 'Reg', (168, 175))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (95, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
30583	28619747	The effects were particularly pronounced in tumors with DNA mismatch repair (MMR) deficiency and a high mutational load, which typically occur in the colon and endometrium.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('colon', 'Disease', (150, 155))	('deficiency', 'Var', (82, 92))	('MMR', 'Gene', (77, 80))	('mutational load', 'Var', (104, 119))	('colon', 'Disease', 'MESH:D015179', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
30591	28619747	demonstrated in a phase II trial that mismatch repair (MMR) deficiency was strongly associated with therapy response to PD-1 blockade in colorectal cancer (CRC) patients as well as a non-CRC cohort.	('associated with', 'Reg', (84, 99))	('deficiency', 'Var', (60, 70))	('PD-1 blockade in colorectal cancer', 'Disease', (120, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('CRC', 'Phenotype', 'HP:0003003', (156, 159))	('CRC', 'Phenotype', 'HP:0003003', (187, 190))	('patients', 'Species', '9606', (161, 169))	('therapy response', 'MPA', (100, 116))	('PD-1 blockade in colorectal cancer', 'Disease', 'MESH:D010300', (120, 154))	('colorectal cancer', 'Phenotype', 'HP:0003003', (137, 154))	('MMR', 'Gene', (55, 58))
30592	28619747	MMR deficiency leads to a typical mutational signature and an exceptionally high mutational load:specifically, the accumulation of numerous insertion/deletion mutations affecting microsatellites, a phenotype termed microsatellite instability (MSI).	('microsatellites', 'Gene', (179, 194))	('insertion/deletion mutations', 'Var', (140, 168))	('MMR deficiency', 'Disease', (0, 14))	('MMR deficiency', 'Disease', 'MESH:C536143', (0, 14))	('MSI', 'Gene', (243, 246))	('MSI', 'Gene', '5928', (243, 246))	('accumulation', 'PosReg', (115, 127))
30593	28619747	MSI-related mutations of microsatellites located in gene-encoding regions result in the generation of a large number of highly immunogenic frameshift peptide neoantigens.	('highly immunogenic frameshift peptide neoantigens', 'MPA', (120, 169))	('mutations', 'Var', (12, 21))	('result in', 'Reg', (74, 83))	('MSI', 'Gene', (0, 3))	('MSI', 'Gene', '5928', (0, 3))
30594	28619747	The high number of these MSI-induced frameshift neoantigens explains the pronounced antitumor immune responses and the success of immune checkpoint blockade in these patients.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('MSI', 'Gene', '5928', (25, 28))	('frameshift', 'Var', (37, 47))	('pronounced', 'PosReg', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('MSI', 'Gene', (25, 28))	('tumor', 'Disease', (88, 93))	('patients', 'Species', '9606', (166, 174))
30609	28619747	Exome sequencing of the tumor confirmed a high mutational load with 239 somatic nucleotide substitutions and 48 somatic insertions and deletions but no chromosomal abnormalities (Fig.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('chromosomal abnormalities', 'Disease', (152, 177))	('mutational', 'Var', (47, 57))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (152, 177))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('deletions', 'Var', (135, 144))	('insertions', 'Var', (120, 130))
30622	28619747	In recent years, after extensive sequencing efforts, several potential targeted therapeutic options have evolved for different subgroups of biliary tract cancer (e.g., directed against HER2 in eCCA and gallbladder cancer or IDH1 and FGFR mutations in iCCA).	('gallbladder cancer', 'Disease', (202, 220))	('IDH1', 'Gene', '3417', (224, 228))	('gallbladder cancer', 'Disease', 'MESH:D005706', (202, 220))	('mutations', 'Var', (238, 247))	('iCCA', 'Gene', (251, 255))	('FGFR', 'Gene', (233, 237))	('biliary tract cancer', 'Disease', 'MESH:D001661', (140, 160))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('IDH1', 'Gene', (224, 228))	('biliary tract cancer', 'Disease', (140, 160))	('HER2', 'Gene', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('HER2', 'Gene', '2064', (185, 189))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (140, 160))
30634	28619747	reported an MSI-positive phenotype in four out of 22 samples of intrahepatic cholangiocarcinoma, defined by mononucleotide markers BAT25 and BAT26 and dinucleotide markers such as D2S123.	('intrahepatic cholangiocarcinoma', 'Disease', (64, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('BAT25', 'Var', (131, 136))	('MSI', 'Gene', (12, 15))	('MSI', 'Gene', '5928', (12, 15))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (77, 95))	('BAT26', 'Var', (141, 146))	('mononucleotide', 'Chemical', '-', (108, 122))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (64, 95))	('D2S123', 'Var', (180, 186))
30638	28619747	Extrahepatic cholangiocarcinoma or gallbladder cancer with an intestinal phenotype may share genetic alterations of carcinomas of the lower gastrointestinal tract, potentially including defects of MMR enzymes and MSI.	('carcinomas of the lower gastrointestinal tract', 'Disease', 'MESH:D004067', (116, 162))	('gallbladder cancer', 'Disease', (35, 53))	('gallbladder cancer', 'Disease', 'MESH:D005706', (35, 53))	('defects', 'Var', (186, 193))	('MMR enzymes', 'Enzyme', (197, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (13, 31))	('MSI', 'Gene', (213, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('MSI', 'Gene', '5928', (213, 216))	('Extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 31))	('carcinomas of the lower gastrointestinal tract', 'Disease', (116, 162))	('Extrahepatic cholangiocarcinoma', 'Disease', (0, 31))
30641	28619747	However, in microsatellite-unstable colorectal cancers, MMR-deficient tumors that were not associated with Lynch syndrome showed a substantially higher response rate to PD-1 blockade compared with Lynch syndrome patients (100% to 27%, P = 0.009).	('colorectal cancers', 'Disease', (36, 54))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('response', 'MPA', (152, 160))	('Lynch syndrome', 'Disease', (107, 121))	('Lynch syndrome', 'Disease', 'MESH:D003123', (107, 121))	('Lynch syndrome', 'Disease', (197, 211))	('patients', 'Species', '9606', (212, 220))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('MMR-deficient tumors', 'Disease', 'MESH:C536928', (56, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('MMR-deficient tumors', 'Disease', (56, 76))	('Lynch syndrome', 'Disease', 'MESH:D003123', (197, 211))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (36, 53))	('colorectal cancers', 'Disease', 'MESH:D015179', (36, 54))	('higher', 'PosReg', (145, 151))	('microsatellite-unstable', 'Var', (12, 35))
30648	28619747	In another study, PD-L1 expression within the tumor front was associated with a 60% decreased survival in iCCA patients.	('iCCA', 'Disease', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PD-L1', 'Gene', (18, 23))	('survival', 'MPA', (94, 102))	('tumor', 'Disease', (46, 51))	('patients', 'Species', '9606', (111, 119))	('expression', 'Var', (24, 34))	('decreased', 'NegReg', (84, 93))	('PD-L1', 'Gene', '29126', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
30657	28619747	In accordance with these findings, typical mutations that lead to loss of HLA class I or II antigen expression in MSI colorectal cancer, most importantly mutations of beta-2-microglobulin (B2M), the essential light chain of the HLA class I complex, were not detected in the patient's tumor.	('HLA class I', 'Protein', (74, 85))	('patient', 'Species', '9606', (274, 281))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('loss', 'NegReg', (66, 70))	('MSI colorectal cancer', 'Disease', 'MESH:D015179', (114, 135))	('beta-2-microglobulin', 'Gene', '567', (167, 187))	('B2M', 'Gene', '567', (189, 192))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('expression', 'MPA', (100, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (118, 135))	('B2M', 'Gene', (189, 192))	('beta-2-microglobulin', 'Gene', (167, 187))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('mutations', 'Var', (154, 163))	('tumor', 'Disease', (284, 289))	('MSI colorectal cancer', 'Disease', (114, 135))
30660	28619747	Another study also noted B2M mutations with consecutive loss of surface expression of HLA class I as an acquired resistance mechanism to PD-1 blockade.	('loss', 'NegReg', (56, 60))	('mutations', 'Var', (29, 38))	('B2M', 'Gene', (25, 28))	('B2M', 'Gene', '567', (25, 28))	('HLA class I', 'Protein', (86, 97))	('surface expression', 'MPA', (64, 82))
30661	28619747	Especially within a microsatellite-unstable tumor with a high mutational load, functional HLA class I and II antigen processing and presentation machineries are supposed to be crucial for an adequate stimulation of cognate CTLs.	('tumor', 'Disease', (44, 49))	('mutational load', 'Var', (62, 77))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
30747	23346539	suggested that high expression of AKT was correlated with improved survival in 24 cases of cholangiocarcinoma in multivariate analysis, and there was a significant association between AKT and pAKT in tumor tissues by Pearson correlation test.	('high', 'Var', (15, 19))	('AKT', 'Gene', (34, 37))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('AKT', 'Gene', '207', (193, 196))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('improved', 'PosReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('AKT', 'Gene', '207', (184, 187))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('survival', 'MPA', (67, 75))	('AKT', 'Gene', (193, 196))	('tumor', 'Disease', (200, 205))	('AKT', 'Gene', (184, 187))	('AKT', 'Gene', '207', (34, 37))	('cholangiocarcinoma', 'Disease', (91, 109))
30750	23346539	studied 22 consecutive patients with cholangiocarcinoma, and the median survival of patients with high expression of CD24 was significantly shorter than those with low expression (p = 0.02).	('CD24', 'Gene', (117, 121))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (37, 55))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (37, 55))	('shorter', 'NegReg', (140, 147))	('patients', 'Species', '9606', (84, 92))	('patients', 'Species', '9606', (23, 31))	('high expression', 'Var', (98, 113))	('CD24', 'Gene', '100133941', (117, 121))	('cholangiocarcinoma', 'Disease', (37, 55))
30753	23346539	In the study of 34 cases of resected cholangiocarcinoma by Keeratichamroen et al., patients with high expression of CD24 had the median survival time of 9 months, whereas it was 24 months in patients with low expression (p = 0.007).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (37, 55))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (37, 55))	('patients', 'Species', '9606', (191, 199))	('CD24', 'Gene', '100133941', (116, 120))	('patients', 'Species', '9606', (83, 91))	('CD24', 'Gene', (116, 120))	('cholangiocarcinoma', 'Disease', (37, 55))	('high expression', 'Var', (97, 112))
30770	30840886	We therefore conducted a pan-cancer analysis of secretome gene expression changes to identify candidate diagnostic biomarkers and to investigate the underlying biological function of these changes.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('changes', 'Var', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))
30888	30840886	BLCA yielded the strongest negative correlation between SB score and log2FC, suggesting that expression increases tend to be associated with low-burden SP genes, whereas the opposite was true for CHOL.	('S', 'Chemical', 'MESH:D013455', (56, 57))	('increases', 'PosReg', (104, 113))	('S', 'Chemical', 'MESH:D013455', (152, 153))	('C', 'Chemical', 'MESH:D002244', (74, 75))	('C', 'Chemical', 'MESH:D002244', (2, 3))	('expression', 'MPA', (93, 103))	('low-burden', 'Var', (141, 151))	('SP', 'Chemical', 'MESH:D021382', (152, 154))	('C', 'Chemical', 'MESH:D002244', (196, 197))
30901	30840886	Furthermore, there are many protein biomarkers in use for the diagnosis or monitoring of different cancer types based on their abundance in serum, plasma, or urine, such as PSA, CA-125, CA19-9, and NuMA for prostate, ovarian, pancreatic, and bladder cancer, respectively.	('S', 'Chemical', 'MESH:D013455', (174, 175))	('C', 'Chemical', 'MESH:D002244', (186, 187))	('CA-125', 'Var', (178, 184))	('pancreatic', 'Disease', 'MESH:D010195', (226, 236))	('ovarian', 'Disease', (217, 224))	('C', 'Chemical', 'MESH:D002244', (178, 179))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('CA19-9', 'Var', (186, 192))	('pancreatic', 'Disease', (226, 236))	('NuMA', 'Gene', (198, 202))	('PSA', 'Disease', (173, 176))	('bladder cancer', 'Disease', 'MESH:D001749', (242, 256))	('bladder cancer', 'Disease', (242, 256))	('cancer', 'Disease', (250, 256))	('bladder cancer', 'Phenotype', 'HP:0009725', (242, 256))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('NuMA', 'Gene', '4926', (198, 202))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('prostate', 'Disease', (207, 215))
30942	30840886	The total number of somatic mutation events (insertion, deletion, or single nucleotide polymorphism) for each primary tumor sample were summed to yield a total mutation burden for each sample.	('deletion', 'Var', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('single nucleotide polymorphism', 'Var', (69, 99))	('primary tumor', 'Disease', (110, 123))	('primary tumor', 'Disease', 'MESH:D009369', (110, 123))
30965	30840886	In this manner, genes with low p values and a positive FC receive a pdir near zero, whereas genes with low p values but a negative FC have a pdir close to one.	('C', 'Chemical', 'MESH:D002244', (56, 57))	('dir', 'Gene', (142, 145))	('dir', 'Gene', (69, 72))	('p values', 'Var', (31, 39))	('C', 'Chemical', 'MESH:D002244', (132, 133))	('dir', 'Gene', '554', (69, 72))	('dir', 'Gene', '554', (142, 145))
31006	28441383	MEK inhibition and antiangiogenic therapies have individually shown modest activity in advanced cholangiocarcinoma, whereas dual inhibition of these pathways has not been previously evaluated.	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('cholangiocarcinoma', 'Disease', (96, 114))	('inhibition', 'Var', (4, 14))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))
31020	28441383	Alterations in this pathway have been reported in up to 35% and 55% of intrahepatic and extrahepatic cholangiocarcinomas, respectively.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('reported', 'Reg', (38, 46))	('Alterations', 'Var', (0, 11))	('intrahepatic and extrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (71, 120))
31026	28441383	Several small studies have previously been conducted with inhibitors of VEGF signalling in cholangiocarcinoma, with modest signs of activity.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('VEGF', 'Gene', (72, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('inhibitors', 'Var', (58, 68))	('VEGF', 'Gene', '7422', (72, 76))	('cholangiocarcinoma', 'Disease', (91, 109))
31030	28441383	Trametinib is an orally available highly specific inhibitor of MEK1 and MEK2 that is approved for BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma.	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('MEK2', 'Gene', '5605', (72, 76))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))	('MEK1', 'Gene', '5604', (63, 67))	('unresectable', 'Disease', (136, 148))	('V600K', 'Var', (112, 117))	('MEK2', 'Gene', (72, 76))	('V600E', 'Mutation', 'rs113488022', (103, 108))	('MEK1', 'Gene', (63, 67))	('V600K', 'Mutation', 'rs121913227', (112, 117))
31095	28441383	Mutations in the RAS/RAF/MEK/ERK pathway as well as PI3 Kinase/AKT have been reported in this entity and could rationally be evaluated as predictive biomarkers of this regimen.	('RAF', 'Gene', (21, 24))	('AKT', 'Gene', (63, 66))	('ERK', 'Gene', '5594', (29, 32))	('MEK', 'Gene', (25, 28))	('MEK', 'Gene', '5609', (25, 28))	('ERK', 'Gene', (29, 32))	('Mutations', 'Var', (0, 9))	('AKT', 'Gene', '207', (63, 66))	('reported', 'Reg', (77, 85))	('RAF', 'Gene', '22882', (21, 24))
31099	28441383	Recently, MEK inhibitors have been found to have important immune modulatory properties, and the VEGF signalling pathway has also been implicated as a mechanism of tumour immune escape.	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('VEGF', 'Gene', (97, 101))	('MEK', 'Gene', (10, 13))	('MEK', 'Gene', '5609', (10, 13))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('tumour', 'Disease', (164, 170))	('VEGF', 'Gene', '7422', (97, 101))	('inhibitors', 'Var', (14, 24))
31110	27981460	Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor.	('HER2', 'Gene', '2064', (42, 46))	('Human epidermal growth factor receptor 2', 'Gene', (0, 40))	('amplification', 'Var', (67, 80))	('epidermal growth factor receptor 3', 'Gene', '2065', (192, 226))	('epidermal growth factor receptor 3', 'Gene', (192, 226))	('gastric cancer', 'Phenotype', 'HP:0012126', (162, 176))	('Human epidermal growth factor receptor 2', 'Gene', '2064', (0, 40))	('breast and gastric cancer', 'Disease', 'MESH:D013274', (151, 176))	('HER3', 'Gene', (228, 232))	('human', 'Species', '9606', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('HER2', 'Gene', '2064', (126, 130))	('overexpression', 'PosReg', (48, 62))	('HER2', 'Gene', (126, 130))	('HER2', 'Gene', (42, 46))	('HER3', 'Gene', '2065', (228, 232))
31111	27981460	The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs).	('amplification', 'Var', (115, 128))	('overexpression', 'PosReg', (96, 110))	('HER3', 'Gene', (91, 95))	('HER2', 'Gene', (82, 86))	('biliary tract cancers', 'Disease', 'MESH:D001661', (132, 153))	('HER2', 'Gene', '2064', (82, 86))	('biliary tract cancers', 'Disease', (132, 153))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('HER3', 'Gene', '2065', (91, 95))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
31112	27981460	An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs.	('AC', 'Phenotype', 'HP:0031524', (180, 182))	('HER3', 'Gene', (241, 245))	('Cancer', 'Disease', 'MESH:D009369', (162, 168))	('HER3', 'Gene', '2065', (241, 245))	('HER2', 'Gene', (229, 233))	('HER2', 'Gene', '2064', (229, 233))	('Oncology', 'Phenotype', 'HP:0002664', (62, 70))	('Oncology', 'Phenotype', 'HP:0002664', (107, 115))	('gene amplification', 'Var', (311, 329))	('Cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Cancer', 'Disease', (162, 168))
31115	27981460	HER2 amplification rate was higher in patients selected by HER2 overexpression compared to "unselected" patients: 57.6 % (95 % CI 16.2-99 %) vs. 17.9 % (95 % CI 0.1-35.4 %), respectively, p value 0.0072.	('higher', 'PosReg', (28, 34))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', (59, 63))	('patients', 'Species', '9606', (38, 46))	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', '2064', (59, 63))	('overexpression', 'Var', (64, 78))	('patients', 'Species', '9606', (104, 112))	('amplification rate', 'MPA', (5, 23))
31117	27981460	Up to 20 % of extrahepatic BTCs appear to be HER2 overexpressed; of these, close to 60 % appear to be HER2 amplified, while HER3 is overexpressed or amplified in about 25 % of patients.	('extrahepatic BTCs', 'Disease', (14, 31))	('patients', 'Species', '9606', (176, 184))	('HER3', 'Gene', (124, 128))	('amplified', 'Var', (107, 116))	('HER3', 'Gene', '2065', (124, 128))	('HER2', 'Gene', (102, 106))	('HER2', 'Gene', (45, 49))	('HER2', 'Gene', '2064', (102, 106))	('HER2', 'Gene', '2064', (45, 49))
31126	27981460	Dimerization induces the activation of the intrinsic tyrosine kinase domain, by phosphorylation of specific tyrosine residues, leading to the activation of different downstream signaling cascades, including the mitogen-activated protein kinase (MAPK) proliferation pathway and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB or Akt) pro-survival pathway (Fig.	('phosphatidylinositol 3-kinase', 'Gene', '5293', (277, 306))	('PKB', 'Gene', (332, 335))	('tyrosine kinase', 'Gene', (53, 68))	('tyrosine', 'Chemical', 'MESH:D014443', (108, 116))	('Dimerization', 'Var', (0, 12))	('activation', 'PosReg', (142, 152))	('Akt', 'Gene', '207', (339, 342))	('tyrosine', 'Chemical', 'MESH:D014443', (53, 61))	('Akt', 'Gene', (339, 342))	('phosphatidylinositol 3-kinase', 'Gene', (277, 306))	('tyrosine kinase', 'Gene', '7294', (53, 68))	('activation', 'PosReg', (25, 35))	('PKB', 'Gene', '207', (332, 335))
31134	27981460	Thus, dysregulation of HER-mediated signaling pathways, through this complex mechanism, results in the growth and spread of cancer cells.	('cancer', 'Disease', (124, 130))	('results in', 'Reg', (88, 98))	('growth', 'CPA', (103, 109))	('dysregulation', 'Var', (6, 19))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('spread', 'CPA', (114, 120))	('HER-mediated signaling pathways', 'Pathway', (23, 54))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
31206	27981460	KRAS/NRAS mutations occur in 6.1-6.5 % of BTCs and they appear to be mutually exclusive with HER2 amplification, at least in ACs.	('AC', 'Phenotype', 'HP:0031524', (125, 127))	('HER2', 'Gene', '2064', (93, 97))	('NRAS', 'Gene', (5, 9))	('NRAS', 'Gene', '4893', (5, 9))	('mutations', 'Var', (10, 19))	('KRAS', 'Gene', (0, 4))	('HER2', 'Gene', (93, 97))	('KRAS', 'Gene', '3845', (0, 4))
31207	27981460	Less frequently, BTCs harbor BRAF mutations (0-8.1 %) or PI3K mutations (7.3-10.2 %), while MET expression measured by IHC ranges from 5.6 to 44.1 %.	('PI3K mutations', 'Var', (57, 71))	('BRAF', 'Gene', '673', (29, 33))	('mutations', 'Var', (34, 43))	('BRAF', 'Gene', (29, 33))
31284	26399446	According to the GLOBOCAN 2012 report, EBV resulted in 59 553 new nasopharyngeal cancer cases and 35 862 deaths in the target countries, with a gender ratio around 2:1.	('nasopharyngeal cancer', 'Disease', (66, 87))	('death', 'Disease', 'MESH:D003643', (105, 110))	('death', 'Disease', (105, 110))	('EBV', 'Species', '10376', (39, 42))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (66, 87))	('EBV', 'Var', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (66, 87))
31303	26399446	Moreover, we estimated the number of cancers based on GLOBOCAN2012, while previous studies used Korean data from 2007.	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('GLOBOCAN2012', 'Var', (54, 66))	('cancers', 'Disease', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
31384	26207380	From August 2003 through September 2009, two phase II clinical trials (NCT00587067 and NCT00410956) evaluating the role of regional chemotherapy in patients with initially unresectable primary liver cancer (either ICC or hepatocellular carcinoma) were conducted at MSKCC; all patients signed IRB-approved consent forms for participation in these trials.	('patients', 'Species', '9606', (276, 284))	('patients', 'Species', '9606', (148, 156))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('primary liver cancer', 'Disease', (185, 205))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (221, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('liver cancer', 'Phenotype', 'HP:0002896', (193, 205))	('NCT00410956', 'Var', (87, 98))	('ICC or hepatocellular carcinoma', 'Disease', 'MESH:C566123', (214, 245))	('ICC or hepatocellular carcinoma', 'Disease', (214, 245))	('primary liver cancer', 'Disease', 'MESH:D006528', (185, 205))
31422	26207380	Table 2 details thirteen qualitative imaging features and demonstrates that VEGF expression was associated with two qualitative imaging features ('tumor-liver difference' and 'attenuation heterogeneity', p<0.05 for both).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('VEGF', 'Gene', (76, 80))	('associated', 'Reg', (96, 106))	('expression', 'Var', (81, 91))	('VEGF', 'Gene', '7422', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
31447	26207380	Furthermore, it was proposed that CD24 may have a role as a new target for directed molecular therapy in cholangiocarcinoma, as decreased tumor cell invasiveness was observed with inhibition of CD24.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (105, 123))	('CD24', 'Gene', '100133941', (194, 198))	('decreased tumor', 'Disease', (128, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('CD24', 'Gene', (194, 198))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (105, 123))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('CD24', 'Gene', '100133941', (34, 38))	('CD24', 'Gene', (34, 38))	('inhibition', 'Var', (180, 190))	('cholangiocarcinoma', 'Disease', (105, 123))	('decreased tumor', 'Disease', 'MESH:D009369', (128, 143))
31464	25336976	A 75-year-old female with lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutation (15-bp in-frame deletion in exon 19 and T790M in exon 20) developed obstructive jaundice during therapy.	('T790M', 'Var', (145, 150))	('epidermal growth factor receptor', 'Gene', '1956', (56, 88))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (26, 45))	('obstructive jaundice', 'Disease', (173, 193))	('EGFR', 'Gene', '1956', (90, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('epidermal growth factor receptor', 'Gene', (56, 88))	('lung adenocarcinoma', 'Disease', (26, 45))	('EGFR', 'Gene', (90, 94))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (26, 45))	('jaundice', 'Phenotype', 'HP:0000952', (185, 193))	('developed', 'Reg', (163, 172))	('T790M', 'Mutation', 'rs121434569', (145, 150))	('obstructive jaundice', 'Disease', 'MESH:D041781', (173, 193))
31467	25336976	Furthermore, peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp analysis showed that the tumor contained the same EGFR mutation as that in the primary lung cancer.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('primary lung cancer', 'Disease', (165, 184))	('primary lung cancer', 'Disease', 'MESH:D008175', (165, 184))	('EGFR', 'Gene', '1956', (136, 140))	('mutation', 'Var', (141, 149))	('EGFR', 'Gene', (136, 140))
31480	25336976	Immunohistochemistry and epidermal growth factor receptor (EGFR) mutation analysis proved that the intraductal tumor was a metastasis from the lung adenocarcinoma.	('epidermal growth factor receptor', 'Gene', (25, 57))	('EGFR', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (143, 162))	('epidermal growth factor receptor', 'Gene', '1956', (25, 57))	('mutation', 'Var', (65, 73))	('intraductal tumor', 'Disease', 'MESH:D002285', (99, 116))	('lung adenocarcinoma', 'Disease', (143, 162))	('intraductal tumor', 'Disease', (99, 116))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (143, 162))	('EGFR', 'Gene', '1956', (59, 63))
31484	25336976	Because peptide nucleic acid-locked nucleic acid (PNA-LNA) polymerase chain reaction (PCR) clamp analysis showed that the primary lung tumor had an EGFR mutation (15-bp in-frame deletion in exon 19, del E746-A750), she was treated with gefitinib as first-line therapy for 14 months.	('E746-A750', 'Mutation', 'p.E746,750A', (203, 212))	('del E746-A750', 'Var', (199, 212))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('lung tumor', 'Disease', (130, 140))	('lung tumor', 'Disease', 'MESH:D008175', (130, 140))	('gefitinib', 'Chemical', 'MESH:D000077156', (236, 245))	('15-bp in-frame deletion', 'Var', (163, 186))	('lung tumor', 'Phenotype', 'HP:0100526', (130, 140))
31488	25336976	T790M EGFR-tyrosine kinase inhibitor-resistant mutation in exon 20, in addition to the EGFR exon 19 deletion mutation, was identified from the pleural effusion.	('pleural effusion', 'Disease', 'MESH:D010996', (143, 159))	('pleural effusion', 'Phenotype', 'HP:0002202', (143, 159))	('pleural effusion', 'Disease', (143, 159))	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', (6, 10))	('EGFR', 'Gene', (87, 91))	('T790M', 'Mutation', 'rs121434569', (0, 5))	('T790M', 'Var', (0, 5))	('EGFR', 'Gene', '1956', (6, 10))
31490	25336976	PNA-LNA PCR clamp analysis of the spinal fluid revealed the same EGFR deletion mutation; however, the T790M mutation could not be detected.	('deletion mutation', 'Var', (70, 87))	('T790M', 'Mutation', 'rs121434569', (102, 107))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))
31504	25336976	PNA-LNA PCR clamp analysis revealed that the specimen had an EGFR exon 19 deletion mutation and T790M mutation in exon 20.	('T790M mutation', 'Var', (96, 110))	('T790M', 'Mutation', 'rs121434569', (96, 101))	('deletion mutation', 'Var', (74, 91))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
31507	25336976	Immunohistochemistry and EGFR mutation analysis were useful to differentiate metastatic intraductal tumor from primary cholangiocarcinoma.	('primary', 'Disease', (111, 118))	('cholangiocarcinoma', 'Disease', (119, 137))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('EGFR', 'Gene', (25, 29))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (119, 137))	('mutation', 'Var', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (119, 137))	('intraductal tumor', 'Disease', (88, 105))	('intraductal tumor', 'Disease', 'MESH:D002285', (88, 105))	('EGFR', 'Gene', '1956', (25, 29))
31516	25336976	PNA-LNA PCR clamp analysis demonstrated that the EGFR mutation status of the primary lung cancer was identical to that of the intraductal tumor.	('primary lung cancer', 'Disease', (77, 96))	('mutation', 'Var', (54, 62))	('EGFR', 'Gene', '1956', (49, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('EGFR', 'Gene', (49, 53))	('primary lung cancer', 'Disease', 'MESH:D008175', (77, 96))	('intraductal tumor', 'Disease', 'MESH:D002285', (126, 143))	('intraductal tumor', 'Disease', (126, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
31517	25336976	EGFR del E746-A750 and T790M mutations have not been reported in cholangiocarcinoma, although there have been reports of other EGFR mutations in exons 20 and 21.	('T790M', 'Mutation', 'rs121434569', (23, 28))	('EGFR', 'Gene', (0, 4))	('T790M', 'Var', (23, 28))	('cholangiocarcinoma', 'Disease', (65, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))	('E746-A750', 'Mutation', 'p.E746,750A', (9, 18))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (65, 83))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', '1956', (127, 131))	('del E746-A750', 'Var', (5, 18))	('EGFR', 'Gene', (127, 131))
31522	25336976	Clinicians should be aware that EGFR mutation analysis of metastatic lesions might lead to a definitive diagnosis.	('mutation analysis', 'Var', (37, 54))	('EGFR', 'Gene', '1956', (32, 36))	('lead to', 'Reg', (83, 90))	('EGFR', 'Gene', (32, 36))
31571	21898484	ASPH over-expression has been observed to contribute to the infiltrative growth pattern of cholangiocarcinoma cells by promoting cell motility.	('cell motility', 'CPA', (129, 142))	('ASPH', 'Gene', (0, 4))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('over-expression', 'Var', (5, 20))	('infiltrative', 'MPA', (60, 72))	('cholangiocarcinoma', 'Disease', (91, 109))	('rat', 'Species', '10116', (66, 69))	('promoting', 'PosReg', (119, 128))
31593	21898484	The OX62+DCs can be further classified as two subsets based on the expression of the CD4 molecule i.e., CD4-OX62+DCs and CD4+OX62+DCs.	('OX62+DCs', 'Chemical', '-', (4, 12))	('CD4+OX62+DCs', 'Var', (121, 133))	('OX62+DCs', 'Chemical', '-', (125, 133))	('OX62+DCs', 'Chemical', '-', (108, 116))	('OX62+DCs', 'Var', (4, 12))	('CD4-OX62+DCs', 'Var', (104, 116))	('CD4', 'Gene', (85, 88))
31601	21898484	The phenotype of DC subpopulations expanded by hFlt3L injection and purified by phagocytosis of magnetic beads was further analyzed after double staining using PE-conjugated anti-CD103 (OX62) or PE-conjugated anti-MHC class II (RT1B) and other FITC-conjugated antibodies (Figure 1C).	('hFlt3L', 'Gene', '2323', (47, 53))	('hFlt3L', 'Gene', (47, 53))	('OX62', 'Chemical', '-', (186, 190))	('anti-CD103', 'Var', (174, 184))	('FITC', 'Chemical', 'MESH:D016650', (244, 248))	('RT1B', 'Gene', (228, 232))	('RT1B', 'Gene', '24738', (228, 232))
31606	21898484	In contrast, the OX62- cells were negative for the macrophage markers CD68 (ED1), CD163 (ED2) and CD169 (ED3).	('CD169', 'Var', (98, 103))	('OX62', 'Chemical', '-', (17, 21))	('CD163', 'Gene', (82, 87))	('CD68', 'Gene', (70, 74))	('CD68', 'Gene', '287435', (70, 74))	('CD163', 'Gene', '312701', (82, 87))
31608	21898484	The DCs isolated by positive selection using the OX62 antibody have been reported to be negative for co-stimulatory molecule (CD40 and CD86) expression.	('OX62', 'Var', (49, 53))	('OX62', 'Chemical', '-', (49, 53))	('CD86', 'Gene', '56822', (135, 139))	('CD86', 'Gene', (135, 139))	('CD40', 'Gene', (126, 130))
31634	21898484	The BDEneu-CL24 cells showed comparable levels of Akt and p-Akt expression; there was a slight reduction of p44/42 MAPK phosphorylation in BDEneu-CL24 compared with BDEneu-p cells.	('Akt', 'Gene', '24185', (60, 63))	('p44', 'Gene', '50689', (108, 111))	('MAPK', 'Gene', (115, 119))	('Akt', 'Gene', '24185', (50, 53))	('MAPK', 'Gene', '50689;50689', (115, 119))	('Akt', 'Gene', (50, 53))	('BDEneu-p', 'Chemical', '-', (165, 173))	('Akt', 'Gene', (60, 63))	('reduction', 'NegReg', (95, 104))	('BDEneu-CL24', 'Var', (139, 150))	('p44', 'Gene', (108, 111))
31647	21898484	The mean tumor volume was significantly less in animals treated with ASPH-loaded DCs compared to those treated with GFP-loaded DCs (p<0.05) (Figure 7B).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('less', 'NegReg', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('ASPH-loaded DCs', 'Var', (69, 84))
31651	21898484	We found that immunotherapy with ASPH-loaded DCs resulted in increased T cell infiltration (CD3+ cells) into tumors by immunohistochemical analysis (Figure 7C).	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('rat', 'Species', '10116', (84, 87))	('ASPH-loaded', 'Var', (33, 44))	('increased', 'PosReg', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('increased T cell', 'Phenotype', 'HP:0100828', (61, 77))	('T cell infiltration', 'CPA', (71, 90))
31673	21898484	Voisine et al demonstrated that the CD4- DCs produced robust amounts of the IL-12 proinflammatory cytokines and induced Th1 responses whereas CD4+ DCs were found to have low levels of IL-12 expression.	('Voisine', 'Chemical', '-', (0, 7))	('induced', 'Reg', (112, 119))	('Th1 responses', 'MPA', (120, 133))	('IL-12', 'Gene', (76, 81))	('IL-12', 'Gene', '64546', (184, 189))	('IL-12', 'Gene', '64546', (76, 81))	('IL-12', 'Gene', (184, 189))	('rat', 'Species', '10116', (21, 24))	('CD4- DCs', 'Var', (36, 44))
31678	21898484	In this study, the freshly purified DCs generated after phagocytosis of magnetic beads from a mixed splenocyte population were negative for CD80 and CD86 antigens but demonstrated broad expression of CD40.	('CD40', 'Var', (200, 204))	('CD80', 'Gene', (140, 144))	('negative', 'NegReg', (127, 135))	('rat', 'Species', '10116', (44, 47))	('CD80', 'Gene', '25408', (140, 144))	('rat', 'Species', '10116', (174, 177))	('CD86', 'Gene', '56822', (149, 153))	('CD86', 'Gene', (149, 153))
31684	21898484	To investigate the mechanism(s) of anti-tumor effects, we examined the tumor-infiltrating lymphocyte population in the tumors treated with GFP-loaded (control) or ASPH-loaded DCs.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', (119, 124))	('rat', 'Species', '10116', (83, 86))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', (71, 76))	('GFP-loaded', 'Var', (139, 149))
31717	34040387	For instance, miR-133a-3p repressed the growth and metastasis of gastric cancer cells via blocking autophagy-mediated glutaminolysis.	('metastasis of gastric cancer', 'Disease', 'MESH:D013274', (51, 79))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('blocking', 'NegReg', (90, 98))	('si', 'Chemical', 'MESH:D012825', (129, 131))	('autophagy-mediated glutaminolysis', 'MPA', (99, 132))	('miR-133a-3p', 'Chemical', '-', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('growth', 'CPA', (40, 46))	('metastasis of gastric cancer', 'Disease', (51, 79))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('miR-133a-3p', 'Var', (14, 25))
31718	34040387	MiRNA-106a has been confirmed to promote breast cancer cells' proliferation, clonogenicity, migration, and invasion but inhibit their apoptosis and chemosensitivity.	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('promote', 'PosReg', (33, 40))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('si', 'Chemical', 'MESH:D012825', (156, 158))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('inhibit', 'NegReg', (120, 127))	('migration', 'CPA', (92, 101))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('invasion', 'CPA', (107, 115))	('clonogenicity', 'CPA', (77, 90))	('MiRNA-106a', 'Var', (0, 10))
31721	34040387	In addition, miR-145-5p targeted NUAK1 to restrain the carcinogenesis of the CHOL cells.	('CHOL', 'CellLine', 'None', (77, 81))	('restrain', 'NegReg', (42, 50))	('NUAK1', 'Gene', '9891', (33, 38))	('NUAK1', 'Gene', (33, 38))	('miR-145-5p', 'Var', (13, 23))	('carcinogenesis of the CHOL cells', 'CPA', (55, 87))	('miR-145-5p', 'Chemical', '-', (13, 23))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('CHOL', 'Phenotype', 'HP:0030153', (77, 81))
31722	34040387	It was also reported that the progression of the CHOL cells could be repressed by miR-145-5p via the sirt3/GDH axis.	('sirt3', 'Gene', (101, 106))	('progression', 'CPA', (30, 41))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('CHOL', 'Phenotype', 'HP:0030153', (49, 53))	('CHOL', 'CellLine', 'None', (49, 53))	('miR-145-5p', 'Var', (82, 92))	('miR-145-5p', 'Chemical', '-', (82, 92))	('GDH', 'Gene', (107, 110))	('GDH', 'Gene', '9563', (107, 110))	('sirt3', 'Gene', '23410', (101, 106))
31779	34040387	For this reason, we chose MAL2 as the potential downstream effector of miR-145-5p that could be targeted by ST8SIA6-AS1.	('miR-145-5p', 'Var', (71, 81))	('ST8SIA6-AS1', 'Gene', '100128098;338596;5729', (108, 119))	('ST8SIA6-AS1', 'Gene', (108, 119))	('miR-145-5p', 'Chemical', '-', (71, 81))
31784	34040387	The expression of ST8SIA6-AS1 was reduced by about 60% in the si-lnc groups compared to the blank control group (Figure 2C).	('si', 'Chemical', 'MESH:D012825', (62, 64))	('reduced', 'NegReg', (34, 41))	('si-lnc', 'Chemical', '-', (62, 68))	('expression', 'MPA', (4, 14))	('si-lnc groups', 'Var', (62, 75))	('ST8SIA6-AS1', 'Gene', '100128098;338596;5729', (18, 29))	('ST8SIA6-AS1', 'Gene', (18, 29))	('si', 'Chemical', 'MESH:D012825', (10, 12))
31785	34040387	It was also found that the viability levels of the si-lnc groups were lower than those of the blank control group in both CCLP and RBE cells (Figure 2D).	('lower', 'NegReg', (70, 75))	('viability levels', 'MPA', (27, 43))	('si-lnc', 'Var', (51, 57))	('si-lnc', 'Chemical', '-', (51, 57))
31786	34040387	Similarly, the proliferation levels in the si-lnc groups declined by 30% reduced compared to the blank control group in both CCLP and RBE cells (Figure 2E).	('declined', 'NegReg', (57, 65))	('reduced', 'NegReg', (73, 80))	('proliferation', 'CPA', (15, 28))	('si-lnc', 'Var', (43, 49))	('si-lnc', 'Chemical', '-', (43, 49))
31787	34040387	Besides, a decrease in the invasion level of the si-lnc group was discovered compared with the blank control group (Figure 2F).	('si', 'Chemical', 'MESH:D012825', (2, 4))	('invasion level', 'CPA', (27, 41))	('si-lnc', 'Var', (49, 55))	('decrease', 'NegReg', (11, 19))	('si-lnc', 'Chemical', '-', (49, 55))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('si', 'Chemical', 'MESH:D012825', (49, 51))
31788	34040387	Additionally, the si-lnc groups demonstrated a 2-fold increase in cell apoptosis compared to the blank control group (Figure 2G).	('si', 'Chemical', 'MESH:D012825', (18, 20))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('increase', 'PosReg', (54, 62))	('si-lnc', 'Chemical', '-', (18, 24))	('cell apoptosis', 'CPA', (66, 80))	('si-lnc', 'Var', (18, 24))
31793	34040387	The luciferase activity results showed that the co-transfection of miR-145-5p mimics and psiCHECK2 ST8SIA6-AS1-wide type (WT) downregulated luciferase activities by about 50% compared to cells transfected with psiCHECK2 ST8SIA6-AS1 mutant (Mut) in both CCLP and RBE cells, meaning miR-145-5p could directly interact with ST8SIA6-AS1 (Figure 3B).	('si', 'Chemical', 'MESH:D012825', (90, 92))	('ST8SIA6-AS1', 'Gene', '100128098;338596;5729', (321, 332))	('ST8SIA6-AS1', 'Gene', '100128098;338596;5729', (99, 110))	('downregulated', 'NegReg', (126, 139))	('ST8SIA6-AS1', 'Gene', (99, 110))	('activities', 'MPA', (151, 161))	('si', 'Chemical', 'MESH:D012825', (211, 213))	('miR-145-5p', 'Chemical', '-', (67, 77))	('luciferase', 'Enzyme', (140, 150))	('ST8SIA6-AS1', 'Gene', (321, 332))	('ST8SIA6-AS1', 'Gene', '100128098;338596;5729', (220, 231))	('miR-145-5p', 'Chemical', '-', (281, 291))	('psiCHECK2', 'Var', (89, 98))	('ST8SIA6-AS1', 'Gene', (220, 231))
31796	34040387	A negative correlation between the miR-145-5p expression and ST8SIA6-AS1 expression level in CHOL tissues was also observed (Figure 3E).	('negative', 'NegReg', (2, 10))	('ST8SIA6-AS1', 'Gene', '100128098;338596;5729', (61, 72))	('miR-145-5p', 'Chemical', '-', (35, 45))	('si', 'Chemical', 'MESH:D012825', (79, 81))	('expression level', 'MPA', (73, 89))	('ST8SIA6-AS1', 'Gene', (61, 72))	('CHOL', 'Phenotype', 'HP:0030153', (93, 97))	('CHOL', 'CellLine', 'None', (93, 97))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('miR-145-5p', 'Var', (35, 45))
31797	34040387	Furthermore, the expression of miR-145-5p in CCLP and RBE cells declined by 50% compared to the normal HIBEC cell (Figure 3F).	('CCLP', 'Disease', (45, 49))	('miR-145-5p', 'Chemical', '-', (31, 41))	('declined', 'NegReg', (64, 72))	('expression', 'MPA', (17, 27))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('miR-145-5p', 'Var', (31, 41))
31799	34040387	As showed in Figure 3G, miR-145-5p level in the si-lnc group increased by 1.5-fold, while ST8SIA6-AS1 level in the si-lnc group declined by 70% compared with the blank control group.	('miR-145-5p level', 'MPA', (24, 40))	('si-lnc', 'Chemical', '-', (48, 54))	('si-lnc', 'Var', (48, 54))	('si-lnc', 'Chemical', '-', (115, 121))	('ST8SIA6-AS1', 'Gene', '100128098;338596;5729', (90, 101))	('increased', 'PosReg', (61, 70))	('miR-145-5p', 'Chemical', '-', (24, 34))	('ST8SIA6-AS1', 'Gene', (90, 101))
31804	34040387	Experimental findings revealed that the miR-145-5p inhibitor accelerated the viability ability of the CHOL cells compared to the blank control group; however, si-lnc counteracted the effect in CCLP and RBE cells (Figure 4A).	('CHOL', 'CellLine', 'None', (102, 106))	('CHOL', 'Phenotype', 'HP:0030153', (102, 106))	('accelerated', 'PosReg', (61, 72))	('si-lnc', 'Chemical', '-', (159, 165))	('miR-145-5p', 'Chemical', '-', (40, 50))	('viability ability', 'CPA', (77, 94))	('si-lnc', 'Var', (159, 165))
31805	34040387	The miR-145-5p inhibitor group enhanced the proliferation abilities of the CHOL cells by 30% compared to the blank control group; however, si-lnc reversed the effect in the tumor cells (Figure 4B).	('CHOL', 'Phenotype', 'HP:0030153', (75, 79))	('CHOL', 'CellLine', 'None', (75, 79))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('enhanced', 'PosReg', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('si-lnc', 'Chemical', '-', (139, 145))	('proliferation abilities', 'CPA', (44, 67))	('si-lnc', 'Var', (139, 145))	('miR-145-5p', 'Chemical', '-', (4, 14))
31806	34040387	Moreover, the miR-145-5p inhibitor group also enhanced the invasion ability of the CHOL cells compared with the blank control group; nonetheless, this enhancement was reversed by si-lnc (Figure 4C).	('CHOL', 'Phenotype', 'HP:0030153', (83, 87))	('miR-145-5p inhibitor', 'Var', (14, 34))	('invasion ability of the CHOL cells', 'CPA', (59, 93))	('si-lnc', 'Chemical', '-', (179, 185))	('CHOL', 'CellLine', 'None', (83, 87))	('enhanced', 'PosReg', (46, 54))	('si', 'Chemical', 'MESH:D012825', (179, 181))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('miR-145-5p', 'Chemical', '-', (14, 24))
31807	34040387	Finally, the apoptosis rate of the miR-145-5p inhibitor group was repressed by 50% with the blank control group; however, while this repressive effect was counteracted by si-lnc (Figure 4D).	('miR-145-5p', 'Chemical', '-', (35, 45))	('si', 'Chemical', 'MESH:D012825', (139, 141))	('miR-145-5p inhibitor', 'Var', (35, 55))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('apoptosis rate', 'CPA', (13, 27))	('si', 'Chemical', 'MESH:D012825', (171, 173))	('si-lnc', 'Chemical', '-', (171, 177))
31809	34040387	Overall, these results demonstrated that by sponging miR-145-5p, ST8SIA6-AS1 could enhance CHOL progression.	('CHOL', 'CellLine', 'None', (91, 95))	('CHOL', 'Phenotype', 'HP:0030153', (91, 95))	('miR-145-5p', 'Var', (53, 63))	('CHOL', 'Disease', (91, 95))	('miR-145-5p', 'Chemical', '-', (53, 63))	('enhance', 'PosReg', (83, 90))	('sponging', 'Var', (44, 52))	('ST8SIA6-AS1', 'Gene', '100128098;338596;5729', (65, 76))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('ST8SIA6-AS1', 'Gene', (65, 76))
31810	34040387	We further confirmed the impacts of miR-145-5p on CHOL development.	('miR-145-5p', 'Var', (36, 46))	('miR-145-5p', 'Chemical', '-', (36, 46))	('CHOL', 'CellLine', 'None', (50, 54))	('impacts', 'Reg', (25, 32))	('CHOL', 'Phenotype', 'HP:0030153', (50, 54))	('CHOL development', 'CPA', (50, 66))
31813	34040387	The RNA pull-down assay results indicated that miR-145-5p interacted with MAL2 in the CCLP and RBE cells (Figure 5C).	('interacted', 'Interaction', (58, 68))	('miR-145-5p', 'Chemical', '-', (47, 57))	('miR-145-5p', 'Var', (47, 57))
31814	34040387	In addition, a negative correlation between the expression of miR-145-5p and MAL2 was found in CHOL tissues (Figure 5D).	('CHOL', 'Phenotype', 'HP:0030153', (95, 99))	('CHOL', 'CellLine', 'None', (95, 99))	('si', 'Chemical', 'MESH:D012825', (54, 56))	('miR-145-5p', 'Var', (62, 72))	('expression', 'MPA', (48, 58))	('negative', 'NegReg', (15, 23))	('miR-145-5p', 'Chemical', '-', (62, 72))	('MAL2', 'Gene', (77, 81))
31816	34040387	In short, our results suggested that miR-145-5p could directly target and repress MAL2 in CHOL cells.	('MAL2', 'Gene', (82, 86))	('miR-145-5p', 'Chemical', '-', (37, 47))	('miR-145-5p', 'Var', (37, 47))	('CHOL', 'CellLine', 'None', (90, 94))	('CHOL', 'Phenotype', 'HP:0030153', (90, 94))	('repress', 'NegReg', (74, 81))
31818	34040387	Our findings revealed that si-MAL2 group had a lower cell viability level compared to the blank control group, while the miR-145-5p inhibitor group demonstrated had a higher cell viability level, which was abrogated by si-MAL2 co-transfection in the CCLP and RBE cells (Figure 6A).	('cell', 'MPA', (53, 57))	('lower', 'NegReg', (47, 52))	('higher', 'PosReg', (167, 173))	('si-MAL2', 'Var', (219, 226))	('cell', 'MPA', (174, 178))	('si-MAL2', 'Var', (27, 34))	('si', 'Chemical', 'MESH:D012825', (219, 221))	('miR-145-5p', 'Chemical', '-', (121, 131))	('miR-145-5p', 'Var', (121, 131))	('si', 'Chemical', 'MESH:D012825', (27, 29))
31819	34040387	Additionally, the si-MAL2 group inhibited cell proliferation by 30% compared with the blank control group, while the cell proliferation level in the miR-145-5p inhibitor group increased by more than 30%.	('miR-145-5p', 'Chemical', '-', (149, 159))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('increased', 'PosReg', (176, 185))	('inhibited', 'NegReg', (32, 41))	('cell proliferation', 'CPA', (42, 60))	('si-MAL2', 'Var', (18, 25))	('cell proliferation level', 'MPA', (117, 141))
31821	34040387	Besides, the si-MAL2 group suppressed the invasion ability of CCLP cells by 75% and that of RBE cells by 50% compared with the blank control group, while an increase in cell invasion was observed in the inhibitor group.	('si', 'Chemical', 'MESH:D012825', (2, 4))	('si-MAL2', 'Var', (13, 20))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('suppressed', 'NegReg', (27, 37))	('si', 'Chemical', 'MESH:D012825', (178, 180))	('invasion ability', 'CPA', (42, 58))	('si', 'Chemical', 'MESH:D012825', (13, 15))
31823	34040387	Furthermore, the apoptosis rate of the si-MAL2 group was enhanced by 2.5-fold compared with the blank control group, while the apoptosis rate of the miR-145-5p inhibitor group was reduced compared with the blank control group.	('miR-145-5p', 'Chemical', '-', (149, 159))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('si', 'Chemical', 'MESH:D012825', (133, 135))	('apoptosis rate', 'CPA', (17, 31))	('si-MAL2', 'Var', (39, 46))	('enhanced', 'PosReg', (57, 65))
31826	34040387	As shown in the Figure 6E, MAL2 silence could increase the BAX expression level and reduce the Bcl-2 expression level, while the miR-145-5p inhibitor produced an opposite result.	('reduce', 'NegReg', (84, 90))	('increase', 'PosReg', (46, 54))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('BAX', 'Gene', '581', (59, 62))	('BAX', 'Gene', (59, 62))	('MAL2 silence', 'Var', (27, 39))	('si', 'Chemical', 'MESH:D012825', (107, 109))	('miR-145-5p', 'Chemical', '-', (129, 139))	('Bcl-2', 'Gene', (95, 100))	('Bcl-2', 'Gene', '596', (95, 100))	('si', 'Chemical', 'MESH:D012825', (69, 71))
31828	34040387	Overall, our findings indicated that miR-145-5p could repress CHOL cells' proliferation and migration but improve CHOL cells' apoptosis by targeting MAL2.	("CHOL cells' proliferation", 'CPA', (62, 87))	('si', 'Chemical', 'MESH:D012825', (132, 134))	('miR-145-5p', 'Chemical', '-', (37, 47))	('miR-145-5p', 'Var', (37, 47))	('improve', 'PosReg', (106, 113))	('apoptosis', 'CPA', (126, 135))	('CHOL', 'Phenotype', 'HP:0030153', (62, 66))	('CHOL', 'CellLine', 'None', (62, 66))	('migration', 'CPA', (92, 101))	('MAL2', 'Gene', (149, 153))	('repress', 'NegReg', (54, 61))	('CHOL', 'Phenotype', 'HP:0030153', (114, 118))	('CHOL', 'CellLine', 'None', (114, 118))
31843	34040387	Zhou et al revealed that miR-145-5p suppressed the proliferation, migration and invasion of gastric cancer epithelial cells via the ANGPT2/NOD_LIKE_RECEPTOR axis.	('invasion', 'CPA', (80, 88))	('suppressed', 'NegReg', (36, 46))	('migration', 'CPA', (66, 75))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('proliferation', 'CPA', (51, 64))	('ANGPT2', 'Gene', '285', (132, 138))	('miR-145-5p', 'Chemical', '-', (25, 35))	('ANGPT2', 'Gene', (132, 138))	('miR-145-5p', 'Var', (25, 35))
31844	34040387	Additionally, the loss of miR-145-5p caused ceruloplasmin interference with the PHD-Iron axis and HIF-2alpha stabilization in lung adenocarcinoma-mediated angiogenesis.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (126, 145))	('loss', 'Var', (18, 22))	('ceruloplasmin', 'Gene', '1356', (44, 57))	('Iron', 'Chemical', 'MESH:D007501', (84, 88))	('miR-145-5p', 'Chemical', '-', (26, 36))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (126, 145))	('HIF-2alpha', 'Gene', (98, 108))	('si', 'Chemical', 'MESH:D012825', (164, 166))	('interference', 'NegReg', (58, 70))	('miR-145-5p', 'Gene', (26, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('HIF-2alpha', 'Gene', '2034', (98, 108))	('ceruloplasmin', 'Gene', (44, 57))	('PHD-Iron', 'MPA', (80, 88))	('lung adenocarcinoma', 'Disease', (126, 145))
31846	34040387	Xiong et al indicated that miR-145-5p suppressed cancer-associated adipocytes (CAA)'s proliferation and invasion abilities by targeting NUAK1 and activating Akt signaling.	('invasion abilities', 'CPA', (104, 122))	('miR-145-5p', 'Var', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('targeting', 'Reg', (126, 135))	('suppressed', 'NegReg', (38, 48))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('Akt', 'Gene', '207', (157, 160))	('NUAK1', 'Gene', '9891', (136, 141))	('miR-145-5p', 'Chemical', '-', (27, 37))	('Akt', 'Gene', (157, 160))	('si', 'Chemical', 'MESH:D012825', (161, 163))	('activating', 'PosReg', (146, 156))	('NUAK1', 'Gene', (136, 141))	('cancer', 'Disease', (49, 55))	('si', 'Chemical', 'MESH:D012825', (108, 110))
31857	34040387	Moreover, miR-145-5p inhibited MAL2 expression, which further suppressed CHOL progression.	('miR-145-5p', 'Chemical', '-', (10, 20))	('MAL2', 'Gene', (31, 35))	('CHOL', 'Phenotype', 'HP:0030153', (73, 77))	('miR-145-5p', 'Var', (10, 20))	('suppressed', 'NegReg', (62, 72))	('CHOL', 'Disease', (73, 77))	('CHOL', 'CellLine', 'None', (73, 77))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('inhibited', 'NegReg', (21, 30))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('expression', 'MPA', (36, 46))
31858	34040387	Previous evidence showed that MAL2 was inhibited by miR-216b-5p, which further reduced chronic constriction injury-induced neuropathic pain in female rats via the Wnt/beta-catenin signaling pathway.	('inhibited', 'NegReg', (39, 48))	('miR-216b-5p', 'Var', (52, 63))	('reduced', 'NegReg', (79, 86))	('rats', 'Species', '10116', (150, 154))	('miR-216b-5p', 'Chemical', '-', (52, 63))	('pain', 'Phenotype', 'HP:0012531', (135, 139))	('constriction injury-induced neuropathic pain', 'Disease', (95, 139))	('constriction injury-induced neuropathic pain', 'Disease', 'MESH:D009437', (95, 139))	('MAL2', 'MPA', (30, 34))	('si', 'Chemical', 'MESH:D012825', (180, 182))
31864	34040387	CHOL, cholangiocarcinoma; lncRNAs, long non-coding RNAs; miRNAs, microRNAs; MAL2, Mal, T cell differentiation protein 2; DEGs, differentially expressed genes; NC, negative control; WT, wide type; Mut, mutant; RIP, RNA Immunoprecipitation.	('cholangiocarcinoma', 'Disease', (6, 24))	('miR', 'Gene', '220972', (57, 60))	('miR', 'Gene', (57, 60))	('CHOL', 'Phenotype', 'HP:0030153', (0, 4))	('CHOL', 'CellLine', 'None', (0, 4))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (6, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (6, 24))	('mutant', 'Var', (201, 207))	('RIP', 'Gene', '8737', (209, 212))	('RIP', 'Gene', (209, 212))	('Mal, T cell differentiation protein 2', 'Gene', '4118', (82, 119))
31927	33437754	The newly obtained prediction accuracies caused by a gene were compared to the original prediction accuracy from the model for the cancer type labeled by TCGA data.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('gene', 'Var', (53, 57))
31945	33437754	The GCNN model with the PPI+singleton graph included all the 7,091 genes and demonstrated a >5% increase in prediction accuracy compared with the PPI graph with a smaller accuracy variation as shown in Table 2, suggesting that the additional 2,647 genes could be important in determining cancer type.	('GCNN', 'Chemical', '-', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Disease', (288, 294))	('prediction', 'MPA', (108, 118))	('PPI+singleton', 'Var', (24, 37))	('increase', 'PosReg', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))
31952	33437754	A total of 68%, 16%, 95.2%, and 72.9%, out of 166 READ samples were classified into COAD cancer type by the co-expression, co-expression+singleton, PPI, and PPI+singleton GCNN model respectively (confusion matrices in Figure 7 and, Figure 8, and further illustrated in Supplement 2, 3, 4, and 5).	('GCNN', 'Chemical', '-', (171, 175))	('D', 'Chemical', 'MESH:D003903', (87, 88))	('PPI+singleton', 'Var', (157, 170))	('COAD cancer', 'Disease', 'MESH:D029424', (84, 95))	('confusion', 'Phenotype', 'HP:0001289', (196, 205))	('D', 'Chemical', 'MESH:D003903', (53, 54))	('COAD cancer', 'Disease', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
31960	33437754	UCS classification performed poorly (misclassification rate of 25%, 25%, 58.9%, and 21.4% for co-expression, co-expression+singleton, PPI model, and PPI+singleton GCNN model, respectively), and most of these misclassified samples were in UCEC as expected.	('PPI+singleton', 'Var', (149, 162))	('co-expression+singleton', 'Var', (109, 132))	('UCEC', 'Disease', (238, 242))	('GCNN', 'Chemical', '-', (163, 167))	('co-expression', 'Var', (94, 107))	('UCS', 'Phenotype', 'HP:0002891', (0, 3))
32106	32887625	Epithelial THBS2 positivity was associated with blood vessel invasion (P = 0.004), and stromal THBS2 positivity was associated with R1 resection (P = 0.011).	('Epithelial', 'CPA', (0, 10))	('THBS2', 'Gene', (95, 100))	('blood vessel invasion', 'CPA', (48, 69))	('THBS2', 'Gene', (11, 16))	('positivity', 'Var', (17, 27))	('THBS2', 'Gene', '7058', (95, 100))	('associated', 'Reg', (32, 42))	('positivity', 'Var', (101, 111))	('THBS2', 'Gene', '7058', (11, 16))	('associated', 'Reg', (116, 126))
32109	32887625	When confounding variables were adjusted with multivariable Cox proportional hazards regression (Additional file 9), positive stromal THBS2 expression was significantly associated with poor DFS (HR 3.95, 95% CI 1.09-14.3; P = 0.037) and tended to be associated with OS (HR 3.34, 95% CI 0.94-11.8; P = 0.062).	('DFS', 'MPA', (190, 193))	('THBS2', 'Gene', (134, 139))	('THBS2', 'Gene', '7058', (134, 139))	('positive', 'Var', (117, 125))	('poor', 'NegReg', (185, 189))	('associated with', 'Reg', (250, 265))
32117	32887625	The TRS consists of different cell types such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages; aberrant lymphatic vasculature; and a remodeled ECM, often with a dense desmoplastic reaction.	('aberrant', 'Var', (120, 128))	('CAFs', 'Disease', 'None', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('CAFs', 'Disease', (80, 84))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
32124	32887625	In pancreatic cancer, THBS2 expression in cancer cells in vitro inhibited invasiveness through downregulation of matrix metalloproteinase-9 and urokinase-type plasminogen activator .	('matrix metalloproteinase-9', 'Gene', (113, 139))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('downregulation', 'NegReg', (95, 109))	('invasiveness', 'CPA', (74, 86))	('expression', 'Var', (28, 38))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('THBS2', 'Gene', '7058', (22, 27))	('urokinase-type plasminogen activator', 'Gene', (144, 180))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('matrix metalloproteinase-9', 'Gene', '4318', (113, 139))	('THBS2', 'Gene', (22, 27))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('urokinase-type plasminogen activator', 'Gene', '5328', (144, 180))	('cancer', 'Disease', (14, 20))	('pancreatic cancer', 'Disease', (3, 20))	('inhibited', 'NegReg', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', (42, 48))
32125	32887625	In contrast, stromal THBS2 expression in pancreatic stellate cells was found to promote cancer cell invasiveness in coculture experiments.	('cancer', 'Disease', (88, 94))	('pancreatic stellate', 'Disease', (41, 60))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('pancreatic stellate', 'Disease', 'MESH:D010195', (41, 60))	('THBS2', 'Gene', (21, 26))	('THBS2', 'Gene', '7058', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('expression', 'Var', (27, 37))	('promote', 'PosReg', (80, 87))
32214	32111094	KRAS mutation occurs in cancers such as pancreatic cancer, cholangiocarcinoma, colorectal cancer, and lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('pancreatic cancer', 'Disease', (40, 57))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (59, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cholangiocarcinoma', 'Disease', (59, 77))	('lung cancer', 'Disease', (102, 113))	('colorectal cancer', 'Disease', (79, 96))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (59, 77))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cancers', 'Disease', (24, 31))	('KRAS', 'Gene', '3845', (0, 4))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (40, 57))	('occurs', 'Reg', (14, 20))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('KRAS', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('pancreatic cancer', 'Disease', 'MESH:D010190', (40, 57))
32260	32111094	EGFR is generally overexpressed or mutated in many solid malignancies and is associated with a poor clinical prognosis.	('mutated', 'Var', (35, 42))	('EGFR', 'Gene', (0, 4))	('overexpressed', 'PosReg', (18, 31))	('malignancies', 'Disease', (57, 69))	('EGFR', 'Gene', '1956', (0, 4))	('malignancies', 'Disease', 'MESH:D009369', (57, 69))
32269	32111094	GEM-implanted tumors exhibited reduced protein levels of EGFR, phospho-EGFR, Ras, PI3K, phospho-PDK, PDK, phospho-AKT, AKT, phospho-mTOR, phospho-GSK3beta, and GSK3beta.	('AKT', 'Gene', '207', (114, 117))	('mTOR', 'Gene', '2475', (132, 136))	('GSK3beta', 'Gene', (146, 154))	('protein levels', 'MPA', (39, 53))	('EGFR', 'Gene', '1956', (71, 75))	('Ras', 'Protein', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('GSK3beta', 'Gene', (160, 168))	('AKT', 'Gene', '207', (119, 122))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('EGFR', 'Gene', (57, 61))	('reduced', 'NegReg', (31, 38))	('GSK3beta', 'Gene', '2931', (146, 154))	('GEM', 'Chemical', '-', (0, 3))	('AKT', 'Gene', (114, 117))	('tumors', 'Disease', (14, 20))	('PDK', 'Protein', (101, 104))	('EGFR', 'Gene', (71, 75))	('mTOR', 'Gene', (132, 136))	('PI3K', 'Protein', (82, 86))	('GSK3beta', 'Gene', '2931', (160, 168))	('EGFR', 'Gene', '1956', (57, 61))	('phospho-PDK', 'Var', (88, 99))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('AKT', 'Gene', (119, 122))
32329	33016889	This model produced average AUCs of 0.8905 and 0.8461, respectively, for DD in the training and testing groups of patients with ECC.	('0.8461', 'Var', (47, 53))	('patients', 'Species', '9606', (114, 122))	('ECC', 'Disease', (128, 131))	('DD', 'Chemical', '-', (73, 75))
32330	33016889	The average AUCs of the LNM in the training and testing groups of patients with ECC were 0.9036 and 0.8889, respectively.	('AUCs', 'MPA', (12, 16))	('0.8889', 'Var', (100, 106))	('0.9036', 'Var', (89, 95))	('patients', 'Species', '9606', (66, 74))
32351	33016889	We retrospectively collected a total of 110 consecutive patients' data (which included 60 men and 50 women) with ECC who underwent radical surgical resection between January 2011 and October 2019 at our hospital (The Affiliated Hospital of Southwest Medical University).	('patients', 'Species', '9606', (56, 64))	('men', 'Species', '9606', (90, 93))	('men', 'Species', '9606', (103, 106))	('ECC', 'Disease', (113, 116))	('October', 'Var', (183, 190))	('women', 'Species', '9606', (101, 106))
32379	33016889	Finally, 30 optimal features were selected from 300 radiomics features of each sequence (T1WI, T2WI, DWI, and ADC, respectively).	('ADC', 'Gene', '34791', (110, 113))	('DWI', 'Disease', (101, 104))	('T2WI', 'Var', (95, 99))	('ADC', 'Gene', (110, 113))
32388	33016889	The min-max algorithm was used to normalize 120 features, including 90 radiomics features from 3 sequences (T1WI, T2WI, and DWI) and 30 ADC values of the tumors, which can eliminate the negative effects caused by different sample dimensions.	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Disease', (154, 160))	('T1WI', 'Var', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('men', 'Species', '9606', (232, 235))	('ADC', 'Gene', '34791', (136, 139))	('T2WI', 'Var', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('ADC', 'Gene', (136, 139))
32392	33016889	The PSO algorithm was used to obtain the optimal penalty parameters c of 7.3607 and g of 0.2132 so as to improve the classification accuracy and the robustness of this prediction model.	('improve', 'PosReg', (105, 112))	('g of 0.2132', 'Var', (84, 95))	('c of 7.3607', 'Var', (68, 79))	('PSO', 'Gene', '51268', (4, 7))	('PSO', 'Gene', (4, 7))
32406	33016889	According to the above calculation results, because the radiology features extracted in each sequence (T1WI, T2WI, DWI, ADC) have satisfactory consistency, no abnormal feature data was found and eliminated.	('ADC', 'Gene', '34791', (120, 123))	('ADC', 'Gene', (120, 123))	('T2WI', 'Var', (109, 113))	('DWI', 'Var', (115, 118))
32416	33016889	Our preliminary findings indicate that the radiological model incorporating the patients' MRI image sequence (T1WI, T2WI, DWI) and ADC values has superior diagnostic performance.	('patients', 'Species', '9606', (80, 88))	('diagnostic', 'MPA', (155, 165))	('DWI', 'Var', (122, 125))	('ADC', 'Gene', (131, 134))	('T2WI', 'Var', (116, 120))	('ADC', 'Gene', '34791', (131, 134))	('T1WI', 'Var', (110, 114))
32417	33016889	In the training and test groups, the average AUC of patients for high, medium, and low DD of ECC were 0.8905 and 0.8461 (the maximum AUC was 0.97), respectively.	('0.8905', 'Var', (102, 108))	('0.8461', 'Var', (113, 119))	('DD', 'Chemical', '-', (87, 89))	('AUC', 'MPA', (45, 48))	('patients', 'Species', '9606', (52, 60))
32418	33016889	The average AUC of patients for LNM of ECC were 0.9036 and 0.8889 (with a maximum AUC of 1.00), respectively.	('0.9036', 'Var', (48, 54))	('0.8889', 'Var', (59, 65))	('patients', 'Species', '9606', (19, 27))
32419	33016889	The entire prediction model has the characteristics of multi-modality and high robustness, which comprehensively considered the radiomics feature of multiple sequences (T1WI, T2WI, DWI, ADC).	('ADC', 'Gene', '34791', (186, 189))	('T2WI', 'Var', (175, 179))	('DWI', 'Var', (181, 184))	('T1WI', 'Var', (169, 173))	('ADC', 'Gene', (186, 189))
32442	33016889	Therefore, another innovation of this study is that we innovatively integrated 90 radiomics features from 3 MRI sequences (T1WI, T2WI, and DWI) and 30 ADC values to improve the prediction accuracy of the PSO-SVM model.	('PSO', 'Gene', '51268', (204, 207))	('ADC', 'Gene', '34791', (151, 154))	('improve', 'PosReg', (165, 172))	('PSO', 'Gene', (204, 207))	('T1WI', 'Var', (123, 127))	('T2WI', 'Var', (129, 133))	('DWI', 'Var', (139, 142))	('ADC', 'Gene', (151, 154))
32452	31028664	Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors Background Mutant isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) enzymes produce the oncometabolite D-2-hydroxyglutarate (2-HG).	('Mutant', 'Var', (156, 162))	('IDH1', 'Gene', '3417', (100, 104))	('patients', 'Species', '9606', (109, 117))	('IDH1', 'Gene', (197, 201))	('IDH1', 'Gene', '3417', (197, 201))	('IDH2', 'Gene', (202, 206))	('tumors', 'Disease', (138, 144))	('mutant', 'Var', (93, 99))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('isocitrate', 'Chemical', 'MESH:C034219', (163, 173))	('2-HG', 'Chemical', 'MESH:C019417', (265, 269))	('IDH1', 'Gene', (100, 104))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (243, 263))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('IDH2', 'Gene', '3418', (202, 206))	('ivosidenib', 'Chemical', 'MESH:C000627630', (50, 60))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
32453	31028664	Ivosidenib (AG-120) is a targeted mutant IDH1 inhibitor under evaluation in a phase 1 dose escalation and expansion study of IDH1-mutant advanced solid tumors including cholangiocarcinoma, chondrosarcoma, and glioma.	('IDH1-mutant', 'Gene', (125, 136))	('chondrosarcoma', 'Disease', (189, 203))	('solid tumors', 'Disease', 'MESH:D009369', (146, 158))	('glioma', 'Disease', 'MESH:D005910', (209, 215))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (189, 203))	('cholangiocarcinoma', 'Disease', (169, 187))	('AG-120', 'Chemical', 'MESH:C000627630', (12, 18))	('glioma', 'Disease', (209, 215))	('solid tumors', 'Disease', (146, 158))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (169, 187))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (169, 187))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('IDH1-mutant', 'Var', (125, 136))	('chondrosarcoma', 'Disease', 'MESH:D002813', (189, 203))
32464	31028664	Mutations in the IDH1 and IDH2 genes are found in multiple hematologic and solid tumors, including acute myeloid leukemia (AML) and glioma.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (99, 121))	('glioma', 'Disease', (132, 138))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('Mutations', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('solid tumors', 'Disease', (75, 87))	('found', 'Reg', (41, 46))	('acute myeloid leukemia', 'Disease', (99, 121))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('leukemia', 'Phenotype', 'HP:0001909', (113, 121))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (105, 121))	('AML', 'Disease', 'MESH:D015470', (123, 126))	('IDH2', 'Gene', (26, 30))	('solid tumors', 'Disease', 'MESH:D009369', (75, 87))	('IDH1', 'Gene', (17, 21))	('IDH2', 'Gene', '3418', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('AML', 'Disease', (123, 126))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (99, 121))
32465	31028664	Mutant IDH enzymes are not catalytically inactive, but rather possess a novel enzymatic activity, catalyzing the reduction of alpha-KG to the oncometabolite D-2-hydroxyglutarate (2-HG).	('IDH', 'Gene', (7, 10))	('2-HG', 'Chemical', 'MESH:C019417', (179, 183))	('alpha-KG to', 'MPA', (126, 137))	('IDH', 'Gene', '3417', (7, 10))	('reduction', 'MPA', (113, 122))	('alpha-KG', 'Chemical', 'MESH:D007656', (126, 134))	('Mutant', 'Var', (0, 6))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (157, 177))
32467	31028664	However, in cells with IDH1/IDH2 mutant enzymes, the accumulation of 2-HG alters a number of downstream cellular activities, causing epigenetic dysregulation and consequently a block in cellular differentiation, leading to tumorigenesis.	('cellular', 'MPA', (186, 194))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('alters', 'Reg', (74, 80))	('tumor', 'Disease', (223, 228))	('IDH2', 'Gene', '3418', (28, 32))	('enzymes', 'Gene', (40, 47))	('2-HG', 'Chemical', 'MESH:C019417', (69, 73))	('causing', 'Reg', (125, 132))	('IDH2', 'Gene', (28, 32))	('mutant', 'Var', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('epigenetic dysregulation', 'MPA', (133, 157))	('block', 'NegReg', (177, 182))	('leading to', 'Reg', (212, 222))
32468	31028664	Ivosidenib (AG-120) is a selective, potent inhibitor of the mutant IDH1 protein.	('protein', 'Protein', (72, 79))	('IDH1', 'Gene', (67, 71))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))	('AG-120', 'Chemical', 'MESH:C000627630', (12, 18))	('mutant', 'Var', (60, 66))
32469	31028664	Preclinical studies showed that treatment with ivosidenib decreased intracellular 2-HG levels in IDH1-mutant AML cells in vitro, and resulted in 2-HG inhibition in tumors in an IDH1-mutant xenograft mouse model.	('mouse', 'Species', '10090', (199, 204))	('ivosidenib', 'Chemical', 'MESH:C000627630', (47, 57))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('AML', 'Disease', 'MESH:D015470', (109, 112))	('2-HG', 'MPA', (145, 149))	('IDH1-mutant', 'Gene', (97, 108))	('decreased', 'NegReg', (58, 67))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('inhibition', 'NegReg', (150, 160))	('AML', 'Disease', (109, 112))	('2-HG', 'Chemical', 'MESH:C019417', (145, 149))	('intracellular 2-HG levels', 'MPA', (68, 93))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('2-HG', 'Chemical', 'MESH:C019417', (82, 86))	('IDH1-mutant', 'Var', (97, 108))
32473	31028664	On the basis of data from that study, ivosidenib received United States Food and Drug Administration (FDA) approval for the treatment of adult patients with R/R AML with a susceptible IDH1 mutation as detected by an FDA-approved test.	('ivosidenib', 'Chemical', 'MESH:C000627630', (38, 48))	('F', 'Chemical', 'MESH:D005461', (102, 103))	('IDH1', 'Gene', (184, 188))	('AML', 'Disease', 'MESH:D015470', (161, 164))	('patients', 'Species', '9606', (143, 151))	('F', 'Chemical', 'MESH:D005461', (216, 217))	('R/R', 'Var', (157, 160))	('F', 'Chemical', 'MESH:D005461', (72, 73))	('AML', 'Disease', (161, 164))
32476	31028664	The primary objective was to assess the safety and tolerability of ivosidenib in patients with advanced solid tumors harboring an IDH1 mutation.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('patients', 'Species', '9606', (81, 89))	('IDH1', 'Gene', (130, 134))	('solid tumors', 'Disease', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('ivosidenib', 'Chemical', 'MESH:C000627630', (67, 77))	('mutation', 'Var', (135, 143))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))
32483	31028664	All patients were required to be at least 18 years of age, and have an advanced solid tumor with an IDH1 mutation, with an expected survival of at least 3 months, and adequate bone marrow, hepatic, and renal function.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutation', 'Var', (105, 113))	('IDH1', 'Gene', (100, 104))	('patients', 'Species', '9606', (4, 12))	('solid tumor', 'Disease', (80, 91))	('solid tumor', 'Disease', 'MESH:D009369', (80, 91))
32530	31028664	The exposure of ivosidenib (Cmax and AUC) generally increased in a less than dose-proportional manner after a single dose ranging from 100 to 1200 mg. At higher dose levels (500, 800, and 900 mg QD), mean AUC0-72h and Cmax in the subgroup of patients with glioma were lower than in the subgroup of patients with non-glioma solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (329, 335))	('Cmax', 'MPA', (218, 222))	('glioma', 'Disease', 'MESH:D005910', (256, 262))	('patients', 'Species', '9606', (298, 306))	('glioma', 'Disease', (256, 262))	('glioma', 'Disease', 'MESH:D005910', (316, 322))	('glioma', 'Phenotype', 'HP:0009733', (316, 322))	('500', 'Var', (174, 177))	('lower', 'NegReg', (268, 273))	('non-glioma solid tumors', 'Disease', 'MESH:D005910', (312, 335))	('AUC0-72h', 'MPA', (205, 213))	('ivosidenib', 'Chemical', 'MESH:C000627630', (16, 26))	('non-glioma solid tumors', 'Disease', (312, 335))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('glioma', 'Phenotype', 'HP:0009733', (256, 262))	('glioma', 'Disease', (316, 322))	('patients', 'Species', '9606', (242, 250))
32540	31028664	The point estimates and 95% CI for slope terms of the power models of AUC0-72h and Cmax after a single dose of ivosidenib on day -3 were 0.455 (95% CI 0.210-0.700) and 0.440 (95% CI 0.233-0.647), respectively, for glioma, and 0.726 (95% CI 0.513-0.938) and 0.625 (95% CI 0.419-0.831), respectively, for non-glioma solid tumors.	('non-glioma solid tumors', 'Disease', (303, 326))	('glioma', 'Disease', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('ivosidenib', 'Gene', (111, 121))	('glioma', 'Disease', (307, 313))	('tumors', 'Phenotype', 'HP:0002664', (320, 326))	('ivosidenib', 'Chemical', 'MESH:C000627630', (111, 121))	('glioma', 'Disease', 'MESH:D005910', (307, 313))	('glioma', 'Phenotype', 'HP:0009733', (307, 313))	('glioma', 'Disease', 'MESH:D005910', (214, 220))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))	('non-glioma solid tumors', 'Disease', 'MESH:D005910', (303, 326))	('0.440', 'Var', (168, 173))
32542	31028664	After multiple administrations of ivosidenib, at cycle 2, day 1, the point estimates and 95% CI for slope terms of the power models for AUC0-tau and Cmax were 0.249 (95% CI -0.109-0.606) and 0.227 (95% CI -0.179-0.634), respectively, for glioma, and 0.402 (95% CI 0.038-0.767) and 0.458 (95% CI 0.151-0.764), respectively, for non-glioma solid tumors.	('non-glioma solid tumors', 'Disease', 'MESH:D005910', (327, 350))	('glioma', 'Disease', (238, 244))	('non-glioma solid tumors', 'Disease', (327, 350))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('glioma', 'Disease', (331, 337))	('0.249', 'Var', (159, 164))	('0.227', 'Var', (191, 196))	('glioma', 'Disease', 'MESH:D005910', (238, 244))	('tumors', 'Phenotype', 'HP:0002664', (344, 350))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('glioma', 'Disease', 'MESH:D005910', (331, 337))	('glioma', 'Phenotype', 'HP:0009733', (331, 337))	('ivosidenib', 'Chemical', 'MESH:C000627630', (34, 44))
32575	31028664	Ivosidenib is mainly metabolized by CYP3A4, and induces CYP3A enzyme activity as suggested by increases in 4beta-OHC:cholesterol ratios.	('4beta-OHC', 'Chemical', '-', (107, 116))	('CYP3A', 'Gene', '1576', (56, 61))	('activity', 'MPA', (69, 77))	('CYP3A', 'Gene', (36, 41))	('4beta-OHC:cholesterol ratios', 'MPA', (107, 135))	('Ivosidenib', 'Var', (0, 10))	('CYP3A4', 'Gene', '1576', (36, 42))	('induces', 'PosReg', (48, 55))	('increases', 'PosReg', (94, 103))	('CYP3A', 'Gene', '1576', (36, 41))	('cholesterol', 'Chemical', 'MESH:D002784', (117, 128))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))	('CYP3A', 'Gene', (56, 61))	('CYP3A4', 'Gene', (36, 42))
32582	31028664	Data from the combined dose escalation and expansion portions confirmed that the dose regimen of 500 mg QD ivosidenib appears appropriate for the treatment of patients with advanced solid tumors with an IDH1 mutation.	('mutation', 'Var', (208, 216))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('ivosidenib', 'Gene', (107, 117))	('ivosidenib', 'Chemical', 'MESH:C000627630', (107, 117))	('solid tumors', 'Disease', (182, 194))	('IDH1', 'Gene', (203, 207))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('solid tumors', 'Disease', 'MESH:D009369', (182, 194))	('patients', 'Species', '9606', (159, 167))
32610	31639067	Changes in the genome often lead to cancer.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('Changes', 'Var', (0, 7))	('lead to', 'Reg', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
32614	31639067	The higher relevance score means that abnormal expression of the gene is more likely to cause malignant tumor production.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('abnormal expression', 'Var', (38, 57))	('malignant tumor', 'Disease', (94, 109))	('malignant tumor', 'Disease', 'MESH:D009369', (94, 109))	('cause', 'Reg', (88, 93))
32667	30939854	Masson's Trichrome-stained livers exhibited a similar pattern of scarring, most pronounced across the hepatobiliary ductal walls with accompanying bridging fibrosis, and a 6 to 7-fold elevation in the blue (collagen) signal in the PCK livers vs. the WT cohort (Figure 5).	('PCK', 'Var', (231, 234))	('to 7', 'Species', '1214577', (174, 178))	('scar', 'Phenotype', 'HP:0100699', (65, 69))	('hepatobiliary', 'Disease', 'MESH:D004066', (102, 115))	('scarring', 'Phenotype', 'HP:0100699', (65, 73))	('hepatobiliary', 'Disease', (102, 115))	('fibrosis', 'Disease', 'MESH:D005355', (156, 164))	('fibrosis', 'Disease', (156, 164))	('elevation', 'PosReg', (184, 193))
32688	30939854	The autosomal recessive Pkhd1 gene mutation in the PCK rat models human ARPKD.	('Pkhd1', 'Gene', (24, 29))	('ARPKD', 'Gene', '5314', (72, 77))	('human', 'Species', '9606', (66, 71))	('mutation', 'Var', (35, 43))	('ARPKD', 'Gene', (72, 77))	('Pkhd1', 'Gene', '301287', (24, 29))	('rat', 'Species', '10116', (55, 58))	('autosomal recessive', 'Disease', (4, 23))
32708	30939854	Cancers were identified using four independent techniques: microscopy by a trained histopathologist, and use of antibodies to Cyokeratin 7, a marker of neoplasms, Ca 19-9, a carbohydrate antigen associated with gastrointestinal cancers, and AFP.	('gastrointestinal cancers', 'Disease', (211, 235))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('neoplasms', 'Disease', (152, 161))	('AFP', 'Gene', (241, 244))	('rat', 'Species', '10116', (182, 185))	('Ca 19-9', 'Var', (163, 170))	('antibodies', 'Var', (112, 122))	('neoplasms', 'Phenotype', 'HP:0002664', (152, 161))	('Cyokeratin 7', 'Gene', (126, 138))	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('associated', 'Reg', (195, 205))	('AFP', 'Gene', '24177', (241, 244))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('rat', 'Species', '10116', (131, 134))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (211, 235))	('neoplasms', 'Disease', 'MESH:D009369', (152, 161))	('carbohydrate antigen', 'Chemical', '-', (174, 194))
32825	24223234	Just like other cancers, it is often associated with inactivation of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancers', 'Disease', (16, 23))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('tumor', 'Disease', (69, 74))	('associated', 'Reg', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('inactivation', 'Var', (53, 65))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
32826	24223234	Genetic mutations in biliary transporter proteins have been linked in childhood onset of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (89, 107))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (89, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (89, 107))	('biliary', 'Protein', (21, 28))	('Genetic mutations', 'Var', (0, 17))	('linked', 'Reg', (60, 66))
32830	24223234	Physical exam revealed anicteric sclerae, soft abdomen with normal bowel sounds, palpable gallbladder and left lobe of the liver, no abdominal tenderness or guarding, no splenomegaly appreciated.	('splenomegaly', 'Disease', 'MESH:D013163', (170, 182))	('splenomegaly', 'Disease', (170, 182))	('anicteric', 'Var', (23, 32))	('abdominal tenderness', 'Disease', (133, 153))	('soft abdomen', 'Disease', (42, 54))	('normal bowel sounds', 'MPA', (60, 79))	('abdominal tenderness', 'Disease', 'None', (133, 153))	('splenomegaly', 'Phenotype', 'HP:0001744', (170, 182))	('bowel sounds', 'Phenotype', 'HP:0030143', (67, 79))
32858	24223234	This clinical sign has been validated in a 2-year prospective cohort study which suggested that the gallbladder volumes measured by MRCP were significantly increased in patients with biliary tract obstruction secondary to neoplasm or stricture compared to the ones caused by choledocholithiasis.	('biliary tract obstruction', 'Phenotype', 'HP:0005230', (183, 208))	('stricture', 'Var', (234, 243))	('biliary tract obstruction', 'Disease', 'MESH:D001661', (183, 208))	('patients', 'Species', '9606', (169, 177))	('MRCP', 'Gene', (132, 136))	('choledocholithiasis', 'Disease', (275, 294))	('biliary tract obstruction', 'Disease', (183, 208))	('increased', 'PosReg', (156, 165))	('neoplasm', 'Phenotype', 'HP:0002664', (222, 230))	('choledocholithiasis', 'Disease', 'MESH:D042883', (275, 294))	('neoplasm', 'Disease', (222, 230))	('neoplasm', 'Disease', 'MESH:D009369', (222, 230))	('gallbladder volumes', 'MPA', (100, 119))
32878	32318579	The modification from the oxidative phosphorylation metabolic pathway to the glycolysis pathway in CCA meets the demands of cancer cell proliferation and provides a favorable environment for tumor development.	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('oxidative phosphorylation metabolic pathway', 'Pathway', (26, 69))	('CCA', 'Disease', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('modification', 'Var', (4, 16))	('men', 'Species', '9606', (204, 207))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('men', 'Species', '9606', (182, 185))	('CCA', 'Phenotype', 'HP:0030153', (99, 102))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('glycolysis pathway', 'Pathway', (77, 95))
32879	32318579	The alteration of metabolic programming in cancer cells is complex and may occur via mutations and epigenetic modifications within oncogenes, tumor suppressor genes, signaling pathways, and glycolytic enzymes.	('epigenetic modifications', 'Var', (99, 123))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('tumor', 'Disease', (142, 147))	('mutations', 'Var', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('occur', 'Reg', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('oncogenes', 'Gene', (131, 140))
32893	32318579	Inborn or acquired defects of the biliary duct in pancreaticobiliary junction allows pancreatic reflux and subsequently leads to chronic cholangitis and increasing risk of CCA.	('cholangitis', 'Disease', (137, 148))	('leads to', 'Reg', (120, 128))	('cholangitis', 'Phenotype', 'HP:0030151', (137, 148))	('CCA', 'Phenotype', 'HP:0030153', (172, 175))	('pancreaticobiliary junction allows pancreatic reflux', 'Disease', 'MESH:D010195', (50, 102))	('defects', 'Var', (19, 26))	('CCA', 'Disease', (172, 175))	('cholangitis', 'Disease', 'MESH:D002761', (137, 148))	('chronic', 'Disease', (129, 136))
32920	32318579	Genetic and epigenetic alterations in oncogenes and tumor suppressor genes may affect cancer metabolism.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('affect', 'Reg', (79, 85))	('tumor', 'Disease', (52, 57))	('epigenetic alterations', 'Var', (12, 34))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Genetic', 'Var', (0, 7))	('cancer metabolism', 'Disease', 'MESH:D009369', (86, 103))	('cancer metabolism', 'Disease', (86, 103))	('oncogenes', 'Gene', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
32921	32318579	Thus, the variations in metabolic activities in the cancer cells are considered as a secondary effect on the cancer development process.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('metabolic activities', 'CPA', (24, 44))	('variations', 'Var', (10, 20))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('men', 'Species', '9606', (123, 126))
32922	32318579	Though tumor cell growth requires more production of the basic cellular macromolecules and metabolites for new cell development and it is well known that changes in tumor cell metabolism aid in cell growth by substantially producing biomolecules.	('tumor', 'Disease', (7, 12))	('changes', 'Var', (154, 161))	('cell growth', 'CPA', (194, 205))	('men', 'Species', '9606', (123, 126))	('producing', 'Reg', (223, 232))	('biomolecules', 'MPA', (233, 245))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('aid', 'PosReg', (187, 190))	('tumor', 'Disease', (165, 170))
32928	32318579	Modifications in oncogenes and tumor suppressors drive unfavorable cell proliferation, and concurrently maintain cellular metabolism to satisfy the biosynthetic burdens of constant cell proliferation.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('unfavorable cell proliferation', 'CPA', (55, 85))	('tumor', 'Disease', (31, 36))	('Modifications', 'Var', (0, 13))	('oncogenes', 'Gene', (17, 26))	('maintain', 'Reg', (104, 112))	('cellular metabolism', 'MPA', (113, 132))
32946	32318579	Cellular stabilization of HIF-1 in normoxia occurs in tumors as an outcome of mutations in the VHL.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('VHL', 'Gene', (95, 98))	('HIF-1', 'Gene', (26, 31))	('VHL', 'Gene', '7428', (95, 98))	('HIF-1', 'Gene', '3091', (26, 31))	('mutations', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
32964	32318579	MiR-218, miR-132 and miR-148a have been reported to inhibit cancer cell proliferation via targeting GLUT1 in bladder, prostate and pancreatic cancer respectively.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('miR-148a', 'Gene', '406940', (21, 29))	('miR-148a', 'Gene', (21, 29))	('bladder', 'Disease', (109, 116))	('prostate', 'Disease', (118, 126))	('MiR-218', 'Var', (0, 7))	('miR-132', 'Gene', '406921', (9, 16))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('pancreatic cancer', 'Disease', 'MESH:D010190', (131, 148))	('targeting', 'Reg', (90, 99))	('cancer', 'Disease', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('pancreatic cancer', 'Disease', (131, 148))	('GLUT1', 'Protein', (100, 105))	('inhibit', 'NegReg', (52, 59))	('cancer', 'Disease', (60, 66))	('miR-132', 'Gene', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
32977	32318579	The reprogramming of glucose metabolism in malignant cells is a multi-factor and multi-step route that can be controlled by carcinogenic signaling processes, and by epigenetic modulations.	('epigenetic', 'Var', (165, 175))	('glucose metabolism', 'Disease', 'MESH:D044882', (21, 39))	('carcinogenic', 'Disease', 'MESH:D063646', (124, 136))	('carcinogenic', 'Disease', (124, 136))	('glucose metabolism', 'Disease', (21, 39))
33016	32280818	All patients with cholangiocarcinoma (biopsy-proven malignancy, or both malignant stricture on cholangiography and cancer antigen 19-9 >100 U/mL) eligible for MRgRT treatment were included without patient selection criteria.	('cancer', 'Disease', (115, 121))	('patient', 'Species', '9606', (197, 204))	('malignancy', 'Disease', 'MESH:D009369', (52, 62))	('cholangiocarcinoma', 'Disease', (18, 36))	('patient', 'Species', '9606', (4, 11))	('malignancy', 'Disease', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('>100 U/mL', 'Var', (135, 144))	('patients', 'Species', '9606', (4, 12))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (18, 36))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (18, 36))
33023	32280818	Normal tissue OAR constraints were set as follows: duodenal loop and stomach V35Gy < 0.5 mL; bowel bag V20Gy < 20 mL; spinal cord and left and right kidneys maximum 12.5 Gy; normal liver >=1000 mL <15 Gy.	('OAR', 'Gene', (14, 17))	('V35Gy', 'Var', (77, 82))	('V20Gy <', 'Var', (103, 110))	('OAR', 'Gene', '4936', (14, 17))
33076	32280818	V35Gy and Dmax are good dosimetric predictors of severe gastroduodenal toxicity, and Dmax >45 Gy and V35Gy >1 mL have been shown to correlate with 50% incidence of late grade >=3 gastroduodenal toxicity (compared with 6% incidence below cutoff values; P = .0015).	('toxicity', 'Disease', (71, 79))	('V35Gy', 'Var', (0, 5))	('Dmax', 'Chemical', '-', (85, 89))	('V35Gy >1 mL', 'Var', (101, 112))	('Dmax', 'Chemical', '-', (10, 14))	('toxicity', 'Disease', 'MESH:D064420', (194, 202))	('toxicity', 'Disease', (194, 202))	('toxicity', 'Disease', 'MESH:D064420', (71, 79))
33224	31555597	Our findings demonstrated that for the ICC patients with low CA19-9, the 1-, 3-, and 5-year OS rates were 77.9, 32.2, and 15.2%, respectively.	('CA19-9', 'Gene', (61, 67))	('patients', 'Species', '9606', (43, 51))	('ICC', 'Disease', (39, 42))	('low', 'Var', (57, 60))	('ICC', 'Disease', 'MESH:C535533', (39, 42))
33299	29666220	In the xenograft study, gemcitabine plus rad001 showed the best therapeutic effect on tumor volume change, and was associated with increased caspase-3 expression, decreased eIF4E expression, as well as overexpression of both death receptor- and mitochondrial apoptotic pathway-related genes.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('increased', 'PosReg', (131, 140))	('expression', 'MPA', (179, 189))	('eIF4E', 'Gene', (173, 178))	('mitochondrial apoptotic pathway-related', 'Pathway', (245, 284))	('caspase-3', 'Protein', (141, 150))	('expression', 'MPA', (151, 161))	('tumor', 'Disease', (86, 91))	('rad001', 'Var', (41, 47))	('gemcitabine', 'Chemical', 'MESH:C056507', (24, 35))	('decreased', 'NegReg', (163, 172))	('overexpression', 'PosReg', (202, 216))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('gemcitabine', 'Var', (24, 35))
33323	29666220	The median effects analysis demonstrated that rad001 and gemcitabine had a synergistic effect on both KRAS mutation (HuCCT1, RBE) and wild-type (TFK-1, YSCCC) cell lines with a combination index (CI)<1 (Fig.	('rad001', 'Var', (46, 52))	('gemcitabine', 'Chemical', 'MESH:C056507', (57, 68))	('KRAS', 'Gene', (102, 106))	('rat', 'Species', '10116', (35, 38))	('KRAS', 'Gene', '3845', (102, 106))
33370	29666220	Specific endogenous metabolites and metabolic fluxes within cells and tissues in vivo and in vitro can be readily identified using 31P, 1H or 13C MRS. Of them, derangement in the choline metabolism during carcinogenesis and treatment has been increasingly recognized in various solid cancers.	('MRS', 'Disease', (146, 149))	('derangement', 'Var', (160, 171))	('carcinogenesis', 'Disease', (205, 219))	('solid cancers', 'Disease', 'MESH:D009369', (278, 291))	('choline', 'Chemical', 'MESH:D002794', (179, 186))	('13C', 'Chemical', '-', (142, 145))	('cancers', 'Phenotype', 'HP:0002664', (284, 291))	('31P', 'Chemical', '-', (131, 134))	('MRS', 'Disease', 'MESH:D008556', (146, 149))	('choline metabolism', 'MPA', (179, 197))	('solid cancers', 'Disease', (278, 291))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('1H', 'Chemical', '-', (136, 138))	('carcinogenesis', 'Disease', 'MESH:D063646', (205, 219))
33384	29666220	reported that blockade of PI3K with LY294002 (a relatively less potent, nonselective inhibitor of PI3K) was associated with a decrease in PC levels as well as an elevation in GPC content in human breast cancer cells.	('LY294002', 'Chemical', 'MESH:C085911', (36, 44))	('PC', 'Chemical', 'MESH:D010767', (138, 140))	('GPC content', 'MPA', (175, 186))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('breast cancer', 'Disease', (196, 209))	('PC levels', 'MPA', (138, 147))	('decrease', 'NegReg', (126, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('LY294002', 'Var', (36, 44))	('human', 'Species', '9606', (190, 195))	('elevation', 'PosReg', (162, 171))	('PC', 'Chemical', 'MESH:D010767', (176, 178))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
33386	29666220	Accordingly, they concluded that the contradictory response of the GPC levels following LY294002 and PI-103 treatments was probably related to other off-target effects of the former inhibitor.	('PI-103', 'Gene', (101, 107))	('LY294002', 'Chemical', 'MESH:C085911', (88, 96))	('PC', 'Chemical', 'MESH:D010767', (68, 70))	('LY294002', 'Var', (88, 96))	('PI-103', 'Chemical', 'MESH:C522973', (101, 107))	('GPC levels', 'MPA', (67, 77))
33393	29666220	The HuCCT1, SSP-25 and RBE cell lines had a KRAS mutation, whereas the remaining three cell lines were KRAS wild type.	('KRAS', 'Gene', (103, 107))	('KRAS', 'Gene', '3845', (103, 107))	('mutation', 'Var', (49, 57))	('KRAS', 'Gene', (44, 48))	('KRAS', 'Gene', '3845', (44, 48))
33403	29666220	Phospho-p38MAPK and phospho-p70S6 kinase were detected by the Bio-Plex phosphoprotein and total protein assay kits (Bio-Rad) according to the manufacturer's protocols.	('phospho-p70S6 kinase', 'Var', (20, 40))	('Rad', 'Gene', '6236', (120, 123))	('Rad', 'Gene', (120, 123))
33434	29666220	Rat Glut-1 (ABI assay ID, Rn01417099), Hk2 (Rn00562457), Hif1a (Rn00577560), Vegf (Rn01511601) and Gapdh (Rn99999916) were designed with Primer Express (ABI/Perkin Elmer) using the GenBank accession number.	('Rn00577560', 'Var', (64, 74))	('Rn01511601', 'Var', (83, 93))	('Rat', 'Species', '10116', (0, 3))	('Rn00562457', 'Var', (44, 54))	('Rn99999916', 'Var', (106, 116))	('Rn01417099', 'Var', (26, 36))
33437	29406621	MiR-433 and miR-22 dysregulations induce HDAC6 overexpression and ciliary loss in cholangiocarcinoma Cholangiocytes normally express primary cilia, a multisensory organelle that detects signals from the cellular environment.	('induce', 'Reg', (34, 40))	('dysregulations', 'Var', (19, 33))	('overexpression', 'PosReg', (47, 61))	('ciliary', 'CPA', (66, 73))	('MiR-433', 'Gene', '574034', (0, 7))	('HDAC6', 'Gene', '10013', (41, 46))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (82, 100))	('primary cilia', 'CPA', (133, 146))	('HDAC6', 'Gene', (41, 46))	('MiR-433', 'Gene', (0, 7))	('loss', 'NegReg', (74, 78))	('miR-22', 'Gene', '407004', (12, 18))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (82, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('miR-22', 'Gene', (12, 18))	('cholangiocarcinoma', 'Disease', (82, 100))
33444	29406621	Conversely, shRNA depletion of Exportin-5 in normal cholangiocytes resulted in increased nuclear retention of precursor miRNAs, decreased mature miRNAs, increased cell proliferation, and shorter cilia.	('increased', 'PosReg', (79, 88))	('Exportin-5', 'Gene', '57510', (31, 41))	('shorter', 'NegReg', (187, 194))	('increased', 'PosReg', (153, 162))	('Exportin-5', 'Gene', (31, 41))	('decreased', 'NegReg', (128, 137))	('depletion', 'Var', (18, 27))	('cell proliferation', 'CPA', (163, 181))	('mature miRNAs', 'MPA', (138, 151))	('nuclear retention', 'MPA', (89, 106))
33513	29406621	To further test the hypothesis, we isolated RNA from nuclear fractions of HuCCT-1 control and Exportin-5 overexpressing cells and found that the nuclear levels of miR-433 precursor forms were reduced upon Exportin-5 overexpression (Figure 4C), suggesting a more efficient export out of the nucleus.	('overexpression', 'Var', (216, 230))	('Exportin-5', 'Gene', '57510', (94, 104))	('miR-433', 'Gene', '574034', (163, 170))	('more', 'PosReg', (257, 261))	('Exportin-5', 'Gene', '57510', (205, 215))	('miR-433', 'Gene', (163, 170))	('Exportin-5', 'Gene', (94, 104))	('reduced', 'NegReg', (192, 199))	('export out', 'MPA', (272, 282))	('Exportin-5', 'Gene', (205, 215))
33521	29406621	Importantly, the downregulation of Exportin-5 induced a decrease in miRNA-433 while increasing the levels of the precursor form (Figure 5D), and, consistent with a nuclear retention of the precursors, the nuclear levels of miRNAs precursor forms were significantly increased upon Exportin-5 knockdown (Figure 5E).	('increasing', 'PosReg', (84, 94))	('levels of the precursor form', 'MPA', (99, 127))	('miRNA-433', 'Gene', (68, 77))	('increased', 'PosReg', (265, 274))	('Exportin-5', 'Gene', '57510', (35, 45))	('miRNA-433', 'Gene', '574034', (68, 77))	('knockdown', 'Var', (291, 300))	('Exportin-5', 'Gene', (35, 45))	('downregulation', 'NegReg', (17, 31))	('Exportin-5', 'Gene', '57510', (280, 290))	('nuclear levels', 'MPA', (205, 219))	('decrease', 'NegReg', (56, 64))	('Exportin-5', 'Gene', (280, 290))
33526	29406621	The loss of primary cilia dysregulates tumorigenic signaling pathways like MAPK and Hh.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('primary cilia', 'Protein', (12, 25))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('MAPK', 'Pathway', (75, 79))	('tumor', 'Disease', (39, 44))	('loss', 'Var', (4, 8))
33529	29406621	Indeed, HDAC6 knockdown in melanoma cells decreased cell growth and colonization.	('decreased', 'NegReg', (42, 51))	('HDAC6', 'Gene', '10013', (8, 13))	('melanoma', 'Disease', (27, 35))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('knockdown', 'Var', (14, 23))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('HDAC6', 'Gene', (8, 13))
33533	29406621	According to the role of their target genes, its aberrant expression functions as tumor suppressors or oncogenes.	('aberrant expression', 'Var', (49, 68))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
33536	29406621	Based on this, Iwaki et al suggested that miR-376c expression is suppressed by HDAC modification and DNA methylation.	('DNA methylation', 'Var', (101, 116))	('suppressed', 'NegReg', (65, 75))	('miR-376c', 'Gene', (42, 50))	('miR-376c', 'Gene', '442913', (42, 50))
33538	29406621	Depletion of Ars2 induces decreased expression of miR-21 and consequent reduction of cell proliferation and invasion rates.	('reduction', 'NegReg', (72, 81))	('cell proliferation', 'CPA', (85, 103))	('invasion rates', 'CPA', (108, 122))	('miR-21', 'Gene', '406991', (50, 56))	('Ars2', 'Gene', (13, 17))	('Depletion', 'Var', (0, 9))	('miR-21', 'Gene', (50, 56))	('decreased', 'NegReg', (26, 35))	('expression', 'MPA', (36, 46))	('Ars2', 'Gene', '51593', (13, 17))
33543	29406621	In agreement with the described mechanism, Melo et al showed that mutations in the Exportin-5 gene is another mechanism to explain deregulated miRNA expressions.	('mutations', 'Var', (66, 75))	('Exportin-5', 'Gene', '57510', (83, 93))	('Exportin-5', 'Gene', (83, 93))	('deregulated miRNA expressions', 'MPA', (131, 160))
33544	29406621	Mutated XPO5 is mainly accumulated in the nucleus of colon-rectal cancer cell lines (HCT-15 and DLD-1) and leads to pre-miRNA being trapped in the nucleus.	('colon-rectal cancer', 'Disease', 'MESH:D012004', (53, 72))	('HCT-15', 'CellLine', 'CVCL:0292', (85, 91))	('colon-rectal cancer', 'Disease', (53, 72))	('XPO5', 'Gene', (8, 12))	('XPO5', 'Gene', '57510', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('leads to', 'Reg', (107, 115))	('rectal cancer', 'Phenotype', 'HP:0100743', (59, 72))	('accumulated', 'PosReg', (23, 34))	('pre-miRNA being trapped', 'MPA', (116, 139))	('Mutated', 'Var', (0, 7))
33546	29406621	Whether XPO5 mutations, as suggested by TCGA database, epigenetic modifications, or other regulatory mechanisms induce the downregulation of Exportin-5 in CCA cells remains to be elucidated.	('Exportin-5', 'Gene', '57510', (141, 151))	('CCA', 'Phenotype', 'HP:0030153', (155, 158))	('XPO5', 'Gene', (8, 12))	('downregulation', 'NegReg', (123, 137))	('XPO5', 'Gene', '57510', (8, 12))	('epigenetic modifications', 'Var', (55, 79))	('Exportin-5', 'Gene', (141, 151))	('mutations', 'Var', (13, 22))
33548	29406621	Additionally, a homozygous single nucleotide polymorphism site on the XPO5 gene in hepatocellular carcinoma patients showed shorter overall survival compared to both wild type and heterozygous SNP genes.	('XPO5', 'Gene', (70, 74))	('XPO5', 'Gene', '57510', (70, 74))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (83, 107))	('overall survival', 'MPA', (132, 148))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (83, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('shorter', 'NegReg', (124, 131))	('hepatocellular carcinoma', 'Disease', (83, 107))	('homozygous single nucleotide polymorphism site', 'Var', (16, 62))	('patients', 'Species', '9606', (108, 116))
33553	29406621	Indeed, consistent with our observations, mature miRNAs are markedly decreased in the cytoplasm and the precursor forms are accumulated in the nucleus of the colorectal cancer cell line HCT116 with XPO5 knockout; however, a significant number of microRNAs are still produced in those cells.	('colorectal cancer', 'Phenotype', 'HP:0003003', (158, 175))	('XPO5', 'Gene', (198, 202))	('colorectal cancer', 'Disease', (158, 175))	('decreased', 'NegReg', (69, 78))	('XPO5', 'Gene', '57510', (198, 202))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('knockout', 'Var', (203, 211))	('HCT116', 'CellLine', 'CVCL:0291', (186, 192))	('colorectal cancer', 'Disease', 'MESH:D015179', (158, 175))	('rectal cancer', 'Phenotype', 'HP:0100743', (162, 175))
33555	29406621	In fact, miR-320, a non-canonical pre-miRNA, is exported by XPO1 and this shuttle involves exporting pri-miRNAs in C. elegans and Drosophila as well as mature miRNAs in mammals.	('miR-320', 'Var', (9, 16))	('XPO1', 'Gene', (60, 64))	('Drosophila', 'Species', '7227', (130, 140))	('C. elegans', 'Species', '6239', (115, 125))	('exporting', 'MPA', (91, 100))	('XPO1', 'Gene', '179160', (60, 64))
33565	28975832	Recent molecular profiling studies have indicated that about 30% to 40% of intrahepatic cholangiocarcinoma cases have actionable mutations.	('mutations', 'Var', (129, 138))	('intrahepatic cholangiocarcinoma', 'Disease', (75, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (75, 106))
33566	28975832	These include fibroblast growth factor receptor (FGFR), isocitrate dehyrogenase 1 (IDH1), epidermal growth factor receptor (EGFR), and BRAF genetic aberrations.	('BRAF', 'Gene', '673', (135, 139))	('IDH1', 'Gene', '3417', (83, 87))	('EGFR', 'Gene', '1956', (124, 128))	('BRAF', 'Gene', (135, 139))	('FGFR', 'Gene', (49, 53))	('isocitrate dehyrogenase 1', 'Gene', (56, 81))	('epidermal growth factor receptor', 'Gene', (90, 122))	('EGFR', 'Gene', (124, 128))	('epidermal growth factor receptor', 'Gene', '1956', (90, 122))	('genetic aberrations', 'Var', (140, 159))	('isocitrate dehyrogenase 1', 'Gene', '3417', (56, 81))	('IDH1', 'Gene', (83, 87))
33567	28975832	Clinical trials targeting these mutations as well as immune therapy using programmed cell death 1 (PD1) inhibitors indicated a promising early signal showing clinical efficacy.	('PD1', 'Gene', '5133', (99, 102))	('mutations', 'Var', (32, 41))	('death', 'Disease', 'MESH:D003643', (90, 95))	('PD1', 'Gene', (99, 102))	('death', 'Disease', (90, 95))
33658	28975832	Next-generation and exome sequencing studies have revealed that 30% to 40% of patients with intrahepatic cholangiocarcinoma have actionable mutations.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (105, 123))	('patients', 'Species', '9606', (78, 86))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (92, 123))	('mutations', 'Var', (140, 149))	('intrahepatic cholangiocarcinoma', 'Disease', (92, 123))
33659	28975832	These include FGFR fusions, IDH, BRAF , and EGFR mutations.	('IDH', 'Gene', (28, 31))	('BRAF', 'Gene', '673', (33, 37))	('mutations', 'Var', (49, 58))	('BRAF', 'Gene', (33, 37))	('IDH', 'Gene', '3417', (28, 31))	('fusions', 'Var', (19, 26))	('FGFR', 'Gene', (14, 18))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))
33663	28975832	Both KRAS and TP53 mutations are associated with an aggressive disease prognosis, while FGFR mutations may signify a relatively indolent disease course of intrahepatic cholangiocarcinoma.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('mutations', 'Var', (93, 102))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (155, 186))	('KRAS', 'Gene', (5, 9))	('mutations', 'Var', (19, 28))	('KRAS', 'Gene', '3845', (5, 9))	('intrahepatic cholangiocarcinoma', 'Disease', (155, 186))	('associated', 'Reg', (33, 43))	('aggressive disease', 'Disease', 'MESH:D001523', (52, 70))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (168, 186))	('aggressive disease', 'Disease', (52, 70))
33664	28975832	During this time, FGFR and IDH mutations have promising agents in clinical trials.	('IDH', 'Gene', '3417', (27, 30))	('IDH', 'Gene', (27, 30))	('FGFR', 'Gene', (18, 22))	('mutations', 'Var', (31, 40))
33665	28975832	An estimated 10% to 15% of cholangiocarcinomas have DNA repair mutations and may be candidates for immune therapies with checkpoint inhibitors.	('mutations', 'Var', (63, 72))	('DNA repair', 'Gene', (52, 62))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (27, 46))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (27, 45))	('cholangiocarcinomas', 'Disease', (27, 46))
33668	28975832	In gastrointestinal malignancies, tumors with microsatellite instability carry a heavy burden of neoantigens, and immunotherapy is very successful in this setting.	('tumors', 'Disease', (34, 40))	('neoantigens', 'MPA', (97, 108))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('microsatellite instability', 'Var', (46, 72))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (3, 32))	('gastrointestinal malignancies', 'Disease', (3, 32))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
33669	28975832	Tran et al used a whole-exomic-sequencing-based approach to demonstrate that tumor-infiltrating lymphocytes (TILs) from a patient with metastatic cholangiocarcinoma contained CD4+ T-helper 1 (TH1) cells that recognize a mutation in ERBB2-interacting protein.	('ERBB2', 'Gene', (232, 237))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (146, 164))	('ERBB2', 'Gene', '2064', (232, 237))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (146, 164))	('patient', 'Species', '9606', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cholangiocarcinoma', 'Disease', (146, 164))	('mutation', 'Var', (220, 228))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
33670	28975832	After adoptive transfer of TILs containing mutation-specific polyfunctional TH1 cells, the patient achieved prolonged partial response.	('TH1', 'Gene', (76, 79))	('patient', 'Species', '9606', (91, 98))	('partial response', 'MPA', (118, 134))	('mutation-specific polyfunctional', 'Var', (43, 75))
33671	28975832	Upon disease progression, the patient was retreated with mutation-reactive TH1 cells and again experienced tumor regression.	('patient', 'Species', '9606', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('mutation-reactive', 'Var', (57, 74))
33672	28975832	These results provide evidence that a CD4+ T-cell response against a mutated antigen can lead to tumor regression.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('CD4+', 'Var', (38, 42))	('mutated', 'Var', (69, 76))	('lead to', 'Reg', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))
33673	28975832	Identification of immunogenic epitopes in the mutations seen in cholangiocarcinoma will be key to success with checkpoint inhibitors.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (64, 82))	('cholangiocarcinoma', 'Disease', (64, 82))	('mutations', 'Var', (46, 55))
33675	28975832	Peptides from the mutated region induce a CD4+ immune response that can potentially be exploited by mutation-specific anti-IDH1 (R132 H) vaccines.	('R132 H', 'Mutation', 'rs121913500', (129, 135))	('Peptides', 'Var', (0, 8))	('IDH1', 'Gene', (123, 127))	('CD4+ immune response', 'MPA', (42, 62))	('IDH1', 'Gene', '3417', (123, 127))
33678	28975832	Recent results with pembrolizumab in pretreated biliary tract cancers having PDL1 expression indicated that 17% of patients have a meaningful response to checkpoint blockade.	('patients', 'Species', '9606', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('PDL1', 'Gene', (77, 81))	('biliary tract cancers', 'Disease', 'MESH:D001661', (48, 69))	('biliary tract cancers', 'Disease', (48, 69))	('expression', 'Var', (82, 92))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('pembrolizumab', 'Chemical', 'MESH:C582435', (20, 33))	('PDL1', 'Gene', '29126', (77, 81))
33723	33739801	It was presumed that anastomosis of small mesenteric vascular branches would reduce portal hypertension and related complications because of their smaller calibre (2-5 mm).	('reduce', 'NegReg', (77, 83))	('hypertension', 'Disease', (91, 103))	('mesenteric vascular branches', 'Phenotype', 'HP:0011934', (42, 70))	('anastomosis', 'Var', (21, 32))	('hypertension', 'Phenotype', 'HP:0000822', (91, 103))	('portal hypertension', 'Phenotype', 'HP:0001409', (84, 103))	('small mesenteric vascular', 'Phenotype', 'HP:0011934', (36, 61))	('hypertension', 'Disease', 'MESH:D006973', (91, 103))
33742	33739801	Anastomosis of small mesenteric vascular branches was expected to reduce portal hypertension, but this complication occurred in 7 (35%) of 20 patients with mesenteric vascular branch anastomosis and in 5 (14%) of 35 patients with celiac trunk branch anastomosis.	('portal hypertension', 'Phenotype', 'HP:0001409', (73, 92))	('hypertension', 'Phenotype', 'HP:0000822', (80, 92))	('vascular branch anastomosis', 'Disease', 'MESH:C563598', (167, 194))	('celiac trunk', 'Phenotype', 'HP:0012327', (230, 242))	('hypertension', 'Disease', (80, 92))	('patients', 'Species', '9606', (216, 224))	('small mesenteric vascular', 'Phenotype', 'HP:0011934', (15, 40))	('hypertension', 'Disease', 'MESH:D006973', (80, 92))	('reduce', 'NegReg', (66, 72))	('patients', 'Species', '9606', (142, 150))	('vascular branch anastomosis', 'Disease', (167, 194))	('mesenteric vascular branches', 'Phenotype', 'HP:0011934', (21, 49))	('celiac trunk branch anastomosis', 'Disease', 'MESH:D000074742', (230, 261))	('Anastomosis', 'Var', (0, 11))	('celiac trunk branch anastomosis', 'Disease', (230, 261))
33758	33739801	Furthermore, PVA results in less hypoxic liver damage than total liver de-arterialization.	('PVA', 'Phenotype', 'HP:0030242', (13, 16))	('hypoxic liver damage', 'Disease', 'MESH:D056486', (33, 53))	('hypoxic liver damage', 'Disease', (33, 53))	('PVA', 'Var', (13, 16))	('less', 'NegReg', (28, 32))
33759	33739801	Moreover, cholestasis, bile duct injury, inflammation, energy state due to elevation in ATP content, hypoxia and hypoxia-associated gene changes were reported to be decreased with PVA compared to liver de-arterialization without reconstruction.	('decreased', 'NegReg', (165, 174))	('ATP', 'Chemical', 'MESH:D000255', (88, 91))	('hypoxia', 'Disease', (101, 108))	('hypoxia', 'Disease', 'MESH:D000860', (113, 120))	('cholestasis', 'Phenotype', 'HP:0001396', (10, 21))	('bile duct injury', 'Disease', (23, 39))	('elevation', 'PosReg', (75, 84))	('hypoxia', 'Disease', (113, 120))	('bile duct injury', 'Disease', 'MESH:D002779', (23, 39))	('ATP content', 'MPA', (88, 99))	('cholestasis', 'Disease', 'MESH:D002779', (10, 21))	('PVA', 'Phenotype', 'HP:0030242', (180, 183))	('inflammation', 'Disease', 'MESH:D007249', (41, 53))	('energy state', 'MPA', (55, 67))	('PVA', 'Var', (180, 183))	('cholestasis', 'Disease', (10, 21))	('hypoxia', 'Disease', 'MESH:D000860', (101, 108))	('inflammation', 'Disease', (41, 53))
33766	33739801	This is supported by the findings of Kondo and colleagues, who reported that arterioportal shunting of the de-arterialized liver increased oxygen saturation in bile ducts from 28% to 57%.	('oxygen saturation in bile ducts', 'MPA', (139, 170))	('arterioportal', 'Var', (77, 90))	('oxygen', 'Chemical', 'MESH:D010100', (139, 145))	('increased', 'PosReg', (129, 138))
33775	33739801	If the proximal segment of the hepatic artery is obstructed, intrahepatic translobar collaterals provide flow to the interrupted system.	('men', 'Species', '9606', (19, 22))	('obstructed', 'Var', (49, 59))	('flow', 'MPA', (105, 109))
33781	33739801	In patients with acute obstruction or resection of the hepatic artery, there is not enough time for formation of collateral arteries, and, therefore, the liver is more vulnerable to hypoxic damage.	('hypoxic damage', 'Disease', 'MESH:D002534', (182, 196))	('acute obstruction', 'Disease', 'MESH:D059787', (17, 34))	('patients', 'Species', '9606', (3, 11))	('resection', 'Var', (38, 47))	('hypoxic damage', 'Disease', (182, 196))	('acute obstruction', 'Disease', (17, 34))
33879	33155663	The sections were then incubated with primary antibodies against: HVEM (1:100), LC-3 (1:200) and p62 (1:200), at 4 C overnight.	('LC-3', 'Gene', '84557', (80, 84))	('HVEM', 'Gene', '8764', (66, 70))	('1:200', 'Var', (102, 107))	('HVEM', 'Gene', (66, 70))	('p62', 'Gene', '23636', (97, 100))	('p62', 'Gene', (97, 100))	('1:200', 'Var', (86, 91))	('LC-3', 'Gene', (80, 84))	('1:100', 'Var', (72, 77))
33923	33155663	Consistent with this, a significantly higher rate of cell apoptosis was detected in RBE cells in the CQ treatment group compared with that in the control group (Fig.	('CQ treatment', 'Var', (101, 113))	('cell apoptosis', 'CPA', (53, 67))	('CQ', 'Chemical', 'MESH:D002738', (101, 103))
33931	33155663	Then, LC3 and p62 expression levels were also detected in RBE cells treated with both IL-6 and compound C. Compared with IL-6-treated alone group, autophagic activity was significantly decreased in both the IL-6 and compound C-treated group (Fig.	('IL-6', 'Gene', (207, 211))	('decreased', 'NegReg', (185, 194))	('LC3', 'Gene', '84557', (6, 9))	('IL-6', 'Gene', '3569', (207, 211))	('IL-6', 'Gene', '3569', (121, 125))	('IL-6', 'Gene', '3569', (86, 90))	('p62', 'Gene', '23636', (14, 17))	('LC3', 'Gene', (6, 9))	('detected', 'Reg', (46, 54))	('autophagic activity', 'CPA', (147, 166))	('p62', 'Gene', (14, 17))	('compound C.', 'Var', (95, 106))	('IL-6', 'Gene', (121, 125))	('IL-6', 'Gene', (86, 90))
33940	33155663	Patients with high IL-6 levels were likely to have significantly poorer survival rate than those with low IL-6 levels (Fig.	('IL-6', 'Gene', (19, 23))	('poorer', 'NegReg', (65, 71))	('IL-6', 'Gene', (106, 110))	('survival rate', 'CPA', (72, 85))	('IL-6', 'Gene', '3569', (19, 23))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('IL-6', 'Gene', '3569', (106, 110))
33974	32059704	The current proposed phase III GAIN study investigates whether induction chemotherapy followed by radical resection in ICC/ECC and re-resection in IGBC (and - if possible - postoperative chemotherapy) prolongs overall survival compared to radical surgery alone for incidental gallbladder carcinoma and primary resectable or borderline resectable cholangiocarcinoma.	('overall survival', 'MPA', (210, 226))	('gallbladder carcinoma', 'Disease', (276, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (355, 364))	('prolongs', 'PosReg', (201, 209))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (346, 364))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (346, 364))	('ICC', 'Disease', (119, 122))	('re-resection', 'Var', (131, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (276, 297))	('cholangiocarcinoma', 'Disease', (346, 364))	('ICC', 'Disease', 'MESH:C535533', (119, 122))	('IGBC', 'Gene', (147, 151))
33988	32059704	Stage adjusted therapy according to the NCCN-, ESMO- and German S3- Guidelines contains liver resection combined with dissection of the regional lymph nodes along the hepatoduodenal ligament in cases of T1b, or more advanced carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('T1b', 'Var', (203, 206))	('carcinomas', 'Phenotype', 'HP:0030731', (225, 235))	('carcinomas', 'Disease', 'MESH:D002277', (225, 235))	('carcinomas', 'Disease', (225, 235))
34004	32059704	Neoadjuvant chemotherapy with gemcitabine plus cisplatin will be administered for 3 cycles preoperatively followed by radical liver resection versus immediate radical liver resection alone with or without adjuvant chemotherapy (investigator's choice) in incidentally detected T2-3N- or pT1-3 N+ gallbladder carcinoma after simple cholecystectomy or in front of radical resection of Biliary Tract Cancer (ICC/ECC).	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (295, 316))	('Biliary Tract Cancer', 'Disease', 'MESH:D001661', (382, 402))	('ICC', 'Disease', (404, 407))	('T2-3N-', 'Var', (276, 282))	('gallbladder carcinoma', 'Disease', (295, 316))	('pT1', 'Gene', (286, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (307, 316))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('Biliary Tract Cancer', 'Phenotype', 'HP:0100574', (382, 402))	('ICC', 'Disease', 'MESH:C535533', (404, 407))	('gemcitabine', 'Chemical', 'MESH:C056507', (30, 41))	('Cancer', 'Phenotype', 'HP:0002664', (396, 402))	('Biliary Tract Cancer', 'Disease', (382, 402))	('pT1', 'Gene', '58492', (286, 289))
34018	32059704	Histologically confirmed incidental gallbladder carcinoma (IGBC) (T2-3N- or T1-3N+ after Cholecystectomy) or Biliary tract cancer (BTC) (intrahepatic, hilar or distal Cholangiocarcinoma (CCA)) scheduled for complete resection (mixed tumor entities with hepatocellular carcinoma are excluded).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('BTC', 'Disease', 'MESH:D001661', (131, 134))	('Biliary tract cancer', 'Disease', 'MESH:D001661', (109, 129))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (36, 57))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (253, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('gallbladder carcinoma', 'Disease', (36, 57))	('BTC', 'Phenotype', 'HP:0100574', (131, 134))	('tumor', 'Disease', (233, 238))	('Biliary tract cancer', 'Phenotype', 'HP:0100574', (109, 129))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('hepatocellular carcinoma', 'Disease', (253, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (167, 185))	('CCA', 'Phenotype', 'HP:0030153', (187, 190))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (167, 185))	('Cholangiocarcinoma', 'Disease', (167, 185))	('CCA', 'Disease', 'MESH:D018281', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('Biliary tract cancer', 'Disease', (109, 129))	('BTC', 'Disease', (131, 134))	('CCA', 'Disease', (187, 190))	('T2-3N- or T1-3N+', 'Var', (66, 82))	('T1-3N+', 'Var', (76, 82))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (253, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
34129	31016414	Moreover, immunopathological examination also revealed that gammaH2AX expression, which is a marker of double-strand DNA injuries, was detected at various sites of the large bile ducts, including the non-neoplastic bile ducts; S100P expression was detected in cholangiocarcinoma as well as premalignant or early malignant lesions, such as BilIN and IPNB, as previously reported.	('S100P', 'Gene', '6286', (227, 232))	('detected', 'Reg', (248, 256))	('IPNB', 'Disease', (349, 353))	('S100P', 'Gene', (227, 232))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (260, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('IPNB', 'Chemical', '-', (349, 353))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (260, 278))	('gammaH2AX', 'Chemical', '-', (60, 69))	('BilIN', 'Disease', (339, 344))	('gammaH2AX', 'Var', (60, 69))	('large bile ducts', 'Phenotype', 'HP:0006560', (168, 184))	('BilIN', 'Chemical', '-', (339, 344))	('cholangiocarcinoma', 'Disease', (260, 278))
34227	29019563	This change has also been observed in the literature: the largest proportion of the resections at the beginning of the LH era consisted of sectionectomy or bisectionectomy, especially of segments II, III, IVB, V and VI7.	('LH', 'Chemical', '-', (119, 121))	('bisectionectomy', 'Disease', (156, 171))	('men', 'Species', '9606', (190, 193))	('sectionectomy', 'Var', (139, 152))
34237	29019563	These drugs are known to be hepatotoxic, given that they lead to steatohepatitis ("yellow-liver") and sinusoidal hypertension ("blue-liver"), respectively.	('hypertension', 'Disease', (113, 125))	('drugs', 'Var', (6, 11))	('hypertension', 'Phenotype', 'HP:0000822', (113, 125))	('hepatotoxic', 'Disease', (28, 39))	('steatohepatitis', 'Disease', (65, 80))	('lead to', 'Reg', (57, 64))	('steatohepatitis', 'Disease', 'MESH:D005234', (65, 80))	('hepatotoxic', 'Disease', 'MESH:D056486', (28, 39))	('hypertension', 'Disease', 'MESH:D006973', (113, 125))
34259	27608843	To further explore the biological effects of DKK1 in HCCA, transient and stable knockdown of DKK1 in two human HCCA cells (QBC939 and FRH0201) were established using small interfering or short hairpin RNA expression vector.	('knockdown', 'Var', (80, 89))	('HCC', 'Phenotype', 'HP:0001402', (111, 114))	('HCC', 'Phenotype', 'HP:0001402', (53, 56))	('DKK1', 'Gene', (93, 97))	('human', 'Species', '9606', (105, 110))
34263	27608843	Subsequent investigations revealed that beta-catenin is an important target of DKK1 and DKK1 exerts its pro-invasion function at least in part through the beta-catenin/ matrix metalloproteinase-7 (MMP-7) signaling pathway.	('beta-catenin', 'Gene', (155, 167))	('MMP-7', 'Gene', (197, 202))	('matrix metalloproteinase-7', 'Gene', '4316', (169, 195))	('matrix metalloproteinase-7', 'Gene', (169, 195))	('pro-invasion function', 'CPA', (104, 125))	('beta-catenin', 'Gene', '1499', (155, 167))	('MMP-7', 'Gene', '4316', (197, 202))	('DKK1', 'Var', (79, 83))	('beta-catenin', 'Gene', (40, 52))	('beta-catenin', 'Gene', '1499', (40, 52))	('DKK1', 'Gene', (88, 92))
34278	27608843	demonstrated that high expression of DKK1 is related to lymphatic metastasis and is indicative of a poor prognosis in intrahepatic cholangiocarcinoma (ICC) patients after surgery.	('patients', 'Species', '9606', (156, 164))	('DKK1', 'Gene', (37, 41))	('intrahepatic cholangiocarcinoma', 'Disease', (118, 149))	('lymphatic metastasis', 'CPA', (56, 76))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (118, 149))	('high', 'Var', (18, 22))	('related', 'Reg', (45, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))
34283	27608843	In general, high DKK1 expression (++ or +++) was observed in 24 of 37 tumor samples (64.9%; Figure 1C-1D), whereas low DKK1 expression (- or +) was noted in 13 of 37 tumor samples (35.1%; Figure 1A-1B).	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('DKK1', 'Gene', (17, 21))	('C-1D', 'Gene', (100, 104))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (166, 171))	('++ or +++', 'Var', (34, 43))	('C-1D', 'Gene', '10438', (100, 104))	('expression', 'MPA', (22, 32))
34286	27608843	A colony formation assay, based on crystal violet staining, revealed that fewer colonies were found in the DKK1-shRNA-treated QBC939 and FRH0201 cells compared to the control(Figure 2C).	('fewer', 'NegReg', (74, 79))	('DKK1-shRNA-treated', 'Var', (107, 125))	('crystal violet', 'Chemical', 'MESH:D005840', (35, 49))	('colonies', 'CPA', (80, 88))
34288	27608843	To this end, both DKK1-shRNA tumor cells and control cells were implanted subcutaneously into nude mice, and the resulting tumor was measured.	('DKK1-shRNA', 'Var', (18, 28))	('nude mice', 'Species', '10090', (94, 103))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
34297	27608843	Consistently, Western blotting indicated that DKK1-shRNA inhibited beta-catenin expression in QBC939 and FRH0201 cells compared with control cells (Figure 4C).	('inhibited', 'NegReg', (57, 66))	('DKK1-shRNA', 'Var', (46, 56))	('beta-catenin', 'Gene', '1499', (67, 79))	('beta-catenin', 'Gene', (67, 79))
34298	27608843	Most importantly, the expression of nuclear beta-catenin was impaired by DKK1-shRNA in QBC939 and FRH0201 cells (Figure 4D).	('DKK1-shRNA', 'Var', (73, 83))	('beta-catenin', 'Gene', (44, 56))	('impaired', 'NegReg', (61, 69))	('beta-catenin', 'Gene', '1499', (44, 56))	('expression', 'MPA', (22, 32))
34305	27608843	Consistently, as shown in Figure 4C, the introduction of shRNA-DKK1 remarkably decreased MMP-7 protein levels in QBC939 and FRH0201 cells.	('decreased', 'NegReg', (79, 88))	('MMP-7', 'Gene', (89, 94))	('shRNA-DKK1', 'Gene', (57, 67))	('MMP-7', 'Gene', '4316', (89, 94))	('introduction', 'Var', (41, 53))
34307	27608843	DKK1 binds to LRP5/6 and dysregulation its interaction with Wnt, resulting in beta-catenin degradation.	('LRP5/6', 'Gene', (14, 20))	('DKK1', 'Gene', (0, 4))	('LRP5/6', 'Gene', '4041;4040', (14, 20))	('binds', 'Interaction', (5, 10))	('dysregulation', 'Var', (25, 38))	('beta-catenin', 'Gene', (78, 90))	('beta-catenin', 'Gene', '1499', (78, 90))	('interaction', 'Interaction', (43, 54))
34311	27608843	Most importantly, implantation of DKK1-shRNA HCCA cells into nude mice impaired their tumor formation capacity in vivo.	('HCC', 'Phenotype', 'HP:0001402', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('impaired', 'NegReg', (71, 79))	('nude mice', 'Species', '10090', (61, 70))	('DKK1-shRNA', 'Var', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
34322	27608843	In addition, the expression of beta-catenin and nuclear beta-catenin were dramatically decreased in DKK1-shRNA QBC939 and FRH0201 cells.	('beta-catenin', 'Gene', (31, 43))	('decreased', 'NegReg', (87, 96))	('beta-catenin', 'Gene', '1499', (31, 43))	('beta-catenin', 'Gene', (56, 68))	('expression', 'MPA', (17, 27))	('beta-catenin', 'Gene', '1499', (56, 68))	('DKK1-shRNA', 'Var', (100, 110))
34330	27608843	DKK1-shRNA markedly decreased beta-catenin and MMP-7 protein levels in QBC939 and FRH0201 cells.	('beta-catenin', 'Gene', '1499', (30, 42))	('MMP-7', 'Gene', (47, 52))	('decreased', 'NegReg', (20, 29))	('MMP-7', 'Gene', '4316', (47, 52))	('beta-catenin', 'Gene', (30, 42))	('DKK1-shRNA', 'Var', (0, 10))
34344	27608843	Western blot analyses were performed as described, protein lysates obtained from the cultured cells were subjected to sodiumdodecylsulfate-polyacrylamidegelelectrophoresis (SDS-PAGE) and were probed with primary antibodies recognizing DKK1 (1:2000), beta-catenin (1:5000) and MMP-7(1:5000).	('MMP-7', 'Gene', '4316', (276, 281))	('SDS', 'Chemical', 'MESH:D012967', (173, 176))	('1:5000', 'Var', (264, 270))	('sodiumdodecylsulfate', 'Chemical', 'MESH:D012967', (118, 138))	('beta-catenin', 'Gene', (250, 262))	('MMP-7', 'Gene', (276, 281))	('DKK1', 'Protein', (235, 239))	('beta-catenin', 'Gene', '1499', (250, 262))
34503	18274843	(2) According to a report on 53 patients with hilar cholangiocarcinoma by Hemming et al., in the group in whom hypertrophy of the future liver remnant was caused by obstruction of the portal vein branch, due to its embolization or cancers, postoperative mortality (3%) was lower than that (21%) in the group without hypertrophy (level IV).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (52, 70))	('patients', 'Species', '9606', (32, 40))	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (46, 70))	('hilar cholangiocarcinoma', 'Disease', (46, 70))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('obstruction', 'Var', (165, 176))	('cancers', 'Disease', (231, 238))	('hypertrophy', 'Disease', (316, 327))	('hypertrophy', 'Disease', 'MESH:D006984', (316, 327))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('hypertrophy', 'Disease', (111, 122))	('hypertrophy', 'Disease', 'MESH:D006984', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('lower', 'NegReg', (273, 278))
34545	18274843	Although the prognosis was significantly poorer in patients with combined vascular resection, it was better compared with that in unresectable patients.	('poorer', 'NegReg', (41, 47))	('patients', 'Species', '9606', (51, 59))	('combined', 'Var', (65, 73))	('patients', 'Species', '9606', (143, 151))
34614	18274843	Knox and Kingston reported, in their case-series study (level IV), that the survival rate after local resection was slightly better than that after PD.	('survival', 'CPA', (76, 84))	('PD', 'Disease', 'MESH:D010300', (148, 150))	('local resection', 'Var', (96, 111))
34618	18274843	(level IV) reported that local resection was indicated for adenoma or T1N0 tumors, whereas Paramythiotis et al.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('adenoma', 'Disease', 'MESH:D000236', (59, 66))	('T1N0', 'Var', (70, 74))	('adenoma', 'Disease', (59, 66))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))
34620	18274843	(level IV) reported that carcinoma was found in 26% of resected patients with a preoperative diagnosis of papillary adenoma, thus concluding that patients with pTis, pT1, N0, M0, G1, or G2 disease were indicated for limited surgery and that local lymph node dissection should be performed for these patients.	('pT1', 'Gene', '58492', (166, 169))	('patients', 'Species', '9606', (64, 72))	('pTis', 'Var', (160, 164))	('carcinoma', 'Disease', (25, 34))	('papillary adenoma', 'Disease', 'MESH:D000236', (106, 123))	('pT1', 'Gene', (166, 169))	('patients', 'Species', '9606', (299, 307))	('papillary adenoma', 'Disease', (106, 123))	('patients', 'Species', '9606', (146, 154))	('carcinoma', 'Disease', 'MESH:D002277', (25, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('G2 disease', 'Var', (186, 196))
34636	29863124	Whole-exome analysis of the cancerous tissues showed hypermutation, substantial strand bias, and unique trinucleotide mutational changes.	('trinucleotide mutational changes', 'Var', (104, 136))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancerous', 'Disease', 'MESH:D009369', (28, 37))	('hypermutation', 'Var', (53, 66))	('strand', 'MPA', (80, 86))	('trinucleotide', 'Chemical', '-', (104, 117))	('cancerous', 'Disease', (28, 37))
34668	29863124	Whole-exome analyses of surgical specimens from four patients with occupational CCA showed an average of 44.8 somatic mutations per Mb in the genome of the CCA tissues; the frequency of somatic mutations was approximately 30-fold higher than that of control common CCA tissues.18 Predominate mutations included C:G-to-T:A transitions with substantial strand bias, and unique trinucleotide mutational changes of GpCpY to GpTpY and NpCpY to NpTpY or NpApY in all of the occupational CCA genomes.	('mutations', 'Var', (292, 301))	('men', 'Species', '9606', (38, 41))	('trinucleotide mutational changes', 'Var', (375, 407))	('patients', 'Species', '9606', (53, 61))	('C:G-to-T', 'Var', (311, 319))	('trinucleotide', 'Chemical', '-', (375, 388))	('GpCpY', 'MPA', (411, 416))
34686	29863124	Whole-exome analysis of the CCA tissues showed hypermutation, C:G-to-T:A transitions with substantial strand bias, and unique trinucleotide mutational changes.	('CCA', 'Disease', (28, 31))	('trinucleotide', 'Chemical', '-', (126, 139))	('hypermutation', 'MPA', (47, 60))	('C:G-to-T', 'Var', (62, 70))	('trinucleotide mutational changes', 'Var', (126, 158))	('strand bias', 'MPA', (102, 113))
34750	27919744	There is strong evidence that H. pylori seropositivity and biliary tract cancer with overall OR 5.47 and, specifically, for extrahepatic (OR 7.01) and intrahepatic cancer (OR 10.67) but not for hepatocellular carcinoma in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) cohort.	('ATBC', 'Chemical', '-', (277, 281))	('Beta-Carotene Cancer', 'Disease', (244, 264))	('extrahepatic', 'Disease', (124, 136))	('H. pylori', 'Disease', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (194, 218))	('biliary tract cancer', 'Disease', (59, 79))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (33, 54))	('Alpha-Tocopherol', 'Chemical', 'MESH:D024502', (226, 242))	('H. pylori', 'Species', '210', (30, 39))	('seropositivity', 'Var', (40, 54))	('intrahepatic cancer', 'Disease', 'MESH:D002780', (151, 170))	('intrahepatic cancer', 'Disease', (151, 170))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (194, 218))	('Beta-Carotene Cancer', 'Disease', 'MESH:D009369', (244, 264))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (59, 79))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Cancer', 'Phenotype', 'HP:0002664', (258, 264))	('hepatocellular carcinoma', 'Disease', (194, 218))	('biliary tract cancer', 'Disease', 'MESH:D001661', (59, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))
34751	27919744	For liver fibrosis, prevalence of cagA H. pylori was directly proportional to severity of liver disease and was more positive in advanced stages of fibrosis (28.2%) compared to early stages (5.9%) in HCV-related chronic hepatitis and cirrhosis.	('liver fibrosis', 'Disease', (4, 18))	('H. pylori', 'Species', '210', (39, 48))	('fibrosis', 'Disease', 'MESH:D005355', (10, 18))	('fibrosis', 'Disease', (10, 18))	('cirrhosis', 'Disease', 'MESH:D005355', (234, 243))	('cagA', 'Var', (34, 38))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (212, 229))	('hepatitis', 'Phenotype', 'HP:0012115', (220, 229))	('liver fibrosis', 'Disease', 'MESH:D008103', (4, 18))	('liver disease', 'Phenotype', 'HP:0001392', (90, 103))	('cirrhosis', 'Phenotype', 'HP:0001394', (234, 243))	('hepatitis', 'Disease', 'MESH:D056486', (220, 229))	('liver disease', 'Disease', 'MESH:D008107', (90, 103))	('cirrhosis', 'Disease', (234, 243))	('hepatitis', 'Disease', (220, 229))	('liver disease', 'Disease', (90, 103))	('liver fibrosis', 'Phenotype', 'HP:0001395', (4, 18))	('positive', 'Reg', (117, 125))	('fibrosis', 'Disease', 'MESH:D005355', (148, 156))	('fibrosis', 'Disease', (148, 156))
34777	27919744	Similarly, significant higher frequencies of cagA-positive H. pylori have been reported during CCA than cholelithiasis and in bile from healthy individuals.	('H. pylori', 'Species', '210', (59, 68))	('cholelithiasis', 'Disease', 'MESH:D002769', (104, 118))	('CCA', 'Disease', (95, 98))	('higher', 'PosReg', (23, 29))	('cagA-positive', 'Var', (45, 58))	('cholelithiasis', 'Phenotype', 'HP:0001081', (104, 118))	('cholelithiasis', 'Disease', (104, 118))
34794	27919744	Moreover, cagA-positive H. pylori has been shown to induce mutation of the gastric carcinoma cell line.	('induce', 'Reg', (52, 58))	('gastric carcinoma', 'Disease', (75, 92))	('H. pylori', 'Species', '210', (24, 33))	('cagA-positive', 'Var', (10, 23))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (75, 92))	('mutation', 'CPA', (59, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('gastric carcinoma', 'Disease', 'MESH:D013274', (75, 92))
34800	27919744	In order to investigate this hypothesis, as well as links between cagPAI-positive H. pylori strains and CCA, we tested the ability of various H. pylori wild-type and isogenic cag mutant strains to adhere and induce pro-inflammatory responses in two CCA cell lines.	('mutant', 'Var', (179, 185))	('tested', 'Reg', (112, 118))	('H. pylori', 'Gene', (142, 151))	('induce', 'Reg', (208, 214))	('H. pylori', 'Species', '210', (142, 151))	('adhere', 'CPA', (197, 203))	('H. pylori', 'Species', '210', (82, 91))	('pro-inflammatory responses', 'CPA', (215, 241))
34843	27919744	Infection with Opisthorchis viverrini is a cogent risk for cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (59, 77))	('Opisthorchis viverrini', 'Species', '6198', (15, 37))	('Opisthorchis viverrini', 'Protein', (15, 37))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (59, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('Infection', 'Var', (0, 9))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (59, 77))
34858	27747285	Interruption of the sphincter of Oddi has been reported to cause overgrowth of bacteria in the common bile duct resulting in cholangitis and recurrent stone formation.	('cholangitis', 'Disease', 'MESH:D002761', (125, 136))	('Interruption', 'Var', (0, 12))	('cholangitis', 'Phenotype', 'HP:0030151', (125, 136))	('cholangitis', 'Disease', (125, 136))	('stone formation', 'Disease', (151, 166))	('overgrowth', 'Phenotype', 'HP:0001548', (65, 75))	('recurrent', 'Disease', (141, 150))	('sphincter of Oddi', 'Disease', (20, 37))	('overgrowth', 'MPA', (65, 75))	('sphincter of Oddi', 'Disease', 'MESH:D046628', (20, 37))
34879	21809359	Cell cycle analyses demonstrated that miR-494 induces a significant G1/S checkpoint reinforcement.	('miR-494', 'Var', (38, 45))	('S', 'Chemical', 'MESH:D013455', (71, 72))	('G1/S checkpoint reinforcement', 'CPA', (68, 97))
34880	21809359	Luciferase reporter assays demonstrated a direct interaction between miR-494 and the 3'-Untranslated Region (UTR) of Cyclin-dependent-kinase 6 (CDK6).	('miR-494', 'Var', (69, 76))	('Cyclin-dependent-kinase 6', 'Gene', '1021', (117, 142))	('CDK6', 'Gene', (144, 148))	('interaction', 'Interaction', (49, 60))	('CDK6', 'Gene', '1021', (144, 148))	('Cyclin-dependent-kinase 6', 'Gene', (117, 142))
34881	21809359	Last, xenograft experiments demonstrated that miR-494 induces a significant cancer growth retardation in-vivo.	('cancer growth retardation', 'Disease', 'MESH:D006130', (76, 101))	('cancer growth retardation', 'Disease', (76, 101))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('miR-494', 'Var', (46, 53))	('growth retardation', 'Phenotype', 'HP:0001510', (83, 101))
34888	21809359	Molecular characterization of CCAs further suggested that inflammation and cholestasis, through modulation of genes involved in DNA damage repair, promote cancer development.	('cholestasis', 'Disease', 'MESH:D002779', (75, 86))	('modulation', 'Var', (96, 106))	('cholestasis', 'Disease', (75, 86))	('promote', 'PosReg', (147, 154))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cholestasis', 'Phenotype', 'HP:0001396', (75, 86))	('inflammation', 'Disease', 'MESH:D007249', (58, 70))	('genes', 'Gene', (110, 115))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('inflammation', 'Disease', (58, 70))
34889	21809359	In addition, microRNAs were also implicated in all solid cancers evaluated to date.	('implicated', 'Reg', (33, 43))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('microRNAs', 'Var', (13, 22))
34891	21809359	Subsequent studies demonstrated that the expression of miRs-7a, -29 and -370 is linked to cholangiocarcinogenesis, either through an IL-6-dependent pathway, or by interacting with Mcl-1.	('interacting', 'Interaction', (163, 174))	('miRs-7a', 'Var', (55, 62))	('linked', 'Reg', (80, 86))	('cholangiocarcinogenesis', 'Disease', (90, 113))	('IL-6', 'Gene', (133, 137))	('Mcl-1', 'Gene', '4170', (180, 185))	('IL-6', 'Gene', '3569', (133, 137))	('Mcl-1', 'Gene', (180, 185))	('S', 'Chemical', 'MESH:D013455', (0, 1))
34895	21809359	To obtain a comprehensive and unbiased view regarding the effects of miR-494 in cancer cells, we performed mRNA arrays on cells overexpressing miR-494 and on negative control, respectively.	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('miR-494', 'Var', (143, 150))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (80, 86))
34897	21809359	These actions appear to converge to restore the G1-S checkpoint, which explains, at least in part, the delayed growth of cells expressing miR-494.	('miR-494', 'Var', (138, 145))	('delayed growth', 'Phenotype', 'HP:0001510', (103, 117))	('G1-S checkpoint', 'MPA', (48, 63))	('S', 'Chemical', 'MESH:D013455', (51, 52))
34926	21809359	Next, we employed Gene Tailor Site-Directed Mutagenesis System (Invitrogen) to introduce mutations in the miR-494 binding site.	('S', 'Chemical', 'MESH:D013455', (56, 57))	('miR-494', 'Gene', (106, 113))	('mutations', 'Var', (89, 98))	('S', 'Chemical', 'MESH:D013455', (30, 31))
34931	21809359	The effect of miR-494 on the wild type or mutant CDK6 3'UTR was calculated as a fraction of the effect exerted by the negative control (NSM).	('S', 'Chemical', 'MESH:D013455', (137, 138))	('CDK6', 'Gene', (49, 53))	('mutant', 'Var', (42, 48))	('CDK6', 'Gene', '1021', (49, 53))
34932	21809359	The raw data allowing direct comparison of wild type and mutant CDK6 3'UTR luciferase activities is available in Supplementary materials.	('activities', 'MPA', (86, 96))	('CDK6', 'Gene', (64, 68))	('CDK6', 'Gene', '1021', (64, 68))	('mutant', 'Var', (57, 63))	('S', 'Chemical', 'MESH:D013455', (113, 114))
34944	21809359	As shown in Figure 1A, miR-494 is uniformly and significantly downregulated in human CCA specimens vs. normal specimens.	('miR-494', 'Var', (23, 30))	('downregulated', 'NegReg', (62, 75))	('CCA', 'Disease', (85, 88))	('human', 'Species', '9606', (79, 84))
34947	21809359	To characterize the function of miR-494 in cancer, miR-494-mimic or non-specific mimic (NSM) were transfected into HuCCT1 cells.	('miR-494-mimic', 'Var', (51, 64))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('S', 'Chemical', 'MESH:D013455', (89, 90))
34950	21809359	Malignant HuCCT1 cells were transfected with miR-494 or NSM and analyzed for Brd-U incorporation.	('S', 'Chemical', 'MESH:D013455', (57, 58))	('miR-494', 'Var', (45, 52))	('NSM', 'Gene', (56, 59))
34951	21809359	As shown in Figure 2B, HuCCT1 cells transfected with miR-494 have significantly decreased BrdU uptake when compared to cells transfected with non-specific mimic, which explains, at least in part, the difference in their growth.	('BrdU', 'MPA', (90, 94))	('decreased', 'NegReg', (80, 89))	('miR-494', 'Var', (53, 60))	('BrdU', 'Chemical', 'MESH:D001973', (90, 94))
34958	21809359	These experiments demonstrate an increased in G0/G1 fraction in miR-494 transfected cells (Figure 2C), consistent with data obtained from BrdU incorporation experiments.	('transfected', 'Var', (72, 83))	('G0/G1 fraction', 'CPA', (46, 60))	('BrdU', 'Chemical', 'MESH:D001973', (138, 142))	('increased', 'PosReg', (33, 42))	('miR-494 transfected', 'Var', (64, 83))
34961	21809359	Of note, the transfection of H69 normal cholangiocytes with miR-494 had no effect on cell cycle progression despite upregulation of miR-494 by 18-fold (Supplementary Figure 2).	('miR-494', 'Var', (132, 139))	('S', 'Chemical', 'MESH:D013455', (152, 153))	('upregulation', 'PosReg', (116, 128))	('miR-494', 'Gene', (60, 67))	('cell cycle progression', 'CPA', (85, 107))
34962	21809359	To study the molecular mechanisms responsible for the miR-494-induced G1/S arrest, we queried IPA in regards to genes impacted by miR-494 that are also involved in the G1/S checkpoint.	('P', 'Chemical', 'MESH:D010758', (95, 96))	('S', 'Chemical', 'MESH:D013455', (73, 74))	('miR-494', 'Var', (130, 137))	('S arrest', 'Disease', (73, 81))	('S arrest', 'Disease', 'MESH:D006323', (73, 81))	('S', 'Chemical', 'MESH:D013455', (171, 172))
34965	21809359	As seen in Figure 4A, expression of miR-494 results in decreased protein levels of CDK6, CDK4, CCND1, CCNE2 and HDAC1.	('protein levels', 'MPA', (65, 79))	('HDAC1', 'Gene', (112, 117))	('CCNE2', 'Gene', (102, 107))	('decreased', 'NegReg', (55, 64))	('CDK6', 'Gene', (83, 87))	('miR-494', 'Var', (36, 43))	('CCNE2', 'Gene', '9134', (102, 107))	('CDK4', 'Gene', (89, 93))	('CCND1', 'Gene', (95, 100))	('CDK6', 'Gene', '1021', (83, 87))	('HDAC1', 'Gene', '3065', (112, 117))	('CDK4', 'Gene', '1019', (89, 93))	('CCND1', 'Gene', '595', (95, 100))
34966	21809359	If the effects of miR-494 on these proteins are significant, then, we hypothesized, the final step in the G1 to S transition checkpoint should be affected.	('miR-494', 'Var', (18, 25))	('S', 'Chemical', 'MESH:D013455', (112, 113))	('affected', 'Reg', (146, 154))	('effects', 'Reg', (7, 14))
34967	21809359	We therefore concluded that treatment of cancer cells with miR-494 reinstates the G1/S checkpoint through the coordinated downregulation of CDK6, CDK4, CCND1, CCNE2 and HDAC1, resulting in decreased phosphorylation of Rb and finally, delayed cell cycle progression.	('HDAC1', 'Gene', '3065', (169, 174))	('delayed', 'NegReg', (234, 241))	('CCND1', 'Gene', '595', (152, 157))	('S', 'Chemical', 'MESH:D013455', (85, 86))	('cancer', 'Disease', (41, 47))	('CDK4', 'Gene', (146, 150))	('CCND1', 'Gene', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('phosphorylation', 'MPA', (199, 214))	('cell cycle progression', 'CPA', (242, 264))	('G1/S checkpoint', 'MPA', (82, 97))	('miR-494', 'Var', (59, 66))	('CDK4', 'Gene', '1019', (146, 150))	('decreased', 'NegReg', (189, 198))	('downregulation', 'NegReg', (122, 136))	('CCNE2', 'Gene', '9134', (159, 164))	('CDK6', 'Gene', '1021', (140, 144))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('reinstates', 'PosReg', (67, 77))	('CCNE2', 'Gene', (159, 164))	('HDAC1', 'Gene', (169, 174))	('CDK6', 'Gene', (140, 144))
34971	21809359	In spite of this modest upregulation of miR-494, cells infected with MIEG3-miR494 behaved similarly to cells transfected with miR-494, displaying restoration of the G1-S checkpoint (Supplementary Figure 3B).	('S', 'Chemical', 'MESH:D013455', (168, 169))	('S', 'Chemical', 'MESH:D013455', (182, 183))	('restoration', 'PosReg', (146, 157))	('MIEG3-miR494', 'Var', (69, 81))	('upregulation', 'PosReg', (24, 36))	('G1-S checkpoint', 'MPA', (165, 180))
34976	21809359	Cells transfected with the CDK6 3'UTR fragment showed an average of 30% reduction in luciferase activity upon treatment with miR-494 compared to a non-specific microRNA mimic (NSM).	('reduction', 'NegReg', (72, 81))	('activity', 'MPA', (96, 104))	('miR-494', 'Var', (125, 132))	('CDK6', 'Gene', (27, 31))	('CDK6', 'Gene', '1021', (27, 31))	('luciferase', 'Enzyme', (85, 95))	('S', 'Chemical', 'MESH:D013455', (177, 178))
34978	21809359	Upon miR-494 binding site mutation, the effect of miR-494 on CDK6 was lost, as evinced by similar luciferase activity between miR-494 and NSM treated cells (p-value = 0.15, Student's unpaired t-test, Figure 4B and Supplementary Figure 4).	('binding', 'Interaction', (13, 20))	('luciferase', 'Enzyme', (98, 108))	('mutation', 'Var', (26, 34))	('CDK6', 'Gene', (61, 65))	('CDK6', 'Gene', '1021', (61, 65))	('S', 'Chemical', 'MESH:D013455', (139, 140))	('S', 'Chemical', 'MESH:D013455', (214, 215))	('S', 'Chemical', 'MESH:D013455', (173, 174))	('activity', 'MPA', (109, 117))	('miR-494', 'Gene', (5, 12))
34981	21809359	Mice formed large tumors in the right flank (HuCCT1-EV) while they had very small nodules in the left flank (HuCCT1-494V, Figure 5A and B).	('HuCCT1-494V', 'Var', (109, 120))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
34986	21809359	In the current study, we report that: 1. miR-494 is downregulated in cancer; 2. miR-494 modulates multiple key players along the canonical G1 to S progression; 3. miR-494 induces a robust G1 arrest contributing, at least in part, to decreased cancer cell growth and 4. miR-494 induces decreased tumor growth in-vivo.	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('miR-494', 'Var', (163, 170))	('miR-494', 'Var', (269, 276))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('S', 'Chemical', 'MESH:D013455', (145, 146))	('cancer', 'Disease', (243, 249))	('decreased', 'NegReg', (285, 294))	('decreased cancer', 'Disease', (233, 249))	('G1 arrest', 'CPA', (188, 197))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('decreased cancer', 'Disease', 'MESH:D009369', (233, 249))	('tumor', 'Disease', (295, 300))	('cancer', 'Disease', (69, 75))
34987	21809359	The current data put forward that the manipulation of a sole miR species results in a significant phenotypic effect, such as decreased cancer cell growth.	('decreased cancer', 'Disease', 'MESH:D009369', (125, 141))	('manipulation', 'Var', (38, 50))	('decreased cancer', 'Disease', (125, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))
34988	21809359	Except for CDK6, miR-494 exerted less than 50% decrease in the level of the proteins tested (CDK4, CCND1, CCNE2, HDAC1 and phospho-RB).	('CDK4', 'Gene', '1019', (93, 97))	('HDAC1', 'Gene', (113, 118))	('decrease', 'NegReg', (47, 55))	('CCNE2', 'Gene', (106, 111))	('CCND1', 'Gene', (99, 104))	('CDK6', 'Gene', (11, 15))	('HDAC1', 'Gene', '3065', (113, 118))	('CDK6', 'Gene', '1021', (11, 15))	('CCNE2', 'Gene', '9134', (106, 111))	('miR-494', 'Var', (17, 24))	('level of the proteins tested', 'MPA', (63, 91))	('CCND1', 'Gene', '595', (99, 104))	('CDK4', 'Gene', (93, 97))
34990	21809359	Our data suggests that miR-494 is a significant modulator of the G1-S transition canonical pathway by controlling expression of proteins involved at multiple steps.	('controlling', 'Reg', (102, 113))	('modulator', 'Reg', (48, 57))	('miR-494', 'Var', (23, 30))	('S', 'Chemical', 'MESH:D013455', (68, 69))	('expression of', 'MPA', (114, 127))	('G1-S transition canonical pathway', 'Pathway', (65, 98))
34993	21809359	We further demonstrate that miR-494 directly interacts with the 3'UTR of CDK6 and results in a decrease of CDK6 at protein level.	('decrease', 'NegReg', (95, 103))	('miR-494', 'Var', (28, 35))	('CDK6', 'Gene', '1021', (107, 111))	('CDK6', 'Gene', (73, 77))	('CDK6', 'Gene', (107, 111))	('CDK6', 'Gene', '1021', (73, 77))	('interacts', 'Interaction', (45, 54))
35183	33003424	was the first to report that patients with pN0M0 disease who underwent an R0 liver resection showed no significant differences in survival when compared to patients with Bismuth type I/II, III, and IV tumors, as the five-year OS rates were 63.1%, 65.6%, and 59.2%, respectively (p > 0.05).	('patients', 'Species', '9606', (156, 164))	('IV tumors', 'Disease', 'MESH:D009369', (198, 207))	('patients', 'Species', '9606', (29, 37))	('IV tumors', 'Disease', (198, 207))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('pN0M0 disease', 'Var', (43, 56))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))
35224	33003424	PHC Perihilar cholangiocarcinoma  AJCC American Joint Committee on Cancer  TNM tumor node metastasis  HPB hepato-pancreato-biliary  CT computed tomography  MRI magnetic resonance imaging  MRCP magnetic resonance cholangiopancreatography  EBD Endoscopic biliary drainage  PTBD Percutaneous transhepatic biliary drainage  PVE portal vein embolization  CLR caudate lobe resection  ASA American Society of Anesthesiologists  CEA carcinoembryonic antigen  CA Cancer Antigen  IQR interquartile range  ANOVA Analysis of variance  OS overall survival  HR hazard ratio  CI confidence interval  AUC Area under the curve  ROC Receiver operating characteristic curve  PVR Portal vein resection  LN Lymph node  MLN Metastasic lymph node  HLT Hoshmer-Lemeshow test  UICC International Union Against Cancer	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('PVE', 'Phenotype', 'HP:0030242', (320, 323))	('Cancer', 'Disease', 'MESH:D009369', (785, 791))	('cholangiocarcinoma', 'Disease', (14, 32))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (14, 32))	('Cancer', 'Disease', (67, 73))	('portal vein embolization', 'Phenotype', 'HP:0030242', (324, 348))	('MLN Metastasic lymph', 'Disease', 'MESH:D009362', (698, 718))	('Cancer', 'Phenotype', 'HP:0002664', (454, 460))	('carcinoembryonic antigen', 'Gene', (425, 449))	('Cancer', 'Disease', 'MESH:D009369', (67, 73))	('Cancer', 'Phenotype', 'HP:0002664', (785, 791))	('CEA', 'Gene', (421, 424))	('cholangiopancreatography  EBD Endoscopic biliary drainage  PTBD Percutaneous transhepatic biliary', 'Disease', 'MESH:D001657', (212, 309))	('Cancer', 'Disease', (454, 460))	('Cancer  TNM tumor node metastasis  HPB hepato-pancreato-biliary', 'Disease', 'MESH:D009362', (67, 130))	('PVR', 'Var', (656, 659))	('Cancer', 'Disease', (785, 791))	('CEA', 'Gene', '1084', (421, 424))	('MLN Metastasic lymph', 'Disease', (698, 718))	('carcinoembryonic antigen', 'Gene', '1084', (425, 449))	('Cancer', 'Disease', 'MESH:D009369', (454, 460))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (14, 32))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
35388	29588543	Importantly, one specific peptide, produced by the cleavage of fibrinogen beta chain (FGB) was frequently identified as cancer biomarker in three previously published CE-MS studies, investigating bladder cancer, renal cell carcinoma and pancreatic cancer respectively.	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('pancreatic cancer', 'Disease', 'MESH:D010190', (237, 254))	('cancer', 'Disease', (120, 126))	('fibrinogen beta chain', 'Gene', '2244', (63, 84))	('FGB', 'Gene', (86, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('cancer', 'Disease', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('pancreatic cancer', 'Disease', (237, 254))	('cleavage', 'Var', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('fibrinogen beta chain', 'Gene', (63, 84))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (212, 232))	('cancer', 'Disease', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('bladder cancer', 'Disease', 'MESH:D001749', (196, 210))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('bladder cancer', 'Disease', (196, 210))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (237, 254))	('bladder cancer', 'Phenotype', 'HP:0009725', (196, 210))	('FGB', 'Gene', '2244', (86, 89))	('renal cell carcinoma', 'Disease', (212, 232))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (212, 232))
35394	29588543	Multiple studies link the G463A polymorphism in the MPO promoter region, which decreases the transcription and activity of MPO, with a lower cancer risk for a variety of human cancers e.g.	('G463A', 'Var', (26, 31))	('MPO', 'Gene', '4353', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('MPO', 'Gene', '4353', (52, 55))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('MPO', 'Gene', (123, 126))	('cancers', 'Disease', (176, 183))	('activity', 'MPA', (111, 119))	('MPO', 'Gene', (52, 55))	('transcription', 'MPA', (93, 106))	('G463A', 'Mutation', 'c.463G>A', (26, 31))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lower', 'NegReg', (135, 140))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('decreases', 'NegReg', (79, 88))	('human', 'Species', '9606', (170, 175))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (176, 182))
35484	20816680	The GeneChip  Rat Expression 230 2.0 Array provides comprehensive coverage of the transcribed rat genome by including over 31,000 probe sets that analyze the expression level of over 30,000 transcripts and variants from over 28,000 well-substantiated rat genes.	('rat', 'Species', '10116', (94, 97))	('variants', 'Var', (206, 214))	('expression', 'MPA', (158, 168))	('Rat', 'Species', '10116', (14, 17))	('rat', 'Species', '10116', (251, 254))
35488	20816680	Arrays exhibiting gapdh 3'/5' < 3.0 and %P > 40% were considered good quality arrays.	('%P > 40', 'Var', (40, 47))	('gapdh', 'Gene', (18, 23))	('gapdh', 'Gene', '108351137', (18, 23))
35490	20816680	These included gene specific probes for the following genes: krt19 (cytokeratin 19), ID# Rn01496870_g1; krt20 (cytokeratin 20), ID# Rn01466577_m1; Sox17 (Sry-related HMG box gene-17), ID# Rn01749232_g1; Erbb2 (neu), ID# Rn00690264_g1; Muc1 (mucin 1), ID # Rn01462585_m1; Areg (amphiregulin), ID# Rn00567471_m1; Mmp7 (metalloproteinase-7; matrilysin), ID# Rn01487001_m1; Acta2 (alpha-smooth muscle actin), ID# Rn01759928_g1; Postn (periostin), ID# Rn01494627_m1; Tnc (tenascin-C), ID# Rn01454953_m1; Hgf (hepatocyte growth factor), ID# Rn00566673_m1; Ctgf (connective tissue growth factor), ID# Rn01537278_g1; Cxcl12 (C-X-C chemokine ligand-12; stromal-derived factor-1), ID# Rn00573260_m1; Cxcr4 (C-X-C chemokine receptor type 4), ID# Rn01483207_m1; Sphk1 (sphingosine kinase1), ID# Rn00682794_g1; Cav (caveolin-1), ID# R00755834_m1; and Hif1a (hypoxia inducible factor 1alpha), ID# Rn00694426_m1.	('matrilysin', 'Gene', (338, 348))	('alpha-smooth muscle actin', 'Gene', '25365', (377, 402))	('mucin 1', 'Gene', '24571', (241, 248))	('alpha-smooth muscle actin', 'Gene', (377, 402))	('amphiregulin', 'Gene', (277, 289))	('ID# R00755834_m1', 'Var', (816, 832))	('Sry-related HMG box gene-17', 'Gene', '312936', (154, 181))	('Acta2', 'Gene', (370, 375))	('Hif1a', 'Gene', '29560', (838, 843))	('mucin 1', 'Gene', (241, 248))	('Erbb2', 'Gene', (203, 208))	('krt20', 'Gene', '286912', (104, 109))	('C-X-C chemokine receptor type 4', 'Gene', '60628', (697, 728))	('Cxcr4', 'Gene', '60628', (690, 695))	('hepatocyte growth factor', 'Gene', (504, 528))	('Mmp7', 'Gene', '25335', (311, 315))	('krt20', 'Gene', (104, 109))	('matrilysin', 'Gene', '25335', (338, 348))	('Sry-related HMG box gene-17', 'Gene', (154, 181))	('Ctgf', 'Gene', '64032', (550, 554))	('ID# Rn00694426_m1', 'Var', (879, 896))	('sphingosine kinase1', 'Gene', '170897', (757, 776))	('tenascin-C', 'Gene', (467, 477))	('neu', 'Gene', (210, 213))	('tenascin-C', 'Gene', '116640', (467, 477))	('connective tissue growth factor', 'Gene', '64032', (556, 587))	('connective tissue growth factor', 'Gene', (556, 587))	('caveolin-1', 'Gene', '25404', (803, 813))	('ID# Rn00682794_g1', 'Var', (779, 796))	('periostin', 'Gene', (431, 440))	('Cxcl12', 'Gene', (609, 615))	('amphiregulin', 'Gene', '29183', (277, 289))	('Cxcl12', 'Gene', '24772', (609, 615))	('Acta2', 'Gene', '81633', (370, 375))	('hypoxia inducible factor 1alpha', 'Gene', (845, 876))	('Erbb2', 'Gene', '24337', (203, 208))	('cytokeratin 19', 'Gene', '360626', (68, 82))	('Mmp7', 'Gene', (311, 315))	('cytokeratin 19', 'Gene', (68, 82))	('Ctgf', 'Gene', (550, 554))	('hypoxia inducible factor 1alpha', 'Gene', '29560', (845, 876))	('krt19', 'Gene', (61, 66))	('caveolin-1', 'Gene', (803, 813))	('Hif1a', 'Gene', (838, 843))	('periostin', 'Gene', '361945', (431, 440))	('C-X-C chemokine ligand-12', 'Gene', '24772', (617, 642))	('cytokeratin 20', 'Gene', (111, 125))	('cytokeratin 20', 'Gene', '286912', (111, 125))	('ID# Rn01483207_m1', 'Var', (731, 748))	('hepatocyte growth factor', 'Gene', '24446', (504, 528))	('C-X-C chemokine receptor type 4', 'Gene', (697, 728))	('sphingosine kinase1', 'Gene', (757, 776))	('krt19', 'Gene', '360626', (61, 66))	('C-X-C chemokine ligand-12', 'Gene', (617, 642))	('neu', 'Gene', '2064', (210, 213))	('Cxcr4', 'Gene', (690, 695))
35565	31533404	Cytokine Production in Cholangiocarcinoma Cells in Response to Clonorchis sinensis Excretory-Secretory Products and Their Putative Protein Components Clonorchis sinensis is a carcinogenic human liver fluke that promotes hepatic inflammatory environments via direct contact or through their excretory-secretory products (ESPs), subsequently leading to cholangitis, periductal fibrosis, liver cirrhosis, and even cholangiocarcinoma (CCA).	('CCA', 'Disease', 'MESH:D018281', (431, 434))	('carcinogenic human liver fluke', 'Disease', 'MESH:D008113', (175, 205))	('liver cirrhosis', 'Disease', 'MESH:D008103', (385, 400))	('Cytokine', 'Gene', (0, 8))	('CCA', 'Disease', (431, 434))	('cholangitis', 'Phenotype', 'HP:0030151', (351, 362))	('Clonorchis sinensis', 'Species', '79923', (150, 169))	('ESP', 'Gene', (320, 323))	('promotes', 'PosReg', (211, 219))	('Clonorchis sinensis', 'Species', '79923', (63, 82))	('ESP', 'Gene', '148713', (320, 323))	('hepatic inflammatory environments', 'MPA', (220, 253))	('liver cirrhosis', 'Disease', (385, 400))	('fibrosis', 'Disease', 'MESH:D005355', (375, 383))	('fibrosis', 'Disease', (375, 383))	('Clonorchis', 'Var', (150, 160))	('carcinogenic human liver fluke', 'Disease', (175, 205))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (411, 429))	('Cholangiocarcinoma Cells', 'Disease', 'MESH:D018281', (23, 47))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (385, 400))	('cholangitis', 'Disease', 'MESH:D002761', (351, 362))	('leading to', 'Reg', (340, 350))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (23, 41))	('cholangiocarcinoma', 'Disease', (411, 429))	('Cholangiocarcinoma Cells', 'Disease', (23, 47))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (411, 429))	('cholangitis', 'Disease', (351, 362))	('Cytokine', 'Gene', '943', (0, 8))	('CCA', 'Phenotype', 'HP:0030153', (431, 434))
35659	31533404	The results from this study imply that a combination of IL-10 and TGF-beta may play a role in controlling host immune responses (the switch from an acute to a chronic infection stage), thereby generating protective immunity to the worm for growth and survival.	('infection', 'Disease', 'MESH:D007239', (167, 176))	('combination', 'Var', (41, 52))	('TGF-beta', 'Gene', (66, 74))	('generating', 'PosReg', (193, 203))	('host immune responses', 'MPA', (106, 127))	('chronic infection', 'Phenotype', 'HP:0031035', (159, 176))	('protective immunity', 'MPA', (204, 223))	('IL-10', 'Gene', (56, 61))	('infection', 'Disease', (167, 176))
35660	31533404	Although inflammatory cytokine production acts as a host defense mechanism against infection or injury, aberrant regulation leads to severe chronic disorders including carcinogenesis.	('cytokine', 'Gene', (22, 30))	('leads to', 'Reg', (124, 132))	('aberrant regulation', 'Var', (104, 123))	('infection or injury', 'Disease', 'MESH:D007239', (83, 102))	('cytokine', 'Gene', '943', (22, 30))	('carcinogenesis', 'Disease', 'MESH:D063646', (168, 182))	('chronic disorders', 'Disease', (140, 157))	('carcinogenesis', 'Disease', (168, 182))	('chronic disorders', 'Disease', 'MESH:D002908', (140, 157))	('infection or injury', 'Disease', (83, 102))
35663	31533404	In addition to TGF-beta/Smad signaling pathway-mediated hepatic fibrosis in mice with clonorchiasis, exposure to IL-6 and TGF-beta1 induces endogenous production of IL-6 and TGF-beta1 in biliary tract cancer cells through positive crosstalk loop, conferring enhanced malignant features such as epithelial-mesenchymal transition, invasion, and chemoresistance.	('hepatic fibrosis', 'Disease', (56, 72))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('TGF-beta1', 'Gene', (174, 183))	('cancer', 'Disease', (201, 207))	('endogenous production', 'MPA', (140, 161))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (187, 207))	('hepatic fibrosis', 'Disease', 'MESH:D008103', (56, 72))	('enhanced', 'PosReg', (258, 266))	('invasion', 'CPA', (329, 337))	('chemoresistance', 'CPA', (343, 358))	('mice', 'Species', '10090', (76, 80))	('malignant features', 'CPA', (267, 285))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (56, 72))	('epithelial-mesenchymal transition', 'CPA', (294, 327))	('TGF-beta1', 'Gene', (122, 131))	('exposure', 'Var', (101, 109))
35665	31533404	In the context of chronic clonorchiasis-associated hepatobiliary abnormalities, constitutive dysregulation of inflammatory cytokines may enhance the more aggressive pathologic process in the bile duct and its surrounding liver tissues, leading to cholangiocarcinogenesis.	('enhance', 'PosReg', (137, 144))	('hepatobiliary abnormalities', 'Disease', (51, 78))	('cytokine', 'Gene', '943', (123, 131))	('cytokine', 'Gene', (123, 131))	('leading to', 'Reg', (236, 246))	('cholangiocarcinogenesis', 'Disease', 'None', (247, 270))	('dysregulation', 'Var', (93, 106))	('more aggressive pathologic process', 'CPA', (149, 183))	('hepatobiliary abnormalities', 'Disease', 'MESH:D002869', (51, 78))	('cholangiocarcinogenesis', 'Disease', (247, 270))
35675	28387377	These insults produce mutations in genes that might alter their expression and/or function, deregulating many physiological pathways and provoke chromosomal damage, events that drive oncogenic transformation and tumour progression.	('expression', 'MPA', (64, 74))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('physiological pathways', 'Pathway', (110, 132))	('chromosomal damage', 'MPA', (145, 163))	('tumour', 'Disease', 'MESH:D009369', (212, 218))	('oncogenic transformation', 'CPA', (183, 207))	('mutations', 'Var', (22, 31))	('tumour', 'Disease', (212, 218))	('genes', 'Gene', (35, 40))	('provoke', 'Reg', (137, 144))	('deregulating', 'Reg', (92, 104))	('drive', 'Reg', (177, 182))
35676	28387377	Different levels of damage produce different responses, such that mild DNA damage induces a reparative response, while severe damage activates cell death in a regulated manner.	('induces', 'Reg', (82, 89))	('damage activates cell death', 'Disease', (126, 153))	('reparative response', 'CPA', (92, 111))	('mild DNA damage', 'Var', (66, 81))	('damage activates cell death', 'Disease', 'MESH:D001926', (126, 153))
35685	28387377	TP53 or FOS are examples of tumour suppressor genes where mutations, deletions and/or repression are implicated in processes related to cancer development.	('mutations', 'Var', (58, 67))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('implicated', 'Reg', (101, 111))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('FOS', 'Gene', (8, 11))	('deletions', 'Var', (69, 78))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (136, 142))	('tumour', 'Disease', (28, 34))	('FOS', 'Gene', '2353', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
35698	28387377	Some techniques measure mRNA expression upon the modification of miRNA expression using luciferase assays or other proteomic assays like pulsed stable isotope labelling with amino acids in cell culture (pSILAC).	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('modification', 'Var', (49, 61))	('mRNA expression', 'MPA', (24, 39))	('measure', 'Reg', (16, 23))
35704	28387377	In addition, the analyses of these signatures in different tumours, accounting for additional factors like gene methylation (MET) and copy number alterations (CNAs), could provide relevant information regarding the signature's stability.	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('tumours', 'Disease', (59, 66))	('copy number alterations', 'Var', (134, 157))
35716	28387377	One such example is the aforementioned TP53, which is often over-expressed in cancer when it carries mutations, although many of these overexpressed mutated variants have lost their original function.	('over-expressed', 'PosReg', (60, 74))	('mutations', 'Var', (101, 110))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('TP53', 'Gene', '7157', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('TP53', 'Gene', (39, 43))
35783	28387377	SYNE1 is the most significantly repressed gene and its dysregulation has been related to glioblastoma and ovarian cancer, among others.	('SYNE1', 'Gene', (0, 5))	('glioblastoma and ovarian cancer', 'Disease', 'MESH:D005909', (89, 120))	('related', 'Reg', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))	('SYNE1', 'Gene', '23345', (0, 5))	('dysregulation', 'Var', (55, 68))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))
35792	28387377	It is well known that methylation and copy number alterations affect gene expression, especially in cancer.	('affect', 'Reg', (62, 68))	('copy number alterations', 'Var', (38, 61))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gene expression', 'MPA', (69, 84))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('methylation', 'Var', (22, 33))
35878	28387377	In prostate cancer, the classification was performed based on tumour grade instead of tumour stage, where good prognosis involved tumours with Gleason score of 6 or 7, and bad prognosis tumours with Gleason score >= 8.	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('tumours', 'Disease', (186, 193))	('tumours', 'Disease', 'MESH:D009369', (130, 137))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('prostate cancer', 'Disease', (3, 18))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('Gleason', 'Var', (143, 150))	('tumour', 'Disease', (186, 192))	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('tumours', 'Disease', 'MESH:D009369', (186, 193))	('tumour', 'Disease', (130, 136))	('bad prognosis tumours', 'Disease', 'MESH:D009369', (172, 193))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Disease', (130, 137))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('bad prognosis tumours', 'Disease', (172, 193))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('tumour', 'Disease', (62, 68))	('tumour', 'Disease', (86, 92))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
35901	26923637	For example, dysregulated circadian clock gene expression and disrupted circadian rhythm is associated with tumor development and progression in experimental models.	('clock', 'Gene', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('progression', 'CPA', (130, 141))	('clock', 'Gene', '9575', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('circadian rhythm', 'MPA', (72, 88))	('disrupted', 'NegReg', (62, 71))	('associated', 'Reg', (92, 102))	('dysregulated', 'Var', (13, 25))
35908	26923637	During tumorigenesis, a group of critical miRNAs, including miR21, miR-141 and miR-29 are aberrantly expressed and regulate CCA development.	('miR21', 'Gene', (60, 65))	('miR-141', 'Gene', (67, 74))	('tumor', 'Disease', (7, 12))	('CCA development', 'CPA', (124, 139))	('miR-141', 'Gene', '406933', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('miR21', 'Gene', '406991', (60, 65))	('miR-29', 'Var', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('regulate', 'Reg', (115, 123))
35928	26923637	Cell proliferation after silencing of miR-34a in the selected cells was examined via MTS assay, while cell invasion was evaluated using a cell invasion assay kit (Chemicon, Temecula, CA).	('miR-34a', 'Gene', (38, 45))	('silencing', 'Var', (25, 34))	('miR-34a', 'Gene', '407040', (38, 45))	('Cell proliferation', 'CPA', (0, 18))
35930	26923637	To determine that knockdown of Per1 reverses the anti-proliferative and anti-invasive effects of the miR-34a inhibitor, we co-transfected Per1 siRNA with miR-34a inhibitor in Mz-ChA-1 cells before measuring cell proliferation.	('knockdown', 'Var', (18, 27))	('miR-34a', 'Gene', '407040', (101, 108))	('miR-34a', 'Gene', (101, 108))	('miR-34a', 'Gene', '407040', (154, 161))	('miR-34a', 'Gene', (154, 161))
35954	26923637	Since Per1 expression and its circadian rhythm was decreased in all CCAs used, we aimed to demonstrate that restoration of Per1 expression decreases the growth of Mz-ChA-1, HuCC-T1 cells.	('circadian rhythm', 'MPA', (30, 46))	('restoration', 'Var', (108, 119))	('Per1', 'Gene', (6, 10))	('expression', 'MPA', (11, 21))	('decreased', 'NegReg', (51, 60))	('decreases', 'NegReg', (139, 148))	('HuCC-T1', 'CellLine', 'CVCL:0324', (173, 180))	('expression', 'MPA', (128, 138))	('Per1', 'Gene', (123, 127))	('growth', 'MPA', (153, 159))
35956	26923637	There were fewer G2/M phase cells in Per1 OE cells compared to EV cells, whereas the number of quiescent cells in G0/G1 phase increased in Per1 OE cells compared to EV cells (Figure 3E).	('EV', 'Chemical', '-', (63, 65))	('G2/M phase cells', 'CPA', (17, 33))	('Per1 OE', 'Var', (139, 146))	('EV', 'Chemical', '-', (165, 167))	('increased', 'PosReg', (126, 135))	('fewer', 'NegReg', (11, 16))
35959	26923637	We also demonstrated that silencing of Per1 expression in H69 cells increased proliferation, but did not affect the invasiveness of these cells (Suppl.	('proliferation', 'CPA', (78, 91))	('silencing', 'Var', (26, 35))	('H69', 'CellLine', 'CVCL:8121', (58, 61))	('Per1', 'Gene', (39, 43))	('increased', 'PosReg', (68, 77))
35972	26923637	Since miR-34a acts as an oncomiR in CCA, we next evaluated whether inhibition of miR-34a affects Per1 expression and circadian rhythm and tumor cell growth or invasion.	('inhibition', 'Var', (67, 77))	('tumor', 'Disease', (138, 143))	('expression', 'MPA', (102, 112))	('CCA', 'Disease', (36, 39))	('affects', 'Reg', (89, 96))	('Per1', 'Gene', (97, 101))	('miR-34a', 'Gene', '407040', (81, 88))	('circadian rhythm', 'MPA', (117, 133))	('invasion', 'CPA', (159, 167))	('miR-34a', 'Gene', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('miR-34a', 'Gene', '407040', (6, 13))	('miR-34a', 'Gene', (6, 13))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
35974	26923637	After inhibition of miR-34a expression, the proliferation of Mz-ChA-1 cells was inhibited at 24, 48 and 72 hr, whereas the proliferation of H69 did not show significant change after inhibition of miR-34a expression (Figure 5C).	('miR-34a', 'Gene', (20, 27))	('expression', 'Var', (28, 38))	('miR-34a', 'Gene', '407040', (196, 203))	('proliferation', 'CPA', (44, 57))	('H69', 'CellLine', 'CVCL:8121', (140, 143))	('inhibition', 'NegReg', (6, 16))	('miR-34a', 'Gene', '407040', (20, 27))	('inhibited', 'NegReg', (80, 89))	('miR-34a', 'Gene', (196, 203))
35976	26923637	Furthermore, silencing of Per1 expression in miR-34a-transfected Mz-ChA-1 cells diminished the inhibition of proliferation in CCA cells (Figure 5C).	('miR-34a', 'Gene', (45, 52))	('inhibition', 'NegReg', (95, 105))	('CCA', 'Disease', (126, 129))	('diminished', 'NegReg', (80, 90))	('miR-34a', 'Gene', '407040', (45, 52))	('Per1', 'Gene', (26, 30))	('silencing', 'Var', (13, 22))
35979	26923637	We demonstrated that the expression of PCNA, VEGF-A, NGF, epithelial-mesenchymal transition (EMT) markers (TIMP2, TIMP3, MMP-3 and MMP9) and the metastasis marker S100A4 were inhibited in the Per1 OE group (Figure 6B).	('NGF', 'Gene', '4803', (53, 56))	('TIMP3', 'Gene', '7078', (114, 119))	('TIMP3', 'Gene', (114, 119))	('MMP-3', 'Gene', '4314', (121, 126))	('epithelial-mesenchymal transition', 'CPA', (58, 91))	('expression', 'MPA', (25, 35))	('VEGF-A', 'Gene', '7422', (45, 51))	('PCNA', 'Gene', (39, 43))	('NGF', 'Gene', (53, 56))	('inhibited', 'NegReg', (175, 184))	('TIMP2', 'Gene', (107, 112))	('MMP9', 'Gene', (131, 135))	('MMP9', 'Gene', '4318', (131, 135))	('MMP-3', 'Gene', (121, 126))	('metastasis', 'CPA', (145, 155))	('VEGF-A', 'Gene', (45, 51))	('PCNA', 'Gene', '5111', (39, 43))	('TIMP2', 'Gene', '7077', (107, 112))	('Per1 OE', 'Var', (192, 199))
35987	26923637	In addition, expression of Serpine1, which is involved in senescence, is decreased after overexpressing Per1 (Figure 8).	('Serpine1', 'Gene', '5054', (27, 35))	('decreased', 'NegReg', (73, 82))	('expression', 'MPA', (13, 23))	('Per1', 'Var', (104, 108))	('Serpine1', 'Gene', (27, 35))	('overexpressing', 'PosReg', (89, 103))
35989	26923637	Restoration of Per1 inhibited proliferation and increased apoptosis of CCA cells in vitro and reduced tumor growth in vivo.	('increased', 'PosReg', (48, 57))	('reduced', 'NegReg', (94, 101))	('Restoration', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('inhibited', 'NegReg', (20, 29))	('apoptosis', 'CPA', (58, 67))	('Per1', 'Gene', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
35991	26923637	Inhibition of miR-34a reduced proliferation and invasiveness of CCA cells.	('miR-34a', 'Gene', '407040', (14, 21))	('invasiveness', 'CPA', (48, 60))	('miR-34a', 'Gene', (14, 21))	('CCA', 'Disease', (64, 67))	('Inhibition', 'Var', (0, 10))	('reduced', 'NegReg', (22, 29))	('proliferation', 'CPA', (30, 43))
35995	26923637	Similarly, deregulation of Per1 was found in pancreatic and hepatocellular cancer.	('pancreatic and hepatocellular cancer', 'Disease', 'MESH:D006528', (45, 81))	('Per1', 'Gene', (27, 31))	('deregulation', 'Var', (11, 23))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (60, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
36006	26923637	Modulation of miR-34a enlarged the amplitude of the 24-hr circadian rhythm of Per1 in Mz-ChA-1 cells and shifted the phase in TFK-1 but did not change the period in our study.	('Modulation', 'Var', (0, 10))	('miR-34a', 'Gene', '407040', (14, 21))	('miR-34a', 'Gene', (14, 21))	('amplitude', 'MPA', (35, 44))	('Per1', 'Gene', (78, 82))	('enlarged', 'PosReg', (22, 30))
36007	26923637	Previous studies demonstrate that modulation of miRNA alters the phase and amplitude of circadian rhythm of clock genes in many organisms.	('miRNA', 'Gene', (48, 53))	('alters', 'Reg', (54, 60))	('circadian rhythm', 'MPA', (88, 104))	('amplitude', 'MPA', (75, 84))	('clock', 'Gene', '9575', (108, 113))	('clock', 'Gene', (108, 113))	('phase', 'MPA', (65, 70))	('modulation', 'Var', (34, 44))
36011	26923637	Here we also found that modulation of Per1 may regulate the CREB complex indicating a bi-directional regulation between CREB and Per1.	('CREB', 'Gene', (60, 64))	('modulation', 'Var', (24, 34))	('CREB', 'Gene', (120, 124))	('Per1', 'Gene', (38, 42))	('regulate', 'Reg', (47, 55))	('CREB', 'Gene', '1385', (60, 64))	('CREB', 'Gene', '1385', (120, 124))
36096	31835877	Glucose Depletion Enhances the Stem Cell Phenotype and Gemcitabine Resistance of Cholangiocarcinoma Organoids through AKT Phosphorylation and Reactive Oxygen Species Cancer cells are strongly dependent on the glycolytic pathway for generation of energy even under aerobic condition through a phenomenon known as the Warburg effect.	('Cancer', 'Phenotype', 'HP:0002664', (166, 172))	('Depletion', 'Var', (8, 17))	('Enhances', 'PosReg', (18, 26))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (81, 99))	('AKT', 'Gene', '207', (118, 121))	('Glucose', 'Chemical', 'MESH:D005947', (0, 7))	('Cholangiocarcinoma Organoids', 'Disease', (81, 109))	('Oxygen', 'Chemical', 'MESH:D010100', (151, 157))	('AKT', 'Gene', (118, 121))	('Gemcitabine', 'Chemical', 'MESH:C056507', (55, 66))	('Stem Cell Phenotype', 'CPA', (31, 50))	('Gemcitabine Resistance', 'CPA', (55, 77))	('Cholangiocarcinoma Organoids', 'Disease', 'MESH:D018281', (81, 109))
36107	31835877	We have recently demonstrated that liver cancer cells can survive even under hypoglycemic condition through microRNA-mediated gene regulation.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('liver cancer', 'Phenotype', 'HP:0002896', (35, 47))	('liver cancer', 'Disease', 'MESH:D006528', (35, 47))	('hypoglycemic condition', 'Phenotype', 'HP:0001943', (77, 99))	('liver cancer', 'Disease', (35, 47))	('hypoglycemic condition', 'Disease', (77, 99))	('microRNA-mediated', 'Var', (108, 125))	('hypoglycemic condition', 'Disease', 'MESH:D009135', (77, 99))
36122	31835877	The drugs employed were LY294002 (Cell Signaling Technology, Danvers, MA, USA) as an inhibitor of phosphatidylinositol 3-kinase (PI3K)-dependent AKT phosphorylation, N-acetylcysteine (NAC, Sigma-Aldrich), Tempol (Santa Cruz Biotechnology, Dallas, TX, USA), Cisplatin (AdipoGen, San Diego, CA, USA) and gemcitabine hydrochloride (Sigma-Aldrich).	('LY294002', 'Var', (24, 32))	('NAC', 'Chemical', 'MESH:D000111', (184, 187))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (98, 127))	('AKT', 'Gene', (145, 148))	('Tempol', 'Chemical', 'MESH:C001803', (205, 211))	('phosphatidylinositol 3-kinase', 'Gene', (98, 127))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (166, 182))	('gemcitabine hydrochloride', 'Chemical', 'MESH:C056507', (302, 327))	('LY294002', 'Chemical', 'MESH:C085911', (24, 32))	('AKT', 'Gene', '207', (145, 148))	('phospho', 'Chemical', 'MESH:C033601', (149, 156))	('Cisplatin', 'Chemical', 'MESH:D002945', (257, 266))
36139	31835877	The numbers of viable cells among CCO1 and CCO2 cultured under Glu (-) condition were significantly reduced in comparison to cells cultured under Glu (+) condition (Figure 1a).	('reduced', 'NegReg', (100, 107))	('Glu', 'Chemical', 'MESH:C094686', (63, 66))	('Glu', 'Var', (63, 66))	('Glu', 'Chemical', 'MESH:C094686', (146, 149))
36152	31835877	The cell viabilities of CCO1 and CCO2 after combination treatment with gemcitabine and cisplatin were significantly increased under Glu (-) condition compared to Glu (+) condition (Figure 2c).	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('combination', 'Interaction', (44, 55))	('Glu', 'Chemical', 'MESH:C094686', (162, 165))	('Glu (-', 'Var', (132, 138))	('increased', 'PosReg', (116, 125))	('gemcitabine', 'Chemical', 'MESH:C056507', (71, 82))	('cell viabilities', 'CPA', (4, 20))	('Glu', 'Chemical', 'MESH:C094686', (132, 135))
36155	31835877	Accordingly, we investigated AKT phosphorylation (Ser473 and Thr308) after culture of cholangiocarcinoma organoids for 7 days under two different glucose conditions.	('Ser473', 'Var', (50, 56))	('glucose', 'Chemical', 'MESH:D005947', (146, 153))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (86, 104))	('AKT', 'Gene', '207', (29, 32))	('Thr308', 'Var', (61, 67))	('phospho', 'Chemical', 'MESH:C033601', (33, 40))	('cholangiocarcinoma organoids', 'Disease', 'MESH:D018281', (86, 114))	('investigated', 'Reg', (16, 28))	('AKT', 'Gene', (29, 32))	('Thr', 'Chemical', 'MESH:C055175', (61, 64))	('Ser', 'Chemical', 'MESH:C530429', (50, 53))	('cholangiocarcinoma organoids', 'Disease', (86, 114))
36156	31835877	Levels of AKT phosphorylation of both Ser473 and Thr308 were weak in CCO1 and CCO2 when cultured under Glu (+) condition, but significantly increased under Glu (-) condition (Figure 3a).	('AKT', 'Gene', '207', (10, 13))	('Glu', 'Chemical', 'MESH:C094686', (156, 159))	('AKT', 'Gene', (10, 13))	('Thr', 'Chemical', 'MESH:C055175', (49, 52))	('Ser', 'Chemical', 'MESH:C530429', (38, 41))	('increased', 'PosReg', (140, 149))	('Ser473', 'Var', (38, 44))	('phospho', 'Chemical', 'MESH:C033601', (14, 21))	('weak', 'NegReg', (61, 65))	('Thr308', 'Var', (49, 55))	('Glu', 'Chemical', 'MESH:C094686', (103, 106))
36157	31835877	We then treated CCO1 and CCO2 with LY294002, the inhibitor of PI3K-dependent AKT phosphorylation.	('LY294002', 'Var', (35, 43))	('AKT', 'Gene', '207', (77, 80))	('phospho', 'Chemical', 'MESH:C033601', (81, 88))	('AKT', 'Gene', (77, 80))	('LY294002', 'Chemical', 'MESH:C085911', (35, 43))
36158	31835877	As shown in Figure 3b, there was no significant difference in the expression of phosphorylated AKT between Glu (+) and Glu (-) conditions in CCO1 and CCO2 after LY294002 treatment.	('phospho', 'Chemical', 'MESH:C033601', (80, 87))	('AKT', 'Gene', '207', (95, 98))	('LY294002', 'Var', (161, 169))	('LY294002', 'Chemical', 'MESH:C085911', (161, 169))	('Glu', 'Chemical', 'MESH:C094686', (119, 122))	('AKT', 'Gene', (95, 98))	('Glu', 'Chemical', 'MESH:C094686', (107, 110))
36162	31835877	As shown in Figure 4a, expression levels of stem cell markers LGR5, CD44, EpCAM, NANOG and OCT4 were significantly reduced in CCO1 and CCO2 cultured under Glu (-) condition when AKT phosphorylation was inhibited by LY294002.	('AKT', 'Gene', (178, 181))	('CD44', 'Gene', '960', (68, 72))	('LY294002', 'Chemical', 'MESH:C085911', (215, 223))	('NANOG', 'Gene', (81, 86))	('EpCAM', 'Gene', (74, 79))	('reduced', 'NegReg', (115, 122))	('CD44', 'Gene', (68, 72))	('OCT4', 'Gene', '5460', (91, 95))	('LGR5', 'Gene', (62, 66))	('AKT', 'Gene', '207', (178, 181))	('LY294002', 'Var', (215, 223))	('phospho', 'Chemical', 'MESH:C033601', (182, 189))	('LGR5', 'Gene', '8549', (62, 66))	('EpCAM', 'Gene', '4072', (74, 79))	('expression levels', 'MPA', (23, 40))	('Glu', 'Chemical', 'MESH:C094686', (155, 158))	('OCT4', 'Gene', (91, 95))	('NANOG', 'Gene', '79923', (81, 86))
36163	31835877	Flow cytometric analysis also demonstrated that the number of LGR5-positive cells was significantly decreased in CCO1 and CCO2 cultured under Glu (-) condition when AKT phosphorylation was inhibited by LY294002 (Figure 4b).	('AKT', 'Gene', (165, 168))	('LY294002', 'Var', (202, 210))	('inhibited', 'NegReg', (189, 198))	('decreased', 'NegReg', (100, 109))	('LGR5', 'Gene', (62, 66))	('LY294002', 'Chemical', 'MESH:C085911', (202, 210))	('LGR5', 'Gene', '8549', (62, 66))	('AKT', 'Gene', '207', (165, 168))	('Glu', 'Chemical', 'MESH:C094686', (142, 145))	('phospho', 'Chemical', 'MESH:C033601', (169, 176))
36164	31835877	As shown in Figure 4c, alterations in the numbers of viable cells in CCO1 and CCO2 after exposure to LY294002 and gemcitabine differed between Glu (+) and Glu (-) culture conditions.	('gemcitabine', 'Chemical', 'MESH:C056507', (114, 125))	('LY294002', 'Var', (101, 109))	('Glu', 'Chemical', 'MESH:C094686', (143, 146))	('alterations', 'Reg', (23, 34))	('Glu', 'Chemical', 'MESH:C094686', (155, 158))	('LY294002', 'Chemical', 'MESH:C085911', (101, 109))
36167	31835877	The number of viable cells in CCO1 and CCO2 was decreased only after treatment with both gemcitabine and LY294002 under Glu (-) condition, suggesting that the resistance of cholangiocarcinoma organoids to gemcitabine under glucose-free condition was dependent on AKT phosphorylation (Figure 4c).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (173, 191))	('gemcitabine', 'Chemical', 'MESH:C056507', (89, 100))	('cholangiocarcinoma organoids', 'Disease', (173, 201))	('glucose', 'Chemical', 'MESH:D005947', (223, 230))	('LY294002', 'Chemical', 'MESH:C085911', (105, 113))	('AKT', 'Gene', '207', (263, 266))	('phospho', 'Chemical', 'MESH:C033601', (267, 274))	('Glu', 'Chemical', 'MESH:C094686', (120, 123))	('LY294002', 'Var', (105, 113))	('gemcitabine', 'Chemical', 'MESH:C056507', (205, 216))	('cholangiocarcinoma organoids', 'Disease', 'MESH:D018281', (173, 201))	('AKT', 'Gene', (263, 266))
36177	31835877	We also employed Tempol as an alternative antioxidant and validated that the levels of ROS were significantly decreased by Tempol as well as NAC in CCO1 and CCO2 cultured under glucose-free condition (Figure 5b).	('ROS', 'MPA', (87, 90))	('glucose', 'Chemical', 'MESH:D005947', (177, 184))	('decreased', 'NegReg', (110, 119))	('levels', 'MPA', (77, 83))	('Tempol', 'Chemical', 'MESH:C001803', (17, 23))	('Tempol', 'Chemical', 'MESH:C001803', (123, 129))	('Tempol', 'Var', (123, 129))	('NAC', 'Chemical', 'MESH:D000111', (141, 144))
36191	31835877	Flow cytometry showed that the number of LGR5-positive cells was significantly increased under Glu (+   -) condition relative to Glu (+   +) condition in CCO1 and CCO2 (Figure 7b).	('increased', 'PosReg', (79, 88))	('LGR5', 'Gene', '8549', (41, 45))	('Glu', 'Chemical', 'MESH:C094686', (95, 98))	('Glu', 'Chemical', 'MESH:C094686', (129, 132))	('LGR5', 'Gene', (41, 45))	('Glu (+   -', 'Var', (95, 105))
36195	31835877	We also confirmed that LY294002, the inhibitor of AKT phosphorylation, decreased the number of LGR5-positive cells in CCO1 and CCO2 cultured under Glu (+   -) condition (Figure 7b).	('LGR5', 'Gene', '8549', (95, 99))	('AKT', 'Gene', '207', (50, 53))	('phospho', 'Chemical', 'MESH:C033601', (54, 61))	('LY294002', 'Chemical', 'MESH:C085911', (23, 31))	('LGR5', 'Gene', (95, 99))	('AKT', 'Gene', (50, 53))	('LY294002', 'Var', (23, 31))	('Glu', 'Chemical', 'MESH:C094686', (147, 150))	('decreased', 'NegReg', (71, 80))
36211	31835877	Here, phosphorylation of AKT was elevated in cholangiocarcinoma organoids under glucose-free condition, and inhibition of AKT phosphorylation by LY294002 led to a decrease of stemness and drug resistance, suggesting that enhancement of the stem cell phenotype in cancer cells under condition of glucose depletion requires AKT phosphorylation.	('drug resistance', 'Phenotype', 'HP:0020174', (188, 203))	('glucose', 'Chemical', 'MESH:D005947', (80, 87))	('cancer', 'Disease', (263, 269))	('phospho', 'Chemical', 'MESH:C033601', (326, 333))	('AKT', 'Gene', '207', (25, 28))	('AKT', 'Gene', '207', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cholangiocarcinoma organoids', 'Disease', (45, 73))	('decrease of stemness', 'Disease', (163, 183))	('decrease of stemness', 'Disease', 'MESH:D020295', (163, 183))	('enhancement', 'PosReg', (221, 232))	('LY294002', 'Var', (145, 153))	('phospho', 'Chemical', 'MESH:C033601', (6, 13))	('phospho', 'Chemical', 'MESH:C033601', (126, 133))	('AKT', 'Gene', (322, 325))	('drug resistance', 'CPA', (188, 203))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('elevated', 'PosReg', (33, 41))	('cholangiocarcinoma organoids', 'Disease', 'MESH:D018281', (45, 73))	('phosphorylation', 'MPA', (6, 21))	('AKT', 'Gene', (122, 125))	('AKT', 'Gene', (25, 28))	('LY294002', 'Chemical', 'MESH:C085911', (145, 153))	('AKT', 'Gene', '207', (322, 325))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (45, 63))	('glucose', 'Chemical', 'MESH:D005947', (295, 302))	('inhibition', 'Var', (108, 118))
36212	31835877	We examined expression levels of genes associated with the AKT signaling such as mTOR and the BCL2 superfamily in cholangiocarcinoma organoids under glucose-free condition after treatment with LY294002, but there was no significant difference in the expression levels of these genes by inhibition of AKT phosphorylation (Supplementary Figure S2).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (114, 132))	('cholangiocarcinoma organoids', 'Disease', (114, 142))	('LY294002', 'Chemical', 'MESH:C085911', (193, 201))	('glucose', 'Chemical', 'MESH:D005947', (149, 156))	('AKT', 'Gene', (59, 62))	('BCL2', 'Gene', '596', (94, 98))	('AKT', 'Gene', (300, 303))	('phospho', 'Chemical', 'MESH:C033601', (304, 311))	('LY294002', 'Var', (193, 201))	('cholangiocarcinoma organoids', 'Disease', 'MESH:D018281', (114, 142))	('AKT', 'Gene', '207', (59, 62))	('BCL2', 'Gene', (94, 98))	('mTOR', 'Gene', (81, 85))	('expression', 'MPA', (12, 22))	('mTOR', 'Gene', '2475', (81, 85))	('inhibition', 'NegReg', (286, 296))	('AKT', 'Gene', '207', (300, 303))
36215	31835877	H2O2 is known to be a more weakly reactive molecule than other intracellular ROS molecules, and is also a candidate intracellular signaling molecule.	('weakly reactive molecule', 'MPA', (27, 51))	('H2O2', 'Var', (0, 4))	('H2O2', 'Chemical', 'MESH:D014867', (0, 4))
36227	31835877	Figure S1: The whole images of Western blotting, Figure S2: (a) Expression of the BCL2 superfamily (BCL2, MCL1 and BAX) in CCO1 and CCO2 cultured without glucose after treatment with the AKT phosphorylation inhibitor (AKTi), LY264002.	('BCL2', 'Gene', (82, 86))	('AKT', 'Gene', '207', (187, 190))	('phospho', 'Chemical', 'MESH:C033601', (191, 198))	('MCL1', 'Gene', '4170', (106, 110))	('LY264002', 'Var', (225, 233))	('BCL2', 'Gene', '596', (100, 104))	('MCL1', 'Gene', (106, 110))	('BCL2', 'Gene', (100, 104))	('AKT', 'Gene', (187, 190))	('AKT', 'Gene', '207', (218, 221))	('glucose', 'Chemical', 'MESH:D005947', (154, 161))	('BCL2', 'Gene', '596', (82, 86))	('BAX', 'Gene', (115, 118))	('BAX', 'Gene', '581', (115, 118))	('AKT', 'Gene', (218, 221))	('LY264002', 'Chemical', 'MESH:C430423', (225, 233))
36243	30881042	Recently, numerous studies indicated that aberrant expression of lncRNAs was involved in tumorigenesis and cancer progression, including CCA.	('involved', 'Reg', (77, 85))	('aberrant expression', 'Var', (42, 61))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('CCA', 'Disease', (137, 140))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('lncRNAs', 'Gene', (65, 72))	('cancer', 'Disease', (107, 113))	('tumor', 'Disease', (89, 94))
36262	30881042	Furthermore, overexpression CCAT1 was significantly correlated with the lymph node metastasis in CCA (OR, 4.75; 95% CI 2.65-8.52; P<0.001) (Figure 2).	('correlated', 'Reg', (52, 62))	('CCA', 'Disease', (97, 100))	('CCAT1', 'Gene', (28, 33))	('overexpression', 'Var', (13, 27))	('CCAT1', 'Gene', '100507056', (28, 33))	('lymph node metastasis', 'CPA', (72, 93))
36269	30881042	By further subgroup analysis, overexpression of CCAT2 was obviously associated with poor OS (HR, 2.00; 95% CI 0.96-3.03; P<0.001).	('poor OS', 'Disease', (84, 91))	('overexpression', 'Var', (30, 44))	('CCAT2', 'Gene', '101805488', (48, 53))	('CCAT2', 'Gene', (48, 53))
36366	30233792	Finally, a high NLR and a high BMI were extracted as independent risk factors for postoperative complications after PD for distal cholangiocarcinoma.	('NLR', 'MPA', (16, 19))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (130, 148))	('PD', 'Disease', 'MESH:D010300', (116, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (130, 148))	('high', 'Var', (11, 15))	('cholangiocarcinoma', 'Disease', (130, 148))
36368	30233792	The authors speculate that this may be because the pancreas of patients with a high BMI contains a large fatty component, which results in a fragile parenchyma (so called 'soft pancreas').	('results in', 'Reg', (128, 138))	('pancreas', 'Disease', (177, 185))	('fragile parenchyma', 'Disease', 'MESH:D010195', (141, 159))	('pancreas', 'Disease', (51, 59))	('pancreas', 'Disease', 'MESH:D010190', (177, 185))	('high', 'Var', (79, 83))	('fragile parenchyma', 'Disease', (141, 159))	('patients', 'Species', '9606', (63, 71))	('pancreas', 'Disease', 'MESH:D010190', (51, 59))
36422	27058753	Patients with CA19-9<466 U/ml were more responsive to chemotherapeutic agents than those with CA19-9>=571 U/ml (88.9% vs 0%, P<0.001).	('Patients', 'Species', '9606', (0, 8))	('responsive to chemotherapeutic agents', 'MPA', (40, 77))	('CA19-9<466 U/ml', 'Var', (14, 29))
36427	27058753	More recently, cisplatin plus GEM resulted in a significant survival advantage without substantial toxicity compared with GEM alone in patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer or ampullary cancer.	('patients', 'Species', '9606', (135, 143))	('toxicity', 'Disease', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cisplatin', 'Var', (15, 24))	('gallbladder cancer', 'Disease', (200, 218))	('cisplatin', 'Chemical', 'MESH:D002945', (15, 24))	('GEM', 'Gene', '2669', (122, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('GEM', 'Gene', (122, 125))	('ampullary cancer', 'Disease', 'MESH:D009369', (222, 238))	('ampullary cancer', 'Disease', (222, 238))	('locally advanced', 'Disease', (149, 165))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (180, 198))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('toxicity', 'Disease', 'MESH:D064420', (99, 107))	('gallbladder cancer', 'Disease', 'MESH:D005706', (200, 218))	('cholangiocarcinoma', 'Disease', (180, 198))	('GEM', 'Gene', (30, 33))	('GEM', 'Gene', '2669', (30, 33))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (180, 198))
36451	27058753	GEM monotherapy also significantly improved OS compared with S-1 monotherapy (hazard ratio for death, 1.96; 95%CI, 1.09-3.50; P=0.024).	('improved', 'PosReg', (35, 43))	('monotherapy', 'Var', (4, 15))	('death', 'Disease', 'MESH:D003643', (95, 100))	('death', 'Disease', (95, 100))	('S-1', 'Gene', (61, 64))	('OS', 'Chemical', '-', (44, 46))	('GEM', 'Gene', '2669', (0, 3))	('GEM', 'Gene', (0, 3))	('S-1', 'Gene', '5707', (61, 64))
36522	27058753	Patients were eligible if they met the following criteria: (1) HC diagnosed by clinical pathological examination or typical radiographic findings; (2) unresectable locally advanced or metastatic disease; (3) except for biliary drainage, no prior treatment for HC, including surgery, radiation or chemotherapy; (4) age>18 years; (5) capable of oral intake; (6) hematologic and biochemical parameters considered as follows: white blood count>3000/mm3, hemoglobin >9.0g/dL, platelet count >100000/mm3, total bilirubin<3.0 times the upper limit of normal (ULN), aspartate/alanine transaminases<5 times the ULN, and creatinine level<1.5 times the ULN.	('>3000/mm3', 'Var', (439, 448))	('bilirubin', 'Chemical', 'MESH:D001663', (505, 514))	('creatinine level', 'MPA', (611, 627))	('Patients', 'Species', '9606', (0, 8))	('upper limit', 'MPA', (529, 540))	('total bilirubin', 'MPA', (499, 514))	('aspartate/alanine transaminases', 'MPA', (558, 589))	('>100000/mm3', 'Var', (486, 497))	('platelet', 'MPA', (471, 479))
36528	27058753	Three doses of S-1 were used based on body surface area (BSA): BSA<=1.25 m2, 80 mg per day; 1.25 m2>BSA<1.5 m2, 100 mg per day; BSA>=1.5 m2, 120 mg per day.	('1.25 m2>', 'Var', (92, 100))	('S-1', 'Gene', '5707', (15, 18))	('S-1', 'Gene', (15, 18))
36588	21177527	While HCCC in mice is reportedly induced by chemicals such as benzidine dihydrochloride and N-2-acetylaminofluorene, treatment-related HCCCs in mice were not observed in the NTP data set of 2-year carcinogenicity studies.	('induced', 'Reg', (33, 40))	('mice', 'Species', '10090', (144, 148))	('mice', 'Species', '10090', (14, 18))	('N-2-acetylaminofluorene', 'Chemical', 'MESH:D015073', (92, 115))	('benzidine dihydrochloride', 'Chemical', 'MESH:C029876', (62, 87))	('N-2-acetylaminofluorene', 'Var', (92, 115))	('HCCC', 'Disease', (6, 10))	('NTP', 'Chemical', '-', (174, 177))
36943	33922362	Indeed, more than 60% of cholangiocarcinoma patients harbour unique gene aberrations including fibroblast growth factor receptor (FGFR) 2 gene translocations, isocitrate dehydrogenase-1 (IDH1) and KRAS proto-oncogene mutations, and receptor tyrosine-protein kinase erbB-2 (ERBB2) amplification.	('ERBB2', 'Gene', '2064', (273, 278))	('FGFR) 2', 'Gene', '2263', (130, 137))	('KRAS', 'Gene', (197, 201))	('fibroblast growth factor receptor', 'Gene', '396762', (95, 128))	('patients', 'Species', '9606', (44, 52))	('amplification', 'Var', (280, 293))	('rat', 'Species', '10116', (77, 80))	('fibroblast growth factor receptor', 'Gene', (95, 128))	('receptor tyrosine-protein kinase erbB-2', 'Gene', (232, 271))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (25, 43))	('rat', 'Species', '10116', (165, 168))	('IDH1', 'Gene', (187, 191))	('cholangiocarcinoma', 'Disease', (25, 43))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (25, 43))	('receptor tyrosine-protein kinase erbB-2', 'Gene', '2064', (232, 271))	('ERBB2', 'Gene', (273, 278))	('IDH1', 'Gene', '3417', (187, 191))	('KRAS', 'Gene', '3845', (197, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('mutations', 'Var', (217, 226))
36965	33922362	Moreover, in a transcriptomic analysis of 10 iCCs, high VEGF expression was associated with TME polarization, restricted T cell infiltration, and poor responsiveness to immunotherapy.	('TME polarization', 'CPA', (92, 108))	('VEGF', 'Gene', (56, 60))	('high', 'Var', (51, 55))	('restricted T cell infiltration', 'CPA', (110, 140))	('VEGF', 'Gene', '7422', (56, 60))	('rat', 'Species', '10116', (134, 137))	('expression', 'MPA', (61, 71))
36976	33922362	The presence of increased circulating neutrophil-to lymphocyte ratio (NLR) has been associated with poor clinical outcome in iCC patients, whilst CD66+ or CD15+ TANs in cholangiocarcinoma have also been correlated with worse survival.	('CD66+', 'Var', (146, 151))	('patients', 'Species', '9606', (129, 137))	('cholangiocarcinoma', 'Disease', (169, 187))	('increased', 'PosReg', (16, 25))	('increased circulating neutrophil', 'Phenotype', 'HP:0011897', (16, 48))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (169, 187))	('CD15', 'Gene', (155, 159))	('circulating neutrophil-to lymphocyte ratio', 'MPA', (26, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('rat', 'Species', '10116', (63, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (169, 187))	('CD15', 'Gene', '2526', (155, 159))	('iCC', 'Disease', (125, 128))
37012	33922362	Interactions between CXCR4 and CXCL12 have been demonstrated to activate the PI3K/AKT and ERK1/2 pathway, and Wnt/beta-caterin signaling pathway.	('CXCL12', 'Gene', (31, 37))	('Wnt/beta-caterin signaling pathway', 'Pathway', (110, 144))	('ERK1/2', 'Gene', (90, 96))	('ERK1/2', 'Gene', '5595;5594', (90, 96))	('Interactions', 'Var', (0, 12))	('CXCR4', 'Gene', '7852', (21, 26))	('CXCL12', 'Gene', '6387', (31, 37))	('AKT', 'Gene', '207', (82, 85))	('CXCR4', 'Gene', (21, 26))	('rat', 'Species', '10116', (55, 58))	('AKT', 'Gene', (82, 85))	('activate', 'PosReg', (64, 72))
37015	33922362	Manipulations of the immune checkpoints PD-1 and CTLA-4 are among the immune escape mechanisms of cancer cells and the PD-1/PD-L1 pathway seems to play a pivotal role in the development of a tumor-tolerant TME in BTC.	('PD-L1', 'Gene', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('CTLA-4', 'Gene', (49, 55))	('BTC', 'Phenotype', 'HP:0100574', (213, 216))	('PD-L1', 'Gene', '29126', (124, 129))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('PD-1', 'Gene', (40, 44))	('cancer', 'Disease', (98, 104))	('tumor', 'Disease', (191, 196))	('CTLA-4', 'Gene', '1493', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('Manipulations', 'Var', (0, 13))
37045	33922362	M7824, also known as bintrafusp alfa, is a first-in-class bifunctional fusion protein immunotherapy, which combines a TGF-beta 'trap' with an anti-PD-L1 immunoglobulin G (IgG) monoclonal antibody, thus simultaneously targeting two immune-suppressive pathways in the TME.	('PD-L1', 'Gene', '29126', (147, 152))	('TGF-beta', 'Gene', (118, 126))	('immune-suppressive pathways', 'Pathway', (231, 258))	('targeting', 'Reg', (217, 226))	('M7824', 'Var', (0, 5))	('PD-L1', 'Gene', (147, 152))	('TGF-beta', 'Gene', '7039', (118, 126))
37047	33922362	Poly adenosine diphosphate-ribose polymerase inhibitors (PARPi) represent a novel class of targeted cancer therapy, by exploiting synthetic lethality in tumours which harbour germline and somatic alterations in DNA damage repair (DDR) genes; whereas their combination with immune-oncology appears to be a promising treatment approach for solid tumors.	('tumours', 'Disease', 'MESH:D009369', (153, 160))	('DDR) genes', 'Gene', (230, 240))	('tumours', 'Disease', (153, 160))	('oncology', 'Phenotype', 'HP:0002664', (280, 288))	('rat', 'Species', '10116', (200, 203))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('adenosine', 'Chemical', 'MESH:D000241', (5, 14))	('solid tumors', 'Disease', (338, 350))	('tumors', 'Phenotype', 'HP:0002664', (344, 350))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('alterations', 'Var', (196, 207))	('solid tumors', 'Disease', 'MESH:D009369', (338, 350))
37048	33922362	The biological rationale behind their synergistic effects has been thoroughly determined; DDR gene aberrations have been associated with genomic instability, immunomodulation of TME, and increased tumor mutational burden (TMB).	('genomic', 'MPA', (137, 144))	('rat', 'Species', '10116', (103, 106))	('rat', 'Species', '10116', (15, 18))	('DDR gene', 'Gene', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('associated', 'Reg', (121, 131))	('increased', 'PosReg', (187, 196))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('aberrations', 'Var', (99, 110))	('tumor', 'Disease', (197, 202))
37049	33922362	DDR mutations have been observed in 28.9-63.5% of BTC, with BRCA mutations occur-ring in less than 7% of these patients.	('BTC', 'Disease', (50, 53))	('BTC', 'Phenotype', 'HP:0100574', (50, 53))	('BRCA', 'Gene', '672', (60, 64))	('DDR', 'Disease', (0, 3))	('observed', 'Reg', (24, 32))	('mutations', 'Var', (4, 13))	('BRCA', 'Gene', (60, 64))	('patients', 'Species', '9606', (111, 119))
37050	33922362	Currently, two early-phase trials (NCT03639935, NCT03991832) are underway to evaluate the efficacy from the combination of PARPi and ICI treatment and uncover the patient population which will potentially derive the greatest benefit from this combo.	('NCT03639935', 'Var', (35, 46))	('patient', 'Species', '9606', (163, 170))	('NCT03991832', 'Var', (48, 59))
37061	33922362	Another phase II trial of personalized peptide vaccine evaluated the feasibility of HLA-matched vaccine peptides in six iCC patients and proved that low levels of IL-6 were significantly associated with improved OS (hazard ratio = 1.123; 95% CI 1.008-1.252; p = 0.035).	('IL-6', 'Gene', (163, 167))	('improved', 'PosReg', (203, 211))	('IL-6', 'Gene', '3569', (163, 167))	('rat', 'Species', '10116', (223, 226))	('low levels', 'Var', (149, 159))	('patients', 'Species', '9606', (124, 132))
37068	33922362	ACT of TILs containing CD4+ erbb2 interacting protein (ERBB2IP) mutation-reactive T cells generated promising results in a patient with metastatic cholangiocarcinoma; the patient achieved a 30% decrease in tumor lesions, with prolonged disease stabilization of 13 months, while the rechallenge with a second T cell infusion resulted in further response.	('rat', 'Species', '10116', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('patient', 'Species', '9606', (123, 130))	('patient', 'Species', '9606', (171, 178))	('cholangiocarcinoma', 'Disease', (147, 165))	('CD4', 'Gene', (23, 26))	('tumor lesions', 'Disease', (206, 219))	('erbb2 interacting protein', 'Gene', (28, 53))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (147, 165))	('erbb2 interacting protein', 'Gene', '55914', (28, 53))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (147, 165))	('CD4', 'Gene', '920', (23, 26))	('mutation-reactive', 'Var', (64, 81))	('tumor lesions', 'Disease', 'MESH:D009369', (206, 219))	('ERBB2IP', 'Gene', '55914', (55, 62))	('ERBB2IP', 'Gene', (55, 62))	('decrease', 'NegReg', (194, 202))
37083	32273758	The siRNA interference was used to knock down USP8 in cholangiocarcinoma cell lines QBC939 and RBE; Hucct-1 cells were transfected with pcDNA3.1-USP8 to up-regulate its expression.	('USP8', 'Gene', (145, 149))	('USP8', 'Gene', '9101', (145, 149))	('USP8', 'Gene', (46, 50))	('Hucct-1', 'CellLine', 'CVCL:0324', (100, 107))	('USP8', 'Gene', '9101', (46, 50))	('knock', 'Var', (35, 40))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (54, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('up-regulate', 'PosReg', (153, 164))	('expression', 'MPA', (169, 179))	('cholangiocarcinoma', 'Disease', (54, 72))	('si', 'Chemical', 'MESH:D012825', (175, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('si', 'Chemical', 'MESH:D012825', (4, 6))
37086	32273758	We demonstrated that knockdown of USP8 significantly inhibited the proliferation, migration and invasion of QBC939 and RBE cells in vitro, while USP8 overexpression showed significant promoting effects on Hucct-1 cells.	('USP8', 'Gene', (145, 149))	('USP8', 'Gene', '9101', (145, 149))	('inhibited', 'NegReg', (53, 62))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('si', 'Chemical', 'MESH:D012825', (172, 174))	('si', 'Chemical', 'MESH:D012825', (160, 162))	('promoting', 'PosReg', (184, 193))	('migration', 'CPA', (82, 91))	('invasion', 'CPA', (96, 104))	('proliferation', 'CPA', (67, 80))	('Hucct-1', 'CellLine', 'CVCL:0324', (205, 212))	('USP8', 'Gene', (34, 38))	('USP8', 'Gene', '9101', (34, 38))	('knockdown', 'Var', (21, 30))	('si', 'Chemical', 'MESH:D012825', (100, 102))
37087	32273758	Moreover, silencing of USP8 also promoted apoptosis in cholangiocarcinoma cells by regulating the Bcl-2/Bax axis and Caspase cascade; up-regulation of USP8 decreased apoptosis in Hucct-1 cells.	('promoted', 'PosReg', (33, 41))	('Caspase', 'Gene', '841;842', (117, 124))	('USP8', 'Gene', (23, 27))	('USP8', 'Gene', '9101', (23, 27))	('Bax', 'Gene', (104, 107))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('Hucct-1', 'CellLine', 'CVCL:0324', (179, 186))	('Bax', 'Gene', '581', (104, 107))	('Bcl-2', 'Gene', (98, 103))	('up-regulation', 'PosReg', (134, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('apoptosis', 'CPA', (42, 51))	('decreased', 'NegReg', (156, 165))	('Bcl-2', 'Gene', '596', (98, 103))	('si', 'Chemical', 'MESH:D012825', (172, 174))	('regulating', 'Reg', (83, 93))	('silencing', 'Var', (10, 19))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (55, 73))	('Caspase', 'Gene', (117, 124))	('cholangiocarcinoma', 'Disease', (55, 73))	('USP8', 'Gene', (151, 155))	('USP8', 'Gene', '9101', (151, 155))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (55, 73))	('apoptosis', 'CPA', (166, 175))
37088	32273758	Importantly, knockdown of USP8 inhibited activation of the Akt signaling pathway by decreasing the phosphorylation level of Akt and up-regulated p53 expression, while USP8 overexpression increased activation of the Akt signaling pathway in Hucct-1 cells.	('decreasing', 'NegReg', (84, 94))	('si', 'Chemical', 'MESH:D012825', (90, 92))	('p53', 'Gene', (145, 148))	('knockdown', 'Var', (13, 22))	('Akt', 'Gene', (124, 127))	('phosphorylation level', 'MPA', (99, 120))	('up-regulated', 'PosReg', (132, 144))	('si', 'Chemical', 'MESH:D012825', (182, 184))	('Akt', 'Gene', '207', (124, 127))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('Akt', 'Gene', (59, 62))	('Hucct-1', 'CellLine', 'CVCL:0324', (240, 247))	('Akt', 'Gene', '207', (59, 62))	('expression', 'MPA', (149, 159))	('si', 'Chemical', 'MESH:D012825', (219, 221))	('si', 'Chemical', 'MESH:D012825', (155, 157))	('p53', 'Gene', '7157', (145, 148))	('USP8', 'Gene', (26, 30))	('USP8', 'Gene', '9101', (26, 30))	('USP8', 'Gene', (167, 171))	('Akt', 'Gene', (215, 218))	('USP8', 'Gene', '9101', (167, 171))	('inhibited', 'NegReg', (31, 40))	('Akt', 'Gene', '207', (215, 218))
37089	32273758	Further, IGF-1 could reverse the inhibitory effects of USP8 knockdown on the Akt signaling pathway and the proliferation of QBC939 and RBE cells.	('Akt', 'Gene', '207', (77, 80))	('IGF-1', 'Gene', '3479', (9, 14))	('IGF-1', 'Gene', (9, 14))	('proliferation', 'CPA', (107, 120))	('Akt', 'Gene', (77, 80))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('knockdown', 'Var', (60, 69))	('USP8', 'Gene', (55, 59))	('USP8', 'Gene', '9101', (55, 59))
37128	32273758	CCK8 assay was performed to examine cell proliferation when USP8 was knocked down.	('knocked down', 'Var', (69, 81))	('USP8', 'Gene', (60, 64))	('USP8', 'Gene', '9101', (60, 64))
37147	32273758	The outcomes showed that silencing of USP8 significantly inhibited the proliferation of QBC939 cells in comparison with control cells (Figure 1D).	('silencing', 'Var', (25, 34))	('inhibited', 'NegReg', (57, 66))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('USP8', 'Gene', (38, 42))	('USP8', 'Gene', '9101', (38, 42))	('proliferation', 'CPA', (71, 84))	('si', 'Chemical', 'MESH:D012825', (25, 27))
37150	32273758	As shown in Figure 1G, knockdown of USP8 resulted in significant decrease in the number of formed colonies in both QBC939 and QBE cells, indicating that down-regulation of USP8 inhibits clonogenic ability of cholangiocarcinoma cells.	('USP8', 'Gene', (36, 40))	('USP8', 'Gene', '9101', (36, 40))	('down-regulation', 'NegReg', (153, 168))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('knockdown', 'Var', (23, 32))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (208, 226))	('number of formed colonies', 'CPA', (81, 106))	('cholangiocarcinoma', 'Disease', (208, 226))	('decrease', 'NegReg', (65, 73))	('inhibits', 'NegReg', (177, 185))	('clonogenic ability of', 'CPA', (186, 207))	('USP8', 'Gene', (172, 176))	('USP8', 'Gene', '9101', (172, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (208, 226))
37151	32273758	As indicated in Figure 1H, the clonogenic ability of Hucct-1 cells was significantly promoted by USP8 overexpression.	('USP8', 'Gene', (97, 101))	('USP8', 'Gene', '9101', (97, 101))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('clonogenic ability of', 'CPA', (31, 52))	('promoted', 'PosReg', (85, 93))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('Hucct-1', 'CellLine', 'CVCL:0324', (53, 60))	('overexpression', 'Var', (102, 116))
37153	32273758	As shown in Figure 2A, the number of migrating QBC939 and QBE cells was both significantly reduced by si-USP8 compared with the corresponding control cells.	('si', 'Chemical', 'MESH:D012825', (77, 79))	('reduced', 'NegReg', (91, 98))	('si', 'Chemical', 'MESH:D012825', (102, 104))	('si-USP8', 'Var', (102, 109))	('QBE cells', 'CPA', (58, 67))
37157	32273758	Hence, we examined the MMP9 activity in cholangiocarcinoma cells after USP8 was silenced.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (40, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('MMP9', 'Gene', (23, 27))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (40, 58))	('USP8', 'Gene', (71, 75))	('USP8', 'Gene', '9101', (71, 75))	('examined', 'Reg', (10, 18))	('silenced', 'Var', (80, 88))	('cholangiocarcinoma', 'Disease', (40, 58))	('MMP9', 'Gene', '4318', (23, 27))	('si', 'Chemical', 'MESH:D012825', (80, 82))
37158	32273758	Gelatin zymography analysis showed that knockdown of USP8 significantly inhibited the MMP9 activity in both QBC939 and QBE cells (Figure 2D).	('USP8', 'Gene', (53, 57))	('USP8', 'Gene', '9101', (53, 57))	('knockdown', 'Var', (40, 49))	('MMP9', 'Gene', '4318', (86, 90))	('MMP9', 'Gene', (86, 90))	('inhibited', 'NegReg', (72, 81))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('si', 'Chemical', 'MESH:D012825', (24, 26))
37165	32273758	To determine whether UPS8 affects the Akt signaling pathway which plays critical roles in cellular physiological function and tumor progression, Western blot analysis was conducted.	('si', 'Chemical', 'MESH:D012825', (163, 165))	('affects', 'Reg', (26, 33))	('si', 'Chemical', 'MESH:D012825', (139, 141))	('Akt', 'Gene', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('UPS8', 'Var', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('Akt', 'Gene', '207', (38, 41))	('si', 'Chemical', 'MESH:D012825', (102, 104))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('tumor', 'Disease', (126, 131))
37167	32273758	Accordingly, the expression of downstream proteins Cyclin D1 and p70S6k was significantly downregulated by loss of USP8 in cholangiocarcinoma cells (Figure 4A-C).	('Cyclin D1', 'Gene', (51, 60))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('cholangiocarcinoma', 'Disease', (123, 141))	('USP8', 'Gene', (115, 119))	('USP8', 'Gene', '9101', (115, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('p70S6k', 'Gene', '6198', (65, 71))	('expression', 'MPA', (17, 27))	('loss', 'Var', (107, 111))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (123, 141))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (123, 141))	('downregulated', 'NegReg', (90, 103))	('Cyclin D1', 'Gene', '595', (51, 60))	('p70S6k', 'Gene', (65, 71))
37168	32273758	In Hucct-1 cells, the expression of p-Akt, Cyclin D1 and p70S6k was up-regulated by USP8 overexpression compared to the control group (Figure 4D).	('si', 'Chemical', 'MESH:D012825', (28, 30))	('p-Akt', 'Gene', '207', (36, 41))	('Hucct-1', 'CellLine', 'CVCL:0324', (3, 10))	('p70S6k', 'Gene', (57, 63))	('p-Akt', 'Gene', (36, 41))	('Cyclin D1', 'Gene', '595', (43, 52))	('USP8', 'Gene', (84, 88))	('USP8', 'Gene', '9101', (84, 88))	('Cyclin D1', 'Gene', (43, 52))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('p70S6k', 'Gene', '6198', (57, 63))	('up-regulated', 'PosReg', (68, 80))	('overexpression', 'Var', (89, 103))	('expression', 'MPA', (22, 32))
37169	32273758	Moreover, IGF-1, the Akt pathway activator, significantly reversed the inhibitory effects of USP8 knockdown on the expression of p-Akt, Cyclin D1 and p70S6k (Figure 4E).	('USP8', 'Gene', '9101', (93, 97))	('p-Akt', 'Gene', (129, 134))	('Akt', 'Gene', (131, 134))	('Cyclin D1', 'Gene', '595', (136, 145))	('knockdown', 'Var', (98, 107))	('Akt', 'Gene', '207', (21, 24))	('p70S6k', 'Gene', (150, 156))	('Cyclin D1', 'Gene', (136, 145))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('IGF-1', 'Gene', '3479', (10, 15))	('Akt', 'Gene', '207', (131, 134))	('Akt', 'Gene', (21, 24))	('p70S6k', 'Gene', '6198', (150, 156))	('IGF-1', 'Gene', (10, 15))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('p-Akt', 'Gene', '207', (129, 134))	('USP8', 'Gene', (93, 97))
37170	32273758	Further, the inhibitory effect of si-USP8 on cell proliferation was significantly reversed by IGF-1 compared to the si-USP8 group (Figure 4G and H).	('IGF-1', 'Gene', '3479', (94, 99))	('IGF-1', 'Gene', (94, 99))	('si-USP8', 'Var', (34, 41))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('cell proliferation', 'CPA', (45, 63))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('si', 'Chemical', 'MESH:D012825', (34, 36))
37178	32273758	In the present study, for the first time, we demonstrated that knockdown of USP8 significantly inhibited the proliferation, migration and invasion of cholangiocarcinoma cells, and decreased the MMP9 activity, while USP8 overexpression showed significant promoting effects, suggesting that USP8 functions as an oncogene in the growth and metastatic ability of cholangiocarcinoma.	('si', 'Chemical', 'MESH:D012825', (81, 83))	('invasion', 'CPA', (138, 146))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (359, 377))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('cholangiocarcinoma', 'Disease', (359, 377))	('si', 'Chemical', 'MESH:D012825', (230, 232))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (359, 377))	('proliferation', 'CPA', (109, 122))	('USP8', 'Gene', (289, 293))	('USP8', 'Gene', '9101', (289, 293))	('USP8', 'Gene', (76, 80))	('USP8', 'Gene', '9101', (76, 80))	('si', 'Chemical', 'MESH:D012825', (142, 144))	('migration', 'CPA', (124, 133))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (150, 168))	('decreased', 'NegReg', (180, 189))	('MMP9', 'Gene', (194, 198))	('MMP9', 'Gene', '4318', (194, 198))	('knockdown', 'Var', (63, 72))	('cholangiocarcinoma', 'Disease', (150, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (368, 377))	('promoting', 'PosReg', (254, 263))	('USP8', 'Gene', (215, 219))	('USP8', 'Gene', '9101', (215, 219))	('si', 'Chemical', 'MESH:D012825', (242, 244))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (150, 168))	('inhibited', 'NegReg', (95, 104))
37181	32273758	Jeong et al show that USP8 prevents extrinsic apoptosis by deubiquitylating and stabilizing the long isoform of FLICE-like inhibitory protein (FLIPL) which is a key regulator of death receptor-mediated apoptosis, and knockdown of USP8 could promote death receptor-induced apoptosis through downregulation of FLIPL and result in up-regulation of cleaved Caspase 8 and cleaved Caspase 3 in HeLa cells.	('si', 'Chemical', 'MESH:D012825', (208, 210))	('FLIPL', 'Gene', (308, 313))	('si', 'Chemical', 'MESH:D012825', (278, 280))	('Caspase 8', 'Gene', (353, 362))	('death receptor-induced apoptosis', 'CPA', (249, 281))	('Caspase 3', 'Gene', '836', (375, 384))	('USP8', 'Gene', (22, 26))	('USP8', 'Gene', '9101', (22, 26))	('knockdown', 'Var', (217, 226))	('downregulation', 'NegReg', (290, 304))	('HeLa', 'CellLine', 'CVCL:0030', (388, 392))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('Caspase 3', 'Gene', (375, 384))	('cleaved', 'MPA', (345, 352))	('promote', 'PosReg', (241, 248))	('USP8', 'Gene', (230, 234))	('USP8', 'Gene', '9101', (230, 234))	('up-regulation', 'PosReg', (328, 341))	('Caspase 8', 'Gene', '841', (353, 362))	('si', 'Chemical', 'MESH:D012825', (42, 44))
37182	32273758	Herein, we found that silencing of USP8 could induce apoptosis in cholangiocarcinoma cells, down-regulate the expression of Bcl-2, and up-regulate the expression of Bax, cleaved Caspase 3 and cleaved Caspase 9.	('Caspase 3', 'Gene', '836', (178, 187))	('Caspase 9', 'Gene', '842', (200, 209))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (66, 84))	('down-regulate', 'NegReg', (92, 105))	('apoptosis', 'CPA', (53, 62))	('cholangiocarcinoma', 'Disease', (66, 84))	('Bcl-2', 'Gene', (124, 129))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (66, 84))	('silencing', 'Var', (22, 31))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('Caspase 9', 'Gene', (200, 209))	('expression', 'MPA', (151, 161))	('Bcl-2', 'Gene', '596', (124, 129))	('Caspase 3', 'Gene', (178, 187))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('Bax', 'Gene', (165, 168))	('expression', 'MPA', (110, 120))	('up-regulate', 'PosReg', (135, 146))	('si', 'Chemical', 'MESH:D012825', (157, 159))	('induce', 'PosReg', (46, 52))	('USP8', 'Gene', (35, 39))	('USP8', 'Gene', '9101', (35, 39))	('cleaved', 'MPA', (170, 177))	('Bax', 'Gene', '581', (165, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('si', 'Chemical', 'MESH:D012825', (59, 61))
37192	32273758	Herein, our data revealed that silencing of USP8 could markedly inhibit activation of the Akt signaling pathway by decreasing the phosphorylation of Akt in cholangiocarcinoma cells.	('si', 'Chemical', 'MESH:D012825', (31, 33))	('phosphorylation', 'MPA', (130, 145))	('silencing', 'Var', (31, 40))	('Akt', 'Gene', (90, 93))	('Akt', 'Gene', (149, 152))	('USP8', 'Gene', (44, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (156, 174))	('USP8', 'Gene', '9101', (44, 48))	('inhibit', 'NegReg', (64, 71))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (156, 174))	('Akt', 'Gene', '207', (149, 152))	('cholangiocarcinoma', 'Disease', (156, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('Akt', 'Gene', '207', (90, 93))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('decreasing', 'NegReg', (115, 125))	('si', 'Chemical', 'MESH:D012825', (94, 96))
37193	32273758	Moreover, the inhibitory effects of USP8 knockdown on the Akt signaling pathway and cell proliferationwerereversed by IGF-1.	('USP8', 'Gene', (36, 40))	('cell proliferationwerereversed', 'CPA', (84, 114))	('USP8', 'Gene', '9101', (36, 40))	('IGF-1', 'Gene', '3479', (118, 123))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('IGF-1', 'Gene', (118, 123))	('Akt', 'Gene', '207', (58, 61))	('Akt', 'Gene', (58, 61))	('knockdown', 'Var', (41, 50))
37195	32273758	In this study, we for the first time demonstrated that USP8 exerts an oncogenic role in the progression of cholangiocarcinoma, decrease in USP8 expression can significantly inhibit cell proliferation, migration and invasion, as well as promote apoptosis in cholangiocarcinoma cells.	('cholangiocarcinoma', 'Disease', (107, 125))	('apoptosis', 'CPA', (244, 253))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (107, 125))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (257, 275))	('inhibit', 'NegReg', (173, 180))	('si', 'Chemical', 'MESH:D012825', (159, 161))	('cholangiocarcinoma', 'Disease', (257, 275))	('expression', 'MPA', (144, 154))	('si', 'Chemical', 'MESH:D012825', (150, 152))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (257, 275))	('decrease', 'Var', (127, 135))	('USP8', 'Gene', (139, 143))	('USP8', 'Gene', '9101', (139, 143))	('promote', 'PosReg', (236, 243))	('invasion', 'CPA', (215, 223))	('cell proliferation', 'CPA', (181, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('si', 'Chemical', 'MESH:D012825', (219, 221))	('si', 'Chemical', 'MESH:D012825', (250, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (107, 125))	('USP8', 'Gene', (55, 59))	('USP8', 'Gene', '9101', (55, 59))
37236	29720881	IHL patients with a serum CEA level higher than 5.0 mug/L carried a 9.176-fold increase in ICC risk (OR=9.176, 95% CI, 3.210-26.231), and patients with a serum CA 19-9 level higher than 143.15 U/mL carried a 4.124-fold increase in ICC risk (OR=4.124, 95% CI, 1.740-9.775).	('increase', 'PosReg', (79, 87))	('ICC', 'Disease', (231, 234))	('ICC', 'Disease', (91, 94))	('CEA', 'Gene', (26, 29))	('patients', 'Species', '9606', (4, 12))	('CEA', 'Gene', '1084', (26, 29))	('patients', 'Species', '9606', (138, 146))	('higher', 'Var', (36, 42))
37251	29720881	To discriminate between IHL-ICC and IHL-IM, the present study showed that the optimal cutoff value for serum CEA was 3.75 mug/L with a sensitivity of 59% and a specificity of 92%.	('CEA', 'Gene', (109, 112))	('CEA', 'Gene', '1084', (109, 112))	('3.75 mug/L', 'Var', (117, 127))
37308	29619414	This patient did have a history of Lynch syndrome (specific mutation unknown), and the literature suggests a possible slight increase in hepatobiliary malignancies with mismatch repair gene mutations.16 In the setting of increased cell turnover due to IgG4-RSC, it is conceivable that progression to CCA could have happened, but it seems unlikely.	('CCA', 'Disease', (300, 303))	('hepatobiliary malignancies', 'Disease', (137, 163))	('patient', 'Species', '9606', (5, 12))	('Lynch syndrome', 'Disease', (35, 49))	('increased', 'PosReg', (221, 230))	('Lynch syndrome', 'Disease', 'MESH:D003123', (35, 49))	('cell turnover', 'CPA', (231, 244))	('hepatobiliary malignancies', 'Disease', 'MESH:D004066', (137, 163))	('CCA', 'Phenotype', 'HP:0030153', (300, 303))	('mutations.16', 'Var', (190, 202))	('RSC', 'Chemical', '-', (257, 260))
37423	27918553	In human ICC cell lines, silencing of Jag1 via specific small interfering RNA reduces proliferation and increases apoptosis.	('silencing', 'Var', (25, 34))	('Jag1', 'Gene', (38, 42))	('human', 'Species', '9606', (3, 8))	('proliferation', 'CPA', (86, 99))	('increases', 'PosReg', (104, 113))	('reduces', 'NegReg', (78, 85))	('apoptosis', 'CPA', (114, 123))
37428	27918553	Importantly, recent genomic studies have identified novel pathways and mutations in ICC, such as FGFR signalling and IDH1/2 mutations, which could be eventually targeted with specific drugs.	('ICC', 'Gene', (84, 87))	('mutations', 'Var', (124, 133))	('FGFR signalling', 'Gene', (97, 112))	('IDH1/2', 'Gene', '15926;269951', (117, 123))	('mutations', 'Var', (71, 80))	('IDH1/2', 'Gene', (117, 123))
37435	27918553	Of note, mutations of genes belonging to the Notch pathway, including Jag1 and Notch2, have been identified in patients with Alagille syndrome, a human genetic disorder characterized by paucity of intrahepatic bile ducts, leading to chronic cholestasis and liver failure.	('liver failure', 'Disease', (257, 270))	('cholestasis', 'Phenotype', 'HP:0001396', (241, 252))	('Jag1', 'Gene', (70, 74))	('mutations', 'Var', (9, 18))	('genetic disorder', 'Disease', 'MESH:D030342', (152, 168))	('cholestasis', 'Disease', 'MESH:D002779', (241, 252))	('Alagille syndrome', 'Disease', (125, 142))	('paucity of intrahepatic bile ducts', 'Phenotype', 'HP:0006571', (186, 220))	('human', 'Species', '9606', (146, 151))	('identified', 'Reg', (97, 107))	('cholestasis', 'Disease', (241, 252))	('Notch2', 'Gene', (79, 85))	('Alagille syndrome', 'Disease', 'MESH:D016738', (125, 142))	('liver failure', 'Disease', 'MESH:D017093', (257, 270))	('liver failure', 'Phenotype', 'HP:0001399', (257, 270))	('genetic disorder', 'Disease', (152, 168))	('patients', 'Species', '9606', (111, 119))
37441	27918553	Also, silencing of Jag1 in human prostate cancer cells decreases cell invasion and in vivo tumour growth.	('tumour growth', 'Disease', 'MESH:D006130', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cell invasion', 'CPA', (65, 78))	('prostate cancer', 'Disease', (33, 48))	('human', 'Species', '9606', (27, 32))	('Jag1', 'Gene', (19, 23))	('decreases', 'NegReg', (55, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (33, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (33, 48))	('silencing', 'Var', (6, 15))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('tumour growth', 'Disease', (91, 104))
37444	27918553	In vivo, we found that while overexpression of Jag1 alone is insufficient to promote liver tumour development, Jag1 cooperates with activated AKT to induce ICC formation.	('promote', 'PosReg', (77, 84))	('liver tumour', 'Disease', 'MESH:D008113', (85, 97))	('insufficient', 'Disease', (61, 73))	('insufficient', 'Disease', 'MESH:D000309', (61, 73))	('Jag1', 'Var', (111, 115))	('liver tumour', 'Phenotype', 'HP:0002896', (85, 97))	('liver tumour', 'Disease', (85, 97))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('ICC formation', 'CPA', (156, 169))
37457	27918553	For this purpose, the Jag1 gene was silenced using specific small interfering RNA (siRNA) in HUCCT1 and KKU-156 ICC cell lines (Figure 2a).	('small interfering', 'Var', (60, 77))	('Jag1 gene', 'Gene', (22, 31))	('KKU-156 ICC cell lines', 'Disease', 'MESH:C566123', (104, 126))	('silenced', 'NegReg', (36, 44))	('KKU-156 ICC cell lines', 'Disease', (104, 126))
37458	27918553	At the molecular level, inhibition of Jag1 by siRNA led, as expected, to the downregulation of Notch canonical targets, such as Hes1 and Hes4 (Figure 2c).	('Jag1', 'Gene', (38, 42))	('downregulation', 'NegReg', (77, 91))	('Hes4', 'Gene', (137, 141))	('inhibition', 'Var', (24, 34))	('Hes4', 'Gene', '57801', (137, 141))
37459	27918553	The present data indicate that inhibition of Jag1 is harmful for the in vitro growth of ICC cells, and Jag1 is a major regulator of Notch signalling in human ICCs.	('human', 'Species', '9606', (152, 157))	('inhibition', 'Var', (31, 41))	('Jag1', 'Gene', (45, 49))
37465	27918553	Histological examination showed that liver parenchyma of Jag1 mice is completely normal (Supplementary Figure 1), indistinguishable from that of wild-type mice, either uninjected (n=5) or injected with empty vector (n=5).	('liver parenchyma', 'Disease', 'MESH:D010195', (37, 53))	('liver parenchyma', 'Disease', (37, 53))	('mice', 'Species', '10090', (62, 66))	('Jag1', 'Var', (57, 61))	('mice', 'Species', '10090', (155, 159))
37485	27918553	For instance, Notch receptors are upregulated in human ICC specimens, and high expression of Notch1 is associated with invasive ICC growth.	('high expression', 'Var', (74, 89))	('upregulated', 'PosReg', (34, 45))	('human', 'Species', '9606', (49, 54))	('Notch1', 'Gene', (93, 99))	('associated with', 'Reg', (103, 118))	('invasive ICC growth', 'Disease', (119, 138))	('Notch receptors', 'Protein', (14, 29))
37492	27918553	This assumption is based on the following body of data: (a) Jag1 is overexpressed in the vast majority of human ICC specimens; (b) modulation of Jag1 levels influences the in vitro growth as well as Notch pathway activities of human ICC cells; and (c) overexpression of Jag1 synergizes with activated AKT/mTOR signalling to promote ICC development in mice.	('growth', 'CPA', (181, 187))	('human', 'Species', '9606', (106, 111))	('influences', 'Reg', (157, 167))	('modulation', 'Var', (131, 141))	('human', 'Species', '9606', (227, 232))	('Jag1', 'Gene', (270, 274))	('mice', 'Species', '10090', (351, 355))	('promote', 'PosReg', (324, 331))	('ICC development', 'CPA', (332, 347))	('Notch pathway', 'Pathway', (199, 212))	('activities', 'MPA', (213, 223))
37500	27918553	Thus, additional studies are necessary to elucidate whether the aforementioned epigenetic modifications may also regulate Jag1 expression in human ICCs.	('regulate', 'Reg', (113, 121))	('expression', 'MPA', (127, 137))	('epigenetic modifications', 'Var', (79, 103))	('human', 'Species', '9606', (141, 146))	('Jag1', 'Gene', (122, 126))
37507	27918553	In a recent study from our lab, we showed that anti-Notch2 and anti-Jag1 antibodies were able to inhibit the growth of ICC-like lesions in AKT/Ras mice.	('mice', 'Species', '10090', (147, 151))	('inhibit', 'NegReg', (97, 104))	('ICC-like', 'Disease', (119, 127))	('anti-Notch2', 'Gene', (47, 58))	('anti-Notch2', 'Var', (47, 58))	('anti-Jag1 antibodies', 'Var', (63, 83))	('antibodies', 'Var', (73, 83))	('growth of', 'CPA', (109, 118))
37508	27918553	However, as AKT/Ras co-expression in the liver induces the occurrence of HCC, ICC and mixed HCC/ICC, the precise therapeutic potential of these anti-Notch antibodies cannot be accurately evaluated in this mouse model.	('induces', 'Reg', (47, 54))	('co-expression', 'Var', (20, 33))	('AKT/Ras', 'Protein', (12, 19))	('ICC', 'Disease', (78, 81))	('mouse', 'Species', '10090', (205, 210))	('HCC', 'Disease', (73, 76))
37509	27918553	Thus, the AKT/Jag1 model might represent an excellent murine model to establish whether anti-Notch2 or anti-Jag1 antibodies can be used for the treatment of this deadly disease.	('anti-Notch2', 'Var', (88, 99))	('murine', 'Species', '10090', (54, 60))	('anti-Jag1', 'Var', (103, 112))
37519	27918553	To block the Notch cascade, high doses of dnRBP-J (20 mug) with low doses of myr-AKT1 (4 mug) and Jag1 (4 mug) were injected.	('AKT1', 'Gene', (81, 85))	('RBP-J', 'Gene', (44, 49))	('AKT1', 'Gene', '11651', (81, 85))	('RBP-J', 'Gene', '19664', (44, 49))	('20 mug', 'Var', (51, 57))
37533	27918553	Membranes were blocked in5% non-fat dry milk in Tris-buffered saline containing 0.1% Tween-20 for 1 h and probed with following specific antibodies for Notch2 (5732), Notch1 (3608), p-AKT (3787), total-AKT (9272) (Cell Signaling Technology Inc), and Jagged1 (Abcam, ab109536).	('Jagged1', 'Gene', '16449', (250, 257))	('Tween-20', 'Chemical', 'MESH:D011136', (85, 93))	('Jagged1', 'Gene', (250, 257))	('p-AKT', 'Var', (182, 187))	('Notch1', 'Var', (167, 173))	('Tris-buffered saline', 'Chemical', '-', (48, 68))	('total-AKT', 'Var', (196, 205))	('Notch2', 'Gene', (152, 158))
37538	27918553	Validated Gene Expression Assays for human Jag1 (Hs01070032_m1), Hes1 (Hs00172878_m1), Hes4 (Hs00368353_g1) and beta-Actin (ID: 4333762T) were purchased from ThermoFisher Scientific.	('Hs01070032_m1', 'Var', (49, 62))	('Hes4', 'Gene', '57801', (87, 91))	('Hs00172878_m1', 'Var', (71, 84))	('Hs00368353_g1', 'Var', (93, 106))	('human', 'Species', '9606', (37, 42))	('Hes4', 'Gene', (87, 91))
37653	21556747	Although no clear associations or conclusions regarding outcome can be made, the longest overall survival was reported in the functional polymorphism TS 5'GC, which causes a lower transcriptional activity of TS, consistent with previous data with treatment with fluoropyrimidines.	('lower', 'NegReg', (174, 179))	("TS 5'GC", 'Gene', (150, 157))	('transcriptional activity', 'MPA', (180, 204))	('fluoropyrimidines', 'Chemical', '-', (262, 279))	('polymorphism', 'Var', (137, 149))
37696	20924217	Other investigators showed that nine distant metastatic lesions were detected by 18F-FDG PET that were not detected using other imaging modalities.	('-FDG', 'Chemical', 'MESH:D019788', (84, 88))	('18F-FDG PET', 'Var', (81, 92))	('distant metastatic lesions', 'CPA', (37, 63))
37717	21760730	ROS causes DNA and cell membrane damage through lipid peroxidation and/or alterations in membrane fluidity.	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('lipid', 'Chemical', 'MESH:D008055', (48, 53))	('DNA', 'Disease', (11, 14))	('membrane fluidity', 'MPA', (89, 106))	('alterations', 'Reg', (74, 85))	('cell membrane damage', 'CPA', (19, 39))	('lipid peroxidation', 'MPA', (48, 66))
37769	21760730	Second, cell death induced by ALA-PDT in HuCC-T1 cells was identified by photomicrographs, as shown in Figure 3B.	('ALA-PDT', 'Var', (30, 37))	('HuCC-T1', 'CellLine', 'CVCL:0324', (41, 48))	('ALA', 'Chemical', 'MESH:C000614854', (30, 33))	('CC', 'Phenotype', 'HP:0030153', (43, 45))	('cell death', 'CPA', (8, 18))
37782	21760730	After irradiation, the PpIX-accumulated tumor cells produced ROS, which destroy tumor cells by apoptosis or necrosis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('necrosis', 'Disease', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PpIX-accumulated', 'Var', (23, 39))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (80, 85))	('necrosis', 'Disease', 'MESH:D009336', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('PpIX', 'Chemical', 'MESH:C028025', (23, 27))	('ROS', 'Chemical', 'MESH:D017382', (61, 64))
38116	23843733	Molecular approaches have revealed the involvement of p53 and beta-catenin mutations in hepatocarcinogenesis.	('beta-catenin', 'Gene', (62, 74))	('involvement', 'Reg', (39, 50))	('p53', 'Gene', (54, 57))	('beta-catenin', 'Gene', '1499', (62, 74))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (88, 108))	('mutations', 'Var', (75, 84))	('p53', 'Gene', '7157', (54, 57))	('hepatocarcinogenesis', 'Disease', (88, 108))
38118	23843733	CA19-9, also known as sialyl Lewis-a (sLea), is a tumor-associated antigen originally isolated from a human colorectal cancer cell line by Koprowski et al..	('CA19-9', 'Var', (0, 6))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('colorectal cancer', 'Disease', (108, 125))	('tumor', 'Disease', (50, 55))	('human', 'Species', '9606', (102, 107))
38151	23843733	However, patients with elevated preoperative CA19-9 levels had a lower 10-year survival rate than those without CA19-9 elevation (P = 0.0020) (Figure 2(a)).	('patients', 'Species', '9606', (9, 17))	('CA19-9', 'Chemical', 'MESH:C086528', (45, 51))	('10-year', 'CPA', (71, 78))	('lower', 'NegReg', (65, 70))	('CA19-9', 'Chemical', 'MESH:C086528', (112, 118))	('CA19-9', 'Var', (45, 51))
38153	23843733	In patients with stage II and III HCCs, those with high CA19-9 levels had slightly lower survival rate than those with low CA19-9 levels, but the difference did not reach statistical significance (P = 0.1238) (Figure 2(c)).	('survival rate', 'CPA', (89, 102))	('CA19-9', 'Chemical', 'MESH:C086528', (56, 62))	('high CA19-9 levels', 'Var', (51, 69))	('lower', 'NegReg', (83, 88))	('patients', 'Species', '9606', (3, 11))	('CA19-9', 'Chemical', 'MESH:C086528', (123, 129))	('HCC', 'Phenotype', 'HP:0001402', (34, 37))
38169	23843733	Multivariate analysis also identified that CA19-9 is an independent prognostic factor for HCC patients.	('HCC', 'Phenotype', 'HP:0001402', (90, 93))	('patients', 'Species', '9606', (94, 102))	('CA19-9', 'Var', (43, 49))	('CA19-9', 'Chemical', 'MESH:C086528', (43, 49))	('HCC', 'Disease', (90, 93))
38182	23843733	In HCC patients, the serum levels of CA19-9 are usually lower than those of gastrointestinal cancer patients.	('patients', 'Species', '9606', (7, 15))	('CA19-9', 'Var', (37, 43))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (76, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lower', 'NegReg', (56, 61))	('patients', 'Species', '9606', (100, 108))	('CA19-9', 'Chemical', 'MESH:C086528', (37, 43))	('HCC', 'Disease', (3, 6))	('HCC', 'Phenotype', 'HP:0001402', (3, 6))	('gastrointestinal cancer', 'Disease', (76, 99))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (76, 99))	('serum levels', 'MPA', (21, 33))
38216	31528094	Although the novel tracer showed good tumor-to-background contrast and good stability in vitro, 18F-FPGLU was metabolically unstable in plasma, urine, and tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('18F-FPGLU', 'Var', (96, 105))	('tumor', 'Disease', (155, 160))	('18F-FPGLU', 'Chemical', 'MESH:C000603314', (96, 105))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
38217	31528094	18F-fluorocholine is another radiotracer used in PET imaging that radiolabels phosphocholine, the major metabolite in cancer cells that is responsible for choline uptake and has a steady distribution that is available within 10 min, demonstrating high sensitivities of 89% for hepatic HCC and 100% for extrahepatic HCC.	('HCC', 'Phenotype', 'HP:0001402', (285, 288))	('HCC', 'Gene', (315, 318))	('cancer', 'Disease', (118, 124))	('choline', 'Chemical', 'MESH:D002794', (85, 92))	('HCC', 'Gene', '619501', (315, 318))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('choline', 'Chemical', 'MESH:D002794', (155, 162))	('HCC', 'Gene', (285, 288))	('radiolabels', 'Var', (66, 77))	('choline', 'Chemical', 'MESH:D002794', (10, 17))	('HCC', 'Phenotype', 'HP:0001402', (315, 318))	('18F-fluorocholine', 'Chemical', 'MESH:C514960', (0, 17))	('HCC', 'Gene', '619501', (285, 288))	('phosphocholine', 'Chemical', 'MESH:D010767', (78, 92))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
38219	31528094	Other promising radiopharmaceuticals currently used in PET-CT include 11C-labeled acetate (11C-ACT) and 11C-labeled choline (11C-CHOL).	('choline', 'Chemical', 'MESH:D002794', (116, 123))	('acetate', 'Chemical', 'MESH:D000085', (82, 89))	('11C-CHOL', 'Chemical', '-', (125, 133))	('11C', 'Chemical', 'MESH:C000615233', (104, 107))	('11C', 'Chemical', 'MESH:C000615233', (125, 128))	('11C', 'Chemical', 'MESH:C000615233', (70, 73))	('11C-labeled', 'Var', (104, 115))	('acetate', 'MPA', (82, 89))	('11C', 'Chemical', 'MESH:C000615233', (91, 94))
38221	31528094	As a substrate, 11C-ACT enters the Krebs cycle for beta-oxidation in fatty acid synthase (FASN) and cholesterol synthesis.	('fatty acid synthase', 'Gene', '2194', (69, 88))	('cholesterol synthesis', 'MPA', (100, 121))	('fatty acid synthase', 'Gene', (69, 88))	('11C', 'Chemical', 'MESH:C000615233', (16, 19))	('FASN', 'Gene', (90, 94))	('cholesterol', 'Chemical', 'MESH:D002784', (100, 111))	('FASN', 'Gene', '2194', (90, 94))	('Krebs', 'Chemical', '-', (35, 40))	('11C-ACT', 'Var', (16, 23))	('beta-oxidation', 'MPA', (51, 65))
38230	31528094	With an appropriate physical half-life (68 min) and good blood clearance, 68Ga-DOTA may be a potential radiotracer for use in imaging HCC.	('68Ga-DOTA', 'Chemical', '-', (74, 83))	('HCC', 'Gene', (134, 137))	('HCC', 'Gene', '619501', (134, 137))	('68Ga-DOTA', 'Var', (74, 83))	('HCC', 'Phenotype', 'HP:0001402', (134, 137))
38231	31528094	Studies have shown that 68Ga-DOTA has a higher sensitivity than 18F-DOTA, as 68Ga-DOTA had a greater PET uptake than 18F-FDG in low-grade neuroendocrine tumors.	('68Ga-DOTA', 'Chemical', '-', (77, 86))	('greater', 'PosReg', (93, 100))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (138, 159))	('PET uptake', 'MPA', (101, 111))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (138, 159))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('18F-FDG', 'Chemical', 'MESH:D019788', (117, 124))	('68Ga-DOTA', 'Chemical', '-', (24, 33))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('18F-DOTA', 'Chemical', '-', (64, 72))	('neuroendocrine tumors', 'Disease', (138, 159))	('68Ga-DOTA', 'Var', (77, 86))
38256	31528094	Although CT, MRI, and bone scintigraphy are recommended for preoperative HCC staging, HCC metastasis to uncommon sites, such as the oral cavity, jaw, thyroid, and adrenal glands, may be detected only by 18F-FDG PET-CT and easily missed by conventional CT and MRI.	('HCC', 'Gene', '619501', (73, 76))	('18F-FDG', 'Var', (203, 210))	('HCC', 'Phenotype', 'HP:0001402', (73, 76))	('jaw', 'Disease', (145, 148))	('HCC', 'Gene', (86, 89))	('18F-FDG', 'Chemical', 'MESH:D019788', (203, 210))	('HCC', 'Gene', (73, 76))	('HCC', 'Gene', '619501', (86, 89))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))	('jaw', 'Disease', 'MESH:D007571', (145, 148))
38273	31528094	18F-FDG PET-CT is a valid prognostic tool in patients with HCC who are candidates for orthotopic liver transplantation (OLT); positivity on PET is the only factor related to early recurrence of HCC after OLT, and the combination of findings on PET and the AFP levels provides even more decisive results.	('HCC', 'Phenotype', 'HP:0001402', (59, 62))	('AFP', 'Gene', (256, 259))	('AFP', 'Gene', '174', (256, 259))	('HCC', 'Gene', '619501', (194, 197))	('HCC', 'Phenotype', 'HP:0001402', (194, 197))	('18F-FDG', 'Chemical', 'MESH:D019788', (0, 7))	('related to', 'Reg', (163, 173))	('HCC', 'Gene', (59, 62))	('patients', 'Species', '9606', (45, 53))	('HCC', 'Gene', '619501', (59, 62))	('positivity', 'Var', (126, 136))	('HCC', 'Gene', (194, 197))
38284	31528094	11C-ACT uptake is related to well-differentiated HCC and a less aggressive cancer or a fair prognosis.	('11C', 'Chemical', 'MESH:C000615233', (0, 3))	('11C-ACT uptake', 'Var', (0, 14))	('HCC', 'Gene', (49, 52))	('HCC', 'Phenotype', 'HP:0001402', (49, 52))	('aggressive cancer', 'Disease', 'MESH:D009369', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('aggressive cancer', 'Disease', (64, 81))	('HCC', 'Gene', '619501', (49, 52))
38313	31528094	YY146 is an anti-CD146 mAb; when conjugated, the zwitterionic near-infrared fluorescence (NIRF) dye ZW800-1 and the chelator deferoxamine (Df) enable the labeling of Df-YY146-ZW800 with 89Zr and its subsequent detection with PET and NIRF imaging.	('Df-YY146-ZW800', 'Var', (166, 180))	('CD146', 'Gene', '4162', (17, 22))	('CD146', 'Gene', (17, 22))	('ZW800', 'Chemical', '-', (175, 180))	('ZW800', 'Chemical', '-', (100, 105))	('YY146', 'Chemical', '-', (169, 174))	('deferoxamine', 'Chemical', 'MESH:D003676', (125, 137))	('Df-YY146', 'Chemical', '-', (166, 174))	('YY146', 'Chemical', '-', (0, 5))
38320	31528094	Although 18F-FDG PET-CT has emerged as an important noninvasive diagnostic tool in HCC, especially in staging and detecting metastatic lesions, the low sensitivity of 18F-FDG PET-CT limits its clinical use, especially for routine surveillance.	('HCC', 'Phenotype', 'HP:0001402', (83, 86))	('18F-FDG', 'Chemical', 'MESH:D019788', (167, 174))	('HCC', 'Gene', (83, 86))	('18F-FDG', 'Chemical', 'MESH:D019788', (9, 16))	('18F-FDG', 'Var', (167, 174))	('HCC', 'Gene', '619501', (83, 86))
38374	28415734	Earlier studies have shown that inflammation, by stimulating angiogenesis and causing localized immunosuppression, will promote and accelerate the formation of a suitable microenvironment where the survival, expansion, accumulation of successive mutations, and epigenetic changes of premalignant cells could be facilitated.	('inflammation', 'Disease', 'MESH:D007249', (32, 44))	('inflammation', 'Disease', (32, 44))	('promote', 'PosReg', (120, 127))	('angiogenesis', 'CPA', (61, 73))	('mutations', 'Var', (246, 255))	('epigenetic changes', 'Var', (261, 279))	('accelerate', 'PosReg', (132, 142))
38378	28415734	At the meantime, neutrophil elevation prompts the secretion of cytokines and chemokines, thus expediting tumor proliferation.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('secretion of cytokines', 'MPA', (50, 72))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('neutrophil elevation', 'Phenotype', 'HP:0011897', (17, 37))	('neutrophil', 'Var', (17, 27))	('expediting', 'PosReg', (94, 104))
38410	25267595	Specific genetic mutations of IDH1/2, BAP1, p53, and KRAS, FGFR gene fusions and alterations in microRNA have all been described in iCCA.	('IDH1/2', 'Gene', '3417;3418', (30, 36))	('FGFR', 'Gene', (59, 63))	('BAP1', 'Gene', (38, 42))	('IDH1/2', 'Gene', (30, 36))	('alterations', 'Reg', (81, 92))	('iCCA', 'Disease', (132, 136))	('KRAS', 'Gene', '3845', (53, 57))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('KRAS', 'Gene', (53, 57))	('microRNA', 'MPA', (96, 104))	('described', 'Reg', (119, 128))	('mutations', 'Var', (17, 26))	('BAP1', 'Gene', '8314', (38, 42))	('fusions', 'Var', (69, 76))
38432	25267595	Isocitrate dehydrogenase(IDH) mutations were more frequently observed in iCCA than in extrahepatic cancers.	('IDH', 'Gene', (25, 28))	('extrahepatic cancers', 'Disease', 'MESH:D001651', (86, 106))	('IDH', 'Gene', '3417', (25, 28))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('iCCA', 'Disease', (73, 77))	('observed', 'Reg', (61, 69))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('extrahepatic cancers', 'Disease', (86, 106))
38434	25267595	Chang et al showed that EGFR mutation was an independent prognostic marker in CCA in addition to tumor stage and differentiation.	('EGFR', 'Gene', '1956', (24, 28))	('mutation', 'Var', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('EGFR', 'Gene', (24, 28))	('tumor', 'Disease', (97, 102))	('CCA', 'Disease', (78, 81))
38435	25267595	No simultaneous EGFR and KRAS mutations were found in extrahepatic cholangiocarcinoma and gallbladder carcinoma.	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (54, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('extrahepatic cholangiocarcinoma', 'Disease', (54, 85))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (90, 111))	('mutations', 'Var', (30, 39))	('EGFR', 'Gene', '1956', (16, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('KRAS', 'Gene', (25, 29))	('gallbladder carcinoma', 'Disease', (90, 111))	('EGFR', 'Gene', (16, 20))	('KRAS', 'Gene', '3845', (25, 29))
38437	25267595	Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in 10-28% of cholangiocarcinomas.	('IDH1', 'Gene', '3417', (58, 62))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (105, 124))	('IDH2', 'Gene', (67, 71))	('reported', 'Reg', (83, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (105, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('cholangiocarcinomas', 'Disease', (105, 124))	('IDH2', 'Gene', '3418', (67, 71))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', (58, 62))
38439	25267595	These mutations result in elevated levels of an oncometabolite, 2-hydroxyglutarate, which is associated with higher DNA CpG methylation and altered histone methylation that accompany a block in cellular differentiation.	('altered', 'Reg', (140, 147))	('levels', 'MPA', (35, 41))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (64, 82))	('elevated', 'PosReg', (26, 34))	('cellular differentiation', 'CPA', (194, 218))	('mutations', 'Var', (6, 15))	('histone methylation', 'MPA', (148, 167))
38440	25267595	Mutations in IDH1 or IDH2 were associated with longer overall survival and were independently associated with a longer time to tumor recurrence after iCCA resection in multivariate analysis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('longer', 'PosReg', (47, 53))	('tumor', 'Disease', (127, 132))	('overall survival', 'MPA', (54, 70))	('IDH1', 'Gene', (13, 17))	('IDH2', 'Gene', (21, 25))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (94, 104))	('IDH1', 'Gene', '3417', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('IDH2', 'Gene', '3418', (21, 25))
38441	25267595	IDH1 and IDH2 mutations were significantly associated with increased levels of p53 in iCCA, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may result in p53 activation.	('mutations', 'Var', (153, 162))	('p53', 'Gene', (194, 197))	('IDH1', 'Gene', (0, 4))	('increased', 'PosReg', (59, 68))	('IDH1', 'Gene', (166, 170))	('p53', 'Gene', '7157', (79, 82))	('mutations', 'Var', (14, 23))	('IDH1', 'Gene', '3417', (0, 4))	('p53', 'Gene', (79, 82))	('levels', 'MPA', (69, 75))	('activation', 'PosReg', (198, 208))	('IDH1', 'Gene', '3417', (166, 170))	('p53', 'Gene', '7157', (116, 119))	('IDH2', 'Gene', (9, 13))	('IDH2', 'Gene', (175, 179))	('IDH2', 'Gene', '3418', (9, 13))	('p53', 'Gene', '7157', (194, 197))	('IDH2', 'Gene', '3418', (175, 179))	('p53', 'Gene', (116, 119))
38445	25267595	BAP1 was frequently mutated in CCA cases without O. viverrini infection.	('BAP1', 'Gene', (0, 4))	('infection', 'Disease', (62, 71))	('infection', 'Disease', 'MESH:D007239', (62, 71))	('O. viverrini', 'Species', '6198', (49, 61))	('BAP1', 'Gene', '8314', (0, 4))	('mutated', 'Var', (20, 27))	('CCA', 'Disease', (31, 34))
38446	25267595	Most of the observed BAP1 mutations were predicted to result in loss of the HCF-1-binding domain and nuclear localization signal, both of which are necessary for the inhibition of cell proliferation and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('BAP1', 'Gene', (21, 25))	('HCF-1-binding', 'Protein', (76, 89))	('mutations', 'Var', (26, 35))	('loss', 'NegReg', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('nuclear localization signal', 'MPA', (101, 128))	('BAP1', 'Gene', '8314', (21, 25))
38447	25267595	Recent studies have reported the presence of FGFR fusions in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('FGFR', 'Gene', (45, 49))	('fusions', 'Var', (50, 57))	('cholangiocarcinoma', 'Disease', (61, 79))
38449	25267595	detected FGFR2 fusion in nine of 66 patients (13.6%) with iCCA, of which seven patients had FGFR2-AHCYL1 fusion and two patients had FGFR2-BICC1.	('fusion', 'Var', (15, 21))	('BICC1', 'Gene', (139, 144))	('patients', 'Species', '9606', (36, 44))	('BICC1', 'Gene', '80114', (139, 144))	('iCCA', 'Disease', (58, 62))	('FGFR2', 'Gene', (9, 14))	('AHCYL1', 'Gene', (98, 104))	('FGFR2', 'Gene', '2263', (9, 14))	('FGFR2', 'Gene', (133, 138))	('FGFR2', 'Gene', '2263', (133, 138))	('FGFR2', 'Gene', (92, 97))	('FGFR2', 'Gene', '2263', (92, 97))	('patients', 'Species', '9606', (79, 87))	('AHCYL1', 'Gene', '10768', (98, 104))	('patients', 'Species', '9606', (120, 128))
38454	25267595	In another patient with a FGFR2-TACC3 fusion with progression on pazopanib, stable disease was noted with treatment using a pan-FGFR inhibitor ponatinib.	('fusion', 'Var', (38, 44))	('men', 'Species', '9606', (111, 114))	('pazopanib', 'Chemical', 'MESH:C516667', (65, 74))	('patient', 'Species', '9606', (11, 18))	('FGFR2', 'Gene', (26, 31))	('ponatinib', 'Chemical', 'MESH:C545373', (143, 152))	('TACC3', 'Gene', '10460', (32, 37))	('FGFR2', 'Gene', '2263', (26, 31))	('TACC3', 'Gene', (32, 37))
38455	25267595	Of note, tyrosine kinase inhibitors that target anaplastic lymphoma kinase (ALK) are particularly effective in the treatment of a distinct subset of lung adenocarcinoma carrying ALK fusions.	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('lung adenocarcinoma', 'Disease', (149, 168))	('ALK', 'Gene', '238', (76, 79))	('anaplastic lymphoma kinase', 'Gene', '238', (48, 74))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (149, 168))	('ALK', 'Gene', (178, 181))	('lymphoma', 'Phenotype', 'HP:0002665', (59, 67))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (48, 67))	('fusions', 'Var', (182, 189))	('anaplastic lymphoma kinase', 'Gene', (48, 74))	('ALK', 'Gene', '238', (178, 181))	('ALK', 'Gene', (76, 79))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (149, 168))	('men', 'Species', '9606', (120, 123))
38456	25267595	These emerging results regarding FGFR2 fusions suggest that oncogenic activation of FGFR2 may represent a therapeutically actionable event and that identification of FGFR2 fusions may have therapeutic implications.	('FGFR2', 'Gene', (166, 171))	('FGFR2', 'Gene', '2263', (166, 171))	('FGFR2', 'Gene', (84, 89))	('fusions', 'Var', (39, 46))	('FGFR2', 'Gene', '2263', (84, 89))	('FGFR2', 'Gene', (33, 38))	('FGFR2', 'Gene', '2263', (33, 38))	('activation', 'PosReg', (70, 80))
38457	25267595	Gain-of-function mutations in KRAS downstream of EGFR represent one of the most frequent mutations found in iCCA (8-54%).	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (49, 53))	('Gain-of-function', 'PosReg', (0, 16))	('iCCA', 'Disease', (108, 112))	('KRAS', 'Gene', (30, 34))	('mutations', 'Var', (17, 26))	('KRAS', 'Gene', '3845', (30, 34))
38458	25267595	Moreover, mutations in KRAS were detected in 30% of bile from patients with primary sclerosing cholangitis (PSC), suggesting that it is an early event contributing to the malignant transformation of cholangiocytes.	('primary sclerosing cholangitis', 'Disease', (76, 106))	('KRAS', 'Gene', (23, 27))	('detected', 'Reg', (33, 41))	('patients', 'Species', '9606', (62, 70))	('mutations', 'Var', (10, 19))	('primary sclerosing cholangitis', 'Disease', 'MESH:D015209', (76, 106))	('KRAS', 'Gene', '3845', (23, 27))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (84, 106))	('cholangitis', 'Phenotype', 'HP:0030151', (95, 106))
38461	25267595	More than 90 different mutations have been described in TP53.	('mutations', 'Var', (23, 32))	('TP53', 'Gene', (56, 60))	('TP53', 'Gene', '7157', (56, 60))
38462	25267595	A review of 10 studies which included 229 cases found a total of 21% (49 patients) with mutations in TP53, ranging from 23% in Asia, 14% in Europe, and 26% in the USA.	('TP53', 'Gene', '7157', (101, 105))	('TP53', 'Gene', (101, 105))	('mutations', 'Var', (88, 97))	('patients', 'Species', '9606', (73, 81))
38465	25267595	Mutant cases were associated with a higher tumor stage at time of resection and a greater likelihood of lymph node involvement.	('lymph node involvement', 'CPA', (104, 126))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Mutant', 'Var', (0, 6))	('tumor', 'Disease', (43, 48))	('men', 'Species', '9606', (122, 125))
38467	25267595	These analyses identified the mutation of TP53, KRAS2, SMAD4, and CDKN2A as frequently mutated genes similar to other prior reports.	('TP53', 'Gene', '7157', (42, 46))	('mutation', 'Var', (30, 38))	('TP53', 'Gene', (42, 46))	('CDKN2A', 'Gene', '1029', (66, 72))	('KRAS2', 'Gene', (48, 53))	('SMAD4', 'Gene', '4089', (55, 60))	('KRAS2', 'Gene', '3845', (48, 53))	('CDKN2A', 'Gene', (66, 72))	('SMAD4', 'Gene', (55, 60))
38468	25267595	Alterations in microRNA are associated with modulation of tumor cell proliferation, alteration in sensitivity to chemotherapy, or alteration in epithelial-mesenchymal transition (EMT).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('associated', 'Reg', (28, 38))	('epithelial-mesenchymal transition', 'CPA', (144, 177))	('Alterations', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('alteration', 'Reg', (130, 140))	('microRNA', 'Protein', (15, 23))
38478	25267595	reported that the combination of beta-catenin negativity with positive expression of vimentin or fibronectin showed worse prognosis whereas beta-catenin positivity with loss of vimentin or fibronectin expression showed the best prognosis.	('beta-catenin', 'Gene', '1499', (140, 152))	('fibronectin', 'Gene', (189, 200))	('negativity', 'Var', (46, 56))	('vimentin', 'Gene', '7431', (177, 185))	('fibronectin', 'Gene', (97, 108))	('positive', 'PosReg', (62, 70))	('beta-catenin', 'Gene', (33, 45))	('vimentin', 'Gene', (177, 185))	('fibronectin', 'Gene', '2335', (189, 200))	('beta-catenin', 'Gene', '1499', (33, 45))	('vimentin', 'Gene', '7431', (85, 93))	('fibronectin', 'Gene', '2335', (97, 108))	('vimentin', 'Gene', (85, 93))	('beta-catenin', 'Gene', (140, 152))
38481	25267595	Overexpression of CD151 was implicated in metastasis and invasion of iCCA.	('invasion', 'CPA', (57, 65))	('iCCA', 'Disease', (69, 73))	('CD151', 'Gene', '977', (18, 23))	('Overexpression', 'Var', (0, 14))	('Ov', 'Species', '6198', (0, 2))	('metastasis', 'CPA', (42, 52))	('implicated', 'Reg', (28, 38))	('CD151', 'Gene', (18, 23))
38483	25267595	reported that 67LR was regulated by GATA6 through binding to its promoter in CCA cells, indicating that aberrant expression of GATA6 correlates with poor prognosis and promotes tumor cell invasion and metastasis, possibly through promoter binding mediated regulation of 67LR.	('67LR', 'Gene', '3921', (14, 18))	('GATA6', 'Gene', '2627', (36, 41))	('GATA6', 'Gene', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('aberrant', 'Var', (104, 112))	('67LR', 'Gene', (270, 274))	('promotes', 'PosReg', (168, 176))	('GATA6', 'Gene', '2627', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('GATA6', 'Gene', (127, 132))	('67LR', 'Gene', '3921', (270, 274))	('tumor', 'Disease', (177, 182))	('67LR', 'Gene', (14, 18))
38495	25267595	Moreover, sensitivity to detect CCA was superior for CYFRA 21-1 as compared with alpha fetoprotein, CEA, and CA 19-9 levels (87% versus 17, 35, and 61%, respectively).	('CEA', 'Gene', '1048', (100, 103))	('CEA', 'Gene', (100, 103))	('CCA', 'Disease', (32, 35))	('CYFRA 21-1', 'Var', (53, 63))
38505	25267595	High DKK1 expression in iCCA tissues was associated with elevated matrix metalloproteinase 9 (MMP9), vascular endothelial growth factor C (VEGF-C) expression, and high lymph node metastasis.	('DKK1', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('vascular endothelial growth factor C', 'Gene', (101, 137))	('VEGF-C', 'Gene', (139, 145))	('expression', 'MPA', (147, 157))	('elevated', 'PosReg', (57, 65))	('matrix metalloproteinase 9', 'Gene', '4318', (66, 92))	('MMP9', 'Gene', (94, 98))	('expression', 'MPA', (10, 20))	('MMP9', 'Gene', '4318', (94, 98))	('high lymph node', 'Phenotype', 'HP:0002716', (163, 178))	('matrix metalloproteinase 9', 'Gene', (66, 92))	('high lymph node metastasis', 'CPA', (163, 189))	('vascular endothelial growth factor C', 'Gene', '7424', (101, 137))	('VEGF-C', 'Gene', '7424', (139, 145))	('DKK1', 'Gene', '22943', (5, 9))
38511	25267595	The bile levels of S100P were increased significantly in patients with cholangiocarcinoma compared with those in patients with lithiasis.	('lithiasis', 'Disease', 'MESH:D020347', (127, 136))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (71, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('bile levels of', 'MPA', (4, 18))	('S100P', 'SUBSTITUTION', 'None', (19, 24))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (71, 89))	('lithiasis', 'Disease', (127, 136))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (113, 121))	('increased', 'PosReg', (30, 39))	('S100P', 'Var', (19, 24))	('cholangiocarcinoma', 'Disease', (71, 89))
38526	25267595	Drugs that can target many of the oncogenic pathways that have been identified such as FGFR2 fusions, IDH mutations, EGFR and others are available, and may form the basis for targeted individualized therapy in the future.	('FGFR2', 'Gene', (87, 92))	('IDH', 'Gene', '3417', (102, 105))	('fusions', 'Var', (93, 100))	('FGFR2', 'Gene', '2263', (87, 92))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('oncogenic pathways', 'Pathway', (34, 52))	('mutations', 'Var', (106, 115))	('IDH', 'Gene', (102, 105))
38585	25954545	We report here our early experience of the use of the modulated intensity with HT for irradiation of hepatobiliary malignant disease in 9 patients with several clinical settings.	('modulated', 'Var', (54, 63))	('hepatobiliary malignant disease', 'Disease', (101, 132))	('hepatobiliary malignant disease', 'Disease', 'MESH:D004066', (101, 132))	('patients', 'Species', '9606', (138, 146))
38617	24897108	Integrative Analysis of Transcriptional Regulatory Network and Copy Number Variation in Intrahepatic Cholangiocarcinoma Transcriptional regulatory network (TRN) is used to study conditional regulatory relationships between transcriptional factors and genes.	('Intrahepatic Cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 119))	('Intrahepatic Cholangiocarcinoma', 'Disease', (88, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('Copy Number Variation', 'Var', (63, 84))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))
38624	24897108	For example, TP53, a well-known tumor suppressor transcription factor, its mutation has been reported associated with cell migration and invasion.	('TP53', 'Gene', (13, 17))	('associated', 'Reg', (102, 112))	('invasion', 'CPA', (137, 145))	('mutation', 'Var', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cell migration', 'CPA', (118, 132))	('TP53', 'Gene', '7157', (13, 17))	('tumor', 'Disease', (32, 37))
38628	24897108	In 2013, Sia et al performed gene expression and copy number variation integrated analysis in ICC samples and classified these samples into two groups: proliferation and inflammation.	('ICC', 'Disease', (94, 97))	('inflammation', 'Disease', 'MESH:D007249', (170, 182))	('inflammation', 'Disease', (170, 182))	('copy number variation', 'Var', (49, 70))
38630	24897108	Regions with amplifications or deletions were identified using GISTIC2.0 (GISTIC2.0 module, GenePattern http://www.broadinstitute.org/cancer/software/genepattern ).	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('deletions', 'Var', (31, 40))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))
38649	24897108	We also found that CNV-TFs YY1, ZSCAN1, MZF1 and DAND5 regulated a large number of genes involved in a variety of signaling pathways; and some non-disease signaling pathways such as Wnt signaling pathway, MAPK signaling pathway and TFG-beta signaling pathway had more than thirteen percent of genes regulated by CNV-TFs or located in genomic variation regions.	('DAND5', 'Gene', '199699', (49, 54))	('YY1', 'Gene', '7528', (27, 30))	('ZSCAN1', 'Gene', '284312', (32, 38))	('non-disease', 'Pathway', (143, 154))	('MZF1', 'Gene', '7593', (40, 44))	('Wnt signaling pathway', 'Pathway', (182, 203))	('TFG-beta signaling pathway', 'Pathway', (232, 258))	('MAPK signaling pathway', 'Pathway', (205, 227))	('YY1', 'Gene', (27, 30))	('MZF1', 'Gene', (40, 44))	('DAND5', 'Gene', (49, 54))	('ZSCAN1', 'Gene', (32, 38))	('CNV-TFs', 'Var', (312, 319))
38650	24897108	This indicates that genomic variation of ICC in these TFs regions can cause dysfunction of a variety of pathways, and some pathways may be fundamentally deregulated.	('pathways', 'Pathway', (123, 131))	('deregulated', 'Reg', (153, 164))	('ICC', 'Gene', (41, 44))	('genomic variation', 'Var', (20, 37))	('cause', 'Reg', (70, 75))	('dysfunction', 'Disease', 'MESH:D006331', (76, 87))	('dysfunction', 'Disease', (76, 87))
38659	24897108	Wnt signaling transmitting signals from outside through cell surface receptors to the inside of the cell, is required for cell differentiation and proliferation, and inhibition of which can induce cell apoptosis and suppress cell proliferation in cholangiocarcinoma cells.	('cholangiocarcinoma', 'Disease', (247, 265))	('cell apoptosis', 'CPA', (197, 211))	('cell proliferation', 'CPA', (225, 243))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (247, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (247, 265))	('induce', 'PosReg', (190, 196))	('suppress', 'NegReg', (216, 224))	('inhibition', 'Var', (166, 176))
38675	24897108	Zaman et al predicted breast cancer subtype-specific drug targets through signaling network assessment of mutations and copy number variations.	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('copy number variations', 'Var', (120, 142))	('mutations', 'Var', (106, 115))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
38678	24897108	Integrative analysis of regulatory modules and KEGG signaling pathway illustrated that the disturbance of genomic variation on signaling pathway can happen on components of pathway which was the focus of previous studies, such as variation of MAP3K7, MAP2K7 and FGFR2 in MAPK signaling, and FZD10 in Wnt signaling; but may also happen more effectively on regulators, such as variation of ZSCAN1, RFX1 which regulate SMAD proteins, the key joints of TGF-beta signaling.	('variation', 'Var', (230, 239))	('MAP2K7', 'Gene', '5609', (251, 257))	('RFX1', 'Gene', (396, 400))	('ZSCAN1', 'Gene', (388, 394))	('FGFR2', 'Gene', (262, 267))	('TGF-beta', 'Gene', '7040', (449, 457))	('FGFR2', 'Gene', '2263', (262, 267))	('MAP3K7', 'Gene', (243, 249))	('SMAD', 'Gene', '4092', (416, 420))	('RFX1', 'Gene', '5989', (396, 400))	('FZD10', 'Gene', (291, 296))	('TGF-beta', 'Gene', (449, 457))	('variation', 'Var', (375, 384))	('ZSCAN1', 'Gene', '284312', (388, 394))	('SMAD', 'Gene', (416, 420))	('FZD10', 'Gene', '11211', (291, 296))	('MAP3K7', 'Gene', '6885', (243, 249))	('MAP2K7', 'Gene', (251, 257))
38710	24639917	H2HR activates Galphas that stimulates cAMP, which leads to different downstream cascade effects.	('cAMP', 'MPA', (39, 43))	('H2HR', 'Chemical', '-', (0, 4))	('H2HR', 'Var', (0, 4))	('stimulates', 'PosReg', (28, 38))
38739	24639917	Inhibition of HDC in rodent tumor samples has resulted in antitumor responses.	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('HDC', 'Protein', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
38756	24639917	H4HR binding of its ligands leads to protective effects in experimental models of gastric mucosal damage, so this seems as if H4HR binding of histamine could lead to pro-cancer responses.	('pro-cancer', 'Disease', 'MESH:D009369', (166, 176))	('lead to', 'Reg', (158, 165))	('H4HR', 'Chemical', '-', (0, 4))	('H4HR', 'Chemical', '-', (126, 130))	('gastric mucosal damage', 'Disease', 'MESH:D013272', (82, 104))	('histamine', 'Chemical', 'MESH:D006632', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('gastric mucosal damage', 'Disease', (82, 104))	('H4HR', 'Var', (126, 130))	('pro-cancer', 'Disease', (166, 176))	('protective effects', 'CPA', (37, 55))
38760	24639917	The causes of pancreatic cancer include the activation of oncogenes, inactivation of tumor suppressor genes, the deregulation of specific signaling pathways, hereditary pancreatitis, and tobacco smoking.	('hereditary pancreatitis', 'Disease', (158, 181))	('tumor', 'Disease', (85, 90))	('oncogenes', 'Protein', (58, 67))	('specific signaling pathways', 'Pathway', (129, 156))	('pancreatic cancer', 'Disease', (14, 31))	('deregulation', 'Reg', (113, 125))	('pancreatitis', 'Phenotype', 'HP:0001733', (169, 181))	('pancreatic cancer', 'Disease', 'MESH:D010190', (14, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tobacco smoking', 'Disease', (187, 202))	('inactivation', 'Var', (69, 81))	('activation', 'PosReg', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('hereditary pancreatitis', 'Disease', 'MESH:C537262', (158, 181))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (14, 31))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tobacco', 'Species', '4097', (187, 194))
38761	24639917	In a cell line derived from human ductal pancreatic carcinoma it was shown that clonogenic growth was inhibited by histamine levels higher than 1 mumol L-1 through H1HR and H2HR, but was stimulated by nanomolar doses of histamine.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('histamine', 'Chemical', 'MESH:D006632', (220, 229))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (41, 61))	('human', 'Species', '9606', (28, 33))	('inhibited', 'NegReg', (102, 111))	('H1HR', 'Chemical', '-', (164, 168))	('H2HR', 'Var', (173, 177))	('H2HR', 'Chemical', '-', (173, 177))	('histamine', 'Chemical', 'MESH:D006632', (115, 124))	('clonogenic growth', 'CPA', (80, 97))	('H1HR', 'Var', (164, 168))	('pancreatic carcinoma', 'Disease', (41, 61))
38762	24639917	Anti-proliferation is induced by H2HR through G0/G1 phase arrest, decrease in phosphoactivated ERK1/ERK2, increase in phosphoactivated P38 expression, and modifications of the Bcl-2 family proteins.	('ERK1', 'Gene', (95, 99))	('G0/G1 phase arrest', 'CPA', (46, 64))	('modifications', 'Reg', (155, 168))	('ERK1', 'Gene', '5595', (95, 99))	('Anti-proliferation', 'CPA', (0, 18))	('rat', 'Species', '10116', (12, 15))	('Bcl-2', 'Gene', (176, 181))	('P38', 'Gene', '5594', (135, 138))	('H2HR', 'Var', (33, 37))	('decrease', 'NegReg', (66, 74))	('increase', 'PosReg', (106, 114))	('phosphoactivated', 'MPA', (118, 134))	('ERK2', 'Gene', '5594', (100, 104))	('Bcl-2', 'Gene', '596', (176, 181))	('ERK2', 'Gene', (100, 104))	('phosphoactivated', 'MPA', (78, 94))	('H2HR', 'Chemical', '-', (33, 37))	('P38', 'Gene', (135, 138))	('expression', 'MPA', (139, 149))
38766	24639917	Data suggests that H3HR increases proliferation through regulation of the cell cycle in normal and tumoral epithelial tissues.	('proliferation', 'CPA', (34, 47))	('increases', 'PosReg', (24, 33))	('tumoral', 'Disease', (99, 106))	('tumoral', 'Disease', 'MESH:D009369', (99, 106))	('H3HR', 'Chemical', '-', (19, 23))	('rat', 'Species', '10116', (41, 44))	('H3HR', 'Var', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cell cycle', 'CPA', (74, 84))
38776	24639917	It has also been shown that the absence or down regulation of HDC, through inhibition of mature myeloid cells or hypermethylation of the HDC promoter, has been experimentally proven to yield a higher rate of colon carcinogenesis.	('absence', 'NegReg', (32, 39))	('colon carcinogenesis', 'Disease', (208, 228))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (208, 228))	('rat', 'Species', '10116', (200, 203))	('hypermethylation', 'Var', (113, 129))	('HDC', 'Gene', (137, 140))	('down regulation', 'NegReg', (43, 58))	('HDC', 'Gene', (62, 65))	('higher', 'PosReg', (193, 199))
38781	24639917	Aside from lack of HDC, CRC tissues generally show abnormalities in H4HR expression.	('H4HR', 'Chemical', '-', (68, 72))	('CRC', 'Phenotype', 'HP:0003003', (24, 27))	('abnormalities', 'Var', (51, 64))	('H4HR', 'Protein', (68, 72))	('expression', 'MPA', (73, 83))
38782	24639917	The over expression of H4HR combined with exposure to histamine has proven to cause growth arrest in CRC, and H4HR stimulation promotes CRC cellular apoptosis.	('growth arrest', 'Disease', (84, 97))	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('H4HR', 'Gene', (23, 27))	('promotes', 'PosReg', (127, 135))	('growth arrest', 'Disease', 'MESH:D006323', (84, 97))	('growth arrest', 'Phenotype', 'HP:0001510', (84, 97))	('over expression', 'PosReg', (4, 19))	('histamine', 'Chemical', 'MESH:D006632', (54, 63))	('CRC', 'Phenotype', 'HP:0003003', (101, 104))	('H4HR', 'Chemical', '-', (110, 114))	('H4HR', 'Var', (110, 114))	('CRC cellular apoptosis', 'CPA', (136, 158))	('H4HR', 'Chemical', '-', (23, 27))
38783	24639917	Neoplastic samples contain decreased levels of H4HR compared to the amount detected in normal colon tissue samples, leading to the hypothesis that H4HR is involved in colon carcinogenesis.	('H4HR', 'Chemical', '-', (47, 51))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (167, 187))	('H4HR', 'Chemical', '-', (147, 151))	('colon carcinogenesis', 'Disease', (167, 187))	('decreased', 'NegReg', (27, 36))	('H4HR', 'Var', (147, 151))	('involved', 'Reg', (155, 163))
38784	24639917	Aside from HRH4, it has also been experimentally verified that inhibition of H2HR through binding of certain antagonists' increases the survival of patients with CRC.	('patients', 'Species', '9606', (148, 156))	('CRC', 'Disease', (162, 165))	('survival', 'CPA', (136, 144))	('inhibition', 'Var', (63, 73))	('H2HR', 'Protein', (77, 81))	('binding', 'Interaction', (90, 97))	('CRC', 'Phenotype', 'HP:0003003', (162, 165))	('HRH4', 'Gene', '59340', (11, 15))	('H2HR', 'Chemical', '-', (77, 81))	('HRH4', 'Gene', (11, 15))	('increases', 'PosReg', (122, 131))
38814	24639917	These restoring responses have different pathways and functions in small and large cholangiocytes that are mediated through the binding of histamine or other agonists to H1HR, H2HR, H3HR, and H4HR.	('H3HR', 'Protein', (182, 186))	('H2HR', 'Protein', (176, 180))	('H4HR', 'Chemical', '-', (192, 196))	('H4HR', 'Var', (192, 196))	('H2HR', 'Chemical', '-', (176, 180))	('binding', 'Interaction', (128, 135))	('histamine', 'Chemical', 'MESH:D006632', (139, 148))	('H1HR', 'Protein', (170, 174))	('H1HR', 'Chemical', '-', (170, 174))	('H3HR', 'Chemical', '-', (182, 186))
38833	24639917	The antiproliferative effects induced by H3HR also decreased VEGFA/C and VEGF-R2/3 expression, demonstrating that H3HR is a possible inhibitor of angiogenesis.	('H3HR', 'Var', (41, 45))	('VEGF-R2/3', 'Gene', '3791;2324', (73, 82))	('VEGFA', 'Gene', '7422', (61, 66))	('H3HR', 'Chemical', '-', (114, 118))	('rat', 'Species', '10116', (15, 18))	('VEGF-R2/3', 'Gene', (73, 82))	('decreased', 'NegReg', (51, 60))	('rat', 'Species', '10116', (102, 105))	('expression', 'MPA', (83, 93))	('VEGFA', 'Gene', (61, 66))	('antiproliferative effects', 'CPA', (4, 29))	('H3HR', 'Chemical', '-', (41, 45))
38841	24639917	This study found that inhibition of HDC (both pharmacologically and genetically) inhibited the growth of cholangiocarcinoma in both cell cultures and in animal tumor models.	('inhibition', 'Var', (22, 32))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (105, 123))	('growth', 'MPA', (95, 101))	('HDC', 'Protein', (36, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (105, 123))	('cholangiocarcinoma', 'Disease', (105, 123))	('inhibited', 'NegReg', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))
38842	24639917	Inhibition of HDC also significantly decreased VEGF expression in vitro and in vivo, but did not alter normal cholangiocyte growth suggesting that this could be a favorable therapy for the treatment of human cholangiocarcinoma.	('VEGF', 'Gene', '7422', (47, 51))	('human', 'Species', '9606', (202, 207))	('expression', 'MPA', (52, 62))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (208, 226))	('cholangiocarcinoma', 'Disease', (208, 226))	('Inhibition', 'Var', (0, 10))	('VEGF', 'Gene', (47, 51))	('HDC', 'Protein', (14, 17))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (208, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('decreased', 'NegReg', (37, 46))
38843	24639917	We refer the reader to Figure 3 that demonstrates that after HDC knockdown in cholangiocarcinoma cells (Mz-HDC), xenograft tumor development was significantly inhibited when compared to the tumors containing normal levels of HDC (Mz-neg).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 96))	('tumor', 'Disease', (123, 128))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (78, 96))	('rat', 'Species', '10116', (44, 47))	('tumor', 'Disease', (190, 195))	('HDC', 'Gene', (61, 64))	('tumors', 'Disease', (190, 196))	('knockdown', 'Var', (65, 74))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('cholangiocarcinoma', 'Disease', (78, 96))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('inhibited', 'NegReg', (159, 168))
38866	33350747	Known prognostic factors after surgery include local clearance (R0 no residual tumor or R1 microscopic residual tumor), lymph node metastasis, primary tumor size, and vascular invasion.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('R0 no', 'Var', (64, 69))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('lymph node metastasis', 'CPA', (120, 141))	('tumor', 'Disease', (112, 117))	('vascular invasion', 'CPA', (167, 184))	('local clearance', 'CPA', (47, 62))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
38900	33350747	Tumors were also more invasive in the MiVi group (P < .001), and for this reason, a greater percentage of patients received adjuvant chemotherapy (NoMiVi 59.5%, MiVi 83.7%, P = .006) and radiotherapy (NoMiVi 26.2%, MiVi 46.9%, P = .015) after surgery.	('adjuvant', 'CPA', (124, 132))	('MiVi', 'Chemical', '-', (149, 153))	('MiVi', 'Chemical', '-', (215, 219))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('invasive', 'CPA', (22, 30))	('patients', 'Species', '9606', (106, 114))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('MiVi', 'Chemical', '-', (161, 165))	('MiVi', 'Var', (38, 42))	('MiVi', 'Chemical', '-', (38, 42))	('MiVi', 'Chemical', '-', (203, 207))
38922	33350747	These findings suggest the presence of MiVi reflects the progression of advanced cancer and are consistent with the findings of a previous study, in which tumor size, MiVi, poor tumor grade, and poor tumor differentiation were independently associated with what in cholangiocarcinoma.	('cancer', 'Disease', (81, 87))	('tumor', 'Disease', (155, 160))	('MiVi', 'Chemical', '-', (167, 171))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (265, 283))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('MiVi', 'Disease', (167, 171))	('tumor', 'Disease', (178, 183))	('cholangiocarcinoma', 'Disease', (265, 283))	('tumor', 'Disease', (200, 205))	('MiVi', 'Chemical', '-', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (265, 283))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('poor', 'Var', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('poor', 'Var', (195, 199))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('associated', 'Reg', (241, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))
38938	33350747	Hu et al reported that MiVi affects the prognosis of ICC patients after resection with curative intent in a retrospective study that included 1089 patients in 11 countries, and concluded MiVi is a significant risk factor of DFS, which is consistent with our results.	('MiVi', 'Var', (187, 191))	('MiVi', 'Chemical', '-', (187, 191))	('patients', 'Species', '9606', (57, 65))	('ICC', 'Disease', (53, 56))	('DFS', 'Disease', (224, 227))	('patients', 'Species', '9606', (147, 155))	('MiVi', 'Chemical', '-', (23, 27))	('affects', 'Reg', (28, 35))	('prognosis', 'MPA', (40, 49))
39016	31236199	Our study showed that Bismuth-Corlette type IV was an independent predictor of survival and was inversely related to survival, and these results are similar to a previous study.	('Corlette', 'Chemical', '-', (30, 38))	('inversely', 'NegReg', (96, 105))	('Bismuth-Corlette', 'Var', (22, 38))	('Bismuth', 'Chemical', 'MESH:D001729', (22, 29))
39025	31236199	The ABC-02 trial by Valle et al explored the addition of cisplatin plus gemcitabine to unresectable and metastatic cholangiocarcinoma and suggested that cisplatin plus gemcitabine resulted in a significant increase in progression-free survival (PFS) (8.0 mo vs 5.0 mo, P < 0.001) and overall survival (OS) (11.7 mo vs 8.1 mo, P < 0.001) compared to gemcitabine alone.	('gemcitabine', 'Chemical', 'MESH:C056507', (349, 360))	('gemcitabine', 'Chemical', 'MESH:C056507', (168, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('gemcitabine', 'Chemical', 'MESH:C056507', (72, 83))	('overall survival', 'CPA', (284, 300))	('cholangiocarcinoma', 'Disease', (115, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (115, 133))	('progression-free survival', 'CPA', (218, 243))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (115, 133))	('increase', 'PosReg', (206, 214))	('cisplatin', 'Var', (153, 162))
39027	31236199	The results of the study by Gusani et al indicate that gemcitabine-based TACE was well-tolerated in patients with unresectable cholangiocarcinoma and that combination therapy (cisplatin or oxaliplatin) prolonged patient survival (OS 11.7 mo) compared to controls.	('cholangiocarcinoma', 'Disease', (127, 145))	('patient survival', 'CPA', (212, 228))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (189, 200))	('cisplatin', 'Chemical', 'MESH:D002945', (176, 185))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (127, 145))	('patient', 'Species', '9606', (212, 219))	('combination', 'Var', (155, 166))	('gemcitabine', 'Chemical', 'MESH:C056507', (55, 66))	('prolonged', 'PosReg', (202, 211))	('TACE', 'Chemical', '-', (73, 77))	('patient', 'Species', '9606', (100, 107))	('patients', 'Species', '9606', (100, 108))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (127, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))
39094	27307284	Secondly, the existence of stenosis at the anastomosis or in the intrahepatic bile duct may induce carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('intrahepatic bile', 'Disease', 'MESH:D002780', (65, 82))	('intrahepatic bile', 'Disease', (65, 82))	('carcinogenesis', 'Disease', (99, 113))	('induce', 'Reg', (92, 98))	('stenosis', 'Var', (27, 35))
39180	25432590	HISORt histology, imaging, serology, other organ involvement, and response to corticosteroid IAC IgG4-associated cholangitis IgG4 immunoglobulin G4 ISD IgG4-associated systemic disease.	('cholangitis', 'Phenotype', 'HP:0030151', (113, 124))	('cholangitis', 'Disease', (113, 124))	('men', 'Species', '9606', (56, 59))	('systemic disease', 'Disease', 'MESH:D034721', (168, 184))	('cholangitis', 'Disease', 'MESH:D002761', (113, 124))	('systemic disease', 'Disease', (168, 184))	('IgG4', 'Var', (125, 129))	('steroid', 'Chemical', 'MESH:D013256', (85, 92))
39185	24939880	Further, 53 of 80 human ICC specimens (66%) exhibited high LCN2 expression and LCN2 knockdown in SNU308 cells decreased cell growth and migration, suggesting LCN2 be an oncogene in human ICC.	('human', 'Species', '9606', (181, 186))	('expression', 'MPA', (64, 74))	('rat', 'Species', '10116', (139, 142))	('knockdown', 'Var', (84, 93))	('human', 'Species', '9606', (18, 23))	('LCN2', 'Gene', '3934', (59, 63))	('decreased', 'NegReg', (110, 119))	('LCN2', 'Gene', '3934', (158, 162))	('LCN2', 'Gene', '3934', (79, 83))	('LCN2', 'Gene', (158, 162))	('LCN2', 'Gene', (59, 63))	('LCN2', 'Gene', (79, 83))
39198	24939880	Regarding CCA, 1alpha,25(OH)2D, the active form of vitamin D, has been shown to inhibit CCA cell growth in vitro, and dysregulation of the local conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, the hormonal form of vitamin D, may lead to enhanced CCA.	('vitamin D', 'Chemical', 'MESH:D014807', (51, 60))	('enhanced', 'PosReg', (251, 259))	('inhibit', 'NegReg', (80, 87))	('CCA', 'Phenotype', 'HP:0030153', (10, 13))	('CCA', 'Disease', (260, 263))	('CCA', 'Disease', (88, 91))	('vitamin D', 'Chemical', 'MESH:D014807', (169, 178))	('vitamin D', 'Chemical', 'MESH:D014807', (228, 237))	('1alpha', 'Chemical', '-', (15, 21))	('25-hydroxyvitamin D', 'Chemical', 'MESH:C104450', (159, 178))	('CCA', 'Phenotype', 'HP:0030153', (260, 263))	('CCA', 'Phenotype', 'HP:0030153', (88, 91))	('dysregulation', 'Var', (118, 131))	('1,25-dihydroxyvitamin D', 'Chemical', 'MESH:C097949', (182, 205))	('vitamin D', 'Chemical', 'MESH:D014807', (196, 205))
39220	24939880	Among the downregulated genes, Lcn2 was found to be the most suppressed by vitamin D supplementation with a 38% and 50% reduction in expression, respectively, in the tumors from +2D and +6D rats compared to the -D rats (Table 1a and Supplemental Fig.S-1).	('suppressed', 'NegReg', (61, 71))	('expression', 'MPA', (133, 143))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('Lcn2', 'Gene', (31, 35))	('+6D', 'Var', (186, 189))	('supplementation', 'Var', (85, 100))	('reduction', 'NegReg', (120, 129))	('+2D', 'Var', (178, 181))	('rats', 'Species', '10116', (190, 194))	('vitamin D', 'Chemical', 'MESH:D014807', (75, 84))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('rats', 'Species', '10116', (214, 218))
39227	24939880	Using RT-qPCR and western blot analyses, we found that 1alpha,25(OH)2D3 caused a dose-dependent downregulation of LCN2 mRNA and protein expression in SNU1079 cells with dramatic upregulation of CYP24 mRNA expression, the most inducible gene expression by 1alpha,25(OH)2D3 (Fig.	('1alpha', 'Chemical', '-', (255, 261))	('25(OH)2D3', 'Chemical', '-', (262, 271))	('LCN2', 'Gene', (114, 118))	('1alpha', 'Chemical', '-', (55, 61))	('SNU1079', 'CellLine', 'CVCL:5008', (150, 157))	('upregulation', 'PosReg', (178, 190))	('downregulation', 'NegReg', (96, 110))	('CYP24', 'Gene', '1591', (194, 199))	('25(OH)2D3', 'Chemical', '-', (62, 71))	('CYP24', 'Gene', (194, 199))	('1alpha,25(OH)2D3', 'Var', (55, 71))	('LCN2', 'Gene', '3934', (114, 118))
39228	24939880	Furthermore, we showed that VDR knockdown by shRNA blunted the 1alpha,25(OH)2D3-dependent LCN2 mRNA downregulation (Fig.	('LCN2', 'Gene', (90, 94))	('25(OH)2D3', 'Chemical', '-', (70, 79))	('1alpha', 'Chemical', '-', (63, 69))	('VDR', 'Gene', '7421', (28, 31))	('knockdown', 'Var', (32, 41))	('downregulation', 'NegReg', (100, 114))	('blunted', 'NegReg', (51, 58))	('LCN2', 'Gene', '3934', (90, 94))	('VDR', 'Gene', (28, 31))
39229	24939880	Given that the added FBS in cell culture medium contained some amount of 1alpha,25(OH)2D3, the higher LCN2 expression in SNU-VDRsi cells than that of SNU-COLsi cells also indicated the downregulation of LCN2 by 1alpha,25(OH)2D3 is VDR-mediated (Fig 4e).Consequently, we concluded that LCN2 expression is regulated by 1alpha,25(OH)2D3 and is mediated through VDR in SNU1079 cells.	('regulated', 'Reg', (304, 313))	('VDR', 'Gene', '7421', (125, 128))	('LCN2', 'Gene', (102, 106))	('LCN2', 'Gene', '3934', (203, 207))	('25(OH)2D3', 'Chemical', '-', (80, 89))	('VDR', 'Gene', (358, 361))	('VDR', 'Gene', (231, 234))	('SNU1079', 'CellLine', 'CVCL:5008', (365, 372))	('1alpha', 'Chemical', '-', (73, 79))	('25(OH)2D3', 'Chemical', '-', (324, 333))	('LCN2', 'Gene', (203, 207))	('1alpha,25(OH)2D3', 'Var', (317, 333))	('1alpha', 'Chemical', '-', (317, 323))	('VDR', 'Gene', '7421', (358, 361))	('LCN2', 'Gene', '3934', (285, 289))	('VDR', 'Gene', '7421', (231, 234))	('mediated', 'Reg', (341, 349))	('FBS', 'Disease', (21, 24))	('VDR', 'Gene', (125, 128))	('25(OH)2D3', 'Chemical', '-', (218, 227))	('FBS', 'Disease', 'MESH:D005198', (21, 24))	('LCN2', 'Gene', '3934', (102, 106))	('1alpha', 'Chemical', '-', (211, 217))	('LCN2', 'Gene', (285, 289))	('expression', 'MPA', (290, 300))
39230	24939880	To further determine LCN2 effect on human CCA cells, we knockdowned LCN2 in another CCA cell line, SNU308, and obtained SNU-COLsi cells (mock knockdown SNU308 cells) and SNU-NGALsi cells (LCN2 knockdwon SNU308 cells)(Figure S-3).	('NGAL', 'Gene', (174, 178))	('LCN2', 'Gene', '3934', (68, 72))	('NGAL', 'Gene', '3934', (174, 178))	('LCN2', 'Gene', '3934', (188, 192))	('CCA', 'Phenotype', 'HP:0030153', (42, 45))	('LCN2', 'Gene', (188, 192))	('LCN2', 'Gene', (68, 72))	('LCN2', 'Gene', '3934', (21, 25))	('knockdowned', 'Var', (56, 67))	('LCN2', 'Gene', (21, 25))	('CCA', 'Phenotype', 'HP:0030153', (84, 87))	('human', 'Species', '9606', (36, 41))
39231	24939880	The cell doubling time was increased to 30.45 hours from 23.6 hours and the migration ability is significantly repressed in SNU308 cells after LCN2 knockdown (Fig 4f).	('repressed', 'NegReg', (111, 120))	('LCN2', 'Gene', '3934', (143, 147))	('LCN2', 'Gene', (143, 147))	('migration ability', 'CPA', (76, 93))	('rat', 'Species', '10116', (79, 82))	('knockdown', 'Var', (148, 157))
39232	24939880	Since the active form of vitamin D, 1alpha,25(OH)2D3 or calcitriol, has been well demonstrated to be a pleiotropic hormone with a variety of anti-tumor actions, combined with the fact that vitamin D deficiency has been associated with a number of cancers incidence, we thus investigated whether vitamin D supplementation could benefit the prevention of ICC initiation and progression under the bleak background of ICC treatment.	('tumor', 'Disease', (146, 151))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('cancers', 'Disease', (247, 254))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('calcitriol', 'Chemical', 'MESH:D002117', (56, 66))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (189, 209))	('vitamin D', 'Chemical', 'MESH:D014807', (295, 304))	('vitamin D', 'Chemical', 'MESH:D014807', (25, 34))	('associated', 'Reg', (219, 229))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancers', 'Disease', 'MESH:D009369', (247, 254))	('vitamin D', 'Chemical', 'MESH:D014807', (189, 198))	('bleak', 'Species', '54556', (394, 399))	('25(OH)2D3', 'Chemical', '-', (43, 52))	('deficiency', 'Var', (199, 209))	('rat', 'Species', '10116', (89, 92))	('1alpha', 'Chemical', '-', (36, 42))	('ICC', 'Disease', (353, 356))
39244	24939880	The tumor incidence and tumor progression in -D and +2D groups are similar (Fig 2b&c), whereas +6D group has significantly lower tumor incidence and progression as compared to -D group (Fig.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('significantly', 'NegReg', (109, 122))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('whereas', 'Var', (87, 94))
39254	24939880	Among the downregulated genes found in our microarray analysis, LCN2 was found to be the most suppressed by vitamin D supplementation.	('LCN2', 'Gene', '3934', (64, 68))	('vitamin D', 'Chemical', 'MESH:D014807', (108, 117))	('LCN2', 'Gene', (64, 68))	('suppressed', 'NegReg', (94, 104))	('supplementation', 'Var', (118, 133))
39265	24939880	Moreover, the roles of LCN2 in ICC have been studied by knocking down LCN2 with siRNA that resulted in a significant reduction in invasiveness, migration and pro-MMP-9 activity of ICC cells.	('reduction', 'NegReg', (117, 126))	('LCN2', 'Gene', (70, 74))	('MMP-9', 'Gene', '4318', (162, 167))	('LCN2', 'Gene', '3934', (23, 27))	('knocking down', 'Var', (56, 69))	('MMP-9', 'Gene', (162, 167))	('LCN2', 'Gene', (23, 27))	('rat', 'Species', '10116', (147, 150))	('invasiveness', 'CPA', (130, 142))	('LCN2', 'Gene', '3934', (70, 74))	('migration', 'CPA', (144, 153))
39266	24939880	To further verify LCN2 role in human ICC, we examined 80 human ICC specimen and 66% of human ICC specimen presented with high expression LCN2, adding the finding that knockdown of LCN2 in SNU308 cells decreased cell growth and migration (Fig 4f), indicating the LCN2 plays as an oncogene in human ICC.	('LCN2', 'Gene', (262, 266))	('LCN2', 'Gene', (180, 184))	('LCN2', 'Gene', '3934', (180, 184))	('human', 'Species', '9606', (57, 62))	('LCN2', 'Gene', '3934', (137, 141))	('human', 'Species', '9606', (87, 92))	('cell growth', 'CPA', (211, 222))	('decreased', 'NegReg', (201, 210))	('LCN2', 'Gene', (137, 141))	('human', 'Species', '9606', (31, 36))	('knockdown', 'Var', (167, 176))	('LCN2', 'Gene', '3934', (262, 266))	('LCN2', 'Gene', '3934', (18, 22))	('rat', 'Species', '10116', (230, 233))	('LCN2', 'Gene', (18, 22))	('human', 'Species', '9606', (291, 296))
39277	24939880	Furthermore, the results showing that the high expression of LCN2 in human ICC specimen, the decreased proliferation and migration of SNU308 cells after LCN2 knockdown, and the 1alpha,25(OH)2D3-induced antiproliferative effect and VDR-dependent downregulation of LCN2 in SNU1079 cells, strongly suggest LCN2 may be a new target against human CCA.	('proliferation', 'CPA', (103, 116))	('LCN2', 'Gene', '3934', (61, 65))	('1alpha', 'Chemical', '-', (177, 183))	('rat', 'Species', '10116', (213, 216))	('CCA', 'Phenotype', 'HP:0030153', (342, 345))	('rat', 'Species', '10116', (110, 113))	('VDR', 'Gene', (231, 234))	('LCN2', 'Gene', (61, 65))	('downregulation', 'NegReg', (245, 259))	('LCN2', 'Gene', '3934', (303, 307))	('antiproliferative effect', 'CPA', (202, 226))	('expression', 'MPA', (47, 57))	('LCN2', 'Gene', '3934', (153, 157))	('rat', 'Species', '10116', (124, 127))	('LCN2', 'Gene', '3934', (263, 267))	('human', 'Species', '9606', (69, 74))	('decreased', 'NegReg', (93, 102))	('VDR', 'Gene', '7421', (231, 234))	('LCN2', 'Gene', (303, 307))	('LCN2', 'Gene', (153, 157))	('LCN2', 'Gene', (263, 267))	('knockdown', 'Var', (158, 167))	('25(OH)2D3', 'Chemical', '-', (184, 193))	('SNU1079', 'CellLine', 'CVCL:5008', (271, 278))	('human', 'Species', '9606', (336, 341))
39301	24939880	FAM dye-labeled TaqMan MGB probes and PCR primers for human LCN2 (HS00194353-m1), CYP24A1 (HS00167999-m1), and VDR (HS01045844-m1) were purchased from Applied Biosystems.	('human', 'Species', '9606', (54, 59))	('CYP24A1', 'Gene', '1591', (82, 89))	('VDR', 'Gene', (111, 114))	('LCN2', 'Gene', '3934', (60, 64))	('LCN2', 'Gene', (60, 64))	('FAM dye', 'Chemical', '-', (0, 7))	('HS00194353-m1', 'Var', (66, 79))	('CYP24A1', 'Gene', (82, 89))	('VDR', 'Gene', '7421', (111, 114))	('HS00167999-m1', 'Var', (91, 104))	('HS01045844-m1', 'Var', (116, 129))
39302	24939880	For the internal positive control, GAPDH (HS99999905-m1) was used with a FAM reporter dye-labeled TaqMan MGB probe.	('GAPDH', 'Gene', (35, 40))	('HS99999905-m1', 'Var', (42, 55))	('GAPDH', 'Gene', '2597', (35, 40))
39345	17921093	In addition, diffuse wall thickening is more commonly caused by acute and chronic cholecystitis, adenomyomatosis, inadequate gallbladder distention, hepatitis, low protein states, and other causes.	('hepatitis', 'Disease', 'MESH:D056486', (149, 158))	('inadequate gallbladder', 'Phenotype', 'HP:0005233', (114, 136))	('acute', 'Disease', (64, 69))	('diffuse wall thickening', 'Disease', (13, 36))	('gallbladder distention', 'Phenotype', 'HP:0003270', (125, 147))	('low', 'Var', (160, 163))	('cholecystitis', 'Phenotype', 'HP:0001082', (82, 95))	('adenomyomatosis', 'Disease', 'None', (97, 112))	('cholecystitis', 'Disease', (82, 95))	('adenomyomatosis', 'Disease', (97, 112))	('hepatitis', 'Disease', (149, 158))	('hepatitis', 'Phenotype', 'HP:0012115', (149, 158))	('cholecystitis', 'Disease', 'MESH:D002764', (82, 95))	('caused', 'Reg', (54, 60))	('inadequate', 'Disease', (114, 124))
39470	19010890	The data presented here represents the first evidence that serotonin metabolism is dysregulated in cholangiocarcinoma and that modulation of serotonin synthesis may represent an alternative target for the development of therapeutic strategies.	('modulation', 'Var', (127, 137))	('serotonin', 'Chemical', 'MESH:D012701', (141, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('serotonin metabolism', 'MPA', (59, 79))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (99, 117))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (99, 117))	('serotonin', 'Chemical', 'MESH:D012701', (59, 68))	('rat', 'Species', '10116', (234, 237))	('dysregulated', 'Reg', (83, 95))	('cholangiocarcinoma', 'Disease', (99, 117))
39484	19010890	In contrast, several studies have also reported that serotonin can inhibit tumor growth, mainly via the specific vasoconstrictive effects of serotonin on the vessels irrigating the tumors.	('serotonin', 'Chemical', 'MESH:D012701', (141, 150))	('inhibit', 'NegReg', (67, 74))	('tumor', 'Disease', (181, 186))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('serotonin', 'Var', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('serotonin', 'Chemical', 'MESH:D012701', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('vasoconstrictive effects', 'MPA', (113, 137))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', (75, 80))
39492	19010890	Furthermore, we demonstrate that the increased secretion of serotonin has growth-promoting effects on cholangiocarcinoma cells and that inhibiting serotonin synthesis significantly blocks cholangiocarcinoma cell proliferation in vitro and in vivo.	('serotonin', 'MPA', (60, 69))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (188, 206))	('serotonin', 'MPA', (147, 156))	('blocks', 'NegReg', (181, 187))	('increased', 'PosReg', (37, 46))	('secretion', 'MPA', (47, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('rat', 'Species', '10116', (23, 26))	('serotonin', 'Chemical', 'MESH:D012701', (60, 69))	('serotonin', 'Chemical', 'MESH:D012701', (147, 156))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (102, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('rat', 'Species', '10116', (219, 222))	('cholangiocarcinoma', 'Disease', (102, 120))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (102, 120))	('increased secretion of serotonin', 'Phenotype', 'HP:0003144', (37, 69))	('growth-promoting effects', 'CPA', (74, 98))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (188, 206))	('inhibiting', 'Var', (136, 146))	('cholangiocarcinoma', 'Disease', (188, 206))
39552	19010890	In addition, the latency of tumor growth (i.e., time taken for tumor volume to increase to 150% of the original size) was increased after CPA treatment compared to vehicle treatment (Figure 6C).	('CPA', 'Var', (138, 141))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('increased', 'PosReg', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('latency', 'MPA', (17, 24))
39557	19010890	The major findings of this study relate to the dysregulation of serotonin metabolism in cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('dysregulation', 'Var', (47, 60))	('cholangiocarcinoma', 'Disease', (88, 106))	('serotonin metabolism', 'MPA', (64, 84))	('serotonin', 'Chemical', 'MESH:D012701', (64, 73))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 106))
39560	19010890	These data suggest that the dysregulation of serotonin metabolism may be a key feature associated with the progression of cholangiocarcinoma and modulation of this metabolic pathway may result in the development of an effective adjunct therapy to treat this deadly disease.	('result in', 'Reg', (186, 195))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (122, 140))	('serotonin metabolism', 'MPA', (45, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('modulation', 'Var', (145, 155))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (122, 140))	('associated', 'Reg', (87, 97))	('dysregulation', 'MPA', (28, 41))	('cholangiocarcinoma', 'Disease', (122, 140))	('serotonin', 'Chemical', 'MESH:D012701', (45, 54))
39562	19010890	Within these tumors, serotonin is thought to stimulate cell proliferation, and cause symptoms of the carcinoid syndrome, including diarrhea, and damage to the valves of the heart.	('rat', 'Species', '10116', (67, 70))	('carcinoid syndrome', 'Disease', 'MESH:D002276', (101, 119))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('carcinoid', 'Phenotype', 'HP:0100570', (101, 110))	('cause', 'Reg', (79, 84))	('cell proliferation', 'CPA', (55, 73))	('diarrhea', 'Disease', 'MESH:D003967', (131, 139))	('stimulate', 'PosReg', (45, 54))	('diarrhea', 'Phenotype', 'HP:0002014', (131, 139))	('carcinoid syndrome', 'Disease', (101, 119))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('diarrhea', 'Disease', (131, 139))	('serotonin', 'Chemical', 'MESH:D012701', (21, 30))	('serotonin', 'Var', (21, 30))
39572	19010890	Because hypermethylation and subsequent silencing of genes such as tumor suppressor genes are a common event in the malignant transformation of cholangiocarcinoma, it is therefore conceivable that hypermethylation of the MAO A promoter contributes to the suppression of expression.	('cholangiocarcinoma', 'Disease', (144, 162))	('MAO A', 'Gene', '4128', (221, 226))	('hypermethylation', 'Var', (8, 24))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (144, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (144, 162))	('hypermethylation', 'Var', (197, 213))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MAO A', 'Gene', (221, 226))	('silencing', 'NegReg', (40, 49))	('tumor', 'Disease', (67, 72))	('expression', 'MPA', (270, 280))
39580	19010890	Here, we show a proliferative effect of serotonin on cholangiocarcinoma growth and the inhibition of serotonin production effectively inhibits tumor growth.	('inhibits', 'NegReg', (134, 142))	('tumor', 'Disease', (143, 148))	('serotonin', 'Chemical', 'MESH:D012701', (101, 110))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (53, 71))	('rat', 'Species', '10116', (23, 26))	('cholangiocarcinoma growth', 'Disease', (53, 78))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (53, 78))	('serotonin', 'Chemical', 'MESH:D012701', (40, 49))	('proliferative effect', 'MPA', (16, 36))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('inhibition', 'Var', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
39581	19010890	Furthermore, we could show that inhibition of the serotonin receptors 5HTR 1A, 5HTR 2A, 5HTR 2B, 5HTR 4 and 5HTR 6 effectively blocked the growth promoting effects of serotonin.	('inhibition', 'Var', (32, 42))	('serotonin', 'Chemical', 'MESH:D012701', (50, 59))	('serotonin receptors 5HTR 1A, 5HTR 2A, 5HTR 2B', 'Gene', '3356', (50, 95))	('serotonin', 'Chemical', 'MESH:D012701', (167, 176))	('blocked', 'NegReg', (127, 134))	('growth promoting effects', 'CPA', (139, 163))
39651	33936676	Pembrolizumab is considered to be an effective therapy for patients with microsatellite instability (MSI)-high cancer.	('microsatellite', 'Var', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (0, 13))	('patients', 'Species', '9606', (59, 67))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
39696	31804374	A 50-year-old right-handed man who did not smoke was diagnosed with a poorly differentiated ICC (T2aN0M0) in segment VI of the liver in February 2017.	('T2aN0M0', 'Var', (97, 104))	('ICC', 'Disease', 'MESH:C535533', (92, 95))	('man', 'Species', '9606', (27, 30))	('ICC', 'Disease', (92, 95))
39712	31804374	A 50-year-old right-handed who did not smoke was diagnosed with a 2.2 cm x 2.5 cm poorly differentiated ICC (T2aN0M0) in segment VI of the liver in February 2017.	('T2aN0M0', 'Var', (109, 116))	('ICC', 'Disease', 'MESH:C535533', (104, 107))	('ICC', 'Disease', (104, 107))
39833	30340457	As an example, oxidatively damaged transferrin released iron ion, which may mediate Fenton reactions and generate additional reactive oxygen species.	('Fenton reactions', 'MPA', (84, 100))	('transferrin', 'Gene', '7018', (35, 46))	('transferrin', 'Gene', (35, 46))	('iron ion', 'MPA', (56, 64))	('iron', 'Chemical', 'MESH:D007501', (56, 60))	('reactive oxygen species', 'MPA', (125, 148))	('mediate', 'Reg', (76, 83))	('oxidatively', 'Var', (15, 26))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (125, 148))
39835	30340457	Epigenetic alterations such as DNA methylation and microRNA dysregulation play vital roles in carcinogenesis, especially in inflammation-related cancers.	('cancers', 'Disease', (145, 152))	('DNA methylation', 'Var', (31, 46))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('inflammation', 'Disease', (124, 136))	('microRNA dysregulation', 'Var', (51, 73))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('inflammation', 'Disease', 'MESH:D007249', (124, 136))	('carcinogenesis', 'Disease', (94, 108))
39841	30340457	Chronic inflammation promotes genetic and epigenetic aberrations, with various pathogeneses.	('epigenetic', 'Var', (42, 52))	('Chronic inflammation', 'Disease', (0, 20))	('genetic and', 'MPA', (30, 41))	('Chronic inflammation', 'Disease', 'MESH:D007249', (0, 20))
39846	30340457	We demonstrated the importance of mutagenic DNA lesions, especially 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG, also known as 8-hydroxy dG; 8-OHdG) and 8-nitroguanine, as a common cancer-causing molecular mechanism.	('8-nitroguanine', 'Chemical', 'MESH:C095838', (154, 168))	('8-OHdG', 'Chemical', 'MESH:C067134', (142, 148))	('8-oxodG', 'Chemical', 'MESH:C067134', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	("8-oxo-7,8-dihydro-2'-deoxyguanosine", 'Chemical', 'MESH:C067134', (68, 103))	('mutagenic', 'Var', (34, 43))	('8-hydroxy dG', 'Chemical', '-', (128, 140))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))
39851	30340457	In addition, inflammation plays a role in the epigenetic alterations in cancer.	('epigenetic alterations', 'Var', (46, 68))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('inflammation', 'Disease', 'MESH:D007249', (13, 25))	('inflammation', 'Disease', (13, 25))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
39861	30340457	Flowcytometric analyses revealed that melatonin increased intracellular ROS levels and induced apoptosis.	('increased', 'PosReg', (48, 57))	('melatonin', 'Var', (38, 47))	('apoptosis', 'CPA', (95, 104))	('ROS', 'Chemical', 'MESH:D017382', (72, 75))	('increased intracellular ROS levels', 'Phenotype', 'HP:0025464', (48, 82))	('intracellular ROS levels', 'MPA', (58, 82))	('melatonin', 'Chemical', 'MESH:D008550', (38, 47))	('induced', 'Reg', (87, 94))
39865	30340457	Stem cells are damaged by ROS/RNS from inflammation, and the resulted mutations can accumulate, which could generate cancer stem cells.	('mutations', 'Var', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('inflammation', 'Disease', 'MESH:D007249', (39, 51))	('RNS', 'Gene', (30, 33))	('RNS', 'Gene', '56975', (30, 33))	('inflammation', 'Disease', (39, 51))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('generate', 'Reg', (108, 116))	('ROS', 'Chemical', 'MESH:D017382', (26, 29))
39871	30340457	Interestingly, EBF1 knockdown in MMNK1 cells upregulated CD133 and Oct3/4 expression with a higher ability of cell migration.	('expression', 'MPA', (74, 84))	('higher', 'PosReg', (92, 98))	('EBF1', 'Gene', (15, 19))	('cell migration', 'CPA', (110, 124))	('Oct3/4', 'Gene', '5460', (67, 73))	('upregulated', 'PosReg', (45, 56))	('Oct3/4', 'Gene', (67, 73))	('EBF1', 'Gene', '1879', (15, 19))	('CD133', 'Gene', (57, 62))	('CD133', 'Gene', '8842', (57, 62))	('knockdown', 'Var', (20, 29))
39878	30340457	IHC staining of CD44v6 and ALDH1A1 was observed in cancer tissues, but that of CD24 was not.	('ALDH1A1', 'Gene', (27, 34))	('CD44v6', 'Var', (16, 22))	('observed', 'Reg', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('ALDH1A1', 'Gene', '216', (27, 34))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('CD24', 'Gene', '100133941', (79, 83))	('cancer', 'Disease', (51, 57))	('CD24', 'Gene', (79, 83))
39880	30340457	Flow cytometric analysis confirmed both CD44v6- and ALDH1A1-positive cells in a small population of a human nasopharyngeal carcinoma cell line.	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (108, 132))	('ALDH1A1', 'Gene', (52, 59))	('nasopharyngeal carcinoma', 'Disease', (108, 132))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (108, 132))	('ALDH1A1', 'Gene', '216', (52, 59))	('CD44v6-', 'Var', (40, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('human', 'Species', '9606', (102, 107))
39901	30340457	Accumulating evidence makes it increasingly clear that epigenetic silencing plays an important role in carcinogenesis via the downregulation of tumor suppressor genes and microRNAs.	('tumor', 'Disease', (144, 149))	('downregulation', 'NegReg', (126, 140))	('epigenetic silencing', 'Var', (55, 75))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('microRNAs', 'Protein', (171, 180))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('carcinogenesis', 'Disease', (103, 117))
39910	30340457	Promoter hypermethylation events can lead to silencing of genes functioning in tumor-relevant pathways.	('tumor', 'Disease', (79, 84))	('Promoter hypermethylation events', 'Var', (0, 32))	('silencing', 'MPA', (45, 54))	('lead to', 'Reg', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
39911	30340457	Together with our collaborators at Guangxi Medical University, we examined aberrant DNA methylation of nasopharyngeal carcinoma tissues of patients in the endemic area of Southern China.	('aberrant', 'Var', (75, 83))	('nasopharyngeal carcinoma tissues', 'Disease', 'MESH:D000077274', (103, 135))	('patients', 'Species', '9606', (139, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (103, 127))	('nasopharyngeal carcinoma tissues', 'Disease', (103, 135))
39913	30340457	Among the upregulated candidate genes, we confirmed promoter DNA hypermethylation of RRAD (RAS associated with diabetes) in biopsy specimens and cancer cell lines.	('cancer', 'Disease', (145, 151))	('diabetes', 'Disease', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('diabetes', 'Disease', 'MESH:D003920', (111, 119))	('RRAD', 'Gene', (85, 89))	('promoter DNA hypermethylation', 'Var', (52, 81))	('RRAD', 'Gene', '6236', (85, 89))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
39915	30340457	We also detected downregulation of RERG (RAS-like estrogen-regulated growth inhibitor) by DNA methylation in the cancer tissues.	('DNA methylation', 'Var', (90, 105))	('RAS-like estrogen-regulated growth inhibitor', 'Gene', '85004', (41, 85))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('downregulation', 'NegReg', (17, 31))	('RAS-like estrogen-regulated growth inhibitor', 'Gene', (41, 85))	('RERG', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
39924	30340457	Combined with the gene expression microarray, we identified candidate genes that are silenced by promoter DNA methylation in cancer tissues.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('promoter DNA methylation', 'Var', (97, 121))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('silenced', 'NegReg', (85, 93))
39927	30340457	We found several differentially methylated candidate genes in nasopharyngeal carcinoma tissues compared to normal nasopharynx tissues that may be useful biomarkers for cancer screening.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (62, 86))	('nasopharyngeal carcinoma tissues', 'Disease', (62, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('differentially methylated', 'Var', (17, 42))	('cancer', 'Disease', (168, 174))	('nasopharyngeal carcinoma tissues', 'Disease', 'MESH:D000077274', (62, 94))
39945	30340457	Liquid biopsy allows for repeated minimally invasive monitoring of tumor clonal evolution (mutation, epigenome alteration) during multistep carcinogenesis.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('epigenome alteration', 'Var', (101, 121))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
39950	30340457	Chronic inflammation promotes genetic and epigenetic aberrations in various pathogeneses.	('genetic', 'Var', (30, 37))	('epigenetic aberrations', 'Var', (42, 64))	('Chronic inflammation', 'Disease', (0, 20))	('Chronic inflammation', 'Disease', 'MESH:D007249', (0, 20))
39964	26700646	In fact, the occlusion of the right portal vein induces compensatory hypertrophy of the left lobe that is on the average of 40% in approximately 4-8 weeks.	('hypertrophy', 'Disease', 'MESH:D006984', (69, 80))	('occlusion', 'Var', (13, 22))	('hypertrophy', 'Disease', (69, 80))
40055	26700646	In contrast to the normal parenchyma, neoplastic lesions base their blood supply exclusively on the arterial inflow; consequently, arterialization of the tumor lesions in a deportalized right liver can produce an increased tumor volume.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('tumor lesions', 'Disease', (154, 167))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('arterialization', 'Var', (131, 146))	('tumor lesions', 'Disease', 'MESH:D051437', (154, 167))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('increased', 'PosReg', (213, 222))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (38, 56))	('tumor', 'Disease', (154, 159))
40069	26700646	Among the other variations proposed, "partial ALPPS", seems to be able to induce an hypertrophy of the FLR similar to that observed in the conventional ALPPS and reduce postoperative mortality and complications by avoiding the complete partition of the liver during step 1; if these findings were confirmed on larger numbers (only 6 cases of partial ALPPS have been reported to date), partial ALPPS could well become the technique of choice.	('reduce', 'NegReg', (162, 168))	('induce', 'Reg', (74, 80))	('hypertrophy', 'Disease', (84, 95))	('variations', 'Var', (16, 26))	('postoperative mortality', 'CPA', (169, 192))	('hypertrophy', 'Disease', 'MESH:D006984', (84, 95))
40074	25803229	MiR-21 promotes intrahepatic cholangiocarcinoma proliferation and growth in vitro and in vivo by targeting PTPN14 and PTEN Intrahepatic cholangiocarcinoma (ICC) constitutes the second-most common primary hepatic malignancy.	('MiR-21', 'Gene', (0, 6))	('hepatic malignancy', 'Phenotype', 'HP:0002896', (204, 222))	('growth', 'CPA', (66, 72))	('intrahepatic cholangiocarcinoma proliferation', 'Disease', (16, 61))	('PTPN14', 'Gene', (107, 113))	('hepatic malignancy', 'Disease', (204, 222))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (136, 154))	('PTEN', 'Gene', (118, 122))	('PTPN14', 'Gene', '5784', (107, 113))	('promotes', 'PosReg', (7, 15))	('MiR-21', 'Gene', '406991', (0, 6))	('hepatic malignancy', 'Disease', 'MESH:D056486', (204, 222))	('intrahepatic cholangiocarcinoma proliferation', 'Disease', 'MESH:D018281', (16, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (29, 47))	('targeting', 'Var', (97, 106))	('Intrahepatic cholangiocarcinoma', 'Disease', (123, 154))	('Intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (123, 154))
40078	25803229	Further experiments showed that inhibition of miR-21 suppressed ICC cell proliferation in vitro and tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('inhibition', 'Var', (32, 42))	('tumor', 'Disease', (100, 105))	('miR-21', 'Gene', '406991', (46, 52))	('ICC', 'Disease', (64, 67))	('miR-21', 'Gene', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('suppressed', 'NegReg', (53, 63))
40079	25803229	Specifically, inhibition of miR-21 induced cell cycle arrest and apoptosis.	('miR-21', 'Gene', (28, 34))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (43, 60))	('apoptosis', 'CPA', (65, 74))	('arrest', 'Disease', 'MESH:D006323', (54, 60))	('inhibition', 'Var', (14, 24))	('miR-21', 'Gene', '406991', (28, 34))	('arrest', 'Disease', (54, 60))
40089	25803229	MiRNAs regulate the expression of a wide variety of target genes, and aberrant expression of miRNAs functions as tumor suppressors or oncogenes according to the role of their target genes.	('miRNAs', 'Gene', (93, 99))	('tumor', 'Disease', (113, 118))	('expression', 'MPA', (20, 30))	('aberrant expression', 'Var', (70, 89))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
40092	25803229	Several aberrantly-expressed serum and tissue miRNAs have been employed as diagnostic or prognostic indicators in multiple cancer types.	('multiple cancer', 'Disease', (114, 129))	('multiple cancer', 'Disease', 'MESH:D009369', (114, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('aberrantly-expressed', 'Var', (8, 28))
40122	25803229	MTT assays revealed that miR-21 inhibitor-transfected HUCCT1 and RBE cells exhibited significantly decreased growth rate than normal control (NC)-transfected cells (P < 0.05; Figure 2B and Figure 2C).	('decreased', 'NegReg', (99, 108))	('miR-21', 'Gene', (25, 31))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('decreased growth rate', 'Phenotype', 'HP:0001510', (99, 120))	('miR-21', 'Gene', '406991', (25, 31))	('growth rate', 'CPA', (109, 120))	('inhibitor-transfected', 'Var', (32, 53))
40123	25803229	Colony formation assays also showed that silencing miR-21 expression resulted in significant tumor growth inhibition (P < 0.05; Figure 2D and Figure 2E).	('silencing', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('miR-21', 'Gene', (51, 57))	('miR-21', 'Gene', '406991', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
40128	25803229	Cells treated with miR-21 inhibitors displayed a significant increase in the percentage of cells in the G1/G0 peak and a decrease in the percentage of cells in the S and G2/M peak (Both P < 0.05; Figure 2J, Figure 2K and Figure 2L).	('inhibitors', 'Var', (26, 36))	('miR-21', 'Gene', '406991', (19, 25))	('decrease', 'NegReg', (121, 129))	('increase', 'PosReg', (61, 69))	('miR-21', 'Gene', (19, 25))
40138	25803229	Luciferase reporter assays demonstrated that miR-21 significantly repressed activity of reporter vectors harboring wild-type 3'-UTRs of PTPN14 and PTEN, whereas mutations of putative miR-21-bingding sites in these 3'-UTR regions abrogated the inhibitory effects of miR-21 (Figure 3A, Figure 3B, Figure 3C).	('miR-21', 'Gene', '406991', (265, 271))	('miR-21', 'Gene', '406991', (183, 189))	('miR-21', 'Gene', (45, 51))	('activity', 'MPA', (76, 84))	('PTPN14', 'Gene', '5784', (136, 142))	('abrogated', 'NegReg', (229, 238))	('miR-21', 'Gene', (265, 271))	('inhibitory effects', 'MPA', (243, 261))	('mutations', 'Var', (161, 170))	('miR-21', 'Gene', (183, 189))	('PTEN', 'Gene', (147, 151))	('miR-21', 'Gene', '406991', (45, 51))	('PTEN', 'Gene', '5728', (147, 151))	('PTPN14', 'Gene', (136, 142))
40146	25803229	In addition, silencing the single-gene expression of PTPN14 or PTEN in miR-21 inhibitor-transduced cells attenuated the inhibitory effect on cell proliferation of HUCCT1 and RBE cells.	('PTEN', 'Gene', '5728', (63, 67))	('PTPN14', 'Gene', '5784', (53, 59))	('single-gene expression', 'Var', (27, 49))	('miR-21', 'Gene', '406991', (71, 77))	('PTPN14', 'Gene', (53, 59))	('miR-21', 'Gene', (71, 77))	('inhibitory effect', 'MPA', (120, 137))	('attenuated', 'NegReg', (105, 115))	('silencing', 'NegReg', (13, 22))	('PTEN', 'Gene', (63, 67))
40147	25803229	More importantly, we found that when the expression of PTPN14 and PTEN were silenced at the same time, inhibition of cell proliferation induced by miR-21 inhibitors was remarkably attenuated (Figure 4A and Figure 4B).	('miR-21', 'Gene', (147, 153))	('PTEN', 'Gene', (66, 70))	('silenced', 'NegReg', (76, 84))	('inhibitors', 'Var', (154, 164))	('attenuated', 'NegReg', (180, 190))	('PTPN14', 'Gene', (55, 61))	('PTEN', 'Gene', '5728', (66, 70))	('cell proliferation', 'CPA', (117, 135))	('PTPN14', 'Gene', '5784', (55, 61))	('miR-21', 'Gene', '406991', (147, 153))	('inhibition', 'NegReg', (103, 113))
40148	25803229	Similarly, we found silencing PTPN14 and/or PTEN could rescue the effects of miR-21 inhibitors on HUCCT1 and RBE cells, as revealed by colony formation assays (Figure 4C), soft agar colony formation assays (Figure 4D), cell cycle assays (Figure 4F, Figure 4G), and tumorigenesis assays (Figure 4H).	('inhibitors', 'MPA', (84, 94))	('colon', 'Disease', 'MESH:D015179', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('agar', 'Chemical', 'MESH:D000362', (177, 181))	('PTPN14', 'Gene', '5784', (30, 36))	('tumor', 'Disease', (265, 270))	('miR-21', 'Gene', '406991', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('colon', 'Disease', (182, 187))	('PTEN', 'Gene', (44, 48))	('cell cycle assays', 'CPA', (219, 236))	('PTEN', 'Gene', '5728', (44, 48))	('PTPN14', 'Gene', (30, 36))	('colon', 'Disease', (135, 140))	('silencing', 'Var', (20, 29))	('colon', 'Disease', 'MESH:D015179', (182, 187))	('miR-21', 'Gene', (77, 83))
40149	25803229	However, we also found silencing PTPN14 and/or PTEN could inhibit apoptosis rates of HUCCT1 and RBE cells induced by miR-21 inhibitors (Figure 4E).	('PTPN14', 'Gene', '5784', (33, 39))	('apoptosis rates', 'CPA', (66, 81))	('miR-21', 'Gene', (117, 123))	('silencing', 'Var', (23, 32))	('PTPN14', 'Gene', (33, 39))	('PTEN', 'Gene', (47, 51))	('inhibit', 'NegReg', (58, 65))	('PTEN', 'Gene', '5728', (47, 51))	('miR-21', 'Gene', '406991', (117, 123))
40156	25803229	Patients with high tissue miR-21 expression exhibited poor 5-year overall and progression-free survival rates in comparison to patients with low miR-21 expression.	('miR-21', 'Gene', '406991', (145, 151))	('progression-free survival rates', 'CPA', (78, 109))	('poor', 'NegReg', (54, 58))	('miR-21', 'Gene', '406991', (26, 32))	('patients', 'Species', '9606', (127, 135))	('Patients', 'Species', '9606', (0, 8))	('miR-21', 'Gene', (145, 151))	('miR-21', 'Gene', (26, 32))	('high tissue', 'Var', (14, 25))
40164	25803229	To test the prognostic value of high tissue miR-21 expression, a Cox proportional hazard model was used.	('high', 'Var', (32, 36))	('miR-21', 'Gene', '406991', (44, 50))	('miR-21', 'Gene', (44, 50))
40168	25803229	Multivariate analyses including age, gender, tumor origination, clinical stage at diagnosis, differentiation status, and miR-21 expression demonstrated that high tissue miR-21expression was an independent predictor for poor overall- and progression-free survival in ICC patients (HR = 3.519 CI = 1.411-5.702, P = 0.021 and HR = 4.157, CI = 1.915-7.421, P = 0.008, respectively).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('miR-21', 'Gene', '406991', (169, 175))	('patients', 'Species', '9606', (270, 278))	('miR-21', 'Gene', (121, 127))	('tumor', 'Disease', (45, 50))	('ICC', 'Disease', (266, 269))	('progression-free survival', 'CPA', (237, 262))	('miR-21', 'Gene', (169, 175))	('poor', 'NegReg', (219, 223))	('high tissue', 'Var', (157, 168))	('miR-21', 'Gene', '406991', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
40169	25803229	Aberrant miRNAs expression patterns have been described in various cancers and alterations in expression of certain miRNAs correlate highly with progression, diagnosis, and prognosis of specific human malignant diseases.	('human', 'Species', '9606', (195, 200))	('alterations', 'Var', (79, 90))	('malignant diseases', 'Disease', 'MESH:D009369', (201, 219))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('malignant diseases', 'Disease', (201, 219))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('described', 'Reg', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('expression', 'MPA', (94, 104))	('miRNAs', 'Protein', (9, 15))	('expression', 'MPA', (16, 26))
40183	25803229	Inhibition of miR-21also has been shown to increase tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('miR-21', 'Gene', '406991', (14, 20))	('tumor', 'Disease', (52, 57))	('miR-21', 'Gene', (14, 20))	('increase', 'PosReg', (43, 51))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
40189	25803229	Thus, modulation of expression of PTEN in ICC can impact on the activity of critical downstream mediators of cell proliferation and tumor progression.	('modulation', 'Var', (6, 16))	('expression', 'MPA', (20, 30))	('activity of critical downstream mediators of', 'MPA', (64, 108))	('impact', 'Reg', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('PTEN', 'Gene', (34, 38))	('PTEN', 'Gene', '5728', (34, 38))
40193	25803229	The Hippo pathway regulates cell numbers by inhibiting cell proliferation and promoting apoptosis through phosphorylation of the transcriptional co-activator YAP in mammals.	('cell numbers', 'CPA', (28, 40))	('apoptosis', 'CPA', (88, 97))	('inhibiting', 'NegReg', (44, 54))	('cell proliferation', 'CPA', (55, 73))	('promoting', 'PosReg', (78, 87))	('YAP', 'Gene', '10413', (158, 161))	('phosphorylation', 'Var', (106, 121))	('YAP', 'Gene', (158, 161))
40228	25803229	Briefly, 10 cm dishes were seeded with 200 viable cells in complete medium and allowed to grow for 24 h. After transfection with miR-21 inhibitors or negative controls for 48 h, the medium was removed, and cells were washed in PBS and incubated for a further 10 days in complete medium.	('miR-21', 'Gene', (129, 135))	('PBS', 'Disease', (227, 230))	('inhibitors', 'Var', (136, 146))	('miR-21', 'Gene', '406991', (129, 135))	('PBS', 'Disease', 'MESH:D011535', (227, 230))
40256	22906985	Inhibition of both IL-6 signaling and DNA methylation restored MAOA levels to those observed in cholangiocytes.	('IL-6', 'Gene', (19, 23))	('MAOA', 'Gene', '4128', (63, 67))	('IL-6', 'Gene', '3569', (19, 23))	('MAOA', 'Gene', (63, 67))	('Inhibition', 'Var', (0, 10))	('restored', 'PosReg', (54, 62))
40265	22906985	A number of studies have explored the possibility that the MAOA promoter can fall under epigenetic control through hypermethylation.	('MAOA', 'Gene', (59, 63))	('fall', 'Phenotype', 'HP:0002527', (77, 81))	('hypermethylation', 'Var', (115, 131))	('MAOA', 'Gene', '4128', (59, 63))
40333	22906985	There was a significant, negative correlation between the degree of methylation and MAOA expression in the CCA samples, although the relatively low correlation coefficient (r = -0.532) suggests that hypermethylation may not be the only factor affecting MAOA expression (Figure 3D).	('MAOA', 'Gene', (253, 257))	('MAOA', 'Gene', (84, 88))	('expression', 'MPA', (89, 99))	('methylation', 'Var', (68, 79))	('negative', 'NegReg', (25, 33))	('MAOA', 'Gene', '4128', (253, 257))	('MAOA', 'Gene', '4128', (84, 88))
40337	22906985	In parallel, MAOA mRNA and protein expression are upregulated in Mz-IL-6 shRNA cells (Figure 4B) in which IL-6 expression has been knocked down to approximately 3% of both the parental cell line (Mz-ChA-1) and the mock transfected Mz-Neo neg cells.	('upregulated', 'PosReg', (50, 61))	('knocked', 'Var', (131, 138))	('Mz-Neo', 'Chemical', '-', (231, 237))	('MAOA', 'Gene', (13, 17))	('IL-6', 'Gene', (68, 72))	('IL-6', 'Gene', (106, 110))	('expression', 'MPA', (111, 121))	('IL-6', 'Gene', '3569', (68, 72))	('IL-6', 'Gene', '3569', (106, 110))	('MAOA', 'Gene', '4128', (13, 17))
40338	22906985	To assess if the knockdown of IL-6 expression is affecting MAOA expression by modulating promoter hypermethylation, we assessed the levels of methylation by bisulfite conversion of DNA followed by pyrosequencing.	('MAOA', 'Gene', '4128', (59, 63))	('bisulfite', 'Chemical', 'MESH:C042345', (157, 166))	('MAOA', 'Gene', (59, 63))	('IL-6', 'Gene', (30, 34))	('promoter hypermethylation', 'MPA', (89, 114))	('IL-6', 'Gene', '3569', (30, 34))	('knockdown', 'Var', (17, 26))	('affecting', 'Reg', (49, 58))	('modulating', 'Reg', (78, 88))
40346	22906985	Conversely, R1 repressor could be found exclusively in the nucleus of Mz-Neo neg cells, whereas knocking down IL-6 expression resulted in increased cytoplasmic accumulation (Figure 5B).	('IL-6', 'Gene', '3569', (110, 114))	('R1', 'Gene', '55536', (12, 14))	('increased', 'PosReg', (138, 147))	('knocking down', 'Var', (96, 109))	('cytoplasmic accumulation', 'MPA', (148, 172))	('Mz-Neo', 'Chemical', '-', (70, 76))	('IL-6', 'Gene', (110, 114))
40358	22906985	We demonstrated that (i) low MAOA immunoreactivity correlates with increased invasiveness, low tumor differentiation and poor survival, (ii) the suppression of MAOA can be attributed to coordinated promoter hypermethylation and IL-6-mediated inhibition of SP-1 transcriptional activity, and (iii) restoration of MAOA has growth suppressing effects and reduces the invasiveness of cholangiocarcinoma cells in vitro.	('MAOA', 'Gene', '4128', (312, 316))	('restoration', 'Var', (297, 308))	('IL-6', 'Gene', '3569', (228, 232))	('low', 'NegReg', (25, 28))	('MAOA', 'Gene', '4128', (160, 164))	('reduces', 'NegReg', (352, 359))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('low tumor', 'Disease', (91, 100))	('IL-6', 'Gene', (228, 232))	('MAOA', 'Gene', (312, 316))	('increased', 'PosReg', (67, 76))	('growth suppressing', 'CPA', (321, 339))	('MAOA', 'Gene', (160, 164))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (380, 398))	('MAOA', 'Gene', '4128', (29, 33))	('cholangiocarcinoma', 'Disease', (380, 398))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (380, 398))	('low tumor', 'Disease', 'MESH:D009800', (91, 100))	('invasiveness', 'CPA', (77, 89))	('MAOA', 'Gene', (29, 33))
40366	22906985	Indeed, our data indicates that restoration of MAOA expression in cholangiocarcinoma not only reduces serotonin secretion from these cells, but also slows tumor growth and inhibits the invasive properties of these cells.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cholangiocarcinoma', 'Disease', (66, 84))	('MAOA', 'Gene', (47, 51))	('serotonin secretion from these cells', 'MPA', (102, 138))	('inhibits', 'NegReg', (172, 180))	('reduces', 'NegReg', (94, 101))	('tumor', 'Disease', (155, 160))	('slows', 'NegReg', (149, 154))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (66, 84))	('restoration', 'Var', (32, 43))	('reduces serotonin secretion', 'Phenotype', 'HP:0003144', (94, 121))	('invasive properties of these cells', 'CPA', (185, 219))	('serotonin', 'Chemical', 'MESH:D012701', (102, 111))	('expression', 'Var', (52, 62))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (66, 84))	('MAOA', 'Gene', '4128', (47, 51))
40383	22906985	Though there was a correlation between the degree of methylation and MAOA expression, the correlation was not so strong as to exclude the possibility of a second independent mechanism for the suppression of MAOA.	('expression', 'MPA', (74, 84))	('MAOA', 'Gene', '4128', (69, 73))	('MAOA', 'Gene', '4128', (207, 211))	('MAOA', 'Gene', (69, 73))	('MAOA', 'Gene', (207, 211))	('methylation', 'Var', (53, 64))
40385	22906985	Lastly, restoration of MAOA expression in cholangiocarcinoma cells inhibited tumor growth and decreased the invasive properties of these cells.	('cholangiocarcinoma', 'Disease', (42, 60))	('MAOA', 'Gene', (23, 27))	('inhibited', 'NegReg', (67, 76))	('invasive properties of these cells', 'CPA', (108, 142))	('expression', 'MPA', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('restoration', 'Var', (8, 19))	('decreased', 'NegReg', (94, 103))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (42, 60))	('MAOA', 'Gene', '4128', (23, 27))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (42, 60))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
40413	24351817	Because of amino acid changes, exendin-4 is resistant to the degradation of the enzyme dipeptidyl peptidase-4 and has a longer half-life than native GLP-1.	('changes', 'Var', (22, 29))	('amino acid changes', 'Var', (11, 29))	('dipeptidyl peptidase-4', 'Gene', '13482', (87, 109))	('dipeptidyl peptidase-4', 'Gene', (87, 109))
40437	24351817	Results showed that mean tumor size was 1742, 1117 and 940 mm3 in oxaliplatin treatment, Exendin-4 treatment and Exendin-4-oxaliplatin treatment, respectively.	('Exendin-4', 'Chemical', 'MESH:D000077270', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (66, 77))	('tumor', 'Disease', (25, 30))	('Exendin-4-oxaliplatin', 'Var', (113, 134))	('Exendin-4-oxaliplatin', 'Chemical', '-', (113, 134))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (123, 134))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('Exendin-4', 'Chemical', 'MESH:D000077270', (113, 122))
40449	24351817	We found that oxaliplatin can inhibit tumor cells' growth, but promote normal cell proliferation.	('normal cell proliferation', 'CPA', (71, 96))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (14, 25))	('inhibit', 'NegReg', (30, 37))	('oxaliplatin', 'Var', (14, 25))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('promote', 'PosReg', (63, 70))
40529	34012964	In vivo experiments showed that circ_0021205 inhibition reduced tumorigenesis in mice.	('mice', 'Species', '10090', (81, 85))	('tumor', 'Disease', (64, 69))	('reduced', 'NegReg', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('circ_0021205', 'Var', (32, 44))
40530	34012964	In addition, mechanisms investigation demonstrated that circ_0021205 exerts its oncogenic function by sponging miR-204-5p to regulate the expression of RAB22A.	('miR-204-5p', 'MPA', (111, 121))	('RAB22A', 'Gene', (152, 158))	('expression', 'Species', '29278', (138, 148))	('expression', 'MPA', (138, 148))	('circ_0021205', 'Var', (56, 68))	('RAB22A', 'Gene', '57403', (152, 158))	('regulate', 'Reg', (125, 133))	('miR-204-5p', 'Chemical', '-', (111, 121))
40540	34012964	In the past decade, it has been found that miRNAs are closely related to the development of cancer and can play the role of tumor suppressor or promoter.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('miRNAs', 'Var', (43, 49))	('past', 'Gene', (7, 11))	('tumor', 'Disease', (124, 129))	('related', 'Reg', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('past', 'Gene', '10938', (7, 11))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
40541	34012964	MiR-204-5p was identified as a tumor-suppressive miRNA, plays a role in cancer development and progression.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('plays', 'Reg', (56, 61))	('MiR-204-5p', 'Chemical', '-', (0, 10))	('MiR-204-5p', 'Var', (0, 10))	('tumor', 'Disease', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('cancer', 'Disease', (72, 78))
40542	34012964	In addition, the deregulation of miRNAs is associated with the progression of many tumors, including cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (101, 119))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('cholangiocarcinoma', 'Disease', (101, 119))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('associated', 'Reg', (43, 53))	('miRNAs', 'Protein', (33, 39))	('deregulation', 'Var', (17, 29))
40555	34012964	The pGL3 Luciferase Reporter Vectors (Promega, United States) containing circ_0021205-WT, circ_0021205-MuT, RAB22A-WT, or RAB22A-MuT sequences were co-transfected with miR-204-5p mimics or NC-mimics into HuCCT1 and KMBC cells.	('RAB22A', 'Gene', '57403', (122, 128))	('HuCCT1', 'CellLine', 'CVCL:0324', (204, 210))	('RAB22A', 'Gene', (108, 114))	('pGL3 Luciferase', 'Gene', (4, 19))	('RAB22A', 'Gene', (122, 128))	('circ_0021205-WT', 'Var', (73, 88))	('miR-204-5p', 'Chemical', '-', (168, 178))	('RAB22A', 'Gene', '57403', (108, 114))	('circ_0021205-MuT', 'Var', (90, 106))
40565	34012964	The primary antibodies used in this study were as shown below: (anti-Ki-67, 1: 200, ab16667, Abcam, United States; anti-PCNA, 1:250, ab265609, Abcam, United States).	('PCNA', 'Gene', (120, 124))	('ab265609', 'Var', (133, 141))	('PCNA', 'Gene', '5111', (120, 124))	('ab16667', 'Var', (84, 91))
40572	34012964	As shown in Figure 1A, the expression of circ_0021205 in CCA tissues was significantly upregulated compared with that in normal tissues.	('CCA', 'Phenotype', 'HP:0030153', (57, 60))	('expression', 'Species', '29278', (27, 37))	('expression', 'MPA', (27, 37))	('circ_0021205', 'Var', (41, 53))	('CCA', 'Disease', (57, 60))	('upregulated', 'PosReg', (87, 98))
40574	34012964	The results showed that the circ_0021205 expression in larger size or advanced stage tumor tissues was higher.	('tumor', 'Disease', (85, 90))	('expression', 'Species', '29278', (41, 51))	('expression', 'MPA', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('circ_0021205', 'Var', (28, 40))	('higher', 'PosReg', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
40575	34012964	In addition, the expression of circ_0021205 in CCA cell lines was also higher than in normal human intrahepatic biliary epithelial cells (Figure 1D).	('higher', 'PosReg', (71, 77))	('expression', 'Species', '29278', (17, 27))	('CCA', 'Phenotype', 'HP:0030153', (47, 50))	('human', 'Species', '9606', (93, 98))	('expression', 'MPA', (17, 27))	('circ_0021205', 'Var', (31, 43))	('CCA', 'Disease', (47, 50))
40576	34012964	HuCCT1 and KMBC cell lines were selected for further study for the relative high or low expression level of circ_0021205 among 6 CCA cell lines.	('CCA', 'Phenotype', 'HP:0030153', (129, 132))	('low', 'NegReg', (84, 87))	('expression level', 'MPA', (88, 104))	('expression', 'Species', '29278', (88, 98))	('circ_0021205', 'Var', (108, 120))	('HuCCT1', 'CellLine', 'CVCL:0324', (0, 6))
40577	34012964	Random hexamer and oligo(dt) 18 were used to amplify circ_0021205 and liner mRNA (WEE1) respectively (Figure 1F), the results showed that circ_0021205 is a circular RNA.	('WEE1', 'Gene', '7465', (82, 86))	('circ_0021205', 'Var', (138, 150))	('WEE1', 'Gene', (82, 86))
40578	34012964	To explore the role of circ_0021205 in CCA, the expression of circ_0021205 was down-regulated in HuCCT1 cells using si-circ_0021205-1 and si-circ_0021205-2 (Figure 2A) and up-regulated in KMBC cells using over-expression vectors (Figure 2B).	('circ_0021205', 'Gene', (62, 74))	('si-circ_0021205-2', 'Var', (138, 155))	('up-regulated', 'PosReg', (172, 184))	('expression', 'Species', '29278', (210, 220))	('expression', 'Species', '29278', (48, 58))	('HuCCT1', 'CellLine', 'CVCL:0324', (97, 103))	('down-regulated', 'NegReg', (79, 93))	('expression', 'MPA', (48, 58))	('si-circ_0021205-1', 'Var', (116, 133))	('expression vectors', 'Species', '29278', (210, 228))	('CCA', 'Phenotype', 'HP:0030153', (39, 42))
40579	34012964	Results of CCK-8 assay showed that the down-regulation of circ_0021205 significantly inhibited CCA cell proliferation, whereas circ_0021205 up-regulation promoted the proliferation of CCA cells (Figures 2C,D).	('CK', 'Gene', '51727', (12, 14))	('circ_0021205', 'Gene', (58, 70))	('inhibited', 'NegReg', (85, 94))	('CCA', 'Disease', (95, 98))	('down-regulation', 'NegReg', (39, 54))	('circ_0021205', 'Var', (127, 139))	('CCA', 'Phenotype', 'HP:0030153', (95, 98))	('up-regulation promoted', 'PosReg', (140, 162))	('proliferation', 'CPA', (167, 180))	('CCA', 'Phenotype', 'HP:0030153', (184, 187))
40582	34012964	As shown in Figure 3A, the expression of circ_0021205 was enriched in AGO2 groups, indicating that circ_0021205 could bind to miRNAs through AGO2 protein.	('miRNAs', 'Protein', (126, 132))	('circ_0021205', 'Var', (99, 111))	('expression', 'Species', '29278', (27, 37))	('bind', 'Interaction', (118, 122))	('AGO2 protein', 'Protein', (141, 153))
40587	34012964	And miR-204-5p mimics significantly decreased the luciferase activity in circ_0021205 WT groups, whereas brought no changes in circ_0021205 MuT groups (Figure 3E).	('luciferase', 'Enzyme', (50, 60))	('miR-204-5p mimics', 'Var', (4, 21))	('activity', 'MPA', (61, 69))	('miR-204-5p', 'Chemical', '-', (4, 14))	('decreased', 'NegReg', (36, 45))
40588	34012964	The results demonstrated that circ_0021205 could directly bind to miR-204-5p.	('miR-204-5p', 'Gene', (66, 76))	('bind', 'Interaction', (58, 62))	('miR-204-5p', 'Chemical', '-', (66, 76))	('circ_0021205', 'Var', (30, 42))
40589	34012964	In addition, the expression of miR-204-5p was significantly increased in HuCCT1 cells transfected with si-circ_0021205, and circ_0021205 over-expression inhibited miR-204-5p expression in KMBC cells (Figure 3F).	('expression', 'Species', '29278', (174, 184))	('miR-204-5p', 'Chemical', '-', (163, 173))	('over-expression', 'PosReg', (137, 152))	('expression', 'Species', '29278', (17, 27))	('HuCCT1', 'CellLine', 'CVCL:0324', (73, 79))	('miR-204-5p expression', 'MPA', (163, 184))	('miR-204-5p', 'Gene', (31, 41))	('expression', 'MPA', (17, 27))	('miR-204-5p', 'Chemical', '-', (31, 41))	('si-circ_0021205', 'Var', (103, 118))	('expression', 'Species', '29278', (142, 152))	('circ_0021205', 'Var', (124, 136))	('increased', 'PosReg', (60, 69))	('inhibited', 'NegReg', (153, 162))
40591	34012964	Through in vitro assays, we also confirmed that miR-204-5p mimics inhibited the proliferation of CCA cells, and miR-204-5p inhibitors enhanced the proliferation ability of CCA cells with detection of proliferation markers and CCK-8 assay (Figures 3H,I).	('proliferation ability', 'CPA', (147, 168))	('enhanced', 'PosReg', (134, 142))	('proliferation', 'CPA', (80, 93))	('CCA', 'Phenotype', 'HP:0030153', (172, 175))	('miR-204-5p', 'Chemical', '-', (112, 122))	('inhibitors', 'Var', (123, 133))	('CCA', 'Phenotype', 'HP:0030153', (97, 100))	('CK', 'Gene', '51727', (227, 229))	('inhibited', 'NegReg', (66, 75))	('miR-204-5p inhibitors', 'Var', (112, 133))	('miR-204-5p', 'Chemical', '-', (48, 58))
40593	34012964	We predicted target genes of miR-204-5p by Starbase 3.0, and RAB22A had been reported to involve in the progression of several cancers.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('RAB22A', 'Gene', '57403', (61, 67))	('miR-204-5p', 'Var', (29, 39))	('miR-204-5p', 'Chemical', '-', (29, 39))	('RAB22A', 'Gene', (61, 67))	('involve', 'Reg', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))
40594	34012964	The putative binding sites between miR-204-5p and RAB22A WT or MuT were shown in Figure 4A.	('miR-204-5p', 'Var', (35, 45))	('binding', 'Interaction', (13, 20))	('RAB22A', 'Gene', (50, 56))	('miR-204-5p', 'Chemical', '-', (35, 45))	('RAB22A', 'Gene', '57403', (50, 56))
40596	34012964	The results showed that miR-204-5p significantly reduced the luciferase activities in RAB22A WT groups, but no changes in RAB22A MuT groups (Figures 4B,C).	('RAB22A', 'Gene', (86, 92))	('RAB22A', 'Gene', '57403', (122, 128))	('activities', 'MPA', (72, 82))	('reduced', 'NegReg', (49, 56))	('luciferase', 'Enzyme', (61, 71))	('RAB22A', 'Gene', '57403', (86, 92))	('RAB22A', 'Gene', (122, 128))	('miR-204-5p', 'Chemical', '-', (24, 34))	('miR-204-5p', 'Var', (24, 34))
40597	34012964	In addition, the data from TGCA showed that the expression of miR-204-5p was negatively correlated with RAB22A levels in human CCA tissues (Figure 4D).	('CCA', 'Phenotype', 'HP:0030153', (127, 130))	('RAB22A', 'Gene', (104, 110))	('expression', 'Species', '29278', (48, 58))	('expression', 'MPA', (48, 58))	('human', 'Species', '9606', (121, 126))	('RAB22A', 'Gene', '57403', (104, 110))	('negatively', 'NegReg', (77, 87))	('miR-204-5p', 'Chemical', '-', (62, 72))	('miR-204-5p', 'Var', (62, 72))
40600	34012964	The results showed that the up-regulation of miR-204-5p significantly inhibited RAB22A expression, whereas miR-204-5p down-regulation increased RAB22A expression (Figures 4E,F).	('RAB22A', 'Gene', (80, 86))	('miR-204-5p', 'Var', (107, 117))	('down-regulation', 'NegReg', (118, 133))	('expression', 'Species', '29278', (151, 161))	('miR-204-5p', 'Chemical', '-', (45, 55))	('RAB22A', 'Gene', '57403', (144, 150))	('expression', 'MPA', (151, 161))	('expression', 'Species', '29278', (87, 97))	('expression', 'MPA', (87, 97))	('RAB22A', 'Gene', (144, 150))	('RAB22A', 'Gene', '57403', (80, 86))	('inhibited', 'NegReg', (70, 79))	('increased', 'PosReg', (134, 143))	('miR-204-5p', 'Chemical', '-', (107, 117))	('up-regulation', 'PosReg', (28, 41))	('miR-204-5p', 'Var', (45, 55))
40602	34012964	These data demonstrated that RAB22A is a target gene of miR-204-5p.	('miR-204-5p', 'Chemical', '-', (56, 66))	('RAB22A', 'Gene', '57403', (29, 35))	('RAB22A', 'Gene', (29, 35))	('miR-204-5p', 'Var', (56, 66))
40603	34012964	To further explore whether circ_0021205 served as a tumor promoter through miR-204-5p/RAB22A axis, rescue experiments were performed using miR-204-5p mimics and inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('RAB22A', 'Gene', (86, 92))	('miR-204-5p', 'Chemical', '-', (139, 149))	('tumor', 'Disease', (52, 57))	('miR-204-5p', 'Chemical', '-', (75, 85))	('circ_0021205', 'Var', (27, 39))	('RAB22A', 'Gene', '57403', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
40604	34012964	Western blot assay showed that knockdown of circ_0021205 decreased RAB22A expression in HuCCT1 cells, while circ_0021205 up-regulation enhanced RAB22A expression in KMBC cells.	('expression', 'MPA', (74, 84))	('expression', 'Species', '29278', (151, 161))	('HuCCT1', 'CellLine', 'CVCL:0324', (88, 94))	('RAB22A', 'Gene', (67, 73))	('RAB22A', 'Gene', '57403', (144, 150))	('expression', 'MPA', (151, 161))	('up-regulation enhanced', 'PosReg', (121, 143))	('RAB22A', 'Gene', (144, 150))	('circ_0021205', 'Var', (108, 120))	('expression', 'Species', '29278', (74, 84))	('decreased', 'NegReg', (57, 66))	('RAB22A', 'Gene', '57403', (67, 73))
40605	34012964	Simultaneously, these effects caused by knocking down or over-expressing circ_0021205 were reversed by miR-204-5p inhibitors or mimics, respectively (Figures 5A,B).	('miR-204-5p', 'Chemical', '-', (103, 113))	('knocking down', 'Var', (40, 53))	('circ_0021205', 'Gene', (73, 85))	('over-expressing', 'PosReg', (57, 72))
40609	34012964	To further explore the role of circ_0021205 in vivo, the HuCCT1 cells transfected with si-NC or si-circ_0021205 were subcutaneously injected into the mice, respectively (n = 6).	('si-NC', 'Var', (87, 92))	('mice', 'Species', '10090', (150, 154))	('si-circ_0021205', 'Var', (96, 111))	('HuCCT1', 'CellLine', 'CVCL:0324', (57, 63))
40612	34012964	We then detect the expression level of miR-204-5p and RAB22A with qPCR and WB, and confirmed that si-circ_0021205 increased the expression level of miR-204-5p and decreased RAB22A level in tumor tissues (Figures 6D,E).	('RAB22A', 'Gene', '57403', (173, 179))	('RAB22A', 'Gene', '57403', (54, 60))	('expression level', 'MPA', (128, 144))	('tumor', 'Disease', (189, 194))	('miR-204-5p', 'Chemical', '-', (39, 49))	('miR-204-5p', 'Chemical', '-', (148, 158))	('RAB22A', 'Gene', (173, 179))	('increased', 'PosReg', (114, 123))	('expression', 'Species', '29278', (19, 29))	('RAB22A', 'Gene', (54, 60))	('expression', 'Species', '29278', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('decreased', 'NegReg', (163, 172))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('si-circ_0021205', 'Var', (98, 113))
40613	34012964	Next, we investigated the proliferation of the cells in the tumors with western blotting and immunohistochemistry staining, and found the expression of Ki-67 and PCNA were significantly decreased after knocking down of circ_0021205 (Figures 6F,G).	('knocking down', 'Var', (202, 215))	('PCNA', 'Gene', '5111', (162, 166))	('Ki-67', 'Gene', (152, 157))	('expression', 'Species', '29278', (138, 148))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('decreased', 'NegReg', (186, 195))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('circ_0021205', 'Var', (219, 231))	('expression', 'MPA', (138, 148))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('PCNA', 'Gene', (162, 166))	('tumors', 'Disease', (60, 66))
40615	34012964	The results revealed that circ_0021205 knockdown could suppress the tumor growth of CCA in vivo.	('tumor', 'Disease', (68, 73))	('CCA', 'Phenotype', 'HP:0030153', (84, 87))	('knockdown', 'Var', (39, 48))	('CCA', 'Disease', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('circ_0021205 knockdown', 'Var', (26, 48))	('suppress', 'NegReg', (55, 63))
40618	34012964	In this study, we found that circ_0021205 was significantly up-regulated in CCA tissues and cells compare with the controls and associated with tumor size and TNM stage.	('tumor', 'Disease', (144, 149))	('circ_0021205', 'Var', (29, 41))	('CCA', 'Disease', (76, 79))	('TNM', 'Gene', '10178', (159, 162))	('up-regulated', 'PosReg', (60, 72))	('associated', 'Reg', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('CCA', 'Phenotype', 'HP:0030153', (76, 79))	('TNM', 'Gene', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
40621	34012964	For example, circCCDC9 suppresses the progression of gastric cancer by regulating CAV1 via miR-6792-3p.	('regulating', 'Reg', (71, 81))	('miR-6792-3p', 'Var', (91, 102))	('CAV1', 'Gene', (82, 86))	('progression', 'CPA', (38, 49))	('suppresses', 'NegReg', (23, 33))	('gastric cancer', 'Disease', (53, 67))	('gastric cancer', 'Disease', 'MESH:D013274', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (53, 67))	('CAV1', 'Gene', '857', (82, 86))	('circCCDC9', 'Gene', (13, 22))
40623	34012964	In our study, RIP experiment and liciferase report assay indicated that circ_0021205 could act as the sponge of miR-204-5p and RAB22A is the target gene of miR-204-5p.	('miR-204-5p', 'Chemical', '-', (156, 166))	('miR-204-5p', 'Var', (112, 122))	('miR-204-5p', 'Chemical', '-', (112, 122))	('RAB22A', 'Gene', '57403', (127, 133))	('RAB22A', 'Gene', (127, 133))	('circ_0021205', 'Var', (72, 84))	('RIP', 'Gene', '8737', (14, 17))	('RIP', 'Gene', (14, 17))
40624	34012964	The rescue experiments demonstrated that circ_0021205 exerts carcinogenic effects in CCA by target RAB22A via miR-204-5p.	('RAB22A', 'Gene', '57403', (99, 105))	('miR-204-5p', 'Chemical', '-', (110, 120))	('miR-204-5p', 'Var', (110, 120))	('carcinogenic', 'Disease', 'MESH:D063646', (61, 73))	('carcinogenic', 'Disease', (61, 73))	('CCA', 'Disease', (85, 88))	('RAB22A', 'Gene', (99, 105))	('circ_0021205', 'Var', (41, 53))	('CCA', 'Phenotype', 'HP:0030153', (85, 88))
40630	34012964	So the manipulation of RAB22A may cause severe side effects in CCA patients.	('patients', 'Species', '9606', (67, 75))	('RAB22A', 'Gene', '57403', (23, 29))	('CCA', 'Phenotype', 'HP:0030153', (63, 66))	('RAB22A', 'Gene', (23, 29))	('CCA', 'Disease', (63, 66))	('manipulation', 'Var', (7, 19))
40632	34012964	Secondly, although the carcinogenic effects of circ_0021205 in CCA were revealed in this study, there also might be other critical circRNAs or mechanisms involved in the development of CCA.	('carcinogenic', 'Disease', 'MESH:D063646', (23, 35))	('carcinogenic', 'Disease', (23, 35))	('circ_0021205', 'Var', (47, 59))	('CCA', 'Phenotype', 'HP:0030153', (185, 188))	('CCA', 'Phenotype', 'HP:0030153', (63, 66))	('CCA', 'Disease', (63, 66))
40633	34012964	In conclusion, this study demonstrates that circ_0021205 promotes CCA progression through miR-204-5p/RAB22A axis, which may provide a potential biomarker for CCA diagnosis.	('circ_0021205', 'Var', (44, 56))	('miR-204-5p', 'Chemical', '-', (90, 100))	('RAB22A', 'Gene', '57403', (101, 107))	('CCA', 'Phenotype', 'HP:0030153', (158, 161))	('RAB22A', 'Gene', (101, 107))	('CCA', 'Phenotype', 'HP:0030153', (66, 69))	('CCA', 'Disease', (66, 69))	('promotes', 'PosReg', (57, 65))
40640	29853658	Preclinical evidence suggests that simultaneous blockade of vascular endothelial growth factor receptor 2 (VEGFR-2) and programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) enhances antitumor effects.	('tumor', 'Disease', (196, 201))	('vascular endothelial growth factor receptor 2', 'Gene', '3791', (60, 105))	('PD-1', 'Gene', (140, 144))	('vascular endothelial growth factor receptor 2', 'Gene', (60, 105))	('PD-L1', 'Gene', '29126', (176, 181))	('VEGFR-2', 'Gene', '3791', (107, 114))	('PD-1', 'Gene', '5133', (140, 144))	('programmed death 1', 'Gene', (120, 138))	('programmed death-ligand 1', 'Gene', (149, 174))	('programmed death-ligand 1', 'Gene', '29126', (149, 174))	('blockade', 'Var', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('VEGFR-2', 'Gene', (107, 114))	('enhances', 'PosReg', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('programmed death 1', 'Gene', '5133', (120, 138))	('PD-L1', 'Gene', (176, 181))
40698	29853658	PD-1 and PD-L1 expression is upregulated in intrahepatic cholangiocarcinoma tumor tissues and was associated with both poor differentiation and stage, whereas increased CD8+ T cells in tumors was associated with better tumor differentiation [28], [29].	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('tumor', 'Disease', (219, 224))	('PD-L1', 'Gene', '29126', (9, 14))	('tumors', 'Disease', (185, 191))	('tumor', 'Disease', (76, 81))	('poor differentiation', 'CPA', (119, 139))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (185, 190))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('upregulated', 'PosReg', (29, 40))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('expression', 'MPA', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('intrahepatic cholangiocarcinoma tumor', 'Disease', (44, 81))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('PD-1', 'Gene', (0, 4))	('PD-1', 'Gene', '5133', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('CD8+ T cells', 'Var', (169, 181))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('associated', 'Reg', (98, 108))	('intrahepatic cholangiocarcinoma tumor', 'Disease', 'MESH:D018281', (44, 81))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('PD-L1', 'Gene', (9, 14))
40746	30249019	Similar to what has been observed for CAFs, a pivotal role of tumor-associated macrophages (TAMs) in CCA progression has been convincingly validated by independent clinical studies, showing that high macrophage density predicts poor prognosis in CCA patients.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('CCA', 'Disease', (246, 249))	('CCA', 'Disease', (101, 104))	('patients', 'Species', '9606', (250, 258))	('tumor', 'Disease', (62, 67))	('high', 'Var', (195, 199))	('TAMs', 'Chemical', '-', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
40790	30249019	Similar to what observed in HCC, a poor clinical outcome of CCA has been associated with molecular alterations in the highly desmoplastic stroma.	('rat', 'Species', '10116', (103, 106))	('CCA', 'Disease', (60, 63))	('associated', 'Reg', (73, 83))	('molecular alterations', 'Var', (89, 110))	('desmoplastic stroma', 'Disease', (125, 144))	('desmoplastic stroma', 'Disease', 'MESH:D018220', (125, 144))
40791	30249019	Indeed, gene overexpression of TGF-beta2, laminin gamma2 subunit, and osteopontin has been significantly correlated with overall survival of patients with CCA.	('TGF-beta2', 'Gene', '7042', (31, 40))	('correlated', 'Reg', (105, 115))	('laminin gamma2 subunit, and osteopontin', 'Gene', '6696', (42, 81))	('overexpression', 'PosReg', (13, 27))	('gene', 'Var', (8, 12))	('CCA', 'Disease', (155, 158))	('patients', 'Species', '9606', (141, 149))	('TGF-beta2', 'Gene', (31, 40))
40801	30249019	Notably, in the early stages of CCA carcinogenesis, alpha-SMA+ CAFs induce the proliferation of non-neoplastic biliary epithelial by inducing apoptosis inhibition.	('proliferation', 'CPA', (79, 92))	('CCA carcinogenesis', 'Disease', 'MESH:C536211', (32, 50))	('induce', 'PosReg', (68, 74))	('alpha-SMA', 'Chemical', '-', (52, 61))	('CAFs', 'Gene', (63, 67))	('CCA carcinogenesis', 'Disease', (32, 50))	('alpha-SMA+', 'Var', (52, 62))	('inducing', 'PosReg', (133, 141))	('apoptosis inhibition', 'CPA', (142, 162))	('rat', 'Species', '10116', (86, 89))
40823	30249019	Mutations, activation, and overexpression of EGFR are associated with a poor outcome in CCA patients.	('EGFR', 'Gene', (45, 49))	('patients', 'Species', '9606', (92, 100))	('CCA', 'Disease', (88, 91))	('Mutations', 'Var', (0, 9))	('overexpression', 'PosReg', (27, 41))	('activation', 'PosReg', (11, 21))	('EGFR', 'Gene', '1956', (45, 49))
40841	30249019	Several studies had reported that in experimental animals Clonorchis sinensis could induce hepatic fibrosis, localized in the hepatic sinusoids in the early stage of the infection, suggesting that excretory/secretory products of the parasite could contribute to developing the fibrogenic process.	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (91, 107))	('hepatic fibrosis', 'Disease', (91, 107))	('infection', 'Disease', (170, 179))	('infection', 'Disease', 'MESH:D007239', (170, 179))	('Clonorchis sinensis', 'Var', (58, 77))	('hepatic fibrosis', 'Disease', 'MESH:D008103', (91, 107))	('induce', 'PosReg', (84, 90))	('contribute', 'Reg', (248, 258))	('Clonorchis sinensis', 'Species', '79923', (58, 77))
40853	30249019	In TLR4 mut mice infected by the parasite, the deposition of collagen and the activation of HSCs were significantly lower than in wild type mice.	('lower', 'NegReg', (116, 121))	('infected', 'Reg', (17, 25))	('TLR4', 'Gene', (3, 7))	('mice', 'Species', '10090', (140, 144))	('HSC', 'Gene', (92, 95))	('TLR4', 'Gene', '21898', (3, 7))	('deposition of', 'CPA', (47, 60))	('HSC', 'Gene', '2523', (92, 95))	('activation', 'CPA', (78, 88))	('mice', 'Species', '10090', (12, 16))	('mut', 'Var', (8, 11))
40867	30249019	Blockade of immune checkpoints reconstitutes normal anti-tumor immunity and this represents a new CCA therapeutic approach.	('Blockade', 'Var', (0, 8))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))
40868	30249019	Monoclonal antibodies to the CTLA-4 (a protein regulating T cell tolerance) have entered clinical cancer therapy and have been proven highly effective in several types of tumor.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('CTLA-4', 'Gene', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('CTLA-4', 'Gene', '1493', (29, 35))	('Monoclonal antibodies', 'Var', (0, 21))
40972	32288384	Univariate analysis suggested CA19-9, preoperative serum total bilirubin, marginal status, pathological differentiation, and lymph nodes status were significant predictors for poor survival (Table 4).	('CA19-9', 'Var', (30, 36))	('bilirubin', 'Chemical', 'MESH:D001663', (63, 72))	('pathological differentiation', 'CPA', (91, 119))
40987	32288384	Consequently, patients with preoperative serum total bilirubin below 10 mg/dL obtained apparent survival benefits than those with that above 10 mg/dL (20 vs 14 months, P = 0.003).	('benefits', 'PosReg', (105, 113))	('survival', 'CPA', (96, 104))	('below 10', 'Var', (63, 71))	('bilirubin', 'Chemical', 'MESH:D001663', (53, 62))	('patients', 'Species', '9606', (14, 22))
41223	28321164	Some studies demonstrated that pancreatic cancers with obstruction of the main pancreatic duct had a lower degree of PEP, possibly due to diminished pancreatic exocrine function and suggested that ES may be unnecessary in such cases.	('diminished pancreatic exocrine function', 'Phenotype', 'HP:0001738', (138, 177))	('PEP', 'Gene', '5550', (117, 120))	('pancreatic duct', 'Disease', (79, 94))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('pancreatic duct', 'Disease', 'MESH:D021441', (79, 94))	('pancreatic exocrine function', 'Disease', 'MESH:C565225', (149, 177))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (31, 49))	('obstruction', 'Var', (55, 66))	('lower', 'NegReg', (101, 106))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('pancreatic exocrine function', 'Disease', (149, 177))	('diminished', 'NegReg', (138, 148))	('pancreatic cancers', 'Disease', 'MESH:D010190', (31, 49))	('pancreatic cancers', 'Disease', (31, 49))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (31, 48))	('PEP', 'Gene', (117, 120))
41260	23630545	Auto-oxidation on the B ring can lead to the formation of 7alpha- and 7beta-hydroxycholesterol; 7-ketocholesterol; 5alpha, 6alpha-epoxycholesterol;5beta, 6beta-epoxycholesterol and cholestan-3beta, 5alpha, 6beta-triol (Figure 1).	('7-ketocholesterol', 'Chemical', 'MESH:C003001', (96, 113))	('lead to', 'Reg', (33, 40))	('6alpha-epoxycholesterol', 'Chemical', '-', (123, 146))	('7alpha- and 7beta-hydroxycholesterol', 'Chemical', '-', (58, 94))	('5alpha', 'Chemical', 'MESH:D001971', (115, 121))	('Auto-oxidation', 'Var', (0, 14))	('5beta', 'Chemical', '-', (147, 152))	('5alpha', 'Chemical', 'MESH:D001971', (198, 204))	('cholestan-3beta', 'Chemical', '-', (181, 196))	('6beta-epoxycholesterol', 'Chemical', '-', (154, 176))	('6beta-triol', 'Chemical', '-', (206, 217))
41302	23630545	Conversely, in patients with mutations in ABCG5/ABCG8, significantly higher proportions of phytosterols are absorbed into plasma, leading to phytosterolemia.	('absorbed into plasma', 'MPA', (108, 128))	('patients', 'Species', '9606', (15, 23))	('ABCG8', 'Gene', '64241', (48, 53))	('phytosterolemia', 'Disease', (141, 156))	('leading to', 'Reg', (130, 140))	('higher proportions', 'PosReg', (69, 87))	('mutations', 'Var', (29, 38))	('phytosterol', 'Chemical', 'MESH:D010840', (91, 102))	('ABCG5', 'Gene', (42, 47))	('phytosterols', 'Chemical', 'MESH:D010840', (91, 103))	('ABCG8', 'Gene', (48, 53))	('ABCG5', 'Gene', '64240', (42, 47))	('phytosterol', 'Chemical', 'MESH:D010840', (141, 152))
41349	23630545	For example, the sulfotransferase SULT2B1b sulfonates 7-ketocholesterol and abrogates its cytotoxic effects.	('abrogates', 'NegReg', (76, 85))	('SULT2B1b', 'Var', (34, 42))	('7-ketocholesterol', 'Chemical', 'MESH:C003001', (54, 71))	('7-ketocholesterol', 'MPA', (54, 71))	('cytotoxic effects', 'CPA', (90, 107))
41351	23630545	This sulfation reaction, which also occurs via SULT2B1b, occurs in human aortic endothelial cells and serves to maintain intracellular lipid homeostasis.	('maintain', 'PosReg', (112, 120))	('lipid', 'Chemical', 'MESH:D008055', (135, 140))	('intracellular lipid homeostasis', 'MPA', (121, 152))	('human', 'Species', '9606', (67, 72))	('SULT2B1b', 'Var', (47, 55))
41355	23630545	Gallstones form through the concerted action of multiple factors such as biliary cholesterol hypersecretion, gallbladder hypomotility, gallbladder mucus hypersecretion, chronic inflammation in the gallbladder, genetic factors such as Lith genes and mutations in the cholesterol efflux transporter ABCG8, and lifestyle and dietary factors.	('Gallstones', 'Disease', (0, 10))	('chronic inflammation', 'Disease', (169, 189))	('cholesterol', 'Chemical', 'MESH:D002784', (266, 277))	('gallbladder hypomotility', 'Disease', 'MESH:D005705', (109, 133))	('Gallstones', 'Phenotype', 'HP:0001081', (0, 10))	('cholesterol', 'Chemical', 'MESH:D002784', (81, 92))	('ABCG8', 'Gene', (297, 302))	('mutations', 'Var', (249, 258))	('gallbladder hypomotility', 'Disease', (109, 133))	('inflammation in the gallbladder', 'Phenotype', 'HP:0001082', (177, 208))	('gallbladder', 'Disease', (135, 146))	('ABCG8', 'Gene', '64241', (297, 302))	('biliary cholesterol hypersecretion', 'Disease', (73, 107))	('chronic inflammation', 'Disease', 'MESH:D007249', (169, 189))
41378	23630545	Taurodeoxycholic acid enhanced, and tauroursodeoxycholic acid diminished, oxysterol-induced apoptosis, suggesting that the composition of bile acids in bile could modify oxysterol-induced apoptosis in these cells.	('modify', 'Reg', (163, 169))	('oxysterol', 'Chemical', 'MESH:D000072376', (170, 179))	('tauroursodeoxycholic acid', 'Chemical', 'MESH:C031655', (36, 61))	('Taurodeoxycholic acid', 'Chemical', 'MESH:D013657', (0, 21))	('bile acids', 'Chemical', 'MESH:D001647', (138, 148))	('diminished', 'NegReg', (62, 72))	('oxysterol', 'Chemical', 'MESH:D000072376', (74, 83))	('tauroursodeoxycholic', 'Var', (36, 56))	('enhanced', 'PosReg', (22, 30))	('oxysterol-induced', 'MPA', (74, 91))
41703	22811587	Intrahepatic infiltration of cisplatin, mitomycin C, and formaldehyde are also known to lead to biliary sclerosing lesions.	('formaldehyde', 'Chemical', 'MESH:D005557', (57, 69))	('biliary sclerosing lesions', 'Disease', (96, 122))	('lead to', 'Reg', (88, 95))	('mitomycin', 'Var', (40, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('mitomycin C', 'Chemical', 'MESH:D016685', (40, 51))
41724	20655862	Opisthorchiasis and Opisthorchis-associated cholangiocarcinoma in Thailand and Laos Liver fluke infection caused by Opisthorchis viverrini is a major public health problem in Thailand and the Lao People's Democratic Republic (Lao PDR; Laos).	("People's Democratic Republic", 'Disease', (196, 224))	('Lao', 'Gene', '259307', (79, 82))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (44, 62))	('Liver fluke infection', 'Disease', (84, 105))	('cholangiocarcinoma', 'Disease', (44, 62))	('Opisthorchiasis', 'Disease', (0, 15))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (44, 62))	('Lao', 'Gene', (235, 238))	('Lao', 'Gene', (226, 229))	('Lao', 'Gene', '259307', (235, 238))	('Opisthorchis', 'Var', (116, 128))	('Lao', 'Gene', '259307', (226, 229))	('Liver fluke infection', 'Disease', 'MESH:D017093', (84, 105))	("People's Democratic Republic", 'Disease', 'MESH:D006212', (196, 224))	('Lao', 'Gene', (192, 195))	('Opisthorchis viverrini', 'Species', '6198', (116, 138))	('Lao', 'Gene', '259307', (192, 195))	('Opisthorchis', 'Species', '147828', (116, 128))	('Opisthorchis', 'Species', '147828', (20, 32))	('Opisthorchis-', 'Phenotype', 'HP:0002179', (20, 33))	('Lao', 'Gene', (79, 82))
41731	20655862	In addition to their detrimental effects on the health, NTDs have a chronic debilitating effect by undermining the physical and cognitive development of individuals resident in areas endemic for NTDs, especially children and women of child bearing age.	('women', 'Species', '9606', (225, 230))	('child', 'Species', '9606', (212, 217))	('NTDs', 'Var', (56, 60))	('children', 'Species', '9606', (212, 220))	('undermining', 'NegReg', (99, 110))	('child', 'Species', '9606', (234, 239))
41771	20655862	Encouragingly, inflammatory biomarkers such as urinary 8oxodG reported in opisthorchiasis and Opisthorchis-associated cholangiocarcinoma are potentially useful for diagnosis, surveillance and control (see).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (118, 136))	('opisthorchiasis', 'Disease', (74, 89))	('cholangiocarcinoma', 'Disease', (118, 136))	('8oxodG', 'Chemical', 'MESH:C067134', (55, 61))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (118, 136))	('Opisthorchis-', 'Phenotype', 'HP:0002179', (94, 107))	('urinary', 'Var', (47, 54))	('Opisthorchis', 'Species', '147828', (94, 106))
41866	20655862	We have divided "control" into four elements: (1) modifications to current control measures; (2) the subsequent behavioral changes in the population; (3) the public health impact of these behavioral changes, and (4) the epidemiological impact, which would be a decline in the prevalence of O. viverrini infection and in the future a decline in the incidence of CCA.	('decline', 'NegReg', (261, 268))	('CCA', 'Disease', (361, 364))	('infection', 'Disease', (303, 312))	('O. viverrini', 'Protein', (290, 302))	('O. viverrini', 'Species', '6198', (290, 302))	('modifications', 'Var', (50, 63))	('infection', 'Disease', 'MESH:D007239', (303, 312))	('changes', 'Var', (199, 206))	('behavioral changes', 'Phenotype', 'HP:0000708', (112, 130))	('behavioral changes', 'Phenotype', 'HP:0000708', (188, 206))	('decline', 'NegReg', (333, 340))
41920	20937455	Dwelling in the bile ducts, Clonorchis induces an inflammatory reaction involved in the malignant transformation of cholangiocytes.	('Clonorchis', 'Species', '79923', (28, 38))	('inflammatory reaction', 'CPA', (50, 71))	('Clonorchis', 'Var', (28, 38))	('induces', 'Reg', (39, 46))
41958	20937455	The prevalence of HBsAg seropositivity and hepatolithiasis was increased from 9 to 48 % and from 1 to 5% respectively in intrahepatic cholangiocarcinoma patients compared to controls.	('HBsAg', 'Gene', (18, 23))	('increased', 'PosReg', (63, 72))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (121, 152))	('patients', 'Species', '9606', (153, 161))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (134, 152))	('hepatolithiasis', 'Disease', (43, 58))	('seropositivity', 'Var', (24, 38))	('intrahepatic cholangiocarcinoma', 'Disease', (121, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('hepatolithiasis', 'Disease', 'None', (43, 58))
41965	20937455	A wide range of molecular alterations have been described in this setting such as inactivation of p16, increased expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2), over-expression of the proto-oncogene c-met and lack of the tumor suppressor caudal-related homeobox gene 2 (CDX2).	('COX-2', 'Gene', '5743', (145, 150))	('CDX2', 'Gene', (290, 294))	('over-expression', 'PosReg', (181, 196))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (156, 172))	('cyclooxygenase-2', 'Gene', (127, 143))	('expression', 'MPA', (113, 123))	('caudal-related homeobox gene 2', 'Gene', '1045', (258, 288))	('p16', 'Gene', (98, 101))	('tumor', 'Disease', (241, 246))	('p16', 'Gene', '1029', (98, 101))	('caudal-related homeobox gene 2', 'Gene', (258, 288))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('inactivation', 'Var', (82, 94))	('lack', 'NegReg', (229, 233))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('COX-2', 'Gene', (145, 150))	('increased', 'PosReg', (103, 112))	('PGE2', 'Chemical', 'MESH:D015232', (174, 178))	('proto-oncogene c-met', 'Gene', (204, 224))	('CDX2', 'Gene', '1045', (290, 294))	('cyclooxygenase-2', 'Gene', '5743', (127, 143))	('proto-oncogene c-met', 'Gene', '4233', (204, 224))
41997	20937455	Therefore, the alteration in GSH content may lead to DNA damage and deregulation of apoptosis in cells of patients with chronic biliary disorders.	('apoptosis', 'CPA', (84, 93))	('DNA damage', 'MPA', (53, 63))	('GSH', 'Protein', (29, 32))	('lead to', 'Reg', (45, 52))	('GSH', 'Chemical', 'MESH:D005978', (29, 32))	('patients', 'Species', '9606', (106, 114))	('chronic biliary disorders', 'Disease', (120, 145))	('chronic biliary disorders', 'Disease', 'MESH:D001657', (120, 145))	('biliary disorders', 'Phenotype', 'HP:0001080', (128, 145))	('alteration', 'Var', (15, 25))
42001	20937455	P53 is usually lost in cholangiocarcinoma cells (20-70%) due to loss of heterozygosity or inactivating mutations.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (23, 41))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (23, 41))	('lost', 'NegReg', (15, 19))	('inactivating mutations', 'Var', (90, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('P53', 'Gene', (0, 3))	('loss', 'NegReg', (64, 68))	('P53', 'Gene', '7157', (0, 3))	('cholangiocarcinoma', 'Disease', (23, 41))
42003	20937455	Inactivation of p16 together with lack of p21Waf1/cip1,p27 Kip1, p57 kip2 and increased cyclin D1 are responsible for cell cycle dysregulation.	('p27 Kip1', 'Gene', (55, 63))	('p27 Kip1', 'Gene', '1027', (55, 63))	('lack', 'NegReg', (34, 38))	('cell cycle dysregulation', 'Phenotype', 'HP:0011018', (118, 142))	('p57 kip2', 'Gene', (65, 73))	('cyclin D1', 'Gene', '595', (88, 97))	('p16', 'Gene', '1029', (16, 19))	('p21Waf1/cip1', 'Gene', '1026', (42, 54))	('cyclin D1', 'Gene', (88, 97))	('p57 kip2', 'Gene', '1028', (65, 73))	('increased', 'PosReg', (78, 87))	('p16', 'Gene', (16, 19))	('Inactivation', 'Var', (0, 12))	('p21Waf1/cip1', 'Gene', (42, 54))
42013	20937455	In in vitro and in animal models, IL-6 over-expression was shown to reduce the expression of miR-370 resulting in the enhancement of p38MAPK activation.	('miR-370', 'Gene', (93, 100))	('p38', 'Gene', '1432', (133, 136))	('expression', 'MPA', (79, 89))	('enhancement', 'PosReg', (118, 129))	('over-expression', 'Var', (39, 54))	('men', 'Species', '9606', (125, 128))	('reduce', 'NegReg', (68, 74))	('IL-6', 'Gene', '3569', (34, 38))	('p38', 'Gene', (133, 136))	('IL-6', 'Gene', (34, 38))	('miR-370', 'Gene', '442915', (93, 100))	('activation', 'PosReg', (141, 151))
42019	20937455	NO may favor the possibility of oncogenic mutations, may inhibit apoptosis through the nitrosylation of caspase 9 and may cause bile ductular cholestasis by inhibiting ion transporters of the biliary cells.	('cause', 'Reg', (122, 127))	('nitrosylation', 'MPA', (87, 100))	('cholestasis', 'Phenotype', 'HP:0001396', (142, 153))	('caspase 9', 'Gene', '842', (104, 113))	('inhibiting', 'NegReg', (157, 167))	('inhibit', 'NegReg', (57, 64))	('apoptosis', 'CPA', (65, 74))	('caspase 9', 'Gene', (104, 113))	('cholestasis', 'Disease', 'MESH:D002779', (142, 153))	('oncogenic', 'CPA', (32, 41))	('ion transporters of the biliary cells', 'MPA', (168, 205))	('cholestasis', 'Disease', (142, 153))	('mutations', 'Var', (42, 51))
42059	20937455	Patients with PSC who show trisomy 7 and or EGFR expression in biliary tract epithelia may be appropriate to consider for chemoprevention with EGFR blockers if they have a higher risk of cholangiocarcinoma.	('EGFR', 'Gene', (143, 147))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (187, 205))	('biliary tract epithelia', 'Disease', (63, 86))	('biliary tract epithelia', 'Disease', 'MESH:D001660', (63, 86))	('PSC', 'Gene', '100653366', (14, 17))	('trisomy 7', 'Var', (27, 36))	('cholangiocarcinoma', 'Disease', (187, 205))	('Patients', 'Species', '9606', (0, 8))	('PSC', 'Gene', (14, 17))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', '1956', (143, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (187, 205))
42081	20069059	However, (CA) 19-9 is also elevated in pancreatic cancer, gastric cancer, and primary biliary cirrhosis and has been shown it gives false positive results.	('gastric cancer', 'Phenotype', 'HP:0012126', (58, 72))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (39, 56))	('CA) 19-9', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('elevated', 'PosReg', (27, 35))	('cirrhosis', 'Phenotype', 'HP:0001394', (94, 103))	('gastric cancer', 'Disease', (58, 72))	('primary biliary cirrhosis', 'Phenotype', 'HP:0002613', (78, 103))	('pancreatic cancer', 'Disease', (39, 56))	('primary biliary cirrhosis', 'Disease', 'MESH:D008105', (78, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (58, 72))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('pancreatic cancer', 'Disease', 'MESH:D010190', (39, 56))	('primary biliary cirrhosis', 'Disease', (78, 103))
42131	20069059	Forty-nine secreted proteins were found only in HuCCA-1 which was marked in Table 2, including laminin 5 beta 3, heat shock 90 kDa protein 1, heat shock 70 kDs protein 8 isoform 1 variant, GRP78 precursor, desmoglein-4 nephroblastoma overexpressed precursor, neutrophil gelatinase-associated lipocalin (lipocalin 2, NGAL), desmoplakin, cathepsin D, DnaJ homolog subfamily B member 11, annexin IV variant, annexin A5, Ras-related protein Rap-1A, RHOV protein, and rotatin isoform CRA_e.	('GRP78', 'Gene', (189, 194))	('lipocalin 2', 'Gene', (303, 314))	('shock', 'Phenotype', 'HP:0031273', (147, 152))	('desmoplakin', 'Gene', (323, 334))	('nephroblastoma', 'Phenotype', 'HP:0002667', (219, 233))	('DnaJ homolog subfamily B member 11', 'Gene', '51726', (349, 383))	('cathepsin D', 'Gene', (336, 347))	('DnaJ homolog subfamily B member 11', 'Gene', (349, 383))	('annexin A5', 'Gene', (405, 415))	('Ras-related protein Rap-1A', 'Gene', (417, 443))	('IV', 'Chemical', 'MESH:C041115', (393, 395))	('annexin A5', 'Gene', '308', (405, 415))	('neutrophil gelatinase-associated lipocalin', 'Gene', '3934', (259, 301))	('lipocalin 2', 'Gene', '3934', (303, 314))	('NGAL', 'Gene', (316, 320))	('cathepsin D', 'Gene', '1509', (336, 347))	('Ras-related protein Rap-1A', 'Gene', '5906', (417, 443))	('desmoplakin', 'Gene', '1832', (323, 334))	('variant', 'Var', (396, 403))	('shock', 'Phenotype', 'HP:0031273', (118, 123))	('NGAL', 'Gene', '3934', (316, 320))	('RHOV', 'Gene', (445, 449))	('nephroblastoma', 'Disease', 'MESH:D009396', (219, 233))	('nephroblastoma', 'Disease', (219, 233))	('neutrophil gelatinase-associated lipocalin', 'Gene', (259, 301))	('CCA', 'Phenotype', 'HP:0030153', (50, 53))	('RHOV', 'Gene', '171177', (445, 449))	('GRP78', 'Gene', '3309', (189, 194))
42148	20069059	Some interesting secreted proteins expressed only in cholangiocarcinoma include laminin 5 beta 3, heat shock 90 kDa protein 1, heat shock 70 kDs protein 8 isoform 1 variant, GRP78 precursor, desmoglein-4 nephroblastoma overexpressed precursor, neutrophil gelatinase-associated lipocalin (lipocalin 2, NGAL), desmoplakin, cathepsin D, DnaJ homolog subfamily B member 11, annexin IV variant, annexin A5, Ras-related protein Rap-1A, RHOV protein, and rotatin isoform CRA_e.	('DnaJ homolog subfamily B member 11', 'Gene', '51726', (334, 368))	('GRP78', 'Gene', '3309', (174, 179))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (53, 71))	('cathepsin D', 'Gene', '1509', (321, 332))	('DnaJ homolog subfamily B member 11', 'Gene', (334, 368))	('NGAL', 'Gene', (301, 305))	('Ras-related protein Rap-1A', 'Gene', (402, 428))	('IV', 'Chemical', 'MESH:C041115', (378, 380))	('neutrophil gelatinase-associated lipocalin', 'Gene', '3934', (244, 286))	('shock', 'Phenotype', 'HP:0031273', (103, 108))	('lipocalin 2', 'Gene', '3934', (288, 299))	('desmoplakin', 'Gene', '1832', (308, 319))	('Ras-related protein Rap-1A', 'Gene', '5906', (402, 428))	('variant', 'Var', (381, 388))	('annexin A5', 'Gene', (390, 400))	('NGAL', 'Gene', '3934', (301, 305))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('annexin A5', 'Gene', '308', (390, 400))	('nephroblastoma', 'Disease', 'MESH:D009396', (204, 218))	('RHOV', 'Gene', (430, 434))	('nephroblastoma', 'Disease', (204, 218))	('neutrophil gelatinase-associated lipocalin', 'Gene', (244, 286))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (53, 71))	('RHOV', 'Gene', '171177', (430, 434))	('lipocalin 2', 'Gene', (288, 299))	('shock', 'Phenotype', 'HP:0031273', (132, 137))	('cathepsin D', 'Gene', (321, 332))	('cholangiocarcinoma', 'Disease', (53, 71))	('desmoplakin', 'Gene', (308, 319))	('nephroblastoma', 'Phenotype', 'HP:0002667', (204, 218))	('GRP78', 'Gene', (174, 179))
42212	17165088	Moreover, COX-2 overexpression was shown to increase cell growth by the activation of E series of prostaglandins (EP receptors).	('activation', 'PosReg', (72, 82))	('cell growth', 'CPA', (53, 64))	('increase', 'PosReg', (44, 52))	('overexpression', 'Var', (16, 30))	('prostaglandins', 'Chemical', 'MESH:D011453', (98, 112))	('COX-2', 'Gene', (10, 15))	('COX-2', 'Gene', '5743', (10, 15))
42251	17165088	Patients with a strong COX-2 expression exhibited a significantly decreased OS, whereas patients classified as COX-2 negative revealed the most favourable OS.	('expression', 'Var', (29, 39))	('COX-2', 'Gene', (111, 116))	('OS', 'Chemical', '-', (76, 78))	('OS', 'Chemical', '-', (155, 157))	('decreased', 'NegReg', (66, 75))	('patients', 'Species', '9606', (88, 96))	('COX-2', 'Gene', '5743', (111, 116))	('COX-2', 'Gene', (23, 28))	('COX-2', 'Gene', '5743', (23, 28))	('Patients', 'Species', '9606', (0, 8))
42258	17165088	In contrast, the proliferative activity increased in tumours with high levels of COX-2, reflected by a higher mean value of proliferating tumour cells.	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('high levels', 'Var', (66, 77))	('tumours', 'Disease', (53, 60))	('tumour', 'Disease', (53, 59))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('COX-2', 'Gene', (81, 86))	('COX-2', 'Gene', '5743', (81, 86))	('proliferative activity', 'CPA', (17, 39))	('increased', 'PosReg', (40, 49))	('higher', 'PosReg', (103, 109))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('tumour', 'Disease', (138, 144))
42266	17165088	Mutations of the RAS and TP53 genes are the most common genetic abnormalities identified both in ICC and cancer of extrahepatic bile duct (BDC).	('ICC', 'Disease', (97, 100))	('TP53', 'Gene', (25, 29))	('RAS', 'Gene', (17, 20))	('Mutations', 'Var', (0, 9))	('genetic abnormalities', 'Disease', 'MESH:D030342', (56, 77))	('cancer of extrahepatic bile duct', 'Disease', (105, 137))	('cancer of extrahepatic bile duct', 'Disease', 'MESH:D001651', (105, 137))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('TP53', 'Gene', '7157', (25, 29))	('genetic abnormalities', 'Disease', (56, 77))
42272	17165088	This finding is in accordance with our results identifying COX-2 overexpression as a predictor of reduced OS.	('COX-2', 'Gene', '5743', (59, 64))	('overexpression', 'Var', (65, 79))	('reduced OS', 'Disease', (98, 108))	('COX-2', 'Gene', (59, 64))	('OS', 'Chemical', '-', (106, 108))
42349	33912224	Massive mucin production by B-IPMN has been reported to results in fistula formation between biliary tract and adjacent organs (such as bowel).	('B-IPMN', 'Var', (28, 34))	('mucin', 'Gene', '100508689', (8, 13))	('fistula', 'Disease', 'MESH:D005402', (67, 74))	('fistula', 'Disease', (67, 74))	('B-IPMN', 'Chemical', '-', (28, 34))	('results in', 'Reg', (56, 66))	('mucin', 'Gene', (8, 13))
42381	33690612	Indeed, changes within the human microbiota, which are roughly designed as dysbiosis, have been associated with the development of colon, oral, and lung cancers.	('lung cancers', 'Phenotype', 'HP:0100526', (148, 160))	('changes', 'Var', (8, 15))	('dysbiosis', 'Disease', 'MESH:D064806', (75, 84))	('associated', 'Reg', (96, 106))	('colon', 'Disease', 'MESH:D003110', (131, 136))	('human', 'Species', '9606', (27, 32))	('lung cancers', 'Disease', (148, 160))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('colon', 'Disease', (131, 136))	('lung cancers', 'Disease', 'MESH:D008175', (148, 160))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('dysbiosis', 'Disease', (75, 84))	('oral', 'Disease', (138, 142))
42382	33690612	Microbiota is thought to generate physiological function alterations, which are likely to promote different diseases, including various cancers.	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('alterations', 'Var', (57, 68))	('promote', 'PosReg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
42668	32083152	There has been an improvement in diagnostic accuracy for LRM observations after the revision of imaging features in LIRADS v2017n and v'18, however, further analysis and studies are required to formulate the best way to diagnose non-HCC tumors in cirrhotic patients with better specificity.	('HCC tumors', 'Disease', (233, 243))	("v'18", 'Var', (134, 138))	('improvement', 'PosReg', (18, 29))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('diagnostic', 'MPA', (33, 43))	('HCC tumors', 'Disease', 'MESH:D006528', (233, 243))	('cirrhotic', 'Disease', 'MESH:D005355', (247, 256))	('patients', 'Species', '9606', (257, 265))	('HCC', 'Phenotype', 'HP:0001402', (233, 236))	('cirrhotic', 'Disease', (247, 256))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('v2017n', 'Var', (123, 129))	('men', 'Species', '9606', (25, 28))
42848	28609656	Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options.	('Intrahepatic cholangiocarcinoma', 'Disease', (127, 158))	('Intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (127, 158))	('ROS', 'Chemical', 'MESH:D017382', (123, 126))	('Tnf', 'Gene', '21926', (21, 24))	('JNK', 'Gene', '26419', (74, 77))	('Chronic Mitochondrial Dysfunction', 'Disease', (85, 118))	('Chronic Mitochondrial Dysfunction', 'Disease', 'MESH:D028361', (85, 118))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('JNK', 'Gene', (74, 77))	('Cholangiocellular Tumorigenesis', 'Phenotype', 'HP:0030153', (34, 65))	('Cholangiocellular Tumorigenesis', 'Disease', (34, 65))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (140, 158))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('Mitochondrial Dysfunction', 'Phenotype', 'HP:0003287', (93, 118))	('ROS', 'Var', (123, 126))	('Tnf', 'Gene', (21, 24))
42851	28609656	Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions.	('cholangiocellular pre-neoplastic lesions', 'Phenotype', 'HP:0030153', (90, 130))	('deletion', 'Var', (54, 62))	('cholangiocellular pre-neoplastic lesions', 'Disease', (90, 130))	('JNK', 'MPA', (67, 70))	('Tnfr1', 'Gene', '21938', (48, 53))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (112, 130))	('reduced', 'NegReg', (82, 89))	('Tnfr1', 'Gene', (48, 53))
42852	28609656	Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('survival', 'CPA', (67, 75))	('Kras', 'Gene', '16653', (97, 101))	('p53', 'Gene', (93, 96))	('enhanced', 'PosReg', (58, 66))	('tumor reduction', 'Disease', (38, 53))	('deletion', 'Var', (22, 30))	('tumor reduction', 'Disease', 'MESH:D007022', (38, 53))	('JNK1/2', 'Gene', '26419;26420', (15, 21))	('Akt', 'Gene', '11651', (79, 82))	('p53', 'Gene', '22060', (93, 96))	('JNK1/2', 'Gene', (15, 21))	('Akt', 'Gene', (79, 82))	('Kras', 'Gene', (97, 101))
42877	28609656	Hepatic Hspd1 deletion induced severe mitochondrial defects.	('induced', 'Reg', (23, 30))	('Hspd1', 'Gene', (8, 13))	('mitochondrial defects', 'Disease', (38, 59))	('mitochondrial defects', 'Disease', 'MESH:D028361', (38, 59))	('deletion', 'Var', (14, 22))
42879	28609656	Postnatal day 2 (P2) and day 7 (P7) Hspd1DeltaLPC livers showed no obvious histological or micro-architectural differences, excluding embryonic developmental defects (Figures S1I and S1J, data not shown).	('embryonic developmental defects', 'Disease', (134, 165))	('Hspd1DeltaLPC', 'Var', (36, 49))	('embryonic developmental defects', 'Disease', 'MESH:D000014', (134, 165))
42880	28609656	From the age of 4 to 6 weeks, Hspd1DeltaLPC mice exhibited weakness and weight loss and had to be euthanized due to severe weight loss at 8-9 weeks of age (Figures 1B, 1C, and S1K).	('weight loss', 'Disease', (123, 134))	('weight loss', 'Disease', 'MESH:D015431', (72, 83))	('weakness', 'Disease', (59, 67))	('weakness', 'Disease', 'MESH:D018908', (59, 67))	('weight loss', 'Phenotype', 'HP:0001824', (123, 134))	('Hspd1DeltaLPC', 'Var', (30, 43))	('weight loss', 'Disease', (72, 83))	('severe weight loss', 'Phenotype', 'HP:0001525', (116, 134))	('weight loss', 'Phenotype', 'HP:0001824', (72, 83))	('weight loss', 'Disease', 'MESH:D015431', (123, 134))	('mice', 'Species', '10090', (44, 48))
42881	28609656	Macroscopic signs of focal fibrosis and necrosis were evident as early as P38 in Hspd1DeltaLPC livers (Figure S1L).	('fibrosis', 'Disease', (27, 35))	('Hspd1DeltaLPC', 'Var', (81, 94))	('fibrosis', 'Disease', 'MESH:D005355', (27, 35))	('necrosis', 'Disease', (40, 48))	('P38', 'Gene', '26416', (74, 77))	('P38', 'Gene', (74, 77))	('necrosis', 'Disease', 'MESH:D009336', (40, 48))
42882	28609656	At 8 weeks, Hspd1DeltaLPC mice had significantly higher liver-to-body weight ratio, pale livers, and yellow-colored serum, indicative of cholestasis (Figures 1D-1F and S1M).	('pale livers', 'Phenotype', 'HP:0002240', (84, 95))	('Hspd1DeltaLPC', 'Var', (12, 25))	('rat', 'Species', '10116', (77, 80))	('cholestasis', 'Disease', 'MESH:D002779', (137, 148))	('liver-to-body weight ratio', 'CPA', (56, 82))	('cholestasis', 'Disease', (137, 148))	('cholestasis', 'Phenotype', 'HP:0001396', (137, 148))	('higher', 'PosReg', (49, 55))	('yellow-colored serum', 'Phenotype', 'HP:0000952', (101, 121))	('pale livers', 'CPA', (84, 95))	('mice', 'Species', '10090', (26, 30))
42894	28609656	Cholangiocellular lesions, characterized by irregular glands, loss of polarity, multi-layering of cells, and frequent mitosis, were evident in 8-week-old Hspd1DeltaLPC livers (Figure 1H).	('loss', 'NegReg', (62, 66))	('mitosis', 'Disease', (118, 125))	('mitosis', 'Disease', 'None', (118, 125))	('Cholangiocellular lesions', 'Disease', (0, 25))	('glands', 'CPA', (54, 60))	('Hspd1DeltaLPC', 'Var', (154, 167))	('Cholangiocellular lesions', 'Disease', 'MESH:D018281', (0, 25))	('polarity', 'MPA', (70, 78))	('Cholangiocellular lesions', 'Phenotype', 'HP:0030153', (0, 25))
42896	28609656	Cholangiocellular lesions were positive for pan-CK, A6, CK19, and Erbb2, and negative for alpha-fetoprotein (Afp) and intestinal lineage markers, underlining the biliary fate of these cells (Figures S2D-S2F).	('negative', 'NegReg', (77, 85))	('Cholangiocellular lesions', 'Disease', (0, 25))	('positive', 'Reg', (31, 39))	('Erbb2', 'Gene', '13866', (66, 71))	('Afp', 'Gene', '11576', (109, 112))	('Cholangiocellular lesions', 'Disease', 'MESH:D018281', (0, 25))	('Cholangiocellular lesions', 'Phenotype', 'HP:0030153', (0, 25))	('Erbb2', 'Gene', (66, 71))	('alpha-fetoprotein', 'Gene', (90, 107))	('Afp', 'Gene', (109, 112))	('CK19', 'Var', (56, 60))	('alpha-fetoprotein', 'Gene', '11576', (90, 107))	('pan-CK', 'Var', (44, 50))
42897	28609656	Furthermore, these lesions co-stained for validated cancer stem cell (CSC) markers CD44v6 and CD90.1, c-Myc, and for collagen IV-positive stromal reaction as seen in human ICC (Figures 1I and S2D).	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('CD4', 'Gene', (83, 86))	('human', 'Species', '9606', (166, 171))	('CD4', 'Gene', '12504', (83, 86))	('CD90.1', 'Var', (94, 100))	('cancer', 'Disease', (52, 58))	('c-Myc', 'Protein', (102, 107))	('ICC', 'Disease', (172, 175))
42898	28609656	Microarray-based comparative genomic hybridization analysis of laser-dissected CK19+ cholangiocellular lesions from independent Hspd1DeltaLPC livers revealed copy-number changes of >9% across the genome compared with controls (Figure 1J).	('cholangiocellular lesions', 'Phenotype', 'HP:0030153', (85, 110))	('rat', 'Species', '10116', (22, 25))	('copy-number changes', 'Var', (158, 177))	('CK19+', 'Gene', (79, 84))
42900	28609656	Transplantation of liver pieces from one out of three 8-week-old Hspd1DeltaLPC donor mice resulted in tumor formation with ICC, but not HCC characteristics, including glandular structures and CK19+ cells in three out of four transplantation experiments in severe combined immunodeficiency Beige recipient mice (Figures 1K and S2H), supporting their malignant potential.	('mice', 'Species', '10090', (85, 89))	('mice', 'Species', '10090', (305, 309))	('immunodeficiency', 'Phenotype', 'HP:0002721', (272, 288))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (263, 288))	('immunodeficiency', 'Disease', 'MESH:D007153', (272, 288))	('immunodeficiency', 'Disease', (272, 288))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Hspd1DeltaLPC', 'Var', (65, 78))	('HCC', 'Phenotype', 'HP:0001402', (136, 139))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (256, 288))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
42905	28609656	Progressive postnatal deletion of Hspd1 was restricted to hepatocytes from 2 weeks post-AAV8 injection on (AAV8-Cre Hspd1loxP/loxP) (Figure S2M), including progressive liver damage, cholestasis, and cholangiocellular proliferation at 6-8 weeks post injection (Figures 1L, 1M, S2N, and S2O).	('cholestasis', 'Phenotype', 'HP:0001396', (182, 193))	('AAV8', 'Chemical', '-', (88, 92))	('cholestasis', 'Disease', 'MESH:D002779', (182, 193))	('deletion', 'Var', (22, 30))	('liver damage', 'Disease', (168, 180))	('cholestasis', 'Disease', (182, 193))	('AAV8', 'Chemical', '-', (107, 111))	('S2N', 'Mutation', 'p.S2N', (276, 279))	('liver damage', 'Disease', 'MESH:D056486', (168, 180))	('rat', 'Species', '10116', (224, 227))	('cholangiocellular proliferation', 'CPA', (199, 230))	('Hspd1', 'Gene', (34, 39))
42907	28609656	Genes involved in mitochondria homeostasis, the mitochondrial respiratory chain, and molecules downstream of CHOP (encoded by Ddit3) capable of regulating cell death were upregulated in Hspd1DeltaLPC livers (Figures S3A and S3B).	('death', 'Disease', 'MESH:D003643', (160, 165))	('rat', 'Species', '10116', (67, 70))	('death', 'Disease', (160, 165))	('Ddit3', 'Gene', '13198', (126, 131))	('CHOP', 'Gene', (109, 113))	('S3B', 'Gene', '11778', (224, 227))	('upregulated', 'PosReg', (171, 182))	('Ddit3', 'Gene', (126, 131))	('mitochondrial respiratory chain', 'Enzyme', (48, 79))	('S3B', 'Gene', (224, 227))	('mitochondria', 'Enzyme', (18, 30))	('Hspd1DeltaLPC', 'Var', (186, 199))	('CHOP', 'Gene', '13198', (109, 113))
42911	28609656	Increased phosphatidylethanolamine-conjugated LC3 (LC3-II) was also observed, providing ultrastructural evidence of mitophagy in Hspd1DeltaLPC hepatocytes (Figures 1A and 2C).	('Hspd1DeltaLPC', 'Var', (129, 142))	('mitophagy', 'CPA', (116, 125))	('LC3-II', 'Gene', '66734', (51, 57))	('LC3', 'Gene', '66734', (51, 54))	('LC3', 'Gene', (51, 54))	('LC3', 'Gene', '66734', (46, 49))	('LC3-II', 'Gene', (51, 57))	('LC3', 'Gene', (46, 49))	('phosphatidylethanolamine', 'Chemical', 'MESH:C483858', (10, 34))
42912	28609656	We next investigated which signaling pathways were activated downstream of ROS: phosphorylation of JNK and Erk1/2, along with HCC markers, were elevated in Hspd1DeltaLPC livers from week 4 (Figure 2D) but not p-p38 MAPK (Figure S3D).	('Erk1/2', 'Gene', '26417;26413', (107, 113))	('p38 MAPK', 'Gene', (211, 219))	('Erk1/2', 'Gene', (107, 113))	('JNK', 'Gene', (99, 102))	('elevated', 'PosReg', (144, 152))	('phosphorylation', 'MPA', (80, 95))	('ROS', 'Chemical', 'MESH:D017382', (75, 78))	('HCC', 'Phenotype', 'HP:0001402', (126, 129))	('p38 MAPK', 'Gene', '26416', (211, 219))	('Hspd1DeltaLPC', 'Var', (156, 169))
42914	28609656	Screening also identified c-Myc, Kras, and Src as the top upregulated pro-survival genes in Hspd1DeltaLPC livers (Figures 2D, 2E, and S3F), the expression of which was mainly restricted to Hspd1- areas by IHC (Figures 2F and S3G-S3I).	('Src', 'Gene', '20779', (43, 46))	('Src', 'Gene', (43, 46))	('Kras', 'Gene', (33, 37))	('Kras', 'Gene', '16653', (33, 37))	('Hspd1DeltaLPC', 'Var', (92, 105))	('upregulated', 'PosReg', (58, 69))	('c-Myc', 'Gene', (26, 31))
42920	28609656	Intriguingly, BHA almost completely blocked cholangiocyte proliferation and development of cholangiocellular lesions (Figures 3E and S4E).	('cholangiocyte proliferation', 'CPA', (44, 71))	('development of cholangiocellular lesions', 'CPA', (76, 116))	('BHA', 'Chemical', 'MESH:D002083', (14, 17))	('blocked', 'NegReg', (36, 43))	('BHA', 'Var', (14, 17))	('cholangiocellular lesions', 'Phenotype', 'HP:0030153', (91, 116))	('rat', 'Species', '10116', (65, 68))
42924	28609656	Analysis of downstream signaling revealed that p-JNK was dampened by BHA (Figures 3G and 3H), while Erk1/2, p38 MAPK, and Eif2a were unaffected (Figures 3G, 3H, and S4I).	('p38 MAPK', 'Gene', (108, 116))	('3H', 'Chemical', 'MESH:D014316', (157, 159))	('Erk1/2', 'Gene', '26417;26413', (100, 106))	('dampened', 'NegReg', (57, 65))	('Eif2a', 'Gene', (122, 127))	('BHA', 'Chemical', 'MESH:D002083', (69, 72))	('Eif2a', 'Gene', '13665', (122, 127))	('p-JNK', 'MPA', (47, 52))	('BHA', 'Var', (69, 72))	('Erk1/2', 'Gene', (100, 106))	('p38 MAPK', 'Gene', '26416', (108, 116))	('3H', 'Chemical', 'MESH:D014316', (89, 91))
42926	28609656	However, CHOP expression was further elevated by BHA (Figures 3G and 3I).	('BHA', 'Chemical', 'MESH:D002083', (49, 52))	('elevated', 'PosReg', (37, 45))	('CHOP', 'Gene', (9, 13))	('BHA', 'Var', (49, 52))	('CHOP', 'Gene', '13198', (9, 13))
42933	28609656	Indeed, cytokines known to activate Kupffer cells, including Ccl2, Ccl5, and interleukin 1beta (IL-1beta), were upregulated in Hspd1DeltaLPC livers and reduced by BHA treatment (Figure S5B).	('interleukin 1beta', 'Gene', (77, 94))	('cytokines', 'MPA', (8, 17))	('Ccl2', 'Gene', (61, 65))	('upregulated', 'PosReg', (112, 123))	('IL-1beta', 'Gene', '16175', (96, 104))	('BHA', 'Chemical', 'MESH:D002083', (163, 166))	('Ccl2', 'Gene', '20296', (61, 65))	('S5B', 'Gene', (185, 188))	('Hspd1DeltaLPC', 'Var', (127, 140))	('S5B', 'Gene', '66998', (185, 188))	('IL-1beta', 'Gene', (96, 104))	('Ccl5', 'Gene', '20304', (67, 71))	('Ccl5', 'Gene', (67, 71))	('interleukin 1beta', 'Gene', '16176', (77, 94))
42935	28609656	Tnf expression was inhibited by the inflammasome inhibitor isoliquiritigenin, but not by inhibitors of several other pathways (Figure S5G).	('Tnf', 'Gene', (0, 3))	('inhibited', 'NegReg', (19, 28))	('inflammasome inhibitor', 'MPA', (36, 58))	('isoliquiritigenin', 'Chemical', 'MESH:C040920', (59, 76))	('expression', 'MPA', (4, 14))	('isoliquiritigenin', 'Var', (59, 76))
42940	28609656	Clodronate significantly reduced Tnf levels in Hspd1DeltaLPC livers (Figure 4I), and cholangiocyte proliferation and development of cholangiocellular lesions were almost entirely abolished (Figures 4H and S5K), while Ki67+ hepatocytes increased up to 1.84-fold (Figures 4J and S5L).	('abolished', 'NegReg', (179, 188))	('S5L', 'Mutation', 'p.S5L', (277, 280))	('cholangiocyte proliferation', 'CPA', (85, 112))	('reduced', 'NegReg', (25, 32))	('Tnf levels', 'MPA', (33, 43))	('Ki67', 'Gene', '17345', (217, 221))	('cholangiocellular lesions', 'Phenotype', 'HP:0030153', (132, 157))	('Hspd1DeltaLPC', 'Var', (47, 60))	('Clodronate', 'Chemical', 'MESH:D004002', (0, 10))	('rat', 'Species', '10116', (106, 109))	('Ki67', 'Gene', (217, 221))	('development of cholangiocellular lesions', 'CPA', (117, 157))
42942	28609656	Clodronate-treated Hspd1DeltaLPC mice displayed no abnormalities up to 4 months (Figure S5N), indicating that cholangiocellular overgrowth in Hspd1DeltaLPC mice is triggered by Tnf from Kupffer cells in response to hepatic mitochondrial dysfunction and oxidative stress.	('cholangiocellular overgrowth', 'Disease', 'MESH:D018281', (110, 138))	('cholangiocellular overgrowth', 'Disease', (110, 138))	('oxidative stress', 'Phenotype', 'HP:0025464', (253, 269))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (223, 248))	('hepatic mitochondrial dysfunction', 'Disease', (215, 248))	('Clodronate', 'Chemical', 'MESH:D004002', (0, 10))	('overgrowth', 'Phenotype', 'HP:0001548', (128, 138))	('mice', 'Species', '10090', (33, 37))	('Hspd1DeltaLPC', 'Var', (142, 155))	('mice', 'Species', '10090', (156, 160))	('hepatic mitochondrial dysfunction', 'Disease', 'MESH:D028361', (215, 248))
42945	28609656	Tnfr1 deficiency altered the response of cholangiocytes to Tnf, but not to Egf and forskolin (Figure 5A), confirming that the mitogenic effect of Tnf is mediated by Tnfr1.	('altered', 'Reg', (17, 24))	('response', 'MPA', (29, 37))	('Tnfr1', 'Gene', '21938', (0, 5))	('Tnfr1', 'Gene', '21938', (165, 170))	('deficiency', 'Var', (6, 16))	('forskolin', 'Chemical', 'MESH:D005576', (83, 92))	('Tnfr1', 'Gene', (0, 5))	('Tnfr1', 'Gene', (165, 170))
42950	28609656	Next, we generated Hspd1DeltaLPC Tnfr1-/- double knockout mice.	('Hspd1DeltaLPC', 'Var', (19, 32))	('Tnfr1', 'Gene', '21938', (33, 38))	('Tnfr1', 'Gene', (33, 38))	('mice', 'Species', '10090', (58, 62))	('rat', 'Species', '10116', (13, 16))
42951	28609656	Loss of Tnfr1 in Hspd1DeltaLPC mice prevented early lethality and significantly reduced liver damage at 8 weeks (Figures 5C, 5D, S5R, and S5S).	('Tnfr1', 'Gene', '21938', (8, 13))	('liver damage', 'Disease', (88, 100))	('Tnfr1', 'Gene', (8, 13))	('liver damage', 'Disease', 'MESH:D056486', (88, 100))	('reduced', 'NegReg', (80, 87))	('S5R', 'Mutation', 'p.S5R', (129, 132))	('mice', 'Species', '10090', (31, 35))	('S5S', 'Mutation', 'p.S5S', (138, 141))	('Loss', 'Var', (0, 4))	('early lethality', 'CPA', (46, 61))	('reduced liver damage', 'Phenotype', 'HP:0001410', (80, 100))	('prevented', 'NegReg', (36, 45))
42953	28609656	Importantly, the prevention of cholangiocellular overgrowth was unlikely to be dependent on the pro-survival or pro-apoptotic function of Tnfr1: equal levels of necrosis were observed in Hspd1DeltaLPC as well as in 6-week-old double knockout mice (Figures 5E and 5F).	('cholangiocellular overgrowth', 'Disease', (31, 59))	('Hspd1DeltaLPC', 'Var', (187, 200))	('necrosis', 'Disease', 'MESH:D009336', (161, 169))	('Tnfr1', 'Gene', '21938', (138, 143))	('overgrowth', 'Phenotype', 'HP:0001548', (49, 59))	('cholangiocellular overgrowth', 'Disease', 'MESH:D018281', (31, 59))	('mice', 'Species', '10090', (242, 246))	('Tnfr1', 'Gene', (138, 143))	('necrosis', 'Disease', (161, 169))
42954	28609656	Likewise, ROS accumulation, as well as the resulting induction of Gpx3, Kupffer cell activation, and Tnf mRNA levels remained unchanged in Hspd1DeltaLPC Tnfr1-/- when compared with Hspd1DeltaLPC mice, suggesting that Kupffer cell activation and Tnf production were not affected by Tnfr1 deletion (Figures 5G, 5H, and S5T).	('mice', 'Species', '10090', (195, 199))	('Tnfr1', 'Gene', (153, 158))	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('Tnfr1', 'Gene', '21938', (281, 286))	('deletion', 'Var', (287, 295))	('Tnfr1', 'Gene', (281, 286))	('Gpx3', 'Gene', (66, 70))	('S5T', 'Mutation', 'p.S5T', (317, 320))	('Gpx3', 'Gene', '14778', (66, 70))	('ROS', 'MPA', (10, 13))	('Tnfr1', 'Gene', '21938', (153, 158))
42959	28609656	Thus, Tnfr1 signaling favors biliary proliferation and neoplasia over hepatocyte proliferation under the conditions of mitochondrial dysfunction, ROS, and liver damage.	('hepatocyte proliferation', 'CPA', (70, 94))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (119, 144))	('neoplasia', 'Disease', (55, 64))	('Tnfr1', 'Gene', '21938', (6, 11))	('favors', 'PosReg', (22, 28))	('rat', 'Species', '10116', (88, 91))	('rat', 'Species', '10116', (44, 47))	('neoplasia', 'Disease', 'MESH:D009369', (55, 64))	('neoplasia', 'Phenotype', 'HP:0002664', (55, 64))	('liver damage', 'Disease', (155, 167))	('ROS', 'Var', (146, 149))	('Tnfr1', 'Gene', (6, 11))	('liver damage', 'Disease', 'MESH:D056486', (155, 167))	('ROS', 'Chemical', 'MESH:D017382', (146, 149))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (119, 144))	('biliary proliferation', 'CPA', (29, 50))	('mitochondrial dysfunction', 'Disease', (119, 144))
42964	28609656	To test the therapeutic potential of JNK inhibition on cholangiocellular overgrowth, the JNK inhibitor SP600125 was administered intraperitoneally (i.p.)	('cholangiocellular overgrowth', 'Disease', 'MESH:D018281', (55, 83))	('SP600125', 'Var', (103, 111))	('cholangiocellular overgrowth', 'Disease', (55, 83))	('overgrowth', 'Phenotype', 'HP:0001548', (73, 83))	('SP600125', 'Chemical', 'MESH:C432165', (103, 111))
42966	28609656	JNK inhibition reduced cholangiocellular lesions, resulting in proper regeneration and eventually functional livers with WT hepatocytes at week 16 (Figures 6D, S6C, and S6D).	('rat', 'Species', '10116', (76, 79))	('S6D', 'Mutation', 'p.S6D', (169, 172))	('S6C', 'Mutation', 'p.S6C', (160, 163))	('inhibition', 'Var', (4, 14))	('cholangiocellular lesions', 'MPA', (23, 48))	('reduced', 'NegReg', (15, 22))	('cholangiocellular lesions', 'Phenotype', 'HP:0030153', (23, 48))	('JNK', 'Gene', (0, 3))
42968	28609656	Since p-JNK was also found in Hspd1- hepatocytes in untreated Hspd1DeltaLPC mice, SP600125 might also exert its role by attenuating hepatocyte injury and/or the carcinogenic signals in Hspd1- hepatocytes.	('hepatocyte injury', 'Disease', 'MESH:D014947', (132, 149))	('hepatocyte injury', 'Disease', (132, 149))	('SP600125', 'Chemical', 'MESH:C432165', (82, 90))	('mice', 'Species', '10090', (76, 80))	('SP600125', 'Var', (82, 90))	('attenuating', 'NegReg', (120, 131))	('carcinogenic signals', 'CPA', (161, 181))
42969	28609656	Indeed, we observed decreased nuclear p-JNK in both hepatocytes and cholangiocytes due to SP600125 treatment, accompanied by reduced necrosis and liver enzymes and abolished c-Myc upregulation (Figures S6F-S6I).	('necrosis', 'Disease', 'MESH:D009336', (133, 141))	('abolished', 'NegReg', (164, 173))	('SP600125', 'Var', (90, 98))	('decreased', 'NegReg', (20, 29))	('upregulation', 'PosReg', (180, 192))	('nuclear p-JNK', 'MPA', (30, 43))	('reduced', 'NegReg', (125, 132))	('necrosis', 'Disease', (133, 141))	('c-Myc', 'MPA', (174, 179))	('SP600125', 'Chemical', 'MESH:C432165', (90, 98))	('liver enzymes', 'MPA', (146, 159))
42970	28609656	Expression of UPR-related and redox signaling-related genes also declined in livers of SP600125-treated Hspd1DeltaLPC mice, concomitant with reduced 8-OHdG staining (Figures S6J and S6K).	('reduced', 'NegReg', (141, 148))	('S6K', 'Mutation', 'p.S6K', (182, 185))	('Expression', 'MPA', (0, 10))	('redox signaling-related genes', 'Gene', (30, 59))	('8-OHdG staining', 'MPA', (149, 164))	('declined', 'NegReg', (65, 73))	('SP600125-treated', 'Var', (87, 103))	('mice', 'Species', '10090', (118, 122))	('8-OHdG', 'Chemical', 'MESH:C067134', (149, 155))	('SP600125', 'Chemical', 'MESH:C432165', (87, 95))
42973	28609656	Tnf-enhanced proliferation of WT cholangiocytes was abrogated by SP600125 treatment (Figure 5A).	('abrogated', 'NegReg', (52, 61))	('proliferation', 'CPA', (13, 26))	('Tnf-enhanced', 'Gene', (0, 12))	('rat', 'Species', '10116', (20, 23))	('SP600125', 'Chemical', 'MESH:C432165', (65, 73))	('SP600125', 'Var', (65, 73))
42976	28609656	SP600125-treated hepatoblasts lacked c-Jun activation (Figures 6E and S6M).	('lacked', 'NegReg', (30, 36))	('SP600125-treated', 'Var', (0, 16))	('SP600125', 'Chemical', 'MESH:C432165', (0, 8))	('S6M', 'Mutation', 'p.S6M', (70, 73))	('c-Jun activation', 'MPA', (37, 53))
42977	28609656	Meanwhile, SP600125 treatment restored expression of hepatocyte markers Hnf4alpha and Afp comparable with controls (Figures 6F, 6G, and S6M).	('SP600125', 'Chemical', 'MESH:C432165', (11, 19))	('restored', 'PosReg', (30, 38))	('SP600125', 'Var', (11, 19))	('Afp', 'Gene', (86, 89))	('Afp', 'Gene', '11576', (86, 89))	('S6M', 'Mutation', 'p.S6M', (136, 139))	('Hnf4alpha', 'Gene', (72, 81))	('Hnf4alpha', 'Gene', '15378', (72, 81))	('expression', 'MPA', (39, 49))	('hepatocyte', 'MPA', (53, 63))
42983	28609656	JNK1/2 knockout in liver parenchymal cells provided a strong survival benefit (e.g., >40 days in Akt/Notch; >25 days in p53/Kras) and significantly reduced tumor incidence in both models (Figures 7C-7F).	('Akt', 'Gene', (97, 100))	('p53', 'Gene', '22060', (120, 123))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('reduced', 'NegReg', (148, 155))	('JNK1/2', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('p53', 'Gene', (120, 123))	('Kras', 'Gene', (124, 128))	('tumor', 'Disease', (156, 161))	('knockout', 'Var', (7, 15))	('Akt', 'Gene', '11651', (97, 100))	('survival benefit', 'CPA', (61, 77))	('Kras', 'Gene', '16653', (124, 128))	('JNK1/2', 'Gene', '26419;26420', (0, 6))
42986	28609656	mICC cells had reduced p-JNK and severe growth defects in the presence of SP600125 (Figures S7J and S7K).	('S7K', 'Mutation', 'p.S7K', (100, 103))	('SP600125', 'Chemical', 'MESH:C432165', (74, 82))	('p-JNK', 'CPA', (23, 28))	('growth defects', 'CPA', (40, 54))	('SP600125', 'Var', (74, 82))	('reduced', 'NegReg', (15, 22))
42987	28609656	mICC cells were subcutaneously injected into mice, resulting in A6+ and p-JNK+ tumors with histological features similar to primary tumors of human ICC patients (Figure S7L).	('ICC', 'Disease', (148, 151))	('A6+', 'Var', (64, 67))	('mice', 'Species', '10090', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('human', 'Species', '9606', (142, 147))	('primary tumors', 'Disease', (124, 138))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('p-JNK+', 'Var', (72, 78))	('tumors', 'Disease', (132, 138))	('primary tumors', 'Disease', 'MESH:D001932', (124, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('patients', 'Species', '9606', (152, 160))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
42994	28609656	Both human ICC cell lines showed a higher sensitivity to SP600125 compared with HCC cell lines (p < 0.001, Figures S8D and S8E).	('HCC', 'Phenotype', 'HP:0001402', (80, 83))	('SP600125', 'Chemical', 'MESH:C432165', (57, 65))	('sensitivity', 'MPA', (42, 53))	('S8E', 'Mutation', 'p.S8E', (123, 126))	('SP600125', 'Var', (57, 65))	('human', 'Species', '9606', (5, 10))
43000	28609656	Tnf/JNK/c-Jun signaling appears to induce a biliary proliferation program in hepatocytes or liver bipotential cells, implicating this pathway in the pathogenesis of human cholangiocellular tumors.	('human', 'Species', '9606', (165, 170))	('Tnf/JNK/c-Jun signaling', 'Var', (0, 23))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('cholangiocellular tumors', 'Phenotype', 'HP:0030153', (171, 195))	('cholangiocellular tumors', 'Disease', 'MESH:D018281', (171, 195))	('induce', 'PosReg', (35, 41))	('biliary proliferation program', 'CPA', (44, 73))	('rat', 'Species', '10116', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('cholangiocellular tumor', 'Phenotype', 'HP:0030153', (171, 194))	('cholangiocellular tumors', 'Disease', (171, 195))
43001	28609656	Examination of human specimens showed that Tnf and p-JNK were found far more frequently in ICC than in HCC, consistent with findings from others, showing that p-c-Jun emanates from infiltrating inflammatory cells in human HCC.	('rat', 'Species', '10116', (187, 190))	('human', 'Species', '9606', (216, 221))	('HCC', 'Phenotype', 'HP:0001402', (103, 106))	('p-c-Jun', 'Var', (159, 166))	('ICC', 'Disease', (91, 94))	('HCC', 'Phenotype', 'HP:0001402', (222, 225))	('human', 'Species', '9606', (15, 20))
43011	28609656	For instance, liver-specific Mapk14 deletion leads to JNK hyperactivation and HCC development in diethylnitrosamine (DEN)-treated mice.	('JNK hyperactivation', 'MPA', (54, 73))	('mice', 'Species', '10090', (130, 134))	('HCC development', 'CPA', (78, 93))	('deletion', 'Var', (36, 44))	('DEN', 'Chemical', 'MESH:D004052', (117, 120))	('Mapk14', 'Gene', (29, 35))	('Mapk14', 'Gene', '26416', (29, 35))	('HCC', 'Phenotype', 'HP:0001402', (78, 81))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (97, 115))
43013	28609656	JNK1 disruption also reverses increased susceptibility to DEN-induced HCC formation in IkkbDeltaHep mice.	('DEN-induced HCC formation', 'CPA', (58, 83))	('DEN', 'Chemical', 'MESH:D004052', (58, 61))	('HCC', 'Phenotype', 'HP:0001402', (70, 73))	('JNK1', 'Gene', '26419', (0, 4))	('mice', 'Species', '10090', (100, 104))	('disruption', 'Var', (5, 15))	('JNK1', 'Gene', (0, 4))	('susceptibility', 'MPA', (40, 54))	('reverses', 'NegReg', (21, 29))
43014	28609656	However, lack of JNK1 plus JNK2 in hepatocytes increases tumor burden, whereas the pro-tumorigenic effects of JNK on HCC are associated with inflammation and require JNK function in non-parenchymal cells such as myeloid cells and hematopoietic cells.	('JNK2', 'Gene', (27, 31))	('inflammation', 'Disease', 'MESH:D007249', (141, 153))	('JNK1', 'Gene', '26419', (17, 21))	('HCC', 'Phenotype', 'HP:0001402', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('inflammation', 'Disease', (141, 153))	('tumor', 'Disease', (87, 92))	('associated', 'Reg', (125, 135))	('JNK1', 'Gene', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('increases', 'PosReg', (47, 56))	('tumor', 'Disease', (57, 62))	('JNK2', 'Gene', '26420', (27, 31))	('lack', 'Var', (9, 13))
43017	28609656	Interestingly, recent NGS characterization of human pediatric liver cancers induced by intrahepatic cholestasis has shown massive gene amplification and rearrangements frequently targeting direct regulators of JNK.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cholestasis', 'Phenotype', 'HP:0001396', (100, 111))	('liver cancer', 'Phenotype', 'HP:0002896', (62, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('targeting', 'Reg', (179, 188))	('liver cancers', 'Phenotype', 'HP:0002896', (62, 75))	('liver cancers', 'Disease', 'MESH:D006528', (62, 75))	('liver cancers', 'Disease', (62, 75))	('intrahepatic cholestasis', 'Phenotype', 'HP:0001406', (87, 111))	('human', 'Species', '9606', (46, 51))	('rearrangements', 'Var', (153, 167))	('intrahepatic cholestasis', 'Disease', 'MESH:D002780', (87, 111))	('intrahepatic cholestasis', 'Disease', (87, 111))
43050	28609656	For JNK inhibition in presence of Tnf, 10 muM of SP600125 (Abcam) was added.	('JNK inhibition', 'MPA', (4, 18))	('SP600125', 'Var', (49, 57))	('SP600125', 'Chemical', 'MESH:C432165', (49, 57))
43073	28609656	For treatment with SP600125 (Abcam), JNK-IN-8 (Merck) or JNK6o (Bio-techne), 800 ~ 1,000 cells/well were seeded in 96-well plates.	('JNK6o', 'Chemical', '-', (57, 62))	('JNK6o', 'Var', (57, 62))	('SP600125', 'Chemical', 'MESH:C432165', (19, 27))	('JNK-IN-8', 'Chemical', '-', (37, 45))	('SP600125', 'Var', (19, 27))
43113	28609656	Primary antibodies against Hspd1 (Santa Cruz), Pcna (Santa Cruz), Gp73 (Santa Cruz), c-Jun (Abcam), p-c-Jun (Cell Signaling), p-JNK, JNK, p-Erk1/2, Erk1/2, CHOP, p-p38 MAPK, p38 MAPK, p-Akt, Akt and Gapdh (all Cell Signaling) and were incubated at 4 C overnight under shaking conditions.	('Akt', 'Gene', '11651', (191, 194))	('Erk1/2', 'Gene', '26417;26413', (148, 154))	('p-c-Jun', 'Var', (100, 107))	('CHOP', 'Gene', '13198', (156, 160))	('Gp73', 'Gene', '105348', (66, 70))	('Gapdh', 'Gene', '14433', (199, 204))	('Pcna', 'Gene', (47, 51))	('c-Jun', 'MPA', (85, 90))	('p38 MAPK', 'Gene', '26416', (164, 172))	('Gp73', 'Gene', (66, 70))	('p38 MAPK', 'Gene', (164, 172))	('Erk1/2', 'Gene', (140, 146))	('Akt', 'Gene', (186, 189))	('p-JNK', 'Var', (126, 131))	('Erk1/2', 'Gene', (148, 154))	('Hspd1', 'Gene', (27, 32))	('CHOP', 'Gene', (156, 160))	('Gapdh', 'Gene', (199, 204))	('Akt', 'Gene', '11651', (186, 189))	('p38 MAPK', 'Gene', '26416', (174, 182))	('Akt', 'Gene', (191, 194))	('Pcna', 'Gene', '18538', (47, 51))	('Erk1/2', 'Gene', '26417;26413', (140, 146))	('p38 MAPK', 'Gene', (174, 182))
43122	28609656	1 mug amplified sample DNA and sex-matched reference DNA was labeled with Cy3 or Cy5, respectively, using the SureTag DNA Labeling Kit (Agilent, Santa Clara, CA) according to the manufacturer's instructions (protocol version 7.3).	('Cy3', 'Var', (74, 77))	('Cy5', 'Var', (81, 84))	('CA', 'Gene', '12310', (158, 160))
43164	32102130	In a meta-analysis performed in 2011 including 19 studies conducted in 15 years on Milan criteria, it was concluded that significantly increased posttransplant survival was expected for patients who met the Milan criteria when compared with those who did not.	('increased', 'PosReg', (135, 144))	('Milan', 'Var', (207, 212))	('patients', 'Species', '9606', (186, 194))	('posttransplant survival', 'CPA', (145, 168))
43169	32102130	It was found that patients meeting the criterion of solitary tumor <=6.5 cm or <=3 nodules with the largest lesion <=4.5 cm and total tumor diameter <=8 cm had 1- and 5-year survival rates of 90% and 75.2% respectively; on the other hand, the 1-year survival rate was 50% for patients beyond this criterion.	('patients', 'Species', '9606', (276, 284))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('patients', 'Species', '9606', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', (134, 139))	('<=8', 'Var', (149, 152))
43191	32102130	These results have demonstrated that down-staging may be a potential method to further expand liver transplant indications in HCC patients beyond defined criteria.	('HCC', 'Gene', (126, 129))	('patients', 'Species', '9606', (130, 138))	('HCC', 'Gene', '619501', (126, 129))	('HCC', 'Phenotype', 'HP:0001402', (126, 129))	('expand liver', 'Phenotype', 'HP:0002240', (87, 99))	('down-staging', 'Var', (37, 49))
43346	32151057	We hypothesized that aberrant expression and function of FoxAs are involved in CCA progression via induction of stem-like cell and tumorigenic properties of the cancer cells.	('involved', 'Reg', (67, 75))	('induction', 'PosReg', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('aberrant expression', 'Var', (21, 40))	('function', 'MPA', (45, 53))	('CCA', 'Phenotype', 'HP:0030153', (79, 82))	('tumor', 'Disease', (131, 136))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('CCA', 'Disease', 'MESH:D018281', (79, 82))	('cancer', 'Disease', (161, 167))	('CCA', 'Disease', (79, 82))	('FoxAs', 'Gene', (57, 62))
43363	32151057	The median survival of CCA patients with high FoxA1 expression was 364 days and the median survival of CCA patients with low FoxA1 expression was 256 days.	('high FoxA1', 'Var', (41, 51))	('CCA', 'Disease', (103, 106))	('CCA', 'Disease', 'MESH:D018281', (23, 26))	('CCA', 'Disease', (23, 26))	('patients', 'Species', '9606', (27, 35))	('CCA', 'Phenotype', 'HP:0030153', (103, 106))	('CCA', 'Disease', 'MESH:D018281', (103, 106))	('CCA', 'Phenotype', 'HP:0030153', (23, 26))	('patients', 'Species', '9606', (107, 115))
43366	32151057	According to the data analysis, low FoxA1 expression was related with short survival rates and high FoxA3 expression was correlated with metastasis status of CCA patients.	('correlated', 'Reg', (121, 131))	('low', 'NegReg', (32, 35))	('patients', 'Species', '9606', (162, 170))	('CCA', 'Phenotype', 'HP:0030153', (158, 161))	('CCA', 'Disease', 'MESH:D018281', (158, 161))	('expression', 'MPA', (42, 52))	('FoxA3', 'Gene', (100, 105))	('FoxA1', 'Gene', (36, 41))	('high', 'Var', (95, 99))	('expression', 'MPA', (106, 116))	('metastasis status', 'CPA', (137, 154))	('CCA', 'Disease', (158, 161))
43374	32151057	The stem cell marker (CD133 and Oct3/4) expression levels were also significantly increased in KKU-213 cells compared to KKU-100 cells, as shown in Figure 3I,J, respectively.	('KKU-213 cells', 'Var', (95, 108))	('Oct3/4', 'Gene', '5460', (32, 38))	('CD133', 'Gene', (22, 27))	('stem cell', 'CPA', (4, 13))	('Oct3/4', 'Gene', (32, 38))	('CD133', 'Gene', '8842', (22, 27))	('increased', 'PosReg', (82, 91))	('expression levels', 'MPA', (40, 57))
43395	32151057	Additionally, high FoxA3 expression CCA cell line (KKU-213) was increased in cell proliferation rate, cell invasion activity, and stem-like cell properties compared to the low FoxA3 expression CCA cell line (KKU-100).	('increased', 'PosReg', (64, 73))	('CCA', 'Disease', (193, 196))	('CCA', 'Disease', (36, 39))	('high', 'Var', (14, 18))	('cell invasion activity', 'CPA', (102, 124))	('CCA', 'Phenotype', 'HP:0030153', (193, 196))	('CCA', 'Phenotype', 'HP:0030153', (36, 39))	('FoxA3', 'Gene', (19, 24))	('CCA', 'Disease', 'MESH:D018281', (193, 196))	('stem-like cell properties', 'CPA', (130, 155))	('cell proliferation rate', 'CPA', (77, 100))	('CCA', 'Disease', 'MESH:D018281', (36, 39))
43425	32151057	The mRNA levels of FoxA1, FoxA3, CD133, Oct3/4 and GAPDH were detected by TaqMan gene expression assay using TaqMan probes (Hs00270129_m1 FoxA1, Hs00270130_m1 FoxA3, Hs01009257_m1 PROM1 (CD133), Hs04260367_gH POU5F1 (Oct3/4) and GAPDH).	('CD133', 'Gene', (33, 38))	('GAPDH', 'Gene', '2597', (51, 56))	('CD133', 'Gene', '8842', (33, 38))	('POU5F1', 'Gene', (209, 215))	('Oct3/4', 'Gene', '5460', (40, 46))	('Oct3/4', 'Gene', (40, 46))	('GAPDH', 'Gene', (51, 56))	('GAPDH', 'Gene', '2597', (229, 234))	('Hs00270129_m1', 'Var', (124, 137))	('Hs01009257_m1', 'Var', (166, 179))	('PROM1', 'Gene', (180, 185))	('PROM1', 'Gene', '8842', (180, 185))	('Hs00270130_m1', 'Var', (145, 158))	('POU5F1', 'Gene', '5460', (209, 215))	('GAPDH', 'Gene', (229, 234))	('Oct3/4', 'Gene', '5460', (217, 223))	('Oct3/4', 'Gene', (217, 223))	('CD133', 'Gene', (187, 192))	('CD133', 'Gene', '8842', (187, 192))
43450	27782193	LCN2 knockdown inhibited CCA cell growth in vitro and in vivo through induction of cell cycle arrest at G0/G1 phases and decreased metastatic potential due to repression of epithelial-mesenchymal transition (EMT).	('inhibited', 'NegReg', (15, 24))	('CCA', 'Phenotype', 'HP:0030153', (25, 28))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (83, 100))	('knockdown', 'Var', (5, 14))	('LCN2', 'Gene', '3934', (0, 4))	('metastatic potential', 'CPA', (131, 151))	('decreased', 'NegReg', (121, 130))	('epithelial-mesenchymal', 'Protein', (173, 195))	('CCA', 'Disease', (25, 28))	('LCN2', 'Gene', (0, 4))	('repression', 'NegReg', (159, 169))	('cell cycle arrest at G0/G1 phases', 'CPA', (83, 116))
43451	27782193	Overexpression of LCN2 in CCA cells increased cell metastatic potential.	('expression', 'Species', '29278', (4, 14))	('increased', 'PosReg', (36, 45))	('Overexpression', 'Var', (0, 14))	('LCN2', 'Gene', '3934', (18, 22))	('CCA', 'Phenotype', 'HP:0030153', (26, 29))	('cell metastatic potential', 'CPA', (46, 71))	('LCN2', 'Gene', (18, 22))
43486	27782193	1B, SNU308-LCN2si cells had an increased number of cells in G0/G1 phase compared to SNU308-COLsi cells (56.26% and 41.44%, respectively), suggesting that knockdown of LCN2 in SNU308 cells induces G0/G1 arrest, thus inhibiting cell growth.	('LCN2', 'Gene', (11, 15))	('induces', 'Reg', (188, 195))	('LCN2', 'Gene', '3934', (167, 171))	('knockdown', 'Var', (154, 163))	('LCN2', 'Gene', (167, 171))	('cell growth', 'CPA', (226, 237))	('LCN2', 'Gene', '3934', (11, 15))	('G0/G1 arrest', 'CPA', (196, 208))	('inhibiting', 'NegReg', (215, 225))
43488	27782193	1C,D, LCN2 knockdown induced higher p21 expression and lower CDK4 and CDK6 expression in SNU308 cells with no obvious impact on p27 and cyclin D3 expression, initiating the G0/G1 arrest noted in Fig.	('CDK4', 'Gene', (61, 65))	('cyclin D3', 'Gene', (136, 145))	('LCN2', 'Gene', (6, 10))	('higher', 'PosReg', (29, 35))	('CDK4', 'Gene', '1019', (61, 65))	('expression', 'Species', '29278', (75, 85))	('knockdown', 'Var', (11, 20))	('CDK6', 'Gene', '1021', (70, 74))	('cyclin D3', 'Gene', '896', (136, 145))	('p21', 'Gene', (36, 39))	('expression', 'Species', '29278', (146, 156))	('p21', 'Gene', '644914', (36, 39))	('CDK6', 'Gene', (70, 74))	('G0/G1 arrest', 'CPA', (173, 185))	('LCN2', 'Gene', '3934', (6, 10))	('p27', 'Gene', '3429', (128, 131))	('lower', 'NegReg', (55, 60))	('p27', 'Gene', (128, 131))	('expression', 'Species', '29278', (40, 50))
43491	27782193	This shows that LCN2 knockdown attenuates metastatic potential.	('metastatic potential', 'CPA', (42, 62))	('LCN2', 'Gene', '3934', (16, 20))	('attenuates', 'NegReg', (31, 41))	('LCN2', 'Gene', (16, 20))	('knockdown', 'Var', (21, 30))
43493	27782193	Figure 2B,C demonstrate that Snail, Slug, Twist, Zeb1, and Zeb2 expression levels decreased in SNU308-LCN2si cells compared to SNU308-COLsi cells, implying that LCN2 knockdown inhibited EMT.	('LCN2', 'Gene', (102, 106))	('Zeb2', 'Gene', '9839', (59, 63))	('Zeb2', 'Gene', (59, 63))	('LCN2', 'Gene', '3934', (161, 165))	('Twist', 'Gene', (42, 47))	('Snail', 'Gene', (29, 34))	('inhibited', 'NegReg', (176, 185))	('Snail', 'Gene', '6615', (29, 34))	('Slug', 'Gene', (36, 40))	('Zeb1', 'Gene', '6935', (49, 53))	('EMT', 'CPA', (186, 189))	('LCN2', 'Gene', (161, 165))	('knockdown', 'Var', (166, 175))	('Twist', 'Gene', '7291', (42, 47))	('Zeb1', 'Gene', (49, 53))	('LCN2', 'Gene', '3934', (102, 106))	('Slug', 'Gene', '6591', (36, 40))	('expression levels', 'MPA', (64, 81))	('decreased', 'NegReg', (82, 91))	('expression', 'Species', '29278', (64, 74))
43497	27782193	2E,F) after LCN2 knockdown.	('LCN2', 'Gene', (12, 16))	('LCN2', 'Gene', '3934', (12, 16))	('knockdown', 'Var', (17, 26))
43505	27782193	Figure 4A reveals that the expression of NDRG1 and NDRG2 was increased after LCN2 knockdown in SNU308 cells but decreased after LCN2 overexpression in RBE cells, as determined by western blot.	('LCN2', 'Gene', (128, 132))	('NDRG2', 'Gene', '57447', (51, 56))	('RB', 'Disease', 'MESH:D012175', (151, 153))	('LCN2', 'Gene', '3934', (77, 81))	('NDRG1', 'Gene', (41, 46))	('NDRG2', 'Gene', (51, 56))	('expression', 'Species', '29278', (27, 37))	('knockdown', 'Var', (82, 91))	('expression', 'MPA', (27, 37))	('LCN2', 'Gene', (77, 81))	('increased', 'PosReg', (61, 70))	('NDRG1', 'Gene', '10397', (41, 46))	('LCN2', 'Gene', '3934', (128, 132))	('decreased', 'NegReg', (112, 121))	('expression', 'Species', '29278', (137, 147))
43517	27782193	After univariate and subsequent multivariate analysis, only LCN2 expression was found to be negatively associated with overall survival (OS) of patients with CCA (p < 0.001, relative risk, 3.615 (1.721-7.592)) (Supplemental Table 2 and Fig.	('LCN2', 'Gene', '3934', (60, 64))	('CCA', 'Phenotype', 'HP:0030153', (158, 161))	('LCN2', 'Gene', (60, 64))	('expression', 'Species', '29278', (65, 75))	('patients', 'Species', '9606', (144, 152))	('negatively', 'NegReg', (92, 102))	('overall survival', 'MPA', (119, 135))	('CCA', 'Disease', (158, 161))	('expression', 'Var', (65, 75))
43527	27782193	We therefore knocked down LCN2 in SNU308 cells and analyzed the distribution of cells at each stage of the cell cycle within the population.	('LCN2', 'Gene', '3934', (26, 30))	('knocked', 'Var', (13, 20))	('LCN2', 'Gene', (26, 30))
43528	27782193	Figure 1B reveals that more SNU308-LCN2si cells were in G0/G1 phase compared to SNU308-COlsi cells, indicating that LCN2 knockdown can induce cell cycle arrest at G0/G1.	('knockdown', 'Var', (121, 130))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (142, 159))	('LCN2', 'Gene', (35, 39))	('cell cycle arrest', 'CPA', (142, 159))	('LCN2', 'Gene', '3934', (116, 120))	('induce', 'Reg', (135, 141))	('LCN2', 'Gene', (116, 120))	('LCN2', 'Gene', '3934', (35, 39))
43534	27782193	1C,D, LCN2 knockdown increased p21 expression with no significant impact on p27.	('increased', 'PosReg', (21, 30))	('p21', 'Gene', (31, 34))	('expression', 'Species', '29278', (35, 45))	('LCN2', 'Gene', '3934', (6, 10))	('expression', 'MPA', (35, 45))	('p21', 'Gene', '644914', (31, 34))	('p27', 'Gene', '3429', (76, 79))	('p27', 'Gene', (76, 79))	('LCN2', 'Gene', (6, 10))	('knockdown', 'Var', (11, 20))
43535	27782193	Taken together, we concluded that LCN2 knockdown in SNU308 cells can retard cell cycle progression at G0/G1 phase by downregulation of CDK4 and CDK6 and upregulation of p21, leading to the inhibition of cell proliferation noted in our previous study.	('cell cycle progression at G0/G1 phase', 'CPA', (76, 113))	('cell proliferation', 'CPA', (203, 221))	('CDK4', 'Gene', (135, 139))	('upregulation', 'PosReg', (153, 165))	('CDK6', 'Gene', (144, 148))	('knockdown', 'Var', (39, 48))	('LCN2', 'Gene', '3934', (34, 38))	('CDK6', 'Gene', '1021', (144, 148))	('p21', 'Gene', (169, 172))	('retard', 'NegReg', (69, 75))	('downregulation', 'NegReg', (117, 131))	('CDK4', 'Gene', '1019', (135, 139))	('p21', 'Gene', '644914', (169, 172))	('LCN2', 'Gene', (34, 38))	('inhibition', 'NegReg', (189, 199))
43536	27782193	Following xenograft of SNU308-LCNsi or SNU308-COLsi tumors into nude mice, tumor growth from SNU308-LCNsi cells was much slower than from SNU308-COLsi cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('nude mice', 'Species', '10090', (64, 73))	('SNU308-LCNsi', 'Var', (93, 105))	('slower', 'NegReg', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (75, 80))
43537	27782193	Collectively, our results suggest that LCN2 knockdown could repress SNU308 cell growth in vitro and in vivo.	('LCN2', 'Gene', '3934', (39, 43))	('LCN2', 'Gene', (39, 43))	('knockdown', 'Var', (44, 53))	('repress', 'NegReg', (60, 67))
43540	27782193	Figure 2B,C demonstrate that all five transcriptional factors were downregulated following LCN2 knockdown in SNU308 cells, indicating that LCN2 knockdown could inhibit EMT progress in CCA cells, attenuating the metastatic potential noted in Fig.	('LCN2', 'Gene', (139, 143))	('inhibit', 'NegReg', (160, 167))	('LCN2', 'Gene', '3934', (91, 95))	('CCA', 'Disease', (184, 187))	('metastatic potential', 'CPA', (211, 231))	('LCN2', 'Gene', (91, 95))	('LCN2', 'Gene', '3934', (139, 143))	('knockdown', 'Var', (144, 153))	('CCA', 'Phenotype', 'HP:0030153', (184, 187))	('EMT progress', 'CPA', (168, 180))	('attenuating', 'NegReg', (195, 206))	('downregulated', 'NegReg', (67, 80))
43544	27782193	Figure 2D shows that SNU308-LCNsi cells expressed E-cadherin more highly than SNU308-COLsi cells, further supporting the finding that the EMT process is attenuated by LCN2 knockdown in SNU308 cells.	('LCN2', 'Gene', '3934', (167, 171))	('E-cadherin', 'Gene', (50, 60))	('E-cadherin', 'Gene', '999', (50, 60))	('attenuated', 'NegReg', (153, 163))	('LCN2', 'Gene', (167, 171))	('EMT process', 'CPA', (138, 149))	('knockdown', 'Var', (172, 181))	('highly', 'PosReg', (66, 72))
43545	27782193	The downregulation of P-cadherin, which is another marker of mesenchymal cells and linked with CCA cell migration, in LCN2 knockdown SNU308 cells also demonstrated EMT process was repressed in SNU308-LCNsi cells (Fig.	('LCN2', 'Gene', '3934', (118, 122))	('P-cadherin', 'Protein', (22, 32))	('LCN2', 'Gene', (118, 122))	('downregulation', 'NegReg', (4, 18))	('knockdown', 'Var', (123, 132))	('CCA', 'Phenotype', 'HP:0030153', (95, 98))
43547	27782193	In CCA, LCN2 knockdown in CCA cells had been shown to repress invasion through reduction of LCN2/MMP-9 complex formation.	('CCA', 'Phenotype', 'HP:0030153', (26, 29))	('LCN2', 'Gene', '3934', (92, 96))	('CCA', 'Phenotype', 'HP:0030153', (3, 6))	('MMP-9', 'Gene', '4318', (97, 102))	('LCN2', 'Gene', (8, 12))	('LCN2', 'Gene', (92, 96))	('MMP-9', 'Gene', (97, 102))	('repress', 'NegReg', (54, 61))	('invasion', 'CPA', (62, 70))	('CCA', 'Disease', (3, 6))	('knockdown', 'Var', (13, 22))	('reduction', 'NegReg', (79, 88))	('LCN2', 'Gene', '3934', (8, 12))
43548	27782193	Our result indicates that knockdown of LCN2 in CCA cells could decrease both intracellular and extracellular MMP-2 and MMP-9 expression, reducing cell invasiveness (Fig.	('reducing', 'NegReg', (137, 145))	('CCA', 'Phenotype', 'HP:0030153', (47, 50))	('LCN2', 'Gene', '3934', (39, 43))	('MMP-9', 'Gene', '4318', (119, 124))	('expression', 'Species', '29278', (125, 135))	('LCN2', 'Gene', (39, 43))	('decrease', 'NegReg', (63, 71))	('knockdown', 'Var', (26, 35))	('cell invasiveness', 'CPA', (146, 163))	('MMP-9', 'Gene', (119, 124))
43555	27782193	4, as we knocked down or overexpressed LCN2 in CCA cells, NDRG1 and NDRG2 protein expression was increased or decreased, respectively (Fig.	('NDRG1', 'Gene', (58, 63))	('expression', 'Species', '29278', (82, 92))	('increased', 'PosReg', (97, 106))	('LCN2', 'Gene', '3934', (39, 43))	('CCA', 'Phenotype', 'HP:0030153', (47, 50))	('overexpressed', 'PosReg', (25, 38))	('NDRG1', 'Gene', '10397', (58, 63))	('LCN2', 'Gene', (39, 43))	('decreased', 'NegReg', (110, 119))	('NDRG2', 'Gene', '57447', (68, 73))	('knocked down', 'Var', (9, 21))	('protein expression', 'MPA', (74, 92))	('NDRG2', 'Gene', (68, 73))
43569	27782193	The expression vector containing coding region of LCN2 (HG10222-M-Y) was purchased from Sino Biological Inc (Beijing, China).	('HG10222-M-Y', 'Var', (56, 67))	('expression', 'Species', '29278', (4, 14))	('LCN2', 'Gene', (50, 54))	('LCN2', 'Gene', '3934', (50, 54))
43576	27782193	FAM dye-labeled TaqMan MGB probes for human NDRG1 (Hs00608387_m1), NDRG2 (Hs01045115_m1), LCN2 (Hs00194353_m1) and beta-actin (Hs01060665_g1) were purchased from Applied Biosystems.	('beta-actin', 'Gene', (115, 125))	('LCN2', 'Gene', (90, 94))	('human', 'Species', '9606', (38, 43))	('NDRG2', 'Gene', '57447', (67, 72))	('Hs01045115_m1', 'Var', (74, 87))	('Hs01060665_g1', 'Var', (127, 140))	('NDRG1', 'Gene', (44, 49))	('Hs00194353_m1', 'Var', (96, 109))	('LCN2', 'Gene', '3934', (90, 94))	('Hs00608387_m1', 'Var', (51, 64))	('NDRG2', 'Gene', (67, 72))	('beta-actin', 'Gene', '728378', (115, 125))	('NDRG1', 'Gene', '10397', (44, 49))
43579	27782193	The DNA fragment containing the enhancer/promoter of the NDRG2 gene (-4253 to -1) was synthesized with primers (Sp6 and 5'-AAGCTTCTATAAATAGAGGGCGATCGC-3') by PCR using pGEM-3NDRG2 as target DNA.	('NDRG2', 'Gene', (174, 179))	('NDRG2', 'Gene', '57447', (57, 62))	('NDRG2', 'Gene', '57447', (174, 179))	('NDRG2', 'Gene', (57, 62))	('-4253', 'Var', (69, 74))
43696	33879742	We observed an inverse association between age and metastasis, that patients with ECCA had a better prognosis than patients with ICCA, and that patients with ECCA in the T1 stage had worse survival than patients with ICCA in the T1 stage.	('metastasis', 'CPA', (51, 61))	('inverse', 'NegReg', (15, 22))	('patients', 'Species', '9606', (115, 123))	('CCA', 'Phenotype', 'HP:0030153', (130, 133))	('ECCA', 'Var', (158, 162))	('CCA', 'Phenotype', 'HP:0030153', (218, 221))	('CCA', 'Phenotype', 'HP:0030153', (159, 162))	('ECCA', 'Disease', (82, 86))	('patients', 'Species', '9606', (144, 152))	('patients', 'Species', '9606', (203, 211))	('patients', 'Species', '9606', (68, 76))	('CCA', 'Phenotype', 'HP:0030153', (83, 86))
43704	33879742	Moreover, with regard to the genetic alterations between ICCA and ECCA, ICCA is more likely to have mutations of PBMR1 and BAP1, while ECCA is more frequently correlated with KRAS and TP53 mutations, significantly impacting patient survival.	('BAP1', 'Gene', (123, 127))	('mutations', 'Var', (100, 109))	('impacting', 'Reg', (214, 223))	('CCA', 'Phenotype', 'HP:0030153', (58, 61))	('CCA', 'Phenotype', 'HP:0030153', (136, 139))	('PBMR1', 'Gene', (113, 118))	('patient', 'Species', '9606', (224, 231))	('CCA', 'Phenotype', 'HP:0030153', (73, 76))	('TP53', 'Gene', '7157', (184, 188))	('TP53', 'Gene', (184, 188))	('CCA', 'Phenotype', 'HP:0030153', (67, 70))	('BAP1', 'Gene', '8314', (123, 127))	('KRAS', 'Gene', (175, 179))	('KRAS', 'Gene', '3845', (175, 179))
43712	33879742	According to the International Classification of Diseases in Oncology (ICD-O-3), tumours with codes 8010, 8020, 8041, 8070, 8140, 8144, 8160, 8161, 8260, 8310, 8480, 8490, 8560 and 8162 are identified as ECCA (C24.0), while those with codes 8010, 8020, 8140, 8160 and 8161 are considered ICCA (C22.1).	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('ICD', 'Disease', 'OMIM:252500', (71, 74))	('Oncology', 'Phenotype', 'HP:0002664', (61, 69))	('ICD', 'Disease', (71, 74))	('tumours', 'Disease', 'MESH:D009369', (81, 88))	('ECCA', 'Disease', (204, 208))	('tumours', 'Disease', (81, 88))	('CCA', 'Phenotype', 'HP:0030153', (289, 292))	('8260', 'Var', (148, 152))	('8310', 'Var', (154, 158))	('CCA', 'Phenotype', 'HP:0030153', (205, 208))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
43730	33879742	For ICCA patients (Table 2), univariate analysis results showed that younger patients (<50 years), those with poorly differentiated or undifferentiated disease, positive lymph nodes, larger tumour size (>5 cm) and advanced tumours (stages T3 and T4) were more likely to have metastasis (P < .001).	('patients', 'Species', '9606', (9, 17))	('tumours', 'Disease', (223, 230))	('tumour', 'Disease', (190, 196))	('metastasis', 'CPA', (275, 285))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('CCA', 'Phenotype', 'HP:0030153', (5, 8))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('T4', 'Var', (246, 248))	('patients', 'Species', '9606', (77, 85))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumour', 'Disease', (223, 229))	('tumours', 'Phenotype', 'HP:0002664', (223, 230))	('undifferentiated disease', 'Disease', 'MESH:D002277', (135, 159))	('undifferentiated disease', 'Disease', (135, 159))	('tumours', 'Disease', 'MESH:D009369', (223, 230))	('tumour', 'Disease', 'MESH:D009369', (190, 196))
43775	33879742	For instance, most patients with early-onset (age <50 years) disease present with a lower prevalence of microsatellite instability and an enhanced frequency of KMT2C and ASXL1 mutations in comparison with late-onset patients.	('mutations', 'Var', (176, 185))	('patients', 'Species', '9606', (19, 27))	('ASXL1', 'Gene', (170, 175))	('KMT2C', 'Gene', '58508', (160, 165))	('KMT2C', 'Gene', (160, 165))	('enhanced', 'PosReg', (138, 146))	('microsatellite instability', 'Disease', 'MESH:D053842', (104, 130))	('patients', 'Species', '9606', (216, 224))	('lower', 'NegReg', (84, 89))	('microsatellite instability', 'Disease', (104, 130))	('ASXL1', 'Gene', '171023', (170, 175))
43798	33301605	For example, lncRNA-EPIC1 is up-regulated in CCA and accelerates the malignant biological behaviors of CCA by targeting Myc [11].	('accelerates', 'PosReg', (53, 64))	('lncRNA-EPIC1', 'Gene', (13, 25))	('malignant biological behaviors of', 'CPA', (69, 102))	('Myc', 'Gene', '4609', (120, 123))	('Myc', 'Gene', (120, 123))	('CCA', 'Phenotype', 'HP:0030153', (45, 48))	('up-regulated', 'PosReg', (29, 41))	('CCA', 'Phenotype', 'HP:0030153', (103, 106))	('CCA', 'Disease', (45, 48))	('targeting', 'Var', (110, 119))
43799	33301605	lncRNA-RMRP contributes to accelerating the tumorigenesis and development of CCA by sponging miR-217 [12].	('miR-217', 'Gene', '406999', (93, 100))	('miR-21', 'Gene', '406991', (93, 99))	('miR-217', 'Gene', (93, 100))	('CCA', 'Disease', (77, 80))	('accelerating', 'PosReg', (27, 39))	('tumorigenesis', 'CPA', (44, 57))	('RMRP', 'Gene', (7, 11))	('development', 'CPA', (62, 73))	('sponging', 'Var', (84, 92))	('miR-21', 'Gene', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('CCA', 'Phenotype', 'HP:0030153', (77, 80))	('RMRP', 'Gene', '6023', (7, 11))
43827	31998650	Although FUNDC1 showed a protective effect on pan-cancer, a high expression level of FUNDC1 was detrimental to the survival of LIHC patients.	('FUNDC1', 'Gene', (9, 15))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('high', 'Var', (60, 64))	('FUNDC1', 'Gene', (85, 91))	('FUNDC1', 'Gene', '139341', (9, 15))	('detrimental', 'NegReg', (96, 107))	('LIHC', 'Disease', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('LIHC', 'Disease', 'MESH:D006528', (127, 131))	('FUNDC1', 'Gene', '139341', (85, 91))	('patients', 'Species', '9606', (132, 140))
43845	31998650	For example, cytotoxic T lymphocyte associated antigen 4 (CTLA4), programmed death-1 (PD-1), and programmed death ligand-1 (PD-L1) inhibitors were found to have promising antitumor effects on malignant melanoma and non-small-cell lung carcinoma.	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('programmed death ligand-1', 'Gene', (97, 122))	('malignant melanoma', 'Phenotype', 'HP:0002861', (192, 210))	('non-small-cell lung carcinoma', 'Disease', (215, 244))	('programmed death-1', 'Gene', '5133', (66, 84))	('non-small-cell lung carcinoma', 'Disease', 'MESH:D002289', (215, 244))	('programmed death-1', 'Gene', (66, 84))	('cytotoxic T lymphocyte associated antigen 4', 'Gene', (13, 56))	('programmed death ligand-1', 'Gene', '29126', (97, 122))	('tumor', 'Disease', (175, 180))	('CTLA4', 'Gene', '1493', (58, 63))	('cytotoxic T lymphocyte associated antigen 4', 'Gene', '1493', (13, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('melanoma', 'Disease', (202, 210))	('inhibitors', 'Var', (131, 141))	('PD-L1', 'Gene', (124, 129))	('PD-L1', 'Gene', '29126', (124, 129))	('CTLA4', 'Gene', (58, 63))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (219, 244))	('PD-1', 'Gene', (86, 90))	('PD-1', 'Gene', '5133', (86, 90))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (215, 244))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
43886	31998650	The findings for lung cancer were partly different from those using PrognoScan, as a high expression of FUNDC1 only benefited LUSC (OS: HR = 0.64, 95 % CI from 0.48 to 0.85 logrank P = 0.0017; RFS: HR = 0.55, 95% CI from 0.33 to 0.91, logrank P = 0.019) (Figures 2C,D) and not LUAD (OS: HR = 0.8, 95% CI from 0.6 to 1.08, logrank P = 0.15; RFS: HR = 1.41, 95% CI from 0.91 to 2.19, logrank P = 0.13) (Figures 3M,N).	('LUSC', 'Disease', (126, 130))	('FUNDC1', 'Gene', (104, 110))	('lung cancer', 'Disease', (17, 28))	('benefited', 'PosReg', (116, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('FUNDC1', 'Gene', '139341', (104, 110))	('LUSC', 'Phenotype', 'HP:0030359', (126, 130))	('high', 'Var', (85, 89))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('LUAD', 'Disease', (277, 281))	('LUAD', 'Disease', 'MESH:C538231', (277, 281))	('LUAD', 'Phenotype', 'HP:0030078', (277, 281))	('LUSC', 'Disease', 'MESH:D002294', (126, 130))
43902	31998650	For progression-free survival (PFS), FUNDC1 expression was significantly hazardous to LIHC patients without hepatitis virus infection (n = 167, HR = 2.1, 95% CI from 1.3 to 3.38, P = 0.0019) but became protective to LIHC patients at stage 2 (n = 84, HR = 0.52, 95% CI from 0.28 to 0.98, P = 0.039) and grade 3 (n = 119, HR = 0.6, 95% CI from 0.36 to 0.98, P = 0.041) (Figure 4).	('LIHC', 'Disease', (86, 90))	('patients', 'Species', '9606', (221, 229))	('hepatitis virus infection', 'Disease', (108, 133))	('patients', 'Species', '9606', (91, 99))	('LIHC', 'Disease', 'MESH:D006528', (86, 90))	('hepatitis', 'Phenotype', 'HP:0012115', (108, 117))	('FUNDC1', 'Gene', (37, 43))	('expression', 'Var', (44, 54))	('hepatitis virus infection', 'Disease', 'MESH:D006525', (108, 133))	('FUNDC1', 'Gene', '139341', (37, 43))	('LIHC', 'Disease', (216, 220))	('LIHC', 'Disease', 'MESH:D006528', (216, 220))
43926	31998650	Mitochondria are essential for human immunity, and aberrant mitochondrial activity affects immune responses.	('aberrant', 'Var', (51, 59))	('mitochondrial activity', 'MPA', (60, 82))	('human', 'Species', '9606', (31, 36))	('immune responses', 'CPA', (91, 107))	('affects', 'Reg', (83, 90))
43927	31998650	For example, some studies have demonstrated that viruses (e.g., HBV in LIHC) can manipulate mitophagy, which enables viruses to promote persistent infection and attenuate the innate immune responses.	('attenuate', 'NegReg', (161, 170))	('innate immune responses', 'CPA', (175, 198))	('mitophagy', 'CPA', (92, 101))	('manipulate', 'Reg', (81, 91))	('infection', 'Disease', (147, 156))	('LIHC', 'Disease', (71, 75))	('infection', 'Disease', 'MESH:D007239', (147, 156))	('persistent infection', 'Phenotype', 'HP:0031035', (136, 156))	('viruses', 'Var', (117, 124))	('LIHC', 'Disease', 'MESH:D006528', (71, 75))	('promote', 'PosReg', (128, 135))
43930	31998650	FUNDC1-mediated mitophagy is negatively regulated by the phosphorylation of FUNDC1, as the phosphorylation of Tyr 18 in the FUNDC1 LC3-interacting region motif can weaken the binding affinity of FUNDC1 to LC3.	('FUNDC1', 'Gene', (76, 82))	('FUNDC1', 'Gene', (124, 130))	('Tyr 18', 'Var', (110, 116))	('mitophagy', 'CPA', (16, 25))	('phosphorylation', 'Var', (91, 106))	('FUNDC1', 'Gene', '139341', (0, 6))	('FUNDC1', 'Gene', '139341', (76, 82))	('FUNDC1', 'Gene', '139341', (124, 130))	('weaken', 'NegReg', (164, 170))	('Tyr', 'Chemical', 'MESH:C042696', (110, 113))	('binding affinity', 'Interaction', (175, 191))	('FUNDC1', 'Gene', (195, 201))	('FUNDC1', 'Gene', '139341', (195, 201))	('FUNDC1', 'Gene', (0, 6))	('LC3', 'Protein', (205, 208))
43938	31998650	Thus, it is reasonable to surmise that FUNDC1 expression may influence patient survival through tumor cell proliferation.	('expression', 'Var', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('influence', 'Reg', (61, 70))	('tumor', 'Disease', (96, 101))	('FUNDC1', 'Gene', (39, 45))	('FUNDC1', 'Gene', '139341', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('patient', 'Species', '9606', (71, 78))	('patient survival', 'CPA', (71, 87))
43942	31998650	One previous study has demonstrated that FUNDC1-mediated mitophagy can suppress hepatocarcinogenesis.	('FUNDC1', 'Gene', (41, 47))	('FUNDC1', 'Gene', '139341', (41, 47))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (80, 100))	('mitophagy', 'Var', (57, 66))	('suppress', 'NegReg', (71, 79))	('hepatocarcinogenesis', 'Disease', (80, 100))
43943	31998650	This study found that the specific knockout of FUNDC1 in hepatocytes promotes the initiation and progression of chemical carcinogen diethylnitrosamine-induced HCC.	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (132, 150))	('FUNDC1', 'Gene', (47, 53))	('progression', 'CPA', (97, 108))	('promotes', 'PosReg', (69, 77))	('knockout', 'Var', (35, 43))	('FUNDC1', 'Gene', '139341', (47, 53))
43944	31998650	The study also found that FUNDC1 transgenic hepatocytes protect against the development of HCC.	('FUNDC1', 'Gene', (26, 32))	('HCC', 'Disease', (91, 94))	('transgenic', 'Var', (33, 43))	('FUNDC1', 'Gene', '139341', (26, 32))
43967	31998650	In 8 datasets in PrognoScan, high FUNDC1 expression levels could be used as an independent risk factor for a poor prognosis in brain, breast, colorectal, and skin cancers (Figure 2).	('high', 'Var', (29, 33))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('colorectal', 'Disease', (142, 152))	('expression', 'MPA', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('skin cancers', 'Disease', (158, 170))	('skin cancers', 'Phenotype', 'HP:0008069', (158, 170))	('brain', 'Disease', (127, 132))	('FUNDC1', 'Gene', (34, 40))	('skin cancers', 'Disease', 'MESH:D012878', (158, 170))	('breast', 'Disease', (134, 140))	('FUNDC1', 'Gene', '139341', (34, 40))
43968	31998650	In addition, a high level of FUNDC1 expression was shown to be related to a poor prognosis in LIHC with micro-vascular invasion but a favorable prognosis in LIHC with AJCC T2 (Figure 4).	('high', 'Var', (15, 19))	('LIHC', 'Disease', (94, 98))	('FUNDC1', 'Gene', (29, 35))	('LIHC', 'Disease', 'MESH:D006528', (94, 98))	('LIHC', 'Disease', (157, 161))	('FUNDC1', 'Gene', '139341', (29, 35))	('LIHC', 'Disease', 'MESH:D006528', (157, 161))	('expression', 'MPA', (36, 46))
43970	31998650	Another major finding from this study is that FUNDC1 expression correlates with diverse immune infiltration levels in cancers, especially in LIHC and LUSC.	('LIHC', 'Disease', (141, 145))	('cancers', 'Disease', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('correlates with', 'Reg', (64, 79))	('immune infiltration levels', 'MPA', (88, 114))	('expression', 'Var', (53, 63))	('FUNDC1', 'Gene', (46, 52))	('LIHC', 'Disease', 'MESH:D006528', (141, 145))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('FUNDC1', 'Gene', '139341', (46, 52))	('LUSC', 'Disease', 'MESH:D002294', (150, 154))	('LUSC', 'Disease', (150, 154))	('LUSC', 'Phenotype', 'HP:0030359', (150, 154))
43994	31998650	These interactions between tumor cells and infiltrating immune cells help explain the findings from this study indicating that TAMs have a positive correlation with FUNDC1 expression in LIHC and that the high expression of FUNDC1 is associated with a worse LIHC patient prognosis.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('FUNDC1', 'Gene', '139341', (223, 229))	('FUNDC1', 'Gene', '139341', (165, 171))	('LIHC', 'Disease', (186, 190))	('tumor', 'Disease', (27, 32))	('FUNDC1', 'Gene', (165, 171))	('associated with', 'Reg', (233, 248))	('LIHC', 'Disease', 'MESH:D006528', (186, 190))	('TAM', 'Gene', '8205', (127, 130))	('expression', 'MPA', (172, 182))	('FUNDC1', 'Gene', (223, 229))	('patient', 'Species', '9606', (262, 269))	('LIHC', 'Disease', (257, 261))	('LIHC', 'Disease', 'MESH:D006528', (257, 261))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('TAM', 'Gene', (127, 130))	('high expression', 'Var', (204, 219))
44088	30975121	High fatality in this cancer also reduced competing risks from other deaths and risk of exposure change from occurrence of this disease.	('reduced', 'NegReg', (34, 41))	('competing', 'MPA', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('death', 'Disease', 'MESH:D003643', (69, 74))	('death', 'Disease', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('High fatality', 'Var', (0, 13))
44159	33537218	Although infiltration of IgG4-positive cells into the stomach, duodenum, and colon are frequently found in patients with IgG4-RD, low specificity of IgG4 immunostaining of biopsies from the gastrointestinal tract other than the ampulla may limit its clinical use in the diagnosis of IgG4-related pancreatobiliary disease.	('colon', 'Disease', (77, 82))	('IgG4-RD', 'Var', (121, 128))	('pancreatobiliary disease', 'Disease', (296, 320))	('colon', 'Disease', 'MESH:D003110', (77, 82))	('patients', 'Species', '9606', (107, 115))
44234	32127951	Numerous studies show that alterations in expression of genes related to mitotic spindle and mitotic checkpoint are involved in chromosomal instability and tumor progression in various malignancies.	('involved', 'Reg', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('malignancies', 'Disease', 'MESH:D009369', (185, 197))	('expression', 'MPA', (42, 52))	('malignancies', 'Disease', (185, 197))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('chromosomal', 'MPA', (128, 139))	('chromosomal instability', 'Phenotype', 'HP:0040012', (128, 151))	('tumor', 'Disease', (156, 161))	('alterations', 'Var', (27, 38))
44241	32127951	High AURKA mRNA expression was associated with poor survival in cholangiocarcinoma patients within different datasets.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (64, 82))	('High AURKA', 'Var', (0, 10))	('poor', 'NegReg', (47, 51))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('patients', 'Species', '9606', (83, 91))	('cholangiocarcinoma', 'Disease', (64, 82))
44244	32127951	Furthermore, AURKA knockdown by siRNA recapitulated the antitumor effect of Alisertib.	('AURKA', 'Gene', (13, 18))	('knockdown', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('recapitulated', 'NegReg', (38, 51))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('Alisertib', 'Chemical', 'MESH:C550258', (76, 85))
44251	32127951	Many studies show that alterations in expression of genes related to mitotic spindle and mitotic checkpoint are involved in chromosomal instability and tumor progression in various solid and hematologic malignancies.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('involved', 'Reg', (112, 120))	('hematologic malignancies', 'Disease', 'MESH:D019337', (191, 215))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('expression', 'MPA', (38, 48))	('hematologic malignancies', 'Disease', (191, 215))	('tumor', 'Disease', (152, 157))	('chromosomal instability', 'Phenotype', 'HP:0040012', (124, 147))	('alterations', 'Var', (23, 34))	('chromosomal', 'MPA', (124, 135))
44255	32127951	Aberrant Aurora kinase A activity has been implicated in oncogenic transformation through the development of chromosomal instability and tumor cell heterogeneity.	('chromosomal instability', 'Phenotype', 'HP:0040012', (109, 132))	('oncogenic transformation', 'CPA', (57, 81))	('tumor', 'Disease', (137, 142))	('Aberrant', 'Var', (0, 8))	('implicated', 'Reg', (43, 53))	('chromosomal instability', 'CPA', (109, 132))	('Aurora kinase A', 'Gene', (9, 24))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('Aurora kinase A', 'Gene', '6790', (9, 24))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('activity', 'MPA', (25, 33))
44260	32127951	We also found that highly expressed AURKA was a negative prognostic marker of cholangiocarcinoma.	('AURKA', 'Protein', (36, 41))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 96))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (78, 96))	('highly expressed', 'Var', (19, 35))	('cholangiocarcinoma', 'Disease', (78, 96))
44298	32127951	These findings indicate that components of the mitotic spindle checkpoint were broadly dysregulated in human cholangiocarcinoma, and part of those genes may be useful biomarkers for cholangiocarcinoma diagnosis.	('cholangiocarcinoma', 'Disease', (182, 200))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (109, 127))	('human', 'Species', '9606', (103, 108))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (182, 200))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (182, 200))	('genes', 'Var', (147, 152))	('dysregulated', 'Reg', (87, 99))	('cholangiocarcinoma', 'Disease', (109, 127))
44302	32127951	In the South Korea Cohort (GSE107943), Kaplan-Meier survival demonstrated that high AURKA mRNA expression was strongly correlated with reduced disease free survival (DFS) time (P<0.0001) and overall survival (OS) time (P=0.0145) (Fig.	('overall survival', 'CPA', (191, 207))	('reduced', 'NegReg', (135, 142))	('high', 'Var', (79, 83))	('AURKA', 'Gene', (84, 89))	('disease free survival', 'CPA', (143, 164))	('OS', 'Chemical', '-', (209, 211))	('mRNA expression', 'MPA', (90, 105))
44305	32127951	Collectively, these data indicate that highly expressed AURKA may be a negative prognostic factor in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (101, 119))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('AURKA', 'Protein', (56, 61))	('cholangiocarcinoma', 'Disease', (101, 119))	('highly expressed', 'Var', (39, 55))	('negative', 'NegReg', (71, 79))
44323	32127951	Furthermore, treatment with Alisertib for 48 h significantly increased Caspase 3/7 activity, suggesting Alisertib may induce caspase-dependent apoptosis in cholangiocarcinoma cells (Fig.	('activity', 'MPA', (83, 91))	('Caspase 3', 'Gene', (71, 80))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (156, 174))	('Caspase 3', 'Gene', '836', (71, 80))	('Alisertib', 'Chemical', 'MESH:C550258', (28, 37))	('increased', 'PosReg', (61, 70))	('caspase-dependent apoptosis', 'CPA', (125, 152))	('Alisertib', 'Var', (104, 113))	('cholangiocarcinoma', 'Disease', (156, 174))	('induce', 'PosReg', (118, 124))	('Alisertib', 'Chemical', 'MESH:C550258', (104, 113))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (156, 174))
44328	32127951	HCCC9810 and HuCCT1 cells were most sensitive to AURKA knockdown consistent with their response to AURKA inhibitor Alisertib.	('knockdown', 'Var', (55, 64))	('HCCC9810', 'CellLine', 'CVCL:6908', (0, 8))	('AURKA', 'Gene', (49, 54))	('HuCCT1', 'CellLine', 'CVCL:0324', (13, 19))	('Alisertib', 'Chemical', 'MESH:C550258', (115, 124))
44329	32127951	Furthermore, AUKRA silencing caused cell cycle arrest in G2/M phase, induced apoptosis and activated Caspase 3/7 activity in HCCC9810 cells (Fig.	('Caspase 3', 'Gene', '836', (101, 110))	('apoptosis', 'CPA', (77, 86))	('silencing', 'Var', (19, 28))	('AUKRA', 'Gene', (13, 18))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (36, 53))	('activated', 'PosReg', (91, 100))	('HCCC9810', 'CellLine', 'CVCL:6908', (125, 133))	('activity', 'MPA', (113, 121))	('induced', 'Reg', (69, 76))	('cell cycle arrest', 'CPA', (36, 53))	('Caspase 3', 'Gene', (101, 110))
44343	32127951	In this study, we found that AURKA was highly expressed in cholangiocarcinoma and high AURKA expression was a good predictor of poor prognosis in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (146, 164))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (146, 164))	('high', 'Var', (82, 86))	('AURKA', 'Gene', (87, 92))	('cholangiocarcinoma', 'Disease', (59, 77))	('cholangiocarcinoma', 'Disease', (146, 164))	('expression', 'MPA', (93, 103))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (59, 77))	('AURKA', 'Gene', (29, 34))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (59, 77))
44345	32127951	Hence, AURKA expression is associated with enhanced proliferation of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('enhanced', 'PosReg', (43, 51))	('tumor', 'Disease', (69, 74))	('AURKA', 'Gene', (7, 12))	('expression', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
44347	32127951	Alisertib (MLN8237) is an orally available ATP-competitive, highly selective inhibitor of AURKA (40-fold selective for AURKA compared with AURKB).	('ATP', 'Chemical', 'MESH:D000255', (43, 46))	('Alisertib', 'Chemical', 'MESH:C550258', (0, 9))	('AURKA', 'Gene', (90, 95))	('MLN8237', 'Chemical', 'MESH:C550258', (11, 18))	('AURKB', 'Gene', '9212', (139, 144))	('MLN8237', 'Var', (11, 18))	('AURKB', 'Gene', (139, 144))
44357	32127951	AURKA inhibition is attractive in cholangiocarcinoma as it has been shown to interact with and control a variety of proteins that play key roles in cholangiocarcinoma pathogenesis such as STAT3 and Mcl-1.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (148, 166))	('Mcl-1', 'Gene', (198, 203))	('proteins', 'Protein', (116, 124))	('control', 'Reg', (95, 102))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (34, 52))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (34, 52))	('cholangiocarcinoma', 'Disease', (148, 166))	('STAT3', 'Gene', '6774', (188, 193))	('inhibition', 'Var', (6, 16))	('Mcl-1', 'Gene', '4170', (198, 203))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (148, 166))	('interact', 'Interaction', (77, 85))	('STAT3', 'Gene', (188, 193))	('cholangiocarcinoma', 'Disease', (34, 52))
44380	27956969	The combination of Ca 19-9 + CEA markers gave an accuracy of 86% in diagnosis of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (81, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (81, 99))	('Ca 19-9 +', 'Var', (19, 28))	('CEA', 'Gene', (29, 32))	('CEA', 'Gene', '1084', (29, 32))	('cholangiocarcinoma', 'Disease', (81, 99))
44692	22536548	In the Boyden chamber assay, NUPR1 siRNA reduced EGF- or FBS-induced migration by 21.1% and 34.6% respectively, compared to SCR siRNA (Fig.	('reduced', 'NegReg', (41, 48))	('EGF', 'Gene', '1950', (49, 52))	('FBS', 'Disease', 'MESH:D005198', (57, 60))	('EGF', 'Gene', (49, 52))	('FBS', 'Disease', (57, 60))	('NUPR1 siRNA', 'Var', (29, 40))
44695	22536548	In this, NUPR1 siRNA reduced EGF- or FBS-induced invasion by 75.4% and 41.4% respectively, compared to SCR siRNA (Fig.	('reduced', 'NegReg', (21, 28))	('EGF', 'Gene', (29, 32))	('FBS', 'Disease', 'MESH:D005198', (37, 40))	('EGF', 'Gene', '1950', (29, 32))	('FBS', 'Disease', (37, 40))	('NUPR1 siRNA', 'Var', (9, 20))
44706	22536548	Knock-down of NUPR1 in LbetaT2 cells decreased in vivo tumorigenicity and increased expressions of cycle regulators such as p21 and p57.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('LbetaT2', 'CellLine', 'CVCL:0398', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Knock-down', 'Var', (0, 10))	('p21', 'Gene', (124, 127))	('tumor', 'Disease', (55, 60))	('NUPR1', 'Gene', (14, 19))	('increased', 'PosReg', (74, 83))	('p57', 'Gene', '12721', (132, 135))	('p21', 'Gene', '237052', (124, 127))	('p57', 'Gene', (132, 135))	('decreased', 'NegReg', (37, 46))	('expressions', 'MPA', (84, 95))
44713	22536548	Knock-down of NUPR1 in pancreatic cancer cells in vitro decreased migration and invasion while increasing cell adhesion.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('invasion', 'CPA', (80, 88))	('increasing', 'PosReg', (95, 105))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (23, 40))	('Knock-down', 'Var', (0, 10))	('decreased', 'NegReg', (56, 65))	('NUPR1', 'Gene', (14, 19))	('pancreatic cancer', 'Disease', (23, 40))	('pancreatic cancer', 'Disease', 'MESH:D010190', (23, 40))	('cell adhesion', 'CPA', (106, 119))
44720	21448164	CpG-island methylation study of liver fluke-related cholangiocarcinoma Genetic changes have been widely reported in association with cholangiocarcinoma (CCA), while epigenetic changes are poorly characterised.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (52, 70))	('cholangiocarcinoma', 'Disease', (133, 151))	('association', 'Interaction', (116, 127))	('cholangiocarcinoma', 'Disease', (52, 70))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (133, 151))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (133, 151))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (52, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('changes', 'Var', (79, 86))	('CCA', 'Phenotype', 'HP:0030153', (153, 156))	('liver fluke', 'Species', '6192', (32, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
44725	21448164	Patients with methylated DcR1 had significantly longer overall survival (Median; 41.7 vs 21.7 weeks, P=0.027).	('overall survival', 'MPA', (55, 71))	('longer', 'PosReg', (48, 54))	('Patients', 'Species', '9606', (0, 8))	('methylated', 'Var', (14, 24))	('DcR1', 'Gene', '8794', (25, 29))	('DcR1', 'Gene', (25, 29))
44726	21448164	Low-protein expression was found in >70% of CCA with methylation of OPCML or DcR1.	('CCA', 'Disease', (44, 47))	('Low-protein', 'NegReg', (0, 11))	('DcR1', 'Gene', (77, 81))	('OPCML', 'Gene', (68, 73))	('DcR1', 'Gene', '8794', (77, 81))	('OPCML', 'Gene', '4978', (68, 73))	('CCA', 'Phenotype', 'HP:0030153', (44, 47))	('methylation', 'Var', (53, 64))
44727	21448164	Aberrant hypermethylation of certain loci is a common event in liver fluke-related CCA and may potentially contribute to cholangiocarcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (130, 144))	('Aberrant hypermethylation', 'Var', (0, 25))	('carcinogenesis', 'Disease', (130, 144))	('liver fluke', 'Species', '6192', (63, 74))	('CCA', 'Phenotype', 'HP:0030153', (83, 86))	('liver fluke-related CCA', 'Disease', (63, 86))	('contribute to', 'Reg', (107, 120))
44747	21448164	Like other tumours, CCA is a result of a multistep process in which genetic and epigenetic aberrations of regulatory genes are accumulated.	('CCA', 'Phenotype', 'HP:0030153', (20, 23))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('CCA', 'Disease', (20, 23))	('tumours', 'Disease', 'MESH:D009369', (11, 18))	('epigenetic aberrations', 'Var', (80, 102))	('tumours', 'Disease', (11, 18))
44748	21448164	For instance, genetic alterations of K-ras and p53 have frequently been reported in CCA.	('genetic alterations', 'Var', (14, 33))	('CCA', 'Phenotype', 'HP:0030153', (84, 87))	('CCA', 'Disease', (84, 87))	('K-ras', 'Gene', (37, 42))	('K-ras', 'Gene', '3845', (37, 42))	('reported', 'Reg', (72, 80))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))
44749	21448164	Aberrant DNA methylation at CpG-islands associated with transcriptional silencing is widely observed in cancers.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Aberrant DNA methylation', 'Var', (0, 24))	('transcriptional', 'MPA', (56, 71))	('silencing', 'NegReg', (72, 81))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
44751	21448164	Hypermethylation in CCA has been reported in tumour suppressor genes related to cell cycle (p16, 14-3-3sigma, p73, p14, p15), apoptosis (DAPK, SEMA3B) and cell adhesion (APC, E-cadherin, TIMP3, THBS1).	('14-3-3sigma', 'Gene', '2810', (97, 108))	('p16', 'Gene', (92, 95))	('TIMP3', 'Gene', (187, 192))	('TIMP3', 'Gene', '7078', (187, 192))	('Hypermethylation', 'Var', (0, 16))	('apoptosis', 'CPA', (126, 135))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('p16', 'Gene', '1029', (92, 95))	('p14', 'Gene', '1029', (115, 118))	('tumour', 'Disease', (45, 51))	('DAPK', 'Gene', (137, 141))	('p15', 'Gene', (120, 123))	('SEMA3B', 'Gene', '7869', (143, 149))	('p14', 'Gene', (115, 118))	('cell cycle', 'CPA', (80, 90))	('DAPK', 'Gene', '1612', (137, 141))	('SEMA3B', 'Gene', (143, 149))	('E-cadherin', 'Gene', (175, 185))	('cell adhesion', 'CPA', (155, 168))	('E-cadherin', 'Gene', '999', (175, 185))	('p15', 'Gene', '1030', (120, 123))	('APC', 'Disease', 'MESH:D011125', (170, 173))	('APC', 'Disease', (170, 173))	('CCA', 'Phenotype', 'HP:0030153', (20, 23))	('p73', 'Gene', '7161', (110, 113))	('p73', 'Gene', (110, 113))	('THBS1', 'Gene', (194, 199))	('CCA', 'Disease', (20, 23))	('THBS1', 'Gene', '7057', (194, 199))	('14-3-3sigma', 'Gene', (97, 108))
44752	21448164	Furthermore, several reports demonstrated hypermethylation of genes involved in DNA repair and carcinogen metabolism, such as hMLH1, MGMT and GSTP1.	('GSTP1', 'Gene', '2950', (142, 147))	('hypermethylation', 'Var', (42, 58))	('hMLH1', 'Gene', (126, 131))	('hMLH1', 'Gene', '4292', (126, 131))	('GSTP1', 'Gene', (142, 147))	('MGMT', 'Gene', '4255', (133, 137))	('MGMT', 'Gene', (133, 137))
44754	21448164	Methylation-specific PCR provides a relatively simple and cost-effective assay that can be used to assess methylation in clinical samples, however, for loci of interest, we have confirmed methylation status by bisulfite pyrosequencing or combined bisulfite restriction analysis (COBRA).	('methylation', 'Var', (188, 199))	('clinical samples', 'Species', '191496', (121, 137))	('confirmed', 'Reg', (178, 187))	('bisulfite', 'Chemical', 'MESH:C042345', (247, 256))	('bisulfite', 'Chemical', 'MESH:C042345', (210, 219))
44781	21448164	The CpG-islands with high frequency of methylation in CCA included 14-3-3sigma, OPCML, SFRP1, HIC1, PTEN and DcR1 (81.4, 72.5, 63.7, 38.2, 35.3 and 28.4%, respectively).	('PTEN', 'Gene', (100, 104))	('SFRP1', 'Gene', '6422', (87, 92))	('OPCML', 'Gene', (80, 85))	('PTEN', 'Gene', '5728', (100, 104))	('methylation', 'Var', (39, 50))	('14-3-3sigma', 'Gene', '2810', (67, 78))	('SFRP1', 'Gene', (87, 92))	('CCA', 'Disease', (54, 57))	('DcR1', 'Gene', '8794', (109, 113))	('OPCML', 'Gene', '4978', (80, 85))	('DcR1', 'Gene', (109, 113))	('HIC1', 'Gene', (94, 98))	('HIC1', 'Gene', '3090', (94, 98))	('CCA', 'Phenotype', 'HP:0030153', (54, 57))	('14-3-3sigma', 'Gene', (67, 78))
44785	21448164	After excluding 14-3-3sigma, 91% (93 out of 102) of CCA samples were methylated in at least one locus out of the 14 loci (OPCML, SFRP1, HIC1, PTEN, DcR1, MINT25, p16, RASSF1A, BLU, DAPK, CASP8, FAS, MGMT and p73).	('CCA', 'Disease', (52, 55))	('PTEN', 'Gene', '5728', (142, 146))	('14-3-3sigma', 'Gene', '2810', (16, 27))	('DAPK', 'Gene', '1612', (181, 185))	('SFRP1', 'Gene', '6422', (129, 134))	('p16', 'Gene', (162, 165))	('OPCML', 'Gene', '4978', (122, 127))	('MGMT', 'Gene', '4255', (199, 203))	('HIC1', 'Gene', (136, 140))	('p16', 'Gene', '1029', (162, 165))	('DcR1', 'Gene', (148, 152))	('FAS', 'Chemical', 'MESH:C038178', (194, 197))	('BLU', 'Gene', (176, 179))	('DcR1', 'Gene', '8794', (148, 152))	('HIC1', 'Gene', '3090', (136, 140))	('RASSF1A', 'Gene', '11186', (167, 174))	('p73', 'Gene', '7161', (208, 211))	('methylated', 'Var', (69, 79))	('p73', 'Gene', (208, 211))	('CASP8', 'Gene', '841', (187, 192))	('MGMT', 'Gene', (199, 203))	('BLU', 'Gene', '51364', (176, 179))	('PTEN', 'Gene', (142, 146))	('SFRP1', 'Gene', (129, 134))	('RASSF1A', 'Gene', (167, 174))	('DAPK', 'Gene', (181, 185))	('OPCML', 'Gene', (122, 127))	('CCA', 'Phenotype', 'HP:0030153', (52, 55))	('CASP8', 'Gene', (187, 192))	('14-3-3sigma', 'Gene', (16, 27))
44791	21448164	In addition, methylation of OPCML was found more frequently in less differentiated type (88% 22 out of 25) than in the well-differentiated types of CCA (67.6% 50 out of 74) (P=0.047).	('OPCML', 'Gene', '4978', (28, 33))	('methylation', 'Var', (13, 24))	('less differentiated type', 'Disease', (63, 87))	('CCA', 'Phenotype', 'HP:0030153', (148, 151))	('OPCML', 'Gene', (28, 33))	('found', 'Reg', (38, 43))
44796	21448164	In the present study, DcR1 CpG island methylation was observed in 28.4% of CCA.	('methylation', 'Var', (38, 49))	('CCA', 'Disease', (75, 78))	('observed', 'Reg', (54, 62))	('DcR1', 'Gene', '8794', (22, 26))	('DcR1', 'Gene', (22, 26))	('CCA', 'Phenotype', 'HP:0030153', (75, 78))
44797	21448164	Interestingly, patients with methylated DcR1 showed longer overall survival than those without (Median; 41.7 vs 21.7 weeks, P=0.027), Figure 4.	('patients', 'Species', '9606', (15, 23))	('DcR1', 'Gene', '8794', (40, 44))	('longer', 'PosReg', (52, 58))	('DcR1', 'Gene', (40, 44))	('methylated', 'Var', (29, 39))	('overall survival', 'MPA', (59, 75))
44798	21448164	The significance of methylated DcR1 on survival raised the question on the role of methylation status of other TRAIL-related genes in CCA.	('methylated', 'Var', (20, 30))	('DcR1', 'Gene', '8794', (31, 35))	('CCA', 'Phenotype', 'HP:0030153', (134, 137))	('TRAIL', 'Gene', '8743', (111, 116))	('DcR1', 'Gene', (31, 35))	('TRAIL', 'Gene', (111, 116))	('CCA', 'Disease', (134, 137))
44801	21448164	Moreover, a trend of correlation of methylation in CpG1 with patient survival was observed (P=0.08, data not shown), similar to that of MSP.	('patient', 'Species', '9606', (61, 68))	('correlation', 'Interaction', (21, 32))	('CpG1', 'Gene', (51, 55))	('patient survival', 'CPA', (61, 77))	('methylation', 'Var', (36, 47))
44807	21448164	However, association of methylated OPCML and DcR1 with patient clinicopathological data supports their role in tumour progression.	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('OPCML', 'Gene', '4978', (35, 40))	('methylated', 'Var', (24, 34))	('association', 'Interaction', (9, 20))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('patient', 'Species', '9606', (55, 62))	('DcR1', 'Gene', '8794', (45, 49))	('tumour', 'Disease', (111, 117))	('OPCML', 'Gene', (35, 40))	('DcR1', 'Gene', (45, 49))
44811	21448164	The OPCML hypermethylation has been reported in several cancers for example, 33.3% of late stage ovarian cancer, 70% of hepatocellular carcinoma, 63.9% of invasive cervical cancer and 57-100% of multiple carcinomas and lymphomas.	('hypermethylation', 'Var', (10, 26))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('late stage ovarian cancer', 'Disease', (86, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('hepatocellular carcinoma', 'Disease', (120, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('lymphomas', 'Phenotype', 'HP:0002665', (219, 228))	('carcinomas and lymphomas', 'Disease', 'MESH:D008223', (204, 228))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('invasive cervical cancer', 'Disease', (155, 179))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancers', 'Disease', (56, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('OPCML', 'Gene', (4, 9))	('invasive cervical cancer', 'Disease', 'MESH:D002583', (155, 179))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (120, 144))	('late stage ovarian cancer', 'Disease', 'MESH:D010051', (86, 111))	('reported', 'Reg', (36, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (120, 144))	('OPCML', 'Gene', '4978', (4, 9))
44812	21448164	We are the first to report OPCML methylation in CCA with high frequency (72.5%) with no methylation in normal adjacent tissue.	('methylation', 'Var', (33, 44))	('OPCML', 'Gene', '4978', (27, 32))	('CCA', 'Phenotype', 'HP:0030153', (48, 51))	('OPCML', 'Gene', (27, 32))	('CCA', 'Disease', (48, 51))
44815	21448164	The highly frequent methylation of SFRP1, HIC1 and PTEN could lead to an increase in proliferation, inhibition of apoptosis and promotion of survival advantage in CCA through increased Wnt/beta-catenin signal transduction through the impaired p53-responsive pathway and activated PI3K and its downstream effectors as previously reported in other cancers.	('HIC1', 'Gene', (42, 46))	('PTEN', 'Gene', (51, 55))	('SFRP1', 'Gene', '6422', (35, 40))	('HIC1', 'Gene', '3090', (42, 46))	('promotion', 'PosReg', (128, 137))	('cancers', 'Disease', 'MESH:D009369', (346, 353))	('proliferation', 'CPA', (85, 98))	('inhibition', 'NegReg', (100, 110))	('PTEN', 'Gene', '5728', (51, 55))	('beta-catenin', 'Gene', (189, 201))	('beta-catenin', 'Gene', '1499', (189, 201))	('CCA', 'Phenotype', 'HP:0030153', (163, 166))	('methylation', 'Var', (20, 31))	('p53', 'Gene', '7157', (243, 246))	('increased', 'PosReg', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('apoptosis', 'CPA', (114, 123))	('CCA', 'Disease', (163, 166))	('PI3K', 'Pathway', (280, 284))	('increase', 'PosReg', (73, 81))	('activated', 'PosReg', (270, 279))	('survival advantage', 'CPA', (141, 159))	('cancers', 'Phenotype', 'HP:0002664', (346, 353))	('cancers', 'Disease', (346, 353))	('p53', 'Gene', (243, 246))	('SFRP1', 'Gene', (35, 40))
44816	21448164	The defect of programmed cell death through p53-dependent pathway has been observed in CCA with mutational inactivation (41.6%) and LOH of p53 (32%) as shown in our previous studies together with p53 deacetylation because of HIC1 methylation (38.2%) in this study.	('HIC1', 'Gene', '3090', (225, 229))	('defect', 'NegReg', (4, 10))	('deacetylation', 'MPA', (200, 213))	('CCA', 'Phenotype', 'HP:0030153', (87, 90))	('p53', 'Gene', (44, 47))	('p53', 'Gene', (139, 142))	('p53', 'Gene', '7157', (44, 47))	('p53', 'Gene', '7157', (139, 142))	('LOH', 'Var', (132, 135))	('mutational inactivation', 'Var', (96, 119))	('p53', 'Gene', '7157', (196, 199))	('HIC1', 'Gene', (225, 229))	('p53', 'Gene', (196, 199))	('programmed cell death', 'CPA', (14, 35))	('CCA', 'Disease', (87, 90))
44820	21448164	Hypermethylation of DcR1 (28.4%), but not death receptors (DR4 and DR5) and other TRAIL signalling-related genes (APAF1, CASP8 and DcR2) in our study indicates the potential use of recombinant TRAIL or TRAIL receptor agonistic monoclonal antibodies as selective anti-tumour therapy in CCA.	('DcR2', 'Gene', '8793', (131, 135))	('tumour', 'Disease', (267, 273))	('TRAIL', 'Gene', '8743', (202, 207))	('Hypermethylation', 'Var', (0, 16))	('TRAIL', 'Gene', '8743', (193, 198))	('CASP8', 'Gene', (121, 126))	('DcR2', 'Gene', (131, 135))	('TRAIL', 'Gene', (82, 87))	('CCA', 'Phenotype', 'HP:0030153', (285, 288))	('TRAIL', 'Gene', (202, 207))	('DR4', 'Gene', (59, 62))	('TRAIL', 'Gene', (193, 198))	('DcR1', 'Gene', (20, 24))	('CCA', 'Disease', (285, 288))	('APAF1', 'Gene', '317', (114, 119))	('DR4', 'Gene', '8797', (59, 62))	('DR5', 'Gene', '8795', (67, 70))	('DcR1', 'Gene', '8794', (20, 24))	('APAF1', 'Gene', (114, 119))	('DR5', 'Gene', (67, 70))	('TRAIL', 'Gene', '8743', (82, 87))	('CASP8', 'Gene', '841', (121, 126))	('tumour', 'Phenotype', 'HP:0002664', (267, 273))	('tumour', 'Disease', 'MESH:D009369', (267, 273))
44822	21448164	Previous studies showed correlation of methylated DcR1 with improved prognosis in malignant mesothelioma and prostate cancer.	('DcR1', 'Gene', '8794', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('DcR1', 'Gene', (50, 54))	('malignant mesothelioma and prostate cancer', 'Disease', 'MESH:C562839', (82, 124))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (82, 104))	('improved', 'PosReg', (60, 68))	('methylated', 'Var', (39, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (109, 124))
44823	21448164	As longer overall survival was observed in methylated DcR1 patients, DcR1 methylation may be useful as a prognostic marker of CCA.	('DcR1', 'Gene', (69, 73))	('CCA', 'Phenotype', 'HP:0030153', (126, 129))	('longer', 'PosReg', (3, 9))	('DcR1', 'Gene', '8794', (54, 58))	('DcR1', 'Gene', (54, 58))	('patients', 'Species', '9606', (59, 67))	('CCA', 'Disease', (126, 129))	('overall survival', 'MPA', (10, 26))	('DcR1', 'Gene', '8794', (69, 73))	('methylated', 'Var', (43, 53))
44824	21448164	In conclusion, promoter hypermethylation has been observed in many genes, which have important roles in carcinogenesis and progression of liver fluke-related CCA.	('CCA', 'Phenotype', 'HP:0030153', (158, 161))	('promoter hypermethylation', 'Var', (15, 40))	('liver fluke', 'Species', '6192', (138, 149))	('liver fluke-related CCA', 'Disease', (138, 161))	('CCA', 'Disease', (158, 161))	('carcinogenesis', 'Disease', 'MESH:D063646', (104, 118))	('carcinogenesis', 'Disease', (104, 118))
44827	19128511	Inhibition of PI3K increases oxaliplatin sensitivity in cholangiocarcinoma cells Resistance of cholangiocarcinoma to chemotherapy is a major problem in cancer treatment.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (95, 113))	('oxaliplatin sensitivity', 'MPA', (29, 52))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (95, 113))	('cholangiocarcinoma', 'Disease', (56, 74))	('increases', 'PosReg', (19, 28))	('PI3K', 'Gene', (14, 18))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (56, 74))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (29, 40))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (56, 74))	('cholangiocarcinoma', 'Disease', (95, 113))
44834	19128511	The combination of oxaliplatin with LY294002, an inhibitor of PI3K, resulted in a remarkable arrest of cell proliferation.	('LY294002', 'Chemical', 'MESH:C085911', (36, 44))	('arrest', 'Disease', 'MESH:D006323', (93, 99))	('cell proliferation', 'CPA', (103, 121))	('LY294002', 'Var', (36, 44))	('arrest', 'Disease', (93, 99))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (19, 30))	('combination', 'Interaction', (4, 15))
44837	19128511	Activation of PI3K might protect cholangiocarcinoma cells from oxaliplatininduced cytotoxicity.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (33, 51))	('cytotoxicity', 'Disease', (82, 94))	('PI3K', 'Var', (14, 18))	('oxaliplatininduced', 'Chemical', '-', (63, 81))	('cholangiocarcinoma', 'Disease', (33, 51))	('cytotoxicity', 'Disease', 'MESH:D064420', (82, 94))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (33, 51))
44852	19128511	In this study, we hypothesize that inhibition of PI3K or its downstream target, mTOR, may be increase oxaliplatin efficacy in treating cholangiocarcinoma.	('increase', 'PosReg', (93, 101))	('mTOR', 'Gene', (80, 84))	('mTOR', 'Gene', '2475', (80, 84))	('cholangiocarcinoma', 'Disease', (135, 153))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (102, 113))	('PI3K', 'Gene', (49, 53))	('inhibition', 'Var', (35, 45))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (135, 153))	('oxaliplatin', 'MPA', (102, 113))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (135, 153))
44863	19128511	For the Akt or mTOR inhibition studies, cells were treated with Vehicle (DMSO), LY294002 (PI3K inhibitor) or RAD001 (mTOR inhibitor), respectively, for 1 hour before the addition of oxaliplatin.	('LY294002', 'Chemical', 'MESH:C085911', (80, 88))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (182, 193))	('mTOR', 'Gene', (117, 121))	('mTOR', 'Gene', '2475', (117, 121))	('Akt', 'Gene', (8, 11))	('RAD001', 'Var', (109, 115))	('mTOR', 'Gene', (15, 19))	('mTOR', 'Gene', '2475', (15, 19))	('LY294002', 'Var', (80, 88))	('DMSO', 'Chemical', 'MESH:D004121', (73, 77))	('Akt', 'Gene', '207', (8, 11))
44873	19128511	For KKU100, the inhibition of cell proliferation was 8.1% +- 3.31 and 15.6% +- 3.30 in cells treated with 100 and 200 muM of oxaliplatin, respectively (Figs.	('KKU100', 'Var', (4, 10))	('cell proliferation', 'CPA', (30, 48))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (125, 136))	('inhibition', 'NegReg', (16, 26))	('muM', 'Gene', '56925', (118, 121))	('muM', 'Gene', (118, 121))
44879	19128511	To evaluate the effect of the PI3K pathway on oxaliplatin resistance, cholangiocarcinoma cells were treated with specific inhibitors of PI3K (LY294002) and mTOR (RAD001), with or without oxaliplatin.	('LY294002', 'Var', (142, 150))	('PI3K', 'Gene', (136, 140))	('cholangiocarcinoma', 'Disease', (70, 88))	('mTOR', 'Gene', (156, 160))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (187, 198))	('mTOR', 'Gene', '2475', (156, 160))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (46, 57))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (70, 88))	('LY294002', 'Chemical', 'MESH:C085911', (142, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))
44881	19128511	When treated with LY294002, the cells clearly exhibit lower levels of Akt and P70S6K phosphorylation compared to what is seen under control conditions.	('P70S6K', 'Gene', '6198', (78, 84))	('Akt', 'Gene', (70, 73))	('LY294002', 'Var', (18, 26))	('P70S6K', 'Gene', (78, 84))	('Akt', 'Gene', '207', (70, 73))	('LY294002', 'Chemical', 'MESH:C085911', (18, 26))	('lower', 'NegReg', (54, 59))
44882	19128511	RAD001 also significantly reduced the phosphorylation of P70S6K, but it increased the phosphorylation of Akt (Figs.	('Akt', 'Gene', '207', (105, 108))	('increased', 'PosReg', (72, 81))	('phosphorylation', 'MPA', (38, 53))	('P70S6K', 'Gene', (57, 63))	('Akt', 'Gene', (105, 108))	('phosphorylation', 'MPA', (86, 101))	('reduced', 'NegReg', (26, 33))	('RAD001', 'Var', (0, 6))	('P70S6K', 'Gene', '6198', (57, 63))
44884	19128511	Cholangiocarcinoma cells were pretreated with either 10 muM LY294002 or 0.5 muM RAD001 for 1 hour, followed by incubation with 0-200 muM oxaliplatin.	('muM', 'Gene', (133, 136))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (137, 148))	('LY294002', 'Chemical', 'MESH:C085911', (60, 68))	('muM', 'Gene', '56925', (133, 136))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (0, 18))	('muM', 'Gene', '56925', (56, 59))	('muM', 'Gene', '56925', (76, 79))	('LY294002', 'Var', (60, 68))	('muM', 'Gene', (56, 59))	('muM', 'Gene', (76, 79))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 18))	('Cholangiocarcinoma', 'Disease', (0, 18))
44885	19128511	Pretreatment with LY294002 resulted in a two-fold increase in the percentage of inhibition of cell proliferation at both 100 and 200 muM of oxaliplatin when compared to the control (RMCCA1; from 14.1% +- 3.76 to 35.1% +- 5.14 at 100 muM oxaliplatin; p = 0.002 and from 28.6% +- 7.25 to 57.4% +- 7.19 at 200 muM oxaliplatin; p = 0.004 and KKU100; from 8.1% +- 2.33 to 20.7% +- 1.98 at 100 muM oxaliplatin; p = 0.09 and from 15.5% +- 4.02 to 30.7% +- 5.10 at 200 muM oxaliplatin; p = 0.01, (Figs.	('inhibition', 'NegReg', (80, 90))	('muM', 'Gene', (233, 236))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (140, 151))	('LY294002', 'Var', (18, 26))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (465, 476))	('muM', 'Gene', '56925', (388, 391))	('muM', 'Gene', (388, 391))	('muM', 'Gene', '56925', (461, 464))	('increase', 'PosReg', (50, 58))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (392, 403))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (311, 322))	('muM', 'Gene', '56925', (133, 136))	('LY294002', 'Chemical', 'MESH:C085911', (18, 26))	('cell proliferation', 'CPA', (94, 112))	('muM', 'Gene', (461, 464))	('muM', 'Gene', (133, 136))	('muM', 'Gene', '56925', (307, 310))	('muM', 'Gene', (307, 310))	('muM', 'Gene', '56925', (233, 236))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (237, 248))
44888	19128511	In order to determine the mechanism by which LY294002 and RAD001 increase oxaliplatin-induced cytotoxicity, TUNEL apoptosis assays were performed.	('increase', 'PosReg', (65, 73))	('LY294002', 'Var', (45, 53))	('RAD001', 'Gene', (58, 64))	('cytotoxicity', 'Disease', 'MESH:D064420', (94, 106))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (74, 85))	('LY294002', 'Chemical', 'MESH:C085911', (45, 53))	('cytotoxicity', 'Disease', (94, 106))
44889	19128511	10 muM LY294002, 0.5 muM RAD001 or control vehicle (DMSO) were added to RMCCA1 cholangiocarcinoma cells, followed by treatment of the cells with 0-200 muM oxaliplatin for 48 hours.	('muM', 'Gene', '56925', (3, 6))	('muM', 'Gene', '56925', (151, 154))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (155, 166))	('muM', 'Gene', '56925', (21, 24))	('cholangiocarcinoma', 'Disease', (79, 97))	('RMCCA1', 'Gene', (72, 78))	('muM', 'Gene', (3, 6))	('LY294002', 'Var', (7, 15))	('muM', 'Gene', (151, 154))	('muM', 'Gene', (21, 24))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (79, 97))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (79, 97))	('LY294002', 'Chemical', 'MESH:C085911', (7, 15))	('DMSO', 'Chemical', 'MESH:D004121', (52, 56))
44890	19128511	Exposure to either LY294002 or RAD001 alone did not significantly alter the number of RMCCA1 apoptotic cells when compared to the control.	('LY294002', 'Var', (19, 27))	('RAD001', 'Gene', (31, 37))	('LY294002', 'Chemical', 'MESH:C085911', (19, 27))
44891	19128511	However, the combination of LY294002 with 100-200 muM oxaliplatin significantly increased the number of apoptotic cells (from 21.8% +- 7.33 to 45.6% +- 6.13 at 100 muM oxaliplatin; p = 0.008 and from 34.5% +- 6.72 to 62.4% +- 6.68 at 200 muM oxaliplatin; p = 0.004).	('oxaliplatin', 'Chemical', 'MESH:D000077150', (168, 179))	('LY294002', 'Var', (28, 36))	('muM', 'Gene', (164, 167))	('increased', 'PosReg', (80, 89))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (242, 253))	('muM', 'Gene', '56925', (238, 241))	('muM', 'Gene', '56925', (50, 53))	('muM', 'Gene', (238, 241))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (54, 65))	('LY294002', 'Chemical', 'MESH:C085911', (28, 36))	('muM', 'Gene', (50, 53))	('muM', 'Gene', '56925', (164, 167))
44894	19128511	3C, the level of cleaved caspase-3 was very low in cholangiocarcinoma cells treated with 10 muM of LY294002, 0.5 muM of RAD001 or oxaliplatin alone.	('muM', 'Gene', (113, 116))	('low', 'NegReg', (44, 47))	('muM', 'Gene', (92, 95))	('LY294002', 'Var', (99, 107))	('cholangiocarcinoma', 'Disease', (51, 69))	('caspase-3', 'Gene', '836', (25, 34))	('LY294002', 'Chemical', 'MESH:C085911', (99, 107))	('muM', 'Gene', '56925', (113, 116))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (130, 141))	('muM', 'Gene', '56925', (92, 95))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (51, 69))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (51, 69))	('caspase-3', 'Gene', (25, 34))
44895	19128511	On the other hand, the level of cleaved caspase-3 was increased in cholangiocarcinoma cells treated with LY294002 in combination with 100 or 200 muM of oxaliplatin.	('muM', 'Gene', '56925', (145, 148))	('LY294002', 'Chemical', 'MESH:C085911', (105, 113))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('caspase-3', 'Gene', (40, 49))	('increased', 'PosReg', (54, 63))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (152, 163))	('LY294002', 'Var', (105, 113))	('muM', 'Gene', (145, 148))	('cholangiocarcinoma', 'Disease', (67, 85))	('level', 'MPA', (23, 28))	('caspase-3', 'Gene', '836', (40, 49))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))
44907	19128511	Our results indeed showed that inhibition of Akt by LY294002 significantly increased oxaliplatin efficacy in inhibiting cell proliferation.	('cell proliferation', 'CPA', (120, 138))	('Akt', 'Gene', (45, 48))	('inhibiting', 'NegReg', (109, 119))	('LY294002', 'Var', (52, 60))	('Akt', 'Gene', '207', (45, 48))	('oxaliplatin', 'MPA', (85, 96))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (85, 96))	('increased', 'PosReg', (75, 84))	('LY294002', 'Chemical', 'MESH:C085911', (52, 60))
44914	19128511	In this study, we demonstrate that inhibition of Akt by LY294002 increases the percentage of apoptotic cells after oxaliplatin treatment.	('increases', 'PosReg', (65, 74))	('LY294002', 'Chemical', 'MESH:C085911', (56, 64))	('LY294002', 'Var', (56, 64))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (115, 126))	('Akt', 'Gene', '207', (49, 52))	('inhibition', 'NegReg', (35, 45))	('Akt', 'Gene', (49, 52))
44915	19128511	In addition, activation of caspase-3 was clearly observed in cholangiocarcinoma cells treated with both LY294002 and oxaliplatin.	('caspase-3', 'Gene', (27, 36))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 79))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (117, 128))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('LY294002', 'Var', (104, 112))	('caspase-3', 'Gene', '836', (27, 36))	('activation', 'PosReg', (13, 23))	('LY294002', 'Chemical', 'MESH:C085911', (104, 112))	('cholangiocarcinoma', 'Disease', (61, 79))
44918	19128511	Inactivation of PI3K and Akt may have deleterious effects on normal cell metabolism.	('PI3K', 'Pathway', (16, 20))	('normal cell metabolism', 'MPA', (61, 83))	('Akt', 'Gene', '207', (25, 28))	('effects', 'Reg', (50, 57))	('Akt', 'Gene', (25, 28))	('Inactivation', 'Var', (0, 12))
44932	19128511	In addition, the number of apoptotic cells and the activation of caspase-3 did not significantly increase when the cells were exposed to both RAD001 and oxaliplatin.	('caspase-3', 'Gene', (65, 74))	('caspase-3', 'Gene', '836', (65, 74))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (153, 164))	('RAD001', 'Var', (142, 148))
44935	19128511	These results are consistent with the recent report that inhibition of mTOR resulted in Akt activation in several human cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Akt', 'Gene', '207', (88, 91))	('inhibition', 'Var', (57, 67))	('activation', 'PosReg', (92, 102))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('mTOR', 'Gene', '2475', (71, 75))	('Akt', 'Gene', (88, 91))	('mTOR', 'Gene', (71, 75))	('human', 'Species', '9606', (114, 119))
44943	34034689	We identified and constructed a 4-lncRNA (AC138430.1, AGAP2-AS1, AP001783.1, and AP005233.2) prognostic signature using regression analysis, and it had the capability to independently predict prognosis.	('AS1', 'Gene', (60, 63))	('AGAP2', 'Gene', '116986', (54, 59))	('AP001783.1', 'Var', (65, 75))	('AP005233.2', 'Var', (81, 91))	('AS1', 'Gene', '5729', (60, 63))	('AGAP2', 'Gene', (54, 59))
44991	34034689	In this study, four survival-related and metabolism-related lncRNAs (AC138430.1, AGAP2-AS1, AP001783.1, and AP005233.2) were identified for prognosis prediction in patients with intrahepatic cholangiocarcinoma based on transcriptome data from public databases, and were verified in an independent cohort via quantitative real-time PCR.	('AS1', 'Gene', '5729', (87, 90))	('AS1', 'Gene', (87, 90))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (178, 209))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (191, 209))	('intrahepatic cholangiocarcinoma', 'Disease', (178, 209))	('AGAP2', 'Gene', '116986', (81, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('AGAP2', 'Gene', (81, 86))	('patients', 'Species', '9606', (164, 172))	('AP005233.2', 'Var', (108, 118))
44997	34034689	Consequently, the mechanism of AP005233.2 in intrahepatic cholangiocarcinoma or other tumours also needs further investigation.	('AP005233.2', 'Var', (31, 41))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (45, 76))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('intrahepatic cholangiocarcinoma', 'Disease', (45, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumours', 'Disease', (86, 93))
45006	34034689	We identified and validated a 4-lncRNA (AC138430.1, AGAP2-AS1, AP001783.1, and AP005233.2) prognostic signature that had a good predictive capability for prognosis in patients with intrahepatic cholangiocarcinoma.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (181, 212))	('AGAP2', 'Gene', (52, 57))	('patients', 'Species', '9606', (167, 175))	('intrahepatic cholangiocarcinoma', 'Disease', (181, 212))	('AS1', 'Gene', (58, 61))	('AP005233.2', 'Var', (79, 89))	('AS1', 'Gene', '5729', (58, 61))	('AGAP2', 'Gene', '116986', (52, 57))	('AP001783.1', 'Var', (63, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (194, 212))
45118	33332768	Cancer treatment has been hampered by tumor heterogeneity, attributed to patient-specific somatic mutations and epigenetic changes.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('epigenetic changes', 'Var', (112, 130))	('tumor', 'Disease', (38, 43))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('patient', 'Species', '9606', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
45197	33332768	Raw files were converted to FASTQ files using bcl2fastq package, and to obtain the UMI counts, fastq reads were aligned to the human reference genome (GRCh38.91) using zUMI package (Parekh et al, 2018) with the following parameters: RD1 16bp, RD2 66bp with a barcode (i7) length of 8 bp.	('human', 'Species', '9606', (127, 132))	('bcl2', 'Gene', (46, 50))	('bcl2', 'Gene', '596', (46, 50))	('RD2 66bp', 'Var', (243, 251))	('RD1 16bp', 'Var', (233, 241))
45341	31346577	Several small studies showed promising results of adjuvant chemotherapy with S-119, 100, 101 or GEM plus cisplatin102 or GEM plus cisplatin plus 5-fluorouracil.103 Several RCT of adjuvant chemotherapy for resected BTC are ongoing; for example, PRODIGE12-ACCORD 18 (GEM plus oxaliplatin; Edeline J, 2017, unpublished data), ASCOT (S-1),104 ACTICCA-1 (NCT02170090; GEM plus cisplatin), NCT02798510 (GEM + cape + radiation vs GEM + cape), and NCT02548195 (GEMOX vs Cape).	('cisplatin', 'Chemical', 'MESH:D002945', (372, 381))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('BTC', 'Phenotype', 'HP:0100574', (214, 217))	('NCT02170090;', 'Var', (350, 362))	('NCT02548195', 'Var', (440, 451))	('NCT02798510', 'Var', (384, 395))	('Cape', 'Chemical', 'MESH:D000069287', (462, 466))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))
45342	31346577	Kobayashi et al105 investigated the impact of neoadjuvant chemoradiation therapy with full-dose GEM and radiation, and reported that the RFS of patients who received NAT was better than that of patients without (3-year RFS: 78% vs 58%, P = 0.0263).	('patients', 'Species', '9606', (144, 152))	('RFS', 'MPA', (137, 140))	('NAT', 'Var', (166, 169))	('patients', 'Species', '9606', (194, 202))
45404	23894567	Hepatocytes and cholangiocytes develop from the same progenitor cells; therefore, the same oncogenic process induced by hepatitis B and hepatitis C in the development of hepatocellular carcinoma may also induce the occurrence of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (229, 247))	('hepatitis B', 'Disease', 'MESH:D006509', (120, 131))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (229, 247))	('hepatitis', 'Var', (136, 145))	('men', 'Species', '9606', (162, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (170, 194))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (170, 194))	('hepatitis B', 'Disease', (120, 131))	('induce', 'Reg', (204, 210))	('hepatocellular carcinoma', 'Disease', (170, 194))	('cholangiocarcinoma', 'Disease', (229, 247))	('hepatitis', 'Phenotype', 'HP:0012115', (120, 129))	('hepatitis', 'Phenotype', 'HP:0012115', (136, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
45421	23894567	reported a high correlation between the presence of H. Pylori in the stomach and in the bile, and H. Pylori in the bile was associated with cholangiocarcinoma.	('H. Pylori', 'Var', (98, 107))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (140, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('H. Pylori', 'Species', '210', (52, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (140, 158))	('H. Pylori', 'Var', (52, 61))	('associated', 'Reg', (124, 134))	('H. Pylori', 'Species', '210', (98, 107))	('cholangiocarcinoma', 'Disease', (140, 158))
45422	23894567	A meta-analysis of 10 case-control studies, which included 205 hepatobiliary tract cancer cases and 263 controls, reported an increased risk of hepatobiliary tract cancer associated with Helicobacter species.	('hepatobiliary tract cancer', 'Disease', 'MESH:D004066', (63, 89))	('hepatobiliary tract cancer', 'Disease', (144, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Helicobacter species', 'Var', (187, 207))	('hepatobiliary tract cancer', 'Disease', (63, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Helicobacter', 'Species', '210', (187, 199))	('hepatobiliary tract cancer', 'Disease', 'MESH:D004066', (144, 170))
45433	23894567	Variations in the estrogen receptor genes were associated with risk of cholangiocarcinoma, supporting the role of estrogen.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (71, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (71, 89))	('Variations', 'Var', (0, 10))	('cholangiocarcinoma', 'Disease', (71, 89))	('associated', 'Reg', (47, 57))	('estrogen receptor genes', 'Gene', (18, 41))
45435	23894567	Levels of plasma testosterone and polymorphisms of genes on the androgen signaling pathway have been shown to influence the risk of hepatocellular carcinoma among male hepatitis B virus carriers.	('hepatitis', 'Phenotype', 'HP:0012115', (168, 177))	('testosterone', 'Chemical', 'MESH:D013739', (17, 29))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (132, 156))	('polymorphisms', 'Var', (34, 47))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (132, 156))	('hepatocellular carcinoma', 'Disease', (132, 156))	('influence', 'Reg', (110, 119))	('hepatitis B virus', 'Species', '10407', (168, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
45440	23894567	Genetic variations conferring differential risk of cholangiocarcinoma have been reported.	('cholangiocarcinoma', 'Disease', (51, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('Genetic variations', 'Var', (0, 18))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (51, 69))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (51, 69))
45479	21179572	Nevertheless, we postulated that this would be a useful signature of the phenotype induced by IL-6 over-expression which has been experimentally shown to increase tumor growth in vivo.	('IL-6', 'Gene', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('IL-6', 'Gene', '3569', (94, 98))	('over-expression', 'Var', (99, 114))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('increase', 'PosReg', (154, 162))
45488	21179572	All three compounds had a mean connectivity score indicating a negative correlation with the query signature: nifedipine (-0.412), nitrendipine (-0.887), and felodipine (-0.596).	('-0.887', 'Var', (145, 151))	('nitrendipine', 'MPA', (131, 143))	('nitrendipine', 'Chemical', 'MESH:D009568', (131, 143))	('negative', 'NegReg', (63, 71))	('felodipine', 'Chemical', 'MESH:D015736', (158, 168))	('-0.412', 'Var', (122, 128))	('nifedipine', 'Chemical', 'MESH:D009543', (110, 120))
45505	21179572	Inhibition of CACNG6 reduced cell viability by 30% in Mz-IL-6 cells.	('reduced', 'NegReg', (21, 28))	('IL-6', 'Gene', (57, 61))	('CACNG6', 'Gene', (14, 20))	('IL-6', 'Gene', '3569', (57, 61))	('cell viability', 'CPA', (29, 43))	('Inhibition', 'Var', (0, 10))	('CACNG6', 'Gene', '59285', (14, 20))
45506	21179572	Moreover, cytotoxicity of felodipine was enhanced in cells treated with siRNA to CANG6 in compared with siRNA control (Figure S2).	('felodipine', 'Chemical', 'MESH:D015736', (26, 36))	('enhanced', 'PosReg', (41, 49))	('cytotoxicity', 'Disease', (10, 22))	('siRNA to CANG6 in', 'Var', (72, 89))	('cytotoxicity', 'Disease', 'MESH:D064420', (10, 22))
45577	33193605	Variations in DNA methylation and gene expression have been extensively studied in other cancers for their role in pathogenesis and disease prognosis, but these studies are very limited in CCA.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('Variations', 'Var', (0, 10))	('cancers', 'Disease', (89, 96))	('CCA', 'Disease', (189, 192))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
45583	33193605	Pathway analysis suggested that cell division, bile secretion, amino acid metabolism, PPAR signaling, hippo signaling were highly affected by gene expression and DNA methylation alterations.	('amino acid metabolism', 'MPA', (63, 84))	('hippo signaling', 'MPA', (102, 117))	('PPAR', 'Gene', (86, 90))	('bile secretion', 'MPA', (47, 61))	('affected', 'Reg', (130, 138))	('cell division', 'CPA', (32, 45))	('PPAR', 'Gene', '5465', (86, 90))	('alterations', 'Var', (178, 189))	('DNA', 'MPA', (162, 165))
45585	33193605	Based on the survival analysis, we conclude that DEPDC1, FUT4, MDK, PACS1, PIWIL4 genes, miR-22, miR-551b microRNAs, and cg27362525 and cg26597242 CpGs can strongly support their use as prognostic markers of CCA.	('MDK', 'Gene', '4192', (63, 66))	('miR-22', 'Gene', (89, 95))	('cg26597242', 'Chemical', '-', (136, 146))	('PACS1', 'Gene', (68, 73))	('cg27362525', 'Chemical', '-', (121, 131))	('CCA', 'Disease', (208, 211))	('miR-551b', 'Gene', (97, 105))	('MDK', 'Gene', (63, 66))	('cg27362525', 'Var', (121, 131))	('PIWIL4', 'Gene', (75, 81))	('FUT4', 'Gene', (57, 61))	('cg26597242', 'Var', (136, 146))	('PACS1', 'Gene', '55690', (68, 73))	('PIWIL4', 'Gene', '143689', (75, 81))	('miR-551b', 'Gene', '693136', (97, 105))	('DEPDC1', 'Gene', (49, 55))	('FUT4', 'Gene', '2526', (57, 61))	('miR-22', 'Gene', '407004', (89, 95))
45604	33193605	A genomic region containing at least two dm-CpGs was considered as a differentially methylated region (DMR).	('DMR', 'Gene', '91833', (103, 106))	('dm-CpGs', 'Chemical', '-', (41, 48))	('DMR', 'Gene', (103, 106))	('dm-CpGs', 'Var', (41, 48))
45616	33193605	Bioconductor package clusterProfiler and the desktop version of GSEA were used for enrichment analysis of DEGs in CCA.	('DEGs', 'Var', (106, 110))	('CCA', 'Disease', (114, 117))	('GSEA', 'Chemical', '-', (64, 68))
45643	33193605	A total of 12,259 differentially methylated CpGs (henceforth mentioned as dm-CpGs) were detected between tumor and normal samples; out of these 9,534 were hypermethylated and 2,725 were hypomethylated (Supplementary Figures S4a,b and Supplementary Table S1).	('hypomethylated', 'Var', (186, 200))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('dm-CpGs', 'Chemical', '-', (74, 81))	('tumor', 'Disease', (105, 110))	('hypermethylated', 'Var', (155, 170))
45650	33193605	But, there is a sub-region in this region which is hypomethylated, this sub-region contains several overexpressed genes, including HOXA3, HOXA9, HOXA10, HIABDH, LOC441204 and hsa-miR196b, with the exception of the HIABDH segment.	('LOC441204', 'Var', (161, 170))	('HOXA9', 'Gene', '3205', (138, 143))	('HOXA3', 'Gene', (131, 136))	('HOXA3', 'Gene', '3200', (131, 136))	('hsa-miR196b', 'Gene', '442920', (175, 186))	('HOXA10', 'Gene', '3206', (145, 151))	('HOXA9', 'Gene', (138, 143))	('HOXA10', 'Gene', (145, 151))	('hsa-miR196b', 'Gene', (175, 186))	('HIABDH', 'Gene', (153, 159))
45664	33193605	Apart from these, miR-21, miR-92b, miR-125a, miR-135b, miR-141, miR-196a, miR-200a, miR-200b, miR-200c, and miR-439 were upregulated, while miR-122, miR-148a, miR-152, miR-378c, miR-383, miR-483, miR-675, and miR-855 were downregulated (Supplementary Table S3).	('miR-200a', 'Gene', '406983', (74, 82))	('miR-439', 'Var', (108, 115))	('miR-483', 'Gene', '619552', (187, 194))	('miR-125a', 'Gene', '406910', (35, 43))	('miR-92b', 'Gene', (26, 33))	('miR-200c', 'Gene', '406985', (94, 102))	('miR-152', 'Gene', '406943', (159, 166))	('miR-125a', 'Gene', (35, 43))	('miR-135b', 'Gene', (45, 53))	('miR-148a', 'Gene', '406940', (149, 157))	('miR-675', 'Gene', '100033819', (196, 203))	('miR-148a', 'Gene', (149, 157))	('miR-122', 'Gene', (140, 147))	('miR-200c', 'Gene', (94, 102))	('upregulated', 'PosReg', (121, 132))	('miR-200a', 'Gene', (74, 82))	('miR-21', 'Gene', '406991', (18, 24))	('miR-200b', 'Gene', (84, 92))	('miR-141', 'Gene', '406933', (55, 62))	('miR-378c', 'Gene', (168, 176))	('miR-92b', 'Gene', '693235', (26, 33))	('miR-378c', 'Gene', '100422867', (168, 176))	('miR-141', 'Gene', (55, 62))	('miR-196a', 'Var', (64, 72))	('miR-675', 'Gene', (196, 203))	('miR-483', 'Gene', (187, 194))	('miR-21', 'Gene', (18, 24))	('miR-383', 'Gene', '494332', (178, 185))	('miR-152', 'Gene', (159, 166))	('miR-200b', 'Gene', '406984', (84, 92))	('miR-122', 'Gene', '406906', (140, 147))	('miR-135b', 'Gene', '442891', (45, 53))	('miR-383', 'Gene', (178, 185))
45674	33193605	KEGG pathway analysis of genes with dm-CpGs pointed to the enrichment of pathways related to cancer, cell division and differentiation, amino acid metabolism, degradation of xenobiotics, and immune response (Supplementary Table S4).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('degradation of xenobiotics', 'MPA', (159, 185))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('dm-CpGs', 'Chemical', '-', (36, 43))	('dm-CpGs', 'Var', (36, 43))	('amino acid metabolism', 'MPA', (136, 157))
45677	33193605	This is to estimate the extent of multiple gene expression that is influenced by local DNA methylation in cholangiocarcinoma.	('local', 'Var', (81, 86))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (106, 124))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (106, 124))	('influenced', 'Reg', (67, 77))	('cholangiocarcinoma', 'Disease', (106, 124))
45689	33193605	We used both p-value and BH adjusted p-value cutoff of 0.01 for differential methylation analysis of distal enhancer region, and observed 16,801 and 19,577 probes significantly hypermethylated and hypomethylated, respectively in CCA.	('hypermethylated', 'Reg', (177, 192))	('hypomethylated', 'Var', (197, 211))	('BH', 'Chemical', '-', (25, 27))	('CCA', 'Disease', (229, 232))
45694	33193605	Similarly, in the case of hypomethylation, 12,251 probe-gene pairs showed a statistically significant correlation (Supplementary Table S6) and are also enriched in 91 Factorbook and JASPAR TF binding sequence motifs with minimum 10 probes per motif.	('correlation', 'Interaction', (102, 113))	('TF', 'Gene', '2152', (189, 191))	('hypomethylation', 'Var', (26, 41))	('significant', 'Reg', (90, 101))	('binding', 'Interaction', (192, 199))
45706	33193605	Alterations in DNA methylation and miRNA expression are commonplace in a variety of tumors and these changes have been perceived as causative factors of oncogenesis in several cancer types.	('methylation', 'Var', (19, 30))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('DNA', 'Protein', (15, 18))	('tumors', 'Disease', (84, 90))	('cancer', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('miRNA expression', 'MPA', (35, 51))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
45707	33193605	Such alterations significantly affect gene expression and this information has been effectively used to identify biomarkers that could discriminate the cancerous cells from normal cells.	('affect', 'Reg', (31, 37))	('cancerous', 'Disease', (152, 161))	('cancerous', 'Disease', 'MESH:D009369', (152, 161))	('gene expression', 'MPA', (38, 53))	('alterations', 'Var', (5, 16))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
45711	33193605	We found that Engrailed Homeobox 1 (EN1) gene had the highest number of dm-CpGs, where most of them were hypermethylated in the gene body and none in the promoter region.	('dm-CpGs', 'Chemical', '-', (72, 79))	('Engrailed Homeobox 1', 'Gene', (14, 34))	('hypermethylated', 'Var', (105, 120))	('EN1', 'Gene', (36, 39))	('dm-CpGs', 'Var', (72, 79))	('Engrailed Homeobox 1', 'Gene', '2019', (14, 34))	('EN1', 'Gene', '2019', (36, 39))
45714	33193605	Genomic sub-region that harbors HOXA3/A9/A10, HIABDH, LOC441204, and miR196b is hypomethylated, and showed overexpression of all of these genes in CCA except HIABDH (p-value > 0.05, corroborating the fact that DNA hypomethylation in general positively affects corresponding gene expression.	('affects', 'Reg', (252, 259))	('HOXA3/A9', 'Gene', '3200', (32, 40))	('HOXA3/A9', 'Gene', (32, 40))	('miR196b', 'Gene', (69, 76))	('expression', 'MPA', (279, 289))	('miR196b', 'Gene', '442920', (69, 76))	('LOC441204', 'Var', (54, 63))	('CCA', 'Disease', (147, 150))	('overexpression', 'PosReg', (107, 121))
45722	33193605	Overall, our results suggest that differential gene expression impacts cell division/differentiation, amino acid metabolism and autophagy pathways in cholangiocarcinoma (Supplementary Table S4).	('cell division/differentiation', 'CPA', (71, 100))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (150, 168))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (150, 168))	('amino acid metabolism', 'MPA', (102, 123))	('differential gene expression', 'Var', (34, 62))	('cholangiocarcinoma', 'Disease', (150, 168))	('impacts', 'Reg', (63, 70))	('autophagy pathways', 'CPA', (128, 146))
45732	33193605	We also observed hypomethylation of FOXC1 TF binding motif and overexpression of FOXC1 in our study, which may have a key role in CCA.	('hypomethylation', 'Var', (17, 32))	('FOXC1', 'Gene', '2296', (36, 41))	('FOXC1', 'Gene', '2296', (81, 86))	('binding', 'Interaction', (45, 52))	('TF', 'Gene', '2152', (42, 44))	('FOXC1', 'Gene', (36, 41))	('FOXC1', 'Gene', (81, 86))	('CCA', 'Disease', (130, 133))	('overexpression', 'PosReg', (63, 77))
45734	33193605	TEAD4 is already a known biomarker for breast cancer, colorectal cancer and prostate cancer; its TF binding motif regions are hypomethylated in CCA.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('TF', 'Gene', '2152', (97, 99))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('colorectal cancer', 'Disease', 'MESH:D015179', (54, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('hypomethylated', 'Var', (126, 140))	('TEAD4', 'Gene', '7004', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('TEAD4', 'Gene', (0, 5))	('prostate cancer', 'Disease', (76, 91))	('colorectal cancer', 'Disease', (54, 71))	('CCA', 'Disease', (144, 147))	('breast cancer', 'Disease', (39, 52))
45739	33193605	As shown in Figure 7, hypermethylated CpG sites in the promoter and TSS regions of GABRA1 and UPS6 (Ubiquitin Specific Peptidase 6), respectively, showed very high AUC values, hence could serve as strong biomarkers of CCA.	('AUC values', 'MPA', (164, 174))	('hypermethylated', 'Var', (22, 37))	('UPS6', 'Gene', (94, 98))	('GABRA1', 'Gene', (83, 89))	('CCA', 'Disease', (218, 221))	('Ubiquitin Specific Peptidase 6', 'Gene', '9098', (100, 130))	('UPS6', 'Gene', '9098', (94, 98))	('GABRA1', 'Gene', '2554', (83, 89))	('Ubiquitin Specific Peptidase 6', 'Gene', (100, 130))
45740	33193605	The effect of promoter methylation of the HOX family of genes in patients' survival has not been reported previously, but promoter hypermethylation of HOXA9 in non-smokers is associated with recurrence-free survival (RFS) in non-small cell lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (240, 251))	('associated with', 'Reg', (175, 190))	('HOXA9', 'Gene', '3205', (151, 156))	('lung cancer', 'Disease', (240, 251))	('promoter hypermethylation', 'Var', (122, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (240, 251))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (225, 251))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (229, 251))	('HOXA9', 'Gene', (151, 156))	('patients', 'Species', '9606', (65, 73))	('recurrence-free', 'CPA', (191, 206))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))
45743	33193605	We also observed hypermethylation of miR-196b and hypomethylation of lncRNA MIR100HG promoter CpG, which are both associated with CCA patients' survival.	('MIR100HG', 'Gene', '399959', (76, 84))	('patients', 'Species', '9606', (134, 142))	('MIR100HG', 'Gene', (76, 84))	('associated with', 'Reg', (114, 129))	('CCA', 'Disease', (130, 133))	('miR-196b', 'Gene', (37, 45))	('hypermethylation', 'Var', (17, 33))	('miR-196b', 'Gene', '442920', (37, 45))	('hypomethylation', 'Var', (50, 65))
45754	33193605	It's been reported that low MDK expressing patient cohorts have better survival and a similar trend was observed in our analysis (Figure 8).	('better', 'PosReg', (64, 70))	('MDK', 'Gene', '4192', (28, 31))	('patient', 'Species', '9606', (43, 50))	('MDK', 'Gene', (28, 31))	('survival', 'MPA', (71, 79))	('low', 'Var', (24, 27))
45762	33193605	Several reports from other cancers showed that patients with high GLUD1, ANXA4, and PLXDC1 expression have low overall survival, but our findings in CCA are contrasting.	('CCA', 'Disease', (149, 152))	('ANXA4', 'Gene', '307', (73, 78))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('ANXA4', 'Gene', (73, 78))	('PLXDC1', 'Gene', '57125', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('overall survival', 'MPA', (111, 127))	('high', 'Var', (61, 65))	('patients', 'Species', '9606', (47, 55))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('GLUD1', 'Gene', '2746', (66, 71))	('PLXDC1', 'Gene', (84, 90))	('low', 'NegReg', (107, 110))	('GLUD1', 'Gene', (66, 71))	('cancers', 'Disease', (27, 34))
45763	33193605	On similar lines, patients having high CD24 expression were shown to have low metastasis-free survival in extrahepatic CCA, but we observed an opposite trend in our findings (Supplementary Table S7).	('CD24', 'Gene', '100133941', (39, 43))	('low', 'NegReg', (74, 77))	('expression', 'Var', (44, 54))	('CD24', 'Gene', (39, 43))	('high', 'Var', (34, 38))	('patients', 'Species', '9606', (18, 26))	('extrahepatic CCA', 'Disease', (106, 122))	('metastasis-free survival', 'CPA', (78, 102))
45775	33193605	Our analysis suggests that expression of DEPDC1, FUT4, MDK, PACS1, PIWIL4, miR-22, miR-551b, and DNA methylation of cg27362525 and cg26597242 could be explored further as potential biomarkers of cholangiocarcinoma.	('PIWIL4', 'Gene', (67, 73))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (195, 213))	('MDK', 'Gene', (55, 58))	('miR-22', 'Gene', '407004', (75, 81))	('miR-22', 'Gene', (75, 81))	('miR-551b', 'Gene', '693136', (83, 91))	('PACS1', 'Gene', '55690', (60, 65))	('cg27362525', 'Var', (116, 126))	('PIWIL4', 'Gene', '143689', (67, 73))	('cg27362525', 'Chemical', '-', (116, 126))	('PACS1', 'Gene', (60, 65))	('cg26597242', 'Var', (131, 141))	('miR-551b', 'Gene', (83, 91))	('MDK', 'Gene', '4192', (55, 58))	('FUT4', 'Gene', '2526', (49, 53))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (195, 213))	('cg26597242', 'Chemical', '-', (131, 141))	('cholangiocarcinoma', 'Disease', (195, 213))	('FUT4', 'Gene', (49, 53))
45831	32270773	The serum levels of CA19-9 (95.3 +- 52.3) in patients with EHCC were higher than in patients with benign biliary disease (62.2 +- 44.4, P = 0.004), and lower than in patients with pancreatic cancer (155.7 +- 94.8, P < 0.001), the differences were statistically significant, but similar to patients with gallbladder carcinoma (75.6 +- 34.8, P = 0.144), the differences were not statistically significant (P < 0.01).	('benign biliary disease', 'Disease', 'MESH:D001660', (98, 120))	('pancreatic cancer', 'Disease', 'MESH:D010190', (180, 197))	('benign biliary disease', 'Disease', (98, 120))	('patients', 'Species', '9606', (45, 53))	('EHCC', 'Disease', (59, 63))	('patients', 'Species', '9606', (84, 92))	('CA19-9', 'Var', (20, 26))	('pancreatic cancer', 'Disease', (180, 197))	('biliary disease', 'Phenotype', 'HP:0001080', (105, 120))	('lower', 'NegReg', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('CA19-9', 'Chemical', 'MESH:C086528', (20, 26))	('serum levels', 'MPA', (4, 16))	('higher', 'PosReg', (69, 75))	('patients', 'Species', '9606', (289, 297))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (303, 324))	('carcinoma', 'Phenotype', 'HP:0030731', (315, 324))	('gallbladder carcinoma', 'Disease', (303, 324))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (180, 197))	('patients', 'Species', '9606', (166, 174))
45842	32270773	According to median level of serum MUC3A levels, 35 patients were divided in to two groups: 15 patients with high MUC3A (>88.8 ng/ml) and 20 patients with low MUC3A levels (<=88.8 ng/ml).	('MUC3A', 'Gene', (159, 164))	('MUC3A', 'Gene', '4584', (35, 40))	('MUC3A', 'Gene', '4584', (114, 119))	('MUC3A', 'Gene', '4584', (159, 164))	('patients', 'Species', '9606', (95, 103))	('MUC3A', 'Gene', (114, 119))	('patients', 'Species', '9606', (141, 149))	('low MUC3A levels', 'Phenotype', 'HP:0032429', (155, 171))	('MUC3A', 'Gene', (35, 40))	('patients', 'Species', '9606', (52, 60))	('>88.8', 'Var', (121, 126))
45847	32270773	Patients with high MUC3A levels had high percentage of lymph node metastasis, surrounding tissue infiltration and UICC stages II b-III.	('surrounding tissue infiltration', 'CPA', (78, 109))	('MUC3A', 'Gene', (19, 24))	('MUC3A', 'Gene', '4584', (19, 24))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('high MUC3A level', 'Phenotype', 'HP:0032428', (14, 30))	('lymph node metastasis', 'CPA', (55, 76))
45851	32270773	Studies have shown that expression of mucin genes is tissue- and cell-specific, and abnormal expression is important in tumorigenesis and cell differentiation, which can promote the malignant progression of tumors.	('mucin', 'Gene', '100508689', (38, 43))	('tumors', 'Disease', (207, 213))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('mucin', 'Gene', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('abnormal', 'Var', (84, 92))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (120, 125))	('promote', 'PosReg', (170, 177))
45870	32270773	High MUC3A expression is an adverse prognostic biomarker for overall survival (OS) and recurrence-free survival (RFS) in postoperative localized clear-cell renal cell carcinoma (ccRCC) patients.	('MUC3A', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (145, 176))	('expression', 'MPA', (11, 21))	('MUC3A', 'Gene', '4584', (5, 10))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (156, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('patients', 'Species', '9606', (185, 193))	('clear-cell renal cell carcinoma', 'Disease', (145, 176))
45885	32064210	Looks can be Deceiving: A Case Report on the Clinical Value of CA 19-9 in Obstructive Jaundice Carbohydrate antigen CA19-9 is a marker that has been used for the diagnosis of pancreatic and biliary malignancies, but it can also be present in benign conditions.	('Jaundice', 'Disease', 'MESH:D007565', (86, 94))	('CA19-9', 'Var', (116, 122))	('pancreatic and biliary malignancies', 'Disease', 'MESH:D001661', (175, 210))	('Jaundice', 'Disease', (86, 94))	('Jaundice', 'Phenotype', 'HP:0000952', (86, 94))	('Carbohydrate', 'Chemical', 'MESH:D002241', (95, 107))
46000	23864881	The apoptosis index of the vorinostat and EGCG combination was approximately three fold higher than that when vorinostat or EGCG was treated alone.	('combination', 'Var', (47, 58))	('higher', 'PosReg', (88, 94))	('vorinostat', 'Chemical', 'MESH:D000077337', (27, 37))	('vorinostat', 'Chemical', 'MESH:D000077337', (110, 120))	('apoptosis index', 'CPA', (4, 19))	('EGCG', 'Chemical', 'MESH:C045651', (42, 46))	('EGCG', 'Chemical', 'MESH:C045651', (124, 128))
46005	23864881	PARP, a protein involved in DNA repair and programmed cell death, also decreased following treatment with the vorinostat and EGCG combination, whereas the single treatments showed obvious increased protein intensities for both vorinostat and EGCG alone.	('EGCG', 'Chemical', 'MESH:C045651', (242, 246))	('vorinostat', 'Chemical', 'MESH:D000077337', (227, 237))	('PARP', 'Gene', '142', (0, 4))	('PARP', 'Gene', (0, 4))	('EGCG', 'Gene', (125, 129))	('vorinostat', 'Chemical', 'MESH:D000077337', (110, 120))	('protein intensities', 'MPA', (198, 217))	('combination', 'Var', (130, 141))	('decreased', 'NegReg', (71, 80))	('EGCG', 'Chemical', 'MESH:C045651', (125, 129))
46010	23864881	As shown in Figure 3(a), vorinostat/EGCG combinations were markedly inhibited invasion of tumor cells compared to single treatment of vorinostat or EGCG; that is, tumor cell invasive capacity was inhibited 13% versus vorinostat single treatment and 45% versus EGCG single treatment.	('vorinostat', 'Chemical', 'MESH:D000077337', (217, 227))	('EGCG', 'Chemical', 'MESH:C045651', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('vorinostat', 'Chemical', 'MESH:D000077337', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('combinations', 'Var', (41, 53))	('inhibited', 'NegReg', (68, 77))	('EGCG', 'Chemical', 'MESH:C045651', (260, 264))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('inhibited', 'NegReg', (196, 205))	('EGCG', 'Chemical', 'MESH:C045651', (148, 152))	('vorinostat', 'Chemical', 'MESH:D000077337', (134, 144))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
46029	23864881	Although cancer cells generate more ROS than those of normal cells, vorinostat induces further oxidative stress in tumor cells and enhances the suppression of cancer cell proliferation.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', (9, 15))	('vorinostat', 'Var', (68, 78))	('oxidative stress', 'Phenotype', 'HP:0025464', (95, 111))	('enhances', 'PosReg', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('ROS', 'MPA', (36, 39))	('oxidative stress', 'MPA', (95, 111))	('tumor', 'Disease', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('suppression', 'CPA', (144, 155))	('induces', 'Reg', (79, 86))	('ROS', 'Chemical', 'MESH:D017382', (36, 39))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('vorinostat', 'Chemical', 'MESH:D000077337', (68, 78))
46043	23864881	Furthermore, EGCG inhibits tyrosine phosphorylation of focal adhesion kinase and MMP-9 activity.	('tyrosine phosphorylation', 'MPA', (27, 51))	('focal adhesion kinase', 'Pathway', (55, 76))	('activity', 'MPA', (87, 95))	('EGCG', 'Chemical', 'MESH:C045651', (13, 17))	('inhibits', 'NegReg', (18, 26))	('EGCG', 'Var', (13, 17))	('MMP-9', 'Gene', '4318', (81, 86))	('MMP-9', 'Gene', (81, 86))	('tyrosine', 'Chemical', 'MESH:D014443', (27, 35))
46129	32385649	Furthermore, cHCC-CCAs with MVI may have worse surgical outcomes with regard to early recurrence than those without MVI.	('cHCC-CCAs', 'Chemical', '-', (13, 22))	('cHCC-CCAs', 'Disease', (13, 22))	('MVI', 'Var', (28, 31))
46159	32385649	In addition, all the lesions were categorized based on the LI-RADS v2018, LR-M (definitely or probably malignant, not HCC specific, including rim APHE, peripheral washout, and delayed and progressive concentric enhancement).	('v2018', 'Var', (67, 72))	('HCC', 'Gene', '619501', (118, 121))	('peripheral washout', 'Disease', (152, 170))	('HCC', 'Gene', (118, 121))	('LR-M', 'Disease', (74, 78))	('rim APHE', 'Disease', (142, 150))
46188	32385649	Moreover, as is well known, fatty changes in HCC are associated with ischemia, which may be related to a reduced normal portal vein blood supply.	('ischemia', 'Disease', 'MESH:D007511', (69, 77))	('HCC', 'Gene', (45, 48))	('reduced', 'NegReg', (105, 112))	('associated', 'Reg', (53, 63))	('ischemia', 'Disease', (69, 77))	('fatty changes', 'Var', (28, 41))	('HCC', 'Gene', '619501', (45, 48))
46197	32385649	It has been reported that MVI is one of the most important prognostic factor for the early recurrence of HCC after hepatic resection or radiofrequency ablation; we also found that cHCC-CCAs with MVI may have worse surgical outcomes with regard to early recurrence than those without MVI.	('cHCC-CCAs', 'Chemical', '-', (180, 189))	('HCC', 'Gene', '619501', (105, 108))	('HCC', 'Gene', (181, 184))	('HCC', 'Gene', '619501', (181, 184))	('HCC', 'Gene', (105, 108))	('MVI', 'Var', (195, 198))
46243	31581864	Immunological examination revealed CK19+, CK20+, Hep-, CDX-2-, CD34-, and Ki67+ (approximately 25%) (see Figure 3(a)).	('Ki67+', 'Chemical', 'MESH:D019394', (74, 79))	('Ki67+', 'Var', (74, 79))	('Hep', 'CellLine', 'CVCL:1906', (49, 52))	('CK20', 'Gene', (42, 46))	('CK20', 'Gene', '54474', (42, 46))	('CK19', 'Gene', (35, 39))	('CDX-2', 'Gene', '1045', (55, 60))	('CDX-2', 'Gene', (55, 60))	('CK19', 'Gene', '3880', (35, 39))	('CD34', 'Gene', '947', (63, 67))	('Hep-', 'Disease', (49, 53))	('CD34', 'Gene', (63, 67))
46245	31581864	Immunological examination revealed MSH2+, MLH1+, PMS2+, MSH6+ (suggesting microsatellite stability), PD-L1(-), and Ki67+ (approximately 90%) (see Figure 3(b)).	('Ki67+', 'Var', (115, 120))	('PMS2', 'Gene', (49, 53))	('MSH6', 'Gene', (56, 60))	('PD-L1', 'Gene', '29126', (101, 106))	('PMS2', 'Gene', '5395', (49, 53))	('MLH1', 'Gene', '4292', (42, 46))	('MSH6', 'Gene', '2956', (56, 60))	('MLH1', 'Gene', (42, 46))	('MSH2', 'Gene', (35, 39))	('MSH2', 'Gene', '4436', (35, 39))	('Ki67+', 'Chemical', 'MESH:D019394', (115, 120))	('PD-L1', 'Gene', (101, 106))
46254	31581864	Several risk factors of this disease have been identified, including hereditary elements, immune deficiency and immune escape of cancer cells, accumulation of genetic mutations and abnormal gene expression, and administration of radiotherapy, chemotherapy, and some drugs.	('immune deficiency', 'Phenotype', 'HP:0002721', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('immune deficiency', 'Disease', (90, 107))	('immune deficiency', 'Disease', 'MESH:D007153', (90, 107))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('immune escape', 'CPA', (112, 125))	('abnormal gene', 'Var', (181, 194))	('accumulation', 'Reg', (143, 155))	('genetic mutations', 'Var', (159, 176))
46294	30934706	In addition, two issues that cannot be ignored are that EUS-FNA for biliary lesion may cause bile peritonitis and needle tract seeding.	('EUS-FNA', 'Var', (56, 63))	('bile peritonitis', 'Disease', (93, 109))	('cause', 'Reg', (87, 92))	('bile peritonitis', 'Disease', 'MESH:D010534', (93, 109))	('biliary lesion', 'Disease', (68, 82))	('needle tract', 'Disease', (114, 126))	('peritonitis', 'Phenotype', 'HP:0002586', (98, 109))
46306	30934706	A 0.035-inch hydrophilic guidewire (M00556051; Boston Scientific Corporation, Natick, MA, USA) and/or a 0.025-inch hydrophilic guidewire (G-260-2545A; Olympus Optical Co., Ltd., Tokyo, Japan) were also used during ERCP.	('G-260-2545A', 'Var', (138, 149))	('G-260-2545A', 'SUBSTITUTION', 'None', (138, 149))	('M00556051;', 'Var', (36, 46))
46321	30934706	There were considerably fewer patients with perihilar biliary stricture in the EUS-FNA group than in the ERCP group.	('perihilar biliary stricture', 'Disease', (44, 71))	('patients', 'Species', '9606', (30, 38))	('EUS-FNA', 'Var', (79, 86))
46467	29254154	reported that patients with the PI-type of ICC without hilar invasion tend to have favorable surgical outcomes than patients with the MF-type.	('PI-type', 'Var', (32, 39))	('ICC', 'Disease', (43, 46))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (14, 22))
46468	29254154	reported that patients with the MF-type of ICC exhibited significantly better survival than patients with the PI-type of ICC after surgical resection.	('survival', 'CPA', (78, 86))	('patients', 'Species', '9606', (92, 100))	('ICC', 'Disease', (43, 46))	('better', 'PosReg', (71, 77))	('patients', 'Species', '9606', (14, 22))	('MF-type', 'Var', (32, 39))
46472	29254154	Because the mechanisms of carcinogenesis may differ among these macroscopic types, the MF-type of ICC often invades into the adjacent liver parenchyma, whereas the PI-type of ICC invades into the hepatic hilum.	('invades', 'Reg', (108, 115))	('carcinogenesis', 'Disease', 'MESH:D063646', (26, 40))	('carcinogenesis', 'Disease', (26, 40))	('ICC', 'Disease', (98, 101))	('MF-type', 'Var', (87, 94))
46499	29254154	In addition, some reported that patients with the PI-type of ICC had significantly better survival than those with the MF-type of ICC.	('patients', 'Species', '9606', (32, 40))	('PI-type', 'Var', (50, 57))	('ICC', 'Disease', (61, 64))	('better', 'PosReg', (83, 89))	('survival', 'CPA', (90, 98))
46520	29254154	The following coding was used: the primary site code for the liver (22.0); the histology code for cholangiocarcinoma (8160); the primary site code for the intrahepatic bile duct (22.1); the histology codes for malignant neoplasm (8000), malignant tumor cells (8001), carcinoma (8010), undifferentiated carcinoma (8020), adenocarcinoma (8140), and cholangiocarcinoma (8160); and a behavior code (3-malignant tumor).	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('malignant neoplasm', 'Disease', (210, 228))	('neoplasm', 'Phenotype', 'HP:0002664', (220, 228))	('intrahepatic bile duct', 'Disease', (155, 177))	('malignant tumor', 'Disease', 'MESH:D018198', (237, 252))	('8140', 'Var', (336, 340))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (98, 116))	('carcinoma', 'Disease', 'MESH:D002277', (267, 276))	('undifferentiated carcinoma', 'Disease', 'MESH:D002277', (285, 311))	('cholangiocarcinoma', 'Disease', (98, 116))	('8010', 'Var', (278, 282))	('carcinoma', 'Disease', 'MESH:D002277', (107, 116))	('intrahepatic bile duct', 'Disease', 'MESH:D002780', (155, 177))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (98, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('carcinoma', 'Disease', (302, 311))	('8020', 'Var', (313, 317))	('carcinoma', 'Phenotype', 'HP:0030731', (325, 334))	('carcinoma', 'Phenotype', 'HP:0030731', (356, 365))	('carcinoma', 'Disease', (325, 334))	('8160', 'Var', (367, 371))	('carcinoma', 'Disease', (356, 365))	('8000', 'Var', (230, 234))	('undifferentiated carcinoma', 'Disease', (285, 311))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('adenocarcinoma', 'Disease', (320, 334))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (347, 365))	('carcinoma', 'Disease', (267, 276))	('carcinoma', 'Disease', 'MESH:D002277', (302, 311))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('cholangiocarcinoma', 'Disease', (347, 365))	('malignant neoplasm', 'Disease', 'MESH:D009369', (210, 228))	('malignant tumor', 'Disease', (397, 412))	('carcinoma', 'Disease', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (407, 412))	('8001', 'Var', (260, 264))	('carcinoma', 'Disease', 'MESH:D002277', (325, 334))	('carcinoma', 'Disease', 'MESH:D002277', (356, 365))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (347, 365))	('malignant tumor', 'Disease', 'MESH:D018198', (397, 412))	('malignant tumor', 'Disease', (237, 252))	('adenocarcinoma', 'Disease', 'MESH:D000230', (320, 334))
46676	33505910	A number of studies have confirmed that malnutrition dramatically increase the occurrence of postoperative complications in cancer patients, negatively affects the anticancer efficacy, length of hospital stay and quality of life of cancer patients, and also speeds up the progress of cancer, leading to poor survival.	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('malnutrition', 'Var', (40, 52))	('cancer', 'Disease', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('quality of life', 'CPA', (213, 228))	('patients', 'Species', '9606', (131, 139))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('malnutrition', 'Phenotype', 'HP:0004395', (40, 52))	('cancer', 'Disease', (284, 290))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('progress', 'CPA', (272, 280))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('affects', 'Reg', (152, 159))	('increase', 'PosReg', (66, 74))	('cancer', 'Disease', (124, 130))	('negatively', 'NegReg', (141, 151))	('patients', 'Species', '9606', (239, 247))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('speeds up', 'NegReg', (258, 267))
46717	33505910	In two studies of patients with hilar cholangiocarcinoma after intrahepatic cholangiocarcinoma and adjuvant therapy, a high CONUT score was identified as an independent predictor of poor OS prognosis.	('cholangiocarcinoma', 'Disease', (38, 56))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (63, 94))	('poor OS', 'Disease', (182, 189))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (38, 56))	('high', 'Var', (119, 123))	('cholangiocarcinoma', 'Disease', (76, 94))	('intrahepatic cholangiocarcinoma', 'Disease', (63, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (38, 56))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (76, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('patients', 'Species', '9606', (18, 26))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (76, 94))
46869	32051799	Oncologist did not recommend anticoagulation for portal vein occlusion and ordered tumor markers evaluation which showed alpha-fetoprotein 14.7 ng/ml (normal: <8.7), CA 19-9 2907 U/ml (normal: < 35), carcinoembryonic antigen (CEA) 5.2 ng/ml (normal: <3.4).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('portal vein occlusion', 'Phenotype', 'HP:0030242', (49, 70))	('vein occlusion', 'Phenotype', 'HP:0025322', (56, 70))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('alpha-fetoprotein', 'MPA', (121, 138))	('vein occlusion', 'Disease', (56, 70))	('carcinoembryonic', 'Disease', (200, 216))	('vein occlusion', 'Disease', 'MESH:D012170', (56, 70))	('CA 19-9 2907 U/ml', 'Var', (166, 183))	('carcinoembryonic', 'Disease', 'None', (200, 216))
46874	32051799	Patient's liver profile worsened during his ICU stay with serum bilirubin escalating up to 12 mg/dl, ALP 470 IU/L, AST 429 IU/L, ALT 362 IU/L, international normalized ratio (INR) 2.8, albumin 1.8.	('ALT 362 IU/L', 'Var', (129, 141))	('liver profile', 'MPA', (10, 23))	('ALP', 'Gene', (101, 104))	('escalating', 'PosReg', (74, 84))	('AST', 'Gene', (115, 118))	('AST', 'Gene', '26503', (115, 118))	('ALP', 'Gene', '250', (101, 104))	('bilirubin', 'Chemical', 'MESH:D001663', (64, 73))	('worsened', 'Reg', (24, 32))	('international normalized ratio', 'MPA', (143, 173))	('Patient', 'Species', '9606', (0, 7))	('serum bilirubin', 'MPA', (58, 73))
46913	31957323	Blockage of PTEN abolished the celastrol-induced PI3K/Akt signaling inhibition.	('Blockage', 'Var', (0, 8))	('celastrol', 'Chemical', 'MESH:C050414', (31, 40))	('Akt', 'Gene', '207', (54, 57))	('PTEN', 'Gene', (12, 16))	('Akt', 'Gene', (54, 57))
46942	31957323	Subsequently, cells were incubated with antibodies for p-Akt (Thr308) (1:200), p-Akt (Ser437) (1:200) or PTEN (1:200) antibodies overnight at 4 C. After that, cells were incubated with an Alexa Fluor-conjugated IgG secondary antibody (1:500, Invitrogen) for 1 hour at room temperature.	('Akt', 'Gene', '207', (81, 84))	('Ser', 'Chemical', 'MESH:C530429', (86, 89))	('Akt', 'Gene', '207', (57, 60))	('Thr308', 'Chemical', 'MESH:C015596', (62, 68))	('PTEN', 'Gene', (105, 109))	('1:200', 'Var', (95, 100))	('Akt', 'Gene', (81, 84))	('Akt', 'Gene', (57, 60))	('Alexa Fluor', 'Chemical', 'MESH:C569686', (188, 199))
46982	31957323	To further elucidate the role of PI3K/Akt pathway in celastrol inhibiting CCA development, we initially pretreated TFK-1 cells with celastrol at different concentrations (0, 5, 10, and 20 micromol/L), then activated or inactivated the pathway by Akt1 transfection and LY294002, respectively.	('Akt', 'Gene', '207', (246, 249))	('CCA', 'Disease', 'MESH:D018281', (74, 77))	('Akt1', 'Gene', '207', (246, 250))	('LY294002', 'Var', (268, 276))	('Akt', 'Gene', (246, 249))	('celastrol', 'Chemical', 'MESH:C050414', (132, 141))	('Akt', 'Gene', (38, 41))	('CCA', 'Disease', (74, 77))	('celastrol', 'Chemical', 'MESH:C050414', (53, 62))	('inhibiting', 'NegReg', (63, 73))	('Akt', 'Gene', '207', (38, 41))	('LY294002', 'Chemical', 'MESH:C085911', (268, 276))	('activated', 'PosReg', (206, 215))	('Akt1', 'Gene', (246, 250))	('inactivated', 'NegReg', (219, 230))
46986	31957323	Compared with the cells only treated with celastrol, the apoptosis-related proteins were reduced after Akt-1 plasmid transfection, but decreased after LY294002 treatment.	('apoptosis-related proteins', 'MPA', (57, 83))	('Akt-1', 'Gene', (103, 108))	('LY294002', 'Chemical', 'MESH:C085911', (151, 159))	('reduced', 'NegReg', (89, 96))	('transfection', 'Var', (117, 129))	('decreased', 'NegReg', (135, 144))	('Akt-1', 'Gene', '207', (103, 108))	('celastrol', 'Chemical', 'MESH:C050414', (42, 51))	('plasmid transfection', 'Var', (109, 129))
46989	31957323	Numerous studies have shown that phosphatase and tensin homolog (PTEN) mutations occur in CCA patients, and PTEN acts as a negative regulator of PI3K/AKT signaling pathway in CCA cells.	('CCA', 'Disease', (90, 93))	('PTEN', 'Gene', (65, 69))	('negative', 'NegReg', (123, 131))	('patients', 'Species', '9606', (94, 102))	('PTEN', 'Gene', (108, 112))	('CCA', 'Disease', 'MESH:D018281', (175, 178))	('AKT', 'Gene', '207', (150, 153))	('mutations', 'Var', (71, 80))	('CCA', 'Disease', 'MESH:D018281', (90, 93))	('CCA', 'Disease', (175, 178))	('AKT', 'Gene', (150, 153))	('occur', 'Reg', (81, 86))
46993	31957323	Data showed this generated knockdown of PTEN-induced upregulation of p-Akt (Thr 308), p-Akt (Ser 473), p-mTOR, and NF-kappaB was reversed by celatrol treatment.	('PTEN-induced', 'Gene', (40, 52))	('knockdown', 'Var', (27, 36))	('Akt', 'Gene', '207', (71, 74))	('Akt', 'Gene', '207', (88, 91))	('Thr', 'Chemical', 'MESH:C055175', (76, 79))	('Akt', 'Gene', (71, 74))	('mTOR', 'Gene', (105, 109))	('upregulation', 'PosReg', (53, 65))	('Akt', 'Gene', (88, 91))	('mTOR', 'Gene', '2475', (105, 109))	('Ser', 'Chemical', 'MESH:C530429', (93, 96))	('celatrol', 'Chemical', 'None', (141, 149))
46999	31957323	In addition, Figure 6B showed the tumors volume change dunning this experimental period, and data showed that tumors grew continuously in the celastrol group, whereas tumor growth was significantly suppressed in vehicle control group.	('celastrol', 'Chemical', 'MESH:C050414', (142, 151))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('celastrol', 'Var', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
47000	31957323	Additionally, the mean weight of tumors in the celastrol group was 0.29 g, whereas that of tumors in the control animals was 0.81 g. (Figure 6C).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('celastrol', 'Var', (47, 56))	('celastrol', 'Chemical', 'MESH:C050414', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))
47004	31957323	Furthermore, HE staining results also showed that the lung metastasis nodules in mice treated with celastrol were significantly smaller than those of mice in the control group.	('mice', 'Species', '10090', (150, 154))	('mice', 'Species', '10090', (81, 85))	('celastrol', 'Var', (99, 108))	('lung metastasis', 'Disease', (54, 69))	('lung metastasis', 'Disease', 'MESH:D009362', (54, 69))	('smaller', 'NegReg', (128, 135))	('celastrol', 'Chemical', 'MESH:C050414', (99, 108))
47029	31957323	In the additionally loss-of-function studies, we downregulated the expression of PTEN in by transfection with siRNA against PTEN, and found that blockage of PTEN-induced significant upregulated PI3K/AKT signaling pathway compared to the control group.	('AKT', 'Gene', (199, 202))	('blockage', 'Var', (145, 153))	('upregulated', 'PosReg', (182, 193))	('loss-of-function', 'NegReg', (20, 36))	('PTEN in', 'Gene', (81, 88))	('PTEN-induced', 'Gene', (157, 169))	('AKT', 'Gene', '207', (199, 202))	('downregulated', 'NegReg', (49, 62))	('expression', 'MPA', (67, 77))
47076	31683902	Modulation of drug transport through decreasing influx and increasing efflux has been shown to be one major mechanism of anticancer drug resistance.	('Modulation', 'Var', (0, 10))	('decreasing', 'NegReg', (37, 47))	('influx', 'MPA', (48, 54))	('drug transport', 'MPA', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('increasing', 'PosReg', (59, 69))	('efflux', 'MPA', (70, 76))	('drug resistance', 'Phenotype', 'HP:0020174', (132, 147))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
47102	31683902	Abnormal functioning of these proteins lead to cell cycle arrest.	('lead to', 'Reg', (39, 46))	('arrest', 'Disease', (58, 64))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (47, 64))	('Abnormal', 'Var', (0, 8))	('arrest', 'Disease', 'MESH:D006323', (58, 64))
47103	31683902	Atractylodin has previously been shown to induce cholangiocarcinoma cell cycle arrest at the G1 phase.	('arrest', 'Disease', 'MESH:D006323', (79, 85))	('induce', 'PosReg', (42, 48))	('cholangiocarcinoma', 'Disease', (49, 67))	('arrest', 'Disease', (79, 85))	('Atractylodin', 'Var', (0, 12))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (68, 85))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (49, 67))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (49, 67))	('Atractylodin', 'Chemical', 'MESH:C106914', (0, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
47110	31683902	NOV-002, the glutathione disulfide mimetic, was shown to suppress tumor cell invasion and metastasis via ErbB2, PI3K, Akt, and RhoA.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('ErbB2', 'Gene', (105, 110))	('tumor', 'Disease', (66, 71))	('glutathione disulfide', 'Chemical', 'MESH:D019803', (13, 34))	('Akt', 'Gene', (118, 121))	('suppress', 'NegReg', (57, 65))	('ErbB2', 'Gene', '2064', (105, 110))	('RhoA', 'Gene', (127, 131))	('RhoA', 'Gene', '387', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('Akt', 'Gene', '207', (118, 121))	('PI3K', 'Var', (112, 116))
47119	31683902	Atractylodin was shown to inhibit wound healing of the cholangiocarcinoma cell CL-6 after 24 and 48 h of exposure.	('cholangiocarcinoma cell CL-6', 'Disease', 'MESH:D018281', (55, 83))	('inhibit', 'NegReg', (26, 33))	('Atractylodin', 'Var', (0, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('Atractylodin', 'Chemical', 'MESH:C106914', (0, 12))	('cholangiocarcinoma cell CL-6', 'Disease', (55, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (55, 73))
47123	31683902	Abnormality of these factors causes hemophilia B and C. The extrinsic pathway is activated by tissue damage outside the blood vessel, which is mainly controlled by the stable factor (VII).	('Abnormality', 'Var', (0, 11))	('hemophilia B', 'Disease', 'MESH:D002836', (36, 48))	('extrinsic pathway', 'Pathway', (60, 77))	('hemophilia B', 'Disease', (36, 48))	('causes', 'Reg', (29, 35))
47124	31683902	Abnormality of factor VII causes hemophilia A.	('Abnormality', 'Var', (0, 11))	('causes', 'Reg', (26, 32))	('hemophilia A', 'Disease', (33, 45))	('hemophilia A', 'Disease', 'MESH:D006467', (33, 45))	('Abnormality of factor VII', 'Phenotype', 'HP:0008169', (0, 25))	('factor VII', 'Protein', (15, 25))
47208	30675407	Enteric hyperoxaluria leading to AON has numerous well-documented causes, including consumption and juicing of oxalate-rich foods (spinach, parsley, peanuts, soy, and star fruit) in weight loss attempts, high intake of vitamin C supplementation, low vitamin B6 intake, toxic ingestions of ethylene glycol (antifreeze), and multiple causes of fat malabsorption (chronic pancreatitis, gastric bypass, medications inhibiting pancreatic lipase, and various causes of colitis including inflammatory bowel disease).	('AON', 'Chemical', '-', (33, 36))	('vitamin C', 'Chemical', 'MESH:D001205', (219, 228))	('low vitamin B6 intake', 'Phenotype', 'HP:0008326', (246, 267))	('fat malabsorption', 'Phenotype', 'HP:0002630', (342, 359))	('malabsorption', 'Phenotype', 'HP:0002024', (346, 359))	('hyperoxaluria', 'Phenotype', 'HP:0003159', (8, 21))	('spinach', 'Species', '3562', (131, 138))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (361, 381))	('hyperoxaluria', 'Disease', 'MESH:D006959', (8, 21))	('parsley', 'Species', '4043', (140, 147))	('vitamin B6', 'Chemical', 'MESH:D025101', (250, 260))	('peanuts', 'Species', '3818', (149, 156))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (481, 507))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (481, 507))	('colitis', 'Phenotype', 'HP:0002583', (463, 470))	('gastric bypass', 'Disease', (383, 397))	('inflammatory bowel disease', 'Disease', (481, 507))	('weight loss', 'Disease', 'MESH:D015431', (182, 193))	('pancreatic lipase', 'Disease', (422, 439))	('low', 'Var', (246, 249))	('ethylene glycol', 'Chemical', 'MESH:D019855', (289, 304))	('fat malabsorption', 'Disease', 'MESH:D008286', (342, 359))	('causes', 'Reg', (332, 338))	('pancreatitis', 'Phenotype', 'HP:0001733', (369, 381))	('weight loss', 'Phenotype', 'HP:0001824', (182, 193))	('AON', 'Disease', (33, 36))	('colitis', 'Disease', (463, 470))	('hyperoxaluria', 'Disease', (8, 21))	('oxalate', 'Chemical', 'MESH:D010070', (111, 118))	('fat malabsorption', 'Disease', (342, 359))	('weight loss', 'Disease', (182, 193))	('inhibiting', 'NegReg', (411, 421))	('pancreatic lipase', 'Disease', 'OMIM:614338', (422, 439))	('pancreatitis', 'Disease', 'MESH:D010195', (369, 381))	('high intake of vitamin C', 'Phenotype', 'HP:0100510', (204, 228))	('colitis', 'Disease', 'MESH:D003092', (463, 470))	('pancreatitis', 'Disease', (369, 381))
47232	27231123	Isocitrate dehydrogenase mutations confer dasatinib hypersensitivity and SRC-dependence in intrahepatic cholangiocarcinoma Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver bile duct malignancy exhibiting frequent isocitrate dehydrogenase (IDH1/IDH2) mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('IDH1/IDH2', 'Gene', (251, 260))	('SRC-dependence in intrahepatic cholangiocarcinoma', 'Disease', (73, 122))	('hypersensitivity', 'Disease', 'MESH:D004342', (52, 68))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('SRC-dependence in intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (73, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('Intrahepatic cholangiocarcinoma', 'Disease', (123, 154))	('mutations', 'Var', (25, 34))	('isocitrate dehydrogenase', 'Gene', '3417', (225, 249))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (136, 154))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (104, 122))	('aggressive liver bile duct malignancy', 'Disease', (167, 204))	('liver bile duct malignancy', 'Phenotype', 'HP:0030153', (178, 204))	('isocitrate dehydrogenase', 'Gene', (225, 249))	('hypersensitivity', 'Disease', (52, 68))	('aggressive liver bile duct malignancy', 'Disease', 'MESH:D001650', (167, 204))	('dasatinib', 'Chemical', 'MESH:D000069439', (42, 51))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))	('Intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (123, 154))
47233	27231123	Through a high-throughput drug screen of a large panel of cancer cell lines including 17 biliary tract cancers, we found that IDH mutant (IDHm) ICC cells demonstrate a striking response to the multi-kinase inhibitor dasatinib, with the highest sensitivity among 682 solid tumor cell lines.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('solid tumor', 'Disease', (266, 277))	('dasatinib', 'Chemical', 'MESH:D000069439', (216, 225))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('biliary tract cancers', 'Disease', 'MESH:D001661', (89, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('biliary tract cancers', 'Disease', (89, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('response', 'MPA', (177, 185))	('solid tumor', 'Disease', 'MESH:D009369', (266, 277))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('rat', 'Species', '10116', (161, 164))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', (103, 109))	('mutant', 'Var', (130, 136))
47234	27231123	Using unbiased proteomics to capture the activated kinome and CRISPR/Cas9-based genome editing to introduce dasatinib-resistant 'gatekeeper' mutant kinases, we identified SRC as a critical dasatinib target in IDHm ICC.	('mutant', 'Var', (141, 147))	('dasatinib', 'Chemical', 'MESH:D000069439', (189, 198))	('SRC', 'Gene', '6714', (171, 174))	('SRC', 'Gene', (171, 174))	('dasatinib', 'Chemical', 'MESH:D000069439', (108, 117))	('gatekeeper', 'Species', '111938', (129, 139))	('IDHm ICC', 'Disease', (209, 217))
47242	27231123	These mutations occur within the isocitrate binding site of IDH1 (R132) or IDH2 (R172, R140) and cause altered enzymatic function, leading to the production of R(-)-2-hydroxyglutarate (2HG), a proposed 'oncometabolite'.	('leading to', 'Reg', (131, 141))	('R132', 'Var', (66, 70))	('enzymatic function', 'MPA', (111, 129))	('R172', 'Var', (81, 85))	('IDH1', 'Gene', (60, 64))	('IDH2', 'Gene', (75, 79))	('cause altered', 'Reg', (97, 110))	('isocitrate', 'Chemical', 'MESH:C034219', (33, 43))	('R(-)-2-hydroxyglutarate', 'Chemical', '-', (160, 183))	('mutations', 'Var', (6, 15))
47244	27231123	In the mouse liver, mutant IDH blocks adult liver progenitor cells from undergoing hepatocyte differentiation as an early event in ICC pathogenesis.	('IDH', 'Gene', (27, 30))	('mouse', 'Species', '10090', (7, 12))	('ICC', 'Disease', (131, 134))	('blocks', 'NegReg', (31, 37))	('mutant', 'Var', (20, 26))
47246	27231123	There is a great deal of interest in the pharmacologic targeting of the mutant IDH enzyme and evidence of highly significant responses in acute myeloid leukemia patients treated with an IDH2 inhibitor.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (138, 160))	('IDH', 'Gene', (79, 82))	('mutant', 'Var', (72, 78))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (138, 160))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (144, 160))	('leukemia', 'Phenotype', 'HP:0001909', (152, 160))	('patients', 'Species', '9606', (161, 169))	('acute myeloid leukemia', 'Disease', (138, 160))
47251	27231123	Sequencing analysis identified two ICC cell lines with IDH1 mutations, RBE (R132S) and SNU-1079 (R132C).	('R132S', 'Var', (76, 81))	('R132C', 'Mutation', 'rs121913499', (97, 102))	('R132C', 'Var', (97, 102))	('R132S', 'Mutation', 'rs121913499', (76, 81))	('IDH1', 'Gene', (55, 59))
47263	27231123	To extend these findings, we generated a set of novel low passage human ICC cell lines from resected tumor specimens, which included an additional line harboring an endogenous IDH1 R132V mutation (designated ICC5).	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('human', 'Species', '9606', (66, 71))	('tumor', 'Disease', (101, 106))	('R132V', 'Mutation', 'p.R132V', (181, 186))	('rat', 'Species', '10116', (33, 36))	('R132V', 'Var', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
47269	27231123	Thus, our data indicate that dasatinib has potent and specific synthetic lethal interactions with IDH mutations in ICC, and that IDH mutant status is associated with distinct vulnerabilities in different cancer types.	('associated', 'Reg', (150, 160))	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('ICC', 'Disease', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('mutations', 'Var', (102, 111))	('IDH', 'Gene', (98, 101))	('dasatinib', 'Chemical', 'MESH:D000069439', (29, 38))	('synthetic', 'MPA', (63, 72))
47273	27231123	We then extended our analysis of the correlation between IDH status and drug sensitivity profiles by comparing cell lines derived from genetically engineered mouse models of ICC harboring IDH2R172K and KrasG12D mutations (SS49 cells) or KrasG12D mutation and p53 deletion (425 and 537 cells).	('p53', 'Gene', '22060', (259, 262))	('mouse', 'Species', '10090', (158, 163))	('drug sensitivity', 'Phenotype', 'HP:0020174', (72, 88))	('deletion', 'Var', (263, 271))	('KrasG12D mutations', 'Var', (202, 220))	('KrasG12D mutation', 'Var', (237, 254))	('IDH2R172K', 'Var', (188, 197))	('p53', 'Gene', (259, 262))	('SS49', 'CellLine', 'CVCL:7027', (222, 226))
47280	27231123	Finally, we developed a human PDX model (SS110) from a resected ICC harboring an IDH1 R132C mutation.	('R132C', 'Mutation', 'rs121913499', (86, 91))	('R132C mutation', 'Var', (86, 100))	('IDH1', 'Gene', (81, 85))	('human', 'Species', '9606', (24, 29))
47286	27231123	To gain insight into the mechanism underlying dasatinib sensitivity, we examined the impact of dasatinib on major oncogenic pathways in IDH WT and mutant ICC cells over a time-course of treatment.	('mutant', 'Var', (147, 153))	('ICC', 'Gene', (154, 157))	('dasatinib', 'Chemical', 'MESH:D000069439', (46, 55))	('dasatinib', 'Chemical', 'MESH:D000069439', (95, 104))
47298	27231123	A threonine residue that allows access to this pocket has been designated as a 'gatekeeper' whose mutation to a more bulky residue, such as isoleucine, leads to loss of inhibitor binding without affecting normal kinase activity.	('gatekeeper', 'Species', '111938', (80, 90))	('mutation', 'Var', (98, 106))	('threonine', 'Chemical', 'MESH:D013912', (2, 11))	('isoleucine', 'Chemical', 'MESH:D007532', (140, 150))	('loss', 'NegReg', (161, 165))	('inhibitor', 'MPA', (169, 178))
47299	27231123	We therefore used CRISPR/Cas9 technology to screen for gatekeeper mutations that could rescue IDHm ICC cells from dasatinib-induced cytotoxicity.	('mutations', 'Var', (66, 75))	('IDHm ICC', 'Disease', (94, 102))	('dasatinib-induced', 'MPA', (114, 131))	('cytotoxicity', 'Disease', 'MESH:D064420', (132, 144))	('rescue', 'PosReg', (87, 93))	('dasatinib', 'Chemical', 'MESH:D000069439', (114, 123))	('gatekeeper', 'Species', '111938', (55, 65))	('cytotoxicity', 'Disease', (132, 144))
47303	27231123	Thus, our data show that SRC inhibition is critical for dasatinib-mediated cytotoxicity in IDH mutant ICC, although we cannot rule out additional targets that may contribute to this effect.	('cytotoxicity', 'Disease', (75, 87))	('dasatinib', 'Chemical', 'MESH:D000069439', (56, 65))	('SRC', 'Gene', '6714', (25, 28))	('cytotoxicity', 'Disease', 'MESH:D064420', (75, 87))	('IDH', 'Gene', (91, 94))	('SRC', 'Gene', (25, 28))	('mutant', 'Var', (95, 101))
47307	27231123	Importantly, this was not unique to SNU-1079 cells, as genome editing to introduce the SRCT341I gatekeeper mutation into a second IDH mutant ICC cell line, RBE, also resulted in marked resistance to dasatinib (shifting IC50 >500 fold) (Figure 4F, top left panel, and Supplementary Figure S5B).	('resulted in', 'Reg', (166, 177))	('dasatinib', 'Chemical', 'MESH:D000069439', (199, 208))	('SRCT341I', 'Gene', (87, 95))	('resistance', 'MPA', (185, 195))	('gatekeeper', 'Species', '111938', (96, 106))	('mutation', 'Var', (107, 115))	('SRCT341I', 'CellLine', 'CVCL:0018', (87, 95))
47308	27231123	In keeping with these results, gatekeeper mutant expression rescued the effect of dasatinib on key signaling pathways, with SRCT341I cells maintaining phospho-p70S6K and phospho-S6 levels upon dasatinib treatment, in contrast to what is seen in parental cells (Figure 4G).	('mutant', 'Var', (42, 48))	('key signaling pathways', 'Pathway', (95, 117))	('gatekeeper', 'Species', '111938', (31, 41))	('p70S6K', 'Gene', (159, 165))	('phospho-S6 levels', 'MPA', (170, 187))	('dasatinib', 'Chemical', 'MESH:D000069439', (193, 202))	('p70S6K', 'Gene', '6198', (159, 165))	('SRCT341I', 'CellLine', 'CVCL:0018', (124, 132))	('dasatinib', 'Chemical', 'MESH:D000069439', (82, 91))
47310	27231123	In further validation studies, shRNA-mediated knockdown of SRC also reduced pS6 levels and abolished growth specifically in IDHm ICC cells (Supplementary Figure S5C and S5D).	('growth', 'MPA', (101, 107))	('knockdown', 'Var', (46, 55))	('pS6', 'Gene', (76, 79))	('SRC', 'Gene', '6714', (59, 62))	('SRC', 'Gene', (59, 62))	('reduced', 'NegReg', (68, 75))	('pS6', 'Gene', '338413', (76, 79))	('IDHm', 'Disease', (124, 128))	('abolished', 'NegReg', (91, 100))
47313	27231123	The discovery of frequent IDH mutations in ICC as well as in other cancers has lead to great enthusiasm for both unraveling their unusual effects on cancer cell biology and interrogating the mutant enzymes as drug targets.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancer', 'Disease', (149, 155))	('cancers', 'Disease', (67, 74))	('cancer', 'Disease', (67, 73))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('ICC', 'Disease', (43, 46))	('IDH', 'Gene', (26, 29))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
47314	27231123	The development of potent, specific, and non-toxic mutant IDH inhibitors, and their effective deployment as single agents in IDHm leukemia represent important advances in oncology.	('IDH inhibitors', 'Gene', (58, 72))	('leukemia', 'Phenotype', 'HP:0001909', (130, 138))	('leukemia', 'Disease', (130, 138))	('leukemia', 'Disease', 'MESH:D007938', (130, 138))	('oncology', 'Phenotype', 'HP:0002664', (171, 179))	('mutant', 'Var', (51, 57))
47316	27231123	Early preclinical work and clinical trials data indicate that mutant IDH inhibition may provide benefit in solid tumors, although the effects appear more modest than those seen in leukemia.	('benefit', 'PosReg', (96, 103))	('mutant', 'Var', (62, 68))	('inhibition', 'NegReg', (73, 83))	('IDH', 'Gene', (69, 72))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('solid tumors', 'Disease', (107, 119))	('leukemia', 'Phenotype', 'HP:0001909', (180, 188))	('leukemia', 'Disease', 'MESH:D007938', (180, 188))	('leukemia', 'Disease', (180, 188))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('solid tumors', 'Disease', 'MESH:D009369', (107, 119))
47321	27231123	We show that IDHm ICCs are profound outliers in their responsiveness to dasatinib, and that SRC gatekeeper mutants confer almost complete protection of these cells.	('SRC', 'Gene', '6714', (92, 95))	('mutants', 'Var', (107, 114))	('SRC', 'Gene', (92, 95))	('dasatinib', 'Chemical', 'MESH:D000069439', (72, 81))	('responsiveness to dasatinib', 'MPA', (54, 81))	('gatekeeper', 'Species', '111938', (96, 106))
47327	27231123	In particular, SRC kinase activity was comparable in IDH WT and mutant cell lines (data not shown) and IDH WT and mutant ICCs in the TCGA database show similar SRC mRNA levels (data not shown).	('SRC', 'Gene', (15, 18))	('SRC', 'Gene', (160, 163))	('SRC', 'Gene', '6714', (15, 18))	('SRC', 'Gene', '6714', (160, 163))	('mutant', 'Var', (114, 120))
47329	27231123	It is noteworthy that all IDHm ICC models evaluated, including both human and murine cells harboring either IDH1 or IDH2 mutations, demonstrated a similar level of sensitivity to dasatinib.	('sensitivity', 'MPA', (164, 175))	('human', 'Species', '9606', (68, 73))	('mutations', 'Var', (121, 130))	('dasatinib', 'Chemical', 'MESH:D000069439', (179, 188))	('rat', 'Species', '10116', (139, 142))	('IDH2', 'Gene', (116, 120))	('murine', 'Species', '10090', (78, 84))	('IDHm ICC', 'Disease', (26, 34))	('IDH1', 'Gene', (108, 112))
47330	27231123	Yet, expression of mutant IDH alone is not sufficient to confer this response, as IDHm cells from other solid tumors (lung cancer and chondrosarcoma) had five- to 100-fold higher IC50 than IDHm ICC (Supplementary Figure S3C).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('IC50', 'MPA', (179, 183))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (134, 148))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('solid tumors', 'Disease', (104, 116))	('higher', 'PosReg', (172, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('mutant', 'Var', (19, 25))	('lung cancer', 'Disease', (118, 129))	('chondrosarcoma', 'Disease', (134, 148))	('chondrosarcoma', 'Disease', 'MESH:D002813', (134, 148))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))
47331	27231123	Thus, IDH mutations confer dasatinib hypersensitivity when present during ICC pathogenesis, but not when expressed exogenously in established tumors, which may reflect the unique selective pressures induced by these mutations or the 2HG oncometabolite during tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('IDH', 'Gene', (6, 9))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumor', 'Disease', (142, 147))	('ICC', 'Disease', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('dasatinib', 'Chemical', 'MESH:D000069439', (27, 36))	('hypersensitivity', 'Disease', 'MESH:D004342', (37, 53))	('mutations', 'Var', (10, 19))	('tumors', 'Disease', (142, 148))	('tumor', 'Disease', (259, 264))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('hypersensitivity', 'Disease', (37, 53))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
47332	27231123	Accordingly, ICC tumors harboring endogenous IDH mutations define a distinct subtype of ICC, with a characteristic transcriptional and epigenetic profile.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('IDH', 'Gene', (45, 48))	('mutations', 'Var', (49, 58))	('ICC tumors', 'Disease', 'MESH:C566123', (13, 23))	('ICC tumors', 'Disease', (13, 23))	('ICC', 'Disease', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
47336	27231123	The possible synergy of dasatinib with mutant IDH inhibitors, for instance, remains an active area of investigation.	('dasatinib', 'Chemical', 'MESH:D000069439', (24, 33))	('IDH', 'Gene', (46, 49))	('mutant', 'Var', (39, 45))
47337	27231123	Unfortunately, our preliminary studies suggest that this combination may be antagonistic in some tumors, which implies a potential role for 2HG or mutant IDH enzymatic activity in maintaining dasatinib hypersensitivity (data not shown).	('mutant', 'Var', (147, 153))	('hypersensitivity', 'Disease', (202, 218))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('dasatinib', 'Chemical', 'MESH:D000069439', (192, 201))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('IDH', 'Gene', (154, 157))	('hypersensitivity', 'Disease', 'MESH:D004342', (202, 218))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
47340	27231123	In this regard, recent genetic studies have revealed a remarkable genetic heterogeneity in these diseases, with numerous recurrent mutations in epigenetic modifiers, receptor tyrosine kinases and tumor suppressor pathways.	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('mutations', 'Var', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', (196, 201))
47351	27231123	To develop an IDH mutant human PDX, we obtained tissue from a fresh resection specimen from a patient with an IDH1 R132C mutant ICC tumor, per our IRB-approved protocol (DFCI# 13-162).	('R132C mutant', 'Var', (115, 127))	('ICC tumor', 'Disease', 'MESH:C566123', (128, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('human', 'Species', '9606', (25, 30))	('R132C', 'Mutation', 'rs121913499', (115, 120))	('patient', 'Species', '9606', (94, 101))	('IDH1', 'Gene', (110, 114))	('ICC tumor', 'Disease', (128, 137))
47362	27231123	The following day, increasing doses of either AGI-5027 (ML309) (gift from Agios Pharmaceuticals), dasatinib (S1021, Selleck Chemicals, Houston, TX), saracatinib (S1006, Selleck Chemicals), bosutinib (S1014, Selleck Chemicals), ponatinib (S1490, Selleck Chemicals), Torin 1 (S2827, Slleck Chemicals), FK866 (S2799, Selleck Chemicals) or DMSO (BP231-100, Fisher Scientific) control was added and the cells were allowed to grow until DMSO-treated wells reached confluency (5-7 days).	('dasatinib', 'Chemical', 'MESH:D000069439', (98, 107))	('Torin', 'Gene', '7001', (265, 270))	('saracatinib', 'Chemical', 'MESH:C515233', (149, 160))	('FK866', 'Chemical', 'MESH:C480543', (300, 305))	('DMSO', 'Chemical', 'MESH:D004121', (431, 435))	('DMSO', 'Chemical', 'MESH:D004121', (336, 340))	('S1021', 'Var', (109, 114))	('bosutinib', 'Chemical', 'MESH:C471992', (189, 198))	('ponatinib', 'Chemical', 'MESH:C545373', (227, 236))	('Torin', 'Gene', (265, 270))
47372	27231123	Membranes were blocked in TBS with 5% non-fat milk and 0.1% Tween  20 (BP 337-500, Fisher Scientific) and probed with antibodies against IDH1 (#3997S, Cell Signaling), IDH2 (NBP2-22166, Novus Biologicals), phospho-p70 S6 Kinase (Thr389) (#9234, Cell Signaling, Danvers, MA), total p70S6K (#2708, Cell Signaling), phospho-S6 (Ser235/236) (#4858, Cell Signaling), total S6 (#2217, Cell Signaling), phospho-ERK1/2 (Thr202/Tyr204) (#9101, Cell Signaling), total ERK1/2 (#4695, Cell Signaling), phosph-STAT3 (Ser727) (#9134, Cell Signaling), total STAT3 (#9139, Cell Signaling), BCL2 (#2872, Cell Signaling), MCL1 (sc-819, Santa Cruz Biotechnology, Dallas, TX), pSRC Y416 (#6943, Cell Signaling), total SRC (#2123, Cell Signaling), or ACTIN (A5316, Sigma-Aldrich, St. Louis, MO) as loading control.	('p70S6K', 'Gene', (281, 287))	('SRC', 'Gene', (698, 701))	('NBP2', 'Gene', (174, 178))	('STAT3', 'Gene', '6774', (497, 502))	('SRC', 'Gene', (658, 661))	('p70S6K', 'Gene', '6198', (281, 287))	('SRC', 'Gene', '6714', (658, 661))	('BCL2', 'Gene', '596', (574, 578))	('MCL1', 'Gene', '4170', (604, 608))	('MCL1', 'Gene', (604, 608))	('NBP2', 'Gene', '10101', (174, 178))	('Y416', 'Chemical', '-', (662, 666))	('SRC', 'Gene', '6714', (698, 701))	('STAT3', 'Gene', (497, 502))	('STAT3', 'Gene', '6774', (543, 548))	('#6943', 'Var', (668, 673))	('BCL2', 'Gene', (574, 578))	('STAT3', 'Gene', (543, 548))
47393	27231123	Crystal violet staining of one of the three wells is shown in Figure 4B, while the second and third wells were used for confirmation of the appropriate SRC mutation and subsequent assays.	('SRC', 'Gene', '6714', (152, 155))	('Crystal violet', 'Chemical', 'MESH:D005840', (0, 14))	('SRC', 'Gene', (152, 155))	('mutation', 'Var', (156, 164))
47406	27231123	A two-tailed Student's t test was used to assess significance for Caspase 3/7 activity assays, histological analysis of % tumor necrosis and the effect of SRC knockdown on proliferation.	('tumor necrosis', 'Disease', (122, 136))	('knockdown', 'Var', (159, 168))	('rat', 'Species', '10116', (179, 182))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('SRC', 'Gene', '6714', (155, 158))	('tumor necrosis', 'Disease', 'MESH:D009336', (122, 136))	('SRC', 'Gene', (155, 158))	('activity', 'MPA', (78, 86))	('Caspase 3', 'Gene', (66, 75))	('Caspase 3', 'Gene', '836', (66, 75))
47408	27231123	IDH mutations define a distinct subtype of intrahepatic cholangiocarcinoma (ICC), a malignancy that is largely refractory to current therapies.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('IDH', 'Gene', (0, 3))	('malignancy', 'Disease', 'MESH:D009369', (84, 94))	('malignancy', 'Disease', (84, 94))	('mutations', 'Var', (4, 13))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (43, 74))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (56, 74))	('intrahepatic cholangiocarcinoma', 'Disease', (43, 74))
47409	27231123	Our work demonstrates that IDH mutant ICC cells are hypersensitive to dasatinib and critically dependent on SRC activity for survival and proliferation, pointing to new therapeutic strategies against these cancers.	('IDH', 'Gene', (27, 30))	('rat', 'Species', '10116', (183, 186))	('mutant', 'Var', (31, 37))	('hypersensitive', 'Disease', 'MESH:D004342', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('hypersensitive', 'Disease', (52, 66))	('rat', 'Species', '10116', (16, 19))	('cancers', 'Disease', (206, 213))	('rat', 'Species', '10116', (145, 148))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('dasatinib', 'Chemical', 'MESH:D000069439', (70, 79))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('SRC', 'Gene', (108, 111))	('SRC', 'Gene', '6714', (108, 111))
47487	32506690	Guiding catheter: 9Fr Branker  Inner catheter: 8Fr JB2 countdown  Micro catheter: Penumbra 5MAX ACE , Velocity  Micro guidewire: CHIKAI 14  Clot retriever: Solitaire 6x40  The right femoral artery was punctured, and the 9Fr long sheath was placed.	('ACE', 'Gene', '1636', (96, 99))	('Solitaire', 'Var', (156, 165))	('ACE', 'Gene', (96, 99))	('6x40', 'Var', (166, 170))
47510	32506690	A meta-analysis of randomized controlled trials found that, compared with UFH, LMWH was associated with a statistically significant reduction in mortality after 3 months of treatment [relative risk = 0.71; 95% confidence interval (CI) = 0.52-0.98] without an increased risk of bleeding (Akl et al., 2011).	('LMWH', 'Var', (79, 83))	('mortality', 'Disease', (145, 154))	('reduction', 'NegReg', (132, 141))	('bleeding', 'Disease', 'MESH:D006470', (277, 285))	('bleeding', 'Disease', (277, 285))	('UFH', 'Chemical', 'MESH:D006493', (74, 77))	('mortality', 'Disease', 'MESH:D003643', (145, 154))	('LMWH', 'Chemical', 'MESH:D006495', (79, 83))
47601	32246704	An EGFR inhibitor was the first targeted drug used for tumor therapy and has been approved for treating metastatic non-small-cell lung cancer, pancreatic cancer, colorectal cancer, and squamous cell carcinoma of the head and neck.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('inhibitor', 'Var', (8, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('EGFR', 'Gene', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (162, 179))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (185, 208))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (143, 160))	('lung cancer', 'Disease', (130, 141))	('squamous cell carcinoma', 'Disease', (185, 208))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('pancreatic cancer', 'Disease', 'MESH:D010190', (143, 160))	('colorectal cancer', 'Disease', 'MESH:D015179', (162, 179))	('EGFR', 'Gene', '1956', (3, 7))	('tumor', 'Disease', (55, 60))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('colorectal cancer', 'Disease', (162, 179))	('pancreatic cancer', 'Disease', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
47647	29903769	YAP was phosphorylated on tyrosine 357 (Y357) in CCA cell lines and PDX models.	('phospho', 'Chemical', 'MESH:C033601', (8, 15))	('CCA', 'Phenotype', 'HP:0030153', (49, 52))	('tyrosine', 'Chemical', 'None', (26, 34))	('Y357', 'Var', (40, 44))	('CCA', 'Disease', (49, 52))
47648	29903769	SRC family kinase (SFK) inhibition with dasatinib resulted in loss of YAPY357 phosphorylation, promoted its translocation from the nucleus to the cytoplasm, and reduced YAP target gene expression; including cell lines expressing a LATS1/2-resistant YAP mutant in which all serine residues were mutated to alanine.	('loss', 'NegReg', (62, 66))	('LATS1', 'Gene', '9113', (231, 236))	('reduced', 'NegReg', (161, 168))	('phosphorylation', 'MPA', (78, 93))	('serine', 'Chemical', 'MESH:C047902', (273, 279))	('promoted', 'PosReg', (95, 103))	('mutant', 'Var', (253, 259))	('expression', 'MPA', (185, 195))	('phospho', 'Chemical', 'MESH:C033601', (78, 85))	('YAPY357', 'Gene', (70, 77))	('SRC', 'Gene', '6714', (0, 3))	('SRC', 'Gene', (0, 3))	('inhibition', 'NegReg', (24, 34))	('alanine', 'Chemical', 'MESH:D000409', (305, 312))	('YAP', 'Gene', (249, 252))	('translocation from the', 'MPA', (108, 130))	('LATS1', 'Gene', (231, 236))	('dasatinib', 'Chemical', 'MESH:C488369', (40, 49))
47651	29903769	Likewise, inducible CRISPR/Cas9-targeted LCK deletion decreased YAPY357 phosphorylation and its nuclear localization.	('nuclear localization', 'MPA', (96, 116))	('YAPY357', 'Protein', (64, 71))	('LCK', 'Gene', (41, 44))	('LCK', 'Gene', '3932', (41, 44))	('decreased', 'NegReg', (54, 63))	('phospho', 'Chemical', 'MESH:C033601', (72, 79))	('deletion', 'Var', (45, 53))
47656	29903769	Alterations in this pathway have been implicated in the pathogenesis of multiple types of cancer, including CCA, although mutations in the pathway components themselves are rare.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Alterations', 'Var', (0, 11))	('CCA', 'Phenotype', 'HP:0030153', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('implicated', 'Reg', (38, 48))	('cancer', 'Disease', (90, 96))	('CCA', 'Disease', (108, 111))
47661	29903769	The role of serine phosphorylation regulating YAP in the context of developmental processes is well described, however emerging data suggests that tyrosine phosphorylation of YAP may also play a role in regulating YAP localization and transcriptional activity, especially in cancer.	('YAP', 'Gene', (175, 178))	('tyrosine phospho', 'Chemical', 'MESH:C033601', (147, 163))	('tyrosine', 'Var', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('regulating', 'Reg', (203, 213))	('serine phospho', 'Chemical', 'MESH:C407063', (12, 26))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('YAP localization', 'MPA', (214, 230))	('transcriptional activity', 'MPA', (235, 259))	('cancer', 'Disease', (275, 281))
47663	29903769	Inhibition of PDGF receptors induced a redistribution of YAP from the nucleus (transcriptionally active) to the cytosol (transcriptionally inactive) even when YAP was mutated at the canonical LATS 1/2 phosphorylation site, serine 127 (S127).	('phospho', 'Chemical', 'MESH:C033601', (201, 208))	('S127', 'Chemical', 'MESH:C000670', (235, 239))	('serine', 'Var', (223, 229))	('redistribution', 'MPA', (39, 53))	('PDGF receptors', 'Gene', (14, 28))	('Inhibition', 'Var', (0, 10))	('LATS 1', 'Gene', (192, 198))	('serine 127', 'Chemical', 'MESH:C078661', (223, 233))	('LATS 1', 'Gene', '9113', (192, 198))
47676	29903769	The following primary antisera were used for immunoblot analysis: actin (C-11 Santa Cruz, Dallas, TX), phospho YAPY357 (ab62751 abcam, Cambridge, MA), phospho YAPS127 (4911 Cell Signaling), total YAP (63.7 Santa Cruz, 4912 CST), lamin B1 (D8P3U Cell Signaling), GAPDH (MAB374 Millipore, Temecula, CA), phospho SRCY416 (2101 Cell Signaling), SRC (L4A1 Cell Signaling), YES (3201 Cell Signaling), LCK (2657 Cell Signaling), FYN (4023 Cell Signaling), LYN (44 Santa Cruz), LATS1 (C66B Cell Signaling), phospho LATS1 (S909 Cell Signaling) and MCL-1 (S-19 Santa Cruz).	('LCK', 'Gene', (395, 398))	('SRCY416', 'CellLine', 'CVCL:3983', (310, 317))	('LATS1', 'Gene', (470, 475))	('phospho', 'Chemical', 'MESH:C033601', (151, 158))	('MCL-1', 'Gene', '4170', (539, 544))	('phospho', 'Chemical', 'MESH:C033601', (499, 506))	('LATS1', 'Gene', '9113', (470, 475))	('phospho', 'Chemical', 'MESH:C033601', (103, 110))	('SRC', 'Gene', '6714', (310, 313))	('SRC', 'Gene', '6714', (341, 344))	('GAPDH', 'Gene', '2597', (262, 267))	('C66B', 'SUBSTITUTION', 'None', (477, 481))	('C66B', 'Var', (477, 481))	('lamin B1', 'Gene', (229, 237))	('FYN', 'Gene', '2534', (422, 425))	('lamin B1', 'Gene', '4001', (229, 237))	('MCL-1', 'Gene', (539, 544))	('phospho YAPS127', 'Chemical', 'MESH:C078661', (151, 166))	('SRC', 'Gene', (310, 313))	('SRC', 'Gene', (341, 344))	('LATS1', 'Gene', (507, 512))	('GAPDH', 'Gene', (262, 267))	('FYN', 'Gene', (422, 425))	('LATS1', 'Gene', '9113', (507, 512))	('LCK', 'Gene', '3932', (395, 398))	('LYN', 'Gene', (449, 452))	('phospho', 'Chemical', 'MESH:C033601', (302, 309))	('LYN', 'Gene', '4067', (449, 452))
47677	29903769	The following primary monoclonal antibody were used for immunofluorescence and/or immunohistochemistry: total YAP (63.7 Santa Cruz), phospho YAPY357 (ab62751 abcam, Cambridge, MA), SOX9 (AB5535 Millipore) and anti-FLAG M2 (F1804 Sigma Adrich).	('phospho', 'Var', (133, 140))	('SOX9', 'Gene', (181, 185))	('SOX9', 'Gene', '6662', (181, 185))	('phospho', 'Chemical', 'MESH:C033601', (133, 140))	('F1804', 'Chemical', 'MESH:D005461', (223, 228))	('ab62751', 'Var', (150, 157))
47708	29903769	Triple mutant pEGFP-YAP Y341,357,394F was prepared in a similar way by consecutive mutations of pENTR-YAP Y357F using primers 5'-AGTGGCACCTTTCACTCTCGAG-3' and 5'-GTTAAGGAAAGGATCTGAGC-3', followed by TTCCCAGACTTCCTTGAAGCCATTC and 5'-ACGGTTCTGCTGTGAGGG-3'.	('EGF', 'Gene', (15, 18))	('mutations', 'Var', (83, 92))	('CCA', 'Phenotype', 'HP:0030153', (218, 221))	('CCA', 'Phenotype', 'HP:0030153', (202, 205))	('EGF', 'Gene', '1950', (15, 18))	('pENTR-YAP', 'Gene', (96, 105))	('Y357F', 'Mutation', 'p.Y357F', (106, 111))
47709	29903769	Finally, pENTR plasmids with mutated YAP were digested with BglII and EcoRI and YAP fragments were inserted into a BglII-EcoRI pEGFP-C3 vector.	('EGF', 'Gene', (128, 131))	('mutated', 'Var', (29, 36))	('EGF', 'Gene', '1950', (128, 131))
47721	29903769	YAPY357 phosphorylation was readily identified in HuCCT-1 and SB1 cells as compared to normal human cholangiocytes (Figure 1A).	('phospho', 'Chemical', 'MESH:C033601', (8, 15))	('HuCCT-1', 'CellLine', 'CVCL:0324', (50, 57))	('YAPY357', 'Var', (0, 7))	('human', 'Species', '9606', (94, 99))	('phosphorylation', 'MPA', (8, 23))
47723	29903769	Similar to our previous observations that phosphorylated YAPY357 was enriched in the nucleus of HuCCT-1 cells, immunohistochemistry also demonstrated significant enrichment of the phosphorylated YAPY357 in the nuclei of tumors from the PDX and our YAP-driven murine model of CCA (Figures 1B,C).	('murine', 'Species', '10090', (259, 265))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('phospho', 'Chemical', 'MESH:C033601', (180, 187))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('CCA', 'Phenotype', 'HP:0030153', (275, 278))	('phosphorylated YAPY357', 'Var', (180, 202))	('YAPY357', 'Var', (195, 202))	('tumors', 'Disease', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('HuCCT-1', 'CellLine', 'CVCL:0324', (96, 103))	('phospho', 'Chemical', 'MESH:C033601', (42, 49))	('CCA', 'Disease', (275, 278))
47726	29903769	In contrast, in CCA a significant proportion of YAP localized to the nucleus is phosphorylated at Y357.	('CCA', 'Phenotype', 'HP:0030153', (16, 19))	('CCA', 'Disease', (16, 19))	('phospho', 'Chemical', 'MESH:C033601', (80, 87))	('Y357', 'Var', (98, 102))
47737	29903769	Similar on-target effects were noted in the PDX including reduced SFKY419 phosphorylation, YAPY357 phosphorylation, and YAP target gene expression (Figures 2B-D).	('phosphorylation', 'MPA', (74, 89))	('YAPY357', 'Var', (91, 98))	('SFKY419', 'Gene', (66, 73))	('expression', 'MPA', (136, 146))	('phospho', 'Chemical', 'MESH:C033601', (74, 81))	('phospho', 'Chemical', 'MESH:C033601', (99, 106))	('SFKY419', 'Chemical', 'MESH:C496616', (66, 73))	('reduced', 'NegReg', (58, 65))
47742	29903769	Only knockdown of LCK was associated with a significant decrease in YAPY357 phosphorylation (Figure 3B).	('phospho', 'Chemical', 'MESH:C033601', (76, 83))	('knockdown', 'Var', (5, 14))	('YAPY357 phosphorylation', 'MPA', (68, 91))	('LCK', 'Gene', (18, 21))	('LCK', 'Gene', '3932', (18, 21))	('decrease', 'NegReg', (56, 64))
47743	29903769	Utilizing the YAP target genes CTGF and CYR61 as markers of YAP co-transcriptional activity we demonstrated downregulation of co-transcriptional activity with knockdown of multiple SFKs; however the most dramatic downregulation of YAP co-transcriptional activity was noted in the siLCK-HuCCT1 cells as compared to a non-targeted control (Figure 3C).	('knockdown', 'Var', (159, 168))	('CTGF', 'Gene', '1490', (31, 35))	('CTGF', 'Gene', (31, 35))	('downregulation', 'NegReg', (213, 227))	('CYR61', 'Gene', (40, 45))	('LCK', 'Gene', (282, 285))	('downregulation', 'NegReg', (108, 122))	('LCK', 'Gene', '3932', (282, 285))	('CYR61', 'Gene', '3491', (40, 45))	('co-transcriptional activity', 'MPA', (126, 153))
47748	29903769	Genetic deletion of LCK was paralleled by a near complete repression of YAPY357 phosphorylation, and subsequent redistribution of nuclear YAP to the cytosol, with undetectable levels at 72 hours (Figures 3E,F).	('phospho', 'Chemical', 'MESH:C033601', (80, 87))	('LCK', 'Gene', (20, 23))	('LCK', 'Gene', '3932', (20, 23))	('YAPY357', 'Protein', (72, 79))	('repression', 'NegReg', (58, 68))	('redistribution', 'MPA', (112, 126))	('deletion', 'Var', (8, 16))
47750	29903769	Utilizing recombinant YAP as a phospho-substrate with LCK in a cell free assay, we were able to directly demonstrate efficient YAP Y357 phosphorylation by LCK (Figure 3G).	('YAP', 'Gene', (127, 130))	('phospho', 'Chemical', 'MESH:C033601', (136, 143))	('LCK', 'Gene', (155, 158))	('Y357', 'Var', (131, 135))	('LCK', 'Gene', '3932', (155, 158))	('phospho', 'Chemical', 'MESH:C033601', (31, 38))	('LCK', 'Gene', (54, 57))	('LCK', 'Gene', '3932', (54, 57))
47757	29903769	The SB1 cells express an epitope-tagged YAP containing the S127A mutation, rendering S127A-YAP insensitive to serine/threonine kinase phosphorylation, providing a useful reagent to determine if YAP subcellular localization may be controlled independent of the canonical serine/threonine kinase cascades.	('S127A', 'SUBSTITUTION', 'None', (85, 90))	('threonine', 'Chemical', 'MESH:C061951', (277, 286))	('phospho', 'Chemical', 'MESH:C033601', (134, 141))	('S127A', 'SUBSTITUTION', 'None', (59, 64))	('serine', 'Chemical', 'MESH:C047902', (270, 276))	('S127A', 'Var', (85, 90))	('S127A', 'Var', (59, 64))	('threonine', 'Chemical', 'MESH:C061951', (117, 126))	('serine', 'Chemical', 'MESH:C047902', (110, 116))
47761	29903769	We identified multiple tyrosine phosphatases associated with S127A-YAP and this association increased following incubation with dasatinib (Table 1).	('tyrosine phosphatases', 'Enzyme', (23, 44))	('S127A', 'Var', (61, 66))	('tyrosine', 'Chemical', 'None', (23, 31))	('associated', 'Reg', (45, 55))	('dasatinib', 'Chemical', 'MESH:C488369', (128, 137))	('S127A', 'SUBSTITUTION', 'None', (61, 66))
47774	29903769	Previous work has demonstrated that SFK may also phosphorylate YAP on tyrosines 341, 357, and 394.	('tyrosines 341', 'Var', (70, 83))	('tyrosines', 'Chemical', 'None', (70, 79))	('phospho', 'Chemical', 'MESH:C033601', (49, 56))	('YAP', 'Protein', (63, 66))
47775	29903769	Therefore, we also examined the role of these tyrosine phospho sites in regulating YAP cellular compartmentation by expressing an eGFP-fusion protein in which these three tyrosine residues were mutated to phenylalanine (Y341F, Y357F, Y394F-YAP-eGFP).	('Y394F-YAP-eGFP', 'Var', (234, 248))	('Y357F', 'Var', (227, 232))	('Y341F', 'Mutation', 'p.Y341F', (220, 225))	('Y394F', 'Mutation', 'p.Y394F', (234, 239))	('tyrosine', 'Chemical', 'None', (171, 179))	('phenylalanine', 'Chemical', 'MESH:C119108', (205, 218))	('tyrosine phospho', 'Chemical', 'MESH:C033601', (46, 62))	('Y341F', 'Var', (220, 225))	('tyrosine', 'Chemical', 'None', (46, 54))	('Y357F', 'Mutation', 'p.Y357F', (227, 232))
47776	29903769	Indeed, Y357F-YAP-eGFP was also excluded from the nucleus; suggesting that phosphorylation of the Y357 residue was sufficient to regulate nuclear retention of YAP in cholangiocarcinoma cells (Figure 4F).	('nuclear retention', 'MPA', (138, 155))	('regulate', 'Reg', (129, 137))	('phospho', 'Chemical', 'MESH:C033601', (75, 82))	('Y357F', 'Mutation', 'p.Y357F', (8, 13))	('cholangiocarcinoma', 'Disease', (166, 184))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (166, 184))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (166, 184))	('Y357', 'Var', (98, 102))
47778	29903769	Taken together, these data suggest a nuclear retention pathway for YAP regulated by tyrosine phosphorylation of Y357 and independent of YAP serine phosphorylation and therefore LATS1 activity.	('LATS1', 'Gene', (177, 182))	('LATS1', 'Gene', '9113', (177, 182))	('serine phospho', 'Chemical', 'MESH:C407063', (140, 154))	('nuclear retention pathway', 'Pathway', (37, 62))	('tyrosine phospho', 'Chemical', 'MESH:C033601', (84, 100))	('Y357', 'Var', (112, 116))
47784	29903769	Collectively, SFK inhibition with dasatinib was tumor suppressive in vitro and in vivo suggesting the LCK-mediated YAP tyrosine phosphorylation pathway in CCA is potentially therapeutically targetable.	('LCK', 'Gene', (102, 105))	('dasatinib', 'Chemical', 'MESH:C488369', (34, 43))	('tumor', 'Disease', (48, 53))	('LCK', 'Gene', '3932', (102, 105))	('CCA', 'Phenotype', 'HP:0030153', (155, 158))	('inhibition', 'Var', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('CCA', 'Disease', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tyrosine phospho', 'Chemical', 'MESH:C033601', (119, 135))
47788	29903769	This serine/threonine kinase relay culminates in phosphorylation of regulatory serine residues on YAP; regulatory serine phosphorylation promotes YAP cytosolic sequestration and/or proteasomal degradation.	('phospho', 'Chemical', 'MESH:C033601', (121, 128))	('promotes', 'PosReg', (137, 145))	('proteasomal degradation', 'MPA', (181, 204))	('serine', 'Chemical', 'MESH:C047902', (5, 11))	('serine phospho', 'Chemical', 'MESH:C407063', (114, 128))	('regulatory serine phosphorylation', 'Var', (103, 136))	('phospho', 'Chemical', 'MESH:C033601', (49, 56))	('serine', 'Chemical', 'MESH:C047902', (79, 85))	('cytosolic sequestration', 'MPA', (150, 173))	('serine', 'Chemical', 'MESH:C047902', (114, 120))	('threonine', 'Chemical', 'MESH:C061951', (12, 21))
47789	29903769	This pathway, which we have termed the cytosolic retention pathway, restrains the activity of YAP; and consistent with these concepts we and others have demonstrated complete exclusion of phosphorylated YAPS127 from the nucleus.	('phosphorylated', 'Var', (188, 202))	('phospho', 'Chemical', 'MESH:C033601', (188, 195))	('activity', 'MPA', (82, 90))	('restrains', 'NegReg', (68, 77))	('exclusion', 'NegReg', (175, 184))	('YAPS127', 'Gene', (203, 210))
47794	29903769	Utilizing an inhibitory paradigm to inform the regulatory pathways, we noted redistribution of S127A-YAP from the nucleus into the cytosol following SFK inhibition.	('S127A', 'SUBSTITUTION', 'None', (95, 100))	('inhibition', 'NegReg', (153, 163))	('S127A', 'Var', (95, 100))	('SFK', 'Gene', (149, 152))	('redistribution', 'MPA', (77, 91))
47795	29903769	This redistribution of S127A-YAP out of the nucleus was accompanied by its association with tyrosine phosphatases and was blocked by a tyrosine phosphatase inhibitor.	('S127A', 'Var', (23, 28))	('tyrosine', 'Chemical', 'None', (92, 100))	('S127A', 'SUBSTITUTION', 'None', (23, 28))	('tyrosine', 'Protein', (92, 100))	('tyrosine', 'Chemical', 'None', (135, 143))	('association', 'Interaction', (75, 86))
47796	29903769	These data suggest a regulatory process whereby YAP tyrosine phosphorylation promotes nuclear retention.	('tyrosine phospho', 'Chemical', 'MESH:C033601', (52, 68))	('YAP tyrosine phosphorylation', 'Var', (48, 76))	('nuclear retention', 'CPA', (86, 103))	('promotes', 'PosReg', (77, 85))
47798	29903769	While S127 is the most comprehensively studied serine residue regulating YAP cellular compartmentation, other potential regulatory serine phosphorylation sites exist in YAP, and one possibility is that the Hippo kinase module could be regulating the subcellular localization by phosphorylation at serines other than S127.	('serine', 'Chemical', 'MESH:C047902', (297, 303))	('S127', 'Chemical', 'MESH:C000670', (316, 320))	('regulating', 'Reg', (235, 245))	('serine phospho', 'Chemical', 'MESH:C407063', (131, 145))	('serine', 'Chemical', 'MESH:C047902', (47, 53))	('S127', 'Var', (6, 10))	('S127', 'Chemical', 'MESH:C000670', (6, 10))	('subcellular localization', 'MPA', (250, 274))	('phospho', 'Chemical', 'MESH:C033601', (138, 145))	('serine', 'Chemical', 'MESH:C047902', (131, 137))	('phospho', 'Chemical', 'MESH:C033601', (278, 285))
47799	29903769	Moreover, LATS1 tyrosine phosphorylation may also negatively regulate LATS1 serine kinase activity.	('tyrosine', 'Var', (16, 24))	('regulate', 'Reg', (61, 69))	('serine', 'Chemical', 'MESH:C047902', (76, 82))	('tyrosine phospho', 'Chemical', 'MESH:C033601', (16, 32))	('LATS1', 'Gene', (10, 15))	('negatively', 'NegReg', (50, 60))	('LATS1', 'Gene', (70, 75))	('LATS1', 'Gene', '9113', (10, 15))	('LATS1', 'Gene', '9113', (70, 75))
47800	29903769	In this scenario, SFK inhibition may increase LATS1 activity and subsequent YAP phosphorylation on multiple serine residues.	('inhibition', 'Var', (22, 32))	('phospho', 'Chemical', 'MESH:C033601', (80, 87))	('activity', 'MPA', (52, 60))	('serine', 'Chemical', 'MESH:C047902', (108, 114))	('increase', 'PosReg', (37, 45))	('LATS1', 'Gene', (46, 51))	('YAP phosphorylation on multiple serine residues', 'MPA', (76, 123))	('LATS1', 'Gene', '9113', (46, 51))
47803	29903769	In IDH1/2 mutated CCA, Saha et al, demonstrated a central role for SRC itself.	('mutated', 'Var', (10, 17))	('SRC', 'Gene', (67, 70))	('CCA', 'Disease', (18, 21))	('IDH', 'Gene', '3417', (3, 6))	('CCA', 'Phenotype', 'HP:0030153', (18, 21))	('IDH', 'Gene', (3, 6))	('SRC', 'Gene', '6714', (67, 70))
47805	29903769	We did however note a decrease in YAP tyrosine phosphorylation and transcriptional activity with siRNA targeted knockdown of LCK.	('tyrosine phospho', 'Chemical', 'MESH:C033601', (38, 54))	('decrease', 'NegReg', (22, 30))	('transcriptional', 'MPA', (67, 82))	('YAP tyrosine phosphorylation', 'MPA', (34, 62))	('knockdown', 'Var', (112, 121))	('LCK', 'Gene', (125, 128))	('LCK', 'Gene', '3932', (125, 128))
47819	29903769	Finally we have generated additional pre-clinical data supporting the role of SFK inhibition in the treatment of intrahepatic cholangiocarcinoma.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:C535533', (113, 144))	('SFK', 'Gene', (78, 81))	('inhibition', 'Var', (82, 92))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (126, 144))	('intrahepatic cholangiocarcinoma', 'Disease', (113, 144))
47906	27069317	Mutations of p53 are clearly involved in the pathogenesis of BEA, and the fact that the mutations were detected in premalignant Barrett's epithelium supports the hypothesis that p53 mutations may be a useful marker for patients at increased risk for development of invasive cancer.	('patients', 'Species', '9606', (219, 227))	('BEA', 'Disease', (61, 64))	('BEA', 'Chemical', '-', (61, 64))	('BEA', 'Phenotype', 'HP:0100580', (61, 64))	('BE', 'Phenotype', 'HP:0100580', (61, 63))	('Mutations', 'Var', (0, 9))	('invasive cancer', 'Disease', (265, 280))	('mutations', 'Var', (182, 191))	('p53', 'Gene', (13, 16))	('p53', 'Gene', (178, 181))	('invasive cancer', 'Disease', 'MESH:D009362', (265, 280))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('p53', 'Gene', '7157', (178, 181))	('p53', 'Gene', '7157', (13, 16))	('involved', 'Reg', (29, 37))
47913	27069317	Recently, oxidative DNA damage was also found to be associated with genetic instability via telomeric dysfunction, leading to p53 mutation and BEA tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('leading to', 'Reg', (115, 125))	('p53', 'Gene', '7157', (126, 129))	('telomeric dysfunction', 'Disease', (92, 113))	('mutation', 'Var', (130, 138))	('BEA', 'Disease', (143, 146))	('BEA', 'Chemical', '-', (143, 146))	('BEA', 'Phenotype', 'HP:0100580', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('BE', 'Phenotype', 'HP:0100580', (143, 145))	('p53', 'Gene', (126, 129))	('telomeric dysfunction', 'Disease', 'MESH:C536801', (92, 113))
47963	27069317	This process could be explained by the accumulation of mutation in progenitor cells, leading to the acquisition of the property of cancer stem cells.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('acquisition', 'PosReg', (100, 111))	('mutation', 'Var', (55, 63))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
47974	27069317	also reported that cytoplasmic expression of CD133 was a significant risk factor for the overall survival and tumor stages III and IVA of hepatocellular carcinoma patients.	('patients', 'Species', '9606', (163, 171))	('CD133', 'Gene', (45, 50))	('cytoplasmic expression', 'Var', (19, 41))	('CD133', 'Gene', '8842', (45, 50))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (138, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('IVA of hepatocellular carcinoma', 'Disease', 'MESH:C538167', (131, 162))	('risk', 'Reg', (69, 73))	('IVA of hepatocellular carcinoma', 'Disease', (131, 162))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
47980	27069317	GERD induces inflammatory responses and tissue injury, which mediate intestinal dysplasia and CD133 expression in apical surface of columnar epithelial cells.	('tissue injury', 'CPA', (40, 53))	('induces', 'Reg', (5, 12))	('intestinal dysplasia', 'Disease', 'MESH:D007410', (69, 89))	('CD133', 'Gene', (94, 99))	('CD133', 'Gene', '8842', (94, 99))	('expression', 'MPA', (100, 110))	('GERD', 'Var', (0, 4))	('inflammatory responses', 'CPA', (13, 35))	('intestinal dysplasia', 'Disease', (69, 89))
48106	22873816	In the intention-to-treat (ITT) analysis, the FS in patients treated with SEMS (97.9%) was significantly higher than in patients treated with PS (84.8%) (p < 0.001).	('higher', 'PosReg', (105, 111))	('SEMS', 'Var', (74, 78))	('patients', 'Species', '9606', (120, 128))	('PS', 'Chemical', '-', (142, 144))	('patients', 'Species', '9606', (52, 60))
48177	22873816	In the ITT analysis, the FS in patients treated with SEMS was significantly higher than that in patients treated with PS overall (P < 0.001) and in Group 1 (P = 0.036), Group 2 (P = 0.008) and Group 3 (P < 0.001).	('SEMS', 'Var', (53, 57))	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (96, 104))	('higher', 'PosReg', (76, 82))	('PS', 'Chemical', '-', (118, 120))
48198	22873816	Kaplan-Meier analysis showed that the cumulative stent patency times were significantly longer in patients treated with SEMS than in those treated with PS (P < 0.0001); the estimated relative risk of occlusion (hazard ratio-HR) was 2.6731-fold higher in the PS group than in the SEMS group, (95% CI 2.1416-3.3365) (Figure 4).	('PS', 'Chemical', '-', (152, 154))	('longer', 'PosReg', (88, 94))	('patients', 'Species', '9606', (98, 106))	('SEMS', 'Var', (120, 124))	('PS', 'Chemical', '-', (258, 260))	('higher', 'PosReg', (244, 250))
48302	31052445	When LATS1/2 S/T kinases are activated, they bind to and phosphorylate YAP/TAZ at five different conserved HxH/R/KxxS/T (H, histidine; R, arginine; K, lysine; x, any amino acid) motifs, including YAP S127 and TAZ S89.	('2 S/T', 'SUBSTITUTION', 'None', (11, 16))	('phosphorylate', 'MPA', (57, 70))	('2 S/T', 'Var', (11, 16))	('arginine', 'Chemical', 'MESH:D001120', (138, 146))	('lysine', 'Chemical', 'MESH:D008239', (151, 157))	('bind', 'Interaction', (45, 49))	('histidine', 'Chemical', 'MESH:D006639', (124, 133))
48311	31052445	It has been shown that PI3-kinase (PI3K), one of the main downstream signaling pathways of RTKs, induces YAP/TAZ nuclear localization through inhibition of LATS activity (Figure 2).	('LATS', 'Gene', '553164', (156, 160))	('inhibition', 'NegReg', (142, 152))	('PI3-kinase', 'Var', (23, 33))	('LATS', 'Gene', (156, 160))	('induces', 'PosReg', (97, 104))	('YAP/TAZ nuclear localization', 'MPA', (105, 133))
48312	31052445	Recently, we provided the first evidence that the Hippo pathway effectors TAZ and YAP are critical mediators of PI3K-induced mammary tumorigenesis and synergistically function together with PI3K in transformation of mammary cells.	('PI3K-induced', 'Var', (112, 124))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (133, 138))
48326	31052445	This tyrosine phosphorylation reduces the affinity of Nedd4 to AMOTL1, resulting in increasing the AMOTL1 and tight junction stability.	('increasing', 'PosReg', (84, 94))	('Nedd4', 'Gene', (54, 59))	('affinity', 'Interaction', (42, 50))	('tyrosine', 'Chemical', 'MESH:D014443', (5, 13))	('Nedd4', 'Gene', '4734', (54, 59))	('tyrosine', 'Var', (5, 13))	('reduces', 'NegReg', (30, 37))
48329	31052445	This phosphorylation site is S175 of AMOT, and has critical role in interaction with F-actin.	('actin', 'Gene', (87, 92))	('actin', 'Gene', '40444', (87, 92))	('S175', 'Var', (29, 33))	('interaction', 'Interaction', (68, 79))
48330	31052445	When LATS phosphorylates Ser-175, it disrupts AMOT interaction with F-actin and reduces F-actin stress fibers and focal adhesions, which subsequently inhibits endothelial cell migration in vitro and zebrafish embryonic angiogenesis in vivo.	('Ser', 'Chemical', 'MESH:D012694', (25, 28))	('zebrafish', 'Species', '7955', (199, 208))	('actin', 'Gene', '40444', (70, 75))	('LATS', 'Gene', '553164', (5, 9))	('phosphorylates Ser-175', 'Var', (10, 32))	('inhibits', 'NegReg', (150, 158))	('Ser-175', 'Var', (25, 32))	('actin', 'Gene', '40444', (90, 95))	('LATS', 'Gene', (5, 9))	('AMOT interaction', 'CPA', (46, 62))	('reduces', 'NegReg', (80, 87))	('endothelial cell migration', 'CPA', (159, 185))	('disrupts', 'NegReg', (37, 45))	('actin', 'Gene', (70, 75))	('actin', 'Gene', (90, 95))
48337	31052445	Furthermore, CD44 deficiency causes reduction in CD31 and vascular endothelial (VE)-cadherin that has been connected with a reduction in tight junction, leading to Ajuba inhibition of LATS.	('LATS', 'Gene', '553164', (184, 188))	('reduction', 'NegReg', (124, 133))	('tight junction', 'MPA', (137, 151))	('LATS', 'Gene', (184, 188))	('reduction', 'NegReg', (36, 45))	('CD31', 'Protein', (49, 53))	('CD44', 'Gene', (13, 17))	('deficiency', 'Var', (18, 28))	('vascular endothelial (VE)-cadherin', 'Gene', '1003', (58, 92))
48376	31052445	Surprisingly, when YAP or TAZ were conditionally knocked out in endothelial cells, mild vascular defects were observed.	('vascular defects', 'Disease', (88, 104))	('knocked out', 'Var', (49, 60))	('TAZ', 'Gene', (26, 29))	('YAP', 'Gene', (19, 22))	('vascular defects', 'Disease', 'MESH:D000783', (88, 104))
48377	31052445	Deleting both YAP and TAZ in mice causes a dramatic defect in blood vessel development at the retinal vasculature, a 21% decrease in radial expansion, a 26% decrease in capillary density, and a 55% decrease in branching frequency.	('decrease', 'NegReg', (198, 206))	('dramatic defect', 'Disease', (43, 58))	('decrease', 'NegReg', (157, 165))	('radial expansion', 'CPA', (133, 149))	('defect in blood vessel', 'Phenotype', 'HP:0002597', (52, 74))	('branching frequency', 'CPA', (210, 229))	('capillary density', 'CPA', (169, 186))	('Deleting', 'Var', (0, 8))	('decrease', 'NegReg', (121, 129))	('dramatic defect', 'Disease', 'MESH:D005128', (43, 58))	('mice', 'Species', '10090', (29, 33))
48379	31052445	Deletion of the LATS1/2 in mice endothelial cells results reduction in YAP/TAZ phosphorylation and cytoplasmic retention.	('mice', 'Species', '10090', (27, 31))	('YAP/TAZ phosphorylation', 'MPA', (71, 94))	('cytoplasmic retention', 'CPA', (99, 120))	('reduction', 'NegReg', (58, 67))	('LATS1/2', 'Gene', (16, 23))	('Deletion', 'Var', (0, 8))
48380	31052445	The retinas of these mice show migration defect with reduced extension distance, which can be partially rescued by overexpressing YAP-S127D (cytoplasmic form of YAP).	('mice', 'Species', '10090', (21, 25))	('extension distance', 'CPA', (61, 79))	('YAP-S127D', 'Var', (130, 139))	('S127D', 'Mutation', 'p.S127D', (134, 139))	('reduced', 'NegReg', (53, 60))	('migration defect', 'Disease', 'MESH:D014085', (31, 47))	('migration defect', 'Disease', (31, 47))
48381	31052445	Intriguingly, deletion of YAP/TAZ, Cdc42, or LATS1/2 in endothelial cells has a very similar phenotype in the retina, implying the possibility of operation in a common pathway in angiogenic tip cell development.	('Cdc42', 'Gene', (35, 40))	('YAP/TAZ', 'Gene', (26, 33))	('LATS1/2', 'Gene', (45, 52))	('Cdc42', 'Gene', '998', (35, 40))	('deletion', 'Var', (14, 22))
48390	31052445	Alternative gene splicing of VEGFA makes several isoforms namely, VEGF121, VEGF165, VEGF189, and VEGF206.	('VEGF206', 'Var', (97, 104))	('VEGFA', 'Gene', '7422', (29, 34))	('VEGFA', 'Gene', (29, 34))	('VEGF189', 'Var', (84, 91))	('VEGF121', 'Var', (66, 73))
48396	31052445	Moreover, endothelia-specific deletion of YAP/TAZ caused severe vascular defects throughout the whole body as well as yolk sac vascularization.	('vascular defects', 'Disease', (64, 80))	('deletion', 'Var', (30, 38))	('caused', 'Reg', (50, 56))	('vascular defects', 'Disease', 'MESH:D000783', (64, 80))	('YAP/TAZ', 'Gene', (42, 49))
48398	31052445	YAP/TAZ knocked down in endothelial cell impairs proper VEGFR2 trafficking and its downstream signaling.	('trafficking', 'MPA', (63, 74))	('VEGFR2', 'Gene', '3791', (56, 62))	('impairs', 'NegReg', (41, 48))	('VEGFR2', 'Gene', (56, 62))	('knocked down', 'Var', (8, 20))
48402	31052445	Ang-2 blockage or selective STAT3 inhibitors attenuate retinal angiogenesis in Tie2Cre-mediated YAP transgenic mice.	('Ang-2', 'Gene', '285', (0, 5))	('Ang-2', 'Gene', (0, 5))	('transgenic mice', 'Species', '10090', (100, 115))	('Tie2', 'Gene', '7010', (79, 83))	('attenuate', 'NegReg', (45, 54))	('blockage', 'Var', (6, 14))	('retinal angiogenesis', 'CPA', (55, 75))	('Tie2', 'Gene', (79, 83))
48413	31052445	Levels of YAP in EDE are higher and those of pS127-YAP are lower in patients with atherosclerotic cerebrovascular disease.	('atherosclerotic cerebrovascular disease', 'Disease', 'MESH:D050197', (82, 121))	('lower', 'NegReg', (59, 64))	('pS127-YAP', 'Var', (45, 54))	('patients', 'Species', '9606', (68, 76))	('atherosclerotic cerebrovascular disease', 'Disease', (82, 121))	('higher', 'PosReg', (25, 31))
48417	31052445	Interestingly, disrupting the YAP-TEAD interaction with verteporfin inhibits Ang II-induced vascular remodeling in mice.	('Ang', 'Gene', (77, 80))	('Ang', 'Gene', '11727', (77, 80))	('verteporfin', 'Chemical', 'MESH:D000077362', (56, 67))	('disrupting', 'Var', (15, 25))	('mice', 'Species', '10090', (115, 119))	('inhibits', 'NegReg', (68, 76))
48424	31052445	Intriguingly, knocking down YAP in these cells in combination therapy with ranibizumab, a VEGF monoclonal antibody, decreased the expression of PCNA, choroidal endothelial cell proliferation, and the incidence as well as leakage area of choroidal neovascularization.	('expression', 'MPA', (130, 140))	('choroidal endothelial cell proliferation', 'CPA', (150, 190))	('knocking down', 'Var', (14, 27))	('PCNA', 'Gene', (144, 148))	('leakage area', 'CPA', (221, 233))	('ranibizumab', 'Chemical', 'MESH:D000069579', (75, 86))	('PCNA', 'Gene', '5111', (144, 148))	('decreased', 'NegReg', (116, 125))	('choroidal neovascularization', 'Phenotype', 'HP:0011506', (237, 265))
48427	31052445	In endothelial cells and during hypoxia conditions total YAP, and p-STAT3 (Tyr705) increases, while pS127-YAP decreases.	('increases', 'PosReg', (83, 92))	('pS127-YAP', 'Var', (100, 109))	('hypoxia conditions', 'Disease', (32, 50))	('YAP', 'MPA', (57, 60))	('hypoxia conditions', 'Disease', 'MESH:D000860', (32, 50))	('Tyr705', 'Chemical', '-', (75, 81))
48434	31052445	Diabetic rats show decreased levels of p-S127-YAP and p-MST, while TAZ and TEAD total proteins are increased in their retinas.	('p-MST', 'MPA', (54, 59))	('TAZ', 'MPA', (67, 70))	('increased', 'PosReg', (99, 108))	('decreased', 'NegReg', (19, 28))	('Diabetic', 'Disease', (0, 8))	('Diabetic', 'Disease', 'MESH:D003920', (0, 8))	('rats', 'Species', '10116', (9, 13))	('p-S127-YAP', 'Var', (39, 49))
48437	31052445	Low-intensity pulsed ultrasound treatment activates YAP and TAZ nuclear localization through LATS inhibition, which can promote angiogenesis and vascular remodeling.	('inhibition', 'Var', (98, 108))	('LATS', 'Gene', (93, 97))	('promote', 'PosReg', (120, 127))	('TAZ nuclear localization', 'MPA', (60, 84))	('vascular remodeling', 'CPA', (145, 164))	('activates', 'PosReg', (42, 51))	('angiogenesis', 'CPA', (128, 140))	('LATS', 'Gene', '553164', (93, 97))
48446	31052445	Knocking down PGC1alpha inhibits YAP-S127A-induced angiogenesis.	('YAP-S127A-induced', 'Var', (33, 50))	('inhibits', 'NegReg', (24, 32))	('Knock', 'Disease', 'MESH:D056304', (0, 5))	('PGC1alpha', 'Gene', (14, 23))	('angiogenesis', 'CPA', (51, 63))	('S127A', 'Mutation', 'rs762471803', (37, 42))	('Knock', 'Disease', (0, 5))
48462	31052445	CD31low cells are more tumorigenic and chemoresistant than CD31high cells due to more efficient reactive oxygen species (ROS) detoxification.	('chemoresistant', 'CPA', (39, 53))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('more', 'PosReg', (81, 85))	('ROS', 'Chemical', 'MESH:D017382', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('CD31low', 'Var', (0, 7))	('more', 'PosReg', (18, 22))	('tumor', 'Disease', (23, 28))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (96, 119))
48464	31052445	Microarray expression profiling of cholangiocarcinoma cells with overexpressed or knocked-down YAP reveal that YAP regulates important genes in proliferation, apoptosis, and angiogenesis.	('knocked-down', 'Var', (82, 94))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (35, 53))	('angiogenesis', 'CPA', (174, 186))	('cholangiocarcinoma', 'Disease', (35, 53))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (35, 53))	('proliferation', 'CPA', (144, 157))	('YAP', 'Gene', (95, 98))	('regulates', 'Reg', (115, 124))	('apoptosis', 'CPA', (159, 168))
48471	31052445	YAP knockout in MSCs inhibits their proliferation, migration, invasion, and pro-angiogenic ability by reducing the activation of beta-catenin and its target genes.	('YAP', 'Gene', (0, 3))	('inhibits', 'NegReg', (21, 29))	('reducing', 'NegReg', (102, 110))	('proliferation', 'CPA', (36, 49))	('migration', 'CPA', (51, 60))	('activation', 'MPA', (115, 125))	('knockout', 'Var', (4, 12))	('beta-catenin', 'Gene', (129, 141))	('invasion', 'CPA', (62, 70))	('pro-angiogenic ability', 'CPA', (76, 98))	('beta-catenin', 'Gene', '1499', (129, 141))
48507	30646854	We analyzed three different PD-L1 antibodies (clones 28-8, SP142, and SP263) that are frequently used and recommended for predictive diagnostic testing in other cancer types.	('SP263', 'Chemical', '-', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('SP263', 'Var', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('PD-L1', 'Gene', (28, 33))	('cancer', 'Disease', (161, 167))	('SP142', 'Chemical', '-', (59, 64))
48510	30646854	Agreement of PD-L1 positivity in tumor cells was moderate for clone 28-8 and SP263 (kappa = 0.44) and poor between 28-8 and SP142 (kappa = 0.13), as well as  SP142 and SP263 (kappa = 0.11), respectively.	('SP263', 'Var', (168, 173))	('SP142', 'Chemical', '-', (124, 129))	('SP142', 'Var', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('SP263', 'Chemical', '-', (77, 82))	('PD-L1', 'Gene', (13, 18))	('tumor', 'Disease', (33, 38))	('SP263', 'Var', (77, 82))	('SP142', 'Chemical', '-', (158, 163))	('SP263', 'Chemical', '-', (168, 173))	('SP142', 'Var', (158, 163))
48522	30646854	Moreover, PD-L1 expression has been shown to correlate with a worse outcome in a meta-analysis including various cancer types and more than 16,000 patient samples, but CCA was not included.	('expression', 'Var', (16, 26))	('patient', 'Species', '9606', (147, 154))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('PD-L1', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
48538	30646854	The complete CCA cohort (n = 170) was analyzed three-times independently by PD-L1 immunohistochemistry employing three different PD-L1 antibodies (28-8, SP142 and SP263, Fig.	('SP263', 'Chemical', '-', (163, 168))	('SP142', 'Var', (153, 158))	('SP142', 'Chemical', '-', (153, 158))	('SP263', 'Var', (163, 168))
48542	30646854	Generally, more cases showed PD-L1 positivity in stroma than in tumor cells (p < 0.01).	('tumor', 'Disease', (64, 69))	('positivity', 'Var', (35, 45))	('PD-L1', 'Protein', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
48545	30646854	Interestingly, agreement between 28-8 and SP263 in tumor cells was only moderate (kappa = 0.44), although the amount of positive tumor samples was similar (11% each).	('SP263', 'Chemical', '-', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('SP263', 'Var', (42, 47))
48548	30646854	In stroma cells, clones 28-8, SP142 and SP263 were positive in 31, 40 and 61% of cases, respectively.	('SP142', 'Chemical', '-', (30, 35))	('SP263', 'Var', (40, 45))	('SP142', 'Gene', (30, 35))	('SP263', 'Chemical', '-', (40, 45))
48552	30646854	PD-L1 expression in > 5% of tumor cells was associated with shortened patient overall survival p < 0.001), whereas stromal PD-L1 expression was not associated with any difference in patient survival (p = 0.89) (Fig.	('shortened', 'NegReg', (60, 69))	('tumor', 'Disease', (28, 33))	('patient', 'Species', '9606', (70, 77))	('patient', 'Species', '9606', (182, 189))	('PD-L1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('patient', 'MPA', (70, 77))	('expression', 'Var', (6, 16))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
48553	30646854	CCA subtype specific analysis for PD-L1 expression in association with patient survival showed decreased overall survival rates in iCCA patients with PD-L1 positivity in > 5% of tumor cells (p = 0.02, Fig.	('decreased', 'NegReg', (95, 104))	('tumor', 'Disease', (178, 183))	('patient', 'Species', '9606', (136, 143))	('PD-L1', 'Gene', (150, 155))	('patients', 'Species', '9606', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('patient', 'Species', '9606', (71, 78))	('positivity in >', 'Var', (156, 171))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
48554	30646854	3b) and decreased overall survival rates by trend in pCCA patients with PD-L1 positivity in > 5% of tumor cells (p = 0.06, Fig.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('patients', 'Species', '9606', (58, 66))	('tumor', 'Disease', (100, 105))	('overall survival rates', 'MPA', (18, 40))	('positivity in > 5', 'Var', (78, 95))	('decreased', 'NegReg', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('PD-L1', 'Gene', (72, 77))
48561	30646854	In agreement with the studies from 2017, we here report PD-L1 positivity in CCA tumor cells in 5%, 4%, and 3% of iCCA, pCCA and dCCA, respectively, which is in line with the study of Sato et al.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('positivity', 'Var', (62, 72))	('tumor', 'Disease', (80, 85))	('PD-L1', 'Gene', (56, 61))
48568	30646854	The impact of using different PD-L1 clones is underlined by a recent study from the ,,Blueprint PD-L1 IHC Assay Comparison Project", which demonstrated that the clones 28-8, 22C3 and SP263 show a similar proportion of positive tumor cells, whereas SP142 stains a lower proportion of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('tumor', 'Disease', (227, 232))	('SP263', 'Chemical', '-', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('SP263', 'Var', (183, 188))	('tumor', 'Disease', (283, 288))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('SP142', 'Chemical', '-', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
48569	30646854	In this study, we could confirm these findings for CCA, as with the clone SP142 only two cases were positive, while using the clones 28-8 and SP263, 18, respectively, 19 tumors were positive.	('CCA', 'Disease', (51, 54))	('SP263', 'Var', (142, 147))	('SP263', 'Chemical', '-', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('SP142', 'Chemical', '-', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', (170, 176))
48570	30646854	While the results obtained with clone 28-8 and SP263 showed moderate agreement (kappa = 0.44, p < 0.01), the agreement of 28-8 with SP142, and of 28-8 with SP263 were rather poor (kappa = 0.13 and kappa = 0.11, p < 0.01).	('SP142', 'Chemical', '-', (132, 137))	('SP142', 'Var', (132, 137))	('SP263', 'Chemical', '-', (47, 52))	('SP263', 'Chemical', '-', (156, 161))	('SP263', 'Var', (47, 52))	('SP263', 'Var', (156, 161))
48578	30646854	Various clinicopathological variables have been associated with PD-L1 positivity, including venous invasion, nodal metastases, high tumor grade and high clinical stage.	('metastases', 'Disease', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('metastases', 'Disease', 'MESH:D009362', (115, 125))	('positivity', 'Var', (70, 80))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('PD-L1', 'Gene', (64, 69))	('tumor', 'Disease', (132, 137))	('venous invasion', 'CPA', (92, 107))	('high clinical stage', 'CPA', (148, 167))
48581	30646854	This could be due to the fact that high PD-L1 levels have been shown to reduce T-cell function and to weaken the host's immune response against the tumor.	('PD-L1 levels', 'Var', (40, 52))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('weaken', 'NegReg', (102, 108))	('T-cell function', 'CPA', (79, 94))	('reduce', 'NegReg', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
48638	27537589	A total of 7 studies investigated the efficacy of targeted therapies including EGFR and VEGFR inhibitors.	('EGFR', 'Gene', (89, 93))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('VEGFR', 'Gene', (88, 93))	('VEGFR', 'Gene', '3791', (88, 93))	('EGFR', 'Gene', '1956', (89, 93))	('inhibitors', 'Var', (94, 104))
48639	27537589	Four trials examined the efficacy of incorporating targeted therapies in addition to GP chemotherapy and reported a significantly higher median PFS (WMD = -1.49; 95% CI -2.56 to -0.43) for patients who used EGFR inhibitors in addition to combination chemotherapy (Fig.	('higher', 'PosReg', (130, 136))	('EGFR', 'Gene', '1956', (207, 211))	('PFS', 'MPA', (144, 147))	('EGFR', 'Gene', (207, 211))	('inhibitors', 'Var', (212, 222))	('patients', 'Species', '9606', (189, 197))
48658	27537589	Grade 3 to 4 leukopenia events (OR = 1.82, 95% CI 0.57-5.83) were significantly less frequent in the S-1 monotherapy group compared with the gemcitabine and S-1.	('S-1', 'Gene', (101, 104))	('S-1', 'Gene', '5707', (157, 160))	('less', 'NegReg', (80, 84))	('leukopenia', 'Phenotype', 'HP:0001882', (13, 23))	('gemcitabine', 'Chemical', 'MESH:C056507', (141, 152))	('S-1', 'Gene', (157, 160))	('S-1', 'Gene', '5707', (101, 104))	('monotherapy', 'Var', (105, 116))	('leukopenia', 'Disease', 'MESH:D007970', (13, 23))	('leukopenia', 'Disease', (13, 23))
48663	27537589	All 4 studies investigating EGFR inhibitors reported no significant differences in hematologic AEs and nonhematologic AEs.	('AEs', 'Chemical', '-', (118, 121))	('hematologic AEs', 'Disease', (83, 98))	('EGFR', 'Gene', '1956', (28, 32))	('AEs', 'Chemical', '-', (95, 98))	('EGFR', 'Gene', (28, 32))	('inhibitors', 'Var', (33, 43))
48682	27537589	Targeted therapy has shown certain benefits in other cancer types, and its effects for BTC are being investigated.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('Targeted', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('benefits', 'PosReg', (35, 43))	('BTC', 'Phenotype', 'HP:0100574', (87, 90))
48720	27612869	His preoperative staging was T4N1M1 stage IV (TNM classification).	('TNM', 'Gene', (46, 49))	('T4N1M1', 'Var', (29, 35))	('TNM', 'Gene', '10178', (46, 49))
48724	27612869	According to the TNM classification, pathological staging was diagnosed as T3N2M1 (stage IV).	('TNM', 'Gene', (17, 20))	('TNM', 'Gene', '10178', (17, 20))	('T3N2M1', 'Var', (75, 81))
48726	27612869	His tumor markers and liver mass decreased, but after a short time, his tumor markers elevated again (CEA 9.5 ng/mL, CA19-9 9027 U/mL).	('tumor', 'Disease', (4, 9))	('liver mass', 'MPA', (22, 32))	('elevated', 'PosReg', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('liver mass decreased', 'Phenotype', 'HP:0001410', (22, 42))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('CEA', 'Gene', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CEA', 'Gene', '1084', (102, 105))	('CA19-9 9027 U/mL', 'Var', (117, 133))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
48862	22391777	Based on the degree of cellular and structural atypia, BilIN is classified into 3 grades namely BilIN-1, BilIN-2, and BilIN-3 indicating low-grade dysplasia, high-grade dysplasia, and carcinoma in situ respectively.	('BilIN', 'Chemical', '-', (96, 101))	('carcinoma', 'Disease', 'MESH:D002277', (184, 193))	('BilIN-3', 'Var', (118, 125))	('BilIN', 'Chemical', '-', (55, 60))	('BilIN-2', 'Chemical', '-', (105, 112))	('BilIN', 'Chemical', '-', (118, 123))	('dysplasia', 'Disease', (169, 178))	('dysplasia', 'Disease', 'MESH:D004476', (147, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('dysplasia', 'Disease', 'MESH:D004476', (169, 178))	('BilIN', 'Chemical', '-', (105, 110))	('BilIN-3', 'Chemical', '-', (118, 125))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (184, 201))	('carcinoma', 'Disease', (184, 193))	('BilIN-1', 'Chemical', '-', (96, 103))	('dysplasia', 'Disease', (147, 156))
48869	22391777	REG1) as well as epigenetic changes occur during the progression of BilIN to carcinoma.	('BilIN to carcinoma', 'Disease', 'MESH:D002277', (68, 86))	('epigenetic changes', 'Var', (17, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('REG1', 'Gene', (0, 4))	('BilIN to carcinoma', 'Disease', (68, 86))	('occur', 'Reg', (36, 41))	('REG1', 'Gene', '80149', (0, 4))
48870	22391777	An increased number of methylated genes such as TMEFF2, HOXA1, NEUROG1 and RUNX3 are seen with the progression from normal to BilIN to carcinoma.	('TMEFF2', 'Gene', '23671', (48, 54))	('HOXA1', 'Gene', (56, 61))	('methylated', 'Var', (23, 33))	('BilIN to carcinoma', 'Disease', 'MESH:D002277', (126, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('HOXA1', 'Gene', '3198', (56, 61))	('NEUROG1', 'Gene', (63, 70))	('seen', 'Reg', (85, 89))	('TMEFF2', 'Gene', (48, 54))	('BilIN to carcinoma', 'Disease', (126, 144))	('RUNX3', 'Gene', '864', (75, 80))	('NEUROG1', 'Gene', '4762', (63, 70))	('RUNX3', 'Gene', (75, 80))
48875	22391777	Although some differences in protein expression such as MUC5AC and Ki67 are more often seen in BilIN associated with biliary tract disease than with non-biliary tract cirrhosis the pathophysiological relevance of these differences is not known.	('biliary tract cirrhosis', 'Phenotype', 'HP:0002613', (153, 176))	('seen', 'Reg', (87, 91))	('BilIN', 'Disease', (95, 100))	('MUC5AC', 'Gene', (56, 62))	('biliary tract disease', 'Disease', 'MESH:D001660', (117, 138))	('non-biliary tract cirrhosis', 'Disease', 'MESH:D008105', (149, 176))	('biliary tract disease', 'Phenotype', 'HP:0001080', (117, 138))	('cirrhosis', 'Phenotype', 'HP:0001394', (167, 176))	('biliary tract disease', 'Disease', (117, 138))	('BilIN', 'Chemical', '-', (95, 100))	('protein expression', 'MPA', (29, 47))	('associated', 'Reg', (101, 111))	('MUC5AC', 'Gene', '4586', (56, 62))	('non-biliary tract cirrhosis', 'Disease', (149, 176))	('Ki67', 'Var', (67, 71))
48879	22391777	IPN-B development has been associated with inactivation of p16INK4A and deregulated expression of MUC1 and MUC2.	('men', 'Species', '9606', (13, 16))	('IPN-B', 'Disease', (0, 5))	('MUC2', 'Gene', (107, 111))	('p16INK4A', 'Gene', (59, 67))	('IPN-B', 'Chemical', '-', (0, 5))	('MUC2', 'Gene', '4583', (107, 111))	('MUC1', 'Gene', (98, 102))	('deregulated expression', 'MPA', (72, 94))	('MUC1', 'Gene', '4582', (98, 102))	('p16INK4A', 'Gene', '1029', (59, 67))	('inactivation', 'Var', (43, 55))
48891	22391777	Polymorphism of natural killer cell receptor G2D gene has been suggested to increase the risk of cholangiocarcinoma.	('Polymorphism', 'Var', (0, 12))	('increase', 'PosReg', (76, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('cholangiocarcinoma', 'Disease', (97, 115))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (97, 115))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))
48938	22391777	Detection of polysomy improves sensitivity to 38% for detection of malignancy and improves specificity to 98%.	('improves', 'PosReg', (22, 30))	('sensitivity', 'MPA', (31, 42))	('malignancy', 'Disease', 'MESH:D009369', (67, 77))	('malignancy', 'Disease', (67, 77))	('polysomy', 'Var', (13, 21))
49014	18548352	In particular, it has been demonstrated that apoptosis activates liver fibrogenesis, by different means, e.g., by the local release of soluble, profibrogenic factors and by the HSC activation that results by their ability to engulf apoptotic bodies.	('liver fibrogenesis', 'Phenotype', 'HP:0001395', (65, 83))	('apoptosis', 'Var', (45, 54))	('activates', 'PosReg', (55, 64))	('liver fibrogenesis', 'CPA', (65, 83))	('rat', 'Species', '10116', (34, 37))
49020	18548352	demonstrated that, in accordance with the concept that cholangiocytes, but not hepatocytes, express ACh receptors, ACh did not affect the functions of hepatocytes, but elicited Ca2+ increase and oscillation in isolated bile duct units (IBDUs), because of both an influx of extracellular Ca2+ and the mobilization of intracellular Ca2+ stores.	('increase', 'PosReg', (182, 190))	('mobilization of intracellular Ca2+ stores', 'MPA', (300, 341))	('influx of extracellular Ca2+', 'MPA', (263, 291))	('oscillation', 'MPA', (195, 206))	('ACh', 'Chemical', 'MESH:D000109', (100, 103))	('Ca2+', 'Chemical', 'MESH:D000069285', (330, 334))	('elicited', 'Reg', (168, 176))	('Ca2+', 'MPA', (177, 181))	('ACh', 'Chemical', 'MESH:D000109', (115, 118))	('rat', 'Species', '10116', (7, 10))	('ACh', 'Var', (115, 118))	('Ca2+', 'Chemical', 'MESH:D000069285', (177, 181))	('Ca2+', 'Chemical', 'MESH:D000069285', (287, 291))
49022	18548352	In that study, it was shown that ACh has no effect on the basal activity of the Cl-/HCO3- exchanger, but it significantly potentiates the stimulatory effect of secretin on this exchanger.	('ACh', 'Var', (33, 36))	('secretin', 'Gene', '24769', (160, 168))	('HCO3', 'Chemical', 'MESH:D001639', (84, 88))	('secretin', 'Gene', (160, 168))	('potentiates', 'PosReg', (122, 133))	('ACh', 'Chemical', 'MESH:D000109', (33, 36))
49026	18548352	Interruption of the cholinergic innervation by vagotomy induces a marked decrease in total bile duct mass caused by both impaired cholangiocyte proliferative capacity and intracellular cAMP levels and enhanced cell death by apoptosis.	('impaired', 'NegReg', (121, 129))	('total bile duct mass', 'MPA', (85, 105))	('Interruption', 'Var', (0, 12))	('cholangiocyte', 'MPA', (130, 143))	('enhanced', 'PosReg', (201, 209))	('apoptosis', 'CPA', (224, 233))	('decrease', 'NegReg', (73, 81))	('cell death', 'CPA', (210, 220))	('cAMP', 'Chemical', 'MESH:D000242', (185, 189))	('intracellular cAMP levels', 'MPA', (171, 196))	('rat', 'Species', '10116', (151, 154))
49034	18548352	Administration of a single intraportal injection of 6-OHDA, which induces degeneration of dopaminergic terminal fibers, blunts the cholangiocyte functional and proliferative responses to cholestasis, and induces cell death by apoptosis.	('rat', 'Species', '10116', (8, 11))	('cholestasis', 'Disease', (187, 198))	('blunts', 'NegReg', (120, 126))	('6-OHDA', 'Var', (52, 58))	('rat', 'Species', '10116', (80, 83))	('apoptosis', 'CPA', (226, 235))	('cholestasis', 'Phenotype', 'HP:0001396', (187, 198))	('dopaminergic terminal fibers', 'MPA', (90, 118))	('cell death', 'CPA', (212, 222))	('6-OHDA', 'Chemical', 'MESH:D016627', (52, 58))	('rat', 'Species', '10116', (167, 170))	('cholangiocyte functional', 'MPA', (131, 155))	('induces', 'Reg', (204, 211))	('cholestasis', 'Disease', 'MESH:D002779', (187, 198))	('degeneration', 'MPA', (74, 86))
49041	18548352	Most interestingly, a marked reduction of bile duct mass is observed both 3 and 7 days after BDL in CGRP receptor knockout mice (Fig.	('reduction', 'NegReg', (29, 38))	('CGRP receptor', 'Gene', (100, 113))	('bile duct mass', 'MPA', (42, 56))	('knockout', 'Var', (114, 122))	('mice', 'Species', '10090', (123, 127))
49044	18548352	Similarly, taurocholic acid administration also prevents the loss of bile ducts induced by adrenergic denervation.	('bile ducts', 'MPA', (69, 79))	('rat', 'Species', '10116', (36, 39))	('taurocholic acid', 'Chemical', 'MESH:D013656', (11, 27))	('loss', 'NegReg', (61, 65))	('prevents', 'NegReg', (48, 56))	('denervation', 'Var', (102, 113))
49053	18548352	In later studies conduced in IBDUs isolated from wild-type and SSTR2-knockout mice, it was also found that somatostatin not only reduces cholangiocyte choleresis, but it also stimulates ductal bile absorption.	('somatostatin', 'Var', (107, 119))	('cholangiocyte choleresis', 'MPA', (137, 161))	('stimulates', 'PosReg', (175, 185))	('mice', 'Species', '10090', (78, 82))	('ductal bile absorption', 'MPA', (186, 208))	('reduces', 'NegReg', (129, 136))
49071	18548352	As a demonstration of the physiological and pathophysiological relevance of estrogens as far as cholangiocyte proliferative response to cholestasis, when BDL male rats were treated in vivo with anti-estrogens like tamoxifen or Ici 182,780 or when BDL female rats were subjected to ovariectomy, the growth of the biliary tree was blunted, and the biliary epithelium underwent programmed cell death by apoptosis.	('rat', 'Species', '10116', (163, 166))	('rat', 'Species', '10116', (117, 120))	('rat', 'Species', '10116', (12, 15))	('growth of the biliary tree', 'CPA', (298, 324))	('programmed cell death', 'CPA', (375, 396))	('underwent', 'Reg', (365, 374))	('cholestasis', 'Disease', (136, 147))	('blunted', 'NegReg', (329, 336))	('anti-estrogens', 'Var', (194, 208))	('rats', 'Species', '10116', (258, 262))	('rats', 'Species', '10116', (163, 167))	('cholestasis', 'Phenotype', 'HP:0001396', (136, 147))	('rat', 'Species', '10116', (258, 261))	('apoptosis', 'CPA', (400, 409))	('tamoxifen', 'Chemical', 'MESH:D013629', (214, 223))	('cholestasis', 'Disease', 'MESH:D002779', (136, 147))
49086	18548352	If, in vitro or in vivo, cholangiocyte-secreted serotonin is neutralized, cholangiocyte proliferation in response to cholestasis further increases.	('serotonin', 'Chemical', 'MESH:D012701', (48, 57))	('cholangiocyte proliferation', 'CPA', (74, 101))	('cholestasis', 'Phenotype', 'HP:0001396', (117, 128))	('rat', 'Species', '10116', (95, 98))	('cholestasis', 'Disease', 'MESH:D002779', (117, 128))	('neutralized', 'Var', (61, 72))	('cholestasis', 'Disease', (117, 128))	('increases', 'PosReg', (137, 146))
49338	32201508	Combination of CA242 and CXCL5 expression (p<0.0001) served as a better prognostic factor than CA242 alone (p=0.006).	('CA242', 'Var', (15, 20))	('CA242', 'Chemical', '-', (15, 20))	('CXCL5', 'Gene', (25, 30))	('CXCL5', 'Gene', '6374', (25, 30))	('CA242', 'Chemical', '-', (95, 100))
49397	32201508	2D and Table 2), the T stage (p=0.004), the N stage (p<0.001), the differentiation status (p=0.001), and high level of CA19-9 (p=0.001) and CA242 (p=0.008) were significantly associated with poor OS (Table 2).	('associated', 'Reg', (175, 185))	('T stage', 'CPA', (21, 28))	('CA19-9', 'Var', (119, 125))	('CA242', 'Var', (140, 145))	('CA19-9', 'Chemical', 'MESH:C086528', (119, 125))	('differentiation status', 'CPA', (67, 89))	('poor OS', 'Disease', (191, 198))	('N stage', 'CPA', (44, 51))	('CA242', 'Chemical', '-', (140, 145))	('OS', 'Chemical', '-', (196, 198))
49398	32201508	The multivariate Cox regression analysis indicated that the T stage (p=0.007), the N stage (p=0.012) the differentiation status (p=0.004), and high level of CA19-9 (p=0.030) were independent prognostic factors (Table 2) and CXCL5 expression was identified as an independent factor in the high CA242 subgroup (HR=2.047, p=0.004, Fig.	('CA19-9', 'Chemical', 'MESH:C086528', (157, 163))	('CA242', 'Chemical', '-', (293, 298))	('high CA242', 'Var', (288, 298))	('CXCL5', 'Gene', (224, 229))	('CXCL5', 'Gene', '6374', (224, 229))
49399	32201508	These results indicated that the combination of CA242 and CXCL5 expression (p<0.0001, Fig.	('CA242', 'Chemical', '-', (48, 53))	('CXCL5', 'Gene', (58, 63))	('CA242', 'Var', (48, 53))	('CXCL5', 'Gene', '6374', (58, 63))
49401	32201508	The results from the SurvExpress also showed that high CXCL5 expression was associated with poor OS in PDAC patients (p=0.00022, Fig.	('OS', 'Chemical', '-', (97, 99))	('PDAC', 'Disease', 'MESH:D021441', (103, 107))	('CXCL5', 'Gene', (55, 60))	('PDAC', 'Phenotype', 'HP:0006725', (103, 107))	('PDAC', 'Disease', (103, 107))	('patients', 'Species', '9606', (108, 116))	('CXCL5', 'Gene', '6374', (55, 60))	('high', 'Var', (50, 54))	('poor OS', 'Disease', (92, 99))
49403	32201508	In the Kaplan-Meier plotter databases, high CXCL5 mRNA expression was found to be correlated with significantly shorter OS among 176 PDAC patients (p=0.02664, Fig.	('patients', 'Species', '9606', (138, 146))	('high', 'Var', (39, 43))	('CXCL5', 'Gene', (44, 49))	('CXCL5', 'Gene', '6374', (44, 49))	('PDAC', 'Disease', (133, 137))	('PDAC', 'Phenotype', 'HP:0006725', (133, 137))	('PDAC', 'Disease', 'MESH:D021441', (133, 137))	('OS', 'Chemical', '-', (120, 122))	('shorter', 'NegReg', (112, 119))
49404	32201508	Overall, CXCL5 overexpression may be a biomarker that indicates poor survival for PDAC patients, especially in the high CA242 group.	('high CA242', 'Var', (115, 125))	('PDAC', 'Disease', 'MESH:D021441', (82, 86))	('patients', 'Species', '9606', (87, 95))	('PDAC', 'Disease', (82, 86))	('PDAC', 'Phenotype', 'HP:0006725', (82, 86))	('CXCL5', 'Gene', (9, 14))	('CA242', 'Chemical', '-', (120, 125))	('CXCL5', 'Gene', '6374', (9, 14))
49435	32201508	The multivariate Cox regression analysis also showed that CXCL5 expression was an independent prognostic marker in the high CA242 subgroup.	('CA242', 'Chemical', '-', (124, 129))	('high CA242', 'Var', (119, 129))	('CXCL5', 'Gene', (58, 63))	('CXCL5', 'Gene', '6374', (58, 63))
49494	32128030	The volume of the posterior section was significantly larger in patients with an RSRL of the Ppost-i type than in patients with normal PV anatomy (P < 0.001).	('RSRL', 'Var', (81, 85))	('patients', 'Species', '9606', (64, 72))	('larger', 'PosReg', (54, 60))	('Ppost-i', 'Gene', (93, 100))	('patients', 'Species', '9606', (114, 122))
49495	32128030	Conversely, in the case of an RSRL, the left umbilical vein is believed to atrophy and the right umbilical vein is believed to persist to form a right-sided UP and round ligament.	('atrophy', 'Disease', (75, 82))	('atrophy', 'Disease', 'MESH:D001284', (75, 82))	('RSRL', 'Var', (30, 34))
49509	32128030	Shindoh et al noted that in RSRL livers, either side of the lateral sectors [S2 and S6+7 (posterior section)] and the dorsal segment of the right paramedian sector were larger than those in patients with typical anatomy, whereas the left paramedian sector (S3+4) and the ventral segment of the right paramedian sector were significantly smaller.	('patients', 'Species', '9606', (190, 198))	('RSRL', 'Var', (28, 32))	('S6+7', 'Var', (84, 88))
49568	29089545	3A, histograms obtained by densitometric analysis revealed no significant difference with regard to cleaved caspase 3 expression between iCCA cells co-cultured with PBMCs vs iCCA cells cultured alone.	('caspase 3', 'Gene', (108, 117))	('caspase 3', 'Gene', '836', (108, 117))	('PBMCs', 'Var', (165, 170))
49582	29089545	These data suggest that PBMCs induced a reduction in the translocation of c-FLIP from the cytoplasm to the nucleus, in accordance with previous findings.	('reduction', 'NegReg', (40, 49))	('PBMCs', 'Var', (24, 29))	('c-FLIP', 'Gene', '8837', (74, 80))	('c-FLIP', 'Gene', (74, 80))	('translocation', 'MPA', (57, 70))
49622	29089545	The high density of TAMs in patients with CCA has been associated with poor prognosis, reduced overall survival and disease-free survival, and metastasis.	('TAMs', 'Protein', (20, 24))	('disease-free survival', 'CPA', (116, 137))	('reduced', 'NegReg', (87, 94))	('overall survival', 'CPA', (95, 111))	('high density', 'Var', (4, 16))	('patients', 'Species', '9606', (28, 36))	('metastasis', 'CPA', (143, 153))	('CCA', 'Disease', (42, 45))
49624	29089545	In parallel, patients affected by iCCA are likely to mount a T-cell immune response against their own tumors and the defects in HLA class I antigen expression in combination with PD-L1 expression by iCCA cells provide them with an immune escape mechanism.	('defects', 'Var', (117, 124))	('HLA class I antigen', 'Gene', (128, 147))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('immune escape', 'CPA', (231, 244))	('mount', 'PosReg', (53, 58))	('T-cell immune response', 'CPA', (61, 83))	('patients', 'Species', '9606', (13, 21))	('HLA class I antigen', 'Gene', '100507436', (128, 147))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('PD-L1', 'Gene', (179, 184))	('expression', 'MPA', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('PD-L1', 'Gene', '29126', (179, 184))
49722	28898276	Recently, the contribution of Msln to fibrosis progression was demonstrated, as its genetic deletion in mice confers protection against experimental cholestatic liver injury.	('cholestatic liver injury', 'Phenotype', 'HP:0002611', (149, 173))	('rat', 'Species', '10116', (70, 73))	('cholestatic liver injury', 'Disease', 'MESH:D056486', (149, 173))	('fibrosis', 'Disease', 'MESH:D005355', (38, 46))	('mice', 'Species', '10090', (104, 108))	('deletion', 'Var', (92, 100))	('fibrosis', 'Disease', (38, 46))	('cholestatic liver injury', 'Disease', (149, 173))
49747	28898276	All constructs were designed, based upon clone sequence homology, so as to insert: 1) HA peptide coding sequence between the 24th and 25th base pairs (bp) of rat Mesothelin consensus coding sequence (NCBI Nucleotide ID: NM_031658.1), resulting in a 9-amino acid insertion between the 8th and 9th amino acids of rat Mesothelin protein sequence (NCBI Protein ID: NP_113846); and 2) Xba1 and Age1 restriction sites at both 5'- (before ATG start codon, NM_031658.1) and 3'-ends (after TGA stop codon, NM_031658.1 [625]) of rat Mesothelin coding sequence.	('NM_031658.1', 'Var', (449, 460))	('NM_031658.1', 'Var', (497, 508))	('rat', 'Species', '10116', (311, 314))	('rat', 'Species', '10116', (158, 161))	('rat', 'Species', '10116', (519, 522))
49764	28898276	Here, we cloned and characterized these previously unknown rat Msln transcript variants expressed in RGF-N2 PF cells.	('variants', 'Var', (79, 87))	('rat', 'Species', '10116', (59, 62))	('Msln', 'Gene', (63, 67))
49773	28898276	Sequence analysis of obtained cDNAs clearly identified clone W as wild-type Msln, while the remaining clones sequences reveal mRNA exon skipping and alternative splice donor site as splicing mechanisms (Fig 2).	('donor', 'Species', '9606', (168, 173))	('mRNA exon skipping', 'MPA', (126, 144))	('alternative splice donor', 'Var', (149, 173))
49780	28898276	Because both anti-HA and anti-MslnSC antibodies detected the Msln splicing isoform with a predicted molecular weight of 24 kDa (in contrast with the anti-rat (specific) MslnCT antibody), this extra band was surmised to represent a reaction artifact potentially resulting from splicing isoform aggregation.	('rat', 'Species', '10116', (154, 157))	('Msln', 'Var', (61, 65))	('detected', 'Reg', (48, 56))
49790	28898276	Of three A, H and W Msln variants predicted to possess a GPI anchor (see Table 2), only clone A and W were observed exhibiting plasma membrane localization (Fig 5).	('GPI', 'Gene', (57, 60))	('variants', 'Var', (25, 33))	('Msln', 'Gene', (20, 24))	('GPI', 'Gene', '292804', (57, 60))
49791	28898276	A similar distribution was also described for S, U and Y Msln variants lacking GPI anchorage.	('GPI', 'Gene', '292804', (79, 82))	('lacking', 'NegReg', (71, 78))	('variants', 'Var', (62, 70))	('GPI', 'Gene', (79, 82))
49801	28898276	We speculate that a potential explanation for this unexplained labeling might be the existence of yet-to-be-described human MSLN splicing variants, distinct from the other variants described in the literature.	('MSLN', 'Gene', (124, 128))	('variants', 'Var', (138, 146))	('MSLN', 'Gene', '10232', (124, 128))	('human', 'Species', '9606', (118, 123))	('rat', 'Species', '10116', (202, 205))
49807	28898276	As suggested for liver myofibroblasts, Msln variants could influence the behavior of cholangiocarcinoma cells, since both Msln and MPF are biologically potent proteins acting as malignant factors to promote directly or indirectly tumorigenesis.	('tumor', 'Disease', (230, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('MPF', 'Gene', (131, 134))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (85, 103))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('promote', 'PosReg', (199, 206))	('influence', 'Reg', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('behavior', 'CPA', (73, 81))	('cholangiocarcinoma', 'Disease', (85, 103))	('variants', 'Var', (44, 52))
49936	24742042	Antibodies against caspase-3 (9662), caspase-7 (9492), caspase-9 (9502), PARP (9532), Mcl-1(5453), and actin (4967) were from Cell Signal Technology (Boston, MA, USA).	('caspase-7', 'Gene', '840', (37, 46))	('caspase-9', 'Gene', (55, 64))	('4967', 'Var', (110, 114))	('Mcl-1', 'Gene', '4170', (86, 91))	('caspase-3', 'Gene', (19, 28))	('PARP', 'Gene', (73, 77))	('Mcl-1', 'Gene', (86, 91))	('9502', 'Var', (66, 70))	('PARP', 'Gene', '142', (73, 77))	('caspase-3', 'Gene', '836', (19, 28))	('caspase-9', 'Gene', '842', (55, 64))	('caspase-7', 'Gene', (37, 46))
50119	32815017	Interestingly, the RSI was not only a prognostic factor for early postoperative morbidity and mortality but also for long-term survival.	('RSI', 'Var', (19, 22))	('mortality', 'Disease', (94, 103))	('mortality', 'Disease', 'MESH:D003643', (94, 103))
50121	32815017	Perhaps unsurprisingly, additional hilar bile duct resections significantly increased the incidence of severe postoperative complications, mainly as a result of insufficiency of the biliodigestive anastomosis and consecutive bile leakage.	('bile leakage', 'Disease', (225, 237))	('biliodigestive anastomosis', 'Disease', (182, 208))	('insufficiency', 'Disease', 'MESH:D000309', (161, 174))	('bile leakage', 'Disease', 'MESH:D003763', (225, 237))	('insufficiency', 'Disease', (161, 174))	('resections', 'Var', (51, 61))
50170	32638296	The variations of right posterior inferior hepatic vein, segment IV hepatic vein, and segment VIII hepatic vein have significant value in the decision-making of liver surgery.	('VIII', 'Gene', (94, 98))	('VIII', 'Gene', '1351', (94, 98))	('variations', 'Var', (4, 14))
50178	32638296	Currently, the definition of complicated liver tumor is controversial; it generally refers to centrally located hepatocellular carcinoma involving the porta hepatis; variations of hepatic artery, portal vein, and hepatic vein within the liver; serious distortion of intrahepatic vessels due to massive compression of tumor; malignant liver tumors with inferior vena cava or even right atrial cancer thrombus; massive benign or malignant tumors of the liver requiring extensive hepatectomy; hepatic tumors involving hepatic segments I and VII that require complex hepatectomy.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('malignant liver tumors', 'Disease', (324, 346))	('tumor', 'Phenotype', 'HP:0002664', (437, 442))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('hepatocellular carcinoma', 'Disease', (112, 136))	('tumor', 'Phenotype', 'HP:0002664', (498, 503))	('tumors', 'Phenotype', 'HP:0002664', (340, 346))	('hepatic tumor', 'Phenotype', 'HP:0002896', (490, 503))	('tumors', 'Phenotype', 'HP:0002664', (498, 504))	('hepatic artery', 'Disease', 'MESH:D056486', (180, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('liver tumor', 'Disease', (41, 52))	('liver tumor', 'Phenotype', 'HP:0002896', (41, 52))	('liver tumor', 'Phenotype', 'HP:0002896', (334, 345))	('tumor', 'Disease', (317, 322))	('hepatic artery', 'Disease', (180, 194))	('tumor', 'Disease', (437, 442))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (112, 136))	('variations', 'Var', (166, 176))	('liver tumor', 'Disease', 'MESH:D008113', (41, 52))	('hepatic tumors', 'Disease', 'MESH:D056486', (490, 504))	('liver tumor', 'Disease', 'MESH:D008113', (334, 345))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', (340, 345))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('hepatic tumors', 'Disease', (490, 504))	('tumor', 'Disease', (498, 503))	('tumor', 'Disease', 'MESH:D009369', (437, 442))	('atrial cancer thrombus', 'Disease', (385, 407))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (340, 345))	('malignant liver tumors', 'Disease', 'None', (324, 346))	('tumors', 'Phenotype', 'HP:0002664', (437, 443))	('liver tumors', 'Phenotype', 'HP:0002896', (334, 346))	('atrial cancer thrombus', 'Disease', 'MESH:D013927', (385, 407))	('tumor', 'Disease', 'MESH:D009369', (498, 503))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (112, 136))	('malignant tumors', 'Disease', (427, 443))	('malignant tumors', 'Disease', 'MESH:D009369', (427, 443))
50266	26940227	Additionally, selective COX-2 inhibitors and aspirin were shown to inhibit vascular endothelial cell proliferation in CCA cell or CCA-conditioned medium and partially prevented CCA cell growth in rats.	('COX-2', 'Enzyme', (24, 29))	('rats', 'Species', '10116', (196, 200))	('inhibit', 'NegReg', (67, 74))	('CCA', 'Phenotype', 'HP:0030153', (130, 133))	('CCA', 'Disease', (177, 180))	('inhibitors', 'Var', (30, 40))	('CCA', 'Phenotype', 'HP:0030153', (118, 121))	('CCA', 'Phenotype', 'HP:0030153', (177, 180))	('vascular endothelial cell proliferation', 'CPA', (75, 114))	('prevented', 'NegReg', (167, 176))
50273	26940227	The effect of aspirin on colonic adenoma risk was shown to modify by variants in the gene encoding the UGT1A6 enzyme, which is responsible for delayed aspirin metabolism.	('colonic adenoma', 'Disease', 'MESH:D000236', (25, 40))	('variants', 'Var', (69, 77))	('colonic adenoma', 'Disease', (25, 40))	('UGT1A6', 'Gene', (103, 109))	('UGT1A6', 'Gene', '54578', (103, 109))	('modify', 'Reg', (59, 65))
50274	26940227	A recent study showed that the association between aspirin use and colorectal cancer varied by polymorphisms of single-nucleotide polymorphism rs2965667 at chromosome 12 and rs16973225 at chromosome 15.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('rs16973225', 'Var', (174, 184))	('rs2965667', 'Var', (143, 152))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('rs16973225', 'Mutation', 'rs16973225', (174, 184))	('single-nucleotide polymorphism', 'Var', (112, 142))	('rs2965667', 'Mutation', 'rs2965667', (143, 152))	('colorectal cancer', 'Disease', (67, 84))
50282	26705830	PDT at low laser power in particular caused extensive survival signaling, as evidenced by the significant upregulation of HIF-1- (P < 0.001) and NF-kB-related (P < 0.001) genes.	('PDT', 'Var', (0, 3))	('HIF-1', 'Gene', '3091', (122, 127))	('NF-kB-related', 'Gene', (145, 158))	('upregulation', 'PosReg', (106, 118))	('HIF-1', 'Gene', (122, 127))	('survival signaling', 'MPA', (54, 72))
50283	26705830	Low-power PDT was less lethal to SK-ChA-1 cells 90 min post-PDT, confirmed by annexin V/propidium iodide staining.	('post-PDT', 'Var', (55, 63))	('SK-ChA-1', 'CellLine', 'CVCL:6952', (33, 41))	('propidium iodide', 'Chemical', 'MESH:D011419', (88, 104))	('annexin V', 'Gene', '308', (78, 87))	('annexin V', 'Gene', (78, 87))
50294	26705830	Third, activation of survival pathways by tumor cells as a result of PDT may lead to insufficient tumor cell death following PDT.	('survival pathways', 'Pathway', (21, 38))	('tumor', 'Disease', (42, 47))	('insufficient tumor', 'Disease', (85, 103))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('PDT', 'Var', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('activation', 'PosReg', (7, 17))	('tumor', 'Disease', (98, 103))	('insufficient tumor', 'Disease', 'MESH:D000309', (85, 103))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
50304	26705830	Cell death was assessed with the SRB protein assay, which revealed that cell viability had decreased to 47.6 % and 51.4 % (normalized to the control group) in the ITL 50 and ITL 500 groups, respectively (Fig.	('cell viability', 'CPA', (72, 86))	('ITL 500', 'Var', (174, 181))	('ITL 50', 'Var', (163, 169))	('SRB', 'Gene', '10575', (33, 36))	('decreased', 'NegReg', (91, 100))	('SRB', 'Gene', (33, 36))
50305	26705830	In addition, SK-ChA-1 cells were stained with annexin V and PI 90 min (Fig.	('SK-ChA-1', 'CellLine', 'CVCL:6952', (13, 21))	('annexin V', 'Gene', (46, 55))	('PI 90', 'Var', (60, 65))	('annexin V', 'Gene', '308', (46, 55))
50312	26705830	SK-ChA-1 control cells and cells that were incubated with ZnPC-ITLs in the dark (ITL) exhibited similar transcriptional responses (Fig.	('ZnPC-ITLs', 'Chemical', '-', (58, 67))	('ZnPC-ITLs', 'Var', (58, 67))	('SK-ChA-1', 'CellLine', 'CVCL:6952', (0, 8))	('transcriptional', 'MPA', (104, 119))
50320	26705830	5a, activator protein 1 (AP-1, consisting of JUN and FOS, amongst others) was upregulated in both the ITL 50 and ITL 500 groups.	('ITL 500', 'Var', (113, 120))	('ITL 50', 'Var', (102, 108))	('upregulated', 'PosReg', (78, 89))	('AP-1', 'Gene', (25, 29))	('activator protein 1', 'Gene', '2353', (4, 23))	('activator protein 1', 'Gene', (4, 23))	('AP-1', 'Gene', '2353', (25, 29))
50321	26705830	Relative to the control group, numerous downstream genes of AP-1 signaling that exert pro-inflammatory and proliferative functions were more highly expressed in the ITL 50 group, including TNF, cyclin D1 (CCND1), heparin-binding EGF-like growth factor (HBEGF), B-cell CLL/lymphoma 3 (BCL3), and jun B proto-oncogene (JUNB) compared to the ITL 500 group.	('jun B proto-oncogene', 'Gene', (295, 315))	('proliferative', 'CPA', (107, 120))	('cyclin D1', 'Gene', '595', (194, 203))	('TNF', 'Gene', '7124', (189, 192))	('HBEGF', 'Gene', (253, 258))	('lymphoma', 'Phenotype', 'HP:0002665', (272, 280))	('heparin-binding EGF-like growth factor', 'Gene', '1839', (213, 251))	('BCL3', 'Gene', '602', (284, 288))	('heparin-binding EGF-like growth factor', 'Gene', (213, 251))	('JUNB', 'Gene', '3726', (317, 321))	('AP-1', 'Gene', '2353', (60, 64))	('more highly expressed', 'PosReg', (136, 157))	('ITL 50', 'Var', (165, 171))	('BCL3', 'Gene', (284, 288))	('CCND1', 'Gene', '595', (205, 210))	('JUNB', 'Gene', (317, 321))	('B-cell CLL/lymphoma 3', 'Gene', (261, 282))	('TNF', 'Gene', (189, 192))	('AP-1', 'Gene', (60, 64))	('jun B proto-oncogene', 'Gene', '3726', (295, 315))	('CCND1', 'Gene', (205, 210))	('cyclin D1', 'Gene', (194, 203))	('HBEGF', 'Gene', '1839', (253, 258))	('B-cell CLL/lymphoma 3', 'Gene', '602', (261, 282))
50328	26705830	Furthermore, expression of various genes involved in glutathione and redox cycling (glutamate-cysteine ligase, catalytic subunit (GCLC), glutamate-cysteine ligase, modifier subunit (GCLM), glutathione reductase (GSR)) were decreased in the ITL 50 group.	('GSR', 'Gene', (212, 215))	('decreased', 'NegReg', (223, 232))	('glutamate-cysteine ligase, catalytic subunit', 'Gene', '2729', (84, 128))	('expression', 'MPA', (13, 23))	('GCLC', 'Gene', '2729', (130, 134))	('glutathione', 'MPA', (53, 64))	('glutathione', 'Chemical', 'MESH:D005978', (189, 200))	('GCLC', 'Gene', (130, 134))	('ITL 50', 'Var', (240, 246))	('redox cycling', 'MPA', (69, 82))	('glutamate-cysteine ligase, modifier subunit (GCLM)', 'Gene', '2730', (137, 187))	('glutathione', 'Chemical', 'MESH:D005978', (53, 64))	('glutamate-cysteine ligase, modifier subunit (GCLM', 'Gene', (137, 186))
50344	26705830	ZnPC-ITL-PDT led to upregulation of endothelin 1 (EDN1), a gene that is downstream of HIF1A and a known vasoconstrictor, in both groups after PDT.	('EDN1', 'Gene', (50, 54))	('EDN1', 'Gene', '1906', (50, 54))	('endothelin 1', 'Gene', '1906', (36, 48))	('HIF1A', 'Gene', (86, 91))	('ZnPC-ITL-PDT', 'Var', (0, 12))	('HIF1A', 'Gene', '3091', (86, 91))	('ZnPC', 'Chemical', 'MESH:C052159', (0, 4))	('upregulation', 'PosReg', (20, 32))	('endothelin 1', 'Gene', (36, 48))
50351	26705830	The experiments demonstrated that (1) ZnPC-ITLs are not toxic in vitro and in vivo at high lipid concentrations, (2) irradiation of SK-ChA-1 cells at high laser power (500 mW, 15 J/cm2) resulted in more profound acute cell death than PDT at low laser power (50 mW, 15 J/cm2), and (3) irradiation of SK-ChA-1 cells at low laser power caused considerable survival signaling after PDT via activation of mainly HIF-1 and NF-kB.	('survival signaling', 'MPA', (353, 371))	('ZnPC-ITLs', 'Chemical', '-', (38, 47))	('NF-kB', 'Protein', (417, 422))	('activation', 'PosReg', (386, 396))	('SK-ChA-1', 'CellLine', 'CVCL:6952', (132, 140))	('PDT', 'Var', (378, 381))	('HIF-1', 'Gene', '3091', (407, 412))	('HIF-1', 'Gene', (407, 412))	('acute cell death', 'CPA', (212, 228))	('lipid', 'Chemical', 'MESH:D008055', (91, 96))	('SK-ChA-1', 'CellLine', 'CVCL:6952', (299, 307))
50353	26705830	Since PDT treatment at low laser power causes moderate ROS production over an extended period of time, cells likely had the opportunity to activate an antioxidant (possibly via NFE2L2) and survival response to remediate the acute effects of ROS and cope with the ROS-induced damage more effectively than cells that were severely damaged by the 500-mW laser irradiation.	('NFE2L2', 'Gene', (177, 183))	('antioxidant', 'MPA', (151, 162))	('ROS', 'Chemical', 'MESH:D017382', (241, 244))	('ROS', 'MPA', (55, 58))	('ROS', 'Chemical', 'MESH:D017382', (55, 58))	('treatment', 'Var', (10, 19))	('NFE2L2', 'Gene', '4780', (177, 183))	('PDT', 'Gene', (6, 9))	('ROS', 'Chemical', 'MESH:D017382', (263, 266))	('activate', 'PosReg', (139, 147))
50357	26705830	PDT-induced mitochondrial damage debilitates electron production and leakage from the electron transport chain, thereby hampering the reduction of WST-1 to the formazan chromophore.	('damage', 'Var', (26, 32))	('debilitates', 'NegReg', (33, 44))	('formazan', 'Chemical', 'MESH:D005562', (160, 168))	('mitochondrial', 'CPA', (12, 25))	('leakage', 'MPA', (69, 76))	('WST-1 to the formazan chromophore', 'MPA', (147, 180))	('WST', 'Chemical', '-', (147, 150))	('reduction', 'MPA', (134, 143))	('hampering', 'NegReg', (120, 129))	('PDT-induced', 'Gene', (0, 11))	('electron production', 'MPA', (45, 64))
50360	26705830	Since the cellular redox state of a cell changes during PDT as a result of the production of ROS and reactive nitrogen species (e.g., peroxynitrite), PDT causes activation of a variety of redox-sensitive proteins and transcription factors.	('PDT', 'Var', (150, 153))	('ROS', 'MPA', (93, 96))	('reactive nitrogen species', 'Chemical', 'MESH:D026361', (101, 126))	('ROS', 'Chemical', 'MESH:D017382', (93, 96))	('peroxynitrite', 'Chemical', 'MESH:D030421', (134, 147))	('redox-sensitive proteins', 'MPA', (188, 212))	('activation', 'PosReg', (161, 171))	('PDT', 'Disease', (56, 59))	('cellular redox state', 'MPA', (10, 30))
50366	26705830	These data indicate that SK-ChA-1 cells treated by low-power PDT attempt to survive, as evidenced by the significant upregulation of HIF-1- (P < 0.001) and NF-kappaB-mediated (P < 0.001) pathways.	('HIF-1', 'Gene', '3091', (133, 138))	('PDT', 'Gene', (61, 64))	('HIF-1', 'Gene', (133, 138))	('NF-kappaB', 'Gene', '4790', (156, 165))	('SK-ChA-1', 'CellLine', 'CVCL:6952', (25, 33))	('upregulation', 'PosReg', (117, 129))	('low-power', 'Var', (51, 60))	('NF-kappaB', 'Gene', (156, 165))
50369	26705830	In our study, SK-ChA-1 cells treated with low-power PDT also demonstrated extensive upregulation of FOS, FOSB, IL8, and TNFAIP3 (log2 fold-changes of 4.42, 2.13, 6.75, and 2.75, respectively).	('SK-ChA-1', 'CellLine', 'CVCL:6952', (14, 22))	('IL8', 'Gene', (111, 114))	('FOS', 'Gene', (100, 103))	('FOSB', 'Gene', '2354', (105, 109))	('upregulation', 'PosReg', (84, 96))	('FOSB', 'Gene', (105, 109))	('TNFAIP3', 'Gene', '7128', (120, 127))	('low-power PDT', 'Var', (42, 55))	('PDT', 'Var', (52, 55))	('TNFAIP3', 'Gene', (120, 127))
50372	26705830	Contrary to expectations, cells in the ITL 50 group downregulated the NFE2L2-mediated pathway (P < 0.001); an effect that was absent in the ITL 500 group.	('NFE2L2', 'Gene', (70, 76))	('downregulated', 'NegReg', (52, 65))	('NFE2L2', 'Gene', '4780', (70, 76))	('ITL', 'Var', (39, 42))
50380	26705830	This pro-survival response was blocked following HIF-1 silencing with siRNA, which augmented PDT efficacy in the Het-1a cells.	('HIF-1', 'Gene', '3091', (49, 54))	('PDT efficacy', 'CPA', (93, 105))	('augmented', 'PosReg', (83, 92))	('silencing', 'Var', (55, 64))	('HIF-1', 'Gene', (49, 54))
50381	26705830	revealed that nanoparticulate delivery of HIF-1 siRNAs to head-and-neck carcinoma (SSC4) xenografts significantly enhanced photosan-PDT efficacy in mice, leading to 40 % tumor regression within 10 days post-PDT.	('HIF-1', 'Gene', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('photosan-PDT', 'Var', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('carcinoma', 'Disease', (72, 81))	('tumor', 'Disease', (170, 175))	('enhanced', 'PosReg', (114, 122))	('mice', 'Species', '10090', (148, 152))	('HIF-1', 'Gene', '3091', (42, 47))	('carcinoma', 'Disease', 'MESH:D002277', (72, 81))
50387	26705830	Moreover, verteporfin-PDT induced epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT-3) signaling in ovarian carcinoma (OVCAR-5) and non-small cell lung cancer (H460) cells.	('STAT-3', 'Gene', '6774', (130, 136))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (187, 209))	('H460', 'CellLine', 'CVCL:0459', (211, 215))	('verteporfin', 'Chemical', 'MESH:D000077362', (10, 21))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (183, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (151, 168))	('signal transducer and activator of transcription 3', 'Gene', '6774', (78, 128))	('EGFR', 'Gene', '1956', (68, 72))	('verteporfin-PDT', 'Var', (10, 25))	('ovarian carcinoma', 'Disease', (151, 168))	('epidermal growth factor receptor', 'Gene', (34, 66))	('non-small cell lung cancer', 'Disease', (183, 209))	('epidermal growth factor receptor', 'Gene', '1956', (34, 66))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (151, 168))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('STAT-3', 'Gene', (130, 136))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (183, 209))	('induced', 'PosReg', (26, 33))	('EGFR', 'Gene', (68, 72))
50389	26705830	Accordingly, siRNA-mediated knockdown of either EGFR or STAT-3 increased PDT efficacy.	('increased', 'PosReg', (63, 72))	('EGFR', 'Gene', '1956', (48, 52))	('PDT efficacy', 'CPA', (73, 85))	('EGFR', 'Gene', (48, 52))	('STAT-3', 'Gene', '6774', (56, 62))	('knockdown', 'Var', (28, 37))	('STAT-3', 'Gene', (56, 62))
50505	33613623	The results revealed that the pathways were mainly enriched in multiple tumor immune mechanisms, the regulation of these pathways can change the tumor cells immune microenvironment and affect the proliferation and migration of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('proliferation', 'CPA', (196, 209))	('change', 'Reg', (134, 140))	('affect', 'Reg', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('regulation', 'Var', (101, 111))	('tumor', 'Disease', (227, 232))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
50520	33579226	Though KRAS mutations were at the first and second actionable rank respectively for the Chinese and Western populations, they were still at a relatively low level of actionable evidence.	('KRAS', 'Gene', '3845', (7, 11))	('mutations', 'Var', (12, 21))	('KRAS', 'Gene', (7, 11))
50543	33579226	The adjust factors were 1.1152 and 0.9738 for the two assays from the MSK dataset, and 0.7875 for the ORI dataset.	('MSK', 'Gene', (70, 73))	('0.7875', 'Var', (87, 93))	('MSK', 'Gene', '150094', (70, 73))
50556	33579226	FGFR2 fusions are most identified in both populations.	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (6, 13))	('FGFR2', 'Gene', '2263', (0, 5))
50567	33579226	For the MSK cohort, 66.27% of patients had actionable mutations (Fig.	('patients', 'Species', '9606', (30, 38))	('mutations', 'Var', (54, 63))	('MSK', 'Gene', '150094', (8, 11))	('MSK', 'Gene', (8, 11))
50571	33579226	ORI cohort had top actionable mutations in KRAS, CDKN2A, PIK3CA, and FGFR2 (Fig.	('CDKN2A', 'Gene', '1029', (49, 55))	('PIK3CA', 'Gene', '5290', (57, 63))	('FGFR2', 'Gene', (69, 74))	('FGFR2', 'Gene', '2263', (69, 74))	('KRAS', 'Gene', (43, 47))	('mutations', 'Var', (30, 39))	('CDKN2A', 'Gene', (49, 55))	('KRAS', 'Gene', '3845', (43, 47))	('PIK3CA', 'Gene', (57, 63))
50572	33579226	MSK cohort had top actionable mutations in IDH1, KRAS, FGFR2, ATM, IDH2, and NRAS (Fig.	('ATM', 'Gene', '472', (62, 65))	('KRAS', 'Gene', '3845', (49, 53))	('IDH2', 'Gene', (67, 71))	('FGFR2', 'Gene', (55, 60))	('NRAS', 'Gene', (77, 81))	('FGFR2', 'Gene', '2263', (55, 60))	('IDH1', 'Gene', (43, 47))	('IDH2', 'Gene', '3418', (67, 71))	('ATM', 'Gene', (62, 65))	('mutations', 'Var', (30, 39))	('IDH1', 'Gene', '3417', (43, 47))	('NRAS', 'Gene', '4893', (77, 81))	('MSK', 'Gene', '150094', (0, 3))	('MSK', 'Gene', (0, 3))	('KRAS', 'Gene', (49, 53))
50574	33579226	4a, BRAF had two mutations (V600E and K601N) in the patients of the ORI cohort with Level_2B and Level_3B actionability, respectively.	('V600E', 'Var', (28, 33))	('K601N', 'Var', (38, 43))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('K601N', 'Mutation', 'rs121913365', (38, 43))	('V600E', 'Mutation', 'rs113488022', (28, 33))	('patients', 'Species', '9606', (52, 60))
50575	33579226	BRAF in the MSK cohort only had one mutation (K601E) with Level_3B actionability.	('K601E', 'Mutation', 'rs121913364', (46, 51))	('MSK', 'Gene', '150094', (12, 15))	('MSK', 'Gene', (12, 15))	('K601E', 'Var', (46, 51))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))
50577	33579226	KRAS had mutations at G12, G13, and Q61 in both cohorts.	('KRAS', 'Gene', '3845', (0, 4))	('KRAS', 'Gene', (0, 4))	('Q61', 'Var', (36, 39))	('G13', 'Var', (27, 30))
50578	33579226	In the ORI cohort, KRAS also had the other mutations at D57 and D154.	('KRAS', 'Gene', '3845', (19, 23))	('KRAS', 'Gene', (19, 23))	('D154', 'Var', (64, 68))
50596	33579226	Currently, NRAS mutation is actionable at level 3B.	('NRAS', 'Gene', '4893', (11, 15))	('mutation', 'Var', (16, 24))	('NRAS', 'Gene', (11, 15))
50597	33579226	Patients with NRAS mutation could be treated with Binimetinib or Binimetinib+Ribociclib.	('Binimetinib', 'Chemical', 'MESH:C581313', (50, 61))	('NRAS', 'Gene', '4893', (14, 18))	('mutation', 'Var', (19, 27))	('Patients', 'Species', '9606', (0, 8))	('Binimetinib', 'Chemical', 'MESH:C581313', (65, 76))	('NRAS', 'Gene', (14, 18))
50599	33579226	About 60 ~ 70% of patients had actionable mutations in the ORI cohort and MSK cohort.	('MSK', 'Gene', '150094', (74, 77))	('MSK', 'Gene', (74, 77))	('mutations', 'Var', (42, 51))	('patients', 'Species', '9606', (18, 26))
50600	33579226	For the actionable mutations, the MSK cohort had a higher actionable level than the ORI cohort, which implied a big potential in the treatment of iCCA for the Chinese population.	('mutations', 'Var', (19, 28))	('actionable level', 'MPA', (58, 74))	('CCA', 'Disease', (147, 150))	('higher', 'PosReg', (51, 57))	('MSK', 'Gene', '150094', (34, 37))	('MSK', 'Gene', (34, 37))	('CCA', 'Disease', 'MESH:C536211', (147, 150))
50601	33579226	Of these actionable mutations, KRAS and IDH1 showed a significant bias in actionability between the Chinese and Western populations.	('actionability', 'MPA', (74, 87))	('KRAS', 'Gene', (31, 35))	('IDH1', 'Gene', (40, 44))	('KRAS', 'Gene', '3845', (31, 35))	('IDH1', 'Gene', '3417', (40, 44))	('mutations', 'Var', (20, 29))
50608	33579226	About 33.33 and 57.89% of patients with FGFR2 fusions could be treated with target therapy at a high actionable level (Level 3A) in the ORI and MSK cohort, respectively.	('MSK', 'Gene', (144, 147))	('fusions', 'Var', (46, 53))	('patients', 'Species', '9606', (26, 34))	('FGFR2', 'Gene', '2263', (40, 45))	('FGFR2', 'Gene', (40, 45))	('MSK', 'Gene', '150094', (144, 147))
50610	33579226	ORI cohort had BRAF mutation V600E at a highly actionable level, 2B.	('BRAF', 'Gene', '673', (15, 19))	('V600E', 'Mutation', 'rs113488022', (29, 34))	('V600E', 'Var', (29, 34))	('BRAF', 'Gene', (15, 19))
50611	33579226	V600E mutation in BRAF was recommended to be treated with Dabrafenib, Dabrafenib+Panitumumab+Trametinib, Dabrafenib+Trametinib, Encorafenib+ Binimetinib, Encorafenib+Cetuximab+Binimetinib, Trametinib, Vemurafenib, or Vemurafenib+Cobimetinib.	('Trametinib', 'Chemical', 'MESH:C560077', (189, 199))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (217, 228))	('Trametinib', 'Chemical', 'MESH:C560077', (93, 103))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (201, 212))	('Dabrafenib', 'Chemical', 'MESH:C561627', (58, 68))	('Cetuximab', 'Chemical', 'MESH:D000068818', (166, 175))	('V600E', 'Var', (0, 5))	('Encorafenib', 'Chemical', 'MESH:C000601108', (154, 165))	('Dabrafenib', 'Chemical', 'MESH:C561627', (105, 115))	('Cobimetinib', 'Chemical', 'MESH:C574276', (229, 240))	('V600E', 'Mutation', 'rs113488022', (0, 5))	('Panitumumab', 'Chemical', 'MESH:D000077544', (81, 92))	('Binimetinib', 'Chemical', 'MESH:C581313', (176, 187))	('Trametinib', 'Chemical', 'MESH:C560077', (116, 126))	('Binimetinib', 'Chemical', 'MESH:C581313', (141, 152))	('BRAF', 'Gene', '673', (18, 22))	('BRAF', 'Gene', (18, 22))	('Encorafenib', 'Chemical', 'MESH:C000601108', (128, 139))	('Dabrafenib', 'Chemical', 'MESH:C561627', (70, 80))
50612	33579226	MSK cohort had K601E mutation with a lower actionability (level 3B).	('actionability', 'MPA', (43, 56))	('K601E', 'Mutation', 'rs121913364', (15, 20))	('K601E', 'Var', (15, 20))	('lower', 'NegReg', (37, 42))	('MSK', 'Gene', '150094', (0, 3))	('MSK', 'Gene', (0, 3))
50613	33579226	K601E mutation in BRAF was recommended to be treated with PLX8394.	('BRAF', 'Gene', (18, 22))	('BRAF', 'Gene', '673', (18, 22))	('K601E', 'Var', (0, 5))	('K601E', 'Mutation', 'rs121913364', (0, 5))
50628	33579226	The frequency of KRAS and IDH1 mutation is similar to the other researches in the coordinate populations.	('mutation', 'Var', (31, 39))	('IDH1', 'Gene', (26, 30))	('KRAS', 'Gene', (17, 21))	('KRAS', 'Gene', '3845', (17, 21))	('IDH1', 'Gene', '3417', (26, 30))
50629	33579226	The higher frequency of KRAS mutations in the Chinese population and IDH1 mutations in the Western population could be associated with large duct and small duct iCCA, respectively.	('KRAS', 'Gene', '3845', (24, 28))	('large duct', 'Disease', (135, 145))	('CCA', 'Disease', (162, 165))	('IDH1', 'Gene', '3417', (69, 73))	('mutations', 'Var', (29, 38))	('mutations', 'Var', (74, 83))	('CCA', 'Disease', 'MESH:C536211', (162, 165))	('KRAS', 'Gene', (24, 28))	('IDH1', 'Gene', (69, 73))	('associated', 'Reg', (119, 129))
50632	33579226	Mutational bias between the two cohorts could be caused by the difference in genetic background, endemic diseases, or special environmental factors.	('endemic diseases', 'Disease', 'MESH:D006043', (97, 113))	('Mutational bias', 'Var', (0, 15))	('endemic diseases', 'Disease', (97, 113))
50634	33579226	Patients with IDH1 mutation were prone to be fluke-negative.	('IDH1', 'Gene', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (19, 27))	('IDH1', 'Gene', '3417', (14, 18))
50636	33579226	Thus the risk factor of highly mutated IDH1 still needs further investigation.	('IDH1', 'Gene', '3417', (39, 43))	('IDH1', 'Gene', (39, 43))	('highly mutated', 'Var', (24, 38))
50637	33579226	Similarly, KRAS mutations were only found associated with negative HBV without any confirmed risk factor.	('KRAS', 'Gene', (11, 15))	('KRAS', 'Gene', '3845', (11, 15))	('mutations', 'Var', (16, 25))
50643	33579226	KRAS and IDH1 mutations account for about 20% ~ 30% of actionable targets with a significant bias in the two populations.	('IDH1', 'Gene', (9, 13))	('IDH1', 'Gene', '3417', (9, 13))	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('KRAS', 'Gene', '3845', (0, 4))
50685	29863155	This newly emerging definition was proposed according to the study of Tsuji et al.18  After surgical resection of ICC, high rates of recurrence of between 46% and 65% are reported.19 There are several prognostic factors reported for predicting survival after surgical resection: lymph node involvement, surgical margin, bile duct infiltration, intrahepatic metastasis, and CA19-9.	('lymph', 'Disease', (279, 284))	('bile duct infiltration', 'Disease', (320, 342))	('CA19-9', 'Var', (373, 379))	('intrahepatic metastasis', 'Disease', 'MESH:D009362', (344, 367))	('intrahepatic metastasis', 'Disease', (344, 367))
50784	22504095	mass > 3 cm (N=21), metastatic disease at transplantation (N=4), or direct tumor biopsy (N=16)), or who had a history of previous malignancy within 5 years (N=7) had significantly worse recurrence-free survival as compared to those within criteria (HR 2.98 (95% CI 1.79-4.95); Figure 4a).	('malignancy', 'Disease', (130, 140))	('recurrence-free survival', 'CPA', (186, 210))	('worse', 'NegReg', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('malignancy', 'Disease', 'MESH:D009369', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('metastatic disease', 'Var', (20, 38))	('tumor', 'Disease', (75, 80))
50850	20592891	We extracted intrahepatic CCA cases (International Classification of Disease (ICD) 10 code C22.1, ICD-Oncology (ICD-O) code 8160, including adenocarcinoma (ICD-O codes 8140, 8161, 8260, 8440, 8480, and 8560), duct carcinoma (ICD-O code 8500), and Klatskin tumor (ICD-O codes 8162), and extrahepatic CCA: ICD 10 code C24.0) from the Korea National Cancer Incidence Database (KNCIDB).	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('duct carcinoma', 'Disease', (209, 223))	('Cancer', 'Disease', 'MESH:D009369', (347, 353))	('duct carcinoma', 'Disease', 'MESH:D021441', (209, 223))	('Klatskin tumor', 'Disease', (247, 261))	('Klatskin tumor', 'Disease', 'MESH:D018285', (247, 261))	('adenocarcinoma', 'Disease', (140, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('Oncology', 'Phenotype', 'HP:0002664', (102, 110))	('8161', 'Var', (174, 178))	('intrahepatic CCA', 'Disease', (13, 29))	('8440', 'Var', (186, 190))	('adenocarcinoma', 'Disease', 'MESH:D000230', (140, 154))	('CCA', 'Phenotype', 'HP:0030153', (299, 302))	('Cancer', 'Phenotype', 'HP:0002664', (347, 353))	('8260', 'Var', (180, 184))	('8560', 'Var', (202, 206))	('ICD-Oncology', 'Disease', 'OMIM:252500', (98, 110))	('8480', 'Var', (192, 196))	('Cancer', 'Disease', (347, 353))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('ICD-Oncology', 'Disease', (98, 110))	('CCA', 'Phenotype', 'HP:0030153', (26, 29))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (13, 29))
50890	29738493	P62 is further a mono or polyubiquitin-binding protein that accumulates in different chronic, toxic, and degenerative diseases due to aggregation of the cytosolic protein.	('degenerative diseases', 'Disease', (105, 126))	('aggregation', 'MPA', (134, 145))	('accumulates', 'PosReg', (60, 71))	('P62', 'Var', (0, 3))	('degenerative diseases', 'Disease', 'MESH:D019636', (105, 126))
50894	29738493	The potential of p62 manipulation for cancer therapeutics will thereby be unveiled.	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('manipulation', 'Var', (21, 33))	('cancer', 'Disease', (38, 44))
50899	29738493	Indeed, p62 through its PB1 domain regulates the activity of PKCzeta and by its binding to this protein activates the PKCzeta-JNK-caspase 3 apoptotic pathway in endothelial cells.	('PB1', 'Gene', '26952', (24, 27))	('PKCzeta', 'Gene', '5590', (118, 125))	('activity', 'MPA', (49, 57))	('activates', 'PosReg', (104, 113))	('caspase', 'Gene', (130, 137))	('PB1', 'Gene', (24, 27))	('p62', 'Var', (8, 11))	('PKCzeta', 'Gene', '5590', (61, 68))	('PKCzeta', 'Gene', (61, 68))	('regulates', 'Reg', (35, 44))	('JNK', 'Gene', (126, 129))	('caspase', 'Gene', '841', (130, 137))	('binding', 'Interaction', (80, 87))	('JNK', 'Gene', '5599', (126, 129))	('PKCzeta', 'Gene', (118, 125))
50907	29738493	This domain is therefore an important factor for NEDD4 function as an autophagic E2 ubiquitin ligase that ubiquitinates p62 and facilitates p62-mediated inclusion body autophagy.	('NEDD4', 'Gene', (49, 54))	('p62', 'Protein', (120, 123))	('facilitates', 'PosReg', (128, 139))	('inclusion body autophagy', 'CPA', (153, 177))	('p62-mediated', 'Var', (140, 152))	('NEDD4', 'Gene', '4734', (49, 54))	('ubiquitinates', 'MPA', (106, 119))
50914	29738493	have discovered that deletion of the p62 PB1 domain has no effect on stress-induced autophagy of the lysosome degradation machinery.	('autophagy of the lysosome degradation machinery', 'CPA', (84, 131))	('PB1', 'Gene', '26952', (41, 44))	('PB1', 'Gene', (41, 44))	('deletion', 'Var', (21, 29))
50916	29738493	Most recently, p62 has been shown to promote tumorigenesis in autophagy-deficient tumor cells by altering NF-kappaB regulation through its PB1 domain.	('autophagy-deficient tumor', 'Disease', (62, 87))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('promote', 'PosReg', (37, 44))	('autophagy-deficient tumor', 'Disease', 'MESH:C564093', (62, 87))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('altering', 'Reg', (97, 105))	('PB1', 'Gene', '26952', (139, 142))	('PB1', 'Gene', (139, 142))	('regulation', 'MPA', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('NF-kappaB', 'Protein', (106, 115))	('tumor', 'Disease', (82, 87))	('p62', 'Var', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
50921	29738493	demonstrated that p62 can interact with RIP and link the aPKCs to activate NF-kappaB involving the TNF-R1/TRADD/RIP/p62/aPKCs/IKKbeta signaling pathway.	('IKKbeta', 'Gene', (126, 133))	('IKKbeta', 'Gene', '3551', (126, 133))	('RIP', 'Gene', '8737', (40, 43))	('AD', 'Phenotype', 'HP:0002511', (108, 110))	('TNF-R1', 'Gene', (99, 105))	('activate', 'PosReg', (66, 74))	('p62', 'Var', (18, 21))	('RIP', 'Gene', (40, 43))	('RIP', 'Gene', '8737', (112, 115))	('RIP', 'Gene', (112, 115))	('NF-kappaB', 'Protein', (75, 84))	('TRADD', 'Gene', '8717', (106, 111))	('TNF-R1', 'Gene', '7132', (99, 105))	('TRADD', 'Gene', (106, 111))	('interact', 'Interaction', (26, 34))
50922	29738493	In addition, p62 is also a significant intermediate in an IL-1 signaling pathway to activate NF-kappaB through the specific adapters such as RIP and TRAF6 (Figure 1A).	('p62', 'Var', (13, 16))	('NF-kappaB', 'Protein', (93, 102))	('TRAF6', 'Gene', (149, 154))	('TRAF6', 'Gene', '7189', (149, 154))	('activate', 'PosReg', (84, 92))	('RIP', 'Gene', '8737', (141, 144))	('RIP', 'Gene', (141, 144))
50923	29738493	In cisplatin-resistant ovarian (SKOV3/DDP) cells, loss of the p62 ZZ domain restored sensitivity to cisplatin treatment.	('cisplatin', 'Chemical', 'MESH:D002945', (3, 12))	('sensitivity to cisplatin treatment', 'MPA', (85, 119))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('p62', 'Protein', (62, 65))	('loss', 'Var', (50, 54))	('restored', 'PosReg', (76, 84))
50926	29738493	Further evidence indicated that XRK3F2 has a relative specificity for p62-ZZ and characterized XRK3F2's capacity to inhibit the growth of primary MM cells and human MM cell lines.	('XRK3F2', 'Gene', (95, 101))	('growth', 'CPA', (128, 134))	('human', 'Species', '9606', (159, 164))	('inhibit', 'NegReg', (116, 123))	('p62-ZZ', 'Var', (70, 76))
50927	29738493	Moreover, the p62 ZZ domain aids the degradation of misfolded protein through autophagy, by its interaction with the N-terminal Arginine of ArginyatedBiP (R-BiP).	('aids', 'PosReg', (28, 32))	('BiP', 'Gene', (150, 153))	('BiP', 'Gene', '2662', (150, 153))	('interaction', 'Interaction', (96, 107))	('BiP', 'Gene', (157, 160))	('degradation of misfolded protein', 'MPA', (37, 69))	('Arginine', 'Chemical', 'MESH:D001120', (128, 136))	('p62', 'Var', (14, 17))	('autophagy', 'CPA', (78, 87))	('BiP', 'Gene', '2662', (157, 160))
50928	29738493	Furthermore, p62 is also an AMPA receptor interacting protein (RIP).	('RIP', 'Gene', '8737', (63, 66))	('p62', 'Var', (13, 16))	('RIP', 'Gene', (63, 66))
50930	29738493	In addition, p62 can also interact with other autophagic effector proteins like as LC3A, LC3B, beclin-1, BNIP3, gamma-aminobutyric acid receptor-associated protein (GABARAP) and GABARAP-like molecules through LIR domain.	('p62', 'Var', (13, 16))	('BNIP3', 'Gene', (105, 110))	('LC3B', 'Gene', (89, 93))	('LC3A', 'Gene', (83, 87))	('BNIP3', 'Gene', '664', (105, 110))	('gamma-aminobutyric acid receptor-associated protein', 'Gene', '11337', (112, 163))	('LC3A', 'Gene', '84557', (83, 87))	('LC3B', 'Gene', '81631', (89, 93))	('beclin-1', 'Gene', (95, 103))	('beclin-1', 'Gene', '8678', (95, 103))	('GABARAP', 'Gene', '11337', (178, 185))	('GABARAP', 'Gene', (178, 185))	('GABARAP', 'Gene', '11337', (165, 172))	('GABARAP', 'Gene', (165, 172))	('interact', 'Interaction', (26, 34))
50932	29738493	Furthermore, knockdown of LC3B results in a significant accumulation of selective substrate p62.	('LC3B', 'Gene', '81631', (26, 30))	('selective substrate p62', 'MPA', (72, 95))	('accumulation', 'PosReg', (56, 68))	('knockdown', 'Var', (13, 22))	('LC3B', 'Gene', (26, 30))
50935	29738493	The LIR mutation is required to impair Spred2-mediated tumor cell death in an autophagy-dependent manner.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('Spred2', 'Gene', '200734', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('mutation', 'Var', (8, 16))	('Spred2', 'Gene', (39, 45))	('impair', 'NegReg', (32, 38))
50937	29738493	The KIR domain of p62 is located next to the LIR domain and resembles the ETGE motif utilized by Nrf2 for its interaction with Keap1.	('Keap1', 'Gene', '9817', (127, 132))	('Keap1', 'Gene', (127, 132))	('p62', 'Var', (18, 21))	('Nrf2', 'Gene', '4780', (97, 101))	('Nrf2', 'Gene', (97, 101))
50939	29738493	However, under abnormal conditions, such as oxidative stress, p62 can also compete with Nrf2 for binding to Keap1.	('Nrf2', 'Gene', (88, 92))	('oxidative stress', 'Phenotype', 'HP:0025464', (44, 60))	('p62', 'Var', (62, 65))	('Keap1', 'Gene', '9817', (108, 113))	('Keap1', 'Gene', (108, 113))	('binding', 'Interaction', (97, 104))	('Nrf2', 'Gene', '4780', (88, 92))
50947	29738493	The earlier results strongly suggest that after amino acid starvation, p62 recognizes the ubiquitinated proteasome and does this through its association with LC3B, and thereby facilitating autophagosomal recognition of the proteasome.	('ubiquitinated proteasome', 'MPA', (90, 114))	('facilitating', 'PosReg', (176, 188))	('LC3B', 'Gene', (158, 162))	('association', 'Interaction', (141, 152))	('LC3B', 'Gene', '81631', (158, 162))	('autophagosomal', 'CPA', (189, 203))	('p62', 'Var', (71, 74))
50948	29738493	In other words, mutation of UBA domain activates TRAF6-NF-kappaB signaling which result is increased osteoclastogenesis.	('mutation', 'Var', (16, 24))	('TRAF6', 'Gene', (49, 54))	('TRAF6', 'Gene', '7189', (49, 54))	('activates', 'PosReg', (39, 48))	('osteoclastogenesis', 'CPA', (101, 119))	('increased', 'PosReg', (91, 100))	('UBA domain', 'Gene', (28, 38))
50951	29738493	It has been proposed that p62 enables to create a complex form between TRAF-6 and aPKC, which form is RANKL-induced in NF-kappaB activation.	('p62', 'Var', (26, 29))	('TRAF-6', 'Gene', '7189', (71, 77))	('RANKL', 'Gene', '8600', (102, 107))	('RANKL', 'Gene', (102, 107))	('activation', 'PosReg', (129, 139))	('TRAF-6', 'Gene', (71, 77))	('NF-kappaB', 'Protein', (119, 128))
50957	29738493	The multifunctional protein p62 interacts with Atg8/LC3 through the LC3-interaction region (LIR) and there is the accumulation of p62 in autophagy-deficient mice.	('mice', 'Species', '10090', (157, 161))	('interacts', 'Interaction', (32, 41))	('p62', 'Var', (130, 133))	('accumulation', 'PosReg', (114, 126))	('autophagy-deficient', 'Disease', (137, 156))	('autophagy-deficient', 'Disease', 'MESH:C564093', (137, 156))
50963	29738493	LC3 is most reliable autophagy marker which can be accumulated that was observed of neurite degeneration by knocking down of Atg7 and Beclin1 after nerve growth factor deprivation.	('Atg7', 'Gene', (125, 129))	('Beclin1', 'Gene', '8678', (134, 141))	('neurite degeneration', 'Disease', (84, 104))	('knocking down', 'Var', (108, 121))	('Atg7', 'Gene', '10533', (125, 129))	('Beclin1', 'Gene', (134, 141))	('neurite degeneration', 'Disease', 'MESH:D009410', (84, 104))
50967	29738493	In contrast, this recent evidence indicates that the absence of Atg8 family LC3/GABARAP proteins could not prevent the formation of autophagosome during PINK1-PARK2-dependent mitophagy.	('absence', 'Var', (53, 60))	('PARK2', 'Gene', '5071', (159, 164))	('GABARAP', 'Gene', '11337', (80, 87))	('GABARAP', 'Gene', (80, 87))	('PARK2', 'Gene', (159, 164))	('PINK1', 'Gene', '65018', (153, 158))	('PINK1', 'Gene', (153, 158))
50970	29738493	There is high accumulation of p62 together with polyubiquitinated proteins aggregates in various chronic, toxic, and degenerative diseases.	('degenerative diseases', 'Disease', 'MESH:D019636', (117, 138))	('chronic', 'Disease', (97, 104))	('degenerative diseases', 'Disease', (117, 138))	('p62', 'Var', (30, 33))	('toxic', 'Disease', (106, 111))
50974	29738493	has reported that growth of liver tumors caused by the inhibition of autophagy is greatly diminished by concomitant deletion of p62 or Nrf2.	('Nrf2', 'Gene', (135, 139))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('autophagy', 'CPA', (69, 78))	('liver tumors', 'Disease', 'MESH:D008113', (28, 40))	('deletion', 'Var', (116, 124))	('p62', 'Gene', (128, 131))	('liver tumors', 'Disease', (28, 40))	('liver tumors', 'Phenotype', 'HP:0002896', (28, 40))	('Nrf2', 'Gene', '4780', (135, 139))	('diminished', 'NegReg', (90, 100))	('growth', 'MPA', (18, 24))	('inhibition', 'NegReg', (55, 65))
50984	29738493	Not only are the high levels of p62 been observed in tumor promotion but they have strongly further been implicated in causing resistance to cancer therapy especially platinum-based therapeutic strategies.	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('resistance', 'CPA', (127, 137))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('implicated', 'Reg', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('platinum', 'Chemical', 'MESH:D010984', (167, 175))	('causing', 'Reg', (119, 126))	('p62', 'Var', (32, 35))	('cancer', 'Disease', (141, 147))
50987	29738493	Through activation of protein kinase C iota (PKCiota)-S phase kinase-associated protein 2 (SKP2) signaling pathway, p62 enhanced cell apoptosis resistance and thus promoted tumor growth.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('enhanced', 'PosReg', (120, 128))	('activation', 'PosReg', (8, 18))	('SKP2', 'Gene', '6502', (91, 95))	('p62', 'Var', (116, 119))	('promoted', 'PosReg', (164, 172))	('tumor', 'Disease', (173, 178))	('cell apoptosis resistance', 'CPA', (129, 154))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('SKP2', 'Gene', (91, 95))
50989	29738493	P62 has been reported to be an anti-inflammatory tumor suppressor through its regulation of the mTORC1/c-Myc-pathway of stromal glucose and amino acid metabolism in epithelial prostate cancer cells.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('glucose', 'Chemical', 'MESH:D005947', (128, 135))	('epithelial prostate cancer', 'Disease', (165, 191))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('c-Myc', 'Gene', (103, 108))	('P62', 'Var', (0, 3))	('tumor', 'Disease', (49, 54))	('mTORC1', 'Gene', '382056', (96, 102))	('c-Myc', 'Gene', '4609', (103, 108))	('epithelial prostate cancer', 'Disease', 'MESH:D011471', (165, 191))	('prostate cancer', 'Phenotype', 'HP:0012125', (176, 191))	('mTORC1', 'Gene', (96, 102))	('regulation', 'Reg', (78, 88))
50991	29738493	High levels of p62 were proven to inhibit E3 ligase RNF168 activity which is crucial for H2A ubiquitination, thereby inhibiting DNA-damage repair mechanism and thus increases sensitivity of cancer cells to radiation.	('increases', 'PosReg', (165, 174))	('cancer', 'Disease', (190, 196))	('activity', 'MPA', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('DNA-damage repair mechanism', 'MPA', (128, 155))	('RNF168', 'Gene', '165918', (52, 58))	('sensitivity', 'CPA', (175, 186))	('RNF168', 'Gene', (52, 58))	('inhibiting', 'NegReg', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('inhibit', 'NegReg', (34, 41))	('p62', 'Var', (15, 18))
50993	29738493	However, the high frequency of tumor-initiation in high p62 expressing cancer cells is an important factor that cannot be denied.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor-initiation', 'Disease', 'MESH:D009369', (31, 47))	('cancer', 'Disease', (71, 77))	('tumor-initiation', 'Disease', (31, 47))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('high p62 expressing', 'Var', (51, 70))
51011	29738493	For example, p62 was observed in cytosolic aggregates formed of PB1-driven p62 oligomers and p62-aPKC.	('PB1', 'Gene', (64, 67))	('PB1', 'Gene', '26952', (64, 67))	('p62', 'Var', (75, 78))
51012	29738493	These were recognized as signal-organizing centers where p62 interacted with caspase-8 and TRAF6 thereby activating the caspase-8 downstream effectors caspases.	('caspase-8', 'Gene', '841', (77, 86))	('p62', 'Var', (57, 60))	('caspase-8', 'Gene', '841', (120, 129))	('caspases', 'Gene', (151, 159))	('caspases', 'Gene', '841', (151, 159))	('interacted', 'Interaction', (61, 71))	('TRAF6', 'Gene', (91, 96))	('TRAF6', 'Gene', '7189', (91, 96))	('caspase-8', 'Gene', (77, 86))	('caspase-8', 'Gene', (120, 129))	('activating', 'PosReg', (105, 115))
51014	29738493	discovered that p62 promoted aggregation of CUL3-modified caspase-8 within p62-dependent foci (Figure 3), thereby leading to full activation and processing of the enzyme and full commitment to cell death.	('CUL3', 'Gene', '8452', (44, 48))	('aggregation', 'MPA', (29, 40))	('CUL3', 'Gene', (44, 48))	('caspase-8', 'Gene', (58, 67))	('caspase-8', 'Gene', '841', (58, 67))	('p62', 'Var', (16, 19))	('processing', 'MPA', (145, 155))	('activation', 'MPA', (130, 140))
51017	29738493	Furthermore, the anti-apoptotic role of p62 causes activation of the p62-PKCiota-SKP2 pathway in esophageal squamous cell carcinoma (ESCC) through stabilizing SKP2 under serum starvation condition.	('p62', 'Var', (40, 43))	('SKP2', 'Gene', '6502', (81, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (97, 131))	('SKP2', 'Gene', (159, 163))	('esophageal squamous cell carcinoma', 'Disease', (97, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('SKP2', 'Gene', '6502', (159, 163))	('SKP2', 'Gene', (81, 85))	('activation', 'PosReg', (51, 61))	('stabilizing', 'MPA', (147, 158))
51030	29738493	However, with this evidence that autophagy-deficient cells accumulate p62, thereby posing another tumorigenic potential, this combinatory strategy may not be the best for most cancers.	('cancers', 'Disease', (176, 183))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('accumulate', 'PosReg', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('autophagy-deficient', 'Disease', (33, 52))	('p62', 'Var', (70, 73))	('tumor', 'Disease', (98, 103))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('autophagy-deficient', 'Disease', 'MESH:C564093', (33, 52))
51035	29843754	Specific PD-1 blockades were approved for treatment of melanoma in 2014 and for treatment of non-small-cell lung cancer in 2015 in the United States, European Union, and Japan.	('blockades', 'Var', (14, 23))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (93, 119))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (97, 119))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('PD-1', 'Gene', (9, 13))	('melanoma', 'Disease', (55, 63))
51037	29843754	The combination of anti-PD-1/PD-L1 with anti-CTLA-4 antibodies is being evaluated in phase 1, 2 or 3 trials, and the results suggest that an anti-PD-1 antibody combined with locoregional therapy or other molecular targeted agents is an effective treatment strategy for HCC.	('HCC', 'Gene', (269, 272))	('anti-PD-1', 'Var', (141, 150))	('rat', 'Species', '10116', (258, 261))	('HCC', 'Gene', '619501', (269, 272))	('HCC', 'Phenotype', 'HP:0001402', (269, 272))
51039	29843754	Epigenetic modulations of checkpoints for improving the tumor microenvironment also expand our knowledge of potential therapeutic targets in improving the tumor microenvironment and restoring immune recognition and immunogenicity.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('immunogenicity', 'MPA', (215, 229))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('Epigenetic modulations', 'Var', (0, 22))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (155, 160))	('improving', 'PosReg', (141, 150))	('immune recognition', 'MPA', (192, 210))	('restoring', 'PosReg', (182, 191))
51053	29843754	Epigenetic modifiers function importantly in priming and enhancing the therapeutic effect of the host immune system on cancer.	('enhancing', 'PosReg', (57, 66))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('Epigenetic modifiers', 'Var', (0, 20))	('therapeutic effect', 'CPA', (71, 89))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
51059	29843754	In 31 HCC patients, it was found the addition of anti-CTLA-4 antibody resulted in an increase in the frequency of tumor-associated antigens (TAA)-specific cytotoxic T cells in 60% of HCC patients, accompanied with enhanced antitumor effect of tumor-specific T cells.	('HCC', 'Gene', '619501', (183, 186))	('HCC', 'Phenotype', 'HP:0001402', (183, 186))	('tumor', 'Disease', (227, 232))	('anti-CTLA-4', 'Gene', (49, 60))	('HCC', 'Gene', (183, 186))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', (243, 248))	('patients', 'Species', '9606', (187, 195))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('HCC', 'Phenotype', 'HP:0001402', (6, 9))	('HCC', 'Gene', '619501', (6, 9))	('increase', 'PosReg', (85, 93))	('enhanced', 'PosReg', (214, 222))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('HCC', 'Gene', (6, 9))	('patients', 'Species', '9606', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('antibody', 'Var', (61, 69))	('anti-CTLA-4 antibody', 'Var', (49, 69))
51060	29843754	Treg-specific CTLA-4 deficiency was shown to affect in vivo Treg suppressive function and promote tumor immunity.	('affect', 'Reg', (45, 51))	('CTLA-4', 'Gene', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('deficiency', 'Var', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Treg suppressive function', 'CPA', (60, 85))	('promote', 'PosReg', (90, 97))	('tumor', 'Disease', (98, 103))
51061	29843754	In a rat liver transplantation model with tumor recurrence, hepatic expressions of CTLA-4, TGF-beta and PD-L1 were increased in the tumor tissues from small-for-size liver graft group compared to whole graft group.	('hepatic expressions', 'MPA', (60, 79))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('increased', 'PosReg', (115, 124))	('TGF-beta', 'Gene', '59086', (91, 99))	('CTLA-4', 'Gene', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('small-for-size', 'Var', (151, 165))	('rat', 'Species', '10116', (5, 8))	('TGF-beta', 'Gene', (91, 99))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('PD-L1', 'Gene', (104, 109))
51063	29843754	HCC-derived Tregs down-regulated CD80/86 expression on splenic DCs in a CTLA-4 dependent manner, and inhibition of CTLA-4 could prevent the Treg-mediated suppression in anti-tumor immune responses.	('tumor', 'Disease', (174, 179))	('inhibition', 'Var', (101, 111))	('CD80', 'Gene', '941', (33, 37))	('CTLA-4', 'Gene', (115, 121))	('expression', 'MPA', (41, 51))	('HCC', 'Gene', (0, 3))	('HCC', 'Phenotype', 'HP:0001402', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('down-regulated', 'NegReg', (18, 32))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('prevent', 'NegReg', (128, 135))	('HCC', 'Gene', '619501', (0, 3))	('CD80', 'Gene', (33, 37))
51073	29843754	It also suggests that the PD-L1/PD-1 immune checkpoint could be targeted in the treatment of particular HCC variants.	('HCC', 'Gene', (104, 107))	('HCC', 'Phenotype', 'HP:0001402', (104, 107))	('HCC', 'Gene', '619501', (104, 107))	('variants', 'Var', (108, 116))
51074	29843754	More recently, 90 HCC patients with PD-L1 expression in peritumoral hepatocytes were demonstrated to have a significantly higher risk of cancer recurrence or metastasis and cancer-related death.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('HCC', 'Phenotype', 'HP:0001402', (18, 21))	('cancer', 'Disease', (173, 179))	('HCC', 'Gene', '619501', (18, 21))	('PD-L1', 'Gene', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('patients', 'Species', '9606', (22, 30))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('rat', 'Species', '10116', (92, 95))	('HCC', 'Gene', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', (137, 143))	('expression', 'Var', (42, 52))	('tumor', 'Disease', (60, 65))	('metastasis', 'Disease', 'MESH:D009362', (158, 168))	('metastasis', 'Disease', (158, 168))
51088	29843754	The expressions of PD-1 and Tim-3 in tumor tissues and tumor adjacent tissues were significantly associated with PD-1 and Tim-3 polymorphisms, with genotype AA of PD-1 rs10204525 and genotypes GT + TT of Tim-3 rs10053538 respectively.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('Tim-3', 'Gene', '84868', (122, 127))	('PD-1', 'Gene', (163, 167))	('PD-1', 'Gene', (19, 23))	('associated', 'Reg', (97, 107))	('PD-1', 'Gene', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Tim-3', 'Gene', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('polymorphisms', 'Var', (128, 141))	('rs10204525', 'Mutation', 'rs10204525', (168, 178))	('Tim-3', 'Gene', (28, 33))	('expressions', 'MPA', (4, 15))	('rs10053538', 'Mutation', 'rs10053538', (210, 220))	('Tim-3', 'Gene', '84868', (204, 209))	('Tim-3', 'Gene', (122, 127))	('rs10053538', 'Var', (210, 220))	('rs10204525', 'Var', (168, 178))	('Tim-3', 'Gene', '84868', (28, 33))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (37, 42))
51092	29843754	Interestingly, blocking LAG-3 increased ex vivo proliferation of CD4+ and CD8+ TIL and effector cytokine production.	('rat', 'Species', '10116', (55, 58))	('CD8', 'Gene', '925', (74, 77))	('TIL', 'Gene', '7096', (79, 82))	('CD4', 'Gene', (65, 68))	('CD4', 'Gene', '920', (65, 68))	('TIL', 'Gene', (79, 82))	('LAG-3', 'Gene', (24, 29))	('increased', 'PosReg', (30, 39))	('ex vivo proliferation', 'CPA', (40, 61))	('blocking', 'Var', (15, 23))	('CD8', 'Gene', (74, 77))
51109	29843754	Patients with tumors exhibiting PD-L1 expression around the tumor front had a lower overall survival than tumor front-positive patients.	('tumor', 'Disease', (14, 19))	('PD-L1', 'Gene', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('expression', 'Var', (38, 48))	('overall survival', 'MPA', (84, 100))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (127, 135))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (60, 65))	('lower', 'NegReg', (78, 83))	('tumor', 'Disease', (106, 111))
51116	29843754	Immunostaining with mAbs detected human leukocyte antigens (HLA) class I defects in 60% of ICC tumors and PD-L1 expression in 30%.	('ICC tumors', 'Disease', 'MESH:C566123', (91, 101))	('defects', 'Var', (73, 80))	('human', 'Species', '9606', (34, 39))	('HLA', 'Gene', (60, 63))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('PD-L1', 'Gene', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('ICC tumors', 'Disease', (91, 101))
51117	29843754	Patients bearing tumors with HLA class I defects and PD-L1 expression had a significantly reduced survival rate.	('defects', 'Var', (41, 48))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('PD-L1', 'Gene', (53, 58))	('reduced', 'NegReg', (90, 97))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('survival rate', 'CPA', (98, 111))	('rat', 'Species', '10116', (107, 110))
51120	29843754	In cancer, two important epigenetic mechanisms include hypermethylation, which is mediated by DNMTs, and histone deacetylation, which is mediated by HDACs.	('hypermethylation', 'Var', (55, 71))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('deacetylation', 'NegReg', (113, 126))	('cancer', 'Disease', (3, 9))	('histone', 'MPA', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
51121	29843754	Epigenetic dysregulation is a crucial mechanism underlying the progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Epigenetic dysregulation', 'Var', (0, 24))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))
51122	29843754	Some epigenetic regulators can act negatively and positively in immune responses and lead to immune evasion, which provides a novel mechanism in immune checkpoint therapy for treatment of cancers.	('immune responses', 'CPA', (64, 80))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('epigenetic regulators', 'Var', (5, 26))	('lead to', 'Reg', (85, 92))	('negatively', 'NegReg', (35, 45))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancers', 'Disease', (188, 195))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('immune evasion', 'MPA', (93, 107))
51123	29843754	Recently, epigenetic modifications of the key immune checkpoints including PD-1, PD-L1, and CTLA-4 were analyzed in non-small cell lung cancer tissues from 39 patients.	('epigenetic', 'Var', (10, 20))	('analyzed', 'Reg', (104, 112))	('PD-1', 'Gene', (75, 79))	('PD-L1', 'Gene', (81, 86))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (116, 142))	('CTLA-4', 'Gene', (92, 98))	('non-small cell lung cancer', 'Disease', (116, 142))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (120, 142))	('patients', 'Species', '9606', (159, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (116, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
51132	29843754	For example, inhibition of the class I HDAC1, HDAC2 and/or HDAC3 led to acetylation of the PD-L1 and PD-L2 promotors, which augmented up-regulation of PD-L1/L2 protein and RNA transcription in melanoma patients, in melanoma cell lines and in a syngeneic mouse model of melanoma.	('HDAC1', 'Gene', (39, 44))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('mouse', 'Species', '10090', (254, 259))	('melanoma', 'Disease', (215, 223))	('melanoma', 'Disease', 'MESH:D008545', (269, 277))	('RNA', 'MPA', (172, 175))	('HDAC3', 'Gene', (59, 64))	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('HDAC1', 'Gene', '3065', (39, 44))	('PD-L1/L2', 'Gene', (151, 159))	('patients', 'Species', '9606', (202, 210))	('augmented up-regulation', 'PosReg', (124, 147))	('melanoma', 'Phenotype', 'HP:0002861', (269, 277))	('melanoma', 'Disease', (269, 277))	('melanoma', 'Disease', 'MESH:D008545', (215, 223))	('HDAC3', 'Gene', '8841', (59, 64))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('PD-L1', 'Gene', (91, 96))	('melanoma', 'Disease', (193, 201))	('melanoma cell lines', 'Disease', 'MESH:D008545', (215, 234))	('inhibition', 'Var', (13, 23))	('HDAC2', 'Gene', '3066', (46, 51))	('acetylation', 'MPA', (72, 83))	('melanoma cell lines', 'Disease', (215, 234))	('HDAC2', 'Gene', (46, 51))	('PD-L2', 'Gene', (101, 106))
51133	29843754	found HDAC6i (ACY-241) reduced PD-L1 production and increased co-stimulatory checkpoint (CD28) levels, and thus suppressed tumor growth in vivo.	('increased', 'PosReg', (52, 61))	('tumor', 'Disease', (123, 128))	('suppressed', 'NegReg', (112, 122))	('reduced PD', 'Phenotype', 'HP:0032198', (23, 33))	('CD28', 'Gene', (89, 93))	('HDAC6i', 'Var', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('reduced', 'NegReg', (23, 30))	('CD28', 'Gene', '940', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('PD-L1 production', 'MPA', (31, 47))
51139	29843754	In human malignant pleural mesothelioma, the levels of miR-15b, miR-16, miR-193a-3p, miR-195, and miR-200c were significantly lower in the immune checkpoint PD-L1-positive samples.	('levels', 'MPA', (45, 51))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (19, 39))	('lower', 'NegReg', (126, 131))	('miR-15b', 'Gene', (55, 62))	('miR-16', 'Gene', '51573', (64, 70))	('malignant pleural mesothelioma', 'Disease', (9, 39))	('human', 'Species', '9606', (3, 8))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (9, 39))	('miR-200c', 'Gene', (98, 106))	('miR-200c', 'Gene', '406985', (98, 106))	('miR-15b', 'Gene', '406949', (55, 62))	('miR-193a-3p', 'Var', (72, 83))	('miR-195', 'Gene', (85, 92))	('miR-195', 'Gene', '406971', (85, 92))	('miR-16', 'Gene', (64, 70))
51140	29843754	Likewise, PD-L1 and miR-138-5p levels were inversely correlated in human colorectal cancer tumors, and miR-138-5p inhibited PD-L1 expression in tumor models in vivo.	('PD-L1', 'Gene', (124, 129))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('expression', 'MPA', (130, 140))	('tumor', 'Disease', (144, 149))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('colorectal cancer tumors', 'Disease', (73, 97))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('miR-138-5p', 'Chemical', '-', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('colorectal cancer tumors', 'Disease', 'MESH:D015179', (73, 97))	('human', 'Species', '9606', (67, 72))	('miR-138-5p', 'Chemical', '-', (103, 113))	('tumor', 'Disease', (91, 96))	('inhibited', 'NegReg', (114, 123))	('miR-138-5p', 'Var', (103, 113))
51147	29843754	Taken together, a wave of translational research highlights the mechanistic and functional link between epigenetic regulation and immune checkpoints in the development and progression of primary tumors including liver cancer.	('epigenetic', 'Var', (104, 114))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('liver cancer', 'Disease', 'MESH:D006528', (212, 224))	('liver cancer', 'Phenotype', 'HP:0002896', (212, 224))	('liver cancer', 'Disease', (212, 224))	('primary tumors', 'Disease', (187, 201))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('primary tumors', 'Disease', 'MESH:D009369', (187, 201))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
51163	29843754	Several studies provided evidence to support increased expression of checkpoint inhibitors on tumor cells following epigenetic treatment, which enhances responses to immune checkpoint therapy.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('epigenetic treatment', 'Var', (116, 136))	('increased', 'PosReg', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('expression', 'MPA', (55, 65))	('tumor', 'Disease', (94, 99))	('checkpoint', 'Gene', (69, 79))	('enhances', 'PosReg', (144, 152))	('responses to immune checkpoint therapy', 'MPA', (153, 191))
51168	29843754	demonstrated that 5-azacytidine, sensitized tumors to anti-CTLA-4 immune checkpoint therapy compared to 5-azacytidine or anti-CTLA-4 alone in a mouse model of melanoma.	('melanoma', 'Disease', (159, 167))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('mouse', 'Species', '10090', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('sensitized', 'PosReg', (33, 43))	('5-azacytidine', 'Chemical', 'MESH:D001374', (18, 31))	('5-azacytidine', 'Var', (18, 31))	('5-azacytidine', 'Chemical', 'MESH:D001374', (104, 117))	('rat', 'Species', '10116', (7, 10))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
51171	29843754	As more data of these combinations is available, it will likely improve outcomes for patients with this rare aggressive group of cancers, and we will also be able to develop further trials to upgrade our understanding of therapies targeting liver cancers.	('combinations', 'Var', (22, 34))	('improve', 'PosReg', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('liver cancers', 'Phenotype', 'HP:0002896', (241, 254))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('liver cancer', 'Phenotype', 'HP:0002896', (241, 253))	('cancers', 'Disease', (129, 136))	('liver cancers', 'Disease', (241, 254))	('liver cancers', 'Disease', 'MESH:D006528', (241, 254))	('cancers', 'Disease', 'MESH:D009369', (247, 254))	('patients', 'Species', '9606', (85, 93))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('cancers', 'Disease', (247, 254))	('outcomes', 'MPA', (72, 80))
51174	29843754	Failure of immune checkpoint inhibitors therapy can result from three categories: (1) mutations of the immunogenicity of cancer itself.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutations', 'Var', (86, 95))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))
51175	29843754	The mutations influence expression of components of antigen-processing and presentation machinery (e.g., transporter associated with antigen processing, HLA class molecules, and beta2 microglobulin), novel tumor-associated antigens (e.g., cancer-testis antigens, neoantigens), and cytokines; (2) expression of alternative immune checkpoint ligands on tumor cells (and/or immune cells).	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('cancer-testis', 'Disease', (239, 252))	('expression', 'MPA', (24, 34))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', (351, 356))	('beta2 microglobulin', 'Gene', '567', (178, 197))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('cancer-testis', 'Disease', 'MESH:D013736', (239, 252))	('influence', 'Reg', (14, 23))	('mutations', 'Var', (4, 13))	('beta2 microglobulin', 'Gene', (178, 197))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
51181	29843754	Epigenetic mechanisms of checkpoint blocking prove to be promising in treating liver cancers and determining patient prognosis.	('liver cancer', 'Phenotype', 'HP:0002896', (79, 91))	('patient', 'Species', '9606', (109, 116))	('liver cancers', 'Phenotype', 'HP:0002896', (79, 92))	('liver cancers', 'Disease', 'MESH:D006528', (79, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('checkpoint', 'Gene', (25, 35))	('liver cancers', 'Disease', (79, 92))	('Epigenetic', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
51240	28179982	Subsequent dilatation of the left liver lobe bile ducts resulted in spontaneous rupture of segment III bile ducts and biloma formation.	('biloma', 'Disease', (118, 124))	('dilatation', 'Phenotype', 'HP:0002617', (11, 21))	('biloma', 'Disease', 'None', (118, 124))	('dilatation', 'Var', (11, 21))
51254	24550739	Genome-wide structural analysis of sequence data revealed recurrent translocation events involving the FGFR2 locus in three of six assessed patients.	('FGFR2', 'Gene', '2263', (103, 108))	('patients', 'Species', '9606', (140, 148))	('translocation events', 'Var', (68, 88))	('FGFR2', 'Gene', (103, 108))
51258	24550739	In an independent non-FGFR2 translocation patient, exome and transcriptome analysis revealed an allele specific somatic nonsense mutation (E384X) in ERRFI1, a direct negative regulator of EGFR activation.	('E384X', 'Mutation', 'p.E384X', (139, 144))	('patient', 'Species', '9606', (42, 49))	('EGFR', 'Gene', '1956', (188, 192))	('FGFR2', 'Gene', (22, 27))	('E384X', 'Var', (139, 144))	('FGFR2', 'Gene', '2263', (22, 27))	('EGFR', 'Gene', (188, 192))	('ERRFI1', 'Gene', (149, 155))
51260	24550739	FGFR2 fusions and ERRFI mutations may represent novel targets in sporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('patients', 'Species', '9606', (162, 170))	('ERRFI', 'Gene', (18, 23))	('sporadic intrahepatic cholangiocarcinoma', 'Disease', (65, 105))	('mutations', 'Var', (24, 33))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('sporadic intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (65, 105))	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (6, 13))	('FGFR2', 'Gene', '2263', (0, 5))
51267	24550739	A fourth tumor contained an error in a gene that controls a very important cellular mechanism in cancer, termed epidermal growth factor pathway (EGFR).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('cancer', 'Disease', (97, 103))	('error', 'Var', (28, 33))	('EGFR', 'Gene', '1956', (145, 149))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('EGFR', 'Gene', (145, 149))	('tumor', 'Disease', (9, 14))	('contained', 'Reg', (15, 24))
51274	24550739	Multiple studies have reported the presence of mutations/allelic loss of known cancer genes in BTC and recently, a prevalence set of 46 patients was used to validate 15 of these genes including: TP53, KRAS, CDKN2A and SMAD4 as well as MLL3, ROBO2, RNF43, GNAS, PEG3, XIRP2, PTEN, RADIL, NCD80, LAMA2 and PCDHA13.	('PCDHA13', 'Gene', '56136', (304, 311))	('BTC', 'Disease', (95, 98))	('KRAS', 'Gene', '3845', (201, 205))	('PTEN', 'Gene', (274, 278))	('MLL3', 'Gene', '58508', (235, 239))	('PEG3', 'Gene', '5178', (261, 265))	('mutations/allelic', 'Var', (47, 64))	('PCDHA13', 'Gene', (304, 311))	('XIRP2', 'Gene', (267, 272))	('TP53', 'Gene', (195, 199))	('KRAS', 'Gene', (201, 205))	('PTEN', 'Gene', '5728', (274, 278))	('RADIL', 'Gene', '55698', (280, 285))	('cancer', 'Disease', (79, 85))	('MLL3', 'Gene', (235, 239))	('LAMA2', 'Gene', '3908', (294, 299))	('loss', 'NegReg', (65, 69))	('CDKN2A', 'Gene', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('SMAD4', 'Gene', (218, 223))	('PEG3', 'Gene', (261, 265))	('LAMA2', 'Gene', (294, 299))	('ROBO2', 'Gene', '6092', (241, 246))	('RNF43', 'Gene', '54894', (248, 253))	('TP53', 'Gene', '7157', (195, 199))	('CDKN2A', 'Gene', '1029', (207, 213))	('GNAS', 'Gene', (255, 259))	('patients', 'Species', '9606', (136, 144))	('XIRP2', 'Gene', '129446', (267, 272))	('RNF43', 'Gene', (248, 253))	('SMAD4', 'Gene', '4089', (218, 223))	('GNAS', 'Gene', '2778', (255, 259))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('RADIL', 'Gene', (280, 285))	('ROBO2', 'Gene', (241, 246))
51275	24550739	Recent studies have also identified recurrent mutations in IDH1 (codon 132) and IDH2 (codons 140 and 172) with a prevalence of 22-23% associated with clear cell/poorly differentiated histology and intrahepatic primary.	('IDH1', 'Gene', '3417', (59, 63))	('associated', 'Reg', (134, 144))	('mutations', 'Var', (46, 55))	('intrahepatic primary', 'Disease', (197, 217))	('IDH1', 'Gene', (59, 63))	('IDH2', 'Gene', '3418', (80, 84))	('clear cell/poorly differentiated histology', 'Disease', (150, 192))	('IDH2', 'Gene', (80, 84))
51276	24550739	Fusions with oncogenic potential involving the kinase gene ROS1 have been identified in patients with BTC with a prevalence of 8.7% in a recent study.	('Fusions', 'Var', (0, 7))	('ROS1', 'Gene', (59, 63))	('patients', 'Species', '9606', (88, 96))	('ROS1', 'Gene', '6098', (59, 63))	('BTC', 'Disease', (102, 105))
51277	24550739	Less frequently, mutations in sporadic BTC have been reported in EGFR , BRAF , NRAS , PIK3CA , APC , CTNNB1 , AKT1 , PTEN , ABCB4 , ABCB11 , and CDH1  as well as amplifications in ERRB2 .	('NRAS', 'Gene', '4893', (79, 83))	('PTEN', 'Gene', (117, 121))	('APC', 'Disease', (95, 98))	('AKT1', 'Gene', (110, 114))	('mutations', 'Var', (17, 26))	('BRAF', 'Gene', '673', (72, 76))	('CTNNB1', 'Gene', (101, 107))	('BRAF', 'Gene', (72, 76))	('EGFR', 'Gene', (65, 69))	('PTEN', 'Gene', '5728', (117, 121))	('BTC', 'Disease', (39, 42))	('PIK3CA', 'Gene', '5290', (86, 92))	('NRAS', 'Gene', (79, 83))	('ABCB4', 'Gene', (124, 129))	('amplifications', 'Var', (162, 176))	('CDH1', 'Gene', '999', (145, 149))	('ERRB2', 'Gene', (180, 185))	('EGFR', 'Gene', '1956', (65, 69))	('AKT1', 'Gene', '207', (110, 114))	('ABCB4', 'Gene', '5244', (124, 129))	('ABCB11', 'Gene', (132, 138))	('CDH1', 'Gene', (145, 149))	('PIK3CA', 'Gene', (86, 92))	('CTNNB1', 'Gene', '1499', (101, 107))	('reported', 'Reg', (53, 61))	('ABCB11', 'Gene', '8647', (132, 138))	('APC', 'Disease', 'MESH:D011125', (95, 98))
51278	24550739	Recently, two independent studies reported the presence of FGFR fusions in cholangiocarcinoma; a single case with FGFR2-AHCYL1  as well as several cases identifying FGFR2-BICC1 fusions.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (75, 93))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (75, 93))	('AHCYL1', 'Gene', (120, 126))	('FGFR', 'Gene', (59, 63))	('BICC1', 'Gene', (171, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('FGFR2', 'Gene', (114, 119))	('fusions', 'Var', (64, 71))	('FGFR2', 'Gene', '2263', (165, 170))	('FGFR2', 'Gene', '2263', (114, 119))	('AHCYL1', 'Gene', '10768', (120, 126))	('BICC1', 'Gene', '80114', (171, 176))	('FGFR2', 'Gene', (165, 170))	('cholangiocarcinoma', 'Disease', (75, 93))
51282	24550739	These data led to the conclusion that the fusion partners are facilitating oligomerization, resulting in FGFR kinase activation in tumors possessing FGFR fusions.	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('fusions', 'Var', (154, 161))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))	('FGFR kinase', 'Enzyme', (105, 116))	('activation', 'PosReg', (117, 127))
51283	24550739	In addition, in vitro and in vivo assessment of the sensitivity of cell lines containing an FGFR2 fusion to an FGFR inhibitor demonstrated sensitivity to treatment only in the fusion containing cells, suggesting the presence of FGFR fusions may be a useful predictor of tumor response to FGFR inhibitors.	('fusion', 'Var', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('FGFR2', 'Gene', '2263', (92, 97))	('FGFR2', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumor', 'Disease', (270, 275))
51289	24550739	Additionally, a non-FGFR fusion patient was found to have allele-specific preferential expression of a loss of function mutation in ERRFI1, a direct negative regulator of EGFR activation.	('EGFR', 'Gene', (171, 175))	('mutation', 'Var', (120, 128))	('loss of function', 'NegReg', (103, 119))	('expression', 'MPA', (87, 97))	('EGFR', 'Gene', '1956', (171, 175))	('patient', 'Species', '9606', (32, 39))	('preferential', 'PosReg', (74, 86))	('ERRFI1', 'Gene', (132, 138))
51290	24550739	Similarly, rapid and robust disease regression was noted in the patient with an ERRFI1 mutant tumor when treated with erlotinib, an EGFR kinase inhibitor.	('disease', 'CPA', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('patient', 'Species', '9606', (64, 71))	('EGFR', 'Gene', '1956', (132, 136))	('erlotinib', 'Chemical', 'MESH:D000069347', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('EGFR', 'Gene', (132, 136))	('tumor', 'Disease', (94, 99))	('mutant', 'Var', (87, 93))	('ERRFI1', 'Gene', (80, 86))
51295	24550739	Patient 5 carried the most stops gained likely contributing to a higher number of pseudogenes in comparison to the others and was also the only patient to carry several predicted high impact mutations affecting splice site acceptor regions ( Figure 1 , light green, percentage <5%).	('pseudogenes', 'MPA', (82, 93))	('Patient', 'Species', '9606', (0, 7))	('mutations', 'Var', (191, 200))	('patient', 'Species', '9606', (144, 151))
51296	24550739	In addition, patient 6 also carried a codon change plus insertion variation.	('codon change', 'Var', (38, 50))	('insertion variation', 'Var', (56, 75))	('patient', 'Species', '9606', (13, 20))
51297	24550739	Genes with mutations in more than one case included CSPG4 (n = 2), GRIN3A (n = 2) and PLXBN3 (n = 2) (Table S1); with half of these predicted to be potentially damaging by SIFT, Polyphen, Mutation Assessor and Mutation Taster.	('GRIN3A', 'Gene', '116443', (67, 73))	('SIFT', 'Disease', (172, 176))	('mutations', 'Var', (11, 20))	('CSPG4', 'Gene', (52, 57))	('CSPG4', 'Gene', '1464', (52, 57))	('damaging', 'Reg', (160, 168))	('GRIN3A', 'Gene', (67, 73))	('SIFT', 'Disease', 'None', (172, 176))
51299	24550739	More importantly, using previously published methods, we identified molecular fusions involving FGFR2 that were felt to be therapeutically relevant in 3 patients.	('FGFR2', 'Gene', '2263', (96, 101))	('FGFR2', 'Gene', (96, 101))	('patients', 'Species', '9606', (153, 161))	('molecular fusions', 'Var', (68, 85))
51300	24550739	Notably, the patients who did not harbor the FGFR2 fusions were negative using the same assay.	('patients', 'Species', '9606', (13, 21))	('fusions', 'Var', (51, 58))	('FGFR2', 'Gene', '2263', (45, 50))	('FGFR2', 'Gene', (45, 50))
51301	24550739	Two of the three patients with FGFR2 fusions (Patients 4 and 6) were treated with FGFR inhibitors while the third patient (Patient 5), experienced clinical decline prior to the availability of results and as such did not receive any further therapy.	('Patients', 'Species', '9606', (46, 54))	('FGFR', 'Gene', (82, 86))	('FGFR2', 'Gene', (31, 36))	('FGFR2', 'Gene', '2263', (31, 36))	('patient', 'Species', '9606', (17, 24))	('Patient', 'Species', '9606', (46, 53))	('fusions', 'Var', (37, 44))	('patients', 'Species', '9606', (17, 25))	('patient', 'Species', '9606', (114, 121))	('Patient', 'Species', '9606', (123, 130))
51302	24550739	Furthermore, overexpression of an SNV in ERRFI1 (E384X), a negative regulator of EGFR, was detected in a non-FGFR2 translocation patient's tumor.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('patient', 'Species', '9606', (129, 136))	('E384X', 'Var', (49, 54))	('E384X', 'Mutation', 'p.E384X', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('overexpression', 'PosReg', (13, 27))	('ERRFI1', 'Gene', (41, 47))	('FGFR2', 'Gene', (109, 114))	('EGFR', 'Gene', '1956', (81, 85))	('FGFR2', 'Gene', '2263', (109, 114))	('EGFR', 'Gene', (81, 85))
51312	24550739	In addition to the variations identified in genes acting in EGFR and/or FGFR signaling pathways, we also report multiple sSNVs and copy number variations (CNVs) ( Figure 4 ) in genes such as HDAC1, TP53, MDM2 and AKT1, acting in interaction networks or regulatory pathways involving the fusion partner genes in patients 5 (BICC1), and 6 (TACC3) ( Table 4 ).	('MDM2', 'Gene', '4193', (204, 208))	('HDAC1', 'Gene', (191, 196))	('copy number variations', 'Var', (131, 153))	('MDM2', 'Gene', (204, 208))	('BICC1', 'Gene', '80114', (323, 328))	('AKT1', 'Gene', '207', (213, 217))	('AKT1', 'Gene', (213, 217))	('HDAC1', 'Gene', '3065', (191, 196))	('TP53', 'Gene', '7157', (198, 202))	('TACC3', 'Gene', '10460', (338, 343))	('patients', 'Species', '9606', (311, 319))	('EGFR', 'Gene', '1956', (60, 64))	('BICC1', 'Gene', (323, 328))	('TACC3', 'Gene', (338, 343))	('TP53', 'Gene', (198, 202))	('EGFR', 'Gene', (60, 64))
51313	24550739	Known mutations in BICC1 have been shown to disrupt canonical Wnt signaling and genes, such as BCL9, involved in this pathway are known to regulate a range of biological processes such as transcription and cell proliferation and carry variations in patient 5 ( Table 4 ).	('BICC1', 'Gene', (19, 24))	('patient', 'Species', '9606', (249, 256))	('regulate', 'Reg', (139, 147))	('BCL9', 'Gene', (95, 99))	('BCL9', 'Gene', '607', (95, 99))	('canonical Wnt signaling', 'Pathway', (52, 75))	('BICC1', 'Gene', '80114', (19, 24))	('cell proliferation', 'CPA', (206, 224))	('transcription', 'CPA', (188, 201))	('disrupt', 'NegReg', (44, 51))	('mutations', 'Var', (6, 15))
51314	24550739	CSPG4, a target that is being investigated for antibody-based immunotherapy in preclinical studies of triple negative breast cancer, is involved in the Wnt signaling pathway, and carries variations in both patients 1 and 2, however, it is not mutated in patient 5.	('involved', 'Reg', (136, 144))	('patient', 'Species', '9606', (206, 213))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('patient', 'Species', '9606', (254, 261))	('patients', 'Species', '9606', (206, 214))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('Wnt signaling pathway', 'Pathway', (152, 173))	('variations', 'Var', (187, 197))	('CSPG4', 'Gene', (0, 5))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('CSPG4', 'Gene', '1464', (0, 5))
51315	24550739	TACC3 is known to mediate central spindle assembly and multiple genes including CDCA8, BUB1, and TACC1, belonging to the TACC3 interaction network exhibit aberrant copy number in patient 6 ( Table 4 ).	('aberrant copy number', 'Var', (155, 175))	('BUB1', 'Gene', (87, 91))	('TACC3', 'Gene', (0, 5))	('CDCA8', 'Gene', (80, 85))	('TACC3', 'Gene', '10460', (121, 126))	('patient', 'Species', '9606', (179, 186))	('TACC1', 'Gene', '6867', (97, 102))	('TACC3', 'Gene', (121, 126))	('CDCA8', 'Gene', '55143', (80, 85))	('central spindle', 'Phenotype', 'HP:0003687', (26, 41))	('TACC3', 'Gene', '10460', (0, 5))	('TACC1', 'Gene', (97, 102))	('BUB1', 'Gene', '699', (87, 91))
51317	24550739	We also note that the DNAH5 gene encoding a dynein protein which is part of the microtubule-associated motor protein complex carries two G C missense mutations in patient 6 (Table S1).	('DNAH5', 'Gene', '1767', (22, 27))	('DNAH5', 'Gene', (22, 27))	('patient', 'Species', '9606', (163, 170))	('missense mutations', 'Var', (141, 159))
51318	24550739	Several genes carrying more than one variation in either the same patient or different patients also included genes with known roles similar to genes in FGFR/EGFR pathways including axon guidance, invasive growth, or cell differentiation (NAV3, LAMC3, PLXNB3, and PTPRK) (Table S1).	('variation', 'Var', (37, 46))	('cell differentiation', 'CPA', (217, 237))	('EGFR', 'Gene', (158, 162))	('LAMC3', 'Gene', '10319', (245, 250))	('axon guidance', 'CPA', (182, 195))	('PLXNB3', 'Gene', (252, 258))	('LAMC3', 'Gene', (245, 250))	('PTPRK', 'Gene', '5796', (264, 269))	('EGFR', 'Gene', '1956', (158, 162))	('patient', 'Species', '9606', (66, 73))	('patient', 'Species', '9606', (87, 94))	('PTPRK', 'Gene', (264, 269))	('NAV3', 'Gene', '89795', (239, 243))	('invasive growth', 'CPA', (197, 212))	('NAV3', 'Gene', (239, 243))	('patients', 'Species', '9606', (87, 95))	('PLXNB3', 'Gene', '5365', (252, 258))
51321	24550739	A biopsy of the liver mass revealed the presence of a poorly differentiated adenocarcinoma that was consistent with intrahepatic cholangiocarcinoma (CK7+, CEA+, CK20+, Hep-par 1-, TTF-1-) ( Table 6 ).	('intrahepatic cholangiocarcinoma', 'Disease', (116, 147))	('adenocarcinoma', 'Disease', 'MESH:D000230', (76, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('Hep', 'CellLine', 'CVCL:1906', (168, 171))	('CK7+', 'Var', (149, 153))	('CK20', 'Gene', '54474', (161, 165))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (129, 147))	('TTF-1-) ( Table 6', 'Gene', '7270', (180, 197))	('CEA+', 'Var', (155, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('poorly', 'Disease', (54, 60))	('adenocarcinoma', 'Disease', (76, 90))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (116, 147))	('CK20', 'Gene', (161, 165))	('TTF-1-) ( Table 6', 'Gene', (180, 197))
51340	24550739	Pathological evaluation of the liver mass was consistent with a moderately differentiated intrahepatic cholangiocarcinoma (CK7+, CK20-, TTF-1-) in the absence of any known risk factors ( Table 6 ).	('TTF-1', 'Gene', '7270', (136, 141))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (90, 121))	('intrahepatic cholangiocarcinoma', 'Disease', (90, 121))	('CK7+', 'Var', (123, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('CK20', 'Gene', (129, 133))	('CK20', 'Gene', '54474', (129, 133))	('TTF-1', 'Gene', (136, 141))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (103, 121))
51356	24550739	He was found to have a 4 cm tumor in his liver determined to be a poorly differentiated intrahepatic cholangiocarcinoma (CK7+, CK20-, TTF1-, CD56-, synatophysin-, Hep-par 1-) with sclerotic features ( Table 6 ).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('tumor', 'Disease', (28, 33))	('sclerotic', 'Disease', (180, 189))	('TTF1', 'Gene', (134, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('Hep', 'CellLine', 'CVCL:1906', (163, 166))	('CD56-', 'Var', (141, 146))	('TTF1', 'Gene', '7270', (134, 138))	('sclerotic', 'Disease', 'MESH:C538213', (180, 189))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 119))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('intrahepatic cholangiocarcinoma', 'Disease', (88, 119))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('CK20', 'Gene', (127, 131))	('CK20', 'Gene', '54474', (127, 131))	('CK7+', 'Var', (121, 125))
51361	24550739	Since our study goal was to identify potential therapeutically relevant events, the novel loss of function mutation in ERRFI1 (E384X) detected in Patient 3's metastatic, recurrent/refractory SIC (Table S1) warranted additional examination.	('SIC', 'Disease', (191, 194))	('E384X', 'Var', (127, 132))	('SIC', 'Disease', 'None', (191, 194))	('Patient', 'Species', '9606', (146, 153))	('ERRFI1', 'Gene', (119, 125))	('loss of function', 'NegReg', (90, 106))	('E384X', 'Mutation', 'p.E384X', (127, 132))	('metastatic', 'CPA', (158, 168))
51362	24550739	Such allele specific expression of the mutated allele from the same tissue specimen suggests nearly complete loss of function of ERRFI1 in this patient's tumor.	('loss of function', 'NegReg', (109, 125))	('patient', 'Species', '9606', (144, 151))	('ERRFI1', 'Gene', (129, 135))	('mutated', 'Var', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
51366	24550739	Integrated analysis of sporadic intrahepatic cholangiocarcinoma (SIC) genomic and transcriptomic data led to the discovery of FGFR2 fusion products in three of six assessed patients ( Table 7  ,   Figures 4   and   11 ).	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('patients', 'Species', '9606', (173, 181))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (45, 63))	('fusion', 'Var', (132, 138))	('FGFR2', 'Gene', '2263', (126, 131))	('FGFR2', 'Gene', (126, 131))	('sporadic intrahepatic cholangiocarcinoma (SIC) genomic', 'Disease', 'MESH:D018281', (23, 77))
51367	24550739	Members of the FGFR family (FGFR1-4) have been associated with mutations, amplifications and translocation events with oncogenic potential.	('amplifications', 'Var', (74, 88))	('mutations', 'Var', (63, 72))	('FGFR1-4', 'Gene', (28, 35))	('FGFR1-4', 'Gene', '2260;2263;2261;2264', (28, 35))	('translocation events', 'CPA', (93, 113))	('associated', 'Reg', (47, 57))
51369	24550739	FGFR2, FGFR3 and FGFR4 have been found to be overexpressed in IDH1/IDH2 mutant biliary cancers, a context seen within Patient 1 in our study (Tables S1 and S6,   Figure 5 ); although, no fusion events were depicted in these studies or in Patient 1.	('Patient', 'Species', '9606', (118, 125))	('overexpressed', 'PosReg', (45, 58))	('FGFR3', 'Gene', (7, 12))	('biliary cancers', 'Disease', 'MESH:D001661', (79, 94))	('FGFR4', 'Gene', '2264', (17, 22))	('FGFR3', 'Gene', '2261', (7, 12))	('biliary cancers', 'Disease', (79, 94))	('mutant', 'Var', (72, 78))	('IDH1', 'Gene', (62, 66))	('FGFR2', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('FGFR4', 'Gene', (17, 22))	('IDH2', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('IDH2', 'Gene', '3418', (67, 71))	('FGFR2', 'Gene', '2263', (0, 5))	('S6,   Figure 5', 'Gene', '6194', (156, 170))	('Patient', 'Species', '9606', (238, 245))	('IDH1', 'Gene', '3417', (62, 66))
51375	24550739	Paradoxically, wildtype FGFR2-IIIb has been described as a tumor suppressor in pre-clinical systems of bladder cancer and prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (122, 137))	('FGFR2', 'Gene', '2263', (24, 29))	('tumor', 'Disease', (59, 64))	('prostate cancer', 'Phenotype', 'HP:0012125', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('bladder cancer', 'Phenotype', 'HP:0009725', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('prostate cancer', 'Disease', (122, 137))	('bladder cancer', 'Disease', 'MESH:D001749', (103, 117))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('wildtype', 'Var', (15, 23))	('FGFR2', 'Gene', (24, 29))	('bladder cancer', 'Disease', (103, 117))
51381	24550739	Comparative pathway analysis of genes carrying mutations/aberrant in copy number identified additional potential therapeutic targets belonging to, or intimately integrated with, the EGFR and FGFR signaling pathways ( Figure 3  , Tables S2, S3, S4).	('EGFR', 'Gene', '1956', (182, 186))	('mutations/aberrant in copy number', 'Var', (47, 80))	('EGFR', 'Gene', (182, 186))
51383	24550739	Patients 3 and 4 harbored aberrations in several genes acting in cadherin signaling pathways (Tables S3, S4), which are important for maintaining cell-cell adhesion.	('aberrations', 'Var', (26, 37))	('Patients', 'Species', '9606', (0, 8))	('genes', 'Gene', (49, 54))	('cadherin', 'Gene', (65, 73))	('cadherin', 'Gene', '999', (65, 73))
51386	24550739	The FGFR tyrosine kinase inhibitors (TKI) dovitinib and NVP-BGJ398 are currently in clinical development and the FGFR TKI ponatinib was recently approved by the FDA for use in treating T315I mutant chronic myelogenous leukemia.	('myelogenous leukemia', 'Disease', (206, 226))	('T315I mutant', 'Var', (185, 197))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (206, 226))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (206, 226))	('ponatinib', 'Chemical', 'MESH:C545373', (122, 131))	('tyrosine', 'Chemical', 'MESH:D014443', (9, 17))	('dovitinib', 'Chemical', 'MESH:C500007', (42, 51))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (198, 226))	('leukemia', 'Phenotype', 'HP:0001909', (218, 226))	('T315I', 'Mutation', 'rs1003638950', (185, 190))
51390	24550739	Larger trials, preferably of a randomized nature with a control arm, need to be conducted to truly define the role of FGFR inhibitors in the treatment of patients with cholangiocarcinoma, particularly those harboring FGFR2 fusions.	('cholangiocarcinoma', 'Disease', (168, 186))	('FGFR2', 'Gene', (217, 222))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (168, 186))	('patients', 'Species', '9606', (154, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (168, 186))	('fusions', 'Var', (223, 230))	('FGFR2', 'Gene', '2263', (217, 222))
51399	24550739	ERRFI1 deletions have been found in glioblastoma multiforme and breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('glioblastoma multiforme', 'Disease', (36, 59))	('glioblastoma', 'Phenotype', 'HP:0012174', (36, 48))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (36, 59))	('deletions', 'Var', (7, 16))	('ERRFI1', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('found', 'Reg', (27, 32))	('breast cancer', 'Disease', (64, 77))
51400	24550739	Consistent with a driver role of this mutation, previously germline homozygous disruption of ERRFI1 in mice induces hyperplasia and adenoma formation in the epithelium and development of spontaneous adenocarcinomas of the lung, gallbladder and biliary tract.	('hyperplasia', 'Disease', 'MESH:D006965', (116, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('mice', 'Species', '10090', (103, 107))	('development', 'CPA', (172, 183))	('induces', 'Reg', (108, 115))	('disruption', 'Var', (79, 89))	('adenoma', 'Disease', 'MESH:D000236', (132, 139))	('adenocarcinomas of the lung', 'Disease', 'MESH:D000077192', (199, 226))	('adenocarcinomas of the lung', 'Disease', (199, 226))	('hyperplasia', 'Disease', (116, 127))	('ERRFI1', 'Gene', (93, 99))	('adenoma', 'Disease', (132, 139))
51402	24550739	Our results suggest immediate and actionable implications for SIC patients with tumors harboring ERFFI1 loss of function mutations or FGFR fusions, given the clinical availability of FDA-approved EGFR and FGFR tyrosine kinase inhibitors.	('EGFR', 'Gene', (196, 200))	('mutations', 'Var', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('FGFR', 'Gene', (134, 138))	('SIC', 'Disease', (62, 65))	('fusions', 'Var', (139, 146))	('loss of function', 'NegReg', (104, 120))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('SIC', 'Disease', 'None', (62, 65))	('EGFR', 'Gene', '1956', (196, 200))	('ERFFI1', 'Gene', (97, 103))	('tyrosine', 'Chemical', 'MESH:D014443', (210, 218))	('patients', 'Species', '9606', (66, 74))
51425	24550739	Translocation detection was based on discordant read evidence in the tumor whole genome sequencing data compared to its corresponding normal data.	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('Translocation', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))
51428	24550739	Mutations of potential clinical relevance were confirmed in a Clinical Laboratory Improvement Amendments (CLIA) laboratory with Sanger sequencing or quantitative PCR.	('CLIA', 'Disease', 'None', (106, 110))	('Mutations', 'Var', (0, 9))	('CLIA', 'Disease', (106, 110))
51494	30251463	Similarly, ABT-199 was demonstrated to reduce tumor formation and tumor burden in a murine model of cholangiocarcinoma.	('reduce', 'NegReg', (39, 45))	('murine', 'Species', '10090', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cholangiocarcinoma', 'Disease', (100, 118))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (46, 51))	('rat', 'Species', '10116', (30, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('ABT', 'Chemical', 'MESH:C002502', (11, 14))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (100, 118))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('ABT-199', 'Var', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
51520	30251463	Other relevant genomic alterations that include fibroblast growth factor receptor 2 (FGFR2) fusions and isocitrate dehydrogenase 1/2 (IDH1/2) mutations have also been reported to have prognostic significance for iCCA patients, and are emerging as novel targeted therapy options (see section below).	('rat', 'Species', '10116', (110, 113))	('IDH1/2', 'Gene', '3417;3418', (134, 140))	('mutations', 'Var', (142, 151))	('iCCA', 'Disease', (212, 216))	('fusions', 'Var', (92, 99))	('IDH1/2', 'Gene', (134, 140))	('fibroblast growth factor receptor 2', 'Gene', (48, 83))	('fibroblast growth factor receptor 2', 'Gene', '2263', (48, 83))	('FGFR2', 'Gene', '2263', (85, 90))	('rat', 'Species', '10116', (27, 30))	('patients', 'Species', '9606', (217, 225))	('FGFR2', 'Gene', (85, 90))
51526	30251463	Here, the recently reported results of an international team using an integrated genomic, epigenetic, and transcriptomic analysis of over 400 iCCA cases from 10 different countries were able to identify a liver-fluke-associated iCCA subtype uniquely enriched in ERBB2 amplifications and TP53 mutations.	('mutations', 'Var', (292, 301))	('rat', 'Species', '10116', (75, 78))	('amplifications', 'Var', (268, 282))	('liver-fluke-associated iCCA', 'Disease', (205, 232))	('ERBB2', 'Gene', (262, 267))	('ERBB2', 'Gene', '2064', (262, 267))	('iCCA', 'Disease', (228, 232))	('liver-fluke', 'Species', '6192', (205, 216))	('TP53', 'Gene', (287, 291))
51533	30251463	IDH mutations occur frequently in iCCA.	('mutations', 'Var', (4, 13))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (0, 3))	('iCCA', 'Disease', (34, 38))
51534	30251463	IDH1 is more common than IDH2 and "hotspot" IDH1/2 mutations are point mutations located in the arginine 132 (R132) residue in IDH1 or the arginine 172 (R172) residue in IDH2.	('IDH2', 'Gene', (170, 174))	('mutations', 'Var', (51, 60))	('IDH1', 'Gene', '3417', (0, 4))	('IDH1', 'Gene', (44, 48))	('IDH2', 'Gene', '3418', (170, 174))	('IDH1/2', 'Gene', (44, 50))	('arginine', 'Chemical', 'MESH:D001120', (96, 104))	('IDH1', 'Gene', (127, 131))	('point mutations', 'Var', (65, 80))	('IDH1', 'Gene', '3417', (44, 48))	('IDH2', 'Gene', (25, 29))	('IDH1', 'Gene', '3417', (127, 131))	('IDH1', 'Gene', (0, 4))	('arginine', 'Chemical', 'MESH:D001120', (139, 147))	('IDH2', 'Gene', '3418', (25, 29))	('IDH1/2', 'Gene', '3417;3418', (44, 50))
51535	30251463	These mutations are ubiquitously higher in iCCA than extrahepatic cholangiocarcinoma.	('higher', 'Reg', (33, 39))	('extrahepatic cholangiocarcinoma', 'Disease', (53, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (66, 84))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (53, 84))	('iCCA', 'Disease', (43, 47))	('mutations', 'Var', (6, 15))
51536	30251463	Mutant IDH loses its normal enzymatic activity and gains a new ability to produce the oncometabolite 2-hydroxyglutarate (2-HG), which can be detected in the tumor and blood.	('enzymatic activity', 'MPA', (28, 46))	('IDH', 'Gene', (7, 10))	('loses', 'NegReg', (11, 16))	('tumor', 'Disease', (157, 162))	('IDH', 'Gene', '3417', (7, 10))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (101, 119))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('2-HG', 'Chemical', 'MESH:C019417', (121, 125))	('Mutant', 'Var', (0, 6))	('ability', 'MPA', (63, 70))	('produce', 'MPA', (74, 81))
51538	30251463	These block the function of mutant IDH1 or IDH2 at nanomolar concentrations, leading to reduced 2-HG levels.	('IDH1', 'Gene', (35, 39))	('mutant', 'Var', (28, 34))	('2-HG levels', 'MPA', (96, 107))	('IDH1', 'Gene', '3417', (35, 39))	('IDH2', 'Gene', (43, 47))	('2-HG', 'Chemical', 'MESH:C019417', (96, 100))	('rat', 'Species', '10116', (68, 71))	('IDH2', 'Gene', '3418', (43, 47))	('reduced', 'NegReg', (88, 95))	('block', 'NegReg', (6, 11))	('function', 'MPA', (16, 24))
51539	30251463	AG-120 is a first-in-class, potent, oral inhibitor of mutant IDH1 and was examined in a phase I study in mutant IDH1 solid tumors including iCCA.	('tumors', 'Disease', (123, 129))	('IDH1', 'Gene', '3417', (112, 116))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('iCCA', 'Disease', (140, 144))	('IDH1', 'Gene', (112, 116))	('IDH1', 'Gene', '3417', (61, 65))	('AG-120', 'Chemical', 'MESH:C000627630', (0, 6))	('IDH1', 'Gene', (61, 65))	('mutant', 'Var', (54, 60))	('mutant', 'Var', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
51540	30251463	AG-120 was well tolerated and of the 73 patients with IDH1 mutant advanced CCA enrolled, 72 patients were evaluable for efficacy.	('IDH1', 'Gene', (54, 58))	('patients', 'Species', '9606', (40, 48))	('mutant', 'Var', (59, 65))	('advanced CCA', 'Disease', (66, 78))	('patients', 'Species', '9606', (92, 100))	('AG-120', 'Chemical', 'MESH:C000627630', (0, 6))	('IDH1', 'Gene', '3417', (54, 58))	('rat', 'Species', '10116', (20, 23))
51542	30251463	All of the patients responding to AG-120 exhibited a reduction in circulating 2-HG levels ranging from 73% to 99%, and a reduction in Ki67 nuclear staining ranging from 22% to 96% from baseline.	('AG-120', 'Chemical', 'MESH:C000627630', (34, 40))	('AG-120', 'Var', (34, 40))	('Ki67 nuclear staining', 'CPA', (134, 155))	('reduction', 'NegReg', (53, 62))	('circulating 2-HG levels', 'MPA', (66, 89))	('patients', 'Species', '9606', (11, 19))	('2-HG', 'Chemical', 'MESH:C019417', (78, 82))	('reduction', 'NegReg', (121, 130))
51543	30251463	A global, phase III, randomized, placebo-controlled study of AG-120 in mutant IDH1 cholangiocarcinoma is ongoing (ClarIDHy) (NCT02073994).	('IDH1 cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('IDH', 'Gene', (118, 121))	('mutant', 'Var', (71, 77))	('IDH1 cholangiocarcinoma', 'Disease', (78, 101))	('IDH', 'Gene', '3417', (118, 121))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('IDH', 'Gene', (78, 81))	('AG-120', 'Gene', (61, 67))	('IDH', 'Gene', '3417', (78, 81))	('AG-120', 'Chemical', 'MESH:C000627630', (61, 67))
51544	30251463	Other IDH1 and IDH2 inhibitors are also now in clinical trials (NCT02273739, NCT02381886, and NCT02481154) and are enrolling patients with iCCA.	('IDH1', 'Gene', '3417', (6, 10))	('IDH2', 'Gene', (15, 19))	('IDH1', 'Gene', (6, 10))	('NCT02381886', 'Var', (77, 88))	('IDH2', 'Gene', '3418', (15, 19))	('NCT02273739', 'Var', (64, 75))	('NCT02481154', 'Var', (94, 105))	('iCCA', 'Disease', (139, 143))	('patients', 'Species', '9606', (125, 133))
51545	30251463	The recent discovery of recurrent FGFR2 fusions in 11-45% of patients with iCCA has rapidly translated this into a promising therapeutic target.	('FGFR2', 'Gene', (34, 39))	('FGFR2', 'Gene', '2263', (34, 39))	('fusions', 'Var', (40, 47))	('patients', 'Species', '9606', (61, 69))	('iCCA', 'Disease', (75, 79))
51546	30251463	Several selective reversible FGFR2 inhibitors have entered clinical trials in iCCA.	('iCCA', 'Disease', (78, 82))	('FGFR2', 'Gene', '2263', (29, 34))	('FGFR2', 'Gene', (29, 34))	('inhibitors', 'Var', (35, 45))
51548	30251463	In the phase II study of BGJ-398 in advanced iCCA with FGFR aberrations after first-line chemotherapy, 61 patients with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) were enrolled.	('fusion', 'Var', (126, 132))	('FGFR2', 'Gene', '2263', (120, 125))	('FGFR', 'Gene', (55, 59))	('mutation', 'Var', (143, 151))	('rat', 'Species', '10116', (64, 67))	('patients', 'Species', '9606', (106, 114))	('amplification', 'Var', (164, 177))	('BGJ-398', 'Chemical', 'MESH:C568950', (25, 32))	('aberrations', 'Var', (60, 71))	('FGFR2', 'Gene', (120, 125))
51549	30251463	The overall response rate was 14.8% (18.8% in patients with FGFR2 fusions), disease control rate was 75.4%, and estimated median PFS was 5.8 months (95% CI, 4.3 to 7.6 months).	('patients', 'Species', '9606', (46, 54))	('to 7', 'Species', '1214577', (161, 165))	('rat', 'Species', '10116', (92, 95))	('rat', 'Species', '10116', (21, 24))	('FGFR2', 'Gene', '2263', (60, 65))	('FGFR2', 'Gene', (60, 65))	('fusions', 'Var', (66, 73))
51552	30251463	Sequencing of cell-free DNA and biopsy samples collected at baseline and post-progression revealed polyclonal secondary mutations in the FGFR2 kinase domain, including the gatekeeper mutation FGFR2 V564F in all three patients.	('FGFR2', 'Gene', (137, 142))	('FGFR2', 'Gene', '2263', (137, 142))	('V564F', 'Mutation', 'p.V564F', (198, 203))	('FGFR2', 'Gene', '2263', (192, 197))	('mutations', 'Var', (120, 129))	('V564F', 'Var', (198, 203))	('patients', 'Species', '9606', (217, 225))	('gatekeeper', 'Species', '111938', (172, 182))	('FGFR2', 'Gene', (192, 197))
51553	30251463	Other selective FGFR inhibitors, including INCB54828 (Incyte, NCT02924376), BAY1163877 (Bayer, NCT01976741), ARQ-087 (Arqule, NCT01752920), and Debio1347 (Debiopharm International, NCT01948297), have also been tested in phase I trial in solid tumors, including iCCA, with early evidence of antitumor activity.	('FGFR', 'Gene', (16, 20))	('tumor', 'Disease', (294, 299))	('tumors', 'Disease', (243, 249))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('BAY1163877', 'Var', (76, 86))	('iCCA', 'Disease', (261, 265))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
51554	30251463	TAS-120, an oral, highly selective, irreversible FGFR1-4 tyrosine kinase inhibitor, has demonstrated inhibition of cancer cell growth in human xenografts of tumors bearing FGFR aberrations and has exhibited potent inhibition against both mutant and wild-type FGFR2.	('rat', 'Species', '10116', (95, 98))	('TAS-120', 'Chemical', '-', (0, 7))	('FGFR2', 'Gene', '2263', (259, 264))	('FGFR1', 'Gene', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('human', 'Species', '9606', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('mutant', 'Var', (238, 244))	('rat', 'Species', '10116', (181, 184))	('inhibition', 'NegReg', (101, 111))	('tumors', 'Disease', (157, 163))	('FGFR', 'Gene', (172, 176))	('FGFR1', 'Gene', '2260', (49, 54))	('cancer', 'Disease', (115, 121))	('aberrations', 'Var', (177, 188))	('FGFR2', 'Gene', (259, 264))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))
51555	30251463	In a Phase I study of TAS-120 in patients with advanced solid tumors, including iCCA, antitumor activity was observed with a response rate of approximately 25% in iCCA patients carrying the FGFR2 fusions.	('TAS-120', 'Chemical', '-', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('patients', 'Species', '9606', (33, 41))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (90, 95))	('FGFR2', 'Gene', (190, 195))	('FGFR2', 'Gene', '2263', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('iCCA', 'Disease', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('patients', 'Species', '9606', (168, 176))	('fusions', 'Var', (196, 203))	('rat', 'Species', '10116', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
51559	30251463	Immune-checkpoint genes and high-mutational load with abundant tumors-specific neoantigens have been reported in iCCA, justifying the use of these checkpoint inhibitors in iCCA.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('reported', 'Reg', (101, 109))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('Immune-checkpoint genes', 'Gene', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('high-mutational load', 'Var', (28, 48))	('iCCA', 'Disease', (113, 117))
51588	29484968	In this way, the expression of tumor suppressor genes can be silenced through abnormal hypermethylation in cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('expression', 'MPA', (17, 27))	('tumor', 'Disease', (31, 36))	('abnormal hypermethylation', 'Var', (78, 103))	('silenced', 'NegReg', (61, 69))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
51629	29484968	DNA methylation may also be useful as a prediction marker for recurrence of cancer in clinical practice, as was reported for gastric cancer in a multicenter prospective cohort study and for prostate cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('prostate cancer', 'Disease', (190, 205))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('methylation', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (133, 139))	('prostate cancer', 'Disease', 'MESH:D011471', (190, 205))	('cancer', 'Disease', (199, 205))	('prostate cancer', 'Phenotype', 'HP:0012125', (190, 205))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('gastric cancer', 'Disease', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
51631	29484968	The HOXA1 is a transcription factor, which is involved in cell differentiation, and hypermethylation of its promoter was reported in other cancers such as lung carcinomas.	('HOXA1', 'Gene', '3198', (4, 9))	('lung carcinomas', 'Disease', (155, 170))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('reported', 'Reg', (121, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('HOXA1', 'Gene', (4, 9))	('lung carcinomas', 'Disease', 'MESH:D008175', (155, 170))	('hypermethylation', 'Var', (84, 100))
51633	29484968	The RASSF1A was reported to be involved in gene inactivation by either allele loss (chromosome 3p) or hypermethylation in CCA.	('CCA', 'Phenotype', 'HP:0030153', (122, 125))	('RASSF1A', 'Gene', (4, 11))	('allele loss', 'Var', (71, 82))	('RASSF1A', 'Gene', '11186', (4, 11))	('CCA', 'Disease', (122, 125))	('hypermethylation', 'Var', (102, 118))
51634	29484968	In addition, the expression of RASSF1A could be recovered by reversal of gene methylation with consequent suppression of cell growth.	('methylation', 'Var', (78, 89))	('RASSF1A', 'Gene', (31, 38))	('expression', 'MPA', (17, 27))	('reversal', 'Var', (61, 69))	('RASSF1A', 'Gene', '11186', (31, 38))
51635	29484968	P16 expression was suppressed in CCA associated with hypermethylation status, and NEUROG1 gene hypermethylation was noted as marker for various types of cancers, especially colon cancer, as already mentioned.	('NEUROG1', 'Gene', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('colon cancer', 'Phenotype', 'HP:0003003', (173, 185))	('cancers', 'Disease', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('suppressed', 'NegReg', (19, 29))	('colon cancer', 'Disease', 'MESH:D015179', (173, 185))	('P16', 'Gene', (0, 3))	('NEUROG1', 'Gene', '4762', (82, 89))	('colon cancer', 'Disease', (173, 185))	('expression', 'MPA', (4, 14))	('CCA', 'Disease', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('P16', 'Gene', '1029', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('hypermethylation status', 'Var', (53, 76))	('CCA', 'Phenotype', 'HP:0030153', (33, 36))
51636	29484968	Moreover, demethylation of gene promoters and increased gene expression were found in a prostate cancer cell line treated with curcumin, a natural antitumor agent.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('prostate cancer', 'Disease', (88, 103))	('increased', 'PosReg', (46, 55))	('tumor', 'Disease', (151, 156))	('curcumin', 'Chemical', 'MESH:D003474', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('demethylation', 'Var', (10, 23))	('prostate cancer', 'Disease', 'MESH:D011471', (88, 103))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))	('gene expression', 'MPA', (56, 71))
51743	19226332	Mitochondrial membrane depolarization, cytosolic cytochrome C expression and apoptosis were increased in cells incubated with EGCG and gemcitabine compared to either agent alone.	('cytochrome C', 'Gene', '54205', (49, 61))	('apoptosis', 'CPA', (77, 86))	('Mitochondrial membrane depolarization', 'MPA', (0, 37))	('EGCG', 'Var', (126, 130))	('cytochrome C', 'Gene', (49, 61))	('increased', 'PosReg', (92, 101))	('EGCG', 'Chemical', 'MESH:C045651', (126, 130))	('gemcitabine', 'Chemical', 'MESH:C056507', (135, 146))
51818	19226332	Similar to our observations with the Mz-ChA-1 cells, EGCG, but not EGC increased chemotherapy-induced apoptosis (Fig 5).	('EGC', 'Chemical', 'MESH:C057580', (53, 56))	('EGCG', 'Chemical', 'MESH:C045651', (53, 57))	('EGCG', 'Var', (53, 57))	('chemotherapy-induced apoptosis', 'CPA', (81, 111))	('EGC', 'Chemical', 'MESH:C057580', (67, 70))
51824	19226332	Our focus now turned to understanding the mechanism by which EGCG could enhance chemotherapy-induced apoptosis.	('EGCG', 'Var', (61, 65))	('EGCG', 'Chemical', 'MESH:C045651', (61, 65))	('chemotherapy-induced apoptosis', 'CPA', (80, 110))	('enhance', 'PosReg', (72, 79))
51839	19226332	The combination of EGCG and gemcitabine decreased tumor growth to the greatest degree, thus corroborating our results found in vitro and supporting the hypothesis that EGCG enhances the sensitivity of Mz-ChA-1 cells to gemcitabine treatment.	('EGCG', 'Chemical', 'MESH:C045651', (19, 23))	('enhances', 'PosReg', (173, 181))	('gemcitabine', 'Chemical', 'MESH:C056507', (219, 230))	('sensitivity', 'MPA', (186, 197))	('decreased tumor', 'Disease', 'MESH:D009369', (40, 55))	('gemcitabine', 'Chemical', 'MESH:C056507', (28, 39))	('EGCG', 'Chemical', 'MESH:C045651', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('decreased tumor', 'Disease', (40, 55))	('EGCG', 'Var', (168, 172))
51856	19226332	Although EGCG acts as an antioxidant by inhibiting lipid peroxidation or trapping reactive oxygen species, EGCG can also enhance oxidative stress by the generation of hydrogen peroxides.	('EGCG', 'Var', (107, 111))	('EGCG', 'Chemical', 'MESH:C045651', (9, 13))	('hydrogen peroxides', 'Chemical', 'MESH:D006861', (167, 185))	('EGCG', 'Chemical', 'MESH:C045651', (107, 111))	('oxidative stress', 'Phenotype', 'HP:0025464', (129, 145))	('oxidative stress', 'MPA', (129, 145))	('lipid', 'Chemical', 'MESH:D008055', (51, 56))	('enhance', 'PosReg', (121, 128))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (82, 105))	('trapping reactive oxygen species', 'MPA', (73, 105))	('hydrogen peroxides', 'MPA', (167, 185))	('lipid peroxidation', 'MPA', (51, 69))	('inhibiting', 'NegReg', (40, 50))
51862	19226332	For most agents, these differences reflected the presence or absence of a gallate moiety, with the catechin-gallates inducing a greater degree of apoptosis compared to the respective catechins alone.	('catechin-gallates', 'Chemical', 'MESH:C417939', (99, 116))	('gallate', 'Chemical', '-', (74, 81))	('inducing', 'Reg', (117, 125))	('catechins', 'Chemical', 'MESH:D002392', (183, 192))	('catechin-gallates', 'Var', (99, 116))	('apoptosis', 'CPA', (146, 155))	('gallate', 'Chemical', '-', (108, 115))
51866	19226332	EGCG and EGC dramatically differ in their ability to bind to Bcl-XL, and the presence of the gallate group in EGCG enhances docking in the BH3 domain.	('EGCG', 'Gene', (110, 114))	('Bcl-XL', 'Gene', '598', (61, 67))	('EGC', 'Chemical', 'MESH:C057580', (0, 3))	('Bcl-XL', 'Gene', (61, 67))	('bind', 'Interaction', (53, 57))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('EGC', 'Chemical', 'MESH:C057580', (110, 113))	('presence', 'Var', (77, 85))	('ability', 'MPA', (42, 49))	('docking', 'Interaction', (124, 131))	('EGCG', 'Chemical', 'MESH:C045651', (110, 114))	('EGC', 'Chemical', 'MESH:C057580', (9, 12))	('gallate', 'Chemical', '-', (93, 100))	('BH3', 'Chemical', 'MESH:C006008', (139, 142))	('enhances', 'PosReg', (115, 123))
51871	19226332	Studies to explore the mechanisms by which EGCG can decrease tumor growth in vivo are also warranted.	('EGCG', 'Chemical', 'MESH:C045651', (43, 47))	('EGCG', 'Var', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('decrease', 'NegReg', (52, 60))	('tumor', 'Disease', (61, 66))
51872	19226332	EGCG can affect several different biological pathways.	('EGCG', 'Var', (0, 4))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('biological pathways', 'Pathway', (34, 53))	('affect', 'Reg', (9, 15))
51873	19226332	The p38 MAPK signaling is aberrantly activated in cholangiocarcinoma, and inhibition of p38 MAPK signaling decreases cholangiocarcinoma growth both in vivo or in vitro However, EGCG has been shown to decrease activation of p38 MAPK in some but not all studies.	('p38', 'Gene', (223, 226))	('inhibition', 'Var', (74, 84))	('p38', 'Gene', '1432', (88, 91))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (50, 68))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (50, 68))	('EGCG', 'Chemical', 'MESH:C045651', (177, 181))	('cholangiocarcinoma', 'Disease', (117, 135))	('decreases cholangiocarcinoma', 'Disease', (107, 135))	('p38', 'Gene', (88, 91))	('p38', 'Gene', '1432', (4, 7))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (117, 135))	('p38', 'Gene', '1432', (223, 226))	('cholangiocarcinoma', 'Disease', (50, 68))	('decreases cholangiocarcinoma', 'Disease', 'MESH:D018281', (107, 135))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (117, 135))	('p38', 'Gene', (4, 7))
51875	19226332	Furthermore, EGCG can inhibit DNA methyltransferase activity in protein extracts and in human cancer cell lines, and reactivate methylation silenced genes.	('EGCG', 'Chemical', 'MESH:C045651', (13, 17))	('activity', 'MPA', (52, 60))	('inhibit', 'NegReg', (22, 29))	('EGCG', 'Var', (13, 17))	('methylation silenced genes', 'MPA', (128, 154))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (88, 93))	('DNA methyltransferase', 'Enzyme', (30, 51))	('reactivate', 'PosReg', (117, 127))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
51876	19226332	Thus, there are multiple mechanisms by which EGCG may have an anti-tumor effect.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('EGCG', 'Chemical', 'MESH:C045651', (45, 49))	('tumor', 'Disease', (67, 72))	('EGCG', 'Var', (45, 49))
51913	24212807	Furthermore, VEGF expression has been shown to be associated with intrahepatic metastasis in cases of intrahepatic cholangiocarcinoma.	('associated with', 'Reg', (50, 65))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (102, 133))	('VEGF', 'Gene', '7422', (13, 17))	('intrahepatic cholangiocarcinoma', 'Disease', (102, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('intrahepatic metastasis', 'Disease', (66, 89))	('VEGF', 'Gene', (13, 17))	('intrahepatic metastasis', 'Disease', 'MESH:D009362', (66, 89))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (115, 133))	('expression', 'Var', (18, 28))
51920	24212807	In an examination conducted using human cholangiocarcinoma cell lines, ZD6474, an inhibitor of VEGFR and EGFR signaling, showed promising anticancer activity.	('ZD6474', 'Chemical', 'MESH:C452423', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('VEGFR', 'Gene', '3791', (95, 100))	('EGFR', 'Gene', '1956', (96, 100))	('human', 'Species', '9606', (34, 39))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (40, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('EGFR', 'Gene', (96, 100))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (40, 58))	('ZD6474', 'Var', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('EGFR', 'Gene', '1956', (105, 109))	('VEGFR', 'Gene', (95, 100))	('EGFR', 'Gene', (105, 109))	('cholangiocarcinoma', 'Disease', (40, 58))	('cancer', 'Disease', (142, 148))
51921	24212807	This study revealed that the absence of KRAS mutation and presence of EGFR amplification may be potentially predictive molecular markers of the sensitivity of cholangiocarcinoma to EGFR-targeted therapy.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('EGFR', 'Gene', (181, 185))	('KRAS', 'Gene', (40, 44))	('EGFR', 'Gene', '1956', (70, 74))	('cholangiocarcinoma', 'Disease', (159, 177))	('EGFR', 'Gene', (70, 74))	('mutation', 'Var', (45, 53))	('KRAS', 'Gene', '3845', (40, 44))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (159, 177))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (159, 177))	('EGFR', 'Gene', '1956', (181, 185))
51964	33864445	Comprehensive analysis of ferritin subunits expression and positive correlations with tumor-associated macrophages and T regulatory cells infiltration in most solid tumors Ferritin is the most important iron storage form and is known to influence tumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Ferritin', 'Var', (172, 180))	('iron', 'Chemical', 'MESH:D007501', (203, 207))	('tumor', 'Disease', (247, 252))	('tumor', 'Disease', (86, 91))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('influence', 'Reg', (237, 246))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (165, 170))
51990	33864445	The results suggested that high FTL (Figure 2B, 2C) or high FTH1 (Figure 2E-2J) mRNA levels were each related to poor OS in several cancer types.	('cancer', 'Disease', (132, 138))	('FTH1', 'Gene', (60, 64))	('mRNA levels', 'MPA', (80, 91))	('FTL', 'Gene', (32, 35))	('related', 'Reg', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('FTH1', 'Gene', '2495', (60, 64))	('high', 'Var', (55, 59))	('FTL', 'Gene', '2512', (32, 35))	('poor OS', 'Disease', (113, 120))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
51993	33864445	FTL expression was significantly associated with PFI in four cancer types (Figure 3A): LGG (HR 1.5, 95% CI 1.26-1.78, P = 3.8 x 10-6), KIRC (HR 1.31, 95% CI 1.06-1.62, P = 1.4 x 10-2), UCEC (HR 1.21, 95% CI 1.00-1.46, P = 4.4 x 10-2), and GBM (HR 1.26, 95% CI 1.02-1.57, P = 3.3 x 10-2).	('FTL', 'Gene', '2512', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('LGG', 'Disease', (87, 90))	('PFI', 'Disease', (49, 52))	('cancer', 'Disease', (61, 67))	('associated', 'Reg', (33, 43))	('expression', 'Var', (4, 14))	('UCEC', 'Disease', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('GBM', 'Disease', (239, 242))	('FTL', 'Gene', (0, 3))	('KIRC', 'Disease', (135, 139))
51995	33864445	As was observed for OS, poor PFI was significantly associated with high FTL (Figure 3B, 3C) or high FTH1 (Figure 3E-3J) mRNA levels in some cancers.	('FTH1', 'Gene', '2495', (100, 104))	('FTL', 'Gene', (72, 75))	('high', 'Var', (95, 99))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('FTH1', 'Gene', (100, 104))	('FTL', 'Gene', '2512', (72, 75))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('mRNA levels', 'MPA', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('PFI', 'MPA', (29, 32))
52016	33864445	Iron is an essential element in supporting cell proliferation and often accumulates in cancer cells; however, excessive levels of Fe2+ can promote the Fenton reaction, production of reactive oxygen species, and cell death through apoptosis and ferroptosis.	('cancer', 'Disease', (87, 93))	('cell death', 'CPA', (211, 221))	('promote', 'PosReg', (139, 146))	('ferroptosis', 'CPA', (244, 255))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('apoptosis', 'CPA', (230, 239))	('Fe2+', 'Var', (130, 134))	('Fe2+', 'Chemical', '-', (130, 134))	('production of reactive oxygen species', 'MPA', (168, 205))	('Fenton reaction', 'MPA', (151, 166))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('Iron', 'Chemical', 'MESH:D007501', (0, 4))	('oxygen', 'Chemical', 'MESH:D010100', (191, 197))
52026	33864445	We found that high FTH1 expression is positively related to poor prognosis in 11 cancers, including HNSC, which is consistent with our previous study.	('HNSC', 'Disease', (100, 104))	('FTH1', 'Gene', (19, 23))	('expression', 'MPA', (24, 34))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('FTH1', 'Gene', '2495', (19, 23))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('high', 'Var', (14, 18))	('HNSC', 'Phenotype', 'HP:0012288', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
52031	33864445	showed that FTH1 is critical for proper functioning of the antioxidant system in ovarian cancer cells, suggesting that inhibition of FTH1 may improve cisplatin-induced cytotoxicity.	('FTH1', 'Gene', (12, 16))	('cytotoxicity', 'Disease', 'MESH:D064420', (168, 180))	('ovarian cancer', 'Phenotype', 'HP:0100615', (81, 95))	('ovarian cancer', 'Disease', 'MESH:D010051', (81, 95))	('FTH1', 'Gene', (133, 137))	('inhibition', 'Var', (119, 129))	('ovarian cancer', 'Disease', (81, 95))	('FTH1', 'Gene', '2495', (12, 16))	('FTH1', 'Gene', '2495', (133, 137))	('cytotoxicity', 'Disease', (168, 180))	('cisplatin-induced', 'MPA', (150, 167))	('improve', 'PosReg', (142, 149))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
52052	33864445	However, whether FTL or FTH1 inhibition can induce M2-to-M1 repolarization will need to be investigated in future studies.	('FTH1', 'Gene', '2495', (24, 28))	('FTL', 'Gene', '2512', (17, 20))	('FTH1', 'Gene', (24, 28))	('FTL', 'Gene', (17, 20))	('M2-to-M1 repolarization', 'MPA', (51, 74))	('inhibition', 'Var', (29, 39))
52072	29879375	IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity Isocitrate dehydrogenase (IDH1)-1 is mutated in various types of human cancer, and the presence of this mutation is associated with improved responses to irradiation and chemotherapy in solid tumor cells.	('IDH1', 'Gene', '3417', (59, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('Isocitrate dehydrogenase', 'Gene', '3417', (110, 134))	('IDH1', 'Gene', (136, 140))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('Isocitrate dehydrogenase', 'Gene', (110, 134))	('IDH1', 'Gene', (0, 4))	('solid tumor', 'Disease', 'MESH:D009369', (296, 307))	('human', 'Species', '9606', (175, 180))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('presence', 'Var', (197, 205))	('IDH1', 'Gene', '3417', (136, 140))	('IDH1', 'Gene', '3417', (0, 4))	('improved', 'PosReg', (242, 250))	('IDH1', 'Gene', (59, 63))	('cancer', 'Disease', (181, 187))	('mutation', 'Var', (214, 222))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', (12, 18))	('solid tumor', 'Disease', (296, 307))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('responses to irradiation', 'CPA', (251, 275))
52073	29879375	Mutated IDH1 (IDH1MUT) enzymes consume NADPH to produce d-2-hydroxyglutarate (d-2HG) resulting in the decreased reducing power needed for detoxification of reactive oxygen species (ROS), for example.	('NADPH', 'Gene', '1666', (39, 44))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (156, 179))	('ROS', 'Chemical', 'MESH:D017382', (181, 184))	('detoxification of reactive oxygen species', 'MPA', (138, 179))	('IDH1', 'Gene', (8, 12))	('IDH1', 'Gene', '3417', (8, 12))	('IDH1', 'Gene', (14, 18))	('d-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (56, 76))	('Mutated', 'Var', (0, 7))	('NADPH', 'Gene', (39, 44))	('decreased', 'NegReg', (102, 111))	('IDH1', 'Gene', '3417', (14, 18))
52082	29879375	Recurring mutations in the NADP+-dependent IDH1/2 genes have been observed in substantial percentages of various cancer types, such as glioma (80%), acute myeloid leukemia (20%), cholangiocarcinoma (20%), melanomas (5-10%), and chondrosarcoma (60%).	('observed', 'Reg', (66, 74))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (179, 197))	('NADP+', 'Chemical', 'MESH:D009249', (27, 32))	('cancer', 'Disease', (113, 119))	('IDH1', 'Gene', '3417', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('acute myeloid leukemia', 'Disease', (149, 171))	('melanomas', 'Phenotype', 'HP:0002861', (205, 214))	('chondrosarcoma', 'Disease', (228, 242))	('chondrosarcoma', 'Disease', 'MESH:D002813', (228, 242))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (155, 171))	('glioma', 'Disease', (135, 141))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (149, 171))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('leukemia', 'Phenotype', 'HP:0001909', (163, 171))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (149, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (228, 242))	('IDH1', 'Gene', (43, 47))	('melanomas', 'Disease', 'MESH:D008545', (205, 214))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (179, 197))	('mutations', 'Var', (10, 19))	('melanomas', 'Disease', (205, 214))	('cholangiocarcinoma', 'Disease', (179, 197))
52084	29879375	The hotspot mutations in IDH1, of which IDH1R132H is the most prevalent, cause loss of enzymatic wild-type IDH1 (IDH1WT) function and lead to a neomorphic IDH1 activity that converts alpha-KG into the oncometabolite d-2-hydroxyglutarate (d-2HG).	('IDH1', 'Gene', (40, 44))	('IDH1', 'Gene', '3417', (107, 111))	('IDH1', 'Gene', '3417', (155, 159))	('activity', 'MPA', (160, 168))	('d-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (216, 236))	('IDH1WT', 'Gene', '3417', (113, 119))	('IDH1', 'Gene', '3417', (113, 117))	('function', 'MPA', (121, 129))	('IDH1', 'Gene', '3417', (25, 29))	('IDH1', 'Gene', '3417', (40, 44))	('neomorphic', 'MPA', (144, 154))	('alpha-KG', 'Chemical', 'MESH:D007656', (183, 191))	('IDH1WT', 'Gene', (113, 119))	('loss', 'NegReg', (79, 83))	('IDH1', 'Gene', (107, 111))	('IDH1', 'Gene', (155, 159))	('lead to', 'Reg', (134, 141))	('IDH1', 'Gene', (113, 117))	('mutations', 'Var', (12, 21))	('IDH1', 'Gene', (25, 29))
52085	29879375	d-2HG exerts its oncogenic effects via competitive inhibition of alpha-KG-dependent dioxygenases, which are essential for epigenetic regulation of gene expression, including that of metabolic genes.	('inhibition', 'NegReg', (51, 61))	('alpha-KG-dependent dioxygenases', 'Enzyme', (65, 96))	('oxygen', 'Chemical', 'MESH:D010100', (86, 92))	('alpha-KG', 'Chemical', 'MESH:D007656', (65, 73))	('oncogenic effects', 'CPA', (17, 34))	('d-2HG', 'Var', (0, 5))
52090	29879375	We have shown that this response is mediated by d-2HG accumulation, which sensitizes cells to irradiation (IR), whereas inhibition of IDH1MUT reduces oxidative stress in IDH1MUT cells and thus protects cells against IR.	('oxidative stress', 'Phenotype', 'HP:0025464', (150, 166))	('d-2HG', 'Var', (48, 53))	('IDH1', 'Gene', (170, 174))	('inhibition', 'Var', (120, 130))	('oxidative stress', 'MPA', (150, 166))	('IDH1', 'Gene', '3417', (170, 174))	('reduces', 'NegReg', (142, 149))	('IDH1', 'Gene', (134, 138))	('IDH1', 'Gene', '3417', (134, 138))
52098	29879375	ROS cause a massive oxidation of redox-sensitive proteins and lipids, leading to, in particular, mitochondrial damage and cell death through various signaling pathways.	('ROS', 'Var', (0, 3))	('lipids', 'Chemical', 'MESH:D008055', (62, 68))	('cell death', 'CPA', (122, 132))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('mitochondrial damage', 'Disease', (97, 117))	('mitochondrial damage', 'Disease', 'MESH:D028361', (97, 117))	('oxidation', 'MPA', (20, 29))
52114	29879375	Cells were treated with cisplatin at 4 h after plating in the presence or absence of 0-1 microM AGI-5198, 0-10 mM d-2HG, or 0-5 muM NAC.	('NAC', 'Chemical', 'MESH:D000111', (132, 135))	('0-10 mM d-2HG', 'Var', (106, 119))	('muM', 'Gene', '56925', (128, 131))	('AGI-5198', 'Gene', (96, 104))	('muM', 'Gene', (128, 131))	('AGI-5198', 'Chemical', 'MESH:C581156', (96, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (24, 33))
52150	29879375	Because cisplatin, but not carboplatin, strongly impairs oxphos and mitochondrial function, we investigated whether, besides the reduced NADPH production capacity, the increased sensitivity of IDH1MUT cells to cisplatin is caused by this metabolic phenotype.	('IDH1', 'Gene', (193, 197))	('cisplatin', 'Var', (8, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (210, 219))	('NADPH', 'Gene', (137, 142))	('carboplatin', 'Chemical', 'MESH:D016190', (27, 38))	('IDH1', 'Gene', '3417', (193, 197))	('impairs', 'NegReg', (49, 56))	('NADPH', 'Gene', '1666', (137, 142))	('cisplatin', 'Chemical', 'MESH:D002945', (8, 17))	('reduced', 'NegReg', (129, 136))
52161	29879375	The mitonuclear protein imbalance after treatment with cisplatin was accompanied by a decreased cellular respiration of IDH1MUT HCT116 cells, indicative of impaired mitochondrial activity.	('mitonuclear protein imbalance', 'MPA', (4, 33))	('cellular respiration', 'MPA', (96, 116))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('imbalance', 'Phenotype', 'HP:0002172', (24, 33))	('decreased', 'NegReg', (86, 95))	('IDH1', 'Gene', (120, 124))	('mitochondrial', 'MPA', (165, 178))	('HCT116', 'CellLine', 'CVCL:0291', (128, 134))	('IDH1', 'Gene', '3417', (120, 124))	('cisplatin', 'Var', (55, 64))
52174	29879375	d-2HG is also known to induce oxidative stress in glia and neurons.	('glia', 'Disease', 'None', (50, 54))	('induce', 'Reg', (23, 29))	('oxidative stress', 'Phenotype', 'HP:0025464', (30, 46))	('glia', 'Disease', (50, 54))	('oxidative stress', 'MPA', (30, 46))	('d-2HG', 'Var', (0, 5))
52178	29879375	5C; i.e., d-2HG sensitized HCT116 cells to cisplatin).	('sensitized', 'Reg', (16, 26))	('HCT116', 'CellLine', 'CVCL:0291', (27, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('d-2HG', 'Var', (10, 15))
52179	29879375	Of note, AGI-5198 was unable to protect IDH1MUT or IDH1WT HCT116 cells against cisplatin in the presence of d-2HG; the protective mechanism of AGI-5198 on IDH1MUT HCT116 cells therefore depends predominantly on the inhibition of IDH1MUT-mediated d-2HG production.	('IDH1', 'Gene', '3417', (51, 55))	('IDH1', 'Gene', (155, 159))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('IDH1', 'Gene', (229, 233))	('IDH1', 'Gene', (40, 44))	('AGI-5198', 'Chemical', 'MESH:C581156', (9, 17))	('IDH1', 'Gene', '3417', (155, 159))	('IDH1', 'Gene', '3417', (229, 233))	('IDH1', 'Gene', '3417', (40, 44))	('HCT116', 'CellLine', 'CVCL:0291', (58, 64))	('AGI-5198', 'Var', (143, 151))	('AGI-5198', 'Chemical', 'MESH:C581156', (143, 151))	('IDH1WT', 'Gene', (51, 57))	('HCT116', 'CellLine', 'CVCL:0291', (163, 169))	('IDH1', 'Gene', (51, 55))	('IDH1WT', 'Gene', '3417', (51, 57))
52197	29879375	In line with our observations, another study has shown that among the platinum-based cytotoxic agents, specifically cisplatin reduces the expression of mitochondrial DNA-encoded genes and protein levels.	('reduces', 'NegReg', (126, 133))	('platinum', 'Chemical', 'MESH:D010984', (70, 78))	('cisplatin', 'Var', (116, 125))	('expression', 'MPA', (138, 148))	('mitochondrial DNA-encoded genes', 'Gene', (152, 183))	('protein levels', 'MPA', (188, 202))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))
52251	28716705	Disruption of normal cholangiocyte function can lead to the development of one of the "cholangiopathies", a diverse collection of chronic liver diseases that are generally chronic, progressive, often lack effective treatment and may be life threatening (Table 1).	('cholangiopathies', 'Disease', (87, 103))	('cholangiopathies', 'Disease', 'None', (87, 103))	('liver diseases', 'Disease', (138, 152))	('liver diseases', 'Disease', 'MESH:D008107', (138, 152))	('liver diseases', 'Phenotype', 'HP:0001392', (138, 152))	('lead to', 'Reg', (48, 55))	('liver disease', 'Phenotype', 'HP:0001392', (138, 151))	('Disruption', 'Var', (0, 10))
52271	28716705	On the basolateral domain, HCO3- enters the cell via the Na+-dependent Cl-/HCO3- exchanger (Na+:HCO3- symporter in rodents), with the Na+ concentration gradient achieved via the Na+/H+ exchanger isoform 1 (NHE1).	('Na+/H+ exchanger isoform 1', 'Gene', '24782', (178, 204))	('Na+/H+ exchanger isoform 1', 'Gene', (178, 204))	('NHE1', 'Gene', (206, 210))	('NHE1', 'Gene', '24782', (206, 210))	('HCO3-', 'Var', (27, 32))
52289	28716705	2), and their disruption has been hypothesized to lead to certain cholangiopathies, such as autosomal dominant polycystic kidney disease (ADPKD), which can lead to cystic liver and kidney disease.	('lead', 'Reg', (50, 54))	('kidney disease', 'Phenotype', 'HP:0000112', (122, 136))	('lead to', 'Reg', (156, 163))	('ADP', 'Chemical', 'MESH:D000244', (138, 141))	('cholangiopathies', 'Disease', (66, 82))	('autosomal dominant polycystic kidney disease', 'Disease', 'MESH:D007690', (92, 136))	('kidney disease', 'Phenotype', 'HP:0000112', (181, 195))	('polycystic kidney', 'Disease', 'MESH:D007690', (111, 128))	('ADPKD', 'Disease', (138, 143))	('autosomal dominant polycystic kidney disease', 'Disease', (92, 136))	('cystic liver and kidney disease', 'Disease', 'MESH:D052177', (164, 195))	('ADPKD', 'Disease', 'MESH:D007690', (138, 143))	('polycystic kidney', 'Phenotype', 'HP:0000113', (111, 128))	('disruption', 'Var', (14, 24))
52295	28716705	Activation of P2Y12 increases intracellular cAMP levels which can then activate a number of cAMP-dependent pathways such as those involving adenylyl cyclase, PKA and a protein called "exchange protein activated by cAMP" (EPAC).	('activate', 'PosReg', (71, 79))	('increases', 'PosReg', (20, 29))	('P2Y12', 'Var', (14, 19))	('cAMP"', 'Gene', (214, 219))	('cAMP"', 'Gene', '316010', (214, 219))	('EPAC', 'Gene', (221, 225))	('EPAC', 'Gene', '59326', (221, 225))	('cAMP-dependent pathways', 'Pathway', (92, 115))	('intracellular cAMP levels', 'MPA', (30, 55))	('adenylyl cyclase', 'MPA', (140, 156))
52297	28716705	It is known that defects in cilia can cause a number of diseases, such as ADPKD, which is caused by mutations in the genes PKD1 or PKD2 (these encode PC-1 and PC-2 respectively).	('PKD1', 'Gene', (123, 127))	('mutations', 'Var', (100, 109))	('PC-1 and PC-2', 'Gene', '25204;25121', (150, 163))	('cause', 'Reg', (38, 43))	('PKD2', 'Gene', '498328', (131, 135))	('cilia', 'CPA', (28, 33))	('PKD2', 'Gene', (131, 135))	('PKD1', 'Gene', '24650', (123, 127))	('ADPKD', 'Disease', (74, 79))	('defects', 'Var', (17, 24))	('caused by', 'Reg', (90, 99))
52301	28716705	Overexpression of HDAC6 in normal cholangiocytes leads to deciliation, both of which are seen in cholangiocarcinoma.	('HDAC6', 'Gene', '84581', (18, 23))	('leads to', 'Reg', (49, 57))	('HDAC6', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('deciliation', 'MPA', (58, 69))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))
52304	28716705	MiR-33a can silence ATP-binding cassette transporter A1 (ABCA1) and ABCG1, which are induced by the ligand-activated transcription factor, Liver X Receptor (LXR) and whose activation can lead to cholesterol efflux from peripheral tissues and enterocytes.	('ABCA1', 'Gene', (57, 62))	('ATP-binding cassette transporter A1', 'Gene', (20, 55))	('ATP-binding cassette transporter A1', 'Gene', '313210', (20, 55))	('ABCA1', 'Gene', '313210', (57, 62))	('MiR-33a', 'Var', (0, 7))	('ABCG1', 'Gene', '85264', (68, 73))	('activation', 'PosReg', (172, 182))	('silence', 'NegReg', (12, 19))	('ABCG1', 'Gene', (68, 73))	('lead to', 'Reg', (187, 194))
52305	28716705	MiR-33a can also suppress ATP8B1, a canalicular phospholipid flippase which maintains hepatic secretory function by stabilizing membrane polarity, and ABCB11, which encodes the bile salt export protein (BSEP), responsible for canalicular bile export.	('ABCB11', 'Gene', (151, 157))	('membrane polarity', 'MPA', (128, 145))	('ATP8B1', 'Gene', '291555', (26, 32))	('hepatic secretory function', 'MPA', (86, 112))	('BSEP', 'Gene', (203, 207))	('bile salt', 'Chemical', 'MESH:D001647', (177, 186))	('bile salt export protein', 'Gene', '83569', (177, 201))	('bile salt export protein', 'Gene', (177, 201))	('ATP8B1', 'Gene', (26, 32))	('MiR-33a', 'Var', (0, 7))	('BSEP', 'Gene', '83569', (203, 207))	('suppress', 'NegReg', (17, 25))	('ABCB11', 'Gene', '83569', (151, 157))
52309	28716705	Additional miRNAs that have been implicated in cholesterol metabolism and bile acid homestasis include miR-122, miR-422a, miR-133.	('miR-122', 'Gene', (103, 110))	('miR-122', 'Gene', '100314023', (103, 110))	('miR-133', 'Var', (122, 129))	('miR-422a', 'Var', (112, 120))
52311	28716705	It has a myriad of roles in hepatic homeostasis, including control of bile acid synthesis through silencing of CYP7A1.	('hepatic homeostasis', 'Disease', 'MESH:D056486', (28, 47))	('CYP7A1', 'Gene', (111, 117))	('bile acid synthesis', 'MPA', (70, 89))	('silencing', 'Var', (98, 107))	('control', 'MPA', (59, 66))	('hepatic homeostasis', 'Disease', (28, 47))
52312	28716705	MiR-422a also silences CYP7A1, thereby providing another pathway to mediate bile acid homeostasis.	('bile acid homeostasis', 'MPA', (76, 97))	('silences', 'NegReg', (14, 22))	('MiR-422a', 'Chemical', '-', (0, 8))	('CYP7A1', 'Gene', (23, 29))	('MiR-422a', 'Var', (0, 8))
52314	28716705	Given that higher levels of proinflammatory cytokine responses with molecules such as tumor necrosis factor (TNF)-alpha and IFN-gamma are associated with primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and biliary atresia, aberrant B7-H1 expression may play a key role in these pathologies.	('TNF', 'Gene', '24835', (109, 112))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (197, 219))	('tumor necrosis', 'Disease', 'MESH:D009336', (86, 100))	('aberrant', 'Var', (247, 255))	('cholangitis', 'Disease', 'MESH:D002761', (208, 219))	('primary biliary cholangitis', 'Disease', (154, 181))	('biliary atresia', 'Disease', (230, 245))	('biliary atresia', 'Disease', 'MESH:D001656', (230, 245))	('tumor necrosis', 'Disease', (86, 100))	('cholangitis', 'Phenotype', 'HP:0030151', (170, 181))	('cholangitis', 'Disease', (208, 219))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('PSC', 'Gene', '100653366', (221, 224))	('cholangitis', 'Phenotype', 'HP:0030151', (208, 219))	('biliary atresia', 'Phenotype', 'HP:0005912', (230, 245))	('proinflammatory cytokine', 'MPA', (28, 52))	('higher', 'PosReg', (11, 17))	('TNF', 'Gene', (109, 112))	('PSC', 'Gene', (221, 224))	('cholangitis', 'Disease', 'MESH:D002761', (170, 181))	('TNF)-alpha', 'Gene', '24835', (109, 119))	('associated', 'Reg', (138, 148))	('primary biliary cholangitis', 'Disease', 'MESH:D008105', (154, 181))	('cholangitis', 'Disease', (170, 181))
52315	28716705	In human cholangiocytes, cytokine signaling in response to microbial exposure can be mediated by miR-98 and let-7.	('let-7', 'Gene', (108, 113))	('cytokine signaling', 'MPA', (25, 43))	('mediated', 'Reg', (85, 93))	('miR-98', 'Var', (97, 103))	('let-7', 'Chemical', '-', (108, 113))
52318	28716705	A number of miRNAs have been associated with cholestasis and specific cholangiopathies.	('cholestasis', 'Phenotype', 'HP:0001396', (45, 56))	('miRNAs', 'Var', (12, 18))	('cholangiopathies', 'Disease', (70, 86))	('cholestasis', 'Disease', 'MESH:D002779', (45, 56))	('cholestasis', 'Disease', (45, 56))	('specific cholangiopathies', 'Disease', (61, 86))	('associated', 'Reg', (29, 39))
52327	28716705	Investigation of miRNA levels in biliary atresia has demonstrated that miRNAs may influence AKT signaling pathways, which can induce hepatic stem cell activation.	('AKT', 'Gene', '24185', (92, 95))	('induce', 'PosReg', (126, 132))	('influence', 'Reg', (82, 91))	('miRNAs', 'Var', (71, 77))	('biliary atresia', 'Disease', (33, 48))	('biliary atresia', 'Phenotype', 'HP:0005912', (33, 48))	('AKT', 'Gene', (92, 95))	('hepatic', 'MPA', (133, 140))
52328	28716705	The suppression of mRNA targets (e.g., friend of GATA [FOG] and the phosphatase and tensin homolog [PTEN]) by miR-200b and miR-21 respectively, can lead to the activation of the AKT pathway, which then leads to cellular growth and migration.	('PTEN', 'Gene', (100, 104))	('miR-21', 'Var', (123, 129))	('suppression', 'NegReg', (4, 15))	('leads to', 'Reg', (202, 210))	('activation', 'PosReg', (160, 170))	('AKT pathway', 'Pathway', (178, 189))	('miR-200b', 'Gene', '100314050', (110, 118))	('PTEN', 'Gene', '50557', (100, 104))	('miR-200b', 'Gene', (110, 118))	('cellular growth', 'CPA', (211, 226))
52334	28716705	In vitro, taurocholate and taurolithocholic acid have been shown to stimulate the proliferation of large, but not small, cholangiocytes, as well as induce secretin receptor gene expression, cAMP levels and Cl-/HCO3- exchanger activity.	('Cl-/HCO3- exchanger activity', 'MPA', (206, 234))	('stimulate', 'PosReg', (68, 77))	('taurolithocholic acid', 'Chemical', 'MESH:D013658', (27, 48))	('secretin receptor', 'Gene', '81779', (155, 172))	('taurolithocholic acid', 'Var', (27, 48))	('cAMP levels', 'MPA', (190, 201))	('proliferation', 'CPA', (82, 95))	('induce', 'PosReg', (148, 154))	('secretin receptor', 'Gene', (155, 172))
52335	28716705	By contrast, ursodeoxycholic acid (UDCA) and tauroursodeoxycholate inhibit overall cholangiocyte proliferation in BDL rats as well as reduce the expression of the cholangiocyte apical bile acid transporter, which in turn is hypothesized to reduce the ability of endogenous bile acids to stimulate proliferative and secretory pathways.	('ursodeoxycholic acid', 'Chemical', 'MESH:D014580', (13, 33))	('inhibit', 'NegReg', (67, 74))	('tauroursodeoxycholate', 'Var', (45, 66))	('reduce', 'NegReg', (134, 140))	('stimulate', 'PosReg', (287, 296))	('cholangiocyte proliferation', 'CPA', (83, 110))	('expression', 'MPA', (145, 155))	('proliferative', 'CPA', (297, 310))	('tauroursodeoxycholate', 'Chemical', 'MESH:C031655', (45, 66))	('apical bile', 'Phenotype', 'HP:0032176', (177, 188))	('ursodeoxycholic', 'Var', (13, 28))
52349	28716705	Apoptosis is also the mechanism by which aberrant ductal proliferation is reversed in the setting of transient biliary obstruction.	('biliary obstruction', 'Disease', 'MESH:D001658', (111, 130))	('biliary obstruction', 'Phenotype', 'HP:0005230', (111, 130))	('aberrant', 'Var', (41, 49))	('biliary obstruction', 'Disease', (111, 130))
52352	28716705	These involve activation of the cyclin-dependent kinase inhibitors (CDKN) p21CIP1 and P16INK4A, which are mediated by the p53 and the retinoblastoma (pRB) proteins respectively.	('activation', 'PosReg', (14, 24))	('pRB', 'Gene', (150, 153))	('retinoblastoma', 'Phenotype', 'HP:0009919', (134, 148))	('CDKN', 'Gene', (68, 72))	('P16INK4A', 'Gene', '25163', (86, 94))	('p21CIP1', 'Var', (74, 81))	('p53', 'Gene', '301300', (122, 125))	('cyclin-dependent', 'Enzyme', (32, 48))	('pRB', 'Gene', '24708', (150, 153))	('retinoblastoma', 'Disease', 'MESH:D012175', (134, 148))	('retinoblastoma', 'Disease', (134, 148))	('P16INK4A', 'Gene', (86, 94))	('p53', 'Gene', (122, 125))
52353	28716705	In in vitro and in vivo experiments, overexpression of constitutively active neuroblastoma RAS viral oncogene homolog (NRAS) has been shown to promote cyclin-dependent kinase inhibitor 2A (CDKN2A)/p16INK4a expression and cholangiocyte senescence in an ETS proto-oncogene 1 (ETS1)-dependent manner.	('ETS proto-oncogene 1', 'Gene', (252, 272))	('expression', 'MPA', (206, 216))	('neuroblastoma RAS viral', 'Disease', (77, 100))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '25163', (151, 187))	('ETS proto-oncogene 1', 'Gene', '24356', (252, 272))	('promote', 'PosReg', (143, 150))	('p16', 'Gene', '25163', (197, 200))	('neuroblastoma RAS viral', 'Disease', 'MESH:D009447', (77, 100))	('overexpression', 'Var', (37, 51))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (151, 187))	('cholangiocyte senescence', 'CPA', (221, 245))	('neuroblastoma', 'Phenotype', 'HP:0003006', (77, 90))	('p16', 'Gene', (197, 200))
52371	28716705	In culture, it has been demonstrated that LPS induces activation of NRAS through Toll-like receptor 4 via NF-kappaB in human cholangiocytes.	('Toll-like receptor 4', 'Gene', '7099', (81, 101))	('Toll-like receptor 4', 'Gene', (81, 101))	('LPS', 'Var', (42, 45))	('activation', 'PosReg', (54, 64))	('NRAS', 'Protein', (68, 72))	('NF-kappaB', 'Protein', (106, 115))
52592	28814880	More importantly, CCA patients with high CD155 expression had a markedly shorter overall survival (P<0.001) and disease-free survival (P<0.001) after surgical resection, and multivariate analysis showed that high CD155 expression was an independent poor prognostic predictor of overall survival and disease-free survival (P<0.001).	('CCA', 'Disease', (18, 21))	('CD155', 'Gene', (41, 46))	('disease-free survival', 'CPA', (112, 133))	('patients', 'Species', '9606', (22, 30))	('CD155', 'Gene', '5817', (213, 218))	('CCA', 'Phenotype', 'HP:0030153', (18, 21))	('shorter', 'NegReg', (73, 80))	('CD155', 'Gene', '5817', (41, 46))	('CD155', 'Gene', (213, 218))	('overall survival', 'CPA', (81, 97))	('high', 'Var', (36, 40))
52652	28814880	Tumor tissues with high CD155 expression had positively greater MVD values than those with low CD155 expression (33.5+-5.8 vs 26.9+-6.5; P<0.05; Figure 4).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('high', 'Var', (19, 23))	('CD155', 'Gene', '5817', (95, 100))	('CD155', 'Gene', '5817', (24, 29))	('greater', 'PosReg', (56, 63))	('MVD values', 'MPA', (64, 74))	('CD155', 'Gene', (95, 100))	('CD155', 'Gene', (24, 29))
52657	28814880	Kaplan-Meier method was applied to construct the survival curves in order to compare the DFS and OS between high CD155 expression and low CD155 expression in patients.	('expression', 'MPA', (119, 129))	('CD155', 'Gene', '5817', (113, 118))	('low', 'NegReg', (134, 137))	('CD155', 'Gene', '5817', (138, 143))	('high', 'Var', (108, 112))	('CD155', 'Gene', (113, 118))	('patients', 'Species', '9606', (158, 166))	('CD155', 'Gene', (138, 143))
52659	28814880	Meanwhile, the DFS of high CD155 expression (12.81+-1.10 months) was also significantly lower than that of low CD155 expression (33.43+-3.12 months, P<0.001) in patients.	('DFS', 'MPA', (15, 18))	('CD155', 'Gene', (111, 116))	('high', 'Var', (22, 26))	('patients', 'Species', '9606', (161, 169))	('CD155', 'Gene', '5817', (27, 32))	('expression', 'MPA', (33, 43))	('lower', 'NegReg', (88, 93))	('CD155', 'Gene', '5817', (111, 116))	('CD155', 'Gene', (27, 32))
52681	28814880	Consistent with previous studies, our results suggested that tumors with high CD155 expression had higher MVD than those with low CD155.	('tumors', 'Disease', (61, 67))	('MVD', 'MPA', (106, 109))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('CD155', 'Gene', '5817', (78, 83))	('higher', 'PosReg', (99, 105))	('CD155', 'Gene', '5817', (130, 135))	('CD155', 'Gene', (78, 83))	('CD155', 'Gene', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('high', 'Var', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
52686	28814880	For example, Nishiwada et al reported that CD155 expression had an independent prognostic value in pancreatic carcinoma, and patients with high CD155 expression had poorer postoperative prognosis than those with low CD155 expression.	('CD155', 'Gene', '5817', (43, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('CD155', 'Gene', '5817', (216, 221))	('CD155', 'Gene', '5817', (144, 149))	('pancreatic carcinoma', 'Disease', (99, 119))	('CD155', 'Gene', (43, 48))	('CD155', 'Gene', (216, 221))	('CD155', 'Gene', (144, 149))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (99, 119))	('high', 'Var', (139, 143))	('patients', 'Species', '9606', (125, 133))
52688	28814880	Consistent with previous studies, Kaplan-Meier survival analysis and log-rank test suggested that CCA patients with high CD155 expression had a significantly shorter DFS and OS than those with low CD155 expression.	('CCA', 'Phenotype', 'HP:0030153', (98, 101))	('shorter', 'NegReg', (158, 165))	('CD155', 'Gene', '5817', (197, 202))	('CD155', 'Gene', (121, 126))	('high', 'Var', (116, 120))	('patients', 'Species', '9606', (102, 110))	('CCA', 'Disease', (98, 101))	('CD155', 'Gene', (197, 202))	('CD155', 'Gene', '5817', (121, 126))
52689	28814880	Univariate analysis revealed that high CD155 expression reduced survival time including OS and DFS.	('survival time', 'CPA', (64, 77))	('CD155', 'Gene', '5817', (39, 44))	('reduced', 'NegReg', (56, 63))	('CD155', 'Gene', (39, 44))	('expression', 'MPA', (45, 55))	('high', 'Var', (34, 38))	('DFS', 'CPA', (95, 98))
52690	28814880	Moreover, multivariate survival analysis showed that high CD155 expression was an independent prognostic factor for unfavorable DFS and OS.	('CD155', 'Gene', (58, 63))	('unfavorable', 'Disease', (116, 127))	('high', 'Var', (53, 57))	('CD155', 'Gene', '5817', (58, 63))
52691	28814880	Therefore, these results suggested that high CD155 expression had a negative influence on prognosis of CCA patients and may be used as a promising prognostic biomarker.	('high', 'Var', (40, 44))	('prognosis', 'CPA', (90, 99))	('CD155', 'Gene', (45, 50))	('CCA', 'Disease', (103, 106))	('negative', 'NegReg', (68, 76))	('CCA', 'Phenotype', 'HP:0030153', (103, 106))	('expression', 'MPA', (51, 61))	('CD155', 'Gene', '5817', (45, 50))	('patients', 'Species', '9606', (107, 115))
52692	28814880	In summary, we, for the first time, revealed that CD155 is overexpressed in CCA tissues and that high CD155 expression is associated with aggressive clinicopathological features and angiogenesis.	('associated', 'Reg', (122, 132))	('overexpressed', 'PosReg', (59, 72))	('CCA', 'Disease', (76, 79))	('CD155', 'Gene', '5817', (102, 107))	('CD155', 'Gene', '5817', (50, 55))	('angiogenesis', 'CPA', (182, 194))	('CD155', 'Gene', (50, 55))	('CCA', 'Phenotype', 'HP:0030153', (76, 79))	('expression', 'MPA', (108, 118))	('CD155', 'Gene', (102, 107))	('high', 'Var', (97, 101))
52693	28814880	More importantly, high CD155 expression serves as an independent predictor of unfavorable prognosis in CCA patients after surgery.	('CCA', 'Disease', (103, 106))	('CD155', 'Gene', (23, 28))	('CCA', 'Phenotype', 'HP:0030153', (103, 106))	('high', 'Var', (18, 22))	('expression', 'MPA', (29, 39))	('patients', 'Species', '9606', (107, 115))	('CD155', 'Gene', '5817', (23, 28))
52700	27190750	Meanwhile, the optimal cut-off value for CA 125 to predict resectability was 25.905 U/ml (sensitivity, 78.6 %; specificity, 67.5 %).	('CA 125', 'Gene', (41, 47))	('resectability', 'Disease', (59, 72))	('CA 125', 'Gene', '94025', (41, 47))	('25.905 U/ml', 'Var', (77, 88))
52736	27190750	Sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) were computed for each cut-off point of CA 19-9, CA 125 and CEA.	('CA 125', 'Gene', (145, 151))	('CEA', 'Gene', (156, 159))	('CEA', 'Gene', '1084', (156, 159))	('CA 19-9', 'Var', (136, 143))	('CA 125', 'Gene', '94025', (145, 151))
52753	27190750	Increased resectability was also witnessed in patients with preoperative tumor size <=3 cm compared with tumor size >3 cm (P < 0.001).	('patients', 'Species', '9606', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', (73, 78))	('Increased', 'PosReg', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('resectability', 'CPA', (10, 23))	('<=3', 'Var', (84, 87))
52768	27190750	Patients with resected disease obviously had preoperative CA 19-9 lesser than 200 U/ml and CA 19-9 was also identified as an independent factor to be associated with tumor resectability.	('associated', 'Reg', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('Patients', 'Species', '9606', (0, 8))	('CA 19-9', 'Var', (91, 98))
52810	26557943	Chronic viral hepatitis B or C, obesity, diabetes, fatty liver disease, alcohol, smoking, polymorphisms of genes, inflammation, and biliary transporters may also be risk factors.	('obesity', 'Disease', (32, 39))	('viral hepatitis', 'Phenotype', 'HP:0006562', (8, 23))	('inflammation', 'Disease', (114, 126))	('Chronic viral hepatitis B', 'Disease', 'MESH:D019694', (0, 25))	('diabetes', 'Disease', 'MESH:D003920', (41, 49))	('Chronic viral hepatitis B', 'Disease', (0, 25))	('fatty liver disease', 'Disease', 'MESH:D005234', (51, 70))	('alcohol', 'Chemical', 'MESH:D000438', (72, 79))	('liver disease', 'Phenotype', 'HP:0001392', (57, 70))	('genes', 'Gene', (107, 112))	('obesity', 'Phenotype', 'HP:0001513', (32, 39))	('fatty liver', 'Phenotype', 'HP:0001397', (51, 62))	('hepatitis', 'Phenotype', 'HP:0012115', (14, 23))	('fatty liver disease', 'Disease', (51, 70))	('polymorphisms', 'Var', (90, 103))	('obesity', 'Disease', 'MESH:D009765', (32, 39))	('diabetes', 'Disease', (41, 49))	('inflammation', 'Disease', 'MESH:D007249', (114, 126))
52872	25903488	To date, it has been shown that hepatolithiasis, primary sclerosing cholangitis, liver flukes, biliary duct cysts, specific toxins (for example, the carcinogenic agent thorotrast), inflammatory bowel disease, and genetic polymorphisms are the major risk factors for CCA.	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (57, 79))	('biliary', 'Disease', (95, 102))	('carcinogenic', 'Disease', (149, 161))	('cholangitis', 'Disease', (68, 79))	('liver flukes', 'Species', '6192', (81, 93))	('cholangitis', 'Phenotype', 'HP:0030151', (68, 79))	('liver flukes', 'Disease', (81, 93))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (181, 207))	('inflammatory bowel disease', 'Disease', (181, 207))	('hepatolithiasis', 'Disease', (32, 47))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (181, 207))	('CCA', 'Disease', (266, 269))	('cholangitis', 'Disease', 'MESH:D002761', (68, 79))	('hepatolithiasis', 'Disease', 'None', (32, 47))	('genetic polymorphisms', 'Var', (213, 234))	('CCA', 'Phenotype', 'HP:0030153', (266, 269))	('carcinogenic', 'Disease', 'MESH:D063646', (149, 161))
52909	25903488	Another study reported that HCV core variants could alleviate TGF-beta cytostatic responses and increase TGF-beta-mediated epithelial-to-mesenchymal transition (EMT), thereby promoting cell invasion and metastasis.	('cell invasion', 'CPA', (185, 198))	('HCV', 'Species', '11103', (28, 31))	('TGF-beta-mediated', 'MPA', (105, 122))	('HCV core', 'Gene', (28, 36))	('TGF-beta cytostatic responses', 'MPA', (62, 91))	('alleviate', 'NegReg', (52, 61))	('increase TGF-beta', 'Phenotype', 'HP:0030269', (96, 113))	('variants', 'Var', (37, 45))	('increase', 'PosReg', (96, 104))	('promoting', 'PosReg', (175, 184))	('metastasis', 'CPA', (203, 213))
52911	25903488	Clearly, based on such results, HCV can lead to hepatocellular carcinoma (HCC).	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (48, 72))	('lead to', 'Reg', (40, 47))	('hepatocellular carcinoma', 'Disease', (48, 72))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (48, 72))	('HCV', 'Var', (32, 35))	('HCC', 'Phenotype', 'HP:0001402', (74, 77))	('HCV', 'Species', '11103', (32, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
52932	24140396	Changes in oncogene and inflammatory signaling pathways, as well as genetic and epigenetic alterations and chromosome aberrations, have been shown to contribute to development of CCA.	('chromosome', 'CPA', (107, 117))	('genetic', 'Var', (68, 75))	('epigenetic alterations', 'Var', (80, 102))	('rat', 'Species', '10116', (95, 98))	('contribute', 'Reg', (150, 160))	('CCA', 'Gene', (179, 182))	('CCA', 'Gene', '2201', (179, 182))	('rat', 'Species', '10116', (122, 125))
52983	24140396	Additional studies have associated variants of genes that regulate DNA repair, inflammation, and carcinogen metabolism with CCA development.	('variants', 'Var', (35, 43))	('CCA', 'Gene', (124, 127))	('CCA', 'Gene', '2201', (124, 127))	('inflammation', 'Disease', 'MESH:D007249', (79, 91))	('inflammation', 'Disease', (79, 91))
52999	24140396	Inflammatory cytokines activate inducible nitric oxide synthase, leading to excess nitric oxide with resultant single-stranded, double-stranded, and oxidative DNA lesions, as well as inhibition of DNA repair enzymes.	('double-stranded', 'MPA', (128, 143))	('inhibition', 'NegReg', (183, 193))	('DNA repair enzymes', 'Enzyme', (197, 215))	('inducible nitric oxide synthase', 'Enzyme', (32, 63))	('excess', 'PosReg', (76, 82))	('oxidative DNA lesions', 'MPA', (149, 170))	('nitric oxide', 'MPA', (83, 95))	('single-stranded', 'Var', (111, 126))	('nitric oxide', 'Chemical', 'MESH:D009569', (83, 95))	('nitric oxide', 'Chemical', 'MESH:D009569', (42, 54))
53005	24140396	Epigenetic silencing of suppressor of cytokine signaling 3 (SOCS3) results in sustained IL6 signaling via STAT3.	('suppressor of cytokine signaling 3', 'Gene', (24, 58))	('SOCS3', 'Gene', (60, 65))	('STAT3', 'Gene', '6774', (106, 111))	('suppressor of cytokine signaling 3', 'Gene', '9021', (24, 58))	('Epigenetic silencing', 'Var', (0, 20))	('SOCS3', 'Gene', '9021', (60, 65))	('STAT3', 'Gene', (106, 111))	('IL6', 'Gene', '3569', (88, 91))	('IL6', 'Gene', (88, 91))
53011	24140396	EGFR inhibitors decrease expression of cyclooxygenase-2 (COX2) by CCA cells.	('decrease', 'NegReg', (16, 24))	('EGFR', 'Gene', (0, 4))	('COX2', 'Gene', (57, 61))	('expression', 'MPA', (25, 35))	('inhibitors', 'Var', (5, 15))	('COX2', 'Gene', '5743', (57, 61))	('CCA', 'Gene', (66, 69))	('cyclooxygenase-2', 'Gene', (39, 55))	('CCA', 'Gene', '2201', (66, 69))	('cyclooxygenase-2', 'Gene', '5743', (39, 55))	('EGFR', 'Gene', '1956', (0, 4))
53024	24140396	A few studies have assessed the roles of genetic factors, such as chromosome aberrations or genetic and epigenetic alterations in tumor suppressor genes and oncogenes, in pathogenesis of human CCA.	('genetic', 'Var', (92, 99))	('epigenetic alterations', 'Var', (104, 126))	('rat', 'Species', '10116', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('rat', 'Species', '10116', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('human', 'Species', '9606', (187, 192))	('CCA', 'Gene', (193, 196))	('tumor', 'Disease', (130, 135))	('CCA', 'Gene', '2201', (193, 196))
53027	24140396	A meta-analysis of 5 studies that used comparative genomics hybridization to analyze 98 iCCAs found copy number losses at 1p, 4q, 8p, 9p, 17p, and 18q and gains at 1q, 5p, 7p, 8q, 17q, and 20q.	('gains', 'PosReg', (155, 160))	('iCCA', 'Gene', (88, 92))	('rat', 'Species', '10116', (44, 47))	('losses', 'NegReg', (112, 118))	('iCCA', 'Gene', '112476', (88, 92))	('copy number', 'Var', (100, 111))
53030	24140396	Mutations were frequently detected in oncogenes and tumor suppressor genes such as those encoding TP53 (mutations in 44.4% of CCAs), KRAS (16.7%), and SMAD family member 4 (16.7%).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('SMAD', 'Gene', '4089;4089;17128', (151, 155))	('tumor', 'Disease', (52, 57))	('CCA', 'Gene', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('SMAD', 'Gene', (151, 155))	('CCA', 'Gene', '2201', (126, 129))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (133, 137))	('oncogenes', 'Gene', (38, 47))	('TP53', 'Gene', '7157', (98, 102))	('KRAS', 'Gene', '3845', (133, 137))	('detected', 'Reg', (26, 34))	('TP53', 'Gene', (98, 102))
53031	24140396	Mutations were also found in MLL3 (14.8% of cases), RNF43 (9.3%), PEG3 (5.6%), and ROBO2 (9.3%).	('PEG3', 'Gene', (66, 70))	('ROBO2', 'Gene', (83, 88))	('Mutations', 'Var', (0, 9))	('ROBO2', 'Gene', '6092', (83, 88))	('MLL3', 'Gene', '58508', (29, 33))	('PEG3', 'Gene', '5178', (66, 70))	('RNF43', 'Gene', (52, 57))	('RNF43', 'Gene', '54894', (52, 57))	('MLL3', 'Gene', (29, 33))
53038	24140396	Activating mutations in KRAS have been frequently detected in CCAs.	('KRAS', 'Gene', '3845', (24, 28))	('Activating mutations', 'Var', (0, 20))	('CCA', 'Gene', (62, 65))	('CCA', 'Gene', '2201', (62, 65))	('detected', 'Reg', (50, 58))	('KRAS', 'Gene', (24, 28))
53041	24140396	In a transcriptome profile analysis of 104 CCAs and 59 matched non-tumor samples (controls), patients could be categorized based on overall survival time, early recurrence, and presence or absence of KRAS mutations; a detailed class comparison identified 4 subclasses of patients.	('CCA', 'Gene', '2201', (43, 46))	('KRAS', 'Gene', (200, 204))	('CCA', 'Gene', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('mutations', 'Var', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('KRAS', 'Gene', '3845', (200, 204))	('patients', 'Species', '9606', (271, 279))	('tumor', 'Disease', (67, 72))	('patients', 'Species', '9606', (93, 101))
53042	24140396	Those with CCAs with altered expression of genes that regulate proteasome activity; with dysregulation of HER2; and with overexpression of EGFR, MET, and Ki67 had the worst outcomes.	('Ki67', 'Var', (154, 158))	('CCA', 'Gene', (11, 14))	('HER2', 'Gene', (106, 110))	('dysregulation', 'Var', (89, 102))	('EGFR', 'Gene', '1956', (139, 143))	('CCA', 'Gene', '2201', (11, 14))	('HER2', 'Gene', '2064', (106, 110))	('overexpression', 'PosReg', (121, 135))	('EGFR', 'Gene', (139, 143))	('expression', 'MPA', (29, 39))	('altered', 'Reg', (21, 28))
53043	24140396	Inactivation of TP53, which regulates the cell cycle, is one of the most common genetic abnormalities in cancer cells and has also been detected during cholangiocarcinogenesis.	('genetic abnormalities', 'Disease', (80, 101))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('carcinogenesis', 'Disease', 'MESH:D063646', (161, 175))	('TP53', 'Gene', '7157', (16, 20))	('genetic abnormalities', 'Disease', 'MESH:D030342', (80, 101))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('carcinogenesis', 'Disease', (161, 175))	('TP53', 'Gene', (16, 20))	('Inactivation', 'Var', (0, 12))	('detected', 'Reg', (136, 144))
53044	24140396	A review of 10 studies, comprising 229 patients with CCA from Europe, Asia, and the US, reported TP53 mutations in 21% of CCAs.	('CCA', 'Gene', (53, 56))	('patients', 'Species', '9606', (39, 47))	('TP53', 'Gene', '7157', (97, 101))	('CCA', 'Gene', '2201', (53, 56))	('CCA', 'Gene', (122, 125))	('CCA', 'Gene', '2201', (122, 125))	('TP53', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))
53047	24140396	IDH1 and IDH2 mutations have been frequently detected in gliomas but rarely observed in other solid tumors.	('detected', 'Reg', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('IDH2', 'Gene', (9, 13))	('solid tumors', 'Disease', (94, 106))	('solid tumors', 'Disease', 'MESH:D009369', (94, 106))	('IDH2', 'Gene', '3418', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('gliomas', 'Disease', (57, 64))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('IDH1', 'Gene', '3417', (0, 4))
53048	24140396	IDH mutations were detected in 22% of CCA specimens:more frequently in iCCAs (28%) than pCCA and dCCAs (7%).	('dCCAs', 'Chemical', '-', (97, 102))	('IDH', 'Gene', (0, 3))	('CCA', 'Gene', (89, 92))	('CCA', 'Gene', (98, 101))	('pCCA', 'Gene', '5095', (88, 92))	('iCCA', 'Gene', (71, 75))	('CCA', 'Gene', '2201', (89, 92))	('CCA', 'Gene', '2201', (98, 101))	('IDH', 'Gene', '3417', (0, 3))	('iCCA', 'Gene', '112476', (71, 75))	('pCCA', 'Gene', (88, 92))	('CCA', 'Gene', '2201', (38, 41))	('CCA', 'Gene', (38, 41))	('CCA', 'Gene', (72, 75))	('mutations', 'Var', (4, 13))	('CCA', 'Gene', '2201', (72, 75))
53049	24140396	Recurrent mutations in IDH1 were observed in a subset of biliary tract tumors samples in a recent broad-based mutation profile analysis of gastrointestinal tumors.	('biliary tract tumors', 'Disease', (57, 77))	('biliary tract tumors', 'Disease', 'MESH:D001661', (57, 77))	('observed', 'Reg', (33, 41))	('IDH1', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('IDH1', 'Gene', '3417', (23, 27))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (139, 162))	('gastrointestinal tumors', 'Disease', (139, 162))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('mutations', 'Var', (10, 19))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (139, 162))	('biliary tract tumors', 'Phenotype', 'HP:0100574', (57, 77))
53050	24140396	A subsequent analysis of 62 CCAs detected IDH1 mutations in only iCCAs.	('iCCA', 'Gene', '112476', (65, 69))	('IDH1', 'Gene', '3417', (42, 46))	('mutations', 'Var', (47, 56))	('CCA', 'Gene', (66, 69))	('CCA', 'Gene', (28, 31))	('CCA', 'Gene', '2201', (66, 69))	('iCCA', 'Gene', (65, 69))	('CCA', 'Gene', '2201', (28, 31))	('IDH1', 'Gene', (42, 46))
53051	24140396	IDH1 and IDH2 mutations were significantly associated with increased levels of p53 and DNA hypermethylation.	('IDH2', 'Gene', (9, 13))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('IDH2', 'Gene', '3418', (9, 13))	('IDH1', 'Gene', (0, 4))	('DNA hypermethylation', 'MPA', (87, 107))	('increased', 'PosReg', (59, 68))	('mutations', 'Var', (14, 23))	('IDH1', 'Gene', '3417', (0, 4))
53052	24140396	Epigenetic changes associated with IDH mutations likely mediate their oncogenic effects.	('IDH', 'Gene', (35, 38))	('Epigenetic changes', 'Var', (0, 18))	('IDH', 'Gene', '3417', (35, 38))	('mutations', 'Var', (39, 48))
53053	24140396	The product of the enzymatic activity of mutant IDH1 and IDH2 is 2-hydroxyglutarate (Figure 2A).	('IDH1', 'Gene', '3417', (48, 52))	('mutant', 'Var', (41, 47))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (65, 83))	('IDH2', 'Gene', (57, 61))	('IDH2', 'Gene', '3418', (57, 61))	('2-hydroxyglutarate', 'MPA', (65, 83))	('IDH1', 'Gene', (48, 52))
53054	24140396	This metabolite might therefore serve as a biomarker for IDH1 and IDH2 mutations, and for a subset of patients that might be treated with IDH inhibitors(Figure 2B).	('IDH', 'Gene', '3417', (57, 60))	('IDH', 'Gene', (66, 69))	('IDH2', 'Gene', '3418', (66, 70))	('IDH', 'Gene', (138, 141))	('IDH', 'Gene', '3417', (66, 69))	('patients', 'Species', '9606', (102, 110))	('IDH', 'Gene', '3417', (138, 141))	('IDH1', 'Gene', (57, 61))	('mutations', 'Var', (71, 80))	('IDH1', 'Gene', '3417', (57, 61))	('IDH2', 'Gene', (66, 70))	('IDH', 'Gene', (57, 60))
53057	24140396	Promoter hypermethylation has been reported to silence tumor suppressor genes including CDKN2 (observed in 17%-83% of CCAs), SOCS3 (in 62%), RASSF1A (in 31%-69%), and APC (in 27%-47%).	('CDKN2', 'Gene', '1029', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CDKN2', 'Gene', (88, 93))	('silence', 'NegReg', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('APC', 'Disease', 'MESH:D011125', (167, 170))	('APC', 'Disease', (167, 170))	('RASSF1A', 'Gene', (141, 148))	('SOCS3', 'Gene', '9021', (125, 130))	('tumor', 'Disease', (55, 60))	('SOCS3', 'Gene', (125, 130))	('RASSF1A', 'Gene', '11186', (141, 148))	('CCA', 'Gene', (118, 121))	('CCA', 'Gene', '2201', (118, 121))	('Promoter hypermethylation', 'Var', (0, 25))
53059	24140396	A recent study identified novel FGFR2 gene fusions in CCA.	('CCA', 'Gene', (54, 57))	('CCA', 'Gene', '2201', (54, 57))	('FGFR2', 'Gene', (32, 37))	('fusions', 'Var', (43, 50))	('FGFR2', 'Gene', '2263', (32, 37))
53064	24140396	Further studies are needed to determine how alterations in miRs contribute to development of CCA, and how these changes might be used to determine patients' prognoses.	('contribute', 'Reg', (64, 74))	('patients', 'Species', '9606', (147, 155))	('alterations', 'Var', (44, 55))	('CCA', 'Gene', '2201', (93, 96))	('CCA', 'Gene', (93, 96))	('miRs', 'Protein', (59, 63))	('rat', 'Species', '10116', (48, 51))
53075	24140396	Wnt-inducible signaling pathway protein 1v (WISP1v) is overexpressed in stroma nests around CCAs, and levels of WISP1v are associated with reduced survival times of patients.	('survival times', 'CPA', (147, 161))	('WISP1', 'Gene', '8840', (44, 49))	('CCA', 'Gene', (92, 95))	('levels', 'Var', (102, 108))	('CCA', 'Gene', '2201', (92, 95))	('WISP1', 'Gene', (112, 117))	('WISP1', 'Gene', (44, 49))	('overexpressed', 'PosReg', (55, 68))	('patients', 'Species', '9606', (165, 173))	('reduced', 'NegReg', (139, 146))	('WISP1', 'Gene', '8840', (112, 117))
53087	24140396	Based on combined evidence, alphaSMA-expressing CAFs appear to be a heterogeneous population of cells that originate from several cell lineages, but not from epithelial cancer cells.	('epithelial cancer', 'Disease', (158, 175))	('alphaSMA-expressing', 'Var', (28, 47))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('epithelial cancer', 'Phenotype', 'HP:0031492', (158, 175))	('CAF', 'Gene', (48, 51))	('epithelial cancer', 'Disease', 'MESH:D000077216', (158, 175))	('CAF', 'Gene', '8850', (48, 51))
53095	24140396	Knockdown of the periostin receptor, the alpha 5 subunit of integrin, with small interfering RNA reduced stimulation of tumor proliferation and invasion by periostin.	('small interfering', 'Var', (75, 92))	('invasion', 'CPA', (144, 152))	('rat', 'Species', '10116', (133, 136))	('tumor', 'Disease', (120, 125))	('periostin', 'Gene', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('periostin', 'Gene', '10631', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('periostin', 'Gene', '10631', (156, 165))	('RNA', 'Gene', (93, 96))	('periostin', 'Gene', (156, 165))
53108	24140396	Animal models of CCA (Table 1) include mice with xenograft tumors,  mice with genetic changes that lead to CCA formation, rats with orthotopic tumors, and animals that develop CCAs following exposure to carcinogens.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('CCA', 'Gene', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('mice', 'Species', '10090', (68, 72))	('rats', 'Species', '10116', (122, 126))	('CCA', 'Gene', (17, 20))	('orthotopic tumors', 'Disease', 'MESH:D009369', (132, 149))	('xenograft tumors', 'Disease', (49, 65))	('CCA', 'Gene', (176, 179))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('xenograft tumors', 'Disease', 'MESH:D009369', (49, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('CCA', 'Gene', '2201', (107, 110))	('orthotopic tumors', 'Disease', (132, 149))	('develop', 'Reg', (168, 175))	('CCA', 'Gene', '2201', (17, 20))	('changes', 'Var', (86, 93))	('CCA', 'Gene', '2201', (176, 179))	('mice', 'Species', '10090', (39, 43))
53114	24140396	Animals with genetic alterations that lead to production of CCAs that resemble human tumors are needed.	('CCA', 'Gene', (60, 63))	('human', 'Species', '9606', (79, 84))	('CCA', 'Gene', '2201', (60, 63))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('rat', 'Species', '10116', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('genetic alterations', 'Var', (13, 32))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
53127	24140396	In these cases, immunohistochemical analysis for cytokeratins 7 and 19 can be useful:tumors positive for cytokeratins can be considered to be mixed hepatocellular-CCA.	('rat', 'Species', '10116', (55, 58))	('rat', 'Species', '10116', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cytokeratins', 'Var', (105, 117))	('CCA', 'Gene', '2201', (163, 166))	('tumors', 'Disease', (85, 91))	('CCA', 'Gene', (163, 166))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
53157	24140396	Detection of polysomy by FISH also been shown to predict the development of malignancies in patients with PSC with no mass and equivocal cytology.	('malignancies', 'Disease', (76, 88))	('PSC', 'Gene', '100653366', (106, 109))	('patients', 'Species', '9606', (92, 100))	('PSC', 'Gene', (106, 109))	('malignancies', 'Disease', 'MESH:D009369', (76, 88))	('polysomy', 'Var', (13, 21))	('predict', 'Reg', (49, 56))
53158	24140396	In a recent study, patients with PSC who had polysomy and levels of CA 19-9 greater than 129 U/ml all went on to develop cancer, mainly within 2 y (Figure 5).	('polysomy', 'Var', (45, 53))	('patients', 'Species', '9606', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('PSC', 'Gene', '100653366', (33, 36))	('develop', 'PosReg', (113, 120))	('cancer', 'Disease', (121, 127))	('PSC', 'Gene', (33, 36))
53187	24140396	Potential therapeutic targets could include the MET tyrosine receptor kinase, the PI3K-Akt-mTOR pathway, and IDH mutations.	('Akt', 'Gene', (87, 90))	('mTOR', 'Gene', '2475', (91, 95))	('mutations', 'Var', (113, 122))	('mTOR', 'Gene', (91, 95))	('IDH', 'Gene', (109, 112))	('Akt', 'Gene', '207', (87, 90))	('MET tyrosine receptor kinase', 'Enzyme', (48, 76))	('IDH', 'Gene', '3417', (109, 112))
53188	24140396	Molecular profiling of tumors, to identify their specific mutations, could make it possible to offer targeted therapiesin personalized treatments (Figure 2B).	('mutations', 'Var', (58, 67))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
53206	31901228	The following exclusion criteria were applied: (1) non-curative-intent surgery such as bypass surgery, (2) surgery without liver resection, and (3) R2 resection (macroscopic residual tumor).	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('R2 resection', 'Var', (148, 160))	('bypass surgery', 'Disease', (87, 101))
53242	31901228	On the other hand, transfusion (2.81 [1.30-6.05], P = 0.008) and LVI (3.22 [1.35-7.63], P = 0.008) were significantly associated with RFS; the same variables were independent risk factors in multivariate analysis (2.82 [1.28-6.20], P = 0.01, and 3.33 [1.34-8.23], P = 0.009, respectively, Table 3).	('RFS', 'Gene', (134, 137))	('transfusion', 'Var', (19, 30))	('RFS', 'Gene', '65211', (134, 137))	('associated', 'Reg', (118, 128))
53261	31901228	Resection of the jaundiced liver could lead to severe morbidity and mortality.	('lead to', 'Reg', (39, 46))	('Resection', 'Var', (0, 9))	('jaundice', 'Phenotype', 'HP:0000952', (17, 25))	('jaundiced liver', 'Disease', 'MESH:D007565', (17, 32))	('jaundiced liver', 'Disease', (17, 32))
53297	31248095	We also used a 0.035-inch hydrophilic guidewire (M00556051; Boston Scientific Corporation, Natick, MA, USA) and/or a 0.025-inch hydrophilic guidewire (G-260-2545A; Olympus Optical Co., Ltd. MTA0025N48S; Medico's Hirata, Inc, Osaka, Japan.	('G-260-2545A', 'Var', (151, 162))	('G-260-2545A', 'SUBSTITUTION', 'None', (151, 162))	('MTA0025N48S', 'Var', (190, 201))
53442	26559312	By comparison, a cross-sectional study of 53 IgG4-SC patients found that mean serum IgG4 level is 516 +- 98 mg/dL (mean +- SE), and the level over 280 mg/dL accounts for up to 50%.	('IgG4', 'Protein', (84, 88))	('516 +- 98 mg/dL', 'Var', (98, 113))	('patients', 'Species', '9606', (53, 61))
53557	26018028	The results showed an increase in the phosphorylation levels of ERK1/2, AMPKalpha, mTOR, HSP27, Bad, PRAS40, p38 and SAPK/JNK in the hypoxic cells compared with those in normoxic cells (P<0.05) (Fig.	('JNK', 'Gene', '5599', (122, 125))	('mTOR', 'Gene', (83, 87))	('PRAS40', 'Gene', '84335', (101, 107))	('mTOR', 'Gene', '2475', (83, 87))	('p38', 'Gene', '5594', (109, 112))	('increase', 'PosReg', (22, 30))	('HSP27', 'Gene', (89, 94))	('ERK1/2', 'Gene', '5595;5594', (64, 70))	('ERK1/2', 'Gene', (64, 70))	('PRAS40', 'Gene', (101, 107))	('SAPK', 'Gene', (117, 121))	('hypoxic', 'Var', (133, 140))	('SAPK', 'Gene', '5601', (117, 121))	('AMPKalpha', 'MPA', (72, 81))	('Bad', 'MPA', (96, 99))	('phosphorylation levels', 'MPA', (38, 60))	('p38', 'Gene', (109, 112))	('JNK', 'Gene', (122, 125))	('HSP27', 'Gene', '3315', (89, 94))
53561	26018028	A significant decrease in cell invasion was identified in cells treated with U0126 compared to that of the control (P<0.05) (Fig.	('U0126', 'Chemical', 'MESH:C113580', (77, 82))	('cell invasion', 'CPA', (26, 39))	('decrease', 'NegReg', (14, 22))	('U0126', 'Var', (77, 82))
53584	26018028	The levels of HIF-1alpha were correlated with phosphoinositide-dependent kinase-1, lactate dehydrogenase A and pyruvate kinase, muscle 2 expression and inhibition of HIF-1alpha repressed pancreatic cancer cell growth.	('HIF-1alpha', 'Gene', '3091', (166, 176))	('HIF-1alpha repressed pancreatic cancer', 'Disease', (166, 204))	('lactate dehydrogenase A', 'Gene', (83, 106))	('pyruvate kinase', 'MPA', (111, 126))	('HIF-1alpha', 'Gene', (14, 24))	('HIF-1alpha repressed pancreatic cancer', 'Disease', 'MESH:D010190', (166, 204))	('lactate dehydrogenase A', 'Gene', '3939', (83, 106))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (187, 204))	('phosphoinositide-dependent', 'MPA', (46, 72))	('HIF-1alpha', 'Gene', (166, 176))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('HIF-1alpha', 'Gene', '3091', (14, 24))	('inhibition', 'Var', (152, 162))
53591	26018028	A previous study demonstrated an involvement of Met in cholangiocarcinoma cell lines by showing that inhibition of Met and ERK activation significantly reduced cell invasion abilities.	('cell invasion abilities', 'CPA', (160, 183))	('inhibition', 'Var', (101, 111))	('cholangiocarcinoma cell', 'Disease', (55, 78))	('Met', 'Protein', (115, 118))	('ERK', 'Gene', '5594', (123, 126))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (55, 78))	('reduced', 'NegReg', (152, 159))	('ERK', 'Gene', (123, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('activation', 'PosReg', (127, 137))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (55, 73))
53596	26018028	Overexpression of this receptor was reported in numerous types of solid tumor and is associated with malignant disease.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('reported', 'Reg', (36, 44))	('malignant disease', 'Disease', 'MESH:D009369', (101, 118))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('malignant disease', 'Disease', (101, 118))	('associated', 'Reg', (85, 95))
53618	19405942	We measured the level of CEA, CA19-9, MMP-7 and MMP-9 in the serum of 44 cholangiocarcinoma and 36 benign biliary tract diseases patients.	('MMP-9', 'Gene', '4318', (48, 53))	('CEA', 'Gene', '1084', (25, 28))	('MMP-7', 'Gene', '4316', (38, 43))	('MMP-9', 'Gene', (48, 53))	('patients', 'Species', '9606', (129, 137))	('CA19-9', 'Var', (30, 36))	('cholangiocarcinoma', 'Disease', (73, 91))	('MMP-7', 'Gene', (38, 43))	('benign biliary tract diseases', 'Disease', (99, 128))	('biliary tract diseases', 'Phenotype', 'HP:0001080', (106, 128))	('benign biliary tract diseases', 'Disease', 'MESH:D001660', (99, 128))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (73, 91))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (73, 91))	('CEA', 'Gene', (25, 28))	('biliary tract disease', 'Phenotype', 'HP:0001080', (106, 127))
53639	19405942	An increase in the serum level of CA19-9 can be detected even in benign bile duct diseases.	('serum level', 'MPA', (19, 30))	('benign bile duct diseases', 'Disease', 'MESH:D001649', (65, 90))	('CA19-9', 'Var', (34, 40))	('bile duct disease', 'Phenotype', 'HP:0001080', (72, 89))	('increase', 'PosReg', (3, 11))	('benign bile duct diseases', 'Disease', (65, 90))
53664	19405942	The median CEA and CA19-9 values in the cholangiocarcinoma group were 8.27 ng/ml (range; 0.85-131.70) and 2176.00 U/ml (range; 0.50-10000.00), respectively.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (40, 58))	('CEA', 'Gene', '1084', (11, 14))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (40, 58))	('CA19-9', 'MPA', (19, 25))	('CEA', 'Gene', (11, 14))	('cholangiocarcinoma', 'Disease', (40, 58))	('2176.00 U/ml', 'Var', (106, 118))
53673	19405942	The sensitivity and specificity for CEA, CA19-9, MMP-9 and MMP-7 are presented in Table 2.	('CEA', 'Gene', (36, 39))	('MMP-9', 'Gene', (49, 54))	('MMP-7', 'Gene', (59, 64))	('MMP-9', 'Gene', '4318', (49, 54))	('CEA', 'Gene', '1084', (36, 39))	('CA19-9', 'Var', (41, 47))	('MMP-7', 'Gene', '4316', (59, 64))
53676	19405942	In a multivariable model using MMP-9 (cut-off value = 15 ng/ml), MMP-7 (cut-off value = 7.4 ng/ml), CEA (cut-off value = 5 ng/ml), CA19-9 (cut-off value = 100 U/ml), MMP-9 (an adjusted odds ratio = 3.76; 95% CI = 1.05-13.47; p = 0.04), MMP-7 (an adjusted odds ratio = 5.33; 95% CI = 1.55-18.31; p = 0.008) and CA19-9 (an adjusted odds ratio = 4.60; 95% CI = 1.23-17.30; p = 0.02) were the independent predictors of cholangiocarcinoma, whereas CEA was not.	('CA19-9', 'Var', (310, 316))	('CEA', 'Gene', '1084', (100, 103))	('cholangiocarcinoma', 'Disease', (415, 433))	('CEA', 'Gene', '1084', (443, 446))	('MMP-9', 'Gene', '4318', (31, 36))	('MMP-7', 'Gene', (236, 241))	('MMP-9', 'Gene', '4318', (166, 171))	('MMP-7', 'Gene', (65, 70))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (415, 433))	('MMP-9', 'Gene', (31, 36))	('MMP-7', 'Gene', '4316', (236, 241))	('MMP-9', 'Gene', (166, 171))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (415, 433))	('CEA', 'Gene', (443, 446))	('MMP-7', 'Gene', '4316', (65, 70))	('CEA', 'Gene', (100, 103))
53708	19405942	Previous studies determined that expression of MMP-7 in cholangiocarcinoma is an unfavorable postoperative prognostic factor for cholangiocarcinoma patients.	('patients', 'Species', '9606', (148, 156))	('MMP-7', 'Gene', (47, 52))	('expression', 'Var', (33, 43))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (129, 147))	('cholangiocarcinoma', 'Disease', (56, 74))	('MMP-7', 'Gene', '4316', (47, 52))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (129, 147))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (56, 74))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (56, 74))	('cholangiocarcinoma', 'Disease', (129, 147))
53795	33330039	Case Report: BAP1 Mutation and RAD21 Amplification as Predictive Biomarkers to PARP Inhibitor in Metastatic Intrahepatic Cholangiocarcinoma Intrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer characterized by a poor prognosis and a limited response to conventional therapies.	('Intrahepatic Cholangiocarcinoma', 'Disease', (108, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (153, 171))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('BAP1', 'Gene', (13, 17))	('RAD21', 'Gene', '5885', (31, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('Intrahepatic cholangiocarcinoma', 'Disease', (140, 171))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('PARP', 'Gene', (79, 83))	('Intrahepatic Cholangiocarcinoma', 'Disease', 'MESH:D018281', (108, 139))	('BAP1', 'Gene', '8314', (13, 17))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('cancer', 'Disease', (202, 208))	('Mutation', 'Var', (18, 26))	('Intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (140, 171))	('RAD21', 'Gene', (31, 36))	('PARP', 'Gene', '142', (79, 83))
53800	33330039	Several lines of evidences indicate that PARP inhibitor administration might be an effective treatment in presence of BAP1 and/or RAD21 alterations since both BAP1 and RAD21 are involved in the DNA repair pathway, BAP1 interacts with BRCA1 and BRCA1-mediated DNA repair pathway alterations enhance the sensitivity to PARP inhibitor administration.	('PARP', 'Gene', '142', (317, 321))	('alterations', 'Var', (278, 289))	('BRCA1', 'Gene', (234, 239))	('PARP', 'Gene', (41, 45))	('alterations', 'Var', (136, 147))	('RAD21', 'Gene', (130, 135))	('PARP', 'Gene', (317, 321))	('RAD21', 'Gene', '5885', (130, 135))	('RAD21', 'Gene', (168, 173))	('PARP', 'Gene', '142', (41, 45))	('enhance', 'PosReg', (290, 297))	('BRCA1-mediated', 'Gene', (244, 258))	('RAD21', 'Gene', '5885', (168, 173))
53805	33330039	These findings have clinical relevance since we have shown PARP inhibitor as a potential treatment for ICC patients harboring BAP1 deletion and RAD21 amplification.	('ICC', 'Disease', (103, 106))	('BAP1', 'Gene', (126, 130))	('PARP', 'Gene', (59, 63))	('RAD21', 'Gene', (144, 149))	('PARP', 'Gene', '142', (59, 63))	('RAD21', 'Gene', '5885', (144, 149))	('patients', 'Species', '9606', (107, 115))	('deletion', 'Var', (131, 139))
53806	33330039	We have also highlighted the utility of NGS platforms to identify targetable mutations within a cancer.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
53816	33330039	FGFR kinase inhibitors have demonstrated anti-tumor activity in ICC patients harboring activating FGFR2 gene fusions.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('fusions', 'Var', (109, 116))	('ICC', 'Disease', (64, 67))	('patients', 'Species', '9606', (68, 76))	('activating', 'PosReg', (87, 97))	('FGFR2', 'Gene', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
53818	33330039	Here, we describe the case of a chemorefractory patient with ICC harboring BAP1 mutation and RAD21 amplification.	('RAD21', 'Gene', '5885', (93, 98))	('BAP1', 'Gene', (75, 79))	('RAD21', 'Gene', (93, 98))	('patient', 'Species', '9606', (48, 55))	('mutation', 'Var', (80, 88))
53825	33330039	Ultrasound guided biopsy of the liver mass demonstrated ICC (CK7+, CK19+, HepPar1-, AFP-).	('CK19+', 'Var', (67, 72))	('ICC', 'Disease', (56, 59))	('AF', 'Disease', 'MESH:D001281', (84, 86))	('Hep', 'CellLine', 'CVCL:1906', (74, 77))
53828	33330039	Genomic analysis of NRAS, KRAS and BRAF V600 by polymerase chain reaction (PCR) sequencing, as well as immunohistochemical (IHC) staining for detection of HER2 amplification were performed on ICC tumor tissue.	('BRAF V600', 'Var', (35, 44))	('ICC tumor', 'Disease', (192, 201))	('ICC tumor', 'Disease', 'MESH:C566123', (192, 201))	('NRAS', 'Gene', (20, 24))	('KRAS', 'Gene', (26, 30))	('KRAS', 'Gene', '3845', (26, 30))	('NRAS', 'Gene', '4893', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
53834	33330039	An IHC analysis of ROS1 rearrangements and NTRK fusions did not demonstrate any alterations ( Supplementary Table 2 ).	('ROS1', 'Gene', (19, 23))	('rearrangements', 'Var', (24, 38))	('NTRK', 'Gene', (43, 47))	('ROS1', 'Gene', '6098', (19, 23))
53835	33330039	A Short Tandem Repeat (STR) analysis by PCR of BAT25, BAT26, D2S123, D5S346, D17S250, NR-21, and MONO-27 showed a Microsatellite Stable (MSS) tumor profile.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('D17S250', 'Var', (77, 84))	('tumor', 'Disease', (142, 147))	('D2S123', 'Var', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('D5S346', 'Var', (69, 75))
53842	33330039	In contrast the Foundation One CDx demonstrated the presence of a deletion in BAP1 (splice site c.581-17_585del22) and amplification of RAD21.	('CDx', 'Chemical', '-', (31, 34))	('RAD21', 'Gene', (136, 141))	('RAD21', 'Gene', '5885', (136, 141))	('c.581-17_585del22', 'Mutation', 'c.581-17_585del22', (96, 113))	('deletion', 'Var', (66, 74))	('BAP1', 'Gene', (78, 82))
53843	33330039	Analysis of BAP1 by sanger sequencing on primary ICC tumor tissue confirmed the presence of BAP1 (splice site 581-17_585del22) alteration ( Figure 3 ).	('ICC tumor', 'Disease', 'MESH:C566123', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('alteration', 'Var', (127, 137))	('ICC tumor', 'Disease', (49, 58))	('581-17_585del22', 'Mutation', 'c.581-17_585del22', (110, 125))	('BAP1', 'Gene', (92, 96))
53844	33330039	Because of the involvement of RAD21 in the DNA repair pathway, the interaction of BAP1 with BRCA1 and the enhanced sensitivity to PARP inhibitor administration in presence of alterations in the BRCA1-mediated DNA repair pathway, it was decided first to treat the patient with FOLFIRI every 2 weeks [irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-fluorouracil (5-FU) 400 mg/m2 intravenous infusion bolus, then 5-FU 2400 mg/m2 intravenous infusion over 46 h] and then to start a PARP inhibitor.	('PARP', 'Gene', '142', (478, 482))	('patient', 'Species', '9606', (263, 270))	('FOLFIRI', 'Chemical', '-', (276, 283))	('PARP', 'Gene', (130, 134))	('involvement', 'Reg', (15, 26))	('RAD21', 'Gene', (30, 35))	('PARP', 'Gene', (478, 482))	('PARP', 'Gene', '142', (130, 134))	('interaction', 'Interaction', (67, 78))	('5-FU', 'Chemical', 'MESH:D005472', (361, 365))	('5-FU', 'Chemical', 'MESH:D005472', (410, 414))	('RAD21', 'Gene', '5885', (30, 35))	('irinotecan', 'Chemical', 'MESH:D000077146', (299, 309))	('alterations', 'Var', (175, 186))
53852	33330039	The current clinical case has provided for the first-time evidence that ICC patients carrying a BAP1 deletion and RAD21 amplification might benefit from a PARP inhibitor treatment.	('RAD21', 'Gene', (114, 119))	('deletion', 'Var', (101, 109))	('benefit', 'PosReg', (140, 147))	('patients', 'Species', '9606', (76, 84))	('PARP', 'Gene', '142', (155, 159))	('BAP1', 'Gene', (96, 100))	('RAD21', 'Gene', '5885', (114, 119))	('PARP', 'Gene', (155, 159))
53854	33330039	Germline heterozygous mutations in BAP1 cause an autosomal dominant condition known as BAP1-cancer syndrome which confers a high susceptibility to the development of several malignancies including mesothelioma, uveal melanoma, renal, cholangio and breast carcinomas.	('BAP1-cancer syndrome', 'Disease', (87, 107))	('breast carcinomas', 'Disease', 'MESH:D001943', (248, 265))	('breast carcinomas', 'Disease', (248, 265))	('BAP1', 'Gene', (35, 39))	('Germline heterozygous mutations', 'Var', (0, 31))	('malignancies', 'Disease', 'MESH:D009369', (174, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('cause', 'Reg', (40, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (255, 265))	('malignancies', 'Disease', (174, 186))	('cholangio', 'Disease', (234, 243))	('uveal melanoma', 'Phenotype', 'HP:0007716', (211, 225))	('breast carcinomas', 'Phenotype', 'HP:0003002', (248, 265))	('susceptibility', 'Reg', (129, 143))	('breast carcinoma', 'Phenotype', 'HP:0003002', (248, 264))	('melanoma', 'Disease', 'MESH:D008545', (217, 225))	('mesothelioma', 'Disease', (197, 209))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mesothelioma', 'Disease', 'MESH:D008654', (197, 209))	('renal', 'Disease', (227, 232))	('BAP1-cancer syndrome', 'Disease', 'MESH:D009369', (87, 107))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('melanoma', 'Disease', (217, 225))
53855	33330039	In the clinical case we have described, we identified a novel mutation in BAP1 (c.581-17_585del22).	('c.581-17_585del22', 'Var', (80, 97))	('BAP1', 'Gene', (74, 78))	('c.581-17_585del22', 'Mutation', 'c.581-17_585del22', (80, 97))
53859	33330039	Protein function impairment by c.581-17_585del22 is most likely to reflect a deletion in the 3'-splice site of BAP1.	('Protein function', 'MPA', (0, 16))	('impairment', 'NegReg', (17, 27))	('c.581-17_585del22', 'Var', (31, 48))	('deletion', 'Var', (77, 85))	('BAP1', 'Gene', (111, 115))	('c.581-17_585del22', 'Mutation', 'c.581-17_585del22', (31, 48))
53861	33330039	As BAP1 interacts with BRCA1, several lines of evidence indicate that alterations in the BRCA-mediated DNA repair pathway confers sensitivity to PARP inhibitor administration.	('alterations', 'Var', (70, 81))	('BRCA', 'Gene', (89, 93))	('PARP', 'Gene', '142', (145, 149))	('BRCA', 'Gene', '672', (23, 27))	('sensitivity', 'MPA', (130, 141))	('BRCA', 'Gene', (23, 27))	('PARP', 'Gene', (145, 149))	('BRCA', 'Gene', '672', (89, 93))
53862	33330039	PARP inhibitors act through synthetic lethality, whereby genetic DNA repair defects are enhanced by drug-induced defects in a compensatory pathway.	('genetic', 'Var', (57, 64))	('defects', 'NegReg', (76, 83))	('PARP', 'Gene', '142', (0, 4))	('PARP', 'Gene', (0, 4))	('enhanced', 'PosReg', (88, 96))
53863	33330039	Carriers of heterozygous BRCA1/2 mutations are sensitive to PARP inhibitor treatment as they lose the wild-type allele during tumorigenesis and thereby become deficient of the homologous recombination (HR) pathway of double-strand break DNA repair by BRCA1/2-null status.	('lose', 'NegReg', (93, 97))	('BRCA1/2', 'Gene', '672;675', (251, 258))	('BRCA1/2', 'Gene', '672;675', (25, 32))	('PARP', 'Gene', (60, 64))	('PARP', 'Gene', '142', (60, 64))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('wild-type', 'MPA', (102, 111))	('deficient', 'NegReg', (159, 168))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('BRCA1/2', 'Gene', (25, 32))	('BRCA1/2', 'Gene', (251, 258))	('tumor', 'Disease', (126, 131))
53865	33330039	In 2014, olaparib was approved as maintenance therapy for platinum-sensitive advanced ovarian cancer with germline mutations in BRCA1/2.	('advanced ovarian cancer', 'Disease', (77, 100))	('germline', 'Var', (106, 114))	('BRCA1/2', 'Gene', (128, 135))	('advanced ovarian cancer', 'Disease', 'MESH:D020178', (77, 100))	('BRCA1/2', 'Gene', '672;675', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('olaparib', 'Chemical', 'MESH:C531550', (9, 17))	('platinum', 'Chemical', 'MESH:D010984', (58, 66))
53866	33330039	In 2016, rucaparib was approved for advanced ovarian cancer with both germline and somatic BRCA1/2 mutations.	('BRCA1/2', 'Gene', (91, 98))	('advanced ovarian cancer', 'Disease', 'MESH:D020178', (36, 59))	('ovarian cancer', 'Phenotype', 'HP:0100615', (45, 59))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('BRCA1/2', 'Gene', '672;675', (91, 98))	('rucaparib', 'Chemical', 'MESH:C531549', (9, 18))	('advanced ovarian cancer', 'Disease', (36, 59))
53868	33330039	Last, in 2018, olaparib and talazoparib were approved for HER2-negative locally advanced or metastatic breast cancer with germline BRCA1/2 mutations.	('mutations', 'Var', (139, 148))	('BRCA1/2', 'Gene', (131, 138))	('talazoparib', 'Chemical', 'MESH:C586365', (28, 39))	('locally advanced', 'Disease', (72, 88))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('BRCA1/2', 'Gene', '672;675', (131, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('olaparib', 'Chemical', 'MESH:C531550', (15, 23))
53870	33330039	It has become clear that any form of HR deficiency in tumors that phenocopies BRCA1/2 mutations, often referred to as BRCAness, may sensitize cells to PARP inhibitors.	('HR deficiency in tumors', 'Disease', 'MESH:D001919', (37, 60))	('mutations', 'Var', (86, 95))	('sensitize', 'Reg', (132, 141))	('BRCAness', 'Disease', (118, 126))	('PARP', 'Gene', (151, 155))	('BRCAness', 'Disease', 'None', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('BRCA1/2', 'Gene', (78, 85))	('HR deficiency in tumors', 'Disease', (37, 60))	('PARP', 'Gene', '142', (151, 155))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('BRCA1/2', 'Gene', '672;675', (78, 85))
53871	33330039	Indeed mutations in DNA damage response genes such as ATM, PRKDC, ATR, RPA1, DSS1, NBN, RAD51, RAD54, CHEK1, CHEK2, FANC genes, ERCC1, POLB, FEN1, and CDK12 have shown synthetic lethality in combination with PARP inhibitors.	('CHEK2', 'Gene', (109, 114))	('ATR', 'Gene', '545', (66, 69))	('RAD51', 'Gene', (88, 93))	('ATM', 'Gene', '472', (54, 57))	('RAD51', 'Gene', '5888', (88, 93))	('POLB', 'Gene', (135, 139))	('CDK12', 'Gene', (151, 156))	('RPA1', 'Gene', '6117', (71, 75))	('RAD54', 'Gene', '8438', (95, 100))	('synthetic lethality', 'CPA', (168, 187))	('RPA1', 'Gene', (71, 75))	('FEN1', 'Gene', (141, 145))	('mutations', 'Var', (7, 16))	('DNA damage response genes', 'Gene', (20, 45))	('NBN', 'Gene', '4683', (83, 86))	('DSS1', 'Gene', (77, 81))	('ATM', 'Gene', (54, 57))	('CHEK1', 'Gene', (102, 107))	('POLB', 'Gene', '5423', (135, 139))	('PARP', 'Gene', '142', (208, 212))	('DSS1', 'Gene', '7979', (77, 81))	('ATR', 'Gene', (66, 69))	('ERCC1', 'Gene', (128, 133))	('PRKDC', 'Gene', '5591', (59, 64))	('PARP', 'Gene', (208, 212))	('PRKDC', 'Gene', (59, 64))	('RAD54', 'Gene', (95, 100))	('FANC genes', 'Gene', (116, 126))	('NBN', 'Gene', (83, 86))
53874	33330039	Some studies on various types of BAP1 mutated cancer cell lines demonstrated the potential efficacy of PARP inhibitors.	('mutated', 'Var', (38, 45))	('PARP', 'Gene', '142', (103, 107))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('PARP', 'Gene', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
53876	33330039	As a result, PARP inhibitors are currently under investigation alone or in combination with other therapies in cancer patients harboring a BAP1 mutant tumor including ICC (ClinicalTrials.gov Identifier: NCT03207347, NCT03786796, NCT03531840, and NCT03375307).	('BAP1', 'Gene', (139, 143))	('NCT03531840', 'Var', (229, 240))	('PARP', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('NCT03786796', 'Var', (216, 227))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', (151, 156))	('PARP', 'Gene', '142', (13, 17))	('ICC', 'Disease', (167, 170))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('mutant', 'Var', (144, 150))	('NCT03375307', 'Var', (246, 257))	('patients', 'Species', '9606', (118, 126))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
53885	33330039	In addition to BAP1 mutations, many other molecular alterations have been described in ICC such as KRAS, BRAF, IDH1, IDH2, EGFR, FGFR2, ROS1, ARID1A, PBRM1, and BRCA1.	('BRCA1', 'Gene', (161, 166))	('PBRM1', 'Gene', (150, 155))	('ICC', 'Disease', (87, 90))	('ROS1', 'Gene', (136, 140))	('IDH2', 'Gene', '3418', (117, 121))	('KRAS', 'Gene', '3845', (99, 103))	('ROS1', 'Gene', '6098', (136, 140))	('IDH1', 'Gene', '3417', (111, 115))	('PBRM1', 'Gene', '55193', (150, 155))	('KRAS', 'Gene', (99, 103))	('IDH2', 'Gene', (117, 121))	('BAP1', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))	('IDH1', 'Gene', (111, 115))
53886	33330039	In the current clinical case, BAP1 mutation is not associated with KRAS, BRAF, IDH1, IDH2, EGFR, FGFR2, ROS1, ARID1A, PBRM1, and BRCA1 alterations but with a RAD21 amplification.	('IDH1', 'Gene', '3417', (79, 83))	('BAP1', 'Gene', (30, 34))	('PBRM1', 'Gene', '55193', (118, 123))	('KRAS', 'Gene', (67, 71))	('IDH2', 'Gene', '3418', (85, 89))	('ROS1', 'Gene', (104, 108))	('IDH2', 'Gene', (85, 89))	('RAD21', 'Gene', (158, 163))	('ROS1', 'Gene', '6098', (104, 108))	('mutation', 'Var', (35, 43))	('KRAS', 'Gene', '3845', (67, 71))	('IDH1', 'Gene', (79, 83))	('PBRM1', 'Gene', (118, 123))	('RAD21', 'Gene', '5885', (158, 163))	('BRCA1', 'Gene', (129, 134))
53888	33330039	Amplification of RAD21 is described in approximately 1.23% of cases reported in the AACR Project Genomics Evidence Neoplasia Information Exchange (AACR Project GENIE), including invasive breast carcinoma, prostate adenocarcinoma, lung adenocarcinoma and colon adenocarcinoma having the greatest prevalence.	('invasive breast carcinoma', 'Disease', 'MESH:D001943', (178, 203))	('Neoplasia', 'Disease', 'MESH:D009369', (115, 124))	('Amplification', 'Var', (0, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('breast carcinoma', 'Phenotype', 'HP:0003002', (187, 203))	('prostate adenocarcinoma', 'Disease', (205, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))	('invasive breast carcinoma', 'Disease', (178, 203))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (205, 228))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (230, 249))	('lung adenocarcinoma and colon adenocarcinoma', 'Disease', 'MESH:D000077192', (230, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('Neoplasia', 'Phenotype', 'HP:0002664', (115, 124))	('RAD21', 'Gene', (17, 22))	('RAD21', 'Gene', '5885', (17, 22))	('Neoplasia', 'Disease', (115, 124))
53890	33330039	Whether RAD21 amplification might enhance the activity of a PARP inhibitor in BAP1 mutant ICC should be further investigated.	('RAD21', 'Gene', (8, 13))	('mutant', 'Var', (83, 89))	('enhance', 'PosReg', (34, 41))	('PARP', 'Gene', (60, 64))	('PARP', 'Gene', '142', (60, 64))	('RAD21', 'Gene', '5885', (8, 13))	('activity', 'MPA', (46, 54))	('BAP1', 'Gene', (78, 82))
53895	33330039	These findings are likely to reflect the different methods utilized to detect potentially oncogenic alterations, the regions of the genes included in the analysis, the potential tumor heterogeneity especially with a low allele frequency of the variants and the percentage of tumor cells in the sample tested.	('tumor', 'Disease', (178, 183))	('variants', 'Var', (244, 252))	('tumor', 'Disease', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
53896	33330039	In our case the novel mutation c.581-17_585del22 of BAP1 was localized on exon 8 of BAP1, at the boundary of intron 7.	('BAP1', 'Gene', (52, 56))	('BAP1', 'Gene', (84, 88))	('c.581-17_585del22', 'Var', (31, 48))	('c.581-17_585del22', 'Mutation', 'c.581-17_585del22', (31, 48))
53897	33330039	However the Oncofocus  Test did not detect the c.581-17_585del22 alteration of BAP1 alteration most likely because this region of the gene was not included in the analysis.	('c.581-17_585del22', 'Var', (47, 64))	('c.581-17_585del22', 'Mutation', 'c.581-17_585del22', (47, 64))	('BAP1', 'Gene', (79, 83))
53900	33330039	As limit of detection range at non-homopolymer context (insertion up to 42 bp and deletion up to 276 bp) is 6-10%, we can assume that the BAP1 c.581-17_585del mutated allele was present with a higher variant fraction in the metastatic tumor tissue analyzed.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('BAP1 c.581-17_585del mutated', 'Var', (138, 166))	('tumor', 'Disease', (235, 240))	('c.581-17_585del', 'Mutation', 'c.581-17_585del', (143, 158))
53902	33330039	Therefore, we can assume that BAP1 c.581-17_585del mutated allele occurred with a high allele frequency, early in ICC oncogenesis.	('c.581-17_585del mutated', 'Var', (35, 58))	('ICC', 'Disease', (114, 117))	('BAP1', 'Gene', (30, 34))	('c.581-17_585del', 'Mutation', 'c.581-17_585del', (35, 50))
53904	33330039	Specifically, BAP1 deletion and RAD21 amplification were identified and effectively targeted by PARP inhibitor administration.	('RAD21', 'Gene', (32, 37))	('PARP', 'Gene', (96, 100))	('BAP1', 'Gene', (14, 18))	('deletion', 'Var', (19, 27))	('RAD21', 'Gene', '5885', (32, 37))	('PARP', 'Gene', '142', (96, 100))
53905	33330039	These results warrant further studies to define the role of PARP inhibitor in ICC harboring BAP1 and RAD21 alterations.	('RAD21', 'Gene', (101, 106))	('RAD21', 'Gene', '5885', (101, 106))	('alterations', 'Var', (107, 118))	('PARP', 'Gene', (60, 64))	('PARP', 'Gene', '142', (60, 64))	('ICC', 'Disease', (78, 81))	('BAP1', 'Gene', (92, 96))
53931	26972709	Aberrant methylation of Wnt pathway genes has been reported in IHCC leading to beta-catenin stabilization and abnormally high levels of Wnt signaling.	('Aberrant', 'Var', (0, 8))	('reported', 'Reg', (51, 59))	('beta-catenin', 'Gene', '1499', (79, 91))	('Wnt pathway genes', 'Gene', (24, 41))	('IHCC', 'Disease', (63, 67))	('methylation', 'MPA', (9, 20))	('beta-catenin', 'Gene', (79, 91))
53990	26972709	The percentage of patients expressing nuclear TCF4 was significantly higher in the HCCA group (86.5%) than the IHCC (64.5%, P<0.001) and CCC groups (41.9%, P<0.001; Figure 4).	('TCF4', 'Gene', (46, 50))	('TCF4', 'Gene', '6925', (46, 50))	('nuclear', 'Var', (38, 45))	('HCCA', 'Disease', (83, 87))	('patients', 'Species', '9606', (18, 26))	('higher', 'PosReg', (69, 75))
54030	26972709	Despite their common pathologic features, the differences in the level of Wnt pathway activation between the IHCC and HCCA groups implies that there may be different molecular mechanisms driving oncogenesis, such as mutations of p53 and K-ras.	('K-ras', 'Gene', '3845', (237, 242))	('Wnt pathway', 'Pathway', (74, 85))	('p53', 'Gene', '7157', (229, 232))	('p53', 'Gene', (229, 232))	('mutations', 'Var', (216, 225))	('K-ras', 'Gene', (237, 242))
54151	30177781	Cases were classified as ICC using ICD-O-3 morphology codes of 8032-8033, 8041, 8050, 8070-8071, 8140-8141, 8160, 8260, 8480, 8481, 8490, and 8560.	('ICC', 'Disease', 'MESH:C535533', (25, 28))	('8260', 'Var', (114, 118))	('8490', 'Var', (132, 136))	('8050', 'Var', (80, 84))	('8560', 'Var', (142, 146))	('8480', 'Var', (120, 124))	('8032-8033', 'Var', (63, 72))	('8160', 'Var', (108, 112))	('ICC', 'Disease', (25, 28))	('ICD-O-3', 'Chemical', 'MESH:C517075', (35, 42))	('8070-8071', 'Var', (86, 95))	('8041', 'Var', (74, 78))	('8140-8141', 'Var', (97, 106))	('8481', 'Var', (126, 130))
54215	30177781	Excess adiposity can cause chronic, low-grade systemic inflammation through decreased adiponectin levels and increased levels of TNF-alpha, IL-6, leptin, free fatty acids, and TLR4.	('TLR4', 'Gene', '7099', (176, 180))	('adiponectin', 'Gene', (86, 97))	('fatty acids', 'Chemical', 'MESH:D005227', (159, 170))	('decreased adiponectin', 'Phenotype', 'HP:0030685', (76, 97))	('Excess adiposity', 'Phenotype', 'HP:0009126', (0, 16))	('decreased', 'NegReg', (76, 85))	('leptin', 'MPA', (146, 152))	('TNF-alpha', 'Gene', '7124', (129, 138))	('inflammation', 'Disease', 'MESH:D007249', (55, 67))	('TLR4', 'Gene', (176, 180))	('IL-6', 'Gene', (140, 144))	('TNF-alpha', 'Gene', (129, 138))	('IL-6', 'Gene', '3569', (140, 144))	('free fatty acids', 'MPA', (154, 170))	('increased', 'PosReg', (109, 118))	('Excess', 'Var', (0, 6))	('adiponectin', 'Gene', '9370', (86, 97))	('inflammation', 'Disease', (55, 67))
54255	28789429	The present study demonstrated that the inhibition of p53 enhanced the sensitivity to chemotherapeutic agents in nutrient-deprived cholangiocarcinoma cells.	('inhibition', 'Var', (40, 50))	('enhanced', 'PosReg', (58, 66))	('p53', 'Gene', (54, 57))	('cholangiocarcinoma', 'Disease', (131, 149))	('p53', 'Gene', '7157', (54, 57))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (131, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))	('sensitivity to chemotherapeutic agents', 'MPA', (71, 109))
54261	28789429	Autophagy may be induced by p53 via transcription-dependent or independent pathways, whereas inhibiting the activity of p53 has also been demonstrated to be sufficient to activate autophagy.	('p53', 'Gene', (28, 31))	('activate', 'PosReg', (171, 179))	('activity', 'MPA', (108, 116))	('p53', 'Gene', '7157', (28, 31))	('p53', 'Gene', '7157', (120, 123))	('autophagy', 'CPA', (180, 189))	('inhibiting', 'Var', (93, 103))	('Autophagy', 'CPA', (0, 9))	('p53', 'Gene', (120, 123))
54307	28789429	QBC939 cells were treated with 3MA for 1 h and then incubated with 5FU or cisplatin for 12 h. The rate of cell death was significantly increased in the combination groups (3MA plus CDDP or 5FU), compared with the 5FU or CDDP group, as assessed by cell morphology (Fig.	('CDDP', 'Chemical', 'MESH:D002945', (220, 224))	('CDDP', 'Chemical', 'MESH:D002945', (181, 185))	('3MA', 'Chemical', 'MESH:C025946', (172, 175))	('3MA', 'Chemical', 'MESH:C025946', (31, 34))	('5FU', 'Chemical', 'MESH:D005472', (67, 70))	('5FU', 'Chemical', 'MESH:D005472', (189, 192))	('QBC939', 'CellLine', 'CVCL:6942', (0, 6))	('cell death', 'CPA', (106, 116))	('increased', 'PosReg', (135, 144))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('5FU', 'Chemical', 'MESH:D005472', (213, 216))	('3MA', 'Var', (172, 175))
54322	28789429	In the present study, the results indicated that p53 is associated with the induction of autophagy during nutrient deprivation; inhibition of p53 was observed to result in the deactivation of autophagy and increased chemosensitivity in nutrient-deprived cholangiocarcinoma cells.	('chemosensitivity', 'CPA', (216, 232))	('cholangiocarcinoma', 'Disease', (254, 272))	('p53', 'Gene', (49, 52))	('increased', 'PosReg', (206, 215))	('p53', 'Gene', (142, 145))	('p53', 'Gene', '7157', (49, 52))	('p53', 'Gene', '7157', (142, 145))	('deactivation', 'NegReg', (176, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (254, 272))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (254, 272))	('inhibition', 'Var', (128, 138))	('autophagy', 'CPA', (192, 201))
54326	28789429	A number of studies have shown that autophagy contributes to chemoresistance and that the inhibition of autophagy enhances chemosensitivity in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('autophagy', 'CPA', (104, 113))	('chemoresistance', 'CPA', (61, 76))	('cancer', 'Disease', (143, 149))	('inhibition', 'Var', (90, 100))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('autophagy', 'CPA', (36, 45))	('enhances', 'PosReg', (114, 122))	('chemosensitivity', 'CPA', (123, 139))
54337	28789429	In conclusion, the data reveals that p53 contributes to cell survival in nutrient-deprived conditions and that the inhibition of p53 increases the chemosensitivity of cholangiocarcinoma cells.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (167, 185))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (167, 185))	('p53', 'Gene', (37, 40))	('increases', 'PosReg', (133, 142))	('p53', 'Gene', (129, 132))	('inhibition', 'Var', (115, 125))	('cholangiocarcinoma', 'Disease', (167, 185))	('chemosensitivity of', 'CPA', (147, 166))	('p53', 'Gene', '7157', (129, 132))	('p53', 'Gene', '7157', (37, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
54338	28789429	Although mutations to p53 are detected in up to 50% of all human tumors, the remainder of tumors maintain the expression of wild-type p53.	('human', 'Species', '9606', (59, 64))	('p53', 'Gene', '7157', (134, 137))	('mutations', 'Var', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('p53', 'Gene', (22, 25))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', (90, 96))	('p53', 'Gene', '7157', (22, 25))	('expression', 'MPA', (110, 120))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('p53', 'Gene', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
54493	22794276	This epigenetic modification affects tumor suppressor genes involved in regulation pathways, cell cycle control, cell adhesion and extracellular matrix degradation, in a sequential and cumulative way.	('cell adhesion', 'CPA', (113, 126))	('epigenetic modification', 'Var', (5, 28))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('extracellular matrix degradation', 'CPA', (131, 163))	('affects', 'Reg', (29, 36))	('regulation pathways', 'Pathway', (72, 91))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('cell cycle', 'CPA', (93, 103))
54517	22794276	Many tumor suppressor genes are silenced by DNA methylation during carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (67, 81))	('carcinogenesis', 'Disease', (67, 81))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('silenced', 'NegReg', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('DNA methylation', 'Var', (44, 59))	('tumor', 'Disease', (5, 10))
54518	22794276	Genes that show oncogenic properties, that is, that exhibit a methylated promoter region in normal cells, can become reactivated in cancer cells by the loss of this methylation, resulting in hypomethylation.	('methylated promoter', 'MPA', (62, 81))	('cancer', 'Disease', (132, 138))	('loss', 'NegReg', (152, 156))	('methylation', 'Var', (165, 176))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('hypomethylation', 'MPA', (191, 206))
54519	22794276	In general, the chromosomal instability, loss of imprint, reactivation of transposable elements and transcriptional silencing of tumor suppressor genes or oncogene activation are of great benefit to the tumor cell.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('chromosomal', 'Var', (16, 27))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('loss', 'NegReg', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('chromosomal instability', 'Phenotype', 'HP:0040012', (16, 39))	('tumor', 'Disease', (129, 134))	('imprint', 'MPA', (49, 56))	('reactivation', 'Var', (58, 70))
54524	22794276	reported that genes TWIST1HOXA1SFRP1PENKGRIN2BCDH13NEUROG1TMEFF2TIMP3MINT2CCND2RASSF1ARUNX3DLC1CRABP1GATA3MT1GSEZ6LSOCS3THBS1 and BCL2 were significantly methylated in extrahepatic cholangiocarcinoma (EHC) tissue samples, at higher levels than in cholecystitis and cholangitis tissues.	('cholecystitis', 'Disease', 'MESH:D002764', (247, 260))	('BCL2', 'Gene', (130, 134))	('methylated', 'Var', (154, 164))	('cholangitis', 'Disease', 'MESH:D002761', (265, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('TWIST1HOXA1SFRP1', 'Gene', (20, 36))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (168, 199))	('TWIST1HOXA1SFRP1', 'Gene', '7291', (20, 36))	('cholangitis', 'Disease', (265, 276))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (181, 199))	('cholangitis', 'Phenotype', 'HP:0030151', (265, 276))	('cholecystitis', 'Disease', (247, 260))	('BCL2', 'Gene', '596', (130, 134))	('extrahepatic cholangiocarcinoma', 'Disease', (168, 199))	('cholecystitis', 'Phenotype', 'HP:0001082', (247, 260))
54527	22794276	Nevertheless, studies have established that aberrant hypermethylation is an important event in the carcinogenesis of GBC (Table 1).	('GBC', 'Disease', (117, 120))	('aberrant hypermethylation', 'Var', (44, 69))	('carcinogenesis', 'Disease', (99, 113))	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))
54531	22794276	In addition, both of them found that the methylation state of DLC1 was an indicator of poor prognosis, and methylation of MGMT is correlated with better survival.	('correlated with', 'Reg', (130, 145))	('DLC1', 'Gene', '10395', (62, 66))	('methylation', 'MPA', (41, 52))	('DLC1', 'Gene', (62, 66))	('MGMT', 'Gene', (122, 126))	('better', 'PosReg', (146, 152))	('methylation', 'Var', (107, 118))	('MGMT', 'Gene', '4255', (122, 126))
54533	22794276	Epigenetic inactivation by methylation in chromosome 3p is a frequent event in patients with GBC, particularly affecting the promoter region of the tumor suppressor genes SEMA3B (3p21.3) and FHIT (3p14.2) with 92% and 66% methylation, respectively.	('promoter region', 'MPA', (125, 140))	('FHIT', 'Gene', '2272', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('GBC', 'Disease', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('p14', 'Gene', '1029', (198, 201))	('tumor', 'Disease', (148, 153))	('p14', 'Gene', (198, 201))	('methylation', 'Var', (27, 38))	('FHIT', 'Gene', (191, 195))	('patients', 'Species', '9606', (79, 87))	('affecting', 'Reg', (111, 120))	('Epigenetic inactivation', 'Var', (0, 23))	('SEMA3B', 'Gene', '7869', (171, 177))	('SEMA3B', 'Gene', (171, 177))
54535	22794276	Epigenetic silencing in this gene has been reported in different human tumors, such as in lung, breast, brain, prostate, pancreas and kidney cancers.	('kidney cancers', 'Phenotype', 'HP:0009726', (134, 148))	('human', 'Species', '9606', (65, 70))	('breast', 'Disease', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung', 'Disease', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Epigenetic silencing', 'Var', (0, 20))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('pancreas and kidney cancers', 'Disease', 'MESH:D010190', (121, 148))	('tumors', 'Disease', (71, 77))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('reported', 'Reg', (43, 51))	('prostate', 'Disease', (111, 119))	('brain', 'Disease', (104, 109))
54537	22794276	When RASSF1A methylation was correlated with immunohistochemical expression, weak or no staining of the tumor cells was observed.	('RASSF1A', 'Gene', '11186', (5, 12))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('methylation', 'Var', (13, 24))	('tumor', 'Disease', (104, 109))	('RASSF1A', 'Gene', (5, 12))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
54538	22794276	The methylation frequency of this gene in cholangiocarcinoma can reach 65%, which, despite the close anatomical relationship with GBC, has different methylation patterns.	('cholangiocarcinoma', 'Disease', (42, 60))	('methylation', 'Var', (4, 15))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (42, 60))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (42, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
54553	22794276	Some mutations of this gene have been detected in gastric, breast and endometrial cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('detected', 'Reg', (38, 46))	('endometrial cancer', 'Phenotype', 'HP:0012114', (70, 88))	('mutations', 'Var', (5, 14))	('breast and endometrial cancer', 'Disease', 'MESH:D016889', (59, 88))	('gastric', 'Disease', (50, 57))
54561	22794276	Therefore, there is a significant correlation between the methylation of CDH1 and the metastatic phenotype in GBC, which has already been described in previous studies on breast cancer.	('metastatic phenotype', 'CPA', (86, 106))	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('GBC', 'Disease', (110, 113))	('CDH1', 'Gene', (73, 77))	('breast cancer', 'Disease', (171, 184))	('CDH1', 'Gene', '999', (73, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('methylation', 'Var', (58, 69))
54562	22794276	Hypermethylation of CDH1 has been reported in two cell lines of biliary tract cancer (SNU-478 and SNU-1079), with silenced mRNA expression.	('biliary tract cancer', 'Disease', 'MESH:D001661', (64, 84))	('biliary tract cancer', 'Disease', (64, 84))	('reported', 'Reg', (34, 42))	('Hypermethylation', 'Var', (0, 16))	('CDH1', 'Gene', '999', (20, 24))	('mRNA', 'MPA', (123, 127))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (64, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('CDH1', 'Gene', (20, 24))
54565	22794276	The loss of p16 expression is usually connected to homozygote deletion, loss of heterozygosity, mutations and methylation.	('p16', 'Gene', '1029', (12, 15))	('loss of heterozygosity', 'Var', (72, 94))	('methylation', 'Var', (110, 121))	('p16', 'Gene', (12, 15))	('loss', 'NegReg', (4, 8))	('expression', 'MPA', (16, 26))	('mutations', 'Var', (96, 105))
54567	22794276	Loss of heterozygosity and homozygote deletion are two different pathways of p16 inactivation and have been shown to be combined with hypermethylation of the promoter in GBC.	('p16', 'Gene', (77, 80))	('Loss of heterozygosity', 'Var', (0, 22))	('p16', 'Gene', '1029', (77, 80))	('deletion', 'Var', (38, 46))	('inactivation', 'NegReg', (81, 93))
54568	22794276	In hepatocellular carcinoma and intrahepatic cholangiocarcinoma, p16 is frequently inactivated by methylation of the promoter and rarely by deletion or mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('p16', 'Gene', '1029', (65, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('methylation', 'Var', (98, 109))	('inactivated', 'NegReg', (83, 94))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (32, 63))	('p16', 'Gene', (65, 68))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (45, 63))	('intrahepatic cholangiocarcinoma', 'Disease', (32, 63))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
54569	22794276	Inactivation of p16 through methylation of the promoter region has been frequently identified in breast, prostate, head and neck, liver, lung, brain, colon and esophageal cancers and cell lines of bladder cancer .	('prostate', 'Disease', (105, 113))	('bladder cancer', 'Disease', (197, 211))	('bladder cancer', 'Disease', 'MESH:D001749', (197, 211))	('identified', 'Reg', (83, 93))	('liver', 'Disease', (130, 135))	('p16', 'Gene', '1029', (16, 19))	('breast', 'Disease', (97, 103))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('methylation', 'Var', (28, 39))	('colon and esophageal cancers', 'Disease', 'MESH:D004938', (150, 178))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('brain', 'Disease', (143, 148))	('Inactivation', 'NegReg', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('p16', 'Gene', (16, 19))	('bladder cancer', 'Phenotype', 'HP:0009725', (197, 211))	('lung', 'Disease', (137, 141))
54572	22794276	Hypermethylation of CDKN2A is also one of the main mechanisms that induce the loss of p16 expression.	('Hypermethylation', 'Var', (0, 16))	('p16', 'Gene', (86, 89))	('loss', 'NegReg', (78, 82))	('expression', 'MPA', (90, 100))	('CDKN2A', 'Gene', (20, 26))	('CDKN2A', 'Gene', '1029', (20, 26))	('p16', 'Gene', '1029', (86, 89))
54576	22794276	The absence of alterations in p16 (methylation, mutation, loss of heterozygosity in chromosome 9p) in cases of GBC means a better overall survival rate, and it is thus considered a significant prognostic factor.	('p16', 'Gene', (30, 33))	('better', 'PosReg', (123, 129))	('loss', 'Var', (58, 62))	('p16', 'Gene', '1029', (30, 33))	('mutation', 'Var', (48, 56))
54577	22794276	A similar relationship has been seen in patients with stage IA non-small cell lung cancer, where the hypermethylation of p16 was related to poorer survival.	('p16', 'Gene', '1029', (121, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (67, 89))	('patients', 'Species', '9606', (40, 48))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (63, 89))	('hypermethylation', 'Var', (101, 117))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (63, 89))	('p16', 'Gene', (121, 124))	('non-small cell lung cancer', 'Disease', (63, 89))	('poorer', 'NegReg', (140, 146))
54581	22794276	The transcriptional repression of Reprimo by methylation was initially confirmed together with other genes in pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('pancreatic cancer', 'Disease', (110, 127))	('pancreatic cancer', 'Disease', 'MESH:D010190', (110, 127))	('methylation', 'Var', (45, 56))	('Reprimo', 'Gene', (34, 41))	('Reprimo', 'Gene', '56475', (34, 41))
54582	22794276	In addition, it was found to be hypermethylated in 16 different types of tumors, with a high percentage in gastric cancer (79%), gallbladder cancer (62%), lymphoma (57%), colorectal cancer (56%), esophageal adenocarcinoma (40%), breast cancer (37%) and leukemia (31%).	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('lymphoma', 'Disease', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (196, 221))	('breast cancer', 'Disease', 'MESH:D001943', (229, 242))	('lymphoma', 'Disease', 'MESH:D008223', (155, 163))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (196, 221))	('tumors', 'Disease', (73, 79))	('breast cancer', 'Disease', (229, 242))	('colorectal cancer', 'Phenotype', 'HP:0003003', (171, 188))	('leukemia', 'Phenotype', 'HP:0001909', (253, 261))	('esophageal adenocarcinoma', 'Disease', (196, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('gastric cancer', 'Disease', (107, 121))	('gallbladder cancer', 'Disease', (129, 147))	('leukemia', 'Disease', (253, 261))	('leukemia', 'Disease', 'MESH:D007938', (253, 261))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('hypermethylated', 'Var', (32, 47))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('colorectal cancer', 'Disease', 'MESH:D015179', (171, 188))	('lymphoma', 'Phenotype', 'HP:0002665', (155, 163))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (133, 147))	('colorectal cancer', 'Disease', (171, 188))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('gallbladder cancer', 'Disease', 'MESH:D005706', (129, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))
54586	22794276	UCHL1 (also known as PGP9.5) is the only gene with a potential oncogenic role that has found to be hypomethylated in the promoter region in GBC.	('PGP9.5', 'Gene', '7345', (21, 27))	('UCHL1', 'Gene', '7345', (0, 5))	('PGP9.5', 'Gene', (21, 27))	('hypomethylated', 'Var', (99, 113))	('UCHL1', 'Gene', (0, 5))
54595	22794276	These results suggest that hypomethylation of the PGP9.5 promoter is a reliable marker in GBC and that DNA hypomethylation might play a significant role in the re-expression of the gene in GBC.	('GBC', 'Disease', (90, 93))	('hypomethylation', 'Var', (27, 42))	('PGP9.5', 'Gene', '7345', (50, 56))	('PGP9.5', 'Gene', (50, 56))	('marker', 'Reg', (80, 86))
54596	22794276	In addition, hypomethylation of UCHL1 had previously been found in its promoter region in colorectal cancer, and lymph node metastasis was significantly associated with a lower frequency of methylation, poorer survival and a high incidence of recurrence.	('hypomethylation', 'Var', (13, 28))	('UCHL1', 'Gene', '7345', (32, 37))	('poorer', 'NegReg', (203, 209))	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('lymph', 'Disease', (113, 118))	('UCHL1', 'Gene', (32, 37))	('methylation', 'MPA', (190, 201))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('found', 'Reg', (58, 63))	('colorectal cancer', 'Disease', (90, 107))	('lower', 'NegReg', (171, 176))
54597	22794276	DNA methylation is the epigenetic alteration most studied in the cancer cell.	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('methylation', 'Var', (4, 15))	('DNA methylation', 'Var', (0, 15))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
54599	22794276	The methylation frequency of promoter regions of some important tumor suppressor genes, such as p16CDH1REPRIMODAPK-1 and SEMA3B, is high in GBC, and has also been well documented in other cancers.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('high', 'Reg', (132, 136))	('tumor', 'Disease', (64, 69))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('p16CDH1REPRIMODAPK-1', 'Var', (96, 116))	('SEMA3B', 'Gene', (121, 127))	('SEMA3B', 'Gene', '7869', (121, 127))	('methylation frequency', 'MPA', (4, 25))	('cancers', 'Disease', (188, 195))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('GBC', 'Disease', (140, 143))
54600	22794276	The tumor suppressor gene p16 is frequently inactivated in a wide variety of human cancers by at least three distinct mechanisms: point mutation, small deletions of both p16 alleles, and methylation of CpG islands.	('tumor', 'Disease', (4, 9))	('p16', 'Gene', (26, 29))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('p16', 'Gene', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('p16', 'Gene', '1029', (170, 173))	('p16', 'Gene', '1029', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('methylation', 'Var', (187, 198))	('point mutation', 'Var', (130, 144))	('small deletions', 'Var', (146, 161))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))
54601	22794276	Other studies have found methylation of the p16 promoter in two of eight (25%) cholangiocarcinomas, and four of seven (57%) tumors analyzed by immunohistochemistry, demonstrated an absence of p16 nuclear staining in primary sclerosing cholangitis-associated cholangiocarcinoma.	('cholangitis', 'Phenotype', 'HP:0030151', (235, 246))	('p16', 'Gene', (44, 47))	('cholangiocarcinoma', 'Disease', (258, 276))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (79, 98))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (258, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('p16', 'Gene', '1029', (44, 47))	('cholangiocarcinomas', 'Disease', (79, 98))	('p16', 'Gene', (192, 195))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (79, 97))	('absence', 'NegReg', (181, 188))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('p16', 'Gene', '1029', (192, 195))	('cholangiocarcinoma', 'Disease', (79, 97))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cholangitis', 'Disease', 'MESH:D002761', (235, 246))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (79, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('tumors', 'Disease', (124, 130))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (224, 246))	('cholangitis', 'Disease', (235, 246))	('nuclear staining', 'MPA', (196, 212))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (258, 276))	('methylation', 'Var', (25, 36))	('tumors', 'Disease', 'MESH:D009369', (124, 130))
54602	22794276	Also, a high frequency of methylation (36 out of 72; 50%) has been reported in cases of intrahepatic and extrahepatic cholangiocarcinoma.	('methylation', 'Var', (26, 37))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (118, 136))	('reported', 'Reg', (67, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('intrahepatic and extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 136))
54603	22794276	The expression of E-cadherin frequently diminishes as the tumor progresses, and abnormalities of E-cadherin expression have been associated with decreased apoptosis in GBC and genomic instability during the process of neoplastic transformation.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('abnormalities', 'Var', (80, 93))	('genomic instability', 'CPA', (176, 195))	('E-cadherin', 'Gene', (97, 107))	('E-cadherin', 'Gene', '999', (97, 107))	('expression', 'MPA', (4, 14))	('decreased', 'NegReg', (145, 154))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('expression', 'MPA', (108, 118))	('GBC', 'Disease', (168, 171))	('diminishes', 'NegReg', (40, 50))	('apoptosis', 'CPA', (155, 164))	('E-cadherin', 'Gene', (18, 28))	('E-cadherin', 'Gene', '999', (18, 28))
54604	22794276	In cholangiocarcinoma, mutations of CDH1 are rare events.	('cholangiocarcinoma', 'Disease', (3, 21))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('mutations', 'Var', (23, 32))	('CDH1', 'Gene', (36, 40))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('CDH1', 'Gene', '999', (36, 40))
54605	22794276	Downregulation of E-cadherin expression is more commonly mediated through DNA methylation, with frequencies between 40% and 48%, while in GBC the frequency is between 11% and 65%.	('Downregulation', 'NegReg', (0, 14))	('DNA methylation', 'Var', (74, 89))	('expression', 'MPA', (29, 39))	('E-cadherin', 'Gene', (18, 28))	('E-cadherin', 'Gene', '999', (18, 28))
54609	22794276	E-cadherin methylation is an early event in gastric carcinogenesis, and is initiated by H. pylori infection.	('H. pylori', 'Disease', (88, 97))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (44, 66))	('infection', 'Disease', 'MESH:D007239', (98, 107))	('H. pylori infection', 'Phenotype', 'HP:0005202', (88, 107))	('methylation', 'Var', (11, 22))	('gastric carcinogenesis', 'Disease', (44, 66))	('E-cadherin', 'Gene', (0, 10))	('E-cadherin', 'Gene', '999', (0, 10))	('initiated', 'Reg', (75, 84))	('H. pylori', 'Species', '210', (88, 97))	('infection', 'Disease', (98, 107))
54617	22794276	Hypomethylation of its promoter has been identified in a subset of human cancers, including GBC, presumably due to its intrinsic oncogenic properties or as a result of transformation.	('cancers', 'Disease', (73, 80))	('identified', 'Reg', (41, 51))	('Hypomethylation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('GBC', 'Disease', (92, 95))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
54618	22794276	However, UCHL1 has been reported to be repressed by methylation in other cancers, such as primary head and neck squamous cell carcinoma and colorectal, ovarian and pancreatic cancers.	('cancers', 'Disease', (73, 80))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (164, 182))	('UCHL1', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (164, 181))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('methylation', 'Var', (52, 63))	('cancers', 'Disease', (175, 182))	('UCHL1', 'Gene', '7345', (9, 14))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('neck squamous cell carcinoma and colorectal, ovarian and pancreatic cancers', 'Disease', 'MESH:D010190', (107, 182))
54626	22794276	Therefore, the study of gene methylation has at least five potential clinical applications: reactivating genes inactivated by methylation using demethylating drugs; identifying tumor cells in biological samples, allowing an early diagnosis since the change in methylation frequently precedes the appearance of advanced tumors; determining the methylation of individual genes or methylation profiles for groups of specific genes; being used as response markers to chemo- or hormone therapy; and allowing the transition between neoplastic and normal tissue to be determined in the surgical section margins according to the gene methylation profile.	('tumor', 'Disease', (319, 324))	('tumors', 'Disease', 'MESH:D009369', (319, 325))	('tumors', 'Disease', (319, 325))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('tumors', 'Phenotype', 'HP:0002664', (319, 325))	('tumor', 'Disease', (177, 182))	('change', 'Var', (250, 256))
54627	22794276	Finally, the reversible nature of the epigenetic changes that occur in cancer must be mentioned as these have made epigenetic therapy possible as a treatment option.	('cancer', 'Disease', (71, 77))	('epigenetic changes', 'Var', (38, 56))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
54628	22794276	This therapy is based on reversing the epigenetic modifications that occur in tumor cells and re-establishing a normal epigenome.	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('epigenetic', 'Var', (39, 49))	('tumor', 'Disease', (78, 83))
54629	22794276	The possibility of reversing DNA methylation and reactivating the affected genes is an attractive option for a new therapeutic target in the treatment of cancer or preneoplastic lesions.	('preneoplastic lesions', 'Disease', (164, 185))	('reactivating', 'Var', (49, 61))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('preneoplastic lesions', 'Disease', 'MESH:D011230', (164, 185))
54630	22794276	Nevertheless, satisfactory results have been reported regarding the use of epigenetic therapy in patients with myelodysplastic syndrome, approved by the Food and Drug Administration in 2004.	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (111, 135))	('epigenetic therapy', 'Var', (75, 93))	('myelodysplastic syndrome', 'Disease', (111, 135))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (111, 135))	('patients', 'Species', '9606', (97, 105))
54643	28638453	There was no significant difference in OS between patients with c-MET overexpression compared to those without (13.7 vs. 14.4 months, respectively; p=0.708).	('overexpression', 'Var', (70, 84))	('c-MET', 'Gene', '4233', (64, 69))	('patients', 'Species', '9606', (50, 58))	('c-MET', 'Gene', (64, 69))
54664	28638453	MET IHC was performed using the rabbit monoclonal primary antibody CONFIRM anti-total MET (SP44) (Ventana Medical Systems, Tucson, AZ, USA) and the Ventana BenchMark XT automated slide processing system (Ventana Medical Systems) according to the manufacturer's protocol.	('rabbit', 'Species', '9986', (32, 38))	('anti-total', 'Var', (75, 85))	('MET (SP44', 'Gene', (86, 95))
54679	28638453	There was no a significant difference in OS between patients with c-MET overexpression and those without (13.7 vs. 14.4 months, respectively; p=0.708) (Fig 2).	('c-MET', 'Gene', '4233', (66, 71))	('c-MET', 'Gene', (66, 71))	('patients', 'Species', '9606', (52, 60))	('overexpression', 'Var', (72, 86))
54690	28638453	Positive MET expression is significantly associated with poor prognosis in patients with IHCC, but not EHCC.	('Positive', 'Var', (0, 8))	('patients', 'Species', '9606', (75, 83))	('IHCC', 'Disease', (89, 93))
54691	28638453	Multiple studies have suggested that MET overexpression is associated with poor survival in various cancers, including IHCC.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('IHCC', 'Disease', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('poor', 'NegReg', (75, 79))	('MET', 'Var', (37, 40))	('overexpression', 'PosReg', (41, 55))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
54699	28638453	reported potent anti-tumor activity of LY2801653, a small molecule inhibitor with potent activity against MET kinase, in xenograft model using human intra- and extrahepatic cholangiocarcinoma cell lines.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (173, 191))	('human', 'Species', '9606', (143, 148))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (160, 191))	('tumor', 'Disease', (21, 26))	('LY2801653', 'Var', (39, 48))	('LY2801653', 'Chemical', 'MESH:C586252', (39, 48))	('extrahepatic cholangiocarcinoma', 'Disease', (160, 191))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
54725	26448923	After performing laparoscopic hepatoduodenal lymphadenectomy using ultrasonic shears (Harmonic scalpel, Ethicon, Cincinnati, OH, USA), the common bile duct was transected at the level of the superior border above the pancreas and the distal margin was evaluated using a frozen biopsy.	('transected', 'Var', (160, 170))	('pancreas', 'Disease', (217, 225))	('pancreas', 'Disease', 'MESH:D010190', (217, 225))
54770	24948044	Quantitative methylation specific PCR (qMSP) of colorectal cancer (n = 164) and normal colorectal mucosa (n = 106) samples showed that all genes were frequently methylated in colorectal cancer (71-92%) with little or no methylation in normal mucosa (0-3%).	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('colorectal cancer', 'Phenotype', 'HP:0003003', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('colorectal cancer', 'Disease', (175, 192))	('colorectal mucosa', 'Disease', 'MESH:D015179', (87, 104))	('methylated', 'Var', (161, 171))	('colorectal cancer', 'Disease', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('colorectal mucosa', 'Disease', (87, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (48, 65))
54771	24948044	Methylation of minimum two of these five genes identified 95% of the tumors with a specificity of 98%, and an area under the receiver operating characteristics curve (AUC) of 0.98.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Methylation', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))
54775	24948044	In conclusion, the high methylation frequency of these genes in colorectal- as well as in gastric-, pancreatic- and bile duct cancer confirmed an epigenetic similarity between gastrointestinal cancer types, and simultaneously demonstrated their potential as biomarkers, particularly for colorectal cancer detection.	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (176, 199))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('pancreatic- and bile duct cancer', 'Disease', 'MESH:D001650', (100, 132))	('colorectal cancer', 'Disease', (287, 304))	('epigenetic', 'Var', (146, 156))	('gastric-', 'Disease', (90, 98))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (176, 199))	('colorectal cancer', 'Disease', 'MESH:D015179', (287, 304))	('bile duct cancer', 'Phenotype', 'HP:0030153', (116, 132))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('colorectal-', 'Disease', (64, 75))	('gastrointestinal cancer', 'Disease', (176, 199))	('methylation frequency', 'Var', (24, 45))	('colorectal cancer', 'Phenotype', 'HP:0003003', (287, 304))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
54779	24948044	Methylation patterns in these genes may therefore provide biomarkers that are especially promising for colorectal cancer detection, with a high combined sensitivity (95%) and specificity (98%).	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('Methylation patterns', 'Var', (0, 20))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('colorectal cancer', 'Disease', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))
54792	24948044	In addition to being frequent, aberrant DNA methylation has been shown to be an early event in tumorigenesis.	('aberrant', 'Var', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('DNA', 'Protein', (40, 43))	('tumor', 'Disease', (95, 100))
54796	24948044	Gastrointestinal tumors further show extremely high frequencies of transition mutations at CpG dinucleotides, and several genes, including APC, MLH1, MGMT, p16INK4a, CDH1, SFRP1, RASSF1A and VIM have been shown to be epigenetically dysregulated across malignancies of the gastrointestinal tract.	('MLH1', 'Gene', '4292', (144, 148))	('CDH1', 'Gene', (166, 170))	('RASSF1A', 'Gene', '11186', (179, 186))	('p16INK4a', 'Gene', (156, 164))	('malignancies of the gastrointestinal tract', 'Phenotype', 'HP:0007378', (252, 294))	('RASSF1A', 'Gene', (179, 186))	('transition mutations', 'Var', (67, 87))	('MGMT', 'Gene', '4255', (150, 154))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (91, 108))	('VIM', 'Gene', '7431', (191, 194))	('APC', 'Gene', '324', (139, 142))	('p16INK4a', 'Gene', '1029', (156, 164))	('Gastrointestinal tumors', 'Disease', 'MESH:D004067', (0, 23))	('VIM', 'Gene', (191, 194))	('malignancies of the gastrointestinal tract', 'Disease', 'MESH:D004067', (252, 294))	('Gastrointestinal tumors', 'Disease', (0, 23))	('SFRP1', 'Gene', (172, 177))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('malignancies of the gastrointestinal tract', 'Disease', (252, 294))	('MLH1', 'Gene', (144, 148))	('CDH1', 'Gene', '999', (166, 170))	('Gastrointestinal tumors', 'Phenotype', 'HP:0007378', (0, 23))	('MGMT', 'Gene', (150, 154))	('APC', 'Gene', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('SFRP1', 'Gene', '6422', (172, 177))
54825	24948044	Following the conversion reaction, which was performed in an MJ Mini Personal Thermal Cycler (Bio-Rad, Hercules, CA), bisulfite converted DNA was purified using the QIAcube (Qiagen) automated pipetting system, and eluted in 40 microl elution buffer.	('Rad', 'Gene', (98, 101))	('Rad', 'Gene', '6236', (98, 101))	('bisulfite', 'Var', (118, 127))	('bisulfite', 'Chemical', 'MESH:C042345', (118, 127))
54840	24948044	The real time RT-PCR reactions were performed as previously described, and included 1x one of the following commercially available TaqMan gene expression assays; CDO1 (Hs00156447_m1), ZNF331 (Hs00367929_m1), ZSCAN18 (Hs00225073_m1), VDAC2 (Hs00748551_s1; control) and PES1 (Hs00362795_g1; control; Life Technologies), 1x TaqMan Universal Mastermix with UNG (Life Technologies) and 10 ng of cDNA in a final reaction volume of 20 microl.	('UNG', 'Gene', '7374', (353, 356))	('UNG', 'Gene', (353, 356))	('ZNF331', 'Gene', '55422', (184, 190))	('ZNF331', 'Gene', (184, 190))	('VDAC2', 'Gene', (233, 238))	('ZSCAN18', 'Gene', '65982', (208, 215))	('VDAC2', 'Gene', '7417', (233, 238))	('Hs00367929_m1', 'Var', (192, 205))	('CDO1', 'Gene', '1036', (162, 166))	('CDO1', 'Gene', (162, 166))	('Hs00225073_m1', 'Var', (217, 230))	('ZSCAN18', 'Gene', (208, 215))	('Hs00156447_m1', 'Var', (168, 181))	('PES1', 'Gene', '23481', (268, 272))	('PES1', 'Gene', (268, 272))
54844	24948044	Across the test and validation sets, methylation of CDO1, SFRP1, ZNF331 and ZSCAN18 was observed in 92%, 92%, 71% and 74% of the colorectal cancer samples, respectively, with minimal methylation in the normal mucosa samples (CDO1, ZNF331 and ZSCAN18, 2%; SFRP1, 3%).	('ZNF331', 'Gene', '55422', (65, 71))	('colorectal cancer', 'Disease', (129, 146))	('ZNF331', 'Gene', (65, 71))	('observed', 'Reg', (88, 96))	('CDO1', 'Gene', (52, 56))	('SFRP1', 'Gene', (255, 260))	('ZNF331', 'Gene', '55422', (231, 237))	('ZNF331', 'Gene', (231, 237))	('CDO1', 'Gene', (225, 229))	('ZSCAN18', 'Gene', '65982', (242, 249))	('SFRP1', 'Gene', '6422', (58, 63))	('CDO1', 'Gene', '1036', (52, 56))	('colorectal cancer', 'Phenotype', 'HP:0003003', (129, 146))	('CDO1', 'Gene', '1036', (225, 229))	('ZSCAN18', 'Gene', '65982', (76, 83))	('SFRP1', 'Gene', '6422', (255, 260))	('methylation', 'Var', (37, 48))	('ZSCAN18', 'Gene', (242, 249))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('SFRP1', 'Gene', (58, 63))	('colorectal cancer', 'Disease', 'MESH:D015179', (129, 146))	('ZSCAN18', 'Gene', (76, 83))
54845	24948044	When including the previously reported qMSP results for DCLK1, methylation of at least two of the five genes was observed in 156 of the 164 colorectal cancers analyzed (95% sensitivity), and in only 2 out of the 106 normal mucosa samples (98% specificity; Fig.	('colorectal cancers', 'Disease', 'MESH:D015179', (140, 158))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('colorectal cancers', 'Disease', (140, 158))	('observed', 'Reg', (113, 121))	('DCLK1', 'Gene', (56, 61))	('methylation', 'Var', (63, 74))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('DCLK1', 'Gene', '9201', (56, 61))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))
54848	24948044	Interestingly, CDO1 was methylation positive in 65% of these samples (data not shown), suggestive of an epigenetic field defect.	('positive', 'Reg', (36, 44))	('CDO1', 'Gene', '1036', (15, 19))	('CDO1', 'Gene', (15, 19))	('methylation', 'Var', (24, 35))
54850	24948044	When comparing methylation status with clinicopathological features and microsatellite instability (MSI) status, significant associations were observed between promoter methylation and BRAF exon 15 mutation for DCLK1 (p = 0.031), ZNF331 (p < 0.001) and ZSCAN18 (p = 0.036), and between methylation and MSI for ZNF331 and ZSCAN18 (p = 0.002 and p < 0.001, respectively).	('DCLK1', 'Gene', (211, 216))	('ZSCAN18', 'Gene', '65982', (321, 328))	('ZNF331', 'Gene', '55422', (310, 316))	('ZNF331', 'Gene', (310, 316))	('ZSCAN18', 'Gene', '65982', (253, 260))	('DCLK1', 'Gene', '9201', (211, 216))	('ZSCAN18', 'Gene', (321, 328))	('promoter', 'MPA', (160, 168))	('BRAF', 'Gene', '673', (185, 189))	('ZSCAN18', 'Gene', (253, 260))	('BRAF', 'Gene', (185, 189))	('ZNF331', 'Gene', '55422', (230, 236))	('ZNF331', 'Gene', (230, 236))	('mutation', 'Var', (198, 206))
54851	24948044	Methylation of all the analyzed genes was additionally significantly more common in tumors located in the colon compared to those in the rectum (p < 0.05).	('Methylation', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('common', 'Reg', (74, 80))	('tumors', 'Disease', (84, 90))
54864	24948044	Methylation of at least two of these five genes was seen in 23 of the 25 gastric cancers and in 18 of the 20 pancreatic cancer samples, giving sensitivities of 92% and 90%, respectively.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (109, 126))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('Methylation', 'Var', (0, 11))	('seen', 'Reg', (52, 56))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('pancreatic cancer', 'Disease', 'MESH:D010190', (109, 126))	('gastric cancers', 'Disease', 'MESH:D013274', (73, 88))	('pancreatic cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gastric cancers', 'Disease', (73, 88))	('gastric cancers', 'Phenotype', 'HP:0012126', (73, 88))
54869	24948044	By analyzing biomarkers originally identified for cholangiocarcinoma in colorectal, gastric and pancreatic cancer, we have demonstrated that CDO1, DCLK1, SFRP1, ZNF331 and ZSCAN18 are frequently methylated across gastrointestinal malignancies.	('ZNF331', 'Gene', (161, 167))	('DCLK1', 'Gene', (147, 152))	('CDO1', 'Gene', '1036', (141, 145))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (213, 242))	('ZSCAN18', 'Gene', '65982', (172, 179))	('gastrointestinal malignancies', 'Disease', (213, 242))	('SFRP1', 'Gene', '6422', (154, 159))	('DCLK1', 'Gene', '9201', (147, 152))	('gastric and pancreatic cancer', 'Disease', 'MESH:D010190', (84, 113))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (50, 68))	('cholangiocarcinoma', 'Disease', (50, 68))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))	('ZSCAN18', 'Gene', (172, 179))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (50, 68))	('methylated', 'Var', (195, 205))	('SFRP1', 'Gene', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('CDO1', 'Gene', (141, 145))	('ZNF331', 'Gene', '55422', (161, 167))
54885	24948044	Colorectal cancer specific methylation of SFRP1 was identified already in 2002, and has later also been demonstrated in other gastrointestinal malignancies, including stomach, liver, pancreas and cholangiocarcinoma.	('SFRP1', 'Gene', '6422', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('SFRP1', 'Gene', (42, 47))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (126, 155))	('methylation', 'Var', (27, 38))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (196, 214))	('gastrointestinal malignancies', 'Disease', (126, 155))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('liver', 'Disease', (176, 181))	('Colorectal cancer', 'Disease', (0, 17))	('stomach', 'Disease', (167, 174))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('pancreas and cholangiocarcinoma', 'Disease', 'MESH:D018281', (183, 214))
54887	24948044	From analyses of one hundred cell lines derived from 17 different cancer types, we found CDO1 to be frequently methylated not only across the gastrointestinal cancer cell lines but also in cell lines from ovary, uterus, lung, urinary bladder, lymphoma and prostate (data not shown).	('cancer', 'Disease', (159, 165))	('lymphoma', 'Disease', 'MESH:D008223', (243, 251))	('cancer', 'Disease', (66, 72))	('CDO1', 'Gene', '1036', (89, 93))	('CDO1', 'Gene', (89, 93))	('lymphoma', 'Phenotype', 'HP:0002665', (243, 251))	('ovary', 'Disease', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (142, 165))	('methylated', 'Var', (111, 121))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (142, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('lymphoma', 'Disease', (243, 251))	('gastrointestinal cancer', 'Disease', (142, 165))	('ovary', 'Disease', 'MESH:D010051', (205, 210))
54889	24948044	By combining microarray analysis and epigenetic treatment of cancer cell lines with several validation steps, CDO1 was identified as methylated and downregulated in breast, bladder, colorectal, esophagus, lung and stomach cancer.	('breast', 'Disease', (165, 171))	('bladder', 'Disease', (173, 180))	('methylated', 'Var', (133, 143))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('CDO1', 'Gene', '1036', (110, 114))	('stomach cancer', 'Disease', 'MESH:D013274', (214, 228))	('CDO1', 'Gene', (110, 114))	('cancer', 'Disease', (222, 228))	('lung', 'Disease', (205, 209))	('cancer', 'Disease', (61, 67))	('esophagus', 'Disease', (194, 203))	('stomach cancer', 'Phenotype', 'HP:0012126', (214, 228))	('downregulated', 'NegReg', (148, 161))	('stomach cancer', 'Disease', (214, 228))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('colorectal', 'Disease', (182, 192))
54898	24948044	With a high methylation frequency also in gastric (96%) and pancreatic (50%) cancer, DCLK1 may serve as a biomarker for gastrointestinal tumorigenesis.	('tumor', 'Disease', (137, 142))	('DCLK1', 'Gene', (85, 90))	('gastric', 'Disease', (42, 49))	('cancer', 'Disease', (77, 83))	('pancreatic', 'Disease', 'MESH:D010195', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('DCLK1', 'Gene', '9201', (85, 90))	('pancreatic', 'Disease', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('methylation', 'Var', (12, 23))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
54899	24948044	This is, to the best of our knowledge, the first time ZNF331 and ZSCAN18 are reported to be hypermethylated in colorectal cancer.	('ZSCAN18', 'Gene', (65, 72))	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('ZNF331', 'Gene', '55422', (54, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('hypermethylated', 'Var', (92, 107))	('ZSCAN18', 'Gene', '65982', (65, 72))	('ZNF331', 'Gene', (54, 60))	('colorectal cancer', 'Disease', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
54901	24948044	Our data support this, in that 80% of the tumor samples analyzed in this study were found to be methylated.	('methylated', 'Var', (96, 106))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
54902	24948044	Zink finger and SCAN domain containing 18 (ZSCAN18) hypermethylation was recently reported in 32% of primary renal cell carcinomas, and RNAi knockdown of this gene was associated with an anchorage-independent growth advantage.	('knockdown', 'Var', (141, 150))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (109, 130))	('hypermethylation', 'Var', (52, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('anchorage-independent growth advantage', 'CPA', (187, 225))	('primary renal cell carcinomas', 'Disease', 'MESH:C538614', (101, 130))	('ZSCAN18', 'Gene', '65982', (43, 50))	('primary renal cell carcinomas', 'Disease', (101, 130))	('ZSCAN18', 'Gene', (43, 50))	('reported', 'Reg', (82, 90))
54903	24948044	Promoter DNA methylation is commonly associated with reduced or lost gene expression, and aberrant promoter methylation may be one mechanism used by cancer cells to silence specific genes, thereby providing them with a growth advantage.	('cancer', 'Disease', (149, 155))	('lost', 'NegReg', (64, 68))	('silence', 'NegReg', (165, 172))	('growth', 'MPA', (219, 225))	('aberrant', 'Var', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('gene expression', 'MPA', (69, 84))	('Promoter DNA', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
54904	24948044	In this study, we observed a strong correlation between the presence of promoter methylation and reduced expression of all the analyzed genes across multiple cell lines from various cancer types.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('promoter methylation', 'Var', (72, 92))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('reduced', 'NegReg', (97, 104))	('cancer', 'Disease', (182, 188))	('expression', 'MPA', (105, 115))
54905	24948044	This negative correlation was further confirmed in colorectal cancer tissue samples for ZNF331 and ZSCAN18, but not for CDO1, indicating that promoter methylation do not reduce expression of CDO1.	('CDO1', 'Gene', '1036', (120, 124))	('CDO1', 'Gene', (120, 124))	('promoter methylation', 'Var', (142, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (51, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('ZNF331', 'Gene', '55422', (88, 94))	('ZSCAN18', 'Gene', '65982', (99, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('ZNF331', 'Gene', (88, 94))	('CDO1', 'Gene', (191, 195))	('colorectal cancer', 'Disease', (51, 68))	('CDO1', 'Gene', '1036', (191, 195))	('ZSCAN18', 'Gene', (99, 106))	('expression', 'MPA', (177, 187))
54906	24948044	However, a notably increased expression was observed for all genes in colon cancer cell lines after epigenetic drug treatment, suggesting that the lack of correlation for CDO1 may be explained by the limited sample size of the unmethylated group.	('colon cancer', 'Phenotype', 'HP:0003003', (70, 82))	('CDO1', 'Gene', '1036', (171, 175))	('CDO1', 'Gene', (171, 175))	('epigenetic drug treatment', 'Var', (100, 125))	('colon cancer', 'Disease', (70, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('increased', 'PosReg', (19, 28))	('expression', 'MPA', (29, 39))	('colon cancer', 'Disease', 'MESH:D015179', (70, 82))
54908	24948044	Also for ZNF331 and ZSCAN18, increased expression was seen after epigenetic treatment in colon cancer cell lines, confirming that the reduced expression of these genes most likely is caused by aberrant promoter methylation.	('ZSCAN18', 'Gene', (20, 27))	('ZNF331', 'Gene', '55422', (9, 15))	('ZNF331', 'Gene', (9, 15))	('expression', 'MPA', (142, 152))	('colon cancer', 'Phenotype', 'HP:0003003', (89, 101))	('reduced', 'NegReg', (134, 141))	('increased', 'PosReg', (29, 38))	('epigenetic treatment', 'Var', (65, 85))	('colon cancer', 'Disease', 'MESH:D015179', (89, 101))	('expression', 'MPA', (39, 49))	('colon cancer', 'Disease', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ZSCAN18', 'Gene', '65982', (20, 27))
54921	24948044	We additionally show that promoter DNA methylation of the analyzed genes is negatively correlated with gene expression in cancer cell lines, and that treatment with epigenetic drugs caused increased expression of the silenced genes.	('expression', 'MPA', (199, 209))	('negatively', 'NegReg', (76, 86))	('cancer', 'Disease', (122, 128))	('promoter', 'MPA', (26, 34))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('gene expression', 'MPA', (103, 118))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('epigenetic drugs', 'Var', (165, 181))	('increased', 'PosReg', (189, 198))
54922	24948044	The frequent and specific methylation of these genes in colorectal cancer makes them promising biomarkers for detection of this malignancy.	('methylation', 'Var', (26, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('malignancy', 'Disease', 'MESH:D009369', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('malignancy', 'Disease', (128, 138))
54943	32990680	Both N- and O-glycosylation are significantly altered in malignant tissues, and such changes can profoundly affect protein function in multiple ways, including protein maturation, localization, folding, cell adhesion, protein trafficking, cell signaling, and immune response.	('cell signaling', 'CPA', (239, 253))	('cell adhesion', 'CPA', (203, 216))	('protein trafficking', 'CPA', (218, 237))	('immune response', 'CPA', (259, 274))	('N', 'Chemical', 'MESH:D009584', (5, 6))	('protein', 'MPA', (160, 167))	('affect', 'Reg', (108, 114))	('changes', 'Var', (85, 92))	('altered', 'Reg', (46, 53))	('protein', 'Protein', (115, 122))	('folding', 'MPA', (194, 201))	('localization', 'MPA', (180, 192))	('O-glycosylation', 'Protein', (12, 27))
54944	32990680	In pancreatic cancer, CA19-9, a carbohydrate antigen, is known to promote activation of EGFR signaling and induce a pancreatitis phenotype and when combined with KrasG12D resulted in the development of pancreatic cancer, demonstrating glycosylation changes are not just biomarkers but can function as drivers of the oncogenic process.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (202, 219))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('CA19-9', 'Var', (22, 28))	('resulted in', 'Reg', (171, 182))	('CA19-9', 'Chemical', 'MESH:C086528', (22, 28))	('activation', 'PosReg', (74, 84))	('pancreatitis', 'Phenotype', 'HP:0001733', (116, 128))	('EGFR', 'Gene', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (202, 219))	('pancreatitis', 'Disease', 'MESH:D010195', (116, 128))	('pancreatic cancer', 'Disease', (3, 20))	('pancreatitis', 'Disease', (116, 128))	('pancreatic cancer', 'Disease', (202, 219))	('induce', 'Reg', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('KrasG12D', 'Var', (162, 170))	('EGFR', 'Gene', '1956', (88, 92))
54953	32990680	To build a set of matched PDX and tumor organoid models, we identified 8 PDX models that have heterogeneous combination of alterations in the common pancreatic cancer oncogenes, such as KRAS, TP53, CDKN2A, SMAD4, c-MYC, GATA6, ERBB2, as well as other genetic alterations in SWI/SNF, DNA damage repair, and axon guidance pathways as determined by exome sequencing analysis of the PDX tumors (Figure 1A).	('PD', 'Disease', 'MESH:D010300', (26, 28))	('N', 'Chemical', 'MESH:D009584', (284, 285))	('pancreatic cancer', 'Disease', 'MESH:D010190', (149, 166))	('KRAS', 'Gene', '3845', (186, 190))	('PD', 'Disease', 'MESH:D010300', (73, 75))	('SMAD4', 'Gene', (206, 211))	('alterations', 'Var', (123, 134))	('tumor', 'Disease', (34, 39))	('KRAS', 'Gene', (186, 190))	('tumor', 'Disease', (383, 388))	('pancreatic cancer', 'Disease', (149, 166))	('GATA6', 'Gene', '2627', (220, 225))	('PD', 'Disease', 'MESH:D010300', (379, 381))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('TP53', 'Gene', (192, 196))	('N', 'Chemical', 'MESH:D009584', (201, 202))	('CDKN2A', 'Gene', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (383, 388))	('c-MYC', 'Gene', '4609', (213, 218))	('SMAD4', 'Gene', '4089', (206, 211))	('PDX tumors', 'Disease', (379, 389))	('tumors', 'Phenotype', 'HP:0002664', (383, 389))	('ERBB2', 'Gene', (227, 232))	('N', 'Chemical', 'MESH:D009584', (279, 280))	('c-MYC', 'Gene', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (149, 166))	('PDX tumors', 'Disease', 'MESH:D009369', (379, 389))	('CDKN2A', 'Gene', '1029', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (383, 388))	('ERBB2', 'Gene', '2064', (227, 232))	('GATA6', 'Gene', (220, 225))	('TP53', 'Gene', '7157', (192, 196))	('axon guidance', 'Pathway', (306, 319))
54960	32990680	Panc014 PDX tumors had glands predominantly cribriform in architecture, with focal regions of poorly differentiated morphology; Panc030 PDX tumors had glands that were confluent, with focal single cells; Panc281 PDX tumors had glands somewhat cribriform/confluent but still easily identifiable as glands, with focal poorly differentiated areas (Figure 1C).	('PDX tumors', 'Disease', 'MESH:D009369', (8, 18))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('PDX tumors', 'Disease', (212, 222))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('PDX tumors', 'Disease', 'MESH:D009369', (136, 146))	('PDX tumors', 'Disease', (8, 18))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('Panc281', 'Var', (204, 211))	('PDX tumors', 'Disease', 'MESH:D009369', (212, 222))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('PDX tumors', 'Disease', (136, 146))
54961	32990680	Overall, the correlation of histopathological features between PDX and organoids was very apparent in Panc014 and Panc281, while in Panc030 it was less clear, demonstrating that organoid cultures mostly retain intermodel variations in histopathology.	('PD', 'Disease', 'MESH:D010300', (63, 65))	('Panc281', 'Var', (114, 121))	('Panc014', 'Var', (102, 109))
54965	32990680	Analysis of GATA6 levels in the 6 models established in PTOM demonstrated that Panc030 and Panc281 expressed high levels of GATA6 compared with the other models (Figure 2A).	('GATA6', 'Gene', '2627', (12, 17))	('levels', 'MPA', (114, 120))	('GATA6', 'Gene', (12, 17))	('Panc030', 'Var', (79, 86))	('Panc281', 'Gene', (91, 98))	('PTOM', 'Chemical', '-', (56, 60))	('GATA6', 'Gene', (124, 129))	('GATA6', 'Gene', '2627', (124, 129))
54969	32990680	Panc030 and Panc281 organoids maintained in PTOM were larger than organoids maintained in WNT media (Figure 2D).	('PTOM', 'Chemical', '-', (44, 48))	('Panc030', 'Var', (0, 7))	('Panc281', 'Gene', (12, 19))	('N', 'Chemical', 'MESH:D009584', (91, 92))
55014	32990680	We classified the derived traits of N-glycans with varying degree of sialylation or fucosylation and observed a high degree of overlap between PDX and PXO samples modified by sialylation and fucosylation (Figure 6C), demonstrating that the most common cancer-associated alterations in glycosylation are also retained in PXO models as present in vivo PDX models.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('PD', 'Disease', 'MESH:D010300', (350, 352))	('cancer', 'Disease', (252, 258))	('PD', 'Disease', 'MESH:D010300', (143, 145))	('alterations', 'Var', (270, 281))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('N-glycans', 'Chemical', '-', (36, 45))	('glycosylation', 'MPA', (285, 298))
55022	32990680	Among these, there were 5 high-mannose glycans (H8N2, H5N2, H6N2, H7N2, H9N2), consistent with previous studies reporting increased levels of high-mannose glycans in pancreatic tumor regions, compared with normal tissues, detected by MALDI imaging mass spectrometry or by lectin probing.	('pancreatic tumor', 'Phenotype', 'HP:0002894', (166, 182))	('H8N2', 'Var', (48, 52))	('pancreatic tumor', 'Disease', (166, 182))	('H5N2', 'Var', (54, 58))	('H7N2', 'Var', (66, 70))	('H6N2', 'Var', (60, 64))	('pancreatic tumor', 'Disease', 'MESH:D010190', (166, 182))	('mannose glycans', 'Chemical', '-', (147, 162))	('increased', 'PosReg', (122, 131))	('H9N2', 'Var', (72, 76))	('H6N2', 'CellLine', 'CVCL:D461', (60, 64))	('H7N2', 'CellLine', 'CVCL:D462', (66, 70))	('H9N2', 'CellLine', 'CVCL:0H95', (72, 76))	('H8N2', 'Species', '402586', (48, 52))	('high-mannose', 'Chemical', '-', (26, 38))	('H5N2', 'Species', '119220', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('high-mannose', 'Chemical', '-', (142, 154))	('mannose glycans', 'Chemical', '-', (31, 46))
55023	32990680	Four other glycans (H3N4F1, H3N2F1, H2N2F1, and H3N3F1) contained Lewis-X epitope (H(1,4)-Falpha(1,3)-N) that was increased in PDAC and colon tumor tissues compared with normal, demonstrating that PXO models retained glycosylation changes previously reported to be associated with PDAC.	('colon tumor', 'Disease', 'MESH:D003110', (136, 147))	('H2N2F1', 'Var', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('H3N2F1', 'Var', (28, 34))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('H3N3F1', 'Var', (48, 54))	('PDAC', 'Disease', (281, 285))	('glycosylation changes', 'MPA', (217, 238))	('PDAC', 'Disease', (127, 131))	('H2N2F1', 'CellLine', 'CVCL:L875', (36, 42))	('PDAC', 'Chemical', '-', (281, 285))	('colon tumor', 'Disease', (136, 147))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('PDAC', 'Phenotype', 'HP:0006725', (281, 285))	('increased', 'PosReg', (114, 123))	('H(1,4)-Falpha(1,3)-N', 'Disease', 'MESH:C567520', (83, 103))	('PDAC', 'Chemical', '-', (127, 131))	('PDAC', 'Phenotype', 'HP:0006725', (127, 131))	('N', 'Chemical', 'MESH:D009584', (102, 103))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('colon tumor', 'Phenotype', 'HP:0100273', (136, 147))	('glycans', 'Chemical', 'MESH:D011134', (11, 18))
55032	32990680	Interestingly, Panc014 segregated away from the rest of the samples (Figure 7A), consistent with fact that Pac014 was derived from a cholangiocarcinoma whereas all other models originated from PDAC, demonstrating our ability to detect distinct EV proteomic profiles among patient-derived models.	('cholangiocarcinoma', 'Disease', (133, 151))	('Pac014', 'Chemical', '-', (107, 113))	('PDAC', 'Phenotype', 'HP:0006725', (193, 197))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (133, 151))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (133, 151))	('derived from', 'Reg', (118, 130))	('PDAC', 'Chemical', '-', (193, 197))	('patient', 'Species', '9606', (272, 279))	('Pac014', 'Var', (107, 113))
55047	32990680	Interestingly, although PDAC patient BIDPA3 (PA3) had at least 30 times higher CA19-9 levels than patients PA4, PA5, and PA6 (Supplemental Table 2), the levels of the pan-EV marker and 4 PDAC candidate markers were not significantly different (Figure 8A), demonstrating a lack of association between CA19-9 levels and the enrichment of the EV markers.	('patient', 'Species', '9606', (29, 36))	('PDAC', 'Phenotype', 'HP:0006725', (187, 191))	('CA19-9', 'Chemical', 'MESH:C086528', (300, 306))	('patient', 'Species', '9606', (98, 105))	('CA19-9', 'Chemical', 'MESH:C086528', (79, 85))	('PDAC', 'Chemical', '-', (24, 28))	('CA19-9 levels', 'MPA', (79, 92))	('patients', 'Species', '9606', (98, 106))	('PDAC', 'Chemical', '-', (187, 191))	('higher', 'PosReg', (72, 78))	('PDAC', 'Phenotype', 'HP:0006725', (24, 28))	('BIDPA3', 'Var', (37, 43))
55065	32990680	Changes in protein N-glycosylation and O-glycosylation can profoundly impact protein maturation, expression, localization, and posttranslational modifications and impact its functions, such as ligand binding and signaling.	('N', 'Chemical', 'MESH:D009584', (19, 20))	('O-glycosylation', 'MPA', (39, 54))	('protein', 'Protein', (11, 18))	('impact', 'Reg', (163, 169))	('ligand binding', 'Interaction', (193, 207))	('protein', 'Protein', (77, 84))	('Changes', 'Var', (0, 7))	('localization', 'MPA', (109, 121))	('posttranslational modifications', 'MPA', (127, 158))	('impact', 'Reg', (70, 76))	('functions', 'MPA', (174, 183))	('expression', 'MPA', (97, 107))
55066	32990680	In addition, aberrant glycosylation could also generate antigens that serve as biomarkers for cancer detection.	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (13, 35))	('antigens', 'MPA', (56, 64))	('glycosylation', 'MPA', (22, 35))	('generate', 'Reg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Disease', (94, 100))	('aberrant', 'Var', (13, 21))
55072	32990680	Consistently in both PDX and PXO models, complex glycans represent the most frequent type of modification, including fucosylated and sialyated glycans.	('glycans', 'Chemical', 'MESH:D011134', (49, 56))	('PD', 'Disease', 'MESH:D010300', (21, 23))	('fucosylated', 'MPA', (117, 128))	('glycans', 'Chemical', 'MESH:D011134', (143, 150))	('sialyated glycans', 'MPA', (133, 150))	('complex', 'Var', (41, 48))
55109	32990680	Permethylation of N-glycans was carried out to increase the sensitivity of MS analysis and performed as outlined in Supplemental Methods.	('N-glycans', 'Chemical', '-', (18, 27))	('Permethylation', 'Var', (0, 14))	('sensitivity', 'MPA', (60, 71))	('increase', 'PosReg', (47, 55))
55156	33167521	Moreover, polymorphisms in the leptin receptor (ObR) gene have been reported to be related to NAFLD.	('leptin receptor', 'Gene', (31, 46))	('leptin receptor', 'Gene', '3953', (31, 46))	('ObR', 'Gene', (48, 51))	('polymorphisms', 'Var', (10, 23))	('NAFLD', 'Disease', (94, 99))	('related', 'Reg', (83, 90))
55159	33167521	Adiponectin levels are reduced in individuals with NAFLD and are inversely related to the severity of steatosis, necroinflammation, and fibrosis.	('NAFLD', 'Var', (51, 56))	('inflammation', 'Disease', 'MESH:D007249', (118, 130))	('steatosis', 'Disease', 'MESH:D005234', (102, 111))	('fibrosis', 'Disease', 'MESH:D005355', (136, 144))	('fibrosis', 'Disease', (136, 144))	('inflammation', 'Disease', (118, 130))	('reduced', 'NegReg', (23, 30))	('Adiponectin levels', 'MPA', (0, 18))	('steatosis', 'Phenotype', 'HP:0001397', (102, 111))	('steatosis', 'Disease', (102, 111))
55163	33167521	Comprehensive crosstalk between adiponectin and its cognate receptors, specifically AdipoR2, in the liver attenuates hepatic lipoinflammation by interacting with hepatic PPARs.	('hepatic', 'MPA', (162, 169))	('AdipoR2', 'Gene', (84, 91))	('liver attenuates hepatic lipoinflammation', 'Disease', (100, 141))	('AdipoR2', 'Gene', '79602', (84, 91))	('liver attenuates hepatic lipoinflammation', 'Disease', 'MESH:D017093', (100, 141))	('crosstalk', 'Var', (14, 23))	('interacting', 'Interaction', (145, 156))
55164	33167521	In addition, adiponectin protects hepatocytes from tumor necrosis factor-alpha (TNF-alpha)-induced death; specifically, adiponectin is a potent TNF-alpha-neutralizing adipokine.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('death', 'Disease', 'MESH:D003643', (99, 104))	('death', 'Disease', (99, 104))	('tumor necrosis factor-alpha', 'Gene', '7124', (51, 78))	('tumor necrosis factor-alpha', 'Gene', (51, 78))	('adiponectin', 'Var', (120, 131))
55166	33167521	Furthermore, the single-nucleotide polymorphism (SNP) rs1501299 in the adiponectin gene might be related to increased NAFLD susceptibility.	('rs1501299', 'Mutation', 'rs1501299', (54, 63))	('increased', 'PosReg', (108, 117))	('rs1501299', 'Var', (54, 63))	('adiponectin', 'Gene', (71, 82))	('NAFLD', 'Disease', (118, 123))	('single-nucleotide polymorphism', 'Var', (17, 47))
55173	33167521	While viral suppression can be achieved in the majority of patients with the high-barrier-to-resistance new-generation of Nuc, HBsAg loss is achieved by PegIFN-alpha and/or Nuc in only 10% of patients after a 5-year follow-up.	('patients', 'Species', '9606', (192, 200))	('HBsAg loss', 'Disease', (127, 137))	('rat', 'Species', '10116', (112, 115))	('patients', 'Species', '9606', (59, 67))	('PegIFN-alpha', 'Chemical', '-', (153, 165))	('HBsAg loss', 'Disease', 'MESH:D014786', (127, 137))	('high-barrier-to-resistance', 'Var', (77, 103))
55178	33167521	In HepG2-HBV-stable cells, HBV replication was found to be upregulated by adiponectin and downregulated by adiponectin-targeting small interfering RNAs.	('HBV', 'Gene', (27, 30))	('HBV', 'Species', '10407', (27, 30))	('adiponectin', 'MPA', (74, 85))	('upregulated', 'PosReg', (59, 70))	('HepG2-HBV', 'CellLine', 'CVCL:0027', (3, 12))	('downregulated', 'NegReg', (90, 103))	('small interfering RNAs', 'Var', (129, 151))	('HBV', 'Species', '10407', (9, 12))
55180	33167521	Particularly in overweight and obese HBV-infected patients, a high HBV load was found to be positively associated with serum adiponectin levels.	('overweight', 'Phenotype', 'HP:0025502', (16, 26))	('obese HBV-infected', 'Disease', (31, 49))	('HBV', 'Species', '10407', (37, 40))	('patients', 'Species', '9606', (50, 58))	('obese HBV-infected', 'Disease', 'MESH:D009765', (31, 49))	('serum adiponectin levels', 'MPA', (119, 143))	('HBV', 'Gene', (67, 70))	('high', 'Var', (62, 66))	('HBV', 'Species', '10407', (67, 70))
55192	33167521	Hepatitis C virus (HCV), a human pathogen responsible for acute and chronic liver disease, has variants classified into eight genotypes and chronically infects an estimated 71.1 million individuals worldwide.	('Hepatitis C virus', 'Disease', (0, 17))	('Hepatitis', 'Phenotype', 'HP:0012115', (0, 9))	('Hepatitis C virus', 'Species', '11103', (0, 17))	('infects', 'Reg', (152, 159))	('liver disease', 'Phenotype', 'HP:0001392', (76, 89))	('liver disease', 'Disease', (76, 89))	('human', 'Species', '9606', (27, 32))	('liver disease', 'Disease', 'MESH:D008107', (76, 89))	('HCV', 'Species', '11103', (19, 22))	('variants', 'Var', (95, 103))
55200	33167521	Regarding genotype-specific characteristics, the connection between steatosis and leptin in patients infected with genotype (G) 1 or G2 HCV has been reported.	('HCV', 'Species', '11103', (136, 139))	('genotype', 'Var', (115, 123))	('steatosis', 'Disease', (68, 77))	('leptin', 'MPA', (82, 88))	('steatosis', 'Disease', 'MESH:D005234', (68, 77))	('patients', 'Species', '9606', (92, 100))	('infected', 'Disease', 'MESH:D007239', (101, 109))	('steatosis', 'Phenotype', 'HP:0001397', (68, 77))	('connection', 'Reg', (49, 59))	('infected', 'Disease', (101, 109))
55223	33167521	However, high serum levels of adiponectin were associated with higher all-cause, liver-unrelated, and liver-related mortality.	('serum levels', 'MPA', (14, 26))	('adiponectin', 'Protein', (30, 41))	('mortality', 'Disease', 'MESH:D003643', (116, 125))	('liver-related', 'Disease', (102, 115))	('mortality', 'Disease', (116, 125))	('all-cause', 'CPA', (70, 79))	('high serum levels of adiponectin', 'Phenotype', 'HP:0030686', (9, 41))	('liver-unrelated', 'Disease', (81, 96))	('higher', 'PosReg', (63, 69))	('high', 'Var', (9, 13))
55269	33167521	In addition, a study of cirrhosis and control patients showed that transplant-free survival was significantly lower among patients with alcoholic liver disease and adiponectin >=17 mug/mL.	('adiponectin', 'Protein', (164, 175))	('patients', 'Species', '9606', (46, 54))	('alcoholic liver disease', 'Disease', 'MESH:D008108', (136, 159))	('liver disease', 'Phenotype', 'HP:0001392', (146, 159))	('alcoholic liver disease', 'Disease', (136, 159))	('cirrhosis', 'Phenotype', 'HP:0001394', (24, 33))	('transplant-free survival', 'CPA', (67, 91))	('lower', 'NegReg', (110, 115))	('patients', 'Species', '9606', (122, 130))	('>=17 mug/mL', 'Var', (176, 187))	('cirrhosis', 'Disease', 'MESH:D005355', (24, 33))	('cirrhosis', 'Disease', (24, 33))
55271	33167521	Emerging evidence has revealed that dysregulated adiponectin-fibroblast growth factor (FGF) 15 (human homolog, FGF19) axis and impaired hepatic adiponectin-FGF15/19 signaling are associated with alcoholic liver damage in rodents and humans.	('associated', 'Reg', (179, 189))	('human', 'Species', '9606', (233, 238))	('hepatic adiponectin-FGF15/19 signaling', 'MPA', (136, 174))	('human', 'Species', '9606', (96, 101))	('FGF19', 'Gene', '9965', (111, 116))	('ob', 'Gene', '16846', (65, 67))	('dysregulated', 'Var', (36, 48))	('alcoholic liver damage', 'Disease', (195, 217))	('FGF19', 'Gene', (111, 116))	('impaired', 'NegReg', (127, 135))	('humans', 'Species', '9606', (233, 239))	('alcoholic liver damage', 'Disease', 'MESH:D008108', (195, 217))
55291	33167521	By stimulating adipogenesis, opposing inflammation, and influencing rates of lipid oxidation and lipolysis, adiponectin critically governs lipid spillover into nonadipose tissues.	('lipolysis', 'MPA', (97, 106))	('adipose', 'Gene', '230796', (163, 170))	('adipose', 'Gene', (163, 170))	('stimulating', 'Reg', (3, 14))	('governs', 'Reg', (131, 138))	('adipogenesis', 'MPA', (15, 27))	('influencing', 'Reg', (56, 67))	('rat', 'Species', '10116', (68, 71))	('inflammation', 'Disease', 'MESH:D007249', (38, 50))	('lipid oxidation', 'MPA', (77, 92))	('lipid', 'Chemical', 'MESH:D008055', (139, 144))	('lipid', 'Chemical', 'MESH:D008055', (77, 82))	('inflammation', 'Disease', (38, 50))	('adiponectin', 'Var', (108, 119))
55307	33167521	High levels of LMW adiponectin are associated with a decreased risk of Barrett's esophagus among patients with GERD.	('LMW', 'Var', (15, 18))	("Barrett's esophagus", 'Disease', (71, 90))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (71, 90))	('GERD', 'Disease', (111, 115))	('GERD', 'Disease', 'MESH:D005764', (111, 115))	('decreased', 'NegReg', (53, 62))	('adiponectin', 'Protein', (19, 30))	('patients', 'Species', '9606', (97, 105))
55337	33167521	Adiponectin expression was significantly suppressed by induction of colitis, and intracolonic silencing of adipoR1 in mice exacerbated TNBS-induced colitis.	('silencing', 'Var', (94, 103))	('Adiponectin expression', 'MPA', (0, 22))	('colitis', 'Phenotype', 'HP:0002583', (68, 75))	('adipoR1', 'Gene', (107, 114))	('colitis', 'Disease', 'MESH:D003092', (148, 155))	('colonic', 'Disease', 'MESH:D003110', (86, 93))	('suppressed', 'NegReg', (41, 51))	('colonic', 'Disease', (86, 93))	('colitis', 'Disease', (148, 155))	('TNBS', 'Chemical', '-', (135, 139))	('colitis', 'Disease', 'MESH:D003092', (68, 75))	('exacerbated', 'PosReg', (123, 134))	('mice', 'Species', '10090', (118, 122))	('colitis', 'Phenotype', 'HP:0002583', (148, 155))	('adipoR1', 'Gene', '72674', (107, 114))	('colitis', 'Disease', (68, 75))
55351	33167521	Intriguingly, high leptin expression was an indicator of favorable tumor features and better survival in CRC patients.	('leptin', 'Protein', (19, 25))	('expression', 'MPA', (26, 36))	('patients', 'Species', '9606', (109, 117))	('CRC', 'Disease', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('high leptin', 'Phenotype', 'HP:0031793', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('high', 'Var', (14, 18))	('CRC', 'Phenotype', 'HP:0003003', (105, 108))	('tumor', 'Disease', (67, 72))
55361	33167521	Furthermore, in human colonic goblet-like HT29-MTX cells expressing ObR, leptin increased mucin secretion by activating protein kinase C (PKC)- and PI3K-dependent pathways.	('activating', 'PosReg', (109, 119))	('leptin increased', 'Phenotype', 'HP:0031793', (73, 89))	('increased', 'PosReg', (80, 89))	('mucin', 'Gene', '100508689', (90, 95))	('colonic goblet', 'Disease', 'MESH:D003110', (22, 36))	('colonic goblet', 'Disease', (22, 36))	('HT29-MTX', 'CellLine', 'CVCL:6834', (42, 50))	('human', 'Species', '9606', (16, 21))	('mucin', 'Gene', (90, 95))	('leptin', 'Protein', (73, 79))	('ObR', 'Var', (68, 71))
55380	33167521	The rs12733285C/T genotype and the A allele of rs1342387 (A/G or A/A) of ADIPOR1 are protective factors for CRC, while the rs266729G/C genotype and the G allele of ADIPOQ are risk factors for colon cancer.	('rs266729', 'Mutation', 'rs266729', (123, 131))	('ADIPOQ', 'Gene', '9370', (164, 170))	('colon cancer', 'Phenotype', 'HP:0003003', (192, 204))	('ADIPOQ', 'Gene', (164, 170))	('rs266729G/C', 'Var', (123, 134))	('rs12733285', 'Mutation', 'rs12733285', (4, 14))	('ADIPOR1', 'Gene', '51094', (73, 80))	('rs12733285C/T', 'Var', (4, 17))	('colon cancer', 'Disease', 'MESH:D015179', (192, 204))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))	('ADIPOR1', 'Gene', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('colon cancer', 'Disease', (192, 204))	('CRC', 'Disease', (108, 111))	('rs1342387', 'Mutation', 'rs1342387', (47, 56))
55388	33167521	In addition, the resistin C-420G and G+299A polymorphisms have potential roles in the genetic predisposition to colon cancer.	('roles', 'Reg', (73, 78))	('colon cancer', 'Phenotype', 'HP:0003003', (112, 124))	('resistin', 'Gene', (17, 25))	('colon cancer', 'Disease', 'MESH:D015179', (112, 124))	('resistin', 'Gene', '56729', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('G+299A', 'Mutation', 'rs3745367', (37, 43))	('G+299A', 'Var', (37, 43))	('colon cancer', 'Disease', (112, 124))	('C-420G', 'Var', (26, 32))	('C-420G', 'Mutation', 'rs1862513', (26, 32))
55397	33167521	High levels of adiponectin were found in BDL rats, reflecting the antifibrotic role of adiponectin, as adiponectin overexpression in activated HSCs was found to reduce the proliferation but augment the apoptosis of HSCs.	('adiponectin', 'Var', (103, 114))	('proliferation', 'CPA', (172, 185))	('rats', 'Species', '10116', (45, 49))	('High levels of adiponectin', 'Phenotype', 'HP:0030686', (0, 26))	('men', 'Species', '9606', (193, 196))	('reduce', 'NegReg', (161, 167))	('apoptosis', 'CPA', (202, 211))	('rat', 'Species', '10116', (179, 182))	('augment', 'NegReg', (190, 197))	('rat', 'Species', '10116', (45, 48))
55400	33167521	Obesity, diabetes, and hyperlipidemia are known risk factors for the development of gallstones, and there is convincing evidence that excess body weight is associated with an increased risk for gallbladder cancer.	('gallstones', 'Disease', 'MESH:D042882', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('gallstone', 'Phenotype', 'HP:0001081', (84, 93))	('hyperlipidemia', 'Phenotype', 'HP:0003077', (23, 37))	('men', 'Species', '9606', (76, 79))	('diabetes', 'Disease', (9, 17))	('gallbladder cancer', 'Disease', (194, 212))	('gallbladder cancer', 'Disease', 'MESH:D005706', (194, 212))	('excess body', 'Var', (134, 145))	('hyperlipidemia', 'Disease', 'MESH:D006949', (23, 37))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('associated', 'Reg', (156, 166))	('excess body weight', 'Phenotype', 'HP:0004324', (134, 152))	('diabetes', 'Disease', 'MESH:D003920', (9, 17))	('hyperlipidemia', 'Disease', (23, 37))	('gallstones', 'Disease', (84, 94))	('gallstones', 'Phenotype', 'HP:0001081', (84, 94))
55409	33167521	A large body of evidence demonstrates that high BMI, as an approximation for general adiposity, is a risk factor for the development of gallbladder cancers.	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('rat', 'Species', '10116', (32, 35))	('men', 'Species', '9606', (128, 131))	('high BMI', 'Var', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('gallbladder cancers', 'Disease', (136, 155))	('risk', 'Reg', (101, 105))	('gallbladder cancers', 'Disease', 'MESH:D005706', (136, 155))
55421	33178590	A total of 10,967 tumor samples comprising 32 cancer types from The Cancer Genome Atlas (TCGA) datasets were analyzed for MET abnormal expression, mutations, and copy number variants (CNVs).	('MET', 'Gene', '79811', (122, 125))	('mutations', 'Var', (147, 156))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', (18, 23))	('cancer', 'Disease', (46, 52))	('MET', 'Gene', (122, 125))	('Cancer', 'Disease', 'MESH:D009369', (68, 74))	('Cancer', 'Disease', (68, 74))	('copy number variants', 'Var', (162, 182))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
55423	33178590	Lung adenocarcinoma (LUAD) has most targetable mutations located in the juxtamembrane domain, and both high expression and amplification of MET are significantly associated with poor prognosis.	('MET', 'Gene', '79811', (140, 143))	('LUAD', 'Phenotype', 'HP:0030078', (21, 25))	('MET', 'Gene', (140, 143))	('mutations', 'Var', (47, 56))	('associated', 'Reg', (162, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('amplification', 'Var', (123, 136))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))
55428	33178590	This study provided significant and comprehensive information regarding MET abnormal expression, alterations (mutations and CNVs), and their clinical associations among 32 cancer types and offered insights into the full MET alteration spectrum and its implications for prognosis and treatment.	('MET', 'Gene', '79811', (220, 223))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('abnormal', 'Var', (76, 84))	('MET', 'Gene', (220, 223))	('alterations', 'Var', (97, 108))	('MET', 'Gene', '79811', (72, 75))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('MET', 'Gene', (72, 75))	('cancer', 'Disease', (172, 178))	('associations', 'Interaction', (150, 162))
55431	33178590	It is frequently activated in human tumors by various mechanisms, such as mutations, amplification, and overexpression, thus leading to malignant transformation and metastasis.	('malignant transformation', 'CPA', (136, 160))	('metastasis', 'CPA', (165, 175))	('leading to', 'Reg', (125, 135))	('human', 'Species', '9606', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('overexpression', 'Var', (104, 118))	('mutations', 'Var', (74, 83))	('activated', 'PosReg', (17, 26))	('amplification', 'Var', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
55434	33178590	Moreover, in esophageal carcinoma (ESCA) and kidney renal papillary cell carcinoma (KIRP), gene amplification with consequent protein overexpression and constitutive kinase activation of MET has been reported.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (13, 33))	('protein', 'Protein', (126, 133))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (13, 33))	('overexpression', 'PosReg', (134, 148))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (52, 82))	('MET', 'Gene', '79811', (187, 190))	('ESCA', 'Phenotype', 'HP:0011459', (35, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('MET', 'Gene', (187, 190))	('kidney renal papillary cell carcinoma', 'Disease', (45, 82))	('gene amplification', 'Var', (91, 109))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (45, 82))	('esophageal carcinoma', 'Disease', (13, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
55437	33178590	Especially in lung cancer, inhibition of MET receptor activity has shown promising results and has become a standard therapy for patients.	('patients', 'Species', '9606', (129, 137))	('MET', 'Gene', (41, 44))	('lung cancer', 'Disease', (14, 25))	('MET', 'Gene', '79811', (41, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('inhibition', 'Var', (27, 37))	('activity', 'MPA', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('lung cancer', 'Disease', 'MESH:D008175', (14, 25))
55451	33178590	Especially, in single- and cross-cancer queries, OQL algorithm can be utilized to accurately identify copy number alterations, mutations, mRNA, and protein expression profiles.	('mRNA', 'MPA', (138, 142))	('copy number alterations', 'Var', (102, 125))	('cross-cancer', 'Disease', (27, 39))	('cross-cancer', 'Disease', 'MESH:D009369', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (127, 136))
55469	33178590	MET mutations were observed most commonly in UCEC (12.3%), SKCM (10.5%), KIRP (8.8%), bladder urothelial carcinoma (BLCA, 4.4%), COADREAD (4.4%), and LUAD (4.2%).	('KIRP', 'Disease', (73, 77))	('MET', 'Gene', '79811', (0, 3))	('bladder urothelial carcinoma', 'Disease', (86, 114))	('observed', 'Reg', (19, 27))	('COADREAD', 'Disease', (129, 137))	('MET', 'Gene', (0, 3))	('UCEC', 'Disease', (45, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('mutations', 'Var', (4, 13))	('SKCM', 'Disease', (59, 63))	('LUAD', 'Phenotype', 'HP:0030078', (150, 154))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (86, 114))
55475	33178590	The most common domains were the other domain (91 samples), Sema domain (83 samples), Pkinase-Tyr domain (69 samples), TIG domain (563-654 aa, 18 samples), TIG domain (742-815 aa, 17 samples), TIG domain (657-728 aa, 12 samples), and PSI domain (7 samples).	('Tyr', 'Chemical', 'MESH:D014443', (94, 97))	('657-728 aa', 'Var', (205, 215))	('Sema', 'Gene', (60, 64))	('Sema', 'Gene', '7869', (60, 64))	('TIG', 'Disease', (119, 122))
55477	33178590	Mutations in KIRP were primarily located in the Pkinase-Tyr domain, approximately three times more than the mutations located in the other domain.	('Tyr', 'Chemical', 'MESH:D014443', (56, 59))	('Mutations', 'Var', (0, 9))	('KIRP', 'Gene', (13, 17))
55478	33178590	Mutations in COADREAD and GBM were mainly located in the Sema domain (Figure 2B and Supplementary Table S3).	('Mutations', 'Var', (0, 9))	('Sema', 'Gene', (57, 61))	('Sema', 'Gene', '7869', (57, 61))	('COADREAD', 'Gene', (13, 21))
55481	33178590	For example, the 1,010-aa mutation was found in seven samples (six samples with X1010 splice, one with D1010fs) and occurred almost exclusively in LUAD (6/7) (Supplementary Figure S2B).	('D1010fs', 'Var', (103, 110))	('D1010fs', 'Mutation', 'p.D1010fsX', (103, 110))	('X1010 splice', 'Var', (80, 92))	('LUAD', 'Phenotype', 'HP:0030078', (147, 151))
55484	33178590	The only other tumor with mutations at this position was LGG (one sample with X1010_splice), but its role was almost unknown to this cancer.	('LGG', 'Disease', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('cancer', 'Disease', (133, 139))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', (15, 20))	('X1010_splice', 'Var', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
55485	33178590	The 1,148-aa mutation in the Pkinase-Tyr domain was also observed in seven samples [six samples with R1148Q (three SKCMs, one BLCA, one BRCA, one COADREAD), one sample with R1148* (one UCEC)].	('R1148*', 'Var', (173, 179))	('observed', 'Reg', (57, 65))	('R1148Q', 'Var', (101, 107))	('Pkinase-Tyr', 'Enzyme', (29, 40))	('R1148Q', 'Mutation', 'p.R1148Q', (101, 107))	('Tyr', 'Chemical', 'MESH:D014443', (37, 40))	('R1148*', 'SUBSTITUTION', 'None', (173, 179))
55487	33178590	The most mutated positions in KIRP (17 of 25 mutations) were located at the Pkinase Tyr domain, especially at the 1,250-aa position (four samples with M1250T) and the 1,092- to 1,094-aa position (three with V1092I, three with H1094Y).	('H1094Y', 'Var', (226, 232))	('V1092I', 'Var', (207, 213))	('M1250T', 'Var', (151, 157))	('H1094Y', 'Mutation', 'p.H1094Y', (226, 232))	('V1092I', 'Mutation', 'p.V1092I', (207, 213))	('Tyr', 'Chemical', 'MESH:D014443', (84, 87))	('M1250T', 'Mutation', 'p.M1250T', (151, 157))	('mutated', 'Reg', (9, 16))
55489	33178590	The most mutated positions in UCEC (3 of 78 mutations) were located at the Pkinase-Tyr domain at the 1,186-aa position (one with L1186F, one with L1186I, one with L1186R), but its oncogenic role was considered unknown.	('L1186F', 'Mutation', 'p.L1186F', (129, 135))	('L1186F', 'Var', (129, 135))	('L1186I', 'Mutation', 'p.L1186I', (146, 152))	('Tyr', 'Chemical', 'MESH:D014443', (83, 86))	('L1186R', 'Mutation', 'p.L1186R', (163, 169))	('L1186I', 'Var', (146, 152))	('L1186R', 'Var', (163, 169))	('mutated', 'Reg', (9, 16))
55490	33178590	D1228Y/A and T222K alterations were found in UCEC (one with D1228Y, one with D1228A, one with T222K) and known to be likely oncogenic and predicted oncogenic, respectively (Supplementary Figure S2D).	('D1228Y', 'SUBSTITUTION', 'None', (60, 66))	('T222K', 'Var', (13, 18))	('D1228A', 'Var', (77, 83))	('D1228Y', 'Var', (60, 66))	('D1228A', 'Mutation', 'p.D1228A', (77, 83))	('D1228Y', 'Mutation', 'p.D1228Y', (0, 6))	('T222K', 'Mutation', 'p.T222K', (94, 99))	('D1228Y', 'SUBSTITUTION', 'None', (0, 6))	('D1228Y', 'Var', (0, 6))	('UCEC', 'Disease', (45, 49))	('D1228Y', 'Mutation', 'p.D1228Y', (60, 66))	('T222K', 'Mutation', 'p.T222K', (13, 18))
55492	33178590	Next, we analyzed the clinical targeted therapy implications of MET mutation using cBioPortal, which could provide the annotation of variants from different databases, including COSMIC, Cancer Hotspots method, CIViC, My Cancer Genome, and OncoKB.	('MET', 'Gene', (64, 67))	('CIViC', 'Disease', 'None', (210, 215))	('MET', 'Gene', '79811', (64, 67))	('Cancer', 'Phenotype', 'HP:0002664', (186, 192))	('CIViC', 'Disease', (210, 215))	('Cancer', 'Disease', (220, 226))	('Cancer', 'Disease', (186, 192))	('Cancer', 'Disease', 'MESH:D009369', (186, 192))	('Cancer', 'Disease', 'MESH:D009369', (220, 226))	('Cancer', 'Phenotype', 'HP:0002664', (220, 226))	('variants', 'Var', (133, 141))
55493	33178590	Thus, for the clinical targeted therapy implications, each MET somatic mutation could be classified into four levels as defined by OncoKB: level 2 (seven mutations), level 3B (one mutation), level 4 (13 mutations), and level NA (290 mutations) (Figure 4A and Supplementary Table S2).	('MET', 'Gene', '79811', (59, 62))	('MET', 'Gene', (59, 62))	('mutations', 'Var', (154, 163))
55500	33178590	Among the 311 samples with MET mutations mentioned above, 129 also harbored MET CNVs (108 with gain, nine with amplification, and 12 with shallow deletion).	('mutations', 'Var', (31, 40))	('MET', 'Gene', (27, 30))	('MET', 'Gene', '79811', (76, 79))	('MET', 'Gene', '79811', (27, 30))	('MET', 'Gene', (76, 79))	('gain', 'PosReg', (95, 99))
55502	33178590	As shown in Figure 5A and Figures 1A,B, KIRP harbored a very high proportion of gain and was also the cancer type with higher MET expression.	('MET', 'Gene', '79811', (126, 129))	('KIRP', 'Var', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('MET', 'Gene', (126, 129))	('gain', 'PosReg', (80, 84))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
55507	33178590	MET alterations were observed most commonly in UCEC (10.21%), SKCM (10.14%), and KIRP (9.89%), in which mutations were more common.	('SKCM', 'Disease', (62, 66))	('MET', 'Gene', '79811', (0, 3))	('alterations', 'Var', (4, 15))	('UCEC', 'Disease', (47, 51))	('MET', 'Gene', (0, 3))	('observed', 'Reg', (21, 29))	('KIRP', 'Disease', (81, 85))
55508	33178590	Other cancer types with dominant MET mutations but at much lower mutation rates included LUAD (3.53%), BLCA (3.89%), COADREAD (3.2%), UCS (3.51%), and PAAD (0.54%).	('COADREAD', 'Disease', (117, 125))	('LUAD', 'Disease', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('UCS', 'Disease', (134, 137))	('PAAD', 'Phenotype', 'HP:0006725', (151, 155))	('PAAD', 'Disease', (151, 155))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('BLCA', 'Disease', (103, 107))	('MET', 'Gene', '79811', (33, 36))	('cancer', 'Disease', (6, 12))	('MET', 'Gene', (33, 36))	('LUAD', 'Phenotype', 'HP:0030078', (89, 93))
55511	33178590	Approximately half of the mutations (29 of 67 mutations) in the Pkinase-Tyr domain also had MET copy gain, while nearly half of the mutations (44 of 90 mutations) in the other function-unknown domain were accompanied by amplification, gain, and shallow deletion.	('Pkinase-Tyr', 'Gene', (64, 75))	('copy', 'MPA', (96, 100))	('mutations', 'Var', (46, 55))	('MET', 'Gene', (92, 95))	('mutations', 'Var', (132, 141))	('gain', 'PosReg', (101, 105))	('amplification', 'MPA', (220, 233))	('Tyr', 'Chemical', 'MESH:D014443', (72, 75))	('mutations', 'Var', (26, 35))	('gain', 'PosReg', (235, 239))	('MET', 'Gene', '79811', (92, 95))
55518	33178590	Moreover, when the survival association analysis was performed only for MET mutation status, MET mutations were associated with poor prognosis in LUAD (Figure 7D).	('mutations', 'Var', (97, 106))	('LUAD', 'Phenotype', 'HP:0030078', (146, 150))	('MET', 'Gene', '79811', (93, 96))	('LUAD', 'Disease', (146, 150))	('MET', 'Gene', '79811', (72, 75))	('MET', 'Gene', (93, 96))	('MET', 'Gene', (72, 75))
55520	33178590	UCEC, SKCM, and KIRP had the highest MET alteration, and mutations accounted for the major proportion.	('MET', 'Gene', (37, 40))	('mutations', 'Var', (57, 66))	('MET', 'Gene', '79811', (37, 40))
55521	33178590	While mutations in UCEC and SKCM were most commonly located in the Sema domain and the other function-unknown domain, mutations in KIRP were primarily located in the Pkinase-Tyr domain, which is more important for treatment selection.	('KIRP', 'Gene', (131, 135))	('located', 'Reg', (52, 59))	('Sema', 'Gene', (67, 71))	('mutations', 'Var', (118, 127))	('Sema', 'Gene', '7869', (67, 71))	('Tyr', 'Chemical', 'MESH:D014443', (174, 177))	('mutations', 'Var', (6, 15))	('UCEC', 'Gene', (19, 23))
55523	33178590	Other cancer types, including LUAD, BLCA, COADREAD, and UCS harbored similar characteristics; all their alteration frequency was between 4 and 6%, and mutation was the primary alteration.	('BLCA', 'Disease', (36, 40))	('LUAD', 'Disease', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutation', 'Var', (151, 159))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('COADREAD', 'Disease', (42, 50))	('UCS', 'Disease', (56, 59))	('LUAD', 'Phenotype', 'HP:0030078', (30, 34))
55524	33178590	Mutations in LUAD are mainly X1010_splices, which are in exon 14, and mutations in this region are known for targeted therapy in clinical practice in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('LUAD', 'Gene', (13, 17))	('X1010_splices', 'Var', (29, 42))	('NSCLC', 'Disease', (150, 155))	('LUAD', 'Phenotype', 'HP:0030078', (13, 17))
55532	33178590	In addition, the prognostic role of MET in LUAD was quite clear, and both high expression and amplification of MET were significantly associated with poor prognosis.	('associated', 'Reg', (134, 144))	('amplification', 'Var', (94, 107))	('high', 'Var', (74, 78))	('MET', 'Gene', '79811', (111, 114))	('MET', 'Gene', (111, 114))	('MET', 'Gene', '79811', (36, 39))	('MET', 'Gene', (36, 39))	('LUAD', 'Phenotype', 'HP:0030078', (43, 47))
55535	33178590	Compared with other cancer types, mutations in KIRP were primarily located in the Pkinase-Tyr domain, which is known for targeted therapy with TKIs.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Tyr', 'Chemical', 'MESH:D014443', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('mutations', 'Var', (34, 43))
55538	33178590	In addition, high expression of MET was discovered in KIRP, and most mutations in KIRP were oncogenic and likely oncogenic; however, there was no association observed between MET expression and patient prognosis in this dataset, although some reports indicated otherwise.	('MET', 'Gene', '79811', (175, 178))	('mutations', 'Var', (69, 78))	('patient', 'Species', '9606', (194, 201))	('MET', 'Gene', (175, 178))	('KIRP', 'Gene', (82, 86))	('MET', 'Gene', '79811', (32, 35))	('MET', 'Gene', (32, 35))
55539	33178590	This paradox could be due to the absence of well-known responsive mutations and the presence of alternative compensatory pathways interacting with MET pathways, such as the MAPK/ERK and PI3K/AKT pathways, which inspired further research on combinatorial therapy strategies in KIRP.	('mutations', 'Var', (66, 75))	('MET', 'Gene', '79811', (147, 150))	('AKT', 'Gene', '207', (191, 194))	('MET', 'Gene', (147, 150))	('AKT', 'Gene', (191, 194))	('ERK', 'Gene', '2048', (178, 181))	('ERK', 'Gene', (178, 181))
55544	33178590	However, several recent reports have showed that passenger mutations may also have critical functional roles in driving cancer, with some authors describing them as mini drivers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (120, 126))	('mutations', 'Var', (59, 68))
55545	33178590	They found that the aggregated impact of putative passenger mutations could provide significant predictive power to distinguish cancer from non-cancer phenotypes.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('non-cancer', 'Disease', 'MESH:D009369', (140, 150))	('cancer', 'Disease', (144, 150))	('non-cancer', 'Disease', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (128, 134))
55546	33178590	The above content implied to us that in some types of cancers, such as UCEC, even most of these mutations belonged to the unknown class; more efforts are needed to determine the meanings of these mutations, which might be found to also have important functional roles in driving tumorigenesis.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('cancers', 'Disease', (54, 61))	('UCEC', 'Disease', (71, 75))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('tumor', 'Disease', (279, 284))	('mutations', 'Var', (196, 205))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('mutations', 'Var', (96, 105))
55547	33178590	In addition, several reports have showed that some gene mutations, like BRAF mutation and ERBB2 mutation, were associated with MSI status in several cancer types.	('cancer', 'Disease', (149, 155))	('BRAF', 'Gene', (72, 76))	('MSI status', 'Disease', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('mutation', 'Var', (77, 85))	('associated', 'Reg', (111, 121))	('mutation', 'Var', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('ERBB2', 'Gene', '2064', (90, 95))	('ERBB2', 'Gene', (90, 95))	('BRAF', 'Gene', '673', (72, 76))
55567	33178590	Some alterations are more involved in the development of tumors, while others participate more in targeted therapy.	('involved', 'Reg', (26, 34))	('participate', 'Reg', (78, 89))	('alterations', 'Var', (5, 16))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
55624	32084210	In this meta-analysis, adjuvant chemotherapy was confirmed to be associated with improved OS, which was coincident with the previous meta-analysis.	('OS', 'Chemical', '-', (90, 92))	('adjuvant chemotherapy', 'Var', (23, 44))	('improved OS', 'Disease', (81, 92))
55636	32084210	From the other hand, next-generation and exome sequencing studies found that 10%~15% of cholangiocarcinoma patients had DNA repair mutations, and 40% of cholangiocarcinoma patients had positive programmed cell death receptor 1 (PDL1) expression, who might be the potential beneficiaries of immunotherapies.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (153, 171))	('mutations', 'Var', (131, 140))	('PDL1', 'Gene', (228, 232))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('positive', 'Reg', (185, 193))	('cholangiocarcinoma', 'Disease', (153, 171))	('cholangiocarcinoma', 'Disease', (88, 106))	('patients', 'Species', '9606', (172, 180))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (153, 171))	('PDL1', 'Gene', '29126', (228, 232))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 106))	('patients', 'Species', '9606', (107, 115))	('DNA repair', 'Gene', (120, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
55758	27000463	The proper classification and diagnosis of ICC have recently become even more critical as specific and potent inhibitors are under clinical development for certain oncogenic mutations that are found at high frequencies in ICC but are rare or absent in other epithelial malignancies.	('ICC', 'Disease', (222, 225))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (258, 281))	('epithelial malignancies', 'Disease', (258, 281))	('mutations', 'Var', (174, 183))	('epithelial malignancies', 'Disease', 'MESH:D002277', (258, 281))	('men', 'Species', '9606', (147, 150))
55764	27000463	Cholangiocarcinoma was identified by diagnostic codes from the World Health Organization's ICD-O coding system, using diagnostic coding criteria enumerated by Tyson et al.. ICC was identified with a topography code of C22.0 (liver) and a histology code of 8140, 8160, 8161, 8480, 8481, or 8500 or with a topography code of C22.1 (intrahepatic bile ducts) and a histology code of 8000, 8010, 8020, 8140, 8160, 8161, 8260, 8480, 8481, 8490, or 8500.	('8160', 'Var', (403, 407))	('8140', 'Var', (397, 401))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (0, 18))	('intrahepatic bile ducts', 'Disease', (330, 353))	('intrahepatic bile ducts', 'Disease', 'MESH:D002780', (330, 353))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 18))	('8480', 'Var', (421, 425))	('Cholangiocarcinoma', 'Disease', (0, 18))
55765	27000463	ECC was identified with a topography code of C24.1 (extrahepatic biliary ducts) and a histology code of 8000, 8010, 8020, 8140, 8160, 8161, 8260, 8480, 8481, 8490, or 8500, or for any case with a topography code of C22.0, C22.1, or C24.0 and a histology code of 8162 (Klatskin tumor).	('8480', 'Var', (146, 150))	('Klatskin tumor', 'Disease', 'MESH:D018285', (268, 282))	('8020', 'Var', (116, 120))	('8140', 'Var', (122, 126))	('8481', 'Var', (152, 156))	('C22.1', 'Var', (222, 227))	('8260', 'Var', (140, 144))	('8161', 'Var', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('8160', 'Var', (128, 132))	('ECC', 'Disease', (0, 3))	('8010', 'Var', (110, 114))	('C24.0', 'Var', (232, 237))	('Klatskin tumor', 'Disease', (268, 282))
55767	27000463	In a revision of the approach of Tyson et al., we included cancers with the topography-histology code pairing of C24.1 and 8020 (carcinoma, undifferentiated type, NOS); Tyson et al.	('carcinoma', 'Disease', 'MESH:D002277', (129, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('carcinoma', 'Disease', (129, 138))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))	('C24.1', 'Var', (113, 118))
55769	27000463	We prospectively excluded cancer cases with topography codes of C24.8 (overlapping sites of the biliary tract) or C24.9 (malignant neoplasm of the biliary tract, unspecified) because these codes are infrequently used and cannot be reliably mapped to ICC, ECC, or other biliary tumor sites (such as the gallbladder or the ampulla of Vater).	('C24.8', 'Var', (64, 69))	('C24.9', 'Var', (114, 119))	('biliary tumor', 'Disease', (269, 282))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('ICC', 'Disease', (250, 253))	('malignant neoplasm of the biliary tract', 'Disease', (121, 160))	('unspecified', 'Species', '32644', (162, 173))	('neoplasm', 'Phenotype', 'HP:0002664', (131, 139))	('biliary tumor', 'Phenotype', 'HP:0100574', (269, 282))	('ECC', 'Disease', (255, 258))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('neoplasm of the biliary tract', 'Phenotype', 'HP:0100574', (131, 160))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('malignant neoplasm of the biliary tract', 'Disease', 'MESH:D001661', (121, 160))	('biliary tumor', 'Disease', 'MESH:D001661', (269, 282))
55795	27000463	As the use of molecular diagnostics for the identification of targetable lesions, such as IDH1/2 mutations and FGFR2 fusions, increases, our ability to accurately diagnose these tumors may also improve, along with our understanding of the true incidence of ICC.	('fusions', 'Var', (117, 124))	('mutations', 'Var', (97, 106))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('FGFR2', 'Gene', (111, 116))	('FGFR2', 'Gene', '2263', (111, 116))	('IDH1/2', 'Gene', '3417;3418', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('IDH1/2', 'Gene', (90, 96))
55804	27000463	Recent progress in molecular genetics and the development of pharmacological inhibitors of pathologic mutations specifically found in ICC, including drugs targeting mutations in IDH1/2 and FGFR2 fusions, provide one avenue to combat this rising challenge.	('IDH1/2', 'Gene', '3417;3418', (178, 184))	('IDH1/2', 'Gene', (178, 184))	('ICC', 'Disease', (134, 137))	('mutations', 'Var', (165, 174))	('men', 'Species', '9606', (53, 56))	('FGFR2', 'Gene', (189, 194))	('FGFR2', 'Gene', '2263', (189, 194))
55919	27176078	CD44 variant-dependent redox status regulation in liver fluke-associated cholangiocarcinoma: A target for cholangiocarcinoma treatment Expression of CD44, especially the variant isoforms (CD44v) of this major cancer stem cell marker, contributes to reactive oxygen species (ROS) defense through stabilizing xCT (a cystine-glutamate transporter) and promoting glutathione synthesis.	('promoting', 'PosReg', (349, 358))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (106, 124))	('variant', 'Var', (170, 177))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (249, 272))	('contributes', 'PosReg', (234, 245))	('xCT', 'Gene', '23657', (307, 310))	('cholangiocarcinoma', 'Disease', (106, 124))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (106, 124))	('CD44', 'Gene', '960', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('CD44', 'Gene', (0, 4))	('glutathione synthesis', 'MPA', (359, 380))	('glutathione', 'Chemical', 'MESH:D005978', (359, 370))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (73, 91))	('glutamate', 'Chemical', 'MESH:D018698', (322, 331))	('CD44', 'Gene', '960', (188, 192))	('cholangiocarcinoma', 'Disease', (73, 91))	('CD44', 'Gene', (188, 192))	('xCT', 'Gene', (307, 310))	('cystine', 'Chemical', 'MESH:D003553', (314, 321))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (73, 91))	('CD44', 'Gene', '960', (149, 153))	('ROS', 'Chemical', 'MESH:D017382', (274, 277))	('liver fluke', 'Species', '6192', (50, 61))	('reactive oxygen species', 'MPA', (249, 272))	('CD44', 'Gene', (149, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('variant-dependent', 'Var', (5, 22))	('cancer', 'Disease', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
55923	27176078	Patients with CCA showed CD44v overexpression and negative-phospho-p38MAPK patients a significantly shorter survival rate than the low CD44v signal and positive-phospho-p38MAPK patients (P = 0.030).	('patients', 'Species', '9606', (177, 185))	('patients', 'Species', '9606', (75, 83))	('CCA', 'Phenotype', 'HP:0030153', (14, 17))	('shorter', 'NegReg', (100, 107))	('Patients', 'Species', '9606', (0, 8))	('CD44v', 'Var', (25, 30))	('overexpression', 'PosReg', (31, 45))	('negative-phospho-p38MAPK', 'Var', (50, 74))	('CCA', 'Disease', (14, 17))	('survival', 'MPA', (108, 116))
55953	27176078	For IHC and immunofluorescent staining, anti-CD44s was purchased from BD Bioscience (BD Bioscience, Tokyo, Japan), anti-CD44v8-10 was purchased from Cosmo Bio (Tokyo, Japan), and anti-total and phospho-p38MAPK (Tyr180/182) was purchased from Cell Signaling Technology (Danvers, MA, USA.)	('CD44s', 'Gene', (45, 50))	('anti-CD44v8-10', 'Var', (115, 129))	('CD44v8-10', 'Chemical', '-', (120, 129))	('CD44s', 'Gene', '960', (45, 50))
55954	27176078	For immunoblotting, anti-LC3B was purchased from Abcam (Cambridge, UK), anti-p21 was purchased from Santa Cruz (Santa Cruz Biotechnology, CA, USA) and anti-beta-actin antibody was purchased from Sigma-Aldrich.	('anti-LC3B', 'Var', (20, 29))	('p21', 'Gene', '644914', (77, 80))	('p21', 'Gene', (77, 80))
55962	27176078	The samples were then exposed to 3% BSA before being incubated at 4 C overnight with primary antibodies (CD44v8-10, phospho-p38MAPK, and p21).	('p21', 'Gene', '644914', (137, 140))	('CD44v8-10', 'Chemical', '-', (105, 114))	('CD44v8-10', 'Var', (105, 114))	('phospho-p38MAPK', 'Var', (116, 131))	('p21', 'Gene', (137, 140))
55985	27176078	The strongest expression of CD44s and CD44v appeared to occur at days 120 and 180 in both dysplasia and the malignant bile duct epithelia (Fig.	('CD44s', 'Gene', '960', (28, 33))	('bile duct epithelia', 'Phenotype', 'HP:0030986', (118, 137))	('CD44s', 'Gene', (28, 33))	('CD44v', 'Var', (38, 43))	('dysplasia and the malignant bile duct epithelia', 'Disease', 'MESH:D001650', (90, 137))
55988	27176078	These results indicate that CD44s and CD44v8-10 are highly expressed during cholangiocarcinogenesis and are related to the increased regulation of redox status.	('increased', 'PosReg', (123, 132))	('CD44s', 'Gene', '960', (28, 33))	('cholangiocarcinogenesis', 'Disease', (76, 99))	('CD44s', 'Gene', (28, 33))	('CD44v8-10', 'Chemical', '-', (38, 47))	('CD44v8-10', 'Var', (38, 47))	('regulation of redox status', 'MPA', (133, 159))	('cholangiocarcinogenesis', 'Disease', 'None', (76, 99))	('related', 'Reg', (108, 115))
55991	27176078	Chronic inflammatory responses of cytokine signaling are the key molecular mechanisms underlying Ov-associated CCA, whereas aberrant growth factor signaling plays a major role in non-Ov associated CCA.35 We thus evaluated the different patterns of CD44v8-10 and p38MAPK expression in Ov- and non-Ov-related CCA liver tissues.	('aberrant growth', 'Phenotype', 'HP:0001507', (124, 139))	('Ov', 'Species', '6198', (183, 185))	('CD44v8-10', 'Gene', (248, 257))	('Ov', 'Species', '6198', (97, 99))	('Ov', 'Species', '6198', (284, 286))	('p38MAPK', 'Var', (262, 269))	('CCA', 'Phenotype', 'HP:0030153', (307, 310))	('CD44v8-10', 'Chemical', '-', (248, 257))	('CCA', 'Phenotype', 'HP:0030153', (197, 200))	('CCA', 'Phenotype', 'HP:0030153', (111, 114))	('Ov', 'Species', '6198', (296, 298))	('CCA', 'Disease', (307, 310))
55992	27176078	Our results showed that there was a negative association between phospho-p38MAPK and CD44v8-10 in Ov-associated CCA patients (76%).	('CCA', 'Phenotype', 'HP:0030153', (112, 115))	('phospho-p38MAPK', 'Var', (65, 80))	('patients', 'Species', '9606', (116, 124))	('CD44v8-10', 'Chemical', '-', (85, 94))	('CD44v8-10', 'Var', (85, 94))	('CCA', 'Disease', (112, 115))	('Ov', 'Species', '6198', (98, 100))	('Ov-associated', 'Disease', (98, 111))	('negative', 'NegReg', (36, 44))
55993	27176078	This was higher than in non-Ov-associated CCA patients (52%), although CD44v8-10high expression was seen in non-Ov-related CCA patients (50%), which was as high as in Ov-related CCA patients (43%; Fig.	('CCA', 'Phenotype', 'HP:0030153', (123, 126))	('patients', 'Species', '9606', (46, 54))	('CD44v8-10', 'Chemical', '-', (71, 80))	('CCA', 'Phenotype', 'HP:0030153', (178, 181))	('Ov', 'Species', '6198', (167, 169))	('CD44v8-10high', 'Var', (71, 84))	('Ov', 'Species', '6198', (112, 114))	('CCA', 'Phenotype', 'HP:0030153', (42, 45))	('non-Ov-related CCA', 'Disease', (108, 126))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (182, 190))	('Ov', 'Species', '6198', (28, 30))	('higher', 'PosReg', (9, 15))
55997	27176078	In addition, the colocalization of CD44v8-10 and phospho-p38MAPK showed a CD44v8-10-positive signal that was inversely correlated with p38MAPK (Fig.	('colocalization', 'Interaction', (17, 31))	('CD44v8-10', 'Chemical', '-', (35, 44))	('CD44v8-10-positive', 'Var', (74, 92))	('CD44v8-10', 'Chemical', '-', (74, 83))
55998	27176078	The CD44v8-10high patients with a negative phospho-p38MAPK had a significantly shorter survival than CD44v8-10low patients with a positive phospho-p38MAPK (P = 0.030; Fig.	('survival', 'MPA', (87, 95))	('negative', 'NegReg', (34, 42))	('shorter', 'NegReg', (79, 86))	('CD44v8-10', 'Chemical', '-', (4, 13))	('patients', 'Species', '9606', (18, 26))	('CD44v8-10', 'Chemical', '-', (101, 110))	('CD44v8-10high', 'Var', (4, 17))	('patients', 'Species', '9606', (114, 122))
56000	27176078	Our observations suggest that CD44v8-10 plays a role in the regulation of the ROS defense system (high CD44v8-10, negative p38MAPK), which is linked to a poor prognosis in CCA patients.	('ROS', 'Chemical', 'MESH:D017382', (78, 81))	('patients', 'Species', '9606', (176, 184))	('CCA', 'Phenotype', 'HP:0030153', (172, 175))	('CD44v8-10', 'Chemical', '-', (30, 39))	('regulation', 'MPA', (60, 70))	('high CD44v8-10', 'Var', (98, 112))	('CD44v8-10', 'Chemical', '-', (103, 112))	('CD44v8-10', 'Var', (103, 112))	('CCA', 'Disease', (172, 175))
56002	27176078	The levels of CD44s, CD44v8-10, and xCT in three human CCA cell lines (KKU-213, KKU-214, and KKU-100) were evaluated by using flow cytometry analysis.	('CD44s', 'Gene', '960', (14, 19))	('CCA', 'Phenotype', 'HP:0030153', (55, 58))	('human', 'Species', '9606', (49, 54))	('CD44v8-10', 'Chemical', '-', (21, 30))	('CD44s', 'Gene', (14, 19))	('CD44v8-10', 'Var', (21, 30))	('xCT', 'Gene', (36, 39))	('KKU-100', 'Disease', 'OMIM:300114', (93, 100))	('KKU-100', 'Disease', (93, 100))	('xCT', 'Gene', '23657', (36, 39))
56007	27176078	Furthermore, CD44 siRNA-transfected cells had a lower xCT signal than control siRNA-transfected cells (Fig.	('xCT', 'Gene', (54, 57))	('xCT', 'Gene', '23657', (54, 57))	('lower', 'NegReg', (48, 53))	('CD44', 'Var', (13, 17))
56008	27176078	These results suggest that CD44v8-10 could stabilize xCT on membranes in CCA cell lines.	('xCT', 'Gene', '23657', (53, 56))	('CCA', 'Phenotype', 'HP:0030153', (73, 76))	('CD44v8-10', 'Chemical', '-', (27, 36))	('xCT', 'Gene', (53, 56))	('CD44v8-10', 'Var', (27, 36))	('CCA', 'Disease', (73, 76))
56010	27176078	The GSH level was clearly decreased whereas the ROS was increased with CD44v8-10 reduction under oxidative stress (Fig.	('ROS', 'MPA', (48, 51))	('CD44v8-10', 'Chemical', '-', (71, 80))	('CD44v8-10', 'Var', (71, 80))	('increased', 'PosReg', (56, 65))	('oxidative stress', 'Phenotype', 'HP:0025464', (97, 113))	('GSH level', 'MPA', (4, 13))	('ROS', 'Chemical', 'MESH:D017382', (48, 51))	('reduction', 'NegReg', (81, 90))	('decreased', 'NegReg', (26, 35))	('GSH', 'Chemical', 'MESH:D005978', (4, 7))
56013	27176078	Our observations showed that SSZ-treated CD44v8-10high-expressing CCA cells had higher ROS levels than SSZ-treated CD44v8-10low-expressing CCA cells.	('CD44v8-10high-expressing', 'Var', (41, 65))	('SSZ', 'Chemical', 'MESH:D012460', (103, 106))	('CCA', 'Phenotype', 'HP:0030153', (66, 69))	('ROS levels', 'MPA', (87, 97))	('higher', 'PosReg', (80, 86))	('ROS', 'Chemical', 'MESH:D017382', (87, 90))	('SSZ', 'Chemical', 'MESH:D012460', (29, 32))	('CD44v8-10', 'Chemical', '-', (41, 50))	('CD44v8-10', 'Chemical', '-', (115, 124))	('CCA', 'Phenotype', 'HP:0030153', (139, 142))	('CCA', 'Disease', (66, 69))
56017	27176078	These results suggest that a CD44v8-10-xCT-dependent ROS defense system exists with high CD44v8-10 and xCT expression, whereas low expression cells were not affected.	('xCT', 'Gene', '23657', (39, 42))	('CD44v8-10', 'Chemical', '-', (89, 98))	('xCT', 'Gene', (103, 106))	('CD44v8-10', 'Var', (89, 98))	('xCT', 'Gene', '23657', (103, 106))	('ROS', 'Chemical', 'MESH:D017382', (53, 56))	('xCT', 'Gene', (39, 42))	('CD44v8-10', 'Chemical', '-', (29, 38))
56019	27176078	The results clearly showed that KKU-213 and KKU-214 were more sensitive to SSZ treatment than KKU-100 (Fig.	('SSZ', 'Chemical', 'MESH:D012460', (75, 78))	('KKU-100', 'Disease', 'OMIM:300114', (94, 101))	('KKU-100', 'Disease', (94, 101))	('sensitive', 'MPA', (62, 71))	('KKU-214', 'Var', (44, 51))
56021	27176078	Our results show that SSZ-treated cells proliferated significantly more slowly than control cells in all cell lines (Fig.	('SSZ-treated', 'Var', (22, 33))	('SSZ', 'Chemical', 'MESH:D012460', (22, 25))	('slowly', 'NegReg', (72, 78))	('proliferated', 'CPA', (40, 52))
56022	27176078	We also showed that phospho-p38MAPK, p21 (cell cycle inhibitor), and LC3B-II (autophagic protein) expression was upregulated after SSZ treatment (Fig.	('upregulated', 'PosReg', (113, 124))	('p21', 'Gene', '644914', (37, 40))	('SSZ', 'Chemical', 'MESH:D012460', (131, 134))	('p21', 'Gene', (37, 40))	('phospho-p38MAPK', 'Var', (20, 35))	('LC3B-II', 'Gene', (69, 76))	('expression', 'MPA', (98, 108))
56023	27176078	4f,g), hence an inhibition of cell proliferation was stimulated by p38MAPK, possibly through p21 signaling, and cell death processes were induced by the autophagic pathway.	('autophagic pathway', 'CPA', (153, 171))	('cell proliferation', 'CPA', (30, 48))	('inhibition', 'NegReg', (16, 26))	('p21', 'Gene', (93, 96))	('cell death processes', 'CPA', (112, 132))	('p21', 'Gene', '644914', (93, 96))	('p38MAPK', 'Var', (67, 74))	('induced', 'Reg', (138, 145))
56034	27176078	We thereby hypothesized that CD44v8-10 might regulate the ROS defense system (high CD44v8-10, negative p38MAPK), linking to the poor prognosis for CCA patients.	('CCA', 'Phenotype', 'HP:0030153', (147, 150))	('ROS', 'Chemical', 'MESH:D017382', (58, 61))	('patients', 'Species', '9606', (151, 159))	('regulate', 'Reg', (45, 53))	('CD44v8-10', 'Chemical', '-', (83, 92))	('CD44v8-10', 'Var', (83, 92))	('ROS defense system', 'MPA', (58, 76))	('CCA', 'Disease', (147, 150))	('high CD44v8-10', 'Var', (78, 92))	('negative', 'NegReg', (94, 102))	('CD44v8-10', 'Chemical', '-', (29, 38))	('CD44v8-10', 'Var', (29, 38))
56036	27176078	Our findings revealed that CD44v8-10 regulates redox status by stabilizing xCT, resulting in a reduced GSH level and decrease in the ROS level.	('CD44v8-10', 'Var', (27, 36))	('xCT', 'Gene', '23657', (75, 78))	('GSH', 'Chemical', 'MESH:D005978', (103, 106))	('GSH level', 'MPA', (103, 112))	('CD44v8-10', 'Chemical', '-', (27, 36))	('reduced', 'NegReg', (95, 102))	('decrease', 'NegReg', (117, 125))	('xCT', 'Gene', (75, 78))	('ROS', 'Chemical', 'MESH:D017382', (133, 136))	('ROS level', 'MPA', (133, 142))
56038	27176078	The alteration of redox status can activate ROS-p38MAPK signaling, resulting in inhibition of cell growth through the accumulation of p21.	('inhibition', 'NegReg', (80, 90))	('p21', 'Gene', '644914', (134, 137))	('activate', 'PosReg', (35, 43))	('alteration', 'Var', (4, 14))	('accumulation', 'PosReg', (118, 130))	('ROS-p38MAPK signaling', 'Pathway', (44, 65))	('ROS', 'Chemical', 'MESH:D017382', (44, 47))	('p21', 'Gene', (134, 137))	('cell growth', 'CPA', (94, 105))
56040	27176078	Recently, it was shown that CD44v8-10, but not CD44s, play roles in the regulation of redox status through specifically interacting with xCT in CSCs.	('regulation of redox status', 'MPA', (72, 98))	('xCT', 'Gene', (137, 140))	('CD44s', 'Gene', (47, 52))	('xCT', 'Gene', '23657', (137, 140))	('CD44v8-10', 'Chemical', '-', (28, 37))	('CD44v8-10', 'Var', (28, 37))	('interacting', 'Interaction', (120, 131))	('CSCs', 'Disease', (144, 148))	('CD44s', 'Gene', '960', (47, 52))
56043	27176078	Moreover, p38MAPK has been reported to contribute to suppression of carcinoma development by inhibiting cell growth and the induction of cell death.	('cell death', 'CPA', (137, 147))	('p38MAPK', 'Var', (10, 17))	('suppression of carcinoma', 'Disease', 'OMIM:146850', (53, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('inhibiting', 'NegReg', (93, 103))	('suppression of carcinoma', 'Disease', (53, 77))	('cell growth', 'CPA', (104, 115))
56047	27176078	We observed that the negative association of CD44v8-10 and p38MAPK expression in Ov-associated CCA patients correlated with clinicopathological data, whereas this was not seen in non-Ov-associated CCA patients.	('patients', 'Species', '9606', (201, 209))	('Ov', 'Species', '6198', (183, 185))	('negative', 'NegReg', (21, 29))	('p38MAPK', 'Var', (59, 66))	('patients', 'Species', '9606', (99, 107))	('CCA', 'Phenotype', 'HP:0030153', (197, 200))	('Ov', 'Species', '6198', (81, 83))	('CD44v8-10', 'Chemical', '-', (45, 54))	('CD44v8-10', 'Var', (45, 54))	('CCA', 'Phenotype', 'HP:0030153', (95, 98))	('Ov-associated CCA', 'Disease', (81, 98))	('expression', 'MPA', (67, 77))
56053	27176078	Atg autophagy-related BSO buthionine sulphoximine CCA cholangiocarcinoma CD44s standard CD44 CD44v CD44 variant CSC cancer stem cell DCF dichlorofluorescein DCFH-DA dichloro-dihydro-fluorescein diacetate GSH reduced glutathione IHC immunohistochemical LC3 microtubule-associated protein 1A/1B-light chain 3 Ov  Opisthorchis viverrini  ROS reactive oxygen species SSZ sulfasalazine Trolox 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid	('ROS', 'Chemical', 'MESH:D017382', (335, 338))	('Ov', 'Species', '6198', (307, 309))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (54, 72))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('CD44s', 'Gene', '960', (73, 78))	('Opisthorchis viverrini', 'Species', '6198', (311, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('variant', 'Var', (104, 111))	('glutathione', 'Chemical', 'MESH:D005978', (216, 227))	('GSH', 'Chemical', 'MESH:D005978', (204, 207))	('dichloro-dihydro-fluorescein diacetate', 'Chemical', '-', (165, 203))	('CCA', 'Phenotype', 'HP:0030153', (50, 53))	('sulfasalazine', 'Chemical', 'MESH:D012460', (367, 380))	('cancer', 'Disease', (116, 122))	('6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid', 'Chemical', 'MESH:C010643', (388, 442))	('dichlorofluorescein', 'Chemical', 'MESH:C037631', (137, 156))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (339, 362))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('Trolox', 'Chemical', '-', (381, 387))	('Ov  Opisthorchis', 'Phenotype', 'HP:0002179', (307, 323))	('CD44s', 'Gene', (73, 78))	('DCF', 'Chemical', 'MESH:D015649', (133, 136))	('DCF', 'Chemical', 'MESH:D015649', (157, 160))	('buthionine sulphoximine', 'Chemical', 'MESH:D019328', (26, 49))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('SSZ', 'Chemical', 'MESH:D012460', (363, 366))	('DCFH-DA', 'Chemical', 'MESH:C029569', (157, 164))	('cholangiocarcinoma', 'Disease', (54, 72))
56059	22290335	Predictors of dropout were CA 19-9 >= 500 U/ml (HR 2.3; P=.04), mass >= 3 cm (HR 2.2; P=.01), malignant brushing or biopsy (HR 3.6; P=.001) and MELD score >= 20 (HR 3.5; P=.02).	('malignant brushing', 'Disease', 'MESH:D009369', (94, 112))	('malignant brushing', 'Disease', (94, 112))	('CA 19-9 >= 500 U/ml', 'Var', (27, 46))	('dropout', 'Disease', (14, 21))
56069	22290335	Intraluminal brushing or biopsy of a dominant stricture on endoscopic retrograde cholangiopancreaticography (ERCP), polysomy on Fluorescence In Situ Hybridization (FISH), elevated tumor marker carbohydrate antigen 19-9 (CA 19-9) and visualization of a mass on imaging, preferably in combination, lead to a sensitivity of only 45-50%, though a specificity of 96-100%.	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('elevated tumor marker carbohydrate antigen 19-', 'Phenotype', 'HP:0032345', (171, 217))	('elevated tumor', 'Disease', (171, 185))	('carbohydrate', 'Chemical', 'MESH:D002241', (193, 205))	('elevated tumor', 'Disease', 'MESH:D009369', (171, 185))	('polysomy', 'Var', (116, 124))	('carbohydrate', 'MPA', (193, 205))
56081	22290335	Diagnosis was established in the presence of 1) positive or strongly suspicious intraluminal brush or biopsy or, 2) a radiographic malignant appearing stricture plus either CA 19-9 > 100 U/ml in the absence of acute bacterial cholangitis, polysomy on FISH (available since 2003), or well-defined mass on cross-sectional imaging.	('bacterial cholangitis', 'Disease', (216, 237))	('CA 19-9', 'Var', (173, 180))	('cholangitis', 'Phenotype', 'HP:0030151', (226, 237))	('bacterial cholangitis', 'Disease', 'MESH:D002761', (216, 237))
56122	22290335	Of variables available at the time of transplant, CA 19-9, residual tumor on the explant, and perineural invasion were significantly associated with increased recurrence risk in univariate analyses.	('tumor', 'Disease', (68, 73))	('perineural invasion', 'CPA', (94, 113))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('CA 19-9', 'Var', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
56131	22290335	Second, although the majority of patients (N=183; 92%) eventually had definite proof of CCA by either pre-transplant intraluminal brushing or biopsy, radiological evidence of a well-defined tumor mass, tumor tissue on explant or CCA recurrence, 16 patients (8%) did not despite having constitutional symptoms, a malignant stricture, CA 19-9 > 100 U/ml and/or positive FISH.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('patients', 'Species', '9606', (33, 41))	('tumor', 'Disease', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('CCA', 'Disease', (88, 91))	('intraluminal brushing', 'Disease', (117, 138))	('intraluminal brushing', 'Disease', 'MESH:C537470', (117, 138))	('tumor', 'Disease', (190, 195))	('CA 19-9 > 100 U/ml', 'Var', (333, 351))	('constitutional symptoms', 'Phenotype', 'HP:0025142', (285, 308))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('patients', 'Species', '9606', (248, 256))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
56186	22290335	Elevated CA 19-9, encasement of the portal vein and, most importantly, residual tumor cells were associated with increased risk for recurrence after transplantation.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (80, 85))	('encasement', 'Var', (18, 28))
56218	23111165	Furthermore, the sensitivities of these markers can be low (25% to 50%) in poorly differentiated HCCs for polyclonal CEA and 50% for CD10) .	('CEA', 'Gene', (117, 120))	('CEA', 'Gene', '1048', (117, 120))	('sensitivities', 'MPA', (17, 30))	('CD10', 'Gene', (133, 137))	('HCC', 'Gene', (97, 100))	('CD10', 'Gene', '4311', (133, 137))	('HCC', 'Gene', '619501', (97, 100))	('polyclonal', 'Var', (106, 116))
56333	20160031	shRNA targeted knockdown of Bax doubled the IC50 for obatoclax, but did not abrogate its cytotoxicity, while knockdown of Bak did not alter the IC50.	('knockdown', 'Var', (15, 24))	('cytotoxicity', 'Disease', 'MESH:D064420', (89, 101))	('cytotoxicity', 'Disease', (89, 101))	('doubled', 'PosReg', (32, 39))	('IC50', 'MPA', (44, 48))	('Bax', 'Gene', (28, 31))	('obatoclax', 'Chemical', 'MESH:C520962', (53, 62))
56353	20160031	Recent data suggest activator BH3-only proteins may directly activate Bax by binding to a site distinct from its BH3 groove, and mutation of lysine 21 (K21E) abolishes Bax activation.	('lysine', 'Chemical', 'MESH:D008239', (141, 147))	('BH3', 'Chemical', 'MESH:C006008', (113, 116))	('activate', 'PosReg', (61, 69))	('BH3', 'Chemical', 'MESH:C006008', (30, 33))	('mutation', 'Var', (129, 137))	('K21E', 'Mutation', 'p.K21E', (152, 156))	('activation', 'MPA', (172, 182))	('Bax', 'CPA', (168, 171))	('abolishes', 'NegReg', (158, 167))	('binding', 'Interaction', (77, 84))	('Bax', 'Protein', (70, 73))
56431	20160031	The activation of the K21E Bax was attenuated as demonstrated by a decrease in the amount of immunoprecipated active Bax following obatoclax treatment as compared to detergent treated protein (Fig 4A).	('rat', 'Species', '10116', (56, 59))	('K21E', 'Var', (22, 26))	('decrease', 'NegReg', (67, 75))	('K21E', 'Mutation', 'p.K21E', (22, 26))	('obatoclax', 'Chemical', 'MESH:C520962', (131, 140))	('amount of immunoprecipated active Bax', 'MPA', (83, 120))
56432	20160031	Additionally, oligomerization of wild-type Bax (trimers and tetramers) in the cell-free system could be demonstrated in a concentration dependent manner with obatoclax treatment and cross-linking (Fig 4B), however the higher order multiples were significantly decreased or absent in the mutant protein.	('rat', 'Species', '10116', (111, 114))	('decreased', 'NegReg', (260, 269))	('obatoclax', 'Chemical', 'MESH:C520962', (158, 167))	('rat', 'Species', '10116', (129, 132))	('absent', 'NegReg', (273, 279))	('mutant', 'Var', (287, 293))	('oligomerization', 'MPA', (14, 29))
56520	32457263	Right trisectionectomy with en bloc portal vein resection for cholangiocarcinoma after preoperative stenting for main portal vein occlusion Deprivation of portal blood flow decreases the hepatic function, thus hepatobiliary cancer patients with total occlusion of the main portal vein (PV) are usually not indicated for major hepatectomy.	('decreases the hepatic function', 'Phenotype', 'HP:0001410', (173, 203))	('cholangiocarcinoma', 'Disease', (62, 80))	('patients', 'Species', '9606', (231, 239))	('vein occlusion', 'Phenotype', 'HP:0025322', (125, 139))	('hepatic function', 'MPA', (187, 203))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('vein occlusion', 'Disease', 'MESH:D012170', (125, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('vein occlusion', 'Disease', (125, 139))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (62, 80))	('trisectionectomy with en bloc portal vein resection', 'Phenotype', 'HP:0031015', (6, 57))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (62, 80))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('decreases', 'NegReg', (173, 182))	('portal vein occlusion', 'Phenotype', 'HP:0030242', (118, 139))	('cancer', 'Disease', (224, 230))	('Deprivation', 'Var', (140, 151))
56528	32457263	Deprivation of portal flow decreases the liver function and interferes functional recovery from obstructive jaundice.	('decreases', 'NegReg', (27, 36))	('Deprivation', 'Var', (0, 11))	('liver function', 'MPA', (41, 55))	('jaundice', 'Phenotype', 'HP:0000952', (108, 116))	('interferes', 'NegReg', (60, 70))	('obstructive jaundice', 'Disease', 'MESH:D041781', (96, 116))	('decreases the liver function', 'Phenotype', 'HP:0001410', (27, 55))	('obstructive jaundice', 'Disease', (96, 116))
56580	29747443	All samples were investigated immunohistochemically for the presence of MSI (expression of MLH1, PMS2, MSH2, and MSH6) as well as by pentaplex polymerase chain reaction for five quasimonomorphic mononucleotide repeats (BAT-25, BAT-26, NR-21, NR-22, and NR-24).	('mononucleotide', 'Chemical', '-', (195, 209))	('BAT-25', 'Var', (219, 225))	('MLH1', 'Gene', '4292', (91, 95))	('MLH1', 'Gene', (91, 95))	('MSH2', 'Gene', (103, 107))	('PMS2', 'Gene', (97, 101))	('MSH2', 'Gene', '4436', (103, 107))	('MSH6', 'Gene', (113, 117))	('PMS2', 'Gene', '5395', (97, 101))	('MSH6', 'Gene', '2956', (113, 117))
56593	29747443	Besides the immunohistochemical evaluation of PD-L1 expression, microsatellite instability (MSI) seems to be associated with an improved clinical response rate: MSI induces somatic hypermutation and consecutively neoepitopes, which might create an immune response.	('PD-L1', 'Gene', (46, 51))	('microsatellite', 'MPA', (64, 78))	('PD-L1', 'Gene', '29126', (46, 51))	('induces', 'Reg', (165, 172))	('neoepitopes', 'MPA', (213, 224))	('MSI', 'Var', (161, 164))
56594	29747443	Moreover, a durable response to immune checkpoint inhibition was shown in a patient with an advanced-stage, microsatellite-unstable CCA.	('patient', 'Species', '9606', (76, 83))	('microsatellite-unstable', 'Var', (108, 131))	('CCA', 'Phenotype', 'HP:0030153', (132, 135))	('CCA', 'Disease', (132, 135))
56605	29747443	Besides immunohistochemistry, MSI was evaluated using five quasimonomorphic mononucleotide repeats (BAT-25, BAT-26, NR-21, NR-22, and NR-24) in a pentaplex PCR, as described in Suraweera et al.	('BAT-26', 'Var', (108, 114))	('NR-24', 'Var', (134, 139))	('BAT-25', 'Var', (100, 106))	('mononucleotide', 'Chemical', '-', (76, 90))	('NR-21', 'Var', (116, 121))
56609	29747443	Recent data suggested that patients with microsatellite-unstable CCA might profit from immune-modulating therapy.	('CCA', 'Disease', (65, 68))	('patients', 'Species', '9606', (27, 35))	('microsatellite-unstable', 'Var', (41, 64))	('CCA', 'Phenotype', 'HP:0030153', (65, 68))
56666	29113399	Our group recently reported that a polymorphism in the gene encoding cytidine deaminase (CDA) may predict the efficacy of gemcitabine-based chemotherapy in patients with advanced BTC.	('patients', 'Species', '9606', (156, 164))	('gemcitabine', 'Chemical', 'MESH:C056507', (122, 133))	('cytidine deaminase', 'Gene', '978', (69, 87))	('polymorphism', 'Var', (35, 47))	('CDA', 'Gene', '978', (89, 92))	('efficacy', 'MPA', (110, 118))	('predict', 'Reg', (98, 105))	('BTC', 'Phenotype', 'HP:0100574', (179, 182))	('cytidine deaminase', 'Gene', (69, 87))	('CDA', 'Gene', (89, 92))
56719	29113399	The expression of the dCK gene and protein and single-nucleotide SNPs in the dCK gene have been closely associated with gemcitabine chemosensitivity in patients with pancreatic cancer.	('dCK', 'Gene', (22, 25))	('gemcitabine', 'Chemical', 'MESH:C056507', (120, 131))	('protein', 'Protein', (35, 42))	('dCK', 'Gene', '43828', (22, 25))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (166, 183))	('expression', 'MPA', (4, 14))	('pancreatic cancer', 'Disease', (166, 183))	('associated with', 'Reg', (104, 119))	('pancreatic cancer', 'Disease', 'MESH:D010190', (166, 183))	('single-nucleotide SNPs', 'Var', (47, 69))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('dCK', 'Gene', '43828', (77, 80))	('patients', 'Species', '9606', (152, 160))	('dCK', 'Gene', (77, 80))
56722	29113399	Several genetic and epigenetic alterations, including gene mutations, amplifications, polymorphic status or altered gene/protein expression and activity, have been associated with gemcitabine response and toxicities.	('altered', 'Reg', (108, 115))	('associated', 'Reg', (164, 174))	('toxicities', 'Disease', (205, 215))	('toxicities', 'Disease', 'MESH:D064420', (205, 215))	('amplifications', 'Var', (70, 84))	('gene mutations', 'Var', (54, 68))	('polymorphic status', 'Var', (86, 104))	('gemcitabine', 'Chemical', 'MESH:C056507', (180, 191))	('gene/protein expression', 'MPA', (116, 139))	('activity', 'MPA', (144, 152))
56765	29113399	Immunohistochemical labeling of hENT1, dCK, RRM1 and CDA was scored as positive, indicating the presence of an intact gene, or negative, indicating a deletion or inactivating mutation of that gene (Figure 4, Supplementary Figure 2).	('dCK', 'Gene', (39, 42))	('CDA', 'Gene', '978', (53, 56))	('dCK', 'Gene', '43828', (39, 42))	('hENT1', 'Gene', (32, 37))	('deletion', 'Var', (150, 158))	('inactivating mutation', 'Var', (162, 183))	('CDA', 'Gene', (53, 56))	('RRM1', 'Gene', '6240', (44, 48))	('hENT1', 'Gene', '2030', (32, 37))	('RRM1', 'Gene', (44, 48))
56842	28056836	In addition, we found that the ICC patients who had LOS <=7 days had significantly lower frequency of comorbidities including atherosclerotic heart disease , congestive heart failure, cirrhosis, viral hepatitis B viral hepatitis C and HIV infection than those with LOS >7 days (p <0.05) (Additional file 1: Table S3).	('atherosclerotic heart disease', 'Disease', 'MESH:D050197', (126, 155))	('hepatitis', 'Phenotype', 'HP:0012115', (219, 228))	('congestive heart failure', 'Phenotype', 'HP:0001635', (158, 182))	('atherosclerotic heart disease', 'Disease', (126, 155))	('congestive heart failure', 'Disease', 'MESH:D006333', (158, 182))	('hepatitis', 'Phenotype', 'HP:0012115', (201, 210))	('lower', 'NegReg', (83, 88))	('cirrhosis', 'Disease', (184, 193))	('congestive heart failure', 'Disease', (158, 182))	('viral hepatitis', 'Phenotype', 'HP:0006562', (213, 228))	('viral hepatitis B viral hepatitis C and HIV infection', 'Disease', 'MESH:D006525', (195, 248))	('LOS <=7 days', 'Var', (52, 64))	('atherosclerotic heart', 'Phenotype', 'HP:0001677', (126, 147))	('patients', 'Species', '9606', (35, 43))	('viral hepatitis', 'Phenotype', 'HP:0006562', (195, 210))	('cirrhosis', 'Phenotype', 'HP:0001394', (184, 193))	('cirrhosis', 'Disease', 'MESH:D005355', (184, 193))
56889	26943695	Because the patency of the right posterior hepatic artery failed to be confirmed, arterioportal shunting (APS) was performed by anastomosing the common hepatic artery to the PV using a left radial artery interposition graft (Fig.	('arterioportal shunting', 'Disease', (82, 104))	('radial artery interposition', 'Phenotype', 'HP:0020118', (190, 217))	('anastomosing', 'Var', (128, 140))	('APS', 'Disease', (106, 109))	('APS', 'Disease', 'MESH:D016884', (106, 109))
56927	25605416	In fact, several reports have shown that hepatectomy with en bloc resection of the caudate lobe and extrahepatic bile duct, lymph node dissection, or resection of portal vein or hepatic artery for HCCA is more likely to result in disease-free resection.	('bil', 'Chemical', '-', (113, 116))	('HCCA', 'Disease', (197, 201))	('disease-free resection', 'CPA', (230, 252))	('hepatectomy', 'Disease', (41, 52))	('resection', 'Var', (150, 159))
56967	25605416	Dysplastic lesions and CIS were defined as R0 resection because it is difficult to distinguish CIS from high-grade dysplastic lesions pathologically, and the presence of CIS at the ductal margin has no impact on survival compared with a negative ductal margin in extrahepatic cholangiocarcinoma.	('Dysplastic lesions', 'Disease', (0, 18))	('CIS', 'Phenotype', 'HP:0030075', (170, 173))	('CIS', 'Phenotype', 'HP:0030075', (95, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (285, 294))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (276, 294))	('Dysplastic lesions', 'Disease', 'MESH:D021782', (0, 18))	('extrahepatic cholangiocarcinoma', 'Disease', (263, 294))	('CIS', 'Phenotype', 'HP:0030075', (23, 26))	('dysplastic lesions', 'Disease', 'MESH:D021782', (115, 133))	('dysplastic lesions', 'Disease', (115, 133))	('presence', 'Var', (158, 166))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (263, 294))
56998	25605416	Four patients (6.1 %) had stage T1 disease, 22 (33.3 %) had T2a, 21 (31.8 %) had T2b, 12 (18.2 %) had T3, and 7 (10.6 %) had T4.	('T2b', 'Var', (81, 84))	('patients', 'Species', '9606', (5, 13))	('stage T1 disease', 'Disease', (26, 42))	('T2a', 'Disease', (60, 63))
57008	25605416	In univariate analysis, significant predictors of decreased DFS were male gender (P = 0.027), preoperative CA19-9 >37 U/mL (P = 0.004), preoperative PTPVE (P = 0.029), operative procedures except for left hepatectomy (P = 0.038), perioperative blood transfusion (P = 0.007), postoperative maximum T-bil >5.0 mg/dL (P = 0.026), positive lymph node (P = 0.001), microvascular invasion (P = 0.005), and lymphovascular invasion (P = 0.048).	('T-bil', 'Chemical', 'MESH:D001663', (297, 302))	('lymphovascular invasion', 'CPA', (400, 423))	('microvascular invasion', 'CPA', (360, 382))	('decreased', 'NegReg', (50, 59))	('CA19-9', 'Var', (107, 113))
57104	26798213	Chronic recurrent infection of the bile ducts is thought to induce biliary stricture, bile stasis, and pigmented biliary stones.	('pigmented biliary stones', 'Disease', 'MESH:D002137', (103, 127))	('biliary stones', 'Phenotype', 'HP:0000787', (113, 127))	('Chronic recurrent infection', 'Phenotype', 'HP:0031035', (0, 27))	('pigmented biliary stones', 'Disease', (103, 127))	('bile stasis', 'Phenotype', 'HP:0001396', (86, 97))	('recurrent infection', 'Phenotype', 'HP:0002719', (8, 27))	('biliary stricture', 'Disease', (67, 84))	('bile stasis', 'Disease', (86, 97))	('infection', 'Var', (18, 27))	('induce', 'Reg', (60, 66))
57114	26798213	In cases of Clonorchis sinensis infestation, cholangiography shows diffuse uniform dilatation of the peripheral intrahepatic bile ducts without a focal obstructive lesion.	('focal obstructive lesion', 'Disease', (146, 170))	('Clonorchis sinensis', 'Species', '79923', (12, 31))	('intrahepatic bile duct', 'Disease', (112, 134))	('intrahepatic bile duct', 'Disease', 'MESH:D002780', (112, 134))	('dilatation', 'Phenotype', 'HP:0002617', (83, 93))	('Clonorchis', 'Var', (12, 22))	('focal obstructive lesion', 'Disease', 'MESH:D005490', (146, 170))
57286	25114889	Upper biliary tract cancers and metachronous double biliary cancers might have a strong genetic predisposition such as loss of heterozygosity, point mutation of k-ras oncogene, or overexpression of the tumor suppressor gene p53.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('p53', 'Gene', (224, 227))	('metachronous double biliary cancers', 'Disease', 'MESH:D016609', (32, 67))	('point mutation', 'Var', (143, 157))	('loss of heterozygosity', 'Var', (119, 141))	('tumor', 'Disease', (202, 207))	('metachronous double biliary cancers', 'Disease', (32, 67))	('p53', 'Gene', '7157', (224, 227))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('biliary tract cancers', 'Disease', 'MESH:D001661', (6, 27))	('biliary tract cancers', 'Disease', (6, 27))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('k-ras', 'Protein', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('overexpression', 'PosReg', (180, 194))
57315	34032720	In the receiver operating characteristic analysis using combinations of the SUV parameters, the 2 groups [eSUV + DeltaSUV (P = .0001, area under the curve [AUC] 0.68) and dSUV + DeltaSUV (P = .0002, AUC 0.71)] showed significantly larger AUC than the other groups applying eSUV or dSUV alone (AUC 0.61 and AUC 0.68).	('dSUV', 'Chemical', '-', (171, 175))	('AUC', 'MPA', (238, 241))	('larger', 'PosReg', (231, 237))	('dSUV + DeltaSUV', 'Var', (171, 186))	('eSUV', 'Chemical', '-', (106, 110))	('eSUV', 'Chemical', '-', (273, 277))	('dSUV', 'Chemical', '-', (281, 285))
57354	34032720	(P = .01) Univariate analysis revealed that the survival was found to be significantly related to eSUV 7.2 (cut-off value 7.2, P < .001), dSUV 7.3 (cut-off value 7.3, P < .001), DeltaSUV 32% (cut-off value 32%, P = .01), age (P < .001), NLR 2.9 (cut-off value 2.9, P = .032) and serum CA19-9 324 (cut-off value 324 U/mL, P = .018) (Fig.	('eSUV', 'Var', (98, 102))	('CA19-9', 'Chemical', 'MESH:C086528', (285, 291))	('dSUV', 'Var', (138, 142))	('dSUV', 'Chemical', '-', (138, 142))	('related', 'Reg', (87, 94))	('eSUV', 'Chemical', '-', (98, 102))
57360	34032720	In the results of the combination of both dSUV 7.3 and DeltaSUV 32% was perfomed for predicting overall survival: the group (N = 22, 9 high dSUV-high DeltaSUV; 11 high dSUV-low DeltaSUV; 2 low dSUV-high DeltaSUV) and the group (33 low dSUV and low DeltaSUV) (Fig.	('dSUV', 'Chemical', '-', (140, 144))	('dSUV', 'Chemical', '-', (168, 172))	('high dSUV-high', 'Var', (135, 149))	('dSUV', 'Chemical', '-', (42, 46))	('high dSUV-low', 'Var', (163, 176))	('dSUV', 'Chemical', '-', (235, 239))	('dSUV', 'Chemical', '-', (193, 197))
57364	34032720	In the ROC analysis, combination of dSUV and DeltaSUV showed a significantly higher predicting value of overall survival than the other subgroups.	('overall survival', 'CPA', (104, 120))	('higher', 'PosReg', (77, 83))	('dSUV', 'Var', (36, 40))	('dSUV', 'Chemical', '-', (36, 40))	('DeltaSUV', 'Var', (45, 53))
57365	34032720	(AUC 0.71) In addition, the groups including high dSUV or DeltaSUV showed a significant poor overall survival than the groups including low dSUV or DeltaSUV.	('high dSUV', 'Var', (45, 54))	('overall survival', 'CPA', (93, 109))	('dSUV', 'Chemical', '-', (140, 144))	('poor', 'NegReg', (88, 92))	('dSUV', 'Chemical', '-', (50, 54))	('DeltaSUV', 'Var', (58, 66))
57366	34032720	Multivariate analysis revealed that overall survival was significantly influenced by dSUV and DeltaSUV.	('dSUV', 'Chemical', '-', (85, 89))	('overall', 'CPA', (36, 43))	('DeltaSUV', 'Var', (94, 102))	('influenced', 'Reg', (71, 81))	('dSUV', 'Var', (85, 89))
57372	34032720	Angela et al investigated that baseline high SUVmax was associated with worse survival through systemic review and meta-analysis in patients with biliary tract cancer.	('high', 'Var', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (146, 166))	('worse', 'NegReg', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('patients', 'Species', '9606', (132, 140))
57379	34032720	Other previous study, Lee et al reported that high SUVmax, SUVpeak, SUVmean, SUVgluc and TLGgluc showed significantly shorter overall survival in univariate analysis and operability was independent prognostic factor in multivariate analysis in patients with ICC.	('high SUVmax', 'Var', (46, 57))	('ICC', 'Disease', (258, 261))	('shorter', 'NegReg', (118, 125))	('patients', 'Species', '9606', (244, 252))	('overall survival', 'MPA', (126, 142))
57387	34032720	But, the prognostic difference between those factors and overall survival was not statistically significant in multivariate analysis, although these factors showed a significantly difference in patients from the high dSUV group than in those from low dSUV group in our study.	('patients', 'Species', '9606', (194, 202))	('dSUV', 'Chemical', '-', (217, 221))	('dSUV', 'Chemical', '-', (251, 255))	('difference', 'Reg', (180, 190))	('high dSUV', 'Var', (212, 221))
57391	34032720	Although the usefulness of %DeltaSUVmax was generally considered acceptable, few reports have been published on its relationship with the prognosis of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('breast cancer', 'Disease', (151, 164))	('%DeltaSUVmax', 'Var', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
57459	33564381	Laboratory findings in both studied methods showed that the levels of liver enzymes and tumor markers CA19-9 were higher in positive cases than in negative ones.	('higher', 'PosReg', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CA19-9', 'Chemical', 'MESH:C086528', (102, 108))	('positive', 'Var', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('levels of liver enzymes', 'MPA', (60, 83))
57460	33564381	However, this increase was significant only in the 19-19-19 CA marker tumor.	('19-19-19', 'Var', (51, 59))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))
57502	31941520	In this comprehensive review and meta-analysis, we found that patients who received ART had a significantly better 5-year OS rate and lower local recurrence rate than those who did not receive ART.	('lower', 'NegReg', (134, 139))	('ART', 'Var', (84, 87))	('local recurrence rate', 'CPA', (140, 161))	('better', 'PosReg', (108, 114))	('patients', 'Species', '9606', (62, 70))	('5-year OS rate', 'CPA', (115, 129))
57504	31941520	reported that ART reduced the risk of death (HR, 0.54; 95% CI 0.44-0.67; p < 0.001) and recurrence (HR, 0.61; 95% CI, 0.38-0.98; p = 0.04) among patients with GBC.	('patients', 'Species', '9606', (145, 153))	('recurrence', 'CPA', (88, 98))	('GBC', 'Disease', (159, 162))	('GBC', 'Disease', 'MESH:D005706', (159, 162))	('death', 'Disease', 'MESH:D003643', (38, 43))	('reduced', 'NegReg', (18, 25))	('death', 'Disease', (38, 43))	('ART', 'Var', (14, 17))
57518	31941520	Given the retrospective nature of these studies on GBC or EHCC patients who underwent surgery, it is reasonable to assume that a majority of the included patients who received ART were selected because of high-risk features, as our study showed that patients who received ART are more likely to have lymph node- and margin-positive disease.	('EHCC', 'Disease', (58, 62))	('GBC', 'Disease', 'MESH:D005706', (51, 54))	('GBC', 'Disease', (51, 54))	('patients', 'Species', '9606', (250, 258))	('EHCC', 'Disease', 'MESH:D018281', (58, 62))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (63, 71))	('ART', 'Var', (272, 275))
57544	31620360	The meta-analysis of these studies indicated a trend that high PD-L1 expression indicated a poor OS, but the result was not statistically significant (HR = 1.62, 95% CI [0.98-2.68], p = 0.063).	('PD-L1', 'Gene', (63, 68))	('PD-L1', 'Gene', '29126', (63, 68))	('high', 'Var', (58, 62))	('expression', 'MPA', (69, 79))
57545	31620360	For DFS, although the pooled result is not statistically significant, it trends toward being significant that high PD-L1 expression indicated improved DFS (HR = 0.80, 95% CI [0.62, 1.04], p = 0.092).	('PD-L1', 'Gene', '29126', (115, 120))	('expression', 'MPA', (121, 131))	('DFS', 'MPA', (151, 154))	('improved', 'PosReg', (142, 150))	('high', 'Var', (110, 114))	('PD-L1', 'Gene', (115, 120))
57574	31620360	The covariates included the publication year, sample size, proportion of males, ethnicity, positivity rate of PD-L1 and proportion of poorly differentiated tumors.	('PD-L1', 'Gene', (110, 115))	('tumors', 'Disease', (156, 162))	('PD-L1', 'Gene', '29126', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('positivity', 'Var', (91, 101))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
57581	31620360	The meta-analysis of these studies showed a trend that high PD-L1 expression indicated a poor OS, but the result was not statistically significant (HR = 1.62, 95% CI [0.98-2.68], p = 0.063), and there was high heterogeneity among the studies (I2 = 88.0%, p < 0.001) (Figure 2).	('PD-L1', 'Gene', '29126', (60, 65))	('PD-L1', 'Gene', (60, 65))	('high', 'Var', (55, 59))	('expression', 'MPA', (66, 76))
57583	31620360	Although the pooled result is not statistically significant, it trends toward being significant that high PD-L1 expression indicated improved DFS (HR = 0.80, 95% CI [0.62, 1.04], p = 0.092) with moderate heterogeneity (I2 = 59.1%, p = 0.087) (Figure 3).	('DFS', 'MPA', (142, 145))	('PD-L1', 'Gene', (106, 111))	('improved', 'PosReg', (133, 141))	('high', 'Var', (101, 105))	('PD-L1', 'Gene', '29126', (106, 111))	('expression', 'MPA', (112, 122))
57609	31620360	Several studies have shown that positive PD-L1 expression is correlated with a significantly worse OS or DFS, but other studies did not support this finding.	('PD-L1', 'Gene', '29126', (41, 46))	('worse', 'NegReg', (93, 98))	('PD-L1', 'Gene', (41, 46))	('positive', 'Var', (32, 40))	('expression', 'MPA', (47, 57))	('DFS', 'Disease', (105, 108))
57611	31620360	For DFS, although the pooled result was not statistically significant, it trended toward being significant that high PD-L1 expression indicated improved DFS.	('PD-L1', 'Gene', '29126', (117, 122))	('improved', 'PosReg', (144, 152))	('expression', 'MPA', (123, 133))	('high', 'Var', (112, 116))	('PD-L1', 'Gene', (117, 122))	('DFS', 'MPA', (153, 156))
57621	31620360	From this point of view, the positivity of PD-L1 suggests the existence of immune surveillance and is linked with an improved prognosis.	('PD-L1', 'Gene', '29126', (43, 48))	('positivity', 'Var', (29, 39))	('PD-L1', 'Gene', (43, 48))
57626	31620360	The expression of PD-L1 in ICs is also an indicator of a higher response rate to PD-L1/PD-1 checkpoint blockade therapy has been shown in some clinical trials.	('higher', 'PosReg', (57, 63))	('PD-L1', 'Gene', (81, 86))	('response', 'MPA', (64, 72))	('PD-1', 'Gene', (87, 91))	('PD-1', 'Gene', '5133', (87, 91))	('PD-L1', 'Gene', '29126', (81, 86))	('expression', 'Var', (4, 14))	('PD-L1', 'Gene', (18, 23))	('PD-L1', 'Gene', '29126', (18, 23))
57635	31620360	Some studies have suggested that PD-L1-positive tumors had prominent immune cell infiltration in CCA, such as CD3+ TILs (represent overall T cells), CD8+ TILs (represent cytotoxic T cells), and tumor-associated macrophages (TAMs) (CD68+, CD163+).	('PD-L1', 'Gene', (33, 38))	('CD163', 'Gene', (238, 243))	('tumors', 'Disease', (48, 54))	('PD-L1', 'Gene', '29126', (33, 38))	('CCA', 'Phenotype', 'HP:0030153', (97, 100))	('tumor', 'Disease', (194, 199))	('CD8', 'Gene', '925', (149, 152))	('CCA', 'Disease', 'MESH:D018281', (97, 100))	('CCA', 'Disease', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('CD8', 'Gene', (149, 152))	('CD163', 'Gene', '9332', (238, 243))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('CD3+', 'Var', (110, 114))	('immune cell infiltration', 'CPA', (69, 93))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
57652	31620360	High PD-L1 predicted a worse prognosis in the studies published before 2018, but no significant correlation was found between PD-L1 and OS in the studies that were published after 2018.	('High', 'Var', (0, 4))	('PD-L1', 'Gene', (5, 10))	('PD-L1', 'Gene', '29126', (5, 10))	('PD-L1', 'Gene', (126, 131))	('PD-L1', 'Gene', '29126', (126, 131))
57762	31450710	Furthermore, CD44v9 expression was correlated with the expression of inflammation-related markers, S100 calcium-binding protein P (S100P) and cyclooxygenase-2 (COX-2), suggesting that CD44v9 might be a novel CCA stem cell marker and may be involved in inflammation-related cancer progression.	('cyclooxygenase-2', 'Gene', '5743', (142, 158))	('involved', 'Reg', (240, 248))	('COX-2', 'Gene', (160, 165))	('inflammation', 'Disease', 'MESH:D007249', (252, 264))	('CCA', 'Phenotype', 'HP:0030153', (208, 211))	('CD44', 'Gene', '960', (184, 188))	('S100P', 'SUBSTITUTION', 'None', (131, 136))	('correlated', 'Reg', (35, 45))	('CD44', 'Gene', (184, 188))	('CCA', 'Disease', 'MESH:D018281', (208, 211))	('inflammation', 'Disease', (69, 81))	('cyclooxygenase-2', 'Gene', (142, 158))	('CCA', 'Disease', (208, 211))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('S100 calcium-binding protein P', 'Gene', (99, 129))	('COX-2', 'Gene', '5743', (160, 165))	('inflammation', 'Disease', (252, 264))	('CD44', 'Gene', '960', (13, 17))	('S100P', 'Var', (131, 136))	('S100 calcium-binding protein P', 'Gene', '6286', (99, 129))	('CD44', 'Gene', (13, 17))	('cancer', 'Disease', (273, 279))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('inflammation', 'Disease', 'MESH:D007249', (69, 81))
57808	31450710	Furthermore, CCA cells with the expression of ALDH displayed decreased E-cadherin expression, and upregulation of vimentin, fibronectin and N-cadherin, in comparison with ALDH cells [.	('N-cadherin', 'Gene', (140, 150))	('vimentin', 'Gene', '7431', (114, 122))	('CCA', 'Phenotype', 'HP:0030153', (13, 16))	('vimentin', 'Gene', (114, 122))	('expression', 'MPA', (82, 92))	('fibronectin', 'Gene', (124, 135))	('expression', 'Var', (32, 42))	('E-cadherin', 'Gene', (71, 81))	('E-cadherin', 'Gene', '999', (71, 81))	('CCA', 'Disease', 'MESH:D018281', (13, 16))	('N-cadherin', 'Gene', '1000', (140, 150))	('upregulation', 'PosReg', (98, 110))	('CCA', 'Disease', (13, 16))	('decreased', 'NegReg', (61, 70))	('fibronectin', 'Gene', '2335', (124, 135))	('ALDH', 'Gene', (46, 50))
57825	31450710	utilized an Ov-induced hamster CCA model, and demonstrated that alteration of TAMs is a characteristic of early CCA and TAMs play key roles in progression and metastasis of CCA.	('CCA', 'Phenotype', 'HP:0030153', (112, 115))	('TAM', 'Chemical', 'MESH:C419191', (120, 123))	('CCA', 'Disease', (173, 176))	('metastasis', 'CPA', (159, 169))	('CCA', 'Disease', 'MESH:D018281', (112, 115))	('CCA', 'Phenotype', 'HP:0030153', (31, 34))	('alteration', 'Var', (64, 74))	('roles', 'Reg', (134, 139))	('rat', 'Species', '10116', (53, 56))	('hamster', 'Species', '10034', (23, 30))	('CCA', 'Disease', (112, 115))	('TAMs', 'Protein', (78, 82))	('CCA', 'Disease', 'MESH:D018281', (31, 34))	('rat', 'Species', '10116', (68, 71))	('CCA', 'Phenotype', 'HP:0030153', (173, 176))	('CCA', 'Disease', 'MESH:D018281', (173, 176))	('TAM', 'Chemical', 'MESH:C419191', (78, 81))	('CCA', 'Disease', (31, 34))
57828	31450710	In CCA, WNT7B was highly expressed in CD68+ TAMs, similarly to that revealed by Boulter et al.	('CD68+', 'Var', (38, 43))	('CCA', 'Phenotype', 'HP:0030153', (3, 6))	('CCA', 'Disease', 'MESH:D018281', (3, 6))	('WNT7B', 'Gene', (8, 13))	('WNT7B', 'Gene', '22422', (8, 13))	('CCA', 'Disease', (3, 6))	('TAM', 'Chemical', 'MESH:C419191', (44, 47))
57840	31450710	In vitro and in vivo evidence demonstrated the role of alpha-SMA+ CAFs in CCA development and drug resistance; inducing CAF apoptosis reduces cancer cells and metastasis in a syngeneic rat CCA model.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('CCA', 'Disease', 'MESH:D018281', (74, 77))	('CCA', 'Disease', (74, 77))	('inducing', 'Var', (111, 119))	('CAF', 'Gene', '8850', (66, 69))	('CAF', 'Gene', (66, 69))	('reduces', 'NegReg', (134, 141))	('apoptosis', 'CPA', (124, 133))	('cancer', 'Disease', (142, 148))	('rat', 'Species', '10116', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('CCA', 'Phenotype', 'HP:0030153', (189, 192))	('CCA', 'Disease', 'MESH:D018281', (189, 192))	('men', 'Species', '9606', (85, 88))	('CAF', 'Gene', '8850', (120, 123))	('CCA', 'Disease', (189, 192))	('CAF', 'Gene', (120, 123))	('drug resistance', 'Phenotype', 'HP:0020174', (94, 109))	('rat', 'Species', '10116', (185, 188))	('CCA', 'Phenotype', 'HP:0030153', (74, 77))
57852	31450710	The ability of CAFs of promoting CCA cell invasion was confirmed in a syngeneic rat model, in which CAF depletion led to tumor growth inhibition and thus prolonged host survival.	('CAF', 'Gene', (15, 18))	('CCA', 'Disease', 'MESH:D018281', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('prolonged', 'PosReg', (154, 163))	('rat', 'Species', '10116', (80, 83))	('CAF', 'Gene', '8850', (15, 18))	('tumor', 'Disease', (121, 126))	('CCA', 'Disease', (33, 36))	('CAF', 'Gene', (100, 103))	('inhibition', 'NegReg', (134, 144))	('promoting', 'PosReg', (23, 32))	('host survival', 'CPA', (164, 177))	('depletion', 'Var', (104, 113))	('CAF', 'Gene', '8850', (100, 103))	('CCA', 'Phenotype', 'HP:0030153', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
57876	31450710	The proinflammatory cytokines, such as TNF-alpha and IL-6, promote the generation of free radicals causing damage to DNA, that cause genetic mutations and finally lead to tumor initiation.	('tumor initiation', 'Disease', (171, 187))	('genetic mutations', 'Var', (133, 150))	('rat', 'Species', '10116', (75, 78))	('cause', 'Reg', (127, 132))	('IL-6', 'Gene', (53, 57))	('tumor initiation', 'Disease', 'MESH:D009369', (171, 187))	('generation of free radicals', 'MPA', (71, 98))	('IL-6', 'Gene', '3569', (53, 57))	('promote', 'PosReg', (59, 66))	('TNF-alpha', 'Gene', '7124', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('lead to', 'Reg', (163, 170))	('TNF-alpha', 'Gene', (39, 48))
57879	31450710	Apart from the soluble factors secreted by cells in the TME, a number of specific pathways associated with cell growth dysregulation, invasion, and metastasis were activated surrounding CSCs in the TME, such as Wnt/beta-catenin, Notch, Hedgehog, MAPK/ERK, and TGFbeta pathways (Figure 1).	('TGFbeta', 'Gene', (260, 267))	('Notch', 'Pathway', (229, 234))	('metastasis', 'CPA', (148, 158))	('TGFbeta', 'Gene', '7040', (260, 267))	('beta-catenin', 'Gene', (215, 227))	('activated', 'PosReg', (164, 173))	('Hedgehog', 'Pathway', (236, 244))	('ERK', 'Gene', '5594', (251, 254))	('CSCs', 'Var', (186, 190))	('ERK', 'Gene', (251, 254))	('beta-catenin', 'Gene', '1499', (215, 227))
57882	31450710	Dysregulation of this pathway encourage the hepatic stem/progenitor cells to self-renew and occurs at the early stage of carcinogenesis.	('Dysregulation', 'Var', (0, 13))	('hepatic stem/progenitor cells', 'CPA', (44, 73))	('carcinogenesis', 'Disease', 'MESH:D063646', (121, 135))	('self-renew', 'CPA', (77, 87))	('encourage', 'PosReg', (30, 39))	('carcinogenesis', 'Disease', (121, 135))
57883	31450710	Notch signaling pathway sustains the hepatic progenitor cells and aberrant expression of Notch receptors 1 and 4 may be critical during iCCA progression.	('hepatic progenitor cells', 'MPA', (37, 61))	('CCA', 'Phenotype', 'HP:0030153', (137, 140))	('iCCA', 'Disease', (136, 140))	('aberrant', 'Var', (66, 74))	('iCCA', 'Disease', 'MESH:C535533', (136, 140))
57912	31450710	AC133-vcMMAF inhibited in vivo tumor growth in SCID mice.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('AC133-vcMMAF', 'Var', (0, 12))	('tumor', 'Disease', (31, 36))	('mice', 'Species', '10090', (52, 56))	('inhibited', 'NegReg', (13, 22))	('SCID', 'Phenotype', 'HP:0004430', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
57918	31450710	AMD3100 significantly affected the cell motility and invasion of CD24+ cells.	('affected', 'Reg', (22, 30))	('AMD3100', 'Var', (0, 7))	('invasion', 'CPA', (53, 61))	('CD24', 'Gene', '100133941', (65, 69))	('cell motility', 'CPA', (35, 48))	('CD24', 'Gene', (65, 69))	('AMD3100', 'Chemical', 'MESH:C088327', (0, 7))
57919	31450710	AMD3100 also abolished the CXCL12-induced phosphorylation of mitogen-activated protein kinase (MEK) 1/2 in CCA cells.	('CXCL12', 'Gene', (27, 33))	('CCA', 'Disease', (107, 110))	('abolished', 'NegReg', (13, 22))	('AMD3100', 'Var', (0, 7))	('CXCL12', 'Gene', '6387', (27, 33))	('CCA', 'Phenotype', 'HP:0030153', (107, 110))	('mitogen-activated protein kinase', 'Gene', (61, 93))	('CCA', 'Disease', 'MESH:D018281', (107, 110))	('MEK', 'Gene', (95, 98))	('mitogen-activated protein kinase', 'Gene', '5609', (61, 93))	('MEK', 'Gene', '5609', (95, 98))	('AMD3100', 'Chemical', 'MESH:C088327', (0, 7))
57920	31450710	showed that U0126 (a MEK/ERK inhibitor) significantly inhibited the motility of the CD24+ cells.	('inhibited', 'NegReg', (54, 63))	('U0126', 'Var', (12, 17))	('MEK', 'Gene', (21, 24))	('CD24', 'Gene', '100133941', (84, 88))	('CD24', 'Gene', (84, 88))	('MEK', 'Gene', '5609', (21, 24))	('ERK', 'Gene', '5594', (25, 28))	('U0126', 'Chemical', 'MESH:C113580', (12, 17))	('ERK', 'Gene', (25, 28))
57946	31450710	proved that inhibition of PD-1 or CTLA-4 as well as induction of tumor necrosis factor receptor superfamily member 18 (GITR) increases the ex vivo effector functions of tumor-infiltrating T cells from patients with CCA, indicating that these may be promising targets for immunotherapy.	('inhibition', 'Var', (12, 22))	('CTLA-4', 'Gene', '1493', (34, 40))	('CTLA-4', 'Gene', (34, 40))	('CCA', 'Phenotype', 'HP:0030153', (215, 218))	('CCA', 'Disease', 'MESH:D018281', (215, 218))	('tumor', 'Disease', (65, 70))	('CCA', 'Disease', (215, 218))	('tumor', 'Disease', (169, 174))	('rat', 'Species', '10116', (181, 184))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('GITR', 'Gene', '8784', (119, 123))	('patients', 'Species', '9606', (201, 209))	('PD-1', 'Gene', (26, 30))	('PD-1', 'Gene', '5133', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('GITR', 'Gene', (119, 123))	('tumor necrosis factor receptor superfamily member 18', 'Gene', '8784', (65, 117))	('ex vivo effector functions', 'CPA', (139, 165))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('increases', 'PosReg', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))
57948	31450710	A number of phase I and II trials are currently assessing the therapeutic efficacies of combination checkpoint inhibitor therapies in advanced BTC including combinations such as ipilimumab (CTLA4 inhibition) and nivolumab (PD1 inhibition) (NCT02834013, NCT02923934 and NCT03101566) or durvalumab (PDL1 inhibition) and tremelimumab (CTLA4 inhibition) (NCT02821754) and may maximize future therapeutic strategies (Table 2).	('NCT03101566', 'Var', (269, 280))	('PD1', 'Gene', '5133', (223, 226))	('CTLA4', 'Gene', (332, 337))	('PD1', 'Gene', (223, 226))	('PDL1', 'Gene', (297, 301))	('BTC', 'Gene', '685', (143, 146))	('NCT02821754', 'Chemical', 'MESH:C079985', (351, 362))	('CTLA4', 'Gene', '1493', (190, 195))	('NCT02923934', 'Var', (253, 264))	('NCT02834013', 'Var', (240, 251))	('CTLA4', 'Gene', (190, 195))	('BTC', 'Gene', (143, 146))	('rat', 'Species', '10116', (402, 405))	('NCT02923934', 'Chemical', 'MESH:C079985', (253, 264))	('CTLA4', 'Gene', '1493', (332, 337))	('PDL1', 'Gene', '29126', (297, 301))
57962	31450710	As immunotherapy is emerging, there are trials investigating its combination with current first-line treatment strategies for advanced BTC including chemotherapy, transarterial catheter chemoembolization and radiofrequency ablation (NCT03111732, NCT03101566, NCT02821754) (Table 2).	('BTC', 'Gene', (135, 138))	('NCT03101566', 'Var', (246, 257))	('rat', 'Species', '10116', (113, 116))	('NCT03111732', 'Var', (233, 244))	('NCT02821754', 'Var', (259, 270))	('NCT02821754', 'Chemical', 'MESH:C079985', (259, 270))	('BTC', 'Gene', '685', (135, 138))	('men', 'Species', '9606', (106, 109))
57976	31450710	CCA Cholangiocarcinoma  iCCA Intrahepatic cholangiocarcinoma  eCCA Extra-hepatic cholangiocarcinoma  pCCA Perihilar cholangiocarcinoma  CSC Cancer stem cell  TME Tumor microenvironment  EMT Epithelial-to-mesenchymal transition  HCC Hepatocellular carcinoma  LCSGJ Liver Cancer Study Group of Japan  MF-iCCA Mass forming intrahepatic cholangiocarcinoma  PI-iCCA Periductal-infiltrating intrahepatic cholangiocarcinoma  IG-iCCA Intraductal-growing intrahepatic cholangiocarcinoma  DDR DNA damage response  TGF-beta Transforming growth factor-beta  HSA Heat-stable antigen  MMP-7 Matrix metalloproteinase-7  CXCR4 CXC chemokine receptor 4  ERK Extracellular signal-regulated kinase  ROS Reactive oxygen species  CD44v9 CD44 variant 9  OV-CCA Opisthorchis viverrini-related cholangiocarcinoma  S100P S100 calcium-binding protein P  CX-2 Cyclooxygenase-2  EpCAM Epithelial cell adhesion molecule  TaMP Tumor-associated microparticle  SOX2 Sex determining region Upsilon-box 2  OS Overall survival  SCF Stem cell factor  SALL4 Sal-like protein 4  CLC Cholangiolocellular carcinoma  EMMPRIN Extracellular matrix metalloproteinase inducer  Sca-1 Stem cell antigen 1  EGF Epidermal growth factor  CAF Cancer-associated fibroblasts  TAM Tumor-associated macrophages  ECM Extracellular matrix  PGE2 Prostaglandin E2  IL Interleukin  VEGF-A Vascular endothelial growth factor-A  TNF-alpha Tumor necrosis factor-alpha  EVs Extracellular vesicles  PDGF Platelet-derived growth factor  FAK Focal adhesion kinase  SCID Severe combined immunodeficiency  xCT Cysteine-glutamate transporter  CTLA4 Cytotoxic Tlymphocyteassociated antigen 4  PD-L1 Programmed death ligand 1  PD-1 Programmed death 1  TRS Tumor reactive stroma  MCP Monocyte chemoattractant protein  SDF Stromal derived factor  Treg T leukocyte immunosuppressive regulators  MNZ Metronidazole  GEM Gemcitabine  ALDH Aldehyde dehydrogenase   FGF Fbroblast growth factor  NO nitric oxide  HGF hepatocyte growth factor  HB-EGF heparin-binding epidermal growth factor  FOX P3 Forkhead box P3  SCID severe combined immunedeficiency  ENT1 equilibrative nucleoside transporter 1  RRM1 ribonucleotide reductase M1	('carcinoma', 'Disease', 'MESH:D002277', (125, 134))	('pCCA', 'Gene', (101, 105))	('CCA', 'Disease', 'MESH:D018281', (422, 425))	('Tumor', 'Phenotype', 'HP:0002664', (897, 902))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:C535533', (385, 416))	('SALL4', 'Gene', (1015, 1020))	('carcinoma', 'Disease', (51, 60))	('Sal-like protein 4', 'Gene', '57167', (1021, 1039))	('CCA', 'Disease', 'MESH:D018281', (25, 28))	('CCA', 'Phenotype', 'HP:0030153', (303, 306))	('CCA', 'Disease', (25, 28))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (4, 22))	('Programmed death ligand 1', 'Gene', (1628, 1653))	('Cholangiocarcinoma', 'Disease', (4, 22))	('glutamate', 'Chemical', 'None', (1550, 1559))	('xCT', 'Gene', '23657', (1537, 1540))	('oxygen', 'Chemical', 'MESH:D010100', (838, 844))	('CCA', 'Phenotype', 'HP:0030153', (0, 3))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (81, 99))	('HCC', 'Phenotype', 'HP:0001402', (228, 231))	('combined immunodeficiency', 'Disease', 'MESH:D016511', (1510, 1535))	('TAM', 'Chemical', 'MESH:C419191', (1223, 1226))	('equilibrative nucleoside transporter 1', 'Gene', (2078, 2116))	('CCA', 'Disease', 'MESH:D018281', (63, 66))	('CCA', 'Disease', (63, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('CTLA4', 'Gene', '1493', (1573, 1578))	('rat', 'Species', '10116', (2085, 2088))	('carcinoma', 'Disease', 'MESH:D002277', (407, 416))	('Tumor', 'Phenotype', 'HP:0002664', (1377, 1382))	('S100 calcium-binding protein P', 'Gene', '6286', (796, 826))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (398, 416))	('cholangiocarcinoma', 'Disease', (770, 788))	('hepatocyte growth factor', 'Gene', '3082', (1936, 1960))	('CCA', 'Disease', (102, 105))	('EMMPRIN', 'Gene', (1076, 1083))	('Tumor', 'Phenotype', 'HP:0002664', (1227, 1232))	('carcinoma', 'Disease', 'MESH:D002277', (1065, 1074))	('Matrix metalloproteinase-7', 'Gene', '4316', (577, 603))	('CLC', 'Disease', 'MESH:D002277', (1041, 1044))	('CCA', 'Disease', (735, 738))	('MMP-7', 'Gene', '4316', (571, 576))	('HCC', 'Disease', 'MESH:D006528', (228, 231))	('CXCR4', 'Gene', (605, 610))	('Transforming growth factor-beta', 'Gene', '7040', (513, 544))	('CTLA4', 'Gene', (1573, 1578))	('VEGF-A', 'Gene', (1322, 1328))	('Vascular endothelial growth factor-A', 'Gene', '7422', (1329, 1365))	('CAF', 'Gene', '8850', (1188, 1191))	('cholangiocarcinoma', 'Disease', (116, 134))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (232, 256))	('Programmed death 1', 'Gene', '5133', (1660, 1678))	('Forkhead box P3', 'Gene', '50943', (2017, 2032))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (459, 477))	('CD44', 'Gene', (709, 713))	('iCCA', 'Disease', 'MESH:C535533', (421, 425))	('Tumor necrosis factor-alpha', 'Gene', (1377, 1404))	('CCA', 'Disease', (422, 425))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (42, 60))	('CCA', 'Disease', 'MESH:D018281', (303, 306))	('Stem cell factor', 'Gene', (997, 1013))	('carcinoma', 'Disease', (407, 416))	('Liver Cancer', 'Phenotype', 'HP:0002896', (264, 276))	('HCC', 'Disease', (228, 231))	('carcinoma', 'Disease', (247, 256))	('iCCA', 'Disease', 'MESH:C535533', (24, 28))	('Cysteine', 'Chemical', 'MESH:D003545', (1541, 1549))	('Opisthorchis viverrini', 'Species', '6198', (739, 761))	('carcinoma', 'Disease', (1065, 1074))	('Matrix metalloproteinase-7', 'Gene', (577, 603))	('SCID', 'Phenotype', 'HP:0004430', (1498, 1502))	('CD44', 'Gene', (716, 720))	('RRM1', 'Gene', (2118, 2122))	('intrahepatic cholangiocarcinoma', 'Disease', (385, 416))	('SOX2', 'Gene', '6657', (929, 933))	('EMMPRIN', 'Gene', '682', (1076, 1083))	('SOX2', 'Gene', (929, 933))	('iCCA', 'Disease', (421, 425))	('Extracellular matrix metalloproteinase inducer', 'Gene', '682', (1084, 1130))	('cholangiocarcinoma', 'Disease', (398, 416))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (81, 99))	('MNZ', 'Chemical', 'MESH:D008795', (1820, 1823))	('Cancer', 'Phenotype', 'HP:0002664', (270, 276))	('iCCA', 'Disease', (24, 28))	('Transforming growth factor-beta', 'Gene', (513, 544))	('xCT', 'Gene', (1537, 1540))	('NO nitric oxide', 'Chemical', 'MESH:D009569', (1915, 1930))	('carcinoma', 'Disease', 'MESH:D002277', (247, 256))	('cholangiocarcinoma', 'Disease', (333, 351))	('SCF', 'Gene', '4254', (993, 996))	('Hepatocellular carcinoma', 'Disease', (232, 256))	('men', 'Species', '9606', (180, 183))	('GEM', 'Chemical', 'MESH:C056507', (1839, 1842))	('PGE2', 'Chemical', 'MESH:D015232', (1283, 1287))	('severe combined immunedeficiency', 'Phenotype', 'HP:0004430', (2039, 2071))	('Gemcitabine', 'Chemical', 'MESH:C056507', (1843, 1854))	('CD44', 'Gene', '960', (709, 713))	('CCA', 'Phenotype', 'HP:0030153', (25, 28))	('Extracellular matrix metalloproteinase inducer', 'Gene', (1084, 1130))	('CAF', 'Gene', (1188, 1191))	('carcinoma', 'Disease', (90, 99))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:C535533', (320, 351))	('ribonucleotide reductase M1', 'Gene', (2123, 2150))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (232, 256))	('Tumor necrosis factor-alpha', 'Gene', '7124', (1377, 1404))	('Liver Cancer', 'Disease', 'MESH:D006528', (264, 276))	('Programmed death ligand 1', 'Gene', '29126', (1628, 1653))	('combined immunedeficiency', 'Phenotype', 'HP:0005387', (2046, 2071))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('S100P', 'SUBSTITUTION', 'None', (790, 795))	('Aldehyde', 'Chemical', 'MESH:D000447', (1861, 1869))	('CCA', 'Disease', (303, 306))	('CD44', 'Gene', '960', (716, 720))	('combined immunodeficiency', 'Disease', (1510, 1535))	('VEGF-A', 'Gene', '7422', (1322, 1328))	('CCA', 'Phenotype', 'HP:0030153', (63, 66))	('CLC', 'Disease', (1041, 1044))	('ERK', 'Gene', (637, 640))	('CCA', 'Disease', 'MESH:D018281', (357, 360))	('S100 calcium-binding protein P', 'Gene', (796, 826))	('CCA', 'Disease', (357, 360))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (42, 60))	('CCA', 'Disease', 'MESH:D018281', (0, 3))	('CCA', 'Disease', (0, 3))	('ENT1', 'Gene', (2073, 2077))	('pCCA', 'Gene', '5095', (101, 105))	('Cancer', 'Phenotype', 'HP:0002664', (1192, 1198))	('eCCA', 'Disease', 'MESH:D018281', (62, 66))	('Cholangiolocellular carcinoma', 'Phenotype', 'HP:0030153', (1045, 1074))	('carcinoma', 'Disease', 'MESH:D002277', (90, 99))	('Epithelial cell adhesion molecule', 'Gene', '4072', (857, 890))	('CCA', 'Phenotype', 'HP:0030153', (102, 105))	('carcinoma', 'Disease', 'MESH:D002277', (342, 351))	('S100P', 'Var', (790, 795))	('carcinoma', 'Disease', 'MESH:D002277', (779, 788))	('carcinoma', 'Disease', 'MESH:D002277', (468, 477))	('CXC chemokine receptor 4', 'Gene', (611, 635))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (770, 788))	('oxygen', 'Chemical', 'MESH:D010100', (693, 699))	('Liver Cancer', 'Disease', (264, 276))	('carcinoma', 'Disease', (13, 22))	('RRM1', 'Gene', '6240', (2118, 2122))	('Programmed death 1', 'Gene', (1660, 1678))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))	('TGF-beta', 'Gene', '7040', (504, 512))	('heparin-binding epidermal growth factor', 'Gene', '1839', (1969, 2008))	('Tumor', 'Phenotype', 'HP:0002664', (1684, 1689))	('HB-EGF', 'Gene', (1962, 1968))	('cholangiocarcinoma', 'Disease', (459, 477))	('HSA', 'Gene', '213', (546, 549))	('SCF', 'Gene', (993, 996))	('ERK', 'Gene', '5594', (637, 640))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (116, 134))	('Stem cell factor', 'Gene', '4254', (997, 1013))	('CXC chemokine receptor 4', 'Gene', '7852', (611, 635))	('EpCAM', 'Gene', '4072', (851, 856))	('HGF', 'Gene', '3082', (1932, 1935))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (4, 22))	('PD-1', 'Gene', (1655, 1659))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('PD-1', 'Gene', '5133', (1655, 1659))	('ENT1', 'Gene', '2030', (2073, 2077))	('equilibrative nucleoside transporter 1', 'Gene', '2030', (2078, 2116))	('TGF-beta', 'Gene', (504, 512))	('Metronidazole', 'Chemical', 'MESH:D008795', (1824, 1837))	('carcinoma', 'Disease', 'MESH:D002277', (13, 22))	('heparin-binding epidermal growth factor', 'Gene', (1969, 2008))	('carcinoma', 'Disease', (342, 351))	('HGF', 'Gene', (1932, 1935))	('cholangiocarcinoma', 'Disease', (42, 60))	('carcinoma', 'Disease', (779, 788))	('ribonucleotide reductase M1', 'Gene', '6240', (2123, 2150))	('carcinoma', 'Disease', (468, 477))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:C535533', (446, 477))	('iCCA', 'Disease', 'MESH:C535533', (302, 306))	('CLC', 'Phenotype', 'HP:0030153', (1041, 1044))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (398, 416))	('intrahepatic cholangiocarcinoma', 'Disease', (320, 351))	('MMP-7', 'Gene', (571, 576))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (1510, 1535))	('cholangiocarcinoma', 'Disease', (81, 99))	('carcinoma', 'Disease', 'MESH:D002277', (51, 60))	('iCCA', 'Disease', 'MESH:C535533', (356, 360))	('Cyclooxygenase-2', 'Gene', '5743', (833, 849))	('Cyclooxygenase-2', 'Gene', (833, 849))	('HB-EGF', 'Gene', '1839', (1962, 1968))	('TNF-alpha', 'Gene', '7124', (1367, 1376))	('HSA', 'Gene', (546, 549))	('intrahepatic cholangiocarcinoma', 'Disease', (446, 477))	('Forkhead box P3', 'Gene', (2017, 2032))	('carcinoma', 'Disease', (125, 134))	('CCA', 'Disease', 'MESH:D018281', (102, 105))	('Tumor', 'Phenotype', 'HP:0002664', (162, 167))	('TNF-alpha', 'Gene', (1367, 1376))	('immunodeficiency', 'Phenotype', 'HP:0002721', (1519, 1535))	('CCA', 'Disease', 'MESH:D018281', (735, 738))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (333, 351))	('iCCA', 'Disease', (302, 306))	('Sal-like protein 4', 'Gene', (1021, 1039))	('CXCR4', 'Gene', '7852', (605, 610))	('Severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (1503, 1535))	('rat', 'Species', '10116', (378, 381))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('Vascular endothelial growth factor-A', 'Gene', (1329, 1365))	('SCID', 'Phenotype', 'HP:0004430', (2034, 2038))	('iCCA', 'Disease', (356, 360))	('hepatocyte growth factor', 'Gene', (1936, 1960))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (333, 351))	('SALL4', 'Gene', '57167', (1015, 1020))	('Cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Epithelial cell adhesion molecule', 'Gene', (857, 890))	('eCCA', 'Disease', (62, 66))	('EpCAM', 'Gene', (851, 856))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
57995	30390491	The distal bile duct was transected at the level of the upper limit of the pancreatic head and was free from cancer.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('pancreatic', 'Disease', 'MESH:D010195', (75, 85))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('pancreatic', 'Disease', (75, 85))	('transected', 'Var', (25, 35))
57996	30390491	After transecting the left and middle hepatic arteries, a clear demarcation between the ischemic and well perfused tissue was seen (Fig.	('ischemic', 'Disease', 'MESH:D007511', (88, 96))	('middle hepatic arteries', 'Disease', 'MESH:D020244', (31, 54))	('transecting', 'Var', (6, 17))	('ischemic', 'Disease', (88, 96))	('middle hepatic arteries', 'Disease', (31, 54))
58079	26838210	The survival curve of the patients created based on low and high OPN expression in CCA tissue is shown in Figure 2AB.	('OPN', 'Gene', '6696', (65, 68))	('OPN', 'Gene', (65, 68))	('patients', 'Species', '9606', (26, 34))	('CCA', 'Phenotype', 'HP:0030153', (83, 86))	('low', 'Var', (52, 55))
58087	26838210	Here we reported in a large number of CCA cases that expression of OPN in tumorous stroma and/or cancerous cells was associated with direct tumor invasion, lymphatic permeation and lymph node metastasis but was not associated with prognosis in CCA patients.	('expression', 'Var', (53, 63))	('cancerous', 'Disease', 'MESH:D009369', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('OPN', 'Gene', (67, 70))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('associated', 'Reg', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('lymph node metastasis', 'CPA', (181, 202))	('cancerous', 'Disease', (97, 106))	('CCA', 'Phenotype', 'HP:0030153', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumorous stroma', 'Disease', (74, 89))	('OPN', 'Gene', '6696', (67, 70))	('CCA', 'Phenotype', 'HP:0030153', (244, 247))	('patients', 'Species', '9606', (248, 256))	('CCA', 'Disease', (38, 41))	('tumorous stroma', 'Disease', 'MESH:D009369', (74, 89))	('lymphatic permeation', 'CPA', (156, 176))	('tumor', 'Disease', (140, 145))
58098	26838210	The expression of OPN in CCA tissue again was found to have a positive association with tumor aggressiveness as described in several earlier studies.	('OPN', 'Gene', '6696', (18, 21))	('CCA', 'Phenotype', 'HP:0030153', (25, 28))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (88, 108))	('OPN', 'Gene', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor aggressiveness', 'Disease', (88, 108))	('expression', 'Var', (4, 14))	('aggressiveness', 'Phenotype', 'HP:0000718', (94, 108))
58115	21423008	In the absence of Hh ligands, Smo activity is repressed by Ptc, but binding of Hh ligands to Ptc relieves this repression and leads to propagation of intracellular signals that ultimately culminate in nuclear localization of Gli factors that trans-activate (generally via Gli1 and Gli2) or trans-repress (generally via a truncated form of Gli3) Hh-target gene expression.	('Gli2', 'Gene', '2736', (281, 285))	('Gli3', 'Gene', (339, 343))	('culminate in', 'Reg', (188, 200))	('Gli1', 'Gene', (272, 276))	('leads to', 'Reg', (126, 134))	('expression', 'MPA', (360, 370))	('Smo', 'Gene', (30, 33))	('relieves', 'NegReg', (97, 105))	('Gli2', 'Gene', (281, 285))	('nuclear localization', 'MPA', (201, 221))	('Gli1', 'Gene', '2735', (272, 276))	('binding', 'Var', (68, 75))	('trans-activate', 'PosReg', (242, 256))	('Smo', 'Gene', '6608', (30, 33))	('Gli3', 'Gene', '2737', (339, 343))	('trans-repress', 'PosReg', (290, 303))
58120	21423008	Moreover, mice with a genetic alteration that impairs silencing of Hh signaling exhibited exacerbated ductular and fibrogenic responses.	('impairs', 'NegReg', (46, 53))	('exacerbated', 'PosReg', (90, 101))	('alteration', 'Var', (30, 40))	('mice', 'Species', '10090', (10, 14))	('silencing', 'MPA', (54, 63))
58122	21423008	In such models, hepatic accumulation of progenitors, myofibroblasts, and liver fibrosis correlate with the level of Hh pathway activation and are significantly amplified in animals with defects that result in excessive Hh pathway activity.	('Hh pathway', 'Pathway', (116, 126))	('liver fibrosis', 'Disease', 'MESH:D008103', (73, 87))	('Hh pathway', 'Pathway', (219, 229))	('defects', 'Var', (186, 193))	('liver fibrosis', 'Phenotype', 'HP:0001395', (73, 87))	('amplified', 'PosReg', (160, 169))	('hepatic accumulation', 'MPA', (16, 36))	('activation', 'PosReg', (127, 137))	('liver fibrosis', 'Disease', (73, 87))	('activity', 'MPA', (230, 238))
58130	21423008	In vitro activation of cholangiocytes with exogenous PDGF-BB induces production of exosomes containing biologically active Ihh and Shh ligands.	('Ihh', 'Gene', '3549', (123, 126))	('production of exosomes containing', 'MPA', (69, 102))	('Shh', 'Gene', (131, 134))	('exogenous', 'Var', (43, 52))	('Shh', 'Gene', '6469', (131, 134))	('Ihh', 'Gene', (123, 126))	('PDGF-BB', 'Gene', (53, 60))
58135	21423008	The Hh repressor Gli3 also localizes to cilia, and thus, ciliary disfunction can result in aberrant Gli3 localization and consequent repression of Hh signaling.	('Gli3', 'Gene', (100, 104))	('ciliary disfunction', 'Disease', (57, 76))	('repression', 'NegReg', (133, 143))	('Gli3', 'Gene', '2737', (17, 21))	('result in', 'Reg', (81, 90))	('localization', 'MPA', (105, 117))	('aberrant', 'Var', (91, 99))	('Gli3', 'Gene', '2737', (100, 104))	('Gli3', 'Gene', (17, 21))
58177	33643901	One explanation may be that tumor cells physically absorb and neutralize ENO1 antibodies expressed and secreted on the surface to reduce circulating levels.	('tumor', 'Disease', (28, 33))	('reduce', 'NegReg', (130, 136))	('circulating levels', 'MPA', (137, 155))	('neutralize', 'Var', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('ENO1', 'Gene', (73, 77))	('ENO1', 'Gene', '2023', (73, 77))
58188	33643901	In this study, the cBio Cancer Genomics Portal (; accessed by April 30, 2020), which is a web tool for mutation analysis and visualization through TCGA cancer genomics profiles, was used for mutation analysis of ENO1.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Cancer', 'Disease', (24, 30))	('Cancer', 'Disease', 'MESH:D009369', (24, 30))	('Cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('ENO1', 'Gene', (212, 216))	('ENO1', 'Gene', '2023', (212, 216))	('mutation', 'Var', (191, 199))
58203	33643901	The highest ENO1 expression was found in EBV-transformed lymphocytes, whereas the lowest was observed in the left ventricle of the heart.	('EBV-transformed', 'Var', (41, 56))	('expression', 'MPA', (17, 27))	('ENO1', 'Gene', (12, 16))	('ENO1', 'Gene', '2023', (12, 16))	('highest', 'PosReg', (4, 11))
58210	33643901	The expression of ENO1 was significantly associated with the prognosis of eight types of cancers, including HNSC (HR = 1.32, P = 0.04), CESC (HR = 1.47, P = 0.04), BLCA (HR = 1.23, P = 0.04), LUAD (HR = 1.36, P = 0.01), SARC (HR = 1.36, P = 0.00), PAAD (HR = 1.65, P = 0.00), KICH (HR = 4.60, P = 0.00), and LIHC (HR = 1.63, P = 0.00), suggesting that high ENO1 expression might be an independent risk factor for these cancers (all HR > 1.00, P < 0.05).	('associated', 'Reg', (41, 51))	('high', 'Var', (352, 356))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', (89, 96))	('KICH', 'Disease', (276, 280))	('LUAD', 'Disease', (192, 196))	('cancers', 'Disease', 'MESH:D009369', (419, 426))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('CESC', 'Disease', (136, 140))	('BLCA', 'Disease', (164, 168))	('ENO1', 'Gene', (18, 22))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Phenotype', 'HP:0002664', (419, 426))	('ENO1', 'Gene', (357, 361))	('cancers', 'Disease', (419, 426))	('ENO1', 'Gene', '2023', (18, 22))	('KICH', 'Disease', 'None', (276, 280))	('HNSC', 'Disease', (108, 112))	('SARC', 'Disease', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (419, 425))	('ENO1', 'Gene', '2023', (357, 361))	('LUAD', 'Phenotype', 'HP:0030078', (192, 196))
58212	33643901	High ENO1 expression was significantly associated with worse OS in CESC (log-rank P = 0.04), BLCA (log-rank P = 0.03), KICH (log-rank P = 0.01), LIHC (log-rank P = 0.00), and SARC (log-rank P = 0.04), and worse DFS in KICH (log-rank P = 0.03) and SARC (log-rank P = 0.07).	('SARC', 'Disease', (175, 179))	('LIHC', 'Disease', (145, 149))	('KICH', 'Disease', 'None', (218, 222))	('High', 'Var', (0, 4))	('ENO1', 'Gene', '2023', (5, 9))	('expression', 'MPA', (10, 20))	('ENO1', 'Gene', (5, 9))	('CESC', 'Disease', (67, 71))	('KICH', 'Disease', 'None', (119, 123))	('KICH', 'Disease', (218, 222))	('KICH', 'Disease', (119, 123))	('BLCA', 'Disease', (93, 97))
58217	33643901	Evidently, 195 samples in the altered group and 10,772 samples in the unaltered group were included for ENO1 mutation analysis.	('ENO1', 'Gene', '2023', (104, 108))	('mutation', 'Var', (109, 117))	('ENO1', 'Gene', (104, 108))
58218	33643901	The results demonstrated that ENO1 was altered in 1.8% of all the included samples, including inframe mutation, missense mutation, truncating mutation, fusion, amplification, and deep deletion ( Figure 6 ).	('truncating', 'MPA', (131, 141))	('amplification', 'Var', (160, 173))	('ENO1', 'Gene', (30, 34))	('deep deletion', 'Var', (179, 192))	('ENO1', 'Gene', '2023', (30, 34))	('altered', 'Reg', (39, 46))	('fusion', 'Var', (152, 158))	('missense mutation', 'Var', (112, 129))
58219	33643901	Furthermore, the prognostic significance of ENO1 mutation was estimated via Kaplan-Meier method.	('ENO1', 'Gene', '2023', (44, 48))	('mutation', 'Var', (49, 57))	('ENO1', 'Gene', (44, 48))
58251	33643901	These findings are consistent with a previous study showing that high ENO1 expression is significantly correlated with DNA replication and cell cycle in hepatocellular carcinoma.	('DNA replication', 'CPA', (119, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('ENO1', 'Gene', (70, 74))	('ENO1', 'Gene', '2023', (70, 74))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (153, 177))	('cell cycle', 'CPA', (139, 149))	('correlated', 'Reg', (103, 113))	('hepatocellular carcinoma', 'Disease', (153, 177))	('high', 'Var', (65, 69))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (153, 177))	('expression', 'MPA', (75, 85))
58259	33643901	Furthermore, the knockdown of ENO1 has been shown to promote apoptosis and induce the arrest of cell cycle in gastric cancer cells.	('gastric cancer', 'Disease', (110, 124))	('apoptosis', 'CPA', (61, 70))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('arrest', 'Disease', (86, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ENO1', 'Gene', (30, 34))	('ENO1', 'Gene', '2023', (30, 34))	('knockdown', 'Var', (17, 26))	('induce', 'Reg', (75, 81))	('promote', 'PosReg', (53, 60))
58264	33643901	Additionally, mutation of ENO1 was analysis, for it was proved that mutation could affect tumor progression; however, ENO1 mutation (1.8%) did not impact on prognosis in this study.	('affect', 'Reg', (83, 89))	('mutation', 'Var', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ENO1', 'Gene', (118, 122))	('tumor', 'Disease', (90, 95))	('ENO1', 'Gene', '2023', (118, 122))	('ENO1', 'Gene', (26, 30))	('ENO1', 'Gene', '2023', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
58268	33643901	In consonance with our results, ENO1 expression was higher in late stages (stages III and IV), particularly that in KICH ( Figure 5E ), meanwhile, high ENO1 expression was significantly associated with worse OS in KICH ( Figure 4I ).	('worse OS', 'Disease', (202, 210))	('expression', 'MPA', (157, 167))	('ENO1', 'Gene', (152, 156))	('KICH', 'Disease', 'None', (214, 218))	('ENO1', 'Gene', '2023', (32, 36))	('ENO1', 'Gene', '2023', (152, 156))	('ENO1', 'Gene', (32, 36))	('KICH', 'Disease', 'None', (116, 120))	('high', 'Var', (147, 151))	('associated', 'Reg', (186, 196))	('higher', 'PosReg', (52, 58))	('KICH', 'Disease', (214, 218))	('expression', 'MPA', (37, 47))	('KICH', 'Disease', (116, 120))
58306	31143705	ICC harbors many genetic aberrations, including mutations in isocitrate dehydrogenase1/2 (IDH1/2), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), KRAS, and BRAF, as well as amplifications of Cyclin D1 (CCND1).	('genetic aberrations', 'Disease', 'MESH:D030342', (17, 36))	('FGFR', 'Gene', (175, 179))	('EGFR', 'Gene', '1956', (133, 137))	('mutations', 'Var', (48, 57))	('CCND1', 'Gene', '595', (238, 243))	('epidermal growth factor receptor', 'Gene', (99, 131))	('CCND1', 'Gene', (238, 243))	('epidermal growth factor receptor', 'Gene', '1956', (99, 131))	('IDH1/2', 'Gene', '3417;3418', (90, 96))	('Cyclin D1', 'Gene', '595', (227, 236))	('EGFR', 'Gene', (133, 137))	('IDH1/2', 'Gene', (90, 96))	('Cyclin D1', 'Gene', (227, 236))	('amplifications', 'Var', (209, 223))	('KRAS', 'Gene', '3845', (182, 186))	('BRAF', 'Gene', '673', (192, 196))	('genetic aberrations', 'Disease', (17, 36))	('BRAF', 'Gene', (192, 196))	('KRAS', 'Gene', (182, 186))
58308	31143705	N6-methyladenosine (m6A) represents a predominant RNA modification that, not surprisingly, regulates tumorigenesis, and tumor progression.	('regulates', 'Reg', (91, 100))	('m6A', 'Gene', '56339', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('N6-methyladenosine', 'Var', (0, 18))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('m6A', 'Gene', (20, 23))	('tumor', 'Disease', (120, 125))
58311	31143705	Then, m6A readers, including YTHDF1-3, YTHDC1, IGF2BPs, and eIF3, discern these m6A modifications to direct RNA alternative splicing, translation, localization, and RNA stability, among other processes.	('localization', 'MPA', (147, 159))	('m6A', 'Gene', '56339', (6, 9))	('eIF3', 'Gene', '8661', (60, 64))	('m6A', 'Gene', (80, 83))	('YTHDF1', 'Gene', (29, 35))	('translation', 'MPA', (134, 145))	('modifications', 'Var', (84, 97))	('YTHDC1', 'Gene', (39, 45))	('direct RNA alternative splicing', 'MPA', (101, 132))	('m6A', 'Gene', '56339', (80, 83))	('eIF3', 'Gene', (60, 64))	('YTHDC1', 'Gene', '91746', (39, 45))	('m6A', 'Gene', (6, 9))	('YTHDF1', 'Gene', '54915', (29, 35))	('RNA', 'MPA', (165, 168))
58314	31143705	FTO mediates multiple RNA modifications, including m6A and m6Am in mRNA and snRNA as well as m1A in tRNA.	('m6A', 'Gene', '56339', (59, 62))	('m6A', 'Gene', '56339', (51, 54))	('FTO', 'Gene', '79068', (0, 3))	('m1A', 'Var', (93, 96))	('FTO', 'Gene', (0, 3))	('m6A', 'Gene', (59, 62))	('m6A', 'Gene', (51, 54))
58317	31143705	However, this process may be suppressed by R-2-hydroxyglutarate (R-2HG) and IDH mutations, which competitively inhibit FTO.	('inhibit', 'NegReg', (111, 118))	('mutations', 'Var', (80, 89))	('IDH', 'Gene', (76, 79))	('FTO', 'Gene', (119, 122))	('R-2-hydroxyglutarate', 'Chemical', '-', (43, 63))	('IDH', 'Gene', '3417', (76, 79))	('FTO', 'Gene', '79068', (119, 122))
58326	31143705	The following primary antibodies were used in this study: Anti-FTO (1:4000, ab124892, Abcam), Anti-alpha-Tubulin (1:1000, sc-69969, Santa Cruz), and Anti-FLAG (1:5000, F1804, SIGMA).	('1:4000', 'Var', (68, 74))	('F1804', 'Var', (168, 173))	('FTO', 'Gene', '79068', (63, 66))	('1:1000', 'Var', (114, 120))	('FTO', 'Gene', (63, 66))
58368	31143705	An association was found between low FTO expression and high CD34 expression in ICC (p = 0.014, Table 1).	('low', 'NegReg', (33, 36))	('expression', 'MPA', (41, 51))	('FTO', 'Gene', (37, 40))	('CD34', 'Gene', (61, 65))	('expression', 'MPA', (66, 76))	('CD34', 'Gene', '947', (61, 65))	('FTO', 'Gene', '79068', (37, 40))	('high', 'Var', (56, 60))
58369	31143705	In addition, FTO expression was also significantly related to the number of WBCs (white blood cells, p = 0.023) and RBCs (red blood cells, p < 0.001), HGB levels (hemoglobin, p < 0.001), AFU levels (alpha-L-Fucosidase, p = 0.01), and ALP level (alkaline phosphatase, p = 0.008) in the serum.	('HGB', 'Gene', '114757', (151, 154))	('HGB', 'Gene', (151, 154))	('FTO', 'Gene', (13, 16))	('AFU levels', 'MPA', (187, 197))	('ALP', 'Gene', '470', (234, 237))	('expression', 'Var', (17, 27))	('related', 'Reg', (51, 58))	('ALP', 'Gene', (234, 237))	('FTO', 'Gene', '79068', (13, 16))
58375	31143705	We first analyzed FTO mutation status and copy number alterations (CNAs) in cholangiocarcinoma using the cBioPortal for Cancer Genomics (http://www.cbioportal.org).	('Cancer', 'Disease', (120, 126))	('copy number alterations', 'Var', (42, 65))	('FTO', 'Gene', '79068', (18, 21))	('cholangiocarcinoma', 'Disease', (76, 94))	('Cancer', 'Disease', 'MESH:D009369', (120, 126))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (76, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (76, 94))	('FTO', 'Gene', (18, 21))
58376	31143705	Neither mutations nor copy number alterations in FTO or other m6A modification enzymes were found in cholangiocarcinoma (Figure 3A).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (101, 119))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('found', 'Reg', (92, 97))	('FTO', 'Gene', '79068', (49, 52))	('cholangiocarcinoma', 'Disease', (101, 119))	('m6A', 'Gene', (62, 65))	('FTO', 'Gene', (49, 52))	('copy number alterations', 'Var', (22, 45))	('m6A', 'Gene', '56339', (62, 65))
58381	31143705	Downregulating FTO insensitized the ICC cells to the cisplatin treatment (Figures 4A,B).	('Downregulating', 'Var', (0, 14))	('FTO', 'Gene', (15, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('FTO', 'Gene', '79068', (15, 18))
58385	31143705	Additionally, ectopic expression of FTO significantly hampered the invasiveness of TFK1 cells (Figures 5D,E), and knockdown of FTO promoted the invasiveness of HCCC-9810 and TFK1 cells (Figures 5F-I).	('invasiveness', 'CPA', (144, 156))	('FTO', 'Gene', (36, 39))	('HCCC-9810', 'CellLine', 'CVCL:6908', (160, 169))	('knockdown', 'Var', (114, 123))	('FTO', 'Gene', (127, 130))	('FTO', 'Gene', '79068', (36, 39))	('hampered', 'NegReg', (54, 62))	('invasiveness of TFK1 cells', 'CPA', (67, 93))	('FTO', 'Gene', '79068', (127, 130))	('promoted', 'PosReg', (131, 139))
58393	31143705	Further analysis of the expression status of 35 genes demonstrated that FTO knockdown induced the expression of COL8A1, TEAD2, and CMTM4, which were upregulated in ICC (Table 2) and that FTO knockdown inhibited the expression of HAO2, NR5A2, CCL19, TCF21, APOA2, NTRK2, DPT FGA, and SCML4, which were downregulated in ICC (Table 2).	('CCL19', 'Gene', (242, 247))	('FTO', 'Gene', (187, 190))	('inhibited', 'NegReg', (201, 210))	('COL8A1', 'Gene', '1295', (112, 118))	('NR5A2', 'Gene', '2494', (235, 240))	('HAO2', 'Gene', '51179', (229, 233))	('knockdown', 'Var', (76, 85))	('NR5A2', 'Gene', (235, 240))	('NTRK2', 'Gene', '4915', (263, 268))	('TCF21', 'Gene', (249, 254))	('FGA', 'Gene', '2243', (274, 277))	('expression', 'MPA', (215, 225))	('FGA', 'Gene', (274, 277))	('SCML4', 'Gene', '256380', (283, 288))	('CMTM4', 'Gene', '146223', (131, 136))	('FTO', 'Gene', '79068', (72, 75))	('ICC', 'Disease', (164, 167))	('HAO2', 'Gene', (229, 233))	('CCL19', 'Gene', '6363', (242, 247))	('FTO', 'Gene', (72, 75))	('TEAD2', 'Gene', (120, 125))	('NTRK2', 'Gene', (263, 268))	('CMTM4', 'Gene', (131, 136))	('TEAD2', 'Gene', '8463', (120, 125))	('FTO', 'Gene', '79068', (187, 190))	('TCF21', 'Gene', '6943', (249, 254))	('COL8A1', 'Gene', (112, 118))	('SCML4', 'Gene', (283, 288))	('upregulated', 'PosReg', (149, 160))	('APOA2', 'Gene', '336', (256, 261))	('APOA2', 'Gene', (256, 261))
58424	31143705	In addition, ectopic expression of FTO significantly hampered the mobility of ICC cells in vitro.	('FTO', 'Gene', '79068', (35, 38))	('mobility of ICC cells in vitro', 'CPA', (66, 96))	('FTO', 'Gene', (35, 38))	('ectopic expression', 'Var', (13, 31))	('hampered', 'NegReg', (53, 61))
58427	31143705	Recently, it has been reported that IDH mutations competitively inhibit RNA demethylation of FTO.	('IDH', 'Gene', (36, 39))	('FTO', 'Gene', '79068', (93, 96))	('mutations', 'Var', (40, 49))	('RNA demethylation', 'MPA', (72, 89))	('inhibit', 'NegReg', (64, 71))	('IDH', 'Gene', '3417', (36, 39))	('FTO', 'Gene', (93, 96))
58428	31143705	FTO is an alpha-ketoglutarate (alpha-KG)-dependent dioxygenase, which is competitively inhibited by R-2-hydroxyglutarate (R-2HG) and the structurally related metabolite D-2-hydorxyglutarate (D2-HG).	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (10, 29))	('FTO', 'Gene', '79068', (0, 3))	('D2-HG', 'Chemical', '-', (191, 196))	('inhibited', 'NegReg', (87, 96))	('FTO', 'Gene', (0, 3))	('D-2-hydorxyglutarate', 'Chemical', '-', (169, 189))	('R-2-hydroxyglutarate', 'Chemical', '-', (100, 120))	('R-2-hydroxyglutarate', 'Var', (100, 120))
58429	31143705	In several studies, the IDH mutations promoted the accumulation of 2-HG in tumors, including ~20% of AMLs and ~15% of ICCs.	('2-HG', 'Protein', (67, 71))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('AML', 'Disease', 'MESH:D015470', (101, 104))	('IDH', 'Gene', (24, 27))	('AML', 'Disease', (101, 104))	('accumulation', 'PosReg', (51, 63))	('IDH', 'Gene', '3417', (24, 27))	('promoted', 'PosReg', (38, 46))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('mutations', 'Var', (28, 37))
58430	31143705	In ICC, the mutant IDH1/2 proteins convert alpha-ketoglutarate (alphaKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple alphaKG-dependent dioxygenases and results in alterations in cell differentiation and survival.	('cell differentiation', 'CPA', (203, 223))	('survival', 'CPA', (228, 236))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (76, 94))	('activity', 'MPA', (121, 129))	('inhibits', 'NegReg', (108, 116))	('IDH1/2', 'Gene', (19, 25))	('mutant', 'Var', (12, 18))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (43, 62))	('alterations', 'Reg', (188, 199))	('IDH1/2', 'Gene', '3417;3418', (19, 25))	('alphaKG-dependent dioxygenases', 'Enzyme', (142, 172))	('proteins', 'Protein', (26, 34))
58431	31143705	These reports suggested that the mutated IDH1/2 promotes ICC by inhibiting the functions of FTO.	('functions', 'MPA', (79, 88))	('inhibiting', 'NegReg', (64, 74))	('IDH1/2', 'Gene', '3417;3418', (41, 47))	('FTO', 'Gene', (92, 95))	('mutated', 'Var', (33, 40))	('promotes', 'PosReg', (48, 56))	('ICC', 'Disease', (57, 60))	('IDH1/2', 'Gene', (41, 47))	('FTO', 'Gene', '79068', (92, 95))
58453	29178939	ATF2, as a downstream effector of MAPK in response to cytokines, is phosphorylated on Thr69 and/or Thr71 by either JNK or p38, and is also activated by the ERK1/2 pathway in two step.	('Thr71', 'Var', (99, 104))	('ATF2', 'Gene', '1386', (0, 4))	('JNK', 'Gene', (115, 118))	('p38', 'Gene', '1432', (122, 125))	('Thr71', 'Chemical', '-', (99, 104))	('response to cytokines', 'MPA', (42, 63))	('JNK', 'Gene', '5599', (115, 118))	('ERK1/2', 'Gene', (156, 162))	('ERK1/2', 'Gene', '5595;5594', (156, 162))	('ATF2', 'Gene', (0, 4))	('p38', 'Gene', (122, 125))	('Thr69', 'Var', (86, 91))	('Thr69', 'Chemical', '-', (86, 91))
58495	29178939	Western blot analysis indicated that CyclinD1 and CDK4 protein levels decreased dramatically when PTHLH expression was deleted in RBE cells (Fig.	('CDK4', 'Gene', '1019', (50, 54))	('CDK4', 'Gene', (50, 54))	('CyclinD1', 'Gene', (37, 45))	('decreased', 'NegReg', (70, 79))	('CyclinD1', 'Gene', '595', (37, 45))	('deleted', 'Var', (119, 126))	('PTHLH expression', 'Gene', (98, 114))
58497	29178939	To investigate whether PTHLH deletion suppresses tumorigenesis in vivo, PTHLH-KD RBE cells (shPTHLHx) were implanted subcutaneously into the right inguen, and vector cells (shCtrl) were implanted into the left inguen of nude mice (n = 5) (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('deletion', 'Var', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('shPTHLHx', 'Chemical', '-', (92, 100))	('suppresses', 'NegReg', (38, 48))	('nude mice', 'Species', '10090', (220, 229))	('PTHLH', 'Gene', (23, 28))
58498	29178939	Consistent with the cell proliferation assay in vitro, tumor growth was significantly decreased in mouse xenografts with shPTHLHx compared with that of shCtrl (Fig.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('mouse', 'Species', '10090', (99, 104))	('shPTHLHx', 'Chemical', '-', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('decreased', 'NegReg', (86, 95))	('shPTHLHx', 'Var', (121, 129))
58504	29178939	PTHLH (1-34) induced a time- and dose-responsive increase of in ATF2 protein expression.	('increase', 'PosReg', (49, 57))	('protein', 'Protein', (69, 76))	('ATF2', 'Gene', (64, 68))	('ATF2', 'Gene', '1386', (64, 68))	('PTHLH', 'Var', (0, 5))
58510	29178939	Interestingly, we further found that the MEK inhibitor U0126 and the JNK inhibitor SP600125 inhibited RBE cell growth, arresting cells at the G0/G1 phase (Fig.	('RBE cell growth', 'CPA', (102, 117))	('inhibited', 'NegReg', (92, 101))	('MEK', 'Gene', (41, 44))	('MEK', 'Gene', '5609', (41, 44))	('cells at the G0/G1 phase', 'CPA', (129, 153))	('JNK', 'Gene', '5599', (69, 72))	('U0126', 'Chemical', 'MESH:C113580', (55, 60))	('SP600125', 'Chemical', 'MESH:C432165', (83, 91))	('SP600125', 'Var', (83, 91))	('arresting', 'NegReg', (119, 128))	('JNK', 'Gene', (69, 72))
58521	29178939	Consistent with this finding, a mutation within this site attenuated the basal level of reporter activity and the binding of ATF2 (Fig.	('attenuated', 'NegReg', (58, 68))	('ATF2', 'Gene', (125, 129))	('basal level of reporter activity', 'MPA', (73, 105))	('ATF2', 'Gene', '1386', (125, 129))	('binding', 'Interaction', (114, 121))	('mutation', 'Var', (32, 40))
58529	29178939	Our findings demonstrate that PTHLH knockdown in ICC cells suppressed tumor growth, while re-expression of PTHLH has the opposite effect, highlighting the role of PTHLH as a critical oncoprotein in ICC progression.	('PTHLH', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('suppressed', 'NegReg', (59, 69))	('knockdown', 'Var', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
58533	29178939	In our previous study, we found that overexpression of the PTHLH (LV-PTHLH), which transfects lentivirus-mediated PTHLHGFP without deleting endogenous PTHLH expression in ICC cells, may enter into the non-proliferative cells (data not show).	('PTHLH', 'Gene', (151, 156))	('LV-PTHLH', 'Gene', '5744', (66, 74))	('LV-PTHLH', 'Gene', (66, 74))	('transfects', 'Var', (83, 93))	('PTHLHGFP', 'Gene', (114, 122))
58536	29178939	In our study, we also found re-expression PTHLH promotes RBE cells migration and specific overexpression PTHLH associates with intrahepatic metastasis in ICC patients.	('PTHLH', 'Gene', (105, 110))	('intrahepatic metastasis', 'Disease', (127, 150))	('PTHLH', 'Gene', (42, 47))	('RBE cells migration', 'CPA', (57, 76))	('intrahepatic metastasis', 'Disease', 'MESH:D009362', (127, 150))	('ICC', 'Disease', (154, 157))	('promotes', 'PosReg', (48, 56))	('patients', 'Species', '9606', (158, 166))	('re-expression', 'Var', (28, 41))	('overexpression', 'PosReg', (90, 104))
58541	29178939	The potential molecular mechanisms could be explained by the finding that the PTHLH protein activates the JNK/ERK1/2-ATF2 axis via interacting with the MAPK scaffolding protein beta-arrestin2, or triggering an early G protein-dependent pathway meditated by PKA and PKC leading to cell cycle proliferation.	('interacting', 'Interaction', (131, 142))	('ATF2', 'Gene', (117, 121))	('PTHLH', 'Var', (78, 83))	('PKC', 'Gene', '5581', (265, 268))	('cell cycle proliferation', 'CPA', (280, 304))	('PKC', 'Gene', (265, 268))	('ERK1/2', 'Gene', (110, 116))	('ATF2', 'Gene', '1386', (117, 121))	('activates', 'PosReg', (92, 101))	('triggering', 'Reg', (196, 206))	('ERK1/2', 'Gene', '5595;5594', (110, 116))	('beta-arrestin2', 'Gene', '409', (177, 191))	('JNK', 'Gene', (106, 109))	('beta-arrestin2', 'Gene', (177, 191))	('early G protein-dependent pathway', 'Pathway', (210, 243))	('JNK', 'Gene', '5599', (106, 109))
58543	29178939	When ERK1/2 and JNK are pharmacologically inhibited in ICC cells (i.e., via U0126 and SP600125), which blocked PTHLH-induced activation of ERK1/2 and JNK signal pathways, and transcriptional activity of ATF2 (Fig.	('activation', 'PosReg', (125, 135))	('SP600125', 'Var', (86, 94))	('SP600125', 'Chemical', 'MESH:C432165', (86, 94))	('JNK', 'Gene', (16, 19))	('transcriptional activity', 'MPA', (175, 199))	('U0126', 'Chemical', 'MESH:C113580', (76, 81))	('ATF2', 'Gene', '1386', (203, 207))	('JNK', 'Gene', (150, 153))	('ERK1/2', 'Gene', (139, 145))	('ERK1/2', 'Gene', '5595;5594', (139, 145))	('JNK', 'Gene', '5599', (16, 19))	('ERK1/2', 'Gene', '5595;5594', (5, 11))	('inhibited', 'NegReg', (42, 51))	('JNK', 'Gene', '5599', (150, 153))	('ERK1/2', 'Gene', (5, 11))	('U0126', 'Var', (76, 81))	('ATF2', 'Gene', (203, 207))
58545	29178939	Previous findings suggested that the deregulation of CyclinD1 expression and CDK4 activation directly lead to some cancer hallmarks by inducing proliferation.	('cancer', 'Disease', (115, 121))	('CyclinD1', 'Gene', (53, 61))	('CDK4', 'Gene', (77, 81))	('expression', 'MPA', (62, 72))	('lead to', 'Reg', (102, 109))	('inducing', 'PosReg', (135, 143))	('activation', 'PosReg', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('CDK4', 'Gene', '1019', (77, 81))	('CyclinD1', 'Gene', '595', (53, 61))	('deregulation', 'Var', (37, 49))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('proliferation', 'CPA', (144, 157))
58546	29178939	We observed that reduced CyclinD1 expression and CDK4 inactivation directly inhibited proliferation, which is consistent with previous reports.	('expression', 'MPA', (34, 44))	('proliferation', 'CPA', (86, 99))	('CyclinD1', 'Gene', (25, 33))	('CDK4', 'Gene', (49, 53))	('inhibited', 'NegReg', (76, 85))	('CyclinD1', 'Gene', '595', (25, 33))	('inactivation', 'Var', (54, 66))	('reduced', 'NegReg', (17, 24))	('CDK4', 'Gene', '1019', (49, 53))
58606	28465630	These are several class II HLA haplotypes including DRB1*0301- DRB3*0101-DQA1*0501-DQB1*0201, DRB1*1301-DRB3*0101-DQA1*0103-DQB1*0603, DRB1*1501-DRB5*0101-DQA1*0102- DQB1*0602, DRB1*0101-DQA1*0101, and B*0801.	('DRB1', 'Gene', '3123', (52, 56))	('DRB1', 'Gene', (52, 56))	('DRB1', 'Gene', (94, 98))	('DRB1', 'Gene', '3123', (135, 139))	('DRB1', 'Gene', '3123', (94, 98))	('B*0801', 'Var', (202, 208))	('DRB1', 'Gene', (135, 139))	('DRB1', 'Gene', '3123', (177, 181))	('DRB1', 'Gene', (177, 181))
58609	28465630	This alteration exposes cholangiocytes to bile acids that could promote injury and inflammation.	('injury and inflammation', 'Disease', 'MESH:D007249', (72, 95))	('bile acids', 'Chemical', 'MESH:D001647', (42, 52))	('promote', 'PosReg', (64, 71))	('alteration', 'Var', (5, 15))
58664	28465630	Type 1 autoimmune pancreatitis (AIP) is the leading manifestation of IgG4-RD, affecting approximately 60% of patients with IgG4-RD, followed by sialadenitis affecting 34% of patients, followed by tubulointerstitial nephritis (23%), dacryoadenitis (23%), and periaortitis (20%).	('patients', 'Species', '9606', (109, 117))	('tubulointerstitial nephritis', 'Disease', (196, 224))	('periaortitis', 'Disease', (258, 270))	('dacryoadenitis', 'Disease', 'MESH:D003607', (232, 246))	('dacryoadenitis', 'Disease', (232, 246))	('autoimmune pancreatitis', 'Disease', 'MESH:D000081012', (7, 30))	('AIP', 'Disease', 'MESH:D017118', (32, 35))	('tubulointerstitial nephritis', 'Phenotype', 'HP:0001970', (196, 224))	('AIP', 'Disease', (32, 35))	('IgG4-RD', 'Var', (123, 130))	('pancreatitis', 'Phenotype', 'HP:0001733', (18, 30))	('sialadenitis', 'Disease', 'MESH:D012793', (144, 156))	('sialadenitis', 'Phenotype', 'HP:0031281', (144, 156))	('tubulointerstitial nephritis', 'Disease', 'MESH:D009395', (196, 224))	('nephritis', 'Phenotype', 'HP:0000123', (215, 224))	('sialadenitis', 'Disease', (144, 156))	('periaortitis', 'Disease', 'MESH:D012185', (258, 270))	('patients', 'Species', '9606', (174, 182))	('autoimmune pancreatitis', 'Disease', (7, 30))
58692	28465630	Individuals with the presence of a dominant stricture and polysomy [5 or more cells which have gained 2 or more chromosomes (3, 7, 17, and band 9p21)] are eventually diagnosed with cholangiocarcinoma with 88% specificity.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (181, 199))	('polysomy [', 'Var', (58, 68))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (181, 199))	('diagnosed with', 'Reg', (166, 180))	('cholangiocarcinoma', 'Disease', (181, 199))
58741	25995671	Infection with a large number of parasites can result in invasion of the pancreatic duct and the parasites may damage ductal epithelial cells and cause inflammation in the pancreas and the bile duct, leading to clonorchiasis-induced pancreatitis.	('inflammation in the pancreas', 'Phenotype', 'HP:0001733', (152, 180))	('damage', 'NegReg', (111, 117))	('pancreatic duct', 'Disease', (73, 88))	('pancreatitis', 'Disease', (233, 245))	('pancreatic duct', 'Disease', 'MESH:D021441', (73, 88))	('result in', 'Reg', (47, 56))	('parasites', 'Var', (97, 106))	('cause', 'Reg', (146, 151))	('pancreatitis', 'Phenotype', 'HP:0001733', (233, 245))	('inflammation in the pancreas', 'Disease', 'MESH:D007249', (152, 180))	('inflammation in the pancreas', 'Disease', (152, 180))	('pancreatitis', 'Disease', 'MESH:D010195', (233, 245))	('leading to', 'Reg', (200, 210))
58765	25995671	Two mechanisms have been proposed by which C. sinensis causes pancreatitis: mechanical obstruction resulting in chemical stimuli by the mixture of the stagnant pancreatic fluid and the metabolites produced by C. sinensis, or inflammation and fibrosis caused by C. sinensis resulting in a back-current of bile into the pancreatic duct.	('C. sinensis', 'Species', '79923', (43, 54))	('pancreatic duct', 'Disease', (318, 333))	('chemical stimuli', 'MPA', (112, 128))	('pancreatitis', 'Phenotype', 'HP:0001733', (62, 74))	('inflammation', 'Disease', 'MESH:D007249', (225, 237))	('pancreatic', 'Disease', 'MESH:D010195', (318, 328))	('C. sinensis', 'Species', '79923', (261, 272))	('mechanical obstruction', 'Disease', (76, 98))	('pancreatitis', 'Disease', 'MESH:D010195', (62, 74))	('pancreatic', 'Disease', (318, 328))	('pancreatic', 'Disease', 'MESH:D010195', (160, 170))	('inflammation', 'Disease', (225, 237))	('pancreatitis', 'Disease', (62, 74))	('C. sinensis', 'Var', (43, 54))	('C. sinensis', 'Species', '79923', (209, 220))	('pancreatic', 'Disease', (160, 170))	('fibrosis', 'Disease', (242, 250))	('pancreatic duct', 'Disease', 'MESH:D021441', (318, 333))	('fibrosis', 'Disease', 'MESH:D005355', (242, 250))
58773	25995671	Therefore, we concluded that C. sinensis was associated with pancreatic mucinous neoplasm.	('mucinous neoplasm', 'Phenotype', 'HP:0031495', (72, 89))	('pancreatic mucinous neoplasm', 'Disease', (61, 89))	('pancreatic mucinous neoplasm', 'Disease', 'MESH:D010190', (61, 89))	('associated', 'Reg', (45, 55))	('C. sinensis', 'Var', (29, 40))	('C. sinensis', 'Species', '79923', (29, 40))	('neoplasm', 'Phenotype', 'HP:0002664', (81, 89))
58866	32511951	In many centres, asymptomatic patients undergoing interventional radiology procedures will have SARS-CoV-2 testing done, if they require general anaesthesia, or even if they require conscious sedation, before having locoregional therapies to mitigate the risk of exposure to staff.	('done', 'Reg', (115, 119))	('SARS-CoV-2', 'Gene', (96, 106))	('SARS-CoV-2', 'Species', '2697049', (96, 106))	('testing', 'Var', (107, 114))	('patients', 'Species', '9606', (30, 38))
58988	28422725	Recent studies have revealed that inhibition of mTOR signaling using rapamycin can enhance sensitivity of cancer cells to cisplatin and doxorubicin.	('mTOR', 'Gene', '2475', (48, 52))	('mTOR', 'Gene', (48, 52))	('inhibition', 'Var', (34, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('doxorubicin', 'Chemical', 'MESH:D004317', (136, 147))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('enhance', 'PosReg', (83, 90))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('rapamycin', 'Chemical', 'MESH:D020123', (69, 78))	('sensitivity', 'MPA', (91, 102))
58989	28422725	Our previous studies also revealed that inhibition of mTOR suppresses human gallbladder carcinoma cell proliferation and enhances the cytotoxicity of 5-fluorouracil (5-FU) by regulating MDR1 expression.	('inhibition', 'Var', (40, 50))	('MDR1', 'Gene', '5243', (186, 190))	('regulating', 'Reg', (175, 185))	('cytotoxicity', 'Disease', 'MESH:D064420', (134, 146))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (150, 164))	('cytotoxicity', 'Disease', (134, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('mTOR', 'Gene', '2475', (54, 58))	('human', 'Species', '9606', (70, 75))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (76, 97))	('mTOR', 'Gene', (54, 58))	('5-FU', 'Chemical', 'MESH:D005472', (166, 170))	('suppresses', 'NegReg', (59, 69))	('enhances', 'PosReg', (121, 129))	('MDR1', 'Gene', (186, 190))	('expression', 'MPA', (191, 201))	('gallbladder carcinoma', 'Disease', (76, 97))
59022	28422725	We found that MG132 increased the protein level of MDR1 in GBC-SD and RBE cell lines, whilst using both MG132 and miR-199a-3p mimics led to lower expression of MDR1 compared to negative controls or the MG132 alone group.	('increased', 'PosReg', (20, 29))	('MDR1', 'Gene', '5243', (160, 164))	('lower', 'NegReg', (140, 145))	('MG132', 'Chemical', 'MESH:C072553', (202, 207))	('MG132', 'Var', (14, 19))	('MDR1', 'Gene', (160, 164))	('MG132', 'Chemical', 'MESH:C072553', (14, 19))	('miR-199a-3p', 'Gene', (114, 125))	('MDR1', 'Gene', (51, 55))	('MG132', 'Chemical', 'MESH:C072553', (104, 109))	('MDR1', 'Gene', '5243', (51, 55))	('expression', 'MPA', (146, 156))	('miR-199a-3p', 'Gene', '406977', (114, 125))	('protein level', 'MPA', (34, 47))
59037	28422725	Inhibitors of mTOR, such as miRNAs, can inhibit tumor cell growth in many cancers by blocking the AKT/mTOR signaling pathway.	('mTOR', 'Gene', '2475', (14, 18))	('tumor', 'Disease', (48, 53))	('inhibit', 'NegReg', (40, 47))	('mTOR', 'Gene', '2475', (102, 106))	('blocking', 'NegReg', (85, 93))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('Inhibitors', 'Var', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('AKT', 'Gene', '207', (98, 101))	('cancers', 'Disease', (74, 81))	('mTOR', 'Gene', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('AKT', 'Gene', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mTOR', 'Gene', (14, 18))
59044	28422725	In our previous study, we demonstrated that MDR1 was regulated by the mTOR signaling pathway, and inhibition of the mTOR signaling pathway potently sensitized gallbladder cancer cells to 5-FU in vitro by suppressing the expression of 5-FU-induced MDR1; thus, we considered whether MDR1 was also involved in miR-199a-3p-mediated cisplatin-high-sensitivity in cholangiocarcinoma cells.	('MDR1', 'Gene', (44, 48))	('inhibition', 'Var', (98, 108))	('mTOR', 'Gene', '2475', (70, 74))	('5-FU', 'Chemical', 'MESH:D005472', (234, 238))	('gallbladder cancer', 'Disease', 'MESH:D005706', (159, 177))	('mTOR', 'Gene', '2475', (116, 120))	('MDR1', 'Gene', (247, 251))	('MDR1', 'Gene', (281, 285))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (358, 376))	('gallbladder cancer', 'Disease', (159, 177))	('MDR1', 'Gene', '5243', (44, 48))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (358, 381))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('mTOR', 'Gene', (70, 74))	('expression', 'MPA', (220, 230))	('cholangiocarcinoma cell', 'Disease', (358, 381))	('miR-199a-3p', 'Gene', (307, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (367, 376))	('MDR1', 'Gene', '5243', (247, 251))	('5-FU', 'Chemical', 'MESH:D005472', (187, 191))	('MDR1', 'Gene', '5243', (281, 285))	('mTOR', 'Gene', (116, 120))	('suppressing', 'NegReg', (204, 215))	('cisplatin', 'Chemical', 'MESH:D002945', (328, 337))	('miR-199a-3p', 'Gene', '406977', (307, 318))
59047	28422725	One was MG132, which can inhibit the ubiquitin degradation of MDR1, the other was CHX, which can inhibit the synthesis of MDR1.	('inhibit', 'NegReg', (97, 104))	('ubiquitin degradation', 'MPA', (37, 58))	('MDR1', 'Gene', (122, 126))	('MDR1', 'Gene', (62, 66))	('MDR1', 'Gene', '5243', (122, 126))	('CHX', 'Chemical', 'MESH:D003513', (82, 85))	('MG132', 'Chemical', 'MESH:C072553', (8, 13))	('inhibit', 'NegReg', (25, 32))	('MG132', 'Var', (8, 13))	('MDR1', 'Gene', '5243', (62, 66))	('synthesis', 'MPA', (109, 118))
59069	28422725	The following antibodies were used: anti-mTOR (1:400 dilution; Cell Signaling, Natick, MA, USA), anti-p-mTOR (2481 and 2448) (1:1000; Cell Signaling), anti-p-4EBP1 (1:1000; Cell Signaling), anti-p-p70s6k (1:1000; Cell Signaling), anti-4EBP1 (1:1000; Abcam, Cambridge, UK), anti-P70s6K (1:1000; Abcam), anti-MDR1 (1:1000; Abcam), anti-GAPDH (1:2000; Abcam), and anti-HRP (1:2000; Cell Signaling).	('mTOR', 'Gene', (104, 108))	('MDR1', 'Gene', '5243', (307, 311))	('anti-GAPDH', 'Var', (329, 339))	('P70s6K', 'Gene', '6198', (278, 284))	('mTOR', 'Gene', '2475', (104, 108))	('4EBP1', 'Gene', '1978', (235, 240))	('p70s6k', 'Gene', '6198', (197, 203))	('4EBP1', 'Gene', (235, 240))	('P70s6K', 'Gene', (278, 284))	('4EBP1', 'Gene', '1978', (158, 163))	('MDR1', 'Gene', (307, 311))	('p70s6k', 'Gene', (197, 203))	('mTOR', 'Gene', (41, 45))	('mTOR', 'Gene', '2475', (41, 45))	('4EBP1', 'Gene', (158, 163))
59252	32330128	Successful molecular subdivision of tumors originating from the same tissue may result in different treatments targeting a specific tumor type, as is found in the case of ERBB2-amplified breast cancer and EGFR mutant lung carcinoma.	('mutant', 'Var', (210, 216))	('EGFR', 'Gene', '1956', (205, 209))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('lung carcinoma', 'Disease', (217, 231))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('ERBB2', 'Gene', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('EGFR', 'Gene', (205, 209))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('tumors', 'Disease', (36, 42))	('breast cancer', 'Disease', (187, 200))	('result in', 'Reg', (80, 89))	('ERBB2', 'Gene', '2064', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('lung carcinoma', 'Disease', 'MESH:D008175', (217, 231))	('tumors', 'Disease', 'MESH:D009369', (36, 42))
59401	31881761	A total of n = 3 patients who had undergone 90Y TARE twice did not experience a significant decline in liver function tests.	('liver function tests', 'MPA', (103, 123))	('90Y', 'Var', (44, 47))	('decline in liver function', 'Phenotype', 'HP:0001410', (92, 117))	('TARE', 'Species', '3908', (48, 52))	('patients', 'Species', '9606', (17, 25))	('decline', 'NegReg', (92, 99))
59407	31881761	Several studies have reported a potential benefit for TARE in ICC, but most confer to patients with limited disease or naive to other anticancer treatments; in some, TARE was able to even achieve a disease reduction allowing for subsequent surgical resection.	('cancer', 'Disease', (138, 144))	('TARE', 'Var', (166, 170))	('TARE', 'Species', '3908', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('ICC', 'Disease', (62, 65))	('TARE', 'Species', '3908', (166, 170))	('ICC', 'Disease', 'MESH:C535533', (62, 65))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('patients', 'Species', '9606', (86, 94))
59420	31881761	Moreover, a bilobar tumor extent was associated with decreased survival rates compared to unilobar disease only, while mere tumor volume interestingly did not show to be a prognostic factor for survival after TARE in advanced ICC.	('ICC', 'Disease', 'MESH:C535533', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('TARE', 'Species', '3908', (209, 213))	('decreased', 'NegReg', (53, 62))	('survival rates', 'MPA', (63, 77))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('ICC', 'Disease', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('bilobar', 'Var', (12, 19))	('tumor', 'Disease', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
59429	31881761	While in the present study, 90Y TARE was applied as a salvage therapy option for ICC, when other anticancer treatments including surgery had failed or disease relapse occurred, 90Y TARE might be combined with other anticancer treatments in a multimodality setting earlier in the course of the disease.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('TARE', 'Species', '3908', (181, 185))	('cancer', 'Disease', (101, 107))	('ICC', 'Disease', (81, 84))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('ICC', 'Disease', 'MESH:C535533', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (219, 225))	('90Y', 'Var', (177, 180))	('TARE', 'Species', '3908', (32, 36))
59431	31881761	These multimodal therapy regimes, including 90Y TARE, have the potential to improve survival and reduce side effects compared to sole chemotherapeutic approaches using high dose regimens.	('side effects', 'CPA', (104, 116))	('90Y TARE', 'Var', (44, 52))	('TARE', 'Species', '3908', (48, 52))	('survival', 'CPA', (84, 92))	('improve', 'PosReg', (76, 83))
59444	31881761	The present study shows that in an advanced disease stage of ICC, 90Y TARE can be applied in a salvage approach, however with poor overall survival, which depends primarily on disease extent.	('ICC', 'Disease', 'MESH:C535533', (61, 64))	('TARE', 'Species', '3908', (70, 74))	('ICC', 'Disease', (61, 64))	('90Y', 'Var', (66, 69))
59447	32071556	We analyzed mRNA expression profiling in large CCA cohorts from the Gene Expression Omnibus (GEO) database (GSE76297, GSE32879, GSE26566, GSE31370, and GSE45001) and The Cancer Genome Atlas (TCGA) database.	('GSE76297', 'Var', (108, 116))	('Cancer', 'Phenotype', 'HP:0002664', (170, 176))	('CCA', 'Disease', 'MESH:D018281', (47, 50))	('CCA', 'Disease', (47, 50))	('GSE26566', 'Var', (128, 136))	('GSE31370', 'Var', (138, 146))
59456	32071556	For example, KRAS mutations were associated with deregulation of epidermal growth factor receptor (EGFR) and ERBB2 signaling network, derangement of genes participating in proteasomal activity could lead to poor prognosis.	('EGFR', 'Gene', '1956', (99, 103))	('EGFR', 'Gene', (99, 103))	('ERBB2', 'Gene', '2064', (109, 114))	('ERBB2', 'Gene', (109, 114))	('epidermal growth factor receptor', 'Gene', (65, 97))	('poor prognosis', 'CPA', (207, 221))	('derangement', 'Var', (134, 145))	('lead to', 'Reg', (199, 206))	('epidermal growth factor receptor', 'Gene', '1956', (65, 97))	('KRAS', 'Gene', (13, 17))	('deregulation', 'MPA', (49, 61))	('KRAS', 'Gene', '3845', (13, 17))	('mutations', 'Var', (18, 27))
59463	32071556	There were five appropriate CCA datasets from the GEO database (GSE76297, GSE32879, GSE26566, GSE31370, and GSE45001) met the following criteria: a).	('GSE26566', 'Var', (84, 92))	('GSE31370', 'Var', (94, 102))	('GSE32879', 'Var', (74, 82))	('GSE76297', 'Var', (64, 72))	('GSE45001', 'Var', (108, 116))	('CCA', 'Disease', 'MESH:D018281', (28, 31))	('CCA', 'Disease', (28, 31))
59481	32071556	Detailed information of the five eligible CCA datasets meets our criteria in the GEO database (GSE76297, GSE32879, GSE26566, GSE31370, and GSE45001) were shown in Table 1.	('GSE31370', 'Var', (125, 133))	('GSE32879', 'Var', (105, 113))	('GSE76297', 'Var', (95, 103))	('CCA', 'Disease', 'MESH:D018281', (42, 45))	('GSE26566', 'Var', (115, 123))	('CCA', 'Disease', (42, 45))	('GSE45001', 'Var', (139, 147))
59482	32071556	After analyzing these CCA datasets using GEO2R, 4005, 6554, 990, 3893, 879 and 399 DEGs were respectively recognized in GSE76297-T/P, GSE26566-T/P, GSE45001-T/P, GSE32879-T/N, GSE26566-T/N, GSE31370-T/N (Figure 1A-F).	('GSE76297-T/P', 'Var', (120, 132))	('GSE31370-T/N', 'Var', (190, 202))	('CCA', 'Disease', (22, 25))	('GSE45001-T/P', 'Var', (148, 160))	('GSE32879-T/N', 'Var', (162, 174))	('GSE26566-T/N', 'Var', (176, 188))	('CCA', 'Disease', 'MESH:D018281', (22, 25))
59490	32071556	Based on the expression status of these 7 mRNAs, a risk-score formula for RFS was constructed as follows: Risk score= (-0.96873 x expression status of CD36) + (-0.03944 x expression status of GGCX) + (0.01064 x expression status of UBASH3B) + (0.04955 x expression status of DBN1) + (0.24927 x expression status of PTTG1) + (0.31598 x expression status of CCNA2) + (0.57201 x expression status of SPATS2).	('SPATS2', 'Gene', '65244', (397, 403))	('UBASH3B', 'Gene', (232, 239))	('GGCX', 'Gene', '2677', (192, 196))	('CCNA2', 'Gene', '890', (356, 361))	('PTTG1', 'Gene', (315, 320))	('CD36', 'Species', '42374', (151, 155))	('PTTG1', 'Gene', '9232', (315, 320))	('-0.96873', 'Var', (119, 127))	('SPATS2', 'Gene', (397, 403))	('UBASH3B', 'Gene', '84959', (232, 239))	('0.01064', 'Var', (201, 208))	('GGCX', 'Gene', (192, 196))	('0.57201 x', 'Var', (366, 375))	('DBN1', 'Gene', '1627', (275, 279))	('0.31598 x', 'Var', (325, 334))	('CCNA2', 'Gene', (356, 361))	('DBN1', 'Gene', (275, 279))
59507	32071556	Univariable Cox analyses of the Ren Ji cohort showed that CA19-9 levels, lymph node metastasis, and the 7-mRNA signature were significant factors that correlated with RFS of CCA (Table S5).	('CCA', 'Disease', 'MESH:D018281', (174, 177))	('Ren', 'Gene', '5972', (32, 35))	('RFS', 'Var', (167, 170))	('Ren', 'Gene', (32, 35))	('CCA', 'Disease', (174, 177))	('Cox', 'Gene', '1351', (12, 15))	('Cox', 'Gene', (12, 15))
59515	32071556	For patients in subgroups of male, CA19-9 <= 37ng/ml, tumor size <= 5cm, mono-modular, negative of lymph node metastasis or distant metastasis, the 7-mRNA signature maintained its predictive value for recurrence-free survival (Figure S6B, S6C, S6E, S6G, S6I, and S6K).	('S6E', 'Var', (244, 247))	('S6K', 'Mutation', 'p.S6K', (263, 266))	('S6I', 'Var', (254, 257))	('S6G', 'Var', (249, 252))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('S6K', 'Var', (263, 266))	('S6C', 'Chemical', 'MESH:C012008', (239, 242))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('S6C', 'Var', (239, 242))	('patients', 'Species', '9606', (4, 12))	('CA19-9 <=', 'Var', (35, 44))	('tumor', 'Disease', (54, 59))	('recurrence-free survival', 'CPA', (201, 225))
59516	32071556	Unfortunately, the 7-mRNA signature lost the prognostic role for patients of female, CA19-9 > 37ng/ml, tumor size > 5cm, multi-modular, positive of lymph node metastasis or positive of distant metastasis, which might be due to the small sample number of these subgroups (Figure S6A, S6D, S6F, S6H, S6J and S6L).	('lymph node metastasis', 'CPA', (148, 169))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('S6L', 'Mutation', 'p.S6L', (306, 309))	('positive', 'Reg', (136, 144))	('CA19-9', 'Gene', (85, 91))	('tumor', 'Disease', (103, 108))	('> 37ng/ml', 'Var', (92, 101))	('S6J', 'Chemical', 'MESH:C077098', (298, 301))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('patients', 'Species', '9606', (65, 73))	('distant metastasis', 'CPA', (185, 203))	('positive', 'Reg', (173, 181))	('lost', 'NegReg', (36, 40))
59534	32071556	reported that exon 2 deletion splice variant of GGCX could result in des-gamma-carboxy prothrombin (DCP) production in HCC cell lines, so, we guessed that GGCX metabolite DCP could play the same role in cholangiocarcinoma.	('GGCX', 'Gene', (155, 159))	('cholangiocarcinoma', 'Disease', (203, 221))	('des-gamma-carboxy prothrombin', 'Gene', '1636', (69, 98))	('deletion splice', 'Var', (21, 36))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (203, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (203, 221))	('GGCX', 'Gene', '2677', (48, 52))	('result in', 'Reg', (59, 68))	('GGCX', 'Gene', '2677', (155, 159))	('GGCX', 'Gene', (48, 52))	('des-gamma-carboxy prothrombin', 'Gene', (69, 98))
59542	32071556	In colorectal cancer, knockdown of CCNA2 inhibited cancer growth by impairing cell cycle .	('cancer', 'Disease', (14, 20))	('CCNA2', 'Gene', (35, 40))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('knockdown', 'Var', (22, 31))	('colorectal cancer', 'Disease', (3, 20))	('CCNA2', 'Gene', '890', (35, 40))	('inhibited', 'NegReg', (41, 50))	('impairing', 'NegReg', (68, 77))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cell cycle', 'CPA', (78, 88))
59632	31239770	Thus, major hepatic resection tends to be associated with an increased risk of postoperative hepatic insufficiency.	('hepatic insufficiency', 'Phenotype', 'HP:0001399', (93, 114))	('postoperative hepatic insufficiency', 'Disease', 'MESH:D000309', (79, 114))	('postoperative hepatic insufficiency', 'Disease', (79, 114))	('major', 'Var', (6, 11))
59671	31239770	Furthermore, the preoperative NLR has shown a significant correlation with poor outcome in hepatocellular carcinoma patients, and a high NLR also showed correlation with early recurrence and poor overall survival in intrahepatic cholangiocarcinoma patients.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (216, 247))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (229, 247))	('patients', 'Species', '9606', (248, 256))	('patients', 'Species', '9606', (116, 124))	('intrahepatic cholangiocarcinoma', 'Disease', (216, 247))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (91, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('hepatocellular carcinoma', 'Disease', (91, 115))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (91, 115))	('high', 'Var', (132, 136))
59712	30200114	In other tumors, such as lung cancer, gene mutations have been suggested as leading to mucin production.	('gene mutations', 'Var', (38, 52))	('mucin', 'Gene', '100508689', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('lung cancer', 'Disease', (25, 36))	('leading', 'Reg', (76, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('mucin', 'Gene', (87, 92))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))
59716	30200114	Sasaki et al have reported that mutations in the telomerase reverse transcriptase promoter might induce transdifferentiation of HCCs and lead to the development of intermediate-cell subtype of combined hepatocellular cholangiocarcinoma.	('HCC', 'Phenotype', 'HP:0001402', (128, 131))	('hepatocellular cholangiocarcinoma', 'Disease', 'MESH:D018281', (202, 235))	('lead to', 'Reg', (137, 144))	('transdifferentiation', 'CPA', (104, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('induce', 'Reg', (97, 103))	('mutations', 'Var', (32, 41))	('hepatocellular cholangiocarcinoma', 'Disease', (202, 235))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (217, 235))	('intermediate-cell subtype', 'Disease', (164, 189))
59719	30200114	Our case supports the hypothesis that mutations of a gene or genes enable HCC cells to produce mucin without or before morphological differentiation to biliary cells, and may help elucidate the mechanism for the development of combined hepatocellular cholangiocarcinoma.	('hepatocellular cholangiocarcinoma', 'Disease', 'MESH:D018281', (236, 269))	('mucin', 'Gene', (95, 100))	('hepatocellular cholangiocarcinoma', 'Disease', (236, 269))	('HCC', 'Phenotype', 'HP:0001402', (74, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (251, 269))	('mucin', 'Gene', '100508689', (95, 100))	('mutations', 'Var', (38, 47))
59754	26684807	Recurrent Amplification at 13q34 Targets at CUL4A, IRS2, and TFDP1 As an Independent Adverse Prognosticator in Intrahepatic Cholangiocarcinoma Amplification of genes at 13q34 has been reported to be associated with tumor proliferation and progression in diverse types of cancers.	('IRS2', 'Gene', (51, 55))	('CUL4A', 'Gene', '8451', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('CUL4A', 'Gene', (44, 49))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (124, 142))	('cancers', 'Phenotype', 'HP:0002664', (271, 278))	('cancers', 'Disease', (271, 278))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('rat', 'Species', '10116', (228, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('Intrahepatic Cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 142))	('Intrahepatic Cholangiocarcinoma', 'Disease', (111, 142))	('TFDP1', 'Gene', (61, 66))	('associated with', 'Reg', (199, 214))	('IRS2', 'Gene', '8660', (51, 55))	('cancers', 'Disease', 'MESH:D009369', (271, 278))	('tumor', 'Disease', (215, 220))	('Amplification', 'Var', (143, 156))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('TFDP1', 'Gene', '7027', (61, 66))
59760	26684807	The SNU1079 cell line containing deletions of the target genes demonstrated decreased protein expression levels and significantly lower numbers of migratory and invasive cells, as opposed to the RBE cell line, which does not contain CN alterations.	('lower', 'NegReg', (130, 135))	('protein expression levels', 'MPA', (86, 111))	('rat', 'Species', '10116', (70, 73))	('decreased', 'NegReg', (76, 85))	('rat', 'Species', '10116', (150, 153))	('deletions', 'Var', (33, 42))	('rat', 'Species', '10116', (240, 243))	('SNU1079', 'CellLine', 'CVCL:5008', (4, 11))
59762	26684807	In contrast, silencing each target gene showed a trend or statistical significance toward inhibition of migratory and invasive capacities in RBE cells.	('inhibition', 'NegReg', (90, 100))	('silencing', 'Var', (13, 22))	('rat', 'Species', '10116', (107, 110))
59763	26684807	In tumor samples, the amplification of each of these genes was associated with poor disease-free survival.	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', (3, 8))	('associated', 'Reg', (63, 73))	('amplification', 'Var', (22, 35))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('disease-free survival', 'CPA', (84, 105))	('poor', 'NegReg', (79, 83))
59764	26684807	Twelve cases (13.9%) demonstrated copy numbers > 4 for all three genes tested (CUL4A, IRS2, and TFDP1), and showed a significant difference in disease-free survival by both univariate and multivariate survival analyses (hazard ratio, 2.69; 95% confidence interval, 1.23 to 5.88; P = 0.013).	('CUL4A', 'Gene', (79, 84))	('rat', 'Species', '10116', (227, 230))	('difference', 'Reg', (129, 139))	('CUL4A', 'Gene', '8451', (79, 84))	('disease-free survival', 'CPA', (143, 164))	('IRS2', 'Gene', (86, 90))	('TFDP1', 'Gene', (96, 101))	('TFDP1', 'Gene', '7027', (96, 101))	('copy numbers', 'Var', (34, 46))	('rat', 'Species', '10116', (28, 31))
59765	26684807	Our data demonstrate that amplification of genes at 13q34 plays an oncogenic role in iCCA featuring adverse disease-free survival, which may provide new directions for targeted therapy.	('iCCA featuring', 'Disease', (85, 99))	('amplification', 'Var', (26, 39))	('rat', 'Species', '10116', (16, 19))
59767	26684807	Amplification is one mechanism for overexpression of oncogenes, a critical step in cancer development and progression.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('Amplification', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('overexpression', 'PosReg', (35, 49))	('cancer', 'Disease', (83, 89))
59768	26684807	Activation mutations, rather than amplification, of genes such as Kirsten rat sarcoma viral oncogene homolog (KRAS), isocitrate dehydrogenase 1 (IDH1), IDH2, B-Raf proto-oncogene, serine/threonine kinase (BRAF), and epidermal growth factor receptor (EGFR), have been shown to have a potential impact on the prognosis of intrahepatic cholangiocarcinoma (iCCA).	('mutations', 'Var', (11, 20))	('IDH1', 'Gene', (145, 149))	('B-Raf', 'Gene', '114486', (158, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (342, 351))	('sarcoma', 'Disease', 'MESH:D012509', (78, 85))	('isocitrate dehydrogenase 1', 'Gene', '24479', (117, 143))	('sarcoma', 'Disease', (78, 85))	('EGFR', 'Gene', (250, 254))	('BRAF', 'Gene', (205, 209))	('KRAS', 'Gene', '24525', (110, 114))	('BRAF', 'Gene', '114486', (205, 209))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (320, 351))	('EGFR', 'Gene', '24329', (250, 254))	('rat', 'Species', '10116', (22, 25))	('intrahepatic cholangiocarcinoma', 'Disease', (320, 351))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('epidermal growth factor receptor', 'Gene', '24329', (216, 248))	('B-Raf', 'Gene', (158, 163))	('rat', 'Species', '10116', (123, 126))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (333, 351))	('KRAS', 'Gene', (110, 114))	('IDH2', 'Gene', (152, 156))	('IDH1', 'Gene', '24479', (145, 149))	('impact', 'Reg', (293, 299))	('epidermal growth factor receptor', 'Gene', (216, 248))	('rat', 'Species', '10116', (74, 77))	('IDH2', 'Gene', '361596', (152, 156))	('isocitrate dehydrogenase 1', 'Gene', (117, 143))
59775	26684807	In our previous genome-wide study of combined HCC and cholangiocarcinoma, we found that amplification of 13q34 was present in the cholangiocarcinoma rather than the HCC component.	('rat', 'Species', '10116', (149, 152))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (130, 148))	('13q34', 'Gene', (105, 110))	('amplification', 'Var', (88, 101))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (54, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (130, 148))	('cholangiocarcinoma', 'Disease', (54, 72))	('cholangiocarcinoma', 'Disease', (130, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
59802	26684807	RC212413) and specific siRNAs targeting IRS2, CUL4A and TFDP1 were purchased from Origene (Origene, MD, USA).	('CUL4A', 'Gene', (46, 51))	('TFDP1', 'Gene', '7027', (56, 61))	('TFDP1', 'Gene', (56, 61))	('CUL4A', 'Gene', '8451', (46, 51))	('RC212413', 'Var', (0, 8))
59829	26684807	CUL4A, IRS2, and TFDP1 were deleted in SNU1079 cells in contrast to normal genomic DNA derived from peripheral blood lymphocytes.	('TFDP1', 'Gene', '7027', (17, 22))	('CUL4A', 'Gene', '8451', (0, 5))	('IRS2', 'Gene', (7, 11))	('TFDP1', 'Gene', (17, 22))	('deleted', 'Var', (28, 35))	('SNU1079', 'CellLine', 'CVCL:5008', (39, 46))	('CUL4A', 'Gene', (0, 5))
59830	26684807	The SNU1079 cell line with deleted genes exhibited decreased protein expression levels, as opposed to the RBE cell line that did not have remarkable CN alterations (Fig 1).	('rat', 'Species', '10116', (156, 159))	('deleted genes', 'Var', (27, 40))	('decreased', 'NegReg', (51, 60))	('protein expression levels', 'MPA', (61, 86))	('genes', 'Var', (35, 40))	('SNU1079', 'CellLine', 'CVCL:5008', (4, 11))
59831	26684807	Compared to RBE cells, SNU1079 cells containing deletions of the target genes had significantly lower numbers of migratory and invasive cells (Fig 2).	('SNU1079', 'CellLine', 'CVCL:5008', (23, 30))	('lower', 'NegReg', (96, 101))	('deletions', 'Var', (48, 57))	('rat', 'Species', '10116', (116, 119))
59834	26684807	SNU1079-IRS2 cells had higher numbers of migratory and invasive cells compared to their control cells (Fig 3D).	('rat', 'Species', '10116', (44, 47))	('higher', 'PosReg', (23, 29))	('SNU1079', 'CellLine', 'CVCL:5008', (0, 7))	('SNU1079-IRS2', 'Var', (0, 12))
59835	26684807	While knockdown of the target genes in RBE cells, which showed no significant impacts on the cellular proliferation due to gene silencing (Fig 4A), RBE-siIRS2 cells showed a trend toward inhibition of the mobility potential and a significant lower degree of migration (P = 0.018), and both RBE-siCUL4A and RBE-siTFDP1cells had significant lower migratory (P = 0.027 and P = 0.037, respectively) and invasive (P = 0.006 and P = 0.011, respectively) capacities than control cells (Fig 4B).	('rat', 'Species', '10116', (348, 351))	('migration', 'CPA', (258, 267))	('CUL4A', 'Gene', (296, 301))	('inhibition', 'NegReg', (187, 197))	('lower', 'NegReg', (339, 344))	('mobility potential', 'CPA', (205, 223))	('CUL4A', 'Gene', '8451', (296, 301))	('rat', 'Species', '10116', (261, 264))	('gene silencing', 'Var', (123, 137))	('rat', 'Species', '10116', (109, 112))	('TFDP1', 'Gene', '7027', (312, 317))	('lower', 'NegReg', (242, 247))	('TFDP1', 'Gene', (312, 317))	('cellular proliferation', 'CPA', (93, 115))
59837	26684807	Kaplan-Meier univariate survival analysis revealed that amplification of CUL4A, IRS2, and TFDP1 was associated with poor DFS.	('DFS', 'CPA', (121, 124))	('CUL4A', 'Gene', (73, 78))	('associated', 'Reg', (100, 110))	('IRS2', 'Gene', (80, 84))	('TFDP1', 'Gene', (90, 95))	('CUL4A', 'Gene', '8451', (73, 78))	('TFDP1', 'Gene', '7027', (90, 95))	('amplification', 'Var', (56, 69))
59840	26684807	Multivariate Cox proportional hazards regression analysis revealed that amplification of the 3-marker combination, consisting of CUL4A, IRS2, and TFDP1 with all copies higher than four might be an independent adverse prognosticator for DFS (Table 4).	('DFS', 'Disease', (236, 239))	('amplification', 'Var', (72, 85))	('TFDP1', 'Gene', '7027', (146, 151))	('TFDP1', 'Gene', (146, 151))	('CUL4A', 'Gene', (129, 134))	('CUL4A', 'Gene', '8451', (129, 134))
59842	26684807	A strong nuclear staining of CUL4A and TFDP1, and increased cytoplasmic staining of IRS2 were identified in tumors with amplification, compared to normal bile ducts and cases with a deletion of target genes (Fig 6).	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('increased', 'PosReg', (50, 59))	('CUL4A', 'Gene', (29, 34))	('amplification', 'Var', (120, 133))	('IRS2', 'Gene', (84, 88))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('TFDP1', 'Gene', '7027', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('nuclear staining', 'MPA', (9, 25))	('cytoplasmic staining', 'MPA', (60, 80))	('CUL4A', 'Gene', '8451', (29, 34))	('TFDP1', 'Gene', (39, 44))
59843	26684807	Amplification of the target genes may be associated with protein expression and influence tumor migration and invasion.	('Amplification', 'Var', (0, 13))	('associated', 'Reg', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('rat', 'Species', '10116', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('invasion', 'CPA', (110, 118))	('influence', 'Reg', (80, 89))	('protein', 'Protein', (57, 64))
59846	26684807	The correlations that we identified suggest that amplifications of CUL4A, IRS2, and TFDP1 are adverse prognosticators of DFS.	('amplifications', 'Var', (49, 63))	('TFDP1', 'Gene', '7027', (84, 89))	('CUL4A', 'Gene', (67, 72))	('IRS2', 'Gene', (74, 78))	('TFDP1', 'Gene', (84, 89))	('DFS', 'Disease', (121, 124))	('CUL4A', 'Gene', '8451', (67, 72))
59849	26684807	In a previous whole-genome study, we found that amplification of 13q34 was identified in five (15.6%) of 32 fresh iCCA samples, similar to the frequency of cases (13.9%) with a CN higher than four for genes CUL4A, IRS2, and TFDP1 found in the present study.	('TFDP1', 'Gene', '7027', (224, 229))	('13q34', 'Gene', (65, 70))	('TFDP1', 'Gene', (224, 229))	('CUL4A', 'Gene', (207, 212))	('IRS2', 'Gene', (214, 218))	('CUL4A', 'Gene', '8451', (207, 212))	('amplification', 'Var', (48, 61))
59852	26684807	Overexpression of IRS2 increases colorectal cell adhesion, similar to observations made for breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('IRS2', 'Gene', (18, 22))	('colorectal cell adhesion', 'CPA', (33, 57))	('Overexpression', 'Var', (0, 14))	('increases', 'PosReg', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
59855	26684807	Amplification of TFDP1 contributing to gene overexpression was reported in HCC, breast cancer, and lung cancer.	('TFDP1', 'Gene', '7027', (17, 22))	('Amplification', 'Var', (0, 13))	('lung cancer', 'Disease', (99, 110))	('HCC', 'Disease', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('TFDP1', 'Gene', (17, 22))	('gene', 'MPA', (39, 43))	('overexpression', 'PosReg', (44, 58))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
59861	26684807	Similar to TFDP1, amplification of CUL4A DNA is also correlated with gene expression.	('CUL4A', 'Gene', (35, 40))	('TFDP1', 'Gene', (11, 16))	('correlated', 'Reg', (53, 63))	('TFDP1', 'Gene', '7027', (11, 16))	('CUL4A', 'Gene', '8451', (35, 40))	('gene expression', 'MPA', (69, 84))	('amplification', 'Var', (18, 31))
59863	26684807	Overexpression of CUL4A is associated with tumor proliferation, progression, and metastasis.	('CUL4A', 'Gene', (18, 23))	('rat', 'Species', '10116', (56, 59))	('progression', 'CPA', (64, 75))	('CUL4A', 'Gene', '8451', (18, 23))	('associated', 'Reg', (27, 37))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('metastasis', 'CPA', (81, 91))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', (43, 48))
59865	26684807	Our findings, along with the previous research, suggest the importance of the target genes as targets for 13q34 amplification and biological implications for tumor progression.	('tumor', 'Disease', (158, 163))	('amplification', 'Var', (112, 125))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
59868	26684807	Although a larger cohort study would be needed to declare the prevalence of 13q34 amplification, this genomic aberration may be used both as a clinical marker and as a therapeutic target in iCCA.	('13q34', 'Gene', (76, 81))	('iCCA', 'Disease', (190, 194))	('amplification', 'Var', (82, 95))	('rat', 'Species', '10116', (114, 117))
59874	25769721	In mice with hepatic deletion of Pten, anti-miR-21 treatment reduced liver tumor growth and prevented tumor development.	('liver tumor', 'Disease', 'MESH:D008113', (69, 80))	('liver tumor', 'Phenotype', 'HP:0002896', (69, 80))	('liver tumor', 'Disease', (69, 80))	('Pten', 'Gene', (33, 37))	('mice', 'Species', '10090', (3, 7))	('Pten', 'Gene', '19211', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('deletion', 'Var', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('prevented', 'NegReg', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('reduced', 'NegReg', (61, 68))	('tumor', 'Disease', (75, 80))
59876	25769721	Notch2 inhibition also occurred in tumors following anti-miR-21 treatment.	('anti-miR-21', 'Var', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('Notch2', 'Gene', (0, 6))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('Notch2', 'Gene', '18129', (0, 6))	('inhibition', 'NegReg', (7, 17))
59878	25769721	Our results identify miR-21 as a key regulator of tumor-initiating cell survival, malignant development and growth in liver cancer, highlighting the role of CD24+ cells in expansion of S100A4+ cancer-associated stromal cells and associated liver fibrosis.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (124, 130))	('liver fibrosis', 'Disease', 'MESH:D008103', (240, 254))	('cancer', 'Disease', (193, 199))	('liver fibrosis', 'Disease', (240, 254))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('liver fibrosis', 'Phenotype', 'HP:0001395', (240, 254))	('S100A4', 'Gene', '20198', (185, 191))	('liver cancer', 'Disease', 'MESH:D006528', (118, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('liver cancer', 'Phenotype', 'HP:0002896', (118, 130))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('liver cancer', 'Disease', (118, 130))	('S100A4', 'Gene', (185, 191))	('expansion', 'Var', (172, 181))	('tumor', 'Disease', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
59880	25769721	Dysregulation of miRNAs affects a wide range of cellular processes including cell proliferation and differentiation.	('differentiation', 'CPA', (100, 115))	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '735281', (17, 20))	('miR', 'Gene', (17, 20))	('cellular processes', 'CPA', (48, 66))	('affects', 'Reg', (24, 31))	('cell proliferation', 'CPA', (77, 95))
59892	25769721	Deletion of the phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN) in hepatocytes leads to steatohepatitis, fibrosis, hepatocyte dysplasia and HCC later in life, reproducing the steps of HCC development observed in human HCC.	('phosphoinositide 3-kinase', 'Gene', (16, 41))	('PI3K', 'Gene', (43, 47))	('HCC', 'Phenotype', 'HP:0001402', (207, 210))	('steatohepatitis', 'Disease', (111, 126))	('phosphoinositide 3-kinase', 'Gene', '5294', (16, 41))	('fibrosis', 'Disease', (128, 136))	('hepatocyte dysplasia', 'Disease', (138, 158))	('fibrosis', 'Disease', 'MESH:D005355', (128, 136))	('HCC', 'Disease', (163, 166))	('leads to', 'Reg', (102, 110))	('Deletion', 'Var', (0, 8))	('HCC', 'Phenotype', 'HP:0001402', (163, 166))	('hepatitis', 'Phenotype', 'HP:0012115', (117, 126))	('hepatocyte dysplasia', 'Disease', 'MESH:D004476', (138, 158))	('PTEN', 'Gene', (81, 85))	('human', 'Species', '9606', (235, 240))	('HCC', 'Phenotype', 'HP:0001402', (241, 244))	('PTEN', 'Gene', '5728', (81, 85))	('steatohepatitis', 'Disease', 'MESH:D005234', (111, 126))
59893	25769721	C57BL/6 mice carrying Pten conditional knockout alleles were crossed with an Albumin (Alb)-Cre-transgenic mouse.	('Alb', 'Gene', '11657', (86, 89))	('Albumin', 'Gene', (77, 84))	('Pten', 'Gene', (22, 26))	('Alb', 'Gene', (86, 89))	('alleles', 'Var', (48, 55))	('Pten', 'Gene', '19211', (22, 26))	('Albumin', 'Gene', '11657', (77, 84))	('Alb', 'Gene', '11657', (77, 80))	('knockout alleles', 'Var', (39, 55))	('Alb', 'Gene', (77, 80))	('mice', 'Species', '10090', (8, 12))	('mouse', 'Species', '10090', (106, 111))
59897	25769721	In the second set, 12 x 7.5 month-old male Pten null mice received anti-miR-21 (25 mg/kg) or placebo by intraperitoneal injection.	('Pten', 'Gene', '19211', (43, 47))	('Pten', 'Gene', (43, 47))	('mice', 'Species', '10090', (53, 57))	('anti-miR-21', 'Var', (67, 78))
59929	25769721	2B), the average tumor burden in anti-miR-21 treated mice was significantly smaller than in placebo treated mice (891 mm3 compared to 2308 mm3, p=0.05) (Fig.	('tumor', 'Disease', (17, 22))	('anti-miR-21', 'Var', (33, 44))	('mice', 'Species', '10090', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('smaller', 'NegReg', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mice', 'Species', '10090', (53, 57))
59930	25769721	The average tumor size in anti-miR-21 treated mice was also significantly smaller than in placebo treated mice (342 mm3 compared to 865 mm3, p=0.05) (Fig.	('smaller', 'NegReg', (74, 81))	('mice', 'Species', '10090', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('anti-miR-21', 'Var', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mice', 'Species', '10090', (46, 50))	('tumor', 'Disease', (12, 17))
59931	25769721	The reduction in tumor size following anti-miR-21 treatment was further demonstrated by the tumor size distribution per mouse in both groups.	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('reduction', 'NegReg', (4, 13))	('anti-miR-21', 'Var', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mouse', 'Species', '10090', (120, 125))
59936	25769721	The majority of tumors in anti-miR-21 treated group were well differentiated HCCs, suggesting that inhibition of miR-21 resulted not only in reduced tumor growth but also in histologically less malignant liver tumors.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('inhibition', 'Var', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('tumors', 'Disease', (16, 22))	('malignant liver tumors', 'Disease', (194, 216))	('HCC', 'Phenotype', 'HP:0001402', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (210, 215))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('liver tumors', 'Phenotype', 'HP:0002896', (204, 216))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('reduced', 'NegReg', (141, 148))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Disease', (16, 21))	('less', 'NegReg', (189, 193))	('miR-21', 'Gene', (113, 119))	('liver tumor', 'Phenotype', 'HP:0002896', (204, 215))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumors', 'Disease', (210, 216))	('tumor', 'Disease', (149, 154))	('malignant liver tumors', 'Disease', 'MESH:D009369', (194, 216))
59940	25769721	To determine the mechanisms by which anti-miR-21 inhibits tumor growth and liver fibrosis, we first evaluated the effects of anti-miR21 treatment on OPN expressing progenitor cells.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('miR21', 'Gene', (130, 135))	('liver fibrosis', 'Disease', (75, 89))	('inhibits', 'NegReg', (49, 57))	('anti-miR-21', 'Var', (37, 48))	('liver fibrosis', 'Disease', 'MESH:D008103', (75, 89))	('miR21', 'Gene', '387140', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('liver fibrosis', 'Phenotype', 'HP:0001395', (75, 89))
59945	25769721	The expression of other hepatic progenitor markers Krt7, Krt19 and of the stem cell marker Prom1 was also significantly reduced upon anti-miR-21 treatment (-2.7-fold; p=0.019; -2.1-fold; p=0.027 and -2.3-fold; p=0.028, respectively).	('hepatic', 'MPA', (24, 31))	('Krt7', 'Gene', (51, 55))	('Krt7', 'Gene', '110310', (51, 55))	('Krt19', 'Gene', (57, 62))	('expression', 'MPA', (4, 14))	('Krt19', 'Gene', '16669', (57, 62))	('anti-miR-21', 'Var', (133, 144))	('Prom1', 'Gene', (91, 96))	('Prom1', 'Gene', '19126', (91, 96))	('reduced', 'NegReg', (120, 127))
59948	25769721	To determine the mechanisms by which anti-miR-21 results in a decrease in progenitor cell population, we treated the human HepaRG liver progenitor cells with 20nM anti-miR-21 oligonucleotide.	('HepaRG', 'CellLine', 'CVCL:9720', (123, 129))	('oligonucleotide', 'Chemical', 'MESH:D009841', (175, 190))	('human', 'Species', '9606', (117, 122))	('anti-miR-21', 'Var', (37, 48))	('progenitor cell population', 'CPA', (74, 100))	('decrease', 'NegReg', (62, 70))
59954	25769721	Approximately 54% of HepaRG cells expressed CD24 while 99% of HepaRG cells expressed CD44 (Fig.	('HepaRG', 'CellLine', 'CVCL:9720', (21, 27))	('HepaRG', 'CellLine', 'CVCL:9720', (62, 68))	('CD44', 'Gene', '960', (85, 89))	('CD44', 'Gene', (85, 89))	('CD24', 'Var', (44, 48))
59956	25769721	The specific effect of miR-21 inhibition on the CD24+ subpopulation of liver progenitor cells was further confirmed in vivo, by immunostaining showing a significant reduction of CD24+ cells in Pten null liver treated with anti-miR-21 from 12.9% to 4.1% (p=0.013) (Fig.	('Pten', 'Gene', '19211', (193, 197))	('anti-miR-21', 'Var', (222, 233))	('CD24+', 'MPA', (178, 183))	('reduction', 'NegReg', (165, 174))	('Pten', 'Gene', (193, 197))
59969	25769721	Runx2 was significantly increased in Pten null tumors compared to adjacent liver (1.5-fold, p=0.011) and anti-miR-21 treatment resulted in a -1.5-fold reduction of Runx2 mRNA in tumors (p=0.009).	('tumors', 'Disease', (47, 53))	('Runx2', 'Gene', (164, 169))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('mRNA', 'MPA', (170, 174))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('anti-miR-21', 'Var', (105, 116))	('Pten', 'Gene', (37, 41))	('Runx2', 'Gene', '12393', (164, 169))	('Runx2', 'Gene', '12393', (0, 5))	('Pten', 'Gene', '19211', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('increased', 'PosReg', (24, 33))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('reduction', 'NegReg', (151, 160))	('Runx2', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
59975	25769721	In contrast, anti-miR-21 treatment resulted in a reduction of Notch2 in tumors (-1.8 fold, p=0.042).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('reduction', 'NegReg', (49, 58))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', (72, 78))	('Notch2', 'Gene', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('Notch2', 'Gene', '18129', (62, 68))	('anti-miR-21', 'Var', (13, 24))
59982	25769721	Together, these results showed that Notch2 is enriched in progenitor cells and mediates the down regulation of OPN by anti-miR-21 treatment.	('Notch2', 'Gene', (36, 42))	('anti-miR-21', 'Var', (118, 129))	('Notch2', 'Gene', '18129', (36, 42))	('OPN', 'Gene', (111, 114))	('down regulation', 'NegReg', (92, 107))
59984	25769721	We treated 7.5-month-old Pten null mice with anti-miR-21 for 6 weeks.	('Pten', 'Gene', '19211', (25, 29))	('anti-miR-21', 'Var', (45, 56))	('mice', 'Species', '10090', (35, 39))	('Pten', 'Gene', (25, 29))
59987	25769721	The average tumor burden in anti-miR-21-treated mice was also significantly smaller than in mice from the placebo treated group (23 mm3 compared to 107 mm3, p=0.039) (Fig.	('anti-miR-21-treated', 'Var', (28, 47))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('mice', 'Species', '10090', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('smaller', 'NegReg', (76, 83))	('mice', 'Species', '10090', (92, 96))
59991	25769721	As observed in the first set of Pten null treated mice, fibrosis was significantly reduced from 14.3% to 7.2% (p=0.014) upon anti-miR-21 treatment (Fig.	('to 7', 'Species', '1214577', (102, 106))	('anti-miR-21', 'Var', (125, 136))	('Pten', 'Gene', (32, 36))	('reduced', 'NegReg', (83, 90))	('Pten', 'Gene', '19211', (32, 36))	('mice', 'Species', '10090', (50, 54))	('fibrosis', 'Disease', (56, 64))	('fibrosis', 'Disease', 'MESH:D005355', (56, 64))
59995	25769721	CD24+ cells have been identified as liver tumor initiating cells and have been associated with higher risk of tumor recurrence.	('associated', 'Reg', (79, 89))	('tumor', 'Disease', (42, 47))	('liver tumor', 'Disease', 'MESH:D008113', (36, 47))	('liver tumor', 'Phenotype', 'HP:0002896', (36, 47))	('liver tumor', 'Disease', (36, 47))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('CD24+ cells', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
59999	25769721	The reduction in tumor incidence and growth following anti-miR-21 treatment in vivo may be the direct consequence of the depletion of CD24+ cell population.	('tumor', 'Disease', (17, 22))	('reduction', 'NegReg', (4, 13))	('anti-miR-21', 'Var', (54, 65))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('growth', 'CPA', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
60001	25769721	This reduction in stem cell population may also explain the reduced malignancy of the tumors and concomitant increased differentiated phenotype following anti-miR-21 treatment.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('malignancy of the tumors', 'Disease', 'MESH:D018198', (68, 92))	('reduction', 'NegReg', (5, 14))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('malignancy of the tumors', 'Disease', (68, 92))	('anti-miR-21', 'Var', (154, 165))	('reduced', 'NegReg', (60, 67))	('stem cell population', 'CPA', (18, 38))	('increased', 'PosReg', (109, 118))	('differentiated phenotype', 'CPA', (119, 143))
60007	25769721	While anti-miR-21 treatment decreased Notch1 expression in adjacent liver, Notch2 expression decreased in tumors following anti-miR-21 treatment.	('Notch2', 'Gene', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('Notch1', 'Gene', (38, 44))	('decreased', 'NegReg', (28, 37))	('expression', 'MPA', (82, 92))	('tumors', 'Disease', (106, 112))	('Notch2', 'Gene', '18129', (75, 81))	('Notch1', 'Gene', '18128', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('decreased', 'NegReg', (93, 102))	('expression', 'MPA', (45, 55))	('anti-miR-21', 'Var', (123, 134))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
60009	25769721	The reduction in tumor incidence and growth following anti-miR-21 treatment in vivo may also be the direct consequence of a reduction in fibrosis and changes in the stroma largely associated with depletion of S100A4+ and of CD24+ cells, and reduction in OPN levels.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('fibrosis', 'Disease', 'MESH:D005355', (137, 145))	('reduction', 'NegReg', (124, 133))	('fibrosis', 'Disease', (137, 145))	('tumor', 'Disease', (17, 22))	('S100A4', 'Gene', '20198', (209, 215))	('changes', 'Reg', (150, 157))	('OPN levels', 'MPA', (254, 264))	('reduction', 'NegReg', (241, 250))	('S100A4', 'Gene', (209, 215))	('anti-miR-21', 'Var', (54, 65))	('growth', 'CPA', (37, 43))	('reduction', 'NegReg', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('depletion', 'MPA', (196, 205))	('CD24+', 'MPA', (224, 229))
60013	25769721	Instead the expression of S100A4 decreased following anti-miR-21 treatment.	('S100A4', 'Gene', (26, 32))	('S100A4', 'Gene', '20198', (26, 32))	('anti-miR-21', 'Var', (53, 64))	('decreased', 'NegReg', (33, 42))	('expression', 'MPA', (12, 22))
60017	25769721	It also suggests that anti-miR-21 may be effective at targeting tumor initiating cells as well as the tumor microenvironment, and therefore shows great promise for clinical studies of liver cancer prevention and treatment.	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (102, 107))	('anti-miR-21', 'Var', (22, 33))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('liver cancer', 'Phenotype', 'HP:0002896', (184, 196))	('liver cancer', 'Disease', 'MESH:D006528', (184, 196))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('liver cancer', 'Disease', (184, 196))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
60018	25769721	Further study is warranted to determine whether anti-miR-21 treatment can be effective as a companion therapeutic agent to drugs killing the tumor cells or as a therapeutic target for the prevention of liver tumor in patients at risk and the prevention of recurrence.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('anti-miR-21', 'Var', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (141, 146))	('liver tumor', 'Disease', (202, 213))	('tumor', 'Disease', (208, 213))	('liver tumor', 'Disease', 'MESH:D008113', (202, 213))	('patients', 'Species', '9606', (217, 225))	('liver tumor', 'Phenotype', 'HP:0002896', (202, 213))
60077	33663617	For example, CHD1L is a well-known activator of ARHGEF9, TCTP, SPOCK1 and NTKL and can also lead to deregulation of p53, TCTP and Nur77.	('NTKL', 'Gene', (74, 78))	('NTKL', 'Gene', '57410', (74, 78))	('TCTP', 'Gene', (57, 61))	('ARHGEF9', 'Gene', (48, 55))	('Nur77', 'Gene', (130, 135))	('SPOCK1', 'Gene', '6695', (63, 69))	('ARHGEF9', 'Gene', '23229', (48, 55))	('TCTP', 'Gene', '7178', (121, 125))	('lead to', 'Reg', (92, 99))	('TCTP', 'Gene', '7178', (57, 61))	('Nur77', 'Gene', '3164', (130, 135))	('SPOCK1', 'Gene', (63, 69))	('TCTP', 'Gene', (121, 125))	('p53', 'Protein', (116, 119))	('deregulation', 'MPA', (100, 112))	('CHD1L', 'Var', (13, 18))
60099	33663617	The HELICc is not an autonomous folding unit, but is an essential part of the helicases that utilize the energy from nucleoside triphosphate hydrolysis to provide fuel for their translocation along DNA and unwinding double-stranded DNA in the process.	('nucleoside triphosphate', 'Chemical', '-', (117, 140))	('translocation along DNA', 'MPA', (178, 201))	('unwinding', 'Var', (206, 215))
60101	33663617	SelS is a disordered protein which has a seleno sulfide bond (between Cys-174 and Sec-188) and a redox potential (- 234 mV).	('redox', 'MPA', (97, 102))	('Cys', 'Chemical', 'MESH:D003545', (70, 73))	('Sec-188', 'Var', (82, 89))	('SelS', 'Gene', (0, 4))	('seleno sulfide', 'Chemical', '-', (41, 55))	('seleno sulfide bond', 'MPA', (41, 60))	('SelS', 'Gene', '55829', (0, 4))	('Cys-174', 'Var', (70, 77))
60110	33663617	PAR is produced by PAR polymerase (PARP), and single-stranded DNA breaks (SSB) and gaps can activate PARP.	('PAR', 'Chemical', 'MESH:D011064', (35, 38))	('PARP', 'Gene', '142', (101, 105))	('PARP', 'Gene', '142', (35, 39))	('PAR', 'Chemical', 'MESH:D011064', (101, 104))	('PAR', 'Chemical', 'MESH:D011064', (19, 22))	('single-stranded DNA', 'Var', (46, 65))	('PARP', 'Gene', (101, 105))	('PAR', 'Chemical', 'MESH:D011064', (0, 3))	('PARP', 'Gene', (35, 39))	('activate', 'PosReg', (92, 100))
60115	33663617	The co-operation between CHD1L and PARP is also related to the nucleotide excision repair of UV-induced DNA damage.	('PARP', 'Gene', '142', (35, 39))	('co-operation', 'Var', (4, 16))	('CHD1L', 'Gene', (25, 30))	('nucleotide excision repair of', 'MPA', (63, 92))	('PARP', 'Gene', (35, 39))	('related', 'Reg', (48, 55))
60118	33663617	Loss of ALC1 confers methyl-methanesulfonate, PARP inhibitors and formyl-dU sensitivity, which is synthetic lethal with homologous recombination deficiency (HRD).	('HRD', 'Disease', 'None', (157, 160))	('formyl-dU sensitivity', 'MPA', (66, 87))	('ALC1', 'Gene', (8, 12))	('formyl-dU', 'Chemical', '-', (66, 75))	('PARP', 'Gene', '142', (46, 50))	('deficiency', 'Disease', (145, 155))	('methyl-methanesulfonate', 'Chemical', 'MESH:D008741', (21, 44))	('deficiency', 'Disease', 'MESH:D007153', (145, 155))	('HRD', 'Disease', (157, 160))	('methyl-methanesulfonate', 'MPA', (21, 44))	('PARP', 'Gene', (46, 50))	('ALC1', 'Gene', '9557', (8, 12))	('Loss', 'Var', (0, 4))
60121	33663617	Inhibiting the production of CHD1L can arrest embryo at the pre-blastocyst stage in mice embryonic stem (ES) cells by microinjecting antisense morpholinone.	('embryo at the pre-blastocyst stage', 'CPA', (46, 80))	('Inhibiting', 'Var', (0, 10))	('arrest', 'Disease', 'MESH:D006323', (39, 45))	('morpholinone', 'Chemical', '-', (143, 155))	('arrest', 'Disease', (39, 45))	('CHD1L', 'Gene', (29, 34))	('mice', 'Species', '10090', (84, 88))
60127	33663617	Three different heterozygous missense variants of CHD1L (variant Gly700Arg, variant Ile765Met and variant Ile827Val) were revealed by sequencing the entire coding region of the CHD1L gene in 61 CAKUT patients and exons 18, 19 and 21 in 24 CAKUT patients.	('CHD1L', 'Gene', (50, 55))	('patients', 'Species', '9606', (200, 208))	('patients', 'Species', '9606', (245, 253))	('Ile765Met', 'Mutation', 'rs148289715', (84, 93))	('Ile827Val', 'Var', (106, 115))	('Ile765Met', 'Var', (84, 93))	('Gly700Arg', 'SUBSTITUTION', 'None', (65, 74))	('Gly700Arg', 'Var', (65, 74))	('Ile827Val', 'Mutation', 'rs148434783', (106, 115))	('CHD1L', 'Gene', (177, 182))
60128	33663617	The interaction between all three CHD1L variants and PARP1 decreased compared with the wild-type CHD1L.	('interaction', 'Interaction', (4, 15))	('decreased', 'NegReg', (59, 68))	('CHD1L', 'Gene', (34, 39))	('PARP1', 'Gene', '142', (53, 58))	('PARP1', 'Gene', (53, 58))	('variants', 'Var', (40, 48))
60132	33663617	CHD1L can promote G1/S transition and DNA synthesis by upregulating cyclins, CDK2, 4 and downregulating P27, Rb and p53 in transgenic mouse models.	('CDK2', 'Gene', (77, 81))	('G1/S transition', 'CPA', (18, 33))	('P27', 'Gene', '12576', (104, 107))	('cyclins', 'Protein', (68, 75))	('upregulating', 'PosReg', (55, 67))	('P27', 'Gene', (104, 107))	('Rb', 'Gene', '19645', (109, 111))	('promote', 'PosReg', (10, 17))	('DNA synthesis', 'MPA', (38, 51))	('p53', 'Protein', (116, 119))	('CDK2', 'Gene', '12566', (77, 81))	('CHD1L', 'Var', (0, 5))	('downregulating', 'NegReg', (89, 103))	('mouse', 'Species', '10090', (134, 139))
60136	33663617	CHD1L could induce G1/S transition by the dysregulation of p53-cyclinE-CDK2 pathway in glioma.	('glioma', 'Disease', (87, 93))	('CDK2', 'Gene', '12566', (71, 75))	('dysregulation', 'Var', (42, 55))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('induce', 'PosReg', (12, 18))	('G1/S', 'Disease', (19, 23))	('CDK2', 'Gene', (71, 75))
60138	33663617	The dysregulation of p53-cyclin D1-CDK2 pathway might be related to CHD1L-induced G1/S transition, while CHD1L might drive EMT and MET and cause metastasis of cholangiocarcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('metastasis', 'CPA', (145, 155))	('cyclin D1', 'Gene', '595', (25, 34))	('dysregulation', 'Var', (4, 17))	('CDK2', 'Gene', '12566', (35, 39))	('MET', 'Gene', '79811', (131, 134))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (159, 177))	('cholangiocarcinoma', 'Disease', (159, 177))	('drive', 'PosReg', (117, 122))	('CDK2', 'Gene', (35, 39))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (159, 177))	('CHD1L', 'Var', (105, 110))	('MET', 'Gene', (131, 134))	('cause', 'Reg', (139, 144))	('EMT', 'CPA', (123, 126))	('cyclin D1', 'Gene', (25, 34))
60141	33663617	Taken together, inappropriate expression of CHD1L target genes and deregulation of CHD1L system may link CHD1L to tumorigenesis by several mechanisms (Fig.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('CHD1L', 'Gene', (83, 88))	('tumor', 'Disease', (114, 119))	('link', 'Reg', (100, 104))	('deregulation', 'Var', (67, 79))	('CHD1L', 'Gene', (105, 110))
60167	33663617	ABCB1 knockdown coupled with CHD1L ectopic expression enhanced the effect of cisplatin on apoptosis of NSCLC cells.	('effect', 'MPA', (67, 73))	('NSCLC', 'Disease', (103, 108))	('ABCB1', 'Gene', (0, 5))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('knockdown', 'Var', (6, 15))	('apoptosis', 'CPA', (90, 99))	('enhanced', 'PosReg', (54, 62))
60172	33663617	However, elevated beta-catenin expression exhibited in the CHD1L-KD group in glioma.	('elevated', 'PosReg', (9, 17))	('beta-catenin', 'Gene', (18, 30))	('beta-catenin', 'Gene', '1499', (18, 30))	('CHD1L-KD', 'Var', (59, 67))	('glioma', 'Disease', (77, 83))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
60176	33663617	p53 protein can upregulate p21 expression, and the latter acts as a Cdk2 inhibitor, inactivating cyclinE-CDk2 complex to control the S phase entry.	('control', 'Reg', (121, 128))	('p21', 'Gene', (27, 30))	('protein', 'Protein', (4, 11))	('inactivating', 'NegReg', (84, 96))	('p21', 'Gene', '644914', (27, 30))	('upregulate', 'PosReg', (16, 26))	('Cdk2', 'Gene', '1017', (68, 72))	('p53', 'Var', (0, 3))	('Cdk2', 'Gene', (68, 72))	('S phase entry', 'MPA', (133, 146))	('CDk2', 'Gene', (105, 109))	('CDk2', 'Gene', '1017', (105, 109))
60182	33663617	Macro domain of CHD1L acts to interact with Nur77, while the CHD1L mutants lacking residues 600-897 cannot interact with Nur77 and prevents Nur77-mediated apoptosis of hepatocellular carcinoma.	('CHD1L', 'Gene', (61, 66))	('Nur77', 'Gene', '3164', (121, 126))	('Nur77', 'Gene', (44, 49))	('Nur77', 'Gene', (140, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('Nur77', 'Gene', '3164', (44, 49))	('mutants', 'Var', (67, 74))	('Nur77', 'Gene', '3164', (140, 145))	('Nur77', 'Gene', (121, 126))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (168, 192))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (168, 192))	('interact', 'Interaction', (30, 38))	('hepatocellular carcinoma', 'Disease', (168, 192))	('prevents', 'NegReg', (131, 139))
60191	33663617	Lysine methylation at a specific site on the histone H3 tails is associated with transcriptional regulation.	('Lysine methylation', 'Var', (0, 18))	('transcriptional regulation', 'MPA', (81, 107))	('associated', 'Reg', (65, 75))	('histone H3 tails', 'Protein', (45, 61))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))
60200	33663617	Full length CHD1 is required in embryonic stem cell differentiation, and loss of the serine-rich region (SRR) renders CHD1 unable to support normal differentiation of ESCs into the three germ layers.	('unable', 'NegReg', (123, 129))	('CHD1', 'Gene', '1105', (12, 16))	('CHD1', 'Gene', '1105', (118, 122))	('loss', 'Var', (73, 77))	('CHD1', 'Gene', (118, 122))	('serine', 'Chemical', 'MESH:D012694', (85, 91))	('CHD1', 'Gene', (12, 16))
60201	33663617	Endothelial-specific deletion of CHD1 leads to loss of definitive hematopoietic progenitors, anemia, and lethality by embryonic day (E)15.5.	('anemia', 'Disease', (93, 99))	('CHD1', 'Gene', '1105', (33, 37))	('anemia', 'Disease', 'MESH:D000740', (93, 99))	('deletion', 'Var', (21, 29))	('loss', 'NegReg', (47, 51))	('anemia', 'Phenotype', 'HP:0001903', (93, 99))	('lethality', 'CPA', (105, 114))	('CHD1', 'Gene', (33, 37))
60202	33663617	CHD1 is the 5q21 tumor suppressor gene, and inactivation of CHD1 abolishes recruitment of androgen receptor (AR) to result in downregulation of AR-responsive genes (eg.	('CHD1', 'Gene', (60, 64))	('CHD1', 'Gene', '1105', (60, 64))	('tumor', 'Disease', (17, 22))	('downregulation', 'NegReg', (126, 140))	('androgen receptor', 'Gene', (90, 107))	('CHD1', 'Gene', (0, 4))	('recruitment', 'MPA', (75, 86))	('AR', 'Gene', '367', (109, 111))	('AR', 'Gene', '367', (144, 146))	('CHD1', 'Gene', '1105', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('androgen receptor', 'Gene', '367', (90, 107))	('abolishes', 'NegReg', (65, 74))	('inactivation', 'Var', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
60204	33663617	Recurrent deletion of CHD1 is a driver of prostate cancer cell invasiveness.	('CHD1', 'Gene', (22, 26))	('prostate cancer', 'Phenotype', 'HP:0012125', (42, 57))	('CHD1', 'Gene', '1105', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('prostate cancer', 'Disease', (42, 57))	('deletion', 'Var', (10, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (42, 57))
60206	33663617	a novel CHD1-RUNX1 fusion collaborated with FLT3-ITD mutation in the development of acute myeloid leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (98, 106))	('acute myeloid leukemia', 'Disease', (84, 106))	('fusion', 'Var', (19, 25))	('CHD1', 'Gene', '1105', (8, 12))	('RUNX1', 'Gene', '861', (13, 18))	('FLT3', 'Gene', '2322', (44, 48))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (84, 106))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (90, 106))	('FLT3', 'Gene', (44, 48))	('RUNX1', 'Gene', (13, 18))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (84, 106))	('CHD1', 'Gene', (8, 12))
60217	33663617	The abnormal expression of CHD1L may be prognostic factor of ACC, HNSC, KICH, KIRC, KIRP, LIHC, LUAD, MESO, SARC and THCA (Fig.	('KICH', 'Disease', 'None', (72, 76))	('ACC', 'Gene', (61, 64))	('LIHC', 'Disease', (90, 94))	('abnormal', 'Var', (4, 12))	('HNSC', 'Disease', (66, 70))	('expression', 'MPA', (13, 23))	('LUAD', 'Disease', (96, 100))	('THCA', 'Chemical', '-', (117, 121))	('CHD1L', 'Gene', (27, 32))	('ACC', 'Gene', '31', (61, 64))	('AR', 'Gene', '367', (109, 111))	('MESO', 'Disease', (102, 106))	('KICH', 'Disease', (72, 76))	('THCA', 'Disease', (117, 121))
60228	33663617	reveal CHD1L manipulation impacts the single-strand DNA break repair response and potentiates PARPi-induced cancer killing through PARP2 trapping.	('PARP2', 'Gene', (131, 136))	('single-strand DNA break repair response', 'MPA', (38, 77))	('impacts', 'Reg', (26, 33))	('PARP', 'Gene', '142', (94, 98))	('PARP', 'Gene', '142', (131, 135))	('CHD1L', 'Gene', (7, 12))	('manipulation', 'Var', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('PARP2', 'Gene', '10038', (131, 136))	('potentiates', 'PosReg', (82, 93))	('PARP', 'Gene', (94, 98))	('PARP', 'Gene', (131, 135))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
60246	33648560	Moreover, TRIP13 was also an unfavorable prognostic biomarker of pCCA, and double high expression of HMGA1/TRIP13 could predict prognosis more sensitively.	('double high', 'Var', (75, 86))	('TRIP13', 'Gene', '9319', (107, 113))	('TRIP13', 'Gene', '9319', (10, 16))	('CCA', 'Phenotype', 'HP:0030153', (66, 69))	('TRIP13', 'Gene', (107, 113))	('TRIP13', 'Gene', (10, 16))	('pCCA', 'Gene', '5095', (65, 69))	('pCCA', 'Gene', (65, 69))
60267	33648560	Under normal conditions, high expression of HMGA1 can occur during embryogenesis and in normal embryonic stem cells and adult stem cells In mature differentiated tissues, HMGA1 is barely detected; however, some ectopic events in cancer, such as oncogenic transcription factors, epigenetic changes, and chromosomal translocation events, can induce abnormal up-regulation of HMGA1.	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('HMGA1', 'Gene', (373, 378))	('epigenetic changes', 'Var', (278, 296))	('chromosomal translocation events', 'Var', (302, 334))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('up-regulation', 'PosReg', (356, 369))
60307	33648560	Stable cell lines with HMGA1 overexpression or knockdown and with TRIP13 knockdown were selected with 4 mug/mL puromycin incubation for 7 days.	('HMGA1', 'Gene', (23, 28))	('overexpression', 'PosReg', (29, 43))	('TRIP13', 'Gene', '9319', (66, 72))	('puromycin', 'Chemical', 'MESH:D011691', (111, 120))	('knockdown', 'Var', (47, 56))	('TRIP13', 'Gene', (66, 72))	('knockdown', 'Var', (73, 82))
60339	33648560	Moreover, high expression of HMGA1 was significantly associated with positive lymphatic invasion and advanced TNM stage (Fig.	('HMGA1', 'Gene', (29, 34))	('TNM', 'Gene', '10178', (110, 113))	('associated', 'Reg', (53, 63))	('high', 'Var', (10, 14))	('TNM', 'Gene', (110, 113))	('positive lymphatic invasion', 'CPA', (69, 96))
60346	33648560	CCK8 and colony formation assays demonstrated that HMGA1 knockdown significantly impaired proliferation, whereas HMGA1 overexpression promoted pCCA proliferation (Fig.	('proliferation', 'CPA', (90, 103))	('HMGA1', 'Gene', (113, 118))	('pCCA', 'Gene', '5095', (143, 147))	('promoted', 'PosReg', (134, 142))	('CCA', 'Phenotype', 'HP:0030153', (144, 147))	('knockdown', 'Var', (57, 66))	('impaired', 'NegReg', (81, 89))	('HMGA1', 'Gene', (51, 56))	('pCCA', 'Gene', (143, 147))
60347	33648560	Stable QBC-939 cells with HMGA1 knockdown or overexpression were injected subcutaneously to establish xenografts in mice.	('mice', 'Species', '10090', (116, 120))	('HMGA1', 'Gene', (26, 31))	('knockdown', 'Var', (32, 41))	('QBC-939', 'Chemical', '-', (7, 14))	('overexpression', 'PosReg', (45, 59))
60348	33648560	The tumor volume and weight of xenografts were extensively decreased by HMGA1 knockdown and increased by HMGA1 overexpression (Fig.	('tumor', 'Disease', (4, 9))	('HMGA1', 'Gene', (105, 110))	('decreased', 'NegReg', (59, 68))	('knockdown', 'Var', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('increased', 'PosReg', (92, 101))	('HMGA1', 'Gene', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('overexpression', 'PosReg', (111, 125))
60363	33648560	2f), and patients with high HMGA1 expression had high TRIP13 expression (Fig.	('patients', 'Species', '9606', (9, 17))	('TRIP13', 'Gene', (54, 60))	('high', 'Var', (23, 27))	('HMGA1', 'Gene', (28, 33))	('TRIP13', 'Gene', '9319', (54, 60))
60369	33648560	In the validation cohort, patients with high expression of TRIP13 had poorer prognoses than those with low expression(P = 0.019) (Fig.	('high expression', 'Var', (40, 55))	('poorer', 'NegReg', (70, 76))	('TRIP13', 'Gene', '9319', (59, 65))	('patients', 'Species', '9606', (26, 34))	('TRIP13', 'Gene', (59, 65))
60370	33648560	Intriguingly, high expression of both TRIP13 and HMGA1 was a more sensitive prognostic factor than TRIP13 or HMGA1 alone (P = 0.0002) (Fig.	('TRIP13', 'Gene', '9319', (38, 44))	('TRIP13', 'Gene', (99, 105))	('TRIP13', 'Gene', (38, 44))	('HMGA1', 'Gene', (49, 54))	('high expression', 'Var', (14, 29))	('TRIP13', 'Gene', '9319', (99, 105))
60378	33648560	CCK8 and colony formation assays demonstrated that TRIP13 knockdown attenuated HMGA1-induced proliferation in QBC-939 and FRH-0201 cells (Fig.	('attenuated', 'NegReg', (68, 78))	('HMGA1-induced', 'Gene', (79, 92))	('proliferation', 'CPA', (93, 106))	('TRIP13', 'Gene', '9319', (51, 57))	('TRIP13', 'Gene', (51, 57))	('QBC-939', 'Chemical', '-', (110, 117))	('knockdown', 'Var', (58, 67))
60379	33648560	Xenografts were established with HMGA1-overexpressing stable cells with or without TRIP13 knockdown, showing that TRIP13 knockdown significantly reduced tumor volume and weight which were increased by HMGA1 overexpression (Fig.	('knockdown', 'Var', (121, 130))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('reduced', 'NegReg', (145, 152))	('overexpression', 'PosReg', (207, 221))	('TRIP13', 'Gene', '9319', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('TRIP13', 'Gene', (83, 89))	('TRIP13', 'Gene', '9319', (114, 120))	('TRIP13', 'Gene', (114, 120))	('increased', 'PosReg', (188, 197))	('HMGA1', 'Gene', (201, 206))
60380	33648560	The migration and invasion of HMGA1-overexpressing QBC-939 and FRH-0201 cells were impaired after TRIP13 knockdown (Fig.	('TRIP13', 'Gene', (98, 104))	('knockdown', 'Var', (105, 114))	('QBC-939', 'Chemical', '-', (51, 58))	('invasion', 'CPA', (18, 26))	('migration', 'CPA', (4, 13))	('impaired', 'NegReg', (83, 91))	('TRIP13', 'Gene', '9319', (98, 104))
60381	33648560	Stable QBC-939 cells with HMGA1 overexpression and/or TRIP13 knockdown were injected into the tail vein, and metastases to the liver was detected with HE staining (Fig.	('TRIP13', 'Gene', (54, 60))	('overexpression', 'PosReg', (32, 46))	('HMGA1', 'Gene', (26, 31))	('metastases', 'Disease', (109, 119))	('knockdown', 'Var', (61, 70))	('QBC-939', 'Chemical', '-', (7, 14))	('TRIP13', 'Gene', '9319', (54, 60))	('HE', 'Chemical', '-', (151, 153))	('metastases', 'Disease', 'MESH:D009362', (109, 119))
60382	33648560	HMGA1 overexpression increased the number of metastatic lesions, whereas silencing of TRIP13 neutralized this effect (Fig.	('silencing', 'Var', (73, 82))	('overexpression increased', 'PosReg', (6, 30))	('TRIP13', 'Gene', '9319', (86, 92))	('HMGA1', 'Gene', (0, 5))	('TRIP13', 'Gene', (86, 92))
60383	33648560	3D sphere formation and EMT biomarker expression showed that TRIP13 knockdown significantly impaired HMGA1-induced cell stemness and the EMT (Fig.	('impaired', 'NegReg', (92, 100))	('knockdown', 'Var', (68, 77))	('HMGA1-induced', 'Gene', (101, 114))	('EMT', 'CPA', (137, 140))	('TRIP13', 'Gene', '9319', (61, 67))	('TRIP13', 'Gene', (61, 67))
60386	33648560	WB, qPCR and luciferase assay showed that TRIP13 knockdown significantly increased the transcription and expression of FBXW7 in both QBC-939 and FRH-0201(Fig.	('FBXW7', 'Gene', '55294', (119, 124))	('increased', 'PosReg', (73, 82))	('knockdown', 'Var', (49, 58))	('TRIP13', 'Gene', '9319', (42, 48))	('FBXW7', 'Gene', (119, 124))	('transcription', 'MPA', (87, 100))	('TRIP13', 'Gene', (42, 48))	('QBC-939', 'Chemical', '-', (133, 140))	('expression', 'MPA', (105, 115))
60389	33648560	Moreover, the FBXW7 knockdown facilitated the proliferation, migration and invasion of pCCA cells, which was attenuated by TRIP13 knockdown (Fig.	('pCCA', 'Gene', (87, 91))	('TRIP13', 'Gene', (123, 129))	('FBXW7', 'Gene', '55294', (14, 19))	('facilitated', 'PosReg', (30, 41))	('proliferation', 'CPA', (46, 59))	('migration', 'CPA', (61, 70))	('FBXW7', 'Gene', (14, 19))	('pCCA', 'Gene', '5095', (87, 91))	('knockdown', 'Var', (20, 29))	('CCA', 'Phenotype', 'HP:0030153', (88, 91))	('TRIP13', 'Gene', '9319', (123, 129))
60390	33648560	Biomarkers of stemness or EMT, and sphere formation assay were performed after silencing TRIP13 or FBXW7 using WB and qRT-PCR (Fig.	('TRIP13', 'Gene', (89, 95))	('sphere formation assay', 'CPA', (35, 57))	('FBXW7', 'Gene', (99, 104))	('stemness', 'CPA', (14, 22))	('EMT', 'CPA', (26, 29))	('silencing', 'Var', (79, 88))	('TRIP13', 'Gene', '9319', (89, 95))	('FBXW7', 'Gene', '55294', (99, 104))
60391	33648560	Consequently, TRIP13 knockdown attenuated stemness and EMT of pCCA cells, while FBXW7 knockdown reversed this tendency, indicating that FBXW7 was involved in the TRIP13-induced stemness and EMT.	('FBXW7', 'Gene', '55294', (136, 141))	('pCCA', 'Gene', (62, 66))	('attenuated stemness', 'Disease', 'MESH:C538265', (31, 50))	('CCA', 'Phenotype', 'HP:0030153', (63, 66))	('attenuated stemness', 'Disease', (31, 50))	('TRIP13', 'Gene', '9319', (14, 20))	('FBXW7', 'Gene', (136, 141))	('TRIP13', 'Gene', '9319', (162, 168))	('TRIP13', 'Gene', (14, 20))	('FBXW7', 'Gene', '55294', (80, 85))	('pCCA', 'Gene', '5095', (62, 66))	('knockdown', 'Var', (21, 30))	('FBXW7', 'Gene', (80, 85))	('TRIP13', 'Gene', (162, 168))
60393	33648560	In QBC-939 and FRH-0201, c-Myc expression was elevated by FBXW7 knockdown and reduced by TRIP13 knockdown (Fig.	('knockdown', 'Var', (96, 105))	('elevated', 'PosReg', (46, 54))	('TRIP13', 'Gene', (89, 95))	('FBXW7', 'Gene', '55294', (58, 63))	('c-Myc', 'Gene', (25, 30))	('QBC-939', 'Chemical', '-', (3, 10))	('FBXW7', 'Gene', (58, 63))	('reduced', 'NegReg', (78, 85))	('knockdown', 'Var', (64, 73))	('TRIP13', 'Gene', '9319', (89, 95))	('c-Myc', 'Gene', '4609', (25, 30))
60397	33648560	Additionally, FBXW7 knockdown substantially decreased ubiquitinated c-Myc in HA-Ubiquitin-overexpressing QBC-939(Fig.	('c-Myc', 'Gene', (68, 73))	('QBC-939', 'Chemical', '-', (105, 112))	('FBXW7', 'Gene', '55294', (14, 19))	('c-Myc', 'Gene', '4609', (68, 73))	('FBXW7', 'Gene', (14, 19))	('knockdown', 'Var', (20, 29))	('decreased', 'NegReg', (44, 53))
60400	33648560	6e and f) and qRT-PCR (Supplementary Figure 8A-C) showed that both 10,058-F4(a c-Myc inhibitor) and c-Myc knockdown significantly decreased expression of HMGA1 and TRIP13.	('c-Myc', 'Gene', (79, 84))	('TRIP13', 'Gene', '9319', (164, 170))	('HMGA1', 'Gene', (154, 159))	('expression', 'MPA', (140, 150))	('10,058-F4', 'Chemical', '-', (67, 76))	('c-Myc', 'Gene', '4609', (100, 105))	('c-Myc', 'Gene', (100, 105))	('TRIP13', 'Gene', (164, 170))	('knockdown', 'Var', (106, 115))	('c-Myc', 'Gene', '4609', (79, 84))	('decreased', 'NegReg', (130, 139))
60403	33648560	Moreover, we knocked down TRIP13 in QBC-939, and demonstrated that TRIP13 can also regulate HMGA1 expression (Fig.	('TRIP13', 'Gene', (67, 73))	('TRIP13', 'Gene', (26, 32))	('HMGA1', 'Gene', (92, 97))	('QBC-939', 'Chemical', '-', (36, 43))	('knocked', 'Var', (13, 20))	('regulate', 'Reg', (83, 91))	('TRIP13', 'Gene', '9319', (67, 73))	('TRIP13', 'Gene', '9319', (26, 32))
60404	33648560	However, it was interesting to note that TRIP13 expression was decreased almost at the same time of HMGA1 knockdown, while HMGA1 expression was attenuated about 24 h later than TRIP13 knockdown (Fig.	('TRIP13', 'Gene', '9319', (41, 47))	('decreased', 'NegReg', (63, 72))	('expression', 'MPA', (48, 58))	('knockdown', 'Var', (106, 115))	('TRIP13', 'Gene', (41, 47))	('TRIP13', 'Gene', '9319', (177, 183))	('HMGA1', 'Gene', (100, 105))	('TRIP13', 'Gene', (177, 183))
60408	33648560	The recently developed small-molecule inhibitor of TRIP13, DCZ0415(10uM), HMGA1 inhibitor Netropsin (10mug/ml), and 10,058-F4(10uM) were used to incubate QBC-939 cells.	('QBC-939', 'Chemical', '-', (154, 161))	('10,058-F4', 'Chemical', '-', (116, 125))	('TRIP13', 'Gene', '9319', (51, 57))	('DCZ0415', 'Chemical', '-', (59, 66))	('TRIP13', 'Gene', (51, 57))	('DCZ0415', 'Var', (59, 66))
60420	33648560	Interestingly, double positive expression of HMGA1 and TRIP13 was a more sensitive biomarker than HMGA1 or TRIP13 alone.	('TRIP13', 'Gene', '9319', (107, 113))	('TRIP13', 'Gene', '9319', (55, 61))	('TRIP13', 'Gene', (107, 113))	('HMGA1', 'Gene', (45, 50))	('TRIP13', 'Gene', (55, 61))	('double positive expression', 'Var', (15, 41))
60446	33648560	Although DCZ0415 and netropsin had tumor-suppressing role in melanoma or medulloblastoma (Lau et al., 2012; Wang et al., 2020), their molecular structure should be modified continuously to improve the water-solubility and permeability to cell.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('water', 'Chemical', 'MESH:D014867', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('permeability', 'MPA', (222, 234))	('DCZ0415', 'Var', (9, 16))	('melanoma or medulloblastoma', 'Disease', 'MESH:D008527', (61, 88))	('tumor', 'Disease', (35, 40))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('water-solubility', 'MPA', (201, 217))	('melanoma or medulloblastoma', 'Disease', (61, 88))	('improve', 'PosReg', (189, 196))	('medulloblastoma', 'Phenotype', 'HP:0002885', (73, 88))	('DCZ0415', 'Chemical', '-', (9, 16))
60460	33648560	Taken together, our findings suggested that postoperative detection of HMGA1 and TRIP13 could help stratify high-risk patients, thus guide individual treatments and facilitate the development of targeted therapies, and that breaking this HMGA1-TRIP13-c-Myc nexus may be a very promising approach to treat pCCA.	('TRIP13', 'Gene', (81, 87))	('HMGA1', 'Gene', (71, 76))	('c-Myc', 'Gene', (251, 256))	('TRIP13', 'Gene', '9319', (81, 87))	('pCCA', 'Gene', '5095', (305, 309))	('patients', 'Species', '9606', (118, 126))	('TRIP13', 'Gene', '9319', (244, 250))	('CCA', 'Phenotype', 'HP:0030153', (306, 309))	('TRIP13', 'Gene', (244, 250))	('pCCA', 'Gene', (305, 309))	('breaking', 'Var', (224, 232))	('c-Myc', 'Gene', '4609', (251, 256))
60571	30885276	Moreover, patients with high HHLA2 expression were more likely to have advanced and metastatic diseases.	('HHLA2', 'Gene', '11148', (29, 34))	('HHLA2', 'Gene', (29, 34))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (10, 18))
60573	30885276	HHLA2 expression was associated with EGFR mutation status and high tumor infiltrating lymphocytes (TILs) density.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('TIL', 'Gene', (99, 102))	('associated', 'Reg', (21, 31))	('expression', 'MPA', (6, 16))	('HHLA2', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('EGFR', 'Gene', '1956', (37, 41))	('HHLA2', 'Gene', '11148', (0, 5))	('tumor', 'Disease', (67, 72))	('EGFR', 'Gene', (37, 41))	('TIL', 'Gene', '7096', (99, 102))	('mutation status', 'Var', (42, 57))
60610	30885276	The validation cohort comprised higher proportions of patients with high HHLA2 expression (training vs validation cohort, 49.0% vs 67.7%, P = 0.023; Fig.	('expression', 'MPA', (79, 89))	('high', 'Var', (68, 72))	('HHLA2', 'Gene', '11148', (73, 78))	('patients', 'Species', '9606', (54, 62))	('HHLA2', 'Gene', (73, 78))
60613	30885276	As detailed in Table 1, high HHLA2 expression was correlated with elevated serum CEA levels in both training and validation cohort (P <= 0.001 for both cohorts).	('HHLA2', 'Gene', (29, 34))	('HHLA2', 'Gene', '11148', (29, 34))	('CEA', 'Gene', '1048', (81, 84))	('expression', 'MPA', (35, 45))	('CEA', 'Gene', (81, 84))	('high', 'Var', (24, 28))	('elevated', 'PosReg', (66, 74))
60621	30885276	Whereas in multivariate analysis, only elevated CA19-9 level (P = 0.009, HR = 2.369, 95%CI 1.242-4.519) and high HHLA2 expression (P = 0.014, HR = 2.459, 95%CI 1.197-5.049) were identified as independent prognostic factors for OS.	('expression', 'MPA', (119, 129))	('CA19-9 level', 'MPA', (48, 60))	('HHLA2', 'Gene', (113, 118))	('elevated', 'PosReg', (39, 47))	('HHLA2', 'Gene', '11148', (113, 118))	('high', 'Var', (108, 112))
60624	30885276	To sum up, high HHLA2 expression was identified as an independent risk factor for OS in both training and validation cohort (Fig.	('HHLA2', 'Gene', '11148', (16, 21))	('expression', 'MPA', (22, 32))	('HHLA2', 'Gene', (16, 21))	('high', 'Var', (11, 15))
60630	30885276	As detailed in Additional file 3: Table S3, high expression of HHLA2 was associated with lower intratumoral CD3+, CD8+ TIL counts (P = 0.018 and 0.033, respectively).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('lower', 'NegReg', (89, 94))	('high expression', 'Var', (44, 59))	('tumor', 'Disease', (100, 105))	('TIL', 'Gene', (119, 122))	('HHLA2', 'Gene', (63, 68))	('CD8', 'Gene', (114, 117))	('HHLA2', 'Gene', '11148', (63, 68))	('CD8', 'Gene', '925', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('TIL', 'Gene', '7096', (119, 122))
60652	30885276	We found that HHLA2 expression was positively associated with serum CEA and CA19-9 levels in the training cohort as well as the presence of LN metastasis, serum CEA and clinical stage in the validation cohort.	('expression', 'Var', (20, 30))	('CEA', 'Gene', (68, 71))	('CA19-9 levels', 'MPA', (76, 89))	('HHLA2', 'Gene', (14, 19))	('CEA', 'Gene', '1048', (68, 71))	('CEA', 'Gene', '1048', (161, 164))	('associated', 'Reg', (46, 56))	('HHLA2', 'Gene', '11148', (14, 19))	('CEA', 'Gene', (161, 164))
60659	30885276	Therefore, targeting HHLA2 may inhibit cancer dissemination through immune-independent pathways and the underlying molecular basis requires further investigation.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('HHLA2', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('immune-independent pathways', 'Pathway', (68, 95))	('targeting', 'Var', (11, 20))	('inhibit', 'NegReg', (31, 38))	('HHLA2', 'Gene', '11148', (21, 26))
60674	30885276	Although no significant correlation was found between HHLA2 expression and the counts of Tregs, patients with high HHLA2 expression were found to have higher ratio of CTLs to Tregs within tumor area.	('tumor', 'Disease', (188, 193))	('HHLA2', 'Gene', '11148', (115, 120))	('HHLA2', 'Gene', (54, 59))	('CTLs', 'CPA', (167, 171))	('HHLA2', 'Gene', '11148', (54, 59))	('higher', 'PosReg', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('high', 'Var', (110, 114))	('patients', 'Species', '9606', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('HHLA2', 'Gene', (115, 120))
60675	30885276	Collectively speaking, the expression of HHLA2 was correlated with an inhibitory TME featured by decreased T cells, CTLs and imbalance between Tregs and CTLs, which indicated the possible role of HHLA2 as an immunotherapeutic target.	('T cells', 'CPA', (107, 114))	('expression', 'Var', (27, 37))	('imbalance', 'Phenotype', 'HP:0002172', (125, 134))	('inhibitory TME', 'Disease', (70, 84))	('CTLs', 'CPA', (116, 120))	('decreased', 'NegReg', (97, 106))	('imbalance', 'MPA', (125, 134))	('HHLA2', 'Gene', (196, 201))	('HHLA2', 'Gene', (41, 46))	('HHLA2', 'Gene', '11148', (196, 201))	('HHLA2', 'Gene', '11148', (41, 46))
60681	30885276	Moreover, targeting PD-L1 can polarize macrophages to a more pro-inflammatory phenotype.	('PD-L1', 'Gene', (20, 25))	('targeting', 'Var', (10, 19))	('polarize', 'Reg', (30, 38))	('PD-L1', 'Gene', '29126', (20, 25))
60718	28975835	Patients receiving liver-directed radiotherapy for HCC have been found to have an increased risk of RILD when compared with patients receiving the same dose of radiotherapy for liver metastases.	('RILD', 'Disease', 'None', (100, 104))	('liver metastases', 'Disease', 'MESH:D009362', (177, 193))	('HCC', 'Phenotype', 'HP:0001402', (51, 54))	('HCC', 'Gene', (51, 54))	('Patients', 'Species', '9606', (0, 8))	('liver metastases', 'Disease', (177, 193))	('liver-directed radiotherapy', 'Var', (19, 46))	('HCC', 'Gene', '619501', (51, 54))	('RILD', 'Disease', (100, 104))	('patients', 'Species', '9606', (124, 132))
60719	28975835	Retrospective series have also demonstrated an increased risk of grade >=2 RILD among patients with Child-Pugh (CP) score B cirrhosis as compared to those patients with CP A cirrhosis.	('CP A cirrhosis', 'Disease', (169, 183))	('cirrhosis', 'Disease', 'MESH:D005355', (124, 133))	('cirrhosis', 'Phenotype', 'HP:0001394', (174, 183))	('cirrhosis', 'Disease', (124, 133))	('RILD', 'Disease', (75, 79))	('cirrhosis', 'Phenotype', 'HP:0001394', (124, 133))	('patients', 'Species', '9606', (155, 163))	('cirrhosis', 'Disease', 'MESH:D005355', (174, 183))	('Child', 'Species', '9606', (100, 105))	('score B', 'Var', (116, 123))	('CP A cirrhosis', 'Disease', 'MESH:D005355', (169, 183))	('RILD', 'Disease', 'None', (75, 79))	('cirrhosis', 'Disease', (174, 183))	('patients', 'Species', '9606', (86, 94))
60783	28975835	A retrospective series of liver-directed conformal radiotherapy from South Korea also demonstrated an improvement in survival rates with increasing radiotherapy doses, with tumor response rates measuring 29.2% in patients treated with total doses <40 Gy, 68.6% in patients treated with total doses of 40 to 50 Gy, and 77.1% in patients treated to total doses >50 Gy.	('<40 Gy', 'Var', (247, 253))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('survival', 'CPA', (117, 125))	('patients', 'Species', '9606', (213, 221))	('patients', 'Species', '9606', (264, 272))	('improvement', 'PosReg', (102, 113))	('patients', 'Species', '9606', (327, 335))
60791	28975835	In addition to the inherent risks associated with arterial embolization in a patient with portal vein thrombosis, the presence of a TVT has also been shown to alter the vasculature in HCC.	('TVT', 'Chemical', '-', (132, 135))	('portal vein thrombosis', 'Phenotype', 'HP:0030242', (90, 112))	('HCC', 'Gene', '619501', (184, 187))	('presence', 'Var', (118, 126))	('vein thrombosis', 'Disease', 'MESH:D020246', (97, 112))	('vein thrombosis', 'Disease', (97, 112))	('vein thrombosis', 'Phenotype', 'HP:0004936', (97, 112))	('HCC', 'Phenotype', 'HP:0001402', (184, 187))	('TVT', 'Gene', (132, 135))	('patient', 'Species', '9606', (77, 84))	('arterial embolization', 'Phenotype', 'HP:0004420', (50, 71))	('vasculature', 'MPA', (169, 180))	('HCC', 'Gene', (184, 187))	('alter', 'Reg', (159, 164))
60816	28975835	A retrospective series of 84 patients with unresectable ICC also reported an improvement in outcomes with radiotherapy, with 1-year OS of 38.5% in patients who received radiotherapy versus 16.4% in patients who did not receive radiotherapy.	('patients', 'Species', '9606', (29, 37))	('ICC', 'Disease', (56, 59))	('radiotherapy', 'Var', (169, 181))	('outcomes', 'MPA', (92, 100))	('patients', 'Species', '9606', (198, 206))	('OS', 'Chemical', '-', (132, 134))	('patients', 'Species', '9606', (147, 155))	('improvement', 'PosReg', (77, 88))
60826	28975835	Specifically, 3-year OS was 73% in patients treated with BED >80.5 Gy versus 38% in patients treated with BED <80.5 Gy (P = .017); 3-year local control was 78% with BED >80.5 Gy versus 48% with BED <80.5 Gy (P = .04).	('OS', 'Chemical', '-', (21, 23))	('BED >80.5 Gy', 'Var', (165, 177))	('local control', 'CPA', (138, 151))	('patients', 'Species', '9606', (84, 92))	('patients', 'Species', '9606', (35, 43))
60906	27288147	Human Umbilical Vein Endothelial Cells (HUVEC) hTERT (a kind gift from Prof Tahara) were cultured in HUVEC Cells Medium (HCM): M199 + 0.25% Heparin + 20% FBS + 1% Penicillin/Streptomycin + 0.5% Endothelial Cells Growth Supplement (ECGS - Sigma Aldrich).	('Human', 'Species', '9606', (0, 5))	('M199 + 0.25', 'Var', (127, 138))	('hTERT', 'Gene', '7015', (47, 52))	('Umbilical Vein Endothelial', 'CellLine', 'CVCL:2G60', (6, 32))	('Heparin', 'Chemical', 'MESH:D006493', (140, 147))	('Penicillin', 'Chemical', 'MESH:D010406', (163, 173))	('Streptomycin', 'Chemical', 'MESH:D013307', (174, 186))	('hTERT', 'Gene', (47, 52))
60915	27288147	Sections were permeabilized with 0.2% TritonX-100 and blocked with 2% bovine serum albumin (#K45-001; PAA laboratories), 0.02% fish skin gelatin (#G7765; Sigma), 10% FBS (#A15-104; PAA laboratories).	('TritonX-100', 'Chemical', 'MESH:D017830', (38, 49))	('#K45-001', 'Var', (92, 100))	('#G7765', 'Var', (146, 152))	('bovine', 'Species', '9913', (70, 76))	('#A15-104', 'Var', (171, 179))
60960	27288147	In our experimental models, PCC (AsPC1, Colo357 and Capan1) exerted a strong anti-angiogenic effect, inhibiting HUVEC survival in 3D co-cultures as well as sprouting angiogenesis of mice aortic rings.	('Capan1', 'CellLine', 'CVCL:0237', (52, 58))	('sprouting angiogenesis of mice aortic rings', 'CPA', (156, 199))	('mice', 'Species', '10090', (182, 186))	('AsPC1', 'CellLine', 'CVCL:0152', (33, 38))	('HUVEC survival in 3D co-cultures', 'CPA', (112, 144))	('anti-angiogenic effect', 'MPA', (77, 99))	('PCC', 'Var', (28, 31))	('inhibiting', 'NegReg', (101, 111))
60970	27288147	Indeed, depleting stroma in murine PDAC models, via either selective deletion of alphaSMA positive fibroblasts or Sonic Hedgehog (SHH) system in cancer cells, resulted in less differentiated, more vascularised and more aggressive tumours with a worsening overall survival in murine models.	('cancer', 'Disease', (145, 151))	('more', 'PosReg', (192, 196))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('SHH', 'Gene', (130, 133))	('aggressive tumours', 'Disease', 'MESH:D001523', (219, 237))	('aggressive tumours', 'Disease', (219, 237))	('Sonic Hedgehog', 'Gene', (114, 128))	('murine', 'Species', '10090', (28, 34))	('deletion', 'Var', (69, 77))	('murine', 'Species', '10090', (275, 281))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('more', 'PosReg', (214, 218))	('tumours', 'Phenotype', 'HP:0002664', (230, 237))	('PDAC', 'Chemical', '-', (35, 39))	('Sonic Hedgehog', 'Gene', '20423', (114, 128))	('SHH', 'Gene', '20423', (130, 133))	('PDAC', 'Phenotype', 'HP:0006725', (35, 39))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('depleting', 'NegReg', (8, 17))	('less', 'NegReg', (171, 175))
61137	16736026	Cases were grouped according to the following categories: neoplasm not otherwise specified (NOS), code M800; carcinoma NOS, M801; adenocarcinoma, M814; hepatocellular carcinoma, M817; cholangiocarcinoma, M816; and 'other' (all other codes) (see Table 1b).	("'other", 'Disease', (214, 220))	('neoplasm', 'Disease', (58, 66))	('M816', 'Var', (204, 208))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (152, 176))	('neoplasm', 'Disease', 'MESH:D009369', (58, 66))	('carcinoma NOS, M801; adenocarcinoma', 'Disease', 'MESH:D000230', (109, 144))	('neoplasm', 'Phenotype', 'HP:0002664', (58, 66))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (152, 176))	('M817', 'Var', (178, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('cholangiocarcinoma', 'Disease', (184, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('hepatocellular carcinoma', 'Disease', (152, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('M814', 'Var', (146, 150))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (184, 202))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (184, 202))
61357	25938440	Moreover, Zhang and his colleagues reconstructed the bile duct defect after choledochectomy using the HRL for a type IIa hilar cholangiocarcinoma in an elderly patient, and subsequently anastomosed the posterior margin of the jejunal limb with the HRL for Roux-en-Y hepaticojejunostomy.	('hilar cholangiocarcinoma', 'Disease', (121, 145))	('patient', 'Species', '9606', (160, 167))	('bile duct defect', 'Disease', (53, 69))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (127, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('anastomosed', 'Var', (186, 197))	('bile duct defect', 'Disease', 'MESH:D001649', (53, 69))	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (121, 145))
61403	20061944	Inhibition of angiogenesis limits fibrosis in animal models, whereas the bile acid, taurocholate, has protective effects in animal models of bile duct and peribiliary vascular plexus damage.	('bile acid', 'Chemical', 'MESH:D001647', (73, 82))	('fibrosis', 'Disease', 'MESH:D005355', (34, 42))	('fibrosis', 'Disease', (34, 42))	('taurocholate', 'Chemical', 'MESH:D013656', (84, 96))	('Inhibition', 'Var', (0, 10))	('angiogenesis', 'CPA', (14, 26))	('bile duct', 'Disease', (141, 150))
61431	20061944	Aberrant angiogenesis is implicated in the progression of hepatic fibrosis and is considered to be a major determinant in the irreversibility of fibrosis.	('angiogenesis', 'CPA', (9, 21))	('Aberrant', 'Var', (0, 8))	('hepatic fibrosis', 'Disease', 'MESH:D008103', (58, 74))	('fibrosis', 'Disease', 'MESH:D005355', (66, 74))	('fibrosis', 'Disease', (66, 74))	('fibrosis', 'Disease', 'MESH:D005355', (145, 153))	('fibrosis', 'Disease', (145, 153))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (58, 74))	('implicated', 'Reg', (25, 35))	('hepatic fibrosis', 'Disease', (58, 74))
61437	20061944	Adenoviral expression of soluble Tie2 prevented both angiogenesis and liver fibrosis induced by carbon tetrachloride (CCl4) and BDL.	('liver fibrosis', 'Disease', 'MESH:D008103', (70, 84))	('angiogenesis', 'CPA', (53, 65))	('prevented', 'NegReg', (38, 47))	('Tie2', 'Gene', (33, 37))	('liver fibrosis', 'Phenotype', 'HP:0001395', (70, 84))	('CCl4', 'Gene', (118, 122))	('carbon tetrachloride', 'Chemical', 'MESH:D002251', (96, 116))	('CCl4', 'Gene', '116637', (118, 122))	('Tie2', 'Gene', '89804', (33, 37))	('liver fibrosis', 'Disease', (70, 84))	('Adenoviral expression', 'Var', (0, 21))
61456	20061944	In vivo, RAMH decreased tumor growth and the expression of VEGF-A and VEGF-C and its receptors.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('VEGF-C', 'Gene', (70, 76))	('decreased', 'NegReg', (14, 23))	('tumor', 'Disease', (24, 29))	('expression', 'MPA', (45, 55))	('VEGF-A', 'Gene', (59, 65))	('RAMH', 'Chemical', '-', (9, 13))	('RAMH', 'Var', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
61457	20061944	In the BDL model of extrahepatic cholestasis, RAMH also inhibits biliary growth of BDL rats by down-regulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway.	('biliary growth', 'CPA', (65, 79))	('cAMP', 'Chemical', '-', (118, 122))	('extrahepatic cholestasis', 'Phenotype', 'HP:0012334', (20, 44))	('extrahepatic cholestasis', 'Disease', (20, 44))	('ELK-1', 'Gene', '314436', (144, 149))	('inhibits', 'NegReg', (56, 64))	('down-regulation', 'NegReg', (95, 110))	('RAMH', 'Chemical', '-', (46, 50))	('rats', 'Species', '10116', (87, 91))	('extrahepatic cholestasis', 'Disease', 'MESH:D001651', (20, 44))	('cholestasis', 'Phenotype', 'HP:0001396', (33, 44))	('ELK-1', 'Gene', (144, 149))	('RAMH', 'Var', (46, 50))
61461	20061944	In fact, inhibiting both VEGFR and EGFR signaling with vandetanib (ZD6474) appears to be promising therapy for cholangiocarcinoma that lack KRAS mutations and/or have EGFR amplification.	('EGFR', 'Gene', (26, 30))	('EGFR', 'Gene', '24329', (35, 39))	('ZD6474', 'Chemical', 'MESH:C452423', (67, 73))	('cholangiocarcinoma', 'Disease', (111, 129))	('mutations', 'Var', (145, 154))	('EGFR', 'Gene', '24329', (167, 171))	('EGFR', 'Gene', '24329', (26, 30))	('EGFR', 'Gene', (35, 39))	('lack', 'NegReg', (135, 139))	('vandetanib', 'Chemical', 'MESH:C452423', (55, 65))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 129))	('inhibiting', 'NegReg', (9, 19))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))	('KRAS', 'Gene', '24525', (140, 144))	('KRAS', 'Gene', (140, 144))	('EGFR', 'Gene', (167, 171))
61462	20061944	Cholangiocarcinoma cell lines possessing KRAS mutations were refractory to vadetanib.	('mutations', 'Var', (46, 55))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (0, 18))	('vadetanib', 'Chemical', '-', (75, 84))	('Cholangiocarcinoma cell lines', 'Disease', (0, 29))	('Cholangiocarcinoma cell lines', 'Disease', 'MESH:D018281', (0, 29))	('KRAS', 'Gene', (41, 45))	('KRAS', 'Gene', '24525', (41, 45))
61470	20061944	Taken together these findings suggest that inhibition of VEGF signaling might be used to treat patients with polycystic liver disease.	('inhibition', 'Var', (43, 53))	('patients', 'Species', '9606', (95, 103))	('polycystic liver disease', 'Disease', 'MESH:C536330', (109, 133))	('polycystic liver disease', 'Disease', (109, 133))	('liver disease', 'Phenotype', 'HP:0001392', (120, 133))	('polycystic liver disease', 'Phenotype', 'HP:0006557', (109, 133))
61475	20061944	The studies reviewed in this article raise the possibility for utilizing the inhibition of angiogenesis and VEGF signaling for the treatment of various biliary tract diseases ranging from biliary fibrosis and cholangiocarcinoma to liver cysts in patients with polycystic liver disease.	('liver cyst', 'Phenotype', 'HP:0001407', (231, 241))	('inhibition', 'Var', (77, 87))	('patients', 'Species', '9606', (246, 254))	('biliary tract diseases', 'Disease', 'MESH:D001660', (152, 174))	('biliary tract diseases', 'Phenotype', 'HP:0001080', (152, 174))	('biliary fibrosis', 'Disease', (188, 204))	('biliary tract disease', 'Phenotype', 'HP:0001080', (152, 173))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (209, 227))	('biliary fibrosis', 'Disease', 'MESH:D005355', (188, 204))	('polycystic liver disease', 'Disease', 'MESH:C536330', (260, 284))	('liver cysts', 'Phenotype', 'HP:0001407', (231, 242))	('liver disease', 'Phenotype', 'HP:0001392', (271, 284))	('polycystic liver disease', 'Disease', (260, 284))	('cholangiocarcinoma to liver cysts', 'Disease', 'MESH:D018281', (209, 242))	('polycystic liver disease', 'Phenotype', 'HP:0006557', (260, 284))	('cholangiocarcinoma to liver cysts', 'Disease', (209, 242))	('biliary tract diseases', 'Disease', (152, 174))
61481	20061944	Manipulation of the signaling mechanisms that regulate angiogenesis may thus represent a new approach to treating cholangiopathies.	('treating cholangiopathies', 'Disease', (105, 130))	('treating cholangiopathies', 'Disease', 'MESH:D019553', (105, 130))	('Manipulation', 'Var', (0, 12))
61524	32373713	However, in the presence of APBDU, cholecystectomy is also recommended due to the increased risk of gall bladder malignancy.	('gall bladder malignancy', 'Disease', 'MESH:D005706', (100, 123))	('bladder malignancy', 'Phenotype', 'HP:0009725', (105, 123))	('gall bladder malignancy', 'Disease', (100, 123))	('APBDU', 'Var', (28, 33))	('cholecystectomy', 'Disease', (35, 50))
61574	32011818	Blood flow after percutaneous PVE, as a separate procedure or as a part of the first stage in PRALPPS, was reduced by coils placed in the right/left portal vein and/or its sectional branches.	('Blood flow', 'MPA', (0, 10))	('reduced', 'NegReg', (107, 114))	('ALPPS', 'Disease', 'None', (96, 101))	('PVE', 'Phenotype', 'HP:0030242', (30, 33))	('coils', 'Var', (118, 123))	('ALPPS', 'Disease', (96, 101))
61605	32011818	Rates of posthepatectomy liver failure and 90-day mortality were 57 and 36 per cent respectively in patients with PHCC20.	('PHCC20', 'Var', (114, 120))	('patients', 'Species', '9606', (100, 108))	('liver failure', 'Phenotype', 'HP:0001399', (25, 38))	('liver failure', 'Disease', 'MESH:D017093', (25, 38))	('liver failure', 'Disease', (25, 38))
61614	32011818	In patients with cholangitis and complications after the first stage of the procedure, functional liver capacity is compromised even further, and an FLR volume of around 40 per cent may be insufficient, especially if major complications develop after the resectional stage.	('cholangitis', 'Phenotype', 'HP:0030151', (17, 28))	('compromised', 'NegReg', (116, 127))	('cholangitis', 'Disease', (17, 28))	('patients', 'Species', '9606', (3, 11))	('functional', 'MPA', (87, 97))	('cholangitis', 'Disease', 'MESH:D002761', (17, 28))	('complications', 'Var', (33, 46))
61687	30259149	The 1-year, 3-year, 5-year, and 10-year cumulative survival rates of patients with non-large blood vessel tumor thrombi were 81.9%, 68.4%, 65.6%, and 65.6%, respectively, and those of patients with large blood vessel tumor thrombi were 49.3%, 12.3%, 12.3%, and 12.3%, respectively.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('blood vessel tumor thrombi', 'Disease', 'MESH:D009383', (204, 230))	('blood vessel tumor', 'Phenotype', 'HP:0100742', (93, 111))	('patients', 'Species', '9606', (184, 192))	('blood vessel tumor', 'Phenotype', 'HP:0100742', (204, 222))	('blood vessel tumor thrombi', 'Disease', (93, 119))	('non-large', 'Var', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('patients', 'Species', '9606', (69, 77))	('blood vessel tumor thrombi', 'Disease', (204, 230))	('blood vessel tumor thrombi', 'Disease', 'MESH:D009383', (93, 119))
61704	30259149	Combined with the features of liver cancer etiology and epidemiology in China, the mean age of patients in these two groups was used as a cutoff value for the binary parameters <= 50 years and > 50 years.	('liver cancer', 'Phenotype', 'HP:0002896', (30, 42))	('liver cancer', 'Disease', 'MESH:D006528', (30, 42))	('liver cancer', 'Disease', (30, 42))	('patients', 'Species', '9606', (95, 103))	('<= 50 years', 'Var', (177, 188))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
61813	27686493	At the junction between the atrophied and hypertrophied lobe or segment, there is usually a change in hepatic contour, or 'step', which results in distortion of the overlying hepatic capsule that can mimic hepatic capsular retraction (Fig.	('change', 'Var', (92, 98))	('hypertrophied lobe', 'Disease', 'MESH:D006984', (42, 60))	('hypertrophied lobe', 'Disease', (42, 60))	('hepatic capsular retraction', 'Disease', (206, 233))	('men', 'Species', '9606', (67, 70))	('hepatic', 'MPA', (102, 109))
61895	27429673	The mean area under the receiver operating characteristic curve for differentiating benign from malignant lesions was significantly greater with MDCT (0.98) when compared to MRI/MRCP (0.86).	('greater', 'PosReg', (132, 139))	('MRI/MRCP', 'Gene', '78996', (174, 182))	('MRI/MRCP', 'Gene', (174, 182))	('MDCT', 'Var', (145, 149))
61928	26260613	Additionally, we demonstrated that the inactivation of the RHOC/AKT/MAPK pathway was involved in the tumor-suppressive functions of HOXD10 in CCC.	('CCC', 'Disease', (142, 145))	('inactivation', 'Var', (39, 51))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('involved', 'Reg', (85, 93))	('tumor', 'Disease', (101, 106))	('AKT', 'Gene', '207', (64, 67))	('AKT', 'Gene', (64, 67))	('CCC', 'Phenotype', 'HP:0030153', (142, 145))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
61935	26260613	In breast cancer cell lines, HOXD10 induces cell phenotypic reversion from highly invasive tumor cells to a non-malignant state in a three-dimensional culture model.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('HOXD10', 'Var', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('cell phenotypic reversion', 'CPA', (44, 69))
61936	26260613	Overexpression or loss of HOXD10 is involved in tumorigenesis characterized as an oncogene or tumor-suppressor because of its importance in cancer cell survival, proliferation, invasion and migration in several malignancies, including breast, gastric, hepatocellular, ovarian, malignant glioma, head and neck, bladder, and colorectal cancer.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('bladder', 'Disease', (310, 317))	('HOXD10', 'Gene', (26, 32))	('colorectal cancer', 'Phenotype', 'HP:0003003', (323, 340))	('ovarian', 'Disease', (268, 275))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Disease', (334, 340))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('malignant glioma', 'Disease', (277, 293))	('malignant glioma', 'Disease', 'MESH:D005910', (277, 293))	('breast', 'Disease', (235, 241))	('tumor-suppressor', 'Gene', '7248', (94, 110))	('colorectal cancer', 'Disease', 'MESH:D015179', (323, 340))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('cancer', 'Disease', (140, 146))	('colorectal cancer', 'Disease', (323, 340))	('malignancies', 'Disease', 'MESH:D009369', (211, 223))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (334, 340))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('involved', 'Reg', (36, 44))	('glioma', 'Phenotype', 'HP:0009733', (287, 293))	('malignancies', 'Disease', (211, 223))	('loss', 'Var', (18, 22))	('tumor-suppressor', 'Gene', (94, 110))	('tumor', 'Disease', (94, 99))	('gastric', 'Disease', (243, 250))	('hepatocellular', 'Disease', (252, 266))
61979	26260613	The prognosis for patients with a positive HOXD10 expression was significantly better than that for patients with a negative HOXD10 expression (Fig.	('positive HOXD10', 'Var', (34, 49))	('better', 'PosReg', (79, 85))	('patients', 'Species', '9606', (100, 108))	('patients', 'Species', '9606', (18, 26))	('HOXD10', 'Var', (43, 49))
61989	26260613	The levels of HOXD10 mRNA and protein in RBE and HCCC-9810 cells transfected with recombinant lentivirus HOXD10 were significantly increased, compared with cells transfected with negative lentivirus HOXD10 and the blank control cells (Fig.	('levels', 'MPA', (4, 10))	('increased', 'PosReg', (131, 140))	('lentivirus', 'Var', (94, 104))	('CCC', 'Phenotype', 'HP:0030153', (50, 53))	('HCCC-9810', 'CellLine', 'CVCL:6908', (49, 58))	('HOXD10', 'Var', (105, 111))
61997	26260613	The percentage of viable cells in the RBE and HCCC-9810 cells with Lv-HOXD10 significantly decreased compared with the Ne-CTRL and the blank control (CTRL) cells (P<0.001).	('HCCC-9810', 'CellLine', 'CVCL:6908', (46, 55))	('Lv-HOXD10', 'Var', (67, 76))	('decreased', 'NegReg', (91, 100))	('CCC', 'Phenotype', 'HP:0030153', (47, 50))
62000	26260613	HOXD10 has been shown to mediate the invasion of breast, gastric, malignant glioma, ovarian, bladder and hepatocellular cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('malignant glioma', 'Disease', 'MESH:D005910', (66, 82))	('invasion', 'CPA', (37, 45))	('gastric', 'Disease', (57, 64))	('HOXD10', 'Var', (0, 6))	('breast', 'Disease', (49, 55))	('bladder and hepatocellular cancer', 'Disease', 'MESH:D001749', (93, 126))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (105, 126))	('ovarian', 'Disease', (84, 91))	('malignant glioma', 'Disease', (66, 82))
62003	26260613	As expected, stable overexpression of HOXD10 significantly decreased the invasive potential of both the RBE and HCCC-9810 cell lines (Fig.	('HCCC-9810', 'CellLine', 'CVCL:6908', (112, 121))	('HOXD10', 'Var', (38, 44))	('decreased', 'NegReg', (59, 68))	('CCC', 'Phenotype', 'HP:0030153', (113, 116))	('overexpression', 'PosReg', (20, 34))	('invasive potential of', 'CPA', (73, 94))
62006	26260613	4A and B, the mRNA and protein expression of MMP2 and MMP9 was significantly inhibited in the Lv-HOXD10 group compared with the Ne-CTRL and CTRL group, while no significant change was observed in the expression of MMP14.	('MMP14', 'Gene', '4323', (214, 219))	('MMP2', 'Gene', (45, 49))	('Lv-HOXD10', 'Var', (94, 103))	('MMP14', 'Gene', (214, 219))	('inhibited', 'NegReg', (77, 86))	('MMP9', 'Gene', (54, 58))
62008	26260613	Since we observed a significant correlation between HOXD10 and RHOC expression and CCC patient prognosis, it was suggested that HOXD10 may inhibit CCC cell growth and metastasis by reducing RHOC signaling.	('CCC', 'Disease', (147, 150))	('CCC', 'Phenotype', 'HP:0030153', (83, 86))	('reducing', 'NegReg', (181, 189))	('CCC', 'Disease', (83, 86))	('inhibit', 'NegReg', (139, 146))	('patient', 'Species', '9606', (87, 94))	('HOXD10', 'Var', (128, 134))	('CCC', 'Phenotype', 'HP:0030153', (147, 150))	('RHOC signaling', 'MPA', (190, 204))
62017	26260613	In the univariate analysis of the present study, we found that the prognosis for patients with a positive HOXD10 protein expression was better than that of patients with a negative HOXD10 protein expression.	('patients', 'Species', '9606', (156, 164))	('better', 'PosReg', (136, 142))	('positive', 'Var', (97, 105))	('patients', 'Species', '9606', (81, 89))	('HOXD10', 'Gene', (106, 112))	('protein', 'Protein', (113, 120))
62023	26260613	Thus, more studies are needed to determine the precise molecular mechanisms by which HOXD10 overexpression inhibits invasion in RBE and HCCC-9810 cell lines.	('HCCC-9810', 'CellLine', 'CVCL:6908', (136, 145))	('HOXD10', 'Gene', (85, 91))	('invasion', 'CPA', (116, 124))	('inhibits', 'NegReg', (107, 115))	('CCC', 'Phenotype', 'HP:0030153', (137, 140))	('overexpression', 'Var', (92, 106))
62037	26260613	In addition, it was reported that HOXD10 is not involved in the inhibition of the tumor growth of primary breast cancer but markedly suppresses the formation of lung metastases in a mouse mammary tumor model.	('HOXD10', 'Var', (34, 40))	('breast cancer', 'Disease', (106, 119))	('tumor', 'Disease', (196, 201))	('mouse', 'Species', '10090', (182, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('suppresses', 'NegReg', (133, 143))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('lung metastases', 'Disease', (161, 176))	('tumor', 'Disease', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('lung metastases', 'Disease', 'MESH:D009362', (161, 176))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
62038	26260613	Thus, whether HOXD10 is anti-tumorigenic or pro-tumorigenic depends on the cell context and the type of stimulus.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('HOXD10', 'Var', (14, 20))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
62043	24673799	Suppressive expression of CD274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma Cholangiocarcinoma is an aggressive malignant tumor originating from intrahepatic or extrahepatic bile ducts.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (110, 128))	('Cholangiocarcinoma', 'Disease', (110, 128))	('cholangiocarcinoma', 'Disease', (91, 109))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('intrahepatic', 'Disease', 'MESH:D002780', (179, 191))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('CD274', 'Gene', '29126', (26, 31))	('intrahepatic', 'Disease', (179, 191))	('malignant tumor', 'Disease', (146, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumorigenesis', 'CPA', (42, 55))	('malignant tumor', 'Disease', 'MESH:D018198', (146, 161))	('increases', 'PosReg', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('Suppressive expression', 'Var', (0, 22))	('CD274', 'Gene', (26, 31))	('cancer', 'Disease', (60, 66))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (110, 128))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
62045	24673799	Here, we demonstrate that CD274 (PD-L1), known as an immunomodulatory ligand, has suppressive effects on CSC-related phenotypes of cholangiocarcinoma.	('CD274', 'Var', (26, 31))	('PD-L1', 'Gene', (33, 38))	('rat', 'Species', '10116', (16, 19))	('PD-L1', 'Gene', '29126', (33, 38))	('cholangiocarcinoma', 'Disease', (131, 149))	('suppressive', 'NegReg', (82, 93))	('CSC-related', 'Disease', (105, 116))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (131, 149))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))
62046	24673799	Using two human cholangiocarcinoma cell lines, RBE and HuCCT1, we attempted to isolate the CD274low and CD274high cells from each cell line, and xenografted them into immunodeficient NOD/scid/gammacnull (NOG) mice.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (16, 34))	('mice', 'Species', '10090', (209, 213))	('human', 'Species', '9606', (10, 15))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (16, 34))	('cholangiocarcinoma', 'Disease', (16, 34))	('CD274low', 'Var', (91, 99))	('CD274high', 'Var', (104, 113))
62047	24673799	We found that the CD274low cells isolated from both RBE and HuCCT1 are highly tumorigenic in NOG mice compared with CD274high cells.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mice', 'Species', '10090', (97, 101))	('CD274low', 'Var', (18, 26))	('tumor', 'Disease', (78, 83))
62048	24673799	Furthermore, the CD274low cells possess several CSC-related characteristics, such as high aldehyde dehydrogenase (ALDH) activity, reduced reactive oxygen species production and a dormant state in the cell cycle.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (138, 161))	('CD274low', 'Var', (17, 25))	('dormant state in the cell cycle', 'CPA', (179, 210))	('reactive oxygen species production', 'MPA', (138, 172))	('reduced', 'NegReg', (130, 137))	('activity', 'MPA', (120, 128))
62050	24673799	These findings are compatible with our observation that clinical cholangiocarcinoma specimens are classified into low and high groups for CD274 expression, and the CD274 low group shows poorer prognosis when compared with the CD274 high group.	('expression', 'MPA', (144, 154))	('cholangiocarcinoma', 'Disease', (65, 83))	('CD274', 'Var', (164, 169))	('clinical', 'Species', '191496', (56, 64))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (65, 83))	('CD274', 'Gene', (138, 143))
62068	24673799	Because CD274 is commonly upregulated on various types of tumors and its receptor, PD-1, is expressed on the majority of tumor-infiltrating lymphocytes including T cells, the tumor cells expressing CD274 are thought to induce suppression of local antitumor T-cell responses.	('tumor', 'Disease', (251, 256))	('CD274', 'Gene', (8, 13))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('CD274', 'Var', (198, 203))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (121, 126))	('rat', 'Species', '10116', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Disease', (175, 180))	('upregulated', 'PosReg', (26, 37))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('suppression', 'NegReg', (226, 237))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
62069	24673799	In contrast to this immunosuppressive effect, CD274 is also known to contribute to the promotion of tumor cell growth and the downregulation of quiescent cells in breast cancer, and not to express exclusively in CD133-positive stem cells in glioma, suggesting a possible involvement of CD274 on regulation of cancer stem cells.	('cancer', 'Disease', (170, 176))	('downregulation', 'NegReg', (126, 140))	('tumor', 'Disease', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('CD274', 'Var', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('glioma', 'Disease', (241, 247))	('promotion', 'PosReg', (87, 96))	('glioma', 'Disease', 'MESH:D005910', (241, 247))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('CD133', 'Gene', (212, 217))	('CD133', 'Gene', '8842', (212, 217))	('cancer', 'Disease', (309, 315))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('glioma', 'Phenotype', 'HP:0009733', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('breast cancer', 'Disease', (163, 176))	('cancer', 'Disease', 'MESH:D009369', (309, 315))
62070	24673799	Here, we demonstrated that CD274 suppresses the CSC-related phenotypes and becomes a prognostic factor for patients with human cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (127, 145))	('suppresses', 'NegReg', (33, 43))	('rat', 'Species', '10116', (16, 19))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (127, 145))	('CD274', 'Var', (27, 32))	('human', 'Species', '9606', (121, 126))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (127, 145))	('CSC-related phenotypes', 'MPA', (48, 70))	('patients', 'Species', '9606', (107, 115))
62097	24673799	S1), and the CD274low and CD274high cells were then xenografted into immunodeficient NOD/scid/gammacnull (NOG) mice.	('CD274high', 'Var', (26, 35))	('mice', 'Species', '10090', (111, 115))	('CD274low', 'Var', (13, 21))
62098	24673799	The CD274low population (1 x 104 cells) formed tumors at all six (6/6) injection sites, whereas the CD274high population formed tumors in one out of six (1/6) injection sites after 25 weeks of xenograft (Fig.1a, Table1A).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('CD274low', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('CD274high', 'Var', (100, 109))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
62100	24673799	The CD274low population (1 x 102 cells) of HuCCT1 formed tumors at three out of four (3/4) injection sites, whereas the CD274high population formed no (0/4) tumor after 23 weeks of xenograft (Fig.1b, Table1B).	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('CD274low', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('HuCCT1', 'Gene', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumor', 'Disease', (57, 62))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
62101	24673799	These results suggest that the CSC of cholangiocarcinoma are enriched in the CD274low population.	('cholangiocarcinoma', 'Disease', (38, 56))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (38, 56))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (38, 56))	('CD274low', 'Var', (77, 85))
62103	24673799	The level of retinoic acids produced by the CD274low population was significantly higher than that produced by the CD274high population (Fig.2c,d) in both RBE and HuCCT1 cells.	('CD274low', 'Var', (44, 52))	('level of retinoic acids produced', 'MPA', (4, 36))	('retinoic acids', 'Chemical', 'MESH:D014212', (13, 27))	('higher', 'PosReg', (82, 88))
62104	24673799	The CD274low and CD274high populations were further assessed for ROS levels.	('CD274low', 'Var', (4, 12))	('ROS', 'Chemical', 'MESH:D017382', (65, 68))	('CD274high', 'Var', (17, 26))	('ROS levels', 'MPA', (65, 75))
62105	24673799	The ROS levels were significantly lower in the CD274low populations than in the CD274high populations derived from both RBE and HuCCT1 cells (Fig.2e,f).	('ROS', 'Chemical', 'MESH:D017382', (4, 7))	('CD274low', 'Var', (47, 55))	('lower', 'NegReg', (34, 39))	('ROS levels', 'MPA', (4, 14))
62106	24673799	These results indicate that the CD274low populations of both cholangiocarcinoma cell lines predominantly exhibit CSC-related characteristics such as high ALDH1 activity and low ROS production.	('ALDH1', 'Gene', '216', (154, 159))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 79))	('high', 'PosReg', (149, 153))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('activity', 'MPA', (160, 168))	('ROS', 'Chemical', 'MESH:D017382', (177, 180))	('ALDH1', 'Gene', (154, 159))	('CD274low', 'Var', (32, 40))	('ROS production', 'MPA', (177, 191))	('CSC-related', 'Disease', (113, 124))	('cholangiocarcinoma', 'Disease', (61, 79))	('low', 'NegReg', (173, 176))
62107	24673799	Because hematopoietic and leukemic stem cells are known to reside largely in the G0 phase, we examined the cell cycle phases of the RBE and HuCCT1-derived CD274low and CD274high populations.	('leukemic', 'Disease', 'MESH:D007938', (26, 34))	('CD274low', 'Var', (155, 163))	('CD274high', 'Var', (168, 177))	('leukemic', 'Disease', (26, 34))
62108	24673799	The CD274low and CD274high populations were stained with the DNA-binding dye propidium iodide for defining the DNA content and an anti-Ki-67 antibody for defining the G0 phase.	('Ki-67', 'Gene', '17345', (135, 140))	('CD274low', 'Var', (4, 12))	('propidium iodide', 'Chemical', 'MESH:D011419', (77, 93))	('Ki-67', 'Gene', (135, 140))	('CD274high', 'Var', (17, 26))
62109	24673799	Most of the CD274low cells from both cell lines were found to be Ki-67-, corresponding to the G0 phase, whereas the CD274high cells showed various phases of the cell cycle (Fig.2g,h).	('CD274low', 'Var', (12, 20))	('Ki-67', 'Gene', '17345', (65, 70))	('Ki-67', 'Gene', (65, 70))
62110	24673799	These results indicate that the CD274low cells derived from both RBE and HuCCT1 exhibit the characteristics of dormancy, which is often detected in the CSC of other types of cancer.	('dormancy', 'CPA', (111, 119))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('CD274low', 'Var', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
62112	24673799	Real-time PCR analyses showed more elevated levels of Oct4, Sox2 and Nanog in the CD274low cells than in the CD274high cells (Fig.2i,j).	('Nanog', 'Gene', (69, 74))	('elevated', 'PosReg', (35, 43))	('CD274low', 'Var', (82, 90))	('Oct4', 'Gene', '5460', (54, 58))	('Sox2', 'Gene', '6657', (60, 64))	('levels', 'MPA', (44, 50))	('Sox2', 'Gene', (60, 64))	('Nanog', 'Gene', '79923', (69, 74))	('Oct4', 'Gene', (54, 58))
62115	24673799	The cell proliferation curves were not significantly different between CD274-knockdown cells and the control (Fig.4b) after the puromycin selection for 14 days.	('rat', 'Species', '10116', (16, 19))	('cell proliferation', 'CPA', (4, 22))	('puromycin', 'Chemical', 'MESH:D011691', (128, 137))	('CD274-knockdown', 'Var', (71, 86))
62116	24673799	The CD274-knockdown cells displayed a higher tumorigenic capability in NOG mice than the control cells (Fig.4c, Table1C).	('mice', 'Species', '10090', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('CD274-knockdown', 'Var', (4, 19))	('tumor', 'Disease', (45, 50))	('higher', 'PosReg', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
62117	24673799	In cell cycle analysis, CD274-knockdown cells exhibit relatively in the G0/G1 phase compared with control cells after puromycin selection for 2 days (Fig.4e).	('CD274-knockdown', 'Var', (24, 39))	('G0/G1 phase', 'CPA', (72, 83))	('puromycin', 'Chemical', 'MESH:D011691', (118, 127))
62122	24673799	We then divided the samples into two groups, CD274-/+ and CD274++, according to the expression level of CD274 in their cancerous areas, and compared the overall survival of patients using the Kaplan-Meier methods.	('patients', 'Species', '9606', (173, 181))	('cancerous areas', 'Disease', (119, 134))	('cancerous areas', 'Disease', 'MESH:D009369', (119, 134))	('CD274', 'Var', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
62125	24673799	In the present study using the two human cholangiocarcinoma cell lines, RBE and HuCCT1, we first demonstrated that the CD274low cells derived from the two cell lines possess higher tumorigenecity in NOG mice compared with the CD274high cells.	('CD274low', 'Var', (119, 127))	('tumor', 'Disease', (181, 186))	('cholangiocarcinoma', 'Disease', (41, 59))	('mice', 'Species', '10090', (203, 207))	('human', 'Species', '9606', (35, 40))	('higher', 'PosReg', (174, 180))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (41, 59))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (41, 59))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('rat', 'Species', '10116', (104, 107))
62129	24673799	In the present study, RBE and HuCCT1-derived CD274low cells resided primarily in the G0 dormant phase and the amount of retinoic acid was significantly increased in CD274low cells.	('CD274low', 'Gene', (45, 53))	('increased', 'PosReg', (152, 161))	('CD274low', 'Var', (165, 173))	('amount of retinoic acid', 'MPA', (110, 133))	('retinoic acid', 'Chemical', 'MESH:D014212', (120, 133))
62131	24673799	In NOG mice transplanted with RBE-derived CD274low cells, the proliferating cells detected using Ki-67 staining colocalized mainly with CD274high cells in tumor tissues, suggesting that the CD274low cells are also relatively dormant in vivo as well as in vitro.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('Ki-67', 'Gene', '17345', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mice', 'Species', '10090', (7, 11))	('tumor', 'Disease', (155, 160))	('Ki-67', 'Gene', (97, 102))	('CD274low', 'Var', (42, 50))	('rat', 'Species', '10116', (69, 72))	('CD274low', 'Var', (190, 198))
62133	24673799	In addition, in vitro cultures of the cholangiocarcinoma cell lines showed that CD274low cells were capable of producing CD274high cells, and vice versa, CD274high cells were also capable of producing CD274low cells, although the transition from CD274high to CD274low was considerably slower (Fig.3b).	('cholangiocarcinoma', 'Disease', (38, 56))	('CD274low', 'MPA', (201, 209))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (38, 56))	('CD274high', 'Var', (154, 163))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (38, 56))	('CD274low', 'Var', (80, 88))	('CD274high cells', 'Var', (121, 136))
62135	24673799	Collectively, these findings suggest that there is a hierarchy in the expression of CD274 on cholangiocarcinoma cells and that CD274low cells tend to be dormant, similar to other CSC, whereas CD274high cells possess a higher proliferative potential than CD274low cells.	('proliferative potential', 'CPA', (225, 248))	('rat', 'Species', '10116', (232, 235))	('higher', 'PosReg', (218, 224))	('CD274', 'Gene', (84, 89))	('CD274low', 'Var', (127, 135))	('cholangiocarcinoma', 'Disease', (93, 111))	('CD274high', 'Var', (192, 201))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))
62136	24673799	Furthermore, because high ALDH and low ROS activities are known to be other characteristics of CSC in several types of cancer, we compared these activities between the CD274low and CD274high populations of RBE and HuCCT1 cells.	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('ALDH', 'Protein', (26, 30))	('high ALDH', 'Protein', (21, 30))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('CD274high', 'Var', (181, 190))	('ROS activities', 'MPA', (39, 53))	('cancer', 'Disease', (119, 125))	('CD274low', 'Var', (168, 176))	('low', 'NegReg', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
62137	24673799	The CD274low populations derived from both cell lines showed higher ALDH and lower ROS activities than the CD274high populations, indicating that the CD274low cells of cholangiocarcinoma carry the characteristics of CSC.	('ROS activities', 'MPA', (83, 97))	('lower', 'NegReg', (77, 82))	('cholangiocarcinoma', 'Disease', (168, 186))	('CD274low', 'Var', (150, 158))	('higher', 'PosReg', (61, 67))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (168, 186))	('ROS', 'Chemical', 'MESH:D017382', (83, 86))	('ALDH', 'MPA', (68, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (168, 186))
62141	24673799	We also found that the mRNA for Nanog, Sox2 and Oct3/4 were increased in the CD274low populations derived from both RBE and HuCCT1 cell lines, indicating that the CD274low population has pluripotent stem cell-like characteristics that correlate with iPS/ES cell-related gene expression.	('Oct3/4', 'Gene', (48, 54))	('CD274low', 'Gene', (77, 85))	('iPS/ES cell-related', 'Disease', (250, 269))	('Nanog', 'Gene', '79923', (32, 37))	('Sox2', 'Gene', '6657', (39, 43))	('mRNA', 'MPA', (23, 27))	('Nanog', 'Gene', (32, 37))	('pluripotent', 'MPA', (187, 198))	('CD274low', 'Var', (163, 171))	('Sox2', 'Gene', (39, 43))	('increased', 'PosReg', (60, 69))	('Oct3/4', 'Gene', '5460', (48, 54))
62142	24673799	The relationship of CD274 expression to tumor aggressiveness, clinicopathological features and overall survival is well known in several human malignancies, such as ovarian, esophageal, pancreatic and non-small-cell lung cancers, indicating that high CD274 expression on these cancer cells in patients induces an immunosuppressive response resulting in tumor progression.	('ovarian', 'Disease', (165, 172))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (40, 60))	('ovarian', 'Disease', 'MESH:D010051', (165, 172))	('lung cancers', 'Disease', 'MESH:D008175', (216, 228))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('lung cancers', 'Disease', (216, 228))	('tumor', 'Disease', (353, 358))	('human', 'Species', '9606', (137, 142))	('malignancies', 'Disease', 'MESH:D009369', (143, 155))	('high', 'Var', (246, 250))	('pancreatic', 'Disease', (186, 196))	('cancer', 'Disease', (277, 283))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('malignancies', 'Disease', (143, 155))	('lung cancers', 'Phenotype', 'HP:0100526', (216, 228))	('tumor', 'Disease', 'MESH:D009369', (353, 358))	('CD274', 'Gene', (251, 256))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('cancer', 'Disease', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Disease', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('tumor aggressiveness', 'Disease', (40, 60))	('immunosuppressive response', 'MPA', (313, 339))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('aggressiveness', 'Phenotype', 'HP:0000718', (46, 60))	('induces', 'Reg', (302, 309))	('patients', 'Species', '9606', (293, 301))	('pancreatic', 'Disease', 'MESH:D010195', (186, 196))
62144	24673799	To resolve these incompatible observations regarding the effects of CD274 on cancer progression, we independently reviewed non-small-cell lung cancer specimens for the expression of CD274 and disease-free survival time and obtained the result that high expression of CD274 in non-small-cell lung cancer specimens tended to shorten the patients' disease-free survival time (data not shown), which confirmed the observations reported previously.	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('CD274', 'Gene', (182, 187))	('lung cancer', 'Disease', (291, 302))	('CD274', 'Gene', (267, 272))	('cancer', 'Disease', (143, 149))	('high expression', 'Var', (248, 263))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', (77, 83))	('disease-free survival time', 'CPA', (345, 371))	('lung cancer', 'Disease', 'MESH:D008175', (291, 302))	('shorten', 'NegReg', (323, 330))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', (138, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (291, 302))	('patients', 'Species', '9606', (335, 343))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', (296, 302))
62151	24673799	In the present study, we revealed that the CD274low cholangiocarcinoma cells have several CSC-related phenotypes.	('cholangiocarcinoma', 'Disease', (52, 70))	('CSC-related', 'Disease', (90, 101))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (52, 70))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (52, 70))	('CD274low', 'Var', (43, 51))
62303	33081075	This effect was found associated with an increased cell cycle arrest in G2/M phase, thus suggesting that as a consequence of the increased gammaH2AX by doxorubicin, beta-caryophyllene stimulates G2/M checkpoint and DNA repair systems in order to block the cell cycle and enable restoring the genome integrity.	('arrest', 'Disease', 'MESH:D006323', (62, 68))	('doxorubicin', 'Chemical', 'MESH:D004317', (152, 163))	('G2/M checkpoint', 'Pathway', (195, 210))	('gammaH2AX', 'Var', (139, 148))	('arrest', 'Disease', (62, 68))	('increased', 'PosReg', (129, 138))	('beta-caryophyllene', 'Chemical', 'MESH:C024714', (165, 183))	('DNA repair systems', 'Pathway', (215, 233))	('genome', 'MPA', (292, 298))	('stimulates', 'PosReg', (184, 194))	('cell cycle', 'CPA', (256, 266))
62338	33081075	Antiproliferative agents, also known as suppressing agents, are able to effectively block or retard carcinogenesis progression, acting through different mechanisms, such as the alteration of metabolic function of cancerous clones, apoptosis induction, inhibition of prosurvival signalings, modulation of growth hormone activity, block of DNA synthesis, and stimulation of terminal differentiation, thus leading to the arrest of proliferation and cell death.	('growth hormone', 'Gene', '2688', (304, 318))	('modulation', 'Var', (290, 300))	('metabolic function', 'MPA', (191, 209))	('syn', 'Gene', '23336', (342, 345))	('arrest', 'Disease', (418, 424))	('inhibition', 'NegReg', (252, 262))	('retard carcinogenesis', 'Disease', (93, 114))	('cell death', 'CPA', (446, 456))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('terminal differentiation', 'CPA', (372, 396))	('cancerous', 'Disease', 'MESH:D009369', (213, 222))	('alteration', 'Reg', (177, 187))	('retard carcinogenesis', 'Disease', 'MESH:D063646', (93, 114))	('syn', 'Gene', (342, 345))	('arrest', 'Disease', 'MESH:D006323', (418, 424))	('apoptosis', 'CPA', (231, 240))	('growth hormone', 'Gene', (304, 318))	('DNA', 'Gene', (338, 341))	('cancerous', 'Disease', (213, 222))
62347	33081075	Similarly, its derivatives were cytotoxic in different cancer cell lines.	('derivatives', 'Var', (15, 26))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cytotoxic', 'CPA', (32, 41))	('cancer', 'Disease', (55, 61))
62349	33081075	highlighted that alpha-humulene induced glutathione depletion and increased ROS production, thus suggesting that a pro-oxidant damage could be responsible for cell damage and death.	('increased', 'PosReg', (66, 75))	('glutathione depletion', 'MPA', (40, 61))	('increased ROS production', 'Phenotype', 'HP:0025464', (66, 90))	('alpha-humulene', 'Chemical', 'MESH:C042686', (17, 31))	('ROS production', 'MPA', (76, 90))	('ROS', 'Chemical', 'MESH:D017382', (76, 79))	('glutathione', 'Chemical', 'MESH:D005978', (40, 51))	('alpha-humulene', 'Var', (17, 31))
62353	33081075	Similarly, isocaryophyllene strongly induced oxidative stress, lipid oxidation, and membrane permeability alteration in L-929 cancer cells, which were correlated with its cytotoxic effects.	('membrane', 'MPA', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lipid oxidation', 'MPA', (63, 78))	('lipid', 'Chemical', 'MESH:D008055', (63, 68))	('induced', 'Reg', (37, 44))	('cancer', 'Disease', (126, 132))	('isocaryophyllene', 'Var', (11, 27))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('isocaryophyllene', 'Chemical', 'MESH:C024714', (11, 27))	('oxidative stress', 'Phenotype', 'HP:0025464', (45, 61))	('oxidative stress', 'MPA', (45, 61))
62355	33081075	Moreover, a possible block of the mitochondrial electron transport chain by isocaryophyllene with a consequent increase in the levels of intracellular reactive oxidative species has been hypothesized.	('increase', 'PosReg', (111, 119))	('block', 'NegReg', (21, 26))	('mitochondrial electron', 'Enzyme', (34, 56))	('isocaryophyllene', 'Chemical', 'MESH:C024714', (76, 92))	('isocaryophyllene', 'Var', (76, 92))	('levels of intracellular reactive oxidative species', 'MPA', (127, 177))
62398	33081075	Under these experimental conditions, HFD was found to markedly increase tumor growth, LN metastasis, tumor cell proliferation, angiogenesis, and lymphangiogenesis, and to decrease cell apoptosis with respect to a normal diet.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('increase', 'PosReg', (63, 71))	('decrease', 'NegReg', (171, 179))	('lymphangiogenesis', 'CPA', (145, 162))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('angiogenesis', 'CPA', (127, 139))	('LN metastasis', 'CPA', (86, 99))	('HFD', 'Var', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cell apoptosis', 'CPA', (180, 194))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
62417	33081075	An aberrant activation of Nrf2 in various cancers contributes to chemoresistance development and inflammation, and is associated with a poor prognosis.	('cancers', 'Disease', (42, 49))	('inflammation', 'Disease', 'MESH:D007249', (97, 109))	('Nrf2', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('aberrant', 'Var', (3, 11))	('inflammation', 'Disease', (97, 109))	('chemoresistance development', 'CPA', (65, 92))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('contributes', 'Reg', (50, 61))	('Nrf2', 'Gene', '4780', (26, 30))	('cancers', 'Disease', 'MESH:D009369', (42, 49))
62421	33081075	A modulation in Akt (cellular homolog of murine thymoma virus Akt8 oncogene) signaling has been found associated with apoptosis induced by alpha-humulene in liver cancer cells.	('apoptosis', 'CPA', (118, 127))	('thymoma', 'Phenotype', 'HP:0100522', (48, 55))	('associated', 'Reg', (102, 112))	('liver cancer', 'Disease', (157, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Akt', 'Pathway', (16, 19))	('modulation', 'Var', (2, 12))	('murine', 'Species', '10090', (41, 47))	('alpha-humulene', 'Chemical', 'MESH:C042686', (139, 153))	('liver cancer', 'Phenotype', 'HP:0002896', (157, 169))	('liver cancer', 'Disease', 'MESH:D006528', (157, 169))
62425	33081075	Upon PI3K activation, Akt is phosphorylated at Ser473 residue by PDK1, thus leading to the inactivation of several pro-apoptotic proteins (e.g., Bcl-2-associated death promoter and caspase-9) and apoptosis inhibition.	('Bcl-2', 'Gene', (145, 150))	('caspase-9', 'Gene', '842', (181, 190))	('Bcl-2', 'Gene', '596', (145, 150))	('PDK1', 'Gene', '5163', (65, 69))	('Ser473', 'Chemical', '-', (47, 53))	('apoptosis inhibition', 'CPA', (196, 216))	('inactivation', 'NegReg', (91, 103))	('Ser473 residue', 'Var', (47, 61))	('PI3K', 'Var', (5, 9))	('PDK1', 'Gene', (65, 69))	('caspase-9', 'Gene', (181, 190))
62446	33081075	It has been originally identified to be a mediator of the IL-6-type cytokine pathway and of the acute phase response, which is activated by the phosphorylation at tyrosine 705 (Tyr705) or serine 727 (Ser727) in response to different stimuli; after activation, it can be transferred to the nucleus, thus acting as a control factor for genes involved in cell proliferation, survival, and self-renewal.	('IL-6', 'Gene', '3569', (58, 62))	('serine', 'Chemical', 'MESH:D012694', (188, 194))	('tyrosine', 'Chemical', 'MESH:D014443', (163, 171))	('Tyr705', 'Var', (177, 183))	('Tyr705', 'Chemical', '-', (177, 183))	('Ser727', 'Var', (200, 206))	('Ser727', 'Chemical', '-', (200, 206))	('IL-6', 'Gene', (58, 62))
62451	33081075	found that STAT3 activation occurred during the treatment with doxorubicin, that is likely to support cell survival and drug resistance.	('doxorubicin', 'Var', (63, 74))	('drug resistance', 'Phenotype', 'HP:0020174', (120, 135))	('activation', 'PosReg', (17, 27))	('STAT3', 'Gene', '6774', (11, 16))	('doxorubicin', 'Chemical', 'MESH:D004317', (63, 74))	('STAT3', 'Gene', (11, 16))
62453	33081075	At the moment, although it is known that complex and not entirely understood mechanisms regulate STAT3 signaling in normal and cancerous cells, inhibiting STAT3 activation seems to represent an interesting novel strategy for cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('inhibiting', 'Var', (144, 154))	('STAT3', 'Gene', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancerous', 'Disease', 'MESH:D009369', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('STAT3', 'Gene', (155, 160))	('cancer', 'Disease', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('STAT3', 'Gene', '6774', (155, 160))	('cancerous', 'Disease', (127, 136))	('STAT3', 'Gene', '6774', (97, 102))
62471	33081075	Therefore, the modulation of cell cycle phases in cancer cells can represent a novel kind of chemopreventive mechanism.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('modulation', 'Var', (15, 25))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cell cycle phases', 'CPA', (29, 46))
62511	33081075	A mechanistic analysis revealed that along with inhibiting the transporters function, beta-caryophyllene and beta-caryophyllene oxide were able to downregulate the protein expression of Pgp, as showed by Western blotting and immunofluorescence analysis.	('Pgp', 'Gene', (186, 189))	('beta-caryophyllene oxide', 'Chemical', 'MESH:C515179', (109, 133))	('Pgp', 'Gene', '5243', (186, 189))	('beta-caryophyllene oxide', 'Var', (109, 133))	('protein expression', 'MPA', (164, 182))	('beta-caryophyllene', 'Chemical', 'MESH:C024714', (109, 127))	('downregulate', 'NegReg', (147, 159))	('beta-caryophyllene', 'Chemical', 'MESH:C024714', (86, 104))	('beta-caryophyllene', 'Var', (86, 104))
62536	33081075	Comparing sesquiterpenes, the cis-configuration of caryophyllane scaffold and the exocyclic double bond, as found in alpha-humulene and isocaryophyllene respectively, seem to be associated with a higher cytotoxicity power.	('isocaryophyllene', 'Chemical', 'MESH:C024714', (136, 152))	('cis-configuration', 'Var', (30, 47))	('alpha-humulene', 'Chemical', 'MESH:C042686', (117, 131))	('cytotoxicity', 'Disease', (203, 215))	('higher', 'PosReg', (196, 202))	('sesquiterpenes', 'Chemical', 'MESH:D012717', (10, 24))	('cytotoxicity', 'Disease', 'MESH:D064420', (203, 215))
62570	32368324	Low SII level was associated with better OS and RFS (both P < 0.05).	('RFS', 'Disease', (48, 51))	('better', 'PosReg', (34, 40))	('RFS', 'Disease', 'MESH:D005198', (48, 51))	('Low', 'Var', (0, 3))
62571	32368324	Multivariate analyses identified multiple tumors, node invasion and high SII level as independent risk factors for OS, while multiple tumors, node invasion and high SII level were identified as independent risk factors for RFS.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('multiple tumors', 'Disease', (125, 140))	('multiple tumors', 'Disease', 'MESH:D009369', (125, 140))	('RFS', 'Disease', (223, 226))	('high SII level', 'Var', (68, 82))	('RFS', 'Disease', 'MESH:D005198', (223, 226))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('multiple tumors', 'Disease', 'MESH:D009369', (33, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('multiple tumors', 'Disease', (33, 48))
62572	32368324	Patients with increased SII level were associated with worse OS and earlier tumor recurrence.	('increased', 'PosReg', (14, 23))	('SII', 'Var', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
62579	32368324	Patients with increased SII level were associated with worse overall survival and earlier tumor recurrence.	('increased', 'PosReg', (14, 23))	('SII level', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('Patients', 'Species', '9606', (0, 8))	('overall', 'MPA', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
62607	32368324	Moreover, the maximum tumor size was larger in high SII group (mean, 6.5 cm) than low group (P < 0.001).	('high SII', 'Var', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('larger', 'PosReg', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))
62614	32368324	In the validation cohort, increased SII and NLR were significantly correlated to worse OS and RFS (Figure 3).	('NLR', 'CPA', (44, 47))	('SII', 'Var', (36, 39))	('RFS', 'Disease', (94, 97))	('increased', 'PosReg', (26, 35))	('worse OS', 'Disease', (81, 89))	('RFS', 'Disease', 'MESH:D005198', (94, 97))
62618	32368324	In the validation cohort, abnormal serum CA-199 level, multiple tumors, node invasion and elevated SII were identified as independent risk factors for both OS and RFS .	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('multiple tumors', 'Disease', (55, 70))	('multiple tumors', 'Disease', 'MESH:D009369', (55, 70))	('serum CA-199 level', 'MPA', (35, 53))	('abnormal serum CA', 'Phenotype', 'HP:0004363', (26, 43))	('RFS', 'Disease', (163, 166))	('RFS', 'Disease', 'MESH:D005198', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('abnormal', 'Var', (26, 34))
62628	32368324	A handful of studies have demonstrated that patients with high SII level were associated with poor survival outcomes in various malignancies, suggesting the feasibility of SII in predicting prognosis.	('patients', 'Species', '9606', (44, 52))	('malignancies', 'Disease', 'MESH:D009369', (128, 140))	('SII', 'MPA', (63, 66))	('high', 'Var', (58, 62))	('survival outcomes', 'CPA', (99, 116))	('malignancies', 'Disease', (128, 140))	('poor', 'NegReg', (94, 98))
62629	32368324	Recently, a meta-analysis by Yang et al pooled outcomes from 22 studies and demonstrated that high SII was associated with poor overall outcomes in patients with various cancers.	('patients', 'Species', '9606', (148, 156))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cancers', 'Disease', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('high SII', 'Var', (94, 102))
62631	32368324	They presented an opposite result and revealed that low SII was significantly poor prognostic predictor for OS and recurrence in patients with early stage HCC.	('patients', 'Species', '9606', (129, 137))	('SII', 'MPA', (56, 59))	('low', 'Var', (52, 55))
62633	32368324	Importantly, this study demonstrated that an elevated SII (> 450) was associated with larger tumor, increased tumor number, node invasion and worse prognosis in patients with surgically treated ICC.	('increased', 'PosReg', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('SII (> 450', 'Var', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (110, 115))	('node invasion', 'CPA', (124, 137))	('patients', 'Species', '9606', (161, 169))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
62642	32368324	Patients with high density of tumor-infiltrating lymphocytes were associated with better prognosis and decreased rate of tumor recurrence.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('decreased', 'NegReg', (103, 112))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('high density', 'Var', (14, 26))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
62645	32368324	Moreover, according to our results, more progressive tumor biologic characteristics was observed in patients with high SII.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('high SII', 'Var', (114, 122))	('patients', 'Species', '9606', (100, 108))	('tumor', 'Disease', (53, 58))
62659	32368324	Low SII level correlated with better OS and RFS (both P < 0.05).	('better', 'PosReg', (30, 36))	('RFS', 'Disease', 'MESH:D005198', (44, 47))	('SII level', 'MPA', (4, 13))	('RFS', 'Disease', (44, 47))	('Low', 'Var', (0, 3))
62776	29589102	Metastasis to regional lymph nodes is independently associated with poor survival in PDAC, although this has not been found in all series.	('PDAC', 'Chemical', '-', (85, 89))	('Metastasis', 'Var', (0, 10))	('poor', 'NegReg', (68, 72))	('PDAC', 'Disease', (85, 89))	('PDAC', 'Phenotype', 'HP:0006725', (85, 89))
62780	29589102	Whilst the N-category of upper gastrointestinal malignancies (N0 no metastasis, N1 metastasis to 1-2 lymph nodes, N2 metastasis to > 2 lymph nodes) performed best, they found that the N-category of the lower gastrointestinal organs (N0 no metastasis, N1 metastasis to 1-3 lymph nodes, N2 metastasis to > 3 lymph nodes) had significantly more prognostic value than that used in the 7th edition of the UICC.	('N0', 'Var', (233, 235))	('N1 metastasis to 1-3', 'Var', (251, 271))	('upper gastrointestinal malignancies', 'Disease', (25, 60))	('N2 metastasis', 'Var', (285, 298))	('upper gastrointestinal malignancies', 'Disease', 'MESH:D005767', (25, 60))
62821	28882106	Sumoylation in p27kip1 via RanBP2 promotes cancer cell growth in cholangiocarcinoma cell line QBC939 Cholangiocarcinoma is one of the deadly disease with poor 5-year survival and poor response to conventional therapies.	('Sumoylation', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('promotes', 'PosReg', (34, 42))	('cholangiocarcinoma', 'Disease', (65, 83))	('p27kip1', 'Gene', (15, 22))	('RanBP2', 'Gene', '5903', (27, 33))	('QBC939', 'CellLine', 'CVCL:6942', (94, 100))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (65, 83))	('Cholangiocarcinoma', 'Disease', (101, 119))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (101, 119))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('p27kip1', 'Gene', '1027', (15, 22))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))	('RanBP2', 'Gene', (27, 33))
62847	28882106	reported that K134 of p27kip1 is responsible for its sumoylation before it is transported through nuclear membrane in 293T/17 and Hela cells in response to TGF-beta.	('TGF-beta', 'Gene', '7040', (156, 164))	('p27kip1', 'Gene', (22, 29))	('K134', 'Var', (14, 18))	('TGF-beta', 'Gene', (156, 164))	('293T', 'CellLine', 'CVCL:0063', (118, 122))	('p27kip1', 'Gene', '1027', (22, 29))	('Hela', 'CellLine', 'CVCL:0030', (130, 134))	('K134', 'Chemical', '-', (14, 18))	('sumoylation', 'MPA', (53, 64))
62867	28882106	All values are shown as mean +- SEM unless otherwise indicated and one way ANOVA was adopted to examine the difference between the CRM-1 knock-down group, blank group and vector group.	('knock-down', 'Var', (137, 147))	('CRM-1', 'Gene', (131, 136))	('CRM-1', 'Gene', '7514', (131, 136))
62869	28882106	In order to further validate the sumoylation site for p27kip1, immunoprecipitation were undertaken by using anti-p27kip1, anti-flag and anti-SUMO1 antibodies, together with flag-p27kip1-WT and K73R point mutated form of p27kip1 constructs.	('p27kip1', 'Gene', '1027', (54, 61))	('p27kip1', 'Gene', (54, 61))	('p27kip1', 'Gene', '1027', (220, 227))	('K73R', 'Mutation', 'rs6740879', (193, 197))	('p27kip1', 'Gene', (113, 120))	('p27kip1', 'Gene', (178, 185))	('p27kip1', 'Gene', (220, 227))	('SUMO1', 'Gene', (141, 146))	('p27kip1', 'Gene', '1027', (113, 120))	('p27kip1', 'Gene', '1027', (178, 185))	('SUMO1', 'Gene', '7341', (141, 146))	('K73R point mutated', 'Var', (193, 211))
62886	28882106	S2) while the level of a K73R point mutated form of p27kip1 in the nucleus cannot be changed by Crm-1 overexpression (Fig.	('K73R', 'Mutation', 'rs6740879', (25, 29))	('p27kip1', 'Gene', (52, 59))	('p27kip1', 'Gene', '1027', (52, 59))	('K73R point mutated', 'Var', (25, 43))	('Crm-1', 'Gene', (96, 101))	('Crm-1', 'Gene', '7514', (96, 101))
62896	28882106	reported that SUMO1 modification can stabilize CDK6 protein and drive the cell cycle and glioblastoma progression.	('CDK6', 'Gene', (47, 51))	('glioblastoma', 'Disease', (89, 101))	('CDK6', 'Gene', '1021', (47, 51))	('drive', 'PosReg', (64, 69))	('modification', 'Var', (20, 32))	('SUMO1', 'Gene', '7341', (14, 19))	('glioblastoma', 'Disease', 'MESH:D005909', (89, 101))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))	('SUMO1', 'Gene', (14, 19))	('stabilize', 'MPA', (37, 46))	('cell cycle', 'CPA', (74, 84))
62900	28882106	reported that K134 of p27kip1 is the sumoylation site in tumor-derived cell in response to TGF-beta.	('p27kip1', 'Gene', (22, 29))	('K134', 'Var', (14, 18))	('TGF-beta', 'Gene', '7040', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('TGF-beta', 'Gene', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('p27kip1', 'Gene', '1027', (22, 29))	('tumor', 'Disease', (57, 62))	('K134', 'Chemical', '-', (14, 18))
62954	27956028	Of those, S. haematobium is the most ubiquitous species in Egypt and in sub-Saharan Africa and causes urogenital schistosomiasis (UGS).	('causes', 'Reg', (95, 101))	('S. haematobium', 'Var', (10, 24))	('urogenital schistosomiasis', 'Disease', (102, 128))	('urogenital schistosomiasis', 'Disease', 'MESH:D012553', (102, 128))	('S. haematobium', 'Species', '6185', (10, 24))
62967	27956028	UGS due to S. haematobium has been consistently reported to be associated with bladder cancer.	('S. haematobium', 'Species', '6185', (11, 25))	('bladder cancer', 'Phenotype', 'HP:0009725', (79, 93))	('associated', 'Reg', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('UGS', 'Var', (0, 3))	('bladder cancer', 'Disease', 'MESH:D001749', (79, 93))	('bladder cancer', 'Disease', (79, 93))
62971	27956028	Another study found that UGS was strongly related to an increased risk of cytological abnormalities in a S. haematobium endemic area of Kenya.	('UGS', 'Var', (25, 28))	('S. haematobium', 'Species', '6185', (105, 119))	('cytological abnormalities', 'Disease', (74, 99))	('related', 'Reg', (42, 49))
62979	27956028	The S. haematobium-derived carcinogens may lead to DNA damage and somatic mutations through chronic inflammation and oxidative stress in oncogenes such as p53, RB (retinoblastoma protein), EGFR (epidermal growth factor receptor), and ERBB2 (erb-b2 receptor tyrosine kinase 2).	('inflammation', 'Disease', (100, 112))	('p53', 'Gene', (155, 158))	('lead', 'Reg', (43, 47))	('retinoblastoma', 'Phenotype', 'HP:0009919', (164, 178))	('EGFR', 'Gene', (189, 193))	('mutations', 'Var', (74, 83))	('epidermal growth factor receptor', 'Gene', (195, 227))	('ERBB2', 'Gene', (234, 239))	('EGFR', 'Gene', '24594857', (189, 193))	('DNA', 'Disease', (51, 54))	('epidermal growth factor receptor', 'Gene', '24594857', (195, 227))	('inflammation', 'Disease', 'MESH:D007249', (100, 112))	('retinoblastoma', 'Disease', 'MESH:D012175', (164, 178))	('retinoblastoma', 'Disease', (164, 178))	('oxidative stress', 'Phenotype', 'HP:0025464', (117, 133))	('S. haematobium', 'Species', '6185', (4, 18))
62992	27956028	Somatic mutations in the p53 gene were examined in Chinese patients with both rectal cancer and S. japonicum infection, and a higher frequency of arginine missense mutations were observed in schistosomal rectal cancer ostensibly induced by schistosome infection compared to non-schistosomiasis rectal cancers.	('rectal cancer', 'Phenotype', 'HP:0100743', (294, 307))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('schistosome infection', 'Phenotype', 'HP:0001981', (240, 261))	('arginine', 'Chemical', 'MESH:D001120', (146, 154))	('p53', 'Gene', (25, 28))	('cancers', 'Phenotype', 'HP:0002664', (301, 308))	('rectal cancer', 'Phenotype', 'HP:0100743', (78, 91))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', (301, 307))	('patients', 'Species', '9606', (59, 67))	('non-schistosomiasis rectal cancers', 'Disease', (274, 308))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('rectal cancer', 'Phenotype', 'HP:0100743', (204, 217))	('induced', 'Reg', (229, 236))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('infection', 'Disease', (109, 118))	('arginine missense mutations', 'Var', (146, 173))	('infection', 'Disease', (252, 261))	('infection', 'Disease', 'MESH:D007239', (109, 118))	('infection', 'Disease', 'MESH:D007239', (252, 261))	('non-schistosomiasis rectal cancers', 'Disease', 'MESH:D012004', (274, 308))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('cancer', 'Disease', (211, 217))	('S. japonicum', 'Species', '6182', (96, 108))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
63002	27956028	Therefore, cancer induction by S. mansoni infection could result from somatic mutations in oncogenes and in the regulation of immune responses that can activate several host signaling cancer pathways (Fig.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mansoni infection', 'Disease', (34, 51))	('mutations', 'Var', (78, 87))	('oncogenes', 'Gene', (91, 100))	('result from', 'Reg', (58, 69))	('S. mansoni', 'Species', '6183', (31, 41))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('activate', 'PosReg', (152, 160))	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('mansoni infection', 'Disease', 'MESH:D012554', (34, 51))
63035	27956028	In this context, it was shown that O. viverrini infection down-regulates RB1 (retinoblastoma 1) and p16INK4 (cyclin-dependent kinase inhibitor 2A) expression and up-regulates cyclin D1 and CDK4 (cyclin-dependent kinase 4) expression during cholangiocarcinoma development.	('expression', 'MPA', (147, 157))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (240, 258))	('CD', 'Disease', 'MESH:D006223', (189, 191))	('cyclin D1', 'Gene', (175, 184))	('cholangiocarcinoma', 'Disease', (240, 258))	('retinoblastoma', 'Phenotype', 'HP:0009919', (78, 92))	('infection', 'Disease', (48, 57))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (240, 258))	('infection', 'Disease', 'MESH:D007239', (48, 57))	('up-regulates', 'PosReg', (162, 174))	('retinoblastoma', 'Disease', (78, 92))	('expression', 'MPA', (222, 232))	('down-regulates', 'NegReg', (58, 72))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (109, 145))	('p16INK4', 'Var', (100, 107))	('RB1', 'Gene', (73, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (109, 145))	('O. viverrini', 'Species', '6198', (35, 47))	('retinoblastoma', 'Disease', 'MESH:D012175', (78, 92))
63046	27956028	Mutations in the tumor suppressor genes p53 and SMAD4 directly affect the related cellular signaling pathways p53 and TGF-b, which both are involved in tumorgenesis.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('affect', 'Reg', (63, 69))	('tumor', 'Disease', (17, 22))	('TGF-b', 'Gene', '7040', (118, 123))	('SMAD4', 'Gene', '4089', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('involved', 'Reg', (140, 148))	('tumor', 'Disease', (152, 157))	('p53', 'Gene', (40, 43))	('Mutations', 'Var', (0, 9))	('cellular signaling pathways p53', 'Pathway', (82, 113))	('SMAD4', 'Gene', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('TGF-b', 'Gene', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
63051	27956028	Pancreatic ducts may harbor C. sinensis, which can lead to squamous metaplasia and mucous gland hyperplasia, and a well-differentiated ductal adenocarcinoma of the pancreas.	('mucous gland hyperplasia', 'Disease', (83, 107))	('C. sinensis', 'Var', (28, 39))	('squamous metaplasia', 'Disease', (59, 78))	('lead to', 'Reg', (51, 58))	('C. sinensis', 'Species', '79923', (28, 39))	('squamous metaplasia', 'Phenotype', 'HP:0002860', (59, 78))	('mucous gland hyperplasia', 'Disease', 'MESH:D006965', (83, 107))	('squamous metaplasia', 'Disease', 'MESH:D008679', (59, 78))	('Pancreatic', 'Disease', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('Pancreatic', 'Disease', 'MESH:D010195', (0, 10))	('ductal adenocarcinoma of the pancreas', 'Disease', 'MESH:D021441', (135, 172))	('ductal adenocarcinoma of the pancreas', 'Disease', (135, 172))
63074	27956028	The chromosome translocation between the c-Myc oncogene and immunoglobulin (Ig) gene loci that leads to deregulation of c-Myc expression together with p53 gene mutations are known to be most relevant in the pathogenesis of Burkitt lymphoma.	('c-Myc', 'Gene', (120, 125))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (223, 239))	('c-Myc', 'Gene', '4609', (41, 46))	('mutations', 'Var', (160, 169))	('lymphoma', 'Phenotype', 'HP:0002665', (231, 239))	('c-Myc', 'Gene', (41, 46))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (223, 239))	('Burkitt lymphoma', 'Disease', (223, 239))	('c-Myc', 'Gene', '4609', (120, 125))	('deregulation', 'MPA', (104, 116))
63101	27956028	Providing a deeper insight into P. falciparum-induced EBV reactivation, a study has uncovered the mechanism that binding between latently EBV-infected B cells and the domain CIDR1alpha of the PfEMP1 protein directly switches the virus into lytic replication and CIDR1alpha stimulates EBV production in peripheral blood mononuclear cells (Fig.	('lytic replication', 'MPA', (240, 257))	('P. falciparum', 'Species', '5833', (32, 45))	('stimulates', 'PosReg', (273, 283))	('switches', 'Reg', (216, 224))	('EBV', 'Species', '10376', (138, 141))	('EBV production', 'MPA', (284, 298))	('EBV', 'Species', '10376', (284, 287))	('EBV', 'Species', '10376', (54, 57))	('CIDR1alpha', 'Var', (262, 272))	('binding', 'Interaction', (113, 120))	('PfEMP1', 'Gene', (192, 198))
63109	27956028	Earlier studies have shown that AID contributes to induce somatic mutations and DNA breaks in immunoglobulin genes and in oncogenes (c-Myc) that lead to c-Myc and IgH translocations.	('mutations', 'Var', (66, 75))	('lead to', 'Reg', (145, 152))	('c-Myc', 'Gene', '4609', (153, 158))	('c-Myc', 'Gene', '4609', (133, 138))	('c-Myc', 'Gene', (153, 158))	('IgH', 'Gene', '3492', (163, 166))	('IgH', 'Gene', (163, 166))	('c-Myc', 'Gene', (133, 138))	('immunoglobulin genes', 'Gene', (94, 114))
63113	27956028	Strongyloides stercoralis, an intestinal nematode, can cause strongyloidiasis and gastrointestinal ulcer.	('strongyloidiasis', 'Disease', (61, 77))	('strongyloidiasis', 'Disease', 'MESH:D013322', (61, 77))	('Strongyloides stercoralis', 'Var', (0, 25))	('gastrointestinal ulcer', 'Disease', 'MESH:D014456', (82, 104))	('Strongyloides stercoralis', 'Species', '6248', (0, 25))	('gastrointestinal ulcer', 'Disease', (82, 104))	('cause', 'Reg', (55, 60))	('gastrointestinal ulcer', 'Phenotype', 'HP:0004398', (82, 104))
63115	27956028	Approximately 50% of individuals chronically infected with S. stercoralis are asymptomatic while symptomatic forms may lead to severe skin pathology, diarrhea, nausea, and abdominal discomfort.	('S. stercoralis', 'Var', (59, 73))	('diarrhea', 'Phenotype', 'HP:0002014', (150, 158))	('S. stercoralis', 'Species', '6248', (59, 73))	('nausea', 'Phenotype', 'HP:0002018', (160, 166))	('diarrhea', 'Disease', (150, 158))	('severe skin pathology', 'Disease', (127, 148))	('lead to', 'Reg', (119, 126))	('diarrhea', 'Disease', 'MESH:D003967', (150, 158))	('abdominal discomfort', 'Disease', (172, 192))	('abdominal discomfort', 'Phenotype', 'HP:0002027', (172, 192))	('nausea', 'Disease', (160, 166))	('nausea', 'Disease', 'MESH:D009325', (160, 166))
63116	27956028	Infection with S. stercoralis may be complicated by autoinfection, which results in a hyperinfection syndrome and is associated with sustained infection, high worm burden and high mortality.	('infection', 'Disease', (91, 100))	('results in', 'Reg', (73, 83))	('infection', 'Disease', 'MESH:D007239', (91, 100))	('infection', 'Disease', (143, 152))	('associated', 'Reg', (117, 127))	('S. stercoralis', 'Var', (15, 29))	('infection', 'Disease', 'MESH:D007239', (143, 152))	('infection', 'Disease', (56, 65))	('infection', 'Disease', 'MESH:D007239', (56, 65))	('S. stercoralis', 'Species', '6248', (15, 29))	('hyperinfection syndrome', 'Disease', (86, 109))	('hyperinfection syndrome', 'Disease', 'MESH:D013577', (86, 109))
63118	27956028	A recent epidemiological study investigated the association of co-infection with S. stercoralis and HTLV-1 with cancers in a large cohort of 5209 cancer patients and showed that S. stercoralis infection was associated with an increased occurrence of cancers.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', (112, 118))	('infection', 'Disease', (66, 75))	('infection', 'Disease', 'MESH:D007239', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('S. stercoralis', 'Var', (178, 192))	('infection', 'Disease', (193, 202))	('S. stercoralis', 'Species', '6248', (178, 192))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('infection', 'Disease', 'MESH:D007239', (193, 202))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancers', 'Disease', 'MESH:D009369', (250, 257))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('HTLV-1', 'Gene', (100, 106))	('HTLV-1', 'Species', '11908', (100, 106))	('cancers', 'Disease', (112, 119))	('S. stercoralis', 'Species', '6248', (81, 95))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('patients', 'Species', '9606', (153, 161))	('cancers', 'Phenotype', 'HP:0002664', (250, 257))	('cancers', 'Disease', (250, 257))	('cancer', 'Disease', (250, 256))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))
63138	27956028	A study examined cytogenetic alterations in patients with chagasic megaesophagus and observed aneuploidies of chromosomes 7, 11, and 17 in 60% and the deletion of the oncogene p53 in 54.5% of 20 study patients; this might increase the risk of tumor development.	('patients', 'Species', '9606', (201, 209))	('tumor', 'Disease', (243, 248))	('patients', 'Species', '9606', (44, 52))	('p53', 'Gene', (176, 179))	('rat', 'Species', '10116', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('deletion', 'Var', (151, 159))	('increase', 'PosReg', (222, 230))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('aneuploidies', 'Var', (94, 106))
63139	27956028	While point mutations in exonic regions of p53, FHIT (fragile histidine triad gene) and CDKN2A (cyclin-dependent kinase Inhibitor 2A) genes or genomic imbalances were not frequent in chagasic megaesophagus, a silent mutation in exon7 of the FHIT gene and copy numbers of the CDKN2A and CEP9 (C-terminally encoded peptide 9) genes might be involved in esophageal carcinogenesis.	('CDKN2A', 'Gene', (88, 94))	('CDKN2A', 'Gene', '1029', (275, 281))	('CEP9', 'Gene', (286, 290))	('fragile histidine triad gene', 'Gene', '2272', (54, 82))	('CDKN2A', 'Gene', '1029', (88, 94))	('involved', 'Reg', (339, 347))	('cyclin-dependent kinase Inhibitor 2A', 'Gene', (96, 132))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (351, 376))	('imbalances', 'Phenotype', 'HP:0002172', (151, 161))	('fragile histidine triad gene', 'Gene', (54, 82))	('esophageal carcinogenesis', 'Disease', (351, 376))	('FHIT', 'Gene', (241, 245))	('FHIT', 'Gene', (48, 52))	('cyclin-dependent kinase Inhibitor 2A', 'Gene', '1029', (96, 132))	('CDKN2A', 'Gene', (275, 281))	('FHIT', 'Gene', '2272', (48, 52))	('FHIT', 'Gene', '2272', (241, 245))	('silent mutation in', 'Var', (209, 227))
63157	27956028	A study utilized the attenuated T. cruzi CL-14 clone to express exogenously a cancer testis antigen (NY-ESO-1) and showed that T. cruzi parasites expressing NY-ESO-1 were able to induce strong NY-ESO-1 specific immune responses both in-vitro and in-vivo.	('NY-ESO-1', 'Var', (157, 165))	('cancer testis', 'Disease', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer testis', 'Phenotype', 'HP:0010788', (78, 91))	('CL-14', 'Disease', 'OMIM:615513', (41, 46))	('induce', 'PosReg', (179, 185))	('T. cruzi', 'Species', '5693', (127, 135))	('cancer testis', 'Disease', 'MESH:D013736', (78, 91))	('CL-14', 'Disease', (41, 46))	('T. cruzi', 'Species', '5693', (32, 40))
63166	27956028	In addition, the mechanisms by which S. stercoralis can induce malignancy together with HTLV-1 and/or directly induce carcinogenesis require further studies.	('carcinogenesis', 'Disease', (118, 132))	('malignancy', 'Disease', 'MESH:D009369', (63, 73))	('induce', 'Reg', (111, 117))	('malignancy', 'Disease', (63, 73))	('S. stercoralis', 'Var', (37, 51))	('S. stercoralis', 'Species', '6248', (37, 51))	('induce', 'PosReg', (56, 62))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))	('HTLV-1', 'Species', '11908', (88, 94))
63325	33376403	The multivariate analysis revealed that poor pathological differentiation (P=0.006; moderate vs well, odds ratio [OR]=2.162, 95% confidence interval [CI] 0.753-6.208, P=0.152; poor vs well, OR=4.839, 95% CI 1.544-15.170, P=0.007), perineural invasion (OR=4.797, 95% CI 1.586-14.510, P=0.005), and high levels of preoperative carbohydrate antigen 19-9 (CA19-9) (OR=2.205, 95% CI 1.208-4.026, P=0.010) were independent risk factors of developing ER after resection.	('ER', 'Gene', '2069', (444, 446))	('CA19-9', 'Chemical', 'MESH:C086528', (352, 358))	('perineural invasion', 'CPA', (231, 250))	('carbohydrate', 'Chemical', 'MESH:D002241', (325, 337))	('poor', 'Var', (40, 44))
63331	33376403	Identification of driver alterations, earlier diagnosis of cancer, monitoring of treatment response, and exploration of resistance mechanisms are crucial to cancer management.	('alterations', 'Var', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
63405	33376403	The univariate analysis demonstrated that patients with positive margin status, high levels of ALP, presence of cholelithiasis, and vascular invasion had poorer OS outcomes, whereas patients that received adjuvant chemotherapy had significantly better OS outcomes.	('cholelithiasis', 'Phenotype', 'HP:0001081', (112, 126))	('ALP', 'Gene', (95, 98))	('vascular invasion', 'CPA', (132, 149))	('cholelithiasis', 'Disease', (112, 126))	('cholelithiasis', 'Disease', 'MESH:D002769', (112, 126))	('patients', 'Species', '9606', (182, 190))	('high levels of ALP', 'Phenotype', 'HP:0003155', (80, 98))	('ALP', 'Gene', '250', (95, 98))	('patients', 'Species', '9606', (42, 50))	('high', 'Var', (80, 84))	('poorer', 'NegReg', (154, 160))
63434	33376403	In this analysis, perineural invasion, pathological differentiation, and high levels of preoperative CA19-9 were identified as independent risk factors for ER of tumors after resection.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('perineural invasion', 'CPA', (18, 37))	('ER', 'Gene', '2069', (156, 158))	('CA19-9', 'Chemical', 'MESH:C086528', (101, 107))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('high', 'Var', (73, 77))
63469	28240521	For patients with the cystic variant and micro-papillary IPNB, there were no tumor-related deaths within 3 years of surgery and median survival was not reached during the follow-up.	('death', 'Disease', 'MESH:D003643', (91, 96))	('death', 'Disease', (91, 96))	('micro-papillary', 'Var', (41, 56))	('IPNB', 'Chemical', '-', (57, 61))	('IPNB', 'Gene', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', (77, 82))
63613	28272287	On univariate Cox proportional hazard analysis, leukopenia at time of LT (WBC<3.500 per mm3) (HR, 4.63; 95% CI, 1.27-16.81; P=0.02) and high INR at time of LT (HR, 5.39; 95% CI, 1.38-18.10; P=0.02) were associated with increased risk of PTLD.	('leukopenia', 'Disease', (48, 58))	('leukopenia', 'Disease', 'MESH:D007970', (48, 58))	('high', 'Var', (136, 140))	('high INR', 'Phenotype', 'HP:0008151', (136, 144))	('PTLD', 'Disease', (237, 241))	('leukopenia', 'Phenotype', 'HP:0001882', (48, 58))	('PTLD', 'Disease', 'MESH:D008232', (237, 241))
63628	28272287	High NLR is a biomarker for chronic inflammation, which can predispose the individual to malignancy and can affect the host immune response .	('malignancy', 'Disease', (89, 99))	('inflammation', 'Disease', 'MESH:D007249', (36, 48))	('High', 'Var', (0, 4))	('affect', 'Reg', (108, 114))	('inflammation', 'Disease', (36, 48))	('host immune response', 'CPA', (119, 139))	('predispose', 'Reg', (60, 70))	('malignancy', 'Disease', 'MESH:D009369', (89, 99))
63744	26178761	Only the presence of micrometastases was identified as an independent predictive factor for survival in patients with pN0 hilar cholangiocarcinoma (Hazard ratio 2.43, 95 % confidence interval 1.16-5.10) (Tables 2).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (128, 146))	('pN0', 'Var', (118, 121))	('metastases', 'Disease', (26, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (122, 146))	('hilar cholangiocarcinoma', 'Disease', (122, 146))	('patients', 'Species', '9606', (104, 112))	('metastases', 'Disease', 'MESH:D009362', (26, 36))
63746	26178761	The current study was undertaken to improve tumor staging by identifying lymph node micrometastases in the pN0 group.	('pN0', 'Var', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('metastases', 'Disease', (89, 99))	('metastases', 'Disease', 'MESH:D009362', (89, 99))	('tumor', 'Disease', (44, 49))
63787	31892986	Kaplan-Meier survival analysis showed that ECC patients with positive Hapto and/or Gremlin1 expression survived significantly shorter than patients with negative Hapto and/or Gremlin1 expression.	('Hapto', 'Gene', (70, 75))	('shorter', 'NegReg', (126, 133))	('positive', 'Var', (61, 69))	('Gremlin1', 'Gene', '26585', (83, 91))	('expression', 'Var', (92, 102))	('patients', 'Species', '9606', (139, 147))	('Hapto', 'Gene', (162, 167))	('ECC', 'Disease', (43, 46))	('patients', 'Species', '9606', (47, 55))	('Gremlin1', 'Gene', (175, 183))	('Gremlin1', 'Gene', (83, 91))	('Gremlin1', 'Gene', '26585', (175, 183))	('Hapto', 'Gene', '3240', (70, 75))	('Hapto', 'Gene', '3240', (162, 167))
63789	31892986	Conclusion: The present study indicated that positive Hapto and/or Gremlin1 expression are closely associated with the pathogenesis, clinical, pathological and biological behaviors, and poor prognosis in ECC.	('Gremlin1', 'Gene', (67, 75))	('ECC', 'Disease', (204, 207))	('positive', 'Var', (45, 53))	('Hapto', 'Gene', '3240', (54, 59))	('Gremlin1', 'Gene', '26585', (67, 75))	('Hapto', 'Gene', (54, 59))	('associated', 'Reg', (99, 109))
63864	31892986	Kaplan-Meier survival curves demonstrated that average overall survival time for patients with Hapto or Gremlin1 positive expression was significantly lower than those with negative Hapto or Gremlin1 expression (P =0.000) (Figure 3).	('Gremlin1', 'Gene', (191, 199))	('Gremlin1', 'Gene', '26585', (104, 112))	('overall survival', 'MPA', (55, 71))	('Hapto', 'Gene', (182, 187))	('positive expression', 'Var', (113, 132))	('patients', 'Species', '9606', (81, 89))	('Gremlin1', 'Gene', '26585', (191, 199))	('lower', 'NegReg', (151, 156))	('Hapto', 'Gene', '3240', (95, 100))	('Gremlin1', 'Gene', (104, 112))	('Hapto', 'Gene', '3240', (182, 187))	('Hapto', 'Gene', (95, 100))
63885	31892986	Previous studies reported that serum Hapto can predict colorectal cancer hepatic metastasis and Hapto promotes colorectal cancer cell invasion, and high serum haptoglobin levels are closely associated with distant metastasis, lymphovascular involvement, lymph node metastasis and increasing tumor burden in bladder cancer.	('promotes', 'PosReg', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('colorectal cancer', 'Phenotype', 'HP:0003003', (55, 72))	('Hapto', 'Gene', (37, 42))	('haptoglobin', 'Gene', '3240', (159, 170))	('associated', 'Reg', (190, 200))	('colorectal cancer hepatic metastasis', 'Disease', 'MESH:D015179', (55, 91))	('lymph node metastasis', 'CPA', (254, 275))	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('high serum haptoglobin levels', 'Phenotype', 'HP:0020180', (148, 177))	('colorectal cancer', 'Disease', (111, 128))	('high', 'Var', (148, 152))	('distant metastasis', 'CPA', (206, 224))	('haptoglobin', 'Gene', (159, 170))	('Hapto', 'Gene', '3240', (96, 101))	('colorectal cancer', 'Disease', 'MESH:D015179', (55, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (307, 321))	('lymphovascular', 'Disease', (226, 240))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('Hapto', 'Gene', (96, 101))	('bladder cancer', 'Disease', (307, 321))	('bladder cancer', 'Disease', 'MESH:D001749', (307, 321))	('Hapto', 'Gene', '3240', (37, 42))	('colorectal cancer hepatic metastasis', 'Disease', (55, 91))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', (291, 296))
63888	31892986	In this study, we found similar results that positive Hapto expression negatively correlated with overall survival and positively correlated with mortality.	('mortality', 'Disease', (146, 155))	('positive', 'Var', (45, 53))	('Hapto', 'Gene', '3240', (54, 59))	('correlated', 'Reg', (82, 92))	('mortality', 'Disease', 'MESH:D003643', (146, 155))	('correlated', 'Reg', (130, 140))	('negatively', 'NegReg', (71, 81))	('Hapto', 'Gene', (54, 59))	('overall survival', 'CPA', (98, 114))
63900	31892986	Liu et al reported that knockdown Gremlin 1 inhibited cell proliferation, angiogenesis, and EMT in colon cancer.	('cell proliferation', 'CPA', (54, 72))	('colon cancer', 'Phenotype', 'HP:0003003', (99, 111))	('Gremlin 1', 'Gene', (34, 43))	('inhibited', 'NegReg', (44, 53))	('colon cancer', 'Disease', 'MESH:D015179', (99, 111))	('angiogenesis', 'CPA', (74, 86))	('colon cancer', 'Disease', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Gremlin 1', 'Gene', '26585', (34, 43))	('EMT', 'CPA', (92, 95))	('knockdown', 'Var', (24, 33))
63901	31892986	Gremlin 1 is involved in regulating colorectal cancer progression, and Davis et al reported that the colorectal cancer patients with high Gremlin 1 expression have significantly shorter disease-free survival compared with the patients with low Gremlin 1 expression.	('colorectal cancer', 'Disease', (36, 53))	('Gremlin 1', 'Gene', (0, 9))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('shorter', 'NegReg', (178, 185))	('Gremlin 1', 'Gene', '26585', (138, 147))	('high', 'Var', (133, 137))	('Gremlin 1', 'Gene', (244, 253))	('patients', 'Species', '9606', (226, 234))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (36, 53))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('Gremlin 1', 'Gene', (138, 147))	('disease-free survival', 'CPA', (186, 207))	('Gremlin 1', 'Gene', '26585', (0, 9))	('colorectal cancer', 'Disease', (101, 118))	('patients', 'Species', '9606', (119, 127))	('colorectal cancer', 'Disease', 'MESH:D015179', (36, 53))	('Gremlin 1', 'Gene', '26585', (244, 253))
63902	31892986	Moreover, Stao et al also found similar results that patients with a high Gremlin 1 mRNA expression have significantly poor prognosis of progression in cervical cancer.	('cervical cancer', 'Disease', (152, 167))	('cervical cancer', 'Disease', 'MESH:D002583', (152, 167))	('mRNA expression', 'MPA', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('patients', 'Species', '9606', (53, 61))	('poor', 'NegReg', (119, 123))	('Gremlin 1', 'Gene', '26585', (74, 83))	('high', 'Var', (69, 73))	('Gremlin 1', 'Gene', (74, 83))
63905	31892986	In the present study, the percentage of cases with positive Hapto and Gremlin1 over-expression was significantly higher in ECC patients with poor differentiation, lymph node metastasis, invasion of surrounding tissues/organs, TNM stage III/IV disease and no resection (biopsy only) than in patients with well differentiation, no lymph node metastasis, no invasion of surrounding tissues/organs, TNM stage I/II disease and radical resection (P<0.05 or P<0.01).	('lymph', 'Disease', (163, 168))	('Gremlin1', 'Gene', '26585', (70, 78))	('patients', 'Species', '9606', (290, 298))	('over-expression', 'PosReg', (79, 94))	('higher', 'PosReg', (113, 119))	('Hapto', 'Gene', '3240', (60, 65))	('ECC', 'Disease', (123, 126))	('patients', 'Species', '9606', (127, 135))	('Gremlin1', 'Gene', (70, 78))	('poor differentiation', 'Var', (141, 161))	('Hapto', 'Gene', (60, 65))
63909	31892986	In conclusion, Hapto and Gremlin1 are involved in the tumorigenesis and progression of ECC, and positive Hapto and Gremlin1 expression were associated with poor prognosis in patients with ECC.	('Hapto', 'Gene', '3240', (15, 20))	('Gremlin1', 'Gene', '26585', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('involved', 'Reg', (38, 46))	('Gremlin1', 'Gene', '26585', (115, 123))	('Gremlin1', 'Gene', (25, 33))	('positive', 'Var', (96, 104))	('Hapto', 'Gene', '3240', (105, 110))	('Hapto', 'Gene', (15, 20))	('ECC', 'Disease', (188, 191))	('expression', 'MPA', (124, 134))	('Hapto', 'Gene', (105, 110))	('patients', 'Species', '9606', (174, 182))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('Gremlin1', 'Gene', (115, 123))	('ECC', 'Disease', (87, 90))
63924	31038586	It has been demonstrated that MMPs-mediated degradation of extracellular matrix can lead to invasion and metastasis of tumor cells  , and abnormal expression of MMPs has prognostic significance in some human malignant tumors  .	('MMPs-mediated', 'Gene', (30, 43))	('degradation of extracellular matrix', 'MPA', (44, 79))	('lead to', 'Reg', (84, 91))	('invasion', 'CPA', (92, 100))	('human', 'Species', '9606', (202, 207))	('abnormal', 'Var', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('MMPs', 'Gene', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('metastasis of tumor cells', 'CPA', (105, 130))
63928	31038586	MMP-9 can attenuate the basement membrane of blood vessels and lymphatic vessels, allowing cancer cells to infiltrate directly into the vasculature to participate in tumor metastasis and invasion.	('attenuate', 'NegReg', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('participate', 'Reg', (151, 162))	('tumor metastasis', 'Disease', 'MESH:D009362', (166, 182))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('MMP-9', 'Var', (0, 5))	('invasion', 'CPA', (187, 195))	('tumor metastasis', 'Disease', (166, 182))
63935	31038586	Their study also found that although MMP-9 overexpression was not associated with patient clinicopathological parameters, overall survival was significantly lower in patients with high MMP-9 expression than in patients with negative or low MMP-9 expression, suggesting that the expression of MMP-9 in tissues is of great significance in the evaluation of postoperative prognosis of intrahepatic cholangiocarcinoma.	('overall survival', 'CPA', (122, 138))	('MMP-9', 'Gene', (185, 190))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (382, 413))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (395, 413))	('intrahepatic cholangiocarcinoma', 'Disease', (382, 413))	('expression', 'MPA', (191, 201))	('high', 'Var', (180, 184))	('lower', 'NegReg', (157, 162))
63940	27788482	Reg family proteins (Reg1A, 1B, 3A/G, 4) are a group of calcium-dependent lectins that promote islet growth in response to inflammation and/or injuries.	('calcium', 'Chemical', 'MESH:D002118', (56, 63))	('islet growth', 'CPA', (95, 107))	('Reg', 'Gene', (0, 3))	('3A/G', 'Var', (32, 36))	('Reg1A', 'Gene', '5967', (21, 26))	('Reg', 'Gene', (21, 24))	('Reg', 'Gene', '5967', (21, 24))	('promote', 'PosReg', (87, 94))	('Reg', 'Gene', '5967', (0, 3))	('inflammation', 'Disease', 'MESH:D007249', (123, 135))	('inflammation', 'Disease', (123, 135))	('3A/G', 'SUBSTITUTION', 'None', (32, 36))	('Reg1A', 'Gene', (21, 26))
63953	27788482	The activation of the K-ras oncogene and inactivation of tumor suppressor genes including CDKN2A and TP53, and transcriptional factor SMAD4/DPC4 have all been implicated.	('CDKN2A', 'Gene', '1029', (90, 96))	('DPC4', 'Gene', '4089', (140, 144))	('DPC4', 'Gene', (140, 144))	('TP53', 'Gene', '7157', (101, 105))	('inactivation', 'Var', (41, 53))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('SMAD4', 'Gene', (134, 139))	('K-ras', 'Gene', (22, 27))	('K-ras', 'Gene', '3845', (22, 27))	('TP53', 'Gene', (101, 105))	('SMAD4', 'Gene', '4089', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('CDKN2A', 'Gene', (90, 96))	('tumor', 'Disease', (57, 62))	('activation', 'PosReg', (4, 14))
63954	27788482	Recent studies suggest that PDAC can also derive from acinar-to-ductal metaplasia (ADM), with additional mutations in K-ras and TP53.	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('PDAC', 'Chemical', '-', (28, 32))	('metaplasia', 'Disease', (71, 81))	('K-ras', 'Gene', (118, 123))	('metaplasia', 'Disease', 'MESH:D008679', (71, 81))	('derive from', 'Reg', (42, 53))	('K-ras', 'Gene', '3845', (118, 123))	('mutations', 'Var', (105, 114))	('PDAC', 'Disease', (28, 32))	('PDAC', 'Phenotype', 'HP:0006725', (28, 32))
63984	27788482	Acinar cells treated with Reg3A exhibited increased duct-like cysts formation (19.3+-2.9% cysts per visual field), comparable with the positive control, TGF-alpha treated cells (26.5+-1.5%).	('increased', 'PosReg', (42, 51))	('TGF-alpha', 'Gene', '7039', (153, 162))	('TGF-alpha', 'Gene', (153, 162))	('Reg3A', 'Var', (26, 31))	('duct-like cysts formation', 'CPA', (52, 77))
64012	27788482	High grade PDAC with low levels of Reg1A and Reg1B showed a statistically significant lower survival rate after tumor resection, when compared to those with low grade PDAC and high levels of Reg1A and Reg1B (P<0.0001, P<0.001 and P<0.001, Figure 4D).	('Reg1B', 'Gene', (45, 50))	('Reg1A', 'Gene', (35, 40))	('Reg1A', 'Gene', '5967', (35, 40))	('Reg1B', 'Gene', (201, 206))	('PDAC', 'Chemical', '-', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('Reg1B', 'Gene', '5968', (45, 50))	('Reg1B', 'Gene', '5968', (201, 206))	('low levels', 'Var', (21, 31))	('lower', 'NegReg', (86, 91))	('Reg1A', 'Gene', (191, 196))	('Reg1A', 'Gene', '5967', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PDAC', 'Phenotype', 'HP:0006725', (11, 15))	('PDAC', 'Phenotype', 'HP:0006725', (167, 171))	('PDAC', 'Chemical', '-', (167, 171))	('tumor', 'Disease', (112, 117))	('survival rate', 'CPA', (92, 105))
64046	27788482	Clinically, low grade tumors tend to have larger tumor volumes when they are diagnosed, and consequently may have the capability to secrete more Reg proteins into the circulation.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('secrete', 'MPA', (132, 139))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('more', 'PosReg', (140, 144))	('Reg', 'Gene', (145, 148))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('low grade', 'Var', (12, 21))	('tumor', 'Disease', (22, 27))	('Reg', 'Gene', '5967', (145, 148))	('tumors', 'Disease', (22, 28))
64047	27788482	In our study population, patients with poorly differentiated PDAC and low levels of Reg1A and Reg1B demonstrated higher mortality than those with well to moderately differentiated PDAC and high levels of Reg1A and Reg1B.	('PDAC', 'Phenotype', 'HP:0006725', (180, 184))	('Reg1B', 'Gene', (94, 99))	('Reg1A', 'Gene', (204, 209))	('Reg1A', 'Gene', '5967', (84, 89))	('Reg1A', 'Gene', '5967', (204, 209))	('Reg1A', 'Gene', (84, 89))	('Reg1B', 'Gene', (214, 219))	('PDAC', 'Chemical', '-', (180, 184))	('PDAC', 'Phenotype', 'HP:0006725', (61, 65))	('Reg1B', 'Gene', '5968', (94, 99))	('low levels', 'Var', (70, 80))	('patients', 'Species', '9606', (25, 33))	('Reg1B', 'Gene', '5968', (214, 219))	('PDAC', 'Chemical', '-', (61, 65))
64048	27788482	The association between poor survival and high histological grade PDAC was established in previous studies.	('high histological', 'Var', (42, 59))	('PDAC', 'Disease', (66, 70))	('PDAC', 'Phenotype', 'HP:0006725', (66, 70))	('PDAC', 'Chemical', '-', (66, 70))
64086	27788482	Western blot was performed to determine the levels of phosphorylated and total Erk1/2 (sc-16982R and sc-154, Santa Cruz, TX, USA).	('sc-16982R', 'Var', (87, 96))	('Erk1/2', 'Gene', '5595;5594', (79, 85))	('Erk1/2', 'Gene', (79, 85))	('sc-154', 'Var', (101, 107))
64252	23884572	While FDG PET-CT can detect occult sites of disease not seen on conventional imaging, it may still fail to identify carcinomatosis due to reduced sensitivity in detection of sub-centimetre lesions (a recognised limitation of PET) and, in particular, small volume peritoneal disease.	('carcinomatosis', 'Disease', 'MESH:D002277', (116, 130))	('reduced', 'NegReg', (138, 145))	('small volume peritoneal disease', 'Disease', (250, 281))	('sub-centimetre lesions', 'Var', (174, 196))	('carcinomatosis', 'Disease', (116, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('FDG', 'Chemical', '-', (6, 9))
64274	23884572	In the study by Anderson et al., FDG-PET led to a change in surgical management in 30 % (11/36) of patients with suspected extra-hepatic cholangiocarcinoma due to detection of unsuspected metastases.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('FDG', 'Chemical', '-', (33, 36))	('extra-hepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (123, 155))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (137, 155))	('patients', 'Species', '9606', (99, 107))	('men', 'Species', '9606', (75, 78))	('FDG-PET', 'Var', (33, 40))	('extra-hepatic cholangiocarcinoma', 'Disease', (123, 155))	('metastases', 'Disease', (188, 198))	('change', 'Reg', (50, 56))	('metastases', 'Disease', 'MESH:D009362', (188, 198))
64285	23884572	We found a single false-positive in a patient with suspected peritoneal disease due to disseminated FDG uptake, however staging laparotomy was negative and appearances had been secondary to cholangitis and bile leak at the time of PET-CT. False-positive FDG uptake due to benign inflammatory causes is well recognised and a degree of caution has to be observed to avoid misinterpretation.	('FDG', 'Chemical', '-', (100, 103))	('FDG', 'Chemical', '-', (254, 257))	('peritoneal disease', 'Disease', (61, 79))	('cholangitis', 'Disease', 'MESH:D002761', (190, 201))	('False-positive', 'Var', (239, 253))	('patient', 'Species', '9606', (38, 45))	('due to', 'Reg', (80, 86))	('cholangitis', 'Phenotype', 'HP:0030151', (190, 201))	('cholangitis', 'Disease', (190, 201))
64309	18701500	Modulation of the leptin-mediated signal could be considered a valid tool for the prevention and treatment of cholangiocarcinoma.	('Modulation', 'Var', (0, 10))	('leptin-mediated signal', 'MPA', (18, 40))	('cholangiocarcinoma', 'Disease', (110, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (110, 128))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (110, 128))
64379	18701500	Moreover, the increase in leptin-induced ERK1/2 phosphorylation was blocked by the preincubation of tumoral cells with both AG490 and PD98059 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('increase in leptin', 'Phenotype', 'HP:0031793', (14, 32))	('PD98059', 'Chemical', 'MESH:C093973', (134, 141))	('tumor', 'Disease', (100, 105))	('PD98059', 'Var', (134, 141))	('blocked', 'NegReg', (68, 75))	('phosphorylation', 'MPA', (48, 63))	('AG490', 'Var', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('ERK1/2', 'Protein', (41, 47))	('AG490', 'Chemical', 'MESH:C095512', (124, 129))
64393	18701500	These animals, because of the faulty long isoform of leptin receptor due to this mutation, do not respond to the action of leptin in the hypothalamus and, therefore, become obese.	('obese', 'Gene', '25608', (173, 178))	('leptin receptor', 'Gene', (53, 68))	('not', 'NegReg', (94, 97))	('mutation', 'Var', (81, 89))	('leptin receptor', 'Gene', '3953', (53, 68))	('hypothalamus', 'Disease', (137, 149))	('hypothalamus', 'Disease', 'MESH:D007029', (137, 149))	('respond', 'MPA', (98, 105))	('obese', 'Gene', (173, 178))
64407	18701500	Immunoblotting analysis and immunohistochemical staining showed a higher expression of leptin protein in cholangiocarcinoma cells of thioacetamide-treated fa/fa obese Zucker compared with thioacetamide-treated lean Zucker rats (Fig.	('cholangiocarcinoma cells', 'Disease', 'MESH:D018281', (105, 129))	('thioacetamide', 'Chemical', 'MESH:D013853', (188, 201))	('thioacetamide', 'Chemical', 'MESH:D013853', (133, 146))	('cholangiocarcinoma cells', 'Disease', (105, 129))	('obese', 'Gene', (161, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (105, 123))	('obese', 'Gene', '25608', (161, 166))	('expression', 'MPA', (73, 83))	('higher', 'PosReg', (66, 72))	('leptin protein', 'Protein', (87, 101))	('thioacetamide-treated', 'Var', (133, 154))	('rats', 'Species', '10116', (222, 226))
64412	18701500	To strengthen the hypothesis that leptin plays an important role in the oncogenic process, we stimulated HuH-28 cholangiocarcinoma cells with leptin 40 ng/mL for 48 hours and we showed that leptin enhances the expression of c-Neu and COX-2 (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('enhances', 'PosReg', (197, 205))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('cholangiocarcinoma cells', 'Disease', 'MESH:D018281', (112, 136))	('HuH-28', 'CellLine', 'CVCL:2955', (105, 111))	('expression', 'MPA', (210, 220))	('cholangiocarcinoma cells', 'Disease', (112, 136))	('c-Neu', 'Protein', (224, 229))	('c-Neu', 'Chemical', '-', (224, 229))	('leptin', 'Var', (190, 196))	('COX-2', 'Gene', '4513', (234, 239))	('COX-2', 'Gene', (234, 239))
64415	18701500	We showed that in vitro: (a) leptin stimulates growth, migration, and prevents apoptosis of HuH-28 cholangiocarcinoma cells; (b) the enhancement of cholangiocarcinoma cell growth by leptin is associated with an increase of STAT-3 and ERK1/2 phosphorylation, without changes in p-AKT; moreover, in vivo (c) genetic ablation of leptin-mediated signaling inhibits cancer development and growth in an animal model of cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (148, 166))	('cholangiocarcinoma cells', 'Disease', 'MESH:D018281', (99, 123))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (99, 117))	('HuH-28', 'CellLine', 'CVCL:2955', (92, 98))	('cholangiocarcinoma', 'Disease', (148, 166))	('cholangiocarcinoma cells', 'Disease', (99, 123))	('STAT-3', 'Gene', (223, 229))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (148, 171))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (148, 166))	('cholangiocarcinoma', 'Disease', (99, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (422, 431))	('AKT', 'Gene', '207', (279, 282))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (99, 122))	('cancer', 'Disease', 'MESH:D009369', (361, 367))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (99, 117))	('cholangiocarcinoma cell', 'Disease', (148, 171))	('STAT-3', 'Gene', '6774', (223, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (413, 431))	('cholangiocarcinoma', 'Disease', (413, 431))	('rat', 'Species', '10116', (58, 61))	('genetic ablation', 'Var', (306, 322))	('cancer', 'Disease', (361, 367))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (413, 431))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('AKT', 'Gene', (279, 282))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('inhibits', 'NegReg', (352, 360))
64432	18701500	Furthermore, because preincubation with AG490, but not with PD98059, reduces p-STAT3 expression in cholangiocarcinoma cells after stimulation by leptin, and the increase of p-ERK1/2 consequent to leptin stimulation is blocked by both AG490 and PD98059, it is evident that JAK/STAT3 is upstream of ERK1/2.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('PD98059', 'Chemical', 'MESH:C093973', (60, 67))	('STAT3', 'Gene', (276, 281))	('cholangiocarcinoma cells', 'Disease', 'MESH:D018281', (99, 123))	('AG490', 'Var', (40, 45))	('AG490', 'Chemical', 'MESH:C095512', (40, 45))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (99, 117))	('reduces', 'NegReg', (69, 76))	('cholangiocarcinoma cells', 'Disease', (99, 123))	('STAT3', 'Gene', '6774', (79, 84))	('AG490', 'Chemical', 'MESH:C095512', (234, 239))	('PD98059', 'Chemical', 'MESH:C093973', (244, 251))	('STAT3', 'Gene', (79, 84))	('STAT3', 'Gene', '6774', (276, 281))
64449	18701500	Zucker fa/fa rats, because of a congenital mutation at long form of leptin receptor (OBRl), possess such receptor nonresponding to the circulating leptin.	('rats', 'Species', '10116', (13, 17))	('mutation', 'Var', (43, 51))	('OBR', 'Gene', (85, 88))	('OBR', 'Gene', '3953', (85, 88))	('leptin receptor', 'Gene', (68, 83))	('leptin receptor', 'Gene', '3953', (68, 83))
64451	18701500	We found that the inactivation of this receptor proper of the obese Zucker fa/fa rats induced a decrease in cholangiocarcinoma development and growth in these animals with respect to their correspondent lean controls.	('growth', 'CPA', (143, 149))	('decrease in cholangiocarcinoma development', 'Disease', 'MESH:D018281', (96, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('decrease in cholangiocarcinoma development', 'Disease', (96, 138))	('rats', 'Species', '10116', (81, 85))	('inactivation', 'Var', (18, 30))	('obese', 'Gene', (62, 67))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (108, 126))	('obese', 'Gene', '25608', (62, 67))
64456	18701500	Moreover, the immunohistochemical analysis of the liver specimens showed a higher expression of leptin protein in cholangiocarcinoma cells of thioacetamide-treated fa/fa Zucker compared with thioacetamide-treated lean Zucker rats.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (114, 132))	('expression', 'MPA', (82, 92))	('higher', 'PosReg', (75, 81))	('thioacetamide-treated', 'Var', (142, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('fa/fa', 'Var', (164, 169))	('thioacetamide', 'Chemical', 'MESH:D013853', (142, 155))	('cholangiocarcinoma cells', 'Disease', 'MESH:D018281', (114, 138))	('rats', 'Species', '10116', (225, 229))	('leptin protein', 'Protein', (96, 110))	('thioacetamide', 'Chemical', 'MESH:D013853', (191, 204))	('cholangiocarcinoma cells', 'Disease', (114, 138))
64548	30300991	TTF-1 positivity has also been reported in 85-95% of small cell lung carcinomas.	('small cell lung carcinomas', 'Disease', (53, 79))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (53, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('positivity', 'Var', (6, 16))	('small cell lung carcinomas', 'Disease', 'MESH:D055752', (53, 79))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (53, 79))	('TTF-1', 'Gene', '7080', (0, 5))	('TTF-1', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
64560	30300991	Both carcinomas are AFP-positive, but CK19 positivity is more frequent in metastatic hepatoid adenocarcinoma than in primary hepatocellular carcinoma.	('CK19', 'Gene', '3880', (38, 42))	('hepatoid adenocarcinoma', 'Disease', (85, 108))	('hepatoid adenocarcinoma', 'Phenotype', 'HP:0012028', (85, 108))	('hepatoid adenocarcinoma', 'Disease', 'MESH:D000230', (85, 108))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (125, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('hepatocellular carcinoma', 'Disease', (125, 149))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (125, 149))	('AFP', 'Gene', (20, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('AFP', 'Gene', '174', (20, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('frequent', 'Reg', (62, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (5, 15))	('positivity', 'Var', (43, 53))	('carcinomas', 'Disease', (5, 15))	('carcinomas', 'Disease', 'MESH:D002277', (5, 15))	('CK19', 'Gene', (38, 42))
64572	26735300	Inhibition of CaM activity in DISC stimulates apoptosis significantly.	('apoptosis', 'CPA', (46, 55))	('CaM', 'Gene', (14, 17))	('Inhibition', 'Var', (0, 10))	('stimulates', 'PosReg', (35, 45))	('CaM', 'Gene', '801', (14, 17))
64581	26735300	Alteration in apoptosis balance (enhancement or diminishment) is linked to various human diseases such as autoimmune and neurodegenerative disorders, and several types of cancers.	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (121, 148))	('linked', 'Reg', (65, 71))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (121, 148))	('neurodegenerative disorders', 'Disease', (121, 148))	('Alteration', 'Var', (0, 10))	('human', 'Species', '9606', (83, 88))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('apoptosis', 'MPA', (14, 23))	('diminishment', 'NegReg', (48, 60))	('cancers', 'Disease', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('autoimmune', 'Disease', 'MESH:D001327', (106, 116))	('autoimmune', 'Disease', (106, 116))
64587	26735300	Activated caspase-8 then cleaves and activates caspase-3, -6 and -7, which target cellular substrates and ultimately execute cell death.	('caspase-8', 'Gene', (10, 19))	('cleaves', 'Var', (25, 32))	('caspase-8', 'Gene', '841', (10, 19))	('caspase-3, -6 and -7', 'Gene', '836;839;840', (47, 67))	('activates', 'PosReg', (37, 46))
64592	26735300	Inhibition of CaM activity in the DISC stimulates apoptosis significantly.	('stimulates', 'PosReg', (39, 49))	('CaM', 'Gene', (14, 17))	('Inhibition', 'Var', (0, 10))	('CaM', 'Gene', '801', (14, 17))	('apoptosis', 'CPA', (50, 59))
64664	26735300	A recent study has shown that FasDD(214-238) binds to Ca2+/CaM with a much weaker affinity (Kd = 19.5 muM) than that observed for the full-length FasDD protein (Kd ~2 muM).	('214-238', 'Var', (36, 43))	('weaker', 'NegReg', (75, 81))	('muM', 'Gene', (102, 105))	('binds', 'Interaction', (45, 50))	('muM', 'Gene', (167, 170))	('FasDD', 'Chemical', '-', (30, 35))	('CaM', 'Gene', (59, 62))	('Ca2+', 'Chemical', 'MESH:D000069285', (54, 58))	('CaM', 'Gene', '801', (59, 62))	('muM', 'Gene', '56925', (102, 105))	('FasDD', 'Chemical', '-', (146, 151))	('muM', 'Gene', '56925', (167, 170))
64677	26735300	As identified by both exact mass measurements and tandem mass spectrometric sequencing, the most abundant peptides are located in the N-terminus (205-238, 205-239, and 205-240) and in the C-terminus (251-288, 259-288 and 262-288).	('205-240', 'Var', (168, 175))	('peptides', 'Chemical', 'MESH:D010455', (106, 114))	('205-239', 'Var', (155, 162))	('251-288', 'Var', (200, 207))	('205-238', 'Var', (146, 153))	('259-288', 'Var', (209, 216))
64700	26735300	As shown in Fig 4, fitting of the ITC data by a single set of identical sites model upon titration of Ca2+/CaM at 450 muM into Fas-Pep1 at 25 muM yielded the following thermodynamic parameters: Kd = 0.3 muM, n = 0.95, DeltaH  = 2.15 kcal/mol and DeltaS  = 37.1 cal/mol/K.	('DeltaH', 'Var', (218, 224))	('CaM', 'Gene', (107, 110))	('CaM', 'Gene', '801', (107, 110))	('muM', 'Gene', '56925', (203, 206))	('muM', 'Gene', '56925', (142, 145))	('muM', 'Gene', '56925', (118, 121))	('muM', 'Gene', (203, 206))	('muM', 'Gene', (142, 145))	('muM', 'Gene', (118, 121))	('Ca2+', 'Chemical', 'MESH:D000069285', (102, 106))	('Fas-Pep1', 'Chemical', '-', (127, 135))
64701	26735300	Likewise, fitting of the ITC data by a single set of identical sites model upon titration of Ca2+/CaM at 195 muM into Fas-Pep2 at 17 muM yielded the following thermodynamic parameters: Kd = 1.1 muM, n = 0.9, DeltaH  = -14.2 kcal/mol and DeltaS  = -18.8 cal/mol/K.	('muM', 'Gene', (133, 136))	('muM', 'Gene', '56925', (194, 197))	('muM', 'Gene', (109, 112))	('CaM', 'Gene', (98, 101))	('muM', 'Gene', '56925', (133, 136))	('Pep2', 'Chemical', '-', (122, 126))	('CaM', 'Gene', '801', (98, 101))	('Ca2+', 'Chemical', 'MESH:D000069285', (93, 97))	('Fas', 'Chemical', '-', (118, 121))	('muM', 'Gene', '56925', (109, 112))	('muM', 'Gene', (194, 197))	('DeltaH', 'Var', (208, 214))
64710	26735300	The most significant chemical shift changes (Deltadelta > 0.2 ppm) were observed for signals corresponding to residues A15, F19, G33, G54, V55, A57, I63, D64, F68, L69, T70, M71, M72, A73, K77, D78, T79, E84, I85, A88, F92, L105, H107, M109, T110, G113, K115, V121, I125, F141, V142, Q143, M144, and M145 (Fig 5).	('V121', 'Var', (260, 264))	('I125', 'Var', (266, 270))	('K115', 'Var', (254, 258))	('G33', 'Var', (129, 132))	('chemical shift', 'MPA', (21, 35))	('G54', 'Var', (134, 137))	('G113', 'Var', (248, 252))	('A15', 'Gene', '28934', (119, 122))	('A57', 'Var', (144, 147))	('T70', 'Var', (169, 172))	('D78', 'Var', (194, 197))	('F92', 'Var', (219, 222))	('I63', 'Var', (149, 152))	('L105', 'Var', (224, 228))	('I85', 'Var', (209, 212))	('K77', 'Gene', '374454', (189, 192))	('M144', 'Var', (290, 294))	('M71', 'Var', (174, 177))	('changes', 'Reg', (36, 43))	('M145', 'Var', (300, 304))	('V142', 'Var', (278, 282))	('Q143', 'Var', (284, 288))	('A88', 'Var', (214, 217))	('F19', 'Var', (124, 127))	('K77', 'Gene', (189, 192))	('M109', 'Var', (236, 240))	('A15', 'Gene', (119, 122))	('L69', 'Var', (164, 167))	('A73', 'Var', (184, 187))	('M72', 'Var', (179, 182))	('D64', 'Var', (154, 157))	('V55', 'Var', (139, 142))	('T79', 'Var', (199, 202))	('F68', 'Var', (159, 162))	('E84', 'Var', (204, 207))	('F141', 'Var', (272, 276))	('T110', 'Var', (242, 246))	('H107', 'Var', (230, 234))
64715	26735300	Among the numerous 1H-15N resonances that exhibited substantial chemical shift changes (Deltadelta > 0.2 ppm) are those corresponding to residues S17, F19, D20, V55, A57, E67, L69, T70, M71, M72, A73, K75, F92, H107, T110, V121, A128, F141, Q143, M144, and T146 (Fig 6).	('M71', 'Var', (186, 189))	('T110', 'Var', (217, 221))	('A73', 'Var', (196, 199))	('Q143', 'Var', (241, 245))	('M72', 'Var', (191, 194))	('S17', 'Var', (146, 149))	('F19', 'Var', (151, 154))	('K75', 'Gene', (201, 204))	('L69', 'Var', (176, 179))	('K75', 'Gene', '9119', (201, 204))	('H107', 'Var', (211, 215))	('A57', 'Var', (166, 169))	('E67', 'Var', (171, 174))	('T146', 'Var', (257, 261))	('1H-15N', 'Chemical', '-', (19, 25))	('F141', 'Var', (235, 239))	('V121', 'Var', (223, 227))	('A128', 'Var', (229, 233))	('M144', 'Var', (247, 251))	('F92', 'Var', (206, 209))	('V55', 'Var', (161, 164))	('D20', 'Var', (156, 159))	('T70', 'Var', (181, 184))
64718	26735300	Overall, the magnitude of shift changes caused by Fas-Pep1 are larger than those observed upon Fas-Pep2 binding (Fig 7) and most of the differences in CSPs upon Fas-Pep2 binding are observed in the central region of Ca2+/CaM (residues 50-90).	('CaM', 'Gene', (221, 224))	('Fas', 'Chemical', '-', (50, 53))	('Fas', 'Chemical', '-', (95, 98))	('Ca2+', 'Chemical', 'MESH:D000069285', (216, 220))	('Pep2', 'Chemical', '-', (99, 103))	('Pep2', 'Chemical', '-', (165, 169))	('CaM', 'Gene', '801', (221, 224))	('Fas-Pep1', 'Chemical', '-', (50, 58))	('Fas', 'Chemical', '-', (161, 164))	('Fas-Pep1', 'Var', (50, 58))	('shift', 'MPA', (26, 31))
64720	26735300	Residues perturbed by binding of Fas-Pep1 do not form a well-defined region but rather spread on both of the N- and C-terminal lobes and central linker, which suggests that Fas-Pep1 either engages a wide interface and/or induced a significant conformational change in the CaM protein.	('conformational change', 'MPA', (243, 264))	('engages', 'Reg', (189, 196))	('Fas-Pep1', 'Chemical', '-', (33, 41))	('Fas-Pep1', 'Chemical', '-', (173, 181))	('wide', 'Protein', (199, 203))	('CaM', 'Gene', (272, 275))	('Fas-Pep1', 'Var', (173, 181))	('induced', 'Reg', (221, 228))	('CaM', 'Gene', '801', (272, 275))
64747	26735300	Only residues 214-227 have been detected in the x-ray structure of Ca2+/CaM bound to FasDD(214-238); no electron density has been detected for residues 228-238.	('FasDD', 'Chemical', '-', (85, 90))	('214-238);', 'Var', (91, 100))	('CaM', 'Gene', (72, 75))	('Ca2+', 'Chemical', 'MESH:D000069285', (67, 71))	('CaM', 'Gene', '801', (72, 75))
64765	26735300	The most pronounced CSPs correspond to residues F12, K13, F16, D20, T34, L48, V55, D56, A57, E67, F68, L69, T70, M71, M72, and A73.	('D56', 'Var', (83, 86))	('K13', 'Gene', '3860', (53, 56))	('K13', 'Gene', (53, 56))	('T70', 'Var', (108, 111))	('E67', 'Var', (93, 96))	('L69', 'Var', (103, 106))	('V55', 'Var', (78, 81))	('F68', 'Var', (98, 101))	('D20', 'Var', (63, 66))	('A73', 'Var', (127, 130))	('M72', 'Var', (118, 121))	('L48', 'Var', (73, 76))	('T34', 'Var', (68, 71))	('M71', 'Var', (113, 116))	('F12', 'Gene', (48, 51))	('F12', 'Gene', '2161', (48, 51))	('A57', 'Var', (88, 91))	('F16', 'Var', (58, 61))
64781	26735300	Addition of a substoichiometric amount of Fas-Pep1 (0.5:1 peptide:Ca2+/CaM) led to a decrease in the intensity of 1H-13C signals of M51, M71, M72, M109, M124 and M145 (Fig 8B, upper panel).	('M145', 'Var', (162, 166))	('CaM', 'Gene', (71, 74))	('Fas-Pep1', 'Chemical', '-', (42, 50))	('13C', 'Chemical', '-', (117, 120))	('CaM', 'Gene', '801', (71, 74))	('Ca2+', 'Chemical', 'MESH:D000069285', (66, 70))	('1H-13C signals', 'MPA', (114, 128))	('M72', 'Var', (142, 145))	('decrease', 'NegReg', (85, 93))	('M51', 'Var', (132, 135))	('M124', 'Var', (153, 157))	('1H', 'Chemical', '-', (114, 116))	('intensity', 'MPA', (101, 110))	('M71', 'Var', (137, 140))	('M109', 'Var', (147, 151))	('Fas-Pep1', 'Gene', (42, 50))
64790	26735300	Our data (Fig 8), however, show that the He signals of M76 and M144 do not exhibit chemical shift changes upon binding of Fas-Pep1, suggesting that these three Met residues are not perturbed by Fas-Pep1 binding.	('M144', 'Var', (63, 67))	('Met', 'Chemical', 'MESH:D008715', (160, 163))	('Fas-Pep1', 'Chemical', '-', (194, 202))	('M76', 'Var', (55, 58))	('Fas-Pep1', 'Chemical', '-', (122, 130))
64818	26735300	The Ca2+/CaM protein adopts a collapsed conformation when bound to peptides with 1-5-10 or 1-8-14 motifs.	('Ca2+', 'Chemical', 'MESH:D000069285', (4, 8))	('bound', 'Interaction', (58, 63))	('CaM', 'Gene', '801', (9, 12))	('1-8-14 motifs', 'Var', (91, 104))	('1-5-10', 'Var', (81, 87))	('adopts', 'Reg', (21, 27))	('collapsed conformation', 'MPA', (30, 52))	('peptides', 'Chemical', 'MESH:D010455', (67, 75))	('CaM', 'Gene', (9, 12))
64897	25701818	However, the same viruses infected parental CC-LP-1 cells, however, their infection levels were increased following claudin-1 expression in this cellular background (Fig.	('CC-LP-1', 'Gene', (44, 51))	('increased', 'PosReg', (96, 105))	('claudin-1', 'Gene', (116, 125))	('expression', 'Var', (126, 136))	('viruses infected parental', 'Disease', (18, 43))	('CC-LP-1', 'Gene', '8495', (44, 51))	('viruses infected parental', 'Disease', 'MESH:D063129', (18, 43))	('infection levels', 'MPA', (74, 90))	('claudin-1', 'Gene', '9076', (116, 125))
64917	25701818	We confirmed that the infectivity of all HCVpp strains tested were claudin-1 dependent in 293T cells and expression of claudin-1 in CC-LP-1 cells significantly enhanced HCVpp entry.	('infectivity', 'MPA', (22, 33))	('claudin-1', 'Gene', '9076', (119, 128))	('CC-LP-1', 'Gene', '8495', (132, 139))	('claudin-1', 'Gene', (67, 76))	('expression', 'Var', (105, 115))	('HCVpp entry', 'MPA', (169, 180))	('293T', 'CellLine', 'CVCL:0063', (90, 94))	('HCVpp', 'Chemical', '-', (41, 46))	('claudin-1', 'Gene', (119, 128))	('CC-LP-1', 'Gene', (132, 139))	('HCVpp', 'Chemical', '-', (169, 174))	('claudin-1', 'Gene', '9076', (67, 76))	('enhanced', 'PosReg', (160, 168))
64930	25701818	Virus particles are secreted in association with apolipoproteins and ApoE expression enhances viral infectivity and virus particle production (; Hueging et al., 2013).	('expression', 'Var', (74, 84))	('ApoE', 'Gene', '348', (69, 73))	('viral infectivity', 'CPA', (94, 111))	('ApoE', 'Gene', (69, 73))	('enhances', 'PosReg', (85, 93))	('virus particle production', 'CPA', (116, 141))	('apolipoproteins', 'Gene', (49, 64))	('apolipoproteins', 'Gene', '348', (49, 64))
64947	25701818	The following primary antibodies were used: anti-CD81 (clone 2s131); (in house); anti-SRBI (gift from Pfizer); anti-claudin-1 (R&D Technologies); anti-occludin (Invitrogen); anti-NS5A-9E10 (C. Rice, Rockefeller University, NY); and anti-CK19 (Vector Laboratories).	('CK19', 'Gene', (237, 241))	('SRBI', 'Gene', '949', (86, 90))	('CD81', 'Gene', '975', (49, 53))	('Rice', 'Species', '4530', (193, 197))	('CK19', 'Gene', '3880', (237, 241))	('claudin-1', 'Gene', (116, 125))	('claudin-1', 'Gene', '9076', (116, 125))	('occludin', 'Gene', '100506658', (151, 159))	('CD81', 'Gene', (49, 53))	('SRBI', 'Gene', (86, 90))	('and', 'Var', (228, 231))	('occludin', 'Gene', (151, 159))
65031	18839982	Digestion of proteins from the cancer sample was carried out in the presence of H218O while the digestion of proteins from the corresponding normal was carried out in the presence of H216O.	('H218O', 'Var', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('H218O', 'Chemical', '-', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('H216O', 'Chemical', '-', (183, 188))	('cancer', 'Disease', (31, 37))
65045	18839982	The following parameters were used for searching the data: fixed modifications: carbamidomethyl modification of cysteines, variable modifications: oxidation of methionines, phosphorylation of serines, threonines and tyrosines, deamidation of asparagines, 18O modification of both C-terminal oxygen atoms on lysine and arginine residues.	('threonines', 'Chemical', 'MESH:D013912', (201, 211))	('tyrosines', 'Chemical', 'MESH:D014443', (216, 225))	('asparagines', 'Chemical', 'MESH:D001216', (242, 253))	('lysine', 'Chemical', 'MESH:D008239', (307, 313))	('oxidation', 'MPA', (147, 156))	('carbamidomethyl', 'Chemical', '-', (80, 95))	('cysteines', 'Chemical', 'MESH:D003545', (112, 121))	('threonines', 'MPA', (201, 211))	('18O modification', 'Var', (255, 271))	('serines', 'Chemical', 'MESH:D012694', (192, 199))	('deamidation', 'MPA', (227, 238))	('18O', 'Chemical', '-', (255, 258))	('methionines', 'Chemical', 'MESH:D008715', (160, 171))	('phosphorylation', 'MPA', (173, 188))	('methionines', 'MPA', (160, 171))	('oxygen', 'Chemical', 'MESH:D010100', (291, 297))	('arginine', 'Chemical', 'MESH:D001120', (318, 326))
65060	18839982	The adjacent bands from both normal and cancer were excised and in-gel trypsin digestion was carried out in the presence of H216O and H218O respectively (Figure 1).	('H218O', 'Chemical', '-', (134, 139))	('H216O', 'Var', (124, 129))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('H216O', 'Chemical', '-', (124, 129))	('cancer', 'Disease', (40, 46))	('H218O', 'Var', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
65097	18839982	Precluding complex formation between IRSp53 and EPS8 severely hampers cell motility and invasiveness of a cancer cell line.	('IRSp53', 'Gene', '10458', (37, 43))	('EPS8', 'Gene', (48, 52))	('EPS8', 'Gene', '2059', (48, 52))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('IRSp53', 'Gene', (37, 43))	('cancer', 'Disease', (106, 112))	('cell motility', 'CPA', (70, 83))	('hampers', 'NegReg', (62, 69))	('complex', 'Var', (11, 18))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
65105	18839982	CIB has also been shown to interact with presenilin-2, which is known to be mutated at high frequencies in familial Alzheimer disease cases.	('familial Alzheimer disease', 'Disease', (107, 133))	('CIB', 'Gene', (0, 3))	('mutated', 'Var', (76, 83))	('CIB', 'Gene', '10519', (0, 3))	('presenilin-2', 'Gene', (41, 53))	('presenilin-2', 'Gene', '5664', (41, 53))	('familial Alzheimer disease', 'Disease', 'MESH:D000544', (107, 133))	('familial Alzheimer disease', 'Phenotype', 'HP:0002511', (107, 133))
65171	32679791	The first phase III study in this field confirmed the highly significant effectiveness of ivosidenib in patients with isocitrate dehydrogenase 1 (IDH1) mutations, and promising results for pemigatinib in patients with fibroblast growth factor receptor 2 (FGFR2) fusions were obtained.	('isocitrate dehydrogenase 1', 'Gene', (118, 144))	('IDH1', 'Gene', (146, 150))	('isocitrate dehydrogenase 1', 'Gene', '3417', (118, 144))	('FGFR2', 'Gene', (255, 260))	('patients', 'Species', '9606', (204, 212))	('mutations', 'Var', (152, 161))	('IDH1', 'Gene', '3417', (146, 150))	('FGFR2', 'Gene', '2263', (255, 260))	('ivosidenib', 'Chemical', 'MESH:C000627630', (90, 100))	('patients', 'Species', '9606', (104, 112))	('pemigatinib', 'Chemical', '-', (189, 200))	('fibroblast growth factor receptor 2', 'Gene', '2263', (218, 253))	('fibroblast growth factor receptor 2', 'Gene', (218, 253))
65174	32679791	The tumor's mutational burden and the occurrence of specific genetic alterations (e.g., affecting tyrosine kinase signaling like FGFR, HER2, KRAS, FGFR2 fusions, or the IDH pathway, as well as chromatin-remodeling genes like ARID1A) correlate with the CCA's anatomic localization within the biliary tract system.	('tumor', 'Disease', (4, 9))	('KRAS', 'Gene', (141, 145))	('mutational', 'Var', (12, 22))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('IDH', 'Gene', '3417', (169, 172))	('ARID1A', 'Gene', (225, 231))	('FGFR2', 'Gene', (147, 152))	('HER2', 'Gene', '2064', (135, 139))	('CCA', 'Phenotype', 'HP:0030153', (252, 255))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('ARID1A', 'Gene', '8289', (225, 231))	('fusions', 'Var', (153, 160))	('FGFR2', 'Gene', '2263', (147, 152))	('CCA', 'Disease', (252, 255))	('tyrosine kinase signaling', 'MPA', (98, 123))	('FGFR', 'Gene', (129, 133))	('affecting', 'Reg', (88, 97))	('HER2', 'Gene', (135, 139))	('IDH', 'Gene', (169, 172))	('rat', 'Species', '10116', (73, 76))
65182	32679791	Its carcinogenic effect is mainly based on molecular mechanisms of chronic inflammation, such as oxidative deoxyribonucleotide acid (DNA) damage, DNA methylation, and modulation of microribonucleic acids (miRNAs), combined with persistent cell proliferation (e.g., due to loss of connexin 32).	('loss', 'NegReg', (272, 276))	('connexin 32', 'Gene', '2705', (280, 291))	('deoxyribonucleotide acid', 'Chemical', '-', (107, 131))	('carcinogenic', 'Disease', 'MESH:D063646', (4, 16))	('oxidative deoxyribonucleotide acid', 'MPA', (97, 131))	('carcinogenic', 'Disease', (4, 16))	('inflammation', 'Disease', 'MESH:D007249', (75, 87))	('inflammation', 'Disease', (75, 87))	('microribonucleic', 'Protein', (181, 197))	('connexin 32', 'Gene', (280, 291))	('modulation', 'Var', (167, 177))	('rat', 'Species', '10116', (251, 254))	('microribonucleic acids', 'Chemical', '-', (181, 203))
65183	32679791	From a molecular point of view, bile ducts display positivity for the hepatocyte growth factor, c-Met, TGF1, and ErbB2, which is similar to the human, highlighting the role of this model for examining CCA, though limited to rats.	('CCA', 'Disease', (201, 204))	('human', 'Species', '9606', (144, 149))	('c-Met', 'Gene', (96, 101))	('ErbB2', 'Gene', (113, 118))	('rats', 'Species', '10116', (224, 228))	('positivity', 'Var', (51, 61))	('hepatocyte growth factor', 'MPA', (70, 94))	('c-Met', 'Gene', '4233', (96, 101))	('TGF1', 'Gene', (103, 107))	('CCA', 'Phenotype', 'HP:0030153', (201, 204))	('ErbB2', 'Gene', '2064', (113, 118))
65188	32679791	TAA provokes a severe inflammatory response of the bile tract, coming along with an intense desmoplastic reaction, making this a valuable model to assess cholangio-carcinogenesis in vivo.	('TAA', 'Var', (0, 3))	('cholangio-carcinogenesis', 'Disease', (154, 178))	('cholangio-carcinogenesis', 'Disease', 'MESH:D063646', (154, 178))	('provokes', 'Reg', (4, 12))
65194	32679791	Whereas DEN is known to cause DNA adducts leading to cancer development, mice receiving either DMN or LMBDL alone do not develop CCA.	('DEN', 'Var', (8, 11))	('CCA', 'Phenotype', 'HP:0030153', (129, 132))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('mice', 'Species', '10090', (73, 77))	('DEN', 'Chemical', 'MESH:D004052', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('leading to', 'Reg', (42, 52))	('DMN', 'Chemical', 'MESH:D004128', (95, 98))
65195	32679791	Induction of chronic cholestasis accelerates progression of CCA, which goes along with the downregulation of miRNA-34a, the upregulation of miRNA-210, and the replacement of Mnt by c-Myc in binding to cyclin D1.	('cyclin D1', 'Gene', '595', (201, 210))	('upregulation', 'PosReg', (124, 136))	('downregulation', 'NegReg', (91, 105))	('cholestasis', 'Phenotype', 'HP:0001396', (21, 32))	('miRNA-34a', 'Gene', '407040', (109, 118))	('cyclin D1', 'Gene', (201, 210))	('replacement', 'Var', (159, 170))	('cholestasis', 'Disease', 'MESH:D002779', (21, 32))	('miRNA-34a', 'Gene', (109, 118))	('CCA', 'Disease', (60, 63))	('rat', 'Species', '10116', (39, 42))	('cholestasis', 'Disease', (21, 32))	('miRNA-210', 'Protein', (140, 149))	('c-Myc', 'Gene', '4609', (181, 186))	('binding', 'Interaction', (190, 197))	('CCA', 'Phenotype', 'HP:0030153', (60, 63))	('Mnt', 'Protein', (174, 177))	('c-Myc', 'Gene', (181, 186))
65199	32679791	In human CCA, the TP53 gene mutations occur at a rate of 3-45%.	('TP53', 'Gene', '7157', (18, 22))	('CCA', 'Disease', (9, 12))	('human', 'Species', '9606', (3, 8))	('CCA', 'Phenotype', 'HP:0030153', (9, 12))	('TP53', 'Gene', (18, 22))	('rat', 'Species', '10116', (49, 52))	('mutations', 'Var', (28, 37))
65200	32679791	CCl4 is a hepatotoxin that is associated with the release of reactive oxygen species.	('hepatotoxin', 'Disease', (10, 21))	('hepatotoxin', 'Disease', 'None', (10, 21))	('CCl4', 'Var', (0, 4))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (61, 84))
65203	32679791	Invasive CCA occurred in about 55% of p53-/- mice and 20% of p53+/- mice.	('mice', 'Species', '10090', (68, 72))	('Invasive CCA', 'Disease', (0, 12))	('mice', 'Species', '10090', (45, 49))	('p53-/-', 'Var', (38, 44))	('CCA', 'Phenotype', 'HP:0030153', (9, 12))
65205	32679791	On a molecular level, CCA from the p53 knockout CCl4 model resemble that of human CCA.	('CCA', 'Phenotype', 'HP:0030153', (82, 85))	('p53', 'Gene', (35, 38))	('knockout', 'Var', (39, 47))	('CCA', 'Disease', (22, 25))	('human', 'Species', '9606', (76, 81))	('CCA', 'Disease', (82, 85))	('CCA', 'Phenotype', 'HP:0030153', (22, 25))
65212	32679791	A new monoclonal antibody was generated that specifically detects the so-called S121 antigen in patient tissue and sera, which is highly increased in CCA patients.	('patient', 'Species', '9606', (154, 161))	('S121', 'Var', (80, 84))	('patient', 'Species', '9606', (96, 103))	('patients', 'Species', '9606', (154, 162))	('CCA', 'Disease', (150, 153))	('increased', 'PosReg', (137, 146))	('rat', 'Species', '10116', (34, 37))	('CCA', 'Phenotype', 'HP:0030153', (150, 153))
65213	32679791	A time course experiment, in which CCA was induced by a combination of O. viverrini and N-nitrosodimethamine in hamsters, suggested that S121 antibody could serve as an early detection marker for CCA.	('CCA', 'Phenotype', 'HP:0030153', (196, 199))	('CCA', 'Phenotype', 'HP:0030153', (35, 38))	('N-nitrosodimethamine', 'Chemical', '-', (88, 108))	('induced', 'Reg', (43, 50))	('S121 antibody', 'Var', (137, 150))	('O. viverrini', 'Species', '6198', (71, 83))	('hamster', 'Species', '10034', (112, 119))	('CCA', 'Disease', (196, 199))	('CCA', 'Disease', (35, 38))
65217	32679791	As tumors can arise spontaneously in fully immunocompetent GEM, these models mimic human CCA quite well, particularly CCA subtypes with a specific mutational pattern, and allow the study of stroma-associated responses towards tumor development at early or advanced stages.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Disease', (3, 8))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('human', 'Species', '9606', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('CCA', 'Disease', (89, 92))	('CCA', 'Phenotype', 'HP:0030153', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('CCA', 'Phenotype', 'HP:0030153', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', (226, 231))	('mutational', 'Var', (147, 157))
65222	32679791	In human CCA, different types of p53 mutations were described and their incidence was reported to be 21%.	('CCA', 'Disease', (9, 12))	('human', 'Species', '9606', (3, 8))	('mutations', 'Var', (37, 46))	('p53', 'Gene', (33, 36))	('CCA', 'Phenotype', 'HP:0030153', (9, 12))
65224	32679791	Most recently, the identification of IDH1 mutations and FGFR2 fusions resulted in a clinical breakthrough, implementing personalized therapies in these patients.	('FGFR2', 'Gene', '2263', (56, 61))	('FGFR2', 'Gene', (56, 61))	('IDH1', 'Gene', (37, 41))	('IDH1', 'Gene', '3417', (37, 41))	('fusions', 'Var', (62, 69))	('mutations', 'Var', (42, 51))	('patients', 'Species', '9606', (152, 160))
65226	32679791	described a murine model for CCA, which is based on the liver-specific deletion of both, Smad4 and Pten, by crossing mice carrying conditional Pten and Smad4 alleles with mice overexpressing a Cre recombinase controlled by an endogenous albumin promoter.	('mice', 'Species', '10090', (171, 175))	('murine', 'Species', '10090', (12, 18))	('Pten', 'Gene', (143, 147))	('Pten', 'Gene', (99, 103))	('CCA', 'Disease', (29, 32))	('Smad4', 'Gene', (152, 157))	('deletion', 'Var', (71, 79))	('mice', 'Species', '10090', (117, 121))	('Smad4', 'Gene', (89, 94))	('CCA', 'Phenotype', 'HP:0030153', (29, 32))
65227	32679791	Since AlbCre recombines loxP sites in precursor cells that might differentiate in both hepatocytes and cholangiocytes, Smad4 and Pten deletions occur in both of these cell types.	('Alb', 'Gene', '11657', (6, 9))	('Pten', 'Gene', (129, 133))	('deletions', 'Var', (134, 143))	('Alb', 'Gene', (6, 9))	('Smad4', 'Gene', (119, 124))
65228	32679791	In these mice, conditional knock-out of Smad4 and Pten is associated with significant hyperplasia of the bile ducts already at 8 weeks of age.	('hyperplasia', 'Disease', (86, 97))	('Pten', 'Gene', (50, 54))	('hyperplasia', 'Disease', 'MESH:D006965', (86, 97))	('Smad4', 'Gene', (40, 45))	('hyperplasia of the bile', 'Phenotype', 'HP:0006560', (86, 109))	('mice', 'Species', '10090', (9, 13))	('knock-out', 'Var', (27, 36))
65233	32679791	Mutations activating the oncogene KRAS are frequent in human CCA.	('CCA', 'Phenotype', 'HP:0030153', (61, 64))	('human', 'Species', '9606', (55, 60))	('CCA', 'Disease', (61, 64))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (34, 38))
65234	32679791	Ikenoue provided a murine model for CCA relying on the simultaneous Alb-Cre-driven activation of mutant KRAS and deletion of Pten.	('Alb', 'Gene', (68, 71))	('deletion', 'Var', (113, 121))	('CCA', 'Disease', (36, 39))	('murine', 'Species', '10090', (19, 25))	('mutant', 'Var', (97, 103))	('CCA', 'Phenotype', 'HP:0030153', (36, 39))	('Alb', 'Gene', '11657', (68, 71))	('Pten', 'Gene', (125, 129))	('KRAS', 'Gene', (104, 108))
65237	32679791	Notably, further studies using tamoxifen-regulatable promotors specific for hepatocytes or cholangiocytes revealed that in the described mutant KRAS/Pten mice, CCA originates from biliary cells.	('mice', 'Species', '10090', (154, 158))	('CCA', 'Disease', (160, 163))	('tamoxifen', 'Chemical', 'MESH:D013629', (31, 40))	('CCA', 'Phenotype', 'HP:0030153', (160, 163))	('mutant', 'Var', (137, 143))
65240	32679791	Mutations of p53 have been identified as a frequent event in human CCA.	('CCA', 'Disease', (67, 70))	('CCA', 'Phenotype', 'HP:0030153', (67, 70))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (13, 16))	('human', 'Species', '9606', (61, 66))
65241	32679791	In this context, O'Dell and colleagues generated mice harboring a conditionally activated KRAS mutation and Tp53 deletion to reflect iCCA.	('CCA', 'Phenotype', 'HP:0030153', (134, 137))	('deletion', 'Var', (113, 121))	('KRAS', 'Gene', (90, 94))	('Tp53', 'Gene', (108, 112))	('rat', 'Species', '10116', (43, 46))	('mice', 'Species', '10090', (49, 53))	('iCCA', 'Disease', (133, 137))	('activated', 'PosReg', (80, 89))	('mutation', 'Var', (95, 103))
65242	32679791	Homozygous mutant mice developed tumors already after 9 weeks and died after a median survival time of about 20 weeks.	('died', 'Disease', 'MESH:D003643', (66, 70))	('mutant', 'Var', (11, 17))	('died', 'Disease', (66, 70))	('mice', 'Species', '10090', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('developed', 'Reg', (23, 32))
65245	32679791	The specific deletion of adult hepatocytes using an adeno-associated vector under the hepatic-specific thyroid-binding globulin promoter (AAV8-TBG-Cre) revealed that mature hepatocytes do not undergo malignant transformation in the lack of an additional hepatic injury.	('deletion', 'Var', (13, 21))	('hepatic injury', 'Disease', (254, 268))	('hepatic injury', 'Disease', 'MESH:D056486', (254, 268))	('malignant transformation', 'CPA', (200, 224))
65247	32679791	These findings indicate that hepatocytes are sensitive to KRAS-Tp53-dependent carcinogenesis and can undergo a phenotypic switch to induce CCA development.	('carcinogenesis', 'Disease', 'MESH:D063646', (78, 92))	('CCA', 'Disease', (139, 142))	('carcinogenesis', 'Disease', (78, 92))	('KRAS-Tp53-dependent', 'Var', (58, 77))	('induce', 'PosReg', (132, 138))	('CCA', 'Phenotype', 'HP:0030153', (139, 142))
65249	32679791	Mutant IDH1/2 occurs in about 20% of human CCA, blocking hepatocyte differentiation from progenitor cells.	('blocking', 'NegReg', (48, 56))	('hepatocyte differentiation', 'MPA', (57, 83))	('IDH1/2', 'Gene', '3417;3418', (7, 13))	('CCA', 'Disease', (43, 46))	('human', 'Species', '9606', (37, 42))	('IDH1/2', 'Gene', (7, 13))	('Mutant', 'Var', (0, 6))	('CCA', 'Phenotype', 'HP:0030153', (43, 46))
65250	32679791	The mutant IDH1 inhibitor ivosidenib (approved for the treatment of AML patients with a susceptible IDH1 mutation) recently demonstrated efficacy in advanced CCA patients with an IDH1 mutation.	('patients', 'Species', '9606', (162, 170))	('mutation', 'Var', (105, 113))	('rat', 'Species', '10116', (131, 134))	('IDH1', 'Gene', '3417', (100, 104))	('IDH1', 'Gene', '3417', (11, 15))	('CCA', 'Phenotype', 'HP:0030153', (158, 161))	('AML', 'Disease', 'MESH:D015470', (68, 71))	('patients', 'Species', '9606', (72, 80))	('ivosidenib', 'Chemical', 'MESH:C000627630', (26, 36))	('IDH1', 'Gene', (179, 183))	('AML', 'Disease', (68, 71))	('IDH1', 'Gene', (100, 104))	('IDH1', 'Gene', '3417', (179, 183))	('IDH1', 'Gene', (11, 15))	('mutation', 'Var', (184, 192))
65251	32679791	demonstrated that mice simultaneously bearing a mutant IDH2 and activating KRAS mutation develop CK19-positive liver lesions with a high prevalence.	('CK19', 'Gene', '16669', (97, 101))	('IDH2', 'Gene', '269951', (55, 59))	('mutant', 'Var', (48, 54))	('CK19', 'Gene', (97, 101))	('mice', 'Species', '10090', (18, 22))	('rat', 'Species', '10116', (7, 10))	('KRAS', 'Gene', (75, 79))	('IDH2', 'Gene', (55, 59))	('mutation', 'Var', (80, 88))
65255	32679791	Overexpression of ErbB2 has been described in about 5-7% of human CCA, with much higher rates in gallbladder carcinoma.	('gallbladder carcinoma', 'Disease', (97, 118))	('CCA', 'Phenotype', 'HP:0030153', (66, 69))	('rat', 'Species', '10116', (88, 91))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (97, 118))	('ErbB2', 'Gene', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('Overexpression', 'Var', (0, 14))	('higher rates', 'PosReg', (81, 93))	('ErbB2', 'Gene', '2064', (18, 23))	('CCA', 'Disease', (66, 69))	('human', 'Species', '9606', (60, 65))
65256	32679791	In line with these data from human, mice overexpressing ArbB2 using the BK5 promoter developed gallbladder carcinoma in about 85% of cases at an extremely young age of 2-3 weeks.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (95, 116))	('ArbB2', 'Gene', (56, 61))	('gallbladder carcinoma', 'Disease', (95, 116))	('mice', 'Species', '10090', (36, 40))	('human', 'Species', '9606', (29, 34))	('overexpressing', 'Var', (41, 55))	('developed', 'PosReg', (85, 94))
65258	32679791	At the molecular level, BK-ErbB-2A demonstrated increased COX-2 levels and an increased activation of the MAPK pathway, which is also observed in human lesions.	('increased', 'PosReg', (48, 57))	('activation', 'PosReg', (88, 98))	('rat', 'Species', '10116', (42, 45))	('BK-ErbB-2A', 'Var', (24, 34))	('human', 'Species', '9606', (146, 151))	('COX-2', 'Gene', '4513', (58, 63))	('MAPK pathway', 'Pathway', (106, 118))	('COX-2', 'Gene', (58, 63))
65261	32679791	A role for Notch in the embryogenesis of the biliary tree was suggested, and aberrations in the Notch pathway were described in many patients with CCA.	('Notch pathway', 'Pathway', (96, 109))	('CCA', 'Phenotype', 'HP:0030153', (147, 150))	('rat', 'Species', '10116', (81, 84))	('patients', 'Species', '9606', (133, 141))	('described', 'Reg', (115, 124))	('aberrations', 'Var', (77, 88))	('CCA', 'Disease', (147, 150))
65263	32679791	developed a transgenic murine model with constitutive Notch overexpression in albumin-expressing cells (Notch1C:AlbCre) to demonstrate that aberrant Notch activity in hepatic progenitor cells promotes differentiation of these cells towards a biliary lineage, contributing to malignant transformation.	('Alb', 'Gene', (112, 115))	('contributing to', 'Reg', (259, 274))	('promotes', 'PosReg', (192, 200))	('Notch', 'Var', (149, 154))	('differentiation', 'CPA', (201, 216))	('murine', 'Species', '10090', (23, 29))	('aberrant Notch', 'Var', (140, 154))	('rat', 'Species', '10116', (130, 133))	('Alb', 'Gene', '11657', (112, 115))	('malignant transformation', 'CPA', (275, 299))
65272	32679791	In brief, they injected a transposon plasmid encoding for mutant KRas-G12V into p53-knock-out mice (p53fl/fl mice and co-delivery of a plasmid for Cre-recombinase) directly into the liver.	('mutant', 'Var', (58, 64))	('G12V', 'Mutation', 'rs121913529', (70, 74))	('mice', 'Species', '10090', (94, 98))	('KRas', 'Gene', (65, 69))	('mice', 'Species', '10090', (109, 113))	('KRas', 'Gene', '16653', (65, 69))
65273	32679791	Subsequent electroporation led to CCA development in all animals within 3-5 weeks, demonstrating the oncogenic potential of KRas-G12V on the background of genetic p53 knock-out.	('led to', 'Reg', (27, 33))	('CCA', 'Phenotype', 'HP:0030153', (34, 37))	('G12V', 'Mutation', 'rs121913529', (129, 133))	('KRas', 'Gene', '16653', (124, 128))	('KRas', 'Gene', (124, 128))	('rat', 'Species', '10116', (20, 23))	('CCA development', 'CPA', (34, 49))	('electroporation', 'Var', (11, 26))	('rat', 'Species', '10116', (90, 93))
65282	32679791	In this context, decreased growth of CCA cells was associated with miRNA-494 upregulation, while an increased tumor growth was observed when miRNA-26a, miRNA-17, miRNA-92, and miRNA-320 were upregulated.	('miRNA-92', 'Gene', '407047', (162, 170))	('growth', 'CPA', (27, 33))	('decreased', 'NegReg', (17, 26))	('miRNA-17', 'Gene', '406952', (152, 160))	('CCA', 'Disease', (37, 40))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('decreased growth', 'Phenotype', 'HP:0001510', (17, 33))	('upregulation', 'PosReg', (77, 89))	('CCA', 'Phenotype', 'HP:0030153', (37, 40))	('miRNA-92', 'Gene', (162, 170))	('miRNA-17', 'Gene', (152, 160))	('miRNA-494', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
65289	32679791	BDEneu cells, with a mutation of the rat neu oncogene, have similar characteristics compared to human disease, e.g., expression of tumor necrosis factor-related apoptosis-inducing ligand, polo-like kinase 2, and hedgehog pathway activation.	('hedgehog pathway', 'Pathway', (212, 228))	('polo-like kinase 2', 'Gene', '10769', (188, 206))	('tumor necrosis', 'Disease', 'MESH:D009336', (131, 145))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('human', 'Species', '9606', (96, 101))	('rat', 'Species', '10116', (37, 40))	('polo-like kinase 2', 'Gene', (188, 206))	('activation', 'PosReg', (229, 239))	('mutation', 'Var', (21, 29))	('tumor necrosis', 'Disease', (131, 145))	('neu', 'Gene', (41, 44))
65410	30448774	In a case that the mis-classification of statin use is nondifferential by case-control status, statin may actually have an even more significant risk reduction on BTCs than currently observed in this study.	('reduction', 'NegReg', (150, 159))	('BTC', 'Gene', (163, 166))	('BTC', 'Gene', '685', (163, 166))	('statin', 'Var', (95, 101))
65477	25435907	We also briefly review the current knowledge of the genomics of cholangiocarcinoma with a focus on BRAF mutations, and make a point of the importance of the establishment of a molecular tumour board for personalized genomic medicine approaches.	('tumour board', 'Disease', (186, 198))	('mutations', 'Var', (104, 113))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (64, 82))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('BRAF', 'Gene', (99, 103))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('tumour board', 'Disease', 'MESH:D009369', (186, 198))	('cholangiocarcinoma', 'Disease', (64, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
65508	25435907	Since the genomic loci targeted in this assay are enriched using loci-specific primers, patient variants existing within those primer sequences may also cause a region to fail enrichment and therefore not achieve 250x coverage.	('patient', 'Species', '9606', (88, 95))	('enrichment', 'MPA', (176, 186))	('variants', 'Var', (96, 104))
65509	25435907	This analysis reported a mutation in BRAF p.V600E c.1799T > A (8819 reads out of a total 16,712 sequence reads for an allele frequency of 52.77).	('p.V600E', 'Mutation', 'rs113488022', (42, 49))	('BRAF', 'Gene', (37, 41))	('p.V600E c.1799T > A', 'Var', (42, 61))	('c.1799T > A', 'Mutation', 'rs113488022', (50, 61))
65529	25435907	The most commonly described activating mutations in ICC genomic studies are KRAS, HER2, MET, as well as hotspot activating missense mutations in genes downstream to epidermal growth factor receptor (EGFR), such as the v-raf murine sarcoma viral oncogene homolog B1 gene (BRAF).	('epidermal growth factor receptor', 'Gene', (165, 197))	('EGFR', 'Gene', (199, 203))	('epidermal growth factor receptor', 'Gene', '13649', (165, 197))	('activating', 'PosReg', (28, 38))	('missense mutations', 'Var', (123, 141))	('KRAS', 'Var', (76, 80))	('mutations', 'Var', (39, 48))	('HER2', 'Gene', (82, 86))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (218, 264))	('BRAF', 'Gene', (271, 275))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', (218, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (231, 238))	('HER2', 'Gene', '13866', (82, 86))
65530	25435907	Mutant BRAF has been implicated in the pathogenesis of many cancers; however, it can also be seen in benign conditions.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('implicated', 'Reg', (21, 31))	('Mutant', 'Var', (0, 6))	('BRAF', 'Gene', (7, 11))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
65531	25435907	A majority of mutations in BRAF occur at codon 600 with the most common changes, including V600E, V600K, and V600R.	('V600K', 'Mutation', 'rs121913227', (98, 103))	('V600E', 'Mutation', 'rs113488022', (91, 96))	('V600K', 'Var', (98, 103))	('V600R', 'Mutation', 'rs121913227', (109, 114))	('V600E', 'Var', (91, 96))	('BRAF', 'Gene', (27, 31))	('V600R', 'Var', (109, 114))
65532	25435907	Other missense substitutions have also been reported, including rare mutations, such as K601E, L597R, and L597S.	('L597R', 'Mutation', 'rs121913366', (95, 100))	('L597S', 'Var', (106, 111))	('L597R', 'Var', (95, 100))	('K601E', 'Mutation', 'rs121913364', (88, 93))	('K601E', 'Var', (88, 93))	('L597S', 'Mutation', 'rs121913368', (106, 111))
65534	25435907	Mutations at exon 15 of BRAF were found in five patients (5 of 141; 4%).	('Mutations at', 'Var', (0, 12))	('BRAF', 'Gene', (24, 28))	('found', 'Reg', (34, 39))	('patients', 'Species', '9606', (48, 56))
65536	25435907	The mutational status of KRAS/ BRAF was significantly associated with poor prognosis, and the BRAF V600E mutation was present in 1/69 cases (1.5%).	('BRAF', 'Gene', (94, 98))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('KRAS/ BRAF', 'Gene', (25, 35))	('V600E', 'Var', (99, 104))	('mutational', 'Var', (4, 14))	('associated', 'Reg', (54, 64))
65538	25435907	Another study using genome-wide analysis and clinical correlation of chromosomal and transcriptional mutations in 34 biliary tract cancer specimens reported 2,354 genes with altered expression in ICC, revealing the exceptional diversity of mutational findings between individual patient specimens.	('mutations', 'Var', (101, 110))	('expression', 'MPA', (182, 192))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (117, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('patient', 'Species', '9606', (279, 286))	('biliary tract cancer', 'Disease', 'MESH:D001661', (117, 137))	('biliary tract cancer', 'Disease', (117, 137))	('altered', 'Reg', (174, 181))
65539	25435907	These were high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumour suppressor).	('SAV1 tumour', 'Disease', (182, 193))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('deletions', 'Var', (107, 116))	('SAV1 tumour', 'Disease', 'MESH:D009369', (182, 193))	('9p21.3', 'Var', (126, 132))
65543	25435907	Specific mutations in BRAF can stimulate this pathway, and the presence of a V600E or K mutation predicts responsiveness to BRAF inhibitors or MEK inhibition.	('MEK', 'Gene', (143, 146))	('MEK', 'Gene', '5609', (143, 146))	('V600E', 'Mutation', 'rs113488022', (77, 82))	('BRAF', 'Gene', (22, 26))	('stimulate', 'PosReg', (31, 40))	('V600E', 'Var', (77, 82))	('responsiveness', 'MPA', (106, 120))
65544	25435907	Three Food and Drug Administration (FDA)-approved agents have demonstrated significant clinical benefits and been approved for use in patients with metastatic melanoma harbouring BRAF mutations: the BRAF inhibitors dabrafenib and vemurafenib and the potent, highly specific inhibitor of MEK1/ MEK2 trametinib.	('melanoma', 'Disease', (159, 167))	('MEK1', 'Gene', '5604', (287, 291))	('vemurafenib', 'Chemical', 'MESH:D000077484', (230, 241))	('MEK1', 'Gene', (287, 291))	('mutations', 'Var', (184, 193))	('dabrafenib', 'Chemical', 'MESH:C561627', (215, 225))	('trametinib', 'Chemical', 'MESH:C560077', (298, 308))	('patients', 'Species', '9606', (134, 142))	('BRAF', 'Gene', (199, 203))	('MEK2', 'Gene', '5605', (293, 297))	('MEK2', 'Gene', (293, 297))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
65545	25435907	Inhibition of the MAP kinase pathway in patients whose tumours contain a V600 mutation in the BRAF gene using either a BRAF inhibitor or a MEK inhibitor is an important target in personalized medicine, particularly in tumours that do not respond to a systemic chemotherapy regimen, or when a standard treatment is not well defined.	('tumours', 'Disease', (55, 62))	('BRAF', 'Gene', (94, 98))	('tumours', 'Phenotype', 'HP:0002664', (218, 225))	('tumours', 'Disease', 'MESH:D009369', (218, 225))	('patients', 'Species', '9606', (40, 48))	('MAP kinase pathway', 'Pathway', (18, 36))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumours', 'Disease', (218, 225))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('MEK', 'Gene', (139, 142))	('MEK', 'Gene', '5609', (139, 142))	('V600', 'Var', (73, 77))	('tumours', 'Disease', 'MESH:D009369', (55, 62))
65546	25435907	When used as single agents, the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib demonstrated superior progression-free survival (PFS) versus chemotherapy in patients with BRAF V600E/K mutant metastatic melanoma.	('superior', 'PosReg', (104, 112))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('MEK', 'Gene', (66, 69))	('dabrafenib', 'Chemical', 'MESH:C561627', (47, 57))	('MEK', 'Gene', '5609', (66, 69))	('V600E', 'Var', (187, 192))	('V600E', 'SUBSTITUTION', 'None', (187, 192))	('trametinib', 'Chemical', 'MESH:C560077', (80, 90))	('patients', 'Species', '9606', (168, 176))	('melanoma', 'Disease', 'MESH:D008545', (213, 221))	('BRAF', 'Gene', (182, 186))	('melanoma', 'Disease', (213, 221))
65547	25435907	There seems to be an advantage in PFS and toxicity profile when a BRAF inhibitor and a MEK inhibitor are used in combinations, and studies indicate that there is a reduced incidence of skin toxicity, including the development of cutaneous squamous carcinoma associated with BRAF inhibition.	('skin toxicity', 'Disease', (185, 198))	('skin toxicity', 'Disease', 'MESH:D012871', (185, 198))	('BRAF', 'Gene', (274, 278))	('cutaneous squamous carcinoma', 'Disease', (229, 257))	('toxicity', 'Disease', 'MESH:D064420', (42, 50))	('PFS', 'MPA', (34, 37))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (239, 257))	('cutaneous squamous carcinoma', 'Phenotype', 'HP:0006739', (229, 257))	('advantage', 'PosReg', (21, 30))	('MEK', 'Gene', (87, 90))	('cutaneous squamous carcinoma', 'Disease', 'MESH:D002294', (229, 257))	('toxicity', 'Disease', (42, 50))	('MEK', 'Gene', '5609', (87, 90))	('inhibition', 'Var', (279, 289))	('toxicity', 'Disease', 'MESH:D064420', (190, 198))	('toxicity', 'Disease', (190, 198))	('reduced', 'NegReg', (164, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
65548	25435907	This presumably results from MEK inhibition that blocks the escape pathway and the subsequent paradoxical activation of the MAPK pathway.	('inhibition', 'Var', (33, 43))	('MEK', 'Gene', '5609', (29, 32))	('MAPK pathway', 'Pathway', (124, 136))	('escape pathway', 'Pathway', (60, 74))	('blocks', 'NegReg', (49, 55))	('activation', 'PosReg', (106, 116))	('MEK', 'Gene', (29, 32))
65550	25435907	In the phase III component of that trial, 423 patients with unresectable or metastatic BRAF V600E/K mutant melanoma were randomly assigned to dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily; n = 211) or dabrafenib plus placebo (n = 212).	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('patients', 'Species', '9606', (46, 54))	('dabrafenib', 'Chemical', 'MESH:C561627', (142, 152))	('V600E', 'SUBSTITUTION', 'None', (92, 97))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('trametinib', 'Chemical', 'MESH:C560077', (179, 189))	('V600E', 'Var', (92, 97))	('BRAF', 'Gene', (87, 91))	('dabrafenib', 'Chemical', 'MESH:C561627', (220, 230))
65557	25435907	Based on the aforementioned, for patients suffering from metastatic BRAF V600E/K mutant malignancies who are ineligible for clinical trials and who are candidates for targeted therapy, it seems biologically advantageous to start with the combination of dabrafenib and trametinib rather than a single agent.	('patients', 'Species', '9606', (33, 41))	('malignancies', 'Disease', (88, 100))	('V600E', 'Var', (73, 78))	('dabrafenib', 'Chemical', 'MESH:C561627', (253, 263))	('trametinib', 'Chemical', 'MESH:C560077', (268, 278))	('V600E', 'SUBSTITUTION', 'None', (73, 78))	('malignancies', 'Disease', 'MESH:D009369', (88, 100))
65569	32378752	Long noncoding RNA ANRIL promotes the malignant progression of cholangiocarcinoma by epigenetically repressing ERRFI1 expression Long noncoding RNAs (lncRNAs) have recently been verified to have significant regulatory functions in many types of human cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('epigenetically', 'Var', (85, 99))	('ANRIL', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('promotes', 'PosReg', (25, 33))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (63, 81))	('cholangiocarcinoma', 'Disease', (63, 81))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('malignant progression', 'CPA', (38, 59))	('cancers', 'Disease', (251, 258))	('human', 'Species', '9606', (245, 250))	('ANRIL', 'Gene', '100048912', (19, 24))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (63, 81))	('cancers', 'Disease', 'MESH:D009369', (251, 258))	('ERRFI1', 'Gene', '54206', (111, 117))	('ERRFI1', 'Gene', (111, 117))	('expression', 'MPA', (118, 128))
65572	32378752	Our data show that ANRIL knockdown greatly inhibited CCA cell proliferation and migration in vitro and in vivo.	('ANRIL', 'Gene', (19, 24))	('inhibited', 'NegReg', (43, 52))	('migration', 'CPA', (80, 89))	('CCA', 'Disease', (53, 56))	('ANRIL', 'Gene', '100048912', (19, 24))	('knockdown', 'Var', (25, 34))	('CCA', 'Phenotype', 'HP:0030153', (53, 56))
65573	32378752	According to the results of RNA sequencing analysis, ANRIL knockdown dramatically altered target genes associated with the cell cycle, cell proliferation, and apoptosis.	('cell cycle', 'CPA', (123, 133))	('ANRIL', 'Gene', (53, 58))	('cell proliferation', 'CPA', (135, 153))	('ANRIL', 'Gene', '100048912', (53, 58))	('knockdown', 'Var', (59, 68))	('altered', 'Reg', (82, 89))
65576	32378752	These data verified the key role of the epigenetic regulation of ANRIL in CCA oncogenesis and indicate its potential as a target for CCA intervention.	('ANRIL', 'Gene', '100048912', (65, 70))	('CCA', 'Disease', (74, 77))	('epigenetic regulation', 'Var', (40, 61))	('ANRIL', 'Gene', (65, 70))	('CCA', 'Phenotype', 'HP:0030153', (74, 77))	('CCA', 'Phenotype', 'HP:0030153', (133, 136))
65578	32378752	Mechanistic investigations indicated that ANRIL could inhibit the expression of ERRFI1 by directly binding to EZH2, which mediated H3K27me3 in the promoter region of ERRFI1, thus accelerating CCA tumorigenesis.	('H3K27me3', 'Var', (131, 139))	('ERRFI1', 'Gene', '54206', (166, 172))	('ERRFI1', 'Gene', (166, 172))	('CCA', 'Phenotype', 'HP:0030153', (192, 195))	('inhibit', 'NegReg', (54, 61))	('accelerating', 'PosReg', (179, 191))	('ANRIL', 'Gene', '100048912', (42, 47))	('CCA tumor', 'Disease', (192, 201))	('CCA tumor', 'Disease', 'MESH:C536211', (192, 201))	('EZH2', 'Gene', (110, 114))	('EZH2', 'Gene', '2146', (110, 114))	('expression', 'MPA', (66, 76))	('ERRFI1', 'Gene', '54206', (80, 86))	('ERRFI1', 'Gene', (80, 86))	('ANRIL', 'Gene', (42, 47))	('binding', 'Interaction', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
65585	32378752	20 ,  21 ,  22  Notably, abnormal lncRNA expression has been proven in many cancers, including CCA.	('abnormal', 'Var', (25, 33))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('CCA', 'Disease', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('lncRNA expression', 'MPA', (34, 51))	('CCA', 'Phenotype', 'HP:0030153', (95, 98))	('proven', 'Reg', (61, 67))
65588	32378752	42  Regarding the underlying molecular mechanism, ANRIL can be induced by the ATM-E2F1 signaling pathway 43  and is required for silencing the p15(INK4B) tumor suppressor gene.	('p15(INK4B) tumor suppressor', 'Gene', (143, 170))	('ATM', 'Gene', (78, 81))	('ANRIL', 'Gene', (50, 55))	('silencing', 'Var', (129, 138))	('E2F1', 'Gene', '1869', (82, 86))	('E2F1', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('ATM', 'Gene', '472', (78, 81))	('p15(INK4B) tumor suppressor', 'Gene', '1030', (143, 170))	('ANRIL', 'Gene', '100048912', (50, 55))
65590	32378752	38  In hepatocellular carcinoma, ANRIL regulates cell apoptosis by epigenetically silencing KLF2.	('regulates', 'Reg', (39, 48))	('ANRIL', 'Gene', (33, 38))	('KLF2', 'Gene', '10365', (92, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (7, 31))	('cell apoptosis', 'CPA', (49, 63))	('ANRIL', 'Gene', '100048912', (33, 38))	('KLF2', 'Gene', (92, 96))	('epigenetically silencing', 'Var', (67, 91))	('hepatocellular carcinoma', 'Disease', (7, 31))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (7, 31))
65594	32378752	Our data showed that ANRIL knockdown greatly inhibited CCA cell proliferation and migration in vitro and in vivo.	('knockdown', 'Var', (27, 36))	('ANRIL', 'Gene', '100048912', (21, 26))	('CCA', 'Phenotype', 'HP:0030153', (55, 58))	('migration', 'CPA', (82, 91))	('ANRIL', 'Gene', (21, 26))	('inhibited', 'NegReg', (45, 54))	('CCA', 'Disease', (55, 58))
65595	32378752	According to the RNA-seq analysis results, ANRIL knockdown dramatically altered target genes associated with the cell cycle, cell proliferation, and apoptosis.	('ANRIL', 'Gene', '100048912', (43, 48))	('apoptosis', 'CPA', (149, 158))	('knockdown', 'Var', (49, 58))	('altered', 'Reg', (72, 79))	('ANRIL', 'Gene', (43, 48))	('cell proliferation', 'CPA', (125, 143))	('cell cycle', 'CPA', (113, 123))
65598	32378752	These data verified the key role of the epigenetic regulation of the lncRNA ANRIL in CCA oncogenesis and indicate its potential as a target for CCA intervention.	('ANRIL', 'Gene', (76, 81))	('CCA', 'Phenotype', 'HP:0030153', (144, 147))	('CCA', 'Disease', (85, 88))	('epigenetic regulation', 'Var', (40, 61))	('ANRIL', 'Gene', '100048912', (76, 81))	('CCA', 'Phenotype', 'HP:0030153', (85, 88))
65627	32378752	Total RNA from ANRIL knockdown and control HuCCT1 cells was separated and quantified.	('ANRIL', 'Gene', '100048912', (15, 20))	('ANRIL', 'Gene', (15, 20))	('HuCCT1', 'CellLine', 'CVCL:0324', (43, 49))	('knockdown', 'Var', (21, 30))
65636	32378752	The qRT-PCR results showed that ANRIL expression was significantly lower in the siRNA-mediated knockdown group than in the si-SC group for the HuCCT1 and RBE cell lines (Figure 2A).	('HuCCT1', 'CellLine', 'CVCL:0324', (143, 149))	('ANRIL', 'Gene', (32, 37))	('si-SC', 'Chemical', '-', (123, 128))	('knockdown', 'Var', (95, 104))	('ANRIL', 'Gene', '100048912', (32, 37))	('lower', 'NegReg', (67, 72))
65638	32378752	The CCK-8 assays revealed that, compared to control cells, ANRIL knockdown cells had significantly lower cell viability for both the HuCCT1 and RBE cell lines (Figure 2B).	('ANRIL', 'Gene', '100048912', (59, 64))	('lower', 'NegReg', (99, 104))	('HuCCT1', 'CellLine', 'CVCL:0324', (133, 139))	('ANRIL', 'Gene', (59, 64))	('knockdown', 'Var', (65, 74))	('cell viability', 'CPA', (105, 119))
65639	32378752	Additionally, the clonogenic formation number was significantly lower in the ANRIL knockdown cells than in the 2 CCA cell lines (Figure 2C).	('lower', 'NegReg', (64, 69))	('clonogenic formation number', 'CPA', (18, 45))	('ANRIL', 'Gene', (77, 82))	('CCA', 'Phenotype', 'HP:0030153', (113, 116))	('ANRIL', 'Gene', '100048912', (77, 82))	('knockdown', 'Var', (83, 92))
65640	32378752	Furthermore, Transwell assays showed that ANRIL knockdown dramatically repressed the migration of cells (Figure 2D).	('migration of cells', 'CPA', (85, 103))	('ANRIL', 'Gene', '100048912', (42, 47))	('repressed', 'NegReg', (71, 80))	('ANRIL', 'Gene', (42, 47))	('knockdown', 'Var', (48, 57))
65645	32378752	The flow cytometry assays revealed that the numbers of cells in the G0/G1 phase were higher and that the numbers of cells in the S and G2/M phases were lower in ANRIL knockdown cells than in control cells (Figure 3B).	('ANRIL', 'Gene', '100048912', (161, 166))	('higher', 'PosReg', (85, 91))	('knockdown', 'Var', (167, 176))	('lower', 'NegReg', (152, 157))	('ANRIL', 'Gene', (161, 166))	('G0/G1 phase', 'CPA', (68, 79))
65648	32378752	At 16 days postinjection, the tumors established in the sh-ANRIL group were dramatically smaller than those in the control group (Figure 4A,B).	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('sh-ANRIL', 'Var', (56, 64))	('sh-ANRIL', 'Chemical', '-', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('smaller', 'NegReg', (89, 96))
65649	32378752	Correspondingly, the average tumor volumes and weights at the final time point were obviously lower in the sh-ANRIL group than in the control vector group (Figure 4C,D).	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('sh-ANRIL', 'Var', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('sh-ANRIL', 'Chemical', '-', (107, 115))	('tumor', 'Disease', (29, 34))	('lower', 'NegReg', (94, 99))
65650	32378752	Our results showed that silencing ANRIL could repress CCA tumor growth in vivo, indicating that the lncRNA ANRIL plays a significant role in CCA tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('ANRIL', 'Gene', '100048912', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('ANRIL', 'Gene', '100048912', (107, 112))	('CCA tumor', 'Disease', (141, 150))	('CCA tumor', 'Disease', 'MESH:C536211', (141, 150))	('CCA', 'Phenotype', 'HP:0030153', (141, 144))	('CCA tumor', 'Disease', (54, 63))	('ANRIL', 'Gene', (34, 39))	('repress', 'NegReg', (46, 53))	('CCA tumor', 'Disease', 'MESH:C536211', (54, 63))	('CCA', 'Phenotype', 'HP:0030153', (54, 57))	('ANRIL', 'Gene', (107, 112))	('silencing', 'Var', (24, 33))
65652	32378752	A set of 1383 mRNAs had a minimum of 1.5-fold increase in abundance, whereas 1350 genes had a decrease in abundance (less than 1.5-fold) after ANRIL silencing (Figure 5A, Table S2).	('ANRIL', 'Gene', '100048912', (143, 148))	('increase', 'PosReg', (46, 54))	('silencing', 'Var', (149, 158))	('abundance', 'MPA', (106, 115))	('ANRIL', 'Gene', (143, 148))	('decrease', 'NegReg', (94, 102))	('abundance', 'MPA', (58, 67))
65653	32378752	To prioritize the most strongly ANRIL-related genes, attention was paid to those most highly expressed following ANRIL knockdown.	('ANRIL', 'Gene', '100048912', (113, 118))	('ANRIL', 'Gene', (32, 37))	('ANRIL', 'Gene', (113, 118))	('knockdown', 'Var', (119, 128))	('ANRIL', 'Gene', '100048912', (32, 37))
65655	32378752	Some of these genes were verified by qRT-PCR after ANRIL knockdown in HuCCT1 and RBE cells (Figure 5C,D).	('ANRIL', 'Gene', '100048912', (51, 56))	('ANRIL', 'Gene', (51, 56))	('knockdown', 'Var', (57, 66))	('HuCCT1', 'CellLine', 'CVCL:0324', (70, 76))
65656	32378752	50  In particular, PRC2, a classical methyltransferase that comprises EZH2, EED, and SUZ12, can serve as a catalyst in both the dimethylation and trimethylation of H3K27me3 to epigenetically repress target gene expression.	('SUZ12', 'Gene', (85, 90))	('PRC2', 'Gene', (19, 23))	('EZH2', 'Gene', '2146', (70, 74))	('EED', 'Gene', '8726', (76, 79))	('epigenetically', 'Var', (176, 190))	('EZH2', 'Gene', (70, 74))	('H3K27me3', 'Var', (164, 172))	('EED', 'Gene', (76, 79))	('SUZ12', 'Gene', '23512', (85, 90))
65663	32378752	The results showed that the ANRIL-suppressed genes were increased by also knocking down EZH2 (Figure 6D,E) in HuCCT1 and RBE cell lines.	('HuCCT1', 'CellLine', 'CVCL:0324', (110, 116))	('EZH2', 'Gene', (88, 92))	('ANRIL', 'Gene', '100048912', (28, 33))	('EZH2', 'Gene', '2146', (88, 92))	('knocking down', 'Var', (74, 87))	('ANRIL', 'Gene', (28, 33))
65665	32378752	Moreover, ERRFI1 protein levels were increased by knocking down EZH2 (Figure 6G) and ANRIL (Figure 6H).	('ANRIL', 'Gene', '100048912', (85, 90))	('ANRIL', 'Gene', (85, 90))	('knocking down', 'Var', (50, 63))	('increased', 'PosReg', (37, 46))	('ERRFI1', 'Gene', '54206', (10, 16))	('ERRFI1', 'Gene', (10, 16))	('protein levels', 'MPA', (17, 31))	('EZH2', 'Gene', (64, 68))	('EZH2', 'Gene', '2146', (64, 68))
65667	32378752	The ChIP assays revealed that ANRIL knockdown reduced the binding of EZH2 to the promoters of ERRFI1 as well as H3K27me3 levels (Figure 6I).	('ANRIL', 'Gene', '100048912', (30, 35))	('binding', 'Interaction', (58, 65))	('EZH2', 'Gene', '2146', (69, 73))	('EZH2', 'Gene', (69, 73))	('knockdown', 'Var', (36, 45))	('reduced', 'NegReg', (46, 53))	('H3K27me3 levels', 'MPA', (112, 127))	('ANRIL', 'Gene', (30, 35))	('ERRFI1', 'Gene', '54206', (94, 100))	('ERRFI1', 'Gene', (94, 100))
65670	32378752	60  In addition, hypermethylation of the ERRFI1 promoter region has been reported to contribute to ERRFI1 transcription inactivation.	('ERRFI1', 'Gene', '54206', (99, 105))	('ERRFI1', 'Gene', (99, 105))	('ERRFI1', 'Gene', '54206', (41, 47))	('ERRFI1', 'Gene', (41, 47))	('hypermethylation', 'Var', (17, 33))	('transcription', 'MPA', (106, 119))
65678	32378752	In addition, ChIP assays revealed that ANRIL knockdown reduced the binding of EZH2 to the promoters of ERRFI1 as well as H3K27me3 levels, leading to increased levels of ERRFI1, which could decelerate CCA growth (Figure 7F).	('H3K27me3 levels', 'MPA', (121, 136))	('ERRFI1', 'Gene', '54206', (169, 175))	('levels', 'MPA', (159, 165))	('ANRIL', 'Gene', (39, 44))	('reduced', 'NegReg', (55, 62))	('increased', 'PosReg', (149, 158))	('decelerate', 'NegReg', (189, 199))	('knockdown', 'Var', (45, 54))	('ERRFI1', 'Gene', '54206', (103, 109))	('ERRFI1', 'Gene', (103, 109))	('ANRIL', 'Gene', '100048912', (39, 44))	('CCA', 'Phenotype', 'HP:0030153', (200, 203))	('binding', 'Interaction', (67, 74))	('CCA growth', 'CPA', (200, 210))	('EZH2', 'Gene', '2146', (78, 82))	('EZH2', 'Gene', (78, 82))	('ERRFI1', 'Gene', (169, 175))
65679	32378752	In conclusion, our results indicated that ANRIL promotes CCA malignancy by binding to EZH2 and then epigenetically repressing ERRFI1 expression in the nucleus.	('expression', 'MPA', (133, 143))	('CCA', 'Phenotype', 'HP:0030153', (57, 60))	('CCA malignancy', 'Disease', (57, 71))	('CCA malignancy', 'Disease', 'MESH:C536211', (57, 71))	('ERRFI1', 'Gene', '54206', (126, 132))	('ANRIL', 'Gene', '100048912', (42, 47))	('ERRFI1', 'Gene', (126, 132))	('EZH2', 'Gene', '2146', (86, 90))	('promotes', 'PosReg', (48, 56))	('epigenetically', 'Var', (100, 114))	('EZH2', 'Gene', (86, 90))	('binding', 'Interaction', (75, 82))	('ANRIL', 'Gene', (42, 47))
65685	32378752	42   We discovered that silencing ANRIL could inhibit CCA cell proliferation and migration in vitro and in vivo.	('ANRIL', 'Gene', '100048912', (34, 39))	('inhibit', 'NegReg', (46, 53))	('CCA', 'Disease', (54, 57))	('ANRIL', 'Gene', (34, 39))	('CCA', 'Phenotype', 'HP:0030153', (54, 57))	('silencing', 'Var', (24, 33))
65697	32378752	ANRIL promotes CCA malignancy through epigenetically regulating ERRFI1 transcription in the nucleus, thus facilitating cell survival and metastasis in CCA.	('epigenetically regulating', 'Var', (38, 63))	('ANRIL', 'Gene', '100048912', (0, 5))	('CCA malignancy', 'Disease', 'MESH:C536211', (15, 29))	('CCA', 'Phenotype', 'HP:0030153', (151, 154))	('promotes', 'PosReg', (6, 14))	('ERRFI1', 'Gene', '54206', (64, 70))	('ERRFI1', 'Gene', (64, 70))	('metastasis', 'CPA', (137, 147))	('ANRIL', 'Gene', (0, 5))	('facilitating', 'PosReg', (106, 118))	('transcription', 'MPA', (71, 84))	('CCA', 'Phenotype', 'HP:0030153', (15, 18))	('CCA malignancy', 'Disease', (15, 29))	('cell survival', 'CPA', (119, 132))
65707	30450012	Similarly, M3-mAChR knock-down also weakened cell migration and perineural invasion.	('weakened', 'NegReg', (36, 44))	('M3-mAChR', 'Gene', '1131', (11, 19))	('knock-down', 'Var', (20, 30))	('cell migration', 'CPA', (45, 59))	('perineural invasion', 'CPA', (64, 83))	('M3-mAChR', 'Gene', (11, 19))
65709	30450012	Notably, AKT knock-down decreased M3-mAChR expression and reversed the downstream effects of this receptor.	('AKT', 'Gene', '207', (9, 12))	('decreased', 'NegReg', (24, 33))	('knock-down', 'Var', (13, 23))	('M3-mAChR', 'Gene', (34, 42))	('AKT', 'Gene', (9, 12))	('M3-mAChR', 'Gene', '1131', (34, 42))
65794	30450012	These data suggest that the invasive capacity of the cholangiocarcinoma cells was decreased owing to antagonism of the pilocarpine-treated cells by atropine.	('atropine', 'Chemical', 'MESH:D001285', (148, 156))	('antagonism', 'Var', (101, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (53, 71))	('cholangiocarcinoma', 'Disease', (53, 71))	('invasive capacity of', 'CPA', (28, 48))	('decreased', 'NegReg', (82, 91))	('pilocarpine', 'Chemical', 'MESH:D010862', (119, 130))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (53, 71))
65796	30450012	Our results show that M3-mAChR expression was downregulated in shM3-treated RBE cells, and the number of migrating cells was reduced.	('M3-mAChR', 'Gene', (22, 30))	('shM3-treated', 'Var', (63, 75))	('reduced', 'NegReg', (125, 132))	('expression', 'MPA', (31, 41))	('downregulated', 'NegReg', (46, 59))	('M3-mAChR', 'Gene', '1131', (22, 30))	('number of migrating cells', 'CPA', (95, 120))
65808	30450012	Treatment these DRG-M3-FRH0201 co-cultured cells with pilocarpine, the number of invading cells was further increased (Fig.	('DRG-M3-FRH0201', 'Var', (16, 30))	('pilocarpine', 'Chemical', 'MESH:D010862', (54, 65))	('increased', 'PosReg', (108, 117))	('men', 'Species', '9606', (5, 8))
65815	30450012	Similarly, shM3-mediated disruption of receptor expression in the RBE cells also resulted in increased expression of PTEN and E-cadherin and decreased expression of AKT, vimentin, and Snail.	('AKT', 'Gene', (165, 168))	('PTEN', 'Gene', (117, 121))	('vimentin', 'Gene', '7431', (170, 178))	('increased', 'PosReg', (93, 102))	('expression', 'MPA', (103, 113))	('PTEN', 'Gene', '5728', (117, 121))	('expression', 'MPA', (151, 161))	('vimentin', 'Gene', (170, 178))	('E-cadherin', 'Gene', (126, 136))	('decreased', 'NegReg', (141, 150))	('E-cadherin', 'Gene', '999', (126, 136))	('disruption', 'Var', (25, 35))	('AKT', 'Gene', '207', (165, 168))	('Snail', 'Pathway', (184, 189))
65826	30450012	Indeed, poor cholangiocarcinoma differentiation was associated with high M3-mAChR expression.	('cholangiocarcinoma', 'Disease', (13, 31))	('M3-mAChR', 'Gene', '1131', (73, 81))	('high', 'Var', (68, 72))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (13, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (13, 31))	('M3-mAChR', 'Gene', (73, 81))
65832	30450012	In fact, abnormal neurotransmitter expression and/or receptor signaling in tumors greatly affects tumor proliferation, differentiation, and metastasis, with receptor agonists increasing these characteristics and receptor antagonists blocking them.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('increasing', 'PosReg', (175, 185))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('abnormal', 'Var', (9, 17))	('receptor signaling', 'MPA', (53, 71))	('neurotransmitter expression', 'MPA', (18, 45))	('metastasis', 'CPA', (140, 150))	('abnormal neurotransmitter expression', 'Phenotype', 'HP:0012535', (9, 45))	('differentiation', 'CPA', (119, 134))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (98, 103))	('affects', 'Reg', (90, 97))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Disease', (75, 81))	('tumor', 'Disease', (75, 80))
65835	30450012	Our data show that when M3-mAChR expression is downregulated via receptor knock-down, the migratory capacity of the affected cholangiocarcinoma cells was low.	('M3-mAChR', 'Gene', '1131', (24, 32))	('knock-down', 'Var', (74, 84))	('low', 'NegReg', (154, 157))	('downregulated', 'NegReg', (47, 60))	('cholangiocarcinoma', 'Disease', (125, 143))	('M3-mAChR', 'Gene', (24, 32))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (125, 143))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (125, 143))	('migratory capacity', 'CPA', (90, 108))
65841	30450012	In addition to its role in migration, we also found that high M3-mAChR expression (via overexpression) promotes perineural invasion, whereas low M3-mAChR expression (via receptor knock-down) was associated with lower levels of perineural invasion.	('M3-mAChR', 'Gene', '1131', (62, 70))	('high', 'Var', (57, 61))	('perineural invasion', 'CPA', (112, 131))	('M3-mAChR', 'Gene', '1131', (145, 153))	('promotes', 'PosReg', (103, 111))	('M3-mAChR', 'Gene', (62, 70))	('M3-mAChR', 'Gene', (145, 153))
65843	30450012	These findings suggest that decreasing M3-mAChR expression via knock-down or antagonist treatment may limit perineural invasion of cholangiocarcinoma tumors in the clinical setting.	('perineural invasion', 'CPA', (108, 127))	('limit', 'NegReg', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('M3-mAChR', 'Gene', (39, 47))	('men', 'Species', '9606', (93, 96))	('cholangiocarcinoma tumors', 'Disease', 'MESH:D018281', (131, 156))	('knock-down', 'Var', (63, 73))	('cholangiocarcinoma tumors', 'Disease', (131, 156))	('decreasing', 'NegReg', (28, 38))	('M3-mAChR', 'Gene', '1131', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))
65851	30450012	Further, knockdown of AKT in FRH0201 cells overexpressing M3-mAChR which resulted in the downregulation of M3-mAChR, Snail, and vimentin expression, whereas the expression of PTEN and E-cadherin was upregulated.	('vimentin', 'Gene', '7431', (128, 136))	('M3-mAChR', 'Gene', '1131', (58, 66))	('E-cadherin', 'Gene', (184, 194))	('E-cadherin', 'Gene', '999', (184, 194))	('knockdown', 'Var', (9, 18))	('vimentin', 'Gene', (128, 136))	('AKT', 'Gene', '207', (22, 25))	('M3-mAChR', 'Gene', '1131', (107, 115))	('expression', 'MPA', (161, 171))	('downregulation', 'NegReg', (89, 103))	('upregulated', 'PosReg', (199, 210))	('AKT', 'Gene', (22, 25))	('M3-mAChR', 'Gene', (58, 66))	('M3-mAChR', 'Gene', (107, 115))	('PTEN', 'Gene', (175, 179))	('PTEN', 'Gene', '5728', (175, 179))	('Snail', 'Protein', (117, 122))
65877	26333855	The fact that anaerobic and Gram-negative bacterial species such as Klebsiella have been isolated from the bile of affected patients has led some authors to postulate a multifactorial model in which a low-protein diet, combined with biliary infection, leads to intrahepatic stone formation.	('intrahepatic stone', 'Disease', (261, 279))	('biliary infection', 'Disease', 'MESH:D001658', (233, 250))	('Klebsiella', 'Disease', (68, 78))	('Klebsiella', 'Disease', 'MESH:D007710', (68, 78))	('biliary infection', 'Disease', (233, 250))	('intrahepatic stone', 'Disease', 'MESH:D002780', (261, 279))	('patients', 'Species', '9606', (124, 132))	('leads to', 'Reg', (252, 260))	('low-protein', 'Var', (201, 212))
65937	25674039	Inhibition of the AKT pathway in cholangiocarcinoma by MK2206 reduces cellular viability via induction of apoptosis Cholangiocarcinoma (CCA) is an aggressive disease with limited effective treatment options.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('reduces', 'NegReg', (62, 69))	('CCA', 'Phenotype', 'HP:0030153', (136, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (33, 51))	('AKT', 'Gene', (18, 21))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))	('apoptosis', 'MPA', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('AKT', 'Gene', '207', (18, 21))	('aggressive disease', 'Disease', 'MESH:D001523', (147, 165))	('MK2206', 'Chemical', 'MESH:C548887', (55, 61))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (33, 51))	('cellular viability', 'CPA', (70, 88))	('cholangiocarcinoma', 'Disease', (33, 51))	('aggressive disease', 'Disease', (147, 165))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (116, 134))	('Cholangiocarcinoma', 'Disease', (116, 134))	('MK2206', 'Var', (55, 61))
65939	25674039	MK2206, an allosteric Akt inhibitor, has been shown to reduce cellular proliferation in other cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('Akt', 'Gene', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cellular proliferation', 'CPA', (62, 84))	('reduce', 'NegReg', (55, 61))	('MK2206', 'Var', (0, 6))	('Akt', 'Gene', '207', (22, 25))	('cancers', 'Disease', (94, 101))
65940	25674039	We hypothesized that MK2206 mediated inhibition of Akt would impact CCA cellular viability.	('CCA', 'Phenotype', 'HP:0030153', (68, 71))	('Akt', 'Gene', (51, 54))	('impact', 'Reg', (61, 67))	('inhibition', 'NegReg', (37, 47))	('MK2206', 'Chemical', 'MESH:C548887', (21, 27))	('Akt', 'Gene', '207', (51, 54))	('CCA', 'Disease', (68, 71))	('MK2206', 'Var', (21, 27))
65941	25674039	Post treatment with MK2206 (0-2 muM), cellular viability was assessed in two human CCA cell lines:CCLP-1 and SG231:using an MTT assay.	('MK2206', 'Chemical', 'MESH:C548887', (20, 26))	('CCLP-1', 'Gene', '8495', (98, 104))	('muM', 'Gene', '56925', (32, 35))	('CCA', 'Phenotype', 'HP:0030153', (83, 86))	('MK2206', 'Var', (20, 26))	('MTT', 'Chemical', 'MESH:C070243', (124, 127))	('muM', 'Gene', (32, 35))	('CCLP-1', 'Gene', (98, 104))	('human', 'Species', '9606', (77, 82))
65942	25674039	Lysates from the MK2206 treated CCA cells were then examined for apoptotic marker expression levels using Western blot analysis.	('apoptotic', 'MPA', (65, 74))	('CCA', 'Phenotype', 'HP:0030153', (32, 35))	('MK2206', 'Chemical', 'MESH:C548887', (17, 23))	('MK2206', 'Var', (17, 23))
65948	25674039	In addition, survivin siRNA further enhanced the antitumor activity of MK2206.	('MK2206', 'Var', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('MK2206', 'Chemical', 'MESH:C548887', (71, 77))	('tumor', 'Disease', (53, 58))	('enhanced', 'PosReg', (36, 44))
65958	25674039	The dysregulation of this pathway has been implicated in the pathogenesis of many cancer types, including CCA.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('CCA', 'Phenotype', 'HP:0030153', (106, 109))	('implicated', 'Reg', (43, 53))	('dysregulation', 'Var', (4, 17))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CCA', 'Disease', (106, 109))
65960	25674039	MK2206, a novel, small molecule, allosteric Akt inhibitor has demonstrated promising efficacy in vitro and in early clinical trial.	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('MK2206', 'Var', (0, 6))	('Akt', 'Gene', '207', (44, 47))	('Akt', 'Gene', (44, 47))
65962	25674039	Thus far, MK2206 has demonstrated moderate single agent anti-tumor efficacy with acceptable toxicity in humans.	('toxicity', 'Disease', (92, 100))	('MK2206', 'Chemical', 'MESH:C548887', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('MK2206', 'Var', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('humans', 'Species', '9606', (104, 110))	('toxicity', 'Disease', 'MESH:D064420', (92, 100))	('tumor', 'Disease', (61, 66))
65963	25674039	Despite one previous report of MK2206 use in cholangiocarcinoma, the mechanism of action in these cells needs significant clarification.	('MK2206', 'Chemical', 'MESH:C548887', (31, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('cholangiocarcinoma', 'Disease', (45, 63))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (45, 63))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (45, 63))	('MK2206', 'Var', (31, 37))
65964	25674039	This study sought to examine the effects of MK2206 on two human CCA cell lines:CCLP-1 and SG231.	('CCLP-1', 'Gene', (79, 85))	('human', 'Species', '9606', (58, 63))	('MK2206', 'Var', (44, 50))	('CCLP-1', 'Gene', '8495', (79, 85))	('MK2206', 'Chemical', 'MESH:C548887', (44, 50))	('CCA', 'Phenotype', 'HP:0030153', (64, 67))
65965	25674039	The effects of MK2206 on CCA cellular proliferation were examined and the mechanism of cellular growth inhibition was identified by Western blot analysis.	('MK2206', 'Var', (15, 21))	('MK2206', 'Chemical', 'MESH:C548887', (15, 21))	('CCA', 'Phenotype', 'HP:0030153', (25, 28))	('CCA', 'Disease', (25, 28))
65966	25674039	By inhibiting Akt phosphorylation via MK2206, it was hypothesized that CCA cellular proliferation would be reduced via induction of apoptosis.	('Akt', 'Gene', (14, 17))	('MK2206', 'Chemical', 'MESH:C548887', (38, 44))	('CCA', 'Disease', (71, 74))	('inhibiting', 'NegReg', (3, 13))	('reduced', 'NegReg', (107, 114))	('MK2206', 'Var', (38, 44))	('Akt', 'Gene', '207', (14, 17))	('CCA', 'Phenotype', 'HP:0030153', (71, 74))
65982	25674039	After treatment with varying concentrations of MK2206 for 96 hours, CCA cells were lysed in RIPA buffer(Thermo Fisher).	('CCA', 'Phenotype', 'HP:0030153', (68, 71))	('RIPA buffer', 'Chemical', '-', (92, 103))	('MK2206', 'Var', (47, 53))	('CCA cells', 'CPA', (68, 77))	('MK2206', 'Chemical', 'MESH:C548887', (47, 53))
65997	25674039	In order to confirm MK2206's mechanism of action and the previously reported specificity, levels of AktSer473, AktThr308, and total Akt expression were examined by Western blot analysis.	('MK2206', 'Chemical', 'MESH:C548887', (20, 26))	('Akt', 'Gene', (100, 103))	('Akt', 'Gene', (111, 114))	('Akt', 'Gene', (132, 135))	('Akt', 'Gene', '207', (100, 103))	('MK2206', 'Var', (20, 26))	('Akt', 'Gene', '207', (132, 135))	('Akt', 'Gene', '207', (111, 114))
65998	25674039	In both CCLP-1 and SG231 cell lines, AktSer473 was significantly reduced in MK2206 treated cells (0.1-2 muM; Figure 2).	('reduced', 'NegReg', (65, 72))	('Akt', 'Gene', '207', (37, 40))	('muM', 'Gene', '56925', (104, 107))	('CCLP-1', 'Gene', (8, 14))	('MK2206', 'Chemical', 'MESH:C548887', (76, 82))	('Akt', 'Gene', (37, 40))	('muM', 'Gene', (104, 107))	('CCLP-1', 'Gene', '8495', (8, 14))	('MK2206', 'Var', (76, 82))
66000	25674039	Ultimately, treatment resulted in a reduction in levels of AktSer473 by >95% in both cell lines (DMSO v. 2 muM MK2206) whereas expression levels of AktThr308, the other phosphorylation site for Akt activation, were not changed by MK2206 treatment.	('Akt', 'Gene', '207', (194, 197))	('Akt', 'Gene', (59, 62))	('muM', 'Gene', '56925', (107, 110))	('Akt', 'Gene', (148, 151))	('MK2206', 'Chemical', 'MESH:C548887', (230, 236))	('MK2206', 'Chemical', 'MESH:C548887', (111, 117))	('Akt', 'Gene', (194, 197))	('reduction', 'NegReg', (36, 45))	('Akt', 'Gene', '207', (59, 62))	('muM', 'Gene', (107, 110))	('MK2206', 'Var', (230, 236))	('DMSO', 'Chemical', 'MESH:D004121', (97, 101))	('Akt', 'Gene', '207', (148, 151))
66006	25674039	Interestingly, survivin, an anti-apoptotic protein was unexpectedly up-regulated in a dose dependent manner upon MK2206 treatment (Figure 2).	('up-regulated', 'PosReg', (68, 80))	('MK2206', 'Chemical', 'MESH:C548887', (113, 119))	('MK2206', 'Var', (113, 119))	('survivin', 'Protein', (15, 23))
66008	25674039	Survivin siRNA transfection resulted in induction of apoptosis as evidenced by the increased expression of cleaved PARP, cleaved caspase-3 whereas decreased expression of cyclin D1 and total PARP proteins compared to nonspecific siRNA transfected cells (Figure 5A).	('apoptosis', 'CPA', (53, 62))	('increased', 'PosReg', (83, 92))	('expression', 'MPA', (157, 167))	('decreased', 'NegReg', (147, 156))	('caspase-3', 'Gene', (129, 138))	('cleaved', 'MPA', (121, 128))	('PARP', 'Gene', '1302', (191, 195))	('cyclin D1', 'Gene', '595', (171, 180))	('expression', 'MPA', (93, 103))	('cyclin D1', 'Gene', (171, 180))	('PARP', 'Gene', '1302', (115, 119))	('caspase-3', 'Gene', '836', (129, 138))	('PARP', 'Gene', (115, 119))	('PARP', 'Gene', (191, 195))	('cleaved', 'MPA', (107, 114))	('transfection', 'Var', (15, 27))
66016	25674039	This, in addition to the known functions of Akt and a previous report demonstrating apoptosis induction upon Akt knockdown, indicates that Akt inhibition could be a potential therapeutic target.	('Akt', 'Gene', '207', (44, 47))	('Akt', 'Gene', '207', (139, 142))	('apoptosis', 'CPA', (84, 93))	('Akt', 'Gene', '207', (109, 112))	('Akt', 'Gene', (139, 142))	('Akt', 'Gene', (44, 47))	('knockdown', 'Var', (113, 122))	('Akt', 'Gene', (109, 112))
66018	25674039	Previous reports have shown that MK2206 may have Akt isoform specificity for Akt 1 and 2, which is consistent with the relative tolerability of MK2206 in clinical trial.	('Akt', 'Gene', '207', (77, 80))	('MK2206', 'Var', (33, 39))	('Akt 1 and 2', 'Gene', '207;208', (77, 88))	('Akt', 'Gene', (77, 80))	('Akt', 'Gene', '207', (49, 52))	('MK2206', 'Chemical', 'MESH:C548887', (33, 39))	('MK2206', 'Chemical', 'MESH:C548887', (144, 150))	('Akt', 'Gene', (49, 52))
66019	25674039	Previous studies, have demonstrated the efficacy of MK2206 as a single agent in other cancer types or in synergistic combination with RAD001 (an mTOR inhibitor) in cholangiocarcinoma cells in vitro.	('cholangiocarcinoma', 'Disease', (164, 182))	('MK2206', 'Chemical', 'MESH:C548887', (52, 58))	('mTOR', 'Gene', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mTOR', 'Gene', '2475', (145, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (164, 182))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (164, 182))	('MK2206', 'Var', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
66020	25674039	demonstrated an increase in p27, a cell cycle inhibitor, upon MK2206 treatment in two of three CCA cell lines (EGI-1, TFK-1, and SK-ChA-1 cell lines).	('MK2206', 'Chemical', 'MESH:C548887', (62, 68))	('p27', 'Gene', '3429', (28, 31))	('p27', 'Gene', (28, 31))	('increase', 'PosReg', (16, 24))	('SK-ChA-1', 'CellLine', 'CVCL:6952', (129, 137))	('MK2206', 'Var', (62, 68))	('CCA', 'Phenotype', 'HP:0030153', (95, 98))
66021	25674039	While some induction of cell cycle arrest in CCA cells upon MK2206 treatment was observed, apoptotic markers were not fully investigated.	('arrest', 'Disease', 'MESH:D006323', (35, 41))	('CCA', 'Phenotype', 'HP:0030153', (45, 48))	('MK2206', 'Var', (60, 66))	('arrest', 'Disease', (35, 41))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (24, 41))	('MK2206', 'Chemical', 'MESH:C548887', (60, 66))
66022	25674039	Examination of protein expression levels post-MK2206 treatment in the present study revealed that MK2206 specifically inhibits phosphorylation at AKTSer473.	('MK2206', 'Chemical', 'MESH:C548887', (98, 104))	('AKT', 'Gene', '207', (146, 149))	('phosphorylation', 'MPA', (127, 142))	('inhibits', 'NegReg', (118, 126))	('AKT', 'Gene', (146, 149))	('MK2206', 'Var', (98, 104))	('MK2206', 'Chemical', 'MESH:C548887', (46, 52))
66027	25674039	The results of this study indicate that MK2206 is effective in reducing CCA cellular proliferation via the induction of apoptosis.	('CCA', 'Disease', (72, 75))	('reducing', 'NegReg', (63, 71))	('MK2206', 'Var', (40, 46))	('CCA', 'Phenotype', 'HP:0030153', (72, 75))	('MK2206', 'Chemical', 'MESH:C548887', (40, 46))
66028	25674039	Interestingly, survivin was up regulated in both CCLP-1 and SG231 upon MK2206 treatment.	('CCLP-1', 'Gene', (49, 55))	('MK2206', 'Var', (71, 77))	('survivin', 'Protein', (15, 23))	('CCLP-1', 'Gene', '8495', (49, 55))	('up regulated', 'PosReg', (28, 40))	('MK2206', 'Chemical', 'MESH:C548887', (71, 77))
66029	25674039	It is speculated that compensatory activation of survivin could be mitigating MK2206 mediated apoptosis induction.	('apoptosis', 'CPA', (94, 103))	('survivin', 'Protein', (49, 57))	('MK2206', 'Var', (78, 84))	('MK2206', 'Chemical', 'MESH:C548887', (78, 84))
66030	25674039	In addition, a recent report on MK2206 use in hepatocellular carcinoma identified survivin as an important downstream mediator upon MK2206 treatment, and found increased apoptosis and reduced viability when survivin knockdown was added to the treatment regimen.	('MK2206', 'Var', (132, 138))	('increased', 'PosReg', (160, 169))	('viability', 'CPA', (192, 201))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (46, 70))	('reduced', 'NegReg', (184, 191))	('hepatocellular carcinoma', 'Disease', (46, 70))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (46, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('MK2206', 'Chemical', 'MESH:C548887', (132, 138))	('MK2206', 'Chemical', 'MESH:C548887', (32, 38))	('apoptosis', 'CPA', (170, 179))
66032	25674039	The combination of survivin siRNA transfection and MK2206 treatment resulted in significant reduction in cell viability when compared to MK2206 treatment alone.	('MK2206', 'Chemical', 'MESH:C548887', (137, 143))	('reduction', 'NegReg', (92, 101))	('MK2206', 'Chemical', 'MESH:C548887', (51, 57))	('survivin', 'Protein', (19, 27))	('MK2206', 'Var', (51, 57))	('cell viability', 'CPA', (105, 119))
66033	25674039	These results suggest that the inhibition of survivin may sensitize the CCLP-1 cells to MK2206 treatment by preventing the activation of pro-survival proteins.	('survivin', 'Protein', (45, 53))	('activation', 'MPA', (123, 133))	('preventing', 'NegReg', (108, 118))	('CCLP-1', 'Gene', (72, 78))	('CCLP-1', 'Gene', '8495', (72, 78))	('inhibition', 'Var', (31, 41))	('MK2206', 'Chemical', 'MESH:C548887', (88, 94))	('pro-survival', 'Protein', (137, 149))
66034	25674039	In the present study, we have demonstrated the effectiveness of MK2206 in inducing apoptosis as a monotherapy in CCA cell lines in vitro.	('MK2206', 'Var', (64, 70))	('CCA', 'Disease', (113, 116))	('inducing', 'MPA', (74, 82))	('apoptosis', 'CPA', (83, 92))	('CCA', 'Phenotype', 'HP:0030153', (113, 116))	('MK2206', 'Chemical', 'MESH:C548887', (64, 70))
66039	25674039	Lastly, autophagy may be playing an important role, as PI3K/mTOR/Akt pathway inhibition has been shown to increase autophagy in CCA cells.	('Akt', 'Gene', (65, 68))	('inhibition', 'Var', (77, 87))	('autophagy', 'CPA', (115, 124))	('mTOR', 'Gene', '2475', (60, 64))	('autophagy', 'CPA', (8, 17))	('Akt', 'Gene', '207', (65, 68))	('CCA', 'Phenotype', 'HP:0030153', (128, 131))	('mTOR', 'Gene', (60, 64))	('increase', 'PosReg', (106, 114))	('CCA', 'Disease', (128, 131))
66056	24679073	Inhibition of LDH-A has been shown to cause a blockade of aerobic glycolysis of tumor cells and to severely diminish the tumorigenicity of neu-initiated mammary tumor cells.	('diminish', 'NegReg', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('LDH-A', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (121, 126))	('neu', 'Gene', (139, 142))	('tumor', 'Disease', (80, 85))	('neu', 'Gene', '2064', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('blockade', 'NegReg', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('Inhibition', 'Var', (0, 10))	('aerobic glycolysis', 'MPA', (58, 76))	('LDH-A', 'Gene', '3939', (14, 19))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
66061	24679073	As a key effector of cell death, ROS inflict oxidative damage on cellular proteins, lipids, and nucleic acids.	('oxidative damage', 'MPA', (45, 61))	('lipids', 'Chemical', 'MESH:D008055', (84, 90))	('ROS', 'Chemical', 'MESH:D017382', (33, 36))	('ROS', 'Var', (33, 36))	('inflict', 'Reg', (37, 44))
66063	24679073	Considering that aerobic glycolysis diminishes cellular ROS in yeast, we hypothesized that silencing LDH-A by blocking aerobic glycolysis might upregulate ROS levels and induce apoptosis of ICC.	('apoptosis', 'CPA', (177, 186))	('LDH-A', 'Gene', '3939', (101, 106))	('ROS levels', 'MPA', (155, 165))	('blocking', 'NegReg', (110, 118))	('ROS', 'Chemical', 'MESH:D017382', (155, 158))	('LDH-A', 'Gene', (101, 106))	('aerobic glycolysis', 'MPA', (119, 137))	('yeast', 'Species', '4932', (63, 68))	('induce', 'Reg', (170, 176))	('upregulate', 'PosReg', (144, 154))	('ROS', 'Chemical', 'MESH:D017382', (56, 59))	('silencing', 'Var', (91, 100))	('upregulate ROS levels', 'Phenotype', 'HP:0025464', (144, 165))
66066	24679073	Furthermore, the inhibition of LDH-A elevated cytoplasmic ROS levels.	('LDH-A', 'Gene', '3939', (31, 36))	('ROS', 'Chemical', 'MESH:D017382', (58, 61))	('elevated', 'PosReg', (37, 45))	('LDH-A', 'Gene', (31, 36))	('inhibition', 'Var', (17, 27))	('cytoplasmic ROS levels', 'MPA', (46, 68))	('elevated cytoplasmic ROS levels', 'Phenotype', 'HP:0025464', (37, 68))
66116	24679073	To investigate the effect of aberrant LDH-A expression in cholangiocarcinoma, RNAi experiments were performed using the HuCCT-1 cell line.	('LDH-A', 'Gene', (38, 43))	('cholangiocarcinoma', 'Disease', (58, 76))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('aberrant', 'Var', (29, 37))	('LDH-A', 'Gene', '3939', (38, 43))
66118	24679073	The CCK-8 assay showed that the proliferation rates of the HuCCT-1 LDH-A knocked-down cell line (RNAi group) were slower than those of the negative control HuCCT-1 cell lines (NC group) (Figure 3).	('LDH-A', 'Gene', '3939', (67, 72))	('proliferation rates', 'CPA', (32, 51))	('LDH-A', 'Gene', (67, 72))	('slower', 'NegReg', (114, 120))	('knocked-down', 'Var', (73, 85))
66119	24679073	Collectively, inhibition of LDH-A resulted in a decrease in the rate of proliferation of HuCCT-1 cells, while apoptosis rates increased.	('LDH-A', 'Gene', (28, 33))	('apoptosis rates', 'CPA', (110, 125))	('decrease', 'NegReg', (48, 56))	('inhibition', 'Var', (14, 24))	('increased', 'PosReg', (126, 135))	('LDH-A', 'Gene', '3939', (28, 33))
66121	24679073	Silencing LDH-A has been reported to increase the OXPHOS capacity and to induce oxidative stress.	('LDH-A', 'Gene', '3939', (10, 15))	('LDH-A', 'Gene', (10, 15))	('OXPHOS capacity', 'MPA', (50, 65))	('oxidative stress', 'MPA', (80, 96))	('increase', 'PosReg', (37, 45))	('induce', 'Reg', (73, 79))	('oxidative stress', 'Phenotype', 'HP:0025464', (80, 96))	('Silencing', 'Var', (0, 9))
66124	24679073	These data suggest that LDH-A expression is linked to the ROS level of ICC and that inhibition of LDH-A increases ROS levels.	('LDH-A', 'Gene', '3939', (24, 29))	('LDH-A', 'Gene', (24, 29))	('ROS', 'Chemical', 'MESH:D017382', (58, 61))	('ROS levels', 'MPA', (114, 124))	('ROS level', 'MPA', (58, 67))	('increases', 'PosReg', (104, 113))	('ROS', 'Chemical', 'MESH:D017382', (114, 117))	('LDH-A', 'Gene', '3939', (98, 103))	('linked', 'Reg', (44, 50))	('LDH-A', 'Gene', (98, 103))	('inhibition', 'Var', (84, 94))	('increases ROS levels', 'Phenotype', 'HP:0025464', (104, 124))
66131	24679073	Earlier studies have shown that attenuation of LDH-A expression causes impairment of tumor maintenance and leads to a reduction in tumor growth in xenograft models of renal cancer.	('tumor', 'Disease', (85, 90))	('renal cancer', 'Phenotype', 'HP:0009726', (167, 179))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('attenuation', 'Var', (32, 43))	('renal cancer', 'Disease', 'MESH:D007680', (167, 179))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('reduction', 'NegReg', (118, 127))	('tumor', 'Disease', (131, 136))	('impairment of tumor', 'Disease', (71, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('impairment of tumor', 'Disease', 'MESH:D015417', (71, 90))	('LDH-A', 'Gene', '3939', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('expression', 'MPA', (53, 63))	('LDH-A', 'Gene', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('renal cancer', 'Disease', (167, 179))
66132	24679073	Here, we observed that knockdown of LDH-A in the ICC cell line HuCCT-1 is associated with the reduction of the proliferation rate and an increase in the apoptosis rate.	('apoptosis rate', 'CPA', (153, 167))	('proliferation rate', 'CPA', (111, 129))	('reduction', 'NegReg', (94, 103))	('knockdown', 'Var', (23, 32))	('increase', 'PosReg', (137, 145))	('LDH-A', 'Gene', '3939', (36, 41))	('LDH-A', 'Gene', (36, 41))
66142	24679073	In general, the results of our experiments indicate that LDH-A is highly expressed in ICC and that inhibition of LDH-A causes remarkable apoptosis of the HuCCT-1 cell line.	('LDH-A', 'Gene', (57, 62))	('apoptosis', 'CPA', (137, 146))	('inhibition', 'Var', (99, 109))	('LDH-A', 'Gene', '3939', (57, 62))	('LDH-A', 'Gene', '3939', (113, 118))	('LDH-A', 'Gene', (113, 118))
66219	32831026	Regarding type 1 IgG4-SC, diagnosis is relatively easy because most patients have AIP lesions in the pancreatic head.	('patients', 'Species', '9606', (68, 76))	('pancreatic head', 'Disease', 'MESH:D010195', (101, 116))	('pancreatic head', 'Disease', (101, 116))	('AIP', 'Var', (82, 85))
66237	32831026	The easily bleeding was observed to be significantly less frequent in IgG4-SC than in ECC, so it is considered that the wall of the dilated vessel of IgG4-SC is strong as compared to fragile tumor vessels.	('easily bleeding', 'Phenotype', 'HP:0011889', (4, 19))	('easily bleeding', 'Disease', (4, 19))	('fragile tumor', 'Disease', (183, 196))	('fragile tumor', 'Disease', 'MESH:D005600', (183, 196))	('IgG4-SC', 'Disease', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('IgG4-SC', 'Var', (150, 157))	('easily bleeding', 'Disease', 'MESH:D006470', (4, 19))
66261	19688828	FOXM1362-370 (YLVPIQFPV), FOXM1373-382 (SLVLQPSVKV), and FOXM1640-649 (GLMDLSTTPL) peptides primed HLA-A2-restricted cytotoxic T lymphocytes (CTLs) in the HLA-A2 transgenic mice.	('FOXM1640-649', 'Var', (57, 69))	('transgenic mice', 'Species', '10090', (162, 177))	('HLA-A', 'Gene', '3105', (99, 104))	('FOXM1362-370', 'Var', (0, 12))	('HLA-A', 'Gene', (99, 104))	('HLA-A', 'Gene', '3105', (155, 160))	('FOXM1373-382', 'Var', (26, 38))	('primed', 'PosReg', (92, 98))	('HLA-A', 'Gene', (155, 160))
66289	19688828	Total RNA of human normal tissues was purchased from Clontech (Palo Alto, CA) and RT-PCR was done as described previously.25 The primer sequences were: FOXM1, 5'-CACCCCAGTGCCAACCGC TACTTG-3' and 5'-AAAGAGGAGCTATCCCCTCCTCAG-3' (that can detect three splicing variants FOXM1a, FOXM1b and FOXM1c) or 5'-CCCTGACAACATCAACTGGTC-3' and 5'-GTCCACCTTCGCTTTTATTGAGT-3' (that cannot detect the variants); GAPDH, 5'-CCCATCACCATCTTCCAGGAGC-3' and 5'-CCAGTGAGCTTCCCGTTCAGC-3'; ACTB, 5'-GAGGTGATAGCATTGCTTTCG-3' and 5'-CAAGTCAGTGTACAGGTAAGC-3'.	('GAPDH', 'Gene', (394, 399))	('human', 'Species', '9606', (13, 18))	('FOXM1b', 'Gene', (275, 281))	('FOXM1b', 'Gene', '2305', (275, 281))	('FOXM1a', 'Var', (267, 273))	('GAPDH', 'Gene', '2597', (394, 399))
66310	19688828	The FOXM1 gene contains 10 exons, 2 of which are alternatively expressed, giving rise to 3 differentially expressed mRNA isoforms.23 Cholangiocarcinoma cell lines, TFK, HuCCT-1, and MEC, and hepatocellular carcinoma cell lines, HepG2 and SK-Hep1 strongly expressed FOXM1b and FOXM1c (FOXM1b < FOXM1c) mRNA (Fig.	('SK-Hep1', 'CellLine', 'CVCL:0525', (238, 245))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (133, 151))	('FOXM1b', 'Gene', '2305', (284, 290))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (133, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('HepG2', 'CellLine', 'CVCL:0027', (228, 233))	('MEC', 'Gene', '56477', (182, 185))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (191, 215))	('FOXM1b', 'Gene', (265, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('hepatocellular carcinoma', 'Disease', (191, 215))	('FOXM1c', 'Var', (276, 282))	('MEC', 'Gene', (182, 185))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (191, 215))	('FOXM1b', 'Gene', (284, 290))	('FOXM1b', 'Gene', '2305', (265, 271))	('Cholangiocarcinoma', 'Disease', (133, 151))
66323	19688828	A series of repeated experiments revealed a reproducible response to FOXM1362-370, FOXM1373-382 and FOXM1640-649 (designated as FOXM1-8, FOXM1-10 and FOXM1-17, respectively; Table 1: Fig.	('FOXM1-17', 'Gene', '2305', (150, 158))	('FOXM1-17', 'Gene', (150, 158))	('FOXM1640-649', 'Var', (100, 112))	('FOXM1-8', 'Gene', '2305', (128, 135))	('FOXM1362-370', 'Var', (69, 81))	('FOXM1-8', 'Gene', (128, 135))	('FOXM1373-382', 'Var', (83, 95))
66326	19688828	To determine whether the immunization of the mice with the FOXM1 peptides caused autoimmunity, a histological analysis was done on various organs isolated from HLA-A2 Tgm immunized with FOXM1-8 or FOXM1-10 peptides.	('FOXM1-8', 'Gene', (186, 193))	('FOXM1-10', 'Var', (197, 205))	('mice', 'Species', '10090', (45, 49))	('autoimmunity', 'Phenotype', 'HP:0002960', (81, 93))	('HLA-A', 'Gene', (160, 165))	('FOXM1-8', 'Gene', '2305', (186, 193))	('Tgm', 'Species', '10090', (167, 170))	('caused', 'Reg', (74, 80))	('FOXM1', 'Gene', (59, 64))	('HLA-A', 'Gene', '3105', (160, 165))
66328	19688828	These results suggest that the CTL response elicited by immunization with FOXM1-8 or FOXM1-10 peptide may not cause damage to normal tissues.	('FOXM1-8', 'Gene', '2305', (74, 81))	('FOXM1-10', 'Var', (85, 93))	('FOXM1-8', 'Gene', (74, 81))	('CTL response', 'CPA', (31, 43))
66347	19688828	Stimulation of PBMCs obtained from healthy donors with FOXM1-8 (YLVPIQFPV), FOXM1-10 (SLVLQPSVKV) and FOXM1-17 (GLMDLSTTPL) peptides resulted in the generation of peptide-reactive CTL lines.	('peptide-reactive CTL lines', 'MPA', (163, 189))	('FOXM1-17', 'Gene', (102, 110))	('FOXM1-8', 'Gene', '2305', (55, 62))	('FOXM1-10', 'Var', (76, 84))	('FOXM1-8', 'Gene', (55, 62))	('FOXM1-17', 'Gene', '2305', (102, 110))
66399	31177590	Among them, seven modules (pink, dark green, orange, tan, turquoise, magenta, and saddle brown) were positively correlated with histological grade G1 and G4, pathological stage III-IV, pathological type (distal), Child-Pugh classification, and Ishak fibrosis stage 3-4.	('fibrosis', 'Disease', 'MESH:D005355', (250, 258))	('fibrosis', 'Disease', (250, 258))	('Child', 'Species', '9606', (213, 218))	('correlated', 'Reg', (112, 122))	('Child-Pugh classification', 'Disease', (213, 238))	('dark green', 'Var', (33, 43))
66424	31177590	With the abnormal regulation of this module's genes, the dysfunction of immune cells facilitates tumor immune evasion and tissue infiltration of tumor cells; moreover, weakened cell adhesion could promote metastasis or movement of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('abnormal regulation', 'Var', (9, 28))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('facilitates', 'PosReg', (85, 96))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (231, 236))	('metastasis', 'CPA', (205, 215))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (145, 150))	('weakened', 'NegReg', (168, 176))	('dysfunction', 'Var', (57, 68))	('cell adhesion', 'CPA', (177, 190))	('promote', 'PosReg', (197, 204))
66425	31177590	Changes in cell metabolism are central to cancer development.31 The mitochondria, which plays a central role in regulating parameters of the metabolism such as energy production, production of biosynthetic precursors, redox status, reactive oxygen species (ROS) generation, cytosolic calcium levels, and the initiation of apoptosis, has been a fascinating focus of oncologic investigation, and somatic mitochondrial DNA (mtDNA) mutations have been identified in some solid tumors, and have been suggested as playing a critical role in carcinogenesis.32 Mutations in mtDNA are enhanced by ROS generated by the oxidative phosphorylation pathway.	('tumors', 'Disease', (473, 479))	('tumors', 'Disease', 'MESH:D009369', (473, 479))	('tumors', 'Phenotype', 'HP:0002664', (473, 479))	('enhanced', 'PosReg', (576, 584))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('ROS', 'Chemical', 'MESH:D017382', (257, 260))	('cancer', 'Disease', (42, 48))	('mtDNA', 'Gene', (566, 571))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('ROS', 'Chemical', 'MESH:D017382', (588, 591))	('tumor', 'Phenotype', 'HP:0002664', (473, 478))	('Mutations', 'Var', (553, 562))
66587	25785331	Intraductal ultrasonography showed portal vein stenosis invaded by a notched lesion with a circular-asymmetric appearance in the main bile duct (Fig.	('vein stenosis', 'Disease', (42, 55))	('asymmetric appearance', 'Phenotype', 'HP:0000324', (100, 121))	('vein stenosis', 'Phenotype', 'HP:0025491', (42, 55))	('vein stenosis', 'Disease', 'MESH:D000071078', (42, 55))	('notched', 'Var', (69, 76))
66725	31683901	In this study, no single genetic alteration could induce tumour formation, but mutant KRAS with repression of other major tumour suppressor genes co-operating was required to induce tumour development.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('induce', 'PosReg', (175, 181))	('tumour', 'Disease', (57, 63))	('KRAS', 'Gene', (86, 90))	('rat', 'Species', '10116', (152, 155))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('mutant', 'Var', (79, 85))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('tumour', 'Disease', (122, 128))	('rat', 'Species', '10116', (37, 40))	('tumour', 'Disease', (182, 188))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
66737	31683901	The classical view of cancer development through cancer cells accumulating consecutive genetic mutations in a multi-step process has been the predominant outlook for the last decades.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('genetic mutations', 'Var', (87, 104))	('cancer', 'Disease', (49, 55))
66750	31683901	showed that the presence of Laminin-5, recently renamed to Laminin-322, was associated with a higher occurrence of metastasis and a worse prognosis in HCC patients.	('Laminin-5', 'Gene', (28, 37))	('metastasis', 'CPA', (115, 125))	('HCC', 'Disease', (151, 154))	('Laminin-322', 'Chemical', '-', (59, 70))	('presence', 'Var', (16, 24))	('patients', 'Species', '9606', (155, 163))	('HCC', 'Phenotype', 'HP:0001402', (151, 154))
66767	31683901	Another effect of the desmoplastic TEE is through an increased rigidity resulting from remodelling proteins, particularly LOXL2 in CCA, crosslinking collagens and elastins.	('rigidity', 'Disease', (63, 71))	('rigidity', 'Phenotype', 'HP:0002063', (63, 71))	('LOXL2', 'Gene', (122, 127))	('rigidity', 'Disease', 'MESH:D009127', (63, 71))	('LOXL2', 'Gene', '4017', (122, 127))	('elastin', 'Gene', '2006', (163, 170))	('elastin', 'Gene', (163, 170))	('increased', 'PosReg', (53, 62))	('CCA', 'Phenotype', 'HP:0030153', (131, 134))	('crosslinking', 'Var', (136, 148))
66783	31683901	For example, in hepatic progenitor cell (HPC)-related HCCs the presence of laminin-332 in vitro induced a phenotypic switch resulting in a more quiescent cell state, and an increased resistance to doxorubicin and sorafenib (Figure 2C).	('presence', 'Var', (63, 71))	('sorafenib', 'Chemical', 'MESH:D000077157', (213, 222))	('doxorubicin', 'Chemical', 'MESH:D004317', (197, 208))	('laminin-332', 'Gene', (75, 86))	('HCC', 'Phenotype', 'HP:0001402', (54, 57))	('phenotypic switch', 'MPA', (106, 123))	('induced', 'Reg', (96, 103))	('increased', 'PosReg', (173, 182))	('more', 'PosReg', (139, 143))
66914	29989102	Many genetic mutations in genes like TP53, KRAS, SMAD4, ABCB11, ARID1A, ATP8B, BRAF, IDH1/2, MLL3 and PBRM1 were reported to be associated with the pathogenesis and progression of CCA.	('MLL3', 'Gene', '58508', (93, 97))	('BRAF', 'Gene', '673', (79, 83))	('associated', 'Reg', (128, 138))	('TP53', 'Gene', (37, 41))	('BRAF', 'Gene', (79, 83))	('KRAS', 'Gene', '3845', (43, 47))	('IDH1/2', 'Gene', '3417;3418', (85, 91))	('ABCB11', 'Gene', (56, 62))	('IDH1/2', 'Gene', (85, 91))	('PBRM1', 'Gene', '55193', (102, 107))	('SMAD4', 'Gene', '4089', (49, 54))	('KRAS', 'Gene', (43, 47))	('ABCB11', 'Gene', '8647', (56, 62))	('MLL3', 'Gene', (93, 97))	('ARID1A', 'Gene', (64, 70))	('PBRM1', 'Gene', (102, 107))	('CCA', 'Phenotype', 'HP:0030153', (180, 183))	('TP53', 'Gene', '7157', (37, 41))	('mutations', 'Var', (13, 22))	('CCA', 'Disease', (180, 183))	('ARID1A', 'Gene', '8289', (64, 70))	('ATP8B', 'Gene', (72, 77))	('SMAD4', 'Gene', (49, 54))
66962	29172284	The overexpression of COX-2 has been reported to stimulate carcinogenesis by activating cell proliferation, suppressing apoptosis and inducing angiogenesis.	('inducing', 'Reg', (134, 142))	('activating', 'PosReg', (77, 87))	('COX-2', 'Gene', '4513', (22, 27))	('overexpression', 'Var', (4, 18))	('apoptosis', 'CPA', (120, 129))	('COX-2', 'Gene', (22, 27))	('angiogenesis', 'CPA', (143, 155))	('carcinogenesis', 'Disease', 'MESH:D063646', (59, 73))	('cell proliferation', 'CPA', (88, 106))	('stimulate', 'PosReg', (49, 58))	('suppressing', 'NegReg', (108, 119))	('carcinogenesis', 'Disease', (59, 73))
66964	29172284	However, the molecular mechanism of how COX-2 inhibition induces apoptosis is unclear.	('COX-2', 'Gene', (40, 45))	('inhibition', 'Var', (46, 56))	('COX-2', 'Gene', '4513', (40, 45))
67032	24212720	The rate of HPLN positivity in 110 patients undergoing exploration for potential curative resection was 30 % and did not vary with histologic subtype (gallbladder vs. cholangiocarcinoma).	('HPLN', 'Gene', (12, 16))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (167, 185))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (167, 185))	('positivity', 'Var', (17, 27))	('cholangiocarcinoma', 'Disease', (167, 185))	('patients', 'Species', '9606', (35, 43))
67036	24212720	On multivariate analysis, HPLN status was an independent predictor of RFS (hazard ratio 3.73, 95 % CI 1.86-7.45; p < 0.01) and DSS (hazard ratio 3.98, 95 % CI 1.89-8.38; p < 0.01).	('RFS', 'Disease', (70, 73))	('DSS', 'Chemical', '-', (127, 130))	('DSS', 'Disease', (127, 130))	('HPLN status', 'Var', (26, 37))
67075	24212720	The median age was 66 years (range 34-82 years) and was similar for patients with positive or negative HPLN.	('patients', 'Species', '9606', (68, 76))	('positive', 'Var', (82, 90))	('HPLN', 'Gene', (103, 107))
67077	24212720	For tumor-related variables, the degree of differentiation, prevalence of papillary subtype, and presence of perineural and vascular invasion were not significantly different for patients with a positive or negative HPLN.	('tumor', 'Disease', (4, 9))	('HPLN', 'Gene', (216, 220))	('positive', 'Var', (195, 203))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('patients', 'Species', '9606', (179, 187))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
67096	24212720	HPLN status was independently associated with death from disease when accounting for margin status and pathologic T stage (HR 3.98, 95 % CI 1.89-8.38; p < 0.01).	('death', 'Disease', (46, 51))	('HPLN status', 'Var', (0, 11))	('death', 'Disease', 'MESH:D003643', (46, 51))	('associated with', 'Reg', (30, 45))
67109	24212720	For patients who did go on to have complete gross resection (R0/R1), HPLN positivity was highly prognostic of recurrence and survival.	('positivity', 'Var', (74, 84))	('HPLN', 'Gene', (69, 73))	('survival', 'CPA', (125, 133))	('patients', 'Species', '9606', (4, 12))	('prognostic', 'Reg', (96, 106))	('recurrence', 'CPA', (110, 120))
67110	24212720	Although we know that some patients with local LN involvement are able to achieve long-term survival, patients with positive HPLN who underwent complete gross resection of their disease in this cohort shared the same survival outcome as patients with unresectable disease.	('positive', 'Var', (116, 124))	('patients', 'Species', '9606', (102, 110))	('patients', 'Species', '9606', (27, 35))	('HPLN', 'Gene', (125, 129))	('patients', 'Species', '9606', (237, 245))
67218	23408390	In addition to potent antifungal and immunosuppressive properties, mTOR inhibitors strongly suppress cellular proliferation, making them attractive anti-cancer agents.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cellular proliferation', 'CPA', (101, 123))	('cancer', 'Disease', (153, 159))	('mTOR', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('suppress', 'NegReg', (92, 100))	('inhibitors', 'Var', (72, 82))
67248	23408390	The importance of the mTOR pathway in carcinogenesis is further underscored by the presence of mutations along the mTOR pathway in familial cancer syndromes.	('carcinogenesis', 'Disease', 'MESH:D063646', (38, 52))	('presence', 'Reg', (83, 91))	('familial cancer syndromes', 'Disease', (131, 156))	('carcinogenesis', 'Disease', (38, 52))	('mTOR pathway', 'Pathway', (115, 127))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('familial cancer syndromes', 'Disease', 'MESH:D009386', (131, 156))
67249	23408390	Examples of such syndromes include Cowden's syndrome (loss of PTEN), Peutz-Jegher's syndrome (loss of LKB1, an activator of AMPK which in turn inhibits the mTOR pathway), tuberous sclerosis and lymphangioleiomyomatosis (loss of TSC1 or TSC2).	('LKB1', 'Gene', (102, 106))	('TSC1', 'Gene', '7248', (228, 232))	('inhibits', 'NegReg', (143, 151))	('PTEN', 'Gene', (62, 66))	("Cowden's syndrome", 'Disease', 'MESH:D006223', (35, 52))	('LKB1', 'Gene', '6794', (102, 106))	('TSC1', 'Gene', (228, 232))	("Peutz-Jegher's syndrome", 'Disease', 'MESH:D010580', (69, 92))	("Peutz-Jegher's syndrome", 'Disease', (69, 92))	('lymphangioleiomyomatosis', 'Phenotype', 'HP:0012798', (194, 218))	('loss', 'Var', (94, 98))	('loss', 'NegReg', (54, 58))	('TSC2', 'Gene', '7249', (236, 240))	("Cowden's syndrome", 'Disease', (35, 52))	('AMPK', 'Gene', '5562', (124, 128))	('TSC2', 'Gene', (236, 240))	('tuberous sclerosis and lymphangioleiomyomatosis', 'Disease', 'MESH:D018192', (171, 218))	('AMPK', 'Gene', (124, 128))
67254	23408390	Inhibition of S6K1 the other branch downstream of mTOR unexpectedly prevented hepatocyte apoptosis, as demonstrated in an in vivo model of S6K1 knockout mice.	('hepatocyte', 'MPA', (78, 88))	('prevented', 'NegReg', (68, 77))	('S6K1', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('mice', 'Species', '10090', (153, 157))
67256	23408390	Mouse models of gene knockouts of components upstream of mTOR have demonstrated the importance of mTOR in liver regeneration after partial hepatectomy.	('liver regeneration', 'CPA', (106, 124))	('gene knockouts', 'Var', (16, 30))	('Mouse', 'Species', '10090', (0, 5))
67260	23408390	The importance of mTOR in hepatocarcinogenesis has been further shown in a mouse model with a liver-specific knockout of Tsc1: the resulting chronic mTOR activation led to sporadic and sequential development of histological features associated with HCC (liver damage, inflammation, necrosis, and regeneration).	('Tsc1', 'Gene', '64930', (121, 125))	('inflammation', 'Disease', 'MESH:D007249', (268, 280))	('necrosis', 'Disease', (282, 290))	('knockout', 'Var', (109, 117))	('inflammation', 'Disease', (268, 280))	('HCC', 'Disease', (249, 252))	('mTOR', 'Gene', (149, 153))	('liver damage', 'Disease', (254, 266))	('activation', 'PosReg', (154, 164))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (26, 46))	('liver damage', 'Disease', 'MESH:D056486', (254, 266))	('mouse', 'Species', '10090', (75, 80))	('necrosis', 'Disease', 'MESH:D009336', (282, 290))	('hepatocarcinogenesis', 'Disease', (26, 46))	('Tsc1', 'Gene', (121, 125))
67264	23408390	Aberrant lipogenesis was increasingly seen in a spectrum of human non-tumorous liver tissue to liver cancer, and was associated with mTOR pathway activation.	('non-tumorous liver tissue to liver cancer', 'Disease', (66, 107))	('lipogenesis', 'MPA', (9, 20))	('tumorous liver', 'Phenotype', 'HP:0002896', (70, 84))	('seen', 'Reg', (38, 42))	('activation', 'PosReg', (146, 156))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Aberrant', 'Var', (0, 8))	('associated', 'Reg', (117, 127))	('non-tumorous liver tissue to liver cancer', 'Disease', 'MESH:D006528', (66, 107))	('Aberrant lipogenesis', 'Phenotype', 'HP:0009125', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('liver cancer', 'Phenotype', 'HP:0002896', (95, 107))	('human', 'Species', '9606', (60, 65))	('mTOR pathway', 'Pathway', (133, 145))
67270	23408390	For example, sirolimus and temsirolimus have been shown to inhibit angiogenesis, correlating with decreased VEGF production and HIF-1 activity in cancer cells.	('VEGF', 'Gene', (108, 112))	('sirolimus', 'Chemical', 'MESH:D020123', (13, 22))	('angiogenesis', 'CPA', (67, 79))	('temsirolimus', 'Var', (27, 39))	('HIF-1 activity in cancer', 'Disease', 'MESH:D009369', (128, 152))	('VEGF', 'Gene', '7422', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('inhibit', 'NegReg', (59, 66))	('decreased', 'NegReg', (98, 107))	('temsirolimus', 'Chemical', 'MESH:C401859', (27, 39))	('sirolimus', 'Chemical', 'MESH:D020123', (30, 39))	('HIF-1 activity in cancer', 'Disease', (128, 152))
67283	23408390	NVP-BEZ235 is such a dual inhibitor: it inhibits PI3K at its ATP-binding domain in addition to preventing the catalytic activity of mTORC1 and mTORC2 complexes.	('mTORC1', 'Gene', (132, 138))	('ATP', 'Gene', (61, 64))	('ATP', 'Gene', '51761', (61, 64))	('NVP-BEZ235', 'Var', (0, 10))	('BEZ235', 'Chemical', 'MESH:C531198', (4, 10))	('mTORC1', 'Gene', '382056', (132, 138))	('preventing', 'NegReg', (95, 105))	('inhibits', 'NegReg', (40, 48))	('mTORC2', 'Gene', (143, 149))	('PI3K', 'Pathway', (49, 53))	('mTORC2', 'Gene', '74343', (143, 149))	('catalytic activity', 'MPA', (110, 128))
67287	23408390	This potent suppression is in contradistinction to the weaker effect of sirolimus, where inhibition of the mTORC1/S6K1 negative feedback loop activates the PI3K/Akt/mTOR pathway to a certain extent.	('activates', 'PosReg', (142, 151))	('sirolimus', 'Chemical', 'MESH:D020123', (72, 81))	('inhibition', 'Var', (89, 99))	('mTORC1', 'Gene', '382056', (107, 113))	('Akt', 'Gene', '207', (161, 164))	('Akt', 'Gene', (161, 164))	('mTORC1', 'Gene', (107, 113))
67291	23408390	There are likely two reasons for this: firstly, the recurrence rate of HCC after liver transplant is low enough that it would be difficult to demonstrate a significant difference in recurrence rates within a randomized trial; secondly, sirolimus is associated with significant intolerable side effects for patients, which has historically led to significant study dropout.	('sirolimus', 'Var', (236, 245))	('HCC', 'Disease', (71, 74))	('sirolimus', 'Chemical', 'MESH:D020123', (236, 245))	('patients', 'Species', '9606', (306, 314))
67312	23408390	A study of comparative genomic hybridization of DNA extracted from 32 cholangiocarcinoma tumors identified copy number gains in various genes along the mTOR pathway.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('cholangiocarcinoma tumors', 'Disease', 'MESH:D018281', (70, 95))	('copy number gains', 'Var', (107, 124))	('cholangiocarcinoma tumors', 'Disease', (70, 95))	('mTOR pathway', 'Pathway', (152, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
67314	23408390	An in vivo mouse model with liver-specific targeted disruption of PTEN and SMAD4 was shown to induce development of hyperplastic foci within the bile ducts exclusively.	('mouse', 'Species', '10090', (11, 16))	('PTEN', 'Gene', (66, 70))	('hyperplastic foci within the', 'CPA', (116, 144))	('SMAD4', 'Gene', '17128', (75, 80))	('SMAD4', 'Gene', (75, 80))	('induce', 'Reg', (94, 100))	('disruption', 'Var', (52, 62))
67325	23408390	Inhibition of PI3K upstream of mTOR affected hepatoblastoma cell growth in vitro through induction of apoptosis.	('mTOR', 'Gene', (31, 35))	('apoptosis', 'CPA', (102, 111))	('PI3K', 'Protein', (14, 18))	('hepatoblastoma', 'Disease', (45, 59))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (45, 59))	('Inhibition', 'Var', (0, 10))	('hepatoblastoma', 'Disease', 'MESH:D018197', (45, 59))	('affected', 'Reg', (36, 44))
67329	23408390	There is accumulating evidence of the efficacy of mTOR inhibition as a chemotherapeutic strategy for hepatocellular carcinoma.	('mTOR', 'Protein', (50, 54))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (101, 125))	('hepatocellular carcinoma', 'Disease', (101, 125))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (101, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('inhibition', 'Var', (55, 65))
67361	21953056	Antisense locked nucleic acids (LNA) were targeted to miR-25 or miR-106b, and compared to Negative Control A LNA (Exiqon, Vedbaek, Denmark).	('Antisense', 'Var', (0, 9))	('miR-25', 'Gene', (54, 60))	('miR-106b', 'Gene', (64, 72))	('miR-106b', 'Gene', '406900', (64, 72))
67397	21953056	The amount of MCM7 in the tumor samples that had high miR-25 was nearly 3-fold higher than those with low miR-25 (Fig.	('higher', 'PosReg', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('MCM7', 'Gene', (14, 18))	('high miR-25', 'Var', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('miR-25', 'Var', (54, 60))	('MCM7', 'Gene', '4176', (14, 18))
67405	21953056	Cellular DR4, but not DR5, Bim, Mcl-1, Caspase-8, or c-FLIP protein expression was efficiently reduced by miR-25 overexpression in KMCH cells (Fig 5C).	('Mcl-1', 'Gene', (32, 37))	('DR4', 'Gene', (9, 12))	('Bim', 'Gene', (27, 30))	('c-FLIP', 'Gene', '8837', (53, 59))	('c-FLIP', 'Gene', (53, 59))	('Bim', 'Gene', '10018', (27, 30))	('Caspase-8', 'Gene', '841', (39, 48))	('DR5', 'Gene', (22, 25))	('Mcl-1', 'Gene', '4170', (32, 37))	('DR5', 'Gene', '8795', (22, 25))	('DR4', 'Gene', '8797', (9, 12))	('miR-25', 'Gene', (106, 112))	('reduced', 'NegReg', (95, 102))	('Caspase-8', 'Gene', (39, 48))	('overexpression', 'Var', (113, 127))
67407	21953056	Conversely, antagonism of miR-25 caused increased DR4 protein expression in KMCH cells.	('antagonism', 'Var', (12, 22))	('DR4', 'Gene', '8797', (50, 53))	('DR4', 'Gene', (50, 53))	('miR-25', 'Gene', (26, 32))	('increased', 'PosReg', (40, 49))
67410	21953056	Antagonism of miR-25 also increased DR4 protein levels when examined by immunofluorescence staining of KMCH cells.	('DR4', 'Gene', '8797', (36, 39))	('DR4', 'Gene', (36, 39))	('Antagonism', 'Var', (0, 10))	('increased', 'PosReg', (26, 35))	('miR-25', 'Gene', (14, 20))
67412	21953056	Quantitation of the fluorescent signal revealed a greater than two-fold increase in DR4 immunoreactivity in LNA-25 transfected cells versus control LNA (CT; Fig.	('increase', 'PosReg', (72, 80))	('DR4', 'Gene', '8797', (84, 87))	('DR4', 'Gene', (84, 87))	('transfected', 'Var', (115, 126))	('immunoreactivity', 'MPA', (88, 104))
67421	21953056	To further assess a potential inverse correlation, we measured DR4 mRNA in patient-derived cholangiocarcinoma samples stratified into high (n = 5) or low (n = 5) miR-25.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('measured', 'Reg', (54, 62))	('high', 'Var', (134, 138))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('DR4', 'Gene', '8797', (63, 66))	('DR4', 'Gene', (63, 66))	('cholangiocarcinoma', 'Disease', (91, 109))	('miR-25', 'Var', (162, 168))	('patient', 'Species', '9606', (75, 82))
67422	21953056	Again, elevated miR-25 was not strictly correlated with low DR4 mRNA (Fig.	('miR-25', 'Protein', (16, 22))	('low', 'Var', (56, 59))	('DR4', 'Gene', '8797', (60, 63))	('DR4', 'Gene', (60, 63))	('elevated', 'PosReg', (7, 15))
67434	21953056	Antagonism of miR-25 caused increased DR4 protein expression and sensitized cells to apoptosis.	('increased', 'PosReg', (28, 37))	('Antagonism', 'Var', (0, 10))	('sensitized', 'Reg', (65, 75))	('DR4', 'Gene', '8797', (38, 41))	('miR-25', 'Gene', (14, 20))	('expression', 'MPA', (50, 60))	('DR4', 'Gene', (38, 41))
67440	21953056	Also, in tumor samples with high miR-25, MCM7 was also elevated.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('MCM7', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('high miR-25', 'Var', (28, 39))	('elevated', 'PosReg', (55, 63))	('miR-25', 'Var', (33, 39))	('MCM7', 'Gene', '4176', (41, 45))
67455	21953056	Surprisingly, we did not find that miR-25 suppressed Bim protein levels or that antagonism of miR-25 increased Bim expression in cholangiocarcinoma cells.	('miR-25', 'Gene', (94, 100))	('Bim', 'Gene', (53, 56))	('Bim', 'Gene', '10018', (53, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (129, 147))	('increased', 'PosReg', (101, 110))	('increased Bim', 'Phenotype', 'HP:0003573', (101, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (129, 147))	('suppressed', 'NegReg', (42, 52))	('antagonism', 'Var', (80, 90))	('Bim', 'Gene', (111, 114))	('Bim', 'Gene', '10018', (111, 114))	('cholangiocarcinoma', 'Disease', (129, 147))
67456	21953056	Because Bim protein levels were not reduced by miR-25 (nor induced by LNA-25), we searched for alternate targets.	('miR-25', 'Var', (47, 53))	('Bim', 'Gene', (8, 11))	('Bim', 'Gene', '10018', (8, 11))
67459	21953056	Additionally, immunofluorescence studies of DR4 and DR5 demonstrated that only DR4 immunoreactivity was increased upon miR-25 antagonism.	('immunoreactivity', 'MPA', (83, 99))	('DR5', 'Gene', (52, 55))	('increased', 'PosReg', (104, 113))	('antagonism', 'Var', (126, 136))	('DR4', 'Gene', '8797', (44, 47))	('DR4', 'Gene', (44, 47))	('miR-25', 'Gene', (119, 125))	('DR5', 'Gene', '8795', (52, 55))	('DR4', 'Gene', '8797', (79, 82))	('DR4', 'Gene', (79, 82))
67461	21953056	Luciferase experiments demonstrated that miR-25 repression of the signal was dependent on the presence of the DR4 3'UTR, and mutation of the putative miR-25 binding site lead to restoration of luciferase expression.	('restoration', 'PosReg', (178, 189))	('luciferase', 'Enzyme', (193, 203))	('miR-25', 'Gene', (150, 156))	('expression', 'MPA', (204, 214))	('DR4', 'Gene', '8797', (110, 113))	('DR4', 'Gene', (110, 113))	('mutation', 'Var', (125, 133))
67466	21953056	We demonstrated that cells can be resensitized to TRAIL-induced apoptosis upon restoration of DR4 protein in miR-25 transfected cells.	('transfected', 'Var', (116, 127))	('TRAIL', 'Gene', (50, 55))	('miR-25', 'Gene', (109, 115))	('TRAIL', 'Gene', '8743', (50, 55))	('DR4', 'Gene', '8797', (94, 97))	('DR4', 'Gene', (94, 97))
67469	21953056	8) is consistent with the observation that Hedgehog inhibition both increased DR4 protein and sensitized to apoptosis.	('DR4', 'Gene', '8797', (78, 81))	('DR4', 'Gene', (78, 81))	('sensitized', 'Reg', (94, 104))	('inhibition', 'Var', (52, 62))	('increased', 'PosReg', (68, 77))	('apoptosis', 'CPA', (108, 117))	('Hedgehog', 'Gene', (43, 51))
67481	32252724	Recurrence-free survival (RFS) was also better in patients with a margin > 0.5 cm than in the < 0.5-0.1 cm or the R1-group, but even without reaching significance.	('> 0.5 cm', 'Var', (73, 81))	('better', 'PosReg', (40, 46))	('patients', 'Species', '9606', (50, 58))	('Recurrence-free survival', 'CPA', (0, 24))
67688	32051893	The strongest dose predictors for G3 + HB toxicity were VBED1040 >= 37 mL and VBED1030 >= 45 mL, but only for patients with hepatic cholangiocarcioma.	('VBED1040 >= 37 mL', 'Var', (56, 73))	('HB toxicity', 'Disease', (39, 50))	('VBED1030', 'Chemical', 'MESH:C444006', (78, 86))	('hepatic cholangiocarcioma', 'Disease', (124, 149))	('HB toxicity', 'Disease', 'MESH:D064420', (39, 50))	('VBED1030 >=', 'Var', (78, 89))	('hepatic cholangiocarcioma', 'Disease', 'MESH:D056486', (124, 149))	('patients', 'Species', '9606', (110, 118))
67751	29956810	The patients were principally divided into 3 groups on the basis of BMI: Underweight (<18.5 kg/m2), normal (>=18.5 to <25.0 kg/m2) and high (>=25.0 kg/m2).	('>=18.5 to <25.0', 'Var', (108, 123))	('<18.5 kg/m2', 'Var', (86, 97))	('patients', 'Species', '9606', (4, 12))
67752	29956810	The high group included two sub-groups: Overweight (>=25 to <30 kg/m2) and obese (>=30 kg/m2).	('obese', 'Disease', 'MESH:D009765', (75, 80))	('Overweight', 'Phenotype', 'HP:0025502', (40, 50))	('>=30 kg/m2', 'Var', (82, 92))	('obese', 'Disease', (75, 80))	('>=25', 'Var', (52, 56))
67790	29956810	The result suggested that high BMI (>=25) was a high risk factor for cancer in the gallbladder, rectum, kidney and uterus.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('high', 'Var', (26, 30))	('cancer', 'Disease', (69, 75))
67829	29956810	We identified a positive correlation between a high BMI and the corresponding two/five-year survival rate in cancer samples (r=0.53, Spearman correlation coefficient, Figs.	('BMI', 'MPA', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('high', 'Var', (47, 51))	('cancer', 'Disease', (109, 115))	('two/five-year survival rate', 'CPA', (78, 105))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
67843	29956810	For example, high levels of testosterone, and estrogen and progesterone are risk factors for prostate cancer and breast cancer, respectively.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate cancer', 'Disease', (93, 108))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('risk factors', 'Reg', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('high', 'Var', (13, 17))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('testosterone', 'Chemical', 'MESH:D013739', (28, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (93, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (93, 108))
67853	29956810	Patients with a low BMI (<18.5) had a reduced incidence for all 38 types of cancer.	('low BMI', 'Phenotype', 'HP:0045082', (16, 23))	('reduced', 'NegReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Patients', 'Species', '9606', (0, 8))	('<18.5', 'Var', (25, 30))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
67899	27440504	Integrin beta6 may help to improve the diagnostic accuracy, and targeting beta6 may be a novel strategy for the treatment of cholangiocarcinoma.	('diagnostic accuracy', 'MPA', (39, 58))	('beta6', 'Chemical', '-', (9, 14))	('cholangiocarcinoma', 'Disease', (125, 143))	('targeting', 'Var', (64, 73))	('beta6', 'Chemical', '-', (74, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (125, 143))	('improve', 'PosReg', (27, 34))	('beta6', 'Gene', (74, 79))	('Integrin beta6', 'Gene', '3694', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (125, 143))	('Integrin beta6', 'Gene', (0, 14))
67942	27440504	Then, we performed Transwell migration and invasion assays in cholangiocarcinoma cells after beta6 silencing.	('Transwell migration', 'CPA', (19, 38))	('cholangiocarcinoma', 'Disease', (62, 80))	('beta6', 'Protein', (93, 98))	('invasion assays', 'CPA', (43, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (62, 80))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (62, 80))	('silencing', 'Var', (99, 108))	('beta6', 'Chemical', '-', (93, 98))
67946	27440504	4A,B, beta6 expression was significantly increased after transfection.	('beta6', 'Protein', (6, 11))	('increased', 'PosReg', (41, 50))	('transfection', 'Var', (57, 69))	('beta6', 'Chemical', '-', (6, 11))	('expression', 'MPA', (12, 22))
67949	27440504	To identify the mechanism underlying the effects of beta6 on invasion in cholangiocarcinoma cells, we measured the mRNA expression of uPA, MMP2, MMP3, and MMP9 using quantitative real-time PCR after silencing or overexpressing beta6.	('MMP3', 'Gene', (145, 149))	('beta6', 'Chemical', '-', (227, 232))	('mRNA', 'MPA', (115, 119))	('cholangiocarcinoma', 'Disease', (73, 91))	('MMP9', 'Gene', '4318', (155, 159))	('MMP9', 'Gene', (155, 159))	('MMP3', 'Gene', '4314', (145, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('uPA', 'Gene', (134, 137))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (73, 91))	('MMP2', 'Gene', (139, 143))	('uPA', 'Gene', '5328', (134, 137))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (73, 91))	('overexpressing', 'PosReg', (212, 226))	('beta6', 'Chemical', '-', (52, 57))	('silencing', 'Var', (199, 208))	('MMP2', 'Gene', '4313', (139, 143))
67957	27440504	First, using the specific Rac1 activity inhibitor NSC23766, we found that Rac1 was essential for the migration and invasion of cholangiocarcinoma cells, as NSC23766 suppressed migration and invasion of RBE cells in a dose-dependent manner (Fig.	('cholangiocarcinoma', 'Disease', (127, 145))	('invasion', 'CPA', (190, 198))	('Rac1', 'Gene', '5879', (74, 78))	('migration', 'CPA', (176, 185))	('Rac1', 'Gene', (26, 30))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (127, 145))	('Rac1', 'Gene', (74, 78))	('Rac1', 'Gene', '5879', (26, 30))	('NSC23766', 'Var', (156, 164))	('suppressed', 'NegReg', (165, 175))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (127, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))
67958	27440504	Then, we demonstrated that overexpression of integrin beta6 could effectively promote the migration and invasion capacity of cholangiocarcinoma cells, whereas NSC23766 significantly inhibited this effect (Fig.	('NSC23766', 'Var', (159, 167))	('promote', 'PosReg', (78, 85))	('migration', 'CPA', (90, 99))	('cholangiocarcinoma', 'Disease', (125, 143))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (125, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('inhibited', 'NegReg', (182, 191))	('invasion capacity', 'CPA', (104, 121))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (125, 143))	('overexpression', 'PosReg', (27, 41))
67960	27440504	In addition, we found that beta6 silencing significantly decreased Rac1-GTPase activity (Fig.	('Rac1', 'Gene', '5879', (67, 71))	('activity', 'MPA', (79, 87))	('Rac1', 'Gene', (67, 71))	('silencing', 'Var', (33, 42))	('beta6', 'Protein', (27, 32))	('beta6', 'Chemical', '-', (27, 32))	('GTP', 'Chemical', 'MESH:D006160', (72, 75))	('decreased', 'NegReg', (57, 66))
67972	27440504	Rac1 silencing significantly decreased the expression of MMP9 at both the mRNA and protein level (Fig.	('silencing', 'Var', (5, 14))	('Rac1', 'Gene', '5879', (0, 4))	('Rac1', 'Gene', (0, 4))	('decreased', 'NegReg', (29, 38))	('MMP9', 'Gene', '4318', (57, 61))	('MMP9', 'Gene', (57, 61))	('expression', 'MPA', (43, 53))
67973	27440504	Moreover, beta6 silencing decreased MMP9 expression, while beta6 overexpression increased the expression of MMP9.	('beta6', 'Protein', (10, 15))	('MMP9', 'Gene', (108, 112))	('expression', 'MPA', (41, 51))	('MMP9', 'Gene', '4318', (108, 112))	('MMP9', 'Gene', (36, 40))	('silencing', 'Var', (16, 25))	('MMP9', 'Gene', '4318', (36, 40))	('beta6', 'Chemical', '-', (10, 15))	('expression', 'MPA', (94, 104))	('beta6', 'Chemical', '-', (59, 64))	('decreased', 'NegReg', (26, 35))
67978	27440504	Consistent with our in vitro findings, our results showed that silencing of beta6 markedly suppressed the growth of RBE xenograft tumors compared with that of the NC group, while beta6 overexpression promoted the growth of tumors (Fig.	('suppressed', 'NegReg', (91, 101))	('tumors', 'Disease', (130, 136))	('beta6', 'Chemical', '-', (76, 81))	('promoted', 'PosReg', (200, 208))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('beta6', 'Gene', (76, 81))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('growth', 'MPA', (106, 112))	('beta6', 'Chemical', '-', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('RBE xenograft tumors', 'Disease', 'MESH:D009369', (116, 136))	('RBE xenograft tumors', 'Disease', (116, 136))	('growth', 'CPA', (213, 219))	('silencing', 'Var', (63, 72))
67979	27440504	The overall mean tumor volume and tumor weight of the LV-sibeta6 group were significantly smaller than those of the LV-NC group, whereas tumors in the LV-beta6 group had a relatively larger volume and weight (Fig.	('tumors', 'Disease', (137, 143))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('LV-sibeta6', 'Var', (54, 64))	('smaller', 'NegReg', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('beta6', 'Chemical', '-', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('beta6', 'Chemical', '-', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
67980	27440504	8D,E, compared with the LV-NC group, beta6 silencing markedly decreased the MMP9 expression in the xenograft tumors, while beta6 overexpression significantly increased the MMP9 expression.	('MMP9', 'Gene', '4318', (172, 176))	('beta6', 'Chemical', '-', (37, 42))	('MMP9', 'Gene', (172, 176))	('xenograft tumors', 'Disease', (99, 115))	('decreased', 'NegReg', (62, 71))	('MMP9', 'Gene', (76, 80))	('beta6', 'Gene', (37, 42))	('MMP9', 'Gene', '4318', (76, 80))	('silencing', 'Var', (43, 52))	('xenograft tumors', 'Disease', 'MESH:D009369', (99, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('beta6', 'Chemical', '-', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
67993	27440504	Previous studies showed that beta6 increases the expression and secretion of MMP2, MMP3 and MMP9, resulting in the degradation of the extracellular matrix and increased tumor cell invasiveness in colon cancer, pancreatic cancer and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('MMP3', 'Gene', (83, 87))	('colon cancer', 'Disease', (196, 208))	('ovarian cancer', 'Disease', 'MESH:D010051', (232, 246))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (210, 227))	('beta6', 'Var', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('increases', 'PosReg', (35, 44))	('secretion', 'MPA', (64, 73))	('MMP2', 'Gene', '4313', (77, 81))	('expression', 'MPA', (49, 59))	('MMP9', 'Gene', (92, 96))	('tumor', 'Disease', (169, 174))	('MMP9', 'Gene', '4318', (92, 96))	('MMP3', 'Gene', '4314', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('beta6', 'Chemical', '-', (29, 34))	('ovarian cancer', 'Disease', (232, 246))	('degradation of the extracellular matrix', 'MPA', (115, 154))	('colon cancer', 'Phenotype', 'HP:0003003', (196, 208))	('pancreatic cancer', 'Disease', 'MESH:D010190', (210, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('ovarian cancer', 'Phenotype', 'HP:0100615', (232, 246))	('increased', 'PosReg', (159, 168))	('pancreatic cancer', 'Disease', (210, 227))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('colon cancer', 'Disease', 'MESH:D015179', (196, 208))	('MMP2', 'Gene', (77, 81))
67995	27440504	As beta6 also promoted the invasiveness of cholangiocarcinoma cells, we explored the effect of beta6 on MMP expression in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (43, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (122, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (43, 61))	('beta6', 'Chemical', '-', (3, 8))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (122, 140))	('beta6', 'Var', (3, 8))	('beta6', 'Chemical', '-', (95, 100))	('promoted', 'PosReg', (14, 22))	('cholangiocarcinoma', 'Disease', (43, 61))	('cholangiocarcinoma', 'Disease', (122, 140))	('invasiveness of', 'CPA', (27, 42))
67999	27440504	Integrin beta6 may functions through the protein kinase C (PKC) pathway in colon cancer, while beta6 may also bind ERK and subsequently activate the ERK-Ets1 pathway in colon cancer and pancreatic cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (75, 87))	('beta6', 'Chemical', '-', (9, 14))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (186, 203))	('beta6', 'Var', (95, 100))	('Ets1', 'Gene', '2113', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('Ets1', 'Gene', (153, 157))	('colon cancer', 'Phenotype', 'HP:0003003', (169, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('ERK', 'Gene', (115, 118))	('colon cancer', 'Disease', 'MESH:D015179', (75, 87))	('beta6', 'Chemical', '-', (95, 100))	('pancreatic cancer', 'Disease', 'MESH:D010190', (186, 203))	('ERK', 'Gene', '5594', (149, 152))	('bind', 'Interaction', (110, 114))	('colon cancer', 'Disease', 'MESH:D015179', (169, 181))	('pancreatic cancer', 'Disease', (186, 203))	('colon cancer', 'Disease', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('functions', 'Reg', (19, 28))	('ERK', 'Gene', (149, 152))	('activate', 'PosReg', (136, 144))	('Integrin beta6', 'Gene', '3694', (0, 14))	('colon cancer', 'Disease', (169, 181))	('Integrin beta6', 'Gene', (0, 14))	('ERK', 'Gene', '5594', (115, 118))
68004	27440504	Therefore, targeting Rac1 may be a promising therapeutic approach for the treatment of cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('Rac1', 'Gene', '5879', (21, 25))	('cholangiocarcinoma', 'Disease', (87, 105))	('Rac1', 'Gene', (21, 25))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (87, 105))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('targeting', 'Var', (11, 20))
68006	27440504	Consistent with these results, our data demonstrated that beta6 promoted the invasiveness of cholangiocarcinoma cells by activating Rac1, as both NSC23766 and Rac1 siRNA could abolish the effect of beta6.	('Rac1', 'Gene', (159, 163))	('promoted', 'PosReg', (64, 72))	('activating', 'Reg', (121, 131))	('cholangiocarcinoma', 'Disease', (93, 111))	('beta6', 'Var', (58, 63))	('beta6', 'Chemical', '-', (198, 203))	('invasiveness of', 'CPA', (77, 92))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('Rac1', 'Gene', '5879', (132, 136))	('beta6', 'Chemical', '-', (58, 63))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('Rac1', 'Gene', '5879', (159, 163))	('Rac1', 'Gene', (132, 136))
68007	27440504	In addition, beta6 could activate Rac1, but it had no effect on total Rac1 expression.	('activate', 'PosReg', (25, 33))	('beta6', 'Var', (13, 18))	('Rac1', 'Gene', '5879', (34, 38))	('Rac1', 'Gene', (34, 38))	('beta6', 'Chemical', '-', (13, 18))	('Rac1', 'Gene', (70, 74))	('Rac1', 'Gene', '5879', (70, 74))
68008	27440504	Mechanistically, we demonstrated that beta6 facilitated F-actin polymerization and induced MMP9 expression by activating Rac1.	('F-actin polymerization', 'MPA', (56, 78))	('beta6', 'Var', (38, 43))	('expression', 'MPA', (96, 106))	('induced', 'PosReg', (83, 90))	('facilitated', 'PosReg', (44, 55))	('activating', 'PosReg', (110, 120))	('beta6', 'Chemical', '-', (38, 43))	('Rac1', 'Gene', '5879', (121, 125))	('MMP9', 'Gene', (91, 95))	('Rac1', 'Gene', (121, 125))	('MMP9', 'Gene', '4318', (91, 95))
68017	27440504	By targeting and activating Rac1, beta6 promotes the development and progression of cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('activating', 'MPA', (17, 27))	('beta6', 'Chemical', '-', (34, 39))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))	('cholangiocarcinoma', 'Disease', (84, 102))	('beta6', 'Var', (34, 39))	('targeting', 'Reg', (3, 12))	('Rac1', 'Gene', '5879', (28, 32))	('progression', 'CPA', (69, 80))	('Rac1', 'Gene', (28, 32))	('development', 'CPA', (53, 64))	('promotes', 'PosReg', (40, 48))
68018	27440504	The perturbation of integrin beta6 may present a potential strategy for the treatment of patients suffering from cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (113, 131))	('integrin beta6', 'Protein', (20, 34))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (113, 131))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (113, 131))	('patients', 'Species', '9606', (89, 97))	('perturbation', 'Var', (4, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))
68079	24512954	Alterations in expression of many of these (p53, p27, bcl-2, NFkappaB) have been described in biliary tract cancers .	('NFkappaB', 'Gene', (61, 69))	('biliary tract cancers', 'Disease', 'MESH:D001661', (94, 115))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (94, 114))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('Alterations', 'Var', (0, 11))	('NFkappaB', 'Gene', '4790', (61, 69))	('p27', 'Gene', '3429', (49, 52))	('bcl-2', 'Gene', '596', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('p53', 'Gene', (44, 47))	('expression', 'MPA', (15, 25))	('p27', 'Gene', (49, 52))	('p53', 'Gene', '7157', (44, 47))	('described', 'Reg', (81, 90))	('biliary tract cancers', 'Disease', (94, 115))	('bcl-2', 'Gene', (54, 59))
68098	24512954	Dose modifications were made for >= grade 3 non-hematologic toxicity, excluding neuropathy; grade 1 neuropathy with pain or grade >= 2 neuropathy without pain; and hematologic toxicity (neutrophil count <= 750/mm3 or platelet count <= 75,000/mm3).	('pain', 'Disease', (154, 158))	('neuropathy', 'Disease', 'MESH:D009422', (100, 110))	('neuropathy', 'Phenotype', 'HP:0009830', (135, 145))	('neuropathy', 'Phenotype', 'HP:0009830', (80, 90))	('pain', 'Phenotype', 'HP:0012531', (154, 158))	('pain', 'Disease', 'MESH:D010146', (116, 120))	('neuropathy', 'Disease', (135, 145))	('hematologic toxicity', 'Disease', (48, 68))	('neuropathy', 'Disease', (80, 90))	('hematologic toxicity', 'Disease', 'MESH:D006402', (48, 68))	('neuropathy with pain', 'Phenotype', 'HP:0000763', (100, 120))	('pain', 'Disease', 'MESH:D010146', (154, 158))	('neuropathy', 'Phenotype', 'HP:0009830', (100, 110))	('neuropathy', 'Disease', 'MESH:D009422', (135, 145))	('neuropathy', 'Disease', 'MESH:D009422', (80, 90))	('neuropathy', 'Disease', (100, 110))	('hematologic toxicity', 'Disease', (164, 184))	('pain', 'Disease', (116, 120))	('hematologic toxicity', 'Disease', 'MESH:D006402', (164, 184))	('pain', 'Phenotype', 'HP:0012531', (116, 120))	('neutrophil count <= 750/mm3', 'Var', (186, 213))
68179	23806079	Ectopic expression of L1cam in gastric cell lines significantly promoted cell proliferation, migration and invasion whereas knockdown of L1cam inhibited cell proliferation, migration and invasion in vitro as well as tumorigenesis and metastasis in vivo.	('knockdown', 'Var', (124, 133))	('tumor', 'Disease', (216, 221))	('promoted', 'PosReg', (64, 72))	('migration', 'CPA', (93, 102))	('migration', 'CPA', (173, 182))	('inhibited', 'NegReg', (143, 152))	('L1cam', 'Gene', (22, 27))	('cell proliferation', 'CPA', (153, 171))	('cell proliferation', 'CPA', (73, 91))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('invasion', 'CPA', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('L1cam', 'Gene', (137, 142))	('invasion', 'CPA', (187, 195))
68180	23806079	The low level of phosphorylated Akt in HGC27 cells was up-regulated after ectopic expression of L1cam, whereas the high level of phosphorylated Akt in SGC7901 cells was suppressed by knockdown of L1cam.	('up-regulated', 'PosReg', (55, 67))	('L1cam', 'Var', (96, 101))	('low level', 'MPA', (4, 13))	('HGC27', 'CellLine', 'CVCL:1279', (39, 44))
68181	23806079	Moreover, the migration and invasion promoted by L1cam overexpression in gastric cancer cells could be abolished by either application of LY294002 (a phosphoinositide-3-kinase inhibitor) or knockdown of endogenous Akt by small interfering RNA.	('overexpression', 'PosReg', (55, 69))	('migration', 'CPA', (14, 23))	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('L1cam', 'Gene', (49, 54))	('knockdown', 'Reg', (190, 199))	('LY294002', 'Var', (138, 146))	('abolished', 'NegReg', (103, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('invasion', 'CPA', (28, 36))	('LY294002', 'Chemical', 'MESH:C085911', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gastric cancer', 'Disease', (73, 87))
68189	23806079	Ectopic expression of L1cam could promote tumor cell proliferation, migration and invasion in several types of cancer, including colon cancer, intrahepatic cholangiocarcinoma, and gallbladder carcinoma .	('colon cancer', 'Phenotype', 'HP:0003003', (129, 141))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (156, 174))	('promote', 'PosReg', (34, 41))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (180, 201))	('cancer', 'Disease', (111, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('gallbladder carcinoma', 'Disease', (180, 201))	('cancer', 'Disease', (135, 141))	('tumor', 'Disease', (42, 47))	('colon cancer', 'Disease', 'MESH:D015179', (129, 141))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('invasion', 'CPA', (82, 90))	('Ectopic expression', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('colon cancer', 'Disease', (129, 141))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('migration', 'CPA', (68, 77))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (143, 174))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('intrahepatic cholangiocarcinoma', 'Disease', (143, 174))	('L1cam', 'Gene', (22, 27))
68191	23806079	reported L1cam was associated with prognosis of pT3-stage patients .	('L1cam', 'Var', (9, 14))	('associated', 'Reg', (19, 29))	('pT3-stage patients', 'Disease', (48, 66))	('patients', 'Species', '9606', (58, 66))
68196	23806079	However, it is still unknown whether L1cam can activate Akt and promote tumor growth and metastasis in gastric cancer.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('activate', 'PosReg', (47, 55))	('promote', 'PosReg', (64, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('tumor', 'Disease', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Akt', 'Pathway', (56, 59))	('L1cam', 'Var', (37, 42))	('gastric cancer', 'Disease', (103, 117))	('metastasis', 'CPA', (89, 99))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
68208	23806079	High expression of L1cam was positively associated with large tumor size (P = 0.001), lymph node invasion (P = 0.007), peritoneal dissemination (P = 0.019), liver metastasis (P = 0.013) and TNM stage (P = 0.002).	('liver metastasis', 'Disease', 'MESH:D009362', (157, 173))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('TNM', 'Gene', (190, 193))	('High', 'Var', (0, 4))	('liver metastasis', 'Disease', (157, 173))	('tumor', 'Disease', (62, 67))	('L1cam', 'Gene', (19, 24))	('lymph node invasion', 'CPA', (86, 105))	('TNM', 'Gene', '10178', (190, 193))	('associated', 'Reg', (40, 50))	('peritoneal dissemination', 'CPA', (119, 143))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
68211	23806079	Univariate analysis demonstrated patients with high L1cam expression tended to have a higher risk of death (HR = 2.73, 95% CI, 1.76-4.25; P < 0.001, Table  2).	('patients', 'Species', '9606', (33, 41))	('high', 'Var', (47, 51))	('L1cam', 'Protein', (52, 57))	('death', 'Disease', 'MESH:D003643', (101, 106))	('death', 'Disease', (101, 106))
68216	23806079	MTT assay showed that ectopic expression of L1cam could significantly promote the proliferative ability in HGC27 cells as compared with control cells (P < 0.05, Figure  3B).	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('ectopic expression', 'Var', (22, 40))	('promote', 'PosReg', (70, 77))	('HGC27', 'CellLine', 'CVCL:1279', (107, 112))	('proliferative ability', 'CPA', (82, 103))	('L1cam', 'Gene', (44, 49))
68217	23806079	Conversely, knockdown of L1cam inhibited growth capacity in SGC7901 cells as indicated by the MTT and colony formation assays (P < 0.05, Figure  3B and C).	('colony formation assays', 'CPA', (102, 125))	('L1cam', 'Gene', (25, 30))	('knockdown', 'Var', (12, 21))	('MTT', 'CPA', (94, 97))	('MTT', 'Chemical', 'MESH:C070243', (94, 97))	('growth capacity', 'CPA', (41, 56))	('inhibited', 'NegReg', (31, 40))
68219	23806079	In order to determine if L1cam could affect apoptosis and the responsiveness to anti-cancer drugs in gastric cancer cells, firstly, we analyzed the effect of L1cam on the apoptosis of gastric cancer cells, the results showed that overexpression or knockdown of L1cam had no significant effect on the apoptosis rate in gastric cancer cells (Figure  4A and B); then cells were treated with different concentrations of oxaliplatin, the results showed that knockdown of L1cam could improve the responsiveness to oxaliplatin in SGC7901 cells while overexpression of L1cam could reduce the apoptosis rate in HGC27 cells (P < 0.05, Figure  4A and B).	('gastric cancer', 'Disease', 'MESH:D013274', (184, 198))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (508, 519))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (318, 332))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (192, 198))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('responsiveness to oxaliplatin', 'MPA', (490, 519))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('gastric cancer', 'Phenotype', 'HP:0012126', (184, 198))	('gastric cancer', 'Phenotype', 'HP:0012126', (318, 332))	('cancer', 'Disease', (326, 332))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (416, 427))	('gastric cancer', 'Disease', (101, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('knockdown', 'Var', (453, 462))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('gastric cancer', 'Disease', (184, 198))	('gastric cancer', 'Disease', (318, 332))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('reduce', 'NegReg', (573, 579))	('improve', 'PosReg', (478, 485))	('apoptosis rate', 'CPA', (584, 598))	('L1cam', 'Gene', (466, 471))	('HGC27', 'CellLine', 'CVCL:1279', (602, 607))
68220	23806079	To analyze the in vivo effects of L1cam on gastric cancer cells, we constructed two stable cell lines by using the lentivirus vector to mediate the knockdown of L1cam in SGC7901 cells; the resulting cells were designated as SGC7901/scramble and SGC7901/sh-L1cam cells respectively.	('gastric cancer', 'Disease', 'MESH:D013274', (43, 57))	('gastric cancer', 'Disease', (43, 57))	('SGC7901', 'Gene', (170, 177))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('gastric cancer', 'Phenotype', 'HP:0012126', (43, 57))	('L1cam', 'Gene', (161, 166))	('knockdown', 'Var', (148, 157))
68223	23806079	The results showed that tumor growth was significantly inhibited in SGC7901/sh-L1cam cells as compared with that of SGC7901/scramble cells (P < 0.05, Figure  5A).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('SGC7901/sh-L1cam', 'Var', (68, 84))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('inhibited', 'NegReg', (55, 64))
68224	23806079	In addition to the difference in tumor volume, we also found tumor tissues formed by injection of SGC7901/scramble cells displayed much stronger staining of L1cam and Ki-67, as detected by immunohistochemical analysis (Figure  5B).	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('stronger', 'PosReg', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('SGC7901/scramble', 'Var', (98, 114))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Ki-67', 'Protein', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (33, 38))	('staining', 'MPA', (145, 153))	('tumor', 'Disease', (61, 66))	('L1cam', 'Protein', (157, 162))
68227	23806079	Consistent with the in vitro results, the incidences of metastasis to lung and liver were significantly less in mice injected with SGC7901/sh-L1cam cells than those of SGC7901/scramble cells (P < 0.05, Figure  5C).	('SGC7901/sh-L1cam', 'Var', (131, 147))	('metastasis to lung', 'Disease', (56, 74))	('metastasis to lung', 'Disease', 'MESH:D009362', (56, 74))	('less', 'NegReg', (104, 108))	('mice', 'Species', '10090', (112, 116))
68228	23806079	These data suggest knockdown of L1cam could also inhibit the tumor growth and metastasis of gastric cancer cells in vivo.	('knockdown', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('metastasis of gastric cancer', 'Disease', (78, 106))	('L1cam', 'Gene', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('metastasis of gastric cancer', 'Disease', 'MESH:D009362', (78, 106))	('inhibit', 'NegReg', (49, 56))	('tumor', 'Disease', (61, 66))
68230	23806079	In addition, the stimulation of cell migration and invasion caused by ectopic expression of L1cam could also be suppressed by LY294002 administration (Figure  6C).	('LY294002', 'Var', (126, 134))	('suppressed', 'NegReg', (112, 122))	('stimulation', 'PosReg', (17, 28))	('LY294002', 'Chemical', 'MESH:C085911', (126, 134))	('L1cam', 'Gene', (92, 97))	('cell migration', 'CPA', (32, 46))	('ectopic expression', 'Var', (70, 88))
68231	23806079	Similarly, the up-regulation of total Akt and phospho-Akt caused by ectopic expression of L1cam in HGC27 cells could be counteracted by knockdown of Akt using siRNA (Figure  6D); the effect on cellular motility caused by L1cam overexpression was also inhibited upon silencing of Akt (Figure  6E).	('L1cam', 'Gene', (90, 95))	('cellular motility', 'CPA', (193, 210))	('up-regulation', 'PosReg', (15, 28))	('HGC27', 'CellLine', 'CVCL:1279', (99, 104))	('silencing', 'Var', (266, 275))	('inhibited', 'NegReg', (251, 260))
68232	23806079	Moreover, treatment of LY294002 in SGC7901 cells could significantly inhibit tumor growth in nude mice (Figure  6F), and the expression of phospho-Akt was reduced in tissues formed by cells that knockdown of L1cam or treated with LY294002 (Figure  6G).	('SGC7901', 'Gene', (35, 42))	('reduced', 'NegReg', (155, 162))	('LY294002', 'Chemical', 'MESH:C085911', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('expression', 'MPA', (125, 135))	('L1cam', 'Gene', (208, 213))	('LY294002', 'Chemical', 'MESH:C085911', (230, 238))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('LY294002', 'Var', (23, 31))	('knockdown', 'Var', (195, 204))	('tumor', 'Disease', (77, 82))	('inhibit', 'NegReg', (69, 76))	('LY294002', 'Var', (230, 238))	('nude mice', 'Species', '10090', (93, 102))
68233	23806079	These results demonstrated that PI3K/Akt signaling was involved in L1cam stimulated cell growth and motility in gastric cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('stimulated', 'PosReg', (73, 83))	('motility', 'CPA', (100, 108))	('gastric cancer', 'Disease', 'MESH:D013274', (112, 126))	('gastric cancer', 'Disease', (112, 126))	('cell growth', 'CPA', (84, 95))	('L1cam', 'Var', (67, 72))	('gastric cancer', 'Phenotype', 'HP:0012126', (112, 126))
68237	23806079	Moreover, expression of L1cam was significantly correlated with aggressive tumor characteristics (tumor size, lymph node invasion, peritoneal dissemination, liver metastasis and TNM stage) and poor prognosis; when the patients were subdivided into two groups according to tumor stage, we found L1cam could better distinguish patients with different outcomes in stage III-IV than in stage I-II patients, however, this might be due to the limited subjects in stage I-II.	('liver metastasis', 'Disease', (157, 173))	('tumor', 'Disease', (98, 103))	('TNM', 'Gene', '10178', (178, 181))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('TNM', 'Gene', (178, 181))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('aggressive tumor', 'Disease', 'MESH:D001523', (64, 80))	('liver metastasis', 'Disease', 'MESH:D009362', (157, 173))	('patients', 'Species', '9606', (393, 401))	('patients', 'Species', '9606', (218, 226))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('stage III-IV', 'Disease', (361, 373))	('L1cam', 'Var', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('aggressive tumor', 'Disease', (64, 80))	('patients', 'Species', '9606', (325, 333))
68244	23806079	In addition, L1cam enables endocytosis of integrins by tumor cells, thus reducing cell adhesion to the extracellular matrix and promoting cell migration .	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cell', 'CPA', (82, 86))	('integrins', 'Protein', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cell migration', 'CPA', (138, 152))	('reducing', 'NegReg', (73, 81))	('tumor', 'Disease', (55, 60))	('promoting', 'PosReg', (128, 137))	('endocytosis of', 'MPA', (27, 41))	('L1cam', 'Var', (13, 18))
68248	23806079	Given that L1cam can promote gastric cancer cell proliferation, migration and invasion in vitro, we further investigated the in vivo effect of L1cam.	('L1cam', 'Var', (11, 16))	('gastric cancer', 'Disease', (29, 43))	('invasion', 'CPA', (78, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (29, 43))	('promote', 'PosReg', (21, 28))	('gastric cancer', 'Phenotype', 'HP:0012126', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('migration', 'CPA', (64, 73))
68249	23806079	To our interest, knockdown of L1cam by lentiviral-mediated short hairpin RNA (shRNA) interference significantly suppressed tumor growth and distant metastasis to lung and liver.	('suppressed', 'NegReg', (112, 122))	('tumor', 'Disease', (123, 128))	('metastasis to lung', 'Disease', (148, 166))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('metastasis to lung', 'Disease', 'MESH:D009362', (148, 166))	('knockdown', 'Var', (17, 26))	('L1cam', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
68252	23806079	In this study, we also found that L1cam could affect the responsiveness to oxaliplatin in gastric cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('L1cam', 'Var', (34, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('affect', 'Reg', (46, 52))	('responsiveness to oxaliplatin', 'MPA', (57, 86))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (75, 86))	('gastric cancer', 'Disease', (90, 104))
68253	23806079	In line with our results, it has been found that L1cam conferred anti-apoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells ; moreover, a recent study demonstrated that inhibiting L1cam by using L1cam antibodies could increase the apoptotic response of tumor cells towards cytostatic drugs in pancreatic and ovarian carcinoma .	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (114, 146))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (114, 146))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('apoptotic response', 'CPA', (260, 278))	('L1cam', 'Gene', (224, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (345, 354))	('tumor', 'Disease', (282, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('inhibiting', 'Var', (198, 208))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (337, 354))	('L1cam', 'Gene', (209, 214))	('pancreatic and ovarian carcinoma', 'Disease', 'MESH:D010051', (322, 354))	('increase', 'PosReg', (247, 255))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('pancreatic ductal adenocarcinoma', 'Disease', (114, 146))
68256	23806079	Ectopic expression of L1cam in ovarian carcinoma cells activates Erk and FAK signal pathways to promote cellular migration, invasion and apoptosis resistance .	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (31, 48))	('ovarian carcinoma', 'Disease', (31, 48))	('Erk', 'Gene', (65, 68))	('invasion', 'CPA', (124, 132))	('apoptosis resistance', 'CPA', (137, 157))	('activates', 'PosReg', (55, 64))	('Erk', 'Gene', '5594', (65, 68))	('Ectopic expression', 'Var', (0, 18))	('promote', 'PosReg', (96, 103))	('cellular migration', 'CPA', (104, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('L1cam', 'Gene', (22, 27))	('FAK', 'Gene', '5747', (73, 76))	('FAK', 'Gene', (73, 76))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (31, 48))
68257	23806079	In human glioma, L1cam stimulated cell motility via binding to integrin receptors, activating FAK, and increasing turnover of focal complexes .	('L1cam', 'Var', (17, 22))	('glioma', 'Disease', (9, 15))	('cell motility', 'CPA', (34, 47))	('human', 'Species', '9606', (3, 8))	('turnover', 'MPA', (114, 122))	('integrin receptors', 'Protein', (63, 81))	('stimulated', 'PosReg', (23, 33))	('binding', 'Interaction', (52, 59))	('increasing', 'PosReg', (103, 113))	('glioma', 'Disease', 'MESH:D005910', (9, 15))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('activating', 'PosReg', (83, 93))	('FAK', 'Gene', '5747', (94, 97))	('FAK', 'Gene', (94, 97))
68258	23806079	L1cam could enhance cell proliferation by mainly activating ERK signaling in intrahepatic cholangiocarcinoma cells .	('intrahepatic cholangiocarcinoma', 'Disease', (77, 108))	('cell proliferation', 'CPA', (20, 38))	('ERK', 'Gene', '5594', (60, 63))	('activating', 'PosReg', (49, 59))	('ERK', 'Gene', (60, 63))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (77, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('enhance', 'PosReg', (12, 19))	('L1cam', 'Var', (0, 5))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))
68259	23806079	In the present study, we found ectopic expression in HGC27 cells activated PI3K/Akt signaling whereas knockdown of L1cam in SGC7901 cells inhibited Akt signaling.	('HGC27', 'CellLine', 'CVCL:1279', (53, 58))	('PI3K/Akt signaling', 'Pathway', (75, 93))	('Akt', 'MPA', (148, 151))	('inhibited', 'NegReg', (138, 147))	('activated', 'PosReg', (65, 74))	('HGC27', 'Gene', (53, 58))	('ectopic expression', 'Var', (31, 49))
68260	23806079	In addition, the increased cellular motilities promoted by L1cam could be eliminated by blocking of PI3K/Akt pathway in gastric cancer cells.	('increased', 'PosReg', (17, 26))	('cellular motilities', 'CPA', (27, 46))	('gastric cancer', 'Disease', (120, 134))	('gastric cancer', 'Disease', 'MESH:D013274', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('blocking', 'NegReg', (88, 96))	('PI3K/Akt pathway', 'Pathway', (100, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (120, 134))	('L1cam', 'Var', (59, 64))
68262	23806079	found that L1cam could activate P13K/Akt pathway to induce cell proliferation and invasion in renal cell carcinoma .	('L1cam', 'Var', (11, 16))	('P13K/Akt pathway', 'Pathway', (32, 48))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (94, 114))	('P13K', 'Mutation', 'p.P13K', (32, 36))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (94, 114))	('invasion', 'CPA', (82, 90))	('cell proliferation', 'CPA', (59, 77))	('induce', 'PosReg', (52, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('renal cell carcinoma', 'Disease', (94, 114))
68310	23806079	To investigate the effect of L1cam on tumor metastasis, the SGC7901/Scramble and SGC7901/sh-L1cam cells (2 x 106 cells/mouse) were injected into the tail vein of two groups of nude mice (ten for each cell group).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('mouse', 'Species', '10090', (119, 124))	('tumor metastasis', 'Disease', 'MESH:D009362', (38, 54))	('tumor metastasis', 'Disease', (38, 54))	('SGC7901/sh-L1cam', 'Var', (81, 97))	('nude mice', 'Species', '10090', (176, 185))
68315	23806079	For administration of LY294002, tumor cells were incubated with 50 muM LY294002 (Cell Signaling Technology) for one hour before performing in vitro assays.	('LY294002', 'Chemical', 'MESH:C085911', (22, 30))	('LY294002', 'Chemical', 'MESH:C085911', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('LY294002', 'Var', (22, 30))	('tumor', 'Disease', (32, 37))	('LY294002', 'Var', (71, 79))
68352	32784671	To examine the cytotoxic effects of BJA on human cholangiocarcinoma (CCA) cell lines, KKU-213, KKU-100, KKU-055 and HuCCA-1 cells were treated with 95% ethanolic extract of BJA (BJA-95), 50% ethanolic extract of BJA (BJA-50) and a water extract of BJA (BJA-W) for 24 h. We found that BJA-95 and BJA-50 inhibited CCA cell viability in a dose-dependent manner.	('BJA-95', 'Chemical', '-', (178, 184))	('ethanol', 'Chemical', 'MESH:D000431', (191, 198))	('ethanol', 'Chemical', 'MESH:D000431', (152, 159))	('BJA', 'Chemical', '-', (295, 298))	('CCA', 'Disease', (312, 315))	('water', 'Chemical', 'MESH:D014867', (231, 236))	('BJA', 'Chemical', '-', (173, 176))	('BJA', 'Chemical', '-', (253, 256))	('BJA', 'Chemical', '-', (284, 287))	('BJA', 'Chemical', '-', (212, 215))	('CCA', 'Phenotype', 'HP:0030153', (118, 121))	('BJA-95', 'Var', (284, 290))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (49, 67))	('BJA-W', 'Chemical', '-', (253, 258))	('BJA-50', 'Gene', (295, 301))	('BJA', 'Chemical', '-', (36, 39))	('CCA', 'Phenotype', 'HP:0030153', (69, 72))	('cholangiocarcinoma', 'Disease', (49, 67))	('BJA', 'Chemical', '-', (178, 181))	('BJA-95', 'Chemical', '-', (284, 290))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (49, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('inhibited', 'NegReg', (302, 311))	('KKU-213', 'CellLine', 'CVCL:M261', (86, 93))	('BJA', 'Chemical', '-', (217, 220))	('BJA', 'Chemical', '-', (248, 251))	('human', 'Species', '9606', (43, 48))	('CCA', 'Phenotype', 'HP:0030153', (312, 315))
68358	32784671	Moreover, BJA-95 significantly upregulated the expression levels of the following pro-apoptotic proteins: Bax, Puma and tBid, whereas it downregulated the apoptosis-inhibiting proteins Bcl-xL and NF-kappaB (Figure 3A).	('tBid', 'MPA', (120, 124))	('BJA-95', 'Var', (10, 16))	('downregulated', 'NegReg', (137, 150))	('BJA-95', 'Chemical', '-', (10, 16))	('apoptosis-inhibiting', 'MPA', (155, 175))	('NF-kappaB', 'Gene', '4790', (196, 205))	('upregulated', 'PosReg', (31, 42))	('Puma', 'MPA', (111, 115))	('NF-kappaB', 'Gene', (196, 205))	('expression levels', 'MPA', (47, 64))	('Bax', 'MPA', (106, 109))
68387	32784671	As is shown in Figure 7, BJA-95 caused the expression of the pro-apoptotic protein Bax and active caspase-3 to increase in all treatment groups, whereas anti-apoptotic Bcl-xL protein expression decreased when compared with the control.	('BJA-95', 'Chemical', '-', (25, 31))	('increase', 'PosReg', (111, 119))	('BJA-95', 'Var', (25, 31))	('caspase-3', 'Gene', (98, 107))	('Bax', 'Protein', (83, 86))	('expression', 'MPA', (43, 53))	('caspase-3', 'Gene', '836', (98, 107))
68397	32784671	Our study found that apoptosis was induced in KKU-213 cells after being treated with BJA-95 for 24 h. Moreover, BJA-95 increased the percentage of cells with the loss of mitochondrial transmembrane potential and the activities of caspase-3, -8 and -9, indicating that BJA-95 could induce KKU-213 cell apoptosis through the mitochondrial and caspase cascade pathways.	('caspase', 'Gene', (341, 348))	('mitochondrial transmembrane potential', 'MPA', (170, 207))	('KKU-213', 'CellLine', 'CVCL:M261', (46, 53))	('induce', 'PosReg', (281, 287))	('caspase', 'Gene', '841;842', (230, 237))	('loss', 'NegReg', (162, 166))	('KKU-213', 'CellLine', 'CVCL:M261', (288, 295))	('caspase-3, -8 and -9', 'Gene', '836;841;842', (230, 250))	('BJA-95', 'Chemical', '-', (268, 274))	('caspase', 'Gene', (230, 237))	('BJA-95', 'Var', (112, 118))	('caspase', 'Gene', '841;842', (341, 348))	('BJA-95', 'Chemical', '-', (112, 118))	('BJA-95', 'Chemical', '-', (85, 91))
68401	32784671	According to our current results, BJA could induce apoptosis in KKU-213 cells; therefore, the other mode of action via autophagy was investigated.	('BJA', 'Chemical', '-', (34, 37))	('apoptosis', 'CPA', (51, 60))	('BJA', 'Var', (34, 37))	('KKU-213', 'CellLine', 'CVCL:M261', (64, 71))
68425	32784671	Primary antibodies against Bax (ab32503), Bid (ab2388), Puma (ab9643), Bcl-xL (ab2568), ATG-5 (ab109490), LC3B (ab58610), beta Actin (ab8227) and peroxidase-labeled secondary antibodies: anti-rabbit IgG (ab97051) and anti-mouse IgG (ab97046), were purchased from Abcam (Cambridge, UK).	('beta Actin', 'Gene', (122, 132))	('beta Actin', 'Gene', '11461', (122, 132))	('mouse', 'Species', '10090', (222, 227))	('ab58610', 'Var', (112, 119))
68427	32784671	Primary antibodies against Beclin-1 (612113) were purchased from BD Biosciences.	('Beclin-1', 'Gene', '8678', (27, 35))	('612113', 'Var', (37, 43))	('Beclin-1', 'Gene', (27, 35))
68429	32784671	Antibodies for immunohistochemistry, anti-Bax (5023), anti-Bcl-xL (2764), were purchased from Cell Signaling Technology, Inc. and anti-active caspase 3 (559565) was purchased from BD Biosciences, (San Jose, CA, USA).	('caspase 3', 'Gene', '836', (142, 151))	('caspase 3', 'Gene', (142, 151))	('559565', 'Var', (153, 159))
68441	32784671	The determination of caspase activity was achieved using DEVD-p-NA, IETD-p-NA and LEHD-p-NA, specific chromogenic substrates of caspase-3, caspase-8 and caspase-9, respectively.	('caspase', 'Gene', '841;842', (21, 28))	('DEVD-p-NA', 'Var', (57, 66))	('LEHD-p-NA', 'Chemical', '-', (82, 91))	('caspase-8', 'Gene', (139, 148))	('caspase-3', 'Gene', '836', (128, 137))	('caspase', 'Gene', (153, 160))	('caspase', 'Gene', (139, 146))	('IETD-p-NA', 'Var', (68, 77))	('caspase-3', 'Gene', (128, 137))	('LEHD-p-NA', 'Var', (82, 91))	('caspase', 'Gene', '841;842', (153, 160))	('caspase', 'Gene', '841;842', (139, 146))	('caspase-9', 'Gene', '842', (153, 162))	('DEVD-p-NA', 'Chemical', '-', (57, 66))	('caspase', 'Gene', (128, 135))	('IETD-p-NA', 'Chemical', '-', (68, 77))	('activity', 'MPA', (29, 37))	('caspase', 'Gene', '841;842', (128, 135))	('caspase-8', 'Gene', '841', (139, 148))	('caspase-9', 'Gene', (153, 162))	('caspase', 'Gene', (21, 28))
68482	29286229	Previous reports have suggested that 5-FU elevates the expression of apoptosis-related protein by down-regulating the Bcl-2 family of genes and induction of the caspase family (Yim et al., 2004).	('5-FU', 'Chemical', 'MESH:D005472', (37, 41))	('elevates', 'PosReg', (42, 50))	('expression', 'MPA', (55, 65))	('caspase', 'Gene', (161, 168))	('Bcl-2', 'Gene', (118, 123))	('down-regulating', 'NegReg', (98, 113))	('Bcl-2', 'Gene', '596', (118, 123))	('caspase', 'Gene', '842', (161, 168))	('apoptosis-related protein', 'Gene', (69, 94))	('5-FU', 'Var', (37, 41))
68490	29286229	Moreover, the combinations of isomorellin/doxorubicin and forbesione/doxorubicin showed significant synergy for inhibition of cell growth and induction of apoptosis in KKU-M156 and KKU-100 cells, respectively, through suppression of the MRP1 protein, NF-kappaB activation, enhanced expression of Bax/Bcl-2 and activation of caspase-9 and caspase-3, while suppressing the expression of survivin, procaspase-9 and procaspase-3 (Hahnvajanawong et al., 2014).	('Bcl-2', 'Gene', (300, 305))	('procaspase-9', 'Protein', (395, 407))	('MRP1', 'Gene', '4194', (237, 241))	('combinations', 'Var', (14, 26))	('doxorubicin', 'Chemical', 'MESH:D004317', (42, 53))	('suppressing', 'NegReg', (355, 366))	('Bcl-2', 'Gene', '596', (300, 305))	('procaspase-3', 'Gene', (412, 424))	('caspase-3', 'Protein', (338, 347))	('MRP1', 'Gene', (237, 241))	('KKU-M156', 'Disease', 'None', (168, 176))	('apoptosis', 'CPA', (155, 164))	('survivin', 'Protein', (385, 393))	('activation', 'PosReg', (310, 320))	('forbesione', 'Chemical', 'MESH:C482271', (58, 68))	('procaspase-3', 'Gene', '836', (412, 424))	('NF-kappaB', 'Gene', (251, 260))	('doxorubicin', 'Chemical', 'MESH:D004317', (69, 80))	('cell growth', 'CPA', (126, 137))	('activation', 'PosReg', (261, 271))	('expression', 'MPA', (371, 381))	('KKU-M156', 'Disease', (168, 176))	('expression', 'MPA', (282, 292))	('inhibition', 'NegReg', (112, 122))	('NF-kappaB', 'Gene', '4790', (251, 260))	('caspase-9', 'Protein', (324, 333))	('suppression', 'NegReg', (218, 229))	('enhanced', 'PosReg', (273, 281))
68528	29286229	The PCR primers for G3PDH, CK19, Apaf-1, Bax, and p53 (Integrated DNA Technologies, Coralville, IA) are listed in Table 1, along with cycling conditions.	('G3PDH', 'Gene', '106022412', (20, 25))	('p53', 'Var', (50, 53))	('Apaf-1', 'Gene', '101832699', (33, 39))	('Apaf-1', 'Gene', (33, 39))	('IA', 'Disease', 'MESH:C536041', (96, 98))	('G3PDH', 'Gene', (20, 25))
68554	29286229	Interestingly, a combination of forbesione with 5-FU resulted in significantly increase in p53 mRNA levels at 1.61-fold compared to drug alone or control group.	('increase', 'PosReg', (79, 87))	('5-FU', 'Var', (48, 52))	('5-FU', 'Chemical', 'MESH:D005472', (48, 52))	('p53 mRNA levels', 'MPA', (91, 106))	('combination', 'Interaction', (17, 28))	('forbesione', 'Chemical', 'MESH:C482271', (32, 42))
68555	29286229	To further illuminate the mechanism of tumor growth suppression, the tumor tissues derived from four groups of hamsters, including the controls, the single drug treatments (2 groups), and the combination treatment group, were stained for CK19, PCNA (a proliferation index) and apoptosis-related proteins (Bcl-2, Bax, caspase-9 and caspase-3).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CK19', 'Var', (238, 242))	('hamster', 'Species', '10034', (111, 118))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('PCNA', 'Gene', (244, 248))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('PCNA', 'Gene', '101830416', (244, 248))	('Bcl-2', 'Gene', (305, 310))	('tumor', 'Disease', (39, 44))	('Bcl-2', 'Gene', '596', (305, 310))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
68619	29527260	Recently the studies with alk-SMase knockout mice clearly showed that both initiation and malignant transformation of colon cancer induced by azoxymethane and DSS was enhanced by about 5 times in the knockout mice comparing with the wild type mice.	('malignant transformation', 'CPA', (90, 114))	('mice', 'Species', '10090', (209, 213))	('enhanced', 'PosReg', (167, 175))	('mice', 'Species', '10090', (45, 49))	('colon cancer', 'Disease', (118, 130))	('mice', 'Species', '10090', (243, 247))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('DSS', 'Chemical', 'MESH:D016264', (159, 162))	('azoxymethane', 'Chemical', 'MESH:D001397', (142, 154))	('azoxymethane', 'Var', (142, 154))	('colon cancer', 'Phenotype', 'HP:0003003', (118, 130))	('colon cancer', 'Disease', 'MESH:D015179', (118, 130))	('malignant transformation of colon', 'Phenotype', 'HP:0100273', (90, 123))	('initiation', 'CPA', (75, 85))
68623	29527260	Second, it cleaves phosphocholine moiety from PAF and inactivates PAF, which is widely expressed in many inflammatory tissues promoting inflammation and tumorigenesis.	('promoting', 'PosReg', (126, 135))	('PAF', 'Gene', (66, 69))	('tumorigenesis', 'CPA', (153, 166))	('cleaves', 'Var', (11, 18))	('phosphocholine', 'Chemical', 'MESH:D010767', (19, 33))	('inactivates', 'NegReg', (54, 65))	('inflammation', 'Disease', 'MESH:D007249', (136, 148))	('inflammation', 'Disease', (136, 148))
68676	29527260	It has been known that high concentration of plasma SM is a risk factor for atherosclerosis.	('atherosclerosis', 'Disease', (76, 91))	('high concentration', 'Var', (23, 41))	('SM', 'Chemical', 'MESH:D013109', (52, 54))	('atherosclerosis', 'Phenotype', 'HP:0002621', (76, 91))	('rat', 'Species', '10116', (35, 38))	('atherosclerosis', 'Disease', 'MESH:D050197', (76, 91))
68682	29527260	Besides the reduction of activity, an abnormal transcript of alk-SMase was identified in both liver cancer HepG2 cells and colon cancer HT29 cells, which is caused by a shift of RNA splice site at transcriptional level, resulting in exon 4 deletion.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('HepG2', 'CellLine', 'CVCL:0027', (107, 112))	('exon', 'Var', (233, 237))	('colon cancer', 'Phenotype', 'HP:0003003', (123, 135))	('alk-SMase', 'Gene', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colon cancer', 'Disease', 'MESH:D015179', (123, 135))	('HT29 cells', 'CellLine', 'CVCL:0320', (136, 146))	('liver cancer', 'Phenotype', 'HP:0002896', (94, 106))	('liver cancer', 'Disease', 'MESH:D006528', (94, 106))	('liver cancer', 'Disease', (94, 106))	('colon cancer', 'Disease', (123, 135))	('activity', 'MPA', (25, 33))
68743	24179538	We previously investigated the expression of CD24 in cholangiocarcinoma specimens and its prognostic significance, and our results demonstrated that high CD24 expression was significantly correlated with lymph node metastasis and positive surgical margins in cholangiocarcinoma patients.	('CD24', 'Gene', '100133941', (154, 158))	('CD24', 'Gene', (45, 49))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (259, 277))	('expression', 'MPA', (159, 169))	('positive surgical margins', 'CPA', (230, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('high', 'Var', (149, 153))	('correlated with', 'Reg', (188, 203))	('CD24', 'Gene', '100133941', (45, 49))	('lymph node metastasis', 'Disease', 'MESH:D009362', (204, 225))	('CD24', 'Gene', (154, 158))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (259, 277))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (53, 71))	('cholangiocarcinoma', 'Disease', (259, 277))	('lymph node metastasis', 'Disease', (204, 225))	('cholangiocarcinoma', 'Disease', (53, 71))	('patients', 'Species', '9606', (278, 286))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (53, 71))
68768	24179538	We previously reported that high CD24 expression significantly correlated with the poor clinical outcomes of cholangiocarcinoma patients and the increased invasiveness of cholangiocarcinoma cells in vitro.	('correlated', 'Reg', (63, 73))	('CD24', 'Gene', '100133941', (33, 37))	('CD24', 'Gene', (33, 37))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (109, 127))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (171, 189))	('expression', 'MPA', (38, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (171, 189))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('increased', 'PosReg', (145, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('cholangiocarcinoma', 'Disease', (171, 189))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (128, 136))	('cholangiocarcinoma', 'Disease', (109, 127))	('invasiveness', 'CPA', (155, 167))
68783	24179538	The results showed that administering AMD3100 clearly suppressed the cell motility of CD24+ cells towards Matrigel.	('suppressed', 'NegReg', (54, 64))	('AMD3100', 'Chemical', 'MESH:C088327', (38, 45))	('AMD3100', 'Var', (38, 45))	('CD24', 'Gene', '100133941', (86, 90))	('CD24', 'Gene', (86, 90))
68786	24179538	In the presence of AMD3100, the invasion ability was significantly inhibited in the CD24+ cells (the number of invasive cells was 55% compared with the untreated cells) and CD24- cells, although to a lesser extent (the number of invasive cells was 87% compared with the untreated cells; Fig.	('AMD3100', 'Var', (19, 26))	('inhibited', 'NegReg', (67, 76))	('CD24', 'Gene', '100133941', (173, 177))	('CD24', 'Gene', (84, 88))	('CD24', 'Gene', (173, 177))	('CD24', 'Gene', '100133941', (84, 88))	('AMD3100', 'Chemical', 'MESH:C088327', (19, 26))	('invasion ability', 'CPA', (32, 48))
68794	24179538	The results of the wound-healing assay showed that U0126 significantly inhibited the motility of the CD24+ cells, while a more muted effect was detected in the CD24- cells (Fig.	('CD24', 'Gene', (101, 105))	('CD24', 'Gene', (160, 164))	('CD24', 'Gene', '100133941', (160, 164))	('inhibited', 'NegReg', (71, 80))	('U0126', 'Chemical', 'MESH:C113580', (51, 56))	('CD24', 'Gene', '100133941', (101, 105))	('U0126', 'Var', (51, 56))
68795	24179538	Additionally, the invasion assay showed that U0126 treatment significantly decreased the numbers of invading CD24+ and CD24- cells, although the treatment appeared to have a more pronounced effect on the CD24+ cells (Fig.	('CD24', 'Gene', '100133941', (204, 208))	('CD24', 'Gene', '100133941', (109, 113))	('CD24', 'Gene', (109, 113))	('CD24', 'Gene', (204, 208))	('U0126', 'Chemical', 'MESH:C113580', (45, 50))	('CD24', 'Gene', '100133941', (119, 123))	('CD24', 'Gene', (119, 123))	('U0126', 'Var', (45, 50))	('decreased', 'NegReg', (75, 84))
68797	24179538	The observed effects of CD24 on cell invasion indicate that its expression may affect tumor invasiveness by altering the expression of genes involved in metastasis.	('affect', 'Reg', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('expression of genes', 'MPA', (121, 140))	('altering', 'Reg', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('expression', 'Var', (64, 74))	('CD24', 'Gene', '100133941', (24, 28))	('CD24', 'Gene', (24, 28))	('cell invasion', 'CPA', (32, 45))
68798	24179538	In the present study, the PCR array system was used to focus on human tumor metastasis and identify genes associated with metastasis that are affected by CD24 expression.	('human', 'Species', '9606', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CD24', 'Gene', '100133941', (154, 158))	('tumor metastasis', 'Disease', 'MESH:D009362', (70, 86))	('CD24', 'Gene', (154, 158))	('affected', 'Reg', (142, 150))	('expression', 'Var', (159, 169))	('tumor metastasis', 'Disease', (70, 86))
68808	24179538	The present study demonstrated that blocking CXCR4 signaling with AMD3100 results in decreased motility and invasion ability in CD24+ and CD24- cells (although to a greater extent in CD24+ cells), indicating that CXCR4 is important in cholangiocarcinoma cell invasiveness.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (235, 253))	('CXCR4', 'Gene', '7852', (213, 218))	('decreased motility', 'Disease', (85, 103))	('CD24', 'Gene', '100133941', (183, 187))	('CD24', 'Gene', '100133941', (128, 132))	('CXCR4', 'Gene', (213, 218))	('cholangiocarcinoma cell invasiveness', 'Disease', 'MESH:D018281', (235, 271))	('decreased motility', 'Disease', 'MESH:D015835', (85, 103))	('CXCR4', 'Gene', '7852', (45, 50))	('cholangiocarcinoma cell invasiveness', 'Disease', (235, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('CD24', 'Gene', (138, 142))	('CXCR4', 'Gene', (45, 50))	('AMD3100', 'Chemical', 'MESH:C088327', (66, 73))	('invasion ability', 'CPA', (108, 124))	('CD24', 'Gene', (183, 187))	('CD24', 'Gene', (128, 132))	('AMD3100', 'Var', (66, 73))	('blocking', 'NegReg', (36, 44))	('CD24', 'Gene', '100133941', (138, 142))
68817	24179538	Consistent with previous studies, the present data showed that U0126 abrogates CD24-induced wound-healing and invasion in the CD24+ and CD24- cells (although this inhibition was less apparent in the CD24- cells), indicating that ERK1/2 activation is markedly correlated with CD24 expression in cholangiocarcinoma.	('CD24', 'Gene', (126, 130))	('CD24', 'Gene', (275, 279))	('CD24', 'Gene', '100133941', (136, 140))	('CD24', 'Gene', '100133941', (79, 83))	('CD24', 'Gene', '100133941', (199, 203))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (294, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('CD24', 'Gene', '100133941', (275, 279))	('ERK1/2', 'Gene', (229, 235))	('CD24', 'Gene', '100133941', (126, 130))	('invasion', 'CPA', (110, 118))	('ERK1/2', 'Gene', '5595;5594', (229, 235))	('U0126', 'Chemical', 'MESH:C113580', (63, 68))	('cholangiocarcinoma', 'Disease', (294, 312))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (294, 312))	('CD24', 'Gene', (136, 140))	('U0126', 'Var', (63, 68))	('CD24', 'Gene', (199, 203))	('abrogates', 'NegReg', (69, 78))	('CD24', 'Gene', (79, 83))	('wound-healing', 'CPA', (92, 105))
68893	20840777	In this study, 1-and 2-year survival rates for patients with unresectable ICC treated with EBRT (n = 35) compared with the non-EBRT group (n = 49) were 38.5% versus 16.4%, and 9.6% versus 4.9%, respectively.	('EBRT', 'Chemical', '-', (127, 131))	('EBRT', 'Chemical', '-', (91, 95))	('patients', 'Species', '9606', (47, 55))	('ICC', 'Disease', (74, 77))	('EBRT', 'Var', (91, 95))
68910	20840777	Results of the present study demonstrate that EBRT was associated with improving survival in patients with unresectable ICC.	('EBRT', 'Chemical', '-', (46, 50))	('improving', 'PosReg', (71, 80))	('EBRT', 'Var', (46, 50))	('survival', 'MPA', (81, 89))	('ICC', 'Disease', (120, 123))	('patients', 'Species', '9606', (93, 101))
68966	32435051	The progression of intrahepatic cholangiocarcinoma is associated with the abnormal expression of miRNAs.	('intrahepatic cholangiocarcinoma', 'Disease', (19, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (32, 50))	('abnormal expression', 'Var', (74, 93))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (19, 50))	('miRNAs', 'Protein', (97, 103))
68969	32435051	Also, miR41 directly regulates BRCA1-associated protein-1 (BAP-1), which has frequent mutations in intrahepatic cholangiocarcinoma, which is associated with reduced prognosis.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('mutations', 'Var', (86, 95))	('intrahepatic cholangiocarcinoma', 'Disease', (99, 130))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('BRCA1-associated protein-1', 'Gene', '8314', (31, 57))	('regulates', 'Reg', (21, 30))	('BAP-1', 'Gene', '8314', (59, 64))	('BRCA1-associated protein-1', 'Gene', (31, 57))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (99, 130))	('miR41', 'Var', (6, 11))	('BAP-1', 'Gene', (59, 64))
68971	32435051	showed that the expression of miR-590-3p was down-regulated in intrahepatic cholangiocarcinoma and showed that miR-590-3p influenced EMT by inhibiting the expression of the Smad interacting protein 1 (SIP1).	('miR-590-3p', 'Var', (111, 121))	('inhibiting', 'NegReg', (140, 150))	('SIP1', 'Gene', (201, 205))	('Smad interacting protein 1', 'Gene', (173, 199))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (63, 94))	('intrahepatic cholangiocarcinoma', 'Disease', (63, 94))	('expression', 'MPA', (155, 165))	('influenced', 'Reg', (122, 132))	('down-regulated', 'NegReg', (45, 59))	('Smad interacting protein 1', 'Gene', '9839', (173, 199))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (76, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('EMT', 'CPA', (133, 136))	('SIP1', 'Gene', '9839', (201, 205))	('miR-590-3p', 'Gene', (30, 40))	('expression', 'MPA', (16, 26))
68985	32435051	In patients with intrahepatic cholangiocarcinoma, high expression of hsa-miR-1308 (P=4.59E-2), hsa-miR-566 (P=4.40E-2), hsa-miR-565 (P=4.53E-2), hsa-miR-3197 (P=1.98E-3), hsa-miR-4327 (P=1.72E-2), hsa-miR-513b (P=4.45E-2), hsa-miR-513c-5p (P=2.52E-2) and low expression of hsa-miR-145-5p (P=2.94E-2), hsa-miR-143-3p (P=1.46E-2), hsa-miR-451a (P=6.69E-3), hsa-miR-27b-3p (P=3.38E-3), hsa-miR-26a-5p (P=2.67E-2), hsa-miR-194-5p (P=2.53E-2), hsa-miR-195-5p (P=8.18E-3), hsa-miR-125b-5p (P=3.53E-2) and hsa-miR-29c-3p (P=1.19E-3) were significantly associated with reduced OS.	('hsa-miR-145', 'Gene', (273, 284))	('hsa-miR-451a', 'Gene', (329, 341))	('hsa-miR-513b', 'Gene', '100313822', (197, 209))	('hsa-miR-513c', 'Gene', (223, 235))	('miR-26a', 'Gene', (387, 394))	('hsa-miR-195', 'Gene', (439, 450))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('hsa-miR-3197', 'Gene', '100423023', (145, 157))	('hsa-miR-3197', 'Gene', (145, 157))	('hsa-miR-4327', 'Gene', (171, 183))	('miR-26a', 'Gene', '407015', (387, 394))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (17, 48))	('hsa-miR-125b-5p', 'Var', (467, 482))	('hsa-miR-513c', 'Gene', '100302114', (223, 235))	('intrahepatic cholangiocarcinoma', 'Disease', (17, 48))	('hsa-miR-194-5p', 'Var', (411, 425))	('patients', 'Species', '9606', (3, 11))	('hsa-miR-195', 'Gene', '406971', (439, 450))	('hsa-miR-513b', 'Gene', (197, 209))	('hsa-miR-4327', 'Gene', '100422891', (171, 183))	('hsa-miR-566', 'Gene', (95, 106))	('hsa-miR-451a', 'Gene', '574411', (329, 341))	('reduced', 'NegReg', (561, 568))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (30, 48))	('hsa-miR-566', 'Gene', '693151', (95, 106))	('hsa-miR-145', 'Gene', '406937', (273, 284))
68997	32435051	The overlap between hub genes from GSE53870 and differentially expressed mRNAs from GSE32879 showed that ESR1 was the only gene that occurred in both GEO datasets.	('ESR1', 'Gene', '2099', (105, 109))	('hub', 'Gene', '1993', (20, 23))	('GSE53870', 'Var', (35, 43))	('hub', 'Gene', (20, 23))	('ESR1', 'Gene', (105, 109))
69003	32435051	In the present study, microRNA (miRNA) and mRNA microarrays from GSE53870 and GSE32879 were downloaded from the Gene Expression Omnibus (GEO) database for intrahepatic cholangiocarcinoma and were used to identify differentially expressed miRNAs (DEMs) in comparison with normal intrahepatic bile ducts.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (155, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('GSE32879', 'Var', (78, 86))	('intrahepatic cholangiocarcinoma', 'Disease', (155, 186))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (168, 186))	('GSE53870', 'Var', (65, 73))
69004	32435051	Kaplan-Meier survival analysis showed that seven upregulated miRNAs (hsa-miR-1308, hsa-miR-566, hsa-miR-565, hsa-miR-3197, hsa-miR-4327, hsa-miR-513b, and hsa-miR-513c-5p) and nine down-regulated DEMs (hsa-miR-145-5p, hsa-miR-143-3p, hsa-miR-451a, hsa-miR-27b-3p, hsa-miR-26a-5p, hsa-miR-194-5p, hsa-miR-195-5p, hsa-miR-125b-5p, and hsa-miR-29c-3p) were associated with the overall survival (OS) of patients with intrahepatic cholangiocarcinoma.	('overall survival', 'MPA', (374, 390))	('hsa-miR-451a', 'Gene', (234, 246))	('hsa-miR-513b', 'Gene', (137, 149))	('hsa-miR-195', 'Gene', (296, 307))	('hsa-miR-194-5p', 'Var', (280, 294))	('hsa-miR-513c', 'Gene', (155, 167))	('miR-26a', 'Gene', (268, 275))	('hsa-miR-4327', 'Gene', (123, 135))	('hsa-miR-566', 'Gene', (83, 94))	('hsa-miR-566', 'Gene', '693151', (83, 94))	('miR-26a', 'Gene', '407015', (268, 275))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (413, 444))	('carcinoma', 'Phenotype', 'HP:0030731', (435, 444))	('upregulated', 'PosReg', (49, 60))	('intrahepatic cholangiocarcinoma', 'Disease', (413, 444))	('hsa-miR-4327', 'Gene', '100422891', (123, 135))	('hsa-miR-513b', 'Gene', '100313822', (137, 149))	('hsa-miR-195', 'Gene', '406971', (296, 307))	('hsa-miR-3197', 'Gene', '100423023', (109, 121))	('hsa-miR-3197', 'Gene', (109, 121))	('hsa-miR-513c', 'Gene', '100302114', (155, 167))	('hsa-miR-145', 'Gene', '406937', (202, 213))	('patients', 'Species', '9606', (399, 407))	('hsa-miR-145', 'Gene', (202, 213))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (426, 444))	('hsa-miR-451a', 'Gene', '574411', (234, 246))
69012	32435051	Several previously published studies have shown that miRNAs are associated with cancer.	('associated', 'Reg', (64, 74))	('miRNAs', 'Var', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
69023	32435051	Mutations of the ESR1 gene have been reported as prognostic factors associated with poor survival.	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (68, 78))	('ESR1', 'Gene', (17, 21))	('ESR1', 'Gene', '2099', (17, 21))
69024	32435051	Previous studies have reported that mutation of ESR1 could affect hormone resistance and reduce the response to treatment.	('affect', 'Reg', (59, 65))	('hormone resistance', 'MPA', (66, 84))	('ESR1', 'Gene', (48, 52))	('reduce', 'NegReg', (89, 95))	('response to treatment', 'MPA', (100, 121))	('ESR1', 'Gene', '2099', (48, 52))	('mutation', 'Var', (36, 44))
69025	32435051	showed that the use of CDK4/6 inhibitors reduced the prevalence of ESR1 mutations.	('reduced', 'NegReg', (41, 48))	('mutations', 'Var', (72, 81))	('CDK4/6', 'Gene', '1019;1021', (23, 29))	('ESR1', 'Gene', '2099', (67, 71))	('CDK4/6', 'Gene', (23, 29))	('ESR1', 'Gene', (67, 71))
69027	32435051	By overlapping the results from the hub genes in GSE53870 and the differentially expressed mRNAs in GSE32879, ESR1 was the only gene in both Gene Expression Omnibus (GEO) datasets.	('hub', 'Gene', (36, 39))	('ESR1', 'Gene', (110, 114))	('GSE53870', 'Var', (49, 57))	('hub', 'Gene', '1993', (36, 39))	('ESR1', 'Gene', '2099', (110, 114))
69033	32435051	ESR1 has been reported as a tumor suppressor in colorectal cancer, and the genetic variation of ESR1 might increase the risk for hepatocellular carcinoma and prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (158, 173))	('ESR1', 'Gene', (0, 4))	('tumor', 'Disease', (28, 33))	('colorectal cancer', 'Phenotype', 'HP:0003003', (48, 65))	('ESR1', 'Gene', (96, 100))	('increase', 'PosReg', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('colorectal cancer', 'Disease', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (129, 153))	('hepatocellular carcinoma and prostate cancer', 'Disease', 'MESH:D011471', (129, 173))	('genetic variation', 'Var', (75, 92))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('ESR1', 'Gene', '2099', (0, 4))	('ESR1', 'Gene', '2099', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (48, 65))
69037	32435051	Also, changes in ECM are associated with the development of hepatocellular carcinoma (HCC) and liver cirrhosis.	('liver cirrhosis', 'Disease', 'MESH:D008103', (95, 110))	('associated', 'Reg', (25, 35))	('ECM', 'Gene', (17, 20))	('liver cirrhosis', 'Disease', (95, 110))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (95, 110))	('changes', 'Var', (6, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (60, 84))	('cirrhosis', 'Phenotype', 'HP:0001394', (101, 110))	('hepatocellular carcinoma', 'Disease', (60, 84))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (60, 84))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))
69048	32435051	The findings from the present study, combined with the findings from previous studies, support the importance of hsa-miR-145-5p, KRAS, and hsa-miR-143-3p in intrahepatic cholangiocarcinoma.	('hsa-miR-145', 'Gene', (113, 124))	('hsa-miR-143-3p', 'Var', (139, 153))	('intrahepatic cholangiocarcinoma', 'Disease', (157, 188))	('KRAS', 'Gene', (129, 133))	('KRAS', 'Gene', '3845', (129, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (170, 188))	('hsa-miR-145', 'Gene', '406937', (113, 124))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (157, 188))
69080	31875638	In particular, cholangiocarcinoma and IgG4-SC had to be distinguished in the present case because patients with AIP may develop carcinoma in several organs based on paraneoplastic syndrome.	('develop', 'PosReg', (120, 127))	('carcinoma', 'Disease', (24, 33))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (15, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('patients', 'Species', '9606', (98, 106))	('paraneoplastic syndrome', 'Disease', (165, 188))	('carcinoma', 'Disease', 'MESH:D009369', (24, 33))	('cholangiocarcinoma', 'Disease', (15, 33))	('carcinoma', 'Disease', (128, 137))	('paraneoplastic syndrome', 'Disease', 'MESH:D010257', (165, 188))	('AIP', 'Var', (112, 115))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (15, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('carcinoma', 'Disease', 'MESH:D009369', (128, 137))
69098	31569444	Dysregulation of the MAPK cascade involves key signaling components and phosphorylation events that play an important role in tumorigenesis.	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('MAPK cascade', 'Pathway', (21, 33))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
69123	31569444	However, during the progression of liver disease, the deletion of Jnk1 significantly exacerbated apoptosis, compensatory proliferation, and carcinogenesis in experimental chronic liver disease.	('liver disease', 'Disease', 'MESH:D008107', (179, 192))	('liver disease', 'Phenotype', 'HP:0001392', (35, 48))	('deletion', 'Var', (54, 62))	('carcinogenesis', 'Disease', 'MESH:D063646', (140, 154))	('liver disease', 'Disease', (35, 48))	('carcinogenesis', 'Disease', (140, 154))	('Jnk1', 'Gene', (66, 70))	('exacerbated', 'PosReg', (85, 96))	('compensatory proliferation', 'CPA', (108, 134))	('Jnk1', 'Gene', '5599', (66, 70))	('liver disease', 'Disease', 'MESH:D008107', (35, 48))	('liver disease', 'Phenotype', 'HP:0001392', (179, 192))	('liver disease', 'Disease', (179, 192))	('rat', 'Species', '10116', (128, 131))	('apoptosis', 'CPA', (97, 106))
69128	31569444	By knocking down Jnk1 but not Jnk2, proliferation of human HCC occurs via upregulation of cmyc and downregulation of p21.	('Jnk1', 'Gene', (17, 21))	('p21', 'Gene', '1026', (117, 120))	('downregulation', 'NegReg', (99, 113))	('p21', 'Gene', (117, 120))	('Jnk2', 'Gene', '5601', (30, 34))	('Jnk1', 'Gene', '5599', (17, 21))	('rat', 'Species', '10116', (43, 46))	('upregulation', 'PosReg', (74, 86))	('human', 'Species', '9606', (53, 58))	('cmyc', 'Protein', (90, 94))	('proliferation', 'CPA', (36, 49))	('Jnk2', 'Gene', (30, 34))	('knocking down', 'Var', (3, 16))
69136	31569444	Another study that tested the antioxidant activity of using guggulsterone, a steroid found in the resin of the guggul plant (Commiphora wightii) in both HuCC-T1 and RBE CCA cell lines, showed that guggulsterone could induce the apoptosis of human CCA cells via ROS-mediated activation of the JNK signaling pathway.	('JNK', 'Gene', '5599', (292, 295))	('apoptosis', 'CPA', (228, 237))	('ROS-mediated', 'Protein', (261, 273))	('induce', 'PosReg', (217, 223))	('human', 'Species', '9606', (241, 246))	('guggulsterone', 'Chemical', 'MESH:C023617', (60, 73))	('HuCC-T1', 'CellLine', 'CVCL:0324', (153, 160))	('activation', 'PosReg', (274, 284))	('guggulsterone', 'Var', (197, 210))	('Commiphora wightii', 'Species', '246360', (125, 143))	('guggulsterone', 'Chemical', 'MESH:C023617', (197, 210))	('JNK', 'Gene', (292, 295))	('steroid', 'Chemical', 'MESH:D013256', (77, 84))
69147	31569444	found that inactivation of p38 by the inhibitor SB203580 or specific siRNA could enhance the anticancer efficacy of single drug or combination of metformin and ATO, especially using ATO alone.	('ATO', 'Chemical', 'MESH:C553022', (160, 163))	('cancer', 'Disease', (97, 103))	('inactivation', 'NegReg', (11, 23))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('p38', 'Gene', '1432', (27, 30))	('ATO', 'Chemical', 'MESH:C553022', (182, 185))	('SB203580', 'Chemical', 'MESH:C093642', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('SB203580', 'Var', (48, 56))	('metformin', 'Chemical', 'MESH:D008687', (146, 155))	('enhance', 'PosReg', (81, 88))	('p38', 'Gene', (27, 30))
69161	31569444	Inhibition of PI3K/AKT signaling effectively blocked the proliferation and invasive behavior of CCA.	('rat', 'Species', '10116', (64, 67))	('invasive behavior', 'CPA', (75, 92))	('Inhibition', 'Var', (0, 10))	('PI3K/AKT signaling', 'Pathway', (14, 32))	('proliferation', 'CPA', (57, 70))	('blocked', 'NegReg', (45, 52))	('CCA', 'Disease', (96, 99))
69162	31569444	using CCA cell lines (SCK and Choi-CK) with inactivation of AKT, showed decreased expression of BCL2, and enhanced expression of BAX, thereby inducing the apoptosis of resistant cells; whilst the inhibition of ERK1/2 activation did not induce apoptosis, but decreased tumor cell growth.	('BAX', 'Gene', '581', (129, 132))	('BCL2', 'Gene', '596', (96, 100))	('BAX', 'Gene', (129, 132))	('inducing', 'PosReg', (142, 150))	('enhanced', 'PosReg', (106, 114))	('expression', 'MPA', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('decreased', 'NegReg', (258, 267))	('decreased', 'NegReg', (72, 81))	('tumor', 'Disease', (268, 273))	('ERK1', 'Gene', '5595', (210, 214))	('BCL2', 'Gene', (96, 100))	('expression', 'MPA', (115, 125))	('ERK1', 'Gene', (210, 214))	('AKT', 'Gene', (60, 63))	('inactivation', 'Var', (44, 56))	('apoptosis', 'CPA', (155, 164))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
69165	31569444	Activation of MET promotes cell invasion and triggers metastasis by directly participating in tumor angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('participating', 'Reg', (77, 90))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cell invasion', 'CPA', (27, 40))	('tumor', 'Disease', (94, 99))	('MET', 'Gene', (14, 17))	('triggers', 'Reg', (45, 53))	('Activation', 'Var', (0, 10))	('metastasis', 'CPA', (54, 64))	('promotes', 'PosReg', (18, 26))
69172	31569444	However, phosphorylated TAK1 activates IKK (IkappaB kinase) and MKK4/7, causing the activation of NF-kappaB and JNK.	('MKK4', 'Gene', '6416', (64, 68))	('TAK1', 'Gene', '6885', (24, 28))	('MKK4', 'Gene', (64, 68))	('activation', 'PosReg', (84, 94))	('TAK1', 'Gene', (24, 28))	('JNK', 'Gene', '5599', (112, 115))	('NF-kappaB', 'Protein', (98, 107))	('JNK', 'Gene', (112, 115))	('phosphorylated', 'Var', (9, 23))	('IKK', 'Enzyme', (39, 42))
69173	31569444	Deletion of TAK1 in liver parenchymal cells (both hepatocytes and cholangiocytes) promotes hepatocyte death, inflammation, fibrosis, and hepatocarcinogenesis, coinciding with biliary ductopenia and cholestasis.	('cholestasis', 'Disease', 'MESH:D002779', (198, 209))	('fibrosis', 'Disease', 'MESH:D005355', (123, 131))	('fibrosis', 'Disease', (123, 131))	('death', 'Disease', 'MESH:D003643', (102, 107))	('hepatocarcinogenesis', 'Disease', (137, 157))	('death', 'Disease', (102, 107))	('promotes', 'PosReg', (82, 90))	('biliary ductopenia', 'Disease', (175, 193))	('cholestasis', 'Disease', (198, 209))	('biliary ductopenia', 'Disease', 'MESH:D001661', (175, 193))	('inflammation', 'Disease', 'MESH:D007249', (109, 121))	('TAK1', 'Gene', '6885', (12, 16))	('inflammation', 'Disease', (109, 121))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (137, 157))	('cholestasis', 'Phenotype', 'HP:0001396', (198, 209))	('TAK1', 'Gene', (12, 16))	('Deletion', 'Var', (0, 8))
69197	31569444	Interestingly, JNK induced phosphorylation of R-SMAD can activate the EMT programming process.	('EMT programming process', 'CPA', (70, 93))	('JNK', 'Gene', (15, 18))	('JNK', 'Gene', '5599', (15, 18))	('phosphorylation', 'Var', (27, 42))	('activate', 'PosReg', (57, 65))	('R-SMAD', 'Protein', (46, 52))
69212	31569444	In addition, neutrophil migration can be induced by the P13K/AKT and MAPKs signaling pathways, which are manifested by the recruitment of neutrophils in CCA.	('CCA', 'Disease', (153, 156))	('P13K', 'Var', (56, 60))	('MAPKs signaling pathways', 'Pathway', (69, 93))	('induced', 'Reg', (41, 48))	('rat', 'Species', '10116', (27, 30))	('neutrophil migration', 'CPA', (13, 33))	('P13K', 'SUBSTITUTION', 'None', (56, 60))
69233	31569444	Simultaneously, epigenetic regulation of IL-6 promotes the progression of CCA by affecting promoter methylation and gene expression in growth regulatory pathways including EGFR.	('affecting', 'Reg', (81, 90))	('gene expression', 'MPA', (116, 131))	('epigenetic regulation', 'Var', (16, 37))	('CCA', 'Disease', (74, 77))	('promoter methylation', 'MPA', (91, 111))	('IL-6', 'Gene', (41, 45))	('promotes', 'PosReg', (46, 54))	('IL-6', 'Gene', '3569', (41, 45))	('growth regulatory pathways', 'Pathway', (135, 161))
69236	31569444	The development of CCA involves genetic alterations of related oncogenes in humans (Table 1).	('CCA', 'Disease', (19, 22))	('humans', 'Species', '9606', (76, 82))	('genetic alterations', 'Var', (32, 51))	('rat', 'Species', '10116', (44, 47))
69237	31569444	Mutations common to tumors all along the chromosome include tumor suppressor genes (TP53, and PTEN), chromatin-remodeling genes (ARID1A, ARID1B, BAP1, PBRM1), and gain of function of oncogenes (KRAS, BRAF, and PIK3CA).	('PTEN', 'Gene', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('TP53', 'Gene', (84, 88))	('BAP1', 'Gene', (145, 149))	('tumor', 'Disease', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('ARID1A', 'Gene', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Disease', (20, 26))	('TP53', 'Gene', '7157', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('PBRM1', 'Gene', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('oncogenes', 'CPA', (183, 192))	('BAP1', 'Gene', '8314', (145, 149))	('gain of function', 'PosReg', (163, 179))	('tumor', 'Disease', (20, 25))
69238	31569444	However, mutations in the ERK/MAPKs pathway components are relatively common in CCA.	('common', 'Reg', (70, 76))	('ERK', 'Gene', '5594', (26, 29))	('CCA', 'Disease', (80, 83))	('mutations', 'Var', (9, 18))	('ERK', 'Gene', (26, 29))
69239	31569444	In particular, KRAS mutations are associated with a decrease in both progression-free, and overall survival in CCA patients.	('patients', 'Species', '9606', (115, 123))	('CCA', 'Disease', (111, 114))	('KRAS', 'Gene', (15, 19))	('overall survival', 'CPA', (91, 107))	('decrease', 'NegReg', (52, 60))	('progression-free', 'CPA', (69, 85))	('mutations', 'Var', (20, 29))
69248	31569444	Even though recent studies have found that modified branched-chain DNA probes for albumin mRNA (used for in situ detection of albumin expression) have a detection rate of 99% for CCA and 100% for liver cancer, these are not detected exclusively in CCA, not even in early stages.	('rat', 'Species', '10116', (163, 166))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('liver cancer', 'Phenotype', 'HP:0002896', (196, 208))	('liver cancer', 'Disease', 'MESH:D006528', (196, 208))	('modified', 'Var', (43, 51))	('liver cancer', 'Disease', (196, 208))	('detection', 'MPA', (153, 162))	('CCA', 'Disease', (179, 182))	('CCA', 'Disease', (248, 251))
69268	31569444	Some clinical studies are currently testing patients with advanced CCA who have FGFR changes (NCT02150967), (NCT01703481), (NCT02699606), and (NCT02265341).	('NCT02150967', 'Chemical', 'MESH:C079985', (94, 105))	('patients', 'Species', '9606', (44, 52))	('NCT01703481', 'Var', (109, 120))	('NCT02265341', 'Var', (143, 154))	('NCT02150967', 'Var', (94, 105))	('NCT02699606', 'Var', (124, 135))	('FGFR', 'Gene', (80, 84))
69270	31569444	The clinical efficacy of BGJ398 is currently under assessment in a phase I clinical study for advanced solid tumors, with FGFR1/FGFR2 amplification or FGFR3 mutation (NCT01004224).	('FGFR3', 'Gene', '2261', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('BGJ398', 'Gene', (25, 31))	('FGFR2', 'Gene', (128, 133))	('FGFR1', 'Gene', (122, 127))	('mutation', 'Var', (157, 165))	('FGFR1', 'Gene', '2260', (122, 127))	('amplification', 'Var', (134, 147))	('solid tumors', 'Disease', (103, 115))	('FGFR3', 'Gene', (151, 156))	('FGFR2', 'Gene', '2263', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('solid tumors', 'Disease', 'MESH:D009369', (103, 115))
69271	31569444	ALK (EML4(echinoderm microtubule-associated protein-like 4)-ALK(anaplastic lymphoma kinase)) and the ROS1 inhibitor Ceritinib are currently being evaluated in a phase II clinical trial of patients with ROS1-positive or ALK-positive advanced-stage pCCA or iCCA (NCT02374489), (NCT02638909), and (NCT02568267).	('ROS1', 'Gene', '6098', (101, 105))	('ROS1', 'Gene', (202, 206))	('lymphoma', 'Disease', 'MESH:D008223', (75, 83))	('NCT02568267', 'Var', (295, 306))	('iCCA', 'Disease', (255, 259))	('ROS1', 'Gene', '6098', (202, 206))	('pCCA', 'Gene', '5095', (247, 251))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (64, 83))	('NCT02638909', 'Var', (276, 287))	('lymphoma', 'Phenotype', 'HP:0002665', (75, 83))	('patients', 'Species', '9606', (188, 196))	('pCCA', 'Gene', (247, 251))	('ROS1', 'Gene', (101, 105))	('Ceritinib', 'Chemical', 'MESH:C586847', (116, 125))	('NCT02374489', 'Var', (261, 272))	('lymphoma', 'Disease', (75, 83))
69274	31569444	PD901, a MEK inhibitor, has been shown to be effective against CCA harboring KRAS oncogenic mutations via inhibition of cell proliferation and modulation of the tumor microenvironment.	('cell proliferation', 'CPA', (120, 138))	('rat', 'Species', '10116', (132, 135))	('PD901', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('mutations', 'Var', (92, 101))	('KRAS', 'Gene', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('MEK', 'Gene', (9, 12))	('MEK', 'Gene', '5609', (9, 12))	('inhibition', 'NegReg', (106, 116))	('CCA', 'Disease', (63, 66))	('tumor', 'Disease', (161, 166))
69280	31569444	Again, it has been reported that hot-spot mutations in the IDH1 and IDH2 genes are frequent in CCA and can promote epigenetic alterations through the regulation of DNA demethylases activity.	('IDH1', 'Gene', '3417', (59, 63))	('epigenetic alterations', 'MPA', (115, 137))	('IDH2', 'Gene', (68, 72))	('CCA', 'Disease', (95, 98))	('IDH2', 'Gene', '3418', (68, 72))	('rat', 'Species', '10116', (130, 133))	('IDH1', 'Gene', (59, 63))	('promote', 'PosReg', (107, 114))	('mutations', 'Var', (42, 51))
69281	31569444	Small molecules that inhibit the neomorphic activity of mutant IDH can reverse DNA methylation, and, in fact, may promote cancer cell differentiation.	('IDH', 'Gene', (63, 66))	('mutant', 'Var', (56, 62))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('IDH', 'Gene', '3417', (63, 66))	('promote', 'PosReg', (114, 121))	('DNA methylation', 'MPA', (79, 94))	('inhibit', 'NegReg', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('neomorphic activity', 'MPA', (33, 52))
69282	31569444	Therefore, small molecule inhibitors of mutant IDH1 or IDH2 have demonstrated efficacy, and, in fact, orally available compounds such as AG-120 have entered clinical trials (inhibitor of mutant IDH1).	('rat', 'Species', '10116', (72, 75))	('IDH2', 'Gene', '3418', (55, 59))	('IDH1', 'Gene', (194, 198))	('IDH1', 'Gene', (47, 51))	('IDH1', 'Gene', '3417', (194, 198))	('mutant', 'Var', (40, 46))	('IDH2', 'Gene', (55, 59))	('IDH1', 'Gene', '3417', (47, 51))
69283	31569444	Preliminary studies treating CCA patients with mutated IDH1 with AG-120 in Phase I clinical trials (dose escalation and dose amplification cohort studies) showed that this inhibitor was safe and effective (NCT02073994).	('IDH1', 'Gene', '3417', (55, 59))	('patients', 'Species', '9606', (33, 41))	('CCA', 'Disease', (29, 32))	('AG-120', 'Gene', (65, 71))	('mutated', 'Var', (47, 54))	('IDH1', 'Gene', (55, 59))
69287	31569444	Several studies have found a subset of CCA patients with high expression of PD-1/PD-L1, suggesting that these patients may be suitable for treatment with PD-1 or PD-L1 inhibitors (NCT02703714, NCT02628067) (Table 1).	('PD-1', 'Gene', '6622', (76, 80))	('NCT02703714', 'Var', (180, 191))	('PD-1', 'Gene', (154, 158))	('PD-L1', 'Gene', (81, 86))	('patients', 'Species', '9606', (43, 51))	('NCT02628067', 'Chemical', 'MESH:C079985', (193, 204))	('PD-L1', 'Gene', '29126', (162, 167))	('CCA', 'Disease', (39, 42))	('PD-L1', 'Gene', '29126', (81, 86))	('PD-1', 'Gene', (76, 80))	('PD-1', 'Gene', '6622', (154, 158))	('patients', 'Species', '9606', (110, 118))	('PD-L1', 'Gene', (162, 167))
69290	31569444	One study using the RBE human CCA cell line treated with SP600125, an inhibitor of JNK, demonstrated enhanced TGF-beta-induced cell apoptosis in a SMAD4-dependent manner, suggesting that JNK inhibition may be an ideal therapeutic candidate for the treatment of human CCA.	('JNK', 'Gene', (187, 190))	('human', 'Species', '9606', (24, 29))	('JNK', 'Gene', '5599', (83, 86))	('TGF-beta', 'Gene', (110, 118))	('JNK', 'Gene', '5599', (187, 190))	('rat', 'Species', '10116', (95, 98))	('SP600125', 'Chemical', 'MESH:C432165', (57, 65))	('human', 'Species', '9606', (261, 266))	('TGF-beta', 'Gene', '7040', (110, 118))	('SP600125', 'Var', (57, 65))	('enhanced', 'PosReg', (101, 109))	('JNK', 'Gene', (83, 86))
69370	31567946	According to Cox regression analysis for DFS, the univariate HR was estimated to be 0.442 (95% CI: 0.242-0.810, P = .008) for the HCC patients and 0.714 (95% CI: 0.365-1.397, P = .325) for the ICC patients, compared to the CHCC patients.	('ICC', 'Disease', (193, 196))	('patients', 'Species', '9606', (197, 205))	('Cox', 'Gene', (13, 16))	('patients', 'Species', '9606', (228, 236))	('HCC', 'Disease', 'MESH:D006528', (130, 133))	('patients', 'Species', '9606', (134, 142))	('0.714', 'Var', (147, 152))	('ICC', 'Disease', 'MESH:C535533', (193, 196))	('HCC', 'Disease', (130, 133))	('HCC', 'Phenotype', 'HP:0001402', (130, 133))	('HCC', 'Disease', (224, 227))	('CHCC', 'Phenotype', 'HP:0030153', (223, 227))	('HCC', 'Disease', 'MESH:D006528', (224, 227))	('HCC', 'Phenotype', 'HP:0001402', (224, 227))	('Cox', 'Gene', '1351', (13, 16))
69373	31567946	But AFP level >=400 ng/ml, tumor number >=2, tumor size >=5 cm, lymph node metastasis, distant metastasis, major and microvascular invasion and positive margin increased the HR by different fold respectively, according to multivariate analysis.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (27, 32))	('increased', 'PosReg', (160, 169))	('tumor', 'Disease', (45, 50))	('lymph node metastasis', 'CPA', (64, 85))	('AFP', 'Gene', (4, 7))	('AFP', 'Gene', '174', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('distant metastasis', 'CPA', (87, 105))	('>=400', 'Var', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
69374	31567946	By OS analysis, the univariate HR was estimated to be 0.325 (95% CI: 0.178-0.596, P < .001) for the HCC patients and 0.578 (95% CI: 0.295-1.131, P = .109) for the ICC patients, compared to the CHCC patients.	('HCC', 'Disease', 'MESH:D006528', (194, 197))	('CHCC', 'Phenotype', 'HP:0030153', (193, 197))	('HCC', 'Disease', (194, 197))	('patients', 'Species', '9606', (198, 206))	('HCC', 'Phenotype', 'HP:0001402', (194, 197))	('ICC', 'Disease', 'MESH:C535533', (163, 166))	('0.578', 'Var', (117, 122))	('patients', 'Species', '9606', (167, 175))	('HCC', 'Disease', (100, 103))	('HCC', 'Disease', 'MESH:D006528', (100, 103))	('patients', 'Species', '9606', (104, 112))	('HCC', 'Phenotype', 'HP:0001402', (100, 103))	('ICC', 'Disease', (163, 166))
69417	31231212	Histamine acts through four different receptor subtypes: H1, H2, H3, and H4 receptors (H1R, H2R, H3R, and H4R).	('H3R', 'Gene', (97, 100))	('H1R', 'Gene', (87, 90))	('Histamine', 'Chemical', 'MESH:D006632', (0, 9))	('H2R', 'Gene', '3274', (92, 95))	('H3R', 'Gene', '11255', (97, 100))	('H4 receptors', 'Protein', (73, 85))	('H4R', 'Var', (106, 109))	('H2R', 'Gene', (92, 95))	('H1R', 'Gene', '3269', (87, 90))
69427	31231212	The discovery of the first selective and potent H4R antagonist JNJ7777120 by Johnson & Johnson Research and Development (now Janssen Pharmaceuticals, Inc.) was essential for evaluating the role of H4R in pathophysiology, including immune reaction-associated pruritus and inflammation.	('pruritus', 'Phenotype', 'HP:0000989', (258, 266))	('including immune reaction-associated', 'Disease', (221, 257))	('men', 'Species', '9606', (115, 118))	('and', 'Disease', (267, 270))	('pruritus', 'Disease', 'MESH:D011537', (258, 266))	('pruritus', 'Disease', (258, 266))	('inflammation', 'Disease', 'MESH:D007249', (271, 283))	('JNJ7777120', 'Var', (63, 73))	('inflammation', 'Disease', (271, 283))	('JNJ7777120', 'Chemical', 'MESH:C484309', (63, 73))
69430	31231212	Recently, the compound JNJ39758979 was developed as a more potent and selective H4R antagonist than JNJ7777120 and it also shows preclinical anti-inflammatory and antipruritic effects.	('JNJ7777120', 'Chemical', 'MESH:C484309', (100, 110))	('anti-inflammatory', 'CPA', (141, 158))	('antipruritic', 'CPA', (163, 175))	('JNJ39758979', 'Var', (23, 34))	('H4R antagonist', 'Protein', (80, 94))
69434	31231212	JNJ39758979 was also tested in a phase 2a trial in adults with uncontrolled asthma without reaching the primary efficacy endpoint.	('asthma', 'Disease', (76, 82))	('asthma', 'Disease', 'MESH:D001249', (76, 82))	('JNJ39758979', 'Var', (0, 11))	('asthma', 'Phenotype', 'HP:0002099', (76, 82))
69441	31231212	A recent phase 2a clinical trial was carried out with the selective H4R antagonist ZPL-3893787, administered orally in patients with moderate to severe atopic dermatitis.	('patients', 'Species', '9606', (119, 127))	('H4R', 'Protein', (68, 71))	('ZPL-3893787', 'Var', (83, 94))	('dermatitis', 'Phenotype', 'HP:0011123', (159, 169))	('rat', 'Species', '10116', (137, 140))	('atopic dermatitis', 'Disease', 'MESH:D003876', (152, 169))	('atopic dermatitis', 'Phenotype', 'HP:0001047', (152, 169))	('ZPL-3893787', 'Chemical', '-', (83, 94))	('atopic dermatitis', 'Disease', (152, 169))
69459	31231212	Patients with high protein expression of H4R in tumor cells exhibited a larger primary tumor size and a greater number of lymph node metastases than those with lower expression.	('larger', 'PosReg', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (48, 53))	('high protein expression', 'Var', (14, 37))	('H4R', 'Protein', (41, 44))	('tumor', 'Disease', (87, 92))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('metastases', 'Disease', (133, 143))	('greater number of lymph node', 'Phenotype', 'HP:0032536', (104, 132))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('metastases', 'Disease', 'MESH:D009362', (133, 143))
69469	31231212	Furthermore, authors demonstrated that deletion and downregulation of H4R gene take place in the progression but not the initiation of stomach cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('H4R', 'Gene', (70, 73))	('stomach cancer', 'Phenotype', 'HP:0012126', (135, 149))	('initiation of stomach cancer', 'Disease', (121, 149))	('deletion', 'Var', (39, 47))	('downregulation', 'NegReg', (52, 66))	('initiation of stomach cancer', 'Disease', 'MESH:D013274', (121, 149))	('rat', 'Species', '10116', (28, 31))
69478	31231212	On the other hand, a previous study showed that JNJ7777120 inhibited histamine-induced cell growth of human CRC cell lines.	('histamine', 'Chemical', 'MESH:D006632', (69, 78))	('inhibited', 'NegReg', (59, 68))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))	('JNJ7777120', 'Var', (48, 58))	('JNJ7777120', 'Chemical', 'MESH:C484309', (48, 58))	('human', 'Species', '9606', (102, 107))
69481	31231212	In addition, it was reported that histidine decarboxylase (HDC) deficiency promoted inflammation-associated CRC.	('HDC', 'Gene', (59, 62))	('histidine decarboxylase', 'Gene', '3067', (34, 57))	('deficiency', 'Var', (64, 74))	('inflammation', 'Disease', 'MESH:D007249', (84, 96))	('promoted', 'PosReg', (75, 83))	('inflammation', 'Disease', (84, 96))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))	('HDC', 'Gene', '3067', (59, 62))	('histidine decarboxylase', 'Gene', (34, 57))
69484	31231212	Administration of L. reuteri and not of an isogenic HDC-deficient L. reuteri mutant that was unable to generate histamine, suppressed carcinogenesis, cancer-associated cytokines, and decreased the relative number of splenic CD11b+Gr-1+ immature myeloid cells, which confirmed the potential antitumorigenic effect of histamine.	('carcinogenesis', 'Disease', 'MESH:D063646', (134, 148))	('rat', 'Species', '10116', (8, 11))	('HDC', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('CD11b', 'Gene', '3684', (224, 229))	('CD11b', 'Gene', (224, 229))	('decreased', 'NegReg', (183, 192))	('cancer', 'Disease', (150, 156))	('HDC', 'Gene', '3067', (52, 55))	('histamine', 'Chemical', 'MESH:D006632', (112, 121))	('L. reuteri', 'Species', '1598', (66, 76))	('L. reuteri', 'Gene', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('mutant', 'Var', (77, 83))	('rat', 'Species', '10116', (107, 110))	('tumor', 'Disease', (294, 299))	('L. reuteri', 'Species', '1598', (18, 28))	('suppressed', 'NegReg', (123, 133))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('carcinogenesis', 'Disease', (134, 148))	('histamine', 'Chemical', 'MESH:D006632', (316, 325))	('tumor', 'Disease', 'MESH:D009369', (294, 299))
69499	31231212	To confirm the exclusive participation of the H4R in these processes, studies were performed in cells with genetic knockdown of the H3R and overexpression of H4R.	('overexpression', 'PosReg', (140, 154))	('H3R', 'Gene', '11255', (132, 135))	('H3R', 'Gene', (132, 135))	('knockdown', 'Var', (115, 124))
69510	31231212	It is important to highlight that high expression of H4R in tumor specimens was associated with increased OS in pancreatic cancer (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('H4R', 'Protein', (53, 56))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('high expression', 'Var', (34, 49))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('men', 'Species', '9606', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('pancreatic cancer', 'Disease', (112, 129))	('tumor', 'Disease', (60, 65))	('pancreatic cancer', 'Disease', 'MESH:D010190', (112, 129))	('OS', 'Chemical', '-', (106, 108))
69548	31231212	Further supporting the critical role of H4R in breast cancer development and progression, He and coworkers demonstrated the presence of polymorphisms of the H4R gene (rs623590, rs11662595, and rs1421125 genotypes of H4R gene) in Chinese Han population, which were associated with the risk of developing breast cancer and the malignant degree of the tumor.	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('rs11662595', 'Var', (177, 187))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('rs623590', 'Var', (167, 175))	('breast cancer', 'Disease', (47, 60))	('rs11662595', 'Mutation', 'rs11662595', (177, 187))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('H4R', 'Gene', (157, 160))	('rs623590', 'Mutation', 'rs623590', (167, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (303, 316))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', (349, 354))	('rat', 'Species', '10116', (114, 117))	('associated', 'Reg', (264, 274))	('rs1421125', 'Mutation', 'rs1421125', (193, 202))	('breast cancer', 'Disease', (303, 316))	('breast cancer', 'Disease', 'MESH:D001943', (303, 316))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('rs1421125', 'Var', (193, 202))	('men', 'Species', '9606', (68, 71))
69550	31231212	All the studies, using different H4R ligands and also genetic down-regulation of H4R, demonstrated that the principal receptor subtype involved in the histamine-induced reduction of proliferation was the H4R.	('proliferation', 'CPA', (182, 195))	('H4R', 'Protein', (81, 84))	('H4R', 'Protein', (204, 207))	('reduction', 'NegReg', (169, 178))	('histamine', 'Chemical', 'MESH:D006632', (151, 160))	('down-regulation', 'NegReg', (62, 77))	('rat', 'Species', '10116', (189, 192))	('genetic', 'Var', (54, 61))	('rat', 'Species', '10116', (93, 96))
69551	31231212	The in vivo administration of histamine or H4R agonists (e.g., JNJ28610244) diminished the tumor growth of human triple negative breast cancer (TNBC) developed in immune-deficient nude mice with MDA-MB-231 cells.	('breast cancer', 'Disease', (129, 142))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (195, 205))	('histamine', 'Chemical', 'MESH:D006632', (30, 39))	('nude mice', 'Species', '10090', (180, 189))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('human', 'Species', '9606', (107, 112))	('rat', 'Species', '10116', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('JNJ28610244', 'Var', (63, 74))	('TNBC', 'Disease', 'None', (144, 148))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('tumor', 'Disease', (91, 96))	('TNBC', 'Disease', (144, 148))	('diminished', 'NegReg', (76, 86))
69552	31231212	On the other hand, tumor doubling time was not significantly modified while mean survival was reduced after the treatment with the H4R antagonist JNJ10191584.	('JNJ10191584', 'Chemical', 'MESH:C506811', (146, 157))	('JNJ10191584', 'Var', (146, 157))	('reduced', 'NegReg', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('men', 'Species', '9606', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('mean survival', 'CPA', (76, 89))
69568	31231212	Furthermore, patients with tumors showing low/medium H4R expression presented a higher OS compared to those with high expression levels (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('H4R', 'Protein', (53, 56))	('low/medium', 'Var', (42, 52))	('patients', 'Species', '9606', (13, 21))	('OS', 'Chemical', '-', (87, 89))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('higher', 'PosReg', (80, 86))
69582	31231212	Likewise, results described in breast cancer, genetic variations of H4R gene were found in a large number of Chinese NSCLC patients.	('NSCLC', 'Disease', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('found', 'Reg', (82, 87))	('genetic variations', 'Var', (46, 64))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('patients', 'Species', '9606', (123, 131))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('H4R', 'Gene', (68, 71))	('breast cancer', 'Disease', (31, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))
69583	31231212	In particular, the loss-of-function polymorphism rs11662595, associated to a higher invasive behavior, was linked to the prognosis, the degree of malignancy, and the metastatic potential of NSCLC.	('rs11662595', 'Mutation', 'rs11662595', (49, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (190, 195))	('invasive behavior', 'CPA', (84, 101))	('higher', 'PosReg', (77, 83))	('metastatic potential', 'CPA', (166, 186))	('malignancy', 'Disease', 'MESH:D009369', (146, 156))	('rs11662595', 'Var', (49, 59))	('NSCLC', 'Disease', (190, 195))	('NSCLC', 'Disease', 'MESH:D002289', (190, 195))	('malignancy', 'Disease', (146, 156))	('loss-of-function', 'NegReg', (19, 35))
69605	31231212	Antagonist JNJ7777120, as mentioned before, shows high selectivity for the human, mouse and rat H4R.	('human', 'Species', '9606', (75, 80))	('rat', 'Species', '10116', (92, 95))	('H4R', 'Protein', (96, 99))	('JNJ7777120', 'Var', (11, 21))	('men', 'Species', '9606', (26, 29))	('JNJ7777120', 'Chemical', 'MESH:C484309', (11, 21))	('mouse', 'Species', '10090', (82, 87))
69612	31231212	Human H4R isoforms are the result of alternative splicing.	('alternative splicing', 'Var', (37, 57))	('Human H4R', 'Protein', (0, 9))	('Human', 'Species', '9606', (0, 5))
69615	31231212	Some polymorphisms of H4R have been reported in cancer, which were associated to malignancy of the disease in a Chinese Han population.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('H4R', 'Gene', (22, 25))	('reported', 'Reg', (36, 44))	('cancer', 'Disease', (48, 54))	('associated', 'Reg', (67, 77))	('malignancy of the disease', 'Disease', 'MESH:D009369', (81, 106))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('malignancy of the disease', 'Disease', (81, 106))	('polymorphisms', 'Var', (5, 18))
69617	31231212	In addition, the study of the alteration frequency of H4R gene in the main cancer types, with available data from cBioPortal, indicated that H4R gene alterations occurred in different percentage depending on cancer type.	('cancer', 'Disease', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('H4R gene', 'Gene', (141, 149))	('rat', 'Species', '10116', (154, 157))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('alterations', 'Var', (150, 161))	('rat', 'Species', '10116', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
69618	31231212	Amplifications and mutations comprised the major types of H4R gene alterations (Figure 3).	('Amplifications', 'Var', (0, 14))	('H4R', 'Gene', (58, 61))	('mutations', 'Var', (19, 28))	('rat', 'Species', '10116', (71, 74))
69631	31231212	In this context, H4R gene alterations (e.g., mutation, deletions, and amplifications) in different cancer types should be studied.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('rat', 'Species', '10116', (30, 33))	('cancer', 'Disease', (99, 105))	('H4R', 'Gene', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('deletions', 'Var', (55, 64))
69643	31231212	H4R ligands exhibit a complex pharmacology, which is related to numerous factors including tissue variability in histamine-induced signaling pathways, functional selectivity, intra and interspecies differences in potency and selectivity, structural homology with H3R, splice variant isoforms, and polymorphisms that could preclude H4R function, together with impairment expression in pathological conditions.	('histamine', 'Chemical', 'MESH:D006632', (113, 122))	('polymorphisms', 'Var', (297, 310))	('men', 'Species', '9606', (365, 368))	('H3R', 'Gene', (263, 266))	('H3R', 'Gene', '11255', (263, 266))
69832	26645826	On account of the fact that BilIN-3 corresponds to a carcinoma in situ, it considered as an overt cancer of the bile ducts.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('carcinoma', 'Disease', 'MESH:D002277', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('cancer', 'Disease', (98, 104))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (53, 70))	('BilIN', 'Chemical', '-', (28, 33))	('carcinoma', 'Disease', (53, 62))	('BilIN-3', 'Var', (28, 35))
69853	26645826	Activating KRAS mutations can be found in up to 95% of PDACs 18.	('KRAS', 'Gene', (11, 15))	('Activating', 'PosReg', (0, 10))	('KRAS', 'Gene', '3845', (11, 15))	('mutations', 'Var', (16, 25))
69854	26645826	It is of particular interest that KRAS mutations are present in 90% of early stage PDACs, as well as in premalignant lesions such as PanINs 19, 20.	('PDACs', 'Disease', (83, 88))	('KRAS', 'Gene', (34, 38))	('KRAS', 'Gene', '3845', (34, 38))	('mutations', 'Var', (39, 48))
69855	26645826	Through the analysis of KRAS mutations in biliary tract neoplasms and their corresponding premalignant lesions, Hsu et al.	('biliary tract neoplasms', 'Disease', 'MESH:D001661', (42, 65))	('KRAS', 'Gene', '3845', (24, 28))	('biliary tract neoplasms', 'Phenotype', 'HP:0100574', (42, 65))	('biliary tract neoplasms', 'Disease', (42, 65))	('mutations', 'Var', (29, 38))	('neoplasm', 'Phenotype', 'HP:0002664', (56, 64))	('neoplasms', 'Phenotype', 'HP:0002664', (56, 65))	('KRAS', 'Gene', (24, 28))
69857	26645826	Moreover, a recent study reports that KRAS mutations are present in 61.1% of the ampullary cancers, but only in 15.2% of bile duct and 2.7% of gallbladder cancers 22.	('ampullary cancer', 'Disease', 'MESH:D009369', (81, 97))	('KRAS', 'Gene', '3845', (38, 42))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('gallbladder cancers', 'Disease', 'MESH:D005706', (143, 162))	('cancers', 'Disease', (91, 98))	('ampullary cancer', 'Disease', (81, 97))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('mutations', 'Var', (43, 52))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('bile duct', 'Disease', (121, 130))	('gallbladder cancers', 'Disease', (143, 162))	('cancers', 'Disease', (155, 162))	('present', 'Reg', (57, 64))	('KRAS', 'Gene', (38, 42))
69858	26645826	One of the key players of physiological apoptotic response, tumor suppressor gene p53, is frequently subject to mutations in CC as well as PDAC.	('subject', 'Reg', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('mutations', 'Var', (112, 121))	('CC', 'Gene', '36377', (125, 127))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('p53', 'Gene', '7157', (82, 85))	('p53', 'Gene', (82, 85))	('tumor', 'Disease', (60, 65))
69860	26645826	In PDAC, p53 mutations can be found in up to 70% of primary, and in more than 50% of metastatic pancreatic cancers 25, 26, 27.	('primary', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('found', 'Reg', (30, 35))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (96, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('mutations', 'Var', (13, 22))	('pancreatic cancers', 'Disease', 'MESH:D010190', (96, 114))	('pancreatic cancers', 'Disease', (96, 114))
69861	26645826	Unlike KRAS, p53 mutations seem to be a late event in the development of PanINs to PDAC 20, 28.	('KRAS', 'Gene', '3845', (7, 11))	('PanINs', 'Disease', (73, 79))	('p53', 'Gene', (13, 16))	('mutations', 'Var', (17, 26))	('p53', 'Gene', '7157', (13, 16))	('KRAS', 'Gene', (7, 11))
69864	26645826	It is of further note that mutant p53 stimulates chemoresistance against gemcitabine, and the reintroduction (reactivation) of p53 increases the cytotoxicity of gemcitabine 31, 32.	('chemoresistance', 'CPA', (49, 64))	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('reintroduction', 'Var', (94, 108))	('cytotoxicity', 'Disease', 'MESH:D064420', (145, 157))	('mutant', 'Var', (27, 33))	('gemcitabine', 'Chemical', 'MESH:C056507', (161, 172))	('increases', 'PosReg', (131, 140))	('stimulates', 'PosReg', (38, 48))	('gemcitabine', 'Chemical', 'MESH:C056507', (73, 84))	('cytotoxicity', 'Disease', (145, 157))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (127, 130))
70021	32207856	The multivariable analyses for major morbidity and mortality were repeated for minor resection only (Table  S2 , supporting information), major resections (Table  S3 , supporting information) and resections for CRLMs (Table  S4 , supporting information).	('mortality', 'Disease', (51, 60))	('minor resection', 'Disease', (79, 94))	('mortality', 'Disease', 'MESH:D003643', (51, 60))	('resections', 'Var', (196, 206))
70055	32207856	Members of the Dutch Hepato Biliary Audit Group who collaborated in this study: M. G. H. Besselink (Cancer Centre Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam); M. T. de Boer (University Medical Centre Groningen, Groningen); C. I. Buis (University Medical Centre Groningen, Groningen); T. M. van Gulik (Cancer Centre Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam); F. J. H. Hoogwater (University Medical Centre Groningen, Groningen); I. Q. Molenaar (University Medical Center Utrecht, Utrecht); C. H. C. Dejong (Maastricht University Medical Centre, Maastricht); C. Verhoef (Erasmus MC, Erasmus University, Rotterdam).	('Cancer', 'Disease', (319, 325))	('Cancer', 'Disease', 'MESH:D009369', (319, 325))	('C. H. C. Dejong', 'Var', (526, 541))	('Cancer', 'Phenotype', 'HP:0002664', (319, 325))	('Cancer', 'Disease', 'MESH:D009369', (100, 106))	('Cancer', 'Disease', (100, 106))	('Cancer', 'Phenotype', 'HP:0002664', (100, 106))
70089	31969123	The levels of four serum tumor markers were recorded with a normal reference level of less than 20 mug/L for AFP, less than 35 U/mL for CA19-9, less than 35 U/mL for CA-125, and less than 5 mug/L for CEA.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('AFP', 'Gene', (109, 112))	('less than 35 U/mL', 'Var', (114, 131))	('tumor', 'Disease', (25, 30))	('AFP', 'Gene', '174', (109, 112))	('CEA', 'Gene', (200, 203))	('CEA', 'Gene', '1084', (200, 203))	('less than 35 U/mL', 'Var', (144, 161))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
70120	31969123	One point is allocated to each of the following if present on imaging: the presence of parenchymal lesion with intraductal lesion, non-thickened hilar bile duct wall, hypoattenuation in portal venous phase, vascular tumor embolus or splenomegaly.	('vascular tumor', 'Phenotype', 'HP:0100742', (207, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('intraductal lesion', 'Disease', (111, 129))	('splenomegaly', 'Disease', 'MESH:D013163', (233, 245))	('vascular tumor embolus', 'Disease', (207, 229))	('hypoattenuation', 'Var', (167, 182))	('vascular tumor embolus', 'Disease', 'MESH:D004617', (207, 229))	('splenomegaly', 'Phenotype', 'HP:0001744', (233, 245))	('parenchymal lesion', 'Disease', (87, 105))	('splenomegaly', 'Disease', (233, 245))	('parenchymal lesion', 'Disease', 'MESH:D017563', (87, 105))	('intraductal lesion', 'Disease', 'MESH:D002285', (111, 129))
70146	31969123	When the drainage of intrahepatic bile duct system is obstructed by either benign or malignant causes, CA19-9 in the bile mucin may permeate into serum and lead to the non-specific elevation of CA19-9 in serum.	('lead to', 'Reg', (156, 163))	('non-specific elevation', 'MPA', (168, 190))	('permeate', 'MPA', (132, 140))	('mucin', 'Gene', (122, 127))	('CA19-9', 'Var', (103, 109))	('intrahepatic bile duct', 'Disease', 'MESH:D002780', (21, 43))	('CA19-9 in serum', 'MPA', (194, 209))	('mucin', 'Gene', '100508689', (122, 127))	('intrahepatic bile duct', 'Disease', (21, 43))
70231	31086460	Recent studies show that human iPSCs may develop gene mutations or alter gene expression during differentiation, which may even lead to tumorigenesis.	('alter', 'Reg', (67, 72))	('gene mutations', 'Var', (49, 63))	('develop', 'Reg', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('human', 'Species', '9606', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('gene expression', 'MPA', (73, 88))	('tumor', 'Disease', (136, 141))	('lead to', 'Reg', (128, 135))
70235	31086460	For example, when liver damage occurs, Lgr5+ cells are usually bile duct epithelial cells and can differentiate into hepatocytes and biliary epithelial cells in the body, thereby causing spontaneous repair of the liver.	('causing', 'Reg', (179, 186))	('Lgr5+', 'Var', (39, 44))	('liver damage', 'Disease', (18, 30))	('liver damage', 'Disease', 'MESH:D056486', (18, 30))	('spontaneous repair', 'CPA', (187, 205))
70245	31086460	At the third stage, DM3189, IWP2, PD0325901, RA, A83-01, Bmp4, and other substances were separately added into Matrigel medium to induce differentiation into hepatocytes, and then PGEC progenitor cells were cocultured with interstitial cells and endothelial cells to form livers organoids (Figure 1A).	('induce', 'PosReg', (130, 136))	('Bmp4', 'Gene', (57, 61))	('PD0325901', 'Var', (34, 43))	('DM3189', 'Chemical', '-', (20, 26))	('Matrigel medium', 'Chemical', '-', (111, 126))	('PD0325901', 'Chemical', 'MESH:C506614', (34, 43))	('DM3189', 'Var', (20, 26))	('Bmp4', 'Gene', '652', (57, 61))
70256	31086460	Through LF organoids, the researchers found that acetaminophen (APAP)-induced fibrosis does not directly activate HSCs but induces hepatocyte damage and then, through hepatocyte injury-dependent HSC activation pathway-induced activation of HSCs, causes an accumulation of ECM (Figure 2B).	('hepatocyte damage', 'Disease', (131, 148))	('causes', 'Reg', (246, 252))	('fibrosis', 'Disease', (78, 86))	('fibrosis', 'Disease', 'MESH:D005355', (78, 86))	('accumulation', 'PosReg', (256, 268))	('induces', 'Reg', (123, 130))	('ECM', 'MPA', (272, 275))	('APAP', 'Chemical', 'MESH:D000082', (64, 68))	('hepatocyte damage', 'Disease', 'MESH:D004194', (131, 148))	('acetaminophen', 'Chemical', 'MESH:D000082', (49, 62))	('acetaminophen', 'Var', (49, 62))	('HSCs', 'Gene', (240, 244))	('activation', 'PosReg', (226, 236))
70268	31086460	For example, ALGS is a gene dominant genetic disease usually caused by an autosomal jag gene mutation, namely, the Notch signaling pathway jag1 mutation.	('ALGS', 'Disease', (13, 17))	('jag1', 'Gene', (139, 143))	('caused by', 'Reg', (61, 70))	('ALGS', 'Disease', 'MESH:D016738', (13, 17))	('mutation', 'Var', (144, 152))	('mutation', 'Var', (93, 101))	('jag1', 'Gene', '182', (139, 143))
70273	31086460	In addition, ATAT, a syndrome caused by a mutation of the SYPANA1 gene, causes antitrypsin deficiency and results in a clinical syndrome characterized by chronic liver disease and chronic obstructive pulmonary disease.	('causes', 'Reg', (72, 78))	('deficiency', 'Disease', (91, 101))	('liver disease', 'Phenotype', 'HP:0001392', (162, 175))	('ATAT', 'Disease', (13, 17))	('liver disease', 'Disease', 'MESH:D008107', (162, 175))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (180, 217))	('mutation', 'Var', (42, 50))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (180, 217))	('results in', 'Reg', (106, 116))	('a syndrome', 'Disease', 'MESH:D013577', (19, 29))	('liver disease', 'Disease', (162, 175))	('ATAT', 'Disease', 'None', (13, 17))	('antitrypsin deficiency', 'Phenotype', 'HP:0032025', (79, 101))	('chronic obstructive pulmonary disease', 'Disease', (180, 217))	('SYPANA1', 'Gene', (58, 65))	('a syndrome', 'Disease', (19, 29))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (188, 217))	('caused by', 'Reg', (30, 39))	('deficiency', 'Disease', 'MESH:D007153', (91, 101))
70276	31086460	Copper storage disease (Wilson disease) is an autosomal recessive genetic disease caused by the loss of COMMD1.	('COMMD1', 'Gene', (104, 110))	('autosomal recessive genetic disease', 'Disease', (46, 81))	('Wilson disease', 'Disease', 'MESH:D006527', (24, 38))	('loss', 'Var', (96, 100))	('Copper storage disease', 'Disease', 'MESH:D006527', (0, 22))	('Wilson disease', 'Disease', (24, 38))	('Copper storage disease', 'Disease', (0, 22))	('autosomal recessive genetic disease', 'Disease', 'MESH:D030342', (46, 81))	('Wilson disease', 'Phenotype', 'HP:0032102', (24, 38))	('COMMD1', 'Gene', '150684', (104, 110))
70279	31086460	In addition, the copper accumulation in the liver-organized organoids was significantly reduced by modifying the COMMD1 gene.	('modifying', 'Var', (99, 108))	('COMMD1', 'Gene', '150684', (113, 119))	('copper accumulation', 'Phenotype', 'HP:0012676', (17, 36))	('copper accumulation', 'MPA', (17, 36))	('COMMD1', 'Gene', (113, 119))	('reduced', 'NegReg', (88, 95))	('copper accumulation in the liver', 'Phenotype', 'HP:0025321', (17, 49))	('copper', 'Chemical', 'MESH:D003300', (17, 23))
70291	31086460	During the culture process, it was further verified that SREBF1, CPT1A, PPARG, and other genes can promote fat accumulation in hepatocytes, and it was also confirmed that etomoxir or L-carnitine could affect fat metabolism in hepatocytes.	('PPARG', 'Gene', (72, 77))	('fat accumulation in hepatocytes', 'Phenotype', 'HP:0006561', (107, 138))	('CPT1A', 'Gene', (65, 70))	('promote', 'PosReg', (99, 106))	('L-carnitine', 'Chemical', 'MESH:D002331', (183, 194))	('genes', 'Var', (89, 94))	('affect', 'Reg', (201, 207))	('CPT1A', 'Gene', '1374', (65, 70))	('PPARG', 'Gene', '5468', (72, 77))	('SREBF1', 'Gene', (57, 63))	('fat accumulation', 'MPA', (107, 123))	('etomoxir', 'Chemical', 'MESH:C054207', (171, 179))	('fat metabolism', 'MPA', (208, 222))	('SREBF1', 'Gene', '6720', (57, 63))
70312	31086460	Genetic analysis shows that liver cancer is usually caused by multiple-gene and multistep mutations in liver tissue, and liver cancer patients rarely have identical oncogenes or the same genes.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (90, 99))	('liver cancer', 'Phenotype', 'HP:0002896', (28, 40))	('liver cancer', 'Disease', 'MESH:D006528', (28, 40))	('patients', 'Species', '9606', (134, 142))	('liver cancer', 'Disease', (28, 40))	('liver cancer', 'Phenotype', 'HP:0002896', (121, 133))	('liver cancer', 'Disease', 'MESH:D006528', (121, 133))	('liver cancer', 'Disease', (121, 133))	('caused by', 'Reg', (52, 61))
70338	31086460	The insensitivity is often caused by the multiple-gene, multistep mutations in liver cancer and by the lack of effective individual preclinical models to screen the systemic chemotherapeutic agents (Figure 4C).	('mutations', 'Var', (66, 75))	('liver cancer', 'Phenotype', 'HP:0002896', (79, 91))	('caused', 'Reg', (27, 33))	('liver cancer', 'Disease', 'MESH:D006528', (79, 91))	('liver cancer', 'Disease', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
70339	31086460	Broutier et al have demonstrated the value of liver cancer organoids in drug sensitivity experiments in vitro and in vivo and initially showed that anti-ERK inhibition (SCH772984) may have a significant inhibitory effect on the progression of hepatocellular carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('drug sensitivity', 'Phenotype', 'HP:0020174', (72, 88))	('SCH772984', 'Chemical', 'MESH:C587178', (169, 178))	('liver cancer', 'Disease', (46, 58))	('inhibitory effect', 'NegReg', (203, 220))	('liver cancer', 'Phenotype', 'HP:0002896', (46, 58))	('liver cancer', 'Disease', 'MESH:D006528', (46, 58))	('anti-ERK inhibition (SCH772984', 'Var', (148, 178))	('SCH772984', 'Var', (169, 178))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (243, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('hepatocellular carcinoma', 'Disease', (243, 267))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (243, 267))
70342	31086460	The CRISPR/Cas9 system, an emerging gene editing technology, can introduce or knock out related genes to activate or inhibit oncogenes and has been widely used to study some tumors.	('knock out', 'Var', (78, 87))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('oncogenes', 'Protein', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('activate', 'PosReg', (105, 113))	('inhibit', 'NegReg', (117, 124))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
70378	31086460	Through gene editing technology, colon cancer organoids with mutated Trp53 were able to cause liver metastasis of colon cancer when they were implanted into nude mice, which further confirmed that Trp53 promotes liver metastasis of colon cancer.	('liver metastasis of colon cancer', 'Disease', (212, 244))	('Trp53', 'Gene', '22059', (69, 74))	('colon cancer', 'Disease', 'MESH:D015179', (114, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('colon cancer', 'Phenotype', 'HP:0003003', (232, 244))	('Trp53', 'Gene', (69, 74))	('colon cancer', 'Phenotype', 'HP:0003003', (33, 45))	('Trp53', 'Gene', '22059', (197, 202))	('nude mice', 'Species', '10090', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('promotes', 'PosReg', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mutated', 'Var', (61, 68))	('Trp53', 'Gene', (197, 202))	('colon cancer', 'Disease', 'MESH:D015179', (33, 45))	('colon cancer', 'Disease', 'MESH:D015179', (232, 244))	('liver metastasis of colon cancer', 'Disease', 'MESH:D009362', (94, 126))	('colon cancer', 'Disease', (33, 45))	('colon cancer', 'Phenotype', 'HP:0003003', (114, 126))	('liver metastasis of colon cancer', 'Disease', 'MESH:D009362', (212, 244))	('liver metastasis of colon cancer', 'Disease', (94, 126))	('cause', 'Reg', (88, 93))
70395	28428711	Further multivariate logistic regression analysis identified high CUL4A expression as the only independent prognostic factor for PHCC.	('CUL4A', 'Gene', (66, 71))	('high', 'Var', (61, 65))	('CUL4A', 'Gene', '8451', (66, 71))	('expression', 'MPA', (72, 82))	('PHCC', 'Disease', (129, 133))
70402	28428711	High CUL4A expression was revealed to be correlated with poor overall survival (OS) and progression-free survival (PFS) of PHCC patients.	('overall', 'MPA', (62, 69))	('High', 'Var', (0, 4))	('poor', 'NegReg', (57, 61))	('expression', 'MPA', (11, 21))	('CUL4A', 'Gene', (5, 10))	('progression-free survival', 'CPA', (88, 113))	('CUL4A', 'Gene', '8451', (5, 10))	('patients', 'Species', '9606', (128, 136))	('PHCC', 'Disease', (123, 127))
70403	28428711	CUL4A expression was detected to be the only independent risk factor for OS and PFS in PHCC.	('CUL4A', 'Gene', '8451', (0, 5))	('risk', 'Reg', (57, 61))	('PFS', 'Disease', (80, 83))	('CUL4A', 'Gene', (0, 5))	('expression', 'Var', (6, 16))
70412	28428711	Furthermore, CUL4A amplification and overexpression have been found in several human cancers, including primary human breast cancer, esophageal squamous cell carcinoma, adrenocortical carcinoma, childhood medulloblastoma, hepatocellular carcinoma, and primary malignant pleural mesothelioma.	('overexpression', 'PosReg', (37, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (270, 290))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (169, 193))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (222, 246))	('human', 'Species', '9606', (112, 117))	('medulloblastoma', 'Disease', 'MESH:D008527', (205, 220))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('medulloblastoma', 'Phenotype', 'HP:0002885', (205, 220))	('human', 'Species', '9606', (79, 84))	('medulloblastoma', 'Disease', (205, 220))	('amplification', 'Var', (19, 32))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (169, 193))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('hepatocellular carcinoma', 'Disease', (222, 246))	('breast cancer', 'Disease', (118, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('adrenocortical carcinoma', 'Disease', (169, 193))	('esophageal squamous cell carcinoma', 'Disease', (133, 167))	('malignant pleural mesothelioma', 'Disease', (260, 290))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancers', 'Disease', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('CUL4A', 'Gene', '8451', (13, 18))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (222, 246))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (133, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('CUL4A', 'Gene', (13, 18))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (260, 290))
70467	28428711	As a result, the cut-off score of the OS for high CUL4A expression is 3.30, and the cut-off score of the PFS for high CUL4A expression is 3.90.	('CUL4A', 'Gene', (118, 123))	('expression', 'MPA', (56, 66))	('high', 'Var', (45, 49))	('CUL4A', 'Gene', (50, 55))	('CUL4A', 'Gene', '8451', (118, 123))	('CUL4A', 'Gene', '8451', (50, 55))
70470	28428711	To evaluate the prognostic potential of CUL4A expression in PHCC, Kaplan-Meier analysis was performed, which showed that high CUL4A expression was associated with a poorer OS rate of PHCC patients (P < 0.001; Figure 2D and E).	('CUL4A', 'Gene', '8451', (40, 45))	('poorer', 'NegReg', (165, 171))	('CUL4A', 'Gene', '8451', (126, 131))	('PHCC', 'Disease', (183, 187))	('expression', 'MPA', (132, 142))	('patients', 'Species', '9606', (188, 196))	('CUL4A', 'Gene', (40, 45))	('CUL4A', 'Gene', (126, 131))	('high', 'Var', (121, 125))
70471	28428711	Moreover, high CULA4 expression was correlated with a lower PFS in PHCC patients (P < 0.001; Figure 3B).	('PFS', 'MPA', (60, 63))	('CULA4 expression', 'Protein', (15, 31))	('high', 'Var', (10, 14))	('PHCC', 'Disease', (67, 71))	('lower', 'NegReg', (54, 59))	('patients', 'Species', '9606', (72, 80))
70475	28428711	As shown in Figure 3A, CUL4A depletion dramatically suppressed the migration of QBC939 cells.	('depletion', 'Var', (29, 38))	('migration of QBC939 cells', 'CPA', (67, 92))	('QBC939', 'CellLine', 'CVCL:6942', (80, 86))	('CUL4A', 'Gene', (23, 28))	('suppressed', 'NegReg', (52, 62))	('CUL4A', 'Gene', '8451', (23, 28))
70476	28428711	Furthermore, the invasiveness of QBC939 cells with CUL4A depletion was markedly reduced in a Matrigel assay (Figure 3B, down).	('CUL4A', 'Gene', (51, 56))	('depletion', 'Var', (57, 66))	('reduced', 'NegReg', (80, 87))	('CUL4A', 'Gene', '8451', (51, 56))	('QBC939', 'CellLine', 'CVCL:6942', (33, 39))	('invasiveness', 'CPA', (17, 29))
70477	28428711	Consistently, CUL4A ectopic expression significantly increased the migration and invasion of FRH0201 cells (Figure 3C and D).	('invasion', 'CPA', (81, 89))	('CUL4A', 'Gene', '8451', (14, 19))	('migration', 'CPA', (67, 76))	('increased', 'PosReg', (53, 62))	('ectopic expression', 'Var', (20, 38))	('CUL4A', 'Gene', (14, 19))
70480	28428711	To explore whether CUL4A could promote the EMT process, we evaluated EMT markers in PHCC cells with CUL4A depletion and control cells.	('CUL4A', 'Gene', (100, 105))	('depletion', 'Var', (106, 115))	('CUL4A', 'Gene', (19, 24))	('CUL4A', 'Gene', '8451', (100, 105))	('CUL4A', 'Gene', '8451', (19, 24))
70481	28428711	CUL4A depletion in QBC939 cells and FRH0201 cells enhanced the expression of E-cadherin, a hall mark of the EMT, in Western blot assays, which is accompanied by decreased expression of vimentin (Figure 4A).	('expression', 'MPA', (171, 181))	('vimentin', 'Gene', (185, 193))	('CUL4A', 'Gene', '8451', (0, 5))	('decreased', 'NegReg', (161, 170))	('E-cadherin', 'Gene', (77, 87))	('E-cadherin', 'Gene', '999', (77, 87))	('expression', 'MPA', (63, 73))	('depletion', 'Var', (6, 15))	('CUL4A', 'Gene', (0, 5))	('enhanced', 'PosReg', (50, 58))	('vimentin', 'Gene', '7431', (185, 193))	('QBC939', 'CellLine', 'CVCL:6942', (19, 25))
70492	28428711	In in vitro assays, ZEB1 deficiency obviously reversed the decreased expression of E-cadherin and increased the expression of vimentin induced by CUL4A overexpression (Figure 5D).	('E-cadherin', 'Gene', (83, 93))	('E-cadherin', 'Gene', '999', (83, 93))	('vimentin', 'Gene', (126, 134))	('decreased', 'NegReg', (59, 68))	('CUL4A', 'Gene', (146, 151))	('deficiency', 'Var', (25, 35))	('CUL4A', 'Gene', '8451', (146, 151))	('expression', 'MPA', (69, 79))	('increased', 'PosReg', (98, 107))	('vimentin', 'Gene', '7431', (126, 134))	('ZEB1', 'Gene', (20, 24))	('ZEB1', 'Gene', '6935', (20, 24))	('expression', 'MPA', (112, 122))
70493	28428711	Furthermore, the increased migratory and invasive capacities induced by CUL4A overexpression were also inhibited by ZEB1 knockdown in the FRH0201 cell line (Figure 5E and F).	('knockdown', 'Var', (121, 130))	('increased', 'PosReg', (17, 26))	('CUL4A', 'Gene', (72, 77))	('overexpression', 'PosReg', (78, 92))	('ZEB1', 'Gene', '6935', (116, 120))	('CUL4A', 'Gene', '8451', (72, 77))	('inhibited', 'NegReg', (103, 112))	('ZEB1', 'Gene', (116, 120))
70502	28428711	In agreement with this, ectopic expression of CUL4A in FRH0201 cells promoted cell migratory and invasive abilities.	('ectopic expression', 'Var', (24, 42))	('CUL4A', 'Gene', '8451', (46, 51))	('promoted', 'PosReg', (69, 77))	('CUL4A', 'Gene', (46, 51))
70507	28428711	In the present study, CUL4A depletion caused rapid regression of EMT features, which is characterized by decreased cell motility and invasive phenotypes.	('regression', 'NegReg', (51, 61))	('invasive phenotypes', 'CPA', (133, 152))	('CUL4A', 'Gene', (22, 27))	('depletion', 'Var', (28, 37))	('cell motility', 'CPA', (115, 128))	('EMT features', 'CPA', (65, 77))	('CUL4A', 'Gene', '8451', (22, 27))	('decreased', 'NegReg', (105, 114))
70513	28428711	In the present study, Western blot assay discovered that the expression of vimentin was up-regulated in CUL4A overexpressing cells, however, the expression of vimentin was decreased in cells with CUL4A knockdown.	('CUL4A', 'Gene', (196, 201))	('vimentin', 'Gene', '7431', (159, 167))	('CUL4A', 'Gene', (104, 109))	('vimentin', 'Gene', (159, 167))	('CUL4A', 'Gene', '8451', (196, 201))	('up-regulated', 'PosReg', (88, 100))	('vimentin', 'Gene', '7431', (75, 83))	('CUL4A', 'Gene', '8451', (104, 109))	('vimentin', 'Gene', (75, 83))	('expression', 'MPA', (61, 71))	('overexpressing', 'Var', (110, 124))
70520	28428711	Considering the positive correlation between CUL4A and ZEB1 in PHCC that was demonstrated in this study, inhibition of CUL4A may be a potential therapeutic strategy for PHCC that can increase the chemotherapy sensitivity and effectiveness through downregulating the expression of ZEB1, especially for patients with CUL4A overexpression.	('expression', 'MPA', (266, 276))	('CUL4A', 'Gene', '8451', (119, 124))	('ZEB1', 'Gene', (280, 284))	('CUL4A', 'Gene', (45, 50))	('inhibition', 'Var', (105, 115))	('CUL4A', 'Gene', '8451', (315, 320))	('increase', 'PosReg', (183, 191))	('ZEB1', 'Gene', '6935', (280, 284))	('patients', 'Species', '9606', (301, 309))	('CUL4A', 'Gene', '8451', (45, 50))	('CUL4A', 'Gene', (315, 320))	('chemotherapy sensitivity', 'CPA', (196, 220))	('ZEB1', 'Gene', (55, 59))	('CUL4A', 'Gene', (119, 124))	('ZEB1', 'Gene', '6935', (55, 59))	('downregulating', 'NegReg', (247, 261))
70633	31231470	The GenBank accession numbers of HBV-host integration sequences are the following: MK905389, MK905390, MK905391, MK905392.	('HBV', 'Species', '10407', (33, 36))	('MK905392', 'Var', (113, 121))	('MK905389', 'Var', (83, 91))	('MK905390', 'Var', (93, 101))	('MK905391', 'Var', (103, 111))
70715	30425881	Radiation therapy is associated with teratogenesis, fetal growth restriction, pregnancy loss, intellectual disability, and malignancy in the offspring depending on the gestational age and dosage of exposure.	('fetal', 'Disease', (52, 57))	('intellectual disability', 'Disease', 'MESH:D008607', (94, 117))	('intellectual disability', 'Phenotype', 'HP:0001249', (94, 117))	('Radiation therapy', 'Var', (0, 17))	('associated with', 'Reg', (21, 36))	('teratogenesis', 'Disease', (37, 50))	('fetal growth restriction', 'Phenotype', 'HP:0001511', (52, 76))	('intellectual disability', 'Disease', (94, 117))	('pregnancy loss', 'CPA', (78, 92))	('malignancy', 'CPA', (123, 133))	('growth restriction', 'Phenotype', 'HP:0001510', (58, 76))
70730	24049642	Cholangiocarcinoma has been associated with mutations in several oncogenes and up to 80% of tumour cells have been shown to exhibit chromosomal aneuploidy.	('chromosomal aneuploidy', 'Disease', 'MESH:D000782', (132, 154))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (0, 18))	('tumour', 'Disease', (92, 98))	('associated', 'Reg', (28, 38))	('mutations', 'Var', (44, 53))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 18))	('oncogenes', 'Gene', (65, 74))	('chromosomal aneuploidy', 'Disease', (132, 154))	('Cholangiocarcinoma', 'Disease', (0, 18))
70731	24049642	They have been shown to improve the overall sensitivity for detecting cholangiocarcinoma and in primary sclerosing cholangitis, where confirmation of cholangiocarcinoma is particularly challenging, presence of polysomy is highly suggestive of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (243, 261))	('cholangiocarcinoma', 'Disease', (70, 88))	('cholangitis', 'Disease', 'MESH:D002761', (115, 126))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (150, 168))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (150, 168))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (243, 261))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (70, 88))	('improve', 'PosReg', (24, 31))	('cholangiocarcinoma', 'Disease', (150, 168))	('cholangiocarcinoma', 'Disease', (243, 261))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (104, 126))	('cholangitis', 'Phenotype', 'HP:0030151', (115, 126))	('cholangitis', 'Disease', (115, 126))	('polysomy', 'Var', (210, 218))
70749	24049642	A recent multicentre study of 89 patients found CLE provided significantly higher diagnostic accuracy for malignant biliary strictures than standard ERCP (90% vs. 73%).	('malignant biliary strictures', 'Disease', (106, 134))	('patients', 'Species', '9606', (33, 41))	('higher', 'PosReg', (75, 81))	('CLE', 'Var', (48, 51))
70805	19358267	Dysregulation of apoptosis can disrupt the equilibrium between cell growth and cell death and is critical in the development of cancer and tumor cell survival.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('disrupt', 'NegReg', (31, 38))	('Dysregulation', 'Var', (0, 13))	('equilibrium', 'MPA', (43, 54))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('apoptosis', 'CPA', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
70819	19358267	The antibody for NF-kappaB1 (p50) recognizes both p50 and p105.	('p50', 'Var', (50, 53))	('p105', 'Gene', '4790', (58, 62))	('p105', 'Gene', (58, 62))	('NF-kappaB1', 'Gene', '18033', (17, 27))	('NF-kappaB1', 'Gene', (17, 27))
70820	19358267	The p105 (p110) precursor contains p50 at its N-terminus and a C-terminal region that, when expressed as a separate molecule, binds to p50 and regulates its activity.	('p50', 'Gene', (135, 138))	('p110', 'Gene', (10, 14))	('p105', 'Gene', (4, 8))	('p110', 'Gene', '100616443', (10, 14))	('p105', 'Gene', '4790', (4, 8))	('regulates', 'Reg', (143, 152))	('p50', 'Var', (35, 38))	('activity', 'MPA', (157, 165))	('binds', 'Interaction', (126, 131))
70824	19358267	Immunofluorescence was performed as previously described using antibodies for NF-kappaB1 (p50) and RelA (p65) or non-immune serum for negative controls.	('p50', 'Var', (90, 93))	('NF-kappaB1', 'Gene', '18033', (78, 88))	('NF-kappaB1', 'Gene', (78, 88))
70872	19358267	Specifically, ~50% of Mz-ChA-1 cells treated with 0.1% DMSO incorporated BrdU (after 2 hours incubation) into their DNA compared to only ~10% of cells stimulated with CAPE (20 muM) (Figure 3a), thus demonstrating decreased cell cycle progression induced by CAPE.	('cell cycle progression', 'CPA', (223, 245))	('decreased', 'NegReg', (213, 222))	('muM', 'Gene', '56925', (176, 179))	('BrdU', 'MPA', (73, 77))	('DMSO', 'Chemical', 'MESH:D004121', (55, 59))	('CAPE', 'Chemical', 'MESH:C055494', (167, 171))	('0.1%', 'Var', (50, 54))	('muM', 'Gene', (176, 179))	('CAPE', 'Chemical', 'MESH:C055494', (257, 261))
70905	19358267	Further, CAPE decreased the expression of both NF-kappaB1 (p50) and RelA (p65) compared to vehicle-treated mice in tumor sections from these animals demonstrated by both immunoblotting and immunohistochemistry.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('decreased', 'NegReg', (14, 23))	('NF-kappaB1', 'Gene', '18033', (47, 57))	('expression', 'MPA', (28, 38))	('tumor', 'Disease', (115, 120))	('NF-kappaB1', 'Gene', (47, 57))	('CAPE', 'Chemical', 'MESH:C055494', (9, 13))	('mice', 'Species', '10090', (107, 111))	('p65', 'Var', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
70907	19358267	Blocking NF-kappaB has been shown to cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents.	('die', 'CPA', (81, 84))	('NF-kappaB', 'Protein', (9, 18))	('Blocking', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (136, 141))
70915	19358267	Further, a study involving hepatocellular carcinoma cells (HCC) has shown that the protein expression of both p50 and p65 was increased in HCC cells compared to normal liver cells.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (27, 51))	('protein expression', 'MPA', (83, 101))	('HCC', 'CellLine', 'CVCL:0C54', (59, 62))	('HCC', 'Disease', (139, 142))	('p65', 'Var', (118, 121))	('p50', 'Var', (110, 113))	('HCC', 'CellLine', 'CVCL:0C54', (139, 142))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (27, 51))	('increased', 'PosReg', (126, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('hepatocellular carcinoma', 'Disease', (27, 51))
70918	19358267	Our data showing the decreased DNA binding activity of NF-kappaB and decreased protein expression of p50 and p65 (both in vitro and in vivo) supports the concept that CAPE may act at both transcriptional and post-transcriptional levels to suppress cholangiocarcinoma growth.	('cholangiocarcinoma growth', 'Disease', (248, 273))	('DNA binding', 'Interaction', (31, 42))	('NF-kappaB', 'Protein', (55, 64))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (248, 273))	('protein expression', 'MPA', (79, 97))	('decreased', 'NegReg', (21, 30))	('decreased', 'NegReg', (69, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))	('suppress', 'NegReg', (239, 247))	('CAPE', 'Chemical', 'MESH:C055494', (167, 171))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (248, 266))	('p65', 'Var', (109, 112))	('p50', 'Gene', (101, 104))
70930	19358267	Deviations in gene expression of anti-apoptotic and pro-apoptotic proteins may play a part in the cause of the many forms of cancer.	('cause', 'Reg', (98, 103))	('Deviations', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('play', 'Reg', (79, 83))
70933	19358267	In agreement with our findings, studies have offered evidence of a dysregulation of the Bcl-2/Bax ratio including a study showing that leutolin increased Bax protein expression with a concurrent decrease in Bcl-2 protein expression in human hepatoma cell lines.	('hepatoma', 'Disease', (241, 249))	('increased', 'PosReg', (144, 153))	('hepatoma', 'Disease', 'MESH:D006528', (241, 249))	('Bax', 'Gene', '581', (94, 97))	('decrease', 'NegReg', (195, 203))	('Bax', 'Gene', (154, 157))	('Bcl-2', 'Gene', (207, 212))	('Bcl-2', 'Gene', (88, 93))	('Bcl-2', 'Gene', '596', (207, 212))	('Bcl-2', 'Gene', '596', (88, 93))	('human', 'Species', '9606', (235, 240))	('Bax', 'Gene', '581', (154, 157))	('expression', 'MPA', (166, 176))	('leutolin', 'Var', (135, 143))	('Bax', 'Gene', (94, 97))
70953	31805897	HER2 gene (ERBB2) amplification is a rare event in non-liver-fluke associated cholangiocarcinogenesis Cholangiocarcinoma is a rapidly fatal cancer entity with a median survival of less than one year.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cholangiocarcinogenesis', 'Disease', 'None', (78, 101))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('ERBB2', 'Gene', (11, 16))	('HER2', 'Gene', (0, 4))	('ERBB2', 'Gene', '2064', (11, 16))	('liver-fluke', 'Species', '6192', (55, 66))	('HER2', 'Gene', '2064', (0, 4))	('amplification', 'Var', (18, 31))	('cholangiocarcinogenesis', 'Disease', (78, 101))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (102, 120))	('Cholangiocarcinoma', 'Disease', (102, 120))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (102, 120))
70956	31805897	In this study, we determined the frequency of amplification of the HER2 gene in a comprehensive and well-characterized European cholangiocarcinoma cohort encompassing 436 patients including intrahepatic (n = 155), proximal (n = 155) and distal (n = 126) cholangiocarcinoma by strict application of a combined immunohistochemical and in situ hybridization algorithm following the current guidelines for HER2 assessment in gastric cancer.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (128, 146))	('HER2', 'Gene', '2064', (402, 406))	('gastric cancer', 'Disease', (421, 435))	('cholangiocarcinoma', 'Disease', (254, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('amplification', 'Var', (46, 59))	('gastric cancer', 'Disease', 'MESH:D013274', (421, 435))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (254, 272))	('HER2', 'Gene', (67, 71))	('cholangiocarcinoma', 'Disease', (128, 146))	('patients', 'Species', '9606', (171, 179))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (254, 272))	('gastric cancer', 'Phenotype', 'HP:0012126', (421, 435))	('HER2', 'Gene', '2064', (67, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (128, 146))	('HER2', 'Gene', (402, 406))	('cancer', 'Phenotype', 'HP:0002664', (429, 435))
70957	31805897	We identified a proportion of 1.4% (n = 6) patients that demonstrated HER2 gene amplification, with the highest rate among the distal cholangiocarcinoma patients (2.4%).	('amplification', 'Var', (80, 93))	('HER2', 'Gene', (70, 74))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (134, 152))	('patients', 'Species', '9606', (153, 161))	('HER2', 'Gene', '2064', (70, 74))	('patients', 'Species', '9606', (43, 51))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (134, 152))	('rat', 'Species', '10116', (64, 67))	('rat', 'Species', '10116', (112, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('cholangiocarcinoma', 'Disease', (134, 152))
70959	31805897	In four of the five patients with HER2 positivity, gene amplification was already present in concomitantly tested high-grade biliary intraepithelial neoplasia (80%).	('biliary intraepithelial neoplasia', 'Disease', (125, 158))	('neoplasia', 'Phenotype', 'HP:0002664', (149, 158))	('biliary intraepithelial neoplasia', 'Disease', 'MESH:D019048', (125, 158))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (133, 158))	('patients', 'Species', '9606', (20, 28))	('HER2', 'Gene', (34, 38))	('positivity', 'Var', (39, 49))	('HER2', 'Gene', '2064', (34, 38))
70961	31805897	This study identifies HER2 gene amplification as a rare event in cholangiocarcinoma of the Western population, occurring already in high-grade BilIN in a subset of patients.	('cholangiocarcinoma', 'Disease', (65, 83))	('HER2', 'Gene', (22, 26))	('amplification', 'Var', (32, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('HER2', 'Gene', '2064', (22, 26))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (65, 83))	('patients', 'Species', '9606', (164, 172))	('BilIN', 'Chemical', '-', (143, 148))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))
70972	31805897	demonstrated that nearly 40% of all cases harbor targetable genetic alterations and that poor prognosis is associated with elevated immune checkpoint molecules.	('rat', 'Species', '10116', (72, 75))	('elevated', 'PosReg', (123, 131))	('rat', 'Species', '10116', (7, 10))	('genetic alterations', 'Var', (60, 79))	('immune checkpoint molecules', 'MPA', (132, 159))
70976	31805897	Dimerization activates the intrinsic tyrosine kinase domain leading to the induction of different downstream signaling cascades, including the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB or Akt) pathway which are essential for cellular proliferation and differentiation.	('Akt', 'Gene', (261, 264))	('Dimerization', 'Var', (0, 12))	('phosphatidylinositol 3-kinase', 'Gene', '5293', (199, 228))	('intrinsic tyrosine kinase domain', 'MPA', (27, 59))	('PKB', 'Gene', '207', (254, 257))	('rat', 'Species', '10116', (314, 317))	('PKB', 'Gene', (254, 257))	('Akt', 'Gene', '207', (261, 264))	('activates', 'PosReg', (13, 22))	('phosphatidylinositol 3-kinase', 'Gene', (199, 228))	('induction', 'Reg', (75, 84))
70996	31805897	Detailed clinicopathological characteristics of the entire cohort stratified for amplification of ERBB2 are provided in Table 2.	('amplification', 'Var', (81, 94))	('ERBB2', 'Gene', '2064', (98, 103))	('rat', 'Species', '10116', (68, 71))	('ERBB2', 'Gene', (98, 103))
71043	31805897	HER2 gene amplification is a genomic alteration found in diverse cancer entities, most commonly known for its predictive role and therapeutic implications in breast and gastric cancer in clinical routine.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('breast and gastric cancer', 'Disease', 'MESH:D001943', (158, 183))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('amplification', 'Var', (10, 23))	('HER2', 'Gene', (0, 4))	('rat', 'Species', '10116', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('HER2', 'Gene', '2064', (0, 4))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
71046	31805897	With a frequency of approximately 1.4%, this study demonstrates that HER2 gene amplification is in fact a rare event in CCA.	('CCA', 'Phenotype', 'HP:0030153', (120, 123))	('HER2', 'Gene', (69, 73))	('rat', 'Species', '10116', (58, 61))	('CCA', 'Disease', (120, 123))	('amplification', 'Var', (79, 92))	('HER2', 'Gene', '2064', (69, 73))
71047	31805897	The reported frequencies for HER2 positivity vary strongly with most studies being conducted in Asia or Southern America.	('HER2', 'Gene', (29, 33))	('positivity', 'Var', (34, 44))	('HER2', 'Gene', '2064', (29, 33))
71053	31805897	Strict adherence to the testing algorithm resulted in a 100% agreement between protein overexpression defined by a 3+ IHC score and gene amplification by dc-ISH, whereas none of the cases with equivocal IHC result was accompanied by gene amplification.	('protein', 'MPA', (79, 86))	('gene amplification', 'Var', (132, 150))	('dc-ISH', 'Chemical', '-', (154, 160))	('overexpression', 'PosReg', (87, 101))
71055	31805897	Inconsistencies between HER2 overexpression and gene amplification may be attributed to gene dysregulation as another mechanism resulting in increased protein levels.	('gene dysregulation', 'Var', (88, 106))	('increased', 'PosReg', (141, 150))	('HER2', 'Gene', (24, 28))	('protein levels', 'MPA', (151, 165))	('HER2', 'Gene', '2064', (24, 28))
71070	31805897	showed that the HER2 inhibitor lapatinib is a potent inhibitor of C611B and HuCCT1 CCA cell growth in vitro.	('lapatinib', 'Chemical', 'MESH:D000077341', (31, 40))	('HER2', 'Gene', (16, 20))	('C611B', 'Var', (66, 71))	('HER2', 'Gene', '2064', (16, 20))	('CCA', 'Phenotype', 'HP:0030153', (83, 86))	('C611B', 'SUBSTITUTION', 'None', (66, 71))
71072	31805897	Though the low number of HER2-positive cases clearly limits generalizability, our data suggests HER2 gene amplification occurring early in cholangiocarcinogenesis, at least in a subset of patients.	('cholangiocarcinogenesis', 'Disease', (139, 162))	('patients', 'Species', '9606', (188, 196))	('amplification', 'Var', (106, 119))	('HER2', 'Gene', (25, 29))	('HER2', 'Gene', (96, 100))	('HER2', 'Gene', '2064', (25, 29))	('HER2', 'Gene', '2064', (96, 100))	('cholangiocarcinogenesis', 'Disease', 'None', (139, 162))
71093	30094069	After a median follow-up of 8.4 months, OS and PFS were worse in patients receiving PDT compared with stent alone group (OS median 6.2 vs 9.8 months (HR 1.56, 95% CI 1.00 to 2.43, p=0.048) and PFS median 3.4 vs 4.3 months (HR 1.43, 95% CI: 0.93 to 2.18, p=0.10), respectively).	('worse', 'NegReg', (56, 61))	('PDT', 'Var', (84, 87))	('patients', 'Species', '9606', (65, 73))
71114	30094069	Lastly, in a three-centre, single-arm phase II trial of 36 patients with locally advanced BTC, we showed that PDT was associated with a low toxicity profile and a median survival of 12 months.	('PDT', 'Var', (110, 113))	('patients', 'Species', '9606', (59, 67))	('toxicity', 'Disease', (140, 148))	('toxicity', 'Disease', 'MESH:D064420', (140, 148))
71177	30094069	There were 39 patients (85%) with any grade 3-4 AE in the PDT arm compared with 30 (65%) in the stenting only group (p=0.030), which was partly due to a difference in bilirubin (37% (PDT+stent) vs 20% (stent alone); p=0.06; table 3).	('PDT', 'Var', (58, 61))	('bilirubin', 'MPA', (167, 176))	('difference', 'Reg', (153, 163))	('bilirubin', 'Chemical', 'MESH:D001663', (167, 176))	('patients', 'Species', '9606', (14, 22))
71178	30094069	There were 36 patients with grade 3-4 liver function (bilirubin, alkaline phosphatase, alanine transaminase and gamma-glutamyltransferase) abnormality in the PDT arm compared with 28 in the stent only arm, the median survival of whom are 5.0 and 9.9 months, respectively (log-rank p=0.017) suggesting a detrimental effect of PDT on liver function that is associated with early death.	('alanine transaminase', 'MPA', (87, 107))	('alkaline phosphatase', 'MPA', (65, 85))	('death', 'Disease', 'MESH:D003643', (377, 382))	('death', 'Disease', (377, 382))	('bilirubin', 'Chemical', 'MESH:D001663', (54, 63))	('patients', 'Species', '9606', (14, 22))	('abnormality', 'Var', (139, 150))
71191	30094069	Several other factors may also have played a role, in that patients randomised to PDT usually underwent an additional ERCP (with a greater risk of cholangitis) compared with the stenting alone group.	('PDT', 'Var', (82, 85))	('underwent', 'Reg', (94, 103))	('cholangitis', 'Phenotype', 'HP:0030151', (147, 158))	('cholangitis', 'Disease', (147, 158))	('patients', 'Species', '9606', (59, 67))	('ERCP', 'Disease', (118, 122))	('cholangitis', 'Disease', 'MESH:D002761', (147, 158))
71192	30094069	In a randomised phase II trial of PDT+-chemotherapy in patients with unresectable hilar cholangiocarcinoma, PDT plus the oral fluoropyrimidine, S-1 was well tolerated and associated with a significant improvement in OS compared with PDT alone (17 vs 8 months, p=0.005).	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('S-1', 'Gene', '5707', (144, 147))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('improvement', 'PosReg', (201, 212))	('PDT', 'Var', (108, 111))	('patients', 'Species', '9606', (55, 63))	('cholangiocarcinoma', 'Disease', (88, 106))	('S-1', 'Gene', (144, 147))	('fluoropyrimidine', 'Chemical', '-', (126, 142))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 106))
71193	30094069	In conclusion, in this multicentre study, patients with BTC who received PDT in addition to optimal stenting had a poorer OS than those with stenting alone, which was only partly explained by fewer patients in the PDT arm receiving palliative chemotherapy.	('PDT', 'Var', (73, 76))	('patients', 'Species', '9606', (42, 50))	('poorer OS', 'MPA', (115, 124))	('patients', 'Species', '9606', (198, 206))
71206	26962281	Partial-liver drainage achieved results as good as those after complete liver drainage with significant improvements in QOL and reduction of the bilirubin level.	('improvements', 'PosReg', (104, 116))	('bilirubin level', 'MPA', (145, 160))	('Partial-liver', 'Var', (0, 13))	('reduction', 'NegReg', (128, 137))	('QOL', 'MPA', (120, 123))	('men', 'Species', '9606', (111, 114))	('bilirubin', 'Chemical', 'MESH:D001663', (145, 154))
71249	26962281	It was confirmed by one of the following: Cholangiography, USG, or CT demonstration of redilatation of bile duct Increase in total serum bilirubin concentration by 1 mg/dl from the preceding value Cholangitis.	('redilatation', 'Var', (87, 99))	('Cholangitis', 'Disease', (197, 208))	('Cholangitis', 'Disease', 'MESH:D002761', (197, 208))	('Cholangitis', 'Phenotype', 'HP:0030151', (197, 208))	('bilirubin', 'Chemical', 'MESH:D001663', (137, 146))	('serum bilirubin concentration', 'Phenotype', 'HP:0002904', (131, 160))	('Increase in total serum bilirubin', 'Phenotype', 'HP:0003573', (113, 146))	('bile duct Increase', 'Phenotype', 'HP:0006560', (103, 121))	('dilatation', 'Phenotype', 'HP:0002617', (89, 99))
71382	26962281	Also, PTBD causes a significant reduction in the bilirubin level and improvement in QOL, irrespective of the level of the block, the amount of liver drained or the type of internalization (ring biliary or stent).	('bilirubin level', 'MPA', (49, 64))	('QOL', 'MPA', (84, 87))	('improvement', 'PosReg', (69, 80))	('PTBD', 'Var', (6, 10))	('men', 'Species', '9606', (76, 79))	('bilirubin', 'Chemical', 'MESH:D001663', (49, 58))	('reduction', 'NegReg', (32, 41))
71400	30563284	On the other hand, gefitinib has been reported to be a radiosensitizer, which inhibits the radiation-induced phosphorylation of epidermal growth factor receptor (EGFR) and the downstream pathway, and therefore enhances radiosensitivity in cholangiocarcinoma cells.	('gefitinib', 'Var', (19, 28))	('radiation-induced', 'CPA', (91, 108))	('epidermal growth factor receptor', 'Gene', '1956', (128, 160))	('radiosensitivity', 'CPA', (219, 235))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (239, 257))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'Gene', (162, 166))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (239, 257))	('epidermal growth factor receptor', 'Gene', (128, 160))	('enhances', 'PosReg', (210, 218))	('gefitinib', 'Chemical', 'MESH:D000077156', (19, 28))	('downstream pathway', 'Pathway', (176, 194))	('inhibits', 'NegReg', (78, 86))	('cholangiocarcinoma', 'Disease', (239, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
71444	30563284	The results shown in Figure 6 indicate that knockdown of p53 further reduced the expression of p53, but did not affect TGF-beta expression in heteronemin-treated cholangiocarcinoma cells.	('heteronemin', 'Chemical', 'MESH:C493748', (142, 153))	('reduced', 'NegReg', (69, 76))	('cholangiocarcinoma', 'Disease', (162, 180))	('TGF-beta', 'Gene', '7040', (119, 127))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (162, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('p53', 'Gene', (57, 60))	('knockdown', 'Var', (44, 53))	('TGF-beta', 'Gene', (119, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (162, 180))	('p53', 'Gene', '7157', (57, 60))	('expression', 'MPA', (81, 91))
71455	30563284	Knockdown of TGF-beta further enhanced heteronemin-induced anti-proliferation (results not shown).	('enhanced', 'PosReg', (30, 38))	('Knockdown', 'Var', (0, 9))	('heteronemin-induced anti-proliferation', 'MPA', (39, 77))	('heteronemin', 'Chemical', 'MESH:C493748', (39, 50))	('TGF-beta', 'Gene', '7040', (13, 21))	('TGF-beta', 'Gene', (13, 21))
71460	30563284	The inactivation of p53 interrupts TGF-beta-induced cellular activities.	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('inactivation', 'Var', (4, 16))	('TGF-beta', 'Gene', (35, 43))	('interrupts', 'NegReg', (24, 34))	('TGF-beta', 'Gene', '7040', (35, 43))
71474	30563284	Cells (2 x 104 cells/well) were seeded in 96-well plates and treated with or without heteronemin (Sigma, St. Louis, MO) for 72 h. Cell proliferation was determined by incubating cells with 200 mL of fresh medium containing MTS (ab197010, Abcam, Cambridge, MA 02139, United States) for 4 h at 37  C. The plates were read using a microplate reader (VersaMax  Tunable Microplate Reader, Molecular Devices, Sunnyvale, CA) to measure the absorbance at 490 nm.	('heteronemin', 'Chemical', 'MESH:C493748', (85, 96))	('ab197010', 'Var', (228, 236))	('absorbance at 490 nm', 'MPA', (433, 453))
71483	30563284	This work was supported by a start-up grant from Taipei Medical University, Taiwan (TMU105-AE1-B41 to YC SH Yang), Ministry of Science and Technology, Taiwan (MOST106-2320-B-038-005 of YC SH Yang), the "TMU Research Center of Cancer Translational Medicine" from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan, by Chair Professor Research Fund to K. Wang and by Chair Professor Research Fund to J. Whang-Peng and by grant of Ministry of Health and Welfare (MOHW107-TDU-B-212-123006 of YC Liu) and by E-DA Hospital, Kaohsiung, Taiwan (EDAHP103036, EDAHP104024 and EDAHP105031 of SL Tey).	('EDAHP103036', 'Var', (634, 645))	('Cancer', 'Disease', (226, 232))	('E-DA', 'Gene', '1896', (600, 604))	('EDAHP104024', 'Var', (647, 658))	('Cancer', 'Disease', 'MESH:D009369', (226, 232))	('Cancer', 'Phenotype', 'HP:0002664', (226, 232))	('EDAHP105031', 'Var', (663, 674))	('E-DA', 'Gene', (600, 604))
71516	29875797	Occlusion of portal vein branches to liver that is to be resected can induce lobar hypertrophy in the future liver remnant.	('Occlusion', 'Var', (0, 9))	('hypertrophy', 'Disease', (83, 94))	('induce', 'Reg', (70, 76))	('hypertrophy', 'Disease', 'MESH:D006984', (83, 94))	('Occlusion of portal vein', 'Phenotype', 'HP:0030242', (0, 24))
71529	29875797	Obstruction of biliary flow leads to jaundice (the most common presenting symptom) with malabsorption and maldigestion through impaired lipid emulsification.	('malabsorption', 'Phenotype', 'HP:0002024', (88, 101))	('impaired lipid emulsification', 'Disease', 'MESH:D052439', (127, 156))	('leads to', 'Reg', (28, 36))	('jaundice', 'Disease', (37, 45))	('jaundice', 'Phenotype', 'HP:0000952', (37, 45))	('Obstruction', 'Var', (0, 11))	('malabsorption', 'Disease', (88, 101))	('maldigestion', 'Disease', (106, 118))	('malabsorption', 'Disease', 'MESH:D008286', (88, 101))	('impaired lipid emulsification', 'Disease', (127, 156))	('jaundice', 'Disease', 'MESH:D007565', (37, 45))
71595	27809873	Recently, promising evidence has shown that non-coding RNAs serve as ideal diagnostic biomarkers and participate in oxidative stress and disease or cancer-related inflammation.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('participate', 'Reg', (101, 112))	('inflammation', 'Disease', (163, 175))	('oxidative stress', 'Phenotype', 'HP:0025464', (116, 132))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('non-coding RNAs', 'Var', (44, 59))	('stress and disease', 'Disease', 'MESH:D004194', (126, 144))	('inflammation', 'Disease', 'MESH:D007249', (163, 175))
71601	27809873	Similarly, dysregulated lncRNAs in CCA may play an important role in CCA promotion and progression through involvement in CCA key pathways, such as inflammation or oxidative stress.	('inflammation', 'Disease', 'MESH:D007249', (148, 160))	('involvement', 'Reg', (107, 118))	('CCA', 'Phenotype', 'HP:0030153', (122, 125))	('dysregulated', 'Var', (11, 23))	('promotion', 'PosReg', (73, 82))	('inflammation', 'Disease', (148, 160))	('CCA', 'Phenotype', 'HP:0030153', (35, 38))	('CCA', 'Phenotype', 'HP:0030153', (69, 72))	('oxidative stress', 'Phenotype', 'HP:0025464', (164, 180))	('CCA', 'Disease', (69, 72))
71616	27809873	The proteins were detected with antibodies against CXCR4 (ab2074, Abcam, USA), IL-6 (SC-7920, Stantacruz, USA), GAPDH (Proteintech Technology, Manchester, UK), and beta-tubulin (32-2600, Invitrogen, USA).	('proteins', 'Protein', (4, 12))	('IL-6', 'Gene', '3569', (79, 83))	('SC-7920', 'Var', (85, 92))	('GAPDH', 'Gene', '2597', (112, 117))	('CXCR4', 'Gene', '7852', (51, 56))	('GAPDH', 'Gene', (112, 117))	('IL-6', 'Gene', (79, 83))	('beta-tubulin', 'Protein', (164, 176))	('CXCR4', 'Gene', (51, 56))
71626	27809873	To identify whether any lncRNA related with inflammation is regulated by oxidative stress, we firstly reanalyzed several GEO data, GSE76743, GSE57539, GSE67106, GSE55146, and GSE70544, and identified 40 lncRNAs responding to oxidative stress or inflammatory response (Fig.	('GSE70544', 'Var', (175, 183))	('oxidative stress', 'Phenotype', 'HP:0025464', (225, 241))	('GSE55146', 'Var', (161, 169))	('GSE67106', 'Var', (151, 159))	('inflammation', 'Disease', 'MESH:D007249', (44, 56))	('GSE57539', 'Var', (141, 149))	('oxidative stress', 'Phenotype', 'HP:0025464', (73, 89))	('inflammation', 'Disease', (44, 56))	('GSE76743', 'Var', (131, 139))
71645	27809873	Furthermore, we also investigated the migration and invasion abilities of RBE cells when knocking down H19 or HULC.	('investigated', 'Reg', (21, 33))	('H19', 'Gene', '283120', (103, 106))	('HULC', 'Gene', '728655', (110, 114))	('H19', 'Gene', (103, 106))	('HULC', 'Gene', (110, 114))	('invasion', 'CPA', (52, 60))	('knocking down', 'Var', (89, 102))
71660	27809873	The results showed that the enrichment of AGO2-immunoprecipitated H19 and HULC was decreased in the let-7a/7b or miR-372/373 inhibitors transfected into RBE cells (Fig.	('miR-372', 'Gene', (113, 120))	('H19', 'Gene', '283120', (66, 69))	('AGO2', 'Gene', '27161', (42, 46))	('H19', 'Gene', (66, 69))	('decreased', 'NegReg', (83, 92))	('enrichment', 'MPA', (28, 38))	('HULC', 'Gene', (74, 78))	('miR-372', 'Gene', '442917', (113, 120))	('AGO2', 'Gene', (42, 46))	('transfected', 'Var', (136, 147))	('let-7a/7b', 'Gene', (100, 109))	('HULC', 'Gene', '728655', (74, 78))
71663	27809873	Additionally, we further testified that both of their target genes IL-6 and CXCR4 are down-regulated when H19 and HULC are knocked down, respectively, in RBE cells under the oxidative stress condition (Fig.	('H19', 'Gene', (106, 109))	('oxidative stress', 'Phenotype', 'HP:0025464', (174, 190))	('CXCR4', 'Gene', (76, 81))	('HULC', 'Gene', (114, 118))	('IL-6', 'Gene', (67, 71))	('IL-6', 'Gene', '3569', (67, 71))	('knocked', 'Var', (123, 130))	('HULC', 'Gene', '728655', (114, 118))	('down-regulated', 'NegReg', (86, 100))	('CXCR4', 'Gene', '7852', (76, 81))	('H19', 'Gene', '283120', (106, 109))
71706	33277810	13  Proliferative heterogeneity, genetic heterogeneity, and tumour microenvironment changes promote tumour progression and potentially hinder the effectiveness of chemotherapy.	('genetic heterogeneity', 'Var', (33, 54))	('promote', 'PosReg', (92, 99))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('tumour', 'Disease', (60, 66))	('hinder', 'NegReg', (135, 141))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('tumour', 'Disease', (100, 106))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))
71714	33277810	19 ,  20 ,  21 ,  22 ,  23  First-line treatment agents such as gemcitabine and cisplatin are associated with several side effects such as nausea, vomiting and anorexia, leading to hydration drug requirement and treatment resistance development.	('leading to', 'Reg', (170, 180))	('vomiting', 'Phenotype', 'HP:0002013', (147, 155))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('anorexia', 'Disease', 'MESH:D000855', (160, 168))	('hydration drug requirement', 'MPA', (181, 207))	('nausea', 'Phenotype', 'HP:0002018', (139, 145))	('vomiting', 'Disease', (147, 155))	('anorexia', 'Disease', (160, 168))	('nausea', 'Disease', (139, 145))	('nausea', 'Disease', 'MESH:D009325', (139, 145))	('vomiting', 'Disease', 'MESH:D014839', (147, 155))	('anorexia', 'Phenotype', 'HP:0002039', (160, 168))	('treatment resistance development', 'CPA', (212, 244))	('gemcitabine', 'Chemical', 'MESH:C056507', (64, 75))	('cisplatin', 'Var', (80, 89))
71726	33277810	36 ,  37  These advances may enhance the efficacy of radiation therapy for CCA as well as improve the level of protection of non-malignant tissues, thereby enhancing the efficacy of radiation treatment in CCA patients.	('radiation therapy', 'CPA', (53, 70))	('CCA', 'Disease', (205, 208))	('advances', 'Var', (16, 24))	('CCA', 'Disease', (75, 78))	('improve', 'PosReg', (90, 97))	('patients', 'Species', '9606', (209, 217))	('CCA', 'Phenotype', 'HP:0030153', (205, 208))	('enhance', 'PosReg', (29, 36))	('CCA', 'Phenotype', 'HP:0030153', (75, 78))	('enhancing', 'PosReg', (156, 165))
71729	33277810	There are significant differences in the prevalence of oncogenic mutations between ICC and ECC, suggesting that the oncogenic processes of these tumour subtypes are different (Table 1).	('ICC', 'Disease', (83, 86))	('tumour', 'Disease', (145, 151))	('ECC', 'Disease', (91, 94))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('mutations', 'Var', (65, 74))
71732	33277810	For instance, recurrent mutations in isocitrate dehydrogenase (IDH)1/2, fibroblast growth factor receptor (FGFR)1-3 and BAP1 were primarily present in ICC, whereas mutations in ARID1B, ELF3 and PRKACB occurred predominantly in ECC; the characteristics associated with the different genetic aberrations in each disease subtype contributed to its unique biological behaviour.	('ECC', 'Disease', (227, 230))	('ELF3', 'Gene', (185, 189))	('present', 'Reg', (140, 147))	('isocitrate dehydrogenase (IDH)1/2', 'Gene', '3417;3418', (37, 70))	('FGFR)1-3', 'Gene', '2260;2263;2261', (107, 115))	('ARID1B', 'Gene', (177, 183))	('PRKACB', 'Gene', '5567', (194, 200))	('ARID1B', 'Gene', '57492', (177, 183))	('ELF3', 'Gene', '1999', (185, 189))	('BAP1', 'Gene', '8314', (120, 124))	('ICC', 'Disease', (151, 154))	('mutations', 'Var', (24, 33))	('PRKACB', 'Gene', (194, 200))	('mutations', 'Var', (164, 173))	('BAP1', 'Gene', (120, 124))
71733	33277810	The fusion of FGFR2 resulted in the ligand-independent activation of receptor tyrosine kinase, which occurs only in patients with ICC, 38  consistent with previous findings.	('FGFR2', 'Gene', (14, 19))	('patients', 'Species', '9606', (116, 124))	('receptor tyrosine kinase', 'Gene', (69, 93))	('fusion', 'Var', (4, 10))	('receptor tyrosine kinase', 'Gene', '5979', (69, 93))	('ligand-independent', 'MPA', (36, 54))	('activation', 'PosReg', (55, 65))
71738	33277810	The total exome sequencing of 108 liver fluke-associated tumours and 101 non-liver fluke-associated tumours revealed 44  that the incidence of IDH1 or IDH2 mutations was higher in cases of ICC unrelated to hepatic fluke, which also led to the deletion of the tumour suppressor gene BAP1.	('tumour', 'Disease', (259, 265))	('hepatic fluke', 'Disease', (206, 219))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('IDH1', 'Gene', (143, 147))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('hepatic fluke', 'Disease', 'MESH:D056486', (206, 219))	('tumour', 'Disease', (100, 106))	('liver fluke-associated tumours', 'Disease', 'MESH:D008113', (77, 107))	('IDH1', 'Gene', '3417', (143, 147))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (57, 63))	('BAP1', 'Gene', '8314', (282, 286))	('tumour', 'Disease', (57, 63))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('mutations', 'Var', (156, 165))	('deletion', 'Var', (243, 251))	('liver fluke-associated tumours', 'Disease', 'MESH:D008113', (34, 64))	('liver fluke-associated tumours', 'Disease', (77, 107))	('ICC', 'Disease', (189, 192))	('higher', 'PosReg', (170, 176))	('BAP1', 'Gene', (282, 286))	('IDH2', 'Gene', (151, 155))	('tumour', 'Phenotype', 'HP:0002664', (259, 265))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('IDH2', 'Gene', '3418', (151, 155))	('tumour', 'Disease', 'MESH:D009369', (259, 265))	('liver fluke-associated tumours', 'Disease', (34, 64))
71739	33277810	However, mutations in the tumour suppressor gene TP53 were associated with a higher incidence of hepatic trematode CCA.	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('TP53', 'Gene', (49, 53))	('tumour', 'Disease', (26, 32))	('mutations', 'Var', (9, 18))	('hepatic trematode CCA', 'Disease', 'MESH:C536211', (97, 118))	('associated', 'Reg', (59, 69))	('CCA', 'Phenotype', 'HP:0030153', (115, 118))	('hepatic trematode CCA', 'Disease', (97, 118))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))
71740	33277810	The Cancer Genome Atlas performed a comprehensive genomic analysis of liver fluke-negative and hepatitis-negative ICC, and reported the presence of inactivating mutations in tumour suppressor genes ARID1A, ARID1B, TP53 and PTEN, and functional mutations in oncogenes IDH1/2, BRAF and KRAS.	('PTEN', 'Gene', (223, 227))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('ARID1B', 'Gene', (206, 212))	('IDH1/2', 'Gene', (267, 273))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('liver fluke-negative and hepatitis-negative ICC', 'Disease', 'MESH:D017093', (70, 117))	('BRAF', 'Gene', '673', (275, 279))	('ARID1B', 'Gene', '57492', (206, 212))	('tumour', 'Disease', (174, 180))	('inactivating mutations', 'Var', (148, 170))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('BRAF', 'Gene', (275, 279))	('TP53', 'Gene', (214, 218))	('ARID1A', 'Gene', '8289', (198, 204))	('ARID1A', 'Gene', (198, 204))	('hepatitis', 'Phenotype', 'HP:0012115', (95, 104))
71741	33277810	45  Consistent with previous studies, IDH1 or IDH2 mutations were detected and expressed only in the ICC subtypes.	('IDH1', 'Gene', '3417', (38, 42))	('ICC', 'Disease', (101, 104))	('mutations', 'Var', (51, 60))	('IDH2', 'Gene', (46, 50))	('IDH2', 'Gene', '3418', (46, 50))	('IDH1', 'Gene', (38, 42))
71748	33277810	52 ,  53 ,  54  When IDH undergoes mutation, the rate of metabolites that produce 2-hydroxyglutaric acid (2-HG) increases, causing extensive epigenetic changes that affect the rates of cell differentiation, growth and hypoxia signalling.	('IDH', 'Gene', (21, 24))	('affect', 'Reg', (165, 171))	('2-HG', 'Chemical', 'MESH:C019417', (106, 110))	('cell differentiation', 'CPA', (185, 205))	('IDH', 'Gene', '3417', (21, 24))	('hypoxia', 'Disease', (218, 225))	('hypoxia', 'Disease', 'MESH:D000860', (218, 225))	('rate', 'MPA', (49, 53))	('growth', 'CPA', (207, 213))	('mutation', 'Var', (35, 43))	('epigenetic changes', 'MPA', (141, 159))	('increases', 'PosReg', (112, 121))	('2-hydroxyglutaric acid', 'Chemical', 'MESH:C019417', (82, 104))
71749	33277810	55  IDH1 mutations have been observed in 7%-36% of ICC cases.	('IDH1', 'Gene', '3417', (4, 8))	('observed', 'Reg', (29, 37))	('mutations', 'Var', (9, 18))	('IDH1', 'Gene', (4, 8))	('ICC', 'Disease', (51, 54))
71753	33277810	61   Although IDH1/2 mutations are relatively commonly reported in gliomas, they were previously thought to have a low incidence in other malignancies.	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('reported', 'Reg', (55, 63))	('malignancies', 'Disease', 'MESH:D009369', (138, 150))	('gliomas', 'Disease', (67, 74))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('malignancies', 'Disease', (138, 150))	('IDH1/2', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
71755	33277810	56 ,  60  Furthermore, IDH mutations are more commonly reported in ICC than in PCC and DCC (23%-28% vs 0%-7%).	('mutations', 'Var', (27, 36))	('ICC', 'Disease', (67, 70))	('reported', 'Reg', (55, 63))	('IDH', 'Gene', (23, 26))	('DCC', 'Chemical', '-', (87, 90))	('IDH', 'Gene', '3417', (23, 26))
71756	33277810	62  Additionally, patients with IDH1/2 mutations who underwent surgery also showed better 1-year overall survival rates than patients without IDH mutations.	('IDH', 'Gene', (142, 145))	('mutations', 'Var', (39, 48))	('overall survival rates', 'CPA', (97, 119))	('IDH', 'Gene', '3417', (142, 145))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('better', 'PosReg', (83, 89))	('patients', 'Species', '9606', (18, 26))	('patients', 'Species', '9606', (125, 133))
71757	33277810	62  The presence of a positive correlation between IDH mutations and prognoses was also observed in a study of 326 ICC cases.	('IDH', 'Gene', '3417', (51, 54))	('ICC', 'Disease', (115, 118))	('IDH', 'Gene', (51, 54))	('mutations', 'Var', (55, 64))
71758	33277810	In that study, IDH mutations were shown to profoundly affect the ICC patients' OS and tumour recurrence rates after surgical resection.	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (19, 28))	('IDH', 'Gene', (15, 18))	('affect', 'Reg', (54, 60))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('patients', 'Species', '9606', (69, 77))	('IDH', 'Gene', '3417', (15, 18))	('tumour', 'Disease', (86, 92))	('ICC', 'Disease', (65, 68))
71760	33277810	Jiao et al evaluated 34 ICC registration groups and showed that the 3-year survival rate in patients with IDH gene mutations was 33%, whereas the corresponding value in those with wild-type IDH gene mutations was 81%.	('mutations', 'Var', (115, 124))	('IDH', 'Gene', '3417', (106, 109))	('patients', 'Species', '9606', (92, 100))	('IDH', 'Gene', (190, 193))	('IDH', 'Gene', '3417', (190, 193))	('IDH', 'Gene', (106, 109))
71761	33277810	However, patients with IDH gene mutations are characterized by older age and a higher tumour grade.	('patients', 'Species', '9606', (9, 17))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (32, 41))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('IDH', 'Gene', (23, 26))	('tumour', 'Disease', (86, 92))	('IDH', 'Gene', '3417', (23, 26))
71762	33277810	57  An analysis of somatic mutations in 200 resected ICC tissues found that IDH1 mutations were the most commonly occurring type.	('IDH1', 'Gene', (76, 80))	('occurring', 'Reg', (114, 123))	('mutations', 'Var', (81, 90))	('IDH1', 'Gene', '3417', (76, 80))
71763	33277810	However, IDH1 mutational status does not seem to affect patients' long-term prognoses.	('patients', 'Species', '9606', (56, 64))	('IDH1', 'Gene', '3417', (9, 13))	('IDH1', 'Gene', (9, 13))	('mutational', 'Var', (14, 24))
71770	33277810	The incidence of FGFR2 fusion is low in mixed hepatocellular carcinoma (HCC)-ICC and is largely absent in HCC and ECC.	('FGFR2', 'Gene', (17, 22))	('low', 'NegReg', (33, 36))	('HCC', 'Phenotype', 'HP:0001402', (72, 75))	('fusion', 'Var', (23, 29))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (46, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('hepatocellular carcinoma', 'Disease', (46, 70))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (46, 70))	('HCC', 'Phenotype', 'HP:0001402', (106, 109))
71775	33277810	71  The carcinogenicity of FIG-ROS has recently been demonstrated in KRAS and TP53 mutations in orthotopic allograft mouse models of ICC.	('KRAS', 'Gene', (69, 73))	('mutations', 'Var', (83, 92))	('ROS', 'Chemical', '-', (31, 34))	('mouse', 'Species', '10090', (117, 122))	('demonstrated', 'Reg', (53, 65))	('ICC', 'Disease', (133, 136))	('TP53', 'Gene', (78, 82))	('carcinogenic', 'Disease', 'MESH:D063646', (8, 20))	('carcinogenic', 'Disease', (8, 20))
71787	33277810	80  In a study in which patients were stratified according to their KRAS status and received GEMOX with or without cetuximab, 47  the combination regimen of cetuximab, gemcitabine and oxaliplatin yielded improved median PFS values (6.7 months vs. 4.1 months; P = .05); the effect did not extend to the median OS value (10.6 months vs. 9.8 months; P = .91).	('gemcitabine', 'Chemical', 'MESH:C056507', (168, 179))	('cetuximab', 'Chemical', 'MESH:D000068818', (115, 124))	('cetuximab', 'Var', (157, 166))	('PFS values', 'MPA', (220, 230))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (184, 195))	('improved', 'PosReg', (204, 212))	('patients', 'Species', '9606', (24, 32))	('cetuximab', 'Chemical', 'MESH:D000068818', (157, 166))	('GEMOX', 'Chemical', '-', (93, 98))
71790	33277810	76 ,  81  VEGF expression is associated with several poor prognostic characteristics, distant ICC metastasis and increased microvascular density in CCA.	('expression', 'Var', (15, 25))	('CCA', 'Disease', (148, 151))	('VEGF', 'Gene', '7422', (10, 14))	('microvascular density', 'CPA', (123, 144))	('CCA', 'Phenotype', 'HP:0030153', (148, 151))	('increased', 'PosReg', (113, 122))	('VEGF', 'Gene', (10, 14))	('distant ICC metastasis', 'CPA', (86, 108))
71797	33277810	Phase I studies focusing on the WT-1 vaccine in combination with gemcitabine showed that patients with T cell response to the WT-1 vaccine had longer OS durations than those treated with gemcitabine alone.	('WT-1', 'Gene', '7490', (32, 36))	('WT-1', 'Gene', (126, 130))	('OS durations', 'MPA', (150, 162))	('gemcitabine', 'Chemical', 'MESH:C056507', (65, 76))	('longer', 'PosReg', (143, 149))	('WT-1', 'Gene', '7490', (126, 130))	('patients', 'Species', '9606', (89, 97))	('gemcitabine', 'Chemical', 'MESH:C056507', (187, 198))	('T cell response', 'Var', (103, 118))	('WT-1', 'Gene', (32, 36))
71809	33277810	The United States Food and Drug Administration has approved the use of anti-PD-1 antibodies (pembrolizumab) for previously treated patients with DNA mismatch repair (MMR) defects and/or microsatellite instability.	('patients', 'Species', '9606', (131, 139))	('pembrolizumab', 'Chemical', 'MESH:C582435', (93, 106))	('microsatellite instability', 'Var', (186, 212))	('defects', 'Var', (171, 178))	('anti-PD-1', 'Gene', (71, 80))
71814	33277810	100  Although the dysregulation of immune checkpoint molecules is associated with a lower degree of histologic differentiation, a more advanced tumour stage and poor prognoses, human leucocyte antigen 1 overexpression seems to have an inverse effect.	('dysregulation of immune checkpoint', 'Phenotype', 'HP:0002958', (18, 52))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('dysregulation', 'Var', (18, 31))	('tumour', 'Disease', (144, 150))	('lower', 'NegReg', (84, 89))	('human', 'Species', '9606', (177, 182))
71900	31382694	Families with BAP1-Tumor Predisposition Syndrome in The Netherlands: Path to Identification and a Proposal for Genetic Screening Guidelines Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1-tumor predisposition syndrome (BAP1-TPDS, OMIM 614327).	('BAP1', 'Gene', '8314', (14, 18))	('cause', 'Reg', (215, 220))	('variants', 'Var', (160, 168))	('BAP1', 'Gene', '8314', (261, 265))	('BAP1-tumor', 'Disease', (225, 235))	('BRCA1-associated protein-1', 'Gene', '8314', (176, 202))	('BAP1', 'Gene', (14, 18))	('BAP1', 'Gene', '8314', (225, 229))	('BAP1-tumor', 'Disease', 'MESH:D009369', (225, 235))	('BAP1', 'Gene', '8314', (204, 208))	('BAP1', 'Gene', (261, 265))	('Tumor', 'Phenotype', 'HP:0002664', (19, 24))	('BAP1', 'Gene', (225, 229))	('BRCA1-associated protein-1', 'Gene', (176, 202))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('BAP1', 'Gene', (204, 208))
71901	31382694	BAP1-TPDS is associated with an increased risk of developing uveal melanoma (UM), cutaneous melanoma (CM), malignant mesothelioma (MMe), renal cell carcinoma (RCC), meningioma, cholangiocarcinoma, multiple non-melanoma skin cancers, and BAP1-inactivated nevi.	('nevi', 'Phenotype', 'HP:0003764', (254, 258))	('skin cancer', 'Phenotype', 'HP:0008069', (219, 230))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 100))	('uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('BAP1-TPDS', 'Var', (0, 9))	('non-melanoma skin cancers', 'Disease', (206, 231))	('meningioma', 'Disease', 'MESH:D008577', (165, 175))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (177, 195))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('renal cell carcinoma', 'Disease', (137, 157))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (137, 157))	('cholangiocarcinoma', 'Disease', (177, 195))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (107, 129))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (177, 195))	('CM', 'Phenotype', 'HP:0012056', (102, 104))	('skin cancers', 'Phenotype', 'HP:0008069', (219, 231))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('malignant mesothelioma', 'Disease', (107, 129))	('MMe', 'Phenotype', 'HP:0100001', (131, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('uveal melanoma', 'Disease', 'MESH:C536494', (61, 75))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (107, 129))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('meningioma', 'Disease', (165, 175))	('uveal melanoma', 'Disease', (61, 75))	('non-melanoma skin cancers', 'Disease', 'MESH:D012878', (206, 231))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (137, 157))	('meningioma', 'Phenotype', 'HP:0002858', (165, 175))	('cutaneous melanoma', 'Disease', (82, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (82, 100))
71905	31382694	We also propose to test germline BAP1 in patients diagnosed with UM <40 years, CM <18 years, MMe <50 years, or RCC <46 years.	('UM', 'Phenotype', 'HP:0007716', (65, 67))	('MMe', 'Phenotype', 'HP:0100001', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('MMe <50 years', 'Var', (93, 106))	('patients', 'Species', '9606', (41, 49))	('CM', 'Phenotype', 'HP:0012056', (79, 81))	('test', 'Reg', (19, 23))	('BAP1', 'Gene', (33, 37))
71907	31382694	Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene underlie the BAP1-tumor predisposition syndrome (BAP1-TPDS, OMIM 614327).	('variants', 'Var', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('BAP1-tumor', 'Disease', (88, 98))	('BRCA1-associated protein-1', 'Gene', (36, 62))	('BAP1-tumor', 'Disease', 'MESH:D009369', (88, 98))	('BRCA1-associated protein-1', 'Gene', '8314', (36, 62))	('BAP1', 'Gene', (64, 68))
71908	31382694	At first, somatic BAP1 mutations were identified in 84% of 31 analyzed metastasized uveal melanoma (UM) and these mutations were found to be associated with metastatic progression of UM.	('UM', 'Phenotype', 'HP:0007716', (100, 102))	('mutations', 'Var', (114, 123))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma', 'Disease', (84, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('UM', 'Phenotype', 'HP:0007716', (183, 185))	('BAP1', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('associated with', 'Reg', (141, 156))	('metastatic progression', 'CPA', (157, 179))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
71910	31382694	Between 2011 and 2013, germline BAP1 variants were also reported in association with cutaneous melanoma (CM), malignant mesothelioma (MMe), and renal cell carcinoma (RCC).	('CM', 'Phenotype', 'HP:0012056', (105, 107))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('BAP1', 'Gene', (32, 36))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (110, 132))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (144, 164))	('MMe', 'Phenotype', 'HP:0100001', (134, 137))	('cutaneous melanoma', 'Disease', (85, 103))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (85, 103))	('malignant mesothelioma', 'Disease', (110, 132))	('association', 'Reg', (68, 79))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (110, 132))	('renal cell carcinoma', 'Disease', (144, 164))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (144, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('RCC', 'Disease', (166, 169))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('variants', 'Var', (37, 45))
71911	31382694	Since then, several malignancies were found to be associated with BAP1 germline pathogenic variants, the syndrome has been termed BAP1-TPDS.	('malignancies', 'Disease', 'MESH:D009369', (20, 32))	('malignancies', 'Disease', (20, 32))	('BAP1', 'Gene', (66, 70))	('variants', 'Var', (91, 99))	('associated', 'Reg', (50, 60))
71917	31382694	The penetrance of pathogenic germline BAP1 variants is high, with 85% of BAP1-TPDS individuals being diagnosed with >=1 tumors.	('pathogenic', 'Reg', (18, 28))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('BAP1', 'Gene', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('variants', 'Var', (43, 51))
71918	31382694	Diagnostic testing of BAP1 is needed to notify individuals carrying a pathogenic variant of BAP1 and their families of their increased cancer risk.	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('variant', 'Var', (81, 88))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('BAP1', 'Gene', (92, 96))
71920	31382694	The low frequency of pathogenic BAP1 variants in unselected patients with BAP1-TPDS-associated malignancies implies that guidelines for the selection of patients with an increased risk of BAP1-TPDS are needed.	('patients', 'Species', '9606', (153, 161))	('malignancies', 'Disease', (95, 107))	('patients', 'Species', '9606', (60, 68))	('BAP1', 'Gene', (32, 36))	('variants', 'Var', (37, 45))	('malignancies', 'Disease', 'MESH:D009369', (95, 107))
71921	31382694	In this cohort study of BAP1-TPDS families in the Netherlands, we describe the various routes to identification of patients with germline BAP1 pathogenic variants, their clinical phenotype, and genotype.	('patients', 'Species', '9606', (115, 123))	('variants', 'Var', (154, 162))	('BAP1', 'Gene', (138, 142))
71931	31382694	The family with variant c.437+1G>T (NL-18) was initially referred by a surgeon based on familial hepatocellular carcinoma, and the occurrence of UM and MMe in this family led to genetic analysis of BAP1.	('MMe', 'Phenotype', 'HP:0100001', (152, 155))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (97, 121))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('variant c.437+1G>T', 'Var', (16, 34))	('c.437+1G>T', 'Mutation', 'c.437+1G>T', (24, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('NL-1', 'Gene', '22871', (36, 40))	('familial hepatocellular carcinoma', 'Disease', (88, 121))	('BAP1', 'Gene', (198, 202))	('NL-1', 'Gene', (36, 40))	('familial hepatocellular carcinoma', 'Disease', 'MESH:D006528', (88, 121))	('c.437+1G>T', 'Var', (24, 34))
71932	31382694	It is likely that the Dutch families, NL-10 and NL-11, with the identical BAP1 germline variant have a common ancestor, however, no overlap in the family trees has been found.	('NL-1', 'Gene', '22871', (38, 42))	('NL-1', 'Gene', '22871', (48, 52))	('variant', 'Var', (88, 95))	('NL-1', 'Gene', (38, 42))	('NL-1', 'Gene', (48, 52))	('BAP1', 'Gene', (74, 78))
71936	31382694	Variant c.200A>G, p.Asp67Gly (NL-21) is located in the protein domain Peptidase C12, ubiquitin carboxyl-terminal hydrolase 1.	('ubiquitin carboxyl-terminal hydrolase 1', 'Gene', '7398', (85, 124))	('NL-2', 'Gene', (30, 34))	('c.200A>G', 'Var', (8, 16))	('p.Asp67Gly', 'Mutation', 'rs863224605', (18, 28))	('NL-2', 'Gene', '51129', (30, 34))	('ubiquitin carboxyl-terminal hydrolase 1', 'Gene', (85, 124))	('c.200A>G', 'Mutation', 'rs780803896', (8, 16))
71940	31382694	A novel missense variant c.1387C>G, p.(Leu463Val) was found in family NL-22, that was affected by multiple cases of CM.	('CM', 'Phenotype', 'HP:0012056', (116, 118))	('affected by', 'Reg', (86, 97))	('NL-2', 'Gene', '51129', (70, 74))	('p.(Leu463Val)', 'Mutation', 'rs35600253', (36, 49))	('c.1387C>G', 'Mutation', 'rs35600253', (25, 34))	('NL-2', 'Gene', (70, 74))	('c.1387C>G', 'Var', (25, 34))
71941	31382694	The mutational changes c.1017_1048del (NL-7) and c.1819delA (NL-13) in the germline BAP1 were not found in parents and a sibling of both probands.	('c.1017_1048del', 'Var', (23, 37))	('NL-1', 'Gene', (61, 65))	('c.1819delA', 'Var', (49, 59))	('c.1017_1048del', 'Mutation', 'c.1017_1048del', (23, 37))	('BAP1', 'Gene', (84, 88))	('c.1819delA', 'Mutation', 'c.1819delA', (49, 59))	('NL-1', 'Gene', '22871', (61, 65))
71942	31382694	The pathogenic variant in ENG (c.1116-1117insT, p.(Lys373*)) was inherited through the paternal lineage.	('p.(Lys373*)', 'SUBSTITUTION', 'None', (48, 59))	('c.1116-1117insT', 'Mutation', 'c.1116_1117insT', (31, 46))	('ENG', 'Gene', (26, 29))	('pathogenic', 'Reg', (4, 14))	('p.(Lys373*', 'Var', (48, 58))	('c.1116-1117insT', 'Var', (31, 46))
71944	31382694	In the remaining three index patients, the germline BAP1 variant was found after they passed away.	('BAP1', 'Gene', (52, 56))	('variant', 'Var', (57, 64))	('patients', 'Species', '9606', (29, 37))	('passed away', 'Phenotype', 'HP:0007185', (86, 97))
71970	31382694	No case of cholangiocarcinoma was reported in our patient population and meningioma was present in one proven carrier of a pathogenic BAP1 gene (1/72, 1.4%), who developed a vestibular schwannoma as well as an UM later in life.	('UM', 'Phenotype', 'HP:0007716', (210, 212))	('meningioma', 'Phenotype', 'HP:0002858', (73, 83))	('BAP1', 'Gene', (134, 138))	('meningioma', 'Disease', 'MESH:D008577', (73, 83))	('cholangiocarcinoma', 'Disease', (11, 29))	('vestibular schwannoma', 'Disease', (174, 195))	('vestibular schwannoma', 'Disease', 'MESH:D009464', (174, 195))	('developed', 'Reg', (162, 171))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (11, 29))	('schwannoma', 'Phenotype', 'HP:0100008', (185, 195))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (11, 29))	('vestibular schwannoma', 'Phenotype', 'HP:0009588', (174, 195))	('gene', 'Var', (139, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('patient', 'Species', '9606', (50, 57))	('meningioma', 'Disease', (73, 83))
71975	31382694	The described cohort in this study is too small to draw conclusions about possible associations of other tumors types to pathogenic BAP1 variants.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('associations', 'Interaction', (83, 95))	('BAP1', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('variants', 'Var', (137, 145))
71982	31382694	De novo germline BAP1 variants were found in families NL-7 and NL-13 (2/21, 9.5%), in both cases, paternity was confirmed.	('NL-1', 'Gene', '22871', (63, 67))	('variants', 'Var', (22, 30))	('NL-1', 'Gene', (63, 67))	('BAP1', 'Gene', (17, 21))
71983	31382694	No additional immunohistochemistry or genetic analysis of tumors in the carriers of germline BAP1 variants has been performed.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('carriers', 'Reg', (72, 80))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('BAP1', 'Gene', (93, 97))	('variants', 'Var', (98, 106))
71984	31382694	Consequently, it is uncertain if the development of the found malignancies are correlated to the aberrant BAP1 allele.	('malignancies', 'Disease', (62, 74))	('aberrant', 'Var', (97, 105))	('BAP1', 'Gene', (106, 110))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))
71988	31382694	When a larger cohort of 30 iris melanomas was analyzed by Van Poppelen et al., these findings were confirmed, with additional mutations observed in SF3B1, but also in the CM-associated genes NRAS, BRAF, PTEN, c-KIT, and TP53.	('TP53', 'Gene', (220, 224))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanomas', 'Phenotype', 'HP:0002861', (32, 41))	('PTEN', 'Gene', (203, 207))	('NRAS', 'Gene', (191, 195))	('iris melanomas', 'Disease', (27, 41))	('mutations', 'Var', (126, 135))	('c-KIT', 'Gene', (209, 214))	('TP53', 'Gene', '7157', (220, 224))	('PTEN', 'Gene', '5728', (203, 207))	('BRAF', 'Gene', (197, 201))	('iris melanomas', 'Disease', 'MESH:D007499', (27, 41))	('BRAF', 'Gene', '673', (197, 201))	('c-KIT', 'Gene', '3815', (209, 214))	('SF3B1', 'Gene', (148, 153))	('iris melanoma', 'Phenotype', 'HP:0011524', (27, 40))	('iris melanomas', 'Phenotype', 'HP:0011524', (27, 41))	('CM', 'Phenotype', 'HP:0012056', (171, 173))	('NRAS', 'Gene', '4893', (191, 195))	('SF3B1', 'Gene', '23451', (148, 153))
71992	31382694	Mutations in the CM driver genes BRAF and NRAS have been found in conjunctival melanoma.	('NRAS', 'Gene', '4893', (42, 46))	('BRAF', 'Gene', '673', (33, 37))	('CM', 'Phenotype', 'HP:0012056', (17, 19))	('BRAF', 'Gene', (33, 37))	('found', 'Reg', (57, 62))	('Mutations', 'Var', (0, 9))	('conjunctival melanoma', 'Disease', (66, 87))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (66, 87))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (66, 87))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('NRAS', 'Gene', (42, 46))
72002	31382694	This could imply that there is a genotype-phenotype relation between the specific BAP1 aberration and the type of malignancy.	('malignancy', 'Disease', 'MESH:D009369', (114, 124))	('BAP1', 'Gene', (82, 86))	('malignancy', 'Disease', (114, 124))	('aberration', 'Var', (87, 97))
72005	31382694	However, mouse models have been established where mice harbor a heterozygous pathogenic variant in BAP1.	('BAP1', 'Gene', (99, 103))	('variant', 'Var', (88, 95))	('mouse', 'Species', '10090', (9, 14))	('pathogenic', 'Reg', (77, 87))	('mice', 'Species', '10090', (50, 54))
72008	31382694	Moreover, MMe arose in a shorter period of time in the BAP1+/- mice after initial exposure (43 weeks vs. 55 weeks, respectively).	('MMe', 'Disease', (10, 13))	('MMe', 'Phenotype', 'HP:0100001', (10, 13))	('mice', 'Species', '10090', (63, 67))	('BAP1+/-', 'Var', (55, 62))
72017	31382694	The mean age at BAP1 germline analysis of the proband (or age at last follow-up in obligate carriers) was 44 years in the 42 carriers of a BAP1 pathogenic variant without BAP1-TPDS core malignancies and 59 years in the remaining 27 BAP1-TPDS patients (age at BAP1 analysis is missing for three patients) that have been diagnosed with UM, CM, MMe and/or RCC (p < 0.001).	('UM', 'Phenotype', 'HP:0007716', (334, 336))	('malignancies', 'Disease', 'MESH:D009369', (186, 198))	('patients', 'Species', '9606', (294, 302))	('MMe', 'Phenotype', 'HP:0100001', (342, 345))	('RCC', 'Disease', (353, 356))	('RCC', 'Phenotype', 'HP:0005584', (353, 356))	('CM', 'Phenotype', 'HP:0012056', (338, 340))	('BAP1', 'Gene', (139, 143))	('variant', 'Var', (155, 162))	('RCC', 'Disease', 'MESH:C538614', (353, 356))	('MMe', 'Disease', (342, 345))	('malignancies', 'Disease', (186, 198))	('patients', 'Species', '9606', (242, 250))
72021	31382694	Testing bias plays a role as well, as patients with a previous medical history of BAP1-TPDS-associated malignancies are more likely to undergo genetic testing.	('undergo', 'Reg', (135, 142))	('genetic testing', 'Var', (143, 158))	('malignancies', 'Disease', 'MESH:D009369', (103, 115))	('patients', 'Species', '9606', (38, 46))	('malignancies', 'Disease', (103, 115))	('BAP1-TPDS-associated', 'Gene', (82, 102))
72026	31382694	However, carriers of a germline BAP1 pathogenic variant tend to develop BAP1-TPDS-associated malignancies at a younger age.	('malignancies', 'Disease', (93, 105))	('malignancies', 'Disease', 'MESH:D009369', (93, 105))	('BAP1', 'Gene', (32, 36))	('develop', 'PosReg', (64, 71))	('variant', 'Var', (48, 55))
72033	31382694	found 12 probands harboring pathogenic germline variants in BAP1 in a group of 17 (71%) patients with >=1 BINs and a suspicious medical or family history.	('patients', 'Species', '9606', (88, 96))	('pathogenic', 'Reg', (28, 38))	('BAP1', 'Gene', (60, 64))	('germline variants', 'Var', (39, 56))
72035	31382694	showed a median age at diagnosis for UM in patients with germline null variants of 53 years (interquartile range: 44-60 years) and a median age of 58 years for missense variants, (interquartile range: 45-69 years), which are both under the reported median age of incidental UM of 66 years in the Netherlands.	('missense variants', 'Var', (160, 177))	('variants', 'Var', (71, 79))	('patients', 'Species', '9606', (43, 51))	('UM', 'Phenotype', 'HP:0007716', (37, 39))	('UM', 'Phenotype', 'HP:0007716', (274, 276))
72040	31382694	The family harboring VUS c.1387C>G, p.Leu463Val (NL-22) would not have been genetically analyzed based on the proposed guidelines.	('p.Leu463Val', 'Mutation', 'rs35600253', (36, 47))	('NL-2', 'Gene', (49, 53))	('c.1387C>G', 'Mutation', 'rs35600253', (25, 34))	('p.Leu463Val', 'Var', (36, 47))	('NL-2', 'Gene', '51129', (49, 53))	('c.1387C>G', 'Var', (25, 34))
72042	31382694	If we apply the proposed guidelines based on BAP1-TPDS-associated malignancies to these families, assuming reported family members are first- or second-degree relatives, 120/141 (85%) families carrying null variants and 18/40 (45%) families carrying missense variants would have been offered genetic analysis.	('missense variants', 'Var', (250, 267))	('BAP1-TPDS-associated', 'Gene', (45, 65))	('null variants', 'Var', (202, 215))	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('malignancies', 'Disease', (66, 78))
72066	31382694	The following table is available online at , Table S1: Malignancies found in proband, tested non-proband carriers and untested members from families with germline variants in BAP1.	('Malignancies', 'Disease', 'MESH:D009369', (55, 67))	('BAP1', 'Gene', (175, 179))	('variants', 'Var', (163, 171))	('Malignancies', 'Disease', (55, 67))
72067	31382694	Data S1: RNA analysis of BAP1 variant c.122+5G>C (NL-17).	('c.122+5G>C', 'Var', (38, 48))	('BAP1', 'Gene', (25, 29))	('c.122+5G>C', 'Mutation', 'c.122+5G>C', (38, 48))	('NL-1', 'Gene', '22871', (50, 54))	('variant c.122+5G>C', 'Var', (30, 48))	('NL-1', 'Gene', (50, 54))
72079	29348486	Mutations were detected in PIK3CA (1 out of 43), KRAS (10 out of 43) and BRAF (2 out of 22), with phosphate and tensin homologue protein loss in 41% (12 out of 29).	('BRAF', 'Gene', '673', (73, 77))	('KRAS', 'Gene', '3845', (49, 53))	('PIK3CA', 'Gene', (27, 33))	('phosphate', 'Chemical', 'MESH:D010710', (98, 107))	('Mutations', 'Var', (0, 9))	('loss', 'NegReg', (137, 141))	('PIK3CA', 'Gene', '5290', (27, 33))	('BRAF', 'Gene', (73, 77))	('KRAS', 'Gene', (49, 53))
72081	29348486	Cellular metabolism, growth and differentiation are dependent on signalling through the phosphatidylinositol 3-kinase (PI3K)/alpha-serine/threonine-protein kinase (AKT)/mammalian target of rapamycin (mTOR) pathway, and dysregulation of this pathway has been shown to drive tumourigenesis.	('AKT', 'Gene', (164, 167))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (88, 117))	('tumour', 'Disease', 'MESH:D009369', (273, 279))	('tumour', 'Disease', (273, 279))	('mTOR', 'Gene', (200, 204))	('dysregulation', 'Var', (219, 232))	('mTOR', 'Gene', '2475', (200, 204))	('phosphatidylinositol 3-kinase', 'Gene', (88, 117))	('AKT', 'Gene', '207', (164, 167))	('tumour', 'Phenotype', 'HP:0002664', (273, 279))	('drive', 'PosReg', (267, 272))	('mammalian target of rapamycin', 'Gene', '2475', (169, 198))	('mammalian target of rapamycin', 'Gene', (169, 198))
72082	29348486	Upregulation of the PI3K/AKT/mTOR pathway attributed to mutations in PIK3CA has been identified in many cancer types, including biliary tract cancer (BTC).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (128, 148))	('mTOR', 'Gene', '2475', (29, 33))	('PIK3CA', 'Gene', (69, 75))	('AKT', 'Gene', '207', (25, 28))	('biliary tract cancer', 'Disease', 'MESH:D001661', (128, 148))	('cancer', 'Disease', (104, 110))	('mutations', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (142, 148))	('BTC', 'Phenotype', 'HP:0100574', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('PIK3CA', 'Gene', '5290', (69, 75))	('biliary tract cancer', 'Disease', (128, 148))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('identified', 'Reg', (85, 95))	('Upregulation', 'PosReg', (0, 12))	('AKT', 'Gene', (25, 28))	('mTOR', 'Gene', (29, 33))
72084	29348486	PTEN mutations lead to activation of the PI3K/AKT pathway, and loss of PTEN function results in increased phosphatidylinositol (3,4,5)-trisphosphate levels and subsequent AKT phosphorylation and modulation of its downstream molecular oncogenic process.	('increased', 'PosReg', (96, 105))	('phosphatidylinositol (3,4,5)-trisphosphate', 'Chemical', 'MESH:C060974', (106, 148))	('AKT', 'Gene', '207', (46, 49))	('phosphorylation', 'MPA', (175, 190))	('mutations', 'Var', (5, 14))	('activation', 'PosReg', (23, 33))	('modulation', 'Reg', (195, 205))	('AKT', 'Gene', (46, 49))	('PTEN', 'Gene', (71, 75))	('AKT', 'Gene', '207', (171, 174))	('PTEN', 'Gene', '5728', (71, 75))	('PTEN', 'Gene', (0, 4))	('loss', 'NegReg', (63, 67))	('PTEN', 'Gene', '5728', (0, 4))	('AKT', 'Gene', (171, 174))
72093	29348486	In preclinical studies, gemcitabine combined with copanlisib demonstrated anti-tumour activity in a mutant BTC model in nude mice.	('copanlisib', 'Gene', (50, 60))	('mutant', 'Var', (100, 106))	('gemcitabine', 'Chemical', 'MESH:C056507', (24, 35))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('nude mice', 'Species', '10090', (120, 129))	('BTC', 'Phenotype', 'HP:0100574', (107, 110))	('copanlisib', 'Chemical', 'MESH:C000589253', (50, 60))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))
72109	29348486	PIK3CA and KRAS mutations were assayed in circulating tumour DNA isolated from pre-treatment plasma samples (collected during the screening period) using beads, emulsions, amplification and magnetics technology (Sysmex Inostics GmbH, Hamburg, Germany).	('KRAS', 'Gene', (11, 15))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Disease', (54, 60))	('KRAS', 'Gene', '3845', (11, 15))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
72119	29348486	Most patients had intrahepatic bile duct cancer (16 patients, 32%) and gallbladder cancer (seven patients, 14%), primarily because of the BTC expansion cohort (23 patients in total).	('patients', 'Species', '9606', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('patients', 'Species', '9606', (5, 13))	('intrahepatic bile duct cancer', 'Disease', (18, 47))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gallbladder cancer', 'Disease', (71, 89))	('gallbladder cancer', 'Disease', 'MESH:D005706', (71, 89))	('BTC', 'Var', (138, 141))	('BTC', 'Phenotype', 'HP:0100574', (138, 141))	('bile duct cancer', 'Phenotype', 'HP:0030153', (31, 47))	('intrahepatic bile duct cancer', 'Disease', 'MESH:D002780', (18, 47))	('patients', 'Species', '9606', (52, 60))	('patients', 'Species', '9606', (97, 105))
72176	29348486	PIK3CA alterations were detected in 2% of patients (1 out of 43; a gene amplification), KRAS mutations in 23% (10 out of 43) and BRAF mutations in 9% (2 out of 22).	('detected', 'Reg', (24, 32))	('mutations', 'Var', (93, 102))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('PIK3CA', 'Gene', (0, 6))	('KRAS', 'Gene', (88, 92))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutations', 'Var', (134, 143))	('KRAS', 'Gene', '3845', (88, 92))	('patients', 'Species', '9606', (42, 50))	('alterations', 'Var', (7, 18))
72178	29348486	Among patients with BTC, the mutation rates for PIK3CA, KRAS and BRAF were 0% (0 out of 22), 18% (4 out of 22) and 22% (2 out of 9), respectively, and PTEN protein loss was observed in 69% of patients (9 out of 13).	('mutation', 'Var', (29, 37))	('KRAS', 'Gene', (56, 60))	('PIK3CA', 'Gene', (48, 54))	('patients', 'Species', '9606', (192, 200))	('KRAS', 'Gene', '3845', (56, 60))	('BRAF', 'Gene', '673', (65, 69))	('patients', 'Species', '9606', (6, 14))	('protein', 'Protein', (156, 163))	('PIK3CA', 'Gene', '5290', (48, 54))	('BTC', 'Phenotype', 'HP:0100574', (20, 23))	('BRAF', 'Gene', (65, 69))	('PTEN', 'Gene', (151, 155))	('loss', 'NegReg', (164, 168))	('PTEN', 'Gene', '5728', (151, 155))
72180	29348486	Two patients with objective tumour response had PTEN protein loss, one in conjunction with a KRAS mutation (patient with cholangiocarcinoma; BTC expansion cohort) and the other with a BRAF mutation (patient with cholangiocarcinoma; initial CisGem safety evaluation cohort) (Figure 3).	('cholangiocarcinoma', 'Disease', (212, 230))	('KRAS', 'Gene', (93, 97))	('BRAF', 'Gene', (184, 188))	('PTEN', 'Gene', '5728', (48, 52))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (212, 230))	('CisGem', 'Chemical', '-', (240, 246))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('tumour', 'Disease', (28, 34))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))	('loss', 'NegReg', (61, 65))	('mutation', 'Var', (98, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('cholangiocarcinoma', 'Disease', (121, 139))	('patient', 'Species', '9606', (199, 206))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (121, 139))	('patients', 'Species', '9606', (4, 12))	('patient', 'Species', '9606', (108, 115))	('BTC', 'Phenotype', 'HP:0100574', (141, 144))	('PTEN', 'Gene', (48, 52))	('patient', 'Species', '9606', (4, 11))	('KRAS', 'Gene', '3845', (93, 97))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (212, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('BRAF', 'Gene', '673', (184, 188))
72206	29348486	The prevalence of KRAS mutations detected in patients with BTC (18%) is also similar to what has been previously reported (~20%), whereas the PIK3CA mutation rate (0%) is lower and the BRAF mutation rate (22%) is higher than what has been reported in previous studies (~10% and 5%, respectively).	('PIK3CA', 'Gene', '5290', (142, 148))	('KRAS', 'Gene', (18, 22))	('KRAS', 'Gene', '3845', (18, 22))	('mutations', 'Var', (23, 32))	('BRAF', 'Gene', '673', (185, 189))	('PIK3CA', 'Gene', (142, 148))	('patients', 'Species', '9606', (45, 53))	('BTC', 'Phenotype', 'HP:0100574', (59, 62))	('BRAF', 'Gene', (185, 189))	('lower', 'NegReg', (171, 176))
72218	29379583	GSK-3beta constitutive activation seems to occur via phosphorylation in tyrosine 216.	('GSK-3beta', 'Protein', (0, 9))	('tyrosine', 'Var', (72, 80))	('phosphorylation', 'MPA', (53, 68))	('tyrosine', 'Chemical', 'MESH:D014443', (72, 80))
72227	29379583	Amino acids have also been shown to inhibit GSK-3; this occurs via the mammalian target of rapamycin (mTOR) and the downstream S6K1 kinase.	('S6K1', 'Gene', '6198', (127, 131))	('mammalian target of rapamycin', 'Gene', '2475', (71, 100))	('S6K1', 'Gene', (127, 131))	('inhibit', 'NegReg', (36, 43))	('mammalian target of rapamycin', 'Gene', (71, 100))	('GSK-3', 'Gene', '56637', (44, 49))	('mTOR', 'Gene', (102, 106))	('mTOR', 'Gene', '2475', (102, 106))	('Amino acids', 'Var', (0, 11))	('GSK-3', 'Gene', (44, 49))
72234	29379583	It has also shown beta-catenin accumulation in the presence of highly active GSK-3, and this is dependent on APC or beta-catenin mutations.	('highly active', 'Var', (63, 76))	('beta-catenin', 'Gene', (18, 30))	('APC', 'Disease', (109, 112))	('GSK-3', 'Gene', '56637', (77, 82))	('beta-catenin', 'Gene', '1499', (18, 30))	('APC', 'Phenotype', 'HP:0005227', (109, 112))	('accumulation', 'PosReg', (31, 43))	('beta-catenin', 'Gene', (116, 128))	('GSK-3', 'Gene', (77, 82))	('APC', 'Disease', 'MESH:D011125', (109, 112))	('beta-catenin', 'Gene', '1499', (116, 128))
72236	29379583	Conversely, upon canonical WNT signaling, inactive GSK-3 fosters cell proliferation by beta-catenin stabilization thus acquiring tumor-promoting activity (Figure 1).	('acquiring', 'PosReg', (119, 128))	('beta-catenin', 'Gene', (87, 99))	('fosters', 'PosReg', (57, 64))	('GSK-3', 'Gene', '56637', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('GSK-3', 'Gene', (51, 56))	('beta-catenin', 'Gene', '1499', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cell proliferation', 'CPA', (65, 83))	('tumor', 'Disease', (129, 134))	('inactive', 'Var', (42, 50))
72247	29379583	For such a reason, upon GSK-3 inhibition, growth factors may lead to both cyclin D1 and c-myc stabilization.	('GSK-3', 'Gene', (24, 29))	('inhibition', 'Var', (30, 40))	('lead to', 'Reg', (61, 68))	('cyclin D1', 'Gene', '595', (74, 83))	('cyclin D1', 'Gene', (74, 83))	('GSK-3', 'Gene', '56637', (24, 29))	('c-myc', 'Gene', '4609', (88, 93))	('c-myc', 'Gene', (88, 93))	('stabilization', 'MPA', (94, 107))
72249	29379583	Therefore, GSK-3 inhibition is able to enhance c-jun potential to stimulate the transcription of several genes including those involved in cell cycle progression.	('c-jun', 'Gene', '3725', (47, 52))	('c-jun', 'Gene', (47, 52))	('GSK-3', 'Gene', (11, 16))	('inhibition', 'Var', (17, 27))	('transcription', 'MPA', (80, 93))	('GSK-3', 'Gene', '56637', (11, 16))	('stimulate', 'PosReg', (66, 75))	('enhance', 'PosReg', (39, 46))
72258	29379583	Moreover, GSK-3beta inhibition significantly reduces hepatic apoptotic cell death in response to D-galactosamine/LPS-induced liver injury and improves the survival of mice with polymicrobial sepsis, ameliorating liver injury, with a mechanism involving its ability to inhibit inflammatory response by modulation of NF-kappaB and CREB activation.	('GSK-3beta', 'Protein', (10, 19))	('modulation', 'Reg', (301, 311))	('liver injury', 'Disease', (212, 224))	('sepsis', 'Phenotype', 'HP:0100806', (191, 197))	('liver injury', 'Disease', 'MESH:D017093', (212, 224))	('liver injury', 'Disease', (125, 137))	('sepsis', 'Disease', 'MESH:D018805', (191, 197))	('survival', 'CPA', (155, 163))	('liver injury', 'Disease', 'MESH:D017093', (125, 137))	('hepatic apoptotic cell death', 'MPA', (53, 81))	('ameliorating', 'PosReg', (199, 211))	('sepsis', 'Disease', (191, 197))	('inhibit', 'NegReg', (268, 275))	('inflammatory response', 'CPA', (276, 297))	('NF-kappaB', 'Gene', (315, 324))	('D-galactosamine', 'Chemical', '-', (97, 112))	('mice', 'Species', '10090', (167, 171))	('LPS', 'Chemical', 'MESH:D008070', (113, 116))	('inhibition', 'Var', (20, 30))	('reduces', 'NegReg', (45, 52))	('improves', 'PosReg', (142, 150))	('NF-kappaB', 'Gene', '18033', (315, 324))
72261	29379583	In fact, on one hand, it has been demonstrated that GSK-3 regulates axins, intracellular beta-catenin antagonists, and cell fate regulators, while on the other hand inhibition of GSK-3 enhances TRAIL-induced apoptosis as well as sorafenib-induced apoptosis in melanoma cells.	('GSK-3', 'Gene', (179, 184))	('melanoma', 'Disease', 'MESH:D008545', (260, 268))	('axins', 'Chemical', '-', (68, 73))	('beta-catenin', 'Gene', '1499', (89, 101))	('axins', 'MPA', (68, 73))	('GSK-3', 'Gene', (52, 57))	('GSK-3', 'Gene', '56637', (179, 184))	('sorafenib', 'Chemical', 'MESH:D000077157', (229, 238))	('TRAIL', 'Gene', '8743', (194, 199))	('enhances', 'PosReg', (185, 193))	('melanoma', 'Phenotype', 'HP:0002861', (260, 268))	('melanoma', 'Disease', (260, 268))	('inhibition', 'Var', (165, 175))	('GSK-3', 'Gene', '56637', (52, 57))	('TRAIL', 'Gene', (194, 199))	('beta-catenin', 'Gene', (89, 101))
72264	29379583	GSK-3beta inhibition leads to beta-catenin activation and tumor cell proliferation.	('beta-catenin', 'Gene', '1499', (30, 42))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('GSK-3beta', 'Protein', (0, 9))	('activation', 'PosReg', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('inhibition', 'Var', (10, 20))	('beta-catenin', 'Gene', (30, 42))
72268	29379583	Signaling through mTORC1 is involved in tumor progression, and remarkably, GSK-3 inhibitors have been shown to inhibit mTORC1 activity.	('mTORC1', 'Gene', '382056', (119, 125))	('inhibit', 'NegReg', (111, 118))	('mTORC1', 'Gene', (18, 24))	('GSK-3', 'Gene', '56637', (75, 80))	('inhibitors', 'Var', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('involved', 'Reg', (28, 36))	('mTORC1', 'Gene', (119, 125))	('mTORC1', 'Gene', '382056', (18, 24))	('GSK-3', 'Gene', (75, 80))	('tumor', 'Disease', (40, 45))	('activity', 'MPA', (126, 134))
72279	29379583	Noteworthy, while activated AKT inhibits GSK-3 through the phosphorylation of GSK-3 at Ser21/Ser9, however, such inactivation does not always affect beta-catenin levels in the cell and does not completely inhibit GSK-3.	('GSK-3', 'Gene', (213, 218))	('Ser9', 'Chemical', '-', (93, 97))	('GSK-3', 'Gene', '56637', (78, 83))	('AKT', 'Gene', (28, 31))	('Ser21', 'Chemical', '-', (87, 92))	('GSK-3', 'Gene', (41, 46))	('beta-catenin', 'Gene', (149, 161))	('GSK-3', 'Gene', '56637', (213, 218))	('phosphorylation', 'MPA', (59, 74))	('inhibits', 'NegReg', (32, 40))	('GSK-3', 'Gene', '56637', (41, 46))	('beta-catenin', 'Gene', '1499', (149, 161))	('GSK-3', 'Gene', (78, 83))	('AKT', 'Gene', '207', (28, 31))	('Ser21/Ser9', 'Var', (87, 97))
72318	29379583	Conversely, treating cells with GSK-3 inhibitors inhibits mTORC1 activity and increases autophagic flux.	('activity', 'MPA', (65, 73))	('GSK-3', 'Gene', '56637', (32, 37))	('mTORC1', 'Gene', '382056', (58, 64))	('autophagic flux', 'CPA', (88, 103))	('inhibits', 'NegReg', (49, 57))	('mTORC1', 'Gene', (58, 64))	('inhibitors', 'Var', (38, 48))	('GSK-3', 'Gene', (32, 37))	('increases', 'PosReg', (78, 87))
72320	29379583	GSK-3 inhibition reduces mTOR and raptor interaction leading to reduced phosphorylation of both p70S6K1 and ULK-1 and to increased autophagic flux.	('autophagic flux', 'CPA', (131, 146))	('ULK-1', 'Gene', '8408', (108, 113))	('S6K1', 'Gene', (99, 103))	('reduces', 'NegReg', (17, 24))	('S6K1', 'Gene', '6198', (99, 103))	('ULK-1', 'Gene', (108, 113))	('increased', 'PosReg', (121, 130))	('GSK-3', 'Gene', '56637', (0, 5))	('phosphorylation', 'CPA', (72, 87))	('raptor', 'Gene', (34, 40))	('inhibition', 'Var', (6, 16))	('reduced', 'NegReg', (64, 71))	('mTOR', 'Gene', '2475', (25, 29))	('raptor', 'Gene', '57521', (34, 40))	('mTOR', 'Gene', (25, 29))	('GSK-3', 'Gene', (0, 5))
72325	29379583	In a prostate cancer cell model, inhibition of GSK-3beta activity leads to a significant increase of AMP/ATP ratio, a strong trigger of AMPK activation, thus leading to autophagy induction.	('inhibition', 'Var', (33, 43))	('autophagy induction', 'CPA', (169, 188))	('prostate cancer', 'Disease', (5, 20))	('AMP', 'Chemical', 'MESH:D000249', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('AMPK', 'Gene', (136, 140))	('leading to', 'Reg', (158, 168))	('AMP/ATP ratio', 'MPA', (101, 114))	('AMPK', 'Gene', '5564', (136, 140))	('activity', 'MPA', (57, 65))	('AMP', 'Chemical', 'MESH:D000249', (136, 139))	('prostate cancer', 'Disease', 'MESH:D011471', (5, 20))	('prostate cancer', 'Phenotype', 'HP:0012125', (5, 20))	('ATP', 'Chemical', 'MESH:D000255', (105, 108))	('GSK-3beta', 'Protein', (47, 56))	('increase', 'PosReg', (89, 97))
72340	29379583	Remarkably, GSK-3 seems to play a key role also in stemness; in fact, inhibition of both GSK-3 and mTORC1 induces a proautophagic gene signature in hematopoietic stem cells, which is crucial to maintain their self-renewal ability.	('GSK-3', 'Gene', '56637', (12, 17))	('mTORC1', 'Gene', '382056', (99, 105))	('induces', 'Reg', (106, 113))	('GSK-3', 'Gene', '56637', (89, 94))	('mTORC1', 'Gene', (99, 105))	('proautophagic gene signature', 'MPA', (116, 144))	('GSK-3', 'Gene', (12, 17))	('inhibition', 'Var', (70, 80))	('GSK-3', 'Gene', (89, 94))
72346	29379583	Given its role in metabolic balance and organelle quality control, an unbalance or malfunction of autophagy pathways in hepatocytes has been associated with the pathogenesis of several liver diseases, including nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver (AFL), viral hepatitis, and liver cancer.	('viral hepatitis', 'Phenotype', 'HP:0006562', (282, 297))	('liver diseases', 'Phenotype', 'HP:0001392', (185, 199))	('autophagy pathways', 'CPA', (98, 116))	('unbalance', 'Var', (70, 79))	('alcoholic fatty liver', 'Phenotype', 'HP:0006573', (214, 235))	('alcoholic fatty liver', 'Phenotype', 'HP:0006573', (253, 274))	('hepatitis', 'Phenotype', 'HP:0012115', (288, 297))	('liver diseases', 'Disease', 'MESH:D008107', (185, 199))	('liver cancer', 'Disease', 'MESH:D006528', (303, 315))	('associated', 'Reg', (141, 151))	('viral hepatitis', 'Disease', 'MESH:D006525', (282, 297))	('alcoholic fatty liver', 'Disease', (214, 235))	('alcoholic fatty liver', 'Disease', (253, 274))	('fatty liver', 'Phenotype', 'HP:0001397', (224, 235))	('liver disease', 'Phenotype', 'HP:0001392', (185, 198))	('malfunction', 'Var', (83, 94))	('liver diseases', 'Disease', (185, 199))	('fatty liver', 'Phenotype', 'HP:0001397', (263, 274))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('liver cancer', 'Phenotype', 'HP:0002896', (303, 315))	('AFL', 'Phenotype', 'HP:0006573', (246, 249))	('liver cancer', 'Disease', (303, 315))	('liver disease', 'Phenotype', 'HP:0001392', (230, 243))	('alcoholic fatty liver', 'Disease', 'MESH:D005234', (214, 235))	('alcoholic fatty liver', 'Disease', 'MESH:D005234', (253, 274))	('viral hepatitis', 'Disease', (282, 297))	('fatty liver disease', 'Disease', 'MESH:D005234', (224, 243))	('AFL', 'Phenotype', 'HP:0006573', (276, 279))	('fatty liver disease', 'Disease', (224, 243))
72359	29379583	It should be noted that selective knockout of autophagy-related genes in mouse HSCs inhibits experimental induced fibrogenesis.	('experimental induced fibrogenesis', 'CPA', (93, 126))	('autophagy-related genes', 'Gene', (46, 69))	('mouse', 'Species', '10090', (73, 78))	('knockout', 'Var', (34, 42))	('HSC', 'Gene', (79, 82))	('inhibits', 'NegReg', (84, 92))	('HSC', 'Gene', '2523', (79, 82))
72368	29379583	Oxidative stress occurs when the balance between reactive oxygen species (ROS) production and elimination is altered leading to accumulation of ROS which profoundly affects lipids, proteins, and DNA.	('proteins', 'MPA', (181, 189))	('ROS', 'Var', (144, 147))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (49, 72))	('ROS', 'Chemical', 'MESH:D017382', (144, 147))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('lipids', 'Chemical', 'MESH:D008055', (173, 179))	('DNA', 'MPA', (195, 198))	('accumulation', 'PosReg', (128, 140))	('affects', 'Reg', (165, 172))	('altered', 'Reg', (109, 116))	('lipids', 'MPA', (173, 179))	('ROS', 'Chemical', 'MESH:D017382', (74, 77))
72372	29379583	More in detail, GSK-3 is able to direct MPT through the phosphorylation of different targets and GSK-3 inhibition is known to protect from MPT.	('MPT', 'MPA', (139, 142))	('GSK-3', 'Gene', '56637', (16, 21))	('GSK-3', 'Gene', (97, 102))	('GSK-3', 'Gene', (16, 21))	('inhibition', 'Var', (103, 113))	('phosphorylation', 'MPA', (56, 71))	('GSK-3', 'Gene', '56637', (97, 102))
72385	29379583	Furthermore, in a model of mesangial cells, cadmium has been demonstrated to be able to induce autophagic cell death through a GSK-3-regulated signal-transduction pathway.	('GSK-3', 'Gene', (127, 132))	('GSK-3', 'Gene', '56637', (127, 132))	('cadmium', 'Var', (44, 51))	('cadmium', 'Chemical', 'MESH:D002104', (44, 51))	('autophagic cell death', 'CPA', (95, 116))
72388	29379583	Conversely, activation of AKT and GSK-3beta inhibition suppresses cytodestructive autophagy in hippocampal neurons.	('GSK-3beta', 'Protein', (34, 43))	('inhibition', 'Var', (44, 54))	('activation', 'PosReg', (12, 22))	('AKT', 'Gene', '207', (26, 29))	('AKT', 'Gene', (26, 29))	('cytodestructive autophagy in hippocampal neurons', 'CPA', (66, 114))	('suppresses', 'NegReg', (55, 65))
72390	29379583	In addition, GSK-3beta-mediated phosphorylation of BCL2 family member MCL1 has been demonstrated to induce axonal autophagy and axonal degeneration.	('BCL2', 'Gene', '596', (51, 55))	('axonal degeneration', 'Disease', (128, 147))	('axonal autophagy', 'CPA', (107, 123))	('phosphorylation', 'Var', (32, 47))	('BCL2', 'Gene', (51, 55))	('induce', 'PosReg', (100, 106))	('MCL1', 'Gene', '4170', (70, 74))	('axonal degeneration', 'Phenotype', 'HP:0040078', (128, 147))	('MCL1', 'Gene', (70, 74))	('axonal degeneration', 'Disease', 'MESH:D009410', (128, 147))
72392	29379583	Modulation of GSK-3 activity via pharmacological intervention may represent a valuable strategy to control autophagy and other conditions.	('activity', 'MPA', (20, 28))	('Modulation', 'Var', (0, 10))	('control', 'PosReg', (99, 106))	('GSK-3', 'Gene', (14, 19))	('autophagy', 'CPA', (107, 116))	('GSK-3', 'Gene', '56637', (14, 19))
72401	29379583	Some GSK-3 inhibitors have been used in clinical trials and are well-tolerated in cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('GSK-3', 'Gene', '56637', (5, 10))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('patients', 'Species', '9606', (89, 97))	('inhibitors', 'Var', (11, 21))	('GSK-3', 'Gene', (5, 10))
72404	29379583	For instance, a specific AKT inhibitor induces apoptosis in T-cell acute lymphoblastic leukemia (ALL) through a mechanism partially dependent on GSK-3 activation.	('AKT', 'Gene', (25, 28))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (67, 95))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (73, 95))	('apoptosis', 'CPA', (47, 56))	('GSK-3', 'Gene', '56637', (145, 150))	('GSK-3', 'Gene', (145, 150))	('leukemia', 'Phenotype', 'HP:0001909', (87, 95))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (67, 95))	('AKT', 'Gene', '207', (25, 28))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (60, 95))	('inhibitor', 'Var', (29, 38))	('acute lymphoblastic leukemia', 'Disease', (67, 95))	('ALL', 'Phenotype', 'HP:0006721', (97, 100))	('induces', 'Reg', (39, 46))
72407	29379583	The selective GSK-3alpha and GSK-3beta inhibitor LY2090314 shows very high cytotoxic activity in melanoma cells, both resistant and nonresistant to BRAF inhibitor.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('cytotoxic activity', 'CPA', (75, 93))	('LY2090314', 'Var', (49, 58))	('BRAF', 'Gene', '673', (148, 152))	('BRAF', 'Gene', (148, 152))
72409	29379583	In vivo confirmation of such data further support the potential efficacy of GSK-3 inhibitors in melanoma.	('GSK-3', 'Gene', (76, 81))	('inhibitors', 'Var', (82, 92))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('GSK-3', 'Gene', '56637', (76, 81))	('melanoma', 'Disease', (96, 104))
72418	29379583	These hypotheses take into account, respectively, telomere shortening dysfunction, forms of DNA damage exciding DNA repair capacity, and mutation of mitochondrial DNA impairing ATP production.	('mutation', 'Var', (137, 145))	('exciding', 'NegReg', (103, 111))	('ATP production', 'MPA', (177, 191))	('impairing', 'NegReg', (167, 176))	('mitochondrial DNA', 'Gene', (149, 166))	('ATP', 'Chemical', 'MESH:D000255', (177, 180))
72421	29379583	Such increase is accompanied by ROS overproduction caused by defective respiration.	('defective', 'Var', (61, 70))	('ROS', 'MPA', (32, 35))	('increase', 'PosReg', (5, 13))	('ROS', 'Chemical', 'MESH:D017382', (32, 35))	('overproduction', 'PosReg', (36, 50))
72424	29379583	Deferoxamine augmented GSK-3 phosphorylation at both serine 9 of GSK-3beta and serine 21 of GSK-3alpha causing strong glycogen accumulation.	('GSK-3', 'Gene', '56637', (23, 28))	('augmented', 'PosReg', (13, 22))	('serine', 'Chemical', 'MESH:D012694', (53, 59))	('GSK-3', 'Gene', '56637', (92, 97))	('GSK-3', 'Gene', (65, 70))	('glycogen accumulation', 'MPA', (118, 139))	('GSK-3', 'Gene', '56637', (65, 70))	('glycogen', 'Chemical', 'MESH:D006003', (118, 126))	('serine', 'Chemical', 'MESH:D012694', (79, 85))	('GSK-3', 'Gene', (23, 28))	('GSK-3', 'Gene', (92, 97))	('Deferoxamine', 'Chemical', 'MESH:D003676', (0, 12))	('serine 21', 'Var', (79, 88))
72428	29379583	Hence, GSK-3 inhibition leads to intracellular ROS overproduction thus stimulating mitochondrial damage.	('overproduction', 'PosReg', (51, 65))	('stimulating', 'Reg', (71, 82))	('GSK-3', 'Gene', (7, 12))	('inhibition', 'Var', (13, 23))	('intracellular ROS', 'MPA', (33, 50))	('GSK-3', 'Gene', '56637', (7, 12))	('mitochondrial damage', 'CPA', (83, 103))	('ROS', 'Chemical', 'MESH:D017382', (47, 50))
72437	29379583	In conclusion, dietary or pharmacological administration of these compounds may represent, at least to some extent, potential alternatives to conventional drugs and still underlies the efficacy of GSK-3 modulation in counteracting aging-related pathologies.	('GSK-3', 'Gene', '56637', (197, 202))	('underlies', 'NegReg', (171, 180))	('modulation', 'Var', (203, 213))	('GSK-3', 'Gene', (197, 202))
72497	27829832	In addition, fibrosis related genes including alpha-SMA and procollagen alpha1(I) were upregulated in the DDC damaged livers, suggesting a concomitant fibrosis in response to DDC toxicity.	('fibrosis', 'Disease', (13, 21))	('alpha-SMA', 'Gene', (46, 55))	('fibrosis', 'Disease', 'MESH:D005355', (13, 21))	('alpha-SMA', 'Gene', '11475', (46, 55))	('fibrosis', 'Disease', 'MESH:D005355', (151, 159))	('procollagen', 'Gene', (60, 71))	('fibrosis', 'Disease', (151, 159))	('toxicity', 'Disease', (179, 187))	('toxicity', 'Disease', 'MESH:D064420', (179, 187))	('DDC', 'Chemical', 'MESH:C530773', (106, 109))	('DDC', 'Chemical', 'MESH:C530773', (175, 178))	('upregulated', 'PosReg', (87, 98))	('DDC', 'Var', (106, 109))
72529	27829832	In vivo overexpression of CCN2/CTGF in hepatocytes does not result in hepatic injury or fibrosis per se but renders the livers more susceptible to the injurious actions of other fibrotic stimuli in mice.	('fibrosis', 'Disease', (88, 96))	('overexpression', 'PosReg', (8, 22))	('mice', 'Species', '10090', (198, 202))	('CCN2/CTGF', 'Var', (26, 35))	('more', 'PosReg', (127, 131))	('hepatic injury', 'Disease', (70, 84))	('hepatic injury', 'Disease', 'MESH:D056486', (70, 84))	('renders', 'Reg', (108, 115))	('susceptible', 'MPA', (132, 143))	('fibrosis', 'Disease', 'MESH:D005355', (88, 96))
72530	27829832	Similarly, CCN4/WISP1 is profibrotic, since blockade of this molecule decreases experimental liver fibrosis in vivo.	('blockade', 'Var', (44, 52))	('WISP1', 'Gene', (16, 21))	('decreases experimental liver fibrosis', 'Disease', 'MESH:D008103', (70, 107))	('CCN4', 'Gene', '8840', (11, 15))	('liver fibrosis', 'Phenotype', 'HP:0001395', (93, 107))	('CCN4', 'Gene', (11, 15))	('WISP1', 'Gene', '8840', (16, 21))	('decreases experimental liver fibrosis', 'Disease', (70, 107))
72533	27829832	Inhibition of CCN3/NOV using small interfering RNA enhances fibrotic gene expression in hepatic stellate cells.	('NOV', 'Gene', '4856', (19, 22))	('fibrotic gene', 'Gene', (60, 73))	('NOV', 'Gene', (19, 22))	('CCN3', 'Gene', (14, 18))	('enhances', 'PosReg', (51, 59))	('CCN3', 'Gene', '4856', (14, 18))	('small interfering', 'Var', (29, 46))
72540	27829832	In this study, we observed that Ccn2/Ctgf had a relatively higher level of induction than other CCN proteins in DDC damaged mouse livers in Figure 1(a).	('induction', 'MPA', (75, 84))	('mouse', 'Species', '10090', (124, 129))	('Ccn2/Ctgf', 'Var', (32, 41))	('DDC', 'Chemical', 'MESH:C530773', (112, 115))	('CCN', 'Chemical', '-', (96, 99))
72553	27829832	Overexpression of CCN4/WISP1v is associated with lymphatic and perineural invasion of CCA tumor cells and a poor clinical prognosis.	('WISP1', 'Gene', (23, 28))	('CCA', 'Phenotype', 'HP:0030153', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('CCA tumor', 'Disease', (86, 95))	('CCN4', 'Gene', (18, 22))	('CCA tumor', 'Disease', 'MESH:C536211', (86, 95))	('CCN4', 'Gene', '8840', (18, 22))	('Overexpression', 'Var', (0, 14))	('WISP1', 'Gene', '8840', (23, 28))	('associated with', 'Reg', (33, 48))
72604	19585622	In addition, ligation of the TGF-beta receptor promotes phosphorylation of death-associated protein 6 (DAXX), which then activates JNK, promoting apoptosis.	('activates', 'PosReg', (121, 130))	('JNK', 'Gene', (131, 134))	('death-associated protein 6', 'Gene', '1616', (75, 101))	('death-associated protein 6', 'Gene', (75, 101))	('promotes', 'PosReg', (47, 55))	('TGF-beta', 'Gene', '7040', (29, 37))	('DAXX', 'Gene', (103, 107))	('TGF-beta', 'Gene', (29, 37))	('ligation', 'Var', (13, 21))	('JNK', 'Gene', '5599', (131, 134))	('phosphorylation', 'MPA', (56, 71))	('promoting', 'PosReg', (136, 145))	('apoptosis', 'CPA', (146, 155))	('DAXX', 'Gene', '1616', (103, 107))
72618	19585622	For instance, in HepG2 cells, a mix of antisense oligonucleotides to mir-17-92 led to increased E2F1 (protein) and E2F3 (mRNA) expression.	('increased', 'PosReg', (86, 95))	('E2F3', 'Gene', (115, 119))	('increased E2F1', 'Phenotype', 'HP:0030269', (86, 100))	('antisense oligonucleotides', 'Var', (39, 65))	('E2F3', 'Gene', '1871', (115, 119))	('HepG2', 'CellLine', 'CVCL:0027', (17, 22))	('oligonucleotides', 'Chemical', 'MESH:D009841', (49, 65))	('E2F1', 'Gene', '1869', (96, 100))	('E2F1', 'Gene', (96, 100))	('mir-17-92', 'Gene', (69, 78))
72625	19585622	Related to Bcl-2 by their Bcl-2 homology domain 3 (BH3) regions, BH3-only proteins are pro-apoptotic, and can act as tumor suppressors.	('Bcl-2', 'Gene', '596', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('BH3', 'Chemical', '-', (65, 68))	('BH3', 'Chemical', '-', (51, 54))	('BH3-only', 'Var', (65, 73))	('tumor', 'Disease', (117, 122))	('Bcl-2', 'Gene', (26, 31))	('Bcl-2', 'Gene', '596', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('Bcl-2', 'Gene', (11, 16))
72626	19585622	The above-mentioned mir-17-92 cluster targets Bim expression in B cells, B cell lymphoma, T cells, lung tissue, and gastric cancer; thus mir-17-92 may act through multiple pathways to promote proliferation and stifle apoptosis (Figure 2).	('act', 'Reg', (151, 154))	('lymphoma', 'Phenotype', 'HP:0002665', (80, 88))	('proliferation', 'CPA', (192, 205))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (73, 88))	('stifle', 'Reg', (210, 216))	('gastric cancer', 'Disease', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('gastric cancer', 'Disease', 'MESH:D013274', (116, 130))	('mir-17-92', 'Var', (137, 146))	('rat', 'Species', '10116', (199, 202))	('gastric cancer', 'Phenotype', 'HP:0012126', (116, 130))	('B cell lymphoma', 'Disease', (73, 88))	('promote', 'PosReg', (184, 191))
72627	19585622	The role of mir-17-92 silencing of Bim in liver cancers remains to be defined.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('liver cancer', 'Phenotype', 'HP:0002896', (42, 54))	('liver cancers', 'Phenotype', 'HP:0002896', (42, 55))	('liver cancers', 'Disease', 'MESH:D006528', (42, 55))	('liver cancers', 'Disease', (42, 55))	('Bim', 'Gene', (35, 38))	('silencing', 'Var', (22, 31))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))
72628	19585622	Mice deficient in Dicer manifest increased Bim protein expression and apoptosis likely due in part to loss of Bim suppression by mir-17-92.	('Bim protein', 'Protein', (43, 54))	('increased Bim', 'Phenotype', 'HP:0003573', (33, 46))	('mir-17-92', 'Var', (129, 138))	('deficient', 'Var', (5, 14))	('increased', 'PosReg', (33, 42))	('loss', 'NegReg', (102, 106))	('Mice', 'Species', '10090', (0, 4))	('apoptosis', 'CPA', (70, 79))	('Bim', 'MPA', (110, 113))	('Dicer', 'Gene', (18, 23))
72629	19585622	By extension, the finding of increased hepatocyte apoptosis in mice with liver-specific Dicer deletion would be consistent with microRNA regulation of a proapoptotic protein, such as Bim, in hepatocytes, but requires further investigation.	('deletion', 'Var', (94, 102))	('hepatocyte apoptosis', 'CPA', (39, 59))	('mice', 'Species', '10090', (63, 67))	('increased', 'PosReg', (29, 38))	('Dicer', 'Gene', (88, 93))
72636	19585622	Consistently, mir-34a was decreased in 76% of HCC patients, all of which had mutated p53.	('HCC', 'Gene', '619501', (46, 49))	('p53', 'Gene', (85, 88))	('patients', 'Species', '9606', (50, 58))	('HCC', 'Phenotype', 'HP:0001402', (46, 49))	('mutated', 'Var', (77, 84))	('HCC', 'Gene', (46, 49))	('decreased', 'NegReg', (26, 35))	('mir-34a', 'Protein', (14, 21))
72650	19585622	Restoring mir-29b expression in cholangiocarcinoma cells sensitizes to apoptosis, and antagonism of mir-29b in non-malignant cells allowed Mcl-1 protein overexpression and apoptosis resistance.	('Mcl-1', 'Gene', (139, 144))	('overexpression', 'PosReg', (153, 167))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (32, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (32, 50))	('mir-29b', 'Gene', '407024', (10, 17))	('Mcl-1', 'Gene', '4170', (139, 144))	('mir-29b', 'Gene', '407024', (100, 107))	('sensitizes', 'Reg', (57, 67))	('apoptosis resistance', 'CPA', (172, 192))	('antagonism', 'Var', (86, 96))	('expression', 'MPA', (18, 28))	('mir-29b', 'Gene', (10, 17))	('mir-29b', 'Gene', (100, 107))	('cholangiocarcinoma', 'Disease', (32, 50))
72660	19585622	GSK3beta phosphorylates beta-catenin causing degradation, thus inhibition of GSK3beta leads to accumulation and transcriptional activity of beta-catenin, including transcription of cyclin D1.	('beta-catenin', 'Gene', (24, 36))	('degradation', 'MPA', (45, 56))	('accumulation', 'PosReg', (95, 107))	('cyclin D1', 'Gene', (181, 190))	('beta-catenin', 'Gene', '1499', (140, 152))	('transcription', 'MPA', (164, 177))	('beta-catenin', 'Gene', '1499', (24, 36))	('GSK3beta', 'Gene', '2932', (0, 8))	('GSK3beta', 'Gene', (77, 85))	('cyclin D1', 'Gene', '595', (181, 190))	('inhibition', 'Var', (63, 73))	('GSK3beta', 'Gene', (0, 8))	('GSK3beta', 'Gene', '2932', (77, 85))	('transcriptional activity', 'MPA', (112, 136))	('beta-catenin', 'Gene', (140, 152))
72673	19585622	In the liver, decreased expression of mir-1-1 in HCC samples was found to be due to CpG methylation of exon 1 and intron 1 of the mir-1-1 gene.	('methylation', 'Var', (88, 99))	('decreased', 'NegReg', (14, 23))	('mir-1-1', 'Gene', '406904;79187', (38, 45))	('expression', 'MPA', (24, 34))	('HCC', 'Gene', (49, 52))	('HCC', 'Phenotype', 'HP:0001402', (49, 52))	('mir-1-1', 'Gene', (38, 45))	('mir-1-1', 'Gene', '406904;79187', (130, 137))	('HCC', 'Gene', '619501', (49, 52))	('mir-1-1', 'Gene', (130, 137))
72675	19585622	Samples from cirrhotic, virally infected livers compared to non-cirrhotic, non-infected samples showed increased expression of a host of microRNAs, including mir-221, -222, -23b, let-7a and let-7d.	('mir-221', 'Gene', (158, 165))	('expression', 'MPA', (113, 123))	('let-7d', 'Gene', (190, 196))	('increased', 'PosReg', (103, 112))	('let-7d', 'Gene', '406886', (190, 196))	('mir-221', 'Gene', '407006', (158, 165))	('let-7a', 'Var', (179, 185))
72678	19585622	Molecular mechanisms causing dysregulated microRNA expression in the liver due to genomic alteration have been described, including chromosomal rearrangement in virally-infected cells and single-nucleotide polymorphism.	('single-nucleotide polymorphism', 'Var', (188, 218))	('rat', 'Species', '10116', (94, 97))	('microRNA expression', 'MPA', (42, 61))
72680	19585622	A separate study described a G to C single nucleotide polymorphism in the stem-loop of the mir-146a precursor sequence associated with HCC in males (GG genotype), and the G allele was processed more efficiently to mature mir-146a.	('rat', 'Species', '10116', (6, 9))	('single nucleotide polymorphism', 'Var', (36, 66))	('HCC', 'Gene', '619501', (135, 138))	('associated with', 'Reg', (119, 134))	('HCC', 'Phenotype', 'HP:0001402', (135, 138))	('mir-146a', 'Gene', (221, 229))	('mir-146a', 'Gene', (91, 99))	('HCC', 'Gene', (135, 138))	('mir-146a', 'Gene', '406938', (221, 229))	('mir-146a', 'Gene', '406938', (91, 99))
72714	33935756	The development of HCC is a multistep process, in which epigenetic changes and genetic alterations accumulate in HCC cells, including mutations and DNA amplification variations, which result in cell signaling pathway variation, ultimately leading to the high heterogeneity of HCC.	('HCC', 'Gene', (19, 22))	('result in', 'Reg', (184, 193))	('HCC', 'Gene', '619501', (276, 279))	('HCC', 'Phenotype', 'HP:0001402', (276, 279))	('rat', 'Species', '10116', (91, 94))	('HCC', 'Gene', (276, 279))	('variation', 'Var', (217, 226))	('HCC', 'Gene', '619501', (19, 22))	('leading to', 'Reg', (239, 249))	('HCC', 'Gene', '619501', (113, 116))	('HCC', 'Phenotype', 'HP:0001402', (113, 116))	('HCC', 'Phenotype', 'HP:0001402', (19, 22))	('cell signaling pathway', 'Pathway', (194, 216))	('mutations', 'Var', (134, 143))	('accumulate', 'PosReg', (99, 109))	('HCC', 'Gene', (113, 116))	('genetic alterations', 'Var', (79, 98))
72716	33935756	The deregulation of FGF signaling is frequently observed in HCC and liver cirrhosis, as well as viral hepatitis.	('deregulation', 'Var', (4, 16))	('viral hepatitis', 'Disease', (96, 111))	('liver cirrhosis', 'Disease', 'MESH:D008103', (68, 83))	('HCC', 'Gene', '619501', (60, 63))	('observed', 'Reg', (48, 56))	('viral hepatitis', 'Disease', 'MESH:D006525', (96, 111))	('HCC', 'Phenotype', 'HP:0001402', (60, 63))	('liver cirrhosis', 'Disease', (68, 83))	('cirrhosis', 'Phenotype', 'HP:0001394', (74, 83))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (68, 83))	('viral hepatitis', 'Phenotype', 'HP:0006562', (96, 111))	('FGF', 'Protein', (20, 23))	('hepatitis', 'Phenotype', 'HP:0012115', (102, 111))	('HCC', 'Gene', (60, 63))
72734	33935756	As shown in Figure 1A, the transcription levels of FGF1, 2, 7, 11-13, 17-19, and 21-22 and FGFR1-4 in hepatocellular tumor tissues are higher than those in normal tissues (Figure 1A); In addition, gene mutations, fusions, and copy number amplification of FGFs/FGFRs are closely related to the occurrence of HCC.	('HCC', 'Gene', '619501', (307, 310))	('HCC', 'Phenotype', 'HP:0001402', (307, 310))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('FGFR1-4', 'Gene', '2260;2263;2261;2264', (91, 98))	('FGFs/FGFRs', 'Gene', (255, 265))	('hepatocellular tumor', 'Phenotype', 'HP:0001402', (102, 122))	('FGFR1-4', 'Gene', (91, 98))	('fusions', 'Var', (213, 220))	('gene mutations', 'Var', (197, 211))	('hepatocellular tumor', 'Disease', 'MESH:D006528', (102, 122))	('HCC', 'Gene', (307, 310))	('transcription levels', 'MPA', (27, 47))	('higher', 'PosReg', (135, 141))	('hepatocellular tumor', 'Disease', (102, 122))	('related', 'Reg', (278, 285))	('copy number amplification', 'Var', (226, 251))
72735	33935756	As shown in Figure 1B, FGF1, 3-7, 9-22 and FGFR1-4 all have different degrees of genetic changes, especially gene copy number amplification and deep deletion.	('FGFR1-4', 'Gene', '2260;2263;2261;2264', (43, 50))	('FGFR1-4', 'Gene', (43, 50))	('deep', 'CPA', (144, 148))	('gene copy number amplification', 'Var', (109, 139))
72745	33935756	The deregulation of FGFR3 with specific siRNA inhibits the HCC cell growth, indicating that FGF2 and its receptors (FGFR3) are essential for HCC proliferation.	('FGFR3', 'Gene', '2261', (20, 25))	('deregulation', 'Var', (4, 16))	('HCC', 'Phenotype', 'HP:0001402', (59, 62))	('HCC', 'Gene', '619501', (141, 144))	('rat', 'Species', '10116', (152, 155))	('FGFR3', 'Gene', (116, 121))	('FGFR3', 'Gene', (20, 25))	('HCC', 'Phenotype', 'HP:0001402', (141, 144))	('HCC', 'Gene', (59, 62))	('inhibits', 'NegReg', (46, 54))	('FGF2', 'Gene', '2247', (92, 96))	('HCC', 'Gene', (141, 144))	('HCC', 'Gene', '619501', (59, 62))	('FGF2', 'Gene', (92, 96))	('FGFR3', 'Gene', '2261', (116, 121))
72749	33935756	It was supported that blocking FGF2 with vascularization inhibitors leads to a significant reduction in tumor size.	('FGF2', 'Gene', '2247', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('blocking', 'Var', (22, 30))	('tumor', 'Disease', (104, 109))	('FGF2', 'Gene', (31, 35))	('reduction', 'NegReg', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
72753	33935756	The latest research claimed that FGF2 single nucleotide polymorphisms (SNPs) rs308379 A allele could be regarded as an independent poor prognostic factor for overall survival in patients with HBV-associated HCC by multivariate Cox analysis.	('single nucleotide polymorphisms', 'Var', (38, 69))	('HCC', 'Gene', '619501', (207, 210))	('HCC', 'Phenotype', 'HP:0001402', (207, 210))	('rs308379', 'Mutation', 'rs308379', (77, 85))	('patients', 'Species', '9606', (178, 186))	('FGF2', 'Gene', '2247', (33, 37))	('rs308379 A', 'Var', (77, 87))	('HCC', 'Gene', (207, 210))	('FGF2', 'Gene', (33, 37))
72756	33935756	These FGF8 variants, FGF17, and FGF18, which act as local paracrine molecules, are presumed to bind and activate FGFR2, FGFR3, and FGFR4.	('FGFR3', 'Gene', '2261', (120, 125))	('FGF17', 'Gene', '8822', (21, 26))	('FGF8', 'Gene', (6, 10))	('FGFR3', 'Gene', (120, 125))	('variants', 'Var', (11, 19))	('FGFR2', 'Gene', '2263', (113, 118))	('activate', 'PosReg', (104, 112))	('FGFR4', 'Gene', (131, 136))	('bind', 'Interaction', (95, 99))	('FGF17', 'Gene', (21, 26))	('FGF18', 'Gene', (32, 37))	('FGFR2', 'Gene', (113, 118))
72761	33935756	The administration of FGF8, FGF17, or FGF18 could resist apoptosis and enhance the survival of serum-starved tumor cells, including HCC-1.2, HepG2, and Hep3B cells, the mechanism studies have found that these effects were mediated by ERK and AKT/mTOR signaling pathways.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('ERK', 'Gene', (234, 237))	('FGF17', 'Gene', '8822', (28, 33))	('FGF8', 'Var', (22, 26))	('AKT', 'Gene', (242, 245))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('HepG2', 'CellLine', 'CVCL:0027', (141, 146))	('HCC', 'Gene', '619501', (132, 135))	('rat', 'Species', '10116', (12, 15))	('HCC', 'Phenotype', 'HP:0001402', (132, 135))	('FGF18', 'Var', (38, 43))	('survival', 'CPA', (83, 91))	('Hep3B', 'CellLine', 'CVCL:0326', (152, 157))	('mTOR', 'Gene', (246, 250))	('HCC', 'Gene', (132, 135))	('AKT', 'Gene', '207', (242, 245))	('resist', 'NegReg', (50, 56))	('apoptosis', 'CPA', (57, 66))	('mTOR', 'Gene', '2475', (246, 250))	('FGF17', 'Gene', (28, 33))	('ERK', 'Gene', '5594', (234, 237))	('enhance', 'PosReg', (71, 78))	('tumor', 'Disease', (109, 114))
72776	33935756	FGF18 overexpression in the liver of transgenic mice induced a marked increase in liver weight and hepatocyte proliferation.	('increase in liver weight', 'Phenotype', 'HP:0002240', (70, 94))	('rat', 'Species', '10116', (117, 120))	('FGF18', 'Gene', (0, 5))	('overexpression', 'Var', (6, 20))	('hepatocyte proliferation', 'CPA', (99, 123))	('transgenic mice', 'Species', '10090', (37, 52))	('increase in liver weight', 'Disease', 'MESH:D017093', (70, 94))	('increase in liver weight', 'Disease', (70, 94))
72779	33935756	Similarly, silencing FGF18 with specific siRNA decreased the viability and clonal proliferation of HCC cell lines, but elevated apoptotic activity in HCC cell lines.	('silencing', 'Var', (11, 20))	('HCC', 'Gene', (150, 153))	('apoptotic activity', 'CPA', (128, 146))	('FGF18', 'Gene', (21, 26))	('HCC', 'Gene', '619501', (150, 153))	('elevated', 'PosReg', (119, 127))	('HCC', 'Gene', '619501', (99, 102))	('rat', 'Species', '10116', (89, 92))	('HCC', 'Phenotype', 'HP:0001402', (150, 153))	('HCC', 'Phenotype', 'HP:0001402', (99, 102))	('clonal proliferation', 'CPA', (75, 95))	('viability', 'CPA', (61, 70))	('HCC', 'Gene', (99, 102))	('decreased', 'NegReg', (47, 56))
72784	33935756	Consistently, FGF18 expression and secretion are upregulated in a high-RPS15 A-expression HCC tumor microenvironment; FGF18 interacts with FGFR3 and contributes to angiogenesis by inducing the Wnt/beta-catenin signaling pathway in endothelial cells.	('RPS15 A', 'Gene', (71, 78))	('interacts', 'Interaction', (124, 133))	('HCC', 'Phenotype', 'HP:0001402', (90, 93))	('expression', 'MPA', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('inducing', 'PosReg', (180, 188))	('HCC tumor', 'Disease', (90, 99))	('FGFR3', 'Gene', '2261', (139, 144))	('Wnt/beta-catenin signaling pathway', 'Pathway', (193, 227))	('secretion', 'MPA', (35, 44))	('angiogenesis', 'CPA', (164, 176))	('HCC tumor', 'Disease', 'MESH:D006528', (90, 99))	('contributes', 'Reg', (149, 160))	('RPS15 A', 'Gene', '6210', (71, 78))	('FGF18', 'Var', (118, 123))	('FGFR3', 'Gene', (139, 144))
72808	33935756	Abnormal FGF15/19-FGFR4 signaling pathway is an important cause of HCC, which is a complex and strongly heterogeneous type of cancer.	('FGF15/19', 'Gene', '9965', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('HCC', 'Gene', '619501', (67, 70))	('HCC', 'Phenotype', 'HP:0001402', (67, 70))	('cause', 'Reg', (58, 63))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('Abnormal', 'Var', (0, 8))	('HCC', 'Gene', (67, 70))	('FGF15/19', 'Gene', (9, 17))
72812	33935756	In childhood hepatoblastoma, FGF19 gene amplification is not as prevalent as in adult HCC (approximately 5%) but significantly related to the degree of aggressiveness.	('aggressiveness', 'Phenotype', 'HP:0000718', (152, 166))	('hepatoblastoma', 'Disease', (13, 27))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (13, 27))	('HCC', 'Gene', (86, 89))	('related', 'Reg', (127, 134))	('aggressiveness', 'Disease', 'MESH:D001523', (152, 166))	('amplification', 'Var', (40, 53))	('HCC', 'Gene', '619501', (86, 89))	('FGF19', 'Gene', (29, 34))	('hepatoblastoma', 'Disease', 'MESH:D018197', (13, 27))	('aggressiveness', 'Disease', (152, 166))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))
72815	33935756	The above studies proved that high levels of FGF19 contribute to the development of HCC, function as an independent prognostic factor for survival, and may predict early recurrence of HCC after curative hepatectomy.	('HCC', 'Gene', (184, 187))	('HCC', 'Gene', '619501', (84, 87))	('HCC', 'Gene', '619501', (184, 187))	('HCC', 'Phenotype', 'HP:0001402', (84, 87))	('contribute', 'Reg', (51, 61))	('HCC', 'Phenotype', 'HP:0001402', (184, 187))	('predict', 'Reg', (156, 163))	('FGF19', 'Gene', (45, 50))	('rat', 'Species', '10116', (196, 199))	('HCC', 'Gene', (84, 87))	('high levels', 'Var', (30, 41))
72826	33935756	FGF15 overexpression accelerates fibrosis and hepatocarcinogenesis via the upregulation of amphiregulin (AR), TGF-beta, and CTGF.	('fibrosis', 'Disease', 'MESH:D005355', (33, 41))	('CTGF', 'Gene', '1490', (124, 128))	('CTGF', 'Gene', (124, 128))	('overexpression', 'Var', (6, 20))	('TGF-beta', 'Gene', (110, 118))	('amphiregulin', 'Gene', (91, 103))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (46, 66))	('FGF15', 'Gene', (0, 5))	('upregulation', 'PosReg', (75, 87))	('accelerates', 'PosReg', (21, 32))	('hepatocarcinogenesis', 'Disease', (46, 66))	('TGF-beta', 'Gene', '7039', (110, 118))	('AR', 'Gene', '374', (105, 107))	('FGF15', 'Gene', '14170', (0, 5))	('rat', 'Species', '10116', (27, 30))	('fibrosis', 'Disease', (33, 41))	('amphiregulin', 'Gene', '374', (91, 103))
72827	33935756	In a nonalcoholic steatohepatitis (NASH)-HCC mouse model, FGF15/FGFR4 signaling plays a critical role in HCC initiation and development via stimulating EMT and Wnt/beta-catenin signaling.	('signaling', 'Var', (70, 79))	('hepatitis', 'Phenotype', 'HP:0012115', (24, 33))	('stimulating', 'PosReg', (140, 151))	('HCC', 'Gene', '619501', (105, 108))	('HCC', 'Phenotype', 'HP:0001402', (105, 108))	('EMT and', 'CPA', (152, 159))	('HCC', 'Gene', (41, 44))	('steatohepatitis', 'Disease', (18, 33))	('mouse', 'Species', '10090', (45, 50))	('steatohepatitis', 'Disease', 'MESH:D005234', (18, 33))	('FGF15', 'Gene', (58, 63))	('HCC', 'Gene', '619501', (41, 44))	('FGF15', 'Gene', '14170', (58, 63))	('HCC', 'Gene', (105, 108))	('HCC', 'Phenotype', 'HP:0001402', (41, 44))	('alcohol', 'Chemical', 'MESH:D000438', (8, 15))
72830	33935756	Its stimulation either through the amplification or overexpression of FGF15/19 in human HCC cells and tissues and its antitumoral effects by knocking down FGF19, FGFR4, or KLB or by the overexpression of dominant-negative FGFR4 variants in liver cancer cells in vitro and in vivo models have been shown to impact HCC cell proliferation, survival, EMT, migration, invasion, and drug resistance.	('KLB', 'Gene', (172, 175))	('FGFR4', 'Gene', (162, 167))	('HCC', 'Gene', '619501', (88, 91))	('HCC', 'Phenotype', 'HP:0001402', (88, 91))	('FGF15/19', 'Gene', '9965', (70, 78))	('tumor', 'Disease', (122, 127))	('HCC', 'Gene', (88, 91))	('overexpression', 'PosReg', (186, 200))	('drug resistance', 'Phenotype', 'HP:0020174', (377, 392))	('EMT', 'CPA', (347, 350))	('liver cancer', 'Disease', 'MESH:D006528', (240, 252))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('FGF19', 'Gene', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('KLB', 'Gene', '152831', (172, 175))	('rat', 'Species', '10116', (355, 358))	('liver cancer', 'Phenotype', 'HP:0002896', (240, 252))	('liver cancer', 'Disease', (240, 252))	('FGFR4', 'Gene', (222, 227))	('rat', 'Species', '10116', (329, 332))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('survival', 'CPA', (337, 345))	('HCC', 'Gene', '619501', (313, 316))	('drug resistance', 'CPA', (377, 392))	('HCC', 'Phenotype', 'HP:0001402', (313, 316))	('invasion', 'CPA', (363, 371))	('stimulation', 'PosReg', (4, 15))	('migration', 'CPA', (352, 361))	('HCC', 'Gene', (313, 316))	('knocking', 'Var', (141, 149))	('impact', 'Reg', (306, 312))	('variants', 'Var', (228, 236))	('FGF15/19', 'Gene', (70, 78))	('human', 'Species', '9606', (82, 87))
72832	33935756	High levels of FGF19 can be used as an independent prognostic factor for survival and may predict early recurrence of HCC after curative hepatectomy.	('HCC', 'Gene', '619501', (118, 121))	('predict', 'Reg', (90, 97))	('HCC', 'Phenotype', 'HP:0001402', (118, 121))	('High levels', 'Var', (0, 11))	('rat', 'Species', '10116', (130, 133))	('HCC', 'Gene', (118, 121))	('FGF19', 'Gene', (15, 20))
72833	33935756	Meanwhile, targeting FGF19 by shRNA or anti-FGF19 antibody neutralization or FGFR kinase inhibitors, LY2874455, BLU-554, and INCB06207, has been shown to inhibit the clonogenicity and tumorigenicity of FGF19 abnormal HCC.	('HCC', 'Phenotype', 'HP:0001402', (217, 220))	('LY2874455', 'Var', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('LY2874455', 'Chemical', 'MESH:C570663', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('FGF19', 'Gene', (202, 207))	('HCC', 'Gene', (217, 220))	('inhibit', 'NegReg', (154, 161))	('BLU-554', 'Var', (112, 119))	('clonogenicity', 'CPA', (166, 179))	('FGF19', 'Gene', (21, 26))	('tumor', 'Disease', (184, 189))	('BLU-554', 'Chemical', '-', (112, 119))	('INCB06207', 'Var', (125, 134))	('HCC', 'Gene', '619501', (217, 220))
72842	33935756	The loss of FGF21 protein in the liver is associated with hyperproliferation and aberrant p53 and TGF-beta/Smad signaling during the development of HCC.	('aberrant', 'Var', (81, 89))	('rat', 'Species', '10116', (70, 73))	('HCC', 'Phenotype', 'HP:0001402', (148, 151))	('associated', 'Reg', (42, 52))	('TGF-beta', 'Gene', '7039', (98, 106))	('protein', 'Protein', (18, 25))	('hyperproliferation', 'Disease', (58, 76))	('HCC', 'Gene', (148, 151))	('FGF21', 'Gene', (12, 17))	('TGF-beta', 'Gene', (98, 106))	('loss', 'NegReg', (4, 8))	('HCC', 'Gene', '619501', (148, 151))
72858	33935756	Preclinical data have demonstrated that nearly 50% of HCC were directly or indirectly caused by FGF/FGFR abnormality.	('abnormality', 'Var', (105, 116))	('caused by', 'Reg', (86, 95))	('FGF/FGFR', 'Gene', (96, 104))	('HCC', 'Gene', '619501', (54, 57))	('rat', 'Species', '10116', (29, 32))	('HCC', 'Phenotype', 'HP:0001402', (54, 57))	('HCC', 'Gene', (54, 57))
72862	33935756	The liver uniquely possesses a complete FGFR4 activating machinery, including FGFR4, FGF19, and KLB, and the specific structure of FGFR4 could be distinguished from that of other FGFRs.	('FGFR4', 'Var', (131, 136))	('FGFR4', 'Enzyme', (40, 45))	('KLB', 'Gene', (96, 99))	('FGFR4', 'Gene', (78, 83))	('KLB', 'Gene', '152831', (96, 99))
72864	33935756	Two different FGFR4 gene polymorphisms have been associated with increased levels of a-fetoprotein in HCC patients.	('FGFR4', 'Gene', (14, 19))	('increased', 'PosReg', (65, 74))	('HCC', 'Gene', (102, 105))	('associated', 'Reg', (49, 59))	('a-fetoprotein', 'Gene', (85, 98))	('HCC', 'Gene', '619501', (102, 105))	('polymorphisms', 'Var', (25, 38))	('a-fetoprotein', 'Gene', '174', (85, 98))	('patients', 'Species', '9606', (106, 114))	('HCC', 'Phenotype', 'HP:0001402', (102, 105))
72866	33935756	As discussed in the FGF19 section, the abnormality of FGF19-FGFR4-KLB is involved in HCC cell proliferation, survival, EMT, migration, and invasion.	('invasion', 'CPA', (139, 147))	('abnormality', 'Var', (39, 50))	('rat', 'Species', '10116', (101, 104))	('migration', 'CPA', (124, 133))	('KLB', 'Gene', (66, 69))	('HCC', 'Gene', '619501', (85, 88))	('HCC', 'Phenotype', 'HP:0001402', (85, 88))	('KLB', 'Gene', '152831', (66, 69))	('rat', 'Species', '10116', (127, 130))	('involved', 'Reg', (73, 81))	('EMT', 'CPA', (119, 122))	('survival', 'CPA', (109, 117))	('HCC', 'Gene', (85, 88))
72870	33935756	Studies showed that the polymorphisms of FGFR1 are related to HBV-related HCC, but they do not have an independent role in tumorigenesis and progression.	('tumor', 'Disease', (123, 128))	('HCC', 'Gene', '619501', (74, 77))	('polymorphisms', 'Var', (24, 37))	('HCC', 'Phenotype', 'HP:0001402', (74, 77))	('FGFR1', 'Gene', '2260', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('FGFR1', 'Gene', (41, 46))	('related', 'Reg', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('HCC', 'Gene', (74, 77))
72872	33935756	FGFR2 fusion mutations are reported in 13-20% of patients with intrahepatic cholangiocarcinoma.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (63, 94))	('intrahepatic cholangiocarcinoma', 'Disease', (63, 94))	('fusion mutations', 'Var', (6, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('patients', 'Species', '9606', (49, 57))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (76, 94))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))
72875	33935756	In cancers, FGFR3-mediating signals are often activated by manifold mechanisms, such as activating receptor mutations, translocations, altered splicing, upregulation of FGFs and/or FGFR3, and defects in negative feedback loops.	('FGFR3', 'Gene', (12, 17))	('activated', 'PosReg', (46, 55))	('mutations', 'Var', (108, 117))	('splicing', 'MPA', (143, 151))	('upregulation', 'PosReg', (153, 165))	('FGFR3', 'Gene', (181, 186))	('FGFs', 'Gene', (169, 173))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('FGFR3', 'Gene', '2261', (12, 17))	('altered', 'Var', (135, 142))	('translocations', 'Var', (119, 133))	('defects', 'Reg', (192, 199))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('negative', 'Pathway', (203, 211))	('FGFR3', 'Gene', '2261', (181, 186))
72883	33935756	Moreover, for intrahepatic cholangiocarcinoma (ICC), which belong to a type of primary carcinoma of the liver, with FGFR2 gene fusion, sorafenib has a preferable clinical treatment effect.	('carcinoma of the liver', 'Disease', (87, 109))	('gene fusion', 'Var', (122, 133))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (14, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('intrahepatic cholangiocarcinoma', 'Disease', (14, 45))	('sorafenib', 'Chemical', 'MESH:D000077157', (135, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('FGFR2', 'Gene', (116, 121))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (27, 45))	('FGFR2', 'Gene', '2263', (116, 121))	('carcinoma of the liver', 'Disease', 'MESH:D008113', (87, 109))
72886	33935756	According to the latest 2020 National Comprehensive Cancer Network (NCCN) guidelines (United States), if FGFR2 gene fusion or rearrangement is clinically detected in cholangiocarcinoma, the targeted drug pemigatinib can be used for treatment, and there is a favorable response.	('pemigatinib', 'Chemical', '-', (204, 215))	('rearrangement', 'Var', (126, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (166, 184))	('cholangiocarcinoma', 'Disease', (166, 184))	('Cancer', 'Disease', (52, 58))	('Cancer', 'Disease', 'MESH:D009369', (52, 58))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (166, 184))	('gene fusion', 'Var', (111, 122))	('FGFR2', 'Gene', (105, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('detected', 'Reg', (154, 162))	('FGFR2', 'Gene', '2263', (105, 110))
72888	33935756	The highly selective FGFR4 inhibitors, such as H3B-6527, can significantly inhibit HCC cell proliferation and benefit patients with mutations in the FGF19 signaling pathway.	('FGFR4', 'Gene', (21, 26))	('HCC', 'Phenotype', 'HP:0001402', (83, 86))	('inhibit', 'NegReg', (75, 82))	('benefit', 'PosReg', (110, 117))	('mutations', 'Var', (132, 141))	('rat', 'Species', '10116', (99, 102))	('HCC', 'Gene', (83, 86))	('FGF19', 'Gene', (149, 154))	('patients', 'Species', '9606', (118, 126))	('HCC', 'Gene', '619501', (83, 86))
72889	33935756	Moreover, FGF/FGFR gene mutation, amplification or gene fusion will cause the continuous activation of FGFR and promote the progression of many tumors.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('progression', 'CPA', (124, 135))	('promote', 'PosReg', (112, 119))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('gene fusion', 'Var', (51, 62))	('activation', 'PosReg', (89, 99))	('mutation', 'Var', (24, 32))	('FGFR', 'Protein', (103, 107))	('amplification', 'Var', (34, 47))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('FGF/FGFR', 'Gene', (10, 18))
72890	33935756	FGFR1-3 gene mutations can be detected in 11% of intrahepatic cholangiocarcinoma (ICC), FGFR2 gene fusion was detected in 11-45% of cholangiocarcinoma (CCA), and the common fusion forms mainly include FGFR2-ZMYM4, FGFR2-BICC1 fusion, etc.	('ZMYM4', 'Gene', '9202', (207, 212))	('cholangiocarcinoma', 'Disease', (132, 150))	('BICC1', 'Gene', (220, 225))	('CCA', 'Phenotype', 'HP:0030153', (152, 155))	('detected', 'Reg', (30, 38))	('FGFR1-3', 'Gene', '2260;2263;2261', (0, 7))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (132, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('FGFR2', 'Gene', (88, 93))	('FGFR2', 'Gene', (201, 206))	('FGFR1-3', 'Gene', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (49, 80))	('FGFR2', 'Gene', (214, 219))	('intrahepatic cholangiocarcinoma', 'Disease', (49, 80))	('FGFR2', 'Gene', '2263', (201, 206))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (62, 80))	('FGFR2', 'Gene', '2263', (88, 93))	('mutations', 'Var', (13, 22))	('detected', 'Reg', (110, 118))	('cholangiocarcinoma', 'Disease', (62, 80))	('FGFR2', 'Gene', '2263', (214, 219))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (62, 80))	('ZMYM4', 'Gene', (207, 212))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (132, 150))	('BICC1', 'Gene', '80114', (220, 225))
72893	33935756	As shown in Table 1, there are several clinical trials of FGF/FGFR inhibitors are in progress, such as multikinase inhibitors anlotinib, regorafenib and nintedanib, pan-FGFR inhibitors erdafitinib, futibatinib, AZD4547, LY2874455.	('regorafenib', 'Chemical', 'MESH:C559147', (137, 148))	('nintedanib', 'Chemical', 'MESH:C530716', (153, 163))	('AZD4547', 'Var', (211, 218))	('erdafitinib', 'Chemical', 'MESH:C000604580', (185, 196))	('futibatinib', 'Chemical', '-', (198, 209))	('LY2874455', 'Var', (220, 229))	('anlotinib', 'Chemical', 'MESH:C000625192', (126, 135))	('AZD4547', 'Chemical', 'MESH:C572463', (211, 218))	('LY2874455', 'Chemical', 'MESH:C570663', (220, 229))
72903	30142840	Negative resection margin, lymph node involvement, poor or moderate differentiation grade was identified as the negative predictor factors of resectable pCCA.	('poor', 'Var', (51, 55))	('lymph node', 'CPA', (27, 37))	('men', 'Species', '9606', (45, 48))
72968	27364974	It was observed that inhibiting TGFbeta1 activity with short hairpin RNA (shRNA) or pharmaceutical agents suppressed CCA development and growth, whereas overexpression of TGFbeta1 enhanced CCA tumor size and promoted intrahepatic metastasis in a rat model.	('inhibiting', 'Var', (21, 31))	('promoted', 'PosReg', (208, 216))	('TGFbeta1', 'Gene', (32, 40))	('rat', 'Species', '10116', (246, 249))	('activity', 'MPA', (41, 49))	('intrahepatic metastasis', 'Disease', (217, 240))	('CCA tumor', 'Disease', (189, 198))	('CCA tumor', 'Disease', 'MESH:C536211', (189, 198))	('CCA', 'Phenotype', 'HP:0030153', (189, 192))	('TGFbeta1', 'Gene', (171, 179))	('suppressed', 'NegReg', (106, 116))	('intrahepatic metastasis', 'Disease', 'MESH:D009362', (217, 240))	('CCA', 'Phenotype', 'HP:0030153', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('enhanced', 'PosReg', (180, 188))	('growth', 'CPA', (137, 143))	('CCA', 'Disease', (117, 120))
72972	27364974	Overexpression of TGFbeta1 was associated with CCA tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('CCA', 'Phenotype', 'HP:0030153', (47, 50))	('CCA tumor', 'Disease', (47, 56))	('associated', 'Reg', (31, 41))	('Overexpression', 'Var', (0, 14))	('TGFbeta1', 'Gene', (18, 26))	('CCA tumor', 'Disease', 'MESH:C536211', (47, 56))
72983	27364974	In this regard, recent studies have demonstrated anti-tumor effects of targeting TGFbeta1 in breast, hepatocellular (HCC), and other carcinomas.	('carcinomas', 'Disease', (133, 143))	('targeting', 'Var', (71, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('rat', 'Species', '10116', (43, 46))	('TGFbeta1', 'Gene', (81, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('breast', 'Disease', (93, 99))	('hepatocellular', 'Disease', (101, 115))	('tumor', 'Disease', (54, 59))	('carcinomas', 'Disease', 'MESH:D002277', (133, 143))
72984	27364974	Based on the previous observations that cirrhosis is one of the major risk factors for HCC development and progression and that inhibiting TGFbeta1 reveals improvement by reducing tumor growth, we hypothesized that TGFbeta1 signaling may contribute to CCA progression.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('contribute', 'Reg', (238, 248))	('reducing', 'NegReg', (171, 179))	('cirrhosis', 'Phenotype', 'HP:0001394', (40, 49))	('TGFbeta1', 'Gene', (139, 147))	('CCA', 'Disease', (252, 255))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('inhibiting', 'Var', (128, 138))	('cirrhosis', 'Disease', 'MESH:D005355', (40, 49))	('tumor', 'Disease', (180, 185))	('improvement', 'PosReg', (156, 167))	('CCA', 'Phenotype', 'HP:0030153', (252, 255))	('cirrhosis', 'Disease', (40, 49))	('HCC', 'Disease', (87, 90))
72993	27364974	In order to determine whether TGFbeta1 promotes this process in biliary epithelial cells, we overexpressed TGFbeta1 in the rat bile duct epithelial cell line which stably overexpresses HER2/Neu oncogene (BDE-Neu) via the lentiviral system and measured subsequent colony number and size in vitro.	('Neu', 'Gene', (190, 193))	('Neu', 'Gene', (208, 211))	('HER2', 'Gene', '2064', (185, 189))	('BDE', 'Gene', (204, 207))	('overexpresses', 'PosReg', (171, 184))	('Neu', 'Gene', '2064', (208, 211))	('overexpressed', 'Var', (93, 106))	('Neu', 'Gene', '2064', (190, 193))	('rat', 'Species', '10116', (123, 126))	('colony number', 'CPA', (263, 276))	('HER2', 'Gene', (185, 189))	('TGFbeta1', 'Gene', (107, 115))	('BDE', 'Gene', '3239', (204, 207))
72995	27364974	It was observed that TGFbeta1 expression significantly enhanced, by 2.5-fold, colony formation in BDE-Neu cells (Fig.	('Neu', 'Gene', (102, 105))	('enhanced', 'PosReg', (55, 63))	('BDE', 'Gene', (98, 101))	('expression', 'Var', (30, 40))	('BDE', 'Gene', '3239', (98, 101))	('Neu', 'Gene', '2064', (102, 105))	('TGFbeta1', 'Gene', (21, 29))
72998	27364974	Inhibition of TGFbeta1 with pharmacological compounds, such as, LY2157299 and SB431542 were found to substantially suppress colony formation in human H1 CCA cells (Fig.	('LY2157299', 'Var', (64, 73))	('LY2157299', 'Chemical', 'MESH:C557799', (64, 73))	('human', 'Species', '9606', (144, 149))	('Inhibition', 'NegReg', (0, 10))	('suppress', 'NegReg', (115, 123))	('SB431542', 'Chemical', 'MESH:C459179', (78, 86))	('SB431542', 'Var', (78, 86))	('H1', 'CellLine', 'CVCL:Z499', (150, 152))	('CCA', 'Phenotype', 'HP:0030153', (153, 156))	('TGFbeta1', 'Gene', (14, 22))	('colony formation', 'CPA', (124, 140))
73002	27364974	In addition, several studies have subsequently demonstrated that targeting TGFbeta1 inhibits tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('TGFbeta1', 'Gene', (75, 83))	('tumor', 'Disease', (93, 98))	('rat', 'Species', '10116', (54, 57))	('targeting', 'Var', (65, 74))	('inhibits', 'NegReg', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
73003	27364974	Targeting TGFbeta1 signaling with pharmacological compounds, such as LY2157299 and SB431542, had a consistent suppressive effect on the growth of RBE and SSP25 cell lines (Fig.	('suppressive', 'NegReg', (110, 121))	('LY2157299', 'Chemical', 'MESH:C557799', (69, 78))	('LY2157299', 'Var', (69, 78))	('growth', 'CPA', (136, 142))	('SB431542', 'Var', (83, 91))	('TGFbeta1 signaling', 'Gene', (10, 28))	('SB431542', 'Chemical', 'MESH:C459179', (83, 91))
73006	27364974	Consistent with previous observations, "knockdown" of TGFbeta1 substantially suppressed cell migration of the human CCA cell lines, RBE and SSP25 (Fig.	('suppressed', 'NegReg', (77, 87))	('TGFbeta1', 'Gene', (54, 62))	('CCA', 'Phenotype', 'HP:0030153', (116, 119))	('knockdown', 'Var', (40, 49))	('human', 'Species', '9606', (110, 115))	('rat', 'Species', '10116', (96, 99))	('cell migration of', 'CPA', (88, 105))
73007	27364974	Consistent with shRNA results, the two pharmacological TGFbeta1 inhibitors reduced CCA cell migration as well but to a lesser degree (Fig.	('CCA', 'Disease', (83, 86))	('rat', 'Species', '10116', (95, 98))	('inhibitors', 'Var', (64, 74))	('reduced', 'NegReg', (75, 82))	('CCA', 'Phenotype', 'HP:0030153', (83, 86))	('TGFbeta1', 'Gene', (55, 63))
73012	27364974	These findings raise the possibility that targeting TGFbeta1 may restrict CCA progression through modulating miR-34a-associated downstream signaling pathways.	('restrict', 'NegReg', (65, 73))	('miR-34a', 'Gene', '407040', (109, 116))	('CCA', 'Disease', (74, 77))	('miR-34a', 'Gene', (109, 116))	('targeting', 'Var', (42, 51))	('modulating', 'Reg', (98, 108))	('CCA', 'Phenotype', 'HP:0030153', (74, 77))	('TGFbeta1', 'Gene', (52, 60))
73015	27364974	To determine whether "knockdown" of TGFbeta1 would inhibit expression and function of these two miR-34a target genes, expression levels were measured in both RBE and SSP25 CCA cells.	('CCA', 'Phenotype', 'HP:0030153', (172, 175))	('knockdown', 'Var', (22, 31))	('expression', 'MPA', (59, 69))	('miR-34a', 'Gene', '407040', (96, 103))	('inhibit', 'NegReg', (51, 58))	('function', 'MPA', (74, 82))	('TGFbeta1', 'Gene', (36, 44))	('miR-34a', 'Gene', (96, 103))
73042	27364974	In this context, expression of TGFbeta1 is highly associated with the development of progressive fibrosis leading to cirrhosis, However, it has been controversial regarding the role of TGFbeta1 expression in tumor development and growth.	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('cirrhosis', 'Disease', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('TGFbeta1', 'Gene', (31, 39))	('fibrosis', 'Disease', (97, 105))	('tumor', 'Disease', (208, 213))	('expression', 'Var', (17, 27))	('fibrosis', 'Disease', 'MESH:D005355', (97, 105))	('cirrhosis', 'Phenotype', 'HP:0001394', (117, 126))	('associated', 'Reg', (50, 60))	('cirrhosis', 'Disease', 'MESH:D005355', (117, 126))
73045	27364974	Thus, targeting TGFbeta1 was predicted to enhance the effectiveness of chemotherapy in breast cancer, for example.	('enhance', 'PosReg', (42, 49))	('TGFbeta1', 'Gene', (16, 24))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('chemotherapy', 'CPA', (71, 83))	('targeting', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))
73049	27364974	Another TGFbeta1 receptor inhibitor, LY-2157299 has completed phase II and has entered phase III clinical trials for several types of tumors and suggest that TGFbeta1 may be a viable oncogenic target.	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Disease', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('LY-2157299', 'Var', (37, 47))	('TGFbeta1', 'Gene', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('LY-2157299', 'Chemical', 'MESH:C557799', (37, 47))
73052	27364974	Previous findings indicate that TGFbeta1 promotes p21 but suppresses cyclin D1 expression, likewise, we also observed that inhibition of TGFbeta1 promotes p21 but inhibits cyclin D1 expression.	('expression', 'MPA', (182, 192))	('TGFbeta1', 'Gene', (137, 145))	('inhibition', 'Var', (123, 133))	('p21', 'Gene', (155, 158))	('cyclin D1', 'Gene', (172, 181))	('p21', 'Gene', '1026', (50, 53))	('promotes', 'PosReg', (41, 49))	('inhibits', 'NegReg', (163, 171))	('cyclin D1', 'Gene', '595', (69, 78))	('suppresses', 'NegReg', (58, 68))	('p21', 'Gene', (50, 53))	('promotes', 'PosReg', (146, 154))	('cyclin D1', 'Gene', '595', (172, 181))	('cyclin D1', 'Gene', (69, 78))	('p21', 'Gene', '1026', (155, 158))
73056	27364974	However, our findings with shTGFbeta1 are compatible with another investigation that suggests TGFbeta1 may transcriptionally regulate the expression of miR-34a which has a tumor suppressor function which implies that shTGFbeta1 may promote miR-34a expression through transcriptional regulation and thus inhibit tumor progression by that proposed mechanism.	('promote', 'PosReg', (232, 239))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('miR-34a', 'Gene', '407040', (152, 159))	('shTGFbeta1', 'Var', (217, 227))	('miR-34a', 'Gene', (240, 247))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('miR-34a', 'Gene', (152, 159))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('expression', 'MPA', (248, 258))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('transcriptional', 'MPA', (267, 282))	('miR-34a', 'Gene', '407040', (240, 247))	('tumor', 'Disease', (311, 316))	('inhibit', 'NegReg', (303, 310))
73057	27364974	In addition, targeting or inhibiting TGFbeta1 mediated signaling may suppress this phenotype and alter tumor progression through miR-34a expression (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('expression', 'MPA', (137, 147))	('inhibiting', 'NegReg', (26, 36))	('TGFbeta1', 'Gene', (37, 45))	('tumor', 'Disease', (103, 108))	('miR-34a', 'Gene', '407040', (129, 136))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('targeting', 'Var', (13, 22))	('miR-34a', 'Gene', (129, 136))	('alter', 'Reg', (97, 102))	('suppress', 'NegReg', (69, 77))
73059	27364974	Although there is uncertainty whether TGFbeta1 promotes CCA oncogenesis, it has been previously demonstrated that inhibiting the kinase activity mediated by TGFbeta1 type II receptor (TGFbetaR2) activation promotes hepatocellular carcinogenesis.	('TGFbeta', 'Gene', (184, 191))	('rat', 'Species', '10116', (103, 106))	('TGFbeta', 'Gene', (157, 164))	('promotes', 'PosReg', (206, 214))	('TGFbeta', 'Gene', '7040;59086', (184, 191))	('inhibiting', 'Var', (114, 124))	('CCA', 'Phenotype', 'HP:0030153', (56, 59))	('kinase activity', 'MPA', (129, 144))	('hepatocellular carcinogenesis', 'Disease', 'MESH:D063646', (215, 244))	('TGFbeta', 'Gene', (38, 45))	('hepatocellular carcinogenesis', 'Disease', (215, 244))	('TGFbeta', 'Gene', '7040;59086', (157, 164))	('TGFbeta', 'Gene', '7040;59086', (38, 45))
73061	27364974	Although there is one study demonstrating that a stromal specific knockout of TGFbetaR2 enhances prostatic oncogenesis, the protein expression results indicate a robust increase of nuclear staining of phosphorylated Smad2 in epithelial cells.	('knockout', 'Var', (66, 74))	('TGFbeta', 'Gene', (78, 85))	('enhances', 'PosReg', (88, 96))	('nuclear staining', 'MPA', (181, 197))	('prostatic', 'Disease', (97, 106))	('Smad2', 'Gene', '4087', (216, 221))	('increase', 'PosReg', (169, 177))	('Smad2', 'Gene', (216, 221))	('TGFbeta', 'Gene', '7040;59086', (78, 85))	('rat', 'Species', '10116', (35, 38))
73067	27364974	Therefore, inhibiting TGFbeta1 signaling could suppress tumor progression and serve as a novel therapeutic target in CCA.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('inhibiting', 'Var', (11, 21))	('TGFbeta1', 'Protein', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('suppress', 'NegReg', (47, 55))	('CCA', 'Phenotype', 'HP:0030153', (117, 120))	('CCA', 'Disease', (117, 120))
73385	30062070	Percutaneous biopsy was done, consistent with moderately differentiated intrahepatic cholangiocarcinoma, which was CK19+, MOC31+, CA19-9+, CK7+, and CK20 negative.	('MOC31+', 'Var', (122, 128))	('CK19', 'Gene', (115, 119))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 103))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('intrahepatic cholangiocarcinoma', 'Disease', (72, 103))	('CK20', 'Gene', (149, 153))	('CK20', 'Gene', '54474', (149, 153))	('CK19', 'Gene', '3880', (115, 119))
73464	28938668	16 studies were identified to examine the effect of cholecystectomy on the risk of cholangiocarcinoma and found that the risk of cholangiocarcinoma was significantly higher in 220,376 patients with cholecystectomy compared with 562,392 healthy populations (OR = 0.72; 95% CI = 0.55-0.90), with significant heterogeneity among studies.	('higher', 'PosReg', (166, 172))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (129, 147))	('patients', 'Species', '9606', (184, 192))	('cholangiocarcinoma', 'Disease', (83, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (129, 147))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('cholecystectomy', 'Var', (198, 213))	('cholangiocarcinoma', 'Disease', (129, 147))
73493	27833076	Knock-down miR-26a could induce an increasing population of SP cells by promoting KRT19 expression.	('SP cells', 'CPA', (60, 68))	('promoting', 'PosReg', (72, 81))	('Knock-down', 'Var', (0, 10))	('expression', 'MPA', (88, 98))	('miR-26a', 'Gene', (11, 18))	('SP', 'Chemical', '-', (60, 62))	('KRT19', 'Gene', (82, 87))	('KRT19', 'Gene', '3880', (82, 87))
73497	27833076	Aberrant decreased miR-26a could promote cell proliferation by regulating KRT19 which play important roles in the pathogenesis of CCA.	('CCA', 'Phenotype', 'HP:0030153', (130, 133))	('promote', 'PosReg', (33, 40))	('Aberrant', 'Var', (0, 8))	('cell proliferation', 'CPA', (41, 59))	('KRT19', 'Gene', '3880', (74, 79))	('decreased', 'NegReg', (9, 18))	('KRT19', 'Gene', (74, 79))	('CCA', 'Disease', (130, 133))	('regulating', 'Reg', (63, 73))	('miR-26a', 'Gene', (19, 26))
73500	27833076	It has been identified that the existence of KRT19 was linked with a poor prognosis for patients diagnosed with CCA.	('CCA', 'Phenotype', 'HP:0030153', (112, 115))	('patients', 'Species', '9606', (88, 96))	('existence', 'Var', (32, 41))	('KRT19', 'Gene', (45, 50))	('KRT19', 'Gene', '3880', (45, 50))	('CCA', 'Disease', (112, 115))
73502	27833076	MiRNAs could act as either oncogene or tumor suppressor gene by regulating cell proliferation, migration, apoptosis and differentiation through a post-transcription level regulation.	('differentiation', 'CPA', (120, 135))	('MiRNAs', 'Var', (0, 6))	('regulating', 'Reg', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('apoptosis', 'CPA', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('migration', 'CPA', (95, 104))	('cell proliferation', 'CPA', (75, 93))
73504	27833076	In this study, we searched the database including miRbase, Target Scan, PicTar and miRNA Target to found the candidate miRNAs which might associate with KRT19.	('KRT19', 'Gene', (153, 158))	('miRNAs', 'Var', (119, 125))	('associate', 'Reg', (138, 147))	('KRT19', 'Gene', '3880', (153, 158))
73509	27833076	Among the six candidates, we found that miR-26a was remarkable decreased in the tumors tissues of CCA patients comparing with the corresponding adjacent (Figure 1B); the rest remains no difference between the two groups (data not shown).	('CCA', 'Phenotype', 'HP:0030153', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('decreased', 'NegReg', (63, 72))	('patients', 'Species', '9606', (102, 110))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('CCA', 'Disease', (98, 101))	('miR-26a', 'Var', (40, 47))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))
73526	27833076	We considered that if miR-26a was associated with KRT19, the SP distribution might be also altered by the dysregulation of miR-26a.	('KRT19', 'Gene', '3880', (50, 55))	('miR-26a', 'Gene', (123, 130))	('dysregulation', 'Var', (106, 119))	('altered', 'Reg', (91, 98))	('SP', 'Chemical', '-', (61, 63))	('SP distribution', 'MPA', (61, 76))	('KRT19', 'Gene', (50, 55))
73534	27833076	Since miR-26a could suppress the cell proliferation and SP population in CCA cell lines, the detailed mechanism still remains unclear.	('miR-26a', 'Var', (6, 13))	('SP', 'Chemical', '-', (56, 58))	('CCA', 'Phenotype', 'HP:0030153', (73, 76))	('suppress', 'NegReg', (20, 28))	('CCA', 'Disease', (73, 76))
73541	27833076	We also found that treating with miR-26a might suppress CCA tumor growth in xenografts, suggesting a therapeutic potential for CCA patients in the future.	('patients', 'Species', '9606', (131, 139))	('CCA', 'Phenotype', 'HP:0030153', (127, 130))	('CCA', 'Disease', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('suppress', 'NegReg', (47, 55))	('CCA', 'Phenotype', 'HP:0030153', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('miR-26a', 'Var', (33, 40))	('tumor', 'Disease', (60, 65))
73542	27833076	Most importantly, we provided evidence that the miR-26a might suppress the tumor growth via decreasing the side population cell percentage resulting in the inhibition of stem-like cells in CCA.	('suppress', 'NegReg', (62, 70))	('inhibition', 'NegReg', (156, 166))	('decreasing', 'NegReg', (92, 102))	('CCA', 'Phenotype', 'HP:0030153', (189, 192))	('miR-26a', 'Var', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('side population cell percentage', 'CPA', (107, 138))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('CCA', 'Disease', (189, 192))	('tumor', 'Disease', (75, 80))
73554	27833076	The absence of KRT19 could reduce the growth and metastasis of HCC in vivo through a "stemness" function.	('reduce', 'NegReg', (27, 33))	('absence', 'Var', (4, 11))	('HCC', 'Disease', (63, 66))	('KRT19', 'Gene', (15, 20))	('HCC', 'Phenotype', 'HP:0001402', (63, 66))	('KRT19', 'Gene', '3880', (15, 20))
73556	27833076	The aberrant expression level of miR-26a in CCA patients was high associated with tumor growth.	('aberrant', 'Var', (4, 12))	('associated', 'Reg', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('CCA', 'Disease', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('expression level', 'MPA', (13, 29))	('tumor', 'Disease', (82, 87))	('patients', 'Species', '9606', (48, 56))	('miR-26a', 'Gene', (33, 40))	('CCA', 'Phenotype', 'HP:0030153', (44, 47))
73660	26421036	Considering that recently a single PTBD with or without ENBD for a few weeks has often been used for biliary decompression for patients with perihilar cholangiocarcinoma, the actual risk of tumor metastasis associated with PTBD may be lower than previously reported.	('cholangiocarcinoma', 'Disease', (151, 169))	('biliary', 'Disease', (101, 108))	('PTBD', 'Var', (223, 227))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('patients', 'Species', '9606', (127, 135))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (151, 169))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (151, 169))	('tumor metastasis', 'Disease', 'MESH:D009362', (190, 206))	('tumor metastasis', 'Disease', (190, 206))
73722	25032731	In a multivariate analysis of 68 patients who received AGC, high hENT1 (P=0.044) and low RRM1 expression (P=0.009) were independently associated with prolonged disease-free survival (DFS), whereas low RRM1 expression (P=0.024) was independently associated with prolonged overall survival (OS).	('RRM1', 'Gene', '6240', (89, 93))	('prolonged', 'PosReg', (150, 159))	('patients', 'Species', '9606', (33, 41))	('RRM1', 'Gene', (89, 93))	('high', 'Var', (60, 64))	('hENT1', 'Gene', '2030', (65, 70))	('low', 'Var', (85, 88))	('RRM1', 'Gene', '6240', (201, 205))	('RRM1', 'Gene', (201, 205))	('hENT1', 'Gene', (65, 70))	('AGC', 'Chemical', '-', (55, 58))	('disease-free survival', 'CPA', (160, 181))
73723	25032731	Moreover, concurrent high hENT1 and low RRM1 expression was a powerful independent predictor of prolonged DFS (P<0.001) and OS (P=0.001) when the combined classification of hENT1 and RRM1 was introduced.	('hENT1', 'Gene', (173, 178))	('low', 'NegReg', (36, 39))	('hENT1', 'Gene', (26, 31))	('RRM1', 'Gene', '6240', (183, 187))	('high', 'Var', (21, 25))	('prolonged DFS', 'Disease', (96, 109))	('expression', 'MPA', (45, 55))	('RRM1', 'Gene', (183, 187))	('RRM1', 'Gene', '6240', (40, 44))	('RRM1', 'Gene', (40, 44))	('hENT1', 'Gene', '2030', (173, 178))	('hENT1', 'Gene', '2030', (26, 31))
73804	25032731	On the basis of these findings, we believe that AGC can provide a survival benefit for patients with resectable cholangiocarcinoma, and identification of biomarkers that could predict the clinical outcome of AGC may contribute to further optimisation of adjuvant chemotherapy for cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (280, 298))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (280, 298))	('AGC', 'Chemical', '-', (208, 211))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 130))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('AGC', 'Var', (48, 51))	('benefit', 'PosReg', (75, 82))	('survival', 'CPA', (66, 74))	('AGC', 'Chemical', '-', (48, 51))	('cholangiocarcinoma', 'Disease', (112, 130))	('cholangiocarcinoma', 'Disease', (280, 298))	('patients', 'Species', '9606', (87, 95))
73817	25032731	The analysis by of data from 12 patients with recurrent biliary carcinoma treated with gemcitabine alone found a trend towards a better response rate in patients with low RRM1 expression compared with those with high RRM1 expression.	('RRM1', 'Gene', (171, 175))	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (153, 161))	('RRM1', 'Gene', '6240', (217, 221))	('RRM1', 'Gene', (217, 221))	('biliary carcinoma', 'Disease', (56, 73))	('gemcitabine', 'Chemical', 'MESH:C056507', (87, 98))	('expression', 'MPA', (176, 186))	('low', 'Var', (167, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('biliary carcinoma', 'Disease', 'MESH:D001661', (56, 73))	('RRM1', 'Gene', '6240', (171, 175))
73820	25032731	The current study revealed that high RRM1 expression was independently associated with poor DFS and OS in patients treated with AGC, but not in those who did not receive AGC.	('high', 'Var', (32, 36))	('AGC', 'Chemical', '-', (170, 173))	('DFS', 'MPA', (92, 95))	('AGC', 'Var', (128, 131))	('poor', 'Disease', (87, 91))	('expression', 'MPA', (42, 52))	('AGC', 'Chemical', '-', (128, 131))	('patients', 'Species', '9606', (106, 114))	('RRM1', 'Gene', '6240', (37, 41))	('RRM1', 'Gene', (37, 41))
73822	25032731	On the other hand, some basic studies have demonstrated that increased expression of RRM1 decreases the formation of metastasis and inhibits the development of carcinogen-induced lung tumours.	('RRM1', 'Gene', (85, 89))	('expression', 'Var', (71, 81))	('decreases', 'NegReg', (90, 99))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('lung tumours', 'Disease', (179, 191))	('inhibits', 'NegReg', (132, 140))	('increased', 'PosReg', (61, 70))	('formation of metastasis', 'CPA', (104, 127))	('lung tumours', 'Disease', 'MESH:D008175', (179, 191))	('tumours', 'Phenotype', 'HP:0002664', (184, 191))	('RRM1', 'Gene', '6240', (85, 89))
73823	25032731	Indeed, a significant correlation between high RRM1 expression and improved outcomes has been reported in a few studies of lung cancer in patients who underwent surgery alone.	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('expression', 'MPA', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('high', 'Var', (42, 46))	('improved', 'PosReg', (67, 75))	('RRM1', 'Gene', '6240', (47, 51))	('outcomes', 'MPA', (76, 84))	('patients', 'Species', '9606', (138, 146))	('RRM1', 'Gene', (47, 51))
73829	25032731	The current results demonstrated that patients with high hENT1 and low RRM1 experienced longer DFS and OS compared with the other three groups.	('low', 'Var', (67, 70))	('hENT1', 'Gene', (57, 62))	('DFS', 'CPA', (95, 98))	('patients', 'Species', '9606', (38, 46))	('RRM1', 'Gene', '6240', (71, 75))	('longer', 'PosReg', (88, 94))	('RRM1', 'Gene', (71, 75))	('hENT1', 'Gene', '2030', (57, 62))
73831	25032731	On the basis of these findings, the combined hENT1 and RRM1 classification enabled us to increase the predictive value of these targets for prognosis in cholangiocarcinoma patients treated with AGC compared with either factor alone and may contribute to the optimisation of adjuvant chemotherapy for resected cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (153, 171))	('cholangiocarcinoma', 'Disease', (309, 327))	('predictive', 'MPA', (102, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('AGC', 'Chemical', '-', (194, 197))	('RRM1', 'Gene', '6240', (55, 59))	('RRM1', 'Gene', (55, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (318, 327))	('cholangiocarcinoma', 'Disease', (153, 171))	('hENT1', 'Gene', '2030', (45, 50))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (309, 327))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (309, 327))	('AGC', 'Var', (194, 197))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (153, 171))	('patients', 'Species', '9606', (172, 180))	('hENT1', 'Gene', (45, 50))	('increase', 'PosReg', (89, 97))
73894	24319501	In addition, according to the fifth edition of the General Rules for Biliary Tract Cancer by the Japanese Society of Biliary Surgery, the tumor was described as Bcrism, nodular-infiltrating type, 2.2 cm, moderate- to well-differentiated adenocarcinoma (tub2 > tub1), pat, sci, infB, ly1, v0, pn0, hinf1, ginf0, panc0, du0, hm1, dm1, em1, pv0, a0, n2 (12c 1/1, 12p 1/8), pT4 pN2 M0 fStage IVb, final curability B.	('Biliary Tract Cancer', 'Disease', 'MESH:D001661', (69, 89))	('dm1', 'Gene', (328, 331))	('tumor', 'Disease', (138, 143))	('hm1', 'Gene', '11066', (323, 326))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('Biliary Tract Cancer', 'Phenotype', 'HP:0100574', (69, 89))	('adenocarcinoma', 'Disease', (237, 251))	('adenocarcinoma', 'Disease', 'MESH:D000230', (237, 251))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Biliary Tract Cancer', 'Disease', (69, 89))	('hm1', 'Gene', (323, 326))	('dm1', 'Gene', '28509', (328, 331))	('pT4 pN2 M0', 'Var', (370, 380))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
73942	32174795	Here, we found that expression of cyclin-dependent kinase 7 (CDK7) was significantly associated with higher tumor grade and worse prognosis in 96 ICC specimens.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('ICC', 'Disease', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('ICC', 'Disease', 'MESH:C535533', (146, 149))	('expression', 'Var', (20, 30))	('tumor', 'Disease', (108, 113))	('cyclin-dependent kinase 7', 'Gene', (34, 59))	('CDK7', 'Gene', (61, 65))	('cyclin-dependent kinase 7', 'Gene', '1022', (34, 59))	('associated', 'Reg', (85, 95))
73943	32174795	Depletion of CDK7 significantly inhibited cell growth, induced a G2/M cell cycle arrest, and reduced the migratory and invasive potential in ICC cells.	('ICC', 'Disease', (141, 144))	('cell growth', 'CPA', (42, 53))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (70, 87))	('ICC', 'Disease', 'MESH:C535533', (141, 144))	('G2/M cell cycle arrest', 'CPA', (65, 87))	('inhibited', 'NegReg', (32, 41))	('reduced', 'NegReg', (93, 100))	('Depletion', 'Var', (0, 9))	('CDK7', 'Gene', (13, 17))	('induced', 'Reg', (55, 62))
73956	32174795	Inhibition of CDK7 activity was shown to impair transcription and cell cycle progression, and suppress tumor growth, suggesting that CDK7 could serve as a therapeutic target in ICC.	('CDK7', 'Protein', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('ICC', 'Disease', (177, 180))	('impair', 'NegReg', (41, 47))	('tumor', 'Disease', (103, 108))	('suppress', 'NegReg', (94, 102))	('ICC', 'Disease', 'MESH:C535533', (177, 180))	('activity', 'MPA', (19, 27))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
73978	32174795	The cells were treated with THZ1 or CDK7 siRNA for 48 h, then harvested, rinsed with phosphate-buffered saline (PBS) at 4  C, and fixed with 70% ice-cold ethanol for 30 minutes on ice.	('phosphate-buffered saline', 'Chemical', '-', (85, 110))	('CDK7 siRNA', 'Var', (36, 46))	('PBS', 'Chemical', '-', (112, 115))	('ethanol', 'Chemical', 'MESH:D000431', (154, 161))	('THZ1', 'Chemical', '-', (28, 32))	('THZ1', 'Var', (28, 32))
73995	32174795	Kaplan-Meier survival analysis demonstrated that, when using the median CDK7 IHC score as cut-off point for stratification, high CDK7 expression was strongly correlated with reduced DFS (P=0.0449) (Figure 1D) and OS (P=0.0128) (Figure 1E) in ICC.	('OS', 'Chemical', '-', (213, 215))	('expression', 'MPA', (134, 144))	('ICC', 'Disease', (242, 245))	('DFS', 'MPA', (182, 185))	('ICC', 'Disease', 'MESH:C535533', (242, 245))	('CDK7', 'Gene', (129, 133))	('reduced', 'NegReg', (174, 181))	('high', 'Var', (124, 128))
73998	32174795	Subsequently, we performed the sphere formation assay to investigate the effect of CDK7 knockdown on the tumorigenicity of RBE and SSP-25 cells.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('knockdown', 'Var', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('CDK7', 'Gene', (83, 87))
74000	32174795	These data suggest that CDK7 knockdown suppresses ICC cell proliferation via induction of cell cycle arrest.	('suppresses', 'NegReg', (39, 49))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (90, 107))	('knockdown', 'Var', (29, 38))	('ICC', 'Disease', (50, 53))	('cell cycle arrest', 'CPA', (90, 107))	('ICC', 'Disease', 'MESH:C535533', (50, 53))	('CDK7', 'Gene', (24, 28))
74002	32174795	Here, we found that THZ1 also reduced cell viability in the two ICC cell lines (IC50=92.17 nM and 148.8 nM in RBE and SSP-25 cells, respectively) (Figure 4A).	('cell viability', 'CPA', (38, 52))	('ICC', 'Disease', (64, 67))	('THZ1', 'Chemical', '-', (20, 24))	('reduced', 'NegReg', (30, 37))	('THZ1', 'Var', (20, 24))	('ICC', 'Disease', 'MESH:C535533', (64, 67))
74003	32174795	Moreover, ectopic expression of CDK7 increased the sensitivity of RBE and SSP-25 cells to THZ1 treatment (Figure 4B), indicating that THZ1 targets CDK7 in ICC cells.	('ICC', 'Disease', (155, 158))	('ICC', 'Disease', 'MESH:C535533', (155, 158))	('CDK7', 'Gene', (32, 36))	('THZ1', 'Chemical', '-', (134, 138))	('sensitivity', 'MPA', (51, 62))	('increased', 'PosReg', (37, 46))	('ectopic expression', 'Var', (10, 28))	('THZ1', 'Chemical', '-', (90, 94))
74009	32174795	qRT-PCR confirmed that protein levels of the downregulated cell cycle genes, AURKA, AURKB, CDC25B, CDK1, CCNA2, and MKI67, were markedly reduced following THZ1 exposure (Figure 6E).	('THZ1', 'Var', (155, 159))	('THZ1', 'Chemical', '-', (155, 159))	('MKI67', 'Gene', (116, 121))	('AURKA', 'Gene', (77, 82))	('protein levels', 'MPA', (23, 37))	('CCNA2', 'Gene', '890', (105, 110))	('MKI67', 'Gene', '4288', (116, 121))	('reduced', 'NegReg', (137, 144))	('CDK1', 'Gene', (99, 103))	('CDK1', 'Gene', '983', (99, 103))	('AURKB', 'Gene', '9212', (84, 89))	('downregulated', 'NegReg', (45, 58))	('AURKA', 'Gene', '6790', (77, 82))	('CCNA2', 'Gene', (105, 110))	('AURKB', 'Gene', (84, 89))	('CDC25B', 'Gene', '994', (91, 97))	('cell cycle genes', 'Gene', (59, 75))	('CDC25B', 'Gene', (91, 97))
74012	32174795	Moreover, qRT-PCR confirmed that THZ1 impaired the transcription of c-Met signaling genes (c-Met, AKT1, PTK2, CRK, PDPK1, and ARF6) (Figure 6E).	('AKT1', 'Gene', (98, 102))	('THZ1', 'Chemical', '-', (33, 37))	('PDPK1', 'Gene', '5170', (115, 120))	('PDPK1', 'Gene', (115, 120))	('THZ1', 'Var', (33, 37))	('CRK', 'Gene', '1398', (110, 113))	('PTK2', 'Gene', '5747', (104, 108))	('transcription', 'MPA', (51, 64))	('ARF6', 'Gene', (126, 130))	('c-Met', 'Gene', (91, 96))	('CRK', 'Gene', (110, 113))	('PTK2', 'Gene', (104, 108))	('ARF6', 'Gene', '382', (126, 130))	('impaired', 'NegReg', (38, 46))	('AKT1', 'Gene', '207', (98, 102))
74023	32174795	In this study, we demonstrated that inhibition of CDK7, a highly expressed transcriptional regulator in ICC, has therapeutic effects on ICC tumor growth and invasion.	('CDK7', 'Gene', (50, 54))	('ICC', 'Disease', 'MESH:C535533', (136, 139))	('inhibition', 'Var', (36, 46))	('ICC', 'Disease', 'MESH:C535533', (104, 107))	('invasion', 'CPA', (157, 165))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('ICC', 'Disease', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('ICC', 'Disease', (104, 107))	('tumor', 'Disease', (140, 145))
74036	32174795	Aberrant super-enhancers (SEs) that recruit the transcription machinery to drive high-level expression of genes are found to establish the dysregulated transcriptional program in cancer cells.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('SE', 'Disease', 'None', (26, 28))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('dysregulated transcriptional', 'MPA', (139, 167))	('cancer', 'Disease', (179, 185))
74046	32174795	Recently, THZ1 was shown to significantly inhibit MCL1 transcription in cholangiocarcinoma cells.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 90))	('cholangiocarcinoma', 'Disease', (72, 90))	('THZ1', 'Chemical', '-', (10, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('THZ1', 'Var', (10, 14))	('inhibit', 'NegReg', (42, 49))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))	('MCL1', 'Gene', (50, 54))
74047	32174795	However, it did not produce the same invasion-defective phenotype seen in ICC cells, providing further evidence that aberrant c-Met expression may be necessary for the inhibitory activity of THZ1 on cell invasion.	('c-Met', 'Protein', (126, 131))	('ICC', 'Disease', (74, 77))	('aberrant', 'Var', (117, 125))	('ICC', 'Disease', 'MESH:C535533', (74, 77))	('THZ1', 'Chemical', '-', (191, 195))
74052	32174795	In some cases, inhibition of CDK activity not only leads to cell cycle arrest, but also induces senescence or apoptosis of tumor cells.	('induces', 'Reg', (88, 95))	('CDK', 'Protein', (29, 32))	('tumor', 'Disease', (123, 128))	('leads to', 'Reg', (51, 59))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (60, 77))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('activity', 'MPA', (33, 41))	('cell cycle arrest', 'CPA', (60, 77))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('apoptosis', 'CPA', (110, 119))	('senescence', 'CPA', (96, 106))	('inhibition', 'Var', (15, 25))
74060	32174795	In summary, our data show that a high level of CDK7 is associated with poor prognosis in patients with ICC.	('ICC', 'Disease', (103, 106))	('ICC', 'Disease', 'MESH:C535533', (103, 106))	('high level', 'Var', (33, 43))	('CDK7', 'Gene', (47, 51))	('patients', 'Species', '9606', (89, 97))
74061	32174795	The phenotypic changes induced in ICC by CDK7 depletion or THZ1 treatment indicate that CDK7 is involved in cell proliferation, tumor sphere formation, migration, invasion, and cell cycle regulation.	('depletion', 'Var', (46, 55))	('tumor', 'Disease', (128, 133))	('migration', 'CPA', (152, 161))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('ICC', 'Disease', 'MESH:C535533', (34, 37))	('involved', 'Reg', (96, 104))	('THZ1', 'Chemical', '-', (59, 63))	('CDK7', 'Gene', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CDK7', 'Gene', (41, 45))	('cell cycle', 'CPA', (177, 187))	('cell proliferation', 'CPA', (108, 126))	('ICC', 'Disease', (34, 37))	('invasion', 'CPA', (163, 171))
74151	28275308	In palliation of unresectable cholangiocarcinoma, PDT seems to be significantly superior to BS alone.	('BS', 'Chemical', '-', (92, 94))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (30, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (30, 48))	('PDT', 'Var', (50, 53))	('cholangiocarcinoma', 'Disease', (30, 48))
74214	28275308	The current systematic review and meta-analysis shows that PDT combined with biliary stenting improves the success of biliary drainage and improves the survival and quality of life in patients with nonresectable cholangiocarcinoma.	('improves', 'PosReg', (94, 102))	('cholangiocarcinoma', 'Disease', (212, 230))	('quality of life', 'CPA', (165, 180))	('patients', 'Species', '9606', (184, 192))	('improves', 'PosReg', (139, 147))	('PDT', 'Var', (59, 62))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (212, 230))	('biliary drainage', 'Disease', (118, 134))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (212, 230))	('success', 'MPA', (107, 114))	('survival', 'CPA', (152, 160))
74287	27223281	Scientific evidence has shown that miRNAs expression can be controlled by various molecular events, including alterations in genome location, epigenetic changes, transcriptional deregulations and alterations in miRNA biogenesis.	('miR', 'Gene', '220972', (211, 214))	('miR', 'Gene', (211, 214))	('alterations', 'Reg', (110, 121))	('epigenetic', 'Var', (142, 152))	('transcriptional', 'MPA', (162, 177))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', (35, 38))	('alterations', 'Reg', (196, 207))	('genome location', 'MPA', (125, 140))
74289	27223281	Aberrant DNA methylation in the promoter regions produced the silencing of miRNAs, modifying the expression of tumor suppressor miRNAs and oncogenic miRNAs.	('miR', 'Gene', '220972', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('miR', 'Gene', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Aberrant DNA methylation', 'Var', (0, 24))	('silencing', 'MPA', (62, 71))	('tumor', 'Disease', (111, 116))	('miR', 'Gene', '220972', (149, 152))	('miR', 'Gene', (149, 152))	('miR', 'Gene', '220972', (128, 131))	('miR', 'Gene', (128, 131))	('expression', 'MPA', (97, 107))	('modifying', 'Reg', (83, 92))
74290	27223281	Moreover Dicer, Drosha and XPO5 inactivation have been shown to induce an altered biogenesis and, therefore, a significant reduction of miRNA levels, leading to an aberrant expression in several cancers.	('Drosha', 'Gene', (16, 22))	('Dicer', 'Gene', '23405', (9, 14))	('Dicer', 'Gene', (9, 14))	('altered', 'Reg', (74, 81))	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))	('XPO5', 'Gene', '57510', (27, 31))	('Drosha', 'Gene', '29102', (16, 22))	('reduction', 'NegReg', (123, 132))	('inactivation', 'Var', (32, 44))	('XPO5', 'Gene', (27, 31))	('expression', 'MPA', (173, 183))	('cancers', 'Disease', (195, 202))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('biogenesis', 'MPA', (82, 92))
74292	27223281	A defect in XPO5 also affects the transportation of pre-miRNAs, provoking the nuclear retention of these precursors.	('affects', 'Reg', (22, 29))	('transportation of', 'MPA', (34, 51))	('XPO5', 'Gene', (12, 16))	('XPO5', 'Gene', '57510', (12, 16))	('defect', 'Var', (2, 8))	('provoking', 'Reg', (64, 73))	('nuclear retention', 'MPA', (78, 95))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))
74358	27223281	demonstrated that 10 of the 667 bile miRNAs studied (miR-9, miR-145*, miR-105, miR-147b, let-7f-2*, let-7i*, miR-302c*, miR-199a-3p, miR-222* and miR-942) were significantly more highly expressed in the malignant group composed of CCA and GBC patients than in the control group (patients with choledocholithiasis).	('miR', 'Gene', '220972', (53, 56))	('miR-302c', 'Gene', (109, 117))	('miR', 'Gene', (109, 112))	('miR', 'Gene', '220972', (37, 40))	('miR', 'Gene', '220972', (60, 63))	('miR-222', 'Gene', '407007', (133, 140))	('miR', 'Gene', (133, 136))	('miR-1', 'Gene', '79187', (60, 65))	('miR', 'Gene', (70, 73))	('miR', 'Gene', '220972', (146, 149))	('CCA', 'Phenotype', 'HP:0030153', (231, 234))	('miR-147b', 'Gene', '100126311', (79, 87))	('miR-942', 'Gene', (146, 153))	('miR', 'Gene', (53, 56))	('miR-1', 'Gene', (70, 75))	('let-7f-2', 'Gene', (89, 97))	('miR', 'Gene', (37, 40))	('miR', 'Gene', (60, 63))	('miR-147b', 'Gene', (79, 87))	('patients', 'Species', '9606', (243, 251))	('CCA', 'Disease', (231, 234))	('miR-302c', 'Gene', '442895', (109, 117))	('miR-1', 'Gene', '79187', (120, 125))	('miR-1', 'Gene', '79187', (79, 84))	('miR-145', 'Gene', '406937', (60, 67))	('miR', 'Gene', (146, 149))	('miR-199a-3p', 'Gene', (120, 131))	('miR-145', 'Gene', (60, 67))	('miR', 'Gene', '220972', (120, 123))	('miR-942', 'Gene', '100126331', (146, 153))	('choledocholithiasis', 'Disease', (293, 312))	('miR-199a-3p', 'Gene', '406977', (120, 131))	('miR-222', 'Gene', (133, 140))	('miR', 'Gene', '220972', (79, 82))	('let-7i*', 'Var', (100, 107))	('patients', 'Species', '9606', (279, 287))	('let-7f-2', 'Gene', '406889', (89, 97))	('miR-1', 'Gene', (60, 65))	('miR-1', 'Gene', '79187', (70, 75))	('miR', 'Gene', '220972', (109, 112))	('choledocholithiasis', 'Disease', 'MESH:D042883', (293, 312))	('miR', 'Gene', '220972', (133, 136))	('miR', 'Gene', (120, 123))	('more highly expressed', 'PosReg', (174, 195))	('miR', 'Gene', (79, 82))	('GBC', 'Disease', (239, 242))	('miR-1', 'Gene', (120, 125))	('miR', 'Gene', '220972', (70, 73))	('miR-1', 'Gene', (79, 84))
74373	27223281	The miRNA-200 cluster (miR-200a, miR-200b and miR-200c) has been associated with human GBC via epigenetic regulation and contributes to bile duct proliferation in the cholestatic liver.	('miR', 'Gene', (46, 49))	('miR-200b', 'Gene', (33, 41))	('miR-200c', 'Gene', (46, 54))	('miR', 'Gene', (23, 26))	('bile duct', 'MPA', (136, 145))	('associated', 'Reg', (65, 75))	('miR', 'Gene', '220972', (4, 7))	('cholestatic liver', 'Phenotype', 'HP:0002611', (167, 184))	('human', 'Species', '9606', (81, 86))	('contributes to', 'Reg', (121, 135))	('miR', 'Gene', (4, 7))	('miR-200a', 'Gene', '406983', (23, 31))	('miR', 'Gene', '220972', (33, 36))	('miR-200b', 'Gene', '406984', (33, 41))	('cholestatic liver', 'Disease', 'MESH:D002779', (167, 184))	('epigenetic', 'Var', (95, 105))	('human GBC', 'Disease', (81, 90))	('miR', 'Gene', '220972', (46, 49))	('miR', 'Gene', (33, 36))	('miR', 'Gene', '220972', (23, 26))	('miR-200c', 'Gene', '406985', (46, 54))	('cholestatic liver', 'Disease', (167, 184))	('miR-200a', 'Gene', (23, 31))	('bile duct proliferation', 'Phenotype', 'HP:0001408', (136, 159))
74383	27223281	Thus, miRNAs in gallstones and/or deregulation of miRNAs involved in cholesterol homeostasis may be critical in the formation of gallstones, providing a new option for primary detection in subjects at risk ofdeveloping a malignancy or GBC development.	('gallstones', 'Disease', (16, 26))	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('gallstones', 'Disease', (129, 139))	('gallstones', 'Disease', 'MESH:D042882', (16, 26))	('deregulation', 'Var', (34, 46))	('gallstone', 'Phenotype', 'HP:0001081', (129, 138))	('gallstones', 'Phenotype', 'HP:0001081', (129, 139))	('gallstones', 'Phenotype', 'HP:0001081', (16, 26))	('gallstone', 'Phenotype', 'HP:0001081', (16, 25))	('men', 'Species', '9606', (246, 249))	('gallstones', 'Disease', 'MESH:D042882', (129, 139))	('miR', 'Gene', '220972', (6, 9))	('miR', 'Gene', (6, 9))	('malignancy', 'Disease', 'MESH:D009369', (221, 231))	('malignancy', 'Disease', (221, 231))	('cholesterol', 'Chemical', 'MESH:D002784', (69, 80))
74390	27223281	in 2008 on patients with diffuse large B-cell lymphoma, finding that high miR-21 expression was associated with relapse-free survival.	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (39, 54))	('lymphoma', 'Phenotype', 'HP:0002665', (46, 54))	('associated with', 'Reg', (96, 111))	('miR-21', 'Gene', '406991', (74, 80))	('relapse-free survival', 'CPA', (112, 133))	('lymphoma', 'Disease', (46, 54))	('high', 'Var', (69, 73))	('patients', 'Species', '9606', (11, 19))	('miR-21', 'Gene', (74, 80))	('expression', 'MPA', (81, 91))	('lymphoma', 'Disease', 'MESH:D008223', (46, 54))
74423	27223281	showed that diagnostic power increases by using a combination of CA19-9 and miR-21 to differentiate BTC patients from healthy volunteers and BBD patients.	('miR-21', 'Gene', '406991', (76, 82))	('patients', 'Species', '9606', (145, 153))	('BTC', 'Disease', (100, 103))	('miR-21', 'Gene', (76, 82))	('CA19-9', 'Chemical', '-', (65, 71))	('increases', 'PosReg', (29, 38))	('diagnostic power', 'MPA', (12, 28))	('CA19-9', 'Var', (65, 71))	('patients', 'Species', '9606', (104, 112))
74470	25575810	Moreover, male ( p < 0.05), gender, an early year of diagnosis (1988-1993), African-American race, intrahepatic bile duct, poor/undifferentiated grade, cholangiocarcinoma or combined hepatocellular and cholangiocarcinomas, higher stage, and larger tumor size ( p < 0.001), were regarded as significant risk factors for a poorer prognosis by univariate analysis (Table 2).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (152, 170))	('tumor', 'Disease', (248, 253))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (152, 170))	('cholangiocarcinoma', 'Disease', (202, 220))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (202, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (202, 221))	('carcinomas', 'Phenotype', 'HP:0030731', (211, 221))	('intrahepatic bile duct', 'Disease', 'MESH:D002780', (99, 121))	('cholangiocarcinoma', 'Disease', (152, 170))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (202, 220))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('intrahepatic bile duct', 'Disease', (99, 121))	('cholangiocarcinomas', 'Disease', (202, 221))	('poor/undifferentiated', 'Var', (123, 144))
74510	22230750	Correlation between promoter methylation of p14ARF, TMS1/ASC, and DAPK, and p53 mutation with prognosis in cholangiocarcinoma To study the methylation status of genes that play a role in the p53-Bax mitochondrial apoptosis pathway and its clinical significance in cholangiocarcinoma.	('Bax', 'Gene', '581', (195, 198))	('ASC', 'Gene', '29108', (57, 60))	('p53', 'Gene', (76, 79))	('cholangiocarcinoma', 'Disease', (107, 125))	('p53', 'Gene', '7157', (191, 194))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (264, 282))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (107, 125))	('p14ARF', 'Gene', '1029', (44, 50))	('TMS1', 'Gene', '29108', (52, 56))	('ASC', 'Gene', (57, 60))	('cholangiocarcinoma', 'Disease', (264, 282))	('TMS1', 'Gene', (52, 56))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (264, 282))	('p53', 'Gene', (191, 194))	('DAPK', 'Gene', (66, 70))	('p14ARF', 'Gene', (44, 50))	('DAPK', 'Gene', '1612', (66, 70))	('mutation', 'Var', (80, 88))	('p53', 'Gene', '7157', (76, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (107, 125))	('Bax', 'Gene', (195, 198))
74514	22230750	We found 66.7% of 36 cholangiocarcinoma patients had methylation of at least one of the tumor suppressor genes analyzed.	('cholangiocarcinoma', 'Disease', (21, 39))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('patients', 'Species', '9606', (40, 48))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (21, 39))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (21, 39))	('tumor', 'Disease', (88, 93))	('methylation', 'Var', (53, 64))
74516	22230750	Combined p53 mutation and DAPK, p14ARF, and/or ASC methylation was detected in 14 cases (38.9%).	('ASC', 'Gene', (47, 50))	('p14ARF', 'Gene', (32, 38))	('DAPK', 'Gene', (26, 30))	('DAPK', 'Gene', '1612', (26, 30))	('mutation', 'Var', (13, 21))	('ASC', 'Gene', '29108', (47, 50))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('detected', 'Reg', (67, 75))	('p14ARF', 'Gene', '1029', (32, 38))
74517	22230750	There were statistically significant differences in the extent of pathologic biology, differentiation, and invasion between patients with combined p53 mutation and DAPK, p14ARF, and/or ASC methylation compared to those without (P < 0.05).	('ASC', 'Gene', (185, 188))	('differences', 'Reg', (37, 48))	('mutation', 'Var', (151, 159))	('DAPK', 'Gene', (164, 168))	('DAPK', 'Gene', '1612', (164, 168))	('ASC', 'Gene', '29108', (185, 188))	('p14ARF', 'Gene', '1029', (170, 176))	('p14ARF', 'Gene', (170, 176))	('p53', 'Gene', '7157', (147, 150))	('invasion', 'CPA', (107, 115))	('patients', 'Species', '9606', (124, 132))	('p53', 'Gene', (147, 150))
74518	22230750	The survival rate of patients with combined DAPK, p14ARF, and ASC methylation and p53 mutation was poorer than other patients (P < 0.05).	('poorer', 'NegReg', (99, 105))	('DAPK', 'Gene', (44, 48))	('ASC', 'Gene', (62, 65))	('DAPK', 'Gene', '1612', (44, 48))	('survival rate', 'CPA', (4, 17))	('ASC', 'Gene', '29108', (62, 65))	('p14ARF', 'Gene', '1029', (50, 56))	('patients', 'Species', '9606', (21, 29))	('p53', 'Gene', (82, 85))	('mutation', 'Var', (86, 94))	('p53', 'Gene', '7157', (82, 85))	('patients', 'Species', '9606', (117, 125))	('p14ARF', 'Gene', (50, 56))
74519	22230750	Our study indicates that methylation of DAPK, p14ARF, and ASC in cholangiocarcinoma is a common event.	('ASC', 'Gene', (58, 61))	('p14ARF', 'Gene', (46, 52))	('ASC', 'Gene', '29108', (58, 61))	('cholangiocarcinoma', 'Disease', (65, 83))	('p14ARF', 'Gene', '1029', (46, 52))	('methylation', 'Var', (25, 36))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (65, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))	('DAPK', 'Gene', (40, 44))	('DAPK', 'Gene', '1612', (40, 44))
74520	22230750	Furthermore, p53 mutation combined with DAPK, p14ARF, and/or ASC methylation correlates with malignancy and poor prognosis.	('ASC', 'Gene', (61, 64))	('p14ARF', 'Gene', (46, 52))	('ASC', 'Gene', '29108', (61, 64))	('mutation', 'Var', (17, 25))	('p14ARF', 'Gene', '1029', (46, 52))	('malignancy', 'Disease', 'MESH:D009369', (93, 103))	('malignancy', 'Disease', (93, 103))	('p53', 'Gene', (13, 16))	('p53', 'Gene', '7157', (13, 16))	('DAPK', 'Gene', (40, 44))	('DAPK', 'Gene', '1612', (40, 44))
74523	22230750	However, some genes in the pathway have latent methylation sites, such as p14ARF, DAPK, and ASC/TMS1, which can be methylated and inactivated resulting in cancer development.	('p14ARF', 'Gene', (74, 80))	('ASC', 'Gene', '29108', (92, 95))	('DAPK', 'Gene', (82, 86))	('DAPK', 'Gene', '1612', (82, 86))	('inactivated', 'Var', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('TMS1', 'Gene', (96, 100))	('methylation', 'Var', (47, 58))	('TMS1', 'Gene', '29108', (96, 100))	('resulting in', 'Reg', (142, 154))	('p14ARF', 'Gene', '1029', (74, 80))	('ASC', 'Gene', (92, 95))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
74542	22230750	The frequency of methylation in cholangiocarcinoma tissue was: p14ARF (24.0%), DAPK (30.6%), and TMS1/ASC (36.1%).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (32, 50))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (32, 50))	('ASC', 'Gene', '29108', (102, 105))	('p14ARF', 'Gene', '1029', (63, 69))	('methylation', 'Var', (17, 28))	('DAPK', 'Gene', (79, 83))	('DAPK', 'Gene', '1612', (79, 83))	('TMS1', 'Gene', (97, 101))	('p14ARF', 'Gene', (63, 69))	('TMS1', 'Gene', '29108', (97, 101))	('cholangiocarcinoma', 'Disease', (32, 50))	('ASC', 'Gene', (102, 105))
74546	22230750	Mutations in p53 were detected in 22 of 36 patients (61.1%).	('patients', 'Species', '9606', (43, 51))	('p53', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', '7157', (13, 16))	('detected', 'Reg', (22, 30))
74547	22230750	Promoter region methylation of p14ARF, DAPK, and TMS1/ASC in cholangiocarcinoma is common.	('ASC', 'Gene', '29108', (54, 57))	('DAPK', 'Gene', (39, 43))	('DAPK', 'Gene', '1612', (39, 43))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 79))	('p14ARF', 'Gene', '1029', (31, 37))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('TMS1', 'Gene', (49, 53))	('p14ARF', 'Gene', (31, 37))	('ASC', 'Gene', (54, 57))	('TMS1', 'Gene', '29108', (49, 53))	('cholangiocarcinoma', 'Disease', (61, 79))	('methylation', 'Var', (16, 27))
74551	22230750	Combined p53 mutation and p14ARF, DAPK, and/or TMS1/ASC methylation was found in 14 out of 36 cases (38.9%).	('TMS1', 'Gene', (47, 51))	('p14ARF', 'Gene', (26, 32))	('found', 'Reg', (72, 77))	('TMS1', 'Gene', '29108', (47, 51))	('mutation', 'Var', (13, 21))	('DAPK', 'Gene', (34, 38))	('DAPK', 'Gene', '1612', (34, 38))	('ASC', 'Gene', (52, 55))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('p14ARF', 'Gene', '1029', (26, 32))	('ASC', 'Gene', '29108', (52, 55))
74552	22230750	Interestingly, p53 mutation and p14ARF, DAPK, and/or TMS1/ASC methylation was often found in mucoid carcinomas and non-differentiated carcinomas, these tumors tended to be poorly differentiated and had a deeper extent of invasion.	('p14ARF', 'Gene', (32, 38))	('mucoid carcinomas', 'Disease', 'MESH:D002277', (93, 110))	('TMS1', 'Gene', '29108', (53, 57))	('mucoid carcinomas', 'Disease', (93, 110))	('tumors', 'Disease', (152, 158))	('TMS1', 'Gene', (53, 57))	('mutation', 'Var', (19, 27))	('carcinomas', 'Disease', (100, 110))	('p53', 'Gene', '7157', (15, 18))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('carcinomas', 'Disease', 'MESH:D002277', (134, 144))	('DAPK', 'Gene', (40, 44))	('ASC', 'Gene', '29108', (58, 61))	('p53', 'Gene', (15, 18))	('p14ARF', 'Gene', '1029', (32, 38))	('DAPK', 'Gene', '1612', (40, 44))	('ASC', 'Gene', (58, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('carcinomas', 'Disease', 'MESH:D002277', (100, 110))	('found', 'Reg', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('carcinomas', 'Disease', (134, 144))
74553	22230750	There was a correlation between the occurrence of p53 mutations and tumor pathology, differentiation, and invasion (P < 0.05) (Table 2).	('tumor', 'Disease', (68, 73))	('mutations', 'Var', (54, 63))	('invasion', 'CPA', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
74556	22230750	The one-, two-, and three-year survival rates of patients with combined methylation of p14ARF, DAPK, and/or TMS1/ASC and p53 mutation was 28.0%, 5.0%, and 0.0%, respectively, with a median survival time of 18.6 months.	('ASC', 'Gene', '29108', (113, 116))	('DAPK', 'Gene', (95, 99))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('TMS1', 'Gene', (108, 112))	('p14ARF', 'Gene', '1029', (87, 93))	('DAPK', 'Gene', '1612', (95, 99))	('methylation', 'Var', (72, 83))	('patients', 'Species', '9606', (49, 57))	('ASC', 'Gene', (113, 116))	('TMS1', 'Gene', '29108', (108, 112))	('p14ARF', 'Gene', (87, 93))
74558	22230750	Combined p53 mutation and p14ARF, DAPK, and/or TMS1/ASC methylation correlated with poor prognosis.	('TMS1', 'Gene', (47, 51))	('p14ARF', 'Gene', (26, 32))	('TMS1', 'Gene', '29108', (47, 51))	('mutation', 'Var', (13, 21))	('DAPK', 'Gene', (34, 38))	('DAPK', 'Gene', '1612', (34, 38))	('ASC', 'Gene', (52, 55))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('p14ARF', 'Gene', '1029', (26, 32))	('ASC', 'Gene', '29108', (52, 55))
74563	22230750	Mammalian cells possess the capacity to epigenetically modify their genomes via the covalent addition of a methyl group to the 5-position of the cytosine ring within the context of the CpG dinucleotide.	('Mammalian', 'Species', '9606', (0, 9))	('cytosine', 'Chemical', 'MESH:D003596', (145, 153))	('genomes', 'MPA', (68, 75))	('epigenetically modify', 'Var', (40, 61))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (185, 201))
74565	22230750	We found that 66.7% of patients had methylation of at least one of the tumor suppressor genes analyzed.	('patients', 'Species', '9606', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('methylation', 'Var', (36, 47))
74566	22230750	The frequency of methylation in cholangiocarcinoma was: p14ARF (24.0%), DAPK (30.6%), and TMS1/ASC (36.1%).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (32, 50))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (32, 50))	('p14ARF', 'Gene', '1029', (56, 62))	('methylation', 'Var', (17, 28))	('p14ARF', 'Gene', (56, 62))	('DAPK', 'Gene', (72, 76))	('ASC', 'Gene', (95, 98))	('TMS1', 'Gene', (90, 94))	('DAPK', 'Gene', '1612', (72, 76))	('cholangiocarcinoma', 'Disease', (32, 50))	('TMS1', 'Gene', '29108', (90, 94))	('ASC', 'Gene', '29108', (95, 98))
74567	22230750	The frequency of methylation in normal adjacent tissues was: DAPK (5.6%) and TMS1/ASC (8.3%).	('ASC', 'Gene', '29108', (82, 85))	('DAPK', 'Gene', (61, 65))	('DAPK', 'Gene', '1612', (61, 65))	('TMS1', 'Gene', '29108', (77, 81))	('methylation', 'Var', (17, 28))	('TMS1', 'Gene', (77, 81))	('ASC', 'Gene', (82, 85))
74577	22230750	Expression of regulators of the p53-Bax mitochondrial apoptosis pathway, including p14ARF, DAPK, and ASC/TMS1, can become inactivated by promoter methylation and lead to the destruction of the pathway.	('inactivated', 'NegReg', (122, 133))	('Bax', 'Gene', (36, 39))	('DAPK', 'Gene', (91, 95))	('TMS1', 'Gene', (105, 109))	('TMS1', 'Gene', '29108', (105, 109))	('DAPK', 'Gene', '1612', (91, 95))	('p14ARF', 'Gene', '1029', (83, 89))	('ASC', 'Gene', (101, 104))	('p53', 'Gene', (32, 35))	('Bax', 'Gene', '581', (36, 39))	('p53', 'Gene', '7157', (32, 35))	('mitochondrial apoptosis pathway', 'Pathway', (40, 71))	('p14ARF', 'Gene', (83, 89))	('promoter methylation', 'Var', (137, 157))	('ASC', 'Gene', '29108', (101, 104))
74578	22230750	Our study indicates that methylation of regulators of the p53-Bax mitochondrial apoptosis pathway is a common epigenetic event in cholangiocarcinoma.	('Bax', 'Gene', '581', (62, 65))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (130, 148))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (130, 148))	('methylation', 'Var', (25, 36))	('Bax', 'Gene', (62, 65))	('p53', 'Gene', (58, 61))	('cholangiocarcinoma', 'Disease', (130, 148))	('p53', 'Gene', '7157', (58, 61))
74579	22230750	Futhermore, we found p53 gene mutation combined with DAPK, p14ARF, and/or ASC methylation in 14 cases (38.9%), which correlated with extent of pathologic biology, differentiation, and invasion of the tumors (P < 0.05).	('p53', 'Gene', (21, 24))	('DAPK', 'Gene', (53, 57))	('DAPK', 'Gene', '1612', (53, 57))	('ASC', 'Gene', '29108', (74, 77))	('p14ARF', 'Gene', '1029', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('mutation', 'Var', (30, 38))	('p53', 'Gene', '7157', (21, 24))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('p14ARF', 'Gene', (59, 65))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('ASC', 'Gene', (74, 77))	('correlated', 'Reg', (117, 127))
74580	22230750	Patients with combined p53 mutation and methylation of tumor suppressor genes tended to have more malignant tumors.	('methylation', 'Var', (40, 51))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('malignant tumors', 'Disease', (98, 114))	('tumor', 'Disease', (55, 60))	('mutation', 'Var', (27, 35))	('tumor', 'Disease', (108, 113))	('malignant tumors', 'Disease', 'MESH:D018198', (98, 114))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('more', 'PosReg', (93, 97))
74581	22230750	Moreover, the one-, two-, and three-year survival rate of patients with combined tumor suppressor gene methylation and p53 mutation was 28.0%, 5.0%, and 0.0%, respectively, with a median survival time of 18.6 months.	('patients', 'Species', '9606', (58, 66))	('mutation', 'Var', (123, 131))	('p53', 'Gene', '7157', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('methylation', 'Var', (103, 114))	('p53', 'Gene', (119, 122))	('tumor', 'Disease', (81, 86))
74583	22230750	Therefore, combined p53 mutation and DAPK, p14ARF, and/or ASC methylation correlates with poor prognosis in cholangiocarcinoma patients.	('ASC', 'Gene', (58, 61))	('p53', 'Gene', (20, 23))	('p14ARF', 'Gene', (43, 49))	('p53', 'Gene', '7157', (20, 23))	('DAPK', 'Gene', (37, 41))	('DAPK', 'Gene', '1612', (37, 41))	('ASC', 'Gene', '29108', (58, 61))	('p14ARF', 'Gene', '1029', (43, 49))	('cholangiocarcinoma', 'Disease', (108, 126))	('patients', 'Species', '9606', (127, 135))	('mutation', 'Var', (24, 32))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (108, 126))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (108, 126))
74586	22230750	Our study indicates the methylation status of regulators of the p53-Bax mitochondrial apoptosis pathway could indicate the biological behavior of cholangiocarcinoma and predict prognosis of these patients, providing a basis for postoperative adjunctive treatment.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (146, 164))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (146, 164))	('predict', 'Reg', (169, 176))	('Bax', 'Gene', (68, 71))	('methylation', 'Var', (24, 35))	('patients', 'Species', '9606', (196, 204))	('cholangiocarcinoma', 'Disease', (146, 164))	('p53', 'Gene', (64, 67))	('Bax', 'Gene', '581', (68, 71))	('indicate', 'Reg', (110, 118))	('p53', 'Gene', '7157', (64, 67))
74588	22230750	In conclusion, 66.7% of 36 cholangiocarcinoma cases had methylation of at least one of the tumor suppressor genes analyzed.	('cholangiocarcinoma', 'Disease', (27, 45))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (27, 45))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (27, 45))	('methylation', 'Var', (56, 67))	('tumor', 'Disease', (91, 96))
74589	22230750	These data indicate that methylation of genes that regulate the p53-Bax mitochondrial apoptosis pathway is a common event cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (122, 140))	('Bax', 'Gene', '581', (68, 71))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (122, 140))	('Bax', 'Gene', (68, 71))	('methylation', 'Var', (25, 36))	('p53', 'Gene', (64, 67))	('cholangiocarcinoma', 'Disease', (122, 140))	('p53', 'Gene', '7157', (64, 67))
74590	22230750	Mutation of the p53 gene was found in 61.1% of cases.	('found', 'Reg', (29, 34))	('p53', 'Gene', '7157', (16, 19))	('p53', 'Gene', (16, 19))	('Mutation', 'Var', (0, 8))
74591	22230750	Combined p53 mutation and DAPK, p14ARF, and/or ASC methylation was found in 38.9% of cases, and these patients had a poorer pathologic biology and prognosis than the other patients.	('ASC', 'Gene', (47, 50))	('p14ARF', 'Gene', (32, 38))	('DAPK', 'Gene', (26, 30))	('DAPK', 'Gene', '1612', (26, 30))	('mutation', 'Var', (13, 21))	('ASC', 'Gene', '29108', (47, 50))	('patients', 'Species', '9606', (102, 110))	('p53', 'Gene', (9, 12))	('found', 'Reg', (67, 72))	('p53', 'Gene', '7157', (9, 12))	('p14ARF', 'Gene', '1029', (32, 38))	('patients', 'Species', '9606', (172, 180))
74754	33676467	Therefore, we generated a PRG, which were defined as the follows: patients with PLR < 143.5 and ALB >= 40 g/L were defined as grade 0; patients with PLR < 143.5 and ALB < 40 g/L or PLR >= 143.5 and ALB >= 40 g/L were defined as grade 1; and patients with PLR >= 143.5 and ALB < 40 g/L were defined as grade 2 (see Additional file 1: Table S1).	('patients', 'Species', '9606', (135, 143))	('ALB', 'Gene', (165, 168))	('ALB', 'Gene', (96, 99))	('ALB', 'Gene', (272, 275))	('PRG', 'Chemical', '-', (26, 29))	('ALB', 'Gene', '213', (165, 168))	('ALB', 'Gene', '213', (198, 201))	('PLR < 143.5', 'Var', (149, 160))	('ALB', 'Gene', (198, 201))	('ALB', 'Gene', '213', (96, 99))	('patients', 'Species', '9606', (241, 249))	('patients', 'Species', '9606', (66, 74))	('ALB', 'Gene', '213', (272, 275))
74763	33676467	Cox's proportional hazards model showed that the CEA, CA19-9, tumor number, VI, lymph node metastasis and the PRG were the independent prognostic predictors for ICC (p < 0.05) (Table 4).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('CA19-9', 'Var', (54, 60))	('tumor', 'Disease', (62, 67))	('CA19-9', 'Chemical', 'MESH:C086528', (54, 60))	('ICC', 'Disease', (161, 164))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('PRG', 'Chemical', '-', (110, 113))
74775	33676467	Besides, the patients with higher PRG tended to have higher levels of CEA and CA19-9, and have greater possibility of VI and lymph node metastasis, all of which had been widely considered to be associated with poor prognosis of ICC and were the indications of and systemic therapy for ICC.	('PRG', 'Gene', (34, 37))	('higher', 'PosReg', (53, 59))	('ICC', 'Disease', (228, 231))	('patients', 'Species', '9606', (13, 21))	('higher', 'Var', (27, 33))	('CA19-9', 'MPA', (78, 84))	('CA19-9', 'Chemical', 'MESH:C086528', (78, 84))	('levels', 'MPA', (60, 66))	('PRG', 'Chemical', '-', (34, 37))	('CEA', 'MPA', (70, 73))
74776	33676467	Therefore, we believe that the ICC patients with high PRG should be advised to receive the neoadjuvant or prolonged systemic therapy to improve the long-term prognosis, although which need more studies to validate.	('PRG', 'Chemical', '-', (54, 57))	('ICC', 'Disease', (31, 34))	('high', 'Var', (49, 53))	('patients', 'Species', '9606', (35, 43))
74794	33676467	Thus, high PLR is associated with poor prognosis in various cancers, including the ICC in the present study.	('ICC', 'Disease', (83, 86))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('high PLR', 'Var', (6, 14))
74797	33676467	Malignancy frequently causes patient malnutrition reflected in hypoalbuminemia, which may in turn affect the host immune response to tumors.	('patient', 'Species', '9606', (29, 36))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('malnutrition', 'Phenotype', 'HP:0004395', (37, 49))	('hypoalbuminemia', 'Disease', 'MESH:D034141', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Malignancy', 'Var', (0, 10))	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (63, 78))	('patient malnutrition', 'Disease', (29, 49))	('hypoalbuminemia', 'Disease', (63, 78))	('affect', 'Reg', (98, 104))	('causes', 'Reg', (22, 28))
74818	33200077	We have both preclinical and clinical evidence of the efficacy of nab-paclitaxel in cholangiocarcinoma, yet no phase 3 trials have been made.	('cholangiocarcinoma', 'Disease', (84, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('nab-paclitaxel', 'Var', (66, 80))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
74852	33200077	Initial clinical improvement in cancer-related asthenia was observed, as well as a significant decrease in CA19-9 blood levels (from 3592 IU/mL in May 2019, after two cycles of FOLFOX, to 1138.8 IU/mL in August 2019, after eight cycles of FOLFOX, Figure 2).	('decrease', 'NegReg', (95, 103))	('1138.8 IU/mL', 'Var', (188, 200))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('CA19-9', 'Chemical', 'MESH:C086528', (107, 113))	('cancer', 'Disease', (32, 38))	('asthenia', 'Disease', 'MESH:D001247', (47, 55))	('asthenia', 'Disease', (47, 55))	('FOLFOX', 'Chemical', '-', (177, 183))	('asthenia', 'Phenotype', 'HP:0025406', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('FOLFOX', 'Chemical', '-', (239, 245))	('improvement', 'PosReg', (17, 28))	('CA19-9 blood levels', 'MPA', (107, 126))
74858	33200077	Distant metastases were not observed, and CA19-9 tumor markers were found to be elevated (3494 IU/mL, Figure 2).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('3494 IU/mL', 'Var', (90, 100))	('elevated', 'PosReg', (80, 88))	('metastases', 'Disease', (8, 18))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('metastases', 'Disease', 'MESH:D009362', (8, 18))	('tumor', 'Disease', (49, 54))	('CA19-9', 'Gene', (42, 48))	('CA19-9', 'Chemical', 'MESH:C086528', (42, 48))
74877	33200077	Several alterations could be identified in some genes, such as RNF43, PTCH1, ATM and ARID1A, as well as in variants of unknown significance.	('ARID1A', 'Gene', (85, 91))	('PTCH1', 'Gene', '5727', (70, 75))	('rat', 'Species', '10116', (12, 15))	('ATM', 'Gene', (77, 80))	('alterations', 'Var', (8, 19))	('ATM', 'Gene', '472', (77, 80))	('RNF43', 'Gene', (63, 68))	('PTCH1', 'Gene', (70, 75))	('RNF43', 'Gene', '54894', (63, 68))	('ARID1A', 'Gene', '8289', (85, 91))
74897	33200077	In the phase 2 trials of first-line nab-paclitaxel combinations, the disease control rate is higher than 50% and ranges from 66% (in combination with gemcitabine) to 84% (in combination with gemcitabine and cisplatin).	('combinations', 'Var', (51, 63))	('rat', 'Species', '10116', (85, 88))	('disease control', 'CPA', (69, 84))	('gemcitabine', 'Chemical', 'MESH:C056507', (191, 202))	('cisplatin', 'Chemical', 'MESH:D002945', (207, 216))	('gemcitabine', 'Chemical', 'MESH:C056507', (150, 161))
74903	33200077	Therefore, while we have evidence of the biological activity of nab-paclitaxel in cholangiocarcinoma, a partial radiological response was not observed.	('biological activity', 'MPA', (41, 60))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (82, 100))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (82, 100))	('nab-paclitaxel', 'Var', (64, 78))	('cholangiocarcinoma', 'Disease', (82, 100))
74904	33200077	We also have preclinical evidence of the efficacy of nab-paclitaxel in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (71, 89))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (71, 89))	('nab-paclitaxel', 'Var', (53, 67))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (71, 89))
74906	33200077	Nab-paclitaxel showed an inhibitory effect on cell proliferation in both mixed- and mucin intrahepatic cholangiocarcinoma primary cultures.	('mucin', 'Gene', (84, 89))	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('Nab-paclitaxel', 'Var', (0, 14))	('inhibitory', 'NegReg', (25, 35))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (90, 121))	('intrahepatic cholangiocarcinoma', 'Disease', (90, 121))	('mucin', 'Gene', '100508689', (84, 89))	('rat', 'Species', '10116', (58, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (103, 121))	('cell proliferation', 'CPA', (46, 64))	('Nab', 'Chemical', '-', (0, 3))
74907	33200077	Additionally, nab-paclitaxel induced a significant increase in apoptotic activity in only mucin-intrahepatic cholangiocarcinoma.	('increase', 'PosReg', (51, 59))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('intrahepatic cholangiocarcinoma', 'Disease', (96, 127))	('mucin', 'Gene', '100508689', (90, 95))	('mucin', 'Gene', (90, 95))	('apoptotic activity', 'CPA', (63, 81))	('nab-paclitaxel', 'Var', (14, 28))
74910	33200077	Only nab-paclitaxel and gemcitabine plus oxaliplatin induced antitumor effect in the rat model.	('oxaliplatin', 'Chemical', 'MESH:D000077150', (41, 52))	('tumor', 'Disease', (65, 70))	('rat', 'Species', '10116', (85, 88))	('gemcitabine', 'Chemical', 'MESH:C056507', (24, 35))	('nab-paclitaxel', 'Var', (5, 19))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
74912	33200077	The genomic alterations identified in our patient's tumor by NGS do not appear to be related to nab-paclitaxel efficacy.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('rat', 'Species', '10116', (16, 19))	('NGS', 'Var', (61, 64))	('patient', 'Species', '9606', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
74918	33200077	Based on this trial, a combination of a taxane, such as nab-paclitaxel, and an FGFR inhibitor in patients with FGFR amplifications would be a viable option for future use in metastatic cholangiocarcinoma patients.	('amplifications', 'Var', (116, 130))	('patients', 'Species', '9606', (204, 212))	('cholangiocarcinoma', 'Disease', (185, 203))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (185, 203))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (185, 203))	('FGFR', 'Gene', (79, 83))	('taxane', 'Chemical', 'MESH:C080625', (40, 46))	('patients', 'Species', '9606', (97, 105))
74958	31875970	We also analyzed 6 public data sets (GSE26566, GSE32958, GSE89749, EGA00001000950, GSE33327, TCGA), including 488 ICC samples and 66 paired nontumor liver samples.	('GSE89749', 'Var', (57, 65))	('GSE26566', 'Var', (37, 45))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
74988	31875970	To cast light on the stroma-cancer interaction in the different immune subtypes, we performed a functional enrichment analysis of the differentially expressed genes and a correlation study between molecular traits and clinical data in 520 ICCs (CIT, GSE26566, GSE33327, GSE89749, and EGA00001000950 data sets).	('CIT', 'Gene', (245, 248))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('GSE33327', 'Var', (260, 268))	('stroma-cancer', 'Disease', 'MESH:D009369', (21, 34))	('stroma-cancer', 'Disease', (21, 34))	('CIT', 'Gene', '11113', (245, 248))	('GSE89749', 'Var', (270, 278))
74989	31875970	The I1 immune desert subtype displays a strong attenuation of tumor and stromal immune signaling, supporting its characterization as immune desert, with most of the down-regulated immune pathways being also hypermethylated (Fig.	('hypermethylated', 'Var', (207, 222))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('immune pathways', 'Pathway', (180, 195))	('down-regulated', 'NegReg', (165, 179))	('tumor', 'Disease', (62, 67))	('attenuation', 'NegReg', (47, 58))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
75002	31875970	We found no significant association between immune subtypes and isocitrate dehydrogenase (IDH) 1, IDH2, KRAS, CTNNB1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, or tumor protein 53 mutations (Fig.	('mutations', 'Var', (210, 219))	('IDH2', 'Gene', (98, 102))	('tumor protein 53', 'Gene', (193, 209))	('CTNNB1', 'Gene', '1499', (110, 116))	('isocitrate dehydrogenase (IDH) 1', 'Gene', '3417', (64, 96))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor protein 53', 'Gene', '7157', (193, 209))	('CTNNB1', 'Gene', (110, 116))	('IDH2', 'Gene', '3418', (98, 102))	('phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, or', 'Gene', '5290', (118, 192))
75078	31270973	Among the HCC variants, those with more fibrotic components than classical HCCs include HCCs expressing stemness-related markers and scirrhous HCCs.	('HCCs', 'Gene', (143, 147))	('HCCs', 'Gene', '3052', (88, 92))	('HCC', 'Gene', '619501', (75, 78))	('HCCs', 'Gene', (75, 79))	('HCC', 'Gene', '619501', (88, 91))	('HCC', 'Gene', (143, 146))	('HCC', 'Gene', (10, 13))	('variants', 'Var', (14, 22))	('HCCs', 'Gene', '3052', (75, 79))	('HCCs', 'Gene', '3052', (143, 147))	('HCC', 'Gene', '619501', (143, 146))	('HCC', 'Gene', '619501', (10, 13))	('HCC', 'Gene', (75, 78))	('HCCs', 'Gene', (88, 92))	('HCC', 'Gene', (88, 91))
75096	31270973	In contrast, among HCC variants, sarcomatous HCCs showed a necrotic tendency since the tumor neovascularization rate could not keep up with the growth rate of sarcomatous components composed of poorly differentiated cells.	('HCC', 'Gene', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('sarcomatous', 'Disease', 'MESH:D018316', (33, 44))	('necrotic tendency', 'Disease', (59, 76))	('sarcomatous', 'Disease', (159, 170))	('HCC', 'Gene', '619501', (19, 22))	('sarcomatous HCCs', 'Disease', (33, 49))	('tumor', 'Disease', (87, 92))	('HCC', 'Gene', (45, 48))	('sarcomatous HCCs', 'Disease', 'MESH:D018316', (33, 49))	('necrotic tendency', 'Disease', 'MESH:C536965', (59, 76))	('sarcomatous', 'Disease', (33, 44))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('variants', 'Var', (23, 31))	('HCC', 'Gene', '619501', (45, 48))	('sarcomatous', 'Disease', 'MESH:D018316', (159, 170))
75149	31270973	demonstrated that a substantial proportion of cHCC-CCs could be categorized as LR-5 (definitely HCC) or LR-4 (probably HCC) on gadoxetic acid-enhanced MRI.	('LR-4', 'Var', (104, 108))	('HCC', 'Gene', (47, 50))	('HCC', 'Gene', (96, 99))	('HCC', 'Gene', '619501', (119, 122))	('HCC', 'Gene', '619501', (47, 50))	('HCC', 'Gene', '619501', (96, 99))	('gadoxetic acid', 'Chemical', 'MESH:C073590', (127, 141))	('HCC', 'Gene', (119, 122))
75206	31270973	Moreover, biopsy may cause complications such as bleeding or track seeding and has the potential to yield false-negative results.	('track seeding', 'CPA', (61, 74))	('cause', 'Reg', (21, 26))	('bleeding', 'Disease', 'MESH:D006470', (49, 57))	('bleeding', 'Disease', (49, 57))	('biopsy', 'Var', (10, 16))
75209	31270973	With LI-RADS, hepatic lesions can be classified according to their relative probability of being benign or an HCC (LR-1 to LR-5), or another hepatic malignant neoplasm (i.e., LR-M) on the basis of CT, MRI, or contrast-enhanced US findings.	('LR-1 to LR-5', 'Gene', '4041', (115, 127))	('HCC', 'Gene', '619501', (110, 113))	('LR-1 to LR-5', 'Gene', (115, 127))	('neoplasm', 'Phenotype', 'HP:0002664', (159, 167))	('hepatic malignant neoplasm', 'Phenotype', 'HP:0002896', (141, 167))	('HCC', 'Gene', (110, 113))	('hepatic malignant neoplasm', 'Disease', (141, 167))	('hepatic malignant neoplasm', 'Disease', 'MESH:D009369', (141, 167))	('LI-RADS', 'Var', (5, 12))	('hepatic lesions', 'Disease', (14, 29))
75275	29262561	Finally, there was a higher cumulative survival rate in patients with serum NY-ESO-1 positivity than in those with serum NY-ESO-1 negativity among the patients with stage III + IV.	('positivity', 'Var', (85, 95))	('patients', 'Species', '9606', (56, 64))	('NY-ESO-1', 'Gene', (76, 84))	('NY-ESO-1', 'Gene', (121, 129))	('patients', 'Species', '9606', (151, 159))	('higher', 'PosReg', (21, 27))	('NY-ESO-1', 'Gene', '1485', (121, 129))	('NY-ESO-1', 'Gene', '1485', (76, 84))	('cumulative survival rate', 'CPA', (28, 52))
75282	29262561	The combined determination of several nonspecific tumor markers, including cancer antigen (CA) 72-4, CA125, CA19-9 and carcinoembryonic antigen (CEA), is an effective method to monitor the treatment efficacy and predict tumor recurrence.	('CA125', 'Gene', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('CEA', 'Gene', (145, 148))	('carcinoembryonic antigen', 'Gene', '1084', (119, 143))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('CEA', 'Gene', '1084', (145, 148))	('tumor', 'Disease', (220, 225))	('cancer', 'Disease', (75, 81))	('carcinoembryonic antigen', 'Gene', (119, 143))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('CA125', 'Gene', '94025', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('CA19-9', 'Var', (108, 114))	('tumor', 'Disease', (50, 55))
75307	29262561	After adjustment of related co-variables in multivariate model included age, gender, smoking, alcohol drinking, AFP, T-Bil and D-Bil, the positivity of serum anti-NY-ESO-1 antibody was correlated with abdominal pain (adjusted odds ratio [aOR] 2.66; 95% CI 1.10-4.47, p = 0.04) in iCCA patients.	('abdominal pain', 'Disease', 'MESH:D015746', (201, 215))	('iCCA', 'Gene', (280, 284))	('Bil', 'Chemical', '-', (129, 132))	('pain', 'Phenotype', 'HP:0012531', (211, 215))	('AFP', 'Gene', (112, 115))	('iCCA', 'Gene', '112476', (280, 284))	('NY-ESO-1', 'Gene', (163, 171))	('Bil', 'Chemical', '-', (119, 122))	('correlated with', 'Reg', (185, 200))	('AFP', 'Gene', '174', (112, 115))	('alcohol drinking', 'Phenotype', 'HP:0030955', (94, 110))	('positivity', 'Var', (138, 148))	('abdominal pain', 'Phenotype', 'HP:0002027', (201, 215))	('patients', 'Species', '9606', (285, 293))	('alcohol', 'Chemical', 'MESH:D000438', (94, 101))	('abdominal pain', 'Disease', (201, 215))	('NY-ESO-1', 'Gene', '1485', (163, 171))
75310	29262561	In iCCA patients at stage I + II, there was no association between the cumulative survival rate and positivity of the serum anti-NY-ESO-1 antibody (p = 0.52) (Figure 2A).	('iCCA', 'Gene', '112476', (3, 7))	('NY-ESO-1', 'Gene', '1485', (129, 137))	('positivity', 'Var', (100, 110))	('iCCA', 'Gene', (3, 7))	('NY-ESO-1', 'Gene', (129, 137))	('patients', 'Species', '9606', (8, 16))
75314	29262561	However, our results suggest a possibility that serum NY-ESO-1 antibody, induced in naturally occurring immune responses, might be a beneficial factor in prolonging the overall survival of iCCA.	('iCCA', 'Gene', '112476', (189, 193))	('NY-ESO-1', 'Gene', '1485', (54, 62))	('serum', 'Var', (48, 53))	('iCCA', 'Gene', (189, 193))	('NY-ESO-1', 'Gene', (54, 62))	('prolonging', 'NegReg', (154, 164))	('beneficial', 'PosReg', (133, 143))
75324	29262561	In ovarian cancer, antibodies against any of the MAGE family antigens (including MAGE-A1, MAGE-A4, MAGE-A3 and MAGE-A10) were correlated with a lower survival rate.	('survival rate', 'CPA', (150, 163))	('MAGE-A10', 'Gene', (111, 119))	('MAGE-A1', 'Gene', (81, 88))	('MAGE-A3', 'Gene', '4102', (99, 106))	('lower', 'NegReg', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('MAGE-A10', 'Gene', '4109', (111, 119))	('antibodies', 'Var', (19, 29))	('MAGE-A4', 'Gene', '4103', (90, 97))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('MAGE-A4', 'Gene', (90, 97))	('MAGE-A3', 'Gene', (99, 106))	('ovarian cancer', 'Disease', (3, 17))	('MAGE-A1', 'Gene', '4100', (111, 118))	('MAGE-A1', 'Gene', (111, 118))	('MAGE-A1', 'Gene', '4100', (81, 88))
75325	29262561	On the other hand, the overall survival of patients with antibodies against CT antigens, including NY-ESO-1 and GAGED2a, was prolonged in lung cancer patients.	('NY-ESO-1', 'Gene', (99, 107))	('antibodies', 'Var', (57, 67))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('patients', 'Species', '9606', (43, 51))	('NY-ESO-1', 'Gene', '1485', (99, 107))	('prolonged', 'PosReg', (125, 134))	('patients', 'Species', '9606', (150, 158))	('lung cancer', 'Disease', (138, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))
75327	29262561	Our results also indicated that, in patients with iCCA, the cumulative survival rate was significantly higher in serum NY-ESO-1-positive patients than in serum NY-ESO-1-negative patients.	('NY-ESO-1', 'Gene', '1485', (160, 168))	('NY-ESO-1', 'Gene', '1485', (119, 127))	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (178, 186))	('iCCA', 'Gene', '112476', (50, 54))	('patients', 'Species', '9606', (137, 145))	('NY-ESO-1', 'Gene', (160, 168))	('higher', 'PosReg', (103, 109))	('serum', 'Var', (113, 118))	('NY-ESO-1', 'Gene', (119, 127))	('cumulative survival', 'CPA', (60, 79))	('iCCA', 'Gene', (50, 54))
75408	29282390	Cytokines will induce nitric oxide synthase, producing excessive amount of nitric oxide, a free radical, which results in damage to the DNA and DNA repair enzymes.	('damage', 'MPA', (122, 128))	('Cytokines', 'Var', (0, 9))	('DNA repair enzymes', 'Enzyme', (144, 162))	('nitric', 'MPA', (22, 28))	('nitric oxide', 'Chemical', 'MESH:D009569', (75, 87))	('nitric oxide', 'Chemical', 'MESH:D009569', (22, 34))	('DNA', 'Enzyme', (136, 139))	('induce', 'Reg', (15, 21))
75425	28661054	PDGFR pharmacologic inhibition led to a redistribution of YAP from the nucleus to cytosol and downregulation of YAP target genes in a human CCA cell line.	('human', 'Species', '9606', (134, 139))	('CCA', 'Phenotype', 'HP:0030153', (140, 143))	('pharmacologic', 'Var', (6, 19))	('PDGFR', 'Gene', (0, 5))	('PDGFR', 'Gene', '5159', (0, 5))	('redistribution', 'MPA', (40, 54))	('downregulation', 'NegReg', (94, 108))
75426	28661054	siRNA silencing of PDGFR-beta similarly downregulated YAP target genes.	('PDGFR-beta', 'Gene', '5159', (19, 29))	('PDGFR-beta', 'Gene', (19, 29))	('YAP target genes', 'Gene', (54, 70))	('downregulated', 'NegReg', (40, 53))	('silencing', 'Var', (6, 15))
75430	28661054	PDGFR inhibition decreased cellular abundance of the survival protein Mcl-1, a known YAP target gene, and accordingly increased cell death in CCA cells in vitro and in vivo.	('decreased', 'NegReg', (17, 26))	('Mcl-1', 'Gene', '4170', (70, 75))	('cellular abundance', 'MPA', (27, 45))	('increased', 'PosReg', (118, 127))	('CCA', 'Phenotype', 'HP:0030153', (142, 145))	('PDGFR', 'Gene', (0, 5))	('inhibition', 'Var', (6, 16))	('Mcl-1', 'Gene', (70, 75))	('PDGFR', 'Gene', '5159', (0, 5))	('cell death', 'CPA', (128, 138))
75432	28661054	Inhibiting this cascade may provide a viable therapeutic strategy for this human malignancy.	('malignancy', 'Disease', 'MESH:D009369', (81, 91))	('human', 'Species', '9606', (75, 80))	('Inhibiting', 'Var', (0, 10))	('malignancy', 'Disease', (81, 91))
75438	28661054	Specifically, phosphorylation of the serine127 residue of YAP by a kinase module consisting of MST1/2 and LATS1/2 sequesters YAP in the cytosol and limits transcriptional activity.	('MST1/2', 'Gene', '4485;6788', (95, 101))	('serine127', 'Var', (37, 46))	('limits', 'NegReg', (148, 154))	('YAP', 'MPA', (125, 128))	('MST1/2', 'Gene', (95, 101))	('LATS1/2', 'Gene', (106, 113))	('transcriptional activity', 'MPA', (155, 179))	('serine127', 'Chemical', '-', (37, 46))	('phosphorylation', 'MPA', (14, 29))	('LATS1/2', 'Gene', '9113;26524', (106, 113))
75440	28661054	Based on the regulatory importance of this serine residue in CCA oncogenesis, we have previously demonstrated the ability to generate intrahepatic CCA in mice following biliary tract transduction with a YAP construct in which serine127 has been mutated to alanine (S127A).	('intrahepatic CCA', 'Disease', 'MESH:C536211', (134, 150))	('serine127 has been mutated to alanine', 'Mutation', 'rs762471803', (226, 263))	('mice', 'Species', '10090', (154, 158))	('CCA', 'Phenotype', 'HP:0030153', (147, 150))	('serine', 'Chemical', 'MESH:D012694', (226, 232))	('CCA', 'Phenotype', 'HP:0030153', (61, 64))	('serine127', 'Var', (226, 235))	('intrahepatic CCA', 'Disease', (134, 150))	('S127A', 'Mutation', 'rs762471803', (265, 270))	('S127A', 'Var', (265, 270))	('serine', 'Chemical', 'MESH:D012694', (43, 49))
75444	28661054	However, recent work has demonstrated that YAP tyrosine phosphorylation by a Src family kinase (SFK) mediates IL-6 inflammation associated carcinogenesis in the colon.	('carcinogenesis', 'Disease', (139, 153))	('inflammation', 'Disease', 'MESH:D007249', (115, 127))	('IL-6', 'Gene', '3569', (110, 114))	('inflammation', 'Disease', (115, 127))	('YAP', 'Var', (43, 46))	('mediates', 'Reg', (101, 109))	('SFK', 'Gene', (96, 99))	('Src', 'Gene', '6714', (77, 80))	('tyrosine', 'Chemical', 'MESH:D014443', (47, 55))	('carcinogenesis', 'Disease', 'MESH:D063646', (139, 153))	('IL-6', 'Gene', (110, 114))	('Src', 'Gene', (77, 80))
75445	28661054	The IL6-GP130 complex phosphorylates SFK on tyrosine416, and, in turn, SFK phosphorylates YAP on tyrosine357.	('tyrosine416', 'Chemical', '-', (44, 55))	('tyrosine416', 'Var', (44, 55))	('tyrosine357', 'Var', (97, 108))	('tyrosine357', 'Chemical', '-', (97, 108))
75446	28661054	The tyrosine phosphorylated YAP may then potentially function as a co-transcriptional activator.	('tyrosine phosphorylated', 'Var', (4, 27))	('YAP', 'Gene', (28, 31))	('tyrosine', 'Chemical', 'MESH:D014443', (4, 12))
75450	28661054	YAP tyrosine phosphorylation also appears to promote its association with the transcription factor TBX5, promoting CCA cell viability by inducing Mcl-1 expression.	('tyrosine', 'Var', (4, 12))	('CCA', 'Disease', (115, 118))	('Mcl-1', 'Gene', '4170', (146, 151))	('tyrosine', 'Chemical', 'MESH:D014443', (4, 12))	('TBX5', 'Gene', (99, 103))	('TBX5', 'Gene', '6910', (99, 103))	('promote', 'PosReg', (45, 52))	('inducing', 'PosReg', (137, 145))	('association', 'Interaction', (57, 68))	('promoting', 'PosReg', (105, 114))	('Mcl-1', 'Gene', (146, 151))	('CCA', 'Phenotype', 'HP:0030153', (115, 118))	('expression', 'MPA', (152, 162))
75456	28661054	The following primary antisera were used for immunoblot analysis: PDGF Receptor (28E1 Cell Signaling, Danvers, MA), actin (C-11 Santa Cruz, Dallas, TX), phospho YAPY357 (ab62751 abcam, Cambridge, MA), phospho YAPS127 (4911 Cell Signaling), total YAP (63.7 Santa Cruz), lamin B1 (D8P3U Cell Signaling), GAPDH (MAB374 Millipore, Temecula, CA), phospho SrcY416 (2101 Cell Signaling), Src (L4A1 Cell Signaling), and Mcl-1 (S-19 Santa Cruz).	('GAPDH', 'Gene', '2597', (302, 307))	('Mcl-1', 'Gene', '4170', (412, 417))	('lamin B1', 'Gene', (269, 277))	('Src', 'Gene', (350, 353))	('Src', 'Gene', (381, 384))	('Src', 'Gene', '6714', (381, 384))	('GAPDH', 'Gene', (302, 307))	('Src', 'Gene', '6714', (350, 353))	('lamin B1', 'Gene', '4001', (269, 277))	('Mcl-1', 'Gene', (412, 417))	('YAPY357', 'Chemical', '-', (161, 168))	('MAB374', 'Var', (309, 315))
75508	28661054	Phospho immunoblot analysis identified abundant phospho-YAPY357 in the nuclear fraction with minimal tyrosine phosphorylated protein in the cytoplasm, while the opposite was observed for phospho-YAPS127 (Fig.	('phospho-YAPY357', 'Var', (48, 63))	('tyrosine phosphorylated', 'MPA', (101, 124))	('YAPY357', 'Chemical', '-', (56, 63))	('tyrosine', 'Chemical', 'MESH:D014443', (101, 109))
75510	28661054	The S127A mutation renders YAP insensitive to serine phosphorylation by LATS1/2, and as such permits examination of YAP subcellular distribution independent of S127 phosphorylation.	('LATS1/2', 'Gene', '9113;26524', (72, 79))	('S127A', 'Mutation', 'rs762471803', (4, 9))	('S127A', 'Var', (4, 9))	('LATS1/2', 'Gene', (72, 79))	('insensitive', 'NegReg', (31, 42))	('serine', 'Chemical', 'MESH:D012694', (46, 52))
75512	28661054	These data suggest that in CCA cells, tyrosine phosphorylation of YAP at Y357 may determine its subcellular localization independent of S127 phosphorylation.	('tyrosine', 'Chemical', 'MESH:D014443', (38, 46))	('subcellular localization', 'MPA', (96, 120))	('YAP', 'Gene', (66, 69))	('tyrosine phosphorylation', 'MPA', (38, 62))	('at Y357', 'Var', (70, 77))	('CCA', 'Phenotype', 'HP:0030153', (27, 30))	('determine', 'Reg', (82, 91))
75528	28661054	Incubation of HuCCT-1 cells with crenolanib results in cell death by apoptosis as assessed by morphology and biochemically as measured by caspase 3/7 activation (Fig.	('crenolanib', 'Var', (33, 43))	('caspase 3', 'Gene', (138, 147))	('caspase 3', 'Gene', '836', (138, 147))	('crenolanib', 'Chemical', 'MESH:C577197', (33, 43))	('activation', 'PosReg', (150, 160))	('apoptosis', 'CPA', (69, 78))	('cell death', 'CPA', (55, 65))	('HuCCT-1', 'CellLine', 'CVCL:0324', (14, 21))
75534	28661054	TUNEL staining demonstrated a significant increase in cell death cells within the tumors of mice treated with crenolanib as compared to vehicle treated controls (Fig.	('crenolanib', 'Chemical', 'MESH:C577197', (110, 120))	('death cells within the tumors', 'Disease', 'MESH:D001929', (59, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('death cells within the tumors', 'Disease', (59, 88))	('crenolanib', 'Var', (110, 120))	('mice', 'Species', '10090', (92, 96))	('increase', 'PosReg', (42, 50))
75536	28661054	However based on the TUNEL staining, crenolanib is tumor suppressive in PDX models likely by restraining PDGFR-YAP signaling.	('PDX', 'Disease', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('restraining', 'NegReg', (93, 104))	('crenolanib', 'Var', (37, 47))	('crenolanib', 'Chemical', 'MESH:C577197', (37, 47))	('PDGFR', 'Gene', (105, 110))	('tumor', 'Disease', (51, 56))	('PDGFR', 'Gene', '5159', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
75538	28661054	These data indicate that: (1) PDGFR signaling can drive YAP co-transcriptional activity; (2) YAP nuclear localization appears to be regulated by SFK-mediated tyrosine phosphorylation; and (3) PDGF inhibition leads to cell death in vitro and in vivo.	('drive', 'PosReg', (50, 55))	('inhibition', 'Var', (197, 207))	('nuclear localization', 'MPA', (97, 117))	('YAP', 'Gene', (56, 59))	('cell death', 'CPA', (217, 227))	('PDGFR', 'Gene', (30, 35))	('PDGFR', 'Gene', '5159', (30, 35))	('tyrosine', 'Chemical', 'MESH:D014443', (158, 166))	('PDGF', 'Gene', (192, 196))
75541	28661054	We were able to demonstrate downregulation of multiple YAP co-transcriptional targets following PDGFR inhibition.	('downregulation', 'NegReg', (28, 42))	('inhibition', 'Var', (102, 112))	('PDGFR', 'Gene', (96, 101))	('PDGFR', 'Gene', '5159', (96, 101))
75544	28661054	YAP phosphorylation on residue S127 by serine/threonine kinases blocks its co-transcriptional activity by promoting its binding to protein 14-4-4 in the cytoplasm as well as targeting it for proteasomal degradation.	('YAP', 'Gene', (0, 3))	('blocks', 'NegReg', (64, 70))	('binding', 'Interaction', (120, 127))	('targeting', 'Reg', (174, 183))	('protein', 'Protein', (131, 138))	('proteasomal degradation', 'MPA', (191, 214))	('promoting', 'PosReg', (106, 115))	('serine', 'Chemical', 'MESH:D012694', (39, 45))	('phosphorylation', 'Var', (4, 19))	('co-transcriptional activity', 'MPA', (75, 102))
75546	28661054	Indeed, we observed that the mutant S127A YAP, which cannot undergo phosphorylation on this residue, still redistributed to the cytoplasm following PDGFE inhibition in our mouse CCA cells.	('CCA', 'Phenotype', 'HP:0030153', (178, 181))	('S127A', 'Var', (36, 41))	('YAP', 'Gene', (42, 45))	('mouse', 'Species', '10090', (172, 177))	('redistributed', 'MPA', (107, 120))	('S127A', 'Mutation', 'rs762471803', (36, 41))
75547	28661054	Our study implicates YAP tyrosine phosphorylation also in the subcellular compartmentation of this transcriptional co-activator; an observation which has been suggested by others.	('tyrosine', 'Var', (25, 33))	('implicates', 'Reg', (10, 20))	('subcellular compartmentation', 'MPA', (62, 90))	('tyrosine', 'Chemical', 'MESH:D014443', (25, 33))
75552	28661054	These results were confirmed utilizing the SFK inhibitor dasatinib, a drug that has recently been shown to be especially effective in models of CCA bearing mutations in isocitrate dehydrogenase.	('dasatinib', 'Chemical', 'MESH:D000069439', (57, 66))	('mutations', 'Var', (156, 165))	('CCA', 'Phenotype', 'HP:0030153', (144, 147))	('CCA', 'Disease', (144, 147))
75556	28661054	The potency of this survival function was manifest when cytotoxicity was observed following PDGFR pharmacologic inhibition both in a cell line and PDX models.	('pharmacologic', 'Var', (98, 111))	('cytotoxicity', 'Disease', 'MESH:D064420', (56, 68))	('PDGFR', 'Gene', (92, 97))	('PDGFR', 'Gene', '5159', (92, 97))	('cytotoxicity', 'Disease', (56, 68))
75559	28661054	Potent SFK inhibitors may prove to be therapeutically beneficial for human CCA, a therapeutic avenue which merits further attention.	('CCA', 'Phenotype', 'HP:0030153', (75, 78))	('inhibitors', 'Var', (11, 21))	('SFK', 'Gene', (7, 10))	('human', 'Species', '9606', (69, 74))
75629	33491760	The expression of miR-340-5p was significantly upregulated after treatment, and overexpression of miR-340-5p inhibited the proliferation of HuCCT-1 cells and decreased the levels of cyclin D1.	('proliferation', 'CPA', (123, 136))	('levels of cyclin D1', 'MPA', (172, 191))	('decreased', 'NegReg', (158, 167))	('miR-340-5p', 'Chemical', '-', (98, 108))	('upregulated', 'PosReg', (47, 58))	('miR-340-5p', 'Var', (98, 108))	('inhibited', 'NegReg', (109, 118))	('expression', 'MPA', (4, 14))	('men', 'Species', '9606', (70, 73))	('HuCCT-1', 'CellLine', 'CVCL:0324', (140, 147))	('miR-340-5p', 'Chemical', '-', (18, 28))
75641	33491760	Numerous anticancer mechanisms for aspirin have been identified, such as inhibition of cyclooxygenase, activating key molecular targets in the AMPK, mTOR, STAT3, and NF-kappaB pathways, decreasing the levels of reactive oxygen species and glucose consumption, inducing autophagy via JNK/p-Bcl2/Beclin-1, AMPK/mTOR, and GSK-3 signaling, inducing apoptosis and mitochondrial dysfunction by increasing oxidative stress, and changing the tumor microenvironment by affecting platelets.	('tumor', 'Disease', 'MESH:D009369', (434, 439))	('mTOR', 'Gene', '2475', (149, 153))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (359, 384))	('GSK-3', 'MPA', (319, 324))	('increasing', 'PosReg', (388, 398))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('inducing', 'PosReg', (336, 344))	('decreasing', 'NegReg', (186, 196))	('oxidative stress', 'MPA', (399, 415))	('Bcl2', 'Gene', (289, 293))	('AMPK', 'Gene', '5564', (304, 308))	('tumor', 'Phenotype', 'HP:0002664', (434, 439))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (359, 384))	('autophagy', 'CPA', (269, 278))	('AMPK', 'Gene', (304, 308))	('aspirin', 'Chemical', 'MESH:D001241', (35, 42))	('mitochondrial dysfunction', 'Disease', (359, 384))	('Bcl2', 'Gene', '596', (289, 293))	('glucose consumption', 'MPA', (239, 258))	('inhibition', 'Var', (73, 83))	('Beclin-1', 'Gene', '8678', (294, 302))	('mTOR', 'Gene', (309, 313))	('STAT3', 'Gene', (155, 160))	('AMPK', 'Gene', (143, 147))	('AMPK', 'Gene', '5564', (143, 147))	('cancer', 'Disease', (13, 19))	('JNK', 'Gene', (283, 286))	('JNK', 'Gene', '5599', (283, 286))	('oxidative stress', 'Phenotype', 'HP:0025464', (399, 415))	('men', 'Species', '9606', (452, 455))	('STAT3', 'Gene', '6774', (155, 160))	('Beclin-1', 'Gene', (294, 302))	('mTOR', 'Gene', '2475', (309, 313))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('platelets', 'MPA', (470, 479))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (211, 234))	('affecting', 'Reg', (460, 469))	('mTOR', 'Gene', (149, 153))	('tumor', 'Disease', (434, 439))	('glucose', 'Chemical', 'MESH:D005947', (239, 246))	('inducing', 'PosReg', (260, 268))	('apoptosis', 'MPA', (345, 354))
75683	33491760	The primer sequences are as follows: miR-340-5p forward, 5'-GCG GTT ATA AAG CAA TGA GA-3' and reverse, 5'-GTG CGT GTC GTG GAG TCG-3'; U6 forward, 5'-GCT TCG GCA GCA CAT ATA CTA AAA T-3' and reverse, 5'-CGC TTC ACG AAT TTG CGT GTC AT-3'.	('miR-340-5p', 'Chemical', '-', (37, 47))	('miR-340-5p', 'Var', (37, 47))	('AAG', 'Gene', (72, 75))	('AAT', 'Gene', '5265', (214, 217))	('AAT', 'Gene', (214, 217))	('AAG', 'Gene', '4350', (72, 75))
75685	33491760	miRNA regulatory network used mirPath v.3 (http://snf-515788.vm.okeanos.grnet.gr); miRGator v3.0 (http://mirgator.kobic.re.kr) and miTarBase (http://mirtarbase.cuhk.edu.cn/php/index.php) online software to reveal the expression of miR-340-5p in related cancer and normal tissue and the relationship with the underlying target gene.	('miR-340-5p', 'Chemical', '-', (231, 241))	('miR-340-5p', 'Var', (231, 241))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Disease', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
75726	33491760	Previous studies have indicated that miR-340-5p has tumor-suppressive properties, and miR-340-5p exhibited functions in different parts in the KEGG pathway analyses of upregulated miRNAs, which included 'prion diseases', 'microRNA in cancer', 'proteoglycans in cancer', and 'signaling pathways regulating pluripotency of stem cells' as well as others (Fig.	('miR-340-5p', 'Chemical', '-', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('tumor', 'Disease', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('upregulated', 'PosReg', (168, 179))	("'prion diseases'", 'Disease', (203, 219))	('miR-340-5p', 'Chemical', '-', (86, 96))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('cancer', 'Disease', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('miR-340-5p', 'Var', (86, 96))	('prion', 'Species', '36469', (204, 209))
75727	33491760	Although the expression of miR-340-5p was not clearly revealed in CCA, it was decreased in most types of cancer (Fig.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('CCA', 'Phenotype', 'HP:0030153', (66, 69))	('miR-340-5p', 'Chemical', '-', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('decreased', 'NegReg', (78, 87))	('miR-340-5p', 'Var', (27, 37))	('CCA', 'Disease', (66, 69))
75728	33491760	The miRNA regulatory network and miRDB database predicted that CCND1 may be a target of miR-340-5p (Fig.	('CCND1', 'Gene', (63, 68))	('miR-340-5p', 'Chemical', '-', (88, 98))	('CCND1', 'Gene', '595', (63, 68))	('miR-340-5p', 'Var', (88, 98))
75730	33491760	After transfection of miR-340-5p mimics, miR-340-5p expression was significantly increased in the HuCCT-1 cells (Fig.	('miR-340-5p', 'Chemical', '-', (22, 32))	('HuCCT-1', 'CellLine', 'CVCL:0324', (98, 105))	('expression', 'MPA', (52, 62))	('miR-340-5p', 'Chemical', '-', (41, 51))	('miR-340-5p', 'Var', (41, 51))	('increased', 'PosReg', (81, 90))
75731	33491760	Transfection of miR-340-5p mimics decreased proliferation in HuCCT-1 cells (Fig.	('miR-340-5p', 'Chemical', '-', (16, 26))	('decreased', 'NegReg', (34, 43))	('miR-340-5p', 'Var', (16, 26))	('HuCCT-1', 'CellLine', 'CVCL:0324', (61, 68))	('proliferation', 'CPA', (44, 57))
75732	33491760	Moreover, overexpression of miR-340-5p decreased the levels of cyclin D1, whereas inhibition induced increased cyclin D1 levels (Fig.	('increased', 'PosReg', (101, 110))	('levels of cyclin D1', 'MPA', (53, 72))	('miR-340-5p', 'Chemical', '-', (28, 38))	('cyclin D1 levels', 'MPA', (111, 127))	('miR-340-5p', 'Var', (28, 38))	('decreased', 'NegReg', (39, 48))
75733	33491760	The colony formation assay indicated that overexpression of miR-340-5p decreased the cell proliferation ability of HuCCT-1 cells (Fig.	('HuCCT-1', 'CellLine', 'CVCL:0324', (115, 122))	('miR-340-5p', 'Chemical', '-', (60, 70))	('miR-340-5p', 'Var', (60, 70))	('cell proliferation ability of HuCCT-1 cells', 'CPA', (85, 128))	('decreased', 'NegReg', (71, 80))
75734	33491760	Therefore, increasing the levels of miR-340-5p inhibited cyclin D1 expression and decreased the cell proliferation ability.	('inhibited', 'NegReg', (47, 56))	('miR-340-5p', 'Chemical', '-', (36, 46))	('miR-340-5p', 'Var', (36, 46))	('increasing', 'PosReg', (11, 21))	('cyclin D1', 'Protein', (57, 66))	('cell proliferation ability', 'CPA', (96, 122))	('expression', 'MPA', (67, 77))	('decreased', 'NegReg', (82, 91))
75735	33491760	As the CCA cell line TKKK did not exhibit response to aspirin, the cell cycle progression in TKKK cells as compared to HuCCT-1 cells was assessed.	('CCA', 'Phenotype', 'HP:0030153', (7, 10))	('HuCCT-1', 'CellLine', 'CVCL:0324', (119, 126))	('cell cycle', 'CPA', (67, 77))	('aspirin', 'Chemical', 'MESH:D001241', (54, 61))	('TKKK', 'Var', (93, 97))
75738	33491760	Expression was lowest in TKKK cells, which may indicate that cell lines with high expression of miR-340-5p are more sensitive to cell cycle arrest with aspirin treatment.	('men', 'Species', '9606', (165, 168))	('cell cycle', 'CPA', (129, 139))	('arrest', 'Disease', (140, 146))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (129, 146))	('sensitive', 'MPA', (116, 125))	('aspirin', 'Chemical', 'MESH:D001241', (152, 159))	('arrest', 'Disease', 'MESH:D006323', (140, 146))	('miR-340-5p', 'Chemical', '-', (96, 106))	('more', 'PosReg', (111, 115))	('miR-340-5p', 'Var', (96, 106))
75762	33491760	miR-340-5p that was significantly upregulated in response to aspirin treatment in cells, was not significantly different in tumor tissue, although the relative quantification (RQ) was slightly increased in the two aspirin-treated groups.	('relative quantification', 'MPA', (151, 174))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('aspirin', 'Chemical', 'MESH:D001241', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('upregulated', 'PosReg', (34, 45))	('tumor', 'Disease', (124, 129))	('miR-340-5p', 'Chemical', '-', (0, 10))	('increased', 'PosReg', (193, 202))	('miR-340-5p', 'Var', (0, 10))	('men', 'Species', '9606', (74, 77))	('aspirin', 'Chemical', 'MESH:D001241', (214, 221))
75763	33491760	Recent studies have indicated that miR-340-5p inhibited non-small cell lung cancer cell growth and metastasis by targeting ZNF503 and suppressed osteo-sarcoma development via targeting STAT3.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (60, 82))	('non-small cell', 'CPA', (56, 70))	('osteo-sarcoma', 'Disease', (145, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('suppressed', 'NegReg', (134, 144))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('miR-340-5p', 'Chemical', '-', (35, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('targeting', 'Reg', (113, 122))	('osteo-sarcoma', 'Disease', 'MESH:D012509', (145, 158))	('men', 'Species', '9606', (166, 169))	('ZNF503', 'Gene', '84858', (123, 129))	('miR-340-5p', 'Var', (35, 45))	('inhibited', 'NegReg', (46, 55))	('STAT3', 'Gene', (185, 190))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (56, 82))	('ZNF503', 'Gene', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('STAT3', 'Gene', '6774', (185, 190))	('lung cancer', 'Disease', (71, 82))
75764	33491760	In the present study, overexpression of miR-340-5p inhibited proliferation in HuCCT-1 cells.	('miR-340-5p', 'Chemical', '-', (40, 50))	('overexpression', 'PosReg', (22, 36))	('miR-340-5p', 'Var', (40, 50))	('HuCCT-1', 'CellLine', 'CVCL:0324', (78, 85))	('inhibited', 'NegReg', (51, 60))
75765	33491760	In addition, overexpression of miR-340-5p decreased the levels of cyclin D1.	('levels of cyclin D1', 'MPA', (56, 75))	('miR-340-5p', 'Chemical', '-', (31, 41))	('decreased', 'NegReg', (42, 51))	('miR-340-5p', 'Var', (31, 41))
75766	33491760	The predicted sequence from the miRDB database and bioinformatics analysis indicated that cyclin D1 may be an miR-340-5p target, and miR-340-5p overexpression decreased cyclin D1 levels in cells; immunohistochemical staining indicated that cyclin D1-positive cells in aspirin-treated mice were reduced compared with control mice.	('miR-340-5p', 'Chemical', '-', (133, 143))	('miR-340-5p', 'Var', (133, 143))	('cyclin D1 levels', 'MPA', (169, 185))	('overexpression', 'PosReg', (144, 158))	('decreased', 'NegReg', (159, 168))	('aspirin', 'Chemical', 'MESH:D001241', (268, 275))	('mice', 'Species', '10090', (324, 328))	('reduced', 'NegReg', (294, 301))	('miR-340-5p', 'Chemical', '-', (110, 120))	('mice', 'Species', '10090', (284, 288))
75767	33491760	Therefore, it is theorized that aspirin works partially through the miR-340-5p/cyclin D1 axis to inhibit HuCCT-1 cell proliferation.	('inhibit', 'NegReg', (97, 104))	('HuCCT-1', 'CellLine', 'CVCL:0324', (105, 112))	('miR-340-5p', 'Chemical', '-', (68, 78))	('miR-340-5p/cyclin', 'Var', (68, 85))	('HuCCT-1 cell proliferation', 'CPA', (105, 131))	('aspirin', 'Chemical', 'MESH:D001241', (32, 39))
75803	33362909	Because of the inconsistent results of the previous evidence, we performed this study using the National Health Insurance Research Database (NHIRD) 2004-2011 of Taiwan to clarify the risk of cholangiocarcinoma after ES/EPBD, ES/EPBD and CCY, and supportive care with no invasive intervention in patients who were admitted to the hospital because of choledocholithiasis.	('choledocholithiasis', 'Disease', (349, 368))	('ES/EPBD', 'Chemical', '-', (216, 223))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (191, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('patients', 'Species', '9606', (295, 303))	('ES/EPBD', 'Var', (225, 232))	('choledocholithiasis', 'Disease', 'MESH:D042883', (349, 368))	('ES/EPBD', 'Chemical', '-', (225, 232))	('cholangiocarcinoma', 'Disease', (191, 209))	('CCY', 'Var', (237, 240))	('ES/EPBD', 'Var', (216, 223))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (191, 209))
75813	33362909	The incidence of subsequent cholangiocarcinoma in patients in the ES/EPBD, ES/EPBD and CCY, or no intervention group was compared with that of the normal population.	('ES/EPBD', 'Var', (66, 73))	('cholangiocarcinoma', 'Disease', (28, 46))	('ES/EPBD', 'Chemical', '-', (66, 73))	('patients', 'Species', '9606', (50, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('ES/EPBD', 'Var', (75, 82))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (28, 46))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (28, 46))	('ES/EPBD', 'Chemical', '-', (75, 82))
75827	33362909	Thirty-nine (7.63%) patients were diagnosed with cholangiocarcinoma in the ES/EPBD group, while 90 cholangiocarcinoma (6.06%) patients were found in the no intervention group and four (4.00%) were diagnosed in the ES/EPBD and CCY group.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (99, 117))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (99, 117))	('cholangiocarcinoma', 'Disease', (49, 67))	('ES/EPBD', 'Var', (75, 82))	('ES/EPBD', 'Chemical', '-', (214, 221))	('patients', 'Species', '9606', (20, 28))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (49, 67))	('patients', 'Species', '9606', (126, 134))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (49, 67))	('cholangiocarcinoma', 'Disease', (99, 117))	('ES/EPBD', 'Chemical', '-', (75, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
75829	33362909	After the exclusion, 12 (2.35%), 11 (0.74%), and 1 (1.00%) subsequent cholangiocarcinoma cases were diagnosed in the ES/EPBD, no intervention, and ES/EPBD and CCY groups, respectively.	('ES/EPBD', 'Var', (117, 124))	('ES/EPBD', 'Chemical', '-', (147, 154))	('cholangiocarcinoma', 'Disease', (70, 88))	('ES/EPBD', 'Chemical', '-', (117, 124))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (70, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))
75834	33362909	The cumulative subsequent cholangiocarcinoma rates in the ES/EPBD, ES/EPBD and CCY, no intervention, and control groups are shown in Figure 3.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (26, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (26, 44))	('ES/EPBD', 'Var', (67, 74))	('ES/EPBD', 'Chemical', '-', (67, 74))	('cholangiocarcinoma', 'Disease', (26, 44))	('ES/EPBD', 'Var', (58, 65))	('ES/EPBD', 'Chemical', '-', (58, 65))
75835	33362909	As for the comparisons between the patients who had undergone ES/EPBD, ES/EPBD and CCY, and no intervention for choledocholithiasis and the normal population, the incidence of cholangiocarcinoma after the first 18 mo was compared using incidence rate/1000 person-years.	('choledocholithiasis', 'Disease', 'MESH:D042883', (112, 131))	('ES/EPBD', 'Chemical', '-', (62, 69))	('cholangiocarcinoma', 'Disease', (176, 194))	('ES/EPBD', 'Var', (71, 78))	('ES/EPBD', 'Chemical', '-', (71, 78))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (176, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (176, 194))	('patients', 'Species', '9606', (35, 43))	('choledocholithiasis', 'Disease', (112, 131))
75836	33362909	In the ES/EPBD group, the incidence of subsequent cholangiocarcinoma was 7.23 (3.92-12.29) per 1000 person-years, which is more than 25 times the incidence in the normal population.	('ES/EPBD', 'Chemical', '-', (7, 14))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (50, 68))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (50, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('cholangiocarcinoma', 'Disease', (50, 68))	('ES/EPBD', 'Var', (7, 14))
75838	33362909	In the ES/EPBD and CCY group, the incidence of subsequent cholangiocarcinoma was 2.54 (0.13-12.55) per 1000 person-years, which was higher than that of the normal population.	('ES/EPBD', 'Chemical', '-', (7, 14))	('cholangiocarcinoma', 'Disease', (58, 76))	('CCY', 'Var', (19, 22))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('ES/EPBD', 'Var', (7, 14))
75840	33362909	The incidence of subsequent cholangiocarcinoma was the highest in the ES/EPBD group, and it was almost equal in the ES/EPBD and CCY and no intervention groups.	('cholangiocarcinoma', 'Disease', (28, 46))	('ES/EPBD', 'Chemical', '-', (116, 123))	('ES/EPBD', 'Chemical', '-', (70, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (28, 46))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (28, 46))	('ES/EPBD', 'Var', (70, 77))
75844	33362909	Meanwhile, the incidence of subsequent cholangiocarcinoma was highest in the ES/EPBD group at 7.23/1000 person-years.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (39, 57))	('ES/EPBD', 'Var', (77, 84))	('cholangiocarcinoma', 'Disease', (39, 57))	('ES/EPBD', 'Chemical', '-', (77, 84))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (39, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
75856	33362909	The comparison among the choledocholithiasis patients who had undergone ES/EPBD, ES/EPBD and CCY, and no intervention showed no statistically significant differences regarding previous risk factors for cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (202, 220))	('ES/EPBD', 'Chemical', '-', (72, 79))	('choledocholithiasis', 'Disease', (25, 44))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (202, 220))	('ES/EPBD', 'Var', (81, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (202, 220))	('patients', 'Species', '9606', (45, 53))	('choledocholithiasis', 'Disease', 'MESH:D042883', (25, 44))	('ES/EPBD', 'Chemical', '-', (81, 88))
75857	33362909	Because the cholangiocarcinoma incidence was obviously higher during the first 6 mo after index admission in the ES/EPBD and ES/EPBD and CCY groups, we considered these events as initial misdiagnoses or concurrent cholangiocarcinoma events.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (12, 30))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (12, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('ES/EPBD', 'Var', (125, 132))	('cholangiocarcinoma', 'Disease', (12, 30))	('ES/EPBD', 'Var', (113, 120))	('ES/EPBD', 'Chemical', '-', (125, 132))	('cholangiocarcinoma', 'Disease', (214, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('higher', 'PosReg', (55, 61))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (214, 232))	('ES/EPBD', 'Chemical', '-', (113, 120))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (214, 232))
75860	33362909	The subsequent cholangiocarcinoma cumulative risk was highest in the ES/EPBD group, and the cumulative risk for subsequent cholangiocarcinoma in the no intervention group gradually exceeded that of the ES/EPBD and CCY group as the observation time went by.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (15, 33))	('highest', 'Reg', (54, 61))	('cholangiocarcinoma', 'Disease', (123, 141))	('ES/EPBD', 'Chemical', '-', (202, 209))	('ES/EPBD', 'Var', (69, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (123, 141))	('ES/EPBD', 'Chemical', '-', (69, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (123, 141))	('cholangiocarcinoma', 'Disease', (15, 33))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (15, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))
75861	33362909	The overall subsequent cholangiocarcinoma hazard ratios were 3.45, 1.31, and 1.0 in the ES/EPBD, ES/EPBD and CCY, and no intervention groups, respectively.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (23, 41))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (23, 41))	('ES/EPBD', 'Var', (97, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('ES/EPBD', 'Var', (88, 95))	('ES/EPBD', 'Chemical', '-', (97, 104))	('cholangiocarcinoma', 'Disease', (23, 41))	('ES/EPBD', 'Chemical', '-', (88, 95))
75873	33362909	Second, although this study used a representative database sample of one million patients, the incidence of cholangiocarcinoma was low, and we could only find 12, 1, and 11 cases in the ES/EPBD, ES/EPBD, and CCY and no intervention groups, respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('ES/EPBD', 'Chemical', '-', (195, 202))	('ES/EPBD', 'Var', (186, 193))	('cholangiocarcinoma', 'Disease', (108, 126))	('patients', 'Species', '9606', (81, 89))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (108, 126))	('ES/EPBD', 'Chemical', '-', (186, 193))	('ES/EPBD', 'Var', (195, 202))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (108, 126))
75885	33362909	This study not only showed different subsequent cholangiocarcinoma risks in the ES/EPBD, ES/EPBD and CCY, and no intervention groups of symptomatic choledocholithiasis patients, but also the significant relationship between the incidence of RBEs and that of subsequent cholangiocarcinoma.	('choledocholithiasis', 'Disease', 'MESH:D042883', (148, 167))	('cholangiocarcinoma', 'Disease', (48, 66))	('cholangiocarcinoma', 'Disease', (269, 287))	('ES/EPBD', 'Disease', (80, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('choledocholithiasis', 'Disease', (148, 167))	('ES/EPBD', 'Chemical', '-', (80, 87))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (48, 66))	('ES/EPBD', 'Var', (89, 96))	('patients', 'Species', '9606', (168, 176))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (269, 287))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (48, 66))	('ES/EPBD', 'Chemical', '-', (89, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (269, 287))
75929	29271385	These results showed that when the expression of DcR3 was knocked down in TFK-1 cells, cell viability decreased.	('DcR3', 'Gene', '8771', (49, 53))	('cell viability', 'CPA', (87, 101))	('DcR3', 'Gene', (49, 53))	('knocked', 'Var', (58, 65))	('expression', 'MPA', (35, 45))	('decreased', 'NegReg', (102, 111))
75933	29271385	Based on the findings of this experiment, it has been demonstrated that apoptosis increased when knocking down the expression of DcR3 in TFK-1 cells.	('knocking down', 'Var', (97, 110))	('DcR3', 'Gene', '8771', (129, 133))	('expression', 'MPA', (115, 125))	('apoptosis', 'CPA', (72, 81))	('DcR3', 'Gene', (129, 133))
75949	29271385	In this study, we found that after the interference of DcR3-siRNA, the proportion of apoptotic cells increased, and cell viability significantly decreased compared with the control.	('DcR3', 'Gene', '8771', (55, 59))	('interference', 'Var', (39, 51))	('DcR3', 'Gene', (55, 59))	('decreased', 'NegReg', (145, 154))	('cell viability', 'CPA', (116, 130))
75971	25473388	In the context of the biliary ducts, disruption of normal luminal flow of bile can lead to obstructive jaundice.	('disruption', 'Var', (37, 47))	('obstructive jaundice', 'Disease', 'MESH:D041781', (91, 111))	('obstructive jaundice', 'Disease', (91, 111))	('lead to', 'Reg', (83, 90))	('jaundice', 'Phenotype', 'HP:0000952', (103, 111))
76075	25143751	TNF-alpha and the TH2 cytokines IL-4 and IL-13, for example, can lead to mutations in the TP53 gene by amplification of activation-induced cytidine deaminase expression.	('TNF-alpha', 'Gene', (0, 9))	('IL-13', 'Gene', (41, 46))	('cytidine deaminase', 'Gene', '978', (139, 157))	('IL-4', 'Gene', '3565', (32, 36))	('expression', 'MPA', (158, 168))	('TP53', 'Gene', '7157', (90, 94))	('IL-4', 'Gene', (32, 36))	('IL-13', 'Gene', '3596', (41, 46))	('amplification', 'PosReg', (103, 116))	('lead to', 'Reg', (65, 72))	('TP53', 'Gene', (90, 94))	('cytidine deaminase', 'Gene', (139, 157))	('TNF-alpha', 'Gene', '7124', (0, 9))	('mutations', 'Var', (73, 82))
76077	25143751	The dimension of genomic instability together with impaired MMR and cell cycle control in chronic inflammation is emphasized by a high frequency of p53 mutations in chronic inflammatory diseases such as rheumatoid arthritis.	('rheumatoid arthritis', 'Disease', (203, 223))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (203, 223))	('mutations', 'Var', (152, 161))	('p53', 'Gene', (148, 151))	('p53', 'Gene', '7157', (148, 151))	('chronic inflammation', 'Disease', 'MESH:D007249', (90, 110))	('arthritis', 'Phenotype', 'HP:0001369', (214, 223))	('chronic inflammation', 'Disease', (90, 110))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (203, 223))
76085	25143751	Persistence of this mutagenic environment in chronic inflammation enables cells to accumulate several mutations that are required for neoplastic transformation.	('chronic inflammation', 'Disease', (45, 65))	('mutations', 'Var', (102, 111))	('chronic inflammation', 'Disease', 'MESH:D007249', (45, 65))
76086	25143751	For example, Kras and p53 gene mutations are very common in patients with GI malignancies.	('mutations', 'Var', (31, 40))	('GI malignancies', 'Disease', (74, 89))	('Kras', 'Gene', (13, 17))	('patients', 'Species', '9606', (60, 68))	('p53', 'Gene', (22, 25))	('common', 'Reg', (50, 56))	('GI malignancies', 'Disease', 'MESH:D009369', (74, 89))	('Kras', 'Gene', '3845', (13, 17))	('p53', 'Gene', '7157', (22, 25))
76110	25143751	Inhibition of IL-1 in a metastatic mouse model actually revealed a distinct decrease in the rate of metastasis.	('Inhibition', 'Var', (0, 10))	('decrease', 'NegReg', (76, 84))	('IL-1', 'Gene', (14, 18))	('mouse', 'Species', '10090', (35, 40))
76144	25143751	Consistently, inhibition of COX-2 inhibits proliferation of Barrett's mucosal cells.	('COX-2', 'Gene', '5743', (28, 33))	('inhibits', 'NegReg', (34, 42))	('proliferation', 'CPA', (43, 56))	('inhibition', 'Var', (14, 24))	('COX-2', 'Gene', (28, 33))
76172	25143751	In contrast with sporadic CRC, p53 mutations occur rather early in disease development, and APC mutations rather late.	('p53', 'Gene', '7157', (31, 34))	('p53', 'Gene', (31, 34))	('APC', 'Disease', 'MESH:D011125', (92, 95))	('APC', 'Disease', (92, 95))	('CRC', 'Phenotype', 'HP:0003003', (26, 29))	('mutations', 'Var', (35, 44))
76173	25143751	Downregulation of tumor-suppressor genes by hypermethylation was often found at sites of chronic inflammation, and recently the role of intestinal pathogens in carcinogenesis has attracted increasing attention.	('carcinogenesis', 'Disease', 'MESH:D063646', (160, 174))	('tumor', 'Disease', (18, 23))	('Downregulation', 'NegReg', (0, 14))	('carcinogenesis', 'Disease', (160, 174))	('chronic inflammation', 'Disease', 'MESH:D007249', (89, 109))	('hypermethylation', 'Var', (44, 60))	('chronic inflammation', 'Disease', (89, 109))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
76178	25143751	As mutations found in hereditary pancreatitis differ from those found in tumors, this epidemiologic observation has to be based on enhanced carcinogenesis due to inflammation.	('inflammation', 'Disease', 'MESH:D007249', (162, 174))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('inflammation', 'Disease', (162, 174))	('carcinogenesis', 'Disease', 'MESH:D063646', (140, 154))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('pancreatitis', 'Phenotype', 'HP:0001733', (33, 45))	('carcinogenesis', 'Disease', (140, 154))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('hereditary pancreatitis', 'Disease', 'MESH:C537262', (22, 45))	('tumors', 'Disease', (73, 79))	('hereditary pancreatitis', 'Disease', (22, 45))	('mutations', 'Var', (3, 12))
76183	25143751	Concomitantly, inhibition of TGF-beta signaling in pancreatic cancer resulted in increased survival.	('survival', 'CPA', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('TGF-beta', 'Gene', '7040', (29, 37))	('pancreatic cancer', 'Disease', (51, 68))	('TGF-beta', 'Gene', (29, 37))	('pancreatic cancer', 'Disease', 'MESH:D010190', (51, 68))	('increased', 'PosReg', (81, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (51, 68))	('inhibition', 'Var', (15, 25))
76188	25143751	Oncogenic Ras (KrasG12D) induces the secretion of IL-6 from different cell types, and genetic inactivation of IL-6 impedes Ras-driven tumorigenesis.	('IL-6', 'Gene', '3569', (110, 114))	('IL-6', 'Gene', (50, 54))	('KrasG12D', 'Gene', '3845', (15, 23))	('impedes', 'NegReg', (115, 122))	('IL-6', 'Gene', '3569', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('genetic inactivation', 'Var', (86, 106))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('IL-6', 'Gene', (110, 114))	('KrasG12D', 'Gene', (15, 23))	('tumor', 'Disease', (134, 139))	('secretion', 'MPA', (37, 46))
76189	25143751	The activation of mutant Kras (KrasG12D) in pancreatic ductal epithelial cells reprograms the tumor microenvironment and is associated with a robust inflammatory response characterized by release of inflammatory cytokines, such as granulocyte macrophage (GM)-CSF.	('Kras', 'Gene', '3845', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutant', 'Var', (18, 24))	('pancreatic', 'Disease', 'MESH:D010195', (44, 54))	('KrasG12D', 'Gene', (31, 39))	('tumor', 'Disease', (94, 99))	('release', 'MPA', (188, 195))	('KrasG12D', 'Gene', '3845', (31, 39))	('Kras', 'Gene', (25, 29))	('pancreatic', 'Disease', (44, 54))	('Kras', 'Gene', (31, 35))	('Kras', 'Gene', '3845', (25, 29))	('activation', 'PosReg', (4, 14))
76193	25143751	Pancreatic epithelial STAT3 deletion and inactivation of IL-6 trans-signaling impairs PanIN formation and inhibits PDAC development.	('inhibits', 'NegReg', (106, 114))	('PDAC', 'Phenotype', 'HP:0006725', (115, 119))	('impairs', 'NegReg', (78, 85))	('IL-6', 'Gene', (57, 61))	('STAT3', 'Gene', '6774', (22, 27))	('inactivation', 'Var', (41, 53))	('PDAC development', 'CPA', (115, 131))	('PanIN formation', 'CPA', (86, 101))	('STAT3', 'Gene', (22, 27))	('IL-6', 'Gene', '3569', (57, 61))	('PDAC', 'Chemical', '-', (115, 119))	('deletion', 'Var', (28, 36))
76213	25143751	Taken together, accumulation of mutations during inflammation-driven fibrosis or cirrhosis is a prerequisite for HCC development.	('cirrhosis', 'Phenotype', 'HP:0001394', (81, 90))	('HCC', 'Disease', (113, 116))	('fibrosis', 'Disease', 'MESH:D005355', (69, 77))	('fibrosis', 'Disease', (69, 77))	('HCC', 'Phenotype', 'HP:0001402', (113, 116))	('cirrhosis', 'Disease', 'MESH:D005355', (81, 90))	('mutations', 'Var', (32, 41))	('inflammation', 'Disease', 'MESH:D007249', (49, 61))	('cirrhosis', 'Disease', (81, 90))	('inflammation', 'Disease', (49, 61))
76236	25143751	Also, eradication of H. pylori leads to regression of GI MALT lymphomas in about 90% of the cases, and H. pylori eradication is the standard therapy for patients affected.	('H. pylori', 'Gene', (21, 30))	('patients', 'Species', '9606', (153, 161))	('H. pylori', 'Species', '210', (21, 30))	('eradication', 'Var', (6, 17))	('lymphomas', 'Phenotype', 'HP:0002665', (62, 71))	('regression', 'NegReg', (40, 50))	('H. pylori', 'Species', '210', (103, 112))	('GI MALT lymphomas', 'Disease', (54, 71))	('GI MALT lymphomas', 'Disease', 'MESH:D018442', (54, 71))	('lymphoma', 'Phenotype', 'HP:0002665', (62, 70))
76240	25143751	In patients with MALT lymphoma, eradication of H. pylori is used to induce remission in these patients.	('H. pylori', 'Species', '210', (47, 56))	('patients', 'Species', '9606', (94, 102))	('lymphoma', 'Phenotype', 'HP:0002665', (22, 30))	('MALT lymphoma', 'Disease', (17, 30))	('patients', 'Species', '9606', (3, 11))	('eradication', 'Var', (32, 43))	('MALT lymphoma', 'Disease', 'MESH:D018442', (17, 30))
76288	33299884	Another study revealed that high body mass index (BMI) was positively associated with the incidence of several types of cancer, while patients with high BMI at the time of initial diagnosis had higher two/five-year survival rates than those with low BMI.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('higher', 'PosReg', (194, 200))	('high BMI', 'Var', (148, 156))	('low BMI', 'Phenotype', 'HP:0045082', (246, 253))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('associated', 'Reg', (70, 80))	('patients', 'Species', '9606', (134, 142))	('high body mass index', 'Phenotype', 'HP:0031418', (28, 48))	('two/five-year survival rates', 'CPA', (201, 229))
76302	33299884	The patients were divided into four groups based on BMI: normal weight (18 kg/m2 <= BMI < 25 kg/m2), high weight (25 kg/m2 <= BMI < 30 kg/m2), obese (30 kg/m2 <= BMI<40 kg/m2), and extremely obese (BMI >= 40 kg/m2).	('obese', 'Disease', 'MESH:D009765', (191, 196))	('25 kg/m2 <=', 'Var', (114, 125))	('30 kg/m2 <= BMI', 'Var', (150, 165))	('obese', 'Disease', 'MESH:D009765', (143, 148))	('obese', 'Disease', (191, 196))	('patients', 'Species', '9606', (4, 12))	('obese', 'Disease', (143, 148))
76312	33299884	Mutations, copy number variations (CNVs), and controlling expression levels of obesity-related genes were downloaded from TCGA.	('Mutations', 'Var', (0, 9))	('obesity', 'Disease', (79, 86))	('obesity', 'Disease', 'MESH:D009765', (79, 86))	('obesity', 'Phenotype', 'HP:0001513', (79, 86))
76339	33299884	As displayed in Figure 2(c), for each of the five obesity-related genes (LEPR, MTCH2, MC4R, LEP, and KCTD15), the patients in a high-expression group had a greater cancer survival rate than those in the low/medium-expression groups (P < 0.05).	('KCTD15', 'Gene', '79047', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('LEP', 'Gene', '3952', (92, 95))	('KCTD15', 'Gene', (101, 107))	('obesity', 'Disease', (50, 57))	('greater', 'PosReg', (156, 163))	('patients', 'Species', '9606', (114, 122))	('LEP', 'Gene', (92, 95))	('obesity', 'Disease', 'MESH:D009765', (50, 57))	('LEPR', 'Gene', '3953', (73, 77))	('cancer', 'Disease', (164, 170))	('LEP', 'Gene', '3952', (73, 76))	('LEPR', 'Gene', (73, 77))	('MC4R', 'Gene', (86, 90))	('high-expression', 'Var', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('MTCH2', 'Gene', '23788', (79, 84))	('LEP', 'Gene', (73, 76))	('obesity', 'Phenotype', 'HP:0001513', (50, 57))	('MC4R', 'Gene', '4160', (86, 90))	('MTCH2', 'Gene', (79, 84))
76342	33299884	For patients with six types of cancer (KIRC, LUAD, LGG, GBM, UCEC, and BLCA), those in the PCSK1 low/medium-expression group had higher survival probability than those in the high-expression group.	('LUAD', 'Phenotype', 'HP:0030078', (45, 49))	('LUAD', 'Disease', (45, 49))	('LGG', 'Disease', (51, 54))	('PCSK1', 'Gene', '5122', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('survival', 'CPA', (136, 144))	('higher', 'PosReg', (129, 135))	('GBM', 'Disease', (56, 59))	('UCEC', 'Disease', (61, 65))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('patients', 'Species', '9606', (4, 12))	('PCSK1', 'Gene', (91, 96))	('cancer', 'Disease', (31, 37))	('low/medium-expression', 'Var', (97, 118))
76343	33299884	However, for patients with SKCM, patients with high expression level of PCSK1 may benefit from a superior survival probability than those with low/medium expression level.	('patients', 'Species', '9606', (33, 41))	('PCSK1', 'Gene', (72, 77))	('survival', 'CPA', (106, 114))	('patients', 'Species', '9606', (13, 21))	('high expression level', 'Var', (47, 68))	('PCSK1', 'Gene', '5122', (72, 77))	('benefit', 'PosReg', (82, 89))
76353	33299884	However, the mutation rates of five obesity-related genes in few cancer tissues were >0.05 (i.e., LEPR in SKCM (0.11), UCEC (0.07), and LUSC (0.07) and PCSK1 in SKCM (0.09) and UCEC (0.06)).	('obesity', 'Disease', 'MESH:D009765', (36, 43))	('obesity', 'Phenotype', 'HP:0001513', (36, 43))	('mutation', 'Var', (13, 21))	('LEPR', 'Gene', (98, 102))	('PCSK1', 'Gene', (152, 157))	('obesity', 'Disease', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('PCSK1', 'Gene', '5122', (152, 157))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('LEPR', 'Gene', '3953', (98, 102))
76358	33299884	Then, for each of the 33 types of cancer, the expression levels of the 13 obesity-related genes were divided into different groups based on the seven factors as follows: (1) patients' gender (male or female), (2) patients' race (African-American, Caucasian, and Asian), (3) menopausal status (premenopause, perimenopause, and postmenopause), (4) history of smoking (smoker, nonsmoker, reformed smoker #1 (<=15 years), and reformed smoker #2 (>15 years)), (5) tumor grade (grade 1, grade 2, grade 3, and grade 4), (6) BMI (normal weight (18 kg/m2 <= BMI < 25 kg/m2), high weight (25 kg/m2 <= BMI < 30 kg/m2), obese (30 kg/m2 <= BMI < 40 kg/m2), and extremely obese (BMI >= 40 kg/m2)), and (7) history of drinking (occasional drinker, social drinker, daily drinker, weekly drinker, and nondrinker).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('menopausal status', 'Phenotype', 'HP:0008209', (274, 291))	('tumor', 'Phenotype', 'HP:0002664', (459, 464))	('patients', 'Species', '9606', (213, 221))	('obese', 'Disease', (658, 663))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('obesity', 'Disease', (74, 81))	('obese', 'Disease', 'MESH:D009765', (658, 663))	('30 kg/m2 <= BMI < 40 kg/m2', 'Var', (615, 641))	('obesity', 'Disease', 'MESH:D009765', (74, 81))	('tumor', 'Disease', (459, 464))	('obese', 'Disease', (608, 613))	('25 kg/m2 <= BMI < 30 kg/m2', 'Var', (579, 605))	('tumor', 'Disease', 'MESH:D009369', (459, 464))	('3 obesity', 'Phenotype', 'HP:0025501', (72, 81))	('obese', 'Disease', 'MESH:D009765', (608, 613))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Disease', (34, 40))	('obesity', 'Phenotype', 'HP:0001513', (74, 81))
76405	33299884	For the majority of obesity-related genes, cancer patients who were in low/medium-expression level group had a superior prognosis than those in the high-expression level group.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('patients', 'Species', '9606', (50, 58))	('cancer', 'Disease', (43, 49))	('obesity', 'Phenotype', 'HP:0001513', (20, 27))	('low/medium-expression level', 'Var', (71, 98))	('obesity', 'Disease', 'MESH:D009765', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('obesity', 'Disease', (20, 27))
76408	33299884	However, for three types of cancer (SKCM, ACC, and LUAD), patients in the high-expression group for GPR120 gene could benefit from a greater prognosis as compared to those in the low/medium-expression level group.	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('high-expression', 'Var', (74, 89))	('benefit', 'PosReg', (118, 125))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('GPR120', 'Gene', '338557', (100, 106))	('GPR120', 'Gene', (100, 106))	('cancer', 'Disease', (28, 34))
76409	33299884	Moreover, for four types of cancer (KIRP, UVM, CESC, and LUSC), patients in the high-expression level group for SH2B1 gene experienced a better prognosis than those in the low/medium-expression level group.	('SH2B1', 'Gene', (112, 117))	('better', 'PosReg', (137, 143))	('high-expression level', 'Var', (80, 101))	('patients', 'Species', '9606', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('UVM', 'Disease', (42, 45))	('CESC', 'Disease', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('SH2B1', 'Gene', '25970', (112, 117))
76414	33299884	According to the Kaplan-Meier survival curves, patients with kidney cancer in the low/medium-expression level group for each of LEPR and NEGR1 genes had a long-time life expectancy in comparison to those in the high-expression level group.	('NEGR1', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('kidney cancer', 'Disease', (61, 74))	('LEPR', 'Gene', '3953', (128, 132))	('patients', 'Species', '9606', (47, 55))	('low/medium-expression level', 'Var', (82, 109))	('kidney cancer', 'Disease', 'MESH:D007680', (61, 74))	('kidney cancer', 'Phenotype', 'HP:0009726', (61, 74))	('LEPR', 'Gene', (128, 132))	('NEGR1', 'Gene', '257194', (137, 142))
76415	33299884	However, patients with kidney cancer in the high-expression level group for each of TMEM18 and SH2B1 genes had a long life expectancy than those who in the low/medium-expression level group.	('TMEM18', 'Gene', '129787', (84, 90))	('kidney cancer', 'Disease', (23, 36))	('SH2B1', 'Gene', '25970', (95, 100))	('patients', 'Species', '9606', (9, 17))	('SH2B1', 'Gene', (95, 100))	('TMEM18', 'Gene', (84, 90))	('high-expression level', 'Var', (44, 65))	('kidney cancer', 'Disease', 'MESH:D007680', (23, 36))	('kidney cancer', 'Phenotype', 'HP:0009726', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
76422	33299884	Once mutations or modify alterations occur for obesity gene, microenvironment probably impacts behavior and adaptive evolution of cancer cells.	('behavior', 'CPA', (95, 103))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('obesity', 'Disease', 'MESH:D009765', (47, 54))	('mutations', 'Var', (5, 14))	('obesity', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('impacts', 'Reg', (87, 94))	('obesity', 'Phenotype', 'HP:0001513', (47, 54))
76500	30918596	In total, 27 patients (5.03%) were diagnosed with cholangiocarcinoma in the ES/EPBD group, while 105 (1.86%) were diagnosed with cholangiocarcinoma in the no intervention group, and 15 (0.86%) were diagnosed in the cholecystectomy group during the follow-up period.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (50, 68))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (129, 147))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (50, 68))	('ES/EPBD', 'Var', (76, 83))	('patients', 'Species', '9606', (13, 21))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (129, 147))	('cholangiocarcinoma', 'Disease', (50, 68))	('cholangiocarcinoma', 'Disease', (129, 147))
76503	30918596	The odds ratio for subsequent cholangiocarcinoma was 3.13 in the ES/EPBD group and 0.61 in cholecystectomy group when compared with the no intervention group.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (30, 48))	('cholangiocarcinoma', 'Disease', (30, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (30, 48))	('ES/EPBD', 'Var', (65, 72))
76523	30918596	The odds ratio of ES/EPBD patients for cholangiocarcinoma was 3.13 when compared with no intervention, indicating that the subsequent cholangiocarcinoma rate was high after ES/EPBD in cholelithiasis patients.	('cholelithiasis', 'Disease', (184, 198))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (134, 152))	('cholelithiasis', 'Disease', 'MESH:D002769', (184, 198))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (39, 57))	('ES/EPBD', 'Var', (173, 180))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (134, 152))	('patients', 'Species', '9606', (26, 34))	('cholangiocarcinoma', 'Disease', (39, 57))	('patients', 'Species', '9606', (199, 207))	('cholangiocarcinoma', 'Disease', (134, 152))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (39, 57))	('cholelithiasis', 'Phenotype', 'HP:0001081', (184, 198))
76546	30918596	Patients underwent ES/EPBD are in a high risk of subsequent cholangiocarcinoma and a follow-up plane should be needed in these kinds of patients.	('cholangiocarcinoma', 'Disease', (60, 78))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (60, 78))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (60, 78))	('ES/EPBD', 'Var', (19, 26))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (136, 144))
76560	23986636	Viability was decreased in cells treated with nanoparticles at acidic pH, whereas cell viability in response to treatment with doxorubicin did not vary according to changes of pH.	('nanoparticles', 'Var', (46, 59))	('doxorubicin', 'Chemical', 'MESH:D004317', (127, 138))	('decreased', 'NegReg', (14, 23))
76568	23986636	Putnam et al reported that polyhistidine-poly(ethylene glycol) (PEG) conjugates have low cytotoxicity against macrophage cells and that their nanocomplexes with DNA have similar transfection efficiency compared with DNA-polylysine complexes.	('polyhistidine-poly(ethylene glycol)', 'Chemical', '-', (27, 62))	('PEG', 'Chemical', '-', (64, 67))	('cytotoxicity', 'Disease', (89, 101))	('polyhistidine-poly', 'Var', (27, 45))	('polylysine', 'Chemical', 'MESH:D011107', (220, 230))	('transfection', 'CPA', (178, 190))	('cytotoxicity', 'Disease', 'MESH:D064420', (89, 101))
76569	23986636	Liu et al reported that pH-sensitive nanoparticles containing PEG-PHS-poly(L-lactic acid) block copolymer showed pH-responsive drug release behavior and enhanced anticancer activity at acidic pH.	('cancer', 'Disease', (166, 172))	('pH-responsive drug release behavior', 'MPA', (113, 148))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('PHS', 'Chemical', 'MESH:C033223', (66, 69))	('block copolymer', 'Chemical', '-', (90, 105))	('PEG', 'Chemical', '-', (62, 65))	('PEG-PHS-poly', 'Var', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('poly(L-lactic acid)', 'Chemical', 'MESH:C033616', (70, 89))	('enhanced', 'PosReg', (153, 161))
76639	23986636	These results might be due to the fact that the drug content of the DexPHS-2 nanoparticles was slightly higher than that of the DexPHS-1 nanoparticles and that higher drug contents induce larger particle sizes.	('DexPHS-2', 'Var', (68, 76))	('higher', 'PosReg', (160, 166))	('higher', 'PosReg', (104, 110))	('drug content', 'MPA', (48, 60))	('particle sizes', 'MPA', (195, 209))	('DexPHS', 'Chemical', '-', (128, 134))	('larger', 'PosReg', (188, 194))	('DexPHS', 'Chemical', '-', (68, 74))
76750	29221199	For the part of functional assays, knockdown of UCA1 could attenuate CCA cell growth both in vitro and in vivo.	('UCA1', 'Gene', (48, 52))	('knockdown', 'Var', (35, 44))	('attenuate', 'NegReg', (59, 68))	('CCA', 'Phenotype', 'HP:0030153', (69, 72))	('CCA', 'Disease', (69, 72))	('UCA1', 'Gene', '652995', (48, 52))
76761	29221199	Recently, aberrant expression of lncRNAs has been shown to be involved in multiple cancer pathogenesis and recognized as oncogenes or tumor suppressors, such as PANDAR, TUG1, H19 and etc.	('H19', 'Gene', (175, 178))	('multiple cancer', 'Disease', (74, 89))	('lncRNAs', 'Protein', (33, 40))	('PANDAR', 'Gene', '101154753', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('PANDAR', 'Gene', (161, 167))	('TUG1', 'Gene', '55000', (169, 173))	('multiple cancer', 'Disease', 'MESH:D009369', (74, 89))	('involved', 'Reg', (62, 70))	('aberrant expression', 'Var', (10, 29))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('TUG1', 'Gene', (169, 173))	('H19', 'Gene', '283120', (175, 178))	('tumor', 'Disease', (134, 139))
76777	29221199	To further explore the clinical significance of aberrant UCA1 expression, the correlation between UCA1 and CCA patients' clinical and pathologic features were investigated.	('CCA', 'Disease', (107, 110))	('UCA1', 'Gene', '652995', (57, 61))	('UCA1', 'Gene', (57, 61))	('CCA', 'Phenotype', 'HP:0030153', (107, 110))	('aberrant', 'Var', (48, 56))	('UCA1', 'Gene', '652995', (98, 102))	('UCA1', 'Gene', (98, 102))	('patients', 'Species', '9606', (111, 119))
76791	29221199	CCK-8 and colony formation assays demonstrated that depletion of UCA1 significantly suppressed the proliferative activity and clone formation quantity of CCLP1 and RBE cells (Figure 2C and 2D).	('UCA1', 'Gene', (65, 69))	('proliferative activity', 'CPA', (99, 121))	('depletion', 'Var', (52, 61))	('clone formation quantity', 'CPA', (126, 150))	('suppressed', 'NegReg', (84, 94))	('UCA1', 'Gene', '652995', (65, 69))
76794	29221199	While the cell population in S phase was reduced remarkedly after UCA1 silenced.	('UCA1', 'Gene', '652995', (66, 70))	('reduced', 'NegReg', (41, 48))	('silenced', 'Var', (71, 79))	('UCA1', 'Gene', (66, 70))	('cell population in S phase', 'CPA', (10, 36))
76797	29221199	While for the two UCA1 knockdown groups, apoptotic cells increased dramatically.	('UCA1', 'Gene', (18, 22))	('apoptotic cells', 'CPA', (41, 56))	('knockdown', 'Var', (23, 32))	('increased', 'PosReg', (57, 66))	('UCA1', 'Gene', '652995', (18, 22))
76798	29221199	Meanwhile, the expression of caspase-3 and caspase-9 were both activated after UCA1 silenced (Figure 3B).	('UCA1', 'Gene', (79, 83))	('caspase-3', 'Gene', '836', (29, 38))	('caspase-3', 'Gene', (29, 38))	('caspase-9', 'Gene', (43, 52))	('expression', 'MPA', (15, 25))	('activated', 'PosReg', (63, 72))	('silenced', 'Var', (84, 92))	('caspase-9', 'Gene', '842', (43, 52))	('UCA1', 'Gene', '652995', (79, 83))
76802	29221199	Given that high expression of UCA1 is associated with lymph node invasion in CCA samples, we introduced wound healing and Transwell assays to shed light on the metastasis-promoting role of UCA1 on CCA.	('associated with', 'Reg', (38, 53))	('lymph node invasion', 'CPA', (54, 73))	('high', 'Var', (11, 15))	('CCA', 'Phenotype', 'HP:0030153', (197, 200))	('UCA1', 'Gene', '652995', (30, 34))	('UCA1', 'Gene', (30, 34))	('UCA1', 'Gene', '652995', (189, 193))	('CCA', 'Phenotype', 'HP:0030153', (77, 80))	('UCA1', 'Gene', (189, 193))
76804	29221199	In line with the results of wound healing assay, Transwell migration assays demonstrated that the cells passed through the membrane were dramatically decreased in the UCA1 depletion groups compared with the si-NC groups (Figure 4B).	('cells passed through the membrane', 'CPA', (98, 131))	('UCA1', 'Gene', '652995', (167, 171))	('UCA1', 'Gene', (167, 171))	('depletion', 'Var', (172, 181))	('decreased', 'NegReg', (150, 159))
76810	29221199	As demonstrated in Figure 5A and 5B, 18 days after inoculation, silencing of UCA1 significantly suppressed the growth of CCA xenografts.	('CCA', 'Disease', (121, 124))	('growth', 'CPA', (111, 117))	('UCA1', 'Gene', '652995', (77, 81))	('CCA', 'Phenotype', 'HP:0030153', (121, 124))	('UCA1', 'Gene', (77, 81))	('suppressed', 'NegReg', (96, 106))	('silencing', 'Var', (64, 73))
76813	29221199	Additionally, silencing of UCA1 also reversed the EMT related markers (Figure 5E).	('silencing', 'Var', (14, 23))	('reversed', 'Reg', (37, 45))	('EMT related markers', 'CPA', (50, 69))	('UCA1', 'Gene', '652995', (27, 31))	('UCA1', 'Gene', (27, 31))
76815	29221199	As a result, we found MMP-9 was down-regulated after silencing of UCA1 proved by Western blot analysis (Figure 5E).	('UCA1', 'Gene', '652995', (66, 70))	('UCA1', 'Gene', (66, 70))	('MMP-9', 'Gene', '4318', (22, 27))	('silencing', 'Var', (53, 62))	('MMP-9', 'Gene', (22, 27))	('down-regulated', 'NegReg', (32, 46))
76821	29221199	The results demonstrated that knockdown of UCA1 did not affect the total expression of AKT proteins but dramatically reduced phosphorylation-AKT (p-AKT) in CCLP1 and RBE cells than that in si-NC cells.	('AKT', 'Gene', '207', (148, 151))	('AKT', 'Gene', (87, 90))	('reduced', 'NegReg', (117, 124))	('AKT', 'Gene', (141, 144))	('UCA1', 'Gene', '652995', (43, 47))	('UCA1', 'Gene', (43, 47))	('AKT', 'Gene', (148, 151))	('knockdown', 'Var', (30, 39))	('AKT', 'Gene', '207', (141, 144))	('AKT', 'Gene', '207', (87, 90))
76829	29221199	A recent research demonstrated that over-expressed UCA1 contributes to poor prognosis in patients with multiple myeloma.	('multiple myeloma', 'Disease', 'MESH:D009101', (103, 119))	('multiple myeloma', 'Phenotype', 'HP:0006775', (103, 119))	('over-expressed', 'Var', (36, 50))	('multiple myeloma', 'Disease', (103, 119))	('patients', 'Species', '9606', (89, 97))	('UCA1', 'Gene', '652995', (51, 55))	('UCA1', 'Gene', (51, 55))
76830	29221199	's study, patients with high expression of UCA1 had worse survival than those with low expression of UCA1.	('UCA1', 'Gene', '652995', (101, 105))	('UCA1', 'Gene', (101, 105))	('UCA1', 'Gene', '652995', (43, 47))	('worse', 'NegReg', (52, 57))	('UCA1', 'Gene', (43, 47))	('high expression', 'Var', (24, 39))	('patients', 'Species', '9606', (10, 18))	('survival', 'MPA', (58, 66))
76833	29221199	Our experiments verified that knockdown of UCA1 resulted in attenuation of CCA cell proliferation by arresting cell cycle.	('arresting', 'NegReg', (101, 110))	('CCA', 'Disease', (75, 78))	('attenuation', 'NegReg', (60, 71))	('cell cycle', 'CPA', (111, 121))	('UCA1', 'Gene', '652995', (43, 47))	('UCA1', 'Gene', (43, 47))	('knockdown', 'Var', (30, 39))	('CCA', 'Phenotype', 'HP:0030153', (75, 78))
76839	29221199	In the present study, the results indicated that UCA1 serves as a defender against CCA cell apoptosis, and apoptosis-associated factors (caspase-3, -9) were both increased followed by knockdown of UCA1.	('knockdown', 'Var', (184, 193))	('increased', 'PosReg', (162, 171))	('UCA1', 'Gene', '652995', (197, 201))	('UCA1', 'Gene', (197, 201))	('CCA', 'Phenotype', 'HP:0030153', (83, 86))	('UCA1', 'Gene', '652995', (49, 53))	('UCA1', 'Gene', (49, 53))	('caspase-3, -9', 'Gene', '836;842', (137, 150))
76843	29221199	Overexpressed UCA1 in CCA samples is associated with positive lymphnode invasion promoted us to explore the potential influence of UCA1 on CCA cell migration and invasion.	('positive lymphnode invasion', 'CPA', (53, 80))	('CCA', 'Phenotype', 'HP:0030153', (22, 25))	('Overexpressed', 'Var', (0, 13))	('UCA1', 'Gene', '652995', (131, 135))	('UCA1', 'Gene', (131, 135))	('associated', 'Reg', (37, 47))	('CCA', 'Phenotype', 'HP:0030153', (139, 142))	('UCA1', 'Gene', '652995', (14, 18))	('UCA1', 'Gene', (14, 18))
76847	29221199	For UCA1, pieces of evidence also documented that ectopic expression of UCA1 boosted cell migration and invasion via activating the vimentin and snail expression, and suppressed E-cadherin and zonula occludens-1 protein levels in gastric cancer.	('cell migration', 'CPA', (85, 99))	('suppressed', 'NegReg', (167, 177))	('UCA1', 'Gene', '652995', (72, 76))	('UCA1', 'Gene', (72, 76))	('gastric cancer', 'Disease', 'MESH:D013274', (230, 244))	('activating', 'PosReg', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('E-cadherin', 'Gene', (178, 188))	('E-cadherin', 'Gene', '999', (178, 188))	('snail', 'Gene', '6615', (145, 150))	('invasion', 'CPA', (104, 112))	('UCA1', 'Gene', '652995', (4, 8))	('gastric cancer', 'Phenotype', 'HP:0012126', (230, 244))	('UCA1', 'Gene', (4, 8))	('ectopic expression', 'Var', (50, 68))	('boosted', 'PosReg', (77, 84))	('snail', 'Gene', (145, 150))	('vimentin', 'Gene', '7431', (132, 140))	('vimentin', 'Gene', (132, 140))	('gastric cancer', 'Disease', (230, 244))
76849	29221199	In line with previous studies on gastric and breast cancers, the Western blotting results demonstrated a reversed EMT markers after silencing of UCA1 in both CCLP1 and RBE cells.	('UCA1', 'Gene', '652995', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('UCA1', 'Gene', (145, 149))	('breast cancers', 'Phenotype', 'HP:0003002', (45, 59))	('silencing', 'Var', (132, 141))	('breast cancers', 'Disease', 'MESH:D001943', (45, 59))	('breast cancers', 'Disease', (45, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('EMT markers', 'CPA', (114, 125))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
76850	29221199	These findings indicated that cell metastasis of CCA determined by EMT-related gene expression could be regulated by UCA1 silencing.	('regulated', 'Reg', (104, 113))	('UCA1', 'Gene', '652995', (117, 121))	('UCA1', 'Gene', (117, 121))	('CCA', 'Phenotype', 'HP:0030153', (49, 52))	('cell metastasis', 'CPA', (30, 45))	('silencing', 'Var', (122, 131))	('CCA', 'Disease', (49, 52))
76853	29221199	By performing Western blotting analysis, we confirmed lower expression of p-AKT and p-GSK3beta in the UCA1 knockdown groups.	('knockdown', 'Var', (107, 116))	('expression', 'MPA', (60, 70))	('AKT', 'Gene', '207', (76, 79))	('GSK3beta', 'Gene', (86, 94))	('GSK3beta', 'Gene', '2932', (86, 94))	('AKT', 'Gene', (76, 79))	('UCA1', 'Gene', '652995', (102, 106))	('UCA1', 'Gene', (102, 106))	('lower', 'NegReg', (54, 59))
76904	26920730	For IHCC, mutations in IDH1/IDH2 are associated with higher survival rates.	('higher', 'PosReg', (53, 59))	('IDH2', 'Gene', '3418', (28, 32))	('IDH1', 'Gene', (23, 27))	('IHCC', 'Disease', (4, 8))	('survival', 'MPA', (60, 68))	('IDH2', 'Gene', (28, 32))	('IDH1', 'Gene', '3417', (23, 27))	('mutations', 'Var', (10, 19))
76906	26920730	In the tumor sample, we identified a recurrent somatic IDH1-mutation affecting Arg132, while in normal liver tissue and peripheral blood, no variants were detected, as expected.	('Arg132', 'Var', (79, 85))	('IDH1', 'Gene', '3417', (55, 59))	('tumor', 'Disease', (7, 12))	('affecting', 'Reg', (69, 78))	('Arg132', 'Chemical', '-', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('IDH1', 'Gene', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
76943	26920730	We analyzed the 10 coding exons of the IDH1 gene by Sanger sequencing and detected the mutation c.394C > T (p.Arg132Cys) in exon 4 of IDH1 in the heterozygous state.	('c.394C > T', 'Var', (96, 106))	('IDH1', 'Gene', (39, 43))	('c.394C > T', 'Mutation', 'rs121913499', (96, 106))	('IDH1', 'Gene', (134, 138))	('IDH1', 'Gene', '3417', (39, 43))	('p.Arg132Cys', 'Mutation', 'rs121913499', (108, 119))	('IDH1', 'Gene', '3417', (134, 138))
76946	26920730	Biochemically, mutations in IDH1/IDH2 impair the substrate affinity of the enzyme and dominantly inhibit wildtype IDH1 activity through the formation of catalytically inactive heterodimers.	('inhibit', 'NegReg', (97, 104))	('IDH1', 'Gene', (114, 118))	('IDH2', 'Gene', (33, 37))	('IDH1', 'Gene', '3417', (28, 32))	('impair', 'NegReg', (38, 44))	('mutations', 'Var', (15, 24))	('wildtype', 'MPA', (105, 113))	('heterodimers', 'Interaction', (176, 188))	('IDH2', 'Gene', '3418', (33, 37))	('IDH1', 'Gene', '3417', (114, 118))	('substrate affinity', 'MPA', (49, 67))	('activity', 'MPA', (119, 127))	('formation of catalytically inactive', 'MPA', (140, 175))	('IDH1', 'Gene', (28, 32))
76948	26920730	They are also associated with Maffucci syndrome: over 80 % of patients with Maffucci syndrome carry somatic mutations in IDH1/IDH2, while IDH1/IDH2 mutations are detected in 14 % of non-syndromic cases with IHCC.	('IDH1', 'Gene', (121, 125))	('Maffucci syndrome', 'Disease', (76, 93))	('Maffucci syndrome', 'Disease', 'MESH:D004687', (76, 93))	('mutations', 'Var', (108, 117))	('IDH1', 'Gene', '3417', (121, 125))	('IDH2', 'Gene', (143, 147))	('IDH1', 'Gene', '3417', (138, 142))	('IDH2', 'Gene', (126, 130))	('patients', 'Species', '9606', (62, 70))	('Maffucci syndrome', 'Disease', (30, 47))	('IDH2', 'Gene', '3418', (143, 147))	('Maffucci syndrome', 'Disease', 'MESH:D004687', (30, 47))	('IDH2', 'Gene', '3418', (126, 130))	('IDH1', 'Gene', (138, 142))
76950	26920730	As enchondromas and gliomas of Maffucci patients carry IDH1/IDH2 mutations while wild-type IDH1/IDH2 is expressed in their healthy tissue it is concluded that heterozygous IDH1/IDH2 mutations occur during embryonic development, leading to mosaicism and acting as triggers of carcinogenesis.	('IDH1', 'Gene', '3417', (172, 176))	('IDH1', 'Gene', '3417', (91, 95))	('carcinogenesis', 'Disease', (275, 289))	('IDH1', 'Gene', (55, 59))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('enchondromas', 'Disease', (3, 15))	('IDH2', 'Gene', (60, 64))	('mosaicism', 'MPA', (239, 248))	('IDH2', 'Gene', '3418', (60, 64))	('carcinogenesis', 'Disease', 'MESH:D063646', (275, 289))	('mutations', 'Var', (182, 191))	('IDH1', 'Gene', '3417', (55, 59))	('leading to', 'Reg', (228, 238))	('gliomas of Maffucci', 'Disease', 'MESH:D004687', (20, 39))	('enchondromas', 'Phenotype', 'HP:0030038', (3, 15))	('enchondroma', 'Phenotype', 'HP:0030038', (3, 14))	('IDH2', 'Gene', (96, 100))	('IDH1', 'Gene', (172, 176))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('IDH2', 'Gene', '3418', (96, 100))	('IDH2', 'Gene', (177, 181))	('patients', 'Species', '9606', (40, 48))	('IDH2', 'Gene', '3418', (177, 181))	('IDH1', 'Gene', (91, 95))	('enchondromas', 'Disease', 'MESH:D002812', (3, 15))	('gliomas of Maffucci', 'Disease', (20, 39))	('mutations', 'Var', (65, 74))
76957	26920730	For IHCC cases, mutations in IDH1/IDH2 are associated with prolonged survival.	('prolonged', 'PosReg', (59, 68))	('IDH1', 'Gene', (29, 33))	('mutations', 'Var', (16, 25))	('IDH1', 'Gene', '3417', (29, 33))	('IHCC', 'Disease', (4, 8))	('IDH2', 'Gene', (34, 38))	('associated', 'Reg', (43, 53))	('IDH2', 'Gene', '3418', (34, 38))
76958	26920730	The probability of tumor recurrence in patients with mutated IDH1/IDH2 intrahepatic cholangiocarcinoma is significantly lower than in those with wild-type IDH1/IDH2 (45 and 81 %, respectively, for a 7 year interval).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('IDH1/IDH2 intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 102))	('IDH1', 'Gene', (155, 159))	('lower', 'NegReg', (120, 125))	('IDH2', 'Gene', '3418', (66, 70))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('patients', 'Species', '9606', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('IDH1', 'Gene', '3417', (155, 159))	('IDH1', 'Gene', '3417', (61, 65))	('IDH2', 'Gene', '3418', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mutated', 'Var', (53, 60))	('IDH1', 'Gene', (61, 65))	('tumor', 'Disease', (19, 24))	('IDH2', 'Gene', (66, 70))	('IDH1/IDH2 intrahepatic cholangiocarcinoma', 'Disease', (61, 102))	('IDH2', 'Gene', (160, 164))
77078	22568523	These included gene-specific primer-probe sets for the following biomarker genes: Krt19 (cytokeratin 19), ID# Rn01496870_g1; Muc1 (mucin 1), ID# Rn01462585_m1; Mmp7 (metalloproteinase-7, matrilysin), ID# Rn01487001_m1; Areg (amphiregulin), ID# Rn00567471_m1; Acta2 (alpha-SMA), ID# Rn01759928_g1; Hgf (hepatocyte growth factor), ID# Rn00566673_m1; Postn (periostin), ID# Rn1494627_m1; Sphk1 (sphingosine kinase 1), ID# Rn00682794_g1; Cxcr4 (C-X-C chemokine receptor 4), ID# Rn01483207_m1; Shh (sonic hedgehog homolog), ID# Rn00568129_m1; SMO (Smoothened), ID# Rn00563043_m1; Gli1 (glioblastoma 1), ID# Rn01504237_m1; Gli2, ID# Rn01408890_m1.	('ID# Rn00563043_m1', 'Var', (556, 573))	('amphiregulin', 'Gene', '29183', (225, 237))	('Hgf', 'Gene', '24446', (297, 300))	('matrilysin', 'Gene', (187, 197))	('Acta2', 'Gene', (259, 264))	('Areg', 'Gene', '29183', (219, 223))	('periostin', 'Gene', '361945', (355, 364))	('sphingosine kinase 1', 'Gene', '170897', (392, 412))	('mucin 1', 'Gene', '24571', (131, 138))	('Mmp7', 'Gene', '25335', (160, 164))	('Smoothened', 'Gene', '25273', (543, 553))	('Sphk1', 'Gene', '170897', (385, 390))	('sonic hedgehog homolog', 'Gene', '29499', (494, 516))	('SMO', 'Gene', (538, 541))	('Muc1', 'Gene', '24571', (125, 129))	('Krt19', 'Gene', '360626', (82, 87))	('mucin 1', 'Gene', (131, 138))	('Gli2', 'Gene', (617, 621))	('matrilysin', 'Gene', '25335', (187, 197))	('amphiregulin', 'Gene', (225, 237))	('ID# Rn01408890_m1', 'Var', (623, 640))	('alpha-SMA', 'Gene', (266, 275))	('Gli2', 'Gene', '304729', (617, 621))	('Hgf', 'Gene', (297, 300))	('C-X-C chemokine receptor 4', 'Gene', (441, 467))	('hepatocyte growth factor', 'Gene', '24446', (302, 326))	('glioblastoma', 'Disease', 'MESH:D005909', (581, 593))	('Muc1', 'Gene', (125, 129))	('Acta2', 'Gene', '81633', (259, 264))	('Shh', 'Gene', (489, 492))	('Mmp7', 'Gene', (160, 164))	('C-X-C chemokine receptor 4', 'Gene', '60628', (441, 467))	('ID# Rn01483207_m1', 'Var', (470, 487))	('SMO', 'Gene', '25273', (538, 541))	('Sphk1', 'Gene', (385, 390))	('glioblastoma', 'Disease', (581, 593))	('Postn', 'Gene', (348, 353))	('ID# Rn00568129_m1', 'Var', (519, 536))	('sphingosine kinase 1', 'Gene', (392, 412))	('glioblastoma', 'Phenotype', 'HP:0012174', (581, 593))	('Shh', 'Gene', '29499', (489, 492))	('Krt19', 'Gene', (82, 87))	('sonic hedgehog homolog', 'Gene', (494, 516))	('cytokeratin 19', 'Gene', '360626', (89, 103))	('periostin', 'Gene', (355, 364))	('cytokeratin 19', 'Gene', (89, 103))	('hepatocyte growth factor', 'Gene', (302, 326))	('Smoothened', 'Gene', (543, 553))	('Postn', 'Gene', '361945', (348, 353))	('alpha-SMA', 'Gene', '25365', (266, 275))	('Areg', 'Gene', (219, 223))	('ID# Rn01504237_m1', 'Var', (598, 615))
77103	22568523	As further demonstrated in Figure 5B versus 5A, and histological sections shown in Figure 6A-D, co-culturing BDEsp-TDEH10 with BDEsp-TDFE4 cells under our 3-D organotypic culture conditions profoundly increased the number of cholangiocarcinoma cell spheroid/duct-like structures formed in the collagen gel matrix over those formed in the absence of BDEsp-TDFE4 cells.	('rat', 'Species', '10116', (18, 21))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (225, 243))	('increased', 'PosReg', (201, 210))	('cholangiocarcinoma cell spheroid', 'Disease', 'MESH:D018281', (225, 257))	('BDEsp-TDEH10', 'Var', (109, 121))	('cholangiocarcinoma cell spheroid', 'Disease', (225, 257))
77106	22568523	Moreover, BDEsp-TDEH10 cholangiocarcinoma cells exhibited significantly increased in vitro invasiveness when assayed in the presence versus absence of BDEsp-TDFE4 CAFsusing the Matrigel invasion chamber.	('BDEsp-TDEH10', 'Var', (10, 22))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (23, 41))	('increased', 'PosReg', (72, 81))	('CAFs', 'Chemical', '-', (163, 167))	('cholangiocarcinoma cell', 'Disease', (23, 46))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (23, 46))
77115	22568523	Unique features distinguishing this novel 3-D co-culture model include: (1) its construction using "phenotypically pure" alpha-SMA-positive CAF and cholangiocarcinoma cell strains derived from desmoplastic ICC formed from spontaneously transformed rat cholangiocytes orthotopically transplanted into syngeneic rat liver; (2) alpha-SMA-positive CAFs and cholangiocarcinoma cells used to establish this organotypic rat cholangiocarcinoma model each exhibited characteristic gene expression profiles for select classes of genes (e.g., matricellular proteins, growth factor/chemokines and receptors, mucins, proteases, integrins, Hh family members) relevant to cholangiocarcinogenesis; (3) the identification of gene expression profiles using this novel 3-D cellular model closely resembled that of tissue samples obtained from parental BDEsp cholangiocarcinoma grown orthotopically; (4) 3-D co-culturing of rat cholangiocarcinoma cells and alpha-SMA-positive CAFs derived from the same rat ICC type significantly enhanced "duct-like" growth and cancer cell migration/invasion, as well as augmented type I collagen deposition into the gel matrix so as to mimic in vitro the desmoplastic stroma of the parental tumor; (5) alpha-SMA-positive CAF-cholangiocarcinoma cell interactions resulted in up-regulated gene expression of Hgf, Cxcr4, and Muc1, each of which has been associated with cholangiocarcinoma cell invasiveness and/or poorer survival outcomes for ICC patients following tumor resection; and HGF produced by alpha-SMA-positive CAFs is an inducer of significant Cxcr4 overexpression in cholangiocarcinoma cells.	('rat', 'Species', '10116', (413, 416))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (908, 926))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (1592, 1610))	('alpha-SMA', 'Gene', '25365', (121, 130))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (353, 371))	('CAF', 'Gene', '8850', (140, 143))	('alpha-SMA', 'Gene', '25365', (937, 946))	('rat', 'Species', '10116', (904, 907))	('CAFs', 'Chemical', '-', (1534, 1538))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (908, 926))	('CAF', 'Gene', '8850', (344, 347))	('rat', 'Species', '10116', (983, 986))	('CAF', 'Gene', '8850', (956, 959))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (1240, 1263))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (353, 371))	('cholangiocarcinoma', 'Disease', (1382, 1400))	('cholangiocarcinoma cell', 'Disease', (908, 931))	('alpha-SMA', 'Gene', (121, 130))	('cancer', 'Disease', 'MESH:D009369', (1042, 1048))	('alpha-SMA', 'Gene', (1217, 1226))	('alpha-SMA', 'Gene', (937, 946))	('cholangiocarcinoma cell invasiveness', 'Disease', (1382, 1418))	('tumor', 'Disease', (1206, 1211))	('Hgf', 'Gene', (1321, 1324))	('rat', 'Species', '10116', (1057, 1060))	('CAF', 'Gene', '8850', (1236, 1239))	('cholangiocarcinoma', 'Disease', (1592, 1610))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (417, 435))	('cholangiocarcinoma', 'Disease', (148, 166))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (148, 171))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (417, 435))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (353, 376))	('CAF', 'Gene', (140, 143))	('Hgf', 'Gene', '24446', (1321, 1324))	('CAF', 'Gene', (344, 347))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (1240, 1258))	('CAF', 'Gene', (956, 959))	('cholangiocarcinoma cell invasiveness', 'Disease', 'MESH:D018281', (1382, 1418))	('growth factor', 'Gene', (556, 569))	('desmoplastic stroma of the parental tumor', 'Disease', (1170, 1211))	('cholangiocarcinoma cell', 'Disease', (1592, 1615))	('Cxcr4 overexpression', 'MPA', (1568, 1588))	('desmoplastic ICC', 'Disease', 'MESH:C566123', (193, 209))	('CAF-cholangiocarcinoma', 'Disease', 'MESH:D018281', (1236, 1258))	('tumor', 'Phenotype', 'HP:0002664', (1478, 1483))	('cholangiocarcinoma', 'Disease', (839, 857))	('rat', 'Species', '10116', (248, 251))	('cancer', 'Disease', (1042, 1048))	('CAF', 'Gene', (1236, 1239))	('cholangiocarcinoma', 'Disease', (908, 926))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (908, 931))	('cholangiocarcinoma', 'Disease', (353, 371))	('CAF', 'Gene', '8850', (1534, 1537))	('alpha-SMA', 'Gene', '25365', (325, 334))	('CAFs', 'Chemical', '-', (344, 348))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (1382, 1400))	('alpha-SMA', 'Gene', '25365', (1515, 1524))	('cholangiocarcinoma cell', 'Disease', (1240, 1263))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (839, 857))	('HGF', 'Var', (1499, 1502))	('CAF-cholangiocarcinoma', 'Disease', (1236, 1258))	('growth factor', 'Gene', '79215', (556, 569))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (148, 166))	('tumor', 'Phenotype', 'HP:0002664', (1206, 1211))	('alpha-SMA', 'Gene', '25365', (1217, 1226))	('cancer', 'Phenotype', 'HP:0002664', (1042, 1048))	('cholangiocarcinoma', 'Disease', (417, 435))	('CAFs', 'Chemical', '-', (956, 960))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (148, 166))	('patients', 'Species', '9606', (1459, 1467))	('rat', 'Species', '10116', (310, 313))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (1592, 1615))	('cholangiocarcinoma', 'Disease', (1240, 1258))	('cholangiocarcinoma cell', 'Disease', (148, 171))	('tumor', 'Disease', (1478, 1483))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (1382, 1405))	('desmoplastic ICC', 'Disease', (193, 209))	('cholangiocarcinoma cell', 'Disease', (353, 376))	('CAF', 'Gene', (1534, 1537))	('tumor', 'Disease', 'MESH:D009369', (1478, 1483))	('Muc1', 'Gene', '24571', (1337, 1341))	('tumor', 'Disease', 'MESH:D009369', (1206, 1211))	('desmoplastic stroma of the parental tumor', 'Disease', 'MESH:D063129', (1170, 1211))	('alpha-SMA', 'Gene', (325, 334))	('Muc1', 'Gene', (1337, 1341))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (839, 857))	('alpha-SMA', 'Gene', (1515, 1524))
77122	22568523	The 3-D organotypic culture model of cholangiocarcinoma described in his study appears to be very well suited to serve as a pathophysiologically relevant in vitro system to investigate key stromal/cancer cell interactions mediated by aberrantly expressed CAF or cholangiocarcinoma genes postulated to accelerate ICC malignancy (-).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (37, 55))	('accelerate', 'PosReg', (301, 311))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (37, 55))	('cholangiocarcinoma', 'Disease', (262, 280))	('interactions', 'Interaction', (209, 221))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('ICC malignancy', 'Disease', 'MESH:C566123', (312, 326))	('cancer', 'Disease', (197, 203))	('ICC malignancy', 'Disease', (312, 326))	('CAF', 'Gene', (255, 258))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (262, 280))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (262, 280))	('aberrantly expressed', 'Var', (234, 254))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cholangiocarcinoma', 'Disease', (37, 55))	('CAF', 'Gene', '8850', (255, 258))	('rat', 'Species', '10116', (307, 310))
77221	30923792	Previous studies have suggested that the proportion of patients with late complications such as cholangitis, hepatolithiasis, and biliary tract cancer after the biliary tract operation seems to be higher in patients with type IV-A CBD than in those with other types of CBD,6, 9, 11, 12 and this study clearly showed that the long-term outcomes were more unfavorable in patients with type IV-A CBD compared to those with other types of CBD in terms of late postoperative complications and survival rate.	('patients', 'Species', '9606', (207, 215))	('late postoperative complications', 'Disease', (451, 483))	('patients', 'Species', '9606', (369, 377))	('cholangitis, hepatolithiasis', 'Disease', 'MESH:D002761', (96, 124))	('biliary tract cancer', 'Disease', 'MESH:D001661', (130, 150))	('biliary tract cancer', 'Disease', (130, 150))	('CBD', 'Chemical', '-', (269, 272))	('CBD', 'Chemical', '-', (393, 396))	('type', 'Var', (221, 225))	('cholangitis', 'Phenotype', 'HP:0030151', (96, 107))	('late postoperative complications', 'Disease', 'MESH:D011183', (451, 483))	('type IV-A CBD', 'Var', (383, 396))	('patients', 'Species', '9606', (55, 63))	('CBD', 'Chemical', '-', (231, 234))	('CBD', 'Chemical', '-', (435, 438))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (130, 150))
77342	23688168	The exogenous expression of Notch1 in glioma cells increased their migratory and invasive capacity.	('Notch1', 'Gene', (28, 34))	('increased', 'PosReg', (51, 60))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('Notch1', 'Gene', '4851', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('exogenous expression', 'Var', (4, 24))	('glioma', 'Disease', (38, 44))
77356	23688168	Moreover, high-level expression of Notch-1 and its ligand Jagged-1 is associated with poor prognosis in breast cancer, bladder cancer, leukemia, and prostate cancer.	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('Jagged-1', 'Gene', '182', (58, 66))	('leukemia', 'Phenotype', 'HP:0001909', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('bladder cancer', 'Disease', 'MESH:D001749', (119, 133))	('Notch-1', 'Gene', '4851', (35, 42))	('bladder cancer', 'Disease', (119, 133))	('leukemia', 'Disease', (135, 143))	('leukemia', 'Disease', 'MESH:D007938', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('bladder cancer', 'Phenotype', 'HP:0009725', (119, 133))	('prostate cancer', 'Disease', 'MESH:D011471', (149, 164))	('Jagged-1', 'Gene', (58, 66))	('prostate cancer', 'Phenotype', 'HP:0012125', (149, 164))	('Notch-1', 'Gene', (35, 42))	('prostate cancer', 'Disease', (149, 164))	('high-level', 'Var', (10, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
77399	23688168	Abnormally high Notch1 expression has been implicated in many malignancies, but the pathological function of Notch1 in ICC has not been well defined.	('Notch1', 'Gene', '4851', (109, 115))	('Abnormally high', 'Var', (0, 15))	('implicated', 'Reg', (43, 53))	('ICC', 'Disease', (119, 122))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('Notch1', 'Gene', (16, 22))	('malignancies', 'Disease', (62, 74))	('Notch1', 'Gene', (109, 115))	('Notch1', 'Gene', '4851', (16, 22))	('expression', 'MPA', (23, 33))
77410	23688168	The aberrant Notch1 expression in both ICC tissues and ICC cells suggests that increased Notch1 expression might be associated with tumor progression.	('increased', 'PosReg', (79, 88))	('Notch1', 'Gene', (89, 95))	('Notch1', 'Gene', '4851', (89, 95))	('expression', 'MPA', (20, 30))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('Notch1', 'Gene', '4851', (13, 19))	('aberrant', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('expression', 'MPA', (96, 106))	('associated', 'Reg', (116, 126))	('tumor', 'Disease', (132, 137))	('Notch1', 'Gene', (13, 19))
77413	23688168	Exogenous expression of Notch1 in glioma cells has been shown to increase their migratory and invasive capacity.	('increase', 'PosReg', (65, 73))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('Exogenous', 'Var', (0, 9))	('glioma', 'Disease', 'MESH:D005910', (34, 40))	('Notch1', 'Gene', '4851', (24, 30))	('glioma', 'Disease', (34, 40))	('Notch1', 'Gene', (24, 30))
77418	23688168	In reciprocal experiments, we examined whether knocking down endogenous Notch1 would inhibit Rac1 activity and cell migration using Notch1 siRNA.	('Notch1', 'Gene', (72, 78))	('cell migration', 'CPA', (111, 125))	('inhibit', 'NegReg', (85, 92))	('Notch1', 'Gene', '4851', (72, 78))	('Notch1', 'Gene', (132, 138))	('Notch1', 'Gene', '4851', (132, 138))	('Rac1', 'Gene', '5879', (93, 97))	('knocking down', 'Var', (47, 60))	('Rac1', 'Gene', (93, 97))
77424	23688168	To exclude the possibility that the increased cell migration was due to Rac1 activation, not cell proliferation, we over expressed and knocked down Notch1 in ICC-9810 cells, which express moderate levels of Notch1.	('ICC-9810', 'CellLine', 'CVCL:6908', (158, 166))	('Notch1', 'Gene', (148, 154))	('Notch1', 'Gene', (207, 213))	('Notch1', 'Gene', '4851', (148, 154))	('Notch1', 'Gene', '4851', (207, 213))	('Rac1', 'Gene', '5879', (72, 76))	('cell migration', 'CPA', (46, 60))	('knocked down', 'Var', (135, 147))	('Rac1', 'Gene', (72, 76))
77428	23688168	Notch activation has been shown to induce an epithelial to mesenchymal transition in breast cancer Given that Notch1 expression was associated with ICC metastasis, we further investigated whether a link exists between Notch1 expression and the EMT phenomenon in ICC.	('associated', 'Reg', (132, 142))	('ICC', 'Disease', (148, 151))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('breast cancer', 'Disease', (85, 98))	('Notch1', 'Gene', '4851', (218, 224))	('induce', 'Reg', (35, 41))	('Notch1', 'Gene', (110, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('Notch1', 'Gene', '4851', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Notch', 'Var', (0, 5))	('epithelial to mesenchymal transition', 'CPA', (45, 81))	('Notch1', 'Gene', (218, 224))
77433	23688168	Four different Notch proteins and the following five known ligands exist in mammals: Delta-like 1, Delta-like 3, Delta-like 4, Jagged 1 and Jagged 2.	('Jagged 1', 'Gene', '182', (127, 135))	('Delta-like 4', 'Var', (113, 125))	('Delta-like 3', 'Gene', (99, 111))	('Jagged 2', 'Gene', (140, 148))	('Jagged 2', 'Gene', '3714', (140, 148))	('Jagged 1', 'Gene', (127, 135))	('Delta-like 3', 'Gene', '10683', (99, 111))
77435	23688168	Indeed, unlike in T-ALL, genetic alterations in Notch genes have not been identified in solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('solid tumors', 'Disease', 'MESH:D009369', (88, 100))	('genetic', 'Var', (25, 32))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('Notch genes', 'Gene', (48, 59))	('solid tumors', 'Disease', (88, 100))
77438	23688168	Taken together, these observations indicate that Notch exerts its effects in solid tumors as a result of aberrant activation of the pathway.	('activation', 'PosReg', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('solid tumors', 'Disease', (77, 89))	('Notch', 'Var', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('solid tumors', 'Disease', 'MESH:D009369', (77, 89))
77439	23688168	Moreover, the cellular interpretation and outcome of aberrant Notch activity is highly dependent on contextual cues, such as interactions with the tumor microenvironment and crosstalk with other signaling pathways.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('Notch activity', 'MPA', (62, 76))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('aberrant', 'Var', (53, 61))
77445	23688168	Taken together, aberrant Notch1 expression in both ICC tissues and ICC cells suggests that increased Notch1 expression might be associated with tumor progression.	('aberrant', 'Var', (16, 24))	('tumor', 'Disease', (144, 149))	('Notch1', 'Gene', (25, 31))	('Notch1', 'Gene', '4851', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('associated', 'Reg', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('expression', 'MPA', (108, 118))	('increased', 'PosReg', (91, 100))	('Notch1', 'Gene', '4851', (101, 107))	('expression', 'MPA', (32, 42))	('Notch1', 'Gene', (101, 107))
77538	21603286	More recently, a case controlled study in the same area revealed that identification of C. sinensis in stool was associated with cholangiocarcinoma with a relative risk of 2.7.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('cholangiocarcinoma', 'Disease', (129, 147))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (129, 147))	('identification', 'Var', (70, 84))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (129, 147))	('C. sinensis', 'Var', (88, 99))	('C. sinensis', 'Species', '79923', (88, 99))	('associated', 'Reg', (113, 123))
77605	28122578	BAP1 dependent expression of long non-coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma Genetic alterations in chromatin modulators such as BRCA-1 associated protein-1 (BAP1) are the most frequent genetic alteration in intrahepatic cholangiocarcinomas (CCA).	('NEAT-1', 'Gene', '283131', (49, 55))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('cholangiocarcinoma', 'Disease', (101, 119))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (264, 282))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (101, 119))	('BAP1', 'Gene', (0, 4))	('cholangiocarcinoma', 'Disease', (264, 282))	('BRCA-1 associated protein-1', 'Gene', '8314', (172, 199))	('CCA', 'Phenotype', 'HP:0030153', (285, 288))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (264, 282))	('BRCA-1 associated protein-1', 'Gene', (172, 199))	('intrahepatic cholangiocarcinomas', 'Disease', (251, 283))	('alterations', 'Var', (128, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('BAP1', 'Gene', '8314', (201, 205))	('gemcitabine', 'Chemical', 'MESH:C056507', (86, 97))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (251, 283))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('BAP1', 'Gene', (201, 205))	('BAP1', 'Gene', '8314', (0, 4))	('NEAT-1', 'Gene', (49, 55))
77609	28122578	Sensitivity to gemcitabine was greater in low BAP1 expressing or BAP1 knockout cells compared with the high BAP1 expressing cells or control haplo-insufficient cells respectively.	('BAP1', 'Gene', '8314', (65, 69))	('BAP1', 'Gene', '8314', (108, 112))	('greater', 'PosReg', (31, 38))	('BAP1', 'Gene', '8314', (46, 50))	('BAP1', 'Gene', (65, 69))	('BAP1', 'Gene', (108, 112))	('BAP1', 'Gene', (46, 50))	('Sensitivity to gemcitabine', 'MPA', (0, 26))	('gemcitabine', 'Chemical', 'MESH:C056507', (15, 26))	('low', 'Var', (42, 45))	('knockout', 'Var', (70, 78))
77613	28122578	Exogenous modulation of NEAT-1 and/or BAP1 expression altered tumor cell phenotype and modulated sensitivity to gemcitabine.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('gemcitabine', 'Chemical', 'MESH:C056507', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('modulation', 'Var', (10, 20))	('sensitivity to gemcitabine', 'MPA', (97, 123))	('BAP1', 'Gene', (38, 42))	('tumor', 'Disease', (62, 67))	('NEAT-1', 'Gene', (24, 30))	('altered', 'Reg', (54, 61))	('NEAT-1', 'Gene', '283131', (24, 30))	('modulated', 'Reg', (87, 96))	('BAP1', 'Gene', '8314', (38, 42))
77618	28122578	Recent studies have identified alterations in chromatin modulators as the most frequent genetic alterations in intrahepatic cholangiocarcinoma (iCCA).	('alterations', 'Var', (31, 42))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 142))	('CCA', 'Phenotype', 'HP:0030153', (145, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('intrahepatic cholangiocarcinoma', 'Disease', (111, 142))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (124, 142))
77619	28122578	Amongst these, mutations in BRCA-1 associated protein-1 (BAP1) are the most common, occurring in 22-24% of cases; however, the clinical impact of mutation or loss of BAP1 in iCCA is yet unknown.	('common', 'Reg', (76, 82))	('occurring', 'Reg', (84, 93))	('mutation', 'Var', (146, 154))	('CCA', 'Phenotype', 'HP:0030153', (175, 178))	('mutations', 'Var', (15, 24))	('BAP1', 'Gene', '8314', (166, 170))	('BRCA-1 associated protein-1', 'Gene', '8314', (28, 55))	('BAP1', 'Gene', '8314', (57, 61))	('BAP1', 'Gene', (166, 170))	('BRCA-1 associated protein-1', 'Gene', (28, 55))	('BAP1', 'Gene', (57, 61))	('loss', 'NegReg', (158, 162))
77664	28122578	In order to identify an appropriate cellular model, we began by first performing BAP1 gene mutation analysis by Sanger sequencing in a panel of human malignant cholangiocyte cell lines, KMBC, HuCCT1, Mz-ChA-1, and CCLP1.	('mutation', 'Var', (91, 99))	('BAP1', 'Gene', (81, 85))	('human', 'Species', '9606', (144, 149))	('CCLP1', 'Gene', '8495', (214, 219))	('HuCCT1', 'CellLine', 'CVCL:0324', (192, 198))	('BAP1', 'Gene', '8314', (81, 85))	('CCLP1', 'Gene', (214, 219))
77665	28122578	We identified several BAP1 mutations that spanned the entire genome (Additional file 2: Table S3).	('mutations', 'Var', (27, 36))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', (22, 26))
77671	28122578	Tumor suppressive effects resulting from BAP1 mutations likely involve additional genetic changes such as deletions of chromosome 3p.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (46, 55))	('deletions', 'Var', (106, 115))	('BAP1', 'Gene', (41, 45))	('Tumor suppressive effects', 'CPA', (0, 25))	('BAP1', 'Gene', '8314', (41, 45))
77677	28122578	We next evaluated the therapeutic sensitivity of CCA cells with low BAP1 (KMBC) or high BAP1 (HuCCT1) expression.	('HuCCT1', 'CellLine', 'CVCL:0324', (94, 100))	('CCA', 'Phenotype', 'HP:0030153', (49, 52))	('BAP1', 'Gene', '8314', (68, 72))	('BAP1', 'Gene', '8314', (88, 92))	('high', 'Var', (83, 87))	('BAP1', 'Gene', (68, 72))	('BAP1', 'Gene', (88, 92))
77692	28122578	In contrast, sensitivity to GSK126, an inhibitor of enhancer of zeste 2 polycomb repressive complex 2 (EZH2) was reduced in KMBC compared with CCLP1 cells (IC50: 49nM vs 3nM).	('CCLP1', 'Gene', '8495', (143, 148))	('sensitivity', 'MPA', (13, 24))	('CCLP1', 'Gene', (143, 148))	('GSK126', 'Chemical', 'MESH:C577920', (28, 34))	('EZH2', 'Gene', '2146', (103, 107))	('EZH2', 'Gene', (103, 107))	('KMBC', 'Var', (124, 128))	('reduced', 'NegReg', (113, 120))
77699	28122578	Pharmacologic inhibition of EZH2 using GSK126 in combination with gemcitabine resulted in a synergistic reduction in cell viability in low BAP1 expressing cells, KMBC compared with high BAP1 expressing, HuCCT1 cells.	('reduction', 'NegReg', (104, 113))	('low', 'Var', (135, 138))	('cell viability', 'CPA', (117, 131))	('gemcitabine', 'Chemical', 'MESH:C056507', (66, 77))	('EZH2', 'Gene', '2146', (28, 32))	('BAP1', 'Gene', '8314', (186, 190))	('BAP1', 'Gene', '8314', (139, 143))	('EZH2', 'Gene', (28, 32))	('HuCCT1', 'CellLine', 'CVCL:0324', (203, 209))	('BAP1', 'Gene', (186, 190))	('BAP1', 'Gene', (139, 143))	('GSK126', 'Chemical', 'MESH:C577920', (39, 45))	('GSK126', 'Var', (39, 45))
77710	28122578	We identified several lncRNAs that were enriched in both siRNA and CRISPR-Cas9 mediated knock-down of BAP1 compared with the respective controls (Fig.	('BAP1', 'Gene', '8314', (102, 106))	('BAP1', 'Gene', (102, 106))	('knock-down', 'Var', (88, 98))
77714	28122578	Using qPCR and primer sets that target both NEAT1_1/NEAT1_2 (Total NEAT1), or NEAT1_1 alone, we observed an increase in both total NEAT-1 and NEAT1_1 with siRNA mediated modulation of BAP1 (Additional file 3).	('NEAT-1', 'Gene', (131, 137))	('NEAT1', 'Gene', (67, 72))	('NEAT1', 'Gene', (78, 83))	('increase', 'PosReg', (108, 116))	('NEAT-1', 'Gene', '283131', (131, 137))	('NEAT1', 'Gene', (44, 49))	('BAP1', 'Gene', '8314', (184, 188))	('NEAT1', 'Gene', '283131', (78, 83))	('NEAT1', 'Gene', '283131', (142, 147))	('BAP1', 'Gene', (184, 188))	('NEAT1', 'Gene', (52, 57))	('NEAT1', 'Gene', (142, 147))	('NEAT1', 'Gene', '283131', (52, 57))	('modulation', 'Var', (170, 180))	('NEAT1', 'Gene', '283131', (67, 72))	('NEAT1', 'Gene', '283131', (44, 49))
77715	28122578	Moreover, the relative proportion of NEAT1_1 to total NEAT-1 was unchanged with BAP1 siRNA, suggesting that alteration in BAP1 equally affects both isoforms.	('NEAT1', 'Gene', (37, 42))	('BAP1', 'Gene', (122, 126))	('BAP1', 'Gene', '8314', (80, 84))	('NEAT-1', 'Gene', (54, 60))	('NEAT-1', 'Gene', '283131', (54, 60))	('BAP1', 'Gene', '8314', (122, 126))	('BAP1', 'Gene', (80, 84))	('alteration', 'Var', (108, 118))	('NEAT1', 'Gene', '283131', (37, 42))
77719	28122578	Exogenous modulation of NEAT-1 expression using siRNA against NEAT-1 (~50% knockdown) in KMBC cells reduced cell proliferation, migration, invasion and colony-forming abilities relative to non-targeting control siRNA treatment (Fig.	('invasion', 'CPA', (139, 147))	('colony-forming abilities', 'CPA', (152, 176))	('modulation', 'Var', (10, 20))	('reduced', 'NegReg', (100, 107))	('migration', 'CPA', (128, 137))	('NEAT-1', 'Gene', (24, 30))	('NEAT-1', 'Gene', (62, 68))	('cell proliferation', 'CPA', (108, 126))	('NEAT-1', 'Gene', '283131', (24, 30))	('NEAT-1', 'Gene', '283131', (62, 68))
77722	28122578	Modulation of NEAT-1 expression using siRNA in KMBC cells significantly altered their response to gemcitabine.	('NEAT-1', 'Gene', (14, 20))	('Modulation', 'Var', (0, 10))	('gemcitabine', 'Chemical', 'MESH:C056507', (98, 109))	('NEAT-1', 'Gene', '283131', (14, 20))	('altered', 'Reg', (72, 79))	('response to gemcitabine', 'MPA', (86, 109))
77726	28122578	Alterations in chromatin modulators like the nuclear deubiquitinating enzyme BAP1 are the most frequently observed genetic alterations reported in intrahepatic CCA, yet the molecular mechanisms by which they modulate cancer cell behavior are unknown.	('intrahepatic CCA', 'Disease', 'MESH:C536211', (147, 163))	('Alterations', 'Var', (0, 11))	('intrahepatic CCA', 'Disease', (147, 163))	('modulate', 'Reg', (208, 216))	('CCA', 'Phenotype', 'HP:0030153', (160, 163))	('BAP1', 'Gene', '8314', (77, 81))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('BAP1', 'Gene', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
77728	28122578	In the present study, we identify alterations in long non-coding RNA gene expression as a contributor to tumor cell phenotype and differential therapeutic sensitivity of CCA cells that is related to BAP1 expression.	('tumor', 'Disease', (105, 110))	('BAP1', 'Gene', (199, 203))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('CCA', 'Phenotype', 'HP:0030153', (170, 173))	('alterations', 'Var', (34, 45))	('long non-coding RNA gene', 'Protein', (49, 73))	('BAP1', 'Gene', '8314', (199, 203))
77729	28122578	Alterations in BAP1 expression in other cancers such as renal cell carcinoma, breast carcinoma, small cell and non-small cell lung cancers, malignant mesothelioma, metastasizing uveal melanoma, and hepatic cancers can arise from chromosomal deletions.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('breast carcinoma', 'Disease', (78, 94))	('non-small cell lung cancers', 'Disease', (111, 138))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('cancers', 'Disease', (131, 138))	('Alterations', 'Var', (0, 11))	('BAP1', 'Gene', '8314', (15, 19))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (111, 138))	('uveal melanoma', 'Disease', 'MESH:C536494', (178, 192))	('uveal melanoma', 'Disease', (178, 192))	('arise', 'Reg', (218, 223))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('hepatic cancers', 'Disease', (198, 213))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (56, 76))	('cancers', 'Disease', (40, 47))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (140, 162))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Disease', (206, 213))	('BAP1', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('uveal melanoma', 'Phenotype', 'HP:0007716', (178, 192))	('hepatic cancers', 'Disease', 'MESH:D008113', (198, 213))	('breast carcinoma', 'Disease', 'MESH:D001943', (78, 94))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (115, 138))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (111, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('malignant mesothelioma', 'Disease', (140, 162))	('renal cell carcinoma', 'Disease', (56, 76))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (140, 162))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (56, 76))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast carcinoma', 'Phenotype', 'HP:0003002', (78, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('lung cancers', 'Phenotype', 'HP:0100526', (126, 138))
77730	28122578	Germline BAP1 mutations have been noted in several of these and other cancers such as meningioma, paraganglioma, basal cell carcinoma, ovarian cancers, and neuroendocrine tumors.	('meningioma', 'Disease', 'MESH:D008577', (86, 96))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (156, 177))	('BAP1', 'Gene', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('ovarian cancers', 'Disease', (135, 150))	('ovarian cancers', 'Disease', 'MESH:D010051', (135, 150))	('paraganglioma', 'Disease', (98, 111))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('paraganglioma', 'Disease', 'MESH:D010235', (98, 111))	('cancers', 'Disease', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (113, 133))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('cancers', 'Disease', (70, 77))	('mutations', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('neuroendocrine tumors', 'Disease', (156, 177))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('meningioma', 'Disease', (86, 96))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (113, 133))	('meningioma', 'Phenotype', 'HP:0002858', (86, 96))	('ovarian cancers', 'Phenotype', 'HP:0100615', (135, 150))	('paraganglioma', 'Phenotype', 'HP:0002668', (98, 111))	('noted', 'Reg', (34, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('BAP1', 'Gene', '8314', (9, 13))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('ovarian cancer', 'Phenotype', 'HP:0100615', (135, 149))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (156, 177))	('basal cell carcinoma', 'Disease', (113, 133))
77731	28122578	Genetic mutations in BAP1 could modulate BAP1 protein expression or could alter BAP1 function in the absence of alterations in protein expression.	('expression', 'MPA', (54, 64))	('alter', 'Reg', (74, 79))	('modulate', 'Reg', (32, 40))	('function', 'MPA', (85, 93))	('BAP1', 'Gene', (21, 25))	('BAP1', 'Gene', (41, 45))	('BAP1', 'Gene', '8314', (80, 84))	('BAP1', 'Gene', (80, 84))	('Genetic mutations', 'Var', (0, 17))	('BAP1', 'Gene', '8314', (21, 25))	('BAP1', 'Gene', '8314', (41, 45))
77732	28122578	Indeed, genetic mutations in BAP1 are variably associated with loss of protein expression.	('genetic mutations', 'Var', (8, 25))	('BAP1', 'Gene', '8314', (29, 33))	('protein expression', 'MPA', (71, 89))	('BAP1', 'Gene', (29, 33))	('loss', 'NegReg', (63, 67))
77736	28122578	As a chromatin modulator, BAP1 is positioned to epigenetically modulate long non-coding RNAs (lncRNAs) and other genes at the intersection of cellular responses to an adverse microenvironment such as enhancement of survival signaling, modulation of cell proliferation and protein synthesis.	('BAP1', 'Gene', (26, 30))	('enhancement', 'PosReg', (200, 211))	('epigenetically', 'Var', (48, 62))	('cell proliferation', 'CPA', (249, 267))	('protein synthesis', 'CPA', (272, 289))	('BAP1', 'Gene', '8314', (26, 30))	('modulate', 'Reg', (63, 71))	('survival signaling', 'CPA', (215, 233))
77739	28122578	A role for NEAT-1 has been described in several types of cancers such as breast, prostate, and lung cancer, with effects on promoting tumor growth through genetic or epigenetic mechanisms.	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('promoting', 'PosReg', (124, 133))	('epigenetic', 'Var', (166, 176))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Disease', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('breast', 'Disease', (73, 79))	('prostate', 'Disease', (81, 89))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('NEAT-1', 'Gene', (11, 17))	('NEAT-1', 'Gene', '283131', (11, 17))	('tumor', 'Disease', (134, 139))
77743	28122578	Examples include reports of lncRNA-HOTAIR in ER-induced tamoxifen resistance in breast cancer, lncRNA-UCA1 in cisplatin-based resistance in ovarian cancer cells, LncRNA-AK022798 in cisplatin-based drug resistance in gastric cancer cells and H19 and lncRNA-ROR in hepatocellular carcinoma cells.	('HOTAIR', 'Gene', '100124700', (35, 41))	('LncRNA-AK022798', 'Var', (162, 177))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('UCA1', 'Gene', '652995', (102, 106))	('tamoxifen', 'Chemical', 'MESH:D013629', (56, 65))	('breast cancer', 'Disease', (80, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (216, 230))	('hepatocellular carcinoma', 'Disease', (263, 287))	('ovarian cancer', 'Disease', (140, 154))	('UCA1', 'Gene', (102, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('ovarian cancer', 'Phenotype', 'HP:0100615', (140, 154))	('HOTAIR', 'Gene', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cisplatin', 'Chemical', 'MESH:D002945', (181, 190))	('gastric cancer', 'Phenotype', 'HP:0012126', (216, 230))	('cisplatin', 'Chemical', 'MESH:D002945', (110, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (263, 287))	('ROR', 'Gene', (256, 259))	('ROR', 'Gene', '100885779', (256, 259))	('ovarian cancer', 'Disease', 'MESH:D010051', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('drug resistance', 'Phenotype', 'HP:0020174', (197, 212))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (263, 287))	('ER-induced tamoxifen resistance', 'MPA', (45, 76))	('gastric cancer', 'Disease', (216, 230))
77747	28122578	Enhanced sensitivity to PARP inhibition has been reported in BAP1-/- cells compared with BAP1+/+ and BAP1+/- cells, as well as in cancer cells harboring inactivating mutations in BRCA1 or-2.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('BAP1', 'Gene', (61, 65))	('BAP1', 'Gene', (89, 93))	('BRCA1', 'Gene', (179, 184))	('BAP1', 'Gene', '8314', (101, 105))	('cancer', 'Disease', (130, 136))	('BAP1', 'Gene', '8314', (89, 93))	('PARP', 'Gene', (24, 28))	('inactivating mutations', 'Var', (153, 175))	('BAP1', 'Gene', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('PARP', 'Gene', '142', (24, 28))	('BAP1', 'Gene', '8314', (61, 65))	('BRCA1', 'Gene', '672', (179, 184))	('sensitivity', 'MPA', (9, 20))	('Enhanced', 'PosReg', (0, 8))
77753	28122578	Knockdown of EZH2 is reported to alter cell cycle regulation and induce G1 arrest leading to apoptosis in CCA cell lines.	('cell', 'MPA', (39, 43))	('EZH2', 'Gene', (13, 17))	('alter', 'Reg', (33, 38))	('EZH2', 'Gene', '2146', (13, 17))	('Knockdown', 'Var', (0, 9))	('CCA', 'Phenotype', 'HP:0030153', (106, 109))	('induce', 'Reg', (65, 71))	('G1 arrest', 'CPA', (72, 81))	('apoptosis', 'CPA', (93, 102))
77754	28122578	We observed an increase in EZH2 protein and reduced SETD8 with siRNA knockdown of BAP1 confirming that EZH2 represents a potential therapeutic target that could be modulated by BAP1.	('BAP1', 'Gene', (82, 86))	('SETD8', 'Gene', '387893', (52, 57))	('EZH2', 'Gene', (27, 31))	('EZH2', 'Gene', '2146', (27, 31))	('EZH2', 'Gene', '2146', (103, 107))	('increase', 'PosReg', (15, 23))	('EZH2', 'Gene', (103, 107))	('BAP1', 'Gene', '8314', (177, 181))	('reduced', 'NegReg', (44, 51))	('BAP1', 'Gene', '8314', (82, 86))	('BAP1', 'Gene', (177, 181))	('knockdown', 'Var', (69, 78))	('SETD8', 'Gene', (52, 57))
77759	28122578	We speculate that low BAP1 expressing cells may have a higher expression of both lncRNA NEAT-1 and EZH2, with a lower sensitivity to EZH2 inhibition.	('EZH2', 'Gene', '2146', (99, 103))	('EZH2', 'Gene', (133, 137))	('NEAT-1', 'Gene', (88, 94))	('EZH2', 'Gene', (99, 103))	('EZH2', 'Gene', '2146', (133, 137))	('expression', 'MPA', (62, 72))	('NEAT-1', 'Gene', '283131', (88, 94))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', (22, 26))	('higher', 'PosReg', (55, 61))	('low', 'Var', (18, 21))
77798	23827861	In rare cases, subjects with IBD undergoing computed tomography or magnetic resonance (MR) enterography have been found to have unsuspected intrahepatic bile duct dilatation, even though they had normal results from biochemical analyses of serum samples for liver function.	('intrahepatic bile duct dilatation', 'Disease', 'MESH:C531647', (140, 173))	('bile duct dilatation', 'Phenotype', 'HP:0006560', (153, 173))	('IBD', 'Phenotype', 'HP:0002037', (29, 32))	('intrahepatic bile duct dilatation', 'Disease', (140, 173))	('intrahepatic bile duct dilatation', 'Phenotype', 'HP:0005209', (140, 173))	('IBD', 'Var', (29, 32))	('dilatation', 'Phenotype', 'HP:0002617', (163, 173))
77847	23827861	However, patients with small-duct PSC survive longer and have a lower cumulative risk for cholangiocarcinoma than patients with large-duct involvement.	('patients', 'Species', '9606', (9, 17))	('PSC', 'Gene', '100653366', (34, 37))	('lower', 'NegReg', (64, 69))	('cholangiocarcinoma', 'Disease', (90, 108))	('PSC', 'Gene', (34, 37))	('men', 'Species', '9606', (146, 149))	('small-duct', 'Var', (23, 33))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (90, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('patients', 'Species', '9606', (114, 122))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))
77857	23827861	Several important observations, coupled with the strong association between certain human leukocyte antigen (HLA) haplotypes and frequency of concurrent extrahepatic autoimmune disorders, support the concept that PSC is an immune-mediated phenomenon.	('haplotypes', 'Var', (114, 124))	('men', 'Species', '9606', (244, 247))	('extrahepatic autoimmune disorders', 'Disease', 'MESH:D001651', (153, 186))	('HLA', 'Gene', '3123', (109, 112))	('PSC', 'Gene', (213, 216))	('HLA', 'Gene', (109, 112))	('human', 'Species', '9606', (84, 89))	('autoimmune disorders', 'Phenotype', 'HP:0002960', (166, 186))	('PSC', 'Gene', '100653366', (213, 216))	('extrahepatic autoimmune disorders', 'Disease', (153, 186))
77864	23827861	However, the picture of genetic predisposition to PSC is not complete; large genetic studies are underway to identify variants associated with PSC and to better determine its association with IBD.	('PSC', 'Gene', (50, 53))	('PSC', 'Gene', '100653366', (143, 146))	('PSC', 'Gene', (143, 146))	('variants', 'Var', (118, 126))	('IBD', 'Phenotype', 'HP:0002037', (192, 195))	('PSC', 'Gene', '100653366', (50, 53))
77866	23827861	Small intestinal bacterial overgrowth and introduction of bacterial antigens to the portal circulation cause pericholangitis in animal models.	('cholangitis', 'Phenotype', 'HP:0030151', (113, 124))	('pericholangitis', 'Disease', (109, 124))	('overgrowth', 'Phenotype', 'HP:0001548', (27, 37))	('pericholangitis', 'Disease', 'None', (109, 124))	('Small intestinal bacterial overgrowth', 'CPA', (0, 37))	('introduction', 'Var', (42, 54))
77875	23827861	Alteration of such barriers could expose cholangiocytes to a variety of substances, such as bile acids, that could promote injury and inflammation.	('injury and inflammation', 'Disease', 'MESH:D007249', (123, 146))	('promote', 'PosReg', (115, 122))	('Alteration', 'Var', (0, 10))	('expose', 'Reg', (34, 40))	('bile acids', 'Chemical', 'MESH:D001647', (92, 102))
77896	23827861	The observation that PSC can still develop after colectomy, and IBD can still develop after liver transplantation has led some to suggest that aberrant homing of lymphocytes between the intestine and liver could be involved in the pathogenesis of PSC.	('PSC', 'Gene', '100653366', (21, 24))	('aberrant', 'Var', (143, 151))	('PSC', 'Gene', '100653366', (247, 250))	('PSC', 'Gene', (21, 24))	('PSC', 'Gene', (247, 250))	('IBD', 'Phenotype', 'HP:0002037', (64, 67))	('involved', 'Reg', (215, 223))
77904	23827861	These observations support a role for aberrant lymphocyte trafficking in the pathogenesis of PSC.	('aberrant lymphocyte', 'Phenotype', 'HP:0004332', (38, 57))	('aberrant', 'Var', (38, 46))	('PSC', 'Gene', (93, 96))	('PSC', 'Gene', '100653366', (93, 96))
77908	23827861	The autoantibodies also increase expression of IL6 and adhesion molecules such as CD44, and could thereby promote lymphocyte proliferation, Ig production, and cell adhesion.	('autoantibodies', 'Var', (4, 18))	('increase', 'PosReg', (24, 32))	('IL6', 'Gene', '3569', (47, 50))	('IL6', 'Gene', (47, 50))	('CD44', 'Gene', '960', (82, 86))	('promote', 'PosReg', (106, 113))	('Ig production', 'MPA', (140, 153))	('cell adhesion', 'CPA', (159, 172))	('CD44', 'Gene', (82, 86))	('lymphocyte proliferation', 'CPA', (114, 138))	('expression', 'MPA', (33, 43))
77916	23827861	Defects in MDR3 have been associated with several cholestatic syndromes, in addition to drug-induced cholestasis.	('cholestasis', 'Disease', (101, 112))	('cholestatic syndromes', 'Disease', (50, 71))	('Defects', 'Var', (0, 7))	('cholestasis', 'Phenotype', 'HP:0001396', (101, 112))	('MDR3', 'Gene', (11, 15))	('cholestasis', 'Disease', 'MESH:D002779', (101, 112))	('cholestatic syndromes', 'Disease', 'MESH:D002779', (50, 71))	('associated', 'Reg', (26, 36))
77920	23827861	Variants and functional mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described in PSC patients.	('PSC', 'Gene', '100653366', (123, 126))	('Variants', 'Var', (0, 8))	('PSC', 'Gene', (123, 126))	('CFTR', 'Gene', '1080', (94, 98))	('cystic fibrosis transmembrane conductance regulator', 'Gene', '1080', (41, 92))	('described', 'Reg', (110, 119))	('patients', 'Species', '9606', (127, 135))	('CFTR', 'Gene', (94, 98))	('mutations', 'Var', (24, 33))
77921	23827861	However, it is not clear how mutations in MDR3 and CFTR contribute to PSC in the majority of patients.	('mutations', 'Var', (29, 38))	('PSC', 'Gene', '100653366', (70, 73))	('MDR3', 'Gene', (42, 46))	('CFTR', 'Gene', (51, 55))	('contribute', 'Reg', (56, 66))	('PSC', 'Gene', (70, 73))	('patients', 'Species', '9606', (93, 101))	('CFTR', 'Gene', '1080', (51, 55))
77923	23827861	In these animals, cholangitis is induced by enteric bacteria cell wall components, infectious agents (such as Cryptosporidium parvum), biliary obstruction, chemicals (such as lithocholic acid), knockout of genes such as Mdr2 or Cftr (in mice), or primary biliary and endothelial cell injury.	('Cftr', 'Gene', (228, 232))	('biliary obstruction', 'Disease', (135, 154))	('knockout', 'Var', (194, 202))	('cholangitis', 'Disease', 'MESH:D002761', (18, 29))	('induced', 'Reg', (33, 40))	('Mdr2', 'Gene', (220, 224))	('Cryptosporidium parvum', 'Species', '5807', (110, 132))	('cholangitis', 'Disease', (18, 29))	('biliary obstruction', 'Disease', 'MESH:D001658', (135, 154))	('mice', 'Species', '10090', (237, 241))	('biliary obstruction', 'Phenotype', 'HP:0005230', (135, 154))	('cholangitis', 'Phenotype', 'HP:0030151', (18, 29))	('lithocholic acid', 'Chemical', 'MESH:D008095', (175, 191))	('Cftr', 'Gene', '1080', (228, 232))	('Mdr2', 'Gene', '18670', (220, 224))
77930	23827861	Unexpectedly, a North American study was stopped early because 28-30 mg/kg/day UDCA increased the risk of disease progression 2-fold, compared with placebo; study endpoints included cirrhosis, varices, cholangiocarcinoma, liver transplantation, or death.	('cirrhosis', 'Disease', (182, 191))	('varices', 'Disease', (193, 200))	('liver transplantation', 'Disease', (222, 243))	('cholangiocarcinoma', 'Disease', (202, 220))	('28-30 mg/kg/day', 'Var', (63, 78))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (202, 220))	('death', 'Disease', (248, 253))	('death', 'Disease', 'MESH:D003643', (248, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('cirrhosis', 'Phenotype', 'HP:0001394', (182, 191))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (202, 220))	('UDCA', 'Gene', (79, 83))	('cirrhosis', 'Disease', 'MESH:D005355', (182, 191))
77932	23827861	Furthermore, high-dose UDCA was associated with an increased risk for colorectal neoplasia among patients with UC, providing further evidence for the toxicity of UDCA at this weight-based dosing range.	('colorectal neoplasia', 'Disease', (70, 90))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (70, 90))	('toxicity', 'Disease', 'MESH:D064420', (150, 158))	('high-dose', 'Var', (13, 22))	('toxicity', 'Disease', (150, 158))	('neoplasia', 'Phenotype', 'HP:0002664', (81, 90))	('patients', 'Species', '9606', (97, 105))
77970	23827861	Interestingly, a large study showed that patients with IBD and an intact colon were at increased risk for PSC recurrence.	('IBD', 'Var', (55, 58))	('PSC', 'Gene', '100653366', (106, 109))	('PSC', 'Gene', (106, 109))	('patients', 'Species', '9606', (41, 49))	('IBD', 'Phenotype', 'HP:0002037', (55, 58))
77992	23827861	At the Mayo Clinic, FISH results are assigned to 1 of 3 categories: negative, trisomy (10 or more cells show 3 copies of chromosomes 7 or 3, and 1 or 2 copies of the other probes) or tetrasomy (10 or more cells show 4 copies of all probes), and polysomy (5 or more cells have gained 2 or more chromosomes).	('Mayo', 'Species', '162683', (7, 11))	('trisomy', 'Disease', (78, 85))	('polysomy', 'Var', (245, 253))	('tetrasomy', 'Disease', (183, 192))
77993	23827861	In a large study of 235 PSC patients, individuals with polysomy (compared to those with trisomy or tetrasomy or negative FISH results) had similar outcomes to those with proven cholangiocarcinoma (Figure 3).	('trisomy or tetrasomy', 'Disease', 'MESH:D058670', (88, 108))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (177, 195))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (177, 195))	('polysomy', 'Var', (55, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('PSC', 'Gene', '100653366', (24, 27))	('PSC', 'Gene', (24, 27))	('cholangiocarcinoma', 'Disease', (177, 195))	('trisomy or tetrasomy', 'Disease', (88, 108))	('patients', 'Species', '9606', (28, 36))
77994	23827861	Among patients with PSC and a dominant stricture, the presence of polysomy identified those with an eventual diagnosis of cholangiocarcinoma with 88% specificity.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (122, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('polysomy', 'Var', (66, 74))	('PSC', 'Gene', '100653366', (20, 23))	('presence', 'Var', (54, 62))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (122, 140))	('PSC', 'Gene', (20, 23))	('patients', 'Species', '9606', (6, 14))	('cholangiocarcinoma', 'Disease', (122, 140))
77995	23827861	The value of FISH was confirmed by the finding that 75% of individuals with persistent polysomy in more than one test develop cholangiocarcinoma after 3 years.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (126, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('polysomy', 'Var', (87, 95))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (126, 144))	('develop', 'PosReg', (118, 125))	('cholangiocarcinoma', 'Disease', (126, 144))
78017	23827861	These findings support the recommendation of colectomy for patients with multi-focal LGD that is flat and found in areas of colitis.	('colitis', 'Disease', 'MESH:D003092', (124, 131))	('colitis', 'Disease', (124, 131))	('men', 'Species', '9606', (32, 35))	('patients', 'Species', '9606', (59, 67))	('colitis', 'Phenotype', 'HP:0002583', (124, 131))	('multi-focal', 'Var', (73, 84))
78057	23717698	Finally, individuals with urine IgG to OV antigen had a greater risk of APF as determined by Odds Ratios (OR = 6.69; 95%CI: 2.87, 15.58) and a greater risk of CCA (OR = 71.13; 95%CI: 15.13, 334.0) than individuals with no detectable level of urine IgG to OV antigen.	('urine IgG to OV antigen', 'Var', (26, 49))	('OV', 'Species', '6198', (39, 41))	('APF', 'Disease', (72, 75))	('OV', 'Species', '6198', (255, 257))	('CCA', 'Disease', (159, 162))
78064	23717698	Moreover, individuals with urine IgG to OV antigen also had elevated risk of bile duct fibrosis and bile duct cancer than individuals with no urine IgG to OV antigen.	('bile duct cancer', 'Phenotype', 'HP:0030153', (100, 116))	('bile duct cancer', 'Disease', (100, 116))	('bile duct cancer', 'Disease', 'MESH:D001650', (100, 116))	('OV', 'Species', '6198', (40, 42))	('fibrosis', 'Disease', 'MESH:D005355', (87, 95))	('fibrosis', 'Disease', (87, 95))	('urine IgG to OV antigen', 'Var', (27, 50))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('OV', 'Species', '6198', (155, 157))
78092	23717698	HE450525 and HE531061).	('HE531061', 'Var', (13, 21))	('HE531061', 'CellLine', 'CVCL:2922', (13, 21))	('HE450525', 'Var', (0, 8))
78140	23717698	Levels of serum IgG (Figure 1 Panel A) and serum IgG1 (Figure 1 Panel B) to OV antigen were significantly higher (P<0.001, for both) in individuals with both lighter (1-499 epg) or heavier (>=500 epg) OV infections compared to EN individuals (no eggs in feces).	('OV', 'Species', '6198', (76, 78))	('>=500 epg', 'Var', (190, 199))	('OV', 'Species', '6198', (201, 203))	('OV infections', 'Disease', (201, 214))	('serum IgG1', 'MPA', (43, 53))	('higher', 'PosReg', (106, 112))	('OV infections', 'Disease', 'MESH:D007239', (201, 214))	('serum IgG', 'MPA', (10, 19))
78143	23717698	Figure 2 Panel D shows that urine levels of IgG to OV antigen were significantly higher (P<0.001) in APF+ individuals than individuals in the EN or APF- groups: i.e., on average, 21 times higher in APF+ individuals than EN individuals and 7 times higher in APF+ individuals than APF- individuals.	('APF+', 'Var', (198, 202))	('higher', 'PosReg', (81, 87))	('higher', 'PosReg', (188, 194))	('OV', 'Species', '6198', (51, 53))	('urine levels of IgG to OV antigen', 'MPA', (28, 61))
78160	23717698	Table S2 shows that serum IgG to OV antigen could also modestly discriminate APF positive individuals from individuals from the EN group, with an AUC of 0.52 and a PPV of 0.52 and an adjusted OR of 2.71 (95%CI: 1.26, 5.84).	('discriminate', 'Reg', (64, 76))	('APF', 'Gene', (77, 80))	('OV', 'Species', '6198', (33, 35))	('positive', 'Var', (81, 89))
78168	23717698	As shown in Table 5, individuals with elevated urine IgG to OV antigen had an increased risk for APF (adjusted OR of 6.69; 95%CI: 2.87, 15.58) and an increased risk for CCA (adjusted OR of 71.13; 95%CI: 15.13, 334.0) than individuals who had no detectable levels of urine IgG to OV antigen.	('OV', 'Species', '6198', (279, 281))	('CCA', 'Disease', (169, 172))	('APF', 'Disease', (97, 100))	('urine IgG to OV antigen', 'Var', (47, 70))	('elevated urine IgG', 'Phenotype', 'HP:0003237', (38, 56))	('OV', 'Species', '6198', (60, 62))	('elevated', 'PosReg', (38, 46))
78295	21266979	These were single item questions F1 (had fevers) and L46 (trouble talking about feelings to family or friends).	('L46', 'Var', (53, 56))	('fever', 'Disease', 'MESH:D005334', (41, 46))	('fevers', 'Phenotype', 'HP:0001945', (41, 47))	('fever', 'Disease', (41, 46))	('fever', 'Phenotype', 'HP:0001945', (41, 46))
78354	31413529	Previous studies have shown that honokiol can inhibit tumour growth both in vitro and in animal models by induction of cell apoptosis in many types of colon, breast, glioblastoma and liver cancers.	('glioblastoma', 'Phenotype', 'HP:0012174', (166, 178))	('honokiol', 'Var', (33, 41))	('honokiol', 'Chemical', 'MESH:C005499', (33, 41))	('inhibit', 'NegReg', (46, 53))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('cell apoptosis', 'CPA', (119, 133))	('tumour', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('colon', 'Disease', (151, 156))	('glioblastoma and liver cancers', 'Disease', 'MESH:D005909', (166, 196))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('liver cancers', 'Phenotype', 'HP:0002896', (183, 196))	('breast', 'Disease', (158, 164))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
78380	31413529	Flow cytometric analysis was carried out using the following antibodies: antihuman CD11c antibody-PE (eBioscience, CA, United States) and antihuman CD14 antibody-FITC (Abcam, Cambridge, United Kindom).	('FITC', 'Chemical', 'MESH:D016650', (162, 166))	('human', 'Species', '9606', (142, 147))	('CD14', 'Gene', (148, 152))	('CD11c', 'Gene', '3687', (83, 88))	('CD11c', 'Gene', (83, 88))	('CD14', 'Gene', '929', (148, 152))	('antihuman', 'Var', (73, 82))	('human', 'Species', '9606', (77, 82))
78434	31413529	However, the efficacy of DCs loaded with tumour cell lysates is limited by antigen processing and presentation, mostly mediated by MHC class II to CD4+ T cells.	('CD4', 'Gene', '920', (147, 150))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('tumour', 'Disease', (41, 47))	('MHC', 'Var', (131, 134))	('CD4', 'Gene', (147, 150))
78437	31413529	One previous study reported that honokiol activates cancer cell apoptosis either by receptor- or mitochondria-mediated mechanisms.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('honokiol', 'Var', (33, 41))	('honokiol', 'Chemical', 'MESH:C005499', (33, 41))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('activates', 'PosReg', (42, 51))
78449	31413529	High expression of HSP90 is associated with poor prognosis in CCA patients.	('HSP90', 'Gene', '3320', (19, 24))	('High', 'Var', (0, 4))	('CCA', 'Phenotype', 'HP:0030153', (62, 65))	('CCA', 'Disease', (62, 65))	('patients', 'Species', '9606', (66, 74))	('HSP90', 'Gene', (19, 24))
78472	31413529	This may be associated with abnormality of STAT3 and the NF-kappaB signalling pathway.	('NF-kappaB', 'Gene', (57, 66))	('STAT3', 'Gene', '6774', (43, 48))	('abnormality', 'Var', (28, 39))	('associated', 'Reg', (12, 22))	('STAT3', 'Gene', (43, 48))	('NF-kappaB', 'Gene', '4790', (57, 66))
78473	31413529	On the other hand, DAMPs function to trigger DC maturation via TLR4/2, which involves p38 MAPK and NF-kappaB downstream signalling pathways.	('NF-kappaB', 'Gene', '4790', (99, 108))	('TLR4/2', 'Gene', (63, 69))	('trigger', 'Reg', (37, 44))	('TLR4/2', 'Gene', '7099;7097', (63, 69))	('NF-kappaB', 'Gene', (99, 108))	('DAMPs', 'Var', (19, 24))
78479	31413529	Moreover, treatment with anthracyclines on some cancer cell lines including prostate cancer, ovarian cancer and acute lymphoblastic leukemia cells could induce nuclear translocation of calreticulin, HSP70 and HSP90 as well as the release of HMGB1, causing maturation of DCs.	('HSP90', 'Gene', '3320', (209, 214))	('calreticulin', 'Gene', (185, 197))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('induce', 'Reg', (153, 159))	('cancer', 'Disease', (48, 54))	('calreticulin', 'Gene', '811', (185, 197))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('ovarian cancer', 'Disease', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (118, 140))	('ovarian cancer', 'Phenotype', 'HP:0100615', (93, 107))	('leukemia', 'Phenotype', 'HP:0001909', (132, 140))	('HSP70', 'Gene', (199, 204))	('DCs', 'Disease', (270, 273))	('HMGB1', 'Gene', (241, 246))	('nuclear translocation', 'MPA', (160, 181))	('cancer', 'Disease', (85, 91))	('HMGB1', 'Gene', '3146', (241, 246))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('acute lymphoblastic leukemia', 'Disease', (112, 140))	('HSP90', 'Gene', (209, 214))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('cancer', 'Disease', (101, 107))	('causing', 'Reg', (248, 255))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('anthracyclines', 'Var', (25, 39))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (112, 140))	('HSP70', 'Gene', '3308', (199, 204))	('maturation', 'Disease', (256, 266))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('release', 'MPA', (230, 237))	('anthracyclines', 'Chemical', 'MESH:D018943', (25, 39))	('ovarian cancer', 'Disease', 'MESH:D010051', (93, 107))	('prostate cancer', 'Disease', (76, 91))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (112, 140))
78596	27829047	The present study identified cytoplasmic WT1 as a novel marker for intrahepatic cholangiocarcinoma.	('WT1', 'Gene', '7490', (41, 44))	('cytoplasmic', 'Var', (29, 40))	('WT1', 'Gene', (41, 44))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (80, 98))	('intrahepatic cholangiocarcinoma', 'Disease', (67, 98))
78607	27829047	CA19-9 and CA125, were also expressed in 90% and 50% of tumors of the intestinal type, respectively (S2 Fig).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('CA125', 'Gene', '94025', (11, 16))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('CA19-9', 'Var', (0, 6))	('CA125', 'Gene', (11, 16))
78619	27829047	Recent studies have demonstrated overexpression of PDX1 and alterations in HES1 expression not only in ductal pancreatic adenocarcinoma, but also in cholangiocarcinoma and biliary intraepithelial neoplasia.	('overexpression', 'PosReg', (33, 47))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (110, 135))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (180, 205))	('neoplasia', 'Phenotype', 'HP:0002664', (196, 205))	('ductal pancreatic adenocarcinoma', 'Disease', (103, 135))	('HES1', 'Gene', '3280', (75, 79))	('PDX1', 'Gene', (51, 55))	('cholangiocarcinoma and biliary intraepithelial neoplasia', 'Disease', 'MESH:D019048', (149, 205))	('HES1', 'Gene', (75, 79))	('ductal pancreatic adenocarcinoma', 'Disease', 'MESH:D021441', (103, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('expression', 'MPA', (80, 90))	('alterations', 'Var', (60, 71))	('PDX1', 'Gene', '3651', (51, 55))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (149, 167))
78778	24949368	The results found that 83% patients with cholangiocarcinoma and underwent an EUS-FNA had peritoneal metastases at the time of operative restaging, as compared to 8% of patients who did not undergo FNA.	('metastases', 'Disease', (100, 110))	('metastases', 'Disease', 'MESH:D009362', (100, 110))	('cholangiocarcinoma', 'Disease', (41, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('EUS-FNA', 'Var', (77, 84))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (41, 59))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (168, 176))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (41, 59))
78798	32694946	Linc00473 potentiates cholangiocarcinoma progression by modulation of DDX5 expression via miR-506 regulation Cholangiocarcinoma (CCA) is a mortal cancer with high mortality, whereas the function and mechanism of occurrence and progression of CCA are still mysterious.	('CCA', 'Phenotype', 'HP:0030153', (129, 132))	('cancer', 'Disease', (146, 152))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (22, 40))	('mortal', 'Disease', 'MESH:D003643', (163, 169))	('mortal', 'Disease', 'MESH:D003643', (139, 145))	('Linc00473', 'Gene', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (109, 127))	('Cholangiocarcinoma', 'Disease', (109, 127))	('Linc00473', 'Gene', '90632', (0, 9))	('mortal', 'Disease', (163, 169))	('mortal', 'Disease', (139, 145))	('mortality', 'Disease', (163, 172))	('miR-506', 'Gene', (90, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('modulation', 'Var', (56, 66))	('DDX5', 'Gene', '1655', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('CCA', 'Phenotype', 'HP:0030153', (242, 245))	('mortality', 'Disease', 'MESH:D003643', (163, 172))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (22, 40))	('DDX5', 'Gene', (70, 74))	('cholangiocarcinoma', 'Disease', (22, 40))	('miR-506', 'Gene', '574511', (90, 97))	('potentiates', 'PosReg', (10, 21))
78805	32694946	Linc00473 knockdown inhibited CCA growth and metastasis.	('Linc00473', 'Gene', '90632', (0, 9))	('Linc00473', 'Gene', (0, 9))	('CCA', 'Disease', (30, 33))	('inhibited', 'NegReg', (20, 29))	('knockdown', 'Var', (10, 19))	('CCA', 'Phenotype', 'HP:0030153', (30, 33))
78815	32694946	lncRNA DANCR regulates proliferation and migration by epigenetically silencing FBP1 in tumorigenesis of CCA.	('CCA', 'Disease', (104, 107))	('DANCR', 'Gene', (7, 12))	('migration', 'CPA', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('DANCR', 'Gene', '57291', (7, 12))	('FBP1', 'Gene', '2203', (79, 83))	('tumor', 'Disease', (87, 92))	('CCA', 'Phenotype', 'HP:0030153', (104, 107))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('proliferation', 'CPA', (23, 36))	('FBP1', 'Gene', (79, 83))	('epigenetically silencing', 'Var', (54, 78))
78851	32694946	The sequences containing the wild-type (WT) or mutated (MUT) region DDX5 and linc00473 were synthesized by GenePharma (Shanghai, China) and inserted into a pmirGLO-Report luciferase vector.	('DDX5', 'Gene', (68, 72))	('linc00473', 'Gene', (77, 86))	('mutated', 'Var', (47, 54))	('DDX5', 'Gene', '1655', (68, 72))	('linc00473', 'Gene', '90632', (77, 86))
78873	32694946	The results documented that high linc00473 expression was an independent predictor of poor survival (Table 2).	('linc00473', 'Gene', (33, 42))	('poor survival', 'CPA', (86, 99))	('high', 'Var', (28, 32))	('expression', 'MPA', (43, 53))	('linc00473', 'Gene', '90632', (33, 42))
78880	32694946	CCK-8 assay revealed that cell proliferation was inhibited in HCCC-9810 and CCLP1 with si-linc00473-1 and si-linc00473-2 transfection compared with that in negative control (si-NC) (Fig.	('linc00473', 'Gene', '90632', (109, 118))	('linc00473', 'Gene', (90, 99))	('HCCC-9810', 'CellLine', 'CVCL:6908', (62, 71))	('CCLP1', 'Gene', (76, 81))	('linc00473', 'Gene', '90632', (90, 99))	('linc00473', 'Gene', (109, 118))	('transfection', 'Var', (121, 133))	('cell proliferation', 'CPA', (26, 44))	('inhibited', 'NegReg', (49, 58))
78885	32694946	The above results indicated that that knockdown of linc00473 could inhibit CCA growth, invasion, and migration abilities of CCA cells.	('migration abilities', 'CPA', (101, 120))	('inhibit', 'NegReg', (67, 74))	('linc00473', 'Gene', (51, 60))	('CCA', 'Disease', (75, 78))	('CCA', 'Phenotype', 'HP:0030153', (124, 127))	('linc00473', 'Gene', '90632', (51, 60))	('invasion', 'CPA', (87, 95))	('CCA', 'Phenotype', 'HP:0030153', (75, 78))	('knockdown', 'Var', (38, 47))
78890	32694946	Expression of a large number of miRNAs was upregulated in cells with knockdown of linc00473 (Fig.	('miRNAs', 'Protein', (32, 38))	('upregulated', 'PosReg', (43, 54))	('linc00473', 'Gene', '90632', (82, 91))	('Expression', 'MPA', (0, 10))	('linc00473', 'Gene', (82, 91))	('knockdown', 'Var', (69, 78))
78892	32694946	The nine miRNAs (miR-15, miR-130, miR-139, miR-142, miR-195, miR-431, miR-545, and miR-506) were screened in both CCLP1 and HCCC-9810 cells (Fig.	('miR-142', 'Gene', (43, 50))	('miR-545', 'Gene', '664614', (70, 77))	('miR-431', 'Gene', '574038', (61, 68))	('miR-139', 'Gene', (34, 41))	('miR-130', 'Var', (25, 32))	('miR-195', 'Gene', (52, 59))	('miR-431', 'Gene', (61, 68))	('miR-545', 'Gene', (70, 77))	('miR-15', 'Var', (17, 23))	('miR-195', 'Gene', '406971', (52, 59))	('HCCC-9810', 'CellLine', 'CVCL:6908', (124, 133))	('miR-139', 'Gene', '406931', (34, 41))	('miR-142', 'Gene', '406934', (43, 50))	('miR-506', 'Gene', '574511', (83, 90))	('miR-506', 'Gene', (83, 90))
78908	32694946	Meanwhile, the western blot results demonstrated that knockdown of linc00473 led to a decrease of DDX5 (Fig.	('linc00473', 'Gene', '90632', (67, 76))	('knockdown', 'Var', (54, 63))	('DDX5', 'Gene', '1655', (98, 102))	('DDX5', 'Gene', (98, 102))	('linc00473', 'Gene', (67, 76))	('decrease', 'NegReg', (86, 94))
78912	32694946	CCK8 assays revealed that the viability of CCA cells was reduced by si-linc00473 transfection and was increased by miR-506 inhibitor transfection (Fig.	('miR-506', 'Gene', (115, 122))	('viability', 'CPA', (30, 39))	('miR-506', 'Gene', '574511', (115, 122))	('transfection', 'Var', (81, 93))	('CCA', 'Disease', (43, 46))	('linc00473', 'Gene', (71, 80))	('increased', 'PosReg', (102, 111))	('reduced', 'NegReg', (57, 64))	('CCA', 'Phenotype', 'HP:0030153', (43, 46))	('linc00473', 'Gene', '90632', (71, 80))
78913	32694946	Compared with that in the control group, the knockdown of linc00473 decreased the number of migratory and invasive cells among CCA cells, but this effect was reversed by co-transfection of the miR-506 inhibitor (Fig.	('linc00473', 'Gene', (58, 67))	('decreased', 'NegReg', (68, 77))	('CCA', 'Phenotype', 'HP:0030153', (127, 130))	('miR-506', 'Gene', '574511', (193, 200))	('miR-506', 'Gene', (193, 200))	('linc00473', 'Gene', '90632', (58, 67))	('knockdown', 'Var', (45, 54))
78930	32694946	The results suggested that linc00473 deletion issued significant inhibition of cell proliferation, migration and invasion, and linc00473 up-regulation promoted tumor growth in nude mice xenografts.	('inhibition', 'NegReg', (65, 75))	('linc00473', 'Gene', (127, 136))	('deletion', 'Var', (37, 45))	('cell proliferation', 'CPA', (79, 97))	('linc00473', 'Gene', (27, 36))	('linc00473', 'Gene', '90632', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('linc00473', 'Gene', '90632', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))	('up-regulation promoted', 'PosReg', (137, 159))	('nude mice', 'Species', '10090', (176, 185))
78931	32694946	To further explore the mechanism by which linc00473 regulated CCA cell proliferation and invasion, we performed bioinformatic analysis and in vitro experimental studies and found that lin00473 could sponge miR-506, which play a role in cancer suppression in various cancers.	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('linc00473', 'Gene', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('CCA', 'Phenotype', 'HP:0030153', (62, 65))	('cancer', 'Disease', (266, 272))	('cancers', 'Disease', (266, 273))	('cancer', 'Disease', (236, 242))	('cancers', 'Disease', 'MESH:D009369', (266, 273))	('linc00473', 'Gene', '90632', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('invasion', 'CPA', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('lin00473', 'Var', (184, 192))	('miR-506', 'Gene', '574511', (206, 213))	('miR-506', 'Gene', (206, 213))	('CCA', 'Disease', (62, 65))
78950	32077341	Some CCA patients have genetic mutations and several therapeutic drugs or antibodies have been introduced to target abnormally expressed proteins.	('CCA', 'Disease', (5, 8))	('patients', 'Species', '9606', (9, 17))	('genetic mutations', 'Var', (23, 40))
78973	32077341	Genetic traits that induce mutations, polymorphisms, or genetic aberrations may increase the risk of CCA development.	('mutations', 'Var', (27, 36))	('CCA development', 'Disease', (101, 116))	('increase', 'PosReg', (80, 88))	('polymorphisms', 'Var', (38, 51))	('rat', 'Species', '10116', (68, 71))
78981	32077341	Genomic sequencing analyses for CCA patients have identified various genetic aberrations, such as mutations/polymorphisms, abnormal amplification, and chromosomal translocation or fusion.	('patients', 'Species', '9606', (36, 44))	('CCA', 'Disease', (32, 35))	('rat', 'Species', '10116', (81, 84))	('fusion', 'Var', (180, 186))	('mutations/polymorphisms', 'Var', (98, 121))	('abnormal amplification', 'Var', (123, 145))	('chromosomal', 'CPA', (151, 162))
78983	32077341	These genes are expressed abnormally because of genetic aberrations, or expressed proteins have different functions due to neomorphic mutations.	('proteins', 'Protein', (82, 90))	('rat', 'Species', '10116', (60, 63))	('mutations', 'Var', (134, 143))
78985	32077341	For example, mutations in IDH genes alter the function of IDH leading to the production and accumulation of an oncometabolite D-2-hydroxyglutarate (2-HG) that contributes to carcinogenesis.	('production', 'MPA', (77, 87))	('alter', 'Reg', (36, 41))	('accumulation of', 'MPA', (92, 107))	('IDH genes', 'Gene', (26, 35))	('2-HG', 'Chemical', 'MESH:C019417', (148, 152))	('carcinogenesis', 'CPA', (174, 188))	('contributes', 'Reg', (159, 170))	('function', 'MPA', (46, 54))	('mutations', 'Var', (13, 22))	('IDH', 'Gene', (58, 61))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (126, 146))	('D-2-hydroxyglutarate', 'MPA', (126, 146))
78986	32077341	IDH inhibitors, AG-221 (enasidenib) and AG-120 (ivosidenib), have been approved by the FDA for various cancers, including CCA.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('enasidenib', 'Chemical', 'MESH:C000605269', (24, 34))	('ivosidenib', 'Chemical', 'MESH:C000627630', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('AG-221', 'Chemical', 'MESH:C000605269', (16, 22))	('CCA', 'Disease', (122, 125))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('AG-120', 'Chemical', 'MESH:C000627630', (40, 46))	('AG-221', 'Var', (16, 22))	('AG-120', 'Var', (40, 46))	('cancers', 'Disease', (103, 110))
78987	32077341	Clinical trials are currently ongoing for AG-221, AG-120, and AG-881 (NCT02577406, NCT01915498, NCT02989857, NCT02989857, NCT02481154, NCT03343197, NCT02632708).	('NCT02577406', 'Var', (70, 81))	('NCT02989857', 'Var', (96, 107))	('NCT03343197', 'Var', (135, 146))	('NCT02481154', 'Var', (122, 133))	('NCT01915498', 'Var', (83, 94))	('AG-120', 'Chemical', 'MESH:C000627630', (50, 56))	('NCT02989857', 'Var', (109, 120))	('NCT02632708', 'Var', (148, 159))	('AG-221', 'Chemical', 'MESH:C000605269', (42, 48))
78988	32077341	DNA sequencing for CCA patients identified genetic alterations or aberrations in FGFR.	('rat', 'Species', '10116', (70, 73))	('patients', 'Species', '9606', (23, 31))	('FGFR', 'Gene', (81, 85))	('CCA', 'Disease', (19, 22))	('genetic alterations', 'Var', (43, 62))	('rat', 'Species', '10116', (55, 58))	('aberrations', 'Var', (66, 77))
78989	32077341	The fusion of FGFR2 with another gene, such as bicaudal C homolog 1 (BICC1), shootin 1 (SHTN1), transforming acidic coiled-coil containing protein 3 (TACC3), or periphilin 1 (PPHLN1), is commonly found in intrahepatic CCA patients.	('FGFR2', 'Gene', (14, 19))	('PPHLN1', 'Gene', '51535', (175, 181))	('BICC1', 'Gene', '80114', (69, 74))	('bicaudal C homolog 1', 'Gene', (47, 67))	('shootin 1', 'Gene', (77, 86))	('bicaudal C homolog 1', 'Gene', '80114', (47, 67))	('PPHLN1', 'Gene', (175, 181))	('patients', 'Species', '9606', (222, 230))	('fusion', 'Var', (4, 10))	('SHTN1', 'Gene', '57698', (88, 93))	('periphilin 1', 'Gene', '51535', (161, 173))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (205, 221))	('BICC1', 'Gene', (69, 74))	('intrahepatic CCA', 'Disease', (205, 221))	('transforming acidic coiled-coil containing protein 3', 'Gene', '10460', (96, 148))	('SHTN1', 'Gene', (88, 93))	('shootin 1', 'Gene', '57698', (77, 86))	('periphilin 1', 'Gene', (161, 173))
78992	32077341	Fusion gene expression of FGFR2-PPHLN1 increases the sensitivity of CCA cell lines to derazantinib, suggesting that this drug can be effective against fusion FGFR in intrahepatic CCA.	('PPHLN1', 'Gene', (32, 38))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (166, 182))	('PPHLN1', 'Gene', '51535', (32, 38))	('sensitivity', 'MPA', (53, 64))	('Fusion gene expression', 'Var', (0, 22))	('intrahepatic CCA', 'Disease', (166, 182))	('increases', 'PosReg', (39, 48))	('derazantinib', 'Chemical', 'MESH:C000621805', (86, 98))
78994	32077341	BGJ398 and Debio1347 are drugs targeting FGFR, and clinical trials are ongoing for them (NCT02150967 and NCT03834220, respectively).	('BGJ398', 'Chemical', 'MESH:C568950', (0, 6))	('NCT03834220', 'Var', (105, 116))	('NCT02150967', 'Var', (89, 100))	('FGFR', 'Gene', (41, 45))	('Debio1347', 'Chemical', 'MESH:C000602562', (11, 20))
78995	32077341	However, some CCA patients have multiple FGFR mutations and develop resistance against these drugs due to secondary FGFR mutations.	('mutations', 'Var', (121, 130))	('FGFR', 'Gene', (116, 120))	('mutations', 'Var', (46, 55))	('FGFR', 'Gene', (41, 45))	('patients', 'Species', '9606', (18, 26))	('develop', 'Reg', (60, 67))	('CCA', 'Disease', (14, 17))	('resistance against these drugs', 'MPA', (68, 98))
78999	32077341	These studies suggest that targeting genes that represent genetic aberrations or variations is a promising strategy developing therapeutic drugs leading to novel treatments or chemotherapies for CCA patients.	('rat', 'Species', '10116', (70, 73))	('rat', 'Species', '10116', (109, 112))	('patients', 'Species', '9606', (199, 207))	('CCA', 'Disease', (195, 198))	('variations', 'Var', (81, 91))
79021	32077341	CCA tumor cells interact with TAMs via CD47, which mediates an anti-phagocytic signal, and high expression of CD47 in CCA cells helps them to escape phagocytosis by TAMs.	('TAMs', 'Chemical', '-', (30, 34))	('CCA tumor', 'Disease', (0, 9))	('high expression', 'Var', (91, 106))	('CCA tumor', 'Disease', 'MESH:C536211', (0, 9))	('TAMs', 'Chemical', '-', (165, 169))	('CD47', 'Gene', (110, 114))	('escape phagocytosis', 'CPA', (142, 161))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
79022	32077341	Administration of an anti-CD47 monoclonal antibody B6H12.2 increased phagocytic ability as well as infiltration of TAMs and decreased colonization of injected KKU-213 cells into the liver in vivo using NOD Rag-2-/-Jak3-/- mice.	('phagocytic ability', 'CPA', (69, 87))	('colonization', 'CPA', (134, 146))	('Jak3', 'Gene', (214, 218))	('mice', 'Species', '10090', (222, 226))	('rat', 'Species', '10116', (8, 11))	('rat', 'Species', '10116', (105, 108))	('infiltration', 'CPA', (99, 111))	('decreased', 'NegReg', (124, 133))	('anti-CD47', 'Gene', (21, 30))	('TAMs', 'Chemical', '-', (115, 119))	('Jak3', 'Gene', '16453', (214, 218))	('KKU-213', 'CellLine', 'CVCL:M261', (159, 166))	('increased', 'PosReg', (59, 68))	('B6H12.2', 'Var', (51, 58))
79027	32077341	Inhibition of this immune checkpoint is a strategy to increase T cell functions and inhibit cancer progression in various malignancies.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('malignancies', 'Disease', 'MESH:D009369', (122, 134))	('increase T cell', 'Phenotype', 'HP:0100828', (54, 69))	('malignancies', 'Disease', (122, 134))	('inhibit', 'NegReg', (84, 91))	('T cell functions', 'CPA', (63, 79))	('increase', 'PosReg', (54, 62))	('rat', 'Species', '10116', (44, 47))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
79035	32077341	Treatments with an agonist for GITR or antagonists for PD-1 or CTLA4 increased proliferation and functions of CCA-derived T cells.	('proliferation', 'CPA', (79, 92))	('increased', 'PosReg', (69, 78))	('CTLA4', 'Gene', '1493', (63, 68))	('CTLA4', 'Gene', (63, 68))	('PD-1', 'Gene', (55, 59))	('GITR', 'Gene', (31, 35))	('GITR', 'Gene', '8784', (31, 35))	('antagonists', 'Var', (39, 50))	('functions', 'CPA', (97, 106))	('rat', 'Species', '10116', (86, 89))
79037	32077341	Clinical trials are currently ongoing for pembrolizumab, a monoclonal antibody against PD-1 (NCT02703714, NCT02628067, NCT03111732), and atezolizumab, a monoclonal antibody against PD-L1 (NCT03201458, NCT03818997).	('pembrolizumab', 'Chemical', 'MESH:C582435', (42, 55))	('atezolizumab', 'Chemical', 'MESH:C000594389', (137, 149))	('NCT02703714', 'Var', (93, 104))	('PD-1', 'Gene', (87, 91))	('NCT03201458', 'Var', (188, 199))
79053	32077341	An in vitro study using human CCA cell line KKU-M055 and KKU-M214 has demonstrated that melatonin induces apoptosis and inhibits cell proliferation of CCA cells showing the anti-cancer effects of melatonin.	('inhibits', 'NegReg', (120, 128))	('cell proliferation', 'CPA', (129, 147))	('human', 'Species', '9606', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('rat', 'Species', '10116', (77, 80))	('melatonin', 'Chemical', 'MESH:D008550', (88, 97))	('apoptosis', 'CPA', (106, 115))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('melatonin', 'Chemical', 'MESH:D008550', (196, 205))	('melatonin', 'Var', (88, 97))	('CCA', 'Disease', (151, 154))	('rat', 'Species', '10116', (141, 144))
79072	32077341	A previous study has demonstrated that DEN administration develops liver tumors in mice, and the disruption of circadian rhythms by 8-hour advance light exposure every two days exacerbates liver damage and tumor development compared to mice with 12-hour light and 12-hour dark cycle.	('disruption', 'Var', (97, 107))	('liver tumors', 'Disease', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mice', 'Species', '10090', (236, 240))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('exacerbates', 'PosReg', (177, 188))	('mice', 'Species', '10090', (83, 87))	('tumor', 'Disease', (73, 78))	('DEN', 'Chemical', 'MESH:D004128', (39, 42))	('liver damage', 'Disease', (189, 201))	('rat', 'Species', '10116', (28, 31))	('liver tumors', 'Disease', 'MESH:D008113', (67, 79))	('rat', 'Species', '10116', (51, 54))	('liver tumors', 'Phenotype', 'HP:0002896', (67, 79))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('liver damage', 'Disease', 'MESH:D056486', (189, 201))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
79076	32077341	Another study has demonstrated that expression levels of clock gene Per1 are downregulated in CCA tissues and CCA cell lines, and overexpression of Per1 inhibits CCA cell line proliferation in vitro and decreases tumor volumes in vivo using xenograft models.	('decreases tumor', 'Disease', 'MESH:D002303', (203, 218))	('rat', 'Species', '10116', (183, 186))	('CCA', 'Disease', (94, 97))	('downregulated', 'NegReg', (77, 90))	('CCA', 'Disease', (162, 165))	('clock', 'Gene', (57, 62))	('clock', 'Gene', '12753', (57, 62))	('inhibits', 'NegReg', (153, 161))	('Per1', 'Gene', (148, 152))	('decreases tumor', 'Disease', (203, 218))	('rat', 'Species', '10116', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('overexpression', 'Var', (130, 144))	('expression levels', 'MPA', (36, 53))	('Per1', 'Gene', (68, 72))
79082	32077341	Administration of TPH1 inhibitor p-chlorophenylalanine decreased tumor size in the xenograft model using Mz-ChA-1 cells, indicating the potential of serotonin as a therapeutic target for CCA.	('rat', 'Species', '10116', (8, 11))	('CCA', 'Disease', (187, 190))	('decreased tumor', 'Disease', (55, 70))	('inhibitor p-chlorophenylalanine', 'Var', (23, 54))	('p-chlorophenylalanine', 'Var', (33, 54))	('serotonin', 'Chemical', 'MESH:D012701', (149, 158))	('TPH1', 'Gene', (18, 22))	('TPH1', 'Gene', '7166', (18, 22))	('decreased tumor', 'Disease', 'MESH:D002303', (55, 70))	('p-chlorophenylalanine decreased', 'Phenotype', 'HP:0500224', (33, 64))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('p-chlorophenylalanine', 'Chemical', 'MESH:D010134', (33, 54))
79086	32077341	A recent study has demonstrated that expression levels of MAOA are decreased in cholangiocytes of Mdr2-/- mice, which are a mouse model of PSC, and administration of antagonists against serotonin receptors 5HTR2A, 5HTR2B, or 5HTR2C improves liver conditions by inhibiting ductular reaction and liver fibrosis.	('5HTR2C', 'Gene', (225, 231))	('Mdr2', 'Gene', (98, 102))	('PSC', 'Gene', '100653366', (139, 142))	('liver fibrosis', 'Phenotype', 'HP:0001395', (294, 308))	('PSC', 'Gene', (139, 142))	('serotonin', 'Chemical', 'MESH:D012701', (186, 195))	('5HTR2C', 'Gene', '15560', (225, 231))	('antagonists', 'Var', (166, 177))	('expression levels', 'MPA', (37, 54))	('MAOA', 'Gene', (58, 62))	('rat', 'Species', '10116', (156, 159))	('mice', 'Species', '10090', (106, 110))	('liver fibrosis', 'Disease', (294, 308))	('ductular reaction', 'CPA', (272, 289))	('mouse', 'Species', '10090', (124, 129))	('liver conditions', 'Disease', (241, 257))	('improves', 'PosReg', (232, 240))	('rat', 'Species', '10116', (26, 29))	('liver fibrosis', 'Disease', 'MESH:D008103', (294, 308))	('inhibiting', 'NegReg', (261, 271))	('decreased', 'NegReg', (67, 76))	('Mdr2', 'Gene', '18670', (98, 102))
79090	32077341	A previous study has demonstrated that expression levels of TH and DDC, as well as dopamine secretion, are upregulated in CCA cell lines and inhibition of dopamine synthesis using DDC inhibitor L-(-)-alpha-methyldopa decreases tumor volumes in a xenograft model in vivo.	('DDC', 'Gene', '1644', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('dopamine', 'Chemical', 'MESH:D004298', (155, 163))	('dopamine', 'Chemical', 'MESH:D004298', (83, 91))	('upregulated', 'PosReg', (107, 118))	('L-(-)-alpha-methyldopa', 'Chemical', '-', (194, 216))	('DDC', 'Gene', '1644', (180, 183))	('decreases tumor', 'Disease', (217, 232))	('expression levels', 'MPA', (39, 56))	('inhibition', 'Var', (141, 151))	('CCA', 'Disease', (122, 125))	('decreases tumor', 'Disease', 'MESH:D002303', (217, 232))	('dopamine secretion', 'MPA', (83, 101))	('DDC', 'Gene', (180, 183))	('rat', 'Species', '10116', (28, 31))	('DDC', 'Gene', (67, 70))
79092	32077341	These findings suggest that antagonists targeting dopamine receptors may have anti-cancer effects against CCA.	('dopamine receptors', 'Protein', (50, 68))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('antagonists', 'Var', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('dopamine', 'Chemical', 'MESH:D004298', (50, 58))	('CCA', 'Disease', (106, 109))	('cancer', 'Disease', (83, 89))
79095	32077341	Further studies are required to elucidate whether agonists or antagonists on specific dopamine receptors represent anti-cancer effects for CCA.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('antagonists', 'Var', (62, 73))	('CCA', 'Disease', (139, 142))	('cancer', 'Disease', (120, 126))	('dopamine', 'Chemical', 'MESH:D004298', (86, 94))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
79096	32077341	A previous study has demonstrated that expression levels of miRNA miR-551b-3p are significantly downregulated in CCA tumor tissues compared to healthy bile duct tissues.	('CCA tumor', 'Disease', (113, 122))	('CCA tumor', 'Disease', 'MESH:C536211', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('downregulated', 'NegReg', (96, 109))	('expression levels', 'MPA', (39, 56))	('miRNA miR-551b-3p', 'Var', (60, 77))	('rat', 'Species', '10116', (28, 31))
79098	32077341	This study has also demonstrated that miR-551b-3p targets cyclin D1 (CCND1), leading to suppressed CCND1 expression, which is associated with CCA cell growth arrest and apoptosis.	('growth arrest', 'Phenotype', 'HP:0001510', (151, 164))	('miR-551b-3p', 'Var', (38, 49))	('suppressed', 'NegReg', (88, 98))	('CCA cell growth arrest', 'Disease', 'MESH:D006323', (142, 164))	('CCND1', 'Gene', '595', (69, 74))	('CCND1', 'Gene', '595', (99, 104))	('CCA cell growth arrest', 'Disease', (142, 164))	('CCND1', 'Gene', (99, 104))	('rat', 'Species', '10116', (27, 30))	('cyclin D1', 'Gene', '595', (58, 67))	('CCND1', 'Gene', (69, 74))	('expression', 'MPA', (105, 115))	('cyclin D1', 'Gene', (58, 67))
79102	32077341	Another study has also demonstrated that miR-186 is significantly downregulated in CCA tissues and found that Microchidia family CW-type zinc finger 2 (MORC2) is the target of miR-186.	('miR-186', 'Gene', (41, 48))	('MORC2', 'Gene', (152, 157))	('CCA', 'Disease', (83, 86))	('miR-186', 'Var', (176, 183))	('rat', 'Species', '10116', (30, 33))	('downregulated', 'NegReg', (66, 79))	('MORC2', 'Gene', '22880', (152, 157))
79108	32077341	Human CCA cell lines CCLP1 and RBE cells expressed higher levels of KCNQ1OT1 than normal cholangiocytes, and inhibition of KCNQ1OT1 decreased cell proliferation and invasion of CCA cells inducing apoptosis.	('Human', 'Species', '9606', (0, 5))	('inhibition', 'Var', (109, 119))	('KCNQ1OT1', 'Gene', (123, 131))	('rat', 'Species', '10116', (154, 157))	('KCNQ1OT1', 'Gene', (68, 76))	('inducing', 'Reg', (187, 195))	('cell proliferation', 'CPA', (142, 160))	('apoptosis', 'CPA', (196, 205))	('invasion', 'CPA', (165, 173))	('decreased', 'NegReg', (132, 141))	('KCNQ1OT1', 'Gene', '10984', (123, 131))	('KCNQ1OT1', 'Gene', '10984', (68, 76))	('levels', 'MPA', (58, 64))
79118	32077341	Inhibition of NNT-AS1 decreased tumor size in vivo using xenograft mouse models with CCLP1 cells.	('NNT-AS1', 'Gene', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('decreased tumor', 'Disease', (22, 37))	('Inhibition', 'Var', (0, 10))	('mouse', 'Species', '10090', (67, 72))	('decreased tumor', 'Disease', 'MESH:D002303', (22, 37))	('NNT-AS1', 'Gene', '100652772', (14, 21))
79131	32077341	Classic approaches of CCA treatments include the administration of antibodies or inhibitors for proteins that are expressed abnormally or have mutations in CCA patients, such as IDH and FGFR2.	('proteins', 'Protein', (96, 104))	('patients', 'Species', '9606', (160, 168))	('IDH', 'Disease', (178, 181))	('FGFR2', 'Gene', (186, 191))	('rat', 'Species', '10116', (57, 60))	('mutations', 'Var', (143, 152))
79132	32077341	Other studies have demonstrated that various signaling pathways are involved in CCA development or progression, and small molecules targeting these pathways, such as antagonists against serotonin receptors, may have the potential as a novel therapeutic drug for CCA.	('CCA', 'Disease', (80, 83))	('serotonin', 'Chemical', 'MESH:D012701', (186, 195))	('rat', 'Species', '10116', (26, 29))	('CCA', 'Disease', (262, 265))	('small', 'Var', (116, 121))
79134	32077341	The development of inhibitors based on genetic mutations or aberrations is a promising therapeutic approach for CCA and several drugs/inhibitors are currently under clinical trials.	('aberrations', 'Var', (60, 71))	('CCA', 'Disease', (112, 115))	('rat', 'Species', '10116', (64, 67))
79135	32077341	For example, the incidence of mutations in CCA cases is 9% for IDH1 and 3% for IDH2.	('IDH2', 'Gene', '3418', (79, 83))	('IDH1', 'Gene', '3417', (63, 67))	('CCA', 'Disease', (43, 46))	('mutations', 'Var', (30, 39))	('IDH2', 'Gene', (79, 83))	('IDH1', 'Gene', (63, 67))
79141	32077341	For example, FGFR2 fusions were identified mainly in intrahepatic CCA, and mutations in IDH1 or IDH2 were rare or not found in extrahepatic CCA.	('intrahepatic CCA', 'Disease', (53, 69))	('IDH2', 'Gene', '3418', (96, 100))	('IDH1', 'Gene', (88, 92))	('fusions', 'Var', (19, 26))	('identified', 'Reg', (32, 42))	('IDH2', 'Gene', (96, 100))	('IDH1', 'Gene', '3417', (88, 92))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (53, 69))	('FGFR2', 'Gene', (13, 18))
79166	32077341	Approaches of immunotherapies include inhibition of immune checkpoints, such as anti-PD-1 antibodies, or activation of T cells by drugs or other hepatic cells, such as DCs, to facilitate CCA cell deaths.	('anti-PD-1', 'Var', (80, 89))	('facilitate', 'PosReg', (176, 186))	('CCA cell deaths', 'Disease', (187, 202))	('CCA cell deaths', 'Disease', 'MESH:C536211', (187, 202))
79183	32077341	For example, overexpression of miR-551b-3p decreased cell proliferation and induced apoptosis in HuCCT-1 cells in vitro as well as decreased tumor volumes in HuCCT-1 xenograft mice in vivo.	('apoptosis', 'CPA', (84, 93))	('HuCCT-1', 'CellLine', 'CVCL:0324', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('decreased tumor', 'Disease', (131, 146))	('miR-551b-3p', 'Var', (31, 42))	('decreased tumor', 'Disease', 'MESH:D002303', (131, 146))	('overexpression', 'PosReg', (13, 27))	('HuCCT-1', 'CellLine', 'CVCL:0324', (158, 165))	('mice', 'Species', '10090', (176, 180))	('cell proliferation', 'CPA', (53, 71))	('decreased', 'NegReg', (43, 52))	('rat', 'Species', '10116', (65, 68))
79191	32077341	Extracellular vesicles could be utilized to manage tumor progression by delivering non-coding RNAs	('non-coding RNAs', 'Var', (83, 98))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
79305	20691980	PARP metabolism is essential for post-translational modification of proteins in eukaryotic cells and inactivation of PARP causes deregulation of deoxyribonucleic acid (DNA) repair and cell death.	('PARP', 'Gene', '142', (117, 121))	('PARP', 'Gene', (0, 4))	('deregulation', 'MPA', (129, 141))	('PARP', 'Gene', (117, 121))	('inactivation', 'Var', (101, 113))	('cell death', 'CPA', (184, 194))	('PARP', 'Gene', '142', (0, 4))
79321	33655556	The VEGF-VEGFR signalling is the most crucial pathway to induce angiogenesis, and inhibiting this cascade has already got success in treating tumours.	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('inhibiting', 'Var', (82, 92))	('tumours', 'Disease', (142, 149))	('angiogenesis', 'CPA', (64, 76))	('VEGFR', 'Gene', '3791', (9, 14))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('induce', 'PosReg', (57, 63))	('VEGFR', 'Gene', (9, 14))
79322	33655556	While both their efficacy and antitumour spectrum are limited, combining FGF/FGFR inhibitors with VEGF/VEGFR inhibitors are an excellent way to optimize the curative effect and expand the antitumour range because their combination can target both tumour cells and the tumour microenvironment.	('tumour', 'Disease', 'MESH:D009369', (268, 274))	('tumour', 'Phenotype', 'HP:0002664', (247, 253))	('tumour', 'Disease', (268, 274))	('FGFR', 'Gene', '2260', (77, 81))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('curative effect', 'CPA', (157, 172))	('tumour', 'Disease', 'MESH:D009369', (247, 253))	('VEGFR', 'Gene', '3791', (103, 108))	('tumour', 'Disease', (34, 40))	('inhibitors', 'Var', (82, 92))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('tumour', 'Disease', (247, 253))	('tumour', 'Phenotype', 'HP:0002664', (268, 274))	('tumour', 'Disease', (192, 198))	('VEGFR', 'Gene', (103, 108))	('FGFR', 'Gene', (77, 81))
79324	33655556	Targeted therapies interfering with oncogenic driver alterations have achieved remarkable success in limited types of cancer with certain driver gene alterations (Nat Rev Clin Oncol, 2017; Lancet Oncol, 2018; Jama, 2019; Lancet, 2017).	('cancer', 'Disease', (118, 124))	('Jama', 'Gene', '50848', (209, 213))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('alterations', 'Var', (150, 161))	('Jama', 'Gene', (209, 213))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
79326	33655556	The FGF-FGFR signalling plays pivotal roles in both the physiological and oncogenic processes (Nat Rev Clin Oncol, 2019), but FGFRs are constitutively active in malignant cells because of the upregulation of FGF and FGFR genetic alterations (Nat Rev Clin Oncol, 2019).	('FGF', 'Gene', (208, 211))	('FGFR', 'Gene', (216, 220))	('FGFR', 'Gene', (126, 130))	('FGFR', 'Gene', '2260', (216, 220))	('genetic alterations', 'Var', (221, 240))	('FGFR', 'Gene', '2260', (126, 130))	('upregulation', 'PosReg', (192, 204))	('FGFR', 'Gene', (8, 12))	('FGFR', 'Gene', '2260', (8, 12))
79330	33655556	Accordingly, inhibition of the VEGF-VEGFR signalling pathway is believed to suppress tumour development (New Engl J Med, 1971).	('VEGFR', 'Gene', '3791', (36, 41))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('suppress', 'NegReg', (76, 84))	('VEGFR', 'Gene', (36, 41))	('tumour', 'Disease', (85, 91))	('inhibition', 'Var', (13, 23))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
79333	33655556	FGFR/VEGFR inhibitors have better effects and broaden the indications in clinical use (Nat Commun, 2020; JAMA Oncol, 2018; The Lancet Oncology, 2020).	('JAMA', 'Gene', '50848', (105, 109))	('FGFR', 'Gene', (0, 4))	('VEGFR', 'Gene', (5, 10))	('JAMA', 'Gene', (105, 109))	('FGFR', 'Gene', '2260', (0, 4))	('Oncology', 'Phenotype', 'HP:0002664', (134, 142))	('effects', 'MPA', (34, 41))	('inhibitors', 'Var', (11, 21))	('VEGFR', 'Gene', '3791', (5, 10))
79338	33655556	Anti-FGF or FGFR therapy is a promising way to treat tumours with FGF and (or) FGFR alterations.	('FGFR', 'Gene', '2260', (12, 16))	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('tumours', 'Disease', (53, 60))	('FGFR', 'Gene', (79, 83))	('alterations', 'Var', (84, 95))	('FGF', 'Gene', (66, 69))	('FGFR', 'Gene', '2260', (79, 83))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('FGFR', 'Gene', (12, 16))
79339	33655556	5  With the accelerated approval of erdafitinib for FGFR-altered urothelial carcinoma in April 2019 and pemigatinib for cholangiocarcinoma with FGFR2 fusion or other rearrangements in April 2020, 6 ,  7  the FGF-FGFR signalling pathway has received more attention.	('FGFR2', 'Gene', '2263', (144, 149))	('fusion', 'Var', (150, 156))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (120, 138))	('pemigatinib', 'Chemical', '-', (104, 115))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (65, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('FGFR', 'Gene', (212, 216))	('FGFR', 'Gene', '2260', (144, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('FGFR', 'Gene', (144, 148))	('FGFR', 'Gene', '2260', (212, 216))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (120, 138))	('FGFR', 'Gene', (52, 56))	('FGFR', 'Gene', '2260', (52, 56))	('erdafitinib', 'Chemical', 'MESH:C000604580', (36, 47))	('FGFR2', 'Gene', (144, 149))	('cholangiocarcinoma', 'Disease', (120, 138))	('urothelial carcinoma', 'Disease', (65, 85))
79341	33655556	5  Combination of the inhibitory of the FGF-FGFR signalling pathway with other mechanisms is a promising way to solve this puzzle.	('FGFR', 'Gene', (44, 48))	('inhibitory', 'Var', (22, 32))	('FGFR', 'Gene', '2260', (44, 48))
79352	33655556	19  Take FGFR1 as an example; seven phosphorylatable tyrosine residues have been identified, that is, Y463, Y583, Y585, Y653, Y654, Y730 and Y766.	('FGFR1', 'Gene', '2260', (9, 14))	('Y653', 'Var', (120, 124))	('Y585', 'Var', (114, 118))	('Y583', 'Var', (108, 112))	('tyrosine', 'Chemical', 'MESH:D014443', (53, 61))	('Y730', 'Var', (132, 136))	('Y654', 'Var', (126, 130))	('FGFR1', 'Gene', (9, 14))	('Y463', 'Var', (102, 106))
79371	33655556	The oncogenic role of FGF-FGFR signalling in driving cancer cell proliferation, survival, migration and invasion is mediated by the upregulation of FGF, FGFR genetic alterations, angiogenesis and immune evasion in the tumour microenvironment.	('FGFR', 'Gene', '2260', (153, 157))	('FGFR', 'Gene', (26, 30))	('cancer', 'Disease', (53, 59))	('upregulation', 'PosReg', (132, 144))	('migration', 'CPA', (90, 99))	('FGFR', 'Gene', (153, 157))	('tumour', 'Disease', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('FGFR', 'Gene', '2260', (26, 30))	('immune', 'MPA', (196, 202))	('angiogenesis', 'CPA', (179, 191))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('genetic alterations', 'Var', (158, 177))	('invasion', 'CPA', (104, 112))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('survival', 'CPA', (80, 88))	('tumour', 'Disease', 'MESH:D009369', (218, 224))	('FGF', 'Gene', (148, 151))
79372	33655556	5   An analysis of 4,853 solid tumours by the next-generation sequencing technique demonstrated FGFR aberrations in 7.1% of cancers.	('solid tumours', 'Disease', (25, 38))	('aberrations', 'Var', (101, 112))	('FGFR', 'Gene', (96, 100))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('FGFR', 'Gene', '2260', (96, 100))	('tumours', 'Phenotype', 'HP:0002664', (31, 38))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('solid tumours', 'Disease', 'MESH:D009369', (25, 38))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
79374	33655556	33   Deregulated gene transcription or amplification can lead to elevated FGFR levels, which can activate FGF-FGFR signalling in a ligand-independent manner.	('FGFR', 'Gene', '2260', (74, 78))	('amplification', 'Var', (39, 52))	('activate', 'PosReg', (97, 105))	('FGFR', 'Gene', '2260', (110, 114))	('FGFR', 'Gene', (110, 114))	('elevated', 'PosReg', (65, 73))	('Deregulated', 'Var', (5, 16))	('FGFR', 'Gene', (74, 78))
79376	33655556	34   Amplification of the FGFR1 gene is the most common in all types of FGFR gene alterations.	('FGFR', 'Gene', (26, 30))	('common', 'Reg', (49, 55))	('FGFR1', 'Gene', (26, 31))	('FGFR1', 'Gene', '2260', (26, 31))	('FGFR', 'Gene', '2260', (26, 30))	('FGFR', 'Gene', (72, 76))	('alterations', 'Var', (82, 93))	('FGFR', 'Gene', '2260', (72, 76))	('34   Amplification', 'Var', (0, 18))
79378	33655556	33  Recent studies described that the rate of FGFR1 amplification was significantly higher in squamous cell lung cancer (SqCLC) and Asians, and FGFR1 amplification may be a potential new therapeutic target for individual patients with specific lung cancer subtypes such as EGFR TKI for Asian patients with lung adenocarcinoma.	('patients', 'Species', '9606', (221, 229))	('lung adenocarcinoma', 'Disease', (306, 325))	('FGFR1', 'Gene', (144, 149))	('FGFR1', 'Gene', (46, 51))	('patients', 'Species', '9606', (292, 300))	('amplification', 'Var', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('higher', 'PosReg', (84, 90))	('EGFR', 'Gene', (273, 277))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (306, 325))	('lung cancer', 'Disease', (244, 255))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (306, 325))	('SqCLC', 'Phenotype', 'HP:0030359', (121, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (94, 119))	('squamous cell lung cancer', 'Disease', (94, 119))	('FGFR1', 'Gene', '2260', (144, 149))	('EGFR', 'Gene', '1956', (273, 277))	('FGFR1', 'Gene', '2260', (46, 51))	('lung cancer', 'Disease', 'MESH:D008175', (244, 255))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (244, 255))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (94, 119))
79381	33655556	37  The relationship between amplification of FGFR1 and prognosis is still in doubt in NSCLC.	('NSCLC', 'Disease', (87, 92))	('amplification', 'Var', (29, 42))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('SCLC', 'Phenotype', 'HP:0030357', (88, 92))	('FGFR1', 'Gene', (46, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('FGFR1', 'Gene', '2260', (46, 51))
79385	33655556	39  FGFR1 amplification is an independent biomarker of a poor prognosis in patients with ER (+) breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('FGFR1', 'Gene', (4, 9))	('patients', 'Species', '9606', (75, 83))	('ER', 'Gene', '2069', (89, 91))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('FGFR1', 'Gene', '2260', (4, 9))	('breast cancer', 'Disease', (96, 109))	('amplification', 'Var', (10, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))
79387	33655556	42  What is more, allelic loss and amplification of FGFR1 can predict chemo- and radiotherapy response in breast cancer.	('amplification', 'Var', (35, 48))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('allelic loss', 'Var', (18, 30))	('FGFR1', 'Gene', (52, 57))	('FGFR1', 'Gene', '2260', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('predict', 'Reg', (62, 69))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
79388	33655556	43  FGFR1 amplification correlating with inadequate response to traditional treatments also happens in osteosarcoma, 44  and the expression of FGFR1 is associated with worse disease-free survival (DFS) and poor overall survival (OS) in head and neck squamous cell carcinoma (HNSCC), 45  oesophageal cancer 46  and colorectal cancer (CRC).	('HNSCC', 'Phenotype', 'HP:0012288', (275, 280))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (236, 273))	('FGFR1', 'Gene', '2260', (4, 9))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('cancer', 'Disease', (325, 331))	('osteosarcoma', 'Phenotype', 'HP:0002669', (103, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (314, 331))	('FGFR1', 'Gene', (143, 148))	('colorectal cancer', 'Disease', (314, 331))	('neck squamous cell carcinoma', 'Disease', (245, 273))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('disease-free', 'Disease', (174, 186))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (245, 273))	('FGFR1', 'Gene', (4, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (250, 273))	('expression', 'Var', (129, 139))	('poor', 'NegReg', (206, 210))	('CRC', 'Phenotype', 'HP:0003003', (333, 336))	('cancer', 'Disease', (299, 305))	('worse', 'NegReg', (168, 173))	('colorectal cancer', 'Disease', 'MESH:D015179', (314, 331))	('cancer', 'Disease', 'MESH:D009369', (325, 331))	('osteosarcoma', 'Disease', (103, 115))	('osteosarcoma', 'Disease', 'MESH:D012516', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('overall', 'MPA', (211, 218))	('FGFR1', 'Gene', '2260', (143, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))
79390	33655556	FGFR2 amplification exists in several cancers.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('amplification', 'Var', (6, 19))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))	('cancers', 'Disease', (38, 45))
79392	33655556	48  High-level FGFR2 amplification is associated with the lower response, resistance to chemotherapy, shorter PFS and shorter OS in gastric cancers.	('shorter', 'NegReg', (102, 109))	('resistance', 'CPA', (74, 84))	('lower', 'NegReg', (58, 63))	('response', 'MPA', (64, 72))	('FGFR2', 'Gene', (15, 20))	('FGFR2', 'Gene', '2263', (15, 20))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	('gastric cancers', 'Disease', 'MESH:D013274', (132, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('amplification', 'Var', (21, 34))	('gastric cancers', 'Disease', (132, 147))	('gastric cancers', 'Phenotype', 'HP:0012126', (132, 147))
79398	33655556	51  FGFR3 amplification is also found in HNSCC, urothelial cancers and CRC.	('HNSCC', 'Phenotype', 'HP:0012288', (41, 46))	('CRC', 'Disease', (71, 74))	('found', 'Reg', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('HNSCC, urothelial cancers', 'Disease', 'MESH:D000077195', (41, 66))	('FGFR3', 'Gene', (4, 9))	('CRC', 'Phenotype', 'HP:0003003', (71, 74))	('amplification', 'Var', (10, 23))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))
79399	33655556	33  High expression of FGFR3 is concerned with poor prognosis in papillary bladder cancers and oligometastatic CRC.	('FGFR3', 'Gene', (23, 28))	('High expression', 'Var', (4, 19))	('oligometastatic CRC', 'Disease', (95, 114))	('papillary bladder cancers', 'Disease', 'MESH:D001749', (65, 90))	('papillary bladder cancers', 'Disease', (65, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CRC', 'Phenotype', 'HP:0003003', (111, 114))	('bladder cancers', 'Phenotype', 'HP:0009725', (75, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))
79406	33655556	37   N546K mutation in the kinase domain of FGFR1 is the most common reported subtype among all the types of FGFR1 mutations.	('FGFR1', 'Gene', (44, 49))	('FGFR1', 'Gene', (109, 114))	('FGFR1', 'Gene', '2260', (44, 49))	('FGFR1', 'Gene', '2260', (109, 114))	('37   N546K', 'Var', (0, 10))	('N546K', 'Mutation', 'rs779707422', (5, 10))
79408	33655556	57 ,  58 ,  59  Other mutations in FGFR1, such as K565E, have also been reported in glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (84, 96))	('glioblastoma', 'Phenotype', 'HP:0012174', (84, 96))	('K565E', 'Var', (50, 55))	('reported', 'Reg', (72, 80))	('K565E', 'Mutation', 'rs869320694', (50, 55))	('FGFR1', 'Gene', (35, 40))	('glioblastoma', 'Disease', (84, 96))	('FGFR1', 'Gene', '2260', (35, 40))
79410	33655556	57   Unlike the mutations in FGFR1, the most common mutations of FGFR2 are S252w and P253R occurring in the extracellular fragment, while K650E/M/N and N549K in FGFR2 are also found in the A-loop.	('FGFR2', 'Gene', (65, 70))	('FGFR2', 'Gene', '2263', (65, 70))	('FGFR1', 'Gene', '2260', (29, 34))	('N549K', 'Var', (152, 157))	('P253R', 'Mutation', 'rs77543610', (85, 90))	('N549K', 'Mutation', 'rs121913476', (152, 157))	('P253R', 'Var', (85, 90))	('S252w', 'Var', (75, 80))	('FGFR2', 'Gene', (161, 166))	('K650E', 'Var', (138, 143))	('FGFR2', 'Gene', '2263', (161, 166))	('FGFR1', 'Gene', (29, 34))	('K650E', 'SUBSTITUTION', 'None', (138, 143))
79411	33655556	FGFR2 mutations are found in up to 12% of endometrial carcinomas, 10% of gastric tumours, approximately 4% of NSCLCs and <2% of urothelial cancers.	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (42, 64))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('urothelial cancers', 'Disease', 'MESH:D014523', (128, 146))	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('endometrial carcinomas', 'Disease', (42, 64))	('FGFR2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))	('NSCLCs', 'Disease', (110, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (54, 64))	('FGFR2', 'Gene', '2263', (0, 5))	('gastric tumours', 'Disease', 'MESH:D013274', (73, 88))	('urothelial cancers', 'Disease', (128, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (42, 64))	('SCLC', 'Phenotype', 'HP:0030357', (111, 115))	('NSCLCs', 'Disease', 'MESH:D002289', (110, 116))	('found', 'Reg', (20, 25))	('gastric tumours', 'Disease', (73, 88))
79412	33655556	61  FGFR2 mutation is an independent prognostic factor in endometrioid endometrial cancer through disrupting cell polarity to enhance migration and invasion.	('enhance', 'PosReg', (126, 133))	('endometrial cancer', 'Phenotype', 'HP:0012114', (71, 89))	('FGFR2', 'Gene', '2263', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mutation', 'Var', (10, 18))	('endometrioid endometrial cancer', 'Disease', 'MESH:D016889', (58, 89))	('migration', 'CPA', (134, 143))	('cell polarity', 'CPA', (109, 122))	('endometrioid endometrial cancer', 'Disease', (58, 89))	('FGFR2', 'Gene', (4, 9))	('invasion', 'CPA', (148, 156))	('disrupting', 'NegReg', (98, 108))
79413	33655556	62  However, a phase II study failed to prove that the proportion of patients who were progression-free at 18 weeks was higher in advanced or metastatic endometrial cancer with FGFR mutations than in FGFR-non-mutated endometrial cancer when treated by dovitinib, a TK inhibitor (TKI) of FGFRs, VEGFRs, PDGFR-beta and c-KIT after first-line chemotherapy.	('FGFR', 'Gene', (287, 291))	('VEGFR', 'Gene', '3791', (294, 299))	('VEGFR', 'Gene', (294, 299))	('patients', 'Species', '9606', (69, 77))	('FGFR', 'Gene', '2260', (200, 204))	('FGFR', 'Gene', '2260', (177, 181))	('FGFR', 'Gene', '2260', (287, 291))	('advanced', 'Disease', (130, 138))	('mutations', 'Var', (182, 191))	('endometrial cancer', 'Phenotype', 'HP:0012114', (217, 235))	('dovitinib', 'Chemical', 'MESH:C500007', (252, 261))	('PDGFR-beta', 'Gene', '5156', (302, 312))	('PDGFR-beta', 'Gene', (302, 312))	('endometrial cancer', 'Phenotype', 'HP:0012114', (153, 171))	('endometrial cancer', 'Disease', (217, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('c-KIT', 'Gene', (317, 322))	('endometrial cancer', 'Disease', (153, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('higher', 'PosReg', (120, 126))	('endometrial cancer', 'Disease', 'MESH:D016889', (217, 235))	('metastatic', 'CPA', (142, 152))	('c-KIT', 'Gene', '3815', (317, 322))	('endometrial cancer', 'Disease', 'MESH:D016889', (153, 171))	('FGFR', 'Gene', (200, 204))	('FGFR', 'Gene', (177, 181))
79414	33655556	63   FGFR3 mutations commonly occur in the extracellular (R248C, S249C) and TM (G370C, Y373C) domains of the receptor, which are found to have the ability to stimulate proliferation in cell lines and lead to the transformation of fibroblasts into tumour cells.	('transformation', 'CPA', (212, 226))	('proliferation', 'CPA', (168, 181))	('R248C', 'Var', (58, 63))	('mutations', 'Var', (11, 20))	('lead to', 'Reg', (200, 207))	('S249C', 'Var', (65, 70))	('R248C', 'Mutation', 'rs121913482', (58, 63))	('tumour', 'Phenotype', 'HP:0002664', (247, 253))	('G370C', 'Mutation', 'rs199740841', (80, 85))	('stimulate', 'PosReg', (158, 167))	('S249C', 'Mutation', 'rs121913483', (65, 70))	('tumour', 'Disease', 'MESH:D009369', (247, 253))	('Y373C', 'Mutation', 'rs121913485', (87, 92))	('tumour', 'Disease', (247, 253))	('G370C', 'Var', (80, 85))	('FGFR3', 'Gene', (5, 10))
79415	33655556	33  75% of muscle-non-invasive bladder cancers (MNIBC) have mutations in FGFR3, while the proportion is around 15% in muscle-invasive bladder cancers (MIBC).	('muscle-invasive bladder cancers', 'Disease', (118, 149))	('bladder cancers', 'Phenotype', 'HP:0009725', (134, 149))	('FGFR3', 'Gene', (73, 78))	('bladder cancers', 'Phenotype', 'HP:0009725', (31, 46))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('muscle-non-invasive bladder cancers', 'Disease', 'MESH:D001749', (11, 46))	('invasive bladder', 'Phenotype', 'HP:0100645', (22, 38))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('muscle-invasive bladder cancers', 'Disease', 'MESH:D001749', (118, 149))	('MIBC', 'Disease', 'None', (151, 155))	('muscle-non-invasive bladder', 'Phenotype', 'HP:0000011', (11, 38))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('invasive bladder', 'Phenotype', 'HP:0100645', (125, 141))	('MIBC', 'Disease', (151, 155))	('mutations', 'Var', (60, 69))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('muscle-non-invasive bladder cancers', 'Disease', (11, 46))
79416	33655556	64  Mutations in FGFR3 indicate a better prognosis in MNIBC, a better response to neoadjuvant chemotherapy in MIBC and disease occurrence or recurrence in bladder cancers.	('MIBC', 'Disease', (110, 114))	('better', 'PosReg', (34, 40))	('MNIBC', 'Disease', (54, 59))	('bladder cancers', 'Phenotype', 'HP:0009725', (155, 170))	('recurrence in bladder', 'Phenotype', 'HP:0012786', (141, 162))	('bladder cancers', 'Disease', 'MESH:D001749', (155, 170))	('MIBC', 'Disease', 'None', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('FGFR3', 'Gene', (17, 22))	('better', 'PosReg', (63, 69))	('Mutations', 'Var', (4, 13))	('bladder cancers', 'Disease', (155, 170))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))
79417	33655556	65  At the same time, FGFR3 S249C mutation in urinary cell-free DNA could predict early-stage (<=pT1) of upper muscle-invasive urothelial carcinoma with 100% positive predictive value.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('FGFR3', 'Gene', (22, 27))	('S249C', 'Var', (28, 33))	('upper muscle-invasive urothelial carcinoma', 'Disease', (105, 147))	('S249C', 'Mutation', 'rs121913483', (28, 33))	('predict', 'Reg', (74, 81))	('upper muscle-invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (105, 147))
79418	33655556	66  Besides, FGFR3 mutations also occur in cervical, vulvar squamous cell carcinoma and breast cancer.	('cervical', 'Disease', (43, 51))	('vulvar squamous cell carcinoma', 'Phenotype', 'HP:0030417', (53, 83))	('occur', 'Reg', (34, 39))	('vulvar squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 83))	('mutations', 'Var', (19, 28))	('FGFR3', 'Gene', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('vulvar squamous cell carcinoma', 'Disease', (53, 83))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
79419	33655556	67 ,  68 ,  69   The kinase domain mutations of FGFR4 (V550E/L and N535D/K) were described in 7% of rhabdomyosarcoma, leading to tumour growth in vivo and drug resistance to all type I and some type II inhibitors in patients.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('FGFR4', 'Gene', (48, 53))	('drug resistance to all', 'MPA', (155, 177))	('leading to', 'Reg', (118, 128))	('V550E', 'Var', (55, 60))	('tumour growth', 'Disease', 'MESH:D006130', (129, 142))	('V550E', 'SUBSTITUTION', 'None', (55, 60))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (100, 116))	('drug resistance', 'Phenotype', 'HP:0020174', (155, 170))	('patients', 'Species', '9606', (216, 224))	('N535D', 'SUBSTITUTION', 'None', (67, 72))	('rhabdomyosarcoma', 'Disease', (100, 116))	('N535D', 'Var', (67, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (100, 116))	('tumour growth', 'Disease', (129, 142))	('described', 'Reg', (81, 90))	('FGFR4', 'Gene', '2264', (48, 53))
79420	33655556	70  Besides, variant rs351855-G/A can lead to germline FGFR4 G388R substitution, subsequently expose a membrane-proximal STAT3-binding site and trigger STAT3 signalling cascade, which can accelerate cancer progression and also contribute to tumour-extrinsic immune evasion.	('STAT3', 'Gene', '6774', (121, 126))	('STAT3', 'Gene', '6774', (152, 157))	('lead', 'Reg', (38, 42))	('cancer', 'Disease', (199, 205))	('contribute', 'Reg', (227, 237))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumour', 'Phenotype', 'HP:0002664', (241, 247))	('tumour', 'Disease', 'MESH:D009369', (241, 247))	('tumour', 'Disease', (241, 247))	('expose', 'PosReg', (94, 100))	('FGFR4', 'Gene', '2264', (55, 60))	('accelerate', 'PosReg', (188, 198))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('variant rs351855-G/A', 'Var', (13, 33))	('G388R', 'Var', (61, 66))	('STAT3', 'Gene', (121, 126))	('STAT3', 'Gene', (152, 157))	('FGFR4', 'Gene', (55, 60))	('rs351855', 'Mutation', 'rs351855', (21, 29))	('trigger', 'Reg', (144, 151))	('G388R', 'Mutation', 'rs351855', (61, 66))
79421	33655556	71  FGFR4 G388R substitution is correlated with poor survival in resected colon cancer and lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('colon cancer', 'Phenotype', 'HP:0003003', (74, 86))	('G388R', 'Mutation', 'rs351855', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('colon cancer', 'Disease', 'MESH:D015179', (74, 86))	('colon cancer', 'Disease', (74, 86))	('G388R', 'Var', (10, 15))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('FGFR4', 'Gene', '2264', (4, 9))	('poor', 'NegReg', (48, 52))	('FGFR4', 'Gene', (4, 9))	('lung cancer', 'Disease', (91, 102))
79427	33655556	77   FGFR2 fusions occur in around 10%-20% of patients with intrahepatic cholangiocarcinoma.	('patients', 'Species', '9606', (46, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('FGFR2', 'Gene', (5, 10))	('FGFR2', 'Gene', '2263', (5, 10))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (60, 91))	('fusions', 'Var', (11, 18))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (73, 91))	('intrahepatic cholangiocarcinoma', 'Disease', (60, 91))
79428	33655556	The major fusion partners of FGFR2 are PPHLN1, AHCYL1, BICC1 and TACC3, which bring the probability of targeted therapy for the patients who have FGFR2 rearrangements.	('BICC1', 'Gene', '80114', (55, 60))	('TACC3', 'Gene', '10460', (65, 70))	('PPHLN1', 'Gene', (39, 45))	('AHCYL1', 'Gene', (47, 53))	('TACC3', 'Gene', (65, 70))	('FGFR2', 'Gene', (146, 151))	('FGFR2', 'Gene', '2263', (146, 151))	('FGFR2', 'Gene', (29, 34))	('FGFR2', 'Gene', '2263', (29, 34))	('AHCYL1', 'Gene', '10768', (47, 53))	('PPHLN1', 'Gene', '51535', (39, 45))	('rearrangements', 'Var', (152, 166))	('BICC1', 'Gene', (55, 60))	('patients', 'Species', '9606', (128, 136))
79429	33655556	78  Several FGFR inhibitors have been tested in phase I or II clinical trial and finally, pemigatinib, an FGFR1-3 inhibitor, received accelerated approval in April 2020 by the FDA for the treatment of patients with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangements based on FIGHT-202 phase II clinical trial, in which 35.5% of patients with FGFR2 fusions or rearrangements achieved an objective response.	('FGFR', 'Gene', '2260', (12, 16))	('FGFR', 'Gene', '2260', (106, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('FGFR2', 'Gene', (307, 312))	('FGFR1-3', 'Gene', (106, 113))	('fusions', 'Var', (426, 433))	('rearrangements', 'Var', (437, 451))	('FGFR', 'Gene', (420, 424))	('pemigatinib', 'Chemical', '-', (90, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (280, 298))	('FGFR2', 'Gene', '2263', (307, 312))	('FGFR', 'Gene', (307, 311))	('cholangiocarcinoma', 'Disease', (280, 298))	('FGFR', 'Gene', '2260', (420, 424))	('patients', 'Species', '9606', (201, 209))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (280, 298))	('FGFR2', 'Gene', (420, 425))	('FGFR', 'Gene', '2260', (307, 311))	('FGFR', 'Gene', (12, 16))	('FGFR', 'Gene', (106, 110))	('patients', 'Species', '9606', (406, 414))	('FGFR2', 'Gene', '2263', (420, 425))	('FGFR1-3', 'Gene', '2260;2263;2261', (106, 113))
79430	33655556	7  Interestingly, FGFR2 fusions also have been found in breast, prostate and thyroid cancer.	('FGFR2', 'Gene', (18, 23))	('FGFR2', 'Gene', '2263', (18, 23))	('breast', 'Disease', (56, 62))	('prostate', 'Disease', (64, 72))	('thyroid cancer', 'Phenotype', 'HP:0002890', (77, 91))	('found', 'Reg', (47, 52))	('thyroid cancer', 'Disease', (77, 91))	('thyroid cancer', 'Disease', 'MESH:D013964', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('fusions', 'Var', (24, 31))
79431	33655556	33   In addition to the presence of FGFR3 amplification and mutations in urothelial carcinoma, FGFR2/3 fusions have also been detected.	('fusions', 'Var', (103, 110))	('FGFR2/3', 'Gene', '2263;2261', (95, 102))	('urothelial carcinoma', 'Disease', (73, 93))	('FGFR3', 'Gene', (36, 41))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (73, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('FGFR2/3', 'Gene', (95, 102))	('mutations', 'Var', (60, 69))
79434	33655556	Other researchers found the fused protein can trigger the MAPK-ERK and JAK-STAT signalling pathways.	('trigger', 'Reg', (46, 53))	('protein', 'Protein', (34, 41))	('JAK-STAT signalling pathways', 'Pathway', (71, 99))	('ERK', 'Gene', '5594', (63, 66))	('ERK', 'Gene', (63, 66))	('fused', 'Var', (28, 33))
79448	33655556	Neutralizing FGF2 and FGFRs inhibit neovascularization and tumour growth in vivo models.	('FGFR', 'Gene', (22, 26))	('FGFR', 'Gene', '2260', (22, 26))	('FGF2', 'Gene', (13, 17))	('tumour growth', 'Disease', (59, 72))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumour growth', 'Disease', 'MESH:D006130', (59, 72))	('neovascularization', 'CPA', (36, 54))	('Neutralizing', 'Var', (0, 12))	('FGF2', 'Gene', '2247', (13, 17))	('inhibit', 'NegReg', (28, 35))
79452	33655556	According to their action mechanism, they can be divided into several categories: (a) small-molecule FGFR TKIs, (b) anti-FGFR antibodies and (c) and FGF ligand traps.	('FGFR', 'Gene', (121, 125))	('FGFR', 'Gene', '2260', (121, 125))	('FGFR', 'Gene', (101, 105))	('FGFR', 'Gene', '2260', (101, 105))	('small-molecule', 'Var', (86, 100))
79460	33655556	94  Responses to FGFR-targeted treatments may be hampered by the activation of bypass signalling pathways and the appearance of secondary drug-resistant FGFR mutations, FGFR amplification without alterations in protein expression, and intratumour heterogeneity.	('FGFR', 'Gene', '2260', (153, 157))	('FGFR', 'Gene', (17, 21))	('FGFR', 'Gene', '2260', (17, 21))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))	('tumour', 'Disease', 'MESH:D009369', (240, 246))	('amplification', 'Var', (174, 187))	('bypass signalling pathways', 'Pathway', (79, 105))	('FGFR', 'Gene', (169, 173))	('mutations', 'Var', (158, 167))	('FGFR', 'Gene', (153, 157))	('tumour', 'Disease', (240, 246))	('FGFR', 'Gene', '2260', (169, 173))
79485	33655556	Y1175, Y951 and Y1214 are the three major VEGFA-dependent phosphorylation sites in VEGFR2.	('Y951', 'Var', (7, 11))	('Y1175', 'Var', (0, 5))	('Y1214', 'Chemical', '-', (16, 21))	('VEGFA', 'Gene', '7422', (42, 47))	('Y1214', 'Var', (16, 21))	('VEGFR2', 'Gene', (83, 89))	('VEGFA', 'Gene', (42, 47))
79486	33655556	105  Phosphorylated Y1175 (pY1175) can bind PLC-gamma, the adaptor protein Shb and the adaptor protein Sck, further promoting the cascade signalling.	('Sck', 'Gene', (103, 106))	('Sck', 'Gene', '25759', (103, 106))	('pY1175', 'Chemical', '-', (27, 33))	('bind', 'Interaction', (39, 43))	('PLC-gamma', 'Protein', (44, 53))	('Shb', 'Gene', (75, 78))	('promoting', 'PosReg', (116, 125))	('cascade signalling', 'MPA', (130, 148))	('Y1175 (pY1175', 'Var', (20, 33))	('Shb', 'Gene', '6461', (75, 78))
79489	33655556	Besides, pY1175 can recruit GAB1 to active the PI3K-AKT pathway.	('GAB1', 'Gene', (28, 32))	('pY1175', 'Var', (9, 15))	('AKT', 'Gene', (52, 55))	('GAB1', 'Gene', '2549', (28, 32))	('pY1175', 'Chemical', '-', (9, 15))	('active', 'PosReg', (36, 42))	('AKT', 'Gene', '207', (52, 55))
79492	33655556	102  Phosphorylated Y951 promotes the formation of complexes between Src through the adaptor protein VRAP/TSAd, resulting in the opening of inter-endothelial junctions, critical for cytoskeletal reorganization and migration.	('Y951', 'Var', (20, 24))	('VRAP', 'Gene', '9047', (101, 105))	('TSAd', 'Gene', (106, 110))	('promotes', 'PosReg', (25, 33))	('opening of inter-endothelial junctions', 'MPA', (129, 167))	('VRAP', 'Gene', (101, 105))	('TSAd', 'Gene', '9047', (106, 110))	('complexes', 'Interaction', (51, 60))	('Src', 'Gene', (69, 72))	('Src', 'Gene', '6714', (69, 72))
79493	33655556	108  Phosphorylated Y1214 associates with VEGF-induced actin remodelling via binding the adaptor protein Nck.	('Nck', 'Gene', '4690', (105, 108))	('Nck', 'Gene', (105, 108))	('binding', 'Interaction', (77, 84))	('Y1214', 'Chemical', '-', (20, 25))	('Y1214', 'Var', (20, 25))
79514	33655556	120 ,  121 ,  122   Besides, a soluble VEGF decoy receptor (Aflibercept, Zaltrap) neutralizing VEGFA, VEGFB and PLGF was approved in 2012 by the FDA to treat metastatic CRC.	('PLGF', 'Gene', '5228', (112, 116))	('neutralizing', 'Var', (82, 94))	('VEGFB', 'Gene', '7423', (102, 107))	('VEGFA', 'Gene', '7422', (95, 100))	('VEGFB', 'Gene', (102, 107))	('CRC', 'Phenotype', 'HP:0003003', (169, 172))	('VEGFA', 'Gene', (95, 100))	('PLGF', 'Gene', (112, 116))	('metastatic CRC', 'Disease', (158, 172))
79523	33655556	127  Researchers have found the combination of FGF-1 and VEGF induced a more significant angiogenic effect than the additive effects of FGF-1 or VEGF alone in vitro quantitative fibrin-based 3-dimensional angiogenesis system.	('FGF-1', 'Gene', '2246', (47, 52))	('FGF-1', 'Gene', (136, 141))	('FGF-1', 'Gene', '2246', (136, 141))	('VEGF', 'Gene', (57, 61))	('combination', 'Var', (32, 43))	('angiogenic effect', 'CPA', (89, 106))	('FGF-1', 'Gene', (47, 52))
79525	33655556	FGF can also induce the VEGFR2 expression in an ERK1/2-dependent pathway, and the expression of VEGFR2 rapidly declines without this interaction.	('ERK1/2', 'Gene', (48, 54))	('induce', 'Reg', (13, 19))	('expression', 'MPA', (82, 92))	('VEGFR2', 'Gene', (24, 30))	('ERK1/2', 'Gene', '5595;5594', (48, 54))	('expression', 'MPA', (31, 41))	('FGF', 'Var', (0, 3))
79534	33655556	137  VEGF/VEGFR, FGF/FGFR and FGFR/VEGFR inhibitors can invert the TME from immunologically 'cold' tumours into 'hot' tumours through immune-supportive effects by decreasing immunosuppressive cells and enhancing infiltration of mature dendritic cells and cytotoxic T lymphocytes.	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('inhibitors', 'Var', (41, 51))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('decreasing', 'NegReg', (163, 173))	('FGFR', 'Gene', (21, 25))	('invert', 'NegReg', (56, 62))	('TME', 'Chemical', '-', (67, 70))	('immunosuppressive cells', 'CPA', (174, 197))	('tumours', 'Disease', (118, 125))	('VEGFR', 'Gene', '3791', (10, 15))	('FGFR', 'Gene', (30, 34))	('FGFR', 'Gene', '2260', (21, 25))	('VEGFR', 'Gene', '3791', (35, 40))	('VEGFR', 'Gene', (10, 15))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('VEGFR', 'Gene', (35, 40))	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('TME', 'CPA', (67, 70))	('FGFR', 'Gene', '2260', (30, 34))	('enhancing', 'PosReg', (202, 211))	('tumours', 'Disease', (99, 106))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))
79535	33655556	138 ,  139 ,  140   The FGFR/VEGFR inhibitors are also reported to arrest the cell cycle in the G0/G1 phase and cause tumour cell apoptosis.	('cause', 'Reg', (112, 117))	('tumour', 'Disease', (118, 124))	('VEGFR', 'Gene', (29, 34))	('VEGFR', 'Gene', '3791', (29, 34))	('arrest', 'NegReg', (67, 73))	('FGFR', 'Gene', (24, 28))	('FGFR', 'Gene', '2260', (24, 28))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('inhibitors', 'Var', (35, 45))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('cell cycle in the G0/G1 phase', 'CPA', (78, 107))
79549	33655556	151  However, dovitinib did not show clinical benefit in endometrial cancer with FGFR2 mutations, glioblastoma with FGFR3-TACC3 gene fusion and urothelial carcinoma with FGFR3 mutations or overexpression.	('urothelial carcinoma', 'Disease', 'MESH:D014523', (144, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('glioblastoma', 'Disease', (98, 110))	('TACC3', 'Gene', (122, 127))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('endometrial cancer', 'Disease', (57, 75))	('FGFR2', 'Gene', '2263', (81, 86))	('FGFR2', 'Gene', (81, 86))	('dovitinib', 'Chemical', 'MESH:C500007', (14, 23))	('TACC3', 'Gene', '10460', (122, 127))	('urothelial carcinoma', 'Disease', (144, 164))	('endometrial cancer', 'Disease', 'MESH:D016889', (57, 75))	('endometrial cancer', 'Phenotype', 'HP:0012114', (57, 75))	('mutations', 'Var', (87, 96))
79551	33655556	153 ,  154   E7090 is an orally non-selective inhibitor of FGFR1-3 and has a slightly lower inhibitory activity on VEGFR2.	('non-selective', 'NegReg', (32, 45))	('lower', 'NegReg', (86, 91))	('E7090', 'Chemical', '-', (13, 18))	('E7090', 'Var', (13, 18))	('FGFR1-3', 'Gene', (59, 66))	('FGFR1-3', 'Gene', '2260;2263;2261', (59, 66))	('inhibitory activity', 'MPA', (92, 111))
79553	33655556	156   Lenvatinib (E7080) is an oral multikinase inhibitor that targets VEGFR1-3, FGFR1-4, RET, c-kit and PDGFRa, obtained considerable success in clinical trials of different cancer types, including NSCLC, thyroid cancer, gastric cancer, HCC, RCC and endometrial cancer.	('HCC', 'Phenotype', 'HP:0001402', (238, 241))	('FGFR1', 'Gene', (81, 86))	('gastric cancer', 'Disease', (222, 236))	('cancer', 'Disease', (263, 269))	('thyroid cancer', 'Disease', 'MESH:D013964', (206, 220))	('cancer', 'Disease', (175, 181))	('RCC', 'Disease', (243, 246))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('NSCLC', 'Phenotype', 'HP:0030358', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('Lenvatinib', 'Chemical', 'MESH:C531958', (6, 16))	('RET', 'Gene', (90, 93))	('thyroid cancer', 'Phenotype', 'HP:0002890', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('c-kit', 'Gene', '3815', (95, 100))	('cancer', 'Disease', (214, 220))	('E7080', 'Var', (18, 23))	('endometrial cancer', 'Phenotype', 'HP:0012114', (251, 269))	('gastric cancer', 'Disease', 'MESH:D013274', (222, 236))	('RCC', 'Disease', 'MESH:C538614', (243, 246))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', (230, 236))	('endometrial cancer', 'Disease', (251, 269))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('VEGFR1-3', 'Gene', '2321;3791;2324', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('endometrial cancer', 'Disease', 'MESH:D016889', (251, 269))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('PDGFRa', 'Gene', '5156', (105, 111))	('FGFR1', 'Gene', '2260', (81, 86))	('SCLC', 'Phenotype', 'HP:0030357', (200, 204))	('PDGFRa', 'Gene', (105, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (222, 236))	('VEGFR1-3', 'Gene', (71, 79))	('thyroid cancer', 'Disease', (206, 220))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('c-kit', 'Gene', (95, 100))	('NSCLC', 'Disease', 'MESH:D002289', (199, 204))	('RET', 'Gene', '5979', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('E7080', 'Chemical', 'MESH:C531958', (18, 23))	('HCC', 'Disease', (238, 241))	('NSCLC', 'Disease', (199, 204))
79561	33655556	Nowadays, as lenvatinib was reported to decrease tumour-associated macrophages and increase infiltration of CD8+ T cells, many clinical trials combining the immune checkpoint inhibitors with lenvatinib are ongoing, and some of them have already got positive results (NCT03609359, NCT02501096).	('NCT03609359', 'Var', (267, 278))	('decrease', 'NegReg', (40, 48))	('increase', 'PosReg', (83, 91))	('lenvatinib', 'Chemical', 'MESH:C531958', (191, 201))	('lenvatinib', 'Gene', (13, 23))	('lenvatinib', 'Chemical', 'MESH:C531958', (13, 23))	('infiltration', 'CPA', (92, 104))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('tumour', 'Disease', (49, 55))
79562	33655556	161 ,  162   Lucitanib (E3810 or AL3810) is a reversible, ATP-competitive TKI that targets FGFR1-2 and VEGFR1-3 in the nM range and exerts antitumour activity in multiple preclinical models, including colon, ovarian, renal and thyroid carcinoma and breast cancer.	('AL3810', 'Var', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('AL3810', 'Chemical', 'MESH:C000595232', (33, 39))	('ATP', 'Chemical', 'MESH:D000255', (58, 61))	('FGFR1', 'Gene', '2260', (91, 96))	('VEGFR1-3', 'Gene', '2321;3791;2324', (103, 111))	('E3810', 'Var', (24, 29))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (227, 244))	('colon, ovarian, renal and thyroid carcinoma', 'Disease', 'MESH:D010051', (201, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (249, 262))	('E3810', 'Chemical', 'MESH:D064750', (24, 29))	('VEGFR1-3', 'Gene', (103, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('breast cancer', 'Disease', 'MESH:D001943', (249, 262))	('breast cancer', 'Disease', (249, 262))	('FGFR1', 'Gene', (91, 96))	('Lucitanib', 'Chemical', 'MESH:C000595232', (13, 22))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('tumour', 'Disease', (143, 149))
79564	33655556	165  Subsequently, the phase II FINESSE study found the ORRs in lucitanib-treated HR+/HER2- metastatic breast cancer with FGFR1 amplification or 11q13 amplification or no amplification were 19%, 0%, and 15%, respectively.	('HER2', 'Gene', (86, 90))	('amplification', 'Var', (128, 141))	('HER2', 'Gene', '2064', (86, 90))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('FGFR1', 'Gene', (122, 127))	('FGFR1', 'Gene', '2260', (122, 127))	('lucitanib', 'Chemical', 'MESH:C000595232', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('11q13 amplification', 'Var', (145, 164))
79565	33655556	39  What is more, the following analyses showed that the ORR in patients with high-level FGFR1 amplification was higher in patients without high-level FGFR1 amplification (22% vs 9%), indicating that FGFR1 may be a biomarker for FGFR inhibitor therapy.	('FGFR', 'Gene', (89, 93))	('FGFR', 'Gene', (151, 155))	('FGFR1', 'Gene', (89, 94))	('FGFR', 'Gene', (229, 233))	('FGFR', 'Gene', '2260', (200, 204))	('FGFR', 'Gene', '2260', (89, 93))	('patients', 'Species', '9606', (123, 131))	('FGFR', 'Gene', '2260', (151, 155))	('FGFR1', 'Gene', (151, 156))	('FGFR1', 'Gene', '2260', (200, 205))	('ORR', 'MPA', (57, 60))	('FGFR', 'Gene', '2260', (229, 233))	('FGFR1', 'Gene', '2260', (89, 94))	('patients', 'Species', '9606', (64, 72))	('higher', 'PosReg', (113, 119))	('amplification', 'Var', (95, 108))	('FGFR1', 'Gene', (200, 205))	('FGFR', 'Gene', (200, 204))	('FGFR1', 'Gene', '2260', (151, 156))
79572	33655556	177   Ponatinib (AP24534) is a multi-TKI targeting SRC, ABL, FGFR, PDGFR and VEGFR, while the inhibition of BCR-ABL is the primary clinical use.	('AP24534', 'Var', (17, 24))	('ABL', 'Gene', '25', (56, 59))	('VEGFR', 'Gene', (77, 82))	('FGFR', 'Gene', (61, 65))	('ABL', 'Gene', (56, 59))	('PDGFR', 'Gene', (67, 72))	('FGFR', 'Gene', '2260', (61, 65))	('PDGFR', 'Gene', '5159', (67, 72))	('ABL', 'Gene', '25', (112, 115))	('BCR-ABL', 'Gene', '25', (108, 115))	('Ponatinib', 'Chemical', 'MESH:C545373', (6, 15))	('ABL', 'Gene', (112, 115))	('SRC', 'Gene', '6714', (51, 54))	('BCR-ABL', 'Gene', (108, 115))	('SRC', 'Gene', (51, 54))	('AP24534', 'Chemical', 'MESH:C545373', (17, 24))	('VEGFR', 'Gene', '3791', (77, 82))
79575	33655556	181  Currently, researchers are trying to discover novel FGFRs inhibitors according to the structure of ponatinib, which have already displayed significant antitumour activities in FGFR1-amplificated H1581 and FGFR2-amplificated SNU-16 xenograft models.	('FGFR', 'Gene', '2260', (57, 61))	('tumour', 'Disease', (160, 166))	('FGFR', 'Gene', (181, 185))	('FGFR2', 'Gene', (210, 215))	('FGFR2', 'Gene', '2263', (210, 215))	('FGFR', 'Gene', (210, 214))	('FGFR1', 'Gene', (181, 186))	('FGFR', 'Gene', '2260', (181, 185))	('FGFR', 'Gene', '2260', (210, 214))	('FGFR1', 'Gene', '2260', (181, 186))	('inhibitors', 'Var', (63, 73))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('ponatinib', 'Chemical', 'MESH:C545373', (104, 113))	('FGFR', 'Gene', (57, 61))	('tumour', 'Disease', 'MESH:D009369', (160, 166))
79577	33655556	Because of the multiple targets of non-selective FGFR/VEGFR inhibitors, their antitumour effects are not limited to FGFR-addicted tumours.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('FGFR', 'Gene', (116, 120))	('inhibitors', 'Var', (60, 70))	('FGFR', 'Gene', '2260', (116, 120))	('tumour', 'Disease', (130, 136))	('VEGFR', 'Gene', (54, 59))	('FGFR', 'Gene', (49, 53))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('FGFR-addicted tumours', 'Disease', (116, 137))	('tumour', 'Disease', (82, 88))	('FGFR-addicted tumours', 'Disease', 'MESH:D009369', (116, 137))	('FGFR', 'Gene', '2260', (49, 53))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('VEGFR', 'Gene', '3791', (54, 59))
79580	33655556	AZD4547 is a selective and reversible TKI of FGFR1-3 and also shows activity against VEGFR2 at nM concentration with IC50 equal to 24 nM.	('VEGFR2', 'Gene', (85, 91))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('activity', 'MPA', (68, 76))	('FGFR1-3', 'Gene', (45, 52))	('AZD4547', 'Var', (0, 7))	('FGFR1-3', 'Gene', '2260;2263;2261', (45, 52))
79583	33655556	However, minimal activities were achieved against tumours harbouring actionable aberration(s) in FGFR1-3, including FGFR1-amplified SqCLC and gastric adenocarcinoma with FGFR2 polysomy or gene amplification.	('FGFR1-3', 'Gene', '2260;2263;2261', (97, 104))	('SqCLC', 'Disease', (132, 137))	('FGFR1', 'Gene', '2260', (116, 121))	('FGFR2', 'Gene', (170, 175))	('tumours', 'Disease', (50, 57))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (142, 164))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('FGFR1-3', 'Gene', (97, 104))	('SqCLC', 'Phenotype', 'HP:0030359', (132, 137))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('polysomy', 'Var', (176, 184))	('FGFR2', 'Gene', '2263', (170, 175))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('gene amplification', 'Var', (188, 206))	('FGFR1', 'Gene', '2260', (97, 102))	('FGFR1', 'Gene', (116, 121))	('gastric adenocarcinoma', 'Disease', (142, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('FGFR1', 'Gene', (97, 102))
79585	33655556	ASP5878 is a selective pan-FGFR inhibitor that exerts its antitumour activity towards tumours with FGFR genetic alterations.	('FGFR', 'Gene', (99, 103))	('genetic alterations', 'Var', (104, 123))	('ASP5878', 'Chemical', 'MESH:C000615784', (0, 7))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('FGFR', 'Gene', '2260', (99, 103))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('FGFR', 'Gene', (27, 31))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('FGFR', 'Gene', '2260', (27, 31))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('tumour', 'Disease', (62, 68))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumour', 'Disease', (86, 92))	('tumours', 'Disease', (86, 93))
79595	33655556	196  In phase I clinical trials, it showed clinical benefits in glioblastoma, cholangiocarcinoma, urothelial and endometrial cancer with FGFR mutations or fusions, while ORRs in other tumour types were below 10%.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 96))	('FGFR', 'Gene', '2260', (137, 141))	('endometrial cancer', 'Disease', 'MESH:D016889', (113, 131))	('fusions', 'Var', (155, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('urothelial', 'Disease', (98, 108))	('mutations', 'Var', (142, 151))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('tumour', 'Disease', (184, 190))	('benefits', 'PosReg', (52, 60))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('FGFR', 'Gene', (137, 141))	('glioblastoma', 'Disease', (64, 76))	('endometrial cancer', 'Phenotype', 'HP:0012114', (113, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (78, 96))	('endometrial cancer', 'Disease', (113, 131))	('cholangiocarcinoma', 'Disease', (78, 96))
79596	33655556	6 ,  197 ,  198  In April 2019, erdafitinib received accelerated approval by the FDA to treat patients with FGFR3 mutated or FGFR2/3 fusion-positive advanced or metastatic urothelial carcinoma after at least one prior platinum-based regimen.	('patients', 'Species', '9606', (94, 102))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (172, 192))	('FGFR2/3', 'Gene', (125, 132))	('mutated', 'Var', (114, 121))	('advanced', 'Disease', (149, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('platinum', 'Chemical', 'MESH:D010984', (218, 226))	('erdafitinib', 'Chemical', 'MESH:C000604580', (32, 43))	('urothelial carcinoma', 'Disease', (172, 192))	('FGFR2/3', 'Gene', '2263;2261', (125, 132))	('FGFR3', 'Gene', (108, 113))
79599	33655556	199   Ly2874455 is a selective pan-FGFR inhibitor, with similar values of IC50 in inhibiting FGFR1-4, which also has inhibitory activity towards VEGFR2 with IC50 equal to 7 nM.	('FGFR', 'Gene', '2260', (35, 39))	('inhibiting', 'NegReg', (82, 92))	('Ly2874455', 'Var', (6, 15))	('Ly2874455', 'Chemical', 'MESH:C570663', (6, 15))	('FGFR1', 'Gene', (93, 98))	('FGFR', 'Gene', '2260', (93, 97))	('FGFR', 'Gene', (93, 97))	('FGFR', 'Gene', (35, 39))	('FGFR1', 'Gene', '2260', (93, 98))
79600	33655556	200  Interestingly, as the inhibition of FGF-induced Erk phosphorylation by Ly2874455 is much easier than that of VEGF-mediated target signalling in vivo, LY2874455 can avoid VEGFR2-mediated hypertension at efficacious doses.	('Ly2874455', 'Chemical', 'MESH:C570663', (76, 85))	('hypertension', 'Phenotype', 'HP:0000822', (191, 203))	('LY2874455', 'Chemical', 'MESH:C570663', (155, 164))	('LY2874455', 'Var', (155, 164))	('hypertension', 'Disease', (191, 203))	('hypertension', 'Disease', 'MESH:D006973', (191, 203))	('Erk', 'Gene', (53, 56))	('Erk', 'Gene', '5594', (53, 56))	('Ly2874455', 'Var', (76, 85))
79603	33655556	141  SOMCL-286 starting from the structure of lucitanib is another FGFR and VEGR2 dual inhibitor and showed significant antitumour effects in SNU-16 xenograft model harbouring aberration in FGFR and VEGFR2.	('FGFR', 'Gene', (67, 71))	('VEGFR2', 'Gene', (199, 205))	('FGFR', 'Gene', '2260', (67, 71))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('aberration', 'Var', (176, 186))	('FGFR', 'Gene', (190, 194))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('FGFR', 'Gene', '2260', (190, 194))	('lucitanib', 'Chemical', 'MESH:C000595232', (46, 55))	('tumour', 'Disease', (124, 130))
79605	33655556	The clinical effects of these drugs vary with different types of FGFR genetic alterations.	('FGFR', 'Gene', (65, 69))	('genetic alterations', 'Var', (70, 89))	('FGFR', 'Gene', '2260', (65, 69))
79606	33655556	The effect of drugs targeting FGFR gene fusion and mutations seems to be better than that of gene amplification, probably mainly because gene amplification does not imply high protein expression.	('FGFR', 'Gene', '2260', (30, 34))	('mutations', 'Var', (51, 60))	('FGFR', 'Gene', (30, 34))
79608	33655556	FGF-FGFR signalling can be abnormally triggered by FGF and FGFR alterations.	('triggered', 'Reg', (38, 47))	('FGFR', 'Gene', (59, 63))	('FGFR', 'Gene', (4, 8))	('FGFR', 'Gene', '2260', (59, 63))	('FGFR', 'Gene', '2260', (4, 8))	('alterations', 'Var', (64, 75))	('FGF', 'Gene', (51, 54))
79616	33655556	The combination of lenvatinib and pembrolizumab has received accelerated approval in patients with advanced endometrial cancer and is undergoing phase III clinical trial in HCC and RCC (NCT03713593, NCT02811861).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('HCC', 'Disease', (173, 176))	('HCC', 'Phenotype', 'HP:0001402', (173, 176))	('endometrial cancer', 'Disease', (108, 126))	('lenvatinib', 'Chemical', 'MESH:C531958', (19, 29))	('patients', 'Species', '9606', (85, 93))	('endometrial cancer', 'Phenotype', 'HP:0012114', (108, 126))	('endometrial cancer', 'Disease', 'MESH:D016889', (108, 126))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('NCT03713593', 'Var', (186, 197))	('pembrolizumab', 'Chemical', 'MESH:C582435', (34, 47))	('RCC', 'Disease', (181, 184))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))
79626	33198722	Cystic fibrosis transmembrane conductance regulator (CFTR)-regulated chloride channels are highly expressed in the gastrointestinal tract and when disrupted, as in CF, there is increased inflammation and cell turnover, which is believed to contribute to this increased risk.	('inflammation', 'Disease', 'MESH:D007249', (187, 199))	('inflammation', 'Disease', (187, 199))	('cell turnover', 'CPA', (204, 217))	('increased', 'PosReg', (177, 186))	('Cystic fibrosis transmembrane conductance regulator', 'Gene', '1080', (0, 51))	('CFTR', 'Gene', '1080', (53, 57))	('disrupted', 'Var', (147, 156))	('CFTR', 'Gene', (53, 57))
79630	33198722	A 26-year-old female with CF (genotype F508del/F508del), with a baseline forced expiratory volume in 1 s (FEV1) of 21% predicted and a 6-l home oxygen requirement, was undergoing evaluation for bilateral lung transplantation.	('oxygen', 'Chemical', 'MESH:D010100', (144, 150))	('F508del', 'DELETION', 'None', (47, 54))	('F508del', 'DELETION', 'None', (39, 46))	('FEV1', 'Phenotype', 'HP:0032342', (106, 110))	('forced expiratory volume in 1 s', 'Phenotype', 'HP:0032342', (73, 104))	('F508del', 'Var', (39, 46))	('F508del', 'Var', (47, 54))
79636	33198722	Serum tumor markers demonstrated normal alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) levels, but a markedly elevated carbohydrate antigen (CA)19-9 level of 5949.5 U/mL (0-36 U/mL), which can be elevated in pancreatic, gastric, hepatobiliary, and colonic malignancies.	('CEA', 'Gene', '1084', (94, 97))	('AFP', 'Gene', (59, 62))	('colonic malignancies', 'Phenotype', 'HP:0100273', (260, 280))	('AFP', 'Gene', '174', (59, 62))	('gastric', 'Disease', (232, 239))	('pancreatic', 'Disease', (220, 230))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('colonic malignancies', 'Disease', (260, 280))	('5949.5 U/mL', 'Var', (170, 181))	('elevated', 'PosReg', (122, 130))	('carcinoembryonic antigen', 'Gene', (68, 92))	('carbohydrate antigen', 'Chemical', '-', (131, 151))	('hepatobiliary', 'Disease', (241, 254))	('tumor', 'Disease', (6, 11))	('CEA', 'Gene', (94, 97))	('alpha-fetoprotein', 'Gene', (40, 57))	('carcinoembryonic antigen', 'Gene', '1084', (68, 92))	('carbohydrate antigen', 'MPA', (131, 151))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('alpha-fetoprotein', 'Gene', '174', (40, 57))	('colonic malignancies', 'Disease', 'MESH:D015179', (260, 280))
79658	33198722	These include deficient anion (Cl- and HCO3-) and fluid transport, impaired release and clearance of mucus which can lead to meconium ileus and distal intestinal obstructive syndrome (DIOS), pancreatic insufficiency, decreased intestinal lumen pH, increased intestinal stem cell pH, abnormal bacterial colonization, microbial dysbiosis, and impaired innate immune responses that lead to chronic inflammation.	('ileus', 'Phenotype', 'HP:0002595', (134, 139))	('pancreatic insufficiency', 'Phenotype', 'HP:0001738', (191, 215))	('intestinal stem cell pH', 'CPA', (258, 281))	('decreased', 'NegReg', (217, 226))	('deficient', 'Var', (14, 23))	('lead to', 'Reg', (117, 124))	('pancreatic insufficiency', 'Disease', 'MESH:D010188', (191, 215))	('innate immune responses', 'CPA', (350, 373))	('dysbiosis', 'Disease', 'MESH:D064806', (326, 335))	('inflammation', 'Disease', (395, 407))	('meconium ileus', 'Phenotype', 'HP:0004401', (125, 139))	('distal intestinal obstructive syndrome', 'Disease', (144, 182))	('impaired', 'NegReg', (67, 75))	('distal intestinal obstructive syndrome', 'Disease', 'MESH:D007415', (144, 182))	('anion', 'MPA', (24, 29))	('release', 'MPA', (76, 83))	('increased', 'PosReg', (248, 257))	('dysbiosis', 'Disease', (326, 335))	('DIOS', 'Chemical', '-', (184, 188))	('pancreatic insufficiency', 'Disease', (191, 215))	('impaired', 'NegReg', (341, 349))	('HCO3-', 'Chemical', 'MESH:D001639', (39, 44))	('meconium ileus', 'Disease', (125, 139))	('inflammation', 'Disease', 'MESH:D007249', (395, 407))
79660	33198722	In addition, CFTR is believed to be a tumor suppressor gene and disruption, as in CF, leads to increased risk for colon cancer and other digestive tract cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Disease', (38, 43))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('CFTR', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('colon cancer', 'Disease', (114, 126))	('cancers', 'Disease', (153, 160))	('disruption', 'Var', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('CFTR', 'Gene', '1080', (13, 17))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('colon cancer', 'Phenotype', 'HP:0003003', (114, 126))	('colon cancer', 'Disease', 'MESH:D015179', (114, 126))
79703	30885278	Other eligibility criteria for implanting port-catheter system were as follows: Eastern Cooperative Oncology Group (ECOG) performance status <=2; Child-Pugh classification A or B; albumin > 2.5 g/dl; alanine aminotransferase and aspartate aminotransferase < 5 times the upper normal limit; total serum bilirubin < 3.0 mg/dl; serum creatinine < 2.0 mg/dl; platelet count > 50,000/mm3 and international normalized ratio (INR) <=1.5.	('> 2.5 g/dl', 'Var', (188, 198))	('alanine aminotransferase', 'Gene', (200, 224))	('serum bilirubin', 'MPA', (296, 311))	('albumin', 'MPA', (180, 187))	('platelet count', 'CPA', (355, 369))	('alanine aminotransferase', 'Gene', '2875', (200, 224))	('bilirubin', 'Chemical', 'MESH:D001663', (302, 311))	('serum creatinine', 'MPA', (325, 341))	('Child', 'Species', '9606', (146, 151))	('total serum bilirubin', 'Phenotype', 'HP:0003573', (290, 311))	('Oncology', 'Phenotype', 'HP:0002664', (100, 108))	('creatinine', 'Chemical', 'MESH:D003404', (331, 341))	('international normalized ratio', 'MPA', (387, 417))
79740	30885278	In 3 patients with intra-procedural microcoils migration to proper hepatic artery, hepatic artery obstruction occurred at 1.3, 2.9 and 7.3 months, in which one recanalized after thrombolysis treatment.	('men', 'Species', '9606', (196, 199))	('patients', 'Species', '9606', (5, 13))	('hepatic artery obstruction', 'Disease', 'MESH:D056486', (83, 109))	('artery obstruction', 'Phenotype', 'HP:0025324', (91, 109))	('hepatic artery obstruction', 'Disease', (83, 109))	('microcoils', 'Var', (36, 46))
79741	30885278	One patient suffered microcoil migration to the right hepatic artery, which did not result in thrombotic hepatic artery occlusion but vessel stenosis.	('artery occlusion', 'Phenotype', 'HP:0025324', (113, 129))	('patient', 'Species', '9606', (4, 11))	('thrombotic hepatic artery occlusion', 'Disease', (94, 129))	('thrombotic hepatic artery occlusion', 'Disease', 'MESH:D013927', (94, 129))	('microcoil', 'Var', (21, 30))
79803	29448202	The median serum CXCL5 levels were 0.4325 ng/mL and 0.601ng/mL in healthy donors and patients with BTCs, respectively.	('CXCL5', 'Gene', '6374', (17, 22))	('0.601ng/mL', 'Var', (52, 62))	('patients', 'Species', '9606', (85, 93))	('CXCL5', 'Gene', (17, 22))
79812	29448202	Univariate analysis with these cut-off points showed that high CXCL12 level was correlated with poor overall survival (median OS, 6.9 vs. 0.9 months in low vs. high CXCL12 level groups; P = .008).	('overall survival', 'MPA', (101, 117))	('CXCL12', 'Gene', (63, 69))	('CXCL12', 'Gene', '6387', (165, 171))	('CXCL12', 'Gene', '6387', (63, 69))	('high', 'Var', (58, 62))	('poor', 'NegReg', (96, 100))	('OS', 'Chemical', '-', (126, 128))	('CXCL12', 'Gene', (165, 171))
79813	29448202	High CXCL5 levels also tended to be associated with shorter survival, but the difference was not statistically significant (median OS, 6.2 vs. 2.0 months in low vs. high CXCL5 level groups; P = .070) (Figure 2).	('CXCL5', 'Gene', (5, 10))	('CXCL5', 'Gene', '6374', (5, 10))	('High', 'Var', (0, 4))	('OS', 'Chemical', '-', (131, 133))	('shorter', 'NegReg', (52, 59))	('survival', 'MPA', (60, 68))	('CXCL5', 'Gene', (170, 175))	('CXCL5', 'Gene', '6374', (170, 175))
79832	29448202	A clinical trial with another CXCR4 antagonist, LY2510924 in combination with immune checkpoint inhibitor durvalumab, is now ongoing in solid tumors (NCT02737072).	('LY2510924', 'Chemical', 'MESH:C000595455', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('solid tumors', 'Disease', (136, 148))	('CXCR4', 'Gene', '7852', (30, 35))	('CXCR4', 'Gene', (30, 35))	('durvalumab', 'Chemical', 'MESH:C000613593', (106, 116))	('LY2510924', 'Var', (48, 57))	('solid tumors', 'Disease', 'MESH:D009369', (136, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))
79838	26657503	Since perihilar cholangiocarcinomas are relatively recalcitrant to PDT, the aims were to (1) determine the expression levels of HIF-1-associated proteins in human perihilar cholangiocarcinomas, (2) investigate the role of HIF-1 in PDT-treated human perihilar cholangiocarcinoma cells, and (3) determine whether HIF-1 inhibition reduces survival signaling and enhances PDT efficacy.	('red', 'Chemical', '-', (328, 331))	('human', 'Species', '9606', (243, 248))	('cholangiocarcinomas', 'Disease', (16, 35))	('HIF-1', 'Gene', '3091', (311, 316))	('HIF-1', 'Gene', (311, 316))	('reduces', 'NegReg', (328, 335))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (173, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (25, 35))	('enhances', 'PosReg', (359, 367))	('cholangiocarcinomas', 'Disease', (173, 192))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (259, 277))	('HIF-1', 'Gene', '3091', (222, 227))	('HIF-1', 'Gene', '3091', (128, 133))	('HIF-1', 'Gene', (128, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('HIF-1', 'Gene', (222, 227))	('carcinomas', 'Phenotype', 'HP:0030731', (182, 192))	('human', 'Species', '9606', (157, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (16, 34))	('PDT efficacy', 'CPA', (368, 380))	('cholangiocarcinoma', 'Disease', (16, 34))	('inhibition', 'Var', (317, 327))	('survival signaling', 'CPA', (336, 354))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (259, 277))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (173, 191))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (16, 34))	('cholangiocarcinoma', 'Disease', (259, 277))	('cholangiocarcinoma', 'Disease', (173, 191))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (16, 35))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (173, 191))
79858	26657503	During normoxia, prolyl-hydroxylases (PHD) and factor inhibiting HIF (FIH) mediate the hydroxylation of Pro402, Pro564, and/or Asn803 of HIF-1alpha.	('hydroxylation', 'MPA', (87, 100))	('Pro564', 'Chemical', '-', (112, 118))	('Asn803', 'Var', (127, 133))	('Pro402', 'Var', (104, 110))	('Pro402', 'Chemical', '-', (104, 110))	('PHD', 'Disease', 'MESH:D011547', (38, 41))	('PHD', 'Disease', (38, 41))	('Asn803', 'Chemical', '-', (127, 133))	('Pro564', 'Var', (112, 118))
79866	26657503	Inhibition of HIF-1 activity and corollary survival signaling may consequently improve the therapeutic efficacy of PDT.	('activity', 'MPA', (20, 28))	('HIF-1', 'Gene', (14, 19))	('therapeutic efficacy', 'CPA', (91, 111))	('improve', 'PosReg', (79, 86))	('Inhibition', 'Var', (0, 10))	('HIF-1', 'Gene', '3091', (14, 19))	('PDT', 'Disease', (115, 118))
79872	26657503	Besides HIF-1 inhibition, ACF was also investigated in the context of its dual topoisomerase I and II inhibitor activity, as discovered by Hassan et al.. Topoisomerases are involved in the cleavage and resealing of DNA breaks during transcription and cell replication, and inhibition of these topoisomerases may lead to cell cycle arrest and apoptosis in dividing cells (reviewed in).	('inhibition', 'Var', (273, 283))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (320, 337))	('apoptosis', 'CPA', (342, 351))	('lead to', 'Reg', (312, 319))	('HIF-1', 'Gene', '3091', (8, 13))	('red', 'Chemical', '-', (132, 135))	('arrest', 'Disease', 'MESH:D006323', (331, 337))	('ACF', 'Chemical', 'MESH:D000167', (26, 29))	('HIF-1', 'Gene', (8, 13))	('arrest', 'Disease', (331, 337))
79873	26657503	The most important findings were that HIF-1 is activated by sublethal PDT in SK-ChA-1 cells.	('HIF-1', 'Gene', (38, 43))	('sublethal PDT', 'Var', (60, 73))	('activated', 'PosReg', (47, 56))	('HIF-1', 'Gene', '3091', (38, 43))	('SK-ChA-1', 'CellLine', 'CVCL:6952', (77, 85))
79890	26657503	Cells exhibited a ZnPC concentration-dependent decrease in cell viability following PDT, whereby the extent of cell death was exacerbated by hypoxia (Figure 2A).	('decrease', 'NegReg', (47, 55))	('cell viability', 'CPA', (59, 73))	('hypoxia', 'Disease', 'MESH:D000860', (141, 148))	('hypoxia', 'Disease', (141, 148))	('PDT', 'Var', (84, 87))	('ZnPC', 'Chemical', 'MESH:C052159', (18, 22))
79903	26657503	PDT treatment was accompanied by a translocation of ACF towards the nucleus under normoxic conditions, which was further characterized by altered cell morphology that entailed cell shrinkage and blebbing (Figure 3B).	('ACF', 'Protein', (52, 55))	('cell shrinkage', 'CPA', (176, 190))	('ACF', 'Chemical', 'MESH:D000167', (52, 55))	('blebbing', 'CPA', (195, 203))	('treatment', 'Var', (4, 13))	('red', 'Chemical', '-', (142, 145))	('PDT', 'Gene', (0, 3))	('translocation', 'MPA', (35, 48))
79920	26657503	Under normoxic conditions, neither ACF nor PDT significantly affected caspase 3/7 levels, however, ACF + PDT resulted in a 8-fold higher caspase 3/7 activity in SK-ChA-1 cells (Figure 4G).	('ACF', 'Chemical', 'MESH:D000167', (35, 38))	('ACF + PDT', 'Var', (99, 108))	('higher', 'PosReg', (130, 136))	('caspase 3', 'Gene', (70, 79))	('caspase 3', 'Gene', '836', (70, 79))	('activity', 'MPA', (149, 157))	('ACF', 'Chemical', 'MESH:D000167', (99, 102))	('caspase 3', 'Gene', (137, 146))	('caspase 3', 'Gene', '836', (137, 146))	('SK-ChA-1', 'CellLine', 'CVCL:6952', (161, 169))
79921	26657503	During hypoxia, PDT resulted in a 4-fold increase in caspase 3/7 activity and ACF + PDT resulted in a 10-fold higher caspase 3/7 activity, indicating that apoptosis constitutes an important mode of cell death following combination treatment of ACF + PDT.	('activity', 'MPA', (65, 73))	('caspase 3', 'Gene', (117, 126))	('ACF', 'Chemical', 'MESH:D000167', (244, 247))	('hypoxia', 'Disease', 'MESH:D000860', (7, 14))	('caspase 3', 'Gene', '836', (117, 126))	('PDT', 'Var', (16, 19))	('caspase 3', 'Gene', '836', (53, 62))	('hypoxia', 'Disease', (7, 14))	('activity', 'MPA', (129, 137))	('caspase 3', 'Gene', (53, 62))	('ACF', 'Chemical', 'MESH:D000167', (78, 81))	('higher', 'PosReg', (110, 116))	('increase', 'PosReg', (41, 49))	('ACF + PDT', 'Var', (78, 87))
79933	26657503	In addition, SERPINE1 was highly induced upon ACF treatment - an effect that was also observed after PDT in the presence of ACF.	('induced', 'PosReg', (33, 40))	('ACF', 'Chemical', 'MESH:D000167', (124, 127))	('ACF', 'Chemical', 'MESH:D000167', (46, 49))	('SERPINE1', 'Gene', '5054', (13, 21))	('SERPINE1', 'Gene', (13, 21))	('ACF', 'Var', (46, 49))
79937	26657503	Topoisomerase I/II inhibition is associated with cell cycle arrest and consequent apoptosis as a result of DNA double-strand breaks (reviewed in).	('Topoisomerase I/II', 'Enzyme', (0, 18))	('apoptosis', 'CPA', (82, 91))	('DNA double-strand breaks', 'Var', (107, 131))	('inhibition', 'NegReg', (19, 29))	('arrest', 'Disease', 'MESH:D006323', (60, 66))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (49, 66))	('arrest', 'Disease', (60, 66))
79938	26657503	In the acute phase after PDT, DNA double-strand breaks were not observed (Figure 4I-4P) but apoptotic signaling was pronounced, particularly in the ACF + PDT and hypoxia groups (Figure 4F and 4G).	('apoptotic signaling', 'CPA', (92, 111))	('ACF', 'Chemical', 'MESH:D000167', (148, 151))	('hypoxia', 'Disease', (162, 169))	('ACF + PDT', 'Var', (148, 157))	('hypoxia', 'Disease', 'MESH:D000860', (162, 169))
79942	26657503	Furthermore, ACF treatment was associated with increased apoptosis, but not necrosis, after 24 and 48 hours (Figure 6E, 6F), which concurred with elevated ROS production in cells (Figure 6G, 6H).	('red', 'Chemical', '-', (137, 140))	('apoptosis', 'CPA', (57, 66))	('ROS', 'Chemical', 'MESH:D017382', (155, 158))	('necrosis', 'Disease', (76, 84))	('treatment', 'Var', (17, 26))	('elevated ROS production', 'Phenotype', 'HP:0025464', (146, 169))	('ACF treatment', 'Var', (13, 26))	('ROS production', 'MPA', (155, 169))	('ACF', 'Chemical', 'MESH:D000167', (13, 16))	('necrosis', 'Disease', 'MESH:D009336', (76, 84))	('elevated', 'PosReg', (146, 154))
79952	26657503	Lastly, ACF pretreatment was associated with S-phase cell cycle arrest and apoptosis and enhanced PDT efficacy, likely via inhibition of HIF-1 inhibition and topoisomerase I/II.	('arrest', 'Disease', (64, 70))	('HIF-1', 'Gene', (137, 142))	('enhanced', 'PosReg', (89, 97))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (53, 70))	('ACF', 'Chemical', 'MESH:D000167', (8, 11))	('apoptosis', 'CPA', (75, 84))	('arrest', 'Disease', 'MESH:D006323', (64, 70))	('pretreatment', 'Var', (12, 24))	('HIF-1', 'Gene', '3091', (137, 142))	('PDT efficacy', 'CPA', (98, 110))
79955	26657503	In mouse mammary carcinoma (BA) xenografts, porfimer-PDT led to an increase in HIF-1alpha, BIRC5, and VEGF protein levels.	('porfimer-PDT', 'Var', (44, 56))	('HIF-1alpha', 'MPA', (79, 89))	('carcinoma', 'Disease', (17, 26))	('mouse', 'Species', '10090', (3, 8))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (9, 26))	('increase', 'PosReg', (67, 75))	('carcinoma', 'Disease', 'MESH:D002277', (17, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('BIRC5', 'MPA', (91, 96))
79956	26657503	Lastly, murine mammary carcinoma (EMT-6) cells that were treated with porfimer sodium-PDT exhibited HIF-1alpha stabilization and its consequent translocation to the nucleus.	('murine', 'Species', '10090', (8, 14))	('EMT-6', 'CellLine', 'CVCL:1923', (34, 39))	('translocation', 'MPA', (144, 157))	('sodium-PDT', 'Var', (79, 89))	('carcinoma', 'Disease', 'MESH:D002277', (23, 32))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (15, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('carcinoma', 'Disease', (23, 32))	('stabilization', 'MPA', (111, 124))	('HIF-1alpha', 'Protein', (100, 110))
79972	26657503	In addition to HIF-1 inhibition, ACF has also been shown to act as a dual topoisomerase I/II inhibitor.	('HIF-1', 'Gene', (15, 20))	('ACF', 'Chemical', 'MESH:D000167', (33, 36))	('HIF-1', 'Gene', '3091', (15, 20))	('ACF', 'Var', (33, 36))
79976	26657503	It should be noted that, although SK-ChA-1 cells have a mutation (at codon 282) in the DNA binding domain of p53, their p53 is still functional.	('p53', 'Gene', '7157', (120, 123))	('p53', 'Gene', (109, 112))	('p53', 'Gene', '7157', (109, 112))	('binding', 'Interaction', (91, 98))	('mutation', 'Var', (56, 64))	('p53', 'Gene', (120, 123))	('SK-ChA-1', 'CellLine', 'CVCL:6952', (34, 42))
80026	26657503	The membranes were incubated overnight at 4 C on a rocker with anti-HIF-1alpha (1:500, clone 54/HIF-1alpha, BD Transduction Laboratories (Franklin Lakes, NJ)) and anti-beta-actin (1:4,000, AC-74, Sigma-Aldrich).	('anti-HIF-1alpha', 'Var', (63, 78))	('beta-actin', 'Gene', (168, 178))	('beta-actin', 'Gene', '728378', (168, 178))
80077	24827630	Two randomized controlled trials have shown a significant survival benefit from PDT in patients with unresectable cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (114, 132))	('cholangiocarcinoma', 'Disease', (114, 132))	('PDT', 'Var', (80, 83))	('patients', 'Species', '9606', (87, 95))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (114, 132))	('survival', 'MPA', (58, 66))
80122	24827630	Even in patients with advanced disease, PDT has been shown to improve survival, quality of life, and performance status compared with biliary stenting in uncontrolled and randomized controlled trials.	('quality of life', 'CPA', (80, 95))	('patients', 'Species', '9606', (8, 16))	('improve', 'PosReg', (62, 69))	('advanced disease', 'Disease', (22, 38))	('survival', 'CPA', (70, 78))	('performance status', 'CPA', (101, 119))	('PDT', 'Var', (40, 43))	('advanced disease', 'Disease', 'MESH:D020178', (22, 38))
80150	31819490	Previous studies investigating genomic characteristics of cholangiocarcinoma have revealed that actionable alterations mainly included IDH1/2, FGFR fusion and sporadic pathogenic mutations in BRCA1/2 and mismatch repair genes.	('BRCA1/2', 'Gene', '672;675', (192, 199))	('cholangiocarcinoma', 'Disease', (58, 76))	('FGFR fusion', 'Gene', (143, 154))	('IDH1/2', 'Gene', (135, 141))	('IDH1/2', 'Gene', '3417;3418', (135, 141))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('BRCA1/2', 'Gene', (192, 199))	('included', 'Reg', (126, 134))	('mutations', 'Var', (179, 188))	('mismatch repair genes', 'Gene', (204, 225))
80192	31819490	Cancer genomic sequencing revealed pathogenic somatic mutations in ATM (c.A1561T; p.R521*) and JAK3 (c.C3239G; p.P1080R).	('p.R521*', 'Mutation', 'p.R521*', (82, 89))	('p.P1080R', 'Var', (111, 119))	('pathogenic', 'Reg', (35, 45))	('p.P1080R', 'Mutation', 'p.P1080R', (111, 119))	('ATM', 'Gene', '472', (67, 70))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('JAK3', 'Gene', '3718', (95, 99))	('c.C3239G; p.P1080R', 'Var', (101, 119))	('JAK3', 'Gene', (95, 99))	('c.A1561T; p.R521*', 'Var', (72, 89))	('c.C3239G', 'Mutation', 'c.3239C>G', (101, 109))	('p.R521*', 'Var', (82, 89))	('c.A1561T', 'Mutation', 'c.1561A>T', (72, 80))	('ATM', 'Gene', (67, 70))
80193	31819490	The PUMCH multidisciplinary tumor board recommended the patient undergo treatment with standard first-line chemotherapy based on gemcitabine for cholangiocarcinoma, alternatively to receive olaparib based on the presence of a pathogenic serine-threonine kinase ATM mutation.	('PUMCH multidisciplinary tumor', 'Disease', (4, 33))	('ATM', 'Gene', '472', (261, 264))	('serine-threonine', 'Chemical', 'MESH:C061951', (237, 253))	('PUMCH multidisciplinary tumor', 'Disease', 'MESH:D009369', (4, 33))	('cholangiocarcinoma', 'Disease', (145, 163))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (145, 163))	('mutation', 'Var', (265, 273))	('ATM', 'Gene', (261, 264))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (145, 163))	('patient', 'Species', '9606', (56, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('pathogenic', 'Reg', (226, 236))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('gemcitabine', 'Chemical', 'MESH:C056507', (129, 140))
80230	31516310	Dietlein and Eschner applied a classifier based on Bayesian spam filtering techniques to exonic mutations and achieved an accuracy of 71% for 23 cancer-derived cell lines.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('exonic mutations', 'Var', (89, 105))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))
80258	31516310	To compute TBSs, the following process is applied: there are 6 types of strand symmetric base substitutions including C>A, C>G, C>T, T>C, T>A, and T>G.	('T>A', 'Var', (138, 141))	('C>G', 'Var', (123, 126))	('T>G', 'Var', (147, 150))	('C>T', 'Var', (128, 131))	('T>C', 'Var', (133, 136))	('C>A', 'Var', (118, 121))	('TBSs', 'Chemical', '-', (11, 15))
80260	31516310	For the CNVs, the levels of amplifications and deletions of cancer driver genes, which are reported by Catalogue of Somatic Mutations in Cancer (COSMIC, Appendix Table C1), are used.	('deletions', 'Var', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('Cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
80338	29619266	Immunohistochemical examinations demonstrated that the carcinoma cell was positive for vimentin, AE1/AE3 (focal), CAM5.2 (focal), CK7 (focal), and CK19 (focal) but negative for EMA, S-100, SMA, desmin, H-caldesmon, DOG-1, HepPar-1, glypican-3, CD34, CD117, PDGFR-Alpha, CK20, bile stain, iron, and mucicarmine.	('carcinoma', 'Disease', 'MESH:D002277', (55, 64))	('vimentin', 'Gene', (87, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('vimentin', 'Gene', '477991', (87, 95))	('CK19', 'Var', (147, 151))	('DOG', 'Species', '9615', (215, 218))	('CK7', 'Gene', '477602', (130, 133))	('desmin', 'Gene', '497091', (194, 200))	('mucicarmine', 'Chemical', 'MESH:C029618', (298, 309))	('carcinoma', 'Disease', (55, 64))	('CD34', 'Gene', '415130', (244, 248))	('CK7', 'Gene', (130, 133))	('CD34', 'Gene', (244, 248))	('HepPar-1, glypican-3', 'Gene', '481056', (222, 242))	('iron', 'Chemical', 'MESH:D007501', (288, 292))	('desmin', 'Gene', (194, 200))
80356	29619266	The survival rate of patients with surgical resection was significantly higher than that in patients without surgical resection.	('survival', 'CPA', (4, 12))	('patients', 'Species', '9606', (92, 100))	('patients', 'Species', '9606', (21, 29))	('higher', 'PosReg', (72, 78))	('surgical resection', 'Var', (35, 53))
80406	26950735	Radiofrequency and microwave ablation are convenient and cost effective for appropriately selected patients (those with tumors <5 cm that are not near a segmental bile duct, liver surface, or major vessel; attempted ablation of larger tumors results in a higher marginal miss rate, the vessels act as a heat sink, and ablation of a branch of the biliary tree can result in a bile leak.)	('marginal miss rate', 'MPA', (262, 280))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('bile leak', 'MPA', (375, 384))	('ablation', 'Var', (318, 326))	('result in', 'Reg', (363, 372))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('patients', 'Species', '9606', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('tumors', 'Disease', (235, 241))
80425	26950735	Such treatments reduce hepatic reserve through various mechanisms; oxaliplatin, for example, has been associated with perisinusoidal and veno-occlusive fibrosis, sinusoidal dilatation, and hemorrhage, and irinotecan with steatohepatitis.	('irinotecan', 'Chemical', 'MESH:D000077146', (205, 215))	('veno-occlusive fibrosis', 'Disease', 'MESH:D006504', (137, 160))	('veno-occlusive fibrosis', 'Disease', (137, 160))	('associated', 'Reg', (102, 112))	('reduce', 'NegReg', (16, 22))	('hepatitis', 'Phenotype', 'HP:0012115', (227, 236))	('hemorrhage', 'Disease', (189, 199))	('sinusoidal dilatation', 'Disease', (162, 183))	('hemorrhage', 'Disease', 'MESH:D006470', (189, 199))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (67, 78))	('dilatation', 'Phenotype', 'HP:0002617', (173, 183))	('steatohepatitis', 'Disease', (221, 236))	('oxaliplatin', 'Var', (67, 78))	('steatohepatitis', 'Disease', 'MESH:D005234', (221, 236))	('hepatic reserve', 'MPA', (23, 38))
80441	26950735	Vascular compromise of the liver can also lead to infarction or atrophy of the liver parenchyma as well as causing thrombotic events in distant organs.	('Vascular', 'Var', (0, 8))	('infarction', 'Disease', (50, 60))	('thrombotic events', 'Phenotype', 'HP:0001907', (115, 132))	('causing', 'Reg', (107, 114))	('thrombotic', 'Disease', 'MESH:D013927', (115, 125))	('thrombotic', 'Disease', (115, 125))	('lead to', 'Reg', (42, 49))	('atrophy of the liver parenchyma', 'Disease', (64, 95))	('infarction', 'Disease', 'MESH:D007238', (50, 60))	('atrophy of the liver parenchyma', 'Disease', 'MESH:D010195', (64, 95))
80504	26950735	For example, Eovist has been shown to increase the signal intensity of normal liver parenchyma on T1-weighted MRI and thus can help define lesions in the liver, distinguishing between benign and malignant processes based on imaging characteristics at each phase of a liver protocol MRI (i.e., the T1-weighted precontrast, arterial, and hepatocyte phases).	('Eovist', 'Chemical', 'MESH:C073590', (13, 19))	('increase', 'PosReg', (38, 46))	('signal intensity', 'MPA', (51, 67))	('Eovist', 'Var', (13, 19))
80506	26950735	For example, Eovist has been used to estimate the distal fall off range for proton radiotherapy, and lack of Eovist uptake has been correlated with histopathological evidence of radiation-induced liver damage.	('fall', 'Phenotype', 'HP:0002527', (57, 61))	('correlated', 'Reg', (132, 142))	('liver damage', 'Disease', (196, 208))	('Eovist', 'Chemical', 'MESH:C073590', (109, 115))	('Eovist', 'Chemical', 'MESH:C073590', (13, 19))	('liver damage', 'Disease', 'MESH:D056486', (196, 208))	('lack', 'Var', (101, 105))
80594	32871859	There were no difference in specificity, sensitivity, PLR, and NLR between MRI and 18F-FDG PET/CT (P > .05), and both of them had ideal diagnostic value for primary tumor.	('primary tumor', 'Disease', 'MESH:D001932', (157, 170))	('primary tumor', 'Disease', (157, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('MRI', 'Var', (75, 78))	('FDG', 'Gene', '23583', (87, 90))	('FDG', 'Gene', (87, 90))
80608	32871859	To the best of our knowledge, this is the first meta-analysis of the accuracy of diagnostic test for comparing MRI and 18F-FDG PET/CT in staging CCA.	('MRI', 'Var', (111, 114))	('FDG', 'Gene', (123, 126))	('CCA', 'Phenotype', 'HP:0030153', (145, 148))	('FDG', 'Gene', '23583', (123, 126))
80609	32871859	In this analysis, both MRI and 18F-FDG PET/CT are beneficial to the detection of primary tumor in CCA without significant statistical differences in diagnostic capacity.	('CCA', 'Phenotype', 'HP:0030153', (98, 101))	('primary tumor', 'Disease', 'MESH:D001932', (81, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('MRI', 'Var', (23, 26))	('CCA', 'Disease', (98, 101))	('FDG', 'Gene', '23583', (35, 38))	('FDG', 'Gene', (35, 38))	('primary tumor', 'Disease', (81, 94))
80620	32871859	Our meta-analysis indicates that both MRI and 18F-FDG PET/CT can provide reasonable diagnostic accuracy for primary tumor of CCA.	('CCA', 'Disease', (125, 128))	('FDG', 'Gene', '23583', (50, 53))	('MRI', 'Var', (38, 41))	('FDG', 'Gene', (50, 53))	('primary tumor', 'Disease', (108, 121))	('CCA', 'Phenotype', 'HP:0030153', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('primary tumor', 'Disease', 'MESH:D001932', (108, 121))
80625	31727977	Functional and topographic effects on DNA methylation in IDH1/2 mutant cancers IDH1/2 mutations are early drivers present in diverse human cancer types arising in various tissue sites.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('IDH1/2', 'Gene', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancer', 'Disease', (71, 77))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('IDH1/2', 'Gene', '3417;3418', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('IDH1/2', 'Gene', '3417;3418', (57, 63))	('human', 'Species', '9606', (133, 138))	('mutant', 'Var', (64, 70))	('IDH1/2', 'Gene', (79, 85))	('cancer', 'Disease', (139, 145))
80626	31727977	IDH1/2 mutation is known to induce a global hypermethylator phenotype.	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('induce', 'Reg', (28, 34))	('mutation', 'Var', (7, 15))	('global hypermethylator phenotype', 'MPA', (37, 69))	('IDH1/2', 'Gene', (0, 6))
80628	31727977	We analyzed DNA methylation data from IDH1/2 mutant acute myeloid leukemia, oligodendroglioma, astrocytoma, solid papillary breast carcinoma with reverse polarity, sinonasal undifferentiated carcinoma and cholangiocarcinoma, which clustered by their embryonal origin.	('sinonasal undifferentiated carcinoma', 'Disease', (164, 200))	('IDH1/2', 'Gene', '3417;3418', (38, 44))	('oligodendroglioma', 'Disease', (76, 93))	('IDH1/2', 'Gene', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('acute myeloid leukemia', 'Disease', (52, 74))	('astrocytoma', 'Phenotype', 'HP:0009592', (95, 106))	('mutant', 'Var', (45, 51))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (52, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (205, 223))	('papillary breast carcinoma', 'Disease', (114, 140))	('papillary breast carcinoma', 'Disease', 'MESH:D001943', (114, 140))	('sinonasal undifferentiated carcinoma', 'Disease', 'MESH:C537344', (164, 200))	('leukemia', 'Phenotype', 'HP:0001909', (66, 74))	('oligodendroglioma', 'Disease', 'MESH:D009837', (76, 93))	('cholangiocarcinoma', 'Disease', (205, 223))	('astrocytoma', 'Disease', 'MESH:D001254', (95, 106))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (52, 74))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (58, 74))	('astrocytoma', 'Disease', (95, 106))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (205, 223))	('breast carcinoma', 'Phenotype', 'HP:0003002', (124, 140))
80629	31727977	Hypermethylated common probes affect predominantly gene bodies while promoters in IDH1/2 mutant cancers remain unmethylated.	('IDH1/2', 'Gene', '3417;3418', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Hypermethylated', 'Var', (0, 15))	('IDH1/2', 'Gene', (82, 88))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('affect', 'Reg', (30, 36))	('cancers', 'Disease', (96, 103))	('gene', 'Protein', (51, 55))
80630	31727977	We demonstrate that some chromosomes, chromosomal arms and chromosomal regions are more affected by IDH1/2 mutations while others remain resistant to IDH1/2 mutation induced methylation changes.	('affected', 'Reg', (88, 96))	('mutations', 'Var', (107, 116))	('IDH1/2', 'Gene', (150, 156))	('IDH1/2', 'Gene', '3417;3418', (100, 106))	('IDH1/2', 'Gene', (100, 106))	('IDH1/2', 'Gene', '3417;3418', (150, 156))
80631	31727977	Therefore IDH1/2 mutations have different methylation effect on different parts of the genome, which may be regulated by different mechanisms.	('methylation', 'MPA', (42, 53))	('IDH1/2', 'Gene', '3417;3418', (10, 16))	('mutations', 'Var', (17, 26))	('IDH1/2', 'Gene', (10, 16))
80635	31727977	Mutations in the IDH1 and IDH2 genes have been found in various tumor types and catalyze reduction of a-KG into a structurally similar oncometabolite 2-hydroxyglutarate (2-HG), which probably functions as an alpha-KG antagonist in numerous metabolic processes.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('IDH2', 'Gene', (26, 30))	('found', 'Reg', (47, 52))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', (17, 21))	('IDH2', 'Gene', '3418', (26, 30))	('2-HG', 'Chemical', 'MESH:C019417', (170, 174))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (150, 168))	('IDH1', 'Gene', '3417', (17, 21))	('alpha-KG', 'Chemical', 'MESH:C029743', (208, 216))
80636	31727977	2-HG is normally produced at a low level (<300 microM) by errors in catalysis during phosphoglycerate dehydrogenase, hydroxyl oxoacetic transferase and malate dehydrogenase reactions.	('errors', 'Var', (58, 64))	('malate dehydrogenase', 'Gene', '4200', (152, 172))	('2-HG', 'Chemical', 'MESH:C019417', (0, 4))	('phosphoglycerate', 'Chemical', 'MESH:C008885', (85, 101))	('catalysis', 'MPA', (68, 77))	('hydroxyl oxoacetic', 'Chemical', 'MESH:C549122', (117, 135))	('malate dehydrogenase', 'Gene', (152, 172))
80638	31727977	In cancers with IDH1/2 mutations, 2-HG levels can reach millimolar concentrations saturating normal clearing mechanisms.	('IDH1/2', 'Gene', (16, 22))	('2-HG', 'Chemical', 'MESH:C019417', (34, 38))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('mutations', 'Var', (23, 32))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('IDH1/2', 'Gene', '3417;3418', (16, 22))	('2-HG levels', 'MPA', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
80640	31727977	Mutations in IDH1/2 genes have been identified in acute myeloid leukemia, glioma, cholangiocarcinoma, sinonasal undifferentiated carcinoma, chondrosarcoma and periosteal chondroma, solid papillary carcinoma with reverse polarity, a rare morphologic subtype of breast carcinoma, and also occur rarely in other tumors like medulloblastoma.	('sinonasal undifferentiated carcinoma', 'Disease', (102, 138))	('tumors', 'Phenotype', 'HP:0002664', (309, 315))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (50, 72))	('papillary carcinoma', 'Disease', 'MESH:D002291', (187, 206))	('breast carcinoma', 'Phenotype', 'HP:0003002', (260, 276))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (56, 72))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (50, 72))	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('breast carcinoma', 'Disease', (260, 276))	('tumors', 'Disease', (309, 315))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (82, 100))	('IDH1/2', 'Gene', (13, 19))	('glioma', 'Disease', (74, 80))	('Mutations', 'Var', (0, 9))	('medulloblastoma', 'Disease', 'MESH:D008527', (321, 336))	('cholangiocarcinoma', 'Disease', (82, 100))	('medulloblastoma', 'Phenotype', 'HP:0002885', (321, 336))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('medulloblastoma', 'Disease', (321, 336))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (82, 100))	('tumors', 'Disease', 'MESH:D009369', (309, 315))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('acute myeloid leukemia', 'Disease', (50, 72))	('chondrosarcoma and periosteal chondroma', 'Disease', 'MESH:D010522', (140, 179))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (140, 154))	('breast carcinoma', 'Disease', 'MESH:D001943', (260, 276))	('sinonasal undifferentiated carcinoma', 'Disease', 'MESH:C537344', (102, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('papillary carcinoma', 'Disease', (187, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('identified', 'Reg', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))
80641	31727977	All somatic IDH mutations occur in key residues within the active site, with hotspots in one of three arginine residues critical for isocitrate binding, specifically IDH1 R132 and the IDH2 R172 and R140 codons.	('IDH2', 'Gene', (184, 188))	('IDH1', 'Gene', (166, 170))	('isocitrate', 'Chemical', 'MESH:D007523', (133, 143))	('IDH1', 'Gene', '3417', (166, 170))	('arginine', 'Chemical', 'MESH:D001127', (102, 110))	('IDH2', 'Gene', '3418', (184, 188))	('mutations', 'Var', (16, 25))	('IDH', 'Gene', (166, 169))	('R172', 'Var', (189, 193))	('IDH', 'Gene', (184, 187))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('IDH', 'Gene', '3417', (166, 169))	('R132', 'Var', (171, 175))	('R140', 'Var', (198, 202))	('IDH', 'Gene', '3417', (184, 187))	('occur', 'Reg', (26, 31))
80642	31727977	Regardless of tumor type, IDH mutant cancers show global DNA hypermethylation when compared to their wild-type counterparts.	('tumor', 'Disease', (14, 19))	('DNA hypermethylation', 'MPA', (57, 77))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancers', 'Disease', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('IDH', 'Gene', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('IDH', 'Gene', '3417', (26, 29))	('mutant', 'Var', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
80643	31727977	In leukemias and gliomas, IDH mutations occur early in tumorigenesis and appear insufficient in driving tumor growth alone unless paired with ATRX loss and TP53 mutation, or loss of 1p/19q.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('leukemias and gliomas', 'Disease', 'MESH:D005910', (3, 24))	('TP53', 'Gene', (156, 160))	('IDH', 'Gene', '3417', (26, 29))	('ATRX loss', 'Disease', 'MESH:C538258', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('mutation', 'Var', (161, 169))	('ATRX loss', 'Disease', (142, 151))	('tumor', 'Disease', (104, 109))	('TP53', 'Gene', '7157', (156, 160))	('mutations', 'Var', (30, 39))	('leukemias', 'Phenotype', 'HP:0001909', (3, 12))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('leukemia', 'Phenotype', 'HP:0001909', (3, 11))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('tumor', 'Disease', (55, 60))	('IDH', 'Gene', (26, 29))	('gliomas', 'Phenotype', 'HP:0009733', (17, 24))
80644	31727977	The prognostic value of IDH1/2 mutations seems to be disease dependent.	('IDH1/2', 'Gene', (24, 30))	('mutations', 'Var', (31, 40))	('IDH1/2', 'Gene', '3417;3418', (24, 30))
80645	31727977	While in gliomas, IDH1/2 mutations are associated with favorable outcome, in other solid tumors and leukemia the effect on prognosis is either less favorable or unclear.	('mutations', 'Var', (25, 34))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('gliomas', 'Disease', (9, 16))	('leukemia', 'Disease', 'MESH:D007938', (100, 108))	('gliomas', 'Disease', 'MESH:D005910', (9, 16))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('gliomas', 'Phenotype', 'HP:0009733', (9, 16))	('leukemia', 'Disease', (100, 108))	('leukemia', 'Phenotype', 'HP:0001909', (100, 108))	('IDH1/2', 'Gene', '3417;3418', (18, 24))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('IDH1/2', 'Gene', (18, 24))
80647	31727977	Since the biochemical effect of IDH mutations is presumably the same in all cancer and cell types, this suggests that the IDH mutations may have different effect in different cell types.	('IDH', 'Gene', (122, 125))	('IDH', 'Gene', '3417', (122, 125))	('mutations', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
80649	31727977	In addition, we also compared DNA methylation profiles of IDH1/2 mutated AML to normal blood controls.	('IDH1/2', 'Gene', '3417;3418', (58, 64))	('AML', 'Disease', (73, 76))	('AML', 'Phenotype', 'HP:0004808', (73, 76))	('IDH1/2', 'Gene', (58, 64))	('AML', 'Disease', 'MESH:D015470', (73, 76))	('mutated', 'Var', (65, 72))
80650	31727977	Next, we sought to elucidate the effects of IDH1/2 mutations on DNA methylation across six IDH mutant cancer types without wild-type tumor comparisons by identifying common hyper- and hypomethylated probes shared among all IDH1/2 mutant tumor types.	('mutations', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('effects', 'Reg', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('hyper-', 'PosReg', (173, 179))	('IDH', 'Gene', (223, 226))	('IDH1/2', 'Gene', '3417;3418', (44, 50))	('IDH1/2', 'Gene', (44, 50))	('cancer', 'Disease', (102, 108))	('IDH', 'Gene', '3417', (223, 226))	('IDH', 'Gene', (91, 94))	('tumor', 'Disease', (133, 138))	('IDH', 'Gene', (44, 47))	('hypomethylated', 'Var', (184, 198))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('IDH1/2', 'Gene', '3417;3418', (223, 229))	('IDH1/2', 'Gene', (223, 229))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('IDH', 'Gene', '3417', (91, 94))	('IDH', 'Gene', '3417', (44, 47))
80651	31727977	While IDH1/2 mutations have been associated with the CpG island hypermethylation, we sought to elucidate whether functionally different parts of the genome, such as gene body, promoter or enhancers are differentially affected by IDH mutation induced DNA methylation changes.	('IDH', 'Gene', (6, 9))	('IDH', 'Gene', '3417', (6, 9))	('IDH1/2', 'Gene', '3417;3418', (6, 12))	('mutation', 'Var', (233, 241))	('affected', 'Reg', (217, 225))	('IDH', 'Gene', (229, 232))	('associated', 'Reg', (33, 43))	('IDH', 'Gene', '3417', (229, 232))	('mutations', 'Var', (13, 22))	('IDH1/2', 'Gene', (6, 12))
80652	31727977	We evaluated whether entire or specific parts of chromosomes show different effect of IDH mutation induced hypermethylation.	('IDH', 'Gene', (86, 89))	('IDH', 'Gene', '3417', (86, 89))	('mutation', 'Var', (90, 98))	('hypermethylation', 'MPA', (107, 123))
80653	31727977	We hypothesized that DNA hyper- and hypomethylation changes that are common across all IDH1/2 mutated cancers of various tissues of origin may represent universal effect of the IDH1/2 mutations on the DNA methylation.	('IDH1/2', 'Gene', (87, 93))	('mutated', 'Var', (94, 101))	('IDH1/2', 'Gene', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('IDH1/2', 'Gene', '3417;3418', (87, 93))	('cancers', 'Disease', (102, 109))	('IDH1/2', 'Gene', '3417;3418', (177, 183))
80655	31727977	In this study we incorporated DNA methylation data from Cancer Genome Atlas (TCGA) profiled IDH mutant and wild-type acute myeloid leukemia (AML, N = 21) and cholangiocarcinoma (N = 9).	('cholangiocarcinoma', 'Disease', (158, 176))	('AML', 'Disease', (141, 144))	('mutant', 'Var', (96, 102))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (117, 139))	('AML', 'Phenotype', 'HP:0004808', (141, 144))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (123, 139))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (158, 176))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (158, 176))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (117, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('IDH', 'Gene', (92, 95))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('AML', 'Disease', 'MESH:D015470', (141, 144))	('acute myeloid leukemia', 'Disease', (117, 139))	('IDH', 'Gene', '3417', (92, 95))
80658	31727977	IDH1/2 mutant brain tumors were compared with IDH wild-type glioblastoma from our previously published cohort.	('glioblastoma', 'Disease', (60, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('IDH', 'Gene', (0, 3))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('mutant', 'Var', (7, 13))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (46, 49))	('IDH', 'Gene', '3417', (46, 49))	('brain tumors', 'Phenotype', 'HP:0030692', (14, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('IDH1/2', 'Gene', (0, 6))	('brain tumor', 'Phenotype', 'HP:0030692', (14, 25))
80660	31727977	We compared hyper- and hypomethylation of IDH1/2 mutated tumors with biologically relevant IDH wild-type tumors when available.	('tumors', 'Disease', (105, 111))	('mutated', 'Var', (49, 56))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('IDH', 'Gene', (42, 45))	('IDH1/2', 'Gene', '3417;3418', (42, 48))	('IDH', 'Gene', '3417', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('IDH', 'Gene', (91, 94))	('IDH1/2', 'Gene', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('IDH', 'Gene', '3417', (91, 94))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
80661	31727977	DNA methylation of IDH mutated AML was compared both with normal non-neoplastic blood DNA sample (leukocytes) and IDH wild-type AML (Fig.	('AML', 'Phenotype', 'HP:0004808', (31, 34))	('AML', 'Disease', (128, 131))	('AML', 'Phenotype', 'HP:0004808', (128, 131))	('IDH', 'Gene', (114, 117))	('IDH', 'Gene', '3417', (114, 117))	('mutated', 'Var', (23, 30))	('IDH', 'Gene', (19, 22))	('AML', 'Disease', 'MESH:D015470', (31, 34))	('AML', 'Disease', 'MESH:D015470', (128, 131))	('IDH', 'Gene', '3417', (19, 22))	('AML', 'Disease', (31, 34))
80662	31727977	IDH1/2 mutated astrocytoma was compared to a balanced cohort of Classic (RTKII) and Mesenchymal glioblastoma (GBM) (Fig.	('astrocytoma', 'Disease', (15, 26))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('GBM', 'Disease', (110, 113))	('Mesenchymal glioblastoma', 'Disease', 'MESH:D005909', (84, 108))	('GBM', 'Disease', 'MESH:D005909', (110, 113))	('astrocytoma', 'Disease', 'MESH:D001254', (15, 26))	('GBM', 'Phenotype', 'HP:0012174', (110, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('Mesenchymal glioblastoma', 'Disease', (84, 108))	('IDH1/2', 'Gene', (0, 6))	('astrocytoma', 'Phenotype', 'HP:0009592', (15, 26))	('mutated', 'Var', (7, 14))
80664	31727977	The analysis of IDH mutated and wild-type cholangiocarcinoma showed a very low number of probes with FDR < 0.05 (n = 980) and was excluded from further analysis.	('cholangiocarcinoma', 'Disease', (42, 60))	('IDH', 'Gene', (16, 19))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (42, 60))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (42, 60))	('IDH', 'Gene', '3417', (16, 19))	('mutated', 'Var', (20, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
80665	31727977	Differential methylation analysis showed that in all four tumor specific comparisons, IDH1/2 mutated tumors had a significantly higher number of hypermethylated gene body and enhancer probes than promoters and significantly higher number of hypomethylated promoter probes than gene bodies and enhancers (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mutated', 'Var', (93, 100))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('IDH1/2', 'Gene', '3417;3418', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('hypermethylated', 'MPA', (145, 160))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('IDH1/2', 'Gene', (86, 92))	('enhancer', 'PosReg', (175, 183))	('higher', 'PosReg', (128, 134))	('tumors', 'Disease', (101, 107))
80666	31727977	The disease specific analysis showed that there was a significant variability in the number of hyper- and hypomethylated probes, with IDH mutated AML showing the highest number of hypermethylated probes (Fig.	('IDH', 'Gene', '3417', (134, 137))	('AML', 'Disease', (146, 149))	('IDH', 'Gene', (134, 137))	('mutated', 'Var', (138, 145))	('AML', 'Phenotype', 'HP:0004808', (146, 149))	('AML', 'Disease', 'MESH:D015470', (146, 149))
80669	31727977	1d), suggesting that other factors such as concurrent driver mutations of IDH wild-type tumors or the tissue of origin play role in tumor type specific methylation changes.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('mutations', 'Var', (61, 70))	('tumor', 'Disease', (132, 137))	('IDH', 'Gene', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('IDH', 'Gene', '3417', (74, 77))	('tumor', 'Disease', (88, 93))
80670	31727977	Interestingly, IDH mutated AML compared to normal blood showed the highest number of differentially hypomethylated promoter probes compared to IDH mutated vs wild-type AML, oligodendroglioma vs RTKI GBM and astrocytoma vs Classic/Mesenchymal (Fig.	('AML', 'Phenotype', 'HP:0004808', (27, 30))	('AML', 'Disease', 'MESH:D015470', (168, 171))	('AML', 'Phenotype', 'HP:0004808', (168, 171))	('AML', 'Disease', (168, 171))	('IDH', 'Gene', (143, 146))	('IDH', 'Gene', (15, 18))	('astrocytoma', 'Phenotype', 'HP:0009592', (207, 218))	('GBM', 'Disease', (199, 202))	('IDH', 'Gene', '3417', (143, 146))	('GBM', 'Disease', 'MESH:D005909', (199, 202))	('mutated', 'Var', (19, 26))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('oligodendroglioma', 'Disease', 'MESH:D009837', (173, 190))	('IDH', 'Gene', '3417', (15, 18))	('astrocytoma', 'Disease', 'MESH:D001254', (207, 218))	('GBM', 'Phenotype', 'HP:0012174', (199, 202))	('oligodendroglioma', 'Disease', (173, 190))	('astrocytoma', 'Disease', (207, 218))	('AML', 'Disease', 'MESH:D015470', (27, 30))	('AML', 'Disease', (27, 30))
80671	31727977	Overall, these findings suggest that global hypermethylation induced by IDH1/2 mutations affects the genome in a function specific manner with strong propensity for hypermethylation of enhancers and gene bodies, while promoters remain hypomethylated.	('affects', 'Reg', (89, 96))	('IDH1/2', 'Gene', '3417;3418', (72, 78))	('hypermethylation', 'MPA', (165, 181))	('IDH1/2', 'Gene', (72, 78))	('global hypermethylation', 'MPA', (37, 60))	('mutations', 'Var', (79, 88))
80672	31727977	Mutations in IDH1 and IDH2 genes lead to global hypermethylation which readily distinguishes mutated tumors from their wild-type counterparts (Fig.	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))	('global hypermethylation', 'MPA', (41, 64))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (22, 26))	('tumors', 'Disease', (101, 107))
80674	31727977	We performed differential methylation analysis of IDH1/2 mutant tumors comparing six different tumor types.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('IDH1/2', 'Gene', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mutant', 'Var', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('IDH1/2', 'Gene', '3417;3418', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (95, 100))
80679	31727977	Despite IDH1/2 mutations supposedly affecting the same enzymes in all cancers, all tumors still clustered based on their tissue of origin and more specifically the embryonal layer.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('affecting', 'Reg', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutations', 'Var', (15, 24))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('IDH1/2', 'Gene', '3417;3418', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))	('IDH1/2', 'Gene', (8, 14))
80681	31727977	Since not all cancers in our study have biologically relevant wild-type counterparts available for comparison, we sought to identify common hyper- and hypomethylated probes in our IDH1/2 mutated tumors by identifying hyper- and hypomethylated probes, which are common across all six IDH1/2 mutated tumor types in our study.	('tumor', 'Disease', (195, 200))	('IDH1/2', 'Gene', '3417;3418', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('IDH1/2', 'Gene', '3417;3418', (283, 289))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('IDH1/2', 'Gene', (180, 186))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Disease', (298, 303))	('IDH1/2', 'Gene', (283, 289))	('hypomethylated', 'Var', (228, 242))	('hyper-', 'Var', (217, 223))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumors', 'Disease', (195, 201))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('cancers', 'Disease', (14, 21))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))
80682	31727977	When analyzing methylated probes across six tumor types, we observed that only a fraction of probes was hyper- or hypomethylated only in one tumor type, while large portion of the probes are hyper- and hypomethylated in two or more cancer types (Fig.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('hypomethylated', 'Var', (114, 128))	('cancer', 'Disease', (232, 238))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
80683	31727977	Approximately 1.4% (1,563/110,560) and 8% (9,814/122,648) probes were hypermethylated only in IDH mutant astrocytomas and acute myeloid leukemias, respectively.	('astrocytomas', 'Disease', (105, 117))	('acute myeloid leukemias', 'Disease', 'MESH:D015470', (122, 145))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (128, 145))	('leukemia', 'Phenotype', 'HP:0001909', (136, 144))	('IDH', 'Gene', (94, 97))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (122, 144))	('IDH', 'Gene', '3417', (94, 97))	('leukemias', 'Phenotype', 'HP:0001909', (136, 145))	('acute myeloid leukemias', 'Disease', (122, 145))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (122, 145))	('hypermethylated', 'Var', (70, 85))	('astrocytomas', 'Disease', 'MESH:D001254', (105, 117))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (128, 144))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))
80684	31727977	In total, 52,161 probes were hypermethylated in all tumor types analyzed in our study.	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('hypermethylated', 'Var', (29, 44))
80686	31727977	2b, Table 1), validating the findings observed in IDH1/2 mutant vs wild-type leukemia analysis (Fig.	('leukemia', 'Disease', (77, 85))	('leukemia', 'Phenotype', 'HP:0001909', (77, 85))	('leukemia', 'Disease', 'MESH:D007938', (77, 85))	('IDH1/2', 'Gene', (50, 56))	('mutant', 'Var', (57, 63))	('IDH1/2', 'Gene', '3417;3418', (50, 56))
80687	31727977	Astrocytomas showed a number of hypermethylated probes that was similar to oligodendroglioma and cholangiocarcinoma, but higher than SNUC and breast carcinoma.	('breast carcinoma', 'Phenotype', 'HP:0003002', (142, 158))	('oligodendroglioma and cholangiocarcinoma', 'Disease', 'MESH:D018281', (75, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('SNUC', 'Disease', (133, 137))	('Astrocytoma', 'Phenotype', 'HP:0009592', (0, 11))	('hypermethylated probes', 'Var', (32, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('breast carcinoma', 'Disease', 'MESH:D001943', (142, 158))	('breast carcinoma', 'Disease', (142, 158))	('higher', 'PosReg', (121, 127))	('SNUC', 'Disease', 'MESH:C537344', (133, 137))	('Astrocytomas', 'Disease', 'MESH:D001254', (0, 12))	('Astrocytomas', 'Disease', (0, 12))
80692	31727977	Once we determined, which hyper- and hypomethylated probes are common across six IDH1/2 mutant tumor types, we sought to determine the distribution of common hyper- and hypomethylated probes across the genome and elucidate what is the ratio of hyper- and hypomethylation in different regions of the genome.	('IDH1/2', 'Gene', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mutant', 'Var', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('IDH1/2', 'Gene', '3417;3418', (81, 87))	('tumor', 'Disease', (95, 100))
80693	31727977	2) suggesting that IDH1/2 mutation induced methylation changes are not limited to a hypermethylator phenotype and that certain regions and probes remain unmethylated in IDH mutant tumors.	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('mutation', 'Var', (26, 34))	('IDH1/2', 'Gene', (19, 25))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('IDH', 'Gene', (169, 172))	('mutant', 'Var', (173, 179))	('IDH', 'Gene', '3417', (19, 22))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('IDH', 'Gene', (19, 22))	('IDH', 'Gene', '3417', (169, 172))	('IDH1/2', 'Gene', '3417;3418', (19, 25))	('changes', 'Reg', (55, 62))	('methylation', 'MPA', (43, 54))
80695	31727977	However, as shown above by differential methylation of IDH mutant and wild-type tumors, gene bodies and enhancers showed hypermethylation while promoters show global hypomethylation.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('IDH', 'Gene', (55, 58))	('mutant', 'Var', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('IDH', 'Gene', '3417', (55, 58))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('methylation', 'MPA', (40, 51))	('hypermethylation', 'MPA', (121, 137))
80696	31727977	Therefore we aimed to confirm whether IDH1/2 mutation induced hyper- and hypomethylation showed similar effect on promoters, enhancers and gene bodies across all six IDH1/2 mutated cancer types including tumors in which we did not have the wild-type tumor or normal tissue for comparison.	('IDH1/2', 'Gene', '3417;3418', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('IDH1/2', 'Gene', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('IDH1/2', 'Gene', '3417;3418', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Disease', (250, 255))	('IDH1/2', 'Gene', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumors', 'Disease', (204, 210))	('hypomethylation', 'MPA', (73, 88))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Disease', (181, 187))	('hyper-', 'MPA', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Disease', (204, 209))	('mutation', 'Var', (45, 53))
80698	31727977	In addition to the functional difference, we further explored whether there are topographic differences between chromosomes and chromosomal regions in addition to the functional variability in DNA methylation induced by IDH1/2 mutations common in all six cancer types.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('mutations', 'Var', (227, 236))	('IDH1/2', 'Gene', '3417;3418', (220, 226))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('IDH1/2', 'Gene', (220, 226))	('DNA methylation', 'MPA', (193, 208))
80700	31727977	3), chromosome 13q enhancers and gene bodies appear the most affected by DNA hypermethylation across all IDH1/2 mutant cancers.	('affected', 'Reg', (61, 69))	('IDH1/2', 'Gene', (105, 111))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('mutant', 'Var', (112, 118))	('hypermethylation', 'Var', (77, 93))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('IDH1/2', 'Gene', '3417;3418', (105, 111))
80701	31727977	The second chromosomal arm with high ratios of both hypermethylated gene body and enhancer probes seems to be 10p, while 18p the lowest fraction of common gene body and enhancer hypermethylated probes in IDH1/2 mutant tumors.	('IDH1/2', 'Gene', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('mutant', 'Var', (211, 217))	('IDH1/2', 'Gene', '3417;3418', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
80702	31727977	The analysis how gene bodies, enhancers and promoters are affected by hyper- and hypomethylation in tumor specific manner is limited by a highly variable number of cases, with some groups being extremely small due to the rarity of tumors.	('tumors', 'Disease', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', (231, 236))	('hyper-', 'Var', (70, 76))	('hypomethylation', 'Var', (81, 96))
80704	31727977	We also observed that certain chromosomal regions almost completely lacked any common hyper- or hypomethylated probes in enhancers, promoters or gene bodies, suggesting that these regions do not contain gene body/promoter or enhancer probes affected by changes in DNA methylation in IDH1/2 mutant cancers.	('IDH1/2', 'Gene', (283, 289))	('cancers', 'Disease', 'MESH:D009369', (297, 304))	('cancers', 'Phenotype', 'HP:0002664', (297, 304))	('cancers', 'Disease', (297, 304))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('IDH1/2', 'Gene', '3417;3418', (283, 289))	('mutant', 'Var', (290, 296))
80706	31727977	This suggests that some areas of the chromosomes may not be the target of DNA methylation changes induced by IDH1/2 mutation in cancers and may be regulated by other epigenetic mechanisms.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('IDH1/2', 'Gene', (109, 115))	('mutation', 'Var', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('regulated', 'Reg', (147, 156))	('IDH1/2', 'Gene', '3417;3418', (109, 115))
80707	31727977	Mutations act in concert when dysregulating cellular signaling in cancer.	('dysregulating cellular signaling', 'MPA', (30, 62))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
80709	31727977	To investigate what cellular functions may be affected across all six IDH1/2 mutant tumor types, we separately analyzed the effect of hyper- and hypomethylation on promoters, enhancers and gene bodies.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('IDH1/2', 'Gene', '3417;3418', (70, 76))	('tumor', 'Disease', (84, 89))	('mutant', 'Var', (77, 83))	('IDH1/2', 'Gene', (70, 76))
80711	31727977	In contrary, GO associated with hypermethylated promoters were enriched (6/10 top GO terms) for genes involved in meiosis and gamete generation, likely playing no role in cancer.	('hypermethylated promoters', 'Var', (32, 57))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('meiosis', 'Disease', (114, 121))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('meiosis', 'Disease', 'MESH:C536875', (114, 121))
80714	31727977	This suggests that only promoters regulating noncritical functions are safe to be hypermethylated in cancer cells and the hypomethylation of enhancers involved in cell differentiation may be the cause of previously observed inability to differentiate observed in IDH mutant cancers.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('hypomethylation', 'Var', (122, 137))	('cancers', 'Disease', 'MESH:D009369', (274, 281))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('cancers', 'Phenotype', 'HP:0002664', (274, 281))	('cancers', 'Disease', (274, 281))	('cancer', 'Disease', (274, 280))	('IDH', 'Gene', (263, 266))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutant', 'Var', (267, 273))	('IDH', 'Gene', '3417', (263, 266))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
80715	31727977	While the biochemical effect of IDH1/2 mutations is well known, the effect on tumorigenesis as well as tumor growth, and tumor progression remains less understood.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (103, 108))	('IDH1/2', 'Gene', (32, 38))	('tumor', 'Disease', (121, 126))	('mutations', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('IDH1/2', 'Gene', '3417;3418', (32, 38))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
80716	31727977	Variable prognosis of IDH1/2 mutant tumors and response to IDH targeted therapy among different tumor types highlights the need to identify common and disease specific effects of IDH1/2 mutations.	('IDH', 'Gene', '3417', (179, 182))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('IDH', 'Gene', '3417', (59, 62))	('IDH1/2', 'Gene', '3417;3418', (22, 28))	('tumor', 'Disease', (36, 41))	('IDH1/2', 'Gene', (22, 28))	('IDH', 'Gene', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('IDH1/2', 'Gene', '3417;3418', (179, 185))	('mutant', 'Var', (29, 35))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('IDH', 'Gene', '3417', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumors', 'Disease', (36, 42))	('IDH1/2', 'Gene', (179, 185))	('IDH', 'Gene', (59, 62))	('IDH', 'Gene', (179, 182))	('tumors', 'Disease', 'MESH:D009369', (36, 42))
80717	31727977	The role of IDH1/2 mutations in cancer has been puzzling since their discovery.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('IDH1/2', 'Gene', (12, 18))	('mutations', 'Var', (19, 28))	('IDH1/2', 'Gene', '3417;3418', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
80718	31727977	While mutations in other metabolic enzymes such as fumarate hydratase and succinate dehydrogenase identified in hereditary leiomyomatosis, renal cell carcinoma and paragangliomas result in loss of function, IDH1/2 mutations are virtually always heterozygous, suggesting a gain of function as a possible carcinogenic mechanism.	('IDH1/2', 'Gene', (207, 213))	('paragangliomas', 'Disease', (164, 178))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (139, 159))	('hereditary leiomyomatosis', 'Disease', (112, 137))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('renal cell carcinoma', 'Disease', (139, 159))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (139, 159))	('mutations', 'Var', (214, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('succinate', 'Chemical', 'MESH:D013386', (74, 83))	('carcinogenic', 'Disease', (303, 315))	('gain of function', 'PosReg', (272, 288))	('fumarate hydratase', 'Gene', (51, 69))	('mutations', 'Var', (6, 15))	('paragangliomas', 'Disease', 'MESH:D010235', (164, 178))	('paragangliomas', 'Phenotype', 'HP:0002668', (164, 178))	('hereditary leiomyomatosis', 'Disease', 'MESH:C535516', (112, 137))	('carcinogenic', 'Disease', 'MESH:D063646', (303, 315))	('gliomas', 'Phenotype', 'HP:0009733', (171, 178))	('loss of function', 'NegReg', (189, 205))	('IDH1/2', 'Gene', '3417;3418', (207, 213))	('fumarate hydratase', 'Gene', '2271', (51, 69))
80719	31727977	A universal feature of IDH1/2 mutant cancers is the CpG island methylator phenotype resulting in global DNA hypermethylation, due to the overproduction of 2-HG regardless of tumor type.	('tumor', 'Disease', (174, 179))	('IDH1/2', 'Gene', '3417;3418', (23, 29))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('global DNA hypermethylation', 'MPA', (97, 124))	('cancers', 'Disease', (37, 44))	('IDH1/2', 'Gene', (23, 29))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('2-HG', 'Chemical', 'MESH:C019417', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('mutant', 'Var', (30, 36))	('overproduction', 'PosReg', (137, 151))
80720	31727977	Our data suggest that CpG islands identified as hypermethylated in IDH mutant cancers are in fact CpG islands with enhancer activity rather than promoters.	('hypermethylated', 'PosReg', (48, 63))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('IDH', 'Gene', (67, 70))	('enhancer', 'PosReg', (115, 123))	('mutant', 'Var', (71, 77))	('cancers', 'Disease', (78, 85))	('IDH', 'Gene', '3417', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
80721	31727977	IDH1/2 mutation alters canonical metabolic pathways including glutamine catabolism and the TCA cycle.	('glutamine catabolism', 'MPA', (62, 82))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('TCA', 'Chemical', 'MESH:C000589078', (91, 94))	('canonical', 'Pathway', (23, 32))	('TCA', 'Pathway', (91, 94))	('mutation', 'Var', (7, 15))	('glutamine', 'Chemical', 'MESH:C578860', (62, 71))	('IDH1/2', 'Gene', (0, 6))	('alters', 'Reg', (16, 22))
80723	31727977	Furthermore, specific tumor types show distinct predisposition to specific IDH1 or IDH2 mutations.	('IDH2', 'Gene', '3418', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('mutations', 'Var', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('IDH1', 'Gene', (75, 79))	('tumor', 'Disease', (22, 27))	('IDH1', 'Gene', '3417', (75, 79))	('IDH2', 'Gene', (83, 87))
80724	31727977	While IDH2 mutations have been observed predominantly in acute myeloid leukemia and later in cholangiocarcinoma and solid papillary carcinoma with reverse polarity, a rare morphologic subtype of breast cancer, IDH1 mutations are strongly associated with low grade gliomas.	('mutations', 'Var', (11, 20))	('IDH1', 'Gene', '3417', (210, 214))	('gliomas', 'Phenotype', 'HP:0009733', (264, 271))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (63, 79))	('IDH2', 'Gene', (6, 10))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (57, 79))	('observed', 'Reg', (31, 39))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (57, 79))	('IDH2', 'Gene', '3418', (6, 10))	('papillary carcinoma', 'Disease', (122, 141))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('mutations', 'Var', (215, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('associated with', 'Reg', (238, 253))	('gliomas', 'Disease', (264, 271))	('papillary carcinoma', 'Disease', 'MESH:D002291', (122, 141))	('breast cancer', 'Disease', 'MESH:D001943', (195, 208))	('breast cancer', 'Disease', (195, 208))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('IDH1', 'Gene', (210, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('gliomas', 'Disease', 'MESH:D005910', (264, 271))	('acute myeloid leukemia', 'Disease', (57, 79))	('cholangiocarcinoma', 'Disease', (93, 111))	('glioma', 'Phenotype', 'HP:0009733', (264, 270))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))
80726	31727977	We show that there are disease specific regions as well as common regions of DNA/chromosomes that are preferentially affected across all IDH mutant cancers.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('IDH', 'Gene', '3417', (137, 140))	('mutant', 'Var', (141, 147))	('cancers', 'Disease', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('IDH', 'Gene', (137, 140))
80727	31727977	IDH mutations do not directly cause hypermethylation, but rather lead to inhibition of demethylases and may preserve previously established tissue/cell-specific differences in DNA methylation patterns occurring before the mutation event.	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('DNA methylation patterns', 'MPA', (176, 200))	('demethylases', 'Enzyme', (87, 99))	('lead to', 'Reg', (65, 72))	('inhibition', 'MPA', (73, 83))	('mutations', 'Var', (4, 13))
80731	31727977	This is concordant with previous observations that IDH mutations "lock" cells in undifferentiated states and prevent terminal differentiation.	('terminal differentiation', 'CPA', (117, 141))	('prevent', 'NegReg', (109, 116))	('IDH', 'Gene', (51, 54))	('mutations', 'Var', (55, 64))	('IDH', 'Gene', '3417', (51, 54))
80733	31727977	While we have observed a striking predisposition, as well as a resistance, of specific chromosomal arms and regions to hypermethylation in IDH1/2 mutant cancers, the major limitation of our study is the two-dimensional nature of our data which prohibits us to examine whether the affected regions interact with each other on a three-dimensional level.	('IDH1/2', 'Gene', (139, 145))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancers', 'Disease', (153, 160))	('mutant', 'Var', (146, 152))	('IDH1/2', 'Gene', '3417;3418', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
80734	31727977	Our study identifies common effects of IDH1/2 mutations on DNA methylation across six cancer types, derived from all three embryological layers.	('mutations', 'Var', (46, 55))	('IDH1/2', 'Gene', (39, 45))	('effects', 'Reg', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('DNA methylation', 'MPA', (59, 74))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('IDH1/2', 'Gene', '3417;3418', (39, 45))	('cancer', 'Disease', (86, 92))
80735	31727977	However it is limited by the fact that only in three cancers, AML, astrocytomas and oligodendroglioma we were able to perform a comparison with biologically relevant wild-type tumors and only in AML we compared the IDH1/2 mutated tumors with the normal tissue.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('AML', 'Phenotype', 'HP:0004808', (195, 198))	('IDH1/2', 'Gene', (215, 221))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('mutated', 'Var', (222, 229))	('tumors', 'Disease', (230, 236))	('AML', 'Disease', 'MESH:D015470', (62, 65))	('astrocytomas and oligodendroglioma', 'Disease', 'MESH:D009837', (67, 101))	('AML', 'Disease', (62, 65))	('AML', 'Phenotype', 'HP:0004808', (62, 65))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('astrocytoma', 'Phenotype', 'HP:0009592', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumors', 'Disease', (176, 182))	('AML', 'Disease', 'MESH:D015470', (195, 198))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('IDH1/2', 'Gene', '3417;3418', (215, 221))	('AML', 'Disease', (195, 198))
80736	31727977	We and others have previously shown that IDH mutation in gliomas leads to loss of insulation between topological domains and aberrant gene activation.	('IDH', 'Gene', (41, 44))	('insulation between topological domains', 'MPA', (82, 120))	('IDH', 'Gene', '3417', (41, 44))	('loss', 'NegReg', (74, 78))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('mutation', 'Var', (45, 53))	('gliomas', 'Disease', (57, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
80737	31727977	Whether there are also three-dimensional chromatin interactions that are common across all IDH1/2 mutant cancers remains to be explored.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('IDH1/2', 'Gene', (91, 97))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mutant', 'Var', (98, 104))	('IDH1/2', 'Gene', '3417;3418', (91, 97))
80739	31727977	Here we show that tumors with IDH1/2 mutations can still be distinguished based on the tissue of origin suggesting that IDH1/2 mutation induced methylation acts on the background of developmental epigenetic changes.	('IDH1/2', 'Gene', '3417;3418', (120, 126))	('mutation', 'Var', (127, 135))	('IDH1/2', 'Gene', (30, 36))	('IDH1/2', 'Gene', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('methylation', 'MPA', (144, 155))	('IDH1/2', 'Gene', '3417;3418', (30, 36))
80740	31727977	In addition to previously described DNA hypermethylation phenotype, IDH1/2 mutant tumors show surprisingly high level of DNA hypomethylation, which is particularly prominent across gene promoters.	('IDH1/2', 'Gene', '3417;3418', (68, 74))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('IDH1/2', 'Gene', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mutant', 'Var', (75, 81))	('DNA hypomethylation', 'MPA', (121, 140))
80741	31727977	In striking contrast, DNA hypermethylation predominantly affects gene body regions and enhancers across all cancers; with exception of enhancers involved in terminal cell and tissue differentiation, which remain unmethylated.	('enhancers across all cancers', 'Disease', (87, 115))	('affects', 'Reg', (57, 64))	('enhancers across all cancers', 'Disease', 'MESH:D009369', (87, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('hypermethylation', 'Var', (26, 42))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))
80742	31727977	This suggests that the CpG hypermethylator phenotype induced by IDH1/2 mutations affects predominantly non-promoter CpG islands with enhancer activity.	('IDH1/2', 'Gene', '3417;3418', (64, 70))	('mutations', 'Var', (71, 80))	('enhancer', 'PosReg', (133, 141))	('IDH1/2', 'Gene', (64, 70))
80750	31727977	All DNA methylation profiles across cancer types were analyzed together regardless of the mutated IDH1 or IDH2 gene, or mutation hotspot.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('mutated', 'Var', (90, 97))	('cancer', 'Disease', (36, 42))	('IDH2', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('IDH1', 'Gene', (98, 102))	('IDH2', 'Gene', '3418', (106, 110))	('IDH1', 'Gene', '3417', (98, 102))
80756	31727977	The InteractiVenn online tool was used to generate Venn diagrams that display both the overlapping and unique hypermethylated or hypomethylated probes between the six tumor types, using default settings.	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('hypomethylated', 'Var', (129, 143))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))	('hypermethylated', 'Var', (110, 125))
80758	31727977	This resulted in lists of probes either commonly hypomethylated or commonly hypermethylated across tumor types.	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('hypomethylated', 'Var', (49, 63))
80759	31727977	The setdiff function then allowed for identification of probes that were uniquely hypomethylated or uniquely hypermethylated for each tumor type.	('hypermethylated', 'Var', (109, 124))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('hypomethylated', 'Var', (82, 96))	('tumor', 'Disease', (134, 139))
80765	31727977	IDH mutated astrocytomas were compared with IDH wild-type glioblastomas (GBM, n = 20), which included samples from a Classic subtype (RTKII, n = 10) and Mesenchymal subtype (n = 10).	('mutated', 'Var', (4, 11))	('astrocytomas', 'Disease', (12, 24))	('IDH', 'Gene', (0, 3))	('GBM', 'Disease', (73, 76))	('IDH', 'Gene', '3417', (0, 3))	('glioblastomas', 'Phenotype', 'HP:0012174', (58, 71))	('glioblastoma', 'Phenotype', 'HP:0012174', (58, 70))	('GBM', 'Disease', 'MESH:D005909', (73, 76))	('IDH', 'Gene', (44, 47))	('glioblastomas', 'Disease', 'MESH:D005909', (58, 71))	('astrocytomas', 'Disease', 'MESH:D001254', (12, 24))	('IDH', 'Gene', '3417', (44, 47))	('GBM', 'Phenotype', 'HP:0012174', (73, 76))	('astrocytoma', 'Phenotype', 'HP:0009592', (12, 23))	('glioblastomas', 'Disease', (58, 71))
80772	31727977	Identified tumor specific hyper- and hypomethylated probes for IDH mutated tumors were then separated into gene body regions, TSS regions, and enhancer regions using the UCSC gene region information provided for each probe by Illumina.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('IDH', 'Gene', (63, 66))	('tumor', 'Disease', (11, 16))	('IDH', 'Gene', '3417', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('hypomethylated', 'Var', (37, 51))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', (75, 80))
80848	26022204	Recent efforts towards molecular characterization have identified a subset of biliary patients that have HER2/neu amplification or mutation.	('amplification', 'Var', (114, 127))	('HER2/neu', 'Gene', '2064', (105, 113))	('biliary', 'Disease', (78, 85))	('patients', 'Species', '9606', (86, 94))	('HER2/neu', 'Gene', (105, 113))	('mutation', 'Var', (131, 139))
80849	26022204	HER2/neu amplification is associated with response to HER2/neu-directed therapy in breast and gastric cancers.	('gastric cancers', 'Phenotype', 'HP:0012126', (94, 109))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('amplification', 'Var', (9, 22))	('HER2/neu', 'Gene', '2064', (54, 62))	('HER2/neu', 'Gene', (54, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('HER2/neu', 'Gene', '2064', (0, 8))	('breast and gastric cancers', 'Disease', 'MESH:D013274', (83, 109))	('associated', 'Reg', (26, 36))	('HER2/neu', 'Gene', (0, 8))
80855	26022204	One patient had HER2/neu mutation and experienced a mixed response after lapatinib therapy.	('lapatinib', 'Chemical', 'MESH:D000077341', (73, 82))	('mutation', 'Var', (25, 33))	('patient', 'Species', '9606', (4, 11))	('HER2/neu', 'Gene', '2064', (16, 24))	('HER2/neu', 'Gene', (16, 24))
80858	26022204	The cholangiocarcinoma cases treated in this series had a higher proportion of HER2/neu mutations, and no radiological responses were seen in these patients despite HER2/neu-directed therapy.	('HER2/neu', 'Gene', (79, 87))	('HER2/neu', 'Gene', (165, 173))	('patients', 'Species', '9606', (148, 156))	('HER2/neu', 'Gene', '2064', (165, 173))	('mutations', 'Var', (88, 97))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (4, 22))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (4, 22))	('HER2/neu', 'Gene', '2064', (79, 87))	('cholangiocarcinoma', 'Disease', (4, 22))
80859	26022204	HER2/neu blockade is a promising treatment strategy for gallbladder cancer patients with gene amplification and deserves further exploration in a multi-center study.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('gene amplification', 'Var', (89, 107))	('gallbladder cancer', 'Disease', (56, 74))	('gallbladder cancer', 'Disease', 'MESH:D005706', (56, 74))	('patients', 'Species', '9606', (75, 83))	('HER2/neu', 'Gene', '2064', (0, 8))	('HER2/neu', 'Gene', (0, 8))
80862	26022204	An estimated 12-15 % of gallbladder cancers have HER2/neu amplification or protein overexpression using commonly accepted criteria for positivity.	('gallbladder cancers', 'Disease', (24, 43))	('HER2/neu', 'Gene', (49, 57))	('protein', 'MPA', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('gallbladder cancers', 'Disease', 'MESH:D005706', (24, 43))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('HER2/neu', 'Gene', '2064', (49, 57))	('amplification', 'Var', (58, 71))
80864	26022204	HER2/neu mutation or amplification has also been reported in cholangiocarcinoma.	('mutation', 'Var', (9, 17))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('reported', 'Reg', (49, 57))	('HER2/neu', 'Gene', '2064', (0, 8))	('amplification', 'Var', (21, 34))	('cholangiocarcinoma', 'Disease', (61, 79))	('HER2/neu', 'Gene', (0, 8))
80868	26022204	The overexpression and amplification of HER2/neu has also been demonstrated in gastricesophageal and endometrial cancer, and in these tumors, it is also usually associated with a worse prognosis.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('gastricesophageal', 'Disease', (79, 96))	('associated', 'Reg', (161, 171))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('amplification', 'Var', (23, 36))	('HER2/neu', 'Gene', '2064', (40, 48))	('HER2/neu', 'Gene', (40, 48))	('endometrial cancer', 'Disease', (101, 119))	('endometrial cancer', 'Phenotype', 'HP:0012114', (101, 119))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('overexpression', 'PosReg', (4, 18))	('endometrial cancer', 'Disease', 'MESH:D016889', (101, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
80883	26022204	The 46 genes in the panel for detection of targetable mutations included the following: AKT1, BRAF, FGFR1, GNAS, IDH1, FGFR2, KRAS, NRAS, PIK3CA, MET, RET, EGFR, JAK2, MPL, PDGFRA, PTEN, TP53, FGFR3, FLT3, KIT, ERBB2, ABL1, HNF1A, HRAS, ATM, RB1, CDH1, SMAD4, STK11, ALK, SRC, SMARCB1, VHL, MLH1, CTNNB1, KDR, FBXW7, APC, CSF1R, NPM1, SMO, ERBB4, CDKN2A, NOTCH1, JAK3, and PTPN11.	('IDH1', 'Gene', '3417', (113, 117))	('ALK', 'Gene', '238', (267, 270))	('PDGFRA', 'Gene', '5156', (173, 179))	('SRC', 'Gene', (272, 275))	('APC', 'Disease', (317, 320))	('FBXW7', 'Gene', (310, 315))	('PTEN', 'Gene', '5728', (181, 185))	('VHL', 'Gene', '7428', (286, 289))	('NRAS', 'Gene', '4893', (132, 136))	('MPL', 'Gene', (168, 171))	('RB1', 'Gene', (242, 245))	('NOTCH1', 'Gene', '4851', (355, 361))	('SMO', 'Gene', '6608', (335, 338))	('KDR', 'Gene', '3791', (305, 308))	('JAK2', 'Gene', '3717', (162, 166))	('FGFR1', 'Gene', (100, 105))	('RB1', 'Gene', '5925', (242, 245))	('SMO', 'Gene', (335, 338))	('KRAS', 'Gene', '3845', (126, 130))	('ERBB2', 'Gene', (211, 216))	('GNAS', 'Gene', '2778', (107, 111))	('NPM1', 'Gene', (329, 333))	('FGFR3', 'Gene', '2261', (193, 198))	('PTEN', 'Gene', (181, 185))	('PIK3CA', 'Gene', '5290', (138, 144))	('KDR', 'Gene', (305, 308))	('TP53', 'Gene', (187, 191))	('NOTCH1', 'Gene', (355, 361))	('ALK', 'Gene', (267, 270))	('PTPN11', 'Gene', '5781', (373, 379))	('EGFR', 'Gene', '1956', (156, 160))	('mutations', 'Var', (54, 63))	('STK11', 'Gene', '6794', (260, 265))	('PIK3CA', 'Gene', (138, 144))	('NPM1', 'Gene', '4869', (329, 333))	('SMAD4', 'Gene', '4089', (253, 258))	('BRAF', 'Gene', '673', (94, 98))	('CDH1', 'Gene', '999', (247, 251))	('TP53', 'Gene', '7157', (187, 191))	('HNF1A', 'Gene', '6927', (224, 229))	('JAK3', 'Gene', '3718', (363, 367))	('HRAS', 'Gene', (231, 235))	('GNAS', 'Gene', (107, 111))	('CDH1', 'Gene', (247, 251))	('NRAS', 'Gene', (132, 136))	('FGFR3', 'Gene', (193, 198))	('HNF1A', 'Gene', (224, 229))	('EGFR', 'Gene', (156, 160))	('ABL1', 'Gene', (218, 222))	('SRC', 'Gene', '6714', (272, 275))	('SMARCB1', 'Gene', (277, 284))	('CSF1R', 'Gene', '1436', (322, 327))	('ATM', 'Gene', '472', (237, 240))	('STK11', 'Gene', (260, 265))	('MPL', 'Gene', '4352', (168, 171))	('SMAD4', 'Gene', (253, 258))	('PTPN11', 'Gene', (373, 379))	('ABL1', 'Gene', '25', (218, 222))	('APC', 'Disease', 'MESH:D011125', (317, 320))	('RET', 'Gene', '5979', (151, 154))	('ERBB4', 'Gene', '2066', (340, 345))	('MLH1', 'Gene', (291, 295))	('JAK3', 'Gene', (363, 367))	('ATM', 'Gene', (237, 240))	('BRAF', 'Gene', (94, 98))	('RET', 'Gene', (151, 154))	('MLH1', 'Gene', '4292', (291, 295))	('FLT3', 'Gene', (200, 204))	('HRAS', 'Gene', '3265', (231, 235))	('KRAS', 'Gene', (126, 130))	('FBXW7', 'Gene', '55294', (310, 315))	('CDKN2A', 'Gene', (347, 353))	('FGFR2', 'Gene', (119, 124))	('FLT3', 'Gene', '2322', (200, 204))	('IDH1', 'Gene', (113, 117))	('SMARCB1', 'Gene', '6598', (277, 284))	('CDKN2A', 'Gene', '1029', (347, 353))	('JAK2', 'Gene', (162, 166))	('ERBB2', 'Gene', '2064', (211, 216))	('CSF1R', 'Gene', (322, 327))	('PDGFRA', 'Gene', (173, 179))	('FGFR1', 'Gene', '2260', (100, 105))	('CTNNB1', 'Gene', (297, 303))	('VHL', 'Gene', (286, 289))	('ERBB4', 'Gene', (340, 345))	('AKT1', 'Gene', '207', (88, 92))	('CTNNB1', 'Gene', '1499', (297, 303))	('AKT1', 'Gene', (88, 92))	('FGFR2', 'Gene', '2263', (119, 124))
80898	26022204	One patient who received lapatinib had a mixed response; this patient had a HER2/neu mutation V777L.	('lapatinib', 'Chemical', 'MESH:D000077341', (25, 34))	('HER2/neu', 'Gene', (76, 84))	('V777L', 'Var', (94, 99))	('patient', 'Species', '9606', (62, 69))	('patient', 'Species', '9606', (4, 11))	('V777L', 'Mutation', 'rs121913471', (94, 99))	('HER2/neu', 'Gene', '2064', (76, 84))
80899	26022204	All other cases had HER2/neu amplification or overexpression.	('HER2/neu', 'Gene', (20, 28))	('overexpression', 'PosReg', (46, 60))	('amplification', 'Var', (29, 42))	('HER2/neu', 'Gene', '2064', (20, 28))
80900	26022204	In all these cases, trastuzumab was associated with partial response (n = 4), stable disease (n = 3), or complete response (n = 1).	('partial response', 'CPA', (52, 68))	('trastuzumab', 'Chemical', 'MESH:D000068878', (20, 31))	('stable disease', 'Disease', (78, 92))	('complete', 'Disease', (105, 113))	('trastuzumab', 'Var', (20, 31))
80907	26022204	Two patients had HER2/neu mutations (V777L and S310F) while the others had amplification using FISH or NGS (Table 3).	('V777L', 'Mutation', 'rs121913471', (37, 42))	('S310F', 'Var', (47, 52))	('V777L', 'Var', (37, 42))	('S310F', 'Mutation', 'rs1057519816', (47, 52))	('HER2/neu', 'Gene', '2064', (17, 25))	('patients', 'Species', '9606', (4, 12))	('HER2/neu', 'Gene', (17, 25))
80911	26022204	HER2/neu gene is a key driver of tumorigenesis and its overexpression as a result of gene amplification is a critical target for therapy in breast cancer.	('overexpression', 'PosReg', (55, 69))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('HER2/neu', 'Gene', '2064', (0, 8))	('gene amplification', 'Var', (85, 103))	('HER2/neu', 'Gene', (0, 8))
80921	26022204	In our retrospective series, the criteria for HER2/neu positivity were stringent and included 3+ protein expression on immunohistochemistry, FISH ratio higher than 2.2 or HER2/neu genetic aberration in a Clinical Laboratory Improvement Amendment (CLIA) compliant laboratory.	('genetic aberration', 'Var', (180, 198))	('HER2/neu', 'Gene', '2064', (46, 54))	('CLIA', 'Disease', (247, 251))	('HER2/neu', 'Gene', (46, 54))	('HER2/neu', 'Gene', '2064', (171, 179))	('HER2/neu', 'Gene', (171, 179))	('CLIA', 'Disease', 'None', (247, 251))
80923	26022204	In gastric cancer, the trastuzumab for gastric adenocarcinoma (ToGA) trial established the benefit of trastuzumab in combination with a fluoropyrimidine plus cisplatin in a randomized phase 3 trial of gastric cancer patients with overexpression or gene amplification of HER2/neu.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (201, 215))	('gene amplification', 'Var', (248, 266))	('fluoropyrimidine', 'Chemical', '-', (136, 152))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (39, 61))	('trastuzumab', 'Chemical', 'MESH:D000068878', (23, 34))	('trastuzumab', 'Chemical', 'MESH:D000068878', (102, 113))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('HER2/neu', 'Gene', '2064', (270, 278))	('gastric cancer', 'Phenotype', 'HP:0012126', (201, 215))	('cisplatin', 'Chemical', 'MESH:D002945', (158, 167))	('overexpression', 'PosReg', (230, 244))	('patients', 'Species', '9606', (216, 224))	('gastric cancer', 'Disease', (3, 17))	('gastric adenocarcinoma', 'Disease', (39, 61))	('gastric cancer', 'Disease', (201, 215))	('HER2/neu', 'Gene', (270, 278))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
80925	26022204	Although the number of cases in this retrospective review is limited, to our knowledge, this is the largest reported case series of gallbladder cancer with HER2/neu amplification or overexpression treated with targeted therapy.	('HER2/neu', 'Gene', '2064', (156, 164))	('HER2/neu', 'Gene', (156, 164))	('gallbladder cancer', 'Disease', (132, 150))	('gallbladder cancer', 'Disease', 'MESH:D005706', (132, 150))	('amplification', 'Var', (165, 178))	('overexpression', 'PosReg', (182, 196))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
80927	26022204	Only one case in our series failed to respond, this tumor had HER2/neu mutation (V777L in the kinase domain).	('HER2/neu', 'Gene', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('V777L', 'Mutation', 'rs121913471', (81, 86))	('tumor', 'Disease', (52, 57))	('V777L in', 'Var', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('HER2/neu', 'Gene', '2064', (62, 70))
80936	26022204	However, to our knowledge this is the first report of HER2/neu amplification as a mechanism of resistance to FGFR inhibitors.	('amplification', 'Var', (63, 76))	('HER2/neu', 'Gene', '2064', (54, 62))	('HER2/neu', 'Gene', (54, 62))
80939	26022204	Two of these cases with cholangiocarcinoma had HER2/neu mutations, which are not known to be responsive to trastuzumab, but may potentially respond to tyrosine kinase inhibitors like lapatinib, neratinib, and canertinib.	('cholangiocarcinoma', 'Disease', (24, 42))	('mutations', 'Var', (56, 65))	('respond', 'Reg', (140, 147))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (24, 42))	('tyrosine kinase inhibitors', 'MPA', (151, 177))	('HER2/neu', 'Gene', '2064', (47, 55))	('lapatinib', 'Chemical', 'MESH:D000077341', (183, 192))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (24, 42))	('trastuzumab', 'Chemical', 'MESH:D000068878', (107, 118))	('canertinib', 'Chemical', 'MESH:C420268', (209, 219))	('HER2/neu', 'Gene', (47, 55))	('neratinib', 'Chemical', 'MESH:C487932', (194, 203))
80940	26022204	HER2/neu-targeted therapy has also not proven to be effective despite the presence of gene amplification in diseases like colon and pancreas cancers.	('colon and pancreas cancers', 'Disease', 'MESH:D010190', (122, 148))	('gene amplification', 'Var', (86, 104))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('HER2/neu', 'Gene', '2064', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('presence', 'Reg', (74, 82))	('HER2/neu', 'Gene', (0, 8))
80941	26022204	demonstrated that trastuzumab disrupts ligand-independent ErbB2/ErbB3/PI3K complexes blocking AKT signaling; when PI3K is mutated or dysfunctional, complex disruption does not inhibit AKT.	('AKT', 'Gene', '207', (94, 97))	('PI3K', 'Gene', (114, 118))	('ErbB3', 'Gene', (64, 69))	('AKT', 'Gene', '207', (184, 187))	('ErbB2', 'Gene', (58, 63))	('AKT', 'Gene', (94, 97))	('ErbB3', 'Gene', '2065', (64, 69))	('trastuzumab', 'Chemical', 'MESH:D000068878', (18, 29))	('AKT', 'Gene', (184, 187))	('ErbB2', 'Gene', '2064', (58, 63))	('blocking', 'NegReg', (85, 93))	('mutated', 'Var', (122, 129))
80942	26022204	Another possible explanation could involve the higher rate of KRAS mutations seen in intrahepatic cholangiocarcinomas as compared with gallbladder cancers, possibly mediating resistance to upstream HER2 blockade.	('KRAS', 'Gene', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('KRAS', 'Gene', '3845', (62, 66))	('gallbladder cancers', 'Disease', (135, 154))	('HER2', 'Gene', (198, 202))	('intrahepatic cholangiocarcinomas', 'Disease', (85, 117))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (98, 116))	('HER2', 'Gene', '2064', (198, 202))	('mutations', 'Var', (67, 76))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (85, 117))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('gallbladder cancers', 'Disease', 'MESH:D005706', (135, 154))
80943	26022204	In summary, HER2/neu-directed therapy is a promising avenue for patients with gallbladder cancer with gene amplification and should be further explored in an international clinical trial.	('HER2/neu', 'Gene', '2064', (12, 20))	('patients', 'Species', '9606', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('HER2/neu', 'Gene', (12, 20))	('gallbladder cancer', 'Disease', (78, 96))	('gallbladder cancer', 'Disease', 'MESH:D005706', (78, 96))	('gene amplification', 'Var', (102, 120))
80970	22805862	In a recent report, patients homozygous for the C allele of the GNB3 825C>T single nucleotide polymorphism exhibited a significantly prolonged survival compared with patients heterozygous for this polymorphism or lacking the C allele.	('GNB3', 'Gene', '2784', (64, 68))	('survival', 'CPA', (143, 151))	('825C>T', 'Mutation', 'rs5443', (69, 75))	('GNB3', 'Gene', (64, 68))	('patients', 'Species', '9606', (166, 174))	('patients', 'Species', '9606', (20, 28))	('825C>T single nucleotide polymorphism', 'Var', (69, 106))	('prolonged', 'PosReg', (133, 142))
81005	22805862	The overall impact of a positive lymph node on the extent of the disease is also reflected by the seventh edition, such that involvement of any lymph node results in tumor stage III.	('results in', 'Reg', (155, 165))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('involvement', 'Var', (125, 136))
81057	28719954	To our knowledge, these findings provide the first demonstration that O. viverrini infected individuals carrying several specific cytokine gene polymorphisms are susceptible to develop fibrosis and CCA.	('CCA', 'Phenotype', 'HP:0030153', (198, 201))	('polymorphisms', 'Var', (144, 157))	('fibrosis', 'Disease', 'MESH:D005355', (185, 193))	('fibrosis', 'Disease', (185, 193))	('CCA', 'Disease', (198, 201))	('develop', 'PosReg', (177, 184))	('O. viverrini', 'Species', '6198', (70, 82))	('susceptible', 'Reg', (162, 173))
81066	28719954	Gene polymorphisms affect the cytokine expression and influence inflammatory processes in response to infectious diseases and cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('infectious diseases', 'Disease', 'MESH:D003141', (102, 121))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('affect', 'Reg', (19, 25))	('infectious diseases', 'Disease', (102, 121))	('cytokine expression', 'MPA', (30, 49))	('polymorphisms', 'Var', (5, 18))	('inflammatory processes', 'CPA', (64, 86))	('influence', 'Reg', (54, 63))
81069	28719954	We now hypothesize that cytokine gene polymorphisms influence cytokine expression profiles, which in turn may result in diverse pathogenic sequelae during infection with O. viverrini.	('cytokine gene', 'Gene', (24, 37))	('O. viverrini', 'Species', '6198', (170, 182))	('infection', 'Disease', (155, 164))	('polymorphisms', 'Var', (38, 51))	('cytokine expression profiles', 'MPA', (62, 90))	('infection', 'Disease', 'MESH:D007239', (155, 164))	('influence', 'Reg', (52, 61))	('result in', 'Reg', (110, 119))
81088	28719954	Table 1 lists the PCR thermal cycling conditions and oligonucleotide primers specific for 5 cytokine gene polymorphisms, IL-1beta -511C/T, IL-6 -174G/C, IFN-gamma +874T/A, LT-alpha +252A/G, and TNF-alpha -308G/A.	('IL-1beta', 'Gene', '3553', (121, 129))	('IL-6', 'Gene', (139, 143))	('+874T/A', 'Mutation', 'rs2430561', (163, 170))	('+252A/G', 'Mutation', 'rs909253', (181, 188))	('IL-6', 'Gene', '3569', (139, 143))	('TNF-alpha', 'Gene', '7124', (194, 203))	('-174G/C', 'SUBSTITUTION', 'None', (144, 151))	('-308G/A', 'Mutation', 'rs1800629', (204, 211))	('LT-alpha', 'Gene', '4049', (172, 180))	('-174G/C', 'Var', (144, 151))	('LT-alpha', 'Gene', (172, 180))	('TNF-alpha', 'Gene', (194, 203))	('IL-1beta', 'Gene', (121, 129))	('IFN-gamma +874T/A', 'Var', (153, 170))	('-511C/T', 'Mutation', 'rs1143634', (130, 137))
81096	28719954	TNF-alpha production was significantly higher in CCA and APF+ groups compared with APF-.	('TNF-alpha', 'Gene', (0, 9))	('higher', 'PosReg', (39, 45))	('TNF-alpha', 'Gene', '7124', (0, 9))	('CCA', 'Phenotype', 'HP:0030153', (49, 52))	('APF+', 'Var', (57, 61))	('CCA', 'Disease', (49, 52))
81098	28719954	Differences were not apparent among the groups for 6 other cytokines, IL-2, IL-4, IL-5, IL-8, IL-10, and IL-12p70.	('IL-10', 'Gene', (94, 99))	('IL-5', 'Gene', '3567', (82, 86))	('IL-4', 'Gene', '3565', (76, 80))	('IL-5', 'Gene', (82, 86))	('IL-8', 'Gene', (88, 92))	('IL-12p70', 'Var', (105, 113))	('IL-2', 'Gene', '3558', (70, 74))	('IL-10', 'Gene', '3586', (94, 99))	('IL-2', 'Gene', (70, 74))	('IL-4', 'Gene', (76, 80))	('IL-8', 'Gene', '3576', (88, 92))
81099	28719954	Overall comparison regardless of CCA or non-CCA groups did not reveal significant differences in levels of cytokines among gene polymorphisms except for LT-alpha, where net cytokine production in LT-alpha +252A/G heterozygous (AG) and homozygous (GG) variants were significantly elevated compared to the wild type (Fig.	('net cytokine production', 'MPA', (169, 192))	('LT-alpha', 'Gene', '4049', (153, 161))	('variants', 'Var', (251, 259))	('CCA', 'Phenotype', 'HP:0030153', (33, 36))	('LT-alpha', 'Gene', (153, 161))	('LT-alpha', 'Gene', '4049', (196, 204))	('LT-alpha', 'Gene', (196, 204))	('+252A/G', 'Mutation', 'rs909253', (205, 212))	('elevated', 'PosReg', (279, 287))	('CCA', 'Phenotype', 'HP:0030153', (44, 47))
81100	28719954	However, when subdividing into CCA and non-CCA groups (APF- and APF+), LT-alpha +254A/G heterozygous (AG), and homozygous (GG) variants showed significantly higher levels of cytokines than the wild type in CCA group; 2.35-fold and 2.24-fold, respectively.	('variants', 'Var', (127, 135))	('CCA', 'Phenotype', 'HP:0030153', (206, 209))	('levels of cytokines', 'MPA', (164, 183))	('LT-alpha', 'Gene', (71, 79))	('LT-alpha', 'Gene', '4049', (71, 79))	('CCA', 'Phenotype', 'HP:0030153', (31, 34))	('higher', 'PosReg', (157, 163))	('CCA', 'Phenotype', 'HP:0030153', (43, 46))	('+254A/G', 'Mutation', 'rs148093456', (80, 87))
81102	28719954	Table 4 presents the genotypes and allele distribution of IL-1beta -511C/T, IL-6 -174G/C, IFN-gamma+874T/A, LT-alpha +254A/G, and TNF-alpha-308G/A polymorphisms in the participants, those with APF-, APF+, and CCA.	('IL-6', 'Gene', (76, 80))	('IL-6', 'Gene', '3569', (76, 80))	('-174G/C', 'Var', (81, 88))	('IL-1beta', 'Gene', '3553', (58, 66))	('IFN-gamma+874T/A', 'Gene', (90, 106))	('-174G/C', 'SUBSTITUTION', 'None', (81, 88))	('participants', 'Species', '9606', (168, 180))	('+254A/G', 'Mutation', 'rs148093456', (117, 124))	('TNF-alpha-308G/A', 'Var', (130, 146))	('IL-1beta', 'Gene', (58, 66))	('LT-alpha', 'Gene', (108, 116))	('-511C/T', 'Mutation', 'rs1143634', (67, 74))	('LT-alpha', 'Gene', '4049', (108, 116))	('CCA', 'Phenotype', 'HP:0030153', (209, 212))
81103	28719954	Comparison among groups did not reveal significant differences in the genotype or allele frequencies for IL-1beta-511C/T, LT-alpha +252A/G, and TNF-alpha-308G/A.	('TNF-alpha-308G/A', 'Var', (144, 160))	('LT-alpha', 'Gene', '4049', (122, 130))	('LT-alpha', 'Gene', (122, 130))	('+252A/G', 'Mutation', 'rs909253', (131, 138))	('IL-1beta-511C/T', 'Gene', (105, 120))
81104	28719954	However, comparing the IL6 -174G/C genotypes between the CCA and non-CCA (APF- or APF+) groups revealed that the presence of heterozygous (GC) genotype associated with CCA (OR=2.35 and 2.95 for APF- vs CCA and APF+ vs CCA, respectively).	('CCA', 'Phenotype', 'HP:0030153', (168, 171))	('CCA', 'Phenotype', 'HP:0030153', (218, 221))	('IL6', 'Gene', (23, 26))	('CCA', 'Phenotype', 'HP:0030153', (57, 60))	('CCA', 'Phenotype', 'HP:0030153', (202, 205))	('CCA', 'Phenotype', 'HP:0030153', (69, 72))	('CCA', 'Disease', (168, 171))	('presence', 'Var', (113, 121))	('GC', 'Gene', (139, 141))	('associated with', 'Reg', (152, 167))	('IL6', 'Gene', '3569', (23, 26))	('-174G/C', 'Mutation', 'rs1800795', (27, 34))
81107	28719954	In the case of TNF-alpha -308G/A polymorphism, only the TNF-alpha -308 A allele appeared to be associated with CCA (OR=1.61 and OR=1.5 in APF- vs CCA and in APF+ vs CCA, respectively).	('TNF-alpha', 'Gene', '7124', (56, 65))	('CCA', 'Disease', (111, 114))	('-308G/A', 'Mutation', 'rs1800629', (25, 32))	('CCA', 'Phenotype', 'HP:0030153', (165, 168))	('TNF-alpha', 'Gene', (56, 65))	('CCA', 'Phenotype', 'HP:0030153', (111, 114))	('TNF-alpha', 'Gene', '7124', (15, 24))	('polymorphism', 'Var', (33, 45))	('CCA', 'Phenotype', 'HP:0030153', (146, 149))	('TNF-alpha', 'Gene', (15, 24))	('associated', 'Reg', (95, 105))
81117	28719954	Synonymous SNPs do not affect the protein sequence, but can still affect the protein conformation such as the silent polymorphism in the MDR1 gene changes substrate specificity.	('MDR1', 'Gene', (137, 141))	('affect', 'Reg', (66, 72))	('silent polymorphism', 'Var', (110, 129))	('MDR1', 'Gene', '5243', (137, 141))	('protein conformation', 'MPA', (77, 97))	('changes', 'Reg', (147, 154))	('substrate specificity', 'MPA', (155, 176))	('SNPs', 'Var', (11, 15))
81118	28719954	Nonsynonymous SNPs change the amino acid sequence of protein and subsequent protein function as shown in cystic fibrosis patients.	('change', 'Reg', (19, 25))	('amino acid sequence of protein', 'MPA', (30, 60))	('cystic fibrosis', 'Disease', (105, 120))	('Nonsynonymous SNPs', 'Var', (0, 18))	('cystic fibrosis', 'Disease', 'MESH:D003550', (105, 120))	('protein function', 'MPA', (76, 92))	('patients', 'Species', '9606', (121, 129))
81119	28719954	For SNPs in our liver fluke associated CCA, we report here that certain cytokine gene polymorphisms affect proinflammatory cytokine production.	('affect', 'Reg', (100, 106))	('cytokine gene', 'Gene', (72, 85))	('polymorphisms', 'Var', (86, 99))	('proinflammatory cytokine production', 'MPA', (107, 142))	('liver fluke', 'Species', '6192', (16, 27))	('CCA', 'Phenotype', 'HP:0030153', (39, 42))
81120	28719954	Accordingly, we hypothesized that cytokine gene polymorphisms may underline variations in inflammatory cytokine response in response to liver fluke infection and downstream biliary tract inflammation and cholangiocarcinogenesis.	('liver fluke infection', 'Disease', (136, 157))	('biliary tract inflammation and cholangiocarcinogenesis', 'Disease', 'MESH:D007249', (173, 227))	('underline variations', 'Reg', (66, 86))	('polymorphisms', 'Var', (48, 61))	('liver fluke infection', 'Disease', 'MESH:D017093', (136, 157))	('inflammatory cytokine response', 'MPA', (90, 120))	('cytokine gene', 'Gene', (34, 47))
81121	28719954	The gene polymorphisms IL-1beta -511C/T, IL6 -174G/C, LT-alpha +252A/G, and TNF-alpha-308G/A generated the high-producer phenotypes, whereas IFN-gamma+874T/A exhibited a low-production phenotype.	('IL6', 'Gene', '3569', (41, 44))	('TNF-alpha-308G/A', 'Var', (76, 92))	('LT-alpha', 'Gene', '4049', (54, 62))	('IL-1beta', 'Gene', (23, 31))	('IL-1beta', 'Gene', '3553', (23, 31))	('LT-alpha', 'Gene', (54, 62))	('IL6', 'Gene', (41, 44))	('+252A/G', 'Mutation', 'rs909253', (63, 70))	('-511C/T', 'Mutation', 'rs1143634', (32, 39))	('high-producer phenotypes', 'MPA', (107, 131))	('-174G/C', 'Mutation', 'rs1800795', (45, 52))
81122	28719954	In agreement with these reports, both LT-alpha +252A/G and TNF-alpha-308G/A heterozygous and homozygous variants showed significant higher levels of cytokine than the wild type.	('higher', 'PosReg', (132, 138))	('+252A/G', 'Mutation', 'rs909253', (47, 54))	('men', 'Species', '9606', (8, 11))	('LT-alpha', 'Gene', '4049', (38, 46))	('TNF-alpha-308G/A', 'Var', (59, 75))	('LT-alpha', 'Gene', (38, 46))	('levels of cytokine', 'MPA', (139, 157))
81123	28719954	Similarly, both IL-1beta -511C/T and IL-6 -174G/C variants produced more cytokines than the wild type, even though the difference was not statistically significant.	('cytokines', 'MPA', (73, 82))	('IL-1beta', 'Gene', (16, 24))	('IL-6', 'Gene', (37, 41))	('-511C/T', 'Mutation', 'rs1143634', (25, 32))	('IL-1beta', 'Gene', '3553', (16, 24))	('IL-6', 'Gene', '3569', (37, 41))	('variants', 'Var', (50, 58))	('-174G/C', 'Mutation', 'rs1800795', (42, 49))
81127	28719954	The present findings revealed that both heterozygous (GC) and homozygous (CC) variant of IL6 -174G>C polymorphisms were associated with cholangiocarcinogenesis in this Thai population.	('-174G>C', 'Mutation', 'rs1800795', (93, 100))	('associated', 'Reg', (120, 130))	('cholangiocarcinogenesis', 'Disease', 'None', (136, 159))	('IL6', 'Gene', (89, 92))	('cholangiocarcinogenesis', 'Disease', (136, 159))	('polymorphisms', 'Var', (101, 114))	('IL6', 'Gene', '3569', (89, 92))
81128	28719954	Given that the heterozygous (GC) and homozygous (CC) variants of IL6 -174G>C are high producer phenotypes, these gene polymorphisms might explain elevated levels of IL-6 during in CCA, as reported earlier.	('CCA', 'Disease', (180, 183))	('levels', 'MPA', (155, 161))	('-174G>C', 'Mutation', 'rs1800795', (69, 76))	('elevated', 'PosReg', (146, 154))	('IL6', 'Gene', '3569', (65, 68))	('IL6', 'Gene', (65, 68))	('IL-6', 'Gene', (165, 169))	('CCA', 'Phenotype', 'HP:0030153', (180, 183))	('IL-6', 'Gene', '3569', (165, 169))	('variants', 'Var', (53, 61))
81130	28719954	In likely fashion, the present findings revealed that the A allele of TNF-alpha -308G/A polymorphism associated with CCA.	('TNF-alpha', 'Gene', '7124', (70, 79))	('TNF-alpha', 'Gene', (70, 79))	('-308G/A', 'Mutation', 'rs1800629', (80, 87))	('CCA', 'Phenotype', 'HP:0030153', (117, 120))	('associated', 'Reg', (101, 111))	('polymorphism', 'Var', (88, 100))	('CCA', 'Disease', (117, 120))
81133	28719954	Here, IFN-gamma+874T>A heterozygous (TA) and homozygous (AA) variants associated with fibrosis, and the IFN-gamma+874T>A homozygous (AA) variant was also associated with CCA.	('variants', 'Var', (61, 69))	('IFN-gamma', 'Gene', '3458', (104, 113))	('CCA', 'Disease', (170, 173))	('IFN-gamma', 'Gene', (104, 113))	('associated with', 'Reg', (70, 85))	('IFN-gamma', 'Gene', '3458', (6, 15))	(', IFN-gamma', 'Gene', '3458', (4, 15))	('fibrosis', 'Disease', 'MESH:D005355', (86, 94))	('fibrosis', 'Disease', (86, 94))	('CCA', 'Phenotype', 'HP:0030153', (170, 173))	('associated', 'Reg', (154, 164))	('IFN-gamma', 'Gene', (6, 15))
81134	28719954	As noted, these variants produce less IFN-gamma than the TT (wild type) genotype.	('IFN-gamma', 'Gene', (38, 47))	('variants', 'Var', (16, 24))	('less', 'NegReg', (33, 37))	('IFN-gamma', 'Gene', '3458', (38, 47))
81215	33726850	Importantly, a variant of CD44 could stabilize xCT (a cystine-glutamate transporter) linked to the ROS defense system via cystine uptake-mediated glutathione synthesis.	('ROS', 'Chemical', 'MESH:D017382', (99, 102))	('variant', 'Var', (15, 22))	('glutamate', 'Chemical', 'MESH:D018698', (62, 71))	('stabilize', 'Reg', (37, 46))	('glutathione', 'Chemical', 'MESH:D005978', (146, 157))	('CD44', 'Gene', (26, 30))	('cystine', 'Chemical', 'MESH:D003553', (54, 61))	('cystine uptake-mediated glutathione synthesis', 'MPA', (122, 167))	('cystine', 'Chemical', 'MESH:D003553', (122, 129))
81231	33726850	KKU-213 is a mixed (papillary and non-papillary) cholangiocarcinoma which was established from a 58-year-old male patient, whereas KKU-100 is a poorly differentiated cholangiocarcinoma established from a 65-year-old female patient.	('KKU-213', 'Var', (0, 7))	('cholangiocarcinoma', 'Disease', (49, 67))	('cholangiocarcinoma', 'Disease', (166, 184))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (49, 67))	('patient', 'Species', '9606', (223, 230))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (49, 67))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (166, 184))	('patient', 'Species', '9606', (114, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (166, 184))
81264	33726850	Previously, we demonstrated that 95% of CCA patients express CD44v9 while 43% of these patients have high expression.	('CCA', 'Phenotype', 'HP:0030153', (40, 43))	('patients', 'Species', '9606', (44, 52))	('CCA', 'Disease', (40, 43))	('CD44v9', 'Var', (61, 67))	('patients', 'Species', '9606', (87, 95))
81265	33726850	Immunohistochemical staining of CD44v9 showed that the level decreased with a combination of CIS and SSZ when compared with CIS alone (Fig.	('SSZ', 'Chemical', 'MESH:D012460', (101, 104))	('CD44v9', 'Gene', (32, 38))	('level', 'MPA', (55, 60))	('decreased', 'NegReg', (61, 70))	('CIS', 'Var', (93, 96))
81267	33726850	The ratio of CD44v9 to CK-19 in a combination of CIS and SSZ was significantly less than CIS alone (Fig.	('SSZ', 'Chemical', 'MESH:D012460', (57, 60))	('less', 'NegReg', (79, 83))	('CD44v9', 'Var', (13, 19))	('CK-19', 'Gene', (23, 28))
81281	33726850	The relative concentration of metabolites among CIS-treated nude mice in the bad responders (n = 2) and good responders (n = 2) showed a 5-hydroxytryptophan level (10658 and 5880, respectively, p = 0.556) and p-hydroxyphenylpyruvate (8079 and 3229, respectively, p = 0.338).	('p-hydroxyphenylpyruvate', 'Chemical', 'MESH:C010590', (209, 232))	('p-hydroxyphenylpyruvate', 'MPA', (209, 232))	('10658', 'Var', (164, 169))	('nude mice', 'Species', '10090', (60, 69))	('5-hydroxytryptophan level', 'MPA', (137, 162))	('8079', 'Var', (234, 238))	('5-hydroxytryptophan', 'Chemical', 'MESH:D006916', (137, 156))
81289	33726850	Our previous report revealed a negative association of CD44v9 and oxidative stress indicator (phospho-p38MAPK) in CCA patients related to Ov infection (76%) that was higher than CCA patients with no Ov association (52%).	('higher', 'PosReg', (166, 172))	('Ov', 'Species', '6198', (138, 140))	('CCA', 'Disease', (114, 117))	('CCA', 'Phenotype', 'HP:0030153', (178, 181))	('oxidative stress indicator', 'MPA', (66, 92))	('CD44v9', 'Var', (55, 61))	('negative', 'NegReg', (31, 39))	('related', 'Reg', (127, 134))	('infection', 'Disease', (141, 150))	('infection', 'Disease', 'MESH:D007239', (141, 150))	('CCA', 'Phenotype', 'HP:0030153', (114, 117))	('oxidative stress', 'Phenotype', 'HP:0025464', (66, 82))	('Ov', 'Species', '6198', (199, 201))	('patients', 'Species', '9606', (182, 190))	('patients', 'Species', '9606', (118, 126))
81292	33726850	However, SSZ improved ROS-mediated apoptosis in CIS treatment in hepatocellular carcinoma (HCC) with high CD44v and xCT expression.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (65, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('hepatocellular carcinoma', 'Disease', (65, 89))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (65, 89))	('HCC', 'Phenotype', 'HP:0001402', (91, 94))	('SSZ', 'Chemical', 'MESH:D012460', (9, 12))	('CD44v', 'MPA', (106, 111))	('ROS-mediated', 'MPA', (22, 34))	('high', 'Var', (101, 105))	('ROS', 'Chemical', 'MESH:D017382', (22, 25))	('improved', 'PosReg', (13, 21))
81294	33726850	In addition, 5-FU resistance was seen in the upregulation of CD44v9 expression by increasing intracellular glutathione and suppressing the drug-induced production of reactive oxygen species (ROS), and SSZ enhanced the drug sensitivity of CD44v9-expressing cells in gastric cancer.	('drug sensitivity', 'CPA', (218, 234))	('gastric cancer', 'Disease', 'MESH:D013274', (265, 279))	('5-FU', 'Chemical', 'MESH:D005472', (13, 17))	('SSZ', 'Chemical', 'MESH:D012460', (201, 204))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (166, 189))	('suppressing', 'NegReg', (123, 134))	('SSZ', 'Var', (201, 204))	('gastric cancer', 'Phenotype', 'HP:0012126', (265, 279))	('drug sensitivity', 'Phenotype', 'HP:0020174', (218, 234))	('increasing', 'PosReg', (82, 92))	('intracellular glutathione', 'MPA', (93, 118))	('ROS', 'Chemical', 'MESH:D017382', (191, 194))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('CD44v9', 'Gene', (61, 67))	('enhanced', 'PosReg', (205, 213))	('upregulation', 'PosReg', (45, 57))	('glutathione', 'Chemical', 'MESH:D005978', (107, 118))	('gastric cancer', 'Disease', (265, 279))
81299	33726850	Recently, Shitara and coworkers showed a reduction of the levels of CD44v-positive cancer stem-like cells and GSH was observed, consistent with the mode of action of SSZ in CSCs.	('GSH', 'Chemical', 'MESH:D005978', (110, 113))	('SSZ', 'Chemical', 'MESH:D012460', (166, 169))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CD44v-positive', 'Var', (68, 82))	('cancer', 'Disease', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('levels', 'MPA', (58, 64))	('reduction', 'NegReg', (41, 50))
81302	33726850	Interestingly, we found an increase in quinolinate for SSZ in the presence of CIS.	('quinolinate', 'MPA', (39, 50))	('CIS', 'Var', (78, 81))	('quinolinate', 'Chemical', 'MESH:D017378', (39, 50))	('increase', 'PosReg', (27, 35))	('SSZ', 'Chemical', 'MESH:D012460', (55, 58))
81310	33726850	Compared with kynurenic acid, picolinic acid is less potent and appears to act via a different mechanism, attenuating calcium-dependent glutamate release and/or chelating endogenous zinc [-].	('calcium', 'Chemical', 'MESH:D002118', (118, 125))	('picolinic acid', 'Var', (30, 44))	('kynurenic acid', 'Chemical', 'MESH:D007736', (14, 28))	('picolinic acid', 'Chemical', 'MESH:C030614', (30, 44))	('chelating endogenous zinc [-]', 'MPA', (161, 190))	('attenuating', 'NegReg', (106, 117))	('calcium-dependent glutamate release', 'MPA', (118, 153))	('glutamate', 'Chemical', 'MESH:D018698', (136, 145))
81317	33726850	Quinolinate can enhance reactive oxygen species (ROS) formation in the tumor microenvironment by several mechanisms, including the formation of redox-active complexes with Fe2+ leading to lipid peroxidation.	('Quinolinate', 'Var', (0, 11))	('Quinolinate', 'Chemical', 'MESH:D017378', (0, 11))	('Fe2+', 'Chemical', '-', (172, 176))	('lipid', 'Chemical', 'MESH:D008055', (188, 193))	('ROS', 'Chemical', 'MESH:D017382', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('lipid peroxidation', 'MPA', (188, 206))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('enhance', 'PosReg', (16, 23))	('tumor', 'Disease', (71, 76))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (24, 47))	('iron', 'Chemical', 'MESH:D007501', (85, 89))	('redox-active', 'MPA', (144, 156))
81325	33726850	Although it was previously reported that serotonin metabolism is dysregulated in cholangiocarcinoma progression and inhibition of serotonin synthesis could suppress the growth rate of non-Ov-associated cell line in an in vivo model, blood plasma of intrahepatic CCA patients in the UK revealed the key metabolites involved in CCA progression that were orotate and orotidine in the pyrimidine pathway.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('CCA', 'Phenotype', 'HP:0030153', (326, 329))	('patients', 'Species', '9606', (266, 274))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (81, 99))	('CCA', 'Phenotype', 'HP:0030153', (262, 265))	('CCA', 'Disease', (326, 329))	('serotonin', 'Chemical', 'MESH:D012701', (130, 139))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (249, 265))	('cholangiocarcinoma', 'Disease', (81, 99))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (81, 99))	('orotidine', 'Chemical', 'MESH:C008714', (364, 373))	('growth rate of non-Ov-associated', 'CPA', (169, 201))	('serotonin', 'Chemical', 'MESH:D012701', (41, 50))	('inhibition', 'Var', (116, 126))	('suppress', 'NegReg', (156, 164))	('pyrimidine pathway', 'Pathway', (381, 399))	('pyrimidine', 'Chemical', 'MESH:C030986', (381, 391))	('dysregulated', 'Reg', (65, 77))	('Ov', 'Species', '6198', (188, 190))	('orotate', 'Chemical', 'MESH:D009963', (352, 359))	('intrahepatic CCA', 'Disease', (249, 265))
81335	33726850	CCA Cholangiocarcinoma SSZ Sulfasalazine CIS Cisplatin GEM Gemcitabine Ov Opisthorchis viverrini CD44 Cluster of differentiation 44 CD44v9 CD44 variant 9 CSCs Cancer stem-like cells ROS Reactive oxygen species GSH Glutathione NMR Nuclear magnetic resonance STOCSY Statistical total correlation spectroscopy MT and WL designed and performed experiments.	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (4, 22))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (4, 22))	('Cholangiocarcinoma', 'Disease', (4, 22))	('ROS', 'Chemical', 'MESH:D017382', (182, 185))	('CCA', 'Phenotype', 'HP:0030153', (0, 3))	('Cancer', 'Phenotype', 'HP:0002664', (159, 165))	('CCA', 'Disease', (0, 3))	('variant', 'Var', (144, 151))	('Cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('Reactive oxygen species', 'Chemical', 'MESH:D017382', (186, 209))	('GSH', 'Chemical', 'MESH:D005978', (210, 213))	('Ov', 'Species', '6198', (71, 73))	('Ov Opisthorchis', 'Phenotype', 'HP:0002179', (71, 86))	('Cancer', 'Disease', (159, 165))	('Sulfasalazine', 'Chemical', 'MESH:D012460', (27, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('GEM', 'Chemical', 'MESH:C056507', (55, 58))	('Gemcitabine', 'Chemical', 'MESH:C056507', (59, 70))	('Opisthorchis viverrini', 'Species', '6198', (74, 96))	('SSZ', 'Chemical', 'MESH:D012460', (23, 26))	('Glutathione', 'Chemical', 'MESH:D005978', (214, 225))	('Cancer', 'Disease', 'MESH:D009369', (159, 165))
81336	28301876	Autophagy inhibitor chloroquine increases sensitivity to cisplatin in QBC939 cholangiocarcinoma cells by mitochondrial ROS The tumor cells have some metabolic characteristics of the original tissues, and the metabolism of the tumor cells is closely related to autophagy.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (77, 95))	('chloroquine', 'Chemical', 'MESH:D002738', (20, 31))	('QBC939', 'CellLine', 'CVCL:6942', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('metabolic characteristics', 'CPA', (149, 174))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('ROS', 'Chemical', 'MESH:D017382', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('QBC939', 'Gene', (70, 76))	('cholangiocarcinoma', 'Disease', (77, 95))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('increases', 'PosReg', (32, 41))	('sensitivity to cisplatin', 'MPA', (42, 66))	('tumor', 'Disease', (127, 132))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (77, 95))	('mitochondrial ROS', 'Var', (105, 122))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', (226, 231))
81338	28301876	We found that QBC939 cells with cisplatin resistance had a higher capacity for glucose uptake, consumption, and lactic acid generation, and higher activity of the pentose phosphate pathway compared with HepG2 cells, and the activity of PPP was further increased after cisplatin treatment in QBC939 cells.	('activity', 'MPA', (224, 232))	('cisplatin', 'Chemical', 'MESH:D002945', (268, 277))	('HepG2', 'CellLine', 'CVCL:0027', (203, 208))	('higher', 'PosReg', (140, 146))	('cisplatin resistance', 'Var', (32, 52))	('lactic acid generation', 'MPA', (112, 134))	('lactic acid', 'Chemical', 'MESH:D019344', (112, 123))	('pentose phosphate', 'Chemical', 'MESH:D010428', (163, 180))	('QBC939', 'CellLine', 'CVCL:6942', (14, 20))	('glucose uptake', 'MPA', (79, 93))	('increased', 'PosReg', (252, 261))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('higher', 'PosReg', (59, 65))	('consumption', 'MPA', (95, 106))	('pentose phosphate pathway', 'Pathway', (163, 188))	('QBC939', 'CellLine', 'CVCL:6942', (291, 297))	('activity', 'MPA', (147, 155))	('glucose', 'Chemical', 'MESH:D005947', (79, 86))
81350	28301876	Disruption of mitochondrial functions can also increase mtROS production and induce cell death.	('ROS', 'Chemical', 'MESH:D017382', (58, 61))	('induce', 'Reg', (77, 83))	('mtROS production', 'MPA', (56, 72))	('increase', 'PosReg', (47, 55))	('cell death', 'CPA', (84, 94))	('mitochondrial functions', 'Protein', (14, 37))	('Disruption', 'Var', (0, 10))
81352	28301876	In addition, cells generating mtROS can further induce mitochondria to produce more ROS and increase the cellular REDOX imbalance.	('ROS', 'MPA', (84, 87))	('increase', 'PosReg', (92, 100))	('mtROS', 'Var', (30, 35))	('REDOX imbalance', 'Phenotype', 'HP:0025463', (114, 129))	('ROS', 'Chemical', 'MESH:D017382', (32, 35))	('mitochondria', 'MPA', (55, 67))	('cellular REDOX imbalance', 'MPA', (105, 129))	('imbalance', 'Phenotype', 'HP:0002172', (120, 129))	('ROS', 'Chemical', 'MESH:D017382', (84, 87))
81353	28301876	Therefore, mtROS is considered to be an important indicator of the REDOX balance, and elevating mtROS may be an effective approach for cancer therapy.	('ROS', 'Chemical', 'MESH:D017382', (98, 101))	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('elevating', 'Var', (86, 95))	('ROS', 'Chemical', 'MESH:D017382', (13, 16))
81361	28301876	It has been speculated that cell metabolism-mediated oxidative stress resistance may be associated with drug resistance in tumor cells, and changing the metabolism-related antioxidant capacity may inhibit tumor cell proliferation.	('cell metabolism-mediated', 'MPA', (28, 52))	('metabolism-related antioxidant capacity', 'MPA', (153, 192))	('oxidative stress', 'Phenotype', 'HP:0025464', (53, 69))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('inhibit', 'NegReg', (197, 204))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('drug resistance', 'Phenotype', 'HP:0020174', (104, 119))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('changing', 'Var', (140, 148))	('associated', 'Reg', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('drug resistance', 'MPA', (104, 119))
81380	28301876	In summary, various ways to enhance the antioxidant ability of tumor cells is closely related to the tumor drug resistance, Inhibition of autophagy may reduce the antioxidant capacity of drug resistant cells by inhibiting a variety of ways, including glucose metabolism, and increase the sensitivity of cisplatin induced death.	('reduce', 'NegReg', (152, 158))	('cisplatin', 'Chemical', 'MESH:D002945', (303, 312))	('glucose metabolism', 'CPA', (251, 269))	('glucose', 'Chemical', 'MESH:D005947', (251, 258))	('increase', 'PosReg', (275, 283))	('sensitivity', 'MPA', (288, 299))	('inhibiting', 'NegReg', (211, 221))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('drug resistance', 'Phenotype', 'HP:0020174', (107, 122))	('antioxidant capacity', 'MPA', (163, 183))	('tumor', 'Disease', (63, 68))	('autophagy', 'CPA', (138, 147))	('enhance', 'PosReg', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', (101, 106))	('antioxidant', 'MPA', (40, 51))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('Inhibition', 'Var', (124, 134))
81415	28301876	The results suggested that the capacity of exogenous ROS resistance in QBC939 cells was more than that in HepG2 cells, and impaired the antioxidant capacity of cells with H2O2 increases sensitivity to cisplatin.	('exogenous ROS resistance', 'MPA', (43, 67))	('more', 'PosReg', (88, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (201, 210))	('antioxidant capacity', 'MPA', (136, 156))	('QBC939', 'Var', (71, 77))	('sensitivity to cisplatin', 'MPA', (186, 210))	('HepG2', 'CellLine', 'CVCL:0027', (106, 111))	('H2O2', 'Chemical', 'MESH:D006861', (171, 175))	('ROS', 'Chemical', 'MESH:D017382', (53, 56))	('QBC939', 'CellLine', 'CVCL:6942', (71, 77))
81418	28301876	The basal level of GSH/GSSG in QBC939 cells was significantly higher than that in HepG2 cells.	('QBC939', 'Var', (31, 37))	('HepG2', 'CellLine', 'CVCL:0027', (82, 87))	('QBC939', 'CellLine', 'CVCL:6942', (31, 37))	('higher', 'PosReg', (62, 68))	('GSH', 'Chemical', '-', (19, 22))	('GSSG', 'Chemical', 'MESH:D019803', (23, 27))
81421	28301876	Compared with HepG2 cells, the overall ROS and mtROS increase was less in QBC939 cells treated with H2O2 (Fig 2C and 2D), indicating that QBC939 cells have a stronger antioxidant ability.	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('H2O2', 'Chemical', 'MESH:D006861', (100, 104))	('H2O2', 'Var', (100, 104))	('QBC939', 'CellLine', 'CVCL:6942', (74, 80))	('mtROS', 'MPA', (47, 52))	('antioxidant ability', 'MPA', (167, 186))	('ROS', 'Chemical', 'MESH:D017382', (49, 52))	('stronger', 'PosReg', (158, 166))	('QBC939', 'CellLine', 'CVCL:6942', (138, 144))	('increase', 'PosReg', (53, 61))	('ROS', 'MPA', (39, 42))	('HepG2', 'CellLine', 'CVCL:0027', (14, 19))	('less', 'NegReg', (66, 70))
81425	28301876	The mean values for glucose consumption and lactic acid production of QBC939 cells were significantly higher under basic condition and decreased less after cisplatin treatment than those of HepG2 cells.	('HepG2', 'CellLine', 'CVCL:0027', (190, 195))	('glucose consumption', 'Disease', 'MESH:D014397', (20, 39))	('decreased less', 'NegReg', (135, 149))	('QBC939', 'Var', (70, 76))	('lactic acid', 'Chemical', 'MESH:D019344', (44, 55))	('glucose consumption', 'Disease', (20, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (156, 165))	('higher', 'PosReg', (102, 108))	('QBC939', 'CellLine', 'CVCL:6942', (70, 76))	('lactic acid production', 'MPA', (44, 66))
81428	28301876	As shown in Fig 3C, the glucose uptake efficiency of QBC939 cells was higher than that of HepG2 cells.	('glucose', 'Chemical', 'MESH:D005947', (24, 31))	('HepG2', 'CellLine', 'CVCL:0027', (90, 95))	('QBC939', 'Var', (53, 59))	('glucose uptake', 'MPA', (24, 38))	('higher', 'PosReg', (70, 76))	('QBC939', 'CellLine', 'CVCL:6942', (53, 59))
81439	28301876	We tested the sensitivity of QBC939 cells to 2-DG or DHEA and/or combined with cisplatin (Fig 4E and 4F).	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('DHEA', 'Var', (53, 57))	('DHEA', 'Chemical', 'MESH:D003687', (53, 57))	('tested', 'Reg', (3, 9))	('2-DG', 'Chemical', 'MESH:D003847', (45, 49))	('QBC939', 'CellLine', 'CVCL:6942', (29, 35))
81451	28301876	We found that Mito-TEMPO significantly inhibited CQ induced intracellular overall ROS and mtROS, as shown in Fig 5C-5E, especially mtROS levels.	('intracellular overall ROS', 'MPA', (60, 85))	('ROS', 'Chemical', 'MESH:D017382', (92, 95))	('ROS', 'Chemical', 'MESH:D017382', (82, 85))	('inhibited', 'NegReg', (39, 48))	('CQ', 'Chemical', 'MESH:D002738', (49, 51))	('Mito-TEMPO', 'Var', (14, 24))	('mtROS', 'MPA', (131, 136))	('Mito', 'Species', '262676', (14, 18))	('mtROS', 'MPA', (90, 95))	('ROS', 'Chemical', 'MESH:D017382', (133, 136))
81457	28301876	By analyzing the apoptosis rate of combination with Mito-TEMPO, we found that Mito-TEMPO significantly decreased the sensitivity to apoptosis induced by CQ alone or combination with cisplatin (Fig 6C).	('cisplatin', 'Chemical', 'MESH:D002945', (182, 191))	('Mito-TEMPO', 'Var', (78, 88))	('decreased', 'NegReg', (103, 112))	('CQ', 'Chemical', 'MESH:D002738', (153, 155))	('Mito', 'Species', '262676', (78, 82))	('combination', 'Interaction', (165, 176))	('sensitivity to apoptosis', 'MPA', (117, 141))	('Mito', 'Species', '262676', (52, 56))
81458	28301876	It is suggested that the increase of sensitivity to CQ and cisplatin induced apoptosis may be related to the increase of mtROS in QBC939 cells, and inhibition of mtROS restrains sensitivity to apoptosis in QBC939 cells treated with CQ and cisplatin.	('sensitivity to apoptosis', 'CPA', (178, 202))	('inhibition', 'Var', (148, 158))	('ROS', 'Chemical', 'MESH:D017382', (123, 126))	('CQ', 'Chemical', 'MESH:D002738', (52, 54))	('apoptosis', 'CPA', (77, 86))	('increase', 'PosReg', (109, 117))	('QBC939', 'CellLine', 'CVCL:6942', (206, 212))	('CQ', 'Chemical', 'MESH:D002738', (232, 234))	('cisplatin', 'Chemical', 'MESH:D002945', (239, 248))	('mtROS', 'MPA', (121, 126))	('increase', 'PosReg', (25, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('QBC939', 'CellLine', 'CVCL:6942', (130, 136))	('restrains', 'NegReg', (168, 177))	('ROS', 'Chemical', 'MESH:D017382', (164, 167))
81462	28301876	These results showed that increasing mtROS may induce opening of mPTPs, leading to a lower membrane potential.	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('mPTPs', 'Gene', (65, 70))	('lower', 'NegReg', (85, 90))	('opening', 'MPA', (54, 61))	('mtROS', 'Var', (37, 42))	('membrane potential', 'MPA', (91, 109))
81469	28301876	Our study indicated that the sensitivity of QBC939 CC cells, which are derived from the liver bile duct epithelium, to cisplatin was significantly lower than that of HepG2 HCC cells (Fig 1A-1D).	('QBC939 CC', 'CellLine', 'CVCL:6942', (44, 53))	('CC', 'Phenotype', 'HP:0030153', (51, 53))	('CC', 'Phenotype', 'HP:0030153', (173, 175))	('lower', 'NegReg', (147, 152))	('HCC', 'Phenotype', 'HP:0001402', (172, 175))	('QBC939 CC', 'Var', (44, 53))	('HepG2 HCC', 'CellLine', 'CVCL:0027', (166, 175))	('sensitivity', 'MPA', (29, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))
81470	28301876	The fluorescence intensity of staining for mtROS and the GSH/GSSG ratio were significantly higher in QBC939 cells than in HepG2 cells (Figs 1E, 1F and 2B).	('GSSG', 'Chemical', 'MESH:D019803', (61, 65))	('fluorescence intensity', 'MPA', (4, 26))	('ROS', 'Chemical', 'MESH:D017382', (45, 48))	('higher', 'PosReg', (91, 97))	('HepG2', 'CellLine', 'CVCL:0027', (122, 127))	('QBC939', 'Var', (101, 107))	('QBC939', 'CellLine', 'CVCL:6942', (101, 107))	('GSH', 'Chemical', '-', (57, 60))	('GSH/GSSG', 'MPA', (57, 65))
81474	28301876	We found that glucose consumption and lactic acid production in QBC939 cells were higher than those in HepG2 cells (Fig 3A-3C), indicating that these CC cells are more dependent on glucose metabolism.	('glucose consumption', 'Disease', 'MESH:D014397', (14, 33))	('glucose consumption', 'Disease', (14, 33))	('higher', 'PosReg', (82, 88))	('lactic acid', 'Chemical', 'MESH:D019344', (38, 49))	('CC', 'Phenotype', 'HP:0030153', (150, 152))	('glucose', 'Chemical', 'MESH:D005947', (14, 21))	('QBC939', 'Var', (64, 70))	('lactic acid production', 'MPA', (38, 60))	('HepG2', 'CellLine', 'CVCL:0027', (103, 108))	('glucose', 'Chemical', 'MESH:D005947', (181, 188))	('QBC939', 'CellLine', 'CVCL:6942', (64, 70))
81477	28301876	Our study also showed that the activity and expression of the key PPP enzyme G6PDH and the NADPH/NADP ratio were higher in QBC939 cells than in HepG2 cells (Fig 3D-3F).	('NADPH', 'Gene', (91, 96))	('activity', 'MPA', (31, 39))	('expression', 'MPA', (44, 54))	('G6PDH', 'Gene', '2539', (77, 82))	('NADPH', 'Gene', '1666', (91, 96))	('QBC939', 'CellLine', 'CVCL:6942', (123, 129))	('NADP', 'Chemical', 'MESH:D009249', (97, 101))	('higher', 'PosReg', (113, 119))	('HepG2', 'CellLine', 'CVCL:0027', (144, 149))	('G6PDH', 'Gene', (77, 82))	('QBC939', 'Var', (123, 129))	('NADP', 'Chemical', 'MESH:D009249', (91, 95))
81478	28301876	We speculate that the efficiency of the PPP is higher in QBC939 cells than in HepG2 cells.	('HepG2', 'CellLine', 'CVCL:0027', (78, 83))	('higher', 'PosReg', (47, 53))	('QBC939', 'Var', (57, 63))	('efficiency', 'MPA', (22, 32))	('QBC939', 'CellLine', 'CVCL:6942', (57, 63))
81479	28301876	Studies have shown that oxidation of the PPP can be activated within a few seconds in human skin cells treated with H2O2, producing more NADPH and enhancing the capacity for oxidation reduction.	('NADPH', 'Gene', (137, 142))	('human', 'Species', '9606', (86, 91))	('NADPH', 'Gene', '1666', (137, 142))	('enhancing', 'PosReg', (147, 156))	('oxidation reduction', 'MPA', (174, 193))	('H2O2', 'Chemical', 'MESH:D006861', (116, 120))	('H2O2', 'Var', (116, 120))	('capacity', 'MPA', (161, 169))
81480	28301876	Our study showed that the sensitivity of QBC939 cells to H2O2 was significantly lower than that of HepG2 cells (Fig 2A, 2C and 2D).	('QBC939', 'CellLine', 'CVCL:6942', (41, 47))	('H2O2', 'Chemical', 'MESH:D006861', (57, 61))	('H2O2', 'Var', (57, 61))	('HepG2', 'CellLine', 'CVCL:0027', (99, 104))	('lower', 'NegReg', (80, 85))	('sensitivity', 'MPA', (26, 37))
81484	28301876	Previous studies have suggested that inhibiting glucose metabolism can increase ROS levels in tumor cells and inhibit tumor proliferation.	('glucose metabolism', 'MPA', (48, 66))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('glucose', 'Chemical', 'MESH:D005947', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('ROS levels', 'MPA', (80, 90))	('increase ROS levels', 'Phenotype', 'HP:0025464', (71, 90))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (118, 123))	('inhibiting', 'Var', (37, 47))	('increase', 'PosReg', (71, 79))	('ROS', 'Chemical', 'MESH:D017382', (80, 83))	('inhibit', 'NegReg', (110, 117))
81487	28301876	Inhibition of the PPP might further increase intracellular ROS levels and inhibit tumor growth.	('ROS', 'Chemical', 'MESH:D017382', (59, 62))	('increase', 'PosReg', (36, 44))	('PPP', 'Gene', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('inhibit', 'NegReg', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Inhibition', 'Var', (0, 10))	('increase intracellular ROS levels', 'Phenotype', 'HP:0025464', (36, 69))	('tumor', 'Disease', (82, 87))	('intracellular ROS levels', 'MPA', (45, 69))
81488	28301876	Indeed, we found that DHEA increased overall ROS and mtROS levels in HepG2 cells (Fig 4A-4D), which were significantly higher than those in QBC939 cells, suggesting that inhibition of the PPP can increase cellular oxidative stress.	('inhibition', 'Var', (170, 180))	('QBC939', 'CellLine', 'CVCL:6942', (140, 146))	('oxidative stress', 'Phenotype', 'HP:0025464', (214, 230))	('cellular oxidative stress', 'MPA', (205, 230))	('ROS', 'Chemical', 'MESH:D017382', (45, 48))	('mtROS levels', 'MPA', (53, 65))	('ROS', 'Chemical', 'MESH:D017382', (55, 58))	('DHEA', 'Chemical', 'MESH:D003687', (22, 26))	('higher', 'PosReg', (119, 125))	('increase', 'PosReg', (196, 204))	('HepG2', 'CellLine', 'CVCL:0027', (69, 74))	('PPP', 'Gene', (188, 191))
81495	28301876	Based on these metabolic characteristics, inhibition of autophagy may increase mtROS production or reduce ROS removal, thus enhancing the level of ROS and either killing tumor cells or inhibiting their proliferation.	('proliferation', 'CPA', (202, 215))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('killing', 'NegReg', (162, 169))	('inhibiting', 'NegReg', (185, 195))	('autophagy', 'CPA', (56, 65))	('increase', 'PosReg', (70, 78))	('ROS', 'Chemical', 'MESH:D017382', (147, 150))	('ROS', 'Protein', (106, 109))	('reduce', 'NegReg', (99, 105))	('mtROS production', 'MPA', (79, 95))	('ROS', 'Chemical', 'MESH:D017382', (106, 109))	('inhibition', 'Var', (42, 52))	('level', 'MPA', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('enhancing', 'PosReg', (124, 133))	('ROS', 'MPA', (147, 150))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))
81502	28301876	Our data further suggested that QBC939 cell may be more dependent on the lysosomal degradation process to maintain the normal function of cells, and inhibition of lysosomal function with CQ can significantly increase the sensitivity of QBC939 cells to cisplatin.	('CQ', 'Chemical', 'MESH:D002738', (187, 189))	('inhibition', 'Var', (149, 159))	('increase', 'PosReg', (208, 216))	('cisplatin', 'Chemical', 'MESH:D002945', (252, 261))	('sensitivity', 'MPA', (221, 232))	('QBC939', 'CellLine', 'CVCL:6942', (32, 38))	('QBC939', 'CellLine', 'CVCL:6942', (236, 242))
81506	28301876	MtROS and apoptosis rate were further increased after the treatment of CQ and cisplatin to QBC939 cells, which could be antagonized by Mito-TEMPO (Fig 6A-6C).	('cisplatin', 'Var', (78, 87))	('Mito', 'Species', '262676', (135, 139))	('CQ', 'Chemical', 'MESH:D002738', (71, 73))	('QBC939', 'CellLine', 'CVCL:6942', (91, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('ROS', 'Chemical', 'MESH:D017382', (2, 5))	('apoptosis rate', 'CPA', (10, 24))	('increased', 'PosReg', (38, 47))
81514	28301876	Our results showed that, compared with 3-MA, the amount of hydroxyl free radicals in QBC939 cells was remarkably increased after CQ treatment (Fig 7E).	('CQ treatment', 'Var', (129, 141))	('QBC939', 'CellLine', 'CVCL:6942', (85, 91))	('hydroxyl free radicals', 'Chemical', '-', (59, 81))	('amount of hydroxyl free radicals', 'MPA', (49, 81))	('CQ', 'Chemical', 'MESH:D002738', (129, 131))	('increased', 'PosReg', (113, 122))	('3-MA', 'Chemical', 'MESH:C025946', (39, 43))
81519	28301876	However, the current study indicates that inhibition of the autophagy-lysosomal pathway might inhibit the REDOX balance mediated from glucose metabolism in CC cells, increase the level of ROS, induce apoptosis, and increase the sensitivity of cells to cisplatin.	('ROS', 'Chemical', 'MESH:D017382', (188, 191))	('increase', 'PosReg', (166, 174))	('REDOX balance mediated from glucose metabolism', 'MPA', (106, 152))	('increase', 'PosReg', (215, 223))	('CC', 'Phenotype', 'HP:0030153', (156, 158))	('inhibition', 'Var', (42, 52))	('inhibit', 'NegReg', (94, 101))	('glucose', 'Chemical', 'MESH:D005947', (134, 141))	('sensitivity', 'MPA', (228, 239))	('autophagy-lysosomal', 'CPA', (60, 79))	('induce', 'Reg', (193, 199))	('level of ROS', 'MPA', (179, 191))	('cisplatin', 'Chemical', 'MESH:D002945', (252, 261))	('apoptosis', 'CPA', (200, 209))
81611	30139566	The presence of lymph node metastases (LNM), high G3, male sex, and age greater 60 years were associated with significantly lower survival according to Kaplan:Meier analysis.	('metastases', 'Disease', 'MESH:D009362', (27, 37))	('lymph', 'Disease', (16, 21))	('lower', 'NegReg', (124, 129))	('survival', 'MPA', (130, 138))	('metastases', 'Disease', (27, 37))	('high G3', 'Var', (45, 52))
81642	32373065	Mutation of Isocitrate Dehydrogenase 1 in Cholangiocarcinoma Impairs Tumor Progression by Inhibiting Isocitrate Metabolism Aim: Isocitrate dehydrogenase 1 (IDH1) is key enzyme involved in cellular metabolism and DNA repair.	('Isocitrate dehydrogenase 1', 'Gene', (128, 154))	('IDH1', 'Gene', (156, 160))	('Isocitrate Dehydrogenase 1', 'Gene', (12, 38))	('Isocitrate dehydrogenase 1', 'Gene', '3417', (128, 154))	('Isocitrate', 'Chemical', 'MESH:C034219', (128, 138))	('Cholangiocarcinoma Impairs Tumor', 'Disease', 'MESH:D018281', (42, 74))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (42, 60))	('Tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Mutation', 'Var', (0, 8))	('Isocitrate Metabolism Aim', 'MPA', (101, 126))	('Inhibiting', 'NegReg', (90, 100))	('Isocitrate', 'Chemical', 'MESH:C034219', (101, 111))	('Isocitrate', 'Chemical', 'MESH:C034219', (12, 22))	('Isocitrate Dehydrogenase 1', 'Gene', '3417', (12, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('Cholangiocarcinoma Impairs Tumor', 'Disease', (42, 74))
81643	32373065	Mutations in IDH1 occur in up to 25% of cholangiocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (40, 59))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (40, 58))	('occur', 'Reg', (18, 23))	('cholangiocarcinomas', 'Disease', (40, 59))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))
81644	32373065	Methods: To compare the features of IDH1 knockout and mutation in cholangiocarcinoma, we firstly constructed the IDH1 knockout and IDH1 mutation cell lines.	('mutation', 'Var', (54, 62))	('cholangiocarcinoma', 'Disease', (66, 84))	('mutation', 'Var', (136, 144))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (66, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (66, 84))
81647	32373065	Results: High frequency of mutated IDH1 was observed in the cholangiocarcinoma and IDH1 R132C was presented in more than 80% of mutations.	('cholangiocarcinoma', 'Disease', (60, 78))	('mutated', 'Var', (27, 34))	('IDH1', 'Gene', (35, 39))	('observed', 'Reg', (44, 52))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (60, 78))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (60, 78))	('R132C', 'Var', (88, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('IDH1', 'Gene', (83, 87))	('R132C', 'Mutation', 'rs121913499', (88, 93))
81648	32373065	Additionally, IDH1 mutation reduced the levels of NADPH and alpha-KG.	('alpha-KG', 'MPA', (60, 68))	('reduced', 'NegReg', (28, 35))	('mutation', 'Var', (19, 27))	('NADPH', 'MPA', (50, 55))	('alpha-KG', 'Chemical', 'MESH:D007656', (60, 68))	('levels', 'MPA', (40, 46))	('IDH1', 'Gene', (14, 18))	('NADPH', 'Chemical', 'MESH:D009249', (50, 55))
81649	32373065	Conclusion: IDH1 plays an important role in cholangiocarcinoma and its mutation impairs tumor progression in part by inhibition of isocitrate metabolism.	('cholangiocarcinoma', 'Disease', (44, 62))	('IDH1', 'Gene', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('mutation', 'Var', (71, 79))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (44, 62))	('isocitrate metabolism', 'MPA', (131, 152))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (44, 62))	('isocitrate', 'Chemical', 'MESH:C034219', (131, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('inhibition', 'NegReg', (117, 127))	('tumor', 'Disease', (88, 93))	('impairs', 'NegReg', (80, 87))
81658	32373065	Genetic alternations are thought to play a critical role in the occurrence and development of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (94, 112))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (94, 112))	('Genetic alternations', 'Var', (0, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (94, 112))
81659	32373065	Mutations in several oncogenes and tumor suppressor genes have been reported to be involved in the carcinogenesis of cholangiocarcinoma.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('carcinogenesis of cholangiocarcinoma', 'Disease', (99, 135))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('involved', 'Reg', (83, 91))	('tumor', 'Disease', (35, 40))	('carcinogenesis of cholangiocarcinoma', 'Disease', 'MESH:D063646', (99, 135))	('Mutations', 'Var', (0, 9))	('oncogenes', 'Gene', (21, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (117, 135))
81660	32373065	For instance, activated KRAS has been reported to be associated with the development of cholangiocarcinoma.	('KRAS', 'Gene', '3845', (24, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('activated', 'Var', (14, 23))	('cholangiocarcinoma', 'Disease', (88, 106))	('associated', 'Reg', (53, 63))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 106))	('KRAS', 'Gene', (24, 28))
81666	32373065	Recently, alternations of IDH1 have been implicated in many types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('IDH1', 'Gene', (26, 30))	('implicated', 'Reg', (41, 51))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('alternations', 'Var', (10, 22))	('cancer', 'Disease', (69, 75))
81667	32373065	In 2008, for the first time, Parsons and colleagues have demonstrated IDH1 mutations in the human genome related to the glioblastoma multiforme.	('glioblastoma multiforme', 'Disease', (120, 143))	('related', 'Reg', (105, 112))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (120, 143))	('mutations', 'Var', (75, 84))	('human', 'Species', '9606', (92, 97))	('IDH1', 'Gene', (70, 74))
81668	32373065	The following studies performed by other groups have further revealed that mutations in IDH1 are associated with leukemia, colon cancer and prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('colon cancer', 'Phenotype', 'HP:0003003', (123, 135))	('IDH1', 'Gene', (88, 92))	('prostate cancer', 'Phenotype', 'HP:0012125', (140, 155))	('prostate cancer', 'Disease', (140, 155))	('colon cancer', 'Disease', 'MESH:D015179', (123, 135))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('colon cancer', 'Disease', (123, 135))	('mutations', 'Var', (75, 84))	('leukemia', 'Phenotype', 'HP:0001909', (113, 121))	('prostate cancer', 'Disease', 'MESH:D011471', (140, 155))	('associated', 'Reg', (97, 107))	('leukemia', 'Disease', (113, 121))	('leukemia', 'Disease', 'MESH:D007938', (113, 121))
81669	32373065	In 2012, Borger and colleagues have revealed IDH1 mutations in cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('mutations', 'Var', (50, 59))	('cholangiocarcinoma', 'Disease', (63, 81))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (63, 81))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (63, 81))	('IDH1', 'Gene', (45, 49))
81670	32373065	Interestingly, mutations in IDH1 have been frequently observed in poorly differentiated tumors.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('mutations', 'Var', (15, 24))	('observed', 'Reg', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('IDH1', 'Gene', (28, 32))
81672	32373065	have reported that mutations in IDH1 are associated with improved response to irradiation and chemotherapy in colon carcinoma and glioblastoma cells.	('colon carcinoma', 'Disease', 'MESH:D003110', (110, 125))	('improved response to irradiation', 'Phenotype', 'HP:0011133', (57, 89))	('glioblastoma', 'Disease', (130, 142))	('IDH1', 'Gene', (32, 36))	('glioblastoma', 'Disease', 'MESH:D005909', (130, 142))	('mutations', 'Var', (19, 28))	('glioblastoma', 'Phenotype', 'HP:0012174', (130, 142))	('colon carcinoma', 'Disease', (110, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('improved', 'PosReg', (57, 65))	('response', 'CPA', (66, 74))
81673	32373065	More recently, they found that IDH mutation in gliomas depended on lactate and the neurotransmitter glutamate as metabolic substrates to rescue cells from the metabolic stress.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('lactate', 'Chemical', 'MESH:D019344', (67, 74))	('IDH', 'Gene', (31, 34))	('metabolic stress', 'MPA', (159, 175))	('gliomas', 'Disease', (47, 54))	('glutamate', 'Chemical', 'MESH:D018698', (100, 109))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('mutation', 'Var', (35, 43))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))
81674	32373065	These results suggested that IDH mutation might affect tumor progression by regulating metabolic stress.	('affect', 'Reg', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('mutation', 'Var', (33, 41))	('metabolic stress', 'MPA', (87, 103))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('IDH', 'Gene', (29, 32))
81675	32373065	In the present study, we aimed to explore the effects of IDH1 mutation on cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (74, 92))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (74, 92))	('IDH1', 'Gene', (57, 61))	('mutation', 'Var', (62, 70))	('cholangiocarcinoma', 'Disease', (74, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
81676	32373065	Furthermore, we revealed the mechanisms of IDH1 mutation underlying the tumor progression of cholangiocarcinoma.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('cholangiocarcinoma', 'Disease', (93, 111))	('IDH1', 'Gene', (43, 47))	('mutation', 'Var', (48, 56))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
81678	32373065	Cell viability of RBE cell line and RBE IDH1 knockout or mutation cells was determined using the MTT assay and cell count assay.	('mutation', 'Var', (57, 65))	('MTT', 'Chemical', 'MESH:C070243', (97, 100))	('RBE IDH1', 'Gene', (36, 44))
81688	32373065	After 1 week acclimatization, the mice were subcutaneously injected with 2 x 106 REB IDH1 KO cells, or REB IDH1 KO cells transfected with wild-type IDH1 or IDH1 R132C mutation plasmids.	('R132C mutation', 'Var', (161, 175))	('mice', 'Species', '10090', (34, 38))	('IDH1', 'Gene', (156, 160))	('R132C', 'Mutation', 'rs121913499', (161, 166))
81701	32373065	The results indicated that IDH1 was mutated at the highest frequency among all mutated genes including TP53, ARID1A, BAP1, and KRAS (Figure 1A).	('TP53', 'Gene', '7157', (103, 107))	('BAP1', 'Gene', '8314', (117, 121))	('TP53', 'Gene', (103, 107))	('mutated', 'Var', (36, 43))	('BAP1', 'Gene', (117, 121))	('KRAS', 'Gene', (127, 131))	('IDH1', 'Gene', (27, 31))	('ARID1A', 'Gene', '8289', (109, 115))	('KRAS', 'Gene', '3845', (127, 131))	('ARID1A', 'Gene', (109, 115))
81702	32373065	We also noticed that mutated TP53 also appeared at a high frequency.	('TP53', 'Gene', '7157', (29, 33))	('mutated', 'Var', (21, 28))	('TP53', 'Gene', (29, 33))
81703	32373065	It is known that TP53 mutations are frequently observed in the occurrence and development of many types of cancer and are implicated to be an important risk factor for tumorigenesis.	('tumor', 'Disease', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('observed', 'Reg', (47, 55))	('TP53', 'Gene', '7157', (17, 21))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('cancer', 'Disease', (107, 113))	('TP53', 'Gene', (17, 21))
81704	32373065	Therefore, we further analyzed the frequency of mutated TP53 in patients with wild-type (WT) or mutated IDH.	('mutated', 'Var', (96, 103))	('TP53', 'Gene', '7157', (56, 60))	('TP53', 'Gene', (56, 60))	('patients', 'Species', '9606', (64, 72))
81705	32373065	Interestingly, we found mutated TP53 with higher frequency in patients with WT IDH than patients with mutated IDH (Figure 1B).	('mutated', 'Var', (24, 31))	('patients', 'Species', '9606', (88, 96))	('TP53', 'Gene', '7157', (32, 36))	('TP53', 'Gene', (32, 36))	('patients', 'Species', '9606', (62, 70))
81706	32373065	The results showed IDH1 R132C was presented in more than 80% of mutation types (Figure 1C).	('R132C', 'Var', (24, 29))	('IDH1', 'Gene', (19, 23))	('R132C', 'Mutation', 'rs121913499', (24, 29))
81707	32373065	Cell count assay and MTT assay demonstrated that cell number and viability were significantly decreased after IDH1 was knocked out (Figures 2B,C).	('MTT', 'Chemical', 'MESH:C070243', (21, 24))	('decreased', 'NegReg', (94, 103))	('cell number', 'CPA', (49, 60))	('knocked out', 'Var', (119, 130))	('IDH1', 'Gene', (110, 114))
81709	32373065	As shown in Figure 2D, the IDH1 R132C mutation and the IDH WT cells were successfully constructed.	('R132C', 'Mutation', 'rs121913499', (32, 37))	('R132C mutation', 'Var', (32, 46))	('IDH1', 'Gene', (27, 31))
81713	32373065	Additionally, no significant difference for cell migration and invasion between cells transfected with plasmids containing IDH1 R132C and cells transfected with vector control (Figures 3C,D).	('R132C', 'Var', (128, 133))	('IDH1', 'Gene', (123, 127))	('invasion', 'CPA', (63, 71))	('R132C', 'Mutation', 'rs121913499', (128, 133))	('cell migration', 'CPA', (44, 58))
81715	32373065	We did not find cells transfected with plasmids containing IDH1 R132C with those changes when compared with cells transfected with vector control (Figure 3E).	('IDH1', 'Gene', (59, 63))	('R132C', 'Mutation', 'rs121913499', (64, 69))	('R132C', 'Var', (64, 69))
81718	32373065	The results demonstrated that the levels of alpha-KG and NADPH were significantly decreased in the IDH KO RBE cells when compared with those in the RBE cells (Figures 4A,C).	('levels', 'MPA', (34, 40))	('alpha-KG and NADPH', 'Gene', '1666', (44, 62))	('decreased', 'NegReg', (82, 91))	('IDH', 'Var', (99, 102))
81720	32373065	Interestingly, when we transfected the IDH KO cells with plasmids containing IDH1 R132C, reductions in alpha-KG and NADPH were observed (Figures 4B,D).	('R132C', 'Mutation', 'rs121913499', (82, 87))	('R132C', 'Var', (82, 87))	('IDH1', 'Gene', (77, 81))	('reductions', 'NegReg', (89, 99))	('alpha-KG and NADPH', 'Gene', '1666', (103, 121))
81722	32373065	These results supported that IDH1 mutation reduced levels of alpha-KG and NADPH.	('reduced', 'NegReg', (43, 50))	('mutation', 'Var', (34, 42))	('alpha-KG and NADPH', 'Gene', '1666', (61, 79))	('IDH1', 'Gene', (29, 33))
81726	32373065	Additionally, the levels of ALDH1 were significantly increased in IDH KO cells transfected with plasmids containing WT IDH1, whereas a reduction in ALDH1 was observed in the IDH KO cells transfected with plasmids containing IDH1 R132C (Figure 5C).	('ALDH1', 'Gene', '216', (28, 33))	('IDH1', 'Var', (119, 123))	('ALDH1', 'Gene', (148, 153))	('ALDH1', 'Gene', '216', (148, 153))	('levels', 'MPA', (18, 24))	('IDH1', 'Var', (224, 228))	('increased', 'PosReg', (53, 62))	('R132C', 'Mutation', 'rs121913499', (229, 234))	('ALDH1', 'Gene', (28, 33))
81729	32373065	We also observed increased cell migration and invasion in the IDH KO cells with plasmids containing ALDH1 (Figures 5G,H).	('increased', 'PosReg', (17, 26))	('ALDH1', 'Gene', (100, 105))	('plasmids', 'Var', (80, 88))	('ALDH1', 'Gene', '216', (100, 105))	('cell migration', 'CPA', (27, 41))	('invasion', 'CPA', (46, 54))
81730	32373065	To further confirm if IDH1 regulated ALDH1 in such events, ALDH1 siRNA was employed to knock down the level of ALDH1 in REB cells (Figure 5I).	('ALDH1', 'Gene', '216', (59, 64))	('ALDH1', 'Gene', (111, 116))	('ALDH1', 'Gene', (37, 42))	('ALDH1', 'Gene', '216', (111, 116))	('knock', 'Var', (87, 92))	('ALDH1', 'Gene', '216', (37, 42))	('ALDH1', 'Gene', (59, 64))
81736	32373065	We further revealed that IDH1 mutation reduced the levels of alpha-KG and NADPH, and IDH1 regulated the expressions of ALDH1 in cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (128, 146))	('regulated', 'Reg', (90, 99))	('alpha-KG and NADPH', 'Gene', '1666', (61, 79))	('mutation', 'Var', (30, 38))	('expressions', 'MPA', (104, 115))	('cholangiocarcinoma', 'Disease', (128, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('IDH1', 'Gene', (85, 89))	('reduced', 'NegReg', (39, 46))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (128, 146))	('IDH1', 'Gene', (25, 29))	('ALDH1', 'Gene', (119, 124))	('ALDH1', 'Gene', '216', (119, 124))
81738	32373065	IDH1 mutations have been identified in many types of cancers including glioma, hepatoma, leukemia, colon cancer and prostate cancer.	('leukemia', 'Phenotype', 'HP:0001909', (89, 97))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('colon cancer', 'Disease', 'MESH:D015179', (99, 111))	('prostate cancer', 'Disease', (116, 131))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('IDH1', 'Gene', (0, 4))	('identified', 'Reg', (25, 35))	('leukemia', 'Disease', 'MESH:D007938', (89, 97))	('leukemia', 'Disease', (89, 97))	('colon cancer', 'Disease', (99, 111))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('hepatoma', 'Disease', 'MESH:D006528', (79, 87))	('cancers', 'Disease', (53, 60))	('glioma', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('colon cancer', 'Phenotype', 'HP:0003003', (99, 111))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('prostate cancer', 'Disease', 'MESH:D011471', (116, 131))	('hepatoma', 'Disease', (79, 87))	('prostate cancer', 'Phenotype', 'HP:0012125', (116, 131))
81740	32373065	In the present study, we identified a high frequency of mutated IDH1 in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (72, 90))	('mutated', 'Var', (56, 63))	('IDH1', 'Gene', (64, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 90))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))
81741	32373065	Besides, we also found a high frequency of TP53 mutation in patients with IDH WT, whereas low frequency of TP53 mutation in patients was accompanied with mutated IDH.	('IDH', 'Disease', (74, 77))	('patients', 'Species', '9606', (60, 68))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('mutation', 'Var', (48, 56))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('patients', 'Species', '9606', (124, 132))
81742	32373065	Adam and colleagues have demonstrated that IDH mutation occurs earlier in the development of glioma and its mutation precedes TP53 mutation.	('glioma', 'Disease', (93, 99))	('TP53', 'Gene', (126, 130))	('mutation', 'Var', (47, 55))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('IDH', 'Gene', (43, 46))	('TP53', 'Gene', '7157', (126, 130))
81743	32373065	Therefore, we speculate that IDH mutation and TP53 mutation occur at different stages in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (89, 107))	('mutation', 'Var', (33, 41))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (89, 107))	('TP53', 'Gene', '7157', (46, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (89, 107))	('IDH', 'Gene', (29, 32))	('TP53', 'Gene', (46, 50))	('mutation', 'Var', (51, 59))	('occur', 'Reg', (60, 65))
81744	32373065	By analyzing the proportions of different mutation types of IDH1, we revealed that IDH1 R132C was presented in more than 80% of mutation types.	('R132C', 'Var', (88, 93))	('IDH1', 'Gene', (83, 87))	('R132C', 'Mutation', 'rs121913499', (88, 93))
81745	32373065	These results are consistent with a previous finding, in which IDH1 mutation was found in 16.88% of patients with cholangiocarcinoma and IDH1 R132C was presented in 12.55% of patients.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (114, 132))	('mutation', 'Var', (68, 76))	('found', 'Reg', (81, 86))	('cholangiocarcinoma', 'Disease', (114, 132))	('R132C', 'Var', (142, 147))	('patients', 'Species', '9606', (100, 108))	('patients', 'Species', '9606', (175, 183))	('R132C', 'Mutation', 'rs121913499', (142, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('IDH1', 'Gene', (63, 67))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (114, 132))
81749	32373065	These results suggested that IDH1 promoted the development of cholangiocarcinoma and its mutation impaired the progression of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (62, 80))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (126, 144))	('IDH1', 'Gene', (29, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('mutation', 'Var', (89, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (126, 144))	('promoted', 'PosReg', (34, 42))	('impaired', 'NegReg', (98, 106))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (62, 80))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (62, 80))	('progression', 'CPA', (111, 122))	('cholangiocarcinoma', 'Disease', (126, 144))
81756	32373065	However, when we transfected the IDH KO cells with plasmids containing IDH1 R132C, reduced alpha-KG and NADPH were observed.	('alpha-KG and NADPH', 'Gene', '1666', (91, 109))	('reduced', 'NegReg', (83, 90))	('IDH1', 'Gene', (71, 75))	('R132C', 'Mutation', 'rs121913499', (76, 81))	('R132C', 'Var', (76, 81))
81758	32373065	The mutations in IDH1 affected the expression of alpha-KG and NADPH, thereby impacting mitochondrial functions in cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (114, 132))	('affected', 'Reg', (22, 30))	('impacting', 'Reg', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('expression', 'MPA', (35, 45))	('mitochondrial functions', 'MPA', (87, 110))	('cholangiocarcinoma', 'Disease', (114, 132))	('IDH1', 'Gene', (17, 21))	('alpha-KG and NADPH', 'Gene', '1666', (49, 67))	('mutations', 'Var', (4, 13))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (114, 132))
81767	32373065	In the in vivo study, IDH increases the tumor volume in mice transplanted with the IDH WT cells.	('IDH', 'Var', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mice', 'Species', '10090', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('increases', 'PosReg', (26, 35))
81824	27619971	MicroRNAs (miRNAs) are a class of highly conserved, endogenous, small non-coding RNA molecules of 18-23 nucleotides in length, which regulate gene expression through complementary base-pairing with target messenger RNAs and subsequent gene silencing.	('gene silencing', 'NegReg', (235, 249))	('regulate', 'Reg', (133, 141))	('complementary base-pairing', 'Var', (166, 192))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('gene expression', 'MPA', (142, 157))
81831	27619971	MicroRNAs (miRNAs) belong to a new class of small non-coding, endogenous RNAs comprising 18-23 nucleotides that negatively regulate gene expression through inducing mRNA degradation or repressing translation by annealing with the complementary sites in 3'-untranslated regions (3'-UTRs) of target mRNAs 16, 17, 18, 19.	('mRNA degradation', 'MPA', (165, 181))	('regulate', 'Reg', (123, 131))	('inducing', 'PosReg', (156, 164))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('annealing', 'Var', (211, 220))	('repressing', 'PosReg', (185, 195))	('negatively', 'NegReg', (112, 122))	('translation', 'MPA', (196, 207))	('gene expression', 'MPA', (132, 147))
81833	27619971	Mutations of miRNA-encoding genes or aberrant expression of miRNAs have been well described in various tumours, including gastric, breast and lung cancers, as well as glioblastoma and melanoma 25, 26, 27.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('miR', 'Gene', '220972', (60, 63))	('melanoma', 'Disease', (184, 192))	('miR', 'Gene', (13, 16))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('miR', 'Gene', (60, 63))	('gastric', 'Disease', (122, 129))	('Mutations', 'Var', (0, 9))	('described', 'Reg', (82, 91))	('tumours', 'Disease', (103, 110))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('glioblastoma', 'Disease', 'MESH:D005909', (167, 179))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('tumours', 'Disease', 'MESH:D009369', (103, 110))	('lung cancers', 'Phenotype', 'HP:0100526', (142, 154))	('aberrant expression', 'Var', (37, 56))	('miR', 'Gene', '220972', (13, 16))	('glioblastoma', 'Disease', (167, 179))	('breast and lung cancers', 'Disease', 'MESH:D001943', (131, 154))	('glioblastoma', 'Phenotype', 'HP:0012174', (167, 179))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))
81877	27619971	Inhibition of miR-21 suppressed ICC cell proliferation, induced cell cycle arrest and apoptosis in vitro and impaired tumour growth in vivo.	('miR-21', 'Gene', '406991', (14, 20))	('ICC', 'Disease', (32, 35))	('impaired tumour growth', 'Disease', (109, 131))	('impaired tumour growth', 'Disease', 'MESH:D006130', (109, 131))	('miR-21', 'Gene', (14, 20))	('suppressed', 'NegReg', (21, 31))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (64, 81))	('arrest', 'Disease', 'MESH:D006323', (75, 81))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('Inhibition', 'Var', (0, 10))	('arrest', 'Disease', (75, 81))	('apoptosis', 'CPA', (86, 95))	('induced', 'Reg', (56, 63))
81884	27619971	Inhibition of miR-214 promoted metastasis of human ICC cells and increased the transcript levels of the epithelial-mesenchymal transition-associated gene Twist, and decreased E-cadherin levels by directly targeting the Twist gene.	('decreased', 'NegReg', (165, 174))	('increased', 'PosReg', (65, 74))	('targeting', 'Reg', (205, 214))	('Twist', 'Gene', (154, 159))	('Twist', 'Gene', '7291', (219, 224))	('miR-214', 'Gene', '406996', (14, 21))	('promoted', 'PosReg', (22, 30))	('E-cadherin', 'Gene', (175, 185))	('metastasis of human ICC cells', 'CPA', (31, 60))	('Twist', 'Gene', (219, 224))	('human', 'Species', '9606', (45, 50))	('E-cadherin', 'Gene', '999', (175, 185))	('Inhibition', 'Var', (0, 10))	('miR-214', 'Gene', (14, 21))	('transcript levels', 'MPA', (79, 96))	('Twist', 'Gene', '7291', (154, 159))
81903	27619971	Restoration of PSMD10 reversed the phenotypic alteration caused by miR-605 in ICC cells.	('PSMD10', 'Gene', (15, 21))	('phenotypic', 'MPA', (35, 45))	('PSMD10', 'Gene', '5716', (15, 21))	('Restoration', 'Var', (0, 11))	('miR-605', 'Gene', (67, 74))	('miR-605', 'Gene', '693190', (67, 74))
81909	27619971	As illustrated in Figure 1, altered expression of miRNAs has significant effects on intracellular signalling network and thereby promoting malignant phenotypes in the development and progression of ICC.	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('altered', 'Var', (28, 35))	('effects', 'Reg', (73, 80))	('development', 'CPA', (167, 178))	('malignant phenotypes', 'CPA', (139, 159))	('intracellular signalling network', 'MPA', (84, 116))	('ICC', 'Disease', (198, 201))	('promoting', 'PosReg', (129, 138))	('expression', 'MPA', (36, 46))
81935	23180967	Undoubtedly, tumor cells in sex hormone-dependent organs can control tumor growth through hormone-receptor antagonists, while sex hormone-independent organs induce apoptosis through PR antagonists.	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('antagonists', 'Var', (107, 118))	('tumor', 'Disease', (69, 74))	('apoptosis', 'CPA', (164, 173))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('hormone-receptor', 'Protein', (90, 106))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('PR', 'Gene', '5241', (182, 184))
81936	23180967	Li's studies have shown that mifepristone can induce progesterone receptor-positive gastric cancer-cell apoptosis.	('gastric cancer', 'Disease', (84, 98))	('mifepristone', 'Var', (29, 41))	('gastric cancer', 'Disease', 'MESH:D013274', (84, 98))	('progesterone receptor', 'Gene', (53, 74))	('progesterone receptor', 'Gene', '5241', (53, 74))	('mifepristone', 'Chemical', 'MESH:D015735', (29, 41))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('induce', 'PosReg', (46, 52))
81958	23180967	The sequence of bax primers was P15'-GAGGGATGATTGCCGCCGT-3', P25'-caaccaccctggtcttggatc-3', and amplification length was 240 bp.	('bax', 'Gene', '581', (16, 19))	("P15'-GAGGGATGATTGCCGCCGT-3", 'Var', (32, 58))	('bax', 'Gene', (16, 19))	("P25'-caaccaccctggtcttggatc-3", 'Var', (61, 89))
81959	23180967	The sequence of bcl-2 primers was P15'-TGCACCTGACGCCCTTCAC-3', P2 5'-AGACAGCCAGGAGAAATCAAACAG-3', and amplification length was 290 bp.	('bcl-2', 'Gene', '596', (16, 21))	("P15'-TGCACCTGACGCCCTTCAC-3", 'Var', (34, 60))	('bcl-2', 'Gene', (16, 21))	("P2 5'-AGACAGCCAGGAGAAATCAAACAG-3", 'Var', (63, 95))
81960	23180967	The sequence of beta-actin primers was P15'-CATGTACGTTGCTATCCAGGC-3', P2 5'-CTCCTTAATGTCACGCACGAT-3', and amplification length was 250 bp.	('beta-actin', 'Gene', (16, 26))	("P15'-CATGTACGTTGCTATCCAGGC-3", 'Var', (39, 67))	('beta-actin', 'Gene', '728378', (16, 26))	("P2 5'-CTCCTTAATGTCACGCACGAT-3", 'Var', (70, 99))
81984	23180967	Li's experimental results showed that mifepristone allowed PR-positive gastric cancer cell lines to reduce in the S/G2/M phase and increase in the G0/G1 phase, and the proliferation index was significantly reduced, helping to induce gastric cancer cells' apoptosis.	('gastric cancer', 'Disease', (71, 85))	('S/G2', 'Var', (114, 118))	('induce', 'PosReg', (226, 232))	('S/G2', 'SUBSTITUTION', 'None', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('gastric cancer', 'Phenotype', 'HP:0012126', (233, 247))	('gastric cancer', 'Disease', 'MESH:D013274', (71, 85))	('reduce', 'NegReg', (100, 106))	('reduced', 'NegReg', (206, 213))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('increase', 'PosReg', (131, 139))	('gastric cancer', 'Disease', (233, 247))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))	('proliferation index', 'CPA', (168, 187))	('PR', 'Gene', '5241', (59, 61))	('mifepristone', 'Chemical', 'MESH:D015735', (38, 50))	('apoptosis', 'CPA', (255, 264))	('gastric cancer', 'Disease', 'MESH:D013274', (233, 247))	('G0/G1 phase', 'CPA', (147, 158))
81999	23180967	Abnormalities in the Fas/Fasl system are associated with tumor occurrence and the development of cancer.	('Fasl', 'Gene', '356', (25, 29))	('cancer', 'Disease', (97, 103))	('associated', 'Reg', (41, 51))	('Abnormalities', 'Var', (0, 13))	('Fasl', 'Gene', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Fas', 'Chemical', 'MESH:C038178', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Fas', 'Chemical', 'MESH:C038178', (21, 24))	('tumor', 'Disease', (57, 62))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
82009	23180967	The results of this study showed that the expression of Fas significantly increased when it was cocultured with IFN-gamma and cholangiocarcinoma cells, making the effect of mifepristone induce a significant increase of apoptosis in cholangiocarcinoma cells, and apoptosis rate was significantly higher than the simple application of the mifepristone group (P < 0.01).	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('Fas', 'Gene', (56, 59))	('expression', 'MPA', (42, 52))	('mifepristone', 'Chemical', 'MESH:D015735', (337, 349))	('mifepristone', 'Var', (173, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (232, 250))	('increased', 'PosReg', (74, 83))	('apoptosis', 'CPA', (219, 228))	('cholangiocarcinoma cells', 'Disease', 'MESH:D018281', (232, 256))	('cholangiocarcinoma cells', 'Disease', (232, 256))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (126, 144))	('Fas', 'Chemical', 'MESH:C038178', (56, 59))	('increase', 'PosReg', (207, 215))	('higher', 'PosReg', (295, 301))	('cholangiocarcinoma cells', 'Disease', 'MESH:D018281', (126, 150))	('mifepristone', 'Chemical', 'MESH:D015735', (173, 185))	('cholangiocarcinoma cells', 'Disease', (126, 150))	('IFN-gamma', 'Gene', '3458', (112, 121))	('IFN-gamma', 'Gene', (112, 121))
82067	22458359	The dilated bile ducts cause dilatation-stenosis-like biliary stricture, which subsequently leads to the abnormality of bile dynamics, causing cholestasis and then inducing biliary tract inflammation.	('inflammation', 'Disease', 'MESH:D007249', (187, 199))	('bile dynamics', 'MPA', (120, 133))	('dilated', 'Var', (4, 11))	('dilatation-stenosis', 'Disease', 'MESH:D002311', (29, 48))	('inflammation', 'Disease', (187, 199))	('inducing', 'Reg', (164, 172))	('dilatation-stenosis', 'Disease', (29, 48))	('cholestasis', 'Disease', 'MESH:D002779', (143, 154))	('abnormality of bile', 'Phenotype', 'HP:0012440', (105, 124))	('abnormality', 'MPA', (105, 116))	('cholestasis', 'Disease', (143, 154))	('causing', 'Reg', (135, 142))	('biliary stricture', 'Disease', (54, 71))	('dilatation', 'Phenotype', 'HP:0002617', (29, 39))	('cholestasis', 'Phenotype', 'HP:0001396', (143, 154))	('leads to', 'Reg', (92, 100))
82116	21488076	from Korea compared 41 patients with CC with 406 controls and reported a strong association between the presence of C. sinensis in the stool and CC (RR 2.7; 95% CI 1.1-6.3).	('C. sinensis', 'Species', '79923', (116, 127))	('patients', 'Species', '9606', (23, 31))	('C. sinensis', 'Gene', (116, 127))	('presence', 'Var', (104, 112))
82212	21488076	In countries such as Korea and Thailand where both HBV and CC are endemic, data show HBV but not HCV as a risk factor for ICC.	('HBV', 'Species', '10407', (85, 88))	('HCV', 'Species', '11103', (97, 100))	('HBV', 'Species', '10407', (51, 54))	('ICC', 'Disease', (122, 125))	('HBV', 'Var', (85, 88))
82233	21488076	Genes coding for enzymes responsible for metabolism of carcinogens, DNA repair, and inflammation have been examined for polymorphic variants that may be associated with increased susceptibility to CC.	('inflammation', 'Disease', 'MESH:D007249', (84, 96))	('variants', 'Var', (132, 140))	('associated', 'Reg', (153, 163))	('inflammation', 'Disease', (84, 96))
82267	30682771	In 2010, ABC-02 trial, the first randomized phase III study in advanced BTC, reported that gemcitabine plus cisplatin has better TCRs (81.4% versus 71.8%, p = 0.049), median progression-free survival (PFS, 8.0 months versus 5.0 months, p < 0.001) and median OS (11.7 months versus 8.1 months, p < 0.001) than gemcitabine alone so the combination of gemcitabine and cisplatin has been considered the standard of care as the first-line treatment in patients with advanced BTC and widely used in clinical practice.	('BTC', 'Gene', '685', (72, 75))	('better', 'PosReg', (122, 128))	('progression-free survival', 'CPA', (174, 199))	('OS', 'Gene', '17451', (258, 260))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (365, 374))	('gemcitabine', 'Chemical', 'MESH:C056507', (309, 320))	('TCRs', 'CPA', (129, 133))	('gemcitabine', 'Var', (91, 102))	('BTC', 'Gene', '685', (470, 473))	('patients', 'Species', '9606', (447, 455))	('BTC', 'Gene', (470, 473))	('gemcitabine', 'Chemical', 'MESH:C056507', (91, 102))	('gemcitabine', 'Chemical', 'MESH:C056507', (349, 360))	('BTC', 'Gene', (72, 75))
82282	30682771	Most of the genetic alterations involve phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) through MAPKinase activation or p53 suppression resulting in activation of mTOR.	('alterations', 'Var', (20, 31))	('activation', 'PosReg', (132, 142))	('mTOR', 'MPA', (189, 193))	('PI3', 'Gene', (67, 70))	('p53', 'Gene', (146, 149))	('mammalian target of rapamycin', 'Gene', '2475', (77, 106))	('mammalian target of rapamycin', 'Gene', (77, 106))	('activation', 'PosReg', (175, 185))	('PI3', 'Gene', '5266', (67, 70))	('p53', 'Gene', '7157', (146, 149))	('MAPKinase', 'Enzyme', (122, 131))	('suppression', 'NegReg', (150, 161))
82305	30682771	Three different genes, PIK3CA, PIK3CB, and PIK3CD, encode three specific p110 isoforms, p110alpha, beta, and delta, respectively, and activating missense mutations of PIK3CA have been found as oncogenic in a variety of cancers.	('PIK3CA', 'Gene', (23, 29))	('PIK3CA', 'Gene', '5290', (167, 173))	('p110', 'Gene', '9733', (88, 92))	('PIK3CB', 'Gene', (31, 37))	('PIK3CB', 'Gene', '5291', (31, 37))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('PIK3CD', 'Gene', '5293', (43, 49))	('activating', 'PosReg', (134, 144))	('PIK3CA', 'Gene', (167, 173))	('PIK3CD', 'Gene', (43, 49))	('PIK3CA', 'Gene', '5290', (23, 29))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('cancers', 'Disease', (219, 226))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('p110', 'Gene', (73, 77))	('p110alpha', 'Gene', (88, 97))	('p110alpha', 'Gene', '5290', (88, 97))	('p110', 'Gene', (88, 92))	('missense mutations', 'Var', (145, 163))	('p110', 'Gene', '9733', (73, 77))
82306	30682771	PIK3CB mutation is rare but has been reported to be activating and oncogenic.	('PIK3CB', 'Gene', '5291', (0, 6))	('mutation', 'Var', (7, 15))	('PIK3CB', 'Gene', (0, 6))
82316	30682771	Dysregulation of the above genes or proteins leads to mTOR activation resulting in tumor progression and survival in BTC.	('BTC', 'Gene', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', (83, 88))	('BTC', 'Gene', '685', (117, 120))	('survival', 'CPA', (105, 113))	('activation', 'PosReg', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('mTOR', 'MPA', (54, 58))
82317	30682771	PIK3CA mutations are commonly found in cancers such colon, breast, gastric, and brain cancers, but such mutations are rarely found in BTC and are associated with poor prognosis.	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancers such colon', 'Disease', (39, 57))	('breast', 'Disease', (59, 65))	('brain cancers', 'Disease', 'MESH:D001932', (80, 93))	('found', 'Reg', (30, 35))	('brain cancers', 'Disease', (80, 93))	('PIK3CA', 'Gene', (0, 6))	('BTC', 'Gene', '685', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('PIK3CA', 'Gene', '5290', (0, 6))	('BTC', 'Gene', (134, 137))	('gastric', 'Disease', (67, 74))	('cancers such colon', 'Disease', 'MESH:D015179', (39, 57))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('mutations', 'Var', (7, 16))
82322	30682771	Therefore, treating BTC cell lines with a small-molecule inhibitor of the IGF1-R was suggested and showed the efficacy of targeting this pathway.	('IGF1-R', 'Gene', '3480', (74, 80))	('BTC', 'Gene', '685', (20, 23))	('small-molecule', 'Var', (42, 56))	('BTC', 'Gene', (20, 23))	('IGF1-R', 'Gene', (74, 80))
82333	30682771	Currently, several compounds such as AZD-2014, MLN0128 (INK128, TAK228), OSI-027, and GDC-0349 have been investigated in clinical trials to prove the clinical significance in cancer treatments.	('MLN0128', 'Chemical', 'MESH:C572449', (47, 54))	('OSI-027', 'Chemical', 'MESH:C568605', (73, 80))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('GDC-0349', 'Chemical', 'MESH:C000620512', (86, 94))	('TAK228', 'Chemical', 'MESH:C572449', (64, 70))	('AZD-2014', 'Chemical', 'MESH:C585537', (37, 45))	('MLN0128', 'Var', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
82334	30682771	Furthermore, NVP-BEZ235, LY3023414, and PF-04691502 are dual PI3K/mTOR inhibitors and have been investigated in clinical trials.	('PI3', 'Gene', '5266', (61, 64))	('LY3023414', 'Var', (25, 34))	('BEZ235', 'Chemical', 'MESH:C531198', (17, 23))	('PF-04691502', 'Var', (40, 51))	('PI3', 'Gene', (61, 64))	('NVP-BEZ235', 'Var', (13, 23))	('LY3023414', 'Chemical', 'MESH:C000621566', (25, 34))
82349	30682771	found metformin increases AMPK phosphorylation and inhibits the activation of mTORC1 complex and can sensitize sorafenib, 5-FU, and As2O3 but not gemcitabine in cholangiocarcinoma cell lines (RBE and HCCC-9810).	('activation', 'MPA', (64, 74))	('gemcitabine', 'Chemical', 'MESH:C056507', (146, 157))	('5-FU', 'MPA', (122, 126))	('5-FU', 'Chemical', 'MESH:D005472', (122, 126))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (161, 179))	('cholangiocarcinoma', 'Disease', (161, 179))	('inhibits', 'NegReg', (51, 59))	('AMPK', 'Gene', (26, 30))	('As2O3', 'Chemical', 'MESH:D000077237', (132, 137))	('AMPK', 'Gene', '5564', (26, 30))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (161, 179))	('increases', 'PosReg', (16, 25))	('sensitize', 'Reg', (101, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('metformin', 'Var', (6, 15))	('mTORC1', 'Gene', (78, 84))	('sorafenib', 'Chemical', 'MESH:D000077157', (111, 120))	('metformin', 'Chemical', 'MESH:D008687', (6, 15))	('mTORC1', 'Gene', '382056', (78, 84))
82352	30682771	Furthermore, Fyn knockdown in CCA cell lines induces AMPK phosphorylation, followed by inhibiting downstream mTOR phosphorylation leading to inhibition of migration and invasion.	('Fyn', 'Gene', '2534', (13, 16))	('inhibition', 'NegReg', (141, 151))	('AMPK', 'Gene', (53, 57))	('downstream mTOR phosphorylation', 'MPA', (98, 129))	('AMPK', 'Gene', '5564', (53, 57))	('CCA', 'Phenotype', 'HP:0030153', (30, 33))	('knockdown', 'Var', (17, 26))	('inhibiting', 'NegReg', (87, 97))	('Fyn', 'Gene', (13, 16))
82361	30682771	MLN0128, a second generation, ATP-competitive mTOR inhibitor, suppress cell growth and induce apoptosis in vitro and in vivo via suppression of both mTORC1 and mTORC2 signaling.	('MLN0128', 'Var', (0, 7))	('suppression', 'NegReg', (129, 140))	('suppress', 'NegReg', (62, 70))	('mTORC2', 'Gene', (160, 166))	('mTORC1', 'Gene', (149, 155))	('ATP', 'Chemical', 'MESH:D000255', (30, 33))	('mTORC2', 'Gene', '74343', (160, 166))	('cell growth', 'CPA', (71, 82))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('mTORC1', 'Gene', '382056', (149, 155))	('induce', 'PosReg', (87, 93))	('apoptosis', 'CPA', (94, 103))
82362	30682771	An important finding in this study was that MLN0128 had better therapeutic efficacy than gemcitabine/oxaliplatin combination (one of the standard chemotherapy regimen) as well as everolimus in the treatment of AKT/YapS127A intrahepatic CCA model.	('gemcitabine', 'Chemical', 'MESH:C056507', (89, 100))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (101, 112))	('better', 'PosReg', (56, 62))	('MLN0128', 'Var', (44, 51))	('therapeutic efficacy', 'CPA', (63, 83))	('YapS127A', 'Mutation', 'rs762471803', (214, 222))	('CCA', 'Phenotype', 'HP:0030153', (236, 239))	('everolimus', 'Chemical', 'MESH:D000068338', (179, 189))	('MLN0128', 'Chemical', 'MESH:C572449', (44, 51))
82363	30682771	In addition, the same group reported that the combination of palbociclib, a CDK4/6 inhibitor, and MLN0128 demonstrated a pronounced, synergistic growth inhibition in intrahepatic CCA cell lines and in AKT/YapS127A mice.	('mice', 'Species', '10090', (214, 218))	('MLN0128', 'Chemical', 'MESH:C572449', (98, 105))	('CCA', 'Phenotype', 'HP:0030153', (179, 182))	('inhibition', 'NegReg', (152, 162))	('YapS127A', 'Mutation', 'rs762471803', (205, 213))	('CDK4/6', 'Gene', '12567;12571', (76, 82))	('MLN0128', 'Var', (98, 105))	('CDK4/6', 'Gene', (76, 82))
82365	30682771	In addition, our group identified both HSP90 overexpression and loss of PTEN were poor prognostic factors in patients with intrahepatic CCA.	('HSP90', 'Gene', '3320', (39, 44))	('CCA', 'Phenotype', 'HP:0030153', (136, 139))	('PTEN', 'Gene', (72, 76))	('patients', 'Species', '9606', (109, 117))	('PTEN', 'Gene', '5728', (72, 76))	('loss', 'Var', (64, 68))	('HSP90', 'Gene', (39, 44))	('overexpression', 'PosReg', (45, 59))
82366	30682771	Thus, the combination of the HSP90 inhibitor (NVP-AUY922) and the PI3K/mTOR inhibitor (NVP-BEZ235) in CCA were evaluated and showed synergistic effects in vitro and in vivo.	('BEZ235', 'Chemical', 'MESH:C531198', (91, 97))	('CCA', 'Phenotype', 'HP:0030153', (102, 105))	('PI3', 'Gene', '5266', (66, 69))	('CCA', 'Disease', (102, 105))	('NVP-AUY922', 'Var', (46, 56))	('HSP90', 'Gene', (29, 34))	('HSP90', 'Gene', '3320', (29, 34))	('PI3', 'Gene', (66, 69))
82371	30682771	Besides direct inhibitors targeting mTOR, suppression of MAPKinase or reactivation p53 alone or in combination with mTOR inhibitors could be reasonably therapeutic strategies in advanced BTC.	('BTC', 'Gene', (187, 190))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('suppression', 'NegReg', (42, 53))	('mTOR', 'Gene', (36, 40))	('MAPKinase', 'Enzyme', (57, 66))	('BTC', 'Gene', '685', (187, 190))	('reactivation', 'Var', (70, 82))
82377	30682771	reported a 31-year-old male patient was diagnosed as stage IV intrahepatic CCA with PIK3CA mutation (E545G), which may result in activating mTOR pathway so patient received everolimus and achieved partial response (PR) after 2-month everolimus and at least 6-month PFS.	('activating', 'MPA', (129, 139))	('PIK3CA', 'Gene', '5290', (84, 90))	('E545G', 'Var', (101, 106))	('mTOR pathway', 'Pathway', (140, 152))	('E545G', 'Mutation', 'rs121913274', (101, 106))	('everolimus', 'Chemical', 'MESH:D000068338', (173, 183))	('patient', 'Species', '9606', (28, 35))	('PIK3CA', 'Gene', (84, 90))	('CCA', 'Phenotype', 'HP:0030153', (75, 78))	('everolimus', 'Chemical', 'MESH:D000068338', (233, 243))	('patient', 'Species', '9606', (156, 163))
82383	30682771	In another phase II study to evaluate the activity of everolimus in 10 patients with PIK3CA amplification/mutation or PTEN loss refractory solid cancer, one patient with CCA with PTEN loss experienced disease control.	('patient', 'Species', '9606', (157, 164))	('PTEN loss', 'Disease', (179, 188))	('PTEN loss', 'Disease', 'MESH:D006223', (118, 127))	('patients', 'Species', '9606', (71, 79))	('PIK3CA', 'Gene', '5290', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('PTEN loss', 'Disease', 'MESH:D006223', (179, 188))	('amplification/mutation', 'Var', (92, 114))	('everolimus', 'Chemical', 'MESH:D000068338', (54, 64))	('CCA', 'Phenotype', 'HP:0030153', (170, 173))	('patient', 'Species', '9606', (71, 78))	('PTEN loss refractory solid cancer', 'Disease', (118, 151))	('PTEN loss refractory solid cancer', 'Disease', 'MESH:D006223', (118, 151))	('PIK3CA', 'Gene', (85, 91))
82389	30682771	In a pilot study enrolling patients with PIK3CA mutant/amplified refractory solid cancer, sirolimus failed to demonstrate the clinical benefit in a patient with hilar cholangiocarcinoma (PIK3CA E545K mutation) who experienced disease progression following the second cycle of sirolimus with PFS of 0.9 months.	('cancer', 'Disease', (82, 88))	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (161, 185))	('hilar cholangiocarcinoma', 'Disease', (161, 185))	('PIK3CA', 'Gene', (187, 193))	('PIK3CA', 'Gene', '5290', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (167, 185))	('patients', 'Species', '9606', (27, 35))	('E545K', 'Mutation', 'rs104886003', (194, 199))	('mutant/amplified', 'Var', (48, 64))	('PIK3CA', 'Gene', (41, 47))	('sirolimus', 'Chemical', 'MESH:D020123', (90, 99))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('patient', 'Species', '9606', (148, 155))	('PIK3CA', 'Gene', '5290', (187, 193))	('sirolimus', 'Chemical', 'MESH:D020123', (276, 285))	('patient', 'Species', '9606', (27, 34))	('E545K mutation', 'Var', (194, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
82405	30682771	This research was supported by CMRPG310231, CMRPG310241, MOST107-2314-B-182A-134-MY3, NMRPG3H6211, CRRPG3F0031-3, and MOST105-2314-B-182A-MY2, NMRPG3F6021-2 to C.-N.Y.	('OS', 'Gene', '17451', (58, 60))	('CRRPG3F0031-3', 'Var', (99, 112))	('CMRPG310231', 'Var', (31, 42))	('CMRPG310241', 'Var', (44, 55))	('NMRPG3F6021-2', 'Var', (143, 156))	('NMRPG3H6211', 'Var', (86, 97))	('OS', 'Gene', '17451', (119, 121))
82490	26755360	In addition to histologic findings, serum IgG4 level is often elevated in patients with IgG4-RD.	('patients', 'Species', '9606', (74, 82))	('serum IgG4 level', 'MPA', (36, 52))	('elevated', 'PosReg', (62, 70))	('IgG4-RD', 'Var', (88, 95))
82497	26755360	Since the patient had type 3 variation of intrahepatic bile duct-prior branching of right posterior Glisson pedicle which made the mass to be located apart from the right posterior duct, the lesion was considered to be resectable.	('variation of intrahepatic bile duct', 'Phenotype', 'HP:0006571', (29, 64))	('patient', 'Species', '9606', (10, 17))	('variation', 'Var', (29, 38))	('intrahepatic bile duct', 'Disease', (42, 64))	('intrahepatic bile duct', 'Disease', 'MESH:D002780', (42, 64))
82553	23177172	The carcinogenetic activity of DEN is exerted in two different ways: (i) by alkylating DNA structures thus causing DNA damage and subsequent cell degeneration and (ii) by inducing reactive oxygen species (ROS) formation through the activation of the cytochrome P450 in hepatocytes.	('DNA damage', 'MPA', (115, 125))	('rat', 'Species', '10116', (152, 155))	('causing', 'Reg', (107, 114))	('DEN', 'Chemical', 'MESH:D004052', (31, 34))	('ROS', 'Chemical', 'MESH:D017382', (205, 208))	('reactive oxygen species', 'MPA', (180, 203))	('cell', 'CPA', (141, 145))	('DNA structures', 'Protein', (87, 101))	('cytochrome P450', 'Enzyme', (250, 265))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (180, 203))	('alkylating', 'Var', (76, 86))	('inducing', 'Reg', (171, 179))
82585	23177172	The main mechanisms related to HCC development in CDD-treated animals are related to the stimulation of oval cells, leading to an increased oxidative stress, DNA damage and genetic mutations or modifications.	('CDD', 'Chemical', '-', (50, 53))	('genetic mutations', 'Var', (173, 190))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (130, 156))	('oxidative stress', 'Phenotype', 'HP:0025464', (140, 156))	('modifications', 'Var', (194, 207))	('HCC', 'Disease', (31, 34))	('DNA damage', 'MPA', (158, 168))	('increased', 'PosReg', (130, 139))	('oxidative stress', 'MPA', (140, 156))
82587	23177172	Ethionine supplementation to CDD enhances oval cell stimulation increasing carcinogenetic potential.	('Ethionine', 'Var', (0, 9))	('carcinogenetic potential', 'CPA', (75, 99))	('CDD', 'Chemical', '-', (29, 32))	('enhances', 'PosReg', (33, 41))	('oval cell stimulation', 'MPA', (42, 63))	('Ethionine', 'Chemical', 'MESH:D005001', (0, 9))
82619	23177172	Other mouse models of HCC have been generated from transgenic mice expressing oncogenes, such as c-Myc, beta-catenin, or from mice with mutation/deletion of several genes: PDGF, TGFbeta1, NEMO, TAK1, alpha-1 antitrypsin and PTEN (tumour suppressor gene that regulates the PKB/akt pathway).	('beta-catenin', 'Gene', (104, 116))	('mice', 'Species', '10090', (126, 130))	('mice', 'Species', '10090', (62, 66))	('rat', 'Species', '10116', (40, 43))	('NEMO', 'Gene', '16151', (188, 192))	('mouse', 'Species', '10090', (6, 11))	('HCC', 'Disease', (22, 25))	('PKB', 'Gene', (272, 275))	('TGFbeta1', 'Gene', (178, 186))	('PTEN', 'Gene', (224, 228))	('TGFbeta1', 'Gene', '21803', (178, 186))	('mutation/deletion', 'Var', (136, 153))	('TAK1', 'Gene', (194, 198))	('akt', 'Gene', '207', (276, 279))	('NEMO', 'Gene', (188, 192))	('transgenic mice', 'Species', '10090', (51, 66))	('TAK1', 'Gene', '26409', (194, 198))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('PDGF', 'Gene', (172, 176))	('PKB', 'Gene', '207;11651', (272, 275))	('tumour', 'Disease', 'MESH:D009369', (230, 236))	('beta-catenin', 'Gene', '12387', (104, 116))	('tumour', 'Disease', (230, 236))	('akt', 'Gene', (276, 279))
82634	23177172	More recently, BDEneu cell implanted rats were treated with JP1584, a small-molecule second mitochondria-derived activator of caspase (smac) mimetic, which resulted in a significant reduction in peritoneal metastatization, as compared to vehicle treated ones.	('JP1584', 'Var', (60, 66))	('smac', 'Gene', (135, 139))	('peritoneal metastatization', 'CPA', (195, 221))	('rats', 'Species', '10116', (37, 41))	('reduction', 'NegReg', (182, 191))	('smac', 'Gene', '66593', (135, 139))
82647	23177172	The molecular phenotype of malignant cells in this model is similar to that of human disease, being positive for COX-2, EGFR, MUC1, MMP-2, MMP-9, c-Met, c-erb-B2, c-Kit and oestrogen receptors.	('c-Kit', 'Gene', '3815', (163, 168))	('human', 'Species', '9606', (79, 84))	('c-erb-B2', 'Gene', (153, 161))	('MMP-2', 'Gene', '4313', (132, 137))	('oestrogen receptors', 'Protein', (173, 192))	('c-erb-B2', 'Gene', '2064', (153, 161))	('c-Met', 'Var', (146, 151))	('MMP-9', 'Gene', '4318', (139, 144))	('MMP-9', 'Gene', (139, 144))	('MUC1', 'Gene', (126, 130))	('MUC1', 'Gene', '4582', (126, 130))	('COX-2', 'Gene', (113, 118))	('EGFR', 'Gene', '1956', (120, 124))	('MMP-2', 'Gene', (132, 137))	('c-Kit', 'Gene', (163, 168))	('EGFR', 'Gene', (120, 124))
82653	23177172	The limited availability of rats with genetic knock down of specific genes hampers the chances of studying the specific role of molecules involved in CCA pathophysiology.	('knock down', 'Var', (46, 56))	('hampers', 'NegReg', (75, 82))	('rats', 'Species', '10116', (28, 32))	('CCA', 'Disease', (150, 153))
82663	23177172	This led the authors to investigate human CCA samples, finding PTEN inactivation by epigenetic modification and loss of expression of SMAD in 71% and 48% (respectively) of the phosphorylated-AKT positive tumours.	('epigenetic modification', 'Var', (84, 107))	('expression', 'MPA', (120, 130))	('tumours', 'Disease', 'MESH:D009369', (204, 211))	('tumours', 'Disease', (204, 211))	('SMAD', 'Gene', (134, 138))	('loss', 'NegReg', (112, 116))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('inactivation', 'NegReg', (68, 80))	('human', 'Species', '9606', (36, 41))	('tumours', 'Phenotype', 'HP:0002664', (204, 211))	('PTEN', 'Gene', (63, 67))
82670	23177172	Mutations of the p53 gene are frequent genomic alterations observed in human intra-hepatic CCA (IH-CCA).	('intra-hepatic CCA', 'Disease', 'MESH:C536211', (77, 94))	('Mutations', 'Var', (0, 9))	('intra-hepatic CCA', 'Disease', (77, 94))	('p53', 'Gene', (17, 20))	('human', 'Species', '9606', (71, 76))	('rat', 'Species', '10116', (51, 54))
82672	23177172	At early time points cholangiocyte death by apoptosis was observed only in p53+/+ and +/- mice, but not in -/- mice.	('apoptosis', 'CPA', (44, 53))	('+/-', 'Var', (86, 89))	('mice', 'Species', '10090', (111, 115))	('mice', 'Species', '10090', (90, 94))	('p53+/+', 'Var', (75, 81))	('cholangiocyte', 'Disease', (21, 34))
82673	23177172	Cytological abnormalities and, shortly after the end of CCl4 administration, foci of early carcinoma were detected only in p53-/- animals.	('p53-/-', 'Var', (123, 129))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('rat', 'Species', '10116', (69, 72))	('carcinoma', 'Disease', (91, 100))
82676	23177172	The p53 genotype had a major impact on tumour development: IH-CCA was detected only in p53-/- and +/- mice (54% and 18%, respectively), with a consistent reduction of tumour latency (29 weeks for -/- mice and 52 weeks for +/- mice) (Table 3).	('IH-CCA', 'Disease', (59, 65))	('mice', 'Species', '10090', (102, 106))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('mice', 'Species', '10090', (226, 230))	('tumour', 'Disease', (167, 173))	('tumour', 'Disease', (39, 45))	('reduction of tumour latency', 'Disease', (154, 181))	('reduction of tumour latency', 'Disease', 'MESH:D009369', (154, 181))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('mice', 'Species', '10090', (200, 204))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('p53-/-', 'Var', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (39, 45))
82699	23177172	This issue has been elegantly evaluated by Prof. Thorgeirsson's group, who compared the global gene expression patterns of 68 HCCs from seven different mouse models and 91 human HCCs from predefined subclasses: the gene expression patterns in HCCs from Myc, E2f1 and Myc E2f1 transgenic mice were most similar to those of the human HCCs better survival group, whereas the expression patterns in HCCs from Myc Tgfalpha transgenic mice and in DEN-induced mouse HCCs were most similar to those of the human HCCs poorer survival group.	('E2f1', 'Gene', '1869', (271, 275))	('mouse', 'Species', '10090', (453, 458))	('transgenic', 'Var', (276, 286))	('transgenic mice', 'Species', '10090', (276, 291))	('human', 'Species', '9606', (498, 503))	('E2f1', 'Gene', (271, 275))	('E2f1', 'Gene', '1869', (258, 262))	('human', 'Species', '9606', (172, 177))	('transgenic mice', 'Species', '10090', (418, 433))	('mouse', 'Species', '10090', (152, 157))	('DEN', 'Chemical', 'MESH:D004052', (441, 444))	('E2f1', 'Gene', (258, 262))	('human', 'Species', '9606', (326, 331))
82735	31636847	Although angiogenesis is required during growth and development, abnormal angiogenesis has been linked to a number of human diseases, including cancer, cardiovascular disease, diabetes, age-related macular degeneration, and diabetic retinopathy.	('diabetic retinopathy', 'Disease', 'MESH:D003930', (224, 244))	('abnormal', 'Var', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('linked', 'Reg', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('age-related macular degeneration', 'Disease', (186, 218))	('diabetes', 'Disease', (176, 184))	('cardiovascular disease', 'Disease', (152, 174))	('diabetic retinopathy', 'Disease', (224, 244))	('cancer', 'Disease', (144, 150))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (152, 174))	('diabetes', 'Disease', 'MESH:D003920', (176, 184))	('human', 'Species', '9606', (118, 123))	('macular degeneration', 'Phenotype', 'HP:0000608', (198, 218))	('retinopathy', 'Phenotype', 'HP:0000488', (233, 244))	('cardiovascular disease', 'Disease', 'MESH:D002318', (152, 174))
82824	31636847	In this study, protein levels of AKT, p-AKT, mTOR, and p-mTOR, all of which are key factors of the PI3K/AKT/ mTOR signaling pathway, were shown to be increased by western blotting (Fig.	('AKT', 'Gene', '11651', (104, 107))	('p-mTOR', 'Var', (55, 61))	('mTOR', 'MPA', (45, 49))	('AKT', 'Gene', (104, 107))	('protein levels', 'MPA', (15, 29))	('AKT', 'Gene', '11651', (33, 36))	('AKT', 'Gene', '11651', (40, 43))	('AKT', 'Gene', (40, 43))	('increased', 'PosReg', (150, 159))	('AKT', 'Gene', (33, 36))
82829	31636847	Together, these findings reveal that 1,2-DCP induced angiogenesis in dermatitis through the P13K/PKB/mTOR pathway in the skin.	('dermatitis', 'Disease', 'MESH:D003872', (69, 79))	('P13K', 'SUBSTITUTION', 'None', (92, 96))	('dermatitis', 'Disease', (69, 79))	('angiogenesis', 'CPA', (53, 65))	('dermatitis', 'Phenotype', 'HP:0011123', (69, 79))	('1,2-DCP', 'Chemical', 'MESH:C004765', (37, 44))	('P13K', 'Var', (92, 96))
82936	20347808	However, because mammals possess 5 different ligands (Jagged 1 and 2, and Delta-like ligand -1, -3 and -4) as well as 4 different Notch receptors (Notch 1-4), and many variations of the gamma-secretase complex, it is highly likely that specificity of ligand/receptor/secretase interaction may play a role in this diversity.	('Notch', 'Gene', (130, 135))	('variations', 'Var', (168, 178))	('Notch', 'Gene', '4851;4853', (147, 152))	('Notch', 'Gene', (147, 152))	('Notch 1', 'Gene', '4851', (147, 154))	('Notch 1', 'Gene', (147, 154))	('Notch', 'Gene', '4851;4853', (130, 135))
82944	20347808	Following trypsinization, Mz-ChA-1 cells (1x106 cells), or lysates from tumors tissue taken from nude mice, chronically treated with either AEA or vehicle as described, were resuspended in lysis buffer as described and sonicated.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('nude mice', 'Species', '10090', (97, 106))	('trypsinization', 'Var', (10, 24))	('AEA', 'Chemical', 'MESH:C078814', (140, 143))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))
83038	20347808	Indeed, a recent clinical pilot study to determine the safety of intracranial administration of the plant-derived, Delta9-tetrahydrocannabinol in patients with glioblastoma demonstrated a marked reduction in Ki67 staining within the tumor.	('glioblastoma', 'Disease', (160, 172))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('glioblastoma', 'Disease', 'MESH:D005909', (160, 172))	('Ki67 staining', 'MPA', (208, 221))	('tumor', 'Disease', (233, 238))	('glioblastoma', 'Phenotype', 'HP:0012174', (160, 172))	('Delta9-tetrahydrocannabinol', 'Var', (115, 142))	('reduction', 'NegReg', (195, 204))	('Delta9-tetrahydrocannabinol', 'Chemical', 'MESH:D013759', (115, 142))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('patients', 'Species', '9606', (146, 154))
83041	20347808	The growth promoting effects of cannabinoids have also been previously demonstrated via the transactivation of the EGFR in a TACE/ADAM17 metalloprotease-dependent manner.	('EGFR', 'Gene', (115, 119))	('growth', 'MPA', (4, 10))	('transactivation', 'Var', (92, 107))	('cannabinoids', 'Chemical', 'MESH:D002186', (32, 44))
83044	20347808	A similar activation of the Notch signaling pathways by cannabinoids has recently been shown in dendritic cells with Delta9-tetrahydrocannabinol decreasing the expression of the Notch ligand Delta 4, and increasing the expression of Jagged 1.	('Delta9-tetrahydrocannabinol', 'Var', (117, 144))	('expression', 'MPA', (160, 170))	('expression', 'Species', '29278', (219, 229))	('Notch', 'Gene', '4851;4853', (178, 183))	('Delta9-tetrahydrocannabinol', 'Chemical', 'MESH:D013759', (117, 144))	('expression', 'MPA', (219, 229))	('Notch', 'Gene', '4851;4853', (28, 33))	('Notch', 'Gene', (178, 183))	('Notch', 'Gene', (28, 33))	('cannabinoids', 'Chemical', 'MESH:D002186', (56, 68))	('expression', 'Species', '29278', (160, 170))	('Jagged 1', 'Gene', (233, 241))	('increasing', 'PosReg', (204, 214))	('decreasing', 'NegReg', (145, 155))	('Delta 4', 'Protein', (191, 198))
83051	20347808	Furthermore, the expression of Notch 2 can antagonize the effects of Notch 1.	('Notch 2', 'Gene', (31, 38))	('Notch 1', 'Gene', (69, 76))	('Notch 2', 'Gene', '4853', (31, 38))	('expression', 'Species', '29278', (17, 27))	('expression', 'Var', (17, 27))	('Notch 1', 'Gene', '4851', (69, 76))
83058	20347808	Furthermore, novel presenilin 2 variants that confer a loss-of-function phenotype, have been reported to occur three times more frequently in breast cancer cases versus controls.	('presenilin 2', 'Gene', '5664', (19, 31))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('presenilin 2', 'Gene', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancer', 'Disease', (142, 155))	('variants', 'Var', (32, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))
83064	33846801	GSG2 knockdown suppresses cholangiocarcinoma progression by regulating cell proliferation, apoptosis and migration Cholangiocarcinoma (CCA) is the second most common type of hepatocellular carcinoma characterized by high aggressiveness and extremely poor patient prognosis.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('knockdown', 'Var', (5, 14))	('patient', 'Species', '9606', (255, 262))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (115, 133))	('hepatocellular carcinoma', 'Disease', (174, 198))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (26, 44))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (115, 133))	('Cholangiocarcinoma', 'Disease', (115, 133))	('cholangiocarcinoma', 'Disease', (26, 44))	('cell proliferation', 'CPA', (71, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('suppresses', 'NegReg', (15, 25))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (26, 44))	('regulating', 'Reg', (60, 70))	('apoptosis', 'CPA', (91, 100))	('GSG2', 'Gene', '83903', (0, 4))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (174, 198))	('aggressiveness', 'Disease', (221, 235))	('GSG2', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('aggressiveness', 'Phenotype', 'HP:0000718', (221, 235))	('aggressiveness', 'Disease', 'MESH:D001523', (221, 235))	('migration', 'CPA', (105, 114))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (174, 198))
83067	33846801	It was further revealed that high expression of GSG2 in CCA had significant clinical significance in predicting disease deterioration.	('high', 'Var', (29, 33))	('CCA', 'Disease', (56, 59))	('GSG2', 'Gene', (48, 52))	('deterioration', 'Disease', (120, 133))	('deterioration', 'Disease', 'MESH:D009800', (120, 133))
83069	33846801	Additionally, GSG2 knockdown inhibited CCA cell migration by suppressing epithelial-mesenchymal transition (EMT)-related proteins, such as N-cadherin and vimentin.	('inhibited', 'NegReg', (29, 38))	('suppressing', 'NegReg', (61, 72))	('knockdown', 'Var', (19, 28))	('GSG2', 'Gene', (14, 18))	('CCA', 'Disease', (39, 42))	('vimentin', 'Gene', '7431', (154, 162))	('N-cadherin', 'Gene', (139, 149))	('vimentin', 'Gene', (154, 162))	('N-cadherin', 'Gene', '1000', (139, 149))
83071	33846801	In vivo experiments further demonstrated that GSG2 knockdown suppressed tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('suppressed', 'NegReg', (61, 71))	('tumor', 'Disease', (72, 77))	('GSG2', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('knockdown', 'Var', (51, 60))
83078	33846801	The molecular mechanisms of CCA have been partially identified in recent years, including isocitrate dehydrogenase (IDH1 and IDH2) mutations and fibroblast growth factor receptor 2 (FGFR2) fusions, as well as gene mutations involved in chromatin remodeling, such as AT-rich interaction domain 1A (ARID1A), protein poly-bromo 1 (PBRM1), and BRCA1-associated protein 1 (BAP1).	('BRCA1-associated protein 1', 'Gene', (340, 366))	('FGFR2', 'Gene', '2263', (182, 187))	('PBRM1', 'Gene', (328, 333))	('ARID1A', 'Gene', '8289', (297, 303))	('IDH2', 'Gene', (125, 129))	('fusions', 'Var', (189, 196))	('IDH2', 'Gene', '3418', (125, 129))	('BAP1', 'Gene', '8314', (368, 372))	('AT-rich interaction domain 1A', 'Gene', (266, 295))	('IDH1', 'Gene', (116, 120))	('AT-rich interaction domain 1A', 'Gene', '8289', (266, 295))	('BRCA1-associated protein 1', 'Gene', '8314', (340, 366))	('FGFR2', 'Gene', (182, 187))	('mutations', 'Var', (131, 140))	('BAP1', 'Gene', (368, 372))	('fibroblast growth factor receptor 2', 'Gene', '2263', (145, 180))	('fibroblast growth factor receptor 2', 'Gene', (145, 180))	('IDH1', 'Gene', '3417', (116, 120))	('ARID1A', 'Gene', (297, 303))	('CCA', 'Disease', (28, 31))
83082	33846801	For instance, GSG2 knockdown was found to inhibit progression and development of pancreatic cancer in vitro and in vivo.	('progression', 'CPA', (50, 61))	('knockdown', 'Var', (19, 28))	('GSG2', 'Gene', (14, 18))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('development', 'CPA', (66, 77))	('inhibit', 'NegReg', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('pancreatic cancer', 'Disease', (81, 98))
83083	33846801	Recently, Yu et al found that GSG2 knockdown inhibited cell proliferation, colony formation and induced apoptosis, and may serve as a potential therapeutic target for prostate cancer therapy.	('knockdown', 'Var', (35, 44))	('GSG2', 'Gene', (30, 34))	('prostate cancer', 'Phenotype', 'HP:0012125', (167, 182))	('apoptosis', 'CPA', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cell proliferation', 'CPA', (55, 73))	('induced', 'Reg', (96, 103))	('colony formation', 'CPA', (75, 91))	('prostate cancer', 'Disease', (167, 182))	('inhibited', 'NegReg', (45, 54))	('prostate cancer', 'Disease', 'MESH:D011471', (167, 182))
83135	33846801	Taken together, high expression of GSG2 in CCA has significant clinical significance in predicting disease deterioration.	('deterioration', 'Disease', 'MESH:D009800', (107, 120))	('high', 'Var', (16, 20))	('CCA', 'Disease', (43, 46))	('expression', 'MPA', (21, 31))	('GSG2', 'Gene', (35, 39))	('deterioration', 'Disease', (107, 120))
83140	33846801	Cell proliferation of the HCCC-9810 and QBC939 cells in the shGSG2 group was obviously slower compared with the shCtrl group.	('slower', 'NegReg', (87, 93))	('shGSG2', 'Var', (60, 66))	('Cell proliferation', 'CPA', (0, 18))	('QBC939', 'CellLine', 'CVCL:6942', (40, 46))
83141	33846801	Moreover, the ratio of apoptotic cells in the shGSG2 groups of HCCC-9810 and QBC939 cells was significantly higher than that in the shCtrl groups (P<0.001) (Fig.	('higher', 'PosReg', (108, 114))	('QBC939', 'CellLine', 'CVCL:6942', (77, 83))	('shGSG2', 'Var', (46, 52))	('apoptotic cells', 'CPA', (23, 38))
83144	33846801	Additionally, the expression of EMT biomarkers was detected by WB, indicating that the protein level of E-cadherin was upregulated in the shGSG2 group compared with the shCtrl group in the HCCC-9810 and QBC939 cells; contrarily, protein expression of N-cadherin and vimentin were downregulated (Fig.	('QBC939', 'CellLine', 'CVCL:6942', (203, 209))	('protein level', 'MPA', (87, 100))	('upregulated', 'PosReg', (119, 130))	('vimentin', 'Gene', '7431', (266, 274))	('N-cadherin', 'Gene', (251, 261))	('vimentin', 'Gene', (266, 274))	('N-cadherin', 'Gene', '1000', (251, 261))	('downregulated', 'NegReg', (280, 293))	('shGSG2', 'Var', (138, 144))	('protein expression', 'MPA', (229, 247))	('E-cadherin', 'Gene', (104, 114))	('E-cadherin', 'Gene', '999', (104, 114))
83145	33846801	Obviously, knockdown of GSG2 inhibited CCA cell migration by suppressing N-cadherin and vimentin.	('inhibited', 'NegReg', (29, 38))	('suppressing', 'NegReg', (61, 72))	('GSG2', 'Gene', (24, 28))	('vimentin', 'Gene', '7431', (88, 96))	('CCA', 'Disease', (39, 42))	('N-cadherin', 'Gene', (73, 83))	('vimentin', 'Gene', (88, 96))	('N-cadherin', 'Gene', '1000', (73, 83))	('knockdown', 'Var', (11, 20))
83148	33846801	The results showed that the expression of GSG2 in the shGSG2 tumor group was significantly lower than that in the shCtrl group, which confirmed the inhibition efficiency of GSG2 in the targeted xenografts derived from the injected HuCCT1 cells.	('lower', 'NegReg', (91, 96))	('shGSG2', 'Var', (54, 60))	('HuCCT1', 'CellLine', 'CVCL:0324', (231, 237))	('GSG2', 'Gene', (42, 46))	('expression', 'MPA', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
83149	33846801	Importantly, the average tumor volume in the shGSG2 group was significantly reduced by 33.85+-10.92 mm3 compared with the shCtrl group (P<0.01) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('reduced', 'NegReg', (76, 83))	('shGSG2', 'Var', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
83150	33846801	In particular, the average tumor weight of mice inoculated with shGSG2 cells was significantly lower than that of the shCtrl group (P<0.01) (Fig.	('mice', 'Species', '10090', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('lower', 'NegReg', (95, 100))	('tumor', 'Disease', (27, 32))	('shGSG2', 'Var', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
83151	33846801	Additionally, in vivo imaging indicated that bioluminescence expression was apparently weaker in the shGSG2 group than that in the shCtrl group (P<0.01), also indicating the lower tumor burden in the shGSG2 group (Fig.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('weaker', 'NegReg', (87, 93))	('shGSG2', 'Var', (101, 107))	('lower', 'NegReg', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('bioluminescence expression', 'MPA', (45, 71))
83152	33846801	Moreover, Ki67 staining displayed that the proliferative activity of tumors in the shGSG2 group was significantly lower than that in the shCtrl group (P<0.01) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('proliferative activity', 'CPA', (43, 65))	('Ki67', 'Chemical', '-', (10, 14))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('lower', 'NegReg', (114, 119))	('shGSG2', 'Var', (83, 89))
83153	33846801	In a word, knockdown of GSG2 impaired tumorigenicity in vivo, which was in accordance with the aforementioned in vitro results.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('GSG2', 'Gene', (24, 28))	('impaired', 'NegReg', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('knockdown', 'Var', (11, 20))
83156	33846801	Through loss-of-function experiments, it was demonstrated that GSG2 knockdown significantly suppressed cell proliferation, migration and tumor growth.	('suppressed', 'NegReg', (92, 102))	('tumor', 'Disease', (137, 142))	('GSG2', 'Gene', (63, 67))	('cell proliferation', 'CPA', (103, 121))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('knockdown', 'Var', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('loss-of-function', 'NegReg', (8, 24))	('migration', 'CPA', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
83157	33846801	Conversely, CCA cell apoptosis was obviously promoted upon GSG2 knockdown, which may have resulted from the regulation of apoptosis-related proteins such as BIM, caspase3, HSP60, p21, p53, IGFBP-2, survivin and TNF-beta.	('TNF-beta', 'Gene', (211, 219))	('TNF-beta', 'Gene', '7124', (211, 219))	('caspase3', 'Gene', (162, 170))	('GSG2', 'Gene', (59, 63))	('p21', 'Gene', (179, 182))	('CCA', 'Disease', (12, 15))	('p21', 'Gene', '644914', (179, 182))	('p53', 'Gene', (184, 187))	('IGFBP-2', 'Gene', (189, 196))	('p53', 'Gene', '7157', (184, 187))	('caspase3', 'Gene', '836', (162, 170))	('IGFBP-2', 'Gene', '3485', (189, 196))	('promoted', 'PosReg', (45, 53))	('BIM', 'Gene', '10018', (157, 160))	('BIM', 'Gene', (157, 160))	('knockdown', 'Var', (64, 73))	('HSP60', 'Gene', (172, 177))	('HSP60', 'Gene', '3329', (172, 177))
83167	33846801	In our study, knockdown of GSG2 inhibited CCA cell migration by inducing EMT, which included E-cadherin upregulation and N-cadherin and vimentin downregulation.	('upregulation', 'PosReg', (104, 116))	('E-cadherin', 'Gene', (93, 103))	('E-cadherin', 'Gene', '999', (93, 103))	('GSG2', 'Gene', (27, 31))	('inhibited', 'NegReg', (32, 41))	('EMT', 'CPA', (73, 76))	('N-cadherin', 'Gene', (121, 131))	('inducing', 'PosReg', (64, 72))	('N-cadherin', 'Gene', '1000', (121, 131))	('knockdown', 'Var', (14, 23))	('downregulation', 'NegReg', (145, 159))	('vimentin', 'Gene', '7431', (136, 144))	('CCA', 'Disease', (42, 45))	('vimentin', 'Gene', (136, 144))
83172	33846801	This study discovered that GSG2 knockdown contributed to downregulation of P-Akt, CCND1, PIK3CA, and upregulation of MAPK9.	('downregulation', 'NegReg', (57, 71))	('Akt', 'Gene', '207', (77, 80))	('upregulation', 'PosReg', (101, 113))	('GSG2', 'Gene', (27, 31))	('PIK3CA', 'Gene', (89, 95))	('MAPK9', 'Gene', (117, 122))	('CCND1', 'Gene', (82, 87))	('Akt', 'Gene', (77, 80))	('knockdown', 'Var', (32, 41))	('PIK3CA', 'Gene', '5290', (89, 95))	('MAPK9', 'Gene', '5601', (117, 122))	('CCND1', 'Gene', '595', (82, 87))
83192	31754527	Sensitivity estimates for helical CT in colorectal liver metastases in another meta-analysis was 64.7%.	('colorectal liver metastases', 'Disease', 'MESH:D009362', (40, 67))	('helical', 'Var', (26, 33))	('colorectal liver metastases', 'Disease', (40, 67))
83318	30323665	Thus, inhibition of COX-2 by aspirin may prevent CCC development through inhibition of inflammatory processes.	('CCC', 'Disease', (49, 52))	('inhibition', 'NegReg', (73, 83))	('inflammatory processes', 'CPA', (87, 109))	('prevent', 'NegReg', (41, 48))	('inhibition', 'Var', (6, 16))	('COX-2', 'Gene', (20, 25))	('COX-2', 'Gene', '5743', (20, 25))	('CCC', 'Phenotype', 'HP:0030153', (49, 52))	('aspirin', 'Chemical', 'MESH:D001241', (29, 36))
83380	27389416	On univariate analysis of variables at patient presentation, predictors of overall survival included albumin >3.0 g/dL, CA19-9 <= 200 U/mL, CEA <= 10 mug/L and patients without a history of cirrhosis or diabetes (Table 2 ).	('patients', 'Species', '9606', (160, 168))	('>3.0', 'Var', (109, 113))	('cirrhosis or diabetes', 'Disease', (190, 211))	('patient', 'Species', '9606', (39, 46))	('CA19-9 <= 200 U/mL', 'Var', (120, 138))	('cirrhosis or diabetes', 'Disease', 'MESH:D005355', (190, 211))	('CEA', 'Gene', (140, 143))	('albumin', 'Gene', (101, 108))	('albumin', 'Gene', '213', (101, 108))	('patient', 'Species', '9606', (160, 167))	('CEA', 'Gene', '1084', (140, 143))	('cirrhosis', 'Phenotype', 'HP:0001394', (190, 199))
83382	27389416	For patients with a serum albumin >3.0 g/dL, the median survival period was 467 days (95% CI 257-572), which is significantly longer than 155 days (95% CI 122-194) in patients with an albumin <=3.0 g/dL (P < 0.01; Figure 1  ).	('serum albumin', 'Gene', (20, 33))	('patients', 'Species', '9606', (167, 175))	('albumin', 'Gene', (184, 191))	('albumin', 'Gene', '213', (184, 191))	('>3.0 g/dL', 'Var', (34, 43))	('albumin', 'Gene', '213', (26, 33))	('patients', 'Species', '9606', (4, 12))	('serum albumin', 'Gene', '213', (20, 33))	('albumin', 'Gene', (26, 33))
83384	27389416	For patients with a CEA > 10 mug/L, the median survival was 188 days (95% CI 84-210), compared with 305.5 days (95% CI 221-469) in patients with CEA <= 10 mug/L (P < 0.01).	('patients', 'Species', '9606', (131, 139))	('CEA', 'Gene', '1084', (20, 23))	('CEA', 'Gene', (145, 148))	('CEA', 'Gene', '1084', (145, 148))	('patients', 'Species', '9606', (4, 12))	('CEA', 'Gene', (20, 23))	('> 10 mug/L', 'Var', (24, 34))
83390	27389416	Elevated tumor markers have been used to aid in the diagnosis of hilar cholangiocarcinoma; the average CEA and CA 19-9 concentrations at presentation were 12.0 +- 2.7 mug/L and 3236.4 +- 1189.7 U/mL, respectively (Table 3 ).	('CEA', 'Gene', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (71, 89))	('CEA', 'Gene', '1084', (103, 106))	('3236.4 +- 1189.7 U/mL', 'Var', (177, 198))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (65, 89))	('hilar cholangiocarcinoma', 'Disease', (65, 89))
83398	27389416	Factors such as CA19-9 <= 200 U/mL, CEA <= 10 mug/L and a medical history without cirrhosis or diabetes may also be associated with increased overall survival, although these are not independent predictors of survival.	('CA19-9 <= 200 U/mL', 'Var', (16, 34))	('overall survival', 'MPA', (142, 158))	('cirrhosis', 'Phenotype', 'HP:0001394', (82, 91))	('CEA', 'Gene', (36, 39))	('cirrhosis or diabetes', 'Disease', (82, 103))	('CEA', 'Gene', '1084', (36, 39))	('increased', 'PosReg', (132, 141))	('cirrhosis or diabetes', 'Disease', 'MESH:D005355', (82, 103))	('<= 10 mug/L', 'Var', (40, 51))
83399	27389416	In early epidemiological studies, lower serum albumin concentrations were associated with an increased risk of cancer-related mortality; further, in gastrointestinal malignancies such as colorectal, gastric and hepatocellular carcinoma, low albumin has been found to be a poor prognostic indicator of survival.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (211, 235))	('serum albumin', 'Gene', '213', (40, 53))	('cancer', 'Disease', (111, 117))	('lower serum albumin', 'Phenotype', 'HP:0003073', (34, 53))	('colorectal', 'Disease', 'MESH:D015179', (187, 197))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (149, 178))	('gastrointestinal malignancies', 'Disease', (149, 178))	('lower', 'NegReg', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('low albumin', 'Phenotype', 'HP:0003073', (237, 248))	('albumin', 'Gene', (241, 248))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (211, 235))	('albumin', 'Gene', '213', (46, 53))	('serum albumin', 'Gene', (40, 53))	('gastric', 'Disease', (199, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('hepatocellular carcinoma', 'Disease', (211, 235))	('low', 'Var', (237, 240))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('colorectal', 'Disease', (187, 197))	('albumin', 'Gene', '213', (241, 248))	('albumin', 'Gene', (46, 53))
83402	27389416	Patients with underlying cirrhosis represented 6% of all patients in our data set and were associated with lower overall survival on univariate analysis; but the absence of cirrhosis was not found to be an independent predictor of survival; thus the relationship between low albumin and prognosis in hilar cholangiocarcinoma cannot be explained by cirrhosis alone.	('lower', 'NegReg', (107, 112))	('low albumin', 'Phenotype', 'HP:0003073', (271, 282))	('albumin', 'Gene', (275, 282))	('cirrhosis', 'Phenotype', 'HP:0001394', (25, 34))	('cirrhosis', 'Disease', 'MESH:D005355', (348, 357))	('cirrhosis', 'Disease', 'MESH:D005355', (173, 182))	('cirrhosis', 'Disease', (25, 34))	('Patients', 'Species', '9606', (0, 8))	('low', 'Var', (271, 274))	('cirrhosis', 'Phenotype', 'HP:0001394', (348, 357))	('cirrhosis', 'Phenotype', 'HP:0001394', (173, 182))	('albumin', 'Gene', '213', (275, 282))	('cirrhosis', 'Disease', (348, 357))	('carcinoma', 'Phenotype', 'HP:0030731', (315, 324))	('cirrhosis', 'Disease', (173, 182))	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (300, 324))	('hilar cholangiocarcinoma', 'Disease', (300, 324))	('patients', 'Species', '9606', (57, 65))	('overall survival', 'MPA', (113, 129))	('cirrhosis', 'Disease', 'MESH:D005355', (25, 34))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (306, 324))
83533	30815737	In a search for more effective treatment options, progress has been made in identifying molecular drivers of oncogenic signaling including IDH mutations and FGFR2 fusions.	('fusions', 'Var', (163, 170))	('FGFR2', 'Gene', (157, 162))	('IDH', 'Gene', (139, 142))	('FGFR2', 'Gene', '2263', (157, 162))	('IDH', 'Gene', '3417', (139, 142))	('mutations', 'Var', (143, 152))
83555	30815737	Some progress has been made with the identification of isocitrate dehydrogenase (IDH) mutations and fibroblast growth factor receptor 2 (FGFR2) fusions as drivers in small subsets of intrahepatic cholangiocarcinoma tumors.	('FGFR2', 'Gene', (137, 142))	('mutations', 'Var', (86, 95))	('intrahepatic cholangiocarcinoma tumors', 'Disease', (183, 221))	('intrahepatic cholangiocarcinoma tumors', 'Disease', 'MESH:D018281', (183, 221))	('FGFR2', 'Gene', '2263', (137, 142))	('IDH', 'Gene', '3417', (81, 84))	('isocitrate dehydrogenase', 'Gene', '3417', (55, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (196, 214))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('fibroblast growth factor receptor 2', 'Gene', '2263', (100, 135))	('fibroblast growth factor receptor 2', 'Gene', (100, 135))	('IDH', 'Gene', (81, 84))	('fusions', 'Var', (144, 151))	('isocitrate dehydrogenase', 'Gene', (55, 79))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
83560	30815737	Furthermore, mutations in Hippo pathway components themselves are uncommon in human CCA, placing additional emphasis on understanding post-translational regulatory mechanisms in driving Hippo/YAP activity in CCA.	('CCA', 'Phenotype', 'HP:0030153', (84, 87))	('Hippo', 'Gene', '37247', (186, 191))	('Hippo', 'Gene', '37247', (26, 31))	('Hippo', 'Gene', (186, 191))	('CCA', 'Phenotype', 'HP:0030153', (208, 211))	('mutations', 'Var', (13, 22))	('human', 'Species', '9606', (78, 83))	('Hippo', 'Gene', (26, 31))
83572	30815737	Phosphorylation of the YAP tyrosine 357 residue has been demonstrated in the setting of both cancer and inflammation.	('cancer', 'Disease', (93, 99))	('inflammation', 'Disease', (104, 116))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tyrosine 357 residue', 'Var', (27, 47))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Phosphorylation', 'MPA', (0, 15))	('demonstrated', 'Reg', (57, 69))	('inflammation', 'Disease', 'MESH:D007249', (104, 116))	('tyrosine', 'Chemical', 'MESH:D014443', (27, 35))
83583	30815737	Evaluation of EGF-mediated inhibition of the Hippo pathway in a mammary cell line, identified phosphoinositide 3-kinase (PI3K) and phosphoinositide-dependent kinase-1 as important downstream mediators of this receptor-mediated regulation, and suggested that PI3K activation may be a conserved mechanism of Hippo inhibition via multiple mitogenic signals.	('Hippo', 'Gene', '37247', (306, 311))	('Hippo', 'Gene', '37247', (45, 50))	('PI3K', 'Var', (258, 262))	('Hippo', 'Gene', (45, 50))	('Hippo', 'Gene', (306, 311))
83597	30815737	Importantly, genetic alterations of YAP and/or other Hippo pathway components appear to be an uncommon event in human CCA and are not likely to represent significant drivers of tumorigenesis.	('tumor', 'Disease', (177, 182))	('CCA', 'Disease', (118, 121))	('Hippo', 'Gene', '37247', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('YAP', 'Gene', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('CCA', 'Phenotype', 'HP:0030153', (118, 121))	('genetic alterations', 'Var', (13, 32))	('human', 'Species', '9606', (112, 117))	('Hippo', 'Gene', (53, 58))
83598	30815737	The recently reported TCGA analysis of CCA specimens demonstrated only 5% of specimens with a mutation in Salvador, and 3% with an NF2 mutation.	('mutation', 'Var', (94, 102))	('NF2', 'Gene', (131, 134))	('NF2', 'Gene', '4771', (131, 134))	('Salvador', 'Gene', '252554', (106, 114))	('Salvador', 'Gene', (106, 114))	('CCA', 'Phenotype', 'HP:0030153', (39, 42))
83605	30815737	Initial studies evaluating the consequence of genetic deletion of Hippo pathway components in murine models demonstrated high levels of mortality, and subsequent conditional knockouts demonstrated tissue overgrowth (especially in the liver) and eventual tumor formation.	('tumor', 'Disease', (254, 259))	('deletion', 'Var', (54, 62))	('Hippo', 'Gene', (66, 71))	('murine', 'Species', '10090', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('overgrowth', 'Phenotype', 'HP:0001548', (204, 214))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('tissue overgrowth', 'CPA', (197, 214))	('Hippo', 'Gene', '37247', (66, 71))
83613	30815737	Interestingly, both activated YAP and myr-AKT are necessary for tumor formation, and omission of IL-33, a potent biliary mitogen, significantly reduces the efficiency of tumor formation from ~ 70% down to ~ 20%.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', (64, 69))	('reduces', 'NegReg', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('omission', 'Var', (85, 93))	('tumor', 'Disease', (170, 175))	('IL-33', 'Gene', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
83625	30815737	Recent work has identified another potential target in a genetic liver cancer model driven by activate (S127A) YAP which was also found to be present in CCA cell lines.	('activate (S127A', 'Var', (94, 109))	('genetic liver cancer', 'Disease', 'MESH:D030342', (57, 77))	('liver cancer', 'Phenotype', 'HP:0002896', (65, 77))	('genetic liver cancer', 'Disease', (57, 77))	('YAP', 'Gene', (111, 114))	('S127A', 'Mutation', 'rs762471803', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('CCA', 'Phenotype', 'HP:0030153', (153, 156))
83626	30815737	utilized a ChIP-Seq/bioinformatics approach to identify YAP-driven targets with enzymatic activity that could be potentially targeted in hepatocytes bearing the S127A mutant YAP as well as the HuCCT1 CCA cell line.	('YAP', 'Gene', (174, 177))	('HuCCT1', 'CellLine', 'CVCL:0324', (193, 199))	('S127A', 'Mutation', 'rs762471803', (161, 166))	('S127A', 'Var', (161, 166))	('CCA', 'Phenotype', 'HP:0030153', (200, 203))
83627	30815737	The investigators identified NUAK2 as a YAP target gene and utilized a semi-specific small molecule inhibitor to demonstrate that inhibition of this enzyme decreased the growth rate of liver cancer cells in vitro as well as the growth rate of HuCCT1 cell line xenografts in mice.	('liver cancer', 'Phenotype', 'HP:0002896', (185, 197))	('inhibition', 'Var', (130, 140))	('liver cancer', 'Disease', 'MESH:D006528', (185, 197))	('NUAK2', 'Gene', '81788', (29, 34))	('liver cancer', 'Disease', (185, 197))	('HuCCT1', 'CellLine', 'CVCL:0324', (243, 249))	('growth rate', 'CPA', (228, 239))	('decreased', 'NegReg', (156, 165))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('mice', 'Species', '10090', (274, 278))	('NUAK2', 'Gene', (29, 34))	('growth rate', 'CPA', (170, 181))
83658	29434290	We observed high immunoreactivity for KI67 in the nuclei and for CK19 in the cytoplasm of components cells of the IHCC organoids and tissues (Fig.	('KI67', 'Chemical', '-', (38, 42))	('CK19', 'Gene', (65, 69))	('CK19', 'Gene', '3880', (65, 69))	('KI67', 'Var', (38, 42))	('immunoreactivity', 'MPA', (17, 33))
83675	29434290	As expected, removal of R-spondin 1, the ligand of LGR5 in Wnt signaling, from EM increased the expression of mature hepatocyte markers to a marked degree (Fig.	('removal', 'Var', (13, 20))	('LGR5', 'Gene', '8549', (51, 55))	('LGR5', 'Gene', (51, 55))	('expression', 'MPA', (96, 106))	('increased', 'PosReg', (82, 91))
83679	29434290	3c, DNA demethylation induced by 5-Aza-CdR significantly increased the expression of markers for mature hepatocytes.	('5-Aza-CdR', 'Var', (33, 42))	('5-Aza-CdR', 'Chemical', '-', (33, 42))	('DNA demethylation', 'MPA', (4, 21))	('increased', 'PosReg', (57, 66))	('expression of', 'MPA', (71, 84))
83715	29434290	As we confirmed that IHCC organoids derived from patient #2 harbor the driver gene mutations including TP53 and IDH1, and can be stably cultured for over one year, we consider these organoids to be a cancer organoid line, although they did not form tumors on SCID mice.	('mutations', 'Var', (83, 92))	('TP53', 'Gene', '7157', (103, 107))	('SCID', 'Disease', 'MESH:D053632', (259, 263))	('IDH1', 'Gene', '3417', (112, 116))	('SCID', 'Disease', (259, 263))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('TP53', 'Gene', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('IDH1', 'Gene', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('patient', 'Species', '9606', (49, 56))	('mice', 'Species', '10090', (264, 268))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))	('tumors', 'Disease', (249, 255))
83723	29434290	8a, Kupffer cells were isolated as F4/80high and CD11blow cells, and recruited macrophages as F4/80low and CD11bhigh cells.	('CD11b', 'Gene', '3684', (107, 112))	('CD11b', 'Gene', '3684', (49, 54))	('CD11b', 'Gene', (107, 112))	('CD11b', 'Gene', (49, 54))	('F4/80low', 'Var', (94, 102))
83739	29434290	Our results indicate that DAPT is important for suppression of genes associated with stemness and EMT, but has less effect on hepatocyte differentiation of IHCC organoids, suggesting that inhibition of Notch signaling is important for reduction of the malignant potential of human IHCC organoids.	('DAPT', 'Chemical', '-', (26, 30))	('inhibition', 'Var', (188, 198))	('reduction', 'NegReg', (235, 244))	('human', 'Species', '9606', (275, 280))	('stemness', 'Disease', (85, 93))	('stemness', 'Disease', 'MESH:D020295', (85, 93))	('malignant potential of human', 'CPA', (252, 280))
83742	29434290	have shown that mutant IDH inhibits HNF4a to block hepatocyte differentiation and promote biliary cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('inhibits', 'NegReg', (27, 35))	('promote', 'PosReg', (82, 89))	('block', 'NegReg', (45, 50))	('hepatocyte differentiation', 'CPA', (51, 77))	('mutant', 'Var', (16, 22))	('biliary cancer', 'Disease', (90, 104))	('HNF4a', 'Gene', '3172', (36, 41))	('HNF4a', 'Gene', (36, 41))	('IDH', 'Gene', (23, 26))	('biliary cancer', 'Disease', 'MESH:D001661', (90, 104))	('IDH', 'Gene', '3417', (23, 26))
83751	29434290	As modulation of the Wnt signaling pathway appears to be critical for transdifferentiation between mature hepatocytes and IHCC cells, inhibition of this pathway might be a promising approach for prevention of IHCC, especially in patients with chronic inflammatory liver diseases such as viral hepatitis.	('patients', 'Species', '9606', (229, 237))	('viral hepatitis', 'Phenotype', 'HP:0006562', (287, 302))	('inhibition', 'Var', (134, 144))	('IHCC', 'Disease', (209, 213))	('liver diseases', 'Phenotype', 'HP:0001392', (264, 278))	('inflammatory liver diseases', 'Disease', 'MESH:D008107', (251, 278))	('viral hepatitis', 'Disease', (287, 302))	('hepatitis', 'Phenotype', 'HP:0012115', (293, 302))	('inflammatory liver diseases', 'Disease', (251, 278))	('viral hepatitis', 'Disease', 'MESH:D006525', (287, 302))
83759	29434290	The xenograft tumor tissues and the surgically resected tumor tissues were cut into small pieces and incubated in digestion buffer for 1 hour at 37  C. The digestion buffer was composed of Dulbecco's modified Eagle medium (DMEM) with 2.5% fetal bovine serum, 0.0125% dispase type II (Thermo Fisher Scientific) and 0.0125% collagenase type XI (Sigma-Aldrich).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (14, 19))	('DMEM', 'Chemical', '-', (223, 227))	('tumor', 'Disease', (56, 61))	("Dulbecco's modified Eagle medium", 'Chemical', '-', (189, 221))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('0.0125%', 'Var', (314, 321))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('bovine', 'Species', '9913', (245, 251))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
83880	27499090	3C, the expression levels of cyclin D1 and CDK4 were reduced in a dose-dependent manner after treatment with Sch B.	('Sch B', 'Chemical', 'MESH:C015499', (109, 114))	('cyclin D1', 'Gene', '595', (29, 38))	('CDK4', 'Gene', (43, 47))	('cyclin D1', 'Gene', (29, 38))	('reduced', 'NegReg', (53, 60))	('CDK4', 'Gene', '1019', (43, 47))	('Sch', 'Var', (109, 112))	('expression levels', 'MPA', (8, 25))
83885	27499090	In addition, PI nucleic acid dye gains entry into late apoptotic and necrotic cells, but not into early apoptotic and living cells.	('entry', 'CPA', (39, 44))	('necrotic', 'Disease', (69, 77))	('PI nucleic acid dye', 'Var', (13, 32))	('gains', 'PosReg', (33, 38))	('necrotic', 'Disease', 'MESH:D009336', (69, 77))
83893	27499090	6A, increased expression of cleaved PARP, Bax, cleaved caspase-9 and cleaved caspase-3, and decreased expression of Bcl-2 was observed after Sch B treatment, which was consistent with apoptosis induced by Sch B.	('cleaved', 'Var', (28, 35))	('Bcl-2', 'Gene', (116, 121))	('Bax', 'Gene', (42, 45))	('PARP', 'Gene', (36, 40))	('increased', 'PosReg', (4, 13))	('caspase-9', 'Gene', (55, 64))	('Bax', 'Gene', '581', (42, 45))	('caspase-3', 'Gene', '836', (77, 86))	('Bcl-2', 'Gene', '596', (116, 121))	('caspase-3', 'Gene', (77, 86))	('Sch B', 'Chemical', 'MESH:C015499', (141, 146))	('cleaved', 'Var', (47, 54))	('decreased', 'NegReg', (92, 101))	('Sch B', 'Chemical', 'MESH:C015499', (205, 210))	('expression', 'MPA', (102, 112))	('cleaved', 'Var', (69, 76))	('expression', 'MPA', (14, 24))	('PARP', 'Gene', '1302', (36, 40))	('caspase-9', 'Gene', '842', (55, 64))
83916	27499090	Caspase-3 cleaves several cellular proteins, including the PARP protein, resulting in morphological changes and DNA fragmentation that eventually lead to apoptosis.	('Caspase-3', 'Gene', (0, 9))	('PARP', 'Gene', '1302', (59, 63))	('PARP', 'Gene', (59, 63))	('apoptosis', 'CPA', (154, 163))	('cleaves', 'Var', (10, 17))	('DNA fragmentation', 'CPA', (112, 129))	('lead to', 'Reg', (146, 153))	('morphological changes', 'CPA', (86, 107))	('Caspase-3', 'Gene', '836', (0, 9))
83921	27499090	Consistent with this result, an obvious decrease of DeltaPsim was observed in CCA cells treated with Sch B.	('decrease', 'NegReg', (40, 48))	('Sch', 'Var', (101, 104))	('Sch B', 'Chemical', 'MESH:C015499', (101, 106))	('DeltaPsim', 'MPA', (52, 61))	('CCA', 'Phenotype', 'HP:0030153', (78, 81))
83962	27642345	The criteria for the diagnosis of liver abscesses after thermal treatment were as follows: 1) a fever of > 38.5 C for more than 3 days, 2) a peripheral blood leukocyte count of > 10 x 109/L or < 4x109/L, 3) repeated chills and fever, 4) positive blood cultures or bacterial cultures by aspiration, and 5) septic shock.	('abscess', 'Phenotype', 'HP:0025615', (40, 47))	('septic shock', 'Disease', (305, 317))	('septic shock', 'Phenotype', 'HP:0100806', (305, 317))	('blood leukocyte count', 'Phenotype', 'HP:0001974', (152, 173))	('septic shock', 'Disease', 'MESH:D012772', (305, 317))	('fever', 'Phenotype', 'HP:0001945', (96, 101))	('liver abscesses', 'Disease', (34, 49))	('liver abscesses', 'Phenotype', 'HP:0100523', (34, 49))	('fever', 'Disease', 'MESH:D005334', (227, 232))	('fever', 'Disease', (227, 232))	('< 4x109/L', 'Var', (193, 202))	('liver abscess', 'Phenotype', 'HP:0100523', (34, 47))	('fever', 'Phenotype', 'HP:0001945', (227, 232))	('aspiration', 'Phenotype', 'HP:0002835', (286, 296))	('chills', 'Phenotype', 'HP:0025143', (216, 222))	('shock', 'Phenotype', 'HP:0031273', (312, 317))	('fever', 'Disease', 'MESH:D005334', (96, 101))	('fever', 'Disease', (96, 101))	('abscesses', 'Phenotype', 'HP:0025615', (40, 49))
84029	27642345	However, in China, many patients with child-pugh class C cirrhosis choose thermal ablation even after receiving detailed information about its risks versus benefits, as there is no other effective therapy except for liver transplantation, which is expensive.	('cirrhosis', 'Phenotype', 'HP:0001394', (57, 66))	('thermal', 'Var', (74, 81))	('patients', 'Species', '9606', (24, 32))	('child', 'Species', '9606', (38, 43))	('C cirrhosis', 'Disease', (55, 66))	('C cirrhosis', 'Disease', 'MESH:D005355', (55, 66))
84033	27642345	Additionally, PEI in tumors close to the bile duct might increase the therapeutic efficacy while decreasing thermal injury to the bile duct, thus reducing the incidence of liver abscesses.	('decreasing', 'NegReg', (97, 107))	('PEI', 'Var', (14, 17))	('abscesses', 'Phenotype', 'HP:0025615', (178, 187))	('tumors', 'Disease', (21, 27))	('therapeutic', 'MPA', (70, 81))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('liver', 'Disease', (172, 177))	('increase', 'PosReg', (57, 65))	('abscess', 'Phenotype', 'HP:0025615', (178, 185))	('reducing', 'NegReg', (146, 154))	('liver abscesses', 'Phenotype', 'HP:0100523', (172, 187))	('liver abscess', 'Phenotype', 'HP:0100523', (172, 185))	('thermal injury to the bile duct', 'MPA', (108, 139))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
84063	26895909	Data were collected taking into account author and institution, publication date, study period, study design, number of patients undergoing laparoscopy, number of completed procedures, number of patients undergoing laparoscopic intraoperative ultrasound (IOUS), number of avoided laparotomies, total number of patients with unresectable disease, number of liver, peritoneal and lymph node metastases, locally advanced disease, other reasons for unresectability, true positives, true negatives, false positives, false negatives, complications following SL and time interval between SL and laparotomy.	('patients', 'Species', '9606', (310, 318))	('unresectable disease', 'Disease', (324, 344))	('metastases', 'Disease', 'MESH:D009362', (389, 399))	('locally', 'Disease', (401, 408))	('patients', 'Species', '9606', (195, 203))	('patients', 'Species', '9606', (120, 128))	('false positives', 'Var', (494, 509))	('metastases', 'Disease', (389, 399))
84156	26388910	reported that the genetic and gene expression alterations may underlie the sarcomatous change or epithelial mesenchymal transition in cholangiocarcinoma.	('underlie', 'Reg', (62, 70))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (134, 152))	('epithelial mesenchymal transition', 'CPA', (97, 130))	('sarcomatous change', 'Disease', (75, 93))	('sarcomatous change', 'Disease', 'MESH:D018316', (75, 93))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (134, 152))	('alterations', 'Var', (46, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('sarcomatous change', 'Phenotype', 'HP:0100242', (75, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('cholangiocarcinoma', 'Disease', (134, 152))
84213	21464819	Furthermore, knocking down the expression of GPR55 prevented the antiproliferative effects of anandamide.	('antiproliferative effects of anandamide', 'MPA', (65, 104))	('knocking down', 'Var', (13, 26))	('GPR55', 'Gene', '9290', (45, 50))	('prevented', 'NegReg', (51, 60))	('GPR55', 'Gene', (45, 50))	('anandamide', 'Chemical', 'MESH:C078814', (94, 104))
84216	21464819	Activation of GPR55 by anandamide or O-1602 increased the amount of Fas in the lipid raft fractions, which could be blocked by pretreatment with the JNK inhibitor.	('anandamide', 'Chemical', 'MESH:C078814', (23, 33))	('GPR55', 'Gene', '9290', (14, 19))	('O-1602', 'Var', (37, 43))	('GPR55', 'Gene', (14, 19))	('lipid', 'Chemical', 'MESH:D008055', (79, 84))	('JNK', 'Gene', '5599', (149, 152))	('Fas', 'Chemical', 'MESH:C038178', (68, 71))	('amount of Fas in the lipid raft fractions', 'MPA', (58, 99))	('increased', 'PosReg', (44, 53))	('O-1602', 'Chemical', 'MESH:C568698', (37, 43))	('JNK', 'Gene', (149, 152))
84248	21464819	Bound Annexin V/biotin complex was detected with Cy2-labeled streptavidin (1:200 dilution in PBS), mounted onto microscope slides with Prolong Antifade Gold containing DAPI and visualized using an Olympus IX-71 inverted confocal microscope.	('Cy2-labeled', 'Var', (49, 60))	('Annexin V', 'Gene', '308', (6, 15))	('Annexin V', 'Gene', (6, 15))	('Cy2', 'Chemical', '-', (49, 52))	('PBS', 'Chemical', 'MESH:D007854', (93, 96))	('DAPI', 'Chemical', '-', (168, 172))
84272	21464819	Furthermore, there was an increase in apoptosis in all cholangiocarcinoma cell lines after O-1602 treatment as demonstrated by Annexin V staining (Supplemental Figure S2).	('Annexin V', 'Gene', '308', (127, 136))	('O-1602', 'Var', (91, 97))	('Annexin V', 'Gene', (127, 136))	('cholangiocarcinoma', 'Disease', (55, 73))	('apoptosis', 'CPA', (38, 47))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (55, 73))	('O-1602', 'Chemical', 'MESH:C568698', (91, 97))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (55, 73))
84273	21464819	Treating in vivo xenograft cholangiocarcinoma tumors with O-1602 significantly inhibited tumor growth (Figure 2B).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('xenograft cholangiocarcinoma tumors', 'Disease', 'MESH:D018281', (17, 52))	('O-1602', 'Chemical', 'MESH:C568698', (58, 64))	('tumor', 'Disease', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('O-1602', 'Var', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('xenograft cholangiocarcinoma tumors', 'Disease', (17, 52))	('inhibited', 'NegReg', (79, 88))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (27, 45))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
84275	21464819	Histological analysis of the excised tumors revealed that all cancer cells within tumors from O-1602-treated and vehicle-treated animals were CK-19 positive, indicating a cholangiocyte phenotype (Supplemental Figure S3).	('cancer cells within tumors', 'Disease', 'MESH:D001929', (62, 88))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('CK-19', 'Gene', (142, 147))	('O-1602-treated', 'Var', (94, 108))	('O-1602', 'Chemical', 'MESH:C568698', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancer cells within tumors', 'Disease', (62, 88))	('tumors', 'Disease', (37, 43))	('CK-19', 'Gene', '3880', (142, 147))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
84277	21464819	Using TUNEL staining as a marker of apoptosis, O-1602 treatment increased the incidence of apoptosis in the cholangiocarcinoma tumors (Supplemental Figure S3).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('apoptosis', 'CPA', (91, 100))	('O-1602', 'Var', (47, 53))	('cholangiocarcinoma tumors', 'Disease', 'MESH:D018281', (108, 133))	('cholangiocarcinoma tumors', 'Disease', (108, 133))	('increased', 'PosReg', (64, 73))	('O-1602', 'Chemical', 'MESH:C568698', (47, 53))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (108, 126))
84283	21464819	Both AEA and O-1602 decreased cell viability in Mz-Neo neg to a similar degree, but failed to have any effect in Mz-GPR55 shRNA cells (Figure 3A).	('AEA', 'Chemical', 'MESH:C078814', (5, 8))	('O-1602', 'Chemical', 'MESH:C568698', (13, 19))	('decreased', 'NegReg', (20, 29))	('Mz-GPR55 shRNA', 'Gene', (113, 127))	('Mz-Neo', 'Chemical', '-', (48, 54))	('O-1602', 'Var', (13, 19))	('Mz-GPR55 shRNA', 'Gene', '9290', (113, 127))	('cell viability', 'CPA', (30, 44))
84284	21464819	Similarly, AEA and O-1602 increased the amount of apoptotic cells in Mz-Neo neg cells, but had no effect in the Mz-GPR55 shRNA cells (Supplemental Figure S5).	('Mz-GPR55 shRNA', 'Gene', (112, 126))	('AEA', 'Chemical', 'MESH:C078814', (11, 14))	('O-1602', 'Var', (19, 25))	('Mz-GPR55 shRNA', 'Gene', '9290', (112, 126))	('increased', 'PosReg', (26, 35))	('Mz-Neo', 'Chemical', '-', (69, 75))	('O-1602', 'Chemical', 'MESH:C568698', (19, 25))
84285	21464819	The growth suppressive effects of AEA and O-1602 were evident in the xenograft model of cholangiocarcinoma using Mz-Neo neg cells (Figure 3B), whereas tumors derived from the implantation of Mz-GPR55 shRNA were not sensitive to AEA or O-1602 (Figure 3B).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 106))	('Mz-GPR55 shRNA', 'Gene', (191, 205))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('O-1602', 'Chemical', 'MESH:C568698', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('AEA', 'Chemical', 'MESH:C078814', (34, 37))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('Mz-Neo', 'Chemical', '-', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('Mz-Neo', 'Var', (113, 119))	('cholangiocarcinoma', 'Disease', (88, 106))	('growth', 'MPA', (4, 10))	('Mz-GPR55 shRNA', 'Gene', '9290', (191, 205))	('O-1602', 'Chemical', 'MESH:C568698', (235, 241))	('AEA', 'Chemical', 'MESH:C078814', (228, 231))
84289	21464819	We then assessed the effects of AEA and O-1602 on these cells in vitro and clearly demonstrated that, as seen above, both AEA and O-1602 decreased cell viability in Mz-Neo neg to a similar degree, but failed to have any effect in Mz-Galpha12 shRNA cells (Figure 4).	('O-1602', 'Chemical', 'MESH:C568698', (40, 46))	('cell viability', 'CPA', (147, 161))	('AEA', 'Var', (122, 125))	('O-1602', 'Var', (130, 136))	('AEA', 'Chemical', 'MESH:C078814', (122, 125))	('Mz-Neo', 'Chemical', '-', (165, 171))	('Galpha12', 'Gene', '2768', (233, 241))	('Galpha12', 'Gene', (233, 241))	('AEA', 'Chemical', 'MESH:C078814', (32, 35))	('decreased', 'NegReg', (137, 146))	('O-1602', 'Chemical', 'MESH:C568698', (130, 136))
84290	21464819	Similarly, AEA and O-1602 increased the amount of apoptotic cells in Mz-Neo neg cells, but had no effect in the Mz-Galpha12 shRNA cells (Supplemental Figure S7), suggesting a dependence on Galpha12 for the antiproliferative effects of AEA and O-1602.	('O-1602', 'Chemical', 'MESH:C568698', (243, 249))	('AEA', 'Chemical', 'MESH:C078814', (11, 14))	('O-1602', 'Var', (19, 25))	('Galpha12', 'Gene', (189, 197))	('Galpha12', 'Gene', '2768', (189, 197))	('O-1602', 'Chemical', 'MESH:C568698', (19, 25))	('apoptotic cells', 'CPA', (50, 65))	('Mz-Neo', 'Chemical', '-', (69, 75))	('Galpha12', 'Gene', '2768', (115, 123))	('Galpha12', 'Gene', (115, 123))	('AEA', 'Chemical', 'MESH:C078814', (235, 238))
84293	21464819	Treatment of Mz-ChA-1 cells with AEA and O-1602 increased JNK activity 1 hr after stimulation, an effect that continued up to 6 hours (Figure 5A).	('increased', 'PosReg', (48, 57))	('AEA', 'Chemical', 'MESH:C078814', (33, 36))	('O-1602', 'Chemical', 'MESH:C568698', (41, 47))	('O-1602', 'Var', (41, 47))	('JNK', 'Gene', (58, 61))	('JNK', 'Gene', '5599', (58, 61))
84296	21464819	Treatment of the Mz-Neo neg cells with AEA and O-1602 caused an increase in JNK activity in a similar manner to that seen in the parental cell line (Figure 5C).	('JNK', 'Gene', (76, 79))	('AEA', 'Chemical', 'MESH:C078814', (39, 42))	('O-1602', 'Var', (47, 53))	('JNK', 'Gene', '5599', (76, 79))	('Mz-Neo', 'Chemical', '-', (17, 23))	('increase', 'PosReg', (64, 72))	('O-1602', 'Chemical', 'MESH:C568698', (47, 53))
84299	21464819	We have previously shown that AEA exerts its tumor-suppressive effects via the stabilization of lipid raft structures and that disrupting lipid rafts prevents these antiproliferative effects.	('AEA', 'Chemical', 'MESH:C078814', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('disrupting', 'Var', (127, 137))	('lipid', 'Chemical', 'MESH:D008055', (138, 143))	('lipid rafts', 'MPA', (138, 149))	('tumor', 'Disease', (45, 50))	('lipid raft structures', 'MPA', (96, 117))	('lipid', 'Chemical', 'MESH:D008055', (96, 101))	('prevents', 'NegReg', (150, 158))	('stabilization', 'MPA', (79, 92))	('antiproliferative effects', 'CPA', (165, 190))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
6750	21464819	Indeed, activation of Notch 1 has been shown to upregulate the expression of Wnt5a in a number of cell models.	('Notch 1', 'Gene', '4851', (22, 29))	('Wnt5a', 'Gene', (77, 82))	('Wnt5a', 'Gene', '7474', (77, 82))	('expression', 'MPA', (63, 73))	('Notch 1', 'Gene', (22, 29))	('activation', 'Var', (8, 18))	('upregulate', 'PosReg', (48, 58))
84352	21464819	Furthermore, our data also suggest that the recruitment of GPR55 and Galpha12 occurs upon receptor activation by AEA and O-1602.	('GPR55', 'Gene', '9290', (59, 64))	('GPR55', 'Gene', (59, 64))	('O-1602', 'Chemical', 'MESH:C568698', (121, 127))	('O-1602', 'Var', (121, 127))	('recruitment', 'MPA', (44, 55))	('Galpha12', 'Gene', (69, 77))	('Galpha12', 'Gene', '2768', (69, 77))	('AEA', 'Chemical', 'MESH:C078814', (113, 116))
84364	21464819	Downstream of these AEA-mediated effects was the recruitment of Fas into lipid rafts, which did not occur in cells with GPR55 or Galpha12 expression knocked down, nor after the pretreatment of cells with a JNK inhibitor.	('knocked', 'Var', (149, 156))	('GPR55', 'Gene', (120, 125))	('Galpha12', 'Gene', (129, 137))	('JNK', 'Gene', '5599', (206, 209))	('Galpha12', 'Gene', '2768', (129, 137))	('AEA', 'Chemical', 'MESH:C078814', (20, 23))	('Fas', 'Chemical', 'MESH:C038178', (64, 67))	('lipid', 'Chemical', 'MESH:D008055', (73, 78))	('JNK', 'Gene', (206, 209))	('GPR55', 'Gene', '9290', (120, 125))	('recruitment', 'MPA', (49, 60))
84526	30971436	BiliSeq improved the sensitivity of pathological evaluation for malignancy from 35% to 77% for biliary brushings and from 52% to 83% for biliary biopsies.	('malignancy', 'Disease', (64, 74))	('biliary brushings', 'Disease', 'MESH:D001661', (95, 112))	('improved', 'PosReg', (8, 16))	('BiliSeq', 'Var', (0, 7))	('biliary brushings', 'Disease', (95, 112))	('malignancy', 'Disease', 'MESH:D009369', (64, 74))
84531	30971436	Additionally, BiliSeq identified alterations that may stratify patients for specific anticancer therapies.	('stratify', 'Reg', (54, 62))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('alterations', 'Var', (33, 44))	('cancer', 'Disease', (89, 95))	('patients', 'Species', '9606', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
84534	30971436	We have developed and validated a highly sensitive, targeted next-generation sequencing (NGS) assay (BiliSeq) within a Clinical Laboratory Improvement Amendments-certified and College of American Pathologists-accredited laboratory for 28 genes that are commonly mutated, amplified and/or deleted in malignant neoplasms involving the bile duct system.	('mutated', 'Var', (262, 269))	('men', 'Species', '9606', (156, 159))	('men', 'Species', '9606', (146, 149))	('men', 'Species', '9606', (152, 155))	('malignant neoplasms', 'Disease', 'MESH:D009369', (299, 318))	('neoplasms', 'Phenotype', 'HP:0002664', (309, 318))	('deleted', 'Var', (288, 295))	('malignant neoplasms', 'Disease', (299, 318))
84535	30971436	A large prospective analysis of ERCP-obtained biliary specimens revealed BiliSeq improved the sensitivity of pathological evaluation for both biliary brushing and biliary biopsy specimens.	('improved', 'PosReg', (81, 89))	('men', 'Species', '9606', (183, 186))	('sensitivity', 'MPA', (94, 105))	('BiliSeq', 'Var', (73, 80))	('men', 'Species', '9606', (59, 62))
84536	30971436	Among patients with primary sclerosing cholangitis, BiliSeq was superior to serum CA19-9 and pathological evaluation in detecting at least high-grade biliary dysplasia.	('biliary dysplasia', 'Disease', 'MESH:D001661', (150, 167))	('cholangitis', 'Phenotype', 'HP:0030151', (39, 50))	('biliary dysplasia', 'Disease', (150, 167))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (28, 50))	('primary sclerosing cholangitis', 'Disease', 'MESH:D015209', (20, 50))	('patients', 'Species', '9606', (6, 14))	('primary sclerosing cholangitis', 'Disease', (20, 50))	('BiliSeq', 'Var', (52, 59))
84546	30971436	To improve the detection of malignant strictures, adjunctive techniques were developed and include digital image analysis, KRAS mutational testing and fluorescence in situ hybridisation.	('mutational testing', 'Var', (128, 146))	('KRAS', 'Gene', '3845', (123, 127))	('KRAS', 'Gene', (123, 127))
84553	30971436	Moreover, a subset of these genomic alterations, such as ATM and ERBB2, may confer susceptibility to specific anticancer therapies.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('susceptibility', 'Reg', (83, 97))	('alterations', 'Var', (36, 47))	('ERBB2', 'Gene', (65, 70))	('ATM', 'Gene', (57, 60))	('ERBB2', 'Gene', '2064', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('ATM', 'Gene', '472', (57, 60))	('cancer', 'Disease', (114, 120))
84585	30971436	Also, pharmacological inhibitors highly specific to individual IDH1 and IDH2 mutations have been developed.	('IDH2', 'Gene', (72, 76))	('IDH1', 'Gene', '3417', (63, 67))	('IDH2', 'Gene', '3418', (72, 76))	('mutations', 'Var', (77, 86))	('IDH1', 'Gene', (63, 67))
84606	30971436	Based on cut-off of >=44 U/mL, serum CA19-9 within the validation cohort had a sensitivity of 81% and specificity of 65% for at least high-grade biliary dysplasia (table 2).	('serum', 'Var', (31, 36))	('biliary dysplasia', 'Disease', 'MESH:D001661', (145, 162))	('CA19-9', 'Gene', (37, 43))	('biliary dysplasia', 'Disease', (145, 162))
84607	30971436	An overall analysis of both training and validation cohorts that included 220 patients with follow-up revealed sensitivities and specificities for serum CA19-9, pathological evaluation and BiliSeq testing of 76% and 69%, 48% and 99%, and 73% and 100%.	('serum', 'Var', (147, 152))	('CA19-9', 'Gene', (153, 159))	('patients', 'Species', '9606', (78, 86))
84622	30971436	Therefore, based on a cut-off of 129 U/mL, serum CA19-9 was associated with a 67% sensitivity and 84% specificity for at least high-grade biliary dysplasia.	('biliary dysplasia', 'Disease', 'MESH:D001661', (138, 155))	('CA19-9', 'Gene', (49, 55))	('serum', 'Var', (43, 48))	('biliary dysplasia', 'Disease', (138, 155))
84636	30971436	Alterations in genes involved in the receptor tyrosine kinase (RTK)/Ras/Mitogen-activated protein (MAP) kinase signalling pathway, which included ERBB2 (n=6), MET (n=4), ALK (n=2), FGFR2 (n=3) and FGFR3 (n=2), were detected in the majority of cases (n=13, 65%).	('FGFR2', 'Gene', (181, 186))	('FGFR2', 'Gene', '2263', (181, 186))	('FGFR3', 'Gene', (197, 202))	('Alterations', 'Var', (0, 11))	('MET', 'Gene', (159, 162))	('receptor tyrosine kinase', 'Gene', (37, 61))	('ERBB2', 'Gene', (146, 151))	('ERBB2', 'Gene', '2064', (146, 151))	('FGFR3', 'Gene', '2261', (197, 202))	('ALK', 'Gene', '238', (170, 173))	('receptor tyrosine kinase', 'Gene', '5979', (37, 61))	('ALK', 'Gene', (170, 173))
84638	30971436	Among the ERBB2-altered malignancies, two patients, whose adenocarcinoma harboured a copy number gain in ERBB2, received targeted chemotherapy to HER2/neu instead of standard chemotherapy alone.	('HER2', 'Gene', '2064', (146, 150))	('ERBB2', 'Gene', (105, 110))	('ERBB2', 'Gene', '2064', (105, 110))	('copy number gain', 'Var', (85, 101))	('adenocarcinoma', 'Disease', (58, 72))	('malignancies', 'Disease', 'MESH:D009369', (24, 36))	('ERBB2', 'Gene', (10, 15))	('adenocarcinoma', 'Disease', 'MESH:D000230', (58, 72))	('HER2', 'Gene', (146, 150))	('ERBB2', 'Gene', '2064', (10, 15))	('neu', 'Gene', '2064', (151, 154))	('malignancies', 'Disease', (24, 36))	('patients', 'Species', '9606', (42, 50))	('neu', 'Gene', (151, 154))
84642	30971436	However, BiliSeq testing detected an ERBB2 copy number gain and a TP53 mutation (p.C242fs*5 and c.723delC).	('ERBB2', 'Gene', (37, 42))	('ERBB2', 'Gene', '2064', (37, 42))	('p.C242fs*5', 'Var', (81, 91))	('c.723delC', 'Var', (96, 105))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('gain', 'PosReg', (55, 59))	('c.723delC', 'Mutation', 'c.723delC', (96, 105))	('p.C242fs*5', 'Mutation', 'p.C242fsX5', (81, 91))
84652	30971436	The patient's corresponding BiliSeq testing revealed a copy number gain in ERBB2 and copy number losses in TP53 and CDKN2A.	('ERBB2', 'Gene', (75, 80))	('ERBB2', 'Gene', '2064', (75, 80))	('CDKN2A', 'Gene', (116, 122))	('copy number', 'Var', (85, 96))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('patient', 'Species', '9606', (4, 11))	('CDKN2A', 'Gene', '1029', (116, 122))	('copy number', 'Var', (55, 66))	('gain', 'PosReg', (67, 71))
84673	30971436	The lowest limit of detection for our NGS assay is approximately 3% of mutant alleles or, for a heterozygous mutation, such as KRAS, 6% tumour cellularity.	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('tumour', 'Disease', (136, 142))	('KRAS', 'Gene', (127, 131))	('mutant', 'Var', (71, 77))	('KRAS', 'Gene', '3845', (127, 131))
84675	30971436	Previous studies using surgical resection material have demonstrated KRAS mutations in cases of low-grade biliary dysplasia and benign cholangiopathy.	('KRAS', 'Gene', (69, 73))	('KRAS', 'Gene', '3845', (69, 73))	('biliary dysplasia', 'Disease', 'MESH:D001661', (106, 123))	('mutations', 'Var', (74, 83))	('biliary dysplasia', 'Disease', (106, 123))	('benign cholangiopathy', 'Disease', (128, 149))	('benign cholangiopathy', 'Disease', 'MESH:D009369', (128, 149))
84676	30971436	Therefore, increasing the sensitivity of BiliSeq for KRAS mutations may result in a decrease in specificity for at least high-grade biliary dysplasia.	('decrease', 'NegReg', (84, 92))	('mutations', 'Var', (58, 67))	('specificity', 'MPA', (96, 107))	('increasing', 'PosReg', (11, 21))	('KRAS', 'Gene', (53, 57))	('biliary dysplasia', 'Disease', 'MESH:D001661', (132, 149))	('KRAS', 'Gene', '3845', (53, 57))	('biliary dysplasia', 'Disease', (132, 149))	('sensitivity', 'MPA', (26, 37))
84678	30971436	For example, mutations in chromatin remodelling genes (eg, ARID1A) and FGFR2 fusion genes are present in up to 20% of intrahepatic cholangiocarcinomas.	('intrahepatic cholangiocarcinomas', 'Disease', (118, 150))	('present', 'Reg', (94, 101))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:C535533', (118, 150))	('ARID1A', 'Gene', '8289', (59, 65))	('ARID1A', 'Gene', (59, 65))	('FGFR2', 'Gene', (71, 76))	('FGFR2', 'Gene', '2263', (71, 76))	('mutations', 'Var', (13, 22))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))
84694	30971436	On relapse or progression after first-line or second-line chemotherapy, comprehensive genomic profiling for a subset of tumours has identified alterations that are potentially targetable or predictive markers of response to specific therapy.	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumours', 'Disease', (120, 127))	('alterations', 'Var', (143, 154))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
84695	30971436	For example, ERBB2 amplification has been reported in intrahepatic cholangiocarcinoma, perihilar/distal cholangiocarcinoma and gallbladder adenocarcinoma with a prevalence of 5%, 17% and 19%, respectively.	('gallbladder adenocarcinoma', 'Disease', 'MESH:D005706', (127, 153))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))	('gallbladder adenocarcinoma', 'Disease', (127, 153))	('amplification', 'Var', (19, 32))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('reported', 'Reg', (42, 50))	('cholangiocarcinoma', 'Disease', (104, 122))	('ERBB2', 'Gene', '2064', (13, 18))	('ERBB2', 'Gene', (13, 18))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (104, 122))	('cholangiocarcinoma', 'Disease', (67, 85))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (104, 122))	('intrahepatic cholangiocarcinoma', 'Disease', (54, 85))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:C535533', (54, 85))
84698	30971436	Within our study, BiliSeq testing identified two patients with ERBB2 amplification: one intrahepatic cholangiocarcinoma and one perihilar cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (101, 119))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('ERBB2', 'Gene', '2064', (63, 68))	('cholangiocarcinoma', 'Disease', (138, 156))	('ERBB2', 'Gene', (63, 68))	('cholangiocarcinoma', 'Disease', (101, 119))	('patients', 'Species', '9606', (49, 57))	('intrahepatic cholangiocarcinoma', 'Disease', (88, 119))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:C535533', (88, 119))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (138, 156))	('amplification', 'Var', (69, 82))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (138, 156))
84747	30849962	Interestingly, CA9 can be released into the circulation by ectodomain shedding, which then influence its biological function.	('biological function', 'MPA', (105, 124))	('influence', 'Reg', (91, 100))	('ectodomain shedding', 'Var', (59, 78))	('CA9', 'Gene', '768', (15, 18))	('CA9', 'Gene', (15, 18))
84750	30849962	IDH1 mutation has been identified in a variety of tumor types, such as glioma, acute myelogenous leukemia, central and periosteal cartilaginous tumors and ICC.	('IDH1', 'Gene', (0, 4))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (79, 105))	('periosteal cartilaginous tumors', 'Disease', (119, 150))	('periosteal cartilaginous tumors', 'Disease', 'MESH:D010522', (119, 150))	('tumor', 'Disease', (50, 55))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (85, 105))	('IDH1', 'Gene', '3417', (0, 4))	('tumor', 'Disease', (144, 149))	('acute myelogenous leukemia', 'Disease', (79, 105))	('glioma', 'Disease', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('identified', 'Reg', (23, 33))	('ICC', 'Disease', (155, 158))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (79, 105))	('leukemia', 'Phenotype', 'HP:0001909', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('mutation', 'Var', (5, 13))
84751	30849962	IDH1 mutation is associated with a good prognosis in patients with glioma but with a worse prognosis in ICC patients.	('patients', 'Species', '9606', (108, 116))	('patients', 'Species', '9606', (53, 61))	('glioma', 'Disease', (67, 73))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('IDH1', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
84783	30849962	However, a higher mortality rate was associated with Beclin-1 expression (HR = 2.39, 95% Confidence Interval [CI]: 1.09-5.24).	('Beclin-1', 'Gene', (53, 61))	('expression', 'Var', (62, 72))	('Beclin-1', 'Gene', '8678', (53, 61))
84786	30849962	In addition to Beclin-1, ARID1A expression was associated with a 1.71-fold higher risk of recurrence (95% CI: 1.06-2.78).	('Beclin-1', 'Gene', '8678', (15, 23))	('ARID1A', 'Gene', '8289', (25, 31))	('expression', 'Var', (32, 42))	('ARID1A', 'Gene', (25, 31))	('recurrence', 'Disease', (90, 100))	('Beclin-1', 'Gene', (15, 23))
84793	30849962	Kaplan-Meier survival curves showed that high levels of Beclin-1 were associated with poor prognosis.	('high levels', 'Var', (41, 52))	('Beclin-1', 'Gene', '8678', (56, 64))	('Beclin-1', 'Gene', (56, 64))
84795	30849962	In contrast, the OS rate for those with high levels of ARID1A expression was lower than that of those with low ARID1A expression, but the difference was not statistically significant (p = 0.07; Fig.	('lower', 'NegReg', (77, 82))	('ARID1A', 'Gene', '8289', (111, 117))	('OS rate', 'MPA', (17, 24))	('ARID1A', 'Gene', (111, 117))	('ARID1A', 'Gene', '8289', (55, 61))	('ARID1A', 'Gene', (55, 61))	('expression', 'Var', (62, 72))	('OS', 'Chemical', '-', (17, 19))
84798	30849962	The expression of CA9 and IDH1 in these double positive Beclin-1 and ARID1A patients was further analyzed.	('patients', 'Species', '9606', (76, 84))	('double positive', 'Var', (40, 55))	('CA9', 'Gene', (18, 21))	('IDH1', 'Gene', (26, 30))	('ARID1A', 'Gene', '8289', (69, 75))	('CA9', 'Gene', '768', (18, 21))	('Beclin-1', 'Gene', (56, 64))	('ARID1A', 'Gene', (69, 75))	('Beclin-1', 'Gene', '8678', (56, 64))	('IDH1', 'Gene', '3417', (26, 30))
84827	30849962	It is likely that IDH1 gene mutation, but not the protein level, is the crucial factor contributing to ICC pathogenesis, mortality and disease recurrence.	('ICC', 'Disease', (103, 106))	('contributing', 'Reg', (87, 99))	('IDH1', 'Gene', '3417', (18, 22))	('mutation', 'Var', (28, 36))	('IDH1', 'Gene', (18, 22))
84828	30849962	Mutation in the IDH1 gene might not significant alter the protein level; thus, histological staining for IDH1 could not be used to diagnose ICC.	('IDH1', 'Gene', (105, 109))	('ICC', 'Disease', (140, 143))	('Mutation', 'Var', (0, 8))	('IDH1', 'Gene', (16, 20))	('IDH1', 'Gene', '3417', (105, 109))	('IDH1', 'Gene', '3417', (16, 20))
84831	30849962	In contrast to Korkeila's immunohistochemical analysis of CA9, disease-free survival was significantly shorter in patients with moderate/strong CA9 staining intensity.	('CA9', 'Gene', (58, 61))	('CA9', 'Gene', (144, 147))	('CA9', 'Gene', '768', (58, 61))	('moderate/strong', 'Var', (128, 143))	('CA9', 'Gene', '768', (144, 147))	('shorter', 'NegReg', (103, 110))	('disease-free survival', 'CPA', (63, 84))	('patients', 'Species', '9606', (114, 122))
84845	30849962	Of importance, patients with high expression of both Beclin-1 and ARID1A had very poor OS and RFS rates.	('Beclin-1', 'Gene', (53, 61))	('patients', 'Species', '9606', (15, 23))	('high expression', 'Var', (29, 44))	('Beclin-1', 'Gene', '8678', (53, 61))	('OS', 'Chemical', '-', (87, 89))	('ARID1A', 'Gene', '8289', (66, 72))	('RFS rates', 'CPA', (94, 103))	('ARID1A', 'Gene', (66, 72))	('poor', 'NegReg', (82, 86))
84918	28844952	For example, IDH catalytic site mutations and constitutively active FGFR2 fusion genes are predominantly identified in iCCA, whereas KRAS mutations and PRKACB fusions genes are identified in pCCA and dCCA.	('PRKACB', 'Gene', (152, 158))	('IDH', 'Gene', '3417', (13, 16))	('CCA', 'Phenotype', 'HP:0030153', (192, 195))	('CCA', 'Phenotype', 'HP:0030153', (120, 123))	('FGFR2', 'Gene', '2263', (68, 73))	('mutations', 'Var', (32, 41))	('KRAS', 'Gene', (133, 137))	('CCA', 'Phenotype', 'HP:0030153', (201, 204))	('PRKACB', 'Gene', '5567', (152, 158))	('identified', 'Reg', (105, 115))	('KRAS', 'Gene', '3845', (133, 137))	('IDH', 'Gene', (13, 16))	('FGFR2', 'Gene', (68, 73))	('iCCA', 'Disease', (119, 123))
84926	28844952	Mutations of CDKN2, also called p16INK4a have been described in 15-20% of CCA, predominantly pCCA and dCCA.	('p16INK4a', 'Gene', (32, 40))	('described', 'Reg', (51, 60))	('dCCA', 'Disease', (102, 106))	('p16', 'Gene', '1029', (32, 35))	('p16INK4a', 'Gene', '1029', (32, 40))	('CDKN2', 'Gene', '1029', (13, 18))	('CCA', 'Disease', (74, 77))	('pCCA', 'Disease', (93, 97))	('CDKN2', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('CCA', 'Phenotype', 'HP:0030153', (103, 106))	('CCA', 'Phenotype', 'HP:0030153', (94, 97))	('p16', 'Gene', (32, 35))	('CCA', 'Phenotype', 'HP:0030153', (74, 77))
84927	28844952	Inactivating mutations result in deregulation of cell cycle control by the INK4 family proteins p16 and p14ARF.	('INK4', 'Gene', (75, 79))	('p16', 'Var', (96, 99))	('p14ARF', 'Gene', '1029', (104, 110))	('Inactivating mutations', 'Var', (0, 22))	('deregulation', 'MPA', (33, 45))	('cell cycle control', 'CPA', (49, 67))	('p14ARF', 'Gene', (104, 110))
84928	28844952	Focal losses of CDKN2A as well as epigenetic silencing were frequently found in a set of 38 CCA analyzed by the Cancer Genome Atlas Network (TCGN).	('epigenetic silencing', 'Var', (34, 54))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('CCA', 'Disease', (92, 95))	('losses', 'NegReg', (6, 12))	('CCA', 'Phenotype', 'HP:0030153', (92, 95))
84930	28844952	As in many malignomas, activating KRAS mutations are frequently detected in all subtypes of CCA and can be found in up to 40% of CCA, predominantly in perihilar and distal CCA.	('malignomas', 'Disease', 'None', (11, 21))	('CCA', 'Phenotype', 'HP:0030153', (129, 132))	('CCA', 'Phenotype', 'HP:0030153', (172, 175))	('CCA', 'Disease', (129, 132))	('mutations', 'Var', (39, 48))	('CCA', 'Disease', (92, 95))	('CCA', 'Phenotype', 'HP:0030153', (92, 95))	('malignomas', 'Disease', (11, 21))	('man', 'Species', '9606', (6, 9))	('KRAS', 'Gene', (34, 38))	('activating', 'PosReg', (23, 33))
84938	28844952	Non-canonical Hh signaling promotes CCA tumor progression and inhibition of this signaling pathway with a specific antagonist to the Hh receptor protein Smoothened resulted in reduced tumor growth and metastasis in a murine model of CCA.	('CCA', 'Phenotype', 'HP:0030153', (233, 236))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('CCA', 'Disease', (36, 39))	('reduced', 'NegReg', (176, 183))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('murine', 'Species', '10090', (217, 223))	('CCA', 'Disease', (233, 236))	('inhibition', 'Var', (62, 72))	('CCA', 'Phenotype', 'HP:0030153', (36, 39))
84939	28844952	Hedgehog signaling inhibitors are approved for use in patients with germ line mutations given rise to basal cell carcinomas.	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (102, 123))	('mutations', 'Var', (78, 87))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (102, 123))	('basal cell carcinomas', 'Disease', (102, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('carcinomas', 'Disease', 'MESH:D002277', (113, 123))	('carcinomas', 'Disease', (113, 123))
84940	28844952	Of the potentially targetable diver mutations specifically found in iCCA, mutations that alter fibroblast growth factor (FGF) signaling, primarily by FGF receptor 2 (FGFR2) gene fusions are among the most frequent, occurring in 10 up to 45% of all iCCA.	('FGF receptor 2', 'Gene', (150, 164))	('FGFR2', 'Gene', (166, 171))	('CCA', 'Phenotype', 'HP:0030153', (69, 72))	('mutations', 'Var', (74, 83))	('iCCA', 'Disease', (248, 252))	('FGF receptor 2', 'Gene', '2263', (150, 164))	('alter', 'Reg', (89, 94))	('CCA', 'Phenotype', 'HP:0030153', (249, 252))
84941	28844952	FGF downstream signaling pathways that become activated by FGF fusion proteins include the RAS-RAF-MEK-MAPK axis.	('activated', 'PosReg', (46, 55))	('RAF', 'Gene', (95, 98))	('FGF', 'Gene', (59, 62))	('RAF', 'Gene', '22882', (95, 98))	('fusion', 'Var', (63, 69))
84943	28844952	The unselective FGFR inhibitor BGJ398 did show anti-tumor activity and acceptable side effects in a phase I clinical trial of 132 patients with solid organ tumors and known FGFR mutations.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('BGJ398', 'Chemical', 'MESH:C568950', (31, 37))	('BGJ398', 'Gene', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('solid organ tumors', 'Disease', 'MESH:D009369', (144, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('anti-tumor activity', 'CPA', (47, 66))	('solid organ tumors', 'Disease', (144, 162))	('mutations', 'Var', (178, 187))	('FGFR', 'Gene', (173, 177))
84944	28844952	An ongoing phase II clinical trial of second-line BGJ398 in CCA patients with FGFR mutations after unsuccessful platinum based first-line treatment reports an astonishing 82% disease control rate in these advanced stage CCA patients (NCT02150967).	('mutations', 'Var', (83, 92))	('FGFR', 'Gene', (78, 82))	('CCA', 'Phenotype', 'HP:0030153', (220, 223))	('CCA', 'Disease', (60, 63))	('platinum', 'Chemical', 'MESH:D010984', (112, 120))	('CCA', 'Phenotype', 'HP:0030153', (60, 63))
84946	28844952	The ATP competitive small molecule kinase inhibitor ARQ 087 has demonstrated anti-proliferative activity in cell lines with various activating FGFR mutations.	('mutations', 'Var', (148, 157))	('FGFR', 'Gene', (143, 147))	('ATP', 'Chemical', 'MESH:D000255', (4, 7))	('ARQ 087', 'Chemical', 'MESH:C000621805', (52, 59))	('anti-proliferative activity', 'MPA', (77, 104))	('activating', 'PosReg', (132, 142))
84947	28844952	Several other FGFR kinase inhibitors, such as AZD4547, TAS120 and CH5183284/Debio 1347 are in early clinical trials after promising pre-clinical results (NCT02052778; NCT01948297).	('TAS120', 'Chemical', '-', (55, 61))	('CH5183284/Debio', 'Var', (66, 81))	('FGFR', 'Gene', (14, 18))	('AZD4547', 'Chemical', 'MESH:C572463', (46, 53))	('CH5183284', 'Chemical', 'MESH:C000602562', (66, 75))
84948	28844952	Ponatinib and pazopanib have demonstrated activity in individual patients with very advanced iCCA and FGFR fusion mutations.	('FGFR', 'Gene', (102, 106))	('activity', 'MPA', (42, 50))	('mutations', 'Var', (114, 123))	('pazopanib', 'Chemical', 'MESH:C516667', (14, 23))	('iCCA', 'Disease', (93, 97))	('Ponatinib', 'Chemical', 'MESH:C545373', (0, 9))	('CCA', 'Phenotype', 'HP:0030153', (94, 97))
84949	28844952	In addition to small molecule inhibitors, the monoclonal antibody FPA144 that is specific for the mutated FGFR2b isoform is currently being tested in patients with malignant tumors that overexpress or have amplified this particular receptor isoform (NCT02318329).	('overexpress', 'PosReg', (186, 197))	('amplified', 'PosReg', (206, 215))	('malignant tumors', 'Disease', (164, 180))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('mutated', 'Var', (98, 105))	('malignant tumors', 'Disease', 'MESH:D018198', (164, 180))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('FGFR2b', 'Gene', (106, 112))
84958	28844952	Kotschy and colleagues recently described S63845, a small molecule BH-3 mimetic that binds and inhibits Mcl1 with high affinity.	('Mcl1', 'Gene', '4170', (104, 108))	('Mcl1', 'Gene', (104, 108))	('S63845', 'Var', (42, 48))	('inhibits', 'NegReg', (95, 103))	('binds', 'Interaction', (85, 90))
84959	28844952	In mechanistic studies S63845 potently killed Mcl1-dependent cancer cells by activation of the BAX/BAK-dependent mitochondrial pathway of apoptosis.	('BAX', 'Gene', '581', (95, 98))	('S63845', 'Var', (23, 29))	('activation', 'PosReg', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('BAK', 'Gene', (99, 102))	('BAX', 'Gene', (95, 98))	('BAK', 'Gene', '578', (99, 102))
84960	28844952	Mutations in the alpha-ketoglutarate synthesizing enzymes IDH 1 and 2 are found in up to 30% of iCCA and much less frequent in pCCA.	('IDH 1 and 2', 'Gene', '3417;3418', (58, 69))	('found', 'Reg', (74, 79))	('IDH 1', 'Gene', '3417', (58, 63))	('iCCA', 'Disease', (96, 100))	('CCA', 'Phenotype', 'HP:0030153', (97, 100))	('Mutations', 'Var', (0, 9))	('CCA', 'Phenotype', 'HP:0030153', (128, 131))	('IDH 1', 'Gene', (58, 63))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (17, 36))
84961	28844952	Several known IDH mutations result in dysfunctional enzymes and lead to increased intracellular levels of 2-hydroxyglutarate which induces epigenetic changes and thus shows a diverse array of oncogenic effects.	('mutations', 'Var', (18, 27))	('IDH', 'Gene', (14, 17))	('increased', 'PosReg', (72, 81))	('intracellular levels of 2-hydroxyglutarate', 'MPA', (82, 124))	('increased intracellular levels', 'Phenotype', 'HP:0003575', (72, 102))	('dysfunctional enzymes', 'MPA', (38, 59))	('result in', 'Reg', (28, 37))	('induces', 'Reg', (131, 138))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (106, 124))	('epigenetic changes', 'MPA', (139, 157))
84962	28844952	AG-120 is an oral selective inhibitor of mutant IDH1 was well tolerated and has demonstrated therapeutic activity with reduction of 2-HG levels in solid tumors including CCA.	('mutant', 'Var', (41, 47))	('IDH1', 'Gene', '3417', (48, 52))	('CCA', 'Disease', (170, 173))	('AG-120', 'Chemical', 'MESH:C000627630', (0, 6))	('2-HG levels', 'MPA', (132, 143))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('IDH1', 'Gene', (48, 52))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('reduction', 'NegReg', (119, 128))	('CCA', 'Phenotype', 'HP:0030153', (170, 173))
84963	28844952	Patients with solid tumors that carry IDH2 mutations can be enrolled in the clinical trials evaluating the inhibitor of mutant IDH2, the orally bioavailable compound AG-221 (NCT02273739).	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('IDH2', 'Gene', (127, 131))	('IDH2', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('Patients', 'Species', '9606', (0, 8))	('IDH2', 'Gene', '3418', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('IDH2', 'Gene', '3418', (38, 42))	('mutant', 'Var', (120, 126))
84973	28844952	The recently described activating ERBB2 kinase mutation V777L was resistant to reversible inhibition by lapatinib but showed sensitivity to the irreversible inhibitor nertatinib.	('lapatinib', 'Chemical', 'MESH:D000077341', (104, 113))	('V777L', 'Var', (56, 61))	('ERBB2', 'Gene', (34, 39))	('V777L', 'Mutation', 'rs121913471', (56, 61))	('nertatinib', 'Chemical', '-', (167, 177))	('activating', 'PosReg', (23, 33))
84987	28844952	CCA Cholangiocarcinoma iCCA Intrahepatic CCA pCCA Perihilar CCA dCCA Distal CCA CDK Cyclin dependent kinase CDKN2A/B Cyclin-dependent kinase inhibitor 2A/B PLK2 Polo-like kinase 2 FGF Fibroblast growth factor HGF Hepatocyte growth factor IDH 1/2 Isocytrate dehydrogenase 1/2 PTP Protein tyrosine phosphatases ARIDA1 AT-rich interactive domain-containing protein 1A	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (4, 22))	('2A/B', 'Var', (112, 116))	('CCA', 'Phenotype', 'HP:0030153', (0, 3))	('CCA', 'Phenotype', 'HP:0030153', (41, 44))	('Cyclin', 'Gene', (84, 90))	('2A/B', 'SUBSTITUTION', 'None', (112, 116))	('Cyclin', 'Gene', '5111', (117, 123))	('2A/B', 'Var', (151, 155))	('2A/B', 'SUBSTITUTION', 'None', (151, 155))	('CCA', 'Phenotype', 'HP:0030153', (24, 27))	('CCA', 'Phenotype', 'HP:0030153', (46, 49))	('Cyclin', 'Gene', '5111', (84, 90))	('Cyclin', 'Gene', (117, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('CCA', 'Phenotype', 'HP:0030153', (60, 63))
85006	27902465	It is also known that trabectedin causes a marked decrease in the production of several cytokines and chemokines secreted by monocytes/macrophages and tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('trabectedin', 'Chemical', 'MESH:D000077606', (22, 33))	('tumor', 'Disease', (151, 156))	('trabectedin', 'Var', (22, 33))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('decrease', 'NegReg', (50, 58))
85011	27902465	We reported that trabectedin inhibits BTC in vitro cell growth and causes a significant delay of tumor growth in vivo in mouse models of human BTC, EGI-1 extrahepatic cholangiocarcinoma xenograft and a new intrahepatic cholangiocarcinoma (ICC) patient-derived tumor xenograft (PDX), causing a decrease of tumor proliferating cells and tumor vessel formation.	('tumor', 'Disease', (260, 265))	('trabectedin', 'Var', (17, 28))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('tumor', 'Disease', (305, 310))	('human', 'Species', '9606', (137, 142))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (167, 185))	('BTC', 'MPA', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('tumor', 'Disease', (97, 102))	('inhibits', 'NegReg', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('delay of tumor', 'Disease', (88, 102))	('trabectedin', 'Chemical', 'MESH:D000077606', (17, 28))	('tumor', 'Disease', (335, 340))	('EGI-1 extrahepatic cholangiocarcinoma xenograft', 'Disease', 'MESH:D018281', (148, 195))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('EGI-1 extrahepatic cholangiocarcinoma xenograft', 'Disease', (148, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('patient', 'Species', '9606', (244, 251))	('tumor', 'Disease', 'MESH:D009369', (335, 340))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (206, 237))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mouse', 'Species', '10090', (121, 126))	('intrahepatic cholangiocarcinoma', 'Disease', (206, 237))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (219, 237))	('delay of tumor', 'Disease', 'MESH:D009369', (88, 102))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('decrease', 'NegReg', (293, 301))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
85033	27902465	Cell migration, significantly reduced by trabectedin treatment, is statistically significant inhibited also by silencing of SYK and LGALS1; the simultaneous silencing of target genes potentiates the anti-migratory effect (Figure 4).	('trabectedin', 'Chemical', 'MESH:D000077606', (41, 52))	('potentiates', 'PosReg', (183, 194))	('Cell migration', 'CPA', (0, 14))	('silencing', 'Var', (111, 120))	('LGALS1', 'Gene', '3956', (132, 138))	('LGALS1', 'Gene', (132, 138))	('reduced', 'NegReg', (30, 37))	('silencing', 'Var', (157, 166))	('anti-migratory effect', 'CPA', (199, 220))	('SYK', 'Gene', (124, 127))	('inhibited', 'NegReg', (93, 102))	('SYK', 'Gene', '6850', (124, 127))
85035	27902465	Similarly to the MT-CHC01, single and combined knock-down of SYK and LGALS1 reduced cell migration in a statistical significant manner (Figure 6), but did not have effect on proliferation (data not shown).	('knock-down', 'Var', (47, 57))	('LGALS1', 'Gene', '3956', (69, 75))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (17, 25))	('SYK', 'Gene', (61, 64))	('LGALS1', 'Gene', (69, 75))	('SYK', 'Gene', '6850', (61, 64))	('cell migration', 'CPA', (84, 98))	('reduced', 'NegReg', (76, 83))
85044	27902465	Interestingly, the microRNA-target prediction analysis showed that SYK is a putative target of all up-regulated microRNAs, while LGALS1 is a predicted target only of miR1207-5p and miR1225-5p.	('SYK', 'Gene', '6850', (67, 70))	('miR1207', 'Gene', '100302175', (166, 173))	('miR1207', 'Gene', (166, 173))	('miR1225-5p', 'Var', (181, 191))	('up-regulated', 'PosReg', (99, 111))	('LGALS1', 'Gene', (129, 135))	('LGALS1', 'Gene', '3956', (129, 135))	('SYK', 'Gene', (67, 70))
85063	27902465	The lack of inhibition of proliferation demonstrated that the silencing of these genes is not sufficient to mimic trabectedin effect, suggesting that a more complex mechanism of drug-targets regulates cell growth.	('silencing', 'Var', (62, 71))	('cell', 'CPA', (201, 205))	('trabectedin', 'Chemical', 'MESH:D000077606', (114, 125))
85067	27902465	The same mechanism could be supposed for miRNA 331-3p, down-regulated by trabectedin and demonstrated to promote proliferation and EMT in hepatocellular carcinoma.	('promote', 'PosReg', (105, 112))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (138, 162))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (138, 162))	('trabectedin', 'Chemical', 'MESH:D000077606', (73, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('hepatocellular carcinoma', 'Disease', (138, 162))	('EMT', 'CPA', (131, 134))	('miRNA 331-3p', 'Var', (41, 53))	('down-regulated', 'NegReg', (55, 69))	('proliferation', 'CPA', (113, 126))
85095	27902465	Further, a validation of the expression of miR-4284, miR 21-5p, and miR-494-3p was performed using TaqMan Assay.	('miR-4284', 'Gene', '100422948', (43, 51))	('miR 21-5p', 'Gene', '406997', (53, 62))	('miR 21-5p', 'Gene', (53, 62))	('miR-494-3p', 'Var', (68, 78))	('miR-4284', 'Gene', (43, 51))
85103	26077733	Aberrations of miRNAs have been shown involved in the progression of this disease.	('Aberrations', 'Var', (0, 11))	('involved', 'Reg', (38, 46))	('miR', 'Gene', '220972', (15, 18))	('miR', 'Gene', (15, 18))
85109	26077733	Smad4 was over-expressed in most of the EHCC patients and was further demonstrated as one of the downstream targets of miR-34a, which was involved in the progression of EHCC.	('EHCC', 'Disease', (40, 44))	('over-expressed', 'PosReg', (10, 24))	('EHCC', 'Disease', (169, 173))	('involved', 'Reg', (138, 146))	('patients', 'Species', '9606', (45, 53))	('CC', 'Phenotype', 'HP:0030153', (171, 173))	('CC', 'Phenotype', 'HP:0030153', (42, 44))	('Smad4', 'Gene', (0, 5))	('Smad4', 'Gene', '4089', (0, 5))	('miR-34a', 'Var', (119, 126))
85122	26077733	As a direct transcriptional target of p53, decreased expression of miR-34a is partly due to the mutations of p53 in tumors.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('miR-34a', 'Gene', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('p53', 'Gene', (109, 112))	('p53', 'Gene', '7157', (109, 112))	('expression', 'MPA', (53, 63))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('decreased', 'NegReg', (43, 52))	('mutations', 'Var', (96, 105))
85124	26077733	Moreover, miR-34a can suppress tumor metastasis and invasion through a variety of signaling pathways in several cancers.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('miR-34a', 'Var', (10, 17))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor metastasis', 'Disease', 'MESH:D009362', (31, 47))	('tumor metastasis', 'Disease', (31, 47))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('suppress', 'NegReg', (22, 30))	('cancers', 'Disease', (112, 119))	('invasion', 'CPA', (52, 60))
85125	26077733	However, the anti-tumor function of miR-34a in EHCC is still not clear yet.	('CC', 'Phenotype', 'HP:0030153', (49, 51))	('tumor', 'Disease', (18, 23))	('EHCC', 'Disease', (47, 51))	('miR-34a', 'Var', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
85132	26077733	We identify miR-34a could mediate TGF-beta/Smad4 signaling pathway induced EMT in the progression of cholangiocarcinoma.	('TGF-beta', 'Gene', (34, 42))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (101, 119))	('mediate', 'Reg', (26, 33))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('miR-34a', 'Var', (12, 19))	('cholangiocarcinoma', 'Disease', (101, 119))	('EMT', 'CPA', (75, 78))	('TGF-beta', 'Gene', '7040', (34, 42))	('Smad4', 'Gene', (43, 48))	('Smad4', 'Gene', '4089', (43, 48))
85172	26077733	To further evaluate the clinical value of miR-34a in EHCC patients, we divided the patients into two groups according to the median value (5.113) of the expression level of miR-34a.	('CC', 'Phenotype', 'HP:0030153', (55, 57))	('patients', 'Species', '9606', (83, 91))	('miR-34a', 'Var', (173, 180))	('EHCC', 'Disease', (53, 57))	('patients', 'Species', '9606', (58, 66))
85188	26077733	Moreover, partial mutation of the perfectly complementary sites in the 3'-UTR of Smad4 abolished the suppressive effect due to the disruption of the interaction between miR-34a and Smad4 (Fig.	('Smad4', 'Gene', '4089', (181, 186))	('abolished', 'NegReg', (87, 96))	('disruption', 'NegReg', (131, 141))	('suppressive effect', 'MPA', (101, 119))	('miR-34a', 'Gene', (169, 176))	('interaction', 'Interaction', (149, 160))	('partial mutation', 'Var', (10, 26))	('Smad4', 'Gene', (81, 86))	('Smad4', 'Gene', '4089', (81, 86))	('Smad4', 'Gene', (181, 186))
85192	26077733	These data suggest that Smad4 expression was primarily inhibited by miR-34a at the translational level.	('expression', 'MPA', (30, 40))	('miR-34a', 'Var', (68, 75))	('inhibited', 'NegReg', (55, 64))	('Smad4', 'Gene', (24, 29))	('Smad4', 'Gene', '4089', (24, 29))
85193	26077733	Together, these results confirmed that Smad4 is a direct target of miR-34a and is regulated by miR-34a in CC cell lines.	('regulated', 'Reg', (82, 91))	('miR-34a', 'Gene', (67, 74))	('Smad4', 'Gene', (39, 44))	('Smad4', 'Gene', '4089', (39, 44))	('miR-34a', 'Var', (95, 102))	('CC', 'Phenotype', 'HP:0030153', (106, 108))
85197	26077733	Western blot analysis showed that compared with TGF-beta treatment alone, transfection of miR-34a mimics increased E-cadherin expression levels while decreasing Smad4 and N-cadherin protein levels (Fig.	('N-cadherin', 'Gene', (171, 181))	('miR-34a', 'Gene', (90, 97))	('TGF-beta', 'Gene', (48, 56))	('N-cadherin', 'Gene', '1000', (171, 181))	('mimics', 'Var', (98, 104))	('decreasing', 'NegReg', (150, 160))	('increased', 'PosReg', (105, 114))	('Smad4', 'Gene', (161, 166))	('Smad4', 'Gene', '4089', (161, 166))	('TGF-beta', 'Gene', '7040', (48, 56))	('E-cadherin', 'Gene', (115, 125))	('E-cadherin', 'Gene', '999', (115, 125))
85201	26077733	These data suggest that miR-34a could antagonize Smad4-mediated TGF-beta induction of EMT in vitro.	('Smad4', 'Gene', (49, 54))	('miR-34a', 'Var', (24, 31))	('Smad4', 'Gene', '4089', (49, 54))	('TGF-beta', 'Gene', '7040', (64, 72))	('TGF-beta', 'Gene', (64, 72))	('antagonize', 'NegReg', (38, 48))	('EMT', 'CPA', (86, 89))
85202	26077733	To further investigate whether miR-34a suppresses cell invasion and migration through TGF-beta/Smad4 signaling pathway in EHCC, both QBC939 and HuCCT1 cells were transfected with miR-34a mimics then treated with or without TGF-beta.	('TGF-beta', 'Gene', '7040', (86, 94))	('CC', 'Phenotype', 'HP:0030153', (124, 126))	('suppresses', 'NegReg', (39, 49))	('miR-34a', 'Var', (31, 38))	('TGF-beta', 'Gene', (223, 231))	('CC', 'Phenotype', 'HP:0030153', (146, 148))	('TGF-beta', 'Gene', '7040', (223, 231))	('TGF-beta', 'Gene', (86, 94))	('cell invasion', 'CPA', (50, 63))	('Smad4', 'Gene', '4089', (95, 100))	('Smad4', 'Gene', (95, 100))	('HuCCT1', 'CellLine', 'CVCL:0324', (144, 150))	('EHCC', 'Disease', (122, 126))	('migration', 'CPA', (68, 77))
85203	26077733	It was found that transfection with miR-34a significantly suppressed cell migration in both QBC939 and HuCCT1 cells.	('cell migration in', 'CPA', (69, 86))	('suppressed', 'NegReg', (58, 68))	('CC', 'Phenotype', 'HP:0030153', (105, 107))	('miR-34a', 'Var', (36, 43))	('HuCCT1', 'CellLine', 'CVCL:0324', (103, 109))
85206	26077733	Moreover, Snail protein expression level was decreased by transfection with miR-34a mimics but increased by transfection with miR-34a inhibitor in both QBC939 and HuCCT1 cells (Fig.	('HuCCT1', 'CellLine', 'CVCL:0324', (163, 169))	('CC', 'Phenotype', 'HP:0030153', (165, 167))	('decreased', 'NegReg', (45, 54))	('Snail', 'Gene', '6615', (10, 15))	('Snail', 'Gene', (10, 15))	('increased', 'PosReg', (95, 104))	('miR-34a', 'Var', (126, 133))
85220	26077733	Recent studies have found that miR-34a represses RhoA, a regulator of cell migration and invasion, by suppressing c-Myc-Skp2-Miz1 transcriptional complex that activates RhoA in human prostate cancer cells.	('RhoA', 'Gene', (49, 53))	('prostate cancer', 'Disease', (183, 198))	('c-Myc', 'Gene', '4609', (114, 119))	('miR-34a', 'Var', (31, 38))	('RhoA', 'Gene', (169, 173))	('RhoA', 'Gene', '387', (49, 53))	('activates', 'PosReg', (159, 168))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('suppressing', 'NegReg', (102, 113))	('RhoA', 'Gene', '387', (169, 173))	('prostate cancer', 'Disease', 'MESH:D011471', (183, 198))	('c-Myc', 'Gene', (114, 119))	('prostate cancer', 'Phenotype', 'HP:0012125', (183, 198))	('Skp2', 'Gene', '6502', (120, 124))	('human', 'Species', '9606', (177, 182))	('Miz1', 'Gene', '7709', (125, 129))	('Skp2', 'Gene', (120, 124))	('Miz1', 'Gene', (125, 129))
85221	26077733	miR-34a was also found to reduce cell proliferation and invasiveness partially through its inhibitory effect on Delta-like 1 (DLL1) in choriocarcinoma.	('DLL1', 'Gene', (126, 130))	('reduce', 'NegReg', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('miR-34a', 'Var', (0, 7))	('inhibitory effect', 'NegReg', (91, 108))	('Delta-like 1', 'Gene', '28514', (112, 124))	('choriocarcinoma', 'Disease', 'MESH:D002822', (135, 150))	('invasiveness', 'CPA', (56, 68))	('choriocarcinoma', 'Disease', (135, 150))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (135, 150))	('Delta-like 1', 'Gene', (112, 124))	('cell proliferation', 'CPA', (33, 51))	('DLL1', 'Gene', '28514', (126, 130))
85223	26077733	Further investigation showed that miR-34a suppresses the activity of a luciferase reporter gene fused with the 3'-UTR of Smad4 mRNA, which is dependent on the miR-34a binding sequence.	('miR-34a', 'Var', (34, 41))	('Smad4', 'Gene', (121, 126))	('Smad4', 'Gene', '4089', (121, 126))	('luciferase reporter gene', 'Enzyme', (71, 95))	('suppresses', 'NegReg', (42, 52))	('activity', 'MPA', (57, 65))
85224	26077733	Our data revealed that miR-34a directly targets the 3'-UTR of Smad4, and that ectopic expression of miR-34a represses Smad4 protein level in CC cell lines.	('Smad4', 'Gene', (62, 67))	('Smad4', 'Gene', '4089', (62, 67))	('miR-34a', 'Var', (100, 107))	('represses', 'NegReg', (108, 117))	('Smad4', 'Gene', (118, 123))	('Smad4', 'Gene', '4089', (118, 123))	('CC', 'Phenotype', 'HP:0030153', (141, 143))
85225	26077733	Interestingly, recent report suggested that miR-34a plays a critical role in the progression of cardiac fibrosis by increasing Smad4 expression to activate TGF-beta1.	('expression', 'MPA', (133, 143))	('activate', 'PosReg', (147, 155))	('increasing', 'PosReg', (116, 126))	('cardiac fibrosis', 'Disease', (96, 112))	('TGF-beta1', 'Gene', '7040', (156, 165))	('TGF-beta1', 'Gene', (156, 165))	('miR-34a', 'Var', (44, 51))	('cardiac fibrosis', 'Disease', 'MESH:D005355', (96, 112))	('Smad4', 'Gene', (127, 132))	('Smad4', 'Gene', '4089', (127, 132))
85241	26077733	Based on the contrasting expression patterns of miR-34a and Smad4 in most of the EHCC tissues and our in vitro data, we proposed that miR-34a is involved in the pathogenesis of EHCC by directly inhibiting the protein expression of Smad4.	('CC', 'Phenotype', 'HP:0030153', (83, 85))	('protein expression', 'MPA', (209, 227))	('Smad4', 'Gene', (231, 236))	('Smad4', 'Gene', '4089', (231, 236))	('Smad4', 'Gene', '4089', (60, 65))	('EHCC', 'Disease', (177, 181))	('Smad4', 'Gene', (60, 65))	('miR-34a', 'Var', (134, 141))	('CC', 'Phenotype', 'HP:0030153', (179, 181))	('inhibiting', 'NegReg', (194, 204))
85253	23295441	The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC.	('HCC', 'Phenotype', 'HP:0001402', (324, 327))	('mutations', 'Var', (206, 215))	('patients', 'Species', '9606', (310, 318))	('KRAS', 'Gene', '3845', (219, 223))	('amplifications', 'Var', (157, 171))	('BRAF', 'Gene', '673', (228, 232))	('BRAF', 'Gene', (228, 232))	('activation', 'PosReg', (50, 60))	('HCC', 'Gene', (324, 327))	('deletions at', 'Var', (184, 196))	('mitogen-activated protein kinase', 'Pathway', (109, 141))	('KRAS', 'Gene', (219, 223))	('oncogenic signaling pathways', 'Pathway', (64, 92))	('HCC', 'Gene', '619501', (324, 327))	('RAS', 'Pathway', (104, 107))
85254	23295441	We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor).	('SAV1 tumor', 'Disease', 'MESH:D009369', (185, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('amplifications', 'Var', (25, 39))	('SAV1 tumor', 'Disease', (185, 195))	('deletions', 'Var', (110, 119))
85256	23295441	The proliferation class has specific copy number alterations, many features of the poor-prognosis signatures for HCC, and is associated with worse outcome.	('associated', 'Reg', (125, 135))	('HCC', 'Phenotype', 'HP:0001402', (113, 116))	('HCC', 'Gene', '619501', (113, 116))	('copy number alterations', 'Var', (37, 60))	('HCC', 'Gene', (113, 116))
85262	23295441	Activating mutations of KRAS, promoter hypermethylation of CDKN2A, and overexpression of MET and HER2 also have been described.	('HER2', 'Gene', (97, 101))	('MET', 'Protein', (89, 92))	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (11, 20))	('overexpression', 'PosReg', (71, 85))	('HER2', 'Gene', '2064', (97, 101))	('KRAS', 'Gene', '3845', (24, 28))	('CDKN2A', 'Gene', '1029', (59, 65))	('CDKN2A', 'Gene', (59, 65))	('promoter', 'MPA', (30, 38))	('KRAS', 'Gene', (24, 28))
85267	23295441	DNA copy number alterations represent a common mechanism driving oncogene and tumor-suppressor alterations.	('DNA', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('copy number alterations', 'Var', (4, 27))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
85300	23295441	Mutations at exon 15 of BRAF were found in 5 patients (5 of 141; 4%), 4 from the proliferation class (4 of 87 vs 1 of 54; P = NS, Supplementary Figure 9C and D).	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (45, 53))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('found', 'Reg', (34, 39))
85304	23295441	P1 was characterized by enrichment of KRAS mutations (6 of 35 vs 4 of 92 in the rest; P = .03), IGF1R and MET signaling pathways, and signatures of poor prognosis, including CC bad prognosis, G3, and S1 (false-discovery rate, < 0.25; Supplementary Table 11).	('IGF1R', 'Gene', '3480', (96, 101))	('MET signaling pathways', 'Pathway', (106, 128))	('KRAS', 'Gene', '3845', (38, 42))	('mutations', 'Var', (43, 52))	('IGF1R', 'Gene', (96, 101))	('KRAS', 'Gene', (38, 42))
85305	23295441	Finally, P3 showed chromosome 7p gains (17 of 28), EGFR overexpression (Supplementary Figure 11A and B; P < .001; Kruskal-Wallis test), EGFR mutations, and enrichment of an EGFR activation signature.	('B; P < .001', 'Species', '39445', (101, 112))	('mutations', 'Var', (141, 150))	('EGFR', 'Gene', (51, 55))	('gains', 'PosReg', (33, 38))	('EGFR', 'Gene', '1956', (173, 177))	('overexpression', 'PosReg', (56, 70))	('EGFR', 'Gene', (173, 177))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))	('EGFR', 'Gene', '1956', (51, 55))
85337	23295441	The expression levels of ORAOV1 were overexpressed significantly in both ICC and HCC patients with 11q13 HLAs, suggesting that this oncogene could be a common driver in liver tumors.	('expression levels', 'MPA', (4, 21))	('liver tumors', 'Phenotype', 'HP:0002896', (169, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('ICC', 'Disease', (73, 76))	('liver tumors', 'Disease', (169, 181))	('HCC', 'Gene', '619501', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('HCC', 'Phenotype', 'HP:0001402', (81, 84))	('patients', 'Species', '9606', (85, 93))	('11q13 HLAs', 'Var', (99, 109))	('liver tumors', 'Disease', 'MESH:D008113', (169, 181))	('ORAOV1', 'Gene', '220064', (25, 31))	('overexpressed', 'PosReg', (37, 50))	('HCC', 'Gene', (81, 84))	('ORAOV1', 'Gene', (25, 31))
85347	23295441	Consistent with the class-specific therapeutic approach, JAK-STAT inhibitors might be specifically more active in the inflammation class.	('JAK-STAT inhibitors', 'Var', (57, 76))	('inflammation', 'Disease', (118, 130))	('inflammation', 'Disease', 'MESH:D007249', (118, 130))
85357	23295441	-  We found a significant enrichment of the signatures related to EGFR, HER2, and MET in our proliferation class, even though no amplification of these receptors was observed in our dataset, suggesting that mechanisms other than amplification (eg, epigenetic changes) could be involved in their activation.	('HER2', 'Gene', (72, 76))	('MET', 'Gene', (82, 85))	('HER2', 'Gene', '2064', (72, 76))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('epigenetic changes', 'Var', (248, 266))
85361	23295441	Two important examples have occurred recently: BRAF mutations were reported in melanoma and EML4-ALK translocations were reported in non-small-cell lung cancer.	('mutations', 'Var', (52, 61))	('EML4', 'Gene', '27436', (92, 96))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('BRAF', 'Gene', (47, 51))	('ALK', 'Gene', '238', (97, 100))	('BRAF', 'Gene', '673', (47, 51))	('reported', 'Reg', (121, 129))	('translocations', 'Var', (101, 115))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (137, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Disease', (148, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('ALK', 'Gene', (97, 100))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('EML4', 'Gene', (92, 96))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
85363	23295441	For instance, we described 4% BRAF mutations, mostly V600E, for which the specific inhibitor PLX-4032 has shown efficacy.	('V600E', 'Mutation', 'rs113488022', (53, 58))	('BRAF', 'Gene', (30, 34))	('V600E', 'Var', (53, 58))	('BRAF', 'Gene', '673', (30, 34))	('PLX-4032', 'Chemical', 'MESH:D000077484', (93, 101))
85374	23295441	Furthermore, SAV1 conditional mutant mice developed liver overgrowth and mixed hepatocholangiocarcinoma tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('overgrowth', 'Phenotype', 'HP:0001548', (58, 68))	('developed', 'Reg', (42, 51))	('liver overgrowth', 'Disease', 'MESH:D008107', (52, 68))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('hepatocholangiocarcinoma tumors', 'Disease', 'MESH:D009369', (79, 110))	('SAV1', 'Gene', (13, 17))	('hepatocholangiocarcinoma tumors', 'Disease', (79, 110))	('liver overgrowth', 'Disease', (52, 68))	('mutant', 'Var', (30, 36))	('mice', 'Species', '10090', (37, 41))
85376	23295441	In our dataset, focal deletion at 14q22.1 was associated significantly with SAV1 reduced gene expression, BIRC2 overexpression, and earlier recurrence.	('SAV1', 'Gene', (76, 80))	('BIRC2', 'Gene', '329', (106, 111))	('focal deletion', 'Var', (16, 30))	('overexpression', 'PosReg', (112, 126))	('gene expression', 'MPA', (89, 104))	('BIRC2', 'Gene', (106, 111))	('reduced', 'NegReg', (81, 88))
85380	23295441	In addition, the copy number alterations provide insight on potential oncogenes and tumor suppressors as novel targets for therapies such as CCND1-p16, FGF19, ROR1, and SAV1, for which entire aberrant networks or specific genes could be targeted in personalized therapy.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('copy number alterations', 'Var', (17, 40))	('p16', 'Gene', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('CCND1', 'Gene', '595', (141, 146))	('tumor', 'Disease', (84, 89))	('FGF19', 'Gene', (152, 157))	('FGF19', 'Gene', '9965', (152, 157))	('ROR1', 'Gene', '4919', (159, 163))	('p16', 'Gene', '1029', (147, 150))	('ROR1', 'Gene', (159, 163))	('CCND1', 'Gene', (141, 146))
85381	23295441	CC     CI confidence interval CNV copy number variations ECC extrahepatic cholangiocarcinoma EGFR epidermal growth factor receptor FFPE formalin-fixed paraffin-embedded HCC hepatocellular carcinoma HLA high-level amplification HR hazard ratio ICC intrahepatic cholangiocarcinoma IL interleukin RTK receptor tyrosine kinase STAT	('receptor tyrosine kinase', 'Gene', (298, 322))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 92))	('EGFR', 'Gene', '1956', (93, 97))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (74, 92))	('formalin', 'Chemical', 'MESH:D005557', (136, 144))	('RTK', 'Gene', (294, 297))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (247, 278))	('intrahepatic cholangiocarcinoma', 'Disease', (247, 278))	('RTK', 'Gene', '5979', (294, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('variations', 'Var', (46, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('paraffin', 'Chemical', 'MESH:D010232', (151, 159))	('epidermal growth factor receptor', 'Gene', (98, 130))	('HCC', 'Gene', '619501', (169, 172))	('HCC', 'Phenotype', 'HP:0001402', (169, 172))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (260, 278))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (173, 197))	('extrahepatic cholangiocarcinoma', 'Disease', (61, 92))	('EGFR', 'Gene', (93, 97))	('epidermal growth factor receptor', 'Gene', '1956', (98, 130))	('HCC', 'Gene', (169, 172))	('receptor tyrosine kinase', 'Gene', '5979', (298, 322))
85430	30740723	Cholangiocarcinoma is often diagnosed in the explant after liver transplantation.41  This meta-analysis also showed acute cellular rejection to be a risk factor for rPSC.	('acute cellular', 'Var', (116, 130))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (0, 18))	('PSC', 'Gene', '100653366', (166, 169))	('PSC', 'Gene', (166, 169))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 18))	('Cholangiocarcinoma', 'Disease', (0, 18))
85539	30766964	Further, Gli1 ablation blunted the IL-33-induced epithelial cell proliferation (Fig.	('rat', 'Species', '10116', (72, 75))	('blunted', 'NegReg', (23, 30))	('epithelial cell proliferation', 'CPA', (49, 78))	('Gli1', 'Gene', (9, 13))	('ablation', 'Var', (14, 22))	('Gli1', 'Gene', '14632', (9, 13))
85544	30766964	Although WT and pCMV-Shh mice exhibited similar increases in Il6 mRNA expression after IL-33 treatment, Gli1 ablation blunted the Il6 mRNA response to IL-33lacZlacZ (Fig.	('blunted', 'NegReg', (118, 125))	('Gli1', 'Gene', (104, 108))	('mice', 'Species', '10090', (25, 29))	('ablation', 'Var', (109, 117))	('increases', 'PosReg', (48, 57))	('Il6', 'Gene', '16193', (61, 64))	('Il6', 'Gene', '16193', (130, 133))	('Il6', 'Gene', (130, 133))	('Il6', 'Gene', (61, 64))	('Shh', 'Gene', (21, 24))	('Gli1', 'Gene', '14632', (104, 108))	('Shh', 'Gene', '20423', (21, 24))
85574	30766964	It was reported that IL-33 promotes cholangiocyte proliferation indirectly through type 2 innate lymphoid cell IL-13.15 However, in our biliary organoid culture, we demonstrated that IL-33 also can directly induce proliferation in biliary progenitor cells.	('rat', 'Species', '10116', (221, 224))	('proliferation', 'CPA', (214, 227))	('rat', 'Species', '10116', (57, 60))	('induce', 'Reg', (207, 213))	('rat', 'Species', '10116', (172, 175))	('biliary progenitor cells', 'CPA', (231, 255))	('cholangiocyte proliferation', 'CPA', (36, 63))	('IL-33', 'Var', (183, 188))
85586	22209942	Overexpression or knockdown of CDK10, respectively, inhibited or promoted cell proliferation, colony formation and migration.	('knockdown', 'Var', (18, 27))	('colony formation', 'CPA', (94, 110))	('cell proliferation', 'CPA', (74, 92))	('migration', 'CPA', (115, 124))	('promoted', 'PosReg', (65, 73))	('CDK10', 'Gene', '8558', (31, 36))	('inhibited', 'NegReg', (52, 61))	('CDK10', 'Gene', (31, 36))
85588	22209942	Overexpression of CDK10 caused malignant cells to become sensitive to chemotherapy and other hostile environments, suggesting that CDK10 functions to regulate survivability of BTC cells.	('survivability', 'CPA', (159, 172))	('regulate', 'Reg', (150, 158))	('CDK10', 'Gene', '8558', (18, 23))	('CDK10', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('CDK10', 'Gene', '8558', (131, 136))	('BTC', 'Phenotype', 'HP:0100574', (176, 179))	('CDK10', 'Gene', (131, 136))
85604	22209942	In CCA and GBC, deletion or loss of heterozygosity (LOH) has been frequently detected for several regions of the long arm of chromosome 16, where CDK10 is located.	('loss of heterozygosity', 'NegReg', (28, 50))	('CCA', 'Phenotype', 'HP:0030153', (3, 6))	('deletion', 'Var', (16, 24))	('detected', 'Reg', (77, 85))	('CDK10', 'Gene', '8558', (146, 151))	('CCA', 'Disease', (3, 6))	('CDK10', 'Gene', (146, 151))
85674	22209942	Conversely, silencing of CDK10 clearly promoted the proliferation of HCCC-9180 and GBC-SD cells (P<0.001 and 0.05, respectively; Fig.	('proliferation', 'CPA', (52, 65))	('promoted', 'PosReg', (39, 47))	('HCCC-9180', 'CellLine', 'CVCL:6908', (69, 78))	('silencing', 'Var', (12, 21))	('CDK10', 'Gene', '8558', (25, 30))	('CDK10', 'Gene', (25, 30))	('GBC-SD cells', 'CPA', (83, 95))
85676	22209942	The results demonstrate that the lack of CDK10 increased proliferation.	('lack', 'Var', (33, 37))	('increased', 'PosReg', (47, 56))	('CDK10', 'Gene', (41, 46))	('proliferation', 'CPA', (57, 70))	('CDK10', 'Gene', '8558', (41, 46))
85678	22209942	3A, overexpression or knockdown of CDK10, respectively, attenuated or promoted colony formation of GBC-SD and HCCC-9180 cells (Fig.	('attenuated', 'NegReg', (56, 66))	('knockdown', 'Var', (22, 31))	('HCCC-9180', 'CellLine', 'CVCL:6908', (110, 119))	('colony formation', 'CPA', (79, 95))	('CDK10', 'Gene', '8558', (35, 40))	('promoted', 'PosReg', (70, 78))	('CDK10', 'Gene', (35, 40))
85679	22209942	Greater numbers of colonies of larger size were formed by knockdown of CDK10 as compared with control RNA, whereas CDK10-overexpressing cells formed only a few small colonies (Fig.	('CDK10', 'Gene', '8558', (71, 76))	('knockdown', 'Var', (58, 67))	('CDK10', 'Gene', (71, 76))	('CDK10', 'Gene', (115, 120))	('CDK10', 'Gene', '8558', (115, 120))	('colonies', 'CPA', (19, 27))
85681	22209942	CDK10 knockdown resulted in a significant increase in cell migration, compared to cells transfected with control RNA (Fig.	('CDK10', 'Gene', (0, 5))	('CDK10', 'Gene', '8558', (0, 5))	('knockdown', 'Var', (6, 15))	('cell migration', 'CPA', (54, 68))	('increase', 'PosReg', (42, 50))
85686	22209942	4A), CDK10 silencing significantly decreased sensitivity to 5-FU for all three cell lines, and overexpression of CDK10 increased sensitivity to 5-FU, conversely.	('silencing', 'Var', (11, 20))	('CDK10', 'Gene', (5, 10))	('sensitivity to 5-FU', 'MPA', (129, 148))	('5-FU', 'Chemical', 'MESH:D005472', (144, 148))	('CDK10', 'Gene', '8558', (113, 118))	('CDK10', 'Gene', (113, 118))	('overexpression', 'PosReg', (95, 109))	('decreased', 'NegReg', (35, 44))	('sensitivity to 5-FU', 'MPA', (45, 64))	('5-FU', 'Chemical', 'MESH:D005472', (60, 64))	('increased', 'PosReg', (119, 128))	('CDK10', 'Gene', '8558', (5, 10))
85688	22209942	For both GBC-SD and HCCC-9180 cells, after overexpression or silencing of CDK10, EADM, CDDP and HCPT showed similar alteration as 5-FU (Fig.	('CDK10', 'Gene', (74, 79))	('5-FU', 'Chemical', 'MESH:D005472', (130, 134))	('CDDP', 'Chemical', 'MESH:D002945', (87, 91))	('HCCC-9180', 'CellLine', 'CVCL:6908', (20, 29))	('overexpression', 'PosReg', (43, 57))	('EADM', 'Chemical', '-', (81, 85))	('HCPT', 'Chemical', 'MESH:C527042', (96, 100))	('silencing', 'Var', (61, 70))	('CDK10', 'Gene', '8558', (74, 79))
85689	22209942	The result indicated that expression of CDK10 influenced resistance to chemotherapy rather than specifically to 5-FU.	('CDK10', 'Gene', (40, 45))	('influenced', 'Reg', (46, 56))	('expression', 'Var', (26, 36))	('CDK10', 'Gene', '8558', (40, 45))	('resistance to chemotherapy', 'MPA', (57, 83))	('5-FU', 'Chemical', 'MESH:D005472', (112, 116))
85698	22209942	In colon cancer cells, the antiproliferative effect of 5-FU results in induction of cell cycle arrest at the G1 phase, and is characterized by an increase in the number of cells in the S phase.	('increase', 'PosReg', (146, 154))	('5-FU', 'Var', (55, 59))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('5-FU', 'Chemical', 'MESH:D005472', (55, 59))	('arrest', 'Disease', 'MESH:D006323', (95, 101))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('arrest', 'Disease', (95, 101))	('antiproliferative effect', 'CPA', (27, 51))	('colon cancer', 'Disease', (3, 15))
85701	22209942	Mock cells (G-M and H-M) treated with 5-FU displayed the expected increase in S phase populations (Fig.	('5-FU', 'Chemical', 'MESH:D005472', (38, 42))	('S phase populations', 'CPA', (78, 97))	('increase', 'PosReg', (66, 74))	('5-FU', 'Var', (38, 42))
85703	22209942	More interesting, G-M cells showed an increase in the number of G2/M phase cells after treatment with 5-FU, while the number of G-CDK10 cells in G2/M phase showed a significant decrease (Fig.	('increase', 'PosReg', (38, 46))	('5-FU', 'Chemical', 'MESH:D005472', (102, 106))	('CDK10', 'Gene', '8558', (130, 135))	('CDK10', 'Gene', (130, 135))	('G2/M phase cells', 'CPA', (64, 80))	('5-FU', 'Var', (102, 106))
85721	22209942	The reason why CDK10 is downregulated in breast cancer with aberrant DNA methylation is still controversial, CDK10 is being investigated as a tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('CDK10', 'Gene', '8558', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('downregulated', 'NegReg', (24, 37))	('tumor', 'Disease', (142, 147))	('CDK10', 'Gene', (109, 114))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('CDK10', 'Gene', '8558', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('aberrant', 'Var', (60, 68))	('CDK10', 'Gene', (15, 20))
85725	22209942	Inhibition of CDK10 expression induced aberrant activation of growth, migration and survivability (including resistance to chemotherapy, serum starvation and hypoxia tolerance) of BTC cells.	('growth', 'CPA', (62, 68))	('migration', 'CPA', (70, 79))	('hypoxia', 'Disease', (158, 165))	('CDK10', 'Gene', '8558', (14, 19))	('hypoxia', 'Disease', 'MESH:D000860', (158, 165))	('CDK10', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('activation', 'PosReg', (48, 58))	('BTC', 'Phenotype', 'HP:0100574', (180, 183))
85733	22209942	Aberrant activation of the MAPK pathway induces aberrant growth and increases the threshold for cell death, resulting in increased survivability of tumor cells.	('increases', 'PosReg', (68, 77))	('activation', 'PosReg', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('Aberrant', 'Var', (0, 8))	('aberrant growth', 'Phenotype', 'HP:0001507', (48, 63))	('increased', 'PosReg', (121, 130))	('tumor', 'Disease', (148, 153))	('threshold', 'MPA', (82, 91))	('growth', 'CPA', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('MAPK pathway', 'Pathway', (27, 39))
85737	22209942	Inactive CDK10 has been shown to lead to a G2/M arrest in mammalian cells, but wild-type CDK10 only shows a modest effect.	('arrest', 'Disease', 'MESH:D006323', (48, 54))	('lead to', 'Reg', (33, 40))	('arrest', 'Disease', (48, 54))	('CDK10', 'Gene', (89, 94))	('CDK10', 'Gene', '8558', (89, 94))	('Inactive', 'Var', (0, 8))	('CDK10', 'Gene', '8558', (9, 14))	('mammalian', 'Species', '9606', (58, 67))	('CDK10', 'Gene', (9, 14))
85744	22209942	More interestingly, after treatment with 5-FU, CDK10-overexpressing cells showed a significantly increase in the G1 phase cells in both the GBC-SD and HCCC-9180 cell lines, and a significant decrease in the G2/M phase cells in GBC-SD.	('5-FU', 'Var', (41, 45))	('G2/M phase cells', 'CPA', (207, 223))	('increase', 'PosReg', (97, 105))	('CDK10', 'Gene', '8558', (47, 52))	('CDK10', 'Gene', (47, 52))	('5-FU', 'Chemical', 'MESH:D005472', (41, 45))	('HCCC-9180', 'CellLine', 'CVCL:6908', (151, 160))	('decrease', 'NegReg', (191, 199))	('G1 phase cells', 'CPA', (113, 127))
85747	22209942	CDK10 restoration inhibits tumor growth, cell migration and survivability, and induces malignant cells to become sensitive to chemotherapy in the biliary tract cancer.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('biliary tract cancer', 'Disease', (146, 166))	('sensitive to chemotherapy', 'MPA', (113, 138))	('restoration', 'Var', (6, 17))	('cell migration', 'CPA', (41, 55))	('CDK10', 'Gene', (0, 5))	('tumor', 'Disease', (27, 32))	('survivability', 'CPA', (60, 73))	('inhibits', 'NegReg', (18, 26))	('CDK10', 'Gene', '8558', (0, 5))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (146, 166))	('induces', 'Reg', (79, 86))	('malignant cells', 'CPA', (87, 102))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('biliary tract cancer', 'Disease', 'MESH:D001661', (146, 166))
85785	21189991	A day after transfection of CDH3 siRNA into HuCCT1 cells in a 6-well plate, cells were transferred and cultured to a 48-well plate until confluent.	('transfection', 'Var', (12, 24))	('HuCCT1', 'CellLine', 'CVCL:0324', (44, 50))	('CDH3 siRNA', 'Gene', (28, 38))
85807	21189991	4, invasion of HuCCT1 cells through the matrigel was significantly reduced when CDH3 was knock-downed.	('HuCCT1', 'CellLine', 'CVCL:0324', (15, 21))	('reduced', 'NegReg', (67, 74))	('knock-downed', 'Var', (89, 101))	('invasion of HuCCT1 cells through the matrigel', 'CPA', (3, 48))	('CDH3', 'Gene', (80, 84))
85811	21189991	Although the expression level of CDH1 was increased, there was no change in CDH2 expression level during CDH3 knockdown (data not shown).	('knockdown', 'Var', (110, 119))	('CDH3', 'Gene', (105, 109))	('increased', 'PosReg', (42, 51))	('CDH2', 'Gene', '1000', (76, 80))	('CDH1', 'Gene', (33, 37))	('expression level', 'MPA', (13, 29))	('expression level', 'MPA', (81, 97))	('CDH1', 'Gene', '999', (33, 37))	('CDH2', 'Gene', (76, 80))
85848	21189991	The expression level of CDH1 or CDH2 was not changed by over-expression or knock-down of CDH3 in ovarian cancer cells.	('knock-down', 'Var', (75, 85))	('ovarian cancer', 'Disease', 'MESH:D010051', (97, 111))	('CDH1', 'Gene', (24, 28))	('CDH1', 'Gene', '999', (24, 28))	('ovarian cancer', 'Disease', (97, 111))	('CDH2', 'Gene', '1000', (32, 36))	('CDH3', 'Gene', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))	('CDH2', 'Gene', (32, 36))
85852	21189991	As such, E-cadherin neutralizing antibody inhibited proliferation of MDCK cells.	('E-cadherin', 'Protein', (9, 19))	('neutralizing antibody', 'Var', (20, 41))	('MDCK', 'CellLine', 'CVCL:0422', (69, 73))	('inhibited', 'NegReg', (42, 51))	('proliferation of MDCK cells', 'CPA', (52, 79))
85970	29615928	Cancer cells are generally rapidly dividing, partially due to the impaired cell cycle control as a result of the aberrantly expressed checkpoint proteins.	('cell cycle control', 'CPA', (75, 93))	('impaired', 'NegReg', (66, 74))	('aberrantly expressed', 'Var', (113, 133))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('rapidly dividing', 'CPA', (27, 43))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
85971	29615928	Indeed, uncontrolled cell cycle progression contributes to carcinogenesis and treatment failure (Evan and Vousden,).	('cell cycle progression', 'CPA', (21, 43))	('Evan', 'Disease', (97, 101))	('Evan', 'Disease', 'MESH:C536380', (97, 101))	('uncontrolled', 'Var', (8, 20))	('Vousden', 'Disease', (106, 113))	('carcinogenesis and treatment failure', 'Disease', 'MESH:D063646', (59, 95))	('contributes', 'Reg', (44, 55))
85981	29615928	CDKL3 also has similar sequences with classical MAPK, and NKIAMRE has a potential MAPK activation motif TDY (Thr 158, Asp159 and Tyr 160) in subdomain VIII.	('NKIAMRE', 'Gene', (58, 65))	('Thr', 'Chemical', 'MESH:D013912', (109, 112))	('VIII', 'Gene', '1351', (151, 155))	('Asp159 and Tyr 160', 'Var', (118, 136))	('CDKL3', 'Gene', (0, 5))	('VIII', 'Gene', (151, 155))	('Asp159', 'Chemical', '-', (118, 124))	('NKIAMRE', 'Gene', '51265', (58, 65))	('Tyr', 'Chemical', 'MESH:D014443', (129, 132))	('MAPK', 'Gene', (82, 86))
85982	29615928	Studies have shown that NKIAMRE could not be activated by epidermal growth factor (EGF), 20% FBS, sorbitol, or anisomycin, but it could be stimulated by phorbol 12-myristate 13-acetate (PMA) through phosphorylation of the TDY motif (Yee et al.,).	('anisomycin', 'Chemical', 'MESH:D000841', (111, 121))	('phorbol 12-myristate 13-acetate', 'Chemical', 'MESH:D013755', (153, 184))	('FBS', 'Disease', (93, 96))	('NKIAMRE', 'Gene', (24, 31))	('PMA', 'Chemical', 'MESH:D013755', (186, 189))	('FBS', 'Disease', 'MESH:D005198', (93, 96))	('sorbitol', 'Chemical', 'MESH:D013012', (98, 106))	('NKIAMRE', 'Gene', '51265', (24, 31))	('phosphorylation', 'Var', (199, 214))
85985	29615928	Indeed, our data in the current study show that CDKL3, like its homolog CDK3, has a significant impact on the cell cycle progression in that knockdown of CDKL3 in RBE cells blocked the cell cycle progression from G0/G1 stage to S stage with simultaneous induction of apoptosis.	('knockdown', 'Var', (141, 150))	('cell cycle progression', 'CPA', (185, 207))	('CDK3', 'Gene', (72, 76))	('CDK3', 'Gene', '1018', (72, 76))	('CDKL3', 'Gene', (154, 159))	('blocked', 'NegReg', (173, 180))
85994	29497050	Here, we show that H-ChC samples contain substantial private mutations from WES analyses, ranging from 33.1 to 86.4%, indicative of substantive intratumor heterogeneity (ITH).	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('ChC', 'Gene', '1213', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mutations', 'Var', (61, 70))	('ChC', 'Gene', (21, 24))	('tumor', 'Disease', (149, 154))
86011	29497050	We find that H-ChC samples contain substantial private mutations as well as private somatic CNVs, indicative of intratumor heterogeneity (ITH) of H-ChC.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('ChC', 'Gene', (15, 18))	('ChC', 'Gene', '1213', (15, 18))	('mutations', 'Var', (55, 64))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('ChC', 'Gene', (148, 151))	('ChC', 'Gene', '1213', (148, 151))
86018	29497050	2a, b for expression of hepatocytic markers Hep and GPC3, vast majority of HCC and H-ChC samples showed positivity with Hep or GPC3 (93.8% for HCC and 80% for H-ChC contained in the HCC component).	('GPC3', 'Gene', '2719', (52, 56))	('ChC', 'Gene', '1213', (85, 88))	('ChC', 'Gene', (85, 88))	('GPC3', 'Gene', (127, 131))	('ChC', 'Gene', (161, 164))	('ChC', 'Gene', '1213', (161, 164))	('HCC', 'Phenotype', 'HP:0001402', (75, 78))	('Hep', 'Gene', (120, 123))	('positivity', 'Var', (104, 114))	('HCC', 'Phenotype', 'HP:0001402', (143, 146))	('GPC3', 'Gene', '2719', (127, 131))	('HCC', 'Phenotype', 'HP:0001402', (182, 185))	('GPC3', 'Gene', (52, 56))
86024	29497050	On average, each H-ChC patient has 159 nonsynonymous SNVs, 6 frameshift indels, 136 CNVs, and 2.6 HBV integration sites (Supplementary Data 2 and 3 and Supplementary Table 3).	('ChC', 'Gene', (19, 22))	('ChC', 'Gene', '1213', (19, 22))	('HBV', 'Species', '10407', (98, 101))	('frameshift indels', 'Var', (61, 78))	('patient', 'Species', '9606', (23, 30))
86025	29497050	Six mutational profiles were observed within tumor samples and the predominant mutational profile C:G>T:A is similar to that of liver cancer summarized by Alexandrov et al..	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('liver cancer', 'Phenotype', 'HP:0002896', (128, 140))	('liver cancer', 'Disease', 'MESH:D006528', (128, 140))	('C:G>T:A', 'Var', (98, 105))	('liver cancer', 'Disease', (128, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
86030	29497050	We classified somatic nonsynonymous mutations as ubiquitous (present in both tumor components) or private (exclusively present either in HCC or iCCA).	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('HCC', 'Disease', (137, 140))	('HCC', 'Phenotype', 'HP:0001402', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('nonsynonymous mutations', 'Var', (22, 45))	('tumor', 'Disease', (77, 82))
86035	29497050	For a given H-ChC sample, the percentage of mutations contained in each signature is consistent between HCC and iCCA (Fig.	('mutations', 'Var', (44, 53))	('HCC', 'Phenotype', 'HP:0001402', (104, 107))	('ChC', 'Gene', (14, 17))	('ChC', 'Gene', '1213', (14, 17))
86044	29497050	In addition, clonal analyses suggested common mutation clusters for all seven H-ChC patients after adjusting for cancer cell fraction (CCF) for each sample using Pyclone (Fig.	('ChC', 'Gene', '1213', (80, 83))	('patients', 'Species', '9606', (84, 92))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('mutation', 'Var', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('ChC', 'Gene', (80, 83))
86049	29497050	Twelve genes, e.g., ACVR2A and APC, that constitute signaling pathways modulating pluripotency of stem cells were mutated in six H-ChC patients (P1-P6) (Supplementary Table 10).	('ChC', 'Gene', (131, 134))	('ChC', 'Gene', '1213', (131, 134))	('patients', 'Species', '9606', (135, 143))	('mutated', 'Var', (114, 121))	('ACVR2A', 'Gene', (20, 26))	('APC', 'Disease', 'MESH:D011125', (31, 34))	('APC', 'Disease', (31, 34))
86050	29497050	Moreover, 12 mutated genes in Wnt and Notch pathways including TP53 and NFATC2/3, which regulate the differentiation of hepatocyte and biliary epithelium, were noted in five H-ChC patients (P1-P4 and P6) (Supplementary Table 11).	('ChC', 'Gene', (176, 179))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('NFATC2/3', 'Gene', (72, 80))	('noted', 'Reg', (160, 165))	('NFATC2/3', 'Gene', '4773;4775', (72, 80))	('mutated', 'Var', (13, 20))	('ChC', 'Gene', '1213', (176, 179))	('patients', 'Species', '9606', (180, 188))
86057	29497050	Univariate analysis with log-rank test showed that EpCAM positivity was significantly associated with poor prognosis of liver cancer patients (P = 0.028; Table 1 and Fig.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('liver cancer', 'Phenotype', 'HP:0002896', (120, 132))	('liver cancer', 'Disease', 'MESH:D006528', (120, 132))	('EpCAM', 'Gene', (51, 56))	('liver cancer', 'Disease', (120, 132))	('patients', 'Species', '9606', (133, 141))	('EpCAM', 'Gene', '4072', (51, 56))	('positivity', 'Var', (57, 67))
86058	29497050	CA199 and margin status were found to be associated with prognosis of liver cancer by multivariate Cox regression analysis (P = 0.001; P = 0.015; Table 2).	('associated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('liver cancer', 'Phenotype', 'HP:0002896', (70, 82))	('CA199', 'Var', (0, 5))	('liver cancer', 'Disease', 'MESH:D006528', (70, 82))	('liver cancer', 'Disease', (70, 82))
86083	29497050	All seven H-ChC patients possess mutated genes involved in cell stemness and differentiation.	('patients', 'Species', '9606', (16, 24))	('ChC', 'Gene', (12, 15))	('ChC', 'Gene', '1213', (12, 15))	('mutated', 'Var', (33, 40))
86085	29497050	In this study, we also found mutated genes in these two pathways in five out of seven H-ChC patient samples.	('mutated genes', 'Var', (29, 42))	('patient', 'Species', '9606', (92, 99))	('ChC', 'Gene', (88, 91))	('ChC', 'Gene', '1213', (88, 91))
86086	29497050	Overall, we demonstrated that some gene mutations might lead to the instability of stem state, whereas others contributed to distinct differentiation of H-ChC.	('contributed to', 'Reg', (110, 124))	('mutations', 'Var', (40, 49))	('ChC', 'Gene', '1213', (155, 158))	('instability', 'MPA', (68, 79))	('ChC', 'Gene', (155, 158))	('lead to', 'Reg', (56, 63))
86096	29497050	In parallel, majority of iCCA and H-ChC samples, those are chiefly CK19+, exhibited positivity for EpCAM.	('ChC', 'Gene', (36, 39))	('ChC', 'Gene', '1213', (36, 39))	('EpCAM', 'Gene', '4072', (99, 104))	('CK19', 'Gene', '3880', (67, 71))	('CK19', 'Gene', (67, 71))	('exhibited', 'Reg', (74, 83))	('positivity', 'Var', (84, 94))	('EpCAM', 'Gene', (99, 104))
86122	29497050	The primary antibodies were hepatocyte (IR624, 1:50, Dako), GPC-3 (ZM-0146, 1:1, ZSGB-Bio), CK7 (1:1, Dako), CK19 (1:50, Dako), EpCAM (HEA125, 1:50, abcam, Cambridge, UK), and c-kit (A4502, 1:1, Dako).	('c-kit', 'Gene', '3815', (176, 181))	('c-kit', 'Gene', (176, 181))	('CK19', 'Gene', (109, 113))	('CK7', 'Gene', (92, 95))	('IR624', 'Var', (40, 45))	('EpCAM', 'Gene', (128, 133))	('GPC-3', 'Gene', (60, 65))	('EpCAM', 'Gene', '4072', (128, 133))	('CK7', 'Gene', '3855', (92, 95))	('CK19', 'Gene', '3880', (109, 113))	('GPC-3', 'Gene', '2719', (60, 65))
86136	29497050	In order to identify potential driver mutations playing significant role in carcinogenesis, we compared sample mutations with known driver mutations with in-house software.	('mutations', 'Var', (111, 120))	('carcinogenesis', 'Disease', (76, 90))	('carcinogenesis', 'Disease', 'MESH:D063646', (76, 90))
86265	26854169	In contrast, the Japanese guidelines already recommend the use of liver specific Gd-EOB-DTPA-MR, because in the hepatocyte specific phase, the vast majority of dysplastic nodules are iso- or hyperintense, whereas most early HCC nodules are hypointense.	('Gd-EOB-DTPA', 'Chemical', 'MESH:C073590', (81, 92))	('dysplastic nodules', 'Disease', (160, 178))	('CC', 'Phenotype', 'HP:0030153', (225, 227))	('HCC', 'Gene', (224, 227))	('dysplastic nodules', 'Disease', 'MESH:D004416', (160, 178))	('iso-', 'Var', (183, 187))	('HCC', 'Gene', '619501', (224, 227))	('HCC', 'Phenotype', 'HP:0001402', (224, 227))
86270	26854169	This is due to the fact that Gd-EOB-DTPA shows much faster wash-out from the blood pool than do iodine-based contrast agents and Gd-DTPA.	('Gd-EOB-DTPA', 'Chemical', 'MESH:C073590', (29, 40))	('faster', 'PosReg', (52, 58))	('wash-out from the blood pool', 'MPA', (59, 87))	('Gd-EOB-DTPA', 'Var', (29, 40))	('iodine', 'Chemical', 'MESH:D007455', (96, 102))	('Gd-DTPA', 'Chemical', 'MESH:D019786', (129, 136))
86336	26854169	While in healthy liver, gadoxetate acid and gadobenate dimeglumine were reported to lead to similar enhancement, gadoxetate acid achieves better liver enhancement in cirrhotic patients.	('patients', 'Species', '9606', (176, 184))	('gadoxetate acid', 'Chemical', '-', (24, 39))	('gadoxetate acid', 'Var', (113, 128))	('gadoxetate acid', 'Chemical', '-', (113, 128))	('gadobenate dimeglumine', 'Chemical', 'MESH:C064572', (44, 66))	('enhancement', 'PosReg', (100, 111))	('liver enhancement', 'MPA', (145, 162))
86518	24010947	Tobacco use (62.5% vs. 28.6, p = 0.08) and a history of prior cardiac disease (67% vs. 35%, p = 0.07) were associated with an increased overall complication rate, which was not statistically significant.	('Tobacco use', 'Var', (0, 11))	('cardiac disease', 'Disease', (62, 77))	('complication', 'CPA', (144, 156))	('cardiac disease', 'Disease', 'MESH:D006331', (62, 77))	('Tobacco', 'Species', '4097', (0, 7))
86542	24010947	Complications in caudatectomy are associated with more advanced disease and tobacco use.	('caudatectomy', 'Disease', (17, 29))	('tobacco', 'Species', '4097', (76, 83))	('Complications', 'Var', (0, 13))	('tobacco use', 'Disease', (76, 87))
86576	33946151	Wavenumbers 2800-3000 cm-1 represent changes associated with lipid structure, the region of 1500-1700 cm-1 is correlated with the secondary structure of proteins, and the fingerprint region (800-1450 cm-1) is related to the changes of nucleic acid and carbohydrate structure.	('lipid', 'Chemical', 'MESH:D008055', (61, 66))	('800-1450 cm-1', 'Var', (191, 204))	('l', 'Gene', '21832', (115, 116))	('secondary', 'MPA', (130, 139))	('l', 'Gene', '21832', (238, 239))	('l', 'Gene', '21832', (211, 212))	('l', 'Gene', '21832', (61, 62))	('carbohydrate', 'Chemical', 'MESH:D002241', (252, 264))
86610	33946151	The spectral peak that occurred at 2960 and 2923 cm-1 corresponded to -CH3 and -CH2- asymmetric stretching, whereas the spectral peak at 2873 and 2852 cm-1 represented -CH3 and -CH2- symmetric stretching.	('l', 'Gene', '21832', (127, 128))	('l', 'Gene', '21832', (11, 12))	('CH2', 'Chemical', '-', (178, 181))	('2960', 'Var', (35, 39))	('-CH3', 'MPA', (70, 74))	('CH2', 'Chemical', '-', (80, 83))
86616	33946151	The score plot of PC-1 (57%) against PC-4 (3%) (Figure 7A) shows clusters of the three samples which are discriminated by their variables related to the loading plot (Figure 7B), especially for the asymmetric and symmetric stretching of -CH2- fatty lipid at 2923 and 2852, amide I at 1664, 1648, and 1617, and at 1236 cm-1 for the asymmetric phosphate stretching (Figure 7B).	('l', 'Gene', '21832', (11, 12))	('l', 'Gene', '21832', (66, 67))	('phosphate', 'Chemical', 'MESH:D010710', (342, 351))	('amide I', 'MPA', (273, 280))	('l', 'Gene', '21832', (153, 154))	('2852', 'Var', (267, 271))	('CH2', 'Chemical', '-', (238, 241))	('lipid', 'Chemical', 'MESH:D008055', (249, 254))	('PC-1', 'CellLine', 'CVCL:0152', (18, 22))	('l', 'Gene', '21832', (134, 135))	('amide', 'Chemical', 'MESH:D000577', (273, 278))	('asymmetric', 'MPA', (198, 208))	('asymmetric phosphate stretching', 'MPA', (331, 362))	('l', 'Gene', '21832', (140, 141))	('l', 'Gene', '21832', (162, 163))	('l', 'Gene', '21832', (186, 187))	('l', 'Gene', '21832', (187, 188))	('l', 'Gene', '21832', (249, 250))	('l', 'Gene', '21832', (91, 92))
86704	33946151	; validation, B.B., K.C., B.K., and K.W.	('B.K.', 'Var', (26, 30))	('l', 'Gene', '21832', (4, 5))	('K.C.', 'Var', (20, 24))	('B.B.', 'Var', (14, 18))
86785	29350267	Furthermore, for the identification of nodal involvement, [18F]-FDG PET-CT has a sensitivity and specificity of 67 and 68%, respectively.	('CT', 'Chemical', 'MESH:D002251', (72, 74))	('nodal', 'Gene', '4838', (39, 44))	('[18F]-FDG', 'Var', (58, 67))	('nodal', 'Gene', (39, 44))
86851	29350267	Backflow of embolization material into the left portal venous system can lead to inadvertent embolization and thrombosis of the portal veins supplying the FRL.	('embolization and thrombosis', 'Phenotype', 'HP:0001907', (93, 120))	('thrombosis', 'Disease', (110, 120))	('Backflow', 'Var', (0, 8))	('thrombosis', 'Disease', 'MESH:D013927', (110, 120))	('lead to', 'Reg', (73, 80))	('embolization', 'CPA', (93, 105))
86899	29350267	Due to stenting of the biliary system and ensuing cholangitis, patients were at increased risk of interstage morbidity and mortality.	('cholangitis', 'Disease', 'MESH:D002761', (50, 61))	('patients', 'Species', '9606', (63, 71))	('cholangitis', 'Disease', (50, 61))	('stenting', 'Var', (7, 15))	('cholangitis', 'Phenotype', 'HP:0030151', (50, 61))
86912	29350267	Biomarkers such as CYFRA21-1 and MUC-5 need to be evaluated in larger cohorts to assess its clinical value.	('MUC-5', 'Gene', (33, 38))	('MUC-5', 'Gene', '4586', (33, 38))	('CYFRA21-1', 'Var', (19, 28))
86987	25623660	However, a subset of PSC patients with polysomy do not manifest CCA even after long-term follow-up.	('PSC', 'Gene', '100653366', (21, 24))	('PSC', 'Gene', (21, 24))	('CCA', 'Disease', (64, 67))	('patients', 'Species', '9606', (25, 33))	('polysomy', 'Var', (39, 47))
86989	25623660	Therefore, our aim is to determine whether patients with MFP are more likely to manifest CCA compared with patients with other chromosomal abnormalities including UFP and other FISH subtypes.	('chromosomal abnormalities', 'Disease', (127, 152))	('patients', 'Species', '9606', (43, 51))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (127, 152))	('CCA', 'Disease', (89, 92))	('MFP', 'Var', (57, 60))	('patients', 'Species', '9606', (107, 115))
86993	25623660	MFP was associated with CCA (hazard ratio (HR), 82.42; 95% confidence interval (CI), 24.50-277.31) and was the strongest predictor of cancer diagnosis.	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('associated', 'Reg', (8, 18))	('MFP', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('CCA', 'Disease', (24, 27))
87006	25623660	It is unknown if patients with multifocal polysomy (MFP) are at a higher risk of CCA compared with those with polysomy in a single location in the biliary tree (i.e., unifocal polysomy, UFP).	('multifocal polysomy', 'Var', (31, 50))	('CCA', 'Disease', (81, 84))	('patients', 'Species', '9606', (17, 25))
87007	25623660	Consequently, our primary aim is to determine if PSC patients with MFP detected on a single exam are more likely to be diagnosed with CCA compared with patients with UFP and other FISH types (serial polysomy, trisomy/tetrasomy, or a negative FISH study).	('patients', 'Species', '9606', (53, 61))	('diagnosed', 'Reg', (119, 128))	('PSC', 'Gene', '100653366', (49, 52))	('trisomy/tetrasomy', 'Var', (209, 226))	('PSC', 'Gene', (49, 52))	('CCA', 'Disease', (134, 137))	('patients', 'Species', '9606', (152, 160))
87024	25623660	Patients with a negative FISH study, trisomy, or tetrasomy were included in the study regardless of the number of areas brushed.	('Patients', 'Species', '9606', (0, 8))	('tetrasomy', 'Var', (49, 58))	('trisomy', 'Disease', (37, 44))
87035	25623660	Ultimately, 371 patients (all with large duct PSC) were included in the primary analyses (negative FISH n=194, trisomy or tetrasomy n=114, UFP n=32, MFP n=31).	('tetrasomy', 'Var', (122, 131))	('patients', 'Species', '9606', (16, 24))	('trisomy', 'Var', (111, 118))	('PSC', 'Gene', '100653366', (46, 49))	('PSC', 'Gene', (46, 49))
87044	25623660	At baseline, patients with MFP were more likely than patients with UFP to have suspicious cytology (45 vs. 13%, P<0.001) and a higher proportion of cells with polysomy (13 vs. 3%, P<0.001).	('polysomy', 'Var', (159, 167))	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (13, 21))	('suspicious cytology', 'CPA', (79, 98))	('MFP', 'Var', (27, 30))
87050	25623660	For example, 29% of UFP patients and 58% of MFP patients (P=0.21) had polysomy detected from sites not associated with a dominant stricture.	('polysomy', 'Var', (70, 78))	('patients', 'Species', '9606', (48, 56))	('UFP', 'Disease', (20, 23))	('patients', 'Species', '9606', (24, 32))
87051	25623660	CCA was detected in 37 patients (negative FISH n=3, trisomy/tetrasomy n=5, UFP n=6, MFP n=23).	('patients', 'Species', '9606', (23, 31))	('trisomy/tetrasomy', 'Var', (52, 69))	('CCA', 'Disease', (0, 3))
87055	25623660	For example, among UFP and MFP patients with a brushing positive for adenocarcinoma (at any time point), 71% had polysomy detected at another region where adenocarcinoma was not detected on routine cytology.	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('adenocarcinoma', 'Disease', (155, 169))	('patients', 'Species', '9606', (31, 39))	('adenocarcinoma', 'Disease', (69, 83))	('polysomy', 'Var', (113, 121))	('adenocarcinoma', 'Disease', 'MESH:D000230', (155, 169))	('adenocarcinoma', 'Disease', 'MESH:D000230', (69, 83))
87056	25623660	Patients with MFP were more likely to be diagnosed with CCA in contrast to those with negative FISH, trisomy or tetrasomy, and UFP (Figure 3).	('Patients', 'Species', '9606', (0, 8))	('MFP', 'Var', (14, 17))	('CCA', 'Disease', (56, 59))
87061	25623660	Of the 28 patients with serial poly somy, 0% (0/8) and 75% (15/20) patients with UFP and MFP (respectively) were diagnosed with CCA.	('patients', 'Species', '9606', (67, 75))	('poly somy', 'Chemical', '-', (31, 40))	('patients', 'Species', '9606', (10, 18))	('poly somy', 'Var', (31, 40))	('CCA', 'Disease', (128, 131))
87071	25623660	Our results also indicate that patients with MFP are more likely to be diagnosed with CCA compared with patients with other FISH findings such as trisomy/tetrasomy and serial polysomy.	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (104, 112))	('MFP', 'Var', (45, 48))	('CCA', 'Disease', (86, 89))
87072	25623660	Indeed, those with MFP were more likely to have a history of weight loss, suspicious cytology, an imaging study suspicious but indeterminate for CCA, or a greater proportion of cells positive for polysomy and serial polysomy when compared with patients with UFP.	('weight loss', 'Phenotype', 'HP:0001824', (61, 72))	('MFP', 'Var', (19, 22))	('positive', 'Reg', (183, 191))	('weight loss', 'Disease', 'MESH:D015431', (61, 72))	('polysomy', 'Var', (196, 204))	('serial polysomy', 'Var', (209, 224))	('patients', 'Species', '9606', (244, 252))	('weight loss', 'Disease', (61, 72))
87078	25623660	For example, a prior study noted 100% (10/10) patients with polysomy, atypical or suspicious cytology, and a CA 19-9 >=129 U/ml were diagnosed with CCA.	('polysomy', 'Var', (60, 68))	('patients', 'Species', '9606', (46, 54))	('CCA', 'Disease', (148, 151))
87080	25623660	In the present study, we focus on PSC patients with polysomy FISH result(s) when multiple biliary sites were sampled in a single exam.	('PSC', 'Gene', (34, 37))	('patients', 'Species', '9606', (38, 46))	('polysomy', 'Var', (52, 60))	('PSC', 'Gene', '100653366', (34, 37))
87085	25623660	We observed that polysomy is frequently found in areas not associated with a dominant stricture and the presence of a dominant stricture was not more common in MFP patients or an independent predictor of CCA.	('polysomy', 'Var', (17, 25))	('patients', 'Species', '9606', (164, 172))	('CCA', 'Disease', (204, 207))
87108	25623660	In conclusion, the current study suggests that MFP is a very strong risk factor for CCA among PSC patients suspected of having biliary cancer but lack a mass lesion on imaging at the time of the initial assessment.	('biliary cancer', 'Disease', (127, 141))	('CCA', 'Disease', (84, 87))	('PSC', 'Gene', '100653366', (94, 97))	('patients', 'Species', '9606', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('PSC', 'Gene', (94, 97))	('MFP', 'Var', (47, 50))	('biliary cancer', 'Disease', 'MESH:D001661', (127, 141))	('risk factor', 'Reg', (68, 79))
87113	25623660	Polysomy, particularly serial polysomy has been associated with cholangiocarcinoma in PSC.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (64, 82))	('associated', 'Reg', (48, 58))	('PSC', 'Gene', '100653366', (86, 89))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('Polysomy', 'Var', (0, 8))	('PSC', 'Gene', (86, 89))	('serial polysomy', 'Var', (23, 38))	('cholangiocarcinoma', 'Disease', (64, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
87114	25623660	However, only a subset of patients with polysomy will be diagnosed with cholangio-carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('patients', 'Species', '9606', (26, 34))	('polysomy', 'Var', (40, 48))	('cholangio-carcinoma', 'Disease', (72, 91))	('cholangio-carcinoma', 'Disease', 'MESH:D002277', (72, 91))	('cholangio-carcinoma', 'Phenotype', 'HP:0030153', (72, 91))
87115	25623660	Compared with other prognostic features, multifocal polysomy is the strongest predictor of cholangiocarcinoma among PSC patients who lack definitive radiographic features of biliary cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('PSC', 'Gene', '100653366', (116, 119))	('biliary cancer', 'Disease', (174, 188))	('PSC', 'Gene', (116, 119))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('biliary cancer', 'Disease', 'MESH:D001661', (174, 188))	('patients', 'Species', '9606', (120, 128))	('cholangiocarcinoma', 'Disease', (91, 109))	('multifocal polysomy', 'Var', (41, 60))
87117	25623660	PSC patients with unifocal polysomy and suspicious cytology are also at an increased risk of cholangiocarcinoma.	('PSC', 'Gene', '100653366', (0, 3))	('cholangiocarcinoma', 'Disease', (93, 111))	('PSC', 'Gene', (0, 3))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('unifocal polysomy', 'Var', (18, 35))	('patients', 'Species', '9606', (4, 12))	('increased risk of cholangiocarcinoma', 'Phenotype', 'HP:0001402', (75, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))
87127	25435928	In the pDC316-siRNA recombinant vector group, the cells migrated more quickly compared with the siRNA-negative control group, and in the RKIP-expressing adenoviral vector group, the cells migrated more slowly compared with the adenoviral negative control group.	('pDC316-siRNA', 'Var', (7, 19))	('RKIP', 'Gene', '5037', (137, 141))	('slowly', 'NegReg', (202, 208))	('RKIP', 'Gene', (137, 141))	('cells migrated', 'CPA', (50, 64))
87134	25435928	The formation of cholangiocarcinoma often proceeds through several steps, including interaction among the cancer-promoting environmental factors, oncogene activation and tumor-suppressor gene inactivation.	('inactivation', 'Var', (192, 204))	('cholangiocarcinoma', 'Disease', (17, 35))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (17, 35))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (17, 35))	('tumor', 'Disease', (170, 175))	('cancer', 'Disease', (106, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('interaction', 'Interaction', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
87216	25435928	Following the silencing or overexpression of RKIP by RKIP siRNA or adenoviral vectors, respectively, RT-qPCR was performed to analyze the mRNA expression levels of RKIP, MMP-9 and TIMP-4, using a quantitative method.	('silencing', 'Var', (14, 23))	('RKIP', 'Gene', (164, 168))	('RKIP', 'Gene', (45, 49))	('MMP-9', 'Gene', '4318', (170, 175))	('TIMP-4', 'Gene', (180, 186))	('TIMP-4', 'Gene', '7079', (180, 186))	('RKIP', 'Gene', '5037', (53, 57))	('MMP-9', 'Gene', (170, 175))	('RKIP', 'Gene', (53, 57))	('overexpression', 'PosReg', (27, 41))	('RKIP', 'Gene', '5037', (164, 168))	('RKIP', 'Gene', '5037', (45, 49))
87266	25435928	Positive RKIP expression in cholangiocarcinoma cells may be be predictive of a better prognosis.	('cholangiocarcinoma', 'Disease', (28, 46))	('RKIP', 'Gene', '5037', (9, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('RKIP', 'Gene', (9, 13))	('expression', 'MPA', (14, 24))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (28, 46))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (28, 46))	('Positive', 'Var', (0, 8))
87275	21339993	We demonstrated that Slug silencing and cisplatin both promote apoptosis by upregulation of PUMA, not by upregulation of E-cadherin.	('upregulation', 'PosReg', (76, 88))	('PUMA', 'Protein', (92, 96))	('promote', 'PosReg', (55, 62))	('Slug', 'Gene', (21, 25))	('apoptosis', 'CPA', (63, 72))	('silencing', 'Var', (26, 35))	('E-cadherin', 'Gene', (121, 131))	('E-cadherin', 'Gene', '999', (121, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))
87276	21339993	Slug silencing significantly sensitized cholangiocarcinoma cells to cisplatin through upregulation of PUMA.	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (40, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('upregulation', 'PosReg', (86, 98))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (40, 58))	('silencing', 'Var', (5, 14))	('Slug', 'Gene', (0, 4))	('sensitized', 'Reg', (29, 39))	('cholangiocarcinoma', 'Disease', (40, 58))	('PUMA', 'MPA', (102, 106))
87277	21339993	Finally, we showed that Slug silencing suppressed the growth of QBC939 xenograft tumors and sensitized the tumor cells to cisplatin through PUMA upregulation and induction of apoptosis.	('tumors', 'Disease', (81, 87))	('upregulation', 'PosReg', (145, 157))	('tumor', 'Disease', (107, 112))	('Slug', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('suppressed', 'NegReg', (39, 49))	('QBC939', 'Gene', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('silencing', 'Var', (29, 38))	('QBC93', 'CellLine', 'CVCL:6942', (64, 69))	('tumor', 'Disease', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('sensitized', 'Reg', (92, 102))	('growth', 'CPA', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('PUMA', 'MPA', (140, 144))	('apoptosis', 'CPA', (175, 184))	('induction', 'Reg', (162, 171))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))
87293	21339993	The aim of this study is to investigate and define the ability and mechanism of Slug silencing to increase the susceptibility of cholangiocarcinoma cell lines to the currently used cytotoxic drug cisplatin.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('cisplatin', 'Chemical', 'MESH:D002945', (196, 205))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (129, 147))	('susceptibility', 'MPA', (111, 125))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (129, 147))	('increase', 'PosReg', (98, 106))	('silencing', 'Var', (85, 94))	('Slug', 'Gene', (80, 84))	('cholangiocarcinoma', 'Disease', (129, 147))
87319	21339993	Endogenous peroxidase activity was quenched by 5% H2O2 (in methanol, v/v) and sections were incubated with terminal deoxynucleotidyl transferase labeling buffer followed with terminal deoxynucleotidyl transferase enzyme and biotinylated nucleotides (for negative control, labeling buffer was used instead of terminal deoxynucleotidyl transferase enzyme).	('methanol', 'Chemical', 'MESH:D000432', (59, 67))	('H2O2', 'Chemical', 'MESH:D006861', (50, 54))	('H2O2', 'Var', (50, 54))	('quenched', 'NegReg', (35, 43))	('Endogenous', 'MPA', (0, 10))	('activity', 'MPA', (22, 30))
87326	21339993	The cell line QBC939 was transiently transfected with Slug siRNA for 48 h to knock down Slug.	('knock', 'Var', (77, 82))	('QBC93', 'CellLine', 'CVCL:6942', (14, 19))	('Slug', 'MPA', (88, 92))
87358	21339993	To determine whether Slug silencing confers antitumor activity in vivo, established 6 x 106 QBC939 cells (stable transfection with Slug siRNA or mock siRNA) were injected into the flanks of 4 to 6 week old female Nude mice (n = 6 per group).	('tumor', 'Disease', (48, 53))	('Nude mice', 'Species', '10090', (213, 222))	('QBC93', 'CellLine', 'CVCL:6942', (92, 97))	('silencing', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
87364	21339993	Analyzing tissue sections from tumors revealed that Slug siRNA, but not mock, significantly increased apoptosis in the tumors as assessed by TUNEL staining (Figure 6C).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (119, 125))	('apoptosis', 'CPA', (102, 111))	('tumors', 'Disease', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('increased', 'PosReg', (92, 101))	('Slug siRNA', 'Var', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
87365	21339993	These data show that Slug silencing effectively inhibits the growth of Cholangiocarcinoma tumors through apoptosis induction.	('Cholangiocarcinoma tumors', 'Disease', (71, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('inhibits', 'NegReg', (48, 56))	('apoptosis', 'CPA', (105, 114))	('Slug', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('Cholangiocarcinoma tumors', 'Disease', 'MESH:D018281', (71, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('silencing', 'Var', (26, 35))	('growth', 'CPA', (61, 67))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (71, 89))
87366	21339993	Slug silencing was found to promote apoptosis by cisplatin in vitro.	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('apoptosis', 'CPA', (36, 45))	('silencing', 'Var', (5, 14))	('Slug', 'Gene', (0, 4))	('promote', 'PosReg', (28, 35))
87372	21339993	These results suggest that Slug silencing enhances the therapeutic response of QBC939 tumors to cisplatin through apoptosis induction.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('apoptosis', 'CPA', (114, 123))	('Slug', 'Gene', (27, 31))	('tumors', 'Disease', (86, 92))	('QBC939', 'Gene', (79, 85))	('silencing', 'Var', (32, 41))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('enhances', 'PosReg', (42, 50))	('therapeutic response', 'MPA', (55, 75))	('QBC93', 'CellLine', 'CVCL:6942', (79, 84))
87376	21339993	Slug is detectable in many types of cancer, and its presence has been associated with poor prognosis in many malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('malignant tumors', 'Disease', (109, 125))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('presence', 'Var', (52, 60))	('malignant tumors', 'Disease', 'MESH:D018198', (109, 125))	('cancer', 'Disease', (36, 42))	('associated', 'Reg', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
87379	21339993	In this report, we demonstrated for the first time that Slug silencing could efficiently promote apoptosis in cholangiocarcinoma cells.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (110, 128))	('promote', 'PosReg', (89, 96))	('silencing', 'Var', (61, 70))	('cholangiocarcinoma', 'Disease', (110, 128))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (110, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('Slug', 'Gene', (56, 60))	('apoptosis', 'CPA', (97, 106))
87381	21339993	Our current findings show that when Slug was knocked down in the QBC939 cells, the PUMA and E-cadherin proteins were upregulated in the cells with the Slug supression.	('E-cadherin', 'Gene', (92, 102))	('E-cadherin', 'Gene', '999', (92, 102))	('upregulated', 'PosReg', (117, 128))	('knocked', 'Var', (45, 52))	('PUMA', 'Protein', (83, 87))	('QBC93', 'CellLine', 'CVCL:6942', (65, 70))
87382	21339993	These data demonstrate that Slug silencing facilitates apoptosis by PUMA upregulation, and not by E-cadherin upregulation.	('facilitates', 'PosReg', (43, 54))	('E-cadherin', 'Gene', (98, 108))	('E-cadherin', 'Gene', '999', (98, 108))	('silencing', 'Var', (33, 42))	('Slug', 'Gene', (28, 32))	('PUMA', 'CPA', (68, 72))	('apoptosis', 'CPA', (55, 64))	('upregulation', 'PosReg', (73, 85))
87383	21339993	Recent studies have demonstrated that Slug silencing increases sensitivity to apoptosis induced by cisplatin, fotemustine, imatinib mesylate, etoposide, or doxorubicin.	('etoposide', 'Chemical', 'MESH:D005047', (142, 151))	('doxorubicin', 'Chemical', 'MESH:D004317', (156, 167))	('fotemustine', 'Chemical', 'MESH:C054368', (110, 121))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (123, 140))	('silencing', 'Var', (43, 52))	('Slug', 'Gene', (38, 42))	('imatinib mesylate', 'MPA', (123, 140))	('sensitivity to apoptosis', 'MPA', (63, 87))	('increases', 'PosReg', (53, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (99, 108))
87384	21339993	Our study demonstrated that Slug silencing markedly enhances cisplatin-induced apoptosis in cholangiocarcinoma cells in vivo and in vitro, and that Slug overexpression could contribute to impaired apoptosis (data not shown).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (92, 110))	('overexpression', 'PosReg', (153, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('impaired apoptosis', 'Disease', (188, 206))	('silencing', 'Var', (33, 42))	('impaired apoptosis', 'Disease', 'MESH:D009422', (188, 206))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('Slug', 'Gene', (28, 32))	('cholangiocarcinoma', 'Disease', (92, 110))	('cisplatin-induced', 'MPA', (61, 78))	('enhances', 'PosReg', (52, 60))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (92, 110))
87389	21339993	In the present study, we found that cisplatin caused significant induction of apoptosis of human cholangiocarcinoma cells in a time and concentration dependent manner and that this was associated with arrest of the cell cycle in G0-G1.	('apoptosis', 'CPA', (78, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))	('cisplatin', 'Var', (36, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('cholangiocarcinoma', 'Disease', (97, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (97, 115))	('human', 'Species', '9606', (91, 96))
87393	21339993	To investigate whether the combination of Slug knockdown and cisplatin treatment can synergistically inhibit tumor growth and increase cholangiocarcinoma cell sensitivity to cisplatin, we used a well-established Xenograft tumor model in severe combined immunodeficient mice.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('mice', 'Species', '10090', (269, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('increase cholangiocarcinoma', 'Disease', (126, 153))	('immunodeficient', 'Disease', 'MESH:D007153', (253, 268))	('immunodeficient', 'Disease', (253, 268))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (174, 183))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (135, 153))	('inhibit', 'NegReg', (101, 108))	('increase cholangiocarcinoma cell', 'Phenotype', 'HP:0001402', (126, 158))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('tumor', 'Disease', (222, 227))	('increase cholangiocarcinoma', 'Disease', 'MESH:D018281', (126, 153))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('knockdown', 'Var', (47, 56))	('Slug', 'Gene', (42, 46))	('tumor', 'Disease', (109, 114))
87394	21339993	Slug silencing or cisplatin alone inhibited Xenograft tumor growth, and the effects of both did reach statistical significance.	('cisplatin', 'Chemical', 'MESH:D002945', (18, 27))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('silencing', 'Var', (5, 14))	('Slug', 'Gene', (0, 4))	('inhibited', 'NegReg', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
87403	19112054	Current theories of the pathogenesis of cholangiocarcinoma are centered on chronic inflammation and aberrant secretion of various growth factors, which lead to subsequent unchecked cell proliferation and neo-angiogenesis among other events.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (40, 58))	('inflammation', 'Disease', (83, 95))	('aberrant', 'Var', (100, 108))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (40, 58))	('cholangiocarcinoma', 'Disease', (40, 58))	('neo-angiogenesis', 'CPA', (204, 220))	('inflammation', 'Disease', 'MESH:D007249', (83, 95))
87411	19112054	Furthermore, the growth promoting effects of estrogen could be partially inhibited by a receptor-based VEGF inhibitor, and that the addition of recombinant VEGF-A to cholangiocarcinoma cells also increased cell proliferation, although to a lesser extent as estrogen.	('increased', 'PosReg', (196, 205))	('VEGF', 'Gene', (103, 107))	('growth promoting', 'CPA', (17, 33))	('VEGF', 'Gene', (156, 160))	('cell proliferation', 'CPA', (206, 224))	('cholangiocarcinoma', 'Disease', (166, 184))	('addition', 'Var', (132, 140))	('VEGF', 'Gene', '7422', (103, 107))	('inhibited', 'NegReg', (73, 82))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (166, 184))	('VEGF', 'Gene', '7422', (156, 160))	('VEGF-A', 'Gene', '7422', (156, 162))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (166, 184))	('VEGF-A', 'Gene', (156, 162))
87416	19112054	There is also an increase in secretion of VEGF during hyperplastic cholangiocyte proliferation seen in an experimental rodent model of extrahepatic biliary obstruction and that treatment of these animals with neutralizing antibodies against VEGF effectively inhibited cell proliferation.	('secretion', 'MPA', (29, 38))	('extrahepatic biliary obstruction', 'Disease', (135, 167))	('cell proliferation', 'CPA', (268, 286))	('neutralizing', 'Var', (209, 221))	('VEGF', 'Gene', '7422', (42, 46))	('extrahepatic biliary obstruction', 'Disease', 'MESH:D001651', (135, 167))	('biliary obstruction', 'Phenotype', 'HP:0005230', (148, 167))	('VEGF', 'Gene', '7422', (241, 245))	('inhibited', 'NegReg', (258, 267))	('extrahepatic biliary obstruction', 'Phenotype', 'HP:0005242', (135, 167))	('increase', 'PosReg', (17, 25))	('VEGF', 'Gene', (42, 46))	('VEGF', 'Gene', (241, 245))
87465	33335955	This study showed that ADC levels were significantly lower in cholangiocarcinoma patients with CKD than those without, regardless of MRI field strength or type of cholangiocarcinoma (Table 2, Table 3, Table 4, Table 5).	('ADC levels', 'MPA', (23, 33))	('cholangiocarcinoma', 'Disease', (62, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('cholangiocarcinoma', 'Disease', (163, 181))	('patients', 'Species', '9606', (81, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('CKD', 'Var', (95, 98))	('ADC', 'Chemical', '-', (23, 26))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (62, 80))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (62, 80))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (163, 181))	('lower', 'NegReg', (53, 58))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (163, 181))	('CKD', 'Phenotype', 'HP:0012622', (95, 98))
87470	33335955	A previous study using 3.0 T MRI have found eGFR and ADC to be significantly correlated, with coefficients of 0.310 (P =  .017) and 0.356(P =  .010) in the renal cortex and medulla, respectively.	('eGFR', 'Gene', (44, 48))	('ADC', 'Chemical', '-', (53, 56))	('0.356', 'Var', (132, 137))	('ADC', 'Gene', (53, 56))
87483	33335955	However, our results show that radiologists can use ADC to detect CKD in cholangiocarcinoma patients regardless of MRI field strength or type of cholangiocarcinoma.	('ADC', 'Chemical', '-', (52, 55))	('cholangiocarcinoma', 'Disease', (73, 91))	('patients', 'Species', '9606', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('cholangiocarcinoma', 'Disease', (145, 163))	('CKD', 'Phenotype', 'HP:0012622', (66, 69))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (145, 163))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (145, 163))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (73, 91))	('CKD', 'Var', (66, 69))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (73, 91))
87487	33052585	Preclinical evidence strongly supports the feasibility of this target and, although dozens of CK2 inhibitors have been described in the literature so far, CX-4945 (silmitasertib) was the first that entered into clinical trials for the treatment of both human haematological and solid tumours.	('tumours', 'Phenotype', 'HP:0002664', (284, 291))	('CK2', 'Gene', (94, 97))	('solid tumours', 'Disease', (278, 291))	('CX-4945', 'Chemical', 'MESH:C555142', (155, 162))	('CK2', 'Gene', '13000', (94, 97))	('solid tumours', 'Disease', 'MESH:D009369', (278, 291))	('human', 'Species', '9606', (253, 258))	('tumour', 'Phenotype', 'HP:0002664', (284, 290))	('CX-4945', 'Var', (155, 162))
87490	33052585	Data from preclinical studies clearly show the ability of CX-4945 to synergistically cooperate with different classes of anti-neoplastic agents, thereby contributing to an orchestrated anti-tumour action against multiple targets.	('contributing to', 'Reg', (153, 168))	('tumour', 'Disease', (190, 196))	('CX-4945', 'Chemical', 'MESH:C555142', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('CX-4945', 'Var', (58, 65))	('tumour', 'Disease', 'MESH:D009369', (190, 196))
87491	33052585	Overall, these promising outcomes support the translation of CX-4945 combined therapies into clinical anti-cancer applications.	('CX-4945', 'Chemical', 'MESH:C555142', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('CX-4945', 'Var', (61, 68))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
87504	33052585	Through the phosphorylation of AKT1 at Ser129, CK2 may also intervene in the pro-survival PI3K/AKT pathway contributing to perpetuate cell survival signalling.	('AKT', 'Gene', '207', (31, 34))	('phospho', 'Chemical', '-', (12, 19))	('phosphorylation', 'Var', (12, 27))	('intervene', 'Reg', (60, 69))	('AKT', 'Gene', (31, 34))	('AKT', 'Gene', '207', (95, 98))	('AKT1', 'Gene', '207', (31, 35))	('cell survival signalling', 'CPA', (134, 158))	('AKT', 'Gene', (95, 98))	('AKT1', 'Gene', (31, 35))	('CK2', 'Gene', (47, 50))	('CK2', 'Gene', '13000', (47, 50))	('perpetuate', 'PosReg', (123, 133))	('Ser129', 'Chemical', '-', (39, 45))
87518	33052585	Additional analysis of the crystal structure revealed two direct interactions between the kinase and its inhibitor: the first one, between the CX-4945 pyridine group with a Val116 residue of the CK2 hinge region, and the second amongst the carboxylate group of CX-4945 and Lys68 of the CK2 beta3 strand (Fig.	('Lys68', 'Chemical', '-', (273, 278))	('CK2', 'Gene', (286, 289))	('CK2', 'Gene', '13000', (195, 198))	('CX-4945', 'Chemical', 'MESH:C555142', (143, 150))	('Val116', 'Chemical', '-', (173, 179))	('CK2', 'Gene', (195, 198))	('CX-4945', 'Chemical', 'MESH:C555142', (261, 268))	('CK2', 'Gene', '13000', (286, 289))	('interactions', 'Interaction', (65, 77))	('pyridine', 'Chemical', 'MESH:C023666', (151, 159))	('carboxylate', 'Chemical', '-', (240, 251))	('CX-4945', 'Var', (143, 150))	('Lys68', 'Var', (273, 278))
87519	33052585	Additional contacts, involving the CX-4945 carboxylate group, are mediated by water molecules, which bridge interactions with Glu81, Asn118, His160, Asp175 and Trp176 residues.	('Glu81', 'Chemical', '-', (126, 131))	('water', 'Chemical', 'MESH:D014867', (78, 83))	('Trp176 residues', 'Var', (160, 175))	('Asn118', 'Chemical', '-', (133, 139))	('carboxylate', 'Chemical', '-', (43, 54))	('contacts', 'Interaction', (11, 19))	('Asn118', 'Var', (133, 139))	('Asp175', 'Var', (149, 155))	('CX-4945', 'Chemical', 'MESH:C555142', (35, 42))	('Asp175', 'Chemical', '-', (149, 155))	('His160', 'Chemical', '-', (141, 147))	('interactions', 'Interaction', (108, 120))	('Trp176', 'Chemical', '-', (160, 166))	('His160', 'Var', (141, 147))	('Glu81', 'Var', (126, 131))
87520	33052585	When administered in cells, CX-4945 has been found to show an extensive anti-proliferative activity, i.e., to promote cell cycle arrest, and to induce caspase activity and apoptosis in various cancer cell lines.	('induce', 'PosReg', (144, 150))	('arrest', 'Disease', (129, 135))	('CX-4945', 'Var', (28, 35))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (118, 135))	('CX-4945', 'Chemical', 'MESH:C555142', (28, 35))	('arrest', 'Disease', 'MESH:D006323', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('promote', 'PosReg', (110, 117))	('apoptosis', 'CPA', (172, 181))	('caspase activity', 'CPA', (151, 167))	('anti-proliferative activity', 'CPA', (72, 99))
87521	33052585	In addition, CX-4945 has been found to strongly inhibit cell migration and differentiation.	('CX-4945', 'Var', (13, 20))	('cell migration', 'CPA', (56, 70))	('CX-4945', 'Chemical', 'MESH:C555142', (13, 20))	('inhibit', 'NegReg', (48, 55))
87525	33052585	The concept of cancer addiction to CK2 implies that it is conceivable that not mere CK2 inhibition, but synergic actions of CK2 inhibitors with other chemotherapeutics may be more efficacious to treat tumours.	('CK2', 'Gene', (124, 127))	('tumours', 'Disease', 'MESH:D009369', (201, 208))	('CK2', 'Gene', '13000', (35, 38))	('cancer', 'Disease', (15, 21))	('inhibition', 'NegReg', (88, 98))	('tumours', 'Disease', (201, 208))	('CK2', 'Gene', (84, 87))	('CK2', 'Gene', '13000', (124, 127))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('CK2', 'Gene', '13000', (84, 87))	('inhibitors', 'Var', (128, 138))	('CK2', 'Gene', (35, 38))	('tumours', 'Phenotype', 'HP:0002664', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
87531	33052585	Recently, it has been shown that CX-4945 enhanced bortezomib-induced apoptosis in a panel of both B- and T-ALL cell lines, as well as in primary ALL blasts from paediatric patients.	('bortezomib-induced', 'Gene', (50, 68))	('bortezomib', 'Chemical', 'MESH:D000069286', (50, 60))	('enhanced', 'PosReg', (41, 49))	('CX-4945', 'Var', (33, 40))	('apoptosis', 'CPA', (69, 78))	('patients', 'Species', '9606', (172, 180))	('CX-4945', 'Chemical', 'MESH:C555142', (33, 40))
87532	33052585	The combined treatment with bortezomib and CX-4945 prompted an endoplasmic reticulum stress-mediated cell death, favouring the accumulation of IRE-1alpha and CHOP, as well as an increased phosphorylation of ERK and EIF2alpha.	('accumulation', 'PosReg', (127, 139))	('CX-4945', 'Chemical', 'MESH:C555142', (43, 50))	('phosphorylation', 'MPA', (188, 203))	('CHOP', 'Gene', '1649', (158, 162))	('ERK', 'Gene', (207, 210))	('ERK', 'Gene', '5594', (207, 210))	('bortezomib', 'Chemical', 'MESH:D000069286', (28, 38))	('IRE-1alpha', 'Gene', (143, 153))	('phospho', 'Chemical', '-', (188, 195))	('CHOP', 'Gene', (158, 162))	('EIF2alpha', 'Gene', '83939', (215, 224))	('IRE-1alpha', 'Gene', '2081', (143, 153))	('CX-4945', 'Var', (43, 50))	('EIF2alpha', 'Gene', (215, 224))	('increased', 'PosReg', (178, 187))
87533	33052585	Moreover, the combination of CX-4945/bortezomib induced an inhibition of the unfolded protein response (UPR) pathway and down-regulation of the anti-apoptotic mediator BCL-XL.	('inhibition', 'NegReg', (59, 69))	('BCL-XL', 'Gene', (168, 174))	('CX-4945/bortezomib', 'Var', (29, 47))	('CX-4945/bortezomib', 'Gene', (29, 47))	('bortezomib', 'Chemical', 'MESH:D000069286', (37, 47))	('BCL-XL', 'Gene', '598', (168, 174))	('combination', 'Interaction', (14, 25))	('down-regulation', 'NegReg', (121, 136))	('CX-4945', 'Chemical', 'MESH:C555142', (29, 36))	('anti-apoptotic', 'MPA', (144, 158))
87536	33052585	In ALL cells, a combined treatment with methotrexate and CX-4945 synergistically inhibited cell proliferation, blocked cell cycle progression in the G2/M phase and promoted the activation of caspases 3/7.	('cell cycle progression in the G2/M phase', 'CPA', (119, 159))	('blocked', 'NegReg', (111, 118))	('caspases 3/7', 'Gene', (191, 203))	('CX-4945', 'Chemical', 'MESH:C555142', (57, 64))	('activation', 'PosReg', (177, 187))	('inhibited', 'NegReg', (81, 90))	('methotrexate', 'Chemical', 'MESH:D008727', (40, 52))	('promoted', 'PosReg', (164, 172))	('caspases 3/7', 'Gene', '836;840', (191, 203))	('CX-4945', 'Var', (57, 64))	('cell proliferation', 'CPA', (91, 109))
87543	33052585	CX-4945 treatment has also been found to be effective in sensitizing multidrug-resistant CEM cells to the action of the anti-mitotic agent vinblastine, as well as in promoting doxorubicin accumulation.	('sensitizing', 'Reg', (57, 68))	('CX-4945', 'Chemical', 'MESH:C555142', (0, 7))	('promoting', 'PosReg', (166, 175))	('vinblastine', 'Chemical', 'MESH:D014747', (139, 150))	('doxorubicin accumulation', 'MPA', (176, 200))	('CX-4945', 'Var', (0, 7))	('doxorubicin', 'Chemical', 'MESH:D004317', (176, 187))	('multidrug-resistant', 'Disease', (69, 88))
87545	33052585	The observations that CX-4945 enhances the effect of vinblastine and facilitates doxorubicin uptake within cells are useful in the context of overcoming the acquisition of chemoresistance by tumour cells, an adverse and common effect that typically arises during long-term chemotherapy.	('tumour', 'Disease', 'MESH:D009369', (191, 197))	('doxorubicin uptake', 'MPA', (81, 99))	('tumour', 'Disease', (191, 197))	('effect', 'MPA', (43, 49))	('doxorubicin', 'Chemical', 'MESH:D004317', (81, 92))	('vinblastine', 'Chemical', 'MESH:D014747', (53, 64))	('CX-4945', 'Var', (22, 29))	('facilitates', 'PosReg', (69, 80))	('enhances', 'PosReg', (30, 38))	('overcoming', 'NegReg', (142, 152))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('CX-4945', 'Chemical', 'MESH:C555142', (22, 29))	('chemoresistance', 'CPA', (172, 187))
87550	33052585	Moreover, in B-ALL cell lines CX-4945 showed a strong synergy with doxorubicin and, most importantly, contributed to overcoming resistance to doxorubicin also in multidrug-resistant B-ALL cells.	('doxorubicin', 'Chemical', 'MESH:D004317', (67, 78))	('synergy', 'MPA', (54, 61))	('overcoming', 'PosReg', (117, 127))	('resistance to doxorubicin', 'MPA', (128, 153))	('CX-4945', 'Var', (30, 37))	('CX-4945', 'Chemical', 'MESH:C555142', (30, 37))	('doxorubicin', 'Chemical', 'MESH:D004317', (142, 153))
87552	33052585	A synergistic anti-cancer response (i.e., arrest of cell growth and promotion of apoptosis) has been observed in different T-ALL cell lines treated with CX-4945 in combination with JQ1, an inhibitor of the BET family member BRD4.	('BRD4', 'Gene', '23476', (224, 228))	('cell growth', 'CPA', (52, 63))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('arrest', 'Disease', (42, 48))	('CX-4945', 'Var', (153, 160))	('apoptosis', 'CPA', (81, 90))	('cancer', 'Disease', (19, 25))	('BRD4', 'Gene', (224, 228))	('CX-4945', 'Chemical', 'MESH:C555142', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('arrest', 'Disease', 'MESH:D006323', (42, 48))
87553	33052585	Aberrant activation of the transcription factor c-Myc mediated by Notch1 is a crucial event in T-ALL initiation, and it was found that both CX-4945 and JQ1 impair this axis (the first hampering Notch-1 signalling, the latter reducing c-Myc expression), thereby contributing to reducing c-Myc transcriptional activity.	('JQ1', 'Var', (152, 155))	('Notch1', 'Gene', (66, 72))	('Notch1', 'Gene', '4851', (66, 72))	('c-Myc', 'Gene', (48, 53))	('c-Myc', 'Gene', (286, 291))	('impair', 'NegReg', (156, 162))	('c-Myc', 'Gene', '4609', (48, 53))	('T-ALL initiation', 'Disease', (95, 111))	('Notch-1', 'Gene', '4851', (194, 201))	('c-Myc', 'Gene', '4609', (286, 291))	('reducing', 'NegReg', (277, 285))	('CX-4945', 'Chemical', 'MESH:C555142', (140, 147))	('T-ALL initiation', 'Disease', 'MESH:D054218', (95, 111))	('Notch-1', 'Gene', (194, 201))	('c-Myc', 'Gene', (234, 239))	('hampering', 'NegReg', (184, 193))	('c-Myc', 'Gene', '4609', (234, 239))	('reducing', 'NegReg', (225, 233))	('CX-4945', 'Var', (140, 147))
87558	33052585	The results of the work of Prins and colleagues showed that CX-4945 can synergistically enhance the anti-proliferative activity of all the three compounds tested.	('CX-4945', 'Var', (60, 67))	('anti-proliferative activity', 'CPA', (100, 127))	('CX-4945', 'Chemical', 'MESH:C555142', (60, 67))	('enhance', 'PosReg', (88, 95))
87564	33052585	More specifically, in acute myelomonocytic leukemia ML-2 cells, through inhibition of CK2, CX-4945 potentiated daunorubicin-induced apoptosis and suppression of cell proliferation.	('acute myelomonocytic leukemia', 'Disease', (22, 51))	('acute myelomonocytic leukemia', 'Disease', 'MESH:D015479', (22, 51))	('daunorubicin', 'Chemical', 'MESH:D003630', (111, 123))	('CK2', 'Gene', '13000', (86, 89))	('suppression', 'NegReg', (146, 157))	('acute myelomonocytic leukemia', 'Phenotype', 'HP:0004820', (22, 51))	('cell proliferation', 'CPA', (161, 179))	('CX-4945', 'Var', (91, 98))	('potentiated', 'PosReg', (99, 110))	('CX-4945', 'Chemical', 'MESH:C555142', (91, 98))	('daunorubicin-induced', 'MPA', (111, 131))	('leukemia', 'Phenotype', 'HP:0001909', (43, 51))	('CK2', 'Gene', (86, 89))	('inhibition', 'NegReg', (72, 82))
87567	33052585	Although BCR-ABL is not a CK2 phosphorylation substrate, it was found that CX-4945 abrogates the CK2/BCR-ABL interaction and, most importantly, contributes to overcoming imatinib-resistance in different CML cell lines.	('CK2', 'Gene', (97, 100))	('BCR-ABL', 'Gene', (9, 16))	('BCR-ABL', 'Gene', '25', (9, 16))	('BCR-ABL', 'Gene', '25', (101, 108))	('CML', 'Disease', 'MESH:D015464', (203, 206))	('imatinib', 'Chemical', 'MESH:D000068877', (170, 178))	('phospho', 'Chemical', '-', (30, 37))	('CK2', 'Gene', (26, 29))	('CX-4945', 'Var', (75, 82))	('CK2', 'Gene', '13000', (97, 100))	('overcoming', 'PosReg', (159, 169))	('CML', 'Disease', (203, 206))	('imatinib-resistance', 'MPA', (170, 189))	('CK2', 'Gene', '13000', (26, 29))	('abrogates', 'NegReg', (83, 92))	('CX-4945', 'Chemical', 'MESH:C555142', (75, 82))	('BCR-ABL', 'Gene', (101, 108))
87568	33052585	Notably, also CX-5011, a derivative of CX-4945, was found to induce apoptosis in CML cells and to promote a synergistic reduction in imatinib-resistant K562 and KCL22 cell viability when used in combination with imatinib and the MEK inhibitor U0126.	('induce', 'PosReg', (61, 67))	('promote', 'PosReg', (98, 105))	('CML', 'Disease', (81, 84))	('apoptosis', 'CPA', (68, 77))	('reduction', 'NegReg', (120, 129))	('CX-5011', 'Var', (14, 21))	('imatinib-resistant', 'MPA', (133, 151))	('imatinib', 'Chemical', 'MESH:D000068877', (133, 141))	('imatinib', 'Chemical', 'MESH:D000068877', (212, 220))	('CX-4945', 'Var', (39, 46))	('MEK', 'Gene', (229, 232))	('K562', 'CellLine', 'CVCL:0004', (152, 156))	('MEK', 'Gene', '5609', (229, 232))	('KCL22', 'CellLine', 'CVCL:2091', (161, 166))	('CX-4945', 'Chemical', 'MESH:C555142', (39, 46))	('U0126', 'Chemical', 'MESH:C113580', (243, 248))	('CML', 'Disease', 'MESH:D015464', (81, 84))
87573	33052585	Interestingly, in ovarian cancer cell lines co-administering CX-4945 and dasatinib synergistically reduced cell proliferation, and promoted caspase activation and apoptosis.	('CX-4945', 'Chemical', 'MESH:C555142', (61, 68))	('apoptosis', 'CPA', (163, 172))	('ovarian cancer', 'Disease', (18, 32))	('activation', 'PosReg', (148, 158))	('dasatinib', 'Chemical', 'MESH:D000069439', (73, 82))	('cell proliferation', 'CPA', (107, 125))	('CX-4945', 'Var', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('reduced', 'NegReg', (99, 106))	('ovarian cancer', 'Disease', 'MESH:D010051', (18, 32))	('ovarian cancer', 'Phenotype', 'HP:0100615', (18, 32))	('dasatinib', 'Gene', (73, 82))	('caspase', 'CPA', (140, 147))	('promoted', 'PosReg', (131, 139))
87577	33052585	showed a synergy between CX-4945 and cisplatin, as well as between CX-4945 and gemcitabine, to inhibit cell cycle progression and proliferation, to promote DNA single- and double-strand breaks and activation of the caspase pathway.	('CX-4945', 'Var', (25, 32))	('cell cycle progression', 'CPA', (103, 125))	('CX-4945', 'Chemical', 'MESH:C555142', (25, 32))	('inhibit', 'NegReg', (95, 102))	('caspase pathway', 'Pathway', (215, 230))	('gemcitabine', 'Chemical', 'MESH:C056507', (79, 90))	('CX-4945', 'Var', (67, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('proliferation', 'CPA', (130, 143))	('promote', 'PosReg', (148, 155))	('CX-4945', 'Chemical', 'MESH:C555142', (67, 74))
87579	33052585	The efficacy of combining CX-4945 with cisplatin and gemcitabine was further confirmed in a recent preclinical study conducted in both in vitro and in vivo cholangiocarcinoma models.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (156, 174))	('CX-4945', 'Var', (26, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('cholangiocarcinoma', 'Disease', (156, 174))	('gemcitabine', 'Chemical', 'MESH:C056507', (53, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('CX-4945', 'Chemical', 'MESH:C555142', (26, 33))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (156, 174))
87580	33052585	The favourable outcomes of this combined therapy are to be traced back to the inactivation of XRCC1 and MDC1 (two enzymes phosphorylated by CK2 and strictly involved in DNA repair) resulting from kinase inhibition mediated by CX-4945.	('CK2', 'Gene', '13000', (140, 143))	('MDC1', 'Gene', (104, 108))	('CX-4945', 'Chemical', 'MESH:C555142', (226, 233))	('XRCC1', 'Gene', '7515', (94, 99))	('kinase', 'Var', (196, 202))	('MDC1', 'Gene', '9656', (104, 108))	('phospho', 'Chemical', '-', (122, 129))	('CK2', 'Gene', (140, 143))	('XRCC1', 'Gene', (94, 99))	('inactivation', 'NegReg', (78, 90))
87581	33052585	Again, CX-4945 appeared to be effective for the treatment of cholangiocarcinoma by eliciting inhibition of cell proliferation and migration, when co-administered with MK2206 (an AKT inhibitor) or LY2157299 (a TGFbetaR1 inhibitor).	('AKT', 'Gene', (178, 181))	('inhibition', 'NegReg', (93, 103))	('LY2157299', 'Chemical', 'MESH:C557799', (196, 205))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 79))	('MK2206', 'Var', (167, 173))	('CX-4945', 'Chemical', 'MESH:C555142', (7, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('LY2157299', 'Var', (196, 205))	('cell proliferation', 'CPA', (107, 125))	('AKT', 'Gene', '207', (178, 181))	('MK2206', 'Chemical', 'MESH:C548887', (167, 173))	('CX-4945', 'Var', (7, 14))	('cholangiocarcinoma', 'Disease', (61, 79))
87587	33052585	The anti-tumour efficacy of combining CX-4945 and paclitaxel was also demonstrated in SNU-1 xenografted mice.	('tumour', 'Disease', (9, 15))	('tumour', 'Disease', 'MESH:D009369', (9, 15))	('CX-4945', 'Chemical', 'MESH:C555142', (38, 45))	('mice', 'Species', '10090', (104, 108))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('paclitaxel', 'Chemical', 'MESH:D017239', (50, 60))	('CX-4945', 'Var', (38, 45))
87593	33052585	Temozolomide is a DNA alkylating agent used in clinical practice to treat patients affected with glioblastoma (GBM) and other brain cancers, including neuroblastoma and astrocytoma, and exerts its anti-tumour activity through methylation of the O6 position of guanosine, which in turn causes the formation of DNA single- and double-strand breaks.	('astrocytoma', 'Phenotype', 'HP:0009592', (169, 180))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('causes', 'Reg', (285, 291))	('tumour', 'Disease', (202, 208))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))	('neuroblastoma', 'Disease', (151, 164))	('brain cancers', 'Disease', (126, 139))	('neuroblastoma', 'Phenotype', 'HP:0003006', (151, 164))	('patients', 'Species', '9606', (74, 82))	('astrocytoma', 'Disease', 'MESH:D001254', (169, 180))	('methylation', 'Var', (226, 237))	('astrocytoma', 'Disease', (169, 180))	('guanosine', 'Chemical', 'MESH:D006151', (260, 269))	('neuroblastoma', 'Disease', 'MESH:D009447', (151, 164))	('glioblastoma', 'Disease', (97, 109))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('Temozolomide', 'Chemical', 'MESH:D000077204', (0, 12))	('brain cancers', 'Disease', 'MESH:D001932', (126, 139))	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
87595	33052585	Therefore, CK2 inhibition mediated by CX-4945 leads to inhibition of the MGMT DNA-repairing activity, thereby potentiating the efficacy of temozolomide.	('inhibition', 'NegReg', (15, 25))	('MGMT', 'Gene', (73, 77))	('CK2', 'Gene', '13000', (11, 14))	('MGMT', 'Gene', '4255', (73, 77))	('CX-4945', 'Chemical', 'MESH:C555142', (38, 45))	('efficacy', 'MPA', (127, 135))	('CK2', 'Gene', (11, 14))	('temozolomide', 'Chemical', 'MESH:D000077204', (139, 151))	('potentiating', 'PosReg', (110, 122))	('inhibition', 'NegReg', (55, 65))	('CX-4945', 'Var', (38, 45))
87603	33052585	Genetic EGFR alterations (mainly amplifications, but also rearrangements, point mutations and deletions) have been found in about 60% of GBM patients, leading to aberrant EGFR signalling and uncontrolled activation of its downstream pathways (MAPK, PI3K/AKT, JAK/STAT and others), that in turn promote cell and tumour growth, apoptosis resistance and angiogenesis.	('EGFR', 'Gene', (171, 175))	('downstream pathways', 'Pathway', (222, 241))	('apoptosis resistance', 'CPA', (326, 346))	('AKT', 'Gene', (254, 257))	('EGFR', 'Gene', '1956', (8, 12))	('patients', 'Species', '9606', (141, 149))	('angiogenesis', 'CPA', (351, 363))	('promote', 'PosReg', (294, 301))	('GBM', 'Gene', (137, 140))	('EGFR', 'Gene', '1956', (171, 175))	('tumour', 'Phenotype', 'HP:0002664', (311, 317))	('AKT', 'Gene', '207', (254, 257))	('tumour growth', 'Disease', 'MESH:D006130', (311, 324))	('EGFR', 'Gene', (8, 12))	('activation', 'PosReg', (204, 214))	('rearrangements', 'Var', (58, 72))	('deletions', 'Var', (94, 103))	('alterations', 'Var', (13, 24))	('tumour growth', 'Disease', (311, 324))
87605	33052585	Interestingly, however, it has been observed that, when administered in conjunction with the EGFR inhibitor gefitinib, CX-4945 exerted a strong anti-proliferative effect on GBM xenolines in vitro.	('EGFR', 'Gene', '1956', (93, 97))	('gefitinib', 'Chemical', 'MESH:D000077156', (108, 117))	('EGFR', 'Gene', (93, 97))	('anti-proliferative effect', 'CPA', (144, 169))	('CX-4945', 'Var', (119, 126))	('CX-4945', 'Chemical', 'MESH:C555142', (119, 126))
87607	33052585	Indeed, co-administration of CX-4945 and erlotinib was able to effectively attenuate the PI3K-AKT-mTOR pathway in both squamous cell carcinoma and non-small cell lung carcinoma (NSCLC) cell lines, leading to reduced activation of AKT and its substrates, thereby inhibiting proliferation and enhancing apoptosis.	('AKT', 'Gene', (230, 233))	('apoptosis', 'CPA', (301, 310))	('AKT', 'Gene', (94, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('mTOR', 'Gene', (98, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (147, 176))	('non-small cell lung carcinoma', 'Disease', (147, 176))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (151, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('reduced', 'NegReg', (208, 215))	('mTOR', 'Gene', '2475', (98, 102))	('activation', 'PosReg', (216, 226))	('AKT', 'Gene', '207', (230, 233))	('erlotinib', 'Chemical', 'MESH:D000069347', (41, 50))	('CX-4945', 'Chemical', 'MESH:C555142', (29, 36))	('AKT', 'Gene', '207', (94, 97))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (119, 142))	('attenuate', 'NegReg', (75, 84))	('enhancing', 'PosReg', (291, 300))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('inhibiting', 'NegReg', (262, 272))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (147, 176))	('proliferation', 'CPA', (273, 286))	('squamous cell carcinoma', 'Disease', (119, 142))	('NSCLC', 'Disease', (178, 183))	('CX-4945', 'Var', (29, 36))
87608	33052585	Importantly, the efficacy of the CX-4945/erlotinib combined therapy was confirmed in an in vivo mouse xenograft model, i.e., it significantly delayed tumour growth compared to the respective monotherapies.	('tumour growth', 'Disease', (150, 163))	('mouse', 'Species', '10090', (96, 101))	('tumour growth', 'Disease', 'MESH:D006130', (150, 163))	('delayed', 'NegReg', (142, 149))	('CX-4945', 'Chemical', 'MESH:C555142', (33, 40))	('CX-4945/erlotinib', 'Var', (33, 50))	('erlotinib', 'Chemical', 'MESH:D000069347', (41, 50))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))
87609	33052585	Furthermore, a potential synergism between CX-4945 and selumetinib was also found to inhibit growth and induce PARP cleavage in NSCLC cell lines.	('growth', 'MPA', (93, 99))	('CX-4945', 'Chemical', 'MESH:C555142', (43, 50))	('selumetinib', 'Chemical', 'MESH:C517975', (55, 66))	('inhibit', 'NegReg', (85, 92))	('NSCLC', 'Disease', (128, 133))	('PARP', 'Gene', '1302', (111, 115))	('induce', 'PosReg', (104, 110))	('PARP', 'Gene', (111, 115))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('CX-4945', 'Var', (43, 50))	('selumetinib', 'Gene', (55, 66))
87616	33052585	The option that simultaneous inhibition of both CK2 and MEK may exert stronger anti-tumour outcomes has been explored in HNSCC cells by co-administration of CX-4945 and PD-0325901, a selective and non-ATP-competitive MEK inhibitor recently entered in clinical trials, whose anti-tumour efficacy has been shown in many preclinical studies in different human cancers [, (https://clinicaltrials.gov/ct2/home)].	('tumour', 'Disease', (84, 90))	('PD-0325901', 'Var', (169, 179))	('HNSCC', 'Disease', (121, 126))	('human', 'Species', '9606', (351, 356))	('MEK', 'Gene', (56, 59))	('CX-4945', 'Chemical', 'MESH:C555142', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (357, 364))	('cancers', 'Disease', (357, 364))	('ATP', 'Chemical', 'MESH:D000255', (201, 204))	('cancer', 'Phenotype', 'HP:0002664', (357, 363))	('PD-0325901', 'Chemical', 'MESH:C506614', (169, 179))	('CK2', 'Gene', '13000', (48, 51))	('tumour', 'Phenotype', 'HP:0002664', (279, 285))	('HNSCC', 'Disease', 'MESH:D000077195', (121, 126))	('MEK', 'Gene', '5609', (217, 220))	('tumour', 'Disease', 'MESH:D009369', (279, 285))	('tumour', 'Disease', (279, 285))	('CK2', 'Gene', (48, 51))	('MEK', 'Gene', (217, 220))	('cancers', 'Disease', 'MESH:D009369', (357, 364))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('MEK', 'Gene', '5609', (56, 59))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
87617	33052585	In these cells, MEK inhibition further potentiated the anti-proliferative effect mediated by CX-4945.	('inhibition', 'Var', (20, 30))	('CX-4945', 'Chemical', 'MESH:C555142', (93, 100))	('potentiated', 'PosReg', (39, 50))	('MEK', 'Gene', (16, 19))	('MEK', 'Gene', '5609', (16, 19))	('anti-proliferative effect', 'MPA', (55, 80))
87618	33052585	Also, the combination of CX-4945 and PD-0325901 was more effective in delaying tumour growth in a mouse model compared to both monotherapies.	('CX-4945', 'Var', (25, 32))	('CX-4945', 'Chemical', 'MESH:C555142', (25, 32))	('tumour growth', 'Disease', (79, 92))	('PD-0325901', 'Chemical', 'MESH:C506614', (37, 47))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumour growth', 'Disease', 'MESH:D006130', (79, 92))	('delaying', 'NegReg', (70, 78))	('mouse', 'Species', '10090', (98, 103))	('PD-0325901', 'Var', (37, 47))
87621	33052585	Moreover, we assessed the combined effects of CK2 inhibition and heat shock stress on proliferation in both HepG2 hepatocellular carcinoma cells and HeLa cervical cancer cells, revealing that CX-4945 pre-treatment strongly enhanced tumour cell thermo-sensitivity.	('HeLa cervical cancer', 'Disease', (149, 169))	('CX-4945', 'Var', (192, 199))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (114, 138))	('shock stress', 'Disease', 'MESH:D000079225', (70, 82))	('enhanced', 'PosReg', (223, 231))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('shock', 'Phenotype', 'HP:0031273', (70, 75))	('tumour', 'Disease', 'MESH:D009369', (232, 238))	('HeLa cervical cancer', 'Disease', 'MESH:D002583', (149, 169))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (114, 138))	('tumour', 'Disease', (232, 238))	('shock stress', 'Disease', (70, 82))	('CK2', 'Gene', '13000', (46, 49))	('CX-4945', 'Chemical', 'MESH:C555142', (192, 199))	('HepG2', 'CellLine', 'CVCL:0027', (108, 113))	('hepatocellular carcinoma', 'Disease', (114, 138))	('CK2', 'Gene', (46, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
87622	33052585	In the last twenty years, the idea to target kinases whose aberrant signalling is related to tumour initiation and/or progression, has been considered as one of the most promising approaches to treat cancer and, indeed kinase inhibitors currently constitute one of the largest families of anti-cancer drugs.	('tumour initiation', 'Disease', 'MESH:D009369', (93, 110))	('aberrant', 'Var', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', (294, 300))	('tumour initiation', 'Disease', (93, 110))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('cancer', 'Disease', (200, 206))
87628	33052585	As we have already mentioned, CX-4945 has reached phases I and II clinical trials to test its anti-tumour activity (https://clinicaltrials.gov/ct2/home).	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('CX-4945', 'Var', (30, 37))	('CX-4945', 'Chemical', 'MESH:C555142', (30, 37))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
87631	33052585	Currently, CX-4945 is being used to treat patients with basal cell carcinoma (NCT03897036), cholangiocarcinoma (NCT02128282), kidney cancer (NCT03571438) and paediatric patients affected with medulloblastoma (NCT03904862).	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (56, 76))	('basal cell carcinoma', 'Disease', (56, 76))	('NCT02128282', 'Var', (112, 123))	('kidney cancer', 'Disease', 'MESH:D007680', (126, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('NCT03571438', 'Var', (141, 152))	('CX-4945', 'Chemical', 'MESH:C555142', (11, 18))	('patients', 'Species', '9606', (42, 50))	('NCT03897036', 'Var', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('kidney cancer', 'Phenotype', 'HP:0009726', (126, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (92, 110))	('patients', 'Species', '9606', (169, 177))	('medulloblastoma', 'Disease', 'MESH:D008527', (192, 207))	('kidney cancer', 'Disease', (126, 139))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (56, 76))	('medulloblastoma', 'Phenotype', 'HP:0002885', (192, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('NCT03897036', 'CellLine', 'None', (78, 89))	('cholangiocarcinoma', 'Disease', (92, 110))	('medulloblastoma', 'Disease', (192, 207))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (92, 110))
87632	33052585	The aims of the ongoing trials are: 1) optimization of CX-4945 treatment by determination of the optimal and maximum tolerated doses; 2) assessment of drug pharmacokinetics and pharmacodynamics; 3) description of CX-4945-related adverse events; 4) demonstration of its anti-tumour activity.	('tumour', 'Phenotype', 'HP:0002664', (274, 280))	('CX-4945-related', 'Var', (213, 228))	('CX-4945', 'Chemical', 'MESH:C555142', (213, 220))	('tumour', 'Disease', 'MESH:D009369', (274, 280))	('tumour', 'Disease', (274, 280))	('CX-4945', 'Chemical', 'MESH:C555142', (55, 62))
87639	33052585	Thus, a combination therapy based on a DNA-damaging agent and CX-4945, to hamper DNA-repair, may likely represent a feasible strategy to increase the vulnerability of tumour cells.	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('tumour', 'Disease', (167, 173))	('CX-4945', 'Chemical', 'MESH:C555142', (62, 69))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('CX-4945', 'Var', (62, 69))
87641	33052585	Finally, it is to be mentioned that CX-4945 has recently been characterized as a methuosis inducer, a new issue that could be relevant in anti-cancer combination therapy.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('CX-4945', 'Var', (36, 43))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('inducer', 'Reg', (91, 98))	('CX-4945', 'Chemical', 'MESH:C555142', (36, 43))	('methuosis', 'Disease', (81, 90))
87642	33052585	When used at high micromolar concentrations, ranging from 10 to 50 muM, CX-4945 promotes a distinctive form of cell death characterized by displacement of large, macro-pinocytic-derived and fluid-filled cytosolic vacuoles, that has been dubbed methuosis (from the Greek word muepsilonthetaupsilonomega, to be drunk).	('CX-4945', 'Var', (72, 79))	('CX-4945', 'Chemical', 'MESH:C555142', (72, 79))	('word muepsilonthetaupsilonomega', 'Disease', 'MESH:D000647', (270, 301))	('word muepsilonthetaupsilonomega', 'Disease', (270, 301))	('displacement', 'MPA', (139, 151))	('cell death', 'CPA', (111, 121))
87643	33052585	We and others have previously reported that the induction of methuosis mediated by CX-4945, as well as its derivative CX-5011, is CK2-independent.	('CK2', 'Gene', '13000', (130, 133))	('methuosis', 'MPA', (61, 70))	('CX-4945', 'Var', (83, 90))	('CX-4945', 'Chemical', 'MESH:C555142', (83, 90))	('CK2', 'Gene', (130, 133))
87646	33052585	Although the concept of off-target effects has a negative connotation, the finding that CX-4945 promotes this non-canonical mechanism of cell death could represent an added value, rather than an obstacle, in the context of anti-cancer combination therapy for at least two reasons: 1) induction of methuosis could represent a feasible anti-tumour approach for those tumours that acquired the ability to escape from apoptosis or that developed resistance to classical apoptosis inducing agents; 2) enhancing macro-pinocytosis, CX-4945 could favour the uptake of additional drugs, thus representing an ideal condition for a pharmacological therapy that involves the use of multiple drugs, as shown in, where doxorubicin accumulation in tumour cells was greatly increased by CX-4945 co-administration, or as suggested by Colin et al.	('tumour', 'Phenotype', 'HP:0002664', (339, 345))	('CX-4945', 'Chemical', 'MESH:C555142', (525, 532))	('tumour', 'Disease', 'MESH:D009369', (339, 345))	('tumour', 'Disease', (339, 345))	('CX-4945', 'Var', (771, 778))	('tumour', 'Phenotype', 'HP:0002664', (733, 739))	('tumour', 'Disease', 'MESH:D009369', (733, 739))	('tumour', 'Disease', (733, 739))	('doxorubicin', 'Chemical', 'MESH:D004317', (705, 716))	('increased', 'PosReg', (758, 767))	('cancer', 'Disease', (228, 234))	('tumours', 'Disease', (365, 372))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('tumour', 'Phenotype', 'HP:0002664', (365, 371))	('tumour', 'Disease', 'MESH:D009369', (365, 371))	('tumours', 'Phenotype', 'HP:0002664', (365, 372))	('CX-4945', 'Chemical', 'MESH:C555142', (771, 778))	('tumour', 'Disease', (365, 371))	('doxorubicin accumulation', 'MPA', (705, 729))	('tumours', 'Disease', 'MESH:D009369', (365, 372))	('CX-4945', 'Chemical', 'MESH:C555142', (88, 95))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
87650	33052585	Although the ability of CX-4945 to effectively promote anti-tumour outcomes by itself has not been fully defined yet, its ability to foster and sustain the action of other anti-neoplastic agents seems evident, thereby contributing to an orchestrated anti-tumour action.	('contributing to', 'Reg', (218, 233))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('tumour', 'Phenotype', 'HP:0002664', (255, 261))	('tumour', 'Disease', (60, 66))	('promote', 'PosReg', (47, 54))	('foster', 'PosReg', (133, 139))	('CX-4945', 'Chemical', 'MESH:C555142', (24, 31))	('tumour', 'Disease', 'MESH:D009369', (255, 261))	('tumour', 'Disease', (255, 261))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('action', 'MPA', (156, 162))	('CX-4945', 'Var', (24, 31))
87685	31979397	Mutant zebrafish with deficient SHH signaling develop abnormal circulation and vascularization such as a single axial vessel with no arterial markers.	('circulation', 'CPA', (63, 74))	('vascularization', 'CPA', (79, 94))	('zebrafish', 'Species', '7955', (7, 16))	('abnormal circulation', 'Phenotype', 'HP:0011028', (54, 74))	('single axial vessel', 'Phenotype', 'HP:0001195', (105, 124))	('Mutant', 'Var', (0, 6))
87691	31979397	According to their transcriptional profiles, MB can be classified into four subtypes: (1) WNT-MBs, (2) SHH-MBs, (3) Group C with abnormal transforming growth factor 1 beta (TGF1beta) pathway, and (4) Group D with tandem duplication of a-synuclein-interacting protein.	('abnormal', 'Reg', (129, 137))	('MB', 'Phenotype', 'HP:0002885', (45, 47))	('MB', 'Disease', 'MESH:D008527', (45, 47))	('TGF1beta', 'Gene', '6885', (173, 181))	('a-synuclein-interacting', 'Protein', (235, 258))	('MB', 'Disease', 'MESH:D008527', (107, 109))	('MB', 'Disease', 'MESH:D008527', (94, 96))	('MB', 'Phenotype', 'HP:0002885', (107, 109))	('MB', 'Phenotype', 'HP:0002885', (94, 96))	('TGF1beta', 'Gene', (173, 181))	('tandem duplication', 'Var', (213, 231))
87694	31979397	SHH-MBs are correlated with aberrations of the components of the SHH pathway (PTCH1, SUFU, GLI transcription factors and SMO).	('PTCH1', 'Gene', (78, 83))	('SUFU', 'Gene', (85, 89))	('MB', 'Disease', 'MESH:D008527', (4, 6))	('SUFU', 'Gene', '51684', (85, 89))	('SMO', 'Gene', (121, 124))	('GLI', 'Gene', (91, 94))	('aberrations', 'Var', (28, 39))	('MB', 'Phenotype', 'HP:0002885', (4, 6))	('PTCH1', 'Gene', '5727', (78, 83))	('GLI', 'Gene', '2735', (91, 94))	('SHH pathway', 'Pathway', (65, 76))
87695	31979397	In particular, several SMO mutations involved in MB tumorigenesis have been found (L225R, N223D, S391N, D338N, D477G, D473H, G457S).	('tumor', 'Disease', (52, 57))	('G457S', 'Mutation', 'p.G457S', (125, 130))	('S391N', 'Var', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('SMO', 'Gene', (23, 26))	('D477G', 'Mutation', 'p.D477G', (111, 116))	('D338N', 'Mutation', 'p.D338N', (104, 109))	('G457S', 'Var', (125, 130))	('D338N', 'Var', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('MB', 'Disease', 'MESH:D008527', (49, 51))	('L225R', 'Var', (83, 88))	('MB', 'Phenotype', 'HP:0002885', (49, 51))	('D473H', 'Mutation', 'rs17710891', (118, 123))	('N223D', 'Mutation', 'p.N223D', (90, 95))	('D473H', 'Var', (118, 123))	('N223D', 'Var', (90, 95))	('D477G', 'Var', (111, 116))	('L225R', 'Mutation', 'p.L225R', (83, 88))	('S391N', 'Mutation', 'p.S391N', (97, 102))
87696	31979397	found that SHH pathway inhibitors may decrease both the proliferation and metastasis of tumors in a mouse MB model.	('MB', 'Disease', 'MESH:D008527', (106, 108))	('SHH', 'Gene', (11, 14))	('metastasis of tumors', 'Disease', (74, 94))	('inhibitors', 'Var', (23, 33))	('MB', 'Phenotype', 'HP:0002885', (106, 108))	('mouse', 'Species', '10090', (100, 105))	('proliferation', 'CPA', (56, 69))	('decrease', 'NegReg', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('metastasis of tumors', 'Disease', 'MESH:D009362', (74, 94))
87713	31979397	In hepatocellular carcinoma (HCC) patients, SMO mutation at the C-terminal lysine (K575M) involves the binding between PTCH and SMO to alleviate SMO from PTCH suppression to activate the downstream signaling.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('HCC', 'Disease', 'MESH:D006528', (29, 32))	('PTCH', 'Gene', (154, 158))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('K575M', 'Mutation', 'rs56383695', (83, 88))	('PTCH', 'Gene', (119, 123))	('SMO', 'MPA', (145, 148))	('lysine', 'Chemical', 'MESH:D008239', (75, 81))	('SMO', 'Gene', (44, 47))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('HCC', 'Disease', (29, 32))	('PTCH', 'Gene', '5727', (154, 158))	('HCC', 'Phenotype', 'HP:0001402', (29, 32))	('mutation', 'Var', (48, 56))	('patients', 'Species', '9606', (34, 42))	('activate', 'PosReg', (174, 182))	('hepatocellular carcinoma', 'Disease', (3, 27))	('alleviate', 'PosReg', (135, 144))	('PTCH', 'Gene', '5727', (119, 123))	('binding', 'Interaction', (103, 110))
87716	31979397	Other authors found that the SMO inhibitor GDC-0499 could inhibit hepatocarcinogenesis in HBx transgenic mice.	('GDC-0499', 'Var', (43, 51))	('transgenic mice', 'Species', '10090', (94, 109))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (66, 86))	('GDC-0499', 'Chemical', '-', (43, 51))	('inhibit', 'NegReg', (58, 65))	('hepatocarcinogenesis', 'Disease', (66, 86))
87720	31979397	found that SMO polymorphisms in transplant recipients are associated with an increased risk of postoperative HCC recurrence.	('associated', 'Reg', (58, 68))	('HCC', 'Disease', (109, 112))	('HCC', 'Disease', 'MESH:D006528', (109, 112))	('HCC', 'Phenotype', 'HP:0001402', (109, 112))	('polymorphisms', 'Var', (15, 28))	('SMO', 'Gene', (11, 14))
87723	31979397	The disruption or change of the liver microenvironment and immune cell composition mainly promotes the malignant transformation and progression of HCC.	('malignant transformation', 'CPA', (103, 127))	('HCC', 'Disease', 'MESH:D006528', (147, 150))	('change', 'Reg', (18, 24))	('HCC', 'Phenotype', 'HP:0001402', (147, 150))	('HCC', 'Disease', (147, 150))	('disruption', 'Var', (4, 14))	('promotes', 'PosReg', (90, 98))	('progression', 'CPA', (132, 143))
87732	31979397	Cyclopamine also inhibited tumor growth and metastasis in a rodent model study.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('Cyclopamine', 'Chemical', 'MESH:C000541', (0, 11))	('tumor', 'Disease', (27, 32))	('inhibited', 'NegReg', (17, 26))	('Cyclopamine', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
87744	31979397	High GLI1 expression is correlated with worse prognosis of gallbladder cancer.	('gallbladder cancer', 'Disease', (59, 77))	('High', 'Var', (0, 4))	('gallbladder cancer', 'Disease', 'MESH:D005706', (59, 77))	('expression', 'MPA', (10, 20))	('GLI1', 'Gene', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
87745	31979397	Moreover, high expression of SHH-signaling molecules SHH, PTCH, and GLI are associated with poor survival in the gallbladder.	('PTCH', 'Gene', '5727', (58, 62))	('poor', 'NegReg', (92, 96))	('GLI', 'Gene', (68, 71))	('associated', 'Reg', (76, 86))	('PTCH', 'Gene', (58, 62))	('high', 'Var', (10, 14))	('SHH', 'Gene', (53, 56))	('GLI', 'Gene', '2735', (68, 71))
87746	31979397	Several mutations of the SHH gene in gallbladder carcinoma could be identified and associated with the carcinogenesis.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('SHH', 'Gene', (25, 28))	('gallbladder carcinoma', 'Disease', (37, 58))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('mutations', 'Var', (8, 17))	('associated', 'Reg', (83, 93))	('carcinogenesis', 'Disease', (103, 117))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (37, 58))
87747	31979397	Patients with high levels of SHH-signaling molecules were found to be associated with unfavorable survival outcomes.	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('associated', 'Reg', (70, 80))
87756	31979397	Aberrant SHH expression occurs in the early stages and during the progression of pancreatic cancer.	('Aberrant', 'Var', (0, 8))	('occurs', 'Reg', (24, 30))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('SHH', 'Gene', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('pancreatic cancer', 'Disease', (81, 98))
87779	31979397	knocked out SMO in fibroblasts to enhance tumor growth.	('tumor', 'Disease', (42, 47))	('enhance', 'PosReg', (34, 41))	('SMO', 'Gene', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('knocked out', 'Var', (0, 11))
87792	31979397	After SMO deletion, fibroblasts overexpressed transforming growth factor-alpha (TGF-alpha) mRNA, and TGF-alpha protein, resulting in activation of epidermal growth factor receptor signaling in acinar cells and in acinar-ductal metaplasia.	('TGF-alpha', 'Gene', (101, 110))	('SMO', 'Gene', (6, 9))	('acinar-ductal metaplasia', 'CPA', (213, 237))	('transforming growth factor-alpha', 'Gene', (46, 78))	('protein', 'Protein', (111, 118))	('TGF-alpha', 'Gene', '7039', (80, 89))	('activation', 'PosReg', (133, 143))	('transforming growth factor-alpha', 'Gene', '7124', (46, 78))	('TGF-alpha', 'Gene', '7039', (101, 110))	('deletion', 'Var', (10, 18))	('overexpressed', 'PosReg', (32, 45))	('TGF-alpha', 'Gene', (80, 89))	('epidermal growth factor receptor signaling', 'MPA', (147, 189))
87795	31979397	demonstrated that using SMO-positive pancreatic cancer cells, GDC-0449 could downregulate SHH signaling genes and reverse fibroblast-induced resistance to doxorubicin.	('downregulate', 'NegReg', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (37, 54))	('fibroblast-induced resistance to doxorubicin', 'MPA', (122, 166))	('reverse', 'NegReg', (114, 121))	('pancreatic cancer', 'Disease', (37, 54))	('doxorubicin', 'Chemical', 'MESH:D004317', (155, 166))	('pancreatic cancer', 'Disease', 'MESH:D010190', (37, 54))	('GDC-0449', 'Chemical', 'MESH:C538724', (62, 70))	('GDC-0449', 'Var', (62, 70))	('SHH signaling genes', 'Gene', (90, 109))
87796	31979397	found that genetic ablation of SMO in stromal fibrosis could disrupt the paracrine SHH signaling with acinar-ductal metaplasia under a Kras G12D mouse model.	('disrupt', 'NegReg', (61, 68))	('SMO', 'Gene', (31, 34))	('G12D', 'Mutation', 'p.G12D', (140, 144))	('mouse', 'Species', '10090', (145, 150))	('genetic ablation', 'Var', (11, 27))	('fibrosis', 'Disease', 'MESH:D005355', (46, 54))	('fibrosis', 'Disease', (46, 54))	('paracrine SHH signaling', 'MPA', (73, 96))
87809	31979397	suggested that mutations to the SHH signaling pathway affect human gastrointestinal function.	('human gastrointestinal function', 'Disease', (61, 92))	('mutations', 'Var', (15, 24))	('SHH', 'Gene', (32, 35))	('affect', 'Reg', (54, 60))	('human', 'Species', '9606', (61, 66))
87813	31979397	Dysregulation of the SHH signaling pathway causes the disruption of gastric differentiation, loss of gastric acid secretion, and the development of cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('gastric differentiation', 'CPA', (68, 91))	('loss', 'NegReg', (93, 97))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('SHH signaling pathway', 'Pathway', (21, 42))	('gastric acid secretion', 'MPA', (101, 123))
87818	31979397	The change of SHH expression induces gastric cancer development.	('induces', 'Reg', (29, 36))	('gastric cancer', 'Disease', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (37, 51))	('SHH', 'Gene', (14, 17))	('change', 'Var', (4, 10))	('gastric cancer', 'Phenotype', 'HP:0012126', (37, 51))
87823	31979397	SHH plays an important role in sustaining gastric epithelial differentiation, and the loss of SHH favors early carcinogenesis.	('carcinogenesis', 'Disease', (111, 125))	('gastric epithelial differentiation', 'CPA', (42, 76))	('loss', 'Var', (86, 90))	('SHH', 'Gene', (94, 97))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))	('favors', 'PosReg', (98, 104))
87825	31979397	Other researchers found that SMO or GLI1 inhibitors impair the migration and invasion of gastric cancer cells.	('impair', 'NegReg', (52, 58))	('GLI1', 'Gene', (36, 40))	('gastric cancer', 'Disease', (89, 103))	('inhibitors', 'Var', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('SMO', 'Gene', (29, 32))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))
87827	31979397	found that GDC-0499 inhibits the proliferation of gastric cancer cell line SGC-7901 and accelerates apoptosis.	('accelerates', 'PosReg', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('GDC-0499', 'Chemical', '-', (11, 19))	('inhibits', 'NegReg', (20, 28))	('gastric cancer', 'Disease', (50, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('SGC', 'Gene', (75, 78))	('GDC-0499', 'Var', (11, 19))	('proliferation', 'CPA', (33, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))	('SGC', 'Gene', '6443', (75, 78))	('apoptosis', 'CPA', (100, 109))
87841	31979397	found that GDC-0449 inhibits the replication of colon cancer cells and triggers apoptosis via downregulating B-cell lymphoma 2 (Bcl-2).	('colon cancer', 'Disease', (48, 60))	('inhibits', 'NegReg', (20, 28))	('lymphoma', 'Phenotype', 'HP:0002665', (116, 124))	('B-cell lymphoma 2', 'Gene', (109, 126))	('Bcl-2', 'Gene', (128, 133))	('downregulating', 'NegReg', (94, 108))	('Bcl-2', 'Gene', '596', (128, 133))	('triggers', 'Reg', (71, 79))	('colon cancer', 'Disease', 'MESH:D015179', (48, 60))	('GDC-0449', 'Chemical', 'MESH:C538724', (11, 19))	('colon cancer', 'Phenotype', 'HP:0003003', (48, 60))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (109, 124))	('B-cell lymphoma 2', 'Gene', '596', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('apoptosis', 'CPA', (80, 89))	('replication', 'CPA', (33, 44))	('GDC-0449', 'Var', (11, 19))
87842	31979397	found that GDC-0499 could suppress and modulate cellular plasticity and invasiveness of colorectal cancer.	('cellular plasticity', 'CPA', (48, 67))	('invasiveness of colorectal cancer', 'Disease', 'MESH:D015179', (72, 105))	('GDC-0499', 'Chemical', '-', (11, 19))	('invasiveness of colorectal cancer', 'Disease', (72, 105))	('modulate', 'Reg', (39, 47))	('GDC-0499', 'Var', (11, 19))	('suppress', 'NegReg', (26, 34))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
87859	31979397	Recently, studies of estrogen receptor (ER)-positive breast cancer (BC) cell lines have revealed that estrogen can increase GLI1 and GLI2.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('BC', 'Phenotype', 'HP:0003002', (68, 70))	('estrogen receptor', 'Gene', (21, 38))	('increase', 'PosReg', (115, 123))	('estrogen receptor', 'Gene', '2099', (21, 38))	('BC', 'Disease', 'MESH:D001943', (68, 70))	('estrogen', 'Var', (102, 110))	('GLI2', 'Gene', (133, 137))	('GLI2', 'Gene', '2736', (133, 137))	('ER', 'Gene', '2099', (40, 42))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))
87866	31979397	Overexpression of GLI1 acts as a predictor in age, ER-positive expression, distant metastasis, short disease-free survival, and short overall survival.	('GLI1', 'Gene', (18, 22))	('ER', 'Gene', '2099', (51, 53))	('distant metastasis', 'CPA', (75, 93))	('expression', 'MPA', (63, 73))	('Overexpression', 'Var', (0, 14))
87884	31979397	Tumor microenvironment cells also include tumor-associated macrophages with aberrant genetic and epigenetic changes that may induce a high expression of signaling molecules to enhance the survival of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('induce', 'Reg', (125, 131))	('high expression of signaling molecules', 'MPA', (134, 172))	('tumor', 'Disease', (200, 205))	('enhance', 'PosReg', (176, 183))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('epigenetic changes', 'Var', (97, 115))
87888	31979397	Mutations in SHH or associated signaling components result in foregut defects in humans.	('defects', 'Disease', 'MESH:D030342', (70, 77))	('humans', 'Species', '9606', (81, 87))	('Mutations', 'Var', (0, 9))	('defects', 'Disease', (70, 77))	('result in', 'Reg', (52, 61))	('SHH', 'Gene', (13, 16))
87889	31979397	Abnormal secretion of SHH causes severe foregut defects and lung hypoplasia.	('causes', 'Reg', (26, 32))	('lung hypoplasia', 'Disease', (60, 75))	('lung hypoplasia', 'Disease', 'MESH:D008171', (60, 75))	('defects', 'Disease', 'MESH:D030342', (48, 55))	('SHH', 'Gene', (22, 25))	('Abnormal', 'Var', (0, 8))	('lung hypoplasia', 'Phenotype', 'HP:0002089', (60, 75))	('defects', 'Disease', (48, 55))
87892	31979397	PTCH knockout is lethal before lung development begins.	('PTCH', 'Gene', (0, 4))	('PTCH', 'Gene', '5727', (0, 4))	('knockout', 'Var', (5, 13))
87896	31979397	reported that hyperactivated SMO could facilitate the proliferation of non-small cell lung cancer cells, and found that HECT and RLD domain containing E3 ubiquitin ligase 4 (HERC4) is inhibited after destabilizing oncoprotein SMO.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (71, 97))	('non-small cell lung cancer', 'Disease', (71, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('destabilizing', 'Var', (200, 213))	('facilitate', 'PosReg', (39, 49))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (75, 97))	('HERC4', 'Gene', '26091', (174, 179))	('proliferation', 'CPA', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('HERC4', 'Gene', (174, 179))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (71, 97))	('inhibited', 'NegReg', (184, 193))
87988	30843343	Definitive data from the NACRAC study are awaited to determine whether neoadjuvant CRT also improves survival (UMIN000000992 and UMIN000001754).	('UMIN000000992', 'Var', (111, 124))	('NACRAC', 'Chemical', '-', (25, 31))	('UMIN000001754', 'Var', (129, 142))	('improves', 'PosReg', (92, 100))	('survival', 'CPA', (101, 109))
88039	30843343	Serum IgG4 is elevated in patients with auto-immune cholangitis, which may sometimes present as an intrahepatic mass.90 However, not all patients with elevated IgG4 have auto-immune cholangitis and patients with elevated IgG4 may also have cancer.	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('patients', 'Species', '9606', (198, 206))	('cholangitis', 'Disease', (182, 193))	('cholangitis', 'Phenotype', 'HP:0030151', (182, 193))	('IgG4', 'Gene', (160, 164))	('patients', 'Species', '9606', (137, 145))	('patients', 'Species', '9606', (26, 34))	('cholangitis', 'Disease', (52, 63))	('Serum IgG4 is elevated', 'Phenotype', 'HP:0032300', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cholangitis', 'Phenotype', 'HP:0030151', (52, 63))	('cholangitis', 'Disease', 'MESH:D002761', (182, 193))	('elevated', 'Var', (151, 159))	('cancer', 'Disease', (240, 246))	('cholangitis', 'Disease', 'MESH:D002761', (52, 63))
88149	30027911	The comparison of the two groups indicated that incidence rate of cholangitis and related infectious indicators were significantly higher in EMBE group than that in EMBE plus ENBD group.	('EMBE', 'Var', (141, 145))	('cholangitis', 'Phenotype', 'HP:0030151', (66, 77))	('cholangitis', 'Disease', (66, 77))	('cholangitis', 'Disease', 'MESH:D002761', (66, 77))	('higher', 'PosReg', (131, 137))
88270	28111425	In the present study, patients with baseline CEA >= 5 ng/mL had worse TTP and OS than those with CEA < 5 ng/mL.	('CEA', 'Gene', '1048', (97, 100))	('worse', 'NegReg', (64, 69))	('CEA', 'Gene', (97, 100))	('CEA', 'Gene', '1048', (45, 48))	('patients', 'Species', '9606', (22, 30))	('TTP', 'Gene', (70, 73))	('TTP', 'Gene', '7538', (70, 73))	('>= 5 ng/mL', 'Var', (49, 59))	('CEA', 'Gene', (45, 48))
88271	28111425	Although CA 19-9 did not have a prognostic role in terms of TTP, patients with CA 19-9 >= 370 U/mL had a worse OS than those with CA 19-9 < 370 U/mL.	('TTP', 'Gene', (60, 63))	('TTP', 'Gene', '7538', (60, 63))	('patients', 'Species', '9606', (65, 73))	('CA 19-9 >= 370 U/mL', 'Var', (79, 98))
88299	27259577	Taken together, our study revealed a novel microRNA signaling pathway involved in cholangiocarcinoma and suggests that manipulation of the miR-410/XIAP pathway could have a therapeutic potential for cholangiocarcinoma.	('XIAP', 'Gene', '331', (147, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('manipulation', 'Var', (119, 131))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (82, 100))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (199, 217))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (199, 217))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (82, 100))	('microRNA signaling pathway', 'Pathway', (43, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('involved', 'Reg', (70, 78))	('cholangiocarcinoma', 'Disease', (82, 100))	('XIAP', 'Gene', (147, 151))	('cholangiocarcinoma', 'Disease', (199, 217))
88308	27259577	Recent studies have reported microRNAs (miR-26a, miR-141, miR-210, miR-31, miR-21 and miR-421) having oncogenic function in CCAs by modulating cell proliferation signaling pathways.	('miR-31', 'Gene', '407035', (67, 73))	('miR-141', 'Gene', '406933', (49, 56))	('miR-21', 'Gene', (58, 64))	('CCAs', 'Disease', (124, 128))	('cell proliferation signaling pathways', 'Pathway', (143, 180))	('miR-21', 'Gene', '406991', (75, 81))	('CCA', 'Phenotype', 'HP:0030153', (124, 127))	('miR-31', 'Gene', (67, 73))	('miR-26a', 'Var', (40, 47))	('modulating', 'Reg', (132, 142))	('miR-421', 'Gene', (86, 93))	('miR-210', 'Gene', (58, 65))	('miR-210', 'Gene', '406992', (58, 65))	('miR-21', 'Gene', '406991', (58, 64))	('miR-141', 'Gene', (49, 56))	('miR-421', 'Gene', '693122', (86, 93))	('miR-21', 'Gene', (75, 81))
88324	27259577	Furthermore, miR-410 and XIAP mRNA expression levels were inversely correlated in human cholangiocarcinoma tissues.	('XIAP', 'Gene', '331', (25, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('miR-410', 'Var', (13, 20))	('XIAP', 'Gene', (25, 29))	('cholangiocarcinoma', 'Disease', (88, 106))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 106))	('human', 'Species', '9606', (82, 87))
88331	27259577	TFK-1 cells were transfected using Fugene6 reagent (Roche) with Renilla reporter constructs (pEZX-MT01, GeneCopoeia) carrying the 3'UTR of XIAP or XIAP 3`UTR mutated.	('XIAP', 'Gene', '331', (147, 151))	('XIAP', 'Gene', (139, 143))	('XIAP', 'Gene', '331', (139, 143))	('mutated', 'Var', (158, 165))	('XIAP', 'Gene', (147, 151))
88333	27259577	Furthermore, caspase 3/7 activity was evaluated in TFK-1 xenograft tumors (day 35) treated with miR-410 or miR-NC and untreated tumors.	('caspase 3', 'Gene', (13, 22))	('caspase 3', 'Gene', '836', (13, 22))	('miR-NC', 'Chemical', '-', (107, 113))	('miR-NC', 'Var', (107, 113))	('xenograft tumors', 'Disease', (57, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('miR-410', 'Var', (96, 103))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('xenograft tumors', 'Disease', 'MESH:D009369', (57, 73))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', (67, 73))	('activity', 'MPA', (25, 33))
88334	27259577	XIAP (#2042), Cleaved Caspase-3 (#9664), Caspase-3 (#9662), PARP (#9542) and Cleaved PARP (#9544) antibodies were purchased from Cell Signaling Technology.	('XIAP', 'Gene', (0, 4))	('XIAP', 'Gene', '331', (0, 4))	('Caspase-3', 'Gene', '836', (22, 31))	('#9542', 'Var', (66, 71))	('PARP', 'Gene', (85, 89))	('PARP', 'Gene', '1302', (85, 89))	('Caspase-3', 'Gene', '836', (41, 50))	('Caspase-3', 'Gene', (41, 50))	('#9662', 'Var', (52, 57))	('Caspase-3', 'Gene', (22, 31))	('#9664', 'Var', (33, 38))	('PARP', 'Gene', '1302', (60, 64))	('PARP', 'Gene', (60, 64))
88335	27259577	We performed invasion assays in TFK-1 cholangiocarcinoma cell line, which was transfected with miR-410 for 48 h, by using standardized condition with BD Biocoat Matrigel Invasion Chamber, as previously described.	('cholangiocarcinoma', 'Disease', (38, 56))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (38, 56))	('miR-410', 'Var', (95, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (38, 56))
88356	27259577	This screen identified 10 microRNAs (miR-21, miR-19a, miR-17-5p, miR-26a, miR-26b, miR-107, miR-106b, miR-27a, miR-103, miR-25) that increased more than 50 % TFK-1 growth and 11 microRNAs (miR-513, miR-200b, miR-198, miR-200c, miR-520e, miR-429, miR-124a, miR-101, miR-29b, miR-494, miR-410) that decreased >50 % cell growth (Fig.	('miR-198', 'Gene', '406975', (208, 215))	('miR-26a', 'Var', (65, 72))	('miR-19a', 'Gene', (45, 52))	('TFK-1 growth', 'CPA', (158, 170))	('miR-103', 'Var', (111, 118))	('miR-429', 'Gene', '554210', (237, 244))	('miR-26b', 'Gene', (74, 81))	('miR-25', 'Gene', (120, 126))	('miR-21', 'Gene', (37, 43))	('miR-27a', 'Gene', (102, 109))	('miR-19a', 'Gene', '406979', (45, 52))	('miR-494', 'Gene', '574452', (274, 281))	('miR-494', 'Gene', (274, 281))	('miR-107', 'Gene', (83, 90))	('miR-520e', 'Gene', '574461', (227, 235))	('miR-200b', 'Gene', (198, 206))	('miR-106b', 'Gene', '406900', (92, 100))	('miR-101', 'Var', (256, 263))	('miR-107', 'Gene', '406901', (83, 90))	('miR-200c', 'Gene', '406985', (217, 225))	('miR-410', 'Var', (283, 290))	('miR-198', 'Gene', (208, 215))	('miR-106b', 'Gene', (92, 100))	('miR-25', 'Gene', '407014', (120, 126))	('increased', 'PosReg', (133, 142))	('miR-29b', 'Gene', '407024', (265, 272))	('miR-429', 'Gene', (237, 244))	('miR-17-5p', 'Gene', '406952', (54, 63))	('miR-124a', 'Gene', (246, 254))	('miR-17-5p', 'Gene', (54, 63))	('miR-200c', 'Gene', (217, 225))	('miR-200b', 'Gene', '406984', (198, 206))	('miR-124a', 'Gene', '406907', (246, 254))	('miR-27a', 'Gene', '407018', (102, 109))	('miR-21', 'Gene', '406991', (37, 43))	('miR-29b', 'Gene', (265, 272))	('miR-26b', 'Gene', '407017', (74, 81))	('decreased', 'NegReg', (297, 306))	('miR-520e', 'Gene', (227, 235))	('cell growth', 'CPA', (313, 324))
88360	27259577	We further assessed the tumor suppressive properties of miR-410 in cholangiocarcinoma, by transfecting miR-410 in TFK-1 cells and performed different functional assays.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('tumor', 'Disease', (24, 29))	('cholangiocarcinoma', 'Disease', (67, 85))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('miR-410', 'Var', (103, 110))	('miR-410', 'Var', (56, 63))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))
88363	27259577	To further examine the role of miR-410 in inducing apoptosis in TFK-1 cells, we performed western blot analysis in TFK-1 cells for cleaved caspase-3 and cleaved PARP, both markers of the intrinsic apoptotic pathway.	('PARP', 'Gene', '1302', (161, 165))	('PARP', 'Gene', (161, 165))	('caspase-3', 'Gene', (139, 148))	('cleaved', 'Var', (153, 160))	('caspase-3', 'Gene', '836', (139, 148))	('miR-410', 'Var', (31, 38))
88370	27259577	We found that miR-410 administration, significantly suppressed TFK-1 xenograft tumor growth (Fig.	('xenograft tumor', 'Disease', 'MESH:D009369', (69, 84))	('suppressed', 'NegReg', (52, 62))	('miR-410', 'Var', (14, 21))	('xenograft tumor', 'Disease', (69, 84))	('TFK-1', 'Gene', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
88371	27259577	These data show that miR-410 suppresses TFK-1 tumor growth in vivo, suggesting its therapeutic potential for cholangiocarcinoma patients.	('suppresses', 'NegReg', (29, 39))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (109, 127))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('miR-410', 'Var', (21, 28))	('tumor', 'Disease', (46, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('TFK-1', 'Gene', (40, 45))	('patients', 'Species', '9606', (128, 136))	('cholangiocarcinoma', 'Disease', (109, 127))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
88374	27259577	We found that miR-410 has a seed region that matches the 3'-untranslated region (UTR) of human XIAP (nucleotides 2264-2271) (Fig.	('human', 'Species', '9606', (89, 94))	('XIAP', 'Gene', '331', (95, 99))	('XIAP', 'Gene', (95, 99))	('miR-410', 'Var', (14, 21))
88379	27259577	On the other hand, mutation of the miR-410 binding site within the XIAP 3'-UTR abolished the ability of miR-410 to regulate the 3'UTR luciferase activity (Fig.	('miR-410', 'Gene', (35, 42))	('mutation', 'Var', (19, 27))	('abolished', 'NegReg', (79, 88))	('activity', 'MPA', (145, 153))	('XIAP', 'Gene', (67, 71))	("3'UTR", 'MPA', (128, 133))	('ability', 'MPA', (93, 100))	('XIAP', 'Gene', '331', (67, 71))	('regulate', 'Reg', (115, 123))
88381	27259577	Transfection of miR-410 in TFK-1 cholangiocarcinoma cells resulted in a significant reduction of XIAP mRNA levels in comparison to cells transfected with miR-NC (Fig.	('miR-410', 'Var', (16, 23))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (33, 51))	('XIAP', 'Gene', (97, 101))	('reduction', 'NegReg', (84, 93))	('XIAP', 'Gene', '331', (97, 101))	('cholangiocarcinoma', 'Disease', (33, 51))	('miR-NC', 'Chemical', '-', (154, 160))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (33, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
88393	27259577	We have identified miR-410 as an important suppressor of cholangiocarcinoma growth both in vitro and in vivo We demonstrated that miR-410 negatively modulates XIAP expression regulating this way the intrinsic apoptotic signaling pathway.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('miR-410', 'Var', (130, 137))	('negatively', 'NegReg', (138, 148))	('XIAP', 'Gene', (159, 163))	('XIAP', 'Gene', '331', (159, 163))	('cholangiocarcinoma growth', 'Disease', (57, 82))	('modulates', 'Reg', (149, 158))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (57, 82))	('intrinsic apoptotic signaling pathway', 'Pathway', (199, 236))
88397	27259577	found that miR-410 negatively regulates pRb/E2Fpathway by directly targeting CDK1 oncogene in breast cancer.	('targeting', 'Reg', (67, 76))	('CDK1', 'Gene', (77, 81))	('CDK1', 'Gene', '983', (77, 81))	('pRb', 'Gene', (40, 43))	('regulates', 'Reg', (30, 39))	('pRb', 'Gene', '5925', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('miR-410', 'Var', (11, 18))	('negatively', 'NegReg', (19, 29))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))
88413	27259577	Furthermore, miR-410 administration could be a therapeutic strategy for cholangiocarcinoma patients that should be further examined in greater detail in cholangiocarcinoma animal models.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (153, 171))	('patients', 'Species', '9606', (91, 99))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 90))	('cholangiocarcinoma', 'Disease', (72, 90))	('miR-410', 'Var', (13, 20))	('cholangiocarcinoma', 'Disease', (153, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (153, 171))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
88512	32486461	The supervised OPLS-DA model showed a good predictive ability to discriminate patient groups from healthy individuals, since Q2X = 0.694 (Figure 2A), triglycerides and, to a lesser extent, oxidized fatty acids and bile acids (all of them increased) and sphingomyelins and glycerophosphatidylcholines (both decreased) being the main contributors to the differences found between patients and control individuals.	('sphingomyelins', 'Chemical', 'MESH:D013109', (253, 267))	('patient', 'Species', '9606', (78, 85))	('Q2X', 'Var', (125, 128))	('sphingomyelins', 'MPA', (253, 267))	('glycerophosphatidylcholines', 'Chemical', '-', (272, 299))	('oxidized fatty acids', 'MPA', (189, 209))	('increased', 'PosReg', (238, 247))	('bile acids', 'MPA', (214, 224))	('triglycerides', 'MPA', (150, 163))	('decreased', 'NegReg', (306, 315))	('patient', 'Species', '9606', (378, 385))	('fatty acids', 'Chemical', 'MESH:D005227', (198, 209))	('bile acids', 'Chemical', 'MESH:D001647', (214, 224))	('glycerophosphatidylcholines', 'MPA', (272, 299))	('patients', 'Species', '9606', (378, 386))	('triglycerides', 'Chemical', 'MESH:D014280', (150, 163))
88554	32486461	Alterations in sphingolipid metabolism have been associated with cell proliferation.	('sphingolipid metabolism', 'Disease', 'MESH:D013106', (15, 38))	('Alterations', 'Var', (0, 11))	('associated', 'Reg', (49, 59))	('cell proliferation', 'CPA', (65, 83))	('sphingolipid metabolism', 'Disease', (15, 38))
88599	32138158	Warburg effect is in large part induced by the transcription factors hypoxia inducible factor 1 alpha (HIF-1alpha) and c-Myc but also, in lesser extent, by other signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)-Akt mammalian target of rapamycin (mTOR) signaling, and the activation of oncogenes and inactivation of tumor suppressors.	('Akt', 'Gene', '207', (231, 234))	('Warburg effect', 'Disease', (0, 14))	('mTOR', 'Gene', '2475', (266, 270))	('HIF-1alpha', 'Gene', '3091', (103, 113))	('oncogenes', 'CPA', (305, 314))	('c-Myc', 'Gene', (119, 124))	('tumor', 'Disease', (335, 340))	('hypoxia inducible factor 1 alpha', 'Gene', '3091', (69, 101))	('hypoxia inducible factor 1 alpha', 'Gene', (69, 101))	('tumor', 'Disease', 'MESH:D009369', (335, 340))	('phosphatidylinositol 3-kinase', 'Gene', '5295', (194, 223))	('c-Myc', 'Gene', '4609', (119, 124))	('inactivation', 'Var', (319, 331))	('HIF-1alpha', 'Gene', (103, 113))	('phosphatidylinositol 3-kinase', 'Gene', (194, 223))	('activation', 'PosReg', (291, 301))	('mTOR', 'Gene', (266, 270))	('Akt', 'Gene', (231, 234))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))
88606	32138158	Moreover, GLUT-1 silencing was able to decrease migration and invasion of CCA cells.	('GLUT-1', 'Gene', (10, 16))	('decrease', 'NegReg', (39, 47))	('invasion of CCA cells', 'CPA', (62, 83))	('silencing', 'Var', (17, 26))	('CCA', 'Phenotype', 'HP:0030153', (74, 77))	('GLUT-1', 'Gene', '6513', (10, 16))
88625	32138158	Moreover, LDH-A silencing inhibited cell growth and promoted HUCCT1 cell death.	('LDH-A', 'Gene', '3939', (10, 15))	('LDH-A', 'Gene', (10, 15))	('inhibited', 'NegReg', (26, 35))	('HUCCT1 cell death', 'CPA', (61, 78))	('cell growth', 'CPA', (36, 47))	('silencing', 'Var', (16, 25))	('promoted', 'PosReg', (52, 60))
88640	32138158	Conversely, the induction of SIRT3 was able to efficiently reduce tumor proliferation via an anti-Warburg effect mediated by the HIF1alpha/PDK1/PDHA1 pathway (Table 1).	('induction', 'Var', (16, 25))	('PDK1', 'Gene', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('anti-Warburg effect', 'CPA', (93, 112))	('tumor', 'Disease', (66, 71))	('HIF1alpha', 'Gene', '3091', (129, 138))	('SIRT3', 'Gene', (29, 34))	('SIRT3', 'Gene', '23410', (29, 34))	('reduce', 'NegReg', (59, 65))	('PDHA1', 'Gene', '5160', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('PDHA1', 'Gene', (144, 149))	('HIF1alpha', 'Gene', (129, 138))	('PDK1', 'Gene', '5163', (139, 143))
88648	32138158	In keeping, also Jiang X. et al., proved that in a xenograft tumor model, Metformin significantly inhibited cell growth in vivo, resulting in decreased tumor volume and weight.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('inhibited', 'NegReg', (98, 107))	('decreased tumor', 'Disease', (142, 157))	('cell growth', 'CPA', (108, 119))	('Metformin', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('Metformin', 'Chemical', 'MESH:D008687', (74, 83))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('decreased tumor', 'Disease', 'MESH:D002303', (142, 157))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
88656	32138158	Indeed, it has been observed that in AKT/Ras mice, which develop both HCC and iCCA, FASN knocking-down prevented only HCC onset (Table 1).	('HCC', 'Disease', (70, 73))	('knocking-down', 'Var', (89, 102))	('mice', 'Species', '10090', (45, 49))	('CCA', 'Phenotype', 'HP:0030153', (79, 82))
88660	32138158	Moreover, SCL27A1 silencing in both HUCCT1 and HuH28 cell lines led to a decrease of cells growth.	('SCL27A1', 'Gene', (10, 17))	('silencing', 'Var', (18, 27))	('cells growth', 'CPA', (85, 97))	('decrease', 'NegReg', (73, 81))	('HuH28', 'CellLine', 'CVCL:2955', (47, 52))
88681	32138158	ABC294640 is an inhibitor of SPHK2 (Ki = 9 microM, 3.4 microg/mL) that depletes S1P promoting autophagy and/or apoptosis in tumor cells.	('ABC294640', 'Var', (0, 9))	('ABC294640', 'Chemical', 'MESH:C548780', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('autophagy', 'CPA', (94, 103))	('tumor', 'Disease', (124, 129))	('depletes', 'NegReg', (71, 79))	('promoting', 'PosReg', (84, 93))	('S1P', 'Protein', (80, 83))	('SPHK2', 'Gene', (29, 34))	('SPHK2', 'Gene', '56848', (29, 34))	('apoptosis', 'CPA', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
88706	32138158	Yothaisong et al., in another work demonstrated the role of JPH203 in inhibiting LAT1 transport activity.	('JPH203', 'Chemical', 'MESH:C548172', (60, 66))	('JPH203', 'Var', (60, 66))	('inhibiting', 'NegReg', (70, 80))	('LAT1', 'Gene', '8140', (81, 85))	('LAT1', 'Gene', (81, 85))
88717	32138158	A suppression of members of the urea cycle, probably due to epigenetic alterations, has been demonstrated in HCC.	('urea', 'Enzyme', (32, 36))	('urea', 'Chemical', 'MESH:D014508', (32, 36))	('HCC', 'Disease', (109, 112))	('epigenetic alterations', 'Var', (60, 82))	('suppression', 'NegReg', (2, 13))
88720	32138158	Regarding amino acids metabolism four amino acids (Lys, Pro, Leu and IIe) were more diversely expressed in iCCA/iCCA-non tumor than in HCC and HCC-non tumor.	('Lys', 'Chemical', 'MESH:D008239', (51, 54))	('iCCA/iCCA-non tumor', 'Disease', (107, 126))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('CCA', 'Phenotype', 'HP:0030153', (113, 116))	('HCC-non tumor', 'Disease', 'MESH:D006528', (143, 156))	('Leu', 'Var', (61, 64))	('Lys', 'Var', (51, 54))	('CCA', 'Phenotype', 'HP:0030153', (108, 111))	('HCC-non tumor', 'Disease', (143, 156))	('Leu', 'Chemical', 'MESH:D007930', (61, 64))	('amino acids metabolism', 'MPA', (10, 32))	('Pro', 'Chemical', 'MESH:D011392', (56, 59))	('iCCA/iCCA-non tumor', 'Disease', 'MESH:D009369', (107, 126))
88726	32138158	In particular, it was demonstrated that high expression of TfR1, with consequent iron uptake, contributes to CCA progression and poorer clinical outcomes (Table 1).	('high', 'Var', (40, 44))	('iron', 'Chemical', 'MESH:D007501', (81, 85))	('CCA', 'Phenotype', 'HP:0030153', (109, 112))	('TfR1', 'Gene', '7037', (59, 63))	('iron uptake', 'MPA', (81, 92))	('CCA', 'Disease', (109, 112))	('TfR1', 'Gene', (59, 63))	('poorer', 'NegReg', (129, 135))
88727	32138158	Accordingly, it has been showed that high ferritin expression in epithelial cells from CCA patients is a negative prognostic index (6) (Table 1).	('patients', 'Species', '9606', (91, 99))	('high', 'Var', (37, 41))	('CCA', 'Phenotype', 'HP:0030153', (87, 90))	('ferritin', 'Protein', (42, 50))	('high ferritin', 'Phenotype', 'HP:0003281', (37, 50))	('CCA', 'Disease', (87, 90))
88729	32138158	In general, the alterations of iron trafficking in cancer cells lead to iron acquisition or decrease iron release (the high iron needs of tumor cells to sustain cell proliferation) and it has been shown that these alterations of cellular iron metabolism are dependent on the direct action of tumor suppressors and oncogenes.	('tumor', 'Disease', (138, 143))	('iron', 'Chemical', 'MESH:D007501', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('iron', 'Chemical', 'MESH:D007501', (238, 242))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('decrease', 'NegReg', (92, 100))	('iron', 'Chemical', 'MESH:D007501', (124, 128))	('iron', 'Chemical', 'MESH:D007501', (31, 35))	('iron', 'Chemical', 'MESH:D007501', (101, 105))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('iron release', 'MPA', (101, 113))	('alterations', 'Var', (16, 27))	('iron acquisition', 'MPA', (72, 88))	('tumor', 'Disease', (292, 297))	('lead to', 'Reg', (64, 71))	('cancer', 'Disease', (51, 57))
88736	32138158	Tumor cells select mutations that enhance signal transduction through pathways that converge upon a set of metabolic processes that contribute to tumorigenic process.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('enhance', 'PosReg', (34, 41))	('tumor', 'Disease', (146, 151))	('mutations', 'Var', (19, 28))	('signal transduction', 'MPA', (42, 61))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
88737	32138158	The rewiring of cancer cells metabolism includes abnormalities in glucose homeostasis and other nutrients such as aminoacid and lipid and impairment of mitochondrial function.	('glucose homeostasis', 'Disease', 'MESH:D044882', (66, 85))	('glucose homeostasis', 'Disease', (66, 85))	('abnormalities', 'Var', (49, 62))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('impairment', 'NegReg', (138, 148))	('abnormalities in glucose homeostasis', 'Phenotype', 'HP:0011014', (49, 85))	('aminoacid', 'MPA', (114, 123))	('impairment of mitochondrial function', 'Phenotype', 'HP:0003287', (138, 174))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('lipid', 'Chemical', 'MESH:D008055', (128, 133))	('mitochondrial function', 'MPA', (152, 174))
88742	32138158	PI3K is a lipid kinase that phosphorylates the 3'-hydroxyl group of the inositol ring of phosphatidylinositol to generate 3'-phosphoinositides.	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (89, 109))	('PI3K', 'Var', (0, 4))	("3'-phosphoinositides", 'Chemical', '-', (122, 142))	('inositol', 'Chemical', 'MESH:D007294', (72, 80))	("3'-phosphoinositides", 'MPA', (122, 142))	('inositol', 'Chemical', 'MESH:D007294', (101, 109))	('lipid', 'Chemical', 'MESH:D008055', (10, 15))
88748	32138158	The lipid phosphatase and tensin homologous (PTEN) is responsible for negative regulation of the pathway and inactivating mutations or deletion of PTEN lead to uncontrolled activation of PI3K/AKT/mTOR signaling.	('deletion', 'Var', (135, 143))	('lipid', 'Chemical', 'MESH:D008055', (4, 9))	('activation', 'PosReg', (173, 183))	('phosphatase', 'Gene', '5728', (10, 21))	('PTEN', 'Gene', '5728', (45, 49))	('mTOR', 'Gene', '2475', (196, 200))	('PTEN', 'Gene', (147, 151))	('mTOR', 'Gene', (196, 200))	('PTEN', 'Gene', (45, 49))	('PTEN', 'Gene', '5728', (147, 151))	('phosphatase', 'Gene', (10, 21))	('inactivating mutations', 'Var', (109, 131))
88753	32138158	Indeed IGFR1 inhibitors NVP-AEW541 and BMS-536924 prevented AKT activation and exerted antiproliferative effects in CCA cells and in a xenograft CCA mouse model.	('BMS-536924', 'Var', (39, 49))	('CCA', 'Phenotype', 'HP:0030153', (116, 119))	('AKT', 'Pathway', (60, 63))	('IGFR1', 'Gene', '100132417', (7, 12))	('CCA', 'Phenotype', 'HP:0030153', (145, 148))	('NVP-AEW541', 'Var', (24, 34))	('activation', 'PosReg', (64, 74))	('CCA', 'Disease', (116, 119))	('mouse', 'Species', '10090', (149, 154))	('prevented', 'NegReg', (50, 59))	('IGFR1', 'Gene', (7, 12))	('antiproliferative effects', 'CPA', (87, 112))
88754	32138158	These alterations lead to PI3K/AKT/mTOR pathway activation, which in turn triggers anabolic processes such as mRNA translation, protein synthesis and post-translational modulation of metabolic enzymes and switch to aerobic glycolysis, supporting enhanced growth, proliferation, chemoresistance.	('anabolic processes', 'MPA', (83, 101))	('alterations', 'Var', (6, 17))	('chemoresistance', 'CPA', (278, 293))	('enhanced', 'PosReg', (246, 254))	('growth', 'CPA', (255, 261))	('metabolic enzymes', 'MPA', (183, 200))	('mTOR', 'Gene', (35, 39))	('triggers', 'Reg', (74, 82))	('mTOR', 'Gene', '2475', (35, 39))	('switch', 'MPA', (205, 211))	('mRNA translation', 'MPA', (110, 126))	('activation', 'PosReg', (48, 58))	('proliferation', 'CPA', (263, 276))	('post-translational', 'MPA', (150, 168))	('protein synthesis', 'MPA', (128, 145))
88755	32138158	Pre-clinical studies demonstrated that the following PI3K inhibitors, LY294002, Buparlisib (BKM120) and PI-103 have significant in vitro activity against CCA cells.	('BKM120', 'Chemical', 'MESH:C571178', (92, 98))	('CCA', 'Disease', (154, 157))	('PI-103', 'Chemical', 'MESH:C522973', (104, 110))	('LY294002', 'Var', (70, 78))	('PI-103', 'Gene', (104, 110))	('Buparlisib', 'Chemical', 'MESH:C571178', (80, 90))	('LY294002', 'Chemical', 'MESH:C085911', (70, 78))	('CCA', 'Phenotype', 'HP:0030153', (154, 157))
88756	32138158	LY294002 inhibited cell proliferation, invasiveness and EMT by decreasing p-AKT and p70S6K levels.	('LY294002', 'Var', (0, 8))	('inhibited', 'NegReg', (9, 18))	('p70S6K', 'Gene', '6198', (84, 90))	('EMT', 'CPA', (56, 59))	('invasiveness', 'CPA', (39, 51))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('p-AKT', 'MPA', (74, 79))	('decreasing', 'NegReg', (63, 73))	('cell proliferation', 'CPA', (19, 37))	('p70S6K', 'Gene', (84, 90))
88757	32138158	Buparlisib demonstrated important anti-proliferative activity in either mutant or wild-type KRAS CCA cells, while the inhibitor PI-103 affect cell proliferation in a xenograft CCA mouse model.	('mutant', 'Var', (72, 78))	('affect', 'Reg', (135, 141))	('anti-proliferative activity', 'CPA', (34, 61))	('mouse', 'Species', '10090', (180, 185))	('CCA', 'Phenotype', 'HP:0030153', (97, 100))	('cell proliferation', 'CPA', (142, 160))	('CCA', 'Phenotype', 'HP:0030153', (176, 179))	('Buparlisib', 'Chemical', 'MESH:C571178', (0, 10))	('PI-103', 'Chemical', 'MESH:C522973', (128, 134))
88763	32138158	Concerning AKT inhibitors the allosteric inhibitors (MK2206) or adenosine triphosphate (ATP)-competitive molecules proved to be effective to impair cell proliferation, survival and in different CCA cell lines.	('AKT', 'Gene', (11, 14))	('ATP', 'Chemical', 'MESH:D000255', (88, 91))	('MK2206', 'Var', (53, 59))	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (64, 86))	('CCA', 'Disease', (194, 197))	('impair', 'NegReg', (141, 147))	('survival', 'CPA', (168, 176))	('cell proliferation', 'CPA', (148, 166))	('CCA', 'Phenotype', 'HP:0030153', (194, 197))	('MK2206', 'Chemical', 'MESH:C548887', (53, 59))
88771	32138158	In another phase II study that aimed to evaluate the activity of Everolimus in 10 patients with PIK3CA amplification/mutation or PTEN loss refractory solid cancer, only one patient with CCA with PTEN loss experienced disease control (, Table 2).	('PTEN loss', 'Disease', (195, 204))	('patient', 'Species', '9606', (82, 89))	('PTEN loss refractory solid cancer', 'Disease', (129, 162))	('PTEN loss refractory solid cancer', 'Disease', 'MESH:D006223', (129, 162))	('patients', 'Species', '9606', (82, 90))	('CCA', 'Phenotype', 'HP:0030153', (186, 189))	('PTEN loss', 'Disease', 'MESH:D006223', (129, 138))	('PIK3CA', 'Gene', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('PIK3CA', 'Gene', '5290', (96, 102))	('PTEN loss', 'Disease', 'MESH:D006223', (195, 204))	('patient', 'Species', '9606', (173, 180))	('Everolimus', 'Chemical', 'MESH:D000068338', (65, 75))	('amplification/mutation', 'Var', (103, 125))
88774	32138158	In a clinical study enrolling patients with PIK3CA mutant/amplified refractory solid cancer, Sirolimus failed to demonstrate the clinical benefit in a patient with hilar CCA (PIK3CA E545K mutation) who experienced disease progression following the second cycle of Sirolimus with PFS of 0.9 months (, Table 2).	('PIK3CA', 'Gene', (175, 181))	('PIK3CA', 'Gene', (44, 50))	('patient', 'Species', '9606', (30, 37))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('patient', 'Species', '9606', (151, 158))	('PIK3CA', 'Gene', '5290', (175, 181))	('E545K', 'Mutation', 'rs104886003', (182, 187))	('PIK3CA', 'Gene', '5290', (44, 50))	('cancer', 'Disease', (85, 91))	('E545K mutation', 'Var', (182, 196))	('Sirolimus', 'Chemical', 'MESH:D020123', (264, 273))	('patients', 'Species', '9606', (30, 38))	('Sirolimus', 'Chemical', 'MESH:D020123', (93, 102))	('mutant/amplified', 'Var', (51, 67))	('CCA', 'Phenotype', 'HP:0030153', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
88790	32138158	Indeed, in in vitro experiments they proved that inhibition of UCP2 suppressed cell proliferation and migration, reversed EMT, and reduced drug resistance as well as spheroid formation.	('spheroid formation', 'CPA', (166, 184))	('cell proliferation', 'CPA', (79, 97))	('suppressed', 'NegReg', (68, 78))	('reversed', 'PosReg', (113, 121))	('drug resistance', 'Phenotype', 'HP:0020174', (139, 154))	('reduced', 'NegReg', (131, 138))	('UCP2', 'Gene', '7351', (63, 67))	('drug resistance', 'CPA', (139, 154))	('inhibition', 'Var', (49, 59))	('UCP2', 'Gene', (63, 67))	('EMT', 'CPA', (122, 125))
88805	32138158	In a recent study, there have been identified endogenous RNAs which modulated the expression of target genes, which could have a role in tumor occurrence and progression in patients with CCA.	('RNAs', 'Protein', (57, 61))	('endogenous', 'Var', (46, 56))	('tumor', 'Disease', (137, 142))	('CCA', 'Disease', (187, 190))	('expression', 'MPA', (82, 92))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('patients', 'Species', '9606', (173, 181))	('role', 'Reg', (129, 133))	('CCA', 'Phenotype', 'HP:0030153', (187, 190))	('modulated', 'Reg', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
88812	32138158	Frequent mutations in the IDH1 and IDH2 genes have been shown in different types of cancer, including CCA.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('CCA', 'Phenotype', 'HP:0030153', (102, 105))	('cancer', 'Disease', (84, 90))	('IDH2', 'Gene', '3418', (35, 39))	('shown', 'Reg', (56, 61))	('mutations', 'Var', (9, 18))	('IDH1', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('CCA', 'Disease', (102, 105))	('IDH1', 'Gene', '3417', (26, 30))	('IDH2', 'Gene', (35, 39))
88816	32138158	Interestingly mIDH preferably provokes an increase in the D-enantiomer of 2-HG rather than the L-enantiomer and these forms can be measured in the serum by gas chromatography coupled to mass spectrometry or liquid chromatography combined with mass spectrometry.	('mIDH', 'Chemical', '-', (14, 18))	('D-enantiomer', 'MPA', (58, 70))	('2-HG', 'Chemical', 'MESH:C019417', (74, 78))	('mIDH', 'Var', (14, 18))	('increase', 'PosReg', (42, 50))
88817	32138158	In the most mIDH, the wild-type IDH function is lost due to mutation of critical amino acid residues in the catalytic domain, IDH1 R132 and IDH2 R172, which normally binds the b-carboxyl group of isocitrate to start catalysis.	('mutation', 'Var', (60, 68))	('IDH', 'Gene', '3417', (140, 143))	('lost', 'NegReg', (48, 52))	('IDH', 'Gene', (32, 35))	('R132', 'Var', (131, 135))	('IDH2', 'Gene', (140, 144))	('IDH1', 'Gene', (126, 130))	('IDH', 'Gene', '3417', (32, 35))	('IDH2', 'Gene', '3418', (140, 144))	('IDH', 'Gene', (13, 16))	('IDH', 'Gene', (126, 129))	('binds', 'Interaction', (166, 171))	('R172', 'Var', (145, 149))	('IDH', 'Gene', (140, 143))	('mIDH', 'Chemical', '-', (12, 16))	('IDH1', 'Gene', '3417', (126, 130))	('IDH', 'Gene', '3417', (13, 16))	('IDH', 'Gene', '3417', (126, 129))	('isocitrate', 'Chemical', 'MESH:C034219', (196, 206))
88818	32138158	In CCA, the most common mutations of IDH1 are R132C (more frequent), R132G and R132L, which are distinct from the R132H mutation found in gliomas; nevertheless, these activating alterations have been shown to increase the serum level of 2-HG in cholangiocarcinoma.	('R132G', 'Mutation', 'rs121913499', (69, 74))	('2-HG', 'Chemical', 'MESH:C019417', (237, 241))	('R132H', 'Mutation', 'rs121913500', (114, 119))	('R132C', 'Var', (46, 51))	('R132C', 'Mutation', 'rs121913499', (46, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('mutations', 'Var', (24, 33))	('R132G', 'Var', (69, 74))	('gliomas', 'Disease', (138, 145))	('serum level of 2-HG', 'MPA', (222, 241))	('R132L', 'Var', (79, 84))	('gliomas', 'Disease', 'MESH:D005910', (138, 145))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (245, 263))	('IDH1', 'Gene', (37, 41))	('cholangiocarcinoma', 'Disease', (245, 263))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (245, 263))	('increase', 'PosReg', (209, 217))	('gliomas', 'Phenotype', 'HP:0009733', (138, 145))	('R132L', 'Mutation', 'rs121913500', (79, 84))	('CCA', 'Phenotype', 'HP:0030153', (3, 6))	('IDH1', 'Gene', '3417', (37, 41))	('CCA', 'Disease', (3, 6))
88819	32138158	The prevalence of IDH2 mutations in CCA is instead R172K, R172M, and R172G.	('R172K', 'Var', (51, 56))	('IDH2', 'Gene', '3418', (18, 22))	('R172M', 'Var', (58, 63))	('R172G', 'Mutation', 'rs1057519906', (69, 74))	('CCA', 'Disease', (36, 39))	('R172M', 'Mutation', 'rs121913503', (58, 63))	('R172K', 'Mutation', 'rs121913503', (51, 56))	('IDH2', 'Gene', (18, 22))	('CCA', 'Phenotype', 'HP:0030153', (36, 39))	('R172G', 'Var', (69, 74))
88820	32138158	Accumulating evidence identifies 2-HG as an oncometabolite, since it interferes with many regulatory pathways involving alpha-ketoglutarate-dependent dioxygenases, including those implicated in epigenetic remodeling and DNA repair.	('regulatory pathways', 'Pathway', (90, 109))	('interferes', 'NegReg', (69, 79))	('2-HG', 'Var', (33, 37))	('alpha-ketoglutarate-dependent dioxygenases', 'MPA', (120, 162))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (120, 139))	('oxygen', 'Chemical', 'MESH:D010100', (152, 158))	('2-HG', 'Chemical', 'MESH:C019417', (33, 37))
88822	32138158	Genomic studies reported that mutations in IDH1/2 were found in approximately 10% (range, 5-36%) of iCCA, whatever the geographical area of the world while mutations in IDH1 were linked to iCCA with a prevalence of about 20% in North America.	('found', 'Reg', (55, 60))	('IDH1/2', 'Gene', (43, 49))	('linked', 'Reg', (179, 185))	('IDH1', 'Gene', (169, 173))	('mutations', 'Var', (156, 165))	('iCCA', 'Disease', (100, 104))	('IDH1', 'Gene', (43, 47))	('IDH1', 'Gene', '3417', (169, 173))	('mutations', 'Var', (30, 39))	('IDH1', 'Gene', '3417', (43, 47))	('IDH1/2', 'Gene', '3417;3418', (43, 49))	('CCA', 'Phenotype', 'HP:0030153', (101, 104))	('CCA', 'Phenotype', 'HP:0030153', (190, 193))
88825	32138158	Of note, mIDH hypermethylates ARID1A promoter can lower the chromatin remodeler expression.	('ARID1A', 'Gene', '8289', (30, 36))	('lower', 'NegReg', (50, 55))	('ARID1A', 'Gene', (30, 36))	('mIDH hypermethylates', 'Var', (9, 29))	('hypermethylates', 'Var', (14, 29))	('chromatin remodeler expression', 'MPA', (60, 90))	('mIDH', 'Chemical', '-', (9, 13))
88826	32138158	A recent study on a large cohort of of iCCA patients (n=496) based on occurrence of mutations in IDH, KRAS and TP53 genes, revealed unique mutational, structural and epigenetic features, which could facilitate prediction of therapeutic sensitivity for each iCCA patient, by evaluating individual genotyping.	('facilitate', 'PosReg', (199, 209))	('patient', 'Species', '9606', (44, 51))	('patients', 'Species', '9606', (44, 52))	('TP53', 'Gene', '7157', (111, 115))	('IDH', 'Gene', (97, 100))	('CCA', 'Phenotype', 'HP:0030153', (258, 261))	('IDH', 'Gene', '3417', (97, 100))	('mutations', 'Var', (84, 93))	('TP53', 'Gene', (111, 115))	('patient', 'Species', '9606', (262, 269))	('KRAS', 'Gene', (102, 106))	('CCA', 'Phenotype', 'HP:0030153', (40, 43))
88829	32138158	The high incidence of IDH mutations in numerous malignant tumors has promoted the development of specific inhibitor compounds resulting in several clinical trials.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('IDH', 'Gene', (22, 25))	('mutations', 'Var', (26, 35))	('IDH', 'Gene', '3417', (22, 25))	('malignant tumors', 'Disease', (48, 64))	('malignant tumors', 'Disease', 'MESH:D009369', (48, 64))
88832	32138158	A follow-up trial in mutated IDH1 CCA patients that are not eligible for curative resection, transplantation, or ablative therapies prior to enrollment, is underway (NCT02989857) with completion date on 11/01/2019.	('CCA', 'Phenotype', 'HP:0030153', (34, 37))	('IDH1', 'Gene', (29, 33))	('IDH1', 'Gene', '3417', (29, 33))	('patients', 'Species', '9606', (38, 46))	('mutated', 'Var', (21, 28))
88833	32138158	Patients with IDH2 mutated solid tumors have been enrolled in a phase I-II clinical trial evaluating the orally bioavailable compound AG-221, an inhibitor of mutant IDH2 (NCT02273739) (Table 2).	('IDH2', 'Gene', '3418', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('IDH2', 'Gene', (165, 169))	('mutated', 'Var', (19, 26))	('Patients', 'Species', '9606', (0, 8))	('IDH2', 'Gene', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('AG-221', 'Chemical', 'MESH:C000605269', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('NCT02273739', 'Var', (171, 182))	('mutant', 'Var', (158, 164))	('tumors', 'Disease', (33, 39))	('IDH2', 'Gene', '3418', (14, 18))
88834	32138158	Very recently, it has been reported that IDH1 mutation in CCA enhanced the formation of intrahepatic biliary organoids (IBOs) and sped up the glucose uptake and glucose metabolism as well as upregulation of some metabolytes in TCA cycle (citrate, fumarate and malate).	('glucose', 'Chemical', 'MESH:D005947', (142, 149))	('intrahepatic biliary organoids', 'Disease', (88, 118))	('glucose metabolism', 'Disease', 'MESH:D044882', (161, 179))	('CCA', 'Phenotype', 'HP:0030153', (58, 61))	('intrahepatic biliary organoids', 'Disease', 'MESH:D001656', (88, 118))	('upregulation', 'PosReg', (191, 203))	('sped up', 'PosReg', (130, 137))	('citrate', 'Chemical', 'MESH:D019343', (238, 245))	('fumarate', 'Chemical', 'MESH:D005650', (247, 255))	('enhanced', 'PosReg', (62, 70))	('malate', 'Chemical', 'MESH:C030298', (260, 266))	('glucose metabolism', 'Disease', (161, 179))	('TCA', 'Chemical', 'MESH:D014233', (227, 230))	('IDH1', 'Gene', (41, 45))	('mutation', 'Var', (46, 54))	('glucose', 'Chemical', 'MESH:D005947', (161, 168))	('IDH1', 'Gene', '3417', (41, 45))	('glucose uptake', 'MPA', (142, 156))
88835	32138158	Interestingly platelet isoform of phosphofructokinse-1 (PFKP), a rate-limiting glycolytic enzyme, was also upregulated and knockdown of its gene reduced IBOs formation, indicating that the induction of glycolysis in mutant IBOs could occur by enhancing the expression of this enzyme.	('enhancing', 'PosReg', (243, 252))	('reduced', 'NegReg', (145, 152))	('PFKP', 'Gene', '5214', (56, 60))	('mutant', 'Var', (216, 222))	('IBOs formation', 'MPA', (153, 167))	('PFKP', 'Gene', (56, 60))	('expression', 'MPA', (257, 267))	('upregulated', 'PosReg', (107, 118))	('IBOs', 'Gene', (223, 227))
88836	32138158	A direct link between the IDH 1 mutation and the expression of PFKP was demonstrated by the decrease of the protein level in mutant IBOs treated with AGI-5198 (a mIDH1 inhibitor) and the increase of the protein level in mutant IBOs treated with 2-HG (Table 2).	('PFKP', 'Gene', (63, 67))	('PFKP', 'Gene', '5214', (63, 67))	('protein level', 'MPA', (203, 216))	('increase', 'PosReg', (187, 195))	('decrease', 'NegReg', (92, 100))	('mIDH1', 'Gene', '15926', (162, 167))	('mutant', 'Var', (125, 131))	('IDH 1', 'Gene', (26, 31))	('protein level', 'MPA', (108, 121))	('mIDH1', 'Gene', (162, 167))	('2-HG', 'Chemical', 'MESH:C019417', (245, 249))	('AGI-5198', 'Chemical', 'MESH:C581156', (150, 158))	('mutation', 'Var', (32, 40))	('IDH 1', 'Gene', '3417', (26, 31))
88837	32138158	In addition, mutant IBOs could sustain survival in ATP depletion conditions by obtaining ATP through the activation of AMPK.	('mutant', 'Var', (13, 19))	('ATP', 'Chemical', 'MESH:D000255', (89, 92))	('AMPK', 'Gene', '5562', (119, 123))	('ATP', 'Chemical', 'MESH:D000255', (51, 54))	('ATP', 'MPA', (89, 92))	('AMPK', 'Gene', (119, 123))	('IBOs', 'Gene', (20, 24))
88838	32138158	These results suggest that IDH mutation drives two-way metabolic rewiring status.	('IDH', 'Gene', (27, 30))	('two-way metabolic rewiring status', 'MPA', (47, 80))	('mutation', 'Var', (31, 39))	('IDH', 'Gene', '3417', (27, 30))
88843	32138158	Particularly in iCCA, while commonly harbors mutations affect IDH1/2, BAP1, KRAS, TP53, SMAD4, and ARID1A.	('TP53', 'Gene', (82, 86))	('ARID1A', 'Gene', (99, 105))	('mutations', 'Var', (45, 54))	('CCA', 'Phenotype', 'HP:0030153', (17, 20))	('BAP1', 'Gene', '8314', (70, 74))	('IDH1/2', 'Gene', '3417;3418', (62, 68))	('SMAD4', 'Gene', (88, 93))	('BAP1', 'Gene', (70, 74))	('IDH1/2', 'Gene', (62, 68))	('TP53', 'Gene', '7157', (82, 86))	('SMAD4', 'Gene', '4089', (88, 93))	('ARID1A', 'Gene', '8289', (99, 105))
88859	32138158	Moreover HIF-1alpha regulated the expression of Rab1a via miR-212-3p.	('Rab1a', 'Gene', '5861', (48, 53))	('expression', 'MPA', (34, 44))	('HIF-1alpha', 'Gene', (9, 19))	('miR-212-3p', 'Var', (58, 68))	('Rab1a', 'Gene', (48, 53))	('HIF-1alpha', 'Gene', '3091', (9, 19))
88861	32138158	It has been demonstrated that Rab1a was overexpressed in iCCA tissues and associated with poor prognosis of iCCA patients and knockdown expression of HIF-1alpha under hypoxia condition decreased the expression of Rab1a expression while miR-212-3p was increased.	('CCA', 'Phenotype', 'HP:0030153', (109, 112))	('decreased', 'NegReg', (185, 194))	('CCA', 'Phenotype', 'HP:0030153', (58, 61))	('expression', 'MPA', (199, 209))	('HIF-1alpha', 'Gene', '3091', (150, 160))	('Rab1a', 'Gene', (30, 35))	('patients', 'Species', '9606', (113, 121))	('hypoxia', 'Disease', (167, 174))	('Rab1a', 'Gene', (213, 218))	('hypoxia', 'Disease', 'MESH:D000860', (167, 174))	('HIF-1alpha', 'Gene', (150, 160))	('knockdown', 'Var', (126, 135))	('Rab1a', 'Gene', '5861', (30, 35))	('associated', 'Reg', (74, 84))	('Rab1a', 'Gene', '5861', (213, 218))
88866	32138158	The specific liver-deletion of VHL in mice lead to steatosis, together with increased lipid droplets formation and betaoxidation down-regulation.	('mice', 'Species', '10090', (38, 42))	('increased', 'PosReg', (76, 85))	('steatosis', 'Disease', 'MESH:D005234', (51, 60))	('steatosis', 'Phenotype', 'HP:0001397', (51, 60))	('increased lipid droplets', 'Phenotype', 'HP:0012240', (76, 100))	('down-regulation', 'NegReg', (129, 144))	('steatosis', 'Disease', (51, 60))	('lipid', 'Chemical', 'MESH:D008055', (86, 91))	('liver-deletion', 'Var', (13, 27))	('lipid droplets formation', 'MPA', (86, 110))	('increased lipid', 'Phenotype', 'HP:0003077', (76, 91))	('VHL', 'Gene', (31, 34))	('betaoxidation', 'MPA', (115, 128))
88878	32138158	Moreover, fatty acid oxidation supports the pro-tumor potential of M2 macrophages and provides a crucial energy source for M2 macrophage polarization.. Additionally, it has been observed that the inhibition of fatty acid oxidation in tumor-associated macrophages promotes antitumorigenic differentiation and inhibits tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', (48, 53))	('fatty acid oxidation', 'MPA', (210, 230))	('fatty acid', 'Chemical', 'MESH:D005227', (210, 220))	('fatty acid', 'Chemical', 'MESH:D005227', (10, 20))	('tumor', 'Disease', (317, 322))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('inhibition', 'Var', (196, 206))	('tumor', 'Disease', (276, 281))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('inhibits', 'NegReg', (308, 316))	('promotes', 'PosReg', (263, 271))
88883	32138158	Funding for this work was partially provided by Italian Foundation of Cancer Research award (IG23117) to Dr. Raggi and (IG17786) to Prof. Marra.	('IG17786', 'Var', (120, 127))	('Cancer', 'Disease', (70, 76))	('Cancer', 'Disease', 'MESH:D009369', (70, 76))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Pro', 'Chemical', 'MESH:D011392', (132, 135))
88889	29848569	The most commonly altered genes in intrahepatic cholangiocarcinoma (IHC) were IDH1 (30%), ARID1A (23%) BAP1 (20%), TP53 (20%) and FGFR2 gene fusions (14%).	('BAP1', 'Gene', '8314', (103, 107))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (35, 66))	('altered', 'Reg', (18, 25))	('IDH1', 'Gene', (78, 82))	('BAP1', 'Gene', (103, 107))	('TP53', 'Gene', '7157', (115, 119))	('ARID1A', 'Gene', '8289', (90, 96))	('IDH1', 'Gene', '3417', (78, 82))	('intrahepatic cholangiocarcinoma', 'Disease', (35, 66))	('ARID1A', 'Gene', (90, 96))	('TP53', 'Gene', (115, 119))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (48, 66))	('FGFR2', 'Gene', (130, 135))	('FGFR2', 'Gene', '2263', (130, 135))	('gene fusions', 'Var', (136, 148))
88891	29848569	Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease.	('patients', 'Species', '9606', (115, 123))	('CDKN2A/B', 'Gene', '1029;1030', (15, 23))	('reduced', 'NegReg', (55, 62))	('Alterations', 'Var', (0, 11))	('survival', 'CPA', (63, 71))	('ERBB2', 'Gene', '2064', (28, 33))	('CDKN2A/B', 'Gene', (15, 23))	('ERBB2', 'Gene', (28, 33))	('time', 'CPA', (76, 80))
88892	29848569	Genetic alterations with potential therapeutic implications were identified in 47% of patients, leading to biomarker directed therapy or clinical trial enrollment in 16% of patients.	('patients', 'Species', '9606', (173, 181))	('Genetic alterations', 'Var', (0, 19))	('leading to', 'Reg', (96, 106))	('patients', 'Species', '9606', (86, 94))
88894	29848569	Alterations in CDKN2A/B and ERBB2 are associated with negative prognostic implications in patients with advanced disease.	('CDKN2A/B', 'Gene', '1029;1030', (15, 23))	('Alterations', 'Var', (0, 11))	('ERBB2', 'Gene', '2064', (28, 33))	('CDKN2A/B', 'Gene', (15, 23))	('ERBB2', 'Gene', (28, 33))	('patients', 'Species', '9606', (90, 98))
88898	29848569	Through targeted deep sequencing of all exons and selected introns of 410 key cancer-associated genes, we identified genetic alterations with potential therapeutic implications in 47% of patients, leading to biomarker directed therapy or clinical trial enrolment in 16% of patients.	('patients', 'Species', '9606', (187, 195))	('patients', 'Species', '9606', (273, 281))	('cancer', 'Disease', (78, 84))	('alterations', 'Var', (125, 136))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('genetic alterations', 'Var', (117, 136))
88899	29848569	Correlation of genetic alterations with clinical outcomes demonstrated that alterations in CDKN2A/B and ERBB2 were associated with reduced overall survival and shorter time to progression on first line chemotherapy.	('alterations', 'Var', (76, 87))	('CDKN2A/B', 'Gene', '1029;1030', (91, 99))	('overall survival', 'MPA', (139, 155))	('reduced', 'NegReg', (131, 138))	('CDKN2A/B', 'Gene', (91, 99))	('ERBB2', 'Gene', '2064', (104, 109))	('shorter', 'NegReg', (160, 167))	('ERBB2', 'Gene', (104, 109))
88904	29848569	Large scale sequencing studies of cholangiocarcinoma have identified multiple recurrent driver alterations with complex interactions.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (34, 52))	('alterations', 'Var', (95, 106))	('cholangiocarcinoma', 'Disease', (34, 52))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (34, 52))
88919	29848569	Genetic alterations were classified as actionable using a scale of 1-4, where levels 1-2A alterations indicated standard therapeutic interventions, likely to be covered by insurance and levels 2B-4 included investigational therapeutic alterations, which may direct a patient towards a clinical trial relevant to that biomarker.	('direct', 'Reg', (258, 264))	('patient', 'Species', '9606', (267, 274))	('alterations', 'Var', (90, 101))
88931	29848569	Potentially oncogenic focal copy number alterations were noted in multiple genes including CDKN2A deletions (8%) and MDM2 (4%), ERBB2 (4%) and MCL1 (4%) amplifications.	('ERBB2', 'Gene', '2064', (128, 133))	('MCL1', 'Gene', '4170', (143, 147))	('CDKN2A', 'Gene', (91, 97))	('oncogenic', 'Reg', (12, 21))	('MCL1', 'Gene', (143, 147))	('CDKN2A', 'Gene', '1029', (91, 97))	('ERBB2', 'Gene', (128, 133))	('MDM2', 'Gene', '4193', (117, 121))	('MDM2', 'Gene', (117, 121))	('deletions', 'Var', (98, 107))
88942	29848569	KRAS, SMAD4 and STK11alterations were more commonly seen in extrahepatic cholangiocarcinoma, whereas mutations in IDH1, BAP1, TP53 and FGFR2 fusions occurred with greater frequency in intrahepatic cases (Figure 1 and Table 3); BAP1 mutations and FGFR2 gene fusions were identified exclusively in patients with intrahepatic cholangiocarcinoma.	('IDH1', 'Gene', (114, 118))	('TP53', 'Gene', (126, 130))	('STK11', 'Gene', '6794', (16, 21))	('SMAD4', 'Gene', (6, 11))	('intrahepatic', 'Disease', (310, 322))	('mutations', 'Var', (232, 241))	('extrahepatic cholangiocarcinoma', 'Disease', (60, 91))	('BAP1', 'Gene', (120, 124))	('IDH1', 'Gene', '3417', (114, 118))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (73, 91))	('fusions', 'Var', (257, 264))	('TP53', 'Gene', '7157', (126, 130))	('KRAS', 'Gene', '3845', (0, 4))	('mutations', 'Var', (101, 110))	('BAP1', 'Gene', '8314', (227, 231))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (60, 91))	('SMAD4', 'Gene', '4089', (6, 11))	('FGFR2', 'Gene', (135, 140))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (310, 341))	('FGFR2', 'Gene', (246, 251))	('intrahepatic cholangiocarcinoma', 'Disease', (310, 341))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (323, 341))	('KRAS', 'Gene', (0, 4))	('STK11', 'Gene', (16, 21))	('intrahepatic', 'Disease', 'MESH:D002780', (184, 196))	('patients', 'Species', '9606', (296, 304))	('FGFR2', 'Gene', '2263', (135, 140))	('intrahepatic', 'Disease', (184, 196))	('BAP1', 'Gene', (227, 231))	('BAP1', 'Gene', '8314', (120, 124))	('FGFR2', 'Gene', '2263', (246, 251))	('intrahepatic', 'Disease', 'MESH:D002780', (310, 322))
88949	29848569	Patients with alterations in CDKN2A/B (n=15, P=0.002), ERBB2 (n=8, P=0.028) and MDM2 (n=7, P=0.026) had significantly shorter time to progression on first line chemotherapy.	('MDM2', 'Gene', (80, 84))	('alterations', 'Var', (14, 25))	('time to', 'MPA', (126, 133))	('CDKN2A/B', 'Gene', '1029;1030', (29, 37))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (118, 125))	('CDKN2A/B', 'Gene', (29, 37))	('ERBB2', 'Gene', (55, 60))	('ERBB2', 'Gene', '2064', (55, 60))	('MDM2', 'Gene', '4193', (80, 84))
88951	29848569	Overall survival from date of diagnosis with locally advanced or metastatic disease was calculated for the 178 patients with stage IV disease either at diagnosis or who recurred following surgery, and was significantly shorter in patients with alterations in CDKN2A/B (n=18, P=0.0015), ERBB2 (n=9, P=0.0015) and KRAS (n=21, P=0.026) (Supplementary figure 1).	('CDKN2A/B', 'Gene', '1029;1030', (259, 267))	('alterations', 'Var', (244, 255))	('shorter', 'NegReg', (219, 226))	('patients', 'Species', '9606', (230, 238))	('ERBB2', 'Gene', '2064', (286, 291))	('locally advanced', 'CPA', (45, 61))	('KRAS', 'Gene', (312, 316))	('CDKN2A/B', 'Gene', (259, 267))	('ERBB2', 'Gene', (286, 291))	('KRAS', 'Gene', '3845', (312, 316))	('patients', 'Species', '9606', (111, 119))
88956	29848569	These included ERBB2 amplification (6 patients), likely pathogenic somatic alterations in TSC1/2 (3) or BRCA1/2 (2 pts), BRAF V600E mutation (1 patient), and MET amplification (1 patient).	('BRAF', 'Gene', (121, 125))	('ERBB2', 'Gene', (15, 20))	('pathogenic', 'Reg', (56, 66))	('BRCA1/2', 'Gene', (104, 111))	('pts', 'Species', '9606', (115, 118))	('TSC1/2 (3)', 'Gene', '7248', (90, 100))	('V600E mutation', 'Var', (126, 140))	('TSC1/2 (3', 'Gene', (90, 99))	('BRCA1/2', 'Gene', '672;675', (104, 111))	('MET', 'MPA', (158, 161))	('patient', 'Species', '9606', (179, 186))	('patient', 'Species', '9606', (144, 151))	('patient', 'Species', '9606', (38, 45))	('V600E', 'Mutation', 'rs113488022', (126, 131))	('patients', 'Species', '9606', (38, 46))	('BRAF', 'Gene', '673', (121, 125))	('amplification', 'Reg', (21, 34))	('ERBB2', 'Gene', '2064', (15, 20))
88959	29848569	Level 3 genetic alterations consisted mainly of known oncogenic mutations in IDH1 (43 patients) and fusion events involving FGFR2 (17 pts).	('FGFR2', 'Gene', (124, 129))	('FGFR2', 'Gene', '2263', (124, 129))	('pts', 'Species', '9606', (134, 137))	('IDH1', 'Gene', (77, 81))	('fusion events', 'CPA', (100, 113))	('mutations', 'Var', (64, 73))	('IDH1', 'Gene', '3417', (77, 81))	('patients', 'Species', '9606', (86, 94))
88960	29848569	Additional potentially actionable mutations present at low frequency, included PIK3CA (n=6), NRAS (n=4), and ERBB2 (n=2) hotspot mutations.	('ERBB2', 'Gene', '2064', (109, 114))	('mutations', 'Var', (129, 138))	('NRAS', 'Gene', '4893', (93, 97))	('ERBB2', 'Gene', (109, 114))	('PIK3CA', 'Gene', (79, 85))	('PIK3CA', 'Gene', '5290', (79, 85))	('mutations', 'Var', (34, 43))	('NRAS', 'Gene', (93, 97))
88970	29848569	The most common actionable findings observed were known hotspot gain of function mutations in IDH1, and rearrangements in FGFR2, which result in constitutive activation of the FGFR2 receptor.	('IDH1', 'Gene', (94, 98))	('FGFR2', 'Gene', (176, 181))	('gain of function', 'PosReg', (64, 80))	('FGFR2', 'Gene', '2263', (176, 181))	('IDH1', 'Gene', '3417', (94, 98))	('rearrangements', 'Var', (104, 118))	('activation', 'PosReg', (158, 168))	('mutations', 'Var', (81, 90))	('FGFR2', 'Gene', '2263', (122, 127))	('FGFR2', 'Gene', (122, 127))
88971	29848569	Notably, alterations in these genes were mutually exclusive suggesting that such alterations identify biologically distinct molecular cholangiocarcinoma subtypes.	('cholangiocarcinoma subtypes', 'Disease', (134, 161))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (134, 152))	('alterations', 'Var', (9, 20))	('alterations', 'Var', (81, 92))	('cholangiocarcinoma subtypes', 'Disease', 'MESH:D018281', (134, 161))
88973	29848569	Fusions involving NTRK1/3 and ROS1 have also previously been identified in patients with cholangiocarcinoma, although we did not observe any in this cohort.	('Fusions', 'Var', (0, 7))	('NTRK1', 'Gene', (18, 23))	('cholangiocarcinoma', 'Disease', (89, 107))	('ROS1', 'Gene', (30, 34))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (89, 107))	('patients', 'Species', '9606', (75, 83))	('ROS1', 'Gene', '6098', (30, 34))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (89, 107))	('NTRK1', 'Gene', '4914', (18, 23))	('identified', 'Reg', (61, 71))
88975	29848569	Several selective inhibitors of the FGF receptors (FGFR1-4) are being tested in molecularly selected population of patients with biliary cancer, and activity with these agents has been most notable in tumors that harbor FGFR2 gene fusions, as opposed to other FGFR alterations such as gene amplification or mutation.	('gene fusions', 'Var', (226, 238))	('FGFR1-4', 'Gene', (51, 58))	('patients', 'Species', '9606', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('FGFR2', 'Gene', (220, 225))	('FGFR2', 'Gene', '2263', (220, 225))	('biliary cancer', 'Disease', (129, 143))	('biliary cancer', 'Disease', 'MESH:D001661', (129, 143))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('FGFR1-4', 'Gene', '2260;2263;2261;2264', (51, 58))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))
88978	29848569	Preliminary results from phase I/II studies of agents targeting FGFR2 alterations and IDH1 mutations indicate that these agents have activity in molecularly selected populations.	('FGFR2', 'Gene', '2263', (64, 69))	('alterations', 'Var', (70, 81))	('IDH1', 'Gene', (86, 90))	('IDH1', 'Gene', '3417', (86, 90))	('mutations', 'Var', (91, 100))	('activity', 'MPA', (133, 141))	('FGFR2', 'Gene', (64, 69))
88979	29848569	Data from 73 patients with IDH1 mutant cholangiocarcinoma treated on a phase 1 study of AG-120, an orally active IDH1 inhibitor in a heavily pre-treated patient population, demonstrated that twenty eight patients (38.5%) were progression free at six months and 15 patients (21%) were progression free at 12 months (PFS12).	('patients', 'Species', '9606', (204, 212))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (39, 57))	('IDH1', 'Gene', (113, 117))	('patient', 'Species', '9606', (13, 20))	('patients', 'Species', '9606', (13, 21))	('IDH1', 'Gene', '3417', (113, 117))	('mutant', 'Var', (32, 38))	('patient', 'Species', '9606', (153, 160))	('patients', 'Species', '9606', (264, 272))	('AG-120', 'Chemical', 'MESH:C000627630', (88, 94))	('cholangiocarcinoma', 'Disease', (39, 57))	('IDH1', 'Gene', (27, 31))	('patient', 'Species', '9606', (264, 271))	('IDH1', 'Gene', '3417', (27, 31))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (39, 57))	('patient', 'Species', '9606', (204, 211))
88980	29848569	Correlative studies indicated that AG-120 treatment inhibited plasma levels of the oncometabolite 2-hydroxyglutarate (2-HG) produced by mutant IDH1 to within levels found in healthy volunteers, and also reduced 2-HG in tumor biopsies; demonstrating an on-target effect of the inhibitor.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('IDH1', 'Gene', '3417', (143, 147))	('tumor', 'Disease', (219, 224))	('reduced', 'NegReg', (203, 210))	('IDH1', 'Gene', (143, 147))	('2-HG', 'MPA', (211, 215))	('AG-120', 'Chemical', 'MESH:C000627630', (35, 41))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (98, 116))	('inhibited', 'NegReg', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('mutant', 'Var', (136, 142))
88981	29848569	An ongoing randomized phase III study is evaluating the activity of AG-120, in patients with advanced IDH1 mutant cholangiocarcinoma that has progressed on prior chemotherapy; additional inhibitors of IDH1 and IDH2 are also in phase I clinical trials.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (114, 132))	('IDH2', 'Gene', '3418', (210, 214))	('AG-120', 'Chemical', 'MESH:C000627630', (68, 74))	('mutant', 'Var', (107, 113))	('IDH1', 'Gene', '3417', (201, 205))	('IDH1', 'Gene', (102, 106))	('cholangiocarcinoma', 'Disease', (114, 132))	('patients', 'Species', '9606', (79, 87))	('IDH1', 'Gene', '3417', (102, 106))	('IDH2', 'Gene', (210, 214))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (114, 132))	('IDH1', 'Gene', (201, 205))
88983	29848569	As has been observed in other cancer types, intrinsic and acquired resistance limit the efficacy of targeted therapies in patients with cholangiocarcinoma with secondary FGFR2 kinase mutations shown to confer resistance to FGFR inhibition have been observed in a minority of patients who had sequencing of tumor tissue or cfDNA following progression of disease on study treatment.	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (136, 154))	('mutations', 'Var', (183, 192))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('FGFR2', 'Gene', (170, 175))	('FGFR2', 'Gene', '2263', (170, 175))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (136, 154))	('tumor', 'Disease', (306, 311))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (275, 283))	('cholangiocarcinoma', 'Disease', (136, 154))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
88986	29848569	Our results support the use of molecular profiling in patients with advanced biliary cancer to identify targetable genetic alterations and thereby facilitate enrollment to clinical trials of molecularly targeted agents with realistic potential for clinical benefit.	('biliary cancer', 'Disease', (77, 91))	('biliary cancer', 'Disease', 'MESH:D001661', (77, 91))	('patients', 'Species', '9606', (54, 62))	('alterations', 'Var', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
88987	29848569	Notably, we identified a signature of mismatch repair deficiency in just one patient (0.5%), a prevalence much lower than that observed in prior limited series.	('deficiency', 'Var', (54, 64))	('patient', 'Species', '9606', (77, 84))	('mismatch repair', 'Protein', (38, 53))
88993	29848569	While our ability to definitively define prognostic implications of particular genetic alterations was limited by the clinical and molecular heterogeneity of the population analyzed, alterations in CDKN2A/B and ERBB2 were consistently associated with shorter overall survival from diagnosis with advanced disease and time to progression on first line chemotherapy.	('shorter', 'NegReg', (251, 258))	('ERBB2', 'Gene', (211, 216))	('ERBB2', 'Gene', '2064', (211, 216))	('overall survival', 'MPA', (259, 275))	('alterations', 'Var', (183, 194))	('CDKN2A/B', 'Gene', '1029;1030', (198, 206))	('CDKN2A/B', 'Gene', (198, 206))	('associated', 'Reg', (235, 245))
88994	29848569	The negative prognostic implications of CDKN2A/B alterations is consistent with findings by Javle et al where results from targeted exon sequencing of 321 biliary tract cancer samples were correlated with clinical outcomes.	('alterations', 'Var', (49, 60))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (155, 175))	('CDKN2A/B', 'Gene', '1029;1030', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('biliary tract cancer', 'Disease', 'MESH:D001661', (155, 175))	('biliary tract cancer', 'Disease', (155, 175))	('CDKN2A/B', 'Gene', (40, 48))
88995	29848569	They additionally found a negative prognostic implication of KRAS and TP53 mutations in BTC, and longer overall survival in patients whose tumor harbored an FGFR2 alteration; ERBB2 was not included in the analysis of survival.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('negative', 'NegReg', (26, 34))	('patients', 'Species', '9606', (124, 132))	('TP53', 'Gene', '7157', (70, 74))	('BTC', 'Gene', (88, 91))	('ERBB2', 'Gene', (175, 180))	('ERBB2', 'Gene', '2064', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('TP53', 'Gene', (70, 74))	('KRAS', 'Gene', (61, 65))	('FGFR2', 'Gene', (157, 162))	('FGFR2', 'Gene', '2263', (157, 162))	('longer', 'PosReg', (97, 103))	('alteration', 'Var', (163, 173))	('KRAS', 'Gene', '3845', (61, 65))
88997	29848569	In summary, we identified multiple potentially actionable genetic alterations in a prospective cohort of patients with cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (119, 137))	('patients', 'Species', '9606', (105, 113))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (119, 137))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (119, 137))	('genetic alterations', 'Var', (58, 77))
89036	26266637	IHCC harbor FGFR fusions, IDH1/2 substitutions, BRAF substitutions, and MET amplification with a low KRAS mutation frequency.	('IDH1/2', 'Gene', (26, 32))	('KRAS', 'Gene', (101, 105))	('KRAS', 'Gene', '3845', (101, 105))	('substitutions', 'Var', (33, 46))	('substitutions', 'Var', (53, 66))	('fusions', 'Var', (17, 24))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('IDH1/2', 'Gene', '3417;3418', (26, 32))	('FGFR', 'Gene', (12, 16))
89037	26266637	EHCC and GBC both have ERBB2 amplifications and PIK3CA/mTOR pathway alterations, but KRAS mutation frequencies are high in EHCC and low in GBC .	('ERBB2', 'Gene', (23, 28))	('mTOR', 'Gene', (55, 59))	('ERBB2', 'Gene', '2064', (23, 28))	('mTOR', 'Gene', '2475', (55, 59))	('PIK3CA', 'Gene', (48, 54))	('amplifications', 'MPA', (29, 43))	('PIK3CA', 'Gene', '5290', (48, 54))	('alterations', 'Reg', (68, 79))	('KRAS', 'Gene', (85, 89))	('mutation', 'Var', (90, 98))	('KRAS', 'Gene', '3845', (85, 89))
89038	26266637	Whole exome and targeted gene sequencing in earlier studies of GBC also revealed frequent mutations in TP53, KRAS, and ERBB3.	('TP53', 'Gene', '7157', (103, 107))	('ERBB3', 'Gene', '2065', (119, 124))	('mutations', 'Var', (90, 99))	('ERBB3', 'Gene', (119, 124))	('TP53', 'Gene', (103, 107))	('KRAS', 'Gene', (109, 113))	('KRAS', 'Gene', '3845', (109, 113))
89070	26266637	Median PFS was 6.1 months (95 % CI 5.1-7.6) with cetuximab and 5.5 months (95 % CI 3.7-6.6) without cetuximab, while median OS was 11.0 months (95 % CI 9.1-13.7) with cetuximab and 12.4 months (95 % CI 8.6-16.0) without cetuximab.	('OS', 'Chemical', '-', (124, 126))	('PFS', 'MPA', (7, 10))	('cetuximab', 'Chemical', 'MESH:D000068818', (49, 58))	('cetuximab', 'Chemical', 'MESH:D000068818', (100, 109))	('cetuximab', 'Chemical', 'MESH:D000068818', (167, 176))	('cetuximab', 'Var', (49, 58))	('cetuximab', 'Chemical', 'MESH:D000068818', (220, 229))
89074	26266637	Median PFS was 6.7 months with cetuximab and 4.1 months without cetuximab (p = 0.05), while median OS was 10.6 months with cetuximab and 9.8 months without cetuximab (p = 0.91).	('cetuximab', 'Chemical', 'MESH:D000068818', (31, 40))	('PFS', 'MPA', (7, 10))	('cetuximab', 'Chemical', 'MESH:D000068818', (156, 165))	('cetuximab', 'Var', (31, 40))	('OS', 'Chemical', '-', (99, 101))	('cetuximab', 'Chemical', 'MESH:D000068818', (64, 73))	('cetuximab', 'Chemical', 'MESH:D000068818', (123, 132))
89075	26266637	KRAS mutations, detected in 36 % of tumors, did not affect the objective response rate (ORR) or PFS .	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('objective response rate', 'CPA', (63, 86))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('KRAS', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('KRAS', 'Gene', '3845', (0, 4))
89117	26266637	However, it did appear to improve the ORR in this trial: 43 % in the cediranib arm compared to 19 % in the placebo arm .	('ORR', 'MPA', (38, 41))	('cediranib', 'Chemical', 'MESH:C500926', (69, 78))	('improve', 'PosReg', (26, 33))	('cediranib', 'Var', (69, 78))
89119	26266637	Sorafenib is an oral multikinase inhibitor that inhibits cell surface tyrosine kinase receptors, including VEGF receptors and PDGF receptor-beta, and blocks downstream intracellular serine/threonine kinases, such as Raf-1, wild-type, and mutant B-Raf, involved in tumor cell proliferation and angiogenesis.	('Raf-1', 'Gene', '5894', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('blocks', 'NegReg', (150, 156))	('VEGF', 'Gene', (107, 111))	('B-Raf', 'Gene', (245, 250))	('PDGF', 'Gene', (126, 130))	('inhibits', 'NegReg', (48, 56))	('tumor', 'Disease', (264, 269))	('B-Raf', 'Gene', '673', (245, 250))	('Raf-1', 'Gene', (216, 221))	('cell surface', 'MPA', (57, 69))	('mutant', 'Var', (238, 244))	('intracellular serine/threonine kinases', 'MPA', (168, 206))	('VEGF', 'Gene', '7422', (107, 111))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (264, 269))
89135	26266637	Median PFS was 105 days (95 % CI 72-155), 114 days (95 % CI 91-193), and 148 days (95 % CI 71-225), while median OS was 228 days (95 % CI 190-364), 284 days (95 % CI 213-359), and 307 days (95 % CI 254-523) for V, V/G, and G/P, respectively.	('V/G', 'Var', (214, 217))	('G/P', 'Var', (223, 226))	('OS', 'Chemical', '-', (113, 115))
89140	26266637	In preclinical studies, CI-1040, a MEK inhibitor, has been investigated in a panel of human cancer cell lines and showed broad activity, particularly in cell lines harboring the BRAF mutation.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('MEK', 'Gene', (35, 38))	('human', 'Species', '9606', (86, 91))	('MEK', 'Gene', '5609', (35, 38))	('CI-1040', 'Chemical', '-', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutation', 'Var', (183, 191))	('BRAF', 'Gene', (178, 182))	('BRAF', 'Gene', '673', (178, 182))	('CI-1040', 'Gene', (24, 31))	('activity', 'MPA', (127, 135))
89141	26266637	One study reported that BRAF mutations were identified in 22 % of cholangiocarcinoma, suggesting the potential role of MEK inhibitors in the management of BTC.	('MEK', 'Gene', (119, 122))	('MEK', 'Gene', '5609', (119, 122))	('cholangiocarcinoma', 'Disease', (66, 84))	('mutations', 'Var', (29, 38))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (66, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (66, 84))
89148	26266637	Abnormal activation and genetic mutations in this pathway predispose to the development of many cancers, and hence, this pathway has gained importance in recent years as a target for drug development.	('activation', 'PosReg', (9, 19))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('predispose to', 'Reg', (58, 71))	('genetic mutations', 'Var', (24, 41))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))
89162	26266637	Nevoid basal cell carcinoma syndrome consisting of multiple basal cell carcinomas is associated with germline loss of function of mutation in PTCH.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('multiple basal cell carcinomas', 'Disease', 'MESH:C537656', (51, 81))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (60, 81))	('mutation', 'Var', (130, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('loss of function', 'NegReg', (110, 126))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (7, 27))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (60, 80))	('basal cell carcinoma syndrome', 'Disease', (7, 36))	('PTCH', 'Gene', '5727', (142, 146))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('PTCH', 'Gene', (142, 146))	('basal cell carcinoma syndrome', 'Disease', 'MESH:D002280', (7, 36))	('multiple basal cell carcinomas', 'Disease', (51, 81))
89163	26266637	PTCH 1 and 2 mutations are also found in 30 % of sporadic basal cell carcinomas.	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (58, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('PTCH 1 and 2', 'Gene', '5727;8643', (0, 12))	('found', 'Reg', (32, 37))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (58, 79))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (58, 79))	('mutations', 'Var', (13, 22))	('basal cell carcinomas', 'Disease', (58, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
89165	26266637	Blockage of the Hedgehog pathway has been shown to decrease survival and proliferation of cancer cells in cholangiocarcinoma cell lines.	('survival', 'CPA', (60, 68))	('Blockage', 'Var', (0, 8))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (106, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('proliferation', 'CPA', (73, 86))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (106, 124))	('Hedgehog pathway', 'Pathway', (16, 32))	('decrease', 'NegReg', (51, 59))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cholangiocarcinoma', 'Disease', (106, 124))
89170	26266637	Alteration of Notch pathways in solid and liquid tumors can lead to oncogenesis.	('Notch pathways', 'Pathway', (14, 28))	('oncogenesis', 'CPA', (68, 79))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('lead to', 'Reg', (60, 67))	('Alteration', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('solid', 'Disease', (32, 37))
89171	26266637	A study revealed that aberrant expression of Notch receptors 1 and 3 may play a role in the cancer progression of BTC.	('aberrant', 'Var', (22, 30))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('role', 'Reg', (80, 84))	('expression', 'MPA', (31, 41))	('Notch', 'Protein', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('play', 'Reg', (73, 77))	('BTC', 'Disease', (114, 117))
89172	26266637	RO-4929097 (a notch signaling inhibitor) is being tested in various phase I and II trials in solid tumors (Table 2).	('solid tumors', 'Disease', 'MESH:D009369', (93, 105))	('RO-4929097', 'Chemical', 'MESH:C545185', (0, 10))	('RO-4929097', 'Var', (0, 10))	('solid tumors', 'Disease', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
89189	26266637	Various mutational profiling studies in cholangiocarcinoma have detected genetic alterations in the FGFR pathway, exclusively in IHCC, and are shown to be associated with a more indolent course.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (40, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('IHCC', 'Disease', (129, 133))	('FGFR pathway', 'Pathway', (100, 112))	('genetic alterations', 'Var', (73, 92))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (40, 58))	('associated', 'Reg', (155, 165))	('cholangiocarcinoma', 'Disease', (40, 58))
89190	26266637	FGFR2 fusions occur in 13.6 % of IHCC.	('IHCC', 'Disease', (33, 37))	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (6, 13))	('FGFR2', 'Gene', '2263', (0, 5))
89191	26266637	BGJ 398, an oral FGFR inhibitor, is being evaluated in a phase II trial in patients with FGFR2 gene fusion/translocation.	('FGFR2', 'Gene', '2263', (89, 94))	('gene fusion/translocation', 'Var', (95, 120))	('BGJ 398', 'Chemical', 'MESH:C568950', (0, 7))	('patients', 'Species', '9606', (75, 83))	('FGFR2', 'Gene', (89, 94))
89194	26266637	IDH mutation results in accumulation of D-2-hydroxyglutarate, predisposing cells to malignant transformation.	('IDH', 'Gene', (0, 3))	('accumulation', 'PosReg', (24, 36))	('IDH', 'Gene', '3417', (0, 3))	('mutation', 'Var', (4, 12))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (40, 60))	('D-2-hydroxyglutarate', 'MPA', (40, 60))
89195	26266637	These mutations are commonly found in gliomas and acute myeloid leukemias.	('acute myeloid leukemias', 'Disease', 'MESH:D015470', (50, 73))	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('found', 'Reg', (29, 34))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (56, 73))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (50, 73))	('leukemias', 'Phenotype', 'HP:0001909', (64, 73))	('acute myeloid leukemias', 'Disease', (50, 73))	('gliomas', 'Disease', (38, 45))	('mutations', 'Var', (6, 15))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
89196	26266637	A study reported IDH 1 and 2 mutations in IHCC (9 of 40, 23 %), but none in EHCC and GBC cases .	('mutations', 'Var', (29, 38))	('IDH 1 and 2', 'Gene', '3417;3418', (17, 28))	('IHCC', 'Gene', (42, 46))
89197	26266637	The effect of IDH inhibitors is currently being evaluated in clinical trials involving solid tumors such as cholangiocarcinoma that harbor these mutations.	('IDH', 'Gene', (14, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mutations', 'Var', (145, 154))	('IDH', 'Gene', '3417', (14, 17))	('solid tumors', 'Disease', (87, 99))	('cholangiocarcinoma', 'Disease', (108, 126))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (108, 126))	('solid tumors', 'Disease', 'MESH:D009369', (87, 99))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (108, 126))
89317	25969643	When the portal vein branch is also obstructed, the atrophy becomes severe.	('atrophy', 'Disease', 'MESH:D001284', (52, 59))	('atrophy', 'Disease', (52, 59))	('vein branch', 'Disease', (16, 27))	('vein branch', 'Disease', 'MESH:D012170', (16, 27))	('obstructed', 'Var', (36, 46))
89341	25969643	PVE is indicated when the FLR is <=20%, <=30%, and <=40% in patients with normal underlying liver, intermediate liver disease, and cirrhosis, respectively.	('PVE', 'Phenotype', 'HP:0030242', (0, 3))	('<=20', 'Var', (33, 37))	('intermediate', 'Disease', (99, 111))	('<=40', 'Var', (51, 55))	('cirrhosis', 'Disease', (131, 140))	('patients', 'Species', '9606', (60, 68))	('liver disease', 'Phenotype', 'HP:0001392', (112, 125))	('liver disease', 'Disease', (112, 125))	('cirrhosis', 'Phenotype', 'HP:0001394', (131, 140))	('cirrhosis', 'Disease', 'MESH:D005355', (131, 140))	('liver disease', 'Disease', 'MESH:D008107', (112, 125))	('<=30', 'Var', (40, 44))
89435	32601222	JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma Obesity is associated with hepatic steatosis and activation of the cJun NH2-terminal kinase (JNK) stress-signaling pathway.	('hepatic steatosis', 'Disease', (117, 134))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('JNK', 'Gene', (183, 186))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (71, 89))	('bile acid', 'Gene', (27, 36))	('activation', 'PosReg', (139, 149))	('intrahepatic cholangiocarcinoma', 'Disease', (58, 89))	('hepatic steatosis', 'Disease', 'MESH:D005234', (117, 134))	('disruption', 'Var', (13, 23))	('bile acid', 'Gene', '230101', (27, 36))	('promotes', 'PosReg', (49, 57))	('JNK', 'Gene', '26419', (0, 3))	('JNK', 'Gene', '26419', (183, 186))	('hepatic steatosis', 'Phenotype', 'HP:0001397', (117, 134))	('steatosis', 'Phenotype', 'HP:0001397', (125, 134))	('Obesity', 'Phenotype', 'HP:0001513', (90, 97))	('JNK', 'Gene', (0, 3))
89437	32601222	This observation suggests that inhibition of JNK signaling may represent a possible treatment for hepatic steatosis.	('hepatic steatosis', 'Phenotype', 'HP:0001397', (98, 115))	('JNK', 'Gene', '26419', (45, 48))	('inhibition', 'Var', (31, 41))	('hepatic steatosis', 'Disease', (98, 115))	('hepatic steatosis', 'Disease', 'MESH:D005234', (98, 115))	('steatosis', 'Phenotype', 'HP:0001397', (106, 115))	('JNK', 'Gene', (45, 48))
89439	32601222	Here we demonstrate that loss of JNK causes changes in cholesterol and bile acid metabolism that promote cholestasis, bile duct proliferation, and intrahepatic cholangiocarcinoma.	('JNK', 'Gene', '26419', (33, 36))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (147, 178))	('changes', 'Reg', (44, 51))	('loss', 'Var', (25, 29))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (160, 178))	('cholestasis', 'Disease', (105, 116))	('intrahepatic cholangiocarcinoma', 'Disease', (147, 178))	('cholestasis', 'Disease', 'MESH:D002779', (105, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('JNK', 'Gene', (33, 36))	('bile duct proliferation', 'Phenotype', 'HP:0001408', (118, 141))	('cholestasis', 'Phenotype', 'HP:0001396', (105, 116))	('bile acid', 'Gene', (71, 80))	('cholesterol', 'Chemical', 'MESH:D002784', (55, 66))	('bile acid', 'Gene', '230101', (71, 80))	('promote', 'PosReg', (97, 104))	('bile duct', 'Disease', (118, 127))
89444	32601222	Indeed, JNK1/2 deficiency in hepatocytes protects against the development of steatosis, suggesting that JNK inhibition represents a possible treatment for this disease.	('JNK1/2', 'Gene', '26419;26420', (8, 14))	('JNK', 'Gene', (8, 11))	('JNK', 'Gene', (104, 107))	('JNK', 'Gene', '26419', (104, 107))	('JNK', 'Gene', '26419', (8, 11))	('deficiency', 'Var', (15, 25))	('steatosis', 'Phenotype', 'HP:0001397', (77, 86))	('steatosis', 'Disease', 'MESH:D005234', (77, 86))	('JNK1/2', 'Gene', (8, 14))	('steatosis', 'Disease', (77, 86))
89471	32601222	We found that the total BA concentration in the blood of LDKO mice was significantly increased compared with LWT mice (Fig.	('LDKO', 'Var', (57, 61))	('mice', 'Species', '10090', (62, 66))	('BA', 'Gene', '230101', (24, 26))	('increased', 'PosReg', (85, 94))	('mice', 'Species', '10090', (113, 117))
89474	32601222	Hepatic expression of genes related to hepatic PC synthesis (Scd2, Chpt1, and Chkb) or hepatocyte-mediated transport of PC (Abcb4 and Atp8b1) and BA (Abc11 and Slc10a1) was markedly increased in LDKO mice (SI Appendix, Fig.	('Slc10a1', 'Gene', '20493', (160, 167))	('increased', 'PosReg', (182, 191))	('LDKO', 'Var', (195, 199))	('Abcb4', 'Gene', (124, 129))	('hepatocyte-mediated transport', 'MPA', (87, 116))	('Chpt1', 'Gene', '212862', (67, 72))	('Atp8b1', 'Gene', (134, 140))	('Slc10a1', 'Gene', (160, 167))	('Chkb', 'Gene', '12651', (78, 82))	('Abcb4', 'Gene', '18670', (124, 129))	('Scd2', 'Gene', (61, 65))	('Scd2', 'Gene', '20250', (61, 65))	('BA', 'Gene', '230101', (146, 148))	('Atp8b1', 'Gene', '54670', (134, 140))	('hepatic PC synthesis', 'Disease', (39, 59))	('PC', 'Chemical', 'MESH:D010713', (120, 122))	('Hepatic expression', 'MPA', (0, 18))	('hepatic PC synthesis', 'Disease', 'MESH:D015324', (39, 59))	('Chkb', 'Gene', (78, 82))	('mice', 'Species', '10090', (200, 204))	('Chpt1', 'Gene', (67, 72))	('PC', 'Chemical', 'MESH:D010713', (47, 49))
89475	32601222	Similarly, increased expression of genes related to cholesterol synthesis (Hmgcs1, Hmgcr) and BA synthesis (Baat, Cyp8b1 and Cyp27a) was detected in LDKO mice (Fig.	('mice', 'Species', '10090', (154, 158))	('increased', 'PosReg', (11, 20))	('Cyp27a', 'Var', (125, 131))	('Baat', 'Gene', '12012', (108, 112))	('Hmgcs1', 'Gene', '208715', (75, 81))	('BA', 'Gene', '230101', (94, 96))	('expression', 'MPA', (21, 31))	('Cyp8b1', 'Gene', '13124', (114, 120))	('Hmgcr', 'Gene', '15357', (83, 88))	('Baat', 'Gene', (108, 112))	('Hmgcr', 'Gene', (83, 88))	('cholesterol', 'Chemical', 'MESH:D002784', (52, 63))	('Hmgcs1', 'Gene', (75, 81))	('Cyp8b1', 'Gene', (114, 120))
89491	32601222	Together, these data confirm that the majority of mature mice with compound deficiency of JNK1 and JNK2 progressively develop intrahepatic cholangiocarcinoma.	('mice', 'Species', '10090', (57, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (139, 157))	('intrahepatic cholangiocarcinoma', 'Disease', (126, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('JNK1', 'Gene', '26419', (90, 94))	('develop', 'PosReg', (118, 125))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (126, 157))	('JNK1', 'Gene', (90, 94))	('JNK2', 'Gene', (99, 103))	('JNK2', 'Gene', '26420', (99, 103))	('compound deficiency', 'Var', (67, 86))
89494	32601222	Moreover, bone morphogenetic protein 4 (Bmp4) mediates cholestasis-induced fibrosis and cooperates with FGF to promote the development of cholangiocytes from hepatoblasts; expression of hepatic Bmp4 was increased in LDKO mice compared with LWT mice (Fig.	('FGF', 'Gene', '395432', (104, 107))	('Bmp4', 'Gene', (194, 198))	('mice', 'Species', '10090', (244, 248))	('bone morphogenetic protein 4', 'Gene', '12159', (10, 38))	('bone morphogenetic protein 4', 'Gene', (10, 38))	('Bmp4', 'Gene', '12159', (194, 198))	('increased', 'PosReg', (203, 212))	('fibrosis', 'Disease', 'MESH:D005355', (75, 83))	('fibrosis', 'Disease', (75, 83))	('Bmp4', 'Gene', (40, 44))	('LDKO', 'Var', (216, 220))	('cholestasis', 'Disease', (55, 66))	('Bmp4', 'Gene', '12159', (40, 44))	('cholestasis', 'Phenotype', 'HP:0001396', (55, 66))	('hepatic', 'MPA', (186, 193))	('expression', 'MPA', (172, 182))	('cholestasis', 'Disease', 'MESH:D002779', (55, 66))	('mice', 'Species', '10090', (221, 225))	('FGF', 'Gene', (104, 107))
89499	32601222	Moreover, histological analysis indicated increased staining of phospho-ERK in cholangiocytes from LDKO mice compared with LWT mice (Fig.	('increased', 'PosReg', (42, 51))	('mice', 'Species', '10090', (127, 131))	('ERK', 'Gene', (72, 75))	('LDKO', 'Var', (99, 103))	('mice', 'Species', '10090', (104, 108))	('ERK', 'Gene', '26413', (72, 75))	('staining', 'MPA', (52, 60))
89501	32601222	Together, these changes in FXR/FGF15/FGFR4/ERK pathway activity may contribute to cholangiocyte proliferation and maturation from hepatoblasts, resulting in bile duct hyperplasia and the development of cholangiocarcinoma detected in LDKO mice.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (202, 220))	('maturation', 'CPA', (114, 124))	('activity', 'MPA', (55, 63))	('cholangiocarcinoma', 'Disease', (202, 220))	('resulting in', 'Reg', (144, 156))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (202, 220))	('ERK', 'Gene', (43, 46))	('contribute', 'Reg', (68, 78))	('bile duct hyperplasia', 'Phenotype', 'HP:0006560', (157, 178))	('FGFR4', 'Gene', '14186', (37, 42))	('bile duct hyperplasia', 'Disease', 'MESH:D001650', (157, 178))	('ERK', 'Gene', '26413', (43, 46))	('FGF15', 'Gene', (31, 36))	('FGF15', 'Gene', '14170', (31, 36))	('changes', 'Var', (16, 23))	('FGFR4', 'Gene', (37, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('mice', 'Species', '10090', (238, 242))	('bile duct hyperplasia', 'Disease', (157, 178))
89502	32601222	We examined hepatic gene expression in chow-fed WT and LDKO mice using RNA-seq data and found evidence for activation of PPARalpha and FXR transcription factors in the liver of LDKO mice compared to LWT mice (SI Appendix, Fig.	('PPARalpha', 'Gene', (121, 130))	('LDKO', 'Var', (177, 181))	('mice', 'Species', '10090', (203, 207))	('mice', 'Species', '10090', (182, 186))	('PPARalpha', 'Gene', '19013', (121, 130))	('FXR transcription factors', 'Gene', (135, 160))	('mice', 'Species', '10090', (60, 64))	('activation', 'PosReg', (107, 117))
89503	32601222	To test the role of PPARalpha, we ablated the Ppara gene in LDKO mice to examine whether PPARalpha is required for the development of intrahepatic cholangiocarcinoma.	('intrahepatic cholangiocarcinoma', 'Disease', (134, 165))	('PPARalpha', 'Gene', '19013', (89, 98))	('PPARalpha', 'Gene', '19013', (20, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('mice', 'Species', '10090', (65, 69))	('ablated', 'Var', (34, 41))	('PPARalpha', 'Gene', (89, 98))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (147, 165))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (134, 165))	('Ppara', 'Gene', (46, 51))	('PPARalpha', 'Gene', (20, 29))	('Ppara', 'Gene', '19013', (46, 51))
89508	32601222	Moreover, CK19 and SOX9 staining were increased in LDKO mice compared with LPPARalphaDKO, consistent with cholangiocyte proliferation.	('PPARalpha', 'Gene', (76, 85))	('CK19', 'Gene', (10, 14))	('SOX9', 'Gene', '20682', (19, 23))	('LDKO', 'Var', (51, 55))	('mice', 'Species', '10090', (56, 60))	('PPARalpha', 'Gene', '19013', (76, 85))	('SOX9', 'Gene', (19, 23))	('CK19', 'Gene', '16669', (10, 14))	('increased', 'PosReg', (38, 47))
89518	32601222	Our findings provide an animal model in which defects in BA homeostasis are linked to cholangiocarcinoma (Fig.	('BA', 'Gene', '230101', (57, 59))	('linked', 'Reg', (76, 82))	('cholangiocarcinoma', 'Disease', (86, 104))	('defects', 'Var', (46, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (86, 104))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (86, 104))
89522	32601222	We report that JNK-mediated repression of PPARalpha causes changes in BA homeostasis which suppress cholangiocyte proliferation.	('JNK', 'Gene', (15, 18))	('PPARalpha', 'Gene', (42, 51))	('suppress', 'NegReg', (91, 99))	('PPARalpha', 'Gene', '19013', (42, 51))	('BA', 'Gene', '230101', (70, 72))	('changes', 'Reg', (59, 66))	('cholangiocyte', 'MPA', (100, 113))	('repression', 'Var', (28, 38))	('JNK', 'Gene', '26419', (15, 18))
89537	32601222	Mice with compound JNK1/2 deficiency in hepatocytes (LDKO) have been described.	('JNK1/2', 'Gene', (19, 25))	('deficiency', 'Var', (26, 36))	('Mice', 'Species', '10090', (0, 4))	('JNK1/2', 'Gene', '26419;26420', (19, 25))
89546	32601222	Immunohistochemistry was performed by staining tissue sections with antibodies against PCNA (biotinylated from Thermofisher MS-106-B; RRID:AB_64272), SOX9 (Abcam ab3697; RRID:AB_304012), glutamine synthetase (Abcam ab73593; RRID:AB_2247588), cytokeratin 19 (Abcam ab15463; RRID:AB_2281021), or phospho-p44/42 MAPK (Thr202/Tyr204) (Cell Signaling Technology #9101).	('Abcam ab15463;', 'Var', (258, 272))	('PCNA', 'Gene', '18538', (87, 91))	('cytokeratin 19', 'Gene', (242, 256))	('SOX9', 'Gene', (150, 154))	('glutamine synthetase', 'Gene', (187, 207))	('Thr202/Tyr204', 'Var', (315, 328))	('PCNA', 'Gene', (87, 91))	('glutamine synthetase', 'Gene', '14645', (187, 207))	('Abcam ab73593;', 'Var', (209, 223))	('Abcam ab3697;', 'Var', (156, 169))	('cytokeratin 19', 'Gene', '16669', (242, 256))	('SOX9', 'Gene', '20682', (150, 154))
89553	32601222	Electrospray ionization in negative mode was used, with the following conditions: gas temperature 350  C, gas flow 8 L/min, nebulizer 10 psi, capillary voltage 2,500 V. MS/MS acquisition was performed in multiple reaction monitoring mode using the specific m/z transitions: [M-H]- ion to 80.2 for taurine-conjugated bile acids and [M-H]- ion to 74 for glycine-conjugated bile acids.	('bile acids', 'Chemical', 'MESH:D001647', (371, 381))	('[M-H]- ion to 80.2', 'Var', (274, 292))	('taurine-conjugated bile acids', 'MPA', (297, 326))	('bile acids', 'Chemical', 'MESH:D001647', (316, 326))	('glycine', 'Chemical', 'MESH:D005998', (352, 359))	('taurine', 'Chemical', 'MESH:D013654', (297, 304))	('[M-H]- ion to', 'Var', (331, 344))	('glycine-conjugated bile acids', 'MPA', (352, 381))
89554	32601222	Free bile acids did not generate characteristic ion fragments, as reported by others, and transition from unfragmented precursor molecular ions 407.1-407.1, 391.3-391.3, and 375.3-375.3 were selected for trihydroxylated, dehydroxylated, and monohydroxylated free bile acids, respectively.	('dehydroxylated', 'Var', (221, 235))	('monohydroxylated', 'Var', (241, 257))	('bile acids', 'Chemical', 'MESH:D001647', (263, 273))	('trihydroxylated', 'Var', (204, 219))	('bile acids', 'Chemical', 'MESH:D001647', (5, 15))
89578	32228636	There was no significant difference in demographic, clinical staging or tumor index between two groups, except positive hepatitis B surface antigen and CA19-9.	('CA19-9', 'Var', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('hepatitis B surface antigen', 'Gene', (120, 147))	('tumor', 'Disease', (72, 77))	('positive hepatitis B surface antigen', 'Phenotype', 'HP:0410369', (111, 147))	('hepatitis', 'Phenotype', 'HP:0012115', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
89650	32228636	showed PNI had no influence in RFS through the univariate and multivariate analyses in their case-control studies, which are not consistent with our results.	('PNI', 'Chemical', '-', (7, 10))	('RFS', 'MPA', (31, 34))	('PNI', 'Var', (7, 10))
89655	32228636	Similarly, a meta-analysis including 19 studies showed that postoperative chemotherapy could improve OS and survival in patients with R1 resection in CCA, but did not benefit patients with R0 resection.	('CCA', 'Disease', (150, 153))	('patients', 'Species', '9606', (175, 183))	('OS', 'Chemical', '-', (101, 103))	('patients', 'Species', '9606', (120, 128))	('survival', 'CPA', (108, 116))	('improve', 'PosReg', (93, 100))	('R1 resection', 'Var', (134, 146))
89671	32228636	In addition, patient characteristics showed PNI positive group with higher CA19-9 level which was revealed to be an independent risk factor in RFS and OS according to results of Cox regression analysis, which has been widely recognized and included in ICC cancer staging system.	('ICC cancer', 'Disease', (252, 262))	('PNI', 'Var', (44, 47))	('OS', 'Chemical', '-', (151, 153))	('RFS', 'Disease', (143, 146))	('patient', 'Species', '9606', (13, 20))	('higher', 'PosReg', (68, 74))	('PNI', 'Chemical', '-', (44, 47))	('ICC cancer', 'Disease', 'MESH:D009369', (252, 262))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('CA19-9 level', 'MPA', (75, 87))
89678	29733835	Mechanisms of MAFG Dysregulation in Cholestatic Liver Injury and Development of Liver Cancer MAF bZIP transcription factor G (MAFG) is activated by the farnesoid X receptor (FXR) to repress bile acid synthesis.	('Liver Cancer', 'Disease', (80, 92))	('X receptor', 'Gene', '9213', (162, 172))	('Cholestatic Liver Injury', 'Disease', (36, 60))	('Cholestatic Liver Injury', 'Phenotype', 'HP:0002611', (36, 60))	('MAFG', 'Gene', '4097', (126, 130))	('MAF bZIP transcription factor G', 'Gene', '4097', (93, 124))	('MAFG', 'Gene', '4097', (14, 18))	('Liver Cancer', 'Disease', 'MESH:D006528', (80, 92))	('Cholestatic Liver Injury', 'Disease', 'MESH:D056486', (36, 60))	('Liver Cancer', 'Phenotype', 'HP:0002896', (80, 92))	('bile acid', 'Chemical', 'MESH:D001647', (190, 199))	('bile acid synthesis', 'MPA', (190, 209))	('Cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Dysregulation', 'Var', (19, 32))	('repress', 'NegReg', (182, 189))	('MAFG', 'Gene', (126, 130))	('X receptor', 'Gene', (162, 172))	('MAFG', 'Gene', (14, 18))	('MAF bZIP transcription factor G', 'Gene', (93, 124))
89723	29733835	MzChA-1, KMCH, Hep3B and HepG2 cells were treated with lithocholic acid (LCA, 0.1-100 muM), SAMe (100 muM), UDCA (100 muM), chenodeoxycholic acid (CDCA, 0.1-100 muM), OCA (0.1-100 muM) or GW4064 (1-50 nM) from one to 16 hours.	('GW4064', 'Var', (188, 194))	('chenodeoxycholic acid', 'Chemical', 'MESH:D002635', (124, 145))	('HepG2', 'CellLine', 'CVCL:0027', (25, 30))	('muM', 'Gene', '56925', (161, 164))	('CDCA', 'Chemical', 'MESH:D002635', (147, 151))	('muM', 'Gene', (161, 164))	('OCA', 'Gene', (167, 170))	('muM', 'Gene', '56925', (86, 89))	('muM', 'Gene', '56925', (118, 121))	('muM', 'Gene', (86, 89))	('muM', 'Gene', (118, 121))	('muM', 'Gene', '56925', (102, 105))	('GW4064', 'Chemical', 'MESH:C412815', (188, 194))	('lithocholic acid', 'Chemical', 'MESH:D008095', (55, 71))	('muM', 'Gene', (102, 105))	('LCA', 'Chemical', 'MESH:D008095', (73, 76))	('OCA', 'Gene', '12096', (167, 170))	('muM', 'Gene', '56925', (180, 183))	('Hep3B', 'CellLine', 'CVCL:0326', (15, 20))	('muM', 'Gene', (180, 183))
89727	29733835	Site-directed mutagenesis was performed to create mutants for the core motifs of FXR, E-box, NF-kappaB and AP-1 elements.	('FXR', 'Gene', (81, 84))	('NF-kappaB', 'Gene', '4790', (93, 102))	('mutants', 'Var', (50, 57))	('AP-1', 'Gene', '3725', (107, 111))	('AP-1', 'Gene', (107, 111))	('NF-kappaB', 'Gene', (93, 102))
89737	29733835	For survival analysis, log-rank test was used to compare the survival ratio differences between samples with altered MAFG (almost all upregulated) versus normal MAFG expressions.	('altered', 'Var', (109, 116))	('rat', 'Species', '10116', (70, 73))	('MAFG', 'Gene', (117, 121))
89744	29733835	Consistently, LCA's inductive effect on the MAFG promoter activity was completely lost when the E-box, AP-1 and NF-kappaB sites were all mutated, but not affected when the FXR binding site was mutated (Fig.	('NF-kappaB', 'Gene', '4790', (112, 121))	('MAFG promoter', 'Gene', (44, 57))	('lost', 'NegReg', (82, 86))	('LCA', 'Chemical', 'MESH:D008095', (14, 17))	('NF-kappaB', 'Gene', (112, 121))	('AP-1', 'Gene', '3725', (103, 107))	('AP-1', 'Gene', (103, 107))	('mutated', 'Var', (137, 144))
89745	29733835	In contrast, OCA's inductive effect on the MAFG promoter activity was lost when the FXR site was mutated, but not when the E-box, AP-1 and NF-kappaB sites were mutated (Fig.	('NF-kappaB', 'Gene', (139, 148))	('AP-1', 'Gene', (130, 134))	('mutated', 'Var', (97, 104))	('OCA', 'Gene', '12096', (13, 16))	('AP-1', 'Gene', '3725', (130, 134))	('OCA', 'Gene', (13, 16))	('lost', 'NegReg', (70, 74))	('NF-kappaB', 'Gene', '4790', (139, 148))	('MAFG promoter', 'Gene', (43, 56))
89762	29733835	We first examined the effects of SAMe, UDCA or both combined on the MAFG promoter activity that is driven by either wild type (WT) or mutant promoter constructs where the NF-kappaB, AP-1 or E-box was mutated.	('NF-kappaB', 'Gene', '4790', (171, 180))	('MAFG promoter', 'Gene', (68, 81))	('NF-kappaB', 'Gene', (171, 180))	('AP-1', 'Gene', (182, 186))	('activity', 'MPA', (82, 90))	('AP-1', 'Gene', '3725', (182, 186))	('mutant', 'Var', (134, 140))
89763	29733835	SAMe or UDCA alone attenuated LCA-mediated induction of both WT and mutant constructs but when they were combined, LCA lost its ability to induce the promoter activity driven by the WT or mutant constructs.	('lost', 'NegReg', (119, 123))	('LCA', 'Chemical', 'MESH:D008095', (30, 33))	('induce', 'MPA', (139, 145))	('promoter activity', 'MPA', (150, 167))	('LCA', 'Chemical', 'MESH:D008095', (115, 118))	('mutant', 'Var', (68, 74))	('attenuated', 'NegReg', (19, 29))	('mutant', 'Var', (188, 194))
89784	29733835	Consistent with our findings, MAFG mRNA levels are higher in multiple HCC databases and in the TGCA database, survival of HCC patients with MAFG alterations (mainly amplification and mRNA upregulation) was significantly reduced (Supplemental Fig.	('rat', 'Species', '10116', (149, 152))	('mRNA levels', 'MPA', (35, 46))	('reduced', 'NegReg', (220, 227))	('MAFG', 'Gene', (140, 144))	('HCC', 'Gene', (122, 125))	('alterations', 'Var', (145, 156))	('HCC', 'Gene', '619501', (122, 125))	('survival', 'CPA', (110, 118))	('upregulation', 'PosReg', (188, 200))	('HCC', 'Gene', (70, 73))	('patients', 'Species', '9606', (126, 134))	('higher', 'PosReg', (51, 57))	('mRNA', 'MPA', (183, 187))	('HCC', 'Gene', '619501', (70, 73))
89790	29733835	GW4064, another FXR agonist, also induced MAFG expression in a dose-dependent manner, with significant effect observed at 1 nM (Supplemental Fig.	('GW4064', 'Chemical', 'MESH:C412815', (0, 6))	('GW4064', 'Var', (0, 6))	('MAFG', 'Gene', (42, 46))	('induced', 'Reg', (34, 41))	('expression', 'MPA', (47, 57))
89792	29733835	GW4064 treatment also led to similar changes at mRNA and protein levels (Supplemental Fig.	('GW4064', 'Chemical', 'MESH:C412815', (0, 6))	('changes', 'Reg', (37, 44))	('GW4064', 'Var', (0, 6))
89793	29733835	Both OCA and GW4064 did not cause any apoptosis at the highest dose under the experimental conditions (Supplemental Figure 11A).	('GW4064', 'Var', (13, 19))	('OCA', 'Gene', '12096', (5, 8))	('OCA', 'Gene', (5, 8))	('GW4064', 'Chemical', 'MESH:C412815', (13, 19))
89804	29733835	Indeed, silencing MAFG protected against the fall in hepatic GSH level and cholestatic liver injury.	('fall', 'NegReg', (45, 49))	('cholestatic liver injury', 'Disease', 'MESH:D056486', (75, 99))	('MAFG', 'Gene', (18, 22))	('silencing', 'Var', (8, 17))	('hepatic GSH level', 'MPA', (53, 70))	('fall', 'Phenotype', 'HP:0002527', (45, 49))	('GSH', 'Chemical', 'MESH:D005978', (61, 64))	('cholestatic liver injury', 'Phenotype', 'HP:0002611', (75, 99))	('cholestatic liver injury', 'Disease', (75, 99))
89813	29733835	Regarding MAFG regulation at the transcriptional level, the human MAFG promoter has four key elements - E-box, AP-1, NF-kappaB and FXR and a mutation of any of these elements lowered the basal promoter activity, suggesting all four are required for basal expression.	('MAFG', 'Gene', (66, 70))	('lowered', 'NegReg', (175, 182))	('NF-kappaB', 'Gene', '4790', (117, 126))	('NF-kappaB', 'Gene', (117, 126))	('AP-1', 'Gene', '3725', (111, 115))	('AP-1', 'Gene', (111, 115))	('mutation', 'Var', (141, 149))	('basal promoter activity', 'MPA', (187, 210))	('human', 'Species', '9606', (60, 65))
89815	29733835	Consistently, mutation of E-box, AP-1 and NF-kappaB sites individually lowered LCA's inductive effect on the MAFG promoter but when all three sites were mutated, LCA lost its ability to induce the MAFG promoter.	('AP-1', 'Gene', '3725', (33, 37))	('AP-1', 'Gene', (33, 37))	('LCA', 'Chemical', 'MESH:D008095', (79, 82))	('inductive effect on the MAFG promoter', 'MPA', (85, 122))	('induce', 'MPA', (186, 192))	('ability', 'MPA', (175, 182))	('NF-kappaB', 'Gene', '4790', (42, 51))	('LCA', 'Chemical', 'MESH:D008095', (162, 165))	('lowered LCA', 'Phenotype', 'HP:0003563', (71, 82))	('mutation', 'Var', (14, 22))	('MAFG promoter', 'MPA', (197, 210))	('NF-kappaB', 'Gene', (42, 51))	('lost', 'NegReg', (166, 170))	('lowered', 'NegReg', (71, 78))
89816	29733835	In contrast, mutation of the FXR binding site had no influence on LCA's inductive effect on the MAFG promoter.	('mutation', 'Var', (13, 21))	('inductive effect', 'MPA', (72, 88))	('LCA', 'Chemical', 'MESH:D008095', (66, 69))
89821	29733835	We investigated MAT2A expression here because its expression often correlates inversely with MAT1A and their functions appear to be the opposite of each other at least in HCC, with MAT1A acting as a tumor suppressor whereas MAT2A acting as an oncogene.	('tumor', 'Disease', (199, 204))	('HCC', 'Gene', (171, 174))	('MAT2A', 'Gene', (16, 21))	('MAT1A', 'Var', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('HCC', 'Gene', '619501', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('expression', 'MPA', (50, 60))
89835	29733835	SAMe has also been shown to inhibit NF-kappaB activation induced by hepatocarcinogens in rat liver and reduce c-MYC expression by hypermethylating the promoter region of c-MYC.	('c-MYC expression', 'MPA', (110, 126))	('hypermethylating', 'Var', (130, 146))	('activation', 'PosReg', (46, 56))	('NF-kappaB', 'Gene', (36, 45))	('rat', 'Species', '10116', (89, 92))	('reduce', 'NegReg', (103, 109))	('hepatocarcinogens', 'Disease', 'MESH:D008113', (68, 85))	('hepatocarcinogens', 'Disease', (68, 85))	('inhibit', 'NegReg', (28, 35))	('NF-kappaB', 'Gene', '4790', (36, 45))
89845	29733835	We verified these findings using our own samples and found that high MAFG expression correlated with tumor grade, vascular invasion, and a history of hepatitis (mainly hepatitis B).	('hepatitis', 'Phenotype', 'HP:0012115', (168, 177))	('expression', 'MPA', (74, 84))	('high', 'Var', (64, 68))	('hepatitis', 'Disease', (168, 177))	('hepatitis', 'Disease', 'MESH:D056486', (150, 159))	('hepatitis B', 'Disease', 'MESH:D006509', (168, 179))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('vascular invasion', 'CPA', (114, 131))	('tumor', 'Disease', (101, 106))	('MAFG', 'Gene', (69, 73))	('hepatitis', 'Disease', 'MESH:D056486', (168, 177))	('hepatitis B', 'Disease', (168, 179))	('correlated', 'Reg', (85, 95))	('hepatitis', 'Phenotype', 'HP:0012115', (150, 159))	('hepatitis', 'Disease', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
89846	29733835	Consistent with our finding that MAT2A enhances MAFG expression, a parallel increase in MAT2A expression was seen in the tumors, especially in those with vascular invasion.	('MAT2A', 'Gene', (88, 93))	('increase', 'PosReg', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('enhances', 'PosReg', (39, 47))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('MAFG', 'Protein', (48, 52))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('expression', 'MPA', (94, 104))	('expression', 'MPA', (53, 63))	('MAT2A', 'Var', (33, 38))
89852	29733835	The effect required FXR, since FXR silencing prevented OCA-mediated changes in gene expression and growth.	('silencing', 'Var', (35, 44))	('growth', 'MPA', (99, 105))	('prevented', 'NegReg', (45, 54))	('gene expression', 'MPA', (79, 94))	('OCA', 'Gene', '12096', (55, 58))	('OCA', 'Gene', (55, 58))
89928	29744055	Moreover, FENa higher than 2%, FEurea higher than 35%, and the presence of isosthenuria are also suggestive of acute tubular injury.	('acute tubular injury', 'Disease', (111, 131))	('acute tubular injury', 'Disease', 'MESH:D007683', (111, 131))	('isosthenuria', 'Disease', (75, 87))	('isosthenuria', 'Disease', 'MESH:C563693', (75, 87))	('FENa', 'Chemical', '-', (10, 14))	('FEurea', 'Var', (31, 37))
89965	25788760	The diagnosis of unspecified bile duct cancer (mainly ICD-10: C24.9) was based on the dominant symptom of stricture(s) in the extra hepatic bile tree above the gallbladder duct that was causing jaundice.	('jaundice', 'Disease', (194, 202))	('jaundice', 'Phenotype', 'HP:0000952', (194, 202))	('unspecified bile duct cancer', 'Disease', (17, 45))	('bile duct cancer', 'Phenotype', 'HP:0030153', (29, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('jaundice', 'Disease', 'MESH:D007565', (194, 202))	('stricture', 'Var', (106, 115))
90038	24581682	Several studies identifying genetic changes in cholangiocarcinoma have been published, but most of the data generated from the single studies need further validation.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (47, 65))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (47, 65))	('genetic changes', 'Var', (28, 43))	('cholangiocarcinoma', 'Disease', (47, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
90042	24581682	The proliferation class (62% of cases) was associated with copy number variations in several oncogenes, including but not restricted to KRAS and BRAF, as well as in genes from RAS, MAPK, and MET signalling networks.	('proliferation class', 'CPA', (4, 23))	('oncogenes', 'Gene', (93, 102))	('KRAS', 'Gene', '3845', (136, 140))	('BRAF', 'Gene', (145, 149))	('MAPK', 'Gene', '5595;5594;5595', (181, 185))	('MAPK', 'Gene', (181, 185))	('RAS', 'Gene', (176, 179))	('KRAS', 'Gene', (136, 140))	('associated', 'Reg', (43, 53))	('copy number variations', 'Var', (59, 81))	('BRAF', 'Gene', '673', (145, 149))
90050	24581682	In another study, transcriptome profiling in 104 patients after cholangiocarcinoma resection in Europe, the USA, and Australia showed that KRAS mutations were associated with deregulation of epidermal growth factor (EGFR) and ERBB2 (also known as HER2) signalling network, which included MET.	('EGFR', 'Gene', (216, 220))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (64, 82))	('ERBB2', 'Gene', '2064', (226, 231))	('ERBB2', 'Gene', (226, 231))	('KRAS', 'Gene', (139, 143))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('epidermal growth factor', 'Gene', (191, 214))	('HER2', 'Gene', (247, 251))	('KRAS', 'Gene', '3845', (139, 143))	('epidermal growth factor', 'Gene', '1950', (191, 214))	('deregulation', 'MPA', (175, 187))	('EGFR', 'Gene', '1950', (216, 220))	('HER2', 'Gene', '2064', (247, 251))	('patients', 'Species', '9606', (49, 57))	('mutations', 'Var', (144, 153))	('cholangiocarcinoma', 'Disease', (64, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
90051	24581682	Derangement of genes participating in proteasomal activity was associated with poor prognosis.	('genes', 'Gene', (15, 20))	('Derangement', 'Var', (0, 11))	('men', 'Species', '9606', (7, 10))
90055	24581682	Among the common cancer-related genes, mutations in TP53 responsible for maintenance of genome integrity was most common (44%), followed by KRAS (17%), and SMAD4 (17%); SMAD4 contributes to the TGFbeta signalling network, which is a key driver of metastatic cancer.	('KRAS', 'Gene', '3845', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('TGFbeta', 'Gene', (194, 201))	('SMAD4', 'Gene', (169, 174))	('TP53', 'Gene', '7157', (52, 56))	('SMAD4', 'Gene', (156, 161))	('contributes', 'Reg', (175, 186))	('SMAD4', 'Gene', '4089', (156, 161))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('TP53', 'Gene', (52, 56))	('mutations', 'Var', (39, 48))	('TGFbeta', 'Gene', '7040', (194, 201))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', (17, 23))	('SMAD4', 'Gene', '4089', (169, 174))	('cancer', 'Disease', (258, 264))	('KRAS', 'Gene', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
90056	24581682	Somatic mutations of genes involved in deactivation of histone modifiers, activation of G proteins, and loss of genome stability were present in 3.7-14.8% of cases in this study with many of the genes being newly implicated in oncogenesis (eg, KMT2C, ROBO2, RNF43, PEG3, and GNAS).	('loss', 'NegReg', (104, 108))	('PEG3', 'Gene', (265, 269))	('ROBO2', 'Gene', (251, 256))	('G proteins', 'Protein', (88, 98))	('GNAS', 'Gene', (275, 279))	('mutations', 'Var', (8, 17))	('ROBO2', 'Gene', '6092', (251, 256))	('activation', 'PosReg', (74, 84))	('RNF43', 'Gene', '54894', (258, 263))	('PEG3', 'Gene', '5178', (265, 269))	('RNF43', 'Gene', (258, 263))	('KMT2C', 'Gene', '58508', (244, 249))	('KMT2C', 'Gene', (244, 249))	('GNAS', 'Gene', '2778', (275, 279))
90057	24581682	Genetic changes in the tumour suppressive gene PTEN in combination with either activated AKT or mTOR were associated with poor patient outcomes in microarray analysis of 221 samples of extrahepatic cholangiocarcinoma.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('mTOR', 'Gene', (96, 100))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (198, 216))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('associated', 'Reg', (106, 116))	('patient', 'Species', '9606', (127, 134))	('Genetic changes', 'Var', (0, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('AKT', 'Gene', '207', (89, 92))	('tumour', 'Disease', (23, 29))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (185, 216))	('PTEN', 'Gene', (47, 51))	('PTEN', 'Gene', '5728', (47, 51))	('AKT', 'Gene', (89, 92))	('mTOR', 'Gene', '2475', (96, 100))	('extrahepatic cholangiocarcinoma', 'Disease', (185, 216))
90058	24581682	However, the correlation between these genetic changes and good outcomes was reported in 101 patients with intrahepatic cholangiocarcinoma in another study, in which mTOR and AKT activation was detected in more differentiated tumours.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (107, 138))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('mTOR', 'Gene', (166, 170))	('tumours', 'Phenotype', 'HP:0002664', (226, 233))	('mTOR', 'Gene', '2475', (166, 170))	('intrahepatic cholangiocarcinoma', 'Disease', (107, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (120, 138))	('AKT', 'Gene', '207', (175, 178))	('tumours', 'Disease', 'MESH:D009369', (226, 233))	('tumours', 'Disease', (226, 233))	('activation', 'PosReg', (179, 189))	('genetic changes', 'Var', (39, 54))	('patients', 'Species', '9606', (93, 101))	('AKT', 'Gene', (175, 178))
90059	24581682	Novel fibroblast growth factor receptor 2 (FGFR2) rearrangements with gene fusion were identified in a subset of patients with cholangiocarcinoma and these mutations are targetable.	('cholangiocarcinoma', 'Disease', (127, 145))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (127, 145))	('patients', 'Species', '9606', (113, 121))	('fibroblast growth factor receptor 2', 'Gene', (6, 41))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (127, 145))	('fibroblast growth factor receptor 2', 'Gene', '2263', (6, 41))	('FGFR2', 'Gene', (43, 48))	('FGFR2', 'Gene', '2263', (43, 48))	('rearrangements', 'Var', (50, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('men', 'Species', '9606', (59, 62))
90069	24581682	Hot-spot mutations of genes encoding IDH1 and IDH2 were recently reported by several groups to be fairly specific to intrahepatic cholangiocarcinoma in various gastrointestinal and biliary cancers (10-23%).	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (117, 148))	('IDH2', 'Gene', (46, 50))	('mutations', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('IDH1', 'Gene', (37, 41))	('IDH2', 'Gene', '3418', (46, 50))	('intrahepatic cholangiocarcinoma', 'Disease', (117, 148))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (130, 148))	('IDH1', 'Gene', '3417', (37, 41))	('gastrointestinal and biliary cancers', 'Disease', 'MESH:D004067', (160, 196))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))
90071	24581682	Importantly, inhibition of IDH gain of function mutations has been reported, which reverses epigenetic methylation and promotes cancer cell differentiation.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('promotes', 'PosReg', (119, 127))	('IDH', 'Gene', (27, 30))	('reverses', 'NegReg', (83, 91))	('epigenetic methylation', 'MPA', (92, 114))	('IDH', 'Gene', '3417', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gain of function', 'PosReg', (31, 47))	('mutations', 'Var', (48, 57))	('cancer', 'Disease', (128, 134))
90130	24581682	Serial polysomy detected by FISH in patients with primary sclerosing cholangitis can identify a subgroup of patients at high risk of development of cholangiocarcinoma compared with patients without polysomy.	('men', 'Species', '9606', (140, 143))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (148, 166))	('primary sclerosing cholangitis', 'Disease', (50, 80))	('polysomy', 'Var', (7, 15))	('patients', 'Species', '9606', (36, 44))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (148, 166))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (58, 80))	('cholangiocarcinoma', 'Disease', (148, 166))	('cholangitis', 'Phenotype', 'HP:0030151', (69, 80))	('patients', 'Species', '9606', (181, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('patients', 'Species', '9606', (108, 116))	('primary sclerosing cholangitis', 'Disease', 'MESH:D015209', (50, 80))
90176	24581682	In the near future we might be able to offer our patients an individualised therapy based on the driver mutation for their particular cancer and practise precision medicine.	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('mutation', 'Var', (104, 112))	('patients', 'Species', '9606', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
90185	33934113	Knocking down MTHFD1 in HyPer-low cells enhanced cellular ROS and restored sensitivity to gemcitabine.	('MTHFD1', 'Gene', '4522', (14, 20))	('Knocking down', 'Var', (0, 13))	('ROS', 'Chemical', 'MESH:D017382', (58, 61))	('gemcitabine', 'Chemical', 'MESH:C056507', (90, 101))	('restored', 'PosReg', (66, 74))	('sensitivity to gemcitabine', 'MPA', (75, 101))	('MTHFD1', 'Gene', (14, 20))	('cellular ROS', 'MPA', (49, 61))	('enhanced', 'PosReg', (40, 48))
90202	33934113	The long-term unsolved questions are what is the heterogeneous cellular redox status in various cancer cells and how do intrinsic ROS affect the constitutive chemoresistance.	('ROS', 'Chemical', 'MESH:D017382', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('affect', 'Reg', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('constitutive chemoresistance', 'CPA', (145, 173))	('intrinsic', 'Var', (120, 129))	('cancer', 'Disease', (96, 102))
90203	33934113	To uncover the correlation between the intrinsic cellular redox status and CCA gemcitabine chemoresistance, we applied a novel tool, the HyPer3 probe, to sort out cellular redox status differences in a subpopulation of CCA cells and found that HyPer-low CCA cells exhibited higher gemcitabine chemoresistance than others with higher MTHFD1 expression.	('gemcitabine', 'CPA', (281, 292))	('gemcitabine', 'Chemical', 'MESH:C056507', (281, 292))	('MTHFD1', 'Gene', (333, 339))	('CCA', 'Phenotype', 'HP:0030153', (219, 222))	('HyPer-low', 'Var', (244, 253))	('gemcitabine', 'Chemical', 'MESH:C056507', (79, 90))	('higher', 'PosReg', (274, 280))	('CCA', 'Phenotype', 'HP:0030153', (254, 257))	('CCA', 'Phenotype', 'HP:0030153', (75, 78))	('MTHFD1', 'Gene', '4522', (333, 339))
90207	33934113	QBC939 and HUCCT1 were all MTHFD1 WT genotype (MTHFD1+/+).	('MTHFD1', 'Gene', (47, 53))	('QBC939', 'Var', (0, 6))	('MTHFD1', 'Gene', '4522', (27, 33))	('QBC939', 'Chemical', '-', (0, 6))	('MTHFD1', 'Gene', (27, 33))	('MTHFD1', 'Gene', '4522', (47, 53))
90232	33934113	Antibody against MTHFD1 (A8661, dilution 1:1000) was from Abclonal; beta-Actin (A1978, dilution 1:1000) was from Sigma-Aldich.	('MTHFD1', 'Gene', (17, 23))	('A8661', 'Var', (25, 30))	('A1978', 'Var', (80, 85))	('MTHFD1', 'Gene', '4522', (17, 23))	('beta-Actin', 'Gene', (68, 78))	('beta-Actin', 'Gene', '728378', (68, 78))
90238	33934113	Once hydrogen peroxide reacts with the OxyR domain in the C-terminus, the disulfide bond between Cys199 and Cys208 immediately forms (Fig.	('Cys199', 'Chemical', '-', (97, 103))	('Cys208', 'Chemical', '-', (108, 114))	('Cys208', 'Var', (108, 114))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (5, 22))	('disulfide', 'Chemical', 'MESH:D004220', (74, 83))	('disulfide bond', 'MPA', (74, 88))	('Cys199', 'Var', (97, 103))
90242	33934113	Exogenous hydrogenous peroxide induced an instantaneous increase in the fluorescence ratios by ~6.0-fold in these two types of CCA cell lines, while exogenous DTT generally led to an inverse decrease in the fluorescence ratios by ~0.8-fold (Fig.	('Exogenous', 'Var', (0, 9))	('CCA', 'Phenotype', 'HP:0030153', (127, 130))	('fluorescence ratios', 'MPA', (72, 91))	('increase', 'PosReg', (56, 64))	('hydrogenous peroxide', 'Chemical', '-', (10, 30))	('DTT', 'Chemical', 'MESH:D004229', (159, 162))
90249	33934113	Due to the larger gap from QBC939 to HUCCT1, we statistically calculated the ratio in QBC939 cells under confocal microscopy, which could be shown as a histogram with three distinct populations, HyPer-mid (81.1% with a mean F488 nm/F405 nm of 0.8~1.7), HyPer-high (14.8% with a mean F488 nm/F405 nm of 0.8~2.8) and HyPer-low (4.1% with a mean F488 nm/F405 nm of 0~0.8) (Fig.	('QBC939', 'Chemical', '-', (86, 92))	('QBC939', 'Chemical', '-', (27, 33))	('F488 nm/F405 nm', 'Var', (283, 298))	('F488 nm/F405 nm', 'Var', (224, 239))
90254	33934113	The correlation was confirmed in the three subpopulations of QBC939, HyPer-mid, HyPer-high, and HyPer-low, by cell-counting kit 8 assays with gradient concentrations (from 0 to 100 muM) of gemcitabine, and HyPer-low CCA cells were characterized by higher resistance to gemcitabine (Fig.	('HyPer-low', 'Var', (96, 105))	('CCA', 'Phenotype', 'HP:0030153', (216, 219))	('HyPer-low', 'Var', (206, 215))	('gemcitabine', 'Chemical', 'MESH:C056507', (269, 280))	('resistance to gemcitabine', 'MPA', (255, 280))	('gemcitabine', 'Chemical', 'MESH:C056507', (189, 200))	('QBC939', 'Var', (61, 67))	('QBC939', 'Chemical', '-', (61, 67))	('higher', 'PosReg', (248, 254))
90259	33934113	We further established that HyPer-low CCA cells possess higher gemcitabine chemoresistance than other subpopulations in vivo.	('gemcitabine', 'MPA', (63, 74))	('CCA', 'Phenotype', 'HP:0030153', (38, 41))	('gemcitabine', 'Chemical', 'MESH:C056507', (63, 74))	('higher', 'PosReg', (56, 62))	('HyPer-low CCA', 'Var', (28, 41))
90275	33934113	Meanwhile, with MTHFD1 knockdown, the ratio of cellular NADPH in HyPer-low cells experienced a dramatic decrease (Fig.	('ratio', 'MPA', (38, 43))	('knockdown', 'Var', (23, 32))	('MTHFD1', 'Gene', '4522', (16, 22))	('NADPH', 'Gene', (56, 61))	('decrease', 'NegReg', (104, 112))	('NADPH', 'Gene', '1666', (56, 61))	('MTHFD1', 'Gene', (16, 22))
90276	33934113	Following MTHFD1 knockdown, both HyPer3 QBC939 cells and HyPer-low subpopulation cells exhibited a notable increase in the fluorescence ratio, while the antioxidant and free radical scavenger N-acetyl-L-cysteine (NAC) effectively reversed the fluorescence ratio increase (Fig.	('fluorescence ratio', 'MPA', (123, 141))	('increase', 'PosReg', (107, 115))	('NAC', 'Chemical', 'MESH:D000111', (213, 216))	('N-acetyl-L-cysteine', 'Chemical', 'MESH:D000111', (192, 211))	('MTHFD1', 'Gene', (10, 16))	('QBC939', 'Chemical', '-', (40, 46))	('knockdown', 'Var', (17, 26))	('MTHFD1', 'Gene', '4522', (10, 16))
90281	33934113	Based on the transformation from gemcitabine chemoresistance to sensitivity after MTHFD1 was knocked down, we hypothesized that antifolates might synergize with gemcitabine to cure patients who are resistant to gemcitabine.	('gemcitabine', 'Chemical', 'MESH:C056507', (161, 172))	('MTHFD1', 'Gene', (82, 88))	('folate', 'Chemical', 'MESH:D005492', (132, 138))	('patients', 'Species', '9606', (181, 189))	('knocked down', 'Var', (93, 105))	('MTHFD1', 'Gene', '4522', (82, 88))	('gemcitabine', 'Chemical', 'MESH:C056507', (33, 44))	('gemcitabine', 'Chemical', 'MESH:C056507', (211, 222))
90292	33934113	Our data show that the HyPer-low subpopulation, which is characterized by a lower cellular redox status, is highly associated with gemcitabine chemoresistance.	('cellular redox status', 'MPA', (82, 103))	('associated', 'Reg', (115, 125))	('lower', 'NegReg', (76, 81))	('gemcitabine', 'Chemical', 'MESH:C056507', (131, 142))	('HyPer-low', 'Var', (23, 32))
90308	33934113	Once MTHFD1 was knocked down by short interfering RNA, severe gemcitabine chemoresistance was greatly alleviated, accompanied by the differences between the cellular redox statuses of the HyPer-low and HyPer-high subpopulations being effectively canceled.	('gemcitabine', 'Chemical', 'MESH:C056507', (62, 73))	('cellular redox statuses', 'MPA', (157, 180))	('MTHFD1', 'Gene', '4522', (5, 11))	('short', 'Protein', (32, 37))	('alleviated', 'NegReg', (102, 112))	('knocked down', 'Var', (16, 28))	('MTHFD1', 'Gene', (5, 11))
90311	33934113	Our data effectively exhibit the severe gemcitabine chemoresistance in HyPer-low CCA cells with high expression of MTHFD1 but neglect to verify the potential possibility that HyPer-low CCA cells have equal CCA stem cells, which should be completed in our future study.	('MTHFD1', 'Gene', '4522', (115, 121))	('CCA', 'Phenotype', 'HP:0030153', (206, 209))	('CCA', 'Phenotype', 'HP:0030153', (185, 188))	('high expression', 'Var', (96, 111))	('gemcitabine', 'CPA', (40, 51))	('MTHFD1', 'Gene', (115, 121))	('gemcitabine', 'Chemical', 'MESH:C056507', (40, 51))	('CCA', 'Phenotype', 'HP:0030153', (81, 84))
90314	33934113	In detail, MTX inhibits dihydrofolate reductase leading to depletion of tetrahydrofolate, which is involved in multiple chemical reactions of homocysteine to methionine, where it acts as a proximal methyl donor.	('dihydrofolate reductase', 'Gene', (24, 47))	('homocysteine', 'Chemical', 'MESH:D006710', (142, 154))	('methionine', 'Chemical', 'MESH:D008715', (158, 168))	('MTX', 'Var', (11, 14))	('tetrahydrofolate', 'Chemical', 'MESH:C030371', (72, 88))	('inhibits', 'NegReg', (15, 23))	('dihydrofolate reductase', 'Gene', '1719', (24, 47))	('MTX', 'Chemical', 'MESH:D008727', (11, 14))	('depletion of tetrahydrofolate', 'MPA', (59, 88))
90323	33805079	In the non-normalization group, patients who underwent R1 resection displayed significantly worse OS than those who underwent R0 resection (median OS, 10.2 vs. 15.7 months; p = 0.016).	('R1 resection', 'Var', (55, 67))	('patients', 'Species', '9606', (32, 40))	('worse', 'NegReg', (92, 97))
90335	33805079	Regarding BTC, some studies have suggested that non-normalization of CA19-9 levels after resection was associated with worse prognosis, and elevated preoperative and postoperative CA19-9 levels were predictive of poor prognosis.	('associated', 'Reg', (103, 113))	('CA19-9', 'Chemical', 'MESH:C086528', (180, 186))	('CA19-9', 'Chemical', 'MESH:C086528', (69, 75))	('CA19-9 levels', 'MPA', (69, 82))	('non-normalization', 'Var', (48, 65))
90354	33805079	The patients were divided into three groups: normal preoperative CA19-9 (CA19-9 <= 37 U/mL), normalization (preoperative CA19-9 >37 U/mL, postoperative CA19-9 <= 37 U/mL), and non-normalization (pre- and postoperative CA19-9 > 37 U/mL) groups.	('CA19-9', 'Chemical', 'MESH:C086528', (121, 127))	('CA19-9', 'Var', (152, 158))	('CA19-9', 'Chemical', 'MESH:C086528', (65, 71))	('CA19-9', 'Chemical', 'MESH:C086528', (73, 79))	('CA19-9', 'Chemical', 'MESH:C086528', (152, 158))	('CA19-9', 'Var', (121, 127))	('CA19-9', 'Chemical', 'MESH:C086528', (218, 224))	('mL', 'Gene', '21832', (232, 234))	('patients', 'Species', '9606', (4, 12))	('mL', 'Gene', '21832', (167, 169))	('mL', 'Gene', '21832', (134, 136))	('mL', 'Gene', '21832', (88, 90))
90379	33805079	The four groups comprised low preoperative/low postoperative CA19-9 (n = 205, 63.7%), high preoperative/low postoperative CA19-9 (n = 28, 8.7%), low preoperative/high postoperative CA19-9 (n = 48, 14.9%), and high preoperative/high postoperative CA19-9 (n = 41, 12.7%).	('CA19-9', 'Chemical', 'MESH:C086528', (61, 67))	('high postop', 'Phenotype', 'HP:0007906', (227, 238))	('high postop', 'Phenotype', 'HP:0007906', (162, 173))	('CA19-9', 'Chemical', 'MESH:C086528', (246, 252))	('CA19-9', 'Chemical', 'MESH:C086528', (122, 128))	('high', 'Var', (86, 90))	('low', 'Var', (145, 148))	('CA19-9', 'Chemical', 'MESH:C086528', (181, 187))
90380	33805079	Patients with a high preoperative/high postoperative CA19-9 had a five-year OS that was considerably poorer (5.9%) than those with low preoperative/low postoperative CA19-9 (31.5%, p < 0.001), high preoperative/low postoperative CA19-9 (28.1%, p = 0.003), or low preoperative/high postoperative CA19-9 (30.0%, p = 0.009).	('CA19-9', 'Var', (53, 59))	('high preoperative/high', 'Var', (16, 38))	('CA19-9', 'Chemical', 'MESH:C086528', (166, 172))	('Patients', 'Species', '9606', (0, 8))	('CA19-9', 'Chemical', 'MESH:C086528', (53, 59))	('CA19-9', 'Chemical', 'MESH:C086528', (229, 235))	('CA19-9', 'Chemical', 'MESH:C086528', (295, 301))	('high postop', 'Phenotype', 'HP:0007906', (276, 287))	('poorer', 'NegReg', (101, 107))	('high postop', 'Phenotype', 'HP:0007906', (34, 45))
90382	33805079	Specifically, patients with low preop/high postop CA19-9 (OR 4.76; 95% CI 1.42-16.02; p = 0.012) and high preop/high postop CA19-9 (OR 6.62; 95% CI 2.10-20.83; p = 0.001) had higher odds of one-year mortality compared to patients with low preop/low postop CA19-9, respectively.	('CA19-9', 'Gene', (50, 56))	('patients', 'Species', '9606', (221, 229))	('low preop/high postop', 'Var', (28, 49))	('high preop/high postop CA19-9', 'Var', (101, 130))	('high postop', 'Phenotype', 'HP:0007906', (38, 49))	('CA19-9', 'Chemical', 'MESH:C086528', (124, 130))	('high postop', 'Phenotype', 'HP:0007906', (112, 123))	('mortality', 'Disease', 'MESH:D003643', (199, 208))	('CA19-9', 'Chemical', 'MESH:C086528', (50, 56))	('CA19-9', 'Chemical', 'MESH:C086528', (256, 262))	('CA19-9', 'Var', (124, 130))	('mortality', 'Disease', (199, 208))	('patients', 'Species', '9606', (14, 22))
90383	33805079	On the other hand, the high preop/low postop CA19-9 group (OR 2.49; 95% CI 0.62-9.97; p = 0.199) did not increase one-year mortality significantly compared to the low preop/low postop CA19-9 group.	('CA19-9', 'Chemical', 'MESH:C086528', (184, 190))	('CA19-9', 'Chemical', 'MESH:C086528', (45, 51))	('mortality', 'Disease', 'MESH:D003643', (123, 132))	('CA19-9', 'Var', (45, 51))	('mortality', 'Disease', (123, 132))
90384	33805079	To assess the effect of the rate of the change in levels in this tumor marker, we calculated this change in patients with preoperative CA19-9 levels > 60 U/mL (n = 169) (Figure 3) using the following formula:  We then categorized patients into four quartiles (Q1-4) based on their DeltaCA19-9 values (Figure 3), with Q1 consisting of patients with the greatest DeltaCA19-9 and Q4 consisting of patients with the smallest DeltaCA19-9.	('DeltaCA19-9', 'Var', (361, 372))	('CA19-9', 'Chemical', 'MESH:C086528', (286, 292))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('CA19-9', 'Chemical', 'MESH:C086528', (135, 141))	('patients', 'Species', '9606', (230, 238))	('patients', 'Species', '9606', (394, 402))	('patients', 'Species', '9606', (108, 116))	('patients', 'Species', '9606', (334, 342))	('CA19-9', 'Chemical', 'MESH:C086528', (366, 372))	('mL', 'Gene', '21832', (156, 158))	('CA19-9', 'Chemical', 'MESH:C086528', (426, 432))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
90393	33805079	Additionally, among patients with persistent high CA19-9 levels after surgery, those who underwent R1 resection displayed significantly worse OS than those who underwent R0 resection.	('CA19-9', 'Chemical', 'MESH:C086528', (50, 56))	('R1 resection', 'Var', (99, 111))	('patients', 'Species', '9606', (20, 28))	('CA19-9 levels', 'MPA', (50, 63))
90465	33159471	11  In contrast, autoantibodies often support the diagnosis and serve as markers of disease severity and progression in other autoimmune disorders.	('support', 'Reg', (38, 45))	('autoimmune disorders', 'Disease', (126, 146))	('autoimmune disorders', 'Phenotype', 'HP:0002960', (126, 146))	('autoimmune disorders', 'Disease', 'MESH:D001327', (126, 146))	('autoantibodies', 'Var', (17, 31))
90514	33159471	Anti-GP24 IgA positivity was linked with the presence of cirrhosis (odds ratio, OR = 2.7, 95% confidence interval, 95%CI = 1.5-5.0; P = 0.001).	('cirrhosis', 'Phenotype', 'HP:0001394', (57, 66))	('cirrhosis', 'Disease', 'MESH:D005355', (57, 66))	('GP2', 'Gene', '2813', (5, 8))	('linked', 'Reg', (29, 35))	('IgA', 'Gene', (10, 13))	('GP2', 'Gene', (5, 8))	('positivity', 'Var', (14, 24))	('IgA', 'Gene', '973', (10, 13))	('GP24 IgA positivity', 'Phenotype', 'HP:0030859', (5, 24))	('cirrhosis', 'Disease', (57, 66))
90519	33159471	Patients with anti-GP21 IgA positivity reported a significantly impaired well-being in both applied questionnaires: two of five domains of PBC-40 (ie Other symptoms [15 vs 13 points, P = 0.04] and Itch [5 vs 3 points, P < 0.01] domains) and 4/8 domains of SF-36 (Physical functioning [85 vs 90 points, P < 0.01], Role limitation-physical [50 vs 75 points, P < 0.01], Role limitation-emotional [67 vs 100 points, P = 0.02] domains, and Physical Component Summary [58 vs 69 points, P = 0.03]).	('GP2', 'Gene', '2813', (19, 22))	('positivity', 'Var', (28, 38))	('impaired', 'NegReg', (64, 72))	('Itch', 'Phenotype', 'HP:0000989', (197, 201))	('Itch', 'Gene', '83737', (197, 201))	('IgA', 'Gene', (24, 27))	('GP2', 'Gene', (19, 22))	('Patients', 'Species', '9606', (0, 8))	('IgA', 'Gene', '973', (24, 27))	('anti-GP21 IgA positivity', 'Phenotype', 'HP:0032376', (14, 38))	('PBC-40', 'Chemical', '-', (139, 145))	('Itch', 'Gene', (197, 201))	('well-being', 'MPA', (73, 83))
90552	33159471	20 ,  22 ,  30 ,  42 ,  43 ,  44  Recent studies indicate that the autoantibodies also may have an impact on the clinical picture of PSC.	('autoantibodies', 'Var', (67, 81))	('impact', 'Reg', (99, 105))	('PSC', 'Gene', (133, 136))	('PSC', 'Gene', '100653366', (133, 136))
90558	33159471	Notably, in both analysed cohorts we also found significant associations between positive PR3-ANCA and exacerbated liver biochemistry, in line with the observations of Stinton et al 18   Our study gave us a unique insight on the potential association between antibodies, disease-related symptoms and patients' quality of life measures.	('PR3', 'Gene', '5657', (90, 93))	('positive', 'Var', (81, 89))	('PR3', 'Gene', (90, 93))	('exacerbated', 'PosReg', (103, 114))	('liver biochemistry', 'MPA', (115, 133))	('patients', 'Species', '9606', (300, 308))
90593	33159471	Finally, in our cohort all cholangiocarcinoma cases were associated with PR3-ANCA/anti-GP2 IgA combined positivity, and both antibodies were predictors of biliary malignancy.	('PR3', 'Gene', (73, 76))	('cholangiocarcinoma', 'Disease', (27, 45))	('GP2', 'Gene', (87, 90))	('IgA', 'Gene', '973', (91, 94))	('PR3', 'Gene', '5657', (73, 76))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (27, 45))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (27, 45))	('positivity', 'Var', (104, 114))	('GP2', 'Gene', '2813', (87, 90))	('biliary malignancy', 'Disease', (155, 173))	('biliary malignancy', 'Disease', 'MESH:D009369', (155, 173))	('IgA', 'Gene', (91, 94))	('associated', 'Reg', (57, 67))
90615	31889904	To date, numerous studies have demonstrated a crucial role for both hypermethylation of tumor suppressor genes and global hypomethylation of oncogenes in cancer development and progression, including in CCA.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CCA', 'Phenotype', 'HP:0030153', (203, 206))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('hypermethylation', 'Var', (68, 84))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', (88, 93))	('CCA', 'Disease', (203, 206))
90617	31889904	In addition, the aberrant methylation of GATA-5, ANGPTL4, and DLEC1 has been shown to participate in the initiation and progression of this disease.	('aberrant', 'Var', (17, 25))	('DLEC1', 'Gene', (62, 67))	('GATA-5', 'Gene', '140628', (41, 47))	('DLEC1', 'Gene', '9940', (62, 67))	('ANGPTL4', 'Gene', '51129', (49, 56))	('ANGPTL4', 'Gene', (49, 56))	('methylation', 'MPA', (26, 37))	('GATA-5', 'Gene', (41, 47))	('participate', 'Reg', (86, 97))
90618	31889904	Over the past decade, gene profiling and next-generation sequencing technology have emerged as indispensable tools for cancer studies because they allow the detection of cancer-related genetic and epigenetic alterations, such as mutations, copy number variations, and DNA methylation changes across more extensive genomic regions.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('mutations', 'Var', (229, 238))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('copy number variations', 'Var', (240, 262))	('DNA methylation changes', 'Var', (268, 291))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
90621	31889904	identified many differentially methylated genes (DMGs) by methylation profiling or whole-genome sequencing that contributed to cholangiocarcinogenesis and might serve as methylation biomarkers in CCA.	('CCA', 'Phenotype', 'HP:0030153', (196, 199))	('DMGs', 'Chemical', '-', (49, 53))	('cholangiocarcinogenesis', 'Disease', 'None', (127, 150))	('differentially methylated genes', 'Var', (16, 47))	('contributed', 'Reg', (112, 123))	('CCA', 'Disease', (196, 199))	('cholangiocarcinogenesis', 'Disease', (127, 150))
90633	31889904	The hypermethylated, downregulated genes were mainly enriched in xenobiotic metabolic process, drug catabolic process, negative regulation of proteolysis, acute-phase response, and monocarboxylic acid metabolic process.	('negative regulation', 'NegReg', (119, 138))	('drug catabolic process', 'MPA', (95, 117))	('downregulated', 'NegReg', (21, 34))	('monocarboxylic acid', 'Chemical', '-', (181, 200))	('xenobiotic', 'Enzyme', (65, 75))	('genes', 'Gene', (35, 40))	('hypermethylated', 'Var', (4, 19))	('acute-phase', 'MPA', (155, 166))
90635	31889904	We found that hypermethylated genes predominantly participated in metabolism-related pathways, including general metabolic pathways, drug or xenobiotic metabolism by cytochrome P450, and cholesterol metabolism.	('drug', 'Enzyme', (133, 137))	('general metabolic', 'Enzyme', (105, 122))	('cytochrome P450', 'Gene', (166, 181))	('metabolism-related', 'Enzyme', (66, 84))	('cytochrome P450', 'Gene', '4051', (166, 181))	('cholesterol', 'MPA', (187, 198))	('participated', 'Reg', (50, 62))	('cholesterol', 'Chemical', 'MESH:D002784', (187, 198))	('hypermethylated genes', 'Var', (14, 35))
90636	31889904	For hypomethylated genes, the most significantly enriched pathways involved the cell cycle (mitotic G1-G1/S phases; G0 and early G1), SLC-mediated transmembrane transport, and signaling by MST1.	('SLC', 'Gene', (134, 137))	('MST1', 'Gene', (189, 193))	('SLC', 'Gene', '6366', (134, 137))	('cell cycle (mitotic G1-G1/S phases', 'CPA', (80, 114))	('MST1', 'Gene', '4485', (189, 193))	('hypomethylated', 'Var', (4, 18))
90648	31889904	DNA methylation is a central epigenetic modification that plays a key role in cellular processes and generally occurs on cytosines that precede a guanine nucleotide.	('guanine nucleotide', 'Chemical', 'MESH:D006150', (146, 164))	('occurs', 'Reg', (111, 117))	('DNA', 'Disease', (0, 3))	('methylation', 'Var', (4, 15))
90650	31889904	To date, numerous studies have demonstrated a crucial role for both hypermethylation of tumor suppressor genes and hypomethylation of oncogenes in cancer development and progression.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('hypermethylation', 'Var', (68, 84))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cancer', 'Disease', (147, 153))	('hypomethylation', 'Var', (115, 130))	('tumor', 'Disease', (88, 93))
90652	31889904	identified many novel methylation-regulated differentially expressed genes involved in colon cancer tumorigenesis and progression by identifying hypermethylated downregulated genes and hypomethylated upregulated genes.	('colon cancer', 'Disease', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('downregulated', 'NegReg', (161, 174))	('differentially expressed', 'MPA', (44, 68))	('methylation-regulated', 'Var', (22, 43))	('tumor', 'Disease', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('upregulated', 'PosReg', (200, 211))	('colon cancer', 'Phenotype', 'HP:0003003', (87, 99))	('colon cancer', 'Disease', 'MESH:D015179', (87, 99))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('hypermethylated', 'Var', (145, 160))
90656	31889904	These findings are reasonable because it is well known that dysregulation of cell cycle progression, including nuclear division, sister chromatid separation, and spindle assembly, is closely related to cancer 1.	('related', 'Reg', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('spindle assembly', 'CPA', (162, 178))	('sister chromatid separation', 'CPA', (129, 156))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cell cycle progression', 'CPA', (77, 99))	('cancer', 'Disease', (202, 208))	('nuclear division', 'CPA', (111, 127))	('dysregulation', 'Var', (60, 73))
90659	31889904	For instance, SGOL1, a member of the shugoshin family of proteins, is thought to protect centromeric cohesion during mitosis, and its dysregulation at centromeres can lead to chromosome missegregation and miotic arrest.	('centromeric', 'MPA', (89, 100))	('dysregulation', 'Var', (134, 147))	('lead to', 'Reg', (167, 174))	('SGOL1', 'Gene', (14, 19))	('chromosome missegregation', 'CPA', (175, 200))	('miotic arrest', 'Disease', (205, 218))	('SGOL1', 'Gene', '151648', (14, 19))	('miotic arrest', 'Disease', 'MESH:D006323', (205, 218))
90660	31889904	found that SGOL1 expression levels are higher in prostate cancer tissues, and SGLO1 knockdown results in the inhibition of tumor cell proliferation, migration, and invasion.	('higher', 'PosReg', (39, 45))	('expression levels', 'MPA', (17, 34))	('tumor', 'Disease', (123, 128))	('SGOL1', 'Gene', (11, 16))	('prostate cancer', 'Disease', 'MESH:D011471', (49, 64))	('migration', 'CPA', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('knockdown', 'Var', (84, 93))	('prostate cancer', 'Phenotype', 'HP:0012125', (49, 64))	('SGLO1', 'Gene', (78, 83))	('inhibition', 'NegReg', (109, 119))	('SGOL1', 'Gene', '151648', (11, 16))	('invasion', 'CPA', (164, 172))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('prostate cancer', 'Disease', (49, 64))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
90663	31889904	Pathway analysis also revealed that the hypomethylated, upregulated genes were enriched in MST1 signaling, which has demonstrated significant effects in multiple types of human cancer.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('upregulated', 'PosReg', (56, 67))	('hypomethylated', 'Var', (40, 54))	('MST1', 'Gene', '4485', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('MST1', 'Gene', (91, 95))	('human', 'Species', '9606', (171, 176))
90668	31889904	In the current study, we found that MST1R was hypomethylated in CCA, which provides a foundation for future research.	('MST1R', 'Gene', '4486', (36, 41))	('hypomethylated', 'Var', (46, 60))	('CCA', 'Disease', (64, 67))	('MST1R', 'Gene', (36, 41))	('CCA', 'Phenotype', 'HP:0030153', (64, 67))
90670	31889904	We also identified the involvement of complement and coagulation cascades, bile secretion, drug metabolism, cholesterol metabolism, and CYP2E1 reactions with these genetic changes.	('genetic changes', 'Var', (164, 179))	('bile secretion', 'MPA', (75, 89))	('drug metabolism', 'MPA', (91, 106))	('involvement', 'Reg', (23, 34))	('CYP2E1', 'Gene', '1571', (136, 142))	('cholesterol metabolism', 'MPA', (108, 130))	('cholesterol', 'Chemical', 'MESH:D002784', (108, 119))	('CYP2E1', 'Gene', (136, 142))
90673	31889904	found that BSEP is typically absent or greatly reduced due to ABCB11 mutations, and 15% of patients with BSEP deficiency developed hepatocellular carcinoma or CCA.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('mutations', 'Var', (69, 78))	('ABCB11', 'Gene', (62, 68))	('BSEP', 'Gene', '8647', (11, 15))	('patients', 'Species', '9606', (91, 99))	('BSEP deficiency', 'Disease', 'MESH:D007153', (105, 120))	('BSEP', 'Gene', (11, 15))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (131, 155))	('CCA', 'Phenotype', 'HP:0030153', (159, 162))	('hepatocellular carcinoma', 'Disease', (131, 155))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (131, 155))	('BSEP', 'Gene', '8647', (105, 109))	('ABCB11', 'Gene', '8647', (62, 68))	('developed', 'Reg', (121, 130))	('BSEP deficiency', 'Disease', (105, 120))	('BSEP', 'Gene', (105, 109))	('reduced', 'NegReg', (47, 54))	('CCA', 'Disease', (159, 162))
90685	31889904	AURKB is also upregulated and hypomethylated in hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (48, 72))	('hepatocellular carcinoma', 'Disease', (48, 72))	('AURKB', 'Gene', (0, 5))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (48, 72))	('hypomethylated', 'Var', (30, 44))	('upregulated', 'PosReg', (14, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('AURKB', 'Gene', '9212', (0, 5))
90686	31889904	However, aberrant methylation of AURKB in CCA has not been previously reported.	('methylation', 'MPA', (18, 29))	('CCA', 'Phenotype', 'HP:0030153', (42, 45))	('AURKB', 'Gene', '9212', (33, 38))	('aberrant', 'Var', (9, 17))	('AURKB', 'Gene', (33, 38))	('CCA', 'Disease', (42, 45))
90694	31889904	Finally, we obtained the MeDEGs by overlapping the DEGs and DMGs from two different datasets (expression dataset GSE119336 and DNA methylation dataset GSE38860) but did not include a dataset that included both expression and methylation data for CCA.	('GSE38860', 'Var', (151, 159))	('DMGs', 'Chemical', '-', (60, 64))	('GSE119336', 'Var', (113, 122))	('CCA', 'Phenotype', 'HP:0030153', (246, 249))
90772	31429524	It is thought that both transarterial chemoembolization (TACE)10 and Y-9011 are safe and effective as palliative therapies for unresectable ICC.	('Y-9011', 'Var', (69, 75))	('TACE', 'Gene', '6868', (57, 61))	('ICC', 'Disease', (140, 143))	('ICC', 'Disease', 'MESH:C535533', (140, 143))	('TACE', 'Gene', (57, 61))
90780	31429524	Lin et al26 examined 102 patients with ICC and saw that higher PD-1+CD4+ and PD-1+CD8+ T cells were found in the high-NLR group while higher amounts of IFN+CD4+ and IFN+CD8+ T cells were seen in the low-NLR group.	('ICC', 'Disease', (39, 42))	('higher', 'PosReg', (56, 62))	('patients', 'Species', '9606', (25, 33))	('ICC', 'Disease', 'MESH:C535533', (39, 42))	('PD-1+CD8+', 'Var', (77, 86))	('high-NLR', 'Var', (113, 121))	('PD-1+CD4+', 'MPA', (63, 72))
90781	31429524	Furthermore, the high-NLR group experienced an increased density of tumor-infiltrating CD3+T cells.	('tumor', 'Disease', (68, 73))	('increased', 'PosReg', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('high-NLR', 'Var', (17, 25))
90835	30631804	Pathological analysis revealed a successful R0 resection of a T3N1M0 moderately differentiated invasive pancreatic ductal adenocarcinoma, invading into the peripancreatic soft tissue, ampulla, duodenal wall, and bile duct (Fig.	('T3N1M0', 'Var', (62, 68))	('pancreatic', 'Disease', (104, 114))	('invasive pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (95, 136))	('pancreatic', 'Disease', 'MESH:D010195', (160, 170))	('invasive pancreatic ductal adenocarcinoma', 'Disease', (95, 136))	('pancreatic', 'Disease', (160, 170))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (104, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('pancreatic', 'Disease', 'MESH:D010195', (104, 114))
90877	28694672	Benefit of everolimus in treatment of an intrahepatic cholangiocarcinoma patient with a PIK3CA mutation Intrahepatic cholangiocarcinoma (ICC) is a relatively rare form of liver cancer with a poor prognosis.	('liver cancer', 'Phenotype', 'HP:0002896', (171, 183))	('PIK3CA', 'Gene', '5290', (88, 94))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (41, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('liver cancer', 'Disease', (171, 183))	('Intrahepatic cholangiocarcinoma', 'Disease', (104, 135))	('Intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (104, 135))	('intrahepatic cholangiocarcinoma', 'Disease', (41, 72))	('patient', 'Species', '9606', (73, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('PIK3CA', 'Gene', (88, 94))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (117, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('everolimus', 'Chemical', 'MESH:D000068338', (11, 21))	('liver cancer', 'Disease', 'MESH:D006528', (171, 183))	('mutation', 'Var', (95, 103))
90879	28694672	There is currently no approved targeted therapy for ICC, although accumulating evidence supports inhibition of the PI3K/Akt/mTOR signaling pathway as a promising therapeutic strategy in the treatment of ICC.	('inhibition', 'Var', (97, 107))	('mTOR', 'Gene', '2475', (124, 128))	('mTOR', 'Gene', (124, 128))	('Akt', 'Gene', '207', (120, 123))	('ICC', 'Disease', (203, 206))	('Akt', 'Gene', (120, 123))
90880	28694672	Here, we report a patient with stage IV ICC harboring a PIK3CA mutation who responded well to the mTOR inhibitor everolimus.	('mutation', 'Var', (63, 71))	('PIK3CA', 'Gene', (56, 62))	('everolimus', 'Chemical', 'MESH:D000068338', (113, 123))	('mTOR', 'Gene', '2475', (98, 102))	('patient', 'Species', '9606', (18, 25))	('mTOR', 'Gene', (98, 102))
90882	28694672	To the best of our knowledge, this is the first clinical case report in the literature of clinical benefit from everolimus treatment in an ICC patient with PIK3CA mutation.	('everolimus', 'Chemical', 'MESH:D000068338', (112, 122))	('mutation', 'Var', (163, 171))	('PIK3CA', 'Gene', (156, 162))	('patient', 'Species', '9606', (143, 150))
90883	28694672	Core tip: We report a stage IV intrahepatic cholangiocarcinoma (ICC) patient harboring a PIK3CA mutation who responded well to the mTOR inhibitor everolimus.	('IV intrahepatic cholangiocarcinoma', 'Disease', (28, 62))	('PIK3CA', 'Gene', (89, 95))	('mTOR', 'Gene', (131, 135))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (44, 62))	('mTOR', 'Gene', '2475', (131, 135))	('mutation', 'Var', (96, 104))	('everolimus', 'Chemical', 'MESH:D000068338', (146, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('patient', 'Species', '9606', (69, 76))	('responded', 'MPA', (109, 118))	('IV intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (28, 62))
90885	28694672	To the best of our knowledge, this is the first clinical case report in the literature of an ICC patient with PIK3CA mutation deriving benefit from everolimus treatment.	('ICC', 'Disease', (93, 96))	('everolimus', 'Chemical', 'MESH:D000068338', (148, 158))	('patient', 'Species', '9606', (97, 104))	('mutation', 'Var', (117, 125))	('PIK3CA', 'Gene', (110, 116))
90891	28694672	Recently, the use of next-generation sequencing (NGS) technologies has enabled the identification of frequently observed actionable molecular alterations that hold the promise of improving the management of advanced ICC patients.	('man', 'Species', '9606', (193, 196))	('patients', 'Species', '9606', (220, 228))	('improving', 'PosReg', (179, 188))	('alterations', 'Var', (142, 153))
90893	28694672	Mutation in PIK3CA has been reported in 8% of ICC patients according to The Cancer Genome Atlas (TCGA) database, and activating mutations of PIK3CA that are related to tumorigenesis and cancer progression have been identified in a broad spectrum of malignant tumors.	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('PIK3CA', 'Gene', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('mutations', 'Var', (128, 137))	('activating', 'PosReg', (117, 127))	('malignant tumors', 'Disease', 'MESH:D018198', (249, 265))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (76, 95))	('malignant tumors', 'Disease', (249, 265))	('ICC', 'Disease', (46, 49))	('tumor', 'Disease', (168, 173))	('patients', 'Species', '9606', (50, 58))	('Cancer Genome Atlas', 'Disease', (76, 95))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('cancer', 'Disease', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('Mutation', 'Var', (0, 8))	('PIK3CA', 'Gene', (141, 147))	('tumor', 'Disease', (259, 264))	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
90894	28694672	Therefore, inhibition of the mTOR pathway represents a promising therapeutic strategy in the treatment of ICC.	('inhibition', 'Var', (11, 21))	('mTOR', 'Gene', (29, 33))	('ICC', 'Disease', (106, 109))	('mTOR', 'Gene', '2475', (29, 33))
90899	28694672	Here, we report a patient with stage IV ICC harboring a PIK3CA mutation who responded well to the mTOR inhibitor everolimus, demonstrating that inhibition of the PI3K/Akt/mTOR signaling pathway is a promising therapeutic avenue for ICC.	('responded', 'MPA', (76, 85))	('Akt', 'Gene', '207', (167, 170))	('ICC', 'Disease', (232, 235))	('mutation', 'Var', (63, 71))	('PIK3CA', 'Gene', (56, 62))	('everolimus', 'Chemical', 'MESH:D000068338', (113, 123))	('mTOR', 'Gene', '2475', (98, 102))	('patient', 'Species', '9606', (18, 25))	('mTOR', 'Gene', (98, 102))	('mTOR', 'Gene', (171, 175))	('Akt', 'Gene', (167, 170))	('mTOR', 'Gene', '2475', (171, 175))
90914	28694672	We detected all genomic alteration types, including base substitutions, insertions and deletions, copy number alterations, and rearrangements, for more than 390 genes commonly associated with cancers.	('rearrangements', 'Var', (127, 141))	('copy number alterations', 'Var', (98, 121))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('associated', 'Reg', (176, 186))	('insertions', 'Var', (72, 82))	('cancers', 'Disease', (192, 199))	('deletions', 'Var', (87, 96))	('base substitutions', 'Var', (52, 70))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
90919	28694672	In January 2016, the genomic profile of the patient revealed three somatic mutations, including E545G mutation of the PIK3CA gene (NM_006218), R132C mutation of the IDH1 gene (NM_005896) and c.714+1G>T mutation of the PBRM1 gene (NM_018313).	('PBRM1', 'Gene', (218, 223))	('PBRM1', 'Gene', '55193', (218, 223))	('E545G', 'Mutation', 'rs121913274', (96, 101))	('patient', 'Species', '9606', (44, 51))	('c.714+1G>T', 'Var', (191, 201))	('R132C', 'Mutation', 'rs121913499', (143, 148))	('R132C mutation', 'Var', (143, 157))	('c.714+1G>T', 'Mutation', 'c.714+1G>T', (191, 201))	('IDH1', 'Gene', (165, 169))	('PIK3CA', 'Gene', (118, 124))	('IDH1', 'Gene', '3417', (165, 169))	('E545G', 'Var', (96, 101))
90920	28694672	As preclinical data suggest that activating mutations in PIK3CA may predict a sensitivity to inhibitors of the PI3K/AKT/mTOR pathway, the patient received everolimus (10 mg orally daily), provided off-label with insurance approval.	('everolimus', 'Chemical', 'MESH:D000068338', (155, 165))	('sensitivity to inhibitors', 'MPA', (78, 103))	('mTOR', 'Gene', '2475', (120, 124))	('AKT', 'Gene', '207', (116, 119))	('mutations', 'Var', (44, 53))	('patient', 'Species', '9606', (138, 145))	('activating', 'PosReg', (33, 43))	('predict', 'Reg', (68, 75))	('mTOR', 'Gene', (120, 124))	('AKT', 'Gene', (116, 119))	('PIK3CA', 'Gene', (57, 63))
90934	28694672	Genomic profiling of the patient revealed three somatic mutations: E545G mutation of PIK3CA and mutations of IDH1 and PBRM1 genes.	('PBRM1', 'Gene', '55193', (118, 123))	('IDH1', 'Gene', (109, 113))	('E545G', 'Var', (67, 72))	('patient', 'Species', '9606', (25, 32))	('IDH1', 'Gene', '3417', (109, 113))	('E545G', 'Mutation', 'rs121913274', (67, 72))	('PBRM1', 'Gene', (118, 123))	('PIK3CA', 'Gene', (85, 91))
90936	28694672	Codon 545 is a hotspot for PIK3CA mutations that are known to activate the PI3K/Akt/mTOR signaling pathway.	('Akt', 'Gene', '207', (80, 83))	('activate', 'PosReg', (62, 70))	('Akt', 'Gene', (80, 83))	('PIK3CA', 'Gene', (27, 33))	('mTOR', 'Gene', '2475', (84, 88))	('mTOR', 'Gene', (84, 88))	('mutations', 'Var', (34, 43))
90937	28694672	However, the E545K substitution is much more common in cancers than the E545G mutation; E545K represents 25% of all PIK3CA mutations whereas E545G has only been reported in a few carcinomas.	('PIK3CA', 'Gene', (116, 122))	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('carcinomas', 'Disease', (179, 189))	('E545G', 'Mutation', 'rs121913274', (72, 77))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('E545K', 'Mutation', 'rs104886003', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('E545K', 'Var', (13, 18))	('E545G', 'Mutation', 'rs121913274', (141, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinomas', 'Disease', 'MESH:D002277', (179, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (179, 189))	('E545K', 'Mutation', 'rs104886003', (88, 93))	('mutations', 'Var', (123, 132))	('cancers', 'Disease', (55, 62))	('E545K', 'Var', (88, 93))
90938	28694672	In vitro research studies comparing the activity of mutant PIK3CA proteins have shown that the E545G substitution displays strong transforming activity in chicken embryo fibroblasts, although its effect is lower than that of the more common E542K and E545K substitutions.	('E545K', 'Mutation', 'rs104886003', (251, 256))	('E542K', 'Mutation', 'rs121913273', (241, 246))	('chicken', 'Species', '9031', (155, 162))	('E545K', 'Var', (251, 256))	('PIK3CA', 'Gene', (59, 65))	('E545G', 'Var', (95, 100))	('transforming activity', 'CPA', (130, 151))	('E545G', 'Mutation', 'rs121913274', (95, 100))
90940	28694672	Mutations in IDH1 and IDH2 are confined to the active site and result in the production of a neomorphic metabolite 2-hydroxyglutarate (2HG), which is normally found in scarce amounts, through NADPH-dependent reduction of 2-OG to the R enantiomer of 2HG.	('IDH2', 'Gene', '3418', (22, 26))	('production', 'MPA', (77, 87))	('NADPH', 'Chemical', 'MESH:D009249', (192, 197))	('2-OG', 'MPA', (221, 225))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (115, 133))	('reduction', 'NegReg', (208, 217))	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('2-OG', 'Chemical', '-', (221, 225))	('IDH1', 'Gene', '3417', (13, 17))	('result in', 'Reg', (63, 72))
90941	28694672	Frequent somatic hotspot mutations in IDH1 have been identified in gliomas, chondrosarcomas, myeloid leukemias, and other cancers.	('chondrosarcomas', 'Phenotype', 'HP:0006765', (76, 91))	('hotspot', 'PosReg', (17, 24))	('gliomas', 'Disease', (67, 74))	('chondrosarcomas', 'Disease', 'MESH:D002813', (76, 91))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancers', 'Disease', (122, 129))	('leukemias', 'Phenotype', 'HP:0001909', (101, 110))	('mutations', 'Var', (25, 34))	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('IDH1', 'Gene', (38, 42))	('chondrosarcomas', 'Disease', (76, 91))	('myeloid leukemias', 'Disease', (93, 110))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('myeloid leukemias', 'Disease', 'MESH:D007951', (93, 110))	('identified', 'Reg', (53, 63))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (93, 110))	('IDH1', 'Gene', '3417', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
90942	28694672	Suppression of endogenous mutant IDH1 expression was recently reported in HT180, a fibrosarcoma cell line with a native IDH1 R132C heterozygous mutation.	('fibrosarcoma', 'Phenotype', 'HP:0100244', (83, 95))	('fibrosarcoma', 'Disease', 'MESH:D005354', (83, 95))	('HT180', 'CellLine', 'CVCL:6261', (74, 79))	('expression', 'MPA', (38, 48))	('IDH1', 'Gene', (33, 37))	('R132C', 'Var', (125, 130))	('R132C', 'Mutation', 'rs121913499', (125, 130))	('IDH1', 'Gene', (120, 124))	('IDH1', 'Gene', '3417', (33, 37))	('fibrosarcoma', 'Disease', (83, 95))	('Suppression', 'NegReg', (0, 11))	('IDH1', 'Gene', '3417', (120, 124))	('endogenous', 'Var', (15, 25))
90946	28694672	The effect of everolimus is clearly proven in many cancers, especially those with PIK3CA mutations.	('everolimus', 'Chemical', 'MESH:D000068338', (14, 24))	('PIK3CA', 'Gene', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('man', 'Species', '9606', (46, 49))	('mutations', 'Var', (89, 98))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
90947	28694672	Phase III clinical trials suggested that patients with HER2-positive advanced breast cancer with PIK3CA mutations could derive a PFS benefit from everolimus.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('mutations', 'Var', (104, 113))	('HER2', 'Gene', '2064', (55, 59))	('everolimus', 'Chemical', 'MESH:D000068338', (146, 156))	('patients', 'Species', '9606', (41, 49))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('HER2', 'Gene', (55, 59))	('PIK3CA', 'Gene', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
90948	28694672	Recent research demonstrated that mTOR pathway activating mutations confer sensitivity to everolimus regardless of cancer type.	('mTOR', 'Gene', '2475', (34, 38))	('mutations', 'Var', (58, 67))	('cancer', 'Disease', (115, 121))	('everolimus', 'Chemical', 'MESH:D000068338', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('sensitivity', 'MPA', (75, 86))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('activating', 'PosReg', (47, 57))	('mTOR', 'Gene', (34, 38))
90961	28694672	To the best of our knowledge, this is the first clinical case report in the literature of benefit from everolimus treatment in an ICC patient with a PIK3CA mutation.	('PIK3CA', 'Gene', (149, 155))	('everolimus', 'Chemical', 'MESH:D000068338', (103, 113))	('patient', 'Species', '9606', (134, 141))	('mutation', 'Var', (156, 164))
90963	28694672	To our knowledge, this case represents the first report of an ICC patient with a PIK3CA mutation who derived benefit from everolimus treatment.	('mutation', 'Var', (88, 96))	('PIK3CA', 'Gene', (81, 87))	('patient', 'Species', '9606', (66, 73))	('everolimus', 'Chemical', 'MESH:D000068338', (122, 132))	('benefit', 'PosReg', (109, 116))
90964	28694672	However, whether the presence of mutation of IDH1 and PBRM1 contributed to the patient's response to targeted therapy is unclear, and the reason for the patient's response to everolimus and prolonged survival has yet to be elucidated.	('IDH1', 'Gene', '3417', (45, 49))	('PBRM1', 'Gene', (54, 59))	('mutation', 'Var', (33, 41))	('PBRM1', 'Gene', '55193', (54, 59))	('response', 'MPA', (89, 97))	('patient', 'Species', '9606', (79, 86))	('contributed', 'Reg', (60, 71))	('patient', 'Species', '9606', (153, 160))	('everolimus', 'Chemical', 'MESH:D000068338', (175, 185))	('IDH1', 'Gene', (45, 49))
90968	28694672	The genomic profile of the patient revealed three somatic mutations, including E545G mutation of the PIK3CA gene, R132C mutation of the IDH1 gene and c.714+1G>T mutation of the PBRM1 gene.	('R132C mutation', 'Var', (114, 128))	('PBRM1', 'Gene', (177, 182))	('PBRM1', 'Gene', '55193', (177, 182))	('patient', 'Species', '9606', (27, 34))	('IDH1', 'Gene', (136, 140))	('c.714+1G>T', 'Var', (150, 160))	('c.714+1G>T', 'Mutation', 'c.714+1G>T', (150, 160))	('IDH1', 'Gene', '3417', (136, 140))	('E545G', 'Var', (79, 84))	('R132C', 'Mutation', 'rs121913499', (114, 119))	('E545G', 'Mutation', 'rs121913274', (79, 84))	('PIK3CA', 'Gene', (101, 107))
90971	28694672	To the best of our knowledge, this is the first clinical case report in the literature of an ICC patient with a PIK3CA mutation deriving benefit from everolimus treatment.	('mutation', 'Var', (119, 127))	('ICC', 'Disease', (93, 96))	('patient', 'Species', '9606', (97, 104))	('everolimus', 'Chemical', 'MESH:D000068338', (150, 160))	('PIK3CA', 'Gene', (112, 118))
90972	28694672	Results observed in this case encourage further research on the activity of everolimus in ICC, based on the presence of PIK3CA mutation.	('mutation', 'Var', (127, 135))	('PIK3CA', 'Gene', (120, 126))	('ICC', 'Disease', (90, 93))	('everolimus', 'Chemical', 'MESH:D000068338', (76, 86))
90974	28694672	In this study, the authors report a stage IV ICC patient harboring a PIK3CA mutation who responded well to the mTOR inhibitor everolimus.	('mTOR', 'Gene', '2475', (111, 115))	('mTOR', 'Gene', (111, 115))	('patient', 'Species', '9606', (49, 56))	('everolimus', 'Chemical', 'MESH:D000068338', (126, 136))	('PIK3CA', 'Gene', (69, 75))	('mutation', 'Var', (76, 84))
91141	26028817	An aberrant change in EGFR might be one of the critical events in carcinogenesis, may occur as a result of receptor gene amplification and/or transcription-mediated protein overexpression, or may occur as a result of mutational activation.	('mutational', 'Var', (217, 227))	('overexpression', 'PosReg', (173, 187))	('occur', 'Reg', (86, 91))	('carcinogenesis', 'Disease', 'MESH:D063646', (66, 80))	('carcinogenesis', 'Disease', (66, 80))	('change', 'Reg', (12, 18))	('EGFR', 'Gene', (22, 26))
91143	26028817	ICC in conjunction with chronic advanced liver disease showed a higher EGFR mutation rate.	('liver disease', 'Disease', 'MESH:D008107', (41, 54))	('higher', 'PosReg', (64, 70))	('rat', 'Species', '10116', (85, 88))	('CC', 'Phenotype', 'HP:0030153', (1, 3))	('ICC', 'Disease', (0, 3))	('liver disease', 'Phenotype', 'HP:0001392', (41, 54))	('mutation', 'Var', (76, 84))	('EGFR', 'Gene', (71, 75))	('liver disease', 'Disease', (41, 54))
91147	26028817	Accumulating evidence has demonstrated that aberrant activity of STAT3 is implicated in carcinogenesis in several cancer types, .	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('carcinogenesis', 'Disease', (88, 102))	('aberrant activity', 'Var', (44, 61))	('rat', 'Species', '10116', (33, 36))	('implicated', 'Reg', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('STAT3', 'Gene', (65, 70))	('carcinogenesis', 'Disease', 'MESH:D063646', (88, 102))	('cancer', 'Disease', (114, 120))
91155	26028817	In a chemically induced mouse model of oral squamous cell carcinoma, inhibition of EGFR-STAT3 signaling with erlotinib can prevent carcinogenesis.	('carcinogenesis', 'Disease', (131, 145))	('mouse', 'Species', '10090', (24, 29))	('oral squamous cell carcinoma', 'Disease', (39, 67))	('prevent', 'NegReg', (123, 130))	('EGFR-STAT3', 'MPA', (83, 93))	('erlotinib', 'Chemical', 'MESH:D000069347', (109, 118))	('carcinogenesis', 'Disease', 'MESH:D063646', (131, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('inhibition', 'Var', (69, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (39, 67))
91161	26028817	In our ICC model, ICC arose after CF within several weeks after withdrawal of 3'Me-DAB.	('CC', 'Phenotype', 'HP:0030153', (8, 10))	("3'Me-DAB", 'Chemical', 'MESH:D008749', (78, 86))	('CC', 'Phenotype', 'HP:0030153', (19, 21))	("3'Me-DAB", 'Var', (78, 86))	('ICC', 'Disease', (18, 21))
91164	26028817	Werneburg et al had reported that bile acids can stimulate the production of TGFalpha and activate the EGFR signaling pathway, and that this EGFR activation promotes the activation of downstream molecules including PI3-K, MAPK or STAT3, resulting in alterations in the cell cycle, cell growth, and cell survival, .	('cell survival', 'CPA', (298, 311))	('MAPK', 'Gene', (222, 226))	('activation', 'PosReg', (170, 180))	('TGFalpha', 'Gene', (77, 85))	('promotes', 'PosReg', (157, 165))	('EGFR signaling pathway', 'Pathway', (103, 125))	('alterations', 'Reg', (250, 261))	('bile acids', 'Chemical', 'MESH:D001647', (34, 44))	('PI3-K', 'Var', (215, 220))	('stimulate', 'PosReg', (49, 58))	('cell cycle', 'CPA', (269, 279))	('activate', 'PosReg', (90, 98))	('STAT3', 'Gene', (230, 235))	('production', 'MPA', (63, 73))	('cell growth', 'CPA', (281, 292))	('rat', 'Species', '10116', (254, 257))	('TGFalpha', 'Gene', '24827', (77, 85))
91182	25610676	A 26-year-old G4P2A2 Caucasian woman consulted our emergency department after being diagnosed with a uterine malignancy in Turkey after curettage for menorrhagia.	('malignancy', 'Disease', (109, 119))	('menorrhagia', 'Disease', (150, 161))	('menorrhagia', 'Phenotype', 'HP:0000132', (150, 161))	('G4P2A2', 'Var', (14, 20))	('menorrhagia', 'Disease', 'MESH:D008595', (150, 161))	('malignancy', 'Disease', 'MESH:D009369', (109, 119))	('uterine malignancy', 'Phenotype', 'HP:0010784', (101, 119))	('woman', 'Species', '9606', (31, 36))	('Turkey', 'Species', '9103', (123, 129))
91250	24748170	Aberrant activation of the Hedgehog pathway has been described for different cancer types.	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('Hedgehog pathway', 'Pathway', (27, 43))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
91336	24748170	It is reported that targeted inhibition of Hedgehog signaling is effective against cancer growth.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('targeted inhibition', 'Var', (20, 39))	('Hedgehog', 'Protein', (43, 51))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
91478	33451059	Only fibroblast growth factor receptor 2 (FGFR2) fusion and isocitrate dehydrogenase (IDH)- and BRAF mutation-enriched populations have survival benefits from the corresponding inhibitors.	('FGFR2', 'Gene', (42, 47))	('survival benefits', 'CPA', (136, 153))	('IDH', 'Gene', (86, 89))	('FGFR2', 'Gene', '2263', (42, 47))	('fibroblast growth factor receptor 2', 'Gene', '2263', (5, 40))	('mutation-enriched', 'Var', (101, 118))	('isocitrate dehydrogenase', 'Gene', (60, 84))	('IDH', 'Gene', '3417', (86, 89))	('isocitrate dehydrogenase', 'Gene', '3417', (60, 84))	('BRAF', 'Gene', (96, 100))	('fibroblast growth factor receptor 2', 'Gene', (5, 40))
91489	33451059	Second, a randomized phase III JCOG 1113 study showed the non-inferiority of gemcitabine and S-1 (GS) to GC with a numerical median OS (15.1 months vs. 13.4 months), which met pre-planned statistical design.	('S-1', 'Var', (93, 96))	('met', 'Gene', (172, 175))	('GC', 'Chemical', '-', (105, 107))	('gemcitabine', 'Chemical', 'MESH:C056507', (77, 88))	('met', 'Gene', '79811', (172, 175))
91500	33451059	The recent whole-exome and targeted sequencing of BTC not only confirmed the frequent mutations in well-known genes including TP53, KRAS and IDH1/2 but also revealed mutations in novel chromatin remodelling-associated genes, such as BAP1, ARID1A and PBRM1.	('mutations', 'Var', (86, 95))	('ARID1A', 'Gene', '8289', (239, 245))	('PBRM1', 'Gene', (250, 255))	('ARID1A', 'Gene', (239, 245))	('mutations', 'Var', (166, 175))	('TP53', 'Gene', (126, 130))	('KRAS', 'Gene', (132, 136))	('BAP1', 'Gene', (233, 237))	('KRAS', 'Gene', '3845', (132, 136))	('IDH1/2', 'Gene', '3417;3418', (141, 147))	('PBRM1', 'Gene', '55193', (250, 255))	('BTC', 'Phenotype', 'HP:0100574', (50, 53))	('IDH1/2', 'Gene', (141, 147))	('TP53', 'Gene', '7157', (126, 130))	('BAP1', 'Gene', '8314', (233, 237))
91501	33451059	In addition, these studies have also identified new, recurrent driver genetic alternations in cholangiocarcinoma, such as FGFR2 fusion and IDH1 mutations that are potentially actionable with available pan-FGFR inhibitors and IDH1 inhibitors.	('FGF', 'Gene', (205, 208))	('IDH1', 'Gene', (225, 229))	('IDH1', 'Gene', (139, 143))	('FGF', 'Gene', '8074', (205, 208))	('cholangiocarcinoma', 'Disease', (94, 112))	('FGF', 'Gene', (122, 125))	('IDH1', 'Gene', '3417', (225, 229))	('IDH1', 'Gene', '3417', (139, 143))	('FGFR2', 'Gene', '2263', (122, 127))	('fusion', 'Var', (128, 134))	('FGFR2', 'Gene', (122, 127))	('FGF', 'Gene', '8074', (122, 125))	('mutations', 'Var', (144, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (94, 112))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (94, 112))	('nab', 'Chemical', '-', (180, 183))
91502	33451059	Notably, there are significant differences in the frequency of mutated genes in IHCC, with or without liver fluke (Opisthorchis viverrini, Ov), or hepatitis B virus infections, reflecting the impact of the causal agents on cholangiocarcinogenesis.	('mutated', 'Var', (63, 70))	('cholangiocarcinogenesis', 'Disease', (223, 246))	('hepatitis B virus infections', 'Phenotype', 'HP:0410369', (147, 175))	('hepatitis', 'Phenotype', 'HP:0012115', (147, 156))	('liver fluke', 'Species', '6192', (102, 113))	('hepatitis B virus infections', 'Disease', 'MESH:D006509', (147, 175))	('Opisthorchis viverrini', 'Species', '6198', (115, 137))	('cholangiocarcinogenesis', 'Disease', 'None', (223, 246))	('IHCC', 'Disease', (80, 84))	('liver fluke', 'Disease', (102, 113))	('hepatitis B virus infections', 'Disease', (147, 175))
91503	33451059	Compared to Ov-related CCAs, mutations in BAP1, IDH1 and IDH2 were more frequently observed in non-Ov-related CCAs.	('BAP1', 'Gene', '8314', (42, 46))	('IDH1', 'Gene', '3417', (48, 52))	('IDH2', 'Gene', (57, 61))	('mutations', 'Var', (29, 38))	('BAP1', 'Gene', (42, 46))	('non-Ov-related', 'Disease', (95, 109))	('IDH2', 'Gene', '3418', (57, 61))	('IDH1', 'Gene', (48, 52))	('observed', 'Reg', (83, 91))
91512	33451059	Patients receiving FOLFOX presented a statistical but modest improvement of median OS compared to those with ASC (6.2 vs. 5.3 months; HR 0.69, p = 0.031).	('median OS', 'MPA', (76, 85))	('ASC', 'Chemical', '-', (109, 112))	('FOLFOX', 'Var', (19, 25))	('Patients', 'Species', '9606', (0, 8))	('FOLFOX', 'Chemical', '-', (19, 25))
91513	33451059	Grade III/IV treatment-related toxicities were more frequent in the FOFLOX arm than those in the ASC arm (59% vs. 39%), including fatigue, neutropenia and infection.	('fatigue', 'Phenotype', 'HP:0012378', (130, 137))	('toxicities', 'Disease', (31, 41))	('neutropenia', 'Disease', (139, 150))	('FOFLOX', 'Var', (68, 74))	('infection', 'Disease', (155, 164))	('infection', 'Disease', 'MESH:D007239', (155, 164))	('fatigue', 'Disease', 'MESH:D005221', (130, 137))	('FOFLOX', 'Chemical', '-', (68, 74))	('fatigue', 'Disease', (130, 137))	('toxicities', 'Disease', 'MESH:D064420', (31, 41))	('neutropenia', 'Disease', 'MESH:D009503', (139, 150))	('ASC', 'Chemical', '-', (97, 100))	('neutropenia', 'Phenotype', 'HP:0001875', (139, 150))
91528	33451059	The common genetic mutations vary between IHCC, EHCC and GBC, with IDH mutation and FGFR rearrangement in IHCC and HER2 aberrations in EHCC and GBC.	('HER2', 'Gene', (115, 119))	('rearrangement', 'Var', (89, 102))	('FGF', 'Gene', (84, 87))	('mutation', 'Var', (71, 79))	('HER2', 'Gene', '2064', (115, 119))	('EHCC', 'Disease', (135, 139))	('FGF', 'Gene', '8074', (84, 87))	('IDH', 'Gene', (67, 70))	('IDH', 'Gene', '3417', (67, 70))	('aberrations', 'Var', (120, 131))
91530	33451059	In IHCC, the aberrant activation of the FGFR signaling pathway leading to tumor cell migration stands for approximately 15 to 20% of patients, with the most common genetic alternation being FGFR2 fusion.	('FGF', 'Gene', (190, 193))	('FGF', 'Gene', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('patients', 'Species', '9606', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('activation', 'PosReg', (22, 32))	('IHCC', 'Disease', (3, 7))	('FGFR2', 'Gene', (190, 195))	('fusion', 'Var', (196, 202))	('FGF', 'Gene', '8074', (190, 193))	('FGF', 'Gene', '8074', (40, 43))	('FGFR2', 'Gene', '2263', (190, 195))	('tumor', 'Disease', (74, 79))
91531	33451059	Notably, the IHCC patients with FGFR2 fusions have been frequently associated with several clinical features, such as female, younger age, early stage and better survival.	('IHCC', 'Disease', (13, 17))	('FGFR2', 'Gene', (32, 37))	('associated', 'Reg', (67, 77))	('FGFR2', 'Gene', '2263', (32, 37))	('patients', 'Species', '9606', (18, 26))	('fusions', 'Var', (38, 45))
91532	33451059	Co-existing TP53 mutation and CDKN2A/B loss were correlated with a shorter median OS.	('CDKN2A/B', 'Gene', (30, 38))	('mutation', 'Var', (17, 25))	('TP53', 'Gene', '7157', (12, 16))	('loss', 'NegReg', (39, 43))	('CDKN2A/B', 'Gene', '1029;1030', (30, 38))	('TP53', 'Gene', (12, 16))
91533	33451059	Recently, multiple pan-FGFR tyrosine kinase inhibitors (TKIs), such as pemigatinib (INCB054828), infigratinib (BGJ398), futibatinib (TAS-120), derazantinib (ARQ087), erdafitinib (JNJ-42756493) and rogoratinib (BAY1163877), have been applied for gemcitabine-refractory IHCC with FGFR genetic alternations.	('pemigatinib', 'Chemical', '-', (71, 82))	('gemcitabine', 'Chemical', 'MESH:C056507', (245, 256))	('rogoratinib', 'Chemical', '-', (197, 208))	('FGF', 'Gene', (23, 26))	('BGJ398', 'Chemical', 'MESH:C568950', (111, 117))	('TAS-120', 'Chemical', '-', (133, 140))	('genetic alternations', 'Var', (283, 303))	('FGF', 'Gene', '8074', (23, 26))	('infigratinib', 'Chemical', 'MESH:C568950', (97, 109))	('futibatinib', 'Chemical', '-', (120, 131))	('FGF', 'Gene', (278, 281))	('derazantinib', 'Chemical', 'MESH:C000621805', (143, 155))	('erdafitinib', 'Chemical', 'MESH:C000604580', (166, 177))	('ARQ087', 'Chemical', 'MESH:C000621805', (157, 163))	('gemcitabine-refractory IHCC', 'Disease', (245, 272))	('FGF', 'Gene', '8074', (278, 281))
91537	33451059	Patients with FGFR2 fusions or translocations had more benefit with a higher ORR (18.8-35.5%) under the treatment of FGFR inhibitors, compared to those with FGFR2 mutation/amplification or other FGF/FGFR alternations.	('FGFR2', 'Gene', '2263', (14, 19))	('FGF', 'Gene', (199, 202))	('higher', 'PosReg', (70, 76))	('FGF', 'Gene', '8074', (199, 202))	('FGF', 'Gene', (157, 160))	('Patients', 'Species', '9606', (0, 8))	('FGF', 'Gene', '8074', (157, 160))	('FGF', 'Gene', (117, 120))	('FGF', 'Gene', (14, 17))	('fusions', 'Var', (20, 27))	('translocations', 'Var', (31, 45))	('FGF', 'Gene', '8074', (117, 120))	('FGF', 'Gene', '8074', (14, 17))	('benefit', 'PosReg', (55, 62))	('FGF', 'Gene', (195, 198))	('FGFR2', 'Gene', (157, 162))	('FGF', 'Gene', '8074', (195, 198))	('ORR', 'MPA', (77, 80))	('FGFR2', 'Gene', (14, 19))	('inhibitors', 'Var', (122, 132))	('FGFR2', 'Gene', '2263', (157, 162))
91538	33451059	In a FIGHT-202 study, patients had treatment-refractory advanced or metastatic cholangiocarcinoma harboring FGFR2 gene fusion or rearrangement and took oral pemigatinib.	('rearrangement', 'Var', (129, 142))	('met', 'Gene', (68, 71))	('cholangiocarcinoma', 'Disease', (79, 97))	('FGFR2', 'Gene', (108, 113))	('patients', 'Species', '9606', (22, 30))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (79, 97))	('FGFR2', 'Gene', '2263', (108, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('gene fusion', 'Var', (114, 125))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (79, 97))	('pemigatinib', 'Chemical', '-', (157, 168))	('met', 'Gene', '79811', (68, 71))
91542	33451059	Based on the promising result, the Food and Drug Administration (FDA) granted accelerated approval to pemigatinib (PEMAZYRE, Incyte Corporation, Wilmington, DE, USA) for the treatment of patients with previously treated cholangiocarcinoma with FGFR2 fusion or other rearrangements in April 2020.	('patients', 'Species', '9606', (187, 195))	('FGFR2', 'Gene', (244, 249))	('FGFR2', 'Gene', '2263', (244, 249))	('cholangiocarcinoma', 'Disease', (220, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('pemigatinib', 'Chemical', '-', (102, 113))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (220, 238))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (220, 238))	('fusion', 'Var', (250, 256))
91544	33451059	The other selective-FGFR inhibitor, BGJ398, showed meaningful efficacy in IHCC patients with FGFR alternations who failed under previous chemotherapy, with 14.8% ORR (18.8% in FGFR2 fusion group, n = 48), 75% DCR and a median PFS 5.8 months among 61 patients.	('FGF', 'Gene', '8074', (93, 96))	('IHCC', 'Disease', (74, 78))	('FGFR2', 'Gene', (176, 181))	('FGF', 'Gene', '8074', (176, 179))	('FGFR2', 'Gene', '2263', (176, 181))	('patients', 'Species', '9606', (250, 258))	('alternations', 'Var', (98, 110))	('FGF', 'Gene', (20, 23))	('ORR', 'MPA', (162, 165))	('BGJ398', 'Chemical', 'MESH:C568950', (36, 42))	('patients', 'Species', '9606', (79, 87))	('FGF', 'Gene', (93, 96))	('FGF', 'Gene', '8074', (20, 23))	('BGJ398', 'Gene', (36, 42))	('FGF', 'Gene', (176, 179))
91547	33451059	Derazantinib (ARQ087), a multi-kinase inhibitor with potent activity against FGFR1-3 kinases and an additional inhibition to RET, platelet-derived growth factor receptors (PDGFR), KIT and SRC, was tested in treatment-refractory IHCC patients with FGFR2 fusions in a phase I/II trial.	('platelet-derived growth factor receptors', 'Gene', (130, 170))	('ARQ087', 'Chemical', 'MESH:C000621805', (14, 20))	('fusions', 'Var', (253, 260))	('KIT', 'Gene', (180, 183))	('IHCC', 'Disease', (228, 232))	('FGFR1-3', 'Gene', '2260;2263;2261', (77, 84))	('SRC', 'Gene', '6714', (188, 191))	('platelet-derived growth factor receptors', 'Gene', '5159', (130, 170))	('FGFR2', 'Gene', (247, 252))	('KIT', 'Gene', '3815', (180, 183))	('FGFR1-3', 'Gene', (77, 84))	('RET', 'Gene', '5979', (125, 128))	('SRC', 'Gene', (188, 191))	('patients', 'Species', '9606', (233, 241))	('PDGFR', 'Gene', (172, 177))	('PDGFR', 'Gene', '5159', (172, 177))	('Derazantinib', 'Chemical', 'MESH:C000621805', (0, 12))	('FGFR2', 'Gene', '2263', (247, 252))	('RET', 'Gene', (125, 128))
91551	33451059	In the dose-escalation phase I TAS120 study (16, 20 and 24 mg QD continuously), 45 IHCC patients harboring FGF/FGFR aberrations who received prior systemic therapies were enrolled.	('FGF', 'Gene', '8074', (107, 110))	('FGF', 'Gene', '8074', (111, 114))	('patients', 'Species', '9606', (88, 96))	('TAS', 'Chemical', 'MESH:D013635', (31, 34))	('aberrations', 'Var', (116, 127))	('FGF', 'Gene', (107, 110))	('FGF', 'Gene', (111, 114))
91552	33451059	Of the 28 patients with FGFR2 gene fusions, the ORR and DCR were 25% and 79%, respectively.	('FGFR2', 'Gene', '2263', (24, 29))	('DCR', 'Disease', (56, 59))	('ORR', 'Disease', (48, 51))	('patients', 'Species', '9606', (10, 18))	('FGFR2', 'Gene', (24, 29))	('gene fusions', 'Var', (30, 42))
91554	33451059	Further trials are currently ongoing in patients with advanced solid tumors harboring FGF/FGFR aberrations, including cholangiocarcinoma (NCT02052778).	('FGF', 'Gene', '8074', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('FGF', 'Gene', '8074', (90, 93))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (118, 136))	('patients', 'Species', '9606', (40, 48))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('cholangiocarcinoma', 'Disease', (118, 136))	('tumors', 'Disease', (69, 75))	('aberrations', 'Var', (95, 106))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('FGF', 'Gene', (86, 89))	('FGF', 'Gene', (90, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (118, 136))
91555	33451059	There are still many ongoing phase I and II trials on FGFR inhibitors in pretreated FGFR-fusion IHCC, such as E7090 (NCT04238715), CPL304110 (NCT04149691), EOC317 (NCT03583125) and INCB062079 (NCT03144661).	('EOC317', 'Chemical', '-', (156, 162))	('FGF', 'Gene', (84, 87))	('FGF', 'Gene', (54, 57))	('E7090 (NCT04238715', 'Var', (110, 128))	('CPL304110 (NCT04149691', 'Var', (131, 153))	('EOC317 (NCT03583125', 'Var', (156, 175))	('NCT04238715', 'Var', (117, 128))	('E7090', 'Chemical', '-', (110, 115))	('FGF', 'Gene', '8074', (84, 87))	('FGF', 'Gene', '8074', (54, 57))	('NCT03583125', 'Var', (164, 175))	('NCT04149691', 'Var', (142, 153))
91556	33451059	Despite the evidence of the therapeutic efficacy of FGFR inhibitors, almost all patients eventually developed acquired resistance.	('acquired resistance', 'MPA', (110, 129))	('inhibitors', 'Var', (57, 67))	('patients', 'Species', '9606', (80, 88))	('FGF', 'Gene', '8074', (52, 55))	('developed', 'Reg', (100, 109))	('FGF', 'Gene', (52, 55))
91558	33451059	Hyperphosphatemia is an on-target AE related to inhibition of FGF23, which regulates the renal excretion of phosphorus and bone absorption.	('Hyperphosphatemia', 'Disease', (0, 17))	('regulates', 'Reg', (75, 84))	('FGF23', 'Gene', '8074', (62, 67))	('renal excretion of phosphorus', 'Disease', 'MESH:D010760', (89, 118))	('inhibition', 'Var', (48, 58))	('Hyperphosphatemia', 'Phenotype', 'HP:0002905', (0, 17))	('renal excretion of phosphorus', 'Disease', (89, 118))	('Hyperphosphatemia', 'Disease', 'MESH:D054559', (0, 17))	('FGF23', 'Gene', (62, 67))
91562	33451059	IDH1/2 mutations are primarily reported in 19-36% of IHCC.	('IHCC', 'Disease', (53, 57))	('reported', 'Reg', (31, 39))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('IDH1/2', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
91563	33451059	However, the prognostic implication of IDH1 mutation remained no conclusion.	('IDH1', 'Gene', '3417', (39, 43))	('IDH1', 'Gene', (39, 43))	('mutation', 'Var', (44, 52))
91564	33451059	Ivosidenib is an IDH1 inhibitor approved in the USA for patients with mutant IDH1 (mIDH1) acute myeloid leukaemia.	('myeloid leukaemia', 'Disease', 'MESH:C580075', (96, 113))	('patients', 'Species', '9606', (56, 64))	('mIDH1', 'Gene', '15926', (83, 88))	('mutant', 'Var', (70, 76))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (90, 113))	('IDH1', 'Gene', (84, 88))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))	('mIDH1', 'Gene', (83, 88))	('IDH1', 'Gene', (77, 81))	('myeloid leukaemia', 'Disease', (96, 113))	('IDH1', 'Gene', (17, 21))	('IDH1', 'Gene', '3417', (84, 88))	('IDH1', 'Gene', '3417', (77, 81))	('IDH1', 'Gene', '3417', (17, 21))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (96, 113))
91565	33451059	The ClarIDHy trial was a randomized, double-blinded, placebo-controlled phase III study designed to evaluate the efficacy of ivosidenib (500 mg once daily) in previously pre-treated IHCC patients harboring IDH1 mutations.	('patients', 'Species', '9606', (187, 195))	('IDH', 'Gene', (206, 209))	('harboring', 'Reg', (196, 205))	('IDH', 'Gene', (8, 11))	('IDH', 'Gene', '3417', (206, 209))	('mutations', 'Var', (211, 220))	('IDH', 'Gene', '3417', (8, 11))	('IHCC', 'Disease', (182, 186))	('ivosidenib', 'Chemical', 'MESH:C000627630', (125, 135))	('IDH1', 'Gene', (206, 210))	('IDH1', 'Gene', '3417', (206, 210))
91566	33451059	Patients receiving ivosidenib had a longer PFS (2.7 vs. 1.4 months, HR 0.37, p < 0.0001) and a comparable OS (10.8 vs. 9.7 months) to those who received the placebo, with 57% of placebo group crossover to ivosidenib when progression.	('ivosidenib', 'Var', (19, 29))	('Patients', 'Species', '9606', (0, 8))	('ivosidenib', 'Chemical', 'MESH:C000627630', (205, 215))	('ivosidenib', 'Chemical', 'MESH:C000627630', (19, 29))	('PFS', 'MPA', (43, 46))
91569	33451059	There are several clinical trials ongoing to test the efficacy and safety of other IDH inhibitors, such as BYA143602, IDH305, FT21012 and AG-881 (NCT02481154, NCT02746081, NCT02381886 and NCT03684811).	('AG-881', 'Chemical', '-', (138, 144))	('IDH305', 'Chemical', '-', (118, 124))	('BYA143602', 'Chemical', '-', (107, 116))	('IDH', 'Gene', (83, 86))	('IDH', 'Gene', (118, 121))	('IDH', 'Gene', '3417', (83, 86))	('IDH', 'Gene', '3417', (118, 121))	('NCT02746081', 'Var', (159, 170))	('NCT02381886', 'Var', (172, 183))	('NCT02481154', 'Var', (146, 157))	('FT21012', 'Chemical', '-', (126, 133))	('NCT03684811', 'Var', (188, 199))
91571	33451059	In 28% to 64% of patients with BTCs, the DDR gene alterations have been identified, including but not limited to, mutations in BRCA1, BRCA2, ATM, ATR, BAP1, BARD1, BRIP1, CHEK2, FAM175A, GEN1, MLH1, MSH2, MSH6, MRE11A, RAD50, RAD51, RAD51C, RAD51D, NBN, PALB2, PMS2, FANCA, FANCD2 and XRCC2.	('RAD51', 'Gene', (233, 238))	('ATM', 'Gene', '472', (141, 144))	('RAD51', 'Gene', '5888', (233, 238))	('MSH6', 'Gene', (205, 209))	('RAD51', 'Gene', (241, 246))	('mutations', 'Var', (114, 123))	('RAD50', 'Gene', '10111', (219, 224))	('RAD51D', 'Gene', '5892', (241, 247))	('MSH2', 'Gene', (199, 203))	('RAD51', 'Gene', '5888', (241, 246))	('PMS2', 'Gene', (261, 265))	('PALB2', 'Gene', '79728', (254, 259))	('CHEK2', 'Gene', '11200', (171, 176))	('MSH6', 'Gene', '2956', (205, 209))	('FANCD2', 'Gene', (274, 280))	('FAM175A', 'Gene', '84142', (178, 185))	('MRE11A', 'Gene', '4361', (211, 217))	('ATR', 'Gene', '545', (146, 149))	('BARD1', 'Gene', '580', (157, 162))	('BAP1', 'Gene', (151, 155))	('FAM175A', 'Gene', (178, 185))	('GEN1', 'Gene', (187, 191))	('MSH2', 'Gene', '4436', (199, 203))	('BRCA2', 'Gene', (134, 139))	('BARD1', 'Gene', (157, 162))	('FANCD2', 'Gene', '2177', (274, 280))	('XRCC2', 'Gene', (285, 290))	('ATM', 'Gene', (141, 144))	('BAP1', 'Gene', '8314', (151, 155))	('MLH1', 'Gene', (193, 197))	('FANCA', 'Gene', '2175', (267, 272))	('GEN1', 'Gene', '348654', (187, 191))	('BRIP1', 'Gene', '83990', (164, 169))	('RAD51D', 'Gene', (241, 247))	('MRE11A', 'Gene', (211, 217))	('NBN', 'Gene', '4683', (249, 252))	('PMS2', 'Gene', '5395', (261, 265))	('patients', 'Species', '9606', (17, 25))	('BTC', 'Phenotype', 'HP:0100574', (31, 34))	('BRCA2', 'Gene', '675', (134, 139))	('MLH1', 'Gene', '4292', (193, 197))	('DDR gene', 'Gene', (41, 49))	('RAD51', 'Gene', (226, 231))	('ATR', 'Gene', (146, 149))	('RAD51C', 'Gene', '5889', (233, 239))	('RAD51', 'Gene', '5888', (226, 231))	('BRCA1', 'Gene', '672', (127, 132))	('RAD50', 'Gene', (219, 224))	('FANCA', 'Gene', (267, 272))	('BRCA1', 'Gene', (127, 132))	('PALB2', 'Gene', (254, 259))	('XRCC2', 'Gene', '7516', (285, 290))	('NBN', 'Gene', (249, 252))	('BRIP1', 'Gene', (164, 169))	('RAD51C', 'Gene', (233, 239))	('CHEK2', 'Gene', (171, 176))
91572	33451059	Patients with DDR genetic mutations had a significantly longer PFS and OS among the ABTC patients who received first-line platinum-containing chemotherapies.	('ABTC', 'Chemical', '-', (84, 88))	('BTC', 'Phenotype', 'HP:0100574', (85, 88))	('Patients', 'Species', '9606', (0, 8))	('longer', 'PosReg', (56, 62))	('DDR', 'Gene', (14, 17))	('patients', 'Species', '9606', (89, 97))	('PFS', 'CPA', (63, 66))	('platinum', 'Chemical', 'MESH:D010984', (122, 130))	('genetic mutations', 'Var', (18, 35))
91573	33451059	BRCA1/2 mutations occur in 1-7% of BTC patients, which frequently come from somatic origin.	('BRCA1/2', 'Gene', '672;675', (0, 7))	('patients', 'Species', '9606', (39, 47))	('occur', 'Reg', (18, 23))	('mutations', 'Var', (8, 17))	('BTC', 'Disease', (35, 38))	('BTC', 'Phenotype', 'HP:0100574', (35, 38))	('BRCA1/2', 'Gene', (0, 7))
91574	33451059	BRCA2 mutation carriers have a lifetime risk of around 5% to develop BTC.	('BRCA2', 'Gene', '675', (0, 5))	('mutation', 'Var', (6, 14))	('BRCA2', 'Gene', (0, 5))	('BTC', 'Disease', (69, 72))	('BTC', 'Phenotype', 'HP:0100574', (69, 72))
91575	33451059	There are two ongoing phase II trials of PARP inhibitor associated with BTC: Niraparib for BAP1 and other DDR pathway deficient neoplasms (NCT03207347) and olaparib for metastatic BTC with somatic or germline DDR mutations after the failure of platinum (NCT04042831).	('BTC', 'Phenotype', 'HP:0100574', (72, 75))	('BAP1', 'Gene', (91, 95))	('platinum', 'Chemical', 'MESH:D010984', (244, 252))	('DDR', 'Gene', (209, 212))	('neoplasms', 'Phenotype', 'HP:0002664', (128, 137))	('met', 'Gene', '79811', (169, 172))	('DDR pathway', 'Pathway', (106, 117))	('PARP', 'Gene', (41, 45))	('Niraparib', 'Chemical', 'MESH:C545685', (77, 86))	('deficient neoplasms', 'Disease', 'MESH:D009369', (118, 137))	('BAP1', 'Gene', '8314', (91, 95))	('olaparib', 'Chemical', 'MESH:C531550', (156, 164))	('met', 'Gene', (169, 172))	('mutations', 'Var', (213, 222))	('PARP', 'Gene', '142', (41, 45))	('deficient neoplasms', 'Disease', (118, 137))	('BTC', 'Phenotype', 'HP:0100574', (180, 183))
91576	33451059	So far, there are no recommendations to assess BRCA1/2 or DDR mutations to routinely in BTC subpopulations.	('BTC', 'Phenotype', 'HP:0100574', (88, 91))	('BRCA1/2', 'Gene', '672;675', (47, 54))	('DDR', 'Gene', (58, 61))	('BRCA1/2', 'Gene', (47, 54))	('mutations', 'Var', (62, 71))
91578	33451059	Interestingly, a recent study suggested that IDH1/2 mutations induce a "BRCAness" phenotype because of an induced defect of homologous recombination.	('mutations', 'Var', (52, 61))	('IDH1/2', 'Gene', '3417;3418', (45, 51))	('induce', 'Reg', (62, 68))	('BRCAness', 'Disease', (72, 80))	('homologous recombination', 'MPA', (124, 148))	('BRCAness', 'Disease', 'None', (72, 80))	('defect', 'NegReg', (114, 120))	('IDH1/2', 'Gene', (45, 51))
91581	33451059	There are many ongoing clinical trials on using the PARP inhibitor in refractory, IDH-mutant CCAs, such as olaparib monotherapy (NCT03212274), olaparib plus durvalumab (NCT03991832) and olaparib plus a small molecule inhibitor targeting ataxia telangiectasia and the Rad3 related protein, ceralasertib (NCT03878095).	('PARP', 'Gene', '142', (52, 56))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (237, 258))	('IDH', 'Gene', '3417', (82, 85))	('olaparib', 'Chemical', 'MESH:C531550', (143, 151))	('CCAs', 'Disease', (93, 97))	('NCT03212274', 'Var', (129, 140))	('ataxia', 'Phenotype', 'HP:0001251', (237, 243))	('olaparib', 'Chemical', 'MESH:C531550', (107, 115))	('NCT03991832', 'Var', (169, 180))	('olaparib', 'Chemical', 'MESH:C531550', (186, 194))	('ataxia telangiectasia', 'Disease', (237, 258))	('PARP', 'Gene', (52, 56))	('durvalumab', 'Chemical', 'MESH:C000613593', (157, 167))	('IDH', 'Gene', (82, 85))	('telangiectasia', 'Phenotype', 'HP:0001009', (244, 258))
91586	33451059	Due to the negative results from the studies of EGFR antibodies as a first-line therapy, such as cetuximab and panitumumab, there have been limited subsequent studies on second- or later-lines of treatment.	('panitumumab', 'Chemical', 'MESH:D000077544', (111, 122))	('EGFR', 'Gene', '1956', (48, 52))	('cetuximab', 'Chemical', 'MESH:D000068818', (97, 106))	('EGFR', 'Gene', (48, 52))	('antibodies', 'Var', (53, 63))
91587	33451059	Response-predicting EGFR mutation to EGFR TKIs involving exons 18, 19 and 21 had ever been described in a cohort of 22 cholangiocarcinoma patients.	('cholangiocarcinoma', 'Disease', (119, 137))	('patients', 'Species', '9606', (138, 146))	('EGFR', 'Gene', (20, 24))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (119, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('mutation', 'Var', (25, 33))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (119, 137))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('EGFR', 'Gene', '1956', (20, 24))
91588	33451059	Of them, 13.6% of patients (n = 3) harbored EGFR mutations with all exon 19 deletion.	('mutations', 'Var', (49, 58))	('harbored', 'Reg', (35, 43))	('EGFR', 'Gene', '1956', (44, 48))	('patients', 'Species', '9606', (18, 26))	('EGFR', 'Gene', (44, 48))
91589	33451059	In another study, 6 of 40 (15%) of BTC patients had response-predicting EGFR mutations and all were within exon 21.	('patients', 'Species', '9606', (39, 47))	('EGFR', 'Gene', '1956', (72, 76))	('response-predicting', 'Reg', (52, 71))	('EGFR', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))	('BTC', 'Phenotype', 'HP:0100574', (35, 38))
91593	33451059	The agents targeting the HER2 signaling pathway, especially HER2 amplification, significantly benefited patients with breast cancers and gastric cancers.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('breast cancers', 'Disease', 'MESH:D001943', (118, 132))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('gastric cancers', 'Disease', 'MESH:D013274', (137, 152))	('HER2', 'Gene', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('breast cancers', 'Phenotype', 'HP:0003002', (118, 132))	('gastric cancers', 'Disease', (137, 152))	('HER2', 'Gene', '2064', (60, 64))	('gastric cancers', 'Phenotype', 'HP:0012126', (137, 152))	('HER2', 'Gene', (25, 29))	('HER2', 'Gene', '2064', (25, 29))	('amplification', 'Var', (65, 78))	('breast cancers', 'Disease', (118, 132))	('patients', 'Species', '9606', (104, 112))	('benefited', 'PosReg', (94, 103))
91595	33451059	In the MyPathway basket trial of trastuzumab plus pertuzumab for BTC harboring HER2 amplification/overexpression and mutation after the failure of previous treatment, the ORR was 7.5% in the amplified patients and 33.3% in the HER2 mutated population.	('patients', 'Species', '9606', (201, 209))	('HER2', 'Gene', '2064', (79, 83))	('trastuzumab plus pertuzumab', 'Disease', 'MESH:D007625', (33, 60))	('HER2', 'Gene', '2064', (227, 231))	('amplification/overexpression', 'PosReg', (84, 112))	('BTC', 'Phenotype', 'HP:0100574', (65, 68))	('mutation', 'Var', (117, 125))	('trastuzumab plus pertuzumab', 'Disease', (33, 60))	('HER2', 'Gene', (79, 83))	('HER2', 'Gene', (227, 231))
91596	33451059	The reasons of higher ORR in HER2 mutated population than that in amplificated/overexpressed population may be due to small case number, which needs further exploration.	('higher', 'PosReg', (15, 21))	('HER2', 'Gene', (29, 33))	('HER2', 'Gene', '2064', (29, 33))	('ORR', 'MPA', (22, 25))	('mutated', 'Var', (34, 41))
91597	33451059	In an ongoing SUMMIT basket trial of a pan-HER TKI, the efficacy of neratinib is currently being assessed in solid tumors harboring EGFR, HER2 or HER3 mutations/amplification.	('HER2', 'Gene', '2064', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('EGFR', 'Gene', '1956', (132, 136))	('HER3', 'Gene', (146, 150))	('neratinib', 'Chemical', 'MESH:C487932', (68, 77))	('EGFR', 'Gene', (132, 136))	('HER3', 'Gene', '2065', (146, 150))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('mutations/amplification', 'Var', (151, 174))	('HER2', 'Gene', (138, 142))
91611	33451059	Recent studies have revealed that the v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation rates are high in certain cancers and the most common is BRAF V600E, with variable mutation rates in different populations.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutation', 'Var', (91, 99))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', '673', (38, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', (38, 83))	('V600E', 'Var', (162, 167))	('V600E', 'SUBSTITUTION', 'None', (162, 167))	('BRAF', 'Gene', (85, 89))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('high', 'Reg', (110, 114))
91612	33451059	A phase II basket trial of Vemurafenib monotherapy used a BRAF kinase inhibitor in previously treated non-melanoma patients with BRAF V600E mutations.	('V600E', 'SUBSTITUTION', 'None', (134, 139))	('patients', 'Species', '9606', (115, 123))	('BRAF', 'Gene', (129, 133))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (27, 38))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('V600E', 'Var', (134, 139))	('melanoma', 'Disease', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
91623	33451059	Furthermore, patients harboring mutations associated with the RAS/RAF/MEK/ERK pathway got a significantly better ORR (40.0% vs. 12.5%) and longer median PFS (5.4 vs. 3.5 months) than those with wild-type tumors.	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('ORR', 'MPA', (113, 116))	('RAF', 'Gene', (66, 69))	('ERK', 'Gene', '5594', (74, 77))	('better', 'PosReg', (106, 112))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('MEK', 'Gene', (70, 73))	('ERK', 'Gene', (74, 77))	('mutations', 'Var', (32, 41))	('tumors', 'Disease', (204, 210))	('MEK', 'Gene', '5609', (70, 73))	('PFS', 'MPA', (153, 156))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('RAF', 'Gene', '22882', (66, 69))
91625	33451059	In the basket-designed ROAR study, dabrafenib (D) plus trametinib (T) was tested in nine different cohorts of 178 patients with rare malignancies harboring BRAF V600E mutations.	('dabrafenib', 'Chemical', 'MESH:C561627', (35, 45))	('BRAF', 'Gene', (156, 160))	('malignancies', 'Disease', (133, 145))	('trametinib', 'Chemical', 'MESH:C560077', (55, 65))	('patients', 'Species', '9606', (114, 122))	('V600E', 'Var', (161, 166))	('V600E', 'SUBSTITUTION', 'None', (161, 166))	('malignancies', 'Disease', 'MESH:D009369', (133, 145))
91635	33451059	The aberrations in PI3K/AKT/mTOR signaling mainly consist of PI3KCA mutations/amplifications, PTEN loss, phosphorylated AKT or mTOR over-expression in BTC.	('mTOR', 'Gene', '2475', (28, 32))	('mutations/amplifications', 'Var', (68, 92))	('AKT', 'Gene', (120, 123))	('PTEN loss', 'Disease', 'MESH:D006223', (94, 103))	('AKT', 'Gene', (24, 27))	('mTOR', 'Gene', (28, 32))	('BTC', 'Phenotype', 'HP:0100574', (151, 154))	('PTEN loss', 'Disease', (94, 103))	('over-expression', 'PosReg', (132, 147))	('AKT', 'Gene', '207', (24, 27))	('mTOR', 'Gene', (127, 131))	('AKT', 'Gene', '207', (120, 123))	('mTOR', 'Gene', '2475', (127, 131))	('phosphorylated', 'MPA', (105, 119))	('PI3KCA', 'Gene', (61, 67))
91670	33451059	Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are oncogenic drivers involving either NTRK1, NTRK2 or NTRK3 genes with corresponding neurotrophic receptors of TRKA, TRKB and TRKC, respectively.	('TRK', 'Gene', '4914', (173, 176))	('TRKC', 'Gene', (188, 192))	('NTRK2', 'Gene', '4915', (107, 112))	('NTRK1', 'Gene', (100, 105))	('fusions', 'Var', (53, 60))	('TRK', 'Gene', '4914', (188, 191))	('TRK', 'Gene', (179, 182))	('TRK', 'Gene', '4914', (108, 111))	('TRK', 'Gene', '4914', (117, 120))	('TRK', 'Gene', '4914', (101, 104))	('TRK', 'Gene', (43, 46))	('NTRK3', 'Gene', '4916', (116, 121))	('TRK', 'Gene', '4914', (179, 182))	('NTRK2', 'Gene', (107, 112))	('NTRK3', 'Gene', (116, 121))	('TRKB', 'Gene', (179, 183))	('TRK', 'Gene', '4914', (43, 46))	('TRK', 'Gene', (173, 176))	('TRKA', 'Gene', '4914', (173, 177))	('TRK', 'Gene', (188, 191))	('TRKB', 'Gene', '4915', (179, 183))	('TRKA', 'Gene', (173, 177))	('TRKC', 'Gene', '4916', (188, 192))	('NTRK1', 'Gene', '4914', (100, 105))	('TRK', 'Gene', (108, 111))	('TRK', 'Gene', (117, 120))	('TRK', 'Gene', (101, 104))
91678	33451059	Due to the exciting efficacy of NTRK inhibitors in agnostic tumors with NTRK fusion, testing BTC patients for NTRK aberrations is reasonable after the failure to first-line chemotherapy.	('fusion', 'Var', (77, 83))	('TRK', 'Gene', (111, 114))	('nab', 'Chemical', '-', (135, 138))	('TRK', 'Gene', '4914', (111, 114))	('TRK', 'Gene', (33, 36))	('TRK', 'Gene', '4914', (33, 36))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('patients', 'Species', '9606', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('TRK', 'Gene', (73, 76))	('TRK', 'Gene', '4914', (73, 76))	('BTC', 'Phenotype', 'HP:0100574', (93, 96))	('tumors', 'Disease', (60, 66))
91685	33451059	In a recent report, high PD-L1 expression was associated with a better response to pembrolizumab in patients with ABTC.	('ABTC', 'Chemical', '-', (114, 118))	('BTC', 'Phenotype', 'HP:0100574', (115, 118))	('PD-L1', 'Gene', '29126', (25, 30))	('response to', 'MPA', (71, 82))	('expression', 'MPA', (31, 41))	('high', 'Var', (20, 24))	('patients', 'Species', '9606', (100, 108))	('PD-L1', 'Gene', (25, 30))	('pembrolizumab', 'Chemical', 'MESH:C582435', (83, 96))
91703	33451059	Interestingly, PARP inhibitors were able to upregulate PD-L1 expression and promote cancer-associated immunosuppression.	('promote', 'PosReg', (76, 83))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('PD-L1', 'Gene', '29126', (55, 60))	('cancer', 'Disease', (84, 90))	('PARP', 'Gene', '142', (15, 19))	('inhibitors', 'Var', (20, 30))	('upregulate', 'PosReg', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('PD-L1', 'Gene', (55, 60))	('expression', 'MPA', (61, 71))	('PARP', 'Gene', (15, 19))
91730	33451059	Currently, the driver mutations with effective inhibitors are limited only to FGFR2 fusion, IDH1, BRAF mutations and potential immune checkpoint blockade, as shown in Table 1.	('mutations', 'Var', (103, 112))	('IDH1', 'Gene', (92, 96))	('IDH1', 'Gene', '3417', (92, 96))	('FGFR2', 'Gene', (78, 83))	('FGFR2', 'Gene', '2263', (78, 83))	('fusion', 'Var', (84, 90))
91816	24955270	On immunohistochemical staining, the neoplastic cells demonstrated staining for CK7, CA 19-9, polyclonal CEA, CD10 (apical), CD56 (focal), and vimentin.	('CD10', 'Gene', '4311', (110, 114))	('CK7', 'Gene', (80, 83))	('CD56', 'Gene', '4684', (125, 129))	('polyclonal', 'Var', (94, 104))	('CEA', 'Gene', (105, 108))	('CK7', 'Gene', '3855', (80, 83))	('CEA', 'Gene', '1084', (105, 108))	('CD56', 'Gene', (125, 129))	('vimentin', 'Gene', '7431', (143, 151))	('vimentin', 'Gene', (143, 151))	('CD10', 'Gene', (110, 114))
91836	24955270	At her latest follow-up visit, the patient's LFTs were mildly elevated with AST of 48 IU/L, ALT of 40 IU/L, and an alkaline phosphatase of 120 IU/L.	('ALT', 'MPA', (92, 95))	('LFTs', 'MPA', (45, 49))	('patient', 'Species', '9606', (35, 42))	('AST', 'Var', (76, 79))	('alkaline phosphatase', 'MPA', (115, 135))	('elevated', 'PosReg', (62, 70))
91837	24955270	Her tumor markers were unremarkable, with CA 19-9 of 15 U/mL, CA-125 of 5 U/mL, and CEA of 1.3 ng/mL.	('tumor', 'Disease', (4, 9))	('CEA', 'Gene', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('CEA', 'Gene', '1084', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CA-125', 'Var', (62, 68))
91917	24955270	Loss of CD10 has been previously reported in intrahepatic clear cell cholangiocarcinomas.	('intrahepatic clear cell cholangiocarcinomas', 'Disease', (45, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('CD10', 'Gene', (8, 12))	('intrahepatic clear cell cholangiocarcinomas', 'Disease', 'MESH:D018281', (45, 88))	('CD10', 'Gene', '4311', (8, 12))	('reported', 'Reg', (33, 41))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (69, 87))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('Loss', 'Var', (0, 4))
91923	24955270	It has been suggested that reactivity for CD56 may be a novel feature of clear cell intrahepatic cholangiocarcinoma.	('CD56', 'Gene', '4684', (42, 46))	('reactivity', 'Var', (27, 37))	('CD56', 'Gene', (42, 46))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('intrahepatic cholangiocarcinoma', 'Disease', (84, 115))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))
92113	21860552	In univariate analysis, tumor size (< 3 cm vs >= 3 cm), TNM stage (I and II vs III and IV), and serum AFP levels (< 400 ng/mL vs >= 400 ng/mL) showed a significant association with poor patient survival (P = 0.018, P = 0.041, P = 0.010, respectively).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('< 400 ng/mL', 'Var', (114, 125))	('AFP', 'Gene', (102, 105))	('AFP', 'Gene', '174', (102, 105))	('TNM stage', 'Disease', (56, 65))	('patient survival', 'CPA', (186, 202))	('poor', 'NegReg', (181, 185))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('patient', 'Species', '9606', (186, 193))
92157	30819129	Chronic inflammation leads to increased exposure of cholangiocytes to the inflammatory mediators interleukin-6, Tumour Necrosis Factor-alpha, Cyclo-oxygenase-2 and Wnt, resulting in progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair genes.	('Tumour Necrosis Factor-alpha', 'Disease', 'MESH:D009336', (112, 140))	('tumour', 'Disease', (207, 213))	('Wnt', 'Gene', '7477;80326', (164, 167))	('Chronic inflammation', 'Disease', (0, 20))	('exposure', 'MPA', (40, 48))	('Chronic inflammation', 'Disease', 'MESH:D007249', (0, 20))	('Cyclo-oxygenase-2', 'Gene', '5743', (142, 159))	('Tumour', 'Phenotype', 'HP:0002664', (112, 118))	('Tumour Necrosis Factor-alpha', 'Disease', (112, 140))	('mutations', 'Var', (194, 203))	('Cyclo-oxygenase-2', 'Gene', (142, 159))	('Wnt', 'Gene', (164, 167))	('interleukin-6', 'Gene', (97, 110))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('DNA mismatch-repair genes', 'Gene', (252, 277))	('interleukin-6', 'Gene', '3569', (97, 110))	('tumour', 'Disease', 'MESH:D009369', (207, 213))	('proto-oncogenes', 'Gene', (232, 247))
92161	30819129	Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholangiocarcinogenesis.	('activation', 'PosReg', (128, 138))	('cholestasis', 'Phenotype', 'HP:0001396', (100, 111))	('inflammation', 'Disease', 'MESH:D007249', (80, 92))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (47, 65))	('genetic/epigenetic mutations', 'Var', (216, 244))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (47, 65))	('reactive cell proliferation', 'CPA', (187, 214))	('carcinogenesis', 'Disease', 'MESH:D063646', (258, 272))	('inflammation', 'Disease', (80, 92))	('cholestasis', 'Disease', 'MESH:D002779', (100, 111))	('carcinogenesis', 'Disease', (258, 272))	('cause', 'Reg', (66, 71))	('cholangiocarcinoma', 'Disease', (47, 65))	('common intracellular pathways', 'Pathway', (142, 171))	('cholestasis', 'Disease', (100, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
92174	30819129	It is proposed that many of these risk factors cause chronic inflammation and cholestasis, resulting in a cycle of reactive cell proliferation, genetic and epigenetic mutations and eventual cholangiocarcinogenesis.	('cholestasis', 'Disease', 'MESH:D002779', (78, 89))	('epigenetic mutations', 'Var', (156, 176))	('cause', 'Reg', (47, 52))	('cholestasis', 'Disease', (78, 89))	('carcinogenesis', 'Disease', 'MESH:D063646', (199, 213))	('reactive cell proliferation', 'CPA', (115, 142))	('genetic', 'Var', (144, 151))	('carcinogenesis', 'Disease', (199, 213))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('inflammation', 'Disease', (61, 73))	('cholestasis', 'Phenotype', 'HP:0001396', (78, 89))
92268	30819129	Lynch syndrome (previously known as hereditary non-polyposis colorectal cancer) is an autosomal dominant disorder caused by a germline mutation of one of the four DNA mismatch repair genes.	('caused by', 'Reg', (114, 123))	('autosomal dominant disorder', 'Disease', (86, 113))	('hereditary non-polyposis colorectal cancer', 'Disease', (36, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('colorectal cancer', 'Phenotype', 'HP:0003003', (61, 78))	('germline mutation', 'Var', (126, 143))	('Lynch syndrome', 'Disease', (0, 14))	('hereditary non-polyposis colorectal cancer', 'Disease', 'MESH:D015179', (36, 78))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (86, 113))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('hereditary non-polyposis colorectal cancer', 'Phenotype', 'HP:0006716', (36, 78))
92272	30819129	Defects in genes coding for bile salt transporter proteins (BSEP/ABCB11, FIC1/ATP8B1 and MDR3/ABCB4) cause cholestasis leading to the release of inflammatory cytokines, chronic inflammation and subsequent cholangiocarcinogenesis.	('cholestasis', 'Phenotype', 'HP:0001396', (107, 118))	('ATP8B1', 'Gene', '5205', (78, 84))	('ABCB4', 'Gene', (94, 99))	('ABCB11', 'Gene', (65, 71))	('cause', 'Reg', (101, 106))	('cholestasis', 'Disease', 'MESH:D002779', (107, 118))	('ABCB11', 'Gene', '8647', (65, 71))	('carcinogenesis', 'Disease', 'MESH:D063646', (214, 228))	('inflammation', 'Disease', 'MESH:D007249', (177, 189))	('Defects', 'Var', (0, 7))	('MDR3', 'Gene', (89, 93))	('release of inflammatory cytokines', 'MPA', (134, 167))	('ATP8B1', 'Gene', (78, 84))	('bile salt', 'Chemical', 'MESH:D001647', (28, 37))	('FIC1', 'Gene', (73, 77))	('ABCB4', 'Gene', '5244', (94, 99))	('MDR3', 'Gene', '5244', (89, 93))	('carcinogenesis', 'Disease', (214, 228))	('FIC1', 'Gene', '5205', (73, 77))	('inflammation', 'Disease', (177, 189))	('BSEP', 'Gene', '8647', (60, 64))	('BSEP', 'Gene', (60, 64))	('cholestasis', 'Disease', (107, 118))
92280	30819129	High concentrations of inflammatory mediators cause progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair (MMR) genes, resulting in cell proliferation.	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('cell proliferation', 'CPA', (168, 186))	('tumour', 'Disease', (77, 83))	('MMR) genes', 'Gene', (143, 153))	('mutations', 'Var', (64, 73))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
92283	30819129	In cholangiocarcinoma, epigenetic silencing of SOCS3 is observed, reducing the negative feedback.	('cholangiocarcinoma', 'Disease', (3, 21))	('SOCS3', 'Gene', (47, 52))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('reducing', 'NegReg', (66, 74))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('SOCS3', 'Gene', '9021', (47, 52))	('negative feedback', 'MPA', (79, 96))	('epigenetic silencing', 'Var', (23, 43))
92291	30819129	This results in multiple somatic gene mutations including in tumour suppressor gene p53 and the MYC proto-oncogene.	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('MYC', 'Gene', (96, 99))	('tumour', 'Disease', (61, 67))	('results in', 'Reg', (5, 15))	('MYC', 'Gene', '4609', (96, 99))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('mutations', 'Var', (38, 47))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
92294	30819129	High COX-2 levels can stimulate growth in cholangiocarcinoma, and COX-2 inhibitors can induce apoptosis and inhibit proliferation by decreasing Akt pathway stimulation and activating p21 and other cyclin-dependent kinase inhibitors.	('growth', 'MPA', (32, 38))	('COX-2', 'Gene', (66, 71))	('cholangiocarcinoma', 'Disease', (42, 60))	('stimulate', 'PosReg', (22, 31))	('activating', 'PosReg', (172, 182))	('decreasing', 'NegReg', (133, 143))	('inhibit', 'NegReg', (108, 115))	('p21', 'Gene', (183, 186))	('Akt pathway', 'Pathway', (144, 155))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (42, 60))	('p21', 'Gene', '644914', (183, 186))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (42, 60))	('proliferation', 'CPA', (116, 129))	('induce', 'PosReg', (87, 93))	('inhibitors', 'Var', (72, 82))	('apoptosis', 'CPA', (94, 103))	('stimulation', 'PosReg', (156, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
92307	30819129	Any obstruction of the flow of bile results in cholestasis and an abnormal accumulation of bile acids within the biliary tree.	('cholestasis', 'Disease', 'MESH:D002779', (47, 58))	('accumulation of bile acids', 'MPA', (75, 101))	('obstruction', 'Var', (4, 15))	('results in', 'Reg', (36, 46))	('cholestasis', 'Disease', (47, 58))	('bile acids', 'Chemical', 'MESH:D001647', (91, 101))	('cholestasis', 'Phenotype', 'HP:0001396', (47, 58))
92314	30819129	taurocholic acid) are known to stimulate cholangiocyte proliferation, and the bile salt glycochenodeoxycholate has been shown to cause oxidative stress to cholangiocytes and cause subsequent genetic alterations.	('cause', 'Reg', (129, 134))	('oxidative stress', 'MPA', (135, 151))	('cholangiocyte proliferation', 'CPA', (41, 68))	('cause', 'Reg', (174, 179))	('bile salt', 'Chemical', 'MESH:D001647', (78, 87))	('glycochenodeoxycholate', 'Var', (88, 110))	('glycochenodeoxycholate', 'Chemical', 'MESH:D005999', (88, 110))	('stimulate', 'PosReg', (31, 40))	('genetic alterations', 'CPA', (191, 210))	('taurocholic acid', 'Chemical', 'MESH:D013656', (0, 16))	('oxidative stress', 'Phenotype', 'HP:0025464', (135, 151))
92351	30819129	Interestingly, genetic variability in cells other than cholangiocytes can be associated with cholangiocarcinoma.	('genetic variability', 'Var', (15, 34))	('cholangiocarcinoma', 'Disease', (93, 111))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('associated', 'Reg', (77, 87))
92361	30819129	With a global prevalence of 25%, the recent identification of NAFLD as a greater risk factor for cholangiocarcinoma than obesity or diabetes is significant and likely to pose an increasing health burden.	('NAFL', 'Chemical', '-', (62, 66))	('cholangiocarcinoma than obesity', 'Disease', (97, 128))	('diabetes', 'Disease', (132, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('obesity', 'Phenotype', 'HP:0001513', (121, 128))	('diabetes', 'Disease', 'MESH:D003920', (132, 140))	('cholangiocarcinoma than obesity', 'Disease', 'MESH:D009765', (97, 128))	('NAFLD', 'Var', (62, 67))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))
92374	30819129	Although these risk factors are variable in cause and nature, the majority of them have a common theme of causing chronic inflammation and cholestasis leading to a series of molecular changes that result in reactive cell proliferation, genetic/epigenetic mutations and cancer development.	('cholestasis', 'Disease', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('reactive cell proliferation', 'CPA', (207, 234))	('causing', 'Reg', (106, 113))	('cholestasis', 'Phenotype', 'HP:0001396', (139, 150))	('inflammation', 'Disease', 'MESH:D007249', (122, 134))	('genetic/epigenetic mutations', 'Var', (236, 264))	('inflammation', 'Disease', (122, 134))	('cholestasis', 'Disease', 'MESH:D002779', (139, 150))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
92473	29334603	TP53 (n=7, 42%), KRAS (n=5, 32%, including G12D in two, G13D in two, and G12A in one), IDH1 (n=3, 16%), and ARID1A (n=2, 11%) were the most frequent genomic alterations in this study population.	('TP53', 'Gene', '7157', (0, 4))	('G13D', 'Var', (56, 60))	('TP53', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (87, 91))	('G12D', 'Var', (43, 47))	('G12A', 'Mutation', 'rs121913529', (73, 77))	('G13D', 'Mutation', 'rs112445441', (56, 60))	('G12D', 'Mutation', 'rs121913529', (43, 47))	('ARID1A', 'Gene', '8289', (108, 114))	('G12A', 'Var', (73, 77))	('KRAS', 'Gene', (17, 21))	('ARID1A', 'Gene', (108, 114))	('IDH1', 'Gene', (87, 91))	('KRAS', 'Gene', '3845', (17, 21))
92474	29334603	Although TP53mutations were not associated with PFS (p=0.43) or OS (p=0.76), KRAS mutations showed a marginal relationship with worse OS (p=0.07) (S2 Fig.	('worse OS', 'Disease', (128, 136))	('PFS', 'Disease', (48, 51))	('TP53', 'Gene', '7157', (9, 13))	('KRAS', 'Gene', (77, 81))	('mutations', 'Var', (82, 91))	('TP53', 'Gene', (9, 13))	('KRAS', 'Gene', '3845', (77, 81))
92476	29334603	Although no statistical significance was observed (p=0.60), there was a trend toward greater tumor shrinkage (> 50%) in patients without KRAS mutations (6/13, 46%) compared with that in patients harboring KRAS mutations (1/5, 20%).	('mutations', 'Var', (142, 151))	('KRAS', 'Gene', (205, 209))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('KRAS', 'Gene', '3845', (205, 209))	('patients', 'Species', '9606', (120, 128))	('KRAS', 'Gene', (137, 141))	('KRAS', 'Gene', '3845', (137, 141))	('patients', 'Species', '9606', (186, 194))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
92489	29334603	In the biomarker analysis using NGS, KRAS mutations were revealed as potential poor prognostic factors for patients with advanced BTC.	('KRAS', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('BTC', 'Phenotype', 'HP:0100574', (130, 133))	('KRAS', 'Gene', '3845', (37, 41))	('patients', 'Species', '9606', (107, 115))
92503	28297679	Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype.	('decreased', 'NegReg', (95, 104))	('mutant', 'Var', (127, 133))	('IDH', 'Gene', (123, 126))	('expression', 'MPA', (105, 115))	('IDH', 'Gene', '3417', (123, 126))	('ARID1A', 'Gene', (53, 59))
92504	28297679	More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA.	('liver tumors', 'Disease', 'MESH:D008113', (99, 111))	('liver tumors', 'Disease', (99, 111))	('IDH', 'Gene', (28, 31))	('liver tumors', 'Phenotype', 'HP:0002896', (99, 111))	('IDH', 'Gene', '3417', (28, 31))	('liver tumor', 'Phenotype', 'HP:0002896', (99, 110))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('associated with', 'Reg', (46, 61))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('CCA', 'Disease', (155, 158))
92517	28297679	Prior studies indicate that iCCAs are unusual among epithelial cancers in having a relatively high rate of missense mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) genes, which encode metabolic enzymes that interconvert isocitrate and alpha-ketoglutarate in central carbon metabolism.	('IDH', 'Gene', (172, 175))	('IDH', 'Gene', '3417', (167, 170))	('epithelial cancers', 'Disease', 'MESH:D000077216', (52, 70))	('IDH', 'Gene', '3417', (172, 175))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (249, 268))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('IDH1', 'Gene', (167, 171))	('missense mutations', 'Var', (107, 125))	('carbon', 'Chemical', 'MESH:D002244', (280, 286))	('IDH1', 'Gene', '3417', (167, 171))	('epithelial cancers', 'Disease', (52, 70))	('IDH', 'Gene', (167, 170))
92518	28297679	These mutations, which are also common in acute myeloid leukemia, low-grade glioma and glioblastoma, and chondrosarcoma, occur at defined hotspots and result in neomorphic enzyme activity, leading to production of high levels of the metabolite (R)-2-hydroxyglutarate (2HG).	('glioma', 'Disease', (76, 82))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (42, 64))	('leukemia', 'Phenotype', 'HP:0001909', (56, 64))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (48, 64))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (105, 119))	('(R)-2-hydroxyglutarate', 'Chemical', '-', (244, 266))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('neomorphic', 'MPA', (161, 171))	('mutations', 'Var', (6, 15))	('acute myeloid leukemia', 'Disease', (42, 64))	('glioblastoma', 'Disease', 'MESH:D005909', (87, 99))	('activity', 'MPA', (179, 187))	('glioblastoma', 'Disease', (87, 99))	('chondrosarcoma', 'Disease', 'MESH:D002813', (105, 119))	('production', 'MPA', (200, 210))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('chondrosarcoma', 'Disease', (105, 119))	('result in', 'Reg', (151, 160))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (42, 64))
92519	28297679	2HG does not participate in normal metabolic processes but instead interferes with the function of enzymes that utilize alpha-ketoglutarate as a co-enzyme, including histone and DNA demethylases, and inhibits the mitochondrial electron transport chain .	('interferes', 'NegReg', (67, 77))	('histone', 'Enzyme', (166, 173))	('inhibits', 'NegReg', (200, 208))	('function', 'MPA', (87, 95))	('2HG', 'Var', (0, 3))	('DNA demethylases', 'Enzyme', (178, 194))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (120, 139))	('enzymes', 'Enzyme', (99, 106))	('mitochondrial', 'MPA', (213, 226))
92520	28297679	Additional recurrent mutations and fusions have been reported in CCAs involving the fibroblast growth factor receptor 2 (FGFR2) gene, as well as in KRAS, BRAF, TP53, and in genes encoding chromatin-modifying enzymes .	('CCAs', 'Disease', (65, 69))	('FGFR2', 'Gene', (121, 126))	('FGFR2', 'Gene', '2263', (121, 126))	('fusions', 'Var', (35, 42))	('mutations', 'Var', (21, 30))
92523	28297679	Most notably, we identify a class of CCAs with distinct transcriptomic, copy number, and methylation profiles that are highly enriched for IDH mutant samples.	('CCAs', 'Disease', (37, 41))	('mutant', 'Var', (143, 149))	('IDH', 'Gene', (139, 142))	('IDH', 'Gene', '3417', (139, 142))
92527	28297679	Consistent with previous studies, we identified inactivating mutations in the tumor suppressor genes ARID1A, ARID1B, BAP1, PBRM1, TP53, STK11, and PTEN, and hotspot gain-of-function mutations in the oncogenes IDH1, IDH2, KRAS, BRAF, and PIK3CA (Figures 1A and S1A; Tables S1 and S3).	('ARID1A', 'Gene', (101, 107))	('PBRM1', 'Gene', (123, 128))	('gain-of-function', 'PosReg', (165, 181))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('IDH', 'Gene', (215, 218))	('PTEN', 'Gene', (147, 151))	('IDH1', 'Gene', '3417', (209, 213))	('IDH', 'Gene', '3417', (215, 218))	('ARID1B', 'Gene', (109, 115))	('TP53', 'Gene', (130, 134))	('mutations', 'Var', (182, 191))	('STK11', 'Gene', (136, 141))	('inactivating mutations', 'Var', (48, 70))	('BAP1', 'Gene', (117, 121))	('tumor', 'Disease', (78, 83))	('IDH', 'Gene', (209, 212))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('IDH1', 'Gene', (209, 213))	('IDH', 'Gene', '3417', (209, 212))
92529	28297679	In two tumors, we identified a recurrent P216L mutation in the regulatory domain of ARAF adjacent to the functionally validated N217I mutation, which suggests an activated state.	('N217I', 'Mutation', 'p.N217I', (128, 133))	('ARAF', 'Gene', (84, 88))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('P216L', 'Var', (41, 46))	('P216L', 'Mutation', 'p.P216L', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
92530	28297679	We also identified two frameshift deletions and one missense mutation S217F  in the albumin gene (ALB), one of the most significantly mutated genes in HCC .	('frameshift deletions', 'Var', (23, 43))	('S217F', 'Mutation', 'p.S217F', (70, 75))	('ALB', 'Gene', (98, 101))	('S217F', 'Var', (70, 75))
92531	28297679	Although analyzed separately, these additional samples corroborated the mutations above and highlighted additional recurrent mutations in the BRCA2, MLL3, APC, NF1, and ELF3 tumor-suppressor genes.	('tumor', 'Disease', (174, 179))	('mutations', 'Var', (125, 134))	('BRCA2', 'Gene', (142, 147))	('NF1', 'Gene', (160, 163))	('APC', 'Disease', 'MESH:D011125', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('APC', 'Disease', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('MLL3', 'Gene', (149, 153))
92532	28297679	An analysis of gene fusions from RNA-seq data identified five samples (13%) that expressed FGFR2 fusion transcripts; this prevalence is consistent with other studies .	('FGFR2', 'Gene', '2263', (91, 96))	('fusion transcripts', 'Var', (97, 115))	('FGFR2', 'Gene', (91, 96))
92533	28297679	Other than the FGFR2-FRK fusion, which resulted in loss of the FGFR2 kinase domain and retention of the FRK kinase domain, the rest of the fusions retained the kinase domain, consisting of FGFR2 exons 1-17 spliced in frame with the partner gene.	('kinase domain', 'MPA', (69, 82))	('FGFR2', 'Gene', '2263', (189, 194))	('kinase', 'MPA', (160, 166))	('fusions', 'Var', (139, 146))	('FGFR2', 'Gene', (15, 20))	('FGFR2', 'Gene', '2263', (15, 20))	('FRK kinase domain', 'MPA', (104, 121))	('FGFR2', 'Gene', '2263', (63, 68))	('loss', 'NegReg', (51, 55))	('FGFR2', 'Gene', (63, 68))	('FGFR2', 'Gene', (189, 194))
92535	28297679	We also observed two missense mutations and one in-frame insertion in FGFR2.	('FGFR2', 'Gene', '2263', (70, 75))	('missense mutations', 'Var', (21, 39))	('FGFR2', 'Gene', (70, 75))
92536	28297679	We further identified low-prevalence cases of focal SCNAs that have been reported in other cancers, including amplification of CDK4/MDM2 and homozygous focal deletion of QKI and SAV1 (Table S1; Figure S1B).	('QKI', 'Gene', (170, 173))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('amplification', 'Var', (110, 123))	('CDK4/MDM2', 'Gene', (127, 136))	('cancers', 'Disease', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('focal SCNAs', 'Disease', (46, 57))
92537	28297679	Epigenetic silencing of CDKN2A was identified in eight cases (21%) and was mutually exclusive with homozygous deletions and mutations (Figures 1, S1D, and S1E).	('identified', 'Reg', (35, 45))	('Epigenetic silencing', 'Var', (0, 20))	('S1D', 'Mutation', 'p.S1D', (146, 149))	('CDKN2A', 'Gene', (24, 30))
92538	28297679	Collectively, CDKN2A was mutated, deleted, or silenced in 47% of cancers, a higher rate than previously appreciated with single platform analyses.	('silenced', 'NegReg', (46, 54))	('deleted', 'Var', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('mutated', 'Var', (25, 32))	('CDKN2A', 'Gene', (14, 20))
92539	28297679	Next, cross-comparing sequencing and copy number data, we found that all mutations in BAP1 and PBRM1 (both located on 3p21) were detected in tumors with 3p loss of heterozygosity, suggesting biallelic inactivation of these genes in near-diploid tumors.	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('PBRM1', 'Gene', (95, 100))	('diploid tumors', 'Disease', (237, 251))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('loss', 'NegReg', (156, 160))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('BAP1', 'Gene', (86, 90))	('detected', 'Reg', (129, 137))	('tumors', 'Disease', (245, 251))	('diploid tumors', 'Disease', 'MESH:C548012', (237, 251))	('mutations', 'Var', (73, 82))
92540	28297679	Cancer cell fractions were higher for the broad or arm-level loss of chromosome 3 than for BAP1 mutations, followed by PBRM1 mutations, suggesting that these events occur chronologically (3p loss, BAP1, PBRM1) in CCA development (Figures S1F and S1G).	('mutations', 'Var', (125, 134))	('BAP1', 'Gene', (91, 95))	('PBRM1', 'Gene', (119, 124))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('PBRM1', 'Gene', (203, 208))	('CCA', 'Disease', (213, 216))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('loss', 'NegReg', (61, 65))	('mutations', 'Var', (96, 105))
92542	28297679	As observed across 31 tumor types analyzed to date, the most common signature was C > T/G > A substitutions at CpG islands (signature #6), followed by signature #1, characterized by AC > AN, AT > AN (Figure 1).	('AT', 'Disease', 'None', (191, 193))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('substitutions', 'Var', (94, 107))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('C > T/G > A substitutions', 'Var', (82, 107))	('tumor', 'Disease', (22, 27))
92545	28297679	Intriguingly, cluster 1 included all seven cases with an IDH1 or IDH2 hotspot mutation, while cluster 2 was enriched in extrahepatic or perihilar CCA, and cluster 3 contained all five FGFR2 fusions.	('IDH', 'Gene', '3417', (57, 60))	('mutation', 'Var', (78, 86))	('IDH', 'Gene', (65, 68))	('IDH', 'Gene', '3417', (65, 68))	('FGFR2', 'Gene', (184, 189))	('IDH1', 'Gene', (57, 61))	('FGFR2', 'Gene', '2263', (184, 189))	('IDH1', 'Gene', '3417', (57, 61))	('IDH', 'Gene', (57, 60))
92546	28297679	Notably, most IDH1/2 mutations (eight of ten) were located in the cluster that most strongly resembled the IDH-mutant-enriched TCGA cluster 1.	('mutations', 'Var', (21, 30))	('IDH', 'Gene', (14, 17))	('IDH', 'Gene', '3417', (14, 17))	('IDH', 'Gene', (107, 110))	('IDH', 'Gene', '3417', (107, 110))	('IDH1', 'Gene', (14, 18))	('IDH1', 'Gene', '3417', (14, 18))
92549	28297679	High mitochondrial gene expression was significantly associated with IDH and PBRM1 mutant samples and low expression with FGFR2-fusion samples (Figure 3B and depicted as a condensed "mitochondrial score" in Figure 3D); these correlations were improved by removing low-purity (<0.65) samples, a possible confounding factor (Figures S3A and S3B).	('PBRM1', 'Gene', (77, 82))	('mutant', 'Var', (83, 89))	('IDH', 'Gene', (69, 72))	('expression', 'MPA', (106, 116))	('High mitochondrial gene expression', 'MPA', (0, 34))	('low', 'NegReg', (102, 105))	('IDH', 'Gene', '3417', (69, 72))	('FGFR2', 'Gene', '2263', (122, 127))	('FGFR2', 'Gene', (122, 127))
92550	28297679	In keeping with potential functional relevance of the differential expression of mitochondrial genes, we identified a relatively higher mitochondrial copy number  in IDH mutant samples and a lower number in FGFR2-fusion samples (Figure 3E).	('higher', 'PosReg', (129, 135))	('IDH', 'Gene', (166, 169))	('mitochondrial copy number', 'MPA', (136, 161))	('IDH', 'Gene', '3417', (166, 169))	('FGFR2', 'Gene', (207, 212))	('mutant', 'Var', (170, 176))	('FGFR2', 'Gene', '2263', (207, 212))	('lower', 'NegReg', (191, 196))
92551	28297679	Examination of the GSE26566 dataset provided an external validation of these findings, again identifying an enrichment of IDH mutants among the tumors with high expression of the mitochondrial gene signature (Figure 3C).	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('IDH', 'Gene', '3417', (122, 125))	('IDH', 'Gene', (122, 125))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('mutants', 'Var', (126, 133))
92552	28297679	This association between this signature and IDH mutations appears to be particular to CCA, since it was not observed upon analysis of TCGA datasets for glioblastoma, low-grade glioma, melanoma, or acute myeloid leukemia TCGA datasets (Figure S3C).	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanoma', 'Disease', (184, 192))	('mutations', 'Var', (48, 57))	('low-grade', 'Disease', (166, 175))	('glioma', 'Disease', (176, 182))	('acute myeloid leukemia', 'Disease', (197, 219))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('leukemia', 'Phenotype', 'HP:0001909', (211, 219))	('glioblastoma', 'Disease', 'MESH:D005909', (152, 164))	('CCA', 'Disease', (86, 89))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (197, 219))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (203, 219))	('IDH', 'Gene', (44, 47))	('glioblastoma', 'Disease', (152, 164))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (197, 219))	('glioblastoma', 'Phenotype', 'HP:0012174', (152, 164))	('IDH', 'Gene', '3417', (44, 47))
92553	28297679	GSEA also identified chromatin modifier gene sets as significantly downregulated in the IDH mutant mRNA cluster (Figure 3A; Tables S5, S6, and S7.	('chromatin modifier gene sets', 'Gene', (21, 49))	('IDH', 'Gene', (88, 91))	('mutant', 'Var', (92, 98))	('IDH', 'Gene', '3417', (88, 91))	('GSEA', 'Chemical', '-', (0, 4))	('downregulated', 'NegReg', (67, 80))
92556	28297679	These results suggest that mitochondrial activity and chromatin modification are linked basic biological events that are also regulated by IDH hotspot mutations in CCA.	('regulated', 'Reg', (126, 135))	('IDH', 'Gene', (139, 142))	('CCA', 'Disease', (164, 167))	('mitochondrial', 'MPA', (27, 40))	('mutations', 'Var', (151, 160))	('IDH', 'Gene', '3417', (139, 142))
92563	28297679	Next, unsupervised clustering of samples using CpG sites that show cancer-specific DNA methylation changes identified four subgroups in our CCA cohort (Figure 4B).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('changes', 'Var', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('CCA', 'Disease', (140, 143))
92566	28297679	All seven IDH mutant tumors were present in cluster 4, along with one IDH-wild-type case that exhibited a gene expression profile similar to that of IDH mutants (see Figure S4A).	('IDH', 'Gene', (10, 13))	('IDH', 'Gene', (149, 152))	('IDH', 'Gene', '3417', (10, 13))	('mutant', 'Var', (14, 20))	('IDH', 'Gene', (70, 73))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('IDH', 'Gene', '3417', (149, 152))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('IDH', 'Gene', '3417', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
92568	28297679	Last, we note that tumors in clusters 2 and 3 had frequent mutation of genes encoding chromatin regulators, including PBRM1 and ARID1A (ten of 20).	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mutation', 'Var', (59, 67))	('ARID1A', 'Gene', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('PBRM1', 'Gene', (118, 123))
92572	28297679	IDH hotspot mutations were present exclusively in COCA2 (p = 0.0004; "IDH COCA"), reflecting the mRNA and methylation specificity noted earlier, and identifying a correlation with copy number cluster 2 ("genomically unstable").	('COCA', 'Species', '289672', (74, 78))	('IDH', 'Gene', (0, 3))	('mutations', 'Var', (12, 21))	('IDH', 'Gene', (70, 73))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', '3417', (70, 73))	('COCA2', 'Gene', (50, 55))	('COCA', 'Species', '289672', (50, 54))
92573	28297679	Patients with IDH COCA tumors were typically nonsmokers, and the tumors exhibited a lower frequency of lymphatic invasion and chromosome arm 8p gains (Figure 4C).	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('IDH COCA tumors', 'Disease', 'MESH:D009369', (14, 29))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('chromosome', 'Var', (126, 136))	('lower', 'NegReg', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('IDH COCA tumors', 'Disease', (14, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('lymphatic invasion', 'CPA', (103, 121))
92576	28297679	COCA4 ("METH3 COCA" contained eight of 12 cases with BAP1 mutations (p = 0.01) and all five FGFR2 fusion cases (p = 0.004).	('mutations', 'Var', (58, 67))	('COCA', 'Species', '289672', (0, 4))	('COCA', 'Species', '289672', (14, 18))	('FGFR2', 'Gene', (92, 97))	('FGFR2', 'Gene', '2263', (92, 97))	('BAP1', 'Gene', (53, 57))
92580	28297679	Nevertheless, these results clearly highlight the molecular distinctness of IDH mutants and the power of integrated multiplatform analyses.	('IDH', 'Gene', '3417', (76, 79))	('IDH', 'Gene', (76, 79))	('mutants', 'Var', (80, 87))
92583	28297679	After intersecting IDH mutant hypermethylated loci with genes with decreased expression in the IDH COCA subtype and filtering for gene-specific anticorrelation between the two platforms, we identified a list of 24 genes whose expression is putatively regulated by IDH mutant hypermethylation (Figures 5A and 5B).	('IDH', 'Gene', (264, 267))	('COCA', 'Species', '289672', (99, 103))	('expression', 'MPA', (226, 236))	('IDH', 'Gene', '3417', (264, 267))	('IDH', 'Gene', '3417', (19, 22))	('IDH', 'Gene', '3417', (95, 98))	('IDH', 'Gene', (19, 22))	('IDH', 'Gene', (95, 98))	('regulated', 'Reg', (251, 260))	('mutant hypermethylation', 'Var', (268, 291))	('mutant', 'Var', (23, 29))
92587	28297679	Moreover, the only IDH mutant to not show ARID1A hypermethylation, A95A, was ARID1A mutant with low expression (Figures 5A and 5E), suggesting that ARID1A mutation and IDH-induced hypermethylation are mutually exclusive due to redundancy.	('ARID1A', 'Gene', (77, 83))	('IDH', 'Gene', '3417', (168, 171))	('expression', 'MPA', (100, 110))	('mutant', 'Var', (84, 90))	('low', 'NegReg', (96, 99))	('IDH', 'Gene', (19, 22))	('IDH', 'Gene', '3417', (19, 22))	('IDH', 'Gene', (168, 171))
92588	28297679	Collectively, these data suggest that IDH mutations result in hypermethylation and silencing of ARID1A, and that impingement of ARID1A is a convergent feature of IDH COCA tumors.	('IDH COCA tumors', 'Disease', (162, 177))	('IDH', 'Gene', (38, 41))	('silencing', 'MPA', (83, 92))	('IDH', 'Gene', (162, 165))	('IDH COCA tumors', 'Disease', 'MESH:D009369', (162, 177))	('ARID1A', 'Gene', (96, 102))	('IDH', 'Gene', '3417', (38, 41))	('IDH', 'Gene', '3417', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('hypermethylation', 'MPA', (62, 78))	('mutations', 'Var', (42, 51))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
92591	28297679	For miRNAs, we note that miRNA-194-5p is significantly upregulated in the IDH COCA subtype and negatively correlated with the chromatin modifier signature (Figures 4 and S5D-S5H).	('correlated', 'Interaction', (106, 116))	('chromatin modifier signature', 'MPA', (126, 154))	('IDH', 'Gene', (74, 77))	('upregulated', 'PosReg', (55, 66))	('miRNA-194-5p', 'Var', (25, 37))	('negatively', 'NegReg', (95, 105))	('IDH', 'Gene', '3417', (74, 77))	('COCA', 'Species', '289672', (78, 82))
92598	28297679	These tumors shared several molecular features with CCA, including mRNA and miRNA expression patterns, DNA methylation, and to a lesser extent copy number (Figure 6B).	('CCA', 'Disease', (52, 55))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('copy number', 'Var', (143, 154))	('miRNA expression patterns', 'MPA', (76, 101))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('DNA', 'MPA', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
92599	28297679	Strikingly, five of those seven samples harbored either hotspot IDH1/2 mutations (n = 4) or an FGFR2 fusion (n = 1), and they were the only cases in the HCC dataset with these mutations.	('FGFR2', 'Gene', '2263', (95, 100))	('IDH1', 'Gene', (64, 68))	('mutations', 'Var', (71, 80))	('IDH1', 'Gene', '3417', (64, 68))	('hotspot', 'PosReg', (56, 63))	('FGFR2', 'Gene', (95, 100))
92600	28297679	Re-examination of their histology revealed that although regions of these seven cases fall within the spectrum of HCC, each of the five tumors with IDH1 or FGFR2 lesions had some features that have also been described in iCCA, including focal to diffuse glandular differentiation, abundant fibrotic stroma (desmoplasia), and in some areas, an anastomosing architecture (Figures S6G-S6L) (; Nakanuma et al., 2012).	('tumors', 'Disease', (136, 142))	('focal to diffuse glandular differentiation', 'CPA', (237, 279))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('anastomosing architecture', 'CPA', (343, 368))	('IDH1', 'Gene', '3417', (148, 152))	('desmoplasia', 'Disease', (307, 318))	('FGFR2', 'Gene', (156, 161))	('fibrotic stroma', 'Disease', (290, 305))	('iCCA', 'Disease', (221, 225))	('lesions', 'Var', (162, 169))	('FGFR2', 'Gene', '2263', (156, 161))	('fibrotic stroma', 'Disease', 'None', (290, 305))	('desmoplasia', 'Disease', 'None', (307, 318))	('HCC', 'Disease', (114, 117))	('fall', 'Phenotype', 'HP:0002527', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('IDH1', 'Gene', (148, 152))
92604	28297679	The prominent enrichment of IDH mutations in molecularly CCA-like HCCs is consistent with previous findings that IDH mutations block liver progenitor cells from undergoing hepatocyte differentiation and shift them toward a cholangiocellular fate.	('IDH', 'Gene', '3417', (113, 116))	('mutations', 'Var', (117, 126))	('IDH', 'Gene', (28, 31))	('block', 'NegReg', (127, 132))	('IDH', 'Gene', '3417', (28, 31))	('HCCs', 'Disease', (66, 70))	('hepatocyte', 'MPA', (172, 182))	('mutations', 'Var', (32, 41))	('shift', 'Reg', (203, 208))	('IDH', 'Gene', (113, 116))	('liver progenitor cells', 'CPA', (133, 155))
92608	28297679	Relevantly, IDH mutants hypermethylate and putatively silence the ARID1A promoter, which may contribute to the lowered chromatin modifier signature expression.	('lowered', 'NegReg', (111, 118))	('ARID1A', 'Gene', (66, 72))	('IDH', 'Gene', (12, 15))	('chromatin modifier signature expression', 'MPA', (119, 158))	('IDH', 'Gene', '3417', (12, 15))	('mutants hypermethylate', 'Var', (16, 38))	('silence', 'NegReg', (54, 61))	('hypermethylate', 'Var', (24, 38))
92609	28297679	Moreover, we identify a group of liver tumors with an atypical histopathology and a highly CCA-like molecular profile that is enriched for IDH mutations, consistent with the emerging view that liver tumors comprise a continuous spectrum .	('liver tumors', 'Phenotype', 'HP:0002896', (33, 45))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('liver tumor', 'Phenotype', 'HP:0002896', (193, 204))	('liver tumor', 'Phenotype', 'HP:0002896', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('liver tumors', 'Disease', 'MESH:D008113', (193, 205))	('IDH', 'Gene', '3417', (139, 142))	('IDH', 'Gene', (139, 142))	('liver tumors', 'Disease', 'MESH:D008113', (33, 45))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('liver tumors', 'Disease', (193, 205))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('liver tumors', 'Disease', (33, 45))	('mutations', 'Var', (143, 152))	('liver tumors', 'Phenotype', 'HP:0002896', (193, 205))
92610	28297679	Furthermore, the complete lack of IDH mutations in otherwise standard HCC from the TCGA set (0/172) has implications about specific functions of mutant IDH in modulating liver cell identity and also underscores the benefit of combined molecular and histopathological diagnosis.	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('liver', 'MPA', (170, 175))	('mutant', 'Var', (145, 151))	('modulating', 'Reg', (159, 169))	('IDH', 'Gene', (152, 155))	('IDH', 'Gene', '3417', (152, 155))
92611	28297679	Although previous studies also identified transcriptionally CCA-like HCC, our results identify IDH and FGFR2 perturbations as associated drivers linked to methylation, miRNA, and copy number similarities.	('FGFR2', 'Gene', (103, 108))	('methylation', 'MPA', (155, 166))	('perturbations', 'Var', (109, 122))	('FGFR2', 'Gene', '2263', (103, 108))	('miRNA', 'MPA', (168, 173))	('IDH', 'Gene', (95, 98))	('IDH', 'Gene', '3417', (95, 98))
92616	28297679	As examples, (1) extrahepatic CCAs have more SMAD4 mutations than iCCAs; (2) a Chinese study found a much lower incidence of IDH (5%), PBRM1 (1%), and BAP1 (1%) mutations in iCCAs; and (3) liver fluke- and/or viral hepatitis-positive cancers have a higher incidence of TP53 mutations and lower incidence of IDH mutations.	('mutations', 'Var', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('TP53', 'Gene', (269, 273))	('viral hepatitis-positive cancers', 'Disease', 'MESH:D006525', (209, 241))	('BAP1', 'Gene', (151, 155))	('extrahepatic CCAs', 'Disease', 'MESH:D001651', (17, 34))	('liver fluke', 'Species', '6192', (189, 200))	('PBRM1', 'Gene', (135, 140))	('viral hepatitis-positive cancers', 'Disease', (209, 241))	('hepatitis', 'Phenotype', 'HP:0012115', (215, 224))	('SMAD4', 'Gene', (45, 50))	('IDH', 'Gene', (307, 310))	('IDH', 'Gene', (125, 128))	('viral hepatitis', 'Phenotype', 'HP:0006562', (209, 224))	('IDH', 'Gene', '3417', (307, 310))	('mutations', 'Var', (161, 170))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))	('IDH', 'Gene', '3417', (125, 128))	('extrahepatic CCAs', 'Disease', (17, 34))	('mutations', 'Var', (274, 283))	('liver fluke-', 'Disease', (189, 201))
92618	28297679	In this regard, the enriched mitochondrial gene signature and coordinate increase in mitochondrial number in IDH mutant CCA is intriguing in light of prior work implicating mutant IDH in the impairment of multiple aspects of cell metabolism.	('increase', 'PosReg', (73, 81))	('mitochondrial', 'MPA', (29, 42))	('IDH', 'Gene', (180, 183))	('IDH', 'Gene', '3417', (180, 183))	('IDH', 'Gene', (109, 112))	('mutant', 'Var', (113, 119))	('increase in mitochondrial number', 'Phenotype', 'HP:0040014', (73, 105))	('IDH', 'Gene', '3417', (109, 112))	('mitochondrial number', 'MPA', (85, 105))
92622	28297679	Notably, prior work has suggested that BAP1, PBRM1, and ARID1A deficiency all result in sensitivity to EZH2 inhibition across cancer types; the association of ARID1A methylation with IDH mutation opens the question of whether EZH2 inhibition might also be effective in this subtype.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('ARID1A deficiency', 'Disease', (56, 73))	('association', 'Interaction', (144, 155))	('IDH', 'Gene', (183, 186))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('ARID1A', 'Gene', (159, 165))	('IDH', 'Gene', '3417', (183, 186))	('mutation', 'Var', (187, 195))	('methylation', 'Var', (166, 177))	('ARID1A deficiency', 'Disease', 'MESH:D007153', (56, 73))
92634	28297679	IDH mutant CCAs have distinct mRNA, copy number, and DNA methylation features IDH mutant CCAs display high mitochondrial and low chromatin modifier gene expression IDH mutant CCAs methylate the ARID1A promoter and show low ARID1A expression Other IDH mutant liver cancers show multiplatform similarities to CCA Farshidfar et al.	('IDH', 'Gene', (247, 250))	('liver cancers', 'Phenotype', 'HP:0002896', (258, 271))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('mutant', 'Var', (82, 88))	('IDH', 'Gene', '3417', (247, 250))	('IDH', 'Gene', (0, 3))	('mutant', 'Var', (168, 174))	('liver cancer', 'Phenotype', 'HP:0002896', (258, 270))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('liver cancers', 'Disease', (258, 271))	('IDH', 'Gene', (78, 81))	('IDH', 'Gene', (164, 167))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', '3417', (78, 81))	('CCA', 'Disease', (307, 310))	('ARID1A expression', 'MPA', (223, 240))	('IDH', 'Gene', '3417', (164, 167))	('liver cancers', 'Disease', 'MESH:D006528', (258, 271))	('low', 'NegReg', (219, 222))	('methylate', 'Var', (180, 189))
92636	28297679	Through multiplatform analyses, they identify a distinct subtype enriched for IDH mutants.	('mutants', 'Var', (82, 89))	('IDH', 'Gene', '3417', (78, 81))	('IDH', 'Gene', (78, 81))
92769	26917546	Serum tumor markers of potential utility in cHCC-CC are CA 19-9 and AFP, which are associated with CC and HCC respectively.	('CC', 'Phenotype', 'HP:0030153', (107, 109))	('CC', 'Phenotype', 'HP:0030153', (49, 51))	('HCC', 'Gene', (106, 109))	('AFP', 'Gene', (68, 71))	('AFP', 'Gene', '174', (68, 71))	('HCC', 'Gene', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('CC', 'Phenotype', 'HP:0030153', (99, 101))	('CA 19-9', 'Var', (56, 63))	('associated', 'Reg', (83, 93))	('HCC', 'Gene', '619501', (106, 109))	('CC', 'Phenotype', 'HP:0030153', (46, 48))	('HCC', 'Gene', '619501', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
92799	12872450	Results of blood biochemical test were as follows: total bilirubin 0.38 mg/dL, albumin 3.3 g/dL, AST/ALT 48/54 IU/L, gamma-GT 544 U/L (normal <50), alkaline phosphatase 316 IU/L (normal 39-117).	('bilirubin', 'Chemical', 'MESH:D001663', (57, 66))	('AST', 'Gene', (97, 100))	('alkaline phosphatase', 'MPA', (148, 168))	('gamma-GT', 'Var', (117, 125))	('total bilirubin', 'MPA', (51, 66))	('AST', 'Gene', '26503', (97, 100))	('albumin', 'MPA', (79, 86))
92888	21933219	Portal vein embolisation has been crucial in reducing rates of liver failure following extended hepatectomy from 20% to 6% and has helped to expand the surgical indications for biliary tract cancer  Perihilar BTC is associated with a five-year survival of 10-40% overall and 30-52% following R0 resection; whereas distal BTC carries a five-year survival rate of 23-50% overall and 27-62% in those undergoing R0 resection (see Figures 1 & 2).	('BTC', 'Chemical', '-', (209, 212))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (177, 197))	('Portal vein embolisation', 'Phenotype', 'HP:0030242', (0, 24))	('reducing', 'NegReg', (45, 53))	('liver failure', 'Phenotype', 'HP:0001399', (63, 76))	('Perihilar', 'Var', (199, 208))	('liver failure', 'Disease', 'MESH:D017093', (63, 76))	('BTC', 'Chemical', '-', (321, 324))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('biliary tract cancer', 'Disease', 'MESH:D001661', (177, 197))	('biliary tract cancer', 'Disease', (177, 197))	('liver failure', 'Disease', (63, 76))
92935	21933219	Interestingly, photosensitising agents such as Photofrin , Foscan , LS11, MACE and 5-aminolevulinic acid (ALA) have shown preferential accumulation in malignant biliary tissue, as compared to normal bile duct tissue.	('ALA', 'Chemical', 'MESH:C000614854', (106, 109))	('5-aminolevulinic acid', 'Chemical', 'MESH:C000614854', (83, 104))	('accumulation', 'PosReg', (135, 147))	('5-aminolevulinic', 'Var', (83, 99))
92936	21933219	In theory, local ablation of spreading tumour or dysplastic epithelium prior to surgery may help to improve R0 resection rates and increase survival, but neo-adjuvant studies are lacking to date.	('tumour', 'Disease', (39, 45))	('increase', 'PosReg', (131, 139))	('survival', 'CPA', (140, 148))	('dysplastic', 'Disease', (49, 59))	('dysplastic', 'Disease', 'MESH:D004416', (49, 59))	('ablation', 'Var', (17, 25))	('R0 resection rates', 'CPA', (108, 126))	('improve', 'PosReg', (100, 107))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))
93000	33903679	However the regimen was not well tolerated; the incidence of thrombocytopenia, neutropenia, and febrile neutropenia were significantly higher in FOLFIRINOX treatment patients.	('thrombocytopenia', 'Phenotype', 'HP:0001873', (61, 77))	('neutropenia', 'Disease', (104, 115))	('neutropenia', 'Disease', (79, 90))	('FOLFIRINOX', 'Var', (145, 155))	('thrombocytopenia', 'Disease', (61, 77))	('febrile neutropenia', 'Disease', (96, 115))	('febrile neutropenia', 'Disease', 'MESH:D009503', (96, 115))	('neutropenia', 'Disease', 'MESH:D009503', (104, 115))	('neutropenia', 'Disease', 'MESH:D009503', (79, 90))	('thrombocytopenia', 'Disease', 'MESH:D013921', (61, 77))	('neutropenia', 'Phenotype', 'HP:0001875', (104, 115))	('neutropenia', 'Phenotype', 'HP:0001875', (79, 90))	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (145, 155))	('higher', 'PosReg', (135, 141))	('patients', 'Species', '9606', (166, 174))
93001	33903679	Dosage iterations of modified FOLFOX-4, FOLFOX-5, and FOLFOX-7 have been used to treat pancreatic, colorectal, and bladder cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('pancreatic', 'Disease', 'MESH:D010195', (87, 97))	('pancreatic', 'Disease', (87, 97))	('colorectal', 'Disease', 'MESH:D015179', (99, 109))	('bladder cancers', 'Disease', (115, 130))	('FOLFOX-7', 'Var', (54, 62))	('modified', 'Var', (21, 29))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('bladder cancers', 'Phenotype', 'HP:0009725', (115, 130))	('colorectal', 'Disease', (99, 109))	('bladder cancers', 'Disease', 'MESH:D001749', (115, 130))
93042	33903679	Red indicated G1 phase and Green indicated S/G2/M phases while unlabeled cells indicated M-G1 transition phase or dead cells.	('G1 phase', 'Disease', (14, 22))	('S/G2', 'Var', (43, 47))	('S/G2', 'SUBSTITUTION', 'None', (43, 47))
93070	33903679	All cells were then graded as Ki-67+ or Ki-67- on this scale.	('Ki-67-', 'Var', (40, 46))	('Ki', 'Chemical', 'MESH:C066186', (30, 32))	('Ki', 'Chemical', 'MESH:C066186', (40, 42))	('Ki-67+', 'Var', (30, 36))
93077	33903679	Also, the number of cells in S/G2/M phase (green line) increases in these wells.	('increases', 'PosReg', (55, 64))	('S/G2', 'Var', (29, 33))	('S/G2', 'SUBSTITUTION', 'None', (29, 33))
93121	33903679	It is important that CAP alone can selectively induce tumor cell death, however our results demonstrate that CAP can potentially reduce the dose of chemotherapeutic drugs needed for cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('CAP', 'Var', (109, 112))	('dose of', 'MPA', (140, 147))	('reduce', 'NegReg', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('CAP', 'Chemical', '-', (109, 112))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Disease', (182, 188))	('CAP', 'Chemical', '-', (21, 24))	('tumor', 'Disease', (54, 59))	('patients', 'Species', '9606', (189, 197))
93126	30615206	Recently, epigenetic processes have been shown to play an important role in cholangiocarcinogenesis.	('carcinogenesis', 'Disease', (85, 99))	('epigenetic processes', 'Var', (10, 30))	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))
93127	30615206	We found recurrent isocitrate dehydrogenase 1 (IDH1) and IDH2 (28%) gene mutations, recurrent arm-length copy number alterations (CNAs), and focal alterations such as deletion of 3p21 or amplification of 12q15, which affect BRCA1 Associated Protein 1, polybromo 1, and mouse double minute 2 homolog.	('isocitrate dehydrogenase 1', 'Gene', (19, 45))	('BRCA1 Associated Protein 1', 'Gene', '104416', (224, 250))	('IDH2', 'Gene', (57, 61))	('amplification', 'Var', (187, 200))	('BRCA1 Associated Protein 1', 'Gene', (224, 250))	('isocitrate dehydrogenase 1', 'Gene', '15926', (19, 45))	('mouse', 'Species', '10090', (269, 274))	('3p21', 'Gene', (179, 183))	('deletion', 'Var', (167, 175))	('polybromo 1', 'Gene', (252, 263))	('affect', 'Reg', (217, 223))	('mutations', 'Var', (73, 82))	('polybromo 1', 'Gene', '66923', (252, 263))
93129	30615206	The IDH group consisted of all samples with IDH1 or IDH2 mutations and showed, together with the H group, a highly disrupted genome, characterized by frequent deletions of chromosome arms 3p and 6q.	('IDH', 'Gene', '3417', (4, 7))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))	('mutations', 'Var', (57, 66))	('IDH', 'Gene', (44, 47))	('deletions', 'Var', (159, 168))	('IDH', 'Gene', '3417', (44, 47))	('IDH', 'Gene', (4, 7))
93133	30615206	Based on histology, iCCAs are subdivided into two groups: a bile duct type that resembles extrahepatic CCA with columnar cells with mucin production, and a cholangiolar type that recapitulates a genuine small-duct iCCA morphological pattern with cell-rich tubuli formed by cuboidal cells without extracellular mucin.2 The bile duct type has a higher frequency of KRAS mutations, whereas the cholangiolar type shows a higher frequency of IDH mutations.2 In addition, it was shown that the mutational landscape is partly subtype-specific, particularly displaying discriminating differences between iCCA versus pCCA and dCCA with, for example, isocitrate dehydrogenase (IDH) mutations almost exclusively detected in iCCA.3, 4 Frequent genetic alterations of epigenetic key players indicate a high impact of epigenetic processes in cholangiocarcinogenesis.5 Deletions and mutations of genes encoding the chromatin remodeling enzymes BAP1, ARID1A, and PBRM16, 7 and gain-of-function mutations of IDH1 and IDH2 8 are the most common alterations perturbing the epigenetic landscape of iCCA.	('CCA', 'Phenotype', 'HP:0030153', (597, 600))	('IDH', 'Gene', (437, 440))	('CCA', 'Phenotype', 'HP:0030153', (215, 218))	('BAP1', 'Gene', (929, 933))	('mutations', 'Var', (978, 987))	('pCCA', 'Gene', (608, 612))	('isocitrate dehydrogenase', 'Gene', (641, 665))	('IDH', 'Gene', (667, 670))	('IDH', 'Gene', (1000, 1003))	('CCA', 'Phenotype', 'HP:0030153', (609, 612))	('CCA', 'Phenotype', 'HP:0030153', (103, 106))	('IDH', 'Gene', '3417', (437, 440))	('carcinogenesis', 'Disease', (837, 851))	('perturbing', 'Reg', (1039, 1049))	('IDH', 'Gene', (991, 994))	('CCA', 'Phenotype', 'HP:0030153', (21, 24))	('epigenetic landscape', 'MPA', (1054, 1074))	('IDH', 'Gene', '3417', (667, 670))	('ARID1A', 'Gene', (935, 941))	('pCCA', 'Gene', '5095', (608, 612))	('carcinogenesis', 'Disease', 'MESH:D063646', (837, 851))	('IDH', 'Gene', '3417', (1000, 1003))	('Deletions', 'Var', (854, 863))	('KRAS', 'Gene', '3845', (363, 367))	('gain-of-function', 'PosReg', (961, 977))	('PBRM1', 'Gene', '55193', (947, 952))	('IDH', 'Gene', '3417', (991, 994))	('isocitrate dehydrogenase', 'Gene', '3417', (641, 665))	('ARID1A', 'Gene', '8289', (935, 941))	('KRAS', 'Gene', (363, 367))	('BAP1', 'Gene', '8314', (929, 933))	('mutations', 'Var', (868, 877))	('PBRM1', 'Gene', (947, 952))
93152	30615206	Recurrent missense mutations in IDH1 were observed in 6 of 36 (17%) patients (Table 2).	('IDH1', 'Gene', (32, 36))	('patients', 'Species', '9606', (68, 76))	('observed', 'Reg', (42, 50))	('missense mutations', 'Var', (10, 28))
93153	30615206	All IDH1 mutations were located in a mutation hotspot and altered the same codon: p.R132C, p.R132G, or p.R132L.19 IDH2 encoding the mitochondrial isozyme of IDH1 displayed three different missense mutations in the same mutation hotspot, leading to p.R172W, p.R172M, or p.R172S.19 IDH1 and IDH2 mutations lead to the production of the oncometabolite 2-hydroxyglutarate, which was shown to inhibit histone and DNA demethylation.20 TP53 was the second most affected gene with two nonsense and two missense mutations in 4 patients.	('p.R172W', 'Var', (248, 255))	('p.R132G', 'Var', (91, 98))	('TP53', 'Gene', (429, 433))	('TP53', 'Gene', '7157', (429, 433))	('patients', 'Species', '9606', (518, 526))	('p.R132C', 'Mutation', 'rs121913499', (82, 89))	('p.R172S', 'Mutation', 'rs1057519736', (269, 276))	('p.R172M', 'Var', (257, 264))	('p.R172M', 'Mutation', 'rs121913503', (257, 264))	('p.R132L', 'Mutation', 'rs121913500', (103, 110))	('p.R132G', 'Mutation', 'rs121913499', (91, 98))	('mutations', 'Var', (294, 303))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (349, 367))	('p.R172W', 'Mutation', 'rs1057519906', (248, 255))
93154	30615206	These mutations all impaired the DNA binding domain of the TP53 protein, as has been observed frequently in iCCA.21 The mutations in IDH1, IDH2, and TP53 were mutually exclusive with each other.	('IDH2', 'Gene', (139, 143))	('CCA', 'Phenotype', 'HP:0030153', (109, 112))	('DNA', 'MPA', (33, 36))	('TP53', 'Gene', (59, 63))	('TP53', 'Gene', '7157', (149, 153))	('IDH1', 'Gene', (133, 137))	('TP53', 'Gene', (149, 153))	('mutations', 'Var', (120, 129))	('impaired', 'NegReg', (20, 28))	('TP53', 'Gene', '7157', (59, 63))	('mutations', 'Var', (6, 15))
93155	30615206	In addition, two missense mutations were found in TGFBR2 and one mutation was found in ARID1A, SF3B1, ROBO1, ROBO2, FBXW7, BRAF, CDKN2A, FGFR2, KDM5A, KRAS, SMARCA4, and GNAS each (Table 2).	('FBXW7', 'Gene', '55294', (116, 121))	('TGFBR2', 'Gene', '7048', (50, 56))	('SMARCA4', 'Gene', '6597', (157, 164))	('missense mutations', 'Var', (17, 35))	('KDM5A', 'Gene', '5927', (144, 149))	('ROBO2', 'Gene', '6092', (109, 114))	('ROBO1', 'Gene', (102, 107))	('CDKN2A', 'Gene', (129, 135))	('TGFBR2', 'Gene', (50, 56))	('KDM5A', 'Gene', (144, 149))	('FGFR2', 'Gene', (137, 142))	('KRAS', 'Gene', '3845', (151, 155))	('SF3B1', 'Gene', (95, 100))	('SMARCA4', 'Gene', (157, 164))	('ROBO1', 'Gene', '6091', (102, 107))	('FBXW7', 'Gene', (116, 121))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('CDKN2A', 'Gene', '1029', (129, 135))	('ROBO2', 'Gene', (109, 114))	('ARID1A', 'Gene', (87, 93))	('GNAS', 'Gene', (170, 174))	('KRAS', 'Gene', (151, 155))	('FGFR2', 'Gene', '2263', (137, 142))	('GNAS', 'Gene', '2778', (170, 174))	('SF3B1', 'Gene', '23451', (95, 100))	('ARID1A', 'Gene', '8289', (87, 93))
93156	30615206	We used HumanMethylation450 BeadChip data to identify recurrent DNA methylation and genomic CNAs.	('CNAs', 'Disease', (92, 96))	('Human', 'Species', '9606', (8, 13))	('methylation', 'Var', (68, 79))
93158	30615206	We identified genes whose expression might be affected by focal deletions or amplifications in our study population by correlation analyses of publicly available CNA and gene expression data from TCGA-CHOL (n = 51) and considered information on known driver genes22 (Table 4).	('expression', 'MPA', (26, 36))	('amplifications', 'Var', (77, 91))	('affected', 'Reg', (46, 54))	('CHOL', 'Chemical', '-', (201, 205))
93161	30615206	Primarily CpG hypermethylation was seen in the iCCA cohort with approximately 37,600 hypermethylated CpGs exhibiting increased methylation by more than 20%.	('methylation', 'MPA', (127, 138))	('hypermethylated', 'Var', (85, 100))	('CCA', 'Phenotype', 'HP:0030153', (48, 51))	('CpGs', 'Chemical', 'MESH:C015772', (101, 105))
93167	30615206	These four groups are characterized by IDH mutation, the degree of acquired genetic and epigenetic alterations, and by LMC profiles (Fig.	('epigenetic alterations', 'Var', (88, 110))	('LMC', 'Chemical', '-', (119, 122))	('genetic', 'Var', (76, 83))	('IDH', 'Gene', (39, 42))	('IDH', 'Gene', '3417', (39, 42))
93169	30615206	1A) and is characterized by the highest proportion of LMC1 (48% versus 23%, 17% and 17%, respectively) and LMC5 (28% versus 22%, 2%, and 8%), low mutation number (4 mutations in 4 of 11 samples sequenced), low frequency of CNA (approximately 40% for 6q deletion and less for the other alterations), and generally low methylation levels.	('LMC', 'Chemical', '-', (54, 57))	('LMC1', 'Disease', (54, 58))	('methylation levels', 'MPA', (317, 335))	('CNA', 'MPA', (223, 226))	('6q deletion', 'Var', (250, 261))	('LMC', 'Chemical', '-', (107, 110))	('low', 'NegReg', (313, 316))	('LMC5', 'Chemical', '-', (107, 111))
93171	30615206	Most of the samples in the IDH group are characterized by mutations in IDH1 or IDH2 (9 out of 10 sequenced), a unique pattern of relatively high methylation values, a high level of CNAs (up to 80% for 3p deletions), and high values of LMC2 (Fig.	('IDH', 'Gene', (27, 30))	('mutations', 'Var', (58, 67))	('CNAs', 'MPA', (181, 185))	('LMC2', 'Chemical', '-', (235, 239))	('IDH', 'Gene', (79, 82))	('LMC2', 'MPA', (235, 239))	('IDH', 'Gene', '3417', (27, 30))	('IDH', 'Gene', '3417', (79, 82))	('methylation values', 'MPA', (145, 163))	('high', 'PosReg', (140, 144))	('IDH', 'Gene', (71, 74))	('IDH', 'Gene', '3417', (71, 74))
93174	30615206	Thus, iCluster analysis revealed four distinct iCCA subgroups with specific methylation patterns, LMCs, CNAs, and mutations.	('CNAs', 'Disease', (104, 108))	('mutations', 'Var', (114, 123))	('CCA', 'Phenotype', 'HP:0030153', (48, 51))	('LMCs', 'Chemical', '-', (98, 102))	('LMCs', 'Disease', (98, 102))	('iCCA', 'Disease', (47, 51))
93179	30615206	Further analyses of known cancer driver genes showed that RPL22, ROBO1, ROBO2, TGFBR1, and TGFBR2 were most frequently altered either by deletion or promoter hypermethylation in all groups (Fig.	('ROBO2', 'Gene', (72, 77))	('RPL22', 'Gene', '6146', (58, 63))	('TGFBR1', 'Gene', '7046', (79, 85))	('TGFBR2', 'Gene', '7048', (91, 97))	('cancer', 'Disease', (26, 32))	('promoter hypermethylation', 'Var', (149, 174))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('deletion', 'Var', (137, 145))	('ROBO1', 'Gene', (65, 70))	('ROBO1', 'Gene', '6091', (65, 70))	('ROBO2', 'Gene', '6092', (72, 77))	('RPL22', 'Gene', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('altered', 'Reg', (119, 126))	('TGFBR2', 'Gene', (91, 97))	('TGFBR1', 'Gene', (79, 85))
93180	30615206	3A).22 The IDH and H groups frequently showed deletions on chromosome arms 3p and 6q, the former harboring the tumor-suppressor genes BAP1, PBRM1, TGFBR2, ROBO1 and ROBO2, the latter ZNF292 and EEF1A1.	('IDH', 'Gene', '3417', (11, 14))	('EEF1A1', 'Gene', '1915', (194, 200))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('ROBO2', 'Gene', '6092', (165, 170))	('BAP1', 'Gene', '8314', (134, 138))	('EEF1A1', 'Gene', (194, 200))	('TGFBR2', 'Gene', (147, 153))	('ROBO2', 'Gene', (165, 170))	('ZNF292', 'Gene', (183, 189))	('BAP1', 'Gene', (134, 138))	('tumor', 'Disease', (111, 116))	('PBRM1', 'Gene', '55193', (140, 145))	('ROBO1', 'Gene', (155, 160))	('deletions', 'Var', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('IDH', 'Gene', (11, 14))	('PBRM1', 'Gene', (140, 145))	('ZNF292', 'Gene', '23036', (183, 189))	('TGFBR2', 'Gene', '7048', (147, 153))	('ROBO1', 'Gene', '6091', (155, 160))
93181	30615206	Both the M and H groups shared amplification of chromosome 1q, whereas amplification of 8q, which harbors the Myc oncogene, predominated in the M group (Fig.	('Myc', 'Gene', '4609', (110, 113))	('Myc', 'Gene', (110, 113))	('amplification', 'Var', (71, 84))	('amplification', 'Var', (31, 44))
93189	30615206	Globally, all four subgroups show a significant increase in their methylation levels, with significant differences between the L and the M versus the H and IDH mutant groups (Supporting Fig.	('methylation levels', 'MPA', (66, 84))	('IDH', 'Gene', (156, 159))	('mutant', 'Var', (160, 166))	('IDH', 'Gene', '3417', (156, 159))	('increase', 'PosReg', (48, 56))
93198	30615206	Clustering analysis of the tumor-specific LMC2-5 profiles showed that LMC2 co-occurred with IDH1 and IDH2 gain-of-function mutation of HCC and CCA but did not include any PDAC cases (Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('HCC', 'Gene', '619501', (135, 138))	('CCA', 'Phenotype', 'HP:0030153', (143, 146))	('mutation', 'Var', (123, 131))	('tumor', 'Disease', (27, 32))	('HCC', 'Phenotype', 'HP:0001402', (135, 138))	('IDH1', 'Gene', (92, 96))	('gain-of-function', 'PosReg', (106, 122))	('PDAC', 'Phenotype', 'HP:0006725', (171, 175))	('LMC2', 'Chemical', '-', (42, 46))	('CCA', 'Disease', (143, 146))	('HCC', 'Gene', (135, 138))	('LMC2', 'Chemical', '-', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('IDH2', 'Gene', (101, 105))	('PDAC', 'Chemical', '-', (171, 175))
93203	30615206	In addition, iCCA cases with amplification of YY1AP1, a potential marker of HCC with hepatic stem/progenitor features, did not cluster together with the IDH-mutant cases that are LMC2-high (Fig.	('YY1AP1', 'Gene', (46, 52))	('HCC', 'Gene', '619501', (76, 79))	('amplification', 'Var', (29, 42))	('LMC2', 'Chemical', '-', (179, 183))	('HCC', 'Phenotype', 'HP:0001402', (76, 79))	('CCA', 'Phenotype', 'HP:0030153', (14, 17))	('IDH', 'Gene', (153, 156))	('HCC', 'Gene', (76, 79))	('YY1AP1', 'Gene', '55249', (46, 52))	('IDH', 'Gene', '3417', (153, 156))
93206	30615206	Taken together, using three TCGA data sets consisting of HCC, CCA and PDAC cases, we found that IDH gain-of-function mutations resulted in distinct LMC2-high profiles, M group iCCA were enriched for bile duct-type iCCA and exhibited similarities with LMC3-high PDAC, whereas H group iCCA had higher LMC4 and the LMC4-high cluster was enriched for cholangiolar-type iCCA.	('bile duct-type iCCA', 'Disease', (199, 218))	('HCC', 'Gene', '619501', (57, 60))	('PDAC', 'Chemical', '-', (261, 265))	('LMC', 'Chemical', '-', (251, 254))	('PDAC', 'Chemical', '-', (70, 74))	('LMC4', 'Chemical', '-', (299, 303))	('gain-of-function', 'PosReg', (100, 116))	('HCC', 'Phenotype', 'HP:0001402', (57, 60))	('LMC', 'Chemical', '-', (299, 302))	('CCA', 'Phenotype', 'HP:0030153', (215, 218))	('LMC', 'Chemical', '-', (148, 151))	('PDAC', 'Phenotype', 'HP:0006725', (261, 265))	('PDAC', 'Phenotype', 'HP:0006725', (70, 74))	('HCC', 'Gene', (57, 60))	('IDH', 'Gene', '3417', (96, 99))	('CCA', 'Phenotype', 'HP:0030153', (62, 65))	('CCA', 'Phenotype', 'HP:0030153', (366, 369))	('CCA', 'Phenotype', 'HP:0030153', (284, 287))	('mutations', 'Var', (117, 126))	('LMC4', 'Chemical', '-', (312, 316))	('LMC', 'Chemical', '-', (312, 315))	('LMC2', 'Chemical', '-', (148, 152))	('CCA', 'Phenotype', 'HP:0030153', (177, 180))	('LMC2-high profiles', 'MPA', (148, 166))	('IDH', 'Gene', (96, 99))
93211	30615206	Importantly, the four iCCA groups resulting from the iCluster analysis are largely different in the proportions of LMCs, which recover cell type-specific hidden methylation patterns.17  Our sequencing analysis confirmed the recurrence of IDH1 and IDH2 gain-of-function mutations (28%) and TP53 loss-of-function mutations (9%) in carcinogenesis of iCCA.	('loss-of-function', 'NegReg', (294, 310))	('gain-of-function', 'PosReg', (252, 268))	('mutations', 'Var', (269, 278))	('IDH1', 'Gene', (238, 242))	('carcinogenesis', 'Disease', 'MESH:D063646', (329, 343))	('TP53', 'Gene', (289, 293))	('TP53', 'Gene', '7157', (289, 293))	('IDH2', 'Gene', (247, 251))	('LMCs', 'Chemical', '-', (115, 119))	('carcinogenesis', 'Disease', (329, 343))	('iCCA', 'Disease', (347, 351))	('CCA', 'Phenotype', 'HP:0030153', (348, 351))	('mutations', 'Var', (311, 320))	('CCA', 'Phenotype', 'HP:0030153', (23, 26))
93212	30615206	Moreover, additional mutations in epigenetic genes other than IDH1 and IDH2 included ARID1A and SMARCA, both involved in chromatin remodeling, and KDM5A, encoding a histone demethylase, highlighting a strong epigenetic component in iCCA carcinogenesis.	('KDM5A', 'Gene', (147, 152))	('ARID1A', 'Gene', (85, 91))	('KDM5A', 'Gene', '5927', (147, 152))	('ARID1A', 'Gene', '8289', (85, 91))	('CCA', 'Phenotype', 'HP:0030153', (233, 236))	('IDH2', 'Gene', (71, 75))	('carcinogenesis', 'Disease', 'MESH:D063646', (237, 251))	('epigenetic genes', 'Gene', (34, 50))	('carcinogenesis', 'Disease', (237, 251))	('IDH1', 'Gene', (62, 66))	('mutations', 'Var', (21, 30))
93213	30615206	Recurrent long-range genomic alterations additionally underscored the importance of known iCCA candidate genes such as BAP1 and PBRM1 on deleted 3p21.16 or MDM2 on amplified 12q15.	('PBRM1', 'Gene', '55193', (128, 133))	('MDM2', 'Gene', (156, 160))	('BAP1', 'Gene', '8314', (119, 123))	('MDM2', 'Gene', '4193', (156, 160))	('PBRM1', 'Gene', (128, 133))	('CCA', 'Phenotype', 'HP:0030153', (91, 94))	('iCCA', 'Gene', (90, 94))	('BAP1', 'Gene', (119, 123))	('deleted', 'Var', (137, 144))
93214	30615206	The latter gene may initiate tumor onset and progression by negatively regulating tumor suppressor p5335 or by a p53-independent mechanism.36 In addition, ARID1A, ROBO1, ROBO2, TGFBR2, CDKN2A, and TP53 were found to be affected by recurrent deletions or amplifications.	('TGFBR2', 'Gene', '7048', (177, 183))	('ROBO1', 'Gene', '6091', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('amplifications', 'Var', (254, 268))	('ARID1A', 'Gene', '8289', (155, 161))	('p53', 'Gene', '7157', (113, 116))	('p53', 'Gene', (113, 116))	('tumor', 'Disease', (82, 87))	('TP53', 'Gene', (197, 201))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('TGFBR2', 'Gene', (177, 183))	('deletions', 'Var', (241, 250))	('CDKN2A', 'Gene', (185, 191))	('ROBO2', 'Gene', '6092', (170, 175))	('affected', 'Reg', (219, 227))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('TP53', 'Gene', '7157', (197, 201))	('p53', 'Gene', '7157', (99, 102))	('ROBO1', 'Gene', (163, 168))	('CDKN2A', 'Gene', '1029', (185, 191))	('ROBO2', 'Gene', (170, 175))	('tumor', 'Disease', (29, 34))	('ARID1A', 'Gene', (155, 161))	('p53', 'Gene', (99, 102))
93218	30615206	The most conspicuous subgroup is the IDH group characterized by gain-of-function IDH1 and IDH2 hotspot mutations in 9 of 10 tumor samples sequenced, many CNAs, DNA hypermethylation, and high LMC2 values.	('LMC2', 'MPA', (191, 195))	('mutations', 'Var', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('IDH', 'Gene', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('gain-of-function', 'PosReg', (64, 80))	('IDH', 'Gene', '3417', (90, 93))	('tumor', 'Disease', (124, 129))	('LMC2', 'Chemical', '-', (191, 195))	('IDH', 'Gene', (81, 84))	('IDH', 'Gene', (37, 40))	('IDH', 'Gene', '3417', (81, 84))	('IDH', 'Gene', '3417', (37, 40))
93219	30615206	The H group has a similarly disrupted genome as the IDH group with frequent deletions of chromosome arms 3p and 6q.	('deletions', 'Var', (76, 85))	('IDH', 'Gene', '3417', (52, 55))	('IDH', 'Gene', (52, 55))
93222	30615206	This is largely in line with the recent finding of Flavahan et al.,47 showing that hypermethylation led to disruption of the insulator function of the CTCF protein in IDH-mutant gliomas and subsequent overexpression of the PDGFRA candidate oncogene.	('CTCF', 'Gene', (151, 155))	('overexpression', 'PosReg', (201, 215))	('IDH', 'Gene', '3417', (167, 170))	('PDGFRA', 'Gene', (223, 229))	('insulator function', 'MPA', (125, 143))	('hypermethylation', 'Var', (83, 99))	('CTCF', 'Gene', '10664', (151, 155))	('PDGFRA', 'Gene', '5156', (223, 229))	('gliomas', 'Disease', 'MESH:D005910', (178, 185))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('gliomas', 'Disease', (178, 185))	('disruption', 'NegReg', (107, 117))	('IDH', 'Gene', (167, 170))
93231	30615206	Finally, IDH gain-of-function mutation is clearly associated with LMC2-high profiles in all cancer types.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutation', 'Var', (30, 38))	('gain-of-function', 'PosReg', (13, 29))	('LMC2', 'Chemical', '-', (66, 70))	('IDH', 'Gene', (9, 12))	('LMC2-high profiles', 'Disease', (66, 84))	('IDH', 'Gene', '3417', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
93235	30615206	Consistent with the low burden of mutations and epigenetic alterations compared with the normal cholangiocytes, the L group exhibited the most favorable outcome with a 3-year survival rate of 91%, compared with 65%, 50%, and 36% for the IDH, H, and M groups, respectively.	('epigenetic alterations', 'Var', (48, 70))	('IDH', 'Gene', '3417', (237, 240))	('IDH', 'Gene', (237, 240))
93239	30949204	EF24 Suppresses Cholangiocellular Carcinoma Progression, Inhibits STAT3 Phosphorylation, and Induces Apoptosis via ROS-Mediated Oxidative Stress Therapeutic options for advanced stage cholangiocellular carcinoma (CCC) are very limited as of today and patients carry an exceptionally poor overall prognosis.	('Induces', 'Reg', (93, 100))	('Cholangiocellular Carcinoma', 'Phenotype', 'HP:0030153', (16, 43))	('Cholangiocellular Carcinoma', 'Disease', (16, 43))	('Cholangiocellular Carcinoma', 'Disease', 'MESH:D018281', (16, 43))	('patients', 'Species', '9606', (251, 259))	('cholangiocellular carcinoma', 'Disease', (184, 211))	('Oxidative Stress', 'Phenotype', 'HP:0025464', (128, 144))	('Inhibits', 'NegReg', (57, 65))	('Suppresses', 'NegReg', (5, 15))	('cholangiocellular carcinoma', 'Phenotype', 'HP:0030153', (184, 211))	('Oxidative Stress', 'Disease', (128, 144))	('cholangiocellular carcinoma', 'Disease', 'MESH:D018281', (184, 211))	('Apoptosis', 'MPA', (101, 110))	('Carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('EF24', 'Var', (0, 4))	('CCC', 'Phenotype', 'HP:0030153', (213, 216))	('STAT3', 'Gene', (66, 71))	('ROS', 'Chemical', 'MESH:D017382', (115, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('STAT3', 'Gene', '6774', (66, 71))	('Oxidative Stress', 'Disease', 'MESH:D004194', (128, 144))
93242	30949204	In CCC cell lines, EF24 inhibited cell viability and induced apoptosis through excessive ROS generation.	('ROS', 'Chemical', 'MESH:D017382', (89, 92))	('apoptosis', 'CPA', (61, 70))	('induced', 'Reg', (53, 60))	('EF24', 'Var', (19, 23))	('excessive ROS generation', 'Phenotype', 'HP:0025464', (79, 103))	('ROS generation', 'MPA', (89, 103))	('inhibited', 'NegReg', (24, 33))	('CCC', 'Phenotype', 'HP:0030153', (3, 6))	('cell viability', 'CPA', (34, 48))
93243	30949204	Moreover, administration of EF24 led to depletion of total intracellular GSH levels, induced mitochondrial depolarization, and abrogated STAT3 phosphorylation.	('STAT3', 'Gene', (137, 142))	('depletion', 'NegReg', (40, 49))	('GSH', 'Chemical', '-', (73, 76))	('mitochondrial depolarization', 'MPA', (93, 121))	('STAT3', 'Gene', '6774', (137, 142))	('EF24', 'Var', (28, 32))	('abrogated', 'NegReg', (127, 136))
93247	30949204	Therefore, the data presented here suggest EF24 as potential therapeutic compound against CCC which might act at least to some extent through ROS-induced oxidative damage, subsequently inducing apoptosis.	('CCC', 'Phenotype', 'HP:0030153', (90, 93))	('oxidative damage', 'MPA', (154, 170))	('apoptosis', 'CPA', (194, 203))	('inducing', 'Reg', (185, 193))	('EF24', 'Var', (43, 47))	('CCC', 'Disease', (90, 93))	('ROS', 'Chemical', 'MESH:D017382', (142, 145))
93256	30949204	This present study identifies the curcumin analog EF24 as potential therapeutic agent with the potential to target cholangiocellular carcinoma cells by enhancing excessive ROS production while at the same time quenching antioxidative response.	('cholangiocellular carcinoma', 'Disease', 'MESH:D018281', (115, 142))	('ROS', 'Chemical', 'MESH:D017382', (172, 175))	('cholangiocellular carcinoma', 'Disease', (115, 142))	('antioxidative response', 'MPA', (220, 242))	('ROS production', 'MPA', (172, 186))	('enhancing', 'PosReg', (152, 161))	('curcumin', 'Chemical', 'MESH:D003474', (34, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('excessive ROS production', 'Phenotype', 'HP:0025464', (162, 186))	('cholangiocellular carcinoma', 'Phenotype', 'HP:0030153', (115, 142))	('quenching', 'NegReg', (210, 219))	('EF24', 'Var', (50, 54))
93294	30949204	As shown in Figure 1(a), EF24 potently inhibited net cell growth of both SNU478 or HuCC-T1 cells, respectively, in a dose- and time-dependent manner.	('SNU478', 'Chemical', '-', (73, 79))	('inhibited', 'NegReg', (39, 48))	('EF24', 'Var', (25, 29))	('HuCC-T1', 'CellLine', 'CVCL:0324', (83, 90))	('net cell growth', 'CPA', (49, 64))
93297	30949204	Flow cytometry analysis of Annexin-V/PI stained SNU478 and HuCC-T1 cells revealed significant induction of apoptosis, including an increase in both early and late apoptotic states, upon treatment with EF24 in a concentration-dependent manner (Figure 2(a)).	('Annexin-V', 'Gene', (27, 36))	('HuCC-T1', 'CellLine', 'CVCL:0324', (59, 66))	('EF24', 'Var', (201, 205))	('apoptosis', 'CPA', (107, 116))	('SNU478', 'Chemical', '-', (48, 54))	('Annexin-V', 'Gene', '308', (27, 36))
93301	30949204	To investigate whether EF24 increases ROS levels in SNU478 and HuCC-T1 cells, we measured total ROS and superoxide levels in EF24-treated cells using flow cytometry.	('ROS levels', 'MPA', (38, 48))	('superoxide', 'Chemical', 'MESH:D013481', (104, 114))	('increases ROS levels', 'Phenotype', 'HP:0025464', (28, 48))	('EF24', 'Var', (23, 27))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('ROS', 'Chemical', 'MESH:D017382', (38, 41))	('HuCC-T1', 'CellLine', 'CVCL:0324', (63, 70))	('SNU478', 'Chemical', '-', (52, 58))
93302	30949204	Interestingly, for both cholangiocellular carcinoma cell lines tested, flow cytometry revealed a significant increase in intracellular superoxide free radical (O2 -) levels upon treatment with EF24 at 5 muM as compared to mock-treated controls; an increase in intracellular total ROS levels was also observed.	('superoxide free radical', 'Chemical', '-', (135, 158))	('cholangiocellular carcinoma', 'Phenotype', 'HP:0030153', (24, 51))	('muM', 'Gene', '56925', (203, 206))	('cholangiocellular carcinoma', 'Disease', 'MESH:D018281', (24, 51))	('increase', 'PosReg', (109, 117))	('O2', 'Chemical', 'MESH:D013481', (160, 162))	('muM', 'Gene', (203, 206))	('cholangiocellular carcinoma', 'Disease', (24, 51))	('ROS', 'Chemical', 'MESH:D017382', (280, 283))	('EF24', 'Var', (193, 197))	('increase in intracellular total ROS levels', 'Phenotype', 'HP:0025464', (248, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
93304	30949204	Additionally, the morphology of the cells was also found to be completely protected from the effects of EF24 when coadministered with NAC (data not shown).	('NAC', 'Chemical', 'MESH:D000111', (134, 137))	('morphology of the cells', 'CPA', (18, 41))	('EF24', 'Var', (104, 108))
93306	30949204	As shown in Figure 3(b), treatment with EF24 significantly depleted total GSH levels.	('total GSH levels', 'MPA', (68, 84))	('EF24', 'Var', (40, 44))	('GSH', 'Chemical', '-', (74, 77))	('depleted', 'NegReg', (59, 67))
93308	30949204	Next, in order to further dissect whether EF24-mediated cytotoxicity and apoptosis in cholangiocarcinoma cell lines is mediated by excessive ROS accumulation, we performed in vitro cell viability, clonogenicity, and apoptosis assays in the absence or presence of NAC (Figure 4).	('NAC', 'Chemical', 'MESH:D000111', (263, 266))	('cytotoxicity', 'Disease', 'MESH:D064420', (56, 68))	('cholangiocarcinoma', 'Disease', (86, 104))	('ROS', 'Chemical', 'MESH:D017382', (141, 144))	('ROS', 'Protein', (141, 144))	('EF24-mediated', 'Var', (42, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('excessive ROS accumulation', 'Phenotype', 'HP:0025464', (131, 157))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (86, 104))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (86, 104))	('cytotoxicity', 'Disease', (56, 68))	('clonogenicity', 'CPA', (197, 210))
93313	30949204	Our results therefore strongly indicate that EF24 increases oxidative stress, possibly by generating exorbitant levels of ROS but also by undermining the ability of cells to detoxify these oxidants, with this shift in oxidative species balance eventually causing induction of apoptosis and cancer cell death.	('ROS', 'Chemical', 'MESH:D017382', (122, 125))	('oxidative stress', 'Phenotype', 'HP:0025464', (60, 76))	('causing', 'Reg', (255, 262))	('undermining', 'NegReg', (138, 149))	('exorbitant', 'MPA', (101, 111))	('ability', 'MPA', (154, 161))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('EF24', 'Var', (45, 49))	('cancer', 'Disease', (290, 296))	('detoxify these oxidants', 'MPA', (174, 197))	('oxidative stress', 'MPA', (60, 76))	('increases', 'PosReg', (50, 59))	('ROS', 'MPA', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('apoptosis', 'CPA', (276, 285))
93317	30949204	As shown in Figure 5, treatment with EF24 led to depolarization of mitochondria and reduction of membrane potential in a dose-dependent manner, with the maximum drop seen at the highest concentration of EF24 administered (c=5 muM) as indicated by a significant decrease in TMRM fluorescence signal intensity.	('muM', 'Gene', '56925', (226, 229))	('depolarization', 'NegReg', (49, 63))	('mitochondria', 'MPA', (67, 79))	('EF24', 'Var', (37, 41))	('reduction', 'NegReg', (84, 93))	('muM', 'Gene', (226, 229))	('TMRM fluorescence signal intensity', 'MPA', (273, 307))	('decrease', 'NegReg', (261, 269))	('EF24', 'Var', (203, 207))	('membrane potential', 'MPA', (97, 115))	('TMRM', 'Chemical', 'MESH:C401833', (273, 277))
93320	30949204	We found that EF24 inhibited STAT3 phosphorylation at tyrosine residue Tyr705 in a dose- and time-dependent manner without affecting total STAT3 protein expression levels (Figure 6).	('inhibited', 'NegReg', (19, 28))	('STAT3', 'Gene', '6774', (139, 144))	('STAT3', 'Gene', '6774', (29, 34))	('STAT3', 'Gene', (139, 144))	('Tyr705', 'Var', (71, 77))	('tyrosine', 'Chemical', 'MESH:D014443', (54, 62))	('STAT3', 'Gene', (29, 34))	('EF24', 'Var', (14, 18))	('Tyr705', 'Chemical', '-', (71, 77))
93322	30949204	Fluorescence images revealed that EF24 prevented nuclear translocation of STAT3 even in the presence of IL-6, whereas mock-treated cells showed nuclear accumulation of STAT3 to a larger extent after IL-6 stimulation (Figure 6(b)).	('prevented', 'NegReg', (39, 48))	('IL-6', 'Gene', '3569', (199, 203))	('nuclear translocation', 'MPA', (49, 70))	('STAT3', 'Gene', '6774', (74, 79))	('EF24', 'Var', (34, 38))	('STAT3', 'Gene', (74, 79))	('STAT3', 'Gene', '6774', (168, 173))	('IL-6', 'Gene', (199, 203))	('STAT3', 'Gene', (168, 173))	('IL-6', 'Gene', (104, 108))	('IL-6', 'Gene', '3569', (104, 108))
93326	30949204	Western blot analysis revealed that both antioxidants, NAC and GEE, completely reverted inhibition of STAT3 phosphorylation by EF24, hence implying that the protective effects are due to their ability to either increase or sustain the intracellular GSH pool.	('GEE', 'Chemical', 'MESH:C042431', (63, 66))	('increase', 'PosReg', (211, 219))	('EF24', 'Var', (127, 131))	('STAT3', 'Gene', '6774', (102, 107))	('GSH', 'Chemical', '-', (249, 252))	('reverted', 'NegReg', (79, 87))	('STAT3', 'Gene', (102, 107))	('NAC', 'Chemical', 'MESH:D000111', (55, 58))
93331	30949204	As shown in Figure 7, treatment with EF24 led to considerable growth retardation of established SNU478 xenograft tumors as compared to controls, with significant differences in average tumor volumes (Figures 7(a) and 7(c)) as well as tumor weights (Figure 7(b)) observed after treatment for three weeks.	('tumor', 'Disease', (234, 239))	('tumors', 'Disease', (113, 119))	('EF24', 'Var', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Disease', (185, 190))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('differences', 'Reg', (162, 173))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('growth retardation', 'Phenotype', 'HP:0001510', (62, 80))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('considerable growth retardation', 'Phenotype', 'HP:0008850', (49, 80))	('growth retardation', 'Disease', 'MESH:D006130', (62, 80))	('growth retardation', 'Disease', (62, 80))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('SNU478', 'Chemical', '-', (96, 102))
93334	30949204	Further, the phosphorylation status of STAT3 found in resected tumor sections correlated with the results obtained in the cell lines and showed markedly reduced levels of p-STAT3 in EF24-treated tumor tissues.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('STAT3', 'Gene', '6774', (173, 178))	('reduced', 'NegReg', (153, 160))	('STAT3', 'Gene', '6774', (39, 44))	('STAT3', 'Gene', (173, 178))	('STAT3', 'Gene', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('EF24-treated', 'Var', (182, 194))	('levels', 'MPA', (161, 167))	('phosphorylation status', 'MPA', (13, 35))
93335	30949204	Of note, strongly increased expression of 8-OHdG, a biomarker for oxidative damage, was found in EF24-treated tumor tissues, thus confirming EF24-mediated increase in oxidative stress in CCC cells in vivo in the xenograft model utilized here.	('increase in oxidative stress', 'Phenotype', 'HP:0025464', (155, 183))	('increase', 'PosReg', (155, 163))	('increased', 'PosReg', (18, 27))	('CCC', 'Phenotype', 'HP:0030153', (187, 190))	('oxidative stress', 'Phenotype', 'HP:0025464', (167, 183))	('8-OHdG', 'Gene', (42, 48))	('expression', 'MPA', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('oxidative stress', 'MPA', (167, 183))	('8-OHdG', 'Chemical', 'MESH:C067134', (42, 48))	('EF24-mediated', 'Var', (141, 154))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
93336	30949204	In this current study, we show that the curcumin analog EF24 inhibits progression of human cholangiocarcinoma using preclinical in vitro and in vivo model systems and that this compound should thus be further evaluated as potential therapeutic agent for this difficult-to-treat malignancy.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('malignancy', 'Disease', 'MESH:D009369', (278, 288))	('curcumin', 'Chemical', 'MESH:D003474', (40, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('malignancy', 'Disease', (278, 288))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('EF24', 'Var', (56, 60))	('progression', 'CPA', (70, 81))	('cholangiocarcinoma', 'Disease', (91, 109))	('human', 'Species', '9606', (85, 90))	('inhibits', 'NegReg', (61, 69))
93339	30949204	Here we show that EF24 inhibits proliferation, migration, and clonogenicity through induction of apoptosis by increasing oxidative stress in cholangiocarcinoma cells.	('oxidative stress', 'MPA', (121, 137))	('cholangiocarcinoma', 'Disease', (141, 159))	('clonogenicity', 'CPA', (62, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('migration', 'CPA', (47, 56))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (141, 159))	('EF24', 'Var', (18, 22))	('proliferation', 'CPA', (32, 45))	('oxidative stress', 'Phenotype', 'HP:0025464', (121, 137))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (141, 159))	('inhibits', 'NegReg', (23, 31))	('increasing', 'PosReg', (110, 120))
93347	30949204	Our experimental data presented in this current study indicate that EF24 increases oxidative stress in human CCC cell by both increasing ROS levels and at the same time depleting cells of GSH, thus ultimately leading to induction of apoptosis.	('ROS', 'Chemical', 'MESH:D017382', (137, 140))	('increases', 'PosReg', (73, 82))	('increasing', 'PosReg', (126, 136))	('human', 'Species', '9606', (103, 108))	('EF24', 'Var', (68, 72))	('leading to induction', 'Reg', (209, 229))	('depleting', 'NegReg', (169, 178))	('CCC', 'Phenotype', 'HP:0030153', (109, 112))	('cells of GSH', 'MPA', (179, 191))	('oxidative stress', 'Phenotype', 'HP:0025464', (83, 99))	('apoptosis', 'CPA', (233, 242))	('oxidative stress', 'MPA', (83, 99))	('GSH', 'Chemical', '-', (188, 191))	('ROS levels', 'MPA', (137, 147))
93349	30949204	Previous studies reported that EF24 and its parent compound curcumin modulate STAT3 phosphorylation.	('curcumin', 'Chemical', 'MESH:D003474', (60, 68))	('STAT3', 'Gene', '6774', (78, 83))	('STAT3', 'Gene', (78, 83))	('modulate', 'Reg', (69, 77))	('EF24', 'Var', (31, 35))
93350	30949204	In line with these reports, we were able to show that treatment with EF24 led to reduced phosphorylation of STAT3 at Y705 in cholangiocarcinoma cells.	('phosphorylation', 'MPA', (89, 104))	('STAT3', 'Gene', '6774', (108, 113))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (125, 143))	('cholangiocarcinoma', 'Disease', (125, 143))	('STAT3', 'Gene', (108, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('reduced', 'NegReg', (81, 88))	('EF24', 'Var', (69, 73))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (125, 143))
93355	30949204	Of note, we were not only able to show that EF24 treatment caused significantly delayed CCC xenograft growth but also, perhaps equally important, did not observe any obvious signs of toxicity conferred by this compound at the administered doses, as opposed to earlier experience with other compounds targeting redox balance in the past.	('CCC xenograft growth', 'CPA', (88, 108))	('EF24', 'Var', (44, 48))	('CCC', 'Phenotype', 'HP:0030153', (88, 91))	('toxicity', 'Disease', 'MESH:D064420', (183, 191))	('toxicity', 'Disease', (183, 191))	('delayed', 'NegReg', (80, 87))
93359	30949204	As opposed to our data presented here, Nimbolide seems to mainly act by increasing total ROS levels, while EF24 was found to also curb antioxidative response mechanisms.	('ROS', 'Chemical', 'MESH:D017382', (89, 92))	('ROS levels', 'MPA', (89, 99))	('curb', 'NegReg', (130, 134))	('Nimbolide', 'Chemical', 'MESH:C042198', (39, 48))	('increasing', 'PosReg', (72, 82))	('EF24', 'Var', (107, 111))	('antioxidative response mechanisms', 'MPA', (135, 168))
93360	30949204	Classic cytotoxic agents such as paclitaxel, doxorubicin, or cisplatin have been shown to induce intracellular ROS production, and it was suggested that resistance of cancer cells to these drugs might correlate with and be potentially due to increase in adaptive antioxidant capacity.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('increase', 'PosReg', (242, 250))	('cancer', 'Disease', (167, 173))	('induce', 'Reg', (90, 96))	('doxorubicin', 'Chemical', 'MESH:D004317', (45, 56))	('paclitaxel', 'Chemical', 'MESH:D017239', (33, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('ROS', 'Chemical', 'MESH:D017382', (111, 114))	('intracellular ROS production', 'MPA', (97, 125))	('paclitaxel', 'Var', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
93362	30949204	Of note, clinical application of EF24 and its parent compound curcumin has long been hampered by poor bioavailability, and a cyclodextrin-based delivery method such as the one employed here is not likely to be a viable option for administration in humans.	('humans', 'Species', '9606', (248, 254))	('cyclodextrin', 'Chemical', 'MESH:D003505', (125, 137))	('bioavailability', 'MPA', (102, 117))	('curcumin', 'Chemical', 'MESH:D003474', (62, 70))	('EF24', 'Var', (33, 37))
93363	30949204	Moreover, more recent studies provide strong evidence to suggest that, in KRAS mutant tumor cells such as pancreatic ductal adenocarcinoma therapeutic synergism of targeting the glutathione antioxidant pathway is to be expected upon combination with inhibitors of the EGFR or AKT pathways, and therefore based on our data presented here future combination studies of EF24 with cetuximab of small molecule AKT inhibitors appear to be equally exciting.	('glutathione antioxidant pathway', 'Pathway', (178, 209))	('AKT', 'Gene', (405, 408))	('glutathione', 'Chemical', 'MESH:D005978', (178, 189))	('AKT', 'Gene', (276, 279))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (106, 138))	('KRAS', 'Gene', '3845', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('EGFR', 'Gene', '1956', (268, 272))	('KRAS', 'Gene', (74, 78))	('pancreatic ductal adenocarcinoma', 'Disease', (106, 138))	('AKT', 'Gene', '207', (405, 408))	('AKT', 'Gene', '207', (276, 279))	('mutant', 'Var', (79, 85))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (106, 138))	('cetuximab', 'Chemical', 'MESH:D000068818', (377, 386))	('tumor', 'Disease', (86, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('EGFR', 'Gene', (268, 272))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
93366	26179201	Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial Cisplatin and gemcitabine is the standard first-line chemotherapy regimen for patients with advanced biliary tract cancer; expression of VEGF and its receptors is associated with adverse outcomes.	('advanced biliary tract cancer', 'Disease', 'MESH:D001661', (98, 127))	('gemcitabine', 'Chemical', 'MESH:C056507', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('advanced biliary tract cancer', 'Disease', (257, 286))	('Cisplatin', 'Chemical', 'MESH:D002945', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('Cediranib', 'Chemical', 'MESH:C500926', (0, 9))	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('patients', 'Species', '9606', (84, 92))	('patients', 'Species', '9606', (243, 251))	('advanced biliary tract cancer', 'Disease', (98, 127))	('expression', 'Var', (288, 298))	('gemcitabine', 'Chemical', 'MESH:C056507', (55, 66))	('VEGF', 'Gene', '7422', (302, 306))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (266, 286))	('associated', 'Reg', (328, 338))	('biliary tract cancer', 'Disease', 'MESH:D001661', (266, 286))	('advanced biliary tract cancer', 'Disease', 'MESH:D001661', (257, 286))	('VEGF', 'Gene', (302, 306))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (107, 127))	('men', 'Species', '9606', (235, 238))	('biliary tract cancer', 'Disease', 'MESH:D001661', (107, 127))
93374	26179201	Patients who received cediranib had more grade 3-4 toxic effects than did patients who received placebo: hypertension (23 [37%] vs 13 [21%]; p=0 05), diarrhoea (eight [13%] vs two [3%]; p=0 05); platelet count decreased (ten [16%] vs four [6%]; p=0 09), white blood cell decreased (15 [24%] vs seven [11%]; p=0 06) and fatigue (16 [24%] vs seven [11%]; p=0 04).	('decreased', 'NegReg', (210, 219))	('fatigue', 'Disease', 'MESH:D005221', (319, 326))	('diarrhoea', 'Phenotype', 'HP:0002014', (150, 159))	('hypertension', 'Disease', 'MESH:D006973', (105, 117))	('platelet count', 'CPA', (195, 209))	('cediranib', 'Var', (22, 31))	('hypertension', 'Disease', (105, 117))	('decreased', 'NegReg', (271, 280))	('Patients', 'Species', '9606', (0, 8))	('cediranib', 'Chemical', 'MESH:C500926', (22, 31))	('white blood cell', 'CPA', (254, 270))	('hypertension', 'Phenotype', 'HP:0000822', (105, 117))	('patients', 'Species', '9606', (74, 82))	('white blood cell decreased', 'Phenotype', 'HP:0001882', (254, 280))	('fatigue', 'Disease', (319, 326))	('diarrhoea', 'Disease', (150, 159))	('fatigue', 'Phenotype', 'HP:0012378', (319, 326))	('platelet count decreased', 'Phenotype', 'HP:0001873', (195, 219))	('diarrhoea', 'Disease', 'MESH:D003967', (150, 159))
93470	26179201	We noted no significant difference between treatment groups with respect to grade 3-4 haematological toxic effects, although patients receiving cediranib had more frequent grade 3-4 decreased platelet counts (table 2).	('men', 'Species', '9606', (48, 51))	('cediranib', 'Var', (144, 153))	('decreased', 'NegReg', (182, 191))	('decreased platelet counts', 'Phenotype', 'HP:0001873', (182, 207))	('decreased platelet', 'Phenotype', 'HP:0005537', (182, 200))	('cediranib', 'Chemical', 'MESH:C500926', (144, 153))	('platelet counts', 'MPA', (192, 207))	('patients', 'Species', '9606', (125, 133))
93471	26179201	We recorded a significantly higher incidence of grade 3-4 hypertension, diarrhoea, and fatigue in patients given cediranib than in those given placebo (table 2).	('fatigue', 'Disease', 'MESH:D005221', (87, 94))	('cediranib', 'Var', (113, 122))	('diarrhoea', 'Disease', (72, 81))	('hypertension', 'Disease', 'MESH:D006973', (58, 70))	('fatigue', 'Disease', (87, 94))	('patients', 'Species', '9606', (98, 106))	('fatigue', 'Phenotype', 'HP:0012378', (87, 94))	('diarrhoea', 'Disease', 'MESH:D003967', (72, 81))	('hypertension', 'Phenotype', 'HP:0000822', (58, 70))	('cediranib', 'Chemical', 'MESH:C500926', (113, 122))	('hypertension', 'Disease', (58, 70))	('diarrhoea', 'Phenotype', 'HP:0002014', (72, 81))
93472	26179201	88 patient deaths were related to biliary tract cancer (43 [86%] in the cediranib group and 45 [90%] in the placebo group).	('deaths', 'Disease', 'MESH:D003643', (11, 17))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (34, 54))	('cediranib', 'Chemical', 'MESH:C500926', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('biliary tract cancer', 'Disease', 'MESH:D001661', (34, 54))	('patient', 'Species', '9606', (3, 10))	('cediranib', 'Var', (72, 81))	('biliary tract cancer', 'Disease', (34, 54))	('deaths', 'Disease', (11, 17))
93479	26179201	At the time of data cutoff, 59 progression-free survival events had occurred in the cediranib group as had 57 in the placebo group.	('cediranib', 'Chemical', 'MESH:C500926', (84, 93))	('progression-free survival', 'CPA', (31, 56))	('cediranib', 'Var', (84, 93))
93486	26179201	Stable disease was noted in 20 (34%) patients in the cediranib group and 25 (46%) in the placebo group.	('patients', 'Species', '9606', (37, 45))	('cediranib', 'Chemical', 'MESH:C500926', (53, 62))	('cediranib', 'Var', (53, 62))	('Stable disease', 'Disease', (0, 14))
93487	26179201	As a result, disease control was achieved by 46 (78%) patients in the cediranib group and by 35 (65%) in the placebo group (p=0 12).	('cediranib', 'Chemical', 'MESH:C500926', (70, 79))	('cediranib', 'Var', (70, 79))	('patients', 'Species', '9606', (54, 62))	('disease', 'Disease', (13, 20))
93489	26179201	Six (10%) patients in the cediranib group and 15 (28%) in the placebo group had progressive disease (including symptomatic progressions [ie, not objectively obsessed] in three in the cediranib group and four in the placebo group).	('cediranib', 'Chemical', 'MESH:C500926', (183, 192))	('progressive disease', 'Disease', (80, 99))	('cediranib', 'Chemical', 'MESH:C500926', (26, 35))	('patients', 'Species', '9606', (10, 18))	('cediranib', 'Var', (26, 35))
93520	26179201	We did not note any unexpected safety signals; the addition of cediranib to cisplatin and gemcitabine did result in a significantly greater incidence of grade 3-4 toxic effects, which were mainly expected off-target toxic effects for VEGF inhibitors (namely hypertension and diarrhoea).	('diarrhoea', 'Disease', 'MESH:D003967', (275, 284))	('diarrhoea', 'Disease', (275, 284))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('VEGF', 'Gene', '7422', (234, 238))	('hypertension', 'Disease', 'MESH:D006973', (258, 270))	('gemcitabine', 'Chemical', 'MESH:C056507', (90, 101))	('cediranib', 'Var', (63, 72))	('hypertension', 'Disease', (258, 270))	('hypertension', 'Phenotype', 'HP:0000822', (258, 270))	('VEGF', 'Gene', (234, 238))	('diarrhoea', 'Phenotype', 'HP:0002014', (275, 284))	('cediranib', 'Chemical', 'MESH:C500926', (63, 72))	('grade 3-4 toxic effects', 'MPA', (153, 176))
93524	26179201	We assessed surrogates of disease volume and biology (other than radiological extent) including assessment of the tumour markers CA19-9, CEA, and CA125 and total CK18.	('tumour', 'Disease', (114, 120))	('CA125', 'Gene', (146, 151))	('CEA', 'Gene', '1084', (137, 140))	('CA19-9', 'Var', (129, 135))	('CK18', 'Gene', (162, 166))	('CA125', 'Gene', '94025', (146, 151))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('CEA', 'Gene', (137, 140))	('CK18', 'Gene', '3875', (162, 166))	('men', 'Species', '9606', (102, 105))
93533	26179201	Our study is, to the best of our knowledge, the first to show the presence of circulating tumour cells in patients with biliary tract cancer and, moreover, that the presence of one or more circulating tumour cells per 7 5 mL of blood is associated with an adverse prognosis.	('tumour', 'Disease', (201, 207))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (120, 140))	('biliary tract cancer', 'Disease', 'MESH:D001661', (120, 140))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('biliary tract cancer', 'Disease', (120, 140))	('patients', 'Species', '9606', (106, 114))	('tumour', 'Disease', 'MESH:D009369', (201, 207))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumour', 'Disease', (90, 96))	('presence', 'Var', (165, 173))
93540	26179201	In our study, increased baseline levels of PDGFbb, one of the targets of cediranib, was associated with a benefit from cediranib consistent with a potential role as a predictive biomarker; this finding would need to be validated in an independent cohort.	('increased', 'PosReg', (14, 23))	('benefit', 'PosReg', (106, 113))	('cediranib', 'Chemical', 'MESH:C500926', (73, 82))	('cediranib', 'Var', (119, 128))	('PDGFbb', 'Gene', (43, 49))	('cediranib', 'Chemical', 'MESH:C500926', (119, 128))
93572	24559536	In brief, from a cohort comprising the entire population receiving care at one of two major tertiary referral hospitals (Massachusetts General Hospital and Brigham and Women's Hospital) or affiliated hospitals and practices in the Greater Boston area, we identified all potential IBD patients with at least one International classification of diseases, 9th edition, clinical modification code for Crohn's disease (555.x) or ulcerative colitis (556.x).	('colitis', 'Phenotype', 'HP:0002583', (435, 442))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (424, 442))	('Women', 'Species', '9606', (168, 173))	('patients', 'Species', '9606', (284, 292))	('ulcerative colitis', 'Disease', (424, 442))	("Crohn's disease", 'Phenotype', 'HP:0100280', (397, 412))	("Crohn's disease", 'Disease', (397, 412))	('555.x', 'Var', (414, 419))	("Crohn's disease", 'Disease', 'MESH:D003424', (397, 412))	('ulcerative colitis', 'Disease', 'MESH:D003093', (424, 442))	('556.x', 'Var', (444, 449))
93663	24478380	Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma Mutations in the IDH1 and IDH2 (IDH1/2) genes occur in ~20% of intrahepatic cholangiocarcinoma (ICC) and lead to accumulation of 2-hydroxyglutarate (2HG) in the tumor tissue.	('IDH2', 'Gene', (188, 192))	('IDH1', 'Gene', '3417', (194, 198))	('IDH2', 'Gene', '3418', (188, 192))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (130, 161))	('occur', 'Reg', (208, 213))	('intrahepatic cholangiocarcinoma', 'Disease', (130, 161))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (27, 45))	('patients', 'Species', '9606', (84, 92))	('lead to', 'Reg', (267, 274))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (225, 256))	('intrahepatic cholangiocarcinoma', 'Disease', (225, 256))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (238, 256))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (143, 161))	('IDH1', 'Gene', (179, 183))	('IDH1', 'Gene', (194, 198))	('tumor', 'Disease', (323, 328))	('accumulation', 'PosReg', (275, 287))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (291, 309))	('Mutations', 'Var', (162, 171))	('IDH1', 'Gene', '3417', (179, 183))	('tumor', 'Disease', 'MESH:D009369', (323, 328))
93664	24478380	However, it remains unknown whether IDH1/2 mutations can lead to high levels of 2HG circulating in the blood and whether serum 2HG can be used as a biomarker for IDH1/2 mutational status and tumor burden in ICC.	('high levels of 2HG', 'MPA', (65, 83))	('IDH1/2', 'Gene', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('lead to', 'Reg', (57, 64))	('mutations', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))
93668	24478380	Circulating levels of 2HG in the Screening cohort were significantly elevated in patients with IDH1/2-mutant (median 478 ng/ml) versus IDH1/2-wild-type (median 118 ng/ml) tumors (p<0.001).	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('patients', 'Species', '9606', (81, 89))	('Circulating levels of', 'MPA', (0, 21))	('elevated', 'PosReg', (69, 77))	('IDH1/2-mutant', 'Gene', (95, 108))	('IDH1/2-mutant', 'Var', (95, 108))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
93671	24478380	This study indicates that circulating 2HG may be a surrogate biomarker of IDH1 or IDH2 mutation status in ICC and that circulating 2HG levels may correlate directly with tumor burden.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('IDH1', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('IDH2', 'Gene', (82, 86))	('tumor', 'Disease', (170, 175))	('IDH2', 'Gene', '3418', (82, 86))	('ICC', 'Disease', (106, 109))	('IDH1', 'Gene', '3417', (74, 78))	('mutation', 'Var', (87, 95))
93677	24478380	Recently, mutations in the genes encoding for isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) have been identified as a significant molecular feature in ~20% of ICC cases.	('ICC cases', 'Disease', (160, 169))	('identified', 'Reg', (103, 113))	('IDH1', 'Gene', (74, 78))	('IDH2', 'Gene', (87, 91))	('IDH1', 'Gene', '3417', (74, 78))	('isocitrate', 'Chemical', 'MESH:C034219', (46, 56))	('mutations', 'Var', (10, 19))	('IDH2', 'Gene', '3418', (87, 91))
93679	24478380	The recurrent cancer mutations in these enzymes confer neomorphic activity through the reduction of alpha-ketoglutarate to the metabolite R(-)-2-hydroxyglutarate (2HG), resulting in 2HG accumulation in the tumor tissue.	('cancer', 'Disease', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('2HG accumulation', 'MPA', (182, 198))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('R(-)-2-hydroxyglutarate', 'Chemical', '-', (138, 161))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('reduction', 'MPA', (87, 96))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (100, 119))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('neomorphic', 'CPA', (55, 65))	('mutations', 'Var', (21, 30))
93680	24478380	High intracellular levels of 2HG have recently been shown to be sufficient for promoting the tumorigenic effects of mutant IDH activity that are associated with enhanced proliferation and impaired differentiation.	('promoting', 'PosReg', (79, 88))	('enhanced', 'PosReg', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('impaired', 'NegReg', (188, 196))	('differentiation', 'CPA', (197, 212))	('IDH', 'Gene', (123, 126))	('mutant', 'Var', (116, 122))	('IDH', 'Gene', '3417', (123, 126))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
93682	24478380	This has partly been hampered by the prevalence of IDH1/2 mutations confined primarily to a small number of cancer types, which is then further limited when considering a relatively rare malignancy such as ICC.	('mutations', 'Var', (58, 67))	('malignancy', 'Disease', 'MESH:D009369', (187, 197))	('ICC', 'Disease', (206, 209))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('malignancy', 'Disease', (187, 197))	('IDH1/2', 'Gene', (51, 57))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
93684	24478380	Since 2HG has been shown to be a membrane diffusible metabolite, it is of interest to determine whether 2HG can be detected in the serum of ICC patients carrying a somatic IDH1 or IDH2 mutation.	('IDH1', 'Gene', '3417', (172, 176))	('IDH2', 'Gene', '3418', (180, 184))	('mutation', 'Var', (185, 193))	('patients', 'Species', '9606', (144, 152))	('ICC', 'Disease', (140, 143))	('IDH1', 'Gene', (172, 176))	('IDH2', 'Gene', (180, 184))
93694	24478380	Specific hotspot mutations in the IDH1 gene at nucleotide positions c.394 and c.395 (amino acid position p.R132) were identified using a multiplexed mutational profiling platform that has been previously described and clinically implemented.	('IDH1', 'Gene', '3417', (34, 38))	('IDH1', 'Gene', (34, 38))	('c.395', 'Var', (78, 83))
93695	24478380	Rare IDH1 mutations that have been reported in other tumor types were not evaluated.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('IDH1', 'Gene', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('IDH1', 'Gene', '3417', (5, 9))	('tumor', 'Disease', (53, 58))	('mutations', 'Var', (10, 19))
93696	24478380	Sanger sequencing was used to identify mutations in the IDH2 gene at exon 4 (including mutations at codons p.140 and p.172) using methods and polymerase chain reaction primers that have been previously reported.	('p.172', 'Var', (117, 122))	('p.140', 'Var', (107, 112))	('IDH2', 'Gene', '3418', (56, 60))	('IDH2', 'Gene', (56, 60))
93702	24478380	A total of 31 diagnosed ICC patients with clinically-determined IDH1 and IDH2 gene mutational status, and with available banked whole blood, comprised the Screening cohort.	('ICC', 'Disease', (24, 27))	('mutational status', 'Var', (83, 100))	('IDH1', 'Gene', (64, 68))	('IDH1', 'Gene', '3417', (64, 68))	('IDH2', 'Gene', (73, 77))	('patients', 'Species', '9606', (28, 36))	('IDH2', 'Gene', '3418', (73, 77))
93705	24478380	In order to expand analysis of ICC patients, a second Validation cohort consisting of 38 ICC patients who underwent surgical resection was then identified and retrospectively genotyped to identify IDH1/2 mutations.	('mutations', 'Var', (204, 213))	('patients', 'Species', '9606', (93, 101))	('IDH1/2', 'Gene', (197, 203))	('patients', 'Species', '9606', (35, 43))
93707	24478380	In the Screening cohort, IDH1 mutations were found in 11 out of 31 patients with ICC, for an overall incidence of 35%.	('patients', 'Species', '9606', (67, 75))	('ICC', 'Disease', (81, 84))	('mutations', 'Var', (30, 39))	('IDH1', 'Gene', (25, 29))	('found', 'Reg', (45, 50))	('IDH1', 'Gene', '3417', (25, 29))
93708	24478380	These included point mutations in IDH1 p.R132C (n=7), p.R132L (n=3) and p.R132G (n=1) (Table 2 and Supplemental Table 1).	('IDH1', 'Gene', '3417', (34, 38))	('p.R132G', 'Mutation', 'rs121913499', (72, 79))	('p.R132G', 'Var', (72, 79))	('IDH1', 'Gene', (34, 38))	('p.R132C', 'Var', (39, 46))	('p.R132L', 'Var', (54, 61))	('p.R132L', 'Mutation', 'rs121913500', (54, 61))	('p.R132C', 'Mutation', 'rs121913499', (39, 46))
93711	24478380	We identified mutations in IDH1 in 4 out of 38 patients (10%) and IDH2 in 3 out of 38 patients (8%), for a combined frequency of IDH1/2 mutations in 18% of the cohort.	('IDH2', 'Gene', '3418', (66, 70))	('IDH1', 'Gene', (129, 133))	('patients', 'Species', '9606', (47, 55))	('IDH1', 'Gene', '3417', (129, 133))	('IDH1', 'Gene', (27, 31))	('IDH2', 'Gene', (66, 70))	('mutations', 'Var', (14, 23))	('IDH1', 'Gene', '3417', (27, 31))	('patients', 'Species', '9606', (86, 94))
93712	24478380	The point mutations included IDH1 p.R132C (n=2) and p.R132L (n=2), as well as IDH2 p.R172W (n=2) and p.R172K (n=1).	('p.R172K', 'Var', (101, 108))	('IDH2', 'Gene', (78, 82))	('IDH1', 'Gene', (29, 33))	('p.R132C', 'Var', (34, 41))	('p.R132C', 'Mutation', 'rs121913499', (34, 41))	('p.R172K', 'Mutation', 'rs121913503', (101, 108))	('IDH1', 'Gene', '3417', (29, 33))	('p.R132L', 'Var', (52, 59))	('IDH2', 'Gene', '3418', (78, 82))	('p.R132L', 'Mutation', 'rs121913500', (52, 59))	('p.R172W', 'Var', (83, 90))	('p.R172W', 'Mutation', 'rs1057519906', (83, 90))
93713	24478380	The frequency of IDH1 mutations was statistically higher in the Screening cohort, and the frequency of IDH2 mutations was significantly greater in the Validation cohort (p=0.04).	('higher', 'PosReg', (50, 56))	('IDH2', 'Gene', '3418', (103, 107))	('IDH1', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('IDH1', 'Gene', '3417', (17, 21))	('IDH2', 'Gene', (103, 107))
93715	24478380	Unlike what has been previously reported, there was no correlation between the presence of IDH1/2 mutations and either the grade of tumor or the histological clear cell changes (Table 3).	('rad', 'Gene', '6236', (124, 127))	('rad', 'Gene', (124, 127))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('IDH1/2', 'Gene', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('mutations', 'Var', (98, 107))	('tumor', 'Disease', (132, 137))
93717	24478380	For patients with a somatic IDH1/2 mutation, the radiological tumor burden and response to therapy at the time of 2-HG measurement are listed in Supplemental Table 2.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('IDH1/2', 'Gene', (28, 34))	('mutation', 'Var', (35, 43))	('patients', 'Species', '9606', (4, 12))	('rad', 'Gene', '6236', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('rad', 'Gene', (49, 52))
93723	24478380	Surprisingly, there were no notable differences between 2HG levels in patients with IDH1/2 mutant ICC across the two cohorts (p=0.68), supporting the robustness of 2HG as a potential means of identifying IDH1/2-mutant versus wild-type ICC patients in a clinical setting.	('IDH1/2', 'Gene', (84, 90))	('patients', 'Species', '9606', (70, 78))	('patients', 'Species', '9606', (239, 247))	('IDH1/2-mutant', 'Gene', (204, 217))	('ICC', 'Disease', (98, 101))	('mutant', 'Var', (91, 97))
93724	24478380	These data combined indicate that a threshold of serum 2HG set at >170 ng/ml can discriminate the presence of an IDH1/2-mutant from an IDH1/2-wild-type ICC tumor using patient blood, with a sensitivity of 83% and a specificity of 90%.	('patient', 'Species', '9606', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('ICC tumor', 'Disease', (152, 161))	('ICC tumor', 'Disease', 'MESH:C566123', (152, 161))	('IDH1/2-mutant', 'Gene', (113, 126))	('IDH1/2-mutant', 'Var', (113, 126))
93725	24478380	While in vitro differences have been reported, it has not been clearly established whether the various mutant forms of IDH1 or IDH2 can produce variable levels of 2HG in vivo.	('mutant', 'Var', (103, 109))	('IDH2', 'Gene', (127, 131))	('2HG', 'MPA', (163, 166))	('IDH1', 'Gene', (119, 123))	('IDH2', 'Gene', '3418', (127, 131))	('IDH1', 'Gene', '3417', (119, 123))
93726	24478380	When evaluating blood collected across all of our ICC patients, albeit a limited sample size, there were no significant differences in the levels of circulating 2HG in patients with a tumor mutant for IDH1 versus IDH2 (p=0.29).	('IDH2', 'Gene', '3418', (213, 217))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('IDH1', 'Gene', '3417', (201, 205))	('IDH2', 'Gene', (213, 217))	('mutant', 'Var', (190, 196))	('tumor', 'Disease', (184, 189))	('patients', 'Species', '9606', (168, 176))	('IDH1', 'Gene', (201, 205))
93727	24478380	However, the high variability that we noted in circulating 2HG levels across the IDH1/2-mutant ICC patients could have reduced the ability to identify more subtle differences.	('ICC', 'Disease', (95, 98))	('circulating 2HG levels', 'MPA', (47, 69))	('patients', 'Species', '9606', (99, 107))	('IDH1/2-mutant', 'Gene', (81, 94))	('reduced', 'NegReg', (119, 126))	('IDH1/2-mutant', 'Var', (81, 94))
93731	24478380	As shown in Figure 2, 2HG levels indeed correlated directly with tumor burden (Spearman's rho 0.89; p=0.0123) in patients with IDH1/2-mutant ICC.	('ICC', 'Disease', (141, 144))	('tumor', 'Disease', (65, 70))	('IDH1/2-mutant', 'Var', (127, 140))	('patients', 'Species', '9606', (113, 121))	('correlated', 'Reg', (40, 50))	('2HG', 'MPA', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
93732	24478380	In this study, we confirmed an increasing body of evidence that ICCs have a relatively high frequency of IDH1 and IDH2 mutation.	('IDH2', 'Gene', (114, 118))	('mutation', 'Var', (119, 127))	('IDH1', 'Gene', (105, 109))	('IDH2', 'Gene', '3418', (114, 118))	('IDH1', 'Gene', '3417', (105, 109))
93735	24478380	There have been tremendous advances in our understanding of how mutant IDH1 and IDH2 drive the tumorigenic process.	('drive', 'Reg', (85, 90))	('IDH2', 'Gene', '3418', (80, 84))	('IDH1', 'Gene', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('IDH1', 'Gene', '3417', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutant', 'Var', (64, 70))	('tumor', 'Disease', (95, 100))	('IDH2', 'Gene', (80, 84))
93736	24478380	It has recently been demonstrated that 2HG in itself is sufficient to disrupt differentiation and promote growth factor independence in leukemic cells.	('promote', 'PosReg', (98, 105))	('2HG', 'Var', (39, 42))	('disrupt', 'NegReg', (70, 77))	('leukemic', 'Disease', (136, 144))	('growth factor independence', 'CPA', (106, 132))	('leukemic', 'Disease', 'MESH:D007938', (136, 144))	('differentiation', 'CPA', (78, 93))
93737	24478380	Therefore, 2HG may very well be the primary oncogenic effector of mutant IDH1 and IDH2 activity.	('IDH1', 'Gene', '3417', (73, 77))	('mutant', 'Var', (66, 72))	('IDH2', 'Gene', (82, 86))	('IDH2', 'Gene', '3418', (82, 86))	('IDH1', 'Gene', (73, 77))
93742	24478380	The neomorphic activity of mutant IDH1 and IDH2 in the production of the cell-permeable 2HG oncometabolite lends itself for use as a circulating biomarker.	('IDH1', 'Gene', '3417', (34, 38))	('mutant', 'Var', (27, 33))	('IDH2', 'Gene', (43, 47))	('IDH2', 'Gene', '3418', (43, 47))	('IDH1', 'Gene', (34, 38))
93749	24478380	From our small cohort analysis, a threshold of circulating 2HG levels >170 ng/ml could predict the presence of an IDH1/2 mutation in an ICC patient with a sensitivity of 83% and a specificity of 90%.	('IDH1/2', 'Gene', (114, 120))	('mutation', 'Var', (121, 129))	('patient', 'Species', '9606', (140, 147))
93753	24478380	In summary, our study suggests that circulating 2HG may serve as a surrogate biomarker of IDH1 or IDH2 mutation status in ICC that is related to tumor burden.	('IDH1', 'Gene', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('IDH1', 'Gene', '3417', (90, 94))	('IDH2', 'Gene', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('ICC', 'Disease', (122, 125))	('mutation', 'Var', (103, 111))	('IDH2', 'Gene', '3418', (98, 102))
93756	24478380	Mutations in the IDH1 and IDH2 (IDH1/2) genes represent a new genetic signature in intrahepatic cholangiocarcinoma (ICC).	('IDH1', 'Gene', (32, 36))	('IDH2', 'Gene', (26, 30))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 114))	('IDH1', 'Gene', '3417', (32, 36))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', (17, 21))	('intrahepatic cholangiocarcinoma', 'Disease', (83, 114))	('IDH2', 'Gene', '3418', (26, 30))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))	('IDH1', 'Gene', '3417', (17, 21))
93757	24478380	While accumulation of 2-hydroxyglutarate (2HG) has been previously detected in the tumor, it remains unknown whether IDH1/2 mutations can lead to high levels of 2HG circulating in the blood.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('lead to', 'Reg', (138, 145))	('mutations', 'Var', (124, 133))	('tumor', 'Disease', (83, 88))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (22, 40))	('IDH1/2', 'Gene', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
93758	24478380	Our exploratory study has provided evidence that elevated circulating levels of 2HG in IDH1/2 mutant ICC patients may serve as a surrogate biomarker of IDH1/2 mutation status in ICC patients.	('IDH1/2', 'Gene', (87, 93))	('ICC', 'Disease', (101, 104))	('patients', 'Species', '9606', (105, 113))	('circulating levels of 2HG', 'MPA', (58, 83))	('mutant', 'Var', (94, 100))	('patients', 'Species', '9606', (182, 190))	('elevated', 'PosReg', (49, 57))
93768	18154639	Kaplan-Maier analysis suggested that the expression of HSP27 significantly worsened the patients' median overall survival (11 +- 3.18 vs 55 +- 4.1 months, P-value = 0.0003).	('HSP27', 'Gene', '3315', (55, 60))	('HSP27', 'Gene', (55, 60))	('patients', 'Species', '9606', (88, 96))	('worsened', 'NegReg', (75, 83))	('overall survival', 'MPA', (105, 121))	('expression', 'Var', (41, 51))
93817	18154639	Kaplan-Maier analysis showed that patients with pHH3 index above cutpoint (2.4%, P-value = 0.034) had a shorter median overall survival (28.5 months) that did the patients with pHH3 index below cutpoint (> 50 months) (P-value = 0.025).	('pHH3 index', 'Var', (48, 58))	('patients', 'Species', '9606', (163, 171))	('pHH3', 'Chemical', '-', (177, 181))	('shorter', 'NegReg', (104, 111))	('patients', 'Species', '9606', (34, 42))	('overall survival', 'MPA', (119, 135))	('pHH3', 'Chemical', '-', (48, 52))
93818	18154639	The aggregate expression of HSPs was significantly associated (P-value = 0.0032) with a marked decrease of overall survival rates: the median survival for those patients with positivity for HSPs expression was 20.9 +- 8.3 months (with 13 deaths out of 21 patients) while was more than 57.5 months for those 10 patients without HSPs expression (only one patient died) with a power of 0.73.	('decrease', 'NegReg', (95, 103))	('positivity', 'Var', (175, 185))	('patients', 'Species', '9606', (310, 318))	('patient', 'Species', '9606', (353, 360))	('patient', 'Species', '9606', (161, 168))	('patient', 'Species', '9606', (255, 262))	('patients', 'Species', '9606', (255, 263))	('overall', 'MPA', (107, 114))	('patients', 'Species', '9606', (161, 169))	('patient', 'Species', '9606', (310, 317))	('HSPs', 'Protein', (190, 194))
93820	18154639	The presence of HSP72 did not affect patients'overall survival (53 vs 28.5 months P-value = 0.155, with a power of 0.51).	('presence', 'Var', (4, 12))	('HSP72', 'Gene', (16, 21))	('HSP72', 'Gene', '3303', (16, 21))	('patients', 'Species', '9606', (37, 45))
93822	18154639	It is interesting to note that the presence of HSP27, in the absence of HSP72, determined the worst median survival (7 +- 3.2 months, with 4 deaths out of 6 patients).	('presence', 'Var', (35, 43))	('HSP72', 'Gene', (72, 77))	('HSP72', 'Gene', '3303', (72, 77))	('patients', 'Species', '9606', (157, 165))	('HSP27', 'Gene', '3315', (47, 52))	('HSP27', 'Gene', (47, 52))
93845	18154639	This observation is in agreement with recent reports indicating that the knock-down of HSP27 with siRNA or oligo anti-sense RNA in tumor cell lines induces apoptosis and enhances sensitivity to chemotherapic treatments Elevated expression of HSP72 either individually or in combination with other HSPs (HSP27 or HSP90) has been widely reported in several solid cancer, and various leukaemia.	('HSP90', 'Gene', '3320', (312, 317))	('enhances', 'PosReg', (170, 178))	('HSP27', 'Gene', '3315', (87, 92))	('sensitivity to chemotherapic treatments', 'MPA', (179, 218))	('HSP27', 'Gene', '3315', (303, 308))	('tumor', 'Disease', (131, 136))	('leukaemia', 'Disease', 'MESH:D007938', (381, 390))	('cancer', 'Disease', 'MESH:D009369', (361, 367))	('apoptosis', 'CPA', (156, 165))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('induces', 'Reg', (148, 155))	('HSP27', 'Gene', (87, 92))	('HSP27', 'Gene', (303, 308))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('HSP72', 'Gene', (242, 247))	('cancer', 'Disease', (361, 367))	('HSP90', 'Gene', (312, 317))	('leukaemia', 'Disease', (381, 390))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('knock-down', 'Var', (73, 83))	('HSP72', 'Gene', '3303', (242, 247))
93848	18154639	In contrast, high HSP72 expression correlated with good prognosis in esophageal, pancreatic and renal cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('HSP72', 'Gene', '3303', (18, 23))	('pancreatic and renal cancer', 'Disease', 'MESH:D007680', (81, 108))	('high', 'Var', (13, 17))	('expression', 'MPA', (24, 34))	('HSP72', 'Gene', (18, 23))	('renal cancer', 'Phenotype', 'HP:0009726', (96, 108))	('esophageal', 'Disease', (69, 79))
93854	18154639	The present study suggests that HSP27 expression facilitates IHCCA progression likely by inhibiting apoptotic cell death, and the assessment of HSP27 expression by immunostaining in IHCCA might help to detect those patients with a high risk of death.	('patients', 'Species', '9606', (215, 223))	('HSP27', 'Gene', '3315', (144, 149))	('inhibiting', 'NegReg', (89, 99))	('HSP27', 'Gene', (32, 37))	('facilitates', 'PosReg', (49, 60))	('expression', 'Var', (38, 48))	('HSP27', 'Gene', '3315', (32, 37))	('IHCCA', 'Disease', (61, 66))	('apoptotic cell death', 'CPA', (100, 120))	('HSP27', 'Gene', (144, 149))
93855	18154639	Accordingly, univariate Cox regression analysis (see Table 2) shows a significant relation between the presence of HSP27 and probability to die.	('presence', 'Var', (103, 111))	('HSP27', 'Gene', (115, 120))	('Cox', 'Gene', '1351', (24, 27))	('HSP27', 'Gene', '3315', (115, 120))	('Cox', 'Gene', (24, 27))
93856	18154639	The development of strategies targeting the modulation of HSP27 expression in IHCCA may allow control over tumor expansion and improve patients' survival.	('HSP27', 'Gene', '3315', (58, 63))	('patients', 'Species', '9606', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('improve', 'PosReg', (127, 134))	('tumor', 'Disease', (107, 112))	('modulation', 'Var', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('HSP27', 'Gene', (58, 63))
93857	18154639	Downregulation of HSP27 gene expression by nucleotide-based therapies or increased phosphorylation (inactivation) of HSP27 protein by specific phosphatase inhibition could also restore tumor cell sensitivity towards apoptosis and chemosensitizes cells to chemotherapy.	('tumor', 'Disease', (185, 190))	('HSP27', 'Gene', (18, 23))	('increased', 'PosReg', (73, 82))	('HSP27', 'Gene', '3315', (117, 122))	('HSP27', 'Gene', (117, 122))	('HSP27', 'Gene', '3315', (18, 23))	('Downregulation', 'NegReg', (0, 14))	('restore', 'PosReg', (177, 184))	('phosphorylation', 'MPA', (83, 98))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('inhibition', 'Var', (155, 165))	('expression', 'MPA', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('protein', 'Protein', (123, 130))
93862	18154639	The expression of HSP27 significantly worsened the patients' median overall survival.	('HSP27', 'Gene', (18, 23))	('HSP27', 'Gene', '3315', (18, 23))	('patients', 'Species', '9606', (51, 59))	('worsened', 'NegReg', (38, 46))	('expression', 'Var', (4, 14))
93890	17376238	Adverse effects included mild leucopenia, thrombocytopenia (80000/mul), mild increase in alkaline phosphatase (200 U/l) and alopecia.	('alopecia', 'Disease', (124, 132))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (42, 58))	('alopecia', 'Phenotype', 'HP:0001596', (124, 132))	('leucopenia', 'Disease', (30, 40))	('80000/mul', 'Var', (60, 69))	('increase in alkaline phosphatase', 'Phenotype', 'HP:0003155', (77, 109))	('thrombocytopenia', 'Disease', (42, 58))	('increase', 'PosReg', (77, 85))	('leucopenia', 'Disease', 'MESH:C536227', (30, 40))	('thrombocytopenia', 'Disease', 'MESH:D013921', (42, 58))
93915	31383016	However, it is currently believed that patients with low TMB, microsatellite stable (MSS), proficient mismatch repair (pMMR) or negative PD-L1 expression are less likely to benefit from PD-1 blockade.	('microsatellite', 'Var', (62, 76))	('patients', 'Species', '9606', (39, 47))	('PD-L1', 'Gene', '29126', (137, 142))	('low', 'Var', (53, 56))	('negative', 'NegReg', (128, 136))	('PD-L1', 'Gene', (137, 142))	('MSS', 'Chemical', '-', (85, 88))	('TMB', 'MPA', (57, 60))	('PD-1', 'Gene', (186, 190))	('PD-1', 'Gene', '5133', (186, 190))	('TMB', 'Chemical', '-', (57, 60))
93916	31383016	Here we provide the first report on the therapeutic responses of ICC patients treated with combined PD-1 blockade with stereotactic body radiotherapy (SBRT) (Cyberknife) in the background of low TMB, MSS, pMMR and negative PD-L1 expression.	('MSS', 'MPA', (200, 203))	('blockade', 'Var', (105, 113))	('low', 'NegReg', (191, 194))	('PD-L1', 'Gene', '29126', (223, 228))	('stereotactic body', 'Phenotype', 'HP:0000733', (119, 136))	('TMB', 'MPA', (195, 198))	('TMB', 'Chemical', '-', (195, 198))	('MSS', 'Chemical', '-', (200, 203))	('PD-1', 'Gene', (100, 104))	('PD-1', 'Gene', '5133', (100, 104))	('pMMR', 'MPA', (205, 209))	('PD-L1', 'Gene', (223, 228))	('patients', 'Species', '9606', (69, 77))	('negative', 'NegReg', (214, 222))	('ICC', 'Disease', (65, 68))	('expression', 'MPA', (229, 239))
93924	31383016	This study provided the first set of evidence for the effectiveness of SBRT and PD-1 blockade combined therapy in late-stage or recurrent ICC patients with low TMB, MSS, pMMR and negative PD-L1 expression, and potentially expanded the indications of the combined therapy to those patients who were previously not suitable for immunotherapy.	('PD-1', 'Gene', '5133', (80, 84))	('patients', 'Species', '9606', (280, 288))	('SBRT', 'Gene', (71, 75))	('negative', 'NegReg', (179, 187))	('TMB', 'MPA', (160, 163))	('MSS', 'Var', (165, 168))	('PD-L1', 'Gene', (188, 193))	('expression', 'MPA', (194, 204))	('TMB', 'Chemical', '-', (160, 163))	('PD-1', 'Gene', (80, 84))	('patients', 'Species', '9606', (142, 150))	('MSS', 'Chemical', '-', (165, 168))	('low', 'NegReg', (156, 159))	('PD-L1', 'Gene', '29126', (188, 193))	('ICC', 'Disease', (138, 141))
93943	31383016	With the combination of SBRT and nivolumab, the diameter of intrahepatic irradiated lesions decreased by 38.9%, and the diameters of nonirradiated lesions by 36.7%~ 47.8% after 13 months of the initiation of combined therapy, achieving overall PR with the sum of the diameter decreased by 40.9%.	('combination', 'Interaction', (9, 20))	('diameter', 'MPA', (48, 56))	('intrahepatic irradiated lesions', 'Disease', (60, 91))	('nivolumab', 'Var', (33, 42))	('intrahepatic irradiated lesions', 'Disease', 'MESH:D002780', (60, 91))	('decreased', 'NegReg', (92, 101))	('nivolumab', 'Chemical', 'MESH:D000077594', (33, 42))
93969	31383016	The combination of immunotherapy (pembrolizumab) with targeted therapy (ramucirumab) was shown to be effective for advanced cholangiocarcinoma, and patients with PD-L1 positive expression exhibited improved overall survival compared with PD-L1 negative patients.	('patients', 'Species', '9606', (148, 156))	('PD-L1', 'Gene', (238, 243))	('PD-L1', 'Gene', '29126', (162, 167))	('cholangiocarcinoma', 'Disease', (124, 142))	('patients', 'Species', '9606', (253, 261))	('ramucirumab', 'Chemical', 'MESH:C543333', (72, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('overall', 'MPA', (207, 214))	('PD-L1', 'Gene', '29126', (238, 243))	('positive expression', 'Var', (168, 187))	('improved', 'PosReg', (198, 206))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (124, 142))	('pembrolizumab', 'Chemical', 'MESH:C582435', (34, 47))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (124, 142))	('PD-L1', 'Gene', (162, 167))
93971	31383016	Combined therapy of PD-1 blockade with chemotherapy emerged very recently as a new option for advanced or recurrent ICC, and a few case reports showed promising results: patients with high TMB or high INDEL mutation frequency achieved marked response to the combined therapy.	('patients', 'Species', '9606', (170, 178))	('TMB', 'Chemical', '-', (189, 192))	('PD-1', 'Gene', (20, 24))	('PD-1', 'Gene', '5133', (20, 24))	('high INDEL mutation', 'Var', (196, 215))
93972	31383016	It appeared that ICC patients with high TMB, MSI-H, dMMR and/or PD-L1 positive expression can benefit from immunotherapy or its combination with targeted therapy or chemotherapy.	('MSI-H', 'Disease', 'MESH:D000848', (45, 50))	('benefit', 'PosReg', (94, 101))	('PD-L1', 'Gene', (64, 69))	('patients', 'Species', '9606', (21, 29))	('TMB', 'Gene', (40, 43))	('dMMR', 'Gene', (52, 56))	('dMMR', 'Chemical', '-', (52, 56))	('MSI-H', 'Disease', (45, 50))	('ICC', 'Disease', (17, 20))	('TMB', 'Chemical', '-', (40, 43))	('high', 'Var', (35, 39))	('PD-L1', 'Gene', '29126', (64, 69))
93984	31383016	Studies on the combination of immunotherapy with chemotherapy or targeted therapy showed that ICC patients with high TMB, dMMR, MSI or positive PD-L1 expression exhibited better response, while most studies on the combination of immunotherapy with radiotherapy in various cancers did not describe the status of TMB, MMR, MSS or PD-L1 expression.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('high', 'Var', (112, 116))	('TMB', 'Chemical', '-', (117, 120))	('PD-L1', 'Gene', (144, 149))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('cancers', 'Disease', (272, 279))	('PD-L1', 'Gene', '29126', (144, 149))	('TMB', 'Chemical', '-', (311, 314))	('ICC', 'Disease', (94, 97))	('MSS', 'Chemical', '-', (321, 324))	('dMMR', 'Chemical', '-', (122, 126))	('MSI', 'Disease', 'None', (128, 131))	('patients', 'Species', '9606', (98, 106))	('MSI', 'Disease', (128, 131))	('cancers', 'Disease', 'MESH:D009369', (272, 279))	('PD-L1', 'Gene', (328, 333))	('TMB', 'Gene', (117, 120))	('expression', 'Var', (150, 160))	('PD-L1', 'Gene', '29126', (328, 333))
93993	31383016	Our cases highlighted the therapeutic potential of the combination of radiotherapy with immunotherapy for late-stage or recurrent ICC patients with low TMB, pMMR, MSS and negative PD-L1 expression, and expanded immunotherapy to those patients who were previously regarded as unsuitable for PD-1 blockade.	('PD-1', 'Gene', (290, 294))	('MSS', 'Chemical', '-', (163, 166))	('negative', 'NegReg', (171, 179))	('PD-L1', 'Gene', '29126', (180, 185))	('TMB', 'MPA', (152, 155))	('PD-1', 'Gene', '5133', (290, 294))	('patients', 'Species', '9606', (134, 142))	('TMB', 'Chemical', '-', (152, 155))	('ICC', 'Disease', (130, 133))	('patients', 'Species', '9606', (234, 242))	('expression', 'MPA', (186, 196))	('MSS', 'Var', (163, 166))	('PD-L1', 'Gene', (180, 185))	('low', 'NegReg', (148, 151))
94123	24396454	With advances in biotechnological techniques and a deepened understanding of the biological behavior of CC, specific markers have been studied, including TP53 gene mutation, cyclins and proliferation indices.	('mutation', 'Var', (164, 172))	('CC', 'Phenotype', 'HP:0030153', (104, 106))	('TP53', 'Gene', '7157', (154, 158))	('TP53', 'Gene', (154, 158))
94151	24396454	The expression of FXYD6 in CC and normal bile duct tissues was evaluated with whole slide scanning under low magnification (x40) and then confirmed under high magnification (x200 and x400).	('FXYD6', 'Gene', '53826', (18, 23))	('CC', 'Phenotype', 'HP:0030153', (27, 29))	('x400', 'Var', (183, 187))	('FXYD6', 'Gene', (18, 23))
94205	22248567	The affinities (KD) of A10-A3 and cA10-A3 for soluble L1CAM were 1.8 nM and 1.9 nM, respectively, as determined by competition ELISA.	('A10-A3', 'Chemical', '-', (23, 29))	('cA10-A3', 'Var', (34, 41))	('L1CAM', 'Protein', (54, 59))	('A10-A3', 'Var', (23, 29))	('A10-A3', 'Chemical', '-', (35, 41))	('affinities', 'MPA', (4, 14))
94206	22248567	A10-A3 inhibited L1CAM homophilic binding and was slowly internalized into the tumor cells, but it did not significantly inhibit proliferation of ICC cells in vitro.	('inhibit', 'NegReg', (121, 128))	('tumor', 'Disease', (79, 84))	('A10-A3', 'Chemical', '-', (0, 6))	('L1CAM', 'Protein', (17, 22))	('inhibited', 'NegReg', (7, 16))	('A10-A3', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
94207	22248567	cA10-A3 mediated antibody-dependent cell-mediated cytotoxicity in vitro and displayed anti-tumor activity in the ICC animal model.	('A10-A3', 'Chemical', '-', (1, 7))	('cytotoxicity', 'Disease', 'MESH:D064420', (50, 62))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('cA10-A3', 'Var', (0, 7))	('cytotoxicity', 'Disease', (50, 62))
94208	22248567	These results suggest that the humanized A10-A3 antibody may have potential as an anticancer agent for the treatment of ICC.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('A10-A3', 'Chemical', '-', (41, 47))	('human', 'Species', '9606', (31, 36))	('A10-A3', 'Var', (41, 47))	('ICC', 'Disease', (120, 123))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
94217	22248567	In addition, ectopic L1CAM expression in carcinoma cells enhances their migration, invasion, and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('migration', 'CPA', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('ectopic', 'Var', (13, 20))	('carcinoma', 'Disease', (41, 50))	('enhances', 'PosReg', (57, 65))	('tumor', 'Disease', (97, 102))	('invasion', 'CPA', (83, 91))	('carcinoma', 'Disease', 'MESH:D002277', (41, 50))	('L1CAM', 'Gene', (21, 26))
94223	22248567	To characterize A10-A3, we performed epitope mapping, which showed that A10-A3 binds to the Ig1 domain of L1CAM.	('A10-A3', 'Chemical', '-', (16, 22))	('A10-A3', 'Chemical', '-', (72, 78))	('binds', 'Interaction', (79, 84))	('A10-A3', 'Var', (72, 78))
94226	22248567	After its purity and integrity was confirmed by SDS-PAGE (Figure 1A, lane 2), the purified hL1-ECD-S1 protein was used as an antigen to determine the affinity of A10-A3 by an indirect ELISA followed by a competition ELISA (Figures 1B and 1C).	('hL1', 'Gene', '3897', (91, 94))	('A10-A3', 'Var', (162, 168))	('hL1', 'Gene', (91, 94))	('ECD', 'Gene', (95, 98))	('affinity', 'Interaction', (150, 158))	('ECD', 'Gene', '11319', (95, 98))	('A10-A3', 'Chemical', '-', (162, 168))	('SDS', 'Chemical', 'MESH:D012967', (48, 51))
94227	22248567	The affinity (KD) of A10-A3 for hL1-ECD-S1 was 1.8 nM.	('A10-A3', 'Chemical', '-', (21, 27))	('hL1', 'Gene', (32, 35))	('ECD', 'Gene', (36, 39))	('A10-A3', 'Var', (21, 27))	('ECD', 'Gene', '11319', (36, 39))	('hL1', 'Gene', '3897', (32, 35))
94231	22248567	In 1 h, A10-A3 effectively bound to the plasma membrane of the cells, and it was internalized into endocytic vesicles of the SCK-LI cells at 6 h after the antibody treatment (Figure 2B).	('bound', 'Interaction', (27, 32))	('A10-A3', 'Var', (8, 14))	('A10-A3', 'Chemical', '-', (8, 14))
94234	22248567	Since A10-A3 binds to the Ig1 domain with a high affinity, it may efficiently block L1CAM homophilic binding.	('A10-A3', 'Var', (6, 12))	('A10-A3', 'Chemical', '-', (6, 12))	('block', 'NegReg', (78, 83))	('L1CAM', 'Protein', (84, 89))
94238	22248567	A10-A3 inhibited the homophilic binding in a dose-dependent manner (Figure 3B).	('homophilic binding', 'Interaction', (21, 39))	('inhibited', 'NegReg', (7, 16))	('A10-A3', 'Chemical', '-', (0, 6))	('A10-A3', 'Var', (0, 6))
94242	22248567	For the inhibition study, cells were preincubated with A10-A3 or control antibody for 3 h and allowed to bind to hL1-ECD-Fc.	('hL1', 'Gene', '3897', (113, 116))	('ECD', 'Gene', (117, 120))	('bind', 'Interaction', (105, 109))	('ECD', 'Gene', '11319', (117, 120))	('hL1', 'Gene', (113, 116))	('A10-A3', 'Chemical', '-', (55, 61))	('A10-A3', 'Var', (55, 61))
94243	22248567	A10-A3 efficiently inhibited the binding between the cells and hL1-ECD-Fc, decreasing the binding to a level that was similar to the binding observed between the cells and Ig5-6/Fn1-5-Fc.	('ECD', 'Gene', '11319', (67, 70))	('inhibited', 'NegReg', (19, 28))	('decreasing', 'NegReg', (75, 85))	('A10-A3', 'Chemical', '-', (0, 6))	('binding', 'Interaction', (90, 97))	('ECD', 'Gene', (67, 70))	('hL1', 'Gene', '3897', (63, 66))	('A10-A3', 'Var', (0, 6))	('binding', 'Interaction', (33, 40))	('hL1', 'Gene', (63, 66))
94245	22248567	The results suggest that A10-A3 specifically inhibits L1CAM homophilic binding.	('inhibits', 'NegReg', (45, 53))	('A10-A3', 'Var', (25, 31))	('A10-A3', 'Chemical', '-', (25, 31))	('L1CAM', 'Protein', (54, 59))
94247	22248567	A10-A3 hardly inhibited the proliferation of the cells (data not shown).	('inhibited', 'NegReg', (14, 23))	('A10-A3', 'Chemical', '-', (0, 6))	('A10-A3', 'Var', (0, 6))
94253	22248567	To evaluate whether cA10-A3 mediates antibody-dependent cell-mediated cytotoxicity (ADCC), a standard lactate dehydrogenase (LDH) assay was performed using SCK-L1 as target cells and human PBMC as effector cells.	('cA10-A3', 'Var', (20, 27))	('cytotoxicity', 'Disease', 'MESH:D064420', (70, 82))	('A10-A3', 'Chemical', '-', (21, 27))	('L1', 'Gene', '3897', (160, 162))	('human', 'Species', '9606', (183, 188))	('cytotoxicity', 'Disease', (70, 82))
94255	22248567	The cA10-A3 was effective in inducing ADCC against SCK-L1 cells in a dose-dependent manner (Figure 4A), and the ADCC activity of antibody at 10 microg/ml concentration was increased with the ratio of E:T 60:1 (Figure 4B).	('A10-A3', 'Chemical', '-', (5, 11))	('ADCC', 'MPA', (38, 42))	('activity', 'MPA', (117, 125))	('cA10-A3', 'Var', (4, 11))	('increased', 'PosReg', (172, 181))	('L1', 'Gene', '3897', (55, 57))	('inducing', 'Reg', (29, 37))	('ADCC', 'MPA', (112, 116))
94258	22248567	The cA10-A3 inhibited the tumor growth in nude mice without affecting body weight (Figure 5).	('inhibited', 'NegReg', (12, 21))	('A10-A3', 'Chemical', '-', (5, 11))	('cA10-A3', 'Var', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('nude mice', 'Species', '10090', (42, 51))
94265	22248567	Anti-L1CAM mAb has displayed therapeutic activity in a mouse model for ovarian carcinoma.	('Anti-L1CAM', 'Var', (0, 10))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (71, 88))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (71, 88))	('mouse', 'Species', '10090', (55, 60))	('ovarian carcinoma', 'Disease', (71, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))
94268	22248567	The cA10-A3 inhibited tumor growth in nude mice, suggesting potential for anti-L1CAM therapeutic antibodies as an anti-cancer agent for the ICC treatment.	('inhibited', 'NegReg', (12, 21))	('A10-A3', 'Chemical', '-', (5, 11))	('cA10-A3', 'Var', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('cancer', 'Disease', (119, 125))	('nude mice', 'Species', '10090', (38, 47))	('tumor', 'Disease', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
94269	22248567	The results of the internalization assay indicated that A10-A3 was internalized into endocytic vesicles, suggesting that the L1CAM bound by A10-A3 may be also internalized.	('A10-A3', 'Chemical', '-', (140, 146))	('internalized', 'MPA', (159, 171))	('A10-A3', 'Var', (140, 146))	('A10-A3', 'Chemical', '-', (56, 62))	('bound', 'Interaction', (131, 136))
94270	22248567	However, the endocytic vesicles were not detected until 3 h after addition of the antibody and were clearly detected at 6 h. This suggests that internalization of A10-A3 proceeds slowly in the cells and thus may not substantially impact the ADCC activity of A10-A3.	('internalization', 'MPA', (144, 159))	('ADCC', 'Enzyme', (241, 245))	('A10-A3', 'Chemical', '-', (258, 264))	('activity', 'MPA', (246, 254))	('impact', 'Reg', (230, 236))	('A10-A3', 'Chemical', '-', (163, 169))	('slowly', 'NegReg', (179, 185))	('A10-A3', 'Var', (163, 169))
94271	22248567	In contrast, a previous study using human epidermoid carcinoma cells showed that anti-EGFR mAb, mAb-225 was internalized into endocytic vesicles within 1 h. L1CAM plays an important role in tumor progression through homophilic binding and heterophilic interaction with other cell surface proteins, such as growth factor receptors and integrins.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('EGFR', 'Gene', '1956', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('epidermoid carcinoma', 'Disease', 'MESH:D002294', (42, 62))	('L1CAM', 'Var', (157, 162))	('epidermoid carcinoma', 'Disease', (42, 62))	('EGFR', 'Gene', (86, 90))	('tumor', 'Disease', (190, 195))	('heterophilic', 'MPA', (239, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('human', 'Species', '9606', (36, 41))	('homophilic', 'MPA', (216, 226))
94272	22248567	For example, the Ig6 domain of L1CAM contains an RGD motif that interacts with alphavbeta3 integrin; inhibition of this binding significantly reduces haptotactic migration of melanoma cells.	('inhibition', 'Var', (101, 111))	('reduces', 'NegReg', (142, 149))	('interacts', 'Interaction', (64, 73))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('melanoma', 'Disease', (175, 183))	('alphavbeta3 integrin', 'Protein', (79, 99))	('L1CAM', 'Gene', (31, 36))
94275	22248567	In the present study, we observed that A10-A3 inhibited L1CAM homophilic binding, but did not significantly inhibit ICC cell proliferation in vitro.	('A10-A3', 'Var', (39, 45))	('L1CAM', 'Protein', (56, 61))	('A10-A3', 'Chemical', '-', (39, 45))	('inhibit', 'NegReg', (108, 115))	('inhibited', 'NegReg', (46, 55))
94278	22248567	It might also be valuable to generate anti-L1CAM antibodies that can inhibit these heterophilic interactions to evaluate their therapeutic potential for the development of more effective anticancer antibodies.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('heterophilic interactions', 'MPA', (83, 108))	('anti-L1CAM', 'Var', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('inhibit', 'NegReg', (69, 76))
94279	22248567	Taken together, our results suggest that cA10-A3 inhibits L1CAM homophilic binding and mediates ADCC, while it is internalized into the tumor cells slowly.	('cA10-A3', 'Var', (41, 48))	('ADCC', 'Disease', (96, 100))	('mediates', 'Reg', (87, 95))	('inhibits', 'NegReg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('A10-A3', 'Chemical', '-', (42, 48))	('L1CAM', 'Protein', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
94280	22248567	The cA10-A3 displayed anti-tumor activity in a human ICC xenograft nude mice model.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('A10-A3', 'Chemical', '-', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cA10-A3', 'Var', (4, 11))	('tumor', 'Disease', (27, 32))	('nude mice', 'Species', '10090', (67, 76))	('human', 'Species', '9606', (47, 52))
94294	22248567	A solution containing 3.165 ng of purified A10-A3 or cA10-A3 and various concentrations (5 x 10-13 - 5 x 10-8 M) of the purified hL1-ECD-S1 protein was preincubated at 37C for 3 h, then the mixture was added to each well coated with 100 ng of hL1-ECD-S1 and subjected to an indirect ELISA.	('ECD', 'Gene', '11319', (133, 136))	('A10-A3', 'Chemical', '-', (54, 60))	('A10-A3', 'Var', (43, 49))	('hL1', 'Gene', '3897', (243, 246))	('ECD', 'Gene', '11319', (247, 250))	('hL1', 'Gene', '3897', (129, 132))	('cA10-A3', 'Var', (53, 60))	('hL1', 'Gene', (243, 246))	('hL1', 'Gene', (129, 132))	('ECD', 'Gene', (133, 136))	('ECD', 'Gene', (247, 250))	('A10-A3', 'Chemical', '-', (43, 49))
94331	33202975	Especially for intrahepatic cholangiocarcinoma (iCCA) novel therapeutic targets have been identified, including fibroblast growth factor receptor 2 gene fusions and isocitrate dehydrogenase 1 and 2 mutations, with molecularly targeted agents having shown evidence of activity in this subgroup of patients.	('fibroblast growth factor receptor 2', 'Gene', '2263', (112, 147))	('CCA', 'Phenotype', 'HP:0030153', (49, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('patients', 'Species', '9606', (296, 304))	('mutations', 'Var', (198, 207))	('isocitrate dehydrogenase', 'Gene', (165, 189))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (28, 46))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (15, 46))	('isocitrate dehydrogenase', 'Gene', '3417', (165, 189))	('fibroblast growth factor receptor 2', 'Gene', (112, 147))	('intrahepatic cholangiocarcinoma', 'Disease', (15, 46))
94342	33202975	In particular, the BTC phenotype is related to the genetic and epigenetic alterations in tumor cells and is also influenced by the molecular cross-talk between the neoplastic cells and the surrounding microenvironment.	('related', 'Reg', (36, 43))	('BTC', 'Phenotype', 'HP:0100574', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('influenced by', 'Reg', (113, 126))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('epigenetic alterations', 'Var', (63, 85))
94345	33202975	Recent positive phase II and III trials of new targeted therapies have been published and the United States Food and Drug Administration (FDA) has approved pemigatinib, a fibroblast growth factor receptor (FGFR) inhibitor, for patients with advanced BTC with FGFR2 gene fusions, previously treated with the standard of care, making pemigatinib the first targeted agent approved for patients with BTC.	('patients', 'Species', '9606', (382, 390))	('pemigatinib', 'Chemical', '-', (156, 167))	('BTC', 'Phenotype', 'HP:0100574', (250, 253))	('FGFR2', 'Gene', (259, 264))	('fusions', 'Var', (270, 277))	('pemigatinib', 'Chemical', '-', (332, 343))	('FGFR2', 'Gene', '2263', (259, 264))	('BTC', 'Phenotype', 'HP:0100574', (396, 399))	('patients', 'Species', '9606', (227, 235))
94350	33202975	Deep sequencing studies have improved our understanding of the genomic complexity in iCCA and have identified the main targetable genetic alterations in the form of isocitrate dehydrogenase (IDH) and FGFR.	('iCCA', 'Disease', (85, 89))	('alterations', 'Var', (138, 149))	('CCA', 'Phenotype', 'HP:0030153', (86, 89))	('IDH', 'Gene', (191, 194))	('isocitrate dehydrogenase', 'Gene', (165, 189))	('IDH', 'Gene', '3417', (191, 194))	('isocitrate dehydrogenase', 'Gene', '3417', (165, 189))	('FGFR', 'Gene', (200, 204))
94351	33202975	Interestingly, the predominant genomic alterations in CCA are associated with epigenetic processes; 10-20% of iCCA tumors present mutations in IDH, with IDH1 and IDH2 being the ones of relevance in cancer, due to their involvement in cell metabolism.	('IDH1', 'Gene', (153, 157))	('iCCA tumors', 'Disease', 'MESH:D009369', (110, 121))	('IDH', 'Gene', '3417', (162, 165))	('IDH', 'Gene', (153, 156))	('IDH', 'Gene', (143, 146))	('cancer', 'Disease', (198, 204))	('IDH1', 'Gene', '3417', (153, 157))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('CCA', 'Phenotype', 'HP:0030153', (111, 114))	('CCA', 'Phenotype', 'HP:0030153', (54, 57))	('IDH2', 'Gene', (162, 166))	('IDH', 'Gene', '3417', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('IDH2', 'Gene', '3418', (162, 166))	('IDH', 'Gene', '3417', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('IDH', 'Gene', (162, 165))	('mutations', 'Var', (130, 139))	('iCCA tumors', 'Disease', (110, 121))
94353	33202975	FGFR2 rearrangement is the most common type of FGFR aberration with prevalence 14%-23% and occurring almost invariably in iCCA.	('CCA', 'Phenotype', 'HP:0030153', (123, 126))	('rearrangement', 'Var', (6, 19))	('iCCA', 'Disease', (122, 126))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))
94354	33202975	BICC1 is the most frequent FGFR2 rearrangement partner (29.7%) whereas, confirming findings from prior studies of whole-genome and targeted exon sequencing of iCCA, FGR2 translocation has been reported as mutually exclusive with IDH1 mutations.	('FGFR2', 'Gene', (27, 32))	('FGFR2', 'Gene', '2263', (27, 32))	('IDH1', 'Gene', (229, 233))	('translocation', 'Var', (170, 183))	('BICC1', 'Gene', (0, 5))	('IDH1', 'Gene', '3417', (229, 233))	('CCA', 'Phenotype', 'HP:0030153', (160, 163))	('FGR2', 'Gene', (165, 169))	('BICC1', 'Gene', '80114', (0, 5))	('mutations', 'Var', (234, 243))
94357	33202975	On the other side, the proliferation class (62%) is characterized by activation of oncogenic signaling pathways (i.e., RAS, MAPK, and MET), mutations in KRAS and BRAF.	('activation', 'PosReg', (69, 79))	('oncogenic signaling pathways', 'Pathway', (83, 111))	('MET', 'Gene', '79811', (134, 137))	('RAS', 'Protein', (119, 122))	('MET', 'Gene', (134, 137))	('KRAS', 'Gene', (153, 157))	('KRAS', 'Gene', '3845', (153, 157))	('MAPK', 'Gene', (124, 128))	('mutations', 'Var', (140, 149))	('BRAF', 'Gene', '673', (162, 166))	('BRAF', 'Gene', (162, 166))
94358	33202975	Importantly, it has also been indicated that mutations tend to cluster together and that tumors with IDH mutations have been found to have specific mRNA, copy number, and increased methylation of the ARID1A promoter.	('methylation', 'MPA', (181, 192))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('copy number', 'MPA', (154, 165))	('IDH', 'Gene', (101, 104))	('mutations', 'Var', (105, 114))	('ARID1A', 'Gene', '8289', (200, 206))	('ARID1A', 'Gene', (200, 206))	('IDH', 'Gene', '3417', (101, 104))	('increased', 'PosReg', (171, 180))	('mRNA', 'MPA', (148, 152))
94359	33202975	In contrast, FGFR2-positive tumors seem to associate with BAP1 mutations.	('mutations', 'Var', (63, 72))	('tumors', 'Disease', (28, 34))	('BAP1', 'Gene', (58, 62))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('associate', 'Reg', (43, 52))	('FGFR2', 'Gene', '2263', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('FGFR2', 'Gene', (13, 18))	('BAP1', 'Gene', '8314', (58, 62))
94366	33202975	The extensive whole-exome and transcriptome (RNASeq) sequencing analysis of 29 GBC in Japanese patients found that 35.8% of them present mutations in the ERBB family of proteins (including their downstream genes).	('mutations', 'Var', (137, 146))	('ERBB', 'Gene', '1956', (154, 158))	('patients', 'Species', '9606', (95, 103))	('ERBB', 'Gene', (154, 158))
94369	33202975	Finally, the presence of activating mutations in PIK3CA and HER2 aberrations have also been identified in GBC, while IDH mutations are absent in this type of cancer.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('IDH', 'Gene', (117, 120))	('activating', 'PosReg', (25, 35))	('HER2', 'Gene', (60, 64))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('mutations', 'Var', (36, 45))	('IDH', 'Gene', '3417', (117, 120))	('cancer', 'Disease', (158, 164))	('HER2', 'Gene', '2064', (60, 64))	('PIK3CA', 'Gene', (49, 55))	('PIK3CA', 'Gene', '5290', (49, 55))	('GBC', 'Disease', (106, 109))
94370	33202975	Given the substantial gap between current knowledge on genetic alterations that affect BTC, unfavorable clinical outcomes, and subsets of tumors harboring significantly different transcriptomic profiles, the attention is currently turning on epigenetic alterations that serve as potential pro-oncogenic lesions leading to disparate patterns of DNA methylation, chromatin remodeling or aberrant expression of non-coding RNA.	('chromatin remodeling', 'CPA', (361, 381))	('epigenetic alterations', 'Var', (242, 264))	('expression', 'MPA', (394, 404))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('methylation', 'Var', (348, 359))	('DNA', 'MPA', (344, 347))	('BTC', 'Phenotype', 'HP:0100574', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
94371	33202975	Altered DNA methylation is one of the earliest molecular alterations that characterize tumor development.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('Altered', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
94372	33202975	In particular, hypermethylation occurring in tumor suppressor promoter is a key determinant for the transcriptional inactivation of a gene.	('transcriptional', 'MPA', (100, 115))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('hypermethylation', 'Var', (15, 31))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
94373	33202975	Moreover, recent investigations have pointed out recurrent inactivating mutations or deletions in multiple chromatin-remodeling genes broadly acting as tumor suppressors, such as ARID1A, PBRM1 and BAP1.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('PBRM1', 'Gene', '55193', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('deletions', 'Var', (85, 94))	('ARID1A', 'Gene', '8289', (179, 185))	('inactivating mutations', 'Var', (59, 81))	('ARID1A', 'Gene', (179, 185))	('tumor', 'Disease', (152, 157))	('BAP1', 'Gene', '8314', (197, 201))	('PBRM1', 'Gene', (187, 192))	('BAP1', 'Gene', (197, 201))
94375	33202975	Since mutations inducing loss of function in ARID1A and BAP1 may also inhibit double-strand break repair (DSR), an increased sensitivity to poly ADP ribose polymerase inhibitors (PARPi) has been postulated.	('BAP1', 'Gene', '8314', (56, 60))	('ARID1A', 'Gene', '8289', (45, 51))	('increased sensitivity to poly ADP ribose polymerase', 'Phenotype', 'HP:0003240', (115, 166))	('loss of function', 'NegReg', (25, 41))	('ARID1A', 'Gene', (45, 51))	('double-strand break repair', 'MPA', (78, 104))	('BAP1', 'Gene', (56, 60))	('inhibit', 'NegReg', (70, 77))	('mutations', 'Var', (6, 15))
94376	33202975	A phase II clinical trial testing the PARPi niraparib is underway (NCT03207347) in CCA and solid tumors carrying mutations of genes that regulate the DSR, including ARID1A and BAP1.	('CCA', 'Disease', (83, 86))	('BAP1', 'Gene', '8314', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('ARID1A', 'Gene', '8289', (165, 171))	('ARID1A', 'Gene', (165, 171))	('CCA', 'Phenotype', 'HP:0030153', (83, 86))	('mutations', 'Var', (113, 122))	('BAP1', 'Gene', (176, 180))	('tumors', 'Disease', (97, 103))	('niraparib', 'Chemical', 'MESH:C545685', (44, 53))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
94378	33202975	IDH mutations alone have been associated with a hypermethylator phenotype at both the DNA and histone level, with nearly 50% of the hypermethylated genes corresponding to silenced genes identified in glioblastomas.	('associated', 'Reg', (30, 40))	('glioblastomas', 'Disease', (200, 213))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (4, 13))	('glioblastomas', 'Phenotype', 'HP:0012174', (200, 213))	('glioblastomas', 'Disease', 'MESH:D005909', (200, 213))
94379	33202975	Whereas IDH1 mutations are more frequent than IDH2 mutations, both mutations are mutually exclusive and tend to appear more frequently in recurrent iCCA (Figure 2).	('IDH2', 'Gene', (46, 50))	('IDH1', 'Gene', (8, 12))	('IDH2', 'Gene', '3418', (46, 50))	('CCA', 'Phenotype', 'HP:0030153', (149, 152))	('IDH1', 'Gene', '3417', (8, 12))	('iCCA', 'Disease', (148, 152))	('mutations', 'Var', (13, 22))	('appear', 'Reg', (112, 118))
94381	33202975	Given the enhanced expression of epithelial-to-mesenchymal transition (EMT) traits observed in IDH mutant tumors, putative genes targeted by such genome-wide epigenetic perturbations are felt to play a role in cell differentiation.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('expression', 'MPA', (19, 29))	('tumors', 'Disease', (106, 112))	('enhanced', 'PosReg', (10, 18))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('IDH', 'Gene', '3417', (95, 98))	('epithelial-to-mesenchymal transition', 'CPA', (33, 69))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('IDH', 'Gene', (95, 98))	('mutant', 'Var', (99, 105))
94382	33202975	Differences across Eastern and Western cohorts have been reported in terms of frequency of IDH mutations, suggesting the impact of environmental and etiological factors represented by prevalence of liver fluke infection and hepatitis.	('hepatitis', 'Disease', (224, 233))	('hepatitis', 'Phenotype', 'HP:0012115', (224, 233))	('liver fluke infection', 'Disease', 'MESH:D017093', (198, 219))	('hepatitis', 'Disease', 'MESH:D056486', (224, 233))	('IDH', 'Gene', (91, 94))	('mutations', 'Var', (95, 104))	('liver fluke infection', 'Disease', (198, 219))	('IDH', 'Gene', '3417', (91, 94))
94384	33202975	Whereas liver flukes are associated with CpG island hypermethylation, iCCA carrying IDH1/2 and BAP1 mutations show a prevalent hypermethylation of the CpG shores (the regions immediately flanking CpG islands), implying that somatic mutations in non-fluke-related iCCA determine the downstream hypermethylation patterns.	('mutations', 'Var', (100, 109))	('IDH1/2', 'Gene', (84, 90))	('BAP1', 'Gene', (95, 99))	('CCA', 'Phenotype', 'HP:0030153', (264, 267))	('hypermethylation', 'MPA', (127, 143))	('liver flukes', 'Species', '6192', (8, 20))	('BAP1', 'Gene', '8314', (95, 99))	('CCA', 'Phenotype', 'HP:0030153', (71, 74))
94386	33202975	IDH mutant CCA display significantly decreased chromatin modifier expression, as well as increased mitochondrial gene expression.	('chromatin modifier expression', 'MPA', (47, 76))	('IDH', 'Gene', (0, 3))	('mutant', 'Var', (4, 10))	('CCA', 'Phenotype', 'HP:0030153', (11, 14))	('IDH', 'Gene', '3417', (0, 3))	('mitochondrial', 'MPA', (99, 112))	('CCA', 'Disease', (11, 14))	('increased', 'PosReg', (89, 98))	('decreased', 'NegReg', (37, 46))
94387	33202975	Consistently, IDH mutants hypermethylate and silence the ARID1A promoter, which may contribute to an overall lowered chromatin modifier expression.	('lowered', 'NegReg', (109, 116))	('mutants hypermethylate', 'Var', (18, 40))	('IDH', 'Gene', (14, 17))	('IDH', 'Gene', '3417', (14, 17))	('silence', 'NegReg', (45, 52))	('chromatin modifier expression', 'MPA', (117, 146))	('hypermethylate', 'Var', (26, 40))	('ARID1A', 'Gene', '8289', (57, 63))	('ARID1A', 'Gene', (57, 63))
94388	33202975	This is in line with an epigenomic "snowball effect" whose existence has been postulated examining the sequence that first involves mutant IDH (acting as an oncogene) and downregulated chromatin modifiers (acting as tumor suppressors) thereafter.	('tumor', 'Disease', (216, 221))	('downregulated', 'NegReg', (171, 184))	('mutant', 'Var', (132, 138))	('chromatin modifiers', 'Protein', (185, 204))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('IDH', 'Gene', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('IDH', 'Gene', '3417', (139, 142))
94403	33202975	Altered FGF signaling is implicated in the progression of a multitude of malignancies such as breast, pancreatic cancer and melanoma.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('FGF', 'Protein', (8, 11))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('malignancies', 'Disease', (73, 85))	('Altered', 'Var', (0, 7))	('breast', 'Disease', (94, 100))	('malignancies', 'Disease', 'MESH:D009369', (73, 85))	('implicated', 'Reg', (25, 35))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
94405	33202975	In May 2020 FDA approved pemigatinib for the second-line treatment of metastatic cholangiocarcinoma patients who harbor FGFR mutations.	('mutations', 'Var', (125, 134))	('FGFR', 'Gene', (120, 124))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (81, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (81, 99))	('patients', 'Species', '9606', (100, 108))	('pemigatinib', 'Chemical', '-', (25, 36))	('cholangiocarcinoma', 'Disease', (81, 99))
94407	33202975	There were three cohorts: patients with FGFR2 fusions or rearrangements (n = 107), patients with other FGF/FGFR alterations (n = 20) and patients with no FGF/FGFR alterations (n = 18).	('fusions', 'Var', (46, 53))	('patients', 'Species', '9606', (137, 145))	('patients', 'Species', '9606', (26, 34))	('FGFR2', 'Gene', (40, 45))	('FGFR2', 'Gene', '2263', (40, 45))	('patients', 'Species', '9606', (83, 91))	('rearrangements', 'Var', (57, 71))
94408	33202975	With a median follow up of 17.8 months 38 (36%) patients with FGFR2 fusions or rearrangements had an objective response, complete in 3 of them.	('FGFR2', 'Gene', (62, 67))	('rearrangements', 'Var', (79, 93))	('FGFR2', 'Gene', '2263', (62, 67))	('fusions', 'Var', (68, 75))	('patients', 'Species', '9606', (48, 56))
94409	33202975	The reported DCR was 82% and restricted to FGFR2 fusion/rearrangement carriers.	('FGFR2', 'Gene', '2263', (43, 48))	('DCR', 'Chemical', '-', (13, 16))	('FGFR2', 'Gene', (43, 48))	('fusion/rearrangement', 'Var', (49, 69))
94414	33202975	In a single arm phase II trial, 71 pretreated patients with FGFR2 fusion received infigratinib with ORR being the primary end point.	('patients', 'Species', '9606', (46, 54))	('fusion', 'Var', (66, 72))	('FGFR2', 'Gene', '2263', (60, 65))	('FGFR2', 'Gene', (60, 65))	('infigratinib', 'Chemical', 'MESH:C568950', (82, 94))
94419	33202975	Further, a post hoc analysis of that study reported DCR 67% in a small subset of 6 patients with FGFR2 amplification or mutations, suggesting the opportunity to explore derazantinib efficacy in other settings besides FGFR2 fusions.	('DCR', 'MPA', (52, 55))	('FGFR2', 'Gene', (97, 102))	('derazantinib', 'Chemical', 'MESH:C000621805', (169, 181))	('FGFR2', 'Gene', '2263', (217, 222))	('FGFR2', 'Gene', '2263', (97, 102))	('mutations', 'Var', (120, 129))	('patients', 'Species', '9606', (83, 91))	('DCR', 'Chemical', '-', (52, 55))	('amplification', 'Var', (103, 116))	('FGFR2', 'Gene', (217, 222))
94421	33202975	Of note erdafitinib has obtained FDA approval for the treatment of urothelial cancer patients harboring FGFR2/3 alterations.	('urothelial cancer', 'Disease', 'MESH:D014523', (67, 84))	('patients', 'Species', '9606', (85, 93))	('FGFR2/3', 'Gene', '2263;2261', (104, 111))	('erdafitinib', 'Chemical', 'MESH:C000604580', (8, 19))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('urothelial cancer', 'Disease', (67, 84))	('alterations', 'Var', (112, 123))	('FGFR2/3', 'Gene', (104, 111))
94423	33202975	IDH mutations have been implicated in the pathogenesis of various tumor types.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('IDH', 'Gene', (0, 3))	('tumor', 'Disease', (66, 71))	('IDH', 'Gene', '3417', (0, 3))	('implicated', 'Reg', (24, 34))	('mutations', 'Var', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
94424	33202975	In iCCA the occurrence of IDH1 mutations is 7-20% and for IDH2 mutations 3%.	('IDH2', 'Gene', '3418', (58, 62))	('mutations', 'Var', (31, 40))	('CCA', 'Phenotype', 'HP:0030153', (4, 7))	('IDH1', 'Gene', (26, 30))	('IDH2', 'Gene', (58, 62))	('IDH1', 'Gene', '3417', (26, 30))
94427	33202975	In a phase I dose escalation and expansion study, ivosidenib, IDH1 inhibitor, was given to 77 patients with previously treated CCA harboring IDH1 mutations.	('IDH1', 'Gene', (141, 145))	('CCA', 'Phenotype', 'HP:0030153', (127, 130))	('mutations', 'Var', (146, 155))	('patients', 'Species', '9606', (94, 102))	('IDH1', 'Gene', '3417', (62, 66))	('IDH1', 'Gene', '3417', (141, 145))	('CCA', 'Disease', (127, 130))	('IDH1', 'Gene', (62, 66))	('ivosidenib', 'Chemical', 'MESH:C000627630', (50, 60))
94433	33202975	BRAF missense mutations have been identified in up to 33% of CCA with the exact frequency of mutation varying depending on the specific subtype of BTC.	('missense mutations', 'Var', (5, 23))	('CCA', 'Phenotype', 'HP:0030153', (61, 64))	('CCA', 'Disease', (61, 64))	('BRAF', 'Gene', '673', (0, 4))	('BTC', 'Phenotype', 'HP:0100574', (147, 150))	('BRAF', 'Gene', (0, 4))	('identified', 'Reg', (34, 44))
94436	33202975	However, case reports of dramatic responses to combined BRAF/MEK inhibitors (dabrafenib and trametinib) exist in patients harboring BRAF V600E mutations, and a BTC cohort of a phase II basket trial showed that the ORR was 47% (95% CI 31-62%) to combination therapy.	('BRAF', 'Gene', (132, 136))	('MEK', 'Gene', (61, 64))	('MEK', 'Gene', '5609', (61, 64))	('BTC', 'Phenotype', 'HP:0100574', (160, 163))	('BRAF', 'Gene', '673', (56, 60))	('patients', 'Species', '9606', (113, 121))	('dabrafenib', 'Chemical', 'MESH:C561627', (77, 87))	('V600E mutations', 'Var', (137, 152))	('V600E', 'Mutation', 'rs113488022', (137, 142))	('BRAF', 'Gene', '673', (132, 136))	('trametinib', 'Chemical', 'MESH:C560077', (92, 102))	('BRAF', 'Gene', (56, 60))
94439	33202975	In breast and stomach cancer evaluation of HER2 amplification in tumor tissue and subsequent treatment with HER2 targeted therapy is now standard of care.	('HER2', 'Gene', (108, 112))	('breast', 'Disease', (3, 9))	('HER2', 'Gene', '2064', (108, 112))	('tumor', 'Disease', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('stomach cancer', 'Phenotype', 'HP:0012126', (14, 28))	('HER2', 'Gene', (43, 47))	('cancer', 'Disease', (22, 28))	('HER2', 'Gene', '2064', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('amplification', 'Var', (48, 61))
94441	33202975	Early phase trials of small number of patients have indicated that pertuzumab plus trastuzumab has activity in HER2 overexpressed and mutated BTC, refractory to chemotherapy.	('HER2', 'Gene', (111, 115))	('BTC', 'Gene', (142, 145))	('pertuzumab plus trastuzumab', 'Disease', (67, 94))	('HER2', 'Gene', '2064', (111, 115))	('patients', 'Species', '9606', (38, 46))	('pertuzumab plus trastuzumab', 'Disease', 'MESH:D007625', (67, 94))	('mutated', 'Var', (134, 141))	('overexpressed', 'Var', (116, 129))	('BTC', 'Phenotype', 'HP:0100574', (142, 145))	('activity', 'MPA', (99, 107))
94450	33202975	In addition, a recent study of second-line regorafenib versus placebo has shown a superior PFS of 3 months (95% CI 2.3-4.9) in the interventional group versus 1.5 months (95% CI 1.2-2.0) in the placebo group.	('PFS', 'MPA', (91, 94))	('regorafenib', 'Chemical', 'MESH:C559147', (43, 54))	('interventional', 'Var', (131, 145))
94453	33202975	Positivity of iCCA for MALT-1 (Mucosa-associated lymphoid tissue protein 1) has been identified as one potential prognostic factor for regorafenib.	('CCA', 'Phenotype', 'HP:0030153', (15, 18))	('Mucosa-associated lymphoid tissue protein 1', 'Gene', (31, 74))	('Mucosa-associated lymphoid tissue protein 1', 'Gene', '10892', (31, 74))	('MALT-1', 'Gene', (23, 29))	('Positivity', 'Var', (0, 10))	('regorafenib', 'Chemical', 'MESH:C559147', (135, 146))	('MALT-1', 'Gene', '10892', (23, 29))
94455	33202975	Although in a small percentage of patients (Figure 2), NTRK gene fusions have been associated with carcinogenesis of iCCA.	('carcinogenesis of iCCA', 'Disease', 'MESH:D063646', (99, 121))	('associated', 'Reg', (83, 93))	('patients', 'Species', '9606', (34, 42))	('CCA', 'Phenotype', 'HP:0030153', (118, 121))	('gene fusions', 'Var', (60, 72))	('carcinogenesis of iCCA', 'Disease', (99, 121))	('NTRK', 'Gene', (55, 59))
94457	33202975	Importantly, NTRK inhibitors (i.e., entrectinib or larotrectinib), have shown promising results with response rate > 75% in tumors harboring NTRK gene fusions, regardless of histology, and are currently being evaluated in clinical trials including advanced BTC (NCT02576431, NCT02568267).	('NTRK', 'Gene', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('entrectinib', 'Chemical', 'MESH:C000607349', (36, 47))	('gene fusions', 'Var', (146, 158))	('BTC', 'Phenotype', 'HP:0100574', (257, 260))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('larotrectinib', 'Chemical', 'MESH:C000609083', (51, 64))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('NCT02576431', 'Var', (262, 273))
94459	33202975	IDH1/2 mutations and FGFR2 gene fusions are the best characterized targets with phase III and phase II evidence, supporting the respective use of IDH- and FGFR-inhibitors in treatment-experienced patients.	('FGFR2', 'Gene', (21, 26))	('IDH', 'Gene', (0, 3))	('FGFR2', 'Gene', '2263', (21, 26))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (146, 149))	('patients', 'Species', '9606', (196, 204))	('IDH', 'Gene', '3417', (146, 149))	('mutations', 'Var', (7, 16))
94502	31861027	We retrospectively collected the following patient data: anesthetic technique; time since the earliest included patient, which served as a surrogate of calendar year; sex; age at the time of surgery; serum hepatitis B surface antigen (HBsAg) positivity; serum hepatitis C virus (HCV) positivity; history of alcoholism; preoperative serum CA19-9 values; Child-Pugh score; and model for end-stage liver disease (MELD) score.	('hepatitis', 'Species', '11103', (260, 269))	('Child-Pugh score', 'Disease', (353, 369))	('patient', 'Species', '9606', (112, 119))	('patient', 'Species', '9606', (43, 50))	('hepatitis', 'Phenotype', 'HP:0012115', (206, 215))	('Child', 'Species', '9606', (353, 358))	('hepatitis', 'Species', '11103', (206, 215))	('end-stage liver disease', 'Disease', 'MESH:D058625', (385, 408))	('hepatitis C virus', 'Disease', (260, 277))	('HCV', 'Disease', 'MESH:D006526', (279, 282))	('end-stage liver disease', 'Disease', (385, 408))	('positivity', 'Var', (242, 252))	('hepatitis', 'Phenotype', 'HP:0012115', (260, 269))	('HCV', 'Disease', (279, 282))	('alcoholism', 'Phenotype', 'HP:0030955', (307, 317))	('hepatitis C virus', 'Disease', 'MESH:D006526', (260, 277))	('liver disease', 'Phenotype', 'HP:0001392', (395, 408))	('positivity', 'Var', (284, 294))
94553	31861027	By contrast, isoflurane enhanced renal cancer cell growth and malignant potential via upregulating HIF-1alpha levels in vitro.	('renal cancer', 'Disease', 'MESH:D007680', (33, 45))	('malignant potential', 'CPA', (62, 81))	('HIF-1alpha', 'Gene', '3091', (99, 109))	('enhanced', 'PosReg', (24, 32))	('upregulating', 'PosReg', (86, 98))	('isoflurane', 'Chemical', 'MESH:D007530', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('renal cancer', 'Disease', (33, 45))	('HIF-1alpha', 'Gene', (99, 109))	('isoflurane', 'Var', (13, 23))	('renal cancer', 'Phenotype', 'HP:0009726', (33, 45))
94616	28161931	In the investigational dataset, 234 patients (68.8%) underwent palliative chemotherapy comprising Gem/Cis (n=120, 35.3%) or other regimens (n=114, 33.5%), including 5-fluorouracil (5-FU) or gemcitabine-based chemotherapy with/without palliative radiotherapy (5-FU monotherapy [n=33, 9.7%], 5-FU/platinum [n=50, 14.7%], 5-FU/adriamycin [n=5, 1.5%], 5-FU/gemcitabine [n=5, 1.5%], gemcitabine monotherapy [n=13, 3.8%], and gemcitabine/oxaliplatin [n=8, 2.4%]).	('5-FU', 'Chemical', 'MESH:D005472', (181, 185))	('5-FU/adriamycin', 'Var', (319, 334))	('5-FU', 'Chemical', 'MESH:D005472', (319, 323))	('5-FU', 'Chemical', 'MESH:D005472', (259, 263))	('5-FU/gemcitabine', 'Var', (348, 364))	('5-FU', 'Chemical', 'MESH:D005472', (348, 352))	('platinum', 'Chemical', 'MESH:D010984', (295, 303))	('5-FU', 'Chemical', 'MESH:D005472', (290, 294))
94633	27216979	FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers.	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('FGFR', 'Gene', (0, 4))	('cancers', 'Disease', (91, 98))	('fusions', 'Var', (5, 12))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
94635	27216979	Using this PDX model, we confirmed the ability of the FGFR inhibitors, ponatinib, dovitinib and BGJ398, to modulate FGFR signaling, inhibit cell proliferation and induce cell apoptosis in cholangiocarcinoma tumors harboring FGFR2 fusions.	('inhibit', 'NegReg', (132, 139))	('cell proliferation', 'CPA', (140, 158))	('FGFR signaling', 'MPA', (116, 130))	('modulate', 'Reg', (107, 115))	('BGJ398', 'Chemical', 'MESH:C568950', (96, 102))	('FGFR2', 'Gene', (224, 229))	('ponatinib', 'Chemical', 'MESH:C545373', (71, 80))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('dovitinib', 'Chemical', 'MESH:C500007', (82, 91))	('BGJ398', 'Gene', (96, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (188, 206))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('induce', 'PosReg', (163, 169))	('fusions', 'Var', (230, 237))	('cholangiocarcinoma tumors', 'Disease', 'MESH:D018281', (188, 213))	('cholangiocarcinoma tumors', 'Disease', (188, 213))	('FGFR', 'Gene', (54, 58))	('cell apoptosis', 'CPA', (170, 184))
94637	27216979	Our findings provide a strong rationale for the investigation of FGFR inhibitors, particularly BGJ398, as a therapeutic option for cholangiocarcinoma patients harboring FGFR2 fusions.	('cholangiocarcinoma', 'Disease', (131, 149))	('FGFR2', 'Gene', (169, 174))	('patients', 'Species', '9606', (150, 158))	('BGJ398', 'Chemical', 'MESH:C568950', (95, 101))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (131, 149))	('fusions', 'Var', (175, 182))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))	('BGJ398', 'Gene', (95, 101))
94644	27216979	Aberrant FGFR pathway activity can enable malignant transformation and promote tumor progression.	('malignant transformation', 'CPA', (42, 66))	('promote', 'PosReg', (71, 78))	('enable', 'PosReg', (35, 41))	('tumor', 'Disease', (79, 84))	('Aberrant', 'Var', (0, 8))	('FGFR pathway', 'Pathway', (9, 21))	('activity', 'MPA', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
94645	27216979	Recent studies have revealed gene fusions of FGFR2 with multiple partners in intrahepatic cholangiocarcinoma (iCCA) as well as in other cancers.	('intrahepatic cholangiocarcinoma', 'Disease', (77, 108))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('FGFR2', 'Gene', (45, 50))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (77, 108))	('gene fusions', 'Var', (29, 41))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
94646	27216979	In recent studies using Next Generation Sequencing, FGFR2 fusions have been identified in 13% to 50% of iCCA patients.	('FGFR2', 'Gene', (52, 57))	('patients', 'Species', '9606', (109, 117))	('iCCA', 'Disease', (104, 108))	('identified', 'Reg', (76, 86))	('fusions', 'Var', (58, 65))
94647	27216979	FGFR2 fusions involving FGFR2-BICC1 and FGFR2-AHCYL1 were identified in 13.6% of patients with iCCA.	('iCCA', 'Disease', (95, 99))	('AHCYL1', 'Gene', (46, 52))	('BICC1', 'Gene', (30, 35))	('AHCYL1', 'Gene', '10768', (46, 52))	('patients', 'Species', '9606', (81, 89))	('BICC1', 'Gene', '80114', (30, 35))	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (6, 13))
94649	27216979	These observations have also been confirmed by studies using an FGFR2 break-apart Fluorescent In Situ Hybridization (FISH) assay, in which FGFR2 fusions were observed in 13% (12 of 96) of iCCA but not in any perihilar or distal cholangiocarcinomas.	('cholangiocarcinomas', 'Disease', (228, 247))	('FGFR2', 'Gene', (139, 144))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (228, 247))	('fusions', 'Var', (145, 152))	('iCCA', 'Disease', (188, 192))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (228, 246))
94651	27216979	Tumors harboring FGFR fusions have demonstrated enhanced sensitivity to FGFR inhibitors, suggesting that cholangiocarcinoma patients with FGFR2 fusions may benefit from targeted FGFR2 kinase inhibition.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (105, 123))	('FGFR2', 'Gene', (138, 143))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (105, 123))	('enhanced', 'PosReg', (48, 56))	('fusions', 'Var', (22, 29))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('benefit', 'PosReg', (156, 163))	('sensitivity', 'MPA', (57, 68))	('fusions', 'Var', (144, 151))	('cholangiocarcinoma', 'Disease', (105, 123))	('patients', 'Species', '9606', (124, 132))
94653	27216979	We hypothesized that since a number of different FGFR2 fusion partners have been identified, there may be differential sensitivity of tumors bearing specific FGFR2 fusions to FGFR inhibitors.	('tumors', 'Disease', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('fusions', 'Var', (164, 171))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('FGFR2', 'Gene', (158, 163))
94667	27216979	To characterize the chromosomal structure and confirm the presence of an FGFR2 gene rearrangement in the LIV31 tumor cells, karyotyping by G-banding, break-apart FISH and chromosomal painting were performed on LIV31 cells and formalin-fixed paraffin-embedded tumor tissue by an experienced FISH technologist as described previously.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('paraffin', 'Chemical', 'MESH:D010232', (241, 249))	('LIV31 tumor', 'Disease', 'MESH:D009369', (105, 116))	('LIV31 tumor', 'Disease', (105, 116))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('FGFR2', 'Gene', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor', 'Disease', (111, 116))	('formalin', 'Chemical', 'MESH:D005557', (226, 234))	('tumor', 'Disease', (259, 264))	('rearrangement', 'Var', (84, 97))
94669	27216979	The 3'clones (RP11-878D21, CTD-2542P10, RP11-984I17, CTD-2291K12 and CTD-3237E5) were labeled by nick translation with Spectrum Green and the 5' clones (CTD-2312O10, RP11-879C17, RP11-454I6 and RP11-135O16) were labeled with Spectrum Orange (Abbott Molecular, Des Plaines, IL).	('RP11', 'Gene', '52528', (166, 170))	('CTD-2291K12', 'Var', (53, 64))	('RP11', 'Gene', '52528', (40, 44))	('RP11', 'Gene', (166, 170))	('RP11', 'Gene', '52528', (194, 198))	('RP11', 'Gene', (40, 44))	('RP11', 'Gene', (194, 198))	('RP11', 'Gene', '52528', (179, 183))	('RP11', 'Gene', '52528', (14, 18))	('RP11', 'Gene', (179, 183))	('RP11', 'Gene', (14, 18))	('CTD-2312O10', 'Var', (153, 164))
94685	27216979	Tumor tissue from 3-4 mice randomly selected from each group was sectioned and stained with H&E or by immunohistochemical staining for p-FGFR, p-FRS2, p-AKT, p-ERK, MMP2, MMP3 and MMP9.	('p-ERK', 'Gene', '13666', (158, 163))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('MMP2', 'Gene', (165, 169))	('MMP3', 'Gene', '17392', (171, 175))	('AKT', 'Gene', '11651', (153, 156))	('FRS2', 'Gene', (145, 149))	('MMP9', 'Gene', (180, 184))	('H&E', 'Chemical', 'MESH:D006371', (92, 95))	('FRS2', 'Gene', '327826', (145, 149))	('MMP3', 'Gene', (171, 175))	('AKT', 'Gene', (153, 156))	('MMP2', 'Gene', '17390', (165, 169))	('for', 'Var', (131, 134))	('mice', 'Species', '10090', (22, 26))	('MMP9', 'Gene', '17395', (180, 184))	('p-ERK', 'Gene', (158, 163))
94690	27216979	After blocking for 10 min in 10% goat serum, sections were incubated at 4 C overnight with polyclonal antibodies against p-FGFR (1:100), p-FRS2 (1:200), p-AKT (1:200), p-ERK (1:400), MMP2 (1:500), MMP3 (1:500), MMP9 (1:500) cleaved caspase-3 (1:400), CD31 (1:600), and Ki-67 (1:400) as mentioned above.	('MMP3', 'Gene', (197, 201))	('FRS2', 'Gene', (139, 143))	('cleaved caspase-3', 'Gene', '12367', (224, 241))	('MMP9', 'Gene', '17395', (211, 215))	('MMP2', 'Gene', '17390', (183, 187))	('goat', 'Species', '9925', (33, 37))	('Ki-67', 'Gene', '17345', (269, 274))	('p-ERK', 'Gene', (168, 173))	('AKT', 'Gene', (155, 158))	('MMP2', 'Gene', (183, 187))	('CD31', 'Gene', '18613', (251, 255))	('MMP9', 'Gene', (211, 215))	('MMP3', 'Gene', '17392', (197, 201))	('FRS2', 'Gene', '327826', (139, 143))	('CD31', 'Gene', (251, 255))	('Ki-67', 'Gene', (269, 274))	('cleaved caspase-3', 'Gene', (224, 241))	('AKT', 'Gene', '11651', (155, 158))	('p-ERK', 'Gene', '13666', (168, 173))	('p-FGFR', 'Var', (121, 127))
94697	27216979	Western immunoblots for FGFR2, p-FGFR, AKT, p-AKT, ERK, p-ERK, FRS2, and p-FRS2were performed on lysates from mouse cholangiocarcinoma tissues.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (116, 134))	('AKT', 'Gene', (46, 49))	('FRS2', 'Gene', (75, 79))	('ERK', 'Gene', (58, 61))	('AKT', 'Gene', (39, 42))	('ERK', 'Gene', (51, 54))	('p-ERK', 'Gene', (56, 61))	('p-FGFR', 'Var', (31, 37))	('mouse', 'Species', '10090', (110, 115))	('ERK', 'Gene', '26413', (58, 61))	('FRS2', 'Gene', (63, 67))	('AKT', 'Gene', '11651', (46, 49))	('ERK', 'Gene', '26413', (51, 54))	('AKT', 'Gene', '11651', (39, 42))	('FRS2', 'Gene', '327826', (75, 79))	('p-ERK', 'Gene', '13666', (56, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))	('cholangiocarcinoma', 'Disease', (116, 134))	('FRS2', 'Gene', '327826', (63, 67))
94698	27216979	After transfer to PVDF membrane, membranes were blocked with 5% BSA and incubated overnight with primary antibodies against p-FGFR (1:1000), FGFR2 (1:200), p-FRS2 (1:1,000), FRS2 (1:1,000), p-ERK (1:1,000), ERK (1:1,000), p-AKT (1:1,000), AKT (1:1,000), and beta-actin (1:5,000).	('beta-actin', 'Gene', (258, 268))	('1:200', 'Var', (148, 153))	('AKT', 'Gene', '11651', (224, 227))	('FRS2', 'Gene', '327826', (174, 178))	('FRS2', 'Gene', '327826', (158, 162))	('beta-actin', 'Gene', '11461', (258, 268))	('PVDF', 'Chemical', 'MESH:C024865', (18, 22))	('p-ERK', 'Gene', (190, 195))	('AKT', 'Gene', '11651', (239, 242))	('ERK', 'Gene', (192, 195))	('p-FGFR', 'Gene', (124, 130))	('ERK', 'Gene', (207, 210))	('ERK', 'Gene', '26413', (192, 195))	('FRS2', 'Gene', (158, 162))	('FRS2', 'Gene', (174, 178))	('FGFR2', 'Gene', (141, 146))	('AKT', 'Gene', (224, 227))	('ERK', 'Gene', '26413', (207, 210))	('p-ERK', 'Gene', '13666', (190, 195))	('AKT', 'Gene', (239, 242))
94718	27216979	RNA sequencing of the LIV31 tumor revealed a fusion between exon 17 of the FGFR2 gene and exon 2 of the CCDC6 gene, resulting in a chimeric mRNA, which was subsequently confirmed by RT-PCR and Sanger sequencing (Fig.	('LIV31 tumor', 'Disease', 'MESH:D009369', (22, 33))	('chimeric mRNA', 'MPA', (131, 144))	('LIV31 tumor', 'Disease', (22, 33))	('fusion', 'Var', (45, 51))	('FGFR2', 'Gene', (75, 80))	('in a', 'Reg', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
94722	27216979	At day 63 of treatment, tumors in ponatinib treated mice had significantly less tumor volume than control mice treated with vehicle, with mean tumor volumes of 619.3 +- 119.5 mm3 vs 1417 +- 206.3 mm3, respectively.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('mice', 'Species', '10090', (106, 110))	('tumor', 'Disease', (143, 148))	('tumors', 'Disease', (24, 30))	('tumor', 'Disease', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mice', 'Species', '10090', (52, 56))	('tumor', 'Disease', (80, 85))	('less', 'NegReg', (75, 79))	('ponatinib', 'Chemical', 'MESH:C545373', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('ponatinib', 'Var', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
94724	27216979	Four of 9 (44%) mice treated with ponatinib had tumor volumes of <400 mm3 whereas none of the 10 mice treated with vehicle had a tumor volume of <400 mm3 at the end of treatment (P<0.05) (Fig.	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('mice', 'Species', '10090', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('ponatinib', 'Chemical', 'MESH:C545373', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('ponatinib', 'Var', (34, 43))	('mice', 'Species', '10090', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
94743	27216979	After 63 days of treatment, mean (SEM) tumor volumes were 412.8 +- 53.82 mm3, 269.7 +- 24.98 and 204.2 +- 30.13 mm3 (N=10) for mice treated with ponatinib, dovitinib, and BGJ398, respectively, significantly less than tumor volumes in control mice treated with vehicle 1210 +- 127.9 mm3 (Fig.	('ponatinib', 'Chemical', 'MESH:C545373', (145, 154))	('less', 'NegReg', (207, 211))	('mice', 'Species', '10090', (127, 131))	('tumor', 'Disease', (217, 222))	('dovitinib', 'Chemical', 'MESH:C500007', (156, 165))	('ponatinib', 'Var', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('BGJ398', 'Chemical', 'MESH:C568950', (171, 177))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', (39, 44))	('BGJ398', 'Var', (171, 177))	('mice', 'Species', '10090', (242, 246))
94744	27216979	The tumor growth curves suggest that at the doses administered, BGJ398 was the most potent of the tested FGFR inhibitors for inhibiting growth of the LIV31 xenografts (Fig.	('tumor', 'Disease', (4, 9))	('FGFR', 'Gene', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('inhibiting', 'NegReg', (125, 135))	('BGJ398', 'Var', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('growth', 'CPA', (136, 142))	('BGJ398', 'Chemical', 'MESH:C568950', (64, 70))
94758	27216979	Gene fusions of FGFR2 with multiple partners have been uncovered in cholangiocarcinoma as well as other cancers.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Gene fusions', 'Var', (0, 12))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (68, 86))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (68, 86))	('FGFR2', 'Gene', (16, 21))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('uncovered', 'Reg', (55, 64))	('cholangiocarcinoma', 'Disease', (68, 86))
94761	27216979	Fusion of FGFR2 with CCDC6 has recently been identified in a breast cancer patient.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Fusion', 'Var', (0, 6))	('breast cancer', 'Disease', (61, 74))	('identified', 'Reg', (45, 55))	('patient', 'Species', '9606', (75, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('CCDC6', 'Gene', (21, 26))	('FGFR2', 'Gene', (10, 15))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
94775	27216979	Therefore, further studies may be needed to explore the effects of combination therapy with FGFR inhibitors and lower dose of gemcitabine and cisplatin in vivo, including studies using sequential administration with gemcitabine being given before the FGFR inhibitors.	('FGFR', 'Gene', (92, 96))	('gemcitabine', 'Chemical', 'MESH:C056507', (216, 227))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('gemcitabine', 'Chemical', 'MESH:C056507', (126, 137))	('inhibitors', 'Var', (97, 107))
94779	27216979	Therefore, FGFR inhibitors may be used as second-line therapies against cholangiocarcinoma with genetic alterations in FGFR, particularly FGFR2 fusion events.	('FGFR', 'Gene', (119, 123))	('genetic alterations', 'Var', (96, 115))	('FGFR2', 'Gene', (138, 143))	('cholangiocarcinoma', 'Disease', (72, 90))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 90))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))	('fusion events', 'Var', (144, 157))
94784	27216979	We showed that all three tested FGFR inhibitors, at dose levels that showed efficacy in other models, significantly inhibited the growth of the FGFR2-CCDC6 fusion mouse xenograft PDX tumors when compared with vehicle.	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('inhibited', 'NegReg', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('FGFR', 'Gene', (32, 36))	('mouse', 'Species', '10090', (163, 168))	('growth', 'CPA', (130, 136))	('FGFR2-CCDC6', 'Gene', (144, 155))	('tumors', 'Disease', (183, 189))	('fusion', 'Var', (156, 162))
94787	27216979	This result was similar to a previous study where daily oral administration with BGJ398 led to substantial tumor growth inhibition resulting in tumor stasis and regression at doses of 15 mg/kg or more in human gastric tumors harboring FGFR2 amplification.	('gastric tumors', 'Phenotype', 'HP:0006753', (210, 224))	('tumor', 'Disease', (107, 112))	('regression', 'NegReg', (161, 171))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('gastric tumors', 'Disease', (210, 224))	('tumor stasis', 'Disease', 'MESH:D014647', (144, 156))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('amplification', 'Var', (241, 254))	('BGJ398', 'Gene', (81, 87))	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('BGJ398', 'Chemical', 'MESH:C568950', (81, 87))	('human', 'Species', '9606', (204, 209))	('FGFR2', 'Gene', (235, 240))	('gastric tumors', 'Disease', 'MESH:D013274', (210, 224))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor stasis', 'Disease', (144, 156))
94790	27216979	Taken together, cholangiocarcinoma xenografts with FGFR fusions were sensitive to the FGFR inhibitors.	('fusions', 'Var', (56, 63))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (16, 34))	('cholangiocarcinoma xenografts', 'Disease', 'MESH:D018281', (16, 45))	('FGFR', 'Gene', (51, 55))	('cholangiocarcinoma xenografts', 'Disease', (16, 45))
94791	27216979	The clinical application of FGFR inhibitors in cholangiocarcinoma will to some extent depend on the frequency of FGFR2 fusions in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (130, 148))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (47, 65))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (47, 65))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (130, 148))	('fusions', 'Var', (119, 126))	('cholangiocarcinoma', 'Disease', (47, 65))	('cholangiocarcinoma', 'Disease', (130, 148))	('FGFR2', 'Gene', (113, 118))
94797	27216979	FGFR inhibitors, ponatinib, dovitinib and BGJ398, inhibit FGFR signaling, and tumor growth in iCCAs harboring FGFR2 fusions.	('BGJ398', 'Chemical', 'MESH:C568950', (42, 48))	('FGFR2', 'Gene', (110, 115))	('inhibit', 'NegReg', (50, 57))	('BGJ398', 'Gene', (42, 48))	('FGFR signaling', 'MPA', (58, 72))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('fusions', 'Var', (116, 123))	('ponatinib', 'Chemical', 'MESH:C545373', (17, 26))	('dovitinib', 'Chemical', 'MESH:C500007', (28, 37))	('tumor', 'Disease', (78, 83))
94799	21251891	Alkaline phosphatase normalization is associated with better prognosis in primary sclerosing cholangitis Primary sclerosing cholangitis results in elevated but fluctuating serum alkaline phosphatase levels that occasionally return to normal.	('normalization', 'Var', (21, 34))	('cholangitis', 'Disease', 'MESH:D002761', (93, 104))	('cholangitis', 'Disease', 'MESH:D002761', (124, 135))	('serum alkaline phosphatase levels', 'Phenotype', 'HP:0003155', (172, 205))	('Alkaline phosphatase', 'Gene', '250', (0, 20))	('alkaline phosphatase', 'Gene', (178, 198))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (113, 135))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (82, 104))	('cholangitis', 'Disease', (124, 135))	('alkaline phosphatase', 'Gene', '250', (178, 198))	('Alkaline phosphatase', 'Gene', (0, 20))	('cholangitis', 'Phenotype', 'HP:0030151', (93, 104))	('cholangitis', 'Disease', (93, 104))	('Primary sclerosing cholangitis', 'Disease', 'MESH:D015209', (105, 135))	('cholangitis', 'Phenotype', 'HP:0030151', (124, 135))	('Primary sclerosing cholangitis', 'Disease', (105, 135))
94807	21251891	When the investigative criteria were applied to a prospective trial, there was again a significant relationship between normalization of alkaline phosphatase and survival in patients receiving ursodeoxycholic acid (P<0.01) and the placebo group (P=0.02).	('alkaline phosphatase', 'Gene', (137, 157))	('ursodeoxycholic acid', 'Var', (193, 213))	('alkaline phosphatase', 'Gene', '250', (137, 157))	('normalization', 'MPA', (120, 133))	('patients', 'Species', '9606', (174, 182))	('ursodeoxycholic acid', 'Chemical', 'MESH:D014580', (193, 213))	('survival', 'CPA', (162, 170))
94847	21251891	Patients with normalization of ALP also had significantly lower AST (47 (33 - 100) vs. 102 (60 - 140), P<0.01) and total bilirubin values (0.8 (0.6 - 1.5) vs. 1.2 (0.8 - 2.2), P=0.04) at diagnosis.	('ALP', 'Gene', '250', (31, 34))	('lower', 'NegReg', (58, 63))	('ALP', 'Gene', (31, 34))	('AST', 'Gene', '26503', (64, 67))	('bilirubin', 'Chemical', 'MESH:D001663', (121, 130))	('lower AST', 'Phenotype', 'HP:0032198', (58, 67))	('Patients', 'Species', '9606', (0, 8))	('AST', 'Gene', (64, 67))	('normalization', 'Var', (14, 27))
94852	21251891	Seventeen (33%) of the patients with persistent abnormalities of ALP levels reached an end point, with 4 (8%) developing cholangiocarcinoma, 9 (17%) receiving a liver transplant due to progression to end-stage liver disease and 4 (8%) dying without cholangiocarcinoma or transplantation.	('abnormalities', 'Var', (48, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (249, 267))	('liver disease', 'Phenotype', 'HP:0001392', (210, 223))	('ALP', 'Gene', '250', (65, 68))	('patients', 'Species', '9606', (23, 31))	('cholangiocarcinoma', 'Disease', (121, 139))	('abnormalities of ALP levels', 'Phenotype', 'HP:0004379', (48, 75))	('cholangiocarcinoma', 'Disease', (249, 267))	('end-stage liver disease', 'Disease', 'MESH:D058625', (200, 223))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (121, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))	('end-stage liver disease', 'Disease', (200, 223))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (249, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('ALP', 'Gene', (65, 68))	('developing', 'Reg', (110, 120))
94854	21251891	Kaplan Meier analysis revealed that patients with normalization have a significantly lower rate of reaching an end point than patients with persistent abnormalities (P= 0.02, Figure 1).	('normalization', 'Var', (50, 63))	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (126, 134))	('lower', 'NegReg', (85, 90))
94865	21251891	Using the criteria of normalization of ALP, there was a significant association between normalization and decreased endpoints in both the UDCA and placebo branches.	('decreased', 'NegReg', (106, 115))	('endpoints', 'MPA', (116, 125))	('ALP', 'Gene', (39, 42))	('normalization', 'Var', (88, 101))	('ALP', 'Gene', '250', (39, 42))	('UDCA', 'Disease', (138, 142))
94866	21251891	Within the UDCA treatment group, 4/20 (20%) with normalization of ALP reached an endpoint while 27/56 (48%) with persistent abnormality reached an endpoint (P<0.01).	('normalization', 'Var', (49, 62))	('ALP', 'Gene', '250', (66, 69))	('ALP', 'Gene', (66, 69))
94875	21251891	Patients with normalization of ALP had a significantly lower incidence of adverse clinical end points during 10-years of clinical follow-up.	('ALP', 'Gene', '250', (31, 34))	('Patients', 'Species', '9606', (0, 8))	('lower', 'NegReg', (55, 60))	('ALP', 'Gene', (31, 34))	('normalization', 'Var', (14, 27))
94878	21251891	Importantly, normalization of ALP was still an indicator of improved prognosis when the other laboratories were adjusted for statistically.	('ALP', 'Gene', '250', (30, 33))	('normalization', 'Var', (13, 26))	('ALP', 'Gene', (30, 33))	('improved', 'PosReg', (60, 68))
94887	21251891	In one study, however, dilatation of dominant strictures decreased ALP values by 17% in PSC patients being treated with UDCA.	('dilatation', 'Phenotype', 'HP:0002617', (23, 33))	('PSC', 'Gene', (88, 91))	('ALP', 'Gene', (67, 70))	('patients', 'Species', '9606', (92, 100))	('ALP', 'Gene', '250', (67, 70))	('PSC', 'Gene', '100653366', (88, 91))	('dilatation', 'Var', (23, 33))	('decreased ALP', 'Phenotype', 'HP:0003282', (57, 70))	('decreased', 'NegReg', (57, 66))
94894	21251891	However, when the data were reassessed using the protocol of normalization of ALP investigated in the current study, there was a significant association between normalization and better prognosis in both the UDCA treatment group and the placebo group.	('UDCA', 'Disease', (208, 212))	('better', 'PosReg', (179, 185))	('ALP', 'Gene', (78, 81))	('normalization', 'Var', (161, 174))	('ALP', 'Gene', '250', (78, 81))
94897	21251891	In addition, the finding that the normalization of ALP levels were associated with improved prognosis is beneficial for patient care.	('ALP', 'Gene', '250', (51, 54))	('patient', 'Species', '9606', (120, 127))	('prognosis', 'CPA', (92, 101))	('normalization', 'Var', (34, 47))	('ALP', 'Gene', (51, 54))
94906	31795195	KRAS/NRAS mutations are common in ICC tumours and 6-32% of patients also have isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations associated with metabolic changes.	('IDH1', 'Gene', (112, 116))	('metabolic changes', 'Disease', (158, 175))	('ICC', 'Disease', (34, 37))	('NRAS', 'Gene', '4893', (5, 9))	('associated', 'Reg', (142, 152))	('patients', 'Species', '9606', (59, 67))	('IDH1', 'Gene', '3417', (112, 116))	('KRAS', 'Gene', '3845', (0, 4))	('ICC', 'Disease', 'MESH:C535533', (34, 37))	('common', 'Reg', (24, 30))	('KRAS', 'Gene', (0, 4))	('IDH2', 'Gene', (121, 125))	('tumours', 'Disease', (38, 45))	('isocitrate dehydrogenase 1', 'Gene', (78, 104))	('isocitrate dehydrogenase 1', 'Gene', '3417', (78, 104))	('NRAS', 'Gene', (5, 9))	('IDH2', 'Gene', '3418', (121, 125))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('mutations', 'Var', (132, 141))	('tumours', 'Phenotype', 'HP:0002664', (38, 45))	('tumours', 'Disease', 'MESH:D009369', (38, 45))	('mutations', 'Var', (10, 19))
94912	31795195	Recurrent somatic SNVs and CNVs were identified in ctDNA from three out of four patients that included both NRAS and IDH1 mutations linked to ICC.	('NRAS', 'Gene', (108, 112))	('ICC', 'Disease', (142, 145))	('patients', 'Species', '9606', (80, 88))	('ICC', 'Disease', 'MESH:C535533', (142, 145))	('IDH1', 'Gene', '3417', (117, 121))	('NRAS', 'Gene', '4893', (108, 112))	('linked', 'Reg', (132, 138))	('mutations', 'Var', (122, 131))	('CN', 'Disease', 'MESH:D007674', (27, 29))	('IDH1', 'Gene', (117, 121))
94913	31795195	Plasma metabolite analysis revealed biomarker metabolites associated with ICC and in particular 2-hydroxyglutarate (2-HG) levels were elevated in both samples from the only patient showing a variant allele in IDH1.	('biomarker metabolites', 'MPA', (36, 57))	('variant', 'Var', (191, 198))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (96, 114))	('ICC', 'Disease', (74, 77))	('2-HG', 'Chemical', 'MESH:C019417', (116, 120))	('IDH1', 'Gene', (209, 213))	('elevated', 'PosReg', (134, 142))	('ICC', 'Disease', 'MESH:C535533', (74, 77))	('patient', 'Species', '9606', (173, 180))	('IDH1', 'Gene', '3417', (209, 213))
94923	31795195	For example, in one study, molecular profiling of tissue DNA from 67 ICC patients was performed, with mutations being detected in 25% of patients.	('ICC', 'Disease', 'MESH:C535533', (69, 72))	('patients', 'Species', '9606', (137, 145))	('mutations', 'Var', (102, 111))	('ICC', 'Disease', (69, 72))	('patients', 'Species', '9606', (73, 81))
94924	31795195	Mutations reported included common single nucleotide variants (SNVs) in KRAS (G12A, G12D, Q61H); PIK3CA; MET (T9921, R970C); BRAF (V600E); EGFR (G719S), and NRAS (Q61R), as well as variants in IDH1, IDH2, PTEN, and TP53.	('IDH2', 'Gene', '3418', (199, 203))	('Q61R', 'Mutation', 'rs11554290', (163, 167))	('PTEN', 'Gene', '5728', (205, 209))	('IDH1', 'Gene', '3417', (193, 197))	('TP53', 'Gene', '7157', (215, 219))	('EGFR', 'Gene', (139, 143))	('G12A', 'Mutation', 'rs121913529', (78, 82))	('NRAS', 'Gene', '4893', (157, 161))	('V600E', 'Mutation', 'rs113488022', (131, 136))	('PIK3CA', 'Gene', '5290', (97, 103))	('Q61H', 'Chemical', 'MESH:C117212', (90, 94))	('MET', 'Chemical', 'MESH:C098756', (105, 108))	('BRAF', 'Gene', '673', (125, 129))	('BRAF', 'Gene', (125, 129))	('G719S', 'Mutation', 'rs28929495', (145, 150))	('R970C', 'Var', (117, 122))	('KRAS', 'Gene', '3845', (72, 76))	('R970C', 'SUBSTITUTION', 'None', (117, 122))	('EGFR', 'Gene', '1956', (139, 143))	('NRAS', 'Gene', (157, 161))	('Q61H', 'Var', (90, 94))	('TP53', 'Gene', (215, 219))	('PIK3CA', 'Gene', (97, 103))	('IDH1', 'Gene', (193, 197))	('PTEN', 'Gene', (205, 209))	('KRAS', 'Gene', (72, 76))	('G12D', 'Mutation', 'rs121913529', (84, 88))	('IDH2', 'Gene', (199, 203))
94925	31795195	Copy number variants (CNVs) have also been reported, including copy number (CN) gains (1p, 1q, 6q, 7p, 11q, 12q) and CN losses (3p, 6q, 8p 9p, 10q, 12p, 12q, 13q, 14q, 16q, 19p, 21q), as have structural variants such as translocations, causing the formation of fusion genes involving FGFR2, ROS1 and NTRK1.	('CN', 'Disease', 'MESH:D007674', (76, 78))	('ROS1', 'Gene', (291, 295))	('3p', 'Var', (128, 130))	('gains', 'PosReg', (80, 85))	('ROS1', 'Gene', '6098', (291, 295))	('NTRK1', 'Gene', (300, 305))	('CN', 'Disease', 'MESH:D007674', (22, 24))	('losses', 'NegReg', (120, 126))	('causing', 'Reg', (236, 243))	('CN', 'Disease', 'MESH:D007674', (117, 119))	('NTRK1', 'Gene', '4914', (300, 305))	('FGFR2', 'Gene', (284, 289))	('FGFR2', 'Gene', '2263', (284, 289))
94929	31795195	Of particular interest for ICC is the association with isocitrate dehydrogenase (IDH) mutations leading to the production of 2-hydroxyglutarate (2-HG).	('mutations', 'Var', (86, 95))	('association', 'Interaction', (38, 49))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (125, 143))	('IDH', 'Gene', '3417', (81, 84))	('isocitrate dehydrogenase', 'Gene', '3417', (55, 79))	('2-HG', 'Chemical', 'MESH:C019417', (145, 149))	('IDH', 'Gene', (81, 84))	('ICC', 'Disease', (27, 30))	('isocitrate dehydrogenase', 'Gene', (55, 79))	('ICC', 'Disease', 'MESH:C535533', (27, 30))
94930	31795195	Mutations in isocitrate dehydrogenase 1 (IDH1) were first identified in exome sequencing analysis of patients with colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('patients', 'Species', '9606', (101, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (115, 132))	('isocitrate dehydrogenase 1', 'Gene', '3417', (13, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (115, 132))	('Mutations', 'Var', (0, 9))	('isocitrate dehydrogenase 1', 'Gene', (13, 39))	('IDH1', 'Gene', (41, 45))	('colorectal cancer', 'Disease', (115, 132))	('IDH1', 'Gene', '3417', (41, 45))
94931	31795195	Hotspot mutations in IDH1 and IDH2 have subsequently been shown to occur in at least 13 types of cancer, including 70% of malignant gliomas, 30% of AML and 5-25% of cholangiocarcinomas.	('cancer', 'Disease', (97, 103))	('IDH2', 'Gene', (30, 34))	('mutations', 'Var', (8, 17))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (165, 184))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('IDH1', 'Gene', (21, 25))	('IDH2', 'Gene', '3418', (30, 34))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('cholangiocarcinomas', 'Disease', (165, 184))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('AML', 'Disease', 'MESH:D015470', (148, 151))	('IDH1', 'Gene', '3417', (21, 25))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('malignant gliomas', 'Disease', 'MESH:D005910', (122, 139))	('AML', 'Disease', (148, 151))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (165, 183))	('occur', 'Reg', (67, 72))	('malignant gliomas', 'Disease', (122, 139))
94932	31795195	Somatic mutations are frequently found at amino acid position 132 of IDH1, such as R132C and R132H, in the catalytic domain of the protein.	('IDH1', 'Gene', '3417', (69, 73))	('R132H', 'Var', (93, 98))	('R132H', 'Mutation', 'rs121913500', (93, 98))	('R132C', 'Var', (83, 88))	('R132C', 'Mutation', 'rs121913499', (83, 88))	('IDH1', 'Gene', (69, 73))
94933	31795195	These mutations have been shown to reduce the ability of IDH1 to decarboxylate isocitrate and lead to an unusual change in enzyme function.	('decarboxylate isocitrate', 'Chemical', 'MESH:D007523', (65, 89))	('change', 'Reg', (113, 119))	('IDH1', 'Gene', (57, 61))	('enzyme function', 'MPA', (123, 138))	('IDH1', 'Gene', '3417', (57, 61))	('reduce', 'NegReg', (35, 41))	('decarboxylate isocitrate', 'MPA', (65, 89))	('mutations', 'Var', (6, 15))	('ability', 'MPA', (46, 53))
94938	31795195	IDH is therefore of emerging interest as a drug target, and intensive studies to develop small molecule inhibitors of mutant IDH enzymes have led to a number of anti-cancer therapeutics.	('cancer', 'Disease', (166, 172))	('IDH', 'Gene', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('led to', 'Reg', (142, 148))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (125, 128))	('mutant', 'Var', (118, 124))	('IDH', 'Gene', '3417', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
94942	31795195	IDH1 mutations producing 2-HG have been found to make ICC cell lines more sensitive to an anti-cancer inhibitor of bromodomain and extraterminal domain (BET) proteins.	('sensitive to an', 'MPA', (74, 89))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('2-HG', 'Chemical', 'MESH:C019417', (25, 29))	('ICC', 'Disease', (54, 57))	('cancer', 'Disease', (95, 101))	('mutations', 'Var', (5, 14))	('bromodomain', 'MPA', (115, 126))	('ICC', 'Disease', 'MESH:C535533', (54, 57))	('more', 'PosReg', (69, 73))	('IDH1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('IDH1', 'Gene', '3417', (0, 4))
94943	31795195	2-Hydroxyglutarate has also be shown to create a homologous recombination defect that sensitizes cancer cells to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors, which could serve as another treatment option for these patients.	('sensitizes', 'Reg', (86, 96))	('cancer', 'Disease', (97, 103))	('2-Hydroxyglutarate', 'Chemical', 'MESH:C019417', (0, 18))	('defect', 'Var', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('patients', 'Species', '9606', (237, 245))	("poly(adenosine 5'-diphosphate-ribose)", 'Chemical', 'MESH:D011064', (113, 150))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
94945	31795195	As the ICC tumours are often inaccessible, the ability to measure IDH mutations and metabolic markers in plasma has potential to help identify and stratify tumours, as well as determine and monitor therapeutic interventions.	('tumours', 'Phenotype', 'HP:0002664', (156, 163))	('IDH', 'Gene', (66, 69))	('mutations', 'Var', (70, 79))	('tumours', 'Disease', 'MESH:D009369', (156, 163))	('IDH', 'Gene', '3417', (66, 69))	('tumours', 'Disease', (156, 163))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('ICC', 'Disease', (7, 10))	('tumours', 'Disease', 'MESH:D009369', (11, 18))	('tumours', 'Disease', (11, 18))	('ICC', 'Disease', 'MESH:C535533', (7, 10))
94963	31795195	Loss of CDKN2A is associated with progression to cancer (Supplementary Figure S2b).	('CDKN2A', 'Gene', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('CDKN2A', 'Gene', '1029', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('Loss', 'Var', (0, 4))	('cancer', 'Disease', (49, 55))
94964	31795195	Focal deletions at chromosome 9p21.3 have been observed in 7-18% of ICC patients.	('observed', 'Reg', (47, 55))	('ICC', 'Disease', (68, 71))	('ICC', 'Disease', 'MESH:C535533', (68, 71))	('Focal deletions', 'Var', (0, 15))	('patients', 'Species', '9606', (72, 80))
94972	31795195	It is presumed that less CN variation in the ctDNA is a reflection of a reduced number of tumour cells carrying those mutations following SIRT.	('mutations', 'Var', (118, 127))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('CN', 'Disease', 'MESH:D007674', (25, 27))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('tumour', 'Disease', (90, 96))
94973	31795195	The focal deletions on chromosome 9 of Patients 2 and 3 provided a higher resolution view (Supplementary Figure S2).	('Patients', 'Species', '9606', (39, 47))	('higher', 'PosReg', (67, 73))	('deletions', 'Var', (10, 19))
94975	31795195	In light of the IDH1 mutations identified in Patient 3 samples, we sought to determine the relative levels of 2-hydroxyglutarate (2-HG) and other metabolites in plasma samples.	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (110, 128))	('2-HG', 'Chemical', 'MESH:C019417', (130, 134))	('IDH1', 'Gene', (16, 20))	('IDH1', 'Gene', '3417', (16, 20))	('Patient', 'Species', '9606', (45, 52))	('mutations', 'Var', (21, 30))
94979	31795195	Plasma samples from Patient 3, (positive for circulating IDH1 mutation R132C) had elevated levels of 2-HG compared with ICC patients not harboring the mutation and controls.	('levels of 2-HG', 'MPA', (91, 105))	('R132C', 'Var', (71, 76))	('R132C', 'Mutation', 'rs121913499', (71, 76))	('mutation R132C', 'Var', (62, 76))	('IDH1', 'Gene', (57, 61))	('2-HG', 'Chemical', 'MESH:C019417', (101, 105))	('elevated', 'PosReg', (82, 90))	('IDH1', 'Gene', '3417', (57, 61))	('ICC', 'Disease', (120, 123))	('ICC', 'Disease', 'MESH:C535533', (120, 123))	('patients', 'Species', '9606', (124, 132))	('Patient', 'Species', '9606', (20, 27))
94980	31795195	2-HG levels therefore correlated directly with ctDNA IDH1 mutation status.	('2-HG levels', 'MPA', (0, 11))	('2-HG', 'Chemical', 'MESH:C019417', (0, 4))	('IDH1', 'Gene', (53, 57))	('correlated', 'Reg', (22, 32))	('mutation', 'Var', (58, 66))	('IDH1', 'Gene', '3417', (53, 57))
94981	31795195	No significant differences in 2-HG levels were observed between ICC patients without the IDH1 R132C mutation and healthy controls.	('2-HG', 'Chemical', 'MESH:C019417', (30, 34))	('ICC', 'Disease', (64, 67))	('patients', 'Species', '9606', (68, 76))	('R132C', 'Mutation', 'rs121913499', (94, 99))	('2-HG levels', 'MPA', (30, 41))	('IDH1', 'Gene', (89, 93))	('R132C mutation', 'Var', (94, 108))	('ICC', 'Disease', 'MESH:C535533', (64, 67))	('IDH1', 'Gene', '3417', (89, 93))
94982	31795195	Lactate levels correlated with 2-HG, with elevated levels in Patient 3, for whom a somatic IDH1 mutation was identified (Figure 2a and Supplementary Figure S3a).	('2-HG', 'MPA', (31, 35))	('Lactate', 'Chemical', 'MESH:D019344', (0, 7))	('Lactate levels', 'MPA', (0, 14))	('mutation', 'Var', (96, 104))	('IDH1', 'Gene', (91, 95))	('2-HG', 'Chemical', 'MESH:C019417', (31, 35))	('IDH1', 'Gene', '3417', (91, 95))	('Patient', 'Species', '9606', (61, 68))	('elevated', 'PosReg', (42, 50))
94991	31795195	We therefore re-examined our WGS data for possible SNV and CNV mutations affecting four genes of the pyrimidine biosynthesis pathway (Supplementary Figure S4): the tri-functional enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase), DHODH (dihydroorotate dehydrogenase), the bi-functional enzyme uridine 5'-monophosphate synthase (UMPS, comprised of orotate phosphoribosyltransferase and OMP decarboxylase), and thymidylate synthetase (TYMS).	('orotate phosphoribosyltransferase', 'Gene', '7372', (391, 424))	('TYMS', 'Gene', '7298', (477, 481))	('DHODH', 'Gene', (274, 279))	('pyrimidine', 'Chemical', 'MESH:C030986', (101, 111))	('mutations', 'Var', (63, 72))	('UMPS', 'Gene', (372, 376))	('dihydroorotate dehydrogenase', 'Gene', '1723', (281, 309))	('DHODH', 'Gene', '1723', (274, 279))	('TYMS', 'Gene', (477, 481))	('orotate phosphoribosyltransferase', 'Gene', (391, 424))	('thymidylate synthetase', 'Gene', '7298', (453, 475))	('carbamoyl-phosphate', 'Chemical', 'MESH:D002221', (191, 210))	('dihydroorotate dehydrogenase', 'Gene', (281, 309))	('thymidylate synthetase', 'Gene', (453, 475))	("uridine 5'-monophosphate synthase", 'Gene', (337, 370))	('UMPS', 'Gene', '7372', (372, 376))	('CN', 'Disease', 'MESH:D007674', (59, 61))	('aspartate', 'Chemical', 'None', (225, 234))	("uridine 5'-monophosphate synthase", 'Gene', '7372', (337, 370))
94995	31795195	Patient 2 also had a germline SNV in CAD (V2115L), which is a variant of unknown significance but is located in a functional domain (aspartate/ornithine transcarbamoylase domain).	('aspartate', 'Chemical', 'None', (133, 142))	('ornithine', 'Chemical', 'MESH:C008973', (143, 152))	('CAD', 'Disease', (37, 40))	('V2115L', 'Var', (42, 48))	('Patient', 'Species', '9606', (0, 7))	('V2115L', 'Mutation', 'p.V2115L', (42, 48))
94996	31795195	The other patient with elevated orotate and orotidine, Patient 4, had four SNVs in three of the genes we examined: a germline variant in TYMS, G5S, and three somatic mutations, CAD, C92R; CAD, D2047fs; and DHODH, A375S.	('Patient', 'Species', '9606', (55, 62))	('C92R', 'Var', (182, 186))	('A375S', 'Mutation', 'p.A375S', (213, 218))	('DHODH', 'Gene', (206, 211))	('TYMS', 'Gene', '7298', (137, 141))	('DHODH', 'Gene', '1723', (206, 211))	('patient', 'Species', '9606', (10, 17))	('orotidine', 'Chemical', 'MESH:C008714', (44, 53))	('D2047fs', 'Mutation', 'p.D2047fsX', (193, 200))	('C92R', 'Mutation', 'p.C92R', (182, 186))	('D2047fs', 'Var', (193, 200))	('CAD', 'Var', (188, 191))	('A375S', 'Var', (213, 218))	('TYMS', 'Gene', (137, 141))	('G5S', 'Mutation', 'rs765119393', (143, 146))
94999	31795195	The circulating NRAS mutations split the metabolic groups, and the IDH1 mutation was only found in Patient 3, however, it cannot be ruled out that a more detailed genomic analysis of the tumour itself could have revealed additional mutations which correlated with the metabolic changes observed.	('tumour', 'Disease', (187, 193))	('IDH1', 'Gene', (67, 71))	('NRAS', 'Gene', (16, 20))	('IDH1', 'Gene', '3417', (67, 71))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('split', 'Reg', (31, 36))	('NRAS', 'Gene', '4893', (16, 20))	('Patient', 'Species', '9606', (99, 106))	('tumour', 'Disease', 'MESH:D009369', (187, 193))	('mutations', 'Var', (21, 30))
95001	31795195	The results nevertheless highlight that ctDNA can provide a relevant and straightforward way to identify and stratify ICC patients and that metabolomics analysis can reveal altered metabolic phenotypes in plasma that both correlate with ctDNA mutation status, and may serve to indicate additional genetic and/or clinical differences of potential relevance in early detection studies.	('ICC', 'Disease', (118, 121))	('mutation', 'Var', (243, 251))	('correlate', 'Reg', (222, 231))	('ICC', 'Disease', 'MESH:C535533', (118, 121))	('metabolic phenotypes', 'MPA', (181, 201))	('patients', 'Species', '9606', (122, 130))	('ctDNA', 'Gene', (237, 242))
95003	31795195	The 50 cancer gene panel detected an IDH1 mutation in one of the four patients (Patient 3).	('patients', 'Species', '9606', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Patient', 'Species', '9606', (80, 87))	('IDH1', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('IDH1', 'Gene', '3417', (37, 41))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('detected', 'Reg', (25, 33))
95004	31795195	This is in good accordance with the reported range of incidence of IDH1 mutations in ICC (5-25%).	('mutations', 'Var', (72, 81))	('IDH1', 'Gene', (67, 71))	('IDH1', 'Gene', '3417', (67, 71))	('ICC', 'Disease', (85, 88))	('ICC', 'Disease', 'MESH:C535533', (85, 88))
95006	31795195	This corresponded with the results of other research where circulating 2-HG levels were predictive of IDH1 mutations in tissue.	('mutations', 'Var', (107, 116))	('circulating 2-HG levels', 'MPA', (59, 82))	('IDH1', 'Gene', (102, 106))	('IDH1', 'Gene', '3417', (102, 106))	('2-HG', 'Chemical', 'MESH:C019417', (71, 75))
95011	31795195	However, although in vitro studies of the IDH1 inhibitors in gliomas have demonstrated a reduction in 2-HG, this has not been linked to response.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('inhibitors', 'Var', (47, 57))	('IDH1', 'Gene', '3417', (42, 46))	('gliomas', 'Disease', (61, 68))	('reduction', 'NegReg', (89, 98))	('2-HG', 'MPA', (102, 106))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('IDH1', 'Gene', (42, 46))	('2-HG', 'Chemical', 'MESH:C019417', (102, 106))
95015	31795195	However, we had obtained WGS data from gDNA and ctDNA samples, and, although coverage was too low to confidently designate SNVs on a genome wide basis, we were able to inspect the WGS data for SNVs and CNVS in the corresponding genes/regions involved in pyrimidine biosynthesis for our ICC cohort.	('ICC', 'Disease', (286, 289))	('SNVs', 'Var', (193, 197))	('ICC', 'Disease', 'MESH:C535533', (286, 289))	('pyrimidine', 'Chemical', 'MESH:C030986', (254, 264))	('CN', 'Disease', 'MESH:D007674', (202, 204))
95018	31795195	The SNV V2115L, whilst a variant of uncertain significance, is in the ATCase domain of the protein, and therefore might have a functional effect.	('V2115L', 'Mutation', 'p.V2115L', (8, 14))	('effect', 'Reg', (138, 144))	('SNV V2115L', 'Var', (4, 14))	('have', 'Reg', (120, 124))
95019	31795195	In addition, this patient also had a trisomy of chromosome 2, where CAD resides, which could predict increased levels of CAD activity that could account for the increased levels of orotate in plasma observed in Patient 2.	('increased', 'PosReg', (101, 110))	('Patient', 'Species', '9606', (211, 218))	('patient', 'Species', '9606', (18, 25))	('levels', 'MPA', (171, 177))	('trisomy', 'Var', (37, 44))
95020	31795195	Similarly, Patient 4, who also had elevated orotate levels, had four SNVs in three genes of the pyrimidine biosynthesis pathway that we examined, including two somatic heterozygous mutations in CAD (C92R and D2047fs) and a somatic variant in DHODH (A375S) as well as a mild germline variant in TYMS (G5S).	('D2047fs', 'Var', (208, 215))	('orotate levels', 'MPA', (44, 58))	('A375S', 'Mutation', 'p.A375S', (249, 254))	('TYMS', 'Gene', '7298', (294, 298))	('CAD', 'Gene', (194, 197))	('A375S', 'Var', (249, 254))	('G5S', 'Mutation', 'rs765119393', (300, 303))	('pyrimidine', 'Chemical', 'MESH:C030986', (96, 106))	('DHODH', 'Gene', (242, 247))	('DHODH', 'Gene', '1723', (242, 247))	('D2047fs', 'Mutation', 'p.D2047fsX', (208, 215))	('Patient', 'Species', '9606', (11, 18))	('C92R', 'Mutation', 'p.C92R', (199, 203))	('TYMS', 'Gene', (294, 298))	('C92R', 'Var', (199, 203))
95021	31795195	The CAD C92R variant may interfere with allosteric regulation and possibly result in a gain of function phenotype (Supplementary Table S3).	('C92R', 'Mutation', 'p.C92R', (8, 12))	('C92R', 'Var', (8, 12))	('gain of function', 'PosReg', (87, 103))	('interfere', 'NegReg', (25, 34))	('allosteric regulation', 'MPA', (40, 61))
95023	31795195	Our frameshift mutation is a somatic mutation present at very low frequency and functional studies would be required to assess its actual effect on orotate levels, whether it acts in combination with the C92R variant, and whether the wild type allele alone is sufficient for activity.	('C92R', 'Mutation', 'p.C92R', (204, 208))	('frameshift mutation', 'Var', (4, 23))	('effect', 'Reg', (138, 144))	('C92R', 'Var', (204, 208))	('orotate levels', 'MPA', (148, 162))
95024	31795195	This patient also had a mutation in DHODH.	('DHODH', 'Gene', (36, 41))	('DHODH', 'Gene', '1723', (36, 41))	('mutation', 'Var', (24, 32))	('patient', 'Species', '9606', (5, 12))
95025	31795195	Notably, compound heterozygous mutations in this gene were identified as the cause of Miller syndrome in the first application of exome sequencing for diagnosis of a rare Mendelian disorder.	('cause', 'Reg', (77, 82))	('Miller syndrome', 'Disease', 'MESH:C537680', (86, 101))	('compound heterozygous mutations', 'Var', (9, 40))	('Mendelian disorder', 'Disease', (171, 189))	('Mendelian disorder', 'Disease', 'MESH:D030342', (171, 189))	('Miller syndrome', 'Disease', (86, 101))
95026	31795195	Analysis of further patients with DHODH mutations showed a loss of DHOdhase activity but paradoxically did not show an increase in the enzyme substrate, DHO, in the urine as expected, but instead elevated levels of orotic acid.	('DHODH', 'Gene', (34, 39))	('DHODH', 'Gene', '1723', (34, 39))	('DHOdhase', 'Enzyme', (67, 75))	('activity', 'MPA', (76, 84))	('DHO', 'Chemical', 'MESH:C488648', (34, 37))	('levels of orotic acid', 'MPA', (205, 226))	('orotic acid', 'Chemical', 'MESH:D009963', (215, 226))	('elevated', 'PosReg', (196, 204))	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (20, 28))	('DHO', 'MPA', (153, 156))	('elevated levels of orotic acid', 'Phenotype', 'HP:0003218', (196, 226))	('DHO', 'Chemical', 'MESH:C488648', (67, 70))	('loss', 'NegReg', (59, 63))	('DHO', 'Chemical', 'MESH:C488648', (153, 156))
95027	31795195	The somatic surface mutation A375S in Patient 4 lies between some of the previously reported variants; therefore, whether this variant per se results in raised orotate merits further investigation.	('Patient', 'Species', '9606', (38, 45))	('raised', 'PosReg', (153, 159))	('orotate', 'MPA', (160, 167))	('A375S', 'Var', (29, 34))	('A375S', 'Mutation', 'p.A375S', (29, 34))
95028	31795195	The raised orotate levels observed in Patients 2 and 4 may therefore be explained by the germline or somatic variants in enzymes of the pyrimidine biosynthesis pathway.	('pyrimidine', 'Chemical', 'MESH:C030986', (136, 146))	('orotate levels', 'MPA', (11, 25))	('variants', 'Var', (109, 117))	('raised', 'PosReg', (4, 10))	('Patients', 'Species', '9606', (38, 46))
95033	31795195	Based on these findings, a larger study in ICC patients is indicated to consider whether genetic and metabolomics changes alter the purine/pyrimidine balance and cellular proliferation in the liver, thereby contributing to the pathogenesis of ICC.	('alter', 'Reg', (122, 127))	('patients', 'Species', '9606', (47, 55))	('contributing', 'Reg', (207, 219))	('ICC', 'Disease', (243, 246))	('ICC', 'Disease', (43, 46))	('ICC', 'Disease', 'MESH:C535533', (243, 246))	('ICC', 'Disease', 'MESH:C535533', (43, 46))	('purine', 'Chemical', 'MESH:D011687', (132, 138))	('purine/pyrimidine balance', 'MPA', (132, 157))	('changes', 'Var', (114, 121))	('pyrimidine', 'Chemical', 'MESH:C030986', (139, 149))	('cellular proliferation', 'CPA', (162, 184))
95039	31795195	It is possible that the increase in orotate may be explained by the variants we identified in pyrimidine biosynthesis genes, although further functional investigation would be required to confirm this conjecture.	('variants', 'Var', (68, 76))	('increase', 'PosReg', (24, 32))	('orotate', 'MPA', (36, 43))	('pyrimidine', 'Chemical', 'MESH:C030986', (94, 104))	('pyrimidine biosynthesis genes', 'Gene', (94, 123))
95041	31795195	Inhibitors of pyrimidine synthesis may target tumour progression, and can sensitise cancer cells to other forms of chemotherapy.	('sensitise cancer', 'Disease', 'MESH:D009369', (74, 90))	('sensitise cancer', 'Disease', (74, 90))	('target', 'Reg', (39, 45))	('tumour', 'Disease', (46, 52))	('Inhibitors', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('pyrimidine', 'Chemical', 'MESH:C030986', (14, 24))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
95044	31795195	Inhibition of pyrimidine biosynthesis with 5-aminoimidazole-4-carboxamide-1-beta-riboside (AICAr) induces apoptosis in multiple myeloma cells, with inhibition of UMPS and increases in orotate, further supporting pyrimidine biosynthesis as a potential molecular target in multiple myeloma cells.	('multiple myeloma', 'Disease', (271, 287))	('pyrimidine', 'Chemical', 'MESH:C030986', (212, 222))	('pyrimidine', 'Chemical', 'MESH:C030986', (14, 24))	('multiple myeloma', 'Disease', (119, 135))	('myeloma cells', 'Disease', (280, 293))	('myeloma cells', 'Disease', 'MESH:D009101', (280, 293))	('UMPS', 'Gene', '7372', (162, 166))	('UMPS', 'Gene', (162, 166))	('multiple myeloma', 'Phenotype', 'HP:0006775', (271, 287))	('inhibition', 'NegReg', (148, 158))	('apoptosis', 'CPA', (106, 115))	('AICAr', 'Gene', (91, 96))	('5-aminoimidazole-4-carboxamide-1-beta-riboside', 'Chemical', 'MESH:C011651', (43, 89))	('Inhibition', 'Var', (0, 10))	('multiple myeloma', 'Phenotype', 'HP:0006775', (119, 135))	('multiple myeloma', 'Disease', 'MESH:D009101', (271, 287))	('induces', 'Reg', (98, 105))	('myeloma cells', 'Disease', (128, 141))	('myeloma cells', 'Disease', 'MESH:D009101', (128, 141))	('orotate', 'MPA', (184, 191))	('multiple myeloma', 'Disease', 'MESH:D009101', (119, 135))	('AICAr', 'Gene', '471', (91, 96))	('increases', 'PosReg', (171, 180))
95045	31795195	It has recently been observed that cholangiocarcinoma patients with high expression of OPRT benefited from postoperative adjuvant chemotherapy with S-1 (an oral fluoropyrimidine, which is an OPRT inhibitor).	('benefited', 'PosReg', (92, 101))	('patients', 'Species', '9606', (54, 62))	('high expression', 'Var', (68, 83))	('cholangiocarcinoma', 'Disease', (35, 53))	('OPRT', 'Gene', '7372', (87, 91))	('S-1', 'Chemical', 'MESH:D013455', (148, 151))	('OPRT', 'Gene', '7372', (191, 195))	('OPRT', 'Gene', (87, 91))	('fluoropyrimidine', 'Chemical', 'MESH:C029269', (161, 177))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (35, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('OPRT', 'Gene', (191, 195))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (35, 53))
95046	31795195	It is possible that different genetic variants of the enzymes in pyrimidine/orotate synthesis, such as the variants we have observed, will be more or less sensitive to these treatments, and, therefore, ctDNA sequencing of these genes and orotate detection by metabolomics could help in selecting better personalised treatment for these patients.	('variants', 'Var', (107, 115))	('less', 'NegReg', (150, 154))	('patients', 'Species', '9606', (336, 344))	('pyrimidine', 'Chemical', 'MESH:C030986', (65, 75))	('sensitive', 'MPA', (155, 164))	('help', 'Reg', (278, 282))
95048	31795195	A further limitation was the 50 cancer gene panel used for targeted sequencing, as it only covered hotspot mutations in the 50 genes most commonly mutated in a broad range of cancers (listed in Supplementary Table S5), whereas the use of a comprehensive and specific upper GI cancer panel, including genes associated with recurrent mutations in ICC such as ARID1A and BAP1, may provide genetic profiling more specific to ICCs.	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('ICC', 'Disease', (345, 348))	('cancer', 'Disease', (175, 181))	('upper GI cancer', 'Disease', (267, 282))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (32, 38))	('ICC', 'Disease', (421, 424))	('ICC', 'Disease', 'MESH:C535533', (345, 348))	('GI cancer', 'Phenotype', 'HP:0007378', (273, 282))	('mutations', 'Var', (332, 341))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancers', 'Disease', (175, 182))	('BAP1', 'Gene', '8314', (368, 372))	('cancer', 'Disease', (276, 282))	('upper GI cancer', 'Disease', 'MESH:D009369', (267, 282))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('ARID1A', 'Gene', (357, 363))	('ICC', 'Disease', 'MESH:C535533', (421, 424))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('ARID1A', 'Gene', '8289', (357, 363))	('BAP1', 'Gene', (368, 372))	('cancers', 'Disease', 'MESH:D009369', (175, 182))
95056	31795195	In summary, we have analysed genetic profiles from ctDNA and plasma metabolomics data from the same ICC patients and found correlations between specific genes and altered metabolite levels, and, for selected gene mutations, direct links to altered metabolites.	('altered metabolite levels', 'MPA', (163, 188))	('mutations', 'Var', (213, 222))	('ICC', 'Disease', (100, 103))	('patients', 'Species', '9606', (104, 112))	('links', 'Interaction', (231, 236))	('ICC', 'Disease', 'MESH:C535533', (100, 103))
95057	31795195	For example, an increase in 2-HG further to somatic mutation in IDH1 was found in one of our patients.	('2-HG further', 'MPA', (28, 40))	('IDH1', 'Gene', (64, 68))	('increase', 'PosReg', (16, 24))	('2-HG', 'Chemical', 'MESH:C019417', (28, 32))	('IDH1', 'Gene', '3417', (64, 68))	('somatic mutation', 'Var', (44, 60))	('patients', 'Species', '9606', (93, 101))
95058	31795195	Results of ongoing clinical trials will be required to assess the efficacy of IDH1 inhibitors in reducing 2-HG levels and improving clinical outcomes for ICC patients with such IDH1 mutations.	('2-HG', 'Chemical', 'MESH:C019417', (106, 110))	('IDH1', 'Gene', (177, 181))	('IDH1', 'Gene', (78, 82))	('ICC', 'Disease', (154, 157))	('improving', 'PosReg', (122, 131))	('reducing', 'NegReg', (97, 105))	('IDH1', 'Gene', '3417', (78, 82))	('ICC', 'Disease', 'MESH:C535533', (154, 157))	('IDH1', 'Gene', '3417', (177, 181))	('patients', 'Species', '9606', (158, 166))	('clinical outcomes', 'MPA', (132, 149))	('mutations', 'Var', (182, 191))	('2-HG levels', 'MPA', (106, 117))
95068	31795195	Ion AmpliSeq  Cancer Hotspot Panel v2 (50 cancer gene panel) was used to detect potentially actionable somatic mutations, using a collection of primers designed to interrogate hotspot regions in 50 genes (207 amplicons) commonly mutated in cancer (ThermoFisher Scientific, Waltham, MA USA).	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('mutated', 'Var', (229, 236))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', (240, 246))
95093	31795195	This minimally invasive approach for the detection of tumour mutations, with complementary metabolite profiling, may also be useful for early detection and disease monitoring in response to therapy.	('tumour', 'Disease', (54, 60))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('mutations', 'Var', (61, 70))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
95100	31371345	Recently, FGFR inhibitors have been developed and utilized in FGFR-mutant cholangiocarcinoma; however, resistance often develops and the genomic determinants of resistance are not fully characterized.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (74, 92))	('FGFR-mutant', 'Gene', (62, 73))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (74, 92))	('cholangiocarcinoma', 'Disease', (74, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('FGFR-mutant', 'Var', (62, 73))
95103	31371345	Additionally, WES revealed an FGFR2 N549H mutation hypothesized to confer resistance to the FGFR inhibitor INCB054828 in a single tumor sample.	('N549H', 'SUBSTITUTION', 'None', (36, 41))	('N549H', 'Var', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('FGFR2', 'Gene', (30, 35))	('tumor', 'Disease', (130, 135))
95104	31371345	This hypothesis was corroborated with in vitro cell-based studies in which cells expressing FGFR2-CLIP1 fusion were sensitive to INCB054828 (IC50 value of 10.16 nM), whereas cells with the addition of the N549H mutation were resistant to INCB054828 (IC50 value of 1527.57 nM).	('FGFR2-CLIP1', 'Gene', (92, 103))	('sensitive', 'Reg', (116, 125))	('fusion', 'Var', (104, 110))	('INCB054828', 'Var', (129, 139))	('N549H', 'SUBSTITUTION', 'None', (205, 210))	('N549H', 'Var', (205, 210))
95105	31371345	Furthermore, the FGFR2 N549H secondary mutation displayed cross-resistance to other selective FGFR inhibitors, but remained sensitive to the nonselective inhibitor, ponatinib.	('FGFR2', 'Gene', (17, 22))	('N549H', 'Var', (23, 28))	('ponatinib', 'Chemical', 'MESH:C545373', (165, 174))	('cross-resistance', 'MPA', (58, 74))	('N549H', 'SUBSTITUTION', 'None', (23, 28))
95107	31371345	In this study, we demonstrate the emergence of a drug resistance mutation and characterize the evolution of tumor subclones within a cholangiocarcinoma disease course.	('cholangiocarcinoma disease', 'Disease', 'MESH:D018281', (133, 159))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('cholangiocarcinoma disease', 'Disease', (133, 159))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('drug resistance', 'Phenotype', 'HP:0020174', (49, 64))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (133, 151))	('tumor', 'Disease', (108, 113))	('mutation', 'Var', (65, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
95111	31371345	The fibroblast growth factor receptor (FGFR) signaling pathway is aberrantly activated in ~20% of cases of intrahepatic cholangiocarcinoma through various genomic alterations including point mutations, copy-number amplifications, and gene fusions.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (107, 138))	('gene fusions', 'Var', (234, 246))	('activated', 'PosReg', (77, 86))	('intrahepatic cholangiocarcinoma', 'Disease', (107, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (120, 138))	('point mutations', 'Var', (185, 200))	('copy-number amplifications', 'Var', (202, 228))
95114	31371345	Although genomic alterations in FGFR correlated with initial clinical responses to FGFR inhibitors, multiple secondary mutations in FGFR and other cellular signaling pathways have been identified in patients after treatment with FGFR inhibitors.	('FGFR', 'Gene', (83, 87))	('FGFR', 'Gene', (132, 136))	('patients', 'Species', '9606', (199, 207))	('FGFR', 'Gene', (32, 36))	('mutations', 'Var', (119, 128))	('identified', 'Reg', (185, 195))
95115	31371345	Thus, elucidating the various acquired mechanisms of drug resistance to FGFR inhibitors will be critical for the development of new therapies to overcome resistance and improve the outcome of patients with FGFR-mutant cancers.	('FGFR-mutant', 'Var', (206, 217))	('FGFR-mutant', 'Gene', (206, 217))	('cancers', 'Disease', 'MESH:D009369', (218, 225))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('patients', 'Species', '9606', (192, 200))	('cancers', 'Disease', (218, 225))	('drug resistance', 'Phenotype', 'HP:0020174', (53, 68))	('FGFR', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
95117	31371345	Both genetic and epigenetic mechanisms within the tumor itself as well as changes in the tumor microenvironment can drive the development of tumor heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('epigenetic', 'Var', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
95123	31371345	Targeted gene panel sequencing using the commercial Guardant360 assay revealed an FGFR2 V564F gatekeeper mutation in plasma circulating tumor DNA (ctDNA) of all three patients and several additional FGFR2 mutations in two of the patients.	('patients', 'Species', '9606', (229, 237))	('gatekeeper', 'Species', '111938', (94, 104))	('V564F', 'Mutation', 'p.V564F', (88, 93))	('patients', 'Species', '9606', (167, 175))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('FGFR2', 'Gene', (82, 87))	('revealed', 'Reg', (70, 78))	('V564F', 'Var', (88, 93))	('tumor', 'Disease', (136, 141))
95127	31371345	Prior research on acquired resistance mutations in KIT, ABL1, and ALK oncogenes with their respective kinase inhibitors demonstrates that cross-resistance and sensitivity for secondary mutations varies widely, and therefore understanding resistance profiles for other FGFR inhibitors will be essential.	('ALK', 'Gene', '238', (66, 69))	('KIT', 'Gene', (51, 54))	('ABL1', 'Gene', '25', (56, 60))	('ABL1', 'Gene', (56, 60))	('ALK', 'Gene', (66, 69))	('mutations', 'Var', (38, 47))
95129	31371345	In the current work, we present a patient with metastatic cholangiocarcinoma harboring a novel FGFR2-CLIP1 gene fusion who demonstrated a partial response followed by disease progression while on treatment with the FGFR-selective kinase inhibitor, INCB054828.	('cholangiocarcinoma', 'Disease', (58, 76))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('patient', 'Species', '9606', (34, 41))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('FGFR2-CLIP1', 'Gene', (95, 106))	('fusion', 'Var', (112, 118))
95131	31371345	Furthermore, we identified a posttreatment secondary kinase mutation in FGFR2 present in a single metastatic tumor sample and characterized its impact on sensitivity to a variety of FGFR inhibitors in vitro.	('mutation', 'Var', (60, 68))	('sensitivity', 'MPA', (154, 165))	('FGFR2', 'Gene', (72, 77))	('impact', 'Reg', (144, 150))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
95135	31371345	He underwent biopsy of one liver lesion, and pathology demonstrated poorly differentiated adenocarcinoma with focal neuroendocrine differentiation (CK7+, CDX2+, synaptophysin/chromogranin+, CK20-, TTF1-, napsin-) consistent with pancreatic or biliary origin.	('CDX2', 'Gene', '1045', (154, 158))	('CK7+', 'Var', (148, 152))	('TTF1', 'Gene', '7270', (197, 201))	('liver lesion', 'Disease', 'MESH:D017093', (27, 39))	('pancreatic', 'Disease', 'MESH:D010195', (229, 239))	('CK20', 'Gene', (190, 194))	('CDX2', 'Gene', (154, 158))	('synaptophysin', 'Gene', (161, 174))	('CK20', 'Gene', '54474', (190, 194))	('pancreatic', 'Disease', (229, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('adenocarcinoma', 'Disease', (90, 104))	('synaptophysin', 'Gene', '6855', (161, 174))	('liver lesion', 'Disease', (27, 39))	('adenocarcinoma', 'Disease', 'MESH:D000230', (90, 104))	('poorly', 'Disease', (68, 74))	('TTF1', 'Gene', (197, 201))
95144	31371345	Based on the presence of this novel FGFR2-CLIP1 fusion in his cancer, at the beginning of October, the patient enrolled in a Phase I/II clinical trial (NCT02393248) evaluating the safety and tolerability of an oral pan-FGFR inhibitor, INCB054828.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('fusion', 'Var', (48, 54))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('patient', 'Species', '9606', (103, 110))	('FGFR2-CLIP1', 'Gene', (36, 47))
95145	31371345	Disease assessment after cycles 3 (November) and 6 (January) showed robust partial response by RECIST criteria, consistent with this novel FGFR2 fusion being a driver of his metastatic cancer (Fig.	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('FGFR2', 'Gene', (139, 144))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('fusion', 'Var', (145, 151))	('cancer', 'Disease', (185, 191))
95150	31371345	He received a single dose of oxaliplatin (190 mg) and fluorouracil (3975 mg).	('190 mg', 'Var', (42, 48))	('fluorouracil', 'Chemical', 'MESH:D005472', (54, 66))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (29, 40))	('3975', 'Var', (68, 72))
95161	31371345	2B) and revealed a total of 979 somatic variants across all tumors (292 unique somatic variants).	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', (60, 66))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('variants', 'Var', (40, 48))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
95165	31371345	Mutational signatures 16 and 19 were common across tumor samples.	('Mutational signatures', 'Var', (0, 21))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
95167	31371345	The somatic single-nucleotide variants (SNVs) called in each tumor sample were subsequently used to build a phylogenetic tree of tumor samples via the neighbor-joining (NJ) method (Fig.	('single-nucleotide', 'Var', (12, 29))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (61, 66))
95170	31371345	We next utilized Canopy to computationally identify and characterize tumor subclones using both synonymous and nonsynonymous somatic SNVs, CNVs, and indels (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('CNVs', 'Var', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('indels', 'Var', (149, 155))
95176	31371345	Of clinical interest, WES revealed an FGFR2 kinase domain mutation, FGFR2 N549H in a single liver tumor, liver #1 (Fig.	('single liver', 'Phenotype', 'HP:0100839', (85, 97))	('liver tumor', 'Disease', 'MESH:D008113', (92, 103))	('liver tumor', 'Phenotype', 'HP:0002896', (92, 103))	('liver tumor', 'Disease', (92, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('N549H', 'SUBSTITUTION', 'None', (74, 79))	('N549H', 'Var', (74, 79))	('FGFR2', 'Gene', (68, 73))	('FGFR2', 'Gene', (38, 43))
95177	31371345	The FGFR2 N549H mutation occurs in the kinase hinge and has been shown to disengage the molecular breaker resulting in ligand-independent constitutive activation of the FGFR2 kinase.	('activation', 'PosReg', (151, 161))	('constitutive', 'MPA', (138, 150))	('N549H', 'SUBSTITUTION', 'None', (10, 15))	('N549H', 'Var', (10, 15))	('FGFR2', 'Gene', (169, 174))	('FGFR2', 'Gene', (4, 9))
95178	31371345	The FGFR2 N549H mutation was assigned uniquely to clone 1, which was the most genetically distinct subclone compared to the patient's normal blood DNA (Fig.	('patient', 'Species', '9606', (124, 131))	('FGFR2', 'Gene', (4, 9))	('N549H', 'SUBSTITUTION', 'None', (10, 15))	('N549H', 'Var', (10, 15))
95180	31371345	ddPCR of all samples confirmed that the FGFR2 N549H mutation was unique to liver #1 (Supplemental Table S1).	('N549H', 'SUBSTITUTION', 'None', (46, 51))	('N549H', 'Var', (46, 51))	('FGFR2', 'Gene', (40, 45))
95181	31371345	This led us to hypothesize that the N549H FGFR2 kinase domain mutation may have been partially responsible for driving resistance to INCB054828 in this patient, occurring along an existing clonal lineage.	('FGFR2', 'Gene', (42, 47))	('N549H', 'SUBSTITUTION', 'None', (36, 41))	('N549H', 'Var', (36, 41))	('resistance', 'MPA', (119, 129))	('patient', 'Species', '9606', (152, 159))
95182	31371345	Driver mutation prediction with CHASM predicted only FGFR2 N549H to be a statistically likely driver (defined as FDR-corrected P <= 0.05) (Supplemental File S9).	('N549H', 'SUBSTITUTION', 'None', (59, 64))	('FGFR2', 'Gene', (53, 58))	('N549H', 'Var', (59, 64))
95183	31371345	To confirm our clinical findings that the FGFR2-CLIP1 fusion is exquisitely sensitive to INCB054828 and explore the hypothesis that the FGFR2 N549H mutation confers resistance to INCB054828, we generated NIH3T3 cells that express either a control (Empty) vector, FGFR2-CLIP1 fusion (FC), or FGFR2-CLIP1 fusion with the N549H secondary mutation (N549H) and confirmed expression by RT-PCR (Fig.	('N549H', 'SUBSTITUTION', 'None', (319, 324))	('N549H', 'Var', (319, 324))	('N549H', 'SUBSTITUTION', 'None', (142, 147))	('N549H', 'Var', (142, 147))	('NIH3T3', 'CellLine', 'CVCL:0594', (204, 210))	('N549H', 'SUBSTITUTION', 'None', (345, 350))	('N549H', 'Var', (345, 350))	('FGFR2-CLIP1', 'Gene', (291, 302))
95184	31371345	Western blot analyses of FGFR2-CLIP1 fusion expression cells demonstrated increases in PI3K/AKT, MAPK/MEK, and FGFR2 signaling pathways with or without N549H (Fig.	('MEK', 'Gene', '5609', (102, 105))	('FGFR2 signaling pathways', 'Pathway', (111, 135))	('FGFR2-CLIP1', 'Gene', (25, 36))	('AKT', 'Gene', '207', (92, 95))	('N549H', 'SUBSTITUTION', 'None', (152, 157))	('N549H', 'Var', (152, 157))	('increases', 'PosReg', (74, 83))	('AKT', 'Gene', (92, 95))	('MEK', 'Gene', (102, 105))
95185	31371345	To evaluate the in vitro sensitivity of cells with the FGFR2-CLIP1 fusion and cells with the FGFR2-CLIP1 N549H to the FGFR inhibitor INCB054828, we treated NIH3T3 Empty, FGFR2-CLIP1, and FGFR2-CLIP1 N549H cells with increasing doses of INCB054828 or vehicle control (DMSO) ranging from 1.0 nM to 5000 nM and assessed cell viability after 72 h. Treatment of NIH3T3 FGFR2-CLIP1 (FC) cells with INCB054828 demonstrated substantial and reproducible inhibition of cell viability with an IC50 value of 10.16 nM (Fig.	('N549H', 'SUBSTITUTION', 'None', (105, 110))	('N549H', 'Var', (105, 110))	('NIH3T3', 'CellLine', 'CVCL:0594', (357, 363))	('INCB054828', 'Var', (392, 402))	('N549H', 'Var', (199, 204))	('N549H', 'SUBSTITUTION', 'None', (199, 204))	('inhibition', 'NegReg', (445, 455))	('NIH3T3', 'CellLine', 'CVCL:0594', (156, 162))	('cell viability', 'CPA', (459, 473))
95186	31371345	Consistent with our hypothesis, the FGFR2-CLIP1 N549H (N549H) cells were resistant to INCB054828 with an IC50 value of 1527.57 nM (Fig.	('N549H', 'SUBSTITUTION', 'None', (48, 53))	('N549H', 'Var', (48, 53))	('N549H', 'SUBSTITUTION', 'None', (55, 60))	('N549H', 'Var', (55, 60))	('FGFR2-CLIP1', 'Gene', (36, 47))
95187	31371345	Thus, these data help explain this patient's clinical course with his initial FGFR2-CLIP1 fusion expressing tumor responding to INCB054828 followed by acquisition of resistance via the N549H mutation.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('FGFR2-CLIP1', 'Gene', (78, 89))	('N549H', 'SUBSTITUTION', 'None', (185, 190))	('N549H', 'Var', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('patient', 'Species', '9606', (35, 42))	('tumor', 'Disease', (108, 113))
95188	31371345	We subsequently extended these in vitro studies to include additional FGFR inhibitors that are currently being evaluated clinically in patients with metastatic cancer and have shown early responses in patients with FGFR-mutant cancers.	('patients', 'Species', '9606', (201, 209))	('patients', 'Species', '9606', (135, 143))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('FGFR-mutant', 'Var', (215, 226))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', (227, 233))	('FGFR', 'Gene', (70, 74))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('cancers', 'Disease', (227, 234))	('FGFR-mutant', 'Gene', (215, 226))	('cancers', 'Disease', 'MESH:D009369', (227, 234))
95189	31371345	AZD4547, BGJ398, and JNJ-42756493 are selective FGFR inhibitors, whereas ponatinib and dovitinib are nonspecific tyrosine kinase inhibitors that target BCR-ABL, VEGFR, PDGFR, SRC, RET, KIT, and FLT1 in addition to FGFR.	('FLT1', 'Gene', '2321', (194, 198))	('BCR-ABL', 'Gene', '25', (152, 159))	('JNJ-42756493', 'Var', (21, 33))	('FGFR', 'Gene', (48, 52))	('SRC', 'Gene', '6714', (175, 178))	('PDGFR', 'Gene', (168, 173))	('dovitinib', 'Chemical', 'MESH:C500007', (87, 96))	('PDGFR', 'Gene', '5159', (168, 173))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('SRC', 'Gene', (175, 178))	('VEGFR', 'Gene', '3791', (161, 166))	('BCR-ABL', 'Gene', (152, 159))	('BGJ398', 'Chemical', 'MESH:C568950', (9, 15))	('RET', 'Gene', '5979', (180, 183))	('BGJ398', 'Var', (9, 15))	('VEGFR', 'Gene', (161, 166))	('RET', 'Gene', (180, 183))	('JNJ', 'Chemical', '-', (21, 24))	('FLT1', 'Gene', (194, 198))	('AZD4547', 'Var', (0, 7))	('ponatinib', 'Chemical', 'MESH:C545373', (73, 82))
95190	31371345	Our results demonstrated that FGFR2-CLIP1 cells were sensitive to AZD4547, BGJ398, JNJ-42756493, and ponatinib with IC50 values of 148.59 nM, 108.39 nM, 23.28 nM, and 166.34 nM, respectively (Fig.	('AZD4547', 'Chemical', 'MESH:C572463', (66, 73))	('JNJ-42756493', 'Var', (83, 95))	('BGJ398', 'Chemical', 'MESH:C568950', (75, 81))	('JNJ', 'Chemical', '-', (83, 86))	('BGJ398', 'Var', (75, 81))	('ponatinib', 'Chemical', 'MESH:C545373', (101, 110))	('AZD4547', 'Var', (66, 73))
95191	31371345	The FGFR2-CLIP1 N549H cells were less sensitive to BGJ398, AZD4547, and JNJ-42756493, as demonstrated by higher IC50 values than the fusion alone (Fig.	('AZD4547', 'Var', (59, 66))	('IC50 values', 'MPA', (112, 123))	('BGJ398', 'Var', (51, 57))	('AZD4547', 'Chemical', 'MESH:C572463', (59, 66))	('higher', 'PosReg', (105, 111))	('BGJ398', 'Chemical', 'MESH:C568950', (51, 57))	('JNJ-42756493', 'Var', (72, 84))	('N549H', 'SUBSTITUTION', 'None', (16, 21))	('N549H', 'Var', (16, 21))	('JNJ', 'Chemical', '-', (72, 75))
95196	31371345	The FGFR2 N549H secondary mutation confers resistance to most FGFR inhibitors, but ponatinib could be used to overcome this acquired drug resistance.	('resistance', 'MPA', (43, 53))	('N549H', 'SUBSTITUTION', 'None', (10, 15))	('N549H', 'Var', (10, 15))	('FGFR', 'Gene', (62, 66))	('ponatinib', 'Chemical', 'MESH:C545373', (83, 92))	('FGFR2', 'Gene', (4, 9))	('drug resistance', 'Phenotype', 'HP:0020174', (133, 148))
95206	31371345	The NJ analysis showed that the liver #1 sample with its unique FGFR2 N549H point mutation is an outlier versus the other liver samples from autopsy.	('N549H', 'SUBSTITUTION', 'None', (70, 75))	('FGFR2', 'Gene', (64, 69))	('N549H', 'Var', (70, 75))
95209	31371345	The FGFR2 N549H mutation in clone 1 was unique to a single liver sample despite our in vitro data confirming its role as a resistance mutation.	('single liver', 'Phenotype', 'HP:0100839', (52, 64))	('FGFR2', 'Gene', (4, 9))	('N549H', 'SUBSTITUTION', 'None', (10, 15))	('N549H', 'Var', (10, 15))
95210	31371345	Each of these samples harbored unique FGFR mutations (K641R and N549H) with only one sample having two FGFR mutations (E565A and K641R).	('E565A', 'Var', (119, 124))	('K641R', 'Mutation', 'rs1057519047', (129, 134))	('N549H', 'SUBSTITUTION', 'None', (64, 69))	('N549H', 'Var', (64, 69))	('FGFR', 'Gene', (38, 42))	('K641R', 'Mutation', 'rs1057519047', (54, 59))	('K641R', 'Var', (129, 134))	('E565A', 'Mutation', 'rs121918506', (119, 124))	('K641R', 'Var', (54, 59))
95219	31371345	In clone 1, the decreased sensitivity is likely due to the FGFR2 N549H point mutation, evolving from a common lineage as clone 2.	('FGFR2', 'Gene', (59, 64))	('N549H', 'SUBSTITUTION', 'None', (65, 70))	('N549H', 'Var', (65, 70))	('sensitivity', 'MPA', (26, 37))	('decreased', 'NegReg', (16, 25))
95222	31371345	Although there was no evidence for PTEN mutations in this patient, transcriptome sequencing would be needed to assess the activation of other pathways.	('patient', 'Species', '9606', (58, 65))	('mutations', 'Var', (40, 49))	('PTEN', 'Gene', (35, 39))	('PTEN', 'Gene', '5728', (35, 39))
95229	31371345	demonstrated that crizotinib-induced resistance mutations in ALK-fusion-positive non-small-cell lung cancer (NSCLC) can be overcome by treatment with ceritinib.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('mutations', 'Var', (48, 57))	('ALK', 'Gene', (61, 64))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ceritinib', 'Chemical', 'MESH:C586847', (150, 159))	('ALK', 'Gene', '238', (61, 64))	('NSCLC', 'Disease', (109, 114))	('crizotinib', 'Chemical', 'MESH:D000077547', (18, 28))
95230	31371345	Furthermore, mutant-selective allosteric inhibitors have shown promise in overcoming the secondary EGFR resistance mutation T790M in NSCLC following EGFR-directed therapy.	('overcoming', 'PosReg', (74, 84))	('EGFR', 'Gene', (99, 103))	('T790M', 'Var', (124, 129))	('EGFR', 'Gene', '1956', (149, 153))	('NSCLC', 'Disease', (133, 138))	('EGFR', 'Gene', (149, 153))	('EGFR', 'Gene', '1956', (99, 103))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))	('T790M', 'Mutation', 'rs121434569', (124, 129))
95231	31371345	Thus, these studies may inform strategies to overcome secondary resistance mutations to FGFR-targeted therapies as several preclinical studies have demonstrated the emergence of a mutation at the gatekeeper residue or other residues within the ATP-binding pocket as well as other mutations in FGFR1-3.	('FGFR1', 'Gene', '2260', (293, 298))	('ATP', 'Chemical', 'MESH:D000255', (244, 247))	('gatekeeper', 'Species', '111938', (196, 206))	('FGFR1', 'Gene', (293, 298))	('mutation at', 'Var', (180, 191))
95232	31371345	Unfortunately, several potent and selective ATP-competitive small molecule FGFR inhibitors currently in clinical trials, including INCB054828, BGJ398, AZD4547, and LY2874455, share structural similarities and are ineffective in overcoming the gatekeeper mutations.	('AZD4547', 'Var', (151, 158))	('BGJ398', 'Chemical', 'MESH:C568950', (143, 149))	('AZD4547', 'Chemical', 'MESH:C572463', (151, 158))	('INCB054828', 'Var', (131, 141))	('FGFR', 'Gene', (75, 79))	('BGJ398', 'Gene', (143, 149))	('gatekeeper', 'Species', '111938', (243, 253))	('LY2874455', 'Var', (164, 173))	('LY2874455', 'Chemical', 'MESH:C570663', (164, 173))	('ATP', 'Chemical', 'MESH:D000255', (44, 47))
95233	31371345	Although not considered a gatekeeper mutation, the FGFR2 N549H mutation is in the vicinity of the ATP binding pocket.	('N549H', 'Var', (57, 62))	('ATP', 'Chemical', 'MESH:D000255', (98, 101))	('FGFR2', 'Gene', (51, 56))	('gatekeeper', 'Species', '111938', (26, 36))	('N549H', 'SUBSTITUTION', 'None', (57, 62))
95234	31371345	Notably, our in vitro findings provide further support for the cross-resistance of multiple FGFR inhibitors, as cells harboring the secondary FGFR mutation N549H were resistant to INCB054828, AZD4547, BGJ398, JNJ-42756493, and dovitinib.	('FGFR', 'Gene', (92, 96))	('JNJ', 'Chemical', '-', (209, 212))	('AZD4547', 'Chemical', 'MESH:C572463', (192, 199))	('BGJ398', 'Chemical', 'MESH:C568950', (201, 207))	('dovitinib', 'Chemical', 'MESH:C500007', (227, 236))	('resistant', 'MPA', (167, 176))	('N549H', 'SUBSTITUTION', 'None', (156, 161))	('N549H', 'Var', (156, 161))
95235	31371345	Because of this, there has been interest in the use of structure-based drug design to develop a class of next-generation inhibitors that would overcome resistance mutations located in the FGFR2 ATP-binding pocket.	('FGFR2', 'Gene', (188, 193))	('mutations', 'Var', (163, 172))	('ATP', 'Chemical', 'MESH:D000255', (194, 197))
95236	31371345	Interestingly, we demonstrated that FGFR2 N549H retained sensitivity to ponatinib.	('N549H', 'SUBSTITUTION', 'None', (42, 47))	('N549H', 'Var', (42, 47))	('sensitivity', 'MPA', (57, 68))	('ponatinib', 'Chemical', 'MESH:C545373', (72, 81))	('FGFR2', 'Gene', (36, 41))
95243	31371345	Furthermore, we identified a posttreatment secondary kinase mutation in FGFR2, present in a single metastatic tumor sample demonstrating the significance of intertumor heterogeneity within the same patient.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('patient', 'Species', '9606', (198, 205))	('FGFR2', 'Gene', (72, 77))	('tumor', 'Disease', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('secondary', 'Var', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
95244	31371345	We characterized the impact of the N549H mutation on sensitivity to different FGFR inhibitors in vitro.	('FGFR', 'Gene', (78, 82))	('N549H', 'SUBSTITUTION', 'None', (35, 40))	('N549H', 'Var', (35, 40))
95265	31371345	Note that Canopy estimates its normal cell fractions based on variant fractions and CNV data, and reported purities can differ from pathologist estimates, likely because different sections of the tumor blocks were sequenced than were reviewed by the pathologist (Supplemental File S5).	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', (196, 201))	('variant', 'Var', (62, 69))
95267	31371345	Results are returned as abilities, such that  where pi1 and pi2 are the abilities of mutations v1 and v2.	('pi1', 'Var', (52, 55))	('pi2', 'Species', '1214577', (60, 63))	('mutations', 'Var', (85, 94))	('pi2', 'Var', (60, 63))
95268	31371345	Isolated genomic DNA was amplified using a custom-designed probe for the FGFR2 N549H point mutation (PrimePCR ddPCR Mutation Assay, Bio-Rad) and the ddPCR Supermix for Probes (Bio-Rad).	('Rad', 'Gene', (180, 183))	('Rad', 'Gene', '6236', (180, 183))	('N549H', 'SUBSTITUTION', 'None', (79, 84))	('N549H', 'Var', (79, 84))	('FGFR2', 'Gene', (73, 78))	('Rad', 'Gene', '6236', (136, 139))	('Rad', 'Gene', (136, 139))
95272	31371345	The ddPCR data were analyzed with QuantaSoft analysis software (Bio-Rad) to obtain fractional abundance of the mutant DNA alleles in the wt/normal background.	('DNA', 'Gene', (118, 121))	('mutant', 'Var', (111, 117))	('Rad', 'Gene', (68, 71))	('Rad', 'Gene', '6236', (68, 71))
95273	31371345	Using site-directed mutagenesis, the FGFR2 N549H mutation was introduced into the fusion by GenScript.	('N549H', 'Var', (43, 48))	('FGFR2', 'Gene', (37, 42))	('N549H', 'SUBSTITUTION', 'None', (43, 48))
95274	31371345	NIH3T3 cells were stably transduced with either empty, FGFR2-CLIP1 or FGFR2-CLIP1 N549H lentiviral vectors.	('N549H', 'Var', (82, 87))	('NIH3T3', 'CellLine', 'CVCL:0594', (0, 6))	('FGFR2-CLIP1', 'Gene', (55, 66))	('FGFR2-CLIP1', 'Gene', (70, 81))	('N549H', 'SUBSTITUTION', 'None', (82, 87))
95277	31371345	cDNA was subsequently PCR amplified with FGFR2-CLIP1 and FGFR2 N549H fusion specific primers (IDT).	('N549H', 'Var', (63, 68))	('FGFR2-CLIP1', 'Gene', (41, 52))	('FGFR2', 'Gene', (57, 62))	('N549H', 'SUBSTITUTION', 'None', (63, 68))
95279	31371345	Western blot assays were carried out using established protocols and probed with the following antibodies: phospho-Akt (Ser473) 1:1000 (Cell Signaling 9271), Total Akt 1:1000 (Cell Signaling 9272), phospho-MEK1/2 1:5000 (Cell Signaling 9154), Total MEK1/2 1:5000 (Cell Signaling 9122), p44/42 MAPK (Erk1/2) 1:5000 (Cell Signaling 9101), Total MAPK 1:5000 (Cell Signaling 9102), phospho-FGF Receptor (Tyr653/654) 1:500 (Cell Signaling 3471), FGF Receptor 2 (D4L2V) 1:500 (Cell Signaling 23328), phospho-PLCgamma1 (Tyr783) 1:1000 (Cell Signaling 14008), PLCgamma1 (D9H10) 1:1000 (Cell Signaling 5690), phospho-FRS2-alpha (Tyr196) 1:1000 (Cell Signaling 3864), FRS2 1:1000 (abcam 10425), phospho-PI3 Kinase p85 (Tyr458)/p55 (Tyr199) 1:1000 (Cell Signaling 4228), PI3 Kinase p85 (19H8) 1:000 (Cell Signaling 4257), beta-actin 1:10000 (Cell Signaling 4967).	('FRS2', 'Gene', (608, 612))	('FRS2-alpha', 'Gene', (608, 618))	('FRS2', 'Gene', '10818', (658, 662))	('MEK1/2', 'Gene', '5604;5605', (206, 212))	('MEK1/2', 'Gene', (206, 212))	('Erk1/2', 'Gene', '5595;5594', (299, 305))	('PLCgamma1', 'Gene', '5335', (502, 511))	('p85', 'Gene', (704, 707))	('p85', 'Gene', '5296', (771, 774))	('Akt', 'Gene', (164, 167))	('p55', 'Gene', (717, 720))	('PLCgamma1', 'Gene', (502, 511))	('Akt', 'Gene', '207', (164, 167))	('FRS2', 'Gene', '10818', (608, 612))	('FRS2-alpha', 'Gene', '10818', (608, 618))	('p85', 'Gene', (771, 774))	('beta-actin', 'Gene', (811, 821))	('Akt', 'Gene', (115, 118))	('beta-actin', 'Gene', '11461', (811, 821))	('FRS2', 'Gene', (658, 662))	('Erk1/2', 'Gene', (299, 305))	('MEK1/2', 'Gene', '5604;5605', (249, 255))	('MEK1/2', 'Gene', (249, 255))	('p44', 'Gene', (286, 289))	('Akt', 'Gene', '207', (115, 118))	('PLCgamma1', 'Gene', '5335', (552, 561))	('p85', 'Gene', '5296', (704, 707))	('p44', 'Gene', '10561', (286, 289))	('PLCgamma1', 'Gene', (552, 561))	('p55', 'Gene', '347376', (717, 720))	('Tyr458', 'Var', (709, 715))
95280	31371345	NIH3T3 Empty, FGFR2-CLIP1, FGFR2-CLIP1 N549H cells were plated at a density of 10,000 cells per well in 96-well plates.	('NIH3T3', 'CellLine', 'CVCL:0594', (0, 6))	('N549H', 'SUBSTITUTION', 'None', (39, 44))	('FGFR2-CLIP1', 'Gene', (27, 38))	('N549H', 'Var', (39, 44))
95281	31371345	Cells were treated for 72 h with either INCB054828 (Incyte), BGJ398 (Cayman Chemical), JNJ-42756493 (Cayman Chemical), AZD-4547 (Cayman Chemical), ponatinib (Cayman Chemical), or dovitinib (Cayman Chemical) ranging from 0.01 to 5000 nM.	('AZD-4547', 'Var', (119, 127))	('JNJ-42756493', 'Var', (87, 99))	('dovitinib', 'Chemical', 'MESH:C500007', (179, 188))	('BGJ398', 'Chemical', 'MESH:C568950', (61, 67))	('AZD-4547', 'Chemical', 'MESH:C572463', (119, 127))	('INCB054828', 'Var', (40, 50))	('ponatinib', 'Chemical', 'MESH:C545373', (147, 156))	('JNJ', 'Chemical', '-', (87, 90))	('BGJ398', 'Gene', (61, 67))
95282	31371345	The FGFR2-CLIP1 fusion gene variant and the secondary FGFR2 mutation identified in the patient have also been deposited to ClinVar  under the accession numbers SCV000927106 and SCV000914229.1.	('patient', 'Species', '9606', (87, 94))	('mutation', 'Var', (60, 68))	('variant', 'Var', (28, 35))	('FGFR2', 'Gene', (54, 59))
95511	30575336	reported observing bile duct and gallbladder wall thickening in 60% of patients with AIP 78.	('AIP', 'Var', (85, 88))	('bile duct', 'Disease', (19, 28))	('patients', 'Species', '9606', (71, 79))
95554	30575336	Lower bile duct strictures are observed in about 80% of patients with AIP.	('AIP', 'Var', (70, 73))	('Lower bile duct strictures', 'Disease', (0, 26))	('patients', 'Species', '9606', (56, 64))	('bile duct stricture', 'Phenotype', 'HP:0030151', (6, 25))
95650	30575336	Endoscopic findings such as a swollen ampulla of Vater and endoscopic biopsy results showing abundant IgG4-positive plasma cell infiltration were noted in 40-80% of patients with IgG4-SC associated with AIP 120, 121, 122.	('IgG', 'Gene', (102, 105))	('IgG', 'Gene', '668542', (179, 182))	('IgG', 'Gene', (179, 182))	('AIP 120', 'Var', (203, 210))	('patients', 'Species', '9606', (165, 173))	('associated', 'Reg', (187, 197))	('IgG', 'Gene', '668542', (102, 105))
95664	30575336	IDUS findings of cholangiocarcinoma include asymmetric wall thickening, notched outer margins, rough inner margins, and homogeneous internal echo in the biliary stricture.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (17, 35))	('cholangiocarcinoma', 'Disease', (17, 35))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (17, 35))	('notched', 'Var', (72, 79))
95768	30575336	In a retrospective multicenter study of 510 patients with AIP 155, the relapse rate achieved with standard steroid therapy for AIP 139 was 10% at 1 year, 11% at 2 years, 25.8% at 3 years, 30.9% at 4 years, and 35.1% at 5 years, finally reaching a plateau at 43% after 7 years.	('patients', 'Species', '9606', (44, 52))	('steroid', 'Chemical', 'MESH:D013256', (107, 114))	('relapse', 'MPA', (71, 78))	('AIP', 'Var', (127, 130))	('AIP', 'Var', (58, 61))
95819	29584696	The high expression of alpha6beta4 integrin has recently been associated with bile duct invasion and lymph node metastasis, as well as overall survival (OS) in patients with ICC, but the relationship between beta4 expression and ICC subclassification has not yet been fully described.	('lymph node metastasis', 'CPA', (101, 122))	('bile duct', 'Disease', (78, 87))	('patients', 'Species', '9606', (160, 168))	('associated with', 'Reg', (62, 77))	('overall survival', 'CPA', (135, 151))	('beta4', 'Gene', '10381', (29, 34))	('beta4', 'Gene', '10381', (208, 213))	('ICC', 'Disease', (174, 177))	('beta4', 'Gene', (29, 34))	('high', 'Var', (4, 8))	('beta4', 'Gene', (208, 213))
95839	29584696	Alcian blue-positive mucus staining was more frequently detected in the cases with high beta4 or beta6 integrin expression than in the cases with low expression (p = 0.011 and 0.018, respectively) (Table 1, Figure 2D).	('beta4 or beta6', 'Gene', '10381', (88, 102))	('beta4 or beta6', 'Gene', (88, 102))	('high', 'Var', (83, 87))	('Alcian blue', 'Chemical', 'MESH:D000423', (0, 11))	('expression', 'MPA', (112, 122))
95843	29584696	Therefore, beta4 expression was significantly associated with laminin-5 expression within tumors (p < 0.001) (Table 1 and Figure 3B), but not in the invasive front portions of tumors, while beta6 expression was significantly associated with tenascin-C expression in the tumor cells, or both tumor cells and the stroma (p = 0.016) (Table 1 and Figure 3A), but not in the stroma within tumor tissues alone.	('tenascin-C', 'Gene', '3371', (241, 251))	('beta4', 'Gene', (11, 16))	('stroma within tumor', 'Disease', (370, 389))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumor', 'Disease', (384, 389))	('beta4', 'Gene', '10381', (11, 16))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', (90, 95))	('expression', 'MPA', (17, 27))	('expression', 'MPA', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('tumor', 'Disease', 'MESH:D009369', (384, 389))	('associated', 'Reg', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('laminin-5', 'Protein', (62, 71))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('stroma within tumor', 'Disease', 'MESH:D001929', (370, 389))	('expression', 'MPA', (252, 262))	('tumor', 'Phenotype', 'HP:0002664', (384, 389))	('tumor', 'Disease', (270, 275))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tenascin-C', 'Gene', (241, 251))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', (90, 96))	('associated', 'Reg', (225, 235))	('tumor', 'Disease', (291, 296))	('beta6', 'Var', (190, 195))
95851	29584696	High expression was related to hepatic vein invasion (p = 0.034) and lymph node metastasis (p = 0.029).	('hepatic vein', 'Disease', (31, 43))	('hepatic vein', 'Disease', 'MESH:D056486', (31, 43))	('High', 'Var', (0, 4))	('lymph node metastasis', 'CPA', (69, 90))
95868	29584696	The proliferation type was characterized by the activation of the rat sarcoma viral oncogene homolog (RAS), MAPK, and c-MET, in which mutations in KRAS and BRAF resulted in a poor prognosis.	('sarcoma', 'Disease', (70, 77))	('BRAF', 'Gene', (156, 160))	('KRAS', 'Gene', '24525', (147, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('BRAF', 'Gene', '114486', (156, 160))	('MAPK', 'Gene', (108, 112))	('c-MET', 'Gene', (118, 123))	('MAPK', 'Gene', '5595;5594;5595', (108, 112))	('c-MET', 'Gene', '24553', (118, 123))	('mutations', 'Var', (134, 143))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))	('rat', 'Species', '10116', (11, 14))	('KRAS', 'Gene', (147, 151))	('rat', 'Species', '10116', (66, 69))
95871	29584696	Additionally, beta6-positive ICC, including the low expression group, was significantly associated with lymph node metastasis, indicating the close relationship between integrin expression and clinicopathological features in ICC, although integrin beta4 and beta6 expression levels were not significantly correlated with OS in the present study.	('integrin beta4', 'Gene', '3691', (239, 253))	('lymph', 'Disease', (104, 109))	('beta4 and beta6', 'Gene', '10381', (248, 263))	('ICC', 'Disease', (225, 228))	('ICC', 'Disease', (29, 32))	('beta6-positive', 'Var', (14, 28))	('associated', 'Reg', (88, 98))	('integrin beta4', 'Gene', (239, 253))
95873	29584696	reported that alpha6 overexpression was significantly correlated with larger tumors, multiple nodules, microvascular/bile duct invasion, and lymphatic metastasis, and an lower OS rate in ICC patients; they indicated that high alpha6 expression enhanced the activation of extracellular signal-regulated kinases (ERK1/2) and protein kinase B (AKT) signals, inducing ICC cell metastasis and invasion.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('AKT', 'Gene', '207', (341, 344))	('patients', 'Species', '9606', (191, 199))	('inducing', 'PosReg', (355, 363))	('ERK1/2', 'Gene', '5595;5594', (311, 317))	('AKT', 'Gene', (341, 344))	('enhanced', 'PosReg', (244, 252))	('invasion', 'CPA', (388, 396))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('alpha6', 'Gene', (226, 232))	('ERK1/2', 'Gene', (311, 317))	('rat', 'Species', '10116', (179, 182))	('high', 'Var', (221, 225))	('ICC', 'Disease', (364, 367))	('activation', 'PosReg', (257, 267))
95928	26608587	In contrast, high expression of ULBP1 was significantly associated with improved overall survival, but not disease-free survival.	('ULBP1', 'Gene', '80329', (32, 37))	('high expression', 'Var', (13, 28))	('improved', 'PosReg', (72, 80))	('overall', 'MPA', (81, 88))	('ULBP1', 'Gene', (32, 37))
95972	26608587	In contrast, high ULBP1 expression was significantly correlated with "well/moderately" differentiated (P = 0.0149), low lymphatic invasion (P = 0.0132), low venous invasion (P = 0.0024), and early TNM stage (P = 0.0010).	('TNM', 'Gene', (197, 200))	('ULBP1', 'Gene', (18, 23))	('low venous invasion', 'CPA', (153, 172))	('high', 'Var', (13, 17))	('expression', 'MPA', (24, 34))	('TNM', 'Gene', '10178', (197, 200))	('low lymphatic invasion', 'CPA', (116, 138))	('ULBP1', 'Gene', '80329', (18, 23))
95979	26608587	Patients with high ULBP1 expression had significantly better overall survival compared to patients with low ULBP1 expression (P = 0.0041; Fig.	('ULBP1', 'Gene', '80329', (108, 113))	('ULBP1', 'Gene', (108, 113))	('ULBP1', 'Gene', '80329', (19, 24))	('high', 'Var', (14, 18))	('ULBP1', 'Gene', (19, 24))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (61, 77))	('expression', 'Var', (25, 35))	('patients', 'Species', '9606', (90, 98))	('better', 'PosReg', (54, 60))
95982	26608587	Interestingly, high expression of multiple NKG2D ligands was significantly associated with overall and disease-free survival (P < 0.0001 and P = 0.0006, respectively; Figs 2d and S2d).	('high', 'Var', (15, 19))	('overall', 'CPA', (91, 98))	('disease-free survival', 'CPA', (103, 124))	('NKG2D', 'Gene', '22914', (43, 48))	('associated', 'Reg', (75, 85))	('NKG2D', 'Gene', (43, 48))
95990	26608587	In addition, high expression of multiple NKG2D ligands was an independent prognostic factor, as determined by multivariate analysis (Table S3).	('high', 'Var', (13, 17))	('NKG2D', 'Gene', (41, 46))	('NKG2D', 'Gene', '22914', (41, 46))
95998	26608587	In this study, we showed that high expression of NKG2D ligands was significantly associated with good prognosis and served as an independent prognostic factor in EHCC.	('EHCC', 'Disease', (162, 166))	('NKG2D', 'Gene', '22914', (49, 54))	('high', 'Var', (30, 34))	('NKG2D', 'Gene', (49, 54))	('associated', 'Reg', (81, 91))
96004	26608587	Indeed, high expression of NKG2D ligands is correlated with good a prognosis in colorectal cancer, breast cancer, and hepatocellular carcinoma,17, 18, 19, 20 but with a poor prognosis in ovarian cancer.21, 25 In our present study, high expression of MICA/B or ULBP2/5/6, individually, showed significant correlation with good overall and disease-free survival in EHCC.	('NKG2D', 'Gene', '22914', (27, 32))	('ovarian cancer', 'Disease', 'MESH:D010051', (187, 201))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (118, 142))	('MICA', 'Gene', '100507436', (250, 254))	('EHCC', 'Disease', (363, 367))	('ULBP2/5/6', 'Gene', (260, 269))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('ovarian cancer', 'Disease', (187, 201))	('hepatocellular carcinoma', 'Disease', (118, 142))	('colorectal cancer', 'Disease', (80, 97))	('high expression', 'Var', (231, 246))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('disease-free survival', 'CPA', (338, 359))	('MICA', 'Gene', (250, 254))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('NKG2D', 'Gene', (27, 32))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ULBP2/5/6', 'Gene', '80328;353091;154064', (260, 269))
96005	26608587	In contrast, high expression of ULBP1 alone significantly correlated with good overall survival.	('high', 'Var', (13, 17))	('overall', 'MPA', (79, 86))	('ULBP1', 'Gene', '80329', (32, 37))	('ULBP1', 'Gene', (32, 37))	('correlated', 'Reg', (58, 68))
96008	26608587	Our data showed that the co-expression of multiple NKG2D ligands was significantly associated with overall survival and acted an independent prognostic factor in EHCC.	('EHCC', 'Disease', (162, 166))	('NKG2D', 'Gene', '22914', (51, 56))	('co-expression', 'Var', (25, 38))	('NKG2D', 'Gene', (51, 56))	('associated', 'Reg', (83, 93))	('overall survival', 'CPA', (99, 115))
96134	32825784	There was consensus in manipulating the stent/tube where the bilirubin was elevated but in the setting of normal bilirubin, this was felt to be appropriate only if there was new or worsening biliary dilation.	('bilirubin', 'Chemical', 'MESH:D001663', (113, 122))	('manipulating', 'Var', (23, 35))	('elevated', 'PosReg', (75, 83))	('bilirubin', 'MPA', (61, 70))	('biliary dilation', 'Phenotype', 'HP:0006560', (191, 207))	('bilirubin', 'Chemical', 'MESH:D001663', (61, 70))	('biliary', 'Disease', (191, 198))
96154	32825784	and Cholangiocarcinoma Foundation; data curation, R.V.I., D.C., M.S.B.	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (4, 22))	('Cholangiocarcinoma', 'Disease', (4, 22))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (4, 22))	('D.C.', 'Var', (58, 62))
96215	32168869	Mutations of IDH1 and 2 frequently occur in iCCA.	('IDH1 and 2', 'Gene', '3417;3418', (13, 23))	('occur', 'Reg', (35, 40))	('CCA', 'Phenotype', 'HP:0030153', (45, 48))	('Mutations', 'Var', (0, 9))	('iCCA', 'Disease', (44, 48))
96217	32168869	Alterations of IDH, through the accumulations of oncometabolites, induces widespread epigenetic changes that have a pleiotropic effect on differentiation, cell growth, and hypoxia signaling.	('accumulations', 'PosReg', (32, 45))	('epigenetic changes', 'MPA', (85, 103))	('oncometabolites', 'MPA', (49, 64))	('induces', 'Reg', (66, 73))	('Alterations', 'Var', (0, 11))	('effect', 'Reg', (128, 134))	('differentiation', 'CPA', (138, 153))	('hypoxia', 'Disease', 'MESH:D000860', (172, 179))	('IDH', 'Gene', (15, 18))	('hypoxia', 'Disease', (172, 179))	('IDH', 'Gene', '3417', (15, 18))	('cell growth', 'CPA', (155, 166))
96220	32168869	IDH1 mutations are more common than IDH2.	('IDH2', 'Gene', (36, 40))	('IDH2', 'Gene', '3418', (36, 40))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('common', 'Reg', (24, 30))	('IDH1', 'Gene', '3417', (0, 4))
96230	32168869	AG-221 (Enasidenib), a selective inhibitor of mutant IDH2, has demonstrated activity in pre-clinical models of acute myeloid leukemia (AML) and is currently being assessed in multiple phases I/II clinical trials in subjects with advanced solid tumors, including iCCA, who harbor an IDH2 mutation (NCT02273739).	('CCA', 'Phenotype', 'HP:0030153', (263, 266))	('AG-221', 'Chemical', 'MESH:C000605269', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (111, 133))	('NCT02273739', 'Var', (297, 308))	('IDH2', 'Gene', (53, 57))	('IDH2', 'Gene', '3418', (53, 57))	('leukemia', 'Phenotype', 'HP:0001909', (125, 133))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (111, 133))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (117, 133))	('IDH2', 'Gene', (282, 286))	('AML', 'Disease', 'MESH:D015470', (135, 138))	('IDH2', 'Gene', '3418', (282, 286))	('AML', 'Phenotype', 'HP:0004808', (135, 138))	('AML', 'Disease', (135, 138))	('Enasidenib', 'Chemical', 'MESH:C000605269', (8, 18))	('mutant', 'Var', (46, 52))	('tumors', 'Disease', (244, 250))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('acute myeloid leukemia', 'Disease', (111, 133))
96231	32168869	Other IDH1 and IDH2 inhibitors are also now in clinical trials (NCT02273739, NCT02381886, and NCT02481154), mainly including patients with iCCA.	('IDH1', 'Gene', '3417', (6, 10))	('IDH2', 'Gene', (15, 19))	('IDH1', 'Gene', (6, 10))	('CCA', 'Phenotype', 'HP:0030153', (140, 143))	('NCT02381886', 'Var', (77, 88))	('IDH2', 'Gene', '3418', (15, 19))	('NCT02273739', 'Var', (64, 75))	('NCT02481154', 'Var', (94, 105))	('iCCA', 'Disease', (139, 143))	('patients', 'Species', '9606', (125, 133))
96232	32168869	The discovery of FGFR alterations in multiple tumor types has boosted scientific interest in the development of FGFR inhibitors.	('FGFR', 'Gene', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('alterations', 'Var', (22, 33))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
96233	32168869	In iCCA recurrent FGFR2 fusions are found in 11% to 45% of patients.	('FGFR2', 'Gene', '2263', (18, 23))	('FGFR2', 'Gene', (18, 23))	('CCA', 'Phenotype', 'HP:0030153', (4, 7))	('iCCA', 'Disease', (3, 7))	('patients', 'Species', '9606', (59, 67))	('fusions', 'Var', (24, 31))
96234	32168869	FGFR2 fusions result in constitutive tyrosine kinase activity, which in turn led to downstream signaling pathways activation, such as RAS-RAF-MEK.	('activation', 'PosReg', (114, 124))	('RAF', 'Gene', (138, 141))	('RAF', 'Gene', '673', (138, 141))	('tyrosine kinase activity', 'MPA', (37, 61))	('MEK', 'Gene', (142, 145))	('MEK', 'Gene', '5609', (142, 145))	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (6, 13))	('FGFR2', 'Gene', '2263', (0, 5))
96235	32168869	BGJ398 (Infigratinib; Novartis AG) is an oral non-selective FGFR inhibitor, assessed in a phase II trial in patients with different FGFR alterations [FGFR2 fusions (n = 48), FGFR2 mutations (n = 8), FGFR2 amplification (n = 3)] after first-line chemotherapy.	('BGJ398', 'Chemical', 'MESH:C568950', (0, 6))	('FGFR2', 'Gene', (174, 179))	('patients', 'Species', '9606', (108, 116))	('mutations', 'Var', (180, 189))	('fusions', 'Var', (156, 163))	('amplification', 'Var', (205, 218))	('FGFR2', 'Gene', '2263', (174, 179))	('BGJ398', 'Gene', (0, 6))	('FGFR2', 'Gene', '2263', (199, 204))	('FGFR2', 'Gene', '2263', (150, 155))	('Infigratinib', 'Chemical', 'MESH:C568950', (8, 20))	('FGFR2', 'Gene', (150, 155))	('FGFR2', 'Gene', (199, 204))
96236	32168869	The overall response rate was 14.8%, almost all with FGFR2 fusions, and median progression-free survival was 5.8 months, and interestingly disease control rate was 75.4%; however, the durability of response was limited.	('fusions', 'Var', (59, 66))	('FGFR2', 'Gene', '2263', (53, 58))	('FGFR2', 'Gene', (53, 58))
96237	32168869	Currently, a phase III clinical trial is evaluating BGJ398 versus chemotherapy with Cisplatin and Gemcitabine in first-line treatment in patients with locally advanced/metastatic CCA with FGFR-2 gene fusions/translocations (NCT03773302).	('BGJ398', 'Var', (52, 58))	('BGJ398', 'Chemical', 'MESH:C568950', (52, 58))	('CCA', 'Phenotype', 'HP:0030153', (179, 182))	('Cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('FGFR-2', 'Gene', '2263', (188, 194))	('patients', 'Species', '9606', (137, 145))	('CCA', 'Disease', (179, 182))	('FGFR-2', 'Gene', (188, 194))	('Gemcitabine', 'Chemical', 'MESH:C056507', (98, 109))
96239	32168869	Analysis of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases showed the emergence of multiple recurrent point mutations of FGFR2 at disease progression.	('tumors', 'Disease', (61, 67))	('metastases', 'Disease', (73, 83))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('FGFR2', 'Gene', (146, 151))	('FGFR2', 'Gene', '2263', (146, 151))	('point mutations', 'Var', (127, 142))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('metastases', 'Disease', 'MESH:D009362', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (61, 66))
96241	32168869	In a phase I study Erdafitinib showed anti-tumor activity only in the 21 patients with FGFR mutations, while 36 patients that did not have confirmed FGFR mutations had no significant response.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('patients', 'Species', '9606', (112, 120))	('mutations', 'Var', (92, 101))	('FGFR', 'Gene', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Erdafitinib', 'Chemical', 'MESH:C000604580', (19, 30))	('tumor', 'Disease', (43, 48))	('patients', 'Species', '9606', (73, 81))
96243	32168869	In the CCA cohort, 3 out of 11 patients with FGFR mutations or fusions had a partial response.	('mutations', 'Var', (50, 59))	('FGFR', 'Gene', (45, 49))	('CCA', 'Phenotype', 'HP:0030153', (7, 10))	('patients', 'Species', '9606', (31, 39))	('CCA', 'Disease', (7, 10))	('fusions', 'Var', (63, 70))
96249	32168869	Interestingly, in pre-clinical models, DZB demonstrated to be active in tumors with FGFR alterations, including fusions, amplifications, and mutations.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mutations', 'Var', (141, 150))	('fusions', 'Var', (112, 119))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('DZB', 'Chemical', 'MESH:C000621805', (39, 42))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('amplifications', 'Var', (121, 135))	('alterations', 'Var', (89, 100))	('FGFR', 'Gene', (84, 88))
96250	32168869	A multicenter, phase I-II clinical trial open-label study enrolled adult patients with unresectable iCCA with FGFR2 fusion, who progressed, were intolerant or not eligible to first-line chemotherapy.	('fusion', 'Var', (116, 122))	('FGFR2', 'Gene', (110, 115))	('FGFR2', 'Gene', '2263', (110, 115))	('iCCA', 'Disease', (100, 104))	('CCA', 'Phenotype', 'HP:0030153', (101, 104))	('patients', 'Species', '9606', (73, 81))
96253	32168869	Additional FGFR-selective inhibitors, such as TAS-120 (NCT02052778), Debio 1347 (NCT01948297), Pemigatinib (NCT02924376, NCT02393248) and Ponatinib, (NCT02265341) are currently in early phase clinical trials in patients with advanced-stage solid-organ malignancies, including iCCA.	('TAS-120', 'Chemical', '-', (46, 53))	('NCT02924376', 'Var', (108, 119))	('CCA', 'Phenotype', 'HP:0030153', (277, 280))	('FGFR-selective', 'Gene', (11, 25))	('patients', 'Species', '9606', (211, 219))	('NCT01948297', 'Var', (81, 92))	('malignancies', 'Disease', (252, 264))	('NCT02393248', 'Var', (121, 132))	('NCT02265341', 'Var', (150, 161))	('iCCA', 'Disease', (276, 280))	('Pemigatinib', 'Chemical', '-', (95, 106))	('Ponatinib', 'Chemical', 'MESH:C545373', (138, 147))	('malignancies', 'Disease', 'MESH:D009369', (252, 264))	('NCT02052778', 'Var', (55, 66))
96254	32168869	Mutations of BRAF are rare but occur mostly in iCCA, with a prevalence of 1%-3%.	('BRAF', 'Gene', '673', (13, 17))	('CCA', 'Phenotype', 'HP:0030153', (48, 51))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('iCCA', 'Disease', (47, 51))
96255	32168869	BRAF mutations at codon 600, mostly V600E, are of interest because they are potentially targetable with BRAF inhibitors.	('V600E', 'Mutation', 'rs113488022', (36, 41))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', '673', (104, 108))	('V600E', 'Var', (36, 41))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', (104, 108))
96262	32168869	Finally, the preliminary results of a basket trial involving patients with BRAF mutation showed, in a cohort of pretreated biliary tract cancer, a response rate of 42% with a median overall survival of 11.7 months.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('BRAF', 'Gene', '673', (75, 79))	('patients', 'Species', '9606', (61, 69))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('BRAF', 'Gene', (75, 79))	('cancer', 'Disease', (137, 143))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (123, 143))	('mutation', 'Var', (80, 88))
96264	32168869	Alterations of epidermal growth factor receptor (ERBB) family have been reported in CCA, mostly in gallbladder cancer (19%) and in pCCA/dCCA (17%), as compared to iCCA (4.8%).	('CCA', 'Phenotype', 'HP:0030153', (137, 140))	('epidermal growth factor receptor', 'Gene', '1956', (15, 47))	('pCCA', 'Gene', '5095', (131, 135))	('ERBB', 'Gene', '1956', (49, 53))	('CCA', 'Phenotype', 'HP:0030153', (164, 167))	('pCCA', 'Gene', (131, 135))	('Alterations', 'Var', (0, 11))	('CCA', 'Disease', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('reported', 'Reg', (72, 80))	('dCCA', 'Chemical', '-', (136, 140))	('gallbladder cancer', 'Disease', (99, 117))	('gallbladder cancer', 'Disease', 'MESH:D005706', (99, 117))	('CCA', 'Phenotype', 'HP:0030153', (132, 135))	('ERBB', 'Gene', (49, 53))	('CCA', 'Phenotype', 'HP:0030153', (84, 87))	('epidermal growth factor receptor', 'Gene', (15, 47))
96276	32168869	The pre-clinical model supports the oncogenic role of FIG-ROS1 fusion in iCAA, and its potential therapeutic target in CCA.	('ROS1', 'Gene', (58, 62))	('iCAA', 'Disease', (73, 77))	('ROS1', 'Gene', '6098', (58, 62))	('fusion', 'Var', (63, 69))	('CCA', 'Phenotype', 'HP:0030153', (119, 122))
96277	32168869	The ALK and ROS1 inhibitor ceritinib and crizotinib are currently being evaluated in two phases II in patients with advanced CCA (NCT02374489, NCT02034981) NTRK gene fusions can drive unregulated cell growth and proliferation in a range of cancer types.	('ROS1', 'Gene', '6098', (12, 16))	('ALK', 'Gene', '238', (4, 7))	('CCA', 'Disease', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('ceritinib', 'Chemical', 'MESH:C586847', (27, 36))	('patients', 'Species', '9606', (102, 110))	('TRK', 'Gene', (157, 160))	('ALK', 'Gene', (4, 7))	('NCT02374489', 'Var', (130, 141))	('TRK', 'Gene', '4914', (157, 160))	('drive', 'PosReg', (178, 183))	('CCA', 'Phenotype', 'HP:0030153', (125, 128))	('NCT02034981', 'Var', (143, 154))	('crizotinib', 'Chemical', 'MESH:D000077547', (41, 51))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('unregulated cell growth', 'CPA', (184, 207))	('cancer', 'Disease', (240, 246))	('ROS1', 'Gene', (12, 16))
96280	32168869	Therefore, Entrectinib is now under evaluation clinical trials in patients harboring ROS1 ALK fusions (NCT02568267) or TRKA (NCT02568267).	('ROS1', 'Gene', (85, 89))	('TRKA', 'Gene', '4914', (119, 123))	('ALK', 'Gene', '238', (90, 93))	('ROS1', 'Gene', '6098', (85, 89))	('Entrectinib', 'Chemical', 'MESH:C000607349', (11, 22))	('fusions (NCT02568267', 'Var', (94, 114))	('ALK', 'Gene', (90, 93))	('NCT02568267', 'Var', (125, 136))	('NCT02568267', 'Var', (103, 114))	('TRKA', 'Gene', (119, 123))	('patients', 'Species', '9606', (66, 74))
96281	32168869	It is known by recent findings that the presence of germline mutation of BRCA1 and BRCA2 confers an increased lifetime risk of developing CCA.	('CCA', 'Disease', (138, 141))	('BRCA2', 'Gene', '675', (83, 88))	('presence', 'Var', (40, 48))	('BRCA1', 'Gene', '672', (73, 78))	('CCA', 'Phenotype', 'HP:0030153', (138, 141))	('BRCA1', 'Gene', (73, 78))	('BRCA2', 'Gene', (83, 88))	('germline mutation', 'Var', (52, 69))
96282	32168869	The Breast Cancer Linkage Consortium reported an estimated relative risk for in BRCA2 mutation carriers of 4.97.	('Breast Cancer', 'Phenotype', 'HP:0003002', (4, 17))	('BRCA2', 'Gene', (80, 85))	('Breast Cancer', 'Disease', (4, 17))	('Cancer', 'Phenotype', 'HP:0002664', (11, 17))	('BRCA2', 'Gene', '675', (80, 85))	('Breast Cancer', 'Disease', 'MESH:D001943', (4, 17))	('mutation', 'Var', (86, 94))
96283	32168869	Cancers harboring these types of mutations are sensitive to DNA damaging therapies and to poly ADP ribose polymerase (PARP) inhibition.	('poly ADP ribose polymerase', 'Gene', '142', (90, 116))	('Cancers', 'Disease', (0, 7))	('poly ADP ribose polymerase', 'Gene', (90, 116))	('PARP', 'Gene', '142', (118, 122))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('mutations', 'Var', (33, 42))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('sensitive', 'Reg', (47, 56))	('PARP', 'Gene', (118, 122))
96285	32168869	Few studies of PARP Niraparib and olaparib are currently ongoing in patients with CCA, and with aberrant DNA genes mutations (NCT04042831, NCT03207347).	('CCA', 'Phenotype', 'HP:0030153', (82, 85))	('NCT04042831', 'Var', (126, 137))	('olaparib', 'Chemical', 'MESH:C531550', (34, 42))	('PARP', 'Gene', '142', (15, 19))	('patients', 'Species', '9606', (68, 76))	('CCA', 'Disease', (82, 85))	('Niraparib', 'Chemical', 'MESH:C545685', (20, 29))	('DNA genes', 'Gene', (105, 114))	('PARP', 'Gene', (15, 19))	('NCT03207347', 'Var', (139, 150))
96295	32168869	Several inhibitors of JAK/STAT are already approved for the treatment of myelofibrosis and are currently under investigation in different cancers.	('myelofibrosis', 'Disease', 'MESH:D055728', (73, 86))	('STAT', 'Gene', '6774', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('myelofibrosis', 'Phenotype', 'HP:0011974', (73, 86))	('STAT', 'Gene', (26, 30))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancers', 'Disease', (138, 145))	('myelofibrosis', 'Disease', (73, 86))	('inhibitors', 'Var', (8, 18))
96297	32168869	Phase II studies in different tumor histologies, including cholangiocarcinoma, are actively recruiting patients (NCT03377179, NCT03414489).	('cholangiocarcinoma', 'Disease', (59, 77))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (59, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('NCT03377179', 'Var', (113, 124))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('NCT03414489', 'Var', (126, 137))	('patients', 'Species', '9606', (103, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (59, 77))	('tumor', 'Disease', (30, 35))
96303	32168869	MET overexpression and amplification have been described both in intrahepatic (12%-58%) and perihilar/distal cholangiocarcinoma (16%) and is associated with shorter survival.	('intrahepatic', 'Disease', (65, 77))	('shorter', 'NegReg', (157, 164))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (109, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('amplification', 'Var', (23, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('overexpression', 'PosReg', (4, 18))	('cholangiocarcinoma', 'Disease', (109, 127))
96307	32168869	Inhibition of CAFs activity has already shown anti-tumor activity in pre-clinical models.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('CAFs', 'Gene', (14, 18))	('tumor', 'Disease', (51, 56))	('activity', 'MPA', (19, 27))	('Inhibition', 'Var', (0, 10))	('CAFs', 'Gene', '6899', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
96314	32168869	According to data from the literature, inhibition of immune checkpoints has shown promising results in several malignancies such as melanoma, non-small cell lung cancer, urothelial carcino-ma, renal-cell carcinoma, head and neck cancer and hepatic cancer.	('head and neck cancer', 'Disease', 'MESH:D006258', (215, 235))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('renal-cell carcinoma', 'Disease', (193, 213))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('renal-cell carcinoma', 'Disease', 'MESH:C538614', (193, 213))	('lung cancer', 'Disease', (157, 168))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (146, 168))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('urothelial carcino', 'Disease', (170, 188))	('malignancies', 'Disease', 'MESH:D009369', (111, 123))	('hepatic cancer', 'Disease', (240, 254))	('malignancies', 'Disease', (111, 123))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('inhibition', 'Var', (39, 49))	('melanoma', 'Disease', (132, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('head and neck cancer', 'Phenotype', 'HP:0012288', (215, 235))	('renal-cell carcinoma', 'Phenotype', 'HP:0005584', (193, 213))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))	('hepatic cancer', 'Disease', 'MESH:D008113', (240, 254))	('hepatic cancer', 'Phenotype', 'HP:0002896', (240, 254))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (142, 168))	('urothelial carcino', 'Disease', 'MESH:D014522', (170, 188))
96322	32168869	The anti-PD-1 antibody pembrolizumab has been approved by the United States Food and Drug Administration for previously treated patients with DNA mismatch repair (MMR) deficiency and/or microsatellite instability (MSI)-high advanced solid tumors, independent of histology, which would include those with CCA.	('tumors', 'Disease', (239, 245))	('deficiency', 'Disease', (168, 178))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('deficiency', 'Disease', 'MESH:D007153', (168, 178))	('CCA', 'Disease', (304, 307))	('microsatellite instability', 'Var', (186, 212))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('CCA', 'Phenotype', 'HP:0030153', (304, 307))	('PD-1 antibody pembrolizumab', 'Disease', (9, 36))	('patients', 'Species', '9606', (128, 136))	('PD-1 antibody pembrolizumab', 'Disease', 'MESH:D010300', (9, 36))
96419	31831956	The p-value was <0.05 indicating a significant association between the presence of H. pylori and the differentiation of these malignancies, the histological subtype,  the macroscopic variety and lymph node's presence.	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('H. pylori', 'Gene', (83, 92))	('H. pylori', 'Species', '210', (83, 92))	('malignancies', 'Disease', (126, 138))	('presence', 'Var', (71, 79))
96433	31831956	Chen DF and al., showed that H. pylori induces apoptosis in human gallbladder epithelial cells which can be explained by the implication of this  pathogen in the activation of factors inhibiting cell proliferation, promoting the expression of regulatory genes like bcl-2, bax and finally inducing cell apoptosis.	('H. pylori', 'Var', (29, 38))	('cell proliferation', 'CPA', (195, 213))	('bax', 'Gene', (272, 275))	('bcl-2', 'Gene', '596', (265, 270))	('bcl-2', 'Gene', (265, 270))	('bax', 'Gene', '581', (272, 275))	('inhibiting', 'NegReg', (184, 194))	('inducing', 'Reg', (288, 296))	('promoting', 'PosReg', (215, 224))	('H. pylori', 'Species', '210', (29, 38))	('human', 'Species', '9606', (60, 65))	('expression', 'MPA', (229, 239))
96533	29327594	Similarly, when evaluating long-term outcomes, liver resection for giant HCC has been associated with a 5-year OS ranging 27% to 53%, with investigators supporting the role for liver resection based on more favorable outcomes as compared to other noncurative options (eg, Transarterial chemoembolization [TACE]).	('HCC', 'Gene', '619501', (73, 76))	('HCC', 'Phenotype', 'HP:0001402', (73, 76))	('TACE', 'Chemical', '-', (305, 309))	('liver resection', 'Var', (47, 62))	('OS', 'Chemical', '-', (111, 113))	('HCC', 'Gene', (73, 76))
96734	28819435	Sufficient treatments of both surgery and radiation therapies may improve prognosis even in advanced stage patients19, 20.	('men', 'Species', '9606', (16, 19))	('prognosis', 'MPA', (74, 83))	('patients', 'Species', '9606', (107, 115))	('patients19', 'Var', (107, 117))
96810	27783997	A recent study revealed that KRAS and TP53 mutations were relatively common in cholangiocarcinoma, particularly in extrahepatic cholangiocarcinoma, while IDH1/2 and BRAF mutations were considerably more prevalent in ICC.	('extrahepatic cholangiocarcinoma', 'Disease', (115, 146))	('TP53', 'Gene', (38, 42))	('KRAS', 'Gene', (29, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('common', 'Reg', (69, 75))	('BRAF', 'Gene', '673', (165, 169))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (79, 97))	('BRAF', 'Gene', (165, 169))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (115, 146))	('TP53', 'Gene', '7157', (38, 42))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (128, 146))	('IDH1/2', 'Gene', '3417;3418', (154, 160))	('cholangiocarcinoma', 'Disease', (79, 97))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (79, 97))	('IDH1/2', 'Gene', (154, 160))	('cholangiocarcinoma', 'Disease', (128, 146))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (128, 146))	('mutations', 'Var', (43, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('KRAS', 'Gene', '3845', (29, 33))
96861	27627808	Preclinical Activity of ARQ 087, a Novel Inhibitor Targeting FGFR Dysregulation Dysregulation of Fibroblast Growth Factor Receptor (FGFR) signaling through amplifications, mutations, and gene fusions has been implicated in a broad array of cancers (e.g.	('FGF', 'Gene', (132, 135))	('mutations', 'Var', (172, 181))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('FGF', 'Gene', (61, 64))	('FGF', 'Gene', '2246;2247;2252', (132, 135))	('gene fusions', 'Var', (187, 199))	('ARQ 087', 'Chemical', 'MESH:C000621805', (24, 31))	('ARQ 087', 'Gene', (24, 31))	('implicated', 'Reg', (209, 219))	('Dysregulation', 'Var', (66, 79))	('array of cancers', 'Disease', (231, 247))	('array of cancers', 'Disease', 'MESH:D009369', (231, 247))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('FGF', 'Gene', '2246;2247;2252', (61, 64))	('amplifications', 'Var', (156, 170))
96866	27627808	Cell proliferation studies demonstrated ARQ 087 has anti-proliferative activity in cell lines driven by FGFR dysregulation, including amplifications, fusions, and mutations.	('ARQ 087', 'Chemical', 'MESH:C000621805', (40, 47))	('amplifications', 'Var', (134, 148))	('anti-proliferative activity', 'MPA', (52, 79))	('mutations', 'Var', (163, 172))	('dysregulation', 'Var', (109, 122))	('fusions', 'Var', (150, 157))	('FGF', 'Gene', '2246;2247;2252', (104, 107))	('FGF', 'Gene', (104, 107))	('ARQ 087', 'Gene', (40, 47))
96868	27627808	In addition, ARQ 087 was effective at inhibiting tumor growth in vivo in FGFR2 altered, SNU-16 and NCI-H716, xenograft tumor models with gene amplifications and fusions.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', (119, 124))	('NCI-H716', 'CellLine', 'CVCL:1581', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('altered', 'Var', (79, 86))	('ARQ 087', 'Chemical', 'MESH:C000621805', (13, 20))	('inhibiting', 'NegReg', (38, 48))	('tumor', 'Disease', (49, 54))	('FGFR2', 'Gene', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('SNU-16', 'Chemical', '-', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
96869	27627808	ARQ 087 is currently being studied in a phase 1/2 clinical trial that includes a sub cohort for intrahepatic cholangiocarcinoma patients with confirmed FGFR2 gene fusions (NCT01752920).	('fusions', 'Var', (163, 170))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('FGFR2', 'Gene', (152, 157))	('intrahepatic cholangiocarcinoma', 'Disease', (96, 127))	('ARQ 087', 'Chemical', 'MESH:C000621805', (0, 7))	('patients', 'Species', '9606', (128, 136))
96872	27627808	Dysregulation in the FGFR tyrosine kinase family has been implicated in a number of human cancers, including cholangiocarcinoma, squamous non-small cell lung cancer (sqNSCLC), small cell lung cancer (SCLC), gastric, breast, ovarian, endometrial, and bladder carcinomas.	('cancers', 'Disease', (90, 97))	('squamous non-small cell lung cancer', 'Disease', (129, 164))	('SCLC', 'Disease', 'MESH:D018288', (200, 204))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (109, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Dysregulation', 'Var', (0, 13))	('SCLC', 'Disease', 'MESH:D018288', (169, 173))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (250, 268))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('implicated', 'Reg', (58, 68))	('bladder carcinomas', 'Disease', 'MESH:D001749', (250, 268))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (176, 198))	('tyrosine', 'Chemical', 'MESH:D014443', (26, 34))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (138, 164))	('FGF', 'Gene', (21, 24))	('bladder carcinomas', 'Disease', (250, 268))	('gastric', 'Disease', (207, 214))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (142, 164))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('SCLC', 'Disease', (200, 204))	('SCLC', 'Disease', (169, 173))	('ovarian', 'Disease', (224, 231))	('ovarian', 'Disease', 'MESH:D010051', (224, 231))	('SCLC', 'Phenotype', 'HP:0030357', (200, 204))	('SCLC', 'Phenotype', 'HP:0030357', (169, 173))	('human', 'Species', '9606', (84, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (258, 268))	('FGF', 'Gene', '2246;2247;2252', (21, 24))	('small cell lung cancer', 'Disease', 'MESH:D055752', (176, 198))	('breast', 'Disease', (216, 222))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('small cell lung cancer', 'Disease', (176, 198))	('endometrial', 'Disease', (233, 244))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('small cell lung cancer', 'Disease', 'MESH:D055752', (142, 164))	('cholangiocarcinoma', 'Disease', (109, 127))	('squamous non-small cell lung cancer', 'Disease', 'MESH:D002289', (129, 164))
96873	27627808	In human cancers, FGFRs have been found to be dysregulated by multiple mechanisms, including aberrant expression, mutations, gene fusions, and amplifications.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('expression', 'Species', '29278', (102, 112))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('amplifications', 'Var', (143, 157))	('FGF', 'Gene', '2246;2247;2252', (18, 21))	('cancers', 'Disease', (9, 16))	('mutations', 'Var', (114, 123))	('human', 'Species', '9606', (3, 8))	('gene fusions', 'Var', (125, 137))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('aberrant expression', 'Var', (93, 112))	('FGF', 'Gene', (18, 21))
96874	27627808	Such genetic alterations have been implicated in the oncogenicity of several tumor models, suggesting that therapeutic targeting of FGFRs may benefit cancer patients.	('FGF', 'Gene', (132, 135))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('FGF', 'Gene', '2246;2247;2252', (132, 135))	('genetic alterations', 'Var', (5, 24))	('patients', 'Species', '9606', (157, 165))	('cancer', 'Disease', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('implicated', 'Reg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
96875	27627808	Inhibition of FGFR in vitro and in vivo has been shown to reduce proliferation of FGFR-dependent cancer cells and induces cell death.	('proliferation', 'CPA', (65, 78))	('cell death', 'CPA', (122, 132))	('cancer', 'Disease', (97, 103))	('FGF', 'Gene', (14, 17))	('FGF', 'Gene', '2246;2247;2252', (14, 17))	('FGF', 'Gene', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('reduce', 'NegReg', (58, 64))	('Inhibition', 'Var', (0, 10))	('induces', 'Reg', (114, 121))	('FGF', 'Gene', '2246;2247;2252', (82, 85))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
96877	27627808	Recently there has been an increased interest in the oncogenic potential of FGFR gene fusions in a number of cancer types including, lung, blood, brain, breast, prostate, and biliary tract..	('FGF', 'Gene', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('FGF', 'Gene', '2246;2247;2252', (76, 79))	('cancer', 'Disease', (109, 115))	('biliary tract..', 'Disease', (175, 190))	('breast', 'Disease', (153, 159))	('prostate', 'Disease', (161, 169))	('blood', 'Disease', (139, 144))	('gene fusions', 'Var', (81, 93))	('lung', 'Disease', (133, 137))	('brain', 'Disease', (146, 151))
96878	27627808	Examples of FGFR fusion driven cancers include: 8p11 myeloproliferative syndrome, a rare stem cell disorder, which contains a number of FGFR1 fusions including FGFR1OP-FGFR1, and glioblastoma multiforme with FGFR3-TACC3 fusions which are found in 3-7% of all GBM.	('fusions', 'Var', (142, 149))	('FGF', 'Gene', (160, 163))	('FGF', 'Gene', (208, 211))	('FGF', 'Gene', (136, 139))	('myeloproliferative syndrome', 'Phenotype', 'HP:0005547', (53, 80))	('8p11 myeloproliferative syndrome', 'Disease', (48, 80))	('FGF', 'Gene', '2246;2247;2252', (168, 171))	('FGF', 'Gene', '2246;2247;2252', (160, 163))	('FGF', 'Gene', '2246;2247;2252', (208, 211))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('glioblastoma', 'Phenotype', 'HP:0012174', (179, 191))	('cancers', 'Disease', (31, 38))	('FGF', 'Gene', (12, 15))	('FGF', 'Gene', '2246;2247;2252', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('FGFR1OP', 'Gene', '11116', (160, 167))	('glioblastoma multiforme', 'Disease', (179, 202))	('TACC3', 'Gene', '10460', (214, 219))	('FGFR1OP', 'Gene', (160, 167))	('TACC3', 'Gene', (214, 219))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (179, 202))	('FGFR3', 'Gene', (208, 213))	('FGF', 'Gene', (168, 171))	('FGFR3', 'Gene', '2261', (208, 213))	('FGF', 'Gene', '2246;2247;2252', (12, 15))	('cancers', 'Disease', 'MESH:D009369', (31, 38))
96879	27627808	One tumor type where gene fusions appear to be particularly common (15-45%) is the intrahepatic form of cholangiocarcinoma (iCCA).	('tumor', 'Disease', (4, 9))	('cholangiocarcinoma', 'Disease', (104, 122))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (104, 122))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (104, 122))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('gene fusions', 'Var', (21, 33))
96881	27627808	A large number of FGFR2 gene fusions have been identified in cholangiocarcinoma, and FGFR inhibitors have shown to be partially effective in reducing tumor burden in patients.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 79))	('FGF', 'Gene', '2246;2247;2252', (18, 21))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('FGF', 'Gene', (85, 88))	('fusions', 'Var', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('reducing', 'NegReg', (141, 149))	('identified', 'Reg', (47, 57))	('FGF', 'Gene', '2246;2247;2252', (85, 88))	('FGF', 'Gene', (18, 21))	('cholangiocarcinoma', 'Disease', (61, 79))	('patients', 'Species', '9606', (166, 174))
96885	27627808	ARQ 087 demonstrated inhibitory activity against FGFR2 amplifications and gene fusions in vitro and in vivo.	('FGFR2', 'Gene', (49, 54))	('ARQ 087', 'Chemical', 'MESH:C000621805', (0, 7))	('amplifications', 'Var', (55, 69))	('gene fusions', 'Var', (74, 86))	('inhibitory activity', 'MPA', (21, 40))
96886	27627808	In multiple xenograft models, ARQ 087 effectively inhibited the growth of FGFR2 driven tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ARQ', 'Var', (30, 33))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('FGFR2', 'Gene', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('growth', 'CPA', (64, 70))	('ARQ 087', 'Chemical', 'MESH:C000621805', (30, 37))	('inhibited', 'NegReg', (50, 59))
96955	27627808	In biochemical assays, ARQ 087 appears to be most potent against FGFR1/2, however activity is also seen in a number of other kinases including RET, VEGFR, and KIT Table 1.	('ARQ', 'Var', (23, 26))	('RET', 'Gene', (143, 146))	('VEGFR', 'Gene', '3791', (148, 153))	('RET', 'Gene', '5979', (143, 146))	('FGFR1/2', 'Gene', '2260;2263', (65, 72))	('FGFR1/2', 'Gene', (65, 72))	('ARQ 087', 'Chemical', 'MESH:C000621805', (23, 30))	('VEGFR', 'Gene', (148, 153))
96958	27627808	We found that ARQ 087 inhibited the phosphorylation of FGFR1, FGFR2, FGFR3, and FGFR4 with EC50 values of < 0.123 muM, 0.185 muM, 0.463 muM, >10 muM respectively Fig 2.	('FGFR2', 'Gene', (62, 67))	('inhibited', 'NegReg', (22, 31))	('FGFR3', 'Gene', '2261', (69, 74))	('muM', 'Gene', '56925', (145, 148))	('muM', 'Gene', (136, 139))	('FGFR4', 'Gene', '2264', (80, 85))	('FGFR4', 'Gene', (80, 85))	('muM', 'Gene', '56925', (114, 117))	('FGFR3', 'Gene', (69, 74))	('muM', 'Gene', (145, 148))	('ARQ 087', 'Chemical', 'MESH:C000621805', (14, 21))	('muM', 'Gene', '56925', (125, 128))	('ARQ', 'Var', (14, 17))	('muM', 'Gene', (125, 128))	('muM', 'Gene', (114, 117))	('FGFR1', 'Gene', (55, 60))	('phosphorylation', 'MPA', (36, 51))	('muM', 'Gene', '56925', (136, 139))
96964	27627808	These data reinforce the biochemical data that suggests ARQ 087 does inhibit kinases outside of the FGFR family in cellular assays.	('FGF', 'Gene', '2246;2247;2252', (100, 103))	('ARQ 087', 'Var', (56, 63))	('kinases', 'Enzyme', (77, 84))	('FGF', 'Gene', (100, 103))	('ARQ 087', 'Chemical', 'MESH:C000621805', (56, 63))	('inhibit', 'NegReg', (69, 76))
96966	27627808	These results demonstrate that ARQ 087 has the greatest potency in cell lines dependent on FGFR-fusions, followed by wild-type FGFR1/2 isoforms.	('FGF', 'Gene', '2246;2247;2252', (127, 130))	('FGF', 'Gene', (91, 94))	('ARQ 087', 'Chemical', 'MESH:C000621805', (31, 38))	('FGF', 'Gene', (127, 130))	('FGFR1/2', 'Gene', (127, 134))	('FGF', 'Gene', '2246;2247;2252', (91, 94))	('ARQ', 'Var', (31, 34))	('FGFR1/2', 'Gene', '2260;2263', (127, 134))	('potency', 'MPA', (56, 63))
96967	27627808	ARQ 087 appears to hit a number of other kinases with equipotency to FGFR3/4.	('FGFR3', 'Gene', (69, 74))	('ARQ 087', 'Chemical', 'MESH:C000621805', (0, 7))	('FGFR3', 'Gene', '2261', (69, 74))	('ARQ', 'Var', (0, 3))
96968	27627808	FGFR pathway inhibition was examined in three solid tumor lines, the colorectal cancer cell line (NCI-H716), and gastric cancer cell lines (SNU-16 and KATO-III), all these cell lines are FGFR2 amplified.	('SNU-16', 'Chemical', '-', (140, 146))	('solid tumor', 'Disease', (46, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('FGF', 'Gene', '2246;2247;2252', (0, 3))	('colorectal cancer', 'Phenotype', 'HP:0003003', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('solid tumor', 'Disease', 'MESH:D009369', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('gastric cancer', 'Disease', (113, 127))	('colorectal cancer', 'Disease', (69, 86))	('amplified', 'Var', (193, 202))	('FGF', 'Gene', (0, 3))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('FGF', 'Gene', '2246;2247;2252', (187, 190))	('NCI-H716', 'CellLine', 'CVCL:1581', (98, 106))	('colorectal cancer', 'Disease', 'MESH:D015179', (69, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('FGF', 'Gene', (187, 190))
96969	27627808	As shown in Fig 3A, ARQ 087 inhibited the phosphorylation of FGFRs in all three cell lines.	('phosphorylation', 'MPA', (42, 57))	('ARQ 087', 'Chemical', 'MESH:C000621805', (20, 27))	('FGF', 'Gene', (61, 64))	('inhibited', 'NegReg', (28, 37))	('FGF', 'Gene', '2246;2247;2252', (61, 64))	('ARQ 087', 'Var', (20, 27))
96970	27627808	Since all three of these cell lines express high levels of FGFR2 protein (NCI-H716, SNU-16, and KATO-III), we surmise that the pFGFR signal knockdown detected in Fig 3A was likely due to the inhibition of pFGFR2.	('FGF', 'Gene', '2246;2247;2252', (206, 209))	('FGF', 'Gene', '2246;2247;2252', (59, 62))	('FGF', 'Gene', '2246;2247;2252', (128, 131))	('FGF', 'Gene', (206, 209))	('SNU-16', 'Chemical', '-', (84, 90))	('FGF', 'Gene', (59, 62))	('NCI-H716', 'CellLine', 'CVCL:1581', (74, 82))	('FGF', 'Gene', (128, 131))	('knockdown', 'Var', (140, 149))
96973	27627808	Based on these results, we conclude that ARQ 087 inhibits the FGFR signaling pathway in these FGFR2 over-expressing cancer cells.	('ARQ 087', 'Var', (41, 48))	('FGF', 'Gene', '2246;2247;2252', (94, 97))	('cancer', 'Disease', (116, 122))	('inhibits', 'NegReg', (49, 57))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('ARQ 087', 'Chemical', 'MESH:C000621805', (41, 48))	('FGF', 'Gene', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('over-expressing', 'PosReg', (100, 115))	('FGF', 'Gene', (94, 97))	('FGF', 'Gene', '2246;2247;2252', (62, 65))
96976	27627808	Here we observed that ARQ 087 inhibits the phosphorylation of FGFR1OP-FGFR1 as well as the downstream marker, pERK Fig 3C.	('FGFR1OP', 'Gene', '11116', (62, 69))	('phosphorylation', 'MPA', (43, 58))	('FGFR1OP', 'Gene', (62, 69))	('pERK', 'Gene', (110, 114))	('ARQ 087', 'Var', (22, 29))	('pERK', 'Gene', '9451', (110, 114))	('ARQ 087', 'Chemical', 'MESH:C000621805', (22, 29))	('inhibits', 'NegReg', (30, 38))
96977	27627808	From this we conclude that ARQ 087 is able to inhibit the FGFR signaling pathway in this FGFR1 fusion driven cell line.	('FGF', 'Gene', '2246;2247;2252', (58, 61))	('ARQ 087', 'Var', (27, 34))	('inhibit', 'NegReg', (46, 53))	('FGF', 'Gene', (89, 92))	('ARQ 087', 'Chemical', 'MESH:C000621805', (27, 34))	('FGF', 'Gene', (58, 61))	('FGF', 'Gene', '2246;2247;2252', (89, 92))
96978	27627808	We then evaluated the anti-proliferative effect of ARQ 087 in a number of cell lines that included cells with amplified FGFR, mutant FGFR, translocated FGFR, or unknown FGFR status.	('FGF', 'Gene', (152, 155))	('FGF', 'Gene', (133, 136))	('anti-proliferative effect', 'MPA', (22, 47))	('ARQ 087', 'Chemical', 'MESH:C000621805', (51, 58))	('FGF', 'Gene', '2246;2247;2252', (152, 155))	('FGF', 'Gene', '2246;2247;2252', (133, 136))	('FGF', 'Gene', '2246;2247;2252', (169, 172))	('FGF', 'Gene', (120, 123))	('translocated', 'Var', (139, 151))	('FGF', 'Gene', (169, 172))	('FGF', 'Gene', '2246;2247;2252', (120, 123))	('mutant', 'Var', (126, 132))
96979	27627808	ARQ 087 demonstrated good potency in cell lines with FGFR2 amplifications and fusions.	('potency', 'MPA', (26, 33))	('ARQ 087', 'Chemical', 'MESH:C000621805', (0, 7))	('fusions', 'Var', (78, 85))	('amplifications', 'Var', (59, 73))	('FGFR2', 'Gene', (53, 58))
96981	27627808	ARQ 087 inhibited multiple cell lines known to have FGFR1 or FGFR3 fusions including; RT4 and RT112 (FGFR3-TACC3), SW-780 (FGFR3-BAIAP2L1), and KG-1(FGFROP2-FGFR1), with GI50 values between 0.13 to 1.4 muM Table 3, suggesting that cell lines containing FGFR fusions are sensitive to ARQ 087.	('GI50', 'Gene', (170, 174))	('muM', 'Gene', '56925', (202, 205))	('TACC3', 'Gene', '10460', (107, 112))	('muM', 'Gene', (202, 205))	('FGF', 'Gene', '2246;2247;2252', (52, 55))	('TACC3', 'Gene', (107, 112))	('FGFR3', 'Gene', (101, 106))	('FGF', 'Gene', (149, 152))	('FGFR3', 'Gene', (61, 66))	('fusions', 'Var', (67, 74))	('FGF', 'Gene', (253, 256))	('ARQ 087', 'Chemical', 'MESH:C000621805', (0, 7))	('FGF', 'Gene', (157, 160))	('FGFR3', 'Gene', '2261', (101, 106))	('FGFR3', 'Gene', '2261', (61, 66))	('ARQ 087', 'Chemical', 'MESH:C000621805', (283, 290))	('FGF', 'Gene', '2246;2247;2252', (61, 64))	('BAIAP2L1', 'Gene', '55971', (129, 137))	('FGF', 'Gene', (101, 104))	('SW-780', 'CellLine', 'CVCL:1728', (115, 121))	('FGF', 'Gene', '2246;2247;2252', (149, 152))	('FGF', 'Gene', (61, 64))	('FGFR3', 'Gene', (123, 128))	('FGF', 'Gene', (123, 126))	('FGF', 'Gene', '2246;2247;2252', (253, 256))	('FGF', 'Gene', (52, 55))	('FGF', 'Gene', '2246;2247;2252', (157, 160))	('FGFR3', 'Gene', '2261', (123, 128))	('inhibited', 'NegReg', (8, 17))	('FGF', 'Gene', '2246;2247;2252', (101, 104))	('BAIAP2L1', 'Gene', (129, 137))	('GI50', 'Gene', '50723', (170, 174))	('FGF', 'Gene', '2246;2247;2252', (123, 126))
96982	27627808	The mechanism by which ARQ 087 inhibits the growth of FGFR kinase dependent cell lines was investigated.	('ARQ', 'Var', (23, 26))	('inhibits', 'NegReg', (31, 39))	('FGF', 'Gene', (54, 57))	('growth', 'MPA', (44, 50))	('FGF', 'Gene', '2246;2247;2252', (54, 57))	('ARQ 087', 'Chemical', 'MESH:C000621805', (23, 30))
96988	27627808	We observed a decrease in XIAP, and an increase in cleaved-PARP, activated-caspase 3, and pP53 Fig 4B.	('PARP', 'Gene', '1302', (59, 63))	('PARP', 'Gene', (59, 63))	('increase', 'PosReg', (39, 47))	('decrease', 'NegReg', (14, 22))	('caspase 3', 'Gene', (75, 84))	('XIAP', 'Gene', (26, 30))	('pP53', 'Var', (90, 94))	('caspase 3', 'Gene', '836', (75, 84))	('XIAP', 'Gene', '331', (26, 30))
96989	27627808	Taken together, these data suggest that ARQ 087 inhibits the proliferation of FGFR amplified cells by inducing G1 cell cycle arrest and apoptosis.	('ARQ 087', 'Chemical', 'MESH:C000621805', (40, 47))	('arrest', 'Disease', 'MESH:D006323', (125, 131))	('inhibits', 'NegReg', (48, 56))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (114, 131))	('apoptosis', 'CPA', (136, 145))	('FGF', 'Gene', (78, 81))	('arrest', 'Disease', (125, 131))	('ARQ 087', 'Var', (40, 47))	('proliferation', 'CPA', (61, 74))	('inducing', 'NegReg', (102, 110))	('FGF', 'Gene', '2246;2247;2252', (78, 81))
97003	27627808	ARQ 087 inhibits FGFR kinase by an ATP competitive mechanism, and is capable of inhibiting both the inactive and fully active forms of the FGFR kinase.	('FGF', 'Gene', (139, 142))	('ARQ 087', 'Chemical', 'MESH:C000621805', (0, 7))	('inhibits', 'NegReg', (8, 16))	('ATP', 'Chemical', 'MESH:D000255', (35, 38))	('FGF', 'Gene', (17, 20))	('inhibiting', 'NegReg', (80, 90))	('FGF', 'Gene', '2246;2247;2252', (139, 142))	('FGF', 'Gene', '2246;2247;2252', (17, 20))	('ARQ 087', 'Var', (0, 7))
97004	27627808	Hence, ARQ 087 delays FGFR activation by inhibiting its autophosphorylation, as well as inhibition of the phosphorylated active kinase.	('FGF', 'Gene', (22, 25))	('ARQ 087', 'Chemical', 'MESH:C000621805', (7, 14))	('inhibition', 'NegReg', (88, 98))	('activation', 'MPA', (27, 37))	('phosphorylated active kinase', 'MPA', (106, 134))	('inhibiting', 'NegReg', (41, 51))	('FGF', 'Gene', '2246;2247;2252', (22, 25))	('ARQ 087', 'Var', (7, 14))	('autophosphorylation', 'MPA', (56, 75))	('delays', 'NegReg', (15, 21))
97006	27627808	In cellular models, ARQ 087 was shown to inhibit FGFR phosphorylation in ectopically-expressing COS-1 cells with essentially equivalent potency for FGFR1 and FGFR2.	('FGF', 'Gene', (148, 151))	('ARQ 087', 'Var', (20, 27))	('FGF', 'Gene', '2246;2247;2252', (49, 52))	('FGF', 'Gene', (158, 161))	('ARQ 087', 'Chemical', 'MESH:C000621805', (20, 27))	('FGF', 'Gene', '2246;2247;2252', (148, 151))	('COS-1', 'CellLine', 'CVCL:0223', (96, 101))	('inhibit', 'NegReg', (41, 48))	('FGF', 'Gene', (49, 52))	('FGF', 'Gene', '2246;2247;2252', (158, 161))	('phosphorylation', 'MPA', (54, 69))
97011	27627808	Among the cell lines that harbored FGFR fusions, amplifications, or mutations, cell lines with FGFR-fusions were among the most sensitive to ARQ 087.	('sensitive', 'MPA', (128, 137))	('FGF', 'Gene', (95, 98))	('FGF', 'Gene', '2246;2247;2252', (35, 38))	('ARQ 087', 'Chemical', 'MESH:C000621805', (141, 148))	('FGF', 'Gene', (35, 38))	('FGF', 'Gene', '2246;2247;2252', (95, 98))	('mutations', 'Var', (68, 77))
97015	27627808	We observe a similar phenomenon with FGFR-fusion harboring cells, ERK activation more potently suppressed by ARQ 087 in both NCI-H716 and SNU-16 cells than FGFR-wild type carrying KATO-III cells Fig 3B.	('ARQ 087', 'Chemical', 'MESH:C000621805', (109, 116))	('ARQ', 'Var', (109, 112))	('suppressed', 'NegReg', (95, 105))	('FGF', 'Gene', (37, 40))	('FGF', 'Gene', (156, 159))	('SNU-16', 'Chemical', '-', (138, 144))	('FGF', 'Gene', '2246;2247;2252', (156, 159))	('NCI-H716', 'CellLine', 'CVCL:1581', (125, 133))	('ERK', 'Gene', '5594', (66, 69))	('FGF', 'Gene', '2246;2247;2252', (37, 40))	('activation', 'PosReg', (70, 80))	('ERK', 'Gene', (66, 69))
97024	27627808	Durable partial and complete regressions were observed in both tumor models that are driven by FGFR2 amplification and fusions (NCI-H716 and SNU-16), and the murine transfected cell line (BaF3/FGFR2).	('tumor', 'Disease', (63, 68))	('amplification', 'Var', (101, 114))	('SNU-16', 'Chemical', '-', (141, 147))	('NCI-H716', 'CellLine', 'CVCL:1581', (128, 136))	('fusions', 'Var', (119, 126))	('murine', 'Species', '10090', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('FGFR2', 'Gene', (95, 100))
97031	27627808	The recent identification of the driver role of FGFR2 fusions in iCCA, as well as other tumor types, provides a promising path forward in the selection of patients that may respond to FGFR inhibitors in a clinical setting.	('FGF', 'Gene', (184, 187))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('fusions', 'Var', (54, 61))	('FGF', 'Gene', '2246;2247;2252', (48, 51))	('iCCA', 'Disease', (65, 69))	('FGF', 'Gene', '2246;2247;2252', (184, 187))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('patients', 'Species', '9606', (155, 163))	('FGF', 'Gene', (48, 51))	('tumor', 'Disease', (88, 93))
97032	27627808	The early experiences with FGFR inhibitors in the clinic highlight the importance of defining the appropriate patient population, and including suitable biomarker assays during clinical screening and enrollment.	('FGF', 'Gene', '2246;2247;2252', (27, 30))	('inhibitors', 'Var', (32, 42))	('patient', 'Species', '9606', (110, 117))	('FGF', 'Gene', (27, 30))
97033	27627808	In conclusion, ARQ 087 is a novel and potent FGFR inhibitor with multi-kinase activity.	('ARQ 087', 'Chemical', 'MESH:C000621805', (15, 22))	('FGF', 'Gene', (45, 48))	('ARQ', 'Var', (15, 18))	('FGF', 'Gene', '2246;2247;2252', (45, 48))
97035	27627808	Preclinical results suggest that genetic alterations of the FGFR pathway:amplification, mutation, and gene fusion, correlate with the activity of ARQ 087 in vitro and in vivo.	('gene fusion', 'Var', (102, 113))	('mutation', 'Var', (88, 96))	('FGF', 'Gene', (60, 63))	('genetic alterations', 'Var', (33, 52))	('ARQ 087', 'Chemical', 'MESH:C000621805', (146, 153))	('activity', 'MPA', (134, 142))	('FGF', 'Gene', '2246;2247;2252', (60, 63))	('amplification', 'Var', (73, 86))
97037	27627808	A clinical response was noted for a patient with intrahepatic cholangiocarcinoma with a known FGFR2 fusion, additionally prolonged stable disease was observed in 10 of 61 patients, including a cholangiocarcinoma, which also had an FGFR2 fusion.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (193, 211))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (193, 211))	('cholangiocarcinoma', 'Disease', (62, 80))	('patient', 'Species', '9606', (171, 178))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (49, 80))	('FGFR2', 'Gene', (94, 99))	('patients', 'Species', '9606', (171, 179))	('fusion', 'Var', (100, 106))	('intrahepatic cholangiocarcinoma', 'Disease', (49, 80))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (62, 80))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (62, 80))	('cholangiocarcinoma', 'Disease', (193, 211))	('patient', 'Species', '9606', (36, 43))
97050	23270094	As an example, the MONTAC code 8163 was expanded to two codes, cholangiocarcinoma (8160) and bile duct cystadenocarcinoma (8161).	('bile duct cystadenocarcinoma', 'Disease', 'MESH:D001649', (93, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('8160', 'Var', (83, 87))	('cholangiocarcinoma', 'Disease', (63, 81))	('bile duct cystadenocarcinoma', 'Disease', (93, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('8161', 'Var', (123, 127))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (63, 81))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (63, 81))	('bile duct cystadenocarcinoma', 'Phenotype', 'HP:0030153', (93, 121))
97051	23270094	The 1990 revision, ICD-O-2, added a code for Klatskin tumor (8162/3) with a site of C22.1=intrahepatic bile duct suggested.	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Klatskin tumor', 'Disease', (45, 59))	('Klatskin tumor', 'Disease', 'MESH:D018285', (45, 59))	('C22.1=intrahepatic', 'Var', (84, 102))
97130	19436294	Besides hepatic lithiasis (25.6%; P<0.001), seropositivity for hepatitis B surface antigen (37.5% of all ICC patients; odds ratio (OR) =4.985, P<0.001) and seropositivity for hepatitis C antibodies (13.1%; OR=2.709; P=0.021) are the primary independent risk factors for ICC.	('hepatitis', 'Disease', (63, 72))	('hepatitis', 'Phenotype', 'HP:0012115', (63, 72))	('patients', 'Species', '9606', (109, 117))	('hepatitis', 'Disease', 'MESH:D056486', (175, 184))	('seropositivity', 'Var', (44, 58))	('ICC', 'Disease', (270, 273))	('hepatic lithiasis', 'Disease', 'MESH:D020347', (8, 25))	('hepatitis B', 'Disease', 'MESH:D006509', (63, 74))	('hepatitis', 'Disease', 'MESH:D056486', (63, 72))	('hepatitis', 'Phenotype', 'HP:0012115', (175, 184))	('seropositivity for hepatitis C antibodies', 'Phenotype', 'HP:0410371', (156, 197))	('hepatitis B', 'Disease', (63, 74))	('hepatic lithiasis', 'Disease', (8, 25))	('hepatitis', 'Disease', (175, 184))
97171	19436294	As shown in Table 3, seropositivity for HBsAg, seroposivity for anti-HCV, and the presence of IHD stones were independent factors associated with ICC.	('IHD stones', 'Disease', 'MESH:D007669', (94, 104))	('IHD stones', 'Disease', (94, 104))	('ICC', 'Disease', (146, 149))	('HBsAg', 'Protein', (40, 45))	('seropositivity', 'Var', (21, 35))	('associated', 'Reg', (130, 140))
97200	19436294	For example, interleukin-6, an inflammatory cytokine, promotes human cholangiocarcinoma cells grown in vivo by inhibiting apoptosis through the activation of miRNAs including miR let-7a and miR370, thereby modulating the activation of STAT-3 pathways (Meng et al, 2007, 2008; Smirnova et al, 2007).	('STAT-3', 'Gene', '6774', (235, 241))	('human', 'CPA', (63, 68))	('STAT-3', 'Gene', (235, 241))	('human', 'Species', '9606', (63, 68))	('apoptosis', 'CPA', (122, 131))	('miR370', 'Gene', '442915', (190, 196))	('interleukin-6', 'Gene', (13, 26))	('modulating', 'Reg', (206, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('cholangiocarcinoma', 'Disease', (69, 87))	('miR370', 'Gene', (190, 196))	('inhibiting', 'NegReg', (111, 121))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (69, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (69, 87))	('miR let-7a', 'Var', (175, 185))	('promotes', 'PosReg', (54, 62))
97208	19436294	Considering that tumour formation is a multi-step process involving the accumulation of mutations over years or even decades before the occurrence of neoplastic transformation, the target cells should be able to proliferate as well as survive in the liver for a long period.	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('mutations', 'Var', (88, 97))	('tumour', 'Disease', (17, 23))
97241	33983055	They first transected the common bile duct and right hepatic artery and then transected the liver without prior mobilization of the right lobe and caudate lobe.	('transected', 'Var', (11, 21))	('transected', 'Var', (77, 87))	('right hepatic artery', 'Disease', (47, 67))	('right hepatic artery', 'Disease', 'MESH:D056486', (47, 67))
97280	33983055	The percentage of patients who underwent biliary drainage before surgery was significantly higher in the transhepatic hilar approach group (P = 0.015).	('higher', 'PosReg', (91, 97))	('patients', 'Species', '9606', (18, 26))	('transhepatic', 'Var', (105, 117))	('biliary drainage', 'Disease', (41, 57))
97281	33983055	However, although the surgical duration was longer, the intraoperative blood loss was significantly less with the transhepatic hilar approach than conventional approach (382.1 vs. 824.4 mL, respectively; P = 0.001).	('less', 'NegReg', (100, 104))	('transhepatic', 'Var', (114, 126))	('intraoperative blood loss', 'Disease', (56, 81))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (56, 81))
97283	33983055	The morbidity and mortality rates tended to be lower in the transhepatic hilar approach group than in the conventional approach group, but the difference did not reach statistical significance.	('lower', 'NegReg', (47, 52))	('mortality', 'Disease', 'MESH:D003643', (18, 27))	('mortality', 'Disease', (18, 27))	('morbidity', 'CPA', (4, 13))	('transhepatic hilar approach', 'Var', (60, 87))
97301	33983055	In the present study, the rate of R0 resection (a significant prognostic factor for patient survival) was significantly higher in the transhepatic hilar approach than in the conventional approach.	('higher', 'PosReg', (120, 126))	('transhepatic', 'Var', (134, 146))	('patient', 'Species', '9606', (84, 91))
97335	29039079	The pathological tumor staging was stage II, T2aN0M0, according to the UICC/AJCC seventh edition staging system.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('T2aN0M0', 'Var', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (17, 22))
97348	29039079	Poor prognostic factors have been reported in HCCA, such as age, preoperative high CA19-9, positive margin status, lymph node metastasis, histological grade, and advanced tumor stage.	('high CA19-9', 'Var', (78, 89))	('HCCA', 'Disease', (46, 50))	('lymph node metastasis', 'CPA', (115, 136))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('CA19', 'Chemical', '-', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('histological', 'CPA', (138, 150))
97387	28835003	This epigenetic regulation of miRNAs in drug transporters or enzymes has a greater impact on drug responses.	('miR', 'Gene', '220972', (30, 33))	('drug responses', 'CPA', (93, 107))	('miR', 'Gene', (30, 33))	('epigenetic regulation', 'Var', (5, 26))	('impact', 'Reg', (83, 89))
97388	28835003	The influence of the epigenetic changes in cancer diseases can be expected to be even greater.	('epigenetic changes', 'Var', (21, 39))	('cancer diseases', 'Disease', 'MESH:D009369', (43, 58))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer diseases', 'Disease', (43, 58))
97390	28835003	The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, and protein level, and also examined epigenetic changes, including those related to miRNA.	('miR', 'Gene', (239, 242))	('miR', 'Gene', '220972', (239, 242))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('epigenetic changes', 'Var', (192, 210))	('examined', 'Reg', (183, 191))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('Cancer Genome Atlas', 'Disease', (4, 23))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('human', 'Species', '9606', (91, 96))
97407	28835003	For evaluate with our founding, we collected expression datasets of miRNA and mRNA for tumor and non-tumor tissues derived from colonic adenocarcinoma (GSE29623) and intrahepatic cholangiocarcinoma and hepatocellular carcinoma patients (GSE57555).	('GSE29623', 'Var', (152, 160))	('miR', 'Gene', '220972', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (202, 226))	('miR', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('patients', 'Species', '9606', (227, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('mRNA', 'MPA', (78, 82))	('tumor', 'Disease', (87, 92))	('colonic adenocarcinoma', 'Disease', 'MESH:D003110', (128, 150))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('colonic adenocarcinoma', 'Disease', (128, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('intrahepatic cholangiocarcinoma and hepatocellular carcinoma', 'Disease', 'MESH:D018281', (166, 226))	('GSE57555', 'Var', (237, 245))	('tumor', 'Disease', (101, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (179, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
97449	28835003	let-7 family members such as let-7, let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g, let-7i, and miR-98 were previously shown to target ADRB2, but to our knowledge this is the first study to show that hsa-miR-98 can also regulate ADRB2 expression.	('let-7e', 'Gene', (68, 74))	('let-7b', 'Gene', '406884', (44, 50))	('expression', 'MPA', (243, 253))	('miR-98', 'Gene', (212, 218))	('let-7e', 'Gene', '406887', (68, 74))	('miR-98', 'Gene', '407054', (104, 110))	('let-7i', 'Gene', '406891', (92, 98))	('let-7c', 'Gene', (52, 58))	('regulate', 'Reg', (228, 236))	('let-7b', 'Gene', (44, 50))	('let-7a', 'Var', (36, 42))	('let-7c', 'Gene', '406885', (52, 58))	('let-7g', 'Gene', '406890', (84, 90))	('let-7i', 'Gene', (92, 98))	('let-7d', 'Gene', '406886', (60, 66))	('ADRB2', 'Gene', '154', (143, 148))	('miR-98', 'Gene', '407054', (212, 218))	('ADRB2', 'Gene', (237, 242))	('ADRB2', 'Gene', '154', (237, 242))	('ADRB2', 'Gene', (143, 148))	('let-7g', 'Gene', (84, 90))	('miR-98', 'Gene', (104, 110))	('hsa-miR-98', 'Gene', '407054', (208, 218))	('let-7f', 'Var', (76, 82))	('hsa-miR-98', 'Gene', (208, 218))	('let-7d', 'Gene', (60, 66))
97467	16871013	In addition, the molecular mechanism as well as the importance of the loss of TrxR in the development of cholangiocarcinoma, following dysplastic transformation of bile duct cells, also remains to be clarified.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (105, 123))	('TrxR', 'Gene', '7296', (78, 82))	('loss', 'Var', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (105, 123))	('dysplastic', 'Disease', 'MESH:D004416', (135, 145))	('dysplastic', 'Disease', (135, 145))	('TrxR', 'Gene', (78, 82))	('cholangiocarcinoma', 'Disease', (105, 123))
97471	16871013	Therefore, it is possible that dysfunction of the intracellular reduction-oxidation (redox) regulatory system may be involved in cholangiocarcinogenesis.	('dysfunction', 'Var', (31, 42))	('involved', 'Reg', (117, 125))	('carcinogenesis', 'Disease', (138, 152))	('carcinogenesis', 'Disease', 'MESH:D063646', (138, 152))
97475	16871013	Therefore, TrxR has been considered to play an important role in regulating the cell growth and death and its dysregulation has been closely linked to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('TrxR', 'Gene', (11, 15))	('linked', 'Reg', (141, 147))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('death', 'Disease', 'MESH:D003643', (96, 101))	('death', 'Disease', (96, 101))	('TrxR', 'Gene', '7296', (11, 15))	('dysregulation', 'Var', (110, 123))	('cell growth', 'CPA', (80, 91))
97554	16871013	In addition, the molecular mechanism and importance of loss of TrxR in the process of the development of cholangiocarcinoma, following dysplastic transformation of bile duct cells, also remains to be clarified.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (105, 123))	('loss', 'Var', (55, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (105, 123))	('dysplastic', 'Disease', 'MESH:D004416', (135, 145))	('dysplastic', 'Disease', (135, 145))	('TrxR', 'Gene', '7296', (63, 67))	('cholangiocarcinoma', 'Disease', (105, 123))	('TrxR', 'Gene', (63, 67))
97658	32764696	Furthermore, a high expression of SFRP1 predicted poor prognosis for ampullary adenocarcinoma patients.	('high', 'Var', (15, 19))	('patients', 'Species', '9606', (94, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('SFRP1', 'Gene', (34, 39))	('adenocarcinoma', 'Disease', (79, 93))	('adenocarcinoma', 'Disease', 'MESH:D000230', (79, 93))
97674	32764696	Genetic mutation of WNT signalling has been observed in ampullary and periampullary cancer, including APC (adenomatosis polyposis coli), AXIN1, SOX9, and FBXW7.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('Genetic mutation', 'Var', (0, 16))	('SOX9', 'Gene', (144, 148))	('AXIN1', 'Gene', (137, 142))	('cancer', 'Disease', (84, 90))	('observed', 'Reg', (44, 52))	('FBXW7', 'Gene', (154, 159))	('APC', 'Disease', (102, 105))	('APC', 'Disease', 'MESH:D011125', (102, 105))	('SOX9', 'Gene', '6662', (144, 148))	('adenomatosis polyposis coli', 'Phenotype', 'HP:0005227', (107, 134))	('adenomatosis polyposis coli', 'Gene', (107, 134))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('adenomatosis polyposis coli', 'Gene', '324', (107, 134))	('WNT signalling', 'Gene', (20, 34))	('AXIN1', 'Gene', '8312', (137, 142))	('FBXW7', 'Gene', '55294', (154, 159))	('ampullary', 'Disease', (56, 65))
97675	32764696	CTNNB1 mutation (catenin beta 1, beta-catenin protein) induces the nuclear accumulation of beta-catenin in ampullary cancer.	('CTNNB1', 'Gene', '1499', (0, 6))	('catenin beta 1', 'Gene', (17, 31))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('nuclear accumulation', 'MPA', (67, 87))	('beta-catenin', 'Gene', (91, 103))	('CTNNB1', 'Gene', (0, 6))	('induces', 'Reg', (55, 62))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('beta-catenin', 'Gene', (33, 45))	('mutation', 'Var', (7, 15))	('catenin beta 1', 'Gene', '1499', (17, 31))	('beta-catenin', 'Gene', '1499', (91, 103))	('cancer', 'Disease', (117, 123))	('beta-catenin', 'Gene', '1499', (33, 45))
97677	32764696	Other mutations have been reported in gastrointestinal and colorectal cancer, such as mutation of APC, CTNNB1, RNF43 (ring finger protein 43), WNT1 (WNT family member 1), and CDH1 (cadherin 1, E-cadherin).	('cadherin 1', 'Gene', (181, 191))	('WNT1', 'Gene', (143, 147))	('WNT1', 'Gene', '7471', (143, 147))	('CTNNB1', 'Gene', '1499', (103, 109))	('RNF43', 'Gene', (111, 116))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('mutation', 'Var', (86, 94))	('reported', 'Reg', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('E-cadherin', 'Gene', (193, 203))	('E-cadherin', 'Gene', '999', (193, 203))	('cadherin 1', 'Gene', '999', (181, 191))	('CTNNB1', 'Gene', (103, 109))	('CDH1', 'Gene', (175, 179))	('ring finger protein 43', 'Gene', (118, 140))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))	('CDH1', 'Gene', '999', (175, 179))	('APC', 'Disease', 'MESH:D011125', (98, 101))	('colorectal cancer', 'Disease', (59, 76))	('APC', 'Disease', (98, 101))	('gastrointestinal', 'Disease', (38, 54))	('ring finger protein 43', 'Gene', '54894', (118, 140))	('RNF43', 'Gene', '54894', (111, 116))
97678	32764696	Thus, the aberrant or non-canonical regulation of WNT signalling possibly contributes to ampullary cancer development.	('WNT signalling', 'Pathway', (50, 64))	('contributes', 'Reg', (74, 85))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('aberrant', 'Var', (10, 18))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
97683	32764696	The methylation of SFRP1 promoter induces gene silencing and has been detected in 29 cancer types.	('detected', 'Reg', (70, 78))	('gene silencing', 'MPA', (42, 56))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('induces', 'Reg', (34, 41))	('methylation', 'Var', (4, 15))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('SFRP1', 'Gene', (19, 24))
97684	32764696	In metastatic renal cell carcinoma, SFRP1 hypomethylation increases SFRP1 expression and activates histone modifications.	('expression', 'MPA', (74, 84))	('increases', 'PosReg', (58, 67))	('hypomethylation', 'Var', (42, 57))	('SFRP1', 'Gene', (36, 41))	('SFRP1', 'Gene', (68, 73))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (14, 34))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (14, 34))	('activates', 'PosReg', (89, 98))	('histone modifications', 'MPA', (99, 120))	('renal cell carcinoma', 'Disease', (14, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
97694	32764696	The correlation between high SFRP1 expression with patients' survival was diverse and was correlated with poor prognoses in bladder carcinoma, kidney renal papillary cell carcinoma, lung squamous cell carcinoma, ovarian cancer, and rectal and stomach adenocarcinoma (Fig.	('expression', 'MPA', (35, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('high', 'Var', (24, 28))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (143, 180))	('ovarian cancer', 'Phenotype', 'HP:0100615', (212, 226))	('patients', 'Species', '9606', (51, 59))	('lung squamous cell carcinoma, ovarian cancer', 'Disease', 'MESH:D002294', (182, 226))	('SFRP1', 'Gene', (29, 34))	('rectal', 'Disease', (232, 238))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (124, 141))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (243, 265))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (187, 210))	('bladder carcinoma', 'Disease', 'MESH:D001749', (124, 141))	('stomach adenocarcinoma', 'Disease', (243, 265))	('kidney renal papillary cell carcinoma', 'Disease', (143, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('bladder carcinoma', 'Disease', (124, 141))
97695	32764696	However, a high expression level of SFRP1 was associated with better prognosis in patients with breast carcinoma, esophageal adenocarcinoma, head and neck squamous cell carcinoma, kidney renal clear cell carcinoma, and pancreatic ductal adenocarcinoma (Fig.	('esophageal adenocarcinoma', 'Disease', (114, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('breast carcinoma', 'Disease', 'MESH:D001943', (96, 112))	('expression level', 'MPA', (16, 32))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (219, 251))	('neck squamous cell carcinoma', 'Disease', (150, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (150, 178))	('breast carcinoma', 'Phenotype', 'HP:0003002', (96, 112))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('patients', 'Species', '9606', (82, 90))	('breast carcinoma', 'Disease', (96, 112))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (180, 213))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (219, 251))	('SFRP1', 'Gene', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('better', 'PosReg', (62, 68))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (114, 139))	('pancreatic ductal adenocarcinoma', 'Disease', (219, 251))	('kidney renal clear cell carcinoma', 'Disease', (180, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('high', 'Var', (11, 15))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (114, 139))
97700	32764696	Low SFRP1 was correlated with poor prognosis of patients in one of the datasets (GSE31210), and high SFRP1 was associated with poor prognosis in a different dataset (jacob-00182-CANDF).	('SFRP1', 'Gene', (4, 9))	('patients', 'Species', '9606', (48, 56))	('SFRP1', 'Gene', (101, 106))	('high', 'Var', (96, 100))	('Low', 'NegReg', (0, 3))
97709	32764696	Low methylation of SFRP1 (high expression of SFRP1) showed a trend of correlation with better prognosis in patients with pancreatic adenocarcinoma and cholangiocarcinoma (Fig.	('methylation', 'MPA', (4, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('pancreatic adenocarcinoma and cholangiocarcinoma', 'Disease', 'MESH:D018281', (121, 169))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (151, 169))	('better', 'PosReg', (87, 93))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (121, 146))	('patients', 'Species', '9606', (107, 115))	('SFRP1', 'Gene', (19, 24))	('Low', 'Var', (0, 3))
97720	32764696	In other cancers, the incidence of SFRP1 alteration was also low (0.4%-3.0% in these 4 kinds of cancer).	('cancer', 'Disease', (9, 15))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('alteration', 'Var', (41, 51))	('SFRP1', 'Gene', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Disease', (96, 102))
97722	32764696	We observe thee co-occurrence of WNT1-RNF43 alteration in two patients, APC-RNF43 in two patients, APC-CDH1 in three patients, and APC-CTNNB1 in one patient (Supplementary Fig.	('RNF43', 'Gene', '54894', (76, 81))	('APC-CDH1', 'Gene', (99, 107))	('RNF43', 'Gene', (76, 81))	('patient', 'Species', '9606', (89, 96))	('alteration', 'Var', (44, 54))	('patient', 'Species', '9606', (62, 69))	('WNT1', 'Gene', '7471', (33, 37))	('WNT1', 'Gene', (33, 37))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (89, 97))	('RNF43', 'Gene', '54894', (38, 43))	('patient', 'Species', '9606', (149, 156))	('patient', 'Species', '9606', (117, 124))	('RNF43', 'Gene', (38, 43))	('patients', 'Species', '9606', (62, 70))	('APC-CDH1', 'Gene', '324;999', (99, 107))
97728	32764696	However, the patients with a high expression of SFRP1 tended to have higher risk of early recurrence within 12 months of operation, and increased proportion of peritoneal carcinomatosis (Table 2).	('early recurrence', 'CPA', (84, 100))	('high expression', 'Var', (29, 44))	('peritoneal carcinomatosis', 'Disease', (160, 185))	('patients', 'Species', '9606', (13, 21))	('SFRP1', 'Gene', (48, 53))	('peritoneal carcinomatosis', 'Disease', 'MESH:D010534', (160, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))
97729	32764696	The disease-specific survival rate of patients with high SFRP1 expression levels was worse than those with low SFRP1 expression levels (Fig.	('SFRP1', 'Gene', (57, 62))	('expression', 'MPA', (63, 73))	('high', 'Var', (52, 56))	('disease-specific survival rate', 'CPA', (4, 34))	('patients', 'Species', '9606', (38, 46))	('worse', 'NegReg', (85, 90))
97763	32764696	Dysregulation of oncogenic WNT signalling has been reported in ampullary adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (73, 87))	('Dysregulation', 'Var', (0, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('adenocarcinoma', 'Disease', (73, 87))	('oncogenic WNT signalling', 'Pathway', (17, 41))
97769	32764696	High SFRP1 expression was correlated with poor prognosis, early recurrence and peritoneal carcinomatosis of ampullary adenocarcinoma patients.	('High', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('expression', 'MPA', (11, 21))	('patients', 'Species', '9606', (133, 141))	('SFRP1', 'Gene', (5, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('peritoneal carcinomatosis of ampullary adenocarcinoma', 'Disease', 'MESH:D010534', (79, 132))
97773	32764696	Interaction between these genes may lead to the non-canonical signalling of SFRP1 and result in cancer dissemination.	('result in', 'Reg', (86, 95))	('lead to', 'Reg', (36, 43))	('non-canonical signalling', 'MPA', (48, 72))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('SFRP1', 'Gene', (76, 81))	('Interaction', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
97777	32764696	The mutation of tumor suppressors (e.g., APC, GSK-3, and AXIN) in the WNT pathway was found to induce nuclear accumulation of beta-catenin.	('beta-catenin', 'Gene', '1499', (126, 138))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('APC', 'Disease', 'MESH:D011125', (41, 44))	('WNT pathway', 'Pathway', (70, 81))	('mutation', 'Var', (4, 12))	('GSK-3', 'Gene', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('APC', 'Disease', (41, 44))	('GSK-3', 'Gene', '2931;2932', (46, 51))	('AXIN', 'Gene', (57, 61))	('tumor', 'Disease', (16, 21))	('nuclear accumulation', 'MPA', (102, 122))	('AXIN', 'Gene', '8312', (57, 61))	('induce', 'PosReg', (95, 101))	('beta-catenin', 'Gene', (126, 138))
97779	32764696	Aberrant nonmembranous beta-catenin expression was observed in intestinal subtype of ampullary cancer.	('intestinal subtype', 'Disease', (63, 81))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('beta-catenin', 'Gene', (23, 35))	('nonmembranous', 'MPA', (9, 22))	('observed', 'Reg', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('beta-catenin', 'Gene', '1499', (23, 35))
97780	32764696	Promoter hypermethylation of SFRP1, SFRP2, SFRP4, and SFRP5 is associated with gene suppression and higher cancer risk.	('SFRP1', 'Gene', (29, 34))	('SFRP4', 'Gene', '6424', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('SFRP2', 'Gene', (36, 41))	('SFRP2', 'Gene', '6423', (36, 41))	('SFRP5', 'Gene', '6425', (54, 59))	('SFRP4', 'Gene', (43, 48))	('suppression', 'NegReg', (84, 95))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('SFRP5', 'Gene', (54, 59))	('gene', 'MPA', (79, 83))	('Promoter hypermethylation', 'Var', (0, 25))
97787	32764696	Upregulation of SFRP1 is detected in metastatic renal cell carcinoma cell lines and the knockdown of SFRP1 by small interfering RNA inhibits the invasive potential.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (48, 68))	('knockdown', 'Var', (88, 97))	('inhibits', 'NegReg', (132, 140))	('invasive potential', 'CPA', (145, 163))	('SFRP1', 'Gene', (101, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('small interfering', 'Var', (110, 127))	('renal cell carcinoma', 'Disease', (48, 68))	('SFRP1', 'Gene', (16, 21))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (48, 68))
97803	32764696	The patients with high SFRP1 staining had a poor prognosis and increased proportion of peritoneal carcinomatosis.	('SFRP1', 'Gene', (23, 28))	('peritoneal carcinomatosis', 'Disease', (87, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('peritoneal carcinomatosis', 'Disease', 'MESH:D010534', (87, 112))	('high', 'Var', (18, 22))	('patients', 'Species', '9606', (4, 12))
97816	32764696	Dysregulation of the WNT pathway is reported in ampullary cancer.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Dysregulation', 'Var', (0, 13))	('WNT pathway', 'Pathway', (21, 32))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
97818	32764696	However, high expression of SFRP1 is correlated with poor prognosis of patients with ampullary adenocarcinoma in our present study.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('adenocarcinoma', 'Disease', (95, 109))	('patients', 'Species', '9606', (71, 79))	('SFRP1', 'Gene', (28, 33))	('adenocarcinoma', 'Disease', 'MESH:D000230', (95, 109))	('high', 'Var', (9, 13))
97941	27347393	The gut microbiome is a key component in the maintenance of health, and alterations in this meta-organ are increasingly being linked to the pathophysiologic basis for a wide variety of diseases .	('linked', 'Reg', (126, 132))	('alterations', 'Var', (72, 83))	('gut microbiome', 'Species', '749906', (4, 18))
97948	27347393	In the mdr2 (-/-) model of PSC, absence of the gut microbiota exacerbated hepatobiliary disease as shown by increased cholangiocyte senescence and more severe phenotypic features of PSC.	('cholangiocyte senescence', 'MPA', (118, 142))	('PSC', 'Gene', '100653366', (182, 185))	('PSC', 'Gene', '100653366', (27, 30))	('absence', 'Var', (32, 39))	('biliary disease', 'Phenotype', 'HP:0001080', (80, 95))	('PSC', 'Gene', (182, 185))	('mdr2', 'Gene', '5244', (7, 11))	('increased', 'PosReg', (108, 117))	('PSC', 'Gene', (27, 30))	('hepatobiliary disease', 'Disease', 'MESH:D004066', (74, 95))	('exacerbated', 'PosReg', (62, 73))	('hepatobiliary disease', 'Disease', (74, 95))	('mdr2', 'Gene', (7, 11))
97960	27347393	These results suggest that aberrant exosomes in PBC selectively induce the expression of co-stimulatory molecules in different subsets of antigen-presenting cells and could contribute to the pathogenesis of PBC .	('contribute', 'Reg', (173, 183))	('induce', 'PosReg', (64, 70))	('aberrant', 'Var', (27, 35))	('PBC', 'Gene', '1737', (48, 51))	('PBC', 'Phenotype', 'HP:0002613', (48, 51))	('PBC', 'Gene', (48, 51))	('PBC', 'Phenotype', 'HP:0002613', (207, 210))	('PBC', 'Gene', (207, 210))	('PBC', 'Gene', '1737', (207, 210))	('expression', 'MPA', (75, 85))
97991	27347393	For example, normalization of alkaline phosphatase is a biomarker of improved survival in PSC and decreased likelihood of requiring orthotopic liver transplantation .	('alkaline phosphatase', 'MPA', (30, 50))	('improved', 'PosReg', (69, 77))	('PSC', 'Gene', '100653366', (90, 93))	('PSC', 'Gene', (90, 93))	('normalization', 'Var', (13, 26))
98073	20594328	The copy number of Slug, Snail and GAPDH mRNA ranged from 218.4 to 83096, 117.8 to 15262, and 1238.56 to 6287429, respectively.	('GAPDH', 'Gene', '2597', (35, 40))	('GAPDH', 'Gene', (35, 40))	('Snail', 'Gene', '6615', (25, 30))	('Snail', 'Gene', (25, 30))	('1238.56', 'Var', (94, 101))
98084	20594328	However, there was no significant correlation between Snail overexpression and E-cadherin expression (Table 2) E-Cadherin mRNA expression was examined in a panel of three cholangiocarcinoma cell lines QBC939, SK-Ch-1, FRH 0201 by real-time PCR and results showed that the cell line FRH 0201 had the highest expression level of E-Cadherin mRNA and the lowest expression of Slug mRNA (Fig 2A).	('Snail', 'Gene', (54, 59))	('E-Cadherin', 'Gene', '999', (111, 121))	('E-Cadherin', 'Gene', (327, 337))	('expression level', 'MPA', (307, 323))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (171, 189))	('Snail', 'Gene', '6615', (54, 59))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (171, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('E-Cadherin', 'Gene', '999', (327, 337))	('FRH 0201', 'Var', (282, 290))	('lowest', 'NegReg', (351, 357))	('QBC939', 'CellLine', 'CVCL:6942', (201, 207))	('expression', 'MPA', (358, 368))	('Slug mRNA', 'MPA', (372, 381))	('E-Cadherin', 'Gene', (111, 121))	('cholangiocarcinoma', 'Disease', (171, 189))
98091	20594328	We tested whether Slug knockdown affected the invasion capabilities of QBC939 cells by using an in vitro invasion assay.	('knockdown', 'Var', (23, 32))	('QBC939', 'CellLine', 'CVCL:6942', (71, 77))	('affected', 'Reg', (33, 41))	('tested', 'Reg', (3, 9))
98096	20594328	Our data revealed direct evidence that transient Slug expression can suppress E-cadherin protein expression and increased the motility and invision potential in QBC939 cells.	('invision potential', 'CPA', (139, 157))	('E-cadherin protein', 'Protein', (78, 96))	('motility', 'CPA', (126, 134))	('transient', 'Var', (39, 48))	('QBC939', 'CellLine', 'CVCL:6942', (161, 167))	('increased', 'PosReg', (112, 121))	('suppress', 'NegReg', (69, 77))
98103	20594328	Genetic mutation of the E-cadherin gene was detected in breast, gastric, and gynecological cancers, which showed a uniform loss of E-cadherin expression .	('gastric', 'Disease', (64, 71))	('Genetic mutation', 'Var', (0, 16))	('E-cadherin', 'Protein', (131, 141))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('breast', 'Disease', (56, 62))	('detected', 'Reg', (44, 52))	('loss', 'NegReg', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('expression', 'MPA', (142, 152))	('E-cadherin gene', 'Gene', (24, 39))
98255	32021438	Kaplan-Meier survival curves showed that the overall survival time of patients with EphB3 positive or dysadherin negative expression was significantly longer than patients with negative EphB3 or positive dysadherin expression (P < 0.01) (Table 4, Figure 3).	('negative', 'NegReg', (113, 121))	('patients', 'Species', '9606', (70, 78))	('survival', 'CPA', (53, 61))	('patients', 'Species', '9606', (163, 171))	('dysadherin', 'Gene', (102, 112))	('dysadherin', 'Gene', '53827', (102, 112))	('longer', 'PosReg', (151, 157))	('EphB3', 'Gene', (186, 191))	('EphB3', 'Gene', (84, 89))	('positive', 'Var', (90, 98))	('dysadherin', 'Gene', (204, 214))	('EphB3', 'Gene', '2049', (186, 191))	('dysadherin', 'Gene', '53827', (204, 214))	('EphB3', 'Gene', '2049', (84, 89))
98256	32021438	Furthermore, we defined four groups by the expression of EphB3 and dysadherin; positive expression of both EphB3 and dysadherin (+/+), positive and negative (+/-); negative and positive (-/+), and both negative (-/-).	('+/-', 'Var', (158, 161))	('EphB3', 'Gene', (107, 112))	('dysadherin', 'Gene', '53827', (117, 127))	('dysadherin', 'Gene', (117, 127))	('EphB3', 'Gene', '2049', (107, 112))	('EphB3', 'Gene', (57, 62))	('negative', 'NegReg', (148, 156))	('dysadherin', 'Gene', '53827', (67, 77))	('dysadherin', 'Gene', (67, 77))	('EphB3', 'Gene', '2049', (57, 62))
98257	32021438	Kaplan-Meier survival curves revealed that the group with EphB3 positive and dysadherin negative expression had longest overall survival time than other groups, and the group with EphB3 negative and dysadherin positive expression had shortest overall survival time than other groups (Table 4, Figure 3).	('negative', 'NegReg', (88, 96))	('dysadherin', 'Gene', (77, 87))	('EphB3', 'Gene', (58, 63))	('dysadherin', 'Gene', '53827', (77, 87))	('expression', 'Var', (97, 107))	('EphB3', 'Gene', (180, 185))	('dysadherin', 'Gene', (199, 209))	('dysadherin', 'Gene', '53827', (199, 209))	('EphB3', 'Gene', '2049', (58, 63))	('overall survival time', 'CPA', (120, 141))	('longest', 'PosReg', (112, 119))	('EphB3', 'Gene', '2049', (180, 185))	('overall survival', 'CPA', (243, 259))
98258	32021438	According to univariate analysis and multivariate analysis using Cox's proportional hazards model, this study found that several clinicopathological parameters negatively correlated with overall survival and positively correlated with mortality, including poorly differentiated type, the positivity of lymph node metastasis, the positivity of surrounding tissues and organs invasion, and advanced TNM stages (III or IV), which are risk factors and independent prognostic predictors (Tables 5 and 6).	('lymph node metastasis', 'CPA', (302, 323))	('poorly differentiated type', 'CPA', (256, 282))	('mortality', 'CPA', (235, 244))	('overall survival', 'CPA', (187, 203))	('TNM', 'Gene', '10178', (397, 400))	('Cox', 'Gene', '1351', (65, 68))	('Cox', 'Gene', (65, 68))	('correlated', 'Reg', (171, 181))	('negatively', 'NegReg', (160, 170))	('TNM', 'Gene', (397, 400))	('correlated', 'Reg', (219, 229))	('positivity', 'Var', (288, 298))
98282	32021438	Xuan found that the EphB3 expression level was negatively correlated to the depth of tumor invasion, lymph node metastasis, TNM stage and differentiation of colorectal cancer, and the overall survival of patients with high EphB3 expression is significantly longer than patients with negative or weak EphB3 expression.	('TNM', 'Gene', '10178', (124, 127))	('EphB3', 'Gene', '2049', (223, 228))	('TNM', 'Gene', (124, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (157, 174))	('patients', 'Species', '9606', (269, 277))	('patients', 'Species', '9606', (204, 212))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colorectal cancer', 'Disease', 'MESH:D015179', (157, 174))	('tumor invasion', 'Disease', (85, 99))	('longer', 'PosReg', (257, 263))	('EphB3', 'Gene', '2049', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('lymph node metastasis', 'CPA', (101, 122))	('EphB3', 'Gene', (223, 228))	('tumor invasion', 'Disease', 'MESH:D009361', (85, 99))	('colorectal cancer', 'Disease', (157, 174))	('EphB3', 'Gene', '2049', (20, 25))	('negatively', 'NegReg', (47, 57))	('high', 'Var', (218, 222))	('EphB3', 'Gene', (300, 305))	('EphB3', 'Gene', (20, 25))
98284	32021438	Similarly, our study found that positive rates of EphB3 expression were significantly higher in cases with well-differentiation, no surrounding tissues and organs invasion, no lymph node metastasis and early TNM stages (I + II), and the patients with positive EphB3 expression exhibited longer survival time than patients with negative EphB3 expression.	('TNM', 'Gene', (208, 211))	('EphB3', 'Gene', '2049', (50, 55))	('EphB3', 'Gene', '2049', (260, 265))	('positive', 'Var', (251, 259))	('EphB3', 'Gene', '2049', (336, 341))	('expression', 'Var', (266, 276))	('expression', 'MPA', (56, 66))	('TNM', 'Gene', '10178', (208, 211))	('well-differentiation', 'CPA', (107, 127))	('higher', 'PosReg', (86, 92))	('EphB3', 'Gene', (50, 55))	('EphB3', 'Gene', (260, 265))	('patients', 'Species', '9606', (237, 245))	('EphB3', 'Gene', (336, 341))	('patients', 'Species', '9606', (313, 321))	('longer', 'PosReg', (287, 293))	('survival time', 'CPA', (294, 307))
98302	32021438	The survival of patients with positive expression of EphB3 was significantly longer than patients with negative expression of EphB3, which was contrary to the relationship between dysadherin expression and patient survival.	('longer', 'PosReg', (77, 83))	('patient', 'Species', '9606', (89, 96))	('patient', 'Species', '9606', (206, 213))	('patients', 'Species', '9606', (16, 24))	('survival', 'CPA', (4, 12))	('EphB3', 'Gene', '2049', (126, 131))	('positive expression', 'Var', (30, 49))	('EphB3', 'Gene', (53, 58))	('dysadherin', 'Gene', '53827', (180, 190))	('patients', 'Species', '9606', (89, 97))	('dysadherin', 'Gene', (180, 190))	('EphB3', 'Gene', (126, 131))	('EphB3', 'Gene', '2049', (53, 58))	('patient', 'Species', '9606', (16, 23))
98361	31832586	In addition, the rate of T3-4 status (46 versus 26 5 per cent; P = 0 012) and extended hepatectomy (42 versus 22 2 per cent; P = 0 006) was significantly higher in patients with an R1-2 resection margin than in those with a clear margin.	('R1-2', 'Gene', '2840;910;913', (181, 185))	('R1-2', 'Gene', (181, 185))	('higher', 'PosReg', (154, 160))	('T3-4 status', 'Var', (25, 36))	('patients', 'Species', '9606', (164, 172))	('extended hepatectomy', 'Disease', (78, 98))
98397	31832586	Using SEER (Surveillance, Epidemiology and End Results) data, it has been shown22 that node positivity is associated with worse survival in patients with cholangiocarcinoma.	('worse', 'NegReg', (122, 127))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (154, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (154, 172))	('patients', 'Species', '9606', (140, 148))	('node positivity', 'Var', (87, 102))	('cholangiocarcinoma', 'Disease', (154, 172))
98408	29216833	Overall, NAFLD was associated with an increased risk for CCA, with pooled OR of 1.95 (95%CI: 1.36-2.79, I 2=76%).	('CCA', 'Phenotype', 'HP:0030153', (57, 60))	('NAFL', 'Chemical', '-', (9, 13))	('CCA', 'Disease', (57, 60))	('NAFLD', 'Var', (9, 14))
98409	29216833	When classified by subtypes, NAFLD was associated with both iCCA and eCCA, with ORs of 2.22 (95%CI: 1.52-3.24, I 2=67%) and 1.55 (95%CI: 1.03-2.33, I 2=69%), respectively.	('CCA', 'Phenotype', 'HP:0030153', (61, 64))	('NAFLD', 'Var', (29, 34))	('NAFL', 'Chemical', '-', (29, 33))	('eCCA', 'Disease', (69, 73))	('associated', 'Reg', (39, 49))	('CCA', 'Phenotype', 'HP:0030153', (70, 73))	('iCCA', 'Disease', (60, 64))
98410	29216833	This meta-analysis suggests that NAFLD may potentially increase the risk of CCA development.	('NAFLD', 'Var', (33, 38))	('NAFL', 'Chemical', '-', (33, 37))	('CCA', 'Phenotype', 'HP:0030153', (76, 79))	('CCA', 'Disease', (76, 79))
98420	29216833	Accumulating evidence suggested that NAFLD was associated with an increased risk of various cancers, including hepatocellular carcinoma (HCC), esophageal, gastric, colorectal, breast, and prostate cancer.	('HCC', 'Gene', (137, 140))	('NAFLD', 'Var', (37, 42))	('esophageal', 'Disease', (143, 153))	('colorectal', 'Disease', 'MESH:D015179', (164, 174))	('associated', 'Reg', (47, 57))	('hepatocellular carcinoma', 'Disease', (111, 135))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('NAFL', 'Chemical', '-', (37, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('breast', 'Disease', (176, 182))	('colorectal', 'Disease', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('prostate cancer', 'Disease', 'MESH:D011471', (188, 203))	('prostate cancer', 'Phenotype', 'HP:0012125', (188, 203))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (111, 135))	('gastric', 'Disease', (155, 162))	('prostate cancer', 'Disease', (188, 203))	('cancers', 'Disease', (92, 99))	('HCC', 'Gene', '619501', (137, 140))	('HCC', 'Phenotype', 'HP:0001402', (137, 140))
98421	29216833	Recent data suggested that NAFLD might increase the risk of CCA, particularly the iCCA subtype.	('iCCA', 'Disease', (82, 86))	('NAFLD', 'Var', (27, 32))	('CCA', 'Disease', (60, 63))	('CCA', 'Phenotype', 'HP:0030153', (83, 86))	('CCA', 'Phenotype', 'HP:0030153', (60, 63))	('NAFL', 'Chemical', '-', (27, 31))
98451	29216833	The present meta-analysis of seven case-control studies found that NAFLD was significantly associated with an increased risk of CCA for both iCCA and eCCA subtypes.	('CCA', 'Phenotype', 'HP:0030153', (151, 154))	('NAFLD', 'Var', (67, 72))	('CCA', 'Phenotype', 'HP:0030153', (142, 145))	('CCA', 'Phenotype', 'HP:0030153', (128, 131))	('NAFL', 'Chemical', '-', (67, 71))	('CCA', 'Disease', (128, 131))	('associated', 'Reg', (91, 101))
98452	29216833	Although the mechanism by which NAFLD causes CCA development has not yet been well studied, it is biologically plausible that NAFLD promotes cholangiocarcinogenesis directly through an induction of hepatic inflammation, or indirectly via cirrhosis.	('hepatic inflammation', 'Phenotype', 'HP:0012115', (198, 218))	('cirrhosis', 'Disease', 'MESH:D005355', (238, 247))	('carcinogenesis', 'Disease', 'MESH:D063646', (150, 164))	('carcinogenesis', 'Disease', (150, 164))	('CCA', 'Phenotype', 'HP:0030153', (45, 48))	('hepatic inflammation', 'Disease', (198, 218))	('cirrhosis', 'Disease', (238, 247))	('NAFL', 'Chemical', '-', (32, 36))	('NAFLD', 'Var', (126, 131))	('promotes', 'PosReg', (132, 140))	('hepatic inflammation', 'Disease', 'MESH:D007249', (198, 218))	('NAFL', 'Chemical', '-', (126, 130))	('cirrhosis', 'Phenotype', 'HP:0001394', (238, 247))
98543	26328266	Initial studies using western immunoblotting suggested that GP73 has high accuracy in detecting HCC, with better sensitivity, specificity and accuracy than AFP, and some ELISA based studies have been positive, however, in general, most studies using ELISA had negative results.	('AFP', 'Gene', '174', (156, 159))	('GP73', 'Var', (60, 64))	('HCC', 'Gene', (96, 99))	('HCC', 'Gene', '619501', (96, 99))	('HCC', 'Phenotype', 'HP:0001402', (96, 99))	('AFP', 'Gene', (156, 159))
98544	26328266	In addition to aiding in surveillance, GP73 has been evaluated as a biomarker for prognosis of patients with HCC.	('HCC', 'Gene', (109, 112))	('patients', 'Species', '9606', (95, 103))	('GP73', 'Var', (39, 43))	('HCC', 'Gene', '619501', (109, 112))	('HCC', 'Phenotype', 'HP:0001402', (109, 112))
98551	26328266	Recent data suggests that HCC patients with increased serum DKK1 may have poorer overall and relapse-free survival than patients with low DKK1.	('relapse-free survival', 'CPA', (93, 114))	('poorer', 'NegReg', (74, 80))	('DKK1', 'Gene', '22943', (60, 64))	('DKK1', 'Gene', (60, 64))	('HCC', 'Gene', '619501', (26, 29))	('overall', 'CPA', (81, 88))	('increased', 'PosReg', (44, 53))	('HCC', 'Phenotype', 'HP:0001402', (26, 29))	('DKK1', 'Gene', (138, 142))	('patients', 'Species', '9606', (30, 38))	('patients', 'Species', '9606', (120, 128))	('DKK1', 'Gene', '22943', (138, 142))	('serum', 'Var', (54, 59))	('increased serum DKK1', 'Phenotype', 'HP:0030269', (44, 64))	('HCC', 'Gene', (26, 29))
98590	26328266	Increasingly, biomarkers are providing clues to tumor heterogeneity and allowing individualization and personalization of therapy for CCA, such as by the identification of isocitrate dehydrogenase (IDH) 1 and 2 mutations and fibroblast growth factor receptor 2 (FGFR2) fusions .	('isocitrate dehydrogenase (IDH) 1 and 2', 'Gene', '3417;3418', (172, 210))	('tumor', 'Disease', (48, 53))	('CCA', 'Phenotype', 'HP:0030153', (134, 137))	('FGFR2', 'Gene', (262, 267))	('FGFR2', 'Gene', '2263', (262, 267))	('fibroblast growth factor receptor 2', 'Gene', '2263', (225, 260))	('mutations', 'Var', (211, 220))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('CCA', 'Disease', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('fusions', 'Var', (269, 276))	('fibroblast growth factor receptor 2', 'Gene', (225, 260))
98598	26328266	Moreover, it has been suggested that the serum CA19-9 is also effective for staging of disease since very high levels (CA19-9 > 1,000U/mL) may be associated with metastatic disease.	('CA19-9', 'Var', (119, 125))	('metastatic disease', 'CPA', (162, 180))	('associated with', 'Reg', (146, 161))	('CA19-9', 'Chemical', 'MESH:C086528', (47, 53))	('CA19-9', 'Chemical', 'MESH:C086528', (119, 125))
98603	26328266	CYFRA21-1 is a soluble serum fragment of cytokeratin 19, and a potential marker for detecting CCA via serum electrochemiluminiscent immunoassay (ECLIA).	('CCA', 'Disease', (94, 97))	('CCA', 'Phenotype', 'HP:0030153', (94, 97))	('cytokeratin 19', 'Gene', '3880', (41, 55))	('CYFRA21-1', 'Var', (0, 9))	('cytokeratin 19', 'Gene', (41, 55))
98604	26328266	A retrospective study comparing CYFRA21-1 to CEA and CA19-9 in patients with histologically confirmed bile tract cancers showed that CYFRA21-1 had better sensitivity and specificity for detecting iCCA than any of the other biomarkers.	('iCCA', 'Disease', (196, 200))	('CEA', 'Gene', '5670', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('CA19-9', 'Chemical', 'MESH:C086528', (53, 59))	('CCA', 'Phenotype', 'HP:0030153', (197, 200))	('patients', 'Species', '9606', (63, 71))	('bile tract cancers', 'Disease', (102, 120))	('CYFRA21-1', 'Var', (133, 142))	('CEA', 'Gene', (45, 48))	('bile tract cancers', 'Disease', 'MESH:D001650', (102, 120))
98605	26328266	Maximal Youden's indexes were used to determine the cutoff for each of the biomarkers studied (3.27 mg/mL, 76.53 U/mL and 2.70 U/mL for CYFRA21-1, CA19-9 and CEA respectively).	('CA19-9', 'Chemical', 'MESH:C086528', (147, 153))	('CEA', 'Gene', (158, 161))	('CA19-9', 'Var', (147, 153))	('CEA', 'Gene', '5670', (158, 161))	('CYFRA21-1', 'Var', (136, 145))
98606	26328266	In a prospective study of patients with PSC, CYFRA21-1 at a cutoff of 1.5 ng/mL was more specific than CA19-9.	('CA19-9', 'Chemical', 'MESH:C086528', (103, 109))	('PSC', 'Disease', (40, 43))	('CYFRA21-1', 'Var', (45, 54))	('PSC', 'Phenotype', 'HP:0030991', (40, 43))	('patients', 'Species', '9606', (26, 34))
98607	26328266	Moreover, CYFRA21-1 was an effective predictor of poor prognosis and recurrence after tumor resection.	('CYFRA21-1', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('poor prognosis', 'CPA', (50, 64))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('recurrence', 'CPA', (69, 79))
98612	26328266	Within patients with malignant disease, high levels of MUC5AC were also associated with poor prognosis.	('MUC5AC', 'Gene', (55, 61))	('malignant disease', 'Disease', 'MESH:D009369', (21, 38))	('MUC5AC', 'Gene', '4586', (55, 61))	('malignant disease', 'Disease', (21, 38))	('high levels', 'Var', (40, 51))	('patients', 'Species', '9606', (7, 15))
98620	26328266	In a meta-analysis of patients with PSC, FISH polysomy showed 51% sensitivity and 93% specificity.	('FISH polysomy', 'Var', (41, 54))	('patients', 'Species', '9606', (22, 30))	('PSC', 'Disease', (36, 39))	('PSC', 'Phenotype', 'HP:0030991', (36, 39))
98623	26328266	have shown that FISH is useful in identifying PSC patients with multifocal polysomy, a subgroup of patients who were more likely to develop CCA and thus could benefit from close surveillance.	('PSC', 'Disease', (46, 49))	('patients', 'Species', '9606', (50, 58))	('CCA', 'Phenotype', 'HP:0030153', (140, 143))	('PSC', 'Phenotype', 'HP:0030991', (46, 49))	('multifocal', 'Var', (64, 74))	('patients', 'Species', '9606', (99, 107))	('develop', 'PosReg', (132, 139))	('CCA', 'Disease', (140, 143))
98624	26328266	In a cohort of patients with PSC and equivocal biliary cytology (atypical or suspicious), patients with FISH polysomy were 76% more likely to develop a pancreaticobiliary tract malignancy within 2 years of cytology findings (P < 0.001).	('patients', 'Species', '9606', (15, 23))	('pancreaticobiliary tract malignancy', 'Disease', 'MESH:D000080222', (152, 187))	('PSC', 'Phenotype', 'HP:0030991', (29, 32))	('develop', 'PosReg', (142, 149))	('pancreaticobiliary tract malignancy', 'Disease', (152, 187))	('FISH polysomy', 'Var', (104, 117))	('patients', 'Species', '9606', (90, 98))
98626	26328266	Tetrasomy is typically associated with biliary stone disease and not with malignancy.	('malignancy', 'Disease', (74, 84))	('biliary stone disease', 'Disease', 'MESH:D002137', (39, 60))	('biliary stone disease', 'Disease', (39, 60))	('malignancy', 'Disease', 'MESH:D009369', (74, 84))	('Tetrasomy', 'Var', (0, 9))	('associated', 'Reg', (23, 33))	('biliary stone', 'Phenotype', 'HP:0000787', (39, 52))
98662	22068162	Furthermore, we demonstrate that PGRN has growth-promoting effects on cholangiocarcinoma via the Akt-dependent phosphorylation and nuclear extrusion of FOXO1, and that knocking down the expression of PGRN slows the growth of cholangiocarcinoma in vitro and in vivo.	('nuclear', 'CPA', (131, 138))	('PGRN', 'Gene', (200, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('knocking down', 'Var', (168, 181))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (225, 243))	('cholangiocarcinoma', 'Disease', (225, 243))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (225, 243))	('FOXO1', 'Gene', '2308', (152, 157))	('slows', 'NegReg', (205, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))	('growth', 'MPA', (215, 221))	('Akt', 'Gene', (97, 100))	('cholangiocarcinoma', 'Disease', (70, 88))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (70, 88))	('FOXO1', 'Gene', (152, 157))	('growth-promoting', 'MPA', (42, 58))	('Akt', 'Gene', '207', (97, 100))	('PGRN', 'Gene', (33, 37))
98672	22068162	For phospho-specific immunoblotting experiments, cells were treated with recombinant human IL-6 (rIL-6), in the presence or absence of ERK1/2 inhibitor, PD98059 (10 microM), or the RSK inhibitor, SL-0101-1 (0.2 microM) for the times indicated.	('rIL-6', 'Gene', (97, 102))	('RSK', 'Gene', '6195', (181, 184))	('ERK1/2', 'Protein', (135, 141))	('RSK', 'Gene', (181, 184))	('SL-0101-1', 'Chemical', '-', (196, 205))	('PD98059', 'Var', (153, 160))	('rIL-6', 'Gene', '24498', (97, 102))	('PD98059', 'Chemical', 'MESH:C093973', (153, 160))	('human', 'Species', '9606', (85, 90))
98714	22068162	There was a significant decrease in the expression of PCNA (a marker of proliferative capacity; figure 7A) and a decrease in cell proliferation (as assessed by cell number after 24 h; figure 7B) in the Mz-PGRN shRNA cells compared with the mock-transfected Mz-neo neg cell line or the parental Mz-ChA-1 cells, suggesting that PGRN exerts a growth-promoting effect on cholangiocarcinoma cells.	('expression', 'MPA', (40, 50))	('cholangiocarcinoma', 'Disease', (367, 385))	('decrease', 'NegReg', (113, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (376, 385))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (367, 385))	('PCNA', 'Gene', '5111', (54, 58))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (367, 385))	('decrease', 'NegReg', (24, 32))	('cell proliferation', 'CPA', (125, 143))	('Mz-PGRN', 'Var', (202, 209))	('PCNA', 'Gene', (54, 58))
98718	22068162	Furthermore, there were significantly fewer PCNA-positive nuclei in the tumours derived from the Mz-PGRN shRNA compared with the Mz-ChA-1-derived tumour (online supplemental figure S8A).	('PCNA', 'Gene', (44, 48))	('tumour', 'Disease', (146, 152))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('PCNA', 'Gene', '5111', (44, 48))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('tumours', 'Disease', (72, 79))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('tumour', 'Disease', (72, 78))	('Mz-PGRN', 'Var', (97, 104))	('fewer', 'NegReg', (38, 43))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
98725	22068162	The malignancy of highly tumorigenic PGRN-expressing cell lines depends on the expression level, since attenuating PGRN mRNA levels greatly inhibits tumour progression.	('malignancy', 'Disease', 'MESH:D009369', (4, 14))	('inhibits', 'NegReg', (140, 148))	('PGRN', 'Protein', (115, 119))	('malignancy', 'Disease', (4, 14))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('mRNA levels', 'MPA', (120, 131))	('tumour', 'Disease', (149, 155))	('attenuating', 'Var', (103, 114))
98740	22068162	Xu et al clearly demonstrated that liver-specific disruption of Smad4 and PTEN led to the development of cholangiocarcinoma, which was associated with increased pAkt.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (105, 123))	('disruption', 'Var', (50, 60))	('Akt', 'Gene', (162, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (105, 123))	('PTEN', 'Gene', (74, 78))	('Smad4', 'Gene', (64, 69))	('PTEN', 'Gene', '5728', (74, 78))	('cholangiocarcinoma', 'Disease', (105, 123))	('Smad4', 'Gene', '4089', (64, 69))	('Akt', 'Gene', '207', (162, 165))
98744	22068162	In this study, we show that a downstream target of Akt is FOXO1 and that phosphorylation of FOXO1 causes inactivation and nuclear extrusion of this protein in cholangiocarcinoma cells.	('nuclear extrusion', 'MPA', (122, 139))	('phosphorylation', 'Var', (73, 88))	('FOXO1', 'Gene', (92, 97))	('FOXO1', 'Gene', '2308', (92, 97))	('Akt', 'Gene', (51, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('FOXO1', 'Gene', '2308', (58, 63))	('inactivation', 'MPA', (105, 117))	('cholangiocarcinoma', 'Disease', (159, 177))	('Akt', 'Gene', '207', (51, 54))	('FOXO1', 'Gene', (58, 63))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (159, 177))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (159, 177))
98746	22068162	Overactivation of Akt and subsequent suppression of FOXO-mediated transcription has also been demonstrated in a number of other tumours.	('tumours', 'Disease', 'MESH:D009369', (128, 135))	('tumours', 'Disease', (128, 135))	('Akt', 'Gene', (18, 21))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('FOXO-mediated transcription', 'MPA', (52, 79))	('suppression', 'NegReg', (37, 48))	('Akt', 'Gene', '207', (18, 21))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('Overactivation', 'Var', (0, 14))
98756	22068162	Inhibition of progranulin function slows cholangiocarcinoma growth.	('progranulin', 'Gene', '2896', (14, 25))	('slows', 'NegReg', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('progranulin', 'Gene', (14, 25))	('Inhibition', 'Var', (0, 10))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (41, 59))	('cholangiocarcinoma growth', 'Disease', (41, 66))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (41, 66))
98768	25880914	Previous studies have shown that miRNAs are dysregulated in many cancers and the aberrantly expressed miRNAs might serve as diagnostic and prognostic biomarkers for various tumors.	('aberrantly', 'Var', (81, 91))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('tumors', 'Disease', (173, 179))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('cancers', 'Disease', (65, 72))
98805	25880914	Three miRNAs (miR-675-5p, miR-652-3p and miR-338-3p) were found to be significantly associated with OS (P < 0.05).	('miR-675-5p', 'Gene', (14, 24))	('miR-675-5p', 'Gene', '102465452', (14, 24))	('OS', 'Chemical', '-', (100, 102))	('miR-652-3p', 'Var', (26, 36))	('associated', 'Reg', (84, 94))	('miR-338', 'Gene', '442906', (41, 48))	('miR-338', 'Gene', (41, 48))
98806	25880914	Of the three miRNAs, miR-675-5p was up-regulated and negatively associated with OS (hazard ratio [HR]: 2.562, confidence interval [CI]: 1.295-4.929), while the other two (miR-652-3p and miR-338-3p) were down-regulated and positively associated with OS (HR: 0.477, CI: 0.247-0.922; HR: 0.498, CI: 0.257-0.966, respectively).	('miR-675-5p', 'Gene', '102465452', (21, 31))	('OS', 'Chemical', '-', (80, 82))	('miR-338', 'Gene', (186, 193))	('associated', 'Interaction', (64, 74))	('up-regulated', 'PosReg', (36, 48))	('miR-338', 'Gene', '442906', (186, 193))	('miR-652-3p', 'Var', (171, 181))	('negatively', 'NegReg', (53, 63))	('OS', 'Chemical', '-', (249, 251))	('miR-675-5p', 'Gene', (21, 31))
98808	25880914	Next, a previously developed strategy was used to establish a formula to calculate the risk score for every patient based on the expression level of the three miRNAs, weighted by regression coefficient: Risk Score = (0.93 x expression level of miR-675-5p) + (-0.726 x expression level of miR-652-3p) + (-0.688 x expression level of miR-338-3p).	('miR-675-5p', 'Gene', (244, 254))	('miR-675-5p', 'Gene', '102465452', (244, 254))	('0.93', 'Var', (217, 221))	('patient', 'Species', '9606', (108, 115))	('miR-652-3p) + (-0.688', 'Var', (288, 309))	('miR-338', 'Gene', '442906', (332, 339))	('miR-338', 'Gene', (332, 339))
98814	25880914	To confirm the miRNA expression level detected by the microarray, we carried out qRT-PCR for miR-675-5p, miR-652-3p, and miR-338-3p in ICC samples and NIBD tissues.	('miR-675-5p', 'Gene', (93, 103))	('miR-338', 'Gene', '442906', (121, 128))	('miR-338', 'Gene', (121, 128))	('miR-675-5p', 'Gene', '102465452', (93, 103))	('miR-652-3p', 'Var', (105, 115))
98815	25880914	The results showed that the expression levels of the three miRNAs detected by microarray significantly correlated with those measured by qRT-PCR (miR-675-5p, R = 0.566, P = 0.0012; miR-652-3p, R = 0.761, P < 0.0001; miR-338-3p, R = 0.623, P = 0.0009) (Figure 3).	('expression levels', 'MPA', (28, 45))	('miR-675-5p', 'Gene', (146, 156))	('miR-675-5p', 'Gene', '102465452', (146, 156))	('miR-652-3p', 'Var', (181, 191))	('miR-338', 'Gene', '442906', (216, 223))	('miR-338', 'Gene', (216, 223))
98827	25880914	Specifically, miR-338 and let-7a were consistently reduced in ICC in the two studies, while the miR-103 was up-regulated in Chen's study and downregulated in our study.	('miR-103', 'Var', (96, 103))	('reduced', 'NegReg', (51, 58))	('up-regulated', 'PosReg', (108, 120))	('let-7a', 'Gene', (26, 32))	('downregulated', 'NegReg', (141, 154))	('ICC', 'Disease', (62, 65))	('miR-338', 'Gene', '442906', (14, 21))	('miR-338', 'Gene', (14, 21))
98839	25880914	Considering that the three miRNAs (miR-675-5p, miR-652-3p and miR-338-3p) are highly dysregulated in ICC and other cancers, these miRNAs may play an important role in ICC carcinogenesis.	('miR-675-5p', 'Gene', (35, 45))	('ICC carcinogenesis', 'Disease', 'MESH:C566123', (167, 185))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('ICC', 'Disease', (101, 104))	('miR-675-5p', 'Gene', '102465452', (35, 45))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('ICC carcinogenesis', 'Disease', (167, 185))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('miR-652-3p', 'Var', (47, 57))	('miR-338', 'Gene', (62, 69))	('miR-338', 'Gene', '442906', (62, 69))
98840	25880914	Therefore, we are conducting further studies on the biological function and the regulation of miR-675-5p and miR-652-3p expression in ICC cells.	('miR-675-5p', 'Gene', (94, 104))	('miR-675-5p', 'Gene', '102465452', (94, 104))	('miR-652-3p', 'Var', (109, 119))
98842	25880914	Kaplan-Meier curve analysis also showed that patients with high-level AFP had much poorer survival than those with low-level AFP (P <0.05, data not shown).	('AFP', 'Gene', '174', (125, 128))	('survival', 'MPA', (90, 98))	('high-level', 'Var', (59, 69))	('AFP', 'Gene', '174', (70, 73))	('poorer', 'NegReg', (83, 89))	('patients', 'Species', '9606', (45, 53))	('AFP', 'Gene', (125, 128))	('AFP', 'Gene', (70, 73))
98857	20947473	Patients with pre operative serum levels of CA19-9 (> 1000 U/ml) and CEA (> 14.4 ng/ml) showed a significant poorer resectability rate and survival than patients with lower CA19-9 and CEA serum levels respectively.	('CEA', 'Gene', (69, 72))	('patients', 'Species', '9606', (153, 161))	('CEA', 'Gene', (184, 187))	('CA19-9', 'Var', (44, 50))	('CA19-9', 'Chemical', 'MESH:C086528', (173, 179))	('CEA', 'Gene', '1048', (184, 187))	('Patients', 'Species', '9606', (0, 8))	('CA19-9', 'Chemical', 'MESH:C086528', (44, 50))	('resectability rate', 'CPA', (116, 134))	('CEA', 'Gene', '1048', (69, 72))	('survival', 'CPA', (139, 147))	('poorer', 'NegReg', (109, 115))
98871	20947473	CA19-9 is a glycolipid synthesized by biliary duct, pancreatic, gastric, colonic, endometrial and salivary epithelial cells.	('pancreatic', 'Disease', (52, 62))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('colonic', 'Disease', 'MESH:D015179', (73, 80))	('colonic', 'Disease', (73, 80))	('CA19-9', 'Var', (0, 6))	('pancreatic', 'Disease', 'MESH:D010195', (52, 62))
98894	20947473	CA19-9 >= 37 U/ml and CEA >= 3.6 ng/ml were considered as elevated.	('CEA', 'Gene', (22, 25))	('CEA', 'Gene', '1048', (22, 25))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('CA19-9', 'Var', (0, 6))
98925	20947473	Furthermore we could demonstrate that the amount of CA19-9 and CEA has a significant correlation to the rate of irresectable tumor masses.	('CEA', 'Gene', (63, 66))	('CA19-9', 'Chemical', 'MESH:C086528', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('correlation', 'Reg', (85, 96))	('tumor', 'Disease', (125, 130))	('CA19-9', 'Var', (52, 58))	('CEA', 'Gene', '1048', (63, 66))
98931	20947473	Preoperatively obtained CA19-9 serum levels > 1000 U/ml and CEA serum levels > 14.4 ng/ml are associated with a nonresectability rate of 64% and 53% respectively in comparison to patients with lower preoperative CA19-9 and CEA serum levels respectively.	('CEA', 'Gene', (223, 226))	('nonresectability', 'CPA', (112, 128))	('CEA', 'Gene', (60, 63))	('CA19-9', 'Gene', (24, 30))	('CEA', 'Gene', '1048', (60, 63))	('patients', 'Species', '9606', (179, 187))	('CA19-9', 'Chemical', 'MESH:C086528', (24, 30))	('CEA', 'Gene', '1048', (223, 226))	('CA19-9', 'Chemical', 'MESH:C086528', (212, 218))	('> 1000 U/ml', 'Var', (44, 55))
98940	34007215	Circ_HIPK3 Knockdown Inhibits Cell Proliferation, Migration and Invasion of Cholangiocarcinoma Partly via Mediating the miR-148a-3p/ULK1 Pathway The incidence of cholangiocarcinoma (CCA) is on the rise in recent years, and its pathogenesis may be associated with the deregulation of circular RNAs (circRNAs).	('Invasion', 'CPA', (64, 72))	('CCA', 'Phenotype', 'HP:0030153', (182, 185))	('Cell Proliferation', 'CPA', (30, 48))	('Cholangiocarcinoma Partly', 'Disease', 'MESH:D018281', (76, 101))	('cholangiocarcinoma', 'Disease', (162, 180))	('ULK1', 'Gene', '8408', (132, 136))	('Knockdown', 'Var', (11, 20))	('Migration', 'CPA', (50, 59))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (76, 94))	('Inhibits', 'NegReg', (21, 29))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (162, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('Cholangiocarcinoma Partly', 'Disease', (76, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (162, 180))	('ULK1', 'Gene', (132, 136))
98948	34007215	In function, circ_HIPK3 knockdown inhibited CCA cell proliferation, migration and invasion and induced apoptosis and cycle arrest.	('arrest', 'Disease', (123, 129))	('induced', 'Reg', (95, 102))	('invasion', 'CPA', (82, 90))	('inhibited', 'NegReg', (34, 43))	('CCA', 'Disease', (44, 47))	('HIPK3', 'Gene', '10114', (18, 23))	('HIPK3', 'Gene', (18, 23))	('apoptosis', 'CPA', (103, 112))	('arrest', 'Disease', 'MESH:D006323', (123, 129))	('knockdown', 'Var', (24, 33))	('migration', 'CPA', (68, 77))	('CCA', 'Phenotype', 'HP:0030153', (44, 47))
98949	34007215	It was confirmed that miR-148a-3p was a target of circ_HIPK3, and ULK1 was a target of miR-148a-3p.	('ULK1', 'Gene', (66, 70))	('miR-148a-3p', 'Chemical', '-', (22, 33))	('miR-148a-3p', 'Var', (87, 98))	('ULK1', 'Gene', '8408', (66, 70))	('miR-148a-3p', 'Var', (22, 33))	('miR-148a-3p', 'Chemical', '-', (87, 98))	('HIPK3', 'Gene', '10114', (55, 60))	('HIPK3', 'Gene', (55, 60))
98950	34007215	Circ_HIPK3 regulated ULK1 expression by targeting miR-148a-3p.	('expression', 'MPA', (26, 36))	('HIPK3', 'Gene', '10114', (5, 10))	('miR-148a-3p', 'Chemical', '-', (50, 61))	('HIPK3', 'Gene', (5, 10))	('miR-148a-3p', 'Var', (50, 61))	('ULK1', 'Gene', (21, 25))	('ULK1', 'Gene', '8408', (21, 25))
98953	34007215	In vivo, circ_HIPK3 knockdown inhibited solid tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('inhibited', 'NegReg', (30, 39))	('tumor', 'Disease', (46, 51))	('HIPK3', 'Gene', '10114', (14, 19))	('HIPK3', 'Gene', (14, 19))	('knockdown', 'Var', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
98965	34007215	MiR-148a-3p was reported to be involved in CCA development, associated with the inhibition of DNA methyltransferase-1 (DNMT-1).	('DNA methyltransferase-1', 'Gene', '1786', (94, 117))	('MiR-148a-3p', 'Var', (0, 11))	('inhibition', 'NegReg', (80, 90))	('DNMT-1', 'Gene', '1786', (119, 125))	('involved', 'Reg', (31, 39))	('CCA', 'Disease', (43, 46))	('DNMT-1', 'Gene', (119, 125))	('MiR-148a-3p', 'Chemical', '-', (0, 11))	('DNA methyltransferase-1', 'Gene', (94, 117))	('CCA', 'Phenotype', 'HP:0030153', (43, 46))
98966	34007215	Interestingly, it is predicted that miR-148a-3p is a target of circ_HIPK3 by bioinformatics tool.	('miR-148a-3p', 'Var', (36, 47))	('miR-148a-3p', 'Chemical', '-', (36, 47))	('HIPK3', 'Gene', '10114', (68, 73))	('HIPK3', 'Gene', (68, 73))
98967	34007215	However, the interplay between miR-148a-3p and circ_HIPK3 in CCA is unclear.	('CCA', 'Phenotype', 'HP:0030153', (61, 64))	('CCA', 'Disease', (61, 64))	('miR-148a-3p', 'Chemical', '-', (31, 42))	('HIPK3', 'Gene', '10114', (52, 57))	('HIPK3', 'Gene', (52, 57))	('miR-148a-3p', 'Var', (31, 42))
98999	34007215	Then, the protein-stained membranes were probed with the primary antibodies, including anti-Snail (ab53519; Abcam, Cambridge, MA, USA), anti-E-cadherin (ab1416; Abcam), anti-ULK1 (ab179458; Abcam) and anti-GAPDH (ab8245; Abcam), followed by the incubation with the secondary antibody (ab205719; Abcam).	('Snail', 'Gene', (92, 97))	('ab179458', 'Var', (180, 188))	('ab8245', 'Var', (213, 219))	('E-cadherin', 'Gene', '999', (141, 151))	('GAPDH', 'Gene', '2597', (206, 211))	('GAPDH', 'Gene', (206, 211))	('Snail', 'Gene', '6615', (92, 97))	('ULK1', 'Gene', (174, 178))	('ULK1', 'Gene', '8408', (174, 178))	('E-cadherin', 'Gene', (141, 151))
99013	34007215	RBE and HCCC-9810 cells were treated with Actinomycin D for diverse time, and the data showed that Actinomycin D treatment significantly weakened the level of linear HIPK3 mRNA but hardly affected the level of circ_HIPK3 (Figure 1C and D), suggesting that circ_HIPK3 was far stable than linear molecules.	('level', 'MPA', (150, 155))	('HIPK3', 'Gene', '10114', (215, 220))	('HCC', 'Phenotype', 'HP:0001402', (8, 11))	('HIPK3', 'Gene', (215, 220))	('weakened', 'NegReg', (137, 145))	('HIPK3', 'Gene', '10114', (166, 171))	('HIPK3', 'Gene', '10114', (261, 266))	('Actinomycin D', 'Chemical', 'MESH:D003609', (99, 112))	('HIPK3', 'Gene', (261, 266))	('HCCC-9810', 'CellLine', 'CVCL:6908', (8, 17))	('Actinomycin', 'Var', (99, 110))	('HIPK3', 'Gene', (166, 171))	('Actinomycin D', 'Chemical', 'MESH:D003609', (42, 55))
99016	34007215	The expression of circ_HIPK3 was strikingly decreased in RBE and HCCC-9810 cells after si-circ_HIPK3 transfection compared to si-NC, while the expression of linear HIPK3 was not changed (Figure 2A and B).	('HIPK3', 'Gene', (23, 28))	('HCC', 'Phenotype', 'HP:0001402', (65, 68))	('HIPK3', 'Gene', '10114', (23, 28))	('HCCC-9810', 'CellLine', 'CVCL:6908', (65, 74))	('HIPK3', 'Gene', '10114', (95, 100))	('HIPK3', 'Gene', (95, 100))	('expression', 'MPA', (4, 14))	('HIPK3', 'Gene', '10114', (164, 169))	('HIPK3', 'Gene', (164, 169))	('transfection', 'Var', (101, 113))	('decreased', 'NegReg', (44, 53))
99017	34007215	MTT assay showed that circ_HIPK3 knockdown notably inhibited cell proliferation (Figure 2C and D).	('knockdown', 'Var', (33, 42))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('HIPK3', 'Gene', '10114', (27, 32))	('HIPK3', 'Gene', (27, 32))	('inhibited', 'NegReg', (51, 60))	('cell proliferation', 'CPA', (61, 79))
99018	34007215	Flow cytometry cell cycle assay introduced that circ_HIPK3 knockdown induced cell cycle arrest at the G0/G1 phase (Figure 2E and F).	('HIPK3', 'Gene', '10114', (53, 58))	('HIPK3', 'Gene', (53, 58))	('arrest', 'Disease', 'MESH:D006323', (88, 94))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (77, 94))	('arrest', 'Disease', (88, 94))	('knockdown', 'Var', (59, 68))
99019	34007215	Colony formation assay presented that circ_HIPK3 knockdown notably suppressed the capacity of colony formation in RBE and HCCC-9810 cells (Figure 2G).	('HCCC-9810', 'CellLine', 'CVCL:6908', (122, 131))	('knockdown', 'Var', (49, 58))	('HIPK3', 'Gene', '10114', (43, 48))	('HIPK3', 'Gene', (43, 48))	('HCC', 'Phenotype', 'HP:0001402', (122, 125))	('suppressed', 'NegReg', (67, 77))	('colony formation in', 'CPA', (94, 113))
99020	34007215	Flow cytometry cell apoptosis assay showed that circ_HIPK3 knockdown effectively induced RBE and HCCC-9810 cell apoptosis (Figure 2H).	('HIPK3', 'Gene', '10114', (53, 58))	('HCC', 'Phenotype', 'HP:0001402', (97, 100))	('HIPK3', 'Gene', (53, 58))	('induced', 'Reg', (81, 88))	('HCCC-9810', 'CellLine', 'CVCL:6908', (97, 106))	('knockdown', 'Var', (59, 68))
99021	34007215	Transwell assay clearly uncovered that circ_HIPK3 knockdown largely weakened the number of migrated and invaded cells (Figure 2I and J).	('HIPK3', 'Gene', '10114', (44, 49))	('knockdown', 'Var', (50, 59))	('HIPK3', 'Gene', (44, 49))	('weakened', 'NegReg', (68, 76))
99023	34007215	Herein, we monitored that circ_HIPK3 knockdown notably suppressed the level of Snail and thus promoted the level of E-cadherin in RBE and HCCC-9810 cells, also indicating that circ_HIPK3 knockdown blocked cell migration and invasion (Figure 2K and L).	('HIPK3', 'Gene', '10114', (31, 36))	('HCC', 'Phenotype', 'HP:0001402', (138, 141))	('blocked', 'NegReg', (197, 204))	('E-cadherin', 'Gene', (116, 126))	('knockdown', 'Var', (37, 46))	('E-cadherin', 'Gene', '999', (116, 126))	('Snail', 'Gene', (79, 84))	('HIPK3', 'Gene', '10114', (181, 186))	('Snail', 'Gene', '6615', (79, 84))	('invasion', 'CPA', (224, 232))	('level', 'MPA', (70, 75))	('suppressed', 'NegReg', (55, 65))	('cell migration', 'CPA', (205, 219))	('HIPK3', 'Gene', (181, 186))	('HCCC-9810', 'CellLine', 'CVCL:6908', (138, 147))	('HIPK3', 'Gene', (31, 36))	('promoted', 'PosReg', (94, 102))
99024	34007215	Overall, these data suggested that circ_HIPK3 knockdown inhibited CCA cell proliferation, migration and invasion.	('HIPK3', 'Gene', '10114', (40, 45))	('knockdown', 'Var', (46, 55))	('HIPK3', 'Gene', (40, 45))	('CCA', 'Phenotype', 'HP:0030153', (66, 69))	('invasion', 'CPA', (104, 112))	('inhibited', 'NegReg', (56, 65))	('CCA', 'Disease', (66, 69))
99027	34007215	The binding sites between miR-148a-3p and circ_HIPK3 were shown in Figure 3A.	('miR-148a-3p', 'Chemical', '-', (26, 37))	('binding', 'Interaction', (4, 11))	('HIPK3', 'Gene', '10114', (47, 52))	('HIPK3', 'Gene', (47, 52))	('miR-148a-3p', 'Var', (26, 37))
99028	34007215	Their relationship was further verified by dual-luciferase reporter assay because the cotransfection of miR-148a-3p and circ_HIPK3-WT reporter plasmid significantly decreased the luciferase activity in RBE and HCCC-9810 cells (Figure 3B and C).	('decreased', 'NegReg', (165, 174))	('activity', 'MPA', (190, 198))	('HCCC-9810', 'CellLine', 'CVCL:6908', (210, 219))	('miR-148a-3p', 'Chemical', '-', (104, 115))	('luciferase', 'Enzyme', (179, 189))	('HIPK3', 'Gene', (125, 130))	('HCC', 'Phenotype', 'HP:0001402', (210, 213))	('HIPK3', 'Gene', '10114', (125, 130))	('miR-148a-3p', 'Var', (104, 115))
99030	34007215	Moreover, the expression of miR-148a-3p was notably decreased in CCA cell lines (RBE and HCCC-9810) and tumor tissues (n=42) compared to non-cancer cell line (HIBEpiC) and normal tissues (n=42), respectively (Figure 3E and F).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('HIBEpiC', 'Disease', 'None', (159, 166))	('miR-148a-3p', 'Chemical', '-', (28, 39))	('HCCC-9810', 'CellLine', 'CVCL:6908', (89, 98))	('decreased', 'NegReg', (52, 61))	('cancer', 'Disease', (141, 147))	('tumor', 'Disease', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('CCA', 'Phenotype', 'HP:0030153', (65, 68))	('expression', 'MPA', (14, 24))	('HCC', 'Phenotype', 'HP:0001402', (89, 92))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('CCA', 'Disease', (65, 68))	('HIBEpiC', 'Disease', (159, 166))	('miR-148a-3p', 'Var', (28, 39))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
99032	34007215	We performed rescue experiments to explore whether circ_HIPK3 affected CCA cell behaviors by mediating miR-148a-3p.	('miR-148a-3p', 'Var', (103, 114))	('CCA', 'Disease', (71, 74))	('affected', 'Reg', (62, 70))	('HIPK3', 'Gene', '10114', (56, 61))	('HIPK3', 'Gene', (56, 61))	('CCA', 'Phenotype', 'HP:0030153', (71, 74))	('miR-148a-3p', 'Chemical', '-', (103, 114))
99033	34007215	The experimental cells were transfected with si-circ_HIPK3, si-NC, si-circ_HIPK3+anti-miR-148a-3p or si-circ_HIPK3+anti-miR-NC.	('HIPK3', 'Gene', '10114', (53, 58))	('HIPK3', 'Gene', (75, 80))	('HIPK3', 'Gene', (53, 58))	('si-NC', 'Var', (60, 65))	('HIPK3', 'Gene', '10114', (75, 80))	('miR', 'Gene', (120, 123))	('HIPK3', 'Gene', '10114', (109, 114))	('HIPK3', 'Gene', (109, 114))	('miR', 'Gene', (86, 89))	('miR-148a-3p', 'Chemical', '-', (86, 97))	('miR', 'Gene', '22877', (120, 123))	('miR', 'Gene', '22877', (86, 89))
99038	34007215	Flow cytometry cell apoptosis assay introduced that the apoptotic rate promoted by circ_HIPK3 knockdown alone was largely suppressed by the reintroduction of anti-miR-148a-3p (Figure 4G).	('knockdown', 'Var', (94, 103))	('HIPK3', 'Gene', (88, 93))	('HIPK3', 'Gene', '10114', (88, 93))	('suppressed', 'NegReg', (122, 132))	('apoptotic rate', 'CPA', (56, 70))	('anti-miR-148a-3p', 'Var', (158, 174))	('miR-148a-3p', 'Chemical', '-', (163, 174))
99040	34007215	Additionally, the level of Snail inhibited by circ_HIPK3 knockdown was recovered by the additional miR-148a-3p inhibition, while the level of E-cadherin reinforced by circ_HIPK3 knockdown was blocked by the additional miR-148a-3p inhibition (Figure 4J and K).	('E-cadherin', 'Gene', (142, 152))	('E-cadherin', 'Gene', '999', (142, 152))	('miR-148a-3p', 'Chemical', '-', (99, 110))	('miR-148a-3p', 'Chemical', '-', (218, 229))	('knockdown', 'Var', (57, 66))	('miR-148a-3p', 'Var', (99, 110))	('Snail', 'Gene', '6615', (27, 32))	('Snail', 'Gene', (27, 32))	('HIPK3', 'Gene', '10114', (172, 177))	('HIPK3', 'Gene', (172, 177))	('HIPK3', 'Gene', '10114', (51, 56))	('HIPK3', 'Gene', (51, 56))	('inhibited', 'NegReg', (33, 42))
99043	34007215	ULK1 was a putative target of miR-148a-3p, with special binding sites between its 3'UTR and miR-148a-3p sequence (Figure 5A).	('ULK1', 'Gene', '8408', (0, 4))	('miR-148a-3p', 'Chemical', '-', (30, 41))	('miR-148a-3p', 'Chemical', '-', (92, 103))	('miR-148a-3p', 'Var', (92, 103))	('binding', 'Interaction', (56, 63))	('ULK1', 'Gene', (0, 4))
99044	34007215	This relationship was validated by dual-luciferase reporter assay, and we found that the cotransfection of miR-148a-3p and ULK1-WT reporter plasmid notably diminished the luciferase activity in RBE and HCCC-9810 cells (Figure 5B and C).	('activity', 'MPA', (182, 190))	('diminished', 'NegReg', (156, 166))	('miR-148a-3p', 'Var', (107, 118))	('HCCC-9810', 'CellLine', 'CVCL:6908', (202, 211))	('luciferase', 'Enzyme', (171, 181))	('ULK1', 'Gene', (123, 127))	('ULK1', 'Gene', '8408', (123, 127))	('miR-148a-3p', 'Chemical', '-', (107, 118))	('HCC', 'Phenotype', 'HP:0001402', (202, 205))
99052	34007215	The expression of ULK1 was markedly depleted in RBE and HCCC-9810 cells transfected with miR-148a-3p but largely recovered in cells transfected with miR-148a-3p+ULK1 (Figure 6A and B).	('ULK1', 'Gene', (18, 22))	('depleted', 'NegReg', (36, 44))	('ULK1', 'Gene', '8408', (18, 22))	('HCC', 'Phenotype', 'HP:0001402', (56, 59))	('miR-148a-3p', 'Chemical', '-', (89, 100))	('expression', 'MPA', (4, 14))	('HCCC-9810', 'CellLine', 'CVCL:6908', (56, 65))	('miR-148a-3p', 'Var', (89, 100))	('ULK1', 'Gene', (161, 165))	('ULK1', 'Gene', '8408', (161, 165))	('miR-148a-3p', 'Chemical', '-', (149, 160))	('recovered', 'PosReg', (113, 122))
99053	34007215	MTT assay showed that cell proliferation was strikingly inhibited in cells transfected with miR-148a-3p alone but partly promoted in cells transfected with miR-148a-3p+ULK1 (Figure 6C and D).	('ULK1', 'Gene', (168, 172))	('ULK1', 'Gene', '8408', (168, 172))	('miR-148a-3p', 'Chemical', '-', (92, 103))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('miR-148a-3p', 'Var', (92, 103))	('inhibited', 'NegReg', (56, 65))	('promoted', 'PosReg', (121, 129))	('miR-148a-3p', 'Chemical', '-', (156, 167))	('cell proliferation', 'CPA', (22, 40))
99054	34007215	Flow cytometry cell cycle assay exhibited that miR-148a-3p enrichment significantly induced RBE and HCCC-9810 cell cycle arrest, while ULK1 reintroduction largely relieved cell cycle arrest (Figure 6E and F).	('arrest', 'Disease', 'MESH:D006323', (121, 127))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (172, 189))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (110, 127))	('ULK1', 'Gene', (135, 139))	('arrest', 'Disease', (121, 127))	('ULK1', 'Gene', '8408', (135, 139))	('HCCC-9810', 'Gene', (100, 109))	('miR-148a-3p', 'Chemical', '-', (47, 58))	('arrest', 'Disease', 'MESH:D006323', (183, 189))	('RBE', 'CPA', (92, 95))	('miR-148a-3p', 'Var', (47, 58))	('HCCC-9810', 'CellLine', 'CVCL:6908', (100, 109))	('induced', 'PosReg', (84, 91))	('arrest', 'Disease', (183, 189))	('HCC', 'Phenotype', 'HP:0001402', (100, 103))
99055	34007215	Colony formation assay showed that miR-148a-3p notably frustrated colony formation ability, while ULK1 reintroduction recovered colony formation ability (Figure 6G).	('miR-148a-3p', 'Var', (35, 46))	('colony', 'MPA', (128, 134))	('ULK1', 'Gene', (98, 102))	('colony formation ability', 'CPA', (66, 90))	('miR-148a-3p', 'Chemical', '-', (35, 46))	('ULK1', 'Gene', '8408', (98, 102))	('frustrated', 'NegReg', (55, 65))
99056	34007215	Flow cytometry cell apoptosis assay revealed that the apoptotic rate of RBE and HCCC-9810 cells induced by miR-148a-3p enrichment was suppressed by the reintroduction of ULK1 (Figure 6H).	('suppressed', 'NegReg', (134, 144))	('ULK1', 'Gene', (170, 174))	('HCC', 'Phenotype', 'HP:0001402', (80, 83))	('ULK1', 'Gene', '8408', (170, 174))	('HCCC-9810', 'CellLine', 'CVCL:6908', (80, 89))	('apoptotic rate', 'CPA', (54, 68))	('miR-148a-3p', 'Chemical', '-', (107, 118))	('miR-148a-3p enrichment', 'Var', (107, 129))
99057	34007215	Transwell assay showed that cell migration and invasion were significantly blocked in RBE and HCCC-9810 cells transfected with miR-148a-3p but notably recovered in cells transfected with miR-148a-3p+ULK1 (Figure 6I and J).	('HCC', 'Phenotype', 'HP:0001402', (94, 97))	('blocked', 'NegReg', (75, 82))	('miR-148a-3p', 'Chemical', '-', (127, 138))	('HCCC-9810', 'CellLine', 'CVCL:6908', (94, 103))	('miR-148a-3p', 'Var', (127, 138))	('ULK1', 'Gene', (199, 203))	('ULK1', 'Gene', '8408', (199, 203))	('miR-148a-3p', 'Chemical', '-', (187, 198))
99058	34007215	In addition, the level of Snail was inhibited by miR-148a-3p transfection alone but recovered by miR-148a-3p+ULK1 transfection, while the level of E-cadherin was stimulated by miR-148a-3p transfection alone but repressed by miR-148a-3p+ULK1 transfection in RBE and HCCC-9810 cells (Figure 6K and L).	('HCC', 'Phenotype', 'HP:0001402', (265, 268))	('Snail', 'Gene', (26, 31))	('inhibited', 'NegReg', (36, 45))	('Snail', 'Gene', '6615', (26, 31))	('ULK1', 'Gene', (109, 113))	('ULK1', 'Gene', (236, 240))	('HCCC-9810', 'CellLine', 'CVCL:6908', (265, 274))	('ULK1', 'Gene', '8408', (109, 113))	('E-cadherin', 'Gene', (147, 157))	('miR-148a-3p', 'Chemical', '-', (224, 235))	('miR-148a-3p', 'Chemical', '-', (49, 60))	('transfection', 'Var', (114, 126))	('miR-148a-3p transfection', 'Var', (49, 73))	('ULK1', 'Gene', '8408', (236, 240))	('E-cadherin', 'Gene', '999', (147, 157))	('miR-148a-3p', 'Chemical', '-', (97, 108))	('miR-148a-3p', 'Chemical', '-', (176, 187))
99067	34007215	The data suggested that circ_HIPK3 knockdown inhibited tumor growth by suppressing ULK1 level via enriching miR-148a-3p level.	('HIPK3', 'Gene', (29, 34))	('knockdown', 'Var', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('ULK1', 'Gene', '8408', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('HIPK3', 'Gene', '10114', (29, 34))	('tumor', 'Disease', (55, 60))	('miR-148a-3p level', 'MPA', (108, 125))	('enriching', 'PosReg', (98, 107))	('inhibited', 'NegReg', (45, 54))	('ULK1', 'Gene', (83, 87))	('miR-148a-3p', 'Chemical', '-', (108, 119))	('suppressing', 'NegReg', (71, 82))
99069	34007215	We used siRNA to mediate circ_HIPK3 knockdown to explore the functional role of circ_HIPK3 and found that circ_HIPK3 knockdown inhibited CCA cell proliferation, migration and invasion.	('CCA', 'Phenotype', 'HP:0030153', (137, 140))	('HIPK3', 'Gene', '10114', (30, 35))	('HIPK3', 'Gene', (30, 35))	('HIPK3', 'Gene', '10114', (85, 90))	('invasion', 'CPA', (175, 183))	('inhibited', 'NegReg', (127, 136))	('HIPK3', 'Gene', (85, 90))	('CCA', 'Disease', (137, 140))	('migration', 'CPA', (161, 170))	('HIPK3', 'Gene', '10114', (111, 116))	('knockdown', 'Var', (117, 126))	('HIPK3', 'Gene', (111, 116))
99070	34007215	For mechanism analysis, miR-148a-3p was discovered to be a target of circ_HIPK3, and ULK1 was a target of miR-148a-3p.	('HIPK3', 'Gene', '10114', (74, 79))	('HIPK3', 'Gene', (74, 79))	('miR-148a-3p', 'Chemical', '-', (106, 117))	('ULK1', 'Gene', '8408', (85, 89))	('ULK1', 'Gene', (85, 89))	('miR-148a-3p', 'Chemical', '-', (24, 35))	('miR-148a-3p', 'Var', (106, 117))	('miR-148a-3p', 'Gene', (24, 35))
99074	34007215	Circ_0000284 (circ_HIPK3) is a splicing variant of HIPK3 mRNA, with multiple biological functions in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('HIPK3', 'Gene', '10114', (19, 24))	('HIPK3', 'Gene', (19, 24))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Circ_0000284', 'Var', (0, 12))	('HIPK3', 'Gene', '10114', (51, 56))	('HIPK3', 'Gene', (51, 56))
99076	34007215	reported that circ_HIPK3 expression was increased in CCA cell lines, tissues and plasma exosomes, and forced expression of circ_0000284 promoted the abilities of CCA cell proliferation, migration and invasion.	('invasion', 'CPA', (200, 208))	('HIPK3', 'Gene', '10114', (19, 24))	('HIPK3', 'Gene', (19, 24))	('CCA', 'Disease', (162, 165))	('expression', 'MPA', (25, 35))	('migration', 'CPA', (186, 195))	('promoted', 'PosReg', (136, 144))	('CCA', 'Phenotype', 'HP:0030153', (162, 165))	('increased', 'PosReg', (40, 49))	('circ_0000284', 'Var', (123, 135))	('CCA', 'Phenotype', 'HP:0030153', (53, 56))
99078	34007215	Largely consistent with these findings, we performed MTT assay and colony formation assay and found that circ_HIPK3 knockdown inhibited CCA cell proliferation and colony formation ability.	('MTT', 'Chemical', 'MESH:C070243', (53, 56))	('CCA', 'Phenotype', 'HP:0030153', (136, 139))	('inhibited', 'NegReg', (126, 135))	('knockdown', 'Var', (116, 125))	('colony formation ability', 'CPA', (163, 187))	('CCA', 'Disease', (136, 139))	('HIPK3', 'Gene', '10114', (110, 115))	('HIPK3', 'Gene', (110, 115))
99079	34007215	Flow cytometry assay showed that circ_HIPK3 knockdown promoted CCA cell cycle arrest and apoptosis.	('arrest', 'Disease', (78, 84))	('promoted', 'PosReg', (54, 62))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (67, 84))	('CCA', 'Phenotype', 'HP:0030153', (63, 66))	('apoptosis', 'CPA', (89, 98))	('HIPK3', 'Gene', '10114', (38, 43))	('HIPK3', 'Gene', (38, 43))	('arrest', 'Disease', 'MESH:D006323', (78, 84))	('knockdown', 'Var', (44, 53))	('CCA', 'Disease', (63, 66))
99081	34007215	These assays highlighted that circ_HIPK3 knockdown inhibited CCA cell growth and metastasis.	('CCA', 'Phenotype', 'HP:0030153', (61, 64))	('HIPK3', 'Gene', '10114', (35, 40))	('CCA', 'Disease', (61, 64))	('inhibited', 'NegReg', (51, 60))	('knockdown', 'Var', (41, 50))	('HIPK3', 'Gene', (35, 40))
99084	34007215	As a result, miR-148a-3p was a putative target of circ_HIPK3 by bioinformatics analysis, which was further verified by dual-luciferase reporter assay.	('HIPK3', 'Gene', '10114', (55, 60))	('miR-148a-3p', 'Var', (13, 24))	('HIPK3', 'Gene', (55, 60))	('miR-148a-3p', 'Chemical', '-', (13, 24))
99085	34007215	Overall the previous studies, miR-148a-3p functioned as a tumor suppressor and blocked the development of numerous cancers, such as bladder cancer and ovarian cancer.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (151, 165))	('tumor', 'Disease', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('numerous cancers', 'Disease', 'MESH:D009369', (106, 122))	('miR-148a-3p', 'Var', (30, 41))	('ovarian cancer', 'Disease', 'MESH:D010051', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('development', 'CPA', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('bladder cancer', 'Disease', 'MESH:D001749', (132, 146))	('bladder cancer', 'Disease', (132, 146))	('miR-148a-3p', 'Chemical', '-', (30, 41))	('numerous cancers', 'Disease', (106, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (132, 146))	('blocked', 'NegReg', (79, 86))	('ovarian cancer', 'Disease', (151, 165))
99087	34007215	Consistent with the idea from these studies, we noticed that miR-148a-3p expression was declined in CCA tissues and cells.	('miR-148a-3p', 'Chemical', '-', (61, 72))	('miR-148a-3p', 'Var', (61, 72))	('CCA', 'Phenotype', 'HP:0030153', (100, 103))	('declined', 'NegReg', (88, 96))	('CCA', 'Disease', (100, 103))
99089	34007215	Previous studies have elucidated that miR-148a-3p participates in cancer processes partly by mediating its target genes.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('participates', 'Reg', (50, 62))	('miR-148a-3p', 'Chemical', '-', (38, 49))	('miR-148a-3p', 'Var', (38, 49))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
99091	34007215	Herein, we proposed that ULK1 was a novel target of miR-148a-3p, which was validated by dual-luciferase reporter assay.	('miR-148a-3p', 'Var', (52, 63))	('ULK1', 'Gene', '8408', (25, 29))	('miR-148a-3p', 'Chemical', '-', (52, 63))	('ULK1', 'Gene', (25, 29))
99101	34007215	Circ_HIPK3 knockdown suppresses cholangiocarcinoma growth and tumorigenesis in vitro and in vivo.	('HIPK3', 'Gene', '10114', (5, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('HIPK3', 'Gene', (5, 10))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (32, 50))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('cholangiocarcinoma growth', 'Disease', (32, 57))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (32, 57))	('suppresses', 'NegReg', (21, 31))	('knockdown', 'Var', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
99102	34007215	Circ_HIPK3 regulates ULK1 expression by targeting miR-148a-3p.	('expression', 'MPA', (26, 36))	('HIPK3', 'Gene', '10114', (5, 10))	('miR-148a-3p', 'Chemical', '-', (50, 61))	('HIPK3', 'Gene', (5, 10))	('targeting', 'Reg', (40, 49))	('miR-148a-3p', 'Var', (50, 61))	('ULK1', 'Gene', (21, 25))	('ULK1', 'Gene', '8408', (21, 25))
99120	32843603	Two separate hepaticojejunostomies were done to the B5+B8 and B67 at the right half and one hepaticojejunostomy was done to the B2+3 at the left half.	('B5+B8', 'Gene', (52, 57))	('B5+B8', 'Gene', '122876', (52, 57))	('B67', 'Var', (62, 65))
99241	31715693	Alveolar echinococcosis (AE) caused by E. multilocularis, which mainly occurs in the liver, is the most harmful echinococcosis in human.	('echinococcosis', 'Disease', (9, 23))	('E. multilocularis', 'Species', '6211', (39, 56))	('echinococcosis', 'Disease', 'MESH:D004443', (9, 23))	('caused', 'Reg', (29, 35))	('echinococcosis', 'Disease', 'MESH:D004443', (112, 126))	('AE', 'Disease', 'MESH:C536591', (25, 27))	('Alveolar echinococcosis', 'Disease', 'MESH:C536591', (0, 23))	('E. multilocularis', 'Var', (39, 56))	('Alveolar echinococcosis', 'Disease', (0, 23))	('echinococcosis', 'Disease', (112, 126))	('human', 'Species', '9606', (130, 135))
99316	28706774	CD14 is known to be a key mediator of the innate immune system, and its common genetic variant has been associated with the development of both alcoholic liver disease and non-alcoholic steatohepatitis.	('CD14', 'Gene', (0, 4))	('non-alcoholic steatohepatitis', 'Disease', 'MESH:D005234', (172, 201))	('alcoholic liver disease', 'Disease', 'MESH:D008108', (144, 167))	('associated with', 'Reg', (104, 119))	('alcoholic liver disease', 'Disease', (144, 167))	('CD14', 'Gene', '929', (0, 4))	('liver disease', 'Phenotype', 'HP:0001392', (154, 167))	('non-alcoholic steatohepatitis', 'Disease', (172, 201))	('variant', 'Var', (87, 94))
99317	28706774	The variant CD14-260C>T polymorphism was associated with the development of DS and an increased risk of cholangitis.	('associated with', 'Reg', (41, 56))	('CD14-260C>T', 'Var', (12, 23))	('cholangitis', 'Phenotype', 'HP:0030151', (104, 115))	('cholangitis', 'Disease', (104, 115))	('DS', 'Chemical', '-', (76, 78))	('cholangitis', 'Disease', 'MESH:D002761', (104, 115))
99318	28706774	The importance of genetic factors in the development of DS in PSC was further emphasised by a recent genome-wide association study which identified the FUT2 secretor status and genotype, the single-nucleotide polymorphism rs601338, as a potential genetic risk factor in PSC, which significantly influences biliary bacterial composition.	('PSC', 'Gene', (270, 273))	('PSC', 'Gene', '100653366', (62, 65))	('rs601338', 'Mutation', 'rs601338', (222, 230))	('rs601338', 'Var', (222, 230))	('PSC', 'Gene', (62, 65))	('FUT2', 'Gene', (152, 156))	('single-nucleotide polymorphism', 'Var', (191, 221))	('FUT2', 'Gene', '2524', (152, 156))	('biliary bacterial composition', 'MPA', (306, 335))	('DS', 'Chemical', '-', (56, 58))	('PSC', 'Gene', '100653366', (270, 273))	('influences', 'Reg', (295, 305))
99319	28706774	Presence of this genotype in PSC has been strongly associated with episodes of cholangitis, fungobilia and the incidence of dominant stenosis .	('PSC', 'Gene', (29, 32))	('cholangitis, fungobilia', 'Disease', 'MESH:D002761', (79, 102))	('dominant stenosis', 'Disease', (124, 141))	('episodes', 'Disease', (67, 75))	('associated', 'Reg', (51, 61))	('cholangitis', 'Phenotype', 'HP:0030151', (79, 90))	('PSC', 'Gene', '100653366', (29, 32))	('Presence', 'Var', (0, 8))	('dominant stenosis', 'Disease', 'MESH:D003251', (124, 141))
99325	28706774	These findings have been confirmed from a German study, namely that the presence of DS in PSC is associated with a worse prognosis and an increased risk of carcinomas both in the bile duct and colon.	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('presence', 'Var', (72, 80))	('carcinomas', 'Disease', 'MESH:D002277', (156, 166))	('PSC', 'Gene', '100653366', (90, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (156, 166))	('DS', 'Chemical', '-', (84, 86))	('carcinomas', 'Disease', (156, 166))	('PSC', 'Gene', (90, 93))
99346	28706774	Moreover, approximately 7% of the population are unable to express CA 19-9 due to genetic variation in the FUT3 gene .	('genetic variation', 'Var', (82, 99))	('FUT3', 'Gene', '2525', (107, 111))	('FUT3', 'Gene', (107, 111))
99353	28706774	Chromosomal polysomy detected by FISH has been shown to identify patients with early cholangiocarcinoma or those patients with a high risk of developing cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (153, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (85, 103))	('patients', 'Species', '9606', (113, 121))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('cholangiocarcinoma', 'Disease', (153, 171))	('patients', 'Species', '9606', (65, 73))	('Chromosomal polysomy', 'Var', (0, 20))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (153, 171))	('cholangiocarcinoma', 'Disease', (85, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
99426	26523273	Loss of heterozygosity imprinting at locus 11p 15.5, nuclear p53 accumulation and p53 mutation are other suggested pathogenesis of the malignancy.	('accumulation', 'PosReg', (65, 77))	('malignancy', 'Disease', 'MESH:D009369', (135, 145))	('Loss', 'NegReg', (0, 4))	('malignancy', 'Disease', (135, 145))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (82, 85))	('mutation', 'Var', (86, 94))	('p53', 'Gene', '7157', (82, 85))	('p53', 'Gene', (61, 64))	('nuclear', 'MPA', (53, 60))
99427	26523273	High expression of polo-like kinase 1 may be related to poorer outcome, but need to get more research outcome.	('polo-like kinase 1', 'Gene', (19, 37))	('polo-like kinase 1', 'Gene', '5347', (19, 37))	('High', 'Var', (0, 4))
99443	26523273	There was also showed that aberrant nuclear immunostaining for beta-catenin is a highly characteristic feature.	('beta-catenin', 'Gene', (63, 75))	('aberrant nuclear', 'Var', (27, 43))	('beta-catenin', 'Gene', '1499', (63, 75))
99451	26523273	But, our case showed that survival time was extended 12 months after the cisplatin, 5-FU, vincristine of 3 cycles chemotherapy and carboplatin, doxofubicin of 4 cycles chemotherapy.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('survival time', 'CPA', (26, 39))	('extended', 'PosReg', (44, 52))	('cisplatin', 'Var', (73, 82))	('vincristine', 'Chemical', 'MESH:D014750', (90, 101))	('doxofubicin', 'Chemical', '-', (144, 155))	('carboplatin', 'Chemical', 'MESH:D016190', (131, 142))	('5-FU', 'Chemical', 'MESH:D005472', (84, 88))
99579	33786118	In the present study, 15.7% of patients converted from laparoscopy to laparotomy due to accidental severe bleeding, anatomical variation and tumors invading the proximal trunk of the portal vein, which is similar to the result for LPD (17.3%) in its infancy.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('anatomical variation', 'Var', (116, 136))	('bleeding', 'Disease', 'MESH:D006470', (106, 114))	('LPD', 'Disease', (231, 234))	('patients', 'Species', '9606', (31, 39))	('bleeding', 'Disease', (106, 114))	('LPD', 'Disease', 'None', (231, 234))
99735	32901457	Previous studies have used various combinations of characteristics such as a short diameter of 1 cm, abnormal round morphology, heterogeneous enhancement, or central necrosis to diagnose LN metastasis.	('diagnose', 'Reg', (178, 186))	('heterogeneous enhancement', 'MPA', (128, 153))	('LN metastasis', 'Disease', (187, 200))	('necrosis', 'Disease', (166, 174))	('abnormal', 'Var', (101, 109))	('necrosis', 'Disease', 'MESH:D009336', (166, 174))
99737	32901457	In terms of LN size, a cutoff of 1 cm for the short diameter is the diagnostic criterion for LN metastasis for other malignancies; metastatic LNs are significantly larger than their non-metastatic counterparts.	('malignancies', 'Disease', (117, 129))	('metastatic', 'Var', (131, 141))	('malignancies', 'Disease', 'MESH:D009369', (117, 129))
99740	32901457	Although imaging studies do not show enough accuracy to assess LN metastasis, LNs greater than 1 cm along the short axis with abnormal round morphology, heterogeneous enhancement, or central necrosis are more likely to be metastatic.	('heterogeneous enhancement', 'MPA', (153, 178))	('LNs', 'Var', (78, 81))	('necrosis', 'Disease', (191, 199))	('metastatic', 'CPA', (222, 232))	('necrosis', 'Disease', 'MESH:D009336', (191, 199))
99744	32901457	The findings from previous studies suggest that patchy parenchymal enhancement, arterial rim enhancement persistent through portal venous phase and perilesional hyperemia on CT and MR, and size discrepancy between T1WI and T2WI as well as T1WI and the hepatobiliary phase on MR are indicative of biliary abscess rather than liver metastasis.	('perilesional hyperemia', 'Disease', (148, 170))	('biliary abscess', 'Disease', (296, 311))	('arterial rim', 'CPA', (80, 92))	('enhancement', 'PosReg', (93, 104))	('enhancement', 'PosReg', (67, 78))	('T1WI', 'Var', (214, 218))	('abscess', 'Phenotype', 'HP:0025615', (304, 311))	('T1WI', 'Var', (239, 243))	('perilesional hyperemia', 'Disease', 'MESH:D006940', (148, 170))
99748	32901457	In a meta-analysis of peritoneal metastases in all cancers, 18F-FDG PET-CT demonstrated good sensitivity (87%) and specificity (92%) for the detection of peritoneal metastasis.	('18F-FDG', 'Chemical', 'MESH:D019788', (60, 67))	('metastases', 'Disease', (33, 43))	('peritoneal', 'Disease', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('18F-FDG', 'Var', (60, 67))	('metastases', 'Disease', 'MESH:D009362', (33, 43))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
99823	31222125	Methylation and transcription patterns are distinct in IDH mutant gliomas compared to other IDH mutant cancers Mutations in isocitrate dehydrogenases 1 and 2 (IDHmut) are present in a variety of cancers, including glioma, acute myeloid leukemia (AML), melanoma, and cholangiocarcinoma.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('isocitrate dehydrogenase', 'Gene', '3417', (124, 148))	('IDH', 'Gene', (159, 162))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (266, 284))	('acute myeloid leukemia', 'Disease', (222, 244))	('mutant', 'Var', (59, 65))	('melanoma', 'Disease', 'MESH:D008545', (252, 260))	('cholangiocarcinoma', 'Disease', (266, 284))	('gliomas', 'Disease', (66, 73))	('glioma', 'Disease', (66, 72))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (266, 284))	('AML', 'Disease', 'MESH:D015470', (246, 249))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('IDH', 'Gene', (55, 58))	('IDH', 'Gene', '3417', (159, 162))	('AML', 'Phenotype', 'HP:0004808', (246, 249))	('AML', 'Disease', (246, 249))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (222, 244))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('isocitrate dehydrogenase', 'Gene', (124, 148))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('Mutations', 'Var', (111, 120))	('cancers', 'Disease', (103, 110))	('leukemia', 'Phenotype', 'HP:0001909', (236, 244))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (222, 244))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (228, 244))	('glioma', 'Disease', (214, 220))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('melanoma', 'Disease', (252, 260))	('IDH', 'Gene', '3417', (55, 58))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))	('IDH', 'Gene', (92, 95))	('glioma', 'Disease', 'MESH:D005910', (214, 220))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('present', 'Reg', (171, 178))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancers', 'Disease', (195, 202))	('IDH', 'Gene', '3417', (92, 95))
99824	31222125	These mutations promote hypermethylation, yet it is only a favorable prognostic marker in glioma, for reasons that are unclear.	('glioma', 'Disease', (90, 96))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('hypermethylation', 'MPA', (24, 40))	('promote', 'Reg', (16, 23))	('mutations', 'Var', (6, 15))
99826	31222125	Using Illumina 450K and RNA-Seq data from The Cancer Genome Atlas, we show that of 365,092 analyzed CpG sites, 70,591 (19%) were hypermethylated in IDHmut gliomas compared to wild-type (IDHwt) gliomas, and only 3%, 2%, and 4% of CpG sites were hypermethylated in IDHmut AML, melanoma, and cholangiocarcinoma, relative to each of their IDHwt counterparts.	('gliomas', 'Disease', 'MESH:D005910', (155, 162))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (289, 307))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (46, 65))	('gliomas', 'Disease', (193, 200))	('AML', 'Disease', 'MESH:D015470', (270, 273))	('hypermethylated', 'Var', (129, 144))	('gliomas', 'Disease', (155, 162))	('cholangiocarcinoma', 'Disease', (289, 307))	('AML', 'Phenotype', 'HP:0004808', (270, 273))	('AML', 'Disease', (270, 273))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (289, 307))	('melanoma', 'Phenotype', 'HP:0002861', (275, 283))	('Cancer Genome Atlas', 'Disease', (46, 65))	('melanoma', 'Disease', (275, 283))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('gliomas', 'Disease', 'MESH:D005910', (193, 200))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('Cancer', 'Phenotype', 'HP:0002664', (46, 52))	('gliomas', 'Phenotype', 'HP:0009733', (193, 200))	('melanoma', 'Disease', 'MESH:D008545', (275, 283))
99830	31222125	In addition to regulating the development of distinct cell lineages, epigenetic modifications can also promote malignant transformation and cancer progression.	('malignant transformation', 'CPA', (111, 135))	('cancer', 'Disease', (140, 146))	('development of distinct cell lineages', 'CPA', (30, 67))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('epigenetic modifications', 'Var', (69, 93))	('promote', 'PosReg', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('regulating', 'Reg', (15, 25))
99832	31222125	The mechanisms by which aberrant methylation occurs, and its consequences in cancer, are becoming better understood.	('methylation', 'Var', (33, 44))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('aberrant methylation', 'Var', (24, 44))
99833	31222125	One such mechanism involves point mutations in isocitrate dehydrogenases 1 and 2 (collectively "IDHmut").	('isocitrate dehydrogenase', 'Gene', (47, 71))	('isocitrate dehydrogenase', 'Gene', '3417', (47, 71))	('point mutations', 'Var', (28, 43))
99834	31222125	These metabolic enzymes normally convert isocitrate into alpha-ketoglutarate, but mutations in key arginine residues that normally bind isocitrate substrate cause a radical change in enzymatic activity, wherein mutant enzyme converts alpha-ketoglutarate into D-2-hydroxyglutarate (D2HG).	('isocitrate', 'Chemical', 'MESH:C034219', (136, 146))	('isocitrate', 'Chemical', 'MESH:C034219', (41, 51))	('converts alpha-ketoglutarate', 'MPA', (225, 253))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (57, 76))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (259, 279))	('arginine', 'Chemical', 'MESH:D001120', (99, 107))	('enzymatic activity', 'MPA', (183, 201))	('mutations', 'Var', (82, 91))	('mutant', 'Var', (211, 217))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (234, 253))	('arginine', 'Gene', (99, 107))	('change', 'Reg', (173, 179))
99835	31222125	D2HG then acts as a competitive inhibitor of other enzymes that require alpha-ketoglutarate as a cofactor, including certain DNA demethylases, leading to genomic CpG hypermethylation and globally altered transcription.	('altered', 'Reg', (196, 203))	('CpG hypermethylation', 'Var', (162, 182))	('hypermethylation', 'Var', (166, 182))	('transcription', 'MPA', (204, 217))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (72, 91))
99838	31222125	In our recently published work, we found that the methylation-dependent suppression of Tissue Factor (TF) contributes to the reduced thrombogenicity and reduced malignancy of IDHmut gliomas, and that methylation and suppression of the gene encoding TF, F3, is far greater in IDHmut gliomas than in other IDHmut cancers.	('thrombogenicity', 'MPA', (133, 148))	('suppression', 'NegReg', (72, 83))	('reduced', 'NegReg', (153, 160))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('Tissue Factor', 'Gene', (87, 100))	('cancers', 'Disease', (311, 318))	('gliomas', 'Phenotype', 'HP:0009733', (182, 189))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('TF', 'Gene', '2152', (249, 251))	('gliomas', 'Disease', (282, 289))	('glioma', 'Phenotype', 'HP:0009733', (282, 288))	('malignancy of IDHmut gliomas', 'Disease', (161, 189))	('malignancy of IDHmut gliomas', 'Disease', 'MESH:D005910', (161, 189))	('gliomas', 'Disease', 'MESH:D005910', (282, 289))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('Tissue Factor', 'Gene', '2152', (87, 100))	('methylation', 'Var', (200, 211))	('gliomas', 'Disease', (182, 189))	('gliomas', 'Phenotype', 'HP:0009733', (282, 289))	('methylation-dependent', 'Var', (50, 71))	('TF', 'Gene', '2152', (102, 104))	('reduced', 'NegReg', (125, 132))	('gliomas', 'Disease', 'MESH:D005910', (182, 189))	('suppression', 'NegReg', (216, 227))
99851	31222125	The number of CpG sites hypermethylated in the other cancers were 13,128 (3%) in AML, 11,763 (3%) in cholangiocarcinoma, and 8,663 (2%) in melanoma relative to each of their IDHwt counterparts (Fig.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (101, 119))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('AML', 'Disease', 'MESH:D015470', (81, 84))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('AML', 'Phenotype', 'HP:0004808', (81, 84))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('cholangiocarcinoma', 'Disease', (101, 119))	('AML', 'Disease', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('hypermethylated', 'Var', (24, 39))
99852	31222125	While smaller sample sizes may have contributed to an overall lower frequency of statistically significant findings for AML, cholangiocarcinoma, and melanoma, differences in beta-values for IDHmut compared to IDHwt tended to be more extreme across CpG sites for gliomas than for the other cancers, regardless of P-value.	('cancers', 'Disease', 'MESH:D009369', (289, 296))	('gliomas', 'Disease', 'MESH:D005910', (262, 269))	('gliomas', 'Phenotype', 'HP:0009733', (262, 269))	('gliomas', 'Disease', (262, 269))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('IDHmut', 'Var', (190, 196))	('cholangiocarcinoma', 'Disease', (125, 143))	('melanoma', 'Disease', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (125, 143))	('AML', 'Disease', 'MESH:D015470', (120, 123))	('glioma', 'Phenotype', 'HP:0009733', (262, 268))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (125, 143))	('AML', 'Disease', (120, 123))	('cancers', 'Phenotype', 'HP:0002664', (289, 296))	('AML', 'Phenotype', 'HP:0004808', (120, 123))	('cancers', 'Disease', (289, 296))
99861	31222125	In particular, many CpG sites with substantial hypermethylation in gliomas (dark blue) consistently showed far more modest differences in methylation for IDHmut versus IDHwt (yellow) in the other tumors, regardless of statistical significance (Fig.	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('tumors', 'Disease', (196, 202))	('gliomas', 'Disease', (67, 74))	('methylation', 'MPA', (138, 149))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('hypermethylation', 'Var', (47, 63))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
99863	31222125	Notably, despite smaller sample sizes for AML, cholangiocarcinoma, and melanoma, statistical analyses did identify unique sites of differential methylation in those tumors (6,271 AML; 4,808 cholangiocarcinoma; 3,519 melanoma).	('AML', 'Disease', (179, 182))	('AML', 'Disease', 'MESH:D015470', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('AML', 'Phenotype', 'HP:0004808', (42, 45))	('AML', 'Disease', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (216, 224))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (190, 208))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (47, 65))	('tumors', 'Disease', (165, 171))	('cholangiocarcinoma', 'Disease', (190, 208))	('cholangiocarcinoma', 'Disease', (47, 65))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (190, 208))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (47, 65))	('methylation', 'Var', (144, 155))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('melanoma', 'Disease', (216, 224))	('AML', 'Disease', 'MESH:D015470', (179, 182))	('AML', 'Phenotype', 'HP:0004808', (179, 182))
99864	31222125	Since those CpG sites were not significantly methylated in IDHmut gliomas, even though the glioma cohort was much larger, these results indicate that a great deal of IDHmut-related CpG site methylation is tissue-specific.	('methylation', 'Var', (190, 201))	('glioma', 'Disease', (66, 72))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('glioma', 'Disease', (91, 97))	('IDHmut-related', 'Disease', (166, 180))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('gliomas', 'Disease', (66, 73))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
99865	31222125	Only 217 similar CpG sites were hypermethylated across all IDHmut cancers, compared to all IDHwt cancers (Fig.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('hypermethylated', 'Var', (32, 47))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('IDHwt cancers', 'Disease', 'MESH:D009369', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('IDHwt cancers', 'Disease', (91, 104))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
99867	31222125	Stratifying IDHmut gliomas into oligodendroglioma and astrocytoma revealed a large amount of similar CpG sites hypermethylated when compared to IDHwt gliomas (Supplemental Fig.	('hypermethylated', 'Var', (111, 126))	('IDHwt gliomas', 'Disease', (144, 157))	('gliomas', 'Disease', 'MESH:D005910', (19, 26))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('gliomas', 'Disease', (19, 26))	('gliomas', 'Disease', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('oligodendroglioma', 'Disease', (32, 49))	('astrocytoma', 'Disease', 'MESH:D001254', (54, 65))	('astrocytoma', 'Phenotype', 'HP:0009592', (54, 65))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))	('oligodendroglioma', 'Disease', 'MESH:D009837', (32, 49))	('astrocytoma', 'Disease', (54, 65))	('IDHwt gliomas', 'Disease', 'MESH:D005910', (144, 157))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
99876	31222125	Glioma GSEA of IDHmut and IDHwt tumors revealed a down-regulation of multiple biological processes; most notable were tissue development (GO:0009888), immune response (GO:0006955), angiogenesis (GO:0001525), and cell proliferation (GO:0008283) (Fig.	('cell proliferation', 'CPA', (212, 230))	('down-regulation', 'NegReg', (50, 65))	('IDHwt tumors', 'Disease', (26, 38))	('tissue development', 'CPA', (118, 136))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('GO:0001525', 'Var', (195, 205))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('immune response', 'CPA', (151, 166))	('GO:0006955', 'Var', (168, 178))	('Glioma', 'Disease', (0, 6))	('angiogenesis', 'CPA', (181, 193))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('IDHwt tumors', 'Disease', 'MESH:D009369', (26, 38))	('GSEA', 'Chemical', '-', (7, 11))
99881	31222125	To compare the effects of IDHmut-induced methylation between different experimental models from the same type of tissue, two publicly available datasets were analyzed: (i) Infinium 450K methylation data from NHAs expressing ectopic R132H IDH1 or IDH1wt for 15 consecutive passages (GSE30339); (ii) Infinium 450K methylation data from NPCs, also expressing ectopic R132H IDH1 or IDH1wt for 15 consecutive passages (GSE94962).	('GSE94962', 'Var', (414, 422))	('IDH1', 'Gene', '3417', (378, 382))	('IDH1', 'Gene', (238, 242))	('R132H', 'Mutation', 'rs121913500', (364, 369))	('GSE30339);', 'Var', (282, 292))	('IDH1', 'Gene', (246, 250))	('IDH1', 'Gene', '3417', (238, 242))	('R132H', 'Var', (232, 237))	('IDH1', 'Gene', '3417', (246, 250))	('IDH1', 'Gene', (378, 382))	('IDH1', 'Gene', (370, 374))	('R132H', 'Mutation', 'rs121913500', (232, 237))	('IDH1', 'Gene', '3417', (370, 374))
99882	31222125	R132H IDH1 had a far greater effect on the methylation of undifferentiated NPCs than of mature NHAs, resulting in 87,541 versus 15,976 hypermethylated CpG sites, respectively (Fig.	('IDH1', 'Gene', '3417', (6, 10))	('R132H', 'Mutation', 'rs121913500', (0, 5))	('hypermethylated', 'MPA', (135, 150))	('IDH1', 'Gene', (6, 10))	('R132H', 'Var', (0, 5))	('methylation', 'MPA', (43, 54))
99883	31222125	The first published case of an IDHmut cancer was in 2006, when a study of over 1,600 breast and colorectal cancers found a single colorectal adenocarcinoma with the R132C variant of IDH1.	('IDH1', 'Gene', '3417', (182, 186))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (130, 155))	('R132C', 'Var', (165, 170))	('R132C', 'Mutation', 'rs121913499', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancers', 'Disease', 'MESH:D015179', (96, 114))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (38, 44))	('colorectal cancers', 'Disease', (96, 114))	('IDH1', 'Gene', (182, 186))	('cancer', 'Disease', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('colorectal adenocarcinoma', 'Disease', (130, 155))
99890	31222125	Assuming that mutations in dividing cells occur in a more or less stochastic fashion, the study of mutation patterns among cancers raises provocative questions regarding the conditions under which specific alterations exert a positive (or negative) evolutionary advantage.	('alterations', 'Var', (206, 217))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Disease', (123, 130))
99895	31222125	Since D2HG acts as a competitive inhibitor of certain demethylating dioxygenases that require alpha-ketoglutarate as a cofactor, the pro-methylating (and pro-oncogenic) effects of IDHmut may depend on the degree to which specific cells express those dioxygenases.	('D2HG', 'Var', (6, 10))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (94, 113))	('demethylating', 'Enzyme', (54, 67))	('pro-methylating', 'MPA', (133, 148))
99897	31222125	For example, AML has a high proportion of mutations in IDH2, whereas the others are mostly IDH1 (Supplementary Figs S3 and S4).	('IDH2', 'Gene', '3418', (55, 59))	('AML', 'Disease', 'MESH:D015470', (13, 16))	('IDH1', 'Gene', (91, 95))	('AML', 'Phenotype', 'HP:0004808', (13, 16))	('AML', 'Disease', (13, 16))	('IDH1', 'Gene', '3417', (91, 95))	('IDH2', 'Gene', (55, 59))	('mutations', 'Var', (42, 51))
99898	31222125	This variant still produces D2HG, but IDH2 is localized to the mitochondrial matrix, while IDH1 is in the cytosol and peroxisomes.	('variant', 'Var', (5, 12))	('D2HG', 'MPA', (28, 32))	('IDH1', 'Gene', (91, 95))	('IDH2', 'Gene', (38, 42))	('IDH1', 'Gene', '3417', (91, 95))	('produces', 'Reg', (19, 27))	('IDH2', 'Gene', '3418', (38, 42))
99899	31222125	IDHmut glioma is distinct in being the only cancer in the entire body to show enrichment for R132H IDH1 (Supplementary Fig.	('R132H', 'Var', (93, 98))	('glioma', 'Disease', 'MESH:D005910', (7, 13))	('glioma', 'Phenotype', 'HP:0009733', (7, 13))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('R132H', 'Mutation', 'rs121913500', (93, 98))	('IDH1', 'Gene', (99, 103))	('IDH1', 'Gene', '3417', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('glioma', 'Disease', (7, 13))
99900	31222125	Indeed, R132H IDH1 is so prevalent in gliomas, compared to other variants that are far more common in other IDHmut cancers, it has become standard practice to routinely screen gliomas with an R132H-specific antibody.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('gliomas', 'Phenotype', 'HP:0009733', (176, 183))	('cancers', 'Disease', (115, 122))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))	('prevalent', 'Reg', (25, 34))	('R132H', 'Mutation', 'rs121913500', (192, 197))	('R132H', 'Mutation', 'rs121913500', (8, 13))	('IDH1', 'Gene', (14, 18))	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('gliomas', 'Disease', (176, 183))	('R132H-specific', 'Var', (192, 206))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('IDH1', 'Gene', '3417', (14, 18))	('gliomas', 'Disease', 'MESH:D005910', (176, 183))	('R132H', 'Var', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gliomas', 'Disease', (38, 45))
99901	31222125	Yet R132H also appears to be the least efficient producer of D2HG, compared to all other IDH1 and IDH2 variants.	('IDH2', 'Gene', (98, 102))	('R132H', 'Var', (4, 9))	('IDH2', 'Gene', '3418', (98, 102))	('R132H', 'Mutation', 'rs121913500', (4, 9))	('IDH1', 'Gene', (89, 93))	('D2HG', 'Var', (61, 65))	('IDH1', 'Gene', '3417', (89, 93))
99903	31222125	Even in IDHmut glioma, which shows the greatest extent of CpG hypermethylation compared to its IDHwt counterpart (Fig.	('glioma', 'Disease', (15, 21))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('hypermethylation', 'Var', (62, 78))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))
99907	31222125	For example, it is well known that EGFR mutation and/or amplification, which occurs in nearly 50% of IDHwt gliomas, is nearly mutually exclusive with IDHmut .	('mutation', 'Var', (40, 48))	('IDHwt gliomas', 'Disease', 'MESH:D005910', (101, 114))	('IDHmut', 'Disease', (150, 156))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('amplification', 'MPA', (56, 69))	('IDHwt gliomas', 'Disease', (101, 114))
99909	31222125	S5a); such silencing would likely diminish any selection pressure toward activating EGFR alterations.	('silencing', 'Var', (11, 20))	('EGFR', 'Gene', '1956', (84, 88))	('activating', 'MPA', (73, 83))	('diminish', 'NegReg', (34, 42))	('EGFR', 'Gene', (84, 88))	('alterations', 'Var', (89, 100))
99910	31222125	Conversely, IDHmut gliomas can have PDGFRA amplification, and the PDGFRA gene is mostly hypomethylated in this subset of gliomas (Supplementary Fig.	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('gliomas', 'Disease', (121, 128))	('PDGFRA', 'Gene', '5156', (66, 72))	('PDGFRA', 'Gene', (66, 72))	('hypomethylated', 'Var', (88, 102))	('gliomas', 'Disease', 'MESH:D005910', (19, 26))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('gliomas', 'Disease', (19, 26))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('PDGFRA', 'Gene', '5156', (36, 42))	('PDGFRA', 'Gene', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
99914	31222125	Analysis of tumor-specific patterns in IDHmut-associated methylation and mRNA transcription yielded other interesting differences, as well as some profound similarities, among IDHmut malignancies (Figs 4 and 5).	('methylation', 'Var', (57, 68))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('malignancies', 'Disease', 'MESH:D009369', (183, 195))	('IDHmut', 'Disease', (176, 182))	('IDHmut-associated', 'Disease', (39, 56))	('mRNA transcription', 'MPA', (73, 91))	('tumor', 'Disease', (12, 17))	('malignancies', 'Disease', (183, 195))
99917	31222125	While neither IDH1 nor IDH2 are classic oncogenes or tumor suppressor genes, and IDHmut is not enough to cause cancer by itself, it may facilitate oncogenesis by extending the window of vulnerability in which additional pro-oncogenic mutations can arise, such as those involving TP53 in IDHmut astrocytomas.	('TP53', 'Gene', '7157', (279, 283))	('IDH2', 'Gene', (23, 27))	('facilitate', 'PosReg', (136, 146))	('astrocytomas', 'Disease', (294, 306))	('oncogenesis', 'CPA', (147, 158))	('cancer', 'Disease', (111, 117))	('TP53', 'Gene', (279, 283))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('IDH2', 'Gene', '3418', (23, 27))	('astrocytoma', 'Phenotype', 'HP:0009592', (294, 305))	('tumor', 'Disease', (53, 58))	('IDH1', 'Gene', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('mutations', 'Var', (234, 243))	('astrocytomas', 'Disease', 'MESH:D001254', (294, 306))	('IDH1', 'Gene', '3417', (14, 18))
99923	31222125	It may also help explain conflicting results in the literature, including why some investigators have found that IDHmut impairs cancer cell malignancy, whereas others have reported no difference, or even that IDHmut enhances malignant behavior.	('IDHmut impairs cancer cell malignancy', 'Disease', 'MESH:D009422', (113, 150))	('IDHmut', 'Var', (209, 215))	('malignant behavior', 'CPA', (225, 243))	('IDHmut impairs cancer cell malignancy', 'Disease', (113, 150))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('enhances', 'PosReg', (216, 224))
99928	31222125	The data are also not merely a consequence of IDHwt gliomas being hypomethylated relative to the other IDHwt cancers, because a direct comparison between IDHmut gliomas and other IDHmut malignancies demonstrate that IDHmut gliomas methylate a greater proportion of their genome (Supplementary Tables S1, S2, and Fig.	('gliomas', 'Disease', 'MESH:D005910', (223, 230))	('IDHwt cancers', 'Disease', 'MESH:D009369', (103, 116))	('gliomas', 'Disease', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (223, 230))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('IDHmut', 'Disease', (216, 222))	('gliomas', 'Disease', (161, 168))	('IDHwt cancers', 'Disease', (103, 116))	('methylate', 'Var', (231, 240))	('IDHwt gliomas', 'Disease', 'MESH:D005910', (46, 59))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('IDHwt gliomas', 'Disease', (46, 59))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('gliomas', 'Disease', 'MESH:D005910', (161, 168))	('gliomas', 'Disease', (223, 230))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('malignancies', 'Disease', 'MESH:D009369', (186, 198))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))	('malignancies', 'Disease', (186, 198))
99941	31222125	In brief, immortalized human astrocytes were modified to express the IDH1 (R132H) mutation, cultured for 15 passages, and DNA extracted for methylation analysis.	('IDH1', 'Gene', '3417', (69, 73))	('R132H', 'Var', (75, 80))	('human', 'Species', '9606', (23, 28))	('R132H', 'Mutation', 'rs121913500', (75, 80))	('IDH1', 'Gene', (69, 73))
99975	30622562	In several types of cancer, such as colorectal cancer, pancreatic carcinoma, hepatocellular carcinoma, and lung cancer, low ALB has broadly been recognized to be a poor prognostic indicator of survival.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('pancreatic carcinoma', 'Disease', (55, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('colorectal cancer', 'Disease', (36, 53))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('low ALB', 'Phenotype', 'HP:0003282', (120, 127))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (55, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (77, 101))	('hepatocellular carcinoma', 'Disease', (77, 101))	('low', 'Var', (120, 123))	('lung cancer', 'Disease', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Phenotype', 'HP:0003003', (36, 53))	('ALB', 'MPA', (124, 127))
100145	30358133	Receiver operating characteristic curve (ROC) analysis showed that serum CA19-9 was significantly better than serum GPC1 in distinguishing PDAC patients from the controls (AUC, 95% CI: 0.908, 0.868-0.947 vs 0.795, 0.749-0.841, respectively).	('PDAC', 'Disease', (139, 143))	('serum CA19-9', 'Var', (67, 79))	('better', 'PosReg', (98, 104))	('CA19', 'Chemical', '-', (73, 77))	('PDAC', 'Phenotype', 'HP:0006725', (139, 143))	('patients', 'Species', '9606', (144, 152))	('PDAC', 'Chemical', '-', (139, 143))
100147	30358133	The overall survival rate was shorter in patients with high levels of serum GPC1 compared to those with low levels of serum GPC1 (log-rank = 5.16, P = 0.023).	('high levels', 'Var', (55, 66))	('patients', 'Species', '9606', (41, 49))	('shorter', 'NegReg', (30, 37))
100181	30358133	Higher serum levels of GPC1 and CA19-9 were found in stage I PDAC samples compared with HC samples (P < 0.001; P < 0.001).	('serum levels', 'MPA', (7, 19))	('CA19-9', 'Var', (32, 38))	('PDAC', 'Disease', (61, 65))	('GPC1', 'Gene', (23, 27))	('PDAC', 'Phenotype', 'HP:0006725', (61, 65))	('Higher', 'PosReg', (0, 6))	('CA19', 'Chemical', '-', (32, 36))	('stage I PDAC', 'Disease', (53, 65))	('PDAC', 'Chemical', '-', (61, 65))
100192	30358133	The sensitivity and specificity of GPC1 (76.92% and 70.85%, respectively) were lower than that of CA19-9 (82.69% and 93.97%, respectively) when comparing PDAC with the controls.	('GPC1', 'Var', (35, 39))	('CA19', 'Chemical', '-', (98, 102))	('PDAC', 'Chemical', '-', (154, 158))	('lower', 'NegReg', (79, 84))	('PDAC', 'Phenotype', 'HP:0006725', (154, 158))
100197	30358133	After excluding CP and BPT, the AUC for CA19-9 (0.914, 95% CI: 0.875-0.953) was greater than GPC1 (0.810, 95% CI: 0.763-0.856) in PDAC compared to HC participants (Figure 4C).	('CP', 'Phenotype', 'HP:0006280', (16, 18))	('AUC', 'MPA', (32, 35))	('CA19-9', 'Var', (40, 46))	('PDAC', 'Phenotype', 'HP:0006725', (130, 134))	('participants', 'Species', '9606', (150, 162))	('PDAC', 'Disease', (130, 134))	('greater', 'PosReg', (80, 87))	('CA19', 'Chemical', '-', (40, 44))	('PDAC', 'Chemical', '-', (130, 134))	('BPT', 'Chemical', '-', (23, 26))
100199	30358133	When comparing the early-stage PDAC with HC participants, the AUC for CA19-9 was higher than that of GPC1 (0.888, 95% CI: 0.824-0.953 vs 0.768, 95% CI: 0.705-0.830; Figure 4D), and the combined sensitivity increased to 93.06%.	('PDAC', 'Chemical', '-', (31, 35))	('higher', 'PosReg', (81, 87))	('CA19', 'Chemical', '-', (70, 74))	('AUC', 'MPA', (62, 65))	('CA19-9', 'Var', (70, 76))	('PDAC', 'Phenotype', 'HP:0006725', (31, 35))	('participants', 'Species', '9606', (44, 56))
100200	30358133	These data indicate that the combination of GPC1 with CA19-9 could enhance the diagnostic value of CA19-9 in PDAC patients.	('CA19', 'Chemical', '-', (99, 103))	('PDAC', 'Disease', (109, 113))	('combination', 'Interaction', (29, 40))	('CA19-9', 'Var', (99, 105))	('GPC1', 'Gene', (44, 48))	('PDAC', 'Phenotype', 'HP:0006725', (109, 113))	('enhance', 'PosReg', (67, 74))	('PDAC', 'Chemical', '-', (109, 113))	('patients', 'Species', '9606', (114, 122))	('CA19', 'Chemical', '-', (54, 58))	('diagnostic value', 'MPA', (79, 95))
100205	30358133	These data indicated that the overall survival is shorter in the groups with high levels of serum GPC1 for both 128 PDAC patients (P = 0.002) and for 52 PDAC patients who had undergone radical surgery (P = 0.023).	('PDAC', 'Phenotype', 'HP:0006725', (153, 157))	('PDAC', 'Phenotype', 'HP:0006725', (116, 120))	('GPC1', 'Protein', (98, 102))	('shorter', 'NegReg', (50, 57))	('PDAC', 'Chemical', '-', (153, 157))	('patients', 'Species', '9606', (158, 166))	('PDAC', 'Chemical', '-', (116, 120))	('high levels', 'Var', (77, 88))	('patients', 'Species', '9606', (121, 129))	('overall survival', 'CPA', (30, 46))
100213	30358133	In addition, Melo et al16 reported that GPC1+ exosomes could serve as a sensitive and specific biomarker for early PDAC detection.	('PDAC', 'Disease', (115, 119))	('PDAC', 'Phenotype', 'HP:0006725', (115, 119))	('PDAC', 'Chemical', '-', (115, 119))	('GPC1+', 'Var', (40, 45))
100220	30358133	As a result, the diagnostic accuracy in the combination of GPC1 and CA19-9 was around 75%, which was much lower than the accuracy of CA19-9 alone (around 90%), so the serum GPC1 was not useful for the detection of PDAC.	('PDAC', 'Disease', (214, 218))	('PDAC', 'Phenotype', 'HP:0006725', (214, 218))	('PDAC', 'Chemical', '-', (214, 218))	('GPC1', 'Var', (59, 63))	('combination', 'Var', (44, 55))	('CA19', 'Chemical', '-', (68, 72))	('CA19', 'Chemical', '-', (133, 137))
100222	30358133	In this study, we found that the overall survival was shorter in the patient group with high levels of serum GPC1 than in the group with low levels.	('GPC1', 'Protein', (109, 113))	('overall survival', 'CPA', (33, 49))	('patient', 'Species', '9606', (69, 76))	('shorter', 'NegReg', (54, 61))	('high levels', 'Var', (88, 99))
100240	30358133	Overall survival is also shorter in PDAC patients with high serum GPC1.	('GPC1', 'Protein', (66, 70))	('PDAC', 'Disease', (36, 40))	('PDAC', 'Phenotype', 'HP:0006725', (36, 40))	('shorter', 'NegReg', (25, 32))	('patients', 'Species', '9606', (41, 49))	('PDAC', 'Chemical', '-', (36, 40))	('Overall survival', 'MPA', (0, 16))	('high serum', 'Var', (55, 65))
100292	33658799	Patients with Lynch syndrome and breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2) genetic aberrations might also be at higher risk for BTCs.	('BTC', 'Phenotype', 'HP:0100574', (148, 151))	('BRCA2', 'Gene', (88, 93))	('Lynch syndrome', 'Disease', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Patients', 'Species', '9606', (0, 8))	('BTCs', 'Chemical', '-', (148, 152))	('genetic aberrations', 'Var', (95, 114))	('BRCA2', 'Gene', '675', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('BTCs', 'Disease', (148, 152))	('Lynch syndrome', 'Disease', 'MESH:D003123', (14, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('BRCA1', 'Gene', '672', (55, 60))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('BRCA1', 'Gene', (55, 60))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('breast cancer', 'Disease', (33, 46))
100319	33658799	Based on the published data, nab-paclitaxel plus GEMCIS therapy achieved prolonged mPFS (11.8 months) and mOS (19.2 months) compared to data from previous studies where BTC patients were treated with GEMCIS only.	('mOS', 'Gene', '17451', (106, 109))	('patients', 'Species', '9606', (173, 181))	('nab-paclitaxel', 'Var', (29, 43))	('nab', 'Chemical', '-', (29, 32))	('paclitaxel', 'Chemical', 'MESH:D017239', (33, 43))	('GEMCIS', 'Chemical', '-', (49, 55))	('GEMCIS', 'Chemical', '-', (200, 206))	('mPFS', 'CPA', (83, 87))	('mOS', 'Gene', (106, 109))	('BTC', 'Phenotype', 'HP:0100574', (169, 172))
100326	33658799	In iCCA, the most frequent genomic alterations are TP53 (27%), CDKN2A/B (27%), K-Ras (22%), ARID1A (18%), and IDH1/2 (19%).	('TP53', 'Gene', (51, 55))	('CDKN2A/B', 'Gene', (63, 71))	('K-Ras', 'Gene', '3845', (79, 84))	('K-Ras', 'Gene', (79, 84))	('IDH1/2', 'Var', (110, 116))	('CDKN2A/B', 'Gene', '1029;1030', (63, 71))	('ARID1A', 'Gene', '8289', (92, 98))	('TP53', 'Gene', '7157', (51, 55))	('ARID1A', 'Gene', (92, 98))
100329	33658799	On the contrary, ERBB2 and TP53 mutations are more common in eCCA and GBC than in iCCA.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('common', 'Reg', (51, 57))	('eCCA', 'Disease', (61, 65))	('GBC', 'Disease', (70, 73))	('ERBB2', 'Gene', '2064', (17, 22))	('mutations', 'Var', (32, 41))	('ERBB2', 'Gene', (17, 22))
100330	33658799	PRKACA or PRKACB fusion was exclusively identified in eCCA, and EGFR, ERBB3 and PTEN mutations specifically occurred in GBC.	('PTEN', 'Gene', (80, 84))	('PRKACB', 'Gene', '5567', (10, 16))	('PTEN', 'Gene', '5728', (80, 84))	('PRKACA', 'Gene', (0, 6))	('ERBB3', 'Gene', '2065', (70, 75))	('ERBB3', 'Gene', (70, 75))	('mutations', 'Var', (85, 94))	('PRKACB', 'Gene', (10, 16))	('PRKACA', 'Gene', '5566', (0, 6))	('EGFR', 'Gene', (64, 68))	('occurred', 'Reg', (108, 116))
100338	33658799	FGFR2 fusions, the major FGFR gene abbreviations, are frequently found in iCCAs with an incidence of 10-45%, but they are rare in eCCAs (less than 5%).	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (6, 13))	('FGFR2', 'Gene', '2263', (0, 5))
100339	33658799	FGFR2 fusion proteins could be activated by the dimerization of their respective partners, thus inducing the activation of downstream oncogenic signaling pathways including RAS-RAF-MEK-ERK/MAPK, PI3K/AKT/mTOR and JAK/STAT pathways.	('inducing', 'Reg', (96, 104))	('MEK', 'Gene', '5609', (181, 184))	('MAPK', 'Gene', '4216', (189, 193))	('mTOR', 'Gene', '2475', (204, 208))	('RAF', 'Gene', (177, 180))	('ERK', 'Gene', '5594', (185, 188))	('AKT', 'Gene', '207', (200, 203))	('MEK', 'Gene', (181, 184))	('fusion proteins', 'Protein', (6, 21))	('FGFR2', 'Gene', (0, 5))	('ERK', 'Gene', (185, 188))	('FGFR2', 'Gene', '2263', (0, 5))	('JAK/STAT pathways', 'Pathway', (213, 230))	('dimerization', 'Var', (48, 60))	('RAF', 'Gene', '22882', (177, 180))	('mTOR', 'Gene', (204, 208))	('activation', 'PosReg', (109, 119))	('MAPK', 'Gene', (189, 193))	('AKT', 'Gene', (200, 203))	('oncogenic signaling pathways', 'Pathway', (134, 162))	('activated', 'PosReg', (31, 40))
100341	33658799	In recent years, numerous studies have illustrated that the FGFR inhibitors play a role in suppressing the growth of biliary tract tumors in cancer patients with FGFR2 gene fusions, particularly inhibiting iCCA development.	('suppressing', 'NegReg', (91, 102))	('patients', 'Species', '9606', (148, 156))	('FGFR2', 'Gene', (162, 167))	('gene fusions', 'Var', (168, 180))	('FGFR2', 'Gene', '2263', (162, 167))	('inhibiting', 'NegReg', (195, 205))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('biliary tract tumors', 'Phenotype', 'HP:0100574', (117, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('biliary tract tumors', 'Disease', (117, 137))	('growth', 'MPA', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('iCCA development', 'CPA', (206, 222))	('biliary tract tumors', 'Disease', 'MESH:D001661', (117, 137))	('cancer', 'Disease', (141, 147))
100343	33658799	BGJ398 (Infigratinib), a selective FGFR kinase inhibitor against FGFR 1-4, exhibited effective therapeutic activity against intrahepatic cholangiocarcinoma harboring FGFR2 fusions.	('FGFR 1-4', 'Gene', (65, 73))	('FGFR 1-4', 'Gene', '2260;2263;2261;2264', (65, 73))	('BGJ398', 'Chemical', 'MESH:C568950', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('FGFR2', 'Gene', (166, 171))	('BGJ398', 'Gene', (0, 6))	('FGFR2', 'Gene', '2263', (166, 171))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (124, 155))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (137, 155))	('intrahepatic cholangiocarcinoma', 'Disease', (124, 155))	('Infigratinib', 'Chemical', 'MESH:C568950', (8, 20))	('fusions', 'Var', (172, 179))
100345	33658799	A single-arm phase II clinical trial assessed the therapeutic activity of BGJ398 in 61 patients with advanced cholangiocarcinoma containing FGFR alterations, including FGFR2 fusions, mutations and amplifications (NCT02150967).	('BGJ398', 'Gene', (74, 80))	('FGFR2', 'Gene', (168, 173))	('FGFR2', 'Gene', '2263', (168, 173))	('mutations', 'Var', (183, 192))	('alterations', 'Var', (145, 156))	('FGFR', 'Gene', (140, 144))	('NCT02150967', 'Var', (213, 224))	('fusions', 'Var', (174, 181))	('cholangiocarcinoma', 'Disease', (110, 128))	('amplifications (NCT02150967', 'Var', (197, 224))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (110, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('BGJ398', 'Chemical', 'MESH:C568950', (74, 80))	('patients', 'Species', '9606', (87, 95))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (110, 128))
100347	33658799	BGJ398 had promising anti-tumor activity especially in patients with FGFR2 fusions.	('BGJ398', 'Chemical', 'MESH:C568950', (0, 6))	('FGFR2', 'Gene', (69, 74))	('fusions', 'Var', (75, 82))	('FGFR2', 'Gene', '2263', (69, 74))	('BGJ398', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Disease', (26, 31))
100348	33658799	Recently, based on this encouraging data, a phase III random controlled trial has started to recruit subjects with cholangiocarcinoma containing FGFR2 gene alterations to evaluate the efficacy and safety of BGJ398 versus chemotherapy (NCT03773302).	('FGFR2', 'Gene', (145, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('alterations', 'Var', (156, 167))	('FGFR2', 'Gene', '2263', (145, 150))	('BGJ398', 'Chemical', 'MESH:C568950', (207, 213))	('cholangiocarcinoma', 'Disease', (115, 133))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (115, 133))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (115, 133))
100349	33658799	A phase II clinical trial was also initiated to further explore the anti-tumor activity of BGJ398 in CCA patients with FGFR2 fusions (NCT04233567).	('BGJ398', 'Gene', (91, 97))	('patients', 'Species', '9606', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('CCA', 'Disease', (101, 104))	('fusions', 'Var', (125, 132))	('FGFR2', 'Gene', '2263', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('BGJ398', 'Chemical', 'MESH:C568950', (91, 97))	('FGFR2', 'Gene', (119, 124))
100354	33658799	Among the 12 iCCA patients with FGFR2 fusions, 2 patients had PRs and one confirmed a stable disease (SD).	('PRs', 'Disease', (62, 65))	('FGFR2', 'Gene', (32, 37))	('FGFR2', 'Gene', '2263', (32, 37))	('patients', 'Species', '9606', (18, 26))	('patients', 'Species', '9606', (49, 57))	('SD', 'Disease', 'MESH:D029461', (102, 104))	('fusions', 'Var', (38, 45))
100355	33658799	This study showed the tolerant toxicity of ARQ 087 and confirmed its therapeutic effect in advanced cancer patients with FGFR gene alterations, particularly iCCA patients.	('patients', 'Species', '9606', (162, 170))	('iCCA', 'Disease', (157, 161))	('ARQ 087', 'Chemical', 'MESH:C000621805', (43, 50))	('toxicity', 'Disease', 'MESH:D064420', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('toxicity', 'Disease', (31, 39))	('alterations', 'Var', (131, 142))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('patients', 'Species', '9606', (107, 115))	('FGFR gene', 'Gene', (121, 130))
100361	33658799	A clinical study reported that TAS-120 showed therapeutic effects in four iCCA patients with FGFR2 fusions who were resistant to the other two FGFR inhibitors (BGJ398 and Debio1347).	('FGFR2', 'Gene', (93, 98))	('FGFR2', 'Gene', '2263', (93, 98))	('Debio1347', 'Chemical', 'MESH:C000602562', (171, 180))	('fusions', 'Var', (99, 106))	('TAS-120', 'Chemical', '-', (31, 38))	('BGJ398', 'Chemical', 'MESH:C568950', (160, 166))	('patients', 'Species', '9606', (79, 87))
100367	33658799	Several trials have showed its meaningful benefit in patients with pretreated iCCA with FGFR2 gene aberrations, thus it might be a promising agent for BTCs treatment.	('iCCA', 'Disease', (78, 82))	('patients', 'Species', '9606', (53, 61))	('benefit', 'PosReg', (42, 49))	('BTCs', 'Chemical', '-', (151, 155))	('gene aberrations', 'Var', (94, 110))	('BTC', 'Phenotype', 'HP:0100574', (151, 154))	('FGFR2', 'Gene', (88, 93))	('FGFR2', 'Gene', '2263', (88, 93))
100370	33658799	A preclinical cell-based study revealed that the cells harboring FGFR2-CLIP1 fusion responded noticeably to Pemigatinib, whereas cells with FGFR2-CLIP1 fusion and N549H mutation both were resistant to this drug.	('FGFR2', 'Gene', '2263', (140, 145))	('fusion', 'Var', (77, 83))	('CLIP1', 'Gene', (71, 76))	('FGFR2', 'Gene', (65, 70))	('FGFR2', 'Gene', '2263', (65, 70))	('N549H', 'Mutation', 'rs1057519045', (163, 168))	('Pemigatinib', 'Chemical', '-', (108, 119))	('CLIP1', 'Gene', '6249', (146, 151))	('responded', 'MPA', (84, 93))	('CLIP1', 'Gene', (146, 151))	('FGFR2', 'Gene', (140, 145))	('CLIP1', 'Gene', '6249', (71, 76))	('N549H', 'Var', (163, 168))
100371	33658799	There is a large-scale single-arm phase 2 trial (FIGHT-202) assessing the safety and therapeutic activity of Pemigatinib in cholangiocarcinoma patients with and without FGFR2 fusions or rearrangements (NCT02924376).	('rearrangements (NCT02924376', 'Var', (186, 213))	('cholangiocarcinoma', 'Disease', (124, 142))	('patients', 'Species', '9606', (143, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('FGFR2', 'Gene', (169, 174))	('NCT02924376', 'Var', (202, 213))	('FGFR2', 'Gene', '2263', (169, 174))	('Pemigatinib', 'Chemical', '-', (109, 120))	('fusions', 'Var', (175, 182))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (124, 142))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (124, 142))
100372	33658799	One hundred and seven of the enrolled 146 patients harbored FGFR2 gene fusions or rearrangements, and this group of patients showed a remarkable objective response: 35.5% (95% CI: 26.5-45.4) of patients achieved objective response (3 had complete responses and 35 had partial responses), and the disease control rate (DCR) was 82% (95% CI: 74-89).	('rearrangements', 'Var', (82, 96))	('patients', 'Species', '9606', (194, 202))	('patients', 'Species', '9606', (116, 124))	('DCR', 'Chemical', '-', (318, 321))	('FGFR2', 'Gene', '2263', (60, 65))	('FGFR2', 'Gene', (60, 65))	('patients', 'Species', '9606', (42, 50))
100375	33658799	Based on these encouraging results, a phase 3 clinical trial (FIGHT-302; NCT03656536) is ongoing to compare pemigatinib with chemotherapy (gemcitabine plus cisplatin) for advanced CCA patients with FGFR2 rearrangements.	('patients', 'Species', '9606', (184, 192))	('cisplatin', 'Chemical', 'MESH:D002945', (156, 165))	('FGFR2', 'Gene', '2263', (198, 203))	('rearrangements', 'Var', (204, 218))	('FGFR2', 'Gene', (198, 203))	('gemcitabine', 'Chemical', 'MESH:C056507', (139, 150))	('pemigatinib', 'Chemical', '-', (108, 119))
100376	33658799	A host of selective TKIs for FGFR, including AZD4547, CH5183284 (Debio 1347), JNJ-42756493, BAY1163877, and dovitinib, are currently under examination in early-phase trials.	('AZD4547', 'Var', (45, 52))	('dovitinib', 'Chemical', 'MESH:C500007', (108, 117))	('AZD4547', 'Chemical', 'MESH:C572463', (45, 52))	('CH5183284', 'Chemical', 'MESH:C000602562', (54, 63))	('BAY1163877', 'Var', (92, 102))	('CH5183284', 'Var', (54, 63))	('FGFR', 'Gene', (29, 33))
100379	33658799	An in vitro study illustrated that the number of cells in gastric cancer cell lines containing FGFR2 gene amplifications would decrease significantly after being treated with pazopanib.	('FGFR2', 'Gene', '2263', (95, 100))	('gastric cancer', 'Phenotype', 'HP:0012126', (58, 72))	('pazopanib', 'Chemical', 'MESH:C516667', (175, 184))	('amplifications', 'Var', (106, 120))	('decrease', 'NegReg', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('gastric cancer', 'Disease', (58, 72))	('gastric cancer', 'Disease', 'MESH:D013274', (58, 72))	('FGFR2', 'Gene', (95, 100))
100386	33658799	According to the data published on clinical trials.gov, a completed phase II trial of 12 BTC patients with FGFR fusions reported a disease control rate of 45.5% (95% CI: 16.8 to 76.6), progression-free survival (PFS) of 2.4 months and overall survival (OS) of 15.7 months (NCT02265341).	('BTC', 'Phenotype', 'HP:0100574', (89, 92))	('progression-free survival', 'CPA', (185, 210))	('fusions', 'Var', (112, 119))	('FGFR', 'Gene', (107, 111))	('disease control', 'CPA', (131, 146))	('OS', 'Gene', '17451', (253, 255))	('patients', 'Species', '9606', (93, 101))
100394	33658799	On a basis of several studies, secondary mutations in FGFR2 kinase domain, mutations in the TKI domain and emergence of new FGFR2 fusions might all be the reasons for resistance.	('mutations', 'Var', (41, 50))	('FGFR2', 'Gene', (124, 129))	('FGFR2', 'Gene', '2263', (124, 129))	('fusions', 'Var', (130, 137))	('FGFR2', 'Gene', (54, 59))	('mutations', 'Var', (75, 84))	('FGFR2', 'Gene', '2263', (54, 59))	('TKI', 'Gene', (92, 95))
100397	33658799	Several studies have indicated that mutant IDH1 (mIDH1) and mutant IDH2 (mIDH2) are "gain of function" mutations, which means that they gain the ability to catalyze the conversion of alpha-KG to 2-hydroxyglutarate (2-HG).	('conversion', 'MPA', (169, 179))	('mIDH2', 'Gene', (73, 78))	('IDH1', 'Gene', '15926', (50, 54))	('IDH1', 'Gene', '15926', (43, 47))	('gain', 'PosReg', (136, 140))	('alpha-KG', 'Chemical', 'MESH:D007656', (183, 191))	('IDH2', 'Gene', (74, 78))	('IDH2', 'Gene', (67, 71))	('mIDH1', 'Gene', '15926', (49, 54))	('catalyze', 'MPA', (156, 164))	('mIDH1', 'Gene', (49, 54))	('2-HG', 'Chemical', 'MESH:C019417', (215, 219))	('IDH1', 'Gene', (50, 54))	('IDH1', 'Gene', (43, 47))	('IDH2', 'Gene', '269951', (74, 78))	('IDH2', 'Gene', '269951', (67, 71))	('mutant', 'Var', (36, 42))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (195, 213))	('mutant', 'Var', (60, 66))	('mIDH2', 'Gene', '269951', (73, 78))
100398	33658799	The accumulation of 2-HG inhibits the alphaKG-dependent dioxygenases which play a part in epigenetic regulation, leading to cell proliferation, suppression of cellular differentiation, angiogenesis and invasion.	('inhibits', 'NegReg', (25, 33))	('2-HG', 'Chemical', 'MESH:C019417', (20, 24))	('cellular differentiation', 'CPA', (159, 183))	('invasion', 'CPA', (202, 210))	('cell proliferation', 'CPA', (124, 142))	('alphaKG-dependent dioxygenases', 'Enzyme', (38, 68))	('suppression', 'NegReg', (144, 155))	('2-HG', 'Var', (20, 24))	('angiogenesis', 'CPA', (185, 197))
100399	33658799	Therefore, mutations in IDH 1/2 genes are highly related to tumorigenesis.	('mutations', 'Var', (11, 20))	('IDH 1/2', 'Gene', '3417;3418', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('IDH 1/2', 'Gene', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('related', 'Reg', (49, 56))	('tumor', 'Disease', (60, 65))
100400	33658799	IDH gene mutations are heterozygous point mutations generally occurring in Arginine 132 of IDH1 and Arginine 140 or Arginine 172 of IDH2.	('Arginine', 'Chemical', 'MESH:D001120', (116, 124))	('IDH', 'Gene', (0, 3))	('Arginine', 'Chemical', 'MESH:D001120', (75, 83))	('IDH2', 'Gene', '269951', (132, 136))	('Arginine', 'Chemical', 'MESH:D001120', (100, 108))	('Arginine 140', 'Var', (100, 112))	('IDH', 'Gene', (132, 135))	('IDH', 'Gene', '3417', (0, 3))	('IDH1', 'Gene', (91, 95))	('Arginine 172', 'Var', (116, 128))	('IDH', 'Gene', '3417', (132, 135))	('IDH', 'Gene', (91, 94))	('occurring', 'Reg', (62, 71))	('IDH1', 'Gene', '15926', (91, 95))	('IDH', 'Gene', '3417', (91, 94))	('IDH2', 'Gene', (132, 136))
100401	33658799	According to genomic profiling, IDH 1/2 mutations were more common in iCCA than in eCCA or GBC, with an incidence ranging from 10% to 36%.	('IDH 1/2', 'Gene', '3417;3418', (32, 39))	('mutations', 'Var', (40, 49))	('iCCA', 'Disease', (70, 74))	('common', 'Reg', (60, 66))	('IDH 1/2', 'Gene', (32, 39))
100402	33658799	The occurrence of IDH1 mutation was higher than IDH2.	('IDH1', 'Gene', '15926', (18, 22))	('IDH2', 'Gene', '269951', (48, 52))	('mutation', 'Var', (23, 31))	('IDH2', 'Gene', (48, 52))	('IDH1', 'Gene', (18, 22))
100403	33658799	To examine the mechanism of IDH1/2 gene mutation driving tumorigenesis, two preclinical studies were conducted.	('mutation', 'Var', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('IDH1/2', 'Gene', (28, 34))	('tumor', 'Disease', (57, 62))
100409	33658799	AG-120 (Ivosidenib), a highly specific inhibitor of mutant IDH1 (mIDH1) enzymes, was developed through optimizing AGI-5198 to enable it to be applied to human therapy.	('mIDH1', 'Gene', '15926', (65, 70))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (8, 18))	('IDH1', 'Gene', '15926', (66, 70))	('mutant', 'Var', (52, 58))	('mIDH1', 'Gene', (65, 70))	('AG-120', 'Chemical', 'MESH:C000627630', (0, 6))	('nab', 'Chemical', '-', (127, 130))	('human', 'Species', '9606', (153, 158))	('IDH1', 'Gene', (59, 63))	('IDH1', 'Gene', '15926', (59, 63))	('IDH1', 'Gene', (66, 70))	('AGI-5198', 'Chemical', 'MESH:C581156', (114, 122))
100411	33658799	An in vitro study confirmed the ability of AG-120 to selectively decrease the 2-HG levels and restore cell differentiation in mIDH1-positive AML cells by inhibiting the mutant IDH1 enzyme.	('AML', 'Disease', (141, 144))	('mIDH1', 'Gene', (126, 131))	('inhibiting', 'NegReg', (154, 164))	('AML', 'Disease', 'MESH:D015470', (141, 144))	('IDH1', 'Gene', '15926', (176, 180))	('IDH1', 'Gene', '15926', (127, 131))	('IDH1', 'Gene', (127, 131))	('enzyme', 'Enzyme', (181, 187))	('restore', 'PosReg', (94, 101))	('mutant', 'Var', (169, 175))	('decrease', 'NegReg', (65, 73))	('AG-120', 'Chemical', 'MESH:C000627630', (43, 49))	('AG-120', 'Gene', (43, 49))	('2-HG levels', 'MPA', (78, 89))	('mIDH1', 'Gene', '15926', (126, 131))	('cell differentiation', 'CPA', (102, 122))	('2-HG', 'Chemical', 'MESH:C019417', (78, 82))	('IDH1', 'Gene', (176, 180))
100412	33658799	AG-120 also lowered 2-HG levels and showed significant mutant IDH1 enzyme inhibition ability in mice with IDH1-R132 mutations.	('IDH1', 'Gene', '15926', (62, 66))	('2-HG levels', 'MPA', (20, 31))	('mice', 'Species', '10090', (96, 100))	('2-HG', 'Chemical', 'MESH:C019417', (20, 24))	('AG-120', 'Chemical', 'MESH:C000627630', (0, 6))	('mutant', 'Var', (55, 61))	('IDH1', 'Gene', (106, 110))	('mutations', 'Var', (116, 125))	('IDH1', 'Gene', (62, 66))	('IDH1', 'Gene', '15926', (106, 110))	('lowered', 'NegReg', (12, 19))
100413	33658799	The published data from a phase I dose escalation study which preliminarily explored the safety and activity of AG-120 in a group of CCA patients with IDH1 mutations was encouraging (NCT02073994).	('mutations', 'Var', (156, 165))	('patients', 'Species', '9606', (137, 145))	('CCA', 'Disease', (133, 136))	('IDH1', 'Gene', (151, 155))	('AG-120', 'Chemical', 'MESH:C000627630', (112, 118))	('IDH1', 'Gene', '15926', (151, 155))
100416	33658799	In addition, when studying the tumor biopsies collected from these patients, scientists found that mutant IDH1 cholangiocarcinoma with a post-dose cytoplasmic decrease upregulated several immune response-related genes such as CTLA4, CXCL10, and CD3G, implying that using AG-120 plus immunotherapies might be a potential regimen.	('CD3G', 'Gene', (245, 249))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('patients', 'Species', '9606', (67, 75))	('AG-120', 'Chemical', 'MESH:C000627630', (271, 277))	('CTLA4', 'Gene', (226, 231))	('tumor', 'Disease', (31, 36))	('upregulated', 'PosReg', (168, 179))	('CXCL10', 'Gene', '3627', (233, 239))	('IDH1 cholangiocarcinoma', 'Disease', 'MESH:D018281', (106, 129))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('CD3G', 'Gene', '917', (245, 249))	('decrease', 'NegReg', (159, 167))	('CXCL10', 'Gene', (233, 239))	('mutant', 'Var', (99, 105))	('IDH1 cholangiocarcinoma', 'Disease', (106, 129))	('CTLA4', 'Gene', '1493', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
100424	33658799	Its activity has been tested by preclinical studies and has moved into clinical trials assessed in patients with advanced malignancies harboring IDHR132 mutations (NCT02381886).	('malignancies', 'Disease', 'MESH:D009369', (122, 134))	('mutations', 'Var', (153, 162))	('IDH', 'Gene', (145, 148))	('malignancies', 'Disease', (122, 134))	('IDH', 'Gene', '3417', (145, 148))	('patients', 'Species', '9606', (99, 107))	('activity', 'MPA', (4, 12))
100425	33658799	Enasidenib is a first-in-class selective inhibitor which is specific to the mutant IDH2 enzyme.	('IDH2', 'Gene', (83, 87))	('mutant', 'Var', (76, 82))	('Enasidenib', 'Chemical', 'MESH:C000605269', (0, 10))	('IDH2', 'Gene', '269951', (83, 87))
100433	33658799	Besides these mIDH inhibitors, a preclinical study discovered that two iCCA cell lines with IDH1 mutations were highly sensitive to multi-tyrosine kinase inhibitors (multi-TKIs), dasatinib and saracatinib.	('mutations', 'Var', (97, 106))	('dasatinib', 'Chemical', 'MESH:D000069439', (179, 188))	('saracatinib', 'Chemical', 'MESH:C515233', (193, 204))	('IDH1', 'Gene', (92, 96))	('sensitive', 'MPA', (119, 128))	('IDH1', 'Gene', '15926', (92, 96))	('mIDH', 'Gene', (14, 18))	('mIDH', 'Gene', '15926', (14, 18))
100435	33658799	This sensitivity to dasatinib has not occurred in all tumor types with IDH mutations, only in mIDH-positive iCCA tissues.	('mIDH', 'Gene', (94, 98))	('dasatinib', 'Chemical', 'MESH:D000069439', (20, 29))	('mIDH', 'Gene', '15926', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('IDH', 'Gene', (71, 74))	('IDH', 'Gene', '3417', (95, 98))	('mutations', 'Var', (75, 84))	('IDH', 'Gene', (95, 98))	('tumor', 'Disease', (54, 59))	('IDH', 'Gene', '3417', (71, 74))
100436	33658799	A phase II clinical trial testing dasatinib in iCCA patients with IDH mutations was completed, but the results have not yet been published (NCT02428855).	('IDH', 'Gene', (66, 69))	('mutations', 'Var', (70, 79))	('dasatinib', 'Chemical', 'MESH:D000069439', (34, 43))	('IDH', 'Gene', '3417', (66, 69))	('patients', 'Species', '9606', (52, 60))	('iCCA', 'Disease', (47, 51))
100438	33658799	As mentioned before, mutant IDH can cause the accumulation of 2-HG, which can significantly decrease homologous recombination repair (HRR) activity by inhibiting the alphaKG-dependent dioxygenases and subsequently improving the sensitivity to PARP inhibitors.	('IDH', 'Gene', (28, 31))	('PARP', 'Gene', (243, 247))	('mutant', 'Var', (21, 27))	('decrease', 'NegReg', (92, 100))	('homologous recombination repair', 'MPA', (101, 132))	('IDH', 'Gene', '3417', (28, 31))	('improving', 'PosReg', (214, 223))	('2-HG', 'Chemical', 'MESH:C019417', (62, 66))	('PARP', 'Gene', '142', (243, 247))	('activity', 'MPA', (139, 147))	('inhibiting', 'NegReg', (151, 161))	('alphaKG-dependent dioxygenases', 'Enzyme', (166, 196))
100439	33658799	Based on these promising results, several PARP inhibitors are being investigated in mIDH CCA patients, including olaparib (NCT03212274, NCT04306367, NCT04298021), rucaparib (NCT03639935, NCT03337087) and niraparib (NCT03207347).	('rucaparib', 'Chemical', 'MESH:C531549', (163, 172))	('NCT03207347', 'Var', (215, 226))	('NCT03639935', 'Var', (174, 185))	('NCT04298021', 'Var', (149, 160))	('niraparib', 'Chemical', 'MESH:C545685', (204, 213))	('NCT03212274', 'Var', (123, 134))	('NCT04306367', 'Var', (136, 147))	('mIDH', 'Gene', (84, 88))	('PARP', 'Gene', (42, 46))	('mIDH', 'Gene', '15926', (84, 88))	('PARP', 'Gene', '142', (42, 46))	('patients', 'Species', '9606', (93, 101))	('olaparib', 'Chemical', 'MESH:C531550', (113, 121))
100440	33658799	Furthermore, a recent report studied tumor samples from 1292 BTC patients showed Breast Cancer Susceptibility Gene (BRCA) mutations with higher rate in subjects with microsatellite instability high (MSI-H) and tumors with higher tumor mutational burden (TMB).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('BTC', 'Phenotype', 'HP:0100574', (61, 64))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('MSI', 'Gene', (199, 202))	('BRCA', 'Gene', '672', (116, 120))	('MSI', 'Gene', '5928', (199, 202))	('Cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Disease', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('Breast Cancer', 'Disease', 'MESH:D001943', (81, 94))	('BRCA', 'Gene', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('Breast Cancer', 'Disease', (81, 94))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Disease', (229, 234))	('patients', 'Species', '9606', (65, 73))	('Breast Cancer', 'Phenotype', 'HP:0003002', (81, 94))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('TMB', 'Chemical', '-', (254, 257))	('tumors', 'Disease', (210, 216))	('tumor', 'Disease', (37, 42))	('mutations', 'Var', (122, 131))
100442	33658799	Cancers with high TMB and MSI-H showed a better response to immunotherapy.	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('MSI', 'Gene', (26, 29))	('TMB', 'Chemical', '-', (18, 21))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('MSI', 'Gene', '5928', (26, 29))	('high TMB', 'Var', (13, 21))
100452	33658799	Amplification of HER2 also leads to HER2 overexpression in several kinds of tumors, which is highly related to tumorigenesis, tumor cell invasion and metastasis.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('Amplification', 'Var', (0, 13))	('leads to', 'Reg', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('HER2', 'Protein', (36, 40))	('tumors', 'Disease', (76, 82))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('HER2', 'Protein', (17, 21))	('overexpression', 'PosReg', (41, 55))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (126, 131))
100453	33658799	Regarding genetic mutations, EGFR mutations are rare, and HER2 mutations have only been identified in a small number of cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('EGFR', 'Gene', (29, 33))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('mutations', 'Var', (34, 43))
100454	33658799	The EGFR mutations were tested in up to 15% of BTCs and the incidence of HER2 mutations in iCCAs was only 0.9%.	('EGFR', 'Gene', (4, 8))	('mutations', 'Var', (9, 18))	('BTCs', 'Chemical', '-', (47, 51))	('BTC', 'Phenotype', 'HP:0100574', (47, 50))
100455	33658799	To date, several preclinical studies tested and confirmed the potential therapeutic effect of EGFR or HER2 inhibitors for BTCs.	('BTCs', 'Chemical', '-', (122, 126))	('tested', 'Reg', (37, 43))	('EGFR', 'Gene', (94, 98))	('BTC', 'Phenotype', 'HP:0100574', (122, 125))	('HER2', 'Protein', (102, 106))	('inhibitors', 'Var', (107, 117))	('BTCs', 'Disease', (122, 126))
100456	33658799	A study carried out by Weidmann et al demonstrated that NVP-AEE788, a dual EGFR/HER2 inhibitor, could more effectively suppress the proliferation of human CCA cell lines in vitro compared to gefitinib and erlotinib (EGFR inhibitors).	('NVP-AEE788', 'Var', (56, 66))	('AEE788', 'Chemical', 'MESH:C489254', (60, 66))	('erlotinib', 'Chemical', 'MESH:D000069347', (205, 214))	('proliferation', 'CPA', (132, 145))	('human', 'Species', '9606', (149, 154))	('suppress', 'NegReg', (119, 127))	('gefitinib', 'Chemical', 'MESH:D000077156', (191, 200))
100459	33658799	Another preclinical study examined the effect of gefitinib (a selective EGFR inhibitor) and GW2974 (a dual EGFR/HER2 inhibitor) in mice with gallbladder carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('gefitinib', 'Chemical', 'MESH:D000077156', (49, 58))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (141, 162))	('mice', 'Species', '10090', (131, 135))	('GW2974', 'Var', (92, 98))	('gallbladder carcinoma', 'Disease', (141, 162))
100464	33658799	Based on the modest benefits showed in phase II studies, a large phase III trial comprised of 268 patients compared the efficacy and safety of erlotinib plus gemcitabine plus oxaliplatin (GEMOX) regimen with GEMOX regimen alone in patients with metastatic BTC (NCT01149122).	('gemcitabine', 'Chemical', 'MESH:C056507', (158, 169))	('metastatic BTC', 'Disease', (245, 259))	('patients', 'Species', '9606', (231, 239))	('BTC', 'Phenotype', 'HP:0100574', (256, 259))	('GEMOX', 'Chemical', '-', (208, 213))	('patients', 'Species', '9606', (98, 106))	('GEMOX', 'Chemical', '-', (188, 193))	('NCT01149122', 'Var', (261, 272))	('erlotinib', 'Chemical', 'MESH:D000069347', (143, 152))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (175, 186))
100474	33658799	K-Ras mutations are regarded as a negative predictive factor for cancer prognosis and the therapeutic efficacy of EGFR inhibitors in colorectal cancer patients.	('colorectal cancer', 'Disease', (133, 150))	('K-Ras', 'Gene', '3845', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('negative', 'NegReg', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('colorectal cancer', 'Disease', 'MESH:D015179', (133, 150))	('patients', 'Species', '9606', (151, 159))	('K-Ras', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (144, 150))	('EGFR', 'Gene', (114, 118))	('colorectal cancer', 'Phenotype', 'HP:0003003', (133, 150))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('mutations', 'Var', (6, 15))
100477	33658799	The data also suggested that K-Ras mutations did not affect the survival of BTC patients.	('patients', 'Species', '9606', (80, 88))	('K-Ras', 'Gene', (29, 34))	('K-Ras', 'Gene', '3845', (29, 34))	('BTC', 'Phenotype', 'HP:0100574', (76, 79))	('mutations', 'Var', (35, 44))
100480	33658799	Vecti-BIL study was designed to compare the therapeutic efficacy of GEMOX with and without panitumumab in chemotherapy-naive BTC patients possessing a wild-type K-Ras status (NCT01389414).	('BTC', 'Phenotype', 'HP:0100574', (125, 128))	('K-Ras', 'Gene', '3845', (161, 166))	('panitumumab', 'Chemical', 'MESH:D000077544', (91, 102))	('patients', 'Species', '9606', (129, 137))	('K-Ras', 'Gene', (161, 166))	('NCT01389414', 'Var', (175, 186))	('GEMOX', 'Chemical', '-', (68, 73))
100484	33658799	HER2 overexpression and gene amplification are the common occurrences in BTCs, leading to the development of specific HER2 inhibitors.	('gene amplification', 'Var', (24, 42))	('overexpression', 'PosReg', (5, 19))	('BTCs', 'Chemical', '-', (73, 77))	('BTC', 'Phenotype', 'HP:0100574', (73, 76))	('HER2', 'Protein', (0, 4))
100513	33658799	Recently, neurotrophic tropomyosin receptor kinase (NTRK) gene fusion has become a promising avenue for cancer targeted therapy.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('gene fusion', 'Var', (58, 69))	('tropomyosin receptor kinase', 'Gene', (23, 50))	('tropomyosin receptor kinase', 'Gene', '4914', (23, 50))	('NTRK', 'Gene', (52, 56))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
100525	33658799	It has proven effective in several clinical trials involving patients with NTRK gene fusions.	('gene fusions', 'Var', (80, 92))	('patients', 'Species', '9606', (61, 69))	('NTRK', 'Gene', (75, 79))
100526	33658799	Larotrectinib (VITRAKVI) is the first pan-TRK inhibitor approved by the US Food and Drug Administration for treating patients with solid tumors harboring NTRK gene fusions.	('solid tumors', 'Disease', 'MESH:D009369', (131, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('gene fusions', 'Var', (159, 171))	('NTRK', 'Gene', (154, 158))	('Larotrectinib', 'Chemical', 'MESH:C000609083', (0, 13))	('patients', 'Species', '9606', (117, 125))	('solid tumors', 'Disease', (131, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
100527	33658799	Promising data published from three multicenter clinical trials (NCT02122913, NCT02637687, NCT02576431) contributed to the accelerated approval of larotrectinib.	('larotrectinib', 'Chemical', 'MESH:C000609083', (147, 160))	('NCT02576431', 'Var', (91, 102))	('NCT02122913', 'Var', (65, 76))
100531	33658799	ONO-7579 is a pan-TRK inhibitor whose anti-tumor effect was demonstrated in a preclinical study using two GBC cell lines: NOZ (harboring K-Ras mutant) and TYGBK-1 (wild-type K-Ras).	('ONO-7579', 'Chemical', 'MESH:C000626972', (0, 8))	('mutant', 'Var', (143, 149))	('K-Ras', 'Gene', '3845', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('K-Ras', 'Gene', '3845', (137, 142))	('K-Ras', 'Gene', (137, 142))	('K-Ras', 'Gene', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
100532	33658799	The results indicated that ONO-7579 could effectively suppress proliferation in the TYGBK-1 cell line, but not in the NOZ cell line, suggesting that ONO-7579 may have a potent anti-tumor effect on GBC cells without K-Ras mutation.	('K-Ras', 'Gene', '3845', (215, 220))	('proliferation', 'CPA', (63, 76))	('tumor', 'Disease', (181, 186))	('ONO-7579', 'Chemical', 'MESH:C000626972', (27, 35))	('K-Ras', 'Gene', (215, 220))	('suppress', 'NegReg', (54, 62))	('ONO-7579', 'Var', (149, 157))	('ONO-7579', 'Chemical', 'MESH:C000626972', (149, 157))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
100540	33658799	K-Ras, N-Ras and B-Raf mutations have been commonly detected in various cancer types such as gastrointestinal cancers, lung cancers and melanomas.	('gastrointestinal cancers', 'Disease', (93, 117))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Disease', (72, 78))	('detected', 'Reg', (52, 60))	('lung cancers', 'Disease', 'MESH:D008175', (119, 131))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('K-Ras', 'Gene', (0, 5))	('mutations', 'Var', (23, 32))	('B-Raf', 'Gene', (17, 22))	('melanomas', 'Disease', 'MESH:D008545', (136, 145))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('lung cancers', 'Disease', (119, 131))	('cancer', 'Disease', (110, 116))	('melanomas', 'Disease', (136, 145))	('lung cancers', 'Phenotype', 'HP:0100526', (119, 131))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (93, 117))	('N-Ras', 'Gene', (7, 12))	('cancer', 'Disease', (124, 130))	('K-Ras', 'Gene', '3845', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('melanomas', 'Phenotype', 'HP:0002861', (136, 145))	('N-Ras', 'Gene', '4893', (7, 12))	('B-Raf', 'Gene', '673', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
100543	33658799	The presence of K-Ras mutations is correlated to worse prognosis.	('K-Ras', 'Gene', '3845', (16, 21))	('mutations', 'Var', (22, 31))	('K-Ras', 'Gene', (16, 21))
100544	33658799	By contrast, N-Ras mutations exist in 3.6% of iCCAs and 2.6% of eCCAs, while B-Raf mutations are only found in 3% to 5% of iCCAs.	('iCCAs', 'Disease', (46, 51))	('B-Raf', 'Gene', '673', (77, 82))	('B-Raf', 'Gene', (77, 82))	('mutations', 'Var', (19, 28))	('N-Ras', 'Gene', '4893', (13, 18))	('N-Ras', 'Gene', (13, 18))
100550	33658799	This phase II study assessed the clinical benefits of vemurafenib in multiple nonmelanoma cancers with B-Raf V600 mutations, including 8 CCA patients.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('CCA', 'Disease', (137, 140))	('multiple nonmelanoma cancers', 'Disease', 'MESH:D009369', (69, 97))	('V600 mutations', 'Var', (109, 123))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('B-Raf', 'Gene', '673', (103, 108))	('B-Raf', 'Gene', (103, 108))	('vemurafenib', 'Chemical', 'MESH:D000077484', (54, 65))	('patients', 'Species', '9606', (141, 149))	('multiple nonmelanoma cancers', 'Disease', (69, 97))
100552	33658799	A reported case showed that a CCA patient with B-Raf V600 mutations achieved complete response after taking vemurafenib, panitumumab, and irinotecan therapy.	('B-Raf', 'Gene', '673', (47, 52))	('B-Raf', 'Gene', (47, 52))	('V600 mutations', 'Var', (53, 67))	('CCA', 'Disease', (30, 33))	('vemurafenib', 'Chemical', 'MESH:D000077484', (108, 119))	('patient', 'Species', '9606', (34, 41))	('panitumumab', 'Chemical', 'MESH:D000077544', (121, 132))	('irinotecan', 'Chemical', 'MESH:D000077146', (138, 148))
100553	33658799	Another B-Raf inhibitor, PLX8394, was investigated by two phase I/II clinical trials in patients with advanced solid tumors including CCA (NCT02428712, NCT02012231).	('solid tumors', 'Disease', 'MESH:D009369', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('B-Raf', 'Gene', '673', (8, 13))	('NCT02012231', 'Var', (152, 163))	('B-Raf', 'Gene', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('patients', 'Species', '9606', (88, 96))	('PLX8394', 'Chemical', 'MESH:C000602642', (25, 32))	('CCA', 'Disease', (134, 137))	('solid tumors', 'Disease', (111, 123))	('NCT02428712', 'Var', (139, 150))
100555	33658799	According to a published case report, a patient with B-Raf V600-mutated iCCA performed exceptional response, including symptomatic and radiological improvement, to dabrafenib plus trametinib (an MEK1/2 inhibitor) dual therapy, causing more clinical trials to be conducted.	('patient', 'Species', '9606', (40, 47))	('V600-mutated', 'Var', (59, 71))	('B-Raf', 'Gene', (53, 58))	('B-Raf', 'Gene', '673', (53, 58))	('trametinib', 'Chemical', 'MESH:C560077', (180, 190))	('dabrafenib', 'Chemical', 'MESH:C561627', (164, 174))	('MEK1/2', 'Gene', '5604;5605', (195, 201))	('MEK1/2', 'Gene', (195, 201))	('iCCA', 'Gene', (72, 76))
100557	33658799	Among 43 patients with B-Raf V600E-mutated BTCs, this regimen achieved an investigator-assessed ORR of 51% and an independent reviewer-assessed ORR of 47%, with a tolerant safety profile.	('BTCs', 'Chemical', '-', (43, 47))	('patients', 'Species', '9606', (9, 17))	('V600E-mutated', 'Var', (29, 42))	('V600E', 'Mutation', 'rs113488022', (29, 34))	('B-Raf', 'Gene', '673', (23, 28))	('ORR', 'MPA', (96, 99))	('B-Raf', 'Gene', (23, 28))	('BTC', 'Phenotype', 'HP:0100574', (43, 46))
100558	33658799	Therefore, the authors suggested that B-Raf V600E mutation testing should be considered in all patients with BTCs.	('patients', 'Species', '9606', (95, 103))	('BTC', 'Phenotype', 'HP:0100574', (109, 112))	('V600E', 'Mutation', 'rs113488022', (44, 49))	('B-Raf', 'Gene', (38, 43))	('B-Raf', 'Gene', '673', (38, 43))	('V600E', 'Var', (44, 49))	('BTCs', 'Chemical', '-', (109, 113))
100573	33658799	A phase I/II trial assessing the combination of binimetinib and capecitabine showed promising antitumor efficacy in BTC patients with MAPK pathway mutations (NCT02773459).	('mutations', 'Var', (147, 156))	('binimetinib', 'Chemical', 'MESH:C581313', (48, 59))	('MAPK', 'Gene', (134, 138))	('MAPK', 'Gene', '4216', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('BTC', 'Disease', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('BTC', 'Phenotype', 'HP:0100574', (116, 119))	('patients', 'Species', '9606', (120, 128))	('tumor', 'Disease', (98, 103))	('capecitabine', 'Chemical', 'MESH:D000069287', (64, 76))
100577	33658799	JSI-1187 is an oral, highly selective Erk 1/2 inhibitor which is mainly used to treat tumors with MAPK pathway mutations.	('mutations', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('MAPK', 'Gene', (98, 102))	('MAPK', 'Gene', '4216', (98, 102))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('JSI-1187', 'Chemical', '-', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('Erk 1/2', 'Gene', '5595;5594', (38, 45))	('Erk 1/2', 'Gene', (38, 45))
100578	33658799	Other Erk inhibitors including LY3214996, LTT462 and Ulixertinib are under clinical evaluation.	('Erk', 'Gene', '5594', (6, 9))	('LY3214996', 'Var', (31, 40))	('LY3214996', 'Chemical', '-', (31, 40))	('LTT462', 'Var', (42, 48))	('Ulixertinib', 'Chemical', 'MESH:C000618314', (53, 64))	('Erk', 'Gene', (6, 9))
100582	33658799	PIP3 subsequently combines with Akt, a serine/threonine kinase also known as protein kinase B (PKB), and activates it.	('Akt', 'Gene', '207', (32, 35))	('serine', 'Chemical', 'MESH:D012694', (39, 45))	('Akt', 'Gene', (32, 35))	('protein kinase B', 'Gene', (77, 93))	('activates', 'PosReg', (105, 114))	('protein kinase B', 'Gene', '2185', (77, 93))	('PKB', 'Gene', '2185', (95, 98))	('PIP3', 'Chemical', '-', (0, 4))	('combines', 'Interaction', (18, 26))	('PKB', 'Gene', (95, 98))	('PIP3', 'Var', (0, 4))
100591	33658799	According to several studies, PI3K mutations were detected in 4.4% of iCCA patients and 6.5% of eCCA patients.	('patients', 'Species', '9606', (101, 109))	('PI3K mutations', 'Var', (30, 44))	('patients', 'Species', '9606', (75, 83))	('detected', 'Reg', (50, 58))	('iCCA', 'Disease', (70, 74))	('mutations', 'Var', (35, 44))
100592	33658799	PTEN mutations were observed in 4.4% of iCCAs and 3.9% of eCCAs.	('mutations', 'Var', (5, 14))	('iCCAs', 'Disease', (40, 45))	('observed', 'Reg', (20, 28))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
100600	33658799	The first study demonstrating the anti-tumor effects of BKM120, also named Buparlisib, in BTC cells was conducted by Jin et al.	('BKM120', 'Var', (56, 62))	('Buparlisib', 'Chemical', 'MESH:C571178', (75, 85))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('BKM120', 'Chemical', 'MESH:C571178', (56, 62))	('BTC', 'Phenotype', 'HP:0100574', (90, 93))	('tumor', 'Disease', (39, 44))
100601	33658799	They found that BKM120 could suppress the proliferation and migration of BTC cells in vitro.	('suppress', 'NegReg', (29, 37))	('BKM120', 'Chemical', 'MESH:C571178', (16, 22))	('BTC', 'Phenotype', 'HP:0100574', (73, 76))	('BKM120', 'Var', (16, 22))
100602	33658799	Furthermore, inhibiting both PI3K and MEK by BKM120 plus MEK162 showed inhibitory effects in BTC cells with both K-Ras mutations and PI3K mutations, which was not achievable by BKM120 alone.	('inhibitory', 'NegReg', (71, 81))	('BKM120', 'Var', (45, 51))	('inhibiting', 'NegReg', (13, 23))	('MEK', 'Gene', '5609', (57, 60))	('K-Ras', 'Gene', '3845', (113, 118))	('MEK', 'Gene', (38, 41))	('K-Ras', 'Gene', (113, 118))	('MEK', 'Gene', '5609', (38, 41))	('MEK162', 'Chemical', 'MESH:C581313', (57, 63))	('BKM120', 'Chemical', 'MESH:C571178', (45, 51))	('BKM120', 'Chemical', 'MESH:C571178', (177, 183))	('mutations', 'Var', (119, 128))	('BTC', 'Phenotype', 'HP:0100574', (93, 96))	('MEK', 'Gene', (57, 60))	('mutations', 'Var', (138, 147))
100603	33658799	However, a phase I trial of BKM120 plus mFOLFOX6 (5-FU/LV plus oxaliplatin) did not show a tolerant safety profile in advanced gastrointestinal tumors, including 4 CCA patients (NCT01571024).	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (127, 150))	('gastrointestinal tumors', 'Disease', (127, 150))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (127, 150))	('LV plus oxaliplatin', 'Disease', (55, 74))	('5-FU', 'Chemical', 'MESH:D005472', (50, 54))	('BKM120', 'Chemical', 'MESH:C571178', (28, 34))	('patients', 'Species', '9606', (168, 176))	('CCA', 'Disease', (164, 167))	('mFOLFOX6', 'Chemical', '-', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('LV plus oxaliplatin', 'Disease', 'MESH:D007625', (55, 74))	('BKM120', 'Var', (28, 34))
100605	33658799	On the contrary, another phase I study demonstrated that BKM120 is safe with a clear evidence of antitumor activity in patients with advanced cancers, including GBC.	('BKM120', 'Chemical', 'MESH:C571178', (57, 63))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Disease', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('BKM120', 'Var', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('GBC', 'Disease', (161, 164))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
100608	33658799	Sakamoto et al used BTC cell lines as a preclinical model to verify that LY3023414, a PI3K/mTOR dual inhibitor, possessed anti-proliferative activity, marking it as a potential new agent for BTC treatment.	('LY3023414', 'Var', (73, 82))	('BTC', 'Phenotype', 'HP:0100574', (191, 194))	('anti-proliferative activity', 'CPA', (122, 149))	('mTOR', 'Gene', (91, 95))	('BTC', 'Phenotype', 'HP:0100574', (20, 23))	('mTOR', 'Gene', '2475', (91, 95))	('LY3023414', 'Chemical', 'MESH:C000621566', (73, 82))
100609	33658799	The main Akt inhibitors, including MK-2206, FPA124 and A-443654, were confirmed to inhibit cell proliferation and migration in various BTC cell lines.	('MK-2206', 'Var', (35, 42))	('FPA124', 'Chemical', '-', (44, 50))	('BTC', 'Phenotype', 'HP:0100574', (135, 138))	('A-443654', 'Var', (55, 63))	('MK-2206', 'Chemical', 'MESH:C548887', (35, 42))	('Akt', 'Gene', (9, 12))	('FPA124', 'Var', (44, 50))	('A-443654', 'Chemical', 'MESH:C504035', (55, 63))	('inhibit', 'NegReg', (83, 90))	('cell proliferation', 'CPA', (91, 109))	('Akt', 'Gene', '207', (9, 12))
100611	33658799	Among these Akt inhibitors, MK-2206 is considered the most promising, as it is the only one to have entered clinical trials so far.	('Akt', 'Gene', '207', (12, 15))	('Akt', 'Gene', (12, 15))	('MK-2206', 'Chemical', 'MESH:C548887', (28, 35))	('MK-2206', 'Var', (28, 35))
100612	33658799	Wilson et al confirmed that MK-2206 could suppress the CCA cell growth by inducting apoptosis in vitro.	('suppress', 'NegReg', (42, 50))	('MK-2206', 'Chemical', 'MESH:C548887', (28, 35))	('apoptosis', 'CPA', (84, 93))	('MK-2206', 'Var', (28, 35))	('Wilson', 'Disease', 'MESH:D006527', (0, 6))	('Wilson', 'Disease', (0, 6))	('inducting', 'Reg', (74, 83))	('CCA', 'Disease', (55, 58))
100626	33658799	Another relevant phase II clinical trial of everolimus in cancer patients with PI3K abbreviation or PTEN loss did not show any general clinical benefit, though the only CCA patient achieved stable disease (NCT02449538).	('PTEN loss', 'Disease', 'MESH:D006223', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('patient', 'Species', '9606', (173, 180))	('cancer', 'Disease', (58, 64))	('everolimus', 'Chemical', 'MESH:D000068338', (44, 54))	('PTEN loss', 'Disease', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('patient', 'Species', '9606', (65, 72))	('patients', 'Species', '9606', (65, 73))	('PI3K abbreviation', 'Var', (79, 96))
100637	33658799	Recently, RNF43 mutations have been highlighted in BTC patients, with an incidence of 9.3% in CCA cases.	('CCA', 'Disease', (94, 97))	('mutations', 'Var', (16, 25))	('RNF43', 'Gene', '54894', (10, 15))	('BTC', 'Phenotype', 'HP:0100574', (51, 54))	('patients', 'Species', '9606', (55, 63))	('RNF43', 'Gene', (10, 15))
100644	33658799	Gene aberrations are regarded as the drivers of tumors.	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('Gene aberrations', 'Var', (0, 16))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
100646	33658799	IDH1/2 mutations and FGFR2 fusions are some of the most promising current targets for BTC targeted therapy, and more data are expected to verify their efficacy in the future.	('FGFR2', 'Gene', (21, 26))	('FGFR2', 'Gene', '2263', (21, 26))	('BTC', 'Phenotype', 'HP:0100574', (86, 89))	('fusions', 'Var', (27, 34))	('IDH1/2', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
100735	32923885	A higher burden of DNA repair mutations and frequency of patients with TMB-H in the Asian IHCCA cohort compared with the Western patients suggests a potential role for DNA repair and immune checkpoint inhibitors in the Asian population.	('TMB-H', 'Gene', (71, 76))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (57, 65))	('TMB-H', 'Chemical', '-', (71, 76))	('mutations', 'Var', (30, 39))	('DNA repair', 'Gene', (19, 29))	('CCA', 'Phenotype', 'HP:0030153', (92, 95))
100740	32923885	Knowledge Generated Asian patients harbored a higher rate of DNA repair gene mutations compared with Western patients.	('DNA repair gene', 'Gene', (61, 76))	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (26, 34))	('rat', 'Species', '10116', (53, 56))	('mutations', 'Var', (77, 86))	('rat', 'Species', '10116', (14, 17))
100748	32923885	IHCCA, in particular, is enriched with a relatively high number of actionable mutations, and early reports indicate several promising leads with targeted therapies for fibroblast growth factor receptor 2 fusion (FGFR), isocitrate dehydrogenase-1 (IDH1), BRAF V600E mutations, and HER2/neu amplification.	('amplification', 'Var', (289, 302))	('HER2', 'Gene', (280, 284))	('V600E mutations', 'Var', (259, 274))	('V600E', 'Mutation', 'rs113488022', (259, 264))	('isocitrate dehydrogenase-1', 'Gene', (219, 245))	('fibroblast growth factor receptor 2', 'Gene', (168, 203))	('isocitrate dehydrogenase-1', 'Gene', '3417', (219, 245))	('HER2', 'Gene', '2064', (280, 284))	('IDH1', 'Gene', (247, 251))	('fibroblast growth factor receptor 2', 'Gene', '2263', (168, 203))	('BRAF', 'Gene', '673', (254, 258))	('IDH1', 'Gene', '3417', (247, 251))	('CCA', 'Phenotype', 'HP:0030153', (2, 5))	('BRAF', 'Gene', (254, 258))	('IHCCA', 'Disease', (0, 5))
100758	32923885	All types of genetic alterations, including single-nucleotide variant (SNV), short and long indels, copy number alterations (CNAs), and gene rearrangement, were called using a suite of bioinformatics pipelines.	('single-nucleotide variant', 'Var', (44, 69))	('rat', 'Species', '10116', (116, 119))	('copy number alterations', 'Disease', (100, 123))	('rat', 'Species', '10116', (25, 28))
100761	32923885	To identify these alterations, tumor cellularity was estimated by allele frequencies of sequenced single-nucleotide polymorphisms (SNPs).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('rat', 'Species', '10116', (22, 25))	('tumor', 'Disease', (31, 36))	('single-nucleotide polymorphisms', 'Var', (98, 129))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
100762	32923885	Oncogenic criteria included: (1) known pathogenic: oncogenic mutations supported by specific functional studies; (2) likely pathogenic: specific functional studies exist on the mutations situated on the same genome loci and structural disrupting mutations on tumor suppressor genes, such as truncations, splicing sites, and frameshifts; (3) confirmed somatic: somatic mutations recorded on the public genomic database, such as COSMIC, and detected at least once in any tumor types.	('tumor', 'Disease', 'MESH:D009369', (469, 474))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('mutations', 'Var', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (469, 474))	('tumor', 'Disease', (469, 474))	('tumor', 'Disease', (259, 264))
100763	32923885	Tumor mutation burden (TMB) was estimated for 157 US patients and 164 Chinese patients with IHCCA by counting its somatic mutations, including coding SNVs and indels per megabase of the sequence examined.	('indels', 'Var', (159, 165))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (78, 86))	('CCA', 'Phenotype', 'HP:0030153', (94, 97))	('IHCCA', 'Disease', (92, 97))	('TMB', 'Chemical', '-', (23, 26))
100796	32923885	A previous study suggested that fluke-related CCAs are enriched with ERBB2 amplification and TP53 mutation, whereas fluke-negative CCAs have a higher rate of IDH1/2, BAP1, FGFR/PRKA GAs, and programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) expression.	('IDH1/2', 'Gene', (158, 164))	('BAP1', 'Gene', '8314', (166, 170))	('TP53', 'Gene', (93, 97))	('rat', 'Species', '10116', (150, 153))	('mutation', 'Var', (98, 106))	('amplification', 'Var', (75, 88))	('PD-L1', 'Gene', (244, 249))	('CCA', 'Phenotype', 'HP:0030153', (46, 49))	('BAP1', 'Gene', (166, 170))	('ERBB2', 'Gene', (69, 74))	('PD-L1', 'Gene', '29126', (244, 249))	('TP53', 'Gene', '7157', (93, 97))	('ERBB2', 'Gene', '2064', (69, 74))	('programmed death-1', 'Gene', (191, 209))	('programmed death-1', 'Gene', '5133', (191, 209))	('fluke-related CCAs', 'Disease', (32, 50))	('PD-1', 'Gene', (211, 215))	('CCA', 'Phenotype', 'HP:0030153', (131, 134))	('PD-1', 'Gene', '5133', (211, 215))
100797	32923885	Furthermore, in a recent genetic profiling study of 103 Chinese patients with IHCCA, it was noted that TP53 mutations were more commonly seen in HBV-related IHCCA, whereas KRAS mutation was more likely occur in HBV-negative IHCCA.	('HBV', 'Species', '10407', (211, 214))	('TP53', 'Gene', '7157', (103, 107))	('patients', 'Species', '9606', (64, 72))	('mutations', 'Var', (108, 117))	('CCA', 'Phenotype', 'HP:0030153', (226, 229))	('TP53', 'Gene', (103, 107))	('CCA', 'Phenotype', 'HP:0030153', (159, 162))	('HBV-related IHCCA', 'Disease', (145, 162))	('HBV', 'Species', '10407', (145, 148))	('CCA', 'Phenotype', 'HP:0030153', (80, 83))	('seen', 'Reg', (137, 141))
100799	32923885	Dysregulation of DNA repair pathway is often associated with accumulation of several GAs and higher TMB.	('TMB', 'Chemical', '-', (100, 103))	('Dysregulation', 'Var', (0, 13))	('associated', 'Reg', (45, 55))	('several GAs', 'MPA', (77, 88))	('DNA repair pathway', 'Pathway', (17, 35))
100802	32923885	In this study, high TMB was associated with longer progression-free survival.	('progression-free survival', 'CPA', (51, 76))	('TMB', 'Chemical', '-', (20, 23))	('longer', 'PosReg', (44, 50))	('high TMB', 'Var', (15, 23))
100803	32923885	Also, pembrolizumab has been approved by the Food and Drug Administration for the DNA mismatch repair deficient (MMR-d) cancers based on a phase II clinical trial that showed a 40% objective response rate and 78% progression-free survival rate in patients with colorectal cancer with MMR-d compared with 0% and 11%, respectively, for MMR-proficient patients.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('rat', 'Species', '10116', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('MMR-d', 'Var', (284, 289))	('patients', 'Species', '9606', (349, 357))	('progression-free survival', 'CPA', (213, 238))	('rat', 'Species', '10116', (200, 203))	('colorectal cancer', 'Phenotype', 'HP:0003003', (261, 278))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('rat', 'Species', '10116', (239, 242))	('patients', 'Species', '9606', (247, 255))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('colorectal cancer', 'Disease', (261, 278))	('pembrolizumab', 'Chemical', 'MESH:C582435', (6, 19))	('colorectal cancer', 'Disease', 'MESH:D015179', (261, 278))
100806	32923885	For instance, BRCA1/2 mutated high-grade serous ovarian carcinoma had significantly higher CD3+ and CD8+ tumor infiltrating lymphocytes, as well as elevated PD-1 and PD-L1 expression, in tumor-associated immune cells compared with tumors without BRCA1/2 mutations.	('elevated', 'PosReg', (148, 156))	('BRCA1/2', 'Gene', '672;675', (14, 21))	('mutated', 'Var', (22, 29))	('tumor', 'Disease', (187, 192))	('PD-L1', 'Gene', (166, 171))	('tumors', 'Disease', (231, 237))	('higher', 'PosReg', (84, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('PD-L1', 'Gene', '29126', (166, 171))	('BRCA1/2', 'Gene', (246, 253))	('tumor', 'Disease', (231, 236))	('CD8', 'Gene', '925', (100, 103))	('tumor', 'Disease', (105, 110))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('rat', 'Species', '10116', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('serous ovarian carcinoma', 'Disease', (41, 65))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('BRCA1/2', 'Gene', '672;675', (246, 253))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (48, 65))	('BRCA1/2', 'Gene', (14, 21))	('PD-1', 'Gene', '5133', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('PD-1', 'Gene', (157, 161))	('CD8', 'Gene', (100, 103))	('expression', 'MPA', (172, 182))	('CD3+', 'MPA', (91, 95))	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (41, 65))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))
100808	32923885	We classified our patients based on the TMB score, and we considered TMB to be high if it was >= 10 mut/Mb based on results of the recently published CheckMate 568 trial that demonstrated 44% overall response rate in patients who had TMB >= 10 mut/Mb when treated with combined nivolumab and ipilimumab (irrespective of PD-L1 expression).	('>= 10 mut/Mb', 'Var', (238, 250))	('ipilimumab', 'Chemical', 'MESH:D000074324', (292, 302))	('TMB', 'Gene', (234, 237))	('PD-L1', 'Gene', '29126', (320, 325))	('TMB', 'Chemical', '-', (234, 237))	('TMB', 'Chemical', '-', (69, 72))	('rat', 'Species', '10116', (209, 212))	('rat', 'Species', '10116', (182, 185))	('patients', 'Species', '9606', (18, 26))	('TMB', 'Chemical', '-', (40, 43))	('nivolumab', 'Chemical', 'MESH:D000077594', (278, 287))	('patients', 'Species', '9606', (217, 225))	('PD-L1', 'Gene', (320, 325))
100863	29863138	Moreover, considering the function of the pancreas, its resection can lead to endocrine and/or exocrine insufficiency, resulting in diabetes, steatorrhea, and/or malnutrition.	('steatorrhea', 'Disease', (142, 153))	('malnutrition', 'Phenotype', 'HP:0004395', (162, 174))	('resection', 'Var', (56, 65))	('endocrine', 'Disease', (78, 87))	('diabetes', 'Disease', (132, 140))	('lead to', 'Reg', (70, 77))	('diabetes', 'Disease', 'MESH:D003920', (132, 140))	('insufficiency', 'Disease', 'MESH:D000309', (104, 117))	('malnutrition', 'Disease', (162, 174))	('steatorrhea', 'Phenotype', 'HP:0002570', (142, 153))	('steatorrhea', 'Disease', 'MESH:D045602', (142, 153))	('insufficiency', 'Disease', (104, 117))	('resulting in', 'Reg', (119, 131))
100888	28775776	And high KCa3.1 expression indicated a worse prognosis in ICC patients.	('ICC', 'Disease', (58, 61))	('high', 'Var', (4, 8))	('KCa3.1', 'Protein', (9, 15))	('patients', 'Species', '9606', (62, 70))	('expression', 'MPA', (16, 26))
100890	28775776	Knockdown of KCa3.1 could achieve the same effects through decreasing NF-kappaB activation.	('Knockdown', 'Var', (0, 9))	('activation', 'MPA', (80, 90))	('NF-kappaB', 'Gene', '4790', (70, 79))	('decreasing', 'NegReg', (59, 69))	('NF-kappaB', 'Gene', (70, 79))	('KCa3.1', 'Gene', (13, 19))
100901	28775776	Owing to the important roles of KCa3.1 involved in cellular functions, the blocker of KCa3.1 channel has been implicated in a variety of diseases for therapeutic potential, including autoimmune diseases and tumors.	('KCa3.1', 'Gene', (86, 92))	('implicated', 'Reg', (110, 120))	('blocker', 'Var', (75, 82))	('autoimmune diseases and tumors', 'Disease', 'MESH:D001327', (183, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (183, 202))
100923	28775776	The primary antibodies used in this experiment were beta-actin (1:4000, ab8227, abcam), KCa3.1 (1:2000, 251868, Abbiotec), matrix metalloproteinase 2, MMP-2 (1:2000, ab92536, abcam), MMP-9 (1:1000, ab76003, abcam), Lamin A/C (1:4000, ab58529, abcam), and Phospho-NF-kappaB p65 (Ser536) (1:2000, 3033, CST).	('NF-kappaB', 'Gene', (263, 272))	('matrix metalloproteinase 2', 'Gene', '4313', (123, 149))	('matrix metalloproteinase 2', 'Gene', (123, 149))	('CST', 'Gene', '106478911', (301, 304))	('NF-kappaB', 'Gene', '4790', (263, 272))	('beta-actin', 'Gene', (52, 62))	('p65', 'Gene', (273, 276))	('MMP-2', 'Gene', (151, 156))	('1:1000', 'Var', (190, 196))	('CST', 'Gene', (301, 304))	('ab76003', 'Var', (198, 205))	('p65', 'Gene', '5970', (273, 276))	('beta-actin', 'Gene', '728378', (52, 62))	('MMP-9', 'Gene', (183, 188))	('MMP-9', 'Gene', '4318', (183, 188))	('Lamin A/C', 'Gene', '4000', (215, 224))	('ab58529', 'Var', (234, 241))	('Lamin A/C', 'Gene', (215, 224))	('MMP-2', 'Gene', '4313', (151, 156))
100947	28775776	Kaplan-Meier analysis revealed ICC patients with high KCa3.1 expression had a worse overall survival than those with low KCa3.1 expression (N=67, P=0.087).	('overall survival', 'MPA', (84, 100))	('KCa3.1', 'Gene', (54, 60))	('high', 'Var', (49, 53))	('patients', 'Species', '9606', (35, 43))	('worse', 'NegReg', (78, 83))	('ICC', 'Disease', (31, 34))
100969	28775776	Cell proliferation assay showed that KCa3.1 silencing significantly decreased the viability of Huh28 and HUCCT1 cells compared to control group (P < 0.05, Fig.	('decreased', 'NegReg', (68, 77))	('Huh28', 'CellLine', 'CVCL:0336', (95, 100))	('HUCCT1', 'CellLine', 'CVCL:0324', (105, 111))	('KCa3.1', 'Gene', (37, 43))	('silencing', 'Var', (44, 53))	('viability', 'CPA', (82, 91))
100970	28775776	We found that knockdown of KCa3.1 significantly decreased the migratory and invasive potential of Huh28 cells and HUCCT1 cells (P < 0.01, Fig.	('KCa3.1', 'Gene', (27, 33))	('Huh28', 'CellLine', 'CVCL:0336', (98, 103))	('HUCCT1', 'CellLine', 'CVCL:0324', (114, 120))	('decreased', 'NegReg', (48, 57))	('knockdown', 'Var', (14, 23))
100972	28775776	The results showed that the level of phospho-NF-kappaB p65 in nuclei was obviously decreased in HUCCT1 cells and reduced (not significantly) in Huh28 cells after KCa3.1 knockdown, compared to control group (Fig.	('knockdown', 'Var', (169, 178))	('level', 'MPA', (28, 33))	('decreased', 'NegReg', (83, 92))	('NF-kappaB', 'Gene', '4790', (45, 54))	('Huh28', 'CellLine', 'CVCL:0336', (144, 149))	('p65', 'Gene', (55, 58))	('NF-kappaB', 'Gene', (45, 54))	('reduced', 'NegReg', (113, 120))	('HUCCT1', 'CellLine', 'CVCL:0324', (96, 102))	('p65', 'Gene', '5970', (55, 58))
100992	28775776	And high KCa3.1 expression not only significantly associated with age, lymph node metastasis and TNM stage, but also indicated a poor overall survival in patients.	('lymph node metastasis', 'Disease', (71, 92))	('poor', 'NegReg', (129, 133))	('KCa3.1', 'Gene', (9, 15))	('patients', 'Species', '9606', (154, 162))	('TNM', 'Gene', '10178', (97, 100))	('high', 'Var', (4, 8))	('overall', 'MPA', (134, 141))	('age', 'CPA', (66, 69))	('expression', 'MPA', (16, 26))	('lymph node metastasis', 'Disease', 'MESH:D009362', (71, 92))	('associated', 'Reg', (50, 60))	('TNM', 'Gene', (97, 100))
101001	28775776	Several studies have reported that the activity of KCa3.1 channels facilitates the Ca2+ influx through setting the cell membrane potential and the driving force for Ca2+ influx in different cell types.	('setting the cell membrane potential', 'MPA', (103, 138))	('activity', 'Var', (39, 47))	('Ca2+', 'Chemical', 'MESH:D000069285', (165, 169))	('KCa3.1', 'Gene', (51, 57))	('Ca2+', 'Chemical', 'MESH:D000069285', (83, 87))	('facilitates', 'PosReg', (67, 78))	('Ca2+ influx', 'MPA', (83, 94))
101011	28775776	Our results demonstrated that knockdown of KCa3.1 reduced the proliferation, migration and invasion of Huh28 cells and HUCCT1 cells.	('proliferation', 'CPA', (62, 75))	('HUCCT1', 'CellLine', 'CVCL:0324', (119, 125))	('migration', 'CPA', (77, 86))	('KCa3.1', 'Gene', (43, 49))	('invasion of Huh28 cells', 'CPA', (91, 114))	('knockdown', 'Var', (30, 39))	('reduced', 'NegReg', (50, 57))	('Huh28', 'CellLine', 'CVCL:0336', (103, 108))
101012	28775776	As for underlying relevant mechanisms, here we examined effect of KCa3.1 knockdown on the activation of the nuclear transcription factor NF-kappaB.	('NF-kappaB', 'Gene', '4790', (137, 146))	('KCa3.1', 'Gene', (66, 72))	('NF-kappaB', 'Gene', (137, 146))	('knockdown', 'Var', (73, 82))
101016	28775776	Our data showed that knockdown of KCa3.1 obviously reduced the activation of NF-kappaB in HUCCT1 cells, while the reduction of activation of NF-kappaB in Huh28 cells was not significant as HUCCT1 cells.	('HUCCT1', 'CellLine', 'CVCL:0324', (90, 96))	('reduced', 'NegReg', (51, 58))	('NF-kappaB', 'Gene', (77, 86))	('Huh28', 'CellLine', 'CVCL:0336', (154, 159))	('NF-kappaB', 'Gene', '4790', (141, 150))	('activation', 'MPA', (63, 73))	('KCa3.1', 'Gene', (34, 40))	('knockdown', 'Var', (21, 30))	('NF-kappaB', 'Gene', (141, 150))	('NF-kappaB', 'Gene', '4790', (77, 86))	('HUCCT1', 'CellLine', 'CVCL:0324', (189, 195))
101017	28775776	And the decreased NF-kappaB activation may have contributed to the anti-tumor effects of KCa3.1 knockdown.	('knockdown', 'Var', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('NF-kappaB', 'Gene', '4790', (18, 27))	('activation', 'PosReg', (28, 38))	('NF-kappaB', 'Gene', (18, 27))	('decreased', 'NegReg', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('KCa3.1', 'Gene', (89, 95))
101046	27339253	Despite the potential risk of recurrent PSC, a recent analysis of all transplant recipients in the United States showed that, among transplant recipients with cholestatic liver disease (PSC or primary biliary cirrhosis), recipients of an LDLT had significantly higher post-transplant graft and patient survival compared with those who received DDLT.	('primary biliary cirrhosis', 'Disease', (193, 218))	('LDLT', 'Var', (238, 242))	('patient', 'Species', '9606', (294, 301))	('PSC', 'Gene', (40, 43))	('cholestatic liver disease', 'Phenotype', 'HP:0002611', (159, 184))	('cirrhosis', 'Phenotype', 'HP:0001394', (209, 218))	('cholestatic liver disease', 'Disease', 'MESH:D008107', (159, 184))	('cholestatic liver disease', 'Disease', (159, 184))	('primary biliary cirrhosis', 'Disease', 'MESH:D008105', (193, 218))	('PSC', 'Gene', '100653366', (186, 189))	('higher', 'PosReg', (261, 267))	('liver disease', 'Phenotype', 'HP:0001392', (171, 184))	('primary biliary cirrhosis', 'Phenotype', 'HP:0002613', (193, 218))	('patient survival', 'CPA', (294, 310))	('DD', 'Chemical', '-', (344, 346))	('PSC', 'Gene', '100653366', (40, 43))	('PSC', 'Gene', (186, 189))
101145	27279267	CRM-1 knockdown inhibits extrahepatic cholangiocarcinoma tumor growth by blocking the nuclear export of p27Kip1 Cholangiocarcinoma is a deadly disease which responds poorly to surgery and conventional chemotherapy or radiotherapy.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('CRM-1', 'Gene', '7514', (0, 5))	('extrahepatic cholangiocarcinoma tumor', 'Disease', 'MESH:D018281', (25, 62))	('blocking', 'NegReg', (73, 81))	('nuclear export', 'MPA', (86, 100))	('p27Kip1', 'Var', (104, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (38, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('inhibits', 'NegReg', (16, 24))	('knockdown', 'Var', (6, 15))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 130))	('Cholangiocarcinoma', 'Disease', (112, 130))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('extrahepatic cholangiocarcinoma tumor', 'Disease', (25, 62))	('CRM-1', 'Gene', (0, 5))
101150	27279267	Through specific short hairpin RNA (shRNA)-mediated knockdown of CRM-1 in the cholangiocarcinoma cell line QBC939, we identified an elevation of cytoplasmic p27Kip1 and a decrease of nuclear p27Kip1.	('elevation', 'PosReg', (132, 141))	('p27Kip1', 'Gene', '1027', (157, 164))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 96))	('decrease', 'NegReg', (171, 179))	('CRM-1', 'Gene', (65, 70))	('p27Kip1', 'Gene', (157, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (78, 96))	('QBC939', 'CellLine', 'CVCL:6942', (107, 113))	('p27Kip1', 'Gene', '1027', (191, 198))	('knockdown', 'Var', (52, 61))	('cholangiocarcinoma', 'Disease', (78, 96))	('p27Kip1', 'Gene', (191, 198))
101152	27279267	Consistent with the findings of the in vitro experiments, in a xenograft mouse model, the tumors formed in the CRM-1 knockdown group were markedly smaller and weighed less than those in the control group in vivo.	('smaller', 'NegReg', (147, 154))	('CRM-1', 'Gene', (111, 116))	('less', 'NegReg', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('weighed', 'CPA', (159, 166))	('mouse', 'Species', '10090', (73, 78))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('knockdown', 'Var', (117, 126))
101236	27279267	Notably, the colony formation assay demonstrated that the colony forming ability of the QBC939 cells was significantly inhibited by the knockdown of CRM-1 as compared with that in the blank and vector groups (Fig.	('knockdown', 'Var', (136, 145))	('inhibited', 'NegReg', (119, 128))	('QBC939', 'CellLine', 'CVCL:6942', (88, 94))	('CRM-1', 'Gene', (149, 154))	('colony forming ability', 'CPA', (58, 80))
101237	27279267	Furthermore, the knockdown of CRM-1 by shRNA reduced the viability of QBC939 cells (Fig.	('reduced', 'NegReg', (45, 52))	('QBC939', 'CellLine', 'CVCL:6942', (70, 76))	('knockdown', 'Var', (17, 26))	('viability', 'CPA', (57, 66))	('CRM-1', 'Gene', (30, 35))
101238	27279267	Additionally, performing the cell cycle analysis of these cells using the PI staining method, revealed marked G1 arrest in the QBC939-shCRM-1 group as compared with that in the blank and control groups (Fig.	('QBC939', 'CellLine', 'CVCL:6942', (127, 133))	('G1 arrest', 'CPA', (110, 119))	('QBC939-shCRM-1', 'Var', (127, 141))
101240	27279267	5A, the CRM-1 knockdown group exhibited markedly smaller tumor volumes as compared with those in the blank and vector groups.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('smaller', 'NegReg', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('knockdown', 'Var', (14, 23))	('CRM-1', 'Gene', (8, 13))	('tumor', 'Disease', (57, 62))
101241	27279267	The xenograft tumors were weighed and the CRM-1 knockdown group clearly produced lighter (Fig.	('xenograft tumors', 'Disease', 'MESH:D009369', (4, 20))	('lighter', 'NegReg', (81, 88))	('CRM-1', 'Gene', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('xenograft tumors', 'Disease', (4, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('knockdown', 'Var', (48, 57))
101249	27279267	The aberrant expression or localization of p27Kip1 weakens its inhibitory effect on the cell cycle, leading to uncontrolled cell growth and carcinogenesis.	('weakens', 'NegReg', (51, 58))	('localization', 'MPA', (27, 39))	('carcinogenesis', 'Disease', 'MESH:D063646', (140, 154))	('p27Kip1', 'Gene', (43, 50))	('aberrant', 'Var', (4, 12))	('uncontrolled', 'MPA', (111, 123))	('carcinogenesis', 'Disease', (140, 154))	('inhibitory effect', 'MPA', (63, 80))	('leading to', 'Reg', (100, 110))	('p27Kip1', 'Gene', '1027', (43, 50))
101251	27279267	Consistent with these previous findings, we found that p27Kip1 expression was decreased in the cholangiocarcinoma tissues compared with that in the chronic cholangitis tissues, suggesting that the aberrant expression of p27Kip1 may be associated with the development and progression of cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (295, 304))	('cholangiocarcinoma tissues', 'Disease', (95, 121))	('p27Kip1', 'Gene', (55, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('p27Kip1', 'Gene', '1027', (55, 62))	('p27Kip1', 'Gene', (220, 227))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (286, 304))	('decreased', 'NegReg', (78, 87))	('chronic cholangitis', 'Disease', 'MESH:D002761', (148, 167))	('aberrant', 'Var', (197, 205))	('chronic cholangitis', 'Disease', (148, 167))	('p27Kip1', 'Gene', '1027', (220, 227))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (95, 113))	('cholangiocarcinoma', 'Disease', (286, 304))	('expression', 'MPA', (63, 73))	('cholangiocarcinoma tissues', 'Disease', 'MESH:D018281', (95, 121))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (286, 304))	('cholangiocarcinoma', 'Disease', (95, 113))	('associated', 'Reg', (235, 245))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (95, 113))	('cholangitis', 'Phenotype', 'HP:0030151', (156, 167))
101254	27279267	These findings suggested that that there may be an association between the aberrant expression of p27Kip1 and the malignancy and clinical stage of cholangiocarcinoma, and that p27Kip1 is transported from the nucleus to the cytoplasm during tumor progression in cholangiocarcinoma.	('aberrant', 'Var', (75, 83))	('p27Kip1', 'Gene', '1027', (176, 183))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (147, 165))	('tumor', 'Disease', (240, 245))	('cholangiocarcinoma', 'Disease', (147, 165))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (147, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('malignancy', 'Disease', 'MESH:D009369', (114, 124))	('association', 'Interaction', (51, 62))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (261, 279))	('expression', 'MPA', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('cholangiocarcinoma', 'Disease', (261, 279))	('p27Kip1', 'Gene', (98, 105))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (261, 279))	('malignancy', 'Disease', (114, 124))	('p27Kip1', 'Gene', '1027', (98, 105))	('p27Kip1', 'Gene', (176, 183))
101270	27279267	Mutation at this site has been shown to cause p27Kip1 to lose its nuclear export capability, indicating that Ser10 phosphorylation may play a critical role in the subcellular distribution and functional status of p27Kip1.	('p27Kip1', 'Gene', '1027', (213, 220))	('nuclear export capability', 'MPA', (66, 91))	('p27Kip1', 'Gene', (46, 53))	('p27Kip1', 'Gene', (213, 220))	('Mutation', 'Var', (0, 8))	('lose', 'NegReg', (57, 61))	('Ser10', 'Chemical', '-', (109, 114))	('p27Kip1', 'Gene', '1027', (46, 53))
101272	27279267	This is consistent with previous findings in neuroglioma which demonstrated that high expression levels of CRM-1 and p27Kip1 closely correlated with malignancy, and that high CRM-1 expression was associated with a poor prognosis.	('expression', 'MPA', (181, 191))	('high expression levels', 'MPA', (81, 103))	('CRM-1', 'Gene', (107, 112))	('malignancy', 'Disease', 'MESH:D009369', (149, 159))	('p27Kip1', 'Gene', '1027', (117, 124))	('malignancy', 'Disease', (149, 159))	('neuroglioma', 'Disease', 'None', (45, 56))	('correlated', 'Reg', (133, 143))	('p27Kip1', 'Gene', (117, 124))	('neuroglioma', 'Disease', (45, 56))	('high', 'Var', (170, 174))
101275	27279267	The aberrant expression of p27Kip1 may result in abnormal cytoplasmic proteolysis coupled with nuclear translocation in cholangiocarcinoma.	('nuclear translocation', 'MPA', (95, 116))	('p27Kip1', 'Gene', '1027', (27, 34))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (120, 138))	('result in', 'Reg', (39, 48))	('aberrant', 'Var', (4, 12))	('abnormal cytoplasmic proteolysis', 'MPA', (49, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (120, 138))	('p27Kip1', 'Gene', (27, 34))	('cholangiocarcinoma', 'Disease', (120, 138))
101281	27279267	In conclusion, the knockdown of CRM-1 may lead to decreases in p27Kip1 levels in the cytoplasm, thereby inhibiting malignant transformation in cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('knockdown', 'Var', (19, 28))	('p27Kip1', 'Gene', '1027', (63, 70))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (143, 161))	('decreases', 'NegReg', (50, 59))	('malignant transformation', 'CPA', (115, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (143, 161))	('inhibiting', 'NegReg', (104, 114))	('CRM-1', 'Gene', (32, 37))	('p27Kip1', 'Gene', (63, 70))	('cholangiocarcinoma', 'Disease', (143, 161))
101321	25547488	RNS induce protein nitration such as 3-nitrotyrosine, an inflammation-associated marker.	('protein nitration', 'MPA', (11, 28))	('induce', 'Reg', (4, 10))	('3-nitrotyrosine', 'Chemical', 'MESH:C002744', (37, 52))	('RNS', 'Var', (0, 3))	('inflammation', 'Disease', 'MESH:D007249', (57, 69))	('3-nitrotyrosine', 'MPA', (37, 52))	('inflammation', 'Disease', (57, 69))
101330	25547488	The oxidatively induced DNA damage typically associated with ROS are apurinic/apyrimidinic (AP) DNA sites, oxidized purines and pyrimidines, single strand and double strand DNA breaks.	('double strand DNA', 'Var', (159, 176))	('apurinic/apyrimidinic', 'MPA', (69, 90))	('single strand', 'Var', (141, 154))	('pyrimidines', 'Chemical', 'MESH:D011743', (128, 139))	('purines', 'Chemical', 'MESH:D011687', (116, 123))	('ROS', 'Disease', (61, 64))	('ROS', 'Chemical', 'MESH:D017382', (61, 64))
101333	25547488	Double strand DNA breaks are the most genotoxic DNA lesions and the unrepaired lesions can lead to neural cell death, leading to neurodegeneration.	('lead to', 'Reg', (91, 98))	('neurodegeneration', 'Phenotype', 'HP:0002180', (129, 146))	('neural cell death', 'CPA', (99, 116))	('Double strand DNA breaks', 'Var', (0, 24))	('neurodegeneration', 'Disease', (129, 146))	('neurodegeneration', 'Disease', 'MESH:D019636', (129, 146))
101334	25547488	Single strand and double strand DNA breaks are typically detected in the brain in Alzheimer's disease and other neurodegenerative diseases.	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (112, 138))	("Alzheimer's disease", 'Disease', (82, 101))	('double strand DNA breaks', 'Var', (18, 42))	('neurodegenerative diseases', 'Disease', (112, 138))	('Single strand', 'Var', (0, 13))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (112, 137))	('detected', 'Reg', (57, 65))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (112, 138))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (82, 101))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (82, 101))
101348	25547488	Moreover, several molecules that are involved in mismatch repair (MMR) and NER also play important roles in preventing mutations due to 8-oxodG formation.	('8-oxodG formation', 'MPA', (136, 153))	('mutations', 'Var', (119, 128))	('8-oxodG', 'Chemical', '-', (136, 143))
101349	25547488	demonstrated, in work with oligonucleotides containing an 8-oxodG, that this lesion can induce template switching, thereby bypassing the damaged base.	('bypassing', 'NegReg', (123, 132))	('template switching', 'MPA', (95, 113))	('oligonucleotides', 'Chemical', 'MESH:D009841', (27, 43))	('8-oxodG', 'Chemical', '-', (58, 65))	('damaged base', 'MPA', (137, 149))	('induce', 'Reg', (88, 94))	('lesion', 'Var', (77, 83))
101351	25547488	Therefore, high formation of 8-oxodG is a potentially mutagenic DNA lesion that leads to the transversion of G:C to T:A (G T transversion) via mis-complementation with deoxyadenosine-5'-triphosphate (dATP) during DNA replication.	('dATP', 'Chemical', 'MESH:C026600', (200, 204))	("deoxyadenosine-5'-triphosphate", 'Chemical', 'MESH:C026600', (168, 198))	('8-oxodG', 'Chemical', '-', (29, 36))	('mis-complementation', 'Var', (143, 162))	('transversion', 'MPA', (93, 105))
101353	25547488	DNA polymerase eta and kappa were involved in the incorporation of dATP opposite 8-nitroguanine during DNA synthesis in a cell-free system associated with trans-lesion DNA synthesis leading to the G T transversion.	('DNA polymerase eta', 'Gene', (0, 18))	('dATP', 'Chemical', 'MESH:C026600', (67, 71))	('G T transversion', 'Var', (197, 213))	('DNA polymerase eta', 'Gene', '5429', (0, 18))	('8-nitroguanine', 'Chemical', 'MESH:C095838', (81, 95))
101354	25547488	DNA polymerase was hypersensitive to nitrative stress, and trans-lesion DNA synthesis past apurinic sites mediated by this polymerase contributes to extensive point mutations.	('hypersensitive', 'Disease', 'MESH:D004342', (19, 33))	('nitrative stress', 'Phenotype', 'HP:0025464', (37, 53))	('hypersensitive', 'Disease', (19, 33))	('point mutations', 'Var', (159, 174))
101358	25547488	This point mutation was also frequently found in KRAS mutation in colorectal cancers.	('KRAS', 'Var', (49, 53))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('colorectal cancers', 'Disease', 'MESH:D015179', (66, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('found', 'Reg', (40, 45))	('colorectal cancers', 'Disease', (66, 84))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
101359	25547488	p53 mutation in lung cancers implies an excess of G T transversion, which is a molecular signature of tobacco smoke mutagens in smoking-associated lung cancers.	('p53', 'Gene', (0, 3))	('lung cancers', 'Disease', (147, 159))	('p53', 'Gene', '7157', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('lung cancers', 'Phenotype', 'HP:0100526', (16, 28))	('tobacco', 'Species', '4097', (102, 109))	('lung cancers', 'Disease', 'MESH:D008175', (147, 159))	('G T transversion', 'MPA', (50, 66))	('lung cancers', 'Disease', (16, 28))	('mutation', 'Var', (4, 12))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('lung cancers', 'Phenotype', 'HP:0100526', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('lung cancers', 'Disease', 'MESH:D008175', (16, 28))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
101372	25547488	The highly oxidized lipofuscin accumulates during aging, and lipofuscin formation may cause impaired lysosomal and proteasomal degradation, metal ion accumulation, increased reactive oxygen species formation, and apoptosis.	('metal', 'Chemical', 'MESH:D008670', (140, 145))	('increased reactive oxygen species', 'Phenotype', 'HP:0025464', (164, 197))	('metal ion accumulation', 'MPA', (140, 162))	('lipofuscin', 'Chemical', 'MESH:D008062', (61, 71))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (174, 197))	('lipofuscin', 'Chemical', 'MESH:D008062', (20, 30))	('impaired', 'NegReg', (92, 100))	('lipofuscin', 'Var', (61, 71))	('apoptosis', 'CPA', (213, 222))	('reactive oxygen species formation', 'MPA', (174, 207))	('increased', 'PosReg', (164, 173))
101374	25547488	demonstrated the colocalization of oxidized-gamma-synuclein with phospho-alpha-synuclein in the brain and the neuronal accumulation of aberrant gamma-synuclein in neurodegenerative diseases, suggesting that gamma-synuclein plays an important role in alpha-synuclein aggregation.	('alpha-synuclein', 'Gene', (73, 88))	('gamma-synuclein', 'Gene', (207, 222))	('neurodegenerative diseases', 'Disease', (163, 189))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (163, 188))	('gamma-synuclein', 'Gene', (44, 59))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (163, 189))	('alpha-synuclein', 'Gene', '6622', (73, 88))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (163, 189))	('gamma-synuclein', 'Gene', '6623', (207, 222))	('alpha-synuclein', 'Gene', (250, 265))	('gamma-synuclein', 'Gene', (144, 159))	('gamma-synuclein', 'Gene', '6623', (44, 59))	('alpha-synuclein', 'Gene', '6622', (250, 265))	('aberrant', 'Var', (135, 143))	('gamma-synuclein', 'Gene', '6623', (144, 159))	('neuronal accumulation', 'Phenotype', 'HP:0002529', (110, 131))
101377	25547488	Such carbonylated proteins were detected in an animal model of the neurotoxic effects of 1-bromopropane (1-BP), suggesting that 1-BP-induced hippocampal damage involves oxidative stress, loss of ATP production, neurotransmitter dysfunction and inhibition of the ubiquitination-proteasome system.	('inhibition', 'NegReg', (244, 254))	('oxidative stress', 'MPA', (169, 185))	('neurotoxic', 'Disease', (67, 77))	('loss', 'NegReg', (187, 191))	('1-BP', 'Chemical', 'MESH:C118559', (105, 109))	('ubiquitination-proteasome system', 'Pathway', (262, 294))	('neurotransmitter dysfunction', 'Disease', 'MESH:D006331', (211, 239))	('ATP', 'Chemical', 'MESH:D000255', (195, 198))	('neurotransmitter dysfunction', 'Disease', (211, 239))	('oxidative stress', 'Phenotype', 'HP:0025464', (169, 185))	('1-BP-induced', 'Var', (128, 140))	('neurotoxic', 'Disease', 'MESH:D020258', (67, 77))	('1-BP', 'Chemical', 'MESH:C118559', (128, 132))	('1-bromopropane', 'Chemical', 'MESH:C118559', (89, 103))	('ATP production', 'MPA', (195, 209))
101379	25547488	HSP70 is known to protect cells from oxidative stress and stabilize the lysosomal membrane, and therefore our results and previous studies suggest that carbonylated HSP70 may induce autophagy of neurons via the lysosomal degradation pathway.	('induce', 'PosReg', (175, 181))	('oxidative stress', 'Phenotype', 'HP:0025464', (37, 53))	('HSP70', 'Gene', '3308', (0, 5))	('autophagy of neurons', 'CPA', (182, 202))	('HSP70', 'Gene', '3308', (165, 170))	('lysosomal degradation pathway', 'Pathway', (211, 240))	('HSP70', 'Gene', (0, 5))	('HSP70', 'Gene', (165, 170))	('carbonylated', 'Var', (152, 164))
101392	25547488	Aggregation of these abnormal proteins further induces oxidative stress via induction of mitochondria dysfunction and ROS production resulting in mitochondria DNA damage that triggers apoptosis.	('mitochondria dysfunction', 'Disease', 'MESH:C564925', (89, 113))	('mitochondria dysfunction', 'Disease', (89, 113))	('induces', 'Reg', (47, 54))	('Aggregation', 'Var', (0, 11))	('induction', 'Reg', (76, 85))	('triggers', 'Reg', (175, 183))	('oxidative stress', 'MPA', (55, 71))	('oxidative stress', 'Phenotype', 'HP:0025464', (55, 71))	('ROS', 'Chemical', 'MESH:D017382', (118, 121))	('ROS', 'Protein', (118, 121))	('proteins', 'Protein', (30, 38))	('mitochondria DNA damage', 'MPA', (146, 169))
101404	25547488	2D-oxyblot and LC-MALDI-TOF/TOF analysis of separated proteins from the bile duct cancer tissues identified R50, K327, and P357 as carbonylated sites in serotransferrin, heat shock protein 70 protein 1 (HSP70.1), and alpha-1-antitrypsin (A1AT), respectively.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('bile duct cancer', 'Phenotype', 'HP:0030153', (72, 88))	('P357', 'Var', (123, 127))	('A1AT', 'Gene', (238, 242))	('R50', 'Var', (108, 111))	('HSP70.1', 'Gene', '3303', (203, 210))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('HSP70.1', 'Gene', (203, 210))	('shock', 'Phenotype', 'HP:0031273', (175, 180))	('heat shock protein 70', 'Gene', (170, 191))	('A1AT', 'Gene', '5265', (238, 242))	('serotransferrin', 'Gene', (153, 168))	('serotransferrin', 'Gene', '7018', (153, 168))	('heat shock protein 70', 'Gene', '3308', (170, 191))	('K327', 'Var', (113, 117))
101405	25547488	Oxidative stress by inflammation caused the carbonylation of serotransferrin, which was coincident with iron accumulation, suggesting that the modified serotransferrin may lead to the accumulation and release of iron ion.	('iron ion', 'MPA', (212, 220))	('serotransferrin', 'Gene', (152, 167))	('serotransferrin', 'Gene', (61, 76))	('iron', 'Chemical', 'MESH:D007501', (212, 216))	('serotransferrin', 'Gene', '7018', (61, 76))	('carbonylation', 'MPA', (44, 57))	('iron', 'Chemical', 'MESH:D007501', (104, 108))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('modified', 'Var', (143, 151))	('lead to', 'Reg', (172, 179))	('inflammation', 'Disease', 'MESH:D007249', (20, 32))	('serotransferrin', 'Gene', '7018', (152, 167))	('inflammation', 'Disease', (20, 32))	('accumulation', 'MPA', (184, 196))	('release', 'MPA', (201, 208))
101411	25547488	Therefore, carbonylation of A1AT may lead to a conformational change and protein dysfunction, which could be involved in the progression of cholangiocarcinoma.	('carbonylation', 'Var', (11, 24))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (140, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('protein dysfunction', 'Disease', 'MESH:D011488', (73, 92))	('lead to', 'Reg', (37, 44))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (140, 158))	('A1AT', 'Gene', '5265', (28, 32))	('protein dysfunction', 'Disease', (73, 92))	('involved', 'Reg', (109, 117))	('A1AT', 'Gene', (28, 32))	('cholangiocarcinoma', 'Disease', (140, 158))	('conformational change', 'MPA', (47, 68))
101414	25547488	Our findings and previous studies suggest that dysfunction due to oxidized protein may lead to all stages of carcinogenesis: tumor initiation, promotion and progression.	('dysfunction', 'MPA', (47, 58))	('tumor initiation', 'Disease', 'MESH:D009369', (125, 141))	('carcinogenesis', 'Disease', 'MESH:D063646', (109, 123))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('carcinogenesis', 'Disease', (109, 123))	('promotion', 'CPA', (143, 152))	('tumor initiation', 'Disease', (125, 141))	('protein', 'Protein', (75, 82))	('lead to', 'Reg', (87, 94))	('oxidized', 'Var', (66, 74))
101417	25547488	These DNA lesions may induce carcinogenesis through the induction of mutation, genetic instability and epigenetic changes.	('carcinogenesis', 'Disease', (29, 43))	('epigenetic', 'CPA', (103, 113))	('genetic', 'CPA', (79, 86))	('mutation', 'Var', (69, 77))	('lesions', 'Var', (10, 17))	('induce', 'Reg', (22, 28))	('carcinogenesis', 'Disease', 'MESH:D063646', (29, 43))
101451	25547488	Several mutations occur in cancer cells suggesting that cancer is a disease of genes, in which a cell ignores growth-limiting signals and forms a tumor that eventually leads to the death of the organism.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('leads to', 'Reg', (168, 176))	('tumor', 'Disease', (146, 151))	('mutations', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
101462	25547488	These studies strongly indicated that in some cases the redox status of the stem cells fails to protect the cells from oxidative damage which contributes to DNA damage, mutation and genetic instability of the CSCs resulting in tumor progression with a poor prognostic outcome.	('mutation', 'Var', (169, 177))	('tumor', 'Disease', (227, 232))	('CSCs', 'Gene', (209, 213))	('genetic instability', 'Var', (182, 201))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('DNA damage', 'MPA', (157, 167))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
101465	25547488	ROS-induced DNA damage such as 8-oxodG and O6-methylguanine and point mutations can interfere with the binding of DNMTs and therefore can lead to hypomethylation by means of inhibiting methylation of adjacent cytosine molecules.	('interfere', 'NegReg', (84, 93))	('point mutations', 'Var', (64, 79))	('8-oxodG', 'Chemical', '-', (31, 38))	('methylation', 'MPA', (185, 196))	('inhibiting', 'NegReg', (174, 184))	('DNMTs', 'Protein', (114, 119))	('O6-methylguanine', 'Var', (43, 59))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('binding', 'Interaction', (103, 110))	('cytosine', 'Chemical', 'MESH:D003596', (209, 217))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (43, 59))	('lead to', 'Reg', (138, 145))	('hypomethylation', 'MPA', (146, 161))
101469	25547488	Epigenetic silencing of tumor suppressor genes plays an important role in EBV-associated neoplasia.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('neoplasia', 'Phenotype', 'HP:0002664', (89, 98))	('tumor', 'Disease', (24, 29))	('neoplasia', 'Disease', (89, 98))	('Epigenetic silencing', 'Var', (0, 20))	('EBV', 'Species', '10376', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('neoplasia', 'Disease', 'MESH:D009369', (89, 98))
101470	25547488	We, and our colleagues, have found promoter hypermethylation in several candidate tumor suppressor genes for EBV-associated nasopharyngeal carcinoma.	('promoter hypermethylation', 'Var', (35, 60))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (124, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (124, 148))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('nasopharyngeal carcinoma', 'Disease', (124, 148))	('EBV', 'Species', '10376', (109, 112))	('EBV-associated', 'Gene', (109, 123))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
101478	25547488	When several carcinogenic events such as mutation and epigenetic changes occur in stem cells under oxidative stress, the cells may acquire the properties of cancer stem cells.	('acquire', 'PosReg', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('carcinogenic', 'Disease', 'MESH:D063646', (13, 25))	('epigenetic changes', 'Var', (54, 72))	('carcinogenic', 'Disease', (13, 25))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('mutation', 'Var', (41, 49))	('cancer', 'Disease', (157, 163))	('oxidative stress', 'Phenotype', 'HP:0025464', (99, 115))
101503	24982670	As a result, they reported that outcome of biliary drainage was poorer among patients with Bismuth III and IV tumors compared to those with Bismuth I and II tumors.	('IV tumors', 'Disease', (107, 116))	('Bismuth III', 'Var', (91, 102))	('IV tumors', 'Disease', 'MESH:D009369', (107, 116))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('II tumors', 'Disease', 'MESH:D009369', (154, 163))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('II tumors', 'Disease', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('biliary drainage', 'MPA', (43, 59))	('poorer', 'NegReg', (64, 70))
101513	33299012	Here we found that BEX2 was highly expressed in CD274low cells, and that BEX2 knockdown decreased the tumorigenicity and G0 phase of cholangiocarcinoma cells.	('cholangiocarcinoma', 'Disease', (133, 151))	('G0 phase', 'CPA', (121, 129))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (133, 151))	('BEX2', 'Gene', (73, 77))	('knockdown', 'Var', (78, 87))	('CD274', 'Gene', '29126', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (133, 151))	('decreased', 'NegReg', (88, 97))	('CD274', 'Gene', (48, 53))	('tumor', 'Disease', (102, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
101515	33299012	Comprehensive screening of BEX2 binding proteins identified E3 ubiquitin ligase complex proteins, FEM1B and CUL2, and a mitochondrial protein TUFM, and further demonstrated that knockdown of BEX2 or TUFM increased mitochondria-related oxygen consumption and decreased tumorigenicity in cholangiocarcinoma cells.	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('CUL2', 'Gene', '8453', (108, 112))	('TUFM', 'Gene', (199, 203))	('decreased', 'NegReg', (258, 267))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (286, 304))	('BEX2', 'Gene', (191, 195))	('tumor', 'Disease', (268, 273))	('increased', 'PosReg', (204, 213))	('cholangiocarcinoma', 'Disease', (286, 304))	('carcinoma', 'Phenotype', 'HP:0030731', (295, 304))	('increased mitochondria', 'Phenotype', 'HP:0041045', (204, 226))	('E3 ubiquitin ligase complex proteins', 'Protein', (60, 96))	('knockdown', 'Var', (178, 187))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (286, 304))	('oxygen', 'Chemical', 'MESH:D010100', (235, 241))	('CUL2', 'Gene', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (268, 273))	('mitochondria-related oxygen consumption', 'MPA', (214, 253))
101519	33299012	For example, an anti-EGFR (epidermal growth factor receptor) antibody had a dramatic response on lung cancer with EGFR mutations.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('epidermal growth factor receptor', 'Gene', (27, 59))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('EGFR', 'Gene', '1956', (114, 118))	('epidermal growth factor receptor', 'Gene', '1956', (27, 59))	('EGFR', 'Gene', (114, 118))	('lung cancer', 'Disease', (97, 108))	('mutations', 'Var', (119, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))
101538	33299012	1A) and we therefore, focused on BEX2 because of the attenuation of tumorigenicity by knock down using shRNA (Fig.	('tumor', 'Disease', (68, 73))	('knock down', 'Var', (86, 96))	('attenuation', 'NegReg', (53, 64))	('shRNA', 'Gene', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
101547	33299012	We also tested if the BEX2 knockdown lines had an altered gemcitabine sensitivity and found that the BEX2-knockdown cells were more sensitive to gemcitabine than the control cells (Fig.	('tested', 'Reg', (8, 14))	('gemcitabine', 'Chemical', 'MESH:C056507', (58, 69))	('more', 'PosReg', (127, 131))	('gemcitabine', 'Chemical', 'MESH:C056507', (145, 156))	('BEX2-knockdown', 'Gene', (101, 115))	('BEX2-knockdown', 'Var', (101, 115))	('altered', 'Reg', (50, 57))	('sensitive to gemcitabine', 'MPA', (132, 156))	('gemcitabine sensitivity', 'MPA', (58, 81))
101549	33299012	We found that G0, defined by Ki67low and weak propidium iodide (PI) labeling, was decreased in the BEX2-knockdown cells compared to that in control cells (Fig.	('Ki67', 'Gene', (29, 33))	('propidium iodide', 'Chemical', 'MESH:D011419', (46, 62))	('Ki67', 'Gene', '17345', (29, 33))	('BEX2-knockdown', 'Gene', (99, 113))	('BEX2-knockdown', 'Var', (99, 113))	('decreased', 'NegReg', (82, 91))
101557	33299012	Overexpression of USF2 caused a clear increase of luciferase activity (Fig.	('increase', 'PosReg', (38, 46))	('luciferase', 'Enzyme', (50, 60))	('USF2', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('activity', 'MPA', (61, 69))	('USF2', 'Gene', '7392', (18, 22))
101559	33299012	The knock down of USF2 resulted in a clear reduction of BEX2 mRNA in HuCCT1 (Fig.	('HuCCT1', 'CellLine', 'CVCL:0324', (69, 75))	('knock down', 'Var', (4, 14))	('reduction', 'NegReg', (43, 52))	('USF2', 'Gene', (18, 22))	('BEX2 mRNA in', 'MPA', (56, 68))	('USF2', 'Gene', '7392', (18, 22))
101565	33299012	Indeed, the amount of BEX2 was increased by treatment with MG132, a well-known proteasomal inhibitor, but not by treatment with the lysosomal inhibitor, NH4Cl (Fig.	('MG132', 'Var', (59, 64))	('MG132', 'Chemical', 'MESH:C072553', (59, 64))	('increased', 'PosReg', (31, 40))	('amount', 'MPA', (12, 18))	('NH4Cl', 'Chemical', '-', (153, 158))
101570	33299012	FEM1B knockdown increased BEX2 expression in HuCCT1-BEX2 cells (Fig.	('BEX2 expression', 'MPA', (26, 41))	('increased', 'PosReg', (16, 25))	('FEM1B', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('HuCCT1', 'CellLine', 'CVCL:0324', (45, 51))
101576	33299012	The extracellular acidification rate (ECAR) was significantly altered in siBEX2#2 but not in siBEX2#1 cells (Supp.	('siBEX2#2', 'Var', (73, 81))	('extracellular acidification rate', 'MPA', (4, 36))	('altered', 'Reg', (62, 69))	('CA', 'Gene', '12310', (39, 41))
101577	33299012	4A) We measured the intracellular ATP level to confirm the alteration of mitochondrial activity; the ATP level was significantly increased by BEX2-knockdown, which is consistent with our flux analyzer results (Fig.	('ATP', 'MPA', (101, 104))	('ATP', 'Chemical', 'MESH:D000255', (34, 37))	('increased', 'PosReg', (129, 138))	('BEX2-knockdown', 'Gene', (142, 156))	('BEX2-knockdown', 'Var', (142, 156))	('ATP', 'Chemical', 'MESH:D000255', (101, 104))
101578	33299012	6D), whereas the ECAR was altered significantly in two mitochondrial protein knock down (PECR and TUFM), but not in other protein knock down (HSPD1 and IVD) (Supp.	('IVD', 'Disease', 'MESH:C538167', (152, 155))	('CA', 'Gene', '12310', (18, 20))	('IVD', 'Disease', (152, 155))	('knock down', 'Var', (77, 87))	('altered', 'Reg', (26, 33))	('PECR', 'Gene', '55825', (89, 93))	('PECR', 'Gene', (89, 93))
101580	33299012	When both BEX2 and TUFM were knocked down, OCR, but not ECAR, increased similar to that in the single BEX2- or TUFM-knockdown lines (Fig.	('knocked down', 'Var', (29, 41))	('increased', 'PosReg', (62, 71))	('OCR', 'MPA', (43, 46))	('BEX2', 'Gene', (10, 14))	('CA', 'Gene', '12310', (57, 59))	('TUFM', 'Gene', (19, 23))
101606	33299012	Although these data suggest that BEX2 is involved in the function of normal stem cells as well as cancer stem cells, our findings shed light on how controlling BEX2 can result in attenuation of CSC phenotypes and therapy resistance.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('controlling', 'Var', (148, 159))	('CSC', 'Disease', (194, 197))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('BEX2', 'Gene', (160, 164))	('cancer', 'Disease', (98, 104))	('attenuation', 'NegReg', (179, 190))	('therapy resistance', 'CPA', (213, 231))
101632	33299012	Non-silencing control siRNA (12935-300), BEX2 siRNAs #1 (HSS131257) and #2 (HSS131258), FEM1B siRNAs #1 (HSS115379) and #2 (HSS115380), TUFM siRNAs #1 (HSS111058) and #2 (HSS111059), HSPD1 siRNA (HSS179400), IVD siRNA (HSS105619), PECR siRNA (HSS125122) were purchased from Invitrogen (Carlsbad, CA, USA).	('HSS115380', 'Var', (124, 133))	('HSS115379', 'Var', (105, 114))	('CA', 'Gene', '12310', (296, 298))	('HSS125122', 'Var', (243, 252))	('HSS111058', 'Var', (152, 161))	('PECR', 'Gene', '55825', (231, 235))	('IVD', 'Disease', (208, 211))	('HSS179400', 'Var', (196, 205))	('IVD', 'Disease', 'MESH:C538167', (208, 211))	('PECR', 'Gene', (231, 235))	('HSS105619', 'Var', (219, 228))	('HSS111059', 'Var', (171, 180))
101666	33299012	GST-BEX2 and deletion mutant constructs were inserted into the pGEX4T3 vector by PCR amplification and expressed in E. coli.	('E. coli', 'Species', '562', (116, 123))	('deletion mutant', 'Var', (13, 28))	('GST-BEX2', 'Gene', (0, 8))
101667	33299012	Cell lysates from GST- BEX2 and deletion mutant constructs were incubated with glutathione magnetic beads (30 ml) for 1 h at 4  C and then washed three times by washing buffer A (50 mM Tris-HCl pH 7.5, 0.3 M NaCl, 0.1% NP-40).	('deletion mutant', 'Var', (32, 47))	('mutant', 'Var', (41, 47))	('glutathione', 'Chemical', 'MESH:D005978', (79, 90))	('GST- BEX2', 'Gene', (18, 27))	('Tris-HCl', 'Chemical', '-', (185, 193))	('NaCl', 'Chemical', 'MESH:D012965', (208, 212))
101752	32106609	A study reported that the modification at C-28 through esterification can lead to the reduction of cytotoxic potential, thus further confirming the role of this carbon moiety in the biological activities reported for RA.	('reduction', 'NegReg', (86, 95))	('C', 'Chemical', 'MESH:D002244', (42, 43))	('C-28', 'Protein', (42, 46))	('carbon', 'Chemical', 'MESH:D002244', (161, 167))	('modification', 'Var', (26, 38))	('RA', 'Chemical', 'MESH:C584473', (217, 219))	('esterification', 'MPA', (55, 69))	('cytotoxic potential', 'CPA', (99, 118))
101772	32106609	The inhibition was conducted by inactivating the Wnt co-receptor LRP6 and phosphorylating GSK-3beta, an activator of downstream target genes c-Myc and Cyclin D1.	('Cyclin D1', 'Gene', (151, 160))	('c-Myc', 'Gene', '4609', (141, 146))	('inactivating', 'Var', (32, 44))	('LRP6', 'Protein', (65, 69))	('c-Myc', 'Gene', (141, 146))	('GSK-3beta', 'Protein', (90, 99))	('Cyclin D1', 'Gene', '595', (151, 160))
101782	32106609	This may be due to the high molecular mass (897.1 D) of RA and poor membrane permeability as a result of the hydrophilic sugars in the RA structure.	('poor', 'NegReg', (63, 67))	('RA', 'Chemical', 'MESH:C584473', (56, 58))	('hydrophilic', 'Var', (109, 120))	('sugars', 'Chemical', 'MESH:D000073893', (121, 127))	('RA', 'Chemical', 'MESH:C584473', (135, 137))	('membrane permeability', 'MPA', (68, 89))
101819	32106609	Another article reported by Guan et al., indicated that RA treatment induces cellular apoptosis and inhibits invasion and angiogenesis through the modulation of P13K/AKT/mTOR signaling pathway.	('P13K', 'Var', (161, 165))	('inhibits', 'NegReg', (100, 108))	('cellular apoptosis', 'CPA', (77, 95))	('mTOR', 'Gene', (170, 174))	('mTOR', 'Gene', '2475', (170, 174))	('P13K', 'SUBSTITUTION', 'None', (161, 165))	('RA', 'Chemical', 'MESH:C584473', (56, 58))	('modulation', 'Reg', (147, 157))	('men', 'Species', '9606', (64, 67))
101836	32106609	In addition, RA mediated cell cycle arrest by modulating cell cycle-related protein cyclin E/D1.	('E/D1', 'SUBSTITUTION', 'None', (91, 95))	('E/D1', 'Var', (91, 95))	('cyclin', 'Gene', (84, 90))	('RA', 'Chemical', 'MESH:C584473', (13, 15))	('arrest', 'Disease', 'MESH:D006323', (36, 42))	('modulating', 'Reg', (46, 56))	('cell cycle-related', 'MPA', (57, 75))	('arrest', 'Disease', (36, 42))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (25, 42))	('cyclin', 'Gene', '5111', (84, 90))
101839	32106609	Therefore, a high level of E/D1 cyclin protein can act as pro-apoptotic factors, possibly involved in the sensitization of cancerous cells toward radiation.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancerous', 'Disease', 'MESH:D009369', (123, 132))	('cyclin', 'Gene', (32, 38))	('E/D1', 'SUBSTITUTION', 'None', (27, 31))	('E/D1', 'Var', (27, 31))	('involved', 'Reg', (90, 98))	('cancerous', 'Disease', (123, 132))	('cyclin', 'Gene', '5111', (32, 38))
101861	32106609	Despite standard treatment, the aberrant metastatic potential of brain tumor cells, and incomplete surgical resection has declined the survival rate of less than one year after diagnosis.	('brain tumor', 'Disease', 'MESH:D001932', (65, 76))	('men', 'Species', '9606', (22, 25))	('survival rate', 'CPA', (135, 148))	('brain tumor', 'Disease', (65, 76))	('declined', 'NegReg', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('aberrant', 'Var', (32, 40))	('rat', 'Species', '10116', (144, 147))	('brain tumor', 'Phenotype', 'HP:0030692', (65, 76))
101869	32106609	However, in this study, the application of autophagy inhibitors class III PI3K and 3-MA, exacerbated the RA mediated apoptosis in U251 glioma cell as noticed with caspase-3 overexpression.	('glioma', 'Disease', (135, 141))	('RA', 'Chemical', 'MESH:C584473', (105, 107))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('3-MA', 'Var', (83, 87))	('RA mediated apoptosis', 'CPA', (105, 126))	('exacerbated', 'PosReg', (89, 100))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('PI3K', 'Var', (74, 78))
101921	32106609	In CRPC cells, RA was reported to selectively target both the full-length AR-FL and splice variant AR-V mRNA expression and increase the growth inhibitory efficacy of docetaxel synergistically in both time- and dose dependent manners.	('C', 'Chemical', 'MESH:D002244', (3, 4))	('increase', 'PosReg', (124, 132))	('RA', 'Chemical', 'MESH:C584473', (15, 17))	('growth inhibitory efficacy', 'MPA', (137, 163))	('AR-V', 'Gene', (99, 103))	('splice variant', 'Var', (84, 98))	('AR', 'Gene', '367', (99, 101))	('AR', 'Gene', '367', (74, 76))	('docetaxel', 'Chemical', 'MESH:D000077143', (167, 176))	('C', 'Chemical', 'MESH:D002244', (6, 7))	('AR-V', 'Gene', '367', (99, 103))
101929	32106609	RA sensitized cholangiocarcinoma cell lines to 5-FU treatment and ameliorated 5-FU resistance in bile duct cancer cells through activating multiple cell cycle and apoptosis-related factors, such as COX-2, Bax, Bcl-2, and cyclins E/D1.	('cholangiocarcinoma', 'Disease', (14, 32))	('COX-2', 'Gene', (198, 203))	('5-FU resistance', 'MPA', (78, 93))	('activating', 'PosReg', (128, 138))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (14, 32))	('E/D1', 'SUBSTITUTION', 'None', (229, 233))	('cyclin', 'Gene', '5111', (221, 227))	('rat', 'Species', '10116', (72, 75))	('COX-2', 'Gene', '4513', (198, 203))	('apoptosis-related', 'CPA', (163, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('ameliorated', 'PosReg', (66, 77))	('men', 'Species', '9606', (57, 60))	('Bax', 'Gene', (205, 208))	('cyclin', 'Gene', (221, 227))	('Bcl-2', 'Gene', (210, 215))	('RA', 'Chemical', 'MESH:C584473', (0, 2))	('Bax', 'Gene', '581', (205, 208))	('5-FU', 'Chemical', 'MESH:D005472', (47, 51))	('E/D1', 'Var', (229, 233))	('5-FU', 'Chemical', 'MESH:D005472', (78, 82))	('bile duct cancer', 'Phenotype', 'HP:0030153', (97, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('bile duct cancer', 'Disease', (97, 113))	('Bcl-2', 'Gene', '596', (210, 215))	('cell cycle', 'CPA', (148, 158))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (14, 32))	('bile duct cancer', 'Disease', 'MESH:D001650', (97, 113))
101932	32106609	Splice variants of AR (AR-V) expression have been proposed to be a mechanism of docetaxel resistance.	('Splice variants', 'Var', (0, 15))	('AR-V', 'Gene', (23, 27))	('AR', 'Gene', '367', (19, 21))	('mechanism', 'Reg', (67, 76))	('AR', 'Gene', '367', (23, 25))	('docetaxel', 'Chemical', 'MESH:D000077143', (80, 89))	('AR-V', 'Gene', '367', (23, 27))	('docetaxel resistance', 'MPA', (80, 100))
102037	30526572	3) Laboratory results with parameters involving, among others, leukocytes, erythrocytes, platelets, albumin, total bilirubin, creatinine, carbohydrate antigen (CA) 19-9, and CA 125.	('creatinine', 'Chemical', 'MESH:D003404', (126, 136))	('bilirubin', 'Chemical', 'MESH:D001663', (115, 124))	('total bilirubin', 'MPA', (109, 124))	('creatinine', 'MPA', (126, 136))	('CA 125', 'Var', (174, 180))
102116	29049401	ICCs were identified by using the ICD-O-3 topography code C22.0 (liver) and morphology codes 8160 and 8161 or topography code C22.1 (intrahepatic bile duct) and morphology codes 8032, 8033, 8070, 8071, 8140, 8141, 8160, 8161, 8260, 8480, 8481, 8490, and 8560.	('8490', 'Var', (244, 248))	('8033', 'Var', (184, 188))	('8560', 'Var', (254, 258))	('8160', 'Var', (214, 218))	('8260', 'Var', (226, 230))	('8071', 'Var', (196, 200))	('8480', 'Var', (232, 236))	('8140', 'Var', (202, 206))	('8481', 'Var', (238, 242))	('C22.1', 'Var', (126, 131))	('intrahepatic bile duct', 'Disease', (133, 155))	('intrahepatic bile duct', 'Disease', 'MESH:D002780', (133, 155))	('8070', 'Var', (190, 194))	('8161', 'Var', (220, 224))	('8141', 'Var', (208, 212))	('C22.0', 'Var', (58, 63))	('C22.1', 'CellLine', 'CVCL:F277', (126, 131))
102154	29049401	This systemic inflammation is believed to contribute to metabolic dysregulation, including onset of insulin resistance and subsequent diabetes, and the development and progression of NAFLD to steatohepatitis, fibrosis, cirrhosis; possibly culminating in development of cholangiocarcinoma.	('diabetes', 'Disease', 'MESH:D003920', (134, 142))	('insulin', 'Gene', (100, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('insulin resistance', 'Phenotype', 'HP:0000855', (100, 118))	('inflammation', 'Disease', (14, 26))	('fibrosis', 'Disease', 'MESH:D005355', (209, 217))	('fibrosis', 'Disease', (209, 217))	('hepatitis', 'Phenotype', 'HP:0012115', (198, 207))	('contribute', 'Reg', (42, 52))	('cirrhosis', 'Disease', 'MESH:D005355', (219, 228))	('diabetes', 'Disease', (134, 142))	('metabolic', 'MPA', (56, 65))	('steatohepatitis', 'Disease', 'MESH:D005234', (192, 207))	('cirrhosis', 'Phenotype', 'HP:0001394', (219, 228))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (269, 287))	('insulin', 'Gene', '3630', (100, 107))	('NAFLD', 'Var', (183, 188))	('steatohepatitis', 'Disease', (192, 207))	('cirrhosis', 'Disease', (219, 228))	('cholangiocarcinoma', 'Disease', (269, 287))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (269, 287))	('inflammation', 'Disease', 'MESH:D007249', (14, 26))
102158	29049401	Additionally, HBV DNA and HCV RNA have been detected in cholangiocarcinoma tissue, and HCV can cause bile duct injury.	('bile duct injury', 'Disease', 'MESH:D002779', (101, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('bile duct injury', 'Disease', (101, 117))	('HCV', 'Var', (87, 90))	('cause', 'Reg', (95, 100))	('cholangiocarcinoma', 'Disease', (56, 74))	('HCV', 'Species', '11103', (87, 90))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (56, 74))	('HCV', 'Species', '11103', (26, 29))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (56, 74))
102213	28693238	Overexpression of galectin-3 was reported as a predictor of poorer prognosis in ovarian carcinoma, nasopharyngeal carcinoma, malignant melanoma, gallbladder carcinoma, osteosarcoma and hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('malignant melanoma', 'Disease', (125, 143))	('Overexpression', 'Var', (0, 14))	('galectin-3', 'Protein', (18, 28))	('osteosarcoma and hepatocellular carcinoma', 'Disease', 'MESH:D012516', (168, 209))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (99, 123))	('osteosarcoma', 'Phenotype', 'HP:0002669', (168, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (185, 209))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (80, 97))	('ovarian carcinoma', 'Disease', (80, 97))	('malignant melanoma', 'Phenotype', 'HP:0002861', (125, 143))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (145, 166))	('malignant melanoma', 'Disease', 'MESH:D008545', (125, 143))	('gallbladder carcinoma', 'Disease', (145, 166))	('nasopharyngeal carcinoma', 'Disease', (99, 123))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (80, 97))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (99, 123))
102256	28693238	Overexpression of galectin-3 was reported as a predictor of poor prognosis in various malignancies, including ovarian carcinoma, nasopharyngeal carcinoma, malignant melanoma, gallbladder carcinoma, osteosarcoma and hepatocellular carcinoma.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (110, 127))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (129, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('Overexpression', 'Var', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('osteosarcoma and hepatocellular carcinoma', 'Disease', 'MESH:D012516', (198, 239))	('osteosarcoma', 'Phenotype', 'HP:0002669', (198, 210))	('malignant melanoma', 'Disease', (155, 173))	('galectin-3', 'Gene', (18, 28))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (129, 153))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (215, 239))	('malignancies', 'Disease', 'MESH:D009369', (86, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('malignancies', 'Disease', (86, 98))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (110, 127))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (175, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('ovarian carcinoma', 'Disease', (110, 127))	('gallbladder carcinoma', 'Disease', (175, 196))	('malignant melanoma', 'Phenotype', 'HP:0002861', (155, 173))	('malignant melanoma', 'Disease', 'MESH:D008545', (155, 173))	('nasopharyngeal carcinoma', 'Disease', (129, 153))
102263	28693238	Previously, inhibition of the kinase activity of glycogen synthase kinase-3beta (GSK-3beta) was shown to result in the induction of EMT through the carboxyl terminus of heat shock protein 70-interacting protein-mediated degradation of Slug.	('degradation', 'MPA', (220, 231))	('glycogen synthase kinase-3beta', 'Gene', (49, 79))	('inhibition', 'Var', (12, 22))	('kinase', 'MPA', (30, 36))	('EMT', 'CPA', (132, 135))	('induction', 'PosReg', (119, 128))	('glycogen synthase kinase-3beta', 'Gene', '2932', (49, 79))	('shock', 'Phenotype', 'HP:0031273', (174, 179))	('Slug', 'Gene', '6591', (235, 239))	('GSK-3beta', 'Gene', '2932', (81, 90))	('GSK-3beta', 'Gene', (81, 90))	('Slug', 'Gene', (235, 239))
102268	28693238	Previously, TGF-beta-induced EMT was reported to be reduced in mice deficient in galectin-3.	('galectin-3', 'Protein', (81, 91))	('reduced', 'NegReg', (52, 59))	('deficient', 'Var', (68, 77))	('mice', 'Species', '10090', (63, 67))	('TGF-beta-induced', 'Gene', (12, 28))
102282	28693238	Elucidating the mechanisms of the translocation of galectin-3 into the nucleus may improve the prognosis of patients with DCC.	('DCC', 'Disease', (122, 125))	('translocation', 'Var', (34, 47))	('improve', 'PosReg', (83, 90))	('DCC', 'Chemical', '-', (122, 125))	('galectin-3', 'Protein', (51, 61))	('patients', 'Species', '9606', (108, 116))
102293	27709523	Finally, within our cohort of patients both the diagnostic and prognostic potentials of S100A6 were similar to those of the clinically established biomarkers CEA and CA19-9.	('CEA', 'Gene', '1084', (158, 161))	('patients', 'Species', '9606', (30, 38))	('S100A6', 'Var', (88, 94))	('CEA', 'Gene', (158, 161))
102295	27709523	However, CCA-patients with elevated S100A6 displayed a trend toward an impaired prognosis compared to patients with lower S100A6 levels, supporting its further evaluation as a prognostic biomarker in CCA.	('prognosis', 'CPA', (80, 89))	('S100A6', 'Var', (36, 42))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (102, 110))	('impaired', 'NegReg', (71, 79))	('CCA-patients', 'Disease', (9, 21))	('CCA', 'Phenotype', 'HP:0030153', (200, 203))	('CCA', 'Phenotype', 'HP:0030153', (9, 12))
102304	27709523	S100A6 (calcyclin) is a 90-amino-acid, 10.5 kDa protein that is predominantly expressed in the cytosol of numerous human cells, including fibroblast, epithelial cells, neuronal cells, lymphocytes, platelets, cardiomyocytes and smooth muscle cells.	('calcyclin', 'Gene', '6277', (8, 17))	('S100A6', 'Var', (0, 6))	('calcyclin', 'Gene', (8, 17))	('human', 'Species', '9606', (115, 120))
102308	27709523	In renal cell carcinoma cells, knockdown of calcium-regulating S100A6 suppressed cell growth via induction of G2/M phase arrest, a finding that has previously been reported in other cell types, and significantly reduced tumor mass in an in vivo mouse model.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (220, 225))	('calcium', 'Chemical', 'MESH:D002118', (44, 51))	('cell growth', 'CPA', (81, 92))	('suppressed', 'NegReg', (70, 80))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 23))	('mouse', 'Species', '10090', (245, 250))	('renal cell carcinoma', 'Disease', (3, 23))	('S100A6', 'Gene', (63, 69))	('G2/M phase arrest', 'CPA', (110, 127))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (3, 23))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('reduced', 'NegReg', (212, 219))	('knockdown', 'Var', (31, 40))
102309	27709523	Furthermore, S100A6 knockdown activated CXCL14-induced apoptosis in a renal cell carcinoma cell line.	('renal cell carcinoma', 'Disease', (70, 90))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (70, 90))	('CXCL14', 'Gene', (40, 46))	('S100A6', 'Gene', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('activated', 'PosReg', (30, 39))	('CXCL14', 'Gene', '9547', (40, 46))	('knockdown', 'Var', (20, 29))
102313	27709523	In cholangiocarcinoma, increased expression levels of S100A6 mRNA and protein were found in a small cohort of tissue specimens of intrahepatic CCA and it was suggested that S100A6 may help to differentiate between intrahepatic CCA and hepatocellular carcinoma (HCC).	('intrahepatic CCA', 'Disease', (130, 146))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (235, 259))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('HCC', 'Gene', '619501', (261, 264))	('HCC', 'Phenotype', 'HP:0001402', (261, 264))	('CCA', 'Phenotype', 'HP:0030153', (143, 146))	('cholangiocarcinoma', 'Disease', (3, 21))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('HCC', 'Gene', (261, 264))	('intrahepatic CCA and hepatocellular carcinoma', 'Disease', 'MESH:C536211', (214, 259))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (130, 146))	('intrahepatic CCA', 'Disease', (214, 230))	('S100A6', 'Var', (173, 179))	('S100A6', 'Gene', (54, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('CCA', 'Phenotype', 'HP:0030153', (227, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('increased', 'PosReg', (23, 32))	('expression levels', 'MPA', (33, 50))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (214, 230))
102315	27709523	Although the cause and exact mechanism of S100A6 secretion into the bloodstream is not fully understood, different studies revealed elevated serum levels of S100A6 in NSCLC, gastric cancer and urothelial carcinoma and suggested its role as a diagnostic and/or prognostic biomarker.	('gastric cancer', 'Phenotype', 'HP:0012126', (174, 188))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('elevated', 'PosReg', (132, 140))	('urothelial carcinoma', 'Disease', (193, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('serum levels', 'MPA', (141, 153))	('gastric cancer', 'Disease', (174, 188))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (193, 213))	('S100A6', 'Var', (157, 163))	('gastric cancer', 'Disease', 'MESH:D013274', (174, 188))	('NSCLC', 'Disease', (167, 172))
102358	27709523	Further analyses revealed that the prognostic value of S100A6 was slightly inferior to INR but superior to CRP, creatinine and patients' age according to ROC curve analysis (Additional file 4: Figure S3).	('CRP', 'Gene', (107, 110))	('CRP', 'Gene', '1401', (107, 110))	('patients', 'Species', '9606', (127, 135))	('creatinine', 'Chemical', 'MESH:D003404', (112, 122))	('S100A6', 'Var', (55, 61))
102370	27709523	Nevertheless, S100A6 serum levels might be indicative for the prognosis of patients with CCA.	('patients', 'Species', '9606', (75, 83))	('CCA', 'Disease', (89, 92))	('S100A6', 'Var', (14, 20))	('serum levels', 'MPA', (21, 33))	('CCA', 'Phenotype', 'HP:0030153', (89, 92))
102371	27709523	Of note, within our cohort of patients, measurements of S100A6 demonstrated a similar prognostic power than that of clinically established biomarkers such as CEA or CA19-9.	('CEA', 'Gene', '1084', (158, 161))	('S100A6', 'Var', (56, 62))	('CEA', 'Gene', (158, 161))	('patients', 'Species', '9606', (30, 38))
102373	27709523	Alterations in the expression of S100 family members represent a common feature of several cancers including gastrointestinal malignancies such as gastric cancer, pancreatic cancer and colorectal adenocarcinoma.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (163, 180))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (109, 138))	('Alterations', 'Var', (0, 11))	('gastrointestinal malignancies', 'Disease', (109, 138))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (185, 210))	('expression', 'MPA', (19, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (147, 161))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (163, 180))	('S100', 'Gene', '6285', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('S100', 'Gene', (33, 37))	('pancreatic cancer', 'Disease', (163, 180))	('gastric cancer', 'Disease', (147, 161))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('colorectal adenocarcinoma', 'Disease', (185, 210))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancers', 'Disease', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (147, 161))
102378	27709523	In accordance with this finding, we showed that S100A6 is significantly overexpressed in human and murine CCA tissue samples, corroborating a pathophysiological role of S100A6 in cholangiocarcinoma.	('human', 'Species', '9606', (89, 94))	('S100A6', 'Var', (169, 175))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (179, 197))	('CCA', 'Phenotype', 'HP:0030153', (106, 109))	('overexpressed', 'PosReg', (72, 85))	('murine', 'Species', '10090', (99, 105))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (179, 197))	('S100A6', 'Var', (48, 54))	('CCA', 'Disease', (106, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('cholangiocarcinoma', 'Disease', (179, 197))
102382	27709523	Moreover, patients with S100A6 serum levels of less than 2234 ng/ml displayed a trend towards a better survival in Kaplan-Meier curve analysis, highlighting that S100A6 serum levels might reflect prognosis-relevant processes in patients with CCA.	('S100A6', 'Var', (162, 168))	('CCA', 'Disease', (242, 245))	('better', 'PosReg', (96, 102))	('patients', 'Species', '9606', (228, 236))	('S100A6', 'Var', (24, 30))	('patients', 'Species', '9606', (10, 18))	('CCA', 'Phenotype', 'HP:0030153', (242, 245))	('reflect', 'Reg', (188, 195))
102385	27709523	Recently, serum levels of S100A2 and S100A6 were found to be higher in patients with NSCLC compared to controls.	('NSCLC', 'Disease', (85, 90))	('S100A6', 'Var', (37, 43))	('S100A2', 'Gene', '6273', (26, 32))	('serum levels', 'MPA', (10, 22))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('S100A2', 'Gene', (26, 32))	('higher', 'PosReg', (61, 67))	('patients', 'Species', '9606', (71, 79))
102386	27709523	Moreover, also in patients with gastric cancer, serum S100A6 levels were elevated and significantly correlated with lymph node metastasis, TNM stage, perineural invasion and vascular invasion, supporting that S100A6 might represent a novel marker indicating patients prognosis independently of the examined tumor entity.	('lymph node metastasis', 'Disease', (116, 137))	('gastric cancer', 'Disease', (32, 46))	('S100A6', 'Var', (209, 215))	('correlated', 'Reg', (100, 110))	('tumor', 'Disease', (307, 312))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('gastric cancer', 'Disease', 'MESH:D013274', (32, 46))	('perineural invasion', 'CPA', (150, 169))	('TNM', 'Gene', '10178', (139, 142))	('patients', 'Species', '9606', (258, 266))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('elevated', 'PosReg', (73, 81))	('TNM', 'Gene', (139, 142))	('serum', 'MPA', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('gastric cancer', 'Phenotype', 'HP:0012126', (32, 46))	('patients', 'Species', '9606', (18, 26))	('lymph node metastasis', 'Disease', 'MESH:D009362', (116, 137))	('S100A6', 'Gene', (54, 60))	('vascular invasion', 'CPA', (174, 191))
102388	27709523	Recent data suggested a prognostic function of CA19-9 but not CEA in patients with CCA.	('CCA', 'Disease', (83, 86))	('CA19-9', 'Var', (47, 53))	('CCA', 'Phenotype', 'HP:0030153', (83, 86))	('CEA', 'Gene', (62, 65))	('patients', 'Species', '9606', (69, 77))	('CEA', 'Gene', '1084', (62, 65))
102397	27709523	CCA-patients with elevated S100A6 levels show a trend toward an impaired prognosis when compared to patients with lower S100A6 levels.	('CCA-patients', 'Disease', (0, 12))	('CCA', 'Phenotype', 'HP:0030153', (0, 3))	('patients', 'Species', '9606', (100, 108))	('patients', 'Species', '9606', (4, 12))	('S100A6 levels', 'Var', (27, 40))
102450	26379735	p53 is a tumor suppressor gene that is located on the short arm of chromosome 17, and the p53 mutation is required for the development of colorectal cancer, and is associated with an increased relative risk of death, and poorer prognosis.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('short arm', 'Phenotype', 'HP:0009824', (54, 63))	('associated with', 'Reg', (164, 179))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('p53', 'Gene', '7157', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('colorectal cancer', 'Disease', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Disease', (9, 14))	('death', 'Disease', 'MESH:D003643', (210, 215))	('death', 'Disease', (210, 215))	('mutation', 'Var', (94, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))
102515	21221877	Recent studies demonstrated that ectopic CDX2 expression has been observed in intestinal metaplasia and carcinoma of the stomach, it might be related to gastric mucosa transformation from gastric to intestinal phenotype, and gastric carcinogenesis.	('observed', 'Reg', (66, 74))	('ectopic', 'Var', (33, 40))	('gastric carcinogenesis', 'Disease', (225, 247))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (78, 99))	('carcinoma of the stomach', 'Disease', (104, 128))	('carcinoma of the stomach', 'Disease', 'MESH:D013274', (104, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('CDX2', 'Gene', (41, 45))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (225, 247))	('intestinal metaplasia', 'Disease', (78, 99))	('expression', 'MPA', (46, 56))	('gastric mucosa', 'Disease', 'MESH:D013274', (153, 167))	('related', 'Reg', (142, 149))	('gastric mucosa', 'Disease', (153, 167))
102516	21221877	We reported here that ectopic CDX2 expression was detected in 49/108 (45.4%) of gallbladder adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('ectopic', 'Var', (22, 29))	('gallbladder adenocarcinoma', 'Disease', 'MESH:D005705', (80, 106))	('detected', 'Reg', (50, 58))	('CDX2', 'Gene', (30, 34))	('gallbladder adenocarcinoma', 'Disease', (80, 106))
102527	21221877	By univariate and multivariate analyses, the expression of CDX2 was associated with a significant survival advantage; CDX2 and tumor stage were independent prognostic factor in patients with biliary tract carcinomas.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('CDX2', 'Gene', (118, 122))	('biliary tract carcinomas', 'Disease', (191, 215))	('tumor', 'Disease', (127, 132))	('patients', 'Species', '9606', (177, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('carcinomas', 'Phenotype', 'HP:0030731', (205, 215))	('CDX2', 'Gene', (59, 63))	('survival advantage', 'CPA', (98, 116))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('expression', 'Var', (45, 55))	('biliary tract carcinomas', 'Disease', 'MESH:D001661', (191, 215))
102542	21221877	Most of positive cases showed intestinal metaplasia., suggesting Hep expression is associated with intestineal metaplasia.	('Hep', 'Chemical', '-', (65, 68))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (30, 51))	('associated', 'Reg', (83, 93))	('Hep expression', 'Var', (65, 79))	('intestineal metaplasia', 'Disease', (99, 121))	('intestineal metaplasia', 'Disease', 'MESH:D008679', (99, 121))	('intestinal metaplasia', 'Disease', (30, 51))
102679	28410994	For example, OSBP1 protein influence sterol metabolism via negative regulation of ABCA1 transporter through modulation of gene expression and protein destabilization.	('protein', 'Var', (19, 26))	('sterol', 'Chemical', 'MESH:D013261', (37, 43))	('ABCA1', 'Gene', (82, 87))	('negative regulation', 'NegReg', (59, 78))	('protein', 'Protein', (142, 149))	('gene expression', 'MPA', (122, 137))	('OSBP1', 'Gene', '5007', (13, 18))	('influence', 'Reg', (27, 36))	('sterol metabolism', 'MPA', (37, 54))	('OSBP1', 'Gene', (13, 18))	('modulation', 'Reg', (108, 118))	('ABCA1', 'Gene', '19', (82, 87))
102699	28410994	Altered oxysterol levels have been observed in patients with Smith-Lemli-Opitz syndrome (SLOS), a disease resulting from mutation in 7-dehydrocholesterol reductase (DHCR7; OMIM: 602858), the enzyme responsible for the reduction of 7-dehydrocholesterol to cholesterol.	('Smith-Lemli-Opitz syndrome', 'Disease', (61, 87))	('DHCR7', 'Gene', '1717', (165, 170))	('patients', 'Species', '9606', (47, 55))	('cholesterol', 'Chemical', 'MESH:D002784', (255, 266))	('7-dehydrocholesterol', 'Chemical', 'MESH:C016705', (231, 251))	('cholesterol', 'Chemical', 'MESH:D002784', (240, 251))	('SLOS', 'Disease', (89, 93))	('reduction of 7-dehydrocholesterol', 'Phenotype', 'HP:0010569', (218, 251))	('SLOS', 'Disease', 'MESH:D019082', (89, 93))	('mutation', 'Var', (121, 129))	('Altered', 'Reg', (0, 7))	('7-dehydrocholesterol', 'Chemical', 'MESH:C016705', (133, 153))	('cholesterol', 'Chemical', 'MESH:D002784', (142, 153))	('7-dehydrocholesterol reductase', 'Gene', (133, 163))	('7-dehydrocholesterol reductase', 'Gene', '1717', (133, 163))	('oxysterol', 'Chemical', 'MESH:D000072376', (8, 17))	('Smith-Lemli-Opitz syndrome', 'Disease', 'MESH:D019082', (61, 87))	('DHCR7', 'Gene', (165, 170))	('oxysterol levels', 'MPA', (8, 24))
102714	28410994	In consistence, LXR mediated expression is decreased in highly proliferating cells and cancer cells, e.g., by oxysterol deprivation or inactivation by sulfation and the addition of LXR ligands inhibits the proliferation.	('LXR', 'Gene', '22260', (181, 184))	('cancer', 'Disease', (87, 93))	('oxysterol', 'Chemical', 'MESH:D000072376', (110, 119))	('rat', 'Species', '10116', (70, 73))	('proliferation', 'CPA', (206, 219))	('sulfation', 'Protein', (151, 160))	('LXR', 'Gene', '22260', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('inhibits', 'NegReg', (193, 201))	('LXR', 'Gene', (16, 19))	('rat', 'Species', '10116', (213, 216))	('LXR', 'Gene', (181, 184))	('inactivation', 'Var', (135, 147))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('decreased', 'NegReg', (43, 52))
102724	28410994	In addition to a series of synthetic selective estrogen receptor modulators (SERMs) used for breast cancer treatment, 27-HC is the first endogenous SERM identified, whereas 25-HC acts rather as an agonistic ligand.	('estrogen receptor', 'Gene', '2099', (47, 64))	('rat', 'Species', '10116', (184, 187))	('ER', 'Gene', '2099', (149, 151))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('ER', 'Gene', '2099', (78, 80))	('27-HC', 'Var', (118, 123))	('estrogen receptor', 'Gene', (47, 64))
102725	28410994	The presence of 25-HC and 27-HC may be associated with resistance to aromatase inhibitors, which block estrogen synthesis, but do not influence the ER protein.	('resistance', 'MPA', (55, 65))	('27-HC', 'Var', (26, 31))	('estrogen synthesis', 'MPA', (103, 121))	('ER', 'Gene', '2099', (148, 150))	('associated', 'Reg', (39, 49))
102736	28410994	Taken together, postmenopausal and obese women have the highest risk of breast cancer relapse linked to 27-HC.	('obese', 'Disease', (35, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('obese', 'Disease', 'MESH:D009765', (35, 40))	('27-HC', 'Var', (104, 109))	('breast cancer', 'Disease', (72, 85))	('women', 'Species', '9606', (41, 46))
102738	28410994	Moreover, higher expression levels of CYP27A1 were found among patients with high tumor grade, i.e., with less differentiated tumor cells.	('CYP27A1', 'Var', (38, 45))	('expression levels', 'MPA', (17, 34))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('high tumor', 'Disease', (77, 87))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('higher', 'PosReg', (10, 16))	('patients', 'Species', '9606', (63, 71))	('high tumor', 'Disease', 'MESH:D009369', (77, 87))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (126, 131))
102739	28410994	CYP27A1 is a potential target for breast carcinoma treatment and is a subject of interest.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('breast carcinoma', 'Disease', (34, 50))	('breast carcinoma', 'Disease', 'MESH:D001943', (34, 50))	('breast carcinoma', 'Phenotype', 'HP:0003002', (34, 50))	('CYP27A1', 'Var', (0, 7))
102765	28410994	The available evidence suggests that oxysterols exert anti-proliferative and pro-apoptotic effects in colon adenocarcinoma cell lines, e.g., 7beta-HC inhibits cell growth and induces apoptotic process in CaCo-2 cell cultures.	('cell growth', 'CPA', (159, 170))	('7beta-HC', 'Var', (141, 149))	('induces', 'Reg', (175, 182))	('oxysterols', 'Chemical', 'MESH:D000072376', (37, 47))	('apoptotic process', 'CPA', (183, 200))	('colon adenocarcinoma', 'Disease', (102, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('CaCo-2', 'CellLine', 'CVCL:0025', (204, 210))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (102, 122))	('rat', 'Species', '10116', (66, 69))	('inhibits', 'NegReg', (150, 158))
102767	28410994	Treatment with a mixture of 7alpha-HC, 7beta-HC, 7-KC, alpha-CE, and beta-CE caused activation of caspases 3 and 7 and release of cytochrome c in vitro.	('activation', 'PosReg', (84, 94))	('release', 'MPA', (119, 126))	('7beta-HC', 'Var', (39, 47))	('7-KC', 'Chemical', 'MESH:C003001', (49, 53))	('alpha-CE', 'Chemical', '-', (55, 63))	('7alpha-HC', 'Var', (28, 37))	('7-KC', 'Var', (49, 53))	('cytochrome c', 'Gene', (130, 142))	('7alpha-HC', 'Chemical', '-', (28, 37))	('beta-CE', 'Chemical', '-', (69, 76))	('caspases', 'Enzyme', (98, 106))	('cytochrome c', 'Gene', '54205', (130, 142))
102768	28410994	In addition, 25-HC is able to induce anoikis, a programmed cell death in response to loss of anchorage, in DLD-1 colon tumor cell line.	('death', 'Disease', 'MESH:D003643', (64, 69))	('death', 'Disease', (64, 69))	('25-HC', 'Var', (13, 18))	('anoikis', 'Disease', (37, 44))	('anoikis', 'Disease', 'None', (37, 44))	('colon tumor', 'Phenotype', 'HP:0100273', (113, 124))	('DLD-1 colon tumor', 'Disease', (107, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('DLD-1 colon tumor', 'Disease', 'MESH:C573012', (107, 124))	('induce', 'Reg', (30, 36))
102776	28410994	The expression level of oxysterol metabolizing cytochrome P450 proteins was evaluated in colorectal carcinoma samples and the overexpression of some enzymes and association with cancer prognosis was found, e.g., the levels of the 27-HC metabolizing enzymes CYP27A1 and CYP7B1 showed similar association to patient prognosis as in breast cancer patients - higher expression of CYP27A1 was associated with poor outcome of patients and increased level of CYP7B1 was associated with good prognosis of patients, suggesting a potential role of 27-HC in patients with colorectal carcinoma.	('colorectal carcinoma', 'Disease', 'MESH:D015179', (89, 109))	('patients', 'Species', '9606', (420, 428))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('CYP27A1', 'Var', (376, 383))	('carcinoma', 'Phenotype', 'HP:0030731', (572, 581))	('cancer', 'Disease', 'MESH:D009369', (337, 343))	('colorectal carcinoma', 'Disease', (561, 581))	('patients', 'Species', '9606', (497, 505))	('patient', 'Species', '9606', (547, 554))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (561, 581))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (330, 343))	('patient', 'Species', '9606', (420, 427))	('patients', 'Species', '9606', (344, 352))	('oxysterol', 'Chemical', 'MESH:D000072376', (24, 33))	('breast cancer', 'Disease', 'MESH:D001943', (330, 343))	('breast cancer', 'Disease', (330, 343))	('cancer', 'Disease', (337, 343))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('patient', 'Species', '9606', (497, 504))	('cancer', 'Disease', (178, 184))	('patient', 'Species', '9606', (344, 351))	('colorectal carcinoma', 'Disease', (89, 109))	('patients', 'Species', '9606', (547, 555))	('patient', 'Species', '9606', (306, 313))
102779	28410994	Moreover, the presence of oxidative derivatives, including oxysterols in biliary ducts, has a direct link to infection and consequently can further impact on disease progression to cancer.	('impact', 'Reg', (148, 154))	('infection', 'Disease', 'MESH:D007239', (109, 118))	('oxysterols', 'Chemical', 'MESH:D000072376', (59, 69))	('presence', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('disease progression', 'CPA', (158, 177))	('cancer', 'Disease', (181, 187))	('link', 'Interaction', (101, 105))	('infection', 'Disease', (109, 118))
102785	28410994	Incorrect or deficient DNA repair frequently leads to carcinogenesis (Figure 3).	('carcinogenesis', 'Disease', 'MESH:D063646', (54, 68))	('leads to', 'Reg', (45, 53))	('carcinogenesis', 'Disease', (54, 68))	('deficient', 'Var', (13, 22))
102795	28410994	Congruently, 7beta-HC had anti-proliferative effects and induced apoptosis via activation of the intrinsic apoptotic pathway in the lung cancer cell line NCI-H460.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('NCI-H460', 'CellLine', 'CVCL:0459', (154, 162))	('anti-proliferative effects', 'CPA', (26, 52))	('7beta-HC', 'Var', (13, 21))	('apoptosis', 'CPA', (65, 74))	('lung cancer', 'Disease', (132, 143))	('activation', 'PosReg', (79, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('rat', 'Species', '10116', (38, 41))	('induced', 'PosReg', (57, 64))	('intrinsic apoptotic pathway', 'Pathway', (97, 124))
102797	28410994	Inactivation of genes coding LXRalpha and LXRbeta leads to chronic inflammation of lung tissue and squamous cell carcinoma-like lesions in mice.	('LXRalpha', 'Gene', (29, 37))	('inflammation', 'Disease', 'MESH:D007249', (67, 79))	('squamous cell carcinoma-like lesions', 'Disease', 'MESH:D002294', (99, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('inflammation', 'Disease', (67, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('squamous cell carcinoma-like lesions', 'Disease', (99, 135))	('mice', 'Species', '10090', (139, 143))	('LXRbeta', 'Gene', (42, 49))	('leads to', 'Reg', (50, 58))	('Inactivation', 'Var', (0, 12))
102798	28410994	Similarly, LXRalpha was shown to be a potential prognostic factor of better survival in non-small-cell lung carcinoma patients.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('LXRalpha', 'Var', (11, 19))	('better', 'PosReg', (69, 75))	('lung carcinoma', 'Disease', (103, 117))	('lung carcinoma', 'Disease', 'MESH:D008175', (103, 117))	('patients', 'Species', '9606', (118, 126))
102801	28410994	In the C6 glioblastoma cell line, 7beta-HC slowed the cell cycle and caused cell death.	('death', 'Disease', 'MESH:D003643', (81, 86))	('slowed', 'NegReg', (43, 49))	('caused', 'Reg', (69, 75))	('death', 'Disease', (81, 86))	('C6 glioblastoma', 'Disease', 'MESH:D005909', (7, 22))	('7beta-HC', 'Var', (34, 42))	('C6 glioblastoma', 'Disease', (7, 22))	('cell cycle', 'CPA', (54, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (10, 22))
102804	28410994	Similarly, ORP4 variant, ORP4L was shown to promote the proliferation of cervical cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('promote', 'PosReg', (44, 51))	('ORP4', 'Gene', (25, 29))	('variant', 'Var', (16, 23))	('ORP4', 'Gene', '23762', (25, 29))	('proliferation', 'CPA', (56, 69))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('ORP4', 'Gene', (11, 15))	('ORP4', 'Gene', '23762', (11, 15))	('rat', 'Species', '10116', (63, 66))
102812	28410994	In the absence of or erroneous DNA repair these changes lead either to cell death or carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('erroneous DNA', 'Var', (21, 34))	('carcinogenesis', 'Disease', (85, 99))	('death', 'Disease', (76, 81))	('death', 'Disease', 'MESH:D003643', (76, 81))	('lead', 'Reg', (56, 60))	('changes', 'Var', (48, 55))
102825	28410994	Also, targeting CYP27A1 or CYP7B1, which regulate the level of 27-HC in cells, may affect roles of LXRs, for example in breast carcinoma.	('breast carcinoma', 'Disease', (120, 136))	('CYP7B1', 'Var', (27, 33))	('affect', 'Reg', (83, 89))	('breast carcinoma', 'Disease', 'MESH:D001943', (120, 136))	('CYP27A1', 'Var', (16, 23))	('LXR', 'Gene', (99, 102))	('breast carcinoma', 'Phenotype', 'HP:0003002', (120, 136))	('LXR', 'Gene', '22260', (99, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
102879	25792843	The inclusion criteria were as follows: BTC deemed to be unresectable, according to the National Comprehensive Cancer Network Guidelines (version 1.2009); Eastern Cooperative Oncology Group performance status of two or lower; lesions that could be evaluated using computed tomography or magnetic resonance imaging; adequate hematological and renal function (white blood cell count >4x109/L; platelet count >100x109/L); and total bilirubin, serum aspartate transaminase, and serum alanine transaminase concentrations less than 1.5 times the upper limit of normal.	('less', 'NegReg', (516, 520))	('serum aspartate transaminase', 'MPA', (440, 468))	('bilirubin', 'Chemical', 'MESH:D001663', (429, 438))	('BTC', 'Phenotype', 'HP:0100574', (40, 43))	('Oncology', 'Phenotype', 'HP:0002664', (175, 183))	('Cancer', 'Disease', 'MESH:D009369', (111, 117))	('Cancer', 'Disease', (111, 117))	('hematological and renal function', 'Disease', 'MESH:D007674', (324, 356))	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('serum alanine transaminase concentrations', 'MPA', (474, 515))	('>100x109/L', 'Var', (406, 416))
102885	25792843	Next, gelatin sponge particles (350-510 mum, Ailikang Medicine Co Ltd, Hangzhou, People's Republic of China) diluted with the same contrast medium were injected through a 1 mL syringe.	('350-510 mum', 'Var', (32, 43))	("People's Republic", 'Disease', (81, 98))	("People's Republic", 'Disease', 'MESH:D006212', (81, 98))
102974	24860985	Vascular encasement by pCCA can lead to atrophy of the affected lobe with compensatory hypertrophy of the contralateral, unaffected lobe.	('lead to', 'Reg', (32, 39))	('atrophy', 'Disease', 'MESH:D001284', (40, 47))	('atrophy', 'Disease', (40, 47))	('pCCA', 'Gene', (23, 27))	('hypertrophy', 'Disease', (87, 98))	('hypertrophy', 'Disease', 'MESH:D006984', (87, 98))	('encasement', 'Var', (9, 19))
102988	24860985	EUS-FNA does carry a significant risk of tumor seeding.	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('EUS-FNA', 'Var', (0, 7))
103006	24860985	Trisomy 7 is frequently detected in the setting of inflammation of the biliary tree.	('Trisomy', 'Var', (0, 7))	('inflammation', 'Disease', 'MESH:D007249', (51, 63))	('inflammation', 'Disease', (51, 63))	('detected', 'Reg', (24, 32))
103009	24860985	PSC patients with FISH polysomy in the absence of other diagnostic features had a significantly higher risk of CCA development if polysomy was confirmed on subsequent FISH analysis compared to patients with non-serial polysomy (69% vs. 18%).	('patients', 'Species', '9606', (193, 201))	('CCA', 'Disease', (111, 114))	('PSC', 'Gene', '100653366', (0, 3))	('PSC', 'Gene', (0, 3))	('patients', 'Species', '9606', (4, 12))	('polysomy', 'Var', (23, 31))
103010	24860985	In the majority of individuals with serial FISH polysomy, a diagnosis of CCA was attained within 6 months of the initial detection of polysomy, although in 4 patients CCA was not diagnosed until 1-2.7 years after initial polysomy result.	('patients', 'Species', '9606', (158, 166))	('polysomy', 'Var', (48, 56))	('CCA', 'Disease', (73, 76))
103013	24860985	Interestingly, all patients with FISH polysomy and CA 19-9 levels >= 129 U/mL had eventual CCA development (90% within the first 2 years).	('CCA development', 'CPA', (91, 106))	('patients', 'Species', '9606', (19, 27))	('FISH polysomy', 'Var', (33, 46))
103020	24860985	In this technique, embolization of the portal vein in the affected lobe is carried out, and this stimulates hypertrophy of the contralateral unaffected lobe.	('embolization of the portal vein', 'Phenotype', 'HP:0030242', (19, 50))	('embolization', 'Var', (19, 31))	('hypertrophy', 'Disease', (108, 119))	('hypertrophy', 'Disease', 'MESH:D006984', (108, 119))	('stimulates', 'Reg', (97, 107))
103035	24860985	The pretransplant dropout rate was 31%, and predictors included CA 19-9 levels >= 500 U/mL, radial diameter of tumor mass >= 3 cm, brushing or biopsy result positive for malignancy, and MELD score >= 20.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('>= 500', 'Var', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('rat', 'Species', '10116', (26, 29))	('tumor', 'Disease', (111, 116))	('malignancy', 'Disease', 'MESH:D009369', (170, 180))	('CA 19-9 levels', 'MPA', (64, 78))	('malignancy', 'Disease', (170, 180))
103050	24860985	Utilization of a stool assay for methylated genes and mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) to diagnose pancreatic cancer was recently reported.	('pancreatic cancer', 'Disease', (123, 140))	('pancreatic cancer', 'Disease', 'MESH:D010190', (123, 140))	('sarcoma', 'Disease', (73, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (123, 140))	('mutant', 'Var', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('rat', 'Species', '10116', (69, 72))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))
103055	24860985	Combining cancer cell directed therapy with stromal CAF deletion represents a novel therapeutic approach in pCCA (Figure 5).	('deletion', 'Var', (56, 64))	('CAF', 'Gene', '8850', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('pCCA', 'Disease', (108, 112))	('CAF', 'Gene', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
103083	31788648	The PV including portal bifurcation was resected and reconstructed by anastomosis between the upstream side of the PV and the inferior vena cava in an end-to-side method (Eck fistula).	('anastomosis', 'Var', (70, 81))	('Eck fistula', 'Disease', 'MESH:D005402', (171, 182))	('Eck fistula', 'Disease', (171, 182))
103125	30046394	Conversely, disrupting integrin-ligand interactions can induce apoptosis via integrin-mediated death (IMD), which is mediated by recruiting and activating caspase-8.	('caspase-8', 'Gene', (155, 164))	('activating', 'PosReg', (144, 154))	('integrin-mediated death', 'Disease', (77, 100))	('integrin-ligand', 'Protein', (23, 38))	('induce', 'PosReg', (56, 62))	('caspase-8', 'Gene', '841', (155, 164))	('apoptosis', 'CPA', (63, 72))	('disrupting', 'Var', (12, 22))	('interactions', 'Interaction', (39, 51))
103202	30046394	The overexpression of alphav integrins (alphavbeta3, alphavbeta5, alphavbeta6) serves as key prognostic, and therapeutic targets in stomach cancers.	('stomach cancers', 'Disease', 'MESH:D013274', (132, 147))	('stomach cancers', 'Disease', (132, 147))	('stomach cancers', 'Phenotype', 'HP:0012126', (132, 147))	('stomach cancer', 'Phenotype', 'HP:0012126', (132, 146))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('alphavbeta6', 'Var', (66, 77))	('overexpression', 'PosReg', (4, 18))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('alphav integrins', 'Protein', (22, 38))
103206	30046394	Inhibition of individual subunits is expected to disrupt cellular signaling and acts to halt tumor metastatic processes, angiogenesis and growth.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('disrupt', 'NegReg', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('growth', 'CPA', (138, 144))	('tumor', 'Disease', (93, 98))	('cellular signaling', 'MPA', (57, 75))	('Inhibition', 'Var', (0, 10))	('halt', 'NegReg', (88, 92))	('angiogenesis', 'CPA', (121, 133))
103218	30046394	Using this relaxed criteria, three plausible targets emerge for BLCA: alpha3beta1, alphavb6, and alpha6b4 (Figure 8A).	('beta1', 'Gene', '10678', (76, 81))	('alpha6b4', 'Var', (97, 105))	('beta1', 'Gene', (76, 81))	('BLCA', 'Chemical', '-', (64, 68))
103236	30046394	Results for each cancer type included, for each of the 27 integrin subunit genes, a log 2 value of expression difference between cancer and normal, a p-value, and a false discovery rate (FDR) adjusted according to the Benjamini-Hochberg method (Supplementary Table 2).	('expression', 'MPA', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('p-value', 'Var', (150, 157))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
103260	29423070	Intrahepatic tumor growth was induced by electroporation of oncogenic transposon-plasmids into the left liver lobe.	('induced by', 'Reg', (30, 40))	('Intrahepatic tumor', 'Disease', 'MESH:D002780', (0, 18))	('Intrahepatic tumor', 'Disease', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('electroporation', 'Var', (41, 56))
103277	29423070	Exposure to Sal likewise resulted in increased DNA fragmentation in p246 and p254 cells, respectively (Figure 2B).	('p254', 'Var', (77, 81))	('Sal', 'Chemical', 'MESH:C010327', (12, 15))	('DNA fragmentation', 'CPA', (47, 64))	('increased', 'PosReg', (37, 46))
103282	29423070	Therefore, local transfection of the liver parenchyma by electroporation with transposon DNA resulted in transposase-mediated oncogenic KRas-G12V-insertion and Akt2-activation combined with Cre-mediated p53-knockout.	('KRas-G12V-insertion', 'Var', (136, 155))	('Akt2', 'Gene', '208', (160, 164))	('Akt2', 'Gene', (160, 164))	('G12V', 'Mutation', 'rs121913529', (141, 145))
103286	29423070	To assess the effect of Sal on autophagy in human CC cells, we treated TFK-1 and EGI-1 cells for 24 h with pharmacological activators (PP242) or inhibitors of autophagy (chloroquine (CQ)), and increasing concentrations of Sal (0.1, 0.5, 2, and 10 microM).	('human', 'Species', '9606', (44, 49))	('Sal', 'Chemical', 'MESH:C010327', (222, 225))	('CQ', 'Chemical', 'MESH:D002738', (183, 185))	('CC', 'Phenotype', 'HP:0030153', (50, 52))	('autophagy', 'CPA', (159, 168))	('PP242', 'Chemical', 'MESH:C572919', (135, 140))	('Sal', 'Chemical', 'MESH:C010327', (24, 27))	('EGI-1', 'CellLine', 'CVCL:1193', (81, 86))	('chloroquine', 'Chemical', 'MESH:D002738', (170, 181))	('PP242', 'Var', (135, 140))
103290	29423070	Activation of autophagy by starvation of exposure to PP242 resulted in an increased amount of autophagic compartments in both TFK-1 and EGI-1 cells, which was counteracted by the addition of CQ (Figure 4B).	('autophagy', 'CPA', (14, 23))	('PP242', 'Var', (53, 58))	('increased', 'PosReg', (74, 83))	('PP242', 'Chemical', 'MESH:C572919', (53, 58))	('CQ', 'Chemical', 'MESH:D002738', (191, 193))	('autophagic compartments', 'CPA', (94, 117))	('EGI-1', 'CellLine', 'CVCL:1193', (136, 141))
103292	29423070	Activation of autophagy in TFK-1 and EGI-1 cells after PP242-incubation was in part counteracted by Sal (Figure 4D).	('autophagy', 'CPA', (14, 23))	('PP242-incubation', 'Var', (55, 71))	('PP242', 'Chemical', 'MESH:C572919', (55, 60))	('Sal', 'Chemical', 'MESH:C010327', (100, 103))	('EGI-1', 'CellLine', 'CVCL:1193', (37, 42))
103297	29423070	This was also observed when autophagy was activated by PP242 (Figure 4E).	('autophagy', 'CPA', (28, 37))	('PP242', 'Var', (55, 60))	('PP242', 'Chemical', 'MESH:C572919', (55, 60))
103313	29423070	This resulted in KRas-activation and p53-knockout in hepatocytes, leading to the development of intrahepatic CC growth.	('p53-knockout', 'Var', (37, 49))	('resulted', 'Reg', (5, 13))	('intrahepatic CC growth', 'Disease', 'MESH:D006130', (96, 118))	('CC', 'Phenotype', 'HP:0030153', (109, 111))	('KRas-activation', 'Var', (17, 32))	('intrahepatic CC growth', 'Disease', (96, 118))
103316	29423070	Additionally, inhibition of intrahepatic tumor spread has an important clinical impact, given that common chemotherapies have to be regarded rather in a palliative context.	('intrahepatic tumor', 'Disease', 'MESH:D002780', (28, 46))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('intrahepatic tumor', 'Disease', (28, 46))	('inhibition', 'Var', (14, 24))
103328	29423070	There are numerous reports indicating that Sal inhibits autophagy and, consequently, impairs tumor cell survival.	('Sal', 'Var', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('impairs tumor', 'Disease', (85, 98))	('autophagy', 'CPA', (56, 65))	('Sal', 'Chemical', 'MESH:C010327', (43, 46))	('impairs tumor', 'Disease', 'MESH:D015417', (85, 98))	('inhibits', 'NegReg', (47, 55))
103360	29423070	In brief, electroporation of sleeping beauty-based oncogenic transposon plasmids into the left liver lobe of 6- to 8-week-old p53fl/fl mice (Strain B6129P2-Trp53tm1Brn/J) resulted in KRas-activation and p53-knockout in hepatocytes, leading to the development of intrahepatic CC growth.	('electroporation', 'Var', (10, 25))	('KRas-activation', 'CPA', (183, 198))	('intrahepatic CC growth', 'Disease', 'MESH:D006130', (262, 284))	('mice (Strain', 'Species', '10090', (135, 147))	('CC', 'Phenotype', 'HP:0030153', (275, 277))	('intrahepatic CC growth', 'Disease', (262, 284))	('p53-knockout', 'CPA', (203, 215))
103456	24497320	SVMs achieved a slightly greater specificity than RFs (90% vs. 88%), but in general MOCA and RFs outperformed SVMs.	('RFs', 'Var', (93, 96))	('MOCA', 'Gene', '1795', (84, 88))	('MOCA', 'Gene', (84, 88))
103473	24497320	MiRs-486-3p and miR-16 make a complementary CCA diagnosis more than any other marker pair, and therefore these miRs combine to have the highest predictive value of any two-miR marker (sensitivity 57% and specificity 98%).	('CCA', 'Gene', (44, 47))	('MiRs-486-3p', 'Var', (0, 11))	('CCA', 'Gene', '2201', (44, 47))	('miR', 'Gene', '220972', (172, 175))	('miR', 'Gene', (172, 175))	('miR-16', 'Gene', (16, 22))	('miR', 'Gene', '220972', (16, 19))	('miR', 'Gene', '220972', (111, 114))	('miR', 'Gene', (16, 19))	('miR', 'Gene', (111, 114))	('miR-16', 'Gene', '51573', (16, 22))	('CCA', 'Phenotype', 'HP:0030153', (44, 47))
103500	24497320	However, there is a growing body of evidence suggesting that utilization of U6 to normalize miR expression in body fluids introduces biases that have the potential of rendering the results un-reproducible and/or unusable in a clinical laboratory setting.	('miR', 'Gene', '220972', (92, 95))	('miR', 'Gene', (92, 95))	('utilization', 'Var', (61, 72))	('rat', 'Species', '10116', (239, 242))
103530	24497320	In contrast, of the 6 patients correctly diagnosed with CCA by CA19-9 but not by our 5-miR panel, only 2 were N0M0 ( Supplementary Table 4).	('patients', 'Species', '9606', (22, 30))	('CCA', 'Gene', (56, 59))	('CCA', 'Phenotype', 'HP:0030153', (56, 59))	('miR', 'Gene', '220972', (87, 90))	('miR', 'Gene', (87, 90))	('CA19-9', 'Var', (63, 69))	('CCA', 'Gene', '2201', (56, 59))
103533	24497320	We conclude that CA 19-9 tends to diagnose advanced CCA, for which surgery may no longer be an option, while our marker panel tends to diagnose early CCA, where surgery is still an option.	('diagnose', 'Reg', (34, 42))	('CCA', 'Gene', (150, 153))	('CA 19-9', 'Var', (17, 24))	('CCA', 'Gene', '2201', (150, 153))	('CCA', 'Phenotype', 'HP:0030153', (52, 55))	('diagnose', 'Reg', (135, 143))	('CCA', 'Gene', (52, 55))	('CCA', 'Gene', '2201', (52, 55))	('CCA', 'Phenotype', 'HP:0030153', (150, 153))
103657	23815976	Injuries of the straight vessel could lead to necrosis of the proximal jejunum.	('necrosis', 'Disease', (46, 54))	('necrosis', 'Disease', 'MESH:D009336', (46, 54))	('Injuries', 'Var', (0, 8))	('lead to', 'Reg', (38, 45))
103694	20458282	In vivo, 5-FU+resveratrol decreased tumor size and increased TUNEL staining to a greater extent than 5-FU alone.	('resveratrol', 'Chemical', 'MESH:D000077185', (14, 25))	('increased', 'PosReg', (51, 60))	('5-FU+resveratrol', 'Var', (9, 25))	('TUNEL staining', 'MPA', (61, 75))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('5-FU', 'Chemical', 'MESH:D005472', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('5-FU', 'Chemical', 'MESH:D005472', (9, 13))	('decreased', 'NegReg', (26, 35))	('tumor', 'Disease', (36, 41))
103696	20458282	Mz-Cyp1b1 cells were more sensitive to chemotherapeutic agents in vitro than mock-transfected cells, and Mz-Cyp1b1-induced tumors were more susceptible to 5-FU treatment.	('Mz-Cyp1b1', 'Var', (0, 9))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('Mz-Cyp1b1-induced', 'Var', (105, 122))	('sensitive', 'MPA', (26, 35))	('5-FU', 'Chemical', 'MESH:D005472', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
103711	20458282	In cholangiocarcinoma cell lines, resveratrol has been shown to perturb cell cycle progression, resulting in an accumulation of cells in the G1/S phase, however the precise mechanism by which this occurs is largely unknown.	('cells in the G1/S phase', 'CPA', (128, 151))	('accumulation', 'PosReg', (112, 124))	('cholangiocarcinoma', 'Disease', (3, 21))	('cell cycle progression', 'CPA', (72, 94))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('resveratrol', 'Var', (34, 45))	('resveratrol', 'Chemical', 'MESH:D000077185', (34, 45))	('perturb', 'NegReg', (64, 71))
103713	20458282	Cyp1b1 has many functions, including the hydroxylation of 17-beta-estradiol, the biotransformation of testosterone as well as the metabolism of xenobiotics such as ethoxyresorufin, theophylline and caffeine.	('biotransformation', 'MPA', (81, 98))	('testosterone', 'Chemical', 'MESH:D013739', (102, 114))	('hydroxylation of 17-beta-estradiol', 'MPA', (41, 75))	('theophylline', 'Chemical', 'MESH:D013806', (181, 193))	('ethoxyresorufin', 'Chemical', 'MESH:C007649', (164, 179))	('caffeine', 'Chemical', 'MESH:D002110', (198, 206))	('metabolism of', 'MPA', (130, 143))	('Cyp1b1', 'Var', (0, 6))	('17-beta-estradiol', 'Chemical', 'MESH:D004958', (58, 75))
103757	20458282	We then wished to determine if the dampened expression of Cyp1b1 in cholangiocarcinoma cells renders them more susceptible to chemotherapeutic agents.	('expression', 'MPA', (44, 54))	('more', 'PosReg', (106, 110))	('Cyp1b1', 'Var', (58, 64))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (68, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (68, 86))	('dampened', 'NegReg', (35, 43))	('susceptible', 'MPA', (111, 122))	('cholangiocarcinoma', 'Disease', (68, 86))
103758	20458282	The mock-transfected cell line (Mz-Neo neg) expressed Cyp1b1 to a similar level as the parental cell line (Mz-ChA-1), where as the stably-transfected Mz-Cyp1b1 shRNA cell line expressed approximately 20% or the parental and mock-transfected cell lines (Figure 6A).	('Mz-Cyp1b1', 'Var', (150, 159))	('Mz-Neo', 'Chemical', '-', (32, 38))	('Cyp1b1', 'Var', (54, 60))
103760	20458282	Indeed, dampened Cyp1b1 expression decreased the dose required to achieve 50% reduction in cell proliferation (IC50; Table 3) We then established xenograft tumors of cholangiocarcinoma using the Mz-Cyp1b1 shRNA and Mz-Neo neg and determined the relative effects of 5-FU on these tumors.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumors of cholangiocarcinoma', 'Disease', (156, 184))	('tumors', 'Disease', (279, 285))	('decreased', 'NegReg', (35, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('tumors of cholangiocarcinoma', 'Disease', 'MESH:D018281', (156, 184))	('dose', 'MPA', (49, 53))	('rat', 'Species', '10116', (103, 106))	('tumors', 'Disease', 'MESH:D009369', (279, 285))	('5-FU', 'Chemical', 'MESH:D005472', (265, 269))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (166, 184))	('Mz-Neo', 'Chemical', '-', (215, 221))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', (156, 162))	('dampened Cyp1b1 expression', 'Var', (8, 34))	('Mz-Cyp1b1', 'Var', (195, 204))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('cell proliferation', 'CPA', (91, 109))
103763	20458282	The amount of PCNA-positive nuclei per field decreased after 5-FU treatment in tumors derived from both the Mz-Cyp1b1 shRNA cell line and the mock-transfected Mz-Neo neg cell line (Figure 8B), however this decrease was more evident in the Mz-ChA-1 shRNA-derived tumors.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('5-FU', 'Chemical', 'MESH:D005472', (61, 65))	('decreased', 'NegReg', (45, 54))	('Mz-Cyp1b1', 'Var', (108, 117))	('tumors', 'Disease', (262, 268))	('PCNA', 'Gene', (14, 18))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('Mz-Neo', 'Chemical', '-', (159, 165))	('PCNA', 'Gene', '5111', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
103765	20458282	Conversely, 5-FU treatment increased the incidence of apoptosis in tumors derived from both cell lines (Figure 8C), however, as expected, the effect was more dramatic in the tumors derived from the Mz-Cyp1b1 shRNA cell line (Figure 8C).	('apoptosis', 'CPA', (54, 63))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('Mz-Cyp1b1', 'Var', (198, 207))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('5-FU', 'Chemical', 'MESH:D005472', (12, 16))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
103768	20458282	In parallel, resveratrol treatment decreased the expression of Cyp1b1 and genetic knockdown of Cyp1b1 rendered the cells and tumors more susceptible to the same chemotherapeutic agents as above, suggesting that the level of Cyp1b1 expression may correlate to the relative chemoresistance of these cells.	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Cyp1b1', 'Var', (95, 101))	('knockdown', 'Var', (82, 91))	('expression', 'MPA', (49, 59))	('tumors', 'Disease', (125, 131))	('decreased', 'NegReg', (35, 44))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('Cyp1b1', 'Var', (63, 69))	('resveratrol', 'Chemical', 'MESH:D000077185', (13, 24))
103784	20458282	Cyp1b1 has previously been shown to play a role in the bioactivation of several procarcinogens to carcinogenic derivatives and also to detoxify several xenobiotic compounds including various chemotherapeutic agents.	('carcinogenic derivatives', 'Disease', 'MESH:C536408', (98, 122))	('carcinogenic derivatives', 'Disease', (98, 122))	('bioactivation', 'MPA', (55, 68))	('detoxify', 'MPA', (135, 143))	('Cyp1b1', 'Var', (0, 6))
103877	17062136	The results of a controlled trial with high dose UDCA for the treatment of PSC has shown a trend towards a prolonged survival in the high dose UDCA group.	('PSC', 'Gene', (75, 78))	('UDCA', 'Chemical', 'MESH:D014580', (143, 147))	('men', 'Species', '9606', (67, 70))	('UDCA', 'Chemical', 'MESH:D014580', (49, 53))	('PSC', 'Gene', '100653366', (75, 78))	('high dose', 'Var', (133, 142))
104035	33623393	Other studies have also reported that anomalous LDL-C rapidly decreases after surgical removal of biliary obstruction, and hypercholesterolemia caused by cholestasis has not been found associated with vascular risk.	('LDL-C', 'Gene', '22796', (48, 53))	('cholestasis', 'Disease', 'MESH:D002779', (154, 165))	('decreases', 'NegReg', (62, 71))	('cholestasis', 'Disease', (154, 165))	('biliary obstruction', 'Disease', 'MESH:D001657', (98, 117))	('anomalous LDL-C', 'Phenotype', 'HP:0031886', (38, 53))	('anomalous', 'Var', (38, 47))	('biliary obstruction', 'Disease', (98, 117))	('hypercholesterolemia', 'Phenotype', 'HP:0003124', (123, 143))	('biliary obstruction', 'Phenotype', 'HP:0005230', (98, 117))	('cholestasis', 'Phenotype', 'HP:0001396', (154, 165))	('hypercholesterolemia', 'Disease', (123, 143))	('hypercholesterolemia', 'Disease', 'MESH:D006937', (123, 143))	('LDL-C', 'Gene', (48, 53))
104065	32117649	During the surgical procedure, a peritoneal carcinomatosis index (PCI) of 4 was found for implants in the 1.5-cm bladder dome, 5-mm implants in both ovaries and uterus, and 5- and 8-mm peritoneal implants in greater omentum.	('implants', 'Var', (90, 98))	('ovaries', 'Disease', 'MESH:D010051', (149, 156))	('peritoneal carcinomatosis', 'Disease', (33, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('ovaries', 'Disease', (149, 156))	('peritoneal carcinomatosis', 'Disease', 'MESH:D010534', (33, 58))
104131	31888442	Therefore, we come to the conclusion that the separability among different types cancers in the dimensionality reduction data of three methods is best by sgLRR method, followed by T-SNE method, and finally by LEE method.	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('sgLRR', 'Var', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
104151	31399555	Further studies demonstrated that CDK7 inhibitor THZ1 inhibited cell viability and induced apoptosis in CCA cells.	('inhibited', 'NegReg', (54, 63))	('CDK7', 'Gene', '1022', (34, 38))	('apoptosis', 'CPA', (91, 100))	('CCA', 'Phenotype', 'HP:0030153', (104, 107))	('THZ1', 'Chemical', '-', (49, 53))	('CDK7', 'Gene', (34, 38))	('THZ1', 'Var', (49, 53))	('induced', 'Reg', (83, 90))	('cell viability', 'CPA', (64, 78))
104156	31399555	MCL1, one of the antiapoptotic BCL2 family members, was significantly inhibited upon THZ1 treatment.	('BCL2', 'Gene', '596', (31, 35))	('MCL1', 'Gene', '4170', (0, 4))	('THZ1', 'Var', (85, 89))	('MCL1', 'Gene', (0, 4))	('THZ1', 'Chemical', '-', (85, 89))	('BCL2', 'Gene', (31, 35))	('treatment', 'Var', (90, 99))	('inhibited', 'NegReg', (70, 79))
104169	31399555	CDK7 has become a potential therapeutic target, and CDK7 inhibitors have entered the clinical trial as promising methods for a variety of malignancies.	('CDK7', 'Gene', '1022', (0, 4))	('inhibitors', 'Var', (57, 67))	('malignancies', 'Disease', 'MESH:D009369', (138, 150))	('CDK7', 'Gene', '1022', (52, 56))	('malignancies', 'Disease', (138, 150))	('CDK7', 'Gene', (0, 4))	('CDK7', 'Gene', (52, 56))
104179	31399555	Antibodies against human cleaved PARP (#5625), BCL-XL (#2764), MCL1 (#5453), and CDK7 (#2916) were purchased from Cell Signaling Technology (Beverly, MA, USA).	('CDK7', 'Gene', '1022', (81, 85))	('#5453', 'Var', (69, 74))	('#2764', 'Var', (55, 60))	('BCL-XL', 'Gene', '598', (47, 53))	('PARP', 'Gene', '142', (33, 37))	('MCL1', 'Gene', '4170', (63, 67))	('CDK7', 'Gene', (81, 85))	('human', 'Species', '9606', (19, 24))	('MCL1', 'Gene', (63, 67))	('#2916', 'Var', (87, 92))	('PARP', 'Gene', (33, 37))	('#5625', 'Var', (39, 44))	('BCL-XL', 'Gene', (47, 53))
104180	31399555	Antibodies against human RNP2 (A300-653A-T), RNP2-p-S2 (A300-654A-T), and RNP2-p-S5 (A304-408A-T) were from Bethyl Laboratories (Montgomery, TX, USA).	('A300-653A-T', 'Var', (31, 42))	('A304-408A-T', 'Var', (85, 96))	('A300-654A-T', 'Var', (56, 67))	('A300-654A-T', 'Mutation', 'c.300_654A,A>T', (56, 67))	('A304-408A-T', 'Mutation', 'c.304_408A,A>T', (85, 96))	('A300-653A-T', 'Mutation', 'c.300_653A,A>T', (31, 42))	('human', 'Species', '9606', (19, 24))	('RNP2', 'Gene', (25, 29))
104226	31399555	BrdU incorporation assay also indicated that THZ1 dramatically inhibited DNA synthesis (Supplementary Fig.	('THZ1', 'Var', (45, 49))	('DNA synthesis', 'MPA', (73, 86))	('THZ1', 'Chemical', '-', (45, 49))	('inhibited', 'NegReg', (63, 72))
104229	31399555	THZ1-induced apoptosis was further evidenced by enhanced Caspase 3/7 activity and poly (ADP-ribose) polymerase (PARP) cleavage (Fig.	('PARP', 'Gene', (112, 116))	('enhanced', 'PosReg', (48, 56))	('apoptosis', 'CPA', (13, 22))	('PARP', 'Gene', '142', (112, 116))	('THZ1', 'Chemical', '-', (0, 4))	('THZ1-induced', 'Var', (0, 12))	('Caspase 3/7 activity and poly (ADP-ribose) polymerase', 'Gene', '142;836', (57, 110))
104232	31399555	By recording tumor volume, we discovered that THZ1 significantly suppressed the xenograft growth (Fig.	('tumor', 'Disease', (13, 18))	('THZ1', 'Chemical', '-', (46, 50))	('xenograft growth', 'CPA', (80, 96))	('suppressed', 'NegReg', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('THZ1', 'Var', (46, 50))
104234	31399555	Of note, THZ1 showed no discernible impact on mice body weight, indicating the bearable toxicity of the treatment (Supplementary Fig.	('THZ1', 'Chemical', '-', (9, 13))	('THZ1', 'Var', (9, 13))	('mice', 'Species', '10090', (46, 50))	('toxicity', 'Disease', 'MESH:D064420', (88, 96))	('toxicity', 'Disease', (88, 96))
104258	31399555	The synergistic apoptosis induction by the co-treatment of THZ1 and ABT-263 was also detected in HuCCT1 and HuH28 cell lines by the Annexin-V/PI assay, Caspase 3/7 activity assay, and cleaved PARP expression (Fig.	('Annexin-V', 'Gene', (132, 141))	('PARP', 'Gene', (192, 196))	('Annexin-V', 'Gene', '308', (132, 141))	('THZ1', 'Chemical', '-', (59, 63))	('ABT-263', 'Gene', (68, 75))	('cleaved', 'Var', (184, 191))	('ABT', 'Chemical', 'MESH:C002502', (68, 71))	('PARP', 'Gene', '142', (192, 196))	('HuH28', 'CellLine', 'CVCL:2955', (108, 113))	('Caspase 3', 'Gene', (152, 161))	('THZ1', 'Gene', (59, 63))	('Caspase 3', 'Gene', '836', (152, 161))
104261	31399555	SiRNA mediated silencing of MCL1 resulted in great reduction in MCL1 protein levels and (Supplementary Fig.	('MCL1', 'Gene', (64, 68))	('reduction', 'NegReg', (51, 60))	('MCL1', 'Gene', '4170', (64, 68))	('silencing', 'Var', (15, 24))	('MCL1', 'Gene', '4170', (28, 32))	('MCL1', 'Gene', (28, 32))
104266	31399555	Not surprisingly, A-1210477, a MCL1 selective inhibitor, also potentiated the antitumor effect of ABT-263 in CCA cells (Supplementary Fig.	('CCA', 'Phenotype', 'HP:0030153', (109, 112))	('MCL1', 'Gene', '4170', (31, 35))	('A-1210477', 'Var', (18, 27))	('CCA', 'Disease', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('ABT', 'Chemical', 'MESH:C002502', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('ABT-263', 'Gene', (98, 105))	('MCL1', 'Gene', (31, 35))	('A-1210477', 'Chemical', 'MESH:C000611392', (18, 27))	('potentiated', 'PosReg', (62, 73))	('tumor', 'Disease', (82, 87))
104274	31399555	Similar to THZ1, ICEC0942 caused a reduction in MCL1 expression and potentiated the antitumor effect of ABT-263 in HuCCT1 and HuH28 cell lines (Fig.	('ABT-263', 'Gene', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('ICEC0942', 'Var', (17, 25))	('HuH28', 'CellLine', 'CVCL:2955', (126, 131))	('potentiated', 'PosReg', (68, 79))	('MCL1', 'Gene', '4170', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('expression', 'MPA', (53, 63))	('MCL1', 'Gene', (48, 52))	('ABT', 'Chemical', 'MESH:C002502', (104, 107))	('THZ1', 'Chemical', '-', (11, 15))	('tumor', 'Disease', (88, 93))	('reduction', 'NegReg', (35, 44))
104303	31399555	In additionally, our results indicate that CDK7 inhibitor THZ1 can rapidly and dramatically inhibit MCL1 synthesis and drive apoptosis in combination with the BCL2/BCL-XL inhibitor in CCA.	('CCA', 'Phenotype', 'HP:0030153', (184, 187))	('drive', 'PosReg', (119, 124))	('BCL-XL', 'Gene', (164, 170))	('CCA', 'Disease', (184, 187))	('BCL2', 'Gene', '596', (159, 163))	('CDK7', 'Gene', (43, 47))	('inhibitor', 'Var', (48, 57))	('inhibit', 'NegReg', (92, 99))	('MCL1', 'Gene', '4170', (100, 104))	('THZ1', 'Chemical', '-', (58, 62))	('apoptosis', 'CPA', (125, 134))	('MCL1', 'Gene', (100, 104))	('BCL2', 'Gene', (159, 163))	('BCL-XL', 'Gene', '598', (164, 170))	('CDK7', 'Gene', '1022', (43, 47))
104378	29532867	H2A.Z knockdown inhibited cell viability and colony formation ability in both CCLP-1 and HCCC-9810 cells (Fig.	('CC', 'Phenotype', 'HP:0030153', (90, 92))	('inhibited', 'NegReg', (16, 25))	('HCCC-9810', 'CellLine', 'CVCL:6908', (89, 98))	('colony formation ability', 'CPA', (45, 69))	('CC', 'Phenotype', 'HP:0030153', (78, 80))	('HCC', 'Phenotype', 'HP:0001402', (89, 92))	('knockdown', 'Var', (6, 15))	('cell viability', 'CPA', (26, 40))
104381	29532867	Through western blot analysis, CDK2, CDK4, cyclinA and Skp2 were demonstrated to be downregulated following H2A.Z knockdown, whereas p21 and p27 were upregulated in both CCLP-1 and HCCC-9810 cells; however, no change was observed in the level of MMP2 after H2A.Z knockdown (Fig.	('Skp2', 'Gene', (55, 59))	('MMP2', 'Gene', '4313', (246, 250))	('CDK4', 'Gene', (37, 41))	('p27', 'Gene', '3429', (141, 144))	('p27', 'Gene', (141, 144))	('Skp2', 'Gene', '6502', (55, 59))	('cyclinA', 'Gene', '890', (43, 50))	('CDK4', 'Gene', '1019', (37, 41))	('HCC', 'Phenotype', 'HP:0001402', (181, 184))	('p21', 'Gene', (133, 136))	('knockdown', 'Var', (263, 272))	('HCCC-9810', 'CellLine', 'CVCL:6908', (181, 190))	('CC', 'Phenotype', 'HP:0030153', (170, 172))	('CDK2', 'Gene', '1017', (31, 35))	('MMP2', 'Gene', (246, 250))	('CDK2', 'Gene', (31, 35))	('p21', 'Gene', '1026', (133, 136))	('cyclinA', 'Gene', (43, 50))	('CC', 'Phenotype', 'HP:0030153', (182, 184))
104384	29532867	The analysis of expression of apoptosis-related proteins by western blotting revealed that H2A.Z knockdown resulted in the downregulation of Bcl-2, and the upregulation of Bak, caspase-9, and both total and cleaved caspase-3 (Fig.	('knockdown', 'Var', (97, 106))	('Bcl-2', 'Gene', '596', (141, 146))	('Bcl-2', 'Gene', (141, 146))	('upregulation', 'PosReg', (156, 168))	('downregulation', 'NegReg', (123, 137))	('caspase-9', 'Gene', (177, 186))	('caspase-3', 'Gene', (215, 224))	('Bak', 'Gene', '578', (172, 175))	('H2A.Z', 'Gene', (91, 96))	('Bak', 'Gene', (172, 175))	('caspase-3', 'Gene', '836', (215, 224))	('caspase-9', 'Gene', '842', (177, 186))
104385	29532867	H2A.Z knockdown significantly decreased the motility and invasion ability of CCLP-1 and HCCC-9810 cells (Fig.	('invasion ability', 'CPA', (57, 73))	('CC', 'Phenotype', 'HP:0030153', (77, 79))	('HCC', 'Phenotype', 'HP:0001402', (88, 91))	('motility', 'CPA', (44, 52))	('CC', 'Phenotype', 'HP:0030153', (89, 91))	('knockdown', 'Var', (6, 15))	('decreased', 'NegReg', (30, 39))	('HCCC-9810', 'CellLine', 'CVCL:6908', (88, 97))
104386	29532867	Notably, H2A.Z knockdown induced E-cadherin expression, while it inhibited the expression of N-cadherin, Slug and Snail in CCLP-1 and HCCC-9810 cells (Fig.	('HCCC-9810', 'CellLine', 'CVCL:6908', (134, 143))	('expression', 'MPA', (44, 54))	('CC', 'Phenotype', 'HP:0030153', (135, 137))	('HCC', 'Phenotype', 'HP:0001402', (134, 137))	('expression', 'MPA', (79, 89))	('E-cadherin', 'Gene', (33, 43))	('knockdown', 'Var', (15, 24))	('E-cadherin', 'Gene', '999', (33, 43))	('H2A.Z', 'Var', (9, 14))	('CC', 'Phenotype', 'HP:0030153', (123, 125))	('inhibited', 'NegReg', (65, 74))	('N-cadherin', 'Gene', (93, 103))	('Slug', 'Gene', '6591', (105, 109))	('Snail', 'Gene', '6615', (114, 119))	('Snail', 'Gene', (114, 119))	('N-cadherin', 'Gene', '1000', (93, 103))	('Slug', 'Gene', (105, 109))
104393	29532867	As expected, H2A.Z knockdown was associated with a higher percentage of TUNEL-positive cells in the tumors, compared with the control group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('knockdown', 'Var', (19, 28))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('higher', 'PosReg', (51, 57))	('H2A.Z', 'Gene', (13, 18))
104396	29532867	In specific, the hydrolysis product of cisplatin can react with DNA, producing crosslinks which can destroy transcription and replication of DNA.	('destroy', 'NegReg', (100, 107))	('replication', 'MPA', (126, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('transcription', 'MPA', (108, 121))	('crosslinks', 'Var', (79, 89))
104398	29532867	Because H2A.Z knockdown induced cell cycle arrest and apoptosis in ICC cell lines, it was hypothesized that H2A.Z knockdown might synergistically act with cisplatin in the therapy of ICC.	('apoptosis', 'CPA', (54, 63))	('ICC', 'Disease', (183, 186))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('CC', 'Phenotype', 'HP:0030153', (68, 70))	('knockdown', 'Var', (14, 23))	('cell cycle arrest', 'CPA', (32, 49))	('CC', 'Phenotype', 'HP:0030153', (184, 186))
104400	29532867	In cell proliferation assays, treatment with cisplatin combined with H2A.Z knockdown inhibited the proliferation of CCLP-1 cells more powerfully than the single treatments of either cisplatin or shRNA (P<0.01; Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (182, 191))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('inhibited', 'NegReg', (85, 94))	('knockdown', 'Var', (75, 84))	('CC', 'Phenotype', 'HP:0030153', (116, 118))	('proliferation', 'CPA', (99, 112))
104404	29532867	Taken together, these results suggested that H2A.Z knockdown increased the sensitivity of ICC cells to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('CC', 'Phenotype', 'HP:0030153', (91, 93))	('increased', 'PosReg', (61, 70))	('sensitivity', 'MPA', (75, 86))	('knockdown', 'Var', (51, 60))
104422	29532867	H2A.Z knockdown inhibited tumor growth and metastasis in vivo via regulation of cell proliferation and EMT.	('inhibited', 'NegReg', (16, 25))	('EMT', 'CPA', (103, 106))	('regulation', 'Reg', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('cell proliferation', 'CPA', (80, 98))	('knockdown', 'Var', (6, 15))	('tumor', 'Disease', (26, 31))
104423	29532867	Furthermore, H2A.Z knockdown improved the efficacy of cisplatin treatment in a ICC xenograft mouse model.	('CC', 'Phenotype', 'HP:0030153', (80, 82))	('mouse', 'Species', '10090', (93, 98))	('knockdown', 'Var', (19, 28))	('cisplatin treatment', 'MPA', (54, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('improved', 'PosReg', (29, 37))	('efficacy', 'MPA', (42, 50))	('H2A.Z', 'Gene', (13, 18))
104500	21460876	For patients with advanced cancers that are unresectable or those with metastatic disease, systemic therapy with gemcitabine plus cisplatin is a first-line approach (Figure 2) A benefit has been demonstrated for gemcitabine plus cisplatin compared to gemcitabine alone, and for chemotherapy based on 5FU compared to the best supportive care.	('gemcitabine', 'Chemical', 'MESH:C056507', (113, 124))	('gemcitabine', 'Chemical', 'MESH:C056507', (212, 223))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('5FU', 'Chemical', 'MESH:D005472', (300, 303))	('gemcitabine', 'Chemical', 'MESH:C056507', (251, 262))	('cisplatin', 'Chemical', 'MESH:D002945', (229, 238))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('patients', 'Species', '9606', (4, 12))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('gemcitabine', 'Var', (212, 223))	('cancers', 'Disease', (27, 34))
104563	21460876	Survival in patients with R1 or R2 resections is much lower, and is comparable to palliative stenting with photodynamic therapy.	('patients', 'Species', '9606', (12, 20))	('R2 resections', 'Var', (32, 45))	('lower', 'NegReg', (54, 59))
104669	31933635	that abnormalities in hepatic function and tumor marker tests combined with transabdominal ultrasonography (US) can be used for early diagnosis of ECCA in patients without jaundice, with resulting resectability of 83% and survival of 50% at 5 years.	('abnormalities in hepatic function', 'Phenotype', 'HP:0001410', (5, 38))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('abnormalities', 'Var', (5, 18))	('hepatic function', 'MPA', (22, 38))	('jaundice', 'Disease', 'MESH:D007565', (172, 180))	('patients', 'Species', '9606', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('CCA', 'Gene', (148, 151))	('jaundice', 'Disease', (172, 180))	('jaundice', 'Phenotype', 'HP:0000952', (172, 180))	('CCA', 'Gene', '2201', (148, 151))
104719	31933635	As shown by Fritcher et al., a combination of FISH probes 1q21, 7p12, 8q24, and 9p21 identified pancreatobiliary malignancies with sensitivity of 93% and specificity of 100%.	('8q24', 'Var', (70, 74))	('pancreatobiliary malignancies', 'Disease', (96, 125))	('pancreatobiliary malignancies', 'Disease', 'MESH:D009369', (96, 125))	('9p21', 'Var', (80, 84))
104787	29851859	Univariate analysis revealed that the statistically significant factors related to OS were CA19-9, TBIL, ALB, CONUT, and PNI.	('CA19-9', 'Var', (91, 97))	('ALB', 'Gene', '213', (105, 108))	('TBIL', 'Chemical', 'MESH:D001663', (99, 103))	('TBIL', 'Disease', (99, 103))	('CONUT', 'Disease', (110, 115))	('ALB', 'Gene', (105, 108))	('PNI', 'Disease', (121, 124))
104841	29851859	Multivariate analysis was further performed, and CA19-9, CONUT [hazard ratio (HR) = 2.02, 95% CI: 1.08-3.80], and PNI (HR = 2.08, 95% CI: 1.01-4.28) were identified as independent prognostic markers of HCCA (Table 2).	('CI', 'Gene', '622408', (94, 96))	('CA19-9', 'Var', (49, 55))	('CI', 'Gene', '622408', (134, 136))	('HCCA', 'Disease', (202, 206))
104842	29851859	According to the above-mentioned results, CA19-9 and TBIL were crucial prognostic markers for HCCA, which were in accordance with previous reports.	('TBIL', 'Chemical', 'MESH:D001663', (53, 57))	('CA19-9', 'Var', (42, 48))	('men', 'Species', '9606', (23, 26))	('TBIL', 'MPA', (53, 57))	('HCCA', 'Disease', (94, 98))
104844	29851859	We found that patients with abnormal CONUT and PNI scores had significantly higher levels of CA19-9 and TBIL (Fig.	('levels of CA19-9', 'MPA', (83, 99))	('TBIL', 'MPA', (104, 108))	('abnormal', 'Var', (28, 36))	('TBIL', 'Chemical', 'MESH:D001663', (104, 108))	('CONUT', 'Disease', (37, 42))	('higher', 'PosReg', (76, 82))	('patients', 'Species', '9606', (14, 22))	('PNI scores', 'Gene', (47, 57))
104850	29851859	The implanted 125I seed has a direct effect on the local lesion, and the radioactivity inside the tumor is much higher than the surrounding normal tissues.	('higher', 'PosReg', (112, 118))	('radioactivity', 'MPA', (73, 86))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('local lesion', 'MPA', (51, 63))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('125I', 'Var', (14, 18))	('tumor', 'Disease', (98, 103))
104866	29851859	First, poor nutritional status is associated with cancer progression, complications, infections, and thus may lead to delayed treatment.	('associated', 'Reg', (34, 44))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('men', 'Species', '9606', (131, 134))	('infections', 'Disease', 'MESH:D007239', (85, 95))	('poor', 'Var', (7, 11))	('infections', 'Disease', (85, 95))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
104875	29851859	In the current study, we also found that pretreatment level of ALB < 35 g/L was associated with worse survival in unresectable HCCA.	('men', 'Species', '9606', (49, 52))	('< 35 g/L', 'Var', (67, 75))	('ALB', 'Gene', (63, 66))	('unresectable HCCA', 'Disease', (114, 131))	('ALB', 'Gene', '213', (63, 66))
104880	29851859	Therefore, low total cholesterol may not only affect intracellular signaling but also impair immune system.	('impair immune system', 'Phenotype', 'HP:0002721', (86, 106))	('intracellular signaling', 'MPA', (53, 76))	('affect', 'Reg', (46, 52))	('impair', 'NegReg', (86, 92))	('cholesterol', 'Chemical', 'MESH:D002784', (21, 32))	('low', 'Var', (11, 14))	('low total cholesterol', 'Phenotype', 'HP:0003146', (11, 32))	('immune system', 'CPA', (93, 106))
104903	29531466	Additionally, patients with four to nine retrieved LNs had a significantly lower overall mortality risk [hazard ratio (HR) = 0.39; 95% confidence interval (CI): 0.20-0.74] and cancer cause-specific mortality risk (HR = 0.32; 95%CI: 0.15-0.66) than other patients.	('lower', 'NegReg', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('mortality', 'CPA', (89, 98))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (176, 182))	('patients', 'Species', '9606', (254, 262))	('LNs', 'Var', (51, 54))	('patients', 'Species', '9606', (14, 22))
104962	29531466	For patients <= 70-years-old, retrieving four to nine LNs resulted in a significantly better survival rate than retrieving one to three LNs in terms of overall survival (Figure 2A) and cancer-specific survival (Figure 3A).	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('better', 'PosReg', (86, 92))	('overall survival', 'CPA', (152, 168))	('survival', 'CPA', (93, 101))	('retrieving', 'Var', (30, 40))	('patients', 'Species', '9606', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
104989	29531466	more retrieved LNs, might belong to another subset of distal cholangiocarcinoma that acts biologically more aggressively.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 79))	('LNs', 'Var', (15, 18))	('cholangiocarcinoma', 'Disease', (61, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))
105012	29531466	Additionally, patients with four to nine retrieved LNs had a significantly lower overall mortality risk (hazard ratio (HR): 0.39; 95% confidence interval (CI): 0.20-0.74) and cancer cause-specific mortality risk (HR: 0.32; 95%CI: 0.15-0.66) than other patients.	('lower', 'NegReg', (75, 80))	('patients', 'Species', '9606', (252, 260))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('mortality', 'CPA', (89, 98))	('patients', 'Species', '9606', (14, 22))	('LNs', 'Var', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
105061	27535234	HPCs are long-life cells that they are competent of surviving long enough to store up DNA damages, and the mutations are shared by lots of inferiors of the mutant progenitor cells; they become tumors more easily than other cell types.	('mutations', 'Var', (107, 116))	('tumors', 'Disease', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('mutant', 'Var', (156, 162))	('tumors', 'Disease', 'MESH:D009369', (193, 199))
105095	27439460	These findings support the need for continued vigilance in malignancy surveillance in patients with limbic encephalitis and early cerebral positron emission tomographic scan abnormalities.	('malignancy', 'Disease', 'MESH:D009369', (59, 69))	('encephalitis', 'Disease', 'MESH:D004660', (107, 119))	('encephalitis', 'Disease', (107, 119))	('continued vigilance', 'Phenotype', 'HP:0032044', (36, 55))	('malignancy', 'Disease', (59, 69))	('encephalitis', 'Phenotype', 'HP:0002383', (107, 119))	('abnormalities', 'Var', (174, 187))	('cerebral positron emission tomographic scan abnormalities', 'Phenotype', 'HP:0012657', (130, 187))	('patients', 'Species', '9606', (86, 94))
105135	27439460	However, the diagnosis of autoimmune-mediated LE based on the detection of anti-VGKC-Ab is not fully supported by recently published guidelines for diagnosis of autoimmune encephalitis.	('anti-VGKC-Ab', 'Var', (75, 87))	('anti-VGKC-Ab', 'Gene', (75, 87))	('autoimmune encephalitis', 'Disease', 'MESH:C535841', (161, 184))	('encephalitis', 'Phenotype', 'HP:0002383', (172, 184))	('autoimmune encephalitis', 'Disease', (161, 184))
105155	27439460	In contrast, the authors of most reports on patients with LE with autoantibodies against surface antigens have described normal metabolism or hypometabolism in mesiotemporal regions.	('hypometabolism', 'Disease', (142, 156))	('autoantibodies', 'Var', (66, 80))	('hypometabolism', 'Disease', 'None', (142, 156))	('patients', 'Species', '9606', (44, 52))
105156	27439460	In this regard, two different pathological mechanisms have been proposed to explain the findings of hypometabolism in the mesiotemporal cortex associated with autoantibodies against surface membrane antigens.	('associated', 'Reg', (143, 153))	('hypometabolism', 'Disease', (100, 114))	('autoantibodies', 'Var', (159, 173))	('hypometabolism', 'Disease', 'None', (100, 114))
105232	24312291	Mean VEGFR-2, Gab1 and MMP-9 ODs in hilar cholangiocarcinoma tissues were 0.2174+-0.009, 0.2193+-0.0092 and 0.2207+-0.0106, respectively, which were significantly higher than the ODs in biliary duct tissues with chronic inflammation (0.175+-0.0024, 0.1761+-0.0046 and 0.1748+-0.0026, respectively).	('VEGFR-2', 'Gene', (5, 12))	('Gab1', 'Gene', (14, 18))	('0.2174+-0.009', 'Var', (74, 87))	('hilar cholangiocarcinoma', 'Disease', (36, 60))	('0.2207+-0.0106', 'Var', (108, 122))	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (36, 60))	('cholangiocarcinoma tissues', 'Disease', 'MESH:D018281', (42, 68))	('inflammation', 'Disease', 'MESH:D007249', (220, 232))	('MMP-9', 'Gene', (23, 28))	('MMP-9', 'Gene', '4318', (23, 28))	('VEGFR-2', 'Gene', '3791', (5, 12))	('0.2193+-0.0092', 'Var', (89, 103))	('higher', 'PosReg', (163, 169))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (42, 60))	('inflammation', 'Disease', (220, 232))	('cholangiocarcinoma tissues', 'Disease', (42, 68))	('Gab1', 'Gene', '2549', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
105245	24312291	As shown in Figure 2C, there was no significant change in total Akt expression, but p-Akt expression was reduced in ICBD-1 cells after Gab1 siRNA interference compared with the NC group, suggesting reduced PI3K/Akt pathway activity.	('Akt', 'Gene', (86, 89))	('siRNA interference', 'Var', (140, 158))	('Akt', 'Gene', '207', (211, 214))	('activity', 'MPA', (223, 231))	('Akt', 'Gene', '207', (64, 67))	('Akt', 'Gene', (211, 214))	('Gab1', 'Gene', '2549', (135, 139))	('Akt', 'Gene', '207', (86, 89))	('expression', 'MPA', (90, 100))	('reduced', 'NegReg', (105, 112))	('Akt', 'Gene', (64, 67))	('Gab1', 'Gene', (135, 139))	('reduced', 'NegReg', (198, 205))	('ICBD-1', 'CellLine', 'CVCL:L093', (116, 122))
105250	24312291	As shown in Figure 2E, F and G, mRNA and protein levels of MMP-9 were both reduced after Gab1 siRNA or VEGFR-2 siRNA interference compared with the NC group in ICBD-1 cells, indicating that either Gab1 or VEGFR-2 interference down-regulated MMP-9 expression in ICBD-1 cells.	('MMP-9', 'Gene', (59, 64))	('MMP-9', 'Gene', '4318', (59, 64))	('MMP-9', 'Gene', '4318', (241, 246))	('down-regulated', 'NegReg', (226, 240))	('Gab1', 'Gene', (89, 93))	('expression', 'MPA', (247, 257))	('MMP-9', 'Gene', (241, 246))	('VEGFR-2', 'Gene', '3791', (103, 110))	('ICBD-1', 'CellLine', 'CVCL:L093', (261, 267))	('VEGFR-2', 'Gene', '3791', (205, 212))	('reduced', 'NegReg', (75, 82))	('VEGFR-2', 'Gene', (103, 110))	('Gab1', 'Gene', (197, 201))	('Gab1', 'Gene', '2549', (197, 201))	('interference', 'Var', (117, 129))	('VEGFR-2', 'Gene', (205, 212))	('ICBD-1', 'CellLine', 'CVCL:L093', (160, 166))	('Gab1', 'Gene', '2549', (89, 93))
105284	24312291	Thus, we suspected a close relationship between high Gab1 expression and malignant biological behaviors (e.g., invasion and metastasis) of hilar cholangiocarcinoma.	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (139, 163))	('hilar cholangiocarcinoma', 'Disease', (139, 163))	('expression', 'MPA', (58, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('Gab1', 'Gene', (53, 57))	('Gab1', 'Gene', '2549', (53, 57))	('high', 'Var', (48, 52))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (145, 163))	('invasion', 'CPA', (111, 119))
105336	22173169	Relative quantification values for gene expression were calculated using the comparative DeltaDeltaCt method normalizing to GAPDH (NM_002046, 87bp amplicon length) or 18S ribosomal RNA (NR_003286.2, 98bp amplicon length).	('NM_002046', 'Var', (131, 140))	('NR_003286.2', 'Var', (186, 197))	('GAPDH', 'Gene', '2597', (124, 129))	('GAPDH', 'Gene', (124, 129))
105337	22173169	When using clinical samples of bile and biliary brushings, expression of CK19 (NM 002276.3) and CD45 (NM 080922.1), markers for biliary epithelial cells and leukocytes respectively, were measured in order to ascertain the primary origin of the RNA.	('CK19', 'Gene', (73, 77))	('clinical samples', 'Species', '191496', (11, 27))	('CK19', 'Gene', '3880', (73, 77))	('CD45', 'Gene', '5788', (96, 100))	('NM', 'Var', (102, 104))	('CD45', 'Gene', (96, 100))
105360	22173169	Validation of a further set of biliary brush samples by individual gene qPCR using the SYBR Green method also confirmed upregulation of MUC4 (fold change 21.4 [95% CI 19.1 to 24.1], n=9) and CD9 (fold change 2.8 [95% CI 2.6 to 3.0], n=11).	('MUC4', 'Gene', (136, 140))	('CD9', 'Gene', '928', (191, 194))	('CD9', 'Gene', (191, 194))	('SYBR Green', 'Chemical', '-', (87, 97))	('MUC4', 'Gene', '4585', (136, 140))	('upregulation', 'PosReg', (120, 132))	('gene', 'Var', (67, 71))
105394	27510297	High GPBAR1 gene expression was found to be an indicator of worse prognosis in gastric and breast cancer patients, and an indication of better prognosis in ovarian cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('ovarian cancer', 'Disease', 'MESH:D010051', (156, 170))	('breast cancer', 'Disease', (91, 104))	('patients', 'Species', '9606', (105, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('ovarian cancer', 'Disease', (156, 170))	('gastric', 'Disease', (79, 86))	('patients', 'Species', '9606', (171, 179))	('GPBAR1', 'Gene', '151306', (5, 11))	('ovarian cancer', 'Phenotype', 'HP:0100615', (156, 170))	('GPBAR1', 'Gene', (5, 11))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
105396	27510297	Negative, weak or mild expression of TGR5 was correlated with younger age, higher plasma level of total/direct bilirubin, higher plasma concentration of CA-125, advanced tumor stage and advanced AJCC TNM stage.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('higher plasma level of total/direct bilirubin', 'Phenotype', 'HP:0003573', (75, 120))	('higher', 'PosReg', (122, 128))	('higher', 'PosReg', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('plasma level of total/direct bilirubin', 'MPA', (82, 120))	('bilirubin', 'Chemical', 'MESH:D001663', (111, 120))	('CA-125', 'Gene', '94025', (153, 159))	('Negative', 'NegReg', (0, 8))	('TGR5', 'Gene', (37, 41))	('CA-125', 'Gene', (153, 159))	('tumor', 'Disease', (170, 175))	('mild', 'Var', (18, 22))	('weak', 'NegReg', (10, 14))
105397	27510297	The disease-specific survival rate was highest in ampullary adenocarcinoma patients with high TGR5 expression and high total bilirubin level.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('highest', 'Reg', (39, 46))	('expression', 'MPA', (99, 109))	('high total bilirubin level', 'Phenotype', 'HP:0002904', (114, 140))	('TGR5', 'Gene', (94, 98))	('patients', 'Species', '9606', (75, 83))	('bilirubin', 'Chemical', 'MESH:D001663', (125, 134))	('total bilirubin level', 'MPA', (119, 140))	('high', 'Var', (89, 93))	('ampullary adenocarcinoma', 'Disease', 'MESH:D000230', (50, 74))	('high total bilirubin', 'Phenotype', 'HP:0003573', (114, 134))	('ampullary adenocarcinoma', 'Disease', (50, 74))
105407	27510297	The accumulation of ROS/RNS was found to cause oxidative DNA damage and further mutation in colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('RNS', 'Gene', '56975', (24, 27))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('accumulation', 'PosReg', (4, 16))	('ROS', 'Chemical', 'MESH:D017382', (20, 23))	('cause', 'Reg', (41, 46))	('colon cancer', 'Disease', (92, 104))	('oxidative DNA damage', 'MPA', (47, 67))	('mutation', 'Var', (80, 88))	('RNS', 'Gene', (24, 27))
105421	27510297	Mild to strong TGR5 staining is associated with poor patient survival, and TCDA increased proliferation of a gastric adenocarcinoma cell line through the TGR5-dependent pathway.	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (109, 131))	('gastric adenocarcinoma', 'Disease', (109, 131))	('proliferation', 'CPA', (90, 103))	('increased', 'PosReg', (80, 89))	('TCDA', 'Var', (75, 79))	('TGR5-dependent pathway', 'Pathway', (154, 176))	('TCDA', 'Chemical', 'MESH:D013655', (75, 79))	('Mild to', 'Var', (0, 7))	('TGR5', 'Protein', (15, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('patient', 'Species', '9606', (53, 60))
105452	27510297	1) revealed that prognosis was poorer in gastric cancer and breast cancer patients with high GPBAR1 gene expression than in those with low expression (Fig.	('high', 'Var', (88, 92))	('breast cancer', 'Disease', (60, 73))	('gastric cancer', 'Phenotype', 'HP:0012126', (41, 55))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('GPBAR1', 'Gene', '151306', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('GPBAR1', 'Gene', (93, 99))	('gastric cancer', 'Disease', (41, 55))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (41, 55))
105454	27510297	Ovarian cancer patients with high GPBAR1 gene expression tended to have a better prognosis than those with low expression (Fig.	('high', 'Var', (29, 33))	('patients', 'Species', '9606', (15, 23))	('GPBAR1', 'Gene', (34, 40))	('Ovarian cancer', 'Disease', 'MESH:D010051', (0, 14))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Ovarian cancer', 'Disease', (0, 14))	('GPBAR1', 'Gene', '151306', (34, 40))
105456	27510297	High GPBAR1 gene expression predicted a trend toward poor prognosis in 12 datasets (Table I) and good prognosis in 15 datasets (Table II).	('GPBAR1', 'Gene', (5, 11))	('GPBAR1', 'Gene', '151306', (5, 11))	('High', 'Var', (0, 4))
105457	27510297	In most datasets, the GPBAR1 gene expression was not significantly correlated with survival and only one dataset in each group displayed predictive power (GSE13507 and GSE8894).	('GSE8894', 'Var', (168, 175))	('GSE8894', 'Chemical', '-', (168, 175))	('GPBAR1', 'Gene', '151306', (22, 28))	('GPBAR1', 'Gene', (22, 28))	('GSE13507', 'Var', (155, 163))
105473	27510297	Negative, weak or mild expression of TGR5 was correlated with younger age (P=0.043) and higher level of direct bilirubin (P=0.023, separately) and tended to be correlated with higher level of total bilirubin (P=0.059), higher plasma level of cancer antigen-125 (CA-125) (P=0.099), advanced tumor stage and AJCC TNM stage (P=0.063 and 0.062, separately) (Table III).	('CA-125', 'Gene', '94025', (262, 268))	('bilirubin', 'Chemical', 'MESH:D001663', (111, 120))	('TGR5', 'Gene', (37, 41))	('plasma level', 'MPA', (226, 238))	('bilirubin', 'Chemical', 'MESH:D001663', (198, 207))	('cancer antigen-125', 'Gene', (242, 260))	('tumor', 'Disease', (290, 295))	('weak', 'NegReg', (10, 14))	('higher', 'PosReg', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('AJCC TNM', 'Disease', (306, 314))	('CA-125', 'Gene', (262, 268))	('Negative', 'NegReg', (0, 8))	('cancer antigen-125', 'Gene', '94025', (242, 260))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('mild', 'Var', (18, 22))	('higher', 'PosReg', (176, 182))	('higher', 'PosReg', (88, 94))	('level', 'MPA', (95, 100))	('total bilirubin', 'MPA', (192, 207))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
105475	27510297	The recurrences in patients with negative, weak or mild TGR5 expression tended to be earlier (within postoperative 12 months) (P=0.089), although the level of TGR5 expression was not associated with recurrence patterns (Table IV).	('TGR5', 'Gene', (56, 60))	('patients', 'Species', '9606', (19, 27))	('mild', 'Var', (51, 55))	('weak', 'NegReg', (43, 47))	('negative', 'NegReg', (33, 41))	('expression', 'MPA', (61, 71))
105486	27510297	Negative, weak or mild TGR5 expression was correlated with elevation of plasma bilirubin.	('bilirubin', 'Chemical', 'MESH:D001663', (79, 88))	('expression', 'MPA', (28, 38))	('TGR5', 'Gene', (23, 27))	('elevation', 'PosReg', (59, 68))	('plasma bilirubin', 'MPA', (72, 88))	('mild', 'Var', (18, 22))
105490	27510297	Nuclear accumulation of beta-catenin promotes WNT activation and cancer progression; however, loss of the beta-catenin protein in ampullary cancer is correlated with poor prognosis.	('beta-catenin', 'Gene', (24, 36))	('beta-catenin', 'Gene', '1499', (106, 118))	('WNT activation', 'CPA', (46, 60))	('ampullary cancer', 'Disease', (130, 146))	('beta-catenin', 'Gene', '1499', (24, 36))	('loss', 'Var', (94, 98))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('beta-catenin', 'Gene', (106, 118))	('ampullary cancer', 'Disease', 'MESH:D009369', (130, 146))	('Nuclear accumulation', 'MPA', (0, 20))
105493	27510297	However, loss of EpCAM is linked to a more aggressive phenotype of ampullary cancer, suggesting that EpCAM may play a different role in ampullary cancer than in other cancers.	('ampullary cancer', 'Disease', (136, 152))	('EpCAM', 'Gene', (101, 106))	('EpCAM', 'Gene', '4072', (17, 22))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('loss', 'Var', (9, 13))	('cancers', 'Disease', (167, 174))	('linked', 'Reg', (26, 32))	('ampullary cancer', 'Disease', 'MESH:D009369', (67, 83))	('EpCAM', 'Gene', '4072', (101, 106))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('EpCAM', 'Gene', (17, 22))	('ampullary cancer', 'Disease', (67, 83))	('ampullary cancer', 'Disease', 'MESH:D009369', (136, 152))
105507	27510297	We analyzed multiple microarray datasets and found that high GPBAR1 gene expression predicted poor prognosis in some datasets, but good prognosis in others (Tables I and II; Fig.	('GPBAR1', 'Gene', '151306', (61, 67))	('GPBAR1', 'Gene', (61, 67))	('high', 'Var', (56, 60))
105516	27510297	Moreover, TGR5 expression is associated with the poor prognosis of patients, suppresses STAT3 signaling and inhibits cell cycle progression, angiogenesis, metastasis and evasion of the immune system in gastric cancer.	('angiogenesis', 'CPA', (141, 153))	('metastasis', 'CPA', (155, 165))	('expression', 'Var', (15, 25))	('cell cycle progression', 'CPA', (117, 139))	('patients', 'Species', '9606', (67, 75))	('suppresses', 'NegReg', (77, 87))	('evasion', 'MPA', (170, 177))	('STAT3', 'Gene', '6774', (88, 93))	('inhibits', 'NegReg', (108, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (202, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('STAT3', 'Gene', (88, 93))	('TGR5', 'Gene', (10, 14))	('gastric cancer', 'Disease', (202, 216))	('gastric cancer', 'Disease', 'MESH:D013274', (202, 216))
105523	27510297	The patients with strong TGR5 expression tended to have a lower plasma level of CA-125, earlier tumor stage, and earlier AJCC TNM stage and also a better disease-specific survival rate, particularly those patients with total bilirubin concentration higher than 2.45 mg/dl.	('bilirubin concentration higher', 'Phenotype', 'HP:0002904', (225, 255))	('patients', 'Species', '9606', (205, 213))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('total bilirubin concentration', 'MPA', (219, 248))	('better', 'PosReg', (147, 153))	('lower', 'NegReg', (58, 63))	('CA-125', 'Gene', '94025', (80, 86))	('CA-125', 'Gene', (80, 86))	('expression', 'Var', (30, 40))	('tumor', 'Disease', (96, 101))	('disease-specific survival rate', 'CPA', (154, 184))	('bilirubin', 'Chemical', 'MESH:D001663', (225, 234))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('TGR5', 'Gene', (25, 29))
105525	27510297	In summary, high TGR5 expression was correlated with lower plasma concentration of total/direct bilirubin, lower plasma level of CA-125, early tumor stage and AJCC TNM stage.	('bilirubin', 'Chemical', 'MESH:D001663', (96, 105))	('high', 'Var', (12, 16))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('plasma concentration of total/direct bilirubin', 'MPA', (59, 105))	('lower', 'NegReg', (107, 112))	('AJCC', 'Disease', (159, 163))	('TGR5', 'Gene', (17, 21))	('lower plasma concentration', 'Phenotype', 'HP:0020171', (53, 79))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('CA-125', 'Gene', (129, 135))	('lower', 'NegReg', (53, 58))	('expression', 'MPA', (22, 32))	('CA-125', 'Gene', '94025', (129, 135))
105526	27510297	High TGR5 expression also predicted a good survival in patients with total bilirubin levelss higher than 2.45 mg/dl.	('total bilirubin levelss', 'MPA', (69, 92))	('High', 'Var', (0, 4))	('TGR5', 'Gene', (5, 9))	('patients', 'Species', '9606', (55, 63))	('bilirubin', 'Chemical', 'MESH:D001663', (75, 84))	('predicted', 'Reg', (26, 35))
105535	22347972	Such variants are common and can result in unusual but explainable patterns of atrophy and hypertrophy.	('atrophy and hypertrophy', 'Disease', 'MESH:D006984', (79, 102))	('variants', 'Var', (5, 13))	('result', 'Reg', (33, 39))
105571	22347972	Variations in hilar biliary anatomy, however, have the potential to change the results of this progression so that the distribution of atrophy and hypertrophy may be more complex (Figs.	('Variations', 'Var', (0, 10))	('change', 'Reg', (68, 74))	('atrophy and hypertrophy', 'Disease', 'MESH:D006984', (135, 158))
105574	22347972	Stenting an atrophic lobe can increase the risk of cholangitis developing subsequently, is unlikely to relieve jaundice and does not reverse the process of atrophy.	('atrophic lobe', 'Disease', 'MESH:D020966', (12, 25))	('jaundice', 'Disease', (111, 119))	('atrophy', 'Disease', 'MESH:D001284', (156, 163))	('Stenting', 'Var', (0, 8))	('jaundice', 'Phenotype', 'HP:0000952', (111, 119))	('atrophic lobe', 'Disease', (12, 25))	('atrophy', 'Disease', (156, 163))	('cholangitis', 'Disease', (51, 62))	('cholangitis', 'Phenotype', 'HP:0030151', (51, 62))	('jaundice', 'Disease', 'MESH:D007565', (111, 119))	('cholangitis', 'Disease', 'MESH:D002761', (51, 62))
105579	22347972	Hilar biliary anatomical variants result in a range of unusual but predictable patterns of segmental atrophy with or without hypertrophy.	('segmental atrophy', 'Disease', 'MESH:C566670', (91, 108))	('variants', 'Var', (25, 33))	('segmental atrophy', 'Disease', (91, 108))	('hypertrophy', 'Disease', (125, 136))	('hypertrophy', 'Disease', 'MESH:D006984', (125, 136))
105585	31978895	Functionally, knocking down ZEB1-AS1 attenuated tumor cell stemness, restrained cellular viability in vitro and in vivo, and inhibited CCA cell migration and invasion by reversing epithelial-mesenchymal transition.	('CCA', 'Disease', 'MESH:D018281', (135, 138))	('ZEB1-AS1', 'Gene', (28, 36))	('knocking down', 'Var', (14, 27))	('CCA', 'Disease', (135, 138))	('restrained', 'NegReg', (69, 79))	('attenuated tumor cell stemness', 'Disease', 'MESH:C538265', (37, 67))	('attenuated tumor cell stemness', 'Disease', (37, 67))	('cellular viability', 'CPA', (80, 98))	('invasion', 'CPA', (158, 166))	('epithelial-mesenchymal transition', 'CPA', (180, 213))	('inhibited', 'NegReg', (125, 134))	('reversing', 'NegReg', (170, 179))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
105586	31978895	For the mechanism, androgen receptor (AR) directly promoted ZEB1-AS1 expression, and further ZEB1-AS1 increased oncogene homeobox B8 (HOXB8) by sponging miR-133b.	('androgen receptor', 'Gene', '367', (19, 36))	('homeobox B8', 'Gene', '3218', (121, 132))	('expression', 'MPA', (69, 79))	('androgen receptor', 'Gene', (19, 36))	('AR', 'Gene', '367', (38, 40))	('ZEB1-AS1', 'Gene', (60, 68))	('promoted', 'PosReg', (51, 59))	('increased', 'PosReg', (102, 111))	('homeobox B8', 'Gene', (121, 132))	('ZEB1-AS1', 'Var', (93, 101))
105596	31978895	Aberrantly expressed lncRNAs can predict a poor prognosis and promote malignant phenotypes of CCA cells, suggesting the potential clinical value of these RNAs.	('Aberrantly expressed', 'Var', (0, 20))	('CCA', 'Disease', (94, 97))	('malignant phenotypes', 'CPA', (70, 90))	('lncRNAs', 'Protein', (21, 28))	('promote', 'PosReg', (62, 69))	('CCA', 'Disease', 'MESH:D018281', (94, 97))
105601	31978895	Subsequently, ZEB1-AS1 dysregulation was confirmed in varieties of digestive system cancers, including hepatocellular carcinoma, gastric cancer, and colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (103, 127))	('dysregulation', 'Var', (23, 36))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 127))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('gastric cancer', 'Disease', (129, 143))	('colorectal cancer', 'Disease', 'MESH:D015179', (149, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('hepatocellular carcinoma', 'Disease', (103, 127))	('gastric cancer', 'Disease', 'MESH:D013274', (129, 143))	('system cancers', 'Disease', (77, 91))	('colorectal cancer', 'Phenotype', 'HP:0003003', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('system cancers', 'Disease', 'MESH:D009369', (77, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (129, 143))	('colorectal cancer', 'Disease', (149, 166))
105615	31978895	Survival correlation was also analysed by means of Kaplan-Meier, and the findings revealed that patients with high ZEB1-AS1 expression had worse overall survival (OS) than those with low ZEB1-AS1 expression (log rank P < 0.001; Figure 1B).	('overall survival', 'MPA', (145, 161))	('ZEB1-AS1', 'Gene', (115, 123))	('high', 'Var', (110, 114))	('worse', 'NegReg', (139, 144))	('patients', 'Species', '9606', (96, 104))
105622	31978895	The proliferation curves displayed that knocking down ZEB1-AS1 inhibited proliferation of CCA cells in comparison with controls (Figure 2C).	('CCA', 'Disease', (90, 93))	('proliferation', 'CPA', (73, 86))	('ZEB1-AS1', 'Gene', (54, 62))	('CCA', 'Disease', 'MESH:D018281', (90, 93))	('inhibited', 'NegReg', (63, 72))	('knocking down', 'Var', (40, 53))
105623	31978895	5-ethynyl-2'-deoxyuridine (EdU) incorporation assay was also carried out to measure cellular viability, and proliferation activity was suppressed in si-ZEB1-AS1 cells (Figure 2D).	('si-ZEB1-AS1', 'Var', (149, 160))	('proliferation activity', 'CPA', (108, 130))	("5-ethynyl-2'-deoxyuridine", 'Chemical', 'MESH:C031086', (0, 25))	('EdU', 'Chemical', 'MESH:C031086', (27, 30))	('suppressed', 'NegReg', (135, 145))
105625	31978895	More importantly, spheroid formation assay verified that ZEB1-AS1 knockdown attenuated tumor stemness in CCA cells (Figure 2F).	('CCA', 'Disease', 'MESH:D018281', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('CCA', 'Disease', (105, 108))	('attenuated', 'NegReg', (76, 86))	('tumor stemness', 'Disease', (87, 101))	('tumor stemness', 'Disease', 'MESH:D020295', (87, 101))	('ZEB1-AS1', 'Gene', (57, 65))	('knockdown', 'Var', (66, 75))
105627	31978895	Increased ZEB1-AS1 facilitated cellular migration and invasion by promoting epithelial-mesenchymal transition (EMT) As confirmed by wound healing assay, cellular motility was repressed by knocking down ZEB1-AS1 in CCA cells (Figure 3A).	('ZEB1-AS1', 'Gene', (10, 18))	('ZEB1-AS1', 'Gene', (202, 210))	('promoting', 'PosReg', (66, 75))	('CCA', 'Disease', 'MESH:D018281', (214, 217))	('invasion', 'CPA', (54, 62))	('cellular migration', 'CPA', (31, 49))	('facilitated', 'PosReg', (19, 30))	('cellular', 'CPA', (153, 161))	('CCA', 'Disease', (214, 217))	('epithelial-mesenchymal transition', 'CPA', (76, 109))	('knocking down', 'Var', (188, 201))
105629	31978895	As shown in Figure 3B, silencing ZEB1-AS1 reduced migratory numbers of CCA cells demonstrated through transwell assay without Matrigel.	('CCA', 'Disease', 'MESH:D018281', (71, 74))	('reduced', 'NegReg', (42, 49))	('CCA', 'Disease', (71, 74))	('silencing', 'Var', (23, 32))	('ZEB1-AS1', 'Gene', (33, 41))
105631	31978895	Results confirmed that knocking down ZEB1-AS1 decreased snail and vimentin expression, whereas E-cadherin expression was increased in CCA cells (Figure 3D).	('snail', 'Gene', (56, 61))	('vimentin', 'Gene', '7431', (66, 74))	('CCA', 'Disease', (134, 137))	('E-cadherin', 'Gene', (95, 105))	('increased', 'PosReg', (121, 130))	('vimentin', 'Gene', (66, 74))	('CCA', 'Disease', 'MESH:D018281', (134, 137))	('snail', 'Gene', '6615', (56, 61))	('E-cadherin', 'Gene', '999', (95, 105))	('knocking down', 'Var', (23, 36))	('decreased', 'NegReg', (46, 55))	('ZEB1-AS1', 'Gene', (37, 45))
105650	31978895	In addition, AGO2 RIP assays further confirmed that miR-133b enriched HOXB8 mRNA in CCA cells (Figure 6I).	('enriched', 'PosReg', (61, 69))	('CCA', 'Disease', 'MESH:D018281', (84, 87))	('HOXB8 mRNA', 'MPA', (70, 80))	('AGO2', 'Gene', (13, 17))	('CCA', 'Disease', (84, 87))	('AGO2', 'Gene', '27161', (13, 17))	('miR-133b', 'Var', (52, 60))
105654	31978895	As displayed in Figure 7C, EdU rescue assay verified that reduction of proliferation caused by ZEB1-AS1 knockdown was saved by silencing miR-133b.	('miR-133b', 'Gene', (137, 145))	('EdU', 'Chemical', 'MESH:C031086', (27, 30))	('proliferation', 'CPA', (71, 84))	('ZEB1-AS1', 'Gene', (95, 103))	('silencing', 'Var', (127, 136))	('knockdown', 'Var', (104, 113))
105655	31978895	Spheroid formation assay also suggested that silencing miR-133b partly rescued suppression of tumor stemness caused through knocking down ZEB1-AS1 (Figure 7D).	('silencing', 'Var', (45, 54))	('suppression', 'NegReg', (79, 90))	('ZEB1-AS1', 'Gene', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('knocking down', 'Var', (124, 137))	('miR-133b', 'Gene', (55, 63))	('tumor stemness', 'Disease', 'MESH:D020295', (94, 108))	('tumor stemness', 'Disease', (94, 108))
105657	31978895	Subsequently, the rescue assays of proliferation, tumor stemness, and invasion also testified that cancer-promoting effect caused by ZEB1-AS1 overexpression was saved by knocking down HOXB8 (Figure 7F-7H), indicating that ZEB1-AS1 promoted malignant progression of CCA partly by promoting HOXB8.	('tumor stemness', 'Disease', (50, 64))	('promoted', 'PosReg', (231, 239))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('knocking', 'Var', (170, 178))	('promoting', 'PosReg', (279, 288))	('cancer', 'Disease', (99, 105))	('CCA', 'Disease', 'MESH:D018281', (265, 268))	('malignant progression', 'CPA', (240, 261))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('HOXB8', 'Gene', (289, 294))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumor stemness', 'Disease', 'MESH:D020295', (50, 64))	('CCA', 'Disease', (265, 268))
105658	31978895	Furthermore, tumor-promoting function generated through silencing miR-133b was saved by knocking down HOXB8 confirmed by the rescue assays of EdU, spheroid formation and transwell (Figure 7I-7K).	('tumor', 'Disease', (13, 18))	('silencing', 'Var', (56, 65))	('HOXB8', 'Gene', (102, 107))	('miR-133b', 'Gene', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('knocking', 'Var', (88, 96))	('EdU', 'Chemical', 'MESH:C031086', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
105661	31978895	As shown in Figure 8A-8D, knocking down ZEB1-AS1 not only depressed tumor volumes throughout the course of cancer growth, but also remarkably inhibited tumor weights.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', (152, 157))	('ZEB1-AS1', 'Gene', (40, 48))	('depressed tumor', 'Disease', 'MESH:D003866', (58, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('inhibited', 'NegReg', (142, 151))	('knocking down', 'Var', (26, 39))	('cancer', 'Disease', (107, 113))	('depressed tumor', 'Disease', (58, 73))
105666	31978895	For example, Sox2 overlapping transcript (Sox2ot) was overexpressed in CCA and related to prognosis of patients; small nucleolar RNA host gene 1 (SNHG1) facilitated proliferation and migration of CCA cells through epigenetically inhibiting cyclin dependent kinase inhibitor 1A (CDKN1A).	('migration', 'CPA', (183, 192))	('cyclin dependent kinase inhibitor 1A', 'Gene', '1026', (240, 276))	('Sox2', 'Gene', (13, 17))	('Sox2', 'Gene', '6657', (42, 46))	('proliferation', 'CPA', (165, 178))	('facilitated', 'PosReg', (153, 164))	('SNHG1', 'Gene', '23642', (146, 151))	('CCA', 'Disease', 'MESH:D018281', (71, 74))	('CCA', 'Disease', (71, 74))	('cyclin dependent kinase inhibitor 1A', 'Gene', (240, 276))	('CDKN1A', 'Gene', (278, 284))	('CDKN1A', 'Gene', '1026', (278, 284))	('Sox2ot', 'Gene', (42, 48))	('CCA', 'Disease', 'MESH:D018281', (196, 199))	('Sox2', 'Gene', '6657', (13, 17))	('CCA', 'Disease', (196, 199))	('epigenetically inhibiting', 'Var', (214, 239))	('small nucleolar RNA host gene 1', 'Gene', '23642', (113, 144))	('small nucleolar RNA host gene 1', 'Gene', (113, 144))	('Sox2', 'Gene', (42, 46))	('SNHG1', 'Gene', (146, 151))	('patients', 'Species', '9606', (103, 111))	('Sox2ot', 'Gene', '347689', (42, 48))
105676	31978895	CCK-8 and EdU assays verified that knocking down ZEB1-AS1 restrained tumor cell proliferation.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('ZEB1-AS1', 'Gene', (49, 57))	('knocking down', 'Var', (35, 48))	('tumor', 'Disease', (69, 74))	('EdU', 'Chemical', 'MESH:C031086', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('restrained', 'NegReg', (58, 68))
105677	31978895	Besides, spheroid formation assay verified that silencing ZEB1-AS1 repressed tumor stemness in CAA cells.	('silencing', 'Var', (48, 57))	('tumor stemness', 'Disease', 'MESH:D020295', (77, 91))	('tumor stemness', 'Disease', (77, 91))	('ZEB1-AS1', 'Gene', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))
105680	31978895	Pertinent to tumor metastasis, wound healing and transwell assays documented that silencing ZEB1-AS1 inhibited migration and invasion of CCLP-1 and QBC939 cells.	('tumor metastasis', 'Disease', 'MESH:D009362', (13, 29))	('migration', 'CPA', (111, 120))	('tumor metastasis', 'Disease', (13, 29))	('silencing', 'Var', (82, 91))	('ZEB1-AS1', 'Gene', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('inhibited', 'NegReg', (101, 110))
105681	31978895	In addition, silencing ZEB1-AS1 reversed EMT, which represented an indispensable process in tumor metastasis, through increasing epithelial markers and decreasing mesenchymal markers.	('tumor metastasis', 'Disease', 'MESH:D009362', (92, 108))	('tumor metastasis', 'Disease', (92, 108))	('increasing', 'PosReg', (118, 128))	('decreasing', 'NegReg', (152, 162))	('mesenchymal markers', 'CPA', (163, 182))	('silencing', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('ZEB1-AS1', 'Gene', (23, 31))	('epithelial', 'MPA', (129, 139))	('EMT', 'CPA', (41, 44))
105692	31978895	In the present study, we demonstrated that ZEB1-AS1 increased HOXB8 by sponging miR-133b, thereby facilitating CCA development.	('CCA', 'Disease', (111, 114))	('increased', 'PosReg', (52, 61))	('HOXB8', 'MPA', (62, 67))	('ZEB1-AS1', 'Var', (43, 51))	('facilitating', 'PosReg', (98, 110))	('miR-133b', 'MPA', (80, 88))	('sponging', 'Var', (71, 79))	('CCA', 'Disease', 'MESH:D018281', (111, 114))
105738	31085159	In UCP2 knockdown cells, glycolysis was inhibited, the mesenchymal markers were downregulated whereas AMPK was activated.	('AMPK', 'Gene', '5563', (102, 106))	('inhibited', 'NegReg', (40, 49))	('knockdown', 'Var', (8, 17))	('AMPK', 'Gene', (102, 106))	('mesenchymal markers', 'CPA', (55, 74))	('UCP2', 'Gene', '7351', (3, 7))	('downregulated', 'NegReg', (80, 93))	('UCP2', 'Gene', (3, 7))	('glycolysis', 'MPA', (25, 35))
105742	31085159	In conclusion, our results demonstrate that the amplified expression of UCP2 contributes to the progression of cholangiocarcinoma through a glycolysis-mediated mechanism.	('amplified', 'Var', (48, 57))	('UCP2', 'Gene', (72, 76))	('cholangiocarcinoma', 'Disease', (111, 129))	('expression', 'MPA', (58, 68))	('contributes', 'Reg', (77, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 129))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))	('UCP2', 'Gene', '7351', (72, 76))	('glycolysis-mediated', 'MPA', (140, 159))
105816	31085159	Cell proliferation assays were performed to determine whether UCP2 knockdown affected cholangiocarcinoma cell growth.	('UCP2', 'Gene', (62, 66))	('cholangiocarcinoma', 'Disease', (86, 104))	('affected', 'Reg', (77, 85))	('knockdown', 'Var', (67, 76))	('UCP2', 'Gene', '7351', (62, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (86, 104))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (86, 104))
105817	31085159	2B, cell growth rates were decreased in the UCP2 knockdown cells compared to that in the control cells.	('UCP2', 'Gene', '7351', (44, 48))	('knockdown', 'Var', (49, 58))	('cell growth rates', 'CPA', (4, 21))	('decreased', 'NegReg', (27, 36))	('UCP2', 'Gene', (44, 48))
105820	31085159	These results indicate that aberrant expression of UCP2 promotes proliferation, migration, and invasion of cholangiocarcinoma cells.	('proliferation', 'CPA', (65, 78))	('invasion', 'CPA', (95, 103))	('migration', 'CPA', (80, 89))	('cholangiocarcinoma', 'Disease', (107, 125))	('UCP2', 'Gene', '7351', (51, 55))	('aberrant expression', 'Var', (28, 47))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (107, 125))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (107, 125))	('promotes', 'PosReg', (56, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('UCP2', 'Gene', (51, 55))
105823	31085159	These characteristic changes indicate that inhibition of UCP2 may reverse the mesenchymal phenotype of cholangiocarcinoma.	('inhibition', 'Var', (43, 53))	('reverse', 'NegReg', (66, 73))	('UCP2', 'Gene', '7351', (57, 61))	('cholangiocarcinoma', 'Disease', (103, 121))	('UCP2', 'Gene', (57, 61))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (103, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (103, 121))	('mesenchymal phenotype', 'CPA', (78, 99))
105825	31085159	3B, the levels of mitochondrial membrane potential were increased in the UCP2 knockdown cells compared to that in the control cells.	('UCP2', 'Gene', (73, 77))	('increased', 'PosReg', (56, 65))	('knockdown', 'Var', (78, 87))	('UCP2', 'Gene', '7351', (73, 77))	('levels of mitochondrial membrane potential', 'MPA', (8, 50))
105827	31085159	3C, the levels of intracellular lactate were decreased in the UCP2 knockdown cells, suggesting that glycolysis is alleviated when UCP2 expression is inhibited.	('UCP2', 'Gene', (62, 66))	('UCP2', 'Gene', '7351', (130, 134))	('lactate', 'Chemical', 'MESH:D019344', (32, 39))	('alleviated', 'NegReg', (114, 124))	('knockdown', 'Var', (67, 76))	('decreased', 'NegReg', (45, 54))	('UCP2', 'Gene', '7351', (62, 66))	('UCP2', 'Gene', (130, 134))	('levels of intracellular lactate', 'MPA', (8, 39))	('glycolysis', 'MPA', (100, 110))
105828	31085159	AMP/ATP levels were measured by HPLC to evaluate the status of energy production in UCP2 knockdown cholangiocarcinoma cells.	('UCP2', 'Gene', '7351', (84, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('ATP', 'Gene', '51761', (4, 7))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (99, 117))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (99, 117))	('AMP', 'Gene', (0, 3))	('UCP2', 'Gene', (84, 88))	('ATP', 'Gene', (4, 7))	('knockdown', 'Var', (89, 98))	('AMP', 'Gene', '353', (0, 3))	('cholangiocarcinoma', 'Disease', (99, 117))
105829	31085159	3D, the ratios of AMP/ATP were increased in the UCP2 knockdown cells compared to that in the control cells.	('UCP2', 'Gene', (48, 52))	('increased', 'PosReg', (31, 40))	('knockdown', 'Var', (53, 62))	('ratios', 'MPA', (8, 14))	('AMP', 'Gene', (18, 21))	('UCP2', 'Gene', '7351', (48, 52))	('ATP', 'Gene', '51761', (22, 25))	('AMP', 'Gene', '353', (18, 21))	('ATP', 'Gene', (22, 25))
105834	31085159	3G, the levels of SOD activity were decreased in the UCP2 knockdown cells compared to that in the control cells (Fig.	('UCP2', 'Gene', '7351', (53, 57))	('SOD', 'Gene', (18, 21))	('levels', 'MPA', (8, 14))	('UCP2', 'Gene', (53, 57))	('SOD', 'Gene', '6647', (18, 21))	('knockdown', 'Var', (58, 67))	('decreased', 'NegReg', (36, 45))
105836	31085159	Not surprising, AMPK activation was detected in the UCP2 knockdown clones of cholangiocarcinoma (Fig.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (77, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('UCP2', 'Gene', (52, 56))	('AMPK', 'Gene', (16, 20))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (77, 95))	('knockdown', 'Var', (57, 66))	('UCP2', 'Gene', '7351', (52, 56))	('cholangiocarcinoma', 'Disease', (77, 95))	('AMPK', 'Gene', '5563', (16, 20))
105846	31085159	Given that UCP2 knockdown reverses the mesenchymal phenotype of cholangiocarcinoma cells, Markers for EMT were detected in HuCCT1 and TFK-1 cells after genipin treatment.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (64, 82))	('genipin', 'Chemical', 'MESH:C007834', (152, 159))	('mesenchymal phenotype of', 'CPA', (39, 63))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('knockdown', 'Var', (16, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('UCP2', 'Gene', '7351', (11, 15))	('cholangiocarcinoma', 'Disease', (64, 82))	('reverses', 'NegReg', (26, 34))	('UCP2', 'Gene', (11, 15))
105863	31085159	Using cholangiocarcinoma cells, our studies demonstrate that highly expressed UCP2 also contributes to EMT, a process known to promote tumor metastasis and invasion.	('invasion', 'CPA', (156, 164))	('UCP2', 'Gene', '7351', (78, 82))	('cholangiocarcinoma', 'Disease', (6, 24))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('EMT', 'CPA', (103, 106))	('contributes', 'PosReg', (88, 99))	('promote', 'PosReg', (127, 134))	('UCP2', 'Gene', (78, 82))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (6, 24))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (6, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('tumor metastasis', 'Disease', 'MESH:D009362', (135, 151))	('highly expressed', 'Var', (61, 77))	('tumor metastasis', 'Disease', (135, 151))
105871	31085159	Inactivation of AMPK drives a metabolic switch to glycolysis.	('AMPK', 'Gene', (16, 20))	('glycolysis', 'MPA', (50, 60))	('metabolic switch', 'MPA', (30, 46))	('AMPK', 'Gene', '5563', (16, 20))	('Inactivation', 'Var', (0, 12))
105873	31085159	The phosphorylation of Akt is a potent inducer for EMT, which activates a series of downstream targets.	('Akt', 'Gene', (23, 26))	('phosphorylation', 'Var', (4, 19))	('Akt', 'Gene', '207', (23, 26))
105875	31085159	Our results demonstrate increased levels of mtROS and decreased levels of SOD activities in UPC2 knockdown cholangiocarcinoma cells, suggesting a link between UCP2, SOD, and mtROS.	('knockdown', 'Var', (97, 106))	('mtROS', 'MPA', (44, 49))	('UCP2', 'Gene', (159, 163))	('SOD', 'Gene', '6647', (74, 77))	('cholangiocarcinoma', 'Disease', (107, 125))	('UPC2', 'Gene', (92, 96))	('SOD', 'Gene', '6647', (165, 168))	('SOD', 'Gene', (74, 77))	('decreased', 'NegReg', (54, 63))	('ROS', 'Chemical', 'MESH:D017382', (176, 179))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (107, 125))	('ROS', 'Chemical', 'MESH:D017382', (46, 49))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (107, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('UCP2', 'Gene', '7351', (159, 163))	('increased', 'PosReg', (24, 33))	('SOD', 'Gene', (165, 168))
105876	31085159	Although ROS are regarded as initiators in cancer, high ROS levels cause cell death and migration inhibition in cancer cells.	('cause', 'Reg', (67, 72))	('migration inhibition', 'CPA', (88, 108))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('high', 'Var', (51, 55))	('ROS', 'Chemical', 'MESH:D017382', (9, 12))	('ROS', 'Chemical', 'MESH:D017382', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('ROS', 'Protein', (56, 59))	('cell death', 'CPA', (73, 83))
105884	31085159	In our study, YB-1 and Snail were downregulated whereas E-cadherin was upregulated in the UCP2 knockdown cells (Fig.	('Snail', 'Gene', '6615', (23, 28))	('downregulated', 'NegReg', (34, 47))	('UCP2', 'Gene', (90, 94))	('YB-1', 'Gene', '4904', (14, 18))	('knockdown', 'Var', (95, 104))	('UCP2', 'Gene', '7351', (90, 94))	('YB-1', 'Gene', (14, 18))	('Snail', 'Gene', (23, 28))	('E-cadherin', 'Gene', (56, 66))	('E-cadherin', 'Gene', '999', (56, 66))	('upregulated', 'PosReg', (71, 82))
105885	31085159	Taken together, suppression of UCP2 inhibits glycolysis, increases mtROS, activates AMPK and inactivates Akt, which might be responsible for the reverse EMT phenotype in cholangiocarcinoma cells.	('UCP2', 'Gene', (31, 35))	('mtROS', 'MPA', (67, 72))	('Akt', 'Gene', '207', (105, 108))	('suppression', 'Var', (16, 27))	('inactivates', 'NegReg', (93, 104))	('activates', 'PosReg', (74, 83))	('Akt', 'Gene', (105, 108))	('AMPK', 'Gene', (84, 88))	('ROS', 'Chemical', 'MESH:D017382', (69, 72))	('cholangiocarcinoma', 'Disease', (170, 188))	('inhibits', 'NegReg', (36, 44))	('increases', 'PosReg', (57, 66))	('UCP2', 'Gene', '7351', (31, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('AMPK', 'Gene', '5563', (84, 88))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (170, 188))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (170, 188))	('glycolysis', 'MPA', (45, 55))
105902	31085159	Inhibition of UCP2 suppresses glycolysis, cell proliferation, migration, spheroid growth; reverses EMT; and reduces drug resistance in cholangiocarcinoma cells.	('migration', 'CPA', (62, 71))	('drug resistance', 'Phenotype', 'HP:0020174', (116, 131))	('spheroid growth', 'CPA', (73, 88))	('suppresses', 'NegReg', (19, 29))	('cholangiocarcinoma', 'Disease', (135, 153))	('glycolysis', 'MPA', (30, 40))	('cell proliferation', 'CPA', (42, 60))	('reduces', 'NegReg', (108, 115))	('drug resistance', 'MPA', (116, 131))	('UCP2', 'Gene', '7351', (14, 18))	('reverses', 'PosReg', (90, 98))	('Inhibition', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('EMT', 'CPA', (99, 102))	('UCP2', 'Gene', (14, 18))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (135, 153))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (135, 153))
105905	31165048	Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics The identification of heterozygous neomorphic isocitrate dehydrogenase (IDH) mutations across multiple cancer types including both solid and hematologic malignancies has revolutionized our understanding of oncogenesis in these malignancies and the potential for targeted therapeutics using small molecule inhibitors.	('isocitrate dehydrogenase', 'Gene', (121, 145))	('IDH', 'Gene', '3417', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('mutations', 'Var', (152, 161))	('Cancer', 'Disease', 'MESH:D009369', (55, 61))	('Isocitrate Dehydrogenase', 'Gene', (7, 31))	('malignancies', 'Disease', 'MESH:D009369', (302, 314))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('malignancies', 'Disease', (302, 314))	('isocitrate dehydrogenase', 'Gene', '3417', (121, 145))	('malignancies', 'Disease', 'MESH:D009369', (228, 240))	('Isocitrate Dehydrogenase', 'Gene', '3417', (7, 31))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('IDH', 'Gene', (147, 150))	('hematologic malignancies', 'Disease', (216, 240))	('malignancies', 'Disease', (228, 240))	('cancer', 'Disease', (178, 184))	('Cancer', 'Disease', (55, 61))	('hematologic malignancies', 'Disease', 'MESH:D019337', (216, 240))
105906	31165048	The neomorphic mutation in IDH generates an oncometabolite product, 2-hydroxyglutarate (2HG), which has been linked to the disruption of metabolic and epigenetic mechanisms responsible for cellular differentiation and is likely an early and critical contributor to oncogenesis.	('IDH', 'Gene', (27, 30))	('IDH', 'Gene', '3417', (27, 30))	('neomorphic mutation', 'Var', (4, 23))	('2HG', 'Chemical', 'MESH:C019417', (88, 91))	('linked', 'Reg', (109, 115))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (68, 86))
105910	31165048	The discovery of mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) in over 80% of low-grade gliomas (LGGs) and secondary glioblastomas has revolutionized pharmaceutical approaches to targeted therapies and the overall glioma classification schema.	('glioma classification schema', 'Disease', (228, 256))	('glioblastomas', 'Disease', 'MESH:D005909', (131, 144))	('glioblastomas', 'Disease', (131, 144))	('IDH1', 'Gene', '3417', (58, 62))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('isocitrate dehydrogenase 1', 'Gene', (30, 56))	('IDH2', 'Gene', (71, 75))	('isocitrate dehydrogenase 1', 'Gene', '3417', (30, 56))	('glioma classification schema', 'Disease', 'MESH:D005910', (228, 256))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('IDH2', 'Gene', '3418', (71, 75))	('gliomas', 'Disease', (102, 109))	('glioblastomas', 'Phenotype', 'HP:0012174', (131, 144))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('mutations', 'Var', (17, 26))	('IDH1', 'Gene', (58, 62))
105911	31165048	Driver mutations in IDH1 and IDH2 have been likewise identified in acute myeloid leukemia (AML), chondrosarcoma, myelodysplastic syndromes, and cholangiocarcinoma.	('IDH1', 'Gene', '3417', (20, 24))	('leukemia', 'Phenotype', 'HP:0001909', (81, 89))	('chondrosarcoma', 'Disease', (97, 111))	('chondrosarcoma', 'Disease', 'MESH:D002813', (97, 111))	('IDH2', 'Gene', (29, 33))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (144, 162))	('IDH2', 'Gene', '3418', (29, 33))	('myeloid leukemia ', 'Gene', (73, 90))	('mutations', 'Var', (7, 16))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (97, 111))	('cholangiocarcinoma', 'Disease', (144, 162))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (113, 138))	('myelodysplastic syndromes', 'Disease', (113, 138))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (144, 162))	('identified', 'Reg', (53, 63))	('IDH1', 'Gene', (20, 24))	('myeloid leukemia ', 'Gene', '861', (73, 90))	('AML', 'Disease', 'MESH:D015470', (91, 94))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (113, 138))	('AML', 'Disease', (91, 94))	('AML', 'Phenotype', 'HP:0004808', (91, 94))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (73, 89))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (67, 89))
105912	31165048	Limitations in current treatment options, particularly in LGG and AML, due to both inefficacy and systemic toxicity, make mutant IDH (mutIDH), and its associated molecular pathways attractive therapeutic targets.	('AML', 'Phenotype', 'HP:0004808', (66, 69))	('AML', 'Disease', (66, 69))	('IDH', 'Gene', '3417', (137, 140))	('AML', 'Disease', 'MESH:D015470', (66, 69))	('toxicity', 'Disease', 'MESH:D064420', (107, 115))	('toxicity', 'Disease', (107, 115))	('IDH', 'Gene', (129, 132))	('mutant', 'Var', (122, 128))	('IDH', 'Gene', (137, 140))	('IDH', 'Gene', '3417', (129, 132))
105917	31165048	Mutations in IDH3 isoforms, which form heterotetrameric complexes in mitochondria, are rarely seen in cancer, but there is some evidence that upregulation of wild-type IDH3 may contribute to various tumorigenic metabolic pathways.	('tumor', 'Disease', (199, 204))	('IDH', 'Gene', '3417', (13, 16))	('contribute', 'Reg', (177, 187))	('upregulation', 'PosReg', (142, 154))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('IDH', 'Gene', '3417', (168, 171))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('IDH', 'Gene', (13, 16))	('IDH', 'Gene', (168, 171))
105918	31165048	The IDH1/2 mutations are heterozygous and neomorphic in that they establish a pathway for the NADPH-dependent conversion of the wild-type IDH product, alpha-ketoglutarate, to 2-hydroxyglutarate (2HG).	('conversion', 'MPA', (110, 120))	('alpha-ketoglutarate', 'MPA', (151, 170))	('mutations', 'Var', (11, 20))	('IDH', 'Gene', (138, 141))	('IDH', 'Gene', '3417', (4, 7))	('IDH1/2', 'Gene', '3417;3418', (4, 10))	('IDH', 'Gene', '3417', (138, 141))	('NADPH', 'Chemical', 'MESH:D009249', (94, 99))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (175, 193))	('IDH1/2', 'Gene', (4, 10))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (151, 170))	('2HG', 'Chemical', 'MESH:C019417', (195, 198))	('IDH', 'Gene', (4, 7))
105920	31165048	Early structural and pharmacokinetic studies show that mutant IDH develops an increased affinity for both the cofactor NADPH and substrate alpha-ketoglutarate.	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (139, 158))	('NADPH', 'Chemical', 'MESH:D009249', (119, 124))	('affinity', 'MPA', (88, 96))	('IDH', 'Gene', '3417', (62, 65))	('NADPH', 'MPA', (119, 124))	('mutant', 'Var', (55, 61))	('increased', 'PosReg', (78, 87))	('IDH', 'Gene', (62, 65))
105921	31165048	In the most common IDH1/2 mutants, the wild-type IDH function of oxidative decarboxylation of isocitrate to alpha-ketoglutarate is lost due to mutation of critical amino acid residues in the catalytic domain, IDH1 R132 and IDH2 R172, which are normally responsible for binding the beta-carboxyl group of isocitrate and initiating catalysis.	('IDH', 'Gene', (49, 52))	('IDH1', 'Gene', '3417', (19, 23))	('oxidative decarboxylation', 'MPA', (65, 90))	('isocitrate', 'Chemical', 'MESH:C034219', (304, 314))	('IDH', 'Gene', '3417', (19, 22))	('IDH1', 'Gene', '3417', (209, 213))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (108, 127))	('IDH', 'Gene', (223, 226))	('IDH', 'Gene', '3417', (49, 52))	('mutants', 'Var', (26, 33))	('mutation', 'Var', (143, 151))	('IDH', 'Gene', '3417', (223, 226))	('isocitrate', 'Chemical', 'MESH:C034219', (94, 104))	('lost', 'NegReg', (131, 135))	('IDH1/2', 'Gene', '3417;3418', (19, 25))	('IDH', 'Gene', (209, 212))	('IDH1', 'Gene', (19, 23))	('IDH1/2', 'Gene', (19, 25))	('IDH1', 'Gene', (209, 213))	('IDH2', 'Gene', (223, 227))	('IDH', 'Gene', (19, 22))	('IDH', 'Gene', '3417', (209, 212))	('IDH2', 'Gene', '3418', (223, 227))
105922	31165048	Interestingly, there is some evidence that, unlike the IDH1 mutant, the IDH2 mutant may not depend on heterodimerization with an IDH wild-type partner for 2HG production.	('IDH2', 'Gene', (72, 76))	('IDH1', 'Gene', '3417', (55, 59))	('IDH', 'Gene', (55, 58))	('IDH2', 'Gene', '3418', (72, 76))	('IDH', 'Gene', (72, 75))	('heterodimerization', 'MPA', (102, 120))	('IDH', 'Gene', '3417', (55, 58))	('IDH', 'Gene', '3417', (72, 75))	('IDH', 'Gene', (129, 132))	('mutant', 'Var', (77, 83))	('IDH1', 'Gene', (55, 59))	('2HG', 'Chemical', 'MESH:C019417', (155, 158))	('IDH', 'Gene', '3417', (129, 132))
105923	31165048	Nevertheless, while the mutant IDH enzyme can exist either as a homodimer or as a heterodimer with the wild-type IDH within cancer cells, all reported oncogenic IDH mutations to date are genetically heterozygous, suggesting that the critical role of mutant IDH is related to its gain-of-function for conversion of the wild-type IDH product, alpha-ketoglutarate, to 2HG.	('IDH', 'Gene', '3417', (113, 116))	('IDH', 'Gene', '3417', (328, 331))	('cancer', 'Disease', (124, 130))	('IDH', 'Gene', (31, 34))	('IDH', 'Gene', '3417', (161, 164))	('IDH', 'Gene', '3417', (257, 260))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (341, 360))	('2HG', 'Chemical', 'MESH:C019417', (365, 368))	('IDH', 'Gene', '3417', (31, 34))	('IDH', 'Gene', (161, 164))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('IDH', 'Gene', (328, 331))	('mutant', 'Var', (250, 256))	('gain-of-function', 'PosReg', (279, 295))	('IDH', 'Gene', (113, 116))	('conversion', 'MPA', (300, 310))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('IDH', 'Gene', (257, 260))
105924	31165048	Accumulation of 2HG, increasingly well-characterized as an oncometabolite, disrupts multiple regulatory cellular pathways involving alpha-ketoglutarate-dependent dioxygenases including those involved in epigenetic remodeling and DNA repair (Figure 1).	('disrupts', 'NegReg', (75, 83))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (132, 151))	('2HG', 'Chemical', 'MESH:C019417', (16, 19))	('alpha-ketoglutarate-dependent dioxygenases', 'Enzyme', (132, 174))	('regulatory cellular pathways', 'Pathway', (93, 121))	('2HG', 'Var', (16, 19))
105926	31165048	Changes in the epigenetic landscape brought on by 2HG-mediated disruption of the ten-eleven translocation (TET) family of 5-methylcytosine (5 mC) hydroxylases (DNA demethylases) and the JmJC domain-containing histone lysine demethylases (KDMs) are hypothesized to promote oncogenesis through DNA and histone hypermethylation and resultant transcriptional dysregulation.	('lysine', 'Chemical', 'MESH:D008239', (217, 223))	('transcriptional dysregulation', 'MPA', (339, 368))	('disruption', 'Var', (63, 73))	('2HG', 'Chemical', 'MESH:C019417', (50, 53))	('oncogenesis', 'CPA', (272, 283))	('DNA', 'Disease', (292, 295))	('hypermethylation', 'Var', (308, 324))	('promote', 'PosReg', (264, 271))	('histone', 'Protein', (300, 307))	('Changes', 'Reg', (0, 7))
105930	31165048	Here, we provide an overview of the current literature on IDH mutations in cancer with a particular emphasis on glioma and AML and the potential for mutIDH as a therapeutic target in these contexts.	('IDH', 'Gene', '3417', (58, 61))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('AML', 'Disease', 'MESH:D015470', (123, 126))	('cancer', 'Disease', (75, 81))	('IDH', 'Gene', (152, 155))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Disease', (112, 118))	('IDH', 'Gene', '3417', (152, 155))	('AML', 'Phenotype', 'HP:0004808', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('AML', 'Disease', (123, 126))	('IDH', 'Gene', (58, 61))	('mutations', 'Var', (62, 71))
105933	31165048	Ten years ago, our understanding of the molecular landscape in glioma was transformed by the first genome-wide analysis of somatic mutations in glioblastoma (GBM) and the identification of recurrent mutations in IDH1 nearly exclusively in secondary GBM.	('GBM', 'Phenotype', 'HP:0012174', (249, 252))	('GBM', 'Phenotype', 'HP:0012174', (158, 161))	('glioblastoma', 'Phenotype', 'HP:0012174', (144, 156))	('glioblastoma', 'Disease', (144, 156))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (144, 156))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH1', 'Gene', (212, 216))	('secondary GBM', 'Disease', (239, 252))	('mutations', 'Var', (199, 208))	('IDH1', 'Gene', '3417', (212, 216))	('glioma', 'Disease', (63, 69))
105934	31165048	Mutations in IDH1 and IDH2 are seen in over 80% of lower-grade gliomas (WHO grades II and III) and secondary GBMs that are thought to later develop from lower-grade lesions.	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('gliomas', 'Disease', (63, 70))	('seen', 'Reg', (31, 35))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (22, 26))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
105935	31165048	The vast majority of somatic IDH mutations (>95%) are seen in IDH1, and the most commonly observed IDH1 mutation occurs at the R132 residue.	('IDH', 'Gene', '3417', (29, 32))	('IDH', 'Gene', '3417', (99, 102))	('IDH', 'Gene', '3417', (62, 65))	('IDH1', 'Gene', '3417', (62, 66))	('mutations', 'Var', (33, 42))	('IDH', 'Gene', (29, 32))	('IDH1', 'Gene', (99, 103))	('R132', 'Var', (127, 131))	('IDH1', 'Gene', (62, 66))	('IDH', 'Gene', (99, 102))	('IDH1', 'Gene', '3417', (99, 103))	('IDH', 'Gene', (62, 65))
105936	31165048	IDH2 mutations, which are mutually exclusive with those in IDH1 and found at a functionally analogous R172 residue, only represent a minority of somatic IDH mutations in glioma.	('IDH1', 'Gene', '3417', (59, 63))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', (59, 62))	('glioma', 'Disease', (170, 176))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', '3417', (59, 62))	('mutations', 'Var', (5, 14))	('IDH2', 'Gene', (0, 4))	('IDH', 'Gene', (153, 156))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('IDH1', 'Gene', (59, 63))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('IDH', 'Gene', '3417', (153, 156))	('IDH2', 'Gene', '3418', (0, 4))
105938	31165048	Up to 94% of IDH-mutant non-1p/19q co-deleted gliomas harbor loss-of-function TP53 mutations and 86% have inactivating ATRX mutations.	('mutations', 'Var', (83, 92))	('IDH', 'Gene', '3417', (13, 16))	('mutations', 'Var', (124, 133))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('ATRX', 'Gene', '546', (119, 123))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('gliomas', 'Disease', (46, 53))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('IDH', 'Gene', (13, 16))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('loss-of-function', 'NegReg', (61, 77))	('ATRX', 'Gene', (119, 123))
105939	31165048	Only few IDH mutant astrocytomas carry IDH wild-type driver mutations or copy number alterations, and those who do (for example CDKN2A or CDKN2B loss) are usually classified as IDH mutant GBM.	('mutant', 'Var', (13, 19))	('CDKN2A', 'Gene', '1029', (128, 134))	('CDKN2B', 'Gene', '1030', (138, 144))	('astrocytomas', 'Disease', 'MESH:D001254', (20, 32))	('IDH', 'Gene', '3417', (39, 42))	('GBM', 'Phenotype', 'HP:0012174', (188, 191))	('loss', 'NegReg', (145, 149))	('IDH', 'Gene', (177, 180))	('astrocytoma', 'Phenotype', 'HP:0009592', (20, 31))	('IDH', 'Gene', (9, 12))	('copy number alterations', 'Var', (73, 96))	('astrocytomas', 'Disease', (20, 32))	('IDH', 'Gene', '3417', (177, 180))	('IDH', 'Gene', (39, 42))	('IDH', 'Gene', '3417', (9, 12))	('mutations', 'Var', (60, 69))	('CDKN2A', 'Gene', (128, 134))	('CDKN2B', 'Gene', (138, 144))
105940	31165048	These robust genomic differences are highly suggestive of a unique mechanism of oncogenesis in the IDH-mutant subgroup and furthermore imply that the IDH mutation is likely an early player in a cell-of-origin, which in its native state is capable of giving rise to both astrocyte and oligodendrocyte lineages.	('IDH', 'Gene', '3417', (99, 102))	('mutation', 'Var', (154, 162))	('giving rise to', 'Reg', (250, 264))	('oncogenesis', 'CPA', (80, 91))	('IDH', 'Gene', (150, 153))	('IDH', 'Gene', (99, 102))	('IDH', 'Gene', '3417', (150, 153))
105944	31165048	In glioma specifically, these genome-wide DNA methylation changes have been shown to establish "insulator dysfunction" or disruption of topologically-associated domains (TADs) and thereby directly influence key transcriptional regulatory pathways related to gliomagenesis.	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('topologically-associated domains', 'MPA', (136, 168))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('influence', 'Reg', (197, 206))	('glioma', 'Disease', 'MESH:D005910', (258, 264))	('glioma', 'Phenotype', 'HP:0009733', (258, 264))	('changes', 'Var', (58, 65))	('disruption', 'NegReg', (122, 132))	('dysfunction', 'Disease', 'MESH:D006331', (106, 117))	('glioma', 'Disease', (3, 9))	('key transcriptional regulatory pathways', 'Pathway', (207, 246))	('dysfunction', 'Disease', (106, 117))	('glioma', 'Disease', (258, 264))	('methylation changes', 'Var', (46, 65))
105945	31165048	As previously mentioned, analyses of clonality among glioma tumor samples suggests that the IDH mutation is a tumor-initiating event in a common progenitor cell, hypothesized by many to be derived from the subventricular zone stem cell niche.	('glioma tumor', 'Disease', (53, 65))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (110, 115))	('mutation', 'Var', (96, 104))	('glioma tumor', 'Disease', 'MESH:D005910', (53, 65))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('IDH', 'Gene', (92, 95))	('tumor', 'Disease', (60, 65))	('IDH', 'Gene', '3417', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
105948	31165048	Recent efforts in developing small molecule inhibitors that target IDH mutation provide a new opportunity for progress in glioma treatment.	('mutation', 'Var', (71, 79))	('glioma', 'Disease', (122, 128))	('IDH', 'Gene', (67, 70))	('IDH', 'Gene', '3417', (67, 70))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
105949	31165048	Around the same time as the identification of recurrent IDH mutations in glioma, Mardis et al.	('glioma', 'Disease', (73, 79))	('IDH', 'Gene', (56, 59))	('IDH', 'Gene', '3417', (56, 59))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('mutations', 'Var', (60, 69))
105950	31165048	published the results of a landmark study in which they sought to pinpoint recurrent mutations in AML that may be associated with the pathogenesis of the malignancy.	('AML', 'Disease', 'MESH:D015470', (98, 101))	('mutations', 'Var', (85, 94))	('associated', 'Reg', (114, 124))	('AML', 'Phenotype', 'HP:0004808', (98, 101))	('AML', 'Disease', (98, 101))	('malignancy', 'Disease', 'MESH:D009369', (154, 164))	('malignancy', 'Disease', (154, 164))
105951	31165048	In this study, the investigators identified for the first time the presence of IDH1 mutations in AML.	('IDH1', 'Gene', '3417', (79, 83))	('AML', 'Phenotype', 'HP:0004808', (97, 100))	('AML', 'Disease', (97, 100))	('mutations', 'Var', (84, 93))	('AML', 'Disease', 'MESH:D015470', (97, 100))	('IDH1', 'Gene', (79, 83))
105952	31165048	8.5% of analyzed samples had an IDH1 mutation at the R132 residue (mutated to either cysteine, histidine, or serine), which is also the site of the overwhelming majority of somatic IDH mutations in glioma.	('serine', 'Chemical', 'MESH:D012694', (109, 115))	('IDH', 'Gene', (181, 184))	('mutation', 'Var', (37, 45))	('IDH1', 'Gene', (32, 36))	('glioma', 'Disease', (198, 204))	('IDH', 'Gene', '3417', (181, 184))	('histidine', 'Chemical', 'MESH:D006639', (95, 104))	('IDH1', 'Gene', '3417', (32, 36))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('glioma', 'Disease', 'MESH:D005910', (198, 204))	('cysteine', 'Chemical', 'MESH:D003545', (85, 93))
105953	31165048	Shortly after the discovery of IDH1 mutations in AML, another landmark study reported the first case of IDH2-mutated AML, in which the R172 residue was mutated to lysine.	('IDH2', 'Gene', '3418', (104, 108))	('lysine', 'Chemical', 'MESH:D008239', (163, 169))	('AML', 'Disease', (49, 52))	('AML', 'Disease', (117, 120))	('IDH1', 'Gene', '3417', (31, 35))	('AML', 'Phenotype', 'HP:0004808', (117, 120))	('AML', 'Phenotype', 'HP:0004808', (49, 52))	('mutations', 'Var', (36, 45))	('IDH2', 'Gene', (104, 108))	('R172', 'Var', (135, 139))	('AML', 'Disease', 'MESH:D015470', (49, 52))	('AML', 'Disease', 'MESH:D015470', (117, 120))	('IDH1', 'Gene', (31, 35))
105954	31165048	Further investigation of AML DNA samples revealed the existence of several additional cases of AML where the IDH2R172 residue was mutated.	('IDH2', 'Gene', (109, 113))	('AML', 'Disease', 'MESH:D015470', (95, 98))	('AML', 'Phenotype', 'HP:0004808', (95, 98))	('AML', 'Disease', (95, 98))	('IDH2', 'Gene', '3418', (109, 113))	('AML', 'Disease', 'MESH:D015470', (25, 28))	('mutated', 'Var', (130, 137))	('AML', 'Phenotype', 'HP:0004808', (25, 28))	('AML', 'Disease', (25, 28))
105955	31165048	Interestingly, this study also found that a majority of the analyzed samples had IDH2 mutations (compared to IDH1 mutations).	('mutations', 'Var', (86, 95))	('IDH1', 'Gene', (109, 113))	('IDH2', 'Gene', (81, 85))	('IDH1', 'Gene', '3417', (109, 113))	('IDH2', 'Gene', '3418', (81, 85))
105956	31165048	This is in stark contrast to glioma, where the majority of IDH mutations are in IDH1.	('mutations', 'Var', (63, 72))	('IDH1', 'Gene', (80, 84))	('IDH', 'Gene', (59, 62))	('glioma', 'Disease', (29, 35))	('IDH1', 'Gene', '3417', (80, 84))	('IDH', 'Gene', '3417', (59, 62))	('IDH', 'Gene', (80, 83))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('IDH', 'Gene', '3417', (80, 83))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))
105958	31165048	The IDH2R140 mutation (in particular, the R140Q variant) is the most common, with the IDH1R132 and IDH2R172 mutations also appearing frequently in the literature.	('R140Q', 'Var', (42, 47))	('IDH1', 'Gene', (86, 90))	('common', 'Reg', (69, 75))	('IDH2', 'Gene', (99, 103))	('IDH1', 'Gene', '3417', (86, 90))	('IDH2', 'Gene', (4, 8))	('R140Q', 'Mutation', 'rs121913502', (42, 47))	('IDH2', 'Gene', '3418', (4, 8))	('IDH2', 'Gene', '3418', (99, 103))
105959	31165048	Other mutations include, but are not limited to, IDH1V71 and IDH1 SNP rs11554137, a GGC to GGT transversion at the glycine residue at codon position 105 with unknown significance.	('rs11554137', 'Mutation', 'rs11554137', (70, 80))	('IDH1', 'Gene', '3417', (49, 53))	('IDH1', 'Gene', (61, 65))	('glycine', 'Chemical', 'MESH:D005998', (115, 122))	('IDH1', 'Gene', '3417', (61, 65))	('IDH1', 'Gene', (49, 53))	('rs11554137', 'Var', (70, 80))
105961	31165048	IDH1 and IDH2 mutations in AML are mutually exclusive, as in glioma.	('AML', 'Phenotype', 'HP:0004808', (27, 30))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('IDH2', 'Gene', (9, 13))	('AML', 'Disease', (27, 30))	('IDH2', 'Gene', '3418', (9, 13))	('glioma', 'Disease', (61, 67))	('AML', 'Disease', 'MESH:D015470', (27, 30))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('glioma', 'Disease', 'MESH:D005910', (61, 67))	('IDH1', 'Gene', '3417', (0, 4))
105983	31165048	Optimization of a lead compound based on differential inhibition of mutIDH1 and wild-type IDH1 enzymes resulted in BAY-1436032, an allosteric inhibitor that binds at the IDH dimer interface (Figure 2).	('IDH1', 'Gene', (90, 94))	('BAY-1436032', 'Var', (115, 126))	('IDH', 'Gene', (90, 93))	('IDH1', 'Gene', '3417', (90, 94))	('IDH', 'Gene', '3417', (90, 93))	('IDH1', 'Gene', (71, 75))	('IDH', 'Gene', (170, 173))	('IDH', 'Gene', (71, 74))	('IDH1', 'Gene', '3417', (71, 75))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (115, 126))	('IDH', 'Gene', '3417', (170, 173))	('IDH', 'Gene', '3417', (71, 74))
105984	31165048	Interestingly, BAY-1436032 demonstrates potent inhibition of all known IDH1R132 mutants with nearly equal efficacy in both human-derived AML cells (IC50 3-16 nM) and genetically engineered cell lines representative of solid tumors (IC50 13-135 nM).	('solid tumors', 'Disease', (218, 230))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('human', 'Species', '9606', (123, 128))	('inhibition', 'NegReg', (47, 57))	('solid tumors', 'Disease', 'MESH:D009369', (218, 230))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('mutants', 'Var', (80, 87))	('IDH1', 'Gene', (71, 75))	('AML', 'Disease', 'MESH:D015470', (137, 140))	('IDH1', 'Gene', '3417', (71, 75))	('AML', 'Phenotype', 'HP:0004808', (137, 140))	('AML', 'Disease', (137, 140))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (15, 26))
105986	31165048	In AML cell lines, BAY-1436032 demonstrated some efficacy in reducing histone methylation as well, but multiple studies have failed to show changes in histone or DNA methylation status in glioma models.	('reducing', 'NegReg', (61, 69))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('BAY-1436032', 'Var', (19, 30))	('glioma', 'Disease', 'MESH:D005910', (188, 194))	('AML', 'Disease', 'MESH:D015470', (3, 6))	('histone methylation', 'MPA', (70, 89))	('glioma', 'Disease', (188, 194))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (19, 30))	('AML', 'Phenotype', 'HP:0004808', (3, 6))	('AML', 'Disease', (3, 6))
105987	31165048	In vivo, however, BAY-1436032 effectively penetrates the blood-brain barrier and has shown prolonged survival in mice with IDHR132H astrocytoma xenographs.	('IDHR132H astrocytoma xenographs', 'Disease', (123, 154))	('astrocytoma', 'Phenotype', 'HP:0009592', (132, 143))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (18, 29))	('BAY-1436032', 'Var', (18, 29))	('mice', 'Species', '10090', (113, 117))	('IDHR132H astrocytoma xenographs', 'Disease', 'MESH:D001254', (123, 154))
105999	31165048	The presentation of mixed results in glioma models is likely due to the fact that certain tumorigenic processes are uncoupled from the IDH1 mutation, and further studies into combination treatment (discussed in a later section) may be warranted.	('IDH1', 'Gene', (135, 139))	('glioma', 'Disease', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('mutation', 'Var', (140, 148))	('IDH1', 'Gene', '3417', (135, 139))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
106000	31165048	Popular hypotheses to explain this changing role of mutIDH include the generation of an epigenetic memory that is indelible by its enzymatic inhibition alone and the accumulation of additional mutations during tumor evolution.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('IDH', 'Gene', (55, 58))	('epigenetic memory', 'MPA', (88, 105))	('tumor', 'Disease', (210, 215))	('IDH', 'Gene', '3417', (55, 58))	('mutations', 'Var', (193, 202))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
106004	31165048	X-ray crystallography reveals that IDH305 binds to an allosteric binding pocket to stabilize the mutIDH1 enzyme in a catalytically inactive conformation.	('stabilize', 'PosReg', (83, 92))	('IDH1', 'Gene', '3417', (100, 104))	('IDH305', 'Var', (35, 41))	('IDH1', 'Gene', (100, 104))	('IDH305', 'Chemical', '-', (35, 41))
106008	31165048	AGI-6780 is a urea sulfonamide inhibitor of the IDH2R140Q mutant enzyme specifically and exhibits non-competitive inhibition with respect to substrate, and uncompetitive inhibition with respect to the NADPH cofactor, operating at an allosteric site at the enzyme's dimer interface (Figure 2).	('non-competitive', 'MPA', (98, 113))	('urea sulfonamide', 'Chemical', '-', (14, 30))	('NADPH', 'Chemical', 'MESH:D009249', (201, 206))	('IDH2R140Q', 'Var', (48, 57))	('AGI-6780', 'Chemical', 'MESH:C581155', (0, 8))
106009	31165048	In early pharmacokinetic studies, AGI-6780 demonstrated time-dependent potency for 2HG reduction in both mutant homodimer and mutant/wild-type heterodimer enzyme contexts as well as in more organic cellular contexts (IC50 11nM in IDH2R140Q-overexpressing U87 cells).	('2HG', 'Chemical', 'MESH:C019417', (83, 86))	('mutant/wild-type', 'Var', (126, 142))	('2HG', 'MPA', (83, 86))	('AGI-6780', 'Chemical', 'MESH:C581155', (34, 42))	('mutant', 'Var', (105, 111))	('reduction', 'NegReg', (87, 96))
106012	31165048	Additional studies have demonstrated that AGI-6780 is not only capable of promoting the expression of differentiation markers such as hemoglobin gamma (HBG) and Kruppel-like factor 1 (KLF1), but that it does so by reversing 2HG-induced DNA and histone hypermethylation in AML cellular models:thereby suggesting that AGI-6780 can manipulate key mechanisms of oncogenesis.	('reversing', 'NegReg', (214, 223))	('AML', 'Disease', (272, 275))	('manipulate', 'Reg', (329, 339))	('KLF1', 'Gene', '10661', (184, 188))	('AGI-6780', 'Chemical', 'MESH:C581155', (316, 324))	('AGI-6780', 'Var', (42, 50))	('AML', 'Phenotype', 'HP:0004808', (272, 275))	('promoting', 'PosReg', (74, 83))	('AML', 'Disease', 'MESH:D015470', (272, 275))	('KLF1', 'Gene', (184, 188))	('expression', 'MPA', (88, 98))	('2HG', 'Chemical', 'MESH:C019417', (224, 227))	('AGI-6780', 'Chemical', 'MESH:C581155', (42, 50))
106025	31165048	Modification of peripheral chemical substituents with additional polar moieties optimized the potency, solubility, clearance and bioavailability profiles of the molecule, yielding Enasidenib (Figure 2).	('bioavailability', 'MPA', (129, 144))	('Enasidenib', 'Chemical', 'MESH:C000605269', (180, 190))	('Modification', 'Var', (0, 12))	('solubility', 'MPA', (103, 113))	('clearance', 'MPA', (115, 124))	('potency', 'MPA', (94, 101))
106028	31165048	Furthermore, treatment of patient-derived blasts with Enasidenib also inhibited cellular proliferation and reversed the histone hypermethylation profile associated with the IDH2 mutation.	('cellular proliferation', 'CPA', (80, 102))	('patient', 'Species', '9606', (26, 33))	('IDH2', 'Gene', (173, 177))	('histone hypermethylation profile', 'MPA', (120, 152))	('mutation', 'Var', (178, 186))	('IDH2', 'Gene', '3418', (173, 177))	('reversed', 'NegReg', (107, 115))	('inhibited', 'NegReg', (70, 79))	('Enasidenib', 'Chemical', 'MESH:C000605269', (54, 64))
106034	31165048	Broad structure-activity relationship profiling directed the substitution of fluorinated cycloalkyl groups in place of cyclohexyl moieties, preventing extensive oxidation of the molecule in the human liver microsome.	('substitution', 'Var', (61, 73))	('human', 'Species', '9606', (194, 199))	('oxidation', 'MPA', (161, 170))	('preventing', 'NegReg', (140, 150))
106036	31165048	However, assessment in early screening however revealed that AG-14100 was a relatively potent cytochrome P450 (CYP) 3A4-inducer, with approximately 70% of the activity of rifampicin.	('rifampicin', 'Chemical', 'MESH:D012293', (171, 181))	('AG-14100', 'Var', (61, 69))	('activity', 'MPA', (159, 167))
106037	31165048	Further functional group substitutions to increase polarity resulted in a molecule with low CYP 3A4 activation, and adequate clearance and potency profiles: AG-120 (Ivosidenib) (Figure 2).	('substitutions', 'Var', (25, 38))	('low', 'NegReg', (88, 91))	('AG-120', 'Chemical', 'MESH:C000627630', (157, 163))	('activation', 'MPA', (100, 110))	('CYP 3A4', 'Gene', (92, 99))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (165, 175))	('CYP 3A4', 'Gene', '1576', (92, 99))
106040	31165048	It possesses equitable potency across various IDH1R132 mutants in a series of cell lines in a selective manner, showing no inhibition of wild-type or mutIDH2 isoforms.	('IDH2', 'Gene', (153, 157))	('IDH1', 'Gene', (46, 50))	('mutants', 'Var', (55, 62))	('IDH2', 'Gene', '3418', (153, 157))	('IDH1', 'Gene', '3417', (46, 50))
106042	31165048	Robust, dose- and time-dependent 2HG depletion has been observed across a host of cell types including human chondrosarcoma cells and mouse-model xenografts, primary human AML myeloblasts, and mutIDH1R132H glioma xenografts (IC50 range 5-13 nM for various IDH1 mutants in vitro).	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('IDH1', 'Gene', (256, 260))	('mouse', 'Species', '10090', (134, 139))	('human', 'Species', '9606', (103, 108))	('human', 'Species', '9606', (166, 171))	('IDH1', 'Gene', (196, 200))	('chondrosarcoma', 'Disease', (109, 123))	('glioma xenografts', 'Disease', 'MESH:D005910', (206, 223))	('chondrosarcoma', 'Disease', 'MESH:D002813', (109, 123))	('IDH1', 'Gene', '3417', (256, 260))	('AML', 'Disease', 'MESH:D015470', (172, 175))	('glioma xenografts', 'Disease', (206, 223))	('IDH1', 'Gene', '3417', (196, 200))	('AML', 'Disease', (172, 175))	('mutants', 'Var', (261, 268))	('AML', 'Phenotype', 'HP:0004808', (172, 175))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (109, 123))	('depletion', 'MPA', (37, 46))	('2HG', 'Chemical', 'MESH:C019417', (33, 36))
106045	31165048	A summary of the completed, ongoing, recruiting, and planned clinical trials of mutIDH inhibitors in AML and other hematological malignancies can be found in Table 2 and will be reviewed below.	('AML', 'Disease', 'MESH:D015470', (101, 104))	('hematological malignancies', 'Phenotype', 'HP:0004377', (115, 141))	('IDH', 'Gene', (83, 86))	('AML', 'Phenotype', 'HP:0004808', (101, 104))	('AML', 'Disease', (101, 104))	('IDH', 'Gene', '3417', (83, 86))	('hematological malignancies', 'Disease', (115, 141))	('hematological malignancies', 'Disease', 'MESH:D019337', (115, 141))	('inhibitors', 'Var', (87, 97))
106061	31165048	A few clinical trials involving Enasidenib are still in the planning stages and are not yet actively recruiting (ClinicalTrials.gov NCT03728335, NCT03720366), and one phase 1 trial investigating pan-inhibitor AG-881 (ClinicalTrials.gov NCT02492737) in advanced hematologic malignancies with either IDH1 or IDH2 mutations concluded in 2018, but no trial results have been released.	('IDH2', 'Gene', (306, 310))	('hematologic malignancies', 'Disease', (261, 285))	('IDH2', 'Gene', '3418', (306, 310))	('AG-881', 'Chemical', '-', (209, 215))	('IDH1', 'Gene', (298, 302))	('mutations', 'Var', (311, 320))	('Enasidenib', 'Chemical', 'MESH:C000605269', (32, 42))	('hematologic malignancies', 'Disease', 'MESH:D019337', (261, 285))	('IDH1', 'Gene', '3417', (298, 302))
106066	31165048	Interestingly, of the 30.4% of patients with complete remission, 21% had no detectible residual IDH1 mutations on digital polymerase chain reaction assay.	('patients', 'Species', '9606', (31, 39))	('IDH1', 'Gene', '3417', (96, 100))	('IDH1', 'Gene', (96, 100))	('mutations', 'Var', (101, 110))
106073	31165048	The previously mentioned currently recruiting phase 1b/2 study investigating biomarker-based treatment of AML also includes an Ivosidenib arm for those patients with IDH1 mutations (ClinicalTrials.gov NCT03013998).	('IDH1', 'Gene', (166, 170))	('IDH1', 'Gene', '3417', (166, 170))	('AML', 'Disease', 'MESH:D015470', (106, 109))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (127, 137))	('mutations', 'Var', (171, 180))	('AML', 'Phenotype', 'HP:0004808', (106, 109))	('patients', 'Species', '9606', (152, 160))	('AML', 'Disease', (106, 109))
106075	31165048	In another currently-recruiting phase 3 study azacitidine is combined with either Ivosidenib or placebo as therapy for previously untreated AML with IDH1 mutations (NCT03173248).	('IDH1', 'Gene', (149, 153))	('IDH1', 'Gene', '3417', (149, 153))	('AML', 'Disease', 'MESH:D015470', (140, 143))	('azacitidine', 'Chemical', 'MESH:D001374', (46, 57))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (82, 92))	('mutations', 'Var', (154, 163))	('AML', 'Disease', (140, 143))	('AML', 'Phenotype', 'HP:0004808', (140, 143))
106083	31165048	A phase 1/2 study is evaluating the use of FT-2102 alone or with azacitidine in patients with AML or MDS carrying IDH1 mutations (ClinicalTrials.gov NCT02719574).	('AML', 'Disease', (94, 97))	('IDH1', 'Gene', (114, 118))	('patients', 'Species', '9606', (80, 88))	('azacitidine', 'Chemical', 'MESH:D001374', (65, 76))	('AML', 'Phenotype', 'HP:0004808', (94, 97))	('MDS', 'Disease', (101, 104))	('FT-2102', 'Chemical', '-', (43, 50))	('MDS', 'Disease', 'MESH:D009190', (101, 104))	('IDH1', 'Gene', '3417', (114, 118))	('AML', 'Disease', 'MESH:D015470', (94, 97))	('mutations', 'Var', (119, 128))
106099	31165048	Forthcoming work with AG-881 includes an additional ongoing phase 1 randomized open-label trial evaluating the ability of pre-treatment with either AG-881 or AG-120 to suppress intra-tumoral 2HG levels in surgical pathology specimens as a measure of pharmacological efficacy (ClinicalTrials.gov NCT03343197).	('AG-881', 'Chemical', '-', (148, 154))	('AG-881', 'Var', (148, 154))	('AG-881', 'Chemical', '-', (22, 28))	('intra-tumoral', 'Disease', 'MESH:D009369', (177, 190))	('2HG', 'Chemical', 'MESH:C019417', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('intra-tumoral', 'Disease', (177, 190))	('suppress', 'NegReg', (168, 176))	('AG-120', 'Chemical', 'MESH:C000627630', (158, 164))	('AG-120', 'Gene', (158, 164))
106101	31165048	These studies are evaluating safety and pharmacology of mutIDH-specific inhibitors such as DS-1001b, IDH305, and FT-2012, Enasidenib, and BAY-1436032 (ClinicalTrials.gov NCT03030066, NCT02381886, NCT03684811, NCT02273739, NCT02746081).	('IDH', 'Gene', (59, 62))	('NCT03684811', 'Var', (196, 207))	('NCT02381886', 'Var', (183, 194))	('NCT02746081', 'Var', (222, 233))	('IDH305', 'Chemical', '-', (101, 107))	('IDH', 'Gene', '3417', (59, 62))	('NCT02273739', 'Var', (209, 220))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (138, 149))	('IDH', 'Gene', (101, 104))	('IDH', 'Gene', '3417', (101, 104))	('Enasidenib', 'Chemical', 'MESH:C000605269', (122, 132))
106110	31165048	As previously discussed, 2017 and 2018 saw the respective publications of the results of two landmark clinical trials in AML: first, a phase 1/2 study of the selective IDH2 mutant inhibitor Enasidenib, and second, a phase 1 dose-escalation and dose-expansion study of the selective IDH1 mutant inhibitor Ivosidenib.	('IDH1', 'Gene', (282, 286))	('IDH2', 'Gene', '3418', (168, 172))	('AML', 'Phenotype', 'HP:0004808', (121, 124))	('AML', 'Disease', (121, 124))	('IDH1', 'Gene', '3417', (282, 286))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (304, 314))	('mutant', 'Var', (173, 179))	('Enasidenib', 'Chemical', 'MESH:C000605269', (190, 200))	('IDH2', 'Gene', (168, 172))	('AML', 'Disease', 'MESH:D015470', (121, 124))
106133	31165048	However, given the extent of hypermethylation induced early in oncogenesis by the IDH mutation, mutIDH inhibitor monotherapy may be insufficient to thoroughly undo these preexisting and persistent global epigenetic alterations keeping the tumor cells in a dedifferentiated state.	('IDH', 'Gene', '3417', (82, 85))	('IDH', 'Gene', '3417', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('hypermethylation', 'MPA', (29, 45))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('insufficient', 'Disease', (132, 144))	('tumor', 'Disease', (239, 244))	('mutation', 'Var', (86, 94))	('insufficient', 'Disease', 'MESH:D000309', (132, 144))	('IDH', 'Gene', (82, 85))	('IDH', 'Gene', (99, 102))
106134	31165048	Preclinical evidence, particularly in glioma, supports the hypothesis that mutIDH assumes a "passenger," rather than a "driver," role soon after the development of the IDH mutation likely due to initiating methylation changes being preserved by epigenetic memory and consequent acquisition of additional driver mutations.	('IDH', 'Gene', '3417', (168, 171))	('methylation', 'MPA', (206, 217))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('mutation', 'Var', (172, 180))	('IDH', 'Gene', (78, 81))	('glioma', 'Disease', (38, 44))	('IDH', 'Gene', '3417', (78, 81))	('IDH', 'Gene', (168, 171))
106136	31165048	In AML, it is known that patients with IDH mutations are up to 14 times more likely to response to DNMT inhibitors.	('AML', 'Disease', 'MESH:D015470', (3, 6))	('mutations', 'Var', (43, 52))	('patients', 'Species', '9606', (25, 33))	('DNMT', 'Gene', '1786', (99, 103))	('IDH', 'Gene', (39, 42))	('DNMT', 'Gene', (99, 103))	('AML', 'Phenotype', 'HP:0004808', (3, 6))	('IDH', 'Gene', '3417', (39, 42))	('AML', 'Disease', (3, 6))
106143	31165048	in human IDH-mutant glioma cell lines found not only that azacitidine reduced cellular proliferation and induced increased expression of astroglial differentiation markers like GFAP, but also that azacitidine worked synergistically with temozolomide to inhibit tumor growth.	('expression', 'MPA', (123, 133))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('cellular proliferation', 'CPA', (78, 100))	('human', 'Species', '9606', (3, 8))	('azacitidine', 'Chemical', 'MESH:D001374', (197, 208))	('IDH', 'Gene', (9, 12))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('inhibit', 'NegReg', (253, 260))	('azacitidine', 'Var', (197, 208))	('IDH', 'Gene', '3417', (9, 12))	('azacitidine', 'Chemical', 'MESH:D001374', (58, 69))	('reduced', 'NegReg', (70, 77))	('GFAP', 'Gene', (177, 181))	('temozolomide', 'Chemical', 'MESH:D000077204', (237, 249))	('increased', 'PosReg', (113, 122))	('tumor', 'Disease', (261, 266))	('glioma', 'Disease', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (261, 266))
106148	31165048	RNA methylation patterns have also been shown to be critical for glioblastoma stem cell self-renewal and tumorigenesis specifically, and as previously discussed, the early molecular insults of IDH mutations and 2HG include competitive inhibition of histone demethylases.	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('histone', 'Protein', (249, 256))	('IDH', 'Gene', (193, 196))	('2HG', 'Chemical', 'MESH:C019417', (211, 214))	('mutations', 'Var', (197, 206))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('glioblastoma', 'Disease', (65, 77))	('IDH', 'Gene', '3417', (193, 196))	('glioblastoma', 'Disease', 'MESH:D005909', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
106151	31165048	Furthermore, downstream oncogenic effects of histone dysregulation in IDH-mutant cancers, such as downregulation of the ATM gene causing an increase in spontaneous DNA damage, continue to become more well understood and suggest that a parallel effort to understand and target epigenetic memory carried in histones, in addition to DNA methylation, should be pursued.	('dysregulation', 'Var', (53, 66))	('downregulation', 'NegReg', (98, 112))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('IDH', 'Gene', (70, 73))	('spontaneous DNA damage', 'MPA', (152, 174))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('IDH', 'Gene', '3417', (70, 73))	('ATM', 'Gene', (120, 123))	('increase', 'PosReg', (140, 148))	('ATM', 'Gene', '472', (120, 123))
106153	31165048	A small case series described two cases of IDH1R132C-mutant AML that, after achieving remission on Ivosidenib, both recurred with new IDH2R140Q mutations.	('AML', 'Disease', 'MESH:D015470', (60, 63))	('IDH1', 'Gene', (43, 47))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (99, 109))	('AML', 'Phenotype', 'HP:0004808', (60, 63))	('IDH1', 'Gene', '3417', (43, 47))	('IDH2R140Q mutations', 'Var', (134, 153))	('AML', 'Disease', (60, 63))
106155	31165048	Additionally, the same research group defined another potential avenue for resistance through mutational changes in conformation of the mutIDH enzyme trans-dimer interface:the precise target of these small molecule therapeutics.	('mutational', 'Var', (94, 104))	('changes', 'Reg', (105, 112))	('IDH', 'Gene', (139, 142))	('IDH', 'Gene', '3417', (139, 142))	('conformation', 'MPA', (116, 128))
106158	31165048	The identification of neomorphic mutations in IDH in several cancer types including glioma and AML has generated robust research and drug discovery efforts to both elucidate critical pathways in oncogenesis and create effective, targeted molecular therapies.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('AML', 'Disease', 'MESH:D015470', (95, 98))	('glioma', 'Disease', (84, 90))	('cancer', 'Disease', (61, 67))	('IDH', 'Gene', (46, 49))	('AML', 'Phenotype', 'HP:0004808', (95, 98))	('neomorphic mutations', 'Var', (22, 42))	('AML', 'Disease', (95, 98))	('IDH', 'Gene', '3417', (46, 49))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('glioma', 'Disease', 'MESH:D005910', (84, 90))
106175	28178311	As a result, we found that genes that show a methylation change larger than 32.2% may influence cancer-related genes via fewer interaction steps and with much higher percentages compared with genes showing a methylation change less than 32.2%.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('fewer', 'NegReg', (121, 126))	('cancer', 'Disease', (96, 102))	('methylation', 'Var', (45, 56))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('influence', 'Reg', (86, 95))	('interaction', 'Interaction', (127, 138))
106182	28178311	It is well established that hypermethylation in promoter regions leads to inactivation, whereas hypomethylation is associated with genomic instability and loss of imprinting, in addition to contributing to cell transformation and the progression of lesions, which may be the key factors in the reproduction and metastasis of cancer cells.	('loss', 'NegReg', (155, 159))	('hypermethylation', 'Var', (28, 44))	('cell transformation', 'CPA', (206, 225))	('hypomethylation', 'Var', (96, 111))	('associated', 'Reg', (115, 125))	('genomic', 'MPA', (131, 138))	('metastasis of cancer', 'Disease', (311, 331))	('inactivation', 'MPA', (74, 86))	('imprinting', 'Protein', (163, 173))	('contributing', 'Reg', (190, 202))	('metastasis of cancer', 'Disease', 'MESH:D009362', (311, 331))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))
106183	28178311	Indeed, both hyper- and hypomethylation have previously been associated with a variety of cancers, including kidney, colon, pancreas, liver and lung cancers.	('kidney', 'Disease', (109, 115))	('cancers', 'Disease', (90, 97))	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('colon, pancreas, liver and lung cancers', 'Disease', 'MESH:D008175', (117, 156))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('hypomethylation', 'Var', (24, 39))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('hyper-', 'Var', (13, 19))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('lung cancers', 'Phenotype', 'HP:0100526', (144, 156))	('associated', 'Reg', (61, 71))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
106184	28178311	Additionally, gene silencing via the hypermethylation of tumor-suppressing genes and activation of tumor-promoting genes via hypomethylation has been demonstrated to favor oncogenesis.	('tumor', 'Disease', (99, 104))	('favor', 'PosReg', (166, 171))	('gene', 'Var', (14, 18))	('oncogenesis', 'CPA', (172, 183))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('hypomethylation', 'Var', (125, 140))	('activation', 'PosReg', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('hypermethylation', 'Var', (37, 53))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (57, 62))
106211	28178311	In this work, we focused on identifying methylation-affected patterns that could potentially result in a cancer state.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('methylation-affected', 'Var', (40, 60))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('result in', 'Reg', (93, 102))
106217	28178311	More specifically, renal papillary cell carcinoma exhibited the greatest number of differentially methylated genes (FDR<0.1), while the number of differentially expressed genes was highest for cholangiocarcinoma, and the thyroid cancer dataset contained the minimum numbers of genes regarding both differential expression and differential methylation.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (193, 211))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (193, 211))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (19, 49))	('renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (19, 49))	('thyroid cancer', 'Disease', (221, 235))	('thyroid cancer', 'Phenotype', 'HP:0002890', (221, 235))	('differentially', 'Var', (83, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('renal papillary cell carcinoma', 'Disease', (19, 49))	('thyroid cancer', 'Disease', 'MESH:D013964', (221, 235))	('cholangiocarcinoma', 'Disease', (193, 211))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
106218	28178311	The numbers of genes showing methylation changes exceeding 15% and 32.2% for each cancer type are illustrated in Table 2.	('methylation', 'Var', (29, 40))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('changes', 'Reg', (41, 48))
106222	28178311	To address these issues, we adopted a graph-based approach and calculated the distances between large methylation changes and potentially cancer-causing driver genes by considering pairwise protein-protein interactions.	('methylation changes', 'Var', (102, 121))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))
106223	28178311	The results revealed that the genes with large methylation changes affected driver genes in fewer steps, except for thyroid cancer.	('thyroid cancer', 'Disease', 'MESH:D013964', (116, 130))	('methylation changes', 'Var', (47, 66))	('thyroid cancer', 'Disease', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('thyroid cancer', 'Phenotype', 'HP:0002890', (116, 130))
106236	28178311	Focusing on the affected genes that were observed only in a single cancer type revealed that the RET gene was affected by high methylation in thyroid cancer (shown in cornflower blue).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('thyroid cancer', 'Phenotype', 'HP:0002890', (142, 156))	('thyroid cancer', 'Disease', (142, 156))	('high methylation', 'Var', (122, 138))	('RET', 'Gene', '5979', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('affected', 'Reg', (110, 118))	('thyroid cancer', 'Disease', 'MESH:D013964', (142, 156))	('RET', 'Gene', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
106238	28178311	Examining cholangiocarcinoma, we observed that the HRAS, KIT, ZBTB16, FAS and NCOA4 genes were altered by high methylation (shown in light sea green).	('cholangiocarcinoma', 'Disease', (10, 28))	('NCOA4', 'Gene', '8031', (78, 83))	('HRAS', 'Gene', (51, 55))	('ZBTB16', 'Gene', (62, 68))	('FAS', 'Gene', (70, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('high methylation', 'Var', (106, 122))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (10, 28))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (10, 28))	('altered', 'Reg', (95, 102))	('KIT', 'Gene', (57, 60))	('HRAS', 'Gene', '3265', (51, 55))	('NCOA4', 'Gene', (78, 83))	('ZBTB16', 'Gene', '7704', (62, 68))
106240	28178311	The ZBTB16 gene is active in the blocking of differentiation; thus, methylation-driven abnormalities in ZBTB16 may lead to cholangiocarcinoma.	('ZBTB16', 'Gene', '7704', (4, 10))	('abnormalities', 'Var', (87, 100))	('cholangiocarcinoma', 'Disease', (123, 141))	('ZBTB16', 'Gene', '7704', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (123, 141))	('ZBTB16', 'Gene', (104, 110))	('ZBTB16', 'Gene', (4, 10))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (123, 141))	('methylation-driven', 'Var', (68, 86))	('lead to', 'Reg', (115, 122))
106243	28178311	In lung squamous cell carcinoma, we detected 15 genes that were altered by high methylation, and six of these genes were observed to be affected only in this type of cancer (shown in magenta).	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('lung squamous cell carcinoma', 'Disease', (3, 31))	('high methylation', 'Var', (75, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('altered', 'Reg', (64, 71))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (3, 31))
106248	28178311	Additionally, in the thyroid cancer dataset, copy number analysis of the RET gene revealed decreases in 5 of the 46 samples, while no sample exhibited an increase in the RET copy number.	('RET', 'Gene', (170, 173))	('thyroid cancer', 'Disease', 'MESH:D013964', (21, 35))	('RET', 'Gene', '5979', (73, 76))	('RET', 'Gene', '5979', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('copy', 'Var', (45, 49))	('thyroid cancer', 'Disease', (21, 35))	('RET', 'Gene', (73, 76))	('thyroid cancer', 'Phenotype', 'HP:0002890', (21, 35))	('decreases', 'NegReg', (91, 100))
106257	28178311	Additionally, based on the idea that large methylation changes might exhibit more rapid effects on the mechanisms leading to cancer states, we defined a large methylation change threshold.	('methylation changes', 'Var', (43, 62))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('changes', 'Var', (55, 62))
106258	28178311	Subsequently, we continued our analysis of the effects of methylation-driven changes on cancer-related genes (driver genes).	('changes', 'Reg', (77, 84))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('methylation-driven', 'Var', (58, 76))
106260	28178311	We found that large methylation changes exerted a major influence on the expression of driver genes in fewer steps (1.95 vs. 2.09, except for thyroid cancer) and at a higher proportion (7.83% vs. 3.00%), although these results varied among different cancer types.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('thyroid cancer', 'Phenotype', 'HP:0002890', (142, 156))	('thyroid cancer', 'Disease', (142, 156))	('cancer', 'Disease', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Disease', (150, 156))	('methylation changes', 'Var', (20, 39))	('expression', 'MPA', (73, 83))	('thyroid cancer', 'Disease', 'MESH:D013964', (142, 156))	('influence', 'Reg', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('changes', 'Var', (32, 39))
106268	28178311	In the present study, AGTR1 was found to exhibit a decreased expression level; hence, in a maximum of three steps, we identified genes that were altered by large methylation changes that signaled decreases in the expression level of AGTR1.	('expression level', 'MPA', (213, 229))	('decreases', 'NegReg', (196, 205))	('altered', 'Reg', (145, 152))	('AGTR1', 'Gene', (233, 238))	('changes', 'Var', (174, 181))	('AGTR1', 'Gene', '185', (233, 238))	('methylation', 'MPA', (162, 173))	('expression level', 'MPA', (61, 77))	('AGTR1', 'Gene', (22, 27))	('AGTR1', 'Gene', '185', (22, 27))
106270	28178311	In summary, our findings suggest that both AGTR1 and IGF1 are frequently observed as changed in variety of cancers and experimentally validating the hits that we find with our method linking large methylation alteration to these changes may reveal their potentially crucial role on overall cancer progression.	('AGTR1', 'Gene', '185', (43, 48))	('cancers', 'Disease', (107, 114))	('IGF1', 'Gene', (53, 57))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (290, 296))	('IGF1', 'Gene', '3479', (53, 57))	('changed', 'Reg', (85, 92))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('methylation alteration', 'Var', (197, 219))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('AGTR1', 'Gene', (43, 48))	('cancer', 'Disease', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
106275	28178311	Moreover, increased methylation-driven expression of the important oncogene SRC was identified in cholangiocarcinoma, hepatocellular carcinoma and colon adenocarcinoma, and SRC has previously been demonstrated to be active in cancer progression.	('SRC', 'Gene', (76, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (98, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (118, 142))	('methylation-driven', 'Var', (20, 38))	('cholangiocarcinoma', 'Disease', (98, 116))	('SRC', 'Gene', '6714', (173, 176))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (147, 167))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (98, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('hepatocellular carcinoma', 'Disease', (118, 142))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('expression', 'MPA', (39, 49))	('increased', 'PosReg', (10, 19))	('SRC', 'Gene', (173, 176))	('colon adenocarcinoma', 'Disease', (147, 167))	('SRC', 'Gene', '6714', (76, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (118, 142))	('cancer', 'Disease', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
106279	28178311	Both of these genes were found to be differentially altered by high methylation in colon cancer in our analysis.	('colon cancer', 'Disease', (83, 95))	('altered', 'Reg', (52, 59))	('colon cancer', 'Phenotype', 'HP:0003003', (83, 95))	('high methylation', 'Var', (63, 79))	('colon cancer', 'Disease', 'MESH:D015179', (83, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
106288	28178311	Additionally, changes in EGFR have been associated with lung cancer, and this gene has been recommended as a drug target.	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('EGFR', 'Gene', (25, 29))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('changes', 'Var', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('EGFR', 'Gene', '1956', (25, 29))	('associated', 'Reg', (40, 50))
106289	28178311	Alterations of AXIN2 have been demonstrated to contribute to carcinogenesis, specifically in lung cancer, and the downregulation of this suppressor via a large methylation change was successfully detected by our method.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('contribute', 'Reg', (47, 57))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('Alterations', 'Var', (0, 11))	('carcinogenesis', 'Disease', (61, 75))	('AXIN2', 'Gene', (15, 20))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('methylation change', 'Var', (160, 178))	('AXIN2', 'Gene', '8313', (15, 20))	('downregulation', 'NegReg', (114, 128))	('carcinogenesis', 'Disease', 'MESH:D063646', (61, 75))
106294	28178311	Because an increase in copy number is generally associated with greater expression, our findings suggest that large methylation changes were the predominant factors underlying the downregulation of these tumor suppressors, which was supported by copy number analyses.	('methylation', 'MPA', (116, 127))	('increase', 'PosReg', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('downregulation', 'NegReg', (180, 194))	('copy number', 'Var', (23, 34))	('expression', 'MPA', (72, 82))	('tumor', 'Disease', (204, 209))	('greater', 'PosReg', (64, 71))
106304	28178311	Although our method reveals important and previously unexplored information about possible methylation-driven changes in different cancer types, whether a large methylation change effectively leads to predicted change in corresponding driver gene in vitro and in vivo remains unknown.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('change', 'Var', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))
106404	27082582	In fact, intraductal RF ablation for nonresectable malignant biliary obstruction could reduce the tumor load and thus delay local tumor growth.	('tumor', 'Disease', (130, 135))	('RF', 'Chemical', '-', (21, 23))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('reduce', 'NegReg', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('malignant biliary obstruction', 'Disease', 'MESH:D009369', (51, 80))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('malignant biliary obstruction', 'Disease', (51, 80))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('biliary obstruction', 'Phenotype', 'HP:0005230', (61, 80))	('tumor', 'Disease', (98, 103))	('ablation', 'Var', (24, 32))	('delay', 'NegReg', (118, 123))
106441	27082582	The mean stricture length was 38.4 +- 10.6 mm in the RF ablation group versus 40.5 +- 9.5 mm in the control group (P = 0.65; Table 2).	('stricture', 'MPA', (9, 18))	('RF ablation', 'Var', (53, 64))	('RF', 'Chemical', '-', (53, 55))
106442	27082582	However, there was a significant improvement in stricture diameter in both the RF ablation (4.2 +- 1.2 vs. 1.0 +- 0.7 mm, P = 0.01) and control groups (3.4 +- 1.4 versus 1.0 +- 0.9 mm, P < 0.01) after stent placement.	('RF', 'Chemical', '-', (79, 81))	('ablation', 'Var', (82, 90))	('improvement', 'PosReg', (33, 44))	('men', 'Species', '9606', (40, 43))	('stricture diameter', 'MPA', (48, 66))	('men', 'Species', '9606', (212, 215))
106459	27082582	The stent patency time was much higher in the RF ablation group than in the control group, indicating that local tumor growth was indeed inhibited.	('tumor', 'Disease', (113, 118))	('inhibited', 'NegReg', (137, 146))	('higher', 'PosReg', (32, 38))	('RF ablation', 'Var', (46, 57))	('stent patency time', 'CPA', (4, 22))	('RF', 'Chemical', '-', (46, 48))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
106479	27082582	The authors suggested that RF ablation may have indirect antitumor effects that improve the survival of the patients.	('survival', 'CPA', (92, 100))	('RF', 'Chemical', '-', (27, 29))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('ablation', 'Var', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('patients', 'Species', '9606', (108, 116))	('improve', 'PosReg', (80, 87))	('tumor', 'Disease', (61, 66))
106492	22824796	Mutations in Isocitrate Dehydrogenase 1 and 2 Occur Frequently in Intrahepatic Cholangiocarcinomas and Share Hypermethylation Targets with Glioblastomas Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas, and thyroid cancer.	('Intrahepatic Cholangiocarcinomas', 'Disease', (66, 98))	('isocitrate', 'Chemical', 'MESH:C034219', (185, 195))	('gliomas', 'Phenotype', 'HP:0009733', (248, 255))	('thyroid cancer', 'Disease', (297, 311))	('myeloid leukemias', 'Disease', 'MESH:D007951', (257, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('IDH2', 'Gene', (220, 224))	('Glioblastomas', 'Disease', (139, 152))	('IDH2', 'Gene', '3418', (220, 224))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (257, 274))	('chondrosarcomas', 'Disease', (276, 291))	('Glioblastomas', 'Disease', 'MESH:D005909', (139, 152))	('Mutations', 'Var', (153, 162))	('Intrahepatic Cholangiocarcinomas', 'Disease', 'MESH:D018281', (66, 98))	('Mutations', 'Var', (0, 9))	('thyroid cancer', 'Disease', 'MESH:D013964', (297, 311))	('Glioblastomas', 'Phenotype', 'HP:0012174', (139, 152))	('reported', 'Reg', (236, 244))	('gliomas', 'Disease', (248, 255))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('IDH1', 'Gene', (211, 215))	('thyroid cancer', 'Phenotype', 'HP:0002890', (297, 311))	('leukemia', 'Phenotype', 'HP:0001909', (265, 273))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (257, 273))	('Glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('leukemias', 'Phenotype', 'HP:0001909', (265, 274))	('gliomas', 'Disease', 'MESH:D005910', (248, 255))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (276, 291))	('IDH1', 'Gene', '3417', (211, 215))	('glioma', 'Phenotype', 'HP:0009733', (248, 254))	('chondrosarcomas', 'Disease', 'MESH:D002813', (276, 291))	('myeloid leukemias', 'Disease', (257, 274))
106493	22824796	We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas.	('IDH2', 'Gene', (23, 27))	('intrahepatic cholangiocarcinomas', 'Disease', (57, 89))	('IDH2', 'Gene', '3418', (23, 27))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (57, 89))	('IDH1', 'Gene', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))	('mutations', 'Var', (28, 37))	('IDH1', 'Gene', '3417', (14, 18))
106494	22824796	Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine (5hmC) and higher 5-methylcytosine (5mC) levels, as well as increased dimethylation of histone H3K79.	('5-methylcytosine', 'Chemical', 'MESH:D044503', (89, 105))	('mutations', 'Var', (11, 20))	('IDH1', 'Gene', '3417', (24, 28))	('IDH2', 'Gene', (32, 36))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('increased', 'PosReg', (131, 140))	('5mC', 'Chemical', 'MESH:D044503', (107, 110))	('lower', 'NegReg', (41, 46))	('higher', 'PosReg', (82, 88))	('IDH2', 'Gene', '3418', (32, 36))	('dimethylation', 'MPA', (141, 154))	('IDH1', 'Gene', (24, 28))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (47, 70))	('histone H3K79', 'Protein', (158, 171))	('5hmC', 'Chemical', 'MESH:C011865', (72, 76))
106495	22824796	Mutations in IDH1 or IDH2 were associated with longer overall survival (p = 0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (p = 0.021).	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('longer', 'PosReg', (47, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('associated', 'Reg', (106, 116))	('overall survival', 'MPA', (54, 70))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (175, 193))	('IDH1', 'Gene', (13, 17))	('tumor', 'Disease', (139, 144))	('IDH2', 'Gene', (21, 25))	('Mutations', 'Var', (0, 9))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (162, 193))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('intrahepatic cholangiocarcinoma', 'Disease', (162, 193))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (21, 25))
106496	22824796	IDH1 and IDH2 mutations are significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation.	('p53', 'Gene', '7157', (240, 243))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (98, 116))	('IDH1', 'Gene', '3417', (193, 197))	('IDH1', 'Gene', (0, 4))	('p53', 'Gene', '7157', (143, 146))	('p53', 'Gene', (240, 243))	('stress', 'MPA', (219, 225))	('intrahepatic cholangiocarcinomas', 'Disease', (85, 117))	('IDH2', 'Gene', (202, 206))	('p53', 'Gene', '7157', (78, 81))	('IDH2', 'Gene', '3418', (202, 206))	('p53', 'Gene', (143, 146))	('mutations', 'Var', (14, 23))	('IDH1', 'Gene', '3417', (0, 4))	('increased', 'PosReg', (58, 67))	('mutations', 'Var', (180, 189))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (85, 117))	('p53', 'Gene', (78, 81))	('levels', 'MPA', (68, 74))	('cause', 'Reg', (211, 216))	('IDH1', 'Gene', (193, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('IDH2', 'Gene', (9, 13))	('IDH2', 'Gene', '3418', (9, 13))	('activation', 'PosReg', (244, 254))
106497	22824796	We identified 2,309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations.	('mutations', 'Var', (97, 106))	('cholangiocarcinomas', 'Disease', (138, 157))	('IDH2', 'Gene', (118, 122))	('IDH1', 'Gene', '3417', (110, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))	('IDH2', 'Gene', '3418', (118, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (72, 91))	('19 cholangiocarcinomas', 'Disease', (69, 91))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (138, 157))	('19 cholangiocarcinomas', 'Disease', 'MESH:D018281', (69, 91))	('IDH1', 'Gene', (110, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (138, 156))	('cholangiocarcinomas', 'Disease', (72, 91))
106498	22824796	Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors.	('IDH1', 'Gene', '3417', (199, 203))	('IDH2', 'Gene', '3418', (207, 211))	('mutations', 'Var', (186, 195))	('IDH1', 'Gene', (74, 78))	('affected', 'Reg', (174, 182))	('gliobastomas', 'Disease', (86, 98))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('tumors', 'Disease', (234, 240))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('IDH1', 'Gene', '3417', (74, 78))	('expression', 'MPA', (156, 166))	('gliobastomas', 'Disease', 'None', (86, 98))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('IDH1', 'Gene', (199, 203))	('IDH2', 'Gene', (207, 211))
106500	22824796	IDH1 and IDH2 represent the most frequently mutated metabolic genes in human cancer, mutated in more than 75% of low grade gliomas and secondary glioblastoma multiforme (GBM), 20% of acute myeloid leukemia (AML), 56% of chondrosarcomas, over 80% of Ollier disease and Maffucci syndrome, and 10% of melanoma.	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('chondrosarcomas', 'Disease', 'MESH:D002813', (220, 235))	('gliomas', 'Disease', (123, 130))	('mutated', 'Var', (85, 92))	('melanoma', 'Disease', 'MESH:D008545', (298, 306))	('IDH1', 'Gene', (0, 4))	('leukemia', 'Phenotype', 'HP:0001909', (197, 205))	('AML', 'Disease', 'MESH:D015470', (207, 210))	('Maffucci syndrome', 'Disease', 'MESH:D004687', (268, 285))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (183, 205))	('AML', 'Phenotype', 'HP:0004808', (207, 210))	('AML', 'Disease', (207, 210))	('chondrosarcomas', 'Disease', (220, 235))	('Ollier disease', 'Disease', 'MESH:D004687', (249, 263))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (189, 205))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (183, 205))	('Ollier disease', 'Phenotype', 'HP:0500045', (249, 263))	('human', 'Species', '9606', (71, 76))	('IDH1', 'Gene', '3417', (0, 4))	('Ollier disease', 'Disease', (249, 263))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('Maffucci syndrome', 'Disease', (268, 285))	('cancer', 'Disease', (77, 83))	('melanoma', 'Phenotype', 'HP:0002861', (298, 306))	('melanoma', 'Disease', (298, 306))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('glioblastoma multiforme', 'Disease', (145, 168))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (220, 235))	('IDH2', 'Gene', (9, 13))	('glioblastoma', 'Phenotype', 'HP:0012174', (145, 157))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (145, 168))	('IDH2', 'Gene', '3418', (9, 13))	('acute myeloid leukemia', 'Disease', (183, 205))
106501	22824796	Tumor mutations targeting IDH1 and IDH2 cause simultaneous loss and gain of activities in the production of alpha-KG and 2-hydroxyglutarate (2-HG), respectively.	('IDH1', 'Gene', '3417', (26, 30))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('IDH2', 'Gene', '3418', (35, 39))	('activities', 'MPA', (76, 86))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (121, 139))	('IDH1', 'Gene', (26, 30))	('2-HG', 'Chemical', 'MESH:C019417', (141, 145))	('loss', 'NegReg', (59, 63))	('gain', 'PosReg', (68, 72))	('alpha-KG and', 'Chemical', '-', (108, 120))	('mutations', 'Var', (6, 15))	('IDH2', 'Gene', (35, 39))
106503	22824796	Thus, IDH1 and IDH2 mutations would be predicted to alter histone and DNA methylation in both cultured cells and primary gliomas.	('IDH1', 'Gene', '3417', (6, 10))	('histone', 'MPA', (58, 65))	('IDH2', 'Gene', (15, 19))	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('gliomas', 'Disease', (121, 128))	('IDH2', 'Gene', '3418', (15, 19))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('DNA methylation', 'MPA', (70, 85))	('alter', 'Reg', (52, 57))	('IDH1', 'Gene', (6, 10))	('mutations', 'Var', (20, 29))
106504	22824796	This model is supported by the finding that the mutations of IDH1 and IDH2 genes occur in a mutually exclusive manner with that of TET2 gene in acute myeloid leukemias.	('myeloid leukemias', 'Phenotype', 'HP:0012324', (150, 167))	('IDH2', 'Gene', '3418', (70, 74))	('myeloid leukemias', 'Disease', 'MESH:D007951', (150, 167))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (144, 166))	('TET2', 'Gene', (131, 135))	('IDH1', 'Gene', (61, 65))	('myeloid leukemias', 'Disease', (150, 167))	('acute myeloid leukemia', 'Disease', (144, 166))	('leukemias', 'Phenotype', 'HP:0001909', (158, 167))	('IDH1', 'Gene', '3417', (61, 65))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (144, 167))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (144, 166))	('IDH2', 'Gene', (70, 74))	('mutations', 'Var', (48, 57))	('TET2', 'Gene', '54790', (131, 135))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (150, 166))
106506	22824796	Tumors with IDH1 or IDH2 mutations would be predicted to have lower TET enzymatic activity, and thus accumulate DNA methylation.	('mutations', 'Var', (25, 34))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('IDH1', 'Gene', (12, 16))	('IDH2', 'Gene', '3418', (20, 24))	('DNA methylation', 'MPA', (112, 127))	('lower', 'NegReg', (62, 67))	('Tumors', 'Disease', (0, 6))	('accumulate', 'PosReg', (101, 111))	('IDH1', 'Gene', '3417', (12, 16))	('TET enzymatic activity', 'MPA', (68, 90))	('IDH2', 'Gene', (20, 24))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TET', 'Chemical', 'MESH:C010349', (68, 71))
106507	22824796	Indeed, glioblastomas with IDH1 mutations exhibited a CpG Island Methylator Phenotype and belonged to a proneural gene expression class with increased PDGFR gene expression and TP53 mutation.	('glioblastomas', 'Disease', 'MESH:D005909', (8, 21))	('glioblastoma', 'Phenotype', 'HP:0012174', (8, 20))	('TP53', 'Gene', (177, 181))	('glioblastomas', 'Disease', (8, 21))	('increased', 'PosReg', (141, 150))	('mutations', 'Var', (32, 41))	('expression', 'MPA', (162, 172))	('TP53', 'Gene', '7157', (177, 181))	('IDH1', 'Gene', (27, 31))	('glioblastomas', 'Phenotype', 'HP:0012174', (8, 21))	('PDGFR', 'Gene', (151, 156))	('CpG Island Methylator', 'MPA', (54, 75))	('IDH1', 'Gene', '3417', (27, 31))	('PDGFR', 'Gene', '5159', (151, 156))
106508	22824796	These molecular correlates suggest that IDH1 mutations may represent early events in the pathogenesis of low-grade gliomas and secondary glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (137, 150))	('mutations', 'Var', (45, 54))	('gliomas', 'Disease', (115, 122))	('IDH1', 'Gene', (40, 44))	('glioblastomas', 'Disease', 'MESH:D005909', (137, 150))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('IDH1', 'Gene', '3417', (40, 44))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioblastomas', 'Disease', (137, 150))	('glioblastoma', 'Phenotype', 'HP:0012174', (137, 149))
106509	22824796	The CpG Island Methylator Phenotype was originally described in colorectal cancer, and has subsequently been associated with mutations in BRAF.	('mutations', 'Var', (125, 134))	('associated', 'Reg', (109, 119))	('described', 'Reg', (51, 60))	('colorectal cancer', 'Disease', (64, 81))	('BRAF', 'Gene', '673', (138, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('BRAF', 'Gene', (138, 142))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))
106510	22824796	Promoter hypermethylation and concomitant silencing of tumor suppressor genes - such as p16, MLH1 and BRCA1 - can accelerate tumor progression.	('BRCA1', 'Gene', (102, 107))	('p16', 'Gene', (88, 91))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (125, 130))	('p16', 'Gene', '1029', (88, 91))	('accelerate', 'PosReg', (114, 124))	('MLH1', 'Gene', '4292', (93, 97))	('BRCA1', 'Gene', '672', (102, 107))	('MLH1', 'Gene', (93, 97))	('silencing', 'NegReg', (42, 51))	('Promoter hypermethylation', 'Var', (0, 25))
106513	22824796	We have discovered that intrahepatic cholangiocarcinoma represents an additional human cancer with frequent mutations in IDH1 and IDH2.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (24, 55))	('cancer', 'Disease', (87, 93))	('IDH1', 'Gene', (121, 125))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (37, 55))	('intrahepatic cholangiocarcinoma', 'Disease', (24, 55))	('mutations', 'Var', (108, 117))	('IDH1', 'Gene', '3417', (121, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('IDH2', 'Gene', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('human', 'Species', '9606', (81, 86))	('IDH2', 'Gene', '3418', (130, 134))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
106515	22824796	Mutations in a handful of candidate genes - including KRAS, BRAF, EGFR, TP53, PIK3CA, and SMAD4 - have been surveyed in cholangiocarcinomas, with varying mutation frequencies in different anatomical regions of the bile duct.	('PIK3CA', 'Gene', (78, 84))	('EGFR', 'Gene', '1956', (66, 70))	('BRAF', 'Gene', (60, 64))	('EGFR', 'Gene', (66, 70))	('BRAF', 'Gene', '673', (60, 64))	('TP53', 'Gene', '7157', (72, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('surveyed', 'Reg', (108, 116))	('PIK3CA', 'Gene', '5290', (78, 84))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (120, 139))	('TP53', 'Gene', (72, 76))	('KRAS', 'Gene', (54, 58))	('Mutations', 'Var', (0, 9))	('SMAD4', 'Gene', '4089', (90, 95))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (120, 138))	('KRAS', 'Gene', '3845', (54, 58))	('cholangiocarcinomas', 'Disease', (120, 139))	('SMAD4', 'Gene', (90, 95))
106516	22824796	In this study, we elucidated the consequences of IDH1 and IDH2 mutations on DNA methylation and gene expression in intrahepatic cholangiocarcinomas and glioblastomas.	('mutations', 'Var', (63, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (128, 146))	('IDH1', 'Gene', '3417', (49, 53))	('IDH2', 'Gene', '3418', (58, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (152, 164))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (115, 147))	('intrahepatic cholangiocarcinomas', 'Disease', (115, 147))	('cholangiocarcinomas and glioblastomas', 'Disease', 'MESH:D005909', (128, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('gene expression', 'MPA', (96, 111))	('glioblastomas', 'Phenotype', 'HP:0012174', (152, 165))	('IDH2', 'Gene', (58, 62))	('IDH1', 'Gene', (49, 53))
106520	22824796	There were 19 predicted mutations, including an Arg132Cys mutation in the hotspot codon of IDH1 and a Pro261Arg mutation in RAF1.	('Pro261Arg', 'Var', (102, 111))	('IDH1', 'Gene', (91, 95))	('Arg132Cys', 'Var', (48, 57))	('RAF1', 'Gene', '5894', (124, 128))	('IDH1', 'Gene', '3417', (91, 95))	('Arg132Cys', 'SUBSTITUTION', 'None', (48, 57))	('RAF1', 'Gene', (124, 128))	('Pro261Arg', 'SUBSTITUTION', 'None', (102, 111))
106521	22824796	We estimated the prevalence of IDH1 and IDH2 mutations by sequencing exon 4 of both genes in 325 additional intrahepatic cholangiocarcinomas.	('mutations', 'Var', (45, 54))	('IDH2', 'Gene', (40, 44))	('intrahepatic cholangiocarcinomas', 'Disease', (108, 140))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (108, 140))	('IDH1', 'Gene', '3417', (31, 35))	('IDH2', 'Gene', '3418', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))	('IDH1', 'Gene', (31, 35))
106522	22824796	We found 22 additional mutations in IDH1 and 11 mutations in IDH2, for a combined frequency of 10% (Table 1).	('IDH1', 'Gene', (36, 40))	('IDH2', 'Gene', (61, 65))	('mutations', 'Var', (23, 32))	('IDH1', 'Gene', '3417', (36, 40))	('IDH2', 'Gene', '3418', (61, 65))
106524	22824796	Notably, 32 of 33 mutations occurred in either the hotspot codon Arg132 of IDH1, or the analogous codon Arg172 of IDH2, which mediates a conformational switch in the enzyme.	('IDH2', 'Gene', (114, 118))	('occurred', 'Reg', (28, 36))	('Arg172', 'Chemical', '-', (104, 110))	('IDH2', 'Gene', '3418', (114, 118))	('IDH1', 'Gene', (75, 79))	('Arg132', 'Chemical', '-', (65, 71))	('IDH1', 'Gene', '3417', (75, 79))	('mutations', 'Var', (18, 27))
106525	22824796	One patient had a novel Ile99Met mutation in IDH1.	('Ile99Met', 'Var', (24, 32))	('IDH1', 'Gene', '3417', (45, 49))	('patient', 'Species', '9606', (4, 11))	('Ile99Met', 'Mutation', 'rs142883642', (24, 32))	('IDH1', 'Gene', (45, 49))
106526	22824796	This mutation was associated with 44% lower catalysis of isocitrate to alpha-KG in vitro, but did not gain the ability to produce 2-HG (Supplementary Figure 1).	('lower', 'NegReg', (38, 43))	('catalysis of isocitrate to alpha-KG', 'MPA', (44, 79))	('alpha-KG', 'Chemical', 'MESH:D007656', (71, 79))	('isocitrate', 'Chemical', 'MESH:C034219', (57, 67))	('mutation', 'Var', (5, 13))	('2-HG', 'Chemical', 'MESH:C019417', (130, 134))
106529	22824796	In the Fudan cohort of 252 patients with follow-up data, the presence of IDH1 or IDH2 mutation was associated with a longer time to recurrence (p = 0.046) (Figure 1A).	('IDH1', 'Gene', '3417', (73, 77))	('IDH2', 'Gene', (81, 85))	('patients', 'Species', '9606', (27, 35))	('presence', 'Var', (61, 69))	('mutation', 'Var', (86, 94))	('IDH2', 'Gene', '3418', (81, 85))	('IDH1', 'Gene', (73, 77))
106530	22824796	The probabilities of tumor recurrence at 1, 4 and 7 years in patients with mutated IDH1 or IDH2 intrahepatic cholangiocarcinomas (10.5%, 45.3% and 45.3%, respectively) were significantly lower than those with wild-type IDH1 or IDH2 (41.7%, 71.5% and 81.3%, respectively).	('IDH2', 'Gene', '3418', (227, 231))	('IDH1', 'Gene', '3417', (219, 223))	('IDH1', 'Gene', '3417', (83, 87))	('IDH2 intrahepatic cholangiocarcinomas', 'Disease', (91, 128))	('tumor', 'Disease', (21, 26))	('IDH2 intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (91, 128))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('IDH2', 'Gene', (91, 95))	('patients', 'Species', '9606', (61, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('mutated', 'Var', (75, 82))	('IDH2', 'Gene', '3418', (91, 95))	('lower', 'NegReg', (187, 192))	('IDH2', 'Gene', (227, 231))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('IDH1', 'Gene', (219, 223))	('IDH1', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
106531	22824796	The subset of patients with IDH2 mutations had marginally longer time to recurrence (p = 0.042, Supplementary Figure 2).	('IDH2', 'Gene', '3418', (28, 32))	('mutations', 'Var', (33, 42))	('longer', 'PosReg', (58, 64))	('IDH2', 'Gene', (28, 32))	('patients', 'Species', '9606', (14, 22))
106532	22824796	In the combined patient cohort, the presence of IDH1 or IDH2 mutation was associated with a longer overall survival (p = 0.028) (Figure 1B).	('IDH2', 'Gene', '3418', (56, 60))	('IDH1', 'Gene', '3417', (48, 52))	('presence', 'Var', (36, 44))	('mutation', 'Var', (61, 69))	('overall survival', 'MPA', (99, 115))	('IDH1', 'Gene', (48, 52))	('IDH2', 'Gene', (56, 60))	('patient', 'Species', '9606', (16, 23))	('longer', 'PosReg', (92, 98))
106533	22824796	In univariate Cox regression analysis, IDH1/2 mutation was significantly associated with time to recurrence (HR=0.512, 95% CI=0.273-0.960, p=0.037).	('time', 'MPA', (89, 93))	('IDH1/2', 'Gene', (39, 45))	('associated', 'Reg', (73, 83))	('Cox', 'Gene', (14, 17))	('Cox', 'Gene', '1351', (14, 17))	('IDH1/2', 'Gene', '3417;3418', (39, 45))	('mutation', 'Var', (46, 54))
106535	22824796	In multivariate analyses, the prognostic values of IDH1/2 mutation for time to recurrence was independent of all other clinical variables tested (HR=0.477, 95% CI=0.254-0.894, p=0.021) (Table 2).	('mutation', 'Var', (58, 66))	('IDH1/2', 'Gene', (51, 57))	('IDH1/2', 'Gene', '3417;3418', (51, 57))
106536	22824796	Reduction of alpha-KG and accumulation of 2-HG resulting from mutations in IDH1 potentially impair the activity of multiple alpha-KG-dependent dioxygenases, including both the TET family of DNA dioxygenases, and histone lysine demethylases.	('accumulation', 'PosReg', (26, 38))	('activity', 'MPA', (103, 111))	('alpha-KG', 'Chemical', 'MESH:D007656', (124, 132))	('alpha-KG-dependent dioxygenases', 'Enzyme', (124, 155))	('alpha-KG', 'Chemical', 'MESH:D007656', (13, 21))	('alpha-KG and', 'Chemical', '-', (13, 25))	('TET family of DNA dioxygenases', 'Enzyme', (176, 206))	('2-HG', 'Chemical', 'MESH:C019417', (42, 46))	('IDH1', 'Gene', (75, 79))	('histone lysine demethylases', 'Enzyme', (212, 239))	('TET', 'Chemical', 'MESH:C010349', (176, 179))	('Reduction', 'NegReg', (0, 9))	('IDH1', 'Gene', '3417', (75, 79))	('mutations', 'Var', (62, 71))	('lysine', 'Chemical', 'MESH:D008239', (220, 226))	('impair', 'NegReg', (92, 98))
106537	22824796	We analyzed 5hmC and 5mC by immunohistochemistry (IHC) in a panel of 36 intrahepatic cholangiocarcinomas: 19 tumors harboring a mutation in either IDH1 or IDH2, and 17 tumors of similar grade but with wild-type IDH1 and IDH2.	('tumors', 'Disease', (168, 174))	('IDH2', 'Gene', (220, 224))	('5mC', 'Chemical', 'MESH:D044503', (21, 24))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (72, 104))	('IDH2', 'Gene', '3418', (220, 224))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mutation', 'Var', (128, 136))	('tumors', 'Disease', (109, 115))	('IDH2', 'Gene', (155, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('IDH2', 'Gene', '3418', (155, 159))	('IDH1', 'Gene', (211, 215))	('IDH1', 'Gene', (147, 151))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('5hmC', 'Chemical', 'MESH:C011865', (12, 16))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('IDH1', 'Gene', '3417', (211, 215))	('intrahepatic cholangiocarcinomas', 'Disease', (72, 104))	('IDH1', 'Gene', '3417', (147, 151))
106538	22824796	Intrahepatic cholangiocarcinoma samples harboring mutant IDH1/2 accumulated significantly lower 5hmC than those containing wild-type IDH1/2.	('Intrahepatic cholangiocarcinoma', 'Disease', (0, 31))	('IDH1/2', 'Gene', (57, 63))	('Intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 31))	('5hmC', 'MPA', (96, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('lower', 'NegReg', (90, 95))	('IDH1/2', 'Gene', (133, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (13, 31))	('mutant', 'Var', (50, 56))	('IDH1/2', 'Gene', '3417;3418', (57, 63))	('5hmC', 'Chemical', 'MESH:C011865', (96, 100))	('IDH1/2', 'Gene', '3417;3418', (133, 139))
106540	22824796	In contrast, cholangiocarcinomas with IDH1 or IDH2 mutations accumulated significantly higher 5mC than those containing wild-type IDH1 or IDH2.	('IDH2', 'Gene', '3418', (138, 142))	('IDH1', 'Gene', '3417', (38, 42))	('mutations', 'Var', (51, 60))	('IDH2', 'Gene', (46, 50))	('5mC', 'Chemical', 'MESH:D044503', (94, 97))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (13, 32))	('IDH2', 'Gene', '3418', (46, 50))	('IDH1', 'Gene', (130, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (13, 31))	('5mC', 'MPA', (94, 97))	('IDH1', 'Gene', (38, 42))	('cholangiocarcinomas', 'Disease', (13, 32))	('IDH2', 'Gene', (138, 142))	('IDH1', 'Gene', '3417', (130, 134))	('higher', 'PosReg', (87, 93))
106541	22824796	The average relative intensity of 5mC was 21.88 +- 7.39% in cholangiocarcinomas with wild-type and increased to 60.39 +- 8.39% (p=0.002) in cholangiocarcinomas harboring a mutant IDH1 or IDH2 (Figure 2B).	('mutant', 'Var', (172, 178))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (140, 159))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (60, 79))	('IDH2', 'Gene', '3418', (187, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (60, 78))	('cholangiocarcinomas', 'Disease', (60, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (140, 158))	('IDH1', 'Gene', (179, 183))	('cholangiocarcinomas', 'Disease', (140, 159))	('increased', 'PosReg', (99, 108))	('5mC', 'Chemical', 'MESH:D044503', (34, 37))	('IDH1', 'Gene', '3417', (179, 183))	('IDH2', 'Gene', (187, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
106542	22824796	These results in cholangiocarcinomas corroborate the previous findings in gliomablastoma that mutation of IDH1 inhibits the activity of the TET family of DNA dioxygenases, resulting in a decrease of cytosine hydroxymethylation with a concurrent increase of DNA methylation.	('TET', 'Chemical', 'MESH:C010349', (140, 143))	('gliomablastoma', 'Disease', 'None', (74, 88))	('increase', 'PosReg', (245, 253))	('inhibits', 'NegReg', (111, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('IDH1', 'Gene', '3417', (106, 110))	('decrease', 'NegReg', (187, 195))	('TET family of DNA dioxygenases', 'Enzyme', (140, 170))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (17, 35))	('cytosine', 'Chemical', 'MESH:D003596', (199, 207))	('cytosine hydroxymethylation', 'MPA', (199, 226))	('activity', 'MPA', (124, 132))	('gliomablastoma', 'Disease', (74, 88))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (17, 36))	('IDH1', 'Gene', (106, 110))	('DNA methylation', 'MPA', (257, 272))	('cholangiocarcinomas', 'Disease', (17, 36))	('mutation', 'Var', (94, 102))
106544	22824796	H3K79 dimethylation levels were significantly elevated in cholangiocarcinoma samples that harbor IDH1 or IDH2 mutation (80.79 +- 4.23%) compared to tumors with wild-type IDH1 and IDH2 (45.00 +- 7.11%, p = 0.0003, Figure 2C).	('IDH1', 'Gene', (97, 101))	('IDH1', 'Gene', '3417', (170, 174))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cholangiocarcinoma', 'Disease', (58, 76))	('IDH1', 'Gene', '3417', (97, 101))	('IDH2', 'Gene', (179, 183))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 76))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('IDH2', 'Gene', '3418', (179, 183))	('IDH2', 'Gene', (105, 109))	('IDH2', 'Gene', '3418', (105, 109))	('mutation', 'Var', (110, 118))	('tumors', 'Disease', (148, 154))	('H3K79', 'Protein', (0, 5))	('elevated', 'PosReg', (46, 54))	('IDH1', 'Gene', (170, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('tumors', 'Disease', 'MESH:D009369', (148, 154))
106545	22824796	These results indicate that mutations of IDH1/2 genes in cholangiocarcinomas caused an inhibition of histone demethylases.	('inhibition', 'NegReg', (87, 97))	('histone', 'Protein', (101, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('IDH1/2', 'Gene', '3417;3418', (41, 47))	('cholangiocarcinomas', 'Disease', (57, 76))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (57, 76))	('IDH1/2', 'Gene', (41, 47))	('mutations', 'Var', (28, 37))
106547	22824796	We found that tumors with IDH1 or IDH2 mutations also exhibited a trend towards higher levels of HIF-1alpha, but the significance of this increase is unclear (p = 0.151, data not shown).	('HIF-1alpha', 'Gene', '3091', (97, 107))	('levels', 'MPA', (87, 93))	('IDH1', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('mutations', 'Var', (39, 48))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('HIF-1alpha', 'Gene', (97, 107))	('IDH2', 'Gene', (34, 38))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('IDH1', 'Gene', '3417', (26, 30))	('higher', 'PosReg', (80, 86))	('IDH2', 'Gene', '3418', (34, 38))
106548	22824796	The cellular effects of, and pathways affected by, mutations in IDH1 and IDH2 remain poorly defined.	('mutations', 'Var', (51, 60))	('IDH1', 'Gene', (64, 68))	('IDH1', 'Gene', '3417', (64, 68))	('IDH2', 'Gene', (73, 77))	('IDH2', 'Gene', '3418', (73, 77))
106549	22824796	IDH1 mutations significantly co-occur with TP53 mutations in over 60% of low-grade astrocytomas, but the mechanism for this enrichment is unclear.	('TP53', 'Gene', '7157', (43, 47))	('astrocytomas', 'Disease', 'MESH:D001254', (83, 95))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('astrocytomas', 'Disease', (83, 95))	('co-occur', 'Reg', (29, 37))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))	('IDH1', 'Gene', '3417', (0, 4))
106550	22824796	A pathology study of multiple biopsies from the same patient has found that IDH1 mutation occurred before the acquisition of p53 mutation and 1p/19q loss of heterozygosity (LOH), suggesting the possibility that IDH1/2 mutation may cause a cellular stress that leads to the activation of p53 and thus increases the pressure to inactivate p53 for glioma development.	('glioma', 'Disease', (345, 351))	('p53', 'Gene', (337, 340))	('activation', 'PosReg', (273, 283))	('IDH1', 'Gene', '3417', (76, 80))	('glioma', 'Disease', 'MESH:D005910', (345, 351))	('p53', 'Gene', '7157', (287, 290))	('cellular', 'MPA', (239, 247))	('mutation', 'Var', (218, 226))	('glioma', 'Phenotype', 'HP:0009733', (345, 351))	('IDH1/2', 'Gene', '3417;3418', (211, 217))	('p53', 'Gene', (287, 290))	('patient', 'Species', '9606', (53, 60))	('IDH1/2', 'Gene', (211, 217))	('IDH1', 'Gene', (211, 215))	('pressure', 'MPA', (314, 322))	('p53', 'Gene', '7157', (125, 128))	('IDH1', 'Gene', (76, 80))	('p53', 'Gene', '7157', (337, 340))	('increases', 'PosReg', (300, 309))	('p53', 'Gene', (125, 128))	('IDH1', 'Gene', '3417', (211, 215))	('cause', 'Reg', (231, 236))
106553	22824796	Thirteen of 19 (68.4%) cholangiocarcinomas with IDH1 or IDH2 mutations were p53-positive, whereas only 28 of 78 (35.9%) cholangiocarcinomas without IDH1 or IDH2 mutations were p53-positive (p = 0.01).	('IDH2', 'Gene', '3418', (56, 60))	('p53', 'Gene', (76, 79))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (120, 139))	('p53', 'Gene', '7157', (176, 179))	('IDH1', 'Gene', (48, 52))	('cholangiocarcinomas', 'Disease', (120, 139))	('IDH2', 'Gene', (156, 160))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (23, 42))	('p53', 'Gene', (176, 179))	('IDH2', 'Gene', '3418', (156, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (120, 138))	('cholangiocarcinomas', 'Disease', (23, 42))	('IDH1', 'Gene', (148, 152))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (23, 41))	('IDH1', 'Gene', '3417', (48, 52))	('mutations', 'Var', (61, 70))	('IDH1', 'Gene', '3417', (148, 152))	('p53', 'Gene', '7157', (76, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('IDH2', 'Gene', (56, 60))
106554	22824796	In addition, the percent of tumor nuclei with p53 staining was higher among tumors with IDH1 or IDH2 mutations.	('IDH2', 'Gene', '3418', (96, 100))	('mutations', 'Var', (101, 110))	('tumor', 'Disease', (28, 33))	('IDH1', 'Gene', (88, 92))	('p53', 'Gene', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('p53', 'Gene', '7157', (46, 49))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('IDH2', 'Gene', (96, 100))	('IDH1', 'Gene', '3417', (88, 92))	('higher', 'PosReg', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
106555	22824796	p53 expression levels were significantly elevated in cholangiocarcinoma samples that harbor IDH1 or IDH2 mutation (49.63 +- 9.45%) compared to tumors with wild-type IDH1 or IDH2 (20.40 +- 3.98%, p = 0.002, Figure 2D).	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('IDH2', 'Gene', (100, 104))	('IDH2', 'Gene', '3418', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('p53', 'Gene', '7157', (0, 3))	('mutation', 'Var', (105, 113))	('IDH2', 'Gene', (173, 177))	('tumors', 'Disease', (143, 149))	('elevated', 'PosReg', (41, 49))	('IDH1', 'Gene', (165, 169))	('IDH2', 'Gene', '3418', (173, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('expression levels', 'MPA', (4, 21))	('p53', 'Gene', (0, 3))	('IDH1', 'Gene', (92, 96))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('IDH1', 'Gene', '3417', (165, 169))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (53, 71))	('IDH1', 'Gene', '3417', (92, 96))	('cholangiocarcinoma', 'Disease', (53, 71))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (53, 71))
106556	22824796	We next determine by direct DNA sequencing whether accumulation of p53 protein levels is associated with mutation in p53 gene as often observed in other type of tumors.	('mutation', 'Var', (105, 113))	('p53', 'Gene', (117, 120))	('tumors', 'Disease', (161, 167))	('p53', 'Gene', '7157', (117, 120))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('p53', 'Gene', (67, 70))	('accumulation', 'PosReg', (51, 63))	('p53', 'Gene', '7157', (67, 70))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))
106557	22824796	Unexpectedly, we found only one mutation in p53 (codon 06-585) in 13 cholangiocarcinoma samples with either IDH1 or IDH2 mutation.	('IDH1', 'Gene', '3417', (108, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('IDH2', 'Gene', (116, 120))	('cholangiocarcinoma', 'Disease', (69, 87))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('mutation', 'Var', (121, 129))	('IDH2', 'Gene', '3418', (116, 120))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (69, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (69, 87))	('IDH1', 'Gene', (108, 112))	('codon 06-585', 'Var', (49, 61))
106558	22824796	In contrast, we found that p53 was mutated in 7 of 11 cholangiocarcinoma samples with with-type IDH1 and IDH2 (Supplementary Table 2).	('mutated', 'Var', (35, 42))	('IDH1', 'Gene', '3417', (96, 100))	('IDH2', 'Gene', (105, 109))	('p53', 'Gene', '7157', (27, 30))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (54, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('IDH2', 'Gene', '3418', (105, 109))	('cholangiocarcinoma', 'Disease', (54, 72))	('IDH1', 'Gene', (96, 100))	('p53', 'Gene', (27, 30))
106559	22824796	These results indicate that in cholangiocarcinoma, IDH1 and IDH2 mutation are associated with increased p53 protein levels, but not p53 gene mutation.	('IDH1', 'Gene', '3417', (51, 55))	('p53', 'Gene', (104, 107))	('IDH2', 'Gene', (60, 64))	('p53', 'Gene', (132, 135))	('cholangiocarcinoma', 'Disease', (31, 49))	('increased', 'PosReg', (94, 103))	('p53', 'Gene', '7157', (104, 107))	('p53', 'Gene', '7157', (132, 135))	('IDH2', 'Gene', '3418', (60, 64))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (31, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('mutation', 'Var', (65, 73))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (31, 49))	('IDH1', 'Gene', (51, 55))
106560	22824796	In order to localize increased DNA methylation in cholangiocarcinomas with IDH1 or IDH2 mutations, we surveyed over 462,000 CpG sites in CpG islands, CpG shores and intragenic regions with the Illumina HumanMethylation450 Beadchip.	('increased', 'PosReg', (21, 30))	('IDH2', 'Gene', '3418', (83, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (50, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('Human', 'Species', '9606', (202, 207))	('mutations', 'Var', (88, 97))	('IDH1', 'Gene', (75, 79))	('cholangiocarcinomas', 'Disease', (50, 69))	('IDH1', 'Gene', '3417', (75, 79))	('IDH2', 'Gene', (83, 87))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (50, 69))
106561	22824796	We profiled DNA methylation for 19 cholangiocarcinomas with mutations in IDH1 or IDH2, as well as 31 cholangiocarcinomas without mutations in these two genes.	('19 cholangiocarcinomas', 'Disease', (32, 54))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('cholangiocarcinomas', 'Disease', (35, 54))	('19 cholangiocarcinomas', 'Disease', 'MESH:D018281', (32, 54))	('IDH1', 'Gene', '3417', (73, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('mutations', 'Var', (60, 69))	('IDH2', 'Gene', (81, 85))	('cholangiocarcinomas', 'Disease', (101, 120))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (35, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('IDH2', 'Gene', '3418', (81, 85))	('IDH1', 'Gene', (73, 77))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (101, 120))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (35, 53))
106562	22824796	Consensus K-means clustering of the 5,000 most informative CpG assays yielded two classes, with 18 of 19 IDH1 or IDH2 mutants segregating in one class (Fisher exact p < 4 x 10-7; Figure 3A).	('IDH2', 'Gene', (113, 117))	('IDH1', 'Gene', (105, 109))	('mutants', 'Var', (118, 125))	('IDH2', 'Gene', '3418', (113, 117))	('IDH1', 'Gene', '3417', (105, 109))	('segregating', 'Reg', (126, 137))
106563	22824796	There were 7 additional cholangiocarcinomas without mutations in IDH1 or IDH2 that clustered with the hypermethylated samples.	('mutations', 'Var', (52, 61))	('IDH1', 'Gene', '3417', (65, 69))	('additional cholangiocarcinomas', 'Disease', (13, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('additional cholangiocarcinomas', 'Disease', 'MESH:D018281', (13, 43))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (24, 42))	('IDH2', 'Gene', (73, 77))	('IDH1', 'Gene', (65, 69))	('IDH2', 'Gene', '3418', (73, 77))
106564	22824796	We used standard t-tests to identify differentially methylated regions between 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with 31 cholangiocarcinomas without mutations in these genes.	('cholangiocarcinomas', 'Disease', (151, 170))	('IDH2', 'Gene', '3418', (128, 132))	('mutations', 'Var', (107, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (82, 101))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (151, 170))	('19 cholangiocarcinomas', 'Disease', 'MESH:D018281', (79, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (82, 100))	('IDH1', 'Gene', (120, 124))	('19 cholangiocarcinomas', 'Disease', (79, 101))	('cholangiocarcinomas', 'Disease', (82, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (151, 169))	('IDH1', 'Gene', '3417', (120, 124))	('IDH2', 'Gene', (128, 132))
106566	22824796	Taken together, these annotations suggest that hypermethylated CpG sites in cholangiocarcinomas may modulate gene expression.	('cholangiocarcinomas', 'Disease', (76, 95))	('gene expression', 'MPA', (109, 124))	('hypermethylated', 'Var', (47, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (76, 95))	('modulate', 'Reg', (100, 108))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (76, 94))
106568	22824796	We compared global gene expression profiles between 7 cholangiocarcinomas with IDH1 or IDH2 mutations and 20 tumors without these mutations.	('IDH1', 'Gene', '3417', (79, 83))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (54, 73))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('cholangiocarcinomas', 'Disease', (54, 73))	('mutations', 'Var', (92, 101))	('IDH2', 'Gene', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('IDH1', 'Gene', (79, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('tumors', 'Disease', (109, 115))	('IDH2', 'Gene', '3418', (87, 91))
106569	22824796	Among the 2,309 genes with increased methylation in tumors with IDH1 or IDH2 mutations, 29 genes had a >=3-fold increase in gene expression and 99 genes had >=3-fold reduction in gene expression (Figure 4A).	('IDH2', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('increased', 'PosReg', (27, 36))	('reduction', 'NegReg', (166, 175))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('methylation', 'Var', (37, 48))	('IDH2', 'Gene', '3418', (72, 76))	('IDH1', 'Gene', (64, 68))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('increase', 'PosReg', (112, 120))	('mutations', 'Var', (77, 86))	('gene expression', 'MPA', (179, 194))	('IDH1', 'Gene', '3417', (64, 68))	('gene expression', 'MPA', (124, 139))
106570	22824796	Genes with both elevated DNA methylation and reduced gene expression could represent potential direct targets of IDH1 and IDH2 mutations.	('reduced', 'NegReg', (45, 52))	('IDH1', 'Gene', (113, 117))	('elevated', 'PosReg', (16, 24))	('IDH2', 'Gene', (122, 126))	('IDH1', 'Gene', '3417', (113, 117))	('DNA methylation', 'MPA', (25, 40))	('IDH2', 'Gene', '3418', (122, 126))	('mutations', 'Var', (127, 136))	('gene expression', 'MPA', (53, 68))
106571	22824796	We used Gene Set Enrichment Analysis to compare the global gene expression profiles of the IDH1/2 mutant and IDH1/2-wild-type cholangiocarcinomas.	('IDH1/2', 'Gene', (109, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('IDH1/2', 'Gene', (91, 97))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (126, 145))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (126, 144))	('cholangiocarcinomas', 'Disease', (126, 145))	('mutant', 'Var', (98, 104))	('IDH1/2', 'Gene', '3417;3418', (91, 97))	('IDH1/2', 'Gene', '3417;3418', (109, 115))
106572	22824796	Notably, 4 overlapping gene sets implicated upregulation of the FGFR signaling pathway, and the FGFR2, FGFR3 and FGFR4 receptor tyrosine kinases were overexpressed at least 3-fold among tumors with IDH1 or IDH2 mutations (FDR q-value = 0.054; Fig.	('FGFR', 'Gene', (64, 68))	('FGFR3', 'Gene', '2261', (103, 108))	('FGFR', 'Gene', (103, 107))	('FGFR', 'Gene', '2263;2261;2264', (113, 117))	('FGFR4', 'Gene', '2264', (113, 118))	('FGFR', 'Gene', '2263;2261;2264', (96, 100))	('IDH1', 'Gene', (198, 202))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('FGFR', 'Gene', '2263;2261;2264', (64, 68))	('FGFR4', 'Gene', (113, 118))	('FGFR2', 'Gene', (96, 101))	('FGFR', 'Gene', '2263;2261;2264', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('upregulation', 'PosReg', (44, 56))	('IDH1', 'Gene', '3417', (198, 202))	('tumors', 'Disease', (186, 192))	('overexpressed', 'PosReg', (150, 163))	('FGFR', 'Gene', (113, 117))	('FGFR2', 'Gene', '2263', (96, 101))	('FGFR', 'Gene', (96, 100))	('mutations', 'Var', (211, 220))	('FGFR3', 'Gene', (103, 108))	('IDH2', 'Gene', (206, 210))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('IDH2', 'Gene', '3418', (206, 210))
106573	22824796	Carboxylic acid transporters, epigenetic regulators and cell proliferation gene sets were downregulated among the cholangiocarcinomas with IDH1 or IDH2 mutations (Supplementary Figure 4).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (114, 132))	('IDH1', 'Gene', (139, 143))	('cholangiocarcinomas', 'Disease', (114, 133))	('mutations', 'Var', (152, 161))	('cell proliferation gene sets', 'Gene', (56, 84))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (114, 133))	('epigenetic regulators', 'MPA', (30, 51))	('downregulated', 'NegReg', (90, 103))	('IDH2', 'Gene', (147, 151))	('IDH2', 'Gene', '3418', (147, 151))	('IDH1', 'Gene', '3417', (139, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('Carboxylic acid transporters', 'MPA', (0, 28))
106576	22824796	We sought to assess whether IDH1 mutations instigate DNA methylation of similar genomic regions, when the mutations occur in the context of different tissue types.	('IDH1', 'Gene', '3417', (28, 32))	('mutations', 'Var', (33, 42))	('instigate', 'Reg', (43, 52))	('DNA methylation', 'MPA', (53, 68))	('IDH1', 'Gene', (28, 32))
106577	22824796	We profiled DNA methylation of 26 glioblastomas with IDH1 mutations, as well as 36 glioblastomas without mutations.	('mutations', 'Var', (58, 67))	('glioblastomas', 'Phenotype', 'HP:0012174', (34, 47))	('IDH1', 'Gene', (53, 57))	('glioblastomas', 'Phenotype', 'HP:0012174', (83, 96))	('glioblastomas', 'Disease', 'MESH:D005909', (34, 47))	('IDH1', 'Gene', '3417', (53, 57))	('glioblastomas', 'Disease', 'MESH:D005909', (83, 96))	('glioblastomas', 'Disease', (34, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (34, 46))	('glioblastomas', 'Disease', (83, 96))	('glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))
106578	22824796	We identified 47,291 hypermethylated CpG sites among 9,394 genes that were associated with IDH1 mutations, at a False Discovery Rate of 1% and a change in methylation beta-value greater than 0.20.	('associated', 'Reg', (75, 85))	('IDH1', 'Gene', '3417', (91, 95))	('mutations', 'Var', (96, 105))	('IDH1', 'Gene', (91, 95))
106582	22824796	Assuming that methylation is associated with gene silencing, these annotations suggest that IDH1-mediated DNA hypermethylation counteracts neuronal differentiation in glioblastomas, and provides further evidence for the model that IDH1 mutations may occur in a neural progenitor cell of origin.	('glioblastomas', 'Phenotype', 'HP:0012174', (167, 180))	('IDH1', 'Gene', (231, 235))	('glioblastomas', 'Disease', 'MESH:D005909', (167, 180))	('IDH1', 'Gene', (92, 96))	('glioblastomas', 'Disease', (167, 180))	('IDH1', 'Gene', '3417', (92, 96))	('IDH1', 'Gene', '3417', (231, 235))	('mutations', 'Var', (236, 245))	('glioblastoma', 'Phenotype', 'HP:0012174', (167, 179))
106583	22824796	We identified the overlap of hypermethylated CpG sites in cholangiocarcinomas or glioblastomas with mutations in IDH1 or IDH2, compared to the same tumor types without mutations.	('mutations', 'Var', (100, 109))	('glioblastomas', 'Phenotype', 'HP:0012174', (81, 94))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('IDH2', 'Gene', '3418', (121, 125))	('IDH1', 'Gene', (113, 117))	('tumor', 'Disease', (148, 153))	('IDH1', 'Gene', '3417', (113, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('cholangiocarcinomas or glioblastomas', 'Disease', (58, 94))	('cholangiocarcinomas or glioblastomas', 'Disease', 'MESH:D005909', (58, 94))	('glioblastoma', 'Phenotype', 'HP:0012174', (81, 93))	('IDH2', 'Gene', (121, 125))
106585	22824796	We integrated the list of hypermethylated genes from methylation arrays with two external gene expression datasets with known IDH1 mutation status: a set of 71 proneural glioblastomas and a set of 27 cholangiocarcinomas.	('IDH1', 'Gene', '3417', (126, 130))	('glioblastomas', 'Disease', (170, 183))	('cholangiocarcinomas', 'Disease', (200, 219))	('glioblastoma', 'Phenotype', 'HP:0012174', (170, 182))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (200, 218))	('IDH1', 'Gene', (126, 130))	('glioblastomas', 'Phenotype', 'HP:0012174', (170, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (200, 219))	('glioblastomas', 'Disease', 'MESH:D005909', (170, 183))	('mutation', 'Var', (131, 139))
106586	22824796	We hypothesized that IDH1 or IDH2 mutations would have similar effects on methylation and gene expression across different patient cohorts.	('IDH2', 'Gene', (29, 33))	('effects', 'Reg', (63, 70))	('patient', 'Species', '9606', (123, 130))	('IDH2', 'Gene', '3418', (29, 33))	('gene expression', 'MPA', (90, 105))	('IDH1', 'Gene', (21, 25))	('methylation', 'MPA', (74, 85))	('IDH1', 'Gene', '3417', (21, 25))	('mutations', 'Var', (34, 43))
106588	22824796	Among the 867 genes that were represented on both microarray platforms, we found 129 genes (15%) with at least two-fold decrease in gene expression among cholangiocarcinomas with IDH1 or IDH2 mutations, and 43 genes (5%) with at least 2-fold decrease among glioblastomas with IDH1 mutations.	('mutations', 'Var', (192, 201))	('IDH1', 'Gene', (276, 280))	('IDH2', 'Gene', '3418', (187, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (154, 173))	('IDH1', 'Gene', '3417', (276, 280))	('decrease', 'NegReg', (120, 128))	('glioblastomas', 'Phenotype', 'HP:0012174', (257, 270))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (154, 172))	('IDH1', 'Gene', (179, 183))	('cholangiocarcinomas', 'Disease', (154, 173))	('glioblastoma', 'Phenotype', 'HP:0012174', (257, 269))	('glioblastomas', 'Disease', 'MESH:D005909', (257, 270))	('gene expression', 'MPA', (132, 147))	('IDH1', 'Gene', '3417', (179, 183))	('IDH2', 'Gene', (187, 191))	('glioblastomas', 'Disease', (257, 270))
106590	22824796	We have discovered intrahepatic cholangiocarcinomas as an additional and fifth major tumor type with frequent mutations (~9%) in IDH1 and IDH2.	('tumor', 'Disease', (85, 90))	('IDH2', 'Gene', '3418', (138, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (32, 50))	('mutations', 'Var', (110, 119))	('IDH1', 'Gene', (129, 133))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (19, 51))	('intrahepatic cholangiocarcinomas', 'Disease', (19, 51))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('IDH1', 'Gene', '3417', (129, 133))	('IDH2', 'Gene', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
106591	22824796	These mutations occurred predominantly in hotspot codons, IDH1 Arg132 and IDH2 Arg172, and were associated with decreased 5-hydroxymethylcytosine, increased DNA methylation, increased H3K79 dimethylation, and increased p53 expression.	('Arg172', 'Chemical', '-', (79, 85))	('decreased', 'NegReg', (112, 121))	('IDH1', 'Gene', '3417', (58, 62))	('expression', 'MPA', (223, 233))	('increased', 'PosReg', (209, 218))	('mutations', 'Var', (6, 15))	('IDH2', 'Gene', (74, 78))	('increased', 'PosReg', (147, 156))	('DNA methylation', 'MPA', (157, 172))	('IDH2', 'Gene', '3418', (74, 78))	('dimethylation', 'MPA', (190, 203))	('H3K79', 'Protein', (184, 189))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (122, 145))	('IDH1', 'Gene', (58, 62))	('p53', 'Gene', '7157', (219, 222))	('5-hydroxymethylcytosine', 'MPA', (122, 145))	('Arg132', 'Chemical', '-', (63, 69))	('increased', 'PosReg', (174, 183))	('p53', 'Gene', (219, 222))
106592	22824796	The prognostic significance of mutations in IDH1 and IDH2 suggests that hypermethylated cholangiocarcinomas may represent a distinct molecular sub-class with a better prognosis.	('mutations', 'Var', (31, 40))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (88, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('IDH2', 'Gene', (53, 57))	('IDH1', 'Gene', (44, 48))	('IDH1', 'Gene', '3417', (44, 48))	('IDH2', 'Gene', '3418', (53, 57))	('cholangiocarcinomas', 'Disease', (88, 107))	('hypermethylated', 'Var', (72, 87))
106594	22824796	They identified IDH1/2 mutations in 9 of 40 (23%) intrahepatic cholangiocarcinoma, but none in 22 extrahepatic cholangiocarcinoma or 25 gallbladder carcinoma.	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (136, 157))	('intrahepatic cholangiocarcinoma', 'Disease', (50, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('IDH1/2', 'Gene', (16, 22))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (98, 129))	('gallbladder carcinoma', 'Disease', (136, 157))	('mutations', 'Var', (23, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (50, 81))	('extrahepatic cholangiocarcinoma', 'Disease', (98, 129))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (63, 81))	('IDH1/2', 'Gene', '3417;3418', (16, 22))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
106595	22824796	In that study, mutations in IDH1 had higher prevalence than mutations in IDH2 (8 out of 9, or 89%), and both mutations were associated with higher levels of 2-hydroxyglutarate.	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (157, 175))	('IDH1', 'Gene', '3417', (28, 32))	('mutations', 'Var', (15, 24))	('prevalence', 'MPA', (44, 54))	('higher', 'PosReg', (140, 146))	('IDH2', 'Gene', (73, 77))	('IDH2', 'Gene', '3418', (73, 77))	('IDH1', 'Gene', (28, 32))
106596	22824796	More recently, Kipp et al found IDH1/2 mutations in 21 of 94 cholangiocarcinomas, including 19 of 67 intrahepatic cholangiocarcinomas.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (114, 132))	('cholangiocarcinomas', 'Disease', (114, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (101, 133))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('intrahepatic cholangiocarcinomas', 'Disease', (101, 133))	('IDH1/2', 'Gene', (32, 38))	('cholangiocarcinomas', 'Disease', (61, 80))	('mutations', 'Var', (39, 48))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (114, 133))	('IDH1/2', 'Gene', '3417;3418', (32, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (61, 80))
106597	22824796	Tumors with IDH1/2 mutations were poorly differentiated with clear cell change.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('IDH1/2', 'Gene', (12, 18))	('mutations', 'Var', (19, 28))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('IDH1/2', 'Gene', '3417;3418', (12, 18))
106598	22824796	Together with this current report, these three studies identified 62 of 433 (14%) intrahepatic cholangiocarcinomas with mutation in either IDH1 or IDH2.	('IDH1', 'Gene', (139, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (95, 113))	('mutation', 'Var', (120, 128))	('intrahepatic cholangiocarcinomas', 'Disease', (82, 114))	('IDH1', 'Gene', '3417', (139, 143))	('IDH2', 'Gene', (147, 151))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (82, 114))	('IDH2', 'Gene', '3418', (147, 151))
106599	22824796	There appears to be clear difference in the frequency of IDH1/2 mutation prevalence, which appears to be lower in Asian patients (7.5%), compared with 23% in the Borger et al cohort, 28% of intrahepatic tumors in the Kipp et al cohort, as well as in 25% (12 of 48) of patients in this current cohort from Mayo Clinic.	('intrahepatic tumors', 'Disease', 'MESH:D002780', (190, 209))	('IDH1/2', 'Gene', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('mutation', 'Var', (64, 72))	('Mayo', 'Species', '162683', (305, 309))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('patients', 'Species', '9606', (120, 128))	('IDH1/2', 'Gene', '3417;3418', (57, 63))	('patients', 'Species', '9606', (268, 276))	('intrahepatic tumors', 'Disease', (190, 209))
106600	22824796	Both the molecular basis and clinical significance of this ethnic difference in IDH1/2 mutations remain to be determined.	('IDH1/2', 'Gene', '3417;3418', (80, 86))	('mutations', 'Var', (87, 96))	('IDH1/2', 'Gene', (80, 86))
106601	22824796	The earliest genetic alterations during the development of secondary GBM are mutations targeting IDH1 and p53 with IDH1 mutations likely occurring before p53 mutation.	('p53', 'Gene', '7157', (106, 109))	('IDH1', 'Gene', (97, 101))	('IDH1', 'Gene', (115, 119))	('IDH1', 'Gene', '3417', (97, 101))	('IDH1', 'Gene', '3417', (115, 119))	('mutations', 'Var', (77, 86))	('p53', 'Gene', (154, 157))	('mutations', 'Var', (120, 129))	('p53', 'Gene', '7157', (154, 157))	('p53', 'Gene', (106, 109))
106602	22824796	This association suggests that IDH1/2 mutation may cause a cellular stress that leads to the activation of p53 and thus increases the pressure to inactivate p53 for glioma development.	('p53', 'Gene', '7157', (157, 160))	('activation', 'PosReg', (93, 103))	('glioma', 'Disease', 'MESH:D005910', (165, 171))	('IDH1/2', 'Gene', '3417;3418', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('mutation', 'Var', (38, 46))	('cause', 'Reg', (51, 56))	('increases', 'PosReg', (120, 129))	('pressure', 'MPA', (134, 142))	('IDH1/2', 'Gene', (31, 37))	('p53', 'Gene', (157, 160))	('glioma', 'Disease', (165, 171))
106603	22824796	Our study showed that mutations in IDH1 or IDH2 likely also cause a cellular stress in cholangiocarcinomas that leads to p53 activation, as seen by the significant increase of p53 protein levels.	('activation', 'PosReg', (125, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('IDH1', 'Gene', (35, 39))	('cause', 'Reg', (60, 65))	('p53', 'Gene', (176, 179))	('cholangiocarcinomas', 'Disease', (87, 106))	('p53', 'Gene', (121, 124))	('IDH2', 'Gene', (43, 47))	('IDH1', 'Gene', '3417', (35, 39))	('p53', 'Gene', '7157', (121, 124))	('p53', 'Gene', '7157', (176, 179))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (87, 106))	('mutations', 'Var', (22, 31))	('IDH2', 'Gene', '3418', (43, 47))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('increase', 'PosReg', (164, 172))
106604	22824796	Unlike secondary GBM, mutations in IDH1 or IDH2 in cholangiocarcinomas are not associated with p53 gene mutation.	('cholangiocarcinomas', 'Disease', (51, 70))	('IDH1', 'Gene', (35, 39))	('associated', 'Reg', (79, 89))	('IDH1', 'Gene', '3417', (35, 39))	('IDH2', 'Gene', (43, 47))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (51, 70))	('p53', 'Gene', (95, 98))	('mutations', 'Var', (22, 31))	('IDH2', 'Gene', '3418', (43, 47))	('p53', 'Gene', '7157', (95, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (51, 69))
106605	22824796	We interpret our result as an indication that unlike GBM, an alteration of a gene downstream p53 pathway, rather than p53 gene itself, may occur in cholangiocarcinomas with IDH1 or IDH2 mutation that has functionally inactivated the p53 pathway and relived the pressure to mutate p53.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (148, 166))	('IDH2', 'Gene', (181, 185))	('p53', 'Gene', (280, 283))	('alteration', 'Reg', (61, 71))	('mutation', 'Var', (186, 194))	('IDH2', 'Gene', '3418', (181, 185))	('p53', 'Gene', '7157', (118, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (148, 167))	('cholangiocarcinomas', 'Disease', (148, 167))	('p53', 'Gene', (118, 121))	('p53', 'Gene', '7157', (93, 96))	('IDH1', 'Gene', (173, 177))	('inactivated', 'PosReg', (217, 228))	('p53', 'Gene', '7157', (233, 236))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (280, 283))	('IDH1', 'Gene', '3417', (173, 177))	('p53', 'Gene', (233, 236))
106606	22824796	A common theme among diverse tumors with mutations in the IDH-TET pathway may be the expansion of progenitor lineages, as a consequence of widespread disruptions in DNA methylation and hydroxymethylation.	('mutations', 'Var', (41, 50))	('IDH', 'Gene', '3417', (58, 61))	('DNA', 'Protein', (165, 168))	('TET', 'Chemical', 'MESH:C010349', (62, 65))	('hydroxymethylation', 'MPA', (185, 203))	('disruptions', 'NegReg', (150, 161))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('expansion', 'PosReg', (85, 94))	('tumors', 'Disease', (29, 35))	('IDH', 'Gene', (58, 61))	('progenitor lineages', 'CPA', (98, 117))
106607	22824796	The impairment of hematopoetic stem cell differentiation can be facilitated by IDH2 mutations or reduced Tet2.	('IDH2', 'Gene', '3418', (79, 83))	('Tet2', 'Gene', (105, 109))	('facilitated', 'PosReg', (64, 75))	('reduced', 'NegReg', (97, 104))	('mutations', 'Var', (84, 93))	('IDH2', 'Gene', (79, 83))	('Tet2', 'Gene', '54790', (105, 109))	('hematopoetic stem cell differentiation', 'CPA', (18, 56))
106608	22824796	Glioblastomas with IDH1 mutations are strongly associated with the expression of marker genes from neuroblast progenitors, and our data indicate that concomitant methylation of neuronal differentiation genes occurs in glioblastomas with IDH1 mutations.	('glioblastomas', 'Phenotype', 'HP:0012174', (218, 231))	('IDH1', 'Gene', '3417', (237, 241))	('IDH1', 'Gene', (19, 23))	('glioblastomas', 'Disease', 'MESH:D005909', (218, 231))	('glioblastomas', 'Disease', (218, 231))	('mutations', 'Var', (242, 251))	('glioblastoma', 'Phenotype', 'HP:0012174', (218, 230))	('methylation', 'MPA', (162, 173))	('Glioblastomas', 'Disease', (0, 13))	('IDH1', 'Gene', '3417', (19, 23))	('Glioblastomas', 'Disease', 'MESH:D005909', (0, 13))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('Glioblastomas', 'Phenotype', 'HP:0012174', (0, 13))	('occurs', 'Reg', (208, 214))	('mutations', 'Var', (24, 33))	('associated', 'Reg', (47, 57))	('IDH1', 'Gene', (237, 241))
106609	22824796	Mutations in the IDH-TET pathway may appear early in tumor progression: IDH1 or TET2 mutations occur at high frequencies in low grade gliomas or myeloproliferative neoplasms, respectively, while subsequent mutations in TP53 or JAK2 coincide with the transition to myeloid leukemias or glioblastomas.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (145, 173))	('myeloid leukemias', 'Disease', 'MESH:D007951', (264, 281))	('neoplasms', 'Phenotype', 'HP:0002664', (164, 173))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('TET2', 'Gene', '54790', (80, 84))	('myeloproliferative neoplasms', 'Disease', (145, 173))	('IDH1', 'Gene', (72, 76))	('IDH', 'Gene', '3417', (17, 20))	('glioblastomas', 'Disease', (285, 298))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (264, 281))	('TP53', 'Gene', (219, 223))	('IDH', 'Gene', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (145, 173))	('glioblastomas', 'Disease', 'MESH:D005909', (285, 298))	('gliomas', 'Disease', (134, 141))	('IDH1', 'Gene', '3417', (72, 76))	('IDH', 'Gene', '3417', (72, 75))	('mutations', 'Var', (85, 94))	('JAK2', 'Gene', '3717', (227, 231))	('TET', 'Chemical', 'MESH:C010349', (80, 83))	('leukemias', 'Phenotype', 'HP:0001909', (272, 281))	('TP53', 'Gene', '7157', (219, 223))	('IDH', 'Gene', (17, 20))	('TET', 'Chemical', 'MESH:C010349', (21, 24))	('leukemia', 'Phenotype', 'HP:0001909', (272, 280))	('TET2', 'Gene', (80, 84))	('gliomas', 'Disease', 'MESH:D005910', (134, 141))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (264, 280))	('glioblastomas', 'Phenotype', 'HP:0012174', (285, 298))	('tumor', 'Disease', (53, 58))	('myeloid leukemias', 'Disease', (264, 281))	('glioblastoma', 'Phenotype', 'HP:0012174', (285, 297))	('JAK2', 'Gene', (227, 231))
106610	22824796	We speculate that the precursor lineages for hepatocytes and cholangiocytes that reside in bile ducts may be expanded in cholangiocarcinomas with mutations in IDH1 or IDH2.	('cholangiocarcinomas', 'Disease', (121, 140))	('IDH1', 'Gene', (159, 163))	('mutations', 'Var', (146, 155))	('IDH1', 'Gene', '3417', (159, 163))	('IDH2', 'Gene', (167, 171))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (121, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))	('IDH2', 'Gene', '3418', (167, 171))
106611	22824796	Tumors with IDH1/2 mutations expressed over 1.6-fold higher levels of the hepatic stem cell lineage markers, EpCAM and NCAM (Supplementary Figure 6).	('NCAM', 'Gene', (119, 123))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('higher', 'PosReg', (53, 59))	('IDH1/2', 'Gene', (12, 18))	('NCAM', 'Gene', '4684', (119, 123))	('hepatic stem cell lineage markers', 'MPA', (74, 107))	('mutations', 'Var', (19, 28))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('EpCAM', 'Gene', (109, 114))	('IDH1/2', 'Gene', '3417;3418', (12, 18))	('EpCAM', 'Gene', '4072', (109, 114))
106612	22824796	This model that invokes a precursor cell of origin within the liver may explain why lower frequencies of IDH1 or IDH2 mutations were observed in extrahepatic cholangiocarcinomas.	('IDH2', 'Gene', (113, 117))	('IDH1', 'Gene', (105, 109))	('mutations', 'Var', (118, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (158, 176))	('IDH2', 'Gene', '3418', (113, 117))	('IDH1', 'Gene', '3417', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('extrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (145, 177))	('extrahepatic cholangiocarcinomas', 'Disease', (145, 177))
106613	22824796	Genome-wide surveys of CpG island methylation indicated that there was significant overlap of DNA hypermethylation between two tumor types with IDH1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mutations', 'Var', (149, 158))	('tumor', 'Disease', (127, 132))	('IDH1', 'Gene', (144, 148))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('IDH1', 'Gene', '3417', (144, 148))
106617	22824796	Genes that accumulate methylation may have low baseline expression in most tumors, and thus an increase in DNA methylation may not silence expression levels further.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('low', 'NegReg', (43, 46))	('baseline expression', 'MPA', (47, 66))	('expression levels', 'MPA', (139, 156))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('DNA', 'MPA', (107, 110))	('tumors', 'Disease', (75, 81))	('methylation', 'Var', (22, 33))
106618	22824796	Further integration of DNA hypermethylated regions with gene expression data will help to identify the target genes whose expression are affected by the mutations in IDH1/2 as the result of altered histone or DNA methylation.	('expression', 'MPA', (122, 132))	('IDH1/2', 'Gene', (166, 172))	('mutations', 'Var', (153, 162))	('DNA methylation', 'MPA', (209, 224))	('IDH1/2', 'Gene', '3417;3418', (166, 172))	('altered', 'Reg', (190, 197))	('histone', 'MPA', (198, 205))
106623	22824796	Glioblastoma biospeciments - including 26 tumors with IDH1 mutations and 36 tumors without IDH1 mutations - were acquired from Affiliated Huashan Hospital of Fudan University.	('Glioblastoma', 'Disease', (0, 12))	('IDH1', 'Gene', (54, 58))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('IDH1', 'Gene', (91, 95))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('IDH1', 'Gene', '3417', (54, 58))	('mutations', 'Var', (59, 68))	('IDH1', 'Gene', '3417', (91, 95))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
106632	22824796	Pyrosequencing confirmation of IDH1 and IDH2 mutations was performed using the primers in.	('mutations', 'Var', (45, 54))	('IDH2', 'Gene', (40, 44))	('IDH1', 'Gene', '3417', (31, 35))	('IDH2', 'Gene', '3418', (40, 44))	('IDH1', 'Gene', (31, 35))
106653	22824796	For each CpG assay, a t statistic was calculated between the logit-transformed beta values for 19 IDH1 or IDH2 mutated cholangiocarcinomas, versus 31 IDH1 and IDH2 wildtype cholangiocarcinomas.	('IDH2', 'Gene', (159, 163))	('IDH2 wildtype cholangiocarcinomas', 'Disease', 'MESH:D018281', (159, 192))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (119, 138))	('mutated', 'Var', (111, 118))	('IDH2', 'Gene', '3418', (159, 163))	('cholangiocarcinomas', 'Disease', (119, 138))	('IDH1', 'Gene', '3417', (98, 102))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (173, 192))	('cholangiocarcinomas', 'Disease', (173, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('IDH1', 'Gene', (150, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (119, 137))	('IDH2', 'Gene', (106, 110))	('IDH2 wildtype cholangiocarcinomas', 'Disease', (159, 192))	('IDH2', 'Gene', '3418', (106, 110))	('IDH1', 'Gene', '3417', (150, 154))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (173, 191))	('IDH1', 'Gene', (98, 102))
106659	22824796	Ingenuity Pathway Analysis annotated the list of 285 genes in intrahepatic cholangiocarcinoma with significant DNA hypermethylation as well as >2.8-fold reduction in gene expression, in IDH1/2-mutated versus IDH1/2-wildtype tumors.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (62, 93))	('IDH1/2', 'Gene', (208, 214))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (75, 93))	('reduction', 'NegReg', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('intrahepatic cholangiocarcinoma', 'Disease', (62, 93))	('tumors', 'Disease', (224, 230))	('hypermethylation', 'Var', (115, 131))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('IDH1/2', 'Gene', '3417;3418', (208, 214))	('IDH1/2', 'Gene', '3417;3418', (186, 192))	('gene expression', 'MPA', (166, 181))	('IDH1/2', 'Gene', (186, 192))
106704	32272125	To improve the diagnostic yield of different sampling techniques, several ancillary tools have been developed and include DNA flow cytometry, digital image analysis, KRAS mutational testing, fluorescence in situ hybridization (FISH), and more recently, next-generation sequencing.	('KRAS', 'Gene', '3845', (166, 170))	('KRAS', 'Gene', (166, 170))	('mutational', 'Var', (171, 181))
106753	32272125	Although we cannot entirely exclude the possibility of sampling error in the histological evaluation of this resected specimen, it is important to note that FISH abnormalities associated with cholangiocarcinoma, such as polysomy (gains of 2 or more chromosomes), have been reported in both low-grade dysplasia (LGD, 11%) and HGD (58%), supporting a metaplasia-LGD-HGD-carcinoma sequence in the development of biliary tumors.	('biliary tumors', 'Phenotype', 'HP:0100574', (409, 423))	('metaplasia-LGD-HGD-carcinoma', 'Disease', (349, 377))	('dysplasia', 'Disease', 'MESH:C536170', (300, 309))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (192, 210))	('tumors', 'Phenotype', 'HP:0002664', (417, 423))	('cholangiocarcinoma', 'Disease', (192, 210))	('FISH abnormalities', 'Disease', (157, 175))	('metaplasia-LGD-HGD-carcinoma', 'Disease', 'MESH:D008679', (349, 377))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (192, 210))	('tumor', 'Phenotype', 'HP:0002664', (417, 422))	('carcinoma', 'Phenotype', 'HP:0030731', (368, 377))	('dysplasia', 'Disease', (300, 309))	('polysomy', 'Var', (220, 228))	('biliary tumors', 'Disease', 'MESH:D001661', (409, 423))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('associated', 'Reg', (176, 186))	('FISH abnormalities', 'Disease', 'MESH:D018376', (157, 175))	('men', 'Species', '9606', (123, 126))	('men', 'Species', '9606', (401, 404))	('biliary tumors', 'Disease', (409, 423))
106792	28260927	Its formation is frequently caused by mutations of the KRAS oncogene, a protein normally involved in the cell proliferation, in combination with the deletion of the p53 tumor suppressor gene.	('KRAS', 'Gene', (55, 59))	('p53', 'Gene', (165, 168))	('p53', 'Gene', '7157', (165, 168))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('KRAS', 'Gene', '3845', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('caused by', 'Reg', (28, 37))	('mutations', 'Var', (38, 47))
106793	28260927	A critical signaling protein downstream of KRAS and p53 mutations is interleukin (IL) 6, which is a serum biomarker for ICC.	('mutations', 'Var', (56, 65))	('interleukin (IL) 6', 'Gene', (69, 87))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('interleukin (IL) 6', 'Gene', '3569', (69, 87))	('KRAS', 'Gene', (43, 47))	('KRAS', 'Gene', '3845', (43, 47))
106802	28260927	Because of similar allelic losses in both HCC-like and ICC-like cells, these tumors are thought to have a monoclonal origin with bidirectional phenotype differentiation.	('tumors', 'Disease', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('allelic losses', 'Var', (19, 33))	('HCC', 'Phenotype', 'HP:0001402', (42, 45))
106819	28260927	In addition to these biomarkers, several other biomarkers have been shown to have an impact on diagnostics, prognostics, and treatment efficacy: HSP27; Akt; HDGF; Mucin 6, cell surface-associated; p16; p-4EBP1; S100A4; alpha-SMA; keratin 903; and TROP2.	('TROP2', 'Gene', (247, 252))	('men', 'Species', '9606', (130, 133))	('TROP2', 'Gene', '4070', (247, 252))	('HSP27', 'Gene', (145, 150))	('HDGF', 'Gene', '3068', (157, 161))	('S100A4', 'Var', (211, 217))	('impact', 'Reg', (85, 91))	('HSP27', 'Gene', '3315', (145, 150))	('p-4EBP1', 'Var', (202, 209))	('Mucin 6', 'Gene', (163, 170))	('Akt', 'Gene', (152, 155))	('Mucin 6', 'Gene', '4588', (163, 170))	('p16', 'Gene', '1029', (197, 200))	('HDGF', 'Gene', (157, 161))	('Akt', 'Gene', '207', (152, 155))	('p16', 'Gene', (197, 200))
106836	28260927	A resection of more than 75% of the total liver volume in a healthy liver and more than 65% of the total liver volume in a compromised liver (eg, due to cirrhosis or fibrosis) is an indication of portal vein embolization (PVE).	('portal vein embolization', 'Disease', (196, 220))	('cirrhosis', 'Disease', 'MESH:D005355', (153, 162))	('portal vein embolization', 'Phenotype', 'HP:0030242', (196, 220))	('cirrhosis', 'Disease', (153, 162))	('resection', 'Var', (2, 11))	('fibrosis', 'Disease', (166, 174))	('PVE', 'Phenotype', 'HP:0030242', (222, 225))	('fibrosis', 'Disease', 'MESH:D005355', (166, 174))	('cirrhosis', 'Phenotype', 'HP:0001394', (153, 162))
106886	28260927	In ICC patients, Y-90 was associated with improved survival, when compared with patients undergoing best supportive care only.	('patients', 'Species', '9606', (80, 88))	('improved', 'PosReg', (42, 50))	('Y-90', 'Var', (17, 21))	('ICC', 'Disease', (3, 6))	('survival', 'MPA', (51, 59))	('patients', 'Species', '9606', (7, 15))
106899	28260927	Targeted therapies (eg, targeting IDH 1 or 2 mutations) are promising but require further evaluation.	('IDH 1', 'Gene', (34, 39))	('mutations', 'Var', (45, 54))	('IDH 1', 'Gene', '3417', (34, 39))
106939	26528072	In 4 cases cholecystectomy with subhepatic drainage was performed, ligature of the right portal branch, metastasectomy and transmesocolic gastroenteroanastomosis.	('transmesocolic gastroenteroanastomosis', 'Disease', (123, 161))	('transmesocolic gastroenteroanastomosis', 'Disease', 'None', (123, 161))	('cholecystectomy', 'Disease', (11, 26))	('ligature', 'Var', (67, 75))
107029	33025818	Patients who are diagnosed with IgG4-RD can have multi-organ involvement, including the pancreas, lacrimal, and salivary glands, orbital or periorbital tissue, pachymeninx, hypophysis, thyroid, lungs, pleura, pericardium, kidneys, prostate, mediastinum, and retroperitoneum.	('prostate', 'Disease', (231, 239))	('thyroid', 'Disease', (185, 192))	('mediastinum', 'Disease', (241, 252))	('IgG4-RD', 'Var', (32, 39))	('Patients', 'Species', '9606', (0, 8))
107068	31014381	Substantial evidence from preclinical models indicates that blocking PD-1/PD-L1 interactions can enhance immune normalization and reinforce anticancer responses.	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('PD-1', 'Gene', (69, 73))	('PD-1', 'Gene', '5133', (69, 73))	('cancer', 'Disease', (144, 150))	('reinforce', 'PosReg', (130, 139))	('enhance', 'PosReg', (97, 104))	('interactions', 'Interaction', (80, 92))	('blocking', 'Var', (60, 68))	('immune normalization', 'CPA', (105, 125))
107074	31014381	Nevertheless, this study suggests that PD-1 blockading may prolong therapeutic durability.	('therapeutic durability', 'CPA', (67, 89))	('PD-1', 'Gene', (39, 43))	('prolong', 'PosReg', (59, 66))	('PD-1', 'Gene', '5133', (39, 43))	('blockading', 'Var', (44, 54))
107079	31014381	The exception to this can be observed in tumors with specific genetic changes, such as MSI-H, deficient mismatch repair (dMMR), and high tumor mutational burden (TMB).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('MSI-H', 'Disease', 'MESH:D000848', (87, 92))	('tumor', 'Disease', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', (41, 46))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('TMB', 'Chemical', '-', (162, 165))	('MSI-H', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('deficient', 'Var', (94, 103))	('dMMR', 'Chemical', '-', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mismatch repair', 'MPA', (104, 119))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
107082	31014381	This may be due to genetic alterations within DNA encoding immunogenic signaling pathway proteins, a lack of sufficient mutation-associated neoantigens (MANAs) in the presence of an immunosuppressive tumor microenvironment, and/or the unmasking of immunogenicity by immune checkpoint inhibitors (ICPIs) to induce an enhanced antitumor response.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('immunosuppressive tumor', 'Disease', (182, 205))	('immunosuppressive tumor', 'Disease', 'MESH:D009369', (182, 205))	('tumor', 'Disease', (329, 334))	('enhanced', 'PosReg', (316, 324))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('DNA', 'Gene', (46, 49))	('alterations', 'Var', (27, 38))
107089	31014381	The efficacy of PD-1/PD-L1 blockades can be lasting for some patients, although tumor development remains a constant threat even under continuous therapy.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('PD-1', 'Gene', '5133', (16, 20))	('blockades', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('patients', 'Species', '9606', (61, 69))	('tumor', 'Disease', (80, 85))	('PD-1', 'Gene', (16, 20))
107092	31014381	At present, the possible mechanisms of acquired immunotherapy resistance appear to include loss-of-function mutations in beta-2-microglobulin (B2M) and Janus kinases (JAK1 and JAK2).	('JAK2', 'Gene', (176, 180))	('beta-2-microglobulin', 'Gene', (121, 141))	('mutations', 'Var', (108, 117))	('B2M', 'Gene', (143, 146))	('B2M', 'Gene', '567', (143, 146))	('JAK1', 'Gene', (167, 171))	('JAK1', 'Gene', '3716', (167, 171))	('JAK2', 'Gene', '3717', (176, 180))	('beta-2-microglobulin', 'Gene', '567', (121, 141))	('loss-of-function', 'NegReg', (91, 107))
107097	31014381	Adding to the aforementioned side effects and drug resistance after immunotherapy, studies indicate that a small number of patients on PD-1 blockades will experience hyper-progression.	('patients', 'Species', '9606', (123, 131))	('hyper-progression', 'MPA', (166, 183))	('drug resistance', 'Phenotype', 'HP:0020174', (46, 61))	('PD-1', 'Gene', (135, 139))	('PD-1', 'Gene', '5133', (135, 139))	('blockades', 'Var', (140, 149))
107100	31014381	conducted an analysis of somatic alterations looking into the biomarkers for hyper-progression and found that copy number alterations in murine double minute 2/4 (MDM2/MDM4), the epidermal growth factor receptor (EGFR), and several genes located on 11q13 are associated with hyper-progression.	('MDM4', 'Gene', '17248', (168, 172))	('epidermal growth factor receptor', 'Gene', (179, 211))	('EGFR', 'Gene', (213, 217))	('epidermal growth factor receptor', 'Gene', '13649', (179, 211))	('MDM4', 'Gene', (168, 172))	('copy number alterations', 'Var', (110, 133))	('murine', 'Species', '10090', (137, 143))	('associated', 'Reg', (259, 269))	('hyper-progression', 'Disease', (275, 292))
107112	31014381	Any abnormality in processing T cell immune clearance can lead to a decrease or even the disappearance of antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('decrease', 'NegReg', (68, 76))	('abnormality', 'Var', (4, 15))	('disappearance', 'NegReg', (89, 102))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('T cell immune clearance', 'CPA', (30, 53))
107115	31014381	Tumors can also escape variant selection and tumor-associated antigen expression loss, as well as co-stimulatory molecule downregulation and immunosuppressive factor secretion.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('downregulation', 'NegReg', (122, 136))	('tumor', 'Disease', (45, 50))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('variant selection', 'Var', (23, 40))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('loss', 'NegReg', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
107134	31014381	Targeted therapies focusing on tumor-specific gene mutation show promise and therefore are likely candidates for further investigation.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('mutation', 'Var', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
107135	31014381	In addition, evidence suggests PD-1/PD-L1 blockades can be combined directly with other immune checkpoint inhibitors (ICPIs), including some immunosuppressive small molecule blockades, having compatible, and theoretically complementary modalities.	('PD-1', 'Gene', '5133', (31, 35))	('blockades', 'Var', (42, 51))	('PD-1', 'Gene', (31, 35))
107148	31014381	On the other hand, CTLA-4 blockades also inhibit the B7-CTLA-4 pathway, which can initiate CD8+ T cell proliferation in lymph nodes and increase the infiltration of CTLs into tumor tissues.	('CD8', 'Gene', (91, 94))	('tumor', 'Disease', (175, 180))	('CD8', 'Gene', '925', (91, 94))	('CTLA-4', 'Gene', (19, 25))	('CTLA-4', 'Gene', (56, 62))	('CTLA-4', 'Gene', '1493', (19, 25))	('infiltration', 'CPA', (149, 161))	('initiate', 'PosReg', (82, 90))	('CTLs into', 'CPA', (165, 174))	('inhibit', 'NegReg', (41, 48))	('increase', 'PosReg', (136, 144))	('blockades', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('CTLA-4', 'Gene', '1493', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
107149	31014381	Additionally, CTLA-4 antagonists may impede tumor inhibition capabilities of Treg cells.	('CTLA-4', 'Gene', (14, 20))	('impede', 'NegReg', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('antagonists', 'Var', (21, 32))	('CTLA-4', 'Gene', '1493', (14, 20))	('tumor', 'Disease', (44, 49))
107156	31014381	Interestingly, the CheckMate-227 study which compared chemotherapy alone with double immunotherapy found that double immunotherapy can improve mPFS as well as ORR in patients suffering lung cancer, irrespective of PD-L1 expression.	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('double immunotherapy', 'Var', (110, 130))	('mPFS', 'CPA', (143, 147))	('lung cancer', 'Disease', (185, 196))	('patients', 'Species', '9606', (166, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('ORR', 'Disease', (159, 162))	('improve', 'PosReg', (135, 142))
107160	31014381	The use of small molecular bioeffectors, such as histone deacetylase (HDAC) inhibitors which enhance the expression of T cell chemokines, may augment response rates to PD-1 blocking immunotherapy.	('HDAC', 'Gene', (70, 74))	('histone deacetylase', 'Gene', '9734', (49, 68))	('HDAC', 'Gene', '9734', (70, 74))	('PD-1', 'Gene', (168, 172))	('enhance', 'PosReg', (93, 100))	('augment', 'PosReg', (142, 149))	('histone deacetylase', 'Gene', (49, 68))	('inhibitors', 'Var', (76, 86))	('PD-1', 'Gene', '5133', (168, 172))	('expression', 'MPA', (105, 115))	('response rates', 'CPA', (150, 164))
107162	31014381	The guiding principle of the synergistic effect for combining small molecule drugs with ICPIs is that this may enhance tumor immunogenicity, which may in turn may enhance the efficacy of immuno-oncological (IO) treatments.	('tumor', 'Disease', (119, 124))	('small', 'Var', (62, 67))	('immuno-oncological', 'CPA', (187, 205))	('enhance', 'PosReg', (163, 170))	('enhance', 'PosReg', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
107168	31014381	Increasing attention is being given to targeted therapies because the identification of actionable oncogenic driver alterations has improved and we are gaining a deeper understanding of the microenvironments in which tumor develop.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('alterations', 'Var', (116, 127))
107169	31014381	Monoclonal antibodies (McAbs) which target tumors mainly include drugs that target tumor-driving genes, inhibit protein kinase complexes by targeting the fusion mutation of EGFR, ALK, etc., or drugs which target angiogenesis (e.g., axitinib or sorafenib).	('sorafenib', 'Chemical', 'MESH:D000077157', (244, 253))	('tumor', 'Disease', (83, 88))	('targeting', 'Reg', (140, 149))	('fusion mutation', 'Var', (154, 169))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('protein', 'Protein', (112, 119))	('ALK', 'Gene', '238', (179, 182))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('ALK', 'Gene', (179, 182))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('EGFR', 'Gene', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('angiogenesis', 'CPA', (212, 224))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('axitinib', 'Chemical', 'MESH:D000077784', (232, 240))	('inhibit', 'NegReg', (104, 111))	('McAbs', 'Chemical', 'MESH:D000911', (23, 28))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
107172	31014381	In a melanoma mouse model, dabrafenib significantly increased the infiltration of CD8+ T cells, and trametinib in BRAF wild-type tumor cells appears to upregulate human leukocyte antigen (HLA) molecule expression while downregulating certain immunosuppressive factors such as PD-L1, IL1, IL8, CD73, and vascular endothelial growth factor A (VEGFA).	('IL1', 'Gene', (283, 286))	('upregulate', 'PosReg', (152, 162))	('expression', 'MPA', (202, 212))	('IL8', 'Gene', (288, 291))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('VEGFA', 'Gene', '22339', (341, 346))	('CD73', 'Gene', '23959', (293, 297))	('CD73', 'Gene', (293, 297))	('tumor', 'Disease', (129, 134))	('trametinib', 'Var', (100, 110))	('infiltration', 'CPA', (66, 78))	('downregulating', 'NegReg', (219, 233))	('vascular endothelial growth factor A', 'Gene', '22339', (303, 339))	('increased', 'PosReg', (52, 61))	('CD8', 'Gene', (82, 85))	('VEGFA', 'Gene', (341, 346))	('IL1', 'Gene', '111343', (283, 286))	('mouse', 'Species', '10090', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('trametinib', 'Chemical', 'MESH:C560077', (100, 110))	('vascular endothelial growth factor A', 'Gene', (303, 339))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('melanoma', 'Disease', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('IL8', 'Gene', '20309', (288, 291))	('CD8', 'Gene', '925', (82, 85))	('human', 'Species', '9606', (163, 168))	('dabrafenib', 'Chemical', 'MESH:C561627', (27, 37))
107187	31014381	PD-1 blockades amplify these abscopal effects, and radiotherapy increases the expression of PD-L1 in tumor cells which suggests intervention compatibility.	('expression', 'MPA', (78, 88))	('PD-1', 'Gene', (0, 4))	('PD-L1', 'Gene', (92, 97))	('PD-1', 'Gene', '5133', (0, 4))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('blockades', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('increases', 'PosReg', (64, 73))
107208	31014381	Similar results have been found in patients with previously untreated metastatic non-squamous NSCLC without EGFR or ALK mutations.	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('EGFR', 'Gene', (108, 112))	('NSCLC', 'Disease', (94, 99))	('ALK', 'Gene', (116, 119))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('mutations', 'Var', (120, 129))	('patients', 'Species', '9606', (35, 43))	('ALK', 'Gene', '238', (116, 119))
107230	31014381	ICPIs in esophageal cancer encourage optimism and combined with an immunotherapy may bring further benefit for those suffering esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('esophageal cancer', 'Disease', (127, 144))	('ICPIs', 'Var', (0, 5))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('esophageal cancer', 'Disease', (9, 26))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (9, 26))
107240	31014381	The results of the ATTRACTION-02 phase III study focusing on heavily pretreated patients with advanced gastric or gastroesophageal junction cancer found OS rates in nivolumab compared with placebo were 27.3% and 11.6% at 12 months, and then 10.6% and 3.2% at 24 months, respectively.	('gastric or gastroesophageal junction cancer', 'Disease', 'MESH:D013274', (103, 146))	('patients', 'Species', '9606', (80, 88))	('OS', 'Gene', '17451', (153, 155))	('nivolumab', 'Chemical', 'MESH:D000077594', (165, 174))	('gastric or gastroesophageal junction cancer', 'Disease', (103, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('nivolumab', 'Var', (165, 174))
107242	31014381	Comparatively, the KEYNOTE-061 trial which focused on pembrolizumab with paclitaxel in patients with advanced gastric cancer whom had developed resistance after platinum and fluoropyrimidine treatment found that pembrolizumab did not significantly improve OS compared to paclitaxel, with an 9.1 month mOS versus 8.3 months.	('gastric cancer', 'Disease', (110, 124))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('paclitaxel', 'Chemical', 'MESH:D017239', (73, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('mOS', 'Gene', (301, 304))	('pembrolizumab', 'Chemical', 'MESH:C582435', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mOS', 'Gene', '17451', (301, 304))	('pembrolizumab', 'Chemical', 'MESH:C582435', (212, 225))	('fluoropyrimidine', 'Chemical', '-', (174, 190))	('OS', 'Gene', '17451', (256, 258))	('platinum', 'Chemical', 'MESH:D010984', (161, 169))	('pembrolizumab', 'Var', (212, 225))	('patients', 'Species', '9606', (87, 95))	('OS', 'Gene', '17451', (302, 304))	('paclitaxel', 'Chemical', 'MESH:D017239', (271, 281))
107254	31014381	Recent results have indicated the potential of PD-1/PD-L1 blockades for the treatment of advanced HCC.	('PD-1', 'Gene', (47, 51))	('HCC', 'Gene', (98, 101))	('PD-1', 'Gene', '5133', (47, 51))	('blockades', 'Var', (58, 67))	('HCC', 'Gene', '619501', (98, 101))	('HCC', 'Phenotype', 'HP:0001402', (98, 101))
107258	31014381	In addition, liver toxicity of PD-1/PD-L1 blockades was lower than that of conventional drugs.	('blockades', 'Var', (42, 51))	('lower', 'NegReg', (56, 61))	('PD-1', 'Gene', (31, 35))	('PD-1', 'Gene', '5133', (31, 35))	('toxicity', 'Disease', 'MESH:D064420', (19, 27))	('toxicity', 'Disease', (19, 27))
107270	31014381	In addition, several clinical trials of PD-1/PD-L1 blockades combined with other types of antitumor therapy are also under way.	('PD-1', 'Gene', '5133', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('blockades', 'Var', (51, 60))	('tumor', 'Disease', (94, 99))	('PD-1', 'Gene', (40, 44))
107272	31014381	In addition, emerging data suggests MMR or MSI-H mutation tumors have a much higher response rate to PD-1/L1 inhibitors, and in cholangiocarcinoma, MSI-H accounting for 5% of gallbladder cancers (GBC), 5-13% of extrahepatic cholangiocarcinoma (ECC), and 10% of intrahepatic cholangiocarcinoma (ICC).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (274, 292))	('gallbladder cancers', 'Disease', 'MESH:D005706', (175, 194))	('extrahepatic cholangiocarcinoma', 'Disease', (211, 242))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('MSI-H', 'Disease', (148, 153))	('cholangiocarcinoma', 'Disease', (274, 292))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (274, 292))	('higher', 'PosReg', (77, 83))	('mutation', 'Var', (49, 57))	('PD-1/L1', 'Gene', (101, 108))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (224, 242))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (211, 242))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (128, 146))	('MSI-H', 'Disease', (43, 48))	('MSI-H', 'Disease', 'MESH:D000848', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('cholangiocarcinoma', 'Disease', (224, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('cholangiocarcinoma', 'Disease', (128, 146))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (224, 242))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (128, 146))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('response', 'MPA', (84, 92))	('tumors', 'Disease', (58, 64))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (261, 292))	('intrahepatic cholangiocarcinoma', 'Disease', (261, 292))	('MSI-H', 'Disease', 'MESH:D000848', (43, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('PD-1/L1', 'Gene', '5133;3897', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('gallbladder cancers', 'Disease', (175, 194))
107275	31014381	One small sample study found after treatment with PD-1 blockades combined with lenvatinib, 3:14 patients had a 21.4% ORR and a 93% DCR.	('DCR', 'Gene', (131, 134))	('blockades', 'Var', (55, 64))	('lenvatinib', 'Chemical', 'MESH:C531958', (79, 89))	('ORR', 'MPA', (117, 120))	('patients', 'Species', '9606', (96, 104))	('PD-1', 'Gene', (50, 54))	('PD-1', 'Gene', '5133', (50, 54))	('DCR', 'Gene', '1637', (131, 134))
107278	31014381	PD-1/L1 blockades combined with a standard chemotherapy is frequently administered as a second-line therapy, although there appears to be an element of trial and error adjustment.	('PD-1/L1', 'Gene', (0, 7))	('PD-1/L1', 'Gene', '5133;3897', (0, 7))	('blockades', 'Var', (8, 17))
107297	31014381	The potential benefit of PD-1/PD-L1 blockades combined with other therapeutic approaches has resulted in a number of trials focusing on resectable pancreatic cancer, broad line resectable pancreatic cancer, and advanced pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (147, 164))	('pancreatic cancer', 'Disease', 'MESH:D010190', (220, 237))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('PD-1', 'Gene', (25, 29))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (188, 205))	('PD-1', 'Gene', '5133', (25, 29))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (147, 164))	('blockades', 'Var', (36, 45))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (220, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('pancreatic cancer', 'Disease', (188, 205))	('pancreatic cancer', 'Disease', (147, 164))	('pancreatic cancer', 'Disease', (220, 237))	('pancreatic cancer', 'Disease', 'MESH:D010190', (188, 205))
107302	31014381	Nevertheless, the colorectal cancer group of phase II clinical trials evaluating the clinical activity of pembrolizumab in patients with progressive metastatic carcinoma has shown that the ORR and DCR of patients with mismatch repair-deficient (dMMR) within 20 weeks were 40 and 90%, respectively.	('patients', 'Species', '9606', (204, 212))	('dMMR', 'Chemical', '-', (245, 249))	('DCR', 'Gene', '1637', (197, 200))	('colorectal cancer', 'Phenotype', 'HP:0003003', (18, 35))	('carcinoma', 'Disease', 'MESH:D002277', (160, 169))	('DCR', 'Gene', (197, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('mismatch repair-deficient', 'Var', (218, 243))	('patients', 'Species', '9606', (123, 131))	('carcinoma', 'Disease', (160, 169))	('colorectal cancer', 'Disease', (18, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('pembrolizumab', 'Chemical', 'MESH:C582435', (106, 119))	('colorectal cancer', 'Disease', 'MESH:D015179', (18, 35))
107303	31014381	For the mismatch repair-proficient (pMMR) group, these values were 0 and 11%, respectively which suggests that mismatch repair status may be used as efficient indicators of PD-1 antibodies, although further research is needed for clarification.	('mismatch', 'Var', (111, 119))	('PD-1', 'Gene', (173, 177))	('PD-1', 'Gene', '5133', (173, 177))
107308	31014381	As mentioned previously, PD-1 inhibitor monotherapy has little effect in patients with microsatellite stable colorectal cancer.	('colorectal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('microsatellite', 'Var', (87, 101))	('PD-1', 'Gene', (25, 29))	('PD-1', 'Gene', '5133', (25, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('patients', 'Species', '9606', (73, 81))
107312	31014381	MEK inhibition upregulates tumor major histocompatibility complex-I expression, promoting intra-tumoral T cell accumulation while improving anti-PD-L1 responses.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('upregulates', 'PosReg', (15, 26))	('MEK', 'Gene', (0, 3))	('tumor', 'Disease', (27, 32))	('promoting', 'PosReg', (80, 89))	('MEK', 'Gene', '5609', (0, 3))	('tumor', 'Disease', (96, 101))	('inhibition', 'Var', (4, 14))	('improving', 'PosReg', (130, 139))	('intra-tumoral T', 'Disease', 'MESH:D009369', (90, 105))	('anti-PD-L1 responses', 'MPA', (140, 160))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('intra-tumoral T', 'Disease', (90, 105))
107341	30444046	Simultaneously, tumor suppressor genes (TSGs) can be inactivated by promoter hypermethylation (Llinas-Arias and Esteller, 2017).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('promoter hypermethylation', 'Var', (68, 93))	('Llinas-Arias', 'Disease', (95, 107))	('inactivated', 'NegReg', (53, 64))	('tumor', 'Disease', (16, 21))	('Llinas-Arias', 'Disease', 'MESH:D005878', (95, 107))
107342	30444046	CpG island hypermethylation in cancer cells is associated with a decrease in histone active marks: histone H3 and H4 acetylation, H3K4 trimethylation, and gain of repressive marks: H3K9me3 and H3K27me3 (Llinas-Arias and Esteller, 2017).	('H3K27me3', 'Var', (193, 201))	('H3K4', 'Protein', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('histone H3', 'Protein', (99, 109))	('hypermethylation', 'Var', (11, 27))	('H3K9me3', 'Protein', (181, 188))	('Llinas-Arias', 'Disease', 'MESH:D005878', (203, 215))	('gain', 'PosReg', (155, 159))	('histone', 'MPA', (77, 84))	('decrease', 'NegReg', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('repressive', 'MPA', (163, 173))	('cancer', 'Disease', (31, 37))	('Llinas-Arias', 'Disease', (203, 215))
107357	30444046	This KRAB-ZNF is upregulated in bladder cancer, while its knockdown induces apoptosis and reduces the viability of cancer cells in in vitro and in vivo experiments (Kawahara et al., 2016).	('induces', 'Reg', (68, 75))	('cancer', 'Disease', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (32, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (32, 46))	('bladder cancer', 'Disease', (32, 46))	('upregulated', 'PosReg', (17, 28))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('reduces', 'NegReg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('ZNF', 'Gene', (10, 13))	('apoptosis', 'CPA', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('knockdown', 'Var', (58, 67))	('ZNF', 'Gene', '284390', (10, 13))
107387	30444046	For breast cancer, we used nine different cell lines representing distinct molecular subtypes: luminal A (MCF7, T47D), luminal B (BT474), basal (BT20, BT549, HS578T, MDA-MB231, MDA-MB468), and HER2 positive (SKBR3).	('T47D', 'CellLine', 'CVCL:0553', (112, 116))	('HER2', 'Gene', (193, 197))	('MDA-MB231', 'CellLine', 'CVCL:0062', (166, 175))	('MDA-MB231', 'Var', (166, 175))	('SKBR3', 'CellLine', 'CVCL:0033', (208, 213))	('MDA-MB468', 'Var', (177, 186))	('HER2', 'Gene', '2064', (193, 197))	('HS578T', 'CellLine', 'CVCL:0332', (158, 164))	('BT549', 'CellLine', 'CVCL:1092', (151, 156))	('MDA-MB468', 'CellLine', 'CVCL:0419', (177, 186))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('MCF7', 'CellLine', 'CVCL:0031', (106, 110))	('BT20', 'Var', (145, 149))	('HS578T', 'Var', (158, 164))
107409	30444046	Interestingly, the majority of the KRAB-ZNFs with an altered mRNA level exhibited reduced expression, while only a small but distinct cluster of 16 KRAB-ZNFs showed upregulation in multiple cancer types (Fig.	('ZNFs', 'Chemical', '-', (40, 44))	('altered', 'Var', (53, 60))	('expression', 'MPA', (90, 100))	('reduced', 'NegReg', (82, 89))	('multiple cancer', 'Disease', (181, 196))	('ZNFs', 'Chemical', '-', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('upregulation', 'PosReg', (165, 177))	('mRNA level', 'MPA', (61, 71))	('multiple cancer', 'Disease', 'MESH:D009369', (181, 196))
107443	30444046	As aberrant splicing is a frequent event in carcinogenesis, we wanted to explore the isoform signature for cancer-associated KRAB-ZNFs in TCGA datasets.	('carcinogenesis', 'Disease', 'MESH:D063646', (44, 58))	('aberrant', 'Var', (3, 11))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('carcinogenesis', 'Disease', (44, 58))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('ZNFs', 'Chemical', '-', (130, 134))	('cancer', 'Disease', (107, 113))
107446	30444046	As expected, we found that a majority of splicing variants (84.5%) were overexpressed in cancer tissues compared to their normal counterparts (Fig.	('splicing variants', 'Var', (41, 58))	('overexpressed', 'PosReg', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
107447	30444046	Out of 490 significant isoforms, 21 variants (4.3%) showed expression only in cancer tissues, 220 variants (44.9%) were strongly overexpressed in cancer compared to normal (>= 2-fold overexpression, with the highest level reaching 652-fold change), and 173 variants (35.3%) showed mild overexpression (FC < 2 and >= 1.2).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('expression', 'MPA', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('variants', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('overexpression', 'PosReg', (286, 300))	('overexpressed', 'PosReg', (129, 142))	('variants', 'Var', (98, 106))
107448	30444046	It is of note that 21 isoforms that fell below the detection threshold in normal samples included mainly truncated and nonsense variants of ZNF695.	('ZNF695', 'Gene', '57116', (140, 146))	('nonsense', 'Var', (119, 127))	('ZNF695', 'Gene', (140, 146))
107453	30444046	ZNF273, the isoform with a 5' partial deletion of the KRAB domain, was switched to three other isoforms, which could be translated to a full-length protein, a variant with a C-terminal partial deletion of the KRAB domain, and a protein devoid of the zinc finger domain.	('ZNF273', 'Gene', (0, 6))	('partial deletion', 'Var', (30, 46))	('ZNF273', 'Gene', '10793', (0, 6))
107458	30444046	Four out of five ZNF273 variants (Fig.	('ZNF273', 'Gene', '10793', (17, 23))	('ZNF273', 'Gene', (17, 23))	('variants', 'Var', (24, 32))
107516	30444046	Finally, our survival analysis indicated that the expression of KRAB-ZNFs may act as a risk factor.	('KRAB-ZNFs', 'Gene', (64, 73))	('ZNFs', 'Chemical', '-', (69, 73))	('expression', 'Var', (50, 60))
107517	30444046	Patients with high expression of five out of 10 analyzed KRAB-ZNFs presented significantly shorter overall survival than those with low expression (Fig.	('ZNFs', 'Chemical', '-', (62, 66))	('overall survival', 'MPA', (99, 115))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('KRAB-ZNFs', 'Gene', (57, 66))	('shorter', 'NegReg', (91, 98))
107519	30444046	In contrast, high expression was associated with better prognosis in the case of ZNF205 (P < 0.001, hazard ratio = 0.5), ZNF707 (P = 0.001, hazard ratio = 0.5), and ZNF789 (P = 0.017, hazard ratio = 0.5) (Fig.	('ZNF205', 'Gene', (81, 87))	('high', 'Var', (13, 17))	('ZNF707', 'Gene', '286075', (121, 127))	('ZNF789', 'Gene', (165, 171))	('ZNF789', 'Gene', '285989', (165, 171))	('better', 'PosReg', (49, 55))	('ZNF205', 'Gene', '7755', (81, 87))	('ZNF707', 'Gene', (121, 127))
107534	30444046	We observed that the majority of variants was detected both in normal and cancer tissues, but as expected, they had a higher level in tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('variants', 'Var', (33, 41))
107535	30444046	The differential expression of KRAB-ZNF splicing isoforms in cancer was reported only by Juarez-Mendez and colleagues (Juarez-Mendez et al., 2013), who demonstrated a specific increase of ZNF695 variants in ovarian cancer compared to normal cells.	('ZNF', 'Gene', (36, 39))	('variants', 'Var', (195, 203))	('increase', 'PosReg', (176, 184))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('ovarian cancer', 'Disease', (207, 221))	('ZNF', 'Gene', (188, 191))	('cancer', 'Disease', (61, 67))	('ZNF', 'Gene', '284390', (36, 39))	('ZNF695', 'Gene', '57116', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ZNF', 'Gene', '284390', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ovarian cancer', 'Disease', 'MESH:D010051', (207, 221))	('ovarian cancer', 'Phenotype', 'HP:0100615', (207, 221))	('ZNF695', 'Gene', (188, 194))
107546	30444046	Furthermore, we have previously shown that ZNF695 was upregulated in pluripotent stem cells compared to more specialized cell types, whereas its knockdown resulted in the loss of self-renewal properties and differentiation of pluripotent stem cells (Oleksiewicz et al., 2017).	('ZNF695', 'Gene', '57116', (43, 49))	('knockdown', 'Var', (145, 154))	('upregulated', 'PosReg', (54, 65))	('self-renewal properties', 'CPA', (179, 202))	('differentiation', 'CPA', (207, 222))	('ZNF695', 'Gene', (43, 49))	('loss', 'NegReg', (171, 175))
107611	29850347	The polyclonal CEA had high sensitivity of about 50-90% for hepatocellular carcinoma.	('polyclonal', 'Var', (4, 14))	('CEA', 'Gene', (15, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('CEA', 'Gene', '5670', (15, 18))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (60, 84))	('hepatocellular carcinoma', 'Disease', (60, 84))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (60, 84))
107637	27685844	Functional studies have shown miRNAs to participate in almost every cellular process including apoptosis, proliferation and differentiation by directly modulating the expression of tumor suppressor genes and oncogenes.	('tumor', 'Disease', (181, 186))	('oncogenes', 'Gene', (208, 217))	('differentiation', 'CPA', (124, 139))	('apoptosis', 'CPA', (95, 104))	('participate', 'Reg', (40, 51))	('miRNAs', 'Var', (30, 36))	('modulating', 'Reg', (152, 162))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('proliferation', 'CPA', (106, 119))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('expression', 'MPA', (167, 177))
107648	27685844	Most patients with unresectable ICC were treated with HAI of floxuridine, with or without intravenous bevacizumab as part of two phase II clinical trials previously published.	('HAI', 'Var', (54, 57))	('patients', 'Species', '9606', (5, 13))	('ICC', 'Disease', (32, 35))	('clinical', 'Species', '191496', (138, 146))	('floxuridine', 'Chemical', 'MESH:D005467', (61, 72))	('bevacizumab', 'Chemical', 'MESH:D000068258', (102, 113))
107770	27301956	These IHC findings strongly supported the diagnosis of ICC with aberrant expression of AFP.	('ICC', 'Disease', (55, 58))	('aberrant expression', 'Var', (64, 83))	('AFP', 'Gene', '174', (87, 90))	('AFP', 'Gene', (87, 90))
107781	27301956	CA19-9 is regarded as a tumor marker of ICC.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('tumor', 'Disease', (24, 29))	('ICC', 'Disease', (40, 43))	('CA19-9', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
107804	27301956	Further, HBx transfection induces human telomerase reverse transcriptase (hTERT) mRNA expression in cultured normal human cholangiocytes, suggesting that HBx may contribute to the carcinogenesis of biliary epithelia.	('human', 'Species', '9606', (34, 39))	('HBx', 'Gene', (154, 157))	('carcinogenesis of biliary epithelia', 'Disease', (180, 215))	('transfection', 'Var', (13, 25))	('carcinogenesis of biliary epithelia', 'Disease', 'MESH:D063646', (180, 215))	('hTERT', 'Gene', '7015', (74, 79))	('hTERT', 'Gene', (74, 79))	('telomerase reverse transcriptase', 'Gene', (40, 72))	('induces', 'PosReg', (26, 33))	('HBx', 'Gene', '944566', (9, 12))	('telomerase reverse transcriptase', 'Gene', '7015', (40, 72))	('contribute', 'Reg', (162, 172))	('HBx', 'Gene', '944566', (154, 157))	('HBx', 'Gene', (9, 12))	('human', 'Species', '9606', (116, 121))
107829	21892300	Laboratory examination showed high bilirubin levels up to 30 mg/dl direct 20 mg/dl indirect 10 mg/dl, increased gamma-GT, SGPT, ALF and highly increased tumor markers (CEA >1000 and CA19-9 >1000 mg/dl) in both patients.	('increased', 'PosReg', (143, 152))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('high bilirubin', 'Phenotype', 'HP:0003573', (30, 44))	('bilirubin levels', 'MPA', (35, 51))	('ALF', 'Gene', '11036', (128, 131))	('ALF', 'Gene', (128, 131))	('bilirubin', 'Chemical', 'MESH:D001663', (35, 44))	('SGPT', 'Gene', (122, 126))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('high bilirubin levels', 'Phenotype', 'HP:0002904', (30, 51))	('patients', 'Species', '9606', (210, 218))	('increased', 'PosReg', (102, 111))	('gamma-GT', 'Protein', (112, 120))	('CEA >1000', 'Var', (168, 177))	('CA19-9', 'MPA', (182, 188))
107898	33396821	A large international study of patients who underwent resection of ICC noted that large tumor size, higher number of tumors, microvascular invasion, N1 or NX disease, suspicious/metastatic lymph nodes on preoperative imaging and R1 resection were associated with a higher likelihood of very early recurrence (<=6 months), suggesting some patients may have benefited from neoadjuvant chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (117, 122))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('patients', 'Species', '9606', (31, 39))	('microvascular', 'Var', (125, 138))	('tumor', 'Disease', (88, 93))	('patients', 'Species', '9606', (338, 346))
107968	33396821	Although the study did not meet its primary end point of improving OS in the intention-to-treat analysis, capecitabine was associated with improved OS in the prespecified sensitivity and perprotocol analyses (53 months versus 36 months, p = 0.028).	('capecitabine', 'Chemical', 'MESH:D000069287', (106, 118))	('capecitabine', 'Var', (106, 118))	('improved', 'PosReg', (139, 147))
108022	30333042	Genetic alterations associated with each metabolic pathway differed between cancers, however, they were a part of cancer drivers in most cancer types.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Genetic alterations', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('metabolic pathway', 'Pathway', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (114, 120))
108032	30333042	We also show that genetic alterations associated with cancer metabolic heterogeneity were a part of cancer drivers in most cancer types.	('genetic alterations', 'Var', (18, 37))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
108059	30333042	Accordingly, aggressive malignant phenotypes of cancer cells obtained by accumulated mutations change metabolic phenotypes to demand energy source represented by carbohydrate and elements for proliferation represented by nucleotide.	('change', 'Reg', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('metabolic phenotypes', 'MPA', (102, 122))	('carbohydrate', 'Chemical', 'MESH:D002241', (162, 174))	('mutations', 'Var', (85, 94))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
108062	30333042	An example of carbohydrate metabolism-related genetic alterations of LGG is presented (Fig.	('carbohydrate', 'Chemical', 'MESH:D002241', (14, 26))	('LGG', 'Gene', (69, 72))	('genetic alterations', 'Var', (46, 65))
108063	30333042	The tumors with high carbohydrate metabolism showed significantly more mutations of EGFR and fewer mutations of FUBP1, CIC, and IDH1.	('FUBP1', 'Gene', (112, 117))	('fewer', 'NegReg', (93, 98))	('IDH1', 'Gene', '3417', (128, 132))	('CIC', 'Gene', '23152', (119, 122))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('EGFR', 'Gene', '1956', (84, 88))	('mutations', 'Var', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CIC', 'Gene', (119, 122))	('FUBP1', 'Gene', '8880', (112, 117))	('EGFR', 'Gene', (84, 88))	('IDH1', 'Gene', (128, 132))	('carbohydrate', 'Chemical', 'MESH:D002241', (21, 33))
108076	30333042	It corresponds to the Darwinian selection of cancer cells which carry driver mutations facilitate cellular survival and growth by changing a favorable metabolic landscape.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('facilitate', 'PosReg', (87, 97))	('cellular survival', 'CPA', (98, 115))	('mutations', 'Var', (77, 86))	('changing', 'Reg', (130, 138))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('favorable metabolic landscape', 'MPA', (141, 170))	('cancer', 'Disease', (45, 51))	('growth', 'CPA', (120, 126))
108077	30333042	The results also suggest that the metabolic change as a hallmark of cancer may be one of the tumorigenesis processes caused by genetic alterations rather than an independent process.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('caused', 'Reg', (117, 123))	('tumor', 'Disease', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('genetic alterations', 'Var', (127, 146))	('metabolic', 'MPA', (34, 43))
108079	30333042	Genetic alterations closely associated with metabolic heterogeneity were a part of cancer drivers in most cancers rather than genes affiliated to metabolic pathways.	('Genetic alterations', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancer', 'Disease', (106, 112))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
108123	26132727	When the cut-off value was defined as the median value, <=15% staining was classified as low expression (P-cadherinlow) and >=15% as high expression (P-cadherinhigh) in ICC and pancreatic cancer patients.	('P-cadherin', 'Gene', '12560', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('P-cadherin', 'Gene', (150, 160))	('>=15%', 'Var', (124, 129))	('ICC', 'Disease', (169, 172))	('<=15', 'Var', (56, 60))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (177, 194))	('patients', 'Species', '9606', (195, 203))	('pancreatic cancer', 'Disease', (177, 194))	('pancreatic cancer', 'Disease', 'MESH:D010190', (177, 194))	('P-cadherin', 'Gene', (105, 115))	('P-cadherin', 'Gene', '12560', (105, 115))
108149	26132727	Multivariate analyses identified high P-cadherin expression to be an independent predictor for DFS in both ICC (hazard ratio [HR] 2.93, P = 0.044, Table1) and pancreatic cancer (HR 2.68, P = 0.005, Table2).	('pancreatic cancer', 'Phenotype', 'HP:0002894', (159, 176))	('DFS', 'Disease', (95, 98))	('high', 'Var', (33, 37))	('ICC', 'Disease', (107, 110))	('P-cadherin', 'Gene', '12560', (38, 48))	('P-cadherin', 'Gene', (38, 48))	('pancreatic cancer', 'Disease', (159, 176))	('expression', 'MPA', (49, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))
108159	26132727	Inhibition of P-cadherin led to significantly fewer invasive cells in the Matrigel cell invasion assay (P = 0.014 in HuCCT1 and P = 0.026 in PK59; Fig.4a).	('fewer', 'NegReg', (46, 51))	('invasive cells in the Matrigel cell invasion assay', 'CPA', (52, 102))	('P-cadherin', 'Gene', '12560', (14, 24))	('P-cadherin', 'Gene', (14, 24))	('Inhibition', 'Var', (0, 10))
108160	26132727	Inhibition of P-cadherin resulted in significantly decreased cell migration (P = 0.002 in HuCCT1 and P = 0.009 in PK59; Fig.4b).	('P-cadherin', 'Gene', '12560', (14, 24))	('decreased', 'NegReg', (51, 60))	('P-cadherin', 'Gene', (14, 24))	('Inhibition', 'Var', (0, 10))	('cell migration', 'CPA', (61, 75))
108161	26132727	Inhibition of P-cadherin had no effect on cell proliferation (P = 0.33 in HuCCT1, P = 0.38 in PK59; Fig.4c).	('P-cadherin', 'Gene', (14, 24))	('Inhibition', 'Var', (0, 10))	('P-cadherin', 'Gene', '12560', (14, 24))
108169	26132727	Of the 10 P-cadherin-positive cases, only 4 contained methylated CDH3 promoter regions (Fig.5c), whereas all 10 P-cadherin-negative cases had methylated CDH3 promoter regions (Fig.5d).	('P-cadherin', 'Gene', (112, 122))	('CDH3', 'Gene', (153, 157))	('CDH3', 'Gene', '1001', (153, 157))	('P-cadherin', 'Gene', (10, 20))	('CDH3', 'Gene', (65, 69))	('P-cadherin', 'Gene', '12560', (10, 20))	('CDH3', 'Gene', '1001', (65, 69))	('P-cadherin', 'Gene', '12560', (112, 122))	('methylated', 'Var', (54, 64))
108171	26132727	Of the 13 P-cadherin positive cases, only 4 cases showed methylated CDH3 promoter regions (Fig.5e), whereas 12 of the 14 P-cadherin negative cases had methylated CDH3 promoter regions (Fig.5f).	('CDH3', 'Gene', (68, 72))	('CDH3', 'Gene', '1001', (68, 72))	('P-cadherin', 'Gene', '12560', (121, 131))	('P-cadherin', 'Gene', (121, 131))	('P-cadherin', 'Gene', (10, 20))	('P-cadherin', 'Gene', '12560', (10, 20))	('CDH3', 'Gene', (162, 166))	('CDH3', 'Gene', '1001', (162, 166))	('methylated', 'Var', (57, 67))
108188	26132727	However, in previous studies on colon cancer and ICC, knockdown of P-cadherin in cancer cells did not induce any change in the expression of EMT markers, including vimentin, slug, snail and twist.	('vimentin', 'Gene', (164, 172))	('cancer', 'Disease', (81, 87))	('slug', 'Gene', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('colon cancer', 'Phenotype', 'HP:0003003', (32, 44))	('snail', 'Gene', (180, 185))	('cancer', 'Disease', (38, 44))	('P-cadherin', 'Gene', (67, 77))	('P-cadherin', 'Gene', '12560', (67, 77))	('colon cancer', 'Disease', 'MESH:D015179', (32, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('expression', 'MPA', (127, 137))	('slug', 'Gene', '6591', (174, 178))	('knockdown', 'Var', (54, 63))	('colon cancer', 'Disease', (32, 44))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('snail', 'Gene', '6615', (180, 185))	('vimentin', 'Gene', '7431', (164, 172))
108197	26132727	In the present study, P-cadherin overexpression was correlated with hypomethylation of the CDH3 promoter, whereas treatment of cells that lacked P-cadherin expression with 5-aza-2'-deoxycytidine induced its expression, accompanied with hypomethylation of the CDH3 promoter region in cholangiocarcinoma and pancreatic cancer cells.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (283, 301))	('CDH3', 'Gene', '1001', (259, 263))	('P-cadherin', 'Gene', '12560', (22, 32))	('P-cadherin', 'Gene', (22, 32))	('hypomethylation', 'Var', (68, 83))	('CDH3', 'Gene', '1001', (91, 95))	('pancreatic cancer', 'Disease', 'MESH:D010190', (306, 323))	('expression', 'MPA', (207, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('overexpression', 'PosReg', (33, 47))	('CDH3', 'Gene', (259, 263))	('P-cadherin', 'Gene', '12560', (145, 155))	('pancreatic cancer', 'Disease', (306, 323))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('P-cadherin', 'Gene', (145, 155))	('hypomethylation', 'MPA', (236, 251))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (172, 194))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (283, 301))	('CDH3', 'Gene', (91, 95))	('cholangiocarcinoma', 'Disease', (283, 301))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (306, 323))
108211	23352938	These samples had altered expression in Notch pathway genes and activation of insulin-like growth factor signaling, despite a low frequency of mutations in regions of NOTCH1 associated with cancer.	('expression', 'MPA', (26, 36))	('insulin-like growth factor signaling', 'Pathway', (78, 114))	('cancer', 'Disease', (190, 196))	('NOTCH1', 'Gene', '18128', (167, 173))	('associated', 'Reg', (174, 184))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('altered', 'Reg', (18, 25))	('NOTCH1', 'Gene', (167, 173))	('activation', 'PosReg', (64, 74))	('Notch pathway genes', 'Gene', (40, 59))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('mutations', 'Var', (143, 152))
108217	23352938	The classic example of pathway dysregulation in the liver is Alagille syndrome characterized by a defective biliary tube formation due to mutation in Notch ligand Jagged1.	('Jagged1', 'Gene', (163, 170))	('Alagille syndrome', 'Disease', 'MESH:D016738', (61, 78))	('mutation', 'Var', (138, 146))	('Alagille syndrome', 'Disease', (61, 78))	('Jagged1', 'Gene', '16449', (163, 170))
108218	23352938	Thus, Notch dysregulation occurs in acute T-cell lymphoblastic leukemia where mutations in C-terminal PEST domain of Notch1 lead to constitutive activation of the pathway.	('activation', 'PosReg', (145, 155))	('T-cell lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (42, 71))	('Notch1', 'Gene', (117, 123))	('leukemia', 'Phenotype', 'HP:0001909', (63, 71))	('T-cell lymphoblastic leukemia', 'Disease', (42, 71))	('constitutive', 'MPA', (132, 144))	('mutations in', 'Var', (78, 90))	('Notch1', 'Gene', '18128', (117, 123))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (49, 71))	('T-cell lymphoblastic leukemia', 'Disease', 'MESH:D054218', (42, 71))
108220	23352938	In cholangiocarcinoma oncogenesis, two recent studies have demonstrated that upon Notch dysregulation, adult hepatocytes can undergo an oncogenic phenotypic switch to acquire characteristics typically attributed to cholangiocarcinoma, including CK19 and SOX19 expression.	('cholangiocarcinoma', 'Disease', (3, 21))	('Notch dysregulation', 'Var', (82, 101))	('SOX19', 'Gene', '20673', (254, 259))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (215, 233))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (215, 233))	('CK19', 'Gene', '16669', (245, 249))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('CK19', 'Gene', (245, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('cholangiocarcinoma', 'Disease', (215, 233))	('cholangiocarcinoma oncogenesis', 'Disease', (3, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('SOX19', 'Gene', (254, 259))	('cholangiocarcinoma oncogenesis', 'Disease', 'MESH:D063646', (3, 33))
108224	23352938	The group reported that aberrant Notch signaling throughout liver development and into adulthood promotes hepatocyte carcinogenesis in a mouse model.	('mouse', 'Species', '10090', (137, 142))	('aberrant', 'Var', (24, 32))	('hepatocyte carcinogenesis', 'Disease', 'MESH:D063646', (106, 131))	('Notch signaling', 'MPA', (33, 48))	('hepatocyte carcinogenesis', 'Disease', (106, 131))	('promotes', 'PosReg', (97, 105))
108233	23352938	In contrast, dysregulation of Notch signaling in another oncogenic context may drive a cholangiocarcinoma phenotype.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('Notch', 'Gene', (30, 35))	('drive', 'Reg', (79, 84))	('dysregulation', 'Var', (13, 26))	('cholangiocarcinoma', 'Disease', (87, 105))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (87, 105))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))
108252	33535978	GSEA indicated that samples with high MRS or TMB also showed an upregulated expression of pathways involved in tumor signaling and the immune response.	('high MRS', 'Var', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('upregulated', 'PosReg', (64, 75))	('TMB', 'Chemical', '-', (45, 48))	('tumor', 'Disease', (111, 116))	('expression', 'MPA', (76, 86))	('GSEA', 'Chemical', '-', (0, 4))
108271	33535978	Improving our understanding of these genetic mutations is vital for selecting prognostic genetic biomarkers, identifying high-risk CCA patients harboring pertinent genetic mutations, and tailoring treatment strategies in clinical practice.	('mutations', 'Var', (172, 181))	('men', 'Species', '9606', (202, 205))	('patients', 'Species', '9606', (135, 143))	('CCA', 'Disease', (131, 134))	('CCA', 'Phenotype', 'HP:0030153', (131, 134))
108272	33535978	Tumor mutation burden (TMB) is defined as the number of somatic (such as missense, deletion, or insertion) mutations per megabase of genome examined.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (107, 116))	('missense', 'Var', (73, 81))	('deletion', 'Var', (83, 91))	('TMB', 'Chemical', '-', (23, 26))
108286	33535978	Comparison of these mutations with those listed in the Cancer Hotspot Mutation database (https://www.cancerhotspots.org/#/home) provided information on whether these mutations are predicted to be putative driver mutations.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('mutations', 'Var', (166, 175))	('cancer', 'Disease', (101, 107))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Cancer', 'Disease', (55, 61))	('Cancer', 'Disease', 'MESH:D009369', (55, 61))	('mutations', 'Var', (20, 29))
108289	33535978	We performed a dimensionality reduction analysis of survival-associated mutant genes using the least absolute shrinkage and selection operator (Lasso) regression, and "survival" and "glmnet" packages in R. Lasso sub-selects prognostic mutant genes by imposing a penalty proportional to the contraction of the regression coefficient.	('mutant', 'Var', (72, 78))	('Lasso', 'Chemical', '-', (144, 149))	('Lasso', 'Chemical', '-', (206, 211))	('mutant', 'Var', (235, 241))	('men', 'Species', '9606', (17, 20))
108301	33535978	Our results revealed that 15 genes (TP53, TTN, KRAS, MUC2, ARID1A, MUC16, BAP1, OBSCN, CSMD3, EPHA2, IDH1, PCLO, LRP1B, PBRM1, and SYNE1) were mutated in more than 20 samples.	('PCLO', 'Gene', '27445', (107, 111))	('CSMD3', 'Gene', (87, 92))	('PBRM1', 'Gene', '55193', (120, 125))	('TTN', 'Gene', (42, 45))	('LRP1B', 'Gene', '53353', (113, 118))	('ARID1A', 'Gene', (59, 65))	('EPHA2', 'Gene', (94, 99))	('TP53', 'Gene', (36, 40))	('PBRM1', 'Gene', (120, 125))	('ARID1A', 'Gene', '8289', (59, 65))	('MUC16', 'Gene', (67, 72))	('OBSCN', 'Gene', (80, 85))	('MUC2', 'Gene', '4583', (53, 57))	('IDH1', 'Gene', (101, 105))	('PCLO', 'Gene', (107, 111))	('EPHA2', 'Gene', '1969', (94, 99))	('OBSCN', 'Gene', '84033', (80, 85))	('SYNE1', 'Gene', (131, 136))	('TP53', 'Gene', '7157', (36, 40))	('BAP1', 'Gene', '8314', (74, 78))	('KRAS', 'Gene', '3845', (47, 51))	('MUC2', 'Gene', (53, 57))	('LRP1B', 'Gene', (113, 118))	('CSMD3', 'Gene', '114788', (87, 92))	('IDH1', 'Gene', '3417', (101, 105))	('SYNE1', 'Gene', '23345', (131, 136))	('KRAS', 'Gene', (47, 51))	('TTN', 'Gene', '7273', (42, 45))	('mutated', 'Var', (143, 150))	('BAP1', 'Gene', (74, 78))	('MUC16', 'Gene', '94025', (67, 72))
108309	33535978	We compared the mutations occurring in our patient cohort with those listed in the Cancer Hotspot Mutation database, and found that 8 (TP53, KRAS, ARID1A, BAP1, IDH1, PBRM1, PIK3CA, and KMT2D) of the top 35 mutations were predicted to be putative driver mutations.	('KRAS', 'Gene', (141, 145))	('patient', 'Species', '9606', (43, 50))	('PBRM1', 'Gene', '55193', (167, 172))	('ARID1A', 'Gene', (147, 153))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('IDH1', 'Gene', '3417', (161, 165))	('PBRM1', 'Gene', (167, 172))	('KMT2D', 'Gene', '8085', (186, 191))	('ARID1A', 'Gene', '8289', (147, 153))	('TP53', 'Gene', '7157', (135, 139))	('PIK3CA', 'Gene', '5290', (174, 180))	('mutations', 'Var', (207, 216))	('Cancer', 'Disease', (83, 89))	('BAP1', 'Gene', '8314', (155, 159))	('Cancer', 'Disease', 'MESH:D009369', (83, 89))	('PIK3CA', 'Gene', (174, 180))	('KMT2D', 'Gene', (186, 191))	('KRAS', 'Gene', '3845', (141, 145))	('BAP1', 'Gene', (155, 159))	('IDH1', 'Gene', (161, 165))	('TP53', 'Gene', (135, 139))
108311	33535978	We performed a PPI network-based analysis using STRING database to determine whether the mutated genes functionally interacted with each other and were involved in tumorigenesis.	('tumor', 'Disease', (164, 169))	('interacted', 'Reg', (116, 126))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('mutated', 'Var', (89, 96))	('involved', 'Reg', (152, 160))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
108313	33535978	In addition, KEGG pathway analysis demonstrated enrichment of mutant genes in several signaling pathways involved in malignancy, such as the PI3K-AKT, MAPK, proteoglycan, and calcium-signaling pathways.	('mutant', 'Var', (62, 68))	('malignancy', 'Disease', 'MESH:D009369', (117, 127))	('AKT', 'Gene', '207', (146, 149))	('proteoglycan', 'Pathway', (157, 169))	('malignancy', 'Disease', (117, 127))	('AKT', 'Gene', (146, 149))	('calcium-signaling pathways', 'Pathway', (175, 201))	('signaling pathways', 'Pathway', (86, 104))	('men', 'Species', '9606', (54, 57))	('MAPK', 'Pathway', (151, 155))	('calcium', 'Chemical', 'MESH:D002118', (175, 182))
108320	33535978	MRS was calculated as follows: MRS = (0.9772 x CDC27) + (3.3262 x AAK1) + (1.0356 x TP53) + (0.8040 x RBM10) + (0.5645 x KRAS) + (1.4581 x IPO5) (Table 2).	('0.9772', 'Var', (38, 44))	('CDC27', 'Gene', (47, 52))	('KRAS', 'Gene', (121, 125))	('IPO5', 'Gene', (139, 143))	('IPO5', 'Gene', '3843', (139, 143))	('AAK1', 'Gene', (66, 70))	('CDC27', 'Gene', '996', (47, 52))	('TP53', 'Gene', '7157', (84, 88))	('RBM10', 'Gene', '8241', (102, 107))	('KRAS)', 'Gene', '3845', (121, 126))	('TP53', 'Gene', (84, 88))	('RBM10', 'Gene', (102, 107))	('AAK1', 'Gene', '22848', (66, 70))
108330	33535978	KM plotter of survival analysis showed that OS was significantly decreased in patients with high TMB compared with those having low TMB (P < 0.001; Fig.	('decreased', 'NegReg', (65, 74))	('patients', 'Species', '9606', (78, 86))	('TMB', 'Chemical', '-', (97, 100))	('TMB', 'Chemical', '-', (132, 135))	('high TMB', 'Var', (92, 100))
108338	33535978	These results demonstrate that crosstalk involved in tumor-signaling pathways and immune-system processes was upregulated in patients with high MRS or TMB (Fig.	('TMB', 'Chemical', '-', (151, 154))	('crosstalk', 'MPA', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('TMB', 'Var', (151, 154))	('upregulated', 'PosReg', (110, 121))	('tumor', 'Disease', (53, 58))	('immune-system processes', 'CPA', (82, 105))	('high MRS', 'Var', (139, 147))	('patients', 'Species', '9606', (125, 133))
108343	33535978	Next, univariate, Lasso, and multivariate Cox regression analyses were used to screen for hub prognostic mutant signature and establish a mutation-risk model for predicting prognosis.	('hub', 'Gene', (90, 93))	('mutant', 'Var', (105, 111))	('hub', 'Gene', '1993', (90, 93))	('Lasso', 'Chemical', '-', (18, 23))
108353	33535978	We investigated the possible link between genetic alternations and patient prognosis, and found that the outcomes of patients with certain genetic mutations were worse than those of wild-type patients; statistically, this finding showed borderline significance.	('mutations', 'Var', (147, 156))	('patient', 'Species', '9606', (192, 199))	('genetic mutations', 'Var', (139, 156))	('patients', 'Species', '9606', (192, 200))	('worse', 'NegReg', (162, 167))	('patient', 'Species', '9606', (117, 124))	('patients', 'Species', '9606', (117, 125))	('patient', 'Species', '9606', (67, 74))
108366	33535978	A study from China demonstrated that in HCC patients who had undergone radical resection, patients with increased TMB tend to show increased risk for recurrence; additionally, they also showed that TMB is an independent risk factor for RFS.	('RFS', 'Disease', 'MESH:D005198', (236, 239))	('patients', 'Species', '9606', (44, 52))	('HCC', 'Gene', (40, 43))	('HCC', 'Gene', '619501', (40, 43))	('TMB', 'Gene', (114, 117))	('TMB', 'Var', (198, 201))	('TMB', 'Chemical', '-', (114, 117))	('patients', 'Species', '9606', (90, 98))	('TMB', 'Chemical', '-', (198, 201))	('RFS', 'Disease', (236, 239))
108382	33535978	In summary, our study demonstrates that mutational signature and TMB were associated with prognosis in patients with iCCA.	('TMB', 'Gene', (65, 68))	('TMB', 'Chemical', '-', (65, 68))	('iCCA', 'Disease', (117, 121))	('CCA', 'Phenotype', 'HP:0030153', (118, 121))	('patients', 'Species', '9606', (103, 111))	('mutational signature', 'Var', (40, 60))	('associated', 'Reg', (74, 84))
108438	31922240	The oligonucleotide primers were purchased from Thermo Fisher Scientific and were as follows: NIS, Hs00166567_m1; GAPDH, Hs02786624_g1 and Hs01060665_g1.	('Hs01060665_g1', 'Var', (139, 152))	('Hs02786624_g1', 'Var', (121, 134))	('NIS', 'Gene', '6528', (94, 97))	('GAPDH', 'Gene', '2597', (114, 119))	('GAPDH', 'Gene', (114, 119))	('Hs00166567_m1', 'Var', (99, 112))	('NIS', 'Gene', (94, 97))
108445	31922240	MS-MLPA analyses were performed using ME002 probemix (MRC-Holland), which can simultaneously detect copy number alterations (CNAs) in 38 tumor suppressor genes and aberrant methylation patterns in a subset of 25 of these genes as previously described.	('tumor', 'Disease', (137, 142))	('copy number alterations', 'Var', (100, 123))	('MRC', 'CellLine', 'CVCL:0440', (54, 57))	('aberrant', 'Var', (164, 172))	('methylation', 'MPA', (173, 184))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
108455	31922240	Additionally, the NIS total expression following exposure to 131I was significantly higher compared to membrane expression (P=0.029).	('131I', 'Var', (61, 65))	('NIS', 'Gene', (18, 21))	('NIS', 'Gene', '6528', (18, 21))	('higher', 'PosReg', (84, 90))
108466	31922240	As regards NIS membrane expression, in the control cells, the expression was significantly lower in the H69 compared to the TFK-1 (P<0.001) and HuCCT1 (P<0.001) cells.	('lower', 'NegReg', (91, 96))	('H69', 'CellLine', 'CVCL:8121', (104, 107))	('CC', 'Phenotype', 'HP:0030153', (146, 148))	('NIS', 'Gene', '6528', (11, 14))	('expression', 'MPA', (62, 72))	('H69', 'Var', (104, 107))	('HuCCT1', 'CellLine', 'CVCL:0324', (144, 150))	('NIS', 'Gene', (11, 14))
108469	31922240	Thus, the H69 cholangiocytes presented a significantly lower NIS total expression compared to the CC cells TFK-1 (P<0.001) and HuCCT1 (P<0.001).	('NIS', 'Gene', '6528', (61, 64))	('CC', 'Phenotype', 'HP:0030153', (129, 131))	('H69', 'Var', (10, 13))	('NIS', 'Gene', (61, 64))	('CC', 'Phenotype', 'HP:0030153', (98, 100))	('lower', 'NegReg', (55, 60))	('HuCCT1', 'CellLine', 'CVCL:0324', (127, 133))	('H69', 'CellLine', 'CVCL:8121', (10, 13))
108494	31922240	In the HuCCT1 cells, following irradiation with 1 Gy, we observed a significant increase in NIS mRNA expression with the increasing time following exposure (2 h, 0.000132+-0.000028; 48 h, 3.736+-0.086, P=0.003; and 12 days, 7.407+-0.390, P=0.003).	('increase', 'PosReg', (80, 88))	('CC', 'Phenotype', 'HP:0030153', (9, 11))	('NIS', 'Gene', (92, 95))	('0.000132+-0.000028', 'Var', (162, 180))	('HuCCT1', 'CellLine', 'CVCL:0324', (7, 13))	('NIS', 'Gene', '6528', (92, 95))
108507	31922240	We analyzed 25 genes for methylation signature, where the ESR1, PAX5, WT1 and CDH13 genes were methylated in both cell lines without and following irradiation with 131I (Fig.	('PAX5', 'Gene', (64, 68))	('methylated', 'Var', (95, 105))	('PAX5', 'Gene', '5079', (64, 68))	('ESR1', 'Gene', (58, 62))	('CDH13', 'Gene', (78, 83))	('WT1', 'Gene', '7490', (70, 73))	('CDH13', 'Gene', '1012', (78, 83))	('WT1', 'Gene', (70, 73))	('ESR1', 'Gene', '2099', (58, 62))
108513	31922240	Additionally, the TFK-1 cells exhibited copy number gains in VHL (3p) and CDH13 (16q).	('VHL', 'Disease', 'MESH:D006623', (61, 64))	('gains', 'PosReg', (52, 57))	('VHL', 'Disease', (61, 64))	('CDH13', 'Gene', (74, 79))	('copy number', 'Var', (40, 51))	('CDH13', 'Gene', '1012', (74, 79))
108514	31922240	Copy number losses were identified in KLLN (10q), PAX6 and CD44 (11p), ATM and CADM1 (11q) and BRCA2 (13q).	('BRCA2', 'Gene', '675', (95, 100))	('CADM1', 'Gene', (79, 84))	('ATM', 'Gene', (71, 74))	('CADM1', 'Gene', '23705', (79, 84))	('KLLN', 'Gene', (38, 42))	('losses', 'NegReg', (12, 18))	('CD44', 'Gene', '960', (59, 63))	('ATM', 'Gene', '472', (71, 74))	('CD44', 'Gene', (59, 63))	('BRCA2', 'Gene', (95, 100))	('Copy number', 'Var', (0, 11))	('PAX6', 'Gene', (50, 54))	('PAX6', 'Gene', '5080', (50, 54))
108515	31922240	Homozygous deletion in CDKN2A (9p) and STK11 (19p) was also found in the TFK-1 cells (Fig.	('STK11', 'Gene', '6794', (39, 44))	('CDKN2A', 'Gene', (23, 29))	('CDKN2A', 'Gene', '1029', (23, 29))	('deletion', 'Var', (11, 19))	('STK11', 'Gene', (39, 44))
108517	31922240	Copy number losses were identified in THBS1 (15q), PYCARD (16p), CDH13 (16q) and STK11 (19p) (Fig.	('THBS1', 'Gene', (38, 43))	('CDH13', 'Gene', '1012', (65, 70))	('THBS1', 'Gene', '7057', (38, 43))	('PYCARD', 'Gene', (51, 57))	('STK11', 'Gene', '6794', (81, 86))	('Copy number losses', 'Var', (0, 18))	('CDH13', 'Gene', (65, 70))	('PYCARD', 'Gene', '29108', (51, 57))	('STK11', 'Gene', (81, 86))
108520	31922240	In the HuCCT1 cells, ESR1 and CDH13 presented both methylation and copy number loss.	('copy number loss', 'Disease', 'MESH:D016388', (67, 83))	('ESR1', 'Gene', (21, 25))	('HuCCT1', 'CellLine', 'CVCL:0324', (7, 13))	('CC', 'Phenotype', 'HP:0030153', (9, 11))	('CDH13', 'Gene', (30, 35))	('methylation', 'Var', (51, 62))	('ESR1', 'Gene', '2099', (21, 25))	('CDH13', 'Gene', '1012', (30, 35))	('copy number loss', 'Disease', (67, 83))
108521	31922240	PAX5, PAX6, WT1, CADM1 and GATA5 presented both methylation and copy number gain.	('CADM1', 'Gene', (17, 22))	('PAX6', 'Gene', (6, 10))	('GATA5', 'Gene', (27, 32))	('GATA5', 'Gene', '140628', (27, 32))	('gain', 'PosReg', (76, 80))	('PAX5', 'Gene', (0, 4))	('CADM1', 'Gene', '23705', (17, 22))	('PAX5', 'Gene', '5079', (0, 4))	('PAX6', 'Gene', '5080', (6, 10))	('WT1', 'Gene', '7490', (12, 15))	('methylation', 'Var', (48, 59))	('copy', 'MPA', (64, 68))	('WT1', 'Gene', (12, 15))
108538	31922240	Therefore, NIS at the cell membrane can be targeted; 131I may be a metabolic radiotherapy agent for the treatment of CC.	('CC', 'Phenotype', 'HP:0030153', (117, 119))	('NIS', 'Gene', '6528', (11, 14))	('131I', 'Var', (53, 57))	('NIS', 'Gene', (11, 14))
108550	31922240	As regards NIS expression, a selectivity for 131I is another explanation for the higher survival rate of cholangiocytes, compared to the CC cells.	('survival', 'CPA', (88, 96))	('131I', 'Var', (45, 49))	('higher', 'PosReg', (81, 87))	('NIS', 'Gene', '6528', (11, 14))	('CC', 'Phenotype', 'HP:0030153', (137, 139))	('NIS', 'Gene', (11, 14))
108551	31922240	The results confirmed that 131I affected all cell lines, with a higher expression in the cancer cells.	('expression', 'MPA', (71, 81))	('higher', 'PosReg', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('131I', 'Var', (27, 31))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
108557	31922240	This type of tumor can be characterized as a stepwise cancer model, where the accumulation of inflammatory-mediated genetic and epigenetic alterations can explain dysplastic lesions that can lead to cancer.	('tumor', 'Disease', (13, 18))	('epigenetic alterations', 'Var', (128, 150))	('lead to', 'Reg', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('dysplastic lesions', 'Disease', 'MESH:D021782', (163, 181))	('cancer', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('dysplastic lesions', 'Disease', (163, 181))
108558	31922240	In this study, cytogenetic, genomic and methylation approaches revealed several numerical and structural chromosomal abnormalities and methylated genes in the CC cells.	('methylated', 'Var', (135, 145))	('chromosomal abnormalities', 'Disease', (105, 130))	('CC', 'Phenotype', 'HP:0030153', (159, 161))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (105, 130))
108560	31922240	However, it is important to continue to describe the possible effects induced by 131I on cholangiocarcinoma, namely its influence on oxidative stress, genotoxicity.	('cholangiocarcinoma', 'Disease', (89, 107))	('oxidative stress', 'Phenotype', 'HP:0025464', (133, 149))	('131I', 'Var', (81, 85))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (89, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (89, 107))	('genotoxicity', 'Disease', (151, 163))	('oxidative stress', 'MPA', (133, 149))	('genotoxicity', 'Disease', 'None', (151, 163))
108561	31922240	Moreover, the influence of NIS gene expression manipulation on the effects of 31I on CC cells, as well as the effects of 131I therapy on animal models remains unclear, and future studies are warranted to address these issues.	('NIS', 'Gene', '6528', (27, 30))	('manipulation', 'Var', (47, 59))	('NIS', 'Gene', (27, 30))	('CC', 'Phenotype', 'HP:0030153', (85, 87))
108642	26168827	Evaluation of Intraductal Ultrasonography, Endoscopic Brush Cytology and K-ras, P53 Gene Mutation in the Early Diagnosis of Malignant Bile Duct Stricture In qualitative diagnosis of bile duct stenosis, single diagnostic measure is difficult to make a correct diagnosis, to combine several diagnostic techniques may be helpful to make an accurate diagnosis.	('K-ras', 'Gene', (73, 78))	('Malignant Bile Duct', 'Disease', 'MESH:D001650', (124, 143))	('P53', 'Gene', '7157', (80, 83))	('Mutation', 'Var', (89, 97))	('Bile Duct Stricture', 'Phenotype', 'HP:0030151', (134, 153))	('K-ras', 'Gene', '3845', (73, 78))	('Malignant Bile Duct', 'Disease', (124, 143))	('bile duct stenosis', 'Phenotype', 'HP:0007678', (182, 200))	('bile duct stenosis', 'Disease', (182, 200))	('P53', 'Gene', (80, 83))
108643	26168827	The aim of this study was to evaluate the value of intraductal ultrasonography (IDUS), endoscopic brush cytology and K-ras, P53 gene mutation in the early diagnosis of malignant biliary stricture.	('P53', 'Gene', '7157', (124, 127))	('mutation', 'Var', (133, 141))	('malignant biliary stricture', 'Disease', (168, 195))	('P53', 'Gene', (124, 127))	('K-ras', 'Gene', (117, 122))	('K-ras', 'Gene', '3845', (117, 122))
108647	26168827	There were obvious statistical significance in the sensitivity and accuracy between IDUS + brush cytology + P53 or IDUS + brush cytology + K-ras and IDUS + brush cytology or IDUS (P < 0.05).	('IDUS', 'Var', (84, 88))	('K-ras', 'Gene', (139, 144))	('K-ras', 'Gene', '3845', (139, 144))	('P53', 'Gene', (108, 111))	('P53', 'Gene', '7157', (108, 111))
108648	26168827	There was no statistical significance in the sensitivity, specificity, positive predictive value, negative predictive value and accuracy between IDUS + brush cytology + P53 and IDUS + brush cytology + K-ras (P > 0.05).	('P53', 'Gene', '7157', (169, 172))	('IDUS', 'Var', (145, 149))	('K-ras', 'Gene', (201, 206))	('K-ras', 'Gene', '3845', (201, 206))	('P53', 'Gene', (169, 172))
108673	26168827	In the detection of brush cytology specimens, gene mutation exists only if one gene mutate among K-ras gene exon 1 and P53 exon 5, 6, 7, 8.	('K-ras', 'Gene', (97, 102))	('K-ras', 'Gene', '3845', (97, 102))	('P53', 'Gene', (119, 122))	('P53', 'Gene', '7157', (119, 122))	('mutate', 'Var', (84, 90))
108675	26168827	The abnormal electrophoresis showed abnormal surge strips, increased and missing strips when K-ras gene exon 1 or P53 gene exon 5, 6, 7, 8 mutated.	('K-ras', 'Gene', (93, 98))	('K-ras', 'Gene', '3845', (93, 98))	('missing', 'NegReg', (73, 80))	('strips', 'MPA', (81, 87))	('mutated', 'Var', (139, 146))	('P53', 'Gene', (114, 117))	('increased', 'PosReg', (59, 68))	('P53', 'Gene', '7157', (114, 117))
108679	26168827	Point mutation was found in the vast majority of all patients, insertional mutagenesis in 4 cases.	('Point mutation', 'Var', (0, 14))	('insertional mutagenesis', 'Var', (63, 86))	('patients', 'Species', '9606', (53, 61))	('found', 'Reg', (19, 24))
108684	26168827	K-ras gene mutation occurred in those patients with malignant biliary stricture comprising three papillary carcinoma, four high differentiated adenocarcinoma, five differentiated adenocarcinoma, five low differentiated adenocarcinoma, three undifferentiated adenocarcinoma, while corresponding, 4, 4, 5, 6 and 3 cases in patients with P53 gene mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('adenocarcinoma', 'Disease', (143, 157))	('P53', 'Gene', '7157', (335, 338))	('patients', 'Species', '9606', (38, 46))	('K-ras', 'Gene', '3845', (0, 5))	('undifferentiated adenocarcinoma', 'Disease', 'MESH:D002277', (241, 272))	('adenocarcinoma', 'Disease', (179, 193))	('patients', 'Species', '9606', (321, 329))	('adenocarcinoma', 'Disease', (258, 272))	('adenocarcinoma', 'Disease', (219, 233))	('papillary carcinoma', 'Disease', (97, 116))	('adenocarcinoma', 'Disease', 'MESH:D000230', (143, 157))	('mutation', 'Var', (11, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('adenocarcinoma', 'Disease', 'MESH:D000230', (179, 193))	('malignant biliary stricture', 'Disease', (52, 79))	('undifferentiated adenocarcinoma', 'Disease', (241, 272))	('adenocarcinoma', 'Disease', 'MESH:D000230', (219, 233))	('papillary carcinoma', 'Disease', 'MESH:D002291', (97, 116))	('K-ras', 'Gene', (0, 5))	('adenocarcinoma', 'Disease', 'MESH:D000230', (258, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('P53', 'Gene', (335, 338))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('occurred', 'Reg', (20, 28))
108705	26168827	Due to the low sensitivity and specificity of serum or bile K-ras, P53 gene mutations in detecting malignant biliary stricture, in recent years, brush cytology has been gradually used to detect K-ras and P53 gene mutations for the diagnosis of malignant bile duct stricture, but the number of reported cases were less, and many of which were tested individual gene without the simultaneous detection of K-ras and P53 gene mutations.	('P53', 'Gene', (204, 207))	('P53', 'Gene', '7157', (67, 70))	('mutations', 'Var', (76, 85))	('P53', 'Gene', '7157', (204, 207))	('K-ras', 'Gene', (194, 199))	('K-ras', 'Gene', (403, 408))	('K-ras', 'Gene', '3845', (194, 199))	('K-ras', 'Gene', '3845', (403, 408))	('K-ras', 'Gene', (60, 65))	('K-ras', 'Gene', '3845', (60, 65))	('mutations', 'Var', (213, 222))	('P53', 'Gene', (413, 416))	('bile duct stricture', 'Phenotype', 'HP:0030151', (254, 273))	('P53', 'Gene', '7157', (413, 416))	('P53', 'Gene', (67, 70))
108707	26168827	detected K-ras gene mutation in 23 cases of bile specimens, 14 cases of bile duct brush cytology, 10 cases of bile duct carcinoma tissue by PCR-single strand conformation polymorphism and DNA sequencing.	('bile duct carcinoma', 'Disease', 'MESH:D001650', (110, 129))	('K-ras', 'Gene', (9, 14))	('K-ras', 'Gene', '3845', (9, 14))	('mutation', 'Var', (20, 28))	('bile duct carcinoma', 'Phenotype', 'HP:0030153', (110, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('bile duct carcinoma', 'Disease', (110, 129))
108723	24889489	We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection.	('mutations', 'Var', (68, 77))	('ICC', 'Disease', (94, 97))	('patients', 'Species', '9606', (104, 112))
108728	24889489	Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('MAP2K1', 'Gene', '5604', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('MAP2K1', 'Gene', (132, 138))	('mutation', 'Var', (106, 114))	('IDH1', 'Gene', (23, 27))	('mutation', 'Var', (120, 128))	('tumor', 'Disease', (35, 40))	('associated', 'Reg', (65, 75))	('PIK3CA', 'Gene', (94, 100))	('IDH1', 'Gene', '3417', (23, 27))	('patients', 'Species', '9606', (6, 14))	('PIK3CA', 'Gene', '5290', (94, 100))
108742	24889489	For example, some groups have reported somatic alterations in the KRAS, TP53, CDKN2A, and SMAD4 (DPC4) genes in cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 130))	('TP53', 'Gene', '7157', (72, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('CDKN2A', 'Gene', (78, 84))	('KRAS', 'Gene', '3845', (66, 70))	('DPC4', 'Gene', (97, 101))	('TP53', 'Gene', (72, 76))	('CDKN2A', 'Gene', '1029', (78, 84))	('SMAD4', 'Gene', '4089', (90, 95))	('DPC4', 'Gene', '4089', (97, 101))	('cholangiocarcinoma', 'Disease', (112, 130))	('alterations', 'Var', (47, 58))	('SMAD4', 'Gene', (90, 95))	('KRAS', 'Gene', (66, 70))
108743	24889489	Other investigators have identified mutations in genes encoding for molecules of the phosphatidylinositide 3-kinase (PI3K) cell-signaling pathway (e.g., PIK3CA, PTEN, and AKT1), as well as for isocitrate dehydrogenase (IDH) 1 and 2.	('PIK3CA', 'Gene', '5290', (153, 159))	('phosphatidylinositide 3-kinase', 'Gene', (85, 115))	('AKT1', 'Gene', (171, 175))	('PTEN', 'Gene', '5728', (161, 165))	('mutations', 'Var', (36, 45))	('isocitrate dehydrogenase (IDH) 1 and 2', 'Gene', '3417;3418', (193, 231))	('PTEN', 'Gene', (161, 165))	('phosphatidylinositide 3-kinase', 'Gene', '5290', (85, 115))	('PIK3CA', 'Gene', (153, 159))	('AKT1', 'Gene', '207', (171, 175))
108746	24889489	Specifically, we sought to define the frequency of well-established cancer gene mutations, assess the association of these mutations with clinical and morphologic features, and correlate mutations with long-term oncologic outcomes in patients with resected ICCs.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('patients', 'Species', '9606', (234, 242))	('cancer', 'Disease', (68, 74))
108751	24889489	Mutational profiling was performed on these nucleic acids, which simultaneously queried for over 150 previously described hotspot mutations across 15 cancer genes, including AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, IDH1, IDH2, KIT, KRAS, MAP2K1, NOTCH1, NRAS, PIK3CA, PTEN, and TP53.	('TP53', 'Gene', (275, 279))	('NRAS', 'Gene', '4893', (251, 255))	('AKT1', 'Gene', (174, 178))	('PIK3CA', 'Gene', (257, 263))	('CTNNB1', 'Gene', '1499', (191, 197))	('IDH1', 'Gene', (212, 216))	('cancer', 'Disease', (150, 156))	('APC', 'Disease', 'MESH:D011125', (180, 183))	('APC', 'Disease', (180, 183))	('KIT', 'Gene', (224, 227))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('TP53', 'Gene', '7157', (275, 279))	('ERBB2', 'Gene', (205, 210))	('MAP2K1', 'Gene', '5604', (235, 241))	('PTEN', 'Gene', (265, 269))	('EGFR', 'Gene', (199, 203))	('IDH2', 'Gene', (218, 222))	('NOTCH1', 'Gene', (243, 249))	('MAP2K1', 'Gene', (235, 241))	('IDH2', 'Gene', '3418', (218, 222))	('KRAS', 'Gene', '3845', (229, 233))	('NRAS', 'Gene', (251, 255))	('IDH1', 'Gene', '3417', (212, 216))	('ERBB2', 'Gene', '2064', (205, 210))	('CTNNB1', 'Gene', (191, 197))	('PTEN', 'Gene', '5728', (265, 269))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('NOTCH1', 'Gene', '4851', (243, 249))	('KRAS', 'Gene', (229, 233))	('mutations', 'Var', (130, 139))	('BRAF', 'Gene', '673', (185, 189))	('PIK3CA', 'Gene', '5290', (257, 263))	('BRAF', 'Gene', (185, 189))	('AKT1', 'Gene', '207', (174, 178))	('EGFR', 'Gene', '1956', (199, 203))
108752	24889489	The SNaPshot genotyping assay is a fast, high-throughput, multiplex mutational profiling method that has the advantage over conventional dideoxy-nucleotide (Sanger) sequencing in that mutations can be detected when mutant DNA comprises as little as 5 % of the total DNA.	('mutations', 'Var', (184, 193))	('DNA', 'Gene', (222, 225))	('dideoxy-nucleotide', 'Chemical', 'MESH:D054306', (137, 155))	('mutant', 'Var', (215, 221))
108776	24889489	Specifically, well-known tumor associated genes such as KRAS (8.6 %) and BRAF (4.9 %) were mutated in roughly 5-10 % of patients.	('BRAF', 'Gene', '673', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('KRAS', 'Gene', (56, 60))	('tumor', 'Disease', (25, 30))	('KRAS', 'Gene', '3845', (56, 60))	('mutated', 'Var', (91, 98))	('patients', 'Species', '9606', (120, 128))	('BRAF', 'Gene', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
108778	24889489	Although only one tumor (0.6 %) was found to have a mutation in the most common hotspot regions of PTEN, the incidence of PIK3CA mutations was higher (n = 7, 4.3 %).	('PIK3CA', 'Gene', (122, 128))	('tumor', 'Disease', (18, 23))	('mutations', 'Var', (129, 138))	('PIK3CA', 'Gene', '5290', (122, 128))	('mutation', 'Var', (52, 60))	('PTEN', 'Gene', (99, 103))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('PTEN', 'Gene', '5728', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
108781	24889489	A genetic mutation in IDH1 was identified in 31 samples (15.5 %), compared with only 9 samples (4.5 %) for IDH2.	('IDH2', 'Gene', '3418', (107, 111))	('genetic mutation', 'Var', (2, 18))	('IDH1', 'Gene', (22, 26))	('IDH1', 'Gene', '3417', (22, 26))	('IDH2', 'Gene', (107, 111))
108782	24889489	Of note, among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation, and to a much lower extent, a mutation in MAP2K1 (4 %).	('patients', 'Species', '9606', (15, 23))	('MAP2K1', 'Gene', '5604', (167, 173))	('IDH1', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('PIK3CA', 'Gene', (103, 109))	('IDH1', 'Gene', '3417', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('MAP2K1', 'Gene', (167, 173))	('mutation', 'Var', (155, 163))	('PIK3CA', 'Gene', '5290', (103, 109))	('mutation', 'Var', (115, 123))	('tumor', 'Disease', (44, 49))	('associated', 'Reg', (74, 84))
108788	24889489	Compared with wild-type tumors, median survival was 20.3 months for KRAS mutant cases (P = 0.07) and 25.5 months for BRAF mutant cases (P = 0.92).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('mutant', 'Var', (73, 79))	('KRAS', 'Gene', (68, 72))	('KRAS', 'Gene', '3845', (68, 72))	('BRAF', 'Gene', '673', (117, 121))	('mutant', 'Var', (122, 128))	('BRAF', 'Gene', (117, 121))
108789	24889489	Cases with either KRAS or BRAF mutations had a median overall survival of 20.3 months (P = 0.17) (Supplemental Fig.	('mutations', 'Var', (31, 40))	('KRAS', 'Gene', (18, 22))	('BRAF', 'Gene', '673', (26, 30))	('men', 'Species', '9606', (104, 107))	('KRAS', 'Gene', '3845', (18, 22))	('BRAF', 'Gene', (26, 30))
108790	24889489	Mutations in the PI3K pathway had a median survival comparable to wild-type cases (PIK3CA mutation only: 37.3 months vs. PIK3CA or PTEN mutation: 43.3 months) (all P > 0.05) (Supplemental Fig.	('PTEN', 'Gene', (131, 135))	('PTEN', 'Gene', '5728', (131, 135))	('PIK3CA', 'Gene', (121, 127))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', (83, 89))	('PI3K pathway', 'Pathway', (17, 29))	('PIK3CA', 'Gene', '5290', (121, 127))	('PIK3CA', 'Gene', '5290', (83, 89))	('men', 'Species', '9606', (181, 184))
108791	24889489	Similarly, no association with mutations in IDH was noted (IDH1 mutation only: 39.3 months vs. IDH2 mutation only: 25.3 months vs. IDH1 or IDH2 mutation: 31.3 months) (all P > 0.05) (Supplemental Fig.	('IDH1', 'Gene', '3417', (59, 63))	('IDH', 'Gene', '3417', (59, 62))	('IDH1', 'Gene', '3417', (131, 135))	('IDH2', 'Gene', (95, 99))	('IDH', 'Gene', '3417', (131, 134))	('IDH', 'Gene', (95, 98))	('IDH2', 'Gene', '3418', (95, 99))	('IDH', 'Gene', '3417', (139, 142))	('IDH', 'Gene', '3417', (95, 98))	('IDH2', 'Gene', (139, 143))	('mutations', 'Var', (31, 40))	('IDH2', 'Gene', '3418', (139, 143))	('IDH', 'Gene', (44, 47))	('IDH1', 'Gene', (59, 63))	('IDH', 'Gene', (59, 62))	('IDH1', 'Gene', (131, 135))	('men', 'Species', '9606', (189, 192))	('IDH', 'Gene', (131, 134))	('IDH', 'Gene', (139, 142))	('IDH', 'Gene', '3417', (44, 47))
108793	24889489	For example, data have suggested an important role in the mutation of the two proto-oncogenes, KRAS and BRAF, among many patients with colon cancer.	('KRAS', 'Gene', '3845', (95, 99))	('colon cancer', 'Disease', (135, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('colon cancer', 'Phenotype', 'HP:0003003', (135, 147))	('mutation', 'Var', (58, 66))	('BRAF', 'Gene', '673', (104, 108))	('KRAS', 'Gene', (95, 99))	('BRAF', 'Gene', (104, 108))	('patients', 'Species', '9606', (121, 129))	('colon cancer', 'Disease', 'MESH:D015179', (135, 147))
108797	24889489	Specifically, genes such as KRAS and BRAF, as well as those such as PIK3CA, IDH1, and IDH2 were mutated in about 5-15 % of patients with ICC.	('mutated', 'Var', (96, 103))	('IDH2', 'Gene', (86, 90))	('KRAS', 'Gene', (28, 32))	('IDH1', 'Gene', (76, 80))	('PIK3CA', 'Gene', (68, 74))	('KRAS', 'Gene', '3845', (28, 32))	('BRAF', 'Gene', '673', (37, 41))	('IDH2', 'Gene', '3418', (86, 90))	('BRAF', 'Gene', (37, 41))	('patients', 'Species', '9606', (123, 131))	('IDH1', 'Gene', '3417', (76, 80))	('PIK3CA', 'Gene', '5290', (68, 74))	('ICC', 'Disease', (137, 140))
108799	24889489	Mutations in KRAS and BRAF have been noted to be important drivers of tumorigenesis in colon cancer and, to a lesser extent, ICC.	('colon cancer', 'Disease', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('BRAF', 'Gene', '673', (22, 26))	('tumor', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('BRAF', 'Gene', (22, 26))	('Mutations', 'Var', (0, 9))	('colon cancer', 'Phenotype', 'HP:0003003', (87, 99))	('KRAS', 'Gene', (13, 17))	('colon cancer', 'Disease', 'MESH:D015179', (87, 99))	('KRAS', 'Gene', '3845', (13, 17))
108800	24889489	Although mutations in KRAS and BRAF have been reported in ICC, the frequency of these mutations has varied considerably, ranging from 5 to 50 %.	('mutations', 'Var', (9, 18))	('KRAS', 'Gene', '3845', (22, 26))	('KRAS', 'Gene', (22, 26))	('reported', 'Reg', (46, 54))	('ICC', 'Disease', (58, 61))	('BRAF', 'Gene', '673', (31, 35))	('BRAF', 'Gene', (31, 35))
108801	24889489	The reasons for the reported wide-ranging incidence of KRAS and BRAF mutations in ICC are likely multifactorial, including possible large variations that can result from deriving proportions from low sample sizes.	('KRAS', 'Gene', (55, 59))	('mutations', 'Var', (69, 78))	('BRAF', 'Gene', '673', (64, 68))	('KRAS', 'Gene', '3845', (55, 59))	('BRAF', 'Gene', (64, 68))
108802	24889489	In addition, some previous studies reported combined data on both ICC and extrahepatic cholangiocarcinoma, which may have a different incidence of KRAS mutations:thereby further confounding these reports.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (74, 105))	('mutations', 'Var', (152, 161))	('ICC', 'Disease', (66, 69))	('extrahepatic cholangiocarcinoma', 'Disease', (74, 105))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('KRAS', 'Gene', (147, 151))	('KRAS', 'Gene', '3845', (147, 151))
108803	24889489	In the current study we identified mutations in KRAS in 8.6 % of cases and BRAF mutations in an additional 4.9 % of cases.	('KRAS', 'Gene', (48, 52))	('mutations', 'Var', (80, 89))	('KRAS', 'Gene', '3845', (48, 52))	('BRAF', 'Gene', '673', (75, 79))	('BRAF', 'Gene', (75, 79))	('mutations', 'Var', (35, 44))
108804	24889489	The identification of KRAS and BRAF mutations in a small subset of patients is consistent with several previous studies.	('patients', 'Species', '9606', (67, 75))	('mutations', 'Var', (36, 45))	('KRAS', 'Gene', '3845', (22, 26))	('KRAS', 'Gene', (22, 26))	('BRAF', 'Gene', '673', (31, 35))	('BRAF', 'Gene', (31, 35))
108805	24889489	Interestingly, although it did not reach significance perhaps as a result of lack of statistical power, KRAS mutation tended to be associated with a worse outcome (Supplemental Fig.	('KRAS', 'Gene', '3845', (104, 108))	('men', 'Species', '9606', (170, 173))	('KRAS', 'Gene', (104, 108))	('mutation', 'Var', (109, 117))
108808	24889489	The identification of KRAS and BRAF mutated tumors may help inform future targeted therapy for ICC.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('ICC', 'Disease', (95, 98))	('mutated', 'Var', (36, 43))	('KRAS', 'Gene', '3845', (22, 26))	('KRAS', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('BRAF', 'Gene', '673', (31, 35))	('BRAF', 'Gene', (31, 35))
108809	24889489	For example, agents such as vemurafenib have antitumor activity in patients with BRAF mutations, whereas patients with KRAS or BRAF mutations are unlikely to be good candidates for EGFR inhibitor therapy.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('mutations', 'Var', (86, 95))	('patients', 'Species', '9606', (105, 113))	('EGFR', 'Gene', (181, 185))	('patients', 'Species', '9606', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('BRAF', 'Gene', '673', (127, 131))	('vemurafenib', 'Chemical', 'MESH:D000077484', (28, 39))	('BRAF', 'Gene', '673', (81, 85))	('tumor', 'Disease', (49, 54))	('BRAF', 'Gene', (127, 131))	('BRAF', 'Gene', (81, 85))	('KRAS', 'Gene', (119, 123))	('KRAS', 'Gene', '3845', (119, 123))	('EGFR', 'Gene', '1956', (181, 185))
108810	24889489	also identified genetic alterations of key signaling molecules and the relevance of EGFR and HER2 targeting in ICC.	('HER2', 'Gene', '2064', (93, 97))	('ICC', 'Disease', (111, 114))	('genetic alterations', 'Var', (16, 35))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (84, 88))	('HER2', 'Gene', (93, 97))
93679	24889489	The recurrent cancer mutations in these enzymes confer neomorphic activity through the reduction of alpha-ketoglutarate to the metabolite R(-)-2-hydroxyglutarate (2HG), resulting in 2HG accumulation in the tumor tissue.	('cancer', 'Disease', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('2HG accumulation', 'MPA', (182, 198))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('R(-)-2-hydroxyglutarate', 'Chemical', '-', (138, 161))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('reduction', 'MPA', (87, 96))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (100, 119))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('neomorphic', 'CPA', (55, 65))	('mutations', 'Var', (21, 30))
108812	24889489	High intracellular levels of 2HG are sufficient for promoting the tumorigenic effects of mutant IDH activity that are associated with enhanced proliferation and impaired differentiation.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('promoting', 'PosReg', (52, 61))	('enhanced', 'PosReg', (134, 142))	('IDH', 'Gene', '3417', (96, 99))	('tumor', 'Disease', (66, 71))	('differentiation', 'CPA', (170, 185))	('impaired', 'NegReg', (161, 169))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('mutant', 'Var', (89, 95))	('IDH', 'Gene', (96, 99))
108814	24889489	For IDH mutations, earlier reports suggested that mutations in IDH1 or IDH2 were associated with a longer overall survival and time to tumor recurrence after resection.	('longer', 'PosReg', (99, 105))	('IDH1', 'Gene', '3417', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('IDH', 'Gene', '3417', (4, 7))	('IDH', 'Gene', (63, 66))	('time', 'CPA', (127, 131))	('mutations', 'Var', (50, 59))	('IDH2', 'Gene', (71, 75))	('tumor', 'Disease', (135, 140))	('IDH', 'Gene', '3417', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('IDH', 'Gene', (71, 74))	('IDH2', 'Gene', '3418', (71, 75))	('overall survival', 'CPA', (106, 122))	('IDH', 'Gene', '3417', (71, 74))	('IDH1', 'Gene', (63, 67))	('IDH', 'Gene', (4, 7))
108815	24889489	However, a recent study showed the opposite trend; subjects with IDH1 or IDH2 mutations had 3-year survival of 33 % compared with 3-year survival of 81 % for subjects with wild-type IDH genes (P = 0.0034).	('IDH1', 'Gene', '3417', (65, 69))	('IDH', 'Gene', (65, 68))	('IDH', 'Gene', '3417', (182, 185))	('IDH', 'Gene', (73, 76))	('IDH', 'Gene', '3417', (65, 68))	('mutations', 'Var', (78, 87))	('IDH', 'Gene', '3417', (73, 76))	('IDH2', 'Gene', (73, 77))	('IDH1', 'Gene', (65, 69))	('IDH2', 'Gene', '3418', (73, 77))	('IDH', 'Gene', (182, 185))
108816	24889489	In the current study, we failed to find any association of IDH1/2 mutation with survival (Supplemental Fig.	('men', 'Species', '9606', (96, 99))	('IDH1/2', 'Gene', (59, 65))	('IDH1/2', 'Gene', '3418;3417', (59, 65))	('mutation', 'Var', (66, 74))
108818	24889489	More recently, exome sequencing has also identified frequent inactivating mutations in multiple chromatin-remodeling genes including BAP1 and ARID1A.	('BAP1', 'Gene', '8314', (133, 137))	('ARID1A', 'Gene', '8289', (142, 148))	('inactivating mutations', 'Var', (61, 83))	('ARID1A', 'Gene', (142, 148))	('BAP1', 'Gene', (133, 137))
108819	24889489	Interestingly, comparisons between fluke-related and non-fluke-related ICCs demonstrated statistically significant differences in some mutation patterns including BAP1, which was more frequently mutated in non-fluke-related ICCs.	('BAP1', 'Gene', '8314', (163, 167))	('significant differences', 'Reg', (103, 126))	('BAP1', 'Gene', (163, 167))	('mutated', 'Var', (195, 202))
108820	24889489	In the current study, we did identify low frequency mutations in some other genes including NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), and CTNNB1 (0.6 %), as well as genes in the PI3K pathway.	('mutations', 'Var', (52, 61))	('PI3K pathway', 'Pathway', (180, 192))	('NRAS', 'Gene', (92, 96))	('CTNNB1', 'Gene', (140, 146))	('MAP2K1', 'Gene', '5604', (120, 126))	('CTNNB1', 'Gene', '1499', (140, 146))	('MAP2K1', 'Gene', (120, 126))	('NRAS', 'Gene', '4893', (92, 96))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
108822	24889489	Previous reports on mutations in the PI3K pathway among patients with ICC are rare.	('PI3K pathway', 'Pathway', (37, 49))	('patients', 'Species', '9606', (56, 64))	('mutations', 'Var', (20, 29))
108829	24889489	SNaPshot genotyping platform has inherent limitations and this may explain, at least in part, why only 57 % of tumors had mutations identified in our study compared with a recent report by Ross et al.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('mutations', 'Var', (122, 131))
108831	24889489	We are planning to expand our initial findings from this study and use more comprehensive genomic technology [i.e., Next-Generation Sequencing (NGS)] for a future study to assess the prevalence and prognostic significance of other mutations including those in the ARID family and others that have been recently reported.	('mutations', 'Var', (231, 240))	('ARID', 'Disease', 'None', (264, 268))	('ARID', 'Disease', (264, 268))
108875	23704979	The same statistical test revealed that to the contrary patients with a higher FLT1 expression had a higher chance for prolonged survival with a median overall survival time of 23.6 months and 40% of patients surviving longer than 3 years (P = 0.006, [HR] = 0.28, 95% CI = 0.07-1.14; Figure 2), whereas patients with a low expression of FLT1 survived 5.3 months in median and none of the patients in this group survived longer than 2 years.	('patients', 'Species', '9606', (56, 64))	('patients', 'Species', '9606', (303, 311))	('FLT1', 'Gene', (79, 83))	('patients', 'Species', '9606', (200, 208))	('FLT1', 'Gene', (337, 341))	('FLT1', 'Gene', '2321', (79, 83))	('FLT1', 'Gene', '2321', (337, 341))	('patients', 'Species', '9606', (388, 396))	('higher', 'Var', (72, 78))	('expression', 'MPA', (84, 94))
108876	23704979	Similar to FLT1 patients with a high HPSE expression had a longer median survival time (P = 0.02, [HR] = 0.34, 95% CI = 0.11-1.04; Figure 3) with nearly one third of the patients living after 3 years, whereas none of the patients with a HPSE expression lower than the 35th percentile reached this time point (median OS = 10.2 months).	('patients', 'Species', '9606', (170, 178))	('high', 'Var', (32, 36))	('HPSE', 'Gene', (37, 41))	('HPSE', 'Gene', '10855', (237, 241))	('patients', 'Species', '9606', (221, 229))	('FLT1', 'Gene', (11, 15))	('patients', 'Species', '9606', (16, 24))	('HPSE', 'Gene', '10855', (37, 41))	('longer', 'PosReg', (59, 65))	('HPSE', 'Gene', (237, 241))	('FLT1', 'Gene', '2321', (11, 15))
108880	23704979	Patients with a low FLT1 expression had a nearly five times higher relative risk (4.74) of dying earlier.	('low', 'Var', (16, 19))	('FLT1', 'Gene', '2321', (20, 24))	('dying', 'Disease', (91, 96))	('Patients', 'Species', '9606', (0, 8))	('FLT1', 'Gene', (20, 24))
108891	23704979	We were able to show that a high EGFR mRNA expression level (>35th percentile) is associated to patients' survival and confers a significantly worsened chance to survive longer than one year (P = 0.04, hazard ratio [HR] = 2.84), whereas patients with lower EGFR expression had a median survival time of more than 3 years (38.5 months).	('associated', 'Reg', (82, 92))	('mRNA expression level', 'MPA', (38, 59))	('EGFR', 'Gene', (257, 261))	('worsened', 'NegReg', (143, 151))	('EGFR', 'Gene', '1956', (33, 37))	('survive longer', 'CPA', (162, 176))	('patients', 'Species', '9606', (96, 104))	('EGFR', 'Gene', (33, 37))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (237, 245))	('EGFR', 'Gene', '1956', (257, 261))
108895	23704979	In preceding works we were able to shed light on a strong association of Hif1a expression with survival in pancreatic cancer and soft tissue sarcomas.	('pancreatic cancer', 'Disease', (107, 124))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (129, 149))	('pancreatic cancer', 'Disease', 'MESH:D010190', (107, 124))	('Hif1a', 'Gene', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('expression', 'Var', (79, 89))	('soft tissue sarcomas', 'Disease', (129, 149))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (129, 149))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (107, 124))	('Hif1a', 'Gene', '3091', (73, 78))
108902	23704979	The independent association of high FLT1 expression with better outcome was supported by a stepwise multivariate Cox proportional hazards regression model.	('Cox', 'Gene', (113, 116))	('expression', 'MPA', (41, 51))	('FLT1', 'Gene', (36, 40))	('high', 'Var', (31, 35))	('FLT1', 'Gene', '2321', (36, 40))	('Cox', 'Gene', '1351', (113, 116))
108905	23704979	Although we were not able to affirm a significant correlation to overall survival we revealed the link of HPSE expression to a higher rate of lymph node invasion, hence a more aggressive tumor type.	('expression', 'Var', (111, 121))	('HPSE', 'Gene', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('link', 'Reg', (98, 102))	('more', 'PosReg', (171, 175))	('aggressive tumor', 'Disease', 'MESH:D001523', (176, 192))	('HPSE', 'Gene', '10855', (106, 110))	('aggressive tumor', 'Disease', (176, 192))	('lymph node invasion', 'CPA', (142, 161))
108916	20226067	Pancreatic adenocarcinoma in type 2 progressive familial intrahepatic cholestasis BSEP disease results from mutations in ABCB11, which encodes the bile salt export pump (BSEP).	('results from', 'Reg', (95, 107))	('BSEP', 'Gene', (82, 86))	('BSEP', 'Gene', '8647', (82, 86))	('ABCB11', 'Gene', (121, 127))	('Pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (0, 25))	('Pancreatic adenocarcinoma', 'Disease', (0, 25))	('familial intrahepatic cholestasis', 'Disease', 'MESH:D002780', (48, 81))	('mutations', 'Var', (108, 117))	('cholestasis', 'Phenotype', 'HP:0001396', (70, 81))	('BSEP', 'Gene', '8647', (170, 174))	('bile salt export pump', 'Gene', '8647', (147, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('BSEP', 'Gene', (170, 174))	('ABCB11', 'Gene', '8647', (121, 127))	('familial intrahepatic cholestasis', 'Disease', (48, 81))	('Pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (0, 25))	('bile salt export pump', 'Gene', (147, 168))	('intrahepatic cholestasis', 'Phenotype', 'HP:0001406', (57, 81))
108921	20226067	Type 2 Progressive Familial Intrahepatic Cholestasis (PFIC-2), also known as BSEP disease, is one of the genetically determined cholestatic diseases and results from mutations in ABCB11, which encodes the bile salt export pump (BSEP) protein responsible for the bulk of conjugated bile salt transport from hepatocytes into biliary canaliculi.	('ABCB11', 'Gene', (179, 185))	('ABCB11', 'Gene', '8647', (179, 185))	('Cholestasis', 'Phenotype', 'HP:0001396', (41, 52))	('Familial Intrahepatic Cholestasis', 'Disease', 'MESH:D002780', (19, 52))	('results from', 'Reg', (153, 165))	('mutations', 'Var', (166, 175))	('Intrahepatic Cholestasis', 'Phenotype', 'HP:0001406', (28, 52))	('Familial Intrahepatic Cholestasis', 'Disease', (19, 52))	('PFIC-2', 'Gene', '8647', (54, 60))	('cholestatic diseases', 'Disease', 'MESH:D002779', (128, 148))	('bile salt', 'Chemical', 'MESH:D001647', (205, 214))	('PFIC-2', 'Gene', (54, 60))	('bile salt export pump', 'Gene', '8647', (205, 226))	('bile salt export pump', 'Gene', (205, 226))	('BSEP', 'Gene', '8647', (228, 232))	('bile salt', 'Chemical', 'MESH:D001647', (281, 290))	('BSEP', 'Gene', (228, 232))	('BSEP', 'Gene', '8647', (77, 81))	('BSEP', 'Gene', (77, 81))	('cholestatic diseases', 'Disease', (128, 148))
108923	20226067	While in most ways the clinical features of PFIC-2 are similar to PFIC-1 (FIC1 disease due to mutations in ATP8B1), it is uniquely associated with substantially increased risk of hepatobiliary cancer.	('ATP8B1', 'Gene', (107, 113))	('mutations', 'Var', (94, 103))	('PFIC-1 (FIC1 disease', 'Disease', 'MESH:C535933', (66, 86))	('associated', 'Reg', (131, 141))	('hepatobiliary cancer', 'Disease', (179, 199))	('hepatobiliary cancer', 'Disease', 'MESH:D004066', (179, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('PFIC-2', 'Gene', (44, 50))	('increased risk of hepatobiliary cancer', 'Phenotype', 'HP:0001402', (161, 199))	('PFIC-2', 'Gene', '8647', (44, 50))	('ATP8B1', 'Gene', '5205', (107, 113))
108930	20226067	The mutation in her ABCB11 gene involves heterozygote missense mutations, one allelic mutation being 1238T>G (Leu413Trp) and the other 3724C>A (Gly1242Ile), as reported elsewhere.	('3724C>A', 'Mutation', 'g.3724C>A', (135, 142))	('Leu413Trp', 'Var', (110, 119))	('ABCB11', 'Gene', '8647', (20, 26))	('Leu413Trp', 'Chemical', '-', (110, 119))	('ABCB11', 'Gene', (20, 26))	('1238T>G', 'Mutation', 'c.1238T>G', (101, 108))	('Gly1242Ile', 'Var', (144, 154))	('Gly1242Ile', 'SUBSTITUTION', 'None', (144, 154))
108953	20226067	Mutations in ATP8B1 (encoding for FIC1) and ABCB11 (encoding for BSEP) are the common causes of PFIC that are associated with relatively low serum gamma-glutamyl transferase (GGT) activity, so called low-GGT PFIC.	('ABCB11', 'Gene', '8647', (44, 50))	('GGT', 'Gene', (175, 178))	('low', 'NegReg', (137, 140))	('ATP8B1', 'Gene', '5205', (13, 19))	('gamma-glutamyl transferase', 'Gene', (147, 173))	('BSEP', 'Gene', '8647', (65, 69))	('BSEP', 'Gene', (65, 69))	('causes', 'Reg', (86, 92))	('Mutations', 'Var', (0, 9))	('GGT', 'Gene', '2678', (204, 207))	('PFIC', 'Disease', (96, 100))	('GGT', 'Gene', (204, 207))	('activity', 'MPA', (180, 188))	('FIC1', 'Gene', (34, 38))	('gamma-glutamyl transferase', 'Gene', '2678', (147, 173))	('ATP8B1', 'Gene', (13, 19))	('FIC1', 'Gene', '5205', (34, 38))	('ABCB11', 'Gene', (44, 50))	('GGT', 'Gene', '2678', (175, 178))
108965	20226067	This family history may imply a genetic risk factor for malignancy above and beyond BSEP disease although the family members may be heterozygotes for the BSEP mutation.	('BSEP', 'Gene', '8647', (154, 158))	('malignancy', 'Disease', 'MESH:D009369', (56, 66))	('BSEP', 'Gene', (154, 158))	('malignancy', 'Disease', (56, 66))	('mutation', 'Var', (159, 167))	('BSEP', 'Gene', '8647', (84, 88))	('BSEP', 'Gene', (84, 88))
108967	20226067	Genetic mutations in pancreatic cancer have included loss of function of tumor suppressor genes CDKN2A/p16, p53 and LKB1/STK11.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('LKB1', 'Gene', (116, 120))	('pancreatic cancer', 'Disease', 'MESH:D010190', (21, 38))	('mutations', 'Var', (8, 17))	('STK11', 'Gene', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('CDKN2A', 'Gene', (96, 102))	('p53', 'Gene', '7157', (108, 111))	('pancreatic cancer', 'Disease', (21, 38))	('tumor', 'Disease', (73, 78))	('p16', 'Gene', (103, 106))	('STK11', 'Gene', '6794', (121, 126))	('CDKN2A', 'Gene', '1029', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('p53', 'Gene', (108, 111))	('p16', 'Gene', '1029', (103, 106))	('LKB1', 'Gene', '6794', (116, 120))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (21, 38))	('loss of function', 'NegReg', (53, 69))
108968	20226067	Mutant KRAS2, aberrant DNA methylation, and inactivation of TP53 and SMAD4 have been implicated.	('DNA methylation', 'MPA', (23, 38))	('SMAD4', 'Gene', '4089', (69, 74))	('aberrant', 'Var', (14, 22))	('KRAS2', 'Gene', (7, 12))	('TP53', 'Gene', '7157', (60, 64))	('KRAS2', 'Gene', '3845', (7, 12))	('inactivation', 'NegReg', (44, 56))	('Mutant', 'Var', (0, 6))	('SMAD4', 'Gene', (69, 74))	('TP53', 'Gene', (60, 64))
108969	20226067	BRCA2 gene mutations are also common.	('BRCA2', 'Gene', '675', (0, 5))	('mutations', 'Var', (11, 20))	('BRCA2', 'Gene', (0, 5))
108982	20226067	BSEP may act as a tumor suppressor gene, and its malfunction may predispose to oncogenesis.	('malfunction', 'Var', (49, 60))	('oncogenesis', 'Disease', (79, 90))	('BSEP', 'Gene', (0, 4))	('predispose', 'Reg', (65, 75))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('BSEP', 'Gene', '8647', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
108987	20226067	Strautnieks and colleagues identified 82 different ABCB11 mutations in 109 families with severe BSEP deficiency.	('mutations', 'Var', (58, 67))	('BSEP deficiency', 'Disease', (96, 111))	('ABCB11', 'Gene', (51, 57))	('BSEP deficiency', 'Disease', 'MESH:D007153', (96, 111))	('ABCB11', 'Gene', '8647', (51, 57))
108990	20226067	Thus, at least in regard to HCC and cholangiocarcinoma, the ABCB11 gene defect appears to be an independent risk factor.	('defect', 'Var', (72, 78))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (36, 54))	('ABCB11', 'Gene', '8647', (60, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (36, 54))	('cholangiocarcinoma', 'Disease', (36, 54))	('ABCB11', 'Gene', (60, 66))	('HCC', 'Disease', (28, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('HCC', 'Phenotype', 'HP:0001402', (28, 31))
109000	20226067	While it is unclear at which point in organ development BSEP expression starts, it can be inferred based on the origin of the cells that mutated BSEP may have an impact on the pancreas.	('impact', 'Reg', (162, 168))	('BSEP', 'Gene', '8647', (145, 149))	('BSEP', 'Gene', '8647', (56, 60))	('BSEP', 'Gene', (145, 149))	('BSEP', 'Gene', (56, 60))	('have', 'Reg', (154, 158))	('pancreas', 'MPA', (176, 184))	('mutated', 'Var', (137, 144))
109001	20226067	Thus the expression pattern of BSEP is not supportive of this hypothesis, but it remains possible that mutated BSEP may predispose to the development of pancreatic adenocarcinoma.	('mutated', 'Var', (103, 110))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (153, 178))	('BSEP', 'Gene', '8647', (31, 35))	('predispose to', 'Reg', (120, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('BSEP', 'Gene', (31, 35))	('BSEP', 'Gene', '8647', (111, 115))	('BSEP', 'Gene', (111, 115))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (153, 178))	('pancreatic adenocarcinoma', 'Disease', (153, 178))
109017	32648580	In breast invasive carcinoma (BRCA) and liver hepatocellular carcinoma (LIHC), high YIF1B expression correlated with a poor disease-free interval (DFI), indicating a role in malignancy progression.	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (40, 70))	('malignancy', 'Disease', 'MESH:D009369', (174, 184))	('BRCA', 'Gene', (30, 34))	('malignancy', 'Disease', (174, 184))	('YIF1B', 'Gene', '90522', (84, 89))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (3, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('breast invasive carcinoma', 'Disease', (3, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (46, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('YIF1B', 'Gene', (84, 89))	('expression', 'MPA', (90, 100))	('high', 'Var', (79, 83))	('disease-free', 'MPA', (124, 136))	('liver hepatocellular carcinoma', 'Disease', (40, 70))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (3, 28))	('BRCA', 'Phenotype', 'HP:0003002', (30, 34))	('BRCA', 'Gene', '672', (30, 34))
109057	32648580	The following survival analyses, using patient data dichotomized for the median expression value in each cancer type (Figure 3), show that survival differences were all significant in OS-related cancer types, and that patients with high expression of YIF1B had worse outcomes (Figure 3).	('significant', 'Reg', (169, 180))	('patient', 'Species', '9606', (39, 46))	('YIF1B', 'Gene', (251, 256))	('patient', 'Species', '9606', (218, 225))	('patients', 'Species', '9606', (218, 226))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('YIF1B', 'Gene', '90522', (251, 256))	('high expression', 'Var', (232, 247))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
109061	32648580	In the following survival analysis, cancer types with high YIF1B expression again exhibited a worse prognosis in comparison with the low expression groups (Figure 5).	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('YIF1B', 'Gene', (59, 64))	('high', 'Var', (54, 58))	('cancer', 'Disease', (36, 42))	('YIF1B', 'Gene', '90522', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
109071	32648580	Their corresponding linear regression graphs show that high YIF1B expression is linked to a possible increased infiltration level by immune cells.	('infiltration level by immune cells', 'MPA', (111, 145))	('increased', 'PosReg', (101, 110))	('expression', 'MPA', (66, 76))	('YIF1B', 'Gene', '90522', (60, 65))	('high', 'Var', (55, 59))	('YIF1B', 'Gene', (60, 65))
109081	32648580	The coefficient values would indicate that YIF1B expression positively correlates with high mutation status in COAD, BLCA and LIHC, but low mutation in THYM, LAML and ESCA (particularly THYM).	('COAD', 'Disease', 'MESH:D029424', (111, 115))	('THYM', 'Phenotype', 'HP:0100522', (152, 156))	('YIF1B', 'Gene', '90522', (43, 48))	('COAD', 'Disease', (111, 115))	('high mutation status', 'Var', (87, 107))	('THYM', 'Phenotype', 'HP:0100522', (186, 190))	('YIF1B', 'Gene', (43, 48))	('ESCA', 'Phenotype', 'HP:0011459', (167, 171))
109087	32648580	Having established a correlation between YIF1B expression and the mutation indicators, TMB and MSI, further investigation of links between YIF1B expression and tumorigenesis mechanisms was warranted, in particular a relationship with MMR defects and methylation of specific tumor suppression genes.	('MMR defects', 'Disease', (234, 245))	('MMR defects', 'Disease', 'MESH:C536928', (234, 245))	('YIF1B', 'Gene', '90522', (139, 144))	('YIF1B', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('TMB', 'Chemical', '-', (87, 90))	('YIF1B', 'Gene', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('tumor', 'Disease', (160, 165))	('methylation', 'Var', (250, 261))	('YIF1B', 'Gene', '90522', (41, 46))
109097	32648580	In follow-on survival analysis, after dichotomizing patients according to their mean YIF1B expression value, patients in the high expression group had worse OS, which is consistent with in the results obtained using TCGA data (Supplementary Figure S1).	('YIF1B', 'Gene', (85, 90))	('patients', 'Species', '9606', (109, 117))	('YIF1B', 'Gene', '90522', (85, 90))	('high', 'Var', (125, 129))	('patients', 'Species', '9606', (52, 60))
109102	32648580	A correlation with disease progression rates was identified for LIHC and BRCA, for which patients with high YIF1B expression suffered from early recurrence of tumor.	('BRCA', 'Phenotype', 'HP:0003002', (73, 77))	('BRCA', 'Gene', '672', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('BRCA', 'Gene', (73, 77))	('YIF1B', 'Gene', (108, 113))	('tumor', 'Disease', (159, 164))	('LIHC', 'Disease', (64, 68))	('high', 'Var', (103, 107))	('patients', 'Species', '9606', (89, 97))	('expression', 'MPA', (114, 124))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('YIF1B', 'Gene', '90522', (108, 113))
109104	32648580	Previous research has shown that YIF1B is involved in anterograde vesicle traffic in cells, transporting 'cargo' proteins (including the serotonin receptor HTR1A) from the endoplasmic reticulum to the cell membrane via the Golgi apparatus; such cell membrane localization being accelerated upon knocking out YIF1B in HeLa cells.	('YIF1B', 'Gene', '90522', (33, 38))	('YIF1B', 'Gene', '90522', (308, 313))	("transporting 'cargo' proteins", 'MPA', (92, 121))	('serotonin', 'Chemical', 'MESH:D012701', (137, 146))	('knocking out', 'Var', (295, 307))	('YIF1B', 'Gene', (33, 38))	('HTR1A', 'Gene', '3350', (156, 161))	('YIF1B', 'Gene', (308, 313))	('accelerated', 'PosReg', (278, 289))	('HeLa', 'CellLine', 'CVCL:0030', (317, 321))	('HTR1A', 'Gene', (156, 161))
109107	32648580	A link to signaling pathways via HTR receptors is the likely reason for association of YIF1B mutations with functional changes to specific proteins in neuronal cells, causing encephalopathy, epilepsy and movement disorder.	('HTR', 'Gene', (33, 36))	('movement disorder', 'Phenotype', 'HP:0100022', (204, 221))	('mutations', 'Var', (93, 102))	('YIF1B', 'Gene', (87, 92))	('specific proteins', 'MPA', (130, 147))	('link', 'Reg', (2, 6))	('association', 'Interaction', (72, 83))	('epilepsy and movement disorder', 'Disease', 'MESH:D004827', (191, 221))	('encephalopathy', 'Disease', 'MESH:D001927', (175, 189))	('epilepsy', 'Phenotype', 'HP:0001250', (191, 199))	('HTR', 'Gene', '7012', (33, 36))	('encephalopathy', 'Phenotype', 'HP:0001298', (175, 189))	('YIF1B', 'Gene', '90522', (87, 92))	('causing', 'Reg', (167, 174))	('encephalopathy', 'Disease', (175, 189))
109122	32648580	Furthermore, COAD patients with high MSI have demonstrated better checkpoint inhibitor responses and survival in both low and high clinical stages.	('high MSI', 'Var', (32, 40))	('COAD', 'Disease', (13, 17))	('better', 'PosReg', (59, 65))	('COAD', 'Disease', 'MESH:D029424', (13, 17))	('checkpoint inhibitor responses', 'MPA', (66, 96))	('patients', 'Species', '9606', (18, 26))	('survival', 'CPA', (101, 109))
109134	32648580	For example, protein activity might be affected in normal or cancer cells by post-transcription modification and/or regulated proteolysis.	('regulated proteolysis', 'MPA', (116, 137))	('affected', 'Reg', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('post-transcription modification', 'Var', (77, 108))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('activity', 'MPA', (21, 29))	('protein', 'Protein', (13, 20))
109304	15608395	The pancreatic enzymes then lead to constant inflammation, epithelial denudation, thinning of the bile duct wall and distal obstruction, and eventually leading to cyst formation.	('inflammation', 'Disease', (45, 57))	('leading to', 'Reg', (152, 162))	('enzymes', 'Var', (15, 22))	('epithelial denudation', 'CPA', (59, 80))	('pancreatic', 'Disease', (4, 14))	('pancreatic', 'Disease', 'MESH:D010195', (4, 14))	('lead to', 'Reg', (28, 35))	('inflammation', 'Disease', 'MESH:D007249', (45, 57))	('thinning', 'CPA', (82, 90))	('cyst', 'Disease', (163, 167))
109350	33142045	Abnormally expressed lncRNAs in CCA, regulated by some upstream molecules, significantly influence the biological behavior of tumor cells and are involved in tumor development through various mechanisms, including interactions with functional proteins, participation in competing for endogenous RNA (ceRNA) regulatory networks, activation of cancer-related signaling pathways and epigenetic modification of gene expression.	('tumor', 'Disease', (158, 163))	('participation', 'Reg', (253, 266))	('epigenetic modification', 'Var', (380, 403))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('influence', 'Reg', (89, 98))	('cancer', 'Disease', (342, 348))	('activation', 'PosReg', (328, 338))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('CCA', 'Phenotype', 'HP:0030153', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('involved', 'Reg', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('interactions', 'Interaction', (214, 226))	('tumor', 'Disease', (126, 131))
109355	33142045	Moreover, the dysregulation of lncRNAs was demonstrated to have strong relevance not only in neurological, cardiovascular, and developmental diseases but also in tumorigenesis [3].	('neurological', 'Disease', (93, 105))	('cardiovascular', 'Disease', (107, 121))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('dysregulation', 'Var', (14, 27))	('developmental diseases', 'Disease', 'MESH:D003141', (127, 149))	('developmental diseases', 'Disease', (127, 149))	('relevance', 'Reg', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
109369	33142045	In cholestatic liver diseases, including primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), the obstruction of bile flow can lead to bile acid accumulation, which not only results in hepatocyte injury and chronic inflammation but also induces liver fibrosis and malignant proliferation of cholangiocytes.	('cholangitis', 'Phenotype', 'HP:0030151', (60, 71))	('obstruction of bile', 'Phenotype', 'HP:0001396', (121, 140))	('hepatocyte injury', 'Disease', 'MESH:D014947', (208, 225))	('PSC', 'Gene', '100653366', (73, 76))	('cholestatic liver diseases', 'Disease', 'MESH:D008107', (3, 29))	('primary biliary cholangitis', 'Disease', 'MESH:D008105', (82, 109))	('induces', 'Reg', (260, 267))	('cholangitis', 'Phenotype', 'HP:0030151', (98, 109))	('liver fibrosis', 'Phenotype', 'HP:0001395', (268, 282))	('obstruction', 'Var', (121, 132))	('sclerosing cholangitis', 'Disease', 'MESH:D015209', (49, 71))	('primary biliary cholangitis', 'Disease', (82, 109))	('PSC', 'Gene', (73, 76))	('liver diseases', 'Phenotype', 'HP:0001392', (15, 29))	('PBC', 'Gene', (111, 114))	('inflammation', 'Disease', 'MESH:D007249', (238, 250))	('chronic', 'MPA', (230, 237))	('PBC', 'Phenotype', 'HP:0002613', (111, 114))	('primary biliary cholangitis', 'Phenotype', 'HP:0002613', (82, 109))	('liver fibrosis', 'Disease', (268, 282))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (49, 71))	('bile acid', 'Chemical', 'MESH:D001647', (158, 167))	('lead to', 'Reg', (150, 157))	('results in', 'Reg', (197, 207))	('malignant proliferation', 'CPA', (287, 310))	('inflammation', 'Disease', (238, 250))	('hepatocyte injury', 'Disease', (208, 225))	('liver disease', 'Phenotype', 'HP:0001392', (15, 28))	('cholestatic liver diseases', 'Phenotype', 'HP:0002611', (3, 29))	('bile acid accumulation', 'MPA', (158, 180))	('cholestatic liver diseases', 'Disease', (3, 29))	('PBC', 'Gene', '1737', (111, 114))	('liver fibrosis', 'Disease', 'MESH:D008103', (268, 282))	('sclerosing cholangitis', 'Disease', (49, 71))
109384	33142045	In addition, high expression of LINC00261 was shown to promote metastasis through the EMT process in CCA [23], while downregulated LINC00261 was found to be associated with poor prognosis in digestive system malignancies, including gastric cancer [24], hepatocellular carcinoma [25], and pancreatic cancer [26].	('gastric cancer', 'Disease', 'MESH:D013274', (232, 246))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (288, 305))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (253, 277))	('malignancies', 'Disease', 'MESH:D009369', (208, 220))	('LINC00261', 'Gene', (32, 41))	('metastasis', 'CPA', (63, 73))	('malignancies', 'Disease', (208, 220))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('gastric cancer', 'Phenotype', 'HP:0012126', (232, 246))	('pancreatic cancer', 'Disease', 'MESH:D010190', (288, 305))	('promote', 'PosReg', (55, 62))	('hepatocellular carcinoma', 'Disease', (253, 277))	('LINC00261', 'Gene', '140828', (32, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('downregulated', 'NegReg', (117, 130))	('CCA', 'Phenotype', 'HP:0030153', (101, 104))	('LINC00261', 'Gene', (131, 140))	('pancreatic cancer', 'Disease', (288, 305))	('gastric cancer', 'Disease', (232, 246))	('CCA', 'Disease', (101, 104))	('high expression', 'Var', (13, 28))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('LINC00261', 'Gene', '140828', (131, 140))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (253, 277))
109401	33142045	[34] demonstrated that under the stimulation of TGF-beta1, lncRNA ASLNCS5088, which was enriched in M2 macrophage-derived exosomes, could be efficiently transferred into fibroblasts, resulting in increased alpha-SMA expression and activation of myofibroblasts.	('increased', 'PosReg', (196, 205))	('alpha-SMA', 'Gene', (206, 215))	('TGF-beta1', 'Gene', '7040', (48, 57))	('myofibroblasts', 'CPA', (245, 259))	('TGF-beta1', 'Gene', (48, 57))	('activation', 'PosReg', (231, 241))	('alpha-SMA', 'Gene', '58', (206, 215))	('ASLNCS5088', 'Var', (66, 76))
109419	33142045	Additionally, lncRNA epigenetic landscape analysis has attributed the overexpression of EPIC1 to recurrent hypomethylation of its host gene across 6475 tumors and 455 cancer cell lines [47].	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('cancer', 'Disease', (167, 173))	('hypomethylation', 'Var', (107, 122))	('EPIC1', 'Gene', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Disease', (152, 158))	('overexpression', 'PosReg', (70, 84))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
109421	33142045	On the other hand, the downregulation of several lncRNAs plays the same role in CCA cells including LINC01714 [63], FENDRR [64], MEG3 [65], and MIR22HG [66].	('downregulation', 'NegReg', (23, 37))	('LINC01714', 'Chemical', '-', (100, 109))	('FENDRR', 'Gene', (116, 122))	('MEG3', 'Gene', (129, 133))	('MIR22HG', 'Gene', (144, 151))	('CCA', 'Disease', (80, 83))	('MIR22HG', 'Gene', '84981', (144, 151))	('MEG3', 'Gene', '55384', (129, 133))	('FENDRR', 'Gene', '400550', (116, 122))	('CCA', 'Phenotype', 'HP:0030153', (80, 83))	('LINC01714', 'Var', (100, 109))
109426	33142045	Zhang et al [60] found that the knockdown of NEAT1 significantly downregulated the levels of Vimentin and N-cadherin but increased E-cadherin expression in CCA cells.	('E-cadherin', 'Gene', '999', (131, 141))	('Vimentin', 'Gene', (93, 101))	('increased', 'PosReg', (121, 130))	('N-cadherin', 'Gene', (106, 116))	('knockdown', 'Var', (32, 41))	('downregulated', 'NegReg', (65, 78))	('NEAT1', 'Gene', '283131', (45, 50))	('CCA', 'Phenotype', 'HP:0030153', (156, 159))	('N-cadherin', 'Gene', '1000', (106, 116))	('Vimentin', 'Gene', '7431', (93, 101))	('NEAT1', 'Gene', (45, 50))	('expression', 'MPA', (142, 152))	('E-cadherin', 'Gene', (131, 141))
109429	33142045	Silencing SPRY4-IT1 in CCA cells can increase the expression levels of E-cadherin and decrease the expression levels of Snail and vimentin [20].	('expression levels', 'MPA', (99, 116))	('Snail', 'Gene', '6615', (120, 125))	('Snail', 'Gene', (120, 125))	('SPRY4-IT1', 'Gene', '100642175', (10, 19))	('E-cadherin', 'Gene', (71, 81))	('E-cadherin', 'Gene', '999', (71, 81))	('SPRY4-IT1', 'Gene', (10, 19))	('expression levels', 'MPA', (50, 67))	('increase', 'PosReg', (37, 45))	('decrease', 'NegReg', (86, 94))	('vimentin', 'Gene', '7431', (130, 138))	('Silencing', 'Var', (0, 9))	('CCA', 'Phenotype', 'HP:0030153', (23, 26))	('vimentin', 'Gene', (130, 138))
109450	33142045	LncRNA UCA1 acts as an anti-apoptotic factor in CCA, and apoptosis-associated factors (caspase-3, and -9) are both increased followed by the knockdown of UCA1.	('knockdown', 'Var', (141, 150))	('increased', 'PosReg', (115, 124))	('caspase-3', 'Gene', '836', (87, 96))	('CCA', 'Phenotype', 'HP:0030153', (48, 51))	('apoptosis-associated', 'CPA', (57, 77))	('UCA1', 'Gene', '652995', (154, 158))	('UCA1', 'Gene', '652995', (7, 11))	('CCA', 'Disease', (48, 51))	('UCA1', 'Gene', (154, 158))	('UCA1', 'Gene', (7, 11))	('caspase-3', 'Gene', (87, 96))
109451	33142045	Subsequent studies also confirmed that downregulated UCA1 increased apoptosis by activating the expression of Bax and suppressing Bcl-2 expression [83].	('downregulated', 'Var', (39, 52))	('increased', 'PosReg', (58, 67))	('expression', 'MPA', (96, 106))	('apoptosis', 'CPA', (68, 77))	('Bax', 'Gene', '581', (110, 113))	('UCA1', 'Gene', '652995', (53, 57))	('UCA1', 'Gene', (53, 57))	('Bcl-2', 'Gene', (130, 135))	('suppressing', 'NegReg', (118, 129))	('Bcl-2', 'Gene', '596', (130, 135))	('Bax', 'Gene', (110, 113))	('activating', 'PosReg', (81, 91))
109457	33142045	In addition, lncRNA RMRP is highly expressed in CCA, and cancer stem cell-related markers Bmi1 and CD24 were found to be significantly decreased after RMRP knockdown, but surprisingly, the expression of CD44 remained unchanged [55].	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('knockdown', 'Var', (156, 165))	('Bmi1', 'Gene', '648', (90, 94))	('cancer', 'Disease', (57, 63))	('RMRP', 'Gene', (20, 24))	('RMRP', 'Gene', (151, 155))	('RMRP', 'Gene', '6023', (20, 24))	('CCA', 'Phenotype', 'HP:0030153', (48, 51))	('CD24', 'Gene', '100133941', (99, 103))	('CD24', 'Gene', (99, 103))	('CD44', 'Gene', '960', (203, 207))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('decreased', 'NegReg', (135, 144))	('Bmi1', 'Gene', (90, 94))	('CD44', 'Gene', (203, 207))	('RMRP', 'Gene', '6023', (151, 155))	('CCA', 'Disease', (48, 51))
109475	33142045	The proliferation and EMT process of CCA cells were notably accelerated by NNT-AS1 overexpression, but after the miR-203 mimic was transfected into CCA cells, both proliferation and EMT were inhibited.	('EMT process', 'CPA', (22, 33))	('inhibited', 'NegReg', (191, 200))	('proliferation', 'CPA', (4, 17))	('overexpression', 'Var', (83, 97))	('accelerated', 'PosReg', (60, 71))	('NNT-AS1', 'Gene', '100652772', (75, 82))	('miR-203', 'Gene', '406986', (113, 120))	('miR-203', 'Gene', (113, 120))	('CCA', 'Phenotype', 'HP:0030153', (148, 151))	('CCA', 'Phenotype', 'HP:0030153', (37, 40))	('NNT-AS1', 'Gene', (75, 82))
109476	33142045	This study also corroborated that NNT-AS1 overexpression promoted the activation of the PI3K/AKT and ERK1/2 signaling pathways by downregulating miR-203.	('overexpression', 'Var', (42, 56))	('PI3', 'Gene', '5266', (88, 91))	('ERK', 'Gene', '5594', (101, 104))	('ERK', 'Gene', (101, 104))	('AKT', 'Gene', (93, 96))	('PI3', 'Gene', (88, 91))	('NNT-AS1', 'Gene', (34, 41))	('NNT-AS1', 'Gene', '100652772', (34, 41))	('downregulating', 'NegReg', (130, 144))	('miR-203', 'Gene', (145, 152))	('AKT', 'Gene', '207', (93, 96))	('miR-203', 'Gene', '406986', (145, 152))
109483	33142045	Currently, cancer is considered a special metabolic disease, and abnormal glutamine metabolism has proven to be a critical hallmark of cancer by participating in carcinogenesis [98].	('cancer', 'Disease', (135, 141))	('abnormal', 'Var', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('metabolic disease', 'Disease', (42, 59))	('abnormal glutamine metabolism', 'Phenotype', 'HP:0010903', (65, 94))	('glutamine', 'Chemical', 'MESH:D005973', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('participating', 'Reg', (145, 158))	('carcinogenesis', 'Disease', 'MESH:D063646', (162, 176))	('metabolic disease', 'Disease', 'MESH:D008659', (42, 59))	('cancer', 'Disease', (11, 17))	('carcinogenesis', 'Disease', (162, 176))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
109491	33142045	Polycomb repressive complex 2 (PRC2) is an extremely conserved protein complex capable of silencing gene expression by methylating lysine 27 on histone H3.	('lysine', 'Chemical', 'MESH:D008239', (131, 137))	('PRC2', 'Gene', (31, 35))	('silencing', 'NegReg', (90, 99))	('methylating lysine 27', 'Var', (119, 140))
109493	33142045	LncRNA SNHG1 can act as an oncogenic molecule of CCA by binding to EZH2, followed by epigenetically suppressing the transcription of CDKN1A in the nucleus [49].	('transcription', 'MPA', (116, 129))	('SNHG1', 'Gene', (7, 12))	('epigenetically', 'Var', (85, 99))	('CDKN1A', 'Gene', (133, 139))	('CCA', 'Phenotype', 'HP:0030153', (49, 52))	('CDKN1A', 'Gene', '1026', (133, 139))	('binding', 'Interaction', (56, 63))	('suppressing', 'NegReg', (100, 111))	('SNHG1', 'Gene', '23642', (7, 12))	('EZH2', 'Gene', (67, 71))	('EZH2', 'Gene', '2146', (67, 71))
109495	33142045	The FBP1 gene encodes a rate-limiting gluconeogenic enzyme, the loss of which can accelerate cancer progression by enhancing aerobic glycolysis, and the antineoplastic role of FBP1 has been verified in multiple cancers including CCA [108].	('FBP1', 'Gene', '2203', (4, 8))	('accelerate', 'PosReg', (82, 92))	('multiple cancers', 'Disease', (202, 218))	('aerobic glycolysis', 'MPA', (125, 143))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('FBP1', 'Gene', '2203', (176, 180))	('FBP1', 'Gene', (4, 8))	('CCA', 'Phenotype', 'HP:0030153', (229, 232))	('enhancing', 'PosReg', (115, 124))	('CCA [', 'Disease', (229, 234))	('FBP1', 'Gene', (176, 180))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('cancer', 'Disease', (93, 99))	('multiple cancers', 'Disease', 'MESH:D009369', (202, 218))	('cancer', 'Disease', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('loss', 'Var', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
109496	33142045	Additionally, upregulated DANCR can promote CCA progression through the epigenetically transcriptional inactivation of FBP1 [52].	('promote', 'PosReg', (36, 43))	('epigenetically transcriptional inactivation', 'Var', (72, 115))	('FBP1', 'Gene', (119, 123))	('CCA', 'Disease', (44, 47))	('upregulated', 'PosReg', (14, 25))	('DANCR', 'Gene', (26, 31))	('FBP1', 'Gene', '2203', (119, 123))	('CCA', 'Phenotype', 'HP:0030153', (44, 47))	('DANCR', 'Gene', '57291', (26, 31))
109502	33142045	Therefore, a lncRNA may play a role in promoting cancer by mediating multiple ways of epigenetic modifications.	('epigenetic', 'Var', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('promoting', 'PosReg', (39, 48))	('cancer', 'Disease', (49, 55))
109504	33142045	Emerging evidence shows that the aberrant overexpression of SETDB1 is closely related to the development of cancer, such as melanoma, breast cancer, and mesothelioma [111, 112, 113].	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('related', 'Reg', (78, 85))	('aberrant', 'Var', (33, 41))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('breast cancer', 'Disease', (134, 147))	('overexpression', 'PosReg', (42, 56))	('mesothelioma', 'Disease', (153, 165))	('cancer', 'Disease', (141, 147))	('SETDB1', 'Gene', (60, 66))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('mesothelioma', 'Disease', 'MESH:D008654', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('SETDB1', 'Gene', '9869', (60, 66))	('cancer', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
109506	33142045	The overexpression of FENDRR inhibited the expression of survivin, a well-studied oncogene, via SETDB1-mediated H3K9 methylation to suppress the proliferation, migration, and invasion of CCA cells (Figure 3B) [64].	('inhibited', 'NegReg', (29, 38))	('FENDRR', 'Gene', (22, 28))	('CCA', 'Disease', (187, 190))	('suppress', 'NegReg', (132, 140))	('SETDB1', 'Gene', (96, 102))	('migration', 'CPA', (160, 169))	('proliferation', 'CPA', (145, 158))	('invasion', 'CPA', (175, 183))	('methylation', 'Var', (117, 128))	('CCA', 'Phenotype', 'HP:0030153', (187, 190))	('FENDRR', 'Gene', '400550', (22, 28))	('expression', 'MPA', (43, 53))	('survivin', 'Gene', (57, 65))	('SETDB1', 'Gene', '9869', (96, 102))
109510	33142045	However, the knockdown of AFAP1-AS1 increased AFAP1 protein and mRNA levels [118].	('AS1', 'Gene', '5729', (32, 35))	('AFAP1', 'Gene', (26, 31))	('AS1', 'Gene', (32, 35))	('AFAP1', 'Gene', '60312', (26, 31))	('increased', 'PosReg', (36, 45))	('mRNA levels [', 'MPA', (64, 77))	('AFAP1', 'Gene', '60312', (46, 51))	('knockdown', 'Var', (13, 22))	('AFAP1', 'Gene', (46, 51))
109515	33142045	Furthermore, CPS1 and CPS1-IT1 knockdown inhibited iCCA cell proliferation and accelerated cell apoptosis [120].	('CPS1', 'Gene', (22, 26))	('iCCA cell proliferation', 'CPA', (51, 74))	('cell apoptosis', 'CPA', (91, 105))	('CPS1', 'Gene', (13, 17))	('CPS1', 'Gene', '1373', (13, 17))	('CPS1-IT1', 'Gene', '29034', (22, 30))	('CPS1', 'Gene', '1373', (22, 26))	('CCA', 'Phenotype', 'HP:0030153', (52, 55))	('inhibited', 'NegReg', (41, 50))	('accelerated', 'PosReg', (79, 90))	('CPS1-IT1', 'Gene', (22, 30))	('knockdown', 'Var', (31, 40))
109523	33142045	In addition, previous studies have shown that the expression of SOX2 was associated with aggressive behavior and poor overall survival in iCCA [127].	('aggressive behavior', 'CPA', (89, 108))	('poor', 'NegReg', (113, 117))	('expression', 'Var', (50, 60))	('SOX2', 'Gene', '6657', (64, 68))	('aggressive behavior', 'Phenotype', 'HP:0000718', (89, 108))	('associated with', 'Reg', (73, 88))	('SOX2', 'Gene', (64, 68))	('CCA', 'Phenotype', 'HP:0030153', (139, 142))
109525	33142045	The PI3K/AKT signaling pathway is aberrantly activated in various cancers, including cholangiocarcinoma, and loss of function of the tumor suppresser gene PTEN can stimulate the activation of this pathway [128].	('AKT', 'Gene', '207', (9, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('PTEN', 'Gene', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('PTEN', 'Gene', '5728', (155, 159))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (85, 103))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('PI3', 'Gene', '5266', (4, 7))	('loss', 'Var', (109, 113))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('AKT', 'Gene', (9, 12))	('tumor', 'Disease', (133, 138))	('cancers', 'Disease', (66, 73))	('PI3', 'Gene', (4, 7))	('cholangiocarcinoma', 'Disease', (85, 103))
109526	33142045	FOXA1 is a pioneer transcription factor, and its mutation can promote the initiation and metastatic progression of prostate cancer [129].	('metastatic progression', 'CPA', (89, 111))	('FOXA1', 'Gene', (0, 5))	('prostate cancer', 'Disease', (115, 130))	('initiation', 'CPA', (74, 84))	('FOXA1', 'Gene', '3169', (0, 5))	('mutation', 'Var', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (115, 130))	('promote', 'PosReg', (62, 69))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))
109529	33142045	Similarly, lncRNA UCA1 knockdown results in significantly lower phosphorylation levels of AKT and GSK3beta.	('UCA1', 'Gene', (18, 22))	('lower', 'NegReg', (58, 63))	('AKT', 'Gene', (90, 93))	('knockdown', 'Var', (23, 32))	('GSK3beta', 'Gene', (98, 106))	('phosphorylation levels', 'MPA', (64, 86))	('GSK3beta', 'Gene', '2931', (98, 106))	('AKT', 'Gene', '207', (90, 93))	('UCA1', 'Gene', '652995', (18, 22))
109546	33142045	The aberrant activation of the Hh signaling pathway is caused by mutations in related genes or by the excessive expression of Hh signaling molecules, such as Patched (Ptch), Smoothened (Smo), and Glioma-associated oncogene 1 (Gli1), whose abnormal expression might contribute to the onset of multiple tumors [136, 137].	('Smo', 'Gene', '6608', (174, 177))	('multiple tumors', 'Disease', 'MESH:D009369', (292, 307))	('Hh', 'Gene', '42737', (126, 128))	('Glioma', 'Phenotype', 'HP:0009733', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('Smo', 'Gene', (174, 177))	('Glioma-associated oncogene 1', 'Gene', (196, 224))	('Hh', 'Gene', '42737', (31, 33))	('Gli1', 'Gene', (226, 230))	('Smoothened', 'Gene', (174, 184))	('Ptch', 'Gene', (167, 171))	('contribute', 'Reg', (265, 275))	('Ptch', 'Gene', '5727', (167, 171))	('multiple tumors', 'Disease', (292, 307))	('Glioma-associated oncogene 1', 'Gene', '2735', (196, 224))	('Patched', 'Gene', '5727', (158, 165))	('Smo', 'Gene', '6608', (186, 189))	('Smoothened', 'Gene', '6608', (174, 184))	('Patched', 'Gene', (158, 165))	('Gli1', 'Gene', '2735', (226, 230))	('Smo', 'Gene', (186, 189))	('activation', 'PosReg', (13, 23))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))	('mutations', 'Var', (65, 74))
109550	33142045	The TGF-beta/Smad signaling pathway participates in a wide range of cellular processes, especially metabolic reprogramming of cancer-associated fibroblasts, and lnc-LFAR1 is involved in the progression of liver fibrosis by regulating the TGF-beta/Smad signaling pathway [140, 141, 142].	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('TGF-beta', 'Gene', (4, 12))	('liver fibrosis', 'Disease', (205, 219))	('Smad', 'Gene', '4089;4089;4090', (13, 17))	('involved', 'Reg', (174, 182))	('Smad', 'Gene', (247, 251))	('lnc-LFAR1', 'Var', (161, 170))	('TGF-beta', 'Gene', (238, 246))	('Smad', 'Gene', '4089;4089;4090', (247, 251))	('TGF-beta', 'Gene', '7039', (4, 12))	('participates', 'Reg', (36, 48))	('liver fibrosis', 'Disease', 'MESH:D008103', (205, 219))	('cancer', 'Disease', (126, 132))	('regulating', 'Reg', (223, 233))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('TGF-beta', 'Gene', '7039', (238, 246))	('liver fibrosis', 'Phenotype', 'HP:0001395', (205, 219))	('Smad', 'Gene', (13, 17))
109553	33142045	For instance, MALAT1 knockdown significantly suppressed the protein level of noncanonical TGF-beta signaling proteins (PI3Kp85alpha and p-Akt) in human osteosarcoma cells [144].	('MALAT1', 'Gene', '378938', (14, 20))	('PI3', 'Gene', '5266', (119, 122))	('Akt', 'Gene', (138, 141))	('TGF-beta', 'Gene', (90, 98))	('osteosarcoma', 'Phenotype', 'HP:0002669', (152, 164))	('suppressed', 'NegReg', (45, 55))	('human', 'Species', '9606', (146, 151))	('osteosarcoma', 'Disease', (152, 164))	('MALAT1', 'Gene', (14, 20))	('PI3', 'Gene', (119, 122))	('protein level', 'MPA', (60, 73))	('osteosarcoma', 'Disease', 'MESH:D012516', (152, 164))	('Akt', 'Gene', '207', (138, 141))	('TGF-beta', 'Gene', '7039', (90, 98))	('knockdown', 'Var', (21, 30))
109562	33142045	As a result of TRAF3 degradation, NIK becomes stabilized, leading to the activation of the noncanonical NF-kappaB pathway [148].	('activation', 'PosReg', (73, 83))	('degradation', 'Var', (21, 32))	('TRAF3', 'Gene', (15, 20))	('NIK', 'Gene', '9020', (34, 37))	('NF-kappaB', 'Gene', '4790', (104, 113))	('NIK', 'Gene', (34, 37))	('TRAF3', 'Gene', '7187', (15, 20))	('NF-kappaB', 'Gene', (104, 113))
109584	33142045	[63] found that LINC01714 knockdown dramatically increased the half-maximal inhibitory concentrations (IC50s) of gemcitabine in gemcitabine-treated CCA cells, while the overexpression of LINC01714 led to the opposite result.	('gemcitabine', 'Chemical', 'MESH:C056507', (113, 124))	('LINC01714', 'Chemical', '-', (187, 196))	('increased', 'PosReg', (49, 58))	('LINC01714', 'Chemical', '-', (16, 25))	('gemcitabine', 'Chemical', 'MESH:C056507', (128, 139))	('knockdown', 'Var', (26, 35))	('CCA', 'Phenotype', 'HP:0030153', (148, 151))	('LINC01714', 'Gene', (16, 25))	('half-maximal inhibitory concentrations', 'MPA', (63, 101))
109585	33142045	Subsequent experiments revealed that LINC01714 enhanced the cytotoxic effect of gemcitabine on CCA cells by modulating phosphorylated FOXO3-Ser318.	('enhanced', 'PosReg', (47, 55))	('FOXO3', 'Gene', (134, 139))	('Ser318', 'Chemical', '-', (140, 146))	('LINC01714', 'Chemical', '-', (37, 46))	('CCA', 'Disease', (95, 98))	('LINC01714', 'Var', (37, 46))	('gemcitabine', 'Chemical', 'MESH:C056507', (80, 91))	('modulating', 'Reg', (108, 118))	('FOXO3', 'Gene', '2309', (134, 139))	('phosphorylated', 'MPA', (119, 133))	('CCA', 'Phenotype', 'HP:0030153', (95, 98))	('cytotoxic effect', 'CPA', (60, 76))
109586	33142045	This observation suggests that LINC01714 may act as a candidate for combinatorial chemotherapy with gemcitabine for CCA patients (Figure 5A).	('LINC01714', 'Var', (31, 40))	('CCA', 'Phenotype', 'HP:0030153', (116, 119))	('gemcitabine', 'Chemical', 'MESH:C056507', (100, 111))	('patients', 'Species', '9606', (120, 128))	('CCA', 'Disease', (116, 119))	('LINC01714', 'Chemical', '-', (31, 40))
109587	33142045	Mutations in the chromatin modulator BRCA-1 associated protein-1 (BAP1) have been identified as the most frequent genetic alterations in CCA, occurring in 22%-24% of cases [157].	('CCA', 'Phenotype', 'HP:0030153', (137, 140))	('BRCA-1 associated protein-1', 'Gene', (37, 64))	('BAP1', 'Gene', '8314', (66, 70))	('BRCA-1 associated protein-1', 'Gene', '8314', (37, 64))	('BAP1', 'Gene', (66, 70))	('Mutations', 'Var', (0, 9))	('CCA', 'Disease', (137, 140))	('alterations', 'Var', (122, 133))
109588	33142045	Parasramka et al [158] found that BAP1 expression could modulate CCA cell sensitivity to gemcitabine, or more specifically, sensitivity to gemcitabine was increased in low BAP1-expressing CCA cells than in high BAP1-expressing CCA cells.	('modulate', 'Reg', (56, 64))	('gemcitabine', 'Chemical', 'MESH:C056507', (89, 100))	('CCA', 'Phenotype', 'HP:0030153', (188, 191))	('sensitivity to gemcitabine', 'MPA', (124, 150))	('BAP1', 'Gene', (34, 38))	('expression', 'Var', (39, 49))	('increased', 'PosReg', (155, 164))	('BAP1', 'Gene', (172, 176))	('BAP1', 'Gene', '8314', (211, 215))	('CCA', 'Phenotype', 'HP:0030153', (65, 68))	('CCA', 'Phenotype', 'HP:0030153', (227, 230))	('sensitivity to gemcitabine', 'MPA', (74, 100))	('CCA', 'Disease', (188, 191))	('gemcitabine', 'Chemical', 'MESH:C056507', (139, 150))	('BAP1', 'Gene', (211, 215))	('CCA', 'Disease', (65, 68))	('BAP1', 'Gene', '8314', (34, 38))	('BAP1', 'Gene', '8314', (172, 176))
109589	33142045	Moreover, lncRNA NEAT1 was identified to be enriched after BAP1 knockdown, and researchers further confirmed that NEAT1 could serve as a functional downstream target of BAP1 involved in drug responses [158] (Figure 5B).	('BAP1', 'Gene', (59, 63))	('NEAT1', 'Gene', '283131', (17, 22))	('BAP1', 'Gene', '8314', (169, 173))	('NEAT1', 'Gene', (17, 22))	('NEAT1', 'Gene', '283131', (114, 119))	('BAP1', 'Gene', (169, 173))	('knockdown', 'Var', (64, 73))	('NEAT1', 'Gene', (114, 119))	('BAP1', 'Gene', '8314', (59, 63))
109595	33142045	However, emerging evidence suggests that the proportion of cells with high expression of cancer stem cell (CSC) markers among the surviving cells is significantly increased in response to 5-Fu, resulting in drug resistance and disease relapse.	('increased', 'PosReg', (163, 172))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('disease relapse', 'CPA', (227, 242))	('drug resistance', 'CPA', (207, 222))	('drug resistance', 'Phenotype', 'HP:0020174', (207, 222))	('resulting in', 'Reg', (194, 206))	('5-Fu', 'Chemical', 'MESH:D005472', (188, 192))	('5-Fu', 'Var', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
109605	33142045	In a study of 935 patients with cholangiocarcinoma, the mutation frequency of BRCA1 in eCCA samples was five times that in iCCA samples [166].	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (32, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (32, 50))	('CCA', 'Phenotype', 'HP:0030153', (124, 127))	('BRCA1', 'Gene', '672', (78, 83))	('mutation', 'Var', (56, 64))	('patients', 'Species', '9606', (18, 26))	('cholangiocarcinoma', 'Disease', (32, 50))	('CCA', 'Phenotype', 'HP:0030153', (88, 91))	('BRCA1', 'Gene', (78, 83))
109623	33142045	With the widespread application of advanced epigenomic technologies and deep RNA-sequencing, a growing number of long noncoding RNAs (lncRNAs) are being identified at a phenomenal rate, and their aberrant expression is closely related to the occurrence and development of multiple cancers, including CCA.	('related to', 'Reg', (227, 237))	('CCA', 'Disease', (300, 303))	('aberrant', 'Var', (196, 204))	('multiple cancers', 'Disease', 'MESH:D009369', (272, 288))	('long', 'Protein', (113, 117))	('CCA', 'Phenotype', 'HP:0030153', (300, 303))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('multiple cancers', 'Disease', (272, 288))
109626	33142045	Dysregulation of lncRNA expression was found to be significantly correlated with the clinicopathological features of CCA patients and the biological characteristics of CCA cells.	('CCA', 'Phenotype', 'HP:0030153', (168, 171))	('Dysregulation', 'Var', (0, 13))	('lncRNA', 'Protein', (17, 23))	('CCA', 'Phenotype', 'HP:0030153', (117, 120))	('patients', 'Species', '9606', (121, 129))	('CCA', 'Disease', (117, 120))	('correlated', 'Reg', (65, 75))
109637	33032609	Logistic regression showed CA19-9 and portal vein system invasion as independent risk factors for lymph node metastases.	('lymph node metastases', 'Disease', 'MESH:D009362', (98, 119))	('CA19-9', 'Chemical', 'MESH:C086528', (27, 33))	('CA19-9', 'Var', (27, 33))	('lymph node metastases', 'Disease', (98, 119))
109639	33032609	Lymph node metastasis is an important factor affecting the long-term survival of distal cholangiocarcinoma patients.CA19-9 and portal vein system invasion are independent risk factors for lymph node metastasis.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('portal vein system invasion', 'CPA', (127, 154))	('distal cholangiocarcinoma', 'Disease', (81, 106))	('distal cholangiocarcinoma', 'Disease', 'MESH:D018281', (81, 106))	('CA19-9', 'Chemical', 'MESH:C086528', (116, 122))	('lymph', 'Disease', (188, 193))	('patients.CA19-9', 'Var', (107, 122))	('patients', 'Species', '9606', (107, 115))
109679	33032609	Univariate analysis identified ALB, DB, CA19-9, differentiation, and portal vein system invasion as the risk factors for lymph node metastases (Table 1).	('lymph node metastases', 'Disease', (121, 142))	('ALB', 'Gene', (31, 34))	('CA19-9', 'Var', (40, 46))	('differentiation', 'CPA', (48, 63))	('portal vein system invasion', 'CPA', (69, 96))	('CA19-9', 'Chemical', 'MESH:C086528', (40, 46))	('ALB', 'Gene', '213', (31, 34))	('lymph node metastases', 'Disease', 'MESH:D009362', (121, 142))
109698	33032609	CA19-9 is a serological marker commonly used in clinical diagnosis and prognosis of cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('cholangiocarcinoma', 'Disease', (84, 102))	('CA19-9', 'Var', (0, 6))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
109701	33032609	The median survival time of patients with increased CA19-9 was significantly lower than that of normal patients (8.5 months vs 16.0 months, p < 0.01), and it also showed CA19-9 was an independent risk factor for the long-term survival (RR = 1.72, 95% CI 1.46-2.02).	('lower', 'NegReg', (77, 82))	('increased', 'PosReg', (42, 51))	('CA19-9', 'Chemical', 'MESH:C086528', (52, 58))	('CA19-9', 'Var', (170, 176))	('CA19-9', 'Chemical', 'MESH:C086528', (170, 176))	('CA19-9', 'Var', (52, 58))	('patients', 'Species', '9606', (103, 111))	('patients', 'Species', '9606', (28, 36))
109702	33032609	Moreover, our data showed that CA19-9 was also significantly correlated with lymph node metastasis, which may be the cause of poor long-term survival in patients with increased CA19-9, especially in the patients with CA19-9 higher than 75.5 U/mL.	('CA19-9', 'Chemical', 'MESH:C086528', (31, 37))	('patients', 'Species', '9606', (153, 161))	('CA19-9', 'Chemical', 'MESH:C086528', (177, 183))	('correlated', 'Reg', (61, 71))	('lymph node metastasis', 'CPA', (77, 98))	('increased', 'PosReg', (167, 176))	('patients', 'Species', '9606', (203, 211))	('CA19-9', 'Var', (31, 37))	('CA19-9', 'Chemical', 'MESH:C086528', (217, 223))	('CA19-9', 'Gene', (177, 183))
109715	33032609	also showed that the median survival time of patients with lymph node metastasis rate < 0.17 was significantly better than those with lymph node metastasis rate >= 0.17 (2.3 years vs 1.4 years, p = 0.002).	('< 0.17', 'Var', (86, 92))	('patients', 'Species', '9606', (45, 53))	('better', 'PosReg', (111, 117))
109736	32181445	Sequencing also identified worse survival in patients with tumors containing tetraploid genomes.	('worse survival', 'NegReg', (27, 41))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('patients', 'Species', '9606', (45, 53))	('tetraploid genomes', 'Var', (77, 95))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
109745	32181445	Patients with tumors containing tetraploid genomes had worse overall survival.	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tetraploid genomes', 'Var', (32, 50))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
109810	32181445	Levels were adequate to detect junctions and copy level changes in all tumor models.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('copy level', 'Var', (45, 55))	('tumor', 'Disease', (71, 76))	('changes', 'Reg', (56, 63))
109814	32181445	Loss of heterozygosity (LOH) was common in the biliary tract tumors.	('biliary tract tumors', 'Disease', (47, 67))	('Loss of heterozygosity', 'Var', (0, 22))	('biliary tract tumors', 'Disease', 'MESH:D001661', (47, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('biliary tract tumors', 'Phenotype', 'HP:0100574', (47, 67))
109819	32181445	For PDX #8, PDX #22 and PDX #16, rearrangements in the CDKN2A locus result in homozygous loss of both copies of the gene (Fig.	('rearrangements', 'Var', (33, 47))	('CDKN2A', 'Gene', '1029', (55, 61))	('CDKN2A', 'Gene', (55, 61))	('loss', 'NegReg', (89, 93))
109824	32181445	Functional driving fusions have also been reported in these genes and NRG1 gene fusions were observed in 2 cases (PDX #12 and 17) and an amplification of FGFR3 in PDX #20.	('NRG1', 'Gene', '3084', (70, 74))	('fusions', 'Var', (80, 87))	('FGFR3', 'Gene', (154, 159))	('FGFR3', 'Gene', '2261', (154, 159))	('NRG1', 'Gene', (70, 74))
109827	32181445	Tetraploid genomes were also commonly observed in the biliary tract tumors.	('biliary tract tumors', 'Disease', 'MESH:D001661', (54, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('biliary tract tumors', 'Phenotype', 'HP:0100574', (54, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('biliary tract tumors', 'Disease', (54, 74))	('observed', 'Reg', (38, 46))	('Tetraploid genomes', 'Var', (0, 18))
109829	32181445	The 12 tumors in the top half of the figure predicted diploid genomes, while the lower 14 tumors containing extensive chromosomal gains with many predicted tetraploid genomes.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('diploid genomes', 'Var', (54, 69))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
109830	32181445	Survival in patients with diploid vs. tetraploid genomes were significantly different.	('patients', 'Species', '9606', (12, 20))	('different', 'Reg', (76, 85))	('diploid', 'Var', (26, 33))
109831	32181445	Patients with tetraploid genomes had significantly worse overall survival than those with diploid tumors (8 months vs. not reached, p <0.01) (Fig.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('diploid tumors', 'Disease', 'MESH:C548012', (90, 104))	('tetraploid genomes', 'Var', (14, 32))	('diploid tumors', 'Disease', (90, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('worse', 'NegReg', (51, 56))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (57, 73))
109832	32181445	Recurrence free survival was similarly worse in patients with tetraploid genomes (5 months vs. 9 months, p = 0.13) though this did not reach statistical significance (Fig.	('Recurrence free survival', 'CPA', (0, 24))	('patients', 'Species', '9606', (48, 56))	('tetraploid genomes', 'Var', (62, 80))	('worse', 'NegReg', (39, 44))
109851	32181445	Over 50% of the tumors predicted tetraploid genomes that strongly correlated with clinical outcomes.	('correlated', 'Reg', (66, 76))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('clinical', 'Species', '191496', (82, 90))	('tetraploid genomes', 'Var', (33, 51))	('tumors', 'Disease', (16, 22))
109852	32181445	Patients who had tumors with diploid genomes had significantly longer survival compared to those who had tetraploid genomes.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('survival', 'MPA', (70, 78))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('Patients', 'Species', '9606', (0, 8))	('diploid genomes', 'Var', (29, 44))	('longer', 'PosReg', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
109854	32181445	The prognostic value of tumor ploidy has previously been shown in primary patient tumors where diploidy was the best predictor for improved long-term survival.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('patient', 'Species', '9606', (74, 81))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('diploidy', 'Var', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('improved', 'PosReg', (131, 139))	('tumor', 'Disease', (82, 87))
109855	32181445	The PDX tumors profiled here showed a high rate of complete or single allele losses in genes previously shown to be altered in biliary tract tumors.	('biliary tract tumors', 'Disease', (127, 147))	('biliary tract tumors', 'Phenotype', 'HP:0100574', (127, 147))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('biliary tract tumors', 'Disease', 'MESH:D001661', (127, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('single allele', 'Var', (63, 76))
109867	32181445	While there is certainly potential for mutational drift from the original tumor, our results are consistent with what is currently known about biliary tract tumors and we utilized only early generation PDX models for all genomic analyses to minimize this as a confounder.	('biliary tract tumors', 'Phenotype', 'HP:0100574', (143, 163))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('biliary tract tumors', 'Disease', (143, 163))	('biliary tract tumors', 'Disease', 'MESH:D001661', (143, 163))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutational', 'Var', (39, 49))	('original tumor', 'Disease', (65, 79))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('original tumor', 'Disease', 'MESH:D009369', (65, 79))
109872	31807010	FGFR2-BICC1: A Subtype Of FGFR2 Oncogenic Fusion Variant In Cholangiocarcinoma And The Response To Sorafenib Fibroblast growth factor receptor (FGFR) family includes four highly conserved receptor tyrosine kinases.	('tyrosine', 'Chemical', 'None', (197, 205))	('Variant', 'Var', (49, 56))	('FGFR2', 'Gene', '2263', (26, 31))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (60, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('Sorafenib', 'Chemical', 'MESH:C471405', (99, 108))	('BICC1', 'Gene', (6, 11))	('FGFR2', 'Gene', '2263', (0, 5))	('FGFR2', 'Gene', (26, 31))	('BICC1', 'Gene', '80114', (6, 11))	('FGFR2', 'Gene', (0, 5))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (60, 78))	('Cholangiocarcinoma', 'Disease', (60, 78))
109875	31807010	In the present work, we present a case of cholangiocarcinoma who had FGFR2-BICC1 rearrangement detected by NGS.	('cholangiocarcinoma', 'Disease', (42, 60))	('FGFR2', 'Gene', (69, 74))	('FGFR2', 'Gene', '2263', (69, 74))	('BICC1', 'Gene', (75, 80))	('BICC1', 'Gene', '80114', (75, 80))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (42, 60))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (42, 60))	('rearrangement', 'Var', (81, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
109877	31807010	The NGS assay showed that the tumor had a FGFR2-BICC1 rearrangement.	('FGFR2', 'Gene', (42, 47))	('FGFR2', 'Gene', '2263', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('BICC1', 'Gene', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('rearrangement', 'Var', (54, 67))	('tumor', 'Disease', (30, 35))	('BICC1', 'Gene', '80114', (48, 53))
109900	31807010	The NGS analysis of the peripheral blood revealed a FGFR2-BICC1 rearrangement, as shown in Figure 3 (3D Medicines, Shanghai China).	('FGFR2', 'Gene', '2263', (52, 57))	('FGFR2', 'Gene', (52, 57))	('BICC1', 'Gene', (58, 63))	('BICC1', 'Gene', '80114', (58, 63))	('rearrangement', 'Var', (64, 77))
109916	31807010	Mutations and amplification of FGFR gene members have been shown to serve as therapeutic targets in a wide range of human malignancies, such as gastric, lung, and bladder cancers.	('bladder cancers', 'Disease', (163, 178))	('gastric', 'Disease', 'MESH:D013274', (144, 151))	('gastric', 'Disease', (144, 151))	('malignancies', 'Disease', 'MESH:D009369', (122, 134))	('malignancies', 'Disease', (122, 134))	('bladder cancers', 'Phenotype', 'HP:0009725', (163, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('Mutations', 'Var', (0, 9))	('bladder cancers', 'Disease', 'MESH:D001749', (163, 178))	('FGFR', 'Gene', (31, 35))	('lung', 'Disease', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('amplification', 'Var', (14, 27))	('human', 'Species', '9606', (116, 121))
109918	31807010	Bladder cancer cells harboring FGFR3 fusion proteins were shown to be more susceptible to pharmacologic inhibition both in vitro and in vivo.	('susceptible', 'MPA', (75, 86))	('fusion', 'Var', (37, 43))	('Bladder cancer', 'Disease', (0, 14))	('FGFR3', 'Gene', '2261', (31, 36))	('Bladder cancer', 'Disease', 'MESH:D001749', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('proteins', 'Protein', (44, 52))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('FGFR3', 'Gene', (31, 36))
109921	31807010	Loss of Bicc1 in Drosophila disrupts the anterior follicle cell migration and affects anterior-posterior patterning, leading to embryos development disorder.	('development disorder', 'Disease', (136, 156))	('anterior-posterior patterning', 'CPA', (86, 115))	('Drosophila disrupts', 'Disease', (17, 36))	('Drosophila disrupts', 'Disease', 'MESH:D019958', (17, 36))	('development disorder', 'Disease', 'MESH:D002658', (136, 156))	('affects', 'Reg', (78, 85))	('anterior follicle cell migration', 'CPA', (41, 73))	('leading to', 'Reg', (117, 127))	('Loss', 'Var', (0, 4))	('Bicc1', 'Gene', (8, 13))
109924	31807010	It remains to be determined whether patients with FGFR2-BICC1 fusion exhibit unique clinicopathologic manifestations.	('BICC1', 'Gene', '80114', (56, 61))	('patients', 'Species', '9606', (36, 44))	('FGFR2', 'Gene', (50, 55))	('fusion', 'Var', (62, 68))	('BICC1', 'Gene', (56, 61))	('FGFR2', 'Gene', '2263', (50, 55))
109925	31807010	In conclusion, the present case provides a first report of a cholangiocarcinoma patient harboring FGFR2-BICC1 fusion who are responded to sorafenib therapy, suggesting the critical role for the diagnostic application of NGS in precision medicine.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('BICC1', 'Gene', '80114', (104, 109))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('sorafenib', 'Chemical', 'MESH:C471405', (138, 147))	('FGFR2', 'Gene', (98, 103))	('fusion', 'Var', (110, 116))	('FGFR2', 'Gene', '2263', (98, 103))	('cholangiocarcinoma', 'Disease', (61, 79))	('BICC1', 'Gene', (104, 109))	('patient', 'Species', '9606', (80, 87))
110008	29875798	Resection of these tumours results in 5-year OS rates of up to 65% compared to 50% after OLT.	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('OS', 'Chemical', '-', (45, 47))	('Resection', 'Var', (0, 9))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
110016	29875798	Data from Asia for example show respectable 5-year OS rates of 56% after HCC resection in the presence of PH compared to 71% in the non-PH group.	('HCC', 'Phenotype', 'HP:0001402', (73, 76))	('OS', 'Chemical', '-', (51, 53))	('CC', 'Phenotype', 'HP:0030153', (74, 76))	('resection', 'Var', (77, 86))	('to 7', 'Species', '1214577', (118, 122))	('HCC', 'Disease', (73, 76))
110077	29875798	Factors independently associated with improved survival are tumour-free resection margins, well-differentiated tumour grading, mass-forming type, absence of satellite nodules, lymph node involvement and vascular or perineural invasion, low CA-19-9 level and completion of adjuvant chemotherapy treatment.	('tumour-free', 'Disease', 'MESH:D000072662', (60, 71))	('lymph node involvement', 'CPA', (176, 198))	('improved', 'PosReg', (38, 46))	('low', 'Var', (236, 239))	('tumour-free', 'Disease', (60, 71))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('men', 'Species', '9606', (299, 302))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('tumour', 'Disease', (60, 66))	('CA-19-9 level', 'MPA', (240, 253))	('men', 'Species', '9606', (194, 197))	('survival', 'MPA', (47, 55))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('mass-forming type', 'CPA', (127, 144))	('tumour', 'Disease', (111, 117))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('vascular or perineural invasion', 'CPA', (203, 234))
110078	29875798	Patients with microscopic tumour involvement with resection margins <1 mm (R1 resection) show limited survival, comparable to palliatively treated patients.	('tumour involvement', 'Disease', (26, 44))	('limited', 'NegReg', (94, 101))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (147, 155))	('microscopic', 'Var', (14, 25))	('survival', 'MPA', (102, 110))	('tumour involvement', 'Disease', 'MESH:D009369', (26, 44))
110080	29875798	In this study comparing 6 months of capecitabine versus observation in over 400 patients, capecitabine was significantly associated with a 25% lower risk of death in the per protocol analysis.	('death', 'Disease', 'MESH:D003643', (157, 162))	('patients', 'Species', '9606', (80, 88))	('capecitabine', 'Var', (90, 102))	('lower', 'NegReg', (143, 148))	('death', 'Disease', (157, 162))	('capecitabine', 'Chemical', 'MESH:D000069287', (90, 102))	('capecitabine', 'Chemical', 'MESH:D000069287', (36, 48))
110097	29464042	YAP-associated chromosomal instability and cholangiocarcinoma in mice Deregulated Hippo pathway signaling is associated with aberrant activation of the downstream effector yes-associated protein (YAP), an emerging key oncogenic mediator in cholangiocarcinoma (CCA).	('YAP', 'Gene', (0, 3))	('yes-associated protein', 'Gene', '22601', (172, 194))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (43, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (240, 258))	('cholangiocarcinoma', 'Disease', (43, 61))	('YAP', 'Gene', (196, 199))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (43, 61))	('cholangiocarcinoma', 'Disease', (240, 258))	('Deregulated', 'Var', (70, 81))	('YAP', 'Gene', '22601', (0, 3))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (240, 258))	('CCA', 'Phenotype', 'HP:0030153', (260, 263))	('chromosomal instability', 'Phenotype', 'HP:0040012', (15, 38))	('YAP', 'Gene', '22601', (196, 199))	('activation', 'PosReg', (134, 144))	('yes-associated protein', 'Gene', (172, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('Hippo pathway signaling', 'Pathway', (82, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))
110107	29464042	These preclinical data imply a role for YAP-mediated chromosomal instability in cholangiocarcinoma, and suggest FOXM1 inhibition as a therapeutic target for CCA.	('CCA', 'Phenotype', 'HP:0030153', (157, 160))	('chromosomal instability', 'MPA', (53, 76))	('FOXM1', 'Gene', (112, 117))	('cholangiocarcinoma', 'Disease', (80, 98))	('CCA', 'Disease', (157, 160))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (80, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (80, 98))	('chromosomal instability', 'Phenotype', 'HP:0040012', (53, 76))	('inhibition', 'Var', (118, 128))
110112	29464042	Deregulation of the Hippo pathway and consequent activation of its downstream effector, the transcriptional co-activator yes-associated protein (YAP), promotes carcinogenesis in a spectrum of malignancies including CCA.	('malignancies', 'Disease', 'MESH:D009369', (192, 204))	('yes-associated protein', 'Gene', '22601', (121, 143))	('carcinogenesis', 'Disease', 'MESH:D063646', (160, 174))	('Deregulation', 'Var', (0, 12))	('carcinogenesis', 'Disease', (160, 174))	('promotes', 'PosReg', (151, 159))	('yes-associated protein', 'Gene', (121, 143))	('malignancies', 'Disease', (192, 204))	('CCA', 'Disease', (215, 218))	('Hippo pathway', 'Pathway', (20, 33))	('CCA', 'Phenotype', 'HP:0030153', (215, 218))	('activation', 'PosReg', (49, 59))
110113	29464042	Indeed, we have previously reported that biliary transduction with constitutively active human YAP (huYAP), YAPS127A, along with murine myristoylated-Akt (muAkt) as a permissive factor, promotes CCA development in mice.	('human', 'Species', '9606', (89, 94))	('YAPS127A', 'Var', (108, 116))	('Akt', 'Gene', '11651', (150, 153))	('CCA development', 'CPA', (195, 210))	('CCA', 'Phenotype', 'HP:0030153', (195, 198))	('murine', 'Species', '10090', (129, 135))	('Akt', 'Gene', '11651', (157, 160))	('Akt', 'Gene', (150, 153))	('YAPS127A', 'Mutation', 'rs762471803', (108, 116))	('Akt', 'Gene', (157, 160))	('promotes', 'PosReg', (186, 194))	('mice', 'Species', '10090', (214, 218))
110116	29464042	Hence, the presence of CIN correlates with poor patient prognosis.	('presence', 'Var', (11, 19))	('CIN', 'Disease', (23, 26))	('CIN', 'Disease', 'MESH:D007674', (23, 26))	('CIN', 'Phenotype', 'HP:0040012', (23, 26))	('patient', 'Species', '9606', (48, 55))
110131	29464042	Although phosphatase and tensin homolog (PTEN) deficiency may promote gankyrin activity, PTEN was also abundant in the cell lines consistent with YAP's pleiotropic oncogenic properties.	('gankyrin', 'Gene', '53380', (70, 78))	('gankyrin', 'Gene', (70, 78))	('promote', 'PosReg', (62, 69))	('PTEN', 'Gene', '19211', (41, 45))	('PTEN', 'Gene', (41, 45))	('PTEN', 'Gene', '19211', (89, 93))	('PTEN', 'Gene', (89, 93))	('deficiency', 'Var', (47, 57))
110134	29464042	Taken together, these findings suggest that murine CCA cells SB1-7 are phenotypically similar to human CCA, display a malignant phenotype (anchorage-independent growth) and abundantly express FLAG-tagged huYAP.	('murine', 'Species', '10090', (44, 50))	('human', 'Species', '9606', (97, 102))	('CCA', 'Phenotype', 'HP:0030153', (51, 54))	('CCA', 'Phenotype', 'HP:0030153', (103, 106))	('malignant', 'CPA', (118, 127))	('huYAP', 'Gene', (204, 209))	('FLAG-tagged', 'Var', (192, 203))
110158	29464042	Small interfering RNA (siRNA)-mediated knockdown of YAP in these cell lines induced significant cell death in SB2-4 and SB7 (Figure 5A).	('SB7', 'Chemical', '-', (120, 123))	('knockdown', 'Var', (39, 48))	('YAP', 'Gene', (52, 55))	('SB2-4', 'Chemical', '-', (110, 115))	('cell death', 'CPA', (96, 106))
110164	29464042	These observations are most compatible with YAP-dependence of these murine CCA cell lines, and suggest that FOXM1 inhibition may be therapeutic in CCA.	('FOXM1', 'Gene', (108, 113))	('CCA', 'Phenotype', 'HP:0030153', (147, 150))	('murine', 'Species', '10090', (68, 74))	('CCA', 'Disease', (147, 150))	('CCA', 'Phenotype', 'HP:0030153', (75, 78))	('inhibition', 'Var', (114, 124))
110166	29464042	These data indicate that: (i) murine cells derived from Akt-YAP driven tumors have phenotypic features of human CCA; (ii) implantation of murine CCA cells results in development of orthotopic tumors which are morphologically and phenotypically similar to human CCA; (iii) the cell lines exhibit aneuploidy and chromosomal instability with upregulation of FOXM1; (iv) the cell lines are YAP-dependent and FOXM1 pharmacologic inhibition causes CCA cell death.	('FOXM1', 'Gene', (355, 360))	('human', 'Species', '9606', (106, 111))	('aneuploidy', 'Disease', 'MESH:D000782', (295, 305))	('tumors', 'Disease', (192, 198))	('Akt', 'Gene', (56, 59))	('chromosomal instability', 'Phenotype', 'HP:0040012', (310, 333))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('Akt', 'Gene', '11651', (56, 59))	('orthotopic tumors', 'Disease', 'MESH:D009369', (181, 198))	('CCA', 'Phenotype', 'HP:0030153', (112, 115))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('CCA', 'Phenotype', 'HP:0030153', (261, 264))	('human', 'Species', '9606', (255, 260))	('murine', 'Species', '10090', (30, 36))	('aneuploidy', 'Disease', (295, 305))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('orthotopic tumors', 'Disease', (181, 198))	('upregulation', 'PosReg', (339, 351))	('murine', 'Species', '10090', (138, 144))	('pharmacologic', 'Var', (410, 423))	('CCA', 'Phenotype', 'HP:0030153', (442, 445))	('FOXM1', 'Gene', (404, 409))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('CCA', 'Phenotype', 'HP:0030153', (145, 148))	('CCA', 'Disease', (442, 445))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
110167	29464042	Accordingly, Hippo signaling deregulation and YAP overexpression has been implicated in a multitude of malignancies including CCA.	('CCA', 'Disease', (126, 129))	('overexpression', 'PosReg', (50, 64))	('CCA', 'Phenotype', 'HP:0030153', (126, 129))	('malignancies', 'Disease', 'MESH:D009369', (103, 115))	('implicated', 'Reg', (74, 84))	('YAP', 'Gene', (46, 49))	('deregulation', 'Var', (29, 41))	('Hippo signaling', 'Protein', (13, 28))	('malignancies', 'Disease', (103, 115))
110175	29464042	Aberrant YAP activity has also recently been implicated as a driver of CIN and aneuploidy.	('CIN and aneuploidy', 'Disease', 'MESH:D000782', (71, 89))	('YAP', 'Protein', (9, 12))	('CIN', 'Phenotype', 'HP:0040012', (71, 74))	('Aberrant', 'Var', (0, 8))
110183	29464042	Interestingly, inhibition of FOXM1 with thiostrepton induced cell death in all seven murine CCA cell lines, implying it is a potential therapeutic target for CCA.	('CCA', 'Phenotype', 'HP:0030153', (158, 161))	('cell death', 'CPA', (61, 71))	('FOXM1', 'Gene', (29, 34))	('thiostrepton', 'Chemical', 'MESH:D013883', (40, 52))	('murine', 'Species', '10090', (85, 91))	('CCA', 'Disease', (92, 95))	('inhibition', 'Var', (15, 25))	('CCA', 'Phenotype', 'HP:0030153', (92, 95))
110192	29464042	The human HCC cells, Huh7, were cultured in DMEM containing glucose (4.5 g/L), penicillin (100 U/mL), streptomycin (100 microg/mL) and 10% FBS (Gibco, Carlsbad, CA, USA) under standard conditions.	('FBS', 'Disease', 'MESH:D005198', (139, 142))	('Huh7', 'Gene', (21, 25))	('human', 'Species', '9606', (4, 9))	('Huh7', 'Gene', '284424', (21, 25))	('HCC', 'Gene', (10, 13))	('glucose', 'Chemical', 'MESH:D005947', (60, 67))	('penicillin', 'Chemical', 'MESH:D010406', (79, 89))	('FBS', 'Disease', (139, 142))	('HCC', 'Gene', '619501', (10, 13))	('streptomycin', 'Chemical', 'MESH:D013307', (102, 114))	('100', 'Var', (116, 119))	('DMEM', 'Chemical', '-', (44, 48))	('HCC', 'Phenotype', 'HP:0001402', (10, 13))
110219	29464042	Additionally, the algorithm used a statistical sliding window segmentation algorithm in order to detect CNVs that are not expected to have junction support, like partial- and whole-chromosome aneuploidy.	('aneuploidy', 'Disease', (192, 202))	('aneuploidy', 'Disease', 'MESH:D000782', (192, 202))	('partial-', 'Var', (162, 170))
110220	29464042	This included any breakpoint junctions and copy number variants that take part in chromosomal rearrangements, partial and whole-chromosome aneuploidy, and integration sites of the transfected huYap and muAkt sequences.	('Akt', 'Gene', '11651', (204, 207))	('variants', 'Var', (55, 63))	('aneuploidy', 'Disease', (139, 149))	('Akt', 'Gene', (204, 207))	('aneuploidy', 'Disease', 'MESH:D000782', (139, 149))
110231	29464042	After permeabilization using Triton-X-100, slides were then blocked for one hour at room temperature with 5% bovine serum albumin (BSA) and 0.1% glycine PBS before being incubated overnight with primary antibody at 4 C. Antibodies were diluted in phosphate buffered saline with 5% BSA at the following dilutions: CK-19 (sc-33119; 1:50) and FOXM1 (sc-376471; 1:100) from Santa Cruz Biotechnology.	('sc-376471;', 'Var', (347, 357))	('Triton-X-100', 'Chemical', 'MESH:D017830', (29, 41))	('CK-19', 'Gene', (313, 318))	('CK-19', 'Gene', '16669', (313, 318))	('glycine', 'Chemical', 'MESH:D005998', (145, 152))	('phosphate buffered saline', 'Chemical', '-', (247, 272))	('serum albumin', 'Gene', '11657', (116, 129))	('serum albumin', 'Gene', (116, 129))	('bovine', 'Species', '9913', (109, 115))	('PBS', 'Chemical', 'MESH:D007854', (153, 156))
110357	27472451	In contrast, it clearly weakened in cells transfected with miR-122 mimics compared with miR-122 mimics negative control and normal control (p<0.05).	('miR-122', 'Gene', '406906', (59, 66))	('miR-122', 'Gene', (59, 66))	('miR-122', 'Gene', '406906', (88, 95))	('miR-122', 'Gene', (88, 95))	('weakened', 'NegReg', (24, 32))	('mimics', 'Var', (67, 73))
110359	27472451	As shown in Figure 4, miR-122 inhibitor transfection can significantly decrease p53 expression level compared with normal control and miR-122 mimics negative control (p<0.05), whereas miR-122 mimics transfection can elevate p53 level (p<0.05).	('p53', 'Gene', (224, 227))	('p53', 'Gene', '7157', (224, 227))	('elevate', 'PosReg', (216, 223))	('decrease', 'NegReg', (71, 79))	('p53', 'Gene', (80, 83))	('miR-122', 'Gene', '406906', (22, 29))	('miR-122', 'Gene', (22, 29))	('miR-122', 'Gene', (184, 191))	('miR-122', 'Gene', '406906', (134, 141))	('miR-122', 'Gene', '406906', (184, 191))	('p53', 'Gene', '7157', (80, 83))	('miR-122', 'Gene', (134, 141))	('transfection', 'Var', (40, 52))
110368	27472451	Its dysregulation is associated with multiple cancers, including thymic carcinoma, hepatic carcinoma, and bile duct carcinoma.	('dysregulation', 'Var', (4, 17))	('carcinoma', 'Disease', 'MESH:D002277', (116, 125))	('multiple cancers', 'Disease', (37, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinoma', 'Disease', (72, 81))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('hepatic carcinoma', 'Disease', (83, 100))	('bile duct carcinoma', 'Disease', 'MESH:D001650', (106, 125))	('hepatic carcinoma', 'Phenotype', 'HP:0001402', (83, 100))	('bile duct carcinoma', 'Phenotype', 'HP:0030153', (106, 125))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('associated', 'Reg', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('multiple cancers', 'Disease', 'MESH:D009369', (37, 53))	('carcinoma', 'Disease', 'MESH:D002277', (72, 81))	('carcinoma', 'Disease', (116, 125))	('hepatic carcinoma', 'Disease', 'MESH:D056486', (83, 100))	('bile duct carcinoma', 'Disease', (106, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Disease', (91, 100))
110395	26096702	In subgroup analyses, CTC >=2 (HR 8.2; 95%CI 1.8-57.5; p<0.01) and CTC >=5 (HR 7.7; 95%CI 1.4-42.9; p=0.02) were both associated with shorter survival among patients with metastasis.	('survival', 'MPA', (142, 150))	('shorter', 'NegReg', (134, 141))	('CTC >=5', 'Var', (67, 74))	('patients', 'Species', '9606', (157, 165))	('CTC >=2', 'Var', (22, 29))
110397	26096702	CTC >=2 (10.5; 95%CI 2.2-40.1; p<0.01) and CTC >=5 (HR 10.2; 95%CI 1.5-42.3; p=0.02) were both associated with shorter survival among patients with perihilar/distal CCA.	('CTC >=5', 'Var', (43, 50))	('CCA', 'Phenotype', 'HP:0030153', (165, 168))	('patients', 'Species', '9606', (134, 142))	('perihilar/distal CCA', 'Disease', (148, 168))	('survival', 'MPA', (119, 127))	('shorter', 'NegReg', (111, 118))
110398	26096702	CTC >=5 was associated with shorter survival of patients with intrahepatic CCA (HR 4.2; 95%CI 1.1-14.1; p=0.04).	('shorter', 'NegReg', (28, 35))	('CTC >=5', 'Var', (0, 7))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (62, 78))	('survival', 'MPA', (36, 44))	('intrahepatic CCA', 'Disease', (62, 78))	('CCA', 'Phenotype', 'HP:0030153', (75, 78))	('patients', 'Species', '9606', (48, 56))
110399	26096702	CTC were associated with more aggressive tumor characteristics and independently associated with survival in patients with CCA.	('CCA', 'Phenotype', 'HP:0030153', (123, 126))	('associated with', 'Reg', (81, 96))	('aggressive tumor', 'Disease', 'MESH:D001523', (30, 46))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('patients', 'Species', '9606', (109, 117))	('aggressive tumor', 'Disease', (30, 46))	('CTC', 'Var', (0, 3))	('CCA', 'Disease', (123, 126))
110414	26096702	Since CTC are generally more likely to enter the bloodstream from larger tumors with a more metastatic phenotype, we tested the hypotheses that (i) CTC are detectable in blood from CCA patients by CellSearch, and (ii) the presence of CTC is independently associated with poor overall survival in patients with CCA.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('CCA', 'Disease', (310, 313))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('associated', 'Reg', (255, 265))	('CCA', 'Phenotype', 'HP:0030153', (181, 184))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tested', 'Reg', (117, 123))	('overall', 'MPA', (276, 283))	('presence', 'Var', (222, 230))	('poor', 'NegReg', (271, 275))	('tumors', 'Disease', (73, 79))	('patients', 'Species', '9606', (185, 193))	('CCA', 'Phenotype', 'HP:0030153', (310, 313))	('patients', 'Species', '9606', (296, 304))
110418	26096702	Therefore, consecutive patients with advanced stage CCA, which was defined as the presence of a primary tumor size >5cm, CA19-9 >1,000 U/mL, and multifocal, bilobar, or metastatic disease, were approached for consent.	('CCA', 'Disease', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Disease', (104, 109))	('CCA', 'Phenotype', 'HP:0030153', (52, 55))	('CA19-9', 'Var', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
110443	26096702	Baseline laboratory results (AST, ALT, bilirubin, and alkaline phosphatase) were comparable except that the mean total bilirubin level was higher in patients with CTC >=5 compared to patients with CTC <5.	('bilirubin', 'Chemical', 'MESH:D001663', (119, 128))	('ALT', 'MPA', (34, 37))	('patients', 'Species', '9606', (149, 157))	('AST', 'Gene', '26503', (29, 32))	('bilirubin', 'MPA', (39, 48))	('total bilirubin level', 'MPA', (113, 134))	('CTC >=5', 'Var', (163, 170))	('bilirubin', 'Chemical', 'MESH:D001663', (39, 48))	('AST', 'Gene', (29, 32))	('higher', 'PosReg', (139, 145))	('patients', 'Species', '9606', (183, 191))
110447	26096702	Patients with CTC >=2 had larger mean tumor size than patients with CTC<2 (9.8 vs. 4.6 cm, P<0.01).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('patients', 'Species', '9606', (54, 62))	('CTC >=2', 'Var', (14, 21))	('Patients', 'Species', '9606', (0, 8))	('larger', 'PosReg', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
110450	26096702	Median CA19-9 was significantly higher in patients with CTC >=2 than in patients with CTC <2 (579 vs. 112 U/mL, P=0.04).	('higher', 'PosReg', (32, 38))	('patients', 'Species', '9606', (42, 50))	('CA19-9', 'MPA', (7, 13))	('CTC', 'Var', (56, 59))	('patients', 'Species', '9606', (72, 80))
110459	26096702	Other tumor related factors, including multinodular disease (HR 2.1; 95%CI 1.1-3.8; P=0.02), bilobar disease (HR 2.4; 95%CI 1.3-4.6; P<0.01), loco-regional lymph node invasion (HR 2.9; 95%CI 1.5-5.6; P<0.01), CA-19-9 >100 U/mL (HR 3.7; 95%CI 1.8-8.2; P<0.01) and distant extrahepatic metastasis (HR 6.0; 95% CI 2.9-12.6; P<0.01) were also significantly associated with poor overall survival.	('overall', 'MPA', (374, 381))	('poor', 'NegReg', (369, 373))	('CA-19-9 >100 U/mL', 'Var', (209, 226))	('distant extrahepatic metastasis', 'CPA', (263, 294))	('loco-regional lymph node invasion', 'CPA', (142, 175))	('bilobar disease', 'Disease', (93, 108))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('multinodular disease', 'Disease', 'MESH:C564546', (39, 59))	('multinodular disease', 'Disease', (39, 59))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
110463	26096702	Similarly, the median survivals were 1 and 8 months in patients with CTC >=5 and CTC <5, respectively (P<0.01) (Figure 2B) and CTC >=5 was associated with shorter overall survival compared to CTC <5 (HR 7.7; 95%CI 1.4-42.9; P=0.02).	('overall survival', 'MPA', (163, 179))	('CTC >=5', 'Var', (127, 134))	('shorter', 'NegReg', (155, 162))	('patients', 'Species', '9606', (55, 63))	('CTC <5', 'Var', (81, 87))
110465	26096702	The median survivals were 5 and 29 months in patients with CTC >=5 and CTC <5, respectively (P=0.02) (Figure 2D); there was a trend towards association of CTC >=5 with shorter overall survival compared to CTC <5 (HR 4.3; 95%CI 1.0-13.8; P=0.06) Similar results were obtained when the analyses were performed in the subgroups of patients with early stage (AJCC/UICC TNM stage 1-2) or advanced stage (AJCC/UICC TNM stage 3-4) CCA.	('TNM', 'Gene', '10178', (409, 412))	('shorter', 'NegReg', (168, 175))	('patients', 'Species', '9606', (328, 336))	('CCA', 'Disease', (424, 427))	('CTC >=5', 'Var', (155, 162))	('TNM', 'Gene', (409, 412))	('TNM', 'Gene', '10178', (365, 368))	('patients', 'Species', '9606', (45, 53))	('CCA', 'Phenotype', 'HP:0030153', (424, 427))	('TNM', 'Gene', (365, 368))
110467	26096702	Similarly, the median survivals were 4 and 12 months in patients with CTC >=5 and CTC <5, respectively (P=0.01) (Figure 3B) and CTC >=5 was associated with shorter overall survival compared to CTC <5 (HR 3.3; 95% CI 1.1-8.6; P=0.04).	('patients', 'Species', '9606', (56, 64))	('CTC >=5', 'Var', (128, 135))	('shorter', 'NegReg', (156, 163))	('overall survival', 'MPA', (164, 180))	('CTC <5', 'Var', (82, 88))
110469	26096702	The median survivals were 5 and >47 months in patients with CTC >=5 and CTC <5, respectively (P<0.01) (Figure 3D); there was an association of CTC 5 with shorter overall survival compared to CTC <5 (HR 28; 95%CI 1.1-707.4; P=0.04) Lastly, the association between CTC and overall survival was examined in the subgroups of patients with iCCA (n=41) vs. pCCA/dCCA (n=47).	('patients', 'Species', '9606', (46, 54))	('overall survival', 'MPA', (162, 178))	('CCA', 'Phenotype', 'HP:0030153', (336, 339))	('CCA', 'Phenotype', 'HP:0030153', (357, 360))	('iCCA', 'Disease', (335, 339))	('patients', 'Species', '9606', (321, 329))	('CTC 5', 'Var', (143, 148))	('CCA', 'Phenotype', 'HP:0030153', (352, 355))	('shorter', 'NegReg', (154, 161))
110472	26096702	Among patients with pCCA/dCCA, the median survivals were 5 and 27 months in patients with CTC 2 and CTC <2, respectively (P<0.01) (Figure 4C), and CTC 2 was associated with shorter overall survival compared to CTC <2 (HR 10.5; 95%CI 2.2-40.1; P<0.01).	('patients', 'Species', '9606', (76, 84))	('CCA', 'Phenotype', 'HP:0030153', (21, 24))	('shorter', 'NegReg', (173, 180))	('CTC 2', 'Var', (147, 152))	('patients', 'Species', '9606', (6, 14))	('pCCA/dCCA', 'Gene', (20, 29))	('CCA', 'Phenotype', 'HP:0030153', (26, 29))	('overall survival', 'MPA', (181, 197))
110481	26096702	CTC >=2 or 5 were associated with more extensive tumor burden, represented by larger tumor size, multinodular disease, bilobar disease, lymph node involvement, and metastatic disease.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('lymph node involvement', 'Disease', (136, 158))	('metastatic disease', 'Disease', (164, 182))	('multinodular disease', 'Disease', 'MESH:C564546', (97, 117))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('multinodular disease', 'Disease', (97, 117))	('CTC >=2 or 5', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('bilobar disease', 'Disease', (119, 134))
110483	26096702	CTC >=2 or 5 were associated with poorer survival in univariate and multivariate analysis: Patients with CTC >=2 had a 2.5 fold-increased risk of earlier death compared to patients with CTC <2 (HR 2.5; 95%CI 1.1-5.4; P=0.02).	('death', 'Disease', 'MESH:D003643', (154, 159))	('Patients', 'Species', '9606', (91, 99))	('death', 'Disease', (154, 159))	('patients', 'Species', '9606', (172, 180))	('CTC >=2', 'Var', (105, 112))
110497	26096702	A landmark study on CTC measured before and after a new line of treatment in 177 metastatic breast cancer patients showed that CTC >=5 per 7.5 mL blood at baseline was associated with poor progression-free survival (2.7 vs. 7.0 months; P<0.01) and overall survival (10.1 vs. >18.0 months; P <0.01).	('poor', 'NegReg', (184, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('progression-free survival', 'CPA', (189, 214))	('overall survival', 'CPA', (248, 264))	('CTC >=5 per', 'Var', (127, 138))	('patients', 'Species', '9606', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
110510	26096702	For example, there were trends that patients with CTC >=2 had poor overall survival in the subgroups of patients without metastatic disease and intrahepatic CCA without statistical significance.	('CCA', 'Phenotype', 'HP:0030153', (157, 160))	('patients', 'Species', '9606', (36, 44))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (144, 160))	('overall survival', 'MPA', (67, 83))	('intrahepatic CCA', 'Disease', (144, 160))	('CTC >=2', 'Var', (50, 57))	('poor', 'NegReg', (62, 66))	('patients', 'Species', '9606', (104, 112))
110618	22420979	In the other studies, hepatitis B infection was defined by presence of HBsAg (6 studies), HBV DNA in serum (1 study), or by ICD9 codes 070.22, 070.23, 070.32, 070.33, V02.61 (1 study).	('070.22', 'Var', (135, 141))	('hepatitis B infection', 'Disease', (22, 43))	('ICD', 'Disease', 'OMIM:252500', (124, 127))	('HBV', 'Species', '10407', (90, 93))	('ICD', 'Disease', (124, 127))	('HBV DNA', 'Gene', (90, 97))	('hepatitis', 'Phenotype', 'HP:0012115', (22, 31))	('hepatitis B infection', 'Disease', 'MESH:D006509', (22, 43))	('hepatitis B infection', 'Phenotype', 'HP:0410369', (22, 43))
110621	22420979	However, the meta-analysis indicated that presence of hepatitis B virus was associated with a combined OR of 5.54, with 95% confidence intervals of 3.19 - 9.63 for IH-CCA.	('hepatitis', 'Phenotype', 'HP:0012115', (54, 63))	('hepatitis B virus', 'Species', '10407', (54, 71))	('hepatitis', 'Disease', (54, 63))	('IH-CCA', 'Disease', (164, 170))	('presence', 'Var', (42, 50))
110624	22420979	HCV was defined by presence of serum anti-HCV+ in 5 studies, or HCV-RNA positivity in serum, or by ICD9 codes 070.41, 070.44, 070.51, 070.54, V02.62 in the rest of the studies.	('HCV', 'Species', '11103', (0, 3))	('HCV', 'Species', '11103', (42, 45))	('070.41', 'Var', (110, 116))	('HCV-RNA', 'Gene', (64, 71))	('HCV', 'Disease', (0, 3))	('ICD', 'Disease', 'OMIM:252500', (99, 102))	('ICD', 'Disease', (99, 102))	('HCV', 'Species', '11103', (64, 67))
110625	22420979	The meta-analysis indicated that the presence of Hepatitis C virus was associated with an overall OR of 4.84, with a 95% confidence interval of 2.41-9.71.	('Hepatitis C virus', 'Species', '11103', (49, 66))	('presence of Hepatitis C virus', 'Phenotype', 'HP:0410371', (37, 66))	('presence', 'Var', (37, 45))	('Hepatitis', 'Phenotype', 'HP:0012115', (49, 58))	('Hepatitis C', 'Disease', (49, 60))
110631	22420979	The diagnosis was based on ICD-9 coding (250.x0, 250.x2) in 5 studies, or based on chart review identifying a history of diabetes or need for diabetic medications in 4 studies.	('diabetes', 'Disease', (121, 129))	('diabetes', 'Disease', 'MESH:D003920', (121, 129))	('diabetic', 'Disease', 'MESH:D003920', (142, 150))	('250.x0', 'Var', (41, 47))	('ICD', 'Disease', 'OMIM:252500', (27, 30))	('diabetic', 'Disease', (142, 150))	('ICD', 'Disease', (27, 30))
110638	22420979	In a total study population of 398,048 patients, alcohol use was associated with an overall OR of 2.81 (95% CI = 1.52-5.21) for IH-CCA.	('alcohol use', 'Var', (49, 60))	('IH-CCA', 'Disease', (128, 134))	('patients', 'Species', '9606', (39, 47))	('alcohol use', 'Phenotype', 'HP:0030955', (49, 60))	('alcohol', 'Chemical', 'MESH:D000438', (49, 56))
110703	30717258	Importantly, as part of the clinical work-up, all cHCC-CCA tumors (100%; 35/35) showed positivity for K19 (Figure 1).	('HCC', 'Phenotype', 'HP:0001402', (51, 54))	('K19', 'Gene', '3880', (102, 105))	('K19', 'Gene', (102, 105))	('CCA', 'Phenotype', 'HP:0030153', (55, 58))	('tumors', 'Disease', (59, 65))	('positivity', 'Var', (87, 97))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('CCA', 'Gene', '2201', (55, 58))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('CCA', 'Gene', (55, 58))	('cHCC', 'Chemical', '-', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
110725	30717258	The proliferation index (Ki-67) was significantly higher in YAP-nuclear-positive HCCs (18/52) compared to YAP-nuclear-negative cases, which all had a low proliferative status.	('higher', 'PosReg', (50, 56))	('HCC', 'Gene', '619501', (81, 84))	('HCC', 'Phenotype', 'HP:0001402', (81, 84))	('proliferation index', 'CPA', (4, 23))	('Ki-67', 'Chemical', '-', (25, 30))	('HCC', 'Gene', (81, 84))	('YAP-nuclear-positive', 'Var', (60, 80))
110737	30717258	This analysis revealed that the presence of YAP in the cytoplasm was a significant predictor of poor overall survival for HCC K19- patients (p = 0.022, HR: 4.395, 95% CI: 1.235-15.637) (Table 3).	('patients', 'Species', '9606', (131, 139))	('overall survival', 'MPA', (101, 117))	('HCC', 'Gene', (122, 125))	('K19', 'Gene', (126, 129))	('presence', 'Var', (32, 40))	('K19', 'Gene', '3880', (126, 129))	('HCC', 'Gene', '619501', (122, 125))	('poor', 'NegReg', (96, 100))	('HCC', 'Phenotype', 'HP:0001402', (122, 125))
110769	30717258	Our univariate analysis of Ki-67 in HCC (Table 3) and previous work of other groups show that Ki-67 positivity has no clear clinical prognostic value in HCC.	('HCC', 'Gene', '619501', (36, 39))	('HCC', 'Gene', '619501', (153, 156))	('HCC', 'Phenotype', 'HP:0001402', (36, 39))	('HCC', 'Phenotype', 'HP:0001402', (153, 156))	('Ki-67', 'Chemical', '-', (27, 32))	('positivity', 'Var', (100, 110))	('HCC', 'Gene', (36, 39))	('Ki-67', 'Chemical', '-', (94, 99))	('HCC', 'Gene', (153, 156))
110802	29416375	Given the important role of SLC proteins in maintaining normal functions of digestive system, dysregulation of these protein in digestive system neoplasms may deliver biological and clinical significance that deserves systemic studies.	('SLC', 'Gene', '6366', (28, 31))	('SLC', 'Gene', (28, 31))	('system neoplasms', 'Disease', 'MESH:D009369', (138, 154))	('digestive system neoplasms', 'Phenotype', 'HP:0007378', (128, 154))	('dysregulation', 'Var', (94, 107))	('system neoplasms', 'Disease', (138, 154))	('neoplasms', 'Phenotype', 'HP:0002664', (145, 154))
110838	29416375	Inhibition of luminal iron can suppress murine intestinal tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('murine', 'Species', '10090', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('Inhibition', 'Var', (0, 10))	('iron', 'Chemical', 'MESH:D007501', (22, 26))	('suppress', 'NegReg', (31, 39))	('luminal', 'Protein', (14, 21))
110854	29416375	Twelve out of 57 (21%) squamous cell carcinoma patients gained response for anti-SLC2A1 antibodies, when a mean+2x standard deviation of healthy donors was used as a cut-off level.	('patients', 'Species', '9606', (47, 55))	('gained', 'PosReg', (56, 62))	('anti-SLC2A1', 'Var', (76, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('response', 'MPA', (63, 71))	('squamous cell carcinoma', 'Disease', (23, 46))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (23, 46))
110855	29416375	Teng et al found that hepatitis B virus pre-S2 mutant can induce the expression of SLC2A1 via EIF4EBP1, YY1, and MYC dependent manner, which contributed to aberrant glucose uptake and lactate production, thereby promoting tumorigenesis in the liver.	('glucose', 'CPA', (165, 172))	('lactate', 'Chemical', 'MESH:D019344', (184, 191))	('lactate production', 'MPA', (184, 202))	('induce', 'PosReg', (58, 64))	('SLC2A1', 'Gene', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('MYC', 'Gene', '4609', (113, 116))	('expression', 'MPA', (69, 79))	('pre-S2', 'Gene', (40, 46))	('hepatitis B virus', 'Species', '10407', (22, 39))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('hepatitis', 'Phenotype', 'HP:0012115', (22, 31))	('MYC', 'Gene', (113, 116))	('promoting', 'PosReg', (212, 221))	('mutant', 'Var', (47, 53))	('glucose', 'Chemical', 'MESH:D005947', (165, 172))
110858	29416375	In gastric cancer, expression of SLC5A8 was epigenetically inactivated, as indicated by the aberrant methylation of SLC5A8 promoter region in 23 of 71 (30%) primary gastric cancer cases.	('aberrant', 'Var', (92, 100))	('expression', 'MPA', (19, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('gastric cancer', 'Phenotype', 'HP:0012126', (165, 179))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('inactivated', 'NegReg', (59, 70))	('SLC5A8', 'Gene', (33, 39))	('methylation', 'MPA', (101, 112))	('SLC5A8', 'Gene', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', (165, 179))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (165, 179))
110867	29416375	Deletion of CAGA elements located within the -273/-222 region of SLC5A8 promoter abolishes its transcription activation by Activin A, and Smad signaling seems to be responsible for Activin A-induced transcription activation of SLC5A8.	('SLC5A8', 'Gene', (65, 71))	('abolishes', 'NegReg', (81, 90))	('CAGA', 'Gene', (12, 16))	('transcription activation', 'MPA', (95, 119))	('CAGA', 'Gene', '6279', (12, 16))	('Deletion', 'Var', (0, 8))
110868	29416375	Using transcriptome sequencing analysis, Palanisamy et al identified that a gene fusions including SLC45A3 can induce neoplastic transformation of prostate cells.	('gene fusions', 'Var', (76, 88))	('induce', 'PosReg', (111, 117))	('SLC45A3', 'Gene', '85414', (99, 106))	('neoplastic transformation of prostate cells', 'CPA', (118, 161))	('SLC45A3', 'Gene', (99, 106))
110873	29416375	Another study by Zhu et al also showed that the genetic variant rs7758229 in SLC22A3 has no correlation with the risk of cancer in Chinese population.	('rs7758229', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('rs7758229', 'Mutation', 'rs7758229', (64, 73))	('SLC22A3', 'Gene', '6581', (77, 84))	('SLC22A3', 'Gene', (77, 84))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
110882	29416375	This was probably mediated by the methylation of SLC22A1 promoter region.	('mediated by', 'Reg', (18, 29))	('SLC22A1', 'Gene', '6580', (49, 56))	('SLC22A1', 'Gene', (49, 56))	('methylation', 'Var', (34, 45))
110891	29416375	Overexpression of SL22A18 induced G2/M cell cycle arrest as well as reduced colony formation of colon cancer cells, and this may inhibit KRAS(G12D)-mediated anchorage-independent growth of cancer cells.	('colon cancer', 'Phenotype', 'HP:0003003', (96, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('arrest', 'Disease', 'MESH:D006323', (50, 56))	('SL22A18', 'Gene', (18, 25))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('KRAS', 'Gene', '3845', (137, 141))	('colon cancer', 'Disease', 'MESH:D015179', (96, 108))	('KRAS', 'Gene', (137, 141))	('G12D', 'Mutation', 'rs121913529', (142, 146))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (39, 56))	('cancer', 'Disease', (102, 108))	('arrest', 'Disease', (50, 56))	('colon cancer', 'Disease', (96, 108))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('inhibit', 'NegReg', (129, 136))	('reduced', 'NegReg', (68, 75))
110892	29416375	Knockdown of Kras promotes SLC22A18, further proving their mutual interaction.	('SLC22A18', 'Gene', (27, 35))	('Knockdown', 'Var', (0, 9))	('Kras', 'Gene', (13, 17))	('Kras', 'Gene', '3845', (13, 17))	('promotes', 'PosReg', (18, 26))	('SLC22A18', 'Gene', '5002', (27, 35))
110893	29416375	By developing an antibody-drug conjugate ASG-5ME, it was found that pancreatic cancer cell viability, as well as xenografted growth of tumor cells, can be prominently reduced by targeting SLC44A4 in pancreatic cancer cells.	('pancreatic cancer', 'Disease', (199, 216))	('pancreatic cancer', 'Disease', 'MESH:D010190', (199, 216))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('tumor', 'Disease', (135, 140))	('targeting', 'Var', (178, 187))	('SLC44A4', 'Gene', (188, 195))	('SLC44A4', 'Gene', '80736', (188, 195))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))	('ASG-5ME', 'Chemical', 'MESH:C583373', (41, 48))	('pancreatic cancer', 'Disease', (68, 85))	('reduced', 'NegReg', (167, 174))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
110894	29416375	In colon cancer, single nucleotide polymorphisms (SNPs) of SLC12A2 were found and showed correlation with a 34% reduced adenoma risk.	('single nucleotide polymorphisms', 'Var', (17, 48))	('SLC12A2', 'Gene', (59, 66))	('SLC12A2', 'Gene', '6558', (59, 66))	('adenoma', 'Disease', 'MESH:D000236', (120, 127))	('adenoma', 'Disease', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('reduced', 'NegReg', (112, 119))	('colon cancer', 'Disease', (3, 15))
110896	29416375	However, expression of SLC12A2 was induced by hyperosmolarity, and induced expression of SLC12A1 in hepatic stellate cells can promote its activation toward myofibroblast-like phenotype.	('promote', 'PosReg', (127, 134))	('activation', 'CPA', (139, 149))	('SLC12A1', 'Gene', (89, 96))	('expression', 'Var', (75, 85))	('SLC12A2', 'Gene', (23, 30))	('SLC12A2', 'Gene', '6558', (23, 30))	('SLC12A1', 'Gene', '6557', (89, 96))
110898	29416375	NKCC1, which was encoded by SLC12A2, was primarily located in the cytoplasm of esophageal carcinoma cells, and depletion of NKCC1 suppressed cell proliferation and rendered G2/M cell cycle arrest.	('SLC12A2', 'Gene', (28, 35))	('SLC12A2', 'Gene', '6558', (28, 35))	('arrest', 'Disease', 'MESH:D006323', (189, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('suppressed', 'NegReg', (130, 140))	('esophageal carcinoma', 'Disease', (79, 99))	('arrest', 'Disease', (189, 195))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (79, 99))	('NKCC1', 'Gene', (0, 5))	('NKCC1', 'Gene', '6558', (0, 5))	('cell proliferation', 'CPA', (141, 159))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (79, 99))	('rendered', 'Reg', (164, 172))	('NKCC1', 'Gene', (124, 129))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (178, 195))	('depletion', 'Var', (111, 120))	('NKCC1', 'Gene', '6558', (124, 129))
110899	29416375	Microarray analysis revealed that knockdown of SLC12A2 initiates G2/M DNA damage pathway-related proteins including MAD2L1, DTL, BLM, CDC20, BRCA1, and E2F5.	('BLM', 'Gene', '641', (129, 132))	('MAD2L1', 'Gene', (116, 122))	('BRCA1', 'Gene', '672', (141, 146))	('initiates', 'PosReg', (55, 64))	('CDC20', 'Gene', (134, 139))	('CDC20', 'Gene', '991', (134, 139))	('BRCA1', 'Gene', (141, 146))	('BLM', 'Gene', (129, 132))	('MAD2L1', 'Gene', '4085', (116, 122))	('E2F5', 'Gene', '1875', (152, 156))	('knockdown', 'Var', (34, 43))	('SLC12A2', 'Gene', (47, 54))	('G2/M DNA damage pathway-related proteins', 'Pathway', (65, 105))	('E2F5', 'Gene', (152, 156))	('SLC12A2', 'Gene', '6558', (47, 54))
110904	29416375	This leads to shorter survival in colon cancer patients with high SLC12A5 expression.	('colon cancer', 'Disease', (34, 46))	('shorter', 'NegReg', (14, 21))	('high', 'Var', (61, 65))	('patients', 'Species', '9606', (47, 55))	('SLC12A5', 'Gene', (66, 73))	('survival', 'MPA', (22, 30))	('colon cancer', 'Phenotype', 'HP:0003003', (34, 46))	('colon cancer', 'Disease', 'MESH:D015179', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('SLC12A5', 'Gene', '57468', (66, 73))
110919	29416375	Chang et al found that expression of SLC7A11 can be suppressed by 15-keto-PGE2, which in turn reduced intracellular glutathione due to the lack of cysteine and halted cell proliferation and survival of pancreatic cancer cells, suggesting silencing of SLC7A11 as a potential strategy to inhibit pancreatic cells under oxidative stress.	('glutathione', 'Chemical', 'MESH:D005978', (116, 127))	('silencing', 'Var', (238, 247))	('oxidative stress', 'Phenotype', 'HP:0025464', (317, 333))	('lack', 'NegReg', (139, 143))	('pancreatic', 'Disease', 'MESH:D010195', (202, 212))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (202, 219))	('survival', 'CPA', (190, 198))	('intracellular glutathione', 'MPA', (102, 127))	('cell proliferation', 'CPA', (167, 185))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (66, 78))	('SLC7A11', 'Gene', (251, 258))	('SLC7A11', 'Gene', '23657', (251, 258))	('pancreatic', 'Disease', (202, 212))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('SLC7A11', 'Gene', (37, 44))	('reduced', 'NegReg', (94, 101))	('pancreatic cancer', 'Disease', 'MESH:D010190', (202, 219))	('SLC7A11', 'Gene', '23657', (37, 44))	('pancreatic', 'Disease', 'MESH:D010195', (294, 304))	('cysteine', 'MPA', (147, 155))	('suppressed', 'NegReg', (52, 62))	('cysteine', 'Chemical', 'MESH:D003545', (147, 155))	('halted', 'NegReg', (160, 166))	('pancreatic cancer', 'Disease', (202, 219))	('pancreatic', 'Disease', (294, 304))
110929	29416375	The mechanism underlying induction of cell proliferation by SLC29A2 overexpression may involve activation of STAT3 signaling pathway.	('cell proliferation', 'CPA', (38, 56))	('SLC29A2', 'Gene', (60, 67))	('STAT3', 'Gene', '6774', (109, 114))	('STAT3', 'Gene', (109, 114))	('overexpression', 'Var', (68, 82))
110935	29416375	Vasuri et al found that two organic anion transporters OATP-1B1 and OATP-1B3, which were encoded by SLCO1B1 and SLCO1B3, respectively, were inversely correlated with the expression of the biliary type keratins K7 and K19, which indicated poor prognosis after liver transplantation in HCC patients.	('OATP-1B3', 'Gene', '28234', (68, 76))	('SLCO1B1', 'Gene', (100, 107))	('OATP-1B1', 'Gene', (55, 63))	('patients', 'Species', '9606', (288, 296))	('HCC', 'Gene', '619501', (284, 287))	('biliary type keratins', 'Protein', (188, 209))	('inversely', 'NegReg', (140, 149))	('SLCO1B3', 'Gene', (112, 119))	('OATP-1B1', 'Gene', '10599', (55, 63))	('HCC', 'Phenotype', 'HP:0001402', (284, 287))	('SLCO1B1', 'Gene', '10599', (100, 107))	('K19', 'Var', (217, 220))	('correlated', 'Reg', (150, 160))	('OATP-1B3', 'Gene', (68, 76))	('SLCO1B3', 'Gene', '28234', (112, 119))	('HCC', 'Gene', (284, 287))	('organic anion transporters', 'MPA', (28, 54))	('expression', 'MPA', (170, 180))
110937	29416375	However, Teft et al found that polymorphism of SLCO1B1 at 388G/G may predict longer progression-free survival (PFS), while SLCO1B3 expression was associated with reduced PFS.	('longer', 'PosReg', (77, 83))	('polymorphism', 'Var', (31, 43))	('SLCO1B1', 'Gene', '10599', (47, 54))	('SLCO1B3', 'Gene', (123, 130))	('SLCO1B1', 'Gene', (47, 54))	('SLCO1B3', 'Gene', '28234', (123, 130))	('progression-free survival', 'CPA', (84, 109))
110944	29416375	Exploratory analysis showed that polymorphisms of SLCO1B1 can affect the pharmacokinetics and pharmacodynamics of irinotecan, as evidenced by more variability of irinotecan and its active metabolite AUC in patients with SLCO1B1 polymorphisms.	('SLCO1B1', 'Gene', '10599', (50, 57))	('affect', 'Reg', (62, 68))	('irinotecan', 'MPA', (162, 172))	('irinotecan', 'Chemical', 'MESH:D000077146', (162, 172))	('SLCO1B1', 'Gene', (220, 227))	('polymorphisms', 'Var', (33, 46))	('pharmacodynamics', 'MPA', (94, 110))	('pharmacokinetics', 'MPA', (73, 89))	('SLCO1B1', 'Gene', '10599', (220, 227))	('SLCO1B1', 'Gene', (50, 57))	('variability', 'MPA', (147, 158))	('active metabolite AUC', 'MPA', (181, 202))	('patients', 'Species', '9606', (206, 214))	('more', 'PosReg', (142, 146))	('irinotecan', 'Chemical', 'MESH:D000077146', (114, 124))
110945	29416375	Huang et al found that genotype GA/AA of SNP rs2306283 of SLCO1B1 and genotype GG of SNP rs1051266 of SLC19A1 were associated with a higher rapid response rate of colorectal cancer to irinotecan plus fluoropyrimidine treatment, while SLCO1B1 SNP also predicted longer PFS.	('SLCO1B1', 'Gene', (234, 241))	('rs1051266', 'Mutation', 'rs1051266', (89, 98))	('SLCO1B1', 'Gene', '10599', (58, 65))	('fluoropyrimidine', 'Chemical', '-', (200, 216))	('SLCO1B1', 'Gene', '10599', (234, 241))	('irinotecan', 'Chemical', 'MESH:D000077146', (184, 194))	('SLCO1B1', 'Gene', (58, 65))	('SNP', 'Var', (41, 44))	('rapid response', 'MPA', (140, 154))	('higher', 'PosReg', (133, 139))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('SLC19A1', 'Gene', (102, 109))	('rs2306283', 'Var', (45, 54))	('SNP', 'Var', (85, 88))	('SLC19A1', 'Gene', '6573', (102, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (163, 180))	('rs2306283', 'Mutation', 'rs2306283', (45, 54))	('colorectal cancer', 'Disease', (163, 180))
110946	29416375	Experimental observation showed that pancreatic cells with high expression of SLCO1B1 and SLCO1B3 were more sensitive to gemcitabine treatment than those with lower expression.	('SLCO1B1', 'Gene', '10599', (78, 85))	('pancreatic', 'Disease', 'MESH:D010195', (37, 47))	('SLCO1B3', 'Gene', '28234', (90, 97))	('pancreatic', 'Disease', (37, 47))	('gemcitabine', 'Chemical', 'MESH:C056507', (121, 132))	('sensitive to gemcitabine treatment', 'MPA', (108, 142))	('high expression', 'Var', (59, 74))	('SLCO1B1', 'Gene', (78, 85))	('SLCO1B3', 'Gene', (90, 97))
110949	29416375	Hypermethylation of SLC19A3 was found in gastric cancer cell lines (57%, 4/7), primary gastric carcinoma tissues (51%, 52/101), and precancerous lesion (intestinal metaplasia) tissues (32%, 8/25).	('intestinal metaplasia', 'Disease', 'MESH:D008679', (153, 174))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (87, 104))	('precancerous lesion', 'Disease', (132, 151))	('gastric cancer', 'Phenotype', 'HP:0012126', (41, 55))	('Hypermethylation', 'Var', (0, 16))	('found', 'Reg', (32, 37))	('precancerous lesion', 'Disease', 'MESH:D011230', (132, 151))	('gastric carcinoma', 'Disease', 'MESH:D013274', (87, 104))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('SLC19A3', 'Gene', '80704', (20, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('intestinal metaplasia', 'Disease', (153, 174))	('gastric carcinoma', 'Disease', (87, 104))	('gastric cancer', 'Disease', (41, 55))	('SLC19A3', 'Gene', (20, 27))	('gastric cancer', 'Disease', 'MESH:D013274', (41, 55))
110985	29416375	Depletion of intracellular zinc can reduce the migratory and invasive ability of cancer cells.	('reduce', 'NegReg', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('Depletion', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
110998	29416375	Although there is still no direct scientific evidence to show that knockdown of SLC22 can cause CHOL, it is postulated that abnormal bile acid secretion and formation caused by SLC22 loss may be associated with bile duct carcinogenesis by mutated cells.	('associated', 'Reg', (195, 205))	('formation', 'MPA', (157, 166))	('loss', 'NegReg', (183, 187))	('SLC', 'Gene', '6366', (177, 180))	('carcinogenesis', 'Disease', (221, 235))	('knockdown', 'Var', (67, 76))	('CHOL', 'Phenotype', 'HP:0030153', (96, 100))	('CHOL', 'Disease', (96, 100))	('SLC', 'Gene', '6366', (80, 83))	('SLC', 'Gene', (177, 180))	('SLC', 'Gene', (80, 83))	('cause', 'Reg', (90, 95))	('bile acid', 'Chemical', 'MESH:D001647', (133, 142))	('carcinogenesis', 'Disease', 'MESH:D063646', (221, 235))	('abnormal bile acid secretion', 'MPA', (124, 152))
110999	29416375	Regarding the critical role of SLC proteins in mediating the initiation, progression, and metastasis of different cancers, which has been critically reviewed elsewhere and in our present review, pharmacologic modulations on the expressions and activities of SLC proteins might deliver potential therapeutic activities on cancers.	('SLC', 'Gene', '6366', (258, 261))	('modulations', 'Var', (209, 220))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('SLC', 'Gene', (258, 261))	('cancers', 'Phenotype', 'HP:0002664', (321, 328))	('cancers', 'Disease', (114, 121))	('cancers', 'Disease', (321, 328))	('SLC', 'Gene', (31, 34))	('cancers', 'Disease', 'MESH:D009369', (321, 328))	('metastasis of different cancers', 'Disease', (90, 121))	('activities', 'MPA', (244, 254))	('metastasis of different cancers', 'Disease', 'MESH:D009362', (90, 121))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('SLC', 'Gene', '6366', (31, 34))
111000	29416375	A series of small molecule modulators of SLC proteins have been discovered with high-throughput screening of large compound libraries, most of which were found to be inhibitors of transporters function.	('modulators', 'Var', (27, 37))	('transporters function', 'MPA', (180, 201))	('SLC', 'Gene', '6366', (41, 44))	('SLC', 'Gene', (41, 44))
111016	29416375	These findings suggest that particular modulators (Figure 2) of SLC family proteins may be potential next-generation therapeutic agents for digestive system neoplasms.	('system neoplasms', 'Disease', 'MESH:D009369', (150, 166))	('digestive system neoplasms', 'Phenotype', 'HP:0007378', (140, 166))	('system neoplasms', 'Disease', (150, 166))	('neoplasms', 'Phenotype', 'HP:0002664', (157, 166))	('SLC', 'Gene', '6366', (64, 67))	('SLC', 'Gene', (64, 67))	('modulators', 'Var', (39, 49))
111019	29416375	Mutation or dysfunction of SLC proteins is, therefore, a risk factor for the occurrence of gastrointestinal malignancies, or it mediates the progression of cancers.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('gastrointestinal malignancies', 'Disease', (91, 120))	('dysfunction of SLC proteins', 'Disease', (12, 39))	('mediates', 'Reg', (128, 136))	('cancers', 'Disease', (156, 163))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (91, 120))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('Mutation', 'Var', (0, 8))	('dysfunction of SLC proteins', 'Disease', 'MESH:D011488', (12, 39))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
111032	29416375	Changes in expression and regulation of SLC family proteins (as summarized in Figure 3) were observed in neoplasms of digestive system and their dysregulation may be associated with increased carcinogenesis, tumor progression, and metastasis, as well as with resistance of cancer cells to chemotherapeutic agents.	('increased', 'PosReg', (182, 191))	('expression', 'MPA', (11, 21))	('metastasis', 'CPA', (231, 241))	('neoplasms', 'Disease', (105, 114))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('regulation', 'MPA', (26, 36))	('SLC', 'Gene', '6366', (40, 43))	('tumor', 'Disease', (208, 213))	('Changes', 'Reg', (0, 7))	('associated', 'Reg', (166, 176))	('dysregulation', 'Var', (145, 158))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('neoplasms', 'Phenotype', 'HP:0002664', (105, 114))	('carcinogenesis', 'Disease', (192, 206))	('neoplasms of digestive system', 'Phenotype', 'HP:0007378', (105, 134))	('cancer', 'Disease', (273, 279))	('carcinogenesis', 'Disease', 'MESH:D063646', (192, 206))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('SLC', 'Gene', (40, 43))	('neoplasms', 'Disease', 'MESH:D009369', (105, 114))
111039	27680563	shRNA-mediated gene knockdown of Fascin significantly inhibited cell proliferation, invasion, and EMT, and shRNA-Fascin markedly inhibited the xenograft tumor volume.	('inhibited', 'NegReg', (129, 138))	('inhibited', 'NegReg', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('invasion', 'CPA', (84, 92))	('shRNA-Fascin', 'Var', (107, 119))	('cell proliferation', 'CPA', (64, 82))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('knockdown', 'Var', (20, 29))	('EMT', 'CPA', (98, 101))
111040	27680563	Silencing of Fascin up-regulated phosphorylation of beta-catenin and decreased its nuclear localization.	('phosphorylation', 'MPA', (33, 48))	('nuclear localization', 'MPA', (83, 103))	('beta-catenin', 'Gene', (52, 64))	('Fascin', 'Gene', (13, 19))	('decreased', 'NegReg', (69, 78))	('beta-catenin', 'Gene', '1499', (52, 64))	('Silencing', 'Var', (0, 9))	('up-regulated', 'PosReg', (20, 32))
111041	27680563	Additionally, knockdown of Fascin led to the upregulation of beta-catenin and E-cadherin expression in plasma membrane fraction of QBC939 cells.	('beta-catenin', 'Gene', '1499', (61, 73))	('expression', 'MPA', (89, 99))	('E-cadherin', 'Gene', (78, 88))	('Fascin', 'Gene', (27, 33))	('QBC939', 'CellLine', 'CVCL:6942', (131, 137))	('beta-catenin', 'Gene', (61, 73))	('E-cadherin', 'Gene', '999', (78, 88))	('knockdown', 'Var', (14, 23))	('upregulation', 'PosReg', (45, 57))
111053	27680563	The latest study suggests that aberrant activation of the Wnt/beta-catenin signaling pathway promotes EMT and progression of tumors.	('beta-catenin', 'Gene', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('aberrant', 'Var', (31, 39))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('activation', 'PosReg', (40, 50))	('beta-catenin', 'Gene', '1499', (62, 74))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('EMT', 'CPA', (102, 105))	('promotes', 'PosReg', (93, 101))
111079	27680563	Taken together, these results indicated that Fascin knockdown suppresses cholangiocarcinoma cancer cell proliferation.	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (73, 91))	('cholangiocarcinoma cancer', 'Disease', (73, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('suppresses', 'NegReg', (62, 72))	('knockdown', 'Var', (52, 61))	('cholangiocarcinoma cancer', 'Disease', 'MESH:D018281', (73, 98))
111092	27680563	Western blot analysis showed that silencing of Fascin in QBC939 cells dramatically increased GSK-3beta and phosphorylated beta-catenin expression compared to controls, and nuclear beta-catenin significantly decreased in Fascin silencing QBC939 cells compared to control cells.	('silencing', 'Var', (227, 236))	('Fascin', 'Protein', (220, 226))	('silencing', 'Var', (34, 43))	('increased', 'PosReg', (83, 92))	('beta-catenin', 'Gene', '1499', (122, 134))	('decreased', 'NegReg', (207, 216))	('GSK-3beta', 'Gene', (93, 102))	('GSK-3beta', 'Gene', '2932', (93, 102))	('beta-catenin', 'Gene', (180, 192))	('QBC939', 'CellLine', 'CVCL:6942', (237, 243))	('beta-catenin', 'Gene', '1499', (180, 192))	('Fascin', 'Protein', (47, 53))	('beta-catenin', 'Gene', (122, 134))	('QBC939', 'CellLine', 'CVCL:6942', (57, 63))
111093	27680563	These data strongly suggested that Fascin knockdown in QBC939 cells leads to inhibition of Wnt/beta-catenin signaling.	('Fascin', 'Protein', (35, 41))	('inhibition', 'NegReg', (77, 87))	('beta-catenin', 'Gene', (95, 107))	('QBC939', 'CellLine', 'CVCL:6942', (55, 61))	('beta-catenin', 'Gene', '1499', (95, 107))	('knockdown', 'Var', (42, 51))
111094	27680563	However, compared with negative controls, the expression of beta-catenin and E-cadherin in plasma membrane fractions was increased in the Fascin knockdown QBC939 cells.	('knockdown', 'Var', (145, 154))	('increased', 'PosReg', (121, 130))	('E-cadherin', 'Gene', (77, 87))	('E-cadherin', 'Gene', '999', (77, 87))	('QBC939', 'CellLine', 'CVCL:6942', (155, 161))	('beta-catenin', 'Gene', (60, 72))	('beta-catenin', 'Gene', '1499', (60, 72))	('expression', 'MPA', (46, 56))
111095	27680563	Silencing of Fascin led to recruitment of beta-catenin and E-cadherin to the plasma membrane of QBC939 cells (Figure 5).	('recruitment', 'MPA', (27, 38))	('Fascin', 'Protein', (13, 19))	('beta-catenin', 'Gene', (42, 54))	('beta-catenin', 'Gene', '1499', (42, 54))	('QBC939', 'CellLine', 'CVCL:6942', (96, 102))	('Silencing', 'Var', (0, 9))	('E-cadherin', 'Gene', (59, 69))	('E-cadherin', 'Gene', '999', (59, 69))
111103	27680563	In MTS, Fascin knockdown inhibits the growth of QBC939 cells.	('inhibits', 'NegReg', (25, 33))	('QBC939', 'CellLine', 'CVCL:6942', (48, 54))	('knockdown', 'Var', (15, 24))	('Fascin', 'Protein', (8, 14))	('growth', 'CPA', (38, 44))
111109	27680563	The cell migration assay showed that the knockdown of Fascin significantly inhibited the migration capacity in QBC939 cells.	('knockdown', 'Var', (41, 50))	('inhibited', 'NegReg', (75, 84))	('QBC939', 'CellLine', 'CVCL:6942', (111, 117))	('migration capacity', 'CPA', (89, 107))
111110	27680563	The transwell invasive assay demonstrated that the knockdown of Fascin significantly repressed the invasiveness of QBC939 cells.	('repressed', 'NegReg', (85, 94))	('QBC939', 'CellLine', 'CVCL:6942', (115, 121))	('invasiveness of QBC939 cells', 'CPA', (99, 127))	('knockdown', 'Var', (51, 60))
111113	27680563	In this work, we found that Fascin knockdown up-regulated epithelial markers such as E-cadherin and down-regulated mesenchymal marker such as vimentin.	('vimentin', 'Gene', '7431', (142, 150))	('knockdown', 'Var', (35, 44))	('epithelial', 'CPA', (58, 68))	('up-regulated', 'PosReg', (45, 57))	('vimentin', 'Gene', (142, 150))	('mesenchymal', 'CPA', (115, 126))	('Fascin', 'Gene', (28, 34))	('down-regulated', 'NegReg', (100, 114))	('E-cadherin', 'Gene', (85, 95))	('E-cadherin', 'Gene', '999', (85, 95))
111119	27680563	These data suggest that Wnt/beta-catenin signaling is strongly suppressed by silencing of Fascin.	('beta-catenin', 'Gene', (28, 40))	('beta-catenin', 'Gene', '1499', (28, 40))	('Fascin', 'Protein', (90, 96))	('silencing', 'Var', (77, 86))	('suppressed', 'NegReg', (63, 73))
111145	15949047	Gallstones, especially larger than 3 cm, chronic inflammation, bacterial infection, polyps, calcified (porcelain) gallbladder, ulcerative colitis, high energy and total carbohydrate intake, and high body mass index in women increase risk.	('Gallstones', 'Disease', (0, 10))	('ulcerative colitis', 'Disease', 'MESH:D003093', (127, 145))	('Gallstones', 'Phenotype', 'HP:0001081', (0, 10))	('bacterial infection', 'Disease', 'MESH:D001424', (63, 82))	('carbohydrate', 'Chemical', 'MESH:D002241', (169, 181))	('polyps', 'Disease', (84, 90))	('bacterial infection', 'Phenotype', 'HP:0002718', (63, 82))	('high energy', 'Var', (147, 158))	('chronic', 'Disease', (41, 48))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (127, 145))	('inflammation', 'Disease', 'MESH:D007249', (49, 61))	('colitis', 'Phenotype', 'HP:0002583', (138, 145))	('high body mass index', 'Phenotype', 'HP:0031418', (194, 214))	('polyps', 'Disease', 'MESH:D011127', (84, 90))	('ulcerative colitis', 'Disease', (127, 145))	('inflammation', 'Disease', (49, 61))	('women', 'Species', '9606', (218, 223))	('bacterial infection', 'Disease', (63, 82))	('calcified', 'Disease', (92, 101))
111247	32393197	Recently, using the large National Cancer Database data, a propensity score matched analysis using resected patients with cholangiocarcinoma indicated that patients who received NAC alone had a superior overall survival compared to those who received AC alone.	('patients', 'Species', '9606', (156, 164))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (122, 140))	('overall', 'MPA', (203, 210))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (122, 140))	('R', 'Chemical', 'MESH:D001120', (0, 1))	('cholangiocarcinoma', 'Disease', (122, 140))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Cancer', 'Disease', (35, 41))	('patients', 'Species', '9606', (108, 116))	('Cancer', 'Disease', 'MESH:D009369', (35, 41))	('NAC', 'Var', (178, 181))	('NAC', 'Chemical', '-', (178, 181))
111332	32393197	The patients with resection had significantly better prognosis compared to the patients without resection (5-year DSS: 43.8% vs. 5.9%, p < 0.001).	('resection', 'Var', (18, 27))	('DSS', 'Gene', '5376', (114, 117))	('patients', 'Species', '9606', (79, 87))	('patients', 'Species', '9606', (4, 12))	('DSS', 'Gene', (114, 117))
111335	32393197	Univariate analysis identified the following poor prognostic factors: preoperative CEA levels (more than 8.5 ng/ml), G3 histological differentiation, pT4, intrahepatic metastasis, and non R0 resection.	('pT4', 'Var', (150, 153))	('CEA', 'Gene', (83, 86))	('CEA', 'Gene', '1084', (83, 86))	('R', 'Chemical', 'MESH:D001120', (188, 189))	('intrahepatic metastasis', 'Disease', 'MESH:D009362', (155, 178))	('intrahepatic metastasis', 'Disease', (155, 178))	('G3 histological', 'CPA', (117, 132))
111353	32393197	The patients with resection had significantly better prognosis compared to those without resection (5-year DSS: 43.8% vs. 5.9%).	('DSS', 'Gene', '5376', (107, 110))	('resection', 'Var', (18, 27))	('DSS', 'Gene', (107, 110))	('patients', 'Species', '9606', (4, 12))
111398	32393197	In the absence of definitive evidence of NAC for localized BTC, using the large National Cancer Database data, a propensity score matched analysis using resected patients with cholangiocarcinoma indicated that selected 278 patients who received NAC alone had a superior overall survival compared to selected 700 patients who received AC alone (MST: 40.3 vs. 32.8 months).	('patients', 'Species', '9606', (162, 170))	('NAC', 'Chemical', '-', (41, 44))	('overall survival', 'MPA', (270, 286))	('Cancer', 'Disease', (89, 95))	('cholangiocarcinoma', 'Disease', (176, 194))	('Cancer', 'Phenotype', 'HP:0002664', (89, 95))	('patients', 'Species', '9606', (312, 320))	('Cancer', 'Disease', 'MESH:D009369', (89, 95))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (176, 194))	('NAC', 'Var', (245, 248))	('NAC', 'Chemical', '-', (245, 248))	('MST', 'Gene', (344, 347))	('patients', 'Species', '9606', (223, 231))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (176, 194))	('superior', 'PosReg', (261, 269))	('MST', 'Gene', '4357', (344, 347))
111408	32393197	Especially, the patients with resection showing preoperative high CEA levels had very poor prognosis, being comparable to the patients without resection.	('high', 'Var', (61, 65))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (126, 134))	('CEA', 'Gene', (66, 69))	('CEA', 'Gene', '1084', (66, 69))
111432	31410063	In vitro data indicate that deletion of ERO1A can inhibit the proliferation and migration of CCA cells and vice versa.	('ERO1A', 'Gene', (40, 45))	('inhibit', 'NegReg', (50, 57))	('CCA', 'Phenotype', 'HP:0030153', (93, 96))	('deletion', 'Var', (28, 36))	('ERO1A', 'Gene', '30001', (40, 45))
111492	31410063	The results showed that patients with high expression of ERO1A had a significantly shorter overall survival (P<0.05), indicating that ERO1A expression in CCA patients may have a significant impact on patient survival (Figure 3A-C).	('CCA', 'Phenotype', 'HP:0030153', (154, 157))	('impact', 'Reg', (190, 196))	('ERO1A', 'Gene', (57, 62))	('patient', 'Species', '9606', (158, 165))	('CCA', 'Disease', (154, 157))	('ERO1A', 'Gene', (134, 139))	('shorter', 'NegReg', (83, 90))	('overall survival', 'MPA', (91, 107))	('high expression', 'Var', (38, 53))	('patient', 'Species', '9606', (24, 31))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (158, 166))	('ERO1A', 'Gene', '30001', (134, 139))	('patient', 'Species', '9606', (200, 207))	('ERO1A', 'Gene', '30001', (57, 62))
111496	31410063	MTT assays (Figure 4C and D) and colony formation assays (Figure 4E and G) showed that ERO1A depletion can inhibit the proliferative capacity in HuCCT1 and QBC939 cells.	('inhibit', 'NegReg', (107, 114))	('ERO1A', 'Gene', '30001', (87, 92))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('proliferative capacity', 'CPA', (119, 141))	('ERO1A', 'Gene', (87, 92))	('depletion', 'Var', (93, 102))
111502	31410063	Disorders in signal transduction of this pathway may cause various diseases, including cancer.	('Disorders', 'Var', (0, 9))	('cancer', 'Disease', (87, 93))	('cause', 'Reg', (53, 58))	('diseases', 'Disease', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
111504	31410063	The results of Western blotting showed that the levels of p-Akt, p-4EBP1, and p-S6 were decreased after silencing ERO1A.	('levels', 'MPA', (48, 54))	('p-S6', 'Gene', '338413', (78, 82))	('Akt', 'Gene', '207', (60, 63))	('silencing', 'Var', (104, 113))	('p-S6', 'Gene', (78, 82))	('4EBP1', 'Gene', '1978', (67, 72))	('Akt', 'Gene', (60, 63))	('ERO1A', 'Gene', '30001', (114, 119))	('4EBP1', 'Gene', (67, 72))	('decreased', 'NegReg', (88, 97))	('ERO1A', 'Gene', (114, 119))
111510	31410063	The overall survival time of patients with high ERO1A expression was significantly shortened, and ERO1A was closely related to pathological and clinical stages.	('expression', 'MPA', (54, 64))	('patients', 'Species', '9606', (29, 37))	('ERO1A', 'Gene', (98, 103))	('high', 'Var', (43, 47))	('ERO1A', 'Gene', '30001', (48, 53))	('shortened', 'NegReg', (83, 92))	('ERO1A', 'Gene', (48, 53))	('ERO1A', 'Gene', '30001', (98, 103))
111514	31410063	However, these markers are not specific because CEA and CA19-9 can be used as diagnostic markers for a variety of cancers and can also be found in some benign diseases such as cholangitis and intrahepatic bile duct stones.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('CEA', 'Gene', (48, 51))	('cancers', 'Disease', (114, 121))	('intrahepatic bile duct stones', 'Disease', 'MESH:D002780', (192, 221))	('CEA', 'Gene', '1084', (48, 51))	('cholangitis', 'Disease', 'MESH:D002761', (176, 187))	('intrahepatic bile duct stones', 'Disease', (192, 221))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cholangitis', 'Disease', (176, 187))	('intrahepatic bile duct stones', 'Phenotype', 'HP:0005209', (192, 221))	('found', 'Reg', (138, 143))	('cholangitis', 'Phenotype', 'HP:0030151', (176, 187))	('CA19-9', 'Var', (56, 62))
111534	31410063	In this study, depletion of ERO1A in HuCCT1 and QBC-939 cells can reduce the expression of p-Akt, p-4EBP1, and p-S6, whereas the result of overexpression of ERO1A is the opposite.	('depletion', 'Var', (15, 24))	('QBC-939', 'CellLine', 'CVCL:6942', (48, 55))	('expression', 'MPA', (77, 87))	('Akt', 'Gene', (93, 96))	('4EBP1', 'Gene', (100, 105))	('ERO1A', 'Gene', '30001', (28, 33))	('ERO1A', 'Gene', (157, 162))	('p-S6', 'Gene', (111, 115))	('ERO1A', 'Gene', (28, 33))	('4EBP1', 'Gene', '1978', (100, 105))	('reduce', 'NegReg', (66, 72))	('p-S6', 'Gene', '338413', (111, 115))	('Akt', 'Gene', '207', (93, 96))	('ERO1A', 'Gene', '30001', (157, 162))
111549	29704257	For instance, fibroblast growth factor receptor (FGFR) gene fusions have been reported almost exclusively in iCCAs.	('gene fusions', 'Var', (55, 67))	('iCCAs', 'Disease', 'None', (109, 114))	('FGFR', 'Gene', (49, 53))	('CCA', 'Phenotype', 'HP:0030153', (110, 113))	('iCCAs', 'Disease', (109, 114))
111550	29704257	FGFR2 gene fusions have been detected in approximately 15% of iCCAs.	('iCCAs', 'Disease', (62, 67))	('iCCAs', 'Disease', 'None', (62, 67))	('CCA', 'Phenotype', 'HP:0030153', (63, 66))	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (11, 18))	('FGFR2', 'Gene', '2263', (0, 5))
111552	29704257	Hence, discovery of the FGFR2 gene fusions in iCCA has garnered much excitement, and there are several FGFR inhibitors being evaluated in clinical trials of CCA patients with tumors containing FGFR2 gene fusions.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('FGFR2', 'Gene', '2263', (24, 29))	('CCA', 'Phenotype', 'HP:0030153', (157, 160))	('CCA', 'Phenotype', 'HP:0030153', (47, 50))	('CCA', 'Disease', 'MESH:D018281', (47, 50))	('CCA', 'Disease', 'MESH:D018281', (157, 160))	('CCA', 'Disease', (47, 50))	('patients', 'Species', '9606', (161, 169))	('CCA', 'Disease', (157, 160))	('FGFR2', 'Gene', (193, 198))	('FGFR2', 'Gene', '2263', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('FGFR2', 'Gene', (24, 29))	('fusions', 'Var', (35, 42))
111554	29704257	E7090 is a selective FGFR inhibitor being evaluated in phase I clinical trial in patients with advanced solid tumors (NCT02275910).	('FGFR', 'Gene', (21, 25))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('solid tumors', 'Disease', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('E7090', 'Var', (0, 5))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))
111558	29704257	In a phase I, dose-escalation and dose-expansion study, BGJ398 was evaluated in 132 patients with advanced solid organ malignancies containing FGFR genetic alterations including FGFR gene fusions, amplifications, and mutations.	('FGFR', 'Gene', (143, 147))	('patients', 'Species', '9606', (84, 92))	('gene fusions', 'Var', (183, 195))	('mutations', 'Var', (217, 226))	('genetic alterations', 'Var', (148, 167))	('malignancies', 'Disease', (119, 131))	('FGFR', 'Gene', (178, 182))	('amplifications', 'Var', (197, 211))	('malignancies', 'Disease', 'MESH:D009369', (119, 131))
111561	29704257	have now reported the results of a multi-center, open-label, phase II study of BGJ398 in patients with advanced or metastatic CCA harboring FGFR genetic alterations who either had prior treatment discontinuation due to toxicity or progressive disease despite gemcitabine-based therapy.	('genetic alterations', 'Var', (145, 164))	('CCA', 'Phenotype', 'HP:0030153', (126, 129))	('FGFR', 'Gene', (140, 144))	('CCA', 'Disease', 'MESH:D018281', (126, 129))	('toxicity', 'Disease', 'MESH:D064420', (219, 227))	('toxicity', 'Disease', (219, 227))	('BGJ398', 'Gene', (79, 85))	('patients', 'Species', '9606', (89, 97))	('CCA', 'Disease', (126, 129))	('gemcitabine', 'Chemical', 'MESH:C056507', (259, 270))
111565	29704257	Of the 61 patients who participated in the study, the majority (n=48) had tumors with FGFR2 gene fusions.	('FGFR2', 'Gene', (86, 91))	('FGFR2', 'Gene', '2263', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('patients', 'Species', '9606', (10, 18))	('gene fusions', 'Var', (92, 104))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
111569	29704257	No response to BGJ398 was observed in the four patients with CCAs harboring FGFR3 amplification.	('CCA', 'Phenotype', 'HP:0030153', (61, 64))	('CCA', 'Disease', 'MESH:D018281', (61, 64))	('patients', 'Species', '9606', (47, 55))	('amplification', 'Var', (82, 95))	('FGFR3', 'Gene', '2261', (76, 81))	('CCA', 'Disease', (61, 64))	('FGFR3', 'Gene', (76, 81))
111577	29704257	This indicates that almost all patients will ultimately have disease progression on BGJ398 therapy, perhaps due to the emergence of secondary FGFR2 active site kinase mutations.	('FGFR2', 'Gene', (142, 147))	('FGFR2', 'Gene', '2263', (142, 147))	('mutations', 'Var', (167, 176))	('patients', 'Species', '9606', (31, 39))	('disease', 'Disease', (61, 68))	('BGJ398', 'Gene', (84, 90))
111578	29704257	An integrative molecular analysis of cell-free circulating tumor DNA, primary tumors, and metastases in three patients with advanced FGFR2 fusion-positive iCCA revealed the emergence of secondary FGFR2 active site kinase mutations, which lead to BGJ398 resistance.	('FGFR2', 'Gene', (196, 201))	('tumor', 'Disease', (59, 64))	('metastases', 'Disease', 'MESH:D009362', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('FGFR2', 'Gene', '2263', (196, 201))	('mutations', 'Var', (221, 230))	('metastases', 'Disease', (90, 100))	('BGJ398 resistance', 'MPA', (246, 263))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Disease', (78, 84))	('FGFR2', 'Gene', (133, 138))	('CCA', 'Phenotype', 'HP:0030153', (156, 159))	('tumor', 'Disease', (78, 83))	('CCA', 'Disease', 'MESH:D018281', (156, 159))	('lead to', 'Reg', (238, 245))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('CCA', 'Disease', (156, 159))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('FGFR2', 'Gene', '2263', (133, 138))	('patients', 'Species', '9606', (110, 118))
111581	29704257	The gatekeeper residue is present in the ATP-binding pocket of FGFR and mutation of this residue inhibits binding of BGJ398, an ATP-competitive FGFR inhibitor.	('binding', 'Interaction', (106, 113))	('ATP', 'Chemical', 'MESH:D000255', (41, 44))	('BGJ398', 'Gene', (117, 123))	('inhibits', 'NegReg', (97, 105))	('ATP', 'Chemical', 'MESH:D000255', (128, 131))	('mutation', 'Var', (72, 80))	('gatekeeper', 'Species', '111938', (4, 14))
111583	29704257	Next-generation covalent irreversible FGFR inhibitors can overcome the gatekeeper mutations and inhibit cells dependent on gatekeeper mutants.	('FGFR', 'Gene', (38, 42))	('gatekeeper', 'Species', '111938', (71, 81))	('cells', 'CPA', (104, 109))	('gatekeeper', 'Species', '111938', (123, 133))	('mutations', 'Var', (82, 91))	('inhibit', 'NegReg', (96, 103))
111584	29704257	TAS-120 is a covalent, irreversible FGFR inhibitor currently under investigation in early phase clinical trials of patients with advanced solid organ malignancy harboring FGF/FGFR genetic alterations (NCT02052778).	('patients', 'Species', '9606', (115, 123))	('genetic alterations', 'Var', (180, 199))	('FGF/FGFR', 'Gene', (171, 179))
111587	29704257	The biology of FGFR2 genetic aberrations in iCCA still needs greater definition.	('CCA', 'Phenotype', 'HP:0030153', (45, 48))	('FGFR2', 'Gene', '2263', (15, 20))	('FGFR2', 'Gene', (15, 20))	('CCA', 'Disease', 'MESH:D018281', (45, 48))	('CCA', 'Disease', (45, 48))	('genetic aberrations', 'Var', (21, 40))
111588	29704257	Nonetheless, it is likely a small subset of iCCA patients may have durable responses to FGFR inhibitors, opening the door slightly for personalized medicine in iCCA.	('CCA', 'Phenotype', 'HP:0030153', (161, 164))	('CCA', 'Disease', 'MESH:D018281', (161, 164))	('CCA', 'Phenotype', 'HP:0030153', (45, 48))	('CCA', 'Disease', 'MESH:D018281', (45, 48))	('CCA', 'Disease', (161, 164))	('patients', 'Species', '9606', (49, 57))	('CCA', 'Disease', (45, 48))	('inhibitors', 'Var', (93, 103))	('FGFR', 'Gene', (88, 92))
111589	29704257	We also note the ongoing studies exploring isocitrate dehydrogenase inhibitors 1 (IDH1) in patients with IDH1 genetic aberrations in iCCA.	('genetic aberrations', 'Var', (110, 129))	('patients', 'Species', '9606', (91, 99))	('CCA', 'Phenotype', 'HP:0030153', (134, 137))	('IDH1', 'Gene', (105, 109))	('CCA', 'Disease', 'MESH:D018281', (134, 137))	('IDH1', 'Gene', (82, 86))	('IDH1', 'Gene', '3417', (105, 109))	('IDH1', 'Gene', '3417', (82, 86))	('CCA', 'Disease', (134, 137))	('isocitrate', 'Chemical', 'MESH:D007523', (43, 53))
111638	29284072	LN positivity, age >=60 years old, and worse tumor grade were all associated with decreased RFS, Table 2.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('LN positivity', 'Var', (0, 13))	('tumor', 'Disease', (45, 50))	('RFS', 'MPA', (92, 95))	('decreased', 'NegReg', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
111677	29284072	al., who examined 157 patients with resected HC, and showed that LN positivity and worse tumor grade imparted significantly decreased survival.	('LN positivity', 'Var', (65, 78))	('patients', 'Species', '9606', (22, 30))	('decreased', 'NegReg', (124, 133))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('survival', 'MPA', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
111701	29018577	Our results showed that placement with radiation-emitting metallic stents (REMS) achieved a longer patency of stent compared with placement with conventional SEMS, and the survival of patients in the REMS group was also better than that of patients in the SEMS group.	('metal', 'Chemical', 'MESH:D008670', (58, 63))	('REMS', 'Var', (200, 204))	('patients', 'Species', '9606', (184, 192))	('survival', 'CPA', (172, 180))	('better', 'PosReg', (220, 226))	('patients', 'Species', '9606', (240, 248))	('patency', 'MPA', (99, 106))	('longer', 'PosReg', (92, 98))
111781	19935794	Molecular alterations such as disruption of the MAPK pathway and activating RAS and B-Raf mutations have been described in these tumours, and these molecular abnormalities may constitute a target for new biological agents (Tannapfel et al, 2003).	('B-Raf', 'Gene', (84, 89))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (90, 99))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('B-Raf', 'Gene', '673', (84, 89))	('MAPK pathway', 'Pathway', (48, 60))	('tumours', 'Disease', 'MESH:D009369', (129, 136))	('activating', 'PosReg', (65, 75))	('molecular abnormalities', 'Disease', (148, 171))	('tumours', 'Disease', (129, 136))	('RAS', 'Gene', (76, 79))	('disruption', 'Reg', (30, 40))	('molecular abnormalities', 'Disease', 'MESH:C567116', (148, 171))
111787	19935794	Moreover, we planned to perform biomarker analysis including the BRAF mutation and VEGFR-2 expression.	('VEGFR-2', 'Gene', '3791', (83, 90))	('BRAF', 'Gene', '673', (65, 69))	('VEGFR-2', 'Gene', (83, 90))	('mutation', 'Var', (70, 78))	('BRAF', 'Gene', (65, 69))
111798	19935794	The sorafenib predefined dose level reductions were level -1: 200 mg po q 12 h; and level -2: 200 mg po per day.	('reductions', 'NegReg', (36, 46))	('level -2: 200 mg', 'Var', (84, 100))	('sorafenib', 'Chemical', 'MESH:D000077157', (4, 13))
111817	19935794	However, G1-2 and G3 drug-related liver toxicity was observed in two (4.3%) and one patient (2.2%), respectively.	('liver toxicity', 'Disease', 'MESH:D056486', (34, 48))	('G1-2', 'Var', (9, 13))	('liver toxicity', 'Disease', (34, 48))	('patient', 'Species', '9606', (84, 91))
111832	19935794	However, patients with an ECOG 0 performance status had a median PFS and a median OS that were significantly longer than did patients with an ECOG 1 performance status: 5.7 vs 2.1 months and 8.8 vs 3.5 months, respectively.	('patients', 'Species', '9606', (9, 17))	('PFS', 'MPA', (65, 68))	('ECOG', 'Var', (26, 30))	('patients', 'Species', '9606', (125, 133))
111925	31579779	We do not know the preoperative IgG4-serum level of the patient, but 2 weeks after surgery, the serum IgG4 level was increased with 299 mg/dL, which is even higher than the cutoff level auf 207 mg/dL.	('patient', 'Species', '9606', (56, 63))	('299 mg/dL', 'Var', (132, 141))	('serum IgG4 level', 'MPA', (96, 112))	('increased', 'PosReg', (117, 126))
111928	31579779	developed a novel quantitative PCR test measuring the IgG4/IgG RNA ratio in the peripheral blood that accurately distinguishes (94% sensitivity, 99% specificity) IgG4-SC from CC and PSC.	('CC', 'Disease', 'MESH:D018281', (175, 177))	('IgG4-SC', 'Var', (162, 169))	('PSC', 'Disease', 'MESH:D015209', (182, 185))	('PSC', 'Disease', (182, 185))	('CC', 'Phenotype', 'HP:0030153', (175, 177))
111968	29348849	Of these metabolites, levels of l-glutamine, uric acid, LPC 16:0, and LPC 18:0 were significantly lower in the serum from IHCC patients, whereas levels of 2PY and FPA were significantly higher (p < 0.01).	('FPA', 'MPA', (163, 166))	('IHCC', 'Disease', (122, 126))	('lower', 'NegReg', (98, 103))	('LPC', 'Chemical', 'MESH:D008244', (56, 59))	('LPC', 'Chemical', 'MESH:D008244', (70, 73))	('uric acid', 'MPA', (45, 54))	('levels', 'MPA', (22, 28))	('LPC', 'Var', (70, 73))	('2PY', 'Chemical', 'MESH:C005211', (155, 158))	('patients', 'Species', '9606', (127, 135))	('uric acid', 'Chemical', 'MESH:D014527', (45, 54))	('2PY', 'MPA', (155, 158))	('higher', 'PosReg', (186, 192))	('LPC 16:0', 'MPA', (56, 64))	('l-glutamine', 'Chemical', 'MESH:D005973', (32, 43))
111991	29348849	Similarly, two metabolites, L-glutamine (HMDB00641) and ureidoisobutyric acid (HMDB02031), were candidates for the origin of the metabolic ion of 147.0764 m/z with an RT of 1.44 min, but MS/MS analysis revealed that the material was in fact L-glutamine (Figure 2).	('HMDB02031', 'Var', (79, 88))	('ureidoisobutyric acid', 'Chemical', '-', (56, 77))	('L-glutamine', 'Chemical', 'MESH:D005973', (241, 252))	('L-glutamine', 'Chemical', 'MESH:D005973', (28, 39))	('HMDB00641', 'Var', (41, 50))
112003	29348849	IHCC patients with high (compared to low) levels of L-glutamine experienced better overall survival (OS) (median; 48.20 months vs. 12.71 months; p = 0.0121) (Figure 6).	('high', 'Var', (19, 23))	('patients', 'Species', '9606', (5, 13))	('overall', 'MPA', (83, 90))	('L-glutamine', 'Chemical', 'MESH:D005973', (52, 63))	('better', 'PosReg', (76, 82))
112004	29348849	We found that six metabolites (L-glutamine, LPC 16:0, LPC 18:0, 2PY, FPA, and uric acid) were candidate predictors of IHCC prognosis (Figures 1-4).	('uric acid', 'Chemical', 'MESH:D014527', (78, 87))	('uric acid', 'MPA', (78, 87))	('L-glutamine', 'Var', (31, 42))	('2PY', 'Chemical', 'MESH:C005211', (64, 67))	('2PY', 'MPA', (64, 67))	('L-glutamine', 'Chemical', 'MESH:D005973', (31, 42))	('LPC 18:0', 'Var', (54, 62))	('LPC', 'Chemical', 'MESH:D008244', (54, 57))	('LPC', 'Chemical', 'MESH:D008244', (44, 47))	('IHCC', 'Disease', (118, 122))	('FPA', 'MPA', (69, 72))	('LPC 16:0', 'Var', (44, 52))
112006	29348849	Nicotinamide, 2PY, and 4PY are metabolites of the intracellular co-enzyme nicotinamide adenine dinucleotide (NAD), and potentially inhibit poly(ADP-ribose)polymerase (PARP)-1, a DNA repair enzyme.	('inhibit', 'NegReg', (131, 138))	('4PY', 'Chemical', '-', (23, 26))	('poly(ADP-ribose)polymerase (PARP)-1', 'Gene', '142', (139, 174))	('Nicotinamide', 'Chemical', 'MESH:D009536', (0, 12))	('nicotinamide adenine dinucleotide', 'Chemical', 'MESH:D009243', (74, 107))	('4PY', 'Var', (23, 26))	('2PY', 'Chemical', 'MESH:C005211', (14, 17))	('NAD', 'Chemical', 'MESH:D009243', (109, 112))
112014	29348849	Therefore, 2PY may be a novel toxin that plays a significant role in the development of uremic toxemia, particularly by acting as a PARP inhibitor.	('PARP', 'Gene', '142', (132, 136))	('2PY', 'Chemical', 'MESH:C005211', (11, 14))	('PARP', 'Gene', (132, 136))	('uremic toxemia', 'Disease', 'MESH:D014115', (88, 102))	('uremic toxemia', 'Disease', (88, 102))	('2PY', 'Var', (11, 14))
112019	29348849	Hypermethylation might protect against the toxic effects of intracellular nicotinamide attributable to cirrhosis-associated catabolism.	('cirrhosis', 'Disease', (103, 112))	('Hypermethylation', 'Var', (0, 16))	('cirrhosis', 'Phenotype', 'HP:0001394', (103, 112))	('cirrhosis', 'Disease', 'MESH:D005355', (103, 112))	('nicotinamide', 'Chemical', 'MESH:D009536', (74, 86))
112021	29348849	Unlike 2PY, the levels of LPC 16:0 and LPC 18:0 decreased in serum from IHCC patients (p < 0.01) (Figure 5), and low levels of LPC 16:0 (compared to high levels) significantly correlated with an improved RFS (median; 15.62 months vs. 9.83 months, p = 0.035) (Figure 6).	('LPC', 'Chemical', 'MESH:D008244', (127, 130))	('LPC', 'Chemical', 'MESH:D008244', (26, 29))	('improved', 'PosReg', (195, 203))	('LPC', 'Var', (127, 130))	('low', 'Var', (113, 116))	('2PY', 'Chemical', 'MESH:C005211', (7, 10))	('RFS', 'MPA', (204, 207))	('levels', 'MPA', (16, 22))	('patients', 'Species', '9606', (77, 85))	('LPC', 'Chemical', 'MESH:D008244', (39, 42))	('IHCC', 'Disease', (72, 76))
112024	29348849	LPA enhances tumor growth, metastasis, and chemoresistance.	('tumor', 'Disease', (13, 18))	('LPA', 'Var', (0, 3))	('chemoresistance', 'CPA', (43, 58))	('enhances', 'PosReg', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('LPA', 'Chemical', 'MESH:C032881', (0, 3))	('metastasis', 'CPA', (27, 37))
112029	29348849	The plasma proportions of 18:1-LPC or 18:2-LPC (in terms of total saturated LPC levels), either individually or combined, are potential biomarkers for CRC.	('18:2-LPC', 'Var', (38, 46))	('LPC', 'Chemical', 'MESH:D008244', (31, 34))	('LPC', 'Chemical', 'MESH:D008244', (76, 79))	('CRC', 'Disease', (151, 154))	('LPC', 'Chemical', 'MESH:D008244', (43, 46))
112055	29348849	The positive ion multiple reaction monitoring (MRM) mode was used for quantitative analysis of L-glutamine, LPC 16:0, LPC 18:0, 2PY, and FPA.	('LPC 18:0', 'Var', (118, 126))	('LPC', 'Chemical', 'MESH:D008244', (108, 111))	('LPC', 'Chemical', 'MESH:D008244', (118, 121))	('LPC 16:0', 'Var', (108, 116))	('2PY', 'Chemical', 'MESH:C005211', (128, 131))	('L-glutamine', 'Var', (95, 106))	('L-glutamine', 'Chemical', 'MESH:D005973', (95, 106))
112078	24312749	Approximately, 80-95% of these tumors have mutations in the KRAS2 gene, and 85-98% of these tumors show mutations, deletions, or hypermethylation in the CDKN2 gene.	('CDKN2', 'Gene', (153, 158))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('mutations', 'Var', (104, 113))	('KRAS2', 'Gene', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('KRAS2', 'Gene', '3845', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('mutations', 'Var', (43, 52))	('hypermethylation', 'Var', (129, 145))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('deletions', 'Var', (115, 124))	('CDKN2', 'Gene', '1029', (153, 158))	('tumors', 'Disease', (92, 98))
112152	24312749	In addition, NDEA increased levels of alanine transaminase, plasma aspartate transaminase, and alpha-fetoprotein.	('increased', 'PosReg', (18, 27))	('alpha-fetoprotein', 'Gene', (95, 112))	('increased levels of alanine', 'Phenotype', 'HP:0003348', (18, 45))	('levels of alanine transaminase', 'MPA', (28, 58))	('NDEA', 'Chemical', 'MESH:D004052', (13, 17))	('NDEA', 'Var', (13, 17))	('increased levels of alanine transaminase', 'Phenotype', 'HP:0031964', (18, 58))	('plasma aspartate transaminase', 'MPA', (60, 89))	('alpha-fetoprotein', 'Gene', '174', (95, 112))
112169	24312749	We also observed increased necrosis in sections from melatonintreated mice compared with control mice (Figure 1A,B).	('melatonin', 'Chemical', 'MESH:D008550', (53, 62))	('increased necrosis', 'Phenotype', 'HP:0010885', (17, 35))	('melatonintreated', 'Var', (53, 69))	('necrosis', 'Disease', 'MESH:D009336', (27, 35))	('mice', 'Species', '10090', (97, 101))	('mice', 'Species', '10090', (70, 74))	('necrosis', 'Disease', (27, 35))
112171	24312749	Overexpression of AANAT was also shown to inhibit cholangiocarcinoma growth.	('AANAT', 'Gene', (18, 23))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (50, 68))	('cholangiocarcinoma growth', 'Disease', (50, 75))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (50, 75))	('Overexpression', 'Var', (0, 14))	('inhibit', 'NegReg', (42, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))
112177	24312749	In a recent study aimed to evaluate the growthinhibiting and apoptosis-inducing effects of melatonin alone or in combination with chemotherapeutic drugs (e.g., Doxorubicin), melatonin was shown to inhibit the growth of HepG2 and Bel-7402 cells in a dose-dependent manner.	('growth', 'CPA', (209, 215))	('Doxorubicin', 'Chemical', 'MESH:D004317', (160, 171))	('Bel-7402', 'CellLine', 'CVCL:5492', (229, 237))	('inhibit', 'NegReg', (197, 204))	('melatonin', 'Chemical', 'MESH:D008550', (91, 100))	('melatonin', 'Chemical', 'MESH:D008550', (174, 183))	('HepG2', 'CellLine', 'CVCL:0027', (219, 224))	('melatonin', 'Var', (174, 183))	('HepG2', 'CPA', (219, 224))
112196	33297469	Genetic variants associated with GBC susceptibility, including polymorphisms within the toll-like receptors TLR2 and TLR4, the cytochrome P450 1A1 (CYP1A1), and the ATP-binding cassette (ABC) transporter ABCG8 genes, represent promising biomarkers for the stratification of patients at higher risk of GBC; thus, showing potential to prioritize cholecystectomy, particularly considering that early diagnosis is difficult due to the absence of specific signs and symptoms.	('ABCG8', 'Gene', (204, 209))	('cytochrome P450 1A1', 'Gene', (127, 146))	('TLR4', 'Gene', '7099', (117, 121))	('patients', 'Species', '9606', (274, 282))	('TLR4', 'Gene', (117, 121))	('CYP1A1', 'Gene', (148, 154))	('CYP1A1', 'Gene', '1543', (148, 154))	('variants', 'Var', (8, 16))	('polymorphisms', 'Var', (63, 76))	('ABCG8', 'Gene', '64241', (204, 209))	('GBC', 'Disease', (33, 36))	('TLR2', 'Gene', '7097', (108, 112))	('cytochrome P450 1A1', 'Gene', '1543', (127, 146))	('TLR2', 'Gene', (108, 112))
112197	33297469	Similarly, our better understanding of the gallbladder carcinogenic processes has led to identify several cellular and molecular events that may influence patient management, including HER2 aberrations, high tumor mutational burden, microsatellite instability, among others.	('gallbladder carcinogenic', 'Disease', 'MESH:D005705', (43, 67))	('gallbladder carcinogenic', 'Disease', (43, 67))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('men', 'Species', '9606', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('patient', 'Species', '9606', (155, 162))	('aberrations', 'Var', (190, 201))	('tumor', 'Disease', (208, 213))	('HER2', 'Gene', (185, 189))	('HER2', 'Gene', '2064', (185, 189))	('influence', 'Reg', (145, 154))	('microsatellite instability', 'Var', (233, 259))
112203	33297469	The main risk factors include cholelithiasis, gallbladder wall calcification, gallbladder polyps >10 mm, primary sclerosing cholangitis, an anomalous junction of the pancreaticobiliary duct, smoking, and obesity.	('obesity', 'Disease', 'MESH:D009765', (204, 211))	('gallbladder wall calcification', 'Disease', (46, 76))	('gallbladder polyps', 'Disease', 'MESH:D011127', (78, 96))	('gallbladder polyps', 'Disease', (78, 96))	('obesity', 'Disease', (204, 211))	('gallbladder wall calcification', 'Disease', 'MESH:D005705', (46, 76))	('sclerosing cholangitis', 'Disease', 'MESH:D015209', (113, 135))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (113, 135))	('cholelithiasis', 'Phenotype', 'HP:0001081', (30, 44))	('cholelithiasis', 'Disease', (30, 44))	('sclerosing cholangitis', 'Disease', (113, 135))	('anomalous', 'Var', (140, 149))	('cholelithiasis', 'Disease', 'MESH:D002769', (30, 44))	('cholangitis', 'Phenotype', 'HP:0030151', (124, 135))	('obesity', 'Phenotype', 'HP:0001513', (204, 211))
112215	33297469	Similarly, Toll-like receptor (TLR) variants TLR2:196 to 174 ins>del (TLR delta22) and TLR4 Ex4+936C>T (rs4986791) have been associated with GBC susceptibility in the Indian population (OR = 1.54/1.96, 95% CI = 1.02-2.24/1.11-2.26, p <= 0.05).	('GBC', 'Disease', (141, 144))	('rs4986791', 'Mutation', 'rs4986791', (104, 113))	('TLR4', 'Gene', (87, 91))	('associated', 'Reg', (125, 135))	('TLR2', 'Gene', '7097', (45, 49))	('Ex4+936C>T', 'Mutation', 'rs4986791', (92, 102))	('Ex4+936C>T', 'Var', (92, 102))	('variants', 'Var', (36, 44))	('TLR2', 'Gene', (45, 49))	('TLR4', 'Gene', '7099', (87, 91))
112221	33297469	When focusing on the genetic pathway of drug metabolism, genetic polymorphisms in the Phase I metabolizing enzyme cytochrome P450 1A1 (CYP1A1), and the Phase II drug-detoxification enzyme glutathione-S-transferase class Mu (GSTM1) are the most studied with respect to GBC risk.	('drug metabolism', 'Disease', 'MESH:D065606', (40, 55))	('GSTM1', 'Gene', (224, 229))	('glutathione', 'Chemical', 'MESH:D005978', (188, 199))	('CYP1A1', 'Gene', (135, 141))	('GBC', 'Disease', (268, 271))	('cytochrome P450 1A1', 'Gene', '1543', (114, 133))	('polymorphisms', 'Var', (65, 78))	('drug metabolism', 'Disease', (40, 55))	('cytochrome P450 1A1', 'Gene', (114, 133))	('CYP1A1', 'Gene', '1543', (135, 141))	('GSTM1', 'Gene', '2944', (224, 229))
112222	33297469	Among the CYP1A1 variants, Ile462Val (rs1048943) has been associated with increased GBC risk in women of Hungarian (OR = 8.9, 95% CI: 2.9-27.4, p < 0.001) and Japanese (OR = 2.70, 95% CI: 1.14-6.40, p < 0.05) origins.	('CYP1A1', 'Gene', (10, 16))	('variants', 'Var', (17, 25))	('Ile462Val', 'Var', (27, 36))	('CYP1A1', 'Gene', '1543', (10, 16))	('rs1048943', 'Mutation', 'rs1048943', (38, 47))	('GBC', 'Disease', (84, 87))	('Ile462Val', 'Chemical', '-', (27, 36))	('women', 'Species', '9606', (96, 101))
112223	33297469	This allele variant has been associated with increased CYP1A1 enzymatic activity, possibly leading to increased conversion of estradiol to 2-OH-E2, suggesting that the female hormone estrogen may facilitate GBC development.	('2-OH-E2', 'Chemical', 'MESH:C001390', (139, 146))	('CYP1A1', 'Gene', (55, 61))	('variant', 'Var', (12, 19))	('facilitate', 'PosReg', (196, 206))	('increased', 'PosReg', (45, 54))	('conversion', 'MPA', (112, 122))	('CYP1A1', 'Gene', '1543', (55, 61))	('increased conversion of estradiol', 'Phenotype', 'HP:0025134', (102, 135))	('GBC development', 'CPA', (207, 222))	('increased', 'PosReg', (102, 111))	('men', 'Species', '9606', (218, 221))	('estradiol', 'Chemical', 'MESH:D004958', (126, 135))
112225	33297469	The analysis showed that carriers of the T allele (versus the GG genotype) of the CYP1A1 IVS1 + 606 marker had a 2-fold risk of GBC (95% CI: 1.3-3.1).	('IVS1 + 606', 'Var', (89, 99))	('CYP1A1', 'Gene', (82, 88))	('CYP1A1', 'Gene', '1543', (82, 88))	('GBC', 'Disease', (128, 131))
112226	33297469	Interestingly, the effect of this variant on GBC risk was more pronounced among lean patients (body mass index < 23; OR = 3.3, 95% CI: 1.8-6.1, p interaction = 0.001).	('patients', 'Species', '9606', (85, 93))	('GBC', 'Disease', (45, 48))	('variant', 'Var', (34, 41))
112232	33297469	Thus, the minor allele of TP53 Arg72Pro polymorphism has been found to contribute to an increased risk of GBC among Japanese men (OR = 4.32, 95% CI: 1.08-17.2) and an increased risk of non-adenocarcinoma GBC in the Hungarian population (OR = 3.8, 95% CI: 1.2-12.8).	('TP53', 'Gene', (26, 30))	('Arg72Pro', 'SUBSTITUTION', 'None', (31, 39))	('adenocarcinoma GBC', 'Disease', (189, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('men', 'Species', '9606', (125, 128))	('Arg72Pro', 'Var', (31, 39))	('adenocarcinoma GBC', 'Disease', 'MESH:D000230', (189, 207))	('TP53', 'Gene', '7157', (26, 30))	('GBC', 'Disease', (106, 109))
112233	33297469	On the other hand, the CC genotype of the TP53 rs1042522 polymorphism is associated with an increased risk of GBC in North Indians (age- and sex-adjusted OR = 2.81, 95% CI: 1.19-6.61, p = 0.02), although no association has been found in populations from Bolivia and Chile.	('TP53', 'Gene', '7157', (42, 46))	('GBC', 'Disease', (110, 113))	('rs1042522', 'Mutation', 'rs1042522', (47, 56))	('TP53', 'Gene', (42, 46))	('rs1042522', 'Var', (47, 56))
112234	33297469	Other genetic variants involved in the DNA repair pathway that have been associated with an increased risk of GBC encompass Asp312Asn in the excision repair cross complementary group 2 (ERCC2) gene, IVS1 + 9G>C in the MutS homolog 2 (MSH2) gene, Ser326Cys in the 8-oxoguanine glycosylase (OGG1) gene, and the EX5-25C>T in the O6-akyl guanine DNA acyltransferase (MGMT) gene.	('ERCC2', 'Gene', '2068', (186, 191))	('GBC', 'Disease', (110, 113))	('men', 'Species', '9606', (169, 172))	('associated', 'Reg', (73, 83))	('IVS1 + 9G>C', 'Mutation', 'rs2303426', (199, 210))	('-25C>T', 'Mutation', 'rs12917', (312, 318))	('Asp312Asn', 'Chemical', '-', (124, 133))	('OGG1', 'Gene', '4968', (289, 293))	('OGG1', 'Gene', (289, 293))	('Ser326Cys', 'SUBSTITUTION', 'None', (246, 255))	('Asp312Asn', 'Var', (124, 133))	('Ser326Cys', 'Var', (246, 255))	('9G>C', 'SUBSTITUTION', 'None', (206, 210))	('MGMT', 'Gene', '4255', (363, 367))	('MutS homolog 2', 'Gene', (218, 232))	('MutS homolog 2', 'Gene', '4436', (218, 232))	('MSH2', 'Gene', (234, 238))	('9G>C', 'Var', (206, 210))	('EX5-25C>T', 'Var', (309, 318))	('ERCC2', 'Gene', (186, 191))	('MSH2', 'Gene', '4436', (234, 238))	('MGMT', 'Gene', (363, 367))
112236	33297469	Among them, an Indian study showed that the frequencies of the death receptor DR4 haplotypes Crs20575Ars20576Ars6557634, Grs20575Ars20576Grs6557634, and Grs20575Crs20576Grs6557634 were significantly higher in GBC as compared to controls (OR = 2.76, 95% CI: 1.71-4.47; OR = 2.09, 95% CI: 1.21-3.62; and OR = 2.80, 95% CI: 1.16-6.76, respectively).	('death', 'Disease', 'MESH:D003643', (63, 68))	('death', 'Disease', (63, 68))	('DR4', 'Gene', (78, 81))	('higher', 'PosReg', (199, 205))	('Crs20575Ars20576Ars6557634', 'Var', (93, 119))	('Grs20575Crs20576Grs6557634', 'Var', (153, 179))	('GBC', 'Disease', (209, 212))	('Grs20575Ars20576Grs6557634', 'Var', (121, 147))	('DR4', 'Gene', '3126', (78, 81))
112237	33297469	On the other hand, low penetrance variants in the caspase 8 (CASP8) gene may affect susceptibility to GBC genotypes, as demonstrated by the evaluation of genotypes and haplotypes of CASP8 polymorphisms in the North Indian population.	('CASP8', 'Gene', (61, 66))	('variants', 'Var', (34, 42))	('caspase 8', 'Gene', '841', (50, 59))	('GBC genotypes', 'Disease', (102, 115))	('low', 'NegReg', (19, 22))	('CASP8', 'Gene', (182, 187))	('caspase 8', 'Gene', (50, 59))	('CASP8', 'Gene', '841', (182, 187))	('affect', 'Reg', (77, 83))	('susceptibility', 'MPA', (84, 98))	('CASP8', 'Gene', '841', (61, 66))
112238	33297469	One of the first GWAS analyses in GBC was conducted in a Japanese cohort of 41 GC patients and 866 controls, which identified 130 single nucleotide polymorphisms (SNPs) that showed a suggestive association with GBC.	('patients', 'Species', '9606', (82, 90))	('GBC', 'Disease', (211, 214))	('single nucleotide polymorphisms', 'Var', (130, 161))
112239	33297469	These SNPs were further examined in a validation cohort of 30 cases and 898 controls, where the SNP rs7504990 found in the deleted in colorectal cancer (DCC, 18q21.3) region showed a significant genome-wide association with GBC susceptibility in the Japanese population (OR = 6.95, 95% CI: 3.43-14.08, combined p = 7.46 x 10-8).	('GBC', 'Disease', (224, 227))	('colorectal cancer', 'Disease', (134, 151))	('DCC', 'Gene', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('DCC', 'Gene', '1630', (153, 156))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))	('rs7504990', 'Var', (100, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('rs7504990', 'Mutation', 'rs7504990', (100, 109))
112240	33297469	Another case-control GWAS conducted in a discovery cohort of 1042 GBC cases and 1709 controls from predominantly North and Northeastern Indian populations, identified a strong association between common genetic variants in the chromosomal region 7q21.12, responsible for both the ABCB1 and ABCB4 genes, and risk of GBC.	('ABCB1', 'Gene', (280, 285))	('ABCB1', 'Gene', '5243', (280, 285))	('ABCB4', 'Gene', '5244', (290, 295))	('ABCB4', 'Gene', (290, 295))	('variants', 'Var', (211, 219))	('GBC', 'Disease', (315, 318))
112241	33297469	The most notable SNPs after replication and meta-analysis were rs1558375 (GWAS p = 3.8 x 10-9; replication p = 0.01; combined p = 2.3 x 10-10), rs17209837 (GWAS p = 2.0 x 10-8; replication p = 0.02; combined p = 2.3 x 10-9), and rs4148808 (GWAS p = 2.4 x 10-8; replication p = 0.008; combined p = 2.7 x 10-9).	('rs17209837', 'Mutation', 'rs17209837', (144, 154))	('rs1558375', 'Mutation', 'rs1558375', (63, 72))	('rs17209837', 'Var', (144, 154))	('rs4148808', 'Mutation', 'rs4148808', (229, 238))	('rs1558375', 'Var', (63, 72))	('rs4148808', 'Var', (229, 238))
112242	33297469	Interestingly, these ABCB1/4 GBC risk variants also showed similar risk effects in Chileans, according to a recent multicenter population-based candidate variant association study that included 255 GBC cases and 2042 controls from a Chilean retrospective study.	('GBC', 'Gene', (29, 32))	('variants', 'Var', (38, 46))	('ABCB1', 'Gene', '5243', (21, 26))	('ABCB1', 'Gene', (21, 26))	('Chileans', 'Disease', (83, 91))
112243	33297469	Genetics variants within the ABCG8 and TRAF3 genes have been reported to confer GBC risk development in Chilean population.	('men', 'Species', '9606', (96, 99))	('ABCG8', 'Gene', (29, 34))	('TRAF3', 'Gene', (39, 44))	('GBC risk', 'Disease', (80, 88))	('confer', 'Reg', (73, 79))	('ABCG8', 'Gene', '64241', (29, 34))	('TRAF3', 'Gene', '7187', (39, 44))	('variants', 'Var', (9, 17))
112245	33297469	After validation of the top-ten candidate variants in an independent cohort, composed of 1643 individuals (626 GSD cases and 1017 controls), only selected variants within the ABCG8 (rs11887534, OR = 1.59, 95% CI: 1.20-2.11, p = 0.001) and TRAF3 (rs12882491, OR = 1.30, 95% CI: 1.09-1.54, p = 0.003,) genes were associated with GSD.	('rs12882491', 'Var', (246, 256))	('TRAF3', 'Gene', (239, 244))	('rs11887534', 'Mutation', 'rs11887534', (182, 192))	('rs11887534', 'Var', (182, 192))	('ABCG8', 'Gene', (175, 180))	('TRAF3', 'Gene', '7187', (239, 244))	('rs12882491', 'Mutation', 'rs12882491', (246, 256))	('GSD', 'Disease', (327, 330))	('GSD', 'Disease', 'MESH:D016098', (111, 114))	('GSD', 'Disease', (111, 114))	('GSD', 'Disease', 'MESH:D016098', (327, 330))	('ABCG8', 'Gene', '64241', (175, 180))	('associated', 'Reg', (311, 321))
112246	33297469	A subsequent examination of these variants in a cohort of 397 GBC patients revealed that both SNPs were associated with this pathology (ABCG8 rs11887534: OR = 1.77, 95% CI: 1.27-2.45, p = 6.9 x 10-4; TRAF3 rs12882491: OR = 1.24, 95% CI: 1.004-1.53, p = 0.045).	('rs11887534', 'Mutation', 'rs11887534', (142, 152))	('TRAF3', 'Gene', (200, 205))	('variants', 'Var', (34, 42))	('rs11887534', 'Var', (142, 152))	('rs12882491', 'Mutation', 'rs12882491', (206, 216))	('rs12882491', 'Var', (206, 216))	('associated', 'Reg', (104, 114))	('ABCG8', 'Gene', (136, 141))	('TRAF3', 'Gene', '7187', (200, 205))	('ABCG8', 'Gene', '64241', (136, 141))	('patients', 'Species', '9606', (66, 74))
112260	33297469	At a cut-off point of >406.5825 ng/mL, ALU247 discriminated GBC (n = 60) from controls (n = 36) with a sensitivity, specificity, and diagnostic accuracy of 80.0%, 86.1%, and 82.2%, respectively.	('ALU247', 'Chemical', '-', (39, 45))	('ALU247', 'Var', (39, 45))	('GBC', 'Disease', (60, 63))	('discriminated', 'Reg', (46, 59))
112262	33297469	used next generation sequencing (NGS) to analyze mutations in DNA isolated from bile and tumor tissue of 30 patients with GBC.	('DNA', 'Gene', (62, 65))	('mutations', 'Var', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('patients', 'Species', '9606', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
112265	33297469	They used targeted deep sequencing and compared bile cfDNA and tumor DNA for single nucleotide variation (SNV)/insertion and deletion (Indel) and copy number variation (CNV), revealing a high sensitivity (94.7% and 75%, respectively) and specificity (99.9% and 98.9%, respectively).	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('single nucleotide variation', 'Var', (77, 104))	('copy number variation', 'Var', (146, 167))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
112271	33297469	The combination of CA 19-9, CA 125, and CA 242 increased the diagnostic specificity, but not its sensitivity, reaching 100% specificity with a positive predictive value (PPV) of 100%.	('CA 125', 'Gene', (28, 34))	('CA 242', 'Var', (40, 46))	('increased', 'PosReg', (47, 56))	('CA 19-9', 'Var', (19, 26))	('CA 125', 'Gene', '94025', (28, 34))	('diagnostic specificity', 'MPA', (61, 83))
112282	33297469	Progression from dysplasia has shown a strong relationship with KRAS and TP53 mutations in tumor tissues.	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('KRAS', 'Gene', (64, 68))	('mutations', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('dysplasia', 'Disease', 'MESH:C536170', (17, 26))	('KRAS', 'Gene', '3845', (64, 68))	('tumor', 'Disease', (91, 96))	('dysplasia', 'Disease', (17, 26))
112319	33297469	Thus, overexpression of p53, mutations in KRAS, amplification of HER2/neu, overexpression of EGFR, among other potential molecular prognostic factors such as microRNAs (recently reviewed by Montalvo-Jave et al.)	('neu', 'Gene', '2064', (70, 73))	('KRAS', 'Gene', (42, 46))	('HER2', 'Gene', '2064', (65, 69))	('p53', 'Gene', (24, 27))	('EGFR', 'Gene', '1956', (93, 97))	('KRAS', 'Gene', '3845', (42, 46))	('p53', 'Gene', '7157', (24, 27))	('neu', 'Gene', (70, 73))	('mutations', 'Var', (29, 38))	('EGFR', 'Gene', (93, 97))	('amplification', 'MPA', (48, 61))	('overexpression', 'PosReg', (6, 20))	('HER2', 'Gene', (65, 69))
112327	33297469	Gallbladder subtypes were significantly enriched for TP53 mutations.	('mutations', 'Var', (58, 67))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))	('Gallbladder', 'Disease', (0, 11))
112328	33297469	Both univariate and multivariate analysis showed strong negative effects on OS in BTC patients harboring mutations in ARID1A (n = 22, p = 0.0011) and KRAS (n = 63, p = 0.0042).	('mutations', 'Var', (105, 114))	('negative', 'NegReg', (56, 64))	('ARID1A', 'Gene', '8289', (118, 124))	('KRAS', 'Gene', (150, 154))	('ARID1A', 'Gene', (118, 124))	('KRAS', 'Gene', '3845', (150, 154))	('patients', 'Species', '9606', (86, 94))
112331	33297469	The last group was enriched for individuals with a diagnosis of perihilar cholangiocarcinoma (PHCC) and GBC (n = 38; 79.2%), whereas patients with intrahepatic cholangiocarcinoma (ICC) were more likely to harbor IDH1-2/BAP1/PBRM1 mutations (n = 14; 60.9%).	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('patients', 'Species', '9606', (133, 141))	('mutations', 'Var', (230, 239))	('PBRM1', 'Gene', '55193', (224, 229))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (147, 178))	('intrahepatic cholangiocarcinoma', 'Disease', (147, 178))	('harbor', 'Reg', (205, 211))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (74, 92))	('IDH1', 'Gene', (212, 216))	('PBRM1', 'Gene', (224, 229))	('cholangiocarcinoma', 'Disease', (74, 92))	('BAP1', 'Gene', '8314', (219, 223))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (160, 178))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (74, 92))	('IDH1', 'Gene', '3417', (212, 216))	('cholangiocarcinoma', 'Disease', (160, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (160, 178))	('BAP1', 'Gene', (219, 223))
112348	33297469	Small series suggested that the presence of SNPs in the cytidine deaminase (CDA) gene were associated with increased efficacy of gemcitabine-based chemotherapy in BTC.	('cytidine deaminase', 'Gene', '978', (56, 74))	('increased', 'PosReg', (107, 116))	('SNPs', 'Var', (44, 48))	('CDA', 'Gene', (76, 79))	('presence', 'Var', (32, 40))	('cytidine deaminase', 'Gene', (56, 74))	('CDA', 'Gene', '978', (76, 79))	('efficacy', 'MPA', (117, 125))	('gemcitabine', 'Chemical', 'MESH:C056507', (129, 140))
112353	33297469	Other series including 623 GBC samples, have shown different results (BRCA2 or ATM mutations in 7.8% of patients; TMB was low).	('ATM', 'Gene', '472', (79, 82))	('mutations', 'Var', (83, 92))	('BRCA2', 'Gene', '675', (70, 75))	('TMB', 'Chemical', '-', (114, 117))	('patients', 'Species', '9606', (104, 112))	('ATM', 'Gene', (79, 82))	('BRCA2', 'Gene', (70, 75))
112354	33297469	The presence of such mutations was suggested to have an impact on response to platinum-based chemotherapy, even though such findings have still not been validated in clinical trials.	('platinum', 'Chemical', 'MESH:D010984', (78, 86))	('impact', 'Reg', (56, 62))	('response', 'MPA', (66, 74))	('mutations', 'Var', (21, 30))
112358	33297469	Unfortunately, GBCs have shown absence of FGFR fusions and IDH mutations, in view of which, current clinical development of targeted therapies remains limited.	('mutations', 'Var', (63, 72))	('IDH', 'Gene', (59, 62))	('IDH', 'Gene', '3417', (59, 62))	('FGFR', 'Gene', (42, 46))	('absence', 'NegReg', (31, 38))	('fusions', 'Var', (47, 54))	('men', 'Species', '9606', (116, 119))
112359	33297469	Main targeted therapy strategies in GBC are focused on targeting HER gene family and other unusual (present in <5-10% of GBC) aberrations such BRAF and RNF43 mutations or TRK-fusions.	('TRK', 'Gene', (171, 174))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('TRK', 'Gene', '4914', (171, 174))	('mutations', 'Var', (158, 167))	('RNF43', 'Gene', '54894', (152, 157))	('RNF43', 'Gene', (152, 157))
112360	33297469	Mutations in the ERBB family of proteins and related pathways were found in ~35% of GBC tumors.	('GBC tumors', 'Disease', 'MESH:D009369', (84, 94))	('ERBB', 'Gene', (17, 21))	('found', 'Reg', (67, 72))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('GBC tumors', 'Disease', (84, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('ERBB', 'Gene', '1956', (17, 21))
112364	33297469	Because of this, such molecules were tested not only in patients showing HER2 overexpression, but also HER2 mutations.	('patients', 'Species', '9606', (56, 64))	('HER2', 'Gene', '2064', (73, 77))	('tested', 'Reg', (37, 43))	('mutations', 'Var', (108, 117))	('overexpression', 'PosReg', (78, 92))	('HER2', 'Gene', (103, 107))	('HER2', 'Gene', (73, 77))	('HER2', 'Gene', '2064', (103, 107))
112365	33297469	Initial findings with pertuzumab combined with trastuzumab in 8 and 3 patients with HER2 amplification and HER2 mutations, respectively, reported an increased objective response rate in those patients with HER-2 mutations (7.5% vs. 33.3%).	('patients', 'Species', '9606', (70, 78))	('HER2', 'Gene', '2064', (107, 111))	('trastuzumab', 'Chemical', 'MESH:D000068878', (47, 58))	('HER2', 'Gene', (84, 88))	('increased', 'PosReg', (149, 158))	('patients', 'Species', '9606', (192, 200))	('pertuzumab', 'Chemical', 'MESH:C485206', (22, 32))	('HER2', 'Gene', '2064', (84, 88))	('mutations', 'Var', (112, 121))	('objective response', 'MPA', (159, 177))	('mutations', 'Var', (212, 221))	('amplification', 'Var', (89, 102))	('HER-2', 'Gene', '2064', (206, 211))	('HER2', 'Gene', (107, 111))	('HER-2', 'Gene', (206, 211))
112366	33297469	Unfortunately, when other HER inhibitors (i.e., neratinib) were tested in HER-2 mutated patients, objective response rate remained low (10%).	('HER-2', 'Gene', '2064', (74, 79))	('HER-2', 'Gene', (74, 79))	('patients', 'Species', '9606', (88, 96))	('mutated', 'Var', (80, 87))	('neratinib', 'Chemical', 'MESH:C487932', (48, 57))	('low', 'NegReg', (131, 134))
112372	33297469	Up to now, the only role of immunotherapy in GBC seems to be limited to patients with mismatch repair and microsatellite instability which even though present in <5% of all patients, represents a robust predictive biomarker in solid tumors (including GBC).	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Disease', (233, 239))	('mismatch repair', 'Var', (86, 101))	('patients', 'Species', '9606', (173, 181))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('microsatellite instability', 'Var', (106, 132))	('patients', 'Species', '9606', (72, 80))
112427	32681390	The risk of male breast cancer was increased for trichloroethylene; OR 1.4 (95% CI 0.7-2.5) for low, and OR 1.9 (95% CI 1.1-3.3) for high score.	('trichloroethylene', 'Var', (49, 66))	('OR 1.4', 'Gene', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('trichloroethylene', 'Chemical', 'MESH:D014241', (49, 66))	('male breast cancer', 'Disease', 'MESH:D018567', (12, 30))	('OR 1.9', 'Gene', '391110', (105, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('OR 1.4', 'Gene', '391107', (68, 74))	('low', 'Var', (96, 99))	('male breast cancer', 'Disease', (12, 30))	('high score', 'Var', (133, 143))	('OR 1.9', 'Gene', (105, 111))
112445	32681390	Alcohol consumption is high in countries included in the Rare Cancer Study, and the risk of male breast cancer increased with alcohol consumption, being more than fivefold for 9 + drinks/day compared with < 1.5 drinks/day; OR 5.62 (95% 1.54-20.52),, Table 3.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('9 + drinks/day', 'Var', (176, 190))	('Cancer', 'Disease', (62, 68))	('alcohol', 'Chemical', 'MESH:D000438', (126, 133))	('Cancer', 'Disease', 'MESH:D009369', (62, 68))	('male breast cancer', 'Disease', 'MESH:D018567', (92, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))	('male breast cancer', 'Disease', (92, 110))
112465	32681390	A French JEM was used in the male breast cancer study to aggregate persons from occupations exposed to organic solvents; indicating an association with trichloroethylene; high exposure OR 1.9 (95% CI 1.1-3.3).	('persons', 'Species', '9606', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('trichloroethylene', 'Var', (152, 169))	('OR 1.9', 'Gene', (185, 191))	('OR 1.9', 'Gene', '391110', (185, 191))	('male breast cancer', 'Disease', 'MESH:D018567', (29, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('trichloroethylene', 'Chemical', 'MESH:D014241', (152, 169))	('male breast cancer', 'Disease', (29, 47))	('association', 'Interaction', (135, 146))
112527	32681390	Glutathione S-transferase genotype and p53 mutations in adenocarcinoma of the small intestine.	('Glutathione', 'Chemical', 'MESH:D005978', (0, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('mutations', 'Var', (43, 52))	('p53', 'Gene', (39, 42))	('adenocarcinoma', 'Disease', (56, 70))	('p53', 'Gene', '7157', (39, 42))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))	('adenocarcinoma of the small intestine', 'Phenotype', 'HP:0040274', (56, 93))
112572	31450767	These alterations lead to an aberrant expression and/or activation of key cytokines, tyrosine kinases, and ultimately transcription factors which control cell fate.	('alterations', 'Var', (6, 17))	('expression', 'MPA', (38, 48))	('rat', 'Species', '10116', (10, 13))	('tyrosine', 'Chemical', 'None', (85, 93))	('tyrosine', 'Enzyme', (85, 93))	('lead to', 'Reg', (18, 25))	('activation', 'PosReg', (56, 66))
112581	31450767	Unsurprisingly, dysregulations of these pathways have been described in CCAs.	('CCAs', 'Disease', (72, 76))	('dysregulations', 'Var', (16, 30))	('CCAs', 'Disease', 'MESH:D018281', (72, 76))
112587	31450767	Such a muting of the HH pathway resulted in a blockage of CCA cell migration and invasion.	('muting', 'Var', (7, 13))	('rat', 'Species', '10116', (70, 73))	('blockage', 'NegReg', (46, 54))	('invasion', 'CPA', (81, 89))	('CCA', 'Disease', 'MESH:D018281', (58, 61))	('HH pathway', 'Pathway', (21, 31))	('CCA', 'Disease', (58, 61))
112589	31450767	High throughput strategies identified numerous genetic, epigenetic, and genomic alterations in CCA, and highlighted specific targetable signaling pathways.	('rat', 'Species', '10116', (18, 21))	('CCA', 'Disease', 'MESH:D018281', (95, 98))	('rat', 'Species', '10116', (84, 87))	('genomic alterations', 'Var', (72, 91))	('CCA', 'Disease', (95, 98))	('epigenetic', 'Var', (56, 66))
112590	31450767	Among them, mutations in isocitrate dehydrogenases genes (IDH1 and IDH2) and chromatin-remodeling genes, including AT-rich interaction domain 1A (ARID1A), as well as gene fusions involving fibroblast growth factor receptor 2 (FGFR2) were frequently detected in CCAs.	('FGFR2', 'Gene', '2263', (226, 231))	('IDH1', 'Gene', '3417', (58, 62))	('IDH2', 'Gene', (67, 71))	('CCAs', 'Disease', (261, 265))	('mutations', 'Var', (12, 21))	('isocitrate', 'Chemical', 'MESH:D007523', (25, 35))	('CCAs', 'Disease', 'MESH:D018281', (261, 265))	('gene fusions', 'Var', (166, 178))	('IDH2', 'Gene', '3418', (67, 71))	('fibroblast growth factor receptor 2', 'Gene', '2263', (189, 224))	('fibroblast growth factor receptor 2', 'Gene', (189, 224))	('detected', 'Reg', (249, 257))	('ARID1A', 'Gene', '8289', (146, 152))	('FGFR2', 'Gene', (226, 231))	('ARID1A', 'Gene', (146, 152))	('IDH1', 'Gene', (58, 62))
112591	31450767	Mutations of the tumor suppressor TP53 are also commonly found in CCAs (44% of cases), so are mutations of KRAS (17% of cases) and SMAD4 (17% of cases).	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('SMAD4', 'Gene', (131, 136))	('tumor', 'Disease', (17, 22))	('TP53', 'Gene', (34, 38))	('KRAS', 'Gene', (107, 111))	('CCAs', 'Disease', (66, 70))	('found', 'Reg', (57, 62))	('CCAs', 'Disease', 'MESH:D018281', (66, 70))	('KRAS', 'Gene', '3845', (107, 111))	('SMAD4', 'Gene', '4089', (131, 136))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('TP53', 'Gene', '7157', (34, 38))
112593	31450767	More recently, protein tyrosine phosphatase non-receptor 3 (PTPN3) was reported to be frequently mutated in iCCA and associated with tumor recurrence.	('PTPN3', 'Gene', (60, 65))	('protein tyrosine phosphatase non-receptor 3', 'Gene', (15, 58))	('CCA', 'Disease', 'MESH:D018281', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('mutated', 'Var', (97, 104))	('CCA', 'Disease', (109, 112))	('associated with', 'Reg', (117, 132))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('protein tyrosine phosphatase non-receptor 3', 'Gene', '5774', (15, 58))	('tumor', 'Disease', (133, 138))	('PTPN3', 'Gene', '5774', (60, 65))
112620	31450767	Hyperactivation of yes-associated protein-1 (Yap1) and transcriptional coactivator with PDZ-binding motif (Taz), due to a genetic depletion of Mps One Binder kinase activator (Mob)1a/1b in mouse liver, results in an increased incidence of combined HCC-CCA and iCCA.	('Yap1', 'Gene', '22601', (45, 49))	('CCA', 'Disease', 'MESH:D018281', (252, 255))	('mouse', 'Species', '10090', (189, 194))	('PDZ', 'Chemical', 'MESH:C113338', (88, 91))	('CCA', 'Disease', (252, 255))	('depletion', 'Var', (130, 139))	('Yap1', 'Gene', (45, 49))	('yes-associated protein-1', 'Gene', (19, 43))	('HCC', 'Disease', 'MESH:D006528', (248, 251))	('CCA', 'Disease', 'MESH:D018281', (261, 264))	('Binder kinase activator (Mob)1a', 'Gene', '232157', (151, 182))	('yes-associated protein-1', 'Gene', '22601', (19, 43))	('HCC', 'Disease', (248, 251))	('CCA', 'Disease', (261, 264))	('HCC', 'Phenotype', 'HP:0001402', (248, 251))
112645	31450767	The findings of this study suggested that interference of the TGFbeta pathway by neutralizing antibodies against TbetaRII in dendritic cells (DC) caused increased activation of effector T cells and, in turn, enhanced targeting and lysis of co-cultured CCA cells by the immune system.	('antibodies', 'Var', (94, 104))	('TGFbeta pathway', 'Pathway', (62, 77))	('CCA cells', 'Disease', (252, 261))	('targeting', 'CPA', (217, 226))	('neutralizing antibodies', 'Var', (81, 104))	('TbetaRII', 'Gene', '7048', (113, 121))	('CCA cells', 'Disease', 'MESH:D018281', (252, 261))	('lysis', 'CPA', (231, 236))	('TbetaRII', 'Gene', (113, 121))	('interference', 'NegReg', (42, 54))	('increased activation', 'PosReg', (153, 173))	('enhanced', 'PosReg', (208, 216))
112655	31450767	The unresponsiveness of advanced cancers to the tumor-restricting properties of TGFbeta is a consequence of either genetic mutations of downstream cytostatic genes that, otherwise, are induced by the pathway, or mutations in components of the core signaling pathway, such as TGFBR2 and SMAD4.	('genetic mutations', 'Var', (115, 132))	('tumor', 'Disease', (48, 53))	('TGFBR2', 'Gene', (275, 281))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('SMAD4', 'Gene', '4089', (286, 291))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (212, 221))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('SMAD4', 'Gene', (286, 291))	('TGFBR2', 'Gene', '7048', (275, 281))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('TGFbeta', 'Gene', (80, 87))
112659	31450767	In many cancers, genes encoding members of the TGFbeta pathway are frequently subject to mutations, reflecting the importance of this pathway in tumor progression.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cancers', 'Disease', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('TGFbeta', 'Gene', (47, 54))	('subject', 'Reg', (78, 85))	('tumor', 'Disease', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('mutations', 'Var', (89, 98))
112661	31450767	Using a large cohort of 103 iCCA patients, Zou and coworkers identified RAS/PI3K, P53, and TGFbeta pathways to be influenced by alterations in the exome.	('RAS/PI3K', 'Pathway', (72, 80))	('CCA', 'Disease', 'MESH:D018281', (29, 32))	('influenced', 'Reg', (114, 124))	('patients', 'Species', '9606', (33, 41))	('alterations', 'Var', (128, 139))	('rat', 'Species', '10116', (132, 135))	('P53', 'Gene', (82, 85))	('P53', 'Gene', '7157', (82, 85))	('CCA', 'Disease', (29, 32))	('TGFbeta pathways', 'Pathway', (91, 107))
112663	31450767	In another study, SMAD4 was mutated in 3.6% of patients with iCCA (n = 55) and in 25% of patients with eCCA (n = 20).	('CCA', 'Disease', (104, 107))	('mutated', 'Var', (28, 35))	('SMAD4', 'Gene', '4089', (18, 23))	('patients', 'Species', '9606', (47, 55))	('CCA', 'Disease', 'MESH:D018281', (62, 65))	('patients', 'Species', '9606', (89, 97))	('CCA', 'Disease', 'MESH:D018281', (104, 107))	('SMAD4', 'Gene', (18, 23))	('CCA', 'Disease', (62, 65))
112664	31450767	Although, this difference in the frequency of SMAD4 mutations between iCCA and eCCA was not statistically significant (P = 0.333), probably as a result of a limited number of eCCA cases, it suggests that eCCA exhibits a molecular phenotype that resembles pancreatic cancer rather than iCCA.	('mutations', 'Var', (52, 61))	('CCA', 'Disease', (286, 289))	('CCA', 'Disease', 'MESH:D018281', (71, 74))	('CCA', 'Disease', (176, 179))	('CCA', 'Disease', (71, 74))	('pancreatic cancer', 'Disease', (255, 272))	('CCA', 'Disease', (205, 208))	('CCA', 'Disease', (80, 83))	('pancreatic cancer', 'Disease', 'MESH:D010190', (255, 272))	('SMAD4', 'Gene', '4089', (46, 51))	('rat', 'Species', '10116', (273, 276))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (255, 272))	('CCA', 'Disease', 'MESH:D018281', (176, 179))	('CCA', 'Disease', 'MESH:D018281', (286, 289))	('CCA', 'Disease', 'MESH:D018281', (205, 208))	('SMAD4', 'Gene', (46, 51))	('CCA', 'Disease', 'MESH:D018281', (80, 83))
112672	31450767	Taken together, these studies suggest that different mechanisms contribute to inactivate SMAD4 and possibly the tumor suppressive arm of the TGFbeta pathway, both in eCCA, involving SMAD4 inactivating point mutations, and in iCCA, involving a transcriptional down-regulation of SMAD4.	('inactivating point mutations', 'Var', (188, 216))	('tumor', 'Disease', (112, 117))	('SMAD4', 'Gene', '4089', (89, 94))	('SMAD4', 'Gene', '4089', (182, 187))	('SMAD4', 'Gene', '4089', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('CCA', 'Disease', 'MESH:D018281', (167, 170))	('down-regulation', 'NegReg', (259, 274))	('inactivate', 'NegReg', (78, 88))	('SMAD4', 'Gene', (89, 94))	('CCA', 'Disease', 'MESH:D018281', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('SMAD4', 'Gene', (182, 187))	('CCA', 'Disease', (167, 170))	('CCA', 'Disease', (226, 229))	('SMAD4', 'Gene', (278, 283))
112679	31450767	Interestingly, inhibition of the kinase activity of MEK diminished the induction of EMT but, in contrast, potentiated the anti-proliferative effects of TGFbeta.	('potentiated', 'PosReg', (106, 117))	('MEK', 'Gene', (52, 55))	('EMT', 'CPA', (84, 87))	('anti-proliferative effects', 'MPA', (122, 148))	('diminished', 'NegReg', (56, 66))	('rat', 'Species', '10116', (134, 137))	('MEK', 'Gene', '5609', (52, 55))	('inhibition', 'Var', (15, 25))
112682	31450767	Moreover, inhibition of the kinase CK2, which is linked to TGFbeta signaling, attenuated proliferation and increased apoptosis of the primary CCA cells.	('proliferation', 'CPA', (89, 102))	('increased', 'PosReg', (107, 116))	('CCA cells', 'Disease', (142, 151))	('CCA cells', 'Disease', 'MESH:D018281', (142, 151))	('apoptosis', 'CPA', (117, 126))	('inhibition', 'Var', (10, 20))	('rat', 'Species', '10116', (96, 99))	('attenuated', 'NegReg', (78, 88))
112691	31450767	Livers from animals overexpressing both hepatitis B virus X (HBx) and hepatitis C virus core (HCP) proteins developed fibrosis and iCCA characterized by activated noncanonical TGFbeta signaling, exemplified by enhanced MAPK and SMAD linker phosphorylation.	('SMAD', 'Gene', (228, 232))	('hepatitis', 'Var', (70, 79))	('noncanonical TGFbeta signaling', 'MPA', (163, 193))	('hepatitis', 'Phenotype', 'HP:0012115', (40, 49))	('hepatitis C virus', 'Species', '11103', (70, 87))	('HBx', 'Disease', 'MESH:D006509', (61, 64))	('activated', 'PosReg', (153, 162))	('HBx', 'Disease', (61, 64))	('developed', 'PosReg', (108, 117))	('hepatitis B virus X', 'Disease', 'MESH:D006509', (40, 59))	('hepatitis', 'Phenotype', 'HP:0012115', (70, 79))	('fibrosis', 'Disease', 'MESH:D005355', (118, 126))	('fibrosis', 'Disease', (118, 126))	('CCA', 'Disease', 'MESH:D018281', (132, 135))	('hepatitis B virus X', 'Disease', (40, 59))	('CCA', 'Disease', (132, 135))	('enhanced', 'PosReg', (210, 218))	('proteins', 'Var', (99, 107))	('SMAD', 'Gene', '4089;4089;4092', (228, 232))
112692	31450767	In addition, in vivo disruption of TGFbeta1 expression by morpholinos attenuated fibrosis and iCCA progression, suggesting the importance of TGFbeta signaling during hepatitis-induced iCCA.	('fibrosis', 'Disease', 'MESH:D005355', (81, 89))	('fibrosis', 'Disease', (81, 89))	('attenuated', 'NegReg', (70, 80))	('CCA', 'Disease', 'MESH:D018281', (95, 98))	('CCA', 'Disease', (95, 98))	('hepatitis', 'Disease', (166, 175))	('hepatitis', 'Phenotype', 'HP:0012115', (166, 175))	('disruption', 'Var', (21, 31))	('CCA', 'Disease', 'MESH:D018281', (185, 188))	('TGFbeta1', 'Gene', (35, 43))	('hepatitis', 'Disease', 'MESH:D056486', (166, 175))	('CCA', 'Disease', (185, 188))
112702	31450767	Interestingly, PTPN3 point mutations (L232R) may disrupt its interaction with TbetaRI, allowing SMAD7/ubiquitin E3 ligase complexes to exert their inhibitory role towards TbetaRI and, thus, abolishing TGFbeta pro-cytostatic effects.	('disrupt', 'NegReg', (49, 56))	('TbetaRI', 'Gene', '7046', (78, 85))	('abolishing', 'NegReg', (190, 200))	('TbetaRI', 'Gene', '7046', (171, 178))	('TbetaRI', 'Gene', (171, 178))	('SMAD7', 'Gene', (96, 101))	('PTPN3', 'Gene', '5774', (15, 20))	('L232R', 'Mutation', 'p.L232R', (38, 43))	('TbetaRI', 'Gene', (78, 85))	('SMAD7', 'Gene', '4092', (96, 101))	('L232R', 'Var', (38, 43))	('TGFbeta pro-cytostatic effects', 'MPA', (201, 231))	('interaction', 'Interaction', (61, 72))	('PTPN3', 'Gene', (15, 20))
112703	31450767	Mutant PTPN3 L232R is frequently found in iCCA and results in loss of its anti-tumorigenic function.	('loss', 'NegReg', (62, 66))	('L232R', 'Mutation', 'p.L232R', (13, 18))	('PTPN3', 'Gene', '5774', (7, 12))	('tumor', 'Disease', (79, 84))	('CCA', 'Disease', 'MESH:D018281', (43, 46))	('CCA', 'Disease', (43, 46))	('PTPN3', 'Gene', (7, 12))	('L232R', 'Var', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
112704	31450767	This finding could be of clinical importance for the subset of patients that carry PTPN3 L232R mutations, although a direct correlation between mutant PTPN3 and inactivation of TGFbeta signaling in iCCA patients was not addressed in this study.	('PTPN3', 'Gene', '5774', (83, 88))	('PTPN3', 'Gene', '5774', (151, 156))	('PTPN3', 'Gene', (151, 156))	('patients', 'Species', '9606', (203, 211))	('patients', 'Species', '9606', (63, 71))	('L232R', 'Var', (89, 94))	('PTPN3', 'Gene', (83, 88))	('L232R', 'Mutation', 'p.L232R', (89, 94))	('CCA', 'Disease', 'MESH:D018281', (199, 202))	('CCA', 'Disease', (199, 202))
112706	31450767	For instance, in HCC, the lncRNA activated by TGFbeta (lncRNA-ATB) is a target gene of TGFbeta signaling and contributes to metastasis by sponging miR-200, thereby stabilizing the EMT transcription factors ZEB1 and ZEB2, and by stabilizing IL11 mRNA, thus favoring tumor cell dissemination.	('IL11', 'Gene', '3589', (240, 244))	('IL11', 'Gene', (240, 244))	('favoring', 'PosReg', (256, 264))	('EMT transcription factors', 'MPA', (180, 205))	('TGFbeta', 'Gene', (46, 53))	('sponging', 'Var', (138, 146))	('tumor', 'Disease', (265, 270))	('HCC', 'Disease', 'MESH:D006528', (17, 20))	('ZEB1', 'Gene', '6935', (206, 210))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('miR-200', 'Gene', (147, 154))	('metastasis', 'CPA', (124, 134))	('stabilizing', 'Reg', (228, 239))	('stabilizing', 'Reg', (164, 175))	('ZEB2', 'Gene', (215, 219))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('HCC', 'Disease', (17, 20))	('HCC', 'Phenotype', 'HP:0001402', (17, 20))	('ZEB2', 'Gene', '9839', (215, 219))	('ZEB1', 'Gene', (206, 210))
112715	31450767	The authors also used RNA interference to deplete TGFB1 and chemical inhibition of TbetaRI kinase activity by LY2157299 and SB431542 to further confirm that both manipulations negatively affected cell growth and migration of RBE and SSP25 CCA cell lines.	('deplete', 'NegReg', (42, 49))	('TbetaRI', 'Gene', (83, 90))	('CCA', 'Disease', 'MESH:D018281', (239, 242))	('negatively', 'NegReg', (176, 186))	('rat', 'Species', '10116', (215, 218))	('TbetaRI', 'Gene', '7046', (83, 90))	('RNA', 'MPA', (22, 25))	('LY2157299', 'Var', (110, 119))	('CCA', 'Disease', (239, 242))	('cell growth', 'CPA', (196, 207))	('TGFB1', 'Gene', '7040', (50, 55))	('SB431542', 'Chemical', 'MESH:C459179', (124, 132))	('affected', 'Reg', (187, 195))	('migration', 'CPA', (212, 221))	('inhibition', 'NegReg', (69, 79))	('TGFB1', 'Gene', (50, 55))
112751	31450767	In addition to these preclinical models, ongoing clinical trials make use of the chimeric antibody M7824, which is composed of the extracellular domain of human TbetaRII and the C-terminus of human anti-PD-L1 heavy chain.	('PD-L1', 'Gene', '29126', (203, 208))	('human', 'Species', '9606', (192, 197))	('human', 'Species', '9606', (155, 160))	('M7824', 'Var', (99, 104))	('TbetaRII', 'Gene', '7048', (161, 169))	('PD-L1', 'Gene', (203, 208))	('TbetaRII', 'Gene', (161, 169))
112752	31450767	M7824 has a double anti-tumor function as it serves as a trap for TGFbeta ligand binding at the tumor microenvironment and restricts the immune checkpoint factor programmed cell death ligand-1 (PD-L1), thereby restoring immune responses against the tumor.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('restoring', 'PosReg', (210, 219))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('immune responses', 'MPA', (220, 236))	('programmed cell death ligand-1', 'Gene', '29126', (162, 192))	('tumor', 'Disease', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('binding', 'Interaction', (81, 88))	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor', 'Disease', (96, 101))	('immune', 'MPA', (137, 143))	('M7824', 'Var', (0, 5))	('TGFbeta', 'Gene', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('PD-L1', 'Gene', (194, 199))	('restricts', 'NegReg', (123, 132))	('PD-L1', 'Gene', '29126', (194, 199))	('programmed cell death ligand-1', 'Gene', (162, 192))
112753	31450767	Thus, a recently started multicenter phase II clinical trial is evaluating M7824 monotherapy in locally advanced or metastatic second line biliary tract cancer, including CCAs and gallbladder cancer (NCT03833661).	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('biliary tract cancer', 'Disease', (139, 159))	('cancer', 'Disease', (153, 159))	('M7824', 'Var', (75, 80))	('biliary tract cancer', 'Disease', 'MESH:D001661', (139, 159))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (139, 159))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('CCAs', 'Disease', (171, 175))	('CCAs', 'Disease', 'MESH:D018281', (171, 175))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
112786	29721058	KRAS mutations and epidermal growth factor receptor (EGFR) overexpression has been observed in many BTC studies.	('epidermal growth factor receptor', 'Gene', '1956', (19, 51))	('mutations', 'Var', (5, 14))	('overexpression', 'PosReg', (59, 73))	('EGFR', 'Gene', '1956', (53, 57))	('epidermal growth factor receptor', 'Gene', (19, 51))	('EGFR', 'Gene', (53, 57))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
112789	29721058	According to recent reports, KRAS mutations are observed in intra- and extra-hepatic cholangiocarcinoma more frequently than in gallbladder cancer, which was observed 4-13% in GBCA, 8.3-42% in ICC and 8.6-24.2% in ECC.	('GBCA', 'Disease', (176, 180))	('ICC', 'Disease', (193, 196))	('extra-hepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (71, 103))	('gallbladder cancer', 'Disease', (128, 146))	('extra-hepatic cholangiocarcinoma', 'Disease', (71, 103))	('KRAS', 'Gene', (29, 33))	('gallbladder cancer', 'Disease', 'MESH:D005706', (128, 146))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('KRAS', 'Gene', '3845', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutations', 'Var', (34, 43))	('observed', 'Reg', (48, 56))
112830	29721058	Analysis of the cholangiocarcinoma and non-cholangiocarcinoma subgroups showed that cholangiocarcinoma exhibited significantly greater benefits from targeted therapy, but only a 6% reduction was observed for non-cholangiocarcinoma, which was not significant.	('non-cholangiocarcinoma', 'Disease', 'MESH:D018281', (208, 230))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (43, 61))	('non-cholangiocarcinoma', 'Disease', 'MESH:D018281', (39, 61))	('cholangiocarcinoma', 'Disease', (212, 230))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (16, 34))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (43, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (16, 34))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('greater benefits', 'PosReg', (127, 143))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (212, 230))	('non-cholangiocarcinoma', 'Disease', (208, 230))	('cholangiocarcinoma', 'Disease', (84, 102))	('targeted therapy', 'Var', (149, 165))	('non-cholangiocarcinoma', 'Disease', (39, 61))	('cholangiocarcinoma', 'Disease', (16, 34))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (212, 230))	('cholangiocarcinoma', 'Disease', (43, 61))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
112832	29721058	Targeted treatment generated a significant 44% reduction in cholangiocarcinoma risk, but only a 6% reduction in non-cholangiocarcinoma, which was not significant.	('cholangiocarcinoma', 'Disease', (60, 78))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (116, 134))	('non-cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 134))	('Targeted treatment', 'Var', (0, 18))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (60, 78))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (60, 78))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))	('reduction', 'NegReg', (47, 56))	('non-cholangiocarcinoma', 'Disease', (112, 134))	('cholangiocarcinoma', 'Disease', (116, 134))
112833	29721058	This result was also supported by recent studies demonstrating that KRAS mutation and EGFR overexpression in BTC, especially in cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (128, 146))	('overexpression', 'PosReg', (91, 105))	('EGFR', 'Gene', '1956', (86, 90))	('BTC', 'Disease', (109, 112))	('cholangiocarcinoma', 'Disease', (128, 146))	('EGFR', 'Gene', (86, 90))	('KRAS', 'Gene', (68, 72))	('KRAS', 'Gene', '3845', (68, 72))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (128, 146))	('mutation', 'Var', (73, 81))
112835	29721058	Although the BINGO and TCOG T1210 trial demonstrated that neither KRAS mutations nor EGFR overexpression improved the selection of patients who respond to therapy, the patients were pooled in a mixed analysis.	('patients', 'Species', '9606', (131, 139))	('EGFR', 'Gene', (85, 89))	('KRAS', 'Gene', '3845', (66, 70))	('mutations', 'Var', (71, 80))	('patients', 'Species', '9606', (168, 176))	('EGFR', 'Gene', '1956', (85, 89))	('KRAS', 'Gene', (66, 70))
112838	29721058	reported that modified GEMOX improved the PFS and OS compared to the best supportive care or fluorouracil.	('GEMOX', 'Chemical', '-', (23, 28))	('modified', 'Var', (14, 22))	('PFS', 'CPA', (42, 45))	('OS', 'Chemical', '-', (50, 52))	('improved', 'PosReg', (29, 37))	('fluorouracil', 'Chemical', 'MESH:D005472', (93, 105))
112857	28684878	In recent years, the expression of HNF-1beta has been reported to be associated with risk for a variety of cancers.	('HNF-1beta', 'Gene', (35, 44))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('associated', 'Reg', (69, 79))	('expression', 'Var', (21, 31))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
112858	28684878	The purpose of this study is to investigate whether the expression of HNF-1beta promotes the malignancy of HCC and its mechanism.	('HCC', 'Phenotype', 'HP:0001402', (107, 110))	('HNF-1beta', 'Gene', (70, 79))	('expression', 'Var', (56, 66))	('malignancy of HCC', 'Disease', (93, 110))	('promotes', 'PosReg', (80, 88))	('malignancy of HCC', 'Disease', 'MESH:D006528', (93, 110))
112861	28684878	The invasion ability and epithelial-mesenchymal transition (EMT)-associated genes were also significantly higher in liver cancer cells overexpressing HNF-1beta than in the control group.	('liver cancer', 'Disease', 'MESH:D006528', (116, 128))	('liver cancer', 'Disease', (116, 128))	('overexpressing', 'Var', (135, 149))	('invasion ability', 'CPA', (4, 20))	('higher', 'PosReg', (106, 112))	('HNF-1beta', 'Gene', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('liver cancer', 'Phenotype', 'HP:0002896', (116, 128))
112863	28684878	In conclusion, high expression of HNF-1beta not only promoted the de-differentiation of HCC cells into liver cancer stem cells through activating the Notch pathway but also enhanced the invasive potential of HCC cells and EMT occurrence, which would contribute to the enhancement of cell migration and invasion.	('HCC', 'Gene', '619501', (88, 91))	('HCC', 'Gene', '619501', (208, 211))	('HCC', 'Phenotype', 'HP:0001402', (208, 211))	('HCC', 'Phenotype', 'HP:0001402', (88, 91))	('activating', 'PosReg', (135, 145))	('HCC', 'Gene', (208, 211))	('HCC', 'Gene', (88, 91))	('de-differentiation', 'CPA', (66, 84))	('EMT occurrence', 'CPA', (222, 236))	('promoted', 'PosReg', (53, 61))	('enhancement', 'PosReg', (268, 279))	('liver cancer', 'Disease', 'MESH:D006528', (103, 115))	('rat', 'Species', '10116', (291, 294))	('Notch pathway', 'Pathway', (150, 163))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('enhanced', 'PosReg', (173, 181))	('HNF-1beta', 'Gene', (34, 43))	('invasion', 'CPA', (302, 310))	('high expression', 'Var', (15, 30))	('liver cancer', 'Phenotype', 'HP:0002896', (103, 115))	('cell migration', 'CPA', (283, 297))	('liver cancer', 'Disease', (103, 115))
112881	28684878	HNF-1beta variants are associated with prostate and ovarian cancer activation.	('prostate and ovarian cancer', 'Disease', 'MESH:D010051', (39, 66))	('variants', 'Var', (10, 18))	('ovarian cancer', 'Phenotype', 'HP:0100615', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('HNF-1beta', 'Gene', (0, 9))	('associated', 'Reg', (23, 33))
112887	28684878	HCC with high HNF-1beta expression exhibited the biliary phenotype and worse prognosis.	('exhibited', 'Reg', (35, 44))	('HCC', 'Gene', (0, 3))	('expression', 'MPA', (24, 34))	('high', 'Var', (9, 13))	('biliary', 'Disease', (49, 56))	('HCC', 'Phenotype', 'HP:0001402', (0, 3))	('HCC', 'Gene', '619501', (0, 3))	('HNF-1beta', 'Gene', (14, 23))
112893	28684878	According to the Kaplan-Meier survival analysis, the HCC patients with high HNF-1beta expression had a significantly poorer DFS.	('HCC', 'Gene', (53, 56))	('HNF-1beta', 'Gene', (76, 85))	('high', 'Var', (71, 75))	('patients', 'Species', '9606', (57, 65))	('poorer', 'NegReg', (117, 123))	('HCC', 'Gene', '619501', (53, 56))	('HCC', 'Phenotype', 'HP:0001402', (53, 56))	('DFS', 'MPA', (124, 127))
112913	28684878	Targeting Notch1 could decreases HCC cell invasion in vitro .	('HCC', 'Gene', (33, 36))	('Notch1', 'Gene', (10, 16))	('HCC', 'Gene', '619501', (33, 36))	('Notch1', 'Gene', '4851', (10, 16))	('HCC', 'Phenotype', 'HP:0001402', (33, 36))	('decreases', 'NegReg', (23, 32))	('Targeting', 'Var', (0, 9))
112932	28684878	More recently, some findings have shown that dual NOTCH and AKT signalling in hepatocytes can lead to their conversion into biliary cells that eventually progress into cholangiocarcinomas, a malignancy typically associated with a ductal origin.	('conversion', 'MPA', (108, 118))	('NOTCH', 'Var', (50, 55))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (168, 187))	('AKT', 'Gene', '207', (60, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('progress', 'Reg', (154, 162))	('lead to', 'Reg', (94, 101))	('AKT', 'Gene', (60, 63))	('malignancy', 'Disease', 'MESH:D009369', (191, 201))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (168, 186))	('malignancy', 'Disease', (191, 201))	('cholangiocarcinomas', 'Disease', (168, 187))
112941	28684878	More recently, some findings have shown that dual Notch and AKT signalling in hepatocytes can lead to their conversion into biliary cells that eventually progress into cholangiocarcinomas, a malignancy typically associated with a ductal origin.	('conversion', 'MPA', (108, 118))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (168, 187))	('Notch', 'Var', (50, 55))	('AKT', 'Gene', '207', (60, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('progress', 'Reg', (154, 162))	('lead to', 'Reg', (94, 101))	('AKT', 'Gene', (60, 63))	('malignancy', 'Disease', 'MESH:D009369', (191, 201))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (168, 186))	('malignancy', 'Disease', (191, 201))	('cholangiocarcinomas', 'Disease', (168, 187))
112943	28684878	Certain gene deletions or mutations can result in a nuclear translocation of N2ICD, which triggers the Notch pathway, maintaining the stemness of the liver CSCs.	('triggers', 'Reg', (90, 98))	('N2ICD', 'Gene', (77, 82))	('maintaining', 'PosReg', (118, 129))	('nuclear translocation', 'MPA', (52, 73))	('result in', 'Reg', (40, 49))	('stemness of the liver CSCs', 'Disease', 'MESH:D017093', (134, 160))	('deletions', 'Var', (13, 22))	('mutations', 'Var', (26, 35))	('stemness of the liver CSCs', 'Disease', (134, 160))	('Notch pathway', 'Pathway', (103, 116))
112985	22098159	Deregulation of Hippo Kinase Signaling in Human Hepatic Malignancies Hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and hepatoblastoma (HB) are the main hepatic malignancies with limited treatment options and high mortality.	('hepatoblastoma', 'Phenotype', 'HP:0002884', (129, 143))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('Hepatic Malignancies', 'Phenotype', 'HP:0002896', (48, 68))	('HCC', 'Gene', '619501', (95, 98))	('HCC', 'Phenotype', 'HP:0001402', (95, 98))	('Hepatic Malignancies', 'Disease', 'MESH:D056486', (48, 68))	('cholangiocarcinoma', 'Disease', (101, 119))	('Hepatocellular carcinoma', 'Disease', (69, 93))	('HCC', 'Gene', (95, 98))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (101, 119))	('HB', 'Phenotype', 'HP:0002884', (145, 147))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (69, 93))	('Hepatic Malignancies', 'Disease', (48, 68))	('CC', 'Phenotype', 'HP:0030153', (121, 123))	('hepatoblastoma', 'Disease', (129, 143))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (69, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('hepatic malignancies', 'Phenotype', 'HP:0002896', (162, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('hepatoblastoma', 'Disease', 'MESH:D018197', (129, 143))	('hepatic malignancies', 'Disease', 'MESH:D056486', (162, 182))	('CC', 'Phenotype', 'HP:0030153', (96, 98))	('Hippo Kinase Signaling', 'MPA', (16, 38))	('Deregulation', 'Var', (0, 12))	('Human', 'Species', '9606', (42, 47))	('hepatic malignancies', 'Disease', (162, 182))
112988	22098159	Increased expression of yes-associated protein (Yap), the downstream effector of the Hippo Kinase pathway, was observed in HCC cells and siRNA-mediated knockdown of Yap resulted in decreased survival of HCC cells.	('CC', 'Phenotype', 'HP:0030153', (204, 206))	('knockdown', 'Var', (152, 161))	('HCC', 'Gene', (123, 126))	('CC', 'Phenotype', 'HP:0030153', (124, 126))	('yes-associated protein', 'Gene', (24, 46))	('Yap', 'Gene', (165, 168))	('HCC', 'Gene', '619501', (123, 126))	('HCC', 'Gene', (203, 206))	('expression', 'MPA', (10, 20))	('Yap', 'Gene', (48, 51))	('yes-associated protein', 'Gene', '10413', (24, 46))	('Increased', 'PosReg', (0, 9))	('HCC', 'Phenotype', 'HP:0001402', (123, 126))	('HCC', 'Gene', '619501', (203, 206))	('survival', 'CPA', (191, 199))	('HCC', 'Phenotype', 'HP:0001402', (203, 206))	('decreased', 'NegReg', (181, 190))
112994	22098159	These data show that Yap induction mediated by inactivation of Lats is observed in hepatic malignancies.	('inactivation', 'Var', (47, 59))	('hepatic malignancies', 'Phenotype', 'HP:0002896', (83, 103))	('hepatic malignancies', 'Disease', (83, 103))	('hepatic malignancies', 'Disease', 'MESH:D056486', (83, 103))	('Yap induction', 'Disease', (21, 34))	('Lats', 'Gene', (63, 67))
112999	22098159	Recent studies show that deregulation of Hippo Kinase pathway, a signaling pathway involved in organ size regulation, results in HCC development in rodents.	('HCC', 'Gene', (129, 132))	('results in', 'Reg', (118, 128))	('deregulation', 'Var', (25, 37))	('Hippo Kinase pathway', 'Pathway', (41, 61))	('HCC', 'Gene', '619501', (129, 132))	('HCC', 'Phenotype', 'HP:0001402', (129, 132))	('CC', 'Phenotype', 'HP:0030153', (130, 132))
113007	22098159	It is also known that dysfunctional Hippo Kinase signaling is involved in cancers of a number of organs including breast, pancreas, and prostate.	('dysfunctional', 'Var', (22, 35))	('pancreas', 'Disease', (122, 130))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('prostate', 'Disease', (136, 144))	('breast', 'Disease', (114, 120))	('involved', 'Reg', (62, 70))	('cancers', 'Disease', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Hippo', 'Protein', (36, 41))
113043	22098159	Yap knockdown was associated with decreased protein expression of Survivin and also resulted in decreased CTGF mRNA expression (Fig 1E).	('Yap', 'Gene', (0, 3))	('knockdown', 'Var', (4, 13))	('decreased', 'NegReg', (34, 43))	('decreased', 'NegReg', (96, 105))	('protein expression', 'MPA', (44, 62))	('CTGF', 'Gene', '1490', (106, 110))	('Survivin', 'Protein', (66, 74))	('CTGF', 'Gene', (106, 110))
113044	22098159	Finally, MTT assay indicated 50% decrease in cell viability after shRNA-mediated Yap knockdown (Fig.	('decrease', 'NegReg', (33, 41))	('cell viability', 'CPA', (45, 59))	('knockdown', 'Var', (85, 94))	('Yap', 'Gene', (81, 84))	('MTT', 'Chemical', 'MESH:C070243', (9, 12))
113054	22098159	In the case of HCC, the same four samples, which had phospho-Yap protein, also had presence of phospho-Lats.	('HCC', 'Phenotype', 'HP:0001402', (15, 18))	('HCC', 'Gene', '619501', (15, 18))	('CC', 'Phenotype', 'HP:0030153', (16, 18))	('phospho-Yap protein', 'Var', (53, 72))	('HCC', 'Gene', (15, 18))
113095	22098159	Taken together, our data indicate that Hippo Kinase dysfunction resulting in increased Yap activation is associated with aggressive and high grade HCC and CC.	('Hippo Kinase', 'Protein', (39, 51))	('HCC', 'Gene', (147, 150))	('CC', 'Phenotype', 'HP:0030153', (148, 150))	('dysfunction', 'Var', (52, 63))	('HCC', 'Gene', '619501', (147, 150))	('HCC', 'Phenotype', 'HP:0001402', (147, 150))	('aggressive', 'Disease', (121, 131))	('increased', 'PosReg', (77, 86))	('associated', 'Reg', (105, 115))	('Yap activation', 'MPA', (87, 101))	('CC', 'Phenotype', 'HP:0030153', (155, 157))
113109	22098159	These data further implicate Lats inactivation in increased Yap activation during HCC, CC and HB pathogenesis.	('CC', 'Phenotype', 'HP:0030153', (87, 89))	('HCC', 'Gene', (82, 85))	('CC', 'Phenotype', 'HP:0030153', (83, 85))	('HB', 'Phenotype', 'HP:0002884', (94, 96))	('inactivation', 'Var', (34, 46))	('Lats', 'Gene', (29, 33))	('increased', 'PosReg', (50, 59))	('HCC', 'Gene', '619501', (82, 85))	('HCC', 'Phenotype', 'HP:0001402', (82, 85))	('Yap activation', 'MPA', (60, 74))
113158	33609394	Serum albumin values just before hepatectomy were significantly lower in the PHLF group than in the no-PHLF group.	('PHLF', 'Var', (77, 81))	('Serum albumin', 'Gene', (0, 13))	('Serum albumin', 'Gene', '213', (0, 13))	('lower', 'NegReg', (64, 69))
113206	32334452	The 5-Fluorouracil (5-FU) is the first-line drug for cholangiocarcinoma but drug resistance results in reduced treatment efficacy (Konstantinidis et al., 2016).	('cholangiocarcinoma ', 'Gene', '3638', (53, 72))	('reduced treatment efficacy', 'Phenotype', 'HP:0020173', (103, 129))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (53, 71))	('reduced', 'NegReg', (103, 110))	('5-FU', 'Chemical', 'MESH:D005472', (20, 24))	('5-Fluorouracil', 'Chemical', 'MESH:D005472', (4, 18))	('drug resistance', 'Phenotype', 'HP:0020174', (76, 91))	('drug resistance', 'Var', (76, 91))	('cholangiocarcinoma ', 'Gene', (53, 72))	('treatment', 'MPA', (111, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
113226	32334452	Percentage of cell viability was calculated as follow:  Cell viability (%) = (OD of treated cells/ OD of control cells) x 100 Analysis of concentration-response curve of EPMC was performed using CalcuSyn  v2.11 software (Biosoft, Cambridge, UK) to obtain IC25, IC50 and IC90 (concentration that inhibits cell growth by 25%, 50%, and 90%, respectively).	('IC25', 'Var', (255, 259))	('EPMC', 'Chemical', 'MESH:C531364', (170, 174))	('cell growth', 'CPA', (304, 315))	('inhibits', 'NegReg', (295, 303))
113258	32334452	At 24 hours, percentage of cell population was significantly higher after exposing to EPMC at both IC25 and IC50 concentrations compared with control [median (95% CI): 47.92 (32.68-48.78)% vs. 17.03 (16.39-17.27)% (p=0.05), and 48.86 (48.59-50.93)% vs. 14.52 (12.73-14.92)% (p=0.05).	('higher', 'PosReg', (61, 67))	('EPMC', 'Chemical', 'MESH:C531364', (86, 90))	('IC50 concentrations', 'Var', (108, 127))	('percentage', 'CPA', (13, 23))
113261	32334452	EPMC exposure for 48 hours at IC25 and IC50 concentrations significantly induced both early and late apoptosis.	('IC50 concentrations', 'Var', (39, 58))	('IC25', 'Var', (30, 34))	('induced', 'Reg', (73, 80))	('EPMC', 'Chemical', 'MESH:C531364', (0, 4))
113265	32334452	EPMC exposure at IC25 and IC50 concentrations for 24 and 48 hours induced apoptosis in a time- and concentration-dependent manners.	('apoptosis', 'CPA', (74, 83))	('IC50', 'Var', (26, 30))	('EPMC', 'Chemical', 'MESH:C531364', (0, 4))
113267	32334452	Effect of EPMC on mdr-1 gene expression  The mdr-1 gene was not significantly upregulated in CL-6 and Caco-2 cells following exposure to EPMC (0.08, 0.8, and 8 microg/ml and 0.2, 2, and 20 microg/ml, respectively) for 24 and 48 hours, compared to control sample (p>0.05) (Figure 5).	('CL-6', 'Gene', (93, 97))	('EPMC', 'Chemical', 'MESH:C531364', (10, 14))	('CL-6', 'Gene', '3638', (93, 97))	('mdr-1', 'Gene', (18, 23))	('mdr-1', 'Gene', (45, 50))	('EPMC', 'Var', (137, 141))	('mdr-1', 'Gene', '5243', (18, 23))	('EPMC', 'Chemical', 'MESH:C531364', (137, 141))	('Caco-2', 'CellLine', 'CVCL:0025', (102, 108))	('mdr-1', 'Gene', '5243', (45, 50))
113279	32334452	EPMC at IC25 and IC50 was found to inhibit wound healing in CL-6 cell line after 24 and 48 hours of exposure.	('CL-6', 'Gene', (60, 64))	('CL-6', 'Gene', '3638', (60, 64))	('IC25', 'Var', (8, 12))	('EPMC', 'Var', (0, 4))	('IC50', 'Var', (17, 21))	('inhibit', 'NegReg', (35, 42))	('EPMC', 'Chemical', 'MESH:C531364', (0, 4))
113290	32334452	EPMC exposure at concentrations of IC25 and IC50 for 24 and 48 hours induced apoptosis in CL-6 cell line according to the nuclear envelope permeability and cell membrane alteration with the appearance of phosphatidylserine (PS) and expression of caspase 3/7.	('CL-6', 'Gene', (90, 94))	('caspase 3/7', 'Gene', '836;840', (246, 257))	('cell membrane alteration', 'CPA', (156, 180))	('caspase 3/7', 'Gene', (246, 257))	('apoptosis', 'CPA', (77, 86))	('nuclear envelope permeability', 'CPA', (122, 151))	('CL-6', 'Gene', '3638', (90, 94))	('IC25', 'Var', (35, 39))	('IC50', 'Var', (44, 48))	('phosphatidylserine', 'MPA', (204, 222))	('expression', 'MPA', (232, 242))	('EPMC', 'Chemical', 'MESH:C531364', (0, 4))
113344	32366840	They demonstrated that deletion of Notch2 skews AKT/Yap-induced ICC pathology towards a more hepatocellular adenoma-like phenotype.	('Notch2', 'Gene', '18129', (35, 41))	('deletion', 'Var', (23, 31))	('adenoma', 'Disease', 'MESH:D000236', (108, 115))	('skews', 'Reg', (42, 47))	('ICC', 'Disease', (64, 67))	('Yap', 'Gene', (52, 55))	('Notch2', 'Gene', (35, 41))	('hepatocellular adenoma', 'Phenotype', 'HP:0012028', (93, 115))	('Yap', 'Gene', '22601', (52, 55))	('adenoma', 'Disease', (108, 115))
113345	32366840	However, deletion of Notch1 in tumor cells does not affect the histological type.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Notch1', 'Gene', (21, 27))	('deletion', 'Var', (9, 17))	('tumor', 'Disease', (31, 36))	('Notch1', 'Gene', '18128', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
113348	32366840	indicates Kras and Tp53 mutations facilitate formation of hepatocyte-derived ICC in the context of chronic liver injury.	('liver injury', 'Disease', 'MESH:D017093', (107, 119))	('formation of hepatocyte-derived ICC', 'MPA', (45, 80))	('Kras', 'Gene', (10, 14))	('Kras', 'Gene', '16653', (10, 14))	('Tp53', 'Gene', (19, 23))	('liver injury', 'Disease', (107, 119))	('mutations', 'Var', (24, 33))	('Tp53', 'Gene', '22059', (19, 23))	('facilitate', 'PosReg', (34, 44))
113349	32366840	By using Alb-Cre;KrasLSL-G12D;Tp53f/f transgenic mice that targeting Kras and Tp53 mutations to the mouse liver, Hill et al.	('mutations', 'Var', (83, 92))	('Tp53', 'Gene', (30, 34))	('Tp53', 'Gene', '22059', (78, 82))	('Tp53', 'Gene', '22059', (30, 34))	('mouse', 'Species', '10090', (100, 105))	('Kras', 'Gene', (17, 21))	('Kras', 'Gene', '16653', (17, 21))	('Alb', 'Gene', '11657', (9, 12))	('Alb', 'Gene', (9, 12))	('transgenic mice', 'Species', '10090', (38, 53))	('Kras', 'Gene', (69, 73))	('Tp53', 'Gene', (78, 82))	('G12D', 'Mutation', 'rs121913529', (25, 29))	('Kras', 'Gene', '16653', (69, 73))
113350	32366840	demonstrated that selective induction of Kras and Tp53 mutations in mature hepatocytes in the setting of liver injury, such as DDC-induced chronic inflammation (3,5-diethoxycarbonyl-1,4-dihydrocollidine), could drive rapid progression of ICC.	('ICC', 'Disease', (238, 241))	('liver injury', 'Disease', (105, 117))	('mutations', 'Var', (55, 64))	('Kras', 'Gene', (41, 45))	('Tp53', 'Gene', (50, 54))	('Kras', 'Gene', '16653', (41, 45))	('inflammation', 'Disease', 'MESH:D007249', (147, 159))	('3,5-diethoxycarbonyl-1,4-dihydrocollidine', 'Chemical', 'MESH:C530773', (161, 202))	('liver injury', 'Disease', 'MESH:D017093', (105, 117))	('DDC', 'Chemical', 'MESH:C530773', (127, 130))	('inflammation', 'Disease', (147, 159))	('Tp53', 'Gene', '22059', (50, 54))
113352	32366840	Indeed, Tp53 has been shown to control plasticity in a number of different cellular contexts and thus Tp53 mutations may facilitate such transdifferentiation events that are implicated in hepatocyte-derived ICC pathogenesis.	('mutations', 'Var', (107, 116))	('facilitate', 'PosReg', (121, 131))	('Tp53', 'Gene', '22059', (102, 106))	('transdifferentiation events', 'CPA', (137, 164))	('Tp53', 'Gene', (8, 12))	('plasticity', 'MPA', (39, 49))	('Tp53', 'Gene', (102, 106))	('Tp53', 'Gene', '22059', (8, 12))
113355	32366840	It is noteworthy that recent exon sequencing revealed a high frequency of mutations in Smad4, a key downstream mediator of TGF-beta signals, in human cholangiocarcinoma.	('Smad4', 'Gene', (87, 92))	('Smad4', 'Gene', '4089', (87, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('human', 'Species', '9606', (144, 149))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (150, 168))	('mutations', 'Var', (74, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (150, 168))	('cholangiocarcinoma', 'Disease', (150, 168))
113356	32366840	Most recently, a new study reveals that hepatocyte-specific deletion of Tgfbr2 and PTEN mediated by AAV8-TBG-Cre promoted hepatocyte-derived ICC formation and reduced survival of mice.	('Tgfbr2', 'Gene', (72, 78))	('mice', 'Species', '10090', (179, 183))	('promoted', 'PosReg', (113, 121))	('deletion', 'Var', (60, 68))	('reduced', 'NegReg', (159, 166))	('hepatocyte-derived ICC formation', 'MPA', (122, 154))	('survival of mice', 'CPA', (167, 183))	('Tgfbr2', 'Gene', '21813', (72, 78))	('AAV8', 'Chemical', '-', (100, 104))	('PTEN', 'Gene', '19211', (83, 87))	('PTEN', 'Gene', (83, 87))
113357	32366840	Mechanistically, deletion of Tgfbr2 promotes the proliferation of cholangiocyte rather than hepatocytes, suggesting the pivotal role of epithelial Tgfbr2 in restricting cholangiocyte proliferation.	('Tgfbr2', 'Gene', (29, 35))	('Tgfbr2', 'Gene', '21813', (147, 153))	('proliferation', 'CPA', (49, 62))	('Tgfbr2', 'Gene', '21813', (29, 35))	('deletion', 'Var', (17, 25))	('cholangiocyte proliferation', 'CPA', (169, 196))	('Tgfbr2', 'Gene', (147, 153))	('promotes', 'PosReg', (36, 44))
113362	32366840	generated a ICC mouse model by co-expression of Fbxw7DeltaF (a dominant negative form of Fbxw7) and AKT plasmids in mice livers.	('Fbxw7DeltaF', 'Var', (48, 59))	('mice', 'Species', '10090', (116, 120))	('ICC', 'Disease', (12, 15))	('mouse', 'Species', '10090', (16, 21))
113364	32366840	Interestingly, selected deletion of c-Myc, as for the downstream targets of FBXW7, completely suppresses hepatocyte-derived ICC formation in AKT/Fbxw7DeltaF mice.	('mice', 'Species', '10090', (157, 161))	('hepatocyte-derived ICC formation', 'MPA', (105, 137))	('c-Myc', 'Gene', '4609', (36, 41))	('deletion', 'Var', (24, 32))	('suppresses', 'NegReg', (94, 104))	('c-Myc', 'Gene', (36, 41))
113370	32366840	They found that inhibition of Ras/MAPK cascade significantly delayed the progression of AKT/YapS127A-induced ICC.	('delayed', 'NegReg', (61, 68))	('AKT/YapS127A-induced ICC', 'Disease', (88, 112))	('Ras/MAPK cascade', 'Pathway', (30, 46))	('YapS127A', 'Mutation', 'rs762471803', (92, 100))	('progression', 'CPA', (73, 84))	('inhibition', 'Var', (16, 26))
113386	32366840	Researchers found that hepatocytes with aberrantly activated oncogenes, if the cell death in their environment is caused by apoptosis, will give rise to HCC; on the other hand, if the cell death is caused by necroptosis, it will lead to ICC.	('lead to', 'Reg', (229, 236))	('give rise to', 'Reg', (140, 152))	('HCC', 'Gene', '619501', (153, 156))	('HCC', 'Phenotype', 'HP:0001402', (153, 156))	('aberrantly', 'Var', (40, 50))	('ICC', 'Disease', (237, 240))	('HCC', 'Gene', (153, 156))
113389	32366840	Interestingly, simultaneous Prdm5 overexpression and Tbx3 knockdown resulted in the development of ICC; however, Tbx3 overexpression combined with Prdm5 knockdown lead to the development of HCC.	('Prdm5', 'Gene', '70779', (28, 33))	('knockdown', 'Var', (58, 67))	('HCC', 'Gene', '619501', (190, 193))	('Prdm5', 'Gene', (147, 152))	('resulted in', 'Reg', (68, 79))	('Prdm5', 'Gene', (28, 33))	('Prdm5', 'Gene', '70779', (147, 152))	('HCC', 'Phenotype', 'HP:0001402', (190, 193))	('lead to', 'Reg', (163, 170))	('ICC', 'Disease', (99, 102))	('Tbx3', 'Gene', '21386', (53, 57))	('Tbx3', 'Gene', '21386', (113, 117))	('HCC', 'Gene', (190, 193))	('Tbx3', 'Gene', (113, 117))	('Tbx3', 'Gene', (53, 57))
113414	32366840	In addition, mutations of TERT promoter and TP53, as well as substantial intratumoral heterogeneity, often appear in cHCC-ICC.	('cHCC-ICC', 'Chemical', '-', (117, 125))	('TERT', 'Gene', (26, 30))	('appear', 'Reg', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('HCC', 'Phenotype', 'HP:0001402', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('TP53', 'Gene', '22059', (44, 48))	('TERT', 'Gene', '21752', (26, 30))	('tumor', 'Disease', (78, 83))	('cHCC-ICC', 'Disease', (117, 125))	('mutations', 'Var', (13, 22))	('TP53', 'Gene', (44, 48))
113417	32366840	Some studies have shown that the NF-kappaB pathway promotes inflammation-related cancer, whereas inhibition of NF-kappaB activity in hepatocytes promotes the spontaneous formation of HCC, indicating that the NF-kappaB pathway function as tumor suppressor in hepatocytes.	('NF-kappaB', 'Gene', (208, 217))	('NF-kappaB', 'Gene', (33, 42))	('HCC', 'Gene', '619501', (183, 186))	('HCC', 'Phenotype', 'HP:0001402', (183, 186))	('inflammation', 'Disease', 'MESH:D007249', (60, 72))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('cancer', 'Disease', (81, 87))	('HCC', 'Gene', (183, 186))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('NF-kappaB', 'Gene', (111, 120))	('NF-kappaB', 'Gene', '18033', (208, 217))	('NF-kappaB', 'Gene', '18033', (33, 42))	('inflammation', 'Disease', (60, 72))	('promotes', 'PosReg', (51, 59))	('inhibition', 'Var', (97, 107))	('NF-kappaB', 'Gene', '18033', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', (238, 243))	('promotes', 'PosReg', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (238, 243))
113418	32366840	A recent study, the first to analyze the role of NF-kB pathway in the progression of cHCC-ICC, indicates that block of NF-kB signaling skews c-Myc-driven HCC pathology towards a more cHCC-ICC-like phenotype.	('c-Myc', 'Gene', '4609', (141, 146))	('HCC', 'Gene', (154, 157))	('HCC', 'Gene', '619501', (184, 187))	('HCC', 'Phenotype', 'HP:0001402', (184, 187))	('HCC', 'Gene', (86, 89))	('HCC', 'Gene', '619501', (154, 157))	('cHCC-ICC', 'Chemical', '-', (183, 191))	('c-Myc', 'Gene', (141, 146))	('HCC', 'Phenotype', 'HP:0001402', (154, 157))	('NF-kB', 'Gene', (119, 124))	('cHCC-ICC', 'Chemical', '-', (85, 93))	('block', 'Var', (110, 115))	('HCC', 'Gene', '619501', (86, 89))	('HCC', 'Gene', (184, 187))	('skews', 'Reg', (135, 140))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))
113422	32366840	Given NF-kappaB deletion led to an increase in infiltrating inflammatory cells, it is reasonable that the chronic inflammatory environment caused by NF-kappaB ablation may modulate the phenotypic transition in this model.	('NF-kappaB', 'Gene', (149, 158))	('increase', 'PosReg', (35, 43))	('deletion', 'Var', (16, 24))	('NF-kappaB', 'Gene', '18033', (149, 158))	('phenotypic transition', 'CPA', (185, 206))	('infiltrating inflammatory cells', 'MPA', (47, 78))	('NF-kappaB', 'Gene', (6, 15))	('modulate', 'Reg', (172, 180))	('NF-kappaB', 'Gene', '18033', (6, 15))	('ablation', 'Var', (159, 167))
113430	32366840	Based on this, we speculate that hepatocytes with aberrantly activated oncogenes, if the cell death in their environment is jointly caused by necroptosis and apoptosis, will give rise to cHCC-ICC (Fig.	('give rise to', 'Reg', (174, 186))	('oncogenes', 'Gene', (71, 80))	('aberrantly', 'Var', (50, 60))	('HCC', 'Phenotype', 'HP:0001402', (188, 191))	('cHCC-ICC', 'Disease', (187, 195))	('cHCC-ICC', 'Chemical', '-', (187, 195))
113433	32366840	For instance, mouse HCC induced by CCl4, diethylnitrosamine (DEN), or aristolochic acid was often accompanied with reactivation of a variety of fetal liver genes, such as Gpc3, Afp, Slpi, Spink3, and Abcd2.	('reactivation', 'MPA', (115, 127))	('Abcd2', 'Gene', '26874', (200, 205))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (41, 59))	('Slpi', 'Gene', (182, 186))	('mouse', 'Species', '10090', (14, 19))	('aristolochic acid', 'Var', (70, 87))	('Slpi', 'Gene', '20568', (182, 186))	('CCl4', 'Var', (35, 39))	('aristolochic acid', 'Chemical', 'MESH:C000228', (70, 87))	('HCC', 'Gene', '619501', (20, 23))	('Afp', 'Gene', '11576', (177, 180))	('Spink3', 'Gene', (188, 194))	('HCC', 'Phenotype', 'HP:0001402', (20, 23))	('DEN', 'Chemical', 'MESH:D004052', (61, 64))	('Gpc3', 'Gene', (171, 175))	('HCC', 'Gene', (20, 23))	('Afp', 'Gene', (177, 180))	('Abcd2', 'Gene', (200, 205))	('fetal liver genes', 'Gene', (144, 161))	('Gpc3', 'Gene', '14734', (171, 175))	('Spink3', 'Gene', '20730', (188, 194))
113434	32366840	Moreover, various transgenic mouse models of HCC have been successfully generated by overexpression of oncogenes such as AKT, Myc, Bmi1, c-Met, Tgfa, E2F1, Ccnd1, Spry2Y55F, and HRASG12V, or genes that encode viral proteins, such as HbsAg, HBX, and SV40 T-Ag (Table 1).	('overexpression', 'PosReg', (85, 99))	('SV40 T-Ag', 'Var', (249, 258))	('E2F1', 'Gene', '13555', (150, 154))	('Spry2Y55F', 'Var', (163, 172))	('Bmi1', 'Gene', '12151', (131, 135))	('Bmi1', 'Gene', (131, 135))	('Myc', 'Gene', (126, 129))	('Ccnd1', 'Gene', (156, 161))	('mouse', 'Species', '10090', (29, 34))	('E2F1', 'Gene', (150, 154))	('HCC', 'Gene', '619501', (45, 48))	('Ccnd1', 'Gene', '12443', (156, 161))	('HCC', 'Phenotype', 'HP:0001402', (45, 48))	('HB', 'Phenotype', 'HP:0002884', (240, 242))	('transgenic', 'Species', '10090', (18, 28))	('Myc', 'Gene', '17869', (126, 129))	('HCC', 'Gene', (45, 48))	('Tgfa', 'Gene', (144, 148))	('c-Met', 'Gene', (137, 142))	('AKT', 'Gene', (121, 124))	('c-Met', 'Gene', '17295', (137, 142))	('Tgfa', 'Gene', '21802', (144, 148))	('HRASG12V', 'Var', (178, 186))
113437	32366840	reveals a novel crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in the progression of HCC.	('HCC', 'Gene', '619501', (115, 118))	('cholesterol biosynthesis pathways', 'Pathway', (59, 92))	('HCC', 'Phenotype', 'HP:0001402', (115, 118))	('lipogenesis', 'MPA', (43, 54))	('aberrant', 'Var', (34, 42))	('cholesterol', 'Chemical', 'MESH:D002784', (59, 70))	('HCC', 'Gene', (115, 118))	('aberrant lipogenesis', 'Phenotype', 'HP:0009125', (34, 54))	('crosstalk', 'Reg', (16, 25))
113452	32366840	reported that the introduction of YAPS127A and PIK3CAH1047R (a constitutively active mutant of PI3K) induces liver cancers with many pathological features.	('liver cancers', 'Disease', 'MESH:D006528', (109, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('liver cancers', 'Disease', (109, 122))	('YAPS127A', 'Mutation', 'rs762471803', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('induces', 'PosReg', (101, 108))	('liver cancer', 'Phenotype', 'HP:0002896', (109, 121))	('YAPS127A', 'Var', (34, 42))	('PIK3CAH1047R', 'Var', (47, 59))	('liver cancers', 'Phenotype', 'HP:0002896', (109, 122))
113474	32366840	Likewise, chronic inflammation microenvironment induced by DDC can also reduce lipid droplets in AKT-NRASG12V tumors.	('DDC', 'Var', (59, 62))	('inflammation', 'Disease', (18, 30))	('lipid droplets', 'MPA', (79, 93))	('lipid', 'Chemical', 'MESH:D008055', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('AKT-NRASG12V', 'Disease', (97, 109))	('reduce', 'NegReg', (72, 78))	('inflammation', 'Disease', 'MESH:D007249', (18, 30))	('DDC', 'Chemical', 'MESH:C530773', (59, 62))
113493	31367249	More PD1+ T cells and/or high PD-L1 expression negatively impacted the prognosis of patients with HBV infection but not those with hepatolithiasis.	('hepatolithiasis', 'Disease', (131, 146))	('PD1+', 'Var', (5, 9))	('HBV infection', 'Disease', (98, 111))	('patients', 'Species', '9606', (84, 92))	('impacted', 'Reg', (58, 66))	('HBV infection', 'Disease', 'MESH:D006509', (98, 111))	('hepatolithiasis', 'Disease', 'None', (131, 146))	('PD-L1', 'Gene', (30, 35))	('prognosis', 'MPA', (71, 80))	('negatively', 'NegReg', (47, 57))	('expression', 'MPA', (36, 46))
113508	31367249	Aberrant PD-L1 expression is detected in many malignancies, such as non-small cell lung cancer, renal cell carcinoma, Hodgkins lymphoma, and HCC.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (96, 116))	('detected', 'Reg', (29, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('non-small cell lung cancer', 'Disease', (68, 94))	('HCC', 'Gene', '619501', (141, 144))	('HCC', 'Phenotype', 'HP:0001402', (141, 144))	('Aberrant', 'Var', (0, 8))	('Hodgkins lymphoma', 'Disease', 'MESH:D006689', (118, 135))	('Hodgkins lymphoma', 'Phenotype', 'HP:0012189', (118, 135))	('malignancies', 'Disease', 'MESH:D009369', (46, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (127, 135))	('HCC', 'Gene', (141, 144))	('expression', 'MPA', (15, 25))	('renal cell carcinoma', 'Disease', (96, 116))	('Hodgkins lymphoma', 'Disease', (118, 135))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (96, 116))	('malignancies', 'Disease', (46, 58))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (72, 94))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (68, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (68, 94))	('PD-L1', 'Gene', (9, 14))
113513	31367249	Further, a study of 54 ICC patients showed that high PD-L1 expression in tumors is associated with lower overall survival.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('PD-L1', 'Gene', (53, 58))	('lower', 'NegReg', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('ICC', 'Disease', 'MESH:C566123', (23, 26))	('overall survival', 'MPA', (105, 121))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('ICC', 'Disease', (23, 26))	('patients', 'Species', '9606', (27, 35))	('tumors', 'Disease', (73, 79))	('high', 'Var', (48, 52))
113530	31367249	Among 160 patients with recorded HBV DNA copy number, 16.9% (27/160) were positive for HBV DNA (above minimum detection level).	('HBV', 'Species', '10407', (33, 36))	('HBV', 'Species', '10407', (87, 90))	('copy number', 'Var', (41, 52))	('HBV DNA', 'Gene', (33, 40))	('positive', 'Reg', (74, 82))	('patients', 'Species', '9606', (10, 18))
113542	31367249	Further, there were significantly more PD1+ T cells in tumor tissues than in adjacent peritumor liver tissues (Figure 1F).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('more', 'PosReg', (34, 38))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', (55, 60))	('PD1+ T', 'Var', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
113548	31367249	PD-L1high ICC patients had shorter OS (p = 0.013) and higher cumulative recurrence rate (p < 0.001) than PD-L1low patients (Figure 2A and B).	('higher', 'PosReg', (54, 60))	('shorter', 'NegReg', (27, 34))	('OS', 'Chemical', '-', (35, 37))	('ICC', 'Disease', 'MESH:C566123', (10, 13))	('ICC', 'Disease', (10, 13))	('patients', 'Species', '9606', (14, 22))	('PD-L1high', 'Var', (0, 9))	('patients', 'Species', '9606', (114, 122))
113549	31367249	Similarly, ICC patients with more PD1+ T cells in tumor tissues had shorter OS (p = 0.013) and higher cumulative recurrence rate (p = 0.022) than patients with less PD1+ T cells (Figure 2C and D).	('patients', 'Species', '9606', (15, 23))	('OS', 'Chemical', '-', (76, 78))	('higher', 'PosReg', (95, 101))	('shorter', 'NegReg', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('ICC', 'Disease', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('ICC', 'Disease', 'MESH:C566123', (11, 14))	('patients', 'Species', '9606', (146, 154))	('tumor', 'Disease', (50, 55))	('PD1+ T cells', 'Var', (34, 46))
113550	31367249	Considering the combined role of PD1 and PD-L1 in regulating T cell function, ICC patients with high expression of both PD1 and PD-L1 had the poorest prognosis among patients with high expression of only PD1 or PD-L1 and patients with low expression of both PD1 and PD-L1 (Figure 2E and F; OS, p = 0.023; cumulative recurrence rate, p = 0.003).	('PD1', 'Gene', (120, 123))	('patients', 'Species', '9606', (221, 229))	('PD-L1', 'Gene', (128, 133))	('patients', 'Species', '9606', (82, 90))	('ICC', 'Disease', (78, 81))	('high expression', 'Var', (96, 111))	('ICC', 'Disease', 'MESH:C566123', (78, 81))	('OS', 'Chemical', '-', (290, 292))	('patients', 'Species', '9606', (166, 174))
113554	31367249	With combined expression of PD1/PD-L1, the hyperactivated PD1/PD-L1 axis was also an independent prognostic predictor for both OS (p = 0.031) and cumulative recurrence rate (p = 0.001) (Table 2).	('PD1/PD-L1', 'Gene', (28, 37))	('expression', 'Var', (14, 24))	('PD1/PD-L1', 'Gene', (58, 67))	('hyperactivated', 'PosReg', (43, 57))	('OS', 'Chemical', '-', (127, 129))
113557	31367249	Similar to expression of PD1+ T cells in the whole cohort, ICC patients with only HBV infection had more PD1+ T cells in tumor tissues than in corresponding liver tissues (68.0+-8.9 vs 45.5+-3.4, respectively; p = 0.001).	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('PD1+ T cells', 'Var', (105, 117))	('only HBV infection', 'Disease', (77, 95))	('only HBV infection', 'Disease', 'MESH:D006509', (77, 95))	('tumor', 'Disease', (121, 126))	('patients', 'Species', '9606', (63, 71))	('ICC', 'Disease', 'MESH:C566123', (59, 62))	('ICC', 'Disease', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
113560	31367249	ICC patients with only HBV infection had higher frequency of high PD-L1 expression (34.5%) compared to patients with hepatolithiasis (0%, p = 0.018) or patients with undefined risk factors (22.4%, p = 0.049).	('only HBV infection', 'Disease', (18, 36))	('hepatolithiasis', 'Disease', 'None', (117, 132))	('high', 'Var', (61, 65))	('expression', 'MPA', (72, 82))	('ICC', 'Disease', (0, 3))	('patients', 'Species', '9606', (103, 111))	('patients', 'Species', '9606', (4, 12))	('ICC', 'Disease', 'MESH:C566123', (0, 3))	('hepatolithiasis', 'Disease', (117, 132))	('PD-L1', 'Gene', (66, 71))	('only HBV infection', 'Disease', 'MESH:D006509', (18, 36))	('patients', 'Species', '9606', (152, 160))
113563	31367249	However, patients with hepatolithiasis had less PD1+ T cells in tumor tissues than in corresponding liver tissues (9.2+-2.5 vs 33.5+-8.0, respectively; p = 0.018).	('patients', 'Species', '9606', (9, 17))	('PD1+ T', 'Var', (48, 54))	('tumor', 'Disease', (64, 69))	('hepatolithiasis', 'Disease', (23, 38))	('less', 'NegReg', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('hepatolithiasis', 'Disease', 'None', (23, 38))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
113565	31367249	For ICC patients with only HBV infection, patients with more PD1+ T cells in tumor tissues had shorter OS (p = 0.026, Figure 3C) and higher cumulative recurrence rates (p = 0.011, Figure 3D) than patients with less PD1+ T cells.	('OS', 'Chemical', '-', (103, 105))	('only HBV infection', 'Disease', (22, 40))	('only HBV infection', 'Disease', 'MESH:D006509', (22, 40))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('higher', 'PosReg', (133, 139))	('PD1+ T cells', 'Var', (61, 73))	('patients', 'Species', '9606', (196, 204))	('ICC', 'Disease', 'MESH:C566123', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ICC', 'Disease', (4, 7))	('patients', 'Species', '9606', (42, 50))	('tumor', 'Disease', (77, 82))	('shorter', 'NegReg', (95, 102))	('patients', 'Species', '9606', (8, 16))
113570	31367249	Among 5 ICC patients with high PD1+ T cells (>19 cells/200x), 4 patients had evident tumor progression, and 1 patient presented stable disease after three cycles of anti-PD1 immunotherapy (Figure 4A and B).	('ICC', 'Disease', (8, 11))	('tumor', 'Disease', (85, 90))	('patients', 'Species', '9606', (12, 20))	('ICC', 'Disease', 'MESH:C566123', (8, 11))	('patient', 'Species', '9606', (64, 71))	('patients', 'Species', '9606', (64, 72))	('PD1+ T cells (>19 cells/200x', 'Var', (31, 59))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('patient', 'Species', '9606', (110, 117))	('patient', 'Species', '9606', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
113571	31367249	Unexpectedly, 2 patients with low PD1+ T cells (<=19 cells/200x) showed evident tumor shrinkage after three cycles of anti-PD1 immunotherapy (Figure 4A and B).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('patients', 'Species', '9606', (16, 24))	('tumor', 'Disease', (80, 85))	('PD1+ T cells', 'Var', (34, 46))
113581	31367249	In addition, ICC patients with HBV infection and overexpressed PD1/PD-L1 signals had poorer prognosis than patients expressing low PD1/PD-L1 signals, although we did not find the same results in ICC patients with hepatolithiasis or patients with undetermined risk factors.	('poorer', 'NegReg', (85, 91))	('patients', 'Species', '9606', (107, 115))	('hepatolithiasis', 'Disease', 'None', (213, 228))	('PD1/PD-L1', 'Gene', (63, 72))	('prognosis', 'MPA', (92, 101))	('patients', 'Species', '9606', (232, 240))	('signals', 'Var', (73, 80))	('overexpressed', 'PosReg', (49, 62))	('hepatolithiasis', 'Disease', (213, 228))	('ICC', 'Disease', 'MESH:C566123', (13, 16))	('HBV infection', 'Disease', (31, 44))	('ICC', 'Disease', (13, 16))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (199, 207))	('ICC', 'Disease', 'MESH:C566123', (195, 198))	('HBV infection', 'Disease', 'MESH:D006509', (31, 44))	('ICC', 'Disease', (195, 198))
113595	31367249	A recent study also showed that blocking PD1/PD-L1 only increased the frequency of tumor-specific T cells in HCC patients but did not restore T cell function.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('HCC', 'Gene', (109, 112))	('PD1/PD-L1', 'Gene', (41, 50))	('increased', 'PosReg', (56, 65))	('tumor', 'Disease', (83, 88))	('patients', 'Species', '9606', (113, 121))	('HCC', 'Gene', '619501', (109, 112))	('HCC', 'Phenotype', 'HP:0001402', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('blocking', 'Var', (32, 40))
113598	31367249	Importantly, our retrospective observation revealed that 2 ICC patients with HBV infection and low PD1+ TILs had a good response to anti-PD1 immunotherapy, although these data needed to be further validated by future randomized controlled trials.	('HBV infection', 'Disease', (77, 90))	('low', 'Var', (95, 98))	('HBV infection', 'Disease', 'MESH:D006509', (77, 90))	('patients', 'Species', '9606', (63, 71))	('ICC', 'Disease', 'MESH:C566123', (59, 62))	('PD1+', 'Gene', (99, 103))	('ICC', 'Disease', (59, 62))
113601	31367249	As such, high PD-L1 expression in ICC patients with HBV infection may induce tumor cells to evade immune surveillance, resulting in a shortened OS and high recurrence rate after curative resection.	('PD-L1', 'Protein', (14, 19))	('expression', 'MPA', (20, 30))	('patients', 'Species', '9606', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('induce', 'Reg', (70, 76))	('HBV infection', 'Disease', (52, 65))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('OS', 'Chemical', '-', (144, 146))	('ICC', 'Disease', (34, 37))	('recurrence', 'MPA', (156, 166))	('HBV infection', 'Disease', 'MESH:D006509', (52, 65))	('ICC', 'Disease', 'MESH:C566123', (34, 37))	('tumor', 'Disease', (77, 82))	('high', 'Var', (9, 13))
113642	31320991	The remaining 21 patients were diagnosed by imaging (dynamic contrast enhanced computed tomography and/or magnetic resonance imaging) as well as detection of elevated tumor markers (CA19-9 and/or CEA).	('CA19-9', 'Var', (182, 188))	('patients', 'Species', '9606', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('elevated tumor', 'Disease', (158, 172))	('CEA', 'Gene', (196, 199))	('elevated tumor', 'Disease', 'MESH:D009369', (158, 172))	('CEA', 'Gene', '1084', (196, 199))
113665	31320991	Of the remaining three patients, one with IHC (#2 in Table 4) experienced deteriorating liver function due to IHC pre-CIRT and died 14.5 months post-CIRT, and two with PHC (#3 and #4 in Table 4) had persistent cholangitis or biliary stenosis pre-CIRT and died at 7.2 and 22.3 months post-CIRT, respectively.	('cholangitis or biliary stenosis', 'Disease', (210, 241))	('deteriorating liver function', 'Phenotype', 'HP:0001410', (74, 102))	('patients', 'Species', '9606', (23, 31))	('biliary stenosis', 'Phenotype', 'HP:0007678', (225, 241))	('cholangitis', 'Phenotype', 'HP:0030151', (210, 221))	('cholangitis or biliary stenosis', 'Disease', 'MESH:D008105', (210, 241))	('IHC', 'Var', (110, 113))	('liver function', 'MPA', (88, 102))	('deteriorating', 'NegReg', (74, 87))
113749	28051802	We included all patients with ICD-O-3 codes of C22.1, C 24.0, 24.8, 24.9, and 23.9.	('patients', 'Species', '9606', (16, 24))	('C22.1', 'Var', (47, 52))	('C22.1', 'CellLine', 'CVCL:F277', (47, 52))	('C 24.0', 'Var', (54, 60))	('ICD', 'Gene', (30, 33))	('ICD', 'Gene', '79158', (30, 33))
113752	28051802	For extrahepatic cholangiocarcinoma, a topography code of C24.0 was used along with histology codes 8010, 8020, 8041, 8070, 8140, 8144, 8160, 8161, 8260, 8310, 8480, 8490 and 8560.	('8041', 'Var', (112, 116))	('8480', 'Var', (160, 164))	('extrahepatic cholangiocarcinoma', 'Disease', (4, 35))	('8160', 'Var', (136, 140))	('8490', 'Var', (166, 170))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (17, 35))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (4, 35))	('8140', 'Var', (124, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('8260', 'Var', (148, 152))	('8310', 'Var', (154, 158))	('8161', 'Var', (142, 146))	('8560', 'Var', (175, 179))	('8144', 'Var', (130, 134))	('8070', 'Var', (118, 122))	('8010', 'Var', (100, 104))
113855	28529557	In the case of G1-G2 hematological and non-hematological toxicity, no dose modification or delay was planned.	('hematological toxicity', 'Disease', (43, 65))	('G1-G2', 'Var', (15, 20))	('hematological toxicity', 'Disease', 'MESH:D006402', (43, 65))
113920	26855082	The results show that CXCR4-inhibition polycation PCX can effectively deliver miR-200c mimic and that the combination treatment consisting of PCX and miR-200c results in cooperative antimigration activity, most likely by coupling the CXCR4 axis blockade with epithelial-to-mesenchymal transition inhibition in the cholangiocarcinoma cells.	('CXCR4', 'Gene', '7852', (22, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (323, 332))	('CXCR4', 'Gene', '7852', (234, 239))	('PCX', 'Chemical', '-', (142, 145))	('miR-200c', 'Gene', (78, 86))	('cholangiocarcinoma', 'Disease', (314, 332))	('CXCR4', 'Gene', (22, 27))	('miR-200c', 'Gene', '406985', (78, 86))	('polycation', 'Var', (39, 49))	('miR-200c', 'Gene', (150, 158))	('miR-200c', 'Gene', '406985', (150, 158))	('CXCR4', 'Gene', (234, 239))	('PCX', 'Chemical', '-', (50, 53))	('antimigration activity', 'MPA', (182, 204))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (314, 332))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (314, 332))
113923	26855082	Dysregulation of microRNA often leads to pathological states such as cancer.	('microRNA', 'Protein', (17, 25))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('leads to', 'Reg', (32, 40))	('cancer', 'Disease', (69, 75))
113924	26855082	In fact, aberrant microRNA expression is found in nearly all human cancers.	('found', 'Reg', (41, 46))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('aberrant', 'Var', (9, 17))	('human', 'Species', '9606', (61, 66))	('microRNA expression', 'MPA', (18, 37))
113947	26855082	Signaling through CXCR4 increases migration of human cholangiocarcinoma cells and inhibition of CXCR4 signaling decreased motility and invasion.	('CXCR4', 'Gene', (96, 101))	('human', 'Species', '9606', (47, 52))	('increases', 'PosReg', (24, 33))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (53, 71))	('CXCR4', 'Gene', (18, 23))	('inhibition', 'Var', (82, 92))	('CXCR4', 'Gene', '7852', (18, 23))	('CXCR4', 'Gene', '7852', (96, 101))	('cholangiocarcinoma', 'Disease', (53, 71))	('decreased', 'NegReg', (112, 121))	('migration', 'CPA', (34, 43))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (53, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
113952	26855082	This was demonstrated in a recent study, which combined inhibition of the CXCR4 axis with siRNA knockdown of Lipocalin-2 (Lcn2) as a way of synergistically reducing migration in metastatic human breast cancer cells.	('knockdown', 'Var', (96, 105))	('CXCR4', 'Gene', '7852', (74, 79))	('Lcn2', 'Gene', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('breast cancer', 'Disease', 'MESH:D001943', (195, 208))	('CXCR4', 'Gene', (74, 79))	('human', 'Species', '9606', (189, 194))	('breast cancer', 'Disease', (195, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('Lipocalin-2', 'Gene', (109, 120))	('Lcn2', 'Gene', '3934', (122, 126))	('reducing', 'NegReg', (156, 164))	('Lipocalin-2', 'Gene', '3934', (109, 120))	('migration', 'CPA', (165, 174))
113954	26855082	The developed PCX polymers effectively block cancer cell invasion by inhibiting the CXCR4/SDF-1 axis, while at the same time, they deliver nucleic acids into the cancer cells for improved anticancer effect.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('improved', 'PosReg', (179, 187))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', (162, 168))	('CXCR4', 'Gene', (84, 89))	('PCX polymers', 'Chemical', '-', (14, 26))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('SDF-1', 'Gene', '6387', (90, 95))	('SDF-1', 'Gene', (90, 95))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('inhibiting', 'NegReg', (69, 79))	('block', 'NegReg', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('nucleic acids', 'Var', (139, 152))	('cancer', 'Disease', (45, 51))	('CXCR4', 'Gene', '7852', (84, 89))
113966	26855082	HuCCT1 cells were grown in high-glucose DMEM supplemented with 10% FBS, penicillin (100 U/mL), streptomycin (100 mug/mL), G418 (50 mug/mL), and insulin (0.5 mug/mL) at 37  C with 5% CO2 in a humidified chamber.	('high-glucose', 'Phenotype', 'HP:0003074', (27, 39))	('100 mug/mL', 'Var', (109, 119))	('glucose', 'Chemical', 'MESH:D005947', (32, 39))	('G418', 'Chemical', 'MESH:C010680', (122, 126))	('CO2', 'Chemical', '-', (182, 185))	('insulin', 'Gene', (144, 151))	('DMEM', 'Chemical', '-', (40, 44))	('streptomycin', 'Chemical', 'MESH:D013307', (95, 107))	('insulin', 'Gene', '3630', (144, 151))	('penicillin', 'Chemical', 'MESH:D010406', (72, 82))	('100 U/mL', 'Var', (84, 92))	('HuCCT1', 'CellLine', 'CVCL:0324', (0, 6))
114013	26855082	As shown in Figure 3, panel A, PCX polyplexes exhibited significant cellular uptake in HuCCT1 cells as indicated by the enhanced fluorescence intensity when compared with untreated cells or cells treated with free FITC-Oligo.	('cellular uptake', 'CPA', (68, 83))	('fluorescence intensity', 'MPA', (129, 151))	('HuCCT1', 'CellLine', 'CVCL:0324', (87, 93))	('PCX', 'Chemical', '-', (31, 34))	('enhanced', 'PosReg', (120, 128))	('FITC-Oligo', 'Chemical', '-', (214, 224))	('polyplexes', 'Var', (35, 45))
114036	26855082	When used to deliver miR-200c, oligofectamine lipoplexes exhibited partial inhibition of wound closure (61% closure).	('inhibition', 'NegReg', (75, 85))	('miR-200c', 'Gene', (21, 29))	('oligofectamine lipoplexes', 'Var', (31, 56))	('miR-200c', 'Gene', '406985', (21, 29))	('lipoplexes', 'Var', (46, 56))	('oligofectamine', 'Chemical', 'MESH:C484027', (31, 45))
114038	26855082	HuCCT1 cells were transfected with PCX/miR-200c polyplexes as before, and 10% FBS was applied to the lower chamber as the chemoattractant to induce the transwell cell migration.	('PCX', 'Chemical', '-', (35, 38))	('transwell', 'CPA', (152, 161))	('miR-200c', 'Gene', (39, 47))	('polyplexes', 'Var', (48, 58))	('miR-200c', 'Gene', '406985', (39, 47))	('HuCCT1', 'CellLine', 'CVCL:0324', (0, 6))
114071	25034289	Inflammatory cells are associated with oxidative stress which can lead to genetic mutations, produce soluble factors such as vascular endothelial growth factor (VEGF) which can promote angiogenesis, generate cytokines which can aid in evasion of apoptosis and promotion of cell proliferation (Figure 1).	('oxidative stress', 'Phenotype', 'HP:0025464', (39, 55))	('promote', 'PosReg', (177, 184))	('genetic mutations', 'Var', (74, 91))	('VEGF', 'Gene', '7422', (161, 165))	('evasion', 'MPA', (235, 242))	('cell proliferation', 'CPA', (273, 291))	('mutations', 'Var', (82, 91))	('lead', 'Reg', (66, 70))	('aid', 'Reg', (228, 231))	('vascular endothelial growth factor', 'Gene', (125, 159))	('vascular endothelial growth factor', 'Gene', '7422', (125, 159))	('promotion', 'PosReg', (260, 269))	('VEGF', 'Gene', (161, 165))	('angiogenesis', 'CPA', (185, 197))
114085	25034289	The epigenetic alterations in biliary tract cancer have recently been reviewed by Jesper Andersen.	('biliary tract cancer', 'Disease', 'MESH:D001661', (30, 50))	('biliary tract cancer', 'Disease', (30, 50))	('epigenetic alterations', 'Var', (4, 26))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (30, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
114086	25034289	He highlighted that several epigenetic changes occur in cholangiocarcinoma by promoter hypermethylation, a mechanism of gene silencing.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (56, 74))	('cholangiocarcinoma', 'Disease', (56, 74))	('promoter hypermethylation', 'Var', (78, 103))	('epigenetic changes', 'Var', (28, 46))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (56, 74))	('occur', 'Reg', (47, 52))
114090	25034289	Isocitrate dehydrogenase (IDH) 1 and 2 are metabolic enzymes, and mutations in genes encoding IDH1 and IDH2 have been demonstrated in 10-23% of CCA patients in several recent studies.	('mutations', 'Var', (66, 75))	('patients', 'Species', '9606', (148, 156))	('demonstrated', 'Reg', (118, 130))	('IDH1', 'Gene', (94, 98))	('IDH2', 'Gene', '3418', (103, 107))	('IDH1', 'Gene', '3417', (94, 98))	('CCA', 'Phenotype', 'HP:0030153', (144, 147))	('Isocitrate dehydrogenase (IDH) 1 and 2', 'Gene', '3417;3418', (0, 38))	('IDH2', 'Gene', (103, 107))	('CCA', 'Disease', (144, 147))
114091	25034289	IDH1 and IDH2 mutations have been associated with epigenetic changes resulting in hypermethylation of several different genes.	('IDH2', 'Gene', (9, 13))	('epigenetic', 'MPA', (50, 60))	('associated', 'Reg', (34, 44))	('IDH2', 'Gene', '3418', (9, 13))	('hypermethylation', 'MPA', (82, 98))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('IDH1', 'Gene', '3417', (0, 4))
114093	25034289	Mutant IDH1 and IDH2 enzymes result in overproduction of 2-hydroxyglutarate, which has potential as a biomarker for these mutations.	('IDH1', 'Gene', '3417', (7, 11))	('IDH2', 'Gene', (16, 20))	('overproduction', 'PosReg', (39, 53))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (57, 75))	('IDH2', 'Gene', '3418', (16, 20))	('Mutant', 'Var', (0, 6))	('IDH1', 'Gene', (7, 11))
114095	25034289	Specific targeted inhibitors of IDH mutations have been developed and tested in animal models where they promote tumor differentiation and inhibit growth.	('tumor', 'Disease', (113, 118))	('promote', 'PosReg', (105, 112))	('growth', 'CPA', (147, 153))	('inhibit', 'NegReg', (139, 146))	('mutations', 'Var', (36, 45))	('IDH', 'Gene', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('IDH', 'Gene', '3417', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
114101	25034289	Suppressor of cytokine signaling 3 (SOCS3), an endogenous feedback inhibitor of IL6, is epigenetically silenced via methylation of its promoter in CCA.	('IL6', 'Gene', (80, 83))	('silenced', 'NegReg', (103, 111))	('CCA', 'Phenotype', 'HP:0030153', (147, 150))	('SOCS3', 'Gene', (36, 41))	('Suppressor of cytokine signaling 3', 'Gene', (0, 34))	('methylation', 'Var', (116, 127))	('CCA', 'Disease', (147, 150))	('IL6', 'Gene', '3569', (80, 83))	('SOCS3', 'Gene', '9021', (36, 41))	('Suppressor of cytokine signaling 3', 'Gene', '9021', (0, 34))
114105	25034289	Indeed, patients with mutations of the NOTCH endogenous ligand, jagged 1, develop Alagille syndrome.	('Alagille syndrome', 'Disease', 'MESH:D016738', (82, 99))	('develop', 'Reg', (74, 81))	('patients', 'Species', '9606', (8, 16))	('jagged 1', 'Gene', '182', (64, 72))	('mutations', 'Var', (22, 31))	('Alagille syndrome', 'Disease', (82, 99))	('jagged 1', 'Gene', (64, 72))
114107	25034289	We have recently developed an interesting animal model of biliary tract cancer by introducing the oncogenes myristoylated AKT and YapS127A into the biliary epithelium using a transposon system.	('YapS127A', 'Var', (130, 138))	('biliary tract cancer', 'Disease', (58, 78))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (58, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('AKT', 'Gene', '207', (122, 125))	('biliary tract cancer', 'Disease', 'MESH:D001661', (58, 78))	('YapS127A', 'Mutation', 'rs762471803', (130, 138))	('myristoylated', 'Var', (108, 121))	('AKT', 'Gene', (122, 125))
114192	31632502	In MVI positive patients, the 5-year OS and 5-year DFS are 16.65%, 5.12%, compared with 19.39%, 16.62% in the negative group, respectively.	('MVI', 'Disease', 'MESH:D017566', (3, 6))	('MVI', 'Disease', (3, 6))	('patients', 'Species', '9606', (16, 24))	('positive', 'Var', (7, 15))
114229	30572520	Genetic testing of the biopsy revealed the KRAS gene mutation in exon 3, with no mutated NRAS or BRAF gene.	('NRAS', 'Gene', '4893', (89, 93))	('mutation', 'Var', (53, 61))	('KRAS', 'Gene', (43, 47))	('NRAS', 'Gene', (89, 93))	('BRAF', 'Gene', (97, 101))	('KRAS', 'Gene', '3845', (43, 47))	('BRAF', 'Gene', '673', (97, 101))
114255	30572520	Serum marker CA19-9, the most widely used serum marker for ICC, tends to have high specificity and low sensitivity, because it can increase in response to other benign or malignant diseases.	('malignant diseases', 'Disease', 'MESH:D009369', (171, 189))	('increase', 'PosReg', (131, 139))	('malignant diseases', 'Disease', (171, 189))	('CA19-9', 'Var', (13, 19))	('ICC', 'Disease', (59, 62))
114257	30572520	In our case, it was difficult to initially diagnose the ICC before chemotherapy because an increase in CA199 is also very common in colorectal liver metastasis, and CT/MRI showed that the 2 tumors in the liver were similarly shaped.	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('CT/MRI', 'Gene', '78996', (165, 171))	('colorectal liver metastasis', 'Disease', (132, 159))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('CT/MRI', 'Gene', (165, 171))	('increase', 'PosReg', (91, 99))	('colorectal liver metastasis', 'Disease', 'MESH:D009362', (132, 159))	('CA199', 'Var', (103, 108))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
114308	29561438	Meanwhile, 18F-FDG-PET scanning detected an 18F-FDG accumulation in the posterior segment of the liver, which was initially presumed as a traumatic change.	('traumatic', 'Disease', 'MESH:D014947', (138, 147))	('18F-FDG accumulation', 'Var', (44, 64))	('traumatic', 'Disease', (138, 147))
114411	28555163	As shown in the upper panel in Figure 2(b), groups containing 1,2-DCP and DCM were clearly separated on the PCA score plot (PC1 versus PC2), whereas groups in the presence and absence of GSTT1 were not well separated.	('GSTT1', 'Gene', (187, 192))	('PC1', 'Gene', '7163', (124, 127))	('PC1', 'Gene', (124, 127))	('PC2', 'Gene', '8535', (135, 138))	('rat', 'Species', '10116', (211, 214))	('PC2', 'Gene', (135, 138))	('rat', 'Species', '10116', (95, 98))	('DCM', 'Var', (74, 77))	('DCM', 'Chemical', 'MESH:D008752', (74, 77))	('1,2-DCP', 'Chemical', 'MESH:C004765', (62, 69))	('GSTT1', 'Gene', '2952', (187, 192))
114413	28555163	These results suggested that GSTT1-dependent metabolic changes in the DCM group were larger than those observed in the 1,2-DCP group.	('GSTT1', 'Gene', '2952', (29, 34))	('GSTT1', 'Gene', (29, 34))	('metabolic', 'MPA', (45, 54))	('DCM', 'Var', (70, 73))	('DCM', 'Chemical', 'MESH:D008752', (70, 73))	('1,2-DCP', 'Chemical', 'MESH:C004765', (119, 126))	('larger', 'PosReg', (85, 91))
114415	28555163	To select components (peaks) corresponding to GSTT1-dependent metabolites, we further processed the data using differential analysis via the SIEVE 2.1 program according to the following criteria (Figure 2(a)) for the initial selection of all extracted peaks: (1) peaks exhibiting obvious increases in the presence of GSTT1 based on a peak-intensity ratio (GSTT1-present group/GSTT1-absent group) > 10 and (2) peak changes in the presence of GSTT1 and a coefficient of variation (standard deviation/mean) < 30.	('GSTT1', 'Gene', (441, 446))	('GSTT1', 'Gene', '2952', (46, 51))	('GSTT1', 'Gene', '2952', (441, 446))	('GSTT1', 'Gene', '2952', (356, 361))	('GSTT1', 'Gene', (356, 361))	('rat', 'Species', '10116', (349, 352))	('presence', 'Var', (305, 313))	('GSTT1', 'Gene', (317, 322))	('GSTT1', 'Gene', '2952', (317, 322))	('GSTT1', 'Gene', '2952', (376, 381))	('increases', 'PosReg', (288, 297))	('GSTT1', 'Gene', (376, 381))	('GSTT1', 'Gene', (46, 51))
114417	28555163	Our analyses revealed seven components representing significantly increased metabolites in the presence of GSTT1 (Table 1).	('increased', 'PosReg', (66, 75))	('metabolites', 'MPA', (76, 87))	('presence', 'Var', (95, 103))	('GSTT1', 'Gene', '2952', (107, 112))	('GSTT1', 'Gene', (107, 112))
114418	28555163	Because differential analysis revealed that two and five components increased in the presence of GSTT1 in the 1,2-DCP and DCM groups, respectively (Table 1), we investigated all seven components by analyzing each mass chromatogram using the Qualbrowser program to screen for differential peaks.	('DCM', 'Chemical', 'MESH:D008752', (122, 125))	('1,2-DCP', 'Chemical', 'MESH:C004765', (110, 117))	('GSTT1', 'Gene', (97, 102))	('presence', 'Var', (85, 93))	('increased', 'PosReg', (68, 77))	('GSTT1', 'Gene', '2952', (97, 102))
114420	28555163	Semiquantitative analyses indicated that #P1 levels in the presence of GSTT1 were slightly higher than those of the control (Figure 3(a)) and that #P2 levels did not differ significantly from those of the control (Figure 3(b)).	('GSTT1', 'Gene', (71, 76))	('#P1', 'Gene', (41, 44))	('higher', 'PosReg', (91, 97))	('GSTT1', 'Gene', '2952', (71, 76))	('#P1', 'Gene', '8706', (41, 44))	('presence', 'Var', (59, 67))
114424	28555163	Elemental analyses based on the obtained accurate mass suggested that the composition formulae for #M1 and #M3 were C11H17O6N3S and C11H19O6N3S, respectively (Table 1), which are similar to that of GSH (C10H17O6N3S).	('C10H17O6N3S', 'Chemical', '-', (203, 214))	('C11H17O6N3S', 'Chemical', '-', (116, 127))	('C11H19O6N3S', 'Chemical', '-', (132, 143))	('GSH', 'Chemical', '-', (198, 201))	('C11H19O6N3S', 'Var', (132, 143))	('C11H17O6N3S', 'Var', (116, 127))	('rat', 'Species', '10116', (45, 48))
114426	28555163	Moreover, #M1 and #M3 levels in the presence of GSTT1 were higher than those observed in the control (Figures 3(c) and 3(d)).	('presence', 'Var', (36, 44))	('GSTT1', 'Gene', '2952', (48, 53))	('#M1', 'MPA', (10, 13))	('GSTT1', 'Gene', (48, 53))	('higher', 'PosReg', (59, 65))
114427	28555163	Additionally, similar analysis revealed that #M4 and #M5 were also more abundant in the presence of GSTT1 than their levels observed in the control (data not shown), although it was difficult to interpret whether #M4 and #M5 were GSH-conjugated forms based on the low degree of similarity between the formula for GSH and those of the putative GSH-conjugates (Table 1).	('#M4', 'Var', (213, 216))	('GSH', 'Chemical', '-', (230, 233))	('GSH', 'Chemical', '-', (313, 316))	('presence', 'Var', (88, 96))	('GSTT1', 'Gene', '2952', (100, 105))	('GSH', 'Chemical', '-', (343, 346))	('GSTT1', 'Gene', (100, 105))
114428	28555163	Although we were unable to identify the chemical structures of #M1 and #M3, they might constitute novel DCM metabolites, given that their formulae have not been reported to the best of our knowledge in the GST-mediated metabolic pathway of DCM.	('DCM', 'Chemical', 'MESH:D008752', (240, 243))	('#M3', 'Var', (71, 74))	('DCM', 'Chemical', 'MESH:D008752', (104, 107))	('#M1', 'Var', (63, 66))
114451	28555163	Although 1,2-DCP and DCM are both dihaloalkanes, the latent molecular basis for cholangiocarcinogenesis may differ between these two chemicals.	('DCM', 'Chemical', 'MESH:D008752', (21, 24))	('dihaloalkanes', 'Chemical', '-', (34, 47))	('cholangiocarcinogenesis', 'Disease', (80, 103))	('1,2-DCP', 'Chemical', 'MESH:C004765', (9, 16))	('cholangiocarcinogenesis', 'Disease', 'None', (80, 103))	('DCM', 'Var', (21, 24))
114502	31992208	All Stage IV patients had M0 status, 10 patients had TxN1M0 (IVA) intrahepatic bile duct cancer, and 3 patients had TxN2M0 (IVB) GB cancer.	('bile duct cancer', 'Phenotype', 'HP:0030153', (79, 95))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('patients', 'Species', '9606', (40, 48))	('IVA', 'Disease', 'MESH:C538167', (61, 64))	('patients', 'Species', '9606', (13, 21))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('intrahepatic bile duct cancer', 'Disease', (66, 95))	('cancer', 'Disease', (89, 95))	('patients', 'Species', '9606', (103, 111))	('intrahepatic bile duct cancer', 'Disease', 'MESH:D001650', (66, 95))	('IVA', 'Disease', (61, 64))	('TxN1M0', 'Var', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
114684	26051390	The failure to repair 8-oxodeoxyguanine is mutagenic and fosters cancer development and progression.	('progression', 'CPA', (88, 99))	('fosters', 'PosReg', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('failure', 'Var', (4, 11))	('cancer', 'Disease', (65, 71))	('8-oxodeoxyguanine', 'Chemical', '-', (22, 39))
114711	26051390	Imaging plays a central role in the detection of CCA and abnormalities seen on imaging often trigger additional investigations aimed at establishing a diagnosis of biliary cancer.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('CCA', 'Phenotype', 'HP:0030153', (49, 52))	('biliary cancer', 'Disease', (164, 178))	('biliary cancer', 'Disease', 'MESH:D001661', (164, 178))	('abnormalities', 'Var', (57, 70))	('trigger', 'Reg', (93, 100))	('CCA', 'Disease', (49, 52))
114745	26051390	FISH polysomy indicating duplication of more than one chromosome is a marker for chromosomal instability, a hallmark of cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('chromosomal instability', 'Phenotype', 'HP:0040012', (81, 104))	('chromosomal instability', 'Disease', (81, 104))	('hallmark of cancer', 'Disease', (108, 126))	('hallmark of cancer', 'Disease', 'MESH:D009369', (108, 126))	('polysomy', 'Var', (5, 13))
114746	26051390	A meta-analysis examined the performance of FISH testing among 690 PSC patients and the pooled sensitivity, specificity, positive and negative likelihood ratio for polysomy and CCA was 51%, 93%, 6.8 and 0.6, respectively.	('polysomy', 'Var', (164, 172))	('CCA', 'Disease', (177, 180))	('patients', 'Species', '9606', (71, 79))	('PSC', 'Gene', '100653366', (67, 70))	('CCA', 'Phenotype', 'HP:0030153', (177, 180))	('PSC', 'Gene', (67, 70))
114748	26051390	Polysomy in the presence of a dominant stricture may increase the probability of cancer.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('Polysomy', 'Var', (0, 8))	('increase', 'PosReg', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
114752	26051390	For example, among PSC patients (without a mass lesion at baseline) suspected of CCA with equivocal cytology (atypical or suspicious) and polysomy, 100% of patients with a CA 19-9 >=129 U/mL compared to 24% of subjects with a CA 19-9 < 129 U/mL were diagnosed with CCA within 3 years.	('patients', 'Species', '9606', (156, 164))	('PSC', 'Gene', (19, 22))	('CA 19-9 >=129 U/mL', 'Var', (172, 190))	('patients', 'Species', '9606', (23, 31))	('CCA', 'Disease', (81, 84))	('CCA', 'Phenotype', 'HP:0030153', (265, 268))	('CA 19-9', 'Chemical', 'MESH:C086528', (226, 233))	('CA 19-9', 'Chemical', 'MESH:C086528', (172, 179))	('PSC', 'Gene', '100653366', (19, 22))	('CCA', 'Phenotype', 'HP:0030153', (81, 84))	('CCA', 'Disease', (265, 268))
114753	26051390	In a separate study, 71% of patients with polysomy (regardless of cytology) and a CA 19-9 >=129 U/mL who lacked a mass lesion on imaging were diagnosed with CCA compared to 37% of individuals with a CA 19-9 < 129 U/mL.	('CCA', 'Phenotype', 'HP:0030153', (157, 160))	('polysomy', 'Var', (42, 50))	('CA 19-9', 'Chemical', 'MESH:C086528', (82, 89))	('diagnosed', 'Reg', (142, 151))	('CA 19-9', 'Chemical', 'MESH:C086528', (199, 206))	('CCA', 'Disease', (157, 160))	('patients', 'Species', '9606', (28, 36))
114755	26051390	However, given the high proportion of individuals with an elevated CA 19-9 and polysomy who were diagnosed with cancer, an increased CA 19-9 should raise concern.	('CA 19-9', 'Chemical', 'MESH:C086528', (67, 74))	('polysomy', 'Var', (79, 87))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('CA 19-9', 'Chemical', 'MESH:C086528', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
114760	26051390	Among those with polysomy and a positive cytology, 71% had polysomy detected at another region of the biliary tree where adenocarcinoma was not detected by routine cytology.	('polysomy', 'Var', (59, 67))	('adenocarcinoma', 'Disease', (121, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('adenocarcinoma', 'Disease', 'MESH:D000230', (121, 135))	('polysomy', 'Var', (17, 25))
114776	26051390	The presence of FISH polysomy in the absence of other diagnostic features of CCA (cross-sectional imaging with mass or dominant stricture +/- positive cytology) may indicate underlying high-grade dysplasia.	('dysplasia', 'Disease', (196, 205))	('dysplasia', 'Disease', 'MESH:D004476', (196, 205))	('CCA', 'Disease', (77, 80))	('FISH polysomy', 'Var', (16, 29))	('CCA', 'Phenotype', 'HP:0030153', (77, 80))
114793	26051390	Compared to non-neoplastic tissue, tumor cells often have a higher proportion of aberrant DNA methylation which can in turn serve a useful biomarker for cancer detection.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (16, 33))	('aberrant DNA methylation', 'Var', (81, 105))	('tumor', 'Disease', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))
114828	26051390	Genetic analysis of a tumor can identify potentially actionable events such as mutations which may be candidates for targeted therapy.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutations', 'Var', (79, 88))
114829	26051390	For instance, patients with fibroblast growth factor receptor 2 (FGFR2) gene fusions had stable disease with ponatinib, an FGFR inhibitor.	('FGFR2', 'Gene', (65, 70))	('FGFR2', 'Gene', '2263', (65, 70))	('fibroblast growth factor receptor 2', 'Gene', (28, 63))	('gene fusions', 'Var', (72, 84))	('ponatinib', 'Chemical', 'MESH:C545373', (109, 118))	('fibroblast growth factor receptor 2', 'Gene', '2263', (28, 63))	('patients', 'Species', '9606', (14, 22))
114830	26051390	However, FGFR2 gene fusions and other mutations such as isocitrate dehydrogenase 1 and 2 mutations tend to occur more frequently in intrahepatic CCA then pCCA.	('pCCA', 'Disease', (154, 158))	('CCA', 'Phenotype', 'HP:0030153', (155, 158))	('occur', 'Reg', (107, 112))	('CCA', 'Phenotype', 'HP:0030153', (145, 148))	('FGFR2', 'Gene', (9, 14))	('FGFR2', 'Gene', '2263', (9, 14))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (132, 148))	('mutations', 'Var', (89, 98))	('intrahepatic CCA', 'Disease', (132, 148))	('fusions', 'Var', (20, 27))
114838	26051390	Although significant progress has been made in recognizing oncogenic pathways and mutational changes in CCA, such studies focusing on CCA in PSC remain to be performed.	('CCA', 'Disease', (104, 107))	('CCA', 'Phenotype', 'HP:0030153', (134, 137))	('PSC', 'Gene', '100653366', (141, 144))	('CCA', 'Phenotype', 'HP:0030153', (104, 107))	('PSC', 'Gene', (141, 144))	('oncogenic pathways', 'CPA', (59, 77))	('mutational changes', 'Var', (82, 100))
114855	18723481	Overexpression of Mcl-1, a potent antiapoptotic member of the Bcl-2 family plays a prominent role in apoptosis resistance upon Apo2L/TRAIL treatment in cholangiocarcinoma cells, as indicated by the observation that targeted knockdown of Mcl-1 by siRNA, cyclin dependent kinase inhibition, or anti-Mcl-1 microRNA silencing restores Apo2L/TRAIL sensitivity.	('Bcl-2', 'Gene', (62, 67))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (152, 170))	('Apo2L', 'Gene', (127, 132))	('TRAIL ', 'Gene', (337, 343))	('Bcl-2', 'Gene', '596', (62, 67))	('Apo2L', 'Gene', '8743', (331, 336))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (152, 170))	('restores', 'PosReg', (322, 330))	('TRAIL ', 'Gene', '8743', (133, 139))	('Apo2L', 'Gene', (331, 336))	('Mcl-1', 'Gene', (237, 242))	('TRAIL ', 'Gene', '8743', (337, 343))	('cholangiocarcinoma', 'Disease', (152, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('knockdown', 'Var', (224, 233))	('TRAIL ', 'Gene', (133, 139))	('Apo2L', 'Gene', '8743', (127, 132))
114878	18723481	KMCH cells stably transfected with S-peptide tagged Mcl-1 were cultured in DMEM supplemented with 10% fetal bovine serum, 100 units/mL penicillin, 100 mug/mL streptomycin, 100 mug/mL gentamicin, and 1200 mug/mL G418.	('G418', 'Var', (211, 215))	('S-peptide tagged', 'Var', (35, 51))	('gentamicin', 'Chemical', 'MESH:D005839', (183, 193))	('Mcl-1', 'Gene', (52, 57))	('bovine', 'Species', '9913', (108, 114))	('G418', 'Chemical', 'MESH:C010680', (211, 215))	('DMEM', 'Chemical', '-', (75, 79))	('penicillin', 'Chemical', 'MESH:D010406', (135, 145))	('streptomycin', 'Chemical', 'MESH:D013307', (158, 170))
114885	18723481	Our previous investigations suggested that Noxa binds much more strongly to S64E Mcl-1 than the unphosphorylatable S64A protein.	('S64E', 'Var', (76, 80))	('Noxa', 'Gene', '5366', (43, 47))	('binds', 'Interaction', (48, 53))	('Noxa', 'Gene', (43, 47))	('S64A', 'Mutation', 'p.S64A', (115, 119))	('S64E', 'Mutation', 'p.S64E', (76, 80))
114898	18723481	After permeabilization with 0.0125% (w/v) CHAPS in PBS and blocking of nonspecific protein binding with 5% normal goat serum (Sigma, St Louis, MO, USA) in PBS containing 5% glycerol and 0.04% sodium azide, cells were incubated overnight at 4 C with antibodies specific for activated Bax (6A7, Exalpha, Maynard, MA) or activated Bak (Bak-NT, Upstate) diluted 1:250 in blocking buffer.	('goat', 'Species', '9925', (114, 118))	('PBS', 'Disease', (155, 158))	('PBS', 'Disease', 'MESH:D011535', (155, 158))	('CHAPS', 'Chemical', 'MESH:C028213', (42, 47))	('glycerol', 'Chemical', 'MESH:D005990', (173, 181))	('Bax', 'Gene', (283, 286))	('Bak-NT', 'Gene', (333, 339))	('Bak', 'Gene', (333, 336))	('Bak', 'Gene', (328, 331))	('0.0125', 'Var', (28, 34))	('Bak', 'Gene', '578', (333, 336))	('Bak', 'Gene', '578', (328, 331))	('sodium azide', 'Chemical', 'MESH:D019810', (192, 204))	('Bak-NT', 'Gene', '578', (333, 339))	('Bax', 'Gene', '581', (283, 286))	('PBS', 'Disease', 'MESH:D011535', (51, 54))	('PBS', 'Disease', (51, 54))
114915	18723481	In untreated KMCH cells, pulldown of S-peptide tagged Mcl-1 co-precipitated Bak (Figure 2B).	('S-peptide tagged', 'Var', (37, 53))	('Mcl-1', 'Gene', (54, 59))	('Bak', 'Gene', (76, 79))	('Bak', 'Gene', '578', (76, 79))	('pulldown', 'Var', (25, 33))
114916	18723481	In cells treated with obatoclax, reduced amounts of Bak were found associated with S-peptide tagged Mcl-1.	('Bak', 'Gene', (52, 55))	('S-peptide tagged', 'Var', (83, 99))	('obatoclax', 'Chemical', 'MESH:C520962', (22, 31))	('Bak', 'Gene', '578', (52, 55))
114925	18723481	We then tested a phosphomimetic Mcl-1 protein (serine 64 replaced by glutamic acid, S64E) previously shown to bind to Noxa.	('Noxa', 'Gene', '5366', (118, 122))	('S64E', 'Mutation', 'p.S64E', (84, 88))	('Noxa', 'Gene', (118, 122))	('serine 64 replaced by glutamic acid', 'Mutation', 'p.S64E', (47, 82))	('S64E', 'Var', (84, 88))	('bind', 'Interaction', (110, 114))
114965	18723481	These observations are consistent with the report that Bak mutants which do not bind Mcl-1 are not spontaneously lethal, but still require further activation to induce cell death.	('Bak', 'Gene', (55, 58))	('mutants', 'Var', (59, 66))	('Bak', 'Gene', '578', (55, 58))
114970	18723481	Interestingly, in addition to siRNA against Bim, the JNK pathway inhibitor SP600125 also prevented Apo2L/TRAIL killing.	('Bim', 'Gene', '10018', (44, 47))	('TRAIL ', 'Gene', '8743', (105, 111))	('prevented', 'NegReg', (89, 98))	('JNK', 'Gene', (53, 56))	('SP600125', 'Chemical', 'MESH:C432165', (75, 83))	('TRAIL ', 'Gene', (105, 111))	('SP600125', 'Var', (75, 83))	('JNK', 'Gene', '5599', (53, 56))	('Apo2L', 'Gene', '8743', (99, 104))	('Apo2L', 'Gene', (99, 104))	('Bim', 'Gene', (44, 47))
115024	32987945	Numerous mutations in genes encoding Ca2+-signaling proteins have been identified in DNA extracted from HCC liver tissue, and a number of Ca2+-signaling proteins are over or under expressed in HCC.	('HCC', 'Phenotype', 'HP:0001402', (104, 107))	('HCC', 'Phenotype', 'HP:0001402', (193, 196))	('Ca2+-', 'Chemical', 'MESH:D000069285', (138, 143))	('mutations', 'Var', (9, 18))	('over', 'PosReg', (166, 170))	('Ca2+-', 'Chemical', 'MESH:D000069285', (37, 42))	('under', 'NegReg', (174, 179))
115060	32987945	Together with other signaling pathways, changes in intracellular Ca2+ can switch cell signaling from proliferation to apoptosis and cell death.	('switch', 'Reg', (74, 80))	('rat', 'Species', '10116', (108, 111))	('cell signaling', 'MPA', (81, 95))	('changes', 'Var', (40, 47))	('Ca2+', 'Chemical', 'MESH:D000069285', (65, 69))
115089	32987945	HCC is one of two main primary liver cancers (i.e., cancers that originate from mutations in hepatocytes or other cell types in the liver) and accounts for about 80% of all liver cancers.	('cancers', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('HCC', 'Disease', (0, 3))	('liver cancer', 'Phenotype', 'HP:0002896', (173, 185))	('HCC', 'Phenotype', 'HP:0001402', (0, 3))	('liver cancers', 'Disease', (173, 186))	('mutations', 'Var', (80, 89))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('primary liver cancers', 'Disease', 'MESH:D006528', (23, 44))	('liver cancers', 'Disease', 'MESH:D006528', (31, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('liver cancers', 'Disease', 'MESH:D006528', (173, 186))	('liver cancer', 'Phenotype', 'HP:0002896', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('liver cancers', 'Phenotype', 'HP:0002896', (31, 44))	('cancers', 'Disease', (37, 44))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('liver cancers', 'Phenotype', 'HP:0002896', (173, 186))	('cancers', 'Disease', (179, 186))	('primary liver cancers', 'Disease', (23, 44))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
115103	32987945	Mutated genes which feature in many HCCs include those encoding proteins which regulate the Wnt/beta-catenin pathway, the p53 cell cycle pathway, telomere maintenance and chromatin structure and function.	('beta-catenin', 'Gene', '1499', (96, 108))	('p53', 'Gene', '7157', (122, 125))	('HCC', 'Phenotype', 'HP:0001402', (36, 39))	('regulate', 'Reg', (79, 87))	('beta-catenin', 'Gene', (96, 108))	('Mutated', 'Var', (0, 7))	('p53', 'Gene', (122, 125))
115126	32987945	Under conditions which foster the initiation and promotion of HCC (chronic inflammation, HBV, HCV, alcohol, non-alcoholic fatty liver disease), liver cancer stem cells can undergo further genetic and epigenetic changes leading to HCC cells and HCC or intrahepatic cholangiocarcinoma.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (251, 282))	('intrahepatic cholangiocarcinoma', 'Disease', (251, 282))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (264, 282))	('HCC', 'Phenotype', 'HP:0001402', (62, 65))	('HCC', 'Phenotype', 'HP:0001402', (230, 233))	('HCC cells', 'Disease', (230, 239))	('fatty liver', 'Phenotype', 'HP:0001397', (122, 133))	('inflammation', 'Disease', 'MESH:D007249', (75, 87))	('HCC', 'Disease', (244, 247))	('HCC', 'Phenotype', 'HP:0001402', (244, 247))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('alcoholic fatty liver disease', 'Disease', (112, 141))	('liver cancer', 'Disease', 'MESH:D006528', (144, 156))	('leading to', 'Reg', (219, 229))	('inflammation', 'Disease', (75, 87))	('liver cancer', 'Phenotype', 'HP:0002896', (144, 156))	('liver disease', 'Phenotype', 'HP:0001392', (128, 141))	('alcoholic fatty liver disease', 'Disease', 'MESH:D005234', (112, 141))	('liver cancer', 'Disease', (144, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('epigenetic changes', 'Var', (200, 218))	('alcoholic fatty liver', 'Phenotype', 'HP:0006573', (112, 133))
115142	32987945	These show that mutations and altered gene expression have been detected in a wide range of Ca2+ channels, transporters and Ca2+-binding proteins.	('Ca2+ channels', 'MPA', (92, 105))	('Ca2+', 'Chemical', 'MESH:D000069285', (124, 128))	('mutations', 'Var', (16, 25))	('Ca2+-', 'Chemical', 'MESH:D000069285', (124, 129))	('Ca2+', 'Chemical', 'MESH:D000069285', (92, 96))
115143	32987945	Moreover, comparison of the genes listed in Table 3 and Table 4 with the Ca2+-signaling proteins listed in Table 1 as potential targets for treatment of HCC indicates that many potential Ca2+-signaling targets are also mutated or under- or overexpressed in HCC.	('under-', 'NegReg', (230, 236))	('men', 'Species', '9606', (145, 148))	('overexpressed', 'PosReg', (240, 253))	('HCC', 'Phenotype', 'HP:0001402', (153, 156))	('Ca2+-', 'Chemical', 'MESH:D000069285', (73, 78))	('Ca2+-', 'Chemical', 'MESH:D000069285', (187, 192))	('HCC', 'Phenotype', 'HP:0001402', (257, 260))	('mutated', 'Var', (219, 226))
115145	32987945	Consequently, it is likely that the observed mutations and alterations in gene expression relate to DNA derived from HCC cells.	('mutations', 'Var', (45, 54))	('HCC', 'Phenotype', 'HP:0001402', (117, 120))	('gene expression', 'MPA', (74, 89))	('rat', 'Species', '10116', (63, 66))	('alterations', 'Reg', (59, 70))
115156	32987945	In Hep-12 cells, inhibition of alpha2delta1 by antibody IB50-1 or knockdown of alpha2delta1 using shRNA induced apoptosis by a mechanism involving decreased phosphorylation of ERK1/2, decreased Bcl2, increased Bax and Bad and activation of caspases 3,8 and 9 (pathway scheme shown in Figure 3).	('Hep-12', 'CellLine', 'CVCL:1906', (3, 9))	('apoptosis', 'CPA', (112, 121))	('Bcl2', 'Gene', '596', (194, 198))	('ERK1/2', 'Gene', (176, 182))	('activation', 'PosReg', (226, 236))	('Bax', 'Gene', '581', (210, 213))	('decreased', 'NegReg', (147, 156))	('increased', 'PosReg', (200, 209))	('phosphorylation', 'MPA', (157, 172))	('inhibition', 'Var', (17, 27))	('ERK1/2', 'Gene', '5595;5594', (176, 182))	('decreased', 'NegReg', (184, 193))	('Bax', 'Gene', (210, 213))	('Bcl2', 'Gene', (194, 198))	('knockdown', 'Var', (66, 75))	('caspases 3,8 and 9', 'Gene', '836;841;842', (240, 258))
115168	32987945	Inhibition of voltage-operated Ca2+ channels and/or InsP3R2 may provide a strategy to inhibit the pathologic roles of these cells.	('rat', 'Species', '10116', (76, 79))	('InsP3R2', 'Gene', (52, 59))	('Ca2+', 'Chemical', 'MESH:D000069285', (31, 35))	('Inhibition', 'Var', (0, 10))	('rat', 'Species', '10116', (25, 28))
115203	32987945	Inhibition of store-operated Ca2+ entry with SKF-96365 in HCC-LM3 cells or knockdown of STIM1 with siRNA decreased migration and invasion, assayed in vitro.	('rat', 'Species', '10116', (118, 121))	('STIM1', 'Gene', (88, 93))	('rat', 'Species', '10116', (23, 26))	('HCC-LM3', 'CellLine', 'CVCL:E956', (58, 65))	('knockdown', 'Var', (75, 84))	('SKF-96365', 'Var', (45, 54))	('Ca2+', 'Chemical', 'MESH:D000069285', (29, 33))	('HCC', 'Phenotype', 'HP:0001402', (58, 61))	('store-operated Ca2+ entry', 'MPA', (14, 39))	('decreased', 'NegReg', (105, 114))	('SKF-96365', 'Chemical', 'MESH:C063159', (45, 54))
115204	32987945	It was concluded that inhibition of store-operated Ca2+ entry is a potential strategy to inhibit HCC migration and invasion.	('inhibition', 'Var', (22, 32))	('HCC', 'Phenotype', 'HP:0001402', (97, 100))	('store-operated Ca2+ entry', 'MPA', (36, 61))	('Ca2+', 'Chemical', 'MESH:D000069285', (51, 55))	('HCC migration', 'CPA', (97, 110))	('rat', 'Species', '10116', (45, 48))	('inhibit', 'NegReg', (89, 96))	('rat', 'Species', '10116', (79, 82))	('invasion', 'CPA', (115, 123))	('rat', 'Species', '10116', (104, 107))
115225	32987945	Experiments employing HepG2 cells provided evidence that 5-flurouracil induces autophagic cell death by inhibiting the PI3K/Akt/mTOR pathway.	('mTOR', 'Gene', (128, 132))	('mTOR', 'Gene', '2475', (128, 132))	('HepG2', 'CellLine', 'CVCL:0027', (22, 27))	('autophagic cell death', 'CPA', (79, 100))	('5-flurouracil', 'Chemical', '-', (57, 70))	('5-flurouracil', 'Var', (57, 70))	('inhibiting', 'NegReg', (104, 114))	('men', 'Species', '9606', (6, 9))
115229	32987945	It was concluded that inhibition of Orai1, coincident with treatment with 5-fluorouracil, may enhance the sensitivity of HCC cells to the drug.	('inhibition', 'Var', (22, 32))	('sensitivity', 'MPA', (106, 117))	('HCC', 'Phenotype', 'HP:0001402', (121, 124))	('Orai1', 'Gene', (36, 41))	('enhance', 'PosReg', (94, 101))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (74, 88))	('Orai1', 'Gene', '84876', (36, 41))	('men', 'Species', '9606', (64, 67))
115235	32987945	Overexpression of TRPC6 was found to enhance cell proliferation and store-operated Ca2+ entry (measured using Fura-2 and a "Ca2+ add back" protocol) while TRPC6 knockdown inhibited cell proliferation and reduced store-operated Ca2+ entry.	('add back', 'Phenotype', 'HP:0002808', (129, 137))	('Ca2+', 'Chemical', 'MESH:D000069285', (227, 231))	('Ca2+', 'Chemical', 'MESH:D000069285', (83, 87))	('inhibited', 'NegReg', (171, 180))	('rat', 'Species', '10116', (57, 60))	('Overexpression', 'Var', (0, 14))	('rat', 'Species', '10116', (221, 224))	('rat', 'Species', '10116', (77, 80))	('store-operated Ca2+ entry', 'MPA', (212, 237))	('knockdown', 'Var', (161, 170))	('enhance', 'PosReg', (37, 44))	('cell proliferation', 'CPA', (181, 199))	('store-operated Ca2+ entry', 'MPA', (68, 93))	('rat', 'Species', '10116', (193, 196))	('TRPC6', 'Gene', (155, 160))	('Ca2+', 'Chemical', 'MESH:D000069285', (124, 128))	('cell proliferation', 'CPA', (45, 63))	('Fura-2', 'Chemical', 'MESH:D016257', (110, 116))	('reduced', 'NegReg', (204, 211))	('TRPC6', 'Gene', (18, 23))
115236	32987945	Knockdown of STIM and Orai also reduced store-operated Ca2+ entry.	('Knockdown', 'Var', (0, 9))	('store-operated Ca2+ entry', 'MPA', (40, 65))	('STIM', 'Gene', (13, 17))	('reduced', 'NegReg', (32, 39))	('Ca2+', 'Chemical', 'MESH:D000069285', (55, 59))	('rat', 'Species', '10116', (49, 52))
115251	32987945	Inhibition of TRPV4 has also been shown to reduce liver fibrosis, a risk factor for HCC.	('reduce', 'NegReg', (43, 49))	('liver fibrosis', 'Disease', (50, 64))	('HCC', 'Phenotype', 'HP:0001402', (84, 87))	('liver fibrosis', 'Disease', 'MESH:D008103', (50, 64))	('TRPV4', 'Protein', (14, 19))	('Inhibition', 'Var', (0, 10))	('liver fibrosis', 'Phenotype', 'HP:0001395', (50, 64))	('reduce liver fibrosis', 'Phenotype', 'HP:0001410', (43, 64))
115252	32987945	Using a mouse model of CCl4-induced liver fibrosis, Fu and colleagues employed the TRPV4 agonist GSK1016790A and inhibitor HC-067,047 in order to activate and inhibit, respectively, TRPV4.	('HC-067,047', 'Disease', 'MESH:D006470', (123, 133))	('liver fibrosis', 'Disease', (36, 50))	('GSK1016790A', 'Var', (97, 108))	('CCl4', 'Chemical', 'MESH:D002251', (23, 27))	('liver fibrosis', 'Disease', 'MESH:D008103', (36, 50))	('GSK1016790A', 'Chemical', 'MESH:C530602', (97, 108))	('activate', 'PosReg', (146, 154))	('TRPV4', 'Protein', (182, 187))	('liver fibrosis', 'Phenotype', 'HP:0001395', (36, 50))	('mouse', 'Species', '10090', (8, 13))	('inhibit', 'NegReg', (159, 166))	('TRPV4', 'Gene', (83, 88))
115254	32987945	Pharmacological activation of TRPV1 provides a potential avenue for killing HCC cells, as suggested for some other cancers.	('HCC', 'Disease', (76, 79))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('activation', 'PosReg', (16, 26))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('HCC', 'Phenotype', 'HP:0001402', (76, 79))	('cancers', 'Disease', (115, 122))	('TRPV1', 'Gene', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Pharmacological', 'Var', (0, 15))
115265	32987945	Knockout of TRPV1 promoted tumorigenesis and noticeably altered liver histology, while administration of capsaicin to mice inhibited tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (27, 32))	('TRPV1', 'Gene', (12, 17))	('rat', 'Species', '10116', (95, 98))	('liver histology', 'MPA', (64, 79))	('altered', 'Reg', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('promoted', 'PosReg', (18, 26))	('Knockout', 'Var', (0, 8))	('tumor', 'Disease', (133, 138))	('mice', 'Species', '10090', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('capsaicin', 'Chemical', 'MESH:D002211', (105, 114))
115271	32987945	CRISPR/Cas9 was used to delete InsP3R3 from HepG2 cells, and these were then used to grow tumors in a nude mouse xenograft model.	('InsP3R3', 'Gene', (31, 38))	('mouse', 'Species', '10090', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('HepG2', 'CellLine', 'CVCL:0027', (44, 49))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('delete', 'Var', (24, 30))
115272	32987945	Tumors derived from InsP3R3 KO HepG2 cells grew less than those derived from WT HepG2 cells.	('HepG2', 'CellLine', 'CVCL:0027', (80, 85))	('InsP3R3 KO', 'Var', (20, 30))	('grew', 'CPA', (43, 47))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('less', 'NegReg', (48, 52))	('HepG2', 'CellLine', 'CVCL:0027', (31, 36))
115276	32987945	Deletion of InsP3R3 from cholangiocarcinoma cell lines decreased proliferation and migration.	('proliferation', 'CPA', (65, 78))	('rat', 'Species', '10116', (72, 75))	('cholangiocarcinoma', 'Disease', (25, 43))	('decreased', 'NegReg', (55, 64))	('InsP3R3', 'Gene', (12, 19))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (25, 43))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (25, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('rat', 'Species', '10116', (86, 89))	('migration', 'CPA', (83, 92))	('Deletion', 'Var', (0, 8))
115278	32987945	Increased expression of InsP3R3 induced an increase in [Ca2+]MT while deletion of InsP3R3 impaired the increase in [Ca2+]MT and caused cell death.	('impaired', 'NegReg', (90, 98))	('deletion', 'Var', (70, 78))	('InsP3R3', 'Gene', (24, 31))	('[Ca2+]MT', 'MPA', (55, 63))	('caused', 'Reg', (128, 134))	('Ca2+', 'Chemical', 'MESH:D000069285', (56, 60))	('Increased', 'PosReg', (0, 9))	('increase', 'PosReg', (43, 51))	('InsP3R3', 'Gene', (82, 89))	('Ca2+', 'Chemical', 'MESH:D000069285', (116, 120))
115294	32987945	In a mouse xenograft HCC model, tumors arising from the implantation of HCC cells expressing high levels of mitochondrial Ca2+ uniporter regulator 1 exhibited enhanced growth compared with that of tumors derived for HCC cells exhibiting low mitochondrial Ca2+ uniporter regulator 1 expression.	('enhanced', 'PosReg', (159, 167))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mitochondrial Ca2+ uniporter regulator 1', 'Gene', (108, 148))	('tumors', 'Disease', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('HCC', 'Phenotype', 'HP:0001402', (72, 75))	('mitochondrial Ca2+ uniporter regulator 1', 'Gene', (241, 281))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('HCC', 'Phenotype', 'HP:0001402', (21, 24))	('mouse', 'Species', '10090', (5, 10))	('tumors', 'Disease', (197, 203))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('high levels', 'Var', (93, 104))	('growth', 'MPA', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('mitochondrial Ca2+ uniporter regulator 1', 'Gene', '63933', (108, 148))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('mitochondrial Ca2+ uniporter regulator 1', 'Gene', '63933', (241, 281))	('HCC', 'Phenotype', 'HP:0001402', (216, 219))
115303	32987945	Experiments with HepG2 HCC cells using the PI3kinase inhibitor LY294002 showed that inhibition of PI3kinase decreased the mitochondrial membrane potential and increased [Ca2+]MT (measured using Rhodamine 2).	('PI3kinase', 'Gene', (98, 107))	('increased', 'PosReg', (159, 168))	('Rhodamine 2', 'Chemical', '-', (194, 205))	('HCC', 'Phenotype', 'HP:0001402', (23, 26))	('decreased', 'NegReg', (108, 117))	('LY294002', 'Chemical', 'MESH:C085911', (63, 71))	('HepG2 HCC', 'CellLine', 'CVCL:0027', (17, 26))	('Ca2+', 'Chemical', 'MESH:D000069285', (170, 174))	('[Ca2+]MT', 'MPA', (169, 177))	('inhibition', 'Var', (84, 94))	('mitochondrial membrane potential', 'MPA', (122, 154))	('men', 'Species', '9606', (6, 9))
115306	32987945	Further, erinacine increased apoptosis, as indicted by increased Bax and caspase-9.	('apoptosis', 'CPA', (29, 38))	('caspase-9', 'Gene', (73, 82))	('Bax', 'Gene', '581', (65, 68))	('increased', 'PosReg', (55, 64))	('caspase-9', 'Gene', '842', (73, 82))	('erinacine', 'Chemical', 'MESH:C000608927', (9, 18))	('erinacine', 'Var', (9, 18))	('Bax', 'Gene', (65, 68))
115307	32987945	Erinacine also enhanced the action of LY294002 on these pathways.	('LY294002', 'Var', (38, 46))	('action', 'MPA', (28, 34))	('LY294002', 'Chemical', 'MESH:C085911', (38, 46))	('enhanced', 'PosReg', (15, 23))	('Erinacine', 'Chemical', 'MESH:C000608927', (0, 9))
115315	32987945	Overexpression of mitofusin-2 in HepG2 HCC cells induced apoptosis and this was blocked by the combination of Ru360, an inhibitor of mitochondrial Ca2+ uptake and heparin, an inhibitor of InsP3-induced ER Ca2+ release.	('Ru360', 'Var', (110, 115))	('apoptosis', 'CPA', (57, 66))	('Ru360', 'Chemical', 'MESH:C112020', (110, 115))	('mitofusin-2', 'Gene', '9927', (18, 29))	('Ca2+', 'Chemical', 'MESH:D000069285', (205, 209))	('HCC', 'Phenotype', 'HP:0001402', (39, 42))	('mitofusin-2', 'Gene', (18, 29))	('heparin', 'Chemical', 'MESH:D006493', (163, 170))	('HepG2 HCC', 'CellLine', 'CVCL:0027', (33, 42))	('Ca2+', 'Chemical', 'MESH:D000069285', (147, 151))
115341	32987945	In a subsequent study, Huang and colleagues, using structural modeling, identified inhibition of CaMKIIgamma as the possible target of tetrandrine action.	('tetrandrine', 'Chemical', 'MESH:C009438', (135, 146))	('inhibition', 'Var', (83, 93))	('CaMKIIgamma', 'Gene', (97, 108))	('CaMKIIgamma', 'Gene', '814', (97, 108))
115344	32987945	Tetrandrine reduced CaMKIIgamma phosphorylation in HCC cells and knockdown of CaMKIIgamma reduced the sensitivity of HCC cells to tetrandrine.	('CaMKIIgamma', 'Gene', (78, 89))	('CaMKIIgamma', 'Gene', '814', (78, 89))	('knockdown', 'Var', (65, 74))	('tetrandrine', 'Chemical', 'MESH:C009438', (130, 141))	('reduced', 'NegReg', (90, 97))	('sensitivity', 'MPA', (102, 113))	('Tetrandrine', 'Chemical', 'MESH:C009438', (0, 11))	('HCC', 'Phenotype', 'HP:0001402', (51, 54))	('HCC', 'Phenotype', 'HP:0001402', (117, 120))	('reduced', 'NegReg', (12, 19))	('CaMKIIgamma', 'Gene', (20, 31))	('CaMKIIgamma', 'Gene', '814', (20, 31))	('phosphorylation', 'MPA', (32, 47))
115350	32987945	Studies conducted using Huh-7 HCC cells and a NOD/SCID mouse HCC model showed that berbamine inhibits HCC cell proliferation and induces HCC cell death.	('induces', 'Reg', (129, 136))	('SCID', 'Disease', 'MESH:D053632', (50, 54))	('Huh-7 HCC', 'CellLine', 'CVCL:0336', (24, 33))	('berbamine', 'Chemical', 'MESH:C027870', (83, 92))	('rat', 'Species', '10116', (118, 121))	('berbamine', 'Var', (83, 92))	('inhibits', 'NegReg', (93, 101))	('mouse', 'Species', '10090', (55, 60))	('HCC', 'Phenotype', 'HP:0001402', (30, 33))	('HCC', 'Phenotype', 'HP:0001402', (61, 64))	('HCC', 'Phenotype', 'HP:0001402', (137, 140))	('HCC', 'Phenotype', 'HP:0001402', (102, 105))	('HCC cell death', 'CPA', (137, 151))	('HCC cell proliferation', 'CPA', (102, 124))	('SCID', 'Disease', (50, 54))
115392	31923345	Although these advances resulted in more refined diagnoses and classifications of glioma tumors, integrating histological and molecular information (e.g., IDH1/2 mutations and 1p/19q codeletion) (Louis et al., 2016), significant improvements in therapies that truly impact on patient outcomes are still lacking.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('mutations', 'Var', (162, 171))	('IDH1/2', 'Gene', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('IDH1/2', 'Gene', '3417;3418', (155, 161))	('glioma tumors', 'Disease', (82, 95))	('glioma tumors', 'Disease', 'MESH:D005910', (82, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('patient', 'Species', '9606', (276, 283))
115394	31923345	Functionally, WNT6 expression was associated with increased GBM cell viability, proliferation, invasion, migration, resistance to TMZ, and stemness capacity (Goncalves et al., 2018).	('resistance to TMZ', 'CPA', (116, 133))	('invasion', 'CPA', (95, 103))	('stemness capacity', 'CPA', (139, 156))	('GBM', 'Phenotype', 'HP:0012174', (60, 63))	('proliferation', 'CPA', (80, 93))	('expression', 'Var', (19, 29))	('increased', 'PosReg', (50, 59))	('GBM cell viability', 'CPA', (60, 78))	('migration', 'CPA', (105, 114))	('TMZ', 'Chemical', 'MESH:D000077204', (130, 133))	('WNT6', 'Gene', (14, 18))
115395	31923345	In vivo, WNT6 accelerated GBM-associated death in mice.	('GBM', 'Phenotype', 'HP:0012174', (26, 29))	('WNT6', 'Var', (9, 13))	('death', 'Disease', 'MESH:D003643', (41, 46))	('death', 'Disease', (41, 46))	('mice', 'Species', '10090', (50, 54))	('accelerated', 'PosReg', (14, 25))
115399	31923345	Agilent G4502A 244K data were used for LGG and GBM (WNT6 and HOXA9-high expression was considered when TCGA level 3 value >= 0 [GBM median value] or 3, respectively), while RNAseq data (Illumina HiSeq 2000 Sequencing System) were downloaded for all cancers (WNT6-high expression was considered when TCGA FPKM-UQ value >= 6800 [GBM median value]) (The Cancer Genome Atlas Research Network, 2008).	('G4502A', 'Var', (8, 14))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('GBM', 'Phenotype', 'HP:0012174', (47, 50))	('cancers', 'Disease', (249, 256))	('Cancer', 'Disease', (351, 357))	('G4502A', 'SUBSTITUTION', 'None', (8, 14))	('Cancer', 'Disease', 'MESH:D009369', (351, 357))	('Cancer', 'Phenotype', 'HP:0002664', (351, 357))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('GBM', 'Phenotype', 'HP:0012174', (327, 330))
115434	31923345	For beta-catenin IF (610153; BD Transduction Laboratories, San Jose, CA, USA, 1 : 200), U87-MSCV and U87-HOXA9 cells plated on coverslips were fixed in 95% EtOH and 5% acetic acid (v/v), followed by incubation in 1% BSA in PBS-0.1% Tween for 1 h, and overnight at 4  C with the primary antibody.	('Tween', 'Chemical', 'MESH:D011136', (232, 237))	('610153;', 'Var', (21, 28))	('EtOH', 'Chemical', 'MESH:D000431', (156, 160))	('acetic acid', 'Chemical', 'MESH:D019342', (168, 179))	('PBS', 'Chemical', 'MESH:D007854', (223, 226))	('MSCV', 'Species', '258023', (92, 96))	('beta-catenin', 'Protein', (4, 16))
115454	31923345	Together, these results show that high WNT6 expression associates with higher glioma grades independently of IDH mutation and 1p/19q codeletion status.	('higher', 'PosReg', (71, 77))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('glioma', 'Disease', 'MESH:D005910', (78, 84))	('WNT6', 'Gene', (39, 43))	('high', 'Var', (34, 38))	('glioma', 'Disease', (78, 84))	('IDH', 'Gene', (109, 112))	('IDH', 'Gene', '3417', (109, 112))
115455	31923345	To understand the mechanisms responsible for WNT6 overexpression in glioma, we started by investigating copy number alterations of the WNT6 locus in LGG (n = 509) and GBM (n = 565) patients from TCGA (Fig.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('WNT6', 'Gene', (135, 139))	('GBM', 'Phenotype', 'HP:0012174', (167, 170))	('copy number alterations', 'Var', (104, 127))	('patients', 'Species', '9606', (181, 189))	('glioma', 'Disease', (68, 74))
115463	31923345	Interestingly, looking for the 28 DNA methylation sites within the WNT6 locus, in 516 LGG and 141 GBM patients, we identified regions that are consistently hypomethylated (e.g., from the 4th probe [cg16256504] to the 8th probe [cg02175741]) or hypermethylated (e.g., 16th probe [cg05618201]) both in LGG and in GBM (Figs 2A and S2), showing a remarkable homogeneity of DNA methylation levels of these particular regions across very heterogeneous glioma samples of different grades.	('GBM', 'Phenotype', 'HP:0012174', (311, 314))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('patients', 'Species', '9606', (102, 110))	('glioma', 'Disease', 'MESH:D005910', (446, 452))	('glioma', 'Phenotype', 'HP:0009733', (446, 452))	('[cg16256504]', 'Var', (197, 209))	('[cg02175741]', 'Var', (227, 239))	('glioma', 'Disease', (446, 452))
115467	31923345	MSP analyses showed that five of the seven cell lines presented 5-Aza-mediated demethylation (A172, SNB19, KNS42, SW1783, and Res186; Fig.	('5-Aza', 'Chemical', 'MESH:D000077209', (64, 69))	('A172', 'Var', (94, 98))	('SNB19', 'Var', (100, 105))	('SW1783', 'Var', (114, 120))	('SW1783', 'CellLine', 'CVCL:1722', (114, 120))	('5-Aza-mediated demethylation', 'MPA', (64, 92))
115468	31923345	Interestingly, 5-Aza treatment successfully increased WNT6 expression in four of these five cell lines (fold changes between 1.7 and 3.15; for KNS42, SW1783, A172, and Res186).	('WNT6 expression', 'MPA', (54, 69))	('increased', 'PosReg', (44, 53))	('5-Aza', 'Chemical', 'MESH:D000077209', (15, 20))	('SW1783', 'CellLine', 'CVCL:1722', (150, 156))	('SW1783', 'Var', (150, 156))
115477	31923345	Interestingly, when performing GSEA to identify transcriptomic signatures reminiscent of WNT6-associated genes in GBM patients (Goncalves et al., 2018), we found that WNT6-negatively correlated genes were enriched for genes upregulated in LAML cells upon HOXA9 knockdown [enrichment score (ES) = -0.26 and false discovery rate, FDR = 0.18; Fig.	('knockdown', 'Var', (261, 270))	('GSEA', 'Chemical', '-', (31, 35))	('upregulated', 'PosReg', (224, 235))	('GBM', 'Phenotype', 'HP:0012174', (114, 117))	('patients', 'Species', '9606', (118, 126))
115479	31923345	This association was not only observed in vitro but also in vivo, as U87+/-HOXA9 tumors grown subcutaneously in nude mice also showed significantly higher expression of WNT6 and beta-catenin (mainly in the nucleus) in HOXA9-positive tumors when compared to HOXA9-negative tumors (Fig.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('nude mice', 'Species', '10090', (112, 121))	('WNT6', 'Protein', (169, 173))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('beta-catenin', 'Protein', (178, 190))	('higher', 'PosReg', (148, 154))	('U87+/-HOXA9', 'Var', (69, 80))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', (272, 278))	('HOXA9-positive', 'Var', (218, 232))	('tumors', 'Disease', (233, 239))	('expression', 'MPA', (155, 165))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
115480	31923345	In addition, cyclin D1, a known transcriptional target of the canonical WNT/beta-catenin pathway, was also upregulated in HOXA9-positive tumors when compared to negative tumors (Fig.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('cyclin D1', 'Gene', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('HOXA9-positive', 'Var', (122, 136))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('cyclin D1', 'Gene', '595', (13, 22))	('upregulated', 'PosReg', (107, 118))	('tumors', 'Disease', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
115484	31923345	Thus, the clinical impact of WNT6 in GBM was evaluated using a multivariable Cox model to adjust to potential confounding effects of other putative prognostic factors, namely patient age, KPS, gender, therapy, IDH mutation status, and HOXA9 expression (Tables 2 and S2).	('GBM', 'Phenotype', 'HP:0012174', (37, 40))	('mutation', 'Var', (214, 222))	('IDH', 'Gene', '3417', (210, 213))	('patient', 'Species', '9606', (175, 182))	('IDH', 'Gene', (210, 213))
115486	31923345	Importantly, IDHwt GBM patients with both WNT6-high and HOXA9-high expression presented a shorter OS (median OS = 290 days) when compared to all other patients (median OS = 425; log-rank P = 0.002; Fig.	('IDH', 'Gene', '3417', (13, 16))	('GBM', 'Phenotype', 'HP:0012174', (19, 22))	('patients', 'Species', '9606', (23, 31))	('shorter', 'NegReg', (90, 97))	('patients', 'Species', '9606', (151, 159))	('HOXA9-high expression', 'Var', (56, 77))	('IDH', 'Gene', (13, 16))
115498	31923345	In contrast, our findings demonstrated that DNA methylation, a critical epigenetic mechanism, associates with WNT6 expression levels in glioma (Figs 2, S2 and S3), similarly to what was observed for other WNT ligands in other cancer types (Carmona et al., 2013; Jung et al., 2015; Kim et al., 2015a; Liu et al., 2016; Xu et al., 2005).	('WNT6', 'Gene', (110, 114))	('DNA', 'MPA', (44, 47))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('cancer', 'Disease', (226, 232))	('glioma', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('methylation', 'Var', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
115500	31923345	Interestingly, most of the CpG sites are more frequently methylated in LGG than GBM patients (19 out of 28; Fig.	('GBM', 'Phenotype', 'HP:0012174', (80, 83))	('LGG', 'Disease', (71, 74))	('methylated', 'Var', (57, 67))	('patients', 'Species', '9606', (84, 92))
115502	31923345	Although DNA methylation was clearly associated with WNT6 expression in glioma, this association was not universal.	('glioma', 'Disease', (72, 78))	('methylation', 'Var', (13, 24))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('WNT6', 'Gene', (53, 57))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('associated', 'Reg', (37, 47))	('DNA', 'MPA', (9, 12))
115512	31923345	Interestingly, WNT6 was also shown to be associated with shorter survival in LGG patients (Dao Trong et al., 2018), where HOXA9 overexpression is not frequent (Pojo et al., 2015).	('patients', 'Species', '9606', (81, 89))	('WNT6', 'Var', (15, 19))	('LGG', 'Disease', (77, 80))	('survival', 'MPA', (65, 73))	('shorter', 'NegReg', (57, 64))
115963	23002431	In support of this notion, inhibition of VEGFR and EGFR signaling with vandetanib (ZD6474, tyrosine kinase inhibitor) can be an important approach for the management of the subset of cholangiocarcinoma that lack KRAS mutations and/or have EGFR amplification.	('KRAS', 'Gene', '3845', (212, 216))	('vandetanib', 'Chemical', 'MESH:C452423', (71, 81))	('EGFR', 'Gene', '1956', (42, 46))	('EGFR', 'Gene', (51, 55))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (183, 201))	('amplification', 'Var', (244, 257))	('EGFR', 'Gene', (42, 46))	('VEGFR', 'Gene', '3791', (41, 46))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (183, 201))	('ZD6474', 'Chemical', 'MESH:C452423', (83, 89))	('EGFR', 'Gene', '1956', (51, 55))	('lack', 'NegReg', (207, 211))	('cholangiocarcinoma', 'Disease', (183, 201))	('KRAS', 'Gene', (212, 216))	('EGFR', 'Gene', '1956', (239, 243))	('mutations', 'Var', (217, 226))	('VEGFR', 'Gene', (41, 46))	('EGFR', 'Gene', (239, 243))
116014	23002431	VEGFR-3 activation induces the proliferation of lymphatic endothelial cells in vitro and the formation of new lymphatic vessels in vivo.	('proliferation', 'CPA', (31, 44))	('VEGFR-3', 'Gene', (0, 7))	('formation of new lymphatic vessels', 'CPA', (93, 127))	('activation', 'Var', (8, 18))	('VEGFR-3', 'Gene', '2324', (0, 7))
116016	23002431	Inhibitors that block VEGF-C/VEGF-D/VEGFR3 signaling could potentially block lymphangiogenesis in addition to angiogenesis, leading to blockage of lymphogenous metastatic spread.	('VEGFR3', 'Gene', (36, 42))	('VEGF-C', 'Gene', '7424', (22, 28))	('blockage', 'NegReg', (135, 143))	('Inhibitors', 'Var', (0, 10))	('VEGFR3', 'Gene', '2324', (36, 42))	('lymphangiogenesis', 'CPA', (77, 94))	('VEGF-C', 'Gene', (22, 28))	('block', 'NegReg', (71, 76))	('angiogenesis', 'CPA', (110, 122))	('lymphogenous metastatic spread', 'CPA', (147, 177))
116030	21303542	Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma The genetics of advanced biliary tract cancers (BTC), which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined.	('biliary tract cancers', 'Disease', 'MESH:D001661', (96, 117))	('extra-hepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (152, 185))	('hepatic cholangiocarcinomas', 'Phenotype', 'HP:0030153', (158, 185))	('gallbladder carcinomas', 'Disease', 'MESH:D005706', (197, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (175, 185))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (197, 218))	('extra-hepatic cholangiocarcinomas', 'Disease', (152, 185))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('PIK3CA', 'Gene', '5290', (29, 35))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (166, 184))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (49, 70))	('biliary tract cancers', 'Disease', (96, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('gallbladder carcinoma', 'Disease', (49, 70))	('gallbladder carcinomas', 'Disease', (197, 219))	('mutations', 'Var', (36, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('PIK3CA', 'Gene', (29, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (209, 219))
116031	21303542	To better characterize mutations in established known oncogenes and tumor suppressor genes we tested a mass spectrometric based platform to interrogate common cancer associated mutations across a panel of 77 formalin fixed paraffin embedded archived BTC cases.	('cancer', 'Disease', (159, 165))	('tumor', 'Disease', (68, 73))	('formalin', 'Chemical', 'MESH:D005557', (208, 216))	('paraffin', 'Chemical', 'MESH:D010232', (223, 231))	('mutations', 'Var', (177, 186))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
116034	21303542	KRAS mutations were identified in 3 (13%) intra-hepatic cholangiocarcinomas and 1 (33%) perihillar cholangiocarcinoma but were not identified in gallbladder carcinomas and extra-hepatic cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (99, 117))	('cholangiocarcinoma', 'Disease', (186, 204))	('gallbladder carcinomas', 'Disease', (145, 167))	('extra-hepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (172, 204))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (186, 204))	('cholangiocarcinoma', 'Disease', (99, 117))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (99, 117))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('intra-hepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (42, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (56, 74))	('gallbladder carcinomas', 'Disease', 'MESH:D005706', (145, 167))	('cholangiocarcinoma', 'Disease', (56, 74))	('mutations', 'Var', (5, 14))	('intra-hepatic cholangiocarcinomas', 'Disease', (42, 75))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (56, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('extra-hepatic cholangiocarcinoma', 'Disease', (172, 204))	('identified', 'Reg', (20, 30))	('KRAS', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('hepatic cholangiocarcinomas', 'Phenotype', 'HP:0030153', (48, 75))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (186, 204))
116035	21303542	The presence of activating mutations in PIK3CA specifically in GBC has clinical implications in both the diagnosis of this cancer type, as well as the potential utility of targeted therapies such as PI3 kinase inhibitors.	('mutations', 'Var', (27, 36))	('GBC', 'Disease', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('PIK3CA', 'Gene', (40, 46))	('PIK3CA', 'Gene', '5290', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('activating', 'PosReg', (16, 26))
116042	21303542	KRAS, BRAF, EGFR, and PIK3CA mutations are found in subsets of both GBC and CC.	('PIK3CA', 'Gene', '5290', (22, 28))	('found', 'Reg', (43, 48))	('PIK3CA', 'Gene', (22, 28))	('mutations', 'Var', (29, 38))	('BRAF', 'Gene', (6, 10))	('EGFR', 'Gene', '1956', (12, 16))	('BRAF', 'Gene', '673', (6, 10))	('GBC', 'Disease', (68, 71))	('EGFR', 'Gene', (12, 16))	('KRAS', 'Gene', (0, 4))
116043	21303542	Mutations in the tumor suppressor genes CDKN2A, TP53 and SMAD4 have also been identified.	('TP53', 'Gene', '7157', (48, 52))	('tumor', 'Disease', (17, 22))	('SMAD4', 'Gene', (57, 62))	('TP53', 'Gene', (48, 52))	('CDKN2A', 'Gene', (40, 46))	('Mutations', 'Var', (0, 9))	('CDKN2A', 'Gene', '1029', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('SMAD4', 'Gene', '4089', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
116046	21303542	HER2NEU gene amplification, EGFR, and KRAS mutation testing are all used routinely clinically to determine an individual's likelihood of benefit from treatment with specific targeted anti-cancer therapies.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('EGFR', 'Gene', '1956', (28, 32))	('mutation', 'Var', (43, 51))	('HER2NEU', 'Gene', (0, 7))	('EGFR', 'Gene', (28, 32))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('HER2NEU', 'Gene', '2064', (0, 7))	('KRAS', 'Gene', (38, 42))
116051	21303542	Using genomic profiling with OncoMap coupled with an analytical mutation-calling algorithm and orthogonal validation step, numerous mutations have been identified in genomic DNA from both frozen and FFPE tumor tissue with a high degree of specificity and sensitivity.	('DNA', 'Gene', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('mutations', 'Var', (132, 141))	('identified', 'Reg', (152, 162))	('tumor', 'Disease', (204, 209))
116052	21303542	The primary goal was to identify novel or "druggable" mutations in biliary carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('mutations', 'Var', (54, 63))	('biliary carcinoma', 'Disease', (67, 84))	('biliary carcinoma', 'Disease', 'MESH:D001661', (67, 84))
116061	21303542	Fishers exact test was applied to determine the association of PIK3CA mutation with GBC.	('association', 'Interaction', (48, 59))	('GBC', 'Disease', (84, 87))	('PIK3CA', 'Gene', (63, 69))	('PIK3CA', 'Gene', '5290', (63, 69))	('mutation', 'Var', (70, 78))	('Fishers', 'Species', '76720', (0, 7))
116062	21303542	Mutations in KRAS, NRAS, and PIK3CA were identified as outlined in Table 1 and 2.	('NRAS', 'Gene', (19, 23))	('NRAS', 'Gene', '4893', (19, 23))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', (29, 35))	('KRAS', 'Gene', (13, 17))	('PIK3CA', 'Gene', '5290', (29, 35))
116066	21303542	Among these activating PIK3CA mutations were unique to gallbladder tumors.	('PIK3CA', 'Gene', (23, 29))	('gallbladder tumors', 'Disease', 'MESH:D005705', (55, 73))	('PIK3CA', 'Gene', '5290', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mutations', 'Var', (30, 39))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('gallbladder tumors', 'Phenotype', 'HP:0100575', (55, 73))	('activating', 'PosReg', (12, 22))	('gallbladder tumors', 'Disease', (55, 73))
116071	21303542	PI3K mutations were specific to carcinomas of the gallbladder and were identified in 4 (12.5%) gallbladder carcinomas, (p = 0.013 vs. CC).	('carcinomas of the gallbladder', 'Disease', 'MESH:D005706', (32, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('carcinomas of the gallbladder', 'Disease', (32, 61))	('carcinomas of the gallbladder', 'Phenotype', 'HP:0100575', (32, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('mutations', 'Var', (5, 14))	('carcinomas', 'Phenotype', 'HP:0030731', (32, 42))	('gallbladder carcinomas', 'Disease', 'MESH:D005706', (95, 117))	('PI3K mutations', 'Var', (0, 14))	('gallbladder carcinomas', 'Disease', (95, 117))
116072	21303542	Of the 4 cases with mutations, 3 were identified in adenocarcinomas, and 1 in an adenosquamous carcinoma.	('identified', 'Reg', (38, 48))	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (81, 104))	('adenosquamous carcinoma', 'Disease', (81, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('adenocarcinomas', 'Disease', 'MESH:D000230', (52, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('adenocarcinomas', 'Disease', (52, 67))	('mutations', 'Var', (20, 29))
116073	21303542	There are no appreciable differences in T stage or patient characteristics between the cohort that showed PI3K mutations and the group of cases that did not (Table 3).	('mutations', 'Var', (111, 120))	('patient', 'Species', '9606', (51, 58))	('PI3K mutations', 'Var', (106, 120))
116074	21303542	Neither of the two gallbladders with high-grade dysplasia showed PI3K mutations.	('PI3K mutations', 'Var', (65, 79))	('dysplasia', 'Disease', 'MESH:D004476', (48, 57))	('dysplasia', 'Disease', (48, 57))
116075	21303542	The cohort included 24 intra-hepatic cholangiocarcinomas in which 3 (13%) KRAS mutations and 1 NRAS (4%) mutation were identified (Table 1).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (37, 55))	('intra-hepatic cholangiocarcinomas', 'Disease', (23, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('hepatic cholangiocarcinomas', 'Phenotype', 'HP:0030153', (29, 56))	('mutations', 'Var', (79, 88))	('NRAS', 'Gene', (95, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('KRAS', 'Gene', (74, 78))	('NRAS', 'Gene', '4893', (95, 99))	('intra-hepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (23, 56))
116077	21303542	One of the three peri-hilar cholangiocarcinomas harbored a mutation in KRAS.	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('KRAS', 'Gene', (71, 75))	('mutation', 'Var', (59, 67))	('harbored', 'Reg', (48, 56))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (28, 47))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (28, 46))	('cholangiocarcinomas', 'Disease', (28, 47))
116080	21303542	Mutations in KRAS, NRAS and PIK3CA, all of which have previously been identified in biliary tract carcinomas (for summary of mutations in BTC see Table 4), were identified in this mutational screen (Reviewed in).	('biliary tract carcinomas', 'Disease', 'MESH:D001661', (84, 108))	('identified', 'Reg', (70, 80))	('NRAS', 'Gene', (19, 23))	('PIK3CA', 'Gene', (28, 34))	('biliary tract carcinomas', 'Disease', (84, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('NRAS', 'Gene', '4893', (19, 23))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', '5290', (28, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('KRAS', 'Gene', (13, 17))
116081	21303542	Furthermore, PIK3CA mutations appear to be confined to gallbladder carcinomas among this cohort.	('gallbladder carcinomas', 'Disease', 'MESH:D005706', (55, 77))	('PIK3CA', 'Gene', (13, 19))	('gallbladder carcinomas', 'Disease', (55, 77))	('PIK3CA', 'Gene', '5290', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('mutations', 'Var', (20, 29))
116082	21303542	Reiner and co-workers have previously identified PIKCA mutations in one of 11 intra-hepatic cholangiocarcinoma and one of 23 GBC previously.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (92, 110))	('identified', 'Reg', (38, 48))	('intra-hepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 110))	('mutations', 'Var', (55, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('PIKCA', 'Gene', (49, 54))	('intra-hepatic cholangiocarcinoma', 'Disease', (78, 110))
116084	21303542	Somatic mutations of the PIK3CA gene, which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), are found across a range of cancers with the highest rates of mutation observed in breast, colon, endometrial, bladder and hepatocellular cancers (COSMIC data base).	('p110alpha', 'Gene', (56, 65))	('cancers', 'Disease', (153, 160))	('found', 'Reg', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('PIK3CA', 'Gene', '5290', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('endometrial', 'Disease', (223, 234))	('phosphatidylinositol 3-kinase', 'Gene', (87, 116))	('colon', 'Disease', (216, 221))	('cancers', 'Phenotype', 'HP:0002664', (263, 270))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (87, 116))	('mutations', 'Var', (8, 17))	('cancers', 'Disease', (263, 270))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('bladder and hepatocellular cancers', 'Disease', 'MESH:D001749', (236, 270))	('PIK3CA', 'Gene', (25, 31))	('breast', 'Disease', (208, 214))	('cancers', 'Disease', 'MESH:D009369', (263, 270))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('p110alpha', 'Gene', '5290', (56, 65))
116085	21303542	The majority of mutations cluster at hotspots within exons 9 and 20, which encode the helical and kinase domains of p110alpha and lead to activation of downstream pro-growth and survival pathways.	('p110alpha', 'Gene', (116, 125))	('mutations', 'Var', (16, 25))	('activation', 'PosReg', (138, 148))	('p110alpha', 'Gene', '5290', (116, 125))
116086	21303542	Importantly mutations in these domains render cancers sensitive to PI3K specific inhibitors pointing towards a role for this emerging class of drugs in cancers harboring these mutations.	('cancers', 'Disease', (152, 159))	('sensitive', 'MPA', (54, 63))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', (46, 53))	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
116087	21303542	The PIK3CA mutations identified in this study, E542K and E545K, are both located in exon 9.	('E545K', 'Var', (57, 62))	('E545K', 'Mutation', 'rs104886003', (57, 62))	('PIK3CA', 'Gene', (4, 10))	('E542K', 'Var', (47, 52))	('PIK3CA', 'Gene', '5290', (4, 10))	('E542K', 'Mutation', 'rs121913273', (47, 52))
116088	21303542	Activation of the PI3K pathway can be achieved through a number of molecular mechanisms, including loss of the PTEN tumor suppressor gene, mutation in EGFR, and amplifications of ERBB2 (HER2NEU), as well as through mutation of PIK3CA, as described above.	('mutation', 'Var', (215, 223))	('mutation', 'Var', (139, 147))	('EGFR', 'Gene', (151, 155))	('ERBB2', 'Gene', '2064', (179, 184))	('PIK3CA', 'Gene', (227, 233))	('loss of the PTEN tumor', 'Disease', (99, 121))	('ERBB2', 'Gene', (179, 184))	('amplifications', 'Var', (161, 175))	('HER2NEU', 'Gene', '2064', (186, 193))	('loss of the PTEN tumor', 'Disease', 'MESH:D006223', (99, 121))	('Activation', 'PosReg', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('PIK3CA', 'Gene', '5290', (227, 233))	('HER2NEU', 'Gene', (186, 193))	('EGFR', 'Gene', '1956', (151, 155))	('PI3K pathway', 'Pathway', (18, 30))
116089	21303542	ERBB2 over-expression and gene amplification is found in ~ 15% of GBC.	('gene amplification', 'Var', (26, 44))	('over-expression', 'PosReg', (6, 21))	('ERBB2', 'Gene', (0, 5))	('ERBB2', 'Gene', '2064', (0, 5))
116091	21303542	A transgenic mutant with constitutive expression of the ErbB2 in the gallbladder epithelium develops GBC with a 100% penetrance and somatic mutation of Pten leads to biliary hyperplasia and intraheaptic cholangiocarcinoma.	('Pten', 'Gene', (152, 156))	('intraheaptic cholangiocarcinoma', 'Disease', (190, 221))	('intraheaptic cholangiocarcinoma', 'Disease', 'MESH:D018281', (190, 221))	('leads to', 'Reg', (157, 165))	('biliary hyperplasia', 'Phenotype', 'HP:0006560', (166, 185))	('mutation', 'Var', (140, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('biliary hyperplasia', 'Disease', (166, 185))	('ErbB2', 'Gene', (56, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (203, 221))	('biliary hyperplasia', 'Disease', 'MESH:D006965', (166, 185))	('ErbB2', 'Gene', '2064', (56, 61))	('Pten', 'Gene', '5728', (152, 156))
116092	21303542	The majority of mutations are identified in intra-hepatic cholangiocarcinomas (13%) and peri-hilar adenocarcinomas (33%).	('adenocarcinomas', 'Disease', 'MESH:D000230', (99, 114))	('intra-hepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (44, 77))	('adenocarcinomas', 'Disease', (99, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('hepatic cholangiocarcinomas', 'Phenotype', 'HP:0030153', (50, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('intra-hepatic cholangiocarcinomas', 'Disease', (44, 77))	('mutations', 'Var', (16, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))
116094	21303542	In general, reported rates of KRAS mutation are somewhat lower in these sites than intra-hepatic cancers (3-20%) with a notable exception being neoplasms that arise in the setting of an anomalous union of the pancreatic and biliary ducts, which have higher rates of KRAS mutation.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('neoplasm', 'Phenotype', 'HP:0002664', (144, 152))	('anomalous', 'Var', (186, 195))	('neoplasms', 'Disease', 'MESH:D009369', (144, 153))	('pancreatic', 'Disease', 'MESH:D010195', (209, 219))	('intra-hepatic cancers', 'Disease', (83, 104))	('neoplasms', 'Phenotype', 'HP:0002664', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutation', 'Var', (35, 43))	('pancreatic', 'Disease', (209, 219))	('lower', 'NegReg', (57, 62))	('KRAS', 'Gene', (30, 34))	('intra-hepatic cancers', 'Disease', 'MESH:D008113', (83, 104))	('neoplasms', 'Disease', (144, 153))
116095	21303542	While our results from the gallbladder are similar to that reported in literature, the data on extra-hepatic neoplasm differs from prior reports that suggest 10-15% of extra-pancreatic cholangiocarcinomas harbor mutations in the KRAS gene.	('pancreatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (174, 204))	('neoplasm', 'Phenotype', 'HP:0002664', (109, 117))	('harbor', 'Reg', (205, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('pancreatic cholangiocarcinomas', 'Disease', (174, 204))	('neoplasm', 'Disease', (109, 117))	('KRAS', 'Gene', (229, 233))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (185, 203))	('hepatic neoplasm', 'Phenotype', 'HP:0002896', (101, 117))	('mutations', 'Var', (212, 221))	('neoplasm', 'Disease', 'MESH:D009369', (109, 117))
116097	21303542	It is possible that the KRAS mutations identified in extra-hepatic bile duct carcinomas in prior studies may represent cases of peri-biliary pancreatic ductal adenocarcinoma.	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('extra-hepatic bile duct carcinomas', 'Disease', (53, 87))	('mutations', 'Var', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('extra-hepatic bile duct carcinomas', 'Phenotype', 'HP:0005242', (53, 87))	('pancreatic ductal adenocarcinoma', 'Disease', (141, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (141, 173))	('extra-hepatic bile duct carcinomas', 'Disease', 'MESH:D001650', (53, 87))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (141, 173))	('KRAS', 'Gene', (24, 28))
116101	21303542	Analysis of the absence of KRAS mutations in extra-hepatic and intrapancreatic biliary carcinoma in comparison to the 4 mutations identified intrahepatic and perihilar cholangiocarcinomas shows this relationship to be insignificant, p = 0.28 (Fishers exact test).	('intrapancreatic biliary carcinoma', 'Disease', (63, 96))	('extra-hepatic', 'Disease', (45, 58))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (168, 187))	('intrahepatic', 'Disease', (141, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('mutations', 'Var', (32, 41))	('intrahepatic', 'Disease', 'MESH:D002780', (141, 153))	('Fishers', 'Species', '76720', (243, 250))	('intrapancreatic biliary carcinoma', 'Disease', 'MESH:D001661', (63, 96))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (168, 186))	('KRAS', 'Gene', (27, 31))	('cholangiocarcinomas', 'Disease', (168, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
116102	21303542	It is possible that the absence of KRAS mutations in extra-hepatic cancers in our screen was a chance event.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('extra-hepatic cancers', 'Disease', (53, 74))	('KRAS', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('extra-hepatic cancers', 'Disease', 'MESH:D008113', (53, 74))
116104	21303542	While this study identified known mutations and points towards an association between PIK3CA mutations and GBC, the rates of validated mutations in genes such as KRAS, particularly in the intra-hepatic cholangiocarcinomas, were lower than expected given the findings of previous studies.	('KRAS', 'Gene', (162, 166))	('mutations', 'Var', (93, 102))	('intra-hepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (188, 221))	('intra-hepatic cholangiocarcinomas', 'Disease', (188, 221))	('association', 'Interaction', (66, 77))	('PIK3CA', 'Gene', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (202, 220))	('carcinomas', 'Phenotype', 'HP:0030731', (211, 221))	('PIK3CA', 'Gene', '5290', (86, 92))	('hepatic cholangiocarcinomas', 'Phenotype', 'HP:0030153', (194, 221))	('GBC', 'Gene', (107, 110))
116108	21303542	Among the three previously published studies BRAF mutations are identified in ~20% of cases in two European BTC collections including both GBC and intra-hepatic CC.	('mutations', 'Var', (50, 59))	('intra-hepatic CC', 'Disease', (147, 163))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('intra-hepatic CC', 'Disease', 'MESH:D056486', (147, 163))
116109	21303542	No BRAF mutations were found in an American cohort.	('BRAF', 'Gene', (3, 7))	('BRAF', 'Gene', '673', (3, 7))	('mutations', 'Var', (8, 17))
116112	21303542	Inhibitors of the PI3K pathways are presently in development including specific inhibitors of p110alpha that have demonstrated efficacy in engineered preclinical models of lung cancer harboring activating point mutations in PIK3CA.	('point mutations', 'Var', (205, 220))	('p110alpha', 'Gene', '5290', (94, 103))	('p110alpha', 'Gene', (94, 103))	('PI3K pathways', 'Pathway', (18, 31))	('lung cancer', 'Disease', (172, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('PIK3CA', 'Gene', (224, 230))	('activating', 'PosReg', (194, 204))	('PIK3CA', 'Gene', '5290', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))
116113	21303542	These results, pointing towards an enrichment of activating PIK3CA mutations in GBC, suggest a potential group of patients with GBC who may also benefit from these agents.	('PIK3CA', 'Gene', (60, 66))	('PIK3CA', 'Gene', '5290', (60, 66))	('activating', 'PosReg', (49, 59))	('mutations', 'Var', (67, 76))	('patients', 'Species', '9606', (114, 122))
116167	32606456	Polymorphisms of host genes encoding enzymes involved in xenobiotic detoxification, DNA repair, multidrug resistance, immune response and folate metabolism have been linked to CCA development.	('met', 'Gene', '79811', (145, 148))	('CCA', 'Disease', (176, 179))	('Polymorphisms', 'Var', (0, 13))	('met', 'Gene', (145, 148))	('men', 'Species', '9606', (187, 190))	('linked', 'Reg', (166, 172))	('folate', 'Chemical', 'MESH:D005492', (138, 144))	('CCA', 'Phenotype', 'HP:0030153', (176, 179))	('drug resistance', 'Phenotype', 'HP:0020174', (101, 116))
116175	32606456	Small bile duct iCCA can be characterized by isocitrate dehydrogenase (IDH1, IDH2) mutations or fibroblast growth factor receptor 2 (FGFR2) fusions.	('mutations', 'Var', (83, 92))	('CCA', 'Phenotype', 'HP:0030153', (17, 20))	('isocitrate dehydrogenase ', 'Gene', '3417', (45, 70))	('fibroblast growth factor receptor 2', 'Gene', (96, 131))	('IDH2', 'Gene', (77, 81))	('Small bile duct iCCA', 'Disease', (0, 20))	('IDH1', 'Gene', (71, 75))	('fibroblast growth factor receptor 2', 'Gene', '2263', (96, 131))	('FGFR2', 'Gene', (133, 138))	('FGFR2', 'Gene', '2263', (133, 138))	('isocitrate dehydrogenase ', 'Gene', (45, 70))	('fusions', 'Var', (140, 147))	('IDH2', 'Gene', '3418', (77, 81))	('IDH1', 'Gene', '3417', (71, 75))	('Small bile', 'Phenotype', 'HP:0030985', (0, 10))
116176	32606456	By contrast, large bile duct iCCA, similar to pCCA and dCCA, shows a high frequency of mutations in KRAS and/or TP53 genes.	('KRAS', 'Gene', (100, 104))	('KRAS', 'Gene', '3845', (100, 104))	('CCA', 'Phenotype', 'HP:0030153', (47, 50))	('CCA', 'Phenotype', 'HP:0030153', (56, 59))	('large bile duct iCCA', 'Disease', (13, 33))	('dCCA', 'Chemical', '-', (55, 59))	('TP53', 'Gene', '7157', (112, 116))	('mutations', 'Var', (87, 96))	('CCA', 'Phenotype', 'HP:0030153', (30, 33))	('TP53', 'Gene', (112, 116))
116177	32606456	Interestingly, dCCA is also associated with ELF3 mutations.	('dCCA', 'Disease', (15, 19))	('mutations', 'Var', (49, 58))	('associated', 'Reg', (28, 38))	('dCCA', 'Chemical', '-', (15, 19))	('ELF3', 'Gene', (44, 48))	('ELF3', 'Gene', '1999', (44, 48))	('CCA', 'Phenotype', 'HP:0030153', (16, 19))
116225	32606456	Massive sequencing studies have improved our understanding of the causal mechanisms in CCA, emphasizing the genomic complexity in prevalent oncogenic modules affecting: cell cycle regulation; DNA damage and genomic instability (TP53, CDKN2A, CCND1, ATM, ROBO2, BRCA1 and BRAC2); MYC amplification; epigenetic regulation including NADPH metabolism (IDH1 and IDH2), de-ubiquitination (BAP1), SWI-SNF complex (PBRM1, ARID1A, ARID1B, ARID2, SMARCA2, SMARCA4 and SMARCAD1) and histone (de-)methylation (MLL2, MML3, KMT2C, KDM4A, KDM5D, KDM6A and KDM6B); kinase signalling (KRAS, ERBB1-3, BRAF, PIK3CA, PTEN, STK11, SMAD4 and FGFR1-3); immune dysregulation (JAK-STAT3 signalling); FGFR2 and PRKCA-PRKCB fusions; the WNT-CTNNB1 pathway (APC); Hippo signalling (NF2, SAV1 deletion); METLL13 amplifications; and deregulated Notch signalling.	('STK11', 'Gene', '6794', (603, 608))	('KDM6A', 'Gene', '7403', (531, 536))	('PBRM1', 'Gene', '55193', (407, 412))	('FGFR1-3', 'Gene', '2260;2263;2261', (620, 627))	('ARID2', 'Gene', '196528', (430, 435))	('PBRM1', 'Gene', (407, 412))	('PRKCA', 'Gene', '5578', (685, 690))	('FGFR1-3', 'Gene', (620, 627))	('KDM6B', 'Gene', (541, 546))	('ARID2', 'Gene', (430, 435))	('IDH1', 'Gene', (348, 352))	('BRAF', 'Gene', '673', (583, 587))	('immune dysregulation', 'MPA', (630, 650))	('CTNNB1', 'Gene', (714, 720))	('SMARCA4', 'Gene', '6597', (446, 453))	('immune dysregulation', 'Phenotype', 'HP:0002958', (630, 650))	('PRKCB', 'Gene', (691, 696))	('IDH2', 'Gene', (357, 361))	('PRKCA', 'Gene', (685, 690))	('BAP1', 'Gene', '8314', (383, 387))	('ARID1B', 'Gene', (422, 428))	('KRAS', 'Gene', (568, 572))	('met', 'Gene', (336, 339))	('SMARCA4', 'Gene', (446, 453))	('CCND1', 'Gene', (242, 247))	('ARID1B', 'Gene', '57492', (422, 428))	('BAP1', 'Gene', (383, 387))	('ARID1A', 'Gene', (414, 420))	('CDKN2A', 'Gene', (234, 240))	('SMARCAD1', 'Gene', (458, 466))	('ROBO2', 'Gene', (254, 259))	('SMAD4', 'Gene', '4089', (610, 615))	('ARID1A', 'Gene', '8289', (414, 420))	('Hippo', 'MPA', (736, 741))	('MLL2', 'Gene', (498, 502))	('CDKN2A', 'Gene', '1029', (234, 240))	('MET', 'Gene', (775, 778))	('BRAF', 'Gene', (583, 587))	('ATM', 'Gene', '472', (249, 252))	('PTEN', 'Gene', '5728', (597, 601))	('STK11', 'Gene', (603, 608))	('SMARCA2', 'Gene', (437, 444))	('SMARCA2', 'Gene', '6595', (437, 444))	('KDM4A', 'Gene', '9682', (517, 522))	('BRCA1', 'Gene', '672', (261, 266))	('ROBO2', 'Gene', '6092', (254, 259))	('fusions', 'Var', (697, 704))	('SAV1', 'Gene', '60485', (759, 763))	('SMARCAD1', 'Gene', '56916', (458, 466))	('CCND1', 'Gene', '595', (242, 247))	('IDH2', 'Gene', '3418', (357, 361))	('PIK3CA', 'Gene', '5290', (589, 595))	('kinase signalling', 'MPA', (549, 566))	('MET', 'Gene', '79811', (775, 778))	('SMAD4', 'Gene', (610, 615))	('ERBB1-3', 'Gene', (574, 581))	('ATM', 'Gene', (249, 252))	('met', 'Gene', (485, 488))	('TP53', 'Gene', (228, 232))	('MLL2', 'Gene', '9757', (498, 502))	('NF2', 'Gene', (754, 757))	('SAV1', 'Gene', (759, 763))	('CTNNB1', 'Gene', '1499', (714, 720))	('KMT2C', 'Gene', '58508', (510, 515))	('PIK3CA', 'Gene', (589, 595))	('KDM6A', 'Gene', (531, 536))	('PTEN', 'Gene', (597, 601))	('KDM6B', 'Gene', '23135', (541, 546))	('KDM5D', 'Gene', '8284', (524, 529))	('FGFR2', 'Gene', (675, 680))	('MYC', 'Gene', '4609', (279, 282))	('STAT3', 'Gene', '6774', (656, 661))	('deregulated Notch signalling', 'MPA', (803, 831))	('APC', 'Gene', '324', (730, 733))	('KRAS', 'Gene', '3845', (568, 572))	('KDM5D', 'Gene', (524, 529))	('IDH1', 'Gene', '3417', (348, 352))	('BRCA1', 'Gene', (261, 266))	('met', 'Gene', '79811', (336, 339))	('met', 'Gene', '79811', (485, 488))	('NF2', 'Gene', '4771', (754, 757))	('PRKCB', 'Gene', '5579', (691, 696))	('APC', 'Gene', (730, 733))	('ERBB1-3', 'Gene', '1956;2064;2065', (574, 581))	('MYC', 'Gene', (279, 282))	('KMT2C', 'Gene', (510, 515))	('CCA', 'Phenotype', 'HP:0030153', (87, 90))	('STAT3', 'Gene', (656, 661))	('TP53', 'Gene', '7157', (228, 232))	('KDM4A', 'Gene', (517, 522))	('amplifications', 'PosReg', (783, 797))	('FGFR2', 'Gene', '2263', (675, 680))
116227	32606456	Indeed, the most clinically significant genomic breakthroughs in iCCA are the discovery of hotspot IDH mutations (IDH1R132 and IDH2R172) that cause an accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), as well as the constitutive active gene fusion event between FGFR2 and many different partners, including the most prevalent (BICC1 (refs), PPHLN1 (ref.	('IDH', 'Gene', '3417', (99, 102))	('IDH1', 'Gene', (114, 118))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (186, 204))	('IDH', 'Gene', '3417', (114, 117))	('PPHLN1', 'Gene', (353, 359))	('BICC1', 'Gene', (339, 344))	('FGFR2', 'Gene', (274, 279))	('met', 'Gene', '79811', (175, 178))	('IDH', 'Gene', (127, 130))	('mutations', 'Var', (103, 112))	('met', 'Gene', (175, 178))	('IDH1', 'Gene', '3417', (114, 118))	('FGFR2', 'Gene', '2263', (274, 279))	('PPHLN1', 'Gene', '51535', (353, 359))	('IDH', 'Gene', '3417', (127, 130))	('accumulation', 'PosReg', (151, 163))	('IDH', 'Gene', (99, 102))	('2-HG', 'Chemical', 'MESH:C019417', (206, 210))	('IDH', 'Gene', (114, 117))	('CCA', 'Phenotype', 'HP:0030153', (66, 69))	('IDH2', 'Gene', (127, 131))	('IDH2', 'Gene', '3418', (127, 131))	('BICC1', 'Gene', '80114', (339, 344))
116230	32606456	These alterations are important as they are driving current marker-based phase III clinical trials testing specific agents targeting these alterations in FGFR2 fusion-positive CCA (NCT03773302) and IDH-mutated CCA (NCT02989857).	('CCA', 'Disease', (176, 179))	('fusion-positive', 'Reg', (160, 175))	('CCA', 'Phenotype', 'HP:0030153', (210, 213))	('rat', 'Species', '10116', (10, 13))	('rat', 'Species', '10116', (143, 146))	('CCA', 'Phenotype', 'HP:0030153', (176, 179))	('NCT03773302', 'Var', (181, 192))	('IDH', 'Gene', (198, 201))	('CCA', 'Disease', (210, 213))	('FGFR2', 'Gene', (154, 159))	('FGFR2', 'Gene', '2263', (154, 159))	('IDH', 'Gene', '3417', (198, 201))
116232	32606456	However, the only detailed genomic association with aetiological risk factors investigated by genome sequencing has been the association with liver fluke infection (Opisthorchis viverrini and Clonorchis sinensis), with fluke-positive tumours showing an overall higher mutational rate (median 4,700 versus 3,143 somatic mutations per tumour) with prevalent mutations in SMAD4 and TP53 as well as ERBB2 amplifications.	('liver fluke infection', 'Disease', 'MESH:D017093', (142, 163))	('tumours', 'Phenotype', 'HP:0002664', (234, 241))	('TP53', 'Gene', (379, 383))	('higher', 'PosReg', (261, 267))	('ERBB2', 'Gene', (395, 400))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('tumour', 'Disease', 'MESH:D009369', (234, 240))	('tumour', 'Disease', (234, 240))	('mutations', 'Var', (356, 365))	('fluke-positive tumours', 'Disease', (219, 241))	('SMAD4', 'Gene', (369, 374))	('mutational', 'MPA', (268, 278))	('ERBB2', 'Gene', '2064', (395, 400))	('fluke-positive tumours', 'Disease', 'MESH:D009369', (219, 241))	('TP53', 'Gene', '7157', (379, 383))	('liver fluke infection', 'Disease', (142, 163))	('tumour', 'Phenotype', 'HP:0002664', (333, 339))	('tumour', 'Disease', 'MESH:D009369', (333, 339))	('Opisthorchis viverrini', 'Species', '6198', (165, 187))	('tumour', 'Disease', (333, 339))	('SMAD4', 'Gene', '4089', (369, 374))	('Clonorchis sinensis', 'Species', '79923', (192, 211))	('rat', 'Species', '10116', (279, 282))
116233	32606456	Furthermore, although not in a high proportion, KRAS mutations have been recurrently found in all CCA subtypes.	('CCA', 'Phenotype', 'HP:0030153', (98, 101))	('KRAS', 'Gene', (48, 52))	('KRAS', 'Gene', '3845', (48, 52))	('mutations', 'Var', (53, 62))	('found', 'Reg', (85, 90))	('CCA', 'Disease', (98, 101))
116234	32606456	A statistically significant association has also been observed between TP53 mutation and HBV infection.	('significant association', 'Reg', (16, 39))	('HBV infection', 'Disease', (89, 102))	('mutation', 'Var', (76, 84))	('HBV infection', 'Disease', 'MESH:D006509', (89, 102))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))
116236	32606456	emphasized the difference in anatomical location of the tumour, highlighting IDH, EPHA2 and BAP1 mutations and FGFR2 fusions in iCCA, whereas extrahepatic tumours specifically show PRKACA and PRKACB fusions as well as mutations in ELF3 (similar to tumours in the ampulla of Vater) and ARID1B.	('mutations', 'Var', (97, 106))	('CCA', 'Phenotype', 'HP:0030153', (129, 132))	('ELF3', 'Gene', '1999', (231, 235))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('tumour', 'Disease', (155, 161))	('fusions', 'Var', (117, 124))	('tumours', 'Disease', (248, 255))	('PRKACB', 'Gene', '5567', (192, 198))	('ARID1B', 'Gene', (285, 291))	('PRKACA', 'Gene', (181, 187))	('tumours', 'Disease', 'MESH:D009369', (155, 162))	('ELF3', 'Gene', (231, 235))	('iCCA', 'Disease', (128, 132))	('IDH', 'Gene', (77, 80))	('BAP1', 'Gene', '8314', (92, 96))	('tumours', 'Phenotype', 'HP:0002664', (248, 255))	('ARID1B', 'Gene', '57492', (285, 291))	('EPHA2', 'Gene', (82, 87))	('tumours', 'Disease', 'MESH:D009369', (248, 255))	('FGFR2', 'Gene', (111, 116))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (248, 254))	('tumour', 'Disease', 'MESH:D009369', (248, 254))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('IDH', 'Gene', '3417', (77, 80))	('tumour', 'Disease', (56, 62))	('BAP1', 'Gene', (92, 96))	('tumours', 'Disease', (155, 162))	('tumour', 'Disease', (248, 254))	('mutations', 'Var', (218, 227))	('extrahepatic tumours', 'Disease', (142, 162))	('extrahepatic tumours', 'Disease', 'MESH:D001651', (142, 162))	('FGFR2', 'Gene', '2263', (111, 116))	('PRKACB', 'Gene', (192, 198))	('PRKACA', 'Gene', '5566', (181, 187))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('EPHA2', 'Gene', '1969', (82, 87))	('fusions', 'Var', (199, 206))	('show', 'Reg', (176, 180))
116238	32606456	Besides linking IDH mutations with the response to ivosidenib, few studies have related genomic alterations to high-throughput drug screening.	('ivosidenib', 'Chemical', 'MESH:C000627630', (51, 61))	('IDH', 'Gene', (16, 19))	('IDH', 'Gene', '3417', (16, 19))	('rat', 'Species', '10116', (100, 103))	('mutations', 'Var', (20, 29))
116239	32606456	used an approach of integrative genomics in a large cohort of iCCAs to elucidate unique mutational signatures, structural variants and epigenomic alterations, emphasizing specific oncogenetic mechanisms in four distinct subsets of patients with potential drug responses and categories: RNA synthesis inhibition, IDH mutant; microtubule modulator, KRAS mutant; topoisomerase inhibition, TP53 mutant; and mTOR inhibitors.	('RNA synthesis', 'MPA', (286, 299))	('KRAS', 'Gene', (347, 351))	('mutant', 'Var', (391, 397))	('patients', 'Species', '9606', (231, 239))	('KRAS', 'Gene', '3845', (347, 351))	('IDH', 'Gene', '3417', (312, 315))	('CCA', 'Phenotype', 'HP:0030153', (63, 66))	('TP53', 'Gene', '7157', (386, 390))	('mTOR', 'Gene', (403, 407))	('rat', 'Species', '10116', (150, 153))	('mTOR', 'Gene', '2475', (403, 407))	('TP53', 'Gene', (386, 390))	('rat', 'Species', '10116', (25, 28))	('IDH', 'Gene', (312, 315))
116240	32606456	Epigenetics was shown to play an important part in the initiation and progression of CCA, affecting tumour phenotype in the absence of changes in DNA sequences.	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('Epigenetics', 'Var', (0, 11))	('CCA', 'Disease', (85, 88))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('affecting', 'Reg', (90, 99))	('tumour', 'Disease', (100, 106))	('CCA', 'Phenotype', 'HP:0030153', (85, 88))
116241	32606456	Deregulated patterns of methylation, histone modifications and aberrant expression of non-coding RNAs promote unbalanced transcription and gene expression that impair cell homeostasis and sustain malignant transformation.	('met', 'Gene', '79811', (24, 27))	('Deregulated', 'Var', (0, 11))	('cell homeostasis', 'CPA', (167, 183))	('aberrant', 'Var', (63, 71))	('met', 'Gene', (24, 27))	('expression', 'MPA', (72, 82))	('promote', 'PosReg', (102, 109))	('patterns', 'MPA', (12, 20))	('sustain', 'PosReg', (188, 195))	('histone', 'MPA', (37, 44))	('impair', 'NegReg', (160, 166))	('malignant transformation', 'CPA', (196, 220))
116242	32606456	Growing evidence supports deregulated methylation motifs in CCA cells compared with their normal counterparts, with a prevalent hypermethylation of multiple CpG sites occurring in CCA.	('deregulated', 'Var', (26, 37))	('met', 'Gene', '79811', (38, 41))	('CCA', 'Disease', (60, 63))	('met', 'Gene', (38, 41))	('met', 'Gene', '79811', (133, 136))	('CCA', 'Phenotype', 'HP:0030153', (60, 63))	('CCA', 'Phenotype', 'HP:0030153', (180, 183))	('met', 'Gene', (133, 136))
116245	32606456	Two sets of hypermethylated CCAs stood out, with an interesting association between CpG island hypermethylation and liver fluke-related tumours, increased mutation rate, downregulation of the DNA demethylation enzyme TET1, upregulation of the histone methyltransferase EZH2 and an increased level of deamination events.	('level', 'MPA', (291, 296))	('met', 'Gene', (17, 20))	('upregulation', 'PosReg', (223, 235))	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('liver fluke-related tumours', 'Disease', (116, 143))	('deamination events', 'MPA', (300, 318))	('rat', 'Species', '10116', (164, 167))	('downregulation', 'NegReg', (170, 184))	('met', 'Gene', '79811', (198, 201))	('increased', 'PosReg', (281, 290))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('met', 'Gene', '79811', (251, 254))	('met', 'Gene', (198, 201))	('met', 'Gene', '79811', (100, 103))	('met', 'Gene', (251, 254))	('met', 'Gene', (100, 103))	('increased', 'PosReg', (145, 154))	('liver fluke-related tumours', 'Disease', 'MESH:D008113', (116, 143))	('CCA', 'Phenotype', 'HP:0030153', (28, 31))	('TET1', 'Enzyme', (217, 221))	('mutation', 'Var', (155, 163))	('met', 'Gene', '79811', (17, 20))
116246	32606456	Conversely, the subgroup of iCCAs with enrichment in IDH1/2 and BAP1 mutations, as well as FGFR translocations, showed hypermethylation of the CpG shores (the regions immediately flanking CpG islands, up to 2 kb away).	('mutations', 'Var', (69, 78))	('men', 'Species', '9606', (45, 48))	('IDH1/2', 'Gene', (53, 59))	('met', 'Gene', '79811', (124, 127))	('met', 'Gene', (124, 127))	('CpG', 'Protein', (143, 146))	('BAP1', 'Gene', '8314', (64, 68))	('IDH1/2', 'Gene', '3417;3418', (53, 59))	('CCA', 'Phenotype', 'HP:0030153', (29, 32))	('BAP1', 'Gene', (64, 68))
116259	32606456	By contrast, the proliferation subclass was enriched in classic oncogenic pathways, including deregulated receptor tyrosine kinase (RTK) signalling, RAS-RAF-ERK, PI3K-AKT-mTOR, insulin growth factor receptor 1, MET, polo-like kinase 1, aurora kinase A, KRAS mutations and stem-like genomic traits as well as a focal deletion in the Hippo pathway (SAV1).	('MET', 'Gene', '79811', (211, 214))	('RAF', 'Gene', '22882', (153, 156))	('stem-like genomic traits', 'CPA', (272, 296))	('rat', 'Species', '10116', (24, 27))	('SAV1', 'Gene', (347, 351))	('mTOR', 'Gene', '2475', (171, 175))	('receptor tyrosine kinase', 'Gene', '5979', (106, 130))	('RAF', 'Gene', (153, 156))	('aurora kinase A', 'Gene', (236, 251))	('deletion', 'Var', (316, 324))	('polo-like kinase 1', 'Gene', (216, 234))	('aurora kinase A', 'Gene', '6790', (236, 251))	('receptor tyrosine kinase', 'Gene', (106, 130))	('ERK', 'Gene', '5594', (157, 160))	('KRAS', 'Gene', '3845', (253, 257))	('MET', 'Gene', (211, 214))	('RTK', 'Gene', (132, 135))	('Hippo pathway', 'Pathway', (332, 345))	('polo-like kinase 1', 'Gene', '5347', (216, 234))	('KRAS', 'Gene', (253, 257))	('ERK', 'Gene', (157, 160))	('SAV1', 'Gene', '60485', (347, 351))	('RTK', 'Gene', '5979', (132, 135))	('mTOR', 'Gene', (171, 175))	('deregulated', 'PosReg', (94, 105))
116261	32606456	Cholangiocarcinogenesis is orchestrated by a complex interplay of extracellular ligands (such as pro-inflammatory cytokines, growth factors and bile acids, among others), which are present in the tumour microenvironment (TME), and increased expression and/or aberrant activation of cell surface receptors and the deregulation of intracellular signalling pathways, finally leading to cell proliferation, survival and genetic and/or epigenetic alterations (Fig.	('genetic and/or', 'CPA', (416, 430))	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('tumour', 'Disease', 'MESH:D009369', (196, 202))	('Cholangiocarcinogenesis', 'Disease', 'None', (0, 23))	('TME', 'Chemical', '-', (221, 224))	('Cholangiocarcinogenesis', 'Disease', (0, 23))	('cell proliferation', 'CPA', (383, 401))	('tumour', 'Disease', (196, 202))	('bile acids', 'Chemical', 'MESH:D001647', (144, 154))	('intracellular signalling pathways', 'Pathway', (329, 362))	('men', 'Species', '9606', (215, 218))	('rat', 'Species', '10116', (395, 398))	('survival', 'CPA', (403, 411))	('leading to', 'Reg', (372, 382))	('increased', 'PosReg', (231, 240))	('rat', 'Species', '10116', (446, 449))	('aberrant', 'Var', (259, 267))	('activation', 'PosReg', (268, 278))	('epigenetic alterations', 'CPA', (431, 453))	('cell', 'Protein', (282, 286))	('rat', 'Species', '10116', (34, 37))
116269	32606456	In this regard, aberrant EGFR, ERBB2 and MET RTK expression has been found in different CCA subclasses that are associated with worse prognosis.	('aberrant', 'Var', (16, 24))	('RTK', 'Gene', (45, 48))	('EGFR', 'Gene', (25, 29))	('MET', 'Gene', (41, 44))	('CCA', 'Disease', (88, 91))	('ERBB2', 'Gene', (31, 36))	('EGFR', 'Gene', '1956', (25, 29))	('RTK', 'Gene', '5979', (45, 48))	('CCA', 'Phenotype', 'HP:0030153', (88, 91))	('ERBB2', 'Gene', '2064', (31, 36))	('found', 'Reg', (69, 74))	('associated', 'Reg', (112, 122))	('MET', 'Gene', '79811', (41, 44))
116271	32606456	Furthermore, RAS-MAPK pathway activation due to KRAS-activating mutations is found in all CCAs without distinction, whereas BRAF mutations are more prevalent in iCCA.	('MAPK', 'Gene', (17, 21))	('KRAS', 'Gene', (48, 52))	('KRAS', 'Gene', '3845', (48, 52))	('MAPK', 'Gene', '5594', (17, 21))	('activation', 'PosReg', (30, 40))	('CCAs', 'Disease', (90, 94))	('BRAF', 'Gene', '673', (124, 128))	('CCA', 'Phenotype', 'HP:0030153', (90, 93))	('CCA', 'Phenotype', 'HP:0030153', (162, 165))	('mutations', 'Var', (64, 73))	('BRAF', 'Gene', (124, 128))
116273	32606456	Besides FGFR2 fusions, ROS1 kinase protein fusions have also been identified in iCCA.	('ROS1', 'Gene', (23, 27))	('identified', 'Reg', (66, 76))	('ROS1', 'Gene', '6098', (23, 27))	('iCCA', 'Disease', (80, 84))	('FGFR2', 'Gene', (8, 13))	('FGFR2', 'Gene', '2263', (8, 13))	('CCA', 'Phenotype', 'HP:0030153', (81, 84))	('fusions', 'Var', (14, 21))
116276	32606456	Mutations in IDH1 and IDH2 lead to the production of high levels of 2-hydroxyglutarate, an oncometabolite that interferes with histone and DNA demethylases and inhibits the mitochondrial electron transport chain.	('IDH2', 'Gene', '3418', (22, 26))	('met', 'Gene', '79811', (145, 148))	('interferes', 'NegReg', (111, 121))	('mitochondrial electron transport chain', 'Pathway', (173, 211))	('met', 'Gene', (145, 148))	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))	('histone', 'Protein', (127, 134))	('Mutations', 'Var', (0, 9))	('met', 'Gene', '79811', (95, 98))	('lead to', 'Reg', (27, 34))	('inhibits', 'NegReg', (160, 168))	('IDH1', 'Gene', '3417', (13, 17))	('met', 'Gene', (95, 98))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (68, 86))	('production', 'MPA', (39, 49))
116278	32606456	Besides epigenetic silencing, inactivating mutations in multiple chromatin-remodelling genes (including BAP1, ARID1A and PBRM1) are common in iCCA.	('CCA', 'Phenotype', 'HP:0030153', (143, 146))	('BAP1', 'Gene', '8314', (104, 108))	('common', 'Reg', (132, 138))	('BAP1', 'Gene', (104, 108))	('ARID1A', 'Gene', '8289', (110, 116))	('iCCA', 'Disease', (142, 146))	('ARID1A', 'Gene', (110, 116))	('PBRM1', 'Gene', (121, 126))	('inactivating mutations', 'Var', (30, 52))	('PBRM1', 'Gene', '55193', (121, 126))
116281	32606456	The Notch pathway is known to be involved in biliary repair, growth, tubulogenesis, fibrosis and maintenance of the stem cell niche; defective Notch function due to JAG1 or NOTCH2 mutations causes impaired regeneration and Alagille syndrome, whereas increased Notch activity has been associated with primary liver tumours.	('JAG1', 'Gene', '182', (165, 169))	('mutations', 'Var', (180, 189))	('impaired regeneration and Alagille syndrome', 'Disease', 'MESH:D016738', (197, 240))	('JAG1', 'Gene', (165, 169))	('defective', 'NegReg', (133, 142))	('tumour', 'Phenotype', 'HP:0002664', (314, 320))	('Notch', 'MPA', (143, 148))	('NOTCH2', 'Gene', (173, 179))	('liver tumours', 'Disease', 'MESH:D008113', (308, 321))	('tumours', 'Phenotype', 'HP:0002664', (314, 321))	('causes', 'Reg', (190, 196))	('fibrosis', 'Disease', 'MESH:D005355', (84, 92))	('fibrosis', 'Disease', (84, 92))	('liver tumours', 'Disease', (308, 321))
116282	32606456	Overexpression or aberrant Notch receptor expression has been reported both in iCCAs and eCCA, including pCCA and dCCA.	('Notch receptor', 'Protein', (27, 41))	('dCCA', 'Chemical', '-', (114, 118))	('CCA', 'Phenotype', 'HP:0030153', (106, 109))	('aberrant', 'Var', (18, 26))	('reported', 'Reg', (62, 70))	('expression', 'MPA', (42, 52))	('eCCA', 'Disease', (89, 93))	('CCA', 'Phenotype', 'HP:0030153', (90, 93))	('CCA', 'Phenotype', 'HP:0030153', (115, 118))	('CCA', 'Phenotype', 'HP:0030153', (80, 83))	('pCCA', 'Disease', (105, 109))	('iCCAs', 'Disease', (79, 84))	('dCCA', 'Disease', (114, 118))
116285	32606456	Similarly, inhibition of NOTCH2, the expression of which has been shown to be related to well-differentiated iCCA, markedly reduced tumour burden in various mouse models of liver cancer (including iCCA), whereas overexpression of NOTCH3 was associated with the development and progression of iCCA, promoting cell survival via PI3K-AKT signalling.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('inhibition', 'Var', (11, 21))	('liver cancer', 'Phenotype', 'HP:0002896', (173, 185))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('mouse', 'Species', '10090', (157, 162))	('liver cancer', 'Disease', (173, 185))	('tumour', 'Disease', (132, 138))	('CCA', 'Phenotype', 'HP:0030153', (110, 113))	('CCA', 'Phenotype', 'HP:0030153', (293, 296))	('promoting', 'PosReg', (298, 307))	('CCA', 'Phenotype', 'HP:0030153', (198, 201))	('cell survival', 'CPA', (308, 321))	('NOTCH2', 'Gene', (25, 31))	('reduced', 'NegReg', (124, 131))	('iCCA', 'Disease', (292, 296))	('associated', 'Reg', (241, 251))	('men', 'Species', '9606', (268, 271))	('liver cancer', 'Disease', 'MESH:D006528', (173, 185))
116286	32606456	The WNT-beta-catenin signalling pathway is also known to be activated in most CCAs, in part as an effect of the release of Wnt ligands by inflammatory macrophages infiltrating the stroma, but also as a consequence of DNA methylation alterations targeting this pathway and/or mutations encoding key components of the canonical WNT-beta-catenin signalling pathway.	('mutations', 'Var', (275, 284))	('rat', 'Species', '10116', (169, 172))	('beta-catenin', 'Gene', (330, 342))	('beta-catenin', 'Gene', (8, 20))	('beta-catenin', 'Gene', '1499', (330, 342))	('DNA', 'Gene', (217, 220))	('met', 'Gene', '79811', (221, 224))	('CCAs', 'Disease', (78, 82))	('activated', 'PosReg', (60, 69))	('beta-catenin', 'Gene', '1499', (8, 20))	('alterations', 'Var', (233, 244))	('rat', 'Species', '10116', (237, 240))	('met', 'Gene', (221, 224))	('CCA', 'Phenotype', 'HP:0030153', (78, 81))
116295	32606456	Genetic alteration of the YAP pathway seems to be uncommon in CCA, according to an integrative genomic analysis of CCA specimens.	('rat', 'Species', '10116', (12, 15))	('Genetic alteration', 'Var', (0, 18))	('CCA', 'Phenotype', 'HP:0030153', (62, 65))	('men', 'Species', '9606', (124, 127))	('YAP', 'Gene', '10413', (26, 29))	('rat', 'Species', '10116', (88, 91))	('CCA', 'Phenotype', 'HP:0030153', (115, 118))	('YAP', 'Gene', (26, 29))	('CCA', 'Disease', (62, 65))
116296	32606456	However, mutations in ARID1A have been reported in up to 14% of CCAs.	('mutations', 'Var', (9, 18))	('reported', 'Reg', (39, 47))	('ARID1A', 'Gene', '8289', (22, 28))	('CCAs', 'Disease', (64, 68))	('ARID1A', 'Gene', (22, 28))	('CCA', 'Phenotype', 'HP:0030153', (64, 67))
116327	32606456	TGFbeta was reported to be pivotal in promoting an iCCA-desmoplastic phenotype in a 3D rat organotypic culture model, and targeting the TGFbeta pathway in thioacetamide-treated rats improved fibrosis and reduced CCA burden.	('iCCA-desmoplastic', 'Disease', (51, 68))	('promoting', 'PosReg', (38, 47))	('TGFbeta', 'Gene', (136, 143))	('CCA', 'Phenotype', 'HP:0030153', (212, 215))	('rat', 'Species', '10116', (177, 180))	('targeting', 'Var', (122, 131))	('improved', 'PosReg', (182, 190))	('CCA burden', 'CPA', (212, 222))	('TGFbeta', 'Gene', (0, 7))	('CCA', 'Phenotype', 'HP:0030153', (52, 55))	('reduced', 'NegReg', (204, 211))	('iCCA-desmoplastic', 'Disease', 'MESH:D018220', (51, 68))	('thioacetamide', 'Chemical', 'MESH:D013853', (155, 168))	('fibrosis', 'Disease', 'MESH:D005355', (191, 199))	('fibrosis', 'Disease', (191, 199))	('rats', 'Species', '10116', (177, 181))	('rat', 'Species', '10116', (87, 90))
116374	32606456	Importantly, whole-exome sequencing revealed that the vast majority of the mutations are retained in liver cancer organoids derived from resected tissues, whereas mutation retention is heterogeneous in biopsy-derived liver cancer organoids.	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('liver cancer', 'Phenotype', 'HP:0002896', (217, 229))	('liver cancer', 'Disease', 'MESH:D006528', (217, 229))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('liver cancer', 'Phenotype', 'HP:0002896', (101, 113))	('liver cancer', 'Disease', 'MESH:D006528', (101, 113))	('liver cancer', 'Disease', (217, 229))	('mutations', 'Var', (75, 84))	('liver cancer', 'Disease', (101, 113))
116376	32606456	As an alternative method, CCA organoids can be established by inducing genetic mutations in healthy organoids via viral transduction and CRISPR-Cas9 genome editing approaches, thus enabling the characterization and elucidation of the roles of oncogenes and/or tumour suppressor genes, either alone or in combination, in cholangiocarcinogenesis.	('tumour', 'Phenotype', 'HP:0002664', (260, 266))	('tumour', 'Disease', 'MESH:D009369', (260, 266))	('cholangiocarcinogenesis', 'Disease', (320, 343))	('met', 'Gene', '79811', (18, 21))	('inducing', 'Reg', (62, 70))	('met', 'Gene', (18, 21))	('genetic mutations', 'Var', (71, 88))	('tumour', 'Disease', (260, 266))	('nab', 'Chemical', '-', (182, 185))	('CCA organoids', 'Chemical', '-', (26, 39))	('cholangiocarcinogenesis', 'Disease', 'None', (320, 343))	('CCA', 'Phenotype', 'HP:0030153', (26, 29))	('mutations', 'Var', (79, 88))
116385	32606456	Detection of cfDNA in plasma samples could also guide potential mutational-based therapeutic interventions as de novo multiple point mutations in FGFR2 kinase domain were detected in cfDNA, primary tumours and metastases from patients with CCA with acquired resistance to the pan-FGFR inhibitor BGJ398 (ref.).	('tumours', 'Phenotype', 'HP:0002664', (198, 205))	('tumours', 'Disease', 'MESH:D009369', (198, 205))	('FGFR2', 'Gene', (146, 151))	('metastases', 'Disease', 'MESH:D009362', (210, 220))	('FGFR2', 'Gene', '2263', (146, 151))	('CCA', 'Phenotype', 'HP:0030153', (240, 243))	('tumours', 'Disease', (198, 205))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('mutations', 'Var', (133, 142))	('BGJ398', 'Chemical', 'MESH:C568950', (295, 301))	('cfDNA', 'Disease', (183, 188))	('patients', 'Species', '9606', (226, 234))	('detected', 'Reg', (171, 179))	('metastases', 'Disease', (210, 220))	('CCA', 'Disease', (240, 243))
116399	32606456	Furthermore, another study identified an extracellular vesicle-derived miRNA panel in bile (miRNAs miR-191, miR-486-3p, miR-1274b and miR-484) for the discrimination of CCA from non-malignant biliary diseases.	('CCA', 'Disease', (169, 172))	('miR-191', 'Gene', (99, 106))	('miR-486-3p', 'Var', (108, 118))	('biliary diseases', 'Disease', 'MESH:D001660', (192, 208))	('miR-484', 'Gene', (134, 141))	('CCA', 'Phenotype', 'HP:0030153', (169, 172))	('biliary diseases', 'Disease', (192, 208))	('miR-484', 'Gene', '619553', (134, 141))	('miR-1274b', 'Var', (120, 129))	('miR-191', 'Gene', '406966', (99, 106))
116403	32606456	In two large and independent cohorts of patients with iCCA who had undergone tumour resection (n = 137 in one study; n = 292 in the other), mutations in KRAS (12-16%) and TP53 (13-20%) were associated with shorter OS and an increased rate of tumour recurrence when compared with patients with IDH1 or IDH2 mutations or an 'undetermined' group (with none of the aforementioned mutations).	('IDH2', 'Gene', (301, 305))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', (77, 83))	('IDH2', 'Gene', '3418', (301, 305))	('tumour', 'Phenotype', 'HP:0002664', (242, 248))	('TP53', 'Gene', (171, 175))	('IDH1', 'Gene', (293, 297))	('tumour', 'Disease', 'MESH:D009369', (242, 248))	('tumour', 'Disease', (242, 248))	('CCA', 'Phenotype', 'HP:0030153', (55, 58))	('KRAS', 'Gene', '3845', (153, 157))	('men', 'Species', '9606', (366, 369))	('IDH1', 'Gene', '3417', (293, 297))	('KRAS', 'Gene', (153, 157))	('patients', 'Species', '9606', (279, 287))	('rat', 'Species', '10116', (234, 237))	('mutations', 'Var', (140, 149))	('TP53', 'Gene', '7157', (171, 175))	('patients', 'Species', '9606', (40, 48))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
116475	32606456	In a preliminary phase III trial in which 185 patients with IDH-1 mutant CCA were randomly assigned to ivosidenib or placebo, ivosidenib showed a benefit in terms of progression free-survival (HR 0.37).	('IDH-1', 'Gene', (60, 65))	('ivosidenib', 'Chemical', 'MESH:C000627630', (126, 136))	('patients', 'Species', '9606', (46, 54))	('mutant', 'Var', (66, 72))	('progression free-survival', 'CPA', (166, 191))	('ivosidenib', 'Chemical', 'MESH:C000627630', (103, 113))	('CCA', 'Phenotype', 'HP:0030153', (73, 76))	('benefit', 'PosReg', (146, 153))	('IDH-1', 'Gene', '3417', (60, 65))	('CCA', 'Disease', (73, 76))
116479	32606456	Furthermore, some pan-tumour studies including patients with neurotrophic RTK fusions (TRK inhibitors) or WNT pathway alterations such as RNF43 mutations (porcupine inhibitors; NCT03447470) are relevant to CCA, but only for a very small percentage of patients.	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('CCA', 'Phenotype', 'HP:0030153', (206, 209))	('TRK', 'Gene', '4914', (87, 90))	('tumour', 'Disease', (22, 28))	('patients', 'Species', '9606', (47, 55))	('CCA', 'Disease', (206, 209))	('RTK', 'Gene', (74, 77))	('patients', 'Species', '9606', (251, 259))	('rat', 'Species', '10116', (122, 125))	('TRK', 'Gene', (87, 90))	('RNF43', 'Gene', (138, 143))	('mutations', 'Var', (144, 153))	('RNF43', 'Gene', '54894', (138, 143))	('RTK', 'Gene', '5979', (74, 77))
116528	32606456	Up to 50% of CCAs have current druggable mutations, amplifications or fusions (for example, IDH1, IDH2, BRAF, FGFR, HER2, PIK3CA, MET, among others), opening a new opportunity for therapeutic intervention that deserves intense basic and clinical research.	('mutations', 'Var', (41, 50))	('PIK3CA', 'Gene', (122, 128))	('CCA', 'Phenotype', 'HP:0030153', (13, 16))	('CCAs', 'Disease', (13, 17))	('IDH2', 'Gene', (98, 102))	('MET', 'Gene', (130, 133))	('IDH1', 'Gene', (92, 96))	('PIK3CA', 'Gene', '5290', (122, 128))	('amplifications', 'Var', (52, 66))	('HER2', 'Gene', (116, 120))	('FGFR', 'Gene', (110, 114))	('IDH1', 'Gene', '3417', (92, 96))	('BRAF', 'Gene', '673', (104, 108))	('HER2', 'Gene', '2064', (116, 120))	('IDH2', 'Gene', '3418', (98, 102))	('BRAF', 'Gene', (104, 108))	('fusions', 'Var', (70, 77))	('MET', 'Gene', '79811', (130, 133))
116529	32606456	In fact, targeting these mutations is amenable and is already a reality in other types of cancer.	('mutations', 'Var', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('nab', 'Chemical', '-', (41, 44))	('men', 'Species', '9606', (39, 42))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
116535	32606456	New technical approaches such as single-cell RNA or DNA sequencing could provide novel critical information about cellular heterogeneity, in both the tumour compartment and the stroma, by capturing genomic and/or genetic alteration with a resolution at the level of the single cell.	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('rat', 'Species', '10116', (225, 228))	('genetic alteration', 'Var', (213, 231))	('tumour', 'Disease', (150, 156))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('men', 'Species', '9606', (164, 167))
116544	32606456	Non-coding RNA, specifically miRNAs, long non-coding RNAs and circular RNAs and circulating proteins and/or metabolites could represent such promising biomarkers, due to their easy detection and stability in biological fluids, either free or encapsulated into extracellular vesicles.	('met', 'Gene', (108, 111))	('met', 'Gene', '79811', (108, 111))	('long non-coding', 'Var', (37, 52))
116555	32606456	Different risk factors, interactions between cancer cells, CSCs and the TME, as well as the evident clonal evolution and genetic and/or epigenetic aberrations contribute to CCA heterogeneity.	('CCA', 'Disease', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('TME', 'Chemical', '-', (72, 75))	('epigenetic aberrations', 'Var', (136, 158))	('CCA', 'Phenotype', 'HP:0030153', (173, 176))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('rat', 'Species', '10116', (151, 154))	('cancer', 'Disease', (45, 51))
116568	31761616	Through in vitro and in vivo experiments, we demonstrated that SPRY4 suppressed FGFR-induced proliferation and migration by inhibiting ERK phosphorylation.	('ERK', 'Gene', '5594', (135, 138))	('migration', 'CPA', (111, 120))	('ERK', 'Gene', (135, 138))	('SPRY4', 'Var', (63, 68))	('inhibiting', 'NegReg', (124, 134))	('suppressed', 'NegReg', (69, 79))	('FGFR-induced', 'Gene', (80, 92))
116569	31761616	Moreover, SPRY4 knockdown was shown to decrease the percentage of cells in the G1 phase and promote the percentage of cells in the S and G2/M phases by increasing cyclin D1 expression, which also required FGFR-induced ERK phosphorylation.	('cyclin D1', 'Gene', '595', (163, 172))	('increasing', 'PosReg', (152, 162))	('promote', 'PosReg', (92, 99))	('decrease', 'NegReg', (39, 47))	('SPRY4', 'Gene', (10, 15))	('cyclin D1', 'Gene', (163, 172))	('ERK', 'Gene', '5594', (218, 221))	('knockdown', 'Var', (16, 25))	('ERK', 'Gene', (218, 221))	('expression', 'MPA', (173, 183))
116570	31761616	SPRY4 expression can be induced by ectopic FGFR2 activation in PHCC.	('SPRY4', 'Gene', (0, 5))	('expression', 'MPA', (6, 16))	('FGFR2', 'Gene', (43, 48))	('ectopic', 'Var', (35, 42))	('FGFR2', 'Gene', '2263', (43, 48))	('induced', 'Reg', (24, 31))	('activation', 'PosReg', (49, 59))
116576	31761616	Through in vitro and in vivo experiments, we demonstrated that SPRY4 could suppress FGFR-induced proliferation and migration of PHCC by inhibiting ERK phosphorylation.	('inhibiting', 'NegReg', (136, 146))	('migration', 'CPA', (115, 124))	('PHCC', 'CPA', (128, 132))	('SPRY4', 'Var', (63, 68))	('ERK', 'Gene', '5594', (147, 150))	('suppress', 'NegReg', (75, 83))	('ERK', 'Gene', (147, 150))	('FGFR-induced', 'Gene', (84, 96))
116577	31761616	Furthermore, we revealed that SPRY4 inhibited proliferation by arresting cells in the G1 phase via a reduction in cyclin D1 expression.	('reduction', 'NegReg', (101, 110))	('inhibited', 'NegReg', (36, 45))	('SPRY4', 'Var', (30, 35))	('cyclin D1', 'Gene', '595', (114, 123))	('cyclin D1', 'Gene', (114, 123))	('proliferation', 'CPA', (46, 59))	('expression', 'MPA', (124, 134))	('cells in the G1 phase', 'CPA', (73, 94))	('arresting', 'NegReg', (63, 72))
116584	31761616	Emerging evidence from comprehensive genetic analyses reveal several actionable mutations in CCA, such as fibroblast growth factor receptor (FGFR) fusion rearrangements and isocitrate dehydrogenase (IDH)-1 and IDH2 mutations.	('CCA', 'Disease', (93, 96))	('IDH2', 'Gene', '3418', (210, 214))	('isocitrate dehydrogenase (IDH)-1', 'Gene', '3417', (173, 205))	('fusion rearrangements', 'Var', (147, 168))	('mutations', 'Var', (215, 224))	('FGFR', 'Gene', (141, 145))	('IDH2', 'Gene', (210, 214))
116586	31761616	In all subtypes of CCA, Kirsten ras sarcoma viral oncogene homolog (KRAS) mutations and FGFR2 fusions are well-identified somatic genetic alterations.	('sarcoma', 'Disease', 'MESH:D012509', (36, 43))	('mutations', 'Var', (74, 83))	('FGFR2', 'Gene', (88, 93))	('CCA', 'Disease', (19, 22))	('KRAS', 'Gene', (68, 72))	('sarcoma', 'Disease', (36, 43))	('KRAS', 'Gene', '3845', (68, 72))	('FGFR2', 'Gene', '2263', (88, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('fusions', 'Var', (94, 101))
116587	31761616	KRAS mutations are associated with poor overall survival, and several independent lines of evidence have demonstrated the role of FGFR2 fusion in CCA tumorigenesis and progression.	('fusion', 'Var', (136, 142))	('CCA', 'Disease', (146, 149))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('FGFR2', 'Gene', (130, 135))	('FGFR2', 'Gene', '2263', (130, 135))	('KRAS', 'Gene', (0, 4))	('tumor', 'Disease', (150, 155))	('KRAS', 'Gene', '3845', (0, 4))
116590	31761616	Both KRAS mutations and FGFR2 fusions constitutively stimulate the MEK/MAPK pathway, and this ectopic activation finally leads to excessive proliferation in tumor cells.	('tumor', 'Disease', (157, 162))	('FGFR2', 'Gene', '2263', (24, 29))	('stimulate', 'PosReg', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('fusions', 'Var', (30, 37))	('KRAS', 'Gene', (5, 9))	('leads to', 'Reg', (121, 129))	('KRAS', 'Gene', '3845', (5, 9))	('MEK', 'Gene', (67, 70))	('MEK', 'Gene', '5609', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mutations', 'Var', (10, 19))	('FGFR2', 'Gene', (24, 29))
116594	31761616	Dysfunction in the SPRY family has been reported to be correlated with progression in several types of cancers, including gastric cancer, breast cancer, liver cancer and prostate cancer.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('prostate cancer', 'Disease', 'MESH:D011471', (170, 185))	('prostate cancer', 'Phenotype', 'HP:0012125', (170, 185))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))	('prostate cancer', 'Disease', (170, 185))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('liver cancer', 'Disease', 'MESH:D006528', (153, 165))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('SPRY', 'Gene', (19, 23))	('cancers', 'Disease', (103, 110))	('Dysfunction', 'Var', (0, 11))	('gastric cancer', 'Disease', (122, 136))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('liver cancer', 'Phenotype', 'HP:0002896', (153, 165))	('breast cancer', 'Disease', (138, 151))	('liver cancer', 'Disease', (153, 165))	('correlated', 'Reg', (55, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('SPRY', 'Gene', '10252;10253;10251;81848;24066', (19, 23))
116596	31761616	For example, SPRY4 was reported to inhibit the tumorigenesis in several tumor types like lung cancer and glioblastoma.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('SPRY4', 'Var', (13, 18))	('glioblastoma', 'Disease', 'MESH:D005909', (105, 117))	('lung cancer', 'Disease', (89, 100))	('tumor', 'Disease', (72, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('glioblastoma', 'Disease', (105, 117))	('inhibit', 'NegReg', (35, 42))	('tumor', 'Disease', (47, 52))
116598	31761616	Moreover, loss of SPRY4 but not of other SPRY members, amplifies RAS signaling in acute myeloid leukemia.	('loss', 'Var', (10, 14))	('SPRY', 'Gene', '10252;10253;10251;81848;24066', (41, 45))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (88, 104))	('SPRY', 'Gene', (41, 45))	('SPRY', 'Gene', '10252;10253;10251;81848;24066', (18, 22))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (82, 104))	('acute myeloid leukemia', 'Disease', (82, 104))	('SPRY', 'Gene', (18, 22))	('RAS signaling', 'MPA', (65, 78))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (82, 104))	('amplifies', 'Reg', (55, 64))
116631	31761616	Approximately 500 mul complete medium or serum-free medium containing FBS, 50 ng/ml FGF2, 100 nM AP24534 or 1 muM ulixertinib was added to the lower chamber.	('muM', 'Gene', '56925', (110, 113))	('ulixertinib', 'Chemical', 'MESH:C000618314', (114, 125))	('AP24534', 'Var', (97, 104))	('AP24534', 'Chemical', 'MESH:C545373', (97, 104))	('muM', 'Gene', (110, 113))	('FGF2', 'Gene', (84, 88))
116633	31761616	Medium with 50 ng/ml FGF2, FBS, 100 nMAP24534 or 1 muM ulixertinib was then added if necessary.	('100 nMAP24534', 'Var', (32, 45))	('muM', 'Gene', '56925', (51, 54))	('AP24534', 'Chemical', 'MESH:C545373', (38, 45))	('ulixertinib', 'Chemical', 'MESH:C000618314', (55, 66))	('muM', 'Gene', (51, 54))
116635	31761616	A total of 3 x 105 cells were seeded in 6-well plates and cultured for 24-48 h in 50 ng/ml FGF2, FBS, 100 nM AP24534 and/or 1 muM ulixertinib.	('muM', 'Gene', '56925', (126, 129))	('FGF2', 'Gene', (91, 95))	('muM', 'Gene', (126, 129))	('AP24534', 'Var', (109, 116))	('AP24534', 'Chemical', 'MESH:C545373', (109, 116))	('ulixertinib', 'Chemical', 'MESH:C000618314', (130, 141))
116638	31761616	In brief, 3 x 105 cells were seeded in 6-well plates and cultured for 24-48 h in 50 ng/ml FGF2, FBS, 100 nM AP24534 and/or 1 muM ulixertinib.	('AP24534', 'Var', (108, 115))	('AP24534', 'Chemical', 'MESH:C545373', (108, 115))	('muM', 'Gene', '56925', (125, 128))	('muM', 'Gene', (125, 128))	('FGF2', 'Gene', (90, 94))	('ulixertinib', 'Chemical', 'MESH:C000618314', (129, 140))
116660	31761616	In our study, high expression of SPRY4 was significantly associated with small tumor size (P = 0.007), negative lymphatic invasion(P = 0.031) and early TNM stage (P = 0.002), indicating that SPRY4 may suppress the proliferation and invasion of PHCC.	('TNM', 'Gene', (152, 155))	('expression', 'MPA', (19, 29))	('suppress', 'NegReg', (201, 209))	('invasion', 'CPA', (232, 240))	('negative lymphatic invasion', 'CPA', (103, 130))	('high', 'Var', (14, 18))	('proliferation', 'CPA', (214, 227))	('TNM', 'Gene', '10178', (152, 155))	('SPRY4', 'Gene', (33, 38))	('small tumor', 'Disease', 'MESH:D058405', (73, 84))	('small tumor', 'Disease', (73, 84))	('SPRY4', 'Var', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
116665	31761616	High expression of FGFR4 was a prognostic biomarker of PHCC, which was in consistent with our previous study.	('FGFR4', 'Gene', '2264', (19, 24))	('FGFR4', 'Gene', (19, 24))	('PHCC', 'Disease', (55, 59))	('High', 'Var', (0, 4))
116666	31761616	Besides FGFR4, high expression of FGFR2 also indicated poor prognosis of PHCC (Fig.	('high', 'Var', (15, 19))	('FGFR2', 'Gene', (34, 39))	('FGFR2', 'Gene', '2263', (34, 39))	('FGFR4', 'Gene', '2264', (8, 13))	('FGFR4', 'Gene', (8, 13))
116668	31761616	3(c)), and patients with high FGFR2 seemed to have higher expression of SPRY4 (Fig.	('patients', 'Species', '9606', (11, 19))	('FGFR2', 'Gene', '2263', (30, 35))	('expression', 'MPA', (58, 68))	('SPRY4', 'Protein', (72, 77))	('high', 'Var', (25, 29))	('FGFR2', 'Gene', (30, 35))	('higher', 'PosReg', (51, 57))
116669	31761616	PHCC cell line QBC939 was incubated in 10 ng/ml FGF2 for 0-72 h. In this long-term activation, SPRY4 expression was elevated by FGF2 (Fig.	('FGF2', 'Var', (128, 132))	('elevated', 'PosReg', (116, 124))	('expression', 'MPA', (101, 111))	('QBC939', 'CellLine', 'CVCL:6942', (15, 21))	('SPRY4', 'Gene', (95, 100))
116676	31761616	Both CCK-8 and colony formation assays showed that SPRY4 knockdown substantially promoted the proliferation of QBC939 cells (Fig.	('QBC939', 'CellLine', 'CVCL:6942', (111, 117))	('promoted', 'PosReg', (81, 89))	('SPRY4', 'Gene', (51, 56))	('knockdown', 'Var', (57, 66))	('proliferation', 'CPA', (94, 107))
116678	31761616	In addition, stable QBC939 cells with SPRY4 knockdown were established and subcutaneously transplanted into nude mice for successful xenograft formation (Fig.	('SPRY4', 'Gene', (38, 43))	('nude mice', 'Species', '10090', (108, 117))	('knockdown', 'Var', (44, 53))	('QBC939', 'CellLine', 'CVCL:6942', (20, 26))
116682	31761616	After SPRY4 knockdown, QBC939 cells were serum-starved for 6 h and incubated in 50 ng/ml FGF2 and 1% FBS for 1-4 days.	('QBC939', 'CellLine', 'CVCL:6942', (23, 29))	('knockdown', 'Var', (12, 21))	('SPRY4', 'Gene', (6, 11))
116683	31761616	Consequently, SPRY4 silencing significantly increased FGF2-induced proliferation of QBC939 cells (Fig.	('FGF2-induced', 'Gene', (54, 66))	('SPRY4', 'Gene', (14, 19))	('proliferation', 'CPA', (67, 80))	('increased', 'PosReg', (44, 53))	('QBC939', 'CellLine', 'CVCL:6942', (84, 90))	('silencing', 'Var', (20, 29))
116684	31761616	Moreover, a pan-inhibitor of FGFR, AP24534 (100 nM), was used to block FGFR signaling.	('AP24534', 'Chemical', 'MESH:C545373', (35, 42))	('AP24534', 'Var', (35, 42))	('FGFR', 'MPA', (71, 75))
116685	31761616	As expected, the FGFR inhibitor AP24534 remarkably decreased FGF2-induced proliferation, while SPRY4 knockdown substantially attenuated this effect (Fig.	('attenuated', 'NegReg', (125, 135))	('AP24534', 'Chemical', 'MESH:C545373', (32, 39))	('decreased', 'NegReg', (51, 60))	('AP24534', 'Var', (32, 39))	('proliferation', 'CPA', (74, 87))	('FGF2-induced', 'Gene', (61, 73))
116686	31761616	AP24534 significantly suppressed the migration of QBC939 cells induced by FGF2, whereas the migration of QBC939 cells enhanced by SPRY4 knockdown (Fig.	('FGF2', 'Gene', (74, 78))	('suppressed', 'NegReg', (22, 32))	('AP24534', 'Var', (0, 7))	('AP24534', 'Chemical', 'MESH:C545373', (0, 7))	('migration', 'CPA', (37, 46))	('knockdown', 'Var', (136, 145))	('enhanced', 'PosReg', (118, 126))	('migration', 'CPA', (92, 101))	('QBC939', 'CellLine', 'CVCL:6942', (50, 56))	('QBC939', 'CellLine', 'CVCL:6942', (105, 111))
116689	31761616	Mice injected with AP24534 had significantly smaller tumor volumes and lower tumor weights (Fig.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('smaller', 'NegReg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('AP24534', 'Var', (19, 26))	('AP24534', 'Chemical', 'MESH:C545373', (19, 26))	('tumor', 'Disease', (53, 58))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', (77, 82))	('lower', 'NegReg', (71, 76))
116692	31761616	SPRY4 silencing was shown to enhance ERK phosphorylation of QBC939 cells in 10% FBS (Fig.	('QBC939', 'CellLine', 'CVCL:6942', (60, 66))	('SPRY4', 'Gene', (0, 5))	('ERK', 'Gene', '5594', (37, 40))	('ERK', 'Gene', (37, 40))	('enhance', 'PosReg', (29, 36))	('silencing', 'Var', (6, 15))
116695	31761616	This FGF2-induced ERK phosphorylation was antagonized by AP24534 and enhanced by SPRY4 silencing in QBC939 cells (Fig.	('ERK', 'Gene', (18, 21))	('enhanced', 'PosReg', (69, 77))	('antagonized', 'NegReg', (42, 53))	('QBC939', 'CellLine', 'CVCL:6942', (100, 106))	('FGF2-induced', 'Gene', (5, 17))	('ERK', 'Gene', '5594', (18, 21))	('AP24534', 'Chemical', 'MESH:C545373', (57, 64))	('SPRY4', 'Gene', (81, 86))	('AP24534', 'Var', (57, 64))
116698	31761616	Both CCK-8 and transwell assays revealed that ERK inhibition could suppress the promotion of proliferation and migration induced by SPRY4 knockdown (Fig.	('ERK', 'Gene', '5594', (46, 49))	('knockdown', 'Var', (138, 147))	('promotion', 'PosReg', (80, 89))	('ERK', 'Gene', (46, 49))	('inhibition', 'NegReg', (50, 60))	('suppress', 'NegReg', (67, 75))	('SPRY4', 'Gene', (132, 137))
116704	31761616	Moreover, in vitro and in vivo experiments, SPRY4 was shown to suppress tumor proliferation.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('suppress', 'NegReg', (63, 71))	('SPRY4', 'Var', (44, 49))
116709	31761616	Furthermore, the cell cycle of QBC939 cells was detected in the presence or absence of AP24534 after SPRY4 silencing.	('absence', 'NegReg', (76, 83))	('cell cycle', 'CPA', (17, 27))	('detected', 'Reg', (48, 56))	('AP24534', 'Var', (87, 94))	('AP24534', 'Chemical', 'MESH:C545373', (87, 94))	('QBC939', 'CellLine', 'CVCL:6942', (31, 37))
116710	31761616	SPRY4 knockdown substantially decreased the proportion of cells in the G1 phase and increased the proportion of cells in the S and G2/M phase, while AP24534 attenuated this effect(Fig.	('G1 phase', 'CPA', (71, 79))	('SPRY4', 'Gene', (0, 5))	('AP24534', 'Var', (149, 156))	('AP24534', 'Chemical', 'MESH:C545373', (149, 156))	('increased', 'PosReg', (84, 93))	('knockdown', 'Var', (6, 15))	('decreased', 'NegReg', (30, 39))
116712	31761616	SPRY4 knockdown promoted the expression of Cyclin D1 but not Cyclin A2 or B1, and AP24534 decreased Cyclin D1 expression, indicating that SPRY4 knockdown increased the proportion of S and G2/M phase cells by promoting Cyclin D1 expression.	('AP24534', 'Chemical', 'MESH:C545373', (82, 89))	('Cyclin D1', 'Gene', (100, 109))	('SPRY4', 'Gene', (138, 143))	('Cyclin D1', 'Gene', '595', (218, 227))	('promoted', 'PosReg', (16, 24))	('Cyclin D1', 'Gene', '595', (43, 52))	('Cyclin D1', 'Gene', (218, 227))	('Cyclin D1', 'Gene', (43, 52))	('decreased', 'NegReg', (90, 99))	('promoting', 'PosReg', (208, 217))	('Cyclin A2', 'Gene', '890', (61, 70))	('expression', 'MPA', (110, 120))	('AP24534', 'Var', (82, 89))	('expression', 'MPA', (29, 39))	('increased', 'PosReg', (154, 163))	('Cyclin A2', 'Gene', (61, 70))	('expression', 'MPA', (228, 238))	('Cyclin D1', 'Gene', '595', (100, 109))
116716	31761616	7(h) and (i)) and decreased in response to AP24534 treatment (Fig.	('decreased', 'NegReg', (18, 27))	('AP24534', 'Chemical', 'MESH:C545373', (43, 50))	('AP24534', 'Var', (43, 50))
116730	31761616	The molecular mechanism by which SPRY4 inhibits ERK phosphorylation is still controversial.	('SPRY4', 'Var', (33, 38))	('ERK', 'Gene', (48, 51))	('inhibits', 'NegReg', (39, 47))	('ERK', 'Gene', '5594', (48, 51))
116739	31761616	RAS mutations and FGFR2 fusions are the most well-accepted molecular features of CCA8.	('FGFR2', 'Gene', (18, 23))	('FGFR2', 'Gene', '2263', (18, 23))	('RAS mutations', 'Var', (0, 13))	('CCA8', 'Disease', (81, 85))	('fusions', 'Var', (24, 31))
116742	31761616	Furthermore, a recent study showed that tumor cells may develop FGFR2 mutations and exhibit resistance to FGFR2 inhibitors.	('FGFR2', 'Gene', '2263', (64, 69))	('mutations', 'Var', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('FGFR2', 'Gene', '2263', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('FGFR2', 'Gene', (106, 111))	('FGFR2', 'Gene', (64, 69))	('resistance', 'CPA', (92, 102))
116743	31761616	Our findings that SPRY4 inhibits ERK activation in PHCC indicated that SPRY4 could also be a potential therapeutic target.	('SPRY4', 'Var', (18, 23))	('ERK', 'Gene', (33, 36))	('ERK', 'Gene', '5594', (33, 36))	('inhibits', 'NegReg', (24, 32))
116749	31761616	Through in vitro and in vivo experiments, we demonstrated that SPRY4 can suppress FGFR-induced proliferation and migration of PHCC cells by inhibiting ERK phosphorylation.	('suppress', 'NegReg', (73, 81))	('inhibiting', 'NegReg', (140, 150))	('SPRY4', 'Var', (63, 68))	('ERK', 'Gene', '5594', (151, 154))	('migration', 'CPA', (113, 122))	('ERK', 'Gene', (151, 154))	('FGFR-induced', 'Gene', (82, 94))
116750	31761616	Furthermore, we revealed that SPRY4 inhibited proliferation by arresting cells in the G1 phase and by reducing Cyclin D1 expression.	('inhibited', 'NegReg', (36, 45))	('Cyclin D1', 'Gene', (111, 120))	('reducing', 'NegReg', (102, 110))	('SPRY4', 'Var', (30, 35))	('expression', 'MPA', (121, 131))	('proliferation', 'CPA', (46, 59))	('cells in the G1 phase', 'CPA', (73, 94))	('arresting', 'NegReg', (63, 72))	('Cyclin D1', 'Gene', '595', (111, 120))
116751	31761616	Our results indicated that SPRY4 may be a potential target for PHCC treatment and suggested that the detection of SPRY4 in PHCC patients can help stratify high- and low-risk patients more effectively, which may guide individualized therapy for PHCC.	('detection', 'Var', (101, 110))	('guide', 'Reg', (211, 216))	('SPRY4', 'Gene', (114, 119))	('patients', 'Species', '9606', (174, 182))	('patients', 'Species', '9606', (128, 136))
116763	27633916	conducted a multiplatform pan-cancer analysis across twelve cancer types and found a subtype consisting of lung squamous, head and neck, and a subset of bladder cancers, which are characterized by TP53 alterations, TP63 amplifications, and deregulation of immune and proliferation genes.	('TP63', 'Gene', (215, 219))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('bladder cancers', 'Phenotype', 'HP:0009725', (153, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancer', 'Disease', (161, 167))	('bladder cancer', 'Phenotype', 'HP:0009725', (153, 167))	('TP53', 'Gene', (197, 201))	('alterations', 'Var', (202, 213))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('TP63', 'Gene', '8626', (215, 219))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('lung squamous', 'Disease', (107, 120))	('bladder cancers', 'Disease', 'MESH:D001749', (153, 168))	('bladder cancers', 'Disease', (153, 168))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('TP53', 'Gene', '7157', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('deregulation', 'Var', (240, 252))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
116765	27633916	also employed a pan-cancer study to demonstrate universal patterns of epigenomic deregulation and distinct processes controlling genome-wide DNA hypo- and hyper-methylation across tumor lineages.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('hyper-methylation', 'Var', (155, 172))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))
116788	27633916	Generally, dysregulation of these cell cycle genes with defects of proteins RB and TP53 will permit persistent cell proliferation of cancer cells and promote tumor progression in the long term.	('defects of proteins RB', 'Disease', 'MESH:D012175', (56, 78))	('TP53', 'Gene', '7157', (83, 87))	('tumor', 'Disease', (158, 163))	('promote', 'PosReg', (150, 157))	('TP53', 'Gene', (83, 87))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('cell proliferation', 'CPA', (111, 129))	('dysregulation', 'Var', (11, 24))	('permit', 'PosReg', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('defects of proteins RB', 'Disease', (56, 78))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cell cycle genes', 'Gene', (34, 50))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
116789	27633916	From another perspective, alterations in cyclin-dependent kinase (CDK) activity often induce and regulate cell cycle defects in tumors.	('cyclin-dependent', 'Protein', (41, 57))	('induce', 'Reg', (86, 92))	('alterations', 'Var', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cell cycle defects', 'CPA', (106, 124))	('activity', 'MPA', (71, 79))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('regulate', 'Reg', (97, 105))	('cell cycle defects', 'Phenotype', 'HP:0011018', (106, 124))
116807	27633916	The deregulation of these functions remind us of the metastasizing features across different cancer types while the specific signatures of these subnetworks imply the distinct mechanisms of metastases.	('deregulation', 'Var', (4, 16))	('cancer', 'Disease', (93, 99))	('metastases', 'Disease', (190, 200))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('metastases', 'Disease', 'MESH:D009362', (190, 200))
116820	27633916	4A) tend to be ER, PR and HER2 negative ones and they have high frequency of TP53 mutations (Fig.	('HER2', 'Gene', (26, 30))	('mutations', 'Var', (82, 91))	('HER2', 'Gene', '2064', (26, 30))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))
116829	27633916	Dysregulation of this gene may influence the remaining genes of this subnetwork, and further accelerates cell differentiation in basal-like tumors (Fig.	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cell differentiation', 'CPA', (105, 125))	('influence', 'Reg', (31, 40))	('accelerates', 'PosReg', (93, 104))
116830	27633916	Previous studies have shown that malignant renal papillary cell carcinoma are marked by the trisomy of chromosomes 7, 16, 17 and the loss of Y chromosome.	('malignant renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (33, 73))	('loss', 'NegReg', (133, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('trisomy', 'Var', (92, 99))	('malignant renal papillary cell carcinoma', 'Disease', (33, 73))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (43, 73))
116841	27633916	We find that the ME scores of the THCA-specific subnetwork are strongly associated with the mutation status of BRAF, NRAS and HRAS, which have relatively high mutation frequency (Fig.	('ME', 'Chemical', '-', (17, 19))	('NRAS', 'Gene', (117, 121))	('HRAS', 'Gene', (126, 130))	('NRAS', 'Gene', '4893', (117, 121))	('THCA', 'Phenotype', 'HP:0002890', (34, 38))	('associated', 'Reg', (72, 82))	('HRAS', 'Gene', '3265', (126, 130))	('BRAF', 'Gene', '673', (111, 115))	('mutation status', 'Var', (92, 107))	('BRAF', 'Gene', (111, 115))
116846	27633916	This subnetwork is associated with FGFR3 mutations (Supplementary Figure S6B), which is a key marker of Ta pathway and therapeutic target of bladder cancer.	('associated', 'Reg', (19, 29))	('mutations', 'Var', (41, 50))	('bladder cancer', 'Disease', (141, 155))	('FGFR3', 'Gene', '2261', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (141, 155))	('FGFR3', 'Gene', (35, 40))	('bladder cancer', 'Disease', 'MESH:D001749', (141, 155))
116848	27633916	A recent study revealed a biological component relating to both Ta pathway and carcinoma in situ pathway, of which one biomarker is early TP53 mutation.	('TP53', 'Gene', '7157', (138, 142))	('carcinoma', 'Disease', (79, 88))	('TP53', 'Gene', (138, 142))	('mutation', 'Var', (143, 151))	('Ta pathway', 'Pathway', (64, 74))	('carcinoma', 'Disease', 'MESH:D002277', (79, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (79, 96))
116852	27633916	We also find 16 cancer type-specific subnetworks which demonstrate strong implications to somatic mutations, SCNAs, DNA methylation alterations and clinical outcomes in some specific cancers.	('cancer', 'Disease', (183, 189))	('cancers', 'Disease', (183, 190))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('mutations', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('implications', 'Reg', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
116854	27633916	Not surprisingly, different cancer-specific subnetworks show very diverse implications to mutation status, SCNAs and others.	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutation status', 'Var', (90, 105))
116863	27633916	With the deepening of understanding of cancer, the nosogenesis is not only restricted to somatic mutations but also to SCNAs, some epigenomic deregulations and so on.	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Disease', (39, 45))	('epigenomic deregulations', 'Var', (131, 155))
116884	27633916	We download the mutation annotation files (MAF) of all 16 cancer types and the output of mutsig2cv which gives if a gene is significantly mutated or not from Broad Institute on July 24, 2015 (Supplementary Table S1).	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutated', 'Var', (138, 145))
116897	27633916	For each cancer, we use LIMMA to detect DEGs relative to normal samples with the TMM normalized data as input.	('DEGs', 'Var', (40, 44))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
116944	26904350	Owing to HPCs' characteristic localization, HPCs cause not only dilatation of the intrahepatic bile ducts, usually with multiple cystic tumors, but also obstructive jaundice and, on occasion, portal hypertension due to the exclusion of biliary and portal flow.	('multiple cystic tumors', 'Disease', 'MESH:C536611', (120, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('hypertension', 'Disease', 'MESH:D006973', (199, 211))	('HPCs', 'Var', (44, 48))	('hypertension', 'Disease', (199, 211))	('portal hypertension', 'Phenotype', 'HP:0001409', (192, 211))	('hypertension', 'Phenotype', 'HP:0000822', (199, 211))	('also obstructive jaundice', 'Disease', 'MESH:D041781', (148, 173))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('multiple cystic tumors', 'Disease', (120, 142))	('cause', 'Reg', (49, 54))	('also obstructive jaundice', 'Disease', (148, 173))	('jaundice', 'Phenotype', 'HP:0000952', (165, 173))	('dilatation', 'MPA', (64, 74))	('dilatation', 'Phenotype', 'HP:0002617', (64, 74))
116988	31222668	Endoscopic retrograde cholangiography (ERC) revealed the defect at the bifurcation of the common hepatic duct (Bismuth-Corlette classification type II) and endoscopic nasobiliary drainage was performed for obstructive jaundice (Fig.	('jaundice', 'Phenotype', 'HP:0000952', (218, 226))	('ER', 'Gene', '2099', (39, 41))	('defect', 'Var', (57, 63))	('obstructive jaundice', 'Disease', 'MESH:D041781', (206, 226))	('obstructive jaundice', 'Disease', (206, 226))
117046	31205529	Metformin Induces Apoptosis and Inhibits Proliferation through the AMP-Activated Protein Kinase and Insulin-like Growth Factor 1 Receptor Pathways in the Bile Duct Cancer Cells Background/Aims: Metformin has been found to have antineoplastic activity in some cancer cells.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('Bile Duct Cancer', 'Phenotype', 'HP:0030153', (154, 170))	('Insulin-like Growth Factor 1 Receptor', 'Gene', (100, 137))	('Inhibits', 'NegReg', (32, 40))	('Metformin', 'Var', (194, 203))	('cancer', 'Disease', (259, 265))	('Bile Duct Cancer', 'Disease', (154, 170))	('antineoplastic activity', 'CPA', (227, 250))	('Metformin', 'Chemical', 'MESH:D008687', (194, 203))	('Cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('Bile Duct Cancer', 'Disease', 'MESH:D001650', (154, 170))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('AMP-Activated Protein Kinase', 'Pathway', (67, 95))	('Proliferation', 'CPA', (41, 54))	('Insulin-like Growth Factor 1 Receptor', 'Gene', '3480', (100, 137))	('Apoptosis', 'CPA', (18, 27))
117047	31205529	This study was performed to determine whether metformin inhibits the proliferation of bile duct cancer cells by inducing apoptosis and its effects on the expression of gene-related proteins involved in cancer growth.	('bile duct cancer', 'Phenotype', 'HP:0030153', (86, 102))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('bile duct cancer', 'Disease', (86, 102))	('inhibits', 'NegReg', (56, 64))	('bile duct cancer', 'Disease', 'MESH:D001650', (86, 102))	('cancer', 'Disease', (96, 102))	('inducing', 'Reg', (112, 120))	('proliferation', 'CPA', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('expression of', 'MPA', (154, 167))	('metformin', 'Var', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('apoptosis', 'CPA', (121, 130))	('metformin', 'Chemical', 'MESH:D008687', (46, 55))	('effects', 'Reg', (139, 146))	('cancer', 'Disease', (202, 208))	('proliferation of bile duct', 'Phenotype', 'HP:0001408', (69, 95))	('proteins', 'Protein', (181, 189))
117052	31205529	Results: Metformin suppressed cell proliferation in bile duct cancer cells by inducing apoptosis.	('Metformin', 'Var', (9, 18))	('cell proliferation', 'CPA', (30, 48))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('suppressed', 'NegReg', (19, 29))	('bile duct cancer', 'Disease', (52, 68))	('Metformin', 'Chemical', 'MESH:D008687', (9, 18))	('apoptosis', 'CPA', (87, 96))	('bile duct cancer', 'Disease', 'MESH:D001650', (52, 68))	('inducing', 'Reg', (78, 86))	('bile duct cancer', 'Phenotype', 'HP:0030153', (52, 68))
117063	31205529	Statin, another metabolic syndrome treatment agent, has been known to reduce the risk of liver cancer, and previous our study also found that statin inhibits the growth in bile duct cancer cells and induces apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('liver cancer', 'Disease', 'MESH:D006528', (89, 101))	('liver cancer', 'Phenotype', 'HP:0002896', (89, 101))	('apoptosis', 'CPA', (207, 216))	('bile duct cancer', 'Disease', (172, 188))	('growth', 'CPA', (162, 168))	('liver cancer', 'Disease', (89, 101))	('inhibits', 'NegReg', (149, 157))	('metabolic syndrome', 'Disease', (16, 34))	('induces', 'Reg', (199, 206))	('metabolic syndrome', 'Disease', 'MESH:D008659', (16, 34))	('bile duct cancer', 'Disease', 'MESH:D001650', (172, 188))	('statin', 'Var', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('bile duct cancer', 'Phenotype', 'HP:0030153', (172, 188))
117066	31205529	In addition, metformin is known to inhibit insulin-like growth factor 1 receptor (IGF-1R) activation, thereby lowering the activity of insulin receptor substrate 1 (IRS-1), and blocking signal transmission through the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/ protein kinase B (Akt) pathway.	('IRS-1', 'Gene', (165, 170))	('metformin', 'Var', (13, 22))	('PI3', 'Gene', (266, 269))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:D019269', (218, 255))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('IGF-1R', 'Gene', '3480', (82, 88))	('lowering', 'NegReg', (110, 118))	('IGF-1R', 'Gene', (82, 88))	('IRS-1', 'Gene', '3667', (165, 170))	('blocking', 'NegReg', (177, 185))	('Akt', 'Gene', (291, 294))	('protein kinase B', 'Gene', '2185', (273, 289))	('insulin-like growth factor 1 receptor', 'Gene', (43, 80))	('Akt', 'Gene', '207', (291, 294))	('protein kinase B', 'Gene', (273, 289))	('activation', 'MPA', (90, 100))	('insulin receptor substrate 1', 'Gene', (135, 163))	('activity', 'MPA', (123, 131))	('inhibit', 'NegReg', (35, 42))	('insulin receptor substrate 1', 'Gene', '3667', (135, 163))	('PI3', 'Gene', '5266', (266, 269))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (43, 80))	('signal transmission', 'MPA', (186, 205))
117070	31205529	We performed this study to determine whether metformin inhibits the proliferation of bile duct cancer cells by inducing apoptosis, and its effects on the expression of gene-related proteins involved in cancer growth, and to identify how metformin affect molecular mechanisms involved in the inhibition of cancer cell growth.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('proliferation of bile duct', 'Phenotype', 'HP:0001408', (68, 94))	('inhibits', 'NegReg', (55, 63))	('metformin', 'Var', (45, 54))	('metformin', 'Chemical', 'MESH:D008687', (45, 54))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('cancer', 'Disease', (95, 101))	('inducing', 'Reg', (111, 119))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('bile duct cancer', 'Phenotype', 'HP:0030153', (85, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('bile duct cancer', 'Disease', (85, 101))	('bile duct cancer', 'Disease', 'MESH:D001650', (85, 101))	('affect', 'Reg', (247, 253))	('proliferation', 'CPA', (68, 81))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (305, 311))	('apoptosis', 'CPA', (120, 129))	('effects', 'Reg', (139, 146))	('metformin', 'Chemical', 'MESH:D008687', (237, 246))	('cancer', 'Disease', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('expression', 'MPA', (154, 164))
117099	31205529	Cells were grown to 60-80% confluency then treated with 60 pmols of either IGR-1R (sc-29358, Santa Cruz Biotechnology), AMPKalpha1 (sc-29673, Santa Cruz Biotechnology), AMPKalpha1/2 (sc-45312, Santa Cruz Biotechnology) or scrambled (sc-Santa cruz Biotechnology) siRNA in the supplied transfection media and incubated for 4 hours at 37 C in a 5% CO2 incubator.	('AMPKalpha1/2', 'Gene', '479351;489571', (169, 181))	('CO2', 'Chemical', '-', (345, 348))	('sc-29358', 'Var', (83, 91))	('AMPKalpha1/2', 'Gene', (169, 181))
117106	31205529	Bile duct cancer cells that did not harbor major mutations (SNU-245) were found to be more effectively suppressed by metformin treatment compared with cells containing several mutations in cancer-associated genes (SNU-1196) as well (Figure 1A-B).	('Bile duct cancer', 'Disease', 'MESH:D001650', (0, 16))	('mutations', 'Var', (49, 58))	('SNU-1196', 'CellLine', 'CVCL:5015', (214, 222))	('SNU', 'Chemical', '-', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('SNU', 'Chemical', '-', (214, 217))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('Bile duct cancer', 'Phenotype', 'HP:0030153', (0, 16))	('suppressed', 'NegReg', (103, 113))	('Bile duct cancer', 'Disease', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('metformin', 'Chemical', 'MESH:D008687', (117, 126))	('cancer', 'Disease', (10, 16))	('cancer', 'Disease', (189, 195))
117110	31205529	Caspase-3 activity, which plays a central role in the execution-phase of cell apoptosis, was also significantly and dose-dependently increased by metformin (Figure 2C-D).	('Caspase-3', 'Gene', (0, 9))	('activity', 'MPA', (10, 18))	('metformin', 'Var', (146, 155))	('metformin', 'Chemical', 'MESH:D008687', (146, 155))	('increased', 'PosReg', (133, 142))	('Caspase-3', 'Gene', '836', (0, 9))
117111	31205529	Additionally, the metformin-induced apoptotic effect was significantly prominent in SNU-245 cells compared with SNU-1196 cells (Figure 2A-D).	('SNU', 'Chemical', '-', (84, 87))	('metformin-induced', 'MPA', (18, 35))	('SNU', 'Chemical', '-', (112, 115))	('SNU-1196', 'CellLine', 'CVCL:5015', (112, 120))	('apoptotic effect', 'CPA', (36, 52))	('SNU-245', 'Var', (84, 91))	('metformin', 'Chemical', 'MESH:D008687', (18, 27))
117126	31205529	IGF-1R silencing induced TSC-2 activation and mTOR inactivation without metformin treatment in FG levels.	('TSC-2', 'Gene', (25, 30))	('inactivation', 'NegReg', (51, 63))	('mTOR', 'Gene', '2475', (46, 50))	('TSC-2', 'Gene', '7249', (25, 30))	('mTOR', 'Gene', (46, 50))	('activation', 'PosReg', (31, 41))	('IGF-1R', 'Gene', '3480', (0, 6))	('metformin', 'Chemical', 'MESH:D008687', (72, 81))	('IGF-1R', 'Gene', (0, 6))	('silencing', 'Var', (7, 16))
117127	31205529	However, IGF-1R silencing maintained metformin-induced TSC-2 activation and mTOR inactivation in HG conditions, which suggests that IGF-1R is another crucial pathway in modulating bile duct cancer cell proliferations in both low and hyperglycemic conditions (Figure 5).	('IGF-1R', 'Gene', (9, 15))	('metformin', 'Chemical', 'MESH:D008687', (37, 46))	('mTOR', 'Gene', (76, 80))	('silencing', 'Var', (16, 25))	('metformin-induced', 'MPA', (37, 54))	('modulating', 'Reg', (169, 179))	('hyperglycemic conditions', 'Disease', (233, 257))	('TSC-2', 'Gene', (55, 60))	('bile duct cancer', 'Phenotype', 'HP:0030153', (180, 196))	('mTOR', 'Gene', '2475', (76, 80))	('bile duct cancer', 'Disease', (180, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('bile duct cancer', 'Disease', 'MESH:D001650', (180, 196))	('hyperglycemic conditions', 'Disease', 'MESH:D006943', (233, 257))	('hyperglycemic condition', 'Phenotype', 'HP:0003074', (233, 256))	('IGF-1R', 'Gene', '3480', (132, 138))	('IGF-1R', 'Gene', (132, 138))	('TSC-2', 'Gene', '7249', (55, 60))	('activation', 'PosReg', (61, 71))	('IGF-1R', 'Gene', '3480', (9, 15))
117131	31205529	This suggests that metformin inhibits growth and migration of bile duct cancer cells, although, this effects were impaired under hyperglycemic conditions.	('metformin', 'Chemical', 'MESH:D008687', (19, 28))	('bile duct cancer', 'Phenotype', 'HP:0030153', (62, 78))	('migration of bile duct cancer', 'Disease', (49, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('hyperglycemic conditions', 'Disease', 'MESH:D006943', (129, 153))	('migration of bile duct cancer', 'Disease', 'MESH:D001650', (49, 78))	('hyperglycemic condition', 'Phenotype', 'HP:0003074', (129, 152))	('hyperglycemic conditions', 'Disease', (129, 153))	('inhibits', 'NegReg', (29, 37))	('metformin', 'Var', (19, 28))
117140	31205529	A meta-analysis study demonstrated that a 31% reduction in overall relative risk was noted in patients taking metformin compared with other antidiabetic drugs, and an inverse association was found to be significant for pancreatic and hepatocellular cancer.	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (234, 255))	('reduction', 'NegReg', (46, 55))	('patients', 'Species', '9606', (94, 102))	('diabetic', 'Disease', 'MESH:D003920', (144, 152))	('diabetic', 'Disease', (144, 152))	('metformin', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('metformin', 'Chemical', 'MESH:D008687', (110, 119))	('pancreatic and hepatocellular cancer', 'Disease', 'MESH:D006528', (219, 255))
117143	31205529	In pancreatic cancer, metformin has been shown to inhibit the growth of human cancer cells in a xenograft mouse model through a mechanism of disrupted cross-talk between the insulin receptor and a G-protein-coupled receptor.	('metformin', 'Var', (22, 31))	('metformin', 'Chemical', 'MESH:D008687', (22, 31))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('insulin receptor', 'Gene', '16337', (174, 190))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('human', 'Species', '9606', (72, 77))	('growth', 'CPA', (62, 68))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('cancer', 'Disease', (78, 84))	('G-protein-coupled receptor', 'Protein', (197, 223))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('disrupted', 'NegReg', (141, 150))	('mouse', 'Species', '10090', (106, 111))	('cancer', 'Disease', (14, 20))	('pancreatic cancer', 'Disease', (3, 20))	('inhibit', 'NegReg', (50, 57))	('cross-talk', 'MPA', (151, 161))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('insulin receptor', 'Gene', (174, 190))
117149	31205529	Our current study also showed similar results, providing additional evidence that metformin inhibits the proliferation of cholangiocarcinoma cells.	('metformin', 'Var', (82, 91))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (122, 140))	('metformin', 'Chemical', 'MESH:D008687', (82, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (122, 140))	('proliferation', 'CPA', (105, 118))	('inhibits', 'NegReg', (92, 100))	('cholangiocarcinoma', 'Disease', (122, 140))
117151	31205529	2) Bile duct cancer cells with mutations in cancer-related genes were resistant to the inhibitory effects of metformin on proliferation compared to cells without mutations in these genes.	('Bile duct cancer', 'Disease', 'MESH:D001650', (3, 19))	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('Bile duct cancer', 'Phenotype', 'HP:0030153', (3, 19))	('metformin', 'Chemical', 'MESH:D008687', (109, 118))	('resistant', 'NegReg', (70, 79))	('cancer', 'Disease', (44, 50))	('Bile duct cancer', 'Disease', (3, 19))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
117152	31205529	3) Metformin inhibited bile duct cancer cell proliferation by inhibiting the IGF-1R/IRS-1 pathway as well as AMPK/mTOR pathway in bile duct cancer cells.	('inhibited', 'NegReg', (13, 22))	('bile duct cancer', 'Phenotype', 'HP:0030153', (23, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('IRS-1', 'Gene', (84, 89))	('bile duct cancer', 'Disease', (23, 39))	('bile duct cancer', 'Disease', 'MESH:D001650', (23, 39))	('mTOR', 'Gene', (114, 118))	('AMPK', 'Gene', '5563', (109, 113))	('IRS-1', 'Gene', '3667', (84, 89))	('IGF-1R', 'Gene', (77, 83))	('mTOR', 'Gene', '2475', (114, 118))	('IGF-1R', 'Gene', '3480', (77, 83))	('bile duct cancer', 'Phenotype', 'HP:0030153', (130, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('bile duct cancer', 'Disease', (130, 146))	('AMPK', 'Gene', (109, 113))	('bile duct cancer', 'Disease', 'MESH:D001650', (130, 146))	('inhibiting', 'NegReg', (62, 72))	('Metformin', 'Var', (3, 12))	('Metformin', 'Chemical', 'MESH:D008687', (3, 12))
117164	31205529	Activation of the IGF-1R causes sequential activation IRS-1, which in turn activates the PI3K/Akt pathway, resulting in activation of mTOR, which is involved in protein synthesis and cell growth.	('IGF-1R', 'Gene', '3480', (18, 24))	('IGF-1R', 'Gene', (18, 24))	('PI3', 'Gene', '5266', (89, 92))	('Akt', 'Gene', (94, 97))	('activation', 'PosReg', (43, 53))	('IRS-1', 'Gene', '3667', (54, 59))	('activation', 'PosReg', (120, 130))	('PI3', 'Gene', (89, 92))	('activates', 'PosReg', (75, 84))	('Activation', 'Var', (0, 10))	('Akt', 'Gene', '207', (94, 97))	('mTOR', 'Gene', (134, 138))	('mTOR', 'Gene', '2475', (134, 138))	('IRS-1', 'Gene', (54, 59))
117168	31205529	In a meta-analysis study to investigate the association between metformin and overall survival in patients with pancreatic cancer and concurrent type 2 diabetes, a borderline significant relative survival benefit was found in metformin-treated patients compared with non-metformin treated patients.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (145, 160))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('patients', 'Species', '9606', (244, 252))	('metformin', 'Chemical', 'MESH:D008687', (64, 73))	('metformin', 'Chemical', 'MESH:D008687', (226, 235))	('patients', 'Species', '9606', (98, 106))	('diabetes', 'Disease', (152, 160))	('metformin-treated', 'Var', (226, 243))	('diabetes', 'Disease', 'MESH:D003920', (152, 160))	('metformin', 'Chemical', 'MESH:D008687', (271, 280))	('pancreatic cancer', 'Disease', (112, 129))	('pancreatic cancer', 'Disease', 'MESH:D010190', (112, 129))	('patients', 'Species', '9606', (289, 297))
117174	31205529	In this study, antiproliferative actions by metformin-induced apoptosis were documented in extrahepatic bile duct cancer cells harboring wild-type and mutant copies of cancer-related genes for the first time.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('antiproliferative actions', 'MPA', (15, 40))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('extrahepatic bile duct cancer', 'Phenotype', 'HP:0005242', (91, 120))	('metformin', 'Chemical', 'MESH:D008687', (44, 53))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('extrahepatic bile duct cancer', 'Disease', 'MESH:D001651', (91, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (168, 174))	('extrahepatic bile duct cancer', 'Disease', (91, 120))	('mutant copies', 'Var', (151, 164))	('bile duct cancer', 'Phenotype', 'HP:0030153', (104, 120))	('cancer', 'Disease', (114, 120))
117298	30420613	SOX9 expression decreases survival of patients with intrahepatic cholangiocarcinoma by conferring chemoresistance Sex-determining region Y-box (SRY-box) containing gene 9 (SOX9) expression confers cancer stem cell features.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('SOX9', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (197, 203))	('expression', 'Var', (5, 15))	('intrahepatic cholangiocarcinoma', 'Disease', (52, 83))	('SOX9', 'Gene', (172, 176))	('SOX9', 'Gene', '6662', (0, 4))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:C535533', (52, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('SOX9', 'Gene', '6662', (172, 176))	('survival', 'MPA', (26, 34))	('patients', 'Species', '9606', (38, 46))	('decreases', 'NegReg', (16, 25))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))
117304	30420613	iCCA patients with high SOX9 expression had shorter survival time than those with low SOX9.	('iCCA', 'Disease', 'MESH:C535533', (0, 4))	('high', 'Var', (19, 23))	('SOX9', 'Gene', (24, 28))	('patients', 'Species', '9606', (5, 13))	('iCCA', 'Disease', (0, 4))	('CCA', 'Phenotype', 'HP:0030153', (1, 4))	('SOX9', 'Gene', '6662', (24, 28))	('survival time', 'CPA', (52, 65))	('SOX9', 'Gene', (86, 90))	('expression', 'MPA', (29, 39))	('shorter', 'NegReg', (44, 51))	('SOX9', 'Gene', '6662', (86, 90))
117305	30420613	In patients receiving chemotherapy, median survival time in patients with low and high levels of SOX9 were 62 and 22 months, respectively.	('high levels', 'Var', (82, 93))	('patients', 'Species', '9606', (60, 68))	('SOX9', 'Gene', (97, 101))	('SOX9', 'Gene', '6662', (97, 101))	('patients', 'Species', '9606', (3, 11))
117307	30420613	When SOX9 was knocked down, gemcitabine-induced apoptosis was markedly increased.	('SOX9', 'Gene', '6662', (5, 9))	('gemcitabine', 'Chemical', 'MESH:C056507', (28, 39))	('knocked down', 'Var', (14, 26))	('increased', 'PosReg', (71, 80))	('SOX9', 'Gene', (5, 9))
117308	30420613	Silencing SOX9 significantly inhibited gemcitabine-induced phosphorylation of checkpoint kinase 1, a key cell cycle checkpoint protein that coordinates the DNA damage response and inhibited the expression of multidrug resistance genes.	('gemcitabine-induced', 'MPA', (39, 58))	('inhibited', 'NegReg', (29, 38))	('drug resistance', 'Phenotype', 'HP:0020174', (213, 228))	('DNA damage response', 'MPA', (156, 175))	('gemcitabine', 'Chemical', 'MESH:C056507', (39, 50))	('checkpoint kinase 1', 'Gene', '1111', (78, 97))	('SOX9', 'Gene', (10, 14))	('SOX9', 'Gene', '6662', (10, 14))	('checkpoint kinase 1', 'Gene', (78, 97))	('phosphorylation', 'MPA', (59, 74))	('expression', 'MPA', (194, 204))	('multidrug resistance genes', 'Gene', (208, 234))	('Silencing', 'Var', (0, 9))	('inhibited', 'NegReg', (180, 189))
117309	30420613	Microarray analyses showed that SOX9 knockdown in CCA cells altered gene signatures associated with multidrug resistance and p53 signalling.	('CCA', 'Disease', 'MESH:D018281', (50, 53))	('CCA', 'Disease', (50, 53))	('p53', 'Gene', (125, 128))	('knockdown', 'Var', (37, 46))	('multidrug', 'MPA', (100, 109))	('p53', 'Gene', '7157', (125, 128))	('drug resistance', 'Phenotype', 'HP:0020174', (105, 120))	('SOX9', 'Gene', (32, 36))	('CCA', 'Phenotype', 'HP:0030153', (50, 53))	('gene signatures', 'MPA', (68, 83))	('altered', 'Reg', (60, 67))	('SOX9', 'Gene', '6662', (32, 36))
117347	30420613	The number of cells with SOX9-positive nuclei was defined as six grades: 0, no detectable positive cells; 1, positive cells <=1%; 2, positive cells >1%, and <=10%; 3, positive cells >10%, and <=33%; 4, positive cells > 33%, and <=66%; 5, positive cells >66%.	('<=10', 'Var', (157, 161))	('SOX9', 'Gene', '6662', (25, 29))	('SOX9', 'Gene', (25, 29))
117354	30420613	siRNA targeting human SOX9 (M-021507-00) and control siRNA (D-001206-14) were purchased from Dharmacon.	('SOX9', 'Gene', (22, 26))	('SOX9', 'Gene', '6662', (22, 26))	('M-021507', 'Chemical', 'MESH:D008775', (28, 36))	('D-001206-14', 'Chemical', 'MESH:C104313', (60, 71))	('M-021507-00', 'Var', (28, 39))	('human', 'Species', '9606', (16, 21))
117389	30420613	However, multivariate analysis showed that among the analysed variables, only SOX9 expression significantly influenced the over survival (OS) of iCCA patients (hazard ratio = 3.614, 95% confidence Interval = 1.493-9.076, P = 0.006, Supplementary Table 4).	('influenced', 'Reg', (108, 118))	('SOX9', 'Gene', '6662', (78, 82))	('iCCA', 'Disease', 'MESH:C535533', (145, 149))	('patients', 'Species', '9606', (150, 158))	('iCCA', 'Disease', (145, 149))	('over survival', 'CPA', (123, 136))	('CCA', 'Phenotype', 'HP:0030153', (146, 149))	('SOX9', 'Gene', (78, 82))	('expression', 'Var', (83, 93))
117390	30420613	Furthermore, Kaplan-Meier analysis and the log-rank test showed that patients with high SOX9 expression had shorter OS and disease free survival (DFS) rates than those with low SOX9 expression (P < 0.01 and P < 0.05, respectively, Fig.	('disease free survival', 'CPA', (123, 144))	('SOX9', 'Gene', '6662', (177, 181))	('shorter', 'NegReg', (108, 115))	('SOX9', 'Gene', (88, 92))	('high', 'Var', (83, 87))	('SOX9', 'Gene', (177, 181))	('patients', 'Species', '9606', (69, 77))	('SOX9', 'Gene', '6662', (88, 92))
117396	30420613	Survival analyses revealed that patients with high SOX9 expression had shorter OS time (P < 0.05, Fig.	('high', 'Var', (46, 50))	('patients', 'Species', '9606', (32, 40))	('SOX9', 'Gene', (51, 55))	('SOX9', 'Gene', '6662', (51, 55))	('expression', 'MPA', (56, 66))	('OS time', 'CPA', (79, 86))	('shorter', 'NegReg', (71, 78))
117400	30420613	Notably, four out of five patients with low SOX9 were still surviving when the follow-up ended (Supplementary Table 5).	('SOX9', 'Gene', '6662', (44, 48))	('SOX9', 'Gene', (44, 48))	('low', 'Var', (40, 43))	('patients', 'Species', '9606', (26, 34))
117403	30420613	To investigate how SOX9 expression in CCA cell might modify their response to chemotherapy, we performed microarray analysis in iCCA CC-SW-1 cells after SOX9 silencing.	('CC-SW-1', 'CellLine', 'CVCL:A429', (133, 140))	('response to chemotherapy', 'MPA', (66, 90))	('SOX9', 'Gene', '6662', (19, 23))	('CCA', 'Phenotype', 'HP:0030153', (129, 132))	('modify', 'Reg', (53, 59))	('CCA', 'Disease', 'MESH:D018281', (129, 132))	('CCA', 'Phenotype', 'HP:0030153', (38, 41))	('CCA', 'Disease', (129, 132))	('iCCA', 'Disease', 'MESH:C535533', (128, 132))	('SOX9', 'Gene', '6662', (153, 157))	('iCCA', 'Disease', (128, 132))	('SOX9', 'Gene', (153, 157))	('CCA', 'Disease', 'MESH:D018281', (38, 41))	('silencing', 'Var', (158, 167))	('SOX9', 'Gene', (19, 23))	('CCA', 'Disease', (38, 41))
117404	30420613	We found that gene expression associated with drug metabolism and ABC transporters such as ABCB1 (MDR1) and ABCC4 (MRP4) was decreased, while genes related with the p53 signalling pathway were increased when SOX9 was knocked down with siRNA (Supplementary Figure 2A).	('SOX9', 'Gene', '6662', (208, 212))	('ABCB1', 'Gene', '5243', (91, 96))	('ABCB1', 'Gene', (91, 96))	('drug metabolism', 'Disease', (46, 61))	('MDR1', 'Gene', (98, 102))	('knocked down', 'Var', (217, 229))	('gene expression', 'MPA', (14, 29))	('ABCC4', 'Gene', (108, 113))	('ABC transporters', 'MPA', (66, 82))	('drug metabolism', 'Disease', 'MESH:D065606', (46, 61))	('p53', 'Gene', '7157', (165, 168))	('decreased', 'NegReg', (125, 134))	('MRP4', 'Gene', (115, 119))	('increased', 'PosReg', (193, 202))	('SOX9', 'Gene', (208, 212))	('ABCC4', 'Gene', '10257', (108, 113))	('MRP4', 'Gene', '10257', (115, 119))	('p53', 'Gene', (165, 168))	('MDR1', 'Gene', '5243', (98, 102))
117411	30420613	Given the key role of phosphorylation of checkpoint kinase 1 (CHEK1) in coordinating the DNA damage response and inhibiting the expression of multidrug resistance genes, we examined whether disruption of SOX9 impacted CHEK1 activation.	('CHEK1', 'Gene', (218, 223))	('drug resistance', 'Phenotype', 'HP:0020174', (147, 162))	('CHEK1', 'Gene', '1111', (62, 67))	('inhibiting', 'NegReg', (113, 123))	('coordinating', 'MPA', (72, 84))	('DNA damage response', 'MPA', (89, 108))	('activation', 'MPA', (224, 234))	('CHEK1', 'Gene', '1111', (218, 223))	('CHEK1', 'Gene', (62, 67))	('checkpoint kinase 1', 'Gene', '1111', (41, 60))	('SOX9', 'Gene', (204, 208))	('expression', 'MPA', (128, 138))	('checkpoint kinase 1', 'Gene', (41, 60))	('disruption', 'Var', (190, 200))	('SOX9', 'Gene', '6662', (204, 208))
117415	30420613	MTT assay showed that knockdown of SOX9 did not have impact on cisplatin-inhibited cell viability in both cells (Supplementary Figure 3A-B).	('cisplatin-inhibited cell', 'MPA', (63, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('knockdown', 'Var', (22, 31))	('SOX9', 'Gene', (35, 39))	('SOX9', 'Gene', '6662', (35, 39))
117416	30420613	In contrast to gemcitabine, administration of cisplatin and/or knockdown of SOX9 did not influence the expression of pCHEK1 (Supplementary Figure 3C-D).	('expression', 'MPA', (103, 113))	('SOX9', 'Gene', (76, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('CHEK1', 'Gene', '1111', (118, 123))	('SOX9', 'Gene', '6662', (76, 80))	('gemcitabine', 'Chemical', 'MESH:C056507', (15, 26))	('CHEK1', 'Gene', (118, 123))	('knockdown', 'Var', (63, 72))
117418	30420613	MTT analyses showed that knockdown of SOX9 expression significantly inhibited cell proliferation in four types of CCA cells (Fig.	('CCA', 'Disease', (114, 117))	('SOX9', 'Gene', (38, 42))	('SOX9', 'Gene', '6662', (38, 42))	('inhibited', 'NegReg', (68, 77))	('CCA', 'Phenotype', 'HP:0030153', (114, 117))	('cell proliferation in four types of', 'CPA', (78, 113))	('CCA', 'Disease', 'MESH:D018281', (114, 117))	('knockdown', 'Var', (25, 34))
117419	30420613	In CC-SW-1 and EGI-1 cells, SOX9 inhibition significantly decreased the proportion of cells staying in G1 phase and increased those in G2/M phase (Fig.	('inhibition', 'Var', (33, 43))	('CC-SW-1', 'CellLine', 'CVCL:A429', (3, 10))	('G2/M phase', 'CPA', (135, 145))	('decreased', 'NegReg', (58, 67))	('SOX9', 'Gene', (28, 32))	('SOX9', 'Gene', '6662', (28, 32))	('increased', 'PosReg', (116, 125))
117422	30420613	We found that knockdown of SOX9 expression decreased EpCAM expression at both RNA and protein levels in CC-SW-1 cells (Fig.	('SOX9', 'Gene', (27, 31))	('CC-SW-1', 'CellLine', 'CVCL:A429', (104, 111))	('SOX9', 'Gene', '6662', (27, 31))	('EpCAM', 'Gene', (53, 58))	('knockdown', 'Var', (14, 23))	('EpCAM', 'Gene', '4072', (53, 58))	('decreased', 'NegReg', (43, 52))
117425	30420613	SOX9 knockdown significantly inhibited the capacity of tumour sphere formation in CC-SW-1 (Fig.	('tumour', 'Disease', (55, 61))	('inhibited', 'NegReg', (29, 38))	('SOX9', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('SOX9', 'Gene', '6662', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('CC-SW-1', 'CellLine', 'CVCL:A429', (82, 89))
117427	30420613	Transwell assay showed that knockdown of SOX9 expression significantly inhibited cell migration in CC-SW-1 cells (Fig.	('CC-SW-1', 'CellLine', 'CVCL:A429', (99, 106))	('SOX9', 'Gene', (41, 45))	('inhibited', 'NegReg', (71, 80))	('SOX9', 'Gene', '6662', (41, 45))	('knockdown', 'Var', (28, 37))	('cell migration in CC-SW-1 cells', 'CPA', (81, 112))
117433	30420613	Of nine patients treated with chemotherapy following surgery, the median survival time reached 62 months in six patients who had low levels of SOX9 expression, whereas survival time was only 22 months in the three patients who had high SOX9 levels.	('SOX9', 'Gene', (236, 240))	('patients', 'Species', '9606', (214, 222))	('SOX9', 'Gene', '6662', (143, 147))	('SOX9', 'Gene', '6662', (236, 240))	('low', 'Var', (129, 132))	('patients', 'Species', '9606', (112, 120))	('expression', 'MPA', (148, 158))	('SOX9', 'Gene', (143, 147))	('patients', 'Species', '9606', (8, 16))
117437	30420613	Further in vitro studies provided the following mechanistic explanations of the observed differences: Microarray, qPCR and western blot analyses showed that disruption of SOX9 with siRNA significantly decreased expression of genes/proteins associated with drug metabolism and multidrug resistance and increased the abundance of genes associated with p53 signalling pathway.	('SOX9', 'Gene', (171, 175))	('drug metabolism', 'Disease', 'MESH:D065606', (256, 271))	('drug resistance', 'Phenotype', 'HP:0020174', (281, 296))	('siRNA', 'Gene', (181, 186))	('SOX9', 'Gene', '6662', (171, 175))	('multidrug resistance', 'MPA', (276, 296))	('decreased', 'NegReg', (201, 210))	('drug metabolism', 'Disease', (256, 271))	('disruption', 'Var', (157, 167))	('abundance of genes', 'MPA', (315, 333))	('increased', 'PosReg', (301, 310))	('expression of genes/proteins', 'MPA', (211, 239))	('p53', 'Gene', '7157', (350, 353))	('p53', 'Gene', (350, 353))
117446	30420613	In contrast to gemcitabine, knockdown of SOX9 did not impact the efficiency of cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('SOX9', 'Gene', (41, 45))	('SOX9', 'Gene', '6662', (41, 45))	('cisplatin', 'MPA', (79, 88))	('knockdown', 'Var', (28, 37))	('gemcitabine', 'Chemical', 'MESH:C056507', (15, 26))
117486	29625048	These integrated subtypes shared mutations, copy-number alterations, pathway commonalities, and micro-environment characteristics that appeared influential in the new molecular taxonomy, beyond any phenotypic contributions from tumor stage or tissue of origin.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))	('copy-number alterations', 'Var', (44, 67))
117500	29625048	Using aneuploidy (AN), CpG hypermethylation (METH), mRNA (MRNA), miRNA (MIR), and protein (P), the resultant number of groups ranged from 10 to 25 (Figure 1).	('hypermethylation', 'Var', (27, 43))	('METH', 'Chemical', '-', (45, 49))	('miRNA', 'MPA', (65, 70))	('mRNA', 'MPA', (52, 56))	('aneuploidy', 'Var', (6, 16))
117504	29625048	Over one-third of the samples displayed relatively sparse aneuploidy in AN7; these were enriched for THCA, LAML, PRAD, and THYM.	('aneuploidy', 'Var', (58, 68))	('amp', 'Chemical', 'MESH:D000249', (23, 26))	('AN7', 'Gene', (72, 75))	('THCA', 'Disease', (101, 105))
117507	29625048	Consistent with previous results, squamous (lung, head and neck, and esophageal) tumors clustered together by aneuploidy patterns, particularly 3p loss and 3q gain (AN3).	('3p loss', 'Var', (144, 151))	('3q gain', 'Var', (156, 163))	('esophageal) tumors clustered', 'Disease', 'MESH:D004938', (69, 97))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
117509	29625048	Despite the exclusion of loci known to be involved in tissue-specific DNA methylation, tumors originating from the same organ often aggregated by cancer-type-specific hypermethylation (Figure 1B; Table S2).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('hypermethylation', 'Var', (167, 183))
117525	29625048	We used clustering of cluster assignments (COCA) algorithm to assess the overlap of platform-specific memberships from each of the five molecular platforms (aneuploidy, mRNA, miRNA, DNA methylation, and RPPA) (Figure 2A).	('COCA', 'Species', '289672', (43, 47))	('miRNA', 'MPA', (175, 180))	('mRNA', 'MPA', (169, 173))	('DNA', 'MPA', (182, 185))	('aneuploidy', 'Var', (157, 167))
117536	29625048	Eight iClusters were dominated by a single tumor type (C24:LAML, C11:LGG [IDH1 mut], C6:OV, C8:UCEC, C12:THCA, C16:PRAD, C26:LIHC, C14:LUAD).	('C26', 'CellLine', 'CVCL:0240', (121, 124))	('IDH1', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('C11', 'Gene', '51728', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('C24:', 'Var', (55, 59))	('IDH1', 'Gene', '3417', (74, 78))	('C12:THCA', 'Var', (101, 109))	('tumor', 'Disease', (43, 48))	('C11', 'Gene', (65, 68))
117537	29625048	Others contained tumors from similar or related cells or tissues: C28:pan-kidney (KIRC, KIRP), C15:SKCM/UVM-melanoma of the skin (SKCM) and eye (UVM), C23:GBM/LGG (IDH1wt), and C5:CNS/ endocrine.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('C15', 'Gene', '51316', (95, 98))	('C23:GBM/LGG', 'Gene', '4691', (151, 162))	('UVM-melanoma of the skin', 'Disease', (104, 128))	('IDH1', 'Gene', (164, 168))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('C15', 'Gene', (95, 98))	('IDH1', 'Gene', '3417', (164, 168))	('C28', 'Var', (66, 69))	('UVM-melanoma of the skin', 'Disease', 'MESH:D008545', (104, 128))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('C23:GBM/LGG', 'Gene', (151, 162))
117541	29625048	C4:pan-GI (CRC) was predominantly COAD and READ with chromosomal instability (CIN) and a distinct aneuploidy profile (Figure 2B).	('CIN', 'Disease', (78, 81))	('COAD', 'Disease', (34, 38))	('pan-GI', 'Var', (3, 9))	('CIN', 'Disease', 'MESH:D007674', (78, 81))	('COAD', 'Disease', 'MESH:D029424', (34, 38))	('chromosomal instability', 'Phenotype', 'HP:0040012', (53, 76))	('chromosomal instability', 'Disease', (53, 76))
117542	29625048	The pan-squamous cohort formed three iClusters (C10, C25, and C27).	('C10', 'Gene', '3226', (48, 51))	('C10', 'Gene', (48, 51))	('C25', 'Var', (53, 56))	('C27', 'Var', (62, 65))
117544	29625048	Even though all squamous iClusters were characterized by chromosome 3q amplification, unique features defined C10:pan-SCC (9p deletion) and C25:pan-SCC (Chr11 amp) (Figure 2B).	('amp', 'Chemical', 'MESH:D000249', (71, 74))	('SCC', 'Gene', (118, 121))	('C10', 'Gene', (110, 113))	('SCC', 'Gene', (148, 151))	('C10', 'Gene', '3226', (110, 113))	('SCC', 'Gene', '6317', (118, 121))	('SCC', 'Gene', '6317', (148, 151))	('amp', 'Chemical', 'MESH:D000249', (159, 162))	('9p deletion', 'Var', (123, 134))
117545	29625048	Among mixed tumor type iClusters, three were defined by copy-number alterations.	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('copy-number alterations', 'Var', (56, 79))
117546	29625048	C7:mixed was characterized by chr9 deletion, C2:BRCA (HER2 amp) mainly consisted of ERBB2-amplified tumors (BRCA, BLCA, and STAD), and C13:mixed (Chr8 del) contained highly aneuploid tumors, including a mixture of BRCA-Basal, UCEC (CN-high subtype), UCS, and BLCA.	('BRCA', 'Gene', '672', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('BRCA', 'Gene', (48, 52))	('amp', 'Chemical', 'MESH:D000249', (59, 62))	('BRCA', 'Gene', (214, 218))	('amp', 'Chemical', 'MESH:D000249', (90, 93))	('tumors', 'Disease', (183, 189))	('BLCA', 'Disease', (259, 263))	('aneuploid tumors', 'Disease', 'MESH:D000782', (173, 189))	('BRCA', 'Gene', (108, 112))	('UCEC', 'Disease', (226, 230))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('HER2', 'Gene', '2064', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('ERBB2', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('C13', 'Gene', (135, 138))	('tumors', 'Disease', (100, 106))	('deletion', 'Var', (35, 43))	('ERBB2', 'Gene', '2064', (84, 89))	('UCS', 'Disease', (250, 253))	('C13', 'Gene', '3229', (135, 138))	('BRCA', 'Gene', '672', (48, 52))	('HER2', 'Gene', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('BRCA', 'Gene', '672', (214, 218))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('aneuploid tumors', 'Disease', (173, 189))
117554	29625048	The silhouette widths ranged from -0.05 to 0.59, with the highest silhouette widths belonging to single-cancer-type-dominant iClusters (C11:LGG [IDH1 mut], C12:THCA, C16:PRAD, and C24:LAML).	('IDH1', 'Gene', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('IDH1', 'Gene', '3417', (145, 149))	('C11', 'Gene', '51728', (136, 139))	('C24:LAML', 'Var', (180, 188))	('C16:PRAD', 'Var', (166, 174))	('cancer', 'Disease', (104, 110))	('C12:THCA', 'Var', (156, 164))	('C11', 'Gene', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
117555	29625048	Interestingly, 6 of the 7 pan-organ system iClusters (pan-GI: C1, C4, C18; pan-SCC: C25, C27, and pan-kidney: C28) had similar ranges of silhouette widths to those of single cancer-type dominant iClusters, suggesting that these were as robust as the cancer-type-dominant iClusters.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('C27', 'Var', (89, 92))	('SCC', 'Gene', (79, 82))	('C18', 'Gene', (70, 73))	('cancer', 'Disease', (250, 256))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('C18', 'Gene', '27241', (70, 73))	('SCC', 'Gene', '6317', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
117556	29625048	iClusters driven by a shared specific chromosomal alteration (e.g., C13:mixed [chr8 del]) tended to compose multiple tumor types and appeared to have among the lowest silhouette widths, suggesting substantial molecular heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mixed [chr8 del]', 'Var', (72, 88))	('tumor', 'Disease', (117, 122))	('C13', 'Gene', (68, 71))	('C13', 'Gene', '3229', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
117573	29625048	Melanomas and lung adenocarcinomas have been shown to have relatively high mutation rates, and we observed similar results with C15:SKCM/UVM and C14:LUAD.	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('C15', 'Gene', (128, 131))	('C14:LUAD', 'Var', (145, 153))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (14, 34))	('mutation', 'MPA', (75, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('Melanomas and lung adenocarcinomas', 'Disease', 'MESH:D000077192', (0, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('C15', 'Gene', '51316', (128, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
117574	29625048	Mutation frequencies varied widely within the two iClusters with the most diverse tumor compositions: C3:mesenchymal (immune) and C20:mixed (stromal/immune).	('C20', 'Var', (130, 133))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
117581	29625048	Despite having very different cancer type compositions, the pan-squamous iClusters C10:pan-SCC, C25:pan-SCC (chr11 amp), and C27:pan-SCC (HPV) shared many pathway characteristics.	('amp', 'Chemical', 'MESH:D000249', (115, 118))	('SCC', 'Gene', '6317', (133, 136))	('HPV', 'Species', '10566', (138, 141))	('C10', 'Gene', (83, 86))	('SCC', 'Gene', '6317', (91, 94))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('SCC', 'Gene', (104, 107))	('C10', 'Gene', '3226', (83, 86))	('C25', 'Var', (96, 99))	('SCC', 'Gene', (91, 94))	('SCC', 'Gene', '6317', (104, 107))	('SCC', 'Gene', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('C27', 'Var', (125, 128))
117585	29625048	In addition, C20:mixed (stromal/immune) contained 32% Pan-GI samples and also displayed strong immune-related signaling.	('amp', 'Chemical', 'MESH:D000249', (62, 65))	('C20:mixed', 'Var', (13, 22))	('Pan-GI', 'Protein', (54, 60))
117586	29625048	Beta-catenin/cell-cell adhesion signaling appeared high in C4:pan-GI (CRC), C18:pan-GI (MSI), and C20:mixed (stromal/immune), but not in the smaller C1:STAD (EBV-CIMP).	('SI', 'Disease', 'None', (89, 91))	('C18', 'Gene', (76, 79))	('C4:pan-GI', 'Var', (59, 68))	('Beta-catenin/cell-cell adhesion signaling', 'MPA', (0, 41))	('C20:mixed', 'Var', (98, 107))	('C18', 'Gene', '27241', (76, 79))	('EBV', 'Species', '10376', (158, 161))	('high', 'PosReg', (51, 55))
117604	29625048	Interrogation of individual iClusters for their differentiating PARADIGM pathway features, canonical pathways, and gene programs amenable to drug targeting identified strong immune-related signaling features for both C3:mesenchymal (immune) and C20:mixed (stromal/immune) tumors, suggesting that they may share potential susceptibility to immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('C20', 'Var', (245, 248))	('tumors', 'Disease', (272, 278))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('C3', 'Var', (217, 219))	('immune-related signaling', 'MPA', (174, 198))	('AR', 'Gene', '367', (65, 67))
117607	29625048	Compared to the seemingly discohesive groupings of the 17 heterogeneous iClusters, the 11 most homogeneous iClusters (C6:OV, C8:UCEC, C11:LGG [IDH1 mut], C12:THCA, C14:LUAD, C15:SKCM/UVM, C16:PRAD, C19:BRCA [luminal], C21:DLBC, C24:LAML, C26:LIHC) had higher silhouette widths, uniform tumor types, and histopathologies, but showed surprising degrees of spatial discohesion in the TumorMap.	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('C21', 'Gene', (218, 221))	('IDH1', 'Gene', (143, 147))	('C11', 'Gene', (134, 137))	('C24:LAML', 'Var', (228, 236))	('higher', 'PosReg', (252, 258))	('Tumor', 'Phenotype', 'HP:0002664', (381, 386))	('C16:PRAD', 'Var', (188, 196))	('C21', 'Gene', '79718', (218, 221))	('C19:BRCA', 'Gene', (198, 206))	('IDH1', 'Gene', '3417', (143, 147))	('tumor', 'Disease', (286, 291))	('C15', 'Gene', '51316', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('C15', 'Gene', (174, 177))	('C26', 'CellLine', 'CVCL:0240', (238, 241))	('silhouette widths', 'CPA', (259, 276))	('C11', 'Gene', '51728', (134, 137))	('C19:BRCA', 'Gene', '672', (198, 206))
117610	29625048	However, exceptions that challenge this concept have also become apparent from such notable examples as the unpredictable clinical responses to a potent BRAF inhibitor across diverse malignancies all expressing the same BRAF mutation.	('BRAF', 'Gene', (153, 157))	('mutation', 'Var', (225, 233))	('BRAF', 'Gene', '673', (220, 224))	('malignancies', 'Disease', 'MESH:D009369', (183, 195))	('BRAF', 'Gene', (220, 224))	('amp', 'Chemical', 'MESH:D000249', (94, 97))	('BRAF', 'Gene', '673', (153, 157))	('malignancies', 'Disease', (183, 195))
117635	29625048	Cervical squamous tumors clustered in high aneuploidy clusters AN1 and AN5.	('squamous tumors', 'Disease', (9, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('squamous tumors', 'Disease', 'MESH:D002294', (9, 24))	('AN1', 'Var', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
117636	29625048	These clusters were also enriched for other Pan-gyn tumors, including ovarian, high-copy number endometrial, and uterine carcinosarcoma.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('high-copy number', 'Var', (79, 95))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('ovarian', 'Disease', (70, 77))	('carcinosarcoma', 'Disease', 'MESH:D002296', (121, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (113, 135))	('carcinosarcoma', 'Disease', (121, 135))
117637	29625048	Gynecologic tumors with fewer copy-number alterations including Luminal breast cancers and other endometrial tumors grouped separately in low aneuploidy clusters AN7 and AN8, respectively.	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('low aneuploidy clusters', 'Disease', 'MESH:D000782', (138, 161))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('copy-number alterations', 'Var', (30, 53))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('low aneuploidy clusters', 'Disease', (138, 161))	('breast cancers', 'Disease', 'MESH:D001943', (72, 86))	('breast cancers', 'Disease', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('endometrial tumors', 'Disease', 'MESH:D016889', (97, 115))	('tumors', 'Disease', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('breast cancers', 'Phenotype', 'HP:0003002', (72, 86))	('AN7', 'Var', (162, 165))	('endometrial tumors', 'Disease', (97, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
117648	29625048	To minimize the influence of variable tumor purity levels on a clustering result, we dichotomized the data using a beta-value of >= 0.3 to define positive DNA methylation and < 0.3 to specify lack of methylation.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('positive DNA methylation', 'Var', (146, 170))
117650	29625048	For clustering analysis of tumors, we selected 3,139 CpG sites that were methylated at a beta-value of >= 0.3 in more than 10% of tumors within any of the 33 cancer types.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('methylated', 'Var', (73, 83))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
117653	29625048	The heatmap was generated using the original beta-values for the top one-third (n = 1,035) of the most variability methylated CpGs across tumors (Figure 1B).	('CpGs', 'Gene', (126, 130))	('methylated', 'Var', (115, 125))	('tumors', 'Disease', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
117654	29625048	We noted that a fraction of ESCA and STAD was found in METH9 with LUAD and PAAD, a result that may be related to the low tumor cellularity of the cancers in this cluster.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('METH', 'Chemical', '-', (55, 59))	('low tumor', 'Disease', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('ESCA', 'Disease', (28, 32))	('METH9', 'Var', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('low tumor', 'Disease', 'MESH:D009800', (117, 126))
117678	29625048	MIR5 contained OV, MIR8 BRCA, MIR12 LGG, MIR13 LIHC, MIR14 THCA, and MIR15 PRAD.	('MIR1', 'Gene', '79187', (69, 73))	('MIR1', 'Gene', (69, 73))	('BRCA', 'Gene', '672', (24, 28))	('MIR12', 'Gene', (30, 35))	('BRCA', 'Gene', (24, 28))	('MIR8', 'Var', (19, 23))	('MIR1', 'Gene', '79187', (53, 57))	('MIR12', 'Gene', '406905', (30, 35))	('MIR1', 'Gene', (53, 57))	('MIR1', 'Gene', '79187', (41, 45))	('MIR1', 'Gene', '79187', (30, 34))	('MIR1', 'Gene', (41, 45))	('MIR1', 'Gene', (30, 34))
117686	29625048	MIR6, the Pan-GI group, was largely COAD and STAD, but also had substantial PAAD, READ and ESCA, with smaller numbers of CHOL and LIHC.	('MIR6', 'Var', (0, 4))	('COAD', 'Disease', (36, 40))	('COAD', 'Disease', 'MESH:D029424', (36, 40))
117840	21253578	Survey of Tyrosine Kinase Signaling Reveals ROS Kinase Fusions in Human Cholangiocarcinoma Cholangiocarcinoma, also known as bile duct cancer, is the second most common primary hepatic carcinoma with a median survival of less than 2 years.	('Fusions', 'Var', (55, 62))	('hepatic carcinoma', 'Disease', 'MESH:D056486', (177, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('bile duct cancer', 'Phenotype', 'HP:0030153', (125, 141))	('bile duct cancer', 'Disease', (125, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('bile duct cancer', 'Disease', 'MESH:D001650', (125, 141))	('ROS', 'Protein', (44, 47))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('Cholangiocarcinoma', 'Disease', (91, 109))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('hepatic carcinoma', 'Disease', (177, 194))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 90))	('Cholangiocarcinoma', 'Disease', (72, 90))	('Human', 'Species', '9606', (66, 71))	('hepatic carcinoma', 'Phenotype', 'HP:0001402', (177, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
117842	21253578	Furthermore, we confirmed the presence of ROS kinase fusions in 8.7% (2 out of 23) of cholangiocarcinoma patients.	('patients', 'Species', '9606', (105, 113))	('presence', 'Reg', (30, 38))	('ROS kinase', 'Protein', (42, 52))	('fusions', 'Var', (53, 60))	('cholangiocarcinoma', 'Disease', (86, 104))	('ROS', 'Chemical', '-', (42, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (86, 104))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (86, 104))
117843	21253578	Expression of the ROS fusions in 3T3 cells confers transforming ability both in vitro and in vivo, and is responsive to its kinase inhibitor.	('ROS', 'Chemical', '-', (18, 21))	('fusions', 'Var', (22, 29))	('transforming ability', 'CPA', (51, 71))	('Expression', 'Species', '29278', (0, 10))	('3T3', 'CellLine', 'CVCL:0594', (33, 36))	('ROS', 'Gene', (18, 21))
117854	21253578	Upon further biochemical and functional analysis, we confirmed the oncogenic property of ROS kinase fusions.	('fusions', 'Var', (100, 107))	('ROS', 'Protein', (89, 92))	('ROS', 'Chemical', '-', (89, 92))
117890	21253578	Thus, we identified 2 patients with ROS kinase fusions in 23 CCA, with a frequency of 8.7%.	('CCA', 'Phenotype', 'HP:0030153', (61, 64))	('patients', 'Species', '9606', (22, 30))	('CCA', 'Disease', (61, 64))	('ROS', 'Chemical', '-', (36, 39))	('fusions', 'Var', (47, 54))	('ROS', 'Protein', (36, 39))
117892	21253578	To this end, we transfected 3T3 cells with retroviral constructs (C- terminal Myc-Tag) containing FIG-ROS(S), FIG-ROS(L), and SLC34A2-ROS(S), respectively.	('3T3', 'CellLine', 'CVCL:0594', (28, 31))	('Myc', 'Gene', (78, 81))	('Myc', 'Gene', '17869', (78, 81))	('ROS', 'Chemical', '-', (114, 117))	('SLC34A2-ROS', 'Var', (126, 137))	('ROS', 'Chemical', '-', (102, 105))	('ROS', 'Chemical', '-', (134, 137))
117896	21253578	Western blot analysis showed that both forms of FIG-ROS fusions activate known downstream effectors of ROS, such as STAT3 and AKT (Figure S2A).	('fusions', 'Var', (56, 63))	('AKT', 'Gene', (126, 129))	('STAT3', 'Gene', (116, 121))	('ROS', 'Chemical', '-', (103, 106))	('ROS', 'Chemical', '-', (52, 55))	('STAT3', 'Gene', '20848', (116, 121))	('FIG-ROS', 'Protein', (48, 55))	('AKT', 'Gene', '11651', (126, 129))	('activate', 'PosReg', (64, 72))
117897	21253578	On the other hand, SLC34A2-ROS(S) has minimal effects on STAT3 and AKT in this system (Figure S2B).	('ROS', 'Chemical', '-', (27, 30))	('AKT', 'Gene', '11651', (67, 70))	('SLC34A2-ROS', 'Var', (19, 30))	('AKT', 'Gene', (67, 70))	('STAT3', 'Gene', '20848', (57, 62))	('STAT3', 'Gene', (57, 62))
117900	21253578	Meanwhile, the presence of either FIG-ROS(L) or SLC34A2-ROS(S) also enabled 3T3 cells to form colonies, although the effect was not as significant as that seen with FIG-ROS(S).	('SLC34A2-ROS', 'Var', (48, 59))	('ROS', 'Chemical', '-', (38, 41))	('3T3', 'CellLine', 'CVCL:0594', (76, 79))	('ROS', 'Chemical', '-', (56, 59))	('ROS', 'Chemical', '-', (169, 172))	('enabled', 'PosReg', (68, 75))
117904	21253578	As shown in Figure 3B (bottom panel), two weeks after being injected with 3T3 cells transduced with either FIG-ROS(S), FIG-ROS(L) or SLC34A2-ROS(S), tumor formation was apparent in all the injected nude mice.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('ROS', 'Chemical', '-', (141, 144))	('nude mice', 'Species', '10090', (198, 207))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('FIG-ROS', 'Var', (119, 126))	('SLC34A2-ROS', 'Var', (133, 144))	('ROS', 'Chemical', '-', (111, 114))	('3T3', 'CellLine', 'CVCL:0594', (74, 77))	('tumor', 'Disease', (149, 154))	('ROS', 'Chemical', '-', (123, 126))	('FIG-ROS', 'Var', (107, 114))
117908	21253578	To ascertain the subcellular localization of FIG-ROS(S), we performed immunofluorescence assay with 3T3 cells stably transfected with the ROS fusion variants with Myc-tag antibody.	('3T3', 'CellLine', 'CVCL:0594', (100, 103))	('ROS', 'Chemical', '-', (138, 141))	('ROS', 'Chemical', '-', (49, 52))	('Myc', 'Gene', (163, 166))	('variants', 'Var', (149, 157))	('Myc', 'Gene', '17869', (163, 166))
117914	21253578	The oncogenecity of FIG-ROS fusions were further evaluated by their abilities to transform interleukin-3 (IL-3)-dependent murine lymphoid BaF3 cells to cytokine-independent growth.	('BaF3', 'CellLine', 'CVCL:0161', (138, 142))	('ROS', 'Chemical', '-', (24, 27))	('murine', 'Species', '10090', (122, 128))	('IL-3', 'Gene', '16187', (106, 110))	('transform', 'Reg', (81, 90))	('FIG-ROS', 'Protein', (20, 27))	('fusions', 'Var', (28, 35))	('IL-3', 'Gene', (106, 110))	('interleukin-3', 'Gene', (91, 104))	('interleukin-3', 'Gene', '16187', (91, 104))
117916	21253578	While both forms of FIG-ROS fusions showed increased tyrosine kinase activity in vitro as compared to control, FIG-ROS(S) has more than 4 fold higher kinase activity than FIG-ROS(L) (Figure S2D).	('FIG-ROS', 'Var', (111, 118))	('ROS', 'Chemical', '-', (24, 27))	('kinase activity', 'MPA', (150, 165))	('tyrosine kinase activity', 'MPA', (53, 77))	('higher', 'PosReg', (143, 149))	('tyrosine', 'Chemical', 'MESH:D014443', (53, 61))	('ROS', 'Chemical', '-', (115, 118))	('increased', 'PosReg', (43, 52))	('increased tyrosine kinase', 'Phenotype', 'HP:0003231', (43, 68))	('ROS', 'Chemical', '-', (175, 178))
117918	21253578	Treatment of TAE684 abolished the growth of BaF3 cells expressing either FIG-ROS(S) or FIG-ROS(L) with IC50 of 10 nM and 1.8 nM, respectively (Figure 4B).	('abolished', 'NegReg', (20, 29))	('TAE684', 'Chemical', 'MESH:C516714', (13, 19))	('growth', 'MPA', (34, 40))	('BaF3', 'CellLine', 'CVCL:0161', (44, 48))	('ROS', 'Chemical', '-', (77, 80))	('ROS', 'Chemical', '-', (91, 94))	('FIG-ROS', 'Var', (87, 94))
117919	21253578	As expected, NPM-ALK expressing Karpas-299 is sensitive to TAE684 with an IC50 of 4.8 nM, similar to the IC50 previously reported.	('TAE684', 'Chemical', 'MESH:C516714', (59, 65))	('Karpas-299', 'CellLine', 'CVCL:1324', (32, 42))	('sensitive', 'MPA', (46, 55))	('Karpas-299', 'Var', (32, 42))
117924	21253578	At 48 h after incubation with TAE684, 85-95% of FIG-ROS expressing cells stained positive for cleaved caspase 3 in several independent experiments.	('TAE684', 'Chemical', 'MESH:C516714', (30, 36))	('ROS', 'Chemical', '-', (52, 55))	('TAE684', 'Var', (30, 36))	('cleaved', 'MPA', (94, 101))	('caspase 3', 'Protein', (102, 111))
117927	21253578	To find out whether TAE684 also inhibits signaling downstream of FIG-ROS, FIG-ROS expressing BaF3 cells were treated with either DMSO or increasing concentrations of TAE684 for 3 hours.	('DMSO', 'Chemical', 'MESH:D004121', (129, 133))	('BaF3', 'CellLine', 'CVCL:0161', (93, 97))	('TAE684', 'Chemical', 'MESH:C516714', (20, 26))	('ROS', 'Chemical', '-', (69, 72))	('TAE684', 'Chemical', 'MESH:C516714', (166, 172))	('signaling', 'MPA', (41, 50))	('inhibits', 'NegReg', (32, 40))	('TAE684', 'Var', (20, 26))	('ROS', 'Chemical', '-', (78, 81))
117928	21253578	As demonstrated in Figure 4D, TAE684 inhibited ROS phosphorylation in a dose dependent manner.	('ROS phosphorylation', 'MPA', (47, 66))	('TAE684', 'Chemical', 'MESH:C516714', (30, 36))	('inhibited', 'NegReg', (37, 46))	('TAE684', 'Var', (30, 36))	('ROS', 'Chemical', '-', (47, 50))
117930	21253578	Clearly, inhibition of FIG-ROS by TAE684 led to a dose-dependent reduction in phosphorylation of STA3, AKT, ERK, and Shp2 in BaF3 cells.	('inhibition', 'NegReg', (9, 19))	('STA3', 'Protein', (97, 101))	('ERK', 'Gene', '13844', (108, 111))	('phosphorylation', 'MPA', (78, 93))	('FIG-ROS', 'Protein', (23, 30))	('ERK', 'Gene', (108, 111))	('ROS', 'Chemical', '-', (27, 30))	('TAE684', 'Chemical', 'MESH:C516714', (34, 40))	('BaF3', 'CellLine', 'CVCL:0161', (125, 129))	('AKT', 'Gene', (103, 106))	('Shp2', 'Gene', (117, 121))	('Shp2', 'Gene', '19247', (117, 121))	('TAE684', 'Var', (34, 40))	('reduction', 'NegReg', (65, 74))	('AKT', 'Gene', '11651', (103, 106))
117933	21253578	These results demonstrate that TAE684 inhibits not only FIG-ROS, but also its crucial downstream signaling molecules.	('TAE684', 'Var', (31, 37))	('inhibits', 'NegReg', (38, 46))	('TAE684', 'Chemical', 'MESH:C516714', (31, 37))	('ROS', 'Chemical', '-', (60, 63))	('FIG-ROS', 'Protein', (56, 63))
117939	21253578	Demethylation of ROS promoter contributes to the elevated expression of ROS kinase in malignant gliomas.	('expression', 'Species', '29278', (58, 68))	('expression', 'MPA', (58, 68))	('malignant gliomas', 'Disease', (86, 103))	('Demethylation', 'Var', (0, 13))	('ROS', 'Gene', (17, 20))	('ROS', 'Chemical', '-', (72, 75))	('malignant gliomas', 'Disease', 'MESH:D005910', (86, 103))	('ROS', 'Protein', (72, 75))	('elevated', 'PosReg', (49, 57))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('ROS', 'Chemical', '-', (17, 20))
117940	21253578	Chromosomal rearrangements involving ROS kinase have been reported in glioblastoma and non-small cell lung cancer.	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('ROS', 'Protein', (37, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (87, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('reported', 'Reg', (58, 66))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (91, 113))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (87, 113))	('glioblastoma', 'Disease', (70, 82))	('ROS', 'Chemical', '-', (37, 40))	('non-small cell lung cancer', 'Disease', (87, 113))	('Chromosomal rearrangements', 'Var', (0, 26))
117941	21253578	Since expression of FIG-ROS in CNS induces glioblastoma formation in vivo , we speculate that expression of FIG-ROS could develop cholangiocarcinoma in vivo as well.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (130, 148))	('expression', 'Species', '29278', (6, 16))	('glioblastoma', 'Disease', (43, 55))	('FIG-ROS', 'Gene', (108, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (43, 55))	('ROS', 'Chemical', '-', (24, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('develop', 'Reg', (122, 129))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (130, 148))	('induces', 'Reg', (35, 42))	('ROS', 'Chemical', '-', (112, 115))	('expression', 'Species', '29278', (94, 104))	('glioblastoma', 'Phenotype', 'HP:0012174', (43, 55))	('cholangiocarcinoma', 'Disease', (130, 148))	('expression', 'Var', (94, 104))
117942	21253578	In the present study, we identified aberrant ROS kinase expression in 8.7% cholangiocarcinoma patients.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (75, 93))	('ROS', 'Chemical', '-', (45, 48))	('patients', 'Species', '9606', (94, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (75, 93))	('ROS', 'Protein', (45, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('expression', 'Species', '29278', (56, 66))	('expression', 'MPA', (56, 66))	('aberrant', 'Var', (36, 44))	('cholangiocarcinoma', 'Disease', (75, 93))
117965	21253578	Sequest (Thermo Fisher Scientific) searches were done against the NCBI human database released on July 02, 2009, (containing 37,391 proteins), allowing for tyrosine phosphorylation (Y+80) and oxidized methionine (M+16) as differential modifications.	('methionine', 'Chemical', 'MESH:D008715', (201, 211))	('Y+80', 'Var', (182, 186))	('oxidized methionine', 'MPA', (192, 211))	('tyrosine', 'Chemical', 'MESH:D014443', (156, 164))	('tyrosine phosphorylation', 'MPA', (156, 180))	('human', 'Species', '9606', (71, 76))
117974	21253578	Wild type FIG and ROS gene was amplified with the use of primer pairs FIG-F3 and FIG-R8, ROS-Ex31F and ROS-GSP2, respectively.	('ROS-Ex31F', 'Var', (89, 98))	('ROS', 'Chemical', '-', (18, 21))	('ROS', 'Chemical', '-', (103, 106))	('ROS', 'Gene', (18, 21))	('ROS', 'Chemical', '-', (89, 92))
118035	33522895	AGAP2-AS1 knockdown significantly inhibited proliferation and caused apoptosis in CCA cells.	('caused', 'Reg', (62, 68))	('inhibited', 'NegReg', (34, 43))	('CCA', 'Disease', (82, 85))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (0, 9))	('AGAP2-AS1', 'Gene', (0, 9))	('knockdown', 'Var', (10, 19))	('proliferation', 'CPA', (44, 57))
118088	33522895	According to the survival analysis of the database, it was also shown that patients with high expression of AGAP2-AS1 had a shorter survival time (Fig.	('AGAP2-AS1', 'Gene', (108, 117))	('high expression', 'Var', (89, 104))	('survival', 'MPA', (132, 140))	('shorter', 'NegReg', (124, 131))	('patients', 'Species', '9606', (75, 83))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (108, 117))
118101	33522895	We knocked down/overexpressed SP1 in CCA cells and found that AGAP2-AS1 changed accordingly (Fig.	('AGAP2-AS1', 'Gene', (62, 71))	('changed', 'Reg', (72, 79))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (62, 71))	('knocked', 'Var', (3, 10))	('SP1', 'Gene', (30, 33))	('down/overexpressed', 'PosReg', (11, 29))
118106	33522895	Similarly, the results of the colony formation assay showed that AGAP2-AS1 knockdown reduced colony formation and survival in HUCCT1 and RBE cells (Fig.	('colony formation', 'CPA', (93, 109))	('AGAP2-AS1', 'Gene', (65, 74))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (65, 74))	('knockdown', 'Var', (75, 84))	('survival', 'CPA', (114, 122))	('reduced', 'NegReg', (85, 92))
118107	33522895	Flow cytometry assay were used to detect the effect of AGAP2-AS1 knockdown on the proliferation of CCA cells by affecting apoptosis.	('affecting', 'Reg', (112, 121))	('apoptosis', 'CPA', (122, 131))	('AGAP2-AS1', 'Gene', (55, 64))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (55, 64))	('knockdown', 'Var', (65, 74))
118116	33522895	These results further confirmed that AGAP2-AS1 participates in the development of CCA through its effect on the proliferation of CCA cells; inhibition of AGAP2-AS1 expression leads to a decrease in the growth of CCA cells.	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (154, 163))	('growth', 'CPA', (202, 208))	('inhibition', 'Var', (140, 150))	('AGAP2-AS1', 'Gene', (37, 46))	('CCA', 'Disease', (82, 85))	('AGAP2-AS1', 'Gene', (154, 163))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (37, 46))	('decrease', 'NegReg', (186, 194))
118120	33522895	related to proliferation and apoptosis of cancer cells and detected the changes of downstream target expression in CCA cells after further knockdown of AGAP2-AS1,including CDKN1A,ADNP2,SLC29A2 by qRT-PCR (Fig.	('AGAP2-AS1', 'Gene', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('knockdown', 'Var', (139, 148))	('ADNP2', 'Gene', '22850', (179, 184))	('CDKN1A', 'Gene', (172, 178))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (152, 161))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('SLC29A2', 'Gene', (185, 192))	('changes', 'Reg', (72, 79))	('CDKN1A', 'Gene', '1026', (172, 178))	('expression', 'MPA', (101, 111))	('SLC29A2', 'Gene', '3177', (185, 192))	('ADNP2', 'Gene', (179, 184))
118126	33522895	The results indicate that EZH2 binds to the CDKN1A promoter region, and knockdown of AGAP2-AS1 reduces binding of EZH2 to the CDKN1A promoter region (Fig.	('EZH2', 'Gene', '2146', (26, 30))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (85, 94))	('EZH2', 'Gene', (26, 30))	('CDKN1A', 'Gene', (44, 50))	('binding', 'Interaction', (103, 110))	('CDKN1A', 'Gene', (126, 132))	('CDKN1A', 'Gene', '1026', (44, 50))	('CDKN1A', 'Gene', '1026', (126, 132))	('AGAP2-AS1', 'Gene', (85, 94))	('EZH2', 'Gene', '2146', (114, 118))	('knockdown', 'Var', (72, 81))	('reduces', 'NegReg', (95, 102))	('EZH2', 'Gene', (114, 118))
118130	33522895	These data indicate that AGAP2-AS1 promotes CCA cell proliferation through an epigenetic silencing portion of EZH2-binding CDKN1A transcription.	('CDKN1A', 'Gene', (123, 129))	('EZH2', 'Gene', (110, 114))	('promotes', 'PosReg', (35, 43))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (25, 34))	('CCA', 'Disease', (44, 47))	('EZH2', 'Gene', '2146', (110, 114))	('CDKN1A', 'Gene', '1026', (123, 129))	('epigenetic', 'Var', (78, 88))	('AGAP2-AS1', 'Gene', (25, 34))
118137	33522895	In this experiment, In addition, we found that the transcription factor SP1 can induce AGAP2-AS1,then we studied the expression of related target genes after knockdown of AGAP2-AS1 in CCA cells, and found that the expression of tumor suppressor gene CDKN1A was significantly increased after knockdown of AGAP2-AS1.	('AGAP2-AS1', 'Gene', (87, 96))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (171, 180))	('CDKN1A', 'Gene', (250, 256))	('increased', 'PosReg', (275, 284))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('CDKN1A', 'Gene', '1026', (250, 256))	('AGAP2-AS1', 'Gene', (304, 313))	('knockdown', 'Var', (291, 300))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('AGAP2-AS1', 'Gene', (171, 180))	('tumor', 'Disease', (228, 233))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (304, 313))	('expression', 'MPA', (214, 224))
118153	33456351	Cholangiocarcinoma patients with high MRPL27 had worse overall survival (OS) and disease-free survival (DFS) compared to those with low MRPL27 (all p < 0.05).	('overall survival', 'CPA', (55, 71))	('disease-free survival', 'CPA', (81, 102))	('patients', 'Species', '9606', (19, 27))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (0, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('worse', 'NegReg', (49, 54))	('high MRPL27', 'Var', (33, 44))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 18))	('Cholangiocarcinoma', 'Disease', (0, 18))
118170	33456351	Mutations of MRPL27 in cholangiocarcinoma patients were identified in cholangiocarcinoma dataset (TCGA, PanCancer Atlas) from cBioPortal for cancer genomics (http://www.cbioportal.org/).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (23, 41))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (23, 41))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cholangiocarcinoma', 'Disease', (70, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('MRPL27', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('Cancer', 'Disease', (107, 113))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (70, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cholangiocarcinoma', 'Disease', (23, 41))	('Cancer', 'Disease', 'MESH:D009369', (107, 113))	('patients', 'Species', '9606', (42, 50))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))	('cancer', 'Disease', (141, 147))
118178	33456351	As shown in Figure 2, cholangiocarcinoma patients with high MRPL27 in tumor tissues had significantly worse OS and DFS compared to those with low MRPL27 levels (HR = 4.6, p = 0.004 and HR = 6.1, p < 0.001, respectively, Figure 2A and 2B).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (22, 40))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (22, 40))	('MRPL27', 'Gene', (60, 66))	('tumor', 'Disease', (70, 75))	('patients', 'Species', '9606', (41, 49))	('cholangiocarcinoma', 'Disease', (22, 40))	('high', 'Var', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
118191	33456351	Currently, several molecular pathways including Notch, receptor tyrosine kinase pathways and PI3K-AKT-mTOR pathway, mutations including KRAS, IDH/IDH2, ROS1, FGFR and BAP1 and cytokines including interleukin-6 were identified dysregulated in cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (242, 260))	('interleukin-6', 'Gene', (196, 209))	('AKT', 'Gene', '207', (98, 101))	('IDH', 'Gene', '3417', (146, 149))	('cholangiocarcinoma', 'Disease', (242, 260))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (242, 260))	('BAP1', 'Gene', (167, 171))	('Notch', 'Pathway', (48, 53))	('receptor tyrosine kinase pathways', 'Pathway', (55, 88))	('IDH', 'Gene', (142, 145))	('FGFR', 'Gene', (158, 162))	('molecular pathways', 'Pathway', (19, 37))	('IDH2', 'Gene', (146, 150))	('KRAS', 'Gene', '3845', (136, 140))	('ROS1', 'Gene', '6098', (152, 156))	('IDH2', 'Gene', '3418', (146, 150))	('IDH', 'Gene', '3417', (142, 145))	('mutations', 'Var', (116, 125))	('KRAS', 'Gene', (136, 140))	('mTOR', 'Gene', (102, 106))	('AKT', 'Gene', (98, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('IDH', 'Gene', (146, 149))	('BAP1', 'Gene', '8314', (167, 171))	('interleukin-6', 'Gene', '3569', (196, 209))	('mTOR', 'Gene', '2475', (102, 106))	('ROS1', 'Gene', (152, 156))
118194	33456351	As a biomarker involved in ribosome production, dyskerin was positive in 56.7% cholangiocarcinoma patients and associated with p53 mutation and a higher proliferative index.	('higher', 'PosReg', (146, 152))	('dyskerin', 'Gene', (48, 56))	('cholangiocarcinoma', 'Disease', (79, 97))	('positive', 'Reg', (61, 69))	('proliferative index', 'CPA', (153, 172))	('associated', 'Reg', (111, 121))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (79, 97))	('patients', 'Species', '9606', (98, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (79, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (127, 130))	('mutation', 'Var', (131, 139))
118245	32682432	Hepatic insufficiency was reported in 8 studies, and the NPBD group had a significantly higher risk of suffering from hepatic insufficiency than the PBD group (OR 3.09, 95% CI 1.15, 8.31; P = 0.03).	('NPBD', 'Var', (57, 61))	('Hepatic insufficiency', 'Disease', (0, 21))	('Hepatic insufficiency', 'Disease', 'MESH:D048550', (0, 21))	('PBD', 'Chemical', '-', (149, 152))	('Hepatic insufficiency', 'Phenotype', 'HP:0001399', (0, 21))	('hepatic insufficiency', 'Phenotype', 'HP:0001399', (118, 139))	('hepatic insufficiency', 'Disease', (118, 139))	('hepatic insufficiency', 'Disease', 'MESH:D048550', (118, 139))	('PBD', 'Chemical', '-', (58, 61))
118277	32682432	Stents in the bile duct system surely led to a higher infection rate (cholangitis, infection, intra-abdominal abscess), which may lead to a higher mortality rate, especially when the liver remnant function (FLR) is < 30%.	('lead', 'Reg', (130, 134))	('abdominal abscess', 'Phenotype', 'HP:0025181', (100, 117))	('infection', 'Disease', (83, 92))	('higher', 'PosReg', (47, 53))	('Stents', 'Var', (0, 6))	('infection', 'Disease', 'MESH:D007239', (83, 92))	('cholangitis', 'Disease', (70, 81))	('mortality', 'Disease', 'MESH:D003643', (147, 156))	('FLR', 'Gene', (207, 210))	('infection', 'Disease', (54, 63))	('cholangitis', 'Phenotype', 'HP:0030151', (70, 81))	('infection', 'Disease', 'MESH:D007239', (54, 63))	('cholangitis', 'Disease', 'MESH:D002761', (70, 81))	('FLR', 'Gene', '645', (207, 210))	('mortality', 'Disease', (147, 156))	('abscess', 'Phenotype', 'HP:0025615', (110, 117))
118309	31727017	reported that adjuvant radiotherapy was associated with an improved survival for patients with R1/R2 resection, but not for those with R0 resection.	('improved', 'PosReg', (59, 67))	('survival', 'MPA', (68, 76))	('patients', 'Species', '9606', (81, 89))	('R1/R2 resection', 'Var', (95, 110))
118344	31727017	Among them, 11 cases had lesions in No.16a2 with no metastases in No.16b1, 6 had lesions in No.16a2 and No.16b1.	('metastases', 'Disease', (52, 62))	('metastases', 'Disease', 'MESH:D009362', (52, 62))	('lesions', 'Var', (25, 32))
118359	31727017	For example, margin recurrences usually be regarded as local failures, and might also be included in the intrahepatic failures.	('intrahepatic failures', 'Disease', 'MESH:D002780', (105, 126))	('intrahepatic failures', 'Disease', (105, 126))	('margin recurrences', 'Var', (13, 31))
118385	31727017	A randomised, controlled, multicentre, phase 3 study (BILCAP) compared capecitabine with observation in resected biliary tract cancer and reported that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy.	('capecitabine', 'Var', (152, 164))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (220, 240))	('patients', 'Species', '9606', (197, 205))	('capecitabine', 'Chemical', 'MESH:C110904', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('biliary tract cancer', 'Disease', 'MESH:D001661', (113, 133))	('biliary tract cancer', 'Disease', (113, 133))	('overall survival', 'MPA', (177, 193))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (113, 133))	('biliary tract cancer', 'Disease', 'MESH:D001661', (220, 240))	('biliary tract cancer', 'Disease', (220, 240))	('capecitabine', 'Chemical', 'MESH:C110904', (152, 164))	('improve', 'PosReg', (169, 176))
118417	28241849	Inactivation of p38 MAPK by SB203580 or specific short interfering RNA (siRNA) promoted the inactivation of mTORC1 in ICC cells treated with metformin and ATO.	('p38 MAPK', 'Gene', '26416', (16, 24))	('SB203580', 'Chemical', 'MESH:C093642', (28, 36))	('inactivation', 'MPA', (92, 104))	('SB203580', 'Var', (28, 36))	('p38 MAPK', 'Gene', (16, 24))	('Inactivation', 'MPA', (0, 12))	('mTORC1', 'Gene', '382056', (108, 114))	('ATO', 'Chemical', 'MESH:D000077237', (155, 158))	('metformin', 'Chemical', 'MESH:D008687', (141, 150))	('mTORC1', 'Gene', (108, 114))
118430	28241849	In 2013, an epidemiological study that included 1828 potential ICC patients reported that, in diabetic patients, metformin use was associated with a 60% reduction in ICC risk.	('metformin', 'Var', (113, 122))	('ICC', 'Disease', (166, 169))	('reduction', 'NegReg', (153, 162))	('patients', 'Species', '9606', (67, 75))	('metformin', 'Chemical', 'MESH:D008687', (113, 122))	('diabetic', 'Disease', 'MESH:D003920', (94, 102))	('patients', 'Species', '9606', (103, 111))	('diabetic', 'Disease', (94, 102))
118456	28241849	Metformin and ATO cooperated to abrogate the activation of mTORC1 (p-mTOR Ser2448, p-p70S6K Thr389, p-Raptor Ser792, p-4E BP1 Thr37/46), as shown in Fig.	('mTOR', 'Gene', '2475', (69, 73))	('mTOR', 'Gene', (69, 73))	('Ser792', 'Chemical', '-', (109, 115))	('abrogate', 'NegReg', (32, 40))	('p-p70S6K Thr389', 'Var', (83, 98))	('mTOR', 'Gene', '2475', (59, 63))	('p-Raptor', 'Species', '126213', (100, 108))	('Thr389', 'Chemical', '-', (92, 98))	('mTORC1', 'Gene', '382056', (59, 65))	('Ser2448', 'Chemical', '-', (74, 81))	('ATO', 'Chemical', 'MESH:D000077237', (14, 17))	('activation', 'PosReg', (45, 55))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('Thr37', 'Chemical', '-', (126, 131))	('mTORC1', 'Gene', (59, 65))	('p-Raptor Ser792', 'Var', (100, 115))	('p-4E BP1 Thr37/46', 'Var', (117, 134))	('mTOR', 'Gene', (59, 63))
118481	28241849	5d-f) revealed that inactivation of p38 MAPK by SB203580 or specific siRNAs promoted the effect of metformin and ATO on ICC cells, implying that metformin-induced abrogation of activated p38 MAPK by ATO may contribute to the metformin-ATO synergism in ICC cells.	('metformin', 'Chemical', 'MESH:D008687', (225, 234))	('ATO', 'Chemical', 'MESH:D000077237', (235, 238))	('p38 MAPK', 'Gene', (187, 195))	('metformin', 'Chemical', 'MESH:D008687', (145, 154))	('p38 MAPK', 'Gene', (36, 44))	('inactivation', 'Var', (20, 32))	('ATO', 'Chemical', 'MESH:D000077237', (113, 116))	('metformin', 'Chemical', 'MESH:D008687', (99, 108))	('abrogation', 'NegReg', (163, 173))	('ATO', 'Chemical', 'MESH:D000077237', (199, 202))	('SB203580', 'Chemical', 'MESH:C093642', (48, 56))	('effect', 'MPA', (89, 95))	('metformin-ATO', 'Chemical', '-', (225, 238))	('p38 MAPK', 'Gene', '26416', (187, 195))	('promoted', 'PosReg', (76, 84))	('p38 MAPK', 'Gene', '26416', (36, 44))	('SB203580', 'Gene', (48, 56))
118483	28241849	Inactivation of AMPK by compound C or specific siRNA partially rescued metformin-induced inhibition of p38 MAPK and partially abrogated metformin plus ATO-induced upregulation of ERK3 and inhibition of mTORC1 in ICC cells (Fig.	('upregulation', 'PosReg', (163, 175))	('p38 MAPK', 'Gene', (103, 111))	('metformin', 'Chemical', 'MESH:D008687', (71, 80))	('mTORC1', 'Gene', '382056', (202, 208))	('ERK3', 'Enzyme', (179, 183))	('AMPK', 'Gene', (16, 20))	('p38 MAPK', 'Gene', '26416', (103, 111))	('metformin', 'Chemical', 'MESH:D008687', (136, 145))	('ATO', 'Chemical', 'MESH:D000077237', (151, 154))	('inhibition', 'NegReg', (188, 198))	('mTORC1', 'Gene', (202, 208))	('abrogated', 'NegReg', (126, 135))	('AMPK', 'Gene', '5563', (16, 20))	('Inactivation', 'Var', (0, 12))	('inhibition', 'MPA', (89, 99))
118485	28241849	For p38 MAPK, inactivation of p38 MAPK by SB203580 or specific siRNA promoted the inactivation of mTORC1 in ICC cells treated with metformin and ATO (Fig.	('mTORC1', 'Gene', '382056', (98, 104))	('p38 MAPK', 'Gene', '26416', (30, 38))	('SB203580', 'Chemical', 'MESH:C093642', (42, 50))	('inactivation', 'Var', (14, 26))	('p38 MAPK', 'Gene', '26416', (4, 12))	('ATO', 'Chemical', 'MESH:D000077237', (145, 148))	('inactivation', 'MPA', (82, 94))	('mTORC1', 'Gene', (98, 104))	('p38 MAPK', 'Gene', (4, 12))	('p38 MAPK', 'Gene', (30, 38))	('metformin', 'Chemical', 'MESH:D008687', (131, 140))
118493	28241849	8a) through inactivation of mTORC1 (Fig.	('mTORC1', 'Gene', (28, 34))	('inactivation', 'Var', (12, 24))	('mTORC1', 'Gene', '382056', (28, 34))
118495	28241849	8d, high ERK3 expression is associated with a better prognosis in ICC patients.	('patients', 'Species', '9606', (70, 78))	('expression', 'MPA', (14, 24))	('high', 'Var', (4, 8))	('ERK3', 'Gene', (9, 13))	('ICC', 'Disease', (66, 69))
118511	28241849	Our results suggested that inactivation of p38 MAPK by the p38 MAPK inhibitor SB203580 or p38 MAPK-specific siRNA could enhance the anticancer effect of single agent or combined metformin and ATO treatment, especially the ATO single-drug treatment.	('SB203580', 'Chemical', 'MESH:C093642', (78, 86))	('enhance', 'PosReg', (120, 127))	('p38 MAPK', 'Gene', (90, 98))	('inactivation', 'Var', (27, 39))	('p38 MAPK', 'Gene', '26416', (43, 51))	('ATO', 'Chemical', 'MESH:D000077237', (222, 225))	('ATO', 'Chemical', 'MESH:D000077237', (192, 195))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('metformin', 'Chemical', 'MESH:D008687', (178, 187))	('p38 MAPK', 'Gene', (43, 51))	('cancer', 'Disease', (136, 142))	('p38 MAPK', 'Gene', '26416', (59, 67))	('p38 MAPK', 'Gene', '26416', (90, 98))	('p38 MAPK', 'Gene', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
118518	28241849	Moreover, we are the first to report that increased expression of ERK3 inhibited ICC cell growth in vitro and in vivo, and high ERK3 expression in tumor samples predicted a better prognosis in ICC patients after tumor resection.	('increased', 'PosReg', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('expression', 'MPA', (133, 143))	('tumor', 'Disease', (147, 152))	('ICC', 'Disease', (193, 196))	('patients', 'Species', '9606', (197, 205))	('inhibited', 'NegReg', (71, 80))	('ICC', 'Disease', (81, 84))	('ERK3', 'Gene', (66, 70))	('ERK3', 'Gene', (128, 132))	('high', 'Var', (123, 127))	('expression', 'MPA', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', (212, 217))
118525	28241849	However, as we described previously, inactivation of p38 MAPK mechanistically bridged the synergistic anticancer effect of metformin and ATO.	('p38 MAPK', 'Gene', '26416', (53, 61))	('ATO', 'Chemical', 'MESH:D000077237', (137, 140))	('p38 MAPK', 'Gene', (53, 61))	('metformin', 'Chemical', 'MESH:D008687', (123, 132))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('inactivation', 'Var', (37, 49))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
118545	28241849	AMPKalpha (#2532) and phosphorylated AMPKalpha (Phospho-Thr172, #2535), mTOR (#2983), phosphorylated mTOR (Phospho-Ser2448, #5536), phosphorylated Raptor (Phospho-Ser792, #2083), phosphorylated p70 S6 kinase (Phospho-Thr389, #9234), phosphorylated 4E-BP1(Phospho-Thr37/46, #2855), cleaved PARP (#5626), cleaved caspase-3(#9661), ERK (#4696), phosphorylated ERK(Phospho-Thr202/Tyr204, #4370), p38 MAPK(#8690), phosphorylated p38 MAPK(Thr180/Tyr182, #4511), and Ki-67 (#9449) were from Cell Signaling Technology, Inc. (Danvers, MA, USA).	('mTOR', 'Gene', '2475', (101, 105))	('PARP', 'Gene', '1302', (289, 293))	('AMPK', 'Gene', (37, 41))	('ERK', 'Gene', (329, 332))	('caspase-3', 'Gene', (311, 320))	('AMPK', 'Gene', '5563', (0, 4))	('#9449', 'Var', (467, 472))	('4E-BP1', 'Gene', (248, 254))	('ERK', 'Gene', '5594', (357, 360))	('PARP', 'Gene', (289, 293))	('Thr', 'Chemical', 'MESH:D013912', (433, 436))	('p38 MAPK', 'Gene', '26416', (392, 400))	('p38 MAPK', 'Gene', '26416', (424, 432))	('Thr', 'Chemical', 'MESH:D013912', (369, 372))	('p38 MAPK', 'Gene', (392, 400))	('p38 MAPK', 'Gene', (424, 432))	('mTOR', 'Gene', (72, 76))	('Thr37', 'Chemical', '-', (263, 268))	('Ser792', 'Chemical', '-', (163, 169))	('Thr', 'Chemical', 'MESH:D013912', (217, 220))	('Thr389', 'Chemical', '-', (217, 223))	('AMPK', 'Gene', (0, 4))	('ERK', 'Gene', (357, 360))	('AMPK', 'Gene', '5563', (37, 41))	('Thr', 'Chemical', 'MESH:D013912', (263, 266))	('Ser2448', 'Chemical', '-', (115, 122))	('mTOR', 'Gene', (101, 105))	('mTOR', 'Gene', '2475', (72, 76))	('ERK', 'Gene', '5594', (329, 332))	('4E-BP1', 'Gene', '1978', (248, 254))	('Thr', 'Chemical', 'MESH:D013912', (56, 59))	('caspase-3', 'Gene', '836', (311, 320))
118546	28241849	Goat anti-rabbit and goat anti-mouse IgG peroxidase-conjugated secondary antibodies (31460 and 31430) were from Thermo-Pierce (Rockford, IL, USA).	('Goat', 'Species', '9925', (0, 4))	('31430', 'Var', (95, 100))	('mouse', 'Species', '10090', (31, 36))	('goat', 'Species', '9925', (21, 25))	('31460', 'Var', (85, 90))	('rabbit', 'Species', '9986', (10, 16))
118597	25931814	In a tumor xenograft study using SNU478 cells, streptochlorin significantly inhibited tumor growth without changes in body weight when compared with the control.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('SNU478', 'Chemical', '-', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (86, 91))	('streptochlorin', 'Chemical', 'MESH:C526070', (47, 61))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (5, 10))	('inhibited', 'NegReg', (76, 85))	('streptochlorin', 'Var', (47, 61))
118604	25931814	Further, although current standard chemotherapy based on platinum and gemcitabine can have positive clinical outcomes, the survival rate has not shown any significant improvement, ie, gemcitabine plus cisplatin has a survival benefit of less than 6 months when compared with single-agent treatment.	('less', 'NegReg', (237, 241))	('cisplatin', 'Chemical', 'MESH:D002945', (201, 210))	('gemcitabine', 'Chemical', 'MESH:C056507', (70, 81))	('gemcitabine', 'Var', (184, 195))	('platinum', 'Chemical', 'MESH:D010984', (57, 65))	('gemcitabine', 'Chemical', 'MESH:C056507', (184, 195))
118607	25931814	Specifically, streptochlorin inhibits activation of nuclear factor kappa B (NFkappaB) and has anti-angiogenic/anti-invasive activity in cancer cells.	('NFkappaB', 'Gene', '4790', (76, 84))	('streptochlorin', 'Chemical', 'MESH:C526070', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('streptochlorin', 'Var', (14, 28))	('activation', 'MPA', (38, 48))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('anti-angiogenic/anti-invasive activity', 'CPA', (94, 132))	('inhibits', 'NegReg', (29, 37))	('NFkappaB', 'Gene', (76, 84))	('nuclear factor kappa B', 'Gene', '4790', (52, 74))	('nuclear factor kappa B', 'Gene', (52, 74))
118685	25931814	Specifically, MMP-9 activity after treatment with streptochlorin 100 muM was almost half that in the control group.	('activity', 'MPA', (20, 28))	('MMP-9', 'Gene', (14, 19))	('streptochlorin', 'Chemical', 'MESH:C526070', (50, 64))	('streptochlorin 100 muM', 'Var', (50, 72))	('MMP-9', 'Gene', '4318', (14, 19))
118688	25931814	When treated with streptochlorin 100 muM, the invasiveness of HuCC-T1 and SNU478 cells decreased by 62.6% and 57.3%, respectively, versus the control.	('streptochlorin', 'Chemical', 'MESH:C526070', (18, 32))	('decreased', 'NegReg', (87, 96))	('invasiveness', 'CPA', (46, 58))	('HuCC-T1', 'CellLine', 'CVCL:0324', (62, 69))	('SNU478', 'Chemical', '-', (74, 80))	('CC', 'Phenotype', 'HP:0030153', (64, 66))	('streptochlorin 100 muM', 'Var', (18, 40))
118693	25931814	The extent and size of metastatic region of HuCC-T1 cells in liver was significantly decreased by treatment of streptochlorin, while the control group showed extensive metastasis of HuCC-T1 cells (Figure 3).	('decreased', 'NegReg', (85, 94))	('HuCC-T1', 'CellLine', 'CVCL:0324', (182, 189))	('CC', 'Phenotype', 'HP:0030153', (184, 186))	('streptochlorin', 'Var', (111, 125))	('CC', 'Phenotype', 'HP:0030153', (46, 48))	('HuCC-T1', 'CellLine', 'CVCL:0324', (44, 51))	('metastasis', 'CPA', (168, 178))	('streptochlorin', 'Chemical', 'MESH:C526070', (111, 125))
118695	25931814	As shown in Figure 4A, expression of mutant p53 decreased in HuCC-T1 and SNU478 cells in response to treatment with streptochlorin 100 muM, while expression of wild-type p53 was slightly increased.	('SNU478', 'Chemical', '-', (73, 79))	('HuCC-T1', 'CellLine', 'CVCL:0324', (61, 68))	('CC', 'Phenotype', 'HP:0030153', (63, 65))	('p53', 'Gene', (170, 173))	('decreased', 'NegReg', (48, 57))	('mutant', 'Var', (37, 43))	('p53', 'Gene', (44, 47))	('streptochlorin', 'Chemical', 'MESH:C526070', (116, 130))	('p53', 'Gene', '7157', (170, 173))	('p53', 'Gene', '7157', (44, 47))	('expression', 'MPA', (23, 33))
118696	25931814	Active caspase-3 was also significantly increased by streptochlorin 100 muM in SNU478 cells, while HuCC-T1 cells showed only small changes (Figure 4B).	('HuCC-T1', 'CellLine', 'CVCL:0324', (99, 106))	('caspase-3', 'Gene', '836', (7, 16))	('CC', 'Phenotype', 'HP:0030153', (101, 103))	('Active', 'MPA', (0, 6))	('streptochlorin 100 muM', 'Var', (53, 75))	('streptochlorin', 'Chemical', 'MESH:C526070', (53, 67))	('increased', 'PosReg', (40, 49))	('caspase-3', 'Gene', (7, 16))	('SNU478', 'Chemical', '-', (79, 85))
118698	25931814	These results indicate clearly that streptochlorin induces apoptosis of CC cells in vitro.	('apoptosis', 'CPA', (59, 68))	('streptochlorin', 'Var', (36, 50))	('streptochlorin', 'Chemical', 'MESH:C526070', (36, 50))	('CC', 'Phenotype', 'HP:0030153', (72, 74))
118702	25931814	Specifically, tumor volume in the streptochlorin-treated group was 6.6 times and 5.4 times smaller than that in the control and vehicle groups, respectively.	('tumor', 'Disease', (14, 19))	('streptochlorin-treated', 'Var', (34, 56))	('streptochlorin', 'Chemical', 'MESH:C526070', (34, 48))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('smaller', 'NegReg', (91, 98))
118704	25931814	Further, apoptotic signaling, such as mutant p53, was significantly decreased by treatment with streptochlorin (Figure S2).	('mutant', 'Var', (38, 44))	('p53', 'Gene', (45, 48))	('decreased', 'NegReg', (68, 77))	('p53', 'Gene', '7157', (45, 48))	('streptochlorin', 'Chemical', 'MESH:C526070', (96, 110))	('apoptotic signaling', 'CPA', (9, 28))
118705	25931814	In particular, mutant p53 expression was very similar in the control and vehicle groups, whereas the streptochlorin + vehicle group showed a significant decrease in mutant p53 expression.	('expression', 'MPA', (26, 36))	('mutant', 'Var', (165, 171))	('streptochlorin +', 'Chemical', 'MESH:C526070', (101, 117))	('p53', 'Gene', (22, 25))	('p53', 'Gene', '7157', (172, 175))	('expression', 'MPA', (176, 186))	('p53', 'Gene', '7157', (22, 25))	('decrease', 'NegReg', (153, 161))	('mutant', 'Var', (15, 21))	('p53', 'Gene', (172, 175))
118709	25931814	Further, streptochlorin increased apoptosis-related signals, such as Bad, Bax, and cytochrome C, and decreased Bcl-2 (Figure S4).	('apoptosis-related signals', 'MPA', (34, 59))	('Bcl-2', 'Gene', (111, 116))	('Bcl-2', 'Gene', '596', (111, 116))	('streptochlorin', 'Chemical', 'MESH:C526070', (9, 23))	('Bax', 'Gene', (74, 77))	('cytochrome C', 'Gene', '54205', (83, 95))	('decreased', 'NegReg', (101, 110))	('streptochlorin', 'Var', (9, 23))	('Bax', 'Gene', '581', (74, 77))	('increased', 'PosReg', (24, 33))	('cytochrome C', 'Gene', (83, 95))	('Bad', 'MPA', (69, 72))
118717	25931814	Lee et al reported that addition of erlotinib to chemotherapy for advanced biliary tract cancer significantly prolonged median progression-free survival when compared with standard chemotherapy using gemcitabine and platinum.	('addition', 'Var', (24, 32))	('progression-free survival', 'CPA', (127, 152))	('biliary tract cancer', 'Disease', (75, 95))	('gemcitabine', 'Chemical', 'MESH:C056507', (200, 211))	('erlotinib', 'Chemical', 'MESH:D000069347', (36, 45))	('prolonged', 'PosReg', (110, 119))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (75, 95))	('biliary tract cancer', 'Disease', 'MESH:D001661', (75, 95))	('platinum', 'Chemical', 'MESH:D010984', (216, 224))	('erlotinib', 'Gene', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
118722	25931814	Only HuCC-T1 and SNU478 cells were selected for further study since SNU1196 and SNU245 showed a very slow proliferation rate and a minimal migration or invasion rate in the wound healing/invasion assay (data not shown).	('invasion rate in the wound healing/invasion assay', 'CPA', (152, 201))	('SNU245', 'Var', (80, 86))	('SNU1196', 'Var', (68, 75))	('minimal', 'NegReg', (131, 138))	('migration', 'CPA', (139, 148))	('SNU478', 'Chemical', '-', (17, 23))	('CC', 'Phenotype', 'HP:0030153', (7, 9))	('HuCC-T1', 'CellLine', 'CVCL:0324', (5, 12))	('slow', 'NegReg', (101, 105))
118723	25931814	Mutant p53 genes are known to accelerate carcinogenesis and transformation of cells while wild-type p53 is associated with cell reapir.	('transformation of cells', 'CPA', (60, 83))	('p53', 'Gene', '7157', (7, 10))	('carcinogenesis', 'Disease', 'MESH:D063646', (41, 55))	('p53', 'Gene', '7157', (100, 103))	('Mutant', 'Var', (0, 6))	('carcinogenesis', 'Disease', (41, 55))	('p53', 'Gene', (7, 10))	('p53', 'Gene', (100, 103))	('accelerate', 'PosReg', (30, 40))
118724	25931814	Mutant p53 was clearly suppressed by treatment with streptochlorin in vitro (Figure 4) and in vivo (Figure S2B), indicating that streptochlorin is effective in regulation of p53 gene expression.	('p53', 'Gene', '7157', (7, 10))	('streptochlorin', 'Chemical', 'MESH:C526070', (129, 143))	('p53', 'Gene', (174, 177))	('Mutant', 'Var', (0, 6))	('p53', 'Gene', (7, 10))	('p53', 'Gene', '7157', (174, 177))	('streptochlorin', 'Chemical', 'MESH:C526070', (52, 66))
118725	25931814	Further, streptochlorin is known to inhibit activation of NFkappaB and angiogenesis, and to induce apoptosis of cancer cells.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('streptochlorin', 'Chemical', 'MESH:C526070', (9, 23))	('inhibit', 'NegReg', (36, 43))	('angiogenesis', 'CPA', (71, 83))	('apoptosis', 'CPA', (99, 108))	('streptochlorin', 'Var', (9, 23))	('NFkappaB', 'Gene', (58, 66))	('NFkappaB', 'Gene', '4790', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('induce', 'PosReg', (92, 98))	('activation', 'MPA', (44, 54))
118726	25931814	Choi et al reported that streptochlorin inhibited angiogenesis in fibrosarcoma cells, and we also observed that streptochlorin effectively inhibited VEGF secretion in an in vitro model (Figure S1) and NFkappaB activation in an in vivo model (Figure S3).	('streptochlorin', 'Chemical', 'MESH:C526070', (25, 39))	('fibrosarcoma', 'Disease', 'MESH:D005354', (66, 78))	('inhibited', 'NegReg', (40, 49))	('VEGF', 'Gene', (149, 153))	('streptochlorin', 'Chemical', 'MESH:C526070', (112, 126))	('fibrosarcoma', 'Disease', (66, 78))	('streptochlorin', 'Var', (112, 126))	('VEGF', 'Gene', '7422', (149, 153))	('NFkappaB', 'Gene', (201, 209))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (66, 78))	('activation', 'PosReg', (210, 220))	('inhibited', 'NegReg', (139, 148))	('NFkappaB', 'Gene', '4790', (201, 209))
118729	25931814	As shown in Figure S3B, expression of NFkappaB, VEGF, and Notch 1 was evidently decreased on treatment with streptochlorin, indicating that streptochlorin also has antiangiogenic and antimetastatic activity.	('VEGF', 'Gene', (48, 52))	('antimetastatic activity', 'CPA', (183, 206))	('streptochlorin', 'Chemical', 'MESH:C526070', (108, 122))	('expression', 'MPA', (24, 34))	('antiangiogenic', 'CPA', (164, 178))	('Notch 1', 'Gene', '4851', (58, 65))	('NFkappaB', 'Gene', (38, 46))	('decreased', 'NegReg', (80, 89))	('VEGF', 'Gene', '7422', (48, 52))	('streptochlorin', 'Chemical', 'MESH:C526070', (140, 154))	('NFkappaB', 'Gene', '4790', (38, 46))	('Notch 1', 'Gene', (58, 65))	('streptochlorin', 'Var', (140, 154))
118737	25931814	We observed that streptochlorin significantly inhibited growth of SNU478-bearing tumors in our animal tumor xenograft study with no significant toxicity (Figure 5), ie, tumor volume growth was inhibited effectively by streptochlorin, with no effect on body weight.	('tumors', 'Disease', (81, 87))	('toxicity', 'Disease', 'MESH:D064420', (144, 152))	('streptochlorin', 'Chemical', 'MESH:C526070', (218, 232))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('growth', 'CPA', (56, 62))	('toxicity', 'Disease', (144, 152))	('tumor', 'Disease', (169, 174))	('streptochlorin', 'Chemical', 'MESH:C526070', (17, 31))	('tumor', 'Disease', (81, 86))	('inhibited', 'NegReg', (193, 202))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('streptochlorin', 'Var', (218, 232))	('inhibited', 'NegReg', (46, 55))	('tumor', 'Disease', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('SNU478', 'Chemical', '-', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
118739	25931814	Mutant p53, MDM2, and PCNA were also decreased in the solid tumor model (Figure S2B).	('MDM2', 'Gene', '4193', (12, 16))	('MDM2', 'Gene', (12, 16))	('solid tumor', 'Disease', (54, 65))	('PCNA', 'Gene', (22, 26))	('solid tumor', 'Disease', 'MESH:D009369', (54, 65))	('p53', 'Gene', '7157', (7, 10))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('PCNA', 'Gene', '5111', (22, 26))	('Mutant', 'Var', (0, 6))	('decreased', 'NegReg', (37, 46))	('p53', 'Gene', (7, 10))
118740	25931814	Further, streptochlorin increased apoptosis signaling, which was correlated with downregulation of antiapoptotic Bcl-2 expression, upregulation of proapoptotic Bax, Bad, and cytochrome c, and activation of caspase-3, as shown in Figures 4 and S2-S4.	('apoptosis signaling', 'MPA', (34, 53))	('expression', 'MPA', (119, 129))	('upregulation', 'PosReg', (131, 143))	('Bcl-2', 'Gene', '596', (113, 118))	('streptochlorin', 'Chemical', 'MESH:C526070', (9, 23))	('Bax', 'Gene', (160, 163))	('downregulation', 'NegReg', (81, 95))	('caspase-3', 'Gene', '836', (206, 215))	('streptochlorin', 'Var', (9, 23))	('activation', 'PosReg', (192, 202))	('Bax', 'Gene', '581', (160, 163))	('Bcl-2', 'Gene', (113, 118))	('cytochrome c', 'Gene', (174, 186))	('increased', 'PosReg', (24, 33))	('Bad', 'MPA', (165, 168))	('caspase-3', 'Gene', (206, 215))	('cytochrome c', 'Gene', '54205', (174, 186))
118741	25931814	These results clearly demonstrate that streptochlorin inhibits growth of solid tumors and induces apoptosis of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('apoptosis', 'CPA', (98, 107))	('tumor', 'Disease', (79, 84))	('streptochlorin', 'Chemical', 'MESH:C526070', (39, 53))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('solid tumors', 'Disease', (73, 85))	('tumor', 'Disease', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('induces', 'Reg', (90, 97))	('streptochlorin', 'Var', (39, 53))	('inhibits', 'NegReg', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('solid tumors', 'Disease', 'MESH:D009369', (73, 85))
118748	25931814	Furthermore, streptochlorin significantly inhibited tumor growth in an animal tumor xenograft study.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('streptochlorin', 'Var', (13, 27))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('inhibited', 'NegReg', (42, 51))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('streptochlorin', 'Chemical', 'MESH:C526070', (13, 27))
118771	20959002	exposure to TCDD (100 ng/kg/day) or PCB126 (1000 ng/kg/day), a significant and similar increase in the incidence and range of non-neoplastic and neoplastic lesions were observed in the livers of female rats (Table 1).	('rats', 'Species', '10116', (202, 206))	('increase', 'PosReg', (87, 95))	('TCDD', 'Chemical', 'MESH:D000072317', (12, 16))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (145, 163))	('PCB126', 'Chemical', 'MESH:C023035', (36, 42))	('PCB126', 'Var', (36, 42))	('100 ng/kg/day', 'Var', (18, 31))
118774	20959002	A significant increase in the incidence of 6 of these non-neoplastic lesions and no neoplastic lesions were also observed following 52 weeks of exposure to TCDD or PCB126, while only hepatocyte hypertrophy was observed following 13 weeks of exposure (Table 1).	('hepatocyte hypertrophy', 'Disease', 'MESH:D006984', (183, 205))	('PCB126', 'Var', (164, 170))	('TCDD', 'Chemical', 'MESH:D000072317', (156, 160))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (58, 76))	('increase', 'PosReg', (14, 22))	('TCDD', 'Gene', (156, 160))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (84, 102))	('hepatocyte hypertrophy', 'Disease', (183, 205))	('PCB126', 'Chemical', 'MESH:C023035', (164, 170))
118785	20959002	Long-Evans rats and Han/Wistar rats exhibit a 1000-fold difference in sensitivity to acute TCDD lethality which is attributed to a point mutation in the AhR protein of Han/Wistar rats.	('rats', 'Species', '10116', (179, 183))	('AhR', 'Gene', (153, 156))	('sensitivity', 'MPA', (70, 81))	('point mutation', 'Var', (131, 145))	('TCDD', 'Chemical', 'MESH:D000072317', (91, 95))	('rats', 'Species', '10116', (11, 15))	('rats', 'Species', '10116', (31, 35))	('Wistar rats', 'Species', '10116', (172, 183))	('Wistar rats', 'Species', '10116', (24, 35))	('attributed to', 'Reg', (115, 128))
118809	20959002	Changes in gene expression associated with TCDD, PCB126 and PCB153 exposure were compared with changes in gene expression associated with rat hepatocellular adenoma (HCA), human HCA and human intrahepatic cholangiocarcinoma (ICC).	('rat', 'Species', '10116', (138, 141))	('PCB153', 'Gene', (60, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (205, 223))	('intrahepatic cholangiocarcinoma', 'Disease', (192, 223))	('hepatocellular adenoma', 'Disease', (142, 164))	('PCB153', 'Chemical', 'MESH:C014024', (60, 66))	('TCDD', 'Chemical', 'MESH:D000072317', (43, 47))	('TCDD', 'Var', (43, 47))	('PCB126', 'Var', (49, 55))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (192, 223))	('human', 'Species', '9606', (172, 177))	('PCB126', 'Chemical', 'MESH:C023035', (49, 55))	('hepatocellular adenoma', 'Phenotype', 'HP:0012028', (142, 164))	('human', 'Species', '9606', (186, 191))	('hepatocellular adenoma', 'Disease', 'MESH:D018248', (142, 164))
118820	20959002	Rats treated with TCDD or PCB126 for 30 weeks, and then with vehicle control for the remainder of the two-year cancer bioassay showed no difference in the incidence of hepatocellular adenoma or cholangiocarcinoma when compared to control animals.	('TCDD', 'Var', (18, 22))	('hepatocellular adenoma', 'Disease', (168, 190))	('Rats', 'Species', '10116', (0, 4))	('hepatocellular adenoma', 'Phenotype', 'HP:0012028', (168, 190))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cholangiocarcinoma', 'Disease', (194, 212))	('PCB126', 'Chemical', 'MESH:C023035', (26, 32))	('hepatocellular adenoma', 'Disease', 'MESH:D018248', (168, 190))	('PCB126', 'Var', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (194, 212))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (194, 212))	('TCDD', 'Chemical', 'MESH:D000072317', (18, 22))
118826	20959002	The non-hepatotoxic PCB153 (Table 1) caused the sustained differential expression of only 9 genes following subchronic and chronic exposure (Figures 1 and 2 and additional files 8 and 9).	('PCB153', 'Var', (20, 26))	('non-hepatotoxic', 'Disease', (4, 19))	('non-hepatotoxic', 'Disease', 'MESH:D056486', (4, 19))	('PCB153', 'Chemical', 'MESH:C014024', (20, 26))
118830	20959002	Only one gene, Psat1 (phosphoserine aminotransferase 1), was found to be shared by the expression signatures of all three compounds (Figures 2 and 3), where its expression was up-regulated 3- to 8-fold following exposure to TCDD, PCB126, and PCB153.	('PCB126', 'Chemical', 'MESH:C023035', (230, 236))	('PCB126', 'Var', (230, 236))	('phosphoserine aminotransferase 1', 'Gene', '293820', (22, 54))	('up-regulated', 'PosReg', (176, 188))	('expression', 'MPA', (161, 171))	('TCDD', 'Chemical', 'MESH:D000072317', (224, 228))	('PCB153', 'Var', (242, 248))	('phosphoserine aminotransferase 1', 'Gene', (22, 54))	('PCB153', 'Chemical', 'MESH:C014024', (242, 248))	('Psat1', 'Gene', '293820', (15, 20))	('Psat1', 'Gene', (15, 20))
118840	20959002	The appearance of HCA and CC was observed with 104 weeks of exposure to TCDD and PCB126, but not at earlier time points or with PCB153.	('TCDD', 'Chemical', 'MESH:D000072317', (72, 76))	('TCDD', 'Gene', (72, 76))	('PCB153', 'Chemical', 'MESH:C014024', (128, 134))	('HCA', 'Disease', (18, 21))	('PCB126', 'Chemical', 'MESH:C023035', (81, 87))	('PCB126', 'Var', (81, 87))
118848	20959002	Additionally, seven genes were identified which exhibited the same differential expression pattern in both rat HCA gene expression studies and in livers from rats exposed for 52 weeks to TCDD and/or PCB126, but not PCB153 (Table 6).	('TCDD', 'Chemical', 'MESH:D000072317', (187, 191))	('PCB126', 'Var', (199, 205))	('HCA gene', 'Gene', (111, 119))	('rats', 'Species', '10116', (158, 162))	('rat', 'Species', '10116', (158, 161))	('PCB153', 'Chemical', 'MESH:C014024', (215, 221))	('PCB126', 'Chemical', 'MESH:C023035', (199, 205))	('rat', 'Species', '10116', (107, 110))
118850	20959002	Toxicological studies conducted by the National Toxicology Program have shown a significant increase in the incidence of hepatic neoplastic and non-neoplastic lesions in female SD rats following chronic exposure to TCDD and PCB126.	('PCB126', 'Chemical', 'MESH:C023035', (224, 230))	('hepatic neoplastic', 'Disease', (121, 139))	('TCDD', 'Chemical', 'MESH:D000072317', (215, 219))	('PCB126', 'Var', (224, 230))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (148, 166))	('hepatic neoplastic', 'Disease', 'MESH:D056486', (121, 139))	('TCDD', 'Gene', (215, 219))	('increase', 'PosReg', (92, 100))	('rats', 'Species', '10116', (180, 184))
118872	20959002	The increase expression of Psat1 following TCDD, PCB126 and PCB153 treatments suggests that its response is not specific to DLCs.	('PCB153', 'Gene', (60, 66))	('expression', 'MPA', (13, 23))	('PCB126', 'Chemical', 'MESH:C023035', (49, 55))	('TCDD', 'Chemical', 'MESH:D000072317', (43, 47))	('Psat1', 'Gene', (27, 32))	('PCB126', 'Var', (49, 55))	('Psat1', 'Gene', '293820', (27, 32))	('increase', 'PosReg', (4, 12))	('PCB153', 'Chemical', 'MESH:C014024', (60, 66))
118881	20959002	Enpp2 (Ectonucleotide pyrophosphatase/phosphodiesterase 2; also known as autotaxin), a tumor cell motility stimulating factor, was up-regulated following TCDD and PCB126 exposure.	('Ectonucleotide pyrophosphatase/phosphodiesterase 2', 'Gene', (7, 57))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Ectonucleotide pyrophosphatase/phosphodiesterase 2', 'Gene', '84050', (7, 57))	('Enpp2', 'Gene', (0, 5))	('PCB126', 'Chemical', 'MESH:C023035', (163, 169))	('PCB126', 'Var', (163, 169))	('tumor', 'Disease', (87, 92))	('up-regulated', 'PosReg', (131, 143))	('Enpp2', 'Gene', '84050', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('autotaxin', 'Gene', '84050', (73, 82))	('TCDD', 'Chemical', 'MESH:D000072317', (154, 158))	('TCDD', 'Var', (154, 158))	('autotaxin', 'Gene', (73, 82))
118895	20959002	Gata6 was also down-regulated following PCB126 exposure and in the human HCA expression profile.	('expression', 'MPA', (77, 87))	('Gata6', 'Gene', (0, 5))	('PCB126', 'Chemical', 'MESH:C023035', (40, 46))	('down-regulated', 'NegReg', (15, 29))	('human', 'Species', '9606', (67, 72))	('PCB126', 'Var', (40, 46))
118904	20959002	It should be noted that of the 50 genes shared by the 52-week gene expression data (TCDD, PCB126, and PCB153) and gene expression data from the published reports of ICC and HCA, only 4 genes (Got2, Ugcg, Stmn1 and Alas1) were found to be differentially expressed by the non-DLC PCB153.	('PCB153', 'Chemical', 'MESH:C014024', (102, 108))	('PCB153', 'Chemical', 'MESH:C014024', (278, 284))	('PCB126', 'Chemical', 'MESH:C023035', (90, 96))	('TCDD', 'Chemical', 'MESH:D000072317', (84, 88))	('Stmn1', 'Gene', (204, 209))	('PCB153', 'Var', (278, 284))
118908	20959002	Gene expression of Alas1, an enzyme involved in heme biosynthesis, was down-regulated in the TCDD, PCB126 and human HCA profiles but up-regulated in the PCB153 expression profile, suggesting that down-regulation of Alas1 may promote tumor development.	('down-regulated', 'NegReg', (71, 85))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('expression', 'MPA', (5, 15))	('down-regulation', 'Var', (196, 211))	('tumor', 'Disease', (233, 238))	('human', 'Species', '9606', (110, 115))	('Alas1', 'Gene', (19, 24))	('up-regulated', 'PosReg', (133, 145))	('Alas1', 'Gene', (215, 220))	('PCB153', 'Chemical', 'MESH:C014024', (153, 159))	('PCB126', 'Chemical', 'MESH:C023035', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('heme', 'Chemical', 'MESH:D006418', (48, 52))	('promote', 'PosReg', (225, 232))	('TCDD', 'Chemical', 'MESH:D000072317', (93, 97))
118957	32334449	Between October 1, 2013 and October 31, 2015, there were 570 major hepato-pancreato-biliary cases.	('hepato-pancreato-biliary', 'Disease', (67, 91))	('October', 'Var', (28, 35))	('hepato-pancreato-biliary', 'Disease', 'MESH:D020065', (67, 91))
119001	32334449	Factors associated with the risk of mortality in pCCA were resection status and positive lymph nodes, while the only factor associated with mortality in dCCA was the presence of positive lymph nodes.	('mortality', 'Disease', 'MESH:D003643', (36, 45))	('dCCA', 'Chemical', '-', (153, 157))	('mortality', 'Disease', 'MESH:D003643', (140, 149))	('pCCA', 'Disease', (49, 53))	('mortality', 'Disease', (36, 45))	('associated', 'Reg', (8, 18))	('mortality', 'Disease', (140, 149))	('positive lymph nodes', 'Var', (80, 100))
119063	32059499	In line with this observation, epigenetic silencing of CDKN2A gene, that encodes the tumor suppressors p16(INK4A) and p14(ARF), has been reported as an early and key molecular event occurring during the latency period between exposure to long asbestos fibers and cell malignant transformation.	('tumor', 'Disease', (85, 90))	('epigenetic silencing', 'Var', (31, 51))	('CDKN2A', 'Gene', '1029', (55, 61))	('cell malignant transformation', 'CPA', (263, 292))	('p16', 'Gene', '1029', (103, 106))	('ARF', 'Disease', 'MESH:D058186', (122, 125))	('p14', 'Gene', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('p16', 'Gene', (103, 106))	('INK4A', 'Gene', '1029', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('p14', 'Gene', '1029', (118, 121))	('ARF', 'Disease', (122, 125))	('CDKN2A', 'Gene', (55, 61))	('asbestos', 'Chemical', 'MESH:D001194', (243, 251))	('INK4A', 'Gene', (107, 112))
119069	32059499	Asbestos fibers may also absorb on their surface ionizing radiations and different types of carcinogens, leading to their accumulation in target cell; in particular, benzo(a)pyrene has high affinity for asbestos fibers and a cooperative mutagenic effect has been reported.	('asbestos', 'Chemical', 'MESH:D001194', (203, 211))	('Asbestos', 'Chemical', 'MESH:D001194', (0, 8))	('benzo(a)pyrene', 'Chemical', 'MESH:D001564', (166, 180))	('benzo', 'Var', (166, 171))	('affinity', 'Interaction', (190, 198))
119074	32059499	Germline mutations of the BRCA1 Associated Protein 1 (BAP1), the only gene that has been proposed to influence environmental carcinogenesis, have been indeed reported to increase cancer risk after minimal exposure to asbestos fibers in animal models.	('Germline mutations', 'Var', (0, 18))	('BRCA1 Associated Protein 1', 'Gene', '8314', (26, 52))	('asbestos', 'Chemical', 'MESH:D001194', (217, 225))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('increase', 'PosReg', (170, 178))	('iron', 'Chemical', 'MESH:D007501', (114, 118))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('BRCA1 Associated Protein 1', 'Gene', (26, 52))	('BAP1', 'Gene', (54, 58))	('cancer', 'Disease', (179, 185))
119077	32059499	Drawing parallels to humans these findings suggest that, compared to wild-type subjects, subjects carrying BAP1 germline mutations may be more susceptible to asbestos carcinogenesis, even when exposed to low levels of fibers.	('asbestos carcinogenesis', 'Disease', (158, 181))	('mutations', 'Var', (121, 130))	('susceptible', 'Reg', (143, 154))	('BAP1', 'Gene', (107, 111))	('humans', 'Species', '9606', (21, 27))	('asbestos carcinogenesis', 'Disease', 'MESH:D063646', (158, 181))
119130	32059499	Due to the inherent capability of self-renewal and longevity, that allow sequential accumulation of genetic mutations over the years, stem cells represent indeed the ideal target for neoplastic transformation triggered by chronic injury.	('chronic injury', 'Disease', (222, 236))	('chronic injury', 'Disease', 'MESH:D020208', (222, 236))	('mutations', 'Var', (108, 117))
119246	30700476	Highly glycosylated MUC1 has been reported to be associated with malignancies in many other organs.	('malignancies', 'Disease', 'MESH:D009369', (65, 77))	('associated', 'Reg', (49, 59))	('malignancies', 'Disease', (65, 77))	('Highly glycosylated', 'Var', (0, 19))	('MUC1', 'Gene', (20, 24))	('MUC1', 'Gene', '4582', (20, 24))
119251	30700476	In addition, although the correlation between the expression of MUC1 in biliary duct-derived cancer and the overall survival (OS) rate for patients with resectable CCA has been analysed with Kaplan-Meier plot in several clinical trials, the result still remains inconclusive.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('patients', 'Species', '9606', (139, 147))	('MUC1', 'Gene', (64, 68))	('MUC1', 'Gene', '4582', (64, 68))	('expression', 'Var', (50, 60))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
119283	30700476	We found that the OS for patients with positive expression of MUC1 was significantly shorter than that of MUC1 negative group.	('shorter', 'NegReg', (85, 92))	('MUC1', 'Gene', (62, 66))	('MUC1', 'Gene', '4582', (62, 66))	('positive expression', 'Var', (39, 58))	('MUC1', 'Gene', (106, 110))	('MUC1', 'Gene', '4582', (106, 110))	('patients', 'Species', '9606', (25, 33))
119287	30700476	In our meta-analysis of the diagnostic capability of markers for CCA, seven prospective trialsand a retrospective study were eligible for diagnostic analysis that showed that the diagnostic capability of CA19-9 was inferior to other molecules, such as WFA-MUC1.	('inferior', 'NegReg', (215, 223))	('WFA-MUC1', 'Gene', '4582', (252, 260))	('CA19-9', 'Chemical', 'MESH:C086528', (204, 210))	('CCA', 'Disease', (65, 68))	('WFA-MUC1', 'Gene', (252, 260))	('CA19-9', 'Var', (204, 210))
119291	30700476	The diagnostic capability of serum WFA-MUC1 was superior to that of CA19-9 (as the data showed, AUC WFA-MUC1 vs AUCCA19-9: 0.77 (95% CI 0.73 to 0.81) vs 0.75 (95% CI 0.71 to 0.79)).	('WFA-MUC1', 'Gene', (35, 43))	('WFA-MUC1', 'Gene', (100, 108))	('CA19-9', 'Chemical', 'MESH:C086528', (115, 121))	('WFA-MUC1', 'Gene', '4582', (100, 108))	('WFA-MUC1', 'Gene', '4582', (35, 43))	('AUC', 'Var', (96, 99))	('CA19-9', 'Chemical', 'MESH:C086528', (68, 74))
119351	30127888	However, the overexpression of CHD1L could reduce the degree of chromatin loosening in tumor cells, which may result in the mismatch of DNA bases, potentially initiating tumorigenesis.	('reduce', 'NegReg', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (87, 92))	('mismatch', 'Var', (124, 132))	('chromatin loosening', 'MPA', (64, 83))	('CHD1L', 'Gene', (31, 36))	('tumor', 'Disease', (170, 175))	('initiating', 'Reg', (159, 169))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('CHD1L', 'Gene', '9557', (31, 36))	('result in', 'Reg', (110, 119))
119357	30127888	The loss of function for DNA MMR could occur upon mutation of a DNA MMR system gene, leading to increased rates of DNA base pair mismatch and activator mutations in proto-oncogenes, or the inactivation of tumor suppressor genes, which eventually results in tumor progression.	('increased', 'PosReg', (96, 105))	('results in', 'Reg', (246, 256))	('tumor', 'Disease', (257, 262))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('loss of function', 'NegReg', (4, 20))	('inactivation', 'NegReg', (189, 201))	('DNA base pair mismatch', 'MPA', (115, 137))	('DNA MMR system', 'Gene', (64, 78))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('mutation', 'Var', (50, 58))
119361	30127888	The downregulation of hMLH1 (including mutation, methylation and loss of heterozygosity) could lead to the loss of DNA MMR function and promote tumor progress.	('tumor', 'Disease', (144, 149))	('promote', 'PosReg', (136, 143))	('mutation', 'Var', (39, 47))	('hMLH1', 'Gene', '4292', (22, 27))	('loss', 'NegReg', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('DNA MMR', 'Protein', (115, 122))	('loss of heterozygosity', 'Var', (65, 87))	('downregulation', 'NegReg', (4, 18))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('methylation', 'Var', (49, 60))	('hMLH1', 'Gene', (22, 27))	('function', 'MPA', (123, 131))
119362	30127888	Zhang et al reported that 90% of HNPCC cases were closely associated with mutations to hMLH1.	('associated', 'Reg', (58, 68))	('hMLH1', 'Gene', (87, 92))	('mutations', 'Var', (74, 83))	('HNPCC', 'Phenotype', 'HP:0006716', (33, 38))	('HNPCC', 'Disease', (33, 38))	('hMLH1', 'Gene', '4292', (87, 92))
119364	30127888	The latest research findings indicate that the methylation status of the hMLH1 gene may be of significance for evaluating the risk of recurrence in rectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('methylation', 'Var', (47, 58))	('rectal cancer', 'Disease', 'MESH:D012004', (148, 161))	('significance', 'Reg', (94, 106))	('hMLH1', 'Gene', (73, 78))	('rectal cancer', 'Disease', (148, 161))	('rectal cancer', 'Phenotype', 'HP:0100743', (148, 161))	('hMLH1', 'Gene', '4292', (73, 78))
119380	30127888	The expression of CHD1L was significantly associated with a history of gallstones, the serum CA19-9 level and TNM staging (P<0.05).	('gallstones', 'Phenotype', 'HP:0001081', (71, 81))	('associated', 'Reg', (42, 52))	('gallstones', 'Disease', 'MESH:D042882', (71, 81))	('CHD1L', 'Gene', (18, 23))	('gallstone', 'Phenotype', 'HP:0001081', (71, 80))	('CHD1L', 'Gene', '9557', (18, 23))	('TNM staging', 'CPA', (110, 121))	('expression', 'Var', (4, 14))	('serum CA19-9 level', 'MPA', (87, 105))	('gallstones', 'Disease', (71, 81))
119394	30127888	Further analysis indicated that high expression of CHD1L was significantly associated with gallstone history, CA19-9 level and TNM stage (P<0.05), and negatively associated with the overall patient survival rate.	('gallstone', 'Disease', 'MESH:D042882', (91, 100))	('CA19-9', 'MPA', (110, 116))	('gallstone', 'Disease', (91, 100))	('negatively', 'NegReg', (151, 161))	('gallstone', 'Phenotype', 'HP:0001081', (91, 100))	('associated', 'Reg', (162, 172))	('CHD1L', 'Gene', (51, 56))	('CHD1L', 'Gene', '9557', (51, 56))	('TNM stage', 'CPA', (127, 136))	('associated', 'Reg', (75, 85))	('high expression', 'Var', (32, 47))	('patient', 'Species', '9606', (190, 197))
119429	30003193	To determine the role of FLR augmentation with PVE and/or biliary drainage, it is our practice to calculate the size of the FLR using volumetric analysis.16 Semiautomated software (Scout  ) is used to outline the contour of the liver, intrahepatic vasculature, and tumor, which allows for a three-dimensional calculation of functional liver that will remain after resection, as a percentage of total preoperative functional liver (Figure 2).16 Shoup et al16 reported that a FLR less than 25% triples the risk of postoperative hepatic insufficiency and is predictive of morbidity and length of hospitalization.	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('hepatic insufficiency', 'Phenotype', 'HP:0001399', (526, 547))	('postoperative hepatic insufficiency', 'Disease', (512, 547))	('less than 25%', 'Var', (478, 491))	('tumor', 'Disease', (265, 270))	('PVE', 'Chemical', '-', (47, 50))	('FLR', 'Var', (474, 477))	('PVE', 'Phenotype', 'HP:0030242', (47, 50))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('triples', 'PosReg', (492, 499))	('postoperative hepatic insufficiency', 'Disease', 'MESH:D000309', (512, 547))
119479	30003193	Augmentation of the FLR with PVE and biliary drainage should be considered in the treatment strategy, especially for patients undergoing extended resections resulting in a small FLR and/or those with underlying hepatic insufficiency from processes such as cholestasis.	('cholestasis', 'Disease', 'MESH:D002779', (256, 267))	('PVE', 'Chemical', '-', (29, 32))	('small', 'Var', (172, 177))	('cholestasis', 'Disease', (256, 267))	('hepatic insufficiency', 'Phenotype', 'HP:0001399', (211, 232))	('cholestasis', 'Phenotype', 'HP:0001396', (256, 267))	('hepatic insufficiency', 'Disease', (211, 232))	('hepatic insufficiency', 'Disease', 'MESH:D000309', (211, 232))	('FLR', 'MPA', (178, 181))	('PVE', 'Phenotype', 'HP:0030242', (29, 32))	('patients', 'Species', '9606', (117, 125))
119507	27322076	Moreover, intraductal RFA may decrease tumor ingrowth and benign epithelial hyperplasia, achieve local tumor control, and prolong stent patency due to substantially increasing the diameter of malignant biliary strictures.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('intraductal', 'Var', (10, 21))	('benign epithelial hyperplasia', 'Disease', 'MESH:D017573', (58, 87))	('achieve', 'PosReg', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', (103, 108))	('decrease', 'NegReg', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('stent patency', 'CPA', (130, 143))	('benign epithelial hyperplasia', 'Disease', (58, 87))	('increasing', 'PosReg', (165, 175))	('tumor', 'Disease', (39, 44))	('prolong', 'PosReg', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
119551	27322076	We agree that intraductal RFA can destroy the tumor tissue to some extent to enlarge the lumen for stent placement, leading to blood vessel loss; this is in agreement with the findings of Monga et al..	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('men', 'Species', '9606', (110, 113))	('lumen', 'MPA', (89, 94))	('men', 'Species', '9606', (162, 165))	('blood', 'MPA', (127, 132))	('tumor', 'Disease', (46, 51))	('enlarge', 'PosReg', (77, 84))	('men', 'Species', '9606', (91, 94))	('enlarge the lumen', 'Phenotype', 'HP:0002617', (77, 94))	('intraductal', 'Var', (14, 25))
119599	27655244	ICC was defined by ICD-10 code C22.1 (Intrahepatic bile duct neoplasms) and ECC was defined by ICD-10 codes, C24.0 (extra-hepatic bile duct neoplasms), C24.8 (Overlapping lesion of biliary tract neoplasm), and C24.9 (biliary tract, unspecified neoplasms).	('biliary tract neoplasm', 'Disease', 'MESH:D001661', (181, 203))	('Intrahepatic bile duct neoplasms', 'Disease', (38, 70))	('neoplasm', 'Phenotype', 'HP:0002664', (244, 252))	('C24.0', 'Var', (109, 114))	('neoplasms', 'Phenotype', 'HP:0002664', (61, 70))	('neoplasms', 'Phenotype', 'HP:0002664', (140, 149))	('biliary tract neoplasm', 'Phenotype', 'HP:0100574', (181, 203))	('neoplasm', 'Phenotype', 'HP:0002664', (61, 69))	('neoplasm', 'Phenotype', 'HP:0002664', (140, 148))	('C24.9', 'Var', (210, 215))	('neoplasms', 'Disease', 'MESH:D009369', (244, 253))	('neoplasm', 'Phenotype', 'HP:0002664', (195, 203))	('C24.8', 'Var', (152, 157))	('unspecified', 'Species', '32644', (232, 243))	('neoplasms', 'Disease', 'MESH:D009369', (61, 70))	('extra-hepatic bile duct neoplasms', 'Disease', 'MESH:D001650', (116, 149))	('neoplasms', 'Disease', 'MESH:D009369', (140, 149))	('C22.1', 'Var', (31, 36))	('neoplasms', 'Disease', (244, 253))	('extra-hepatic bile duct neoplasms', 'Disease', (116, 149))	('neoplasms', 'Disease', (61, 70))	('neoplasms', 'Disease', (140, 149))	('Intrahepatic bile duct neoplasms', 'Disease', 'MESH:D002780', (38, 70))	('biliary tract neoplasm', 'Disease', (181, 203))	('neoplasms', 'Phenotype', 'HP:0002664', (244, 253))
119769	30588199	The Prognostic Value of Cytokeratin and Sal-Like Protein 4 Expression in Hepatocellular Carcinoma and Intra-Hepatic Cholangiocarcinoma in Taiwan Background: We previously reported that modulation of cytokeratin18 induces pleomorphism of liver cells, higher cell motility, and higher drug sensitivity to sorafenib treatment of hepatoma cells.	('cytokeratin18', 'Gene', '3875', (199, 212))	('induces', 'Reg', (213, 220))	('cytokeratin18', 'Gene', (199, 212))	('Intra-Hepatic Cholangiocarcinoma', 'Disease', (102, 134))	('modulation', 'Var', (185, 195))	('higher', 'PosReg', (276, 282))	('hepatoma', 'Disease', 'MESH:D006528', (326, 334))	('higher cell motility', 'CPA', (250, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('sorafenib', 'Chemical', 'MESH:D000077157', (303, 312))	('Sal-Like Protein 4', 'Gene', (40, 58))	('Intra-Hepatic Cholangiocarcinoma', 'Disease', 'MESH:D018281', (102, 134))	('Hepatocellular Carcinoma', 'Phenotype', 'HP:0001402', (73, 97))	('drug sensitivity', 'Phenotype', 'HP:0020174', (283, 299))	('Sal-Like Protein 4', 'Gene', '57167', (40, 58))	('Carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('pleomorphism', 'CPA', (221, 233))	('hepatoma', 'Disease', (326, 334))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))
119784	30588199	We have identified the pleomorphism of these cancer cells is caused by instability and disorganization of the cytoskeleton system.	('pleomorphism', 'Var', (23, 35))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('caused', 'Reg', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))
119787	30588199	We recently reported that by affecting the expression and organization of CK18, a plectin deficiency partially augments the cytoskeleton and induces pleomorphic changes in liver cells.	('CK18', 'Gene', '3875', (74, 78))	('organization', 'MPA', (58, 70))	('plectin', 'Gene', '5339', (82, 89))	('cytoskeleton', 'MPA', (124, 136))	('induces', 'Reg', (141, 148))	('augments', 'NegReg', (111, 119))	('pleomorphic changes', 'CPA', (149, 168))	('deficiency', 'Var', (90, 100))	('CK18', 'Gene', (74, 78))	('affecting', 'Reg', (29, 38))	('expression', 'MPA', (43, 53))	('plectin', 'Gene', (82, 89))
119789	30588199	Moreover, we have shown that plectin deficiency and increased E-cadherin in hepatoma cells are associated with higher rates of cell motility, collective cell migration, as well as higher drug sensitivity to sorafenib treatment.	('increased', 'PosReg', (52, 61))	('drug sensitivity', 'Phenotype', 'HP:0020174', (187, 203))	('plectin', 'Gene', '5339', (29, 36))	('drug sensitivity', 'MPA', (187, 203))	('hepatoma', 'Disease', (76, 84))	('hepatoma', 'Disease', 'MESH:D006528', (76, 84))	('cell motility', 'CPA', (127, 140))	('sorafenib', 'Chemical', 'MESH:D000077157', (207, 216))	('plectin', 'Gene', (29, 36))	('E-cadherin', 'Gene', (62, 72))	('higher', 'PosReg', (111, 117))	('collective cell migration', 'CPA', (142, 167))	('deficiency', 'Var', (37, 47))	('higher', 'PosReg', (180, 186))	('E-cadherin', 'Gene', '999', (62, 72))
119795	30588199	The relationship between tumor transformation and CK18 modulation in HCC was established in our previous study using an in vitro experiment model.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('HCC', 'Phenotype', 'HP:0001402', (69, 72))	('modulation', 'Var', (55, 65))	('tumor', 'Disease', (25, 30))	('HCC', 'Gene', (69, 72))	('CK18', 'Gene', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('HCC', 'Gene', '619501', (69, 72))	('CK18', 'Gene', '3875', (50, 54))
119854	30588199	Considering the correlation between CK expression and patient survival in HCC, we found that only CK19 expression was significantly associated with reduced OS and DFS in HCC patients.	('patient', 'Species', '9606', (54, 61))	('HCC', 'Gene', '619501', (170, 173))	('patient', 'Species', '9606', (174, 181))	('HCC', 'Gene', '619501', (74, 77))	('reduced', 'NegReg', (148, 155))	('HCC', 'Phenotype', 'HP:0001402', (170, 173))	('HCC', 'Phenotype', 'HP:0001402', (74, 77))	('OS', 'Chemical', '-', (156, 158))	('patients', 'Species', '9606', (174, 182))	('CK19', 'Gene', (98, 102))	('DFS', 'Disease', (163, 166))	('expression', 'Var', (103, 113))	('HCC', 'Gene', (170, 173))	('HCC', 'Gene', (74, 77))	('CK19', 'Gene', '3880', (98, 102))
119891	30588199	reported that knockdown of SALL4 inhibits malignant phenotypes of ICC cells by regulating PTEN/PI3K/Akt and Wnt/beta-catenin signaling and repressing the epithelial-mesenchymal transition process.	('Akt', 'Gene', (100, 103))	('beta-catenin', 'Gene', (112, 124))	('PTEN', 'Gene', (90, 94))	('repressing', 'NegReg', (139, 149))	('PTEN', 'Gene', '5728', (90, 94))	('regulating', 'Reg', (79, 89))	('Akt', 'Gene', '207', (100, 103))	('SALL4', 'Gene', '57167', (27, 32))	('knockdown', 'Var', (14, 23))	('inhibits', 'NegReg', (33, 41))	('malignant phenotypes of', 'CPA', (42, 65))	('SALL4', 'Gene', (27, 32))	('beta-catenin', 'Gene', '1499', (112, 124))	('epithelial-mesenchymal transition process', 'CPA', (154, 195))
119902	28832761	We found that combined salinomycin with doxorubicin treatment resulted in a significant decrease in cell viability compared with doxorubicin or salinomycin treatment alone in two cholangiocarcinoma cell lines (RBE and Huh-28).	('Huh-28', 'CellLine', 'CVCL:0336', (218, 224))	('salinomycin', 'Chemical', 'MESH:C010327', (23, 34))	('decrease', 'NegReg', (88, 96))	('salinomycin', 'Chemical', 'MESH:C010327', (144, 155))	('doxorubicin', 'Chemical', 'MESH:D004317', (40, 51))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (179, 197))	('cell viability', 'CPA', (100, 114))	('doxorubicin', 'Chemical', 'MESH:D004317', (129, 140))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (179, 197))	('salinomycin', 'Var', (23, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('cholangiocarcinoma', 'Disease', (179, 197))
119943	28832761	However, combined salinomycin with doxorubicin treatment for 48 h resulted in a significant decrease in cell viability compared with doxorubicin or salinomycin treatment alone in RBE and Huh-28 cells (Figure 1).	('decrease', 'NegReg', (92, 100))	('salinomycin', 'Var', (18, 29))	('cell viability', 'CPA', (104, 118))	('doxorubicin', 'Chemical', 'MESH:D004317', (133, 144))	('salinomycin', 'Chemical', 'MESH:C010327', (18, 29))	('salinomycin', 'Chemical', 'MESH:C010327', (148, 159))	('Huh-28', 'CellLine', 'CVCL:0336', (187, 193))	('doxorubicin', 'Chemical', 'MESH:D004317', (35, 46))
119958	28832761	Overexpression of the AMP-activated protein kinase family member 5 (ARK5), a novel human AMP-activated protein kinase family member, was previously shown to decrease the sensitivity of HCC cells to doxorubicin.	('ARK5', 'Gene', (68, 72))	('doxorubicin', 'Chemical', 'MESH:D004317', (198, 209))	('AMP-activated protein kinase family member 5', 'Gene', (22, 66))	('decrease', 'NegReg', (157, 165))	('human', 'Species', '9606', (83, 88))	('sensitivity', 'MPA', (170, 181))	('Overexpression', 'Var', (0, 14))	('ARK5', 'Gene', '9891', (68, 72))	('HCC', 'Phenotype', 'HP:0001402', (185, 188))	('AMP-activated protein kinase family member 5', 'Gene', '9891', (22, 66))
119978	28832761	Moreover, we found that twist knockdown could block the synergistic effect of salinomycin and doxorubicin.	('doxorubicin', 'MPA', (94, 105))	('block', 'NegReg', (46, 51))	('doxorubicin', 'Chemical', 'MESH:D004317', (94, 105))	('salinomycin', 'Chemical', 'MESH:C010327', (78, 89))	('knockdown', 'Var', (30, 39))	('synergistic effect', 'MPA', (56, 74))
119984	28832761	Furthermore, ARK5 appears to regulate the expression of the EMT related markers E-cadherin and vimentin in cholangiocarcinoma cells; in particular, downregulation of ARK5 increased the expression of E-cadherin and decreases the expression of vimentin.	('ARK5', 'Gene', (13, 17))	('expression', 'MPA', (185, 195))	('cholangiocarcinoma', 'Disease', (107, 125))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (107, 125))	('increased', 'PosReg', (171, 180))	('vimentin', 'Gene', '7431', (95, 103))	('vimentin', 'Gene', (95, 103))	('E-cadherin', 'Gene', (199, 209))	('E-cadherin', 'Gene', '999', (199, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('expression', 'MPA', (228, 238))	('E-cadherin', 'Gene', (80, 90))	('E-cadherin', 'Gene', '999', (80, 90))	('vimentin', 'Gene', '7431', (242, 250))	('vimentin', 'Gene', (242, 250))	('ARK5', 'Gene', '9891', (166, 170))	('downregulation', 'Var', (148, 162))	('decreases', 'NegReg', (214, 223))	('ARK5', 'Gene', (166, 170))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (107, 125))	('ARK5', 'Gene', '9891', (13, 17))
120029	26033685	Because hilar cholangiocarcinoma can be notoriously difficult to pathologically diagnose prior to resection, clinical diagnosis requires the presence of a malignant-appearing biliary stricture and at least one of the following: (1) a mass lesion on cross-sectional imaging at the location of the malignant-appearing stricture; (2) endoluminal biopsy or cytology positive for cholangiocarcinoma; (3) polysomy by fluorescent in situ hybridization; or (4) CA 19-9 >100.	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (8, 32))	('hilar cholangiocarcinoma', 'Disease', (8, 32))	('CA 19-9 >100', 'Var', (453, 465))	('cholangiocarcinoma', 'Disease', (14, 32))	('cholangiocarcinoma', 'Disease', (375, 393))	('polysomy', 'Var', (399, 407))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (14, 32))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (375, 393))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (14, 32))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (375, 393))
120072	23599762	CD79alpha and CD79beta belong to the Ig gene superfamily and contain one extracellular Ig-like domain, a transmembrane alpha-helical region and a cytoplasmic domain.	('CD79beta', 'Gene', (14, 22))	('CD79beta', 'Gene', '974', (14, 22))	('CD79alpha', 'Var', (0, 9))
120108	23599762	CD79alpha, also known as Igalpha, is encoded by mouse B cell-specific gene 1 (mb-1).	('Igalpha', 'Gene', (25, 32))	('Igalpha', 'Gene', '12518', (25, 32))	('mouse', 'Species', '10090', (48, 53))	('CD79alpha', 'Var', (0, 9))	('B cell-specific gene 1 (mb-1', 'Gene', '12518', (54, 82))
120112	23599762	CD79alpha expression precedes immunoglobulin heavy-chain gene rearrangement and CD20 expression, and disappears later than CD20 in the plasma cell.	('expression', 'MPA', (85, 95))	('CD20', 'Gene', (123, 127))	('CD79alpha', 'Var', (0, 9))	('CD20', 'Gene', '54474', (80, 84))	('CD20', 'Gene', (80, 84))	('CD20', 'Gene', '54474', (123, 127))
120127	23599762	Tumor cells exhibited positivity for Hepatocyte, MOC31, CEA and CK19, and negativity for CD117 and AFP.	('Hepatocyte', 'MPA', (37, 47))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CEA', 'Gene', (56, 59))	('AFP', 'Gene', (99, 102))	('CEA', 'Gene', '5670', (56, 59))	('MOC31', 'Var', (49, 54))	('AFP', 'Gene', '174', (99, 102))	('CK19', 'Gene', (64, 68))	('CK19', 'Gene', '3880', (64, 68))	('CD117', 'Gene', '3815', (89, 94))	('CD117', 'Gene', (89, 94))
120166	33377990	A role of the bicarbonate umbrella in PSC pathogenesis is supported by the association of PSC with gene sequence variations of TGR5, a cholangiocellular bile acid receptor promoting chloride and bicarbonate secretion, and by downregulation of the TGR5 protein in cholangiocytes of PSC patients.	('TGR5', 'Gene', '151306', (247, 251))	('PSC', 'Gene', (90, 93))	('variations', 'Var', (113, 123))	('promoting', 'PosReg', (172, 181))	('PSC', 'Gene', (281, 284))	('TGR5', 'Gene', '151306', (127, 131))	('bile acid', 'Chemical', 'MESH:D001647', (153, 162))	('TGR5', 'Gene', (247, 251))	('protein', 'Protein', (252, 259))	('chloride', 'Chemical', 'MESH:D002712', (182, 190))	('association', 'Interaction', (75, 86))	('PSC', 'Gene', '100653366', (38, 41))	('TGR5', 'Gene', (127, 131))	('bicarbonate', 'Chemical', 'MESH:D001639', (14, 25))	('downregulation', 'NegReg', (225, 239))	('bicarbonate', 'Chemical', 'MESH:D001639', (195, 206))	('PSC', 'Gene', '100653366', (90, 93))	('PSC', 'Gene', (38, 41))	('patients', 'Species', '9606', (285, 293))	('PSC', 'Gene', '100653366', (281, 284))
120167	33377990	Also associations with PSC of other gene variants encoding for stabilizers of the apical cholangiocyte membrane of cholangiocytes are suggestive of defects of the biliary bicarbonate umbrella in PSC.	('variants', 'Var', (41, 49))	('PSC', 'Gene', (23, 26))	('defects', 'NegReg', (148, 155))	('PSC', 'Gene', '100653366', (195, 198))	('bicarbonate', 'Chemical', 'MESH:D001639', (171, 182))	('PSC', 'Gene', (195, 198))	('biliary bicarbonate umbrella', 'MPA', (163, 191))	('associations', 'Reg', (5, 17))	('PSC', 'Gene', '100653366', (23, 26))
120250	33377990	They are equivalent in terms of survival, incidence of biliary strictures, recurrent PSC and cholangiocarcinoma, but duct-to-duct anastomosis has been shown to have a lower incidence of ascending cholangitis and should therefore be considered as the method of choice.	('lower', 'NegReg', (167, 172))	('PSC', 'Gene', (85, 88))	('cholangitis', 'Phenotype', 'HP:0030151', (196, 207))	('cholangitis', 'Disease', (196, 207))	('cholangiocarcinoma', 'Disease', (93, 111))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('cholangitis', 'Disease', 'MESH:D002761', (196, 207))	('PSC', 'Gene', '100653366', (85, 88))	('duct-to-duct anastomosis', 'Var', (117, 141))
120269	33377990	Nevertheless, opinions differ on the role of UDCA in the treatment of PSC, mainly due to the fact that despite a marked improvement of serum markers of cholestasis, no significant improvement of transplant-free survival was found in UDCA-treated patients in this study endpoint underpowered trials with low (13-15 mg/kg; n = 102), moderate (17-23 mg/kg; n = 198) or very high daily doses (28-30 mg/kg, n = 150), when compared to placebo.	('men', 'Species', '9606', (62, 65))	('UDCA', 'Chemical', 'MESH:D014580', (45, 49))	('cholestasis', 'Disease', (152, 163))	('patients', 'Species', '9606', (246, 254))	('UDCA', 'Chemical', 'MESH:D014580', (233, 237))	('men', 'Species', '9606', (187, 190))	('PSC', 'Gene', '100653366', (70, 73))	('cholestasis', 'Phenotype', 'HP:0001396', (152, 163))	('cholestasis', 'Disease', 'MESH:D002779', (152, 163))	('PSC', 'Gene', (70, 73))	('men', 'Species', '9606', (127, 130))	('13-15 mg/kg', 'Var', (308, 319))
120272	33377990	Nevertheless, discontinuation of UDCA has been shown to cause worsening of symptoms, of serum liver tests and of the Mayo Risk Score and should therefore be well justified in patients stable on therapy.	('serum liver tests', 'MPA', (88, 105))	('UDCA', 'Gene', (33, 37))	('symptoms', 'MPA', (75, 83))	('Mayo', 'Species', '162683', (117, 121))	('worsening', 'NegReg', (62, 71))	('patients', 'Species', '9606', (175, 183))	('Mayo', 'Gene', (117, 121))	('discontinuation', 'Var', (14, 29))	('UDCA', 'Chemical', 'MESH:D014580', (33, 37))
120286	33377990	Its engineered non-tumorigenic FGF19 analogue, NGM282 (aldafermin) resulted in a phase II trial to decrease in serum transaminases and robust reduction of markers of fibrogenesis (ELF score, pro-C3), but had no effect on serum markers of cholestasis such as ALP levels.	('reduction', 'NegReg', (142, 151))	('NGM282', 'Chemical', '-', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('ALP', 'Gene', '250', (258, 261))	('cholestasis', 'Phenotype', 'HP:0001396', (238, 249))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('FGF19', 'Gene', (31, 36))	('decrease', 'NegReg', (99, 107))	('FGF19', 'Gene', '9965', (31, 36))	('tumor', 'Disease', (19, 24))	('cholestasis', 'Disease', 'MESH:D002779', (238, 249))	('NGM282', 'Var', (47, 53))	('serum transaminases', 'MPA', (111, 130))	('aldafermin', 'Chemical', '-', (55, 65))	('ALP', 'Gene', (258, 261))	('cholestasis', 'Disease', (238, 249))
120307	31731200	Interrogating these models revealed multiple mechanisms of MAPK signaling activation in BTC, including co-occurrence of low-activity BRAF and MEK mutations with receptor tyrosine kinase overexpression.	('overexpression', 'PosReg', (186, 200))	('receptor tyrosine kinase', 'Gene', '5979', (161, 185))	('BTC', 'Gene', '685', (88, 91))	('mutations', 'Var', (146, 155))	('BRAF', 'Gene', '673', (133, 137))	('BTC', 'Gene', (88, 91))	('MEK', 'Gene', (142, 145))	('BRAF', 'Gene', (133, 137))	('activation', 'PosReg', (74, 84))	('MEK', 'Gene', '5609', (142, 145))	('receptor tyrosine kinase', 'Gene', (161, 185))
120308	31731200	Finally, BTC cell lines with altered ERBB2 or FGFRs were exquisitely sensitive to specific targeted agents, whereas surprisingly, IDH1-mutant lines did not respond to IDH1 inhibitors in vitro.	('ERBB2', 'Gene', (37, 42))	('ERBB2', 'Gene', '2064', (37, 42))	('BTC', 'Gene', (9, 12))	('sensitive', 'Reg', (69, 78))	('FGFRs', 'Gene', (46, 51))	('IDH1', 'Gene', (130, 134))	('IDH1', 'Gene', (167, 171))	('altered', 'Var', (29, 36))	('IDH1', 'Gene', '3417', (130, 134))	('IDH1', 'Gene', '3417', (167, 171))	('BTC', 'Gene', '685', (9, 12))
120316	31731200	Initial sequencing studies aiming to characterize the genomic landscape of BTCs identified a series of recurrently mutated genes, including loss-of-function mutations in the tumor suppressors TP53 and SMAD4 and the epigenetic modifiers ARID1A, ARID2, and BAP1, whereas activating mutations in KRAS, PIK3CA, and NRAS were the most common oncogenic events.	('loss-of-function', 'NegReg', (140, 156))	('BAP1', 'Gene', (255, 259))	('PIK3CA', 'Gene', (299, 305))	('SMAD4', 'Gene', '4089', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('BTC', 'Gene', '685', (75, 78))	('mutations', 'Var', (157, 166))	('NRAS', 'Gene', (311, 315))	('ARID2', 'Gene', '196528', (244, 249))	('TP53', 'Gene', (192, 196))	('ARID1A', 'Gene', '8289', (236, 242))	('BTC', 'Gene', (75, 78))	('KRAS', 'Gene', '3845', (293, 297))	('PIK3CA', 'Gene', '5290', (299, 305))	('ARID1A', 'Gene', (236, 242))	('ARID2', 'Gene', (244, 249))	('tumor', 'Disease', (174, 179))	('KRAS', 'Gene', (293, 297))	('SMAD4', 'Gene', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('NRAS', 'Gene', '4893', (311, 315))	('TP53', 'Gene', '7157', (192, 196))
120317	31731200	More recent studies identified fusions involving PRKACA and PRKACB as other potential driver events, as well as mutations in ROBO2, RNF43, RASA1, STK11, and MAP2K4.	('ROBO2', 'Gene', (125, 130))	('MAP2K4', 'Gene', (157, 163))	('RNF43', 'Gene', (132, 137))	('PRKACB', 'Gene', (60, 66))	('RNF43', 'Gene', '54894', (132, 137))	('RASA1', 'Gene', '5921', (139, 144))	('PRKACA', 'Gene', (49, 55))	('RASA1', 'Gene', (139, 144))	('mutations', 'Var', (112, 121))	('STK11', 'Gene', (146, 151))	('PRKACA', 'Gene', '5566', (49, 55))	('PRKACB', 'Gene', '5567', (60, 66))	('MAP2K4', 'Gene', '6416', (157, 163))	('ROBO2', 'Gene', '6092', (125, 130))	('fusions', 'Var', (31, 38))	('STK11', 'Gene', '6794', (146, 151))
120318	31731200	These studies also identified potential therapeutically exploitable targets including mutations and amplifications of members of the ERBB family of receptor tyrosine kinases, IDH1 mutations, and FGFR2 fusions; however, in many cases it remains to be determined whether these genomic alterations can be exploited for therapeutic benefit.	('FGFR2', 'Gene', '2263', (195, 200))	('mutations', 'Var', (86, 95))	('mutations', 'Var', (180, 189))	('fusions', 'Var', (201, 208))	('ERBB', 'Gene', (133, 137))	('receptor tyrosine kinase', 'Gene', (148, 172))	('IDH1', 'Gene', (175, 179))	('receptor tyrosine kinase', 'Gene', '5979', (148, 172))	('ERBB', 'Gene', '1956', (133, 137))	('FGFR2', 'Gene', (195, 200))	('IDH1', 'Gene', '3417', (175, 179))
120330	31731200	The dominant somatic substitution pattern observed in primary BTCs are C > T/G > A transitions that are enriched at CpG dinucleotides, followed by T > C/A > G transitions and C > A/T > G transversions.	('C > A/T > G', 'Var', (175, 186))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (116, 133))	('C > T/G > A', 'Var', (71, 82))	('T > C/A > G', 'Var', (147, 158))	('BTC', 'Gene', '685', (62, 65))	('BTC', 'Gene', (62, 65))
120332	31731200	A similar distribution of somatic substitution patterns was observed in BTC cell lines, with C > T (0.49 +- 0.03) transitions as the dominant pattern observed, followed by T > C (0.15 +- 0.02) transitions and C > A transversions (0.14 +- 0.04) (Figure 1D).	('BTC', 'Gene', '685', (72, 75))	('C > A transversions', 'Var', (209, 228))	('transitions', 'Var', (114, 125))	('BTC', 'Gene', (72, 75))
120333	31731200	In primary BTC, two predominant mutational signatures have been identified: (A/C/G)CG>(A/C/G)TG previously defined as Signature 1 by Alexandrov et al., which is the result of an endogenous mutational process initiated by spontaneous deamination of 5-methylcytosine, and TC(A/C/T)>TG(A/C/T) and TCN > TTN, which is similar to the previously defined APOBEC-associated signature (Signature 2).	('TC', 'Chemical', 'MESH:D013667', (270, 272))	('A/C/G', 'Var', (77, 82))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (248, 264))	('TC', 'Chemical', 'MESH:D013667', (294, 296))	('TTN', 'Gene', '7273', (300, 303))	('BTC', 'Gene', '685', (11, 14))	('BTC', 'Gene', (11, 14))	('TG', 'Chemical', 'MESH:D013866', (93, 95))	('TTN', 'Gene', (300, 303))	('TG', 'Chemical', 'MESH:D013866', (280, 282))	('TCN', 'Chemical', '-', (294, 297))	('TC(A/C/T)>TG(A/C/T', 'Var', (270, 288))	('TC', 'Chemical', 'MESH:D013667', (12, 14))
120339	31731200	As expected, cell lines harboring truncating TP53 mutations had significantly lower TP53 mRNA expression compared with TP53 wild-type cell lines or cell lines harboring TP53 point mutations (Figure 2C).	('TP53', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (45, 49))	('truncating', 'Var', (34, 44))	('mutations', 'Var', (50, 59))	('TP53', 'Gene', '7157', (169, 173))	('TP53', 'Gene', (119, 123))	('TP53', 'Gene', '7157', (84, 88))	('TP53', 'Gene', (169, 173))	('TP53', 'Gene', (84, 88))	('TP53', 'Gene', '7157', (119, 123))	('lower', 'NegReg', (78, 83))
120340	31731200	Furthermore, immunohistochemical staining of the cell lines revealed high TP53 protein expression in mutant cell lines compared with wild-type lines or lines harboring truncating mutations (Figure 2D).	('protein', 'Protein', (79, 86))	('high', 'PosReg', (69, 73))	('mutant', 'Var', (101, 107))	('expression', 'MPA', (87, 97))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))
120341	31731200	We also identified three cell lines harboring mutations in the WNT pathway (KKU-M055, APC frameshift; TGBC18TKB, CTNNB1 T41A; and SNU-869, CTNNB1 S45P).	('TG', 'Chemical', 'MESH:D013866', (102, 104))	('CTNNB1', 'Gene', (113, 119))	('frameshift', 'Var', (90, 100))	('mutations', 'Var', (46, 55))	('CTNNB1', 'Gene', '1499', (139, 145))	('T41A', 'Var', (120, 124))	('WNT pathway', 'Pathway', (63, 74))	('TGBC18TKB', 'Gene', (102, 111))	('APC', 'Disease', 'MESH:D011125', (86, 89))	('APC', 'Disease', (86, 89))	('S45P', 'Mutation', 'rs121913407', (146, 150))	('CTNNB1', 'Gene', '1499', (113, 119))	('T41A', 'Mutation', 'rs121913412', (120, 124))	('CTNNB1', 'Gene', (139, 145))
120342	31731200	KKU-M055 cells also harbored a deletion of APC (Chr5 q22.2) consistent with loss of heterozygosity.	('APC', 'Disease', 'MESH:D011125', (43, 46))	('APC', 'Disease', (43, 46))	('deletion', 'Var', (31, 39))
120344	31731200	Notably, inactivating mutations in the E3 ubiquitin ligase RNF43 have also been reported to enhance canonical Wnt signaling due to failure to degrade FZD receptors on the cell surface, and we identified one cell line, Sk-ChA-1, harboring a biallelic inactivating RNF43 mutation, which also had low levels of RNF43 mRNA expression (Figure S1B).	('RNF43', 'Gene', (263, 268))	('RNF43', 'Gene', '54894', (263, 268))	('biallelic inactivating', 'Var', (240, 262))	('RNF43', 'Gene', '54894', (308, 313))	('Sk-ChA-1', 'CellLine', 'CVCL:6952', (218, 226))	('inactivating mutations', 'Var', (9, 31))	('RNF43', 'Gene', (308, 313))	('canonical Wnt signaling', 'MPA', (100, 123))	('RNF43', 'Gene', '54894', (59, 64))	('RNF43', 'Gene', (59, 64))	('enhance', 'PosReg', (92, 99))	('mutation', 'Var', (269, 277))
120345	31731200	Surprisingly, however, TOPFLASH activity and Wnt target gene expression was not elevated in this line (Figures S2A and S2B), and Sk-ChA-1 cells were not preferentially sensitive to exogenous Wnt ligand (Figure S2C), collectively indicating that the inactivating RNF43 mutation in this line does not activate the Wnt pathway.	('Wnt pathway', 'Pathway', (312, 323))	('Sk-ChA-1', 'CellLine', 'CVCL:6952', (129, 137))	('TOPFLASH activity', 'MPA', (23, 40))	('mutation', 'Var', (268, 276))	('RNF43', 'Gene', '54894', (262, 267))	('RNF43', 'Gene', (262, 267))
120349	31731200	Confirming the deletion of CDKN2A and the adjacently located CDKN2B, mRNA expression of these genes was significantly lower in cell lines harboring homozygous deletions (Figure 3B).	('deletion', 'Var', (15, 23))	('CDKN2B', 'Gene', (61, 67))	('CDKN2B', 'Gene', '1030', (61, 67))	('mRNA expression', 'MPA', (69, 84))	('CDKN2A', 'Gene', (27, 33))	('lower', 'NegReg', (118, 123))	('CDKN2A', 'Gene', '1029', (27, 33))
120358	31731200	Notably, examination of the histopathology of the primary tumors in the mesenchymal cluster confirmed that case TCGA-ZU-A8S4 was a sarcomatoid carcinoma showing spindle cell (mesenchymal) morphology with no evidence of gland formation, whereas case TCGA-W5-AA2H showed some gland formation but also a high degree of tumor budding, forming small clusters of spindle shaped tumor cells (Figure S6).	('tumor', 'Phenotype', 'HP:0002664', (372, 377))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (131, 152))	('TCGA-ZU-A8S4', 'Var', (112, 124))	('sarcomatoid carcinoma', 'Disease', (131, 152))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', (372, 377))	('tumor', 'Disease', 'MESH:D009369', (372, 377))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('TC', 'Chemical', 'MESH:D013667', (249, 251))	('tumors', 'Disease', (58, 64))	('TC', 'Chemical', 'MESH:D013667', (112, 114))	('tumor', 'Disease', (316, 321))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (131, 152))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
120360	31731200	We identified one cell line (SNU-1079, intrahepatic) harboring an IDH1 R132C hotspot mutation, which was confirmed using Sanger sequencing (Figure S7A inset).	('hotspot', 'PosReg', (77, 84))	('R132C', 'Var', (71, 76))	('R132C', 'Mutation', 'rs121913499', (71, 76))	('IDH1', 'Gene', '3417', (66, 70))	('SNU-1079', 'CellLine', 'CVCL:5008', (29, 37))	('IDH1', 'Gene', (66, 70))
120361	31731200	Consistent with the neomorphic advantage conferred by this mutation, levels of the oncometabolite R-2-hydroxy-glutarate (2-HG) were markedly elevated in culture medium and cell pellets from this line (Figure S7A).	('2-HG', 'Chemical', '-', (121, 125))	('elevated', 'PosReg', (141, 149))	('R-2-hydroxy-glutarate', 'Chemical', '-', (98, 119))	('mutation', 'Var', (59, 67))	('levels of the', 'MPA', (69, 82))
120364	31731200	As observed in SNU-1079 cells, AG-120 failed to inhibit growth of the IDH1R132L organoid, with instead a modest but significant increase in cell proliferation observed (Figure S7D).	('cell proliferation', 'CPA', (140, 158))	('increase', 'PosReg', (128, 136))	('AG-120', 'Chemical', 'MESH:C000627630', (31, 37))	('AG-120', 'Var', (31, 37))	('IDH1', 'Gene', '3417', (70, 74))	('SNU-1079', 'CellLine', 'CVCL:5008', (15, 23))	('inhibit', 'NegReg', (48, 55))	('IDH1', 'Gene', (70, 74))
120365	31731200	Recent studies have suggested that mutant IDH may promote cholangiocarcinoma development by suppressing HNF4A expression and blocking hepatocyte differentiation, and initial data from clinical trials of AG-120 in IDH1 mutant cholangiocarcinoma have reported an upregulation of liver-specific genes in serial biopsy samples.	('IDH', 'Gene', (42, 45))	('promote', 'PosReg', (50, 57))	('HNF4A', 'Gene', '3172', (104, 109))	('AG-120', 'Chemical', 'MESH:C000627630', (203, 209))	('mutant', 'Var', (35, 41))	('HNF4A', 'Gene', (104, 109))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('IDH', 'Gene', (213, 216))	('upregulation', 'PosReg', (261, 273))	('suppressing', 'NegReg', (92, 103))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (225, 243))	('cholangiocarcinoma', 'Disease', (58, 76))	('IDH', 'Gene', '3417', (42, 45))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 76))	('cholangiocarcinoma', 'Disease', (225, 243))	('IDH1', 'Gene', (213, 217))	('IDH', 'Gene', '3417', (213, 216))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (225, 243))	('expression', 'MPA', (110, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('IDH1', 'Gene', '3417', (213, 217))	('hepatocyte', 'MPA', (134, 144))	('blocking', 'NegReg', (125, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('mutant', 'Var', (218, 224))
120367	31731200	Finally, as increased benefit of IDH1 mutant BTCs to chemotherapy was recently reported, we assessed the sensitivity of this line to gemcitabine.	('mutant', 'Var', (38, 44))	('gemcitabine', 'Chemical', 'MESH:C056507', (133, 144))	('IDH1', 'Gene', (33, 37))	('IDH1', 'Gene', '3417', (33, 37))	('BTC', 'Gene', '685', (45, 48))	('BTC', 'Gene', (45, 48))
120370	31731200	Mutations in the ERBB family of receptor tyrosine kinases, particularly ERBB2 and ERBB3, occur in ~10% of BTCs and we identified one cell line, TGBC18TKB, which carried two hotspot mutations in ERBB2 (S310F and R678Q) (Figure 5A), which have been previously reported in primary BTC.	('ERBB3', 'Gene', (82, 87))	('S310F', 'Mutation', 'rs1057519816', (201, 206))	('ERBB2', 'Gene', (72, 77))	('BTC', 'Gene', (278, 281))	('ERBB', 'Gene', (194, 198))	('ERBB', 'Gene', (82, 86))	('ERBB', 'Gene', (17, 21))	('ERBB', 'Gene', '1956', (194, 198))	('receptor tyrosine kinase', 'Gene', '5979', (32, 56))	('ERBB2', 'Gene', '2064', (72, 77))	('ERBB3', 'Gene', '2065', (82, 87))	('ERBB', 'Gene', '1956', (17, 21))	('ERBB', 'Gene', '1956', (82, 86))	('TG', 'Chemical', 'MESH:D013866', (144, 146))	('R678Q', 'Mutation', 'rs1057519862', (211, 216))	('R678Q', 'Var', (211, 216))	('BTC', 'Gene', '685', (106, 109))	('receptor tyrosine kinase', 'Gene', (32, 56))	('ERBB2', 'Gene', (194, 199))	('S310F', 'Var', (201, 206))	('ERBB', 'Gene', (72, 76))	('ERBB', 'Gene', '1956', (72, 76))	('BTC', 'Gene', '685', (278, 281))	('BTC', 'Gene', (106, 109))	('ERBB2', 'Gene', '2064', (194, 199))
120371	31731200	Notably, mRNA expression of ERBB2 was also highly elevated in TGBC18TKB cells (Figure 5B).	('TG', 'Chemical', 'MESH:D013866', (62, 64))	('mRNA expression', 'MPA', (9, 24))	('elevated', 'PosReg', (50, 58))	('ERBB2', 'Gene', '2064', (28, 33))	('ERBB2', 'Gene', (28, 33))	('TGBC18TKB', 'Var', (62, 71))
120373	31731200	Copy number analysis of this cell line revealed an amplification in ERBB2 (Figure 3A), which was confirmed by qRT-PCR and in situ hybridization (Figures 5C and 5D).	('amplification', 'Var', (51, 64))	('ERBB2', 'Gene', '2064', (68, 73))	('ERBB2', 'Gene', (68, 73))
120376	31731200	Specifically, KRAS mutations were identified in 8/22 cell lines, whereas amplification of KRAS was observed in three cell lines of which one line (NOZ) also harbored a KRAS mutation (Table S5).	('KRAS', 'Gene', '3845', (14, 18))	('KRAS', 'Gene', '3845', (168, 172))	('KRAS', 'Gene', (90, 94))	('KRAS', 'Gene', '3845', (90, 94))	('KRAS', 'Gene', (14, 18))	('KRAS', 'Gene', (168, 172))	('mutation', 'Var', (173, 181))
120377	31731200	In addition, we identified two cell lines harboring low-activity BRAF mutations (TGBC18TKB, BRAFI581L, N582T, and Sk-Ch-A1, BRAFD594T) (Table S5).	('N582T', 'Var', (103, 108))	('BRAF', 'Gene', '673', (92, 96))	('N582T', 'Mutation', 'rs757254917', (103, 108))	('TGBC18TKB', 'Gene', (81, 90))	('BRAF', 'Gene', (92, 96))	('BRAF', 'Gene', '673', (124, 128))	('BRAF', 'Gene', '673', (65, 69))	('BRAF', 'Gene', (65, 69))	('BRAF', 'Gene', (124, 128))	('TG', 'Chemical', 'MESH:D013866', (81, 83))
120379	31731200	The identification of ERBB2 hotspot mutations in TGBC18TKB cells (Figure 5A) is consistent with this mechanism.	('ERBB2', 'Gene', '2064', (22, 27))	('ERBB2', 'Gene', (22, 27))	('TG', 'Chemical', 'MESH:D013866', (49, 51))	('mutations', 'Var', (36, 45))	('hotspot', 'PosReg', (28, 35))	('TGBC18TKB', 'Gene', (49, 58))
120380	31731200	Similarly, we identified a truncating mutation in RASA1 in Sk-Ch-A1 cells (Table S2 and Figure S1), which encodes the Ras GTPase-activating protein p120-RasGAP, which suppresses RAS signaling by converting RAS to the inactive GDP-bound form.	('p120-RasGAP', 'Gene', (148, 159))	('GDP', 'Chemical', 'MESH:D006153', (226, 229))	('p120-RasGAP', 'Gene', '5921', (148, 159))	('suppresses', 'NegReg', (167, 177))	('RASA1', 'Gene', '5921', (50, 55))	('RASA1', 'Gene', (50, 55))	('truncating mutation', 'Var', (27, 46))	('RAS signaling', 'MPA', (178, 191))
120381	31731200	We also identified one cell line (KKU-M055) with a K57N mutation in MAP2K1 (MEK1), which has been previously observed in lung adenocarcinoma and melanoma (Figure 6A).	('lung adenocarcinoma and melanoma', 'Disease', 'MESH:D000077192', (121, 153))	('K57N', 'Var', (51, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('observed', 'Reg', (109, 117))	('MAP2K1', 'Gene', '5604', (68, 74))	('K57N', 'Mutation', 'rs869025608', (51, 55))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (121, 140))	('MAP2K1', 'Gene', (68, 74))	('MEK1', 'Gene', '5604', (76, 80))	('MEK1', 'Gene', (76, 80))
120382	31731200	As with low-activity BRAF mutations, MAP2K1K57N was recently classified as a class II MEK mutant, which is partially dependent on upstream RAF to drive ERK signaling and likely acts as an amplifier of RAS signaling.	('ERK', 'Gene', '5594', (152, 155))	('MEK', 'Gene', (86, 89))	('ERK', 'Gene', (152, 155))	('RAF', 'Gene', '22882', (22, 25))	('BRAF', 'Gene', '673', (21, 25))	('MEK', 'Gene', '5609', (86, 89))	('RAF', 'Gene', (22, 25))	('RAF', 'Gene', '22882', (139, 142))	('BRAF', 'Gene', (21, 25))	('MAP2K1K57N', 'Var', (37, 47))	('RAF', 'Gene', (139, 142))
120383	31731200	Notably, compared with MEKWT G415 cells, MEKK57N mutant KKU-M055 cells were highly resistant to growth inhibition or signaling inhibition induced by the allosteric MEK inhibitor trametinib or the ERK inhibitor SCH772984 (Figures 6B-6E).	('MEK', 'Gene', (164, 167))	('resistant', 'NegReg', (83, 92))	('MEK', 'Gene', '5609', (164, 167))	('mutant', 'Var', (49, 55))	('MEK', 'Gene', (41, 44))	('MEK', 'Gene', '5609', (41, 44))	('trametinib', 'Chemical', 'MESH:C560077', (178, 188))	('SCH772984', 'Chemical', 'MESH:C587178', (210, 219))	('ERK', 'Gene', '5594', (196, 199))	('growth', 'MPA', (96, 102))	('signaling inhibition', 'MPA', (117, 137))	('ERK', 'Gene', (196, 199))	('MEK', 'Gene', (23, 26))	('MEK', 'Gene', '5609', (23, 26))
120384	31731200	Time course experiments also demonstrated that SCH772984 increased levels of active CRAF (pCRAF S338) in both MAP2KK57N mutant and WT cell lines (Figure 6F), which is an expected effect of this drug due to relief of ERK-mediated inhibitory phosphorylation of CRAF.	('CRAF', 'Gene', '5894', (91, 95))	('K57N', 'Mutation', 'rs869025608', (115, 119))	('levels', 'MPA', (67, 73))	('CRAF', 'Gene', (91, 95))	('SCH772984', 'Chemical', 'MESH:C587178', (47, 56))	('CRAF', 'Gene', '5894', (84, 88))	('CRAF', 'Gene', (259, 263))	('CRAF', 'Gene', (84, 88))	('active', 'MPA', (77, 83))	('increased', 'PosReg', (57, 66))	('ERK', 'Gene', '5594', (216, 219))	('CRAF', 'Gene', '5894', (259, 263))	('MAP2KK57N mutant', 'Var', (110, 126))	('ERK', 'Gene', (216, 219))	('SCH772984', 'Var', (47, 56))
120385	31731200	However, although pERK levels remained suppressed in MEKWT G415 cells after 6 h, they were strongly reactivated in MEKK57N mutant KKU-M055 cells, consistent with the MAP2KK57N acting to amplify BRAF/MAPK/ERK signaling (Figure 6F).	('BRAF', 'Gene', '673', (194, 198))	('ERK', 'Gene', '5594', (204, 207))	('BRAF', 'Gene', (194, 198))	('ERK', 'Gene', '5594', (19, 22))	('K57N', 'Mutation', 'rs869025608', (118, 122))	('pERK', 'Gene', (18, 22))	('ERK', 'Gene', (204, 207))	('K57N', 'Mutation', 'rs869025608', (171, 175))	('pERK', 'Gene', '9451', (18, 22))	('ERK', 'Gene', (19, 22))	('MEK', 'Gene', '5609', (53, 56))	('MEK', 'Gene', (115, 118))	('MEK', 'Gene', '5609', (115, 118))	('MEK', 'Gene', (53, 56))	('suppressed', 'NegReg', (39, 49))	('mutant', 'Var', (123, 129))	('reactivated', 'PosReg', (100, 111))
120388	31731200	Furthermore, KKU-M055 cells were highly sensitive to the FGFR inhibitors BGJ398 and erdafitinib both in vitro and in vivo (Figures 7B-7E), suggesting proliferation of KKU-M055 cells is driven by FGFR1, with the MEKK57N mutation likely acting to amplify FGFR-driven MAPK signaling.	('FGFR1', 'Gene', (195, 200))	('MEKK57N', 'Var', (211, 218))	('BGJ398', 'Chemical', 'MESH:C568950', (73, 79))	('FGFR1', 'Gene', '2260', (195, 200))	('amplify', 'PosReg', (245, 252))	('erdafitinib', 'Chemical', 'MESH:C000604580', (84, 95))	('proliferation', 'CPA', (150, 163))
120406	31731200	In this regard, we tested a series of therapeutic targets established in other cancers for which we identified the corresponding endogenous genetic change in a BTC cell line.	('cancers', 'Disease', (79, 86))	('BTC', 'Gene', '685', (160, 163))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('BTC', 'Gene', (160, 163))	('genetic change', 'Var', (140, 154))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
120407	31731200	We identified the R132C hotspot mutation in IDH1 in the SNU-1079 line, which had corresponding high levels of the onco-metabolite 2-HG.	('high levels of the onco-metabolite 2-HG', 'MPA', (95, 134))	('SNU-1079', 'CellLine', 'CVCL:5008', (56, 64))	('IDH1', 'Gene', (44, 48))	('R132C', 'Var', (18, 23))	('R132C', 'Mutation', 'rs121913499', (18, 23))	('2-HG', 'Chemical', '-', (130, 134))	('IDH1', 'Gene', '3417', (44, 48))
120408	31731200	Notably, this cell line had the lowest mutational load among the cell lines and interestingly did not harbor mutations in any other established tumor suppressor genes or oncogenes, consistent with a potential epigenetic mechanism of tumor promotion in IDH mutant cancers.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('IDH', 'Gene', '3417', (252, 255))	('lowest', 'NegReg', (32, 38))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', (233, 238))	('cancers', 'Disease', 'MESH:D009369', (263, 270))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancers', 'Phenotype', 'HP:0002664', (263, 270))	('mutational', 'Var', (39, 49))	('cancers', 'Disease', (263, 270))	('promotion', 'PosReg', (239, 248))	('IDH', 'Gene', (252, 255))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('mutant', 'Var', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
120409	31731200	The inhibitor of mutant IDH1, AGI-5198, inhibits colony formation of glioma cells transformed with mutant IDH1; however, despite lowering of 2-HG levels, AGI-5198 or its clinically used derivative AG-120, had no effect on proliferation of SNU-1079 cells.	('glioma', 'Disease', (69, 75))	('2-HG levels', 'MPA', (141, 152))	('2-HG', 'Chemical', '-', (141, 145))	('IDH1', 'Gene', '3417', (24, 28))	('lowering', 'NegReg', (129, 137))	('IDH1', 'Gene', '3417', (106, 110))	('colony formation', 'CPA', (49, 65))	('AG-120', 'Chemical', 'MESH:C000627630', (197, 203))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('IDH1', 'Gene', (106, 110))	('AGI-5198', 'Chemical', 'MESH:C581156', (154, 162))	('SNU-1079', 'CellLine', 'CVCL:5008', (239, 247))	('IDH1', 'Gene', (24, 28))	('inhibits', 'NegReg', (40, 48))	('AGI-5198', 'Chemical', 'MESH:C581156', (30, 38))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('mutant', 'Var', (99, 105))	('mutant', 'Var', (17, 23))
120410	31731200	Similarly, we observed that a PDO harboring an IDH1R132L mutation was also refractory to AG-120.	('IDH1', 'Gene', '3417', (47, 51))	('mutation', 'Var', (57, 65))	('IDH1', 'Gene', (47, 51))	('AG-120', 'Chemical', 'MESH:C000627630', (89, 95))
120411	31731200	These effects are consistent with pre-clinical studies in IDH1 mutant chondrosarcoma, as well as recent clinical evidence in cholangiocarcinoma where objective responses were only observed in 6% of IDH1 mutant patients treated with AG-120.	('mutant', 'Var', (203, 209))	('IDH1', 'Gene', '3417', (58, 62))	('mutant', 'Var', (63, 69))	('chondrosarcoma', 'Disease', 'MESH:D002813', (70, 84))	('cholangiocarcinoma', 'Disease', (125, 143))	('IDH1', 'Gene', (198, 202))	('chondrosarcoma', 'Disease', (70, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('IDH1', 'Gene', '3417', (198, 202))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (70, 84))	('patients', 'Species', '9606', (210, 218))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (125, 143))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (125, 143))	('AG-120', 'Chemical', 'MESH:C000627630', (232, 238))	('IDH1', 'Gene', (58, 62))
120412	31731200	Notably, the outcomes of the ClarIDHy phase III trial were recently reported in which IDH1 mutant cholangiocarcinoma patients treated with AG-120 (ivosidenib) experienced a significant improvement in progression-free survival (2.7 months) compared with patients treated with placebo (1.4 months).	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('IDH', 'Gene', (86, 89))	('ivosidenib', 'Chemical', 'MESH:C000627630', (147, 157))	('IDH1', 'Gene', (86, 90))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (98, 116))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (98, 116))	('IDH', 'Gene', '3417', (86, 89))	('IDH1', 'Gene', '3417', (86, 90))	('patients', 'Species', '9606', (253, 261))	('progression-free survival', 'CPA', (200, 225))	('AG-120', 'Chemical', 'MESH:C000627630', (139, 145))	('IDH', 'Gene', (33, 36))	('cholangiocarcinoma', 'Disease', (98, 116))	('patients', 'Species', '9606', (117, 125))	('mutant', 'Var', (91, 97))	('IDH', 'Gene', '3417', (33, 36))	('improvement', 'PosReg', (185, 196))
120413	31731200	Consistent with our findings in pre-clinical models, objective response were rare (2.4%), raising the possibility that inhibition of mutant IDH1 may elicit anti-tumour activity through non-cell autonomous mechanisms.	('IDH1', 'Gene', '3417', (140, 144))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('inhibition', 'Var', (119, 129))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('elicit', 'Reg', (149, 155))	('IDH1', 'Gene', (140, 144))	('tumour', 'Disease', (161, 167))	('mutant', 'Var', (133, 139))
120415	31731200	On the other hand, we detected two cell lines harboring mutations and amplification of members of the ERBB receptor family, which demonstrated sensitivity to ERBB2-targeting agents.	('mutations', 'Var', (56, 65))	('ERBB', 'Gene', '1956', (158, 162))	('ERBB', 'Gene', (102, 106))	('ERBB2', 'Gene', '2064', (158, 163))	('ERBB2', 'Gene', (158, 163))	('ERBB', 'Gene', (158, 162))	('ERBB', 'Gene', '1956', (102, 106))	('amplification', 'Var', (70, 83))
120416	31731200	These findings are consistent with case reports and small clinical studies reporting clinical responses of BTCs to ERBB2 targeted agents and collectively support the fact that ERBB2 amplification/mutations represent a promising therapeutic target in BTC.	('BTC', 'Gene', (107, 110))	('BTC', 'Gene', (250, 253))	('BTC', 'Gene', '685', (107, 110))	('ERBB2', 'Gene', '2064', (176, 181))	('ERBB2', 'Gene', '2064', (115, 120))	('ERBB2', 'Gene', (176, 181))	('ERBB2', 'Gene', (115, 120))	('amplification/mutations', 'Var', (182, 205))	('BTC', 'Gene', '685', (250, 253))
120417	31731200	An important finding of the current study is the identification of multiple mechanisms of ERK-MAPK pathway deregulation in BTC, whereby in addition to identifying mutations in KRAS in 36% of the cell lines, we identified KRAS amplifications in three lines, inactivating mutations in BRAF in two lines and a MAP2K1K57T mutation in one cell line.	('MAP2K1', 'Gene', '5604', (307, 313))	('ERK', 'Gene', (90, 93))	('inactivating mutations', 'Var', (257, 279))	('mutations', 'Var', (163, 172))	('BTC', 'Gene', '685', (123, 126))	('BRAF', 'Gene', (283, 287))	('KRAS', 'Gene', (176, 180))	('MAP2K1', 'Gene', (307, 313))	('KRAS', 'Gene', (221, 225))	('BRAF', 'Gene', '673', (283, 287))	('KRAS', 'Gene', '3845', (176, 180))	('BTC', 'Gene', (123, 126))	('KRAS', 'Gene', '3845', (221, 225))	('ERK', 'Gene', '5594', (90, 93))
120418	31731200	Notably, both inactivating BRAF mutations and the MAP2K1K57T mutation have been suggested to act as amplifiers of ERK-MAPK signaling and frequently co-exist with mutations in upstream components of the ERK-MAPK pathway.	('MAP2K1', 'Gene', '5604', (50, 56))	('ERK', 'Gene', (114, 117))	('MAP2K1', 'Gene', (50, 56))	('BRAF', 'Gene', '673', (27, 31))	('mutations', 'Var', (32, 41))	('ERK', 'Gene', '5594', (202, 205))	('ERK', 'Gene', '5594', (114, 117))	('BRAF', 'Gene', (27, 31))	('amplifiers', 'MPA', (100, 110))	('ERK', 'Gene', (202, 205))
120419	31731200	Indeed, detailed investigation of the cell lines harboring these mutations identified a co-existent activating ERBB2 mutation in BRAF mutant (I581L, N582T) TGBC18TKB cells, an inactivating RASA1 mutation in BRAF-mutant Sk-ChA-1 cells, and high levels of FGFR1 expression in MAP2K1K57N mutant KKU-M055 cells.	('BRAF', 'Gene', (207, 211))	('BRAF', 'Gene', '673', (207, 211))	('I581L', 'Mutation', 'p.I581L', (142, 147))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('ERBB2', 'Gene', '2064', (111, 116))	('FGFR1', 'Gene', (254, 259))	('activating', 'PosReg', (100, 110))	('N582T', 'Mutation', 'rs757254917', (149, 154))	('RASA1', 'Gene', '5921', (189, 194))	('FGFR1', 'Gene', '2260', (254, 259))	('TG', 'Chemical', 'MESH:D013866', (156, 158))	('ERBB2', 'Gene', (111, 116))	('Sk-ChA-1', 'CellLine', 'CVCL:6952', (219, 227))	('RASA1', 'Gene', (189, 194))	('mutation', 'Var', (117, 125))	('mutant', 'Var', (134, 140))
120420	31731200	An important implication of these findings is that tumors found to harbor low-activity "amplifier mutations" in the MAPK pathway in commonly used cancer gene panel sequencing tests should be further interrogated for amplifications or overexpression of RTKs, as this may yield robust therapeutic targets.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutations', 'Var', (98, 107))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('MAPK pathway', 'Pathway', (116, 128))	('low-activity', 'NegReg', (74, 86))
120421	31731200	Proof of concept of this approach was our finding that MAP2K1K57N mutant KKU-M055 cells express high levels of FGFR1 and are exquisitely sensitive to FGFR inhibition.	('FGFR1', 'Gene', (111, 116))	('MAP2K1K57N', 'Var', (55, 65))	('FGFR1', 'Gene', '2260', (111, 116))
120424	31731200	This finding is consistent with observations in liposarcoma, where cell lines harboring FRS2 amplifications have also been reported to be sensitive to FGFR inhibitors.	('liposarcoma', 'Phenotype', 'HP:0012034', (48, 59))	('liposarcoma', 'Disease', 'MESH:D008080', (48, 59))	('FRS2', 'Gene', '10818', (88, 92))	('sensitive', 'Reg', (138, 147))	('amplifications', 'Var', (93, 107))	('FRS2', 'Gene', (88, 92))	('liposarcoma', 'Disease', (48, 59))
120425	31731200	Importantly, gene fusions involving FGFR2 occur in 7%-14% of intrahepatic cholangiocarcinomas, and these tumors have been reported to be clinically responsive to FGFR inhibitors.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('occur', 'Reg', (42, 47))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (74, 92))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('intrahepatic cholangiocarcinomas', 'Disease', (61, 93))	('FGFR2', 'Gene', '2263', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (61, 93))	('FGFR2', 'Gene', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('gene fusions', 'Var', (13, 25))
120426	31731200	Although we did not identify any cell lines harboring FGFR2 fusions, our findings suggest that the subset of BTCs driven by aberrant FGFR signaling and amenable to FGFR inhibition extend beyond those harboring FGFR2 fusions alone.	('BTC', 'Gene', '685', (109, 112))	('FGFR2', 'Gene', (210, 215))	('FGFR', 'Protein', (133, 137))	('FGFR2', 'Gene', '2263', (210, 215))	('BTC', 'Gene', (109, 112))	('aberrant', 'Var', (124, 132))	('FGFR2', 'Gene', (54, 59))	('FGFR2', 'Gene', '2263', (54, 59))	('driven by', 'Reg', (114, 123))
120457	30064463	Patients with high circ-CER expression have significantly worse overall survival (OS) than those with low circ-CER expression.	('worse', 'NegReg', (58, 63))	('high circ-CER expression', 'Var', (14, 38))	('overall survival', 'MPA', (64, 80))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (82, 84))
120465	30064463	In addition, the overexpression of hsa_circ_0000064 in lung cancer is positively correlated with T and N stage.	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('hsa_circ_0000064', 'Var', (35, 51))	('lung cancer', 'Disease', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('overexpression', 'PosReg', (17, 31))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('T and', 'Disease', (97, 102))
120469	30064463	A recent study has identified two circRNAs (hsa_circ_0122662 and hsa_circ_0001358) in five patients with DCIS/IDC and the MCF-7 invasive breast cancer cell line.	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('patients', 'Species', '9606', (91, 99))	('hsa_circ_0122662', 'Var', (44, 60))	('MCF-7 invasive breast cancer', 'Disease', (122, 150))	('MCF-7 invasive breast cancer', 'Disease', 'MESH:D001943', (122, 150))	('hsa_circ_0001358', 'Var', (65, 81))	('IDC', 'Gene', '4000', (110, 113))	('IDC', 'Gene', (110, 113))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
120475	30064463	The combination of hsa_circ_006054, hsa_circ_100219, and hsa_circ_406697 provides valuable insights into the diagnosis of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('hsa_circ_406697', 'Var', (57, 72))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('hsa_circ_006054', 'Var', (19, 34))
120480	30064463	A total of 25 binding sites of circ-Foxo3 for eight miRNAs (miR-22, miR-136, miR-138, miR-149, miR-433, miR-762, miR-3614-5p, and miR-3622b-5p) are detected, and transfection of these miRNAs into MDA-MB-231 cells can reduce apoptosis.	('miR-762', 'Gene', '100313837', (104, 111))	('miR', 'Gene', (77, 80))	('miR', 'Gene', '220972', (68, 71))	('miR', 'Gene', '220972', (60, 63))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (196, 206))	('binding', 'Interaction', (14, 21))	('miR', 'Gene', '220972', (52, 55))	('miR-22', 'Gene', '407004', (60, 66))	('miR-762', 'Gene', (104, 111))	('miR-22', 'Gene', (60, 66))	('miR', 'Gene', '220972', (113, 116))	('miR', 'Gene', (68, 71))	('miR', 'Gene', (60, 63))	('miR-149', 'Gene', (86, 93))	('miR', 'Gene', '220972', (130, 133))	('Foxo3', 'Gene', (36, 41))	('miR', 'Gene', '220972', (104, 107))	('miR-433', 'Gene', (95, 102))	('miR', 'Gene', (52, 55))	('miR', 'Gene', '220972', (184, 187))	('miR', 'Gene', '220972', (95, 98))	('miR', 'Gene', (113, 116))	('reduce', 'NegReg', (217, 223))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (130, 133))	('apoptosis', 'CPA', (224, 233))	('miR-149', 'Gene', '406941', (86, 93))	('transfection', 'Var', (162, 174))	('miR', 'Gene', (104, 107))	('miR-136', 'Gene', (68, 75))	('Foxo3', 'Gene', '2309', (36, 41))	('miR', 'Gene', (184, 187))	('miR-136', 'Gene', '406927', (68, 75))	('miR', 'Gene', '220972', (77, 80))	('miR', 'Gene', (95, 98))	('miR', 'Gene', (86, 89))	('miR-433', 'Gene', '574034', (95, 102))
120483	30064463	In addition, circ_000911 is poorly expressed in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('breast cancer', 'Disease', (48, 61))	('circ_000911', 'Var', (13, 24))
120484	30064463	In vitro experiments have confirmed that upregulation of circ_000911 increases Notch1 expression via binding to miR-449a, thereby suppressing the proliferation, invasion, and metastasis of breast cancer cells.	('suppressing', 'NegReg', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('increases', 'PosReg', (69, 78))	('proliferation', 'CPA', (146, 159))	('Notch1', 'Gene', (79, 85))	('miR-449a', 'Gene', '554213', (112, 120))	('circ_000911', 'Var', (57, 68))	('invasion', 'CPA', (161, 169))	('metastasis of breast cancer', 'Disease', 'MESH:D009362', (175, 202))	('expression', 'MPA', (86, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('Notch1', 'Gene', '4851', (79, 85))	('binding', 'Interaction', (101, 108))	('metastasis of breast cancer', 'Disease', (175, 202))	('upregulation', 'PosReg', (41, 53))	('miR-449a', 'Gene', (112, 120))
120485	30064463	In contrast, hsa_circ_0001982, hsa_circ_0005239, and hsa_circ_0008717 are upregulated in breast cancer, and knockdown of their expressions inhibits cell proliferation and promotes apoptosis.	('knockdown', 'Var', (108, 117))	('hsa_circ_0008717', 'Var', (53, 69))	('promotes', 'PosReg', (171, 179))	('upregulated', 'PosReg', (74, 85))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('cell proliferation', 'CPA', (148, 166))	('inhibits', 'NegReg', (139, 147))	('apoptosis', 'CPA', (180, 189))
120486	30064463	circ_0006528 is highly expressed in chemotherapy-resistant breast cancer cell lines, and the sensitivity of these cells to chemotherapy is significantly increased after knocking down circ_0006528.	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('increased', 'PosReg', (153, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('sensitivity', 'MPA', (93, 104))	('knocking down circ_0006528', 'Var', (169, 195))	('circ_0006528', 'Var', (183, 195))
120489	30064463	Several dysregulated circRNAs are found in ESCC, including hsa_circ_000167, hsa_circ_001059, hsa_circ_0067934, and circ-ITCH.	('-ITCH', 'Phenotype', 'HP:0000989', (119, 124))	('ESCC', 'Disease', (43, 47))	('ITCH', 'Gene', (120, 124))	('hsa_circ_000167', 'Var', (59, 74))	('hsa_circ_001059', 'Var', (76, 91))	('ITCH', 'Gene', '83737', (120, 124))	('hsa_circ_0067934', 'Var', (93, 109))
120492	30064463	identified more than 3700 human circRNAs, among which hsa_circ_000167 and hsa_circ_001059 in the KYSE-150R human radiation-resistant esophageal cancer cell line are significantly different from the KYSE-150 parental cell line.	('hsa_circ_001059', 'Var', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('human', 'Species', '9606', (107, 112))	('esophageal cancer', 'Disease', (133, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('human', 'Species', '9606', (26, 31))
120494	30064463	found that hsa_circ_0067934 encoded by PRKCI is upregulated in 51 cases of ESCC tissues compared to adjacent noncancerous tissues, and they reported that hsa_circ_0067934 is associated with poor tumor differentiation and advanced TNM stage.	('TNM', 'Gene', '10178', (230, 233))	('tumor', 'Disease', (195, 200))	('associated', 'Reg', (174, 184))	('PRKCI', 'Gene', '5584', (39, 44))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('PRKCI', 'Gene', (39, 44))	('ESCC', 'Disease', (75, 79))	('hsa_circ_0067934', 'Var', (154, 170))	('TNM', 'Gene', (230, 233))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('upregulated', 'PosReg', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
120495	30064463	Silencing hsa_circ_0067934 by siRNA induces cell cycle arrest and inhibits proliferation and migration of ESCC cells.	('arrest', 'Disease', 'MESH:D006323', (55, 61))	('induces', 'Reg', (36, 43))	('inhibits', 'NegReg', (66, 74))	('arrest', 'Disease', (55, 61))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (44, 61))	('Silencing', 'Var', (0, 9))	('hsa_circ_0067934', 'Gene', (10, 26))
120496	30064463	Given that TNM staging is applied to predict patient outcomes, hsa_circ_0067934 may serve as a potential prognostic marker for ESCC.	('TNM', 'Gene', '10178', (11, 14))	('ESCC', 'Disease', (127, 131))	('TNM', 'Gene', (11, 14))	('patient', 'Species', '9606', (45, 52))	('hsa_circ_0067934', 'Var', (63, 79))
120501	30064463	Hsa_circ_0047905, hsa_circ_0087198, and hsa_circ_0138960 are also highly expressed in gastric cancer tissues.	('gastric cancer', 'Disease', 'MESH:D013274', (86, 100))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('Hsa_circ_0047905', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric cancer', 'Disease', (86, 100))	('hsa_circ_0138960', 'Var', (40, 56))
120505	30064463	Knockdown of hsa_circ_0000096 reduces the expression of cyclin D1, CDK6, matrix metalloproteinase (MPP)-2, and MMP-9, and it significantly inhibits cell proliferation and migration and blocks cell cycle (preventing gastric cancer cells from leaving G0/G1 phase to enter S phase), as well as inhibits tumor growth in a xenograft nude mouse model.	('matrix metalloproteinase (MPP)-2', 'Gene', '50997', (73, 105))	('CDK6', 'Gene', (67, 71))	('expression', 'MPA', (42, 52))	('gastric cancer', 'Disease', (215, 229))	('cyclin D1', 'Gene', '12443', (56, 65))	('cyclin D1', 'Gene', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('mouse', 'Species', '10090', (333, 338))	('cell cycle', 'CPA', (192, 202))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('gastric cancer', 'Disease', 'MESH:D013274', (215, 229))	('inhibits', 'NegReg', (291, 299))	('blocks', 'NegReg', (185, 191))	('inhibits', 'NegReg', (139, 147))	('gastric cancer', 'Phenotype', 'HP:0012126', (215, 229))	('reduces', 'NegReg', (30, 37))	('hsa_circ_0000096', 'Var', (13, 29))	('tumor', 'Disease', (300, 305))	('MMP-9', 'Gene', '17395', (111, 116))	('MMP-9', 'Gene', (111, 116))	('cell proliferation', 'CPA', (148, 166))	('tumor', 'Disease', 'MESH:D009369', (300, 305))
120506	30064463	The circRNA database shows that hsa_circ_0000096 can interact with 17 different types of miRNAs.	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', (89, 92))	('hsa_circ_0000096', 'Var', (32, 48))	('interact', 'Interaction', (53, 61))
120507	30064463	Downregulation of hsa_circ_0000096 results in a decrease in miR-224 (a modulator of CD40) and an increase in miR-200a (targeting E-cadherin).	('increase', 'PosReg', (97, 105))	('Downregulation', 'NegReg', (0, 14))	('miR-224', 'Gene', (60, 67))	('miR-224', 'Gene', '407009', (60, 67))	('E-cadherin', 'Gene', (129, 139))	('E-cadherin', 'Gene', '999', (129, 139))	('CD40', 'Gene', '958', (84, 88))	('decrease', 'NegReg', (48, 56))	('hsa_circ_0000096', 'Var', (18, 34))	('CD40', 'Gene', (84, 88))	('miR-200a', 'Gene', (109, 117))	('miR-200a', 'Gene', '406983', (109, 117))
120511	30064463	Hsa_circ_002059 has also been confirmed to be downregulated in gastric cancer tissues.	('gastric cancer', 'Disease', (63, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (63, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (63, 77))	('downregulated', 'NegReg', (46, 59))	('Hsa_circ_002059', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
120515	30064463	Hsa_circ_0000190 is considered to have better sensitivity and specificity compared to CEA and CA19-9.	('Hsa_circ_0000190', 'Var', (0, 16))	('CEA', 'Gene', (86, 89))	('CEA', 'Gene', '5670', (86, 89))
120517	30064463	Hsa_circ_0014717 is also lowly expressed in gastric cancer, and such downregulation is associated with distant metastasis and clinical staging.	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lowly', 'NegReg', (25, 30))	('gastric cancer', 'Disease', (44, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('distant metastasis', 'CPA', (103, 121))	('Hsa_circ_0014717', 'Var', (0, 16))	('downregulation', 'NegReg', (69, 83))
120518	30064463	Hsa_circ_0000181, hsa_circ_0001649, hsa_circ_0000520, hsa_circ_0003159, and hsa_circ_0074362 are also lowly expressed in tissues or plasma of gastric cancer patients, and their expression is negatively correlated with distant metastasis and TNM staging.	('Hsa_circ_0000181', 'Var', (0, 16))	('TNM', 'Gene', '10178', (241, 244))	('gastric cancer', 'Disease', (142, 156))	('gastric cancer', 'Disease', 'MESH:D013274', (142, 156))	('distant metastasis', 'CPA', (218, 236))	('hsa_circ_0003159', 'Var', (54, 70))	('hsa_circ_0074362', 'Var', (76, 92))	('patients', 'Species', '9606', (157, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (142, 156))	('TNM', 'Gene', (241, 244))	('negatively', 'NegReg', (191, 201))	('hsa_circ_0000520', 'Var', (36, 52))	('correlated', 'Reg', (202, 212))	('expression', 'MPA', (177, 187))	('lowly', 'NegReg', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('hsa_circ_0001649', 'Var', (18, 34))
120519	30064463	The plasma levels of hsa_circ_0001017 and hsa_circ_0061276 are also downregulated, making them suitable for the diagnosis and prognosis of gastric cancer.	('gastric cancer', 'Disease', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('gastric cancer', 'Disease', 'MESH:D013274', (139, 153))	('downregulated', 'NegReg', (68, 81))	('hsa_circ_0001017', 'Var', (21, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (139, 153))	('hsa_circ_0061276', 'Var', (42, 58))	('plasma levels', 'MPA', (4, 17))
120520	30064463	Moreover, hsa_circ_0000745 is expressed at a higher level in gastric cancer tissues than normal tissues, and its expression in plasma of gastric cancer patients is also higher than that of healthy controls.	('expression', 'MPA', (113, 123))	('higher', 'PosReg', (169, 175))	('gastric cancer', 'Disease', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('gastric cancer', 'Disease', 'MESH:D013274', (61, 75))	('gastric cancer', 'Disease', (137, 151))	('gastric cancer', 'Disease', 'MESH:D013274', (137, 151))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))	('higher', 'PosReg', (45, 51))	('hsa_circ_0000745', 'Var', (10, 26))	('patients', 'Species', '9606', (152, 160))	('gastric cancer', 'Phenotype', 'HP:0012126', (137, 151))
120521	30064463	Hsa_circ_0000745 expression in gastric cancer tissues and plasma is associated with tumor differentiation and lymph node metastasis, respectively, and plasma hsa_circ_0000745 combined with CEA has a greater diagnostic value for gastric cancer.	('CEA', 'Gene', '5670', (189, 192))	('lymph node metastasis', 'CPA', (110, 131))	('associated', 'Reg', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (228, 242))	('gastric cancer', 'Disease', (228, 242))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (31, 45))	('Hsa_circ_0000745', 'Gene', (0, 16))	('gastric cancer', 'Phenotype', 'HP:0012126', (228, 242))	('tumor', 'Disease', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('hsa_circ_0000745', 'Var', (158, 174))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('CEA', 'Gene', (189, 192))	('gastric cancer', 'Disease', 'MESH:D013274', (31, 45))	('gastric cancer', 'Disease', (31, 45))
120533	30064463	In addition, hsa_circ_0001649, hsa_circ_0003906, and circRNA derived from ITCH78 are also downregulated in CRC, and the first two circRNAs are related to the pathological differentiation of CRC and may be used as diagnostic indicators of CRC.	('CRC', 'Disease', (238, 241))	('CRC', 'Disease', (107, 110))	('CRC', 'Phenotype', 'HP:0030731', (238, 241))	('ITCH', 'Gene', (74, 78))	('CRC', 'Phenotype', 'HP:0030731', (107, 110))	('CRC', 'Disease', (190, 193))	('CRC', 'Phenotype', 'HP:0030731', (190, 193))	('hsa_circ_0001649', 'Var', (13, 29))	('downregulated', 'NegReg', (90, 103))	('ITCH', 'Gene', '83737', (74, 78))
120538	30064463	As a positive regulator of CRC cell proliferation and invasion, hsa_circ_001569 exhibits higher expression in CRC tissues than noncancerous tissues.	('hsa_circ_001569', 'Var', (64, 79))	('CRC', 'Disease', (110, 113))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('CRC', 'Phenotype', 'HP:0030731', (110, 113))	('cancer', 'Disease', (130, 136))	('expression', 'MPA', (96, 106))	('higher', 'PosReg', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('CRC', 'Phenotype', 'HP:0030731', (27, 30))
120554	30064463	Comparison of three syngeneic CRC cell lines with different KRAS mutation status, including DLD-1, DKO-1, and DKs-8, has shown that extracellular circRNAs are more abundant than intracellular circRNAs, and most circRNAs are downregulated in the KRAS-mutated CRC cell lines.	('downregulated', 'NegReg', (224, 237))	('KRAS', 'Gene', (245, 249))	('KRAS', 'Gene', (60, 64))	('KRAS', 'Gene', '3845', (245, 249))	('mutation', 'Var', (65, 73))	('CRC', 'Phenotype', 'HP:0030731', (30, 33))	('KRAS', 'Gene', '3845', (60, 64))	('extracellular circRNAs', 'MPA', (132, 154))	('CRC', 'Phenotype', 'HP:0030731', (258, 261))
120555	30064463	circRNA is associated with KRAS mutations, and it is a promising biomarker of CRC, especially for KRAS-mutated CRC.	('KRAS', 'Gene', '3845', (27, 31))	('associated', 'Reg', (11, 21))	('CRC', 'Phenotype', 'HP:0030731', (111, 114))	('mutations', 'Var', (32, 41))	('CRC', 'Disease', (78, 81))	('CRC', 'Phenotype', 'HP:0030731', (78, 81))	('KRAS', 'Gene', (98, 102))	('KRAS', 'Gene', (27, 31))	('KRAS', 'Gene', '3845', (98, 102))
120567	30064463	Hsa_circ_0001649 was also lowly expressed in HCC tissues compared to normal tissues, and the expression level of hsa_circ_0001649 is related to tumor size and tumor thrombus.	('HCC', 'Phenotype', 'HP:0001402', (45, 48))	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('hsa_circ_0001649', 'Var', (113, 129))	('related', 'Reg', (133, 140))	('HCC', 'Gene', (45, 48))	('tumor thrombus', 'Disease', (159, 173))	('tumor', 'Disease', (159, 164))	('expression', 'MPA', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor thrombus', 'Disease', 'MESH:D013927', (159, 173))	('HCC', 'Gene', '619501', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
120572	30064463	The expression level of hsa_circ_0005986 in HCC cell lines, including HepG2, Huh7, SMMC7721, HCCLM3, MHCC97H, and MHCC97L, is significantly lower than that in the L02 normal liver cell line.	('lower', 'NegReg', (140, 145))	('SMMC7721', 'CellLine', 'CVCL:0534', (83, 91))	('hsa_circ_0005986', 'Var', (24, 40))	('Huh7', 'Gene', (77, 81))	('Huh7', 'Gene', '284424', (77, 81))	('HCC', 'Gene', '619501', (102, 105))	('HCC', 'Phenotype', 'HP:0001402', (102, 105))	('HepG2', 'CellLine', 'CVCL:0027', (70, 75))	('HCC', 'Gene', '619501', (93, 96))	('HCC', 'Phenotype', 'HP:0001402', (93, 96))	('HCC', 'Gene', (102, 105))	('HCC', 'Gene', '619501', (44, 47))	('HCC', 'Gene', (93, 96))	('HCC', 'Phenotype', 'HP:0001402', (44, 47))	('expression level', 'MPA', (4, 20))	('HCC', 'Gene', (44, 47))	('HCC', 'Gene', '619501', (115, 118))	('HCC', 'Phenotype', 'HP:0001402', (115, 118))	('HCC', 'Gene', (115, 118))
120573	30064463	Both hsa_circ_0005986 and Notch1 mRNA can bind to miR-129-5p, and downregulation of hsa_circ_0005986 releases miR-129-5p to decrease the level of Notch1 mRNA, accelerating the cell proliferation by promoting G0/G1 to S phase transition.	('miR-129-5p', 'Gene', '100302178', (110, 120))	('level', 'MPA', (137, 142))	('miR-129-5p', 'Gene', (110, 120))	('downregulation', 'Var', (66, 80))	('Notch1', 'Gene', (26, 32))	('G0/G1 to S phase transition', 'CPA', (208, 235))	('accelerating', 'PosReg', (159, 171))	('miR-129-5p', 'Gene', '100302178', (50, 60))	('Notch1', 'Gene', (146, 152))	('miR-129-5p', 'Gene', (50, 60))	('promoting', 'PosReg', (198, 207))	('cell proliferation', 'CPA', (176, 194))	('hsa_circ_0005986', 'Gene', (84, 100))	('decrease', 'NegReg', (124, 132))	('Notch1', 'Gene', '4851', (146, 152))	('Notch1', 'Gene', '4851', (26, 32))
120576	30064463	ciRS-7 (hsa_circ_0001946) is significantly upregulated in HCC tissues and is negatively correlated with miR-7 expression.	('ciRS-7', 'Gene', '103611090', (0, 6))	('upregulated', 'PosReg', (43, 54))	('HCC', 'Gene', (58, 61))	('miR-7', 'Gene', (104, 109))	('miR-7', 'Gene', '10859', (104, 109))	('HCC', 'Gene', '619501', (58, 61))	('ciRS-7', 'Gene', (0, 6))	('negatively', 'NegReg', (77, 87))	('HCC', 'Phenotype', 'HP:0001402', (58, 61))	('hsa_circ_0001946', 'Var', (8, 24))
120578	30064463	When ciRS-7 is knocked down, miR-7 is released and proliferation and invasion of HCC cells are also significantly inhibited.	('knocked down', 'Var', (15, 27))	('ciRS-7', 'Gene', (5, 11))	('HCC', 'Gene', '619501', (81, 84))	('miR-7', 'Gene', (29, 34))	('HCC', 'Phenotype', 'HP:0001402', (81, 84))	('released', 'PosReg', (38, 46))	('ciRS-7', 'Gene', '103611090', (5, 11))	('miR-7', 'Gene', '10859', (29, 34))	('HCC', 'Gene', (81, 84))	('inhibited', 'NegReg', (114, 123))
120584	30064463	Knockdown of has_circ_0067934 significantly inhibits the proliferation, invasion, and metastasis of Hep3B and HuH7 cells and induces apoptosis.	('HuH7', 'Gene', (110, 114))	('apoptosis', 'CPA', (133, 142))	('Hep3B', 'CellLine', 'CVCL:0326', (100, 105))	('has_circ_0067934', 'Var', (13, 29))	('HuH7', 'Gene', '284424', (110, 114))	('induces', 'Reg', (125, 132))	('inhibits', 'NegReg', (44, 52))	('invasion', 'CPA', (72, 80))	('metastasis', 'CPA', (86, 96))
120585	30064463	Hsa_circ_0005075 is considered to be closely related to cell adhesion, which is an important part of tumor cell proliferation and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('Hsa_circ_0005075', 'Var', (0, 16))	('cell', 'CPA', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
120586	30064463	A recent study showed that the expression level of hsa_circ_0005075 is significantly different between HCC and normal liver tissues and is related to HCC tumor size.	('HCC', 'Gene', (150, 153))	('different', 'Reg', (85, 94))	('related', 'Reg', (139, 146))	('HCC', 'Phenotype', 'HP:0001402', (103, 106))	('HCC tumor', 'Disease', 'MESH:D006528', (150, 159))	('HCC', 'Gene', '619501', (103, 106))	('HCC', 'Gene', '619501', (150, 153))	('hsa_circ_0005075', 'Var', (51, 67))	('HCC', 'Phenotype', 'HP:0001402', (150, 153))	('HCC', 'Gene', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('expression level', 'MPA', (31, 47))	('HCC tumor', 'Disease', (150, 159))
120587	30064463	Larger tumor sizes correlated with higher expression of hsa_circ_0005075.	('tumor', 'Disease', (7, 12))	('expression', 'MPA', (42, 52))	('hsa_circ_0005075', 'Var', (56, 72))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('higher', 'PosReg', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
120588	30064463	Thus, hsa_circ_0005075 has the potential to become an ideal biomarker for HCC.	('HCC', 'Gene', '619501', (74, 77))	('hsa_circ_0005075', 'Var', (6, 22))	('HCC', 'Gene', (74, 77))	('HCC', 'Phenotype', 'HP:0001402', (74, 77))
120598	30064463	Hsa_circ_0046701 is highly expressed in glioma tissues.	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('glioma', 'Disease', (40, 46))	('Hsa_circ_0046701', 'Var', (0, 16))	('glioma', 'Disease', 'MESH:D005910', (40, 46))
120599	30064463	Silencing hsa_circ_0046701 upregulates miR-142, resulting in a decrease of ITGB8 and inhibition of cell proliferation and invasion.	('ITGB8', 'Gene', '3696', (75, 80))	('ITGB8', 'Gene', (75, 80))	('inhibition', 'NegReg', (85, 95))	('decrease', 'NegReg', (63, 71))	('miR-142', 'Gene', '406934', (39, 46))	('hsa_circ_0046701', 'Gene', (10, 26))	('upregulates', 'PosReg', (27, 38))	('miR-142', 'Gene', (39, 46))	('Silencing', 'Var', (0, 9))
120601	30064463	circ-SHKBP1 is highly expressed in high-grade gliomas, and knockdown of circ-SHKBP1 significantly inhibits cell proliferation and metastasis.	('SHKBP1', 'Gene', (5, 11))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('SHKBP1', 'Gene', '92799', (77, 83))	('SHKBP1', 'Gene', (77, 83))	('gliomas', 'Disease', (46, 53))	('SHKBP1', 'Gene', '92799', (5, 11))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('knockdown', 'Var', (59, 68))	('inhibits', 'NegReg', (98, 106))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
120605	30064463	Silencing cZNF292 inactivates the Wnt/beta-catenin signaling pathway in U87MG and U251 cells, thereby arresting cell cycle and inhibiting cell proliferation.	('beta-catenin', 'Gene', (38, 50))	('cZNF292', 'Gene', (10, 17))	('arrest', 'Disease', (102, 108))	('inactivates', 'NegReg', (18, 29))	('Silencing', 'Var', (0, 9))	('beta-catenin', 'Gene', '1499', (38, 50))	('inhibiting', 'NegReg', (127, 137))	('U87MG', 'CellLine', 'CVCL:0022', (72, 77))	('cell proliferation', 'CPA', (138, 156))	('cell cycle', 'CPA', (112, 122))	('U251', 'CellLine', 'CVCL:0021', (82, 86))	('arrest', 'Disease', 'MESH:D006323', (102, 108))
120606	30064463	Hsa_circ_022705 (circ-FBXW7) is lowly expressed in glioma tissues and cells, and it is positively correlated with the prognosis of patients with glioma.	('patients', 'Species', '9606', (131, 139))	('glioma', 'Disease', (145, 151))	('glioma', 'Disease', (51, 57))	('correlated with', 'Reg', (98, 113))	('FBXW7', 'Gene', (22, 27))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('FBXW7', 'Gene', '55294', (22, 27))	('Hsa_circ_022705', 'Var', (0, 15))
120608	30064463	Upregulation of FBXW7-185aa significantly inhibits the proliferation of tumor cells, while silencing this protein promotes the malignant phenotype.	('Upregulation', 'PosReg', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('FBXW7', 'Gene', (16, 21))	('inhibits', 'NegReg', (42, 50))	('tumor', 'Disease', (72, 77))	('malignant phenotype', 'CPA', (127, 146))	('promotes', 'PosReg', (114, 122))	('silencing', 'Var', (91, 100))	('FBXW7', 'Gene', '55294', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
120621	30064463	High-throughput microarray analysis has been used to identify six circRNAs that are differentially expressed in bladder cancer and normal tissues as follows: circPTK2 (hsa_circ_0005273), circTCF25 (hsa_circ_0041103), circBC048201 (hsa_circ_0061265), and circZFR (hsa_circ_0072088) are significantly upregulated and circTRIM24 (hsa_circ_0082582) and circFAM169A (hsa_circ_0007158) are downregulated.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('PTK2', 'Gene', '5747', (162, 166))	('bladder cancer', 'Disease', (112, 126))	('bladder cancer', 'Disease', 'MESH:D001749', (112, 126))	('hsa_circ_0061265', 'Var', (231, 247))	('upregulated', 'PosReg', (299, 310))	('bladder cancer', 'Phenotype', 'HP:0009725', (112, 126))	('PTK2', 'Gene', (162, 166))
120636	30064463	Hsa_circ_0000977 is abnormally upregulated in pancreatic cancer tissues, and silencing hsa_circ_0000977 inhibits cell proliferation and induces cell cycle arrest.	('arrest', 'Disease', 'MESH:D006323', (155, 161))	('cell proliferation', 'CPA', (113, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (46, 63))	('inhibits', 'NegReg', (104, 112))	('pancreatic cancer', 'Disease', (46, 63))	('silencing', 'Var', (77, 86))	('arrest', 'Disease', (155, 161))	('pancreatic cancer', 'Disease', 'MESH:D010190', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('hsa_circ_0000977', 'Gene', (87, 103))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (144, 161))	('induces', 'Reg', (136, 143))
120637	30064463	The interaction of hsa_circ_0000977, hsa-miR-874-3p, and PLK1A has been verified by dual luciferase reporter assay and fluorescence in situ hybridization (FISH) assay, and inhibition of hsa_circ_0000977 can reduce the expression of PLK1.	('reduce', 'NegReg', (207, 213))	('miR', 'Gene', '220972', (41, 44))	('PLK1', 'Gene', (57, 61))	('miR', 'Gene', (41, 44))	('inhibition', 'Var', (172, 182))	('PLK1', 'Gene', (232, 236))	('PLK1', 'Gene', '5347', (232, 236))	('PLK1', 'Gene', '5347', (57, 61))	('expression', 'MPA', (218, 228))
120638	30064463	In animal experiments, silencing hsa_circ_0000977 inhibits tumor growth.	('hsa_circ_0000977', 'Gene', (33, 49))	('tumor', 'Disease', (59, 64))	('silencing', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('inhibits', 'NegReg', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
120647	30064463	The circRNA encoded by UBAP2 is the most prominently upregulated circRNA in osteosarcoma tissues, and patients with high circUBAP2 expression are often associated with a poor OS.	('UBAP2', 'Gene', (23, 28))	('osteosarcoma tissues', 'Disease', (76, 96))	('OS', 'Chemical', '-', (175, 177))	('UBAP2', 'Gene', '55833', (23, 28))	('high', 'Var', (116, 120))	('patients', 'Species', '9606', (102, 110))	('osteosarcoma', 'Phenotype', 'HP:0002669', (76, 88))	('osteosarcoma tissues', 'Disease', 'MESH:D012516', (76, 96))	('UBAP2', 'Gene', (125, 130))	('poor OS', 'Disease', (170, 177))	('upregulated', 'PosReg', (53, 64))	('UBAP2', 'Gene', '55833', (125, 130))
120649	30064463	Hsa_circ_0001564 is significantly overexpressed in osteosarcoma tissues and cells.	('osteosarcoma', 'Phenotype', 'HP:0002669', (51, 63))	('osteosarcoma tissues', 'Disease', 'MESH:D012516', (51, 71))	('Hsa_circ_0001564', 'Var', (0, 16))	('osteosarcoma tissues', 'Disease', (51, 71))	('overexpressed', 'PosReg', (34, 47))
120652	30064463	Hsa_circ_0009910 is also overexpressed in osteosarcoma cells.	('osteosarcoma', 'Disease', (42, 54))	('overexpressed', 'PosReg', (25, 38))	('osteosarcoma', 'Phenotype', 'HP:0002669', (42, 54))	('osteosarcoma', 'Disease', 'MESH:D012516', (42, 54))	('Hsa_circ_0009910', 'Var', (0, 16))
120653	30064463	Knockdown of circ_0009910 inhibits the proliferation of osteosarcoma cells, leading to cell cycle arrest and apoptosis.	('arrest', 'Disease', (98, 104))	('inhibits', 'NegReg', (26, 34))	('apoptosis', 'CPA', (109, 118))	('osteosarcoma', 'Phenotype', 'HP:0002669', (56, 68))	('osteosarcoma', 'Disease', (56, 68))	('proliferation', 'CPA', (39, 52))	('osteosarcoma', 'Disease', 'MESH:D012516', (56, 68))	('circ_0009910', 'Var', (13, 25))	('arrest', 'Disease', 'MESH:D006323', (98, 104))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (87, 104))
120654	30064463	However, inhibition of miR-449a eliminates this effect.	('inhibition', 'Var', (9, 19))	('miR-449a', 'Gene', '554213', (23, 31))	('miR-449a', 'Gene', (23, 31))
120655	30064463	As the sponge of miR-449a, circ_0009910 upregulates the functional target gene IL6R and promotes the development of osteosarcoma.	('promotes', 'PosReg', (88, 96))	('IL6R', 'Gene', '3570', (79, 83))	('miR-449a', 'Gene', (17, 25))	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('upregulates', 'PosReg', (40, 51))	('osteosarcoma', 'Disease', 'MESH:D012516', (116, 128))	('miR-449a', 'Gene', '554213', (17, 25))	('IL6R', 'Gene', (79, 83))	('circ_0009910', 'Var', (27, 39))	('osteosarcoma', 'Disease', (116, 128))
120656	30064463	In osteosarcoma cells and tissues, hsa_circRNA_103801 is upregulated, while hsa_circRNA_104980 is downregulated.	('osteosarcoma', 'Disease', (3, 15))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('hsa_circRNA_103801', 'Var', (35, 53))	('upregulated', 'PosReg', (57, 68))
120657	30064463	The potential target miRNAs for hsa_circRNA_103801 include hsa-miR-338-3p, hsa-miR-370-3p, and hsa-miR-877-3p, which are involved in the HIF-1, Rap1, PI3K-Akt, VEGF, and angiogenesis pathways.	('HIF-1', 'Gene', (137, 142))	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', (99, 102))	('miR', 'Gene', '220972', (21, 24))	('VEGF', 'Gene', (160, 164))	('miR', 'Gene', (21, 24))	('Rap1', 'Gene', '5906', (144, 148))	('Rap1', 'Gene', (144, 148))	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', (79, 82))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (63, 66))	('Akt', 'Gene', '207', (155, 158))	('HIF-1', 'Gene', '3091', (137, 142))	('VEGF', 'Gene', '7422', (160, 164))	('hsa_circRNA_103801', 'Var', (32, 50))	('Akt', 'Gene', (155, 158))
120658	30064463	The potential target miRNAs for hsa_circRNA_104980 are hsa-miR-660-3p and hsa-miR-1298-3p, which participate in the tight junction pathway.	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('hsa_circRNA_104980', 'Var', (32, 50))	('miR', 'Gene', '220972', (59, 62))	('miR', 'Gene', (59, 62))
120666	30064463	In addition, the OS rate of ccRCC patients with high expression of circ-RIAT1 is superior to that of patients with low circ-RIAT1.	('patients', 'Species', '9606', (101, 109))	('circ-RIAT1', 'Disease', (119, 129))	('circ-RIAT1', 'Disease', 'None', (67, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (28, 33))	('circ-RIAT1', 'Disease', 'None', (119, 129))	('patients', 'Species', '9606', (34, 42))	('ccRCC', 'Disease', (28, 33))	('high expression', 'Var', (48, 63))	('circ-RIAT1', 'Disease', (67, 77))	('OS', 'Chemical', '-', (17, 19))
120674	30064463	Hsa_circ_0022383 and hsa_circ_0022392 are the most significantly downregulated circRNAs and derived from FADS2 gene.	('FADS2', 'Gene', '9415', (105, 110))	('FADS2', 'Gene', (105, 110))	('circRNAs', 'MPA', (79, 87))	('downregulated', 'NegReg', (65, 78))	('Hsa_circ_0022383', 'Var', (0, 16))
120681	30064463	Functional analysis has revealed that knockdown of circRNA_100290 reduces CDK6 expression, induces G1/S arrest, and significantly inhibits the proliferation of SCC9 cell lines.	('circRNA_100290', 'Var', (51, 65))	('S arrest', 'Disease', (102, 110))	('SCC9', 'CellLine', 'CVCL:1685', (160, 164))	('CDK6', 'Gene', (74, 78))	('expression', 'MPA', (79, 89))	('reduces', 'NegReg', (66, 73))	('S arrest', 'Disease', 'MESH:D006323', (102, 110))	('proliferation of SCC9 cell lines', 'CPA', (143, 175))	('induces', 'Reg', (91, 98))	('inhibits', 'NegReg', (130, 138))
120682	30064463	In a nude mouse model, interference with circRNA_100290 also reduces tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mouse', 'Species', '10090', (10, 15))	('tumor', 'Disease', (69, 74))	('reduces', 'NegReg', (61, 68))	('circRNA_100290', 'Var', (41, 55))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
120687	30064463	Overexpression of ciRS-7 is closely related to later TNM staging, lymph node infiltration, and postoperative recurrence.	('lymph node infiltration', 'CPA', (66, 89))	('related', 'Reg', (36, 43))	('TNM', 'Gene', (53, 56))	('ciRS-7', 'Gene', '103611090', (18, 24))	('ciRS-7', 'Gene', (18, 24))	('Overexpression', 'Var', (0, 14))	('TNM', 'Gene', '10178', (53, 56))
120688	30064463	The OS of cholangiocarcinoma patients with high ciRS-7 expression is inferior to that of patients with low ciRS-7 expression.	('cholangiocarcinoma', 'Disease', (10, 28))	('patients', 'Species', '9606', (29, 37))	('ciRS-7', 'Gene', '103611090', (48, 54))	('ciRS-7', 'Gene', '103611090', (107, 113))	('OS', 'Chemical', '-', (4, 6))	('high', 'Var', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('ciRS-7', 'Gene', (48, 54))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (10, 28))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (10, 28))	('patients', 'Species', '9606', (89, 97))	('ciRS-7', 'Gene', (107, 113))	('expression', 'Var', (55, 65))
120691	30064463	Overexpression of hsa_circ_0001649 inhibits cell proliferation, migration, and invasion but induces apoptosis of KMBC and Huh-28 cells.	('Huh-28', 'CellLine', 'CVCL:0336', (122, 128))	('induces', 'Reg', (92, 99))	('cell proliferation', 'CPA', (44, 62))	('inhibits', 'NegReg', (35, 43))	('invasion', 'CPA', (79, 87))	('migration', 'CPA', (64, 73))	('apoptosis', 'CPA', (100, 109))	('hsa_circ_0001649', 'Var', (18, 34))
120693	30064463	circRNA-000284 is significantly upregulated in cervical cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cervical cancer', 'Disease', (47, 62))	('cervical cancer', 'Disease', 'MESH:D002583', (47, 62))	('circRNA-000284', 'Var', (0, 14))	('upregulated', 'PosReg', (32, 43))
120694	30064463	It promotes the proliferation and invasion of cervical cancer cells and that knockdown of circRNA-000284 causes G0/G1 cell cycle arrest, resulting in inhibition of cell proliferation and invasion.	('cervical cancer', 'Disease', 'MESH:D002583', (46, 61))	('arrest', 'Disease', (129, 135))	('cervical cancer', 'Disease', (46, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (118, 135))	('cell proliferation', 'CPA', (164, 182))	('knockdown', 'Var', (77, 86))	('invasion', 'CPA', (34, 42))	('inhibition', 'NegReg', (150, 160))	('promotes', 'PosReg', (3, 11))	('arrest', 'Disease', 'MESH:D006323', (129, 135))	('circRNA-000284', 'Gene', (90, 104))	('proliferation', 'CPA', (16, 29))	('invasion', 'CPA', (187, 195))
120695	30064463	miR-506 is a miRNA related to circRNA-000284, and circRNA-000284 positively regulates the expression of Snail-2 which is a target gene of miR-506.	('Snail-2', 'Gene', '6591', (104, 111))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('Snail-2', 'Gene', (104, 111))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('miR', 'Gene', '220972', (138, 141))	('circRNA-000284', 'Var', (50, 64))	('miR', 'Gene', (138, 141))	('expression', 'MPA', (90, 100))	('regulates', 'Reg', (76, 85))	('miR-506', 'Gene', '574511', (0, 7))	('miR-506', 'Gene', (0, 7))	('miR-506', 'Gene', '574511', (138, 145))	('miR-506', 'Gene', (138, 145))
120697	30064463	Thus, circRNA-000284 is expected to be a new therapeutic target for cervical cancer.	('circRNA-000284', 'Var', (6, 20))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cervical cancer', 'Disease', (68, 83))	('cervical cancer', 'Disease', 'MESH:D002583', (68, 83))
120703	30064463	The combination of hsa_circ_006054, hsa_circ_100219, and hsa_circ_406697 is helpful for the diagnosis of breast cancer.	('hsa_circ_406697', 'Var', (57, 72))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('hsa_circ_006054', 'Var', (19, 34))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
120704	30064463	Hsa_circ_0067934, a potential prognostic marker for ESCC, is overexpressed in ESCC tissues and correlates with poor differentiation and more advanced TNM staging.	('differentiation', 'CPA', (116, 131))	('TNM', 'Gene', (150, 153))	('Hsa_circ_0067934', 'Var', (0, 16))	('ESCC', 'Disease', (52, 56))	('TNM', 'Gene', '10178', (150, 153))	('overexpressed', 'PosReg', (61, 74))	('poor', 'NegReg', (111, 115))
120706	30064463	The downregulation of circMTO1, circ-ITCH, and cSMARCA5 or upregulation of circRNA_100338 in HCC is associated with poor prognosis.	('HCC', 'Gene', '619501', (93, 96))	('-ITCH', 'Phenotype', 'HP:0000989', (36, 41))	('ITCH', 'Gene', (37, 41))	('HCC', 'Phenotype', 'HP:0001402', (93, 96))	('SMARCA5', 'Gene', '8467', (48, 55))	('HCC', 'Gene', (93, 96))	('MTO1', 'Gene', '25821', (26, 30))	('downregulation', 'NegReg', (4, 18))	('ITCH', 'Gene', '83737', (37, 41))	('MTO1', 'Gene', (26, 30))	('upregulation', 'PosReg', (59, 71))	('SMARCA5', 'Gene', (48, 55))	('circRNA_100338', 'Var', (75, 89))
120708	30064463	Overexpression of ciRS-7 in cholangiocarcinoma is significantly correlated with later TNM staging, lymph node infiltration, and postoperative recurrence, and it may be an independent negative prognostic biomarker with good sensitivity and specificity.	('cholangiocarcinoma', 'Disease', (28, 46))	('TNM', 'Gene', '10178', (86, 89))	('ciRS-7', 'Gene', '103611090', (18, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (28, 46))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (28, 46))	('ciRS-7', 'Gene', (18, 24))	('TNM', 'Gene', (86, 89))	('lymph', 'Disease', (99, 104))	('Overexpression', 'Var', (0, 14))	('correlated', 'Reg', (64, 74))
120709	30064463	Hsa_circ_0001649 has been reported to have potential diagnostic and prognostic value in gastric cancer, CRC, HCC, and cholangiocarcinoma, and it may be a sensitive indicator for distant metastasis in gastric cancer and HCC.	('gastric cancer', 'Disease', 'MESH:D013274', (200, 214))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('HCC', 'Gene', '619501', (109, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (200, 214))	('HCC', 'Phenotype', 'HP:0001402', (109, 112))	('Hsa_circ_0001649', 'Var', (0, 16))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('CRC', 'Disease', (104, 107))	('HCC', 'Gene', (109, 112))	('HCC', 'Gene', '619501', (219, 222))	('HCC', 'Phenotype', 'HP:0001402', (219, 222))	('gastric cancer', 'Disease', (200, 214))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (118, 136))	('CRC', 'Phenotype', 'HP:0030731', (104, 107))	('gastric cancer', 'Disease', (88, 102))	('HCC', 'Gene', (219, 222))	('cholangiocarcinoma', 'Disease', (118, 136))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (118, 136))
120711	30064463	Overexpression of circ-LDLRAD3 in pancreatic cancer is significantly correlated with venous and lymphatic infiltration as well as distant metastasis, and it is also a potential diagnostic marker for pancreatic cancer.	('pancreatic cancer', 'Disease', (199, 216))	('correlated', 'Reg', (69, 79))	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('pancreatic cancer', 'Disease', 'MESH:D010190', (199, 216))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('LDLRAD3', 'Gene', (23, 30))	('distant metastasis', 'CPA', (130, 148))	('LDLRAD3', 'Gene', '143458', (23, 30))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('Overexpression', 'Var', (0, 14))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))	('pancreatic cancer', 'Disease', (34, 51))
120713	30064463	For example, hsa_circ_002059, hsa_circ_0001017, and hsa_circ_0061276 can be stably detected in the plasma of gastric cancer patients.	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric cancer', 'Disease', (109, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('hsa_circ_0001017', 'Var', (30, 46))	('hsa_circ_0061276', 'Var', (52, 68))	('patients', 'Species', '9606', (124, 132))	('hsa_circ_002059', 'Var', (13, 28))
120716	30064463	The sensitivity and specificity of hsa_circ_0000190 as a diagnostic marker for gastric cancer are even better than that of CEA and CA19-9.	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('hsa_circ_0000190', 'Var', (35, 51))	('CEA', 'Gene', (123, 126))	('CEA', 'Gene', '5670', (123, 126))	('gastric cancer', 'Disease', (79, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))
120717	30064463	The plasma level of hsa_circ_0000745 in gastric cancer patients is related to lymph node metastasis, and it has a good diagnostic value in combination with CEA.	('related', 'Reg', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('CEA', 'Gene', (156, 159))	('gastric cancer', 'Disease', (40, 54))	('lymph node metastasis', 'CPA', (78, 99))	('plasma level', 'MPA', (4, 16))	('gastric cancer', 'Disease', 'MESH:D013274', (40, 54))	('CEA', 'Gene', '5670', (156, 159))	('hsa_circ_0000745', 'Var', (20, 36))	('patients', 'Species', '9606', (55, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (40, 54))
120720	30064463	Alternatively, it is possible to interfere with back-splicing by antisense oligonucleotides that are complementary to the back-splice signals in the precursor mRNA.	('antisense oligonucleotides', 'Var', (65, 91))	('oligonucleotides', 'Chemical', 'MESH:D009841', (75, 91))	('interfere', 'Reg', (33, 42))	('back-splicing', 'MPA', (48, 61))
120726	30064463	Because some circRNAs serve as a template for protein expression, cassettes containing tumor suppressor proteins can convert circRNAs into an effective treatment method for tumors.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Disease', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('cassettes', 'Var', (66, 75))
120738	28588705	GALNT14 genotype is associated with perineural invasion, lymph node metastasis and overall survival in resected cholangiocarcinoma Cholangiocarcinoma is a rare, sporadic and aggressive type of cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('associated', 'Reg', (20, 30))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 130))	('aggressive type of cancer', 'Disease', 'MESH:D009369', (174, 199))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('aggressive type of cancer', 'Disease', (174, 199))	('Cholangiocarcinoma', 'Disease', (131, 149))	('perineural invasion', 'CPA', (36, 55))	('lymph node metastasis', 'CPA', (57, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (131, 149))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('GALNT14', 'Gene', (0, 7))	('cholangiocarcinoma', 'Disease', (112, 130))	('genotype', 'Var', (8, 16))	('GALNT14', 'Gene', '79623', (0, 7))
120759	28588705	Numerous molecular changes have been identified in cholangiocarcinoma, including the inactivation of tumor suppressor genes [tumor protein 53, anaphase-promoting complex, mothers against decapentaplegic homolog 4 (SMAD4) and cyclin dependent kinase inhibitor 2A], somatic mutations or the upregulation of oncogenes [e.g.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('SMAD4', 'Gene', (214, 219))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (51, 69))	('mothers against decapentaplegic homolog 4', 'Gene', (171, 212))	('inactivation', 'Var', (85, 97))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('cholangiocarcinoma', 'Disease', (51, 69))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('SMAD4', 'Gene', '4089', (214, 219))	('cyclin dependent kinase inhibitor 2A', 'Gene', (225, 261))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (51, 69))	('tumor protein 53', 'Gene', (125, 141))	('tumor protein 53', 'Gene', '7157', (125, 141))	('upregulation', 'PosReg', (289, 301))	('mothers against decapentaplegic homolog 4', 'Gene', '4089', (171, 212))	('cyclin dependent kinase inhibitor 2A', 'Gene', '1029', (225, 261))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', (125, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
120767	28588705	A leading single nucleotide polymorphism, rs9679162, was identified to be associated with chemotherapy response, time-to-tumor progression and overall survival in a previous study of patients with HCC at Barcelona Clinic Liver Cancer (BCLC) Stage C. The genotypes were also identified to correlate with the therapeutic response in TACE-treated patients with HCC at BCLC Stage B.	('Clinic Liver Cancer', 'Disease', (214, 233))	('HCC', 'Phenotype', 'HP:0001402', (358, 361))	('HCC', 'Gene', '619501', (197, 200))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Liver Cancer', 'Phenotype', 'HP:0002896', (221, 233))	('rs9679162', 'Var', (42, 51))	('rs9679162', 'Mutation', 'rs9679162', (42, 51))	('HCC', 'Phenotype', 'HP:0001402', (197, 200))	('tumor', 'Disease', (121, 126))	('HCC', 'Gene', (358, 361))	('Cancer', 'Phenotype', 'HP:0002664', (227, 233))	('patients', 'Species', '9606', (183, 191))	('HCC', 'Gene', (197, 200))	('HCC', 'Gene', '619501', (358, 361))	('Clinic Liver Cancer', 'Disease', 'MESH:D006528', (214, 233))	('patients', 'Species', '9606', (344, 352))	('associated', 'Reg', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
120769	28588705	Furthermore, germline mutations in GALNT14 were associated with an increased risk of hereditary neuroblastoma and GALNT14 was recently identified as an embryonic lethal gene based on studies in consanguineous families.	('GALNT14', 'Gene', '79623', (35, 42))	('GALNT14', 'Gene', (114, 121))	('GALNT14', 'Gene', '79623', (114, 121))	('associated', 'Reg', (48, 58))	('neuroblastoma', 'Phenotype', 'HP:0003006', (96, 109))	('germline mutations', 'Var', (13, 31))	('hereditary neuroblastoma', 'Disease', 'MESH:D009447', (85, 109))	('GALNT14', 'Gene', (35, 42))	('hereditary neuroblastoma', 'Disease', (85, 109))
120771	28588705	The present study examined the association between the prognosis of patients with resected cholangiocarcinoma and the GALNT14 genotype.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('GALNT14', 'Gene', '79623', (118, 125))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('genotype', 'Var', (126, 134))	('patients', 'Species', '9606', (68, 76))	('cholangiocarcinoma', 'Disease', (91, 109))	('GALNT14', 'Gene', (118, 125))
120779	28588705	Associations between the GALNT14 rs9679162 genotypes and clinical factors were analyzed using univariate and multivariate linear regressions.	('GALNT14', 'Gene', '79623', (25, 32))	('rs9679162', 'Var', (33, 42))	('rs9679162', 'Mutation', 'rs9679162', (33, 42))	('GALNT14', 'Gene', (25, 32))
120792	28588705	Amongst all the clinicopathological parameters, two tumor characteristics, perineural invasion and lymph node metastasis, were determined to be independently associated with the GALNT14 genotype 'TT' (multivariate analysis, P=0.035 and P=0.005, respectively; Table III).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('perineural invasion', 'CPA', (75, 94))	('GALNT14', 'Gene', (178, 185))	('lymph node metastasis', 'CPA', (99, 120))	('GALNT14', 'Gene', '79623', (178, 185))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('genotype', 'Var', (186, 194))
120793	28588705	The percentage of perineural invasion was significantly higher in patients with the 'TT' genotype, compared with those with a 'non-TT' genotype (P=0.004; Fig.	('higher', 'PosReg', (56, 62))	("'TT'", 'Var', (84, 88))	('perineural invasion', 'CPA', (18, 37))	('patients', 'Species', '9606', (66, 74))
120794	28588705	Similarly, the frequency of lymph node metastasis was significantly higher in patients with the 'TT' genotype, compared with the 'non-TT' genotype (P=0.011; Fig.	('genotype', 'Var', (101, 109))	("'TT' genotype", 'Var', (96, 109))	('patients', 'Species', '9606', (78, 86))	('higher', 'PosReg', (68, 74))	('lymph node metastasis', 'CPA', (28, 49))
120846	19896103	MUC1 has been demonstrated to be a statistically significant risk factor for predicting poor survival outcome after surgery in mass-forming intrahepatic cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (153, 171))	('intrahepatic cholangiocarcinoma', 'Disease', (140, 171))	('rat', 'Species', '10116', (21, 24))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (140, 171))	('MUC1', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
120849	19896103	MUC2, which is primarily expressed in goblet cells of the normal small intestine and colon, has further been shown in intrahepatic papillary ductal neoplasms to be closely related to aberrant expression of the caudal-related homeodomain intestine-specific transcription factor CDX2 and to correlate with a more favorable prognosis.	('MUC2', 'Gene', (0, 4))	('colon', 'Disease', (85, 90))	('MUC2', 'Gene', '4583', (0, 4))	('intrahepatic papillary ductal neoplasms', 'Disease', (118, 157))	('CDX2', 'Gene', (277, 281))	('expression', 'MPA', (192, 202))	('intrahepatic papillary ductal neoplasms', 'Disease', 'MESH:D002291', (118, 157))	('aberrant', 'Var', (183, 191))	('CDX2', 'Gene', '1045', (277, 281))	('related', 'Reg', (172, 179))	('colon', 'Disease', 'MESH:D015179', (85, 90))	('neoplasms', 'Phenotype', 'HP:0002664', (148, 157))
120852	19896103	Interestingly, multivariate analysis has also demonstrated the Ki-67 index, a marker of cell proliferative activity, to be a significant independent risk factor for poor prognosis in intrahepatic cholangiocarcinoma.	('Ki-67', 'Var', (63, 68))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (183, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (196, 214))	('rat', 'Species', '10116', (53, 56))	('intrahepatic cholangiocarcinoma', 'Disease', (183, 214))	('rat', 'Species', '10116', (100, 103))
120855	19896103	Shibahara et al reported that patients with MUC4 and ErbB2 double-positive intrahepatic cholangiocarcinomas had a significantly worse outcome after surgical resection than those with MUC4 and ErbB2 double-negative tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('double-positive', 'Var', (59, 74))	('MUC4', 'Gene', '4585', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Disease', (214, 220))	('ErbB2', 'Gene', '2064', (192, 197))	('MUC4', 'Gene', (44, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('patients', 'Species', '9606', (30, 38))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('MUC4', 'Gene', '4585', (183, 187))	('ErbB2', 'Gene', (192, 197))	('MUC4', 'Gene', (183, 187))	('intrahepatic cholangiocarcinomas', 'Disease', (75, 107))	('ErbB2', 'Gene', '2064', (53, 58))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (75, 107))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('worse', 'NegReg', (128, 133))	('ErbB2', 'Gene', (53, 58))
120866	19896103	Among serum levels of carcinoembryonic antigen, CA19-9, MMP-7, and MMP-9, only serum MMP-7 was determined to be significantly higher in cholangiocarcinoma patients compared with patients diagnosed with benign biliary tract diseases.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (136, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('higher', 'PosReg', (126, 132))	('MMP-7', 'Gene', (85, 90))	('patients', 'Species', '9606', (178, 186))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (136, 154))	('patients', 'Species', '9606', (155, 163))	('CA19-9', 'Var', (48, 54))	('MMP-9', 'Gene', '4318', (67, 72))	('MMP-7', 'Gene', '4316', (85, 90))	('benign biliary tract diseases', 'Disease', (202, 231))	('biliary tract diseases', 'Phenotype', 'HP:0001080', (209, 231))	('MMP-7', 'Gene', (56, 61))	('MMP-9', 'Gene', (67, 72))	('cholangiocarcinoma', 'Disease', (136, 154))	('MMP-7', 'Gene', '4316', (56, 61))	('benign biliary tract diseases', 'Disease', 'MESH:D001660', (202, 231))
120872	19896103	In the presumably only reported study to date concerning CTGF in intrahepatic cholangiocarcinoma, Gardini et al demonstrated that patients with intrahepatic cholangiocarcinoma expressing high levels of CTGF had a better prognosis with less chance of tumor recurrence than low or negative expressers.	('CTGF', 'Gene', (202, 206))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (144, 175))	('intrahepatic cholangiocarcinoma', 'Disease', (144, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (65, 96))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (78, 96))	('rat', 'Species', '10116', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('intrahepatic cholangiocarcinoma', 'Disease', (65, 96))	('high levels', 'Var', (187, 198))	('patients', 'Species', '9606', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (157, 175))	('tumor', 'Disease', (250, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
120879	19896103	In vitro analysis further revealed the ability of transfected WISP1v to stimulate human HuCCT1 cholangiocarcinoma cell migration, which was dependent on activation of the p38 mitogen-activated protein kinase (MAPK) pathway.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (95, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('activation', 'PosReg', (153, 163))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (95, 113))	('WISP1', 'Gene', '8840', (62, 67))	('human', 'Species', '9606', (82, 87))	('p38 mitogen-activated protein kinase', 'Gene', (171, 207))	('WISP1', 'Gene', (62, 67))	('p38 mitogen-activated protein kinase', 'Gene', '1432', (171, 207))	('transfected', 'Var', (50, 61))	('rat', 'Species', '10116', (122, 125))	('stimulate', 'PosReg', (72, 81))	('cholangiocarcinoma', 'Disease', (95, 113))	('human', 'CPA', (82, 87))
120904	19896103	Multivariate analysis further revealed high alpha-SMA to be an independent prognostic factor for intrahepatic cholangiocarcinoma.	('high', 'Var', (39, 43))	('alpha-SMA', 'Protein', (44, 53))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (97, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('intrahepatic cholangiocarcinoma', 'Disease', (97, 128))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (110, 128))	('alpha-SMA', 'Chemical', '-', (44, 53))
120927	19896103	Survival analysis showed that intrahepatic cholangiocarcinoma patients with positive TSP-1 expression had a tendency for shorter survival than those negative for TSP-1; TSP-1 expression correlated with the desmoplastic response in the tumor.	('intrahepatic cholangiocarcinoma', 'Disease', (30, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (43, 61))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('TSP-1', 'Gene', '7057', (85, 90))	('desmoplastic', 'Disease', 'MESH:D018220', (206, 218))	('TSP-1', 'Gene', (169, 174))	('TSP-1', 'Gene', '7057', (162, 167))	('patients', 'Species', '9606', (62, 70))	('expression', 'Var', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('TSP-1', 'Gene', '7057', (169, 174))	('shorter', 'NegReg', (121, 128))	('desmoplastic', 'Disease', (206, 218))	('TSP-1', 'Gene', (85, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('TSP-1', 'Gene', (162, 167))	('tumor', 'Disease', (235, 240))	('positive', 'Var', (76, 84))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (30, 61))	('correlated with', 'Reg', (186, 201))
121047	33601338	Although abnormal miR-29b expression has been linked to tumorigenesis in several cancers, its role in cholangiocarcinoma remains largely unknown.	('expression', 'MPA', (26, 36))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (102, 120))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('linked to', 'Reg', (46, 55))	('miR-29b', 'Gene', '407024', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('tumor', 'Disease', (56, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (102, 120))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('abnormal', 'Var', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cholangiocarcinoma', 'Disease', (102, 120))	('miR-29b', 'Gene', (18, 25))
121055	33601338	DNMT3B silencing, in turn, led to increased CDKN2B expression.	('DNMT3B', 'Gene', '1789', (0, 6))	('CDKN2B', 'Gene', (44, 50))	('expression', 'MPA', (51, 61))	('CDKN2B', 'Gene', '1030', (44, 50))	('DNMT3B', 'Gene', (0, 6))	('increased', 'PosReg', (34, 43))	('silencing', 'Var', (7, 16))
121063	33601338	Abnormally expressed miRNAs have been broadly implicated in cholangiocarcinoma pathogenesis.	('cholangiocarcinoma', 'Disease', (60, 78))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (60, 78))	('implicated', 'Reg', (46, 56))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (60, 78))	('miRNAs', 'Protein', (21, 27))	('Abnormally expressed', 'Var', (0, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
121084	33601338	These findings suggest that miR-29b inhibits the proliferation of cholangiocarcinoma cells by upregulating CDKN2B expression through demethylation of its promoter.	('CDKN2B', 'Gene', '1030', (107, 113))	('miR-29b', 'Gene', '407024', (28, 35))	('demethylation', 'Var', (133, 146))	('upregulating', 'PosReg', (94, 106))	('cholangiocarcinoma', 'Disease', (66, 84))	('proliferation', 'CPA', (49, 62))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (66, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('inhibits', 'NegReg', (36, 44))	('miR-29b', 'Gene', (28, 35))	('expression', 'MPA', (114, 124))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (66, 84))	('CDKN2B', 'Gene', (107, 113))
121087	33601338	Subsequently, we verified through qRT-PCR and western blot assays that LV-miR-29b transfection decreased both mRNA and protein levels of DNMT3B in QBC939 cells (Figure 3E and 3F).	('decreased', 'NegReg', (95, 104))	('transfection', 'Var', (82, 94))	('miR-29b', 'Gene', (74, 81))	('QBC939', 'CellLine', 'CVCL:6942', (147, 153))	('DNMT3B', 'Gene', (137, 143))	('DNMT3B', 'Gene', '1789', (137, 143))	('miR-29b', 'Gene', '407024', (74, 81))
121095	33601338	Through MSP analysis, a decrease in CDKN2B promoter methylation was detected after short hairpin RNA-mediated DNMT3B knockdown (Figure 4H).	('DNMT3B', 'Gene', (110, 116))	('DNMT3B', 'Gene', '1789', (110, 116))	('CDKN2B', 'Gene', (36, 42))	('decrease', 'NegReg', (24, 32))	('CDKN2B', 'Gene', '1030', (36, 42))	('promoter methylation', 'MPA', (43, 63))	('knockdown', 'Var', (117, 126))
121096	33601338	Accordingly, DNMT3B silencing led to increased expression of CDKN2B mRNA and protein (Figure 4K and 4L).	('mRNA and', 'MPA', (68, 76))	('CDKN2B', 'Gene', (61, 67))	('CDKN2B', 'Gene', '1030', (61, 67))	('increased', 'PosReg', (37, 46))	('DNMT3B', 'Gene', (13, 19))	('DNMT3B', 'Gene', '1789', (13, 19))	('silencing', 'Var', (20, 29))	('expression', 'MPA', (47, 57))
121113	33601338	Accordingly, aberrant or accidental methylation of the promoter of tumor-related genes has been observed in a wide variety of malignancies.	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('malignancies', 'Disease', (126, 138))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('observed', 'Reg', (96, 104))	('methylation', 'Var', (36, 47))	('aberrant', 'Var', (13, 21))
121151	33601338	Wild type (WT) and mutant (Mut) DNMT3B 3'UTRs containing the predicted miR-29b target sites were synthesized by GenePharma and then cloned into pmirGLO vectors (Promega, USA).	('miR-29b', 'Gene', (71, 78))	('DNMT3B', 'Gene', (32, 38))	('DNMT3B', 'Gene', '1789', (32, 38))	('mutant', 'Var', (19, 25))	('miR-29b', 'Gene', '407024', (71, 78))
121166	33173343	Cell experiments showed that inhibiting TUG1 expression or up-regulating miR-29a expression could inhibit cholangiocarcinoma cells from proliferation and invasion, and promote their apoptosis, while up-regulating TUG1 or inhibiting miR-29a could promote the proliferation and invasion but inhibit the apoptosis.	('apoptosis', 'CPA', (301, 310))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (106, 124))	('promote', 'PosReg', (168, 175))	('apoptosis', 'CPA', (182, 191))	('miR-29a', 'Gene', (232, 239))	('miR-29a', 'Gene', '407021', (232, 239))	('cholangiocarcinoma', 'Disease', (106, 124))	('expression', 'MPA', (81, 91))	('promote', 'PosReg', (246, 253))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (106, 124))	('miR-29a', 'Gene', (73, 80))	('miR-29a', 'Gene', '407021', (73, 80))	('invasion', 'CPA', (154, 162))	('inhibiting', 'Var', (29, 39))	('up-regulating', 'PosReg', (199, 212))	('proliferation', 'CPA', (258, 271))	('TUG1', 'Gene', (40, 44))	('inhibit', 'NegReg', (289, 296))	('expression', 'Protein', (45, 55))	('invasion', 'CPA', (276, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('inhibit', 'NegReg', (98, 105))	('up-regulating', 'PosReg', (59, 72))
121167	33173343	Rescue experiment showed that overexpressing miR-29a could reverse the effects of high TUG1 expression on cholangiocarcinoma cells.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (106, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('TUG1', 'Gene', (87, 91))	('miR-29a', 'Gene', (45, 52))	('miR-29a', 'Gene', '407021', (45, 52))	('high', 'Var', (82, 86))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (106, 124))	('cholangiocarcinoma', 'Disease', (106, 124))
121217	33173343	Moreover, TUG1 expression in QBC939 and HuH28 cells was higher than that in other cholangiocarcinoma cells, so the two cells were selected for follow-up experiments.	('HuH28', 'CellLine', 'CVCL:2955', (40, 45))	('QBC939', 'Var', (29, 35))	('TUG1', 'Gene', (10, 14))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (82, 100))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (82, 100))	('expression', 'MPA', (15, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('higher', 'PosReg', (56, 62))	('cholangiocarcinoma', 'Disease', (82, 100))
121221	33173343	According to the detection of cell biological behaviors, compared with those in the Si-NC group, cell proliferation and invasion remarkably reduced, the apoptotic rate remarkably increased, and Bax and Caspase-3 expression remarkably increased, as well as Bcl-2 expression remarkably decreased in the Si-TUG1 group (P<0.05);.Compared with the pcDNA3.1 group, the proliferation and invasion remarkably increased, the apoptotic rate remarkably decreased, and Bax and Caspase-3 expression remarkably decreased, as well as Bcl-2 expression remarkably increased in the pcDNA3.1 TUG1 group (P<0.05).	('Caspase-3', 'Gene', (202, 211))	('Bax', 'Gene', (194, 197))	('Bax', 'Gene', '581', (457, 460))	('proliferation', 'CPA', (363, 376))	('Bax', 'Gene', '581', (194, 197))	('increased', 'PosReg', (401, 410))	('Caspase-3', 'Gene', '836', (465, 474))	('expression', 'MPA', (525, 535))	('apoptotic rate', 'CPA', (416, 430))	('Bcl-2', 'Gene', (519, 524))	('Caspase-3', 'Gene', '836', (202, 211))	('invasion', 'CPA', (381, 389))	('pcDNA3.1', 'Var', (564, 572))	('expression', 'MPA', (475, 485))	('Caspase-3', 'Gene', (465, 474))	('decreased', 'NegReg', (442, 451))	('Bcl-2', 'Gene', (256, 261))	('decreased', 'NegReg', (497, 506))	('increased', 'PosReg', (547, 556))	('Bcl-2', 'Gene', '596', (519, 524))	('Bcl-2', 'Gene', '596', (256, 261))	('Bax', 'Gene', (457, 460))
121228	33173343	For further confirming that TUG1 affects cholangiocarcinoma cells by regulating miR-29a, we co-transfected pcDNA3.1 TUG1 and miR-29a-mimics or si-TUG1 and miR-29a-inhibitor into QBC939 and HuH28 cells.	('cholangiocarcinoma', 'Disease', (41, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('si-TUG1', 'Var', (143, 150))	('miR-29a', 'Gene', (155, 162))	('miR-29a', 'Gene', '407021', (155, 162))	('HuH28', 'CellLine', 'CVCL:2955', (189, 194))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (41, 59))	('miR-29a', 'Gene', '407021', (80, 87))	('miR-29a', 'Gene', (125, 132))	('miR-29a', 'Gene', '407021', (125, 132))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (41, 59))	('miR-29a', 'Gene', (80, 87))
121253	33173343	Subsequent co-transfection experiment showed that overexpressing miR-29a could reverse the effects of high TUG1 expression on cholangiocarcinoma cells.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (126, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('high', 'Var', (102, 106))	('miR-29a', 'Gene', (65, 72))	('miR-29a', 'Gene', '407021', (65, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (126, 144))	('cholangiocarcinoma', 'Disease', (126, 144))
121261	32906832	Conversely, when we deleted C/EBPdelta in pancreatic cancer cells, we observed accelerated growth.	('pancreatic cancer', 'Disease', (42, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (42, 59))	('growth', 'MPA', (91, 97))	('deleted', 'Var', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (42, 59))	('C/EBPdelta', 'Gene', '1052', (28, 38))	('accelerated', 'PosReg', (79, 90))	('C/EBPdelta', 'Gene', (28, 38))
121262	32906832	We suggest that reactivating C/EBPdelta can suppress tumor growth and formation of metastases, thereby improving patient survival.	('patient', 'Species', '9606', (113, 120))	('C/EBPdelta', 'Gene', '1052', (29, 39))	('metastases', 'Disease', (83, 93))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('C/EBPdelta', 'Gene', (29, 39))	('metastases', 'Disease', 'MESH:D009362', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('suppress', 'NegReg', (44, 52))	('reactivating', 'Var', (16, 28))	('tumor', 'Disease', (53, 58))	('improving', 'PosReg', (103, 112))
121268	32906832	Furthermore, loss of C/EBPdelta correlated with increased lymph node involvement and shorter overall survival in pancreatic ductal adenocarcinoma patients.	('shorter', 'NegReg', (85, 92))	('increased', 'PosReg', (48, 57))	('increased lymph node involvement', 'Phenotype', 'HP:0002716', (48, 80))	('overall', 'MPA', (93, 100))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (113, 145))	('men', 'Species', '9606', (76, 79))	('pancreatic ductal adenocarcinoma', 'Disease', (113, 145))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (113, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('C/EBPdelta', 'Gene', '1052', (21, 31))	('lymph node involvement', 'CPA', (58, 80))	('loss', 'Var', (13, 17))	('patients', 'Species', '9606', (146, 154))	('C/EBPdelta', 'Gene', (21, 31))
121286	32906832	Mutations in genes such as TP53, SMAD4, PTEN, and CDKN2A are present in over 70% of pancreatic ductal adenocarcinomas, and mutations in these tumor suppressors are well known to drive tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('drive', 'Reg', (178, 183))	('SMAD4', 'Gene', '4089', (33, 38))	('TP53', 'Gene', (27, 31))	('CDKN2A', 'Gene', (50, 56))	('tumor', 'Disease', (184, 189))	('Mutations', 'Var', (0, 9))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (84, 117))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('PTEN', 'Gene', (40, 44))	('tumor', 'Disease', (142, 147))	('CDKN2A', 'Gene', '1029', (50, 56))	('pancreatic ductal adenocarcinomas', 'Disease', (84, 117))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('TP53', 'Gene', '7157', (27, 31))	('present', 'Reg', (61, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('SMAD4', 'Gene', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('PTEN', 'Gene', '5728', (40, 44))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (84, 116))	('mutations', 'Var', (123, 132))
121287	32906832	As opposed to their clear biological relevance, mutations in tumor suppressor genes typically are of limited therapeutic value.	('mutations', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (61, 66))
121335	32906832	Similar to the 100 cells per well approach, CEBPD over-expression decreased the clonogenic capacity of PANC-1 cells.	('over-expression', 'Var', (50, 65))	('CEBPD', 'Gene', '1052', (44, 49))	('decreased', 'NegReg', (66, 75))	('clonogenic capacity of PANC-1 cells', 'CPA', (80, 115))	('PANC-1', 'CellLine', 'CVCL:0480', (103, 109))	('CEBPD', 'Gene', (44, 49))
121354	32906832	Considering the finding that over-expressing C/EBPdelta reduces the proliferation of pancreatic ductal adenocarcinoma cells, thereby decreasing their malignant potential, we next asked whether silencing C/EBPdelta would conversely trigger proliferation.	('C/EBPdelta', 'Gene', (203, 213))	('C/EBPdelta', 'Gene', (45, 55))	('proliferation', 'CPA', (68, 81))	('over-expressing', 'PosReg', (29, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('pancreatic ductal adenocarcinoma', 'Disease', (85, 117))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (85, 117))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (85, 117))	('decreasing', 'NegReg', (133, 143))	('silencing', 'Var', (193, 202))	('reduces', 'NegReg', (56, 63))	('C/EBPdelta', 'Gene', '1052', (203, 213))	('C/EBPdelta', 'Gene', '1052', (45, 55))	('malignant potential', 'CPA', (150, 169))
121366	32906832	As C/EBPdelta induces growth arrest, it is tempting to speculate that the loss of C/EBPdelta conversely facilitates tumorigenesis.	('C/EBPdelta', 'Gene', (3, 13))	('growth arrest', 'Disease', (22, 35))	('growth arrest', 'Disease', 'MESH:D006323', (22, 35))	('facilitates', 'PosReg', (104, 115))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('C/EBPdelta', 'Gene', '1052', (82, 92))	('growth arrest', 'Phenotype', 'HP:0001510', (22, 35))	('loss', 'Var', (74, 78))	('C/EBPdelta', 'Gene', '1052', (3, 13))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('C/EBPdelta', 'Gene', (82, 92))	('tumor', 'Disease', (116, 121))
121373	32906832	Conversely, shRNA-dependent silencing of C/EBPdelta enhances proliferation in a dose-dependent manner strongly suggesting that C/EBPdelta expression levels negatively correlate with the proliferative capacity of pancreatic ductal adenocarcinoma cells.	('C/EBPdelta', 'Gene', (41, 51))	('C/EBPdelta', 'Gene', (127, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('C/EBPdelta', 'Gene', '1052', (127, 137))	('negatively', 'NegReg', (156, 166))	('pancreatic ductal adenocarcinoma', 'Disease', (212, 244))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (212, 244))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (212, 244))	('C/EBPdelta', 'Gene', '1052', (41, 51))	('proliferation', 'CPA', (61, 74))	('silencing', 'Var', (28, 37))	('enhances', 'PosReg', (52, 60))	('N', 'Chemical', 'MESH:D009584', (15, 16))	('proliferative capacity', 'CPA', (186, 208))
121374	32906832	Next to driving proliferation and clonogenicity of pancreatic ductal adenocarcinoma cells, loss of C/EBPdelta also seems to promote anchorage-independent growth.	('clonogenicity', 'CPA', (34, 47))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('C/EBPdelta', 'Gene', '1052', (99, 109))	('promote', 'PosReg', (124, 131))	('C/EBPdelta', 'Gene', (99, 109))	('loss', 'Var', (91, 95))	('pancreatic ductal adenocarcinoma', 'Disease', (51, 83))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (51, 83))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (51, 83))	('anchorage-independent growth', 'CPA', (132, 160))
121380	32906832	Irrespective of the actual mechanism, the reduced overall survival in pancreatic ductal adenocarcinoma patients with low C/EBPdelta levels might be directly linked to the increased lymph node metastases in these patients.	('metastases', 'Disease', 'MESH:D009362', (192, 202))	('low', 'Var', (117, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('reduced', 'NegReg', (42, 49))	('C/EBPdelta', 'Gene', (121, 131))	('patients', 'Species', '9606', (212, 220))	('overall', 'MPA', (50, 57))	('metastases', 'Disease', (192, 202))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (70, 102))	('patients', 'Species', '9606', (103, 111))	('pancreatic ductal adenocarcinoma', 'Disease', (70, 102))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (70, 102))	('increased', 'PosReg', (171, 180))	('C/EBPdelta', 'Gene', '1052', (121, 131))
121384	32906832	Indeed, genes such as TP53, SMAD4, PTEN, and CDKN2A are well-known tumor suppressors and mutations in these genes, which are present in over 70% of pancreatic ductal adenocarcinomas, drive tumor progression.	('mutations', 'Var', (89, 98))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('TP53', 'Gene', (22, 26))	('CDKN2A', 'Gene', '1029', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('SMAD4', 'Gene', (28, 33))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (148, 181))	('drive', 'Reg', (183, 188))	('pancreatic ductal adenocarcinomas', 'Disease', (148, 181))	('PTEN', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('TP53', 'Gene', '7157', (22, 26))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (148, 180))	('tumor', 'Disease', (189, 194))	('SMAD4', 'Gene', '4089', (28, 33))	('PTEN', 'Gene', '5728', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('CDKN2A', 'Gene', (45, 51))
121404	32906832	CEBPD expression levels were derived from two different datasets, i.e., GSE62452 (updated version of GSE28735 with an extra 16 tumor and control biopsies) and GSE16515.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('CEBPD', 'Gene', '1052', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('GSE16515', 'Var', (159, 167))	('CEBPD', 'Gene', (0, 5))
121435	32906832	For constitutive over-expression of C/EBPdelta, a third-generation lentiviral system using pHEF-1TIG-CEBPD-IRES-EGFP or pHEF-1TIG-IRES-EGFP, pMDLg/pRRE (Addgene #12251), pRSV-Rev (Addgene # 12253) and pMD2.G (Addgene #12259) was employed to stably transduce PANC-1 and MIA-PaCa-2 cells.	('Addgene # 12253', 'Var', (180, 195))	('over-expression', 'PosReg', (17, 32))	('C/EBPdelta', 'Gene', '1052', (36, 46))	('CEBPD', 'Gene', (101, 106))	('C/EBPdelta', 'Gene', (36, 46))	('CEBPD', 'Gene', '1052', (101, 106))	('Addgene #12259', 'Var', (209, 223))	('PANC-1', 'CellLine', 'CVCL:0480', (258, 264))	('MIA-PaCa-2', 'CellLine', 'CVCL:0428', (269, 279))	('pRSV', 'Species', '12205', (170, 174))
121469	32906832	We selected clones TRCN0000013695 (shCEBPD #1), TRCN0000013696 (shCEBPD #2), TRCN0000013693 (shCEBPD #3) and TRCN0000013694 (shCEBPD #4) against CEBPD and SHC004 against turboGFP as control.	('CEBPD', 'Gene', (95, 100))	('CEBPD', 'Gene', (127, 132))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('N', 'Chemical', 'MESH:D009584', (112, 113))	('CEBPD', 'Gene', (66, 71))	('CEBPD', 'Gene', '1052', (95, 100))	('CEBPD', 'Gene', (145, 150))	('CEBPD', 'Gene', '1052', (127, 132))	('CEBPD', 'Gene', (37, 42))	('CEBPD', 'Gene', '1052', (66, 71))	('TRCN0000013696', 'Var', (48, 62))	('TRCN0000013693', 'Var', (77, 91))	('CEBPD', 'Gene', '1052', (145, 150))	('N', 'Chemical', 'MESH:D009584', (51, 52))	('CEBPD', 'Gene', '1052', (37, 42))	('N', 'Chemical', 'MESH:D009584', (80, 81))
121472	32906832	740588.50, Macherey-Nagel GmbH and Co. KG, Duren, Germany) and incorporated in a 3rd generation lentivirus using pMDLg/pRRE (Addgene #12251), pRSV-Rev (Addgene # 12253) and pMD2.G (Addgene #12259).	('Addgene # 12253', 'Var', (152, 167))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('pRSV', 'Species', '12205', (142, 146))	('Addgene #12251', 'Var', (125, 139))
121486	32906832	; formal analysis, L.H., J.D., P.Y.H., K.C., J.J.T.H.R., M.P.G.D., Q.P., M.P.P., M.F.B.	('J.J.T.H', 'CellLine', 'CVCL:M891', (45, 52))	('J.J.T.H.R.', 'Var', (45, 55))	('Q.P.', 'Var', (67, 71))	('M.P.G.D.', 'Var', (57, 65))	('K.C.', 'Var', (39, 43))	('P.Y.H.', 'Var', (31, 37))	('M.P.P.', 'Var', (73, 79))
121488	32906832	; writing-review and editing, L.H., J.D., O.R.B., M.G.H.B., F.D., G.K.J.H., P.Y.H., K.C., J.J.T.H.R., M.P.G.D., Q.P., M.P.P., M.F.B.	('J.J.T.H', 'CellLine', 'CVCL:M891', (90, 97))	('Q.P.', 'Var', (112, 116))	('M.P.G.D.', 'Var', (102, 110))	('K.C.', 'Var', (84, 88))	('J.J.T.H.R.', 'Var', (90, 100))	('M.P.P.', 'Var', (118, 124))
121500	30583689	Consistent with this observation, treatment with rhinacanthin-C was associated with a decrease in the expression levels of FAK, p-FAK, MMP-2, and a decrease in the levels of p38-, JNK1/2- and ERK1/2-MAPK pathways as well as inhibiting NF-kappaB/p65 expression and translocation of NF-kappaB/p65 to the nucleus.	('NF-kappaB', 'Gene', '4790', (281, 290))	('p65', 'Gene', (291, 294))	('FAK', 'Gene', (123, 126))	('rhinacanthin-C', 'Var', (49, 63))	('JNK1/2', 'Gene', '5599;5601', (180, 186))	('p65', 'Gene', '5970', (245, 248))	('p38', 'Gene', '5594', (174, 177))	('MMP-2', 'Gene', (135, 140))	('decrease', 'NegReg', (86, 94))	('decrease', 'NegReg', (148, 156))	('expression levels', 'MPA', (102, 119))	('expression', 'MPA', (249, 259))	('rhinacanthin-C', 'Chemical', 'MESH:C515073', (49, 63))	('FAK', 'Gene', '5747', (123, 126))	('translocation', 'MPA', (264, 277))	('FAK', 'Gene', (130, 133))	('JNK1/2', 'Gene', (180, 186))	('p65', 'Gene', '5970', (291, 294))	('levels', 'MPA', (164, 170))	('NF-kappaB', 'Gene', (235, 244))	('FAK', 'Gene', '5747', (130, 133))	('inhibiting', 'NegReg', (224, 234))	('p38', 'Gene', (174, 177))	('NF-kappaB', 'Gene', '4790', (235, 244))	('p65', 'Gene', (245, 248))	('NF-kappaB', 'Gene', (281, 290))
121518	30583689	Therefore, inhibition of MAPK pathways might have the potential to inhibit proliferation, angiogenesis, invasion and metastasis of tumors.	('inhibit', 'NegReg', (67, 74))	('angiogenesis', 'CPA', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('MAPK pathways', 'Pathway', (25, 38))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('inhibition', 'Var', (11, 21))	('metastasis of tumors', 'Disease', 'MESH:D009362', (117, 137))	('invasion', 'CPA', (104, 112))	('proliferation', 'CPA', (75, 88))	('metastasis of tumors', 'Disease', (117, 137))
121543	30583689	After blocking with Tris-buffered saline containing 0.1% Tween-20 and 5% skimmed milk at 37oC for 1 h, the membranes were incubated at 4 oC overnight with primary antibodies against MMP-2, MMP-9, ERK1/2, phosphorylated ERK1/2, JNK, phosphorylated JNK, p38, phosphorylated p38, and NF-kappaB p65 or beta-actin or histone H1 and subsequently incubated with the appropriate secondary antibody (anti-mouse or anti-rabbit).	('JNK', 'Gene', '5599', (247, 250))	('MMP-9', 'Gene', (189, 194))	('NF-kappaB', 'Gene', '4790', (281, 290))	('p65', 'Gene', (291, 294))	('mouse', 'Species', '10090', (396, 401))	('rabbit', 'Species', '9986', (410, 416))	('p38', 'Gene', '5594', (252, 255))	('MMP-2', 'Gene', (182, 187))	('phosphorylated', 'Var', (257, 271))	('beta-actin', 'Gene', (298, 308))	('p65', 'Gene', '5970', (291, 294))	('phosphorylated', 'Var', (232, 246))	('p38', 'Gene', (272, 275))	('JNK', 'Gene', (227, 230))	('ERK1/2', 'Gene', (196, 202))	('histone H1', 'Protein', (312, 322))	('JNK', 'Gene', '5599', (227, 230))	('p38', 'Gene', (252, 255))	('NF-kappaB', 'Gene', (281, 290))	('beta-actin', 'Gene', '728378', (298, 308))	('p38', 'Gene', '5594', (272, 275))	('JNK', 'Gene', (247, 250))
121549	30583689	As shown in Figure 3B and 3C, rhinacanthin-C caused a significant delay in migration of KKU-M156 cells into the wound area compared with the DMSO-treated group, whereas the migration of Vero cells was only slightly affected (Figure 3A and 3C).	('DMSO', 'Chemical', 'MESH:D004121', (141, 145))	('delay', 'NegReg', (66, 71))	('migration', 'CPA', (75, 84))	('rhinacanthin-C', 'Var', (30, 44))	('rhinacanthin-C', 'Chemical', 'MESH:C515073', (30, 44))
121567	30583689	This is the first report showing that rhinacanthin-C can decrease cancer-cell invasion by suppressing the MAPK pathway and reducing expression of MMP-2 and uPA.	('MMP-2', 'Protein', (146, 151))	('decrease', 'NegReg', (57, 65))	('reducing', 'NegReg', (123, 131))	('uPA', 'Gene', (156, 159))	('rhinacanthin-C', 'Chemical', 'MESH:C515073', (38, 52))	('rhinacanthin-C', 'Var', (38, 52))	('uPA', 'Gene', '5328', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('suppressing', 'NegReg', (90, 101))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('expression', 'MPA', (132, 142))	('cancer', 'Disease', (66, 72))	('MAPK pathway', 'Pathway', (106, 118))
121571	30583689	Tyr397 phosphorylation through integrin-mediated cell adhesion to the extracellular matrix produces a binding site for different intracellular signaling molecules, such as the Src family kinases, phosphatidylinositol 3'-kinase, phospholipase C (PLC), growth factor receptor-bound protein 7, growth factor receptor-binding protein 2 (Grb2) and SOS to activate Ras/mitogen-activated protein kinase signaling (Mon et al., 2006; Ohta et al., 2007).	('Grb2', 'Gene', (333, 337))	('activate', 'PosReg', (350, 358))	('Tyr397', 'Chemical', '-', (0, 6))	('SOS', 'Disease', (343, 346))	('Ras/mitogen-activated', 'MPA', (359, 380))	('Tyr397 phosphorylation', 'Var', (0, 22))	('growth factor receptor-bound protein 7, growth factor receptor-binding protein 2', 'Gene', '2886', (251, 331))	('Grb2', 'Gene', '2885', (333, 337))	('phosphorylation', 'Var', (7, 22))	('SOS', 'Disease', 'MESH:D006504', (343, 346))
121582	30583689	We have also clearly shown that rhinacanthin-C significantly inhibits the expression of phospho-FAK, p38, phospho-p38, ERK1/2, phospho-ERK1/2, JNK1/2 and phospho-JNK1/2 that are all upstream of NF-kappaB, resulting in decreased activity and levels of MMP-2, MMP-9 and uPA.	('JNK1/2', 'Gene', '5599;5601', (143, 149))	('p38', 'Gene', (101, 104))	('rhinacanthin-C', 'Var', (32, 46))	('expression', 'MPA', (74, 84))	('p38', 'Gene', (114, 117))	('JNK1/2', 'Gene', (143, 149))	('FAK', 'Gene', (96, 99))	('rhinacanthin-C', 'Chemical', 'MESH:C515073', (32, 46))	('p38', 'Gene', '5594', (101, 104))	('uPA', 'Gene', (268, 271))	('ERK1/2', 'Gene', (119, 125))	('inhibits', 'NegReg', (61, 69))	('uPA', 'Gene', '5328', (268, 271))	('p38', 'Gene', '5594', (114, 117))	('FAK', 'Gene', '5747', (96, 99))	('JNK1/2', 'Gene', '5599;5601', (162, 168))	('activity', 'MPA', (228, 236))	('phospho-ERK1/2', 'Var', (127, 141))	('NF-kappaB', 'Gene', (194, 203))	('levels of MMP-2', 'MPA', (241, 256))	('NF-kappaB', 'Gene', '4790', (194, 203))	('decreased', 'NegReg', (218, 227))	('MMP-9', 'MPA', (258, 263))	('JNK1/2', 'Gene', (162, 168))
121589	30583689	Here, we have demonstrated for the first time that rhinacanthin-C exerts inhibitory effects on the migration and invasion properties of KKU-M156 cells in a dose-dependent manner, as well as inhibiting the activities of MMP-2 and uPA.	('inhibitory', 'NegReg', (73, 83))	('uPA', 'Gene', (229, 232))	('invasion properties', 'CPA', (113, 132))	('activities', 'CPA', (205, 215))	('MMP-2', 'CPA', (219, 224))	('rhinacanthin-C', 'Var', (51, 65))	('uPA', 'Gene', '5328', (229, 232))	('rhinacanthin-C', 'Chemical', 'MESH:C515073', (51, 65))	('migration', 'CPA', (99, 108))	('inhibiting', 'NegReg', (190, 200))
121717	28890310	Continued validation and modification of the calculator may improve performance for other outcomes and for other patient subgroups, especially those with malignancy and those undergoing higher risk operations.	('patient', 'Species', '9606', (113, 120))	('modification', 'Var', (25, 37))	('malignancy', 'Disease', 'MESH:D009369', (154, 164))	('performance', 'MPA', (68, 79))	('malignancy', 'Disease', (154, 164))	('improve', 'PosReg', (60, 67))
121719	20146264	IL-6 can increase expression of DNA methyltransferase 1 (DNMT-1) and epigenetically regulate the expression of several genes, including microRNAs (miRNAs).	('regulate', 'Reg', (84, 92))	('DNMT-1', 'Gene', (57, 63))	('increase', 'PosReg', (9, 17))	('miR', 'Gene', '220972', (147, 150))	('miR', 'Gene', (147, 150))	('IL-6', 'Gene', (0, 4))	('expression', 'MPA', (18, 28))	('DNA methyltransferase 1', 'Gene', (32, 55))	('epigenetically', 'Var', (69, 83))	('DNA methyltransferase 1', 'Gene', '1786', (32, 55))	('expression', 'MPA', (97, 107))
121731	20146264	Although DNMT-1 is considerably more active on hemimethylated DNA as compared with unmethylated substrate in vitro, it is active also in de novo methylation similar to other DNMTs.	('de novo methylation', 'MPA', (137, 156))	('DNMT', 'Gene', '1786', (9, 13))	('DNMT', 'Gene', (9, 13))	('hemimethylated', 'Var', (47, 61))	('active', 'MPA', (37, 43))	('DNMT', 'Gene', '1786', (174, 178))	('active', 'MPA', (122, 128))	('DNMT', 'Gene', (174, 178))	('more', 'PosReg', (32, 36))
121736	20146264	Several tumor suppressor genes such as Rassf1a and p16INK4 have been shown to be modulated by promoter hypermethylation in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (123, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('p16INK4', 'Gene', '1029', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('p16INK4', 'Gene', (51, 58))	('promoter hypermethylation', 'Var', (94, 119))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (123, 141))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (123, 141))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('Rassf1a', 'Gene', '11186', (39, 46))	('modulated', 'Reg', (81, 90))	('tumor', 'Disease', (8, 13))	('Rassf1a', 'Gene', (39, 46))
121754	20146264	A reporter construct with random mutations within the putative shared recognition sequence was also constructed (DNMT1-MUT).	('DNMT1', 'Gene', (113, 118))	('DNMT1', 'Gene', '1786', (113, 118))	('mutations', 'Var', (33, 42))
121774	20146264	Thus, we postulated that alterations in miRNA expression could represent a mechanism by which IL-6 induces DNMT-1 expression.	('alterations', 'Var', (25, 36))	('IL-6', 'Gene', (94, 98))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('induces', 'PosReg', (99, 106))	('DNMT-1', 'Gene', (107, 113))	('expression', 'MPA', (114, 124))
121779	20146264	Alterations in methylation have been implicated in several malignancies, including cholangiocarcinoma.	('implicated', 'Reg', (37, 47))	('cholangiocarcinoma', 'Disease', (83, 101))	('Alterations', 'Var', (0, 11))	('malignancies', 'Disease', 'MESH:D009369', (59, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('malignancies', 'Disease', (59, 71))	('methylation', 'MPA', (15, 26))
121803	20146264	Next, the studies were repeated with random mutations in the shared recognition sequence, which resulted in abolition of the reporter activation by miR-148a and miR-152 precursors.	('miR-152', 'Gene', '406943', (161, 168))	('miR-152', 'Gene', (161, 168))	('mutations', 'Var', (44, 53))	('miR-148a', 'Gene', '406940', (148, 156))	('reporter activation', 'MPA', (125, 144))	('miR-148a', 'Gene', (148, 156))	('abolition', 'NegReg', (108, 117))
121811	20146264	In contrast, Rassf1a and p16INK4a were significantly increased by 5-aza-CdR treatment, indicating that these genes might be regulated by DNMT-1 through promoter methylation mechanisms.	('Rassf1a', 'Gene', (13, 20))	('5-aza-CdR', 'Var', (66, 75))	('p16INK4a', 'Gene', (25, 33))	('increased', 'PosReg', (53, 62))	('Rassf1a', 'Gene', '11186', (13, 20))	('p16INK4a', 'Gene', '1029', (25, 33))
121824	20146264	We hypothesize that aberrant expression of miR-148a and miR-152 can inhibit tumor cell growth The role of aberrant methylation in the pathobiology of cholangiocarcinoma is becoming increasingly recognized, but remains poorly understood.	('miR-148a', 'Gene', (43, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (150, 168))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('inhibit', 'NegReg', (68, 75))	('aberrant expression', 'Var', (20, 39))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (150, 168))	('miR-152', 'Gene', '406943', (56, 63))	('miR-152', 'Gene', (56, 63))	('cholangiocarcinoma', 'Disease', (150, 168))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('miR-148a', 'Gene', '406940', (43, 51))
121825	20146264	Similar to observations from many other cancers, alterations in DNA methylation can modulate the expression of specific oncogenes and tumor suppressor genes involved in cholangiocarcinoma growth.	('DNA', 'Gene', (64, 67))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('alterations', 'Var', (49, 60))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (169, 187))	('cholangiocarcinoma growth', 'Disease', (169, 194))	('modulate', 'Reg', (84, 92))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('oncogenes', 'Gene', (120, 129))	('cancers', 'Disease', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (169, 194))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('expression', 'MPA', (97, 107))	('tumor', 'Disease', (134, 139))
121826	20146264	While the focus of most studies has been on the identification of gene transcripts that are regulated by methylation, the mechanisms by which methylation itself is regulated in tumor-specific circumstances has received less attention.	('methylation', 'Var', (105, 116))	('regulated', 'Reg', (92, 101))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))
121834	20146264	Hypermethylation at promoter CpG islands and inactivation of multiple tumor suppressor genes are common in cholangiocarcinoma, and contribute to tumor growth.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('inactivation', 'Var', (45, 57))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Disease', (70, 75))	('cholangiocarcinoma', 'Disease', (107, 125))	('tumor', 'Disease', (145, 150))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (107, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (107, 125))	('contribute', 'Reg', (131, 141))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
121837	20146264	Aberrant DNMT-1 expression has been detected in several tumors, including liver tumors, supporting a role for DNMT-1 in tumorigenesis.	('liver tumors', 'Disease', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('detected', 'Reg', (36, 44))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', (80, 86))	('DNMT-1', 'Gene', (9, 15))	('Aberrant', 'Var', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('liver tumors', 'Disease', 'MESH:D008113', (74, 86))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('liver tumors', 'Phenotype', 'HP:0002896', (74, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
121843	20146264	Rassf1a has been shown to be the most frequently (65%) hypermethylated tumor suppressor gene in cholangiocarcinoma compared to normal cholangiocytes and is silenced both in extrahepatic and intrahepatic bile ducts tumors.	('bile ducts tumors', 'Phenotype', 'HP:0030153', (203, 220))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('silenced', 'NegReg', (156, 164))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))	('Rassf1a', 'Gene', '11186', (0, 7))	('intrahepatic bile ducts tumors', 'Disease', (190, 220))	('Rassf1a', 'Gene', (0, 7))	('cholangiocarcinoma', 'Disease', (96, 114))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 114))	('tumor', 'Disease', (214, 219))	('tumor', 'Disease', (71, 76))	('hypermethylated', 'Var', (55, 70))	('intrahepatic bile ducts tumors', 'Phenotype', 'HP:0005209', (190, 220))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('intrahepatic bile ducts tumors', 'Disease', 'MESH:D002780', (190, 220))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))
121845	20146264	Inactivation of Rassf1a can thus enhance cellular proliferative capacity.	('cellular proliferative capacity', 'CPA', (41, 72))	('Rassf1a', 'Gene', '11186', (16, 23))	('enhance', 'PosReg', (33, 40))	('Rassf1a', 'Gene', (16, 23))	('Inactivation', 'Var', (0, 12))
121847	20146264	Inactivation of the p16INK4a gene is also a frequent event in human cholangiocarcinoma.	('human', 'Species', '9606', (62, 67))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (68, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (68, 86))	('p16INK4a', 'Gene', (20, 28))	('p16INK4a', 'Gene', '1029', (20, 28))	('Inactivation', 'Var', (0, 12))	('cholangiocarcinoma', 'Disease', (68, 86))
121939	19683206	They also summarise the clinical trial data on PDT for cholangiocarcinoma and conclude that current evidence suggests PDT improves the outcome of patients with this difficult disease, but that further studies are required.	('improves', 'PosReg', (122, 130))	('cholangiocarcinoma', 'Disease', (55, 73))	('outcome', 'MPA', (135, 142))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (55, 73))	('PDT', 'Var', (118, 121))	('patients', 'Species', '9606', (146, 154))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (55, 73))
121940	19683206	In this respect, a phase III trial (PHOTOSTENT-02) is underway in the UK (EudraCT number 2005-001173-96) which aims to determine whether PDT improves the survival and quality of life of patients with locally advanced or metastatic biliary tract cancer.	('PDT', 'Var', (137, 140))	('biliary tract cancer', 'Disease', (231, 251))	('survival', 'CPA', (154, 162))	('locally advanced', 'Disease', (200, 216))	('quality of life', 'CPA', (167, 182))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (231, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('biliary tract cancer', 'Disease', 'MESH:D001661', (231, 251))	('patients', 'Species', '9606', (186, 194))	('improves', 'PosReg', (141, 149))
121955	32416072	Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome.	('intrahepatic cholangiocarcinoma', 'Disease', (245, 276))	('cholangiocarcinoma', 'Disease', (258, 276))	('Isocitrate dehydrogenase 1', 'Gene', (157, 183))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (258, 276))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (51, 69))	('IDH1', 'Gene', '3417', (185, 189))	('cholangiocarcinoma', 'Disease', (51, 69))	('mutations', 'Var', (191, 200))	('IDH1', 'Gene', (14, 18))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (51, 69))	('cancer', 'Disease', (300, 306))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('IDH1', 'Gene', '3417', (14, 18))	('patients', 'Species', '9606', (231, 239))	('Isocitrate dehydrogenase 1', 'Gene', '3417', (157, 183))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (258, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (245, 276))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))	('IDH1', 'Gene', (185, 189))
121956	32416072	The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120):a small-molecule targeted inhibitor of mutated IDH1:in patients with previously treated IDH1-mutant cholangiocarcinoma.	('IDH1', 'Gene', (193, 197))	('mutated', 'Var', (144, 151))	('IDH1', 'Gene', (152, 156))	('ivosidenib', 'Chemical', 'MESH:C000627630', (85, 95))	('patients', 'Species', '9606', (160, 168))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (205, 223))	('IDH1', 'Gene', '3417', (152, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('IDH1', 'Gene', '3417', (193, 197))	('AG-120', 'Chemical', 'MESH:C000627630', (97, 103))	('cholangiocarcinoma', 'Disease', (205, 223))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (205, 223))
121966	32416072	Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated.	('ivosidenib', 'Chemical', 'MESH:C000627630', (58, 68))	('ivosidenib', 'Chemical', 'MESH:C000627630', (96, 106))	('ivosidenib', 'Var', (58, 68))	('Progression-free survival', 'CPA', (0, 25))	('improved', 'PosReg', (44, 52))
121967	32416072	This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma.	('IDH1', 'Gene', '3417', (79, 83))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('mutations', 'Var', (56, 65))	('IDH1', 'Gene', '3417', (51, 55))	('IDH1', 'Gene', (51, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('IDH1', 'Gene', (79, 83))	('cholangiocarcinoma', 'Disease', (91, 109))
121968	32416072	Isocitrate dehydrogenase 1 (IDH1) mutations are detected in approximately 13% (9%) of intrahepatic cholangiocarcinomas globally, with varying frequency.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('IDH1', 'Gene', '3417', (28, 32))	('detected', 'Reg', (48, 56))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (99, 117))	('Isocitrate dehydrogenase 1', 'Gene', '3417', (0, 26))	('Isocitrate dehydrogenase 1', 'Gene', (0, 26))	('intrahepatic cholangiocarcinomas', 'Disease', (86, 118))	('mutations', 'Var', (34, 43))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (86, 118))	('IDH1', 'Gene', (28, 32))
121969	32416072	Preclinical data show the role of IDH mutations in cholangio carcinoma pathogenesis through their effect on liver progenitor cell differentiation and proliferation.	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('cholangio carcinoma', 'Disease', 'MESH:D009369', (51, 70))	('cholangio carcinoma', 'Disease', (51, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('cholangio carcinoma', 'Phenotype', 'HP:0030153', (51, 70))	('mutations', 'Var', (38, 47))	('effect', 'Reg', (98, 104))	('liver progenitor cell differentiation', 'CPA', (108, 145))	('proliferation', 'CPA', (150, 163))
121976	32416072	IDH1 mutation status was confirmed centrally by next-generation sequencing on formalin-fixed, paraffin-embedded tumour tissue (from a banked tumour sample collected preferably within the last 3 years or a fresh tumour biopsy) by means of the Oncomine Focus Assay (Thermo Fisher Scientific, Waltham, MA, USA) in a Clinical Laboratory Improvement Amendments-certified laboratory (appendix p 5).	('tumour', 'Disease', 'MESH:D009369', (211, 217))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('tumour', 'Disease', (211, 217))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumour', 'Disease', (112, 118))	('formalin', 'Chemical', 'MESH:D005557', (78, 86))	('paraffin', 'Chemical', 'MESH:D010232', (94, 102))	('tumour', 'Disease', (141, 147))	('ment', 'Gene', (350, 354))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('ment', 'Gene', '54964', (350, 354))	('ment', 'Gene', (340, 344))	('ment', 'Gene', '54964', (340, 344))	('IDH1', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
122000	32416072	Blood samples were drawn before and after dosing to establish circulating plasma concentrations of ivosidenib and D-2-hydroxyglutarate (2-HG), an oncometabolite that accumulates as a result of IDH mutations.	('2-HG', 'Chemical', 'MESH:C019417', (136, 140))	('ivosidenib', 'Chemical', 'MESH:C000627630', (99, 109))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (114, 134))	('IDH', 'Gene', (193, 196))	('mutations', 'Var', (197, 206))	('IDH', 'Gene', '3417', (193, 196))
122023	32416072	Baseline demographic and disease characteristics were similar in the ivosidenib and placebo groups; among all 185 patients, R132C was the most prevalent IDH1 mutation (129 [70%]), 171 (92%) had metastatic disease, and 86 (46%) had received two previous lines of therapy (table 1).	('IDH1', 'Gene', (153, 157))	('IDH1', 'Gene', '3417', (153, 157))	('ivosidenib', 'Chemical', 'MESH:C000627630', (69, 79))	('R132C', 'Var', (124, 129))	('R132C', 'Mutation', 'rs121913499', (124, 129))	('patients', 'Species', '9606', (114, 122))	('metastatic disease', 'CPA', (194, 212))
122057	32416072	The decline from baseline at cycle 2 day 1 on the EORTC QLQ-C30 physical functioning subscale (higher score denoting better functioning) was significantly less for patients in the ivosidenib group (n=62; least squares mean -3 4 [SE 1 81]) than for patients in the placebo group (n=20; -13 1 [3 04]; difference 9 8 [95% CI 2 8-16 7]; p=0 0059; appendix pp 15, 24).	('physical functioning subscale', 'MPA', (64, 93))	('decline', 'NegReg', (4, 11))	('EORTC', 'MPA', (50, 55))	('patients', 'Species', '9606', (248, 256))	('ivosidenib', 'Chemical', 'MESH:C000627630', (180, 190))	('patients', 'Species', '9606', (164, 172))	('ivosidenib', 'Var', (180, 190))	('less', 'NegReg', (155, 159))
122062	32416072	This randomised, phase 3 study shows the clinical benefit of targeting mutant IDH1 in patients with advanced, IDH1-mutant cholangiocarcinoma.	('IDH1', 'Gene', '3417', (110, 114))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (122, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('IDH1', 'Gene', (78, 82))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (122, 140))	('mutant', 'Var', (71, 77))	('IDH1', 'Gene', '3417', (78, 82))	('IDH1', 'Gene', (110, 114))	('cholangiocarcinoma', 'Disease', (122, 140))	('patients', 'Species', '9606', (86, 94))
122066	32416072	The disease control rate associated with ivosidenib was primarily driven by stable disease, reflecting the mechanism of action of ivosidenib, which is specific to epigenetic modifications promoting cellular differentiation rather than a direct cytotoxic mechanism.	('ivosidenib', 'Chemical', 'MESH:C000627630', (41, 51))	('cellular differentiation', 'CPA', (198, 222))	('epigenetic modifications', 'Var', (163, 187))	('promoting', 'PosReg', (188, 197))	('stable disease', 'Disease', (76, 90))	('ivosidenib', 'Chemical', 'MESH:C000627630', (130, 140))
122076	32416072	Although median overall survival in patients receiving ivosidenib was longer than in those receiving placebo, the difference was not significant; this might be partly attributed to the effect of the placebo-ivosidenib crossover and the data not being mature at the time of primary analysis (42% of events).	('patients', 'Species', '9606', (36, 44))	('overall survival', 'MPA', (16, 32))	('ivosidenib', 'Chemical', 'MESH:C000627630', (55, 65))	('longer', 'PosReg', (70, 76))	('ivosidenib', 'Chemical', 'MESH:C000627630', (207, 217))	('ivosidenib', 'Var', (55, 65))
122086	32416072	We identified several reports describing mutations in the gene for the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) in approximately 20% of patients with intrahepatic cholangiocarcinoma.	('mutations', 'Var', (41, 50))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (173, 191))	('isocitrate dehydrogenase 1', 'Gene', '3417', (88, 114))	('isocitrate dehydrogenase 1', 'Gene', (88, 114))	('IDH1', 'Gene', (116, 120))	('IDH1', 'Gene', '3417', (116, 120))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (160, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('patients', 'Species', '9606', (146, 154))	('intrahepatic cholangiocarcinoma', 'Disease', (160, 191))
122088	32416072	Ivosidenib is a potent, oral inhibitor of mutated IDH1.	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))	('IDH1', 'Gene', '3417', (50, 54))	('IDH1', 'Gene', (50, 54))	('mutated', 'Var', (42, 49))
122094	32416072	This study of ivosidenib shows a benefit of targeting mutant IDH1 in patients with advanced, IDH1-mutant cholangiocarcinoma, and highlights the clinical relevance of tumour mutation profiling in the management of this rare cancer with poor outcomes.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('tumour', 'Disease', (166, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('patients', 'Species', '9606', (69, 77))	('cancer', 'Disease', (223, 229))	('ment', 'Gene', (205, 209))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (105, 123))	('benefit', 'PosReg', (33, 40))	('cholangiocarcinoma', 'Disease', (105, 123))	('IDH1', 'Gene', (93, 97))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (105, 123))	('ivosidenib', 'Chemical', 'MESH:C000627630', (14, 24))	('IDH1', 'Gene', (61, 65))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('mutant', 'Var', (54, 60))	('ment', 'Gene', '54964', (205, 209))	('IDH1', 'Gene', '3417', (93, 97))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('IDH1', 'Gene', '3417', (61, 65))
122101	32164621	In this 78 patient cohort, high TB was significantly associated with advanced tumor status (pT4: 50.0% vs 22.2%, p = 0.007, pN1/2: 70.8% vs 39.6%, p = 0.011, M1: 20.8% vs 1.9%) and higher histological grade (G3: 25.0% vs 5.7%, p = 0.014).	('pN1/2', 'Gene', (124, 129))	('TB', 'Chemical', '-', (32, 34))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('pN1/2', 'Gene', '5270;351', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('patient', 'Species', '9606', (11, 18))	('high TB', 'Var', (27, 34))	('tumor', 'Disease', (78, 83))
122102	32164621	Disease specific survival (DSS) in high TB was significantly inferior compared to that in low TB group (3-y DSS 14.5% vs 67.7%, p < 0.001).	('DSS', 'Gene', '5376', (108, 111))	('Disease specific survival', 'Gene', (0, 25))	('TB', 'Chemical', '-', (40, 42))	('inferior', 'NegReg', (61, 69))	('Disease specific survival', 'Gene', '5376', (0, 25))	('DSS', 'Gene', (27, 30))	('DSS', 'Gene', '5376', (27, 30))	('DSS', 'Gene', (108, 111))	('TB', 'Chemical', '-', (94, 96))	('high TB', 'Var', (35, 42))
122103	32164621	Interestingly, DSS in high TB showed similar to survival in unresected patients.	('DSS', 'Gene', (15, 18))	('DSS', 'Gene', '5376', (15, 18))	('patients', 'Species', '9606', (71, 79))	('high', 'Var', (22, 26))	('TB', 'Chemical', '-', (27, 29))
122104	32164621	In addition, high TB was also associated with advanced tumor status and poor prognosis in patients with neoadjuvant therapy.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('high', 'Var', (13, 17))	('tumor', 'Disease', (55, 60))	('TB', 'Chemical', '-', (18, 20))	('patients', 'Species', '9606', (90, 98))
122105	32164621	Multivariate analysis identified high TB as an independent poor prognostic factors for DSS (HR: 5.206, p = 0.001).	('DSS', 'Gene', (87, 90))	('high', 'Var', (33, 37))	('TB', 'Chemical', '-', (38, 40))	('DSS', 'Gene', '5376', (87, 90))
122106	32164621	This study demonstrated that high TB was strongly associated with advanced tumor status and poor prognosis in resected perihilar cholangiocarcinoma patients.	('high', 'Var', (29, 33))	('patients', 'Species', '9606', (148, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (129, 147))	('TB', 'Chemical', '-', (34, 36))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (129, 147))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('associated', 'Reg', (50, 60))	('tumor', 'Disease', (75, 80))	('cholangiocarcinoma', 'Disease', (129, 147))
122107	32164621	High TB can be a novel poor prognostic factor in resected perihilar cholangiocarcinoma regardless of neoadjuvant therapy.	('TB', 'Chemical', '-', (5, 7))	('cholangiocarcinoma regardless', 'Disease', 'MESH:D018281', (68, 97))	('High', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (68, 86))	('cholangiocarcinoma regardless', 'Disease', (68, 97))
122116	32164621	demonstrated that high TB grade was an independent adverse prognostic factor in 195 perihilar cholangiocarcinoma patients by multivariate analysis.	('TB', 'Chemical', '-', (23, 25))	('patients', 'Species', '9606', (113, 121))	('cholangiocarcinoma', 'Disease', (94, 112))	('high', 'Var', (18, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (94, 112))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (94, 112))
122123	32164621	In the field of rectal and esophageal carcinoma, where the use of neoadjuvant therapy is common, there are several reports showing the prognostic significance of high TB in patients who underwent neoajuvant therapy.	('TB', 'Chemical', '-', (167, 169))	('neoajuvant', 'Chemical', '-', (196, 206))	('esophageal carcinoma', 'Disease', (27, 47))	('patients', 'Species', '9606', (173, 181))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (27, 47))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (27, 47))	('rectal', 'Disease', (16, 22))	('high', 'Var', (162, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))
122124	32164621	These studies have reported the association between high TB and poor prognosis in patients underwent neoadjuvant therapy for esophageal carcinoma and rectal carcinoma.	('rectal carcinoma', 'Phenotype', 'HP:0100743', (150, 166))	('rectal carcinoma', 'Disease', (150, 166))	('patients', 'Species', '9606', (82, 90))	('esophageal carcinoma', 'Disease', (125, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('high', 'Var', (52, 56))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (125, 145))	('rectal carcinoma', 'Disease', 'MESH:D012004', (150, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (125, 145))	('TB', 'Chemical', '-', (57, 59))
122172	32164621	In terms of histologically factors, high TB patients had higher rates of tumor with grade G3 (25% vs. 5.6%, p = 0.013), pT4 (50.0% vs. 22.2%, p = 0.014), lymph node metastasis (70.8% vs. 38.9%, p = 0.009), and distant metastasis (20.8% vs. 1.9%, p = 0.004).	('high TB', 'Var', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('patients', 'Species', '9606', (44, 52))	('higher', 'PosReg', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('pT4', 'CPA', (120, 123))	('tumor', 'Disease', (73, 78))	('TB', 'Chemical', '-', (41, 43))	('lymph node metastasis', 'CPA', (154, 175))	('distant metastasis', 'CPA', (210, 228))
122177	32164621	Interestingly, DSS after initial treatment in high TB patients did not show statistical difference compared to that in 28 unresected patients having locally advanced tumor at our institution in the same period.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('DSS', 'Gene', (15, 18))	('men', 'Species', '9606', (38, 41))	('DSS', 'Gene', '5376', (15, 18))	('high TB', 'Var', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('patients', 'Species', '9606', (54, 62))	('patients', 'Species', '9606', (133, 141))	('tumor', 'Disease', (166, 171))	('TB', 'Chemical', '-', (51, 53))
122180	32164621	Among the patients with neoadjuvant therapy, high TB patients had a significantly higher rate of combined vascular resection (90.9% vs. 48.0%, p = 0.015) compared to low TB patients.	('TB', 'Chemical', '-', (50, 52))	('TB', 'Chemical', '-', (170, 172))	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (173, 181))	('combined vascular resection', 'CPA', (97, 124))	('patients', 'Species', '9606', (10, 18))	('high TB', 'Var', (45, 52))
122184	32164621	In the patients with neoadjuvant therapy, high TB patients had significantly poor survival as compared to low TB patients (p < 0.001 in DSS, p = 0.001 in RFS).	('TB', 'Chemical', '-', (47, 49))	('patients', 'Species', '9606', (50, 58))	('poor', 'NegReg', (77, 81))	('patients', 'Species', '9606', (113, 121))	('DSS', 'Gene', (136, 139))	('DSS', 'Gene', '5376', (136, 139))	('survival', 'MPA', (82, 90))	('TB', 'Chemical', '-', (110, 112))	('patients', 'Species', '9606', (7, 15))	('high TB', 'Var', (42, 49))
122187	32164621	As shown in Table 4, pre-operative CEA level (>= 5 ng/ml), histological grade G3, T4, N1/2, M1, LV invasion, non-curative resection, and High TB, were identified as poor prognostic factors for DSS by univariate analysis.	('CEA', 'Gene', (35, 38))	('High TB', 'Var', (137, 144))	('DSS', 'Gene', (193, 196))	('DSS', 'Gene', '5376', (193, 196))	('CEA', 'Gene', '5670', (35, 38))	('N1/2', 'Var', (86, 90))	('TB', 'Chemical', '-', (142, 144))
122191	32164621	Among four patient classifications, notably, DSS in only patients with high TB did not show significantly difference compared to DSS in 28 unresected patients.	('patient', 'Species', '9606', (150, 157))	('patient', 'Species', '9606', (57, 64))	('DSS', 'Gene', (129, 132))	('high TB', 'Var', (71, 78))	('patients', 'Species', '9606', (57, 65))	('DSS', 'Gene', '5376', (129, 132))	('patient', 'Species', '9606', (11, 18))	('patients', 'Species', '9606', (150, 158))	('DSS', 'Gene', (45, 48))	('TB', 'Chemical', '-', (76, 78))	('DSS', 'Gene', '5376', (45, 48))
122194	32164621	In all patients, high TB was significantly associated with advanced tumor status including rates of pT4, pN1/2, M1, and histological grade 3.	('tumor', 'Disease', (68, 73))	('pT4', 'Disease', (100, 103))	('TB', 'Chemical', '-', (22, 24))	('high TB', 'Var', (17, 24))	('pN1/2', 'Gene', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('pN1/2', 'Gene', '5270;351', (105, 110))	('associated', 'Reg', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('patients', 'Species', '9606', (7, 15))
122195	32164621	Survival in patients with high TB was significantly inferior than that in patients with low TB.	('patients', 'Species', '9606', (12, 20))	('high', 'Var', (26, 30))	('TB', 'Chemical', '-', (92, 94))	('Survival', 'MPA', (0, 8))	('patients', 'Species', '9606', (74, 82))	('TB', 'Chemical', '-', (31, 33))	('inferior', 'NegReg', (52, 60))
122196	32164621	By multivariate analysis, high TB was identified as one of independent poor prognostic factors for DSS among 4 factors including regional lymph node metastasis, LV invasion, and non-curative resection.	('DSS', 'Gene', '5376', (99, 102))	('DSS', 'Gene', (99, 102))	('TB', 'Chemical', '-', (31, 33))	('high', 'Var', (26, 30))
122198	32164621	In addition, the impact of high TB in patients with neoadjuvant therapy showed similar results, withhigh TB significantly associated with advanced tumor status and poor prognosis.	('associated', 'Reg', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('TB', 'Chemical', '-', (32, 34))	('TB', 'Chemical', '-', (105, 107))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('patients', 'Species', '9606', (38, 46))	('withhigh', 'Var', (96, 104))
122201	32164621	demonstrated high TB as an independent adverse prognostic factor in multivariate analysis, along with higher T stage, lymph node metastasis, and resected margin positive invasive carcinoma.	('invasive carcinoma', 'Disease', 'MESH:D009361', (170, 188))	('high', 'Var', (13, 17))	('invasive carcinoma', 'Disease', (170, 188))	('TB', 'Chemical', '-', (18, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))
122217	32164621	reported similar results to the current study: that the high TB grade was associated with poor histological differentiation, higher pT factor, regional lymph node metastasis, and a higher rate of residual invasive tumor in the resected margin.	('TB', 'Chemical', '-', (61, 63))	('pT factor', 'MPA', (132, 141))	('invasive tumor', 'Disease', 'MESH:D009361', (205, 219))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('poor histological differentiation', 'CPA', (90, 123))	('invasive tumor', 'Disease', (205, 219))	('higher', 'PosReg', (125, 131))	('regional lymph node metastasis', 'CPA', (143, 173))	('high', 'Var', (56, 60))
122223	32164621	There are several reports showing the significance of high TB in patients who underwent neoajuvant therapy for rectal and esophageal carcinoma.	('esophageal carcinoma', 'Disease', (122, 142))	('high', 'Var', (54, 58))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (122, 142))	('rectal', 'Disease', (111, 117))	('TB', 'Chemical', '-', (59, 61))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (122, 142))	('neoajuvant', 'Chemical', '-', (88, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('patients', 'Species', '9606', (65, 73))
122241	32164621	Our present study demonstrated that high TB at the invasive front of tumors in resected perihilar cholangiocarcinoma patients with or without neoadjuvant therapy, is strongly associated with advanced tumor status and poor prognosis, including DSS/RFS.	('DSS', 'Gene', (243, 246))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (98, 116))	('cholangiocarcinoma', 'Disease', (98, 116))	('patients', 'Species', '9606', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (98, 116))	('DSS', 'Gene', '5376', (243, 246))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', (200, 205))	('TB', 'Chemical', '-', (41, 43))	('high', 'Var', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('associated with', 'Reg', (175, 190))	('tumors', 'Disease', (69, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
122242	32164621	High TB could be a novel prognostic factor in resected perihilar cholangiocarcinoma even if patients received neoadjuvant therapy.	('High', 'Var', (0, 4))	('TB', 'Chemical', '-', (5, 7))	('cholangiocarcinoma', 'Disease', (65, 83))	('patients', 'Species', '9606', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (65, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))
122277	30979003	Figure 1 shows the in vitro growth inhibition of sensitive and resistant cells after GEM treatment; MT-CHC01R1.5 cells presented a remarkable resistance at high doses (until 10 muM) compared to the parental cell line.	('resistance', 'MPA', (142, 152))	('muM', 'Gene', '56925', (177, 180))	('GEM', 'Chemical', 'MESH:C056507', (85, 88))	('MT-CHC01R1.5', 'Var', (100, 112))	('MT-CHC01R1.5', 'CellLine', 'CVCL:4Z41', (100, 112))	('muM', 'Gene', (177, 180))
122284	30979003	The difference was highly appreciable in the colony formation assay (Figure 2B); indeed, the number of colonies with more than 10 cells was significantly different between the GEM sensitive and resistant clones (82.66 +- 6.42 for MT-CHC01 vs. 23.66 +- 1.5 for MT-CHC01R1.5; p = 0.0001).	('different', 'Reg', (154, 163))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (260, 268))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (230, 238))	('GEM', 'Chemical', 'MESH:C056507', (176, 179))	('MT-CHC01R1.5', 'CellLine', 'CVCL:4Z41', (260, 272))	('MT-CHC01', 'Var', (230, 238))
122286	30979003	As shown in Figure 3, a significant S phase expansion was observed in MT-CHC01R1.5 cells compared to MT-CHC01 parental cells after 24 h of culture (77.24% vs. 58.82% of cells, respectively, p < 0.001), reflecting the enhanced doubling time of resistant clone.	('MT-CHC01R1.5', 'Var', (70, 82))	('MT-CHC01R1.5', 'CellLine', 'CVCL:4Z41', (70, 82))	('enhanced', 'PosReg', (217, 225))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (70, 78))	('expansion', 'PosReg', (44, 53))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (101, 109))	('S phase', 'CPA', (36, 43))
122291	30979003	Indeed, after 3 weeks, tumors reached a volume ranging from 372 to 1242 mm3 in MT-CHC01 xenografts and from 282 to 1007 mm3 in MT-CHC01R1.5 xenografts.	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (127, 135))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('MT-CHC01R1.5', 'CellLine', 'CVCL:4Z41', (127, 139))	('MT-CHC01', 'Var', (79, 87))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
122292	30979003	Interestingly, at the fourth week, the growth curves clearly separated in favor of mice inoculated with GEM sensitive cells (p = 0.0001; mean volume 1477.9 +- 599.9 and 707.4 +- 376.4 mm3 for MT-CHC01 and MT-CHC01R1.5 xenografts, respectively).	('MT-CHC01R1.5', 'Var', (205, 217))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (192, 200))	('MT-CHC01R1.5', 'CellLine', 'CVCL:4Z41', (205, 217))	('GEM', 'Chemical', 'MESH:C056507', (104, 107))	('mice', 'Species', '10090', (83, 87))	('MT-CHC01', 'Var', (192, 200))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (205, 213))
122322	30979003	Biologically, the GEM resistant clone presented an increase in doubling time (25.3 vs. 49.1 h for MT-CHC01 and MT-CHC01R1.5, respectively) as already observed in other GEM-resistant models, including CCA.	('increase', 'PosReg', (51, 59))	('MT-CHC01R1.5', 'CellLine', 'CVCL:4Z41', (111, 123))	('doubling time', 'MPA', (63, 76))	('GEM', 'Chemical', 'MESH:C056507', (18, 21))	('CCA', 'Disease', (200, 203))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (111, 119))	('MT-CHC01', 'Var', (98, 106))	('GEM', 'Chemical', 'MESH:C056507', (168, 171))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (98, 106))
122324	30979003	Concordantly, a statistically significant decrease in the tumor growth of MT-CHC01R1.5 was observed after four weeks from the in vivo injection compared to the parental counterpart.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('MT-CHC01R1.5', 'Var', (74, 86))	('MT-CHC01R1.5', 'CellLine', 'CVCL:4Z41', (74, 86))	('decrease', 'NegReg', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
122335	30979003	Nab-paclitaxel was also FDA-approved in advanced breast cancer after failure of previous chemotherapy, and in combination with carboplatin in non-small cell lung cancer.	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('non-small cell lung cancer', 'Disease', (142, 168))	('carboplatin', 'Chemical', 'MESH:D016190', (127, 138))	('Nab-paclitaxel', 'Var', (0, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (142, 168))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (146, 168))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (142, 168))	('Nab', 'Chemical', '-', (0, 3))
122346	30979003	Taken together, these data suggest that MT-CHC01R1.5 cells were able to protect themselves from the drug's cytotoxic effects.	('MT-CHC01R1.5', 'Var', (40, 52))	('MT-CHC01R1.5', 'CellLine', 'CVCL:4Z41', (40, 52))	('cytotoxic', 'CPA', (107, 116))
122412	30979003	The following are available online at , Figure S1: ATP production of MT-CHC01 and MT-CHC01R1.5 cells, Figure S2: Volcano plot obtained with the deregulated genes in MT-CHC01R1.5 compared to MT-CHC01 parental cells.	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (82, 90))	('MT-CHC01R1.5', 'Gene', (165, 177))	('MT-CHC01R1.5', 'CellLine', 'CVCL:4Z41', (82, 94))	('deregulated genes', 'Var', (144, 161))	('ATP', 'Chemical', 'MESH:D000255', (51, 54))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (165, 173))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (69, 77))	('MT-CHC01R1.5', 'CellLine', 'CVCL:4Z41', (165, 177))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (190, 198))
122442	29360137	Biopsy-based tissue samples are common for diagnosis and tumor characterization, such as molecular profiling, but may not contain salient tumor components, and intratumoral heterogeneity of most cHCC-CCA can lead to incorrect diagnosis if a biopsy does not contain adequate tissue.	('CCA', 'Phenotype', 'HP:0030153', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (138, 143))	('lead to', 'Reg', (208, 215))	('HCC', 'Gene', (196, 199))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('HCC', 'Gene', '619501', (196, 199))	('CCA', 'Chemical', '-', (200, 203))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (57, 62))	('HCC', 'Phenotype', 'HP:0001402', (196, 199))	('heterogeneity', 'Var', (173, 186))	('tumor', 'Disease', (165, 170))
122487	29360137	Such results are in accord with previous data comparing loss of heterozygosity using 400 microsatellite markers, p53, and beta-catenin mutations in a series of 15 cHCC-CCAs with 9 iCCAs, and 137 HCCs, suggesting that cHCC-CCA were genetically closer to iCCA than to HCC.	('CCA', 'Phenotype', 'HP:0030153', (168, 171))	('HCC', 'Gene', (218, 221))	('CCA', 'Chemical', '-', (254, 257))	('beta-catenin', 'Gene', '1499', (122, 134))	('iCCA', 'Chemical', '-', (253, 257))	('p53', 'Gene', (113, 116))	('CCA', 'Chemical', '-', (222, 225))	('iCCA', 'Chemical', '-', (180, 184))	('CCA', 'Chemical', '-', (181, 184))	('mutations', 'Var', (135, 144))	('CCA', 'Phenotype', 'HP:0030153', (254, 257))	('HCC', 'Gene', '619501', (164, 167))	('HCC', 'Phenotype', 'HP:0001402', (164, 167))	('CCA', 'Phenotype', 'HP:0030153', (222, 225))	('HCC', 'Gene', (164, 167))	('HCC', 'Gene', '619501', (266, 269))	('CCA', 'Phenotype', 'HP:0030153', (181, 184))	('HCC', 'Phenotype', 'HP:0001402', (266, 269))	('HCC', 'Gene', '619501', (195, 198))	('HCC', 'Phenotype', 'HP:0001402', (195, 198))	('HCC', 'Gene', (266, 269))	('CCA', 'Chemical', '-', (168, 171))	('HCC', 'Gene', '619501', (218, 221))	('HCC', 'Gene', (195, 198))	('HCC', 'Phenotype', 'HP:0001402', (218, 221))	('p53', 'Gene', '7157', (113, 116))	('beta-catenin', 'Gene', (122, 134))
122492	29360137	In addition, mutations of KRAS and IDH genes were more frequent in the hepatitisnegative tumors, whereas the TERT promoter mutation was more frequent in cHCC-CCA and HCCs, which mainly developed in a background of chronic hepatitis.	('TERT', 'Gene', '7015', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('hepatitisnegative tumors', 'Disease', (71, 95))	('HCC', 'Gene', '619501', (166, 169))	('CCA', 'Phenotype', 'HP:0030153', (158, 161))	('HCC', 'Phenotype', 'HP:0001402', (166, 169))	('chronic hepatitis', 'Disease', 'MESH:D056487', (214, 231))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (214, 231))	('hepatitis', 'Phenotype', 'HP:0012115', (71, 80))	('hepatitis', 'Phenotype', 'HP:0012115', (222, 231))	('HCC', 'Gene', (166, 169))	('KRAS', 'Gene', '3845', (26, 30))	('frequent', 'Reg', (55, 63))	('hepatitisnegative tumors', 'Disease', 'MESH:D009369', (71, 95))	('chronic hepatitis', 'Disease', (214, 231))	('HCC', 'Gene', '619501', (154, 157))	('HCC', 'Phenotype', 'HP:0001402', (154, 157))	('TERT', 'Gene', (109, 113))	('KRAS', 'Gene', (26, 30))	('mutations', 'Var', (13, 22))	('frequent', 'Reg', (141, 149))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('HCC', 'Gene', (154, 157))	('IDH genes', 'Gene', (35, 44))	('CCA', 'Chemical', '-', (158, 161))
122495	29360137	Clonality is further supported by the demonstration of significant correlation in the copy number variation between iCCA and HCC components of the classical type of cHCC-CCA.	('HCC', 'Gene', '619501', (166, 169))	('iCCA', 'Disease', (116, 120))	('HCC', 'Gene', '619501', (125, 128))	('HCC', 'Phenotype', 'HP:0001402', (125, 128))	('HCC', 'Phenotype', 'HP:0001402', (166, 169))	('CCA', 'Chemical', '-', (117, 120))	('iCCA', 'Chemical', '-', (116, 120))	('CCA', 'Chemical', '-', (170, 173))	('CCA', 'Phenotype', 'HP:0030153', (117, 120))	('copy number variation', 'Var', (86, 107))	('HCC', 'Gene', (166, 169))	('CCA', 'Phenotype', 'HP:0030153', (170, 173))	('HCC', 'Gene', (125, 128))
122497	29360137	Whereas the worse prognosis for HCC with K19 positivity has been well demonstrated, there is good prognostic evidence from two recent Asian clinicopathological studies for CLC: One compared CLC to iCCA and another compared ciCCA-CLC to iCCA without CLC.	('CCA', 'Phenotype', 'HP:0030153', (198, 201))	('HCC', 'Gene', '619501', (32, 35))	('CCA', 'Phenotype', 'HP:0030153', (237, 240))	('HCC', 'Phenotype', 'HP:0001402', (32, 35))	('positivity', 'Var', (45, 55))	('K19', 'Gene', (41, 44))	('K19', 'Gene', '3880', (41, 44))	('CCA', 'Phenotype', 'HP:0030153', (225, 228))	('iCCA', 'Chemical', '-', (236, 240))	('iCCA', 'Chemical', '-', (197, 201))	('HCC', 'Gene', (32, 35))	('iCCA', 'Chemical', '-', (224, 228))
122528	29360137	Second, continued molecular profiling of well-defined cHCC-CCA needs to be performed; we need to know whether these tumors are associated with unique genetic signatures, genetic aberrations, or epigenetic markers.	('tumors', 'Disease', (116, 122))	('genetic aberrations', 'Disease', (170, 189))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('associated', 'Reg', (127, 137))	('CCA', 'Chemical', '-', (59, 62))	('epigenetic', 'Var', (194, 204))	('HCC', 'Phenotype', 'HP:0001402', (55, 58))	('HCC', 'Gene', (55, 58))	('CCA', 'Phenotype', 'HP:0030153', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('genetic aberrations', 'Disease', 'MESH:D030342', (170, 189))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('HCC', 'Gene', '619501', (55, 58))
122649	24679154	Alterations in tumor suppressor activity of p53 and Rb and overexpression of EGFR and ErbB2, MMP-2 and MMP-9 are characteristic for muscle invasive phenotypes (MIBC).	('MMP-9', 'Gene', '4318', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('Alterations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('MMP-9', 'Gene', (103, 108))	('MMP-2', 'Gene', (93, 98))	('MMP-2', 'Gene', '4313', (93, 98))	('muscle invasive phenotypes', 'Disease', (132, 158))	('ErbB2', 'Gene', (86, 91))	('p53', 'Gene', (44, 47))	('tumor', 'Disease', (15, 20))	('EGFR', 'Gene', '1956', (77, 81))	('overexpression', 'PosReg', (59, 73))	('p53', 'Gene', '7157', (44, 47))	('EGFR', 'Gene', (77, 81))	('ErbB2', 'Gene', '2064', (86, 91))	('MIBC', 'Chemical', '-', (160, 164))
122667	24679154	In this approach three fluorescent cyanine dyes (Cy2, Cy3, and Cy5) of identical charge, similar molecular mass and different fluorescent properties, are used to label the proteins before separation.	('proteins', 'Protein', (172, 180))	('Cy2', 'Var', (49, 52))	('Cy3', 'Chemical', '-', (54, 57))	('Cy5', 'Var', (63, 66))	('Cy2', 'Chemical', '-', (49, 52))	('Cy3', 'Var', (54, 57))	('Cy5', 'Chemical', 'MESH:C085321', (63, 66))	('cyanine', 'Chemical', 'MESH:C009469', (35, 42))
122691	24679154	designed an inter-laboratory study based on the quantification of 8 predefined peptides from S100A7, S100A8, S100A12, and IL1RN proteins.	('S100A7', 'Var', (93, 99))	('IL1RN', 'Gene', '3557', (122, 127))	('S100A12', 'Var', (109, 116))	('IL1RN', 'Gene', (122, 127))	('peptides', 'Chemical', 'MESH:D010455', (79, 87))	('S100A8', 'Var', (101, 107))
122720	24679154	In parallel, in vitro studies showed decreased EGF-induced migration in cofilin knock-down T24 cells.	('cofilin', 'Gene', '1072', (72, 79))	('EGF-induced', 'Protein', (47, 58))	('cofilin', 'Gene', (72, 79))	('knock-down', 'Var', (80, 90))	('decreased', 'NegReg', (37, 46))
122757	24679154	further evaluated the CKD273 peptide marker model for its diagnostic utility in a longitudinal study, where 316 urine samples were employed, including patients with diabetes type 1 and 2.	('diabetes type', 'Disease', 'MESH:D003922', (165, 178))	('CKD273', 'Var', (22, 28))	('diabetes type', 'Disease', (165, 178))	('patients', 'Species', '9606', (151, 159))
122845	20219134	In a further investigation, after applying alpha-2 adrenergic receptor agonist, uK14, they found that uK14 could inhibit the growth of CCA by stimulating tumor cells.	('growth', 'CPA', (125, 131))	('CCA', 'Disease', (135, 138))	('uK14', 'Var', (102, 106))	('inhibit', 'NegReg', (113, 120))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('CCA', 'Phenotype', 'HP:0030153', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('stimulating', 'PosReg', (142, 153))	('tumor', 'Disease', (154, 159))
122868	20219134	In fact, EGFR-activated Tyr-PK could facilitate DNA synthesis and cause cell proliferation and differentiation.	('Tyr', 'Chemical', 'MESH:D014443', (24, 27))	('Tyr-PK', 'Var', (24, 30))	('EGFR', 'Gene', '1956', (9, 13))	('cell proliferation', 'CPA', (72, 90))	('EGFR', 'Gene', (9, 13))	('facilitate', 'PosReg', (37, 47))	('differentiation', 'CPA', (95, 110))	('cause', 'Reg', (66, 71))	('DNA synthesis', 'MPA', (48, 61))
122879	32143356	Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components.	('proteins', 'Protein', (158, 166))	('Cholangiocarcinoma', 'Disease', (49, 67))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (49, 67))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (49, 67))	('mutated', 'Var', (150, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
122882	32143356	This review collects clinical evidence of autophagy deregulation during cholangiocarcinogenesis together with preclinical reports evaluating compounds that modulate autophagy to induce cholangiocarcinoma (CCA) cell death.	('cholangiocarcinoma', 'Disease', (185, 203))	('modulate', 'Var', (156, 164))	('cholangiocarcinogenesis', 'Disease', (72, 95))	('induce', 'PosReg', (178, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (185, 203))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (185, 203))	('clinical', 'Species', '191496', (113, 121))	('CCA', 'Phenotype', 'HP:0030153', (205, 208))	('cholangiocarcinogenesis', 'Disease', 'None', (72, 95))	('clinical', 'Species', '191496', (21, 29))
122884	32143356	Preclinical efficacy of autophagy modulators promoting CCA cell death, reducing invasiveness capacity and resensitizing CCA cells to chemotherapy open novel therapeutic avenues to design more specific and efficient strategies to treat this aggressive cancer.	('reducing', 'NegReg', (71, 79))	('promoting', 'PosReg', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('CCA', 'Phenotype', 'HP:0030153', (120, 123))	('CCA', 'Phenotype', 'HP:0030153', (55, 58))	('modulators', 'Var', (34, 44))	('invasiveness capacity', 'CPA', (80, 101))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('rat', 'Species', '10116', (217, 220))	('cancer', 'Disease', (251, 257))	('CCA', 'Disease', (55, 58))	('clinical', 'Species', '191496', (3, 11))
122916	32143356	HOPS is a conserved protein complex consisting of vacuolar protein sorting 11 (Vps11), Vps16, Vps18, Vps33, Vps39 and Vps41 and mediates autophagosome-lysosome fusion through interaction with SNARE syntaxin 17.	('autophagosome-lysosome fusion', 'CPA', (137, 166))	('interaction', 'Interaction', (175, 186))	('HOPS', 'Gene', (0, 4))	('vacuolar protein sorting 11', 'Gene', '55823', (50, 77))	('mediates', 'Reg', (128, 136))	('Vps41', 'Gene', '27072', (118, 123))	('vacuolar protein sorting 11', 'Gene', (50, 77))	('Vps11', 'Gene', (79, 84))	('Vps18', 'Gene', '57617', (94, 99))	('Vps39', 'Gene', '23339', (108, 113))	('Vps39', 'Gene', (108, 113))	('Vps11', 'Gene', '55823', (79, 84))	('Vps41', 'Gene', (118, 123))	('Vps33', 'Var', (101, 106))	('Vps18', 'Gene', (94, 99))	('Vps16', 'Gene', (87, 92))	('Vps16', 'Gene', '64601', (87, 92))
122925	32143356	In addition, monoallelic deletions of Beclin1 gene have been described in 40-75% of human cancers of the breast, ovary and prostate.	('ovary', 'Disease', (113, 118))	('cancers', 'Disease', (90, 97))	('breast', 'Disease', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Beclin1', 'Gene', (38, 45))	('prostate', 'Disease', (123, 131))	('cancers of the breast', 'Phenotype', 'HP:0100013', (90, 111))	('human', 'Species', '9606', (84, 89))	('described', 'Reg', (61, 70))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('monoallelic deletions', 'Var', (13, 34))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
122926	32143356	Consonant with these results, silencing of ATG5 results in the accumulation of p62 protein aggregates, defective mitochondria and poorly folded proteins, events that induce ROS (reactive oxygen species) production.	('defective', 'MPA', (103, 112))	('p62', 'Gene', '8878', (79, 82))	('accumulation', 'PosReg', (63, 75))	('p62', 'Gene', (79, 82))	('ATG5', 'Gene', '9474', (43, 47))	('ROS', 'Chemical', 'MESH:D017382', (173, 176))	('induce', 'Reg', (166, 172))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (178, 201))	('silencing', 'Var', (30, 39))	('ATG5', 'Gene', (43, 47))
122931	32143356	Oncogenic mutations in RAS are found in about 30% of human cancers and are tumors with high proliferative and metastatic potential.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('rat', 'Species', '10116', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('human', 'Species', '9606', (53, 58))	('mutations', 'Var', (10, 19))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('RAS', 'Gene', (23, 26))	('cancers', 'Disease', (59, 66))	('tumors', 'Disease', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))
122938	32143356	The identification of genetic and epigenetic alterations and the increased knowledge about the molecular pathophysiological mechanisms governing cholangiocarcinogenesis and tumor recurrence, resistance and metastasis have allowed the development of more specific therapies, although clinical results evaluating specific molecular agents demonstrate no or only very modest survival benefits of the agents tested.	('rat', 'Species', '10116', (344, 347))	('genetic', 'Var', (22, 29))	('cholangiocarcinogenesis and tumor', 'Disease', 'MESH:D009369', (145, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('clinical', 'Species', '191496', (283, 291))	('epigenetic alterations', 'Var', (34, 56))	('rat', 'Species', '10116', (49, 52))
122953	32143356	In a small study on 54 clinical samples of iCCA, 7.4% of cases were KRAS mutated and associated with higher tumor stage and worse long-term overall survival, as well as a greater likelihood of lymph node involvement.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('mutated', 'Var', (73, 80))	('higher', 'PosReg', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('lymph node involvement', 'CPA', (193, 215))	('tumor', 'Disease', (108, 113))	('KRAS', 'Gene', (68, 72))	('worse', 'NegReg', (124, 129))	('clinical samples', 'Species', '191496', (23, 39))	('CCA', 'Phenotype', 'HP:0030153', (44, 47))
122954	32143356	Moreover, in a murine model of iCCA development harboring KRAS mutation and p53 inactivation, two of the most common genetic alterations in CCA, KRAS mutation collaborates with p53 deletion to cause hepatic transformation and reduced survival.	('hepatic', 'MPA', (199, 206))	('cause', 'Reg', (193, 198))	('rat', 'Species', '10116', (166, 169))	('KRAS', 'Gene', (145, 149))	('survival', 'CPA', (234, 242))	('mutation', 'Var', (150, 158))	('p53', 'Gene', (177, 180))	('rat', 'Species', '10116', (129, 132))	('murine', 'Species', '10090', (15, 21))	('CCA', 'Phenotype', 'HP:0030153', (140, 143))	('CCA', 'Phenotype', 'HP:0030153', (32, 35))	('deletion', 'Var', (181, 189))	('reduced', 'NegReg', (226, 233))
122957	32143356	This data correlates with human iCCA cell lines mutated in KRAS and with p53 deficiency, which show elevated autophagy compared with normal iCCA cells, and CQ also inhibited the growth of these cells, similar to the situation described for pancreatic and lung cancers.	('growth', 'CPA', (178, 184))	('deficiency', 'Var', (77, 87))	('p53', 'Gene', (73, 76))	('autophagy', 'CPA', (109, 118))	('cancers', 'Phenotype', 'HP:0002664', (260, 267))	('lung cancer', 'Phenotype', 'HP:0100526', (255, 266))	('pancreatic and lung cancers', 'Disease', 'MESH:D008175', (240, 267))	('inhibited', 'NegReg', (164, 173))	('CCA', 'Phenotype', 'HP:0030153', (141, 144))	('CQ', 'Chemical', 'MESH:D002738', (156, 158))	('lung cancers', 'Phenotype', 'HP:0100526', (255, 267))	('elevated', 'PosReg', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('human', 'Species', '9606', (26, 31))	('CCA', 'Phenotype', 'HP:0030153', (33, 36))
122959	32143356	Alterations in c-MET, the overactivation of which leads to activation of MAPK, PI3K/Akt and STAT pathways, correlates with high grade, invasiveness and poor prognosis in CCA, and its inhibition promoted autophagy in lung cancer cells, further linking c-MET-mediated autophagy inhibition in carcinogenesis.	('overactivation', 'PosReg', (26, 40))	('MAPK', 'Pathway', (73, 77))	('inhibition', 'NegReg', (183, 193))	('Alterations', 'Var', (0, 11))	('CCA', 'Disease', (170, 173))	('c-MET', 'Gene', '4233', (15, 20))	('activation', 'PosReg', (59, 69))	('lung cancer', 'Disease', 'MESH:D008175', (216, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('carcinogenesis', 'Disease', (290, 304))	('Akt', 'Gene', (84, 87))	('c-MET', 'Gene', (15, 20))	('autophagy', 'CPA', (203, 212))	('Akt', 'Gene', '207', (84, 87))	('carcinogenesis', 'Disease', 'MESH:D063646', (290, 304))	('c-MET', 'Gene', '4233', (251, 256))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('rat', 'Species', '10116', (4, 7))	('c-MET', 'Gene', (251, 256))	('promoted', 'PosReg', (194, 202))	('STAT', 'Gene', '6774', (92, 96))	('lung cancer', 'Disease', (216, 227))	('STAT', 'Gene', (92, 96))	('CCA', 'Phenotype', 'HP:0030153', (170, 173))
122960	32143356	The gain of function mutation in ERBB2 and EGFR genes correlates with malignancy in human cholangiocytes, cancer progression and poor survival, and treatment with tyrosine kinase inhibitors induced protective autophagy in different cancer types, suggesting that the combination with autophagy inhibitors could increase the efficacy of these compounds.	('ERBB2', 'Gene', '2064', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('malignancy', 'Disease', 'MESH:D009369', (70, 80))	('cancer', 'Disease', (232, 238))	('malignancy', 'Disease', (70, 80))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('mutation', 'Var', (21, 29))	('gain of function', 'PosReg', (4, 20))	('EGFR', 'Gene', '1956', (43, 47))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('human', 'Species', '9606', (84, 89))	('EGFR', 'Gene', (43, 47))	('ERBB2', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
122961	32143356	Similarly, FGFR2 fusion genes that result in altered cell morphology and increased cell proliferation have been described in CCA.	('fusion genes', 'Var', (17, 29))	('altered', 'Reg', (45, 52))	('increased', 'PosReg', (73, 82))	('CCA', 'Disease', (125, 128))	('FGFR2', 'Gene', '2263', (11, 16))	('rat', 'Species', '10116', (95, 98))	('cell proliferation', 'CPA', (83, 101))	('CCA', 'Phenotype', 'HP:0030153', (125, 128))	('cell morphology', 'CPA', (53, 68))	('FGFR2', 'Gene', (11, 16))
122962	32143356	It has been shown that FGFR alterations suppress autophagy, which could be associated with initial steps of carcinogenesis, and genetic or pharmacological FGFR inhibition in vitro induces protective autophagy in lung and breast cancer; therefore, inhibition of autophagy increases anticancer efficacy of FGFR inhibitors in these cells.	('rat', 'Species', '10116', (32, 35))	('autophagy', 'CPA', (49, 58))	('inhibition', 'NegReg', (160, 170))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('breast cancer', 'Disease', (221, 234))	('carcinogenesis', 'Disease', (108, 122))	('autophagy', 'CPA', (261, 270))	('FGFR', 'Gene', (23, 27))	('alterations', 'Var', (28, 39))	('suppress', 'NegReg', (40, 48))	('inhibition', 'Var', (247, 257))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('cancer', 'Disease', (285, 291))	('lung', 'Disease', (212, 216))	('cancer', 'Disease', (228, 234))	('increases', 'PosReg', (271, 280))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('FGFR', 'Gene', (155, 159))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
122964	32143356	Loss of SMAD4 is also frequently observed in CCA in the distal common bile duct, and it has also been shown to render pancreatic cancer radioresistance through promotion of autophagy; hence, a combination with autophagy inhibitors also could potentially apply to these mutated tumors.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('SMAD4', 'Gene', (8, 13))	('observed', 'Reg', (33, 41))	('render', 'PosReg', (111, 117))	('radioresistance', 'CPA', (136, 151))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (118, 135))	('promotion', 'PosReg', (160, 169))	('CCA', 'Phenotype', 'HP:0030153', (45, 48))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('pancreatic cancer', 'Disease', (118, 135))	('autophagy', 'CPA', (173, 182))	('SMAD4', 'Gene', '4089', (8, 13))	('pancreatic cancer', 'Disease', 'MESH:D010190', (118, 135))	('CCA', 'Disease', (45, 48))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('Loss', 'Var', (0, 4))	('tumors', 'Disease', (277, 283))
122965	32143356	Adenomatous Polyposis Coli (APC) is an additional tumor suppressor commonly mutated in CCA and may be responsible for the early stages of carcinogenesis, stages where dysfunctional autophagy has also been detected in clinical samples and in xenografts during tumor formation.	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('responsible', 'Reg', (102, 113))	('CCA', 'Phenotype', 'HP:0030153', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor', 'Disease', (50, 55))	('carcinogenesis', 'Disease', (138, 152))	('Adenomatous Polyposis Coli', 'Disease', 'MESH:D011125', (0, 26))	('CCA', 'Disease', (87, 90))	('mutated', 'Var', (76, 83))	('Adenomatous Polyposis Coli', 'Phenotype', 'HP:0005227', (0, 26))	('APC', 'Phenotype', 'HP:0005227', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('APC', 'Disease', 'MESH:D011125', (28, 31))	('carcinogenesis', 'Disease', 'MESH:D063646', (138, 152))	('APC', 'Disease', (28, 31))	('Adenomatous Polyposis Coli', 'Disease', (0, 26))	('clinical samples', 'Species', '191496', (217, 233))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (259, 264))
122967	32143356	HDAC6 inhibition restores ciliary expression and decreases tumor growth in CCA, a mechanism that has been shown to be mediated by autophagy inhibition in colorectal cancer, multiple myeloma and neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (194, 207))	('HDAC6', 'Gene', (0, 5))	('colorectal cancer', 'Disease', (154, 171))	('multiple myeloma', 'Disease', 'MESH:D009101', (173, 189))	('ciliary expression', 'MPA', (26, 44))	('decreases tumor', 'Disease', (49, 64))	('restores', 'PosReg', (17, 25))	('multiple myeloma', 'Disease', (173, 189))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (154, 171))	('HDAC6', 'Gene', '10013', (0, 5))	('decreases tumor', 'Disease', 'MESH:D002303', (49, 64))	('CCA', 'Phenotype', 'HP:0030153', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('neuroblastoma', 'Disease', (194, 207))	('CCA', 'Disease', (75, 78))	('multiple myeloma', 'Phenotype', 'HP:0006775', (173, 189))	('neuroblastoma', 'Phenotype', 'HP:0003006', (194, 207))	('inhibition', 'Var', (6, 16))	('colorectal cancer', 'Disease', 'MESH:D015179', (154, 171))
122970	32143356	Frequent mutations in both DNA methylation IDH1 and IDH2 have been reported in 10% of iCCA, which are associated with hypermethylation of CpG shore, resulting in an altered state in the cellular process of differentiation.	('altered', 'Reg', (165, 172))	('IDH2', 'Gene', '3418', (52, 56))	('associated', 'Reg', (102, 112))	('cellular process of differentiation', 'CPA', (186, 221))	('mutations', 'Var', (9, 18))	('CCA', 'Phenotype', 'HP:0030153', (87, 90))	('IDH1', 'Gene', (43, 47))	('iCCA', 'Disease', (86, 90))	('IDH1', 'Gene', '3417', (43, 47))	('reported', 'Reg', (67, 75))	('IDH2', 'Gene', (52, 56))
122974	32143356	Moreover, miR-124 has been described to induce cytotoxic autophagy in CCA through the EZH2-STAT3 pathway in vitro and in vivo.	('CCA', 'Disease', (70, 73))	('STAT3', 'Gene', '6774', (91, 96))	('EZH2', 'Gene', '2146', (86, 90))	('miR-124', 'Var', (10, 17))	('CCA', 'Phenotype', 'HP:0030153', (70, 73))	('cytotoxic autophagy', 'CPA', (47, 66))	('EZH2', 'Gene', (86, 90))	('STAT3', 'Gene', (91, 96))	('induce', 'PosReg', (40, 46))
122986	32143356	Beclin1 plays a relevant role linking autophagy, apoptosis and differentiation, and its inactivation and consequent deficiency in autophagy was correlated with malignant transformation, although existing data on the prognostic role of Beclin1 in human carcinomas is contradictory, appearing under- and overexpressed in distinct human cancers.	('Beclin1', 'Gene', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('deficiency', 'NegReg', (116, 126))	('carcinomas', 'Disease', 'MESH:D009369', (252, 262))	('malignant transformation', 'CPA', (160, 184))	('cancers', 'Phenotype', 'HP:0002664', (334, 341))	('carcinomas', 'Phenotype', 'HP:0030731', (252, 262))	('correlated', 'Reg', (144, 154))	('human', 'Species', '9606', (246, 251))	('autophagy', 'CPA', (130, 139))	('carcinomas', 'Disease', (252, 262))	('human', 'Species', '9606', (328, 333))	('cancers', 'Disease', 'MESH:D009369', (334, 341))	('apoptosis', 'CPA', (49, 58))	('autophagy', 'CPA', (38, 47))	('inactivation', 'Var', (88, 100))	('cancers', 'Disease', (334, 341))
122992	32143356	In another recent study, Chen and colleagues demonstrated for the first time that LC3B is an independent biomarker for overall survival and progression-free survival in iCCA patients, and that high LC3B staining significantly associates with poor tumor differentiation, tumor stage, early relapse and bad long term survival.	('high', 'Var', (193, 197))	('rat', 'Species', '10116', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('LC3B', 'Gene', (82, 86))	('LC3B', 'Gene', '81631', (198, 202))	('tumor', 'Disease', (247, 252))	('associates with', 'Reg', (226, 241))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('LC3B', 'Gene', '81631', (82, 86))	('patients', 'Species', '9606', (174, 182))	('CCA', 'Phenotype', 'HP:0030153', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('iCCA', 'Disease', (169, 173))	('early relapse', 'CPA', (283, 296))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('LC3B', 'Gene', (198, 202))	('tumor', 'Disease', (270, 275))
122995	32143356	This genetic variant resulted in the accumulation of p62, indicative of impaired autophagy in the tumors of carriers compared with noncarrier tumors, confirming autophagy pathway perturbation as a novel cancer driver mechanism in human tumorigenesis in correlation with the detection of impaired autophagy in BilIN lesions.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Disease', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', (98, 103))	('human', 'Species', '9606', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumors', 'Disease', (142, 148))	('p62', 'Gene', '8878', (53, 56))	('p62', 'Gene', (53, 56))	('tumor', 'Disease', (142, 147))	('accumulation', 'PosReg', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cancer', 'Disease', (203, 209))	('variant', 'Var', (13, 20))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('BilIN lesions', 'Disease', (309, 322))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('impaired', 'NegReg', (72, 80))	('perturbation', 'NegReg', (179, 191))	('BilIN lesions', 'Disease', 'MESH:D001768', (309, 322))	('autophagy', 'CPA', (81, 90))	('tumor', 'Disease', (236, 241))
122999	32143356	Epigenetic alterations are frequent in CCA, such as miR-124, which was found significantly downregulated in the tumor tissue of patients and in CCA cell lines, and its administration in vitro induced cytotoxic autophagy in CCA cells, supporting a protumoral role of epigenomic-mediated inhibition of autophagy.	('Epigenetic alterations', 'Var', (0, 22))	('cytotoxic autophagy', 'CPA', (200, 219))	('downregulated', 'NegReg', (91, 104))	('rat', 'Species', '10116', (176, 179))	('rat', 'Species', '10116', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('CCA', 'Phenotype', 'HP:0030153', (144, 147))	('CCA', 'Phenotype', 'HP:0030153', (223, 226))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('induced', 'Reg', (192, 199))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('CCA', 'Disease', (39, 42))	('miR-124', 'Var', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Disease', (112, 117))	('patients', 'Species', '9606', (128, 136))	('tumor', 'Disease', (250, 255))	('CCA', 'Phenotype', 'HP:0030153', (39, 42))
123002	32143356	Two different trials are exploring the inhibition of autophagy in CCA using CQ (NCT02496741-completed) and hydroxychloroquine (HCQ) (NCT03377179-recruiting).	('CQ', 'Chemical', 'MESH:D002738', (76, 78))	('CCA', 'Phenotype', 'HP:0030153', (66, 69))	('CQ', 'Chemical', 'MESH:D002738', (128, 130))	('NCT03377179-recruiting', 'Var', (133, 155))	('HCQ', 'Chemical', 'MESH:D006886', (127, 130))	('autophagy', 'CPA', (53, 62))	('hydroxychloroquine', 'Chemical', 'MESH:D006886', (107, 125))	('CCA', 'Disease', (66, 69))
123003	32143356	The study involving CQ explores safety, recommended phase 2 dose and efficacy of metformin and CQ combinatory treatment in IDH1/2 mutated solid tumors, alteration found in around 20% of iCCA patients.	('solid tumors', 'Disease', 'MESH:D009369', (138, 150))	('IDH1/2', 'Gene', '3417;3418', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('rat', 'Species', '10116', (156, 159))	('patients', 'Species', '9606', (191, 199))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('IDH1/2', 'Gene', (123, 129))	('metformin', 'Chemical', 'MESH:D008687', (81, 90))	('solid tumors', 'Disease', (138, 150))	('CQ', 'Chemical', 'MESH:D002738', (95, 97))	('CCA', 'Phenotype', 'HP:0030153', (187, 190))	('mutated', 'Var', (130, 137))	('CQ', 'Chemical', 'MESH:D002738', (20, 22))
123005	32143356	The study using HCQ combines this autophagy inhibitor with ABC294640 (Opaganib), a first-in-class sphingosine kinase-2 (SK2)-selective inhibitor.	('autophagy', 'CPA', (34, 43))	('ABC294640', 'Var', (59, 68))	('HCQ', 'Chemical', 'MESH:D006886', (16, 19))	('ABC294640', 'Chemical', 'MESH:C548780', (59, 68))	('SK2', 'Gene', '56848', (120, 123))	('sphingosine kinase-2', 'Gene', '56848', (98, 118))	('Opaganib', 'Chemical', 'MESH:C548780', (70, 78))	('sphingosine kinase-2', 'Gene', (98, 118))	('SK2', 'Gene', (120, 123))
123009	32143356	Among mTOR inhibitors, Everolimus is administered as monotherapy (NCT01525719:unknown and NCT00973713:unknown), in combination with gemcitabine and oxaliplatin (NCT02836847:recruiting) and with FOLFIRINOX (NCT03768375:recruiting), and sorafenib is administered alone (NCT00238212:completed), in combination with gemcitabine and cisplatin (NCT00919061:completed), with gemcitabine and oxaliplatin (NCT00955721:terminated and NCT02836847:recruiting), with erlotinib (EGFR inhibitor) (NCT01093222:completed) and with FOLFIRINOX (NCT03768375:recruiting).	('cisplatin', 'Chemical', 'MESH:D002945', (328, 337))	('gemcitabine', 'Chemical', 'MESH:C056507', (312, 323))	('NCT02836847', 'Var', (424, 435))	('gemcitabine', 'Chemical', 'MESH:C056507', (368, 379))	('EGFR', 'Gene', '1956', (465, 469))	('gemcitabine', 'Chemical', 'MESH:C056507', (132, 143))	('EGFR', 'Gene', (465, 469))	('mTOR', 'Gene', '2475', (6, 10))	('mTOR', 'Gene', (6, 10))
123010	32143356	Two studies using MK-2206 AKT inhibitor were found administered as monotherapy (NCT01859182:terminated and NCT01425879:completed) and one with BKM120 PI3K inhibitor as monotherapy (NCT01501604:terminated).	('MK-2206', 'Var', (18, 25))	('AKT', 'Gene', '207', (26, 29))	('BKM120', 'Chemical', 'MESH:C571178', (143, 149))	('MK-2206', 'Chemical', 'MESH:C548887', (18, 25))	('AKT', 'Gene', (26, 29))
123030	32143356	Moreover, salinomycin inhibited KRAS and p53 mutated CCA tumor grothw in vivo, in correlation with the potential use of this strategy to treat KRAS-driven tumors.	('inhibited', 'NegReg', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('KRAS', 'Gene', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('p53', 'Gene', (41, 44))	('salinomycin', 'Chemical', 'MESH:C010327', (10, 21))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('rat', 'Species', '10116', (127, 130))	('CCA', 'Phenotype', 'HP:0030153', (53, 56))	('CCA tumor', 'Disease', 'MESH:C536211', (53, 62))	('mutated', 'Var', (45, 52))	('CCA tumor', 'Disease', (53, 62))
123039	32143356	A wide variety of anticancer compounds induce autophagy in CCA, making it necessary to discern whether it is a protective autophagy promoted by cancer cells as an adaptive mechanism, therefore inhibition of autophagy leads to a potentiation of their cytotoxic effects, or if on the contrary, mediates drug mechanism of cancer cell death induction.	('inhibition', 'Var', (193, 203))	('potentiation', 'PosReg', (228, 240))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (22, 28))	('CCA', 'Phenotype', 'HP:0030153', (59, 62))	('cancer', 'Disease', (319, 325))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('cytotoxic effects', 'CPA', (250, 267))	('CCA', 'Disease', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
123049	32143356	Beclin1 activation is crucial for dihydroartemisinin action since its genetic depletion or its pharmacologically-mediated degradation inhibits autophagy activation and partially protects CCA cells from dihydroartemisinin treatment.	('inhibits', 'NegReg', (134, 142))	('autophagy activation', 'CPA', (143, 163))	('depletion', 'Var', (78, 87))	('protects', 'NegReg', (178, 186))	('CCA', 'Disease', (187, 190))	('genetic depletion', 'Var', (70, 87))	('CCA', 'Phenotype', 'HP:0030153', (187, 190))	('dihydroartemisinin', 'Chemical', 'MESH:C039060', (34, 52))	('dihydroartemisinin', 'Chemical', 'MESH:C039060', (202, 220))
123054	32143356	Decitabine (a cytosine analog, DNA demethylating agent) and miR-124 (associated with STAT3 signaling) induce an epigenomic induction of autophagy, while phenformin (diabetes therapeutic biguanide compound) and ABTL0812 (hydroxylated variant of linoleic acid) induce autophagy-mediated CCA cell death by activating LKB1-AMPK pathway and by inducing ER stress activation and AKT/mTOR pathway inhibition, respectively.	('AKT', 'Gene', (373, 376))	('diabetes', 'Disease', 'MESH:D003920', (165, 173))	('AMPK', 'Gene', '5562', (319, 323))	('activating', 'PosReg', (303, 313))	('mTOR', 'Gene', '2475', (377, 381))	('LKB1', 'Gene', '6794', (314, 318))	('CCA', 'Phenotype', 'HP:0030153', (285, 288))	('LKB1', 'Gene', (314, 318))	('phenformin', 'Chemical', 'MESH:D010629', (153, 163))	('STAT3', 'Gene', (85, 90))	('AKT', 'Gene', '207', (373, 376))	('linoleic acid', 'Chemical', 'MESH:D019787', (244, 257))	('miR-124', 'Var', (60, 67))	('diabetes', 'Disease', (165, 173))	('activation', 'PosReg', (358, 368))	('autophagy-mediated', 'CPA', (266, 284))	('ABTL0812', 'Gene', (210, 218))	('Decitabine', 'Chemical', 'MESH:D000077209', (0, 10))	('STAT3', 'Gene', '6774', (85, 90))	('AMPK', 'Gene', (319, 323))	('induce', 'PosReg', (259, 265))	('cytosine', 'Chemical', 'MESH:D003596', (14, 22))	('ER stress', 'Pathway', (348, 357))	('ABTL0812', 'Chemical', '-', (210, 218))	('autophagy', 'CPA', (136, 145))	('mTOR', 'Gene', (377, 381))	('inducing', 'PosReg', (339, 347))
123057	32143356	Another epigenetic factor, miR-124, induces a tumor-suppressive effect in CCA by inducing autophagic flux, leading to autophagy-related cell death in a mechanism involving EZH2-STAT3-signaling axis.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('STAT3', 'Gene', '6774', (177, 182))	('EZH2', 'Gene', '2146', (172, 176))	('miR-124', 'Var', (27, 34))	('tumor', 'Disease', (46, 51))	('CCA', 'Disease', (74, 77))	('STAT3', 'Gene', (177, 182))	('EZH2', 'Gene', (172, 176))	('induces', 'PosReg', (36, 43))	('autophagy-related cell death', 'CPA', (118, 146))	('inducing', 'PosReg', (81, 89))	('autophagic flux', 'CPA', (90, 105))	('CCA', 'Phenotype', 'HP:0030153', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
123058	32143356	Silencing of Beclin1 or ATG5 abrogated miR-124 anticancer effects and its overexpression in xenograft models resulted in autophagy-mediated suppression of tumorigenicity through STAT3 activation, Bcl-2 downregulation and Beclin1 expression, which indicates that it acts at the initiation of autophagy.	('tumor', 'Disease', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Silencing', 'Var', (0, 9))	('ATG5', 'Gene', '9474', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('miR-124', 'Gene', (39, 46))	('Bcl-2', 'Gene', (196, 201))	('activation', 'PosReg', (184, 194))	('abrogated', 'NegReg', (29, 38))	('suppression', 'NegReg', (140, 151))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('Bcl-2', 'Gene', '596', (196, 201))	('ATG5', 'Gene', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('overexpression', 'PosReg', (74, 88))	('downregulation', 'NegReg', (202, 216))	('autophagy-mediated', 'CPA', (121, 139))	('Beclin1', 'Gene', (221, 228))	('expression', 'MPA', (229, 239))	('STAT3', 'Gene', (178, 183))	('Beclin1', 'Gene', (13, 20))	('STAT3', 'Gene', '6774', (178, 183))	('cancer', 'Disease', (51, 57))
123061	32143356	Hu and colleagues showed that phenformin inhibits complex 1 of mitochondria, increasing intracellular AMP and inducing the activation of LKB1-AMPK axis, leading to mTOR inhibition.	('intracellular AMP', 'MPA', (88, 105))	('phenformin', 'Chemical', 'MESH:D010629', (30, 40))	('increasing', 'PosReg', (77, 87))	('inhibits', 'NegReg', (41, 49))	('LKB1', 'Gene', '6794', (137, 141))	('AMP', 'Chemical', 'MESH:D000249', (142, 145))	('inducing', 'NegReg', (110, 118))	('mTOR', 'Gene', (164, 168))	('LKB1', 'Gene', (137, 141))	('AMP', 'Chemical', 'MESH:D000249', (102, 105))	('activation', 'PosReg', (123, 133))	('AMPK', 'Gene', '5562', (142, 146))	('AMPK', 'Gene', (142, 146))	('phenformin', 'Var', (30, 40))	('mTOR', 'Gene', '2475', (164, 168))
123071	32143356	In xenograft models, ABTL0812 potentiated gemcitabine plus cisplatin anticancer efficacy by upregulating TRIB3 and CHOP levels, two markers that have been validated for the first time as surrogate pharmacodynamic biomarkers in endometrial and lung cancer patients.	('CHOP', 'Gene', (115, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (243, 254))	('cancer', 'Disease', (248, 254))	('cancer', 'Disease', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('gemcitabine', 'Chemical', 'MESH:C056507', (42, 53))	('ABTL0812', 'Var', (21, 29))	('TRIB3', 'Gene', '57761', (105, 110))	('lung cancer', 'Disease', (243, 254))	('endometrial', 'Disease', 'MESH:D014591', (227, 238))	('TRIB3', 'Gene', (105, 110))	('patients', 'Species', '9606', (255, 263))	('ABTL0812', 'Chemical', '-', (21, 29))	('CHOP', 'Gene', '1649', (115, 119))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('endometrial', 'Disease', (227, 238))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('potentiated', 'PosReg', (30, 41))	('lung cancer', 'Disease', 'MESH:D008175', (243, 254))	('upregulating', 'PosReg', (92, 104))
123079	32143356	Autophagy may act as tumor suppressor at the early stages of cancer development, impeding the appearance of oncogenic mutations through the clearance of impaired macromolecules and organelles that cause DNA damage and chromatin instability.	('oncogenic', 'Gene', (108, 117))	('chromatin', 'MPA', (218, 227))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', (21, 26))	('mutations', 'Var', (118, 127))	('cancer', 'Disease', (61, 67))	('clearance', 'MPA', (140, 149))	('impeding', 'NegReg', (81, 89))	('DNA damage', 'MPA', (203, 213))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
123085	32143356	These genetic alterations could mediate cholangiocyte oncogenic transformation through the inhibition of autophagy, cooperating with their proliferative and prosurvival-derived effects.	('rat', 'Species', '10116', (18, 21))	('rat', 'Species', '10116', (146, 149))	('cholangiocyte oncogenic', 'Disease', (40, 63))	('inhibition', 'NegReg', (91, 101))	('autophagy', 'CPA', (105, 114))	('mediate', 'Reg', (32, 39))	('genetic alterations', 'Var', (6, 25))	('rat', 'Species', '10116', (121, 124))
123088	32143356	Thongchot and colleagues found a positive correlation between HIF-1alpha (hypoxia-inducible factor 1-alpha) with BNIP3 (pro-apoptotic member of Bcl2 family) and PI3KC3 (component of Beclin1-PI3K complex), which associated with poor prognosis and lymph node metastasis in CCA samples, reflecting an hypoxic stress that activates autophagy as prosurvival and invasive mechanism.	('HIF-1alpha', 'Gene', (62, 72))	('hypoxic stress', 'Disease', 'MESH:D000079225', (298, 312))	('BNIP3', 'Gene', (113, 118))	('Bcl2', 'Gene', (144, 148))	('associated', 'Reg', (211, 221))	('CCA', 'Phenotype', 'HP:0030153', (271, 274))	('BNIP3', 'Gene', '664', (113, 118))	('hypoxia-inducible factor 1-alpha', 'Gene', (74, 106))	('lymph node metastasis', 'CPA', (246, 267))	('HIF-1alpha', 'Gene', '3091', (62, 72))	('Bcl2', 'Gene', '596', (144, 148))	('hypoxia-inducible factor 1-alpha', 'Gene', '3091', (74, 106))	('PI3KC3', 'Var', (161, 167))	('autophagy', 'CPA', (328, 337))	('CCA', 'Disease', (271, 274))	('hypoxic stress', 'Disease', (298, 312))
123091	32143356	Interestingly, when autophagy is impaired in these cells by ATG7 deletion, mice died from inflammation rather than from tumor-derived effects such as lung or liver metastatic, further reinforcing the idea of autophagy activation as a mediator of survival and growth in CCA.	('autophagy', 'CPA', (20, 29))	('inflammation', 'Disease', 'MESH:D007249', (90, 102))	('rat', 'Species', '10116', (103, 106))	('mice', 'Species', '10090', (75, 79))	('inflammation', 'Disease', (90, 102))	('impaired', 'NegReg', (33, 41))	('CCA', 'Phenotype', 'HP:0030153', (269, 272))	('ATG7', 'Gene', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('deletion', 'Var', (65, 73))	('tumor', 'Disease', (120, 125))
123096	32143356	A wide variety of anticancer compounds induce protective autophagy in CCA including chemotherapy and the inhibition of autophagy accelerated apoptosis and chemosensitized CCA cells.	('CCA', 'Phenotype', 'HP:0030153', (171, 174))	('inhibition', 'Var', (105, 115))	('rat', 'Species', '10116', (135, 138))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('accelerated', 'PosReg', (129, 140))	('CCA', 'Phenotype', 'HP:0030153', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('apoptosis', 'CPA', (141, 150))	('autophagy', 'CPA', (119, 128))
123099	32143356	Inhibiting autophagy would block the activation of autophagy as a mechanism of resistance and could potentially decrease CCA metastatic potential; therefore, clinical results of this study would be of great help for further design of novel therapeutic strategies involving autophagy inhibitors in CCA.	('CCA', 'Disease', (121, 124))	('clinical', 'Species', '191496', (158, 166))	('Inhibiting', 'Var', (0, 10))	('autophagy', 'CPA', (11, 20))	('decrease', 'NegReg', (112, 120))	('CCA', 'Disease', (297, 300))	('autophagy', 'CPA', (51, 60))	('block', 'NegReg', (27, 32))	('CCA', 'Phenotype', 'HP:0030153', (121, 124))	('CCA', 'Phenotype', 'HP:0030153', (297, 300))	('rat', 'Species', '10116', (254, 257))
123108	32143356	In recent studies, the low Beclin1/high Bcl-xL population, but not the low-Beclin1/low-Bcl-xL population of HCC patients, was associated with the most aggressive disease and tumor differentiation, and similar results were observed between Beclin1 and apoptotic markers Bcl-2 and Bax and between Beclin1 and HIF-1alpha.	('Bcl-2', 'Gene', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('Bax', 'Gene', (279, 282))	('associated', 'Reg', (126, 136))	('Bax', 'Gene', '581', (279, 282))	('Bcl-2', 'Gene', '596', (269, 274))	('HIF-1alpha', 'Gene', (307, 317))	('Bcl-xL', 'Gene', (40, 46))	('HCC', 'Phenotype', 'HP:0001402', (108, 111))	('Bcl-xL', 'Gene', '598', (40, 46))	('aggressive disease', 'Disease', (151, 169))	('Bcl-xL', 'Gene', (87, 93))	('tumor', 'Disease', (174, 179))	('low', 'Var', (23, 26))	('patients', 'Species', '9606', (112, 120))	('aggressive disease', 'Disease', 'MESH:D001523', (151, 169))	('Bcl-xL', 'Gene', '598', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('HIF-1alpha', 'Gene', '3091', (307, 317))
123116	32143356	Similarly, ABTL0812 induces impairment of Des-1 activity, resulting in the accumulation of Dh-Cer and activation of UPR response, which, in combination with TRIB3-mediated AKT/mTOR axis inhibition, triggers cytotoxic autophagy in CCA cells.	('ABTL0812', 'Var', (11, 19))	('impairment', 'NegReg', (28, 38))	('ABTL0812', 'Chemical', '-', (11, 19))	('accumulation', 'PosReg', (75, 87))	('AKT', 'Gene', (172, 175))	('activity', 'MPA', (48, 56))	('Des-1', 'Gene', '8560', (42, 47))	('CCA', 'Phenotype', 'HP:0030153', (230, 233))	('mTOR', 'Gene', (176, 180))	('CCA', 'Disease', (230, 233))	('mTOR', 'Gene', '2475', (176, 180))	('AKT', 'Gene', '207', (172, 175))	('TRIB3', 'Gene', '57761', (157, 162))	('triggers', 'Reg', (198, 206))	('Des-1', 'Gene', (42, 47))	('cytotoxic autophagy', 'CPA', (207, 226))	('UPR', 'MPA', (116, 119))	('Dh-Cer', 'Chemical', 'MESH:C109343', (91, 97))	('TRIB3', 'Gene', (157, 162))	('Dh-Cer', 'Protein', (91, 97))
123133	32143356	In human pancreatic cancer cells, Beclin1 genetic inhibition promotes autophagy and decreases gemcitabine-induced apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (9, 26))	('autophagy', 'CPA', (70, 79))	('Beclin1', 'Gene', (34, 41))	('genetic inhibition', 'Var', (42, 60))	('promotes', 'PosReg', (61, 69))	('human', 'Species', '9606', (3, 8))	('gemcitabine', 'Chemical', 'MESH:C056507', (94, 105))	('pancreatic cancer', 'Disease', 'MESH:D010190', (9, 26))	('gemcitabine-induced', 'MPA', (94, 113))	('pancreatic cancer', 'Disease', (9, 26))	('decreases', 'NegReg', (84, 93))
123135	32143356	Comparing ER stress and autophagy basal levels between CCA cells with different relevant mutations can be helpful for understanding how mutations regulate autophagy and in which subtype of patients autophagy inhibition would be more efficacious, such as KRAS and p53-mutated CCA, or in which autophagy activation would offer better outcome, such in those with impaired autophagy or higher expression of ER stress markers.	('higher', 'PosReg', (382, 388))	('p53-mutated', 'Var', (263, 274))	('CCA', 'Phenotype', 'HP:0030153', (55, 58))	('CCA', 'Phenotype', 'HP:0030153', (275, 278))	('autophagy', 'CPA', (369, 378))	('mutations', 'Var', (136, 145))	('expression', 'MPA', (389, 399))	('patients', 'Species', '9606', (189, 197))	('CCA', 'Disease', (275, 278))	('KRAS', 'Var', (254, 258))
123259	23810312	However, the presence of a genetically mutated KRAS protein, which is a downstream signaling protein in the EGFR signaling cascade, causes a decreased or lack of response to cetuximab, resulting in a worse prognosis compared to patients with the wild-type KRAS protein.	('response', 'MPA', (162, 170))	('a', 'Gene', '100689452', (229, 230))	('a', 'Gene', '100689452', (80, 81))	('a', 'Gene', '100689452', (198, 199))	('a', 'Gene', '100689452', (181, 182))	('cetuximab', 'Chemical', 'MESH:D000068818', (174, 183))	('a', 'Gene', '100689452', (127, 128))	('a', 'Gene', '100689452', (117, 118))	('a', 'Gene', '100689452', (70, 71))	('EGFR', 'Gene', '1956', (108, 112))	('patients', 'Species', '9606', (228, 236))	('prognosis', 'MPA', (206, 215))	('presence', 'Var', (13, 21))	('a', 'Gene', '100689452', (133, 134))	('KRAS', 'Gene', '3845', (256, 260))	('a', 'Gene', '100689452', (220, 221))	('a', 'Gene', '100689452', (146, 147))	('a', 'Gene', '100689452', (155, 156))	('a', 'Gene', '100689452', (139, 140))	('a', 'Gene', '100689452', (124, 125))	('KRAS', 'Gene', (256, 260))	('a', 'Gene', '100689452', (34, 35))	('KRAS', 'Gene', '3845', (47, 51))	('a', 'Gene', '100689452', (42, 43))	('EGFR', 'Gene', (108, 112))	('protein', 'Protein', (52, 59))	('KRAS', 'Gene', (47, 51))	('a', 'Gene', '100689452', (25, 26))	('a', 'Gene', '100689452', (87, 88))
123514	23810312	The addition of 90Y radioembolization to chemotherapy has shown significantly prolonged times to tumor progression compared to chemotherapy alone [(15.9 months vs. 9.7 months, P<0.001) and (18.6 vs. 3.6 months, P<0.0005)] with a trend toward prolonged 2-year survival in one study (39% vs. 29%, P=0.06) and statistically significant longer median survival in a second study (29.4 vs. 12.8 months, P=0.02) (level I and level 2 evidence).	('a', 'Gene', '100689452', (72, 73))	('a', 'Gene', '100689452', (238, 239))	('a', 'Gene', '100689452', (303, 304))	('a', 'Gene', '100689452', (32, 33))	('a', 'Gene', '100689452', (119, 120))	('a', 'Gene', '100689452', (316, 317))	('prolonged', 'PosReg', (78, 87))	('a', 'Gene', '100689452', (55, 56))	('tumor', 'Disease', (97, 102))	('a', 'Gene', '100689452', (140, 141))	('a', 'Gene', '100689452', (21, 22))	('a', 'Gene', '100689452', (4, 5))	('90Y', 'Var', (16, 19))	('a', 'Gene', '100689452', (227, 228))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('times', 'MPA', (88, 93))	('a', 'Gene', '100689452', (353, 354))	('a', 'Gene', '100689452', (329, 330))	('prolonged', 'PosReg', (242, 251))	('a', 'Gene', '100689452', (185, 186))	('a', 'Gene', '100689452', (359, 360))	('a', 'Gene', '100689452', (265, 266))	('a', 'Gene', '100689452', (344, 345))	('a', 'Gene', '100689452', (414, 415))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('a', 'Gene', '100689452', (50, 51))	('a', 'Gene', '100689452', (256, 257))	('a', 'Gene', '100689452', (136, 137))	('a', 'Gene', '100689452', (309, 310))
123628	23810312	The American Urological Association includes thermal ablation as an acceptable treatment option for T1 renal masses (<=7 cm) in high-risk surgical patients with the understanding that, while thermal ablative therapies have shown similar distant recurrence-free survival rates to surgery, there may be an increased risk of local recurrence, particularly for T1b tumors (4-7 cm) (level 3 evidence).	('a', 'Gene', '100689452', (56, 57))	('a', 'Gene', '100689452', (65, 66))	('a', 'Gene', '100689452', (341, 342))	('T1b', 'Var', (357, 360))	('a', 'Gene', '100689452', (325, 326))	('a', 'Gene', '100689452', (301, 302))	('a', 'Gene', '100689452', (181, 182))	('a', 'Gene', '100689452', (62, 63))	('a', 'Gene', '100689452', (110, 111))	('a', 'Gene', '100689452', (267, 268))	('a', 'Gene', '100689452', (348, 349))	('a', 'Gene', '100689452', (53, 54))	('patients', 'Species', '9606', (147, 155))	('tumors', 'Phenotype', 'HP:0002664', (361, 367))	('a', 'Gene', '100689452', (30, 31))	('a', 'Gene', '100689452', (234, 235))	('a', 'Gene', '100689452', (212, 213))	('a', 'Gene', '100689452', (196, 197))	('a', 'Gene', '100689452', (21, 22))	('a', 'Gene', '100689452', (219, 220))	('a', 'Gene', '100689452', (172, 173))	('A', 'Gene', '100689452', (24, 25))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('a', 'Gene', '100689452', (148, 149))	('a', 'Gene', '100689452', (82, 83))	('a', 'Gene', '100689452', (74, 75))	('tumors', 'Disease', (361, 367))	('a', 'Gene', '100689452', (106, 107))	('a', 'Gene', '100689452', (68, 69))	('a', 'Gene', '100689452', (10, 11))	('a', 'Gene', '100689452', (202, 203))	('a', 'Gene', '100689452', (241, 242))	('a', 'Gene', '100689452', (50, 51))	('a', 'Gene', '100689452', (295, 296))	('tumors', 'Disease', 'MESH:D009369', (361, 367))	('a', 'Gene', '100689452', (144, 145))	('a', 'Gene', '100689452', (199, 200))	('A', 'Gene', '100689452', (4, 5))	('renal masses', 'Phenotype', 'HP:0009726', (103, 115))	('a', 'Gene', '100689452', (309, 310))	('a', 'Gene', '100689452', (271, 272))
123679	21333016	CC also develops after the liver-specific targeted disruption of the tumor suppressors SMAD4 and PTEN .	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('PTEN', 'Gene', (97, 101))	('tumor', 'Disease', (69, 74))	('PTEN', 'Gene', '5728', (97, 101))	('SMAD4', 'Gene', '4089', (87, 92))	('disruption', 'Var', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('SMAD4', 'Gene', (87, 92))
123770	21333016	E2Fs 1-3 are characterized as "activator E2Fs" since their binding to promoters results in increased transcription, while E2Fs 4 and 5 are "repressor E2Fs" since they form complexes with p130, HDACs, and other factors to block transcription.	('E2Fs', 'Var', (0, 4))	('binding', 'Interaction', (59, 66))	('transcription', 'MPA', (227, 240))	('complexes', 'Interaction', (172, 181))	('p130', 'Gene', (187, 191))	('block', 'NegReg', (221, 226))	('transcription', 'MPA', (101, 114))	('p130', 'Gene', '22930', (187, 191))	('increased', 'PosReg', (91, 100))	('E2Fs', 'Var', (122, 126))
123824	20934950	On percutaneous T-tube cholangiogram performed after one cycle of chemotherapy, there was an irregular polypoid filling defect at the bifurcation of the left and right hepatic ducts, which was thought to be causing partial obstruction of the right hepatic duct and delayed filling, suspicious for interval growth of the tumor infiltrating the duct in a region more typical for a Klatskin-type tumor (Fig.	('polypoid', 'Var', (103, 111))	('Klatskin-type tumor', 'Disease', 'MESH:D018285', (379, 398))	('delayed', 'MPA', (265, 272))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('tumor', 'Disease', 'MESH:D009369', (393, 398))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('tumor', 'Phenotype', 'HP:0002664', (393, 398))	('obstruction of the right hepatic duct', 'Disease', (223, 260))	('tumor', 'Disease', (320, 325))	('tumor', 'Disease', (393, 398))	('obstruction of the right hepatic duct', 'Disease', 'MESH:D056486', (223, 260))	('Klatskin-type tumor', 'Disease', (379, 398))
123845	31300360	Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study Isocitrate dehydrogenase-1 (IDH1) is mutated in up to 25% of cholangiocarcinomas, especially intrahepatic cholangiocarcinoma.	('IDH1', 'Gene', '3417', (51, 55))	('IDH1', 'Gene', (136, 140))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (169, 187))	('patients', 'Species', '9606', (37, 45))	('cholangiocarcinoma', 'Disease', (169, 187))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (201, 232))	('IDH1', 'Gene', '3417', (136, 140))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (169, 187))	('intrahepatic cholangiocarcinoma', 'Disease', (201, 232))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (214, 232))	('ivosidenib', 'Chemical', 'MESH:C000627630', (23, 33))	('mutated', 'Var', (145, 152))	('cholangiocarcinoma', 'Disease', (72, 90))	('cholangiocarcinoma', 'Disease', (214, 232))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 90))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (169, 188))	('IDH1', 'Gene', (51, 55))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (214, 232))	('cholangiocarcinomas', 'Disease', (169, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (178, 188))
123866	31300360	Gain-of-function mutations within the isocitrate dehydrogenase (IDH)-1 enzyme are among the most common driver genetic alterations in cholangiocarcinoma, particularly in intrahepatic cholangiocarcinoma, where they have been reported to occur in up to 25% of patients.	('isocitrate dehydrogenase (IDH)-1', 'Gene', '3417', (38, 70))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (134, 152))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (183, 201))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (134, 152))	('Gain-of-function', 'PosReg', (0, 16))	('cholangiocarcinoma', 'Disease', (183, 201))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (170, 201))	('patients', 'Species', '9606', (258, 266))	('intrahepatic cholangiocarcinoma', 'Disease', (170, 201))	('mutations', 'Var', (17, 26))	('cholangiocarcinoma', 'Disease', (134, 152))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (183, 201))
123867	31300360	These mutations result in the excessive production of the oncometabolite D-2-hydroxyglutarate (2-HG), reduction of the endogenous intermediary metabolite alpha-ketoglutarate, and consequent stimulation of multiple oncogenic processes, including aberrant metabolism and widespread epigenetic dysregulation.	('widespread epigenetic dysregulation', 'CPA', (269, 304))	('production', 'MPA', (40, 50))	('2-HG', 'Chemical', 'MESH:C019417', (95, 99))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (73, 93))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (154, 173))	('oncogenic processes', 'CPA', (214, 233))	('reduction', 'NegReg', (102, 111))	('metabolism', 'MPA', (254, 264))	('mutations', 'Var', (6, 15))	('stimulation', 'PosReg', (190, 201))
123868	31300360	Thus, mutant IDH1 (mIDH1) represents a therapeutic target in cholangiocarcinoma.	('mutant', 'Var', (6, 12))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('IDH1', 'Gene', (13, 17))	('mIDH1', 'Gene', '15926', (19, 24))	('mIDH1', 'Gene', (19, 24))	('cholangiocarcinoma', 'Disease', (61, 79))
123869	31300360	Preclinical work showed that treatment of in-vitro IDH1-mutant mouse hepatoblasts with a mIDH1 inhibitor resulted in reduction of 2-HG production and restoration of cellular differentiation, providing a rationale for the clinical use of mIDH1 inhibitors.	('reduction', 'NegReg', (117, 126))	('IDH1-mutant', 'Gene', (51, 62))	('mIDH1', 'Gene', (89, 94))	('mouse', 'Species', '10090', (63, 68))	('mIDH1', 'Gene', '15926', (237, 242))	('2-HG production', 'MPA', (130, 145))	('cellular differentiation', 'CPA', (165, 189))	('mIDH1', 'Gene', (237, 242))	('restoration', 'PosReg', (150, 161))	('IDH1-mutant', 'Var', (51, 62))	('mIDH1', 'Gene', '15926', (89, 94))	('2-HG', 'Chemical', 'MESH:C019417', (130, 134))
123870	31300360	Ivosidenib (Agios Pharmaceuticals, Inc, Cambridge, MA, USA) is an oral, potent inhibitor of mIDH1, approved in the USA for the treatment of acute myeloid leukaemia with a susceptible IDH1 mutation, as detected by a US Food & Drug Administration-approved test, in newly diagnosed adults aged 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy and adults with relapsed or refractory disease.	('acute myeloid leukaemia', 'Disease', (140, 163))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (146, 163))	('mutation', 'Var', (188, 196))	('mIDH1', 'Gene', (92, 97))	('refractory disease', 'Disease', 'MESH:D000069279', (417, 435))	('mIDH1', 'Gene', '15926', (92, 97))	('acute myeloid leukaemia', 'Disease', 'MESH:D015470', (140, 163))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))	('refractory disease', 'Disease', (417, 435))	('IDH1', 'Gene', (183, 187))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (140, 163))
123874	31300360	Patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and an advanced solid tumour that had recurred or progressed following standard therapy with a documented IDH1 mutation by local testing were eligible for escalation.	('mutation', 'Var', (215, 223))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('Oncology', 'Phenotype', 'HP:0002664', (60, 68))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))	('Patients', 'Species', '9606', (0, 8))	('IDH1', 'Gene', (210, 214))
123876	31300360	Additional eligibility criteria were adequate bone marrow function (absolute neutrophil count >=1 5 x 109 cells per L, haemoglobin >=9 g/dL, and platelets >=75 x 109 per L), adequate hepatic function (total bilirubin <=1 5 times the upper limit of normal, except for patients with Gilbert's syndrome, and aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase <=2 5 times the upper limit of normal), adequate renal function (serum creatinine <=2 times the upper limit of normal and creatinine clearance >40 mL/min), recovery from the toxic manifestations of previous treatments, and a minimum expected survival of at least 3 months.	('>=9', 'Var', (131, 134))	('hepatic function', 'MPA', (183, 199))	('alanine aminotransferase', 'Gene', (333, 357))	('patients', 'Species', '9606', (267, 275))	("Gilbert's syndrome", 'Disease', (281, 299))	('alanine aminotransferase', 'Gene', '2875', (333, 357))	('bone marrow function', 'CPA', (46, 66))	("Gilbert's syndrome", 'Disease', 'MESH:D005878', (281, 299))	('creatinine clearance', 'MPA', (506, 526))	('creatinine', 'Chemical', 'MESH:D003404', (506, 516))	('creatinine', 'Chemical', 'MESH:D003404', (455, 465))	('renal function', 'MPA', (433, 447))
123891	31300360	Exploratory assessments on archived and fresh-frozen tumour samples included confirmation of baseline mIDH1 status and identification of co-occurring mutations by next-generation sequencing and Ki-67 proliferation marker by immunohistochemistry (appendix p 4-5).	('mIDH1', 'Gene', (102, 107))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('p 4-5', 'Gene', '5705;201780;347051', (255, 260))	('tumour', 'Disease', (53, 59))	('p 4-5', 'Gene', (255, 260))	('mutations', 'Var', (150, 159))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('Ki-67', 'Chemical', '-', (194, 199))	('mIDH1', 'Gene', '15926', (102, 107))
123946	31300360	New known or likely oncogenic mutations emerged at an allele frequency of 5% or more during treatment in six of these patients, spanning seven genes from multiple functional pathways (table 3).	('oncogenic', 'Gene', (20, 29))	('patients', 'Species', '9606', (118, 126))	('mutations', 'Var', (30, 39))
123972	31300360	Of note, emergence of a secondary IDH1 or IDH2 mutation in two patients with mIDH1-cholangiocarcinoma with previously prolonged stable disease was observed (one of which has been previously reported by Harding and colleagues).	('mIDH1', 'Gene', (77, 82))	('cholangiocarcinoma', 'Disease', (83, 101))	('mutation', 'Var', (47, 55))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('IDH2', 'Gene', (42, 46))	('mIDH1', 'Gene', '15926', (77, 82))	('patients', 'Species', '9606', (63, 71))	('IDH1', 'Gene', (34, 38))	('IDH2', 'Gene', '3418', (42, 46))
123988	31300360	Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) are reported in up to 25% of patients with intrahepatic cholangiocarcinoma and result in overproduction of the oncometabolite D-2-hydroxyglutarate (2-HG).	('2-HG', 'Chemical', 'MESH:C019417', (216, 220))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 142))	('Mutations', 'Var', (0, 9))	('isocitrate dehydrogenase 1', 'Gene', (34, 60))	('patients', 'Species', '9606', (97, 105))	('intrahepatic cholangiocarcinoma', 'Disease', (111, 142))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (194, 214))	('isocitrate dehydrogenase 1', 'Gene', '3417', (34, 60))	('IDH1', 'Gene', (62, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (124, 142))	('overproduction', 'PosReg', (157, 171))
123989	31300360	Preclinical work showed that treatment of IDH1-mutant mouse hepatoblasts with a mutant IDH1 (mIDH1) inhibitor in vitro resulted in reduction of 2-HG production and restoration of cellular differentiation, providing a rationale for the clinical use of mIDH1 inhibitors.	('restoration', 'PosReg', (164, 175))	('reduction', 'NegReg', (131, 140))	('2-HG', 'Chemical', 'MESH:C019417', (144, 148))	('2-HG production', 'MPA', (144, 159))	('mutant', 'Var', (80, 86))	('cellular differentiation', 'CPA', (179, 203))	('mIDH1', 'Gene', (251, 256))	('mIDH1', 'Gene', (93, 98))	('mIDH1', 'Gene', '15926', (93, 98))	('inhibitor', 'Var', (100, 109))	('IDH1', 'Gene', (87, 91))	('IDH1-mutant', 'Var', (42, 53))	('mouse', 'Species', '10090', (54, 59))	('mIDH1', 'Gene', '15926', (251, 256))
123995	31300360	The identification of specific, relevant genetic mutations justifies a targeted therapy approach (eg, mIDH1).	('mIDH1', 'Gene', (102, 107))	('mIDH1', 'Gene', '15926', (102, 107))	('mutations', 'Var', (49, 58))
124004	32899345	The rate of targetable alterations identified was 40.2% across all successfully-analysed samples (39 iCCA; 6 non-iCCA): IDH1 mutations (19.1% of individual patients), FGFR2 alterations (10.1% and 5.6% of individual patients had FGFR2 fusions and mutations, respectively); 10.6% of all patients (12.4% of patients with successfully analysed samples) entered trials with matched targeted therapies as a consequence.	('patients', 'Species', '9606', (156, 164))	('mutations', 'Var', (125, 134))	('patients', 'Species', '9606', (215, 223))	('IDH1', 'Gene', '3417', (120, 124))	('patients', 'Species', '9606', (304, 312))	('alterations', 'Var', (173, 184))	('mutations', 'Var', (246, 255))	('IDH1', 'Gene', (120, 124))	('FGFR2', 'Gene', (228, 233))	('FGFR2', 'Gene', '2263', (228, 233))	('patients', 'Species', '9606', (285, 293))	('FGFR2', 'Gene', '2263', (167, 172))	('FGFR2', 'Gene', (167, 172))	('fusions', 'Var', (234, 241))
124005	32899345	A total of 15 patients (16.6%) harboured alterations in DNA damage repair (DDR) genes; when treated with platinum-based chemotherapy, there was a trend towards increased partial response rate (21.4% vs. 15.9%; p-value 0.653), radiological benefit rate (64.3% vs. 36.2%; p-value 0.071), and longer OS (median OS 20.4 months (95% CI 7.9-26.7) vs. 13.3 (95 CI 11.0-16.4); Cox Regression HR 0.79 (95% CI 0.39-1.61), p-value 0.527).	('increased', 'PosReg', (160, 169))	('platinum', 'Chemical', 'MESH:D010984', (105, 113))	('DDR) genes;', 'Gene', (75, 86))	('radiological benefit', 'CPA', (226, 246))	('partial response', 'CPA', (170, 186))	('patients', 'Species', '9606', (14, 22))	('DNA damage repair (DDR) genes', 'Gene', (56, 85))	('alterations', 'Var', (41, 52))
124012	32899345	The development of targeted therapies is significantly impacting the care and management of patients with advanced iCCA, for whom inhibitors of fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH) mutations are becoming a reality.	('isocitrate dehydrogenase', 'Gene', (197, 221))	('isocitrate dehydrogenase', 'Gene', '3417', (197, 221))	('FGFR', 'Gene', (179, 183))	('IDH', 'Gene', (223, 226))	('patients', 'Species', '9606', (92, 100))	('mutations', 'Var', (228, 237))	('IDH', 'Gene', '3417', (223, 226))	('iCCA', 'Disease', (115, 119))	('fusions', 'Var', (185, 192))	('impacting', 'Reg', (55, 64))
124013	32899345	Alternative potential targets for future "Precision Medicine" strategies in BTC may include chromatin remodeling genes (ARID1, BAP1, and PBRM1) and other aberrations such as BRAF and RNF43 mutations, HER2 and HER3 amplifications or NTRK fusions.	('RNF43', 'Gene', '54894', (183, 188))	('BAP1', 'Gene', (127, 131))	('RNF43', 'Gene', (183, 188))	('HER2', 'Gene', (200, 204))	('ARID1', 'Gene', (120, 125))	('NTRK', 'Gene', (232, 236))	('HER2', 'Gene', '2064', (200, 204))	('PBRM1', 'Gene', (137, 142))	('BRAF', 'Gene', '673', (174, 178))	('PBRM1', 'Gene', '55193', (137, 142))	('BRAF', 'Gene', (174, 178))	('BTC', 'Phenotype', 'HP:0100574', (76, 79))	('BAP1', 'Gene', '8314', (127, 131))	('HER3', 'Gene', (209, 213))	('mutations', 'Var', (189, 198))	('amplifications', 'Var', (214, 228))	('HER3', 'Gene', '2065', (209, 213))
124014	32899345	The potential clinical implications of molecular profiling are not limited to the used of targeted therapies; the identification of DNA damage repair aberrations have been associated with better responses to platinum-based chemotherapy strategies and could therefore enable tailoring of chemotherapy choice.	('better', 'PosReg', (188, 194))	('enable', 'Reg', (267, 273))	('platinum', 'Chemical', 'MESH:D010984', (208, 216))	('responses', 'MPA', (195, 204))	('aberrations', 'Var', (150, 161))	('DNA damage repair', 'Gene', (132, 149))
124023	32899345	Good concordance (92%) for IDH1 mutation identification between tumour tissue and ctDNA was also reported in the ClarIDHy phase III trial, exploring the role of ivosidenib in IDH1-mutant iCCA.	('IDH', 'Gene', (27, 30))	('IDH', 'Gene', '3417', (175, 178))	('ivosidenib', 'Chemical', 'MESH:C000627630', (161, 171))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('IDH', 'Gene', '3417', (27, 30))	('IDH', 'Gene', (117, 120))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', (64, 70))	('IDH1', 'Gene', (175, 179))	('mutation', 'Var', (32, 40))	('IDH', 'Gene', '3417', (117, 120))	('iCCA', 'Disease', (187, 191))	('IDH1', 'Gene', (27, 31))	('IDH', 'Gene', (175, 178))	('IDH1', 'Gene', '3417', (27, 31))	('IDH1', 'Gene', '3417', (175, 179))
124032	32899345	In addition to the presence/absence of pathogenic aberrations and fusions, data on mutant allele frequency (MAF), microsatellite instability (MSI) and tumour mutational burden (TMB) were collected whenever reported.	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('mutant', 'Var', (83, 89))	('microsatellite instability', 'MPA', (114, 140))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('TMB', 'Chemical', '-', (177, 180))	('tumour', 'Disease', (151, 157))
124034	32899345	Targetable findings were those for whom potential treatment strategies were available, such as, but not limited to, FGFR2 fusions or mutations, IDH1 mutations, and HER2/3 amplifications.	('mutations', 'Var', (149, 158))	('fusions', 'Var', (122, 129))	('HER2', 'Gene', (164, 168))	('mutations', 'Var', (133, 142))	('IDH1', 'Gene', (144, 148))	('FGFR2', 'Gene', (116, 121))	('HER2', 'Gene', '2064', (164, 168))	('FGFR2', 'Gene', '2263', (116, 121))	('IDH1', 'Gene', '3417', (144, 148))	('amplifications', 'Var', (171, 185))
124056	32899345	When analysis was solely focused on pathological molecular findings (Table 3) the most frequent alterations identified were TP53 mutations (24.7% of individual patients with at least 1 successfully-analysed sample), KRAS mutations (27.0% of individual patients with at least 1 successfully-analysed sample), followed by IDH1 mutations (19.1% of individual patients with at least 1 successfully-analysed sample), CDKN2A mutations (12.4% of individual patients with at least 1 successfully-analysed sample), and FGFR2 alterations (10.1% and 5.6% of individual patients with at least 1 successfully-analysed sample had FGFR2 fusions and mutations, respectively).	('IDH1', 'Gene', (320, 324))	('TP53', 'Gene', (124, 128))	('patients', 'Species', '9606', (450, 458))	('patients', 'Species', '9606', (356, 364))	('FGFR2', 'Gene', (616, 621))	('KRAS', 'Gene', '3845', (216, 220))	('mutations', 'Var', (221, 230))	('patients', 'Species', '9606', (252, 260))	('IDH1', 'Gene', '3417', (320, 324))	('mutations', 'Var', (634, 643))	('FGFR2', 'Gene', (510, 515))	('FGFR2', 'Gene', '2263', (616, 621))	('fusions', 'Var', (622, 629))	('KRAS', 'Gene', (216, 220))	('TP53', 'Gene', '7157', (124, 128))	('CDKN2A', 'Gene', (412, 418))	('FGFR2', 'Gene', '2263', (510, 515))	('patients', 'Species', '9606', (558, 566))	('patients', 'Species', '9606', (160, 168))	('mutations', 'Var', (129, 138))	('CDKN2A', 'Gene', '1029', (412, 418))
124057	32899345	The main targetable findings were IDH1 mutations and FGFR2 fusions, present in 19.1% and 10.1% of patients successfully analysed.	('IDH1', 'Gene', '3417', (34, 38))	('patients', 'Species', '9606', (98, 106))	('mutations', 'Var', (39, 48))	('FGFR2', 'Gene', (53, 58))	('FGFR2', 'Gene', '2263', (53, 58))	('IDH1', 'Gene', (34, 38))	('fusions', 'Var', (59, 66))
124058	32899345	FGFR2 mutations were identified in 5.6% of individual successful-analysed patients.	('FGFR2', 'Gene', (0, 5))	('patients', 'Species', '9606', (74, 82))	('FGFR2', 'Gene', '2263', (0, 5))	('mutations', 'Var', (6, 15))
124060	32899345	Figure 2 provides detail regarding the FGFR2 and IDH1 alterations identified for individual patients.	('IDH1', 'Gene', '3417', (49, 53))	('patients', 'Species', '9606', (92, 100))	('FGFR2', 'Gene', (39, 44))	('FGFR2', 'Gene', '2263', (39, 44))	('alterations', 'Var', (54, 65))	('IDH1', 'Gene', (49, 53))
124062	32899345	The most frequent IDH1 mutation reported was C382R.	('IDH1', 'Gene', '3417', (18, 22))	('C382R', 'Mutation', 'p.C382R', (45, 50))	('IDH1', 'Gene', (18, 22))	('C382R', 'Var', (45, 50))
124063	32899345	Presence of BAP1 mutations were noted in two patients with FGFR2 mutations and four patients with FGFR2 fusions.	('FGFR2', 'Gene', (59, 64))	('FGFR2', 'Gene', '2263', (59, 64))	('patients', 'Species', '9606', (84, 92))	('BAP1', 'Gene', '8314', (12, 16))	('FGFR2', 'Gene', (98, 103))	('patients', 'Species', '9606', (45, 53))	('FGFR2', 'Gene', '2263', (98, 103))	('BAP1', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('mutations', 'Var', (65, 74))
124065	32899345	Neither the presence of IDH1 mutations nor FGFR2 fusions impacted on OSsample (Cox Regression p-value > 0.1).	('IDH1', 'Gene', '3417', (24, 28))	('OSsample', 'Disease', (69, 77))	('mutations', 'Var', (29, 38))	('IDH1', 'Gene', (24, 28))	('FGFR2', 'Gene', (43, 48))	('FGFR2', 'Gene', '2263', (43, 48))	('impacted', 'Reg', (57, 65))	('fusions', 'Var', (49, 56))
124072	32899345	There was adequate concordance in identification of targetable findings such as FGFR2 alterations and IDH1/IDH2 mutations (concordance 3/3; 100%); one patient with an FGFR2 fusion identified in one of the panels was not included as the fusion quality control failed in the second panel, and thus fusions were not tested for.	('IDH2', 'Gene', '3418', (107, 111))	('FGFR2', 'Gene', (80, 85))	('patient', 'Species', '9606', (151, 158))	('FGFR2', 'Gene', '2263', (80, 85))	('IDH1', 'Gene', (102, 106))	('mutations', 'Var', (112, 121))	('FGFR2', 'Gene', '2263', (167, 172))	('IDH1', 'Gene', '3417', (102, 106))	('FGFR2', 'Gene', (167, 172))	('IDH2', 'Gene', (107, 111))	('alterations', 'Var', (86, 97))
124076	32899345	Of these nine patients, three patients, two patients, and one patient were identified to have an IDH-1 mutation, FGFR-2 fusion, and FGFR-2 mutation in the tumour sample, respectively.	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('patients', 'Species', '9606', (14, 22))	('FGFR-2', 'Gene', '2263', (132, 138))	('tumour', 'Disease', (155, 161))	('mutation', 'Var', (139, 147))	('patients', 'Species', '9606', (44, 52))	('FGFR-2', 'Gene', (132, 138))	('patient', 'Species', '9606', (62, 69))	('IDH-1', 'Gene', '3417', (97, 102))	('patients', 'Species', '9606', (30, 38))	('patient', 'Species', '9606', (30, 37))	('fusion', 'Var', (120, 126))	('FGFR-2', 'Gene', '2263', (113, 119))	('patient', 'Species', '9606', (14, 21))	('FGFR-2', 'Gene', (113, 119))	('mutation', 'Var', (103, 111))	('patient', 'Species', '9606', (44, 51))	('IDH-1', 'Gene', (97, 102))
124083	32899345	The most frequently identified pathological molecular alterations were TP53 mutations (58.3%), IDH1 mutations (16.7%), FGFR2 mutation/fusion (16.7%), NF1 mutations (16.7%), and ALK fusion (8.3%) (Table S8), accounting for targetable findings in 5 of the 12 patients (41.7%) (4 iCCA and 1 GBC).	('mutations', 'Var', (100, 109))	('mutations', 'Var', (76, 85))	('iCCA', 'Disease', (277, 281))	('FGFR2', 'Gene', '2263', (119, 124))	('NF1', 'Gene', (150, 153))	('ALK', 'Gene', '238', (177, 180))	('NF1', 'Gene', '4763', (150, 153))	('IDH1', 'Gene', (95, 99))	('mutation/fusion', 'Var', (125, 140))	('patients', 'Species', '9606', (257, 265))	('mutations', 'Var', (154, 163))	('TP53', 'Gene', '7157', (71, 75))	('IDH1', 'Gene', '3417', (95, 99))	('TP53', 'Gene', (71, 75))	('ALK', 'Gene', (177, 180))	('FGFR2', 'Gene', (119, 124))
124084	32899345	Of the 89 patients with successfully-analysed samples, 15 (16.6%) had at least one pathogenic mutation in a DDR gene (Table S9).	('DDR gene', 'Gene', (108, 116))	('mutation', 'Var', (94, 102))	('patients', 'Species', '9606', (10, 18))
124085	32899345	The most frequently mutated genes in these 15 patients were ATM (26.6%) and BAP1 (46.6%).	('patients', 'Species', '9606', (46, 54))	('ATM', 'Gene', (60, 63))	('BAP1', 'Gene', '8314', (76, 80))	('BAP1', 'Gene', (76, 80))	('ATM', 'Gene', '472', (60, 63))	('mutated', 'Var', (20, 27))
124086	32899345	Baseline characteristics were compared between patients with and without mutations in DDR genes (Table S9), with no significant differences identified between both cohorts.	('patients', 'Species', '9606', (47, 55))	('DDR genes', 'Gene', (86, 95))	('mutations', 'Var', (73, 82))
124088	32899345	Of these 89 patients, 81 were treated with platinum-based chemotherapy (14 with mutations in DDR genes).	('DDR genes', 'Gene', (93, 102))	('patients', 'Species', '9606', (12, 20))	('platinum', 'Chemical', 'MESH:D010984', (43, 51))	('mutations', 'Var', (80, 89))
124089	32899345	However, those patients treated with platinum-based chemotherapy harbouring DDR mutations (vs. DDR wild-type) showed a trend towards improved partial response rate (21.4% vs. 15.9%), radiological benefit (64.3% vs. 36.2%) and OS benefit (OStreatment: median 20.4 months (95% CI 7.9-26.7) vs. 13.3 (95% CI 11.0-16.4); Cox Regression HR 0.79 (95% CI 0.39-1.61), p-value 0.527) (Figure 5, Supplementary Materials 6).	('partial response rate', 'CPA', (142, 163))	('patients', 'Species', '9606', (15, 23))	('mutations', 'Var', (80, 89))	('OS benefit', 'CPA', (226, 236))	('platinum', 'Chemical', 'MESH:D010984', (37, 45))	('improved', 'PosReg', (133, 141))	('DDR', 'Gene', (76, 79))	('radiological benefit', 'CPA', (183, 203))
124094	32899345	This study also demonstrates that molecular profiling can identify a subpopulation of patients with mutations in DDR genes, who may derive more benefit from platinum-based chemotherapy or other therapeutics targeting the DDR pathway.	('mutations', 'Var', (100, 109))	('DDR genes', 'Gene', (113, 122))	('benefit', 'PosReg', (144, 151))	('platinum', 'Chemical', 'MESH:D010984', (157, 165))	('patients', 'Species', '9606', (86, 94))
124097	32899345	In addition to the above-mentioned benefits favouring ctDNA-based molecular profiling in the absence of sufficient tissue, adequate concordance between tissue and ctDNA findings for patients with paired samples was demonstrated in this study (100% for FGFR2 and IDH1 alterations, which are currently of the most clinical relevance and interest in patients with iCCA in particular).	('IDH1', 'Gene', '3417', (262, 266))	('alterations', 'Var', (267, 278))	('patients', 'Species', '9606', (182, 190))	('FGFR2', 'Gene', (252, 257))	('iCCA', 'Disease', (361, 365))	('FGFR2', 'Gene', '2263', (252, 257))	('patients', 'Species', '9606', (347, 355))	('IDH1', 'Gene', (262, 266))
124103	32899345	Almost half of patients (40.2%) had potentially targetable alterations identified, mainly FGFR2 mutations and fusions and IDH1 mutations in patients with advanced iCCA, as expected.	('patients', 'Species', '9606', (15, 23))	('FGFR2', 'Gene', (90, 95))	('FGFR2', 'Gene', '2263', (90, 95))	('IDH1', 'Gene', (122, 126))	('patients', 'Species', '9606', (140, 148))	('iCCA', 'Disease', (163, 167))	('IDH1', 'Gene', '3417', (122, 126))	('mutations', 'Var', (127, 136))	('fusions', 'Var', (110, 117))	('mutations', 'Var', (96, 105))
124104	32899345	These profiling data match other previous observations, such as the co-existence of FGFR2 and BAP1 alterations, the episodic co-existence of cases with both fusions/mutations of FGFR2 and IDH1 mutations (which are not mutually exclusive) and BICC1 as the most frequent FGFR2 fusion partners.	('BICC1', 'Gene', (242, 247))	('BAP1', 'Gene', '8314', (94, 98))	('FGFR2', 'Gene', (269, 274))	('FGFR2', 'Gene', '2263', (269, 274))	('fusions/mutations', 'Var', (157, 174))	('IDH1', 'Gene', (188, 192))	('FGFR2', 'Gene', (84, 89))	('BICC1', 'Gene', '80114', (242, 247))	('mutations', 'Var', (193, 202))	('FGFR2', 'Gene', '2263', (84, 89))	('IDH1', 'Gene', '3417', (188, 192))	('FGFR2', 'Gene', '2263', (178, 183))	('BAP1', 'Gene', (94, 98))	('FGFR2', 'Gene', (178, 183))
124105	32899345	A significant prognostic impact for either FGFR2 fusions or IDH1 mutations was not identified, in contrast to prior unconfirmed hypotheses.	('IDH1', 'Gene', (60, 64))	('IDH1', 'Gene', '3417', (60, 64))	('FGFR2', 'Gene', (43, 48))	('FGFR2', 'Gene', '2263', (43, 48))	('fusions', 'Var', (49, 56))
124106	32899345	There was adequate concordance when paired tissue samples were analysed with two different platforms, mainly FGFR2 and IDH1 alterations.	('alterations', 'Var', (124, 135))	('IDH1', 'Gene', (119, 123))	('IDH1', 'Gene', '3417', (119, 123))	('FGFR2', 'Gene', (109, 114))	('FGFR2', 'Gene', '2263', (109, 114))
124108	32899345	Mutations in DDR genes were identified in up to 15 patients (16.6%), who, when treated with platinum-based chemotherapy, seemed to derive an increased benefit, in overall survival and radiological benefit.	('radiological benefit', 'CPA', (184, 204))	('benefit', 'PosReg', (151, 158))	('overall survival', 'CPA', (163, 179))	('DDR genes', 'Gene', (13, 22))	('Mutations', 'Var', (0, 9))	('platinum', 'Chemical', 'MESH:D010984', (92, 100))	('patients', 'Species', '9606', (51, 59))
124109	32899345	Identification of mutations in DDR genes could also help identifying patients who may benefit from other therapeutics targeting the DDR pathway such as poly ADP ribose polymerase (PARP) inhibitors or agents targeting Ataxia-Telangiesctasia mutated (ATM) or Ataxia telangiectasia and Rad3 related (ATR).	('ATR', 'Gene', (297, 300))	('Ataxia-Telangiesctasia mutated', 'Gene', (217, 247))	('poly ADP ribose polymerase', 'Gene', '142', (152, 178))	('PARP', 'Gene', '142', (180, 184))	('ATM', 'Gene', (249, 252))	('-Telangiesctasia', 'Phenotype', 'HP:0001009', (223, 239))	('poly ADP ribose polymerase', 'Gene', (152, 178))	('Ataxia telangiectasia and Rad3 related', 'Gene', '545', (257, 295))	('telangiectasia', 'Phenotype', 'HP:0001009', (264, 278))	('DDR genes', 'Gene', (31, 40))	('Ataxia-Telangiesctasia mutated', 'Gene', '472', (217, 247))	('ATR', 'Gene', '545', (297, 300))	('Ataxia', 'Phenotype', 'HP:0001251', (217, 223))	('ATM', 'Gene', '472', (249, 252))	('Ataxia', 'Phenotype', 'HP:0001251', (257, 263))	('patients', 'Species', '9606', (69, 77))	('PARP', 'Gene', (180, 184))	('mutations', 'Var', (18, 27))
124120	32899345	The following are available online at , Table S1: Baseline characteristics by sample type, Table S2: Pathological molecular findings by primary tumour, Table S3: Pathological molecular findings for individual patients diagnosed with intrahepatic cholangiocarcinoma, Table S4: Pathological molecular findings for individual patients diagnosed with extrahepatic cholangiocarcinoma, Table S5: Pathological molecular findings for individual patient diagnosed with gallbladder adenocarcinoma, Table S6: Pathological molecular findings for individual patients diagnosed with ampullary carcinoma, Table S7: Paired tissue samples, Table S8: ctDNA prior to treatment, Table S9: Baseline characteristics by presence/absence of DDR gene alterations.	('DDR', 'Gene', (717, 720))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (360, 378))	('gallbladder adenocarcinoma', 'Disease', 'MESH:D000230', (460, 486))	('alterations', 'Var', (726, 737))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (347, 378))	('carcinoma', 'Disease', 'MESH:D009369', (369, 378))	('patient', 'Species', '9606', (437, 444))	('carcinoma', 'Phenotype', 'HP:0030731', (477, 486))	('patients', 'Species', '9606', (323, 331))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (233, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('carcinoma', 'Disease', (255, 264))	('intrahepatic cholangiocarcinoma', 'Disease', (233, 264))	('carcinoma', 'Disease', (477, 486))	('patients', 'Species', '9606', (545, 553))	('carcinoma', 'Phenotype', 'HP:0030731', (579, 588))	('patient', 'Species', '9606', (545, 552))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (246, 264))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('carcinoma', 'Disease', (579, 588))	('gallbladder adenocarcinoma', 'Disease', (460, 486))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('presence/absence', 'NegReg', (697, 713))	('tumour', 'Disease', (144, 150))	('carcinoma', 'Disease', 'MESH:D009369', (477, 486))	('patients', 'Species', '9606', (209, 217))	('carcinoma', 'Disease', 'MESH:D009369', (255, 264))	('patient', 'Species', '9606', (323, 330))	('extrahepatic cholangiocarcinoma', 'Disease', (347, 378))	('patient', 'Species', '9606', (209, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (369, 378))	('carcinoma', 'Disease', 'MESH:D009369', (579, 588))	('carcinoma', 'Disease', (369, 378))
124121	32899345	; recruitment of patients: all authors (A.L., Z.K., M.B., C.B., D.B., H.S., C.T., M.G.M., R.A.H., J.W.V.	('R.A.H.', 'Var', (90, 96))	('M.G.M.', 'Var', (82, 88))	('C.T.', 'Var', (76, 80))	('D.B.', 'Var', (64, 68))	('patients', 'Species', '9606', (17, 25))	('C.B.', 'Var', (58, 62))
124260	26504879	Duplication of the extrahepatic bile duct is a rare anomaly of the biliary system.	('anomaly of the biliary system', 'Phenotype', 'HP:0004297', (52, 81))	('anomaly of the biliary system', 'Disease', 'MESH:D001656', (52, 81))	('anomaly of the biliary', 'Phenotype', 'HP:0012440', (52, 74))	('Duplication', 'Var', (0, 11))	('anomaly of the biliary system', 'Disease', (52, 81))
124379	32365487	RNA-sequencing analysis showed that silencing of TESC decreases the level of FOXM1, leading to cell cycle arrest.	('level', 'MPA', (68, 73))	('FOXM1', 'MPA', (77, 82))	('arrest', 'Disease', (106, 112))	('TESC', 'Gene', (49, 53))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (95, 112))	('decreases', 'NegReg', (54, 63))	('silencing', 'Var', (36, 45))	('arrest', 'Disease', 'MESH:D006323', (106, 112))
124382	32365487	In vivo experiments revealed that knockdown of TESC significantly attenuates tumor cell growth.	('TESC', 'Gene', (47, 51))	('attenuates', 'NegReg', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('knockdown', 'Var', (34, 43))	('tumor', 'Disease', (77, 82))
124391	32365487	Aberrant regulation of the cell cycle has been implicated in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('Aberrant', 'Var', (0, 8))	('cell cycle', 'CPA', (27, 37))	('cancer', 'Disease', (61, 67))	('implicated', 'Reg', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
124415	32365487	MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltertrazolium bromide) and clonogenic assays indicated that TESC silencing significantly attenuated cell proliferation (Figure 3c,d; Figure S5a,b).	('3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltertrazolium bromide', 'Chemical', '-', (5, 66))	('silencing', 'Var', (110, 119))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('rat', 'Species', '10116', (157, 160))	('cell proliferation', 'CPA', (145, 163))	('attenuated', 'NegReg', (134, 144))	('TESC', 'Gene', (105, 109))
124416	32365487	In contrast, ectopic expression of TESC in HUCCT1 cells enhanced cell proliferation (Figure S5c).	('rat', 'Species', '10116', (77, 80))	('HUCCT1', 'CellLine', 'CVCL:0324', (43, 49))	('enhanced', 'PosReg', (56, 64))	('cell proliferation', 'CPA', (65, 83))	('ectopic expression', 'Var', (13, 31))	('TESC', 'Gene', (35, 39))
124417	32365487	Cell cycle analysis revealed that knockdown of TESC results in G2/M cell cycle arrest in RBE and HUCCT1 cells (Figure 3e and Figure S5d).	('arrest', 'Disease', 'MESH:D006323', (79, 85))	('TESC', 'Gene', (47, 51))	('HUCCT1', 'CellLine', 'CVCL:0324', (97, 103))	('arrest', 'Disease', (79, 85))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (68, 85))	('knockdown', 'Var', (34, 43))
124418	32365487	TESC silencing inhibited the ability of migration (Figure S6) and induced apoptosis (Figure 3f).	('apoptosis', 'CPA', (74, 83))	('inhibited', 'NegReg', (15, 24))	('silencing', 'Var', (5, 14))	('rat', 'Species', '10116', (43, 46))	('TESC', 'Protein', (0, 4))	('induced', 'Reg', (66, 73))
124421	32365487	Clonogenic assays revealed that knockdown of FOXM1 attenuates the proliferation of RBE cells (Figure S7a).	('FOXM1', 'Gene', (45, 50))	('rat', 'Species', '10116', (73, 76))	('knockdown', 'Var', (32, 41))	('attenuates', 'NegReg', (51, 61))
124422	32365487	Similar to the results of TESC knockdown, FOXM1 silencing attenuated cell proliferation via G2/M cell cycle arrest (Figure S7b).	('cell cycle arrest', 'Phenotype', 'HP:0011018', (97, 114))	('silencing', 'Var', (48, 57))	('attenuated', 'NegReg', (58, 68))	('rat', 'Species', '10116', (81, 84))	('arrest', 'Disease', 'MESH:D006323', (108, 114))	('cell proliferation', 'CPA', (69, 87))	('arrest', 'Disease', (108, 114))	('FOXM1', 'Gene', (42, 47))
124428	32365487	Consistently, pharmacologic inhibition of EGFR as well as STAT3 with gefitinib, an EGFR inhibitor, and WP1066, a STAT3 inhibitor, respectively, attenuated the TGF-alpha-induced upregulation of TESC (Figure S9).	('attenuated', 'NegReg', (144, 154))	('gefitinib', 'Chemical', 'MESH:D000077156', (69, 78))	('WP1066', 'Var', (103, 109))	('upregulation', 'PosReg', (177, 189))	('TESC', 'MPA', (193, 197))	('TGF-alpha-induced', 'Protein', (159, 176))
124429	32365487	The MTT and clonogenic assays indicated that TGF-alpha treatment promoted cell proliferation, whereas TESC as well as FOXM1 silencing suppressed TGF-alpha-induced cell proliferation (Figure 6c,d).	('suppressed', 'NegReg', (134, 144))	('cell proliferation', 'CPA', (74, 92))	('silencing', 'Var', (124, 133))	('FOXM1', 'Gene', (118, 123))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('promoted', 'PosReg', (65, 73))	('rat', 'Species', '10116', (175, 178))	('cell proliferation', 'CPA', (163, 181))	('rat', 'Species', '10116', (86, 89))
124433	32365487	The results demonstrate that knockdown of TESC significantly attenuated tumor growth and reduced tumor weight (Figure 7a,b), suggesting that TESC plays an important role in ICC progression.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('ICC', 'Disease', (173, 176))	('knockdown', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('reduced tumor weight', 'Disease', 'MESH:D015431', (89, 109))	('rat', 'Species', '10116', (19, 22))	('TESC', 'Gene', (42, 46))	('attenuated tumor', 'Disease', (61, 77))	('attenuated tumor', 'Disease', 'MESH:C538265', (61, 77))	('reduced tumor weight', 'Disease', (89, 109))
124436	32365487	The level of Ki67 was also lower in TESC-silenced group, indicating the proliferation ability was suppressed (Figure S10).	('Ki67', 'Var', (13, 17))	('suppressed', 'NegReg', (98, 108))	('proliferation ability', 'CPA', (72, 93))	('lower', 'NegReg', (27, 32))	('rat', 'Species', '10116', (79, 82))
124441	32365487	Notably, the knockdown of endogenous TESC in response to doxycycline caused significant tumor shrinkage (Figure 7c,d).	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('doxycycline', 'Chemical', 'MESH:D004318', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('knockdown', 'Var', (13, 22))	('tumor', 'Disease', (88, 93))
124451	32365487	Although TESC expression has also been reported in various types of cancer and potentiates cell proliferation and tumorigenicity, the mechanism behind TESC-mediated oncogenesis is unclear.	('expression', 'Var', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('rat', 'Species', '10116', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('potentiates', 'PosReg', (79, 90))	('cell proliferation', 'CPA', (91, 109))	('TESC', 'Gene', (9, 13))
124458	32365487	Taken together, these data suggest that the TESC level is tightly regulated by various mechanisms, and aberrant expression of TESC caused by misregulation accelerates tumor progression in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (188, 206))	('TESC', 'Gene', (126, 130))	('aberrant', 'Var', (103, 111))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('accelerates', 'PosReg', (155, 166))	('misregulation', 'Var', (141, 154))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (188, 206))	('rat', 'Species', '10116', (161, 164))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))	('cholangiocarcinoma', 'Disease', (188, 206))
124479	32365487	Sections were dewaxed and subjected to heat-based antigen retrieval with 10 mM sodium citrate buffer (pH 6.0) at 121  C. Cholangiocarcinoma cells were infected with viruses carrying pLKO.1-shTESC, pLKO.1-FOXM1, or pLKO.1-Screamble control.	('infected', 'Disease', 'MESH:D007239', (151, 159))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (121, 139))	('Cholangiocarcinoma', 'Disease', (121, 139))	('sodium citrate', 'Chemical', 'MESH:D000077559', (79, 93))	('infected', 'Disease', (151, 159))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))	('pLKO.1-shTESC', 'Var', (182, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('pLKO.1-FOXM1', 'Var', (197, 209))
124495	32365487	In this study, we observed that high expression of TESC is associated with poor prognosis of patients with cholangiocarcinoma.	('TESC', 'Gene', (51, 55))	('cholangiocarcinoma', 'Disease', (107, 125))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (107, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (107, 125))	('patients', 'Species', '9606', (93, 101))	('high expression', 'Var', (32, 47))
124500	32365487	The following are available online at , Figure S1: Identification of genes that contribute to tumorigenesis in cholangiocarcinoma, Figure S2: TESC expression profile in the TCGA database, Figure S3: The expression of CHP1 and CHP2 in ICC, Figure S4: TESC is expressed in caerulein-treated rats, Figure S5: TESC regulates tumor proliferation, Figure S6: Knockdown of TESC inhibits the ability of migration, Figure S7: FOXM1 regulates tumor growth, Figure S8: TESC regulates the G2/M transition through FOXM1, Figure S9: Inhibition of EGFR-STAT3 signaling blocked TGF-alpha-induced TESC expression, Figure S10: Hematoxylin and eosin (H&E) and immunohistochemical staining of TESC and FOXM1, Figure S11: Doxycycline-inducible knockdown of TESC impairs colony formation in vitro, Figure S12: Immunoblotting files with densitometry data, Table S1: Reagents used in this study, Table S2: Primers used for qPCR, Table S3: Primers used for ChIP, Table S4: Antibodies used for immunoblotting, Table S5: shRNA clones used in this study, Table S6: Gene expression profiling data used in this study.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('TESC', 'NegReg', (736, 740))	('tumor', 'Disease', (433, 438))	('impairs colony formation in', 'CPA', (741, 768))	('CHP1', 'Species', '10857', (217, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('rats', 'Species', '10116', (289, 293))	('tumor', 'Disease', (321, 326))	('tumor', 'Disease', 'MESH:D009369', (433, 438))	('Doxycycline-inducible', 'Var', (701, 722))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))	('tumor', 'Phenotype', 'HP:0002664', (433, 438))	('cholangiocarcinoma', 'Disease', (111, 129))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 129))	('rat', 'Species', '10116', (289, 292))	('tumor', 'Disease', (94, 99))	('caerulein', 'Chemical', 'MESH:D002108', (271, 280))	('rat', 'Species', '10116', (398, 401))	('CHP2', 'Species', '105154', (226, 230))	('rat', 'Species', '10116', (334, 337))
124504	32365487	This work was financially supported by the TMU Research Center of Cancer Translational Medicine from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan and by Health and Welfare Surcharge of Tobacco Products grant MOHW108-TDU-B-212-124014, MOHW108-TDU-B-212-124026, and MOHW108-TDU-B-212-124020, and by the Ministry of Science and Technology MOST-108-2321-B-038-003.	('MOHW108-TDU-B-212-124020', 'Var', (367, 391))	('Tobacco', 'Species', '4097', (288, 295))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('MOHW108-TDU-B-212-124014', 'Var', (311, 335))	('Cancer', 'Disease', (66, 72))	('Cancer', 'Disease', 'MESH:D009369', (66, 72))	('MOHW108-TDU-B-212-124026', 'Var', (337, 361))
124627	28994423	Moreover, NGS revealed driver mutations in 24 patients, including KRAS, TP53, and CDKN2A aberrations.	('patients', 'Species', '9606', (46, 54))	('TP53', 'Gene', '7157', (72, 76))	('KRAS', 'Gene', '3845', (66, 70))	('CDKN2A', 'Gene', (82, 88))	('TP53', 'Gene', (72, 76))	('mutations', 'Var', (30, 39))	('CDKN2A', 'Gene', '1029', (82, 88))	('KRAS', 'Gene', (66, 70))
124685	28994423	Comprehensive whole-exome and transcriptome sequencing in a large cohort of 260 patients with biliary tract cancers, including 145 with iCCA, 86 with pCCA/dCCA, and 29 with gallbladder cancer, revealed potentially targetable genetic driver alterations in ~40% of patients.	('alterations', 'Var', (240, 251))	('iCCA', 'Disease', (136, 140))	('patients', 'Species', '9606', (80, 88))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('patients', 'Species', '9606', (263, 271))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('gallbladder cancer', 'Disease', (173, 191))	('gallbladder cancer', 'Disease', 'MESH:D005706', (173, 191))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('biliary tract cancers', 'Disease', 'MESH:D001661', (94, 115))	('biliary tract cancers', 'Disease', (94, 115))	('bladder cancer', 'Phenotype', 'HP:0009725', (177, 191))
124687	28994423	For example, recurrent mutations in IDH1, IDH2, FGFR1, FGFR2, FGFR3, EPHA2, and BAP1 were noted predominantly in iCCAs, whereas ARID1B, ELF3, PBRM1, PRKACA, and PRKACB mutations occurred preferentially in pCCA/dCCA.	('ARID1B', 'Gene', (128, 134))	('BAP1', 'Gene', '8314', (80, 84))	('FGFR2', 'Gene', '2263', (55, 60))	('FGFR1', 'Gene', (48, 53))	('EPHA2', 'Gene', (69, 74))	('FGFR3', 'Gene', (62, 67))	('PRKACA', 'Gene', (149, 155))	('ARID1B', 'Gene', '57492', (128, 134))	('ELF3', 'Gene', '1999', (136, 140))	('PBRM1', 'Gene', '55193', (142, 147))	('PRKACB', 'Gene', '5567', (161, 167))	('FGFR3', 'Gene', '2261', (62, 67))	('mutations', 'Var', (23, 32))	('PBRM1', 'Gene', (142, 147))	('BAP1', 'Gene', (80, 84))	('ELF3', 'Gene', (136, 140))	('IDH1', 'Gene', (36, 40))	('EPHA2', 'Gene', '1969', (69, 74))	('IDH2', 'Gene', (42, 46))	('FGFR1', 'Gene', '2260', (48, 53))	('PRKACA', 'Gene', '5566', (149, 155))	('IDH2', 'Gene', '3418', (42, 46))	('FGFR2', 'Gene', (55, 60))	('PRKACB', 'Gene', (161, 167))	('IDH1', 'Gene', '3417', (36, 40))	('pCCA/dCCA', 'Disease', (205, 214))
124688	28994423	Notably, fibroblast growth factor receptor 2 (FGFR2) fusions that result in ligand-independent activation of this receptor-tyrosine kinase were identified exclusively in patients with iCCA, consistent with prior observations.	('patients', 'Species', '9606', (170, 178))	('fusions', 'Var', (53, 60))	('FGFR2', 'Gene', (46, 51))	('FGFR2', 'Gene', '2263', (46, 51))	('activation', 'PosReg', (95, 105))	('iCCA', 'Disease', (184, 188))	('fibroblast growth factor receptor 2', 'Gene', (9, 44))	('fibroblast growth factor receptor 2', 'Gene', '2263', (9, 44))
124691	28994423	Inactivating mutations in ELF3 have since been identified in dCCA samples in two other genomic analyses; thus, the ETS-related transcription factor ELF3 probably acts as a tumour suppressor in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (193, 211))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (193, 211))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('ELF3', 'Gene', (148, 152))	('ELF3', 'Gene', '1999', (148, 152))	('Inactivating mutations', 'Var', (0, 22))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('tumour', 'Disease', (172, 178))	('ELF3', 'Gene', '1999', (26, 30))	('cholangiocarcinoma', 'Disease', (193, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('ELF3', 'Gene', (26, 30))
124693	28994423	The most common alterations involved ARID1A, IDH1, IDH2, and TP53 (each identified in 36% of the tumours), as well as MCL1 (amplified in 21% of tumours).	('TP53', 'Gene', (61, 65))	('MCL1', 'Gene', '4170', (118, 122))	('tumours', 'Disease', (97, 104))	('IDH2', 'Gene', (51, 55))	('IDH1', 'Gene', (45, 49))	('tumours', 'Disease', (144, 151))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('tumours', 'Disease', 'MESH:D009369', (97, 104))	('IDH2', 'Gene', '3418', (51, 55))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('alterations', 'Var', (16, 27))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumours', 'Disease', 'MESH:D009369', (144, 151))	('ARID1A', 'Gene', (37, 43))	('TP53', 'Gene', '7157', (61, 65))	('IDH1', 'Gene', '3417', (45, 49))	('ARID1A', 'Gene', '8289', (37, 43))	('MCL1', 'Gene', (118, 122))
124694	28994423	Discrete carcinogenic exposures might induce distinct somatic alterations in patients with cholangiocarcinomas, as highlighted by whole-exome sequencing data from 108 liver-fluke-related and 101 non-liver-fluke-related tumours: non-liver-fluke-related iCCAs had a higher prevalence of mutations in IDH1 or IDH2 (encoding isocitrate dehydrogenase [NADP] cytoplasmic (IDH1) and mitochondrial (IDH2)), and loss-of-function mutations in the tumour-suppressor gene BAP1 (encoding the epigenetic regulator BRCA1-associated protein 1 (BAP1)).	('tumour', 'Phenotype', 'HP:0002664', (219, 225))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('IDH1', 'Gene', (366, 370))	('tumour', 'Disease', 'MESH:D009369', (219, 225))	('tumour', 'Disease', (219, 225))	('liver-fluke', 'Species', '6192', (232, 243))	('BAP1', 'Gene', (460, 464))	('mutations', 'Var', (420, 429))	('patients', 'Species', '9606', (77, 85))	('BAP1', 'Gene', '8314', (528, 532))	('IDH1', 'Gene', '3417', (366, 370))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (91, 110))	('carcinogenic', 'Disease', (9, 21))	('IDH2', 'Gene', (306, 310))	('mutations', 'Var', (285, 294))	('IDH2', 'Gene', '3418', (306, 310))	('liver-fluke', 'Species', '6192', (167, 178))	('IDH2', 'Gene', (391, 395))	('cholangiocarcinomas', 'Disease', (91, 110))	('IDH1', 'Gene', (298, 302))	('liver-fluke', 'Species', '6192', (199, 210))	('BRCA1', 'Gene', '672', (500, 505))	('loss-of-function', 'NegReg', (403, 419))	('tumour', 'Phenotype', 'HP:0002664', (437, 443))	('tumours', 'Disease', (219, 226))	('tumour', 'Disease', 'MESH:D009369', (437, 443))	('carcinogenic', 'Disease', 'MESH:D063646', (9, 21))	('IDH2', 'Gene', '3418', (391, 395))	('BRCA1', 'Gene', (500, 505))	('BAP1', 'Gene', (528, 532))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('tumour', 'Disease', (437, 443))	('tumours', 'Phenotype', 'HP:0002664', (219, 226))	('tumours', 'Disease', 'MESH:D009369', (219, 226))	('IDH1', 'Gene', '3417', (298, 302))	('BAP1', 'Gene', '8314', (460, 464))
124695	28994423	By contrast, mutations in the tumour-suppressor gene TP53 were a more frequent occurrence in liver-fluke-related cholangiocarcinomas.	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (113, 132))	('frequent occurrence', 'Reg', (70, 89))	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (113, 131))	('tumour', 'Disease', (30, 36))	('TP53', 'Gene', '7157', (53, 57))	('cholangiocarcinomas', 'Disease', (113, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('mutations', 'Var', (13, 22))	('liver-fluke', 'Species', '6192', (93, 104))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('TP53', 'Gene', (53, 57))
124697	28994423	An integrated genomic analysis of predominantly liver-fluke-negative, hepatitis-negative iCCAs by The Cancer Genome Atlas (TCGA) investigators identified inactivating mutations in tumour-suppressor genes, including ARID1A, ARID1B, BAP1, TP53, and PTEN, and gain-of-function mutations in the oncogenes IDH1, IDH2, BRAF, and KRAS : recapitulating the aforementioned findings.	('ARID1B', 'Gene', (223, 229))	('KRAS', 'Gene', (323, 327))	('TP53', 'Gene', (237, 241))	('ARID1B', 'Gene', '57492', (223, 229))	('BAP1', 'Gene', (231, 235))	('inactivating mutations', 'Var', (154, 176))	('IDH2', 'Gene', (307, 311))	('IDH2', 'Gene', '3418', (307, 311))	('IDH1', 'Gene', (301, 305))	('gain-of-function', 'PosReg', (257, 273))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (102, 121))	('PTEN', 'Gene', (247, 251))	('ARID1A', 'Gene', (215, 221))	('TP53', 'Gene', '7157', (237, 241))	('Cancer Genome Atlas', 'Disease', (102, 121))	('hepatitis', 'Phenotype', 'HP:0012115', (70, 79))	('IDH1', 'Gene', '3417', (301, 305))	('BRAF', 'Gene', '673', (313, 317))	('hepatitis', 'Disease', 'MESH:D056486', (70, 79))	('BRAF', 'Gene', (313, 317))	('PTEN', 'Gene', '5728', (247, 251))	('liver-fluke', 'Species', '6192', (48, 59))	('ARID1A', 'Gene', '8289', (215, 221))	('men', 'Species', '9606', (354, 357))	('hepatitis', 'Disease', (70, 79))	('KRAS', 'Gene', '3845', (323, 327))	('BAP1', 'Gene', '8314', (231, 235))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('Cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('tumour', 'Disease', (180, 186))
124699	28994423	Consistent with prior reports, mutations in IDH1 or IDH2 were detected exclusively in iCCA, and were highly enriched in a novel, distinct molecular iCCA subtype identified through cluster-of-cluster analysis of gene-expression, DNA-methylation, and copy-number profiles.	('detected', 'Reg', (62, 70))	('IDH2', 'Gene', '3418', (52, 56))	('mutations', 'Var', (31, 40))	('IDH1', 'Gene', (44, 48))	('IDH1', 'Gene', '3417', (44, 48))	('iCCA', 'Disease', (86, 90))	('IDH2', 'Gene', (52, 56))
124700	28994423	Interestingly, this subtype was associated with high and low levels of mitochondrial and chromatin-modifier gene expression, respectively, including probable epigenetic silencing of ARID1A, which encodes a subunit of the SWI/SNF chromatin-remodelling complex.	('epigenetic silencing', 'Var', (158, 178))	('ARID1A', 'Gene', '8289', (182, 188))	('low', 'NegReg', (57, 60))	('mitochondrial', 'MPA', (71, 84))	('ARID1A', 'Gene', (182, 188))
124701	28994423	Two other molecular subtypes of iCCA were defined, one comprising tumours enriched for BAP1 mutations and/or FGFR2 fusions, and the other enriched for CCND1 amplification.	('fusions', 'Var', (115, 122))	('BAP1', 'Gene', '8314', (87, 91))	('CCND1', 'Gene', '595', (151, 156))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('BAP1', 'Gene', (87, 91))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('mutations', 'Var', (92, 101))	('FGFR2', 'Gene', (109, 114))	('iCCA', 'Disease', (32, 36))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('tumours', 'Disease', (66, 73))	('CCND1', 'Gene', (151, 156))	('FGFR2', 'Gene', '2263', (109, 114))
124702	28994423	Several selective and nonselective small-molecule inhibitors of FGFRs are currently being investigated in early phase clinical trials involving patients with advanced-stage solid-organ malignancies, including cholangiocarcinoma (Supplementary information S1 (table)).	('cholangiocarcinoma', 'Disease', (209, 227))	('solid-organ malignancies', 'Disease', (173, 197))	('inhibitors', 'Var', (50, 60))	('solid-organ malignancies', 'Disease', 'MESH:D009369', (173, 197))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (209, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (209, 227))	('patients', 'Species', '9606', (144, 152))	('men', 'Species', '9606', (235, 238))	('FGFRs', 'Gene', (64, 69))
124703	28994423	The pan-FGFR inhibitor NVP-BGJ398, having demonstrated potential in preclinical models of cholangiocarcinoma, is currently being investigated in a phase II study in patients with advanced-stage cholangiocarcinoma harbouring FGFR alterations (NCT02150967).	('NVP-BGJ398', 'Gene', (23, 33))	('cholangiocarcinoma', 'Disease', (90, 108))	('FGFR', 'Gene', (224, 228))	('alterations', 'Var', (229, 240))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (90, 108))	('cholangiocarcinoma', 'Disease', (194, 212))	('patients', 'Species', '9606', (165, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (194, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (194, 212))
124706	28994423	In a phase I dose-escalation study (NCT01703481), erdafitinib had a manageable safety profile at doses associated with clinical responses; among 23 response-evaluable patients with solid tumours harbouring FGFR-pathway alterations, four patients had a confirmed response to treatment with erdafitinib, one had an unconfirmed partial response, and 16 had stable disease.	('men', 'Species', '9606', (279, 282))	('alterations', 'Var', (219, 230))	('patients', 'Species', '9606', (167, 175))	('solid tumours', 'Disease', 'MESH:D009369', (181, 194))	('erdafitinib', 'Chemical', 'MESH:C000604580', (289, 300))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('solid tumours', 'Disease', (181, 194))	('FGFR-pathway', 'Gene', (206, 218))	('patients', 'Species', '9606', (237, 245))	('erdafitinib', 'Chemical', 'MESH:C000604580', (50, 61))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))
124708	28994423	Other FGFR-selective inhibitors currently being evaluated in patients with advanced-stage solid-organ malignancies include derazantinib (NCT01752920), TAS-120 (NCT02052778), Debio 1347 (NCT01948297), and INCB054828 (NCT02924376, NCT02393248).	('solid-organ malignancies', 'Disease', (90, 114))	('solid-organ malignancies', 'Disease', 'MESH:D009369', (90, 114))	('FGFR-selective', 'Gene', (6, 20))	('NCT01948297', 'Var', (186, 197))	('NCT02052778', 'Var', (160, 171))	('NCT01752920', 'Var', (137, 148))	('patients', 'Species', '9606', (61, 69))	('NCT02924376', 'Var', (216, 227))	('derazantinib', 'Chemical', 'MESH:C000621805', (123, 135))
124709	28994423	Ponatinib, a nonselective tyrosine-kinase inhibitor, has shown promising efficacy in patients with advanced-stage iCCA with FGFR2 fusions, and is currently being evaluated in a phase II trial in this population (NCT02265341; Supplementary information S1 (table)).	('FGFR2', 'Gene', (124, 129))	('FGFR2', 'Gene', '2263', (124, 129))	('fusions', 'Var', (130, 137))	('patients', 'Species', '9606', (85, 93))	('men', 'Species', '9606', (231, 234))	('Ponatinib', 'Chemical', 'MESH:C545373', (0, 9))	('iCCA', 'Disease', (114, 118))
124710	28994423	Inhibition of heat-shock protein 90 (HSP90) is an alternative to direct FGFR-kinase inhibition in FGFR2-fusion-driven cancers.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('shock', 'Phenotype', 'HP:0031273', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('FGFR2', 'Gene', (98, 103))	('Inhibition', 'Var', (0, 10))	('FGFR2', 'Gene', '2263', (98, 103))	('heat-shock protein 90', 'Gene', (14, 35))	('HSP90', 'Gene', (37, 42))	('HSP90', 'Gene', '3320', (37, 42))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('heat-shock protein 90', 'Gene', '3320', (14, 35))
124715	28994423	In a mouse orthotopic allograft model, expression of the FIG-ROS1 fusion accelerated iCCA tumour development and inactivation of this fusion had the converse effect, indicating that ROS1 fusions are potent oncoproteins and a potential therapeutic target in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (257, 275))	('men', 'Species', '9606', (104, 107))	('fusions', 'Var', (187, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('fusion', 'Var', (66, 72))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (257, 275))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (257, 275))	('mouse', 'Species', '10090', (5, 10))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('accelerated', 'PosReg', (73, 84))	('FIG-ROS1', 'Gene', (57, 65))	('tumour', 'Disease', (90, 96))	('inactivation', 'Var', (113, 125))
124718	28994423	Entrectinib, a selective tyrosine-kinase inhibitor with activity against ROS1 and ALK (as well as TRKA, TRKB, and TRKC), is also being evaluated in a phase II study involving patients with advanced-stage solid tumours harbouring ROS1 or ALK fusions (NCT02568267).	('ALK', 'Protein', (237, 240))	('ROS1', 'Protein', (73, 77))	('advanced-stage solid tumours', 'Disease', (189, 217))	('Entrectinib', 'Chemical', 'MESH:C000607349', (0, 11))	('ROS1', 'Var', (229, 233))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('patients', 'Species', '9606', (175, 183))	('TRKC', 'Gene', '4916', (114, 118))	('tumours', 'Phenotype', 'HP:0002664', (210, 217))	('advanced-stage solid tumours', 'Disease', 'MESH:D006223', (189, 217))	('TRKC', 'Gene', (114, 118))
124719	28994423	Activating mutations of the proto-oncogene KRAS are a frequent occurrence (11-25%, depending on disease subtype) in cholangiocarcinomas, and are associated with unfavourable progression-free survival (PFS) and overall survival.	('progression-free survival', 'CPA', (174, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (116, 135))	('Activating mutations', 'Var', (0, 20))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))	('associated', 'Reg', (145, 155))	('cholangiocarcinomas', 'Disease', (116, 135))	('KRAS', 'Gene', (43, 47))	('KRAS', 'Gene', '3845', (43, 47))
124725	28994423	BRAF mutations can also occur in cholangiocarcinoma (predominantly in iCCAs), albeit at a low frequency (3-5%).	('occur', 'Reg', (24, 29))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (33, 51))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('cholangiocarcinoma', 'Disease', (33, 51))	('BRAF', 'Gene', (0, 4))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (33, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
124726	28994423	In eight patients with BRAF V600-mutated cholangiocarcinoma, treatment with the oral BRAF inhibitor vemurafenib led to a partial response in one patient.	('patients', 'Species', '9606', (9, 17))	('men', 'Species', '9606', (66, 69))	('V600-mutated', 'Var', (28, 40))	('BRAF', 'Gene', '673', (23, 27))	('cholangiocarcinoma', 'Disease', (41, 59))	('vemurafenib', 'Chemical', 'MESH:D000077484', (100, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('BRAF', 'Gene', (23, 27))	('BRAF', 'Gene', (85, 89))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (41, 59))	('BRAF', 'Gene', '673', (85, 89))	('patient', 'Species', '9606', (145, 152))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (41, 59))	('patient', 'Species', '9606', (9, 16))
124735	28994423	The aforementioned genetic profiling studies have revealed that mutations affecting epigenetic regulators, such as IDH1, IDH2, BAP1, and ARID1A, are common in cholangiocarcinomas; thus, epigenetic therapies are a promising endeavour.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('BAP1', 'Gene', (127, 131))	('ARID1A', 'Gene', '8289', (137, 143))	('ARID1A', 'Gene', (137, 143))	('IDH1', 'Gene', (115, 119))	('IDH2', 'Gene', '3418', (121, 125))	('common', 'Reg', (149, 155))	('men', 'Species', '9606', (9, 12))	('IDH1', 'Gene', '3417', (115, 119))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (159, 178))	('mutations', 'Var', (64, 73))	('BAP1', 'Gene', '8314', (127, 131))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (159, 177))	('IDH2', 'Gene', (121, 125))	('cholangiocarcinomas', 'Disease', (159, 178))
124736	28994423	Small-molecule inhibitors of mutant IDH1 or IDH2 have shown favourable efficacy in preclinical studies; consequently, orally bioavailable inhibitors have entered clinical trials.	('IDH1', 'Gene', (36, 40))	('IDH2', 'Gene', (44, 48))	('mutant', 'Var', (29, 35))	('IDH2', 'Gene', '3418', (44, 48))	('IDH1', 'Gene', '3417', (36, 40))
124737	28994423	Preliminary results from a phase I trial of AG-120 (NCT02073994; Supplementary information S1 (table)), an inhibitor of mutant IDH1, in a dose-escalation and dose-expansion cohort of patients with cholangiocarcinoma harbouring IDH1 mutations indicated a favourable safety profile.	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (197, 215))	('AG-120', 'Chemical', 'MESH:C000627630', (44, 50))	('IDH1', 'Gene', '3417', (227, 231))	('men', 'Species', '9606', (71, 74))	('IDH1', 'Gene', (127, 131))	('mutations', 'Var', (232, 241))	('cholangiocarcinoma', 'Disease', (197, 215))	('IDH1', 'Gene', '3417', (127, 131))	('IDH1', 'Gene', (227, 231))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (197, 215))	('mutant', 'Var', (120, 126))	('patients', 'Species', '9606', (183, 191))
124740	28994423	Enasidenib, a first-in-class, oral, selective inhibitor of mutant IDH2, has demonstrated activity in preclinical models of acute myeloid leukaemia (AML).	('IDH2', 'Gene', '3418', (66, 70))	('Enasidenib', 'Chemical', 'MESH:C000605269', (0, 10))	('acute myeloid leukaemia', 'Disease', (123, 146))	('mutant', 'Var', (59, 65))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (129, 146))	('AML', 'Disease', (148, 151))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (123, 146))	('IDH2', 'Gene', (66, 70))	('AML', 'Disease', 'MESH:D015470', (148, 151))
124741	28994423	Consequently, enasidenib has been granted priority review by the FDA for patients with AML harbouring an IDH2 mutation.	('IDH2', 'Gene', (105, 109))	('AML', 'Disease', (87, 90))	('enasidenib', 'Chemical', 'MESH:C000605269', (14, 24))	('IDH2', 'Gene', '3418', (105, 109))	('mutation', 'Var', (110, 118))	('patients', 'Species', '9606', (73, 81))	('AML', 'Disease', 'MESH:D015470', (87, 90))
124743	28994423	Of note, IDH-mutant iCCA cells are dependent on SRC activity for survival; the SRC kinase inhibitor dasatinib induced tumour regression of mouse IDH-mutant tumour xenografts.	('tumour', 'Disease', (118, 124))	('tumour', 'Disease', (156, 162))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('IDH-mutant', 'Var', (145, 155))	('mouse', 'Species', '10090', (139, 144))	('dasatinib', 'Chemical', 'MESH:D000069439', (100, 109))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (156, 162))
124745	28994423	In addition, the TCGA analysis suggests that IDH-mutant cholangiocarcinomas probably have epigenetic silencing of the SWI/SNF chromatin-remodelling complex protein ARID1A.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('cholangiocarcinomas', 'Disease', (56, 75))	('ARID1A', 'Gene', '8289', (164, 170))	('ARID1A', 'Gene', (164, 170))	('epigenetic silencing', 'Var', (90, 110))	('IDH-mutant', 'Var', (45, 55))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (56, 75))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (56, 74))
124746	28994423	In fact, mutation or silencing of SWI/SNF chromatin remodelling subunits, including ARID1A, ARID1B, ARID2, BAP1, PBRM1, SMARCA2, SMARCA4, and SMARCAD1, is a frequent occurrence in cholangiocarcinomas (and other cancers).	('ARID2', 'Gene', (100, 105))	('PBRM1', 'Gene', '55193', (113, 118))	('silencing', 'NegReg', (21, 30))	('cancers', 'Disease', 'MESH:D009369', (211, 218))	('PBRM1', 'Gene', (113, 118))	('ARID1B', 'Gene', (92, 98))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (180, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('mutation', 'Var', (9, 17))	('SMARCA4', 'Gene', '6597', (129, 136))	('SWI/SNF', 'Gene', (34, 41))	('BAP1', 'Gene', '8314', (107, 111))	('ARID1B', 'Gene', '57492', (92, 98))	('SMARCAD1', 'Gene', '56916', (142, 150))	('cholangiocarcinomas', 'Disease', (180, 199))	('ARID1A', 'Gene', (84, 90))	('ARID2', 'Gene', '196528', (100, 105))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (180, 198))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('SMARCAD1', 'Gene', (142, 150))	('cancers', 'Disease', (211, 218))	('SMARCA2', 'Gene', (120, 127))	('SMARCA2', 'Gene', '6595', (120, 127))	('BAP1', 'Gene', (107, 111))	('ARID1A', 'Gene', '8289', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('SMARCA4', 'Gene', (129, 136))
124747	28994423	Notably, tumours with mutations in genes encoding members of the SWI/SNF complex are dependent on the histone methyltransferase activity of EZH2 and, hence, are potentially susceptible to EZH2 inhibitors.	('EZH2', 'Gene', (188, 192))	('histone', 'MPA', (102, 109))	('tumours', 'Disease', 'MESH:D009369', (9, 16))	('activity', 'MPA', (128, 136))	('EZH2', 'Gene', '2146', (140, 144))	('dependent', 'Reg', (85, 94))	('tumours', 'Disease', (9, 16))	('EZH2', 'Gene', (140, 144))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (22, 31))	('EZH2', 'Gene', '2146', (188, 192))	('tumours', 'Phenotype', 'HP:0002664', (9, 16))
124752	28994423	The recurrent, inactivating mutations in chromatin regulators, including BAP1, ARID1A, ARID1B, ARID2, PBRM1, SMARCA2, SMARCA4, and SMARCAD1, support the notion that cholangiocarcinoma has an epigenetically-inclined mutational spectrum.	('cholangiocarcinoma', 'Disease', (165, 183))	('SMARCA2', 'Gene', (109, 116))	('SMARCA2', 'Gene', '6595', (109, 116))	('BAP1', 'Gene', (73, 77))	('SMARCAD1', 'Gene', '56916', (131, 139))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (165, 183))	('PBRM1', 'Gene', '55193', (102, 107))	('ARID1B', 'Gene', (87, 93))	('SMARCAD1', 'Gene', (131, 139))	('ARID2', 'Gene', '196528', (95, 100))	('SMARCA4', 'Gene', (118, 125))	('ARID1B', 'Gene', '57492', (87, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('PBRM1', 'Gene', (102, 107))	('inactivating mutations', 'Var', (15, 37))	('ARID1A', 'Gene', (79, 85))	('ARID2', 'Gene', (95, 100))	('mutations', 'Var', (28, 37))	('BAP1', 'Gene', '8314', (73, 77))	('ARID1A', 'Gene', '8289', (79, 85))	('SMARCA4', 'Gene', '6597', (118, 125))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (165, 183))
124758	28994423	Anetumab ravtansine, an anti-mesothelin antibody-drug conjugate, is being tested in a phase I trial open for enrolment of patients with advanced-stage cholangiocarcinoma with aberrant mesothelin expression (NCT03102320; Supplementary information S1 (table)).	('ravtansine', 'Chemical', 'MESH:D008453', (9, 19))	('cholangiocarcinoma', 'Disease', (151, 169))	('mesothelin', 'Gene', (184, 194))	('mesothelin', 'Gene', (29, 39))	('aberrant', 'Var', (175, 183))	('Anetumab', 'Chemical', '-', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('NCT03102320;', 'Var', (207, 219))	('men', 'Species', '9606', (114, 117))	('mesothelin', 'Gene', '10232', (184, 194))	('patients', 'Species', '9606', (122, 130))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (151, 169))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (151, 169))	('mesothelin', 'Gene', '10232', (29, 39))	('men', 'Species', '9606', (226, 229))
124760	28994423	These agents are approved treatments for breast cancer, and are in clinical trials for a range of other solid-organ malignancies (NCT03065062, NCT02022982), although the efficacy of these agents remains to be evaluated in patients with cholangiocarcinoma.	('solid-organ malignancies', 'Disease', (104, 128))	('solid-organ malignancies', 'Disease', 'MESH:D009369', (104, 128))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (236, 254))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (236, 254))	('men', 'Species', '9606', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('patients', 'Species', '9606', (222, 230))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('NCT02022982', 'Var', (143, 154))	('cholangiocarcinoma', 'Disease', (236, 254))	('NCT03065062', 'Var', (130, 141))
124765	28994423	A phase II trial of the PARP inhibitor niraparib is, however, planned in patients with advanced-stage malignancies, including cholangiocarcinoma, and with known mutations in BAP1 and other DNA double-strand break repair pathway genes : excluding, for an unspecified reason, BRCA1/2 mutations (NCT03207347; Supplementary information S1 (table)).	('malignancies', 'Disease', 'MESH:D009369', (102, 114))	('BRCA1', 'Gene', (274, 279))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (126, 144))	('BAP1', 'Gene', (174, 178))	('niraparib', 'Chemical', 'MESH:C545685', (39, 48))	('BAP1', 'Gene', '8314', (174, 178))	('unspecified', 'Species', '32644', (254, 265))	('PARP', 'Gene', (24, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (126, 144))	('malignancies', 'Disease', (102, 114))	('BRCA1', 'Gene', '672', (274, 279))	('men', 'Species', '9606', (312, 315))	('PARP', 'Gene', '142', (24, 28))	('patients', 'Species', '9606', (73, 81))	('mutations', 'Var', (282, 291))	('cholangiocarcinoma', 'Disease', (126, 144))
124776	28994423	Notably, transcriptome sequencing and clustering of gene-expression profiles revealed a subgroup of patients with cholangiocarcinomas with a high mutational load, resulting in abundant tumour-specific neoantigens, and enrichment for expression of immune-related genes, including genes encoding inhibitory immune-checkpoint proteins.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (114, 132))	('men', 'Species', '9606', (224, 227))	('cholangiocarcinomas', 'Disease', (114, 133))	('expression', 'MPA', (233, 243))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('abundant', 'PosReg', (176, 184))	('mutational load', 'Var', (146, 161))	('patients', 'Species', '9606', (100, 108))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (114, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('tumour', 'Disease', (185, 191))
124788	28994423	The most-studied biomarker to date is the PD-1 ligand, PD-L1; any expression of PD-L1 on tumour cells, and/or higher levels of tumour PD-L1 expression have both been associated with sensitivity to immune-checkpoint- inhibitor monotherapy in some tumour types, including melanoma and non-small-cell lung cancer (NSCLC), but with conflicting results in other diseases.	('lung cancer', 'Phenotype', 'HP:0100526', (298, 309))	('melanoma', 'Phenotype', 'HP:0002861', (270, 278))	('melanoma', 'Disease', (270, 278))	('PD-L1', 'Gene', (80, 85))	('PD-L1', 'Gene', (134, 139))	('PD-L1', 'Gene', '29126', (80, 85))	('PD-1', 'Gene', (42, 46))	('PD-1', 'Gene', '5133', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('PD-L1', 'Gene', '29126', (134, 139))	('expression', 'Var', (66, 76))	('PD-L1', 'Gene', (55, 60))	('sensitivity', 'MPA', (182, 193))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('PD-L1', 'Gene', '29126', (55, 60))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('melanoma', 'Disease', 'MESH:D008545', (270, 278))	('associated with', 'Reg', (166, 181))	('non-small-cell lung cancer', 'Disease', (283, 309))	('tumour', 'Phenotype', 'HP:0002664', (246, 252))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (283, 309))	('tumour', 'Disease', 'MESH:D009369', (246, 252))	('NSCLC', 'Disease', 'MESH:D002289', (311, 316))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', (246, 252))	('tumour PD-L1', 'Disease', 'MESH:D010300', (127, 139))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('tumour', 'Disease', (127, 133))	('NSCLC', 'Disease', (311, 316))	('tumour PD-L1', 'Disease', (127, 139))
124793	28994423	One example is the presence of tumour DNA mismatch repair (MMR) deficiency and/or microsatellite instability (MSI), which is associated with high rates and durability of responses to immune-checkpoint blockade across multiple tumour types.	('microsatellite', 'MPA', (82, 96))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('deficiency', 'Var', (64, 74))	('tumour', 'Disease', 'MESH:D009369', (226, 232))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('tumour', 'Disease', (226, 232))	('tumour', 'Disease', (31, 37))
124797	28994423	In a whole-exome-sequencing study of 231 cholangiocarcinoma tumour samples, a median of 39 and 35 somatic nonsynonymous mutations were identified in intrahepatic and extrahepatic cholangiocarcinomas, respectively; overall, ~6% of the cholangiocarcinomas had evidence of hypermutation (mutation rates of >11.13 per megabase; median number of 641 nonsilent mutations), with concurrent MMR deficiency and/or MSI detected in about 36% of these hypermutated tumours.	('intrahepatic and extrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (149, 198))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('cholangiocarcinoma tumour', 'Disease', (41, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (41, 59))	('MMR deficiency', 'Disease', (383, 397))	('tumours', 'Disease', (453, 460))	('cholangiocarcinoma tumour', 'Disease', 'MESH:D018281', (41, 66))	('tumour', 'Phenotype', 'HP:0002664', (453, 459))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (179, 198))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (234, 253))	('tumours', 'Phenotype', 'HP:0002664', (453, 460))	('tumours', 'Disease', 'MESH:D009369', (453, 460))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('cholangiocarcinomas', 'Disease', (179, 198))	('cholangiocarcinomas', 'Disease', (234, 253))	('MMR deficiency', 'Disease', 'MESH:C536143', (383, 397))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (234, 252))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (179, 197))	('hypermutation', 'Var', (270, 283))
124805	28994423	Among 86 patients with MMR-deficient tumours, encompassing 12 different tumour types including cholangiocarcinoma (n = 4), PD-1 blockade with pembrolizumab resulted in objective radiographic responses in 53% of patients, and in 25% of patients with cholangiocarcinoma (one of the patients with cholangiocarcinoma had a complete response, and the other three had stable disease, for a disease-control rate of 100%); median PFS and overall survival were not reached at the time of publication.	('PD-1', 'Gene', (123, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (249, 267))	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('PD-1', 'Gene', '5133', (123, 127))	('tumour', 'Disease', (37, 43))	('cholangiocarcinoma', 'Disease', (249, 267))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (249, 267))	('pembrolizumab', 'Chemical', 'MESH:C582435', (142, 155))	('patients', 'Species', '9606', (211, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('patients', 'Species', '9606', (235, 243))	('blockade', 'Var', (128, 136))	('MMR-deficient tumours', 'Disease', 'MESH:C536143', (23, 44))	('patients', 'Species', '9606', (280, 288))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (95, 113))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (294, 312))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('MMR-deficient tumours', 'Disease', (23, 44))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('cholangiocarcinoma', 'Disease', (95, 113))	('cholangiocarcinoma', 'Disease', (294, 312))	('patients', 'Species', '9606', (9, 17))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (95, 113))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (294, 312))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
124811	28994423	In addition, FISH could potentially be used to detect novel gene fusions in patients with cholangiocarcinoma.	('patients', 'Species', '9606', (76, 84))	('cholangiocarcinoma', 'Disease', (90, 108))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (90, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('gene fusions', 'Var', (60, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))
124814	28994423	Emerging therapies that hold considerable promise include FGFR inhibitors and IDH1 and/or IDH2 inhibitors, as well as immunotherapies.	('IDH2', 'Gene', '3418', (90, 94))	('IDH1', 'Gene', (78, 82))	('FGFR', 'Gene', (58, 62))	('IDH1', 'Gene', '3417', (78, 82))	('inhibitors', 'Var', (63, 73))	('IDH2', 'Gene', (90, 94))
124834	28054282	A 70-year-old man had visited a local physician and had increased levels of biliary enzymes at medical check-up: serum aspartate aminotransferase (72 IU/l), alanine aminotransferase (212 IU/l), alkaline phosphatase (555 IU/l), gamma glutamyl transpeptidase (218 IU/l), and total bilirubin (0.4 mg/dL).	('serum aspartate aminotransferase', 'MPA', (113, 145))	('levels', 'MPA', (66, 72))	('alanine aminotransferase', 'MPA', (157, 181))	('increased', 'PosReg', (56, 65))	('gamma glutamyl transpeptidase', 'Gene', (227, 256))	('total bilirubin', 'MPA', (273, 288))	('555 IU/l', 'Var', (216, 224))	('bilirubin', 'Chemical', 'MESH:D001663', (279, 288))	('218 IU/l', 'Var', (258, 266))	('man', 'Species', '9606', (14, 17))	('212 IU/l', 'Var', (183, 191))	('gamma glutamyl transpeptidase', 'Gene', '102724197', (227, 256))	('serum aspartate aminotransferase', 'Phenotype', 'HP:0031956', (113, 145))	('alkaline', 'MPA', (194, 202))
124876	33805513	A three-marker model was constructed by using miR-21, miR-122 and CA19-9, which showed an AUC of 0.853 (95% CI: 0.824-0.879; sensitivity: 73.0%, specificity: 87.4%) to differentiate iCCA from controls.	('CA19-9', 'Chemical', 'MESH:C086528', (66, 72))	('iCCA', 'Disease', (182, 186))	('miR-122', 'Gene', '406906', (54, 61))	('miR-122', 'Gene', (54, 61))	('CA19-9', 'Gene', (66, 72))	('miR-21', 'Var', (46, 52))
124877	33805513	The results were similar for diagnosing early (stages 0-I) iCCA patients (AUC: 0.848) and CA19-9negative iCCA patients (AUC: 0.795).	('CA19-9negative', 'Var', (90, 104))	('CA19-9', 'Chemical', 'MESH:C086528', (90, 96))	('patients', 'Species', '9606', (64, 72))	('iCCA', 'Disease', (59, 63))	('patients', 'Species', '9606', (110, 118))
124879	33805513	This model showed a great clinical value especially for the diagnosis of early iCCA and CA19-9negative iCCA.	('early iCCA', 'Disease', (73, 83))	('CA19-9negative', 'Var', (88, 102))	('CA19-9', 'Chemical', 'MESH:C086528', (88, 94))
124935	33805513	The diagnostic performance of the three-marker model (AUC = 0.795, 95% CI, 0.763-0.824) for CA19-9negative iCCA patients was similar to two-miR model (AUC = 0.794, 95% CI, 0.762-0.823, Table 4).	('CA19-9negative', 'Var', (92, 106))	('miR', 'Gene', '220972', (140, 143))	('miR', 'Gene', (140, 143))	('patients', 'Species', '9606', (112, 120))	('iCCA', 'Disease', (107, 111))	('CA19-9', 'Chemical', 'MESH:C086528', (92, 98))
124947	33805513	As such, we constructed a logistic regression model (combining miR-21, miR-122, and CA19-9) which showed a higher diagnostic power for iCCA.	('miR-122', 'Gene', '406906', (71, 78))	('CA19-9', 'Chemical', 'MESH:C086528', (84, 90))	('miR-21', 'Var', (63, 69))	('miR-122', 'Gene', (71, 78))	('iCCA', 'Disease', (135, 139))
124948	33805513	Currently, CA19-9negative iCCA patients lack tumor marker for disease diagnosis and treatment monitoring.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('CA19-9', 'Chemical', 'MESH:C086528', (11, 17))	('tumor', 'Disease', (45, 50))	('lack', 'NegReg', (40, 44))	('patients', 'Species', '9606', (31, 39))	('CA19-9negative', 'Var', (11, 25))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
124955	33805513	This phenomenon may be ascribed to the fact that miR-122 is the most abundant miRNA in the liver, persistent chronic inflammation and subsequent injuries to the liver in iCCA patients lead to a release of miR-122 to the circulation.	('miR', 'Gene', (205, 208))	('inflammation', 'Disease', (117, 129))	('miR', 'Gene', '220972', (78, 81))	('release', 'MPA', (194, 201))	('miR', 'Gene', (78, 81))	('inflammation', 'Disease', 'MESH:D007249', (117, 129))	('miR-122', 'Gene', (205, 212))	('miR-122', 'Gene', '406906', (205, 212))	('injuries', 'Var', (145, 153))	('patients', 'Species', '9606', (175, 183))	('miR', 'Gene', '220972', (49, 52))	('miR', 'Gene', (49, 52))	('miR', 'Gene', '220972', (205, 208))	('persistent chronic inflammation', 'Phenotype', 'HP:0031035', (98, 129))	('miR-122', 'Gene', '406906', (49, 56))	('miR-122', 'Gene', (49, 56))
124962	33805513	In our results, the diagnostic power was also higher when only healthy individuals were selected as controls in the subgroup analysis (0.838 and 0.834 for CA19-9 and miR-21 respectively).	('CA19-9', 'Chemical', 'MESH:C086528', (155, 161))	('CA19-9', 'Var', (155, 161))	('miR-21', 'Gene', (166, 172))	('higher', 'PosReg', (46, 52))
124974	31239773	In the validation cohort, the NRIs of prediction score vs American Joint Committee on Cancer 7th TNM staging system at 1-year and 5-year were 0.185 (95% CI, 0.090-0.279, P<0.001) and 0.425 (95% CI, 0.044-0.806, P=0.03), respectively.	('TNM', 'Gene', '10178', (97, 100))	('0.425', 'Var', (183, 188))	('Cancer', 'Disease', 'MESH:D009369', (86, 92))	('Cancer', 'Disease', (86, 92))	('Cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TNM', 'Gene', (97, 100))
125050	30906543	Aberrant mRNA splicing generates oncogenic RNA isoforms and contributes to the development and progression of cholangiocarcinoma Cholangiocarcinoma is a lethal biliary cancer, with an unclear molecular pathogenesis.	('oncogenic RNA isoforms', 'MPA', (33, 55))	('Cholangiocarcinoma', 'Disease', (129, 147))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (129, 147))	('biliary cancer', 'Disease', (160, 174))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (129, 147))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('biliary cancer', 'Disease', 'MESH:D001661', (160, 174))	('cholangiocarcinoma', 'Disease', (110, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('contributes to', 'Reg', (60, 74))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (110, 128))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (110, 128))	('Aberrant mRNA splicing', 'Var', (0, 22))
125051	30906543	Aberrant alternative splicing has been reported to serve a role in tumor initiation, maintenance and metastasis in several types of human cancer, including cholangiocarcinoma.	('cancer', 'Disease', (138, 144))	('Aberrant alternative splicing', 'Var', (0, 29))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (156, 174))	('tumor initiation', 'Disease', 'MESH:D009369', (67, 83))	('metastasis', 'CPA', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cholangiocarcinoma', 'Disease', (156, 174))	('human', 'Species', '9606', (132, 137))	('tumor initiation', 'Disease', (67, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (156, 174))
125053	30906543	In addition, factors that influence this aberrant splicing that may be relevant as therapeutic targets or prognosis markers for cholangiocarcinoma are discussed.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (128, 146))	('aberrant splicing', 'Var', (41, 58))	('cholangiocarcinoma', 'Disease', (128, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (128, 146))
125059	30906543	The molecular pathogenesis of CCA usually involves abnormal signal transduction and pro-inflammatory secretion, facilitated by gene mutations and epigenetic dysregulations (on a set of oncogenes and tumor suppressor genes).	('tumor', 'Disease', (199, 204))	('gene mutations', 'Var', (127, 141))	('epigenetic dysregulations', 'Var', (146, 171))	('CCA', 'Disease', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('pro-inflammatory secretion', 'MPA', (84, 110))	('CCA', 'Phenotype', 'HP:0030153', (30, 33))
125060	30906543	Several lines of evidence also indicate that the abnormal expression of growth factors and receptors, the RAS/RAF/ dual specificity mitogen-activated protein kinase kinase 1 pathway, and the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin pathway may be involved with CCA initiation, maintenance, and metastasis.	('dual specificity mitogen-activated protein kinase kinase 1', 'Gene', '5604', (115, 173))	('AKT', 'Gene', '207', (246, 249))	('phosphatidylinositol 3 kinase', 'Gene', (191, 220))	('CCA', 'Disease', (310, 313))	('abnormal', 'Var', (49, 57))	('RAF', 'Gene', (110, 113))	('phosphatidylinositol 3 kinase', 'Gene', '5294', (191, 220))	('RAF', 'Gene', '22882', (110, 113))	('mammalian target of rapamycin', 'Gene', '2475', (251, 280))	('mammalian target of rapamycin', 'Gene', (251, 280))	('AKT', 'Gene', (246, 249))	('CCA', 'Phenotype', 'HP:0030153', (310, 313))	('involved', 'Reg', (296, 304))
125063	30906543	A number of reports demonstrated a correlation between aberrant AS and tumor initiation/progression.	('aberrant AS', 'Var', (55, 66))	('tumor initiation', 'Disease', (71, 87))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor initiation', 'Disease', 'MESH:D009369', (71, 87))
125064	30906543	The truncated oncogenic forms of the proteins, resulted from aberrant AS involved in cancer cell growth, apoptosis, drug resistance and angiogenesis.	('drug resistance', 'CPA', (116, 131))	('drug resistance', 'Phenotype', 'HP:0020174', (116, 131))	('truncated', 'Var', (4, 13))	('apoptosis', 'CPA', (105, 114))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('angiogenesis', 'CPA', (136, 148))	('cancer', 'Disease', (85, 91))	('involved', 'Reg', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
125065	30906543	Aberrant splicing of macrophage-stimulating protein receptor (RON) and Racl promoted angiogenesis and epithelial mesenchymal transition (EMT) phenotypes.	('Racl', 'Gene', (71, 75))	('RON', 'Gene', '4486', (62, 65))	('macrophage-stimulating protein receptor', 'Gene', '4486', (21, 60))	('Aberrant splicing', 'Var', (0, 17))	('angiogenesis', 'CPA', (85, 97))	('RON', 'Gene', (62, 65))	('promoted', 'PosReg', (76, 84))	('macrophage-stimulating protein receptor', 'Gene', (21, 60))	('epithelial mesenchymal transition', 'CPA', (102, 135))
125067	30906543	In the present review, evidence is presented that supports important roles for aberrant splicing and the spliced isoforms of the genes, in CCA carcinogenesis and cancer aggressiveness.	('aggressiveness', 'Phenotype', 'HP:0000718', (169, 183))	('CCA carcinogenesis', 'Disease', (139, 157))	('aberrant splicing', 'Var', (79, 96))	('cancer aggressiveness', 'Disease', (162, 183))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('CCA carcinogenesis', 'Disease', 'MESH:C536211', (139, 157))	('CCA', 'Phenotype', 'HP:0030153', (139, 142))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (162, 183))
125069	30906543	The global cancer-specific transcript variants of five cancers demonstrated protein metabolism and modification are the most prevalent functional processes in cancer.	('cancer', 'Disease', (159, 165))	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('prevalent', 'Reg', (125, 134))	('variants', 'Var', (38, 46))	('cancers', 'Disease', (55, 62))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('modification', 'MPA', (99, 111))	('cancer', 'Disease', (55, 61))	('protein metabolism', 'MPA', (76, 94))
125070	30906543	As mentioned previously, aberrant AS has been discovered and proven to have functional involvement in the initiation and progression of cancer.	('involvement', 'Reg', (87, 98))	('aberrant AS', 'Var', (25, 36))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
125081	30906543	Although the mechanism by which the CD44 spliced isoform may suppress p38 is still unclear, this observation appeared to be clinically relevant, since patients with CD44v overexpression and negative-phosphorylated (phospho)-p38MAPK have significantly shorter survival times compared with low CD44v expression and positive-phospho-p38(MAPK).	('shorter', 'NegReg', (251, 258))	('p38', 'Gene', (224, 227))	('p38', 'Gene', (70, 73))	('CD44', 'Gene', (36, 40))	('overexpression', 'PosReg', (171, 185))	('negative-phosphorylated', 'Var', (190, 213))	('survival times', 'CPA', (259, 273))	('CD44', 'Gene', '960', (165, 169))	('p38', 'Gene', '1432', (330, 333))	('p38', 'Gene', '1432', (224, 227))	('suppress', 'NegReg', (61, 69))	('patients', 'Species', '9606', (151, 159))	('CD44', 'Gene', '960', (292, 296))	('CD44', 'Gene', (165, 169))	('CD44', 'Gene', (292, 296))	('p38', 'Gene', '1432', (70, 73))	('p38', 'Gene', (330, 333))	('CD44', 'Gene', '960', (36, 40))
125083	30906543	WISP1 comprises 4 domains, including insulin-like growth factor-binding protein (IGFBP), VWC, thrombospondin-1 (TSP-1) and CT domains and is known to have variants with biological functions.	('TSP-1', 'Gene', '7057', (112, 117))	('IGFBP', 'Gene', (81, 86))	('WISP1', 'Gene', '8840', (0, 5))	('variants', 'Var', (155, 163))	('thrombospondin-1', 'Gene', (94, 110))	('WISP1', 'Gene', (0, 5))	('thrombospondin-1', 'Gene', '7057', (94, 110))	('TSP-1', 'Gene', (112, 117))
125084	30906543	A WISP1 variant lacking exon 3 (WISP1v) loses its VWC domain, which is thought to participate in protein complex formation.	('variant', 'Var', (8, 15))	('WISP1', 'Gene', (2, 7))	('WISP1', 'Gene', (32, 37))	('VWC domain', 'MPA', (50, 60))	('loses', 'NegReg', (40, 45))	('WISP1', 'Gene', '8840', (32, 37))	('WISP1', 'Gene', '8840', (2, 7))
125086	30906543	WISP1v overexpression enhanced the invasive phenotype in gastric carcinoma cells, while wild-type WISP1 exhibited no such potential.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('gastric carcinoma', 'Disease', 'MESH:D013274', (57, 74))	('WISP1', 'Gene', '8840', (0, 5))	('overexpression', 'Var', (7, 21))	('WISP1', 'Gene', (98, 103))	('gastric carcinoma', 'Disease', (57, 74))	('WISP1', 'Gene', (0, 5))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (57, 74))	('invasive phenotype in', 'CPA', (35, 56))	('enhanced', 'PosReg', (22, 30))	('WISP1', 'Gene', '8840', (98, 103))
125095	30906543	Cancer cells overexpressing the NEK2A isoform demonstrated a significant increase in colony formation compared with control cells and small interfering (si)RNA-based depletion of NEK2a resulted in the halting of cancer cell proliferation.	('halting', 'NegReg', (201, 208))	('increase', 'PosReg', (73, 81))	('NEK2a', 'Gene', '4751', (179, 184))	('NEK2A', 'Gene', '4751', (32, 37))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('NEK2a', 'Gene', (179, 184))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('colony formation', 'CPA', (85, 101))	('NEK2A', 'Gene', (32, 37))	('depletion', 'Var', (166, 175))	('small', 'Var', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
125099	30906543	Overexpression of TFF2 is commonly identified in several types of cancer, implicating it in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (92, 106))	('TFF2', 'Gene', (18, 22))	('carcinogenesis', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Overexpression', 'Var', (0, 14))	('TFF2', 'Gene', '7032', (18, 22))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
125106	30906543	Exon 3 skipping of FOXP3, resulting in an amino acid frameshift, has been reported in CCA.	('FOXP3', 'Gene', '50943', (19, 24))	('amino acid frameshift', 'Var', (42, 63))	('skipping', 'Var', (7, 15))	('CCA', 'Phenotype', 'HP:0030153', (86, 89))	('FOXP3', 'Gene', (19, 24))	('CCA', 'Disease', (86, 89))
125113	30906543	p53 has been identified as a gene that frequently mutates in a large number of CCA cases, suggesting that a perturbed p53 pathway facilitates CCA carcinogenesis.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('CCA carcinogenesis', 'Disease', (142, 160))	('p53', 'Gene', (118, 121))	('CCA', 'Phenotype', 'HP:0030153', (79, 82))	('p53', 'Gene', '7157', (118, 121))	('perturbed', 'Var', (108, 117))	('CCA', 'Phenotype', 'HP:0030153', (142, 145))	('CCA carcinogenesis', 'Disease', 'MESH:C536211', (142, 160))	('facilitates', 'PosReg', (130, 141))
125117	30906543	Accordingly, suppression of Delta133p53 promoted apoptosis, which correlated with an upregulation of pro-apoptotic Bax and a downregulation of anti-apoptotic Bcl-2.	('Bcl-2', 'Gene', '596', (158, 163))	('Bax', 'Gene', (115, 118))	('promoted', 'PosReg', (40, 48))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('suppression', 'Var', (13, 24))	('Bax', 'Gene', '581', (115, 118))	('upregulation', 'PosReg', (85, 97))	('downregulation', 'NegReg', (125, 139))	('apoptosis', 'CPA', (49, 58))	('Bcl-2', 'Gene', (158, 163))	('Bcl', 'Phenotype', 'HP:0012191', (158, 161))
125144	30906543	The prominent role of the aberrant AS in carcinogenesis has been demonstrated, indicating that AS may be a good target for cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('aberrant', 'Var', (26, 34))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('carcinogenesis', 'Disease', 'MESH:D063646', (41, 55))	('cancer', 'Disease', (123, 129))	('carcinogenesis', 'Disease', (41, 55))
125145	30906543	Aberrant AS can be manipulated in several steps: For example, Pre-Trans-Splicing Molecule (PTM) is the artificial sequence that can reprogram mRNA through replacement of the 3'exon, 5'exon and internal exon.	('artificial sequence', 'Species', '32630', (103, 122))	("3'exon", 'Protein', (174, 180))	('replacement', 'Var', (155, 166))
125146	30906543	The results demonstrated that the trans-splicing molecule reduced the number of mutant p53 transcripts in the transfected cells, which resulted in cell cycle arrest, apoptosis and tumor xenograft suppression with colorectal cancer and hepatocellular carcinoma cells.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('resulted in', 'Reg', (135, 146))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (235, 259))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('mutant', 'Var', (80, 86))	('p53', 'Gene', '7157', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('colorectal cancer', 'Disease', 'MESH:D015179', (213, 230))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (235, 259))	('transcripts', 'MPA', (91, 102))	('apoptosis', 'CPA', (166, 175))	('cell cycle arrest', 'CPA', (147, 164))	('colorectal cancer', 'Disease', (213, 230))	('p53', 'Gene', (87, 90))	('trans-splicing', 'Var', (34, 48))	('hepatocellular carcinoma', 'Disease', (235, 259))	('tumor', 'Disease', (180, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('reduced', 'NegReg', (58, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (213, 230))
125155	30906543	The data revealed that mutations in splicing factor 3B subunit 1A (SF3B1), which encodes the core component of U2 snRNP, is linked to erroneous 3' splice site selection.	('splicing factor 3B subunit 1A', 'Gene', '23451', (36, 65))	('SF3B1', 'Gene', '23451', (67, 72))	('linked', 'Reg', (124, 130))	('erroneous', 'Var', (134, 143))	('splicing factor 3B subunit 1A', 'Gene', (36, 65))	('mutations', 'Var', (23, 32))	('SF3B1', 'Gene', (67, 72))
125156	30906543	The results demonstrated that the SF3B1 K700E mutation led to differential splicing in uveal melanoma and breast cancer.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('breast cancer', 'Disease', (106, 119))	('uveal melanoma', 'Disease', (87, 101))	('splicing', 'MPA', (75, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('SF3B1', 'Gene', (34, 39))	('K700E', 'Mutation', 'rs559063155', (40, 45))	('differential', 'Reg', (62, 74))	('K700E', 'Var', (40, 45))	('SF3B1', 'Gene', '23451', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('uveal melanoma', 'Phenotype', 'HP:0007716', (87, 101))	('uveal melanoma', 'Disease', 'MESH:C536494', (87, 101))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
125157	30906543	In addition, luminal B and progesterone receptor-negative breast cancer patients with additional SF3B1 mutations have significantly shorter survival times.	('mutations', 'Var', (103, 112))	('progesterone receptor', 'Gene', (27, 48))	('progesterone receptor', 'Gene', '5241', (27, 48))	('SF3B1', 'Gene', '23451', (97, 102))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('shorter', 'NegReg', (132, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('SF3B1', 'Gene', (97, 102))	('survival times', 'CPA', (140, 154))	('patients', 'Species', '9606', (72, 80))
125159	30906543	Previous studies demonstrated that a natural product, FR901464 and its methylated derivative, spliceostatin A, as well as E7107, specifically inhibit spliceosome assembly through SF3B1 and lead to halted splicing reactions.	('spliceosome assembly', 'MPA', (150, 170))	('inhibit', 'NegReg', (142, 149))	('FR901464', 'Chemical', 'MESH:C104486', (54, 62))	('SF3B1', 'Gene', (179, 184))	('E7107', 'Var', (122, 127))	('halted splicing reactions', 'MPA', (197, 222))	('FR901464', 'Var', (54, 62))	('SF3B1', 'Gene', '23451', (179, 184))
125161	30906543	Not only does the altered expression of splicing regulators affect AS, but the alteration of the phosphorylation status of the splicing factor/modulator was also implicated in cancer progression.	('implicated', 'Reg', (162, 172))	('phosphorylation status', 'MPA', (97, 119))	('altered', 'Var', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('affect', 'Reg', (60, 66))	('alteration', 'Reg', (79, 89))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
125163	30906543	A previous study demonstrated that CLKs and SRSF protein kinases (SRPKs) are targets for kinase inhibitors to modulate AS; treatment with Cpd-1, Cpd-2, and Cpd-3 significantly reduced the levels of phosphorylated SR proteins, therefore affecting the splicing pattern of multiple genes and inducing cell apoptosis.	('Cpd-3', 'Gene', (156, 161))	('levels of phosphorylated', 'MPA', (188, 212))	('affecting', 'Reg', (236, 245))	('SR protein', 'Gene', (213, 223))	('Cpd-3', 'Gene', '1165', (156, 161))	('SR protein', 'Gene', '10921', (213, 223))	('splicing pattern', 'MPA', (250, 266))	('reduced', 'NegReg', (176, 183))	('cell apoptosis', 'CPA', (298, 312))	('inducing', 'Reg', (289, 297))	('Cpd-2', 'Var', (145, 150))	('Cpd-1', 'Gene', (138, 143))	('Cpd-1', 'Gene', '1167', (138, 143))
125167	30906543	The SSO-mediated skipping of exon 6 results in decreased MDM4 levels and reduced melanoma growth.	('skipping', 'Var', (17, 25))	('exon', 'Gene', (29, 33))	('melanoma growth', 'Disease', 'MESH:D008545', (81, 96))	('MDM4', 'Gene', (57, 61))	('reduced', 'NegReg', (73, 80))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('MDM4', 'Gene', '4194', (57, 61))	('melanoma growth', 'Disease', (81, 96))	('decreased', 'NegReg', (47, 56))
125174	30906543	The present review summarized the experimental evidence for and clinical relevance of the verification of significant effects of aberrant mRNA splicing of well-characterized genes with respect to CCA initiation and aggressiveness.	('aggressiveness', 'Disease', (215, 229))	('CCA', 'Phenotype', 'HP:0030153', (196, 199))	('aggressiveness', 'Phenotype', 'HP:0000718', (215, 229))	('effects', 'Reg', (118, 125))	('CCA', 'Disease', (196, 199))	('aggressiveness', 'Disease', 'MESH:D001523', (215, 229))	('aberrant mRNA splicing', 'Var', (129, 151))
125176	30906543	Interestingly, certain of the cancer-specific variants may serve as potential targets for CCA prognosis including  2TFF2 and  133p53, which demonstrate their clinical impact on patient survival.	('CCA', 'Disease', (90, 93))	('TFF2', 'Gene', '7032', (116, 120))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('CCA', 'Phenotype', 'HP:0030153', (90, 93))	('variants', 'Var', (46, 54))	('p53', 'Gene', (129, 132))	('TFF2', 'Gene', (116, 120))	('p53', 'Gene', '7157', (129, 132))	('patient', 'Species', '9606', (177, 184))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
125189	29171037	EMT may also lead to the conversion of nontumorigenic cells to cancer stem cells,12, 18 thus facilitating the metastatic spread of solid tumors during tumor progression.19  Alternatively, intratumor heterogeneity could be due to epigenetic events, such as DNA methylation and/or histone modifications.	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('due', 'Reg', (222, 225))	('DNA methylation', 'Var', (256, 271))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', (193, 198))	('solid tumors', 'Disease', (131, 143))	('cancer', 'Disease', (63, 69))	('tumor', 'Disease', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('solid tumors', 'Disease', 'MESH:D009369', (131, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Disease', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('histone', 'Protein', (279, 286))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
125194	29171037	In total, we determined the keratin-7 phenotype in 1,043 single cell-derived subclones, comprising the three different keratin-7 expression phenotypes (i.e., heterogeneous K7het, positive K7pos, negative K7neg).	('positive K7pos', 'Var', (179, 193))	('negative', 'NegReg', (195, 203))	('K7het', 'Chemical', '-', (172, 177))	('K7neg', 'Chemical', '-', (204, 209))	('K7het', 'Var', (172, 177))
125208	29171037	We used two different subclones in early (10-15 passages) and late (>20 passages) passages each, representing the three keratin-7 phenotypes (K7het, K7pos, K7neg), in the experiment.	('K7pos', 'Var', (149, 154))	('K7het', 'Var', (142, 147))	('K7het', 'Chemical', '-', (142, 147))	('K7neg', 'Chemical', '-', (156, 161))
125225	29171037	We detected seven variants above the call threshold including a BRAF V600E mutation, which has been described in cholangiocarcinoma with poor prognosis.43 Importantly, the same seven variants were found in the original human tumor sample and the derived cell culture subclones (http://onlinelibrary.wiley.com/doi/10.1002/hep.29679/suppinfo).	('cholangiocarcinoma', 'Disease', (113, 131))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('BRAF', 'Gene', '673', (64, 68))	('human', 'Species', '9606', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (113, 131))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (113, 131))	('BRAF', 'Gene', (64, 68))	('variants', 'Var', (183, 191))	('tumor', 'Disease', (225, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('V600E', 'Mutation', 'rs113488022', (69, 74))
125230	29171037	K7het subclones yielded daughter subclones corresponding to all three keratin-7 subclonal types, that is, K7neg, K7pos, and K7het (Fig.	('K7neg', 'Chemical', '-', (106, 111))	('K7pos', 'Var', (113, 118))	('K7het', 'Chemical', '-', (0, 5))	('K7het', 'Chemical', '-', (124, 129))	('K7neg', 'Var', (106, 111))	('K7het', 'Var', (124, 129))
125232	29171037	Interestingly, 14% of K7pos subclones (which were originally derived from K7het parental clones) gave rise to K7het daughter subclones, which demonstrates the reversibility of phenotype switching (Fig.	('K7het', 'Chemical', '-', (74, 79))	('K7het', 'Chemical', '-', (110, 115))	('K7pos', 'Var', (22, 27))	('K7het', 'Var', (110, 115))
125234	29171037	Transcriptional profiling (RNA-seq) of K7pos and K7neg subclones identified 78 DEGs, of which 44 were significantly overexpressed and 34 underexpressed in K7neg clones compared to K7pos clones (fold change >=2.0, P < 0.05).	('K7neg', 'Var', (155, 160))	('K7neg', 'Chemical', '-', (49, 54))	('underexpressed', 'NegReg', (137, 151))	('K7neg', 'Chemical', '-', (155, 160))	('overexpressed', 'PosReg', (116, 129))
125246	29171037	Treatment of K7neg subclones with 5-aza-dC caused keratin-7 protein reexpression and increased the percentage of keratin-7-positive cells in a time-dependent and dose-dependent manner (Fig.	('5-aza-dC', 'Var', (34, 42))	('K7neg', 'Chemical', '-', (13, 18))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (34, 42))	('increased', 'PosReg', (85, 94))	('keratin-7 protein', 'Protein', (50, 67))
125248	29171037	We verified these results with MeDIP-seq of three independently derived K7pos and K7neg f1 subclones, which showed a significant increase in DNA methylation at the CpG islands associated within the KRT7 promoter in all K7neg clones compared to K7pos cells (Fig.	('K7neg', 'Var', (219, 224))	('K7neg', 'Chemical', '-', (82, 87))	('KRT7', 'Gene', (198, 202))	('K7neg', 'Chemical', '-', (219, 224))	('increase', 'PosReg', (129, 137))	('DNA methylation', 'MPA', (141, 156))	('KRT7', 'Gene', '3855', (198, 202))
125258	29171037	Only K7het and K7neg subclones established tumors, whereas none of the K7pos subclones led to visible tumor growth at any of the injected sites (n = 8 per clonal type) (Fig.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('K7het', 'Chemical', '-', (5, 10))	('K7het', 'Var', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('K7neg', 'Chemical', '-', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('K7neg', 'Var', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors', 'Disease', (43, 49))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (102, 107))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
125268	29171037	Importantly, in the investigated subclones of the primary tumor cell culture epigenetic mechanisms, such as DNA methylation, stabilized stochastically generated phenotypes, rather than generating tumor heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (196, 201))	('methylation', 'Var', (112, 123))	('stochastically generated phenotypes', 'MPA', (136, 171))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('stabilized', 'Reg', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
125270	29171037	We identified distinct self-propagating subclones characterized either as essentially stable (K7pos or K7neg) or as unstable clones (K7het).	('K7het', 'Chemical', '-', (133, 138))	('K7neg', 'Chemical', '-', (103, 108))	('K7neg', 'Var', (103, 108))	('K7pos', 'Var', (94, 99))
125274	29171037	Mechanistically, we showed that hypermethylation of the KRT7 promoter is involved in silencing KRT7 expression in stable K7neg subclones.	('KRT7', 'Gene', '3855', (95, 99))	('KRT7', 'Gene', (95, 99))	('expression', 'MPA', (100, 110))	('KRT7', 'Gene', '3855', (56, 60))	('silencing', 'NegReg', (85, 94))	('hypermethylation', 'Var', (32, 48))	('K7neg', 'Chemical', '-', (121, 126))	('KRT7', 'Gene', (56, 60))
125287	29171037	Moreover, there was a greater take rate of xenografts after injection of K7het subclones (12 tumors developed at 16 injection sites) compared to K7neg subclones (6 tumors developed at 16 injection sites) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('take rate', 'CPA', (30, 39))	('K7neg', 'Chemical', '-', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('greater', 'PosReg', (22, 29))	('K7het', 'Chemical', '-', (73, 78))	('tumors', 'Disease', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('K7het', 'Var', (73, 78))
125290	29171037	The observation that K7het-injected mice developed more and larger tumors than K7neg-injected mice favors the latter hypothesis.	('K7neg', 'Chemical', '-', (79, 84))	('K7het-injected', 'Var', (21, 35))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('K7het', 'Chemical', '-', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mice', 'Species', '10090', (94, 98))	('mice', 'Species', '10090', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))
125304	27113512	Although the 5-year overall survival of N1 patients was only slightly affected by TNLE, the 5-year overall survival of N0 patients increased significantly with TNLE.	('TNLE', 'Chemical', '-', (82, 86))	('increased', 'PosReg', (131, 140))	('patients', 'Species', '9606', (43, 51))	('TNLE', 'Var', (160, 164))	('patients', 'Species', '9606', (122, 130))	('TNLE', 'Chemical', '-', (160, 164))
125314	27113512	When compared with other prognostic factors, such as margin status, grade of tumor differentiation, and carbohydrate antigen 19-9 serum level, the presence of metastatic LNs has been demonstrated to be one of the strongest predictors of poor prognosis.	('carbohydrate antigen', 'Chemical', '-', (104, 124))	('metastatic LNs', 'CPA', (159, 173))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('presence', 'Var', (147, 155))
125321	27113512	In addition, TNLE can impact the likelihood of identifying metastatic LNs and have implications for accurately staging patients.	('TNLE', 'Chemical', '-', (13, 17))	('metastatic LNs', 'CPA', (59, 73))	('impact', 'Reg', (22, 28))	('implications', 'Reg', (83, 95))	('patients', 'Species', '9606', (119, 127))	('TNLE', 'Var', (13, 17))
125372	27113512	In addition, increasing the TNLE, the rate of metastatic LNs was statistically different, ranging from 27.8% when the TNLE was 1 to 3, to 51.5% when the TNLE was 4 to 10, and to 62.2% when the TNLN was >10 (both p < 0.001; Fig.	('TNLN', 'Chemical', '-', (193, 197))	('TNLE', 'Var', (28, 32))	('TNLE', 'Chemical', '-', (28, 32))	('metastatic LNs', 'CPA', (46, 60))	('TNLE', 'Chemical', '-', (153, 157))	('TNLE', 'Chemical', '-', (118, 122))
125411	27113512	These results from the Bayesian model were confirmed by the finding that the 5-year OS rate of N0 <4 TNLE patients (19.7%) tended to be worse compared with the 5-year OS rate of N0 >=4 TNLE patients (26.2%; p = 0.08).	('worse', 'NegReg', (136, 141))	('patients', 'Species', '9606', (190, 198))	('N0 <4 TNLE', 'Var', (95, 105))	('TNLE', 'Chemical', '-', (185, 189))	('OS', 'Chemical', '-', (84, 86))	('TNLE', 'Chemical', '-', (101, 105))	('patients', 'Species', '9606', (106, 114))	('OS', 'Chemical', '-', (167, 169))
125412	27113512	The incidence of metastatic LNs was about doubled when we compared TNLE <4 to >=4, and the incidence of metastatic LNs was similar when comparing TNLE 4 to 10 vs TNLE >10 (Fig.	('metastatic', 'CPA', (17, 27))	('TNLE', 'Var', (146, 150))	('TNLE', 'Chemical', '-', (162, 166))	('TNLE', 'Chemical', '-', (146, 150))	('TNLE', 'Chemical', '-', (67, 71))
125457	27474881	Furthermore, we observed that systemic injection of miR-195-loaded, stroma-derived EVs inhibited CCA tumor growth and prolonged survival in a rat model of CCA.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('miR-195-loaded', 'Var', (52, 66))	('CCA tumor', 'Disease', (97, 106))	('CCA tumor', 'Disease', 'MESH:C536211', (97, 106))	('inhibited', 'NegReg', (87, 96))	('survival', 'CPA', (128, 136))	('prolonged', 'PosReg', (118, 127))	('rat', 'Species', '10116', (142, 145))
125499	27474881	Specifically, we generated LX2 cells that overexpressed either miR-195 (LX2-miR-195 mimic) or a control miR (LX2-NSM) and then examined their effects on the growth of co-cultured CCA cells.	('miR-195', 'Var', (63, 70))	('overexpressed', 'PosReg', (42, 55))	('LX2', 'CellLine', 'CVCL:5792', (27, 30))	('LX2', 'CellLine', 'CVCL:5792', (72, 75))	('rat', 'Species', '10116', (21, 24))	('LX2', 'CellLine', 'CVCL:5792', (109, 112))
125500	27474881	In each instance, we observed significantly less growth and invasiveness of CCA cells that were co-cultured with LX2-miR-195 cells as compared to CCA cells that were co-cultured with LX2-NSM cells (Fig.	('LX2', 'CellLine', 'CVCL:5792', (113, 116))	('LX2-miR-195', 'Var', (113, 124))	('less', 'NegReg', (44, 48))	('growth', 'CPA', (49, 55))	('invasiveness', 'CPA', (60, 72))	('LX2', 'CellLine', 'CVCL:5792', (183, 186))
125502	27474881	Despite the absence of direct contact between the cell types, diffusible factors released by LX2-miR-195 cells still caused a significant inhibition in the growth, invasiveness, and migration of CCA cells (Fig.	('invasiveness', 'CPA', (164, 176))	('migration', 'CPA', (182, 191))	('inhibition', 'NegReg', (138, 148))	('LX2', 'CellLine', 'CVCL:5792', (93, 96))	('growth', 'CPA', (156, 162))	('CCA', 'Disease', (195, 198))	('LX2-miR-195', 'Var', (93, 104))	('rat', 'Species', '10116', (185, 188))
125503	27474881	To test if EVs alone can induce a phenotypic change in cancer cells, we isolated EVs from LX2 cell and loaded them with miR-195 and non-specific mimic (NSM), respectively.	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('LX2', 'CellLine', 'CVCL:5792', (90, 93))	('miR-195', 'Var', (120, 127))	('cancer', 'Disease', (55, 61))
125511	27474881	With the exception of miR-195, expectedly found to be overexpressed 1,580 fold in EVs from LX2 cells transfected with miR-195 vs. NSM, the other miR species appeared to be expressed at similar levels, further arguing that transfecting LX2 cells with miR-195 does not change the composition of EVs (Fig 3C).	('LX2', 'CellLine', 'CVCL:5792', (91, 94))	('LX2', 'CellLine', 'CVCL:5792', (235, 238))	('overexpressed', 'PosReg', (54, 67))	('miR-195', 'Var', (118, 125))
125515	27474881	Furthermore, we observed that EVs collected from LX2-miR-195 cells contained elevated levels of miR-195 (Fig.	('miR-195', 'Var', (96, 103))	('elevated', 'PosReg', (77, 85))	('LX2-miR-195', 'Var', (49, 60))	('LX2', 'CellLine', 'CVCL:5792', (49, 52))
125524	27474881	Consistent with the reduced growth of tumors in treated animals, we observed that Ki67 expression was significantly lower in cancers from animals injected with miR-195-loaded EVs (relative to its levels in tumors from animals injected with the same amount of miR-NSM-loaded EVs; Fig.	('miR-195-loaded', 'Var', (160, 174))	('lower', 'NegReg', (116, 121))	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('cancers', 'Disease', (125, 132))	('miR-NSM', 'Gene', (259, 266))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumors', 'Disease', (206, 212))	('Ki67', 'Gene', (82, 86))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('expression', 'MPA', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('miR-NSM', 'Gene', '220972', (259, 266))
125528	27474881	These findings indicate that the miR-195-loaded EVs cause reduced tumor size at least in part by inhibiting CCA cell growth and degree of desmoplasia.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('inhibiting', 'NegReg', (97, 107))	('tumor', 'Disease', (66, 71))	('desmoplasia', 'Disease', (138, 149))	('desmoplasia', 'Disease', 'None', (138, 149))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('CCA cell growth', 'CPA', (108, 123))	('reduced', 'NegReg', (58, 65))	('miR-195-loaded', 'Var', (33, 47))
125529	27474881	The only difference between the experimental and control EVs was the sequence of the transfected miR (miR-195 vs. miR-NSM).	('miR-NSM', 'Gene', (114, 121))	('miR-195', 'Var', (102, 109))	('miR-NSM', 'Gene', '220972', (114, 121))
125530	27474881	Therefore, it is reasonable to presume that miR-195-loaded EVs were exerting their effects on CCA cells by delivering miR-195 into the tumor cells and suppressing the expression of miR-195 targets.	('CCA', 'Disease', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('miR-195', 'Var', (118, 125))	('tumor', 'Disease', (135, 140))	('suppressing', 'NegReg', (151, 162))	('expression', 'MPA', (167, 177))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
125532	27474881	As expected, the abundance of miR-195 was significantly and selectively elevated in the tumors from animals injected with miR-195-loaded EVs (Fig.	('elevated', 'PosReg', (72, 80))	('abundance', 'MPA', (17, 26))	('miR-195-loaded', 'Var', (122, 136))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('miR-195', 'Protein', (30, 37))
125548	27474881	We found that recipient CCA cells SG231 appear to increase miR-195 levels significantly more in response to treatment with EVs-miR-195 from donor LX2 cells vs. donor HEK293T or donor HeLa cells (Fig.	('donor', 'Species', '9606', (160, 165))	('donor', 'Species', '9606', (177, 182))	('increase', 'PosReg', (50, 58))	('miR-195 levels', 'MPA', (59, 73))	('donor', 'Species', '9606', (140, 145))	('LX2', 'CellLine', 'CVCL:5792', (146, 149))	('EVs-miR-195', 'Var', (123, 134))	('HeLa', 'CellLine', 'CVCL:0030', (183, 187))	('HEK293T', 'CellLine', 'CVCL:0063', (166, 173))
125549	27474881	In contrast, recipient CCA cells TFK1 cells appear to be less effectively transduced by EVs from donor LX2 cells or donor HECK293T vs. EVs from donor HeLa cells.	('donor', 'Species', '9606', (97, 102))	('transduced', 'MPA', (74, 84))	('less', 'NegReg', (57, 61))	('LX2', 'CellLine', 'CVCL:5792', (103, 106))	('HeLa', 'CellLine', 'CVCL:0030', (150, 154))	('donor', 'Species', '9606', (144, 149))	('HECK293T', 'Var', (122, 130))	('donor', 'Species', '9606', (116, 121))	('HECK293', 'CellLine', 'CVCL:0045', (122, 129))
125562	27474881	For example, VEGF, CDC42, CDK1, CDK4, CDK6, and CDC25 were previously reported to be downregulated by miR-195 in HCC.	('VEGF', 'Gene', '7422', (13, 17))	('downregulated', 'NegReg', (85, 98))	('CDK4', 'Gene', (32, 36))	('CDK1', 'Gene', '983', (26, 30))	('CDK4', 'Gene', '1019', (32, 36))	('CDK1', 'Gene', (26, 30))	('HCC', 'Gene', '619501', (113, 116))	('CDK6', 'Gene', (38, 42))	('HCC', 'Gene', (113, 116))	('VEGF', 'Gene', (13, 17))	('CDK6', 'Gene', '1021', (38, 42))	('miR-195', 'Var', (102, 109))	('CDC25', 'Gene', (48, 53))	('CDC42', 'Gene', '998', (19, 24))	('CDC25', 'Gene', '995', (48, 53))	('CDC42', 'Gene', (19, 24))
125563	27474881	Given that almost all investigators studying the anti-neoplastic effects of miR-195 expression focused on distinct target genes, it is likely that miR-195 mediates its effects by simultaneously suppressing multiple pro-neoplastic factors in each of these cancers, including CCA.	('suppressing', 'NegReg', (194, 205))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('CCA', 'Disease', (274, 277))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('miR-195', 'Gene', (76, 83))	('miR-195', 'Var', (147, 154))	('cancers', 'Disease', 'MESH:D009369', (255, 262))	('cancers', 'Disease', (255, 262))
125584	27733196	Univariate analysis demonstrated a significant association between high levels of serum CRP and adverse cancer-specific survival (P = 0.001) and recurrence-free survival (P < 0.001).	('CRP', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CRP', 'Gene', '1401', (88, 91))	('high levels', 'Var', (67, 78))	('recurrence-free survival', 'CPA', (145, 169))	('high levels of serum CRP', 'Phenotype', 'HP:0011227', (67, 91))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
125600	27733196	Other novel molecular biomarkers, such as hepatoma-derived growth factor, SOX4, loss of FBXW7 expression, Homer1, and inactivation of Smad4, seem to be associated with poor IHCC patient prognosis.	('Homer1', 'Gene', '9456', (106, 112))	('IHCC', 'Disease', (173, 177))	('FBXW7', 'Gene', (88, 93))	('hepatoma-derived growth factor', 'Gene', '3068', (42, 72))	('patient', 'Species', '9606', (178, 185))	('SOX4', 'Gene', (74, 78))	('SOX4', 'Gene', '6659', (74, 78))	('hepatoma-derived growth factor', 'Gene', (42, 72))	('loss', 'Var', (80, 84))	('inactivation', 'Var', (118, 130))	('expression', 'MPA', (94, 104))	('Smad4', 'Gene', '4089', (134, 139))	('associated', 'Reg', (152, 162))	('FBXW7', 'Gene', '55294', (88, 93))	('Smad4', 'Gene', (134, 139))	('Homer1', 'Gene', (106, 112))
125656	27733196	Patients with high serum CRP level showed a significant trend toward worse RFS compared to the RFS of patients with low serum CRP levels (P < 0.001, Kaplan-Meier Method) (Fig.	('high serum CRP', 'Phenotype', 'HP:0011227', (14, 28))	('patients', 'Species', '9606', (102, 110))	('CRP', 'Gene', '1401', (126, 129))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('CRP', 'Gene', (25, 28))	('CRP', 'Gene', (126, 129))	('CRP', 'Gene', '1401', (25, 28))
125673	27733196	More importantly, high CRP level was significantly correlated with poor survival and found to be independently predictive of survival in patients with perihilar cholangiocarcinoma as evidenced by the in the univariate and multivariate analyses.	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('cholangiocarcinoma', 'Disease', (161, 179))	('CRP', 'Gene', (23, 26))	('poor', 'NegReg', (67, 71))	('patients', 'Species', '9606', (137, 145))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (161, 179))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (161, 179))	('CRP', 'Gene', '1401', (23, 26))	('high', 'Var', (18, 22))	('predictive', 'Reg', (111, 121))	('high CRP level', 'Phenotype', 'HP:0011227', (18, 32))
125704	26868125	Establishment of a patient-derived intrahepatic cholangiocarcinoma xenograft model with KRAS mutation Intrahepatic cholangiocarcinoma (ICC) is an aggressive, highly lethal tumors and lacks of effective chemo and targeted therapies.	('Intrahepatic cholangiocarcinoma', 'Disease', (102, 133))	('Intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (102, 133))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('patient', 'Species', '9606', (19, 26))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('intrahepatic cholangiocarcinoma xenograft', 'Disease', 'MESH:D018281', (35, 76))	('KRAS', 'Gene', (88, 92))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (48, 66))	('KRAS', 'Gene', '3845', (88, 92))	('mutation', 'Var', (93, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (115, 133))	('intrahepatic cholangiocarcinoma xenograft', 'Disease', (35, 76))
125732	26868125	After the quantification with Nanodrop, 2 mug of genomic DNA of both tumor and control from Promega (Human Genomic DNA Female N 30742202/male N 30993901) were labeled with CY5-dCTPs and CY3-dCTP, respectively, and hybridized on glass arrays (2 X105 K) at 65C  for 40 hours at 20 rpm.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CY5-dCTPs', 'Chemical', 'MESH:C544355', (172, 181))	('tumor', 'Disease', (69, 74))	('CY3-dCTP', 'Var', (186, 194))	('CY5-dCTPs', 'Protein', (172, 181))	('Human', 'Species', '9606', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('X105 K', 'Mutation', 'p.X105K', (244, 250))	('CY3-dCTP', 'Chemical', '-', (186, 194))
125734	26868125	External datasets: GSE26566 and GSE47764 datasets, containing normal bile duct gene and miRNA expression profiles respectively, were downloaded from the GEO website (http://www.ncbi.nlm.nih.gov/geo/).	('GSE47764', 'Var', (32, 40))	('miR', 'Gene', (88, 91))	('miR', 'Gene', '220972', (88, 91))
125739	26868125	For formalin fixed and paraffin embedded (FFPE) tumor the neoplastic area was obtained by laser microdissection (VSL-337ND-S, Spectra-Physics, Mountain View, CA).	('tumor', 'Disease', (48, 53))	('formalin', 'Chemical', 'MESH:D005557', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('paraffin', 'Chemical', 'MESH:D010232', (23, 31))	('VSL-337ND-S', 'Var', (113, 124))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
125754	26868125	Genes list was filtered on adjusted p-value (<0,00001) and the most significant 300 probes were analyzed for Gene Ontology; we found that down-regulated genes are involved in blood coagulation, inflammation response, and in lipid metabolism; on the contrary, up-regulated genes globally affected DNA biosynthesis processes, as nucleosome assembly and organization, translation, underlying that tumor cells are more active rather than normal cells.	('tumor', 'Disease', (394, 399))	('affected', 'Reg', (287, 295))	('translation', 'MPA', (365, 376))	('blood coagulation', 'Disease', (175, 192))	('inflammation', 'Disease', (194, 206))	('organization', 'MPA', (351, 363))	('inflammation', 'Disease', 'MESH:D007249', (194, 206))	('up-regulated', 'PosReg', (259, 271))	('lipid', 'Chemical', 'MESH:D008055', (224, 229))	('genes', 'Var', (272, 277))	('blood coagulation', 'Disease', 'MESH:D001778', (175, 192))	('tumor', 'Disease', 'MESH:D009369', (394, 399))	('down-regulated', 'NegReg', (138, 152))	('DNA biosynthesis', 'MPA', (296, 312))	('nucleosome assembly', 'MPA', (327, 346))	('tumor', 'Phenotype', 'HP:0002664', (394, 399))
125759	26868125	Furthermore, we analyzed if PDX acquired peculiar characteristics in terms of microRNA expression; Additional file 5: Table S5 showed that only let-7a-5p, miR-15b-5p, let-7d-5p, miR-200b-5p were down-regulated in PDX compared to primary tumor.	('down-regulated', 'NegReg', (195, 209))	('miR', 'Gene', '220972', (178, 181))	('miR', 'Gene', (178, 181))	('primary tumor', 'Disease', (229, 242))	('let-7a-5p', 'Var', (144, 153))	('PDX', 'Disease', (213, 216))	('miR', 'Gene', '220972', (155, 158))	('miR', 'Gene', (155, 158))	('let-7d-5p', 'Var', (167, 176))	('primary tumor', 'Disease', 'MESH:D009369', (229, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
125761	26868125	6, only the sequence of K-RAS exon 2 is mutated (G12D mutation) in the primary tumor (panel B) and is maintained in PDX (panel C).	('K-RAS', 'Gene', '3845', (24, 29))	('G12D mutation', 'Var', (49, 62))	('K-RAS', 'Gene', (24, 29))	('primary tumor', 'Disease', (71, 84))	('G12D', 'Mutation', 'rs121913529', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('primary tumor', 'Disease', 'MESH:D009369', (71, 84))
125768	26868125	We can speculate that the presence of K-RAS mutation in our PDX model could be a driver of the more aggressive phenotype, thus explaining the successful engraftment, as shown in colorectal cancer PDX model.	('colorectal cancer', 'Phenotype', 'HP:0003003', (178, 195))	('K-RAS', 'Gene', '3845', (38, 43))	('K-RAS', 'Gene', (38, 43))	('colorectal cancer', 'Disease', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('presence', 'Var', (26, 34))	('colorectal cancer', 'Disease', 'MESH:D015179', (178, 195))
125769	26868125	K-RAS mutations are one of the biological determinants of anti-EGFR target therapy resistance in colorectal cancer.	('EGFR', 'Gene', '1956', (63, 67))	('K-RAS', 'Gene', (0, 5))	('colorectal cancer', 'Disease', 'MESH:D015179', (97, 114))	('EGFR', 'Gene', (63, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colorectal cancer', 'Disease', (97, 114))	('mutations', 'Var', (6, 15))	('K-RAS', 'Gene', '3845', (0, 5))
125770	26868125	Although the role of K-RAS in response to the anti-EGFR therapy in CCA is controversial, this model could be suitable for the evaluation of the effectiveness of alternative therapies in K-RAS mutated patients for whom anti- EGFR therapies are unfit.	('K-RAS', 'Gene', '3845', (21, 26))	('CCA', 'Disease', (67, 70))	('patients', 'Species', '9606', (200, 208))	('EGFR', 'Gene', (51, 55))	('EGFR', 'Gene', (224, 228))	('K-RAS', 'Gene', (21, 26))	('K-RAS', 'Gene', '3845', (186, 191))	('mutated', 'Var', (192, 199))	('K-RAS', 'Gene', (186, 191))	('EGFR', 'Gene', '1956', (51, 55))	('EGFR', 'Gene', '1956', (224, 228))
125836	21537364	5), so we performed an intraoperative cholangiography that confirmed the presence of an aberrant posterior hepatic duct (VI-VII segment) (fig.	('aberrant', 'Var', (88, 96))	('VI-VII segment', 'Disease', (121, 135))	('VI-VII segment', 'Disease', 'MESH:C537538', (121, 135))
125872	32962091	Deregulated FGFR signaling plays an important role in tumor development and progression in different cancer types.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('Deregulated', 'Var', (0, 11))	('FGFR', 'Protein', (12, 16))	('cancer', 'Disease', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', (54, 59))
125874	32962091	In this review, we describe the most frequent FGFR aberrations in human cancer.	('aberrations', 'Var', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('FGFR', 'Gene', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
125877	32962091	Mutations (single nucleotide variants, SNVs) of FGFRs have been described in different tumor types.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('FGFRs', 'Gene', (48, 53))	('tumor', 'Disease', (87, 92))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('described', 'Reg', (64, 73))
125880	32962091	The growing therapeutic relevance of FGFR alterations, including fusions, in different cancer types has greatly supported the development of a variety of novel agents along with the improvement of diagnostic tests.	('cancer', 'Disease', (87, 93))	('alterations', 'Var', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('FGFR', 'Gene', (37, 41))
125888	32962091	Alternative splicing in the D3 domain of FGFR1, 2, and 3, generates isoforms IIIb and IIIc with different FGF-binding specificity.	('FGFR1', 'Gene', (41, 46))	('FGFR1', 'Gene', '2260', (41, 46))	('Alternative splicing in', 'Var', (0, 23))
125889	32962091	Alternative splicing and switching from epithelial to mesenchymal isoforms are involved in the epithelial-to-mesenchymal transition and in tumor progression.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('involved', 'Reg', (79, 87))	('epithelial-to-mesenchymal transition', 'CPA', (95, 131))	('Alternative splicing', 'Var', (0, 20))
125890	32962091	However, no data on the involvement of this phenomenon in the growth of cancer addicted to FGFR fusions are available.	('FGFR', 'Gene', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('fusions', 'Var', (96, 103))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
125900	32962091	Other pathways are activated by FGFRs, including JAK/STAT, p38MAPK, Jun N-terminal kinase, and RSK2.	('RSK2', 'Gene', (95, 99))	('JAK/STAT', 'Var', (49, 57))	('activated', 'PosReg', (19, 28))	('Jun N-terminal kinase', 'Gene', '5599', (68, 89))	('p38MAPK', 'Var', (59, 66))	('RSK2', 'Gene', '6197', (95, 99))	('FGFRs', 'Gene', (32, 37))	('Jun N-terminal kinase', 'Gene', (68, 89))
125901	32962091	Deregulated FGFR signaling is observed in various tumor types.	('Deregulated', 'Var', (0, 11))	('FGFR', 'Protein', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
125902	32962091	A recent study that analyzed the FGFR genomic alterations in 4853 tumor samples by next-generation sequencing (NGS), described the presence of FGFR alterations in 7.1% of cases.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('FGFR', 'Gene', (143, 147))	('alterations', 'Var', (148, 159))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('FGFR', 'Gene', (33, 37))
125903	32962091	Genetic aberrations of FGFR1 are more frequently observed in human cancers (2.86%), followed by alterations in FGFR3 (2.21%), FGFR2 (1.77%), and FGFR4 (1.54%).	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('FGFR1', 'Gene', (23, 28))	('FGFR2', 'Gene', '2263', (126, 131))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('FGFR1', 'Gene', '2260', (23, 28))	('FGFR4', 'Gene', '2264', (145, 150))	('FGFR4', 'Gene', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Genetic aberrations', 'Var', (0, 19))	('FGFR3', 'Gene', (111, 116))	('observed', 'Reg', (49, 57))	('FGFR2', 'Gene', (126, 131))	('human', 'Species', '9606', (61, 66))
125904	32962091	Gene amplifications are the most frequent FGFR alterations reported in human cancers accounting for 66% of all FGFR aberrations.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('FGFR', 'Gene', (42, 46))	('Gene amplifications', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('human', 'Species', '9606', (71, 76))
125906	32962091	FGFR1 amplification is frequently observed in breast, lung, and colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (64, 76))	('colon cancer', 'Disease', 'MESH:D015179', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('breast', 'Disease', (46, 52))	('colon cancer', 'Disease', (64, 76))	('observed', 'Reg', (34, 42))	('amplification', 'Var', (6, 19))	('lung', 'Disease', (54, 58))
125907	32962091	FGFR2 amplification is less frequent (0.34%) and has been described in some cancer types, including breast, gastric, and esophageal carcinoma.	('described', 'Reg', (58, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('breast', 'Disease', (100, 106))	('gastric', 'Disease', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('esophageal carcinoma', 'Disease', (121, 141))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (121, 141))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (121, 141))	('amplification', 'Var', (6, 19))	('FGFR2', 'Gene', (0, 5))	('cancer', 'Disease', (76, 82))	('FGFR2', 'Gene', '2263', (0, 5))
125910	32962091	FGFR mutations are less frequent than FGFR amplifications, representing 26% of the aberrations detected in FGFR-altered tumors.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('FGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
125911	32962091	Mutations in FGFR1 have been observed in 1.12% of cases, with a prevalence in lung, colon, breast, endometrial adenocarcinoma, and glioblastoma multiforme.	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (131, 154))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (99, 125))	('prevalence', 'Reg', (64, 74))	('observed', 'Reg', (29, 37))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('FGFR1', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('FGFR1', 'Gene', '2260', (13, 18))	('endometrial adenocarcinoma', 'Disease', (99, 125))	('lung', 'Disease', (78, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('glioblastoma multiforme', 'Disease', (131, 154))	('breast', 'Disease', (91, 97))	('colon', 'Disease', (84, 89))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (99, 125))
125912	32962091	The most frequent FGFR1 activating mutation is the N546K (0.12%) in the kinase domain of the receptor that alters the tyrosine auto-phosphorylation with an increased kinase activation.	('kinase', 'MPA', (166, 172))	('activating', 'PosReg', (24, 34))	('activation', 'PosReg', (173, 183))	('tyrosine auto-phosphorylation', 'MPA', (118, 147))	('tyrosine', 'Chemical', 'MESH:D014443', (118, 126))	('N546K', 'Var', (51, 56))	('increased', 'PosReg', (156, 165))	('N546K', 'Mutation', 'rs779707422', (51, 56))	('alters', 'Reg', (107, 113))	('FGFR1', 'Gene', (18, 23))	('FGFR1', 'Gene', '2260', (18, 23))
125913	32962091	Mutations in FGFR2 and FGFR3 are more frequent (1.36% and 1.83%, respectively).	('FGFR3', 'Gene', (23, 28))	('Mutations', 'Var', (0, 9))	('FGFR2', 'Gene', (13, 18))	('FGFR2', 'Gene', '2263', (13, 18))
125914	32962091	The most common FGFR2 activating mutations are the S252W mutation in the extracellular domain (0.17%), the N549K mutation in the tyrosine kinase domain (0.06%), and the C382R mutation affecting the transmembrane domain of the receptor (0.06%).	('S252W', 'Var', (51, 56))	('C382R', 'Mutation', 'rs121913474', (169, 174))	('N549K', 'Var', (107, 112))	('N549K', 'Mutation', 'rs121913476', (107, 112))	('S252W', 'Mutation', 'rs79184941', (51, 56))	('C382R', 'Var', (169, 174))	('FGFR2', 'Gene', (16, 21))	('FGFR2', 'Gene', '2263', (16, 21))	('tyrosine', 'Chemical', 'MESH:D014443', (129, 137))	('affecting', 'Reg', (184, 193))	('activating', 'PosReg', (22, 32))
125915	32962091	The most frequent FGFR3 activating mutation is the S249C missense mutation that resides in the extracellular domain of the receptor (0.54%).	('activating', 'PosReg', (24, 34))	('S249C', 'Mutation', 'rs121913483', (51, 56))	('S249C missense', 'Var', (51, 65))	('FGFR3', 'Gene', (18, 23))
125916	32962091	The FGFR3 S249C mutation is relatively frequent in bladder cancer (66.6%).	('bladder cancer', 'Disease', (51, 65))	('frequent', 'Reg', (39, 47))	('S249C', 'Var', (10, 15))	('S249C', 'Mutation', 'rs121913483', (10, 15))	('FGFR3', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (51, 65))	('bladder cancer', 'Disease', 'MESH:D001749', (51, 65))
125917	32962091	FGFR4-activating mutations are rare and are detected in some pediatric tumors, such as rhabdomyosarcoma.	('FGFR4', 'Gene', (0, 5))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (87, 103))	('detected', 'Reg', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (87, 103))	('FGFR4', 'Gene', '2264', (0, 5))	('tumors', 'Disease', (71, 77))	('rhabdomyosarcoma', 'Disease', (87, 103))	('mutations', 'Var', (17, 26))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
125918	32962091	A novel oncogenic mutation of FGFR4 (G636C) has been recently discovered in gastric cancer.	('G636C', 'Mutation', 'c.636G>C', (37, 42))	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('G636C', 'Var', (37, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('FGFR4', 'Gene', '2264', (30, 35))	('FGFR4', 'Gene', (30, 35))	('gastric cancer', 'Disease', (76, 90))
125919	32962091	FGFR fusions have been described in several tumor types, although the incidence is low (8%).	('FGFR', 'Gene', (0, 4))	('fusions', 'Var', (5, 12))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('described', 'Reg', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
125921	32962091	Fusion genes between FGFR1-2-3 and multiple partners have been identified in several tumor types (Table 1).	('tumor', 'Disease', (85, 90))	('Fusion genes', 'Var', (0, 12))	('identified', 'Reg', (63, 73))	('FGFR1', 'Gene', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('FGFR1', 'Gene', '2260', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
125923	32962091	FGFR1 fusions are rare in solid tumors.	('solid tumors', 'Disease', (26, 38))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('solid tumors', 'Disease', 'MESH:D009369', (26, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('fusions', 'Var', (6, 13))
125924	32962091	A FGFR1-HOOK3 gene fusion has been observed in gastrointestinal stromal tumor (GIST).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('fusion', 'Var', (19, 25))	('FGFR1', 'Gene', (2, 7))	('FGFR1', 'Gene', '2260', (2, 7))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (47, 77))	('HOOK3', 'Gene', (8, 13))	('gastrointestinal stromal tumor', 'Disease', (47, 77))	('GIST', 'Phenotype', 'HP:0100723', (79, 83))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (47, 77))	('observed', 'Reg', (35, 43))	('HOOK3', 'Gene', '84376', (8, 13))
125926	32962091	These fusions involve the N-terminus of the FGFR1 protein and the coiled coil of the fusion partners to induce activation of the receptor and downstream signaling.	('activation', 'PosReg', (111, 121))	('FGFR1', 'Gene', (44, 49))	('receptor', 'MPA', (129, 137))	('FGFR1', 'Gene', '2260', (44, 49))	('fusions', 'Var', (6, 13))
125929	32962091	FGFR2 fusions are the most frequent FGFR fusions.	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (6, 13))	('FGFR2', 'Gene', '2263', (0, 5))
125930	32962091	As compared with the other member of the FGFR family, FGFR2 had several reported partners and FGFR2 fusions are particularly common in cholangiocarcinoma.	('common', 'Reg', (125, 131))	('fusions', 'Var', (100, 107))	('FGFR2', 'Gene', (94, 99))	('cholangiocarcinoma', 'Disease', (135, 153))	('FGFR2', 'Gene', '2263', (94, 99))	('FGFR2', 'Gene', (54, 59))	('FGFR2', 'Gene', '2263', (54, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (135, 153))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (135, 153))
125931	32962091	In this regard, FGFR2-AHCYL, FGFR2-BICC1, FGFR2-PPHLN1, and FGFR2-TACC3 fusions have been frequently described in patients with intrahepatic cholangiocarcinoma, although over 100 different FGFR2 partners have been reported in this disease.	('described', 'Reg', (101, 110))	('FGFR2', 'Gene', '2263', (29, 34))	('FGFR2', 'Gene', (60, 65))	('FGFR2', 'Gene', (42, 47))	('BICC1', 'Gene', '80114', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('FGFR2', 'Gene', '2263', (60, 65))	('BICC1', 'Gene', (35, 40))	('patients', 'Species', '9606', (114, 122))	('PPHLN1', 'Gene', (48, 54))	('FGFR2', 'Gene', '2263', (42, 47))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (128, 159))	('FGFR2', 'Gene', (16, 21))	('intrahepatic cholangiocarcinoma', 'Disease', (128, 159))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (141, 159))	('fusions', 'Var', (72, 79))	('FGFR2', 'Gene', (189, 194))	('PPHLN1', 'Gene', '51535', (48, 54))	('FGFR2', 'Gene', (29, 34))	('FGFR2', 'Gene', '2263', (16, 21))	('FGFR2', 'Gene', '2263', (189, 194))
125932	32962091	The FGFR2-CCDC6 fusion has been demonstrated to induce cancer cell proliferation and tumorigenesis in vivo.	('tumor', 'Disease', (85, 90))	('FGFR2', 'Gene', (4, 9))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('FGFR2', 'Gene', '2263', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('induce', 'PosReg', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('CCDC6', 'Gene', '8030', (10, 15))	('CCDC6', 'Gene', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('fusion', 'Var', (16, 22))	('cancer', 'Disease', (55, 61))
125935	32962091	Two FGFR2-KIAA1598 fusions and other FGFR2 fusions with novel partners (CIT, ERC1, LZTFL1, POC1B, SORBS1, TP73, TXLNA) have been recently identified in a large cohort (n = 26054) of lung cancer patients.	('POC1B', 'Gene', (91, 96))	('ERC1', 'Gene', (77, 81))	('lung cancer', 'Disease', (182, 193))	('KIAA1598', 'Gene', '57698', (10, 18))	('FGFR2', 'Gene', '2263', (37, 42))	('CIT', 'Gene', '11113', (72, 75))	('FGFR2', 'Gene', '2263', (4, 9))	('TP73', 'Gene', (106, 110))	('POC1B', 'Gene', '282809', (91, 96))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('CIT', 'Gene', (72, 75))	('LZTFL1', 'Gene', '54585', (83, 89))	('patients', 'Species', '9606', (194, 202))	('KIAA1598', 'Gene', (10, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('fusions', 'Var', (19, 26))	('fusions', 'Var', (43, 50))	('SORBS1', 'Gene', '10580', (98, 104))	('TP73', 'Gene', '7161', (106, 110))	('SORBS1', 'Gene', (98, 104))	('TXLNA', 'Gene', '200081', (112, 117))	('FGFR2', 'Gene', (37, 42))	('LZTFL1', 'Gene', (83, 89))	('ERC1', 'Gene', '23085', (77, 81))	('TXLNA', 'Gene', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('FGFR2', 'Gene', (4, 9))
125936	32962091	FGFR3 fusions are more commonly observed in glioblastoma, bladder, and lung cancer.	('glioblastoma', 'Disease', (44, 56))	('glioblastoma', 'Disease', 'MESH:D005909', (44, 56))	('observed', 'Reg', (32, 40))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('FGFR3', 'Gene', (0, 5))	('glioblastoma', 'Phenotype', 'HP:0012174', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('bladder', 'Disease', (58, 65))	('fusions', 'Var', (6, 13))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
125937	32962091	The majority of FGFR3 fusions are with transforming acidic coiled-coil 3 (TACC3) and result from the in-frame fusion of the FGFR3 N-terminus with the TACC3 C-terminus.	('FGFR3', 'Gene', (16, 21))	('transforming acidic coiled-coil 3', 'Gene', (39, 72))	('TACC3 C', 'Mutation', 'c.3TACC>C', (150, 157))	('fusions', 'Var', (22, 29))	('transforming acidic coiled-coil 3', 'Gene', '10460', (39, 72))	('FGFR3', 'Gene', (124, 129))
125938	32962091	FGFR3-TACC3 fusions have been described in different tumor types, including glioma, lung cancer, bladder cancer, head and neck squamous cancer, lung squamous cell carcinoma, and cervical cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('glioma', 'Disease', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Disease', (105, 111))	('head and neck squamous cancer', 'Disease', 'MESH:D006258', (113, 142))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('squamous cancer', 'Phenotype', 'HP:0002860', (127, 142))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('described', 'Reg', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('fusions', 'Var', (12, 19))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (144, 172))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('bladder cancer', 'Disease', 'MESH:D001749', (97, 111))	('bladder cancer', 'Disease', (97, 111))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))	('lung cancer', 'Disease', (84, 95))	('FGFR3-TACC3', 'Gene', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('lung squamous cell carcinoma', 'Disease', (144, 172))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (144, 172))	('cancer', 'Disease', (187, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('head and neck squamous cancer', 'Phenotype', 'HP:0012288', (113, 142))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('tumor', 'Disease', (53, 58))
125941	32962091	The presence of the FGFR3-TACC3 fusion increased the proliferation of cancer cell lines and induced tumorigenesis in mice.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('induced', 'Reg', (92, 99))	('FGFR3-TACC3', 'Gene', (20, 31))	('tumor', 'Disease', (100, 105))	('mice', 'Species', '10090', (117, 121))	('fusion', 'Var', (32, 38))	('increased', 'PosReg', (39, 48))	('cancer', 'Disease', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
125945	32962091	Recently, FGFR4 fusions (ANO3-FGFR4, NSD1-FGFR4) have been identified in NSCLC patients.	('FGFR4', 'Gene', (42, 47))	('FGFR4', 'Gene', '2264', (10, 15))	('FGFR4', 'Gene', (10, 15))	('fusions', 'Var', (16, 23))	('identified', 'Reg', (59, 69))	('NSD1', 'Gene', '64324', (37, 41))	('ANO3', 'Gene', '63982', (25, 29))	('FGFR4', 'Gene', '2264', (42, 47))	('NSCLC', 'Disease', (73, 78))	('patients', 'Species', '9606', (79, 87))	('FGFR4', 'Gene', '2264', (30, 35))	('NSD1', 'Gene', (37, 41))	('FGFR4', 'Gene', (30, 35))	('ANO3', 'Gene', (25, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))
125948	32962091	Intrachromosomal rearrangements, which account for about 50% of FGFR2 fusions in intrahepatic cholangiocarcinoma, can also lead to false-negative results of FISH analysis.	('FGFR2', 'Gene', '2263', (64, 69))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (81, 112))	('FGFR2', 'Gene', (64, 69))	('fusions', 'Var', (70, 77))	('intrahepatic cholangiocarcinoma', 'Disease', (81, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (94, 112))
125949	32962091	Recently, a novel RNA-FISH assay allowed the detection of FGFR3-TACC3 fusions in bladder cancer.	('FGFR3-TACC3', 'Gene', (58, 69))	('bladder cancer', 'Disease', 'MESH:D001749', (81, 95))	('bladder cancer', 'Disease', (81, 95))	('bladder cancer', 'Phenotype', 'HP:0009725', (81, 95))	('fusions', 'Var', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
125953	32962091	Anchored multiplex PCR has been recently used to identify various FGFR2 fusions in cholangiocarcinoma clinical samples.	('FGFR2', 'Gene', (66, 71))	('FGFR2', 'Gene', '2263', (66, 71))	('cholangiocarcinoma', 'Disease', (83, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('fusions', 'Var', (72, 79))
125954	32962091	The improvement of diagnostic strategies for detection of FGFR alterations allowed the identification of a number of FGFR fusions that might potentially predict the outcome of cancer patients.	('alterations', 'Var', (63, 74))	('predict', 'Reg', (153, 160))	('FGFR', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('fusions', 'Var', (122, 129))	('FGFR', 'Gene', (117, 121))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('patients', 'Species', '9606', (183, 191))
125956	32962091	In this regard, a study evaluated the presence of FGFR2 translocations in 152 cholangiocarcinoma and 4 intraductal papillary neoplasms of the bile duct by FISH.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 96))	('papillary neoplasms', 'Disease', (115, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (78, 96))	('FGFR2', 'Gene', '2263', (50, 55))	('FGFR2', 'Gene', (50, 55))	('cholangiocarcinoma', 'Disease', (78, 96))	('neoplasms', 'Phenotype', 'HP:0002664', (125, 134))	('papillary neoplasms', 'Disease', 'MESH:D002291', (115, 134))	('translocations', 'Var', (56, 70))
125957	32962091	Thirteen specimens were positive for FGFR2 translocations.	('positive', 'Reg', (24, 32))	('FGFR2', 'Gene', (37, 42))	('FGFR2', 'Gene', '2263', (37, 42))	('translocations', 'Var', (43, 57))
125958	32962091	The median cancer-specific survival interval for patients carrying FGFR2 translocations was significantly longer (123 months) than that for patients without FGFR2 translocations (37 months, P = 0.039).	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('translocations', 'Var', (73, 87))	('longer', 'PosReg', (106, 112))	('FGFR2', 'Gene', (67, 72))	('FGFR2', 'Gene', '2263', (67, 72))	('FGFR2', 'Gene', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('patients', 'Species', '9606', (140, 148))	('patients', 'Species', '9606', (49, 57))	('cancer', 'Disease', (11, 17))	('FGFR2', 'Gene', '2263', (157, 162))
125959	32962091	In a study in which 377 patients with biliary tract cancer were enrolled, 95 FGFR genetic alterations, including 63 FGFR2 fusions, were detected.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (38, 58))	('patients', 'Species', '9606', (24, 32))	('genetic alterations', 'Var', (82, 101))	('FGFR2', 'Gene', (116, 121))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('FGFR2', 'Gene', '2263', (116, 121))	('cancer', 'Disease', (52, 58))	('FGFR', 'Gene', (77, 81))
125960	32962091	Patients with FGFR alterations experienced significantly longer overall survival (OS) than patients without FGFR aberrations (37 vs. 20 months; P <0.001).	('longer', 'PosReg', (57, 63))	('patients', 'Species', '9606', (91, 99))	('FGFR', 'Gene', (14, 18))	('overall survival', 'MPA', (64, 80))	('Patients', 'Species', '9606', (0, 8))	('alterations', 'Var', (19, 30))
125961	32962091	In a recent study in patients with fluke associated-intrahepatic cholangiocarcinoma, the presence of rare FGFR2 fusions indicated a trend toward better OS compared with that of fusion-negative tumors, although the difference was not statistically significant.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (52, 83))	('FGFR2', 'Gene', '2263', (106, 111))	('intrahepatic cholangiocarcinoma', 'Disease', (52, 83))	('fusions', 'Var', (112, 119))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('patients', 'Species', '9606', (21, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('better', 'PosReg', (145, 151))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('FGFR2', 'Gene', (106, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))	('presence', 'Var', (89, 97))
125962	32962091	The presence of FGFR genomic alterations, including FGFR2 fusions genes identified by NGS in 55 patients with intrahepatic cholangiocarcinoma, has been associated with an indolent disease course and prolonged survival.	('FGFR', 'Gene', (16, 20))	('fusions genes', 'Var', (58, 71))	('FGFR2', 'Gene', (52, 57))	('FGFR2', 'Gene', '2263', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (110, 141))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (123, 141))	('intrahepatic cholangiocarcinoma', 'Disease', (110, 141))	('patients', 'Species', '9606', (96, 104))	('associated with', 'Reg', (152, 167))	('presence', 'Var', (4, 12))
125964	32962091	Interestingly, one patient with an FGFR2-NOL4 fusion and a co-existing BAP1 mutation had a rapidly progressive course.	('patient', 'Species', '9606', (19, 26))	('FGFR2', 'Gene', (35, 40))	('mutation', 'Var', (76, 84))	('FGFR2', 'Gene', '2263', (35, 40))	('NOL4', 'Gene', '8715', (41, 45))	('BAP1', 'Gene', '8314', (71, 75))	('fusion', 'Var', (46, 52))	('BAP1', 'Gene', (71, 75))	('NOL4', 'Gene', (41, 45))
125966	32962091	In this study, KRAS and BRAF mutations were mutually exclusive with FGFR2 fusions.	('KRAS', 'Gene', (15, 19))	('mutations', 'Var', (29, 38))	('FGFR2', 'Gene', '2263', (68, 73))	('fusions', 'Var', (74, 81))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('KRAS', 'Gene', '3845', (15, 19))	('FGFR2', 'Gene', (68, 73))
125967	32962091	The prognostic significance of FGFR1-3 fusions was explored in NSCLC.	('NSCLC', 'Disease', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('fusions', 'Var', (39, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('FGFR1', 'Gene', (31, 36))	('FGFR1', 'Gene', '2260', (31, 36))
125973	32962091	Different clinical trials of non-selective TKIs are ongoing in patients with FGFR alterations (Table 3).	('patients', 'Species', '9606', (63, 71))	('alterations', 'Var', (82, 93))	('FGFR', 'Gene', (77, 81))
125975	32962091	In this regard, in a study of dovitinib in 13 patients with Bacillus Calmette-Guerin (BCG)-refractory urothelial carcinoma and FGFR3 alterations, three patients had FGFR3 mutations.	('patients', 'Species', '9606', (46, 54))	('alterations', 'Var', (133, 144))	('FGFR3', 'Gene', (165, 170))	('dovitinib', 'Chemical', 'MESH:C500007', (30, 39))	('FGFR3', 'Gene', (127, 132))	('Bacillus Calmette-Guerin', 'Species', '33892', (60, 84))	('urothelial carcinoma', 'Disease', (102, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('BCG', 'Species', '33892', (86, 89))	('mutations', 'Var', (171, 180))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (102, 122))	('patients', 'Species', '9606', (152, 160))
125976	32962091	The response rate (RR) was 8% with only one complete response (CR) in a patient carrying the FGFR3 S249C mutation.	('patient', 'Species', '9606', (72, 79))	('S249C', 'Var', (99, 104))	('FGFR3', 'Gene', (93, 98))	('S249C', 'Mutation', 'rs121913483', (99, 104))
125978	32962091	In a clinical study in FGFR2-mutant or wild-type endometrial cancer patients treated with dovitinib, the RR in the FGFR2 mutant group was 5% (11% for all patients); only 1/22 FGFR2 mutant patients achieved a partial response (PR).	('mutant', 'Var', (181, 187))	('endometrial cancer', 'Disease', (49, 67))	('mutant', 'Var', (121, 127))	('FGFR2', 'Gene', (115, 120))	('FGFR2', 'Gene', '2263', (115, 120))	('FGFR2', 'Gene', (23, 28))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (188, 196))	('patients', 'Species', '9606', (68, 76))	('endometrial cancer', 'Phenotype', 'HP:0012114', (49, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('FGFR2', 'Gene', '2263', (23, 28))	('endometrial cancer', 'Disease', 'MESH:D016889', (49, 67))	('FGFR2', 'Gene', (175, 180))	('dovitinib', 'Chemical', 'MESH:C500007', (90, 99))	('FGFR2', 'Gene', '2263', (175, 180))
125979	32962091	Treatment with derazantinib produced an overall RR (ORR) of 20.7%, a disease control rate (DCR) of 82.8%, and a median progression-free survival (PFS) of 5.7 months in patients with advanced, unresectable intrahepatic cholangiocarcinoma and FGFR2 fusions who progressed after chemotherapy.	('DCR', 'Chemical', '-', (91, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('FGFR2', 'Gene', (241, 246))	('FGFR2', 'Gene', '2263', (241, 246))	('derazantinib', 'Chemical', 'MESH:C000621805', (15, 27))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (218, 236))	('fusions', 'Var', (247, 254))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (205, 236))	('disease control', 'Disease', (69, 84))	('patients', 'Species', '9606', (168, 176))	('intrahepatic cholangiocarcinoma', 'Disease', (205, 236))
125983	32962091	In particular, erdafitinib has been approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma with FGFR3 or FGFR2 genetic alterations, including R248C, S249C, G370C, and Y373C mutations and FGFR3-TACC3 fusions, on the basis of the BLC2001 trial.	('urothelial carcinoma', 'Disease', (111, 131))	('Y373C', 'Mutation', 'rs121913485', (208, 213))	('FGFR2', 'Gene', (146, 151))	('locally advanced', 'Disease', (80, 96))	('erdafitinib', 'Chemical', 'MESH:C000604580', (15, 26))	('FGFR3', 'Gene', (137, 142))	('S249C', 'Mutation', 'rs121913483', (190, 195))	('R248C', 'Var', (183, 188))	('FGFR2', 'Gene', '2263', (146, 151))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (111, 131))	('patients', 'Species', '9606', (66, 74))	('S249C', 'Var', (190, 195))	('R248C', 'Mutation', 'rs121913482', (183, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('Y373C mutations', 'Var', (208, 223))	('G370C', 'Mutation', 'rs199740841', (197, 202))	('G370C', 'Var', (197, 202))
125986	32962091	Pemigatinib was granted FDA-accelerated approval in April 2020 for the treatment of cholangiocarcinoma patients with FGFR2 fusions or rearrangements.	('rearrangements', 'Var', (134, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('Pemigatinib', 'Chemical', '-', (0, 11))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('FGFR2', 'Gene', (117, 122))	('FGFR2', 'Gene', '2263', (117, 122))	('cholangiocarcinoma', 'Disease', (84, 102))	('fusions', 'Var', (123, 130))	('patients', 'Species', '9606', (103, 111))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
125987	32962091	The efficacy of the drug was evaluated in the FIGHT-202 study in 107 patients with cholangiocarcinoma and FGFR2 gene fusions.	('cholangiocarcinoma', 'Disease', (83, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('FGFR2', 'Gene', '2263', (106, 111))	('gene fusions', 'Var', (112, 124))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('patients', 'Species', '9606', (69, 77))	('FGFR2', 'Gene', (106, 111))
125988	32962091	No CRs or PRs were observed in patients with other FGF/FGFR alterations or no FGF/FGFR alterations.	('alterations', 'Var', (60, 71))	('PRs', 'CPA', (10, 13))	('patients', 'Species', '9606', (31, 39))	('CRs', 'CPA', (3, 6))
125989	32962091	A number of different reversible competitive inhibitors directed against multiple FGFRs (e.g., erdafitinib, pemigatinib, infigratinib, rogaratinib, AZD4547, Debio1347) are in clinical development in patients with hematologic and solid tumors who carry FGFR alterations (Table 4).	('alterations', 'Var', (257, 268))	('hematologic', 'Disease', (213, 224))	('solid tumors', 'Disease', 'MESH:D009369', (229, 241))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('Debio1347', 'Chemical', 'MESH:C000602562', (157, 166))	('infigratinib', 'Chemical', 'MESH:C568950', (121, 133))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('AZD4547', 'Chemical', 'MESH:C572463', (148, 155))	('patients', 'Species', '9606', (199, 207))	('solid tumors', 'Disease', (229, 241))	('erdafitinib', 'Chemical', 'MESH:C000604580', (95, 106))	('pemigatinib', 'Chemical', '-', (108, 119))
125992	32962091	In a phase II trial of AZD4547 in patients with advanced cancers with FGFR1-3 aberrations, PRs were observed in 4 of 48 (8%) patients, including 2 patients with FGFR mutations and 2 with FGFR3-TACC3 fusions.	('PRs', 'Disease', (91, 94))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('patients', 'Species', '9606', (147, 155))	('FGFR1', 'Gene', (70, 75))	('observed', 'Reg', (100, 108))	('aberrations', 'Var', (78, 89))	('patients', 'Species', '9606', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('AZD4547', 'Chemical', 'MESH:C572463', (23, 30))	('FGFR1', 'Gene', '2260', (70, 75))	('patients', 'Species', '9606', (125, 133))
125993	32962091	The 6-month PFS rate was low for patients with FGFR amplifications (0%) and for patients carrying FGFR mutations (6%) and higher for patients with FGFR fusions (56%).	('FGFR', 'Gene', (47, 51))	('mutations', 'Var', (103, 112))	('FGFR', 'Gene', (98, 102))	('patients', 'Species', '9606', (33, 41))	('patients', 'Species', '9606', (80, 88))	('higher', 'PosReg', (122, 128))	('patients', 'Species', '9606', (133, 141))	('PFS', 'Disease', (12, 15))	('amplifications', 'Var', (52, 66))	('low', 'NegReg', (25, 28))
125995	32962091	In a multicenter, open label, phase II study on infigratinib in chemotherapy-refractory advanced or metastatic cholangiocarcinoma with FGFR alterations, including 48 FGFR2 fusions, all responsive cases harbored FGFR2 fusions.	('cholangiocarcinoma', 'Disease', (111, 129))	('FGFR2', 'Gene', (166, 171))	('FGFR2', 'Gene', '2263', (166, 171))	('infigratinib', 'Chemical', 'MESH:C568950', (48, 60))	('FGFR2', 'Gene', '2263', (211, 216))	('FGFR2', 'Gene', (211, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('alterations', 'Var', (140, 151))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 129))	('FGFR', 'Gene', (135, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))
125996	32962091	The RR was 14.8 % and the DCR 75.4% (18.8% and 83.3% for patients with FGFR2 fusions, respectively).	('DCR', 'Chemical', '-', (26, 29))	('patients', 'Species', '9606', (57, 65))	('fusions', 'Var', (77, 84))	('FGFR2', 'Gene', '2263', (71, 76))	('FGFR2', 'Gene', (71, 76))
125997	32962091	Reduced target lesion size in at least one disease evaluation was observed in 36/48 patients with tumors bearing FGFR2 fusions.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('patients', 'Species', '9606', (84, 92))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('FGFR2', 'Gene', '2263', (113, 118))	('Reduced', 'NegReg', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('fusions', 'Var', (119, 126))	('FGFR2', 'Gene', (113, 118))
125998	32962091	Only few studies with selective reversible FGFR-TKIs are planned in patients specifically carrying only FGFR fusions, presumably due to the low frequency of these alterations (Table 4).	('patients', 'Species', '9606', (68, 76))	('FGFR', 'Gene', (104, 108))	('fusions', 'Var', (109, 116))
125999	32962091	In this regard, a study exploring the effects of AZD4547 is ongoing in patients with glioma and the FGFR3-TACC3 fusion (ClinicalTrials.gov Identifier: NCT02824133).	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('AZD4547', 'Var', (49, 56))	('AZD4547', 'Chemical', 'MESH:C572463', (49, 56))	('patients', 'Species', '9606', (71, 79))	('glioma', 'Disease', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
126000	32962091	Infigratinib is under evaluation in a phase III study as first-line treatment for patients with cholangiocarcinoma and FGFR2 gene fusions/translocations (ClinicalTrials.gov Identifier: NCT03773302) and in a phase I study in patients with high-grade glioma and FGFR3-TACC3 translocations (ClinicalTrials.gov Identifier: NCT04424966).	('glioma', 'Disease', 'MESH:D005910', (249, 255))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('Infigratinib', 'Chemical', 'MESH:C568950', (0, 12))	('FGFR2', 'Gene', '2263', (119, 124))	('patients', 'Species', '9606', (82, 90))	('cholangiocarcinoma', 'Disease', (96, 114))	('gene fusions/translocations', 'Var', (125, 152))	('glioma', 'Disease', (249, 255))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 114))	('fusions/translocations', 'Var', (130, 152))	('patients', 'Species', '9606', (224, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))	('FGFR2', 'Gene', (119, 124))
126003	32962091	In a trial exploring futibatinib in previously treated cholangiocarcinoma patients with FGFR alterations, 20/28 patients carrying FGFR2 fusions experienced tumor shrinkage and 7/28 confirmed PR.	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('alterations', 'Var', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('patients', 'Species', '9606', (74, 82))	('fusions', 'Var', (136, 143))	('cholangiocarcinoma', 'Disease', (55, 73))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Disease', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (55, 73))	('FGFR2', 'Gene', (130, 135))	('FGFR2', 'Gene', '2263', (130, 135))	('futibatinib', 'Chemical', '-', (21, 32))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (55, 73))	('FGFR', 'Gene', (88, 92))
126005	32962091	The irreversible FGFR inhibitor futibatinib is currently under evaluation in a phase III clinical study in patients with advanced cholangiocarcinoma harboring FGFR2 gene rearrangements (ClinicalTrials.gov Identifier: NCT04093362).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (130, 148))	('FGFR2', 'Gene', (159, 164))	('futibatinib', 'Chemical', '-', (32, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (130, 148))	('FGFR2', 'Gene', '2263', (159, 164))	('rearrangements', 'Var', (170, 184))	('cholangiocarcinoma', 'Disease', (130, 148))	('patients', 'Species', '9606', (107, 115))
126007	32962091	However, the results of clinical trials have clearly demonstrated that only tumors carrying genetic alterations of the FGFRs such as mutations or fusions might respond to treatment with FGFR inhibitors, at least when used as single agents.	('fusions', 'Var', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('mutations', 'Var', (133, 142))	('respond', 'Reg', (160, 167))	('FGFRs', 'Gene', (119, 124))
126009	32962091	In the last years, the rapid improvement in the development of drugs targeting FGFR alterations, including fusions, combined with the availability of ever more efficient diagnostic tests, allowed the selection of patients who might benefit from FGFR inhibitors.	('FGFR', 'Gene', (79, 83))	('alterations', 'Var', (84, 95))	('patients', 'Species', '9606', (213, 221))
126010	32962091	However, some issues should be considered, such as the need of adequate tools for the detection of FGFR genetic alterations, the identification of the mechanisms of resistance to FGFR inhibitors and the possibility of performing clinical trials specifically for patients with rare alterations.	('patients', 'Species', '9606', (262, 270))	('alterations', 'Var', (112, 123))	('FGFR', 'Gene', (99, 103))
126013	32962091	Analysis of cfDNA for the detection of FGFR fusions might also serve as a non-invasive tool for monitoring patients undergoing FGFR-targeted therapies and for the identification of biomarkers of resistance.	('patients', 'Species', '9606', (107, 115))	('FGFR', 'Gene', (39, 43))	('fusions', 'Var', (44, 51))
126016	32962091	Interestingly, one FGFR2 point mutation (p.V564F) was identified in all patients, suggesting a relevant role of this genomic alteration in the resistance to anti-FGFR agents.	('p.V564F', 'Mutation', 'p.V564F', (41, 48))	('FGFR2', 'Gene', '2263', (19, 24))	('FGFR2', 'Gene', (19, 24))	('p.V564F', 'Var', (41, 48))	('patients', 'Species', '9606', (72, 80))
126017	32962091	A recent study in patients with fusion-positive intrahepatic cholangiocarcinoma who progressed on BGJ398 or Debio1347 revealed that treatment with the FGFR irreversible inhibitor futibatinib might overcome the acquired resistance to FGFR reversible inhibitors.	('Debio1347', 'Var', (108, 117))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (48, 79))	('BGJ398', 'Gene', (98, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('intrahepatic cholangiocarcinoma', 'Disease', (48, 79))	('patients', 'Species', '9606', (18, 26))	('futibatinib', 'Chemical', '-', (179, 190))	('BGJ398', 'Chemical', 'MESH:C568950', (98, 104))	('Debio1347', 'Chemical', 'MESH:C000602562', (108, 117))
126021	32962091	Basket trials, in which a sufficient number of patients with specific genetic alterations can be enrolled, regardless of the tumor type, are required, in order to study the significance of these alterations in a larger population and to offer a personalized treatment to patients carrying these rare genomic aberrations.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Disease', (125, 130))	('alterations', 'Var', (78, 89))	('patients', 'Species', '9606', (271, 279))
126022	32962091	In conclusion, the awareness that FGFR alterations, including fusions, play an important role in cancer has greatly enhanced the clinical development of FGFR inhibitors together with the improvement of NGS-based molecular tests.	('enhanced', 'PosReg', (116, 124))	('cancer', 'Disease', (97, 103))	('FGFR', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('alterations', 'Var', (39, 50))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
126035	29930804	In earlier reports, genetic alterations were identified to be involved in CCA carcinogenesis, including point mutations in p53, B-Raf proto-oncogene serine/threonine kinase and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog.	('CCA carcinogenesis', 'Disease', 'MESH:C536211', (74, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('rat', 'Species', '10116', (32, 35))	('involved', 'Reg', (62, 70))	('p53', 'Gene', (123, 126))	('rat', 'Species', '10116', (195, 198))	('CCA carcinogenesis', 'Disease', (74, 92))	('sarcoma', 'Disease', 'MESH:D012509', (199, 206))	('point mutations', 'Var', (104, 119))	('sarcoma', 'Disease', (199, 206))
126040	29930804	For example, inhibitors of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, including lovastatin, atorvastatin and simvastatin, and of cyclooxygenase-2 (COX-2), including celecoxib, have potential preventative effects on CCA carcinogenesis.	('atorvastatin', 'Chemical', 'MESH:D000069059', (97, 109))	('CCA carcinogenesis', 'Disease', (220, 238))	('COX-2', 'Gene', (152, 157))	('lovastatin', 'Chemical', 'MESH:D008148', (85, 95))	('inhibitors', 'Var', (13, 23))	('COX-2', 'Gene', '5743', (152, 157))	('3-hydroxy-3-methylglutaryl (HMG)-CoA reductase', 'Gene', '3156', (27, 73))	('CCA carcinogenesis', 'Disease', 'MESH:C536211', (220, 238))	('simvastatin', 'Chemical', 'MESH:D019821', (114, 125))	('celecoxib', 'Chemical', 'MESH:D000068579', (170, 179))	('cyclooxygenase-2', 'Gene', (134, 150))	('cyclooxygenase-2', 'Gene', '5743', (134, 150))
126062	29930804	The Kaplan-Meier curve demonstrated that the altered genes group was associated with a significantly lower survival rate (P=0.0947; Fig.	('altered genes', 'Var', (45, 58))	('survival rate', 'CPA', (107, 120))	('rat', 'Species', '10116', (30, 33))	('lower', 'NegReg', (101, 106))	('rat', 'Species', '10116', (116, 119))
126084	29930804	According to the survival analysis, patients with CCA in the altered gene group had a lower rate of OS compared with those patients with no alterations in the DEGs of interest.	('altered gene', 'Var', (61, 73))	('patients', 'Species', '9606', (36, 44))	('CCA', 'Disease', (50, 53))	('patients', 'Species', '9606', (123, 131))	('lower', 'NegReg', (86, 91))	('rat', 'Species', '10116', (92, 95))	('rat', 'Species', '10116', (144, 147))
126085	29930804	Genetic alterations in cell metabolism may contribute to poor prognosis in human cancers.	('Genetic alterations', 'Var', (0, 19))	('cell metabolism', 'MPA', (23, 38))	('rat', 'Species', '10116', (12, 15))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('human', 'Species', '9606', (75, 80))
126100	29930804	Cimetidine, a histamine type 2 antagonist, is used to treat heartburn and peptic ulcer; however, data also indicates that cimetidine may contribute to growth inhibition and apoptosis induction in CCA in vitro and in vivo.	('histamine', 'Chemical', 'MESH:D006632', (14, 23))	('heartburn', 'Phenotype', 'HP:0002020', (60, 69))	('Cimetidine', 'Chemical', 'MESH:D002927', (0, 10))	('growth inhibition', 'CPA', (151, 168))	('apoptosis induction', 'CPA', (173, 192))	('ulcer', 'Disease', 'MESH:D014456', (81, 86))	('peptic ulcer', 'Phenotype', 'HP:0004398', (74, 86))	('cimetidine', 'Chemical', 'MESH:D002927', (122, 132))	('CCA', 'Disease', (196, 199))	('ulcer', 'Disease', (81, 86))	('cimetidine', 'Var', (122, 132))
126159	28261696	Patients with definite stones or strictures in other peripheral branches of intrahepatic bile ducts undergo major hepatectomy, regardless of the symptoms and irrespective of the presence of atrophy.	('intrahepatic bile duct', 'Disease', (76, 98))	('intrahepatic bile duct', 'Disease', 'MESH:D002780', (76, 98))	('atrophy', 'Disease', 'MESH:D001284', (190, 197))	('strictures', 'Var', (33, 43))	('atrophy', 'Disease', (190, 197))	('Patients', 'Species', '9606', (0, 8))	('hepatectomy', 'Disease', (114, 125))
126456	31336279	This can provide formulation stability and in some cases PEGylation has been shown to enhance PS delivery to tumors.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('enhance', 'PosReg', (86, 93))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('PEGylation', 'Var', (57, 67))	('PEG', 'Chemical', 'MESH:D011092', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('S', 'Chemical', 'MESH:D013455', (95, 96))	('tumors', 'Disease', (109, 115))
126487	31336279	When liposomes loaded with Photofrin or free PS were used for PDT of U87 human glioma athymic nude mice xenografts and 9L rat gliosarcomas, liposomal Photofrin showed better accumulation of the drug in tumors and enhanced tumor cell killing.	('accumulation', 'MPA', (174, 186))	('Photofrin', 'Chemical', 'MESH:D017323', (27, 36))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('S', 'Chemical', 'MESH:D013455', (46, 47))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('glioma athymic', 'Disease', 'MESH:D005910', (79, 93))	('tumor', 'Disease', (202, 207))	('human', 'Species', '9606', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('gliosarcomas', 'Disease', 'MESH:D018316', (126, 138))	('Photofrin', 'Chemical', 'MESH:D017323', (150, 159))	('better', 'PosReg', (167, 173))	('nude mice', 'Species', '10090', (94, 103))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('U87', 'CellLine', 'CVCL:0022', (69, 72))	('enhanced', 'PosReg', (213, 221))	('tumor', 'Disease', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumors', 'Disease', (202, 208))	('gliosarcomas', 'Disease', (126, 138))	('glioma athymic', 'Disease', (79, 93))	('liposomal', 'Var', (140, 149))	('rat', 'Species', '10116', (122, 125))
126495	31336279	BPD-MA has not only been used for AMD applications, but has been explored extensively for tumor suppression.	('AMD', 'Disease', (34, 37))	('BPD-MA', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('AMD', 'Disease', 'MESH:D006009', (34, 37))	('BPD-MA', 'Chemical', '-', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
126502	31336279	Further, when 2,3-dihydro-5,15-di(3,5-dihydroxyphenyl)porphyrin (SIM01), a new diphenylchlorin PS encapsulated in DMPC based liposomes, were studied in vivo in HT29 human adenocarcinoma mice xenografts, it showed significant tissue uptake and phototoxicity of SIM01 leading to significant cellular destruction.	('DMPC', 'Chemical', 'MESH:D004134', (114, 118))	('adenocarcinoma', 'Disease', (171, 185))	('human', 'Species', '9606', (165, 170))	('2,3-dihydro-5,15-di(3,5-dihydroxyphenyl)porphyrin', 'Chemical', 'MESH:C481258', (14, 63))	('S', 'Chemical', 'MESH:D013455', (65, 66))	('adenocarcinoma', 'Disease', 'MESH:D000230', (171, 185))	('phototoxicity', 'Disease', (243, 256))	('S', 'Chemical', 'MESH:D013455', (96, 97))	('HT29', 'CellLine', 'CVCL:0320', (160, 164))	('cellular destruction', 'CPA', (289, 309))	('mice', 'Species', '10090', (186, 190))	('SIM01', 'Var', (260, 265))	('diphenylchlorin PS', 'Chemical', '-', (79, 97))	('tissue uptake', 'CPA', (225, 238))	('S', 'Chemical', 'MESH:D013455', (260, 261))	('phototoxicity', 'Disease', 'MESH:D017484', (243, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
126563	31336279	It has been shown that increasing PEGylation of Fospeg-like liposomes can increase blood circulation times while avoiding the skin toxicity compared to the photosensitizers without liposomal formulation.	('skin toxicity', 'Disease', 'MESH:D012871', (126, 139))	('Fospeg', 'Chemical', '-', (48, 54))	('increasing', 'PosReg', (23, 33))	('blood circulation times', 'CPA', (83, 106))	('increase', 'PosReg', (74, 82))	('PEGylation', 'Var', (34, 44))	('skin toxicity', 'Disease', (126, 139))	('PEG', 'Chemical', 'MESH:D011092', (34, 37))
126614	31336279	This demonstrated that incorporation of Sphingomyelin into IRT-PoP liposomes enabled rapid light-triggered IRT release and enhanced serum stability as compared to the other formulations.	('enhanced', 'PosReg', (123, 131))	('serum stability', 'MPA', (132, 147))	('PoP', 'Chemical', '-', (63, 66))	('rat', 'Species', '10116', (12, 15))	('IRT', 'Chemical', 'MESH:D000077146', (59, 62))	('IRT', 'Chemical', 'MESH:D000077146', (107, 110))	('rat', 'Species', '10116', (30, 33))	('incorporation', 'Var', (23, 36))	('S', 'Chemical', 'MESH:D013455', (40, 41))
126671	31336279	In vitro studies showed significant improvement in tumor cell killing owing to better targeting with folate liposomes as well as the combined effect of UCNPs and MC540.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('targeting', 'MPA', (86, 95))	('tumor', 'Disease', (51, 56))	('folate', 'Protein', (101, 107))	('improvement', 'PosReg', (36, 47))	('better', 'PosReg', (79, 85))	('folate', 'Chemical', 'MESH:D005492', (101, 107))	('combined', 'Interaction', (133, 141))	('MC540', 'Var', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
126675	31336279	When upconversion liposomes (made with DMPC, DSPE-MPEG-2000, one of the sensitizers and/or one of the annihilators) was mixed with ruthenium functionalized liposomes and irradiated, the energy transfer in TTA-UC was capable of triggering hydrolysis of Ru-S bond in the Ruthenium functionalized liposomes.	('S', 'Chemical', 'MESH:D013455', (255, 256))	('ruthenium', 'Chemical', 'MESH:D012428', (131, 140))	('Ru', 'Chemical', 'MESH:D012428', (269, 271))	('energy', 'Var', (186, 192))	('DMPC', 'Chemical', 'MESH:D004134', (39, 43))	('Ru', 'Chemical', 'MESH:D012428', (252, 254))	('triggering', 'Reg', (227, 237))	('S', 'Chemical', 'MESH:D013455', (46, 47))	('Ruthenium', 'Chemical', 'MESH:D012428', (269, 278))	('hydrolysis', 'MPA', (238, 248))	('TTA-UC', 'Chemical', '-', (205, 211))
126681	31336279	In vitro studies showed loss in P. acnes viability and in vivo studies showed reduced swelling and thickness of nude mice skin infected by P. acnes.	('skin infected', 'Disease', 'MESH:D007239', (122, 135))	('P. acnes', 'Species', '1747', (139, 147))	('acnes', 'Phenotype', 'HP:0001061', (142, 147))	('P. acnes', 'Var', (139, 147))	('acnes', 'Phenotype', 'HP:0001061', (35, 40))	('thickness', 'CPA', (99, 108))	('swelling', 'Disease', 'MESH:D004487', (86, 94))	('nude mice', 'Species', '10090', (112, 121))	('skin infected', 'Disease', (122, 135))	('swelling', 'Disease', (86, 94))	('reduced', 'NegReg', (78, 85))	('acne', 'Phenotype', 'HP:0001061', (142, 146))	('acne', 'Phenotype', 'HP:0001061', (35, 39))	('loss', 'NegReg', (24, 28))	('P. acnes', 'Species', '1747', (32, 40))
126688	31336279	In vitro studies showed over 99% killing of bacterial growth on implants caused by Escherichia coli and Staphylococcus aureus with PFA and in vivo studies showed much improved treatment results in rats with PFH - IR780 liposomes on Ti implants with bacterial infection.	('improved', 'PosReg', (167, 175))	('rats', 'Species', '10116', (197, 201))	('PFH', 'Chemical', 'MESH:C078626', (207, 210))	('PFA', 'Chemical', '-', (131, 134))	('bacterial growth', 'CPA', (44, 60))	('bacterial infection', 'Phenotype', 'HP:0002718', (249, 268))	('PFH -', 'Var', (207, 212))	('Escherichia coli', 'Species', '562', (83, 99))	('Staphylococcus aureus', 'Species', '1280', (104, 125))	('bacterial infection', 'Disease', 'MESH:D001424', (249, 268))	('bacterial infection', 'Disease', (249, 268))
126703	31336279	The use of CHOL can improve liposome stability, and PEGylated liposomes enable longer blood circulation.	('PEG', 'Chemical', 'MESH:D011092', (52, 55))	('PEGylated', 'Var', (52, 61))	('improve', 'PosReg', (20, 27))	('CHOL', 'Chemical', 'MESH:D002784', (11, 15))	('longer blood circulation', 'CPA', (79, 103))	('liposome stability', 'MPA', (28, 46))
126799	29302349	Ectopic expression of Notch 1 in fluorescently labelled adult hepatocytes, using viral delivery of Cre induces co-expression of hepatocyte and biliary markers as well as changes in polarity and morphology so that the cells adopt a more biliary morphology.	('Notch 1', 'Gene', '4851', (22, 29))	('changes', 'Reg', (170, 177))	('co-expression', 'MPA', (111, 124))	('Ectopic expression', 'Var', (0, 18))	('Notch 1', 'Gene', (22, 29))	('induces', 'Reg', (103, 110))	('polarity', 'MPA', (181, 189))	('hepatocyte', 'MPA', (128, 138))	('adopt', 'Reg', (223, 228))	('biliary morphology', 'CPA', (236, 254))
126807	29302349	This effect has been borne out in a model where kRas mutation and Pten deletion are used to induce CC under control of the Albumin promoter.	('Alb', 'Gene', (123, 126))	('deletion', 'Var', (71, 79))	('Alb', 'Gene', '213', (123, 126))	('kRas mutation', 'Var', (48, 61))	('Pten', 'Gene', '5728', (66, 70))	('Pten', 'Gene', (66, 70))
126815	29302349	To confirm the requirement of Notch signal in this conversion, the authors of the study used a construct to either overexpress the intracellular fragment of Notch1 (N1-ICD) (Alb-CreERT2;R26RNotch/+) or delete the principal effector of canonical Notch, Hes1 (Alb-CreER T2;Hes1 fl/fl).	('Alb', 'Gene', '213', (258, 261))	('Notch1', 'Gene', (157, 163))	('ERT2', 'Gene', '5595', (181, 185))	('Alb', 'Gene', (174, 177))	('R26RNotch/+', 'Var', (186, 197))	('overexpress', 'PosReg', (115, 126))	('Hes1', 'Gene', (252, 256))	('Notch1', 'Gene', '4851', (157, 163))	('Alb', 'Gene', (258, 261))	('Hes1', 'Gene', (271, 275))	('Hes1', 'Gene', '3280', (252, 256))	('Alb', 'Gene', '213', (174, 177))	('Hes1', 'Gene', '3280', (271, 275))	('ERT2', 'Gene', (181, 185))	('delete', 'Var', (202, 208))
126818	29302349	The resulting tumours expressed eYFP demonstrating they arose from hepatocytes.	('rat', 'Species', '10116', (44, 47))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('eYFP', 'Var', (32, 36))	('expressed', 'Reg', (22, 31))	('tumours', 'Disease', (14, 21))	('tumours', 'Disease', 'MESH:D009369', (14, 21))
126823	29302349	The implication that differing cells of origin in tumours between patients and potentially within one individual suggests huge divergence of somatic mutation profiles, differences in epigenetic landscapes, activation of signalling pathways and ultimately may well explain the large variability in patient response to therapy.	('patient', 'Species', '9606', (297, 304))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('differences', 'Reg', (168, 179))	('tumours', 'Disease', (50, 57))	('patient', 'Species', '9606', (66, 73))	('signalling pathways', 'Pathway', (220, 239))	('epigenetic landscapes', 'MPA', (183, 204))	('activation', 'Reg', (206, 216))	('mutation', 'Var', (149, 157))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('patients', 'Species', '9606', (66, 74))
126829	29302349	For example, loss of function mutations of JAG1 and less frequently NOTCH2 result in Alagille's syndrome; an autosomal dominant disorder resulting in a failure of development of the intrahepatic bile ducts leading to cholestasis and jaundice.	('NOTCH2', 'Gene', (68, 74))	('loss of function', 'NegReg', (13, 29))	('JAG1', 'Gene', (43, 47))	('jaundice', 'Phenotype', 'HP:0000952', (233, 241))	('cholestasis', 'Disease', 'MESH:D002779', (217, 228))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (109, 136))	("Alagille's syndrome", 'Disease', (85, 104))	('NOTCH2', 'Gene', '4853', (68, 74))	('jaundice', 'Disease', 'MESH:D007565', (233, 241))	('cholestasis', 'Disease', (217, 228))	("Alagille's syndrome", 'Disease', 'MESH:D016738', (85, 104))	('mutations', 'Var', (30, 39))	('JAG1', 'Gene', '182', (43, 47))	('jaundice', 'Disease', (233, 241))	('autosomal dominant disorder', 'Disease', (109, 136))	('cholestasis', 'Phenotype', 'HP:0001396', (217, 228))
126832	29302349	Over-expression of N1-ICD under albumin and alphaFP promoters in developing mouse liver results in HCC with 100% penetrance without the appearance of CC.	('HCC', 'Disease', (99, 102))	('mouse', 'Species', '10090', (76, 81))	('N1-ICD', 'Var', (19, 25))
126837	29302349	Furthermore, there is evidence that genetic deletion of the atypical receptor Notch3 can inhibit CC development and progression in mouse and that Notch3 is able to promote tumour cell survival through activation of the PI3K/AKT pathway.	('activation', 'PosReg', (201, 211))	('Notch3', 'Gene', (78, 84))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('PI3K/AKT pathway', 'Pathway', (219, 235))	('promote', 'PosReg', (164, 171))	('mouse', 'Species', '10090', (131, 136))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('inhibit', 'NegReg', (89, 96))	('tumour', 'Disease', (172, 178))	('genetic deletion', 'Var', (36, 52))	('Notch3', 'Var', (146, 152))
126843	29302349	Disruption of the pathway through liver-specific knock out of WW45, a homolog of Drosophila Salvador, similarly results in liver enlargement accompanied by an HPC response, mediated through phosphorylation and hyperactivation of the downstream effector, Yap.	('liver enlargement', 'Disease', (123, 140))	('Yap', 'Gene', '10413', (254, 257))	('hyperactivation', 'PosReg', (210, 225))	('WW45', 'Gene', (62, 66))	('Drosophila', 'Species', '7227', (81, 91))	('Yap', 'Gene', (254, 257))	('liver enlargement', 'Disease', 'MESH:D006529', (123, 140))	('liver enlargement', 'Phenotype', 'HP:0002240', (123, 140))	('HPC response', 'MPA', (159, 171))	('Salvador', 'Gene', '252554', (92, 100))	('Salvador', 'Gene', (92, 100))	('knock out', 'Var', (49, 58))	('phosphorylation', 'MPA', (190, 205))
126845	29302349	Furthermore, transposon-delivery of YAP and constitutively activated AKT (myr-AKT) results in the development of CC in mouse when coupled with BDL, with tumours exhibiting biliary but not hepatocellular markers, confirming YAP to be oncogenic in CC.	('tumours', 'Disease', 'MESH:D009369', (153, 160))	('tumours', 'Disease', (153, 160))	('mouse', 'Species', '10090', (119, 124))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('transposon-delivery', 'Var', (13, 32))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))
126848	29302349	Mutations in the core canonical Wnt pathway have been shown to drive several gastrointestinal and other cancers, most notably colorectal cancer where mutations in APC and less so in beta-catenin are known oncogenes.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Wnt', 'Gene', (32, 35))	('colorectal cancer', 'Disease', (126, 143))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Wnt', 'Gene', '114487', (32, 35))	('drive', 'PosReg', (63, 68))	('gastrointestinal', 'Disease', (77, 93))	('Mutations', 'Var', (0, 9))	('mutations', 'Var', (150, 159))	('APC', 'Disease', 'MESH:D011125', (163, 166))	('colorectal cancer', 'Disease', 'MESH:D015179', (126, 143))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('APC', 'Disease', (163, 166))	('gastrointestinal', 'Disease', 'MESH:D005767', (77, 93))
126850	29302349	In a subset of liver fluke-associated intrahepatic CCs, however, mutations in the E3 ligase, RNF43 ((Ring Finger Protein 43, a negative regulator of Wnt signalling) were found in 7.4% of CC from patients with liver fluke and 3.5% of non-liver fluke-associated CC.	('liver fluke', 'Species', '6192', (15, 26))	('found', 'Reg', (170, 175))	('liver fluke', 'Species', '6192', (209, 220))	('Wnt', 'Gene', '114487', (149, 152))	('intrahepatic CCs', 'Disease', (38, 54))	('RNF43', 'Gene', (93, 98))	('liver fluke', 'Species', '6192', (237, 248))	('intrahepatic CCs', 'Disease', 'MESH:D002780', (38, 54))	('patients', 'Species', '9606', (195, 203))	('RNF43', 'Gene', '54894', (93, 98))	('Wnt', 'Gene', (149, 152))	('liver fluke', 'Disease', (209, 220))	('mutations', 'Var', (65, 74))
126853	29302349	Loss of function mutations in RNF43 that, therefore, promote Wnt signalling through failing to downregulate the receptor following stimulation thus allow the Fzd receptor to be hyperactivated.	('downregulate', 'NegReg', (95, 107))	('Fzd receptor', 'MPA', (158, 170))	('Wnt', 'Gene', (61, 64))	('hyperactivated', 'PosReg', (177, 191))	('RNF43', 'Gene', (30, 35))	('RNF43', 'Gene', '54894', (30, 35))	('Loss of function', 'NegReg', (0, 16))	('Wnt', 'Gene', '114487', (61, 64))	('mutations', 'Var', (17, 26))	('promote', 'PosReg', (53, 60))
126857	29302349	Further evidence of disruption of the canonical Wnt pathway has been through demonstration of methylation of Wnt pathway regulators, particularly the secreted frizzled-related protein family (SFRPs), which act as soluble negative modulators of Wnt signalling.	('Wnt', 'Gene', '114487', (244, 247))	('Wnt', 'Gene', '114487', (48, 51))	('Wnt', 'Gene', (109, 112))	('rat', 'Species', '10116', (84, 87))	('Wnt', 'Gene', '114487', (109, 112))	('Wnt', 'Gene', (244, 247))	('methylation', 'Var', (94, 105))	('Wnt', 'Gene', (48, 51))
126858	29302349	Epigenetic silencing of SFRP2 is proposed to act to stabilise beta-catenin as competition at the Frizzled receptor is reduced or lost, although in this study no correlation was demonstrated between SFRP2 and beta-catenin positivity (nuclear or cytoplasmic) in human tissue.	('stabilise', 'MPA', (52, 61))	('SFRP2', 'Gene', '6423', (24, 29))	('SFRP2', 'Gene', (24, 29))	('rat', 'Species', '10116', (184, 187))	('reduced', 'NegReg', (118, 125))	('competition', 'MPA', (78, 89))	('Epigenetic silencing', 'Var', (0, 20))	('SFRP2', 'Gene', '6423', (198, 203))	('lost', 'NegReg', (129, 133))	('SFRP2', 'Gene', (198, 203))	('human', 'Species', '9606', (260, 265))	('beta-catenin', 'Protein', (62, 74))
126859	29302349	As well as proliferation, the canonical Wnt pathway is also capable of regulating the expression of transcribed-ultraconserved regions (T-UCRs), long non-coding RNAs, which are involved in various cancers.	('rat', 'Species', '10116', (18, 21))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('Wnt', 'Gene', (40, 43))	('long non-coding RNAs', 'Var', (145, 165))	('various cancers', 'Disease', 'MESH:D009369', (189, 204))	('expression', 'MPA', (86, 96))	('Wnt', 'Gene', '114487', (40, 43))	('various cancers', 'Disease', (189, 204))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('involved', 'Reg', (177, 185))
126890	29302349	in the rat TAA model of CC, here the deletion of TAMs by liposomal chlodronate significantly reduced tumour size, induced tumour cell apoptosis and reduced Wnt signalling.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('liposomal chlodronate', 'Chemical', '-', (57, 78))	('deletion', 'Var', (37, 45))	('Wnt', 'Gene', '114487', (156, 159))	('tumour', 'Disease', (101, 107))	('reduced', 'NegReg', (148, 155))	('reduced', 'NegReg', (93, 100))	('tumour', 'Disease', (122, 128))	('tumour cell apoptosis', 'Disease', 'MESH:C538614', (122, 143))	('tumour cell apoptosis', 'Disease', (122, 143))	('TAMs', 'Chemical', '-', (49, 53))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('rat', 'Species', '10116', (7, 10))	('TAMs', 'Gene', (49, 53))	('induced', 'Reg', (114, 121))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('Wnt', 'Gene', (156, 159))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))
126900	28545228	Aberrant DNA Methylation as a Biomarker and a Therapeutic Target of Cholangiocarcinoma Cholangiocarcinoma is an epithelial malignancy arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile duct.	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (68, 86))	('Cholangiocarcinoma', 'Disease', (68, 86))	('malignancy', 'Disease', (123, 133))	('Aberrant', 'Var', (0, 8))	('Cholangiocarcinoma', 'Disease', (87, 105))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (68, 86))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (87, 105))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('epithelial malignancy', 'Phenotype', 'HP:0031492', (112, 133))	('malignancy', 'Disease', 'MESH:D009369', (123, 133))
126902	28545228	Aberrant DNA methylation and histone modification induce silencing of tumor suppressor genes and chromosomal instability during carcinogenesis.	('carcinogenesis', 'Disease', (128, 142))	('tumor suppressor', 'Gene', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('chromosomal instability', 'CPA', (97, 120))	('Aberrant', 'Var', (0, 8))	('carcinogenesis', 'Disease', 'MESH:D063646', (128, 142))	('histone', 'Protein', (29, 36))	('tumor suppressor', 'Gene', '7248', (70, 86))	('DNA', 'Protein', (9, 12))	('silencing', 'MPA', (57, 66))	('chromosomal instability', 'Phenotype', 'HP:0040012', (97, 120))
126904	28545228	Silencing of these tumor suppressor genes and miRNAs plays critical roles in the initiation and progression of cholangiocarcinoma.	('tumor suppressor', 'Gene', (19, 35))	('cholangiocarcinoma', 'Disease', (111, 129))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor suppressor', 'Gene', '7248', (19, 35))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 129))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))	('Silencing', 'Var', (0, 9))
126906	28545228	Aberrant DNA methylation of tumor suppressor genes and miRNAs could be a powerful biomarker for the diagnosis and treatment of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (127, 145))	('tumor suppressor', 'Gene', '7248', (28, 44))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (127, 145))	('Aberrant DNA methylation', 'Var', (0, 24))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (127, 145))	('tumor suppressor', 'Gene', (28, 44))	('miRNAs', 'Gene', (55, 61))
126907	28545228	Epigenetic therapy with DNA methylation inhibitors holds considerable promise for the treatment of cholangiocarcinoma through the reactivation of tumor suppressor genes and miRNAs as well as the induction of an anti-viral immune response.	('miRNAs', 'Gene', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (99, 117))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (99, 117))	('tumor suppressor', 'Gene', '7248', (146, 162))	('Epigenetic', 'Var', (0, 10))	('reactivation', 'MPA', (130, 142))	('cholangiocarcinoma', 'Disease', (99, 117))	('tumor suppressor', 'Gene', (146, 162))
126920	28545228	Epigenetic alterations can be induced by aging and chronic inflammation.	('induced', 'Reg', (30, 37))	('inflammation', 'Disease', 'MESH:D007249', (59, 71))	('inflammation', 'Disease', (59, 71))	('Epigenetic alterations', 'Var', (0, 22))
126921	28545228	Aberrant DNA methylation and histone modification induce silencing of tumor suppressor genes and chromosomal instability, leading to the initiation and progression of various cancers.	('tumor suppressor', 'Gene', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('chromosomal instability', 'CPA', (97, 120))	('Aberrant', 'Var', (0, 8))	('histone', 'Protein', (29, 36))	('tumor suppressor', 'Gene', '7248', (70, 86))	('DNA', 'Protein', (9, 12))	('leading to', 'Reg', (122, 132))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('silencing', 'MPA', (57, 66))	('chromosomal instability', 'Phenotype', 'HP:0040012', (97, 120))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
126922	28545228	We and other groups have revealed that epigenetic alterations including DNA methylation regulate not only protein-coding genes but also non-coding genes such as miRNAs in cancer cells.	('regulate', 'Reg', (88, 96))	('protein-coding', 'Protein', (106, 120))	('epigenetic alterations', 'Var', (39, 61))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('DNA', 'Gene', (72, 75))	('methylation', 'Var', (76, 87))	('miRNAs', 'Gene', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
126924	28545228	Aberrant DNA methylation at CpG island promoters of tumor suppressor genes is frequently observed in various human malignancies including cholangiocarcinoma.	('tumor suppressor', 'Gene', (52, 68))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('human', 'Species', '9606', (109, 114))	('tumor suppressor', 'Gene', '7248', (52, 68))	('Aberrant DNA methylation', 'Var', (0, 24))	('cholangiocarcinoma', 'Disease', (138, 156))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (138, 156))	('observed', 'Reg', (89, 97))	('malignancies', 'Disease', 'MESH:D009369', (115, 127))	('malignancies', 'Disease', (115, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (138, 156))
126927	28545228	In this review, we summarize the current knowledge regarding aberrant DNA methylation of important tumor suppressor genes and miRNAs in cholangiocarcinoma as well as effects of DNA methylation inhibitors on cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (207, 225))	('aberrant', 'Var', (61, 69))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (207, 225))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (136, 154))	('tumor suppressor', 'Gene', (99, 115))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (136, 154))	('cholangiocarcinoma', 'Disease', (207, 225))	('tumor suppressor', 'Gene', '7248', (99, 115))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cholangiocarcinoma', 'Disease', (136, 154))
126932	28545228	One of the most powerful biomarkers in cancer is DNA methylation of tumor suppressor genes.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor suppressor', 'Gene', (68, 84))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor suppressor', 'Gene', '7248', (68, 84))	('DNA methylation', 'Var', (49, 64))
126935	28545228	Several studies have demonstrated that DNA hypermethylation on the promoter region of the hMLH1 gene is associated with a poor prognosis of patients with cholangiocarcinoma.	('DNA hypermethylation', 'Var', (39, 59))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (154, 172))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (154, 172))	('hMLH1', 'Gene', (90, 95))	('associated', 'Reg', (104, 114))	('patients', 'Species', '9606', (140, 148))	('hMLH1', 'Gene', '4292', (90, 95))	('cholangiocarcinoma', 'Disease', (154, 172))
126937	28545228	A negative correlation between promoter DNA methylation and gene expression has been observed for the DCLK1, CDO1, ZSCAN18, and ZNF331 genes, suggesting that aberrant DNA methylation of these genes indicates epigenetic similarities among gastrointestinal cancers such as colon, pancreatic, and bile duct cancer.	('ZNF331', 'Gene', '55422', (128, 134))	('ZNF331', 'Gene', (128, 134))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (238, 262))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('pancreatic', 'Disease', 'MESH:D010195', (278, 288))	('gastrointestinal cancers', 'Disease', (238, 262))	('ZSCAN18', 'Gene', '65982', (115, 122))	('DCLK1', 'Gene', (102, 107))	('colon', 'Disease', 'MESH:D015179', (271, 276))	('aberrant', 'Var', (158, 166))	('colon', 'Disease', (271, 276))	('DCLK1', 'Gene', '9201', (102, 107))	('pancreatic', 'Disease', (278, 288))	('CDO1', 'Gene', (109, 113))	('ZSCAN18', 'Gene', (115, 122))	('bile duct cancer', 'Phenotype', 'HP:0030153', (294, 310))	('bile duct cancer', 'Disease', (294, 310))	('CDO1', 'Gene', '1036', (109, 113))	('bile duct cancer', 'Disease', 'MESH:D001650', (294, 310))
126939	28545228	Recent studies have shown that p16 (INK4a) and p14 (ARF) are inactivated by DNA hypermethylation in cholangiocarcinoma, which may result in cell cycle dysregulation.	('p16', 'Gene', '1029', (31, 34))	('INK4a', 'Gene', (36, 41))	('p14', 'Gene', (47, 50))	('cell cycle dysregulation', 'Phenotype', 'HP:0011018', (140, 164))	('ARF', 'Disease', (52, 55))	('cholangiocarcinoma', 'Disease', (100, 118))	('p14', 'Gene', '1029', (47, 50))	('result in', 'Reg', (130, 139))	('hypermethylation', 'Var', (80, 96))	('cell cycle dysregulation', 'CPA', (140, 164))	('p16', 'Gene', (31, 34))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (100, 118))	('ARF', 'Disease', 'MESH:D058186', (52, 55))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))	('inactivated', 'NegReg', (61, 72))	('INK4a', 'Gene', '1029', (36, 41))
126940	28545228	demonstrated that the death-associated protein kinase (DAPK) gene is suppressed by promoter hypermethylation in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 130))	('death-associated protein kinase', 'Gene', '1612', (22, 53))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('suppressed', 'NegReg', (69, 79))	('DAPK', 'Gene', (55, 59))	('DAPK', 'Gene', '1612', (55, 59))	('cholangiocarcinoma', 'Disease', (112, 130))	('promoter hypermethylation', 'Var', (83, 108))	('death-associated protein kinase', 'Gene', (22, 53))
126942	28545228	In addition, it has been reported that p53 mutation combined with DNA methylation of the DAPK, p14 (ARF), and ASC genes correlates with malignancy and poor prognosis of patients with cholangiocarcinoma.	('malignancy', 'Disease', (136, 146))	('patients', 'Species', '9606', (169, 177))	('mutation', 'Var', (43, 51))	('DAPK', 'Gene', '1612', (89, 93))	('ASC', 'Gene', (110, 113))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (183, 201))	('DAPK', 'Gene', (89, 93))	('p53', 'Gene', (39, 42))	('correlates with', 'Reg', (120, 135))	('cholangiocarcinoma', 'Disease', (183, 201))	('p14', 'Gene', (95, 98))	('malignancy', 'Disease', 'MESH:D009369', (136, 146))	('p53', 'Gene', '7157', (39, 42))	('ASC', 'Gene', '29108', (110, 113))	('ARF', 'Disease', 'MESH:D058186', (100, 103))	('ARF', 'Disease', (100, 103))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (183, 201))	('p14', 'Gene', '1029', (95, 98))
126946	28545228	reported that hypermethylation of multiple CpG sites of genes associated with a stem cell-like phenotype is a common molecular aberration in cholangiocarcinoma, indicating that aberrant DNA methylation plays a critical role in "cancer stemness" of cholangiocarcinoma.	('"cancer stemness" of cholangiocarcinoma', 'Disease', (227, 266))	('hypermethylation', 'Var', (14, 30))	('"cancer stemness" of cholangiocarcinoma', 'Disease', 'MESH:D018281', (227, 266))	('cholangiocarcinoma', 'Disease', (141, 159))	('cholangiocarcinoma', 'Disease', (248, 266))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (141, 159))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (141, 159))	('aberrant', 'Var', (177, 185))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (248, 266))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (248, 266))
126959	28545228	Accelerated proliferation of biliary epithelial cells promotes aberrant DNA methylation of tumor suppressor genes, leading to the initiation of cholangiocarcinoma.	('leading to', 'Reg', (115, 125))	('tumor suppressor', 'Gene', (91, 107))	('initiation of cholangiocarcinoma', 'Disease', 'MESH:D018281', (130, 162))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (144, 162))	('aberrant', 'Var', (63, 71))	('tumor suppressor', 'Gene', '7248', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('initiation of cholangiocarcinoma', 'Disease', (130, 162))	('DNA methylation', 'MPA', (72, 87))
126960	28545228	previously reported that IL-6 contributes to the growth of cholangiocarcinoma cells through aberrant DNA methylation on the promoter region of tumor suppressor genes.	('aberrant', 'Var', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('cholangiocarcinoma', 'Disease', (59, 77))	('tumor suppressor', 'Gene', (143, 159))	('IL-6', 'Gene', (25, 29))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (59, 77))	('growth', 'MPA', (49, 55))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (59, 77))	('IL-6', 'Gene', '3569', (25, 29))	('tumor suppressor', 'Gene', '7248', (143, 159))	('DNA methylation', 'MPA', (101, 116))
126962	28545228	These findings suggest that persistent cytokine stimulation in biliary epithelial cells could promote the initiation and progression of tumors via epigenetic alterations.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('initiation', 'CPA', (106, 116))	('progression', 'CPA', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('promote', 'PosReg', (94, 101))	('epigenetic alterations', 'Var', (147, 169))
126963	28545228	showed that suppression of the tumor suppressor liver kinase B1 (LKB1) due to aberrant DNA methylation is associated with enhanced Wnt signaling and malignant characteristics of human cholangiocarcinoma.	('liver kinase B1', 'Gene', (48, 63))	('aberrant', 'Var', (78, 86))	('tumor suppressor', 'Gene', '7248', (31, 47))	('enhanced', 'PosReg', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('human', 'Species', '9606', (178, 183))	('DNA', 'Protein', (87, 90))	('LKB1', 'Gene', (65, 69))	('suppression', 'NegReg', (12, 23))	('cholangiocarcinoma', 'Disease', (184, 202))	('LKB1', 'Gene', '6794', (65, 69))	('malignant characteristics of human', 'CPA', (149, 183))	('Wnt signaling', 'MPA', (131, 144))	('tumor suppressor', 'Gene', (31, 47))	('liver kinase B1', 'Gene', '6794', (48, 63))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (184, 202))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (184, 202))
126964	28545228	The expression of the LKB1 gene was suppressed in cholangiocarcinoma tissues relative to adjacent normal tissues and knockdown of LKB1 enhanced the growth, migration, and invasion of tumors, along with the activation of Wnt signaling.	('LKB1', 'Gene', (130, 134))	('LKB1', 'Gene', '6794', (22, 26))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (50, 68))	('LKB1', 'Gene', '6794', (130, 134))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (50, 68))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('migration', 'CPA', (156, 165))	('growth', 'CPA', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('cholangiocarcinoma', 'Disease', (50, 68))	('enhanced', 'PosReg', (135, 143))	('tumors', 'Disease', (183, 189))	('LKB1', 'Gene', (22, 26))	('knockdown', 'Var', (117, 126))
126966	28545228	In cancer cells, tumor suppressor genes are silenced by DNA hypermethylation on CpG island promoter regions.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor suppressor', 'Gene', (17, 33))	('silenced', 'NegReg', (44, 52))	('cancer', 'Disease', (3, 9))	('DNA hypermethylation', 'Var', (56, 76))	('tumor suppressor', 'Gene', '7248', (17, 33))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
126973	28545228	reported that treatment of cholangiocarcinoma cells with 5-Aza-CdR inhibited cell growth and induced apoptosis by the reactivation of p53-BAX mitochondrial apoptosis genes.	('p53', 'Gene', '7157', (134, 137))	('inhibited', 'NegReg', (67, 76))	('reactivation', 'PosReg', (118, 130))	('cholangiocarcinoma', 'Disease', (27, 45))	('5-Aza-CdR', 'Var', (57, 66))	('mitochondrial apoptosis genes', 'Gene', (142, 171))	('cell growth', 'CPA', (77, 88))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (27, 45))	('BAX', 'Gene', (138, 141))	('BAX', 'Gene', '581', (138, 141))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (27, 45))	('apoptosis', 'CPA', (101, 110))	('p53', 'Gene', (134, 137))	('induced', 'Reg', (93, 100))
126974	28545228	demonstrated that knockdown of the major DNA methyltransferase DNMT1 restores the expression levels of tumor suppressor genes, which results in the inhibition of the proliferation of cholangiocarcinoma cells.	('knockdown', 'Var', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('inhibition', 'NegReg', (148, 158))	('tumor suppressor', 'Gene', '7248', (103, 119))	('proliferation', 'CPA', (166, 179))	('DNMT1', 'Gene', '1786', (63, 68))	('cholangiocarcinoma', 'Disease', (183, 201))	('restores', 'PosReg', (69, 77))	('DNMT1', 'Gene', (63, 68))	('expression levels', 'MPA', (82, 99))	('tumor suppressor', 'Gene', (103, 119))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (183, 201))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (183, 201))
126975	28545228	These findings suggest that various tumor suppressor genes are inhibited by DNMT1-induced DNA hypermethylation in their promoter regions, which enhances the proliferation, migration and invasion of cholangiocarcinoma cells.	('invasion', 'CPA', (186, 194))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (198, 216))	('DNMT1', 'Gene', (76, 81))	('tumor suppressor', 'Gene', (36, 52))	('DNMT1', 'Gene', '1786', (76, 81))	('tumor suppressor', 'Gene', '7248', (36, 52))	('cholangiocarcinoma', 'Disease', (198, 216))	('DNA hypermethylation', 'Var', (90, 110))	('enhances', 'PosReg', (144, 152))	('inhibited', 'NegReg', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('proliferation', 'CPA', (157, 170))	('migration', 'CPA', (172, 181))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (198, 216))
126976	28545228	The biological effects of tumor suppressor genes frequently methylated in cholangiocarcinoma are summarized in Table 1.	('tumor suppressor', 'Gene', (26, 42))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (74, 92))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (74, 92))	('tumor suppressor', 'Gene', '7248', (26, 42))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('cholangiocarcinoma', 'Disease', (74, 92))	('methylated', 'Var', (60, 70))
126983	28545228	The deregulation of miRNAs induces the initiation and progression of cancers by modifying their target tumor suppressor genes or oncogenes.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('deregulation', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('progression', 'CPA', (54, 65))	('modifying', 'Reg', (80, 89))	('tumor suppressor', 'Gene', '7248', (103, 119))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('induces', 'Reg', (27, 34))	('miRNAs', 'Gene', (20, 26))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('tumor suppressor', 'Gene', (103, 119))	('cancers', 'Disease', (69, 76))
126988	28545228	In addition, several studies have shown that tumor suppressor miRNAs are regulated by DNA methylation.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor suppressor', 'Gene', '7248', (45, 61))	('tumor suppressor', 'Gene', (45, 61))	('regulated', 'Reg', (73, 82))	('DNA methylation', 'Var', (86, 101))
126989	28545228	reported that the expression of DNA methyltransferases was increased by IL-6 overexpression and the tumor suppressor miR-370 was inactivated by DNA methylation in cholangiocarcinoma cells.	('tumor suppressor', 'Gene', '7248', (100, 116))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (163, 181))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('IL-6', 'Gene', '3569', (72, 76))	('methylation', 'Var', (148, 159))	('cholangiocarcinoma', 'Disease', (163, 181))	('miR-370', 'Gene', '442915', (117, 124))	('expression', 'MPA', (18, 28))	('miR-370', 'Gene', (117, 124))	('overexpression', 'Var', (77, 91))	('increased', 'PosReg', (59, 68))	('tumor suppressor', 'Gene', (100, 116))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (163, 181))	('inactivated', 'NegReg', (129, 140))	('IL-6', 'Gene', (72, 76))
126993	28545228	These findings define a mechanism by which inflammation-associated cytokines can epigenetically modulate gene expression and contribute to the initiation and development of cholangiocarcinoma.	('gene expression', 'MPA', (105, 120))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (173, 191))	('cholangiocarcinoma', 'Disease', (173, 191))	('epigenetically', 'Var', (81, 95))	('inflammation', 'Disease', 'MESH:D007249', (43, 55))	('modulate', 'Reg', (96, 104))	('contribute', 'Reg', (125, 135))	('inflammation', 'Disease', (43, 55))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (173, 191))
126996	28545228	The direct target genes and biological functions of miRNAs frequently methylated in cholangiocarcinoma are summarized in Table 2.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('methylated', 'Var', (70, 80))	('cholangiocarcinoma', 'Disease', (84, 102))	('miRNAs', 'Gene', (52, 58))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
127000	28545228	previously showed that DNA demethylation exerts a tumor-suppressive effect on colon cancers by inducing tumor differentiation.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('colon cancer', 'Phenotype', 'HP:0003003', (78, 90))	('colon cancers', 'Disease', (78, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('DNA demethylation', 'Var', (23, 40))	('inducing', 'PosReg', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('colon cancers', 'Phenotype', 'HP:0003003', (78, 91))	('colon cancers', 'Disease', 'MESH:D015179', (78, 91))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
127003	28545228	This suggested that the promoters of transcriptional factor genes regulating cell differentiation were silenced by DNA hypermethylation in colon cancer cells to sustain their undifferentiated status.	('silenced', 'NegReg', (103, 111))	('colon cancer', 'Disease', 'MESH:D015179', (139, 151))	('colon cancer', 'Disease', (139, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('promoters', 'MPA', (24, 33))	('hypermethylation', 'Var', (119, 135))	('colon cancer', 'Phenotype', 'HP:0003003', (139, 151))
127010	28545228	We demonstrated that 5-Aza-CdR shrinks intestinal tumor organoids derived from Apcmin/+ mice.	('shrinks', 'NegReg', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('5-Aza-CdR', 'Var', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mice', 'Species', '10090', (88, 92))	('tumor', 'Disease', (50, 55))
127011	28545228	We revealed that the expression of interferon-responsive genes such as Irf7, Rig1 and Mda5 was increased by DNA methylation inhibition in tumor organoids after 5-Aza-CdR treatment or Dnmt1 knockdown.	('Dnmt1', 'Gene', '1786', (183, 188))	('inhibition', 'NegReg', (124, 134))	('Rig1', 'Gene', (77, 81))	('DNA', 'Protein', (108, 111))	('tumor', 'Disease', (138, 143))	('Mda5', 'Gene', '64135', (86, 90))	('methylation', 'Var', (112, 123))	('expression', 'MPA', (21, 31))	('Irf7', 'Gene', '3665', (71, 75))	('Rig1', 'Gene', '5920', (77, 81))	('Mda5', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('Dnmt1', 'Gene', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('increased', 'PosReg', (95, 104))	('Irf7', 'Gene', (71, 75))
127014	28545228	showed that DNA methylation inhibitors can upregulate transcripts and protein of PD-L1, a key ligand mediator of immune tolerance.	('upregulate', 'PosReg', (43, 53))	('methylation inhibitors', 'Var', (16, 38))	('PD-L1', 'Gene', (81, 86))	('protein', 'MPA', (70, 77))	('inhibitors', 'Var', (28, 38))	('PD-L1', 'Gene', '29126', (81, 86))	('transcripts', 'MPA', (54, 65))
127019	28545228	Although herceptin has improved the relapse-free survival of patients with breast cancer, it is still very difficult to eliminate the cancer completely, because cancers have various mutations and different forms of aberrant epigenetic status.	('cancer', 'Disease', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))	('cancer', 'Disease', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('patients', 'Species', '9606', (61, 69))	('cancer', 'Disease', (134, 140))	('improved', 'PosReg', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('epigenetic status', 'Var', (224, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('relapse-free survival', 'CPA', (36, 57))	('herceptin', 'Chemical', 'MESH:D000068878', (9, 18))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('breast cancer', 'Disease', (75, 88))	('cancer', 'Disease', 'MESH:D009369', (134, 140))
127020	28545228	In this respect, chromatin-modifying drugs have great promise for cancer therapy because the modification of epigenetic status alone can inhibit various tumor characteristics such as proliferation, migration, invasion, and dedifferentiation.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('migration', 'CPA', (198, 207))	('invasion', 'CPA', (209, 217))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('inhibit', 'NegReg', (137, 144))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('epigenetic status', 'Var', (109, 126))	('modification', 'Var', (93, 105))	('dedifferentiation', 'CPA', (223, 240))	('cancer', 'Disease', (66, 72))
127022	28545228	In conclusion, aberrant DNA methylation of tumor suppressor genes and miRNAs could be a powerful biomarker for the diagnosis and treatment of cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (142, 160))	('tumor suppressor', 'Gene', '7248', (43, 59))	('tumor suppressor', 'Gene', (43, 59))	('cholangiocarcinoma', 'Disease', (142, 160))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('aberrant', 'Var', (15, 23))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (142, 160))	('miRNAs', 'Gene', (70, 76))
127023	28545228	Epigenetic therapy with DNA methylation inhibitors hold considerable promise for the treatment of cholangiocarcinoma through the reactivation of tumor suppressor genes and miRNAs as well as the induction of an anti-viral immune response.	('tumor suppressor', 'Gene', (145, 161))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (98, 116))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (98, 116))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor suppressor', 'Gene', '7248', (145, 161))	('Epigenetic', 'Var', (0, 10))	('reactivation', 'MPA', (129, 141))	('miRNAs', 'Gene', (172, 178))	('cholangiocarcinoma', 'Disease', (98, 116))
127026	24243779	In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1.	('germline mutation', 'Var', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('patients', 'Species', '9606', (64, 72))	('BAP1', 'Gene', '8314', (135, 139))	('hereditary cancer', 'Disease', 'MESH:D009369', (92, 109))	('BAP1', 'Gene', (135, 139))	('hereditary cancer', 'Disease', (92, 109))
127028	24243779	We identified three patients with germline pathogenic mutations (c.2050 C>T, pGln684*; c.1182C>G, p.Tyr394*, and c.1882_1885delTCAC, p. Ser628Profs*8) in BAP1.	('pGln684*; c.1182C>G', 'Var', (77, 96))	('c.2050 C>T', 'Mutation', 'rs387906848', (65, 75))	('BAP1', 'Gene', (154, 158))	('pathogenic', 'Reg', (43, 53))	('c.1882_1885delTCAC', 'Var', (113, 131))	('p.Tyr394*', 'Mutation', 'p.Y394*', (98, 107))	('patients', 'Species', '9606', (20, 28))	('c.2050 C>T', 'Var', (65, 75))	('p. Ser628Profs*8', 'Var', (133, 149))	('c.1182C>G', 'Var', (87, 96))	('p.Tyr394*', 'Var', (98, 107))	('c.1882_1885delTCAC', 'Mutation', 'c.1882_1885delTCAC', (113, 131))	('BAP1', 'Gene', '8314', (154, 158))	('Ser628Profs', 'Chemical', '-', (136, 147))	('c.1182C>G', 'Mutation', 'c.1182C>G', (87, 96))
127031	24243779	The results of this study confirm the association between germline BAP1 mutation and predisposition to UM, mesothelioma, CM and RCC.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('CM', 'Disease', 'MESH:D009202', (121, 123))	('mesothelioma', 'Disease', (107, 119))	('germline', 'Var', (58, 66))	('BAP1', 'Gene', '8314', (67, 71))	('association', 'Reg', (38, 49))	('mutation', 'Var', (72, 80))	('mesothelioma', 'Disease', 'MESH:D008654', (107, 119))	('BAP1', 'Gene', (67, 71))
127034	24243779	Germline mutations in the BAP1 gene have been identified in a small number of families with hereditary cancers.	('Germline mutations', 'Var', (0, 18))	('BAP1', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('hereditary cancers', 'Disease', (92, 110))	('identified', 'Reg', (46, 56))	('hereditary cancers', 'Disease', 'MESH:D009369', (92, 110))	('BAP1', 'Gene', '8314', (26, 30))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))
127039	24243779	Proper characterization of the phenotype is crucial to define diagnostic criteria and design management and follow-up protocols for patients with germline BAP1 mutations.	('BAP1', 'Gene', '8314', (155, 159))	('mutations', 'Var', (160, 169))	('BAP1', 'Gene', (155, 159))	('men', 'Species', '9606', (99, 102))	('patients', 'Species', '9606', (132, 140))
127040	24243779	In the following study, we report three additional patients with germline BAP1 mutations, including one presenting with metastatic adenocarcinoma likely from a cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (160, 178))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (160, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('germline', 'Var', (65, 73))	('BAP1', 'Gene', '8314', (74, 78))	('adenocarcinoma', 'Disease', (131, 145))	('patients', 'Species', '9606', (51, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('cholangiocarcinoma', 'Disease', (160, 178))	('BAP1', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))	('adenocarcinoma', 'Disease', 'MESH:D000230', (131, 145))
127051	24243779	Immunohistochemistry was carried out on tumor tissues from FUM103 (III.1) and FUM064 (III-12).	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('FUM064', 'Var', (78, 84))
127056	24243779	Out of the 50 patients tested, we identified three with pathogenic mutations in BAP1 and 4 with variants of uncertain significance: c.2057-4G>T (rs149499021) in two different patients, both c.2057-22A>C (rs144083199) and c.*45C>G (rs56898787) in a third patient and c. 932-58_59delTG in a fourth patient (Table 1).	('rs56898787', 'Var', (231, 241))	('c. 932-58_59delTG', 'Mutation', 'c.932-58_59delTG', (266, 283))	('c.2057-22A>C (rs144083199', 'Var', (190, 215))	('BAP1', 'Gene', '8314', (80, 84))	('rs144083199', 'Var', (204, 215))	('c. 932-58_59delTG', 'Var', (266, 283))	('patients', 'Species', '9606', (14, 22))	('c.2057-22A>C', 'Mutation', 'rs144083199', (190, 202))	('rs149499021', 'Var', (145, 156))	('c.2057-4G>T', 'Mutation', 'rs149499021', (132, 143))	('c.2057-4G>T (rs149499021', 'Var', (132, 156))	('patient', 'Species', '9606', (175, 182))	('rs149499021', 'Mutation', 'rs149499021', (145, 156))	('patient', 'Species', '9606', (254, 261))	('BAP1', 'Gene', (80, 84))	('rs56898787', 'Mutation', 'rs56898787', (231, 241))	('patient', 'Species', '9606', (14, 21))	('pathogenic', 'Reg', (56, 66))	('c.*45C>G', 'Mutation', 'rs56898787', (221, 229))	('c.*45C>G (rs56898787', 'Var', (221, 241))	('patient', 'Species', '9606', (296, 303))	('patients', 'Species', '9606', (175, 183))	('rs144083199', 'Mutation', 'rs144083199', (204, 215))
127057	24243779	A germline truncating mutation (c.2050 C>T, p.Gln684*) of BAP1 was identified in the proband (IV.1), who presented with UM (age 41), an epithelial malignancy of unknown origin at the porta hepatis with distant metastasis (age 42) and an unclassified spindle cell proliferation in her thigh (age 42).	('malignancy', 'Disease', 'MESH:D009369', (147, 157))	('malignancy', 'Disease', (147, 157))	('p.Gln684*', 'Var', (44, 53))	('BAP1', 'Gene', (58, 62))	('c.2050 C>T', 'Mutation', 'rs387906848', (32, 42))	('distant metastasis', 'CPA', (202, 220))	('epithelial malignancy', 'Phenotype', 'HP:0031492', (136, 157))	('BAP1', 'Gene', '8314', (58, 62))	('c.2050 C>T', 'Var', (32, 42))	('unclassified spindle cell proliferation in', 'CPA', (237, 279))	('p.Gln684*', 'Mutation', 'rs387906848', (44, 53))
127060	24243779	A paternal cousin once-removed (III-12) presenting with peritoneal papillary tumor was also positive for the same mutation; thus, making their parents and the proband's paternal grandmother obligate carriers of the same mutation.	('mutation', 'Var', (114, 122))	('papillary tumor', 'Disease', (67, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('papillary tumor', 'Disease', 'MESH:D002291', (67, 82))
127066	24243779	2B) with strong expression in nontumor tissue suggesting biallelic inactivation of BAP1 in the tumor tissue.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('biallelic', 'Var', (57, 66))	('BAP1', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))	('BAP1', 'Gene', '8314', (83, 87))
127068	24243779	A germline truncating mutation c.1182C>G, p.Tyr394* was identified in the proband (III.1) who presented with a metastatic adenocarcinoma to the rib and a hepatic focal lesion.	('adenocarcinoma', 'Disease', (122, 136))	('hepatic focal lesion', 'Disease', 'MESH:D056486', (154, 174))	('adenocarcinoma', 'Disease', 'MESH:D000230', (122, 136))	('p.Tyr394*', 'Var', (42, 51))	('c.1182C>G', 'Var', (31, 40))	('p.Tyr394*', 'Mutation', 'p.Y394*', (42, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('c.1182C>G', 'Mutation', 'c.1182C>G', (31, 40))	('hepatic focal lesion', 'Disease', (154, 174))
127079	24243779	A germline frameshift mutation c.1882_1885delTCAC, p. Ser628Profs*8in BAP1 was identified in the index case, her son and a great maternal aunt, who presented with invasive breast cancer (Figs.	('Ser628Profs', 'Chemical', '-', (54, 65))	('invasive breast cancer', 'Disease', 'MESH:D001943', (163, 185))	('p. Ser628Profs*8in', 'Var', (51, 69))	('c.1882_1885delTCAC', 'Mutation', 'c.1882_1885delTCAC', (31, 49))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('BAP1', 'Gene', '8314', (70, 74))	('invasive breast cancer', 'Disease', (163, 185))	('c.1882_1885delTCAC', 'Var', (31, 49))	('BAP1', 'Gene', (70, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))
127083	24243779	The association of germline BAP1 mutation with increased risks for UM, mesothelioma, CM, RCC, and MBAITs is now fairly well established.	('mesothelioma', 'Disease', (71, 83))	('BAP1', 'Gene', '8314', (28, 32))	('mutation', 'Var', (33, 41))	('mesothelioma', 'Disease', 'MESH:D008654', (71, 83))	('BAP1', 'Gene', (28, 32))	('MBAITs', 'Disease', (98, 104))	('RCC', 'Disease', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('CM', 'Disease', 'MESH:D009202', (85, 87))	('germline', 'Var', (19, 27))
127085	24243779	In the present study, we report three new families with germline pathogenic mutations in BAP1.	('BAP1', 'Gene', '8314', (89, 93))	('mutations', 'Var', (76, 85))	('BAP1', 'Gene', (89, 93))
127086	24243779	One of the mutations (p.Q684*) has been previously reported in another hereditary mesothelioma/UM family.	('mesothelioma', 'Disease', (82, 94))	('p.Q684*', 'Mutation', 'rs387906848', (22, 29))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('reported', 'Reg', (51, 59))	('p.Q684*', 'Var', (22, 29))
127087	24243779	The two other mutations (p.Tyr394* and p. Ser628Profs*8) have not been previously reported.	('p.Tyr394*', 'Mutation', 'p.Y394*', (25, 34))	('p.Tyr394*', 'Var', (25, 34))	('Ser628Profs', 'Chemical', '-', (42, 53))	('p. Ser628Profs*', 'Var', (39, 54))
127088	24243779	Cancers reported in patients with germline BAP1 mutation in our study included cancers associated with BAP1 hereditary cancer predisposition syndrome, such as UM, CM, RCC and mesothelioma, as well as, other cancers such as hepatic cholangiocarcinoma and breast carcinoma.	('BAP1', 'Gene', '8314', (103, 107))	('hepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (223, 249))	('BAP1', 'Gene', (43, 47))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('germline', 'Var', (34, 42))	('CM', 'Disease', 'MESH:D009202', (163, 165))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cancers', 'Disease', (207, 214))	('BAP1', 'Gene', (103, 107))	('hereditary cancer', 'Disease', (108, 125))	('breast carcinoma', 'Disease', 'MESH:D001943', (254, 270))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancers', 'Disease', (79, 86))	('mesothelioma', 'Disease', (175, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (231, 249))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('hereditary cancer', 'Disease', 'MESH:D009369', (108, 125))	('mesothelioma', 'Disease', 'MESH:D008654', (175, 187))	('BAP1', 'Gene', '8314', (43, 47))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('mutation', 'Var', (48, 56))	('RCC', 'Disease', (167, 170))	('breast carcinoma', 'Phenotype', 'HP:0003002', (254, 270))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('breast carcinoma', 'Disease', (254, 270))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('hepatic cholangiocarcinoma', 'Disease', (223, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
127098	24243779	WDPM has been recently reported by another group in two siblings with germline mutation in BAP1.	('BAP1', 'Gene', '8314', (91, 95))	('BAP1', 'Gene', (91, 95))	('WDPM', 'Disease', (0, 4))	('germline mutation', 'Var', (70, 87))
127101	24243779	An earlier study by our group suggested that the frequency of germline mutation in BAP1 is low (1/53) in patients with UM, even in those with strong personal or family histories of cancer.	('germline mutation', 'Var', (62, 79))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('BAP1', 'Gene', (83, 87))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('BAP1', 'Gene', '8314', (83, 87))
127103	24243779	Whether other cancers seen in other mutation carriers in these families are coincidental or due to the mutation has yet to be definitively established.	('cancers', 'Disease', (14, 21))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutation', 'Var', (103, 111))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))
127104	24243779	Germline mutation in BAP1 has been observed in one patient in our study as well as reported in a few high-risk breast cancer families suggesting that breast cancer could be part of the phenotype.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('BAP1', 'Gene', (21, 25))	('breast cancer', 'Disease', (150, 163))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('observed', 'Reg', (35, 43))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('patient', 'Species', '9606', (51, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (111, 124))	('Germline mutation', 'Var', (0, 17))	('BAP1', 'Gene', '8314', (21, 25))
127107	24243779	Nevertheless, it appears clear that carrying a BAP1 germline mutation puts an individual at significantly increased risk of cancer.	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('BAP1', 'Gene', '8314', (47, 51))	('germline mutation', 'Var', (52, 69))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('BAP1', 'Gene', (47, 51))
127112	24243779	The high frequency of germline BAP1 mutations in patients presenting with metastatic disease suggests that UM is more aggressive in these patients.	('metastatic disease', 'Disease', (74, 92))	('BAP1', 'Gene', '8314', (31, 35))	('mutations', 'Var', (36, 45))	('BAP1', 'Gene', (31, 35))	('patients', 'Species', '9606', (49, 57))	('patients', 'Species', '9606', (138, 146))
127114	24243779	In conclusion, germline BAP1 mutations appear to predispose patients to an increasing spectrum of cancers including UM, CM, mesothelioma, and RCC.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('predispose', 'Reg', (49, 59))	('BAP1', 'Gene', (24, 28))	('patients', 'Species', '9606', (60, 68))	('mutations', 'Var', (29, 38))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('mesothelioma', 'Disease', (124, 136))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('CM', 'Disease', 'MESH:D009202', (120, 122))	('mesothelioma', 'Disease', 'MESH:D008654', (124, 136))	('BAP1', 'Gene', '8314', (24, 28))
127117	24243779	Finally, the current evidence justifies establishment of surveillance protocols for early diagnosis of UM and CM in patients with germline mutation in BAP1.	('men', 'Species', '9606', (49, 52))	('BAP1', 'Gene', (151, 155))	('patients', 'Species', '9606', (116, 124))	('germline mutation', 'Var', (130, 147))	('CM', 'Disease', 'MESH:D009202', (110, 112))	('BAP1', 'Gene', '8314', (151, 155))
127128	23355033	Up to 50 % of patients with NAFLD will develop nonalcoholic steatohepatitis (NASH), cirrhosis, and/or hepatocellular carcinoma (HCC).	('hepatitis', 'Phenotype', 'HP:0012115', (66, 75))	('cirrhosis', 'Disease', 'MESH:D005355', (84, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('HCC', 'Phenotype', 'HP:0001402', (128, 131))	('cirrhosis', 'Phenotype', 'HP:0001394', (84, 93))	('nonalcoholic steatohepatitis', 'Disease', (47, 75))	('nonalcoholic steatohepatitis', 'Disease', 'MESH:D065626', (47, 75))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (102, 126))	('HCC', 'Gene', (128, 131))	('cirrhosis', 'Disease', (84, 93))	('NAFLD', 'Var', (28, 33))	('patients', 'Species', '9606', (14, 22))	('develop', 'PosReg', (39, 46))	('HCC', 'Gene', '619501', (128, 131))	('hepatocellular carcinoma', 'Disease', (102, 126))
127164	23355033	Hepatic steatosis, lobular inflammation, and hepatocyte ballooning were all more extensive in NASH specimens compared to specimens without NASH.	('men', 'Species', '9606', (126, 129))	('Hepatic steatosis', 'Phenotype', 'HP:0001397', (0, 17))	('Hepatic steatosis', 'Disease', 'MESH:D005234', (0, 17))	('men', 'Species', '9606', (104, 107))	('hepatocyte ballooning', 'Disease', 'MESH:D054549', (45, 66))	('hepatocyte ballooning', 'Disease', (45, 66))	('lobular inflammation', 'Disease', (19, 39))	('extensive', 'PosReg', (81, 90))	('Hepatic steatosis', 'Disease', (0, 17))	('steatosis', 'Phenotype', 'HP:0001397', (8, 17))	('NASH', 'Var', (94, 98))	('lobular inflammation', 'Disease', 'MESH:D007249', (19, 39))
127183	23355033	reported that patients with ICC were more likely to have each component of and the overall diagnosis of the metabolic syndrome compared with matched controls:causing the authors to suggest that NAFLD may be a cause of "idiopathic" ICC.	('NAFLD', 'Var', (194, 199))	('cause', 'Reg', (209, 214))	('metabolic syndrome', 'Disease', 'MESH:D008659', (108, 126))	('metabolic syndrome', 'Disease', (108, 126))	('patients', 'Species', '9606', (14, 22))	('ICC', 'Disease', (28, 31))
127214	21354147	Immunoblotting and immunoprecipitation assays were performed to determine the levels of PTEN and related signaling molecules in human cholangiocarcinoma cells with overexpression or knockdown of mPGES-1.	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('cholangiocarcinoma cells', 'Disease', 'MESH:D018281', (134, 158))	('mPGES-1', 'Gene', (195, 202))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (134, 152))	('cholangiocarcinoma cells', 'Disease', (134, 158))	('overexpression', 'PosReg', (164, 178))	('human', 'Species', '9606', (128, 133))	('PTEN', 'Chemical', '-', (88, 92))	('knockdown', 'Var', (182, 191))	('mPGES-1', 'Gene', '64292', (195, 202))
127217	21354147	In SCID mice with tumor xenografts, mPGES-1 overexpression accelerated tumor formation and increased tumor weight (P<0.01), whereas mPGES-1 knockdown delayed tumor formation and reduced tumor weight (P<0.01).	('tumor', 'Disease', (186, 191))	('mPGES-1', 'Gene', '64292', (132, 139))	('mPGES-1', 'Gene', '64292', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mPGES-1', 'Gene', (132, 139))	('overexpression', 'Var', (44, 58))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mPGES-1', 'Gene', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('SCID', 'Disease', 'MESH:D053632', (3, 7))	('increased', 'PosReg', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('reduced', 'NegReg', (178, 185))	('delayed', 'NegReg', (150, 157))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('SCID', 'Disease', (3, 7))	('accelerated', 'PosReg', (59, 70))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('mice', 'Species', '10090', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
127239	21354147	Indeed, inhibition of COX-2 has been found to efficiently prevent the growth and invasion of cholangiocarcinoma cells in vitro and in animal models.	('cholangiocarcinoma cells', 'Disease', (93, 117))	('growth', 'CPA', (70, 76))	('invasion', 'CPA', (81, 89))	('prevent', 'NegReg', (58, 65))	('COX-2', 'Gene', (22, 27))	('COX-2', 'Gene', '5743', (22, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('cholangiocarcinoma cells', 'Disease', 'MESH:D018281', (93, 117))	('inhibition', 'Var', (8, 18))
127241	21354147	However, as some COX-2 inhibitors are known to be associated with increased cardiovascular side effect, there is an urgent and practical need to identify COX-2 downstream target for effective anti-tumor therapy with less side effect.	('COX-2', 'Gene', '5743', (17, 22))	('cardiovascular', 'Disease', (76, 90))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('inhibitors', 'Var', (23, 33))	('COX-2', 'Gene', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('COX-2', 'Gene', '5743', (154, 159))	('tumor', 'Disease', (197, 202))	('COX-2', 'Gene', (17, 22))
127246	21354147	It has been shown that the absence of functional PTEN leads to constitutive activation of downstream components of the PI3K pathway including AKT (protein kinase B).	('PI3', 'Gene', '5266', (119, 122))	('AKT', 'Gene', '207', (142, 145))	('PTEN', 'Chemical', '-', (49, 53))	('AKT', 'Gene', (142, 145))	('PI3', 'Gene', (119, 122))	('absence', 'Var', (27, 34))	('activation', 'PosReg', (76, 86))	('PTEN', 'Gene', (49, 53))
127251	21354147	The growth curves of the cell lines with overexpression or knockdown of mPGES-1 were determined by direct cell counting and WST-1 assay.	('knockdown', 'Var', (59, 68))	('mPGES-1', 'Gene', (72, 79))	('mPGES-1', 'Gene', '64292', (72, 79))
127255	21354147	Western blotting analysis was performed to determine the level of PI3K and its related signaling molecules including epidermal growth factor receptor (EGFR), pEGFR(tyr845), PI3K, pPI3K, AKT, pAKT, mammalian target of rapamycin (mTOR), pmTOR, Toll-like receptor 4 (TLR4), nuclear factor-kappaB (NFkappaB), P62, cyclinD1, survivin, and myeloid cell leukemia-1 (Mcl-1) in cells with overexpression or knockdown of mPGES-1.	('TLR4', 'Gene', '7099', (264, 268))	('mPGES-1', 'Gene', '64292', (411, 418))	('epidermal growth factor receptor', 'Gene', (117, 149))	('PI3', 'Gene', (180, 183))	('AKT', 'Gene', '207', (186, 189))	('mPGES-1', 'Gene', (411, 418))	('EGFR', 'Gene', '1956', (159, 163))	('TLR4', 'Gene', (264, 268))	('P62', 'Gene', '23636', (305, 308))	('AKT', 'Gene', '207', (192, 195))	('Toll-like receptor 4', 'Gene', '7099', (242, 262))	('epidermal growth factor receptor', 'Gene', '1956', (117, 149))	('cyclinD1', 'Gene', '595', (310, 318))	('PI3', 'Gene', (66, 69))	('mammalian target of rapamycin', 'Gene', (197, 226))	('P62', 'Gene', (305, 308))	('myeloid cell leukemia', 'Phenotype', 'HP:0012324', (334, 355))	('leukemia', 'Phenotype', 'HP:0001909', (347, 355))	('myeloid cell leukemia-1', 'Gene', '4170', (334, 357))	('PI3', 'Gene', '5266', (173, 176))	('myeloid cell leukemia-1', 'Gene', (334, 357))	('Toll-like receptor 4', 'Gene', (242, 262))	('EGFR', 'Gene', (151, 155))	('NFkappaB', 'Gene', '4790', (294, 302))	('cyclinD1', 'Gene', (310, 318))	('Mcl-1', 'Gene', '4170', (359, 364))	('AKT', 'Gene', (186, 189))	('EGFR', 'Gene', (159, 163))	('PI3', 'Gene', '5266', (180, 183))	('knockdown', 'Var', (398, 407))	('AKT', 'Gene', (192, 195))	('PI3', 'Gene', (173, 176))	('NFkappaB', 'Gene', (294, 302))	('PI3', 'Gene', '5266', (66, 69))	('Mcl-1', 'Gene', (359, 364))	('EGFR', 'Gene', '1956', (151, 155))	('mammalian target of rapamycin', 'Gene', '2475', (197, 226))
127274	21354147	To investigate the role of mPGES-1 in cholangiocarcinoma cell growth, we constructed cholangiocarcinoma cell lines with stable overexpression or depletion of mPGES1.	('cholangiocarcinoma', 'Disease', (38, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('mPGES-1', 'Gene', '64292', (27, 34))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (38, 56))	('mPGES-1', 'Gene', (27, 34))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (85, 103))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('mPGES1', 'Gene', (158, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (38, 56))	('overexpression', 'PosReg', (127, 141))	('mPGES1', 'Gene', '64292', (158, 164))	('cholangiocarcinoma', 'Disease', (85, 103))	('depletion', 'Var', (145, 154))
127282	21354147	In contrast, RNAi knockdown of mPGES-1 significantly inhibited tumor cell growth.	('tumor', 'Disease', (63, 68))	('knockdown', 'Var', (18, 27))	('inhibited', 'NegReg', (53, 62))	('mPGES-1', 'Gene', '64292', (31, 38))	('mPGES-1', 'Gene', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
127288	21354147	Conversely, when mPGES-1 was knocked down, the tumor weight decreased to approximately half of the control tumor weight (0.23 + 0.04 grams versus 0.57 + 0.15 grams, p<0.01).	('mPGES-1', 'Gene', '64292', (17, 24))	('knocked down', 'Var', (29, 41))	('decreased', 'NegReg', (60, 69))	('mPGES-1', 'Gene', (17, 24))	('tumor', 'Disease', (107, 112))	('weight decreased', 'Phenotype', 'HP:0004325', (53, 69))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (47, 52))
127290	21354147	On the other hand, the time of tumor appearance was prolonged in the mPGES-1 knockdown group (16.21 + 3.99 days) compared to the control group (10.81 + 3.08 days) (p<0.01).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('mPGES-1', 'Gene', '64292', (69, 76))	('knockdown', 'Var', (77, 86))	('mPGES-1', 'Gene', (69, 76))	('prolonged', 'PosReg', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
127299	21354147	To further address this, flow cytometry was performed in the stably transfected cell lines with mPGES-1 overexpression or knockdown.	('knockdown', 'Var', (122, 131))	('mPGES-1', 'Gene', '64292', (96, 103))	('overexpression', 'PosReg', (104, 118))	('mPGES-1', 'Gene', (96, 103))
127301	21354147	Conversely, the cells with mPGES-1 knockdown showed a significant increase in G0/G1 phase cells (70.1+15.5% versus 41.3+7.1%, p<0.01) and a significant decrease in S phase cells (20.3+3.2% versus 49.5+10.7%).	('knockdown', 'Var', (35, 44))	('increase', 'PosReg', (66, 74))	('mPGES-1', 'Gene', '64292', (27, 34))	('mPGES-1', 'Gene', (27, 34))	('G0/G1 phase cells', 'CPA', (78, 95))	('S phase cells', 'CPA', (164, 177))	('decrease', 'NegReg', (152, 160))
127302	21354147	We observed that the percentages of G2 phase cells were not significantly altered in cells with mPGES-1 overexpression or knockdown (p>0.05).	('mPGES-1', 'Gene', '64292', (96, 103))	('G2 phase cells', 'CPA', (36, 50))	('mPGES-1', 'Gene', (96, 103))	('knockdown', 'Var', (122, 131))	('overexpression', 'PosReg', (104, 118))
127308	21354147	The wound healing assay showed that mPGES-1 overexpression promoted cellular injury repair and/or migration at 8 and 24h, while mPGES-1 knockdown inhibited this process (Figure 3D).	('injury', 'Disease', (77, 83))	('migration at 8 and', 'CPA', (98, 116))	('injury', 'Disease', 'MESH:D058186', (77, 83))	('mPGES-1', 'Gene', '64292', (128, 135))	('mPGES-1', 'Gene', (128, 135))	('promoted', 'PosReg', (59, 67))	('mPGES-1', 'Gene', '64292', (36, 43))	('overexpression', 'Var', (44, 58))	('mPGES-1', 'Gene', (36, 43))
127318	21354147	Accordingly, depletion of PTEN by siRNA partially prevented mPGES-1 knockdown-induced inhibition of tumor cell growth (Figure 4E).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('knockdown-induced', 'Var', (68, 85))	('mPGES-1', 'Gene', '64292', (60, 67))	('depletion', 'MPA', (13, 22))	('prevented', 'NegReg', (50, 59))	('PTEN', 'Chemical', '-', (26, 30))	('mPGES-1', 'Gene', (60, 67))	('inhibition', 'NegReg', (86, 96))
127323	21354147	Accordingly, RT-PCR analysis revealed that mPGES-1 overexpression inhibited EGR1-induced accumulation of PTEN mRNA.	('mPGES-1', 'Gene', (43, 50))	('overexpression', 'Var', (51, 65))	('EGR1', 'Gene', (76, 80))	('EGR1', 'Gene', '1958', (76, 80))	('inhibited', 'NegReg', (66, 75))	('PTEN', 'Chemical', '-', (105, 109))	('PTEN mRNA', 'MPA', (105, 114))	('mPGES-1', 'Gene', '64292', (43, 50))
127330	21354147	As shown in Figures 6A-C, the level of SUM-EGR1 is decreased in mPGES-1 overexpressed cells but increased in mPGES-1 depleted cells.	('increased', 'PosReg', (96, 105))	('mPGES-1', 'Gene', (64, 71))	('SUM-EGR1', 'Gene', '1958', (39, 47))	('overexpressed', 'Var', (72, 85))	('decreased', 'NegReg', (51, 60))	('SUM-EGR1', 'Gene', (39, 47))	('mPGES-1', 'Gene', '64292', (109, 116))	('mPGES-1', 'Gene', '64292', (64, 71))	('mPGES-1', 'Gene', (109, 116))
127336	21354147	Likewise, the CHIP assay in EGR1 overexpressed cells also showed higher sumoylated protein binding to PTEN promoter in cells with mPGES-1 knockdown compared to cells with mPGES-1 overexpression (Supplementary Figure 6).	('knockdown', 'Var', (138, 147))	('PTEN', 'Chemical', '-', (102, 106))	('EGR1', 'Gene', (28, 32))	('mPGES-1', 'Gene', (171, 178))	('EGR1', 'Gene', '1958', (28, 32))	('CHIP', 'Disease', (14, 18))	('sumoylated protein', 'MPA', (72, 90))	('PTEN', 'Protein', (102, 106))	('mPGES-1', 'Gene', '64292', (130, 137))	('CHIP', 'Disease', 'None', (14, 18))	('binding', 'Interaction', (91, 98))	('higher', 'PosReg', (65, 71))	('mPGES-1', 'Gene', '64292', (171, 178))	('mPGES-1', 'Gene', (130, 137))
127341	21354147	It is of note that the level of ARF/P14, a critical cell cycle relative gene implication in PTEN regulation, was increased when mPGES-1 was knocked down but decreased when mPGES-1 was overexpressed.	('knocked down', 'Var', (140, 152))	('mPGES-1', 'Gene', (172, 179))	('ARF/P14', 'Gene', (32, 39))	('mPGES-1', 'Gene', '64292', (128, 135))	('mPGES-1', 'Gene', (128, 135))	('increased', 'PosReg', (113, 122))	('PTEN', 'Chemical', '-', (92, 96))	('ARF/P14', 'Gene', '1029', (32, 39))	('mPGES-1', 'Gene', '64292', (172, 179))
127349	21354147	Furthermore, mPGES-1 overexpression increased tumor cell migration and repair ability, whereas mPGES-1 knockdown reduced tumor cell migration and repair.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('overexpression', 'Var', (21, 35))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('mPGES-1', 'Gene', (13, 20))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('increased', 'PosReg', (36, 45))	('mPGES-1', 'Gene', '64292', (95, 102))	('repair ability', 'CPA', (71, 85))	('reduced', 'NegReg', (113, 120))	('repair', 'CPA', (146, 152))	('mPGES-1', 'Gene', '64292', (13, 20))	('mPGES-1', 'Gene', (95, 102))
127353	21354147	This finding is noteworthy, as disruption of PTEN has been implicated in the development and progression of a number of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('human', 'Species', '9606', (120, 125))	('PTEN', 'Chemical', '-', (45, 49))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('disruption', 'Var', (31, 41))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('implicated', 'Reg', (59, 69))	('PTEN', 'Gene', (45, 49))
127354	21354147	Although mutations of PTEN have not been reported in human cholangiocarcinomas, loss of functional PTEN has been implicated in cholangiocarcinogenesis.	('cholangiocarcinomas', 'Disease', (59, 78))	('PTEN', 'Chemical', '-', (99, 103))	('carcinogenesis', 'Disease', 'MESH:D063646', (136, 150))	('carcinogenesis', 'Disease', (136, 150))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (59, 78))	('loss', 'Var', (80, 84))	('implicated', 'Reg', (113, 123))	('PTEN', 'Gene', (22, 26))	('human', 'Species', '9606', (53, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('PTEN', 'Gene', (99, 103))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (59, 77))	('PTEN', 'Chemical', '-', (22, 26))
127355	21354147	In a murine model of intrahepatic cholangiocarcinoma, disruption of the PTEN gene was associated with increased level of p-AKT and mTOR, suggesting that PTEN may regulate cholangiocarcinogenesis by affecting its downstream genes.	('regulate', 'Reg', (162, 170))	('carcinogenesis', 'Disease', 'MESH:D063646', (180, 194))	('affecting', 'Reg', (198, 207))	('disruption', 'Var', (54, 64))	('intrahepatic cholangiocarcinoma', 'Disease', (21, 52))	('murine', 'Species', '10090', (5, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('AKT', 'Gene', '207', (123, 126))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (34, 52))	('PTEN', 'Chemical', '-', (72, 76))	('PTEN', 'Chemical', '-', (153, 157))	('mTOR', 'MPA', (131, 135))	('increased', 'PosReg', (102, 111))	('PTEN gene', 'Gene', (72, 81))	('AKT', 'Gene', (123, 126))	('carcinogenesis', 'Disease', (180, 194))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (21, 52))
127356	21354147	Consistent with the observations that loss of PTEN protein is a prognostic factor in other malignancies, Chung et al showed that loss of PTEN expression is associated with more aggressive tumor growth parameters and worse survival outcome in cholangiocarcinoma patients.	('patients', 'Species', '9606', (261, 269))	('malignancies', 'Disease', (91, 103))	('aggressive tumor', 'Disease', (177, 193))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (242, 260))	('aggressive tumor', 'Disease', 'MESH:D001523', (177, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('loss', 'Var', (129, 133))	('PTEN', 'Gene', (137, 141))	('cholangiocarcinoma', 'Disease', (242, 260))	('more', 'PosReg', (172, 176))	('malignancies', 'Disease', 'MESH:D009369', (91, 103))	('PTEN', 'Chemical', '-', (137, 141))	('PTEN', 'Chemical', '-', (46, 50))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (242, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))
127367	21354147	We observed that mPGES-1 overexpression noticeably decreased EGR1-PTEN binding; in contrast mPGES-1 knockdown enhanced EGR1-PTEN binding.	('mPGES-1', 'Gene', '64292', (17, 24))	('knockdown', 'Var', (100, 109))	('EGR1', 'Gene', '1958', (119, 123))	('mPGES-1', 'Gene', (17, 24))	('EGR1', 'Gene', '1958', (61, 65))	('PTEN', 'Chemical', '-', (124, 128))	('PTEN', 'Chemical', '-', (66, 70))	('decreased', 'NegReg', (51, 60))	('enhanced', 'PosReg', (110, 118))	('EGR1', 'Gene', (119, 123))	('EGR1', 'Gene', (61, 65))	('binding', 'Interaction', (71, 78))	('mPGES-1', 'Gene', '64292', (92, 99))	('binding', 'Interaction', (129, 136))	('mPGES-1', 'Gene', (92, 99))
127395	30761385	Molecular Modeling and Functional Analysis of Exome Sequencing-Derived Variants of Unknown Significance Identify a Novel, Constitutively Active FGFR2 Mutant in Cholangiocarcinoma Genomic testing has increased the quantity of information available to oncologists.	('FGFR2', 'Gene', '2263', (144, 149))	('Mutant', 'Var', (150, 156))	('Active', 'PosReg', (137, 143))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (160, 178))	('Cholangiocarcinoma', 'Disease', (160, 178))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (160, 178))	('FGFR2', 'Gene', (144, 149))
127396	30761385	Unfortunately, many identified sequence alterations are variants of unknown significance (VUSs), which thus limit the clinician's ability to use these findings to inform treatment.	('sequence alterations', 'Var', (31, 51))	('VUS', 'Chemical', '-', (90, 93))	('limit', 'NegReg', (108, 113))	('rat', 'Species', '10116', (44, 47))
127403	30761385	Filtering for mutations in genes that were therapeutically targetable and predicted to affect protein function reduced these to 522VUSs of interest, including a large number of kinases.	('affect', 'Reg', (87, 93))	('reduced', 'NegReg', (111, 118))	('VUS', 'Chemical', '-', (131, 134))	('protein function', 'MPA', (94, 110))	('mutations', 'Var', (14, 23))
127405	30761385	Three VUSs (FGFR2 F276C, FGFR4 R78H, and KDR G539R) showed increased basal or ligand-stimulated ERK phosphorylation compared with their wild-type counterparts, which suggests that they support transformation.	('KDR', 'Gene', (41, 44))	('FGFR4', 'Gene', '2264', (25, 30))	('FGFR4', 'Gene', (25, 30))	('R78H', 'Var', (31, 35))	('F276C', 'Var', (18, 23))	('VUS', 'Chemical', '-', (6, 9))	('FGFR2', 'Gene', (12, 17))	('F276C', 'Mutation', 'p.F276C', (18, 23))	('basal', 'MPA', (69, 74))	('KDR', 'Gene', '3791', (41, 44))	('ERK', 'Gene', '5594', (96, 99))	('FGFR2', 'Gene', '2263', (12, 17))	('G539R', 'Mutation', 'rs55716939', (45, 50))	('increased', 'PosReg', (59, 68))	('ERK', 'Gene', (96, 99))	('R78H', 'Mutation', 'rs200146267', (31, 35))	('ligand-stimulated', 'MPA', (78, 95))
127406	30761385	Treatment of a patient who carried FGFR2 F276C with an FGFR inhibitor resulted in significant and sustained tumor response with clinical benefit.	('patient', 'Species', '9606', (15, 22))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('FGFR2', 'Gene', (35, 40))	('FGFR2', 'Gene', '2263', (35, 40))	('tumor', 'Disease', (108, 113))	('F276C', 'Mutation', 'p.F276C', (41, 46))	('F276C', 'Var', (41, 46))	('FGF', 'Gene', (35, 38))	('FGF', 'Gene', (55, 58))	('FGF', 'Gene', '2247', (35, 38))	('FGF', 'Gene', '2247', (55, 58))
127412	30761385	For example, BRAF V600E is well accepted as a therapeutic target in metastatic melanoma.	('BRAF V600E', 'Var', (13, 23))	('V600E', 'Mutation', 'p.V600E', (18, 23))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
127415	30761385	Although some recurrent mutations within oncogenic proteins have been characterized as having an effect on protein function and thus, the promotion of transformation, novel VUSs identified through clinical genomic testing often are lacking functional information.	('transformation', 'CPA', (151, 165))	('effect', 'Reg', (97, 103))	('VUS', 'Chemical', '-', (173, 176))	('mutations', 'Var', (24, 33))	('protein function', 'MPA', (107, 123))
127429	30761385	More than 4,300 single nucleotide variants were reported from 308 patient tumors (Data Supplement).	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('single nucleotide variants', 'Var', (16, 42))	('patient', 'Species', '9606', (66, 73))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
127430	30761385	VUSs, which constitute mutations that are functionally uncharacterized or previously unreported in the COSMIC (Catalogue of Somatic Mutations in Cancer) database, comprised the majority (89%) of the point mutations observed in this cohort (Fig 1A).	('VUS', 'Chemical', '-', (0, 3))	('point mutations', 'Var', (199, 214))	('Cancer', 'Phenotype', 'HP:0002664', (145, 151))	('Cancer', 'Disease', (145, 151))	('VUSs', 'Disease', (0, 4))	('Cancer', 'Disease', 'MESH:D009369', (145, 151))
127433	30761385	Protein class analysis demonstrated that RTKs and serine/threonine kinases represent the largest therapeutically targetable functional classes, with mutations in both hematologic and solid tumors (Fig 1B).	('solid tumors', 'Disease', 'MESH:D009369', (183, 195))	('mutations', 'Var', (149, 158))	('RTK', 'Gene', '5979', (41, 44))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('rat', 'Species', '10116', (30, 33))	('solid tumors', 'Disease', (183, 195))	('RTK', 'Gene', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('hematologic', 'Disease', (167, 178))
127444	30761385	FGFR4 variant R78H is located in the extracellular first immunoglobulin-like domain 1 (Ig1).	('variant R78H', 'Var', (6, 18))	('R78H', 'Var', (14, 18))	('R78H', 'Mutation', 'rs200146267', (14, 18))	('FGFR4', 'Gene', '2264', (0, 5))	('FGFR4', 'Gene', (0, 5))
127445	30761385	Although Ig2 and Ig3 domains of the receptor are involved in binding FGF, the FGFR4 R78H VUS in the Ig1isnot involved in ligandinteraction(Fig 2A).	('ligandinteraction', 'MPA', (121, 138))	('VUS', 'Chemical', '-', (89, 92))	('R78H', 'Mutation', 'rs200146267', (84, 88))	('FGF', 'Gene', (78, 81))	('FGFR4', 'Gene', '2264', (78, 83))	('FGFR4', 'Gene', (78, 83))	('FGF', 'Gene', '2247', (78, 81))	('FGF', 'Gene', (69, 72))	('involved', 'Reg', (109, 117))	('R78H VUS', 'Var', (84, 92))	('FGF', 'Gene', '2247', (69, 72))
127447	30761385	Cellular localization of WT and R78H FGFR4 was also similar and exhibited mainly a plasma membrane distribution with intracellular labeling of probable Golgi membranes (Fig 2E).	('R78H', 'Mutation', 'rs200146267', (32, 36))	('R78H', 'Var', (32, 36))	('FGFR4', 'Gene', '2264', (37, 42))	('FGFR4', 'Gene', (37, 42))
127448	30761385	However, R78H FGFR4 exhibited a small, but significantly elevated FGF2-stimulated phospho-ERK (pERK) level compared with WT (Figs 2B and 2D).	('FGFR4', 'Gene', (14, 19))	('FGF2', 'Gene', '2247', (66, 70))	('ERK', 'Gene', (90, 93))	('elevated FGF2', 'Phenotype', 'HP:0030269', (57, 70))	('R78H', 'Mutation', 'rs200146267', (9, 13))	('elevated', 'PosReg', (57, 65))	('FGF2', 'Gene', (66, 70))	('R78H', 'Var', (9, 13))	('ERK', 'Gene', '5594', (96, 99))	('ERK', 'Gene', '5594', (90, 93))	('ERK', 'Gene', (96, 99))	('FGFR4', 'Gene', '2264', (14, 19))
127449	30761385	Two KDR VUSs, G55E and G539R, are located in the extracellular domain in proximity to amino acids that form disulfide bonds (C53 and C530); thus, these amino acid substitutions may potentially affect neighboring disulfide bonds.	('G539R', 'Var', (23, 28))	('KDR', 'Gene', (4, 7))	('G539R', 'Mutation', 'rs55716939', (23, 28))	('C530', 'Var', (133, 137))	('disulfide', 'Chemical', 'MESH:D004220', (108, 117))	('neighboring disulfide bonds', 'MPA', (200, 227))	('affect', 'Reg', (193, 199))	('VUS', 'Chemical', '-', (8, 11))	('G55E', 'Var', (14, 18))	('G55E', 'Mutation', 'p.G55E', (14, 18))	('KDR', 'Gene', '3791', (4, 7))	('disulfide', 'Chemical', 'MESH:D004220', (212, 221))	('C53', 'Var', (125, 128))
127450	30761385	Expression of WT and VUS KDR proteins in KMCH-1 cells demonstrated that G539R KDR was more highly expressed than WT (Figs 3A and 3B).	('KDR', 'Gene', (25, 28))	('VUS', 'Chemical', '-', (21, 24))	('KDR', 'Gene', '3791', (78, 81))	('rat', 'Species', '10116', (61, 64))	('KDR', 'Gene', '3791', (25, 28))	('KMCH-1', 'CellLine', 'CVCL:7970', (41, 47))	('G539R', 'Var', (72, 77))	('KDR', 'Gene', (78, 81))	('G539R', 'Mutation', 'rs55716939', (72, 77))
127451	30761385	In contrast, G55E exhibited decreased expression of full-length (approximately 200 kDa) KDR compared with the WT form, with the appearance of a novel approximately 70- to 80-kDa polypeptide doublet in this variant as detected with FLAG antibody (Fig 3A), which suggests that G55E KDR is less stable than the WT protein.	('KDR', 'Gene', '3791', (88, 91))	('KDR', 'Gene', '3791', (280, 283))	('decreased', 'NegReg', (28, 37))	('expression', 'MPA', (38, 48))	('G55E', 'Var', (13, 17))	('G55E', 'Mutation', 'p.G55E', (13, 17))	('G55E', 'Var', (275, 279))	('KDR', 'Gene', (280, 283))	('G55E', 'Mutation', 'p.G55E', (275, 279))	('KDR', 'Gene', (88, 91))
127453	30761385	KDR variants and WT exhibited a similar punctate distribution by immunofluorescence (Fig 3D).	('punctate', 'MPA', (40, 48))	('KDR', 'Gene', (0, 3))	('KDR', 'Gene', '3791', (0, 3))	('variants', 'Var', (4, 12))
127454	30761385	VUSs G251E, V484M, and T643M of PDGFRA and variants V258L and V316M of PDGFRB were investigated.	('T643M', 'Mutation', 'p.T643M', (23, 28))	('V484M', 'Var', (12, 17))	('V258L', 'Var', (52, 57))	('G251E', 'Var', (5, 10))	('VUS', 'Chemical', '-', (0, 3))	('V316M', 'Var', (62, 67))	('V316M', 'Mutation', 'rs41287112', (62, 67))	('V484M', 'Mutation', 'rs149031291', (12, 17))	('PDGFRB', 'Gene', (71, 77))	('PDGFRA', 'Gene', (32, 38))	('PDGFRB', 'Gene', '5159', (71, 77))	('V258L', 'Mutation', 'p.V258L', (52, 57))	('PDGFRA', 'Gene', '5156', (32, 38))	('T643M', 'Var', (23, 28))	('G251E', 'SUBSTITUTION', 'None', (5, 10))
127455	30761385	All variants fall in the extracellular domain of their respective receptor except T643M, which occurs within the PDGFRB kinase domain.	('PDGFRB', 'Gene', (113, 119))	('T643M', 'Mutation', 'p.T643M', (82, 87))	('fall', 'Phenotype', 'HP:0002527', (13, 17))	('PDGFRB', 'Gene', '5159', (113, 119))	('T643M', 'Var', (82, 87))
127458	30761385	Although predicted in silico to be benign, FGFR2 K41E, identified in an acute myeloid leukemia, was selected for additional study because of its location in the extracellular Ig1 of FGFR2 and its unknown effect on ligand binding in nearby Ig2 and Ig3 (Data Supplement).	('FGFR2', 'Gene', (182, 187))	('FGFR2', 'Gene', '2263', (182, 187))	('myeloid leukemia', 'Disease', 'MESH:D007951', (78, 94))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (78, 94))	('leukemia', 'Phenotype', 'HP:0001909', (86, 94))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (72, 94))	('K41E', 'Var', (49, 53))	('FGFR2', 'Gene', (43, 48))	('myeloid leukemia', 'Disease', (78, 94))	('FGFR2', 'Gene', '2263', (43, 48))	('K41E', 'Mutation', 'rs1212310813', (49, 53))
127459	30761385	The FGFR2 F276C mutation identified here from a cholangiocarcinoma was also in a single cholangiocarcinoma in the COSMIC database but has not been characterized.	('cholangiocarcinoma', 'Disease', (48, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('F276C', 'Mutation', 'p.F276C', (10, 15))	('FGFR2', 'Gene', '2263', (4, 9))	('F276C', 'Var', (10, 15))	('cholangiocarcinoma', 'Disease', (88, 106))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (48, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (48, 66))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 106))	('FGFR2', 'Gene', (4, 9))
127461	30761385	A different amino acid substitution at the same residue, F276V, has been reported in Crouzon syndrome.	('F276V', 'Mutation', 'rs1057519036', (57, 62))	('F276V', 'Var', (57, 62))	('Crouzon syndrome', 'Disease', (85, 101))	('Crouzon syndrome', 'Phenotype', 'HP:0004439', (85, 101))	('Crouzon syndrome', 'Disease', 'MESH:D003394', (85, 101))
127462	30761385	Modeling of WT and F276C FGFR2 showed that the extracellular receptor of FGFR2 contains an intrinsic disulfide bond between C278 and C342 in Ig3 (Fig 4A, shown in gold).	('FGFR2', 'Gene', (25, 30))	('disulfide', 'Chemical', 'MESH:D004220', (101, 110))	('FGFR2', 'Gene', '2263', (25, 30))	('FGFR2', 'Gene', (73, 78))	('FGFR2', 'Gene', '2263', (73, 78))	('C342', 'Var', (133, 137))	('C278', 'Var', (124, 128))	('F276C', 'Mutation', 'p.F276C', (19, 24))
127463	30761385	Residue F276 is proximal to the disulfide bridge, which suggests that F276C disrupts normal disulfide linkages.	('F276', 'Var', (8, 12))	('F276C', 'Var', (70, 75))	('disulfide', 'Chemical', 'MESH:D004220', (92, 101))	('F276C', 'Mutation', 'p.F276C', (70, 75))	('disulfide', 'Chemical', 'MESH:D004220', (32, 41))	('disrupts', 'NegReg', (76, 84))	('normal disulfide linkages', 'MPA', (85, 110))
127464	30761385	Alignment of residue F276 is highly conserved from zebrafish to humans, which suggests that its alteration disrupts normal protein function (Fig 4B).	('humans', 'Species', '9606', (64, 70))	('zebrafish', 'Species', '7955', (51, 60))	('disrupts', 'NegReg', (107, 115))	('F276', 'Var', (21, 25))	('normal', 'MPA', (116, 122))	('alteration', 'Var', (96, 106))	('protein', 'Protein', (123, 130))	('rat', 'Species', '10116', (100, 103))
127466	30761385	When FGFR2 proteins were expressed in KMCH-1 cells, immunofluorescence microscopy showed that the WT and K41E FGFR2 proteins were localized mainly to the cell surface and occurred on intracellular structures, likely endosomes and the Golgi apparatus (Fig 4C).	('K41E', 'Var', (105, 109))	('K41E', 'Mutation', 'rs1212310813', (105, 109))	('FGFR2', 'Gene', (110, 115))	('FGFR2', 'Gene', '2263', (110, 115))	('FGFR2', 'Gene', (5, 10))	('FGFR2', 'Gene', '2263', (5, 10))	('KMCH-1', 'CellLine', 'CVCL:7970', (38, 44))	('occurred', 'Reg', (171, 179))	('rat', 'Species', '10116', (244, 247))	('proteins', 'Protein', (116, 124))
127468	30761385	However, the F276C variant was expressed at a higher level and the K41E variant at a lower level compared with WT (Fig 4D), although cells were transfected with equal amounts of DNA for the different FGFR2 constructs.	('K41E', 'Var', (67, 71))	('F276C', 'Mutation', 'p.F276C', (13, 18))	('K41E', 'Mutation', 'rs1212310813', (67, 71))	('F276C', 'Var', (13, 18))	('FGFR2', 'Gene', (200, 205))	('FGFR2', 'Gene', '2263', (200, 205))
127470	30761385	Because the F276C FGFR2 variant is expressed at higher levels than WT when equal amounts of DNA were used, a lower ratio of F276C construct DNA was used for transfection in the following experiments so that resulting levels of WT and F276C FGFR2 proteins were comparable (Figs 4E and 4F): KMCH-1 cells transfected with FGFR2 constructs were treated for 16 hours in serum-free media with FGF2, lysed, and analyzed by Western blot.	('FGFR2', 'Gene', (240, 245))	('FGFR2', 'Gene', '2263', (240, 245))	('FGFR2', 'Gene', (18, 23))	('FGFR2', 'Gene', '2263', (18, 23))	('rat', 'Species', '10116', (115, 118))	('KMCH-1', 'CellLine', 'CVCL:7970', (289, 295))	('FGF2', 'Gene', (387, 391))	('F276C', 'Mutation', 'p.F276C', (234, 239))	('F276C', 'Mutation', 'p.F276C', (124, 129))	('FGF2', 'Gene', '2247', (387, 391))	('F276C', 'Mutation', 'p.F276C', (12, 17))	('F276C', 'Var', (12, 17))	('FGFR2', 'Gene', '2263', (319, 324))	('FGFR2', 'Gene', (319, 324))
127472	30761385	The expression of WT or K41E FGFR2 in the absence of FGF2 increased pERK levels beyond control levels, and treatment with FGF2 led to approximately fivefold increases in pERK compared with control for both WT and K41E.	('FGF2', 'Gene', (53, 57))	('increased', 'PosReg', (58, 67))	('FGF2', 'Gene', (122, 126))	('K41E', 'Var', (24, 28))	('FGFR2', 'Gene', (29, 34))	('FGFR2', 'Gene', '2263', (29, 34))	('FGF2', 'Gene', '2247', (53, 57))	('ERK', 'Gene', '5594', (171, 174))	('FGF2', 'Gene', '2247', (122, 126))	('ERK', 'Gene', (171, 174))	('K41E', 'Mutation', 'rs1212310813', (24, 28))	('K41E', 'Mutation', 'rs1212310813', (213, 217))	('increases', 'PosReg', (157, 166))	('ERK', 'Gene', '5594', (69, 72))	('ERK', 'Gene', (69, 72))
127473	30761385	However, expression of F276C FGFR2 significantly increased the pERK level in the absence of FGF2 compared with WT FGFR2, with little increase upon treatment with FGF2 (Figs 4E and 4G).	('FGF2', 'Gene', '2247', (162, 166))	('increased', 'PosReg', (49, 58))	('ERK', 'Gene', '5594', (64, 67))	('FGFR2', 'Gene', (114, 119))	('FGFR2', 'Gene', '2263', (114, 119))	('FGFR2', 'Gene', (29, 34))	('FGF2', 'Gene', (162, 166))	('FGFR2', 'Gene', '2263', (29, 34))	('FGF2', 'Gene', '2247', (92, 96))	('ERK', 'Gene', (64, 67))	('F276C', 'Mutation', 'p.F276C', (23, 28))	('F276C', 'Var', (23, 28))	('FGF2', 'Gene', (92, 96))
127474	30761385	Similarly high constitutive activity of F276C versus WT was observed in PANC1 cells and KMBC cholangiocarcinoma cells.	('F276C', 'Mutation', 'p.F276C', (40, 45))	('F276C', 'Var', (40, 45))	('cholangiocarcinoma', 'Disease', (93, 111))	('PANC1', 'CellLine', 'CVCL:0480', (72, 77))	('constitutive activity', 'MPA', (15, 36))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))
127475	30761385	In summary, F276C FGFR2 has high expression, altered cellular distribution, and increased constitutive activity compared with WT.	('altered', 'Reg', (45, 52))	('FGFR2', 'Gene', (18, 23))	('FGFR2', 'Gene', '2263', (18, 23))	('increased', 'PosReg', (80, 89))	('constitutive activity', 'MPA', (90, 111))	('cellular distribution', 'MPA', (53, 74))	('expression', 'MPA', (33, 43))	('F276C', 'Mutation', 'p.F276C', (12, 17))	('F276C', 'Var', (12, 17))
127476	30761385	Finally, the sensitivity of WT and F276C FGFR2 activities to treatment with the FGFR inhibitor BGJ398 were compared.	('FGF', 'Gene', (80, 83))	('FGFR2', 'Gene', (41, 46))	('FGFR2', 'Gene', '2263', (41, 46))	('FGF', 'Gene', '2247', (80, 83))	('FGF', 'Gene', (41, 44))	('F276C', 'Var', (35, 40))	('BGJ398', 'Chemical', 'MESH:C568950', (95, 101))	('F276C', 'Mutation', 'p.F276C', (35, 40))	('FGF', 'Gene', '2247', (41, 44))
127477	30761385	KMCH-1 cells were transfected with WT or F276C constructs and were incubated for 16 hours the next day with FGF2 in serum-free media.	('FGF2', 'Gene', '2247', (108, 112))	('F276C', 'Mutation', 'p.F276C', (41, 46))	('F276C', 'Var', (41, 46))	('FGF2', 'Gene', (108, 112))	('KMCH-1', 'CellLine', 'CVCL:7970', (0, 6))
127479	30761385	At concentrations between 0 and 100 nM, ERK phosphorylation was similarly partially inhibited by BGJ398 in cells that expressed WT or F276C, and both FGFR2 forms were completely inhibited by BGJ398 at 200 nM (Figs 5A and 5B).	('F276C', 'Var', (134, 139))	('F276C', 'Mutation', 'p.F276C', (134, 139))	('ERK', 'Gene', '5594', (40, 43))	('BGJ398', 'Chemical', 'MESH:C568950', (97, 103))	('ERK', 'Gene', (40, 43))	('FGFR2', 'Gene', '2263', (150, 155))	('inhibited', 'NegReg', (178, 187))	('BGJ398', 'Chemical', 'MESH:C568950', (191, 197))	('BGJ398', 'Gene', (97, 103))	('FGFR2', 'Gene', (150, 155))	('rat', 'Species', '10116', (10, 13))	('inhibited', 'NegReg', (84, 93))
127480	30761385	These studies demonstrate that the F276C FGFR2 variant has comparable sensitivity to BGJ398 relative to WT.	('FGFR2', 'Gene', '2263', (41, 46))	('FGFR2', 'Gene', (41, 46))	('sensitivity', 'MPA', (70, 81))	('F276C', 'Var', (35, 40))	('rat', 'Species', '10116', (21, 24))	('F276C', 'Mutation', 'p.F276C', (35, 40))	('BGJ398', 'Chemical', 'MESH:C568950', (85, 91))
127481	30761385	The FGFR2 F276C VUS was identified as a result of targeted sequencing of a tumor from a 57-year-old male with advanced, multifocal, intrahepatic cholangiocarcinoma.	('F276C', 'Mutation', 'p.F276C', (10, 15))	('FGFR2', 'Gene', '2263', (4, 9))	('F276C', 'Var', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (132, 163))	('VUS', 'Chemical', '-', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('intrahepatic cholangiocarcinoma', 'Disease', (132, 163))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (145, 163))	('FGFR2', 'Gene', (4, 9))	('tumor', 'Disease', (75, 80))
127485	30761385	The FGFR2 F276C VUS was reported and confirmed to be a somatic event (data not shown).	('FGFR2', 'Gene', (4, 9))	('VUS', 'Disease', (16, 19))	('F276C', 'Mutation', 'p.F276C', (10, 15))	('F276C', 'Var', (10, 15))	('VUS', 'Chemical', '-', (16, 19))	('FGFR2', 'Gene', '2263', (4, 9))
127487	30761385	As a result of our in vitro studies of F276C, a mechanism of action has now been correlated with this observed clinical response of the tumor to BGJ398.	('BGJ398', 'Chemical', 'MESH:C568950', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('F276C', 'Var', (39, 44))	('tumor', 'Disease', (136, 141))	('F276C', 'Mutation', 'p.F276C', (39, 44))
127490	30761385	Few mutations have extensive preclinical and clinical evidence that support the effectiveness of targeted therapies, and genomic testing often reveals that tumors have numerous VUSs, including variant sequences for which no functional data are available.	('variant', 'Var', (193, 200))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('VUS', 'Chemical', '-', (177, 180))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Disease', (156, 162))
127502	30761385	FGFR2 F276C was identified as a VUS of potential interest because of the presence of several factors, including prediction of a deleterious effect by two algorithms, 3D modeling that suggests an increase in activity on the basis of its location in the ligand-binding Ig3, and proximity to a key disulfide bond.	('F276C', 'Mutation', 'p.F276C', (6, 11))	('activity', 'MPA', (207, 215))	('F276C', 'Var', (6, 11))	('disulfide', 'Chemical', 'MESH:D004220', (295, 304))	('FGFR2', 'Gene', (0, 5))	('VUS', 'Chemical', '-', (32, 35))	('FGFR2', 'Gene', '2263', (0, 5))	('increase', 'PosReg', (195, 203))
127503	30761385	Germline mutations of residues to and from cysteine in this region of FGFR2 (eg,Y328C, C278F) have been reported to allow the formation of aberrant disulfide bonds and to induce constitutive receptor dimerization and activation, which lead to a variety of skeletal and craniosynostosis disorders (eg, Crouzon and Pfeiffer syndromes).	('allow', 'Reg', (116, 121))	('FGFR2', 'Gene', '2263', (70, 75))	('formation', 'Reg', (126, 135))	('Crouzon', 'Disease', (301, 308))	('C278F', 'Var', (87, 92))	('lead to', 'Reg', (235, 242))	('disulfide bonds', 'MPA', (148, 163))	('dimerization', 'Interaction', (200, 212))	('Y328C', 'Mutation', 'rs121918493', (80, 85))	('constitutive', 'MPA', (178, 190))	('disulfide', 'Chemical', 'MESH:D004220', (148, 157))	('activation', 'MPA', (217, 227))	('craniosynostosis disorders', 'Disease', 'MESH:D003398', (269, 295))	('Y328C', 'Var', (80, 85))	('craniosynostosis disorders', 'Disease', (269, 295))	('induce', 'PosReg', (171, 177))	('C278F', 'Mutation', 'rs776587763', (87, 92))	('FGFR2', 'Gene', (70, 75))	('cysteine', 'Chemical', 'MESH:D003545', (43, 51))	('craniosynostosis', 'Phenotype', 'HP:0001363', (269, 285))
127504	30761385	Our molecular modeling combined with the demonstration that F276C FGFR2 is more highly expressed and constitutively active than the WT receptor suggests that this mutation alters disulfide bonds, which alters receptor dimerization and activity similarly to the FGFR2 mutations seen in craniosynostosis syndromes.	('receptor dimerization', 'MPA', (209, 230))	('F276C', 'Mutation', 'p.F276C', (60, 65))	('F276C', 'Var', (60, 65))	('FGFR2', 'Gene', (261, 266))	('FGFR2', 'Gene', (66, 71))	('FGFR2', 'Gene', '2263', (66, 71))	('craniosynostosis', 'Phenotype', 'HP:0001363', (285, 301))	('craniosynostosis syndromes', 'Disease', (285, 311))	('FGFR2', 'Gene', '2263', (261, 266))	('alters', 'Reg', (172, 178))	('craniosynostosis syndromes', 'Disease', 'MESH:D003398', (285, 311))	('alters', 'Reg', (202, 208))	('activity', 'MPA', (235, 243))	('disulfide', 'Chemical', 'MESH:D004220', (179, 188))	('disulfide bonds', 'MPA', (179, 194))	('rat', 'Species', '10116', (48, 51))
127505	30761385	By using in vitro studies, we show that the F276C FGFR2 variant is sensitive to BGJ398, a pan-FGFR inhibitor, which was also reflected clinically in the response of a patient's tumor when treated with BGJ398 as part of a clinical trial (Fig 5).	('F276C', 'Mutation', 'p.F276C', (44, 49))	('FGF', 'Gene', (50, 53))	('F276C', 'Var', (44, 49))	('BGJ398', 'Chemical', 'MESH:C568950', (80, 86))	('patient', 'Species', '9606', (167, 174))	('FGF', 'Gene', '2247', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('BGJ398', 'Chemical', 'MESH:C568950', (201, 207))	('FGFR2', 'Gene', '2263', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('FGFR2', 'Gene', (50, 55))	('tumor', 'Disease', (177, 182))	('FGF', 'Gene', (94, 97))	('FGF', 'Gene', '2247', (94, 97))	('sensitive', 'Reg', (67, 76))
127507	30761385	However, additional studies, such as the testing of BGJ398 effectiveness in impeding growth of organoids or xenografts that express WT versus F276C, are needed to confirm that FGFR2 F276C is actionable.	('BGJ398', 'Chemical', 'MESH:C568950', (52, 58))	('FGFR2', 'Gene', (176, 181))	('FGFR2', 'Gene', '2263', (176, 181))	('impeding', 'NegReg', (76, 84))	('F276C', 'Mutation', 'p.F276C', (182, 187))	('BGJ398', 'Gene', (52, 58))	('F276C', 'Var', (182, 187))	('F276C', 'Mutation', 'p.F276C', (142, 147))	('F276C', 'Var', (142, 147))	('growth', 'CPA', (85, 91))
127654	25691459	These findings were extended by the demonstration that overexpressing miR26a or miR26b decreased 15-PGDH protein levels, reversed omega-3 PUFA-induced accumulation of 15-PGDH protein and prevented omega-3 PUFA-induced inhibition of cholangiocarcinoma cell growth.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('omega-3', 'Chemical', 'MESH:D015525', (130, 137))	('PUFA', 'Gene', '9933', (205, 209))	('PUFA', 'Gene', (138, 142))	('15-PGDH protein levels', 'MPA', (97, 119))	('decreased', 'NegReg', (87, 96))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (232, 250))	('miR26b', 'Gene', (80, 86))	('cholangiocarcinoma', 'Disease', (232, 250))	('miR26b', 'Gene', '407017', (80, 86))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (232, 250))	('15-PGDH', 'MPA', (167, 174))	('accumulation', 'PosReg', (151, 163))	('PUFA', 'Gene', '9933', (138, 142))	('reversed', 'NegReg', (121, 129))	('PUFA', 'Gene', (205, 209))	('prevented', 'NegReg', (187, 196))	('miR26a', 'Var', (70, 76))	('omega-3', 'Chemical', 'MESH:D015525', (197, 204))
127663	25691459	Overexpression of COX-2 in human CCA cells enhances PGE2 production and promotes tumor growth, whereas depletion of COX-2 reduces PGE2 production and prevents growth.	('reduces', 'NegReg', (122, 129))	('COX-2', 'Gene', '5743', (18, 23))	('PGE2', 'Chemical', 'MESH:D015232', (130, 134))	('CCA', 'Phenotype', 'HP:0030153', (33, 36))	('PGE2 production', 'MPA', (130, 145))	('human', 'Species', '9606', (27, 32))	('enhances', 'PosReg', (43, 51))	('PGE2', 'Chemical', 'MESH:D015232', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('promotes', 'PosReg', (72, 80))	('COX-2', 'Gene', (116, 121))	('depletion', 'Var', (103, 112))	('growth', 'MPA', (159, 165))	('COX-2', 'Gene', '5743', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('COX-2', 'Gene', (18, 23))	('PGE2 production', 'MPA', (52, 67))	('tumor', 'Disease', (81, 86))
127664	25691459	PGE2 treatment is known to increase CCA cell growth and prevent apoptosis.	('treatment', 'Var', (5, 14))	('PGE2', 'Chemical', 'MESH:D015232', (0, 4))	('CCA', 'Disease', (36, 39))	('apoptosis', 'CPA', (64, 73))	('PGE2', 'Gene', (0, 4))	('CCA', 'Phenotype', 'HP:0030153', (36, 39))	('increase', 'PosReg', (27, 35))
127665	25691459	Accordingly, inhibition of COX-2 by molecular and pharmacological approaches prevents the growth and invasion of CCA cells in vitro and in animal models.	('COX-2', 'Gene', '5743', (27, 32))	('inhibition', 'Var', (13, 23))	('CCA', 'Phenotype', 'HP:0030153', (113, 116))	('CCA', 'Disease', (113, 116))	('prevents', 'NegReg', (77, 85))	('COX-2', 'Gene', (27, 32))
127667	25691459	However, as some COX-2 inhibitors are known to be associated with increased cardiovascular side effect, there is an urgent and practical need to identify COX-2 downstream target for effective anti-CCA therapy with fewer side effects.	('COX-2', 'Gene', '5743', (17, 22))	('inhibitors', 'Var', (23, 33))	('COX-2', 'Gene', (154, 159))	('CCA', 'Phenotype', 'HP:0030153', (197, 200))	('COX-2', 'Gene', '5743', (154, 159))	('cardiovascular side effect', 'MPA', (76, 102))	('COX-2', 'Gene', (17, 22))
127673	25691459	The lipid mediators derived from omega-6 and omega-3 PUFA are metabolically distinct and often have opposing physiological and pathological functions; for example, omega-6 PUFA-derived eicosanoids tend to promote inflammation and carcinogenesis, while omega-3 PUFA-derived lipid mediators largely inhibit inflammation and prevent carcinogenesis (or less promotional for inflammation and proliferation).	('PUFA', 'Gene', (53, 57))	('lipid', 'Chemical', 'MESH:D008055', (4, 9))	('PUFA', 'Gene', (260, 264))	('eicosanoids', 'Chemical', 'MESH:D015777', (185, 196))	('inflammation', 'Disease', 'MESH:D007249', (370, 382))	('PUFA', 'Gene', (172, 176))	('inflammation', 'Disease', (213, 225))	('carcinogenesis', 'Disease', (330, 344))	('omega-6', 'Chemical', '-', (164, 171))	('lipid', 'Chemical', 'MESH:D008055', (273, 278))	('inflammation', 'Disease', 'MESH:D007249', (305, 317))	('carcinogenesis', 'Disease', 'MESH:D063646', (330, 344))	('inflammation', 'Disease', (370, 382))	('promote', 'PosReg', (205, 212))	('PUFA', 'Gene', '9933', (53, 57))	('PUFA', 'Gene', '9933', (260, 264))	('prevent', 'NegReg', (322, 329))	('inhibit', 'NegReg', (297, 304))	('PUFA', 'Gene', '9933', (172, 176))	('carcinogenesis', 'Disease', (230, 244))	('inflammation', 'Disease', (305, 317))	('carcinogenesis', 'Disease', 'MESH:D063646', (230, 244))	('omega-3', 'Chemical', 'MESH:D015525', (252, 259))	('omega-6', 'Var', (164, 171))	('inflammation', 'Disease', 'MESH:D007249', (213, 225))	('omega-6', 'Chemical', '-', (33, 40))	('omega-3', 'Chemical', 'MESH:D015525', (45, 52))
127715	25691459	The spleen was identified, and 1 x 106 cells (with or without 15-PGDH knockdown) in a total volume of 100microl PBS were injected into the spleen.	('15-PGDH', 'Protein', (62, 69))	('PBS', 'Gene', (112, 115))	('PBS', 'Gene', '1131', (112, 115))	('knockdown', 'Var', (70, 79))
127726	25691459	Sequence analysis identified four conserved microRNAs (miR26a, miR26b, miR1297, miR4465) that are complementary to the 15-PGDH 3'UTR (Figure 2A and Supplementary Figure S2).	('miR26a', 'Var', (55, 61))	('miR4465', 'Gene', (80, 87))	('miR26b', 'Gene', (63, 69))	('miR1297', 'Gene', (71, 78))	('miR4465', 'Gene', '100616180', (80, 87))	('miR26b', 'Gene', '407017', (63, 69))	('miR1297', 'Gene', '100302187', (71, 78))
127727	25691459	Among these 4 microRNAs, miR26a and miR26b were found to be highly expressed in cholangiocarcinoma cells relative to the other two (miR1297, miR4465) (Supplementary Figure S2).	('miR4465', 'Gene', (141, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('miR26b', 'Gene', '407017', (36, 42))	('miR1297', 'Gene', (132, 139))	('cholangiocarcinoma', 'Disease', (80, 98))	('miR4465', 'Gene', '100616180', (141, 148))	('highly', 'PosReg', (60, 66))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (80, 98))	('miR1297', 'Gene', '100302187', (132, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (80, 98))	('miR26b', 'Gene', (36, 42))	('miR26a', 'Var', (25, 31))
127732	25691459	As shown in Figure 2E, overexpression of miR26a or miR26b significantly reduced 15-PGDH protein in both CCLP1 and TFK-1 cells and the effects were reversed by anti-miR26.	('miR26b', 'Gene', '407017', (51, 57))	('reduced', 'NegReg', (72, 79))	('miR26b', 'Gene', (51, 57))	('15-PGDH protein', 'Protein', (80, 95))	('miR26a', 'Var', (41, 47))
127733	25691459	We next measured the 15-PGDH 3'UTR-luciferase reporter activities in miR26a or miR26b overexpressed or control cells.	('miR26a', 'Var', (69, 75))	('15-PGDH', 'Protein', (21, 28))	('activities', 'MPA', (55, 65))	('miR26b', 'Gene', (79, 85))	('miR26b', 'Gene', '407017', (79, 85))
127735	25691459	Accordingly, we observed that overexpression of miR26a or miR26b prevented DHA-induced 15-PGDH protein accumulation (Figure 2G).	('miR26b', 'Gene', (58, 64))	('prevented', 'NegReg', (65, 74))	('DHA-induced', 'Disease', (75, 86))	('15-PGDH protein', 'Protein', (87, 102))	('miR26a', 'Var', (48, 54))	('miR26b', 'Gene', '407017', (58, 64))	('DHA', 'Chemical', 'MESH:D004281', (75, 78))
127739	25691459	The pattern of CTDSPL and CTDSP1 alterations appears to be similar to their intronic microRNAs, suggesting that miR26a/b and their host genes are co-regulated by omega-6 PUFA in cholangiocarcinoma cells.	('cholangiocarcinoma', 'Disease', (178, 196))	('CTDSPL', 'Gene', '10217', (15, 21))	('miR26a/b', 'Gene', (112, 120))	('CTDSPL', 'Gene', (15, 21))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (178, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('omega-6', 'Chemical', '-', (162, 169))	('alterations', 'Var', (33, 44))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (178, 196))	('CTDSP1', 'Gene', '58190', (26, 32))	('PUFA', 'Gene', '9933', (170, 174))	('PUFA', 'Gene', (170, 174))	('CTDSP1', 'Gene', (26, 32))
127746	25691459	To further determine the role of miR26/15-PGDH in omega-3 PUFA-induced inhibition of cholangiocarcinoma cell growth, we evaluated the growth parameters of tumor cells overexpressing Fat1 and/or miR26a.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('miR26a', 'Var', (194, 200))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (85, 103))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('tumor', 'Disease', (155, 160))	('Fat1', 'Gene', (182, 186))	('PUFA', 'Gene', '9933', (58, 62))	('omega-3', 'Chemical', 'MESH:D015525', (50, 57))	('PUFA', 'Gene', (58, 62))	('cholangiocarcinoma', 'Disease', (85, 103))	('Fat1', 'Gene', '2195', (182, 186))
127753	25691459	We observed that administration of exogenous DHA to SCID mice significantly decreased tumor growth when the mice were inoculated with control vector tumor cells and that 15-PGDH knockdown reversed DHA effect in vivo (Figure 7).	('mice', 'Species', '10090', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('decreased', 'NegReg', (76, 85))	('DHA', 'Chemical', 'MESH:D004281', (45, 48))	('mice', 'Species', '10090', (108, 112))	('tumor', 'Disease', (149, 154))	('SCID', 'Disease', (52, 56))	('knockdown', 'Var', (178, 187))	('DHA', 'Chemical', 'MESH:D004281', (197, 200))	('SCID', 'Disease', 'MESH:D053632', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
127760	25691459	Thus, omega-3 PUFA may represent a non-toxic therapeutic agent for treatment of human cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (86, 104))	('PUFA', 'Gene', '9933', (14, 18))	('PUFA', 'Gene', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('human', 'Species', '9606', (80, 85))	('omega-3', 'Var', (6, 13))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (86, 104))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (86, 104))	('omega-3', 'Chemical', 'MESH:D015525', (6, 13))
127762	25691459	Our previous study has shown that omega-3 PUFAs inhibit cholangiocarcinoma cell growth in part through inhibition of Wnt/beta-catenin and COX-2 signaling pathways.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (56, 74))	('COX-2', 'Gene', '5743', (138, 143))	('cholangiocarcinoma', 'Disease', (56, 74))	('beta-catenin', 'Gene', (121, 133))	('inhibit', 'NegReg', (48, 55))	('beta-catenin', 'Gene', '1499', (121, 133))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (56, 74))	('omega-3 PUFAs', 'Chemical', '-', (34, 47))	('COX-2', 'Gene', (138, 143))	('omega-3', 'Var', (34, 41))	('inhibition', 'NegReg', (103, 113))
127770	25691459	Since the cardiovascular side effect associated with COX-2 inhibitors is largely due to inhibition of the antithrombotic prostacyclin (PGI2), induction or reaction of 15-PGDH is expected to block CCA growth without inhibiting PGI2 and thus incurring no significant side effect.	('15-PGDH', 'Var', (167, 174))	('cardiovascular', 'Disease', (10, 24))	('prostacyclin', 'Chemical', 'MESH:D011464', (121, 133))	('CCA', 'Phenotype', 'HP:0030153', (196, 199))	('inhibition', 'NegReg', (88, 98))	('COX-2', 'Gene', (53, 58))	('block', 'NegReg', (190, 195))	('COX-2', 'Gene', '5743', (53, 58))	('PGI2', 'Chemical', 'MESH:D011464', (135, 139))	('CCA', 'Disease', (196, 199))	('PGI2', 'Chemical', 'MESH:D011464', (226, 230))
127773	25691459	Direct targeting of 15-PGDH by miR26a/b was demonstrated by the observations that miR26a/b inhibits 15-PGDH 3'UTR luciferase reporter activity and that miR26a/b overexpression prevents omega-3 PUFA-induced 15-PGDH protein accumulation.	('miR26a/b', 'Var', (82, 90))	('15-PGDH protein', 'Protein', (206, 221))	('15-PGDH', 'MPA', (100, 107))	('PUFA', 'Gene', '9933', (193, 197))	('miR26a/b', 'Var', (152, 160))	('inhibits', 'NegReg', (91, 99))	('omega-3', 'Chemical', 'MESH:D015525', (185, 192))	('PUFA', 'Gene', (193, 197))	('prevents', 'NegReg', (176, 184))
127774	25691459	We noted that knockdown of 15-PGDH did not reverse cholangiocarcinoma growth as potently as miR26a overexpression; this aspect may be explained by the facts that miR26s enhance Wnt/beta-catenin signaling via inhibiting GSK-3beta and that GSK-3beta is another target of omega-3 PUFA.	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (51, 76))	('omega-3', 'Chemical', 'MESH:D015525', (269, 276))	('PUFA', 'Gene', (277, 281))	('GSK-3beta', 'Gene', '2932', (219, 228))	('miR26s', 'Chemical', '-', (162, 168))	('beta-catenin', 'Gene', '1499', (181, 193))	('GSK-3beta', 'Gene', '2932', (238, 247))	('GSK-3beta', 'Gene', (238, 247))	('miR26s', 'Var', (162, 168))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (51, 69))	('enhance', 'PosReg', (169, 176))	('PUFA', 'Gene', '9933', (277, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('inhibiting', 'NegReg', (208, 218))	('beta-catenin', 'Gene', (181, 193))	('GSK-3beta', 'Gene', (219, 228))	('cholangiocarcinoma growth', 'Disease', (51, 76))
127794	23200007	Oncological opinion supports the use of palliative chemotherapy, with the recently published ABC-02 study reporting that cisplatin plus gemcitabine, compared with gemcitabine alone, was associated with a significant survival advantage (11.7 vs 8.1 months, p<0.001) without the addition of substantial toxicity.	('toxicity', 'Disease', 'MESH:D064420', (301, 309))	('toxicity', 'Disease', (301, 309))	('ABC', 'Gene', (93, 96))	('survival advantage', 'CPA', (216, 234))	('cisplatin', 'Chemical', 'MESH:D002945', (121, 130))	('gemcitabine', 'Chemical', 'MESH:C056507', (163, 174))	('ABC', 'Gene', '10058', (93, 96))	('gemcitabine', 'Chemical', 'MESH:C056507', (136, 147))	('cisplatin', 'Var', (121, 130))
127798	23200007	PDT has been used for palliation in patients with unresectable cholangiocarcinoma, with small single-centre studies reporting an improvement in cholestasis, quality of life and survival of patients treated with stenting plus PDT compared with historical controls treated with stenting alone.	('survival', 'CPA', (177, 185))	('unresectable', 'Disease', (50, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('cholestasis', 'Disease', 'MESH:D002779', (144, 155))	('patients', 'Species', '9606', (36, 44))	('cholangiocarcinoma', 'Disease', (63, 81))	('cholestasis', 'Disease', (144, 155))	('quality of life', 'CPA', (157, 172))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (63, 81))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (63, 81))	('improvement', 'PosReg', (129, 140))	('patients', 'Species', '9606', (189, 197))	('PDT', 'Var', (225, 228))	('cholestasis', 'Phenotype', 'HP:0001396', (144, 155))
127870	23200007	In a randomised study of 32 patients with unresectable cholangiocarcinoma (histologically proven in 63%) using Photosan-3 (a haematoporphyrin derivative), the median survival time after randomisation was 21 months for the PDT group compared with 7 months for the control group.	('PDT', 'Var', (222, 225))	('Photosan-3', 'Chemical', 'MESH:C071875', (111, 121))	('cholangiocarcinoma', 'Disease', (55, 73))	('haematoporphyrin', 'Chemical', 'MESH:D006415', (125, 141))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (55, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('patients', 'Species', '9606', (28, 36))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (55, 73))
127878	23200007	The preliminary results indicate that patients with biliary tract cancer who received PDT plus stenting actually had a poorer overall survival than those who had stenting alone, which was only partly explained by fewer PDT plus stenting patients receiving subsequent palliative chemotherapy.	('poorer', 'NegReg', (119, 125))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (52, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('PDT', 'Var', (86, 89))	('biliary tract cancer', 'Disease', 'MESH:D001661', (52, 72))	('patients', 'Species', '9606', (38, 46))	('overall survival', 'MPA', (126, 142))	('patients', 'Species', '9606', (237, 245))	('biliary tract cancer', 'Disease', (52, 72))
127962	15064556	Recurrent pyogenic cholangitis is characterized by decreased branching and abrupt tapering ("arrowhead" appearance) of the peripheral hepatic ducts as a result of stenosis of the peripheral ducts.	('pyogenic cholangitis', 'Disease', (10, 30))	('stenosis', 'Var', (163, 171))	('decreased', 'NegReg', (51, 60))	('pyogenic cholangitis', 'Disease', 'MESH:D002761', (10, 30))	('tapering', 'CPA', (82, 90))	('branching', 'MPA', (61, 70))	('cholangitis', 'Phenotype', 'HP:0030151', (19, 30))
127974	31109923	Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio1347.	('FGFR2', 'Gene', (143, 148))	('Debio1347', 'Chemical', 'MESH:C000602562', (194, 203))	('FGFR2', 'Gene', '2263', (143, 148))	('mutations', 'Var', (149, 158))	('resistance', 'MPA', (170, 180))	('BGJ398', 'Chemical', 'MESH:C568950', (184, 190))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('TAS-120', 'Chemical', '-', (107, 114))	('tumor', 'Disease', (44, 49))	('patient', 'Species', '9606', (67, 74))
127982	31109923	The resulting chimeric FGFR2 proteins are constitutively active and promote proliferation or transformation of several cell types.	('rat', 'Species', '10116', (83, 86))	('promote', 'PosReg', (68, 75))	('proteins', 'Protein', (29, 37))	('FGFR2', 'Gene', (23, 28))	('proliferation', 'CPA', (76, 89))	('transformation of several cell types', 'CPA', (93, 129))	('FGFR2', 'Gene', '2263', (23, 28))	('chimeric', 'Var', (14, 22))
127983	31109923	The frequency of FGFR2 fusions in ICC is considerably higher than that reported for any other malignancy (data retrieved from http://www.cbioportal.org).	('FGFR2', 'Gene', (17, 22))	('FGFR2', 'Gene', '2263', (17, 22))	('malignancy', 'Disease', 'MESH:D009369', (94, 104))	('fusions', 'Var', (23, 30))	('malignancy', 'Disease', (94, 104))	('ICC', 'Disease', (34, 37))
127984	31109923	Activating FGFR2 point mutations and amplification or overexpression of FGFR1-3 are also observed in subsets of patients with ICC.	('Activating', 'PosReg', (0, 10))	('FGFR2', 'Gene', '2263', (11, 16))	('overexpression', 'PosReg', (54, 68))	('amplification', 'Var', (37, 50))	('patients', 'Species', '9606', (112, 120))	('point mutations', 'Var', (17, 32))	('FGFR1-3', 'Gene', (72, 79))	('ICC', 'Disease', (126, 129))	('FGFR1-3', 'Gene', '2260;2263;2261', (72, 79))	('FGFR2', 'Gene', (11, 16))
127988	31109923	The most clinically advanced FGFR-selective compound in cholangiocarcinoma is the ATP-competitive FGFR1-3 inhibitor, BGJ398 (infigratinib), which demonstrated efficacy in a phase II trial of patients with advanced refractory cholangiocarcinoma harboring FGFR fusions, amplifications, or point mutations.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (56, 74))	('point mutations', 'Var', (287, 302))	('patients', 'Species', '9606', (191, 199))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (225, 243))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (225, 243))	('ATP', 'Chemical', 'MESH:D000255', (82, 85))	('FGFR', 'Gene', (254, 258))	('cholangiocarcinoma', 'Disease', (56, 74))	('amplifications', 'Var', (268, 282))	('BGJ398', 'Chemical', 'MESH:C568950', (117, 123))	('fusions', 'Var', (259, 266))	('FGFR1-3', 'Gene', '2260;2263;2261', (98, 105))	('rat', 'Species', '10116', (153, 156))	('FGFR1-3', 'Gene', (98, 105))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (56, 74))	('rat', 'Species', '10116', (130, 133))	('infigratinib', 'Chemical', 'MESH:C568950', (125, 137))	('cholangiocarcinoma', 'Disease', (225, 243))
127992	31109923	We recently reported genomic characterization of pre- and post-progression cell-free circulating tumor DNA (ctDNA) and tumor biopsies in three patients with FGFR2 fusion-positive ICCs treated with BGJ398; this study revealed the emergence of the FGFR2 V565F gatekeeper mutation at progression in all three patients, two of whom also had additional FGFR2 kinase domain mutations.	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('FGFR2', 'Gene', (348, 353))	('V565F', 'Var', (252, 257))	('FGFR2', 'Gene', (246, 251))	('V565F', 'SUBSTITUTION', 'None', (252, 257))	('tumor', 'Disease', (97, 102))	('patients', 'Species', '9606', (143, 151))	('BGJ398', 'Chemical', 'MESH:C568950', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('FGFR2', 'Gene', (157, 162))	('gatekeeper', 'Species', '111938', (258, 268))	('FGFR2', 'Gene', '2263', (348, 353))	('FGFR2', 'Gene', '2263', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('FGFR2', 'Gene', '2263', (157, 162))	('patients', 'Species', '9606', (306, 314))
127993	31109923	Rapid autopsy in one patient revealed three different FGFR2 kinase domain mutations in spatially distinct metastases, highlighting the additional challenge of inter-lesional heterogeneity in addressing acquired resistance to an ATP-competitive FGFR inhibitor in ICC.	('metastases', 'Disease', 'MESH:D009362', (106, 116))	('patient', 'Species', '9606', (21, 28))	('mutations', 'Var', (74, 83))	('FGFR2', 'Gene', (54, 59))	('FGFR2', 'Gene', '2263', (54, 59))	('ATP', 'Chemical', 'MESH:D000255', (228, 231))	('metastases', 'Disease', (106, 116))
127996	31109923	Preliminary results from a phase I basket study of TAS-120 in patients with refractory advanced solid tumors showed an ORR of 25.0% and a DCR of 78.6% in 28 patients with ICC harboring FGFR2 fusions, including some patients who had received prior therapy with an ATP-competitive FGFR inhibitor.	('ATP', 'Chemical', 'MESH:D000255', (263, 266))	('patients', 'Species', '9606', (215, 223))	('fusions', 'Var', (191, 198))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('patients', 'Species', '9606', (157, 165))	('FGFR2', 'Gene', '2263', (185, 190))	('TAS-120', 'Chemical', '-', (51, 58))	('DCR', 'Chemical', '-', (138, 141))	('patients', 'Species', '9606', (62, 70))	('FGFR2', 'Gene', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
127997	31109923	Here, we report the results of clinical and translational studies of TAS-120 in the treatment of patients with FGFR2 fusion-positive ICC who progressed on BGJ398 or Debio1347, including patients in whom secondary FGFR2 kinase mutations were detected just prior to TAS-120 initiation.	('BGJ398', 'Var', (155, 161))	('FGFR2', 'Gene', (111, 116))	('ICC', 'Disease', (133, 136))	('FGFR2', 'Gene', '2263', (213, 218))	('BGJ398', 'Chemical', 'MESH:C568950', (155, 161))	('Debio1347', 'Var', (165, 174))	('FGFR2', 'Gene', '2263', (111, 116))	('Debio1347', 'Chemical', 'MESH:C000602562', (165, 174))	('TAS-120', 'Chemical', '-', (264, 271))	('TAS-120', 'Chemical', '-', (69, 76))	('fusion-positive', 'Reg', (117, 132))	('progressed', 'PosReg', (141, 151))	('FGFR2', 'Gene', (213, 218))	('patients', 'Species', '9606', (186, 194))	('patients', 'Species', '9606', (97, 105))
128002	31109923	The patients' clinical characteristics and FGFR2 gene alterations are summarized in Table 1A and 1B.	('rat', 'Species', '10116', (58, 61))	('FGFR2', 'Gene', '2263', (43, 48))	('FGFR2', 'Gene', (43, 48))	('patients', 'Species', '9606', (4, 12))	('alterations', 'Var', (54, 65))
128003	31109923	No additional cancer-relevant genomic alterations were detected in the pre-treatment biopsies, with the exception of copy number increases of the FGFR1 and MYC loci in the biopsy from patient #3 (see Methods for specific genotyping assays used for the different samples).	('cancer', 'Disease', (14, 20))	('MYC', 'Gene', '4609', (156, 159))	('patient', 'Species', '9606', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('MYC', 'Gene', (156, 159))	('increases', 'PosReg', (129, 138))	('FGFR1', 'Gene', (146, 151))	('copy number', 'Var', (117, 128))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('rat', 'Species', '10116', (42, 45))	('FGFR1', 'Gene', '2260', (146, 151))
128006	31109923	ctDNA analysis at that time revealed two new FGFR2 kinase domain mutations, K660M and K715R (Figure 1B) (amino acids are numbered according to FGFR2-IIIb splice isoform [NM_001144913.1] since FGFR2 fusions in ICC are expressed in this context; the equivalent mutations in the one amino acid shorter IIIc isoform are K659M and K714R).	('FGFR2', 'Gene', (143, 148))	('FGFR2', 'Gene', '2263', (143, 148))	('K714R', 'Var', (326, 331))	('FGFR2', 'Gene', (45, 50))	('FGFR2', 'Gene', '2263', (45, 50))	('K715R', 'Chemical', '-', (86, 91))	('K659M', 'Var', (316, 321))	('K659M', 'SUBSTITUTION', 'None', (316, 321))	('FGFR2', 'Gene', '2263', (192, 197))	('K660M', 'Var', (76, 81))	('K660M', 'SUBSTITUTION', 'None', (76, 81))	('K714R', 'SUBSTITUTION', 'None', (326, 331))	('K715R', 'Var', (86, 91))	('FGFR2', 'Gene', (192, 197))
128008	31109923	The patient subsequently received TAS-120, which resulted in a maximum response of -77% and suppression of K660M and K715R below the level of detection in ctDNA.	('K715R', 'Chemical', '-', (117, 122))	('patient', 'Species', '9606', (4, 11))	('K660M', 'SUBSTITUTION', 'None', (107, 112))	('K660M', 'Var', (107, 112))	('TAS-120', 'Chemical', '-', (34, 41))	('suppression', 'NegReg', (92, 103))	('K715R', 'Var', (117, 122))
128010	31109923	A third FGFR2 mutation, the gatekeeper V565F, emerged in the ctDNA during the final months of TAS-120 treatment and was detected in a post-progression tumor biopsy.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('V565F', 'SUBSTITUTION', 'None', (39, 44))	('V565F', 'Var', (39, 44))	('tumor', 'Disease', (151, 156))	('FGFR2', 'Gene', (8, 13))	('FGFR2', 'Gene', '2263', (8, 13))	('TAS-120', 'Chemical', '-', (94, 101))	('gatekeeper', 'Species', '111938', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
128014	31109923	ctDNA analysis at that time revealed five mutations in the FGFR2 kinase domain (N550H, N550K, V565F, E566A, and K660M).	('N550K', 'SUBSTITUTION', 'None', (87, 92))	('K660M', 'Var', (112, 117))	('FGFR2', 'Gene', (59, 64))	('V565F', 'Var', (94, 99))	('V565F', 'SUBSTITUTION', 'None', (94, 99))	('FGFR2', 'Gene', '2263', (59, 64))	('E566A', 'Var', (101, 106))	('K660M', 'SUBSTITUTION', 'None', (112, 117))	('E566A', 'Chemical', '-', (101, 106))	('N550K', 'Var', (87, 92))	('N550H', 'SUBSTITUTION', 'None', (80, 85))	('N550H', 'Var', (80, 85))
128015	31109923	Two of these mutations were observed in a tumor biopsy of a progressing satellite liver lesion obtained in parallel : V565F and K660M, as previously reported (amino acid numbering is updated here to reflect expression of the FGFR2-IIIb splice isoform [NM_001144913.1]).	('tumor', 'Disease', (42, 47))	('V565F', 'SUBSTITUTION', 'None', (118, 123))	('V565F', 'Var', (118, 123))	('K660M', 'SUBSTITUTION', 'None', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('satellite liver lesion obtained', 'Disease', (72, 103))	('FGFR2', 'Gene', (225, 230))	('FGFR2', 'Gene', '2263', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('K660M', 'Var', (128, 133))	('satellite liver lesion obtained', 'Disease', 'MESH:D017093', (72, 103))
128018	31109923	While the spatial location of each mutation was unknown, this heterogeneous response to TAS-120 was reflected in ctDNA analysis where levels of some mutations (N550H, K660M) dropped below the level of detection before eventually rebounding at the time of disease progression, and others stabilized (N550K, E566A) or increased (V565F) during therapy (Figure 1C).	('V565F', 'Var', (327, 332))	('N550K', 'SUBSTITUTION', 'None', (299, 304))	('K660M', 'Var', (167, 172))	('TAS-120', 'Chemical', '-', (88, 95))	('N550H', 'Var', (160, 165))	('increased', 'PosReg', (316, 325))	('E566A', 'Var', (306, 311))	('dropped', 'NegReg', (174, 181))	('K660M', 'SUBSTITUTION', 'None', (167, 172))	('E566A', 'Chemical', '-', (306, 311))	('N550H', 'SUBSTITUTION', 'None', (160, 165))	('N550K', 'Var', (299, 304))	('V565F', 'SUBSTITUTION', 'None', (327, 332))
128019	31109923	A sixth FGFR2 mutation (V563L) emerged in ctDNA during TAS-120 therapy and was detected in a biopsy obtained upon disease progression.	('V563L', 'SUBSTITUTION', 'None', (24, 29))	('FGFR2', 'Gene', (8, 13))	('V563L', 'Var', (24, 29))	('FGFR2', 'Gene', '2263', (8, 13))	('TAS-120', 'Chemical', '-', (55, 62))
128022	31109923	He then had two post-progression liver biopsies obtained 2.5 months apart on distinct liver lesions with intervening cytotoxic chemotherapy : the first revealed an FGFR2 H683L mutation (CCF=0.23) and the second revealed three FGFR2 mutations (N550H, CCF=0.093; N550T, CCF=0.108; and M538I, CCF=0.19).	('N550H', 'SUBSTITUTION', 'None', (243, 248))	('N550T', 'Var', (261, 266))	('FGFR2', 'Gene', '2263', (226, 231))	('N550H', 'Var', (243, 248))	('liver lesions', 'Disease', 'MESH:D017093', (86, 99))	('H683L', 'Chemical', '-', (170, 175))	('M538I', 'SUBSTITUTION', 'None', (283, 288))	('H683L', 'Var', (170, 175))	('FGFR2', 'Gene', '2263', (164, 169))	('liver lesions', 'Disease', (86, 99))	('FGFR2', 'Gene', (226, 231))	('N550T', 'SUBSTITUTION', 'None', (261, 266))	('M538I', 'Var', (283, 288))	('FGFR2', 'Gene', (164, 169))
128023	31109923	TAS-120 treatment was initiated immediately after this second biopsy, and ctDNA analysis of plasma collected at this baseline timepoint revealed one of these five mutations (H683L) and one additional mutation (L618V).	('H683L', 'Var', (174, 179))	('H683L', 'Chemical', '-', (174, 179))	('TAS-120', 'Chemical', '-', (0, 7))	('L618V', 'SUBSTITUTION', 'None', (210, 215))	('L618V', 'Var', (210, 215))
128025	31109923	ctDNA analysis during treatment showed a modest decline of L618V and H683L levels (Figure 1D).	('L618V', 'SUBSTITUTION', 'None', (59, 64))	('decline', 'NegReg', (48, 55))	('L618V', 'Var', (59, 64))	('H683L', 'Chemical', '-', (69, 74))	('H683L levels', 'MPA', (69, 81))
128026	31109923	As the tumor progressed, ctDNA analysis revealed the gradual emergence of mutations seen on baseline biopsy (N550H, N550T, M538I) and other previously undetectable mutations (V565L, E566A).	('E566A', 'Var', (182, 187))	('E566A', 'Chemical', '-', (182, 187))	('tumor', 'Disease', (7, 12))	('N550H', 'Var', (109, 114))	('N550T', 'SUBSTITUTION', 'None', (116, 121))	('M538I', 'Var', (123, 128))	('V565L', 'Var', (175, 180))	('V565L', 'SUBSTITUTION', 'None', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('M538I', 'SUBSTITUTION', 'None', (123, 128))	('N550T', 'Var', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('N550H', 'SUBSTITUTION', 'None', (109, 114))
128034	31109923	The patient eventually experienced growth of a single liver lesion at 17.2 months, and at that time, analysis of ctDNA and tumor biopsy demonstrated the emergence of FGFR2 N550K (Table 1B).	('tumor', 'Disease', (123, 128))	('liver lesion', 'Disease', (54, 66))	('FGFR2', 'Gene', (166, 171))	('FGFR2', 'Gene', '2263', (166, 171))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('rat', 'Species', '10116', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('single liver', 'Phenotype', 'HP:0100839', (47, 59))	('N550K', 'Var', (172, 177))	('growth', 'MPA', (35, 41))	('N550K', 'SUBSTITUTION', 'None', (172, 177))	('liver lesion', 'Disease', 'MESH:D017093', (54, 66))
128036	31109923	Importantly, in this setting, TAS-120 demonstrated marked clinical benefit, highlighting the critical dependence of these tumors on sustained FGFR signaling and pointing to the importance of these FGFR2 kinase domain mutations as a common mechanism of clinical acquired resistance to FGFR inhibition.	('tumors', 'Disease', (122, 128))	('TAS-120', 'Chemical', '-', (30, 37))	('domain mutations', 'Var', (210, 226))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('FGFR2', 'Gene', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('FGFR2', 'Gene', '2263', (197, 202))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('rat', 'Species', '10116', (45, 48))
128037	31109923	Collectively, the assessment of clonal dynamics in ctDNA suggests that TAS-120 has differential activity against individual FGFR2 secondary mutations compared to ATP-competitive FGFR inhibitors.	('TAS-120', 'Chemical', '-', (71, 78))	('FGFR2', 'Gene', (124, 129))	('FGFR2', 'Gene', '2263', (124, 129))	('mutations', 'Var', (140, 149))	('ATP', 'Chemical', 'MESH:D000255', (162, 165))
128038	31109923	Understanding the spectrum of activity of various FGFR inhibitors against commonly observed acquired FGFR2 mutations may lead to strategies to overcome or delay resistance.	('FGFR2', 'Gene', (101, 106))	('FGFR2', 'Gene', '2263', (101, 106))	('rat', 'Species', '10116', (131, 134))	('mutations', 'Var', (107, 116))
128043	31109923	Genomic analysis revealed that ICC13-7 cells harbored an FGFR2-OPTN fusion (Supplemental Figure S1B), whereas all other cell lines lacked FGFR fusions.	('fusion', 'Var', (68, 74))	('OPTN', 'Gene', '10133', (63, 67))	('OPTN', 'Gene', (63, 67))	('FGFR2', 'Gene', '2263', (57, 62))	('FGFR2', 'Gene', (57, 62))
128044	31109923	Moreover, while CCLP-1 cells lacked fusions, intragenic mutations, or copy number gains of FGFR genes, they showed greatly increased expression of wild type FGFR1 (IIIc isoform) as well as the FGF20 ligand compared to the other cell lines analyzed (Supplementary Figure S1C-E).	('FGF20', 'Gene', '26281', (193, 198))	('increased', 'PosReg', (123, 132))	('expression', 'MPA', (133, 143))	('FGFR1', 'Gene', (157, 162))	('FGF20', 'Gene', (193, 198))	('FGFR1', 'Gene', '2260', (157, 162))	('FGFR genes', 'Gene', (91, 101))	('copy number gains', 'Var', (70, 87))	('CCLP-1', 'Gene', (16, 22))	('lacked', 'NegReg', (29, 35))	('CCLP-1', 'Gene', '8495', (16, 22))
128045	31109923	Thus, biliary tract cancer cell lines with activating molecular alterations in the pathway are specifically dependent on FGFR signaling for growth in vitro.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (6, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('rat', 'Species', '10116', (68, 71))	('alterations', 'Var', (64, 75))	('cancer', 'Disease', (20, 26))	('activating', 'PosReg', (43, 53))
128047	31109923	BGJ398 treatment (50 nM) led to rapid inhibition of the MEK/ERK pathway as reflected by decreased pFRS2 (Y196), pSHP2 (Y542), pMEK1/2 (S217/221), and pERK1/2 (T202/Y204), whereas minimal effects were observed on the PI3K pathway, as determined by pAKT (T308 and S473) (Figure 2C, D).	('BGJ398', 'Chemical', 'MESH:C568950', (0, 6))	('MEK', 'Gene', (127, 130))	('MEK1/2', 'Gene', (127, 133))	('Y542', 'Var', (119, 123))	('ERK', 'Gene', (60, 63))	('SHP2', 'Gene', (113, 117))	('inhibition', 'NegReg', (38, 48))	('MEK', 'Gene', (56, 59))	('decreased', 'NegReg', (88, 97))	('FRS2', 'Gene', (99, 103))	('AKT', 'Gene', '207', (248, 251))	('Y196', 'Var', (105, 109))	('ERK', 'Gene', '5594', (151, 154))	('ERK1/2', 'Gene', (151, 157))	('S473', 'Var', (262, 266))	('ERK1/2', 'Gene', '5595;5594', (151, 157))	('FRS2', 'Gene', '10818', (99, 103))	('ERK', 'Gene', (151, 154))	('pERK', 'Gene', '9451', (150, 154))	('AKT', 'Gene', (248, 251))	('pERK', 'Gene', (150, 154))	('MEK', 'Gene', '5609', (127, 130))	('BGJ398', 'Gene', (0, 6))	('ERK', 'Gene', '5594', (60, 63))	('S217/221', 'Var', (135, 143))	('SHP2', 'Gene', '5781', (113, 117))	('MEK', 'Gene', '5609', (56, 59))	('MEK1/2', 'Gene', '5604;5605', (127, 133))
128051	31109923	To corroborate these results in vivo, we screened a collection of patient-derived xenograft (PDX) models of ICC for FGFR alterations, and identified a model harboring a FGFR2-KIAA1217 fusion (designated MG69) (Supplemental Figure S1G).	('rat', 'Species', '10116', (125, 128))	('alterations', 'Var', (121, 132))	('KIAA1217', 'Gene', (175, 183))	('KIAA1217', 'Gene', '56243', (175, 183))	('FGFR', 'Gene', (116, 120))	('patient', 'Species', '9606', (66, 73))	('FGFR2', 'Gene', (169, 174))	('FGFR2', 'Gene', '2263', (169, 174))	('rat', 'Species', '10116', (10, 13))
128053	31109923	Moreover, FGFR inhibition suppressed MEK/ERK and SHP2 activity, but not PI3K signaling, in MG69 PDX tumors (Figure 2G).	('inhibition suppressed', 'NegReg', (15, 36))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('SHP2', 'Gene', '5781', (49, 53))	('SHP2', 'Gene', (49, 53))	('FGFR', 'Gene', (10, 14))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('activity', 'MPA', (54, 62))	('MG69', 'Var', (91, 95))	('ERK', 'Gene', '5594', (41, 44))	('MEK', 'Gene', (37, 40))	('ERK', 'Gene', (41, 44))	('MEK', 'Gene', '5609', (37, 40))
128055	31109923	To gain insight into the clinical landscape of secondary FGFR2 resistance mutations, we subsequently leveraged our FGFR-driven ICC cell line models to study the spectrum of FGFR2 kinase domain mutations emerging upon clinical acquired resistance to BGJ398 (N550K, V565F, E566A, K660M, and K715R) or Debio1347 (M538I, H683L), or to both (N550H, L618V).	('FGFR2', 'Gene', '2263', (173, 178))	('H683L', 'Var', (317, 322))	('K715R', 'Chemical', '-', (289, 294))	('V565F', 'Var', (264, 269))	('N550H', 'Var', (337, 342))	('N550K', 'Var', (257, 262))	('M538I', 'SUBSTITUTION', 'None', (310, 315))	('K660M', 'SUBSTITUTION', 'None', (278, 283))	('V565F', 'SUBSTITUTION', 'None', (264, 269))	('FGFR2', 'Gene', (57, 62))	('N550K', 'SUBSTITUTION', 'None', (257, 262))	('Debio1347', 'Chemical', 'MESH:C000602562', (299, 308))	('M538I', 'Var', (310, 315))	('E566A', 'Chemical', '-', (271, 276))	('K660M', 'Var', (278, 283))	('L618V', 'SUBSTITUTION', 'None', (344, 349))	('FGFR2', 'Gene', '2263', (57, 62))	('BGJ398', 'Chemical', 'MESH:C568950', (249, 255))	('L618V', 'Var', (344, 349))	('K715R', 'Var', (289, 294))	('E566A', 'Var', (271, 276))	('N550H', 'SUBSTITUTION', 'None', (337, 342))	('FGFR2', 'Gene', (173, 178))	('H683L', 'Chemical', '-', (317, 322))
128056	31109923	We engineered these mutations into a retroviral vector expressing the FGFR2-PHGDH fusion, which we observed in an ICC (see Methods).	('FGFR2', 'Gene', '2263', (70, 75))	('FGFR2', 'Gene', (70, 75))	('PHGDH', 'Gene', '26227', (76, 81))	('PHGDH', 'Gene', (76, 81))	('mutations', 'Var', (20, 29))
128057	31109923	CCLP-1 cells were infected with retroviruses expressing the FGFR2-PHGDH fusion with a wild type or mutant FGFR2 kinase domain or empty vector control.	('CCLP-1', 'Gene', (0, 6))	('PHGDH', 'Gene', '26227', (66, 71))	('FGFR2', 'Gene', '2263', (106, 111))	('infected', 'Disease', 'MESH:D007239', (18, 26))	('CCLP-1', 'Gene', '8495', (0, 6))	('infected', 'Disease', (18, 26))	('FGFR2', 'Gene', (60, 65))	('FGFR2', 'Gene', '2263', (60, 65))	('mutant', 'Var', (99, 105))	('FGFR2', 'Gene', (106, 111))	('PHGDH', 'Gene', (66, 71))
128058	31109923	Of the mutations that arose in patients treated with BGJ398, N550K, L618V, and K660M resulted in prominent resistance to the drug in vitro (25- to 39-fold increase in IC50), with the V565F gatekeeper conferring the greatest level of resistance (326-fold) (Figure 3A, top panel; Supplementary Figures S2A and B show immunoblots for expression of the FGFR2 fusions and crystal violet staining of cells at a single drug concentration).	('V565F', 'SUBSTITUTION', 'None', (183, 188))	('V565F', 'Var', (183, 188))	('increase', 'PosReg', (155, 163))	('FGFR2', 'Gene', '2263', (349, 354))	('L618V', 'SUBSTITUTION', 'None', (68, 73))	('L618V', 'Var', (68, 73))	('K660M', 'SUBSTITUTION', 'None', (79, 84))	('rat', 'Species', '10116', (424, 427))	('N550K', 'Var', (61, 66))	('K660M', 'Var', (79, 84))	('resistance to the drug', 'MPA', (107, 129))	('N550K', 'SUBSTITUTION', 'None', (61, 66))	('patients', 'Species', '9606', (31, 39))	('BGJ398', 'Chemical', 'MESH:C568950', (53, 59))	('crystal violet', 'Chemical', 'MESH:D005840', (367, 381))	('FGFR2', 'Gene', (349, 354))	('gatekeeper', 'Species', '111938', (189, 199))	('BGJ398', 'Gene', (53, 59))
128059	31109923	The N550H and E566A mutants caused weaker effects (7- to 8-fold) and K715R did not affect BGJ398 sensitivity.	('N550H', 'SUBSTITUTION', 'None', (4, 9))	('E566A', 'Chemical', '-', (14, 19))	('BGJ398', 'Chemical', 'MESH:C568950', (90, 96))	('K715R', 'Chemical', '-', (69, 74))	('N550H', 'Var', (4, 9))	('K715R', 'Var', (69, 74))	('E566A', 'Var', (14, 19))
128061	31109923	Finally, BGJ398 remained effective against the M538I and H683L mutations (3- to 4-fold increase in IC50), which were found in the setting of clinical resistance to Debio1347 treatment and have not been observed clinically upon BGJ398 therapy.	('BGJ398', 'Chemical', 'MESH:C568950', (227, 233))	('H683L', 'Chemical', '-', (57, 62))	('M538I', 'Var', (47, 52))	('increase', 'PosReg', (87, 95))	('BGJ398', 'Chemical', 'MESH:C568950', (9, 15))	('Debio1347', 'Chemical', 'MESH:C000602562', (164, 173))	('M538I', 'SUBSTITUTION', 'None', (47, 52))	('H683L', 'Var', (57, 62))
128063	31109923	The magnitude of resistance provoked by the different mutants was lower than that observed for BGJ398, although this drug is considerably less potent against FGFR signaling overall.	('BGJ398', 'Chemical', 'MESH:C568950', (95, 101))	('mutants', 'Var', (54, 61))	('lower', 'NegReg', (66, 71))	('resistance', 'MPA', (17, 27))
128064	31109923	The most pronounced resistance to Debio1347 was seen with the N550K, L618V, and K660M mutations (12- to 17-fold increase in IC50), while M538I, N550H, and E566A produced intermediate effects (4- to 8-fold), H683L had a modest effect, and K715R did not significantly affect responsiveness to the drug.	('N550K', 'SUBSTITUTION', 'None', (62, 67))	('K660M', 'SUBSTITUTION', 'None', (80, 85))	('N550H', 'SUBSTITUTION', 'None', (144, 149))	('H683L', 'Chemical', '-', (207, 212))	('E566A', 'Var', (155, 160))	('E566A', 'Chemical', '-', (155, 160))	('M538I', 'Var', (137, 142))	('L618V', 'Var', (69, 74))	('N550H', 'Var', (144, 149))	('L618V', 'SUBSTITUTION', 'None', (69, 74))	('increase', 'PosReg', (112, 120))	('Debio1347', 'Chemical', 'MESH:C000602562', (34, 43))	('K715R', 'Chemical', '-', (238, 243))	('K660M', 'Var', (80, 85))	('N550K', 'Var', (62, 67))	('M538I', 'SUBSTITUTION', 'None', (137, 142))
128066	31109923	Notably, TAS-120 showed only minimal or modest changes in activity against each of the acquired FGFR2 mutations (2- to 7-fold IC50 increase) with the exception of V565F (103-fold) (Figure 3A, bottom panel).	('V565F', 'Var', (163, 168))	('IC50', 'MPA', (126, 130))	('FGFR2', 'Gene', (96, 101))	('FGFR2', 'Gene', '2263', (96, 101))	('increase', 'PosReg', (131, 139))	('TAS-120', 'Chemical', '-', (9, 16))	('V565F', 'SUBSTITUTION', 'None', (163, 168))
128067	31109923	To extend these findings, we modeled clonal outgrowth during acquired resistance using a pooled clone system, in which all nine mutant clones were pooled at an initial abundance of 1% amidst a background of cells expressing the WT FGFR2 fusion (Figure 3B and Supplementary Figure S2C).	('FGFR2', 'Gene', '2263', (231, 236))	('FGFR2', 'Gene', (231, 236))	('mutant', 'Var', (128, 134))
128070	31109923	Notably, treatment with 50 nM BGJ398 led to outgrowth of the resistance mutations observed in patients 1 and 2 (N550H, N550K, V565F, E566A, K660M) or previously observed in the setting of BGJ398 resistance (e.g.	('BGJ398', 'Gene', (30, 36))	('patients', 'Species', '9606', (94, 102))	('N550H', 'Var', (112, 117))	('K660M', 'Var', (140, 145))	('K660M', 'SUBSTITUTION', 'None', (140, 145))	('E566A', 'Var', (133, 138))	('V565F', 'SUBSTITUTION', 'None', (126, 131))	('V565F', 'Var', (126, 131))	('N550K', 'Var', (119, 124))	('outgrowth', 'PosReg', (44, 53))	('E566A', 'Chemical', '-', (133, 138))	('N550K', 'SUBSTITUTION', 'None', (119, 124))	('N550H', 'SUBSTITUTION', 'None', (112, 117))	('BGJ398', 'Chemical', 'MESH:C568950', (30, 36))	('BGJ398', 'Chemical', 'MESH:C568950', (188, 194))
128072	31109923	BGJ398 prevented the outgrowth of M538I detected only in Patient 3 who was treated with Debio1347.	('BGJ398', 'Chemical', 'MESH:C568950', (0, 6))	('Debio1347', 'Chemical', 'MESH:C000602562', (88, 97))	('BGJ398', 'Gene', (0, 6))	('M538I', 'Var', (34, 39))	('Patient', 'Species', '9606', (57, 64))	('outgrowth', 'CPA', (21, 30))	('M538I', 'SUBSTITUTION', 'None', (34, 39))
128073	31109923	Conversely, outgrowth of each of these mutations was observed upon treatment with 200 nM Debio1347, with the exception of V565F, consistent with the clinical course of Patient 3.	('outgrowth', 'PosReg', (12, 21))	('Debio1347', 'Gene', (89, 98))	('V565F', 'SUBSTITUTION', 'None', (122, 127))	('V565F', 'Var', (122, 127))	('Debio1347', 'Chemical', 'MESH:C000602562', (89, 98))	('Patient', 'Species', '9606', (168, 175))
128074	31109923	Finally, in the presence of 10 nM TAS-120 only outgrowth of V565F, and to a lesser extent, E566A, and N550K, were observed.	('V565F', 'SUBSTITUTION', 'None', (60, 65))	('V565F', 'Var', (60, 65))	('TAS-120', 'Chemical', '-', (34, 41))	('N550K', 'Var', (102, 107))	('E566A', 'Var', (91, 96))	('N550K', 'SUBSTITUTION', 'None', (102, 107))	('E566A', 'Chemical', '-', (91, 96))
128076	31109923	Interestingly, higher concentrations of BGJ398 or TAS-120 were able to suppress outgrowth of all resistance mutations with the exception of V565F, highlighting the potential importance of drug exposure in suppressing resistant clones.	('BGJ398', 'Gene', (40, 46))	('TAS-120', 'Chemical', '-', (50, 57))	('outgrowth', 'CPA', (80, 89))	('rat', 'Species', '10116', (29, 32))	('V565F', 'SUBSTITUTION', 'None', (140, 145))	('V565F', 'Var', (140, 145))	('suppress', 'NegReg', (71, 79))	('BGJ398', 'Chemical', 'MESH:C568950', (40, 46))	('TAS-120', 'Gene', (50, 57))
128078	31109923	Three of the mutations (K660M, N550H, and L618V) that emerged during BGJ398 treatment decreased in abundance when treatment was switched to TAS-120, consistent with our ctDNA analyses showing that TAS-120 led to decreases in the clonal abundance in K660M (Patient 1 and 2), N550H (in Patient 2), and L618V (in Patient 3).	('Patient', 'Species', '9606', (310, 317))	('L618V', 'SUBSTITUTION', 'None', (300, 305))	('L618V', 'Var', (300, 305))	('BGJ398', 'Gene', (69, 75))	('Patient', 'Species', '9606', (284, 291))	('TAS-120', 'Chemical', '-', (197, 204))	('K660M', 'Var', (249, 254))	('BGJ398', 'Chemical', 'MESH:C568950', (69, 75))	('N550H', 'Var', (274, 279))	('K660M', 'SUBSTITUTION', 'None', (24, 29))	('abundance', 'MPA', (99, 108))	('clonal abundance', 'MPA', (229, 245))	('L618V', 'SUBSTITUTION', 'None', (42, 47))	('K660M', 'Var', (24, 29))	('L618V', 'Var', (42, 47))	('TAS-120', 'Chemical', '-', (140, 147))	('N550H', 'SUBSTITUTION', 'None', (31, 36))	('Patient', 'Species', '9606', (256, 263))	('decreased', 'NegReg', (86, 95))	('N550H', 'Var', (31, 36))	('N550H', 'SUBSTITUTION', 'None', (274, 279))	('K660M', 'SUBSTITUTION', 'None', (249, 254))	('decreases', 'NegReg', (212, 221))
128079	31109923	Conversely, V565F continued to increase and E566A and N550K levels stabilized, but failed to decrease upon TAS-120 treatment, similar to the clinical observations in ctDNA from Patient 2.	('V565F', 'SUBSTITUTION', 'None', (12, 17))	('V565F', 'Var', (12, 17))	('Patient', 'Species', '9606', (177, 184))	('N550K', 'Var', (54, 59))	('N550K', 'SUBSTITUTION', 'None', (54, 59))	('E566A', 'Var', (44, 49))	('TAS-120', 'Chemical', '-', (107, 114))	('E566A', 'Chemical', '-', (44, 49))	('increase', 'PosReg', (31, 39))
128082	31109923	CCLP-1 cells expressing N550K, V565F, L618V, and K660M retained robust levels of pFRS2, pSHP2, pMEK, and pERK upon treatment with 50 nM BGJ398, whereas signaling by the other mutants was inhibited partially (N550H, E566A) or strongly (H683L) (Figure 3D and Supplemental Figure S2A).	('CCLP-1', 'Gene', (0, 6))	('L618V', 'SUBSTITUTION', 'None', (38, 43))	('L618V', 'Var', (38, 43))	('N550H', 'SUBSTITUTION', 'None', (208, 213))	('pERK', 'Gene', '9451', (105, 109))	('pERK', 'Gene', (105, 109))	('FRS2', 'Gene', (82, 86))	('SHP2', 'Gene', '5781', (89, 93))	('H683L', 'Chemical', '-', (235, 240))	('inhibited', 'NegReg', (187, 196))	('K660M', 'SUBSTITUTION', 'None', (49, 54))	('N550K', 'Var', (24, 29))	('SHP2', 'Gene', (89, 93))	('BGJ398', 'Gene', (136, 142))	('N550H', 'Var', (208, 213))	('FRS2', 'Gene', '10818', (82, 86))	('CCLP-1', 'Gene', '8495', (0, 6))	('MEK', 'Gene', '5609', (96, 99))	('E566A', 'Chemical', '-', (215, 220))	('K660M', 'Var', (49, 54))	('BGJ398', 'Chemical', 'MESH:C568950', (136, 142))	('N550K', 'SUBSTITUTION', 'None', (24, 29))	('V565F', 'Var', (31, 36))	('MEK', 'Gene', (96, 99))	('E566A', 'Var', (215, 220))	('V565F', 'SUBSTITUTION', 'None', (31, 36))
128083	31109923	Treatment with TAS-120 (50 nM) effectively suppressed signaling by all mutants except V565F.	('signaling', 'MPA', (54, 63))	('V565F', 'SUBSTITUTION', 'None', (86, 91))	('V565F', 'Var', (86, 91))	('suppressed', 'NegReg', (43, 53))	('TAS-120', 'Chemical', '-', (15, 22))
128084	31109923	Finally, Debio1347 (200 nM) showed reduced potency against most of the mutants but remained relatively active against the V565F gatekeeper mutation compared to the other two inhibitors.	('Debio1347', 'Chemical', 'MESH:C000602562', (9, 18))	('gatekeeper', 'Species', '111938', (128, 138))	('reduced', 'NegReg', (35, 42))	('potency', 'MPA', (43, 50))	('V565F', 'SUBSTITUTION', 'None', (122, 127))	('V565F', 'Var', (122, 127))
128085	31109923	All three inhibitors were effective against K715R.	('K715R', 'Var', (44, 49))	('effective', 'Reg', (26, 35))	('K715R', 'Chemical', '-', (44, 49))
128086	31109923	We confirmed our findings for a subset of the FGFR2 mutants in ICC13-7 cells via cell viability assays and immunoblot for signaling proteins (Supplemental Figure S2D-F).	('FGFR2', 'Gene', '2263', (46, 51))	('FGFR2', 'Gene', (46, 51))	('mutants', 'Var', (52, 59))
128087	31109923	Thus, we demonstrate in relevant in vitro ICC models that TAS-120 has activity against multiple secondary FGFR2 resistance mutations, which likely accounts for the benefit of TAS-120 seen in patients who previously progressed on BGJ398 or Debio1347.	('patients', 'Species', '9606', (191, 199))	('Debio1347', 'Chemical', 'MESH:C000602562', (239, 248))	('activity', 'MPA', (70, 78))	('TAS-120', 'Chemical', '-', (58, 65))	('rat', 'Species', '10116', (16, 19))	('FGFR2', 'Gene', '2263', (106, 111))	('TAS-120', 'Chemical', '-', (175, 182))	('BGJ398', 'Chemical', 'MESH:C568950', (229, 235))	('FGFR2', 'Gene', (106, 111))	('mutations', 'Var', (123, 132))
128090	31109923	Accordingly, modeling data indicate that TAS-120 and BGJ398 resistance to V565F is due to steric clash preventing access of these drugs into the ATP-binding pocket.	('V565F', 'SUBSTITUTION', 'None', (74, 79))	('V565F', 'Var', (74, 79))	('TAS-120', 'Chemical', '-', (41, 48))	('ATP', 'Chemical', 'MESH:D000255', (145, 148))	('access', 'MPA', (114, 120))	('BGJ398', 'Chemical', 'MESH:C568950', (53, 59))	('BGJ398', 'Gene', (53, 59))	('preventing', 'NegReg', (103, 113))
128091	31109923	TAS-120 remains effective against V565I, likely due to less severe hindrance caused by the smaller isoleucine side chain.	('isoleucine side chain', 'MPA', (99, 120))	('V565I', 'SUBSTITUTION', 'None', (34, 39))	('TAS-120', 'Chemical', '-', (0, 7))	('isoleucine', 'Chemical', 'MESH:D007532', (99, 109))	('V565I', 'Var', (34, 39))
128092	31109923	Debio1347 lacks the bulky dimethoxy phenyl group, and rather possesses a benzimidazole moiety predicted to have stabilizing contacts with V565F, which may account for its relative potency against FGFR2 V565F.	('FGFR2', 'Gene', (196, 201))	('V565F', 'Var', (138, 143))	('FGFR2', 'Gene', '2263', (196, 201))	('V565F', 'SUBSTITUTION', 'None', (138, 143))	('lacks', 'NegReg', (10, 15))	('contacts', 'Interaction', (124, 132))	('rat', 'Species', '10116', (54, 57))	('Debio1347', 'Chemical', 'MESH:C000602562', (0, 9))	('benzimidazole', 'Chemical', 'MESH:C031000', (73, 86))	('V565F', 'SUBSTITUTION', 'None', (202, 207))	('V565F', 'Var', (202, 207))	('stabilizing', 'MPA', (112, 123))
128093	31109923	Notably, TAS-120 retained activity against several mutations that confer BGJ398 and Debio1347 resistance by altering conformational dynamics of FGFR2 rather than directly interacting with mutated residues.	('Debio1347', 'Gene', (84, 93))	('FGFR2', 'Gene', '2263', (144, 149))	('mutations', 'Var', (51, 60))	('Debio1347', 'Chemical', 'MESH:C000602562', (84, 93))	('TAS-120', 'Chemical', '-', (9, 16))	('altering', 'Reg', (108, 116))	('rat', 'Species', '10116', (150, 153))	('BGJ398', 'Chemical', 'MESH:C568950', (73, 79))	('BGJ398', 'Gene', (73, 79))	('conformational dynamics', 'MPA', (117, 140))	('activity', 'MPA', (26, 34))	('FGFR2', 'Gene', (144, 149))
128094	31109923	In particular, N550H/K and E566A stabilize the active conformation of the kinase by disrupting a network of hydrogen bonds that serve as an autoinhibitory molecular break, K660M forces the A loop of the kinase into an active conformation, and L618V disrupts stabilizing interactions between this residue and an Asp-Phe-Gly (DFG) motif that otherwise favors binding of BGJ398 and Debio1347.	('active conformation', 'MPA', (47, 66))	('Asp-Phe-Gly', 'Chemical', 'MESH:C553185', (311, 322))	('K660M', 'Var', (172, 177))	('hydrogen', 'Chemical', 'MESH:D006859', (108, 116))	('stabilize', 'Reg', (33, 42))	('E566A', 'Chemical', '-', (27, 32))	('BGJ398', 'Gene', (368, 374))	('favors', 'PosReg', (350, 356))	('N550H', 'SUBSTITUTION', 'None', (15, 20))	('stabilizing interactions', 'MPA', (258, 282))	('Debio1347', 'Chemical', 'MESH:C000602562', (379, 388))	('disrupting', 'NegReg', (84, 94))	('E566A', 'Var', (27, 32))	('DFG', 'Chemical', '-', (324, 327))	('network of hydrogen bonds', 'MPA', (97, 122))	('L618V', 'SUBSTITUTION', 'None', (243, 248))	('BGJ398', 'Chemical', 'MESH:C568950', (368, 374))	('L618V', 'Var', (243, 248))	('disrupts', 'NegReg', (249, 257))	('N550H', 'Var', (15, 20))	('binding', 'Interaction', (357, 364))	('A loop', 'MPA', (189, 195))	('K660M', 'SUBSTITUTION', 'None', (172, 177))
128095	31109923	Thus, BGJ398 and Debio1347 appear not to act on the active kinase conformation, whereas the covalent binding mode of TAS-120 may permit effective target engagement irrespective of conformation, as observed for the irreversible pan-FGFR inhibitor, FIIN-2.	('BGJ398', 'Chemical', 'MESH:C568950', (6, 12))	('BGJ398', 'Gene', (6, 12))	('TAS-120', 'Gene', (117, 124))	('Debio1347', 'Chemical', 'MESH:C000602562', (17, 26))	('Debio1347', 'Var', (17, 26))	('TAS-120', 'Chemical', '-', (117, 124))	('permit', 'Reg', (129, 135))
128096	31109923	Finally, the specific impairment of Debio1347 activity versus FGFR2 M538I may relate to interactions with the adjacent M539 residue that contribute to the binding of this drug.	('FGFR2', 'Gene', (62, 67))	('M538I', 'SUBSTITUTION', 'None', (68, 73))	('FGFR2', 'Gene', '2263', (62, 67))	('binding', 'Interaction', (155, 162))	('Debio1347', 'Chemical', 'MESH:C000602562', (36, 45))	('M538I', 'Var', (68, 73))	('Debio1347 activity', 'MPA', (36, 54))	('interactions', 'Interaction', (88, 100))
128099	31109923	We also find that the spectrum of secondary FGFR2 resistance mutations differs across agents and that structural studies of these agents bound to FGFR provide a molecular basis for these differences.	('FGFR2', 'Gene', (44, 49))	('FGFR2', 'Gene', '2263', (44, 49))	('mutations', 'Var', (61, 70))
128102	31109923	The efficacy seen across several early phase clinical trials of FGFR2 inhibitors in patients with advanced refractory ICC represents a breakthrough in a disease with no FDA-approved targeted therapies to date.	('advanced refractory ICC', 'Disease', (98, 121))	('FGFR2', 'Gene', '2263', (64, 69))	('patients', 'Species', '9606', (84, 92))	('inhibitors', 'Var', (70, 80))	('FGFR2', 'Gene', (64, 69))
128104	31109923	TAS-120 was designed to overcome FGFR kinase domain mutations, taking advantage of the improved potency and specificity afforded by its covalent binding mode and distinct orientation in the ATP-binding pocket of FGFRs.	('ATP', 'Chemical', 'MESH:D000255', (190, 193))	('improved', 'PosReg', (87, 95))	('binding', 'Interaction', (145, 152))	('TAS-120', 'Chemical', '-', (0, 7))	('potency', 'MPA', (96, 103))	('FGFR', 'Gene', (33, 37))	('domain mutations', 'Var', (45, 61))
128106	31109923	Covalent small molecule kinase inhibitors have demonstrated success in multiple malignancies and have gained FDA approval in EGFR mutant non-small cell lung cancer (afatinib, osimertinib), ERBB2/HER2 mutant breast cancer (neratinib), and BTK mutant chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, and mantle cell lymphoma (ibrutinib).	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (257, 277))	('lymphoma', 'Phenotype', 'HP:0002665', (328, 336))	("Waldenstrom's macroglobulinemia", 'Disease', 'MESH:D008258', (279, 310))	("Waldenstrom's macroglobulinemia", 'Disease', (279, 310))	('ibrutinib', 'Chemical', 'MESH:C551803', (338, 347))	('mutant', 'Var', (200, 206))	('cell lymphoma', 'Phenotype', 'HP:0012191', (323, 336))	('mutant', 'Var', (130, 136))	('HER2', 'Gene', (195, 199))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (249, 277))	('BTK', 'Gene', (238, 241))	('BTK', 'Gene', '695', (238, 241))	('afatinib', 'Chemical', 'MESH:D000077716', (165, 173))	('EGFR', 'Gene', '1956', (125, 129))	('lung cancer', 'Disease', 'MESH:D008175', (152, 163))	('rat', 'Species', '10116', (54, 57))	('leukemia', 'Phenotype', 'HP:0001909', (269, 277))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('ERBB2', 'Gene', (189, 194))	('malignancies', 'Disease', 'MESH:D009369', (80, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('lymphocytic leukemia', 'Disease', (257, 277))	('malignancies', 'Disease', (80, 92))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (316, 336))	("Waldenstrom's macroglobulinemia", 'Phenotype', 'HP:0005508', (279, 310))	('mantle cell lymphoma', 'Disease', (316, 336))	('ERBB2', 'Gene', '2064', (189, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('HER2', 'Gene', '2064', (195, 199))	('osimertinib', 'Chemical', 'MESH:C000596361', (175, 186))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('neratinib', 'Chemical', 'MESH:C487932', (222, 231))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (137, 163))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (141, 163))	('EGFR', 'Gene', (125, 129))	('breast cancer', 'Disease', 'MESH:D001943', (207, 220))	('mutant', 'Var', (242, 248))	('rat', 'Species', '10116', (224, 227))	('breast cancer', 'Disease', (207, 220))	('lung cancer', 'Disease', (152, 163))
128108	31109923	The inhibitors exhibit unique in vitro profiles, and the key findings included: a) the mutations that conferred greatest resistance to BGJ398 were N550K, V565F, L618V, and K660M; b) the mutations that conferred greatest resistance to Debio1347 were N550K, L618V, and K660M, c) Debio1347 largely retained activity against the V565F gatekeeper mutation; and d) TAS-120 remained active against all mutations except V565F, with modest reduction in activity against E566A and N550K.	('N550K', 'Var', (249, 254))	('V565F', 'Var', (154, 159))	('K660M', 'Var', (172, 177))	('N550K', 'Var', (147, 152))	('N550K', 'Var', (471, 476))	('N550K', 'SUBSTITUTION', 'None', (249, 254))	('Debio1347', 'Chemical', 'MESH:C000602562', (277, 286))	('gatekeeper', 'Species', '111938', (331, 341))	('V565F', 'SUBSTITUTION', 'None', (154, 159))	('N550K', 'SUBSTITUTION', 'None', (147, 152))	('N550K', 'SUBSTITUTION', 'None', (471, 476))	('L618V', 'SUBSTITUTION', 'None', (161, 166))	('L618V', 'Var', (161, 166))	('E566A', 'Chemical', '-', (461, 466))	('V565F', 'Var', (325, 330))	('Debio1347', 'Chemical', 'MESH:C000602562', (234, 243))	('BGJ398', 'Gene', (135, 141))	('V565F', 'Var', (412, 417))	('K660M', 'SUBSTITUTION', 'None', (267, 272))	('L618V', 'SUBSTITUTION', 'None', (256, 261))	('L618V', 'Var', (256, 261))	('E566A', 'Var', (461, 466))	('BGJ398', 'Chemical', 'MESH:C568950', (135, 141))	('Debio1347', 'Gene', (234, 243))	('V565F', 'SUBSTITUTION', 'None', (325, 330))	('K660M', 'SUBSTITUTION', 'None', (172, 177))	('activity', 'MPA', (304, 312))	('V565F', 'SUBSTITUTION', 'None', (412, 417))	('TAS-120', 'Chemical', '-', (359, 366))	('K660M', 'Var', (267, 272))
128110	31109923	Moreover, it will be important to establish the extent to which pre-existing FGFR2 mutations impact time to treatment failure, as observed in EGFR mutant non-small-cell lung cancer.	('mutant', 'Var', (147, 153))	('mutations', 'Var', (83, 92))	('lung cancer', 'Disease', 'MESH:D008175', (169, 180))	('FGFR2', 'Gene', '2263', (77, 82))	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('FGFR2', 'Gene', (77, 82))	('lung cancer', 'Disease', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('impact', 'Reg', (93, 99))	('time', 'MPA', (100, 104))
128112	31109923	ddPCR analysis of ctDNA showed that the mutation allele frequencies for several FGFR2 mutations decreased upon TAS-120 treatment : K660M in patient 1, N550H and K660M in patient 2, and L618V and H683L in patient 3 : pointing to the activity of TAS-120 against these alleles in the clinic.	('K660M', 'SUBSTITUTION', 'None', (161, 166))	('K660M', 'Var', (131, 136))	('TAS-120', 'Chemical', '-', (111, 118))	('K660M', 'Var', (161, 166))	('decreased', 'NegReg', (96, 105))	('H683L', 'Chemical', '-', (195, 200))	('TAS-120', 'Chemical', '-', (244, 251))	('mutations', 'Var', (86, 95))	('L618V', 'SUBSTITUTION', 'None', (185, 190))	('L618V', 'Var', (185, 190))	('N550H', 'SUBSTITUTION', 'None', (151, 156))	('H683L', 'Var', (195, 200))	('FGFR2', 'Gene', (80, 85))	('patient', 'Species', '9606', (204, 211))	('FGFR2', 'Gene', '2263', (80, 85))	('patient', 'Species', '9606', (140, 147))	('N550H', 'Var', (151, 156))	('K660M', 'SUBSTITUTION', 'None', (131, 136))	('patient', 'Species', '9606', (170, 177))
128113	31109923	Similarly, the sustained increase or emergence of V565F upon TAS-120 in patients 1-3 is consistent with the in vitro resistance studies, as was the lack of reduction in levels of E566A and N550K.	('V565F', 'SUBSTITUTION', 'None', (50, 55))	('V565F', 'Var', (50, 55))	('TAS-120', 'Chemical', '-', (61, 68))	('N550K', 'Var', (189, 194))	('N550K', 'SUBSTITUTION', 'None', (189, 194))	('E566A', 'Var', (179, 184))	('E566A', 'Chemical', '-', (179, 184))	('patients', 'Species', '9606', (72, 80))
128114	31109923	These data, if validated prospectively in larger clinical cohorts, may provide support for a new paradigm in which particular FGFR resistance mutations, detected in serial ctDNA or tumor biopsies, could inform the choice of subsequent FGFR targeted therapies.	('mutations', 'Var', (142, 151))	('tumor', 'Disease', (181, 186))	('FGFR', 'Gene', (126, 130))	('inform', 'Reg', (203, 209))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
128115	31109923	The precedent for this is emerging in advanced ALK fusion positive NSCLC where specific ALK kinase domain mutations that arise at the time of crizotinib resistance determine which second-generation inhibitor should be used for next line treatment.	('crizotinib', 'Chemical', 'MESH:D000077547', (142, 152))	('ALK', 'Gene', (88, 91))	('rat', 'Species', '10116', (191, 194))	('ALK', 'Gene', (47, 50))	('mutations', 'Var', (106, 115))	('ALK', 'Gene', '238', (88, 91))	('ALK', 'Gene', '238', (47, 50))
128116	31109923	To guide such strategies in ICC, it will be important to also establish the full spectrum of mechanisms of resistance to TAS-120, including validating the functional impact of V563L, which emerged upon progression on TAS-120 treatment in patient 2.	('V563L', 'SUBSTITUTION', 'None', (176, 181))	('rat', 'Species', '10116', (16, 19))	('TAS-120', 'Chemical', '-', (217, 224))	('TAS-120', 'Chemical', '-', (121, 128))	('patient', 'Species', '9606', (238, 245))	('ICC', 'Disease', (28, 31))	('V563L', 'Var', (176, 181))
128124	31109923	In patient 3, the three FGFR2 mutations identified in the baseline TAS-120 liver biopsy sample went undetected by both targeted sequencing and ddPCR in the corresponding plasma sample, possibly reflecting low tumor shedding and emphasizing the complementary benefits of tumor biopsy and ctDNA analysis.	('FGFR2', 'Gene', '2263', (24, 29))	('low tumor', 'Disease', 'MESH:D009800', (205, 214))	('patient', 'Species', '9606', (3, 10))	('TAS-120', 'Chemical', '-', (67, 74))	('mutations', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('emphasizing the complementary benefits of tumor', 'Disease', 'MESH:D009369', (228, 275))	('low tumor', 'Disease', (205, 214))	('emphasizing the complementary benefits of tumor', 'Disease', (228, 275))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('FGFR2', 'Gene', (24, 29))
128125	31109923	In patient 1, two FGFR2 kinase domain mutations arose at the time of progression on BGJ398 but only one conferred resistance in functional modeling, underscoring the importance of functionally validating putative resistance mutations discovered on ctDNA or tumor tissue analysis.	('FGFR2', 'Gene', '2263', (18, 23))	('FGFR2', 'Gene', (18, 23))	('tumor', 'Disease', (257, 262))	('patient', 'Species', '9606', (3, 10))	('BGJ398', 'Chemical', 'MESH:C568950', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('mutations', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))
128130	31109923	The data are consistent with SHP2/MEK/ERK activation being the principle effector of FGFR in normal physiology and with the frequent presence of concurrent PIK3CA activating mutations with FGFR2 fusions in ICC indicating the potential independence of these pathways.	('FGFR2', 'Gene', '2263', (189, 194))	('PIK3CA', 'Gene', '5290', (156, 162))	('MEK', 'Gene', (34, 37))	('MEK', 'Gene', '5609', (34, 37))	('SHP2', 'Gene', '5781', (29, 33))	('SHP2', 'Gene', (29, 33))	('activating', 'PosReg', (163, 173))	('mutations', 'Var', (174, 183))	('fusions', 'Var', (195, 202))	('ERK', 'Gene', '5594', (38, 41))	('PIK3CA', 'Gene', (156, 162))	('ERK', 'Gene', (38, 41))	('FGFR2', 'Gene', (189, 194))
128131	31109923	While our studies suggested that FGFR2 fusions with different partners had comparable outputs, further studies will be required to fully address the potential differential impact of N-terminus partners on oncoprotein localization, inhibitor sensitivity, and downstream signaling targets, as reported for fusions involving the ROS1 RTK.	('ROS1', 'Gene', (326, 330))	('ROS1', 'Gene', '6098', (326, 330))	('fusions', 'Var', (39, 46))	('FGFR2', 'Gene', '2263', (33, 38))	('FGFR2', 'Gene', (33, 38))
128146	31109923	We report FGFR2 kinase domain mutations as the amino acid number of the FGFR2-IIIb splice isoform [NM_001144913.1], which is the primary isoform expressed in FGFR2 fusion-positive ICC, Commercial genotyping tests (e.g.	('FGFR2', 'Gene', '2263', (158, 163))	('FGFR2', 'Gene', '2263', (10, 15))	('FGFR2', 'Gene', (72, 77))	('FGFR2', 'Gene', '2263', (72, 77))	('mutations', 'Var', (30, 39))	('FGFR2', 'Gene', (10, 15))	('FGFR2', 'Gene', (158, 163))
128147	31109923	Guardant) and our prior report designate mutations using the one amino acid shorter FGFR2-IIIc isoform (NM_000141.4) as the reference sequence.	('mutations', 'Var', (41, 50))	('FGFR2', 'Gene', (84, 89))	('FGFR2', 'Gene', '2263', (84, 89))
128153	31109923	The SFA is a targeted RNA-sequencing method of Anchored Multiplex PCR to detect FGFR2 fusions, and the methodology has been previously described.	('fusions', 'Var', (86, 93))	('FGFR2', 'Gene', (80, 85))	('FGFR2', 'Gene', '2263', (80, 85))
128157	31109923	The ddPCR data were analyzed with QuantaSoft analysis software (Bio-Rad) to obtain Fractional Abundance of the mutant DNA alleles in the wild-type/normal background.	('DNA', 'Gene', (118, 121))	('mutant', 'Var', (111, 117))	('Rad', 'Gene', (68, 71))	('Rad', 'Gene', '6236', (68, 71))
128170	31109923	All FGFR2 mutations were introduced into the pMSCV vector using the same kit.	('FGFR2', 'Gene', '2263', (4, 9))	('mutations', 'Var', (10, 19))	('FGFR2', 'Gene', (4, 9))
128205	31109923	The ddPCR data were analyzed with QuantaSoft analysis software (Bio-Rad) to obtain fractional abundance of the mutant DNA alleles in the wild-type (WT)/normal background.	('DNA', 'Gene', (118, 121))	('mutant', 'Var', (111, 117))	('Rad', 'Gene', (68, 71))	('Rad', 'Gene', '6236', (68, 71))
128209	31109923	The loop structure (V488-V496) was modeled so that the S atom of C492 and the terminal carbon of acrylamide in TAS-120 made a covalent bond using the Molecular Operating Environment (MOE) from Chemical Computing Group (https://www.chemcomp.com/).	('rat', 'Species', '10116', (163, 166))	('covalent', 'MPA', (126, 134))	('C492', 'Var', (65, 69))	('acrylamide', 'Chemical', 'MESH:D020106', (97, 107))	('carbon', 'Chemical', 'MESH:D002244', (87, 93))	('TAS-120', 'Chemical', '-', (111, 118))	('made', 'Reg', (119, 123))
128211	31109923	We demonstrate that the irreversible FGFR inhibitor TAS-120 provides clinical benefit in patients with resistance to BGJ398 or Debio1347 and overcomes several FGFR2 mutations in ICC models.	('FGFR2', 'Gene', (159, 164))	('BGJ398', 'Chemical', 'MESH:C568950', (117, 123))	('FGFR2', 'Gene', '2263', (159, 164))	('patients', 'Species', '9606', (89, 97))	('ICC', 'Disease', (178, 181))	('Debio1347', 'Chemical', 'MESH:C000602562', (127, 136))	('mutations', 'Var', (165, 174))	('rat', 'Species', '10116', (10, 13))	('TAS-120', 'Chemical', '-', (52, 59))
128262	27896655	After transecting the right hepatic artery and portal vein, the left hepatic artery (and middle hepatic artery) and portal vein and left hepatic artery are skeletonized to the right side of the umbilical plate.	('middle hepatic artery', 'Disease', 'MESH:D020244', (89, 110))	('transecting', 'Var', (6, 17))	('middle hepatic artery', 'Disease', (89, 110))
128265	27896655	During right hepatectomy, there are also two (or three) bile duct orifices at the transected plate: the internal sectional bile duct (B4) and external sectional bile duct (B2 + B3) (or independently B4, B2, B3).	('B2 + B3', 'Var', (172, 179))	('B2, B3', 'Gene', (203, 209))	('B2, B3)', 'Gene', '28907;680', (203, 210))
128274	27896655	In the TNM staging system by the UICC (7th edition), pT stage was identified in pT1 in one patient (4.3%), pT2a in four patients (17.4%), pT2b in six patients (26.1%), pT3 in 10 patients (43.5%), and pT4 in two patients (8.7%).	('pT3', 'Gene', '7694', (168, 171))	('patient', 'Species', '9606', (150, 157))	('patients', 'Species', '9606', (211, 219))	('pT1', 'Gene', '58492', (80, 83))	('patient', 'Species', '9606', (178, 185))	('patient', 'Species', '9606', (120, 127))	('patients', 'Species', '9606', (178, 186))	('pT3', 'Gene', (168, 171))	('patients', 'Species', '9606', (150, 158))	('pT1', 'Gene', (80, 83))	('patients', 'Species', '9606', (120, 128))	('pT2b', 'Var', (138, 142))	('patient', 'Species', '9606', (91, 98))	('patient', 'Species', '9606', (211, 218))
128376	24944999	However, the enhancement pattern of hemangioma on Gd-EOB-DTPA-enhanced MRI is different from that on dynamic CT and MRI with extracellular contrast media, such as iodine and Gd-DTPA.	('Gd-EOB-DTPA', 'Chemical', '-', (50, 61))	('hemangioma', 'Phenotype', 'HP:0001028', (36, 46))	('hemangioma', 'Disease', (36, 46))	('iodine', 'Chemical', 'MESH:D007455', (163, 169))	('Gd-DTPA', 'Chemical', 'MESH:D019786', (174, 181))	('hemangioma', 'Disease', 'MESH:D006391', (36, 46))	('enhancement', 'PosReg', (13, 24))	('Gd-EOB-DTPA-enhanced', 'Var', (50, 70))	('men', 'Species', '9606', (20, 23))
128377	24944999	Washout of Gd-EOB-DTPA from the blood pool is much faster than that of iodine contrast media and Gd-DTPA.	('Gd-DTPA', 'Chemical', 'MESH:D019786', (97, 104))	('faster', 'PosReg', (51, 57))	('Washout', 'MPA', (0, 7))	('Gd-EOB-DTPA', 'Chemical', '-', (11, 22))	('iodine', 'Chemical', 'MESH:D007455', (71, 77))	('Gd-EOB-DTPA', 'Var', (11, 22))
128385	24944999	AP shunts usually exhibit iso-enhancement in hepatocyte-phase images on Gd-EOB-DTPA-enhanced MRI, indicating no decrease of Gd-EOB-DTPA uptake in the liver parenchyma.	('Gd-EOB-DTPA', 'Chemical', '-', (72, 83))	('liver parenchyma', 'Disease', (150, 166))	('hepatocyte-phase images', 'MPA', (45, 68))	('Gd-EOB-DTPA-enhanced', 'Var', (72, 92))	('men', 'Species', '9606', (37, 40))	('iso-enhancement', 'MPA', (26, 41))	('Gd-EOB-DTPA', 'Chemical', '-', (124, 135))	('liver parenchyma', 'Disease', 'MESH:D010195', (150, 166))
128408	24944999	Moreover, they take up SPIO and Gd-EOB-DTPA and commonly show iso- or hyperintensity in the hepatocyte phase of Gd-EOB-DTPA-enhanced MRI, in contrast to malignant liver tumors and hepatocellular adenoma, the majority of which demonstrate hypointensity.	('Gd-EOB-DTPA-enhanced', 'Var', (112, 132))	('liver tumor', 'Phenotype', 'HP:0002896', (163, 174))	('SPIO', 'Chemical', 'MESH:C065507', (23, 27))	('malignant liver tumors', 'Disease', (153, 175))	('Gd-EOB-DTPA', 'Chemical', '-', (32, 43))	('hepatocellular adenoma', 'Disease', (180, 202))	('Gd-EOB-DTPA', 'Chemical', '-', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('hepatocellular adenoma', 'Phenotype', 'HP:0012028', (180, 202))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('liver tumors', 'Phenotype', 'HP:0002896', (163, 175))	('malignant liver tumors', 'Disease', 'MESH:D009369', (153, 175))	('iso-', 'MPA', (62, 66))	('hepatocellular adenoma', 'Disease', 'MESH:D018248', (180, 202))
128433	24944999	It also shows hypointensity of the hepatocyte phase of Gd-EOB-DTPA-enhanced MRI; consequently, differentiating it from HCC may be difficult.	('Gd-EOB-DTPA-enhanced', 'Var', (55, 75))	('HCC', 'Gene', '619501', (119, 122))	('HCC', 'Phenotype', 'HP:0001402', (119, 122))	('Gd-EOB-DTPA', 'Chemical', '-', (55, 66))	('HCC', 'Gene', (119, 122))
128565	19445727	The positive staining for p-EKR1/2 and PI3-K were 63/108 (58.3%) and 55/108 (50.9%) in gallbladder adenocarcinoma; 14/46 (30.4%) and 5/46 (10.1%) in peri-tumor tissues; 3/15 (20%) and 3/15 (20%) in adenomatous polyps; and 4/35 (11.4%) and 3/35 (8.6%) in chronic cholecystitis.	('adenomatous polyps', 'Phenotype', 'HP:0005227', (198, 216))	('gallbladder adenocarcinoma', 'Disease', 'MESH:D005705', (87, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('chronic cholecystitis', 'Disease', (254, 275))	('PI3', 'Gene', '5266', (39, 42))	('adenomatous polyps', 'Disease', 'MESH:D018256', (198, 216))	('gallbladder adenocarcinoma', 'Disease', (87, 113))	('PI3', 'Gene', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('p-EKR1/2', 'Var', (26, 34))	('chronic cholecystitis', 'Disease', 'MESH:D002764', (254, 275))	('adenomatous polyps', 'Disease', (198, 216))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cholecystitis', 'Phenotype', 'HP:0001082', (262, 275))	('tumor', 'Disease', (154, 159))
128566	19445727	The positive rate of p-ERK1/2 or PI3-K in gallbladder adenocarcinoma was significantly higher than that in peri-tumor tissue (both, P < 0.01), adenomatous polyps (p-ERK1/2, P < 0.01; PI3-K, P < 0.05), and chronic cholecystitis (both, P < 0.01).	('adenomatous polyps', 'Disease', (143, 161))	('PI3', 'Gene', (183, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('gallbladder adenocarcinoma', 'Disease', (42, 68))	('PI3', 'Gene', (33, 36))	('p-ERK1/2', 'Var', (21, 29))	('chronic cholecystitis', 'Disease', (205, 226))	('PI3', 'Gene', '5266', (33, 36))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (143, 161))	('cholecystitis', 'Phenotype', 'HP:0001082', (213, 226))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PI3', 'Gene', '5266', (183, 186))	('tumor', 'Disease', (112, 117))	('adenomatous polyps', 'Disease', 'MESH:D018256', (143, 161))	('gallbladder adenocarcinoma', 'Disease', 'MESH:D005705', (42, 68))	('chronic cholecystitis', 'Disease', 'MESH:D002764', (205, 226))	('higher', 'PosReg', (87, 93))
128577	19445727	The development of cancer in man involves multiple genetic changes that often lead to dysfunction of certain signaling pathways controlling cell fate, cell growth, and cell survival or cell death.	('signaling pathways', 'Pathway', (109, 127))	('man', 'Species', '9606', (29, 32))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('lead to', 'Reg', (78, 85))	('cancer', 'Disease', (19, 25))	('dysfunction', 'MPA', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('changes', 'Var', (59, 66))
128584	19445727	Both EKR1/2 and AKT can be activated by a number of factors including EGFR, inflammation signals mediated by cytokine receptors, mutation of oncogenes such as Ras and Raf, and bile acids.	('inflammation', 'Disease', 'MESH:D007249', (76, 88))	('mutation', 'Var', (129, 137))	('inflammation', 'Disease', (76, 88))	('EGFR', 'Gene', '1956', (70, 74))	('bile acids', 'Chemical', 'MESH:D001647', (176, 186))	('EKR1/2 and AKT', 'Gene', '207', (5, 19))	('EGFR', 'Gene', (70, 74))	('activated', 'PosReg', (27, 36))
128625	19445727	58.3% and 50.9% of the specimens showed strong positive staining for p-ERK1/2 and PI3-K, respectively, indicating that both p-ERK1/2 and PI3-K/AKT might be potential biomarkers of gallbladder cancer.	('PI3', 'Gene', '5266', (137, 140))	('gallbladder cancer', 'Disease', (180, 198))	('PI3', 'Gene', '5266', (82, 85))	('gallbladder cancer', 'Disease', 'MESH:D005706', (180, 198))	('AKT', 'Gene', '207', (143, 146))	('PI3', 'Gene', (82, 85))	('p-ERK1/2', 'Var', (124, 132))	('PI3', 'Gene', (137, 140))	('AKT', 'Gene', (143, 146))	('p-ERK1/2', 'Gene', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
128626	19445727	Compared to benign lesions and peri-tumor tissues, positive staining for p-ERK1/2 and PI3-K in gallbladder adenocarcinoma was significantly higher.	('higher', 'PosReg', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('PI3', 'Gene', '5266', (86, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('gallbladder adenocarcinoma', 'Disease', 'MESH:D005705', (95, 121))	('p-ERK1/2', 'Var', (73, 81))	('PI3', 'Gene', (86, 89))	('tumor', 'Disease', (36, 41))	('gallbladder adenocarcinoma', 'Disease', (95, 121))
128628	19445727	Moreover, p-ERK1/2 and PI3-K staining was more frequently detected in gallbladder adenocarcinoma cases with larger tumor size, lymph node metastasis, and surrounding tissue invasion compared to cases with smaller tumor size, without metastasis or tissue invasion (Table 2).	('tumor', 'Disease', (213, 218))	('PI3', 'Gene', '5266', (23, 26))	('gallbladder adenocarcinoma', 'Disease', 'MESH:D005705', (70, 96))	('detected', 'Reg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('gallbladder adenocarcinoma', 'Disease', (70, 96))	('tumor', 'Disease', (115, 120))	('p-ERK1/2', 'Var', (10, 18))	('PI3', 'Gene', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('lymph node metastasis', 'CPA', (127, 148))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
128636	19445727	demonstrated that expression of p-AKT may be associated with improved survival.	('improved', 'PosReg', (61, 69))	('AKT', 'Gene', (34, 37))	('AKT', 'Gene', '207', (34, 37))	('survival', 'CPA', (70, 78))	('expression', 'Var', (18, 28))
128643	19445727	Mutations of oncogenes have also been identified in cholangiocarcinoma.	('identified', 'Reg', (38, 48))	('cholangiocarcinoma', 'Disease', (52, 70))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (52, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('Mutations', 'Var', (0, 9))	('oncogenes', 'Gene', (13, 22))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (52, 70))
128644	19445727	For example, K-Ras and B-Raf mutations were found in 22% and 45% of cholangiocarcinoma, respectively.	('B-Raf', 'Gene', '673', (23, 28))	('B-Raf', 'Gene', (23, 28))	('K-Ras', 'Gene', '3845', (13, 18))	('mutations', 'Var', (29, 38))	('found', 'Reg', (44, 49))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (68, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (68, 86))	('K-Ras', 'Gene', (13, 18))	('cholangiocarcinoma', 'Disease', (68, 86))
128651	19445727	Our study also indicates that there is a positive correlation between the frequency of p-ERK1/2 and PI3-K expression, suggesting a possible cross-talk of the two pathways in gallbladder adenocarcinoma.	('gallbladder adenocarcinoma', 'Disease', (174, 200))	('cross-talk', 'Reg', (140, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('PI3', 'Gene', '5266', (100, 103))	('p-ERK1/2', 'Var', (87, 95))	('PI3', 'Gene', (100, 103))	('gallbladder adenocarcinoma', 'Disease', 'MESH:D005705', (174, 200))
128678	32468022	However, these aforementioned promising targeted therapies were only viable for a relatively small percentage of patients with CCA with the specific IDH1 and FGFR mutations aforementioned.	('CCA', 'Phenotype', 'HP:0030153', (127, 130))	('mutations', 'Var', (163, 172))	('IDH1', 'Gene', (149, 153))	('patients', 'Species', '9606', (113, 121))	('FGFR', 'Gene', (158, 162))	('IDH1', 'Gene', '3417', (149, 153))	('CCA', 'Disease', (127, 130))
128685	32468022	It is hypothesized that CSCs survive following the initial stages of cancer therapy and thereby facilitate relapse and metastasis, where they are responsible for acquired resistance to conventional cancer treatment regimens, including radiation therapy and the more recently discovered immunotherapy.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('facilitate', 'PosReg', (96, 106))	('CSCs', 'Var', (24, 28))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
128692	32468022	The presence of CD133 along with other suspected CSC markers has also been associated with poorer overall survival in patients with CCA.	('CCA', 'Disease', (132, 135))	('patients', 'Species', '9606', (118, 126))	('CD133', 'Gene', (16, 21))	('CCA', 'Phenotype', 'HP:0030153', (132, 135))	('presence', 'Var', (4, 12))	('poorer', 'NegReg', (91, 97))	('overall', 'MPA', (98, 105))
128693	32468022	In a previous study of 29 patients with intrahepatic CCA who had undergone major hepatectomies, only 8% of CD133+ patients remained alive 5 years following surgery, compared with 57% among CD133- patients (P=0.02).	('patients', 'Species', '9606', (196, 204))	('patients', 'Species', '9606', (26, 34))	('CD133+', 'Var', (107, 113))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (40, 56))	('patients', 'Species', '9606', (114, 122))	('intrahepatic CCA', 'Disease', (40, 56))	('CCA', 'Phenotype', 'HP:0030153', (53, 56))
128697	32468022	In some carcinomas of epithelial origin, variant isoforms of CD44 have been implicated in tumor metastasis and invasion.	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('carcinomas', 'Disease', 'MESH:D009369', (8, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (8, 18))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('CD44', 'Gene', (61, 65))	('implicated', 'Reg', (76, 86))	('tumor metastasis', 'Disease', (90, 106))	('tumor metastasis', 'Disease', 'MESH:D009362', (90, 106))	('carcinomas', 'Disease', (8, 18))	('variant', 'Var', (41, 48))	('invasion', 'CPA', (111, 119))
128701	32468022	The CD44high/CD24low cell phenotype has been repeatedly utilized as a signature of CSCs in breast tumors, where they were demonstrated to be chemoresistant following chemotherapy.	('breast tumors', 'Phenotype', 'HP:0100013', (91, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('breast tumors', 'Disease', 'MESH:D001943', (91, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('breast tumors', 'Disease', (91, 104))	('CD44high/CD24low', 'Var', (4, 20))
128702	32468022	In CCA cell lines, a shift from CD44high/CD24high to CD44high/CD24low was observed in cells resistant to epidermal growth factor receptor inhibition.	('epidermal growth factor receptor', 'Gene', '1956', (105, 137))	('CD44high/CD24low', 'Var', (53, 69))	('CCA', 'Phenotype', 'HP:0030153', (3, 6))	('CD44high/CD24high', 'Var', (32, 49))	('epidermal growth factor receptor', 'Gene', (105, 137))
128703	32468022	By contrast, pharmacological depletion of ROS scavengers resulted in increased sensitivity to radiotherapy and depleted clonogenicity in the CD24+CD90+-enriched cell population, suggesting that the CD24+CD90+ combination may be responsible for mediating resistance to radiation in CSCs.	('depletion', 'Var', (29, 38))	('CD90', 'Gene', (203, 207))	('increased', 'PosReg', (69, 78))	('CD90', 'Gene', '7070', (146, 150))	('clonogenicity', 'CPA', (120, 133))	('CD90', 'Gene', (146, 150))	('ROS', 'Chemical', 'MESH:D017382', (42, 45))	('sensitivity to radiotherapy', 'MPA', (79, 106))	('depleted', 'NegReg', (111, 119))	('CD90', 'Gene', '7070', (203, 207))
128706	32468022	Wnt signaling was previously demonstrated to be simultaneously decreased in colon cancer cells following EpCAM knockdown.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('knockdown', 'Var', (111, 120))	('colon cancer', 'Disease', 'MESH:D015179', (76, 88))	('Wnt signaling', 'MPA', (0, 13))	('colon cancer', 'Disease', (76, 88))	('decreased', 'NegReg', (63, 72))	('EpCAM', 'Gene', (105, 110))	('colon cancer', 'Phenotype', 'HP:0003003', (76, 88))
128708	32468022	In accordance with in vitro studies of the individual tumorigenic potential of CSC markers, CD44+CD24+EpCAM+ cells isolated from extrahepatic CCA xenografts in immuno-compromised mouse exhibited higher tumorigenicity compared with those of the CD44-CD24-EpCAM- phenotype.	('mouse', 'Species', '10090', (179, 184))	('tumor', 'Disease', (202, 207))	('higher', 'PosReg', (195, 201))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('CD44+CD24+EpCAM+', 'Var', (92, 108))	('CCA', 'Phenotype', 'HP:0030153', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
128710	32468022	In addition, ALDH1 expression has been demonstrated to potentiate mesenchymal properties in the CCA cell line TFK-1.	('mesenchymal properties', 'CPA', (66, 88))	('CCA', 'Phenotype', 'HP:0030153', (96, 99))	('expression', 'Var', (19, 29))	('potentiate', 'PosReg', (55, 65))	('ALDH1', 'Gene', (13, 18))	('ALDH1', 'Gene', '216', (13, 18))
128717	32468022	Likewise in CCA, co-expression of OCT4 and Nanog was found to be associated with the most inferior of the clinical outcomes.	('CCA', 'Disease', (12, 15))	('Nanog', 'Gene', '79923', (43, 48))	('co-expression', 'Var', (17, 30))	('CCA', 'Phenotype', 'HP:0030153', (12, 15))	('Nanog', 'Gene', (43, 48))	('OCT4', 'Gene', '5460', (34, 38))	('OCT4', 'Gene', (34, 38))
128728	32468022	Intriguingly, the introduction of activated YAP1 and myristoylated AKT in the biliary tract, coupled with biliary ligation, triggered CCA formation in an IL-6-dependent manner within 6-8 weeks in >70% of the mice tested.	('myristoylated', 'Var', (53, 66))	('AKT', 'Gene', '11651', (67, 70))	('CCA', 'Phenotype', 'HP:0030153', (134, 137))	('CCA formation', 'CPA', (134, 147))	('AKT', 'Gene', (67, 70))	('triggered', 'Reg', (124, 133))	('IL-6', 'Gene', (154, 158))	('IL-6', 'Gene', '16193', (154, 158))	('YAP1', 'Gene', (44, 48))	('mice', 'Species', '10090', (208, 212))
128735	32468022	This previous study also showed that knocking down YAP1 expression can significantly reduce the spheroid forming and proliferative capacity of NSCLC.	('NSCLC', 'Disease', (143, 148))	('YAP1', 'Gene', (51, 55))	('reduce', 'NegReg', (85, 91))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('knocking down', 'Var', (37, 50))
128740	32468022	The combination of verteporfin and rapamycin was previously found to inhibit intrahepatic CCA cell proliferation and tumor growth, where verteporfin activated mTOR whilst inhibiting STAT3 phosphorylation in CCA.	('STAT3', 'Gene', (182, 187))	('activated', 'PosReg', (149, 158))	('intrahepatic CCA', 'Disease', (77, 93))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('inhibiting', 'NegReg', (171, 181))	('verteporfin', 'Chemical', 'MESH:D000077362', (19, 30))	('tumor', 'Disease', (117, 122))	('mTOR', 'Gene', (159, 163))	('verteporfin', 'Var', (137, 148))	('mTOR', 'Gene', '2475', (159, 163))	('CCA', 'Phenotype', 'HP:0030153', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('verteporfin', 'Chemical', 'MESH:D000077362', (137, 148))	('CCA', 'Phenotype', 'HP:0030153', (207, 210))	('STAT3', 'Gene', '6774', (182, 187))	('inhibit', 'NegReg', (69, 76))	('rapamycin', 'Chemical', 'MESH:D020123', (35, 44))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (77, 93))
128742	32468022	In a recent study, LEE011 was found to inhibit cyclin-dependent kinase 6 (CDK6), whilst CA3 inhibited YAP1, using both in vivo and in vitro models of esophageal cancer.	('esophageal cancer', 'Disease', (150, 167))	('LEE011', 'Var', (19, 25))	('esophageal cancer', 'Disease', 'MESH:D004938', (150, 167))	('CDK6', 'Gene', (74, 78))	('inhibited', 'NegReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('CDK6', 'Gene', '1021', (74, 78))	('cyclin-dependent kinase 6', 'Gene', (47, 72))	('inhibit', 'NegReg', (39, 46))	('CA3', 'Gene', '761', (88, 91))	('cyclin-dependent kinase 6', 'Gene', '1021', (47, 72))	('CA3', 'Gene', (88, 91))	('YAP1', 'Gene', (102, 106))
128744	32468022	Combined treatment using both CA3 and LEE011 reduced tumor volume to a greater degree compared with either treatment alone.	('reduced', 'NegReg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('CA3', 'Gene', (30, 33))	('LEE011', 'Var', (38, 44))	('CA3', 'Gene', '761', (30, 33))
128757	32468022	In addition, overexpression of NICD in mouse livers has been previously found to induce cystic CCA tumor development.	('induce', 'PosReg', (81, 87))	('cystic CCA tumor', 'Disease', (88, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('NICD', 'Var', (31, 35))	('mouse', 'Species', '10090', (39, 44))	('CCA', 'Phenotype', 'HP:0030153', (95, 98))	('cystic CCA tumor', 'Disease', 'MESH:C536211', (88, 104))
128761	32468022	Notably, CRC is initiated by mutations in genes such as adenomatous polyposis coli (APC), which activates the Wnt/beta-catenin pathway.	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (56, 82))	('adenomatous polyposis coli', 'Gene', '324', (56, 82))	('CRC', 'Disease', (9, 12))	('adenomatous polyposis coli', 'Gene', (56, 82))	('APC', 'Disease', (84, 87))	('mutations', 'Var', (29, 38))	('initiated by', 'Reg', (16, 28))	('APC', 'Phenotype', 'HP:0005227', (84, 87))	('Wnt/beta-catenin pathway', 'Pathway', (110, 134))	('activates', 'PosReg', (96, 105))	('APC', 'Disease', 'MESH:D011125', (84, 87))
128762	32468022	Mutations in this complex, including that of APC, can lead to beta-catenin accumulation in the cytosol.	('lead to', 'Reg', (54, 61))	('APC', 'Phenotype', 'HP:0005227', (45, 48))	('APC', 'Disease', 'MESH:D011125', (45, 48))	('Mutations', 'Var', (0, 9))	('beta-catenin accumulation in the cytosol', 'MPA', (62, 102))	('APC', 'Disease', (45, 48))
128764	32468022	It has been previously reported that the canonical Wnt/beta-catenin signaling pathway is activated in human CCA, where the inhibition of Wnt/beta-catenin signaling reduced proliferation whilst inducing apoptosis in vivo.	('canonical Wnt/beta-catenin signaling pathway', 'Pathway', (41, 85))	('proliferation', 'CPA', (172, 185))	('inhibition', 'Var', (123, 133))	('CCA', 'Phenotype', 'HP:0030153', (108, 111))	('inducing', 'Reg', (193, 201))	('activated', 'PosReg', (89, 98))	('apoptosis', 'CPA', (202, 211))	('human', 'Species', '9606', (102, 107))	('CCA', 'Disease', (108, 111))	('reduced', 'NegReg', (164, 171))
128766	32468022	LY2090314 is a glycogen synthase kinase 3 inhibitor, which induces the accumulation of beta-catenin (Fig.	('LY2090314', 'Var', (0, 9))	('accumulation', 'PosReg', (71, 83))	('LY2090314', 'Chemical', 'MESH:C584053', (0, 9))	('beta-catenin', 'Protein', (87, 99))
128767	32468022	It has been shown that LY2090314 treatment in conjunction with nab-paclitaxel in a preclinical model of pancreatic cancer prolonged mice survival.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (104, 121))	('prolonged', 'PosReg', (122, 131))	('pancreatic cancer', 'Disease', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (104, 121))	('paclitaxel', 'Chemical', 'MESH:D017239', (67, 77))	('mice', 'Species', '10090', (132, 136))	('LY2090314', 'Var', (23, 32))	('LY2090314', 'Chemical', 'MESH:C584053', (23, 32))	('nab', 'Chemical', '-', (63, 66))
128768	32468022	However, regimens consisting of LY2090314 in combination with pemetrexed and carboplatin, demonstrated suboptimal safety profiles and minimal clinical efficacy in patients with advanced pancreatic cancer in a previous phase I clinical trial.	('patients', 'Species', '9606', (163, 171))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (186, 203))	('pancreatic cancer', 'Disease', (186, 203))	('pemetrexed', 'Chemical', 'MESH:D000068437', (62, 72))	('pancreatic cancer', 'Disease', 'MESH:D010190', (186, 203))	('LY2090314', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('LY2090314', 'Chemical', 'MESH:C584053', (32, 41))	('carboplatin', 'Chemical', 'MESH:D016190', (77, 88))
128773	32468022	Genetic variations in the JAK/STAT signaling pathway appear to be associated with CRC.	('JAK', 'Gene', (26, 29))	('JAK', 'Gene', '3716;3717', (26, 29))	('associated', 'Reg', (66, 76))	('CRC', 'Disease', (82, 85))	('Genetic variations', 'Var', (0, 18))
128774	32468022	Notably, abnormalities in STAT3 have been revealed to be involved in the oncogenesis of a number of cancers, where it was demonstrated that STAT3 and both JAK1 and JAK2 are involved in CRC cell growth, survival, invasion and migration through the regulation of target gene expression, including Bcl-2, E-cadherin, vascular endothelial growth factor and matrix metalloproteinases.	('matrix metalloproteinases', 'Enzyme', (353, 378))	('STAT3', 'Gene', '6774', (26, 31))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('involved', 'Reg', (57, 65))	('JAK1', 'Gene', '3716', (155, 159))	('STAT3', 'Gene', (140, 145))	('vascular endothelial growth factor', 'Gene', '7422', (314, 348))	('abnormalities', 'Var', (9, 22))	('JAK2', 'Gene', '3717', (164, 168))	('migration', 'CPA', (225, 234))	('survival', 'CPA', (202, 210))	('STAT3', 'Gene', '6774', (140, 145))	('vascular endothelial growth factor', 'Gene', (314, 348))	('E-cadherin', 'Gene', (302, 312))	('Bcl-2', 'Gene', (295, 300))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('involved', 'Reg', (173, 181))	('E-cadherin', 'Gene', '999', (302, 312))	('JAK1', 'Gene', (155, 159))	('cancers', 'Disease', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('invasion', 'CPA', (212, 220))	('JAK2', 'Gene', (164, 168))	('STAT3', 'Gene', (26, 31))	('Bcl-2', 'Gene', '596', (295, 300))
128778	32468022	In addition, napabucasin has been shown to inhibit colony formation and significantly downregulate the expression of several stemness-related genes, including CSC markers ALDH1 and CD133 in CCA cells.	('ALDH1', 'Gene', '216', (171, 176))	('expression', 'MPA', (103, 113))	('inhibit', 'NegReg', (43, 50))	('napabucasin', 'Chemical', 'MESH:C000621033', (13, 24))	('napabucasin', 'Var', (13, 24))	('ALDH1', 'Gene', (171, 176))	('CCA', 'Phenotype', 'HP:0030153', (190, 193))	('CD133', 'Gene', (181, 186))	('colony formation', 'CPA', (51, 67))	('downregulate', 'NegReg', (86, 98))	('stemness-related genes', 'Gene', (125, 147))
128849	31881008	Another study also showed that high expression of PD-L1 was associated with inferior OS in patients with colorectal cancer.	('patients', 'Species', '9606', (91, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (105, 122))	('PD-L1', 'Gene', (50, 55))	('inferior OS', 'Disease', (76, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('high', 'Var', (31, 35))	('colorectal cancer', 'Disease', (105, 122))	('associated', 'Reg', (60, 70))
128850	31881008	A comprehensive meta-analysis of 50 studies with 11,383 patients demonstrated that PD-L1 expression on IHC was associated with poor OS and with several clinicopathological factors in patients with lung cancer.	('patients', 'Species', '9606', (56, 64))	('poor OS', 'Disease', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('lung cancer', 'Disease', 'MESH:D008175', (197, 208))	('associated', 'Reg', (111, 121))	('expression', 'Var', (89, 99))	('PD-L1', 'Gene', (83, 88))	('lung cancer', 'Disease', (197, 208))	('lung cancer', 'Phenotype', 'HP:0100526', (197, 208))	('patients', 'Species', '9606', (183, 191))
128851	31881008	In the present meta-analysis, the pooled data showed that high PD-L1 expression was predictive of poor OS, in line with the results of previous studies on other cancers.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('expression', 'MPA', (69, 79))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('PD-L1', 'Gene', (63, 68))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('high', 'Var', (58, 62))	('cancers', 'Disease', (161, 168))	('poor OS', 'Disease', (98, 105))
128887	30908307	A phase II study in patients with fibroblast growth factor receptor 2 (FGFR2) fusions revealed that a selective pan-FGFR kinase inhibitor showed significant clinical effect against cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('fibroblast growth factor receptor 2', 'Gene', '2263', (34, 69))	('fibroblast growth factor receptor 2', 'Gene', (34, 69))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (181, 199))	('fusions', 'Var', (78, 85))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (181, 199))	('patients', 'Species', '9606', (20, 28))	('FGFR2', 'Gene', (71, 76))	('FGFR2', 'Gene', '2263', (71, 76))	('cholangiocarcinoma', 'Disease', (181, 199))
128889	30908307	In addition, other biomarker-driven clinical trials for BTC, which target BRAF, MEK, and IDH1/2, are currently ongoing (NCT02034110, NCT01242605, NCT02989857, NCT02273739, NCT02428855, and NCT02073994).	('IDH1/2', 'Gene', '3417;3418', (89, 95))	('NCT02034110', 'Var', (120, 131))	('MEK', 'Gene', '5609', (80, 83))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('NCT01242605', 'Var', (133, 144))	('IDH1/2', 'Gene', (89, 95))	('NCT02989857', 'Var', (146, 157))	('NCT02428855', 'Var', (172, 183))	('MEK', 'Gene', (80, 83))	('BTC', 'Phenotype', 'HP:0100574', (56, 59))	('NCT02073994', 'Var', (189, 200))	('NCT02273739', 'Var', (159, 170))
128932	30908307	We identified 80 SNVs and 8 INDELs in 39 genes in total, and the filtered normal-tumor analyses revealed 28 pathogenic alterations in 14 genes.	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('SNVs', 'Var', (17, 21))	('tumor', 'Disease', (81, 86))
128937	30908307	Alterations in TP53 (75.0%) and KRAS (41.7%) were frequently identified as pathogenic alterations (Figure 5a).	('Alterations', 'Var', (0, 11))	('KRAS', 'Gene', (32, 36))	('KRAS', 'Gene', '3845', (32, 36))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))
128940	30908307	Alterations in BRAF and SMARCB1 were identified only in intrahepatic cholangiocarcinoma, and alterations in SMAD4 were identified only in extrahepatic cholangiocarcinoma.	('BRAF', 'Gene', '673', (15, 19))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (69, 87))	('extrahepatic cholangiocarcinoma', 'Disease', (138, 169))	('BRAF', 'Gene', (15, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('alterations', 'Var', (93, 104))	('Alterations', 'Var', (0, 11))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (56, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('SMAD4', 'Gene', '4089', (108, 113))	('intrahepatic cholangiocarcinoma', 'Disease', (56, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (151, 169))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (138, 169))	('SMARCB1', 'Gene', '6598', (24, 31))	('SMARCB1', 'Gene', (24, 31))	('SMAD4', 'Gene', (108, 113))
128941	30908307	In the 2 GBC samples diagnosed as adenosquamous carcinoma, pathogenic gene alterations in TP53, CDKN2A, RB1, PIK3CA, and SMARCB1 were identified in one sample, while no gene alteration was identified in the other despite the large amount of malignant cells observed upon hematoxylin and eosin staining (Figure 6).	('CDKN2A', 'Gene', '1029', (96, 102))	('RB1', 'Gene', (104, 107))	('PIK3CA', 'Gene', (109, 115))	('SMARCB1', 'Gene', (121, 128))	('SMARCB1', 'Gene', '6598', (121, 128))	('PIK3CA', 'Gene', '5290', (109, 115))	('TP53', 'Gene', '7157', (90, 94))	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (34, 57))	('hematoxylin', 'Chemical', 'MESH:D006416', (271, 282))	('RB1', 'Gene', '5925', (104, 107))	('alterations', 'Var', (75, 86))	('adenosquamous carcinoma', 'Disease', (34, 57))	('TP53', 'Gene', (90, 94))	('eosin', 'Chemical', 'MESH:D004801', (287, 292))	('CDKN2A', 'Gene', (96, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
128943	30908307	We achieved deep sequencing coverage and identified pathogenic alterations in 95.2% (20/21) of the patients with BTC using EUS-FNA samples.	('patients', 'Species', '9606', (99, 107))	('BTC', 'Phenotype', 'HP:0100574', (113, 116))	('alterations', 'Var', (63, 74))	('pathogenic', 'Reg', (52, 62))
128954	30908307	In the current study, KRAS alterations were identified in GBC specimens, whereas a previous report using a larger cohort reported the absence of the KRAS alteration in this type of BTC.	('men', 'Species', '9606', (67, 70))	('KRAS', 'Gene', (149, 153))	('KRAS', 'Gene', '3845', (149, 153))	('KRAS', 'Gene', (22, 26))	('BTC', 'Phenotype', 'HP:0100574', (181, 184))	('KRAS', 'Gene', '3845', (22, 26))	('alterations', 'Var', (27, 38))
128957	30908307	Therefore, the identified KRAS alterations in GBC in the present study are considered to be consistent with prior data.	('alterations', 'Var', (31, 42))	('KRAS', 'Gene', '3845', (26, 30))	('KRAS', 'Gene', (26, 30))
128963	30908307	Effective targeted molecular therapies for BTC, as well as gastric cancer with HER2 mutations, or colorectal cancer with KRAS mutations have never been established due to the wide variety of pathogenic alterations involved.	('colorectal cancer', 'Disease', (98, 115))	('HER2', 'Gene', '2064', (79, 83))	('KRAS', 'Gene', (121, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (59, 73))	('BTC', 'Disease', (43, 46))	('KRAS', 'Gene', '3845', (121, 125))	('rectal cancer', 'Phenotype', 'HP:0100743', (102, 115))	('BTC', 'Phenotype', 'HP:0100574', (43, 46))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('mutations', 'Var', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('gastric cancer', 'Disease', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (59, 73))	('HER2', 'Gene', (79, 83))
128978	30377340	Data about the prevalence of high-level microsatellite instability in cholangiocarcinoma (CCA) has been conflicting.	('CCA', 'Disease', (90, 93))	('cholangiocarcinoma', 'Disease', (70, 88))	('CCA', 'Phenotype', 'HP:0030153', (90, 93))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (70, 88))	('CCA', 'Disease', 'MESH:D018281', (90, 93))	('microsatellite instability', 'Var', (40, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))
128991	30377340	Molecular events occurring during the development of cholangiocarcinoma are heterogeneous and likely follow a multistep process encompassing alterations of several tumour suppressor genes such as KRAS and TP53.	('alterations', 'Var', (141, 152))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (53, 71))	('TP53', 'Gene', '7157', (205, 209))	('TP53', 'Gene', (205, 209))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('tumour', 'Disease', (164, 170))	('cholangiocarcinoma', 'Disease', (53, 71))	('KRAS', 'Gene', (196, 200))	('KRAS', 'Gene', '3845', (196, 200))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (53, 71))
128996	30377340	However, the true percentage of microsatellite-unstable non-liver-fluke-associated cholangiocarcinoma is unclear.	('microsatellite-unstable', 'Var', (32, 55))	('cholangiocarcinoma', 'Disease', (83, 101))	('liver-fluke', 'Species', '6192', (60, 71))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))
128997	30377340	Therefore, we aimed to determine frequency and characteristics of high-level microsatellite instability in a large and well-characterised German cohort of cholangiocarcinoma, including all subtypes.	('microsatellite instability', 'Var', (77, 103))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (155, 173))	('cholangiocarcinoma', 'Disease', (155, 173))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (155, 173))
129010	30377340	A comprehensive cholangiocarcinoma cohort including all anatomical subtypes has been evaluated for microsatellite instability status.	('microsatellite', 'Var', (99, 113))	('cholangiocarcinoma cohort', 'Disease', 'MESH:D018281', (16, 41))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (16, 34))	('cholangiocarcinoma cohort', 'Disease', (16, 41))
129012	30377340	Four (1.3%) out of 308 analysed cholangiocarcinomas showed high-level microsatellite instability.	('cholangiocarcinomas', 'Disease', (32, 51))	('microsatellite', 'Var', (70, 84))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (32, 50))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (32, 51))
129019	30377340	Analysis of cholangiocarcinoma subtypes showed that two microsatellite-unstable cases were intrahepatic (2/159, 1.3%) and two cases were perihilar extrahepatic cholangiocarcinomas (2/106, 1.9%), whereas all distal extrahepatic cholangiocarcinomas (n = 43) were microsatellite-stable (Table 1).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (12, 30))	('extrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (214, 246))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (160, 178))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (160, 178))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (12, 30))	('cholangiocarcinoma', 'Disease', (227, 245))	('extrahepatic cholangiocarcinomas', 'Disease', (214, 246))	('extrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (147, 179))	('cholangiocarcinoma', 'Disease', (12, 30))	('extrahepatic cholangiocarcinomas', 'Disease', (147, 179))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (227, 245))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (227, 245))	('microsatellite-unstable', 'Var', (56, 79))	('cholangiocarcinoma', 'Disease', (160, 178))
129020	30377340	Correlation with clinicopathological data showed that three of four microsatellite-unstable cases were detected in younger cholangiocarcinoma patients (younger than median patient age group: 31-63 years; Table 1).	('cholangiocarcinoma', 'Disease', (123, 141))	('patient', 'Species', '9606', (172, 179))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (123, 141))	('microsatellite-unstable', 'Var', (68, 91))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (123, 141))	('patient', 'Species', '9606', (142, 149))	('patients', 'Species', '9606', (142, 150))
129022	30377340	Three of four detected microsatellite-unstable patients (two intrahepatic, one perihilar cholangiocarcinomas) showed an atypical histomorphology, i.e., showing not the typical acinar/tubular/glandular/not otherwise specified pancreatobiliary phenotype, but displaying infrequent histologic patterns in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (89, 107))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (89, 108))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (89, 107))	('microsatellite-unstable', 'Var', (23, 46))	('cholangiocarcinoma', 'Disease', (302, 320))	('patients', 'Species', '9606', (47, 55))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (89, 107))	('cholangiocarcinomas', 'Disease', (89, 108))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (302, 320))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (302, 320))
129023	30377340	In detail, both microsatellite-unstable intrahepatic cholangiocarcinomas showed a predominantly papillary, partly mucinous histomorphology.	('intrahepatic cholangiocarcinomas', 'Disease', (40, 72))	('microsatellite-unstable', 'Var', (16, 39))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:C535533', (40, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (53, 71))
129024	30377340	One of two detected microsatellite-unstable perihilar cholangiocarcinomas had a predominantly solid and cribriform histology.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('microsatellite-unstable', 'Var', (20, 43))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (54, 73))	('cholangiocarcinomas', 'Disease', (54, 73))
129025	30377340	The other detected microsatellite-unstable perihilar cholangiocarcinoma had the typical acinar/tubular/glandular/not otherwise specified pancreatobiliary phenotype.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (53, 71))	('microsatellite-unstable', 'Var', (19, 42))	('pancreatobiliary', 'Disease', (137, 153))	('cholangiocarcinoma', 'Disease', (53, 71))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (53, 71))
129026	30377340	Furthermore, in one of the two detected microsatellite-unstable intrahepatic cholangiocarcinomas, an infrequent precursor lesion (intraductal papillary neoplasia of bile duct) was detected.	('microsatellite-unstable', 'Var', (40, 63))	('neoplasia', 'Phenotype', 'HP:0002664', (152, 161))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (77, 95))	('intrahepatic cholangiocarcinomas', 'Disease', (64, 96))	('intraductal papillary neoplasia of bile duct', 'Disease', (130, 174))	('intraductal papillary neoplasia of bile duct', 'Disease', 'MESH:C565310', (130, 174))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:C535533', (64, 96))
129028	30377340	All 4 microsatellite-unstable cholangiocarcinomas showed positive lymph nodes (pN1) and a high UICC stage (UICC stage III; Table 1).	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (30, 49))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (30, 48))	('cholangiocarcinomas', 'Disease', (30, 49))	('pN1', 'Gene', '5270', (79, 82))	('microsatellite-unstable', 'Var', (6, 29))	('pN1', 'Gene', (79, 82))
129030	30377340	However, this did not reach statistical significance, probably due to the low number of detected microsatellite-unstable cholangiocarcinomas (Fig.	('cholangiocarcinomas', 'Disease', (121, 140))	('microsatellite-unstable', 'Var', (97, 120))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (121, 140))
129032	30377340	We performed a correlation analysis of high-level microsatellite instability status with the quantity and quality of tumour-infiltrating immune cells, Major histocompatibility Complex class I (MHC I), and Programmed Death-Ligand 1 (PD-L1) expression in the same cholangiocarcinoma cohort.	('PD-L1', 'Gene', (232, 237))	('cholangiocarcinoma cohort', 'Disease', (262, 287))	('Programmed Death-Ligand 1', 'Gene', '29126', (205, 230))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('PD-L1', 'Gene', '29126', (232, 237))	('microsatellite', 'Var', (50, 64))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (262, 280))	('cholangiocarcinoma cohort', 'Disease', 'MESH:D018281', (262, 287))	('tumour', 'Disease', (117, 123))	('Programmed Death-Ligand 1', 'Gene', (205, 230))
129033	30377340	This revealed a significant higher number of tumour-infiltrating immune cells (particularly intratumoural CD8 + T cells, FOXP3 + regulatory T cells (Tregs), and CD20 + B cells) compared to all other microsatellite-stable cases of the cohort (n = 308, Table 2).	('tumour', 'Disease', (97, 103))	('CD8', 'Gene', (106, 109))	('CD20 +', 'Var', (161, 167))	('CD8', 'Gene', '925', (106, 109))	('FOXP3', 'Gene', (121, 126))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('higher', 'PosReg', (28, 34))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('FOXP3', 'Gene', '50943', (121, 126))	('tumour', 'Disease', 'MESH:D009369', (97, 103))	('tumour', 'Disease', (45, 51))
129034	30377340	In addition, three of the four detected microsatellite-unstable cases showed high or moderate Major histocompatibility Complex class I antigen expression level on the tumour cells.	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('microsatellite-unstable', 'Var', (40, 63))	('tumour', 'Disease', (167, 173))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('expression level', 'MPA', (143, 159))
129037	30377340	However, probably due to the low number of microsatellite-unstable CCA, this finding reached only borderline statistical significance (see Supplementary table 1 and Supplementary figure 2).	('CCA', 'Disease', (67, 70))	('microsatellite-unstable', 'Var', (43, 66))	('Supplementary figure 2', 'Disease', 'MESH:D017034', (165, 187))	('CCA', 'Phenotype', 'HP:0030153', (67, 70))	('Supplementary figure 2', 'Disease', (165, 187))	('CCA', 'Disease', 'MESH:D018281', (67, 70))
129040	30377340	In the present study, we used sensitive mononucleotide repeats, which are more specific for detecting DNA mismatch repair deficiency than di- or tetranucleotide markers, thereby reaching highest sensitivity of high-level microsatellite instability testing.	('mononucleotide', 'Chemical', 'MESH:D009537', (40, 54))	('mismatch repair deficiency', 'Disease', (106, 132))	('mononucleotide repeats', 'Var', (40, 62))	('mismatch repair deficiency', 'Disease', 'MESH:C536928', (106, 132))	('DNA', 'Gene', (102, 105))
129041	30377340	In fact, literature studies using mononucleotide repeats for the detection of high-level microsatellite instability in cholangiocarcinoma generally reported a much lower prevalence of high-level microsatellite instability.	('cholangiocarcinoma', 'Disease', (119, 137))	('mononucleotide', 'Chemical', 'MESH:D009537', (34, 48))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (119, 137))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (119, 137))	('microsatellite', 'Var', (89, 103))
129042	30377340	All microsatellite-unstable cholangiocarcinomas could be confirmed by immunohistochemistry.	('microsatellite-unstable', 'Var', (4, 27))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (28, 46))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (28, 47))	('cholangiocarcinomas', 'Disease', (28, 47))
129043	30377340	As the immunohistochemical analysis of DNA mismatch repair proteins did not show a consistent pattern of expression losses of one specific protein or of protein combinations, we presume that heterogeneous molecular events are underlying mismatch repair deficiency and high-level microsatellite instability in cholangiocarcinomas.	('mismatch repair deficiency', 'Disease', 'MESH:C536928', (237, 263))	('microsatellite instability', 'Var', (279, 305))	('cholangiocarcinomas', 'Disease', (309, 328))	('mismatch repair deficiency', 'Disease', (237, 263))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (309, 328))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (309, 327))
129044	30377340	Although the classical high-level microsatellite instability phenotype, known from microsatellite-unstable colorectal cancers was not fully recapitulated in the detected microsatellite-unstable cholangiocarcinomas, three out of four detected microsatellite-unstable cholangiocarcinomas (two intrahepatic cholangiocarcinomas and one perihilar cholangiocarcinoma) did not show the typical pancreatobiliary acinar/tubular/glandular histomorphology but displayed a papillary, mucinous or solid histologic phenotype.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (266, 284))	('cholangiocarcinoma', 'Disease', (194, 212))	('cholangiocarcinoma', 'Disease', (266, 284))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (194, 212))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (266, 284))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (342, 360))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (304, 322))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('colorectal cancers', 'Disease', (107, 125))	('cholangiocarcinoma', 'Disease', (342, 360))	('microsatellite-unstable', 'Var', (242, 265))	('cholangiocarcinoma', 'Disease', (304, 322))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (342, 360))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (266, 285))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (304, 322))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cholangiocarcinomas', 'Disease', (266, 285))	('intrahepatic cholangiocarcinomas', 'Disease', (291, 323))	('pancreatobiliary acinar', 'Disease', (387, 410))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:C535533', (291, 323))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (194, 213))	('pancreatobiliary acinar', 'Disease', 'MESH:D018267', (387, 410))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (304, 323))	('colorectal cancers', 'Disease', 'MESH:D015179', (107, 125))	('cholangiocarcinomas', 'Disease', (194, 213))	('cholangiocarcinomas', 'Disease', (304, 323))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (194, 212))
129047	30377340	However, the other three microsatellite-unstable cholangiocarcinomas showed no infrequent precursor lesion and were not associated with any risk factor.	('microsatellite-unstable', 'Var', (25, 48))	('cholangiocarcinomas', 'Disease', (49, 68))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (49, 67))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (49, 68))
129048	30377340	As the number of microsatellite-unstable cases is low in the presented cohort, these extraordinary findings in this microsatellite-unstable intrahepatic cholangiocarcinoma might be a pure coincidence.	('microsatellite-unstable', 'Var', (116, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (153, 171))	('intrahepatic cholangiocarcinoma', 'Disease', (140, 171))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:C535533', (140, 171))
129052	30377340	Although the overall frequency of high-level microsatellite instability in cholangiocarcinoma specimens is low with less than 2% in the present cohort, microsatellite instability testing of cholangiocarcinoma should be considered if the patients have a chance to benefit from immune checkpoint blockade.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (190, 208))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (75, 93))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (75, 93))	('microsatellite', 'Var', (152, 166))	('cholangiocarcinoma', 'Disease', (190, 208))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (190, 208))	('patients', 'Species', '9606', (237, 245))	('cholangiocarcinoma', 'Disease', (75, 93))
129053	30377340	Recent studies demonstrated that patients with microsatellite-unstable cholangiocarcinomas in fact may show significant clinical responses towards treatment with anti-PD-1 or anti-PD-L1 antibodies.	('PD-1', 'Gene', (167, 171))	('PD-1', 'Gene', '5133', (167, 171))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (71, 89))	('PD-L1', 'Gene', '29126', (180, 185))	('patients', 'Species', '9606', (33, 41))	('microsatellite-unstable', 'Var', (47, 70))	('cholangiocarcinomas', 'Disease', (71, 90))	('PD-L1', 'Gene', (180, 185))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (71, 90))
129057	30377340	Importantly, microsatellite-unstable cholangiocarcinomas shared typical characteristics of microsatellite-unstable tumours of different origin, most importantly microsatellite-unstable colorectal cancers, as microsatellite-unstable cholangiocarcinomas showed a typical immune phenotype.	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (37, 56))	('microsatellite-unstable tumours', 'Disease', 'MESH:D053842', (91, 122))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (37, 55))	('colorectal cancer', 'Phenotype', 'HP:0003003', (185, 202))	('microsatellite-unstable tumours', 'Disease', (91, 122))	('colorectal cancers', 'Disease', 'MESH:D015179', (185, 203))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (232, 250))	('colorectal cancers', 'Disease', (185, 203))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('cholangiocarcinomas', 'Disease', (232, 251))	('microsatellite-unstable', 'Var', (161, 184))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('cholangiocarcinomas', 'Disease', (37, 56))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (232, 251))
129059	30377340	We detected high numbers of intraepithelial CD8 + T cells, FOXP3 + regulatory T cells (Tregs), and CD20 + B cells and high/moderate Major histocompatibility Complex class I expression levels in microsatellite-unstable cholangiocarcinomas; all these parameters have been shown to be correlated with better patient survival in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (218, 236))	('CD8', 'Gene', (44, 47))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (325, 343))	('CD8', 'Gene', '925', (44, 47))	('FOXP3', 'Gene', (59, 64))	('patient', 'Species', '9606', (305, 312))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (218, 236))	('better', 'PosReg', (298, 304))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (325, 343))	('cholangiocarcinomas', 'Disease', (218, 237))	('CD20 + B', 'Var', (99, 107))	('FOXP3', 'Gene', '50943', (59, 64))	('expression', 'MPA', (173, 183))	('cholangiocarcinoma', 'Disease', (218, 236))	('cholangiocarcinoma', 'Disease', (325, 343))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (218, 237))
129060	30377340	The detection of enhanced expression of Major histocompatibility Complex class I antigen is compatible with an enhanced local anti-tumoural immune response in microsatellite-unstable compared to microsatellite-stable cholangiocarcinomas, although further functional studies are required to determine immune cell specificity and function in microsatellite-unstable cholangiocarcinomas.	('expression', 'MPA', (26, 36))	('tumour', 'Disease', (131, 137))	('enhanced', 'PosReg', (17, 25))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (217, 236))	('enhanced', 'PosReg', (111, 119))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (364, 383))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (364, 382))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (217, 235))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('microsatellite-unstable', 'Var', (159, 182))	('cholangiocarcinomas', 'Disease', (217, 236))	('cholangiocarcinomas', 'Disease', (364, 383))
129062	30377340	This is in line with the situation in colorectal cancer, in which mononucleotide repeat-based microsatellite instability testing by polymerase chain reaction also has a higher sensitivity than immunohistochemical methods, however, with much smaller differences between the methods comparing to the situation in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (311, 329))	('colorectal cancer', 'Phenotype', 'HP:0003003', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (311, 329))	('microsatellite instability', 'MPA', (94, 120))	('mononucleotide', 'Chemical', 'MESH:D009537', (66, 80))	('colorectal cancer', 'Disease', (38, 55))	('sensitivity', 'MPA', (176, 187))	('mononucleotide repeat-based', 'Var', (66, 93))	('colorectal cancer', 'Disease', 'MESH:D015179', (38, 55))	('cholangiocarcinoma', 'Disease', (311, 329))
129066	30209701	Ivosidenib: First Global Approval Ivosidenib (Tibsovo ) is a small molecule, orally available inhibitor of mutated cytosolic isocitrate dehydrogenase 1 (IDH1) that is being developed by Agios Pharmaceuticals for the treatment of cancer in patients with IDH1 mutations.	('mutations', 'Var', (258, 267))	('IDH1', 'Gene', (153, 157))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('Tibsovo', 'Chemical', 'MESH:C000627630', (46, 53))	('IDH1', 'Gene', (253, 257))	('IDH1', 'Gene', '3417', (253, 257))	('patients', 'Species', '9606', (239, 247))	('IDH1', 'Gene', '3417', (153, 157))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (34, 44))	('isocitrate dehydrogenase 1', 'Gene', '3417', (125, 151))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('isocitrate dehydrogenase 1', 'Gene', (125, 151))
129067	30209701	The mutated form of the IDH1 enzyme produces a metabolite, 2-hydroxyglutarate (2-HG), which is thought to play a role in the formation and progression of acute myeloid leukaemia (AML), gliomas and other cancers.	('AML', 'Disease', (179, 182))	('gliomas', 'Phenotype', 'HP:0009733', (185, 192))	('IDH1', 'Gene', (24, 28))	('acute myeloid leukaemia', 'Disease', (154, 177))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (59, 77))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (154, 177))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('gliomas', 'Disease', (185, 192))	('mutated', 'Var', (4, 11))	('IDH1', 'Gene', '3417', (24, 28))	('role', 'Reg', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('gliomas', 'Disease', 'MESH:D005910', (185, 192))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (160, 177))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (154, 177))	('2-HG', 'Chemical', 'MESH:C019417', (79, 83))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('AML', 'Disease', 'MESH:D015470', (179, 182))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('AML', 'Phenotype', 'HP:0004808', (179, 182))	('cancers', 'Disease', (203, 210))
129070	30209701	This article summarizes the milestones in the development of ivosidenib leading to this first approval in the USA for the treatment of patients with relapsed or refractory AML with a susceptible IDH1 mutation.	('relapsed', 'Disease', (149, 157))	('AML', 'Phenotype', 'HP:0004808', (172, 175))	('mutation', 'Var', (200, 208))	('patients', 'Species', '9606', (135, 143))	('IDH1', 'Gene', (195, 199))	('AML', 'Disease', 'MESH:D015470', (172, 175))	('AML', 'Disease', (172, 175))	('ivosidenib', 'Chemical', 'MESH:C000627630', (61, 71))	('IDH1', 'Gene', '3417', (195, 199))
129078	30209701	Recurrent mutations in IDH1 and IDH2 genes have been identified in several cancers, including AML, myelodysplastic syndromes and myeloproliferative neoplasms, and cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (163, 181))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (129, 157))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (163, 181))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('IDH1', 'Gene', (23, 27))	('AML', 'Disease', 'MESH:D015470', (94, 97))	('myelodysplastic syndromes and myeloproliferative neoplasms', 'Disease', 'MESH:D054437', (99, 157))	('AML', 'Disease', (94, 97))	('AML', 'Phenotype', 'HP:0004808', (94, 97))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (99, 124))	('identified', 'Reg', (53, 63))	('IDH1', 'Gene', '3417', (23, 27))	('neoplasms', 'Phenotype', 'HP:0002664', (148, 157))	('IDH2', 'Gene', (32, 36))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('IDH2', 'Gene', '3418', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (10, 19))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (163, 181))
129079	30209701	Mutated IDH enzymes acquire gain-of-function activity, converting NADPH and alphaKG to NADP+ and the oncometabolite D-2-hydroxyglutarate (2-HG).	('IDH', 'Gene', (8, 11))	('NADP+', 'Chemical', 'MESH:D009249', (87, 92))	('2-HG', 'Chemical', 'MESH:C019417', (138, 142))	('IDH', 'Gene', '3417', (8, 11))	('NADPH', 'Chemical', 'MESH:D009249', (66, 71))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (116, 136))	('D-2-hydroxyglutarate', 'MPA', (116, 136))	('Mutated', 'Var', (0, 7))
129080	30209701	Ivosidenib has been approved by the US FDA for the treatment of patients with relapsed or refractory AML with a susceptible IDH1 mutation.	('AML', 'Disease', 'MESH:D015470', (101, 104))	('patients', 'Species', '9606', (64, 72))	('mutation', 'Var', (129, 137))	('IDH1', 'Gene', '3417', (124, 128))	('AML', 'Phenotype', 'HP:0004808', (101, 104))	('relapsed', 'Disease', (78, 86))	('AML', 'Disease', (101, 104))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))	('IDH1', 'Gene', (124, 128))
129099	30209701	In vitro ivosidenib inhibited selected IDH1 R132 mutants at much lower concentrations than wild-type IDH1.	('IDH1', 'Gene', (101, 105))	('mutants', 'Var', (49, 56))	('IDH1', 'Gene', '3417', (101, 105))	('IDH1', 'Gene', (39, 43))	('R132 mutants', 'Var', (44, 56))	('IDH1', 'Gene', '3417', (39, 43))	('inhibited', 'NegReg', (20, 29))	('ivosidenib', 'Chemical', 'MESH:C000627630', (9, 19))
129100	30209701	Ivosidenib was shown to be highly selective for IDH1 mutants and did not inhibit wild-type or mutant isoforms of IDH2.	('IDH2', 'Gene', (113, 117))	('IDH1', 'Gene', '3417', (48, 52))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))	('IDH2', 'Gene', '3418', (113, 117))	('mutants', 'Var', (53, 60))	('IDH1', 'Gene', (48, 52))
129102	30209701	In vitro, ivosidenib inhibited invasion and migration of chondrosarcoma cells bearing an IDH1 mutation.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (57, 71))	('ivosidenib', 'Chemical', 'MESH:C000627630', (10, 20))	('chondrosarcoma', 'Disease', (57, 71))	('inhibited', 'NegReg', (21, 30))	('chondrosarcoma', 'Disease', 'MESH:D002813', (57, 71))	('IDH1', 'Gene', (89, 93))	('mutation', 'Var', (94, 102))	('IDH1', 'Gene', '3417', (89, 93))
129104	30209701	In vitro, ivosidenib plus azacitidine enhanced cell differentiation (46-fold versus 25-fold with ivosidenib alone and 1-fold with azacitidine alone) and potentiated cell death compared with either agent alone.	('potentiated', 'PosReg', (153, 164))	('enhanced', 'PosReg', (38, 46))	('ivosidenib', 'Chemical', 'MESH:C000627630', (10, 20))	('azacitidine', 'Chemical', 'MESH:D001374', (26, 37))	('cell death', 'CPA', (165, 175))	('azacitidine', 'Chemical', 'MESH:D001374', (130, 141))	('ivosidenib', 'Chemical', 'MESH:C000627630', (97, 107))	('ivosidenib', 'Var', (10, 20))	('cell differentiation', 'CPA', (47, 67))
129105	30209701	In phase 1, open-label studies of patients with IDH1 mutation-bearing advanced haematological malignancies (NCT02074839) or advanced solid tumours (including cholangiocarcinoma; NCT02073994), ivosidenib 500 mg/day reduced plasma 2-HG levels by > 90%, and to levels similar to those in healthy subjects.	('cholangiocarcinoma', 'Disease', (158, 176))	('advanced solid tumours', 'Disease', (124, 146))	('tumours', 'Phenotype', 'HP:0002664', (139, 146))	('ivosidenib', 'Chemical', 'MESH:C000627630', (192, 202))	('haematological malignancies', 'Disease', (79, 106))	('haematological malignancies', 'Disease', 'MESH:D019337', (79, 106))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (158, 176))	('IDH1', 'Gene', '3417', (48, 52))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (158, 176))	('advanced solid tumours', 'Disease', 'MESH:D006223', (124, 146))	('mutation-bearing', 'Reg', (53, 69))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('patients', 'Species', '9606', (34, 42))	('reduced', 'NegReg', (214, 221))	('NCT02074839', 'Var', (108, 119))	('2-HG', 'Chemical', 'MESH:C019417', (229, 233))	('IDH1', 'Gene', (48, 52))	('plasma 2-HG levels', 'MPA', (222, 240))
129107	30209701	Ivosidenib-induced inhibition of mutant IDH1 and 2-HG levels in the plasma were positively correlated with those in tumour biopsies from patients with cholangiocarcinoma.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('cholangiocarcinoma', 'Disease', (151, 169))	('IDH1', 'Gene', (40, 44))	('2-HG levels', 'MPA', (49, 60))	('tumour', 'Disease', (116, 122))	('2-HG', 'Chemical', 'MESH:C019417', (49, 53))	('patients', 'Species', '9606', (137, 145))	('IDH1', 'Gene', '3417', (40, 44))	('inhibition', 'NegReg', (19, 29))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (151, 169))	('mutant', 'Var', (33, 39))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (151, 169))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
129130	30209701	Patients aged >= 18 years, with an ECOG PS of 0-2 and documented IDH1-mutated haematological cancer received ivosidenib in 28-day cycles (100 mg twice daily or 300-1200 mg once daily in the dose escalation phase, and 500 mg once daily in the dose expansion phase).	('IDH1', 'Gene', '3417', (65, 69))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('300-1200 mg', 'Var', (160, 171))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Patients', 'Species', '9606', (0, 8))	('IDH1', 'Gene', (65, 69))	('haematological cancer', 'Phenotype', 'HP:0004377', (78, 99))	('ivosidenib', 'Chemical', 'MESH:C000627630', (109, 119))
129134	30209701	Among 34 ivosidenib recipients with CR or CRh, the mean levels of IDH1 mutations in bone marrow mononuclear cells and neutrophils decreased over time, and 7 (21%) patients had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay (p = 0.003 for the association between clearance of mutation and CR or CRh).	('levels', 'MPA', (56, 62))	('IDH1', 'Gene', '3417', (199, 203))	('patients', 'Species', '9606', (163, 171))	('IDH1', 'Gene', '3417', (66, 70))	('CRh', 'Gene', (42, 45))	('CR', 'Gene', '1401', (42, 44))	('mutations', 'Var', (204, 213))	('CR', 'Gene', '1401', (36, 38))	('CRh', 'Gene', '1392', (328, 331))	('mutations', 'Var', (71, 80))	('CR', 'Gene', '1401', (322, 324))	('CR', 'Gene', '1401', (328, 330))	('ivosidenib', 'Chemical', 'MESH:C000627630', (9, 19))	('IDH1', 'Gene', (199, 203))	('IDH1', 'Gene', (66, 70))	('decreased', 'NegReg', (130, 139))	('CRh', 'Gene', '1392', (42, 45))	('CRh', 'Gene', (328, 331))
129136	30209701	An ongoing, open-label phase 1b/2 study (NCT02677922) is assessing the efficacy of ivosidenib 500 mg/day or enasidenib 100 mg or 200 mg once daily in combination with subcutaneous azacitidine 75 mg/m2/day for 7 days/cycle in patients aged >= 18 years with newly diagnosed (de novo or secondary) untreated AML with IDH1 or IDH2 mutation who were ineligible for intensive chemotherapy.	('IDH2', 'Gene', (322, 326))	('AML', 'Disease', 'MESH:D015470', (305, 308))	('patients', 'Species', '9606', (225, 233))	('IDH1', 'Gene', (314, 318))	('enasidenib', 'Chemical', 'MESH:C000605269', (108, 118))	('AML', 'Disease', (305, 308))	('IDH2', 'Gene', '3418', (322, 326))	('ivosidenib', 'Chemical', 'MESH:C000627630', (83, 93))	('azacitidine', 'Chemical', 'MESH:D001374', (180, 191))	('IDH1', 'Gene', '3417', (314, 318))	('AML', 'Phenotype', 'HP:0004808', (305, 308))	('mutation', 'Var', (327, 335))
129137	30209701	Interim results (data cut-off 15 March 2018) showed that in patients with IDH1 mutation, ivosidenib 500 mg/day in combination with subcutaneous azacitidine was associated with an ORR of 78% (18/23), and in patients with IDH2 mutation, enasidenib (100 mg once daily) plus azacitidine was associated with an ORR of 67% (4/6 patients).	('IDH1', 'Gene', (74, 78))	('patients', 'Species', '9606', (60, 68))	('patients', 'Species', '9606', (322, 330))	('ivosidenib', 'Chemical', 'MESH:C000627630', (89, 99))	('patients', 'Species', '9606', (206, 214))	('mutation', 'Var', (79, 87))	('IDH2', 'Gene', (220, 224))	('IDH1', 'Gene', '3417', (74, 78))	('azacitidine', 'Chemical', 'MESH:D001374', (144, 155))	('enasidenib', 'Chemical', 'MESH:C000605269', (235, 245))	('IDH2', 'Gene', '3418', (220, 224))	('azacitidine', 'Chemical', 'MESH:D001374', (271, 282))
129140	30209701	Another ongoing, open-label, multicentre, phase 1 study (NCT02632708) is assessing the efficacy of ivosidenib or enasidenib in combination with standard induction chemotherapy in patients aged >= 18 years with previously untreated AML (de novo or secondary) with locally documented IDH1 and/or IDH2 mutation.	('IDH1', 'Gene', (282, 286))	('AML', 'Disease', 'MESH:D015470', (231, 234))	('ivosidenib', 'Chemical', 'MESH:C000627630', (99, 109))	('IDH2', 'Gene', (294, 298))	('IDH1', 'Gene', '3417', (282, 286))	('AML', 'Phenotype', 'HP:0004808', (231, 234))	('AML', 'Disease', (231, 234))	('mutation', 'Var', (299, 307))	('IDH2', 'Gene', '3418', (294, 298))	('patients', 'Species', '9606', (179, 187))	('enasidenib', 'Chemical', 'MESH:C000605269', (113, 123))
129142	30209701	The CR rates with ivosidenib and enasidenib were 63% and 50%, respectively, CRi/CRP rates were 13% and 12%, MLFS rates were 3% and 20%, partial response rates were 7% and 0%, and 7% and 10% of patients had persistent disease.	('ivosidenib', 'Var', (18, 28))	('CR', 'Gene', '1401', (80, 82))	('patients', 'Species', '9606', (193, 201))	('MLFS', 'Disease', (108, 112))	('MLFS', 'Disease', 'None', (108, 112))	('CR', 'Gene', '1401', (76, 78))	('CRP', 'Gene', (80, 83))	('CRP', 'Gene', '1401', (80, 83))	('ivosidenib', 'Chemical', 'MESH:C000627630', (18, 28))	('enasidenib', 'Chemical', 'MESH:C000605269', (33, 43))	('CR', 'Gene', '1401', (4, 6))
129146	30209701	Eligible patients had measurable disease (based on RECIST 1.1) that had recurred or progressed after standard therapy, ECOG PS of 0 or 1 and documented IDH1 mutated advanced solid tumours.	('patients', 'Species', '9606', (9, 17))	('IDH1', 'Gene', (152, 156))	('advanced solid tumours', 'Disease', 'MESH:D006223', (165, 187))	('IDH1', 'Gene', '3417', (152, 156))	('tumours', 'Phenotype', 'HP:0002664', (180, 187))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('advanced solid tumours', 'Disease', (165, 187))	('mutated', 'Var', (157, 164))
129179	30209701	The US FDA has approved the Abbott RealTime IDH1 polymerase chain reaction (PCR) assay, developed collaboratively by Agios Pharmaceuticals and Abbott as a companion diagnostic for the detection of IDH1 mutations in the blood or bone marrow of patients with AML.	('AML', 'Disease', (257, 260))	('patients', 'Species', '9606', (243, 251))	('IDH1', 'Gene', (197, 201))	('IDH1', 'Gene', (44, 48))	('CR', 'Gene', '1401', (77, 79))	('AML', 'Disease', 'MESH:D015470', (257, 260))	('IDH1', 'Gene', '3417', (44, 48))	('IDH1', 'Gene', '3417', (197, 201))	('AML', 'Phenotype', 'HP:0004808', (257, 260))	('mutations', 'Var', (202, 211))
129180	30209701	The PCR assay, when used with the Abbott m2000rt System, qualitatively detects single nucleotide variants (SNVs) coding five IDH1 R132 mutations (R132C, R132H, R132G, R132S and R132L) in DNA extracted from human blood (EDTA) or bone marrow (EDTA).	('EDTA', 'Chemical', 'MESH:D004492', (241, 245))	('EDTA', 'Chemical', 'MESH:D004492', (219, 223))	('R132S', 'Mutation', 'rs121913499', (167, 172))	('human', 'Species', '9606', (206, 211))	('R132G', 'Var', (160, 165))	('IDH1', 'Gene', '3417', (125, 129))	('R132H', 'Var', (153, 158))	('R132L', 'Var', (177, 182))	('R132C', 'Var', (146, 151))	('CR', 'Gene', '1401', (5, 7))	('R132H', 'Mutation', 'rs121913500', (153, 158))	('R132C', 'Mutation', 'rs121913499', (146, 151))	('R132S', 'Var', (167, 172))	('R132L', 'Mutation', 'rs121913500', (177, 182))	('IDH1', 'Gene', (125, 129))	('R132G', 'Mutation', 'rs121913499', (160, 165))
129181	30209701	It is recommended that patients negative for IDH1 mutations at diagnosis should be retested at relapse, as IDH1 mutations may emerge during treatment and at relapse.	('IDH1', 'Gene', '3417', (45, 49))	('IDH1', 'Gene', (107, 111))	('mutations', 'Var', (50, 59))	('IDH1', 'Gene', '3417', (107, 111))	('patients', 'Species', '9606', (23, 31))	('IDH1', 'Gene', (45, 49))
129182	30209701	A phase 1, multicentre, dose-escalation and dose-expansion study is assessing the safety, pharmacokinetics, pharmacodynamics and efficacy of ivosidenib in advanced haematological malignancies with an IDH1 mutation (NCT02074839).	('IDH1', 'Gene', (200, 204))	('IDH1', 'Gene', '3417', (200, 204))	('ivosidenib', 'Chemical', 'MESH:C000627630', (141, 151))	('haematological malignancies', 'Disease', 'MESH:D019337', (164, 191))	('haematological malignancies', 'Disease', (164, 191))	('NCT02074839', 'Var', (215, 226))
129183	30209701	Another open-label, multicentre, phase 1 study (NCT02632708) is determining the safety of ivosidenib and enasidenib, in combination with standard induction and consolidation chemotherapy, in patients aged >= 18 years with previously untreated AML with locally documented IDH1 and/or IDH2 mutation.	('mutation', 'Var', (288, 296))	('IDH1', 'Gene', '3417', (271, 275))	('IDH2', 'Gene', (283, 287))	('patients', 'Species', '9606', (191, 199))	('AML', 'Disease', 'MESH:D015470', (243, 246))	('ivosidenib', 'Chemical', 'MESH:C000627630', (90, 100))	('IDH1', 'Gene', (271, 275))	('AML', 'Disease', (243, 246))	('IDH2', 'Gene', '3418', (283, 287))	('AML', 'Phenotype', 'HP:0004808', (243, 246))	('enasidenib', 'Chemical', 'MESH:C000605269', (105, 115))
129188	30209701	A multicentre, phase 1 dose-escalation and dose-expansion study is evaluating the safety, pharmacokinetics, pharmacodynamics and efficacy of ivosidenib in patients with advanced solid tumours with IDH1 mutations.	('advanced solid tumours', 'Disease', (169, 191))	('IDH1', 'Gene', (197, 201))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('ivosidenib', 'Chemical', 'MESH:C000627630', (141, 151))	('patients', 'Species', '9606', (155, 163))	('advanced solid tumours', 'Disease', 'MESH:D006223', (169, 191))	('IDH1', 'Gene', '3417', (197, 201))	('tumours', 'Phenotype', 'HP:0002664', (184, 191))	('mutations', 'Var', (202, 211))
129190	30209701	A randomized, double-blind, multicentre, placebo-controlled phase 3 study is underway that will assess the efficacy and safety of ivosidenib in 186 previously-treated patients with nonresectable or metastatic cholangiocarcinoma with an IDH1 mutation (NCT02989857).	('cholangiocarcinoma', 'Disease', (209, 227))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (209, 227))	('patients', 'Species', '9606', (167, 175))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (209, 227))	('IDH1', 'Gene', (236, 240))	('mutation', 'Var', (241, 249))	('IDH1', 'Gene', '3417', (236, 240))	('ivosidenib', 'Chemical', 'MESH:C000627630', (130, 140))
129193	30209701	On the 20 July 2018, ivosidenib received its first global approval in the USA for the treatment of adults with relapsed or refractory AML with a susceptible IDH1 mutation, as detected by an FDA-approved test.	('ivosidenib', 'Chemical', 'MESH:C000627630', (21, 31))	('AML', 'Disease', 'MESH:D015470', (134, 137))	('IDH1', 'Gene', (157, 161))	('AML', 'Disease', (134, 137))	('mutation', 'Var', (162, 170))	('IDH1', 'Gene', '3417', (157, 161))	('AML', 'Phenotype', 'HP:0004808', (134, 137))	('relapsed', 'Disease', (111, 119))
129273	28975830	For example, in a recent meta-analysis, genotype 1b was found to be associated with a 78% increased risk of HCC relative to all other genotypes and a 60% increased risk among patients with cirrhosis.	('cirrhosis', 'Disease', (189, 198))	('HCC', 'Phenotype', 'HP:0001402', (108, 111))	('genotype 1b', 'Var', (40, 51))	('cirrhosis', 'Phenotype', 'HP:0001394', (189, 198))	('patients', 'Species', '9606', (175, 183))	('HCC', 'Gene', (108, 111))	('cirrhosis', 'Disease', 'MESH:D005355', (189, 198))	('HCC', 'Gene', '619501', (108, 111))
129274	28975830	However, genotype 3 is currently considered the most difficulty to eradicate and is associated with highest risk of cirrhosis (incidence rate of 30 per 1000 person-years) and HCC (incidence rate of 7.9 per 1000 person-years).	('cirrhosis', 'Phenotype', 'HP:0001394', (116, 125))	('HCC', 'Gene', (175, 178))	('cirrhosis', 'Disease', 'MESH:D005355', (116, 125))	('HCC', 'Gene', '619501', (175, 178))	('genotype 3', 'Var', (9, 19))	('person', 'Species', '9606', (211, 217))	('HCC', 'Phenotype', 'HP:0001402', (175, 178))	('cirrhosis', 'Disease', (116, 125))	('person', 'Species', '9606', (157, 163))
129287	28975830	As is the case for a number of other cancers, tobacco use has consistently been associated with an increased risk of developing HCC and has been labeled as a risk factor for liver cancer by the World Health Organization International Agency for Research on Cancer.	('tobacco', 'Species', '4097', (46, 53))	('liver cancer', 'Disease', (174, 186))	('HCC', 'Phenotype', 'HP:0001402', (128, 131))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tobacco use', 'Var', (46, 57))	('liver cancer', 'Phenotype', 'HP:0002896', (174, 186))	('cancers', 'Disease', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('Cancer', 'Phenotype', 'HP:0002664', (257, 263))	('Cancer', 'Disease', (257, 263))	('HCC', 'Gene', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Cancer', 'Disease', 'MESH:D009369', (257, 263))	('HCC', 'Gene', '619501', (128, 131))	('liver cancer', 'Disease', 'MESH:D006528', (174, 186))
129294	28975830	For example, NAFLD is now the leading cause of cirrhosis in the United States.	('cirrhosis', 'Phenotype', 'HP:0001394', (47, 56))	('cirrhosis', 'Disease', 'MESH:D005355', (47, 56))	('cause', 'Reg', (38, 43))	('cirrhosis', 'Disease', (47, 56))	('NAFLD', 'Var', (13, 18))
129343	28975830	alpha 1-antitrypsin deficiency is associated with an increased risk of both cirrhosis and HCC.	('HCC', 'Phenotype', 'HP:0001402', (90, 93))	('deficiency', 'Var', (20, 30))	('cirrhosis', 'Disease', (76, 85))	('alpha 1-antitrypsin', 'Gene', (0, 19))	('HCC', 'Gene', (90, 93))	('alpha 1-antitrypsin', 'Gene', '5265', (0, 19))	('alpha 1-antitrypsin deficiency', 'Phenotype', 'HP:0032025', (0, 30))	('cirrhosis', 'Phenotype', 'HP:0001394', (76, 85))	('HCC', 'Gene', '619501', (90, 93))	('cirrhosis', 'Disease', 'MESH:D005355', (76, 85))
129368	28975830	The results demonstrated that that Metformin use was associated with a decreased risk relative to no medication (relative risk [RR]: 0.49; 95% CI: 0.25-0.97), insulin (RR: 0.30; 95% CI: 0.18-0.50), and sulfonylurea (RR: 0.44; 95% CI: 0.27-0.72), but not thiazolidinediones.	('insulin', 'Gene', '3630', (159, 166))	('Metformin', 'Var', (35, 44))	('sulfonylurea', 'Chemical', 'MESH:D013453', (202, 214))	('Metformin', 'Chemical', 'MESH:D008687', (35, 44))	('thiazolidinediones', 'Chemical', 'MESH:D045162', (254, 272))	('insulin', 'Gene', (159, 166))	('decreased', 'NegReg', (71, 80))
129369	28975830	Similarly, thiazolidinediones were associated with a decreased risk relative to insulin (RR: 0.33; 95% CI: 0.14-0.78).	('insulin', 'Gene', '3630', (80, 87))	('thiazolidinediones', 'Chemical', 'MESH:D045162', (11, 29))	('thiazolidinediones', 'Var', (11, 29))	('decreased', 'NegReg', (53, 62))	('insulin', 'Gene', (80, 87))
129374	28975830	The findings from the previously mentioned Liver Cancer Pooling Project also suggested a decreased HCC risk associated with caffeinated coffee consumption but no effect on ICC risk.	('Liver Cancer', 'Disease', 'MESH:D006528', (43, 55))	('caffeinated coffee', 'Chemical', '-', (124, 142))	('HCC', 'Gene', '619501', (99, 102))	('HCC', 'Phenotype', 'HP:0001402', (99, 102))	('Liver Cancer', 'Disease', (43, 55))	('Liver Cancer', 'Phenotype', 'HP:0002896', (43, 55))	('men', 'Species', '9606', (33, 36))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('caffeinated coffee', 'Var', (124, 142))	('HCC', 'Gene', (99, 102))	('decreased', 'NegReg', (89, 98))
129384	28883618	CG200745, an HDAC inhibitor, induces anti-tumour effects in cholangiocarcinoma cell lines via miRNAs targeting the Hippo pathway Cholangiocarcinoma is a devastating malignancy with fatal complications that exhibits low response and resistance to chemotherapy.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (60, 78))	('cholangiocarcinoma', 'Disease', (60, 78))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('malignancy', 'Disease', 'MESH:D009369', (165, 175))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (60, 78))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('CG200745', 'Var', (0, 8))	('tumour', 'Disease', (42, 48))	('HDAC', 'Gene', '9734', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (129, 147))	('malignancy', 'Disease', (165, 175))	('HDAC', 'Gene', (13, 17))	('Hippo', 'Pathway', (115, 120))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (129, 147))	('Cholangiocarcinoma', 'Disease', (129, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('CG200745', 'Chemical', 'MESH:C572619', (0, 8))	('miRNAs', 'Var', (94, 100))
129385	28883618	Here, we evaluated the anticancer effects of CG200745, a novel histone deacetylase inhibitor, either alone or in combination with standard chemotherapy drugs in cholangiocarcinoma cells.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('CG200745', 'Chemical', 'MESH:C572619', (45, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('cholangiocarcinoma', 'Disease', (161, 179))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (161, 179))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (161, 179))	('CG200745', 'Var', (45, 53))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
129386	28883618	CG200745 dose-dependently reduced the viability of cholangiocarcinoma cells in vitro and decreased tumour volume and weight in a xenograft model.	('CG200745', 'Chemical', 'MESH:C572619', (0, 8))	('viability', 'CPA', (38, 47))	('cholangiocarcinoma', 'Disease', (51, 69))	('decreased tumour volume', 'Disease', (89, 112))	('CG200745', 'Var', (0, 8))	('reduced', 'NegReg', (26, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (51, 69))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (51, 69))	('decreased tumour volume', 'Disease', 'MESH:D009369', (89, 112))
129387	28883618	Administering CG200745 along with other chemotherapeutic agents including gemcitabine, 5-fluorouracil (5-FU), cisplatin, oxaliplatin, or gemcitabine plus cisplatin further decreased cholangiocarcinoma cell viability, with a combination index < 1 that indicated synergistic action.	('gemcitabine', 'Chemical', 'MESH:C056507', (74, 85))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (121, 132))	('gemcitabine', 'Chemical', 'MESH:C056507', (137, 148))	('cholangiocarcinoma', 'Disease', (182, 200))	('cisplatin', 'Chemical', 'MESH:D002945', (110, 119))	('CG200745', 'Chemical', 'MESH:C572619', (14, 22))	('decreased', 'NegReg', (172, 181))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (182, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (182, 200))	('5-FU', 'Chemical', 'MESH:D005472', (103, 107))	('CG200745', 'Var', (14, 22))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (87, 101))	('cisplatin', 'Chemical', 'MESH:D002945', (154, 163))
129388	28883618	CG200745 also enhanced the sensitivity of gemcitabine-resistant cells to gemcitabine and 5-FU, thereby decreasing cell viability and inducing apoptosis.	('CG200745', 'Chemical', 'MESH:C572619', (0, 8))	('5-FU', 'Chemical', 'MESH:D005472', (89, 93))	('enhanced', 'PosReg', (14, 22))	('sensitivity', 'MPA', (27, 38))	('gemcitabine', 'Chemical', 'MESH:C056507', (42, 53))	('cell viability', 'CPA', (114, 128))	('CG200745', 'Var', (0, 8))	('gemcitabine', 'Chemical', 'MESH:C056507', (73, 84))	('decreasing', 'NegReg', (103, 113))	('apoptosis', 'CPA', (142, 151))	('inducing', 'Reg', (133, 141))
129389	28883618	This was accompanied by downregulation of YAP, TEAD4, TGF-beta2, SMAD3, NOTCH3, HES5, Axl, and Gas6 and upregulation of the miRNAs miR-22-3p, miR-22-5p, miR-194-5p, miR-194-3p, miR-194-5p, miR-210-3p, and miR-509-3p.	('upregulation', 'PosReg', (104, 116))	('miR-210-3p', 'Var', (189, 199))	('miR-22-3p', 'Gene', (131, 140))	('SMAD3', 'Gene', '4088', (65, 70))	('Axl', 'Gene', '558', (86, 89))	('miR-194-5p', 'Var', (153, 163))	('miR-194-5p', 'Var', (177, 187))	('Axl', 'Gene', (86, 89))	('HES5', 'Gene', '388585', (80, 84))	('miR-194-3p', 'Var', (165, 175))	('miR-509-3p', 'Gene', '100847022', (205, 215))	('SMAD3', 'Gene', (65, 70))	('Gas6', 'Gene', '2621', (95, 99))	('Gas6', 'Gene', (95, 99))	('YAP', 'MPA', (42, 45))	('TEAD4', 'Gene', (47, 52))	('NOTCH3', 'Gene', '4854', (72, 78))	('miR-22-3p', 'Gene', '407008', (131, 140))	('TGF-beta2', 'Gene', (54, 63))	('miR-509-3p', 'Gene', (205, 215))	('HES5', 'Gene', (80, 84))	('downregulation', 'NegReg', (24, 38))	('NOTCH3', 'Gene', (72, 78))	('miR-22-5p', 'Var', (142, 151))
129390	28883618	The Ingenuity Pathway Analysis revealed that CG200745 mainly targets the Hippo signalling pathway by inducing miR-509-3p expression.	('miR-509-3p', 'Gene', (110, 120))	('CG200745', 'Chemical', 'MESH:C572619', (45, 53))	('Hippo signalling pathway', 'Pathway', (73, 97))	('inducing', 'Reg', (101, 109))	('CG200745', 'Var', (45, 53))	('miR-509-3p', 'Gene', '100847022', (110, 120))
129391	28883618	Thus, CG200745 inhibits cholangiocarcinoma growth in vitro and in vivo, and acts synergistically when administered in combination with standard chemotherapeutic agents, enabling dose reduction.	('cholangiocarcinoma', 'Disease', (24, 42))	('CG200745', 'Chemical', 'MESH:C572619', (6, 14))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (24, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (24, 42))	('CG200745', 'Var', (6, 14))	('inhibits', 'NegReg', (15, 23))
129392	28883618	CG200745 is therefore expected to improve the outcome of cholangiocarcinoma patients who exhibit resistance to conventional therapies.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (57, 75))	('patients', 'Species', '9606', (76, 84))	('CG200745', 'Chemical', 'MESH:C572619', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('improve', 'PosReg', (34, 41))	('CG200745', 'Var', (0, 8))	('cholangiocarcinoma', 'Disease', (57, 75))
129399	28883618	Hyper- or hypoacetylation of oncogenes and tumour suppressor genes, respectively, is frequently observed in cancer cells.	('oncogenes', 'Gene', (29, 38))	('tumour', 'Disease', 'MESH:D009369', (43, 49))	('tumour', 'Disease', (43, 49))	('hypoacetylation', 'Var', (10, 25))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Hyper-', 'Var', (0, 6))	('observed', 'Reg', (96, 104))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
129402	28883618	HDAC inhibitors have been shown to suppress cell proliferation in vitro and in vivo , and can also rapidly alter micro (mi)RNA levels to induce cell apoptosis in breast and pancreatic cancer and cholangiocarcinoma cells.	('HDAC', 'Gene', (0, 4))	('induce', 'Reg', (137, 143))	('breast and pancreatic cancer', 'Disease', 'MESH:D010190', (162, 190))	('HDAC', 'Gene', '9734', (0, 4))	('cell proliferation', 'CPA', (44, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (173, 190))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (195, 213))	('inhibitors', 'Var', (5, 15))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (195, 213))	('cell apoptosis', 'CPA', (144, 158))	('alter', 'Reg', (107, 112))	('cholangiocarcinoma', 'Disease', (195, 213))	('suppress', 'NegReg', (35, 43))
129406	28883618	CG200745 is an intravenous hydroxamate-based pan-HDAC inhibitor similar to vorinostat whose anti-proliferative effect has been demonstrated in several types of cancer cells, including prostate cancer, renal cell carcinoma, and colon cancer, either alone or in combination with other chemotherapy drugs.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Disease', (193, 199))	('HDAC', 'Gene', '9734', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('colon cancer', 'Disease', 'MESH:D015179', (227, 239))	('renal cell carcinoma', 'Disease', (201, 221))	('HDAC', 'Gene', (49, 53))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (201, 221))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('CG200745', 'Var', (0, 8))	('prostate cancer', 'Disease', 'MESH:D011471', (184, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('prostate cancer', 'Phenotype', 'HP:0012125', (184, 199))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('anti-proliferative', 'MPA', (92, 110))	('colon cancer', 'Disease', (227, 239))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('prostate cancer', 'Disease', (184, 199))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('CG200745', 'Chemical', 'MESH:C572619', (0, 8))	('hydroxamate', 'Chemical', '-', (27, 38))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (201, 221))	('cancer', 'Disease', (233, 239))	('colon cancer', 'Phenotype', 'HP:0003003', (227, 239))	('vorinostat', 'Chemical', 'MESH:D000077337', (75, 85))
129407	28883618	CG200745 was five times more effective than vorinostat in acetylating histone H3 in a colon cancer cell line, and induced acetylation of the tumour suppressor p53, leading to cancer cell death.	('p53', 'Gene', '7157', (159, 162))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('colon cancer', 'Disease', (86, 98))	('cancer cell death', 'Disease', (175, 192))	('p53', 'Gene', (159, 162))	('CG200745', 'Var', (0, 8))	('cancer cell death', 'Disease', 'MESH:D003643', (175, 192))	('leading to', 'Reg', (164, 174))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('CG200745', 'Chemical', 'MESH:C572619', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('acetylation', 'MPA', (122, 133))	('histone H3', 'Protein', (70, 80))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('acetylating', 'MPA', (58, 69))	('tumour', 'Disease', (141, 147))	('colon cancer', 'Disease', 'MESH:D015179', (86, 98))	('vorinostat', 'Chemical', 'MESH:D000077337', (44, 54))
129408	28883618	A previous study showed that treatment with HDAC inhibitor combined with other chemotherapy drugs resulted in an enhanced anti-proliferative effect and reduced toxicity in cholangiocarcinoma cells, and we recently demonstrated that CG200745 has anti-proliferative and synergistic effects in pancreatic cancer cells.	('cholangiocarcinoma', 'Disease', (172, 190))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (172, 190))	('toxicity', 'Disease', (160, 168))	('pancreatic cancer', 'Disease', 'MESH:D010190', (291, 308))	('CG200745', 'Var', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('reduced', 'NegReg', (152, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('pancreatic cancer', 'Disease', (291, 308))	('HDAC', 'Gene', '9734', (44, 48))	('CG200745', 'Chemical', 'MESH:C572619', (232, 240))	('anti-proliferative', 'CPA', (245, 263))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (291, 308))	('anti-proliferative effect', 'CPA', (122, 147))	('synergistic effects', 'CPA', (268, 287))	('HDAC', 'Gene', (44, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (172, 190))	('toxicity', 'Disease', 'MESH:D064420', (160, 168))	('enhanced', 'PosReg', (113, 121))
129409	28883618	In this study, we investigated the anti-tumour effects of CG200745 in cholangiocarcinoma both in vitro and in vivo when administered alone or in combination with gemcitabine, 5-fluorouracil (5-FU), cisplatin, and oxaliplatin.	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('CG200745', 'Chemical', 'MESH:C572619', (58, 66))	('tumour', 'Disease', (40, 46))	('cholangiocarcinoma', 'Disease', (70, 88))	('gemcitabine', 'Chemical', 'MESH:C056507', (162, 173))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (70, 88))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (175, 189))	('cisplatin', 'Chemical', 'MESH:D002945', (198, 207))	('5-FU', 'Chemical', 'MESH:D005472', (191, 195))	('CG200745', 'Var', (58, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (213, 224))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))
129410	28883618	We assessed whether CG200745 can overcome the resistance of cholangiocarcinoma cells to gemcitabine and 5-FU, two standard chemotherapy drugs.	('cholangiocarcinoma', 'Disease', (60, 78))	('gemcitabine', 'Chemical', 'MESH:C056507', (88, 99))	('CG200745', 'Chemical', 'MESH:C572619', (20, 28))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (60, 78))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (60, 78))	('resistance', 'MPA', (46, 56))	('5-FU', 'Chemical', 'MESH:D005472', (104, 108))	('CG200745', 'Var', (20, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
129417	28883618	Histone H3 acetylation was increased and expression of the apoptotic proteins p21 and B cell lymphoma (Bcl)-associated X protein (BAX) was induced by CG200745 treatment (Fig.	('p21', 'Gene', '644914', (78, 81))	('increased', 'PosReg', (27, 36))	('expression', 'MPA', (41, 51))	('lymphoma', 'Phenotype', 'HP:0002665', (93, 101))	('CG200745', 'Var', (150, 158))	('B cell lymphoma (Bcl)-associated X protein (BAX)', 'Gene', '581', (86, 134))	('Histone H3', 'Protein', (0, 10))	('acetylation', 'MPA', (11, 22))	('induced', 'PosReg', (139, 146))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (86, 101))	('cell lymphoma', 'Phenotype', 'HP:0012191', (88, 101))	('CG200745', 'Chemical', 'MESH:C572619', (150, 158))	('p21', 'Gene', (78, 81))	('B cell lymphoma (Bcl)-associated X protein (BAX', 'Gene', (86, 133))
129418	28883618	Moreover, CG200745 inhibited the expression of multidrug resistance (MDR) genes including ABCG2 and multidrug resistance-associated protein (MRP)4; human equilibrative nucleoside transporter (hENT)1; the ABC transporters MRP1 and MRP3; and HDAC class II isozymes including HDAC4 and HDAC7 in SNU-1196, SNU-1196/GR, and SNU-308 cells (Figs 1e,f and.	('HDAC', 'Gene', '9734', (240, 244))	('CG200745', 'Var', (10, 18))	('HDAC', 'Gene', (273, 277))	('expression', 'MPA', (33, 43))	('SNU', 'Chemical', '-', (292, 295))	('MRP1', 'Gene', (221, 225))	('HDAC', 'Gene', (240, 244))	('SNU', 'Chemical', '-', (302, 305))	('inhibited', 'NegReg', (19, 28))	('HDAC7', 'Gene', '51564', (283, 288))	('ABCG2', 'Gene', (90, 95))	('hENT)1', 'Gene', '2030', (192, 198))	('drug resistance', 'Phenotype', 'HP:0020174', (52, 67))	('ABCG2', 'Gene', '9429', (90, 95))	('drug resistance', 'Phenotype', 'HP:0020174', (105, 120))	('ABC', 'Gene', '10058', (204, 207))	('MRP3', 'Gene', (230, 234))	('CG200745', 'Chemical', 'MESH:C572619', (10, 18))	('SNU-1196', 'Chemical', '-', (302, 310))	('HDAC4', 'Gene', '9759', (273, 278))	('human', 'Species', '9606', (148, 153))	('ABC', 'Gene', '10058', (90, 93))	('multidrug resistance-associated protein (MRP)4', 'Gene', '10257', (100, 146))	('ABC', 'Gene', (204, 207))	('HDAC', 'Gene', '9734', (283, 287))	('MRP3', 'Gene', '8714', (230, 234))	('HDAC7', 'Gene', (283, 288))	('SNU-1196', 'Chemical', '-', (292, 300))	('ABC', 'Gene', (90, 93))	('MRP1', 'Gene', '4363', (221, 225))	('HDAC4', 'Gene', (273, 278))	('HDAC', 'Gene', (283, 287))	('SNU', 'Chemical', '-', (319, 322))	('HDAC', 'Gene', '9734', (273, 277))
129421	28883618	Upon treatment with 0.25 and 0.5 muM CG200745, the IC50 values of gemcitabine (0.038 muM) against SNU-1196 cells decreased to 0.002 and < 0.0001 muM, respectively; those of cisplatin (4.898 muM) decreased to 0.562 and 0.105 muM, respectively; and those of 5-FU (104.713 muM) decreased to 1.862 and 0.01 muM, respectively.	('IC50', 'MPA', (51, 55))	('muM', 'Gene', '56925', (145, 148))	('gemcitabine', 'Chemical', 'MESH:C056507', (66, 77))	('muM', 'Gene', (145, 148))	('SNU-1196', 'Chemical', '-', (98, 106))	('CG200745', 'Chemical', 'MESH:C572619', (37, 45))	('decreased', 'NegReg', (113, 122))	('muM', 'Gene', '56925', (224, 227))	('muM', 'Gene', '56925', (303, 306))	('muM', 'Gene', (224, 227))	('muM', 'Gene', (303, 306))	('muM', 'Gene', '56925', (33, 36))	('muM', 'Gene', '56925', (270, 273))	('muM', 'Gene', (270, 273))	('muM', 'Gene', (33, 36))	('5-FU', 'Chemical', 'MESH:D005472', (256, 260))	('muM', 'Gene', '56925', (190, 193))	('cisplatin', 'Chemical', 'MESH:D002945', (173, 182))	('muM', 'Gene', '56925', (85, 88))	('decreased', 'NegReg', (195, 204))	('muM', 'Gene', (190, 193))	('muM', 'Gene', (85, 88))	('CG200745', 'Var', (37, 45))
129422	28883618	Similarly, the IC50 values of oxaliplatin (3.236 muM) decreased to 1.585 and 0.25 muM in the presence of 0.25 and 0.5 muM CG200745, respectively (Supplementary Table 1a).	('CG200745', 'Chemical', 'MESH:C572619', (122, 130))	('muM', 'Gene', '56925', (49, 52))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (30, 41))	('muM', 'Gene', (82, 85))	('0.25', 'Var', (105, 109))	('muM', 'Gene', (49, 52))	('muM', 'Gene', '56925', (118, 121))	('CG200745', 'Var', (122, 130))	('IC50', 'MPA', (15, 19))	('decreased', 'NegReg', (54, 63))	('oxaliplatin', 'MPA', (30, 41))	('muM', 'Gene', (118, 121))	('muM', 'Gene', '56925', (82, 85))
129423	28883618	In SNU-308 cells, upon treatment with 0.5 and 1.0 muM CG200745, the IC50 values of gemcitabine (1.413 muM) decreased to 0.32 and 0.13 muM, respectively; those of cisplatin (3.80 muM) decreased to 2.34 and 1.82 muM, respectively; and those of 5-FU (74.131 muM) decreased to 44.67 and 17.78 muM, respectively.	('muM', 'Gene', '56925', (210, 213))	('muM', 'Gene', (178, 181))	('muM', 'Gene', '56925', (289, 292))	('muM', 'Gene', (210, 213))	('gemcitabine', 'Chemical', 'MESH:C056507', (83, 94))	('muM', 'Gene', '56925', (50, 53))	('muM', 'Gene', (289, 292))	('muM', 'Gene', (50, 53))	('5-FU', 'Chemical', 'MESH:D005472', (242, 246))	('muM', 'Gene', '56925', (255, 258))	('muM', 'Gene', (255, 258))	('decreased', 'NegReg', (183, 192))	('CG200745', 'Var', (54, 62))	('SNU', 'Chemical', '-', (3, 6))	('muM', 'Gene', '56925', (102, 105))	('muM', 'Gene', '56925', (134, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (162, 171))	('muM', 'Gene', (102, 105))	('muM', 'Gene', (134, 137))	('decreased', 'NegReg', (107, 116))	('CG200745', 'Chemical', 'MESH:C572619', (54, 62))	('IC50', 'MPA', (68, 72))	('muM', 'Gene', '56925', (178, 181))
129424	28883618	Similarly, the IC50 values of oxaliplatin (6.918 muM) decreased to 4.57 and 2.82 muM in the presence of 0.5 and 1.0 muM CG200745, respectively (Supplementary Table 2a).	('muM', 'Gene', '56925', (49, 52))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (30, 41))	('muM', 'Gene', (116, 119))	('CG200745', 'Var', (120, 128))	('muM', 'Gene', '56925', (116, 119))	('muM', 'Gene', (49, 52))	('muM', 'Gene', '56925', (81, 84))	('decreased', 'NegReg', (54, 63))	('IC50', 'MPA', (15, 19))	('oxaliplatin', 'MPA', (30, 41))	('CG200745', 'Chemical', 'MESH:C572619', (120, 128))	('muM', 'Gene', (81, 84))
129427	28883618	In SNU-1196, for instance, CG200745 exhibited synergistic cytotoxicity at different gemcitabine concentrations (0.001 to 10.0 muM), with CI values of 0.27 to 0.59 in the presence of 0.25 or 0.5 muM CG200745, respectively (Supplementary Table 1b).	('CG200745', 'Chemical', 'MESH:C572619', (27, 35))	('muM', 'Gene', '56925', (126, 129))	('muM', 'Gene', '56925', (194, 197))	('muM', 'Gene', (126, 129))	('CG200745', 'Var', (27, 35))	('cytotoxicity', 'Disease', (58, 70))	('synergistic', 'MPA', (46, 57))	('CG200745', 'Chemical', 'MESH:C572619', (198, 206))	('muM', 'Gene', (194, 197))	('SNU-1196', 'Chemical', '-', (3, 11))	('gemcitabine', 'Chemical', 'MESH:C056507', (84, 95))	('cytotoxicity', 'Disease', 'MESH:D064420', (58, 70))
129428	28883618	Moreover, 0.038 muM of gemcitabine was required to achieve 50% inhibition; however, a 19-fold or lower concentration was required to achieve the same IC50 with 0.25 muM CG200745 and 100-fold or lower concentration was required with 0.5 muM CG200745 (Supplementary Table 1a, Dose reduction index).	('muM', 'Gene', '56925', (165, 168))	('CG200745', 'Var', (169, 177))	('CG200745', 'Chemical', 'MESH:C572619', (240, 248))	('muM', 'Gene', (165, 168))	('muM', 'Gene', '56925', (16, 19))	('muM', 'Gene', '56925', (236, 239))	('CG200745', 'Var', (240, 248))	('CG200745', 'Chemical', 'MESH:C572619', (169, 177))	('muM', 'Gene', (16, 19))	('gemcitabine', 'Chemical', 'MESH:C056507', (23, 34))	('muM', 'Gene', (236, 239))
129429	28883618	Other drugs also showed synergism and favourable dose reduction with CG200745 (Supplementary Tables 1a,b and 2a,b).	('CG200745', 'Chemical', 'MESH:C572619', (69, 77))	('synergism', 'Interaction', (24, 33))	('CG200745', 'Var', (69, 77))
129430	28883618	Likewise, synergistic concentration-dependent cytotoxicity was observed in triple combinations of gemcitabine plus cisplatin in combination with CG200745 in both cell lines (0.5 muM for SNU-1196 and 1.0 muM for SNU-308) (Fig.	('gemcitabine', 'Chemical', 'MESH:C056507', (98, 109))	('SNU', 'Chemical', '-', (186, 189))	('muM', 'Gene', '56925', (203, 206))	('SNU-1196', 'Chemical', '-', (186, 194))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('cytotoxicity', 'Disease', 'MESH:D064420', (46, 58))	('muM', 'Gene', (178, 181))	('SNU', 'Chemical', '-', (211, 214))	('muM', 'Gene', (203, 206))	('SNU-1196', 'Var', (186, 194))	('CG200745', 'Chemical', 'MESH:C572619', (145, 153))	('cytotoxicity', 'Disease', (46, 58))	('muM', 'Gene', '56925', (178, 181))
129431	28883618	CG200745 was found to reduce the expression of c-MET and increase that of cleaved Caspase-3, which was associated with increased apoptosis (Fig.	('CG200745', 'Chemical', 'MESH:C572619', (0, 8))	('c-MET', 'Gene', '4233', (47, 52))	('reduce', 'NegReg', (22, 28))	('apoptosis', 'CPA', (129, 138))	('CG200745', 'Var', (0, 8))	('c-MET', 'Gene', (47, 52))	('increase', 'PosReg', (57, 65))	('expression', 'MPA', (33, 43))	('Caspase-3', 'Gene', (82, 91))	('Caspase-3', 'Gene', '836', (82, 91))	('increased', 'PosReg', (119, 128))
129434	28883618	The IC50 of gemcitabine decreased from 2.291 to 0.209 and 0.048 muM in the presence of 0.25 and 0.5 muM CG200745, respectively (Fig.	('IC50', 'MPA', (4, 8))	('decreased', 'NegReg', (24, 33))	('muM', 'Gene', (64, 67))	('muM', 'Gene', '56925', (100, 103))	('CG200745', 'Chemical', 'MESH:C572619', (104, 112))	('muM', 'Gene', (100, 103))	('gemcitabine', 'Chemical', 'MESH:C056507', (12, 23))	('CG200745', 'Var', (104, 112))	('muM', 'Gene', '56925', (64, 67))
129435	28883618	The IC50 of 5-FU (229.0 muM) decreased to 35.481, 6.761, and 0.417 muM upon treatment with 0.25, 0.5, and 1.0 muM CG20074, respectively (Fig.	('IC50', 'MPA', (4, 8))	('muM', 'Gene', '56925', (110, 113))	('muM', 'Gene', '56925', (24, 27))	('muM', 'Gene', '56925', (67, 70))	('muM', 'Gene', (24, 27))	('CG20074', 'Var', (114, 121))	('muM', 'Gene', (110, 113))	('decreased', 'NegReg', (29, 38))	('muM', 'Gene', (67, 70))	('5-FU', 'Chemical', 'MESH:D005472', (12, 16))	('CG20074', 'Chemical', '-', (114, 121))
129437	28883618	Addition of CG200745 also increased the levels of cleaved Caspase-3 and poly (ADP ribose) polymerase (PARP), which was associated with increased apoptosis (Fig.	('CG200745', 'Var', (12, 20))	('Caspase-3', 'Gene', (58, 67))	('PARP', 'Gene', (102, 106))	('Caspase-3', 'Gene', '836', (58, 67))	('increased', 'PosReg', (135, 144))	('CG200745', 'Chemical', 'MESH:C572619', (12, 20))	('PARP', 'Gene', '142', (102, 106))	('levels', 'MPA', (40, 46))	('increased', 'PosReg', (26, 35))	('apoptosis', 'CPA', (145, 154))
129438	28883618	Thus, CG200745 increased the sensitivity of cells to gemcitabine plus 5-FU in a dose-dependent manner.	('CG200745', 'Chemical', 'MESH:C572619', (6, 14))	('increased', 'PosReg', (15, 24))	('5-FU', 'Chemical', 'MESH:D005472', (70, 74))	('CG200745', 'Var', (6, 14))	('gemcitabine', 'Chemical', 'MESH:C056507', (53, 64))	('sensitivity', 'MPA', (29, 40))
129440	28883618	Average tumour volumes were 340.6 +- 57.1 and 599.4 +- 205.1 mm3 for the SNU-1196 group and 398.8 +- 67.42 and 959.0 +- 73.80 mm3 for the SNU-1196/GR group injected with CG200745 and saline, respectively (Fig.	('tumour', 'Disease', (8, 14))	('SNU-1196', 'Chemical', '-', (73, 81))	('CG200745', 'Chemical', 'MESH:C572619', (170, 178))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('CG200745', 'Var', (170, 178))	('saline', 'Chemical', 'MESH:D012965', (183, 189))	('tumour', 'Disease', 'MESH:D009369', (8, 14))	('SNU-1196', 'Chemical', '-', (138, 146))
129441	28883618	Average tumour weights were 0.200 +- 0.024 and 0.469 +- 0.162 g for the SNU-1196 group and 0.217 +- 0.026 and 0.543 +- 0.055 g for the SNU-1196/GR group injected with CG200745 and saline, respectively (Fig.	('tumour', 'Disease', (8, 14))	('SNU-1196', 'Chemical', '-', (72, 80))	('CG200745', 'Var', (167, 175))	('SNU-1196', 'Chemical', '-', (135, 143))	('saline', 'Chemical', 'MESH:D012965', (180, 186))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('tumour', 'Disease', 'MESH:D009369', (8, 14))	('CG200745', 'Chemical', 'MESH:C572619', (167, 175))
129443	28883618	All mice treated with CG200745 showed a < 10% decrease in body weight as compared to saline-treated animals.	('saline', 'Chemical', 'MESH:D012965', (85, 91))	('mice', 'Species', '10090', (4, 8))	('body weight', 'CPA', (58, 69))	('CG200745', 'Var', (22, 30))	('CG200745', 'Chemical', 'MESH:C572619', (22, 30))	('decrease', 'NegReg', (46, 54))
129446	28883618	The relationships between gene and miRNA expression patterns among CG200745-treated and untreated SNU-1196 and SNU-1196/GR cells were estimated by hierarchical clustering (Supplementary Fig.	('CG200745-treated', 'Var', (67, 83))	('SNU-1196', 'Chemical', '-', (111, 119))	('miRNA', 'MPA', (35, 40))	('CG200745', 'Chemical', 'MESH:C572619', (67, 75))	('SNU-1196', 'Chemical', '-', (98, 106))
129448	28883618	The top statistically significant pathway was Hippo signalling; genes in this pathway including yes-associated protein (YAP), tafazzin (TAZ), and cluster of differentiation 44 were downregulated upon CG200745 treatment (Fig.	('cluster of differentiation', 'Gene', (146, 172))	('downregulated', 'NegReg', (181, 194))	('TAZ', 'Gene', '6901', (136, 139))	('yes-associated protein', 'Gene', (96, 118))	('TAZ', 'Gene', (136, 139))	('CG200745', 'Chemical', 'MESH:C572619', (200, 208))	('tafazzin', 'Gene', (126, 134))	('yes-associated protein', 'Gene', '10413', (96, 118))	('tafazzin', 'Gene', '6901', (126, 134))	('CG200745', 'Var', (200, 208))
129450	28883618	Microarray and qRT-PCR analyses revealed that miR-22-3p, miR-22-5p, miR-194-5p, miR-194-3p, miR-194-5p, and miR-210-3p were overexpressed in SNU-1196 and SNU-1196/GR cells treated with CG200745 (Fig.	('SNU-1196', 'Chemical', '-', (141, 149))	('miR-22-3p', 'Gene', (46, 55))	('overexpressed', 'PosReg', (124, 137))	('miR-210-3p', 'Var', (108, 118))	('miR-22-3p', 'Gene', '407008', (46, 55))	('CG200745', 'Chemical', 'MESH:C572619', (185, 193))	('miR-194-3p', 'Var', (80, 90))	('miR-22-5p', 'Var', (57, 66))	('miR-194-5p', 'Var', (92, 102))	('CG200745', 'Var', (185, 193))	('SNU-1196', 'Chemical', '-', (154, 162))	('miR-194-5p', 'Var', (68, 78))
129455	28883618	Moreover, Acetylated histone H3 and cleaved-Caspase 3 were upregulated whereas YAP, TEAD4, and TGF-beta2 were downregulated in mice treated with CG200745 relative to controls irrespective of the injected cell line.	('mice', 'Species', '10090', (127, 131))	('cleaved-Caspase', 'MPA', (36, 51))	('upregulated', 'PosReg', (59, 70))	('TGF-beta2', 'Gene', (95, 104))	('CG200745', 'Chemical', 'MESH:C572619', (145, 153))	('downregulated', 'NegReg', (110, 123))	('Acetylated', 'MPA', (10, 20))	('CG200745', 'Var', (145, 153))
129456	28883618	MiR-509-3p expression was also induced by CG200745 treatment (Fig.	('MiR-509-3p', 'Gene', (0, 10))	('CG200745', 'Chemical', 'MESH:C572619', (42, 50))	('CG200745', 'Var', (42, 50))	('MiR-509-3p', 'Gene', '100847022', (0, 10))	('induced', 'Reg', (31, 38))
129461	28883618	Here we demonstrate that a novel HDAC inhibitor, CG200745, selectively targets Hippo signalling in cholangiocarcinoma cells to suppress proliferation and induce apoptosis, acting either alone or synergistically with conventional chemotherapy drugs.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('induce', 'PosReg', (154, 160))	('CG200745', 'Chemical', 'MESH:C572619', (49, 57))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (99, 117))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (99, 117))	('HDAC', 'Gene', (33, 37))	('HDAC', 'Gene', '9734', (33, 37))	('apoptosis', 'CPA', (161, 170))	('CG200745', 'Var', (49, 57))	('suppress', 'NegReg', (127, 135))	('cholangiocarcinoma', 'Disease', (99, 117))	('Hippo signalling', 'MPA', (79, 95))	('proliferation', 'CPA', (136, 149))
129462	28883618	Moreover, CG200745 enhanced the sensitivity of gemcitabine-resistant cholangiocarcinoma cells to these drugs.	('CG200745', 'Chemical', 'MESH:C572619', (10, 18))	('gemcitabine', 'Chemical', 'MESH:C056507', (47, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('cholangiocarcinoma', 'Disease', (69, 87))	('CG200745', 'Var', (10, 18))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (69, 87))	('sensitivity', 'MPA', (32, 43))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (69, 87))	('enhanced', 'PosReg', (19, 27))
129463	28883618	We recently reported that CG200745 either alone or combined with gemcitabine/erlotinib had synergistic anti-tumour effects in pancreatic cancer cells.	('tumour', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('pancreatic cancer', 'Disease', 'MESH:D010190', (126, 143))	('gemcitabine', 'Chemical', 'MESH:C056507', (65, 76))	('CG200745', 'Var', (26, 34))	('erlotinib', 'Chemical', 'MESH:D000069347', (77, 86))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (126, 143))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('CG200745', 'Chemical', 'MESH:C572619', (26, 34))	('tumour', 'Disease', 'MESH:D009369', (108, 114))	('pancreatic cancer', 'Disease', (126, 143))
129464	28883618	In cholangiocarcinoma cells, CG200745 dose-dependently inhibited the proliferation of SNU-1196, SNU-1196/GR, and SNU-308 cells, an effect that was more potent than those of vorinostat and entinostat, which show 2- to 50-fold higher IC50 values in vitro.	('CG200745', 'Var', (29, 37))	('cholangiocarcinoma', 'Disease', (3, 21))	('proliferation', 'CPA', (69, 82))	('SNU-1196', 'Chemical', '-', (86, 94))	('SNU', 'Chemical', '-', (113, 116))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('vorinostat', 'Chemical', 'MESH:D000077337', (173, 183))	('CG200745', 'Chemical', 'MESH:C572619', (29, 37))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('SNU', 'Chemical', '-', (96, 99))	('SNU', 'Chemical', '-', (86, 89))	('entinostat', 'Chemical', 'MESH:C118739', (188, 198))	('inhibited', 'NegReg', (55, 64))	('SNU-1196', 'Chemical', '-', (96, 104))
129465	28883618	In a xenograft model, tumour volume and weight were reduced in both SNU-1196 and SNU-1196/GR groups administered CG200745, with < 10% decreases in body weight.	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('tumour', 'Disease', (22, 28))	('reduced', 'NegReg', (52, 59))	('CG200745', 'Var', (113, 121))	('SNU-1196', 'Chemical', '-', (68, 76))	('SNU-1196', 'Chemical', '-', (81, 89))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('CG200745', 'Chemical', 'MESH:C572619', (113, 121))
129467	28883618	In human trials, CG200745 showed no toxicity at the tested doses, although a number of patients experienced grade 3 and 4 hematologic toxicity with symptoms such as anaemia and neutropenia that lasted for 1 week, as well as grade 1 and 2 toxicity including mild fatigue and anorexia.	('human', 'Species', '9606', (3, 8))	('fatigue', 'Disease', (262, 269))	('CG200745', 'Var', (17, 25))	('fatigue', 'Phenotype', 'HP:0012378', (262, 269))	('toxicity', 'Disease', (238, 246))	('anorexia', 'Phenotype', 'HP:0002039', (274, 282))	('toxicity', 'Disease', 'MESH:D064420', (134, 142))	('neutropenia', 'Disease', (177, 188))	('toxicity', 'Disease', 'MESH:D064420', (36, 44))	('anorexia', 'Disease', (274, 282))	('CG200745', 'Chemical', 'MESH:C572619', (17, 25))	('fatigue', 'Disease', 'MESH:D005221', (262, 269))	('toxicity', 'Disease', (134, 142))	('anaemia', 'Disease', 'MESH:D000740', (165, 172))	('anaemia', 'Disease', (165, 172))	('neutropenia', 'Disease', 'MESH:D009503', (177, 188))	('toxicity', 'Disease', (36, 44))	('neutropenia', 'Phenotype', 'HP:0001875', (177, 188))	('anorexia', 'Disease', 'MESH:D000855', (274, 282))	('toxicity', 'Disease', 'MESH:D064420', (238, 246))	('hematologic toxicity', 'Disease', (122, 142))	('anaemia', 'Phenotype', 'HP:0001903', (165, 172))	('patients', 'Species', '9606', (87, 95))	('hematologic toxicity', 'Disease', 'MESH:D006402', (122, 142))
129470	28883618	CG200745 showed synergistic anti-tumour effects with gemcitabine, 5-FU, cisplatin, and oxaliplatin in these cells, while combined treatment of low-dose chemotherapy drugs and CG200745 showed greater inhibition of cell proliferation than either agent alone.	('CG200745', 'Chemical', 'MESH:C572619', (0, 8))	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('CG200745', 'Chemical', 'MESH:C572619', (175, 183))	('tumour', 'Disease', (33, 39))	('CG200745', 'Var', (175, 183))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (87, 98))	('5-FU', 'Chemical', 'MESH:D005472', (66, 70))	('CG200745', 'Var', (0, 8))	('gemcitabine', 'Chemical', 'MESH:C056507', (53, 64))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('tumour', 'Disease', 'MESH:D009369', (33, 39))
129472	28883618	We found that the triple combination of gemcitabine, cisplatin, and CG200745 (0.5 muM) had both additive and synergistic effects and that the presence of CG200745 decreased IC50 by approximately 4-fold relative to treatment with gemcitabine plus cisplatin only.	('muM', 'Gene', (82, 85))	('CG200745', 'Var', (68, 76))	('CG200745', 'Var', (154, 162))	('IC50', 'MPA', (173, 177))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (246, 255))	('decreased', 'NegReg', (163, 172))	('gemcitabine', 'Chemical', 'MESH:C056507', (229, 240))	('gemcitabine', 'Chemical', 'MESH:C056507', (40, 51))	('CG200745', 'Chemical', 'MESH:C572619', (68, 76))	('muM', 'Gene', '56925', (82, 85))	('CG200745', 'Chemical', 'MESH:C572619', (154, 162))
129473	28883618	The above-described effects may be due to CG200745-induced gene expression.	('CG200745', 'Chemical', 'MESH:C572619', (42, 50))	('CG200745-induced', 'Var', (42, 58))	('CG200745-induced', 'Reg', (42, 58))
129475	28883618	TGF-beta pathway-associated genes including TGF-beta and SMAD and Notch signalling-associated genes were also downregulated in SNU-1196 and SNU-1196/GR cells.	('SMAD', 'Gene', (57, 61))	('TGF-beta', 'Gene', '7040;7042;21808', (44, 52))	('Notch', 'Gene', (66, 71))	('SNU-1196/GR', 'Var', (140, 151))	('TGF-beta', 'Gene', '7040;7042;21808', (0, 8))	('Notch', 'Gene', '4854', (66, 71))	('SNU-1196', 'Chemical', '-', (140, 148))	('TGF-beta', 'Gene', (44, 52))	('SNU-1196', 'Chemical', '-', (127, 135))	('downregulated', 'NegReg', (110, 123))	('SNU-1196', 'Var', (127, 135))	('TGF-beta', 'Gene', (0, 8))
129476	28883618	A previous study demonstrated that expression of the apoptosis-inducing genes AXL and GAS6 was decreased by CG200745 treatment.	('decreased', 'NegReg', (95, 104))	('CG200745', 'Chemical', 'MESH:C572619', (108, 116))	('AXL', 'Gene', '558', (78, 81))	('expression', 'MPA', (35, 45))	('AXL', 'Gene', (78, 81))	('CG200745', 'Var', (108, 116))	('GAS6', 'Gene', (86, 90))	('GAS6', 'Gene', '2621', (86, 90))
129477	28883618	Interestingly, we observed that CG200745 altered the expression levels of miR-22-3p, miR-22-5p, miR-194-5p, miR-194-3p, miR-194-5p, miR-210-3p, and miR-509-3p.	('miR-509-3p', 'Gene', '100847022', (148, 158))	('CG200745', 'Var', (32, 40))	('miR-194-5p', 'Var', (96, 106))	('miR-509-3p', 'Gene', (148, 158))	('altered', 'Reg', (41, 48))	('miR-194-3p', 'Var', (108, 118))	('miR-210-3p', 'Var', (132, 142))	('miR-22-3p', 'Gene', (74, 83))	('miR-22-3p', 'Gene', '407008', (74, 83))	('CG200745', 'Chemical', 'MESH:C572619', (32, 40))	('miR-194-5p', 'Var', (120, 130))	('miR-22-5p', 'Var', (85, 94))	('expression levels', 'MPA', (53, 70))
129488	28883618	The expression of HDAC4, HDAC7, hENT1, and ABC transporters MRP1 and MRP3 in SNU-1196, SNU-1196/GR, and SNU-308 cells was also reduced by CG200745 treatment.	('HDAC7', 'Gene', '51564', (25, 30))	('expression', 'MPA', (4, 14))	('MRP1', 'Gene', '4363', (60, 64))	('SNU', 'Chemical', '-', (87, 90))	('CG200745', 'Chemical', 'MESH:C572619', (138, 146))	('SNU', 'Chemical', '-', (77, 80))	('HDAC7', 'Gene', (25, 30))	('reduced', 'NegReg', (127, 134))	('hENT1', 'Gene', '2030', (32, 37))	('MRP1', 'Gene', (60, 64))	('SNU-1196', 'Chemical', '-', (87, 95))	('hENT1', 'Gene', (32, 37))	('HDAC4', 'Gene', '9759', (18, 23))	('MRP3', 'Gene', (69, 73))	('ABC', 'Gene', '10058', (43, 46))	('ABC', 'Gene', (43, 46))	('SNU-1196', 'Chemical', '-', (77, 85))	('CG200745', 'Var', (138, 146))	('MRP3', 'Gene', '8714', (69, 73))	('SNU', 'Chemical', '-', (104, 107))	('HDAC4', 'Gene', (18, 23))
129490	28883618	A decrease in HDAC4 expression may result from upregulation of miRNAs targeting HDAC proteins, given that miR-22-3p was shown to target HDAC4 and that miR-22-3p expression was increased by CG200745 treatment.	('CG200745', 'Chemical', 'MESH:C572619', (189, 197))	('miR-22-3p', 'Gene', (106, 115))	('HDAC4', 'Gene', (136, 141))	('HDAC4', 'Gene', '9759', (14, 19))	('HDAC', 'Gene', '9734', (136, 140))	('expression', 'MPA', (161, 171))	('HDAC', 'Gene', '9734', (80, 84))	('upregulation', 'PosReg', (47, 59))	('HDAC', 'Gene', (136, 140))	('HDAC4', 'Gene', (14, 19))	('miR-22-3p', 'Gene', '407008', (151, 160))	('HDAC', 'Gene', '9734', (14, 18))	('HDAC', 'Gene', (80, 84))	('CG200745', 'Var', (189, 197))	('miR-22-3p', 'Gene', (151, 160))	('HDAC', 'Gene', (14, 18))	('decrease', 'NegReg', (2, 10))	('expression', 'MPA', (20, 30))	('HDAC4', 'Gene', '9759', (136, 141))	('miR-22-3p', 'Gene', '407008', (106, 115))
129495	28883618	Resistance to gemcitabine can arise from elevated expression of multidrug-resistance genes or an increase in the number of ALDH-positive cells CSCs; combined use of CG200745 with gemcitabine or 5-FU in SNU-1196/GR cells resulted in more potent inhibition of cell growth.	('inhibition', 'NegReg', (244, 254))	('gemcitabine', 'Chemical', 'MESH:C056507', (179, 190))	('CG200745', 'Chemical', 'MESH:C572619', (165, 173))	('gemcitabine', 'Chemical', 'MESH:C056507', (14, 25))	('CG200745', 'Var', (165, 173))	('SNU-1196', 'Chemical', '-', (202, 210))	('5-FU', 'Chemical', 'MESH:D005472', (194, 198))	('cell growth', 'CPA', (258, 269))
129496	28883618	It is worth noting that the IC50 of SNU-1196/GR to gemcitabine decreased more than 10 fold with 0.25 muM CG200745 and 45 fold with 0.5 muM CG200745 as compared to gemcitabine alone; the CI and DRI clearly demonstrated both the additive and synergistic effects of gemcitabine and CG200745.	('CG200745', 'Var', (105, 113))	('CG200745', 'Chemical', 'MESH:C572619', (279, 287))	('CG200745', 'Var', (139, 147))	('SNU-1196', 'Chemical', '-', (36, 44))	('decreased', 'NegReg', (63, 72))	('gemcitabine', 'Chemical', 'MESH:C056507', (51, 62))	('gemcitabine', 'Chemical', 'MESH:C056507', (163, 174))	('muM', 'Gene', '56925', (101, 104))	('muM', 'Gene', '56925', (135, 138))	('CG200745', 'Var', (279, 287))	('CG200745', 'Chemical', 'MESH:C572619', (105, 113))	('CG200745', 'Chemical', 'MESH:C572619', (139, 147))	('muM', 'Gene', (101, 104))	('muM', 'Gene', (135, 138))	('0.25', 'Var', (96, 100))	('gemcitabine', 'Chemical', 'MESH:C056507', (263, 274))
129499	28883618	In conclusion, our study characterised the novel HDAC inhibitor CG200745, which demonstrated anti-tumour effects against cholangiocarcinoma cells in vitro and in vivo with additive and synergistic effects when used in combination with standard chemotherapy drugs.	('HDAC', 'Gene', (49, 53))	('CG200745', 'Var', (64, 72))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('HDAC', 'Gene', '9734', (49, 53))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('cholangiocarcinoma', 'Disease', (121, 139))	('tumour', 'Disease', (98, 104))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (121, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('CG200745', 'Chemical', 'MESH:C572619', (64, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))
129500	28883618	Given the treatment complications such as drug resistance and toxicity associated with conventional therapies, adding CG200745 to the chemotherapeutic regimen could be a safer treatment for cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (190, 208))	('drug resistance', 'Phenotype', 'HP:0020174', (42, 57))	('toxicity', 'Disease', 'MESH:D064420', (62, 70))	('CG200745', 'Chemical', 'MESH:C572619', (118, 126))	('cholangiocarcinoma', 'Disease', (190, 208))	('toxicity', 'Disease', (62, 70))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (190, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('CG200745', 'Var', (118, 126))
129531	28883618	The effect of CG200745 combined with gemcitabine, cisplatin, 5-FU, oxaliplatin, and gemcitabine plus cisplatin on cancer cell viability was evaluated in SNU-1196, SNU-1196/GR, and SNU-308 cells using the fixed-ratio method.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('SNU', 'Chemical', '-', (180, 183))	('5-FU', 'Chemical', 'MESH:D005472', (61, 65))	('SNU', 'Chemical', '-', (153, 156))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('CG200745', 'Chemical', 'MESH:C572619', (14, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('SNU-1196', 'Chemical', '-', (163, 171))	('SNU-1196', 'Chemical', '-', (153, 161))	('CG200745', 'Var', (14, 22))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('SNU', 'Chemical', '-', (163, 166))	('gemcitabine', 'Chemical', 'MESH:C056507', (84, 95))	('gemcitabine', 'Chemical', 'MESH:C056507', (37, 48))	('cancer', 'Disease', (114, 120))
129598	25983747	The monitoring ions were set as m/z 876   308 for paclitaxel and m/z 237   194 for the IS.	('paclitaxel', 'Disease', (50, 60))	('m/z 876   308', 'Var', (32, 45))	('m/z 237   194', 'Var', (65, 78))	('paclitaxel', 'Chemical', 'MESH:D017239', (50, 60))
129618	25983747	Western blotting revealed that the PEM induced expression of cleaved caspase-3, a characteristic of apoptosis, in xenografted tumors (Figure 1(e)).	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('F', 'Chemical', 'MESH:D005461', (134, 135))	('PEM', 'Gene', (35, 38))	('PEM', 'Gene', '4582', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cleaved', 'Var', (61, 68))	('caspase-3', 'Gene', (69, 78))	('expression', 'MPA', (47, 57))
129654	25983747	However, MSCPM-II could be expected to have an antitumor effect by suppressing tumor in-growth from a combination of systemic or radiation treatment.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (51, 56))	('MSCPM-II', 'Var', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('suppressing', 'NegReg', (67, 78))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
129657	25983747	The hallmarks of cancers are deregulation of the cell cycle machinery, self-sufficiency of growth signals, insensitivity to growth inhibitory signals, evasion of apoptosis, tissue invasion, metastasis, and sustained angiogenesis.	('metastasis', 'CPA', (190, 200))	('growth signals', 'CPA', (91, 105))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('deregulation', 'Var', (29, 41))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('self-sufficiency', 'MPA', (71, 87))	('evasion', 'MPA', (151, 158))	('sufficiency of growth', 'Phenotype', 'HP:0001510', (76, 97))	('insensitivity', 'MPA', (107, 120))	('cell cycle machinery', 'CPA', (49, 69))	('tissue invasion', 'CPA', (173, 188))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
129659	25983747	In this study, we showed that the cancer signal transduction pathways were changed by the PEM implanted in pancreatic/cholangiocarcinoma xenografted tumors.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (118, 136))	('pancreatic/cholangiocarcinoma xenografted tumors', 'Disease', 'MESH:D018281', (107, 155))	('implanted', 'Var', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('PEM', 'Gene', (90, 93))	('changed', 'Reg', (75, 82))	('pancreatic/cholangiocarcinoma xenografted tumors', 'Disease', (107, 155))	('PEM', 'Gene', '4582', (90, 93))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', (34, 40))
129661	25983747	Activated mTORC1 regulates protein synthesis by directly phosphorylating S6K and 4E-BP1, which are translation-initiating factors important for cap-dependent mRNA translation and to increase the level of proteins needed for cell cycle progression, proliferation, and angiogenesis.	('S6K', 'Var', (73, 76))	('increase', 'PosReg', (182, 190))	('4E-BP1', 'Gene', '1978', (81, 87))	('level of proteins needed', 'MPA', (195, 219))	('proliferation', 'CPA', (248, 261))	('cell cycle progression', 'CPA', (224, 246))	('mTORC1', 'Gene', '382056', (10, 16))	('regulates', 'Reg', (17, 26))	('angiogenesis', 'CPA', (267, 279))	('4E-BP1', 'Gene', (81, 87))	('mTORC1', 'Gene', (10, 16))	('protein synthesis', 'MPA', (27, 44))
129679	25229838	Notably, NAE1 was identified as an independent prognosticator for postoperative recurrence (P=0.009) and a combination of NEDD8 and NAE1 provided a better power for predicting patient clinical outcomes.	('NAE1', 'Gene', (132, 136))	('NEDD8', 'Gene', '4738', (122, 127))	('NEDD8', 'Gene', (122, 127))	('NAE1', 'Gene', '8883', (132, 136))	('NAE1', 'Gene', '8883', (9, 13))	('NAE1', 'Gene', (9, 13))	('combination', 'Var', (107, 118))	('patient', 'Species', '9606', (176, 183))
129680	25229838	In vitro treatment with MLN4924, a small-molecule NEDD8-activating enzyme inhibitor, led to a dose-dependent decrease of viability in both established and primary cholangiocarcinoma cell lines.	('NEDD8', 'Gene', (50, 55))	('decrease', 'NegReg', (109, 117))	('MLN4924', 'Var', (24, 31))	('NEDD8', 'Gene', '4738', (50, 55))	('cholangiocarcinoma', 'Disease', (163, 181))	('MLN4924', 'Chemical', 'MESH:C539933', (24, 31))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (163, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (163, 181))	('viability', 'MPA', (121, 130))
129682	25229838	By blocking cullins neddylation, MLN4924 inactivated Cullin-Ring ligase (CRL) and caused the accumulation of CRL substrates that triggered cell cycle arrest, senescence or apoptosis.	('inactivated', 'NegReg', (41, 52))	('cullins neddylation', 'Protein', (12, 31))	('Cullin-Ring ligase', 'Protein', (53, 71))	('MLN4924', 'Chemical', 'MESH:C539933', (33, 40))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (139, 156))	('accumulation', 'PosReg', (93, 105))	('MLN4924', 'Var', (33, 40))	('triggered', 'Reg', (129, 138))	('apoptosis', 'CPA', (172, 181))	('cell cycle arrest', 'CPA', (139, 156))	('CRL', 'Protein', (109, 112))	('senescence', 'CPA', (158, 168))	('blocking', 'NegReg', (3, 11))
129683	25229838	Meanwhile, MLN4924 was well-tolerated and significantly inhibited tumor growth in xenograft model of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (101, 119))	('MLN4924', 'Var', (11, 18))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('tumor', 'Disease', (66, 71))	('cholangiocarcinoma', 'Disease', (101, 119))	('MLN4924', 'Chemical', 'MESH:C539933', (11, 18))	('inhibited', 'NegReg', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
129688	25229838	This requires the dysregulation of ubiquitin-proteasome pathway that results in permanent activation of pro-tumor signal cascade.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('activation', 'PosReg', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('dysregulation', 'Var', (18, 31))	('ubiquitin-proteasome pathway', 'Pathway', (35, 63))
129689	25229838	Therefore, modulating the ubiquitin-proteasome pathway represents an attractive anticancer strategy.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('ubiquitin-proteasome pathway', 'Pathway', (26, 54))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('modulating', 'Var', (11, 21))
129696	25229838	Recently, MLN4924, an investigational small-molecule inhibitor of NEDD8-activating enzyme (NAE), has shown antitumor activity in various cancer xenograft models.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('MLN4924', 'Var', (10, 17))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Disease', (111, 116))	('NEDD8', 'Gene', '4738', (66, 71))	('NEDD8', 'Gene', (66, 71))	('cancer', 'Disease', (137, 143))	('MLN4924', 'Chemical', 'MESH:C539933', (10, 17))	('NAE', 'Chemical', '-', (91, 94))
129697	25229838	Mechanistically, MLN4924 abrogates cullin neddylation, inactivates CRL, and thus causes accumulation of CRL substrates, which eventually triggers DNA damage, cell cycle arrest, apoptosis and/or senescence in a broad panel of tumor cells.	('apoptosis', 'CPA', (177, 186))	('cell cycle arrest', 'CPA', (158, 175))	('abrogates', 'NegReg', (25, 34))	('senescence', 'CPA', (194, 204))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('cullin', 'Protein', (35, 41))	('causes', 'Reg', (81, 87))	('DNA damage', 'MPA', (146, 156))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (158, 175))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('triggers', 'Reg', (137, 145))	('tumor', 'Disease', (225, 230))	('CRL', 'Protein', (67, 70))	('MLN4924', 'Chemical', 'MESH:C539933', (17, 24))	('CRL substrates', 'MPA', (104, 118))	('MLN4924', 'Var', (17, 24))	('accumulation', 'PosReg', (88, 100))	('inactivates', 'NegReg', (55, 66))
129698	25229838	Due to its potent anticancer efficacy and well-tolerated toxicity in preclinical studies, MLN4924 is currently tested in several Phase I clinical trials for cancer therapy.	('MLN4924', 'Chemical', 'MESH:C539933', (90, 97))	('toxicity', 'Disease', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('MLN4924', 'Var', (90, 97))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('toxicity', 'Disease', 'MESH:D064420', (57, 65))
129699	25229838	In the present study, we investigated the expression of neddylation pathway in human ICC, and tested the preclinical activity of the NEDD8-activating enzyme inhibitor MLN4924 against ICC cells.	('investigated', 'Reg', (25, 37))	('human', 'Species', '9606', (79, 84))	('MLN4924', 'Chemical', 'MESH:C539933', (167, 174))	('ICC', 'Disease', (85, 88))	('MLN4924', 'Var', (167, 174))	('NEDD8', 'Gene', '4738', (133, 138))	('NEDD8', 'Gene', (133, 138))
129701	25229838	In established and primary cell lines and xenograft model of ICC, we demonstrated that inhibition of neddylation was a promising strategy for treatment of this malignancy.	('malignancy', 'Disease', (160, 170))	('neddylation', 'Protein', (101, 112))	('malignancy', 'Disease', 'MESH:D009369', (160, 170))	('ICC', 'Disease', (61, 64))	('inhibition', 'Var', (87, 97))
129707	25229838	Univariate analyses revealed that high expression of NEDD8, NAE1, and UBC12 were significantly associated with high risks of postoperative recurrence in ICC patients (Fig.	('ICC', 'Disease', (153, 156))	('UBC12', 'Gene', '9040', (70, 75))	('NAE1', 'Gene', '8883', (60, 64))	('patients', 'Species', '9606', (157, 165))	('NAE1', 'Gene', (60, 64))	('high', 'Var', (34, 38))	('NEDD8', 'Gene', (53, 58))	('associated', 'Reg', (95, 105))	('UBC12', 'Gene', (70, 75))	('NEDD8', 'Gene', '4738', (53, 58))
129713	25229838	Patients with high expression of NAE1 were 1.62 times more likely to suffer from tumor recurrence than those with low expression (HR, 1.62; 95%CI, 1.13-2.33), similar to the predictive power of tumor vascular invasion (HR, 1.65; 95%CI, 1.12-2.43; P = 0.011).	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('NAE1', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('NAE1', 'Gene', '8883', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('tumor', 'Disease', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('suffer', 'Reg', (69, 75))
129720	25229838	Patients with simultaneously high expression of NEDD8 and NAE1 had a strikingly shorter TTR (median, 13.5 months) than patients with NEDD8low/NAE1low (median, 81.0 months) (P = 0.002) (Fig.	('NAE1', 'Gene', (58, 62))	('NAE1', 'Gene', '8883', (58, 62))	('NAE1', 'Gene', '8883', (142, 146))	('high expression', 'Var', (29, 44))	('NAE1', 'Gene', (142, 146))	('patients', 'Species', '9606', (119, 127))	('NEDD8', 'Gene', '4738', (48, 53))	('NEDD8', 'Gene', (48, 53))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (80, 87))	('TTR', 'MPA', (88, 91))	('NEDD8', 'Gene', '4738', (133, 138))	('NEDD8', 'Gene', (133, 138))
129722	25229838	Multivariate Cox analysis, adopting conventional clinicopathologic features, confirmed that the combination of NEDD8 and NAE1 was an independent prognostic factor for TTR (Supplementary Table S4).	('NAE1', 'Gene', (121, 125))	('NAE1', 'Gene', '8883', (121, 125))	('Cox', 'Gene', (13, 16))	('combination', 'Var', (96, 107))	('NEDD8', 'Gene', (111, 116))	('TTR', 'Disease', (167, 170))	('NEDD8', 'Gene', '4738', (111, 116))	('Cox', 'Gene', '1351', (13, 16))
129724	25229838	Considering the clinical significance of overactivated neddylation pathway in ICC, we further tested the efficacy of MLN4924, a specific inhibitor of NAE, on cholangiocarcinoma cells QBC939 and RBE.	('tested', 'Reg', (94, 100))	('cholangiocarcinoma', 'Disease', (158, 176))	('NAE', 'Chemical', '-', (150, 153))	('MLN4924', 'Var', (117, 124))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (158, 176))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (158, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('QBC939', 'CellLine', 'CVCL:6942', (183, 189))	('MLN4924', 'Chemical', 'MESH:C539933', (117, 124))
129726	25229838	3B) cell proliferation assays, MLN4924 significantly inhibited the proliferation of cells in a dose-dependent manner.	('MLN4924', 'Chemical', 'MESH:C539933', (31, 38))	('MLN4924', 'Var', (31, 38))	('inhibited', 'NegReg', (53, 62))	('proliferation of cells', 'CPA', (67, 89))
129727	25229838	Likewise, MLN4924 caused a dose-dependent inhibition of colony formation of QBC939 and RBE cells (Fig.	('MLN4924', 'Var', (10, 17))	('colony formation', 'CPA', (56, 72))	('QBC939', 'CellLine', 'CVCL:6942', (76, 82))	('inhibition', 'NegReg', (42, 52))	('MLN4924', 'Chemical', 'MESH:C539933', (10, 17))
129728	25229838	In four primary ICC cell lines, MLN4924 effectively suppressed growth of two cell lines with the IC50 of 0.378 or 0.629 muM, respectively (Supplementary Fig.	('MLN4924', 'Var', (32, 39))	('growth', 'CPA', (63, 69))	('suppressed', 'NegReg', (52, 62))	('MLN4924', 'Chemical', 'MESH:C539933', (32, 39))
129730	25229838	Thus, these data demonstrated that MLN4924 was a potent inhibitor of cell proliferation and survival in ICC cells.	('inhibitor', 'NegReg', (56, 65))	('survival', 'CPA', (92, 100))	('MLN4924', 'Var', (35, 42))	('cell proliferation', 'CPA', (69, 87))	('MLN4924', 'Chemical', 'MESH:C539933', (35, 42))
129731	25229838	In addition, potential synergy was observed between MLN4924 and cisplatin, an agent used for clinical management of ICC (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (52, 59))	('synergy', 'Interaction', (23, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('MLN4924', 'Var', (52, 59))
129732	25229838	3D), suggesting that MLN4924 favorably impact the anti-tumor activity of cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('impact', 'Reg', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('MLN4924', 'Chemical', 'MESH:C539933', (21, 28))	('MLN4924', 'Var', (21, 28))
129733	25229838	Triggering cell-cycle disturbance, apoptosis, and senescence were reported to be responsible for anti-tumor effects of MLN4924.	('tumor', 'Disease', (102, 107))	('senescence', 'CPA', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('MLN4924', 'Chemical', 'MESH:C539933', (119, 126))	('cell-cycle disturbance', 'CPA', (11, 33))	('MLN4924', 'Var', (119, 126))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('apoptosis', 'CPA', (35, 44))
129735	25229838	In line with the role as a G2-M regulator, sharp increases of cell cycle inhibitors p21, p27, WEE1 (a well defined CRL substrate and an inhibitor of G2-M phase transition), and obvious decrease of a hallmark of M phase, p-Histone H3 (p-H3, ser10), were observed in QBC939 and RBE cells (Fig.	('p27', 'Gene', '3429', (89, 92))	('p27', 'Gene', (89, 92))	('WEE1', 'Gene', '7465', (94, 98))	('cell cycle', 'CPA', (62, 72))	('WEE1', 'Gene', (94, 98))	('p-Histone', 'Var', (220, 229))	('QBC939', 'CellLine', 'CVCL:6942', (265, 271))	('decrease', 'NegReg', (185, 193))	('increases', 'PosReg', (49, 58))	('ser10', 'Chemical', '-', (240, 245))	('p21', 'Gene', (84, 87))	('p21', 'Gene', '644914', (84, 87))
129738	25229838	In QBC939 cells, MLN4924 induced apoptosis as reflected by a shrunk morphology in shape (a feature of apoptosis), cleaved caspase 3 and PARP (Fig.	('cleaved', 'CPA', (114, 121))	('apoptosis', 'CPA', (33, 42))	('QBC939', 'CellLine', 'CVCL:6942', (3, 9))	('PARP', 'Gene', (136, 140))	('shrunk morphology in shape', 'CPA', (61, 87))	('MLN4924', 'Chemical', 'MESH:C539933', (17, 24))	('PARP', 'Gene', '142', (136, 140))	('MLN4924', 'Var', (17, 24))	('caspase 3', 'Protein', (122, 131))
129739	25229838	In contrast, in RBE cells, MLN4924 triggered senescence as demonstrated by an enlarged and flattened cellular shape as well as the expression of senescence-associated beta-galactosidase (Fig.	('enlarged', 'PosReg', (78, 86))	('senescence', 'CPA', (45, 55))	('MLN4924', 'Var', (27, 34))	('expression', 'MPA', (131, 141))	('MLN4924', 'Chemical', 'MESH:C539933', (27, 34))
129743	25229838	To further confirm the anti-tumor effects by targeting NAE1 in vivo, MLN4924 was administered to QBC939 subcutaneous xenografts, and the kinetic growth of tumors was monitored.	('NAE1', 'Gene', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('NAE1', 'Gene', '8883', (55, 59))	('tumor', 'Disease', (28, 33))	('MLN4924', 'Var', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('QBC939', 'CellLine', 'CVCL:6942', (97, 103))	('QBC939', 'Gene', (97, 103))	('MLN4924', 'Chemical', 'MESH:C539933', (69, 76))
129747	25229838	At the end point of MLN4924 treatment, tumors of both treated and control groups were collected, imaged (Fig.	('tumors', 'Disease', (39, 45))	('MLN4924', 'Var', (20, 27))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('MLN4924', 'Chemical', 'MESH:C539933', (20, 27))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
129750	25229838	The results clearly indicated that MLN4924 had a strong anti-tumor activity against cholangiocarcinoma in vivo and was well tolerated in mice.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('MLN4924', 'Var', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cholangiocarcinoma', 'Disease', (84, 102))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MLN4924', 'Chemical', 'MESH:C539933', (35, 42))	('tumor', 'Disease', (61, 66))	('mice', 'Species', '10090', (137, 141))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
129752	25229838	The results showed a marked decrease of PCNA and Ki-67 intensities indicating the suppression of cell proliferation, and an obvious increase in TUNEL staining indicating the induction of apoptosis in MLN4924 treated tumors, as compared with control tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('apoptosis', 'CPA', (187, 196))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('increase', 'PosReg', (132, 140))	('MLN4924', 'Chemical', 'MESH:C539933', (200, 207))	('PCNA', 'Gene', '5111', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumors', 'Disease', (216, 222))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('decrease', 'NegReg', (28, 36))	('MLN4924', 'Var', (200, 207))	('cell proliferation', 'CPA', (97, 115))	('TUNEL staining', 'MPA', (144, 158))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('suppression', 'NegReg', (82, 93))	('tumors', 'Disease', (249, 255))	('PCNA', 'Gene', (40, 44))
129755	25229838	Herein, for the first time, we revealed the clinical significance of neddylation pathway overactivation and reported preclinical evaluation of inhibiting this pathway using MLN4924, a potent and selective small-molecule inhibitor of NEDD8-activating enzyme, in ICC.	('neddylation pathway', 'Pathway', (69, 88))	('overactivation', 'PosReg', (89, 103))	('MLN4924', 'Chemical', 'MESH:C539933', (173, 180))	('NEDD8', 'Gene', (233, 238))	('inhibiting', 'NegReg', (143, 153))	('MLN4924', 'Var', (173, 180))	('NEDD8', 'Gene', '4738', (233, 238))
129757	25229838	Moreover, we demonstrated that MLN4924 had a broad tumoricidal activity both in vivo and in vitro.	('MLN4924', 'Var', (31, 38))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('MLN4924', 'Chemical', 'MESH:C539933', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
129758	25229838	Similarly, we and others recently had reported that neddylation pathway was overactivated in several types of human cancer and inhibition of this pathway significantly inhibited tumor growth.	('tumor', 'Disease', (178, 183))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('human', 'Species', '9606', (110, 115))	('inhibition', 'Var', (127, 137))	('inhibited', 'NegReg', (168, 177))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('neddylation pathway', 'Pathway', (52, 71))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('overactivated', 'PosReg', (76, 89))
129760	25229838	The therapeutic potential of modulating components of the UPS and UBL conjugation pathways in cancer has been demonstrated by the proteasome inhibitor bortezomib (Velcade; Millennium Pharmaceuticals).	('UPS', 'Disease', (58, 61))	('modulating', 'Var', (29, 39))	('bortezomib', 'Chemical', 'MESH:D000069286', (151, 161))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Velcade', 'Chemical', 'MESH:D000069286', (163, 170))	('UPS', 'Disease', 'MESH:D017118', (58, 61))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
129763	25229838	More importantly, NAE1 was identified as an independent factor for postoperative recurrence and a combination of NAE1 and NEDD8 provided a better prediction for patient prognosis.	('NAE1', 'Gene', '8883', (18, 22))	('combination', 'Var', (98, 109))	('NEDD8', 'Gene', '4738', (122, 127))	('NAE1', 'Gene', (18, 22))	('NEDD8', 'Gene', (122, 127))	('patient', 'Species', '9606', (161, 168))	('NAE1', 'Gene', '8883', (113, 117))	('NAE1', 'Gene', (113, 117))
129765	25229838	Then, we demonstrated significant anti-tumor and chemosensitizing/synergizing effects of MLN4924 both in established and primary cholangiocarcinoma cell lines, as well as in mice xenograft model with low toxicity.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (129, 147))	('mice', 'Species', '10090', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (129, 147))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('MLN4924', 'Chemical', 'MESH:C539933', (89, 96))	('toxicity', 'Disease', 'MESH:D064420', (204, 212))	('tumor', 'Disease', (39, 44))	('toxicity', 'Disease', (204, 212))	('MLN4924', 'Var', (89, 96))	('chemosensitizing/synergizing', 'CPA', (49, 77))	('cholangiocarcinoma', 'Disease', (129, 147))
129766	25229838	Interestingly, MLN4924 induced cell death via either apoptosis or cellular senescence in a cell line-dependent manner.	('apoptosis', 'CPA', (53, 62))	('MLN4924', 'Chemical', 'MESH:C539933', (15, 22))	('cellular senescence', 'CPA', (66, 85))	('cell death', 'CPA', (31, 41))	('MLN4924', 'Var', (15, 22))
129767	25229838	Mechanistically, the anticancer efficacy of MLN4924 is mainly attributed to the inhibition of CRL activity and the accumulation of CRL substrates.	('inhibition', 'NegReg', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('MLN4924', 'Chemical', 'MESH:C539933', (44, 51))	('MLN4924', 'Var', (44, 51))	('accumulation', 'PosReg', (115, 127))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('CRL activity', 'CPA', (94, 106))	('CRL substrates', 'MPA', (131, 145))
129768	25229838	For examples, MLN4924 treatment led to the accumulation of (a) G2-M phase transition inhibitor WEE1 that led to G2 phase cell cycle arrest, (b) DNA replication licensing protein CDT1 and ORC1 that triggered DNA re-replication stress and DNA damage, (c) tumor suppressor p21 and p27 that resulted in cell senescence, and (d) pro-apoptotic proteins such as NOXA that induced apoptosis.	('ORC1', 'Gene', '4998', (187, 191))	('NOXA', 'Gene', (355, 359))	('p27', 'Gene', '3429', (278, 281))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('p27', 'Gene', (278, 281))	('ORC1', 'Gene', (187, 191))	('led to', 'Reg', (105, 111))	('p21', 'Gene', (270, 273))	('p21', 'Gene', '644914', (270, 273))	('MLN4924', 'Chemical', 'MESH:C539933', (14, 21))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (121, 138))	('G2 phase cell cycle arrest', 'CPA', (112, 138))	('accumulation', 'PosReg', (43, 55))	('WEE1', 'Gene', '7465', (95, 99))	('CDT1', 'Gene', '81620', (178, 182))	('CDT1', 'Gene', (178, 182))	('DNA re-replication', 'MPA', (207, 225))	('tumor', 'Disease', (253, 258))	('DNA damage', 'MPA', (237, 247))	('cell senescence', 'CPA', (299, 314))	('MLN4924', 'Var', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('NOXA', 'Gene', '5366', (355, 359))	('WEE1', 'Gene', (95, 99))
129770	25229838	NOXA) which plays a critical role in cell fate determination (apoptosis vs senescence) upon neddylation disruption with MLN4924.	('NOXA', 'Gene', (0, 4))	('MLN4924', 'Var', (120, 127))	('NOXA', 'Gene', '5366', (0, 4))	('MLN4924', 'Chemical', 'MESH:C539933', (120, 127))
129772	25229838	Considering that induction of NF-kappaB signaling was an important mechanism of resistance to many chemotherapeutic and targeted agents, MLN4924 may be helpful to overcome NF-kappaB-related treatment resistance.	('NF-kappaB', 'Gene', '4790', (30, 39))	('NF-kappaB', 'Gene', '4790', (172, 181))	('NF-kappaB', 'Gene', (30, 39))	('MLN4924', 'Chemical', 'MESH:C539933', (137, 144))	('NF-kappaB', 'Gene', (172, 181))	('MLN4924', 'Var', (137, 144))
129773	25229838	The anti-tumor potential of MLN4924 in ICC was largely in line with those findings in hematological malignancies and other solid tumors, supporting the rationale to develop phase I trials for evaluating MLN4924 in ICC.	('hematological malignancies', 'Phenotype', 'HP:0004377', (86, 112))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('MLN4924', 'Var', (203, 210))	('solid tumors', 'Disease', (123, 135))	('MLN4924', 'Var', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('ICC', 'Disease', (39, 42))	('solid tumors', 'Disease', 'MESH:D009369', (123, 135))	('tumor', 'Disease', (9, 14))	('hematological malignancies', 'Disease', (86, 112))	('hematological malignancies', 'Disease', 'MESH:D019337', (86, 112))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('MLN4924', 'Chemical', 'MESH:C539933', (203, 210))	('MLN4924', 'Chemical', 'MESH:C539933', (28, 35))
129774	25229838	However, one of the primary ICC cell line with the lowest expression of NAE1 were highly resistant to MLN4924 treatment, indicating the presence of primary resistance to MLN4924 in ICC, and highlighting the need for precise patient selection according to the activation status of neddylation pathway.	('MLN4924', 'Chemical', 'MESH:C539933', (170, 177))	('NAE1', 'Gene', (72, 76))	('NAE1', 'Gene', '8883', (72, 76))	('patient', 'Species', '9606', (224, 231))	('MLN4924', 'Var', (170, 177))	('lowest', 'NegReg', (51, 57))	('MLN4924', 'Chemical', 'MESH:C539933', (102, 109))	('ICC', 'Disease', (181, 184))
129775	25229838	Similarly, treatment-induced mutations of NAEbeta/UBA3 were reported to lead to secondary resistance to MLN4924 in leukemia, further mandating the development of combinational regiments including MLN4924 or novel next-generation NAE inhibitors.	('MLN4924', 'Chemical', 'MESH:C539933', (104, 111))	('NAE', 'Chemical', '-', (229, 232))	('MLN4924', 'Var', (104, 111))	('mutations', 'Var', (29, 38))	('UBA3', 'Gene', '9039', (50, 54))	('MLN4924', 'Chemical', 'MESH:C539933', (196, 203))	('leukemia', 'Disease', 'MESH:D007938', (115, 123))	('leukemia', 'Disease', (115, 123))	('lead to', 'Reg', (72, 79))	('NAE', 'Chemical', '-', (42, 45))	('leukemia', 'Phenotype', 'HP:0001909', (115, 123))	('UBA3', 'Gene', (50, 54))	('secondary resistance', 'MPA', (80, 100))
129776	25229838	In summary, our study demonstrated that neddylation pathway was upregulated/overactivated in ICC and served as a promising therapeutic target, which provided impetus for clinical trials of MLN4924 in the treatment of ICC.	('ICC', 'Disease', (93, 96))	('MLN4924', 'Var', (189, 196))	('neddylation pathway', 'Pathway', (40, 59))	('MLN4924', 'Chemical', 'MESH:C539933', (189, 196))	('upregulated/overactivated', 'PosReg', (64, 89))
129777	25229838	Due to the primary resistance to MLN4924, expression status of neddylation pathway may provide a base for appropriate patient enrollment, although further validation was need.	('MLN4924', 'Chemical', 'MESH:C539933', (33, 40))	('neddylation pathway', 'Pathway', (63, 82))	('MLN4924', 'Var', (33, 40))	('patient', 'Species', '9606', (118, 125))
129795	25229838	For in vivo studies, MLN4924 was dissolved in 10% 2-hydroxypropyl-b-cyclodextrin (HPBCD), and the solution of MLN4924 was freshly made every week and stored in dark at room temperature before use.	('MLN4924', 'Chemical', 'MESH:C539933', (110, 117))	('MLN4924', 'Var', (110, 117))	('MLN4924', 'Chemical', 'MESH:C539933', (21, 28))	('2-hydroxypropyl-b-cyclodextrin', 'Chemical', '-', (50, 80))	('MLN4924', 'Var', (21, 28))
129803	25229838	Cells treated with MLN4924 or DMSO were harvested and fixed in 70% ethanol at -20 C overnight, and stained with propidium iodide (PI, 36 mug/ml, Sigma) containing RNAase (10 mug/ml, Sigma) at 37 C for 15 min, then analyzed for apoptosis and cell cycle profile by CyAnTM ADP (Beckman Coulter) as previously described.	('MLN4924', 'Chemical', 'MESH:C539933', (19, 26))	('cell cycle', 'CPA', (241, 251))	('ethanol', 'Chemical', 'MESH:D000431', (67, 74))	('DMSO', 'Chemical', 'MESH:D004121', (30, 34))	('MLN4924', 'Var', (19, 26))	('apoptosis', 'CPA', (227, 236))	('propidium iodide', 'Chemical', 'MESH:D011419', (112, 128))
129875	33306714	Univariate analyses showed that patients with NLR >=3 had significantly worse 2-year DFS and 5-year OS rates.	('OS rates', 'CPA', (100, 108))	('patients', 'Species', '9606', (32, 40))	('worse', 'NegReg', (72, 77))	('DFS', 'CPA', (85, 88))	('NLR >=3', 'Var', (46, 53))
129946	33306714	Although their study showed portal invasion was more frequent in patients with >50% IHC cells within the tumor than in patients with <=50% IHC cells, but there was no statistically significant difference.	('portal invasion', 'CPA', (28, 43))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('patients', 'Species', '9606', (65, 73))	('tumor', 'Disease', (105, 110))	('IHC', 'Var', (84, 87))
129965	33306714	13 Jul 2020  PONE-D-20-07323 Elevated neutrophil-to-lymphocyte ratio and predominance of intrahepatic cholangiocarcinoma prediction of poor hepatectomy outcomes in  patients with combined hepatocellular-cholangiocarcinoma PLOS ONE Dear Dr. Chen, Thank you for submitting your manuscript to PLOS ONE.	('intrahepatic cholangiocarcinoma', 'Disease', (89, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('hepatocellular-cholangiocarcinoma', 'Disease', (188, 221))	('PONE-D-20-07323', 'Var', (13, 28))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (102, 120))	('PONE-D-20-07323', 'Chemical', '-', (13, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (203, 221))	('patients', 'Species', '9606', (165, 173))	('hepatocellular-cholangiocarcinoma', 'Disease', 'MESH:D018281', (188, 221))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (89, 120))	('Elevated', 'PosReg', (29, 37))
129991	33306714	The cut-offs values of CEA, CA199 and AFP were the upper limit of normal range in our hospital.	('CEA', 'Gene', (23, 26))	('AFP', 'Gene', (38, 41))	('CEA', 'Gene', '1084', (23, 26))	('CA199', 'Var', (28, 33))	('AFP', 'Gene', '174', (38, 41))
130013	33306714	5 Oct 2020  Elevated neutrophil-to-lymphocyte ratio and predominance of intrahepatic cholangiocarcinoma prediction of poor hepatectomy outcomes in  patients with combined hepatocellular-cholangiocarcinoma PONE-D-20-07323R1 Dear Dr. Chen, We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.	('patients', 'Species', '9606', (148, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('neutrophil-to-lymphocyte ratio', 'MPA', (21, 51))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 103))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('hepatocellular-cholangiocarcinoma', 'Disease', (171, 204))	('intrahepatic cholangiocarcinoma', 'Disease', (72, 103))	('hepatocellular-cholangiocarcinoma', 'Disease', 'MESH:D018281', (171, 204))	('Oct', 'Gene', '5362', (2, 5))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (186, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('PONE-D-20-07323', 'Chemical', '-', (205, 220))	('PONE-D-20-07323R1', 'Var', (205, 222))	('Oct', 'Gene', (2, 5))	('Elevated', 'PosReg', (12, 20))
130016	33306714	2 Dec 2020  PONE-D-20-07323R1  Elevated neutrophil-to-lymphocyte ratio and predominance of intrahepatic cholangiocarcinoma prediction of poor hepatectomy outcomes in patients with combined hepatocellular-cholangiocarcinoma  Dear Dr. Chen: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE.	('intrahepatic cholangiocarcinoma', 'Disease', (91, 122))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (204, 222))	('PONE-D-20-07323R1', 'Var', (12, 29))	('hepatocellular-cholangiocarcinoma', 'Disease', 'MESH:D018281', (189, 222))	('Elevated', 'PosReg', (31, 39))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('hepatocellular-cholangiocarcinoma', 'Disease', (189, 222))	('PONE-D-20-07323', 'Chemical', '-', (12, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (104, 122))	('patients', 'Species', '9606', (166, 174))
130047	28420720	We have identified structurally novel "drug-like" inhibitors of SK1 and SK2, and ABC294640 was selected as the first compound in this program for clinical testing.	('ABC294640', 'Var', (81, 90))	('ABC294640', 'Chemical', 'MESH:C548780', (81, 90))	('SK2', 'Gene', (72, 75))	('SK1', 'Gene', '8877', (64, 67))	('SK1', 'Gene', (64, 67))	('SK2', 'Gene', '56848', (72, 75))
130048	28420720	ABC294640 is an inhibitor of SK2 (Ki = 9 muM, 3.4 mug/mL) and is competitive with respect to sphingosine, which greatly reduces its potential for off-target inhibition of protein kinases.	('ABC294640', 'Var', (0, 9))	('ABC294640', 'Chemical', 'MESH:C548780', (0, 9))	('reduces', 'NegReg', (120, 127))	('SK2', 'Gene', '56848', (29, 32))	('protein kinases', 'Pathway', (171, 186))	('SK2', 'Gene', (29, 32))	('sphingosine', 'Chemical', 'MESH:D013110', (93, 104))	('off-target', 'MPA', (146, 156))
130049	28420720	ABC294640 depletes S1P and elevates ceramide in tumor cells, suppresses signaling through pERK and pAKT, and promotes autophagy and/or apoptosis in tumor cells.	('apoptosis', 'CPA', (135, 144))	('elevates', 'PosReg', (27, 35))	('ABC294640', 'Chemical', 'MESH:C548780', (0, 9))	('S1P', 'Chemical', 'MESH:C060506', (19, 22))	('ABC294640', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('promotes', 'PosReg', (109, 117))	('autophagy', 'CPA', (118, 127))	('pERK', 'Gene', (90, 94))	('pERK', 'Gene', '9451', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('ceramide', 'MPA', (36, 44))	('suppresses', 'NegReg', (61, 71))	('tumor', 'Disease', (148, 153))	('ceramide', 'Chemical', 'MESH:D002518', (36, 44))	('depletes S1P', 'MPA', (10, 22))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
130050	28420720	ABC294640 down-regulates the expression of c-Myc in a variety of tumor cell lines, and also reduces androgen receptor expression in prostate cancer cells.	('ABC294640', 'Var', (0, 9))	('prostate cancer', 'Disease', (132, 147))	('androgen receptor', 'Gene', (100, 117))	('ABC294640', 'Chemical', 'MESH:C548780', (0, 9))	('tumor', 'Disease', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('prostate cancer', 'Disease', 'MESH:D011471', (132, 147))	('c-Myc', 'Gene', '4609', (43, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('androgen receptor', 'Gene', '367', (100, 117))	('reduces', 'NegReg', (92, 99))	('down-regulates', 'NegReg', (10, 24))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('reduces androgen receptor expression', 'Phenotype', 'HP:0030349', (92, 128))	('expression', 'MPA', (29, 39))	('c-Myc', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
130051	28420720	ABC294640 was also recently shown to inhibit dihydroceramide desaturase, which accounts for the marked increases in dihydroceramides in cells treated with the drug.	('dihydroceramides', 'Chemical', 'MESH:C109343', (116, 132))	('ABC294640', 'Var', (0, 9))	('ABC294640', 'Chemical', 'MESH:C548780', (0, 9))	('increases', 'PosReg', (103, 112))	('ceramide', 'Chemical', 'MESH:D002518', (123, 131))	('inhibit', 'NegReg', (37, 44))	('ceramide', 'Chemical', 'MESH:D002518', (52, 60))	('dihydroceramide desaturase', 'Enzyme', (45, 71))	('dihydroceramides', 'MPA', (116, 132))
130054	28420720	As a pharmacodynamic marker, ABC294640 reduces plasma S1P levels up to 50% at therapeutically efficacious drug doses.	('plasma S1P levels', 'MPA', (47, 64))	('S1P', 'Chemical', 'MESH:C060506', (54, 57))	('ABC294640', 'Chemical', 'MESH:C548780', (29, 38))	('reduces', 'NegReg', (39, 46))	('ABC294640', 'Var', (29, 38))
130095	28420720	The plasma Cmax levels of ABC294640 were comparable at Day 1 and Day 28 at all dose levels, and as shown in Figure 2C, the plasma Cmax (combining data for Day 1 with Day 28, as well as 250 mg qd with 250 mg bid) was approximately dose-proportional between 250 and 500 mg (2.68 +- 1.44 (n=18) and 5.16 +- 4.29 (n=12) mug/mL, respectively, p<0.05).	('bid', 'Gene', (207, 210))	('ABC294640', 'Chemical', 'MESH:C548780', (26, 35))	('ABC294640', 'Var', (26, 35))	('bid', 'Gene', '637', (207, 210))
130100	28420720	In rats, ABC294640 is metabolized by CYP3A4 and CYP2D6 to two products (M1=N-oxide and M2=hydroxypyridyl), which reach Cmaxs of approximately 14% and 7%, respectively, of that of the parent drug (unpublished data).	('CYP2D6', 'Gene', '171522', (48, 54))	('rats', 'Species', '10116', (3, 7))	('CYP2D6', 'Gene', (48, 54))	('N-oxide', 'Chemical', '-', (75, 82))	('ABC294640', 'Var', (9, 18))	('ABC294640', 'Chemical', 'MESH:C548780', (9, 18))	('CYP3A4', 'Var', (37, 43))
130108	28420720	However, ABC294640 treatment caused reproducible acute decreases in plasma S1P levels that reached a minimum at 12 hours after ABC294640 treatment and recovered to baseline by 24 hours (Figure 3E).	('plasma S1P levels', 'MPA', (68, 85))	('ABC294640', 'Chemical', 'MESH:C548780', (127, 136))	('ABC294640', 'Var', (127, 136))	('decreases', 'NegReg', (55, 64))	('S1P', 'Chemical', 'MESH:C060506', (75, 78))	('ABC294640', 'Var', (9, 18))	('ABC294640', 'Chemical', 'MESH:C548780', (9, 18))
130121	28420720	Pharmaceutically tractable inhibitors of SK1 and/or SK2, such as ABC294640, provide a new approach for harnessing medical benefits potentially offered from modulating the ceramide/S1P rheostat.	('ceramide', 'Chemical', 'MESH:D002518', (171, 179))	('SK2', 'Gene', '56848', (52, 55))	('SK2', 'Gene', (52, 55))	('SK1', 'Gene', (41, 44))	('ABC294640', 'Chemical', 'MESH:C548780', (65, 74))	('S1P', 'Chemical', 'MESH:C060506', (180, 183))	('inhibitors', 'Var', (27, 37))	('SK1', 'Gene', '8877', (41, 44))	('modulating', 'Reg', (156, 166))	('ceramide/S1P rheostat', 'MPA', (171, 192))
130134	28420720	In cholangiocarcinoma cells, ABC294640 inhibits proliferation and induces caspase-dependent apoptosis, an effect that is enhanced by pharmacologic inhibition of autophagy or concurrent use of sorafenib.	('cholangiocarcinoma', 'Disease', (3, 21))	('ABC294640', 'Chemical', 'MESH:C548780', (29, 38))	('proliferation', 'CPA', (48, 61))	('induces', 'Reg', (66, 73))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('ABC294640', 'Var', (29, 38))	('inhibits', 'NegReg', (39, 47))	('caspase-dependent apoptosis', 'CPA', (74, 101))	('sorafenib', 'Chemical', 'MESH:D000077157', (192, 201))
130138	28420720	In addition to cholangiocarcinoma, nonclinical studies demonstrate the potential for ABC294640 in multiple tumor types, including lung, prostate, colorectal, ovarian and liver cancers, multiple myeloma, lymphoma and leukemia.	('multiple myeloma', 'Disease', (185, 201))	('leukemia', 'Disease', 'MESH:D007938', (216, 224))	('tumor', 'Disease', (107, 112))	('leukemia', 'Disease', (216, 224))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('prostate', 'Disease', (136, 144))	('liver cancers', 'Phenotype', 'HP:0002896', (170, 183))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('lymphoma', 'Disease', (203, 211))	('lymphoma', 'Disease', 'MESH:D008223', (203, 211))	('multiple myeloma', 'Phenotype', 'HP:0006775', (185, 201))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (15, 33))	('ABC294640', 'Chemical', 'MESH:C548780', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('cholangiocarcinoma', 'Disease', (15, 33))	('colorectal, ovarian and liver cancers', 'Disease', 'MESH:D015179', (146, 183))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (15, 33))	('multiple myeloma', 'Disease', 'MESH:D009101', (185, 201))	('leukemia', 'Phenotype', 'HP:0001909', (216, 224))	('ABC294640', 'Var', (85, 94))	('lymphoma', 'Phenotype', 'HP:0002665', (203, 211))	('lung', 'Disease', (130, 134))
130139	28420720	Clinical trials of ABC294640 are ongoing in hepatocellular carcinoma (NCT02939807), relapsed/refractory diffuse large B cell lymphoma (NCT02229981) and refractory/relapsed multiple myeloma (NCT02757326).	('multiple myeloma', 'Disease', 'MESH:D009101', (172, 188))	('NCT02229981', 'Var', (135, 146))	('multiple myeloma', 'Phenotype', 'HP:0006775', (172, 188))	('large B cell', 'Phenotype', 'HP:0005404', (112, 124))	('multiple myeloma', 'Disease', (172, 188))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (118, 133))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (44, 68))	('hepatocellular carcinoma', 'Disease', (44, 68))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (44, 68))	('B cell lymphoma', 'Disease', 'MESH:D016393', (118, 133))	('B cell lymphoma', 'Disease', (118, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('ABC294640', 'Gene', (19, 28))	('ABC294640', 'Chemical', 'MESH:C548780', (19, 28))	('lymphoma', 'Phenotype', 'HP:0002665', (125, 133))
130142	28420720	We have developed ABC294640, the first-in-class clinical inhibitor of SK2, and herein report data from the first-in-human clinical trial of ABC294640.	('ABC294640', 'Chemical', 'MESH:C548780', (140, 149))	('SK2', 'Gene', (70, 73))	('ABC294640', 'Var', (18, 27))	('ABC294640', 'Chemical', 'MESH:C548780', (18, 27))	('SK2', 'Gene', '56848', (70, 73))	('human', 'Species', '9606', (116, 121))
130149	25971332	In cell culture, PRR11 silencing resulted in decreased cellular proliferation, cell migration, tumor growth of QBC939 cells.	('cellular proliferation', 'CPA', (55, 77))	('cell migration', 'CPA', (79, 93))	('PRR11', 'Gene', (17, 22))	('QBC939', 'CellLine', 'CVCL:6942', (111, 117))	('decreased', 'NegReg', (45, 54))	('silencing', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
130150	25971332	Microarray analysis revealed that several genes involved in cell proliferation, cell adhesion, and cell migration were altered in PRR11-knockout cells, including: vimentin (VIM), Ubiquitin carboxyl-terminal hydrolase 1 (UCHL1), early growth response protein (EGR1), and System A amino acid transporter1 (SNAT1).	('UCHL1', 'Gene', '7398', (220, 225))	('cell proliferation', 'CPA', (60, 78))	('vimentin', 'Gene', '7431', (163, 171))	('cell adhesion', 'CPA', (80, 93))	('vimentin', 'Gene', (163, 171))	('altered', 'Reg', (119, 126))	('cell migration', 'CPA', (99, 113))	('UCHL1', 'Gene', (220, 225))	('System A amino acid transporter1', 'Gene', (270, 302))	('EGR1', 'Gene', (259, 263))	('PRR11-knockout', 'Gene', (130, 144))	('EGR1', 'Gene', '1958', (259, 263))	('PRR11-knockout', 'Var', (130, 144))	('SNAT1', 'Gene', '81539', (304, 309))	('Ubiquitin carboxyl-terminal hydrolase 1', 'Gene', (179, 218))	('System A amino acid transporter1', 'Gene', '81539', (270, 302))	('VIM', 'Gene', '7431', (173, 176))	('VIM', 'Gene', (173, 176))	('Ubiquitin carboxyl-terminal hydrolase 1', 'Gene', '7398', (179, 218))	('SNAT1', 'Gene', (304, 309))
130151	25971332	Silencing PRR11 inhibited the expression of UCHL1, EGR1, and SNAT1 proteins, with immunoassays revealing a significant correlation among the levels of these four proteins.	('SNAT1', 'Gene', '81539', (61, 66))	('inhibited', 'NegReg', (16, 25))	('expression', 'MPA', (30, 40))	('EGR1', 'Gene', '1958', (51, 55))	('PRR11', 'Gene', (10, 15))	('UCHL1', 'Gene', (44, 49))	('UCHL1', 'Gene', '7398', (44, 49))	('proteins', 'Protein', (67, 75))	('Silencing', 'Var', (0, 9))	('SNAT1', 'Gene', (61, 66))	('EGR1', 'Gene', (51, 55))
130154	25971332	Dysregulation of the cell cycle components promotes tumor formation, and, therefore, the proteins controlling cell cycle progression are potential targets for anticancer strategies.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('promotes', 'PosReg', (43, 51))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (0, 31))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
130156	25971332	Silencing PRR11 induces S-phase arrest, inhibiting cell viability and tumorigenic potential.	('S-phase arrest', 'CPA', (24, 38))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('PRR11', 'Gene', (10, 15))	('tumor', 'Disease', (70, 75))	('cell viability', 'CPA', (51, 65))	('induces', 'Reg', (16, 23))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('inhibiting', 'NegReg', (40, 50))
130157	25971332	Additionally, in silico analysis has suggested that high expression of PRR11 is significantly associated with poor prognosis in lung cancer patients.	('PRR11', 'Gene', (71, 76))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('lung cancer', 'Disease', (128, 139))	('associated', 'Reg', (94, 104))	('patients', 'Species', '9606', (140, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('high expression', 'Var', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
130162	25971332	PRR11 was silenced in a HC cell line in order to profile its biological role in the disease, and it was found that PRR11 knockdown results in decreased tumorigenicity.	('knockdown', 'Var', (121, 130))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('a HC', 'CellLine', 'CVCL:X173', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('decreased', 'NegReg', (142, 151))	('tumor', 'Disease', (152, 157))	('PRR11', 'Gene', (115, 120))
130163	25971332	The potential mechanisms by which its knockdown resulted in anticancer effects were also investigated and discussed.	('knockdown', 'Var', (38, 47))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
130175	25971332	Serum tumor marker levels, specifically CA199, were associated with tumor stage, tumor recurrence, and worse overall survival.	('tumor', 'Disease', (68, 73))	('associated', 'Reg', (52, 62))	('CA199', 'Var', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('CA199', 'Chemical', '-', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
130186	25971332	Multivariable analysis showed that PRR11positivity, rather than other clinical variables, was an independent predictor of tumor recurrence (Table 2).	('tumor', 'Disease', (122, 127))	('PRR11positivity', 'Var', (35, 50))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))
130188	25971332	As expected, patients with PRR11- negative tumor had a more favorable time to recurrence than those with any level of PRR11 positive tumor (p = 0.002, vs. PRR11+ tumor; p < 0.001, vs. PRR11 ++ and +++ tumor, Figure 3B).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', (43, 48))	('PRR11- negative', 'Var', (27, 42))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
130200	25971332	Silencing of PRR11 expression (Figure 4I and 4i) significantly inhibited tumor growth as determined by both tumor weight and tumor size, as well as the expression of proliferation related indicators (Ki67), in the PRR11-KO inoculated mice compared with the control group (Figure S4).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('Ki67', 'Gene', (200, 204))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('PRR11', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('mice', 'Species', '10090', (234, 238))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', (125, 130))	('Ki67', 'Gene', '17345', (200, 204))	('tumor', 'Disease', (73, 78))	('inhibited', 'NegReg', (63, 72))	('Silencing', 'Var', (0, 9))	('expression', 'MPA', (152, 162))	('PRR11-KO', 'Var', (214, 222))
130201	25971332	Since silencing PRR11 lead to marked inhibition of tumor cell growth and increased survival, the transcriptional effects of PRR11 expression was probed using cDNA array, specifically by comparing the gene expression patterns between PRR11-KO and wild-type cells.	('increased', 'PosReg', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('inhibition', 'NegReg', (37, 47))	('tumor', 'Disease', (51, 56))	('PRR11', 'Gene', (16, 21))	('survival', 'CPA', (83, 91))	('silencing', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
130211	25971332	Alteration of cell cycle regulatory proteins is an essential step in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (69, 83))	('Alteration', 'Var', (0, 10))	('carcinogenesis', 'Disease', (69, 83))
130229	25971332	Interestingly, expression of PRR11 was found to be associated with a higher level of serum CA199.	('expression', 'Var', (15, 25))	('CA199', 'Chemical', '-', (91, 96))	('associated', 'Reg', (51, 61))	('PRR11', 'Gene', (29, 34))	('higher', 'PosReg', (69, 75))
130232	25971332	Overexpression of PRR11 in HC tumor cells may predict a more aggressive clinical behavior.	('aggressive clinical behavior', 'CPA', (61, 89))	('HC tumor', 'Disease', 'MESH:D009369', (27, 35))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (61, 89))	('PRR11', 'Gene', (18, 23))	('predict', 'Reg', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Overexpression', 'Var', (0, 14))	('HC tumor', 'Disease', (27, 35))
130236	25971332	In lung cancer, silencing PRR11 induced S-phase arrest, inhibition of cell proliferation and invasion and especially tumor growth.	('inhibition', 'NegReg', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('tumor', 'Disease', (117, 122))	('cell proliferation', 'CPA', (70, 88))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('silencing', 'Var', (16, 25))	('invasion', 'CPA', (93, 101))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('S-phase arrest', 'CPA', (40, 54))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('PRR11', 'Gene', (26, 31))
130237	25971332	PRR11 knockdown leads to dysregulation of several pathways and genes involved in cell cycle and tumorigenesis.	('PRR11', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('genes', 'Gene', (63, 68))	('knockdown', 'Var', (6, 15))	('dysregulation', 'MPA', (25, 38))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
130238	25971332	In present study, it was confirmed that PRR11-KO inhibited cell proliferation and migration, as well as induced S-phase arrest, in vitro and transplanted tumor growth in vivo.	('cell proliferation', 'CPA', (59, 77))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('S-phase arrest', 'CPA', (112, 126))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('induced', 'Reg', (104, 111))	('PRR11-KO', 'Var', (40, 48))	('inhibited', 'NegReg', (49, 58))	('tumor', 'Disease', (154, 159))
130239	25971332	Moreover, we found that genes related with cell proliferation, cell adhesion, cell motion, cell motility, and cell migration were significantly altered following PRR11 knockdown, implicating a critical role of PRR11 in tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('cell motility', 'CPA', (91, 104))	('cell motion', 'CPA', (78, 89))	('altered', 'Reg', (144, 151))	('cell adhesion', 'CPA', (63, 76))	('tumor', 'Disease', (219, 224))	('cell migration', 'CPA', (110, 124))	('genes', 'Gene', (24, 29))	('PRR11', 'Gene', (162, 167))	('knockdown', 'Var', (168, 177))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('cell proliferation', 'CPA', (43, 61))
130240	25971332	Expression of vimentin (VIM) mRNA and protein was also down-regulated when PRR11 was silenced, indicating a potential role of PRR11 in the initiation of EMT (which is supported by the finding that knockdown increased expression of E-cadherin).	('vimentin', 'Gene', '7431', (14, 22))	('silenced', 'Var', (85, 93))	('vimentin', 'Gene', (14, 22))	('E-cadherin', 'Gene', (231, 241))	('Expression', 'MPA', (0, 10))	('expression', 'MPA', (217, 227))	('E-cadherin', 'Gene', '999', (231, 241))	('increased', 'PosReg', (207, 216))	('knockdown', 'Var', (197, 206))	('VIM', 'Gene', '7431', (24, 27))	('down-regulated', 'NegReg', (55, 69))	('PRR11', 'Gene', (75, 80))	('VIM', 'Gene', (24, 27))
130244	25971332	Ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) belongs to the family of de-ubiquitinating enzymes (DUBs), deregulation of which causes tumor- inhibiting or -promoting functions in human cancer cells.	('UCHL1', 'Gene', '7398', (41, 46))	('Ubiquitin carboxyl-terminal hydrolase 1', 'Gene', (0, 39))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('human', 'Species', '9606', (181, 186))	('UCHL1', 'Gene', (41, 46))	('cancer', 'Disease', (187, 193))	('deregulation', 'Var', (107, 119))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('Ubiquitin carboxyl-terminal hydrolase 1', 'Gene', '7398', (0, 39))	('tumor', 'Disease', (136, 141))
130253	25971332	In addition to reduced expression of UCHL1, EGR1, and SNAT1 mRNA, silencing PRR11 diminished their protein levels by Western blot analysis.	('SNAT1', 'Gene', '81539', (54, 59))	('silencing', 'Var', (66, 75))	('UCHL1', 'Gene', '7398', (37, 42))	('diminished', 'NegReg', (82, 92))	('expression', 'MPA', (23, 33))	('EGR1', 'Gene', (44, 48))	('protein levels', 'MPA', (99, 113))	('UCHL1', 'Gene', (37, 42))	('PRR11', 'Gene', (76, 81))	('reduced', 'NegReg', (15, 22))	('EGR1', 'Gene', '1958', (44, 48))	('SNAT1', 'Gene', (54, 59))
130254	25971332	Co-expression of PRR11, UCHL1, EGR1, and SNAT1 was found to be a frequent event in HC tumor samples, indicating a cross-talk among these four proteins.	('HC tumor', 'Disease', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('EGR1', 'Gene', (31, 35))	('HC tumor', 'Disease', 'MESH:D009369', (83, 91))	('cross-talk', 'Disease', 'MESH:D020922', (114, 124))	('PRR11', 'Gene', (17, 22))	('SNAT1', 'Gene', (41, 46))	('SNAT1', 'Gene', '81539', (41, 46))	('cross-talk', 'Disease', (114, 124))	('Co-expression', 'Var', (0, 13))	('EGR1', 'Gene', '1958', (31, 35))	('UCHL1', 'Gene', '7398', (24, 29))	('UCHL1', 'Gene', (24, 29))
130259	25971332	Targeting PRR11 caused inhibition of cell growth and tumor survival by reversing EMT and inhibiting activity of key regulators involved in cell migration and invasion.	('PRR11', 'Gene', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('inhibiting', 'NegReg', (89, 99))	('inhibition', 'NegReg', (23, 33))	('cell growth', 'CPA', (37, 48))	('cell migration', 'CPA', (139, 153))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('EMT', 'CPA', (81, 84))	('tumor', 'Disease', (53, 58))	('Targeting', 'Var', (0, 9))	('reversing', 'NegReg', (71, 80))	('activity', 'MPA', (100, 108))
130260	25971332	These findings strongly support an oncogenic role for PRR11 in HC and suggest that inhibition of PRR11 may be a future therapeutic target in the treatment of HC patients.	('inhibition', 'Var', (83, 93))	('patients', 'Species', '9606', (161, 169))	('PRR11', 'Gene', (97, 102))	('PRR11', 'Gene', (54, 59))
130273	25971332	After de-paraffinization, rehydration and antigen retrieval using an autoclave-oven-technique, sections were incubated with anti-PRR11 (HPA023923, SIGMA-ALDRICH), UCHL1 (HPA005993, SIGMA-ALDRICH), SNAT1 (ab59721, abcam ), and EGR1 (ab54966, abcam ) at 4 C overnight.	('EGR1', 'Gene', '1958', (226, 230))	('HPA023923', 'Var', (136, 145))	('UCHL1', 'Gene', (163, 168))	('UCHL1', 'Gene', '7398', (163, 168))	('HPA005993', 'Var', (170, 179))	('paraffin', 'Chemical', 'MESH:D010232', (9, 17))	('EGR1', 'Gene', (226, 230))	('SNAT1', 'Gene', (197, 202))	('SNAT1', 'Gene', '81539', (197, 202))
130289	25971332	In situ tumor transplantation of hilar cholangiocarcinoma was carried out by inoculating BALB/C-nu mice (male; age: 4 weeks; 5/group) with cell suspensions (1*107 QBC939 WT or PRR-11-KO cells) injected into the hepatic hilar area.	('mice', 'Species', '10090', (99, 103))	('PRR-11', 'Gene', '55771', (176, 182))	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (33, 57))	('situ tumor', 'Disease', 'MESH:D002278', (3, 13))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (39, 57))	('hilar cholangiocarcinoma', 'Disease', (33, 57))	('1*107 QBC939', 'Var', (157, 169))	('QBC939', 'CellLine', 'CVCL:6942', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('PRR-11', 'Gene', (176, 182))	('situ tumor', 'Disease', (3, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
130331	32083210	Similar to the spearman correlation results, the regional quintile-based mean mutation density data of HCCs and Mixed showed relatively higher association with the liver tissue H3K4me1 level comparing to the stomach tissue H3K4me1 level, while the mean mutation data for ICCs and BTCAs displayed higher association towards the stomach tissue H3K4me1, with ICCs as a lesser extent (Figure 1b).	('association', 'Interaction', (143, 154))	('mutation', 'Var', (78, 86))	('higher', 'PosReg', (136, 142))	('liver tissue H3K4me1 level', 'MPA', (164, 190))	('BTCAs', 'Chemical', '-', (280, 285))	('ICC', 'Disease', (356, 359))	('ICC', 'Disease', (271, 274))	('HCC', 'Disease', (103, 106))	('ICC', 'Disease', 'MESH:C535533', (271, 274))	('HCC', 'Disease', 'MESH:D006528', (103, 106))	('ICC', 'Disease', 'MESH:C535533', (356, 359))
130373	32083210	Furthermore, spearman correlation values between the regional mutation frequency of aggregated samples grouped by HBV or HCV infection status and normal liver tissue H3K4me1 chromatin mark level was higher for HCV-infected ICCs compared with any other ICCs with different virus infection status, and this result was fully replicated when using H3K4me1 chromatin marks derived from HBV or HCV-infected liver tissues, thus providing additional evidences (Table S2).	('virus infection status', 'Disease', (272, 294))	('ICC', 'Disease', (252, 255))	('HCV', 'Species', '11103', (210, 213))	('regional mutation', 'MPA', (53, 70))	('ICC', 'Disease', 'MESH:C535533', (223, 226))	('HCV', 'Species', '11103', (121, 124))	('higher', 'PosReg', (199, 205))	('HBV', 'Species', '10407', (381, 384))	('HCV-infected', 'Var', (210, 222))	('virus infection status', 'Disease', 'MESH:D014412', (272, 294))	('ICC', 'Disease', 'MESH:C535533', (252, 255))	('HBV', 'Species', '10407', (114, 117))	('H3K4me1 chromatin mark level', 'MPA', (166, 194))	('ICC', 'Disease', (223, 226))	('HCV', 'Species', '11103', (388, 391))
130391	32083210	Moreover, the top chromatin marks associated with the mutational landscape of 256 HCCs were mostly derived from liver tissue and the top correlative chromatin marks for 12 of BTCAs were from the stomach tissue, which are also concordant to the previous studies on HCCs and DCCs.	('HCC', 'Disease', (82, 85))	('HCC', 'Disease', 'MESH:D006528', (82, 85))	('HCC', 'Disease', 'MESH:D006528', (264, 267))	('mutational', 'Var', (54, 64))	('HCC', 'Disease', (264, 267))	('BTCAs', 'Chemical', '-', (175, 180))
130396	32083210	In the case of ICCs, mouse models either utilizing thioacetamide administration or Trp53 genetic loss can direct different cell types (hepatocytes vs cholangiocytes) into ICCs with concomitant Notch signaling activation.	('Notch', 'Gene', (193, 198))	('genetic', 'Var', (89, 96))	('Trp53', 'Gene', (83, 88))	('loss', 'NegReg', (97, 101))	('mouse', 'Species', '10090', (21, 26))	('ICC', 'Disease', (15, 18))	('ICC', 'Disease', 'MESH:C535533', (15, 18))	('Trp53', 'Gene', '22059', (83, 88))	('activation', 'PosReg', (209, 219))	('thioacetamide', 'Chemical', 'MESH:D013853', (51, 64))	('ICC', 'Disease', (171, 174))	('Notch', 'Gene', '4851;4853;18129', (193, 198))	('ICC', 'Disease', 'MESH:C535533', (171, 174))
130425	32083210	We constructed a total of 1000 random forest trees to predict regional mutation density from a total of 423 chromatin features and employed greedy backward elimination to pick out the top 20 chromatin marks.	('mutation', 'Var', (71, 79))	('pick', 'Gene', (171, 175))	('pick', 'Gene', '9463', (171, 175))
130470	29579789	Those who used PZQ were 2.02 times more likely to develop CCA than those who had not (pooled OR=2.02; 95% CI: 1.59, 2.57) (Figure 8).	('PZQ', 'Chemical', '-', (15, 18))	('develop', 'PosReg', (50, 57))	('CCA', 'Disease', (58, 61))	('PZQ', 'Var', (15, 18))
130486	29579789	By comparison, the present study found a strong association between PZQ and risk of CCA (OR=2.02, 95% CI: 1.59, 2.57).	('PZQ', 'Chemical', '-', (68, 71))	('CCA', 'Disease', (84, 87))	('PZQ', 'Var', (68, 71))
130492	29579789	Palmer and Patel (2012) demonstrated the risk of intrahepatic CCA associated with liquor consumption.	('intrahepatic CCA', 'Disease', (49, 65))	('liquor consumption', 'Var', (82, 100))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (49, 65))
130496	29579789	(Aishima and Oda, 2015) Chronic liquor consumption is associated with intrahepatic rather than extrahepatic CCA.	('intrahepatic', 'Disease', (70, 82))	('Chronic liquor consumption', 'Var', (24, 50))	('associated', 'Reg', (54, 64))	('intrahepatic', 'Disease', 'MESH:D002780', (70, 82))
130509	24303007	Moreover, the cholangiocarcinoma patients with lymph node metastasis (N1) had a lower Beclin 1 level than that of N0 subgroup (P=0.012).	('patients', 'Species', '9606', (33, 41))	('cholangiocarcinoma', 'Disease', (14, 32))	('lymph node metastasis', 'Var', (47, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (14, 32))	('lower', 'NegReg', (80, 85))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (14, 32))	('Beclin 1 level', 'MPA', (86, 100))
130512	24303007	Importantly, our stratified univariate and multivariate analysis confirmed that Beclin 1 lowly expressed ICC had an inferior PFS as well as overall survival than ECC, particularly than that of Beclin 1 highly expressed ECC patients.	('inferior', 'NegReg', (116, 124))	('Beclin 1', 'Gene', (80, 88))	('lowly expressed', 'Var', (89, 104))	('PFS', 'MPA', (125, 128))	('patients', 'Species', '9606', (223, 231))	('overall', 'MPA', (140, 147))
130519	24303007	Overexpression of EGFR, for example, was occurred in 27.4% ICC subgroup and 19.2% ECC subgroup, predicted a poor outcome as well as a high risk to tumor recurrence.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('Overexpression', 'Var', (0, 14))	('ICC', 'Disease', (59, 62))
130526	24303007	In human breast, prostate and ovarian tumors, the monoallelical deletion of Beclin 1 gene was occurred in 40-75% of patients.	('monoallelical deletion', 'Var', (50, 72))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('human', 'Species', '9606', (3, 8))	('Beclin 1', 'Gene', (76, 84))	('patients', 'Species', '9606', (116, 124))	('ovarian tumors', 'Disease', (30, 44))	('ovarian tumors', 'Phenotype', 'HP:0100615', (30, 44))	('breast', 'Disease', (9, 15))	('prostate', 'Disease', (17, 25))	('ovarian tumors', 'Disease', 'MESH:D010051', (30, 44))
130527	24303007	Moreover, blockade of Beclin 1 by siRNA, even under p53 mutation context, could significantly decrease the accumulation of autophagosomes and sensitize resistant breast, pharyngeal, cervical, lung and rectum cancer cells to radiotherapy.	('rectum cancer', 'Phenotype', 'HP:0100743', (201, 214))	('sensitize', 'Reg', (142, 151))	('rectum cancer', 'Disease', 'MESH:D012004', (201, 214))	('blockade', 'NegReg', (10, 18))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('cervical', 'Disease', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('accumulation', 'MPA', (107, 119))	('Beclin', 'Protein', (22, 28))	('pharyngeal', 'Disease', (170, 180))	('mutation', 'Var', (56, 64))	('rectum cancer', 'Disease', (201, 214))	('lung', 'Disease', (192, 196))	('decrease', 'NegReg', (94, 102))
130593	24303007	Here, we found that the cholangiocarcinoma patients with lymph node metastasis (N1 stage) had a lower level of Beclin 1 than that of N0 stage patients (IHC score: 3.45+-2.82 VS 4.60+-2.97, Figure 2B).	('cholangiocarcinoma', 'Disease', (24, 42))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (24, 42))	('lymph node metastasis', 'Var', (57, 78))	('patients', 'Species', '9606', (43, 51))	('lower', 'NegReg', (96, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (24, 42))	('level of Beclin 1', 'MPA', (102, 119))	('patients', 'Species', '9606', (142, 150))
130595	24303007	These findings indicated that Beclin 1 inactivation might be a frequent risk factor to lymph node invasiveness regardless of intraheptic or extrahepatic cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (153, 171))	('lymph node invasiveness regardless of intraheptic or extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (87, 171))	('risk', 'Reg', (72, 76))	('inactivation', 'Var', (39, 51))	('Beclin', 'Protein', (30, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
130664	23682242	A recent meta-analysis found no difference in fatigue, mortality, histologic progression or development of cholangiocarcinoma for standard or high dose UDCA.	('fatigue', 'Disease', 'MESH:D005221', (46, 53))	('cholangiocarcinoma', 'Disease', (107, 125))	('high dose', 'Var', (142, 151))	('fatigue', 'Disease', (46, 53))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (107, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (107, 125))	('fatigue', 'Phenotype', 'HP:0012378', (46, 53))
130666	23682242	Cystic fibrosis transmembrane conductance regulators (CFTR) abnormalities have been detected in some patients with PSC.	('patients', 'Species', '9606', (101, 109))	('CFTR', 'Gene', (54, 58))	('CFTR', 'Gene', '1080', (54, 58))	('Cystic fibrosis transmembrane conductance regulators', 'Gene', '1080', (0, 52))	('abnormalities', 'Var', (60, 73))	('detected', 'Reg', (84, 92))	('PSC', 'Gene', '100653366', (115, 118))	('PSC', 'Gene', (115, 118))
130671	23682242	In an experimental animal model, norUDCA was associated with significantly improved liver tests and histology when compared to UDCA treatment.	('improved', 'PosReg', (75, 83))	('histology', 'CPA', (100, 109))	('norUDCA', 'Var', (33, 40))	('norUDCA', 'Chemical', 'MESH:C081331', (33, 40))	('liver tests', 'MPA', (84, 95))
130679	23682242	Pre-transplant colectomy in patients with IBD may be protective against recurrence; whereas prolonged use of steroids and the presence of UC has been shown to be associated with the development of recurrent PSC.	('UC', 'Phenotype', 'HP:0100279', (138, 140))	('associated with', 'Reg', (162, 177))	('PSC', 'Gene', '100653366', (207, 210))	('IBD', 'Phenotype', 'HP:0002037', (42, 45))	('presence', 'Var', (126, 134))	('patients', 'Species', '9606', (28, 36))	('steroids', 'Chemical', 'MESH:D013256', (109, 117))	('PSC', 'Gene', (207, 210))
130697	23682242	The majority of the studies examining FISH in PSC utilized centromeric probe against chromosomes 3, 7, and 17 and a locus-specific probe (9p21).	('PSC', 'Gene', (46, 49))	('centromeric', 'Var', (59, 70))	('PSC', 'Gene', '100653366', (46, 49))
130699	23682242	However, the detection of FISH polysomy was associated with a sensitivity of 46% and specificity of 88% for CCA in PSC.	('FISH polysomy', 'Var', (26, 39))	('CCA', 'Phenotype', 'HP:0030153', (108, 111))	('PSC', 'Gene', '100653366', (115, 118))	('CCA', 'Disease', (108, 111))	('PSC', 'Gene', (115, 118))
130700	23682242	Patients with a positive FISH polysomy and no CCA were more likely to have a lower CA-19-9, lower Mayo risk score, lower bilirubin, and lower occurrence of dominant strictures compared to those with CCA.	('lower', 'NegReg', (77, 82))	('bilirubin', 'MPA', (121, 130))	('Mayo risk score', 'MPA', (98, 113))	('CCA', 'Phenotype', 'HP:0030153', (199, 202))	('FISH polysomy', 'Var', (25, 38))	('bilirubin', 'Chemical', 'MESH:D001663', (121, 130))	('lower', 'NegReg', (115, 120))	('Patients', 'Species', '9606', (0, 8))	('CCA', 'Phenotype', 'HP:0030153', (46, 49))	('CA-19-9', 'MPA', (83, 90))	('Mayo', 'Species', '162683', (98, 102))	('lower', 'NegReg', (92, 97))
130739	23682242	However, high dose UDCA was associated with an increased risk of neoplasia development (predominately LGD).	('high dose', 'Var', (9, 18))	('neoplasia', 'Disease', (65, 74))	('neoplasia', 'Phenotype', 'HP:0002664', (65, 74))	('neoplasia', 'Disease', 'MESH:D009369', (65, 74))
130798	33525332	Dysregulation of epithelial homeostasis has been associated with breast cancer initiation and progression.	('epithelial homeostasis', 'MPA', (17, 39))	('breast cancer initiation', 'Disease', 'MESH:D001943', (65, 89))	('Dysregulation', 'Var', (0, 13))	('associated', 'Reg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('breast cancer initiation', 'Disease', (65, 89))
130814	33525332	One study showed that SSRI fluoxetine might have an anticarcinogenic effect and enhance chemosensitivity.	('enhance', 'PosReg', (80, 87))	('carcinogenic', 'Disease', 'MESH:D063646', (56, 68))	('fluoxetine', 'Chemical', 'MESH:D005473', (27, 37))	('SSRI', 'Var', (22, 26))	('carcinogenic', 'Disease', (56, 68))	('chemosensitivity', 'CPA', (88, 104))
130817	33525332	Nicotine stimulates the proliferation of SCLC cells, and being a strong secretagogue, it also stimulates the release of serotonin from these cells.	('SCLC', 'Disease', 'MESH:D018288', (41, 45))	('proliferation', 'CPA', (24, 37))	('Nicotine', 'Chemical', 'MESH:D009538', (0, 8))	('Nicotine', 'Var', (0, 8))	('serotonin', 'Chemical', 'MESH:D012701', (120, 129))	('SCLC', 'Disease', (41, 45))	('release of serotonin', 'MPA', (109, 129))	('stimulates', 'PosReg', (94, 104))	('stimulates', 'PosReg', (9, 19))
130838	33525332	Furthermore, inhibition of serotonin synthesis blocked the growth of CC cell lines.	('serotonin', 'Chemical', 'MESH:D012701', (27, 36))	('growth', 'CPA', (59, 65))	('inhibition', 'Var', (13, 23))	('serotonin synthesis', 'MPA', (27, 46))	('blocked', 'NegReg', (47, 54))
130901	33525332	Although SSRIs increase serotonin levels in synaptic cleft and plasma, surprisingly, they do not contribute to tumorigenesis.	('increase serotonin', 'Phenotype', 'HP:0003144', (15, 33))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('increase', 'PosReg', (15, 23))	('SSRIs', 'Var', (9, 14))	('tumor', 'Disease', (111, 116))	('serotonin levels', 'MPA', (24, 40))	('SSRIs increase', 'Phenotype', 'HP:0002922', (9, 23))	('serotonin', 'Chemical', 'MESH:D012701', (24, 33))
131122	31324166	Absence of an embryonic stem cell DNA methylation signature in human cancer Differentiated cells that arise from stem cells in early development contain DNA methylation features that provide a memory trace of their fetal cell origin (FCO).	('human', 'Species', '9606', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('methylation', 'Var', (157, 168))	('FCO', 'Chemical', '-', (234, 237))	('cancer', 'Disease', (69, 75))
131143	31324166	Programming the cancer stem cell phenotypes are genetic alterations and epigenetic changes in chromatin structure and DNA methylation.	('chromatin structure', 'Protein', (94, 113))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('epigenetic changes', 'Var', (72, 90))	('DNA methylation', 'MPA', (118, 133))	('genetic alterations', 'Var', (48, 67))
131144	31324166	The consequence of cancer stem cell epigenetic alterations is to unleash cellular plasticity that favors oncogenic cellular reprogramming.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('cellular plasticity', 'CPA', (73, 92))	('epigenetic alterations', 'Var', (36, 58))	('oncogenic cellular reprogramming', 'CPA', (105, 137))	('favors', 'PosReg', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
131156	31324166	We were able to add nontumor normal samples of cervix, brain, adrenal gland and stomach from GEO data sets GSE46306, GSE80970, GSE77871 and GSE103186 to cervical squamous cell carcinoma and endocervical adenocarcinoma, glioblastoma multiforme, pheochromocytoma and stomach adenocarcinoma projects on TCGA.	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (162, 185))	('endocervical adenocarcinoma', 'Disease', (190, 217))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (265, 287))	('GSE46306', 'Var', (107, 115))	('pheochromocytoma', 'Disease', (244, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (244, 260))	('squamous cell carcinoma', 'Disease', (162, 185))	('glioblastoma multiforme', 'Disease', (219, 242))	('glioblastoma', 'Phenotype', 'HP:0012174', (219, 231))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (219, 242))	('GSE77871', 'Var', (127, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('GSE80970', 'Var', (117, 125))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (190, 217))	('tumor', 'Disease', (23, 28))	('stomach adenocarcinoma', 'Disease', (265, 287))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('GSE103186', 'Var', (140, 149))	('pheochromocytoma', 'Disease', 'MESH:D010673', (244, 260))
131207	31324166	We applied the FCO algorithm to GEO data sets GSE80241, representing 6 pancreatic ductal adenocarcinoma stem cell samples, and GSE92462, including 22 glioma stem cell samples.	('pancreatic ductal adenocarcinoma', 'Disease', (71, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (71, 103))	('FCO', 'Chemical', '-', (15, 18))	('GSE80241', 'Var', (46, 54))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (71, 103))	('glioma', 'Disease', (150, 156))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
131209	31324166	Further, among 27 FCO CpGs, 3 (cg10338787, cg17310258 and cg16154155) are associated with EZH2.	('cg17310258', 'Chemical', '-', (43, 53))	('cg17310258', 'Var', (43, 53))	('cg16154155', 'Var', (58, 68))	('EZH2', 'Gene', '2146', (90, 94))	('cg10338787', 'Chemical', '-', (31, 41))	('EZH2', 'Gene', (90, 94))	('cg16154155', 'Chemical', '-', (58, 68))	('FCO', 'Chemical', '-', (18, 21))	('associated', 'Reg', (74, 84))	('cg10338787', 'Var', (31, 41))
131210	31324166	We plotted the methylation beta values of these three loci in pancreatic carcinoma samples, normal pancreatic tissue samples and pancreatic cancer stem cell samples from GEO data sets GSE53051 and GSE80241.	('pancreatic carcinoma', 'Disease', (62, 82))	('GSE53051', 'Var', (184, 192))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('GSE80241', 'Var', (197, 205))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (62, 82))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('pancreatic cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
131231	31324166	The former model is supported by recent research indicating that heterogeneous tumor cells develop over time as cancer stem cells differentiate via genetic and epigenetic alterations.	('tumor', 'Disease', (79, 84))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('epigenetic alterations', 'Var', (160, 182))	('genetic', 'Var', (148, 155))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
131235	31324166	Further, our observation of a diminished FCO in tumors is seemingly at odds with reports that DNA hypermethylation in cancer preferentially targets the subset of polycomb repressor loci in cancer stem cells that are developmental regulators.	('cancer', 'Disease', (118, 124))	('FCO', 'MPA', (41, 44))	('diminished', 'NegReg', (30, 40))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('FCO', 'Chemical', '-', (41, 44))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('hypermethylation', 'Var', (98, 114))	('cancer', 'Disease', (189, 195))
131274	31324166	DCK was supported by the Kansas IDeA Network of Biomedical Research Excellence (K-INBRE) Bioinformatics Core, supported in part by the National Institute of General Medical Science award P20GM103418, and NIH grant P30CA168524.	('P20GM103418', 'Var', (187, 198))	('DCK', 'Gene', (0, 3))	('DCK', 'Gene', '1633', (0, 3))
131275	31324166	The datasets analyzed during the current study are available on The Cancer Genome Atlas (TCGA) https://portal.gdc.cancer.gov and the Gene Expression Omnibus data repository https://www.ncbi.nlm.nih.gov/geo/ (Accession numbers: GSE49656, GSE53051, GSE52068, GSE52826, GSE52955, GSE54503, GSE56044, GSE75546, GSE77871, GSE85845, GSE76938, GSE112047, GSE101961, GSE72245, GSE106600, GSE80241, GSE92462).	('GSE85845', 'Var', (317, 325))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('GSE112047', 'Var', (337, 346))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('GSE76938', 'Var', (327, 335))	('GSE56044', 'Var', (287, 295))	('GSE52955', 'Var', (267, 275))	('GSE72245', 'Var', (359, 367))	('GSE80241', 'Var', (380, 388))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (68, 87))	('GSE101961', 'Var', (348, 357))	('GSE53051', 'Var', (237, 245))	('GSE75546', 'Var', (297, 305))	('GSE106600', 'Var', (369, 378))	('Cancer Genome Atlas', 'Disease', (68, 87))	('GSE92462', 'Var', (390, 398))	('GSE77871', 'Var', (307, 315))	('cancer', 'Disease', (114, 120))
131300	28669153	The likelihood of developing CC in PSC increases with advanced age, smoking and drinking habit, concurrent prolonged IBH, presence of colorectal cancer, dysplasia in ulcerative colitis, high bilirubin level, prior proctocolectomy, biliary calculi and presence of specific gene polymorphism in NKG2D (Natural killer group 2, member D).	('high bilirubin level', 'MPA', (186, 206))	('biliary calculi', 'Disease', (231, 246))	('IBH', 'Chemical', '-', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('bilirubin', 'Chemical', 'MESH:D001663', (191, 200))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (166, 184))	('biliary calculi', 'Disease', 'MESH:D042882', (231, 246))	('NKG2D', 'Gene', (293, 298))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('presence', 'Var', (251, 259))	('presence', 'Var', (122, 130))	('colitis', 'Phenotype', 'HP:0002583', (177, 184))	('colorectal cancer', 'Disease', (134, 151))	('NKG2D', 'Gene', '22914', (293, 298))	('dysplasia in ulcerative colitis', 'Disease', 'MESH:D003093', (153, 184))	('dysplasia in ulcerative colitis', 'Disease', (153, 184))	('high bilirubin level', 'Phenotype', 'HP:0002904', (186, 206))	('biliary calculi', 'Phenotype', 'HP:0000787', (231, 246))	('high bilirubin', 'Phenotype', 'HP:0003573', (186, 200))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))	('PSC', 'Disease', (35, 38))
131301	28669153	Generally, chronic inflammation, high cell turnover, cytokines and growth factor release leads to proliferation and mutation of mutated cells (Diagram 1).	('leads to', 'Reg', (89, 97))	('mutation', 'Var', (116, 124))	('inflammation', 'Disease', 'MESH:D007249', (19, 31))	('inflammation', 'Disease', (19, 31))	('proliferation', 'CPA', (98, 111))
131309	28669153	Other factors responsible for CC development: EGFR (epidermal growth factor receptor) and ErbB2, IL-6, apoptosis and cell life, mechanisms associated with inflammation, NO and COX2, leptin, microRNA (miR-141, miR-200, miR-370, miR29b), epigenetic changes (hypermethylation etc.	('ErbB2', 'Gene', '2064', (90, 95))	('COX2', 'Gene', '4513', (176, 180))	('miR29b', 'Gene', (227, 233))	('EGFR', 'Gene', '1956', (46, 50))	('inflammation', 'Disease', (155, 167))	('miR-141', 'Gene', '406933', (200, 207))	('ErbB2', 'Gene', (90, 95))	('men', 'Species', '9606', (40, 43))	('miR-200', 'Var', (209, 216))	('epigenetic changes', 'Var', (236, 254))	('miR-141', 'Gene', (200, 207))	('IL-6', 'Gene', '3569', (97, 101))	('miR29b', 'Gene', '407024', (227, 233))	('miR-370', 'Gene', (218, 225))	('epidermal growth factor receptor', 'Gene', (52, 84))	('EGFR', 'Gene', (46, 50))	('epidermal growth factor receptor', 'Gene', '1956', (52, 84))	('IL-6', 'Gene', (97, 101))	('COX2', 'Gene', (176, 180))	('miR-370', 'Gene', '442915', (218, 225))	('inflammation', 'Disease', 'MESH:D007249', (155, 167))
131312	28669153	It activates carcinogenesis through mutation in oncogenes, chromosomal aneuploidy (PSC-associated CC) via ErbB2, p42/44 mitogen activated protein kinase (MAPK) (Khan et al., 2014; Patel., 2014; Fan et al., 2012; Francis et al., 2010; Wise et al., 2008; Andersen et al., 2012).	('p42', 'Gene', (113, 116))	('ErbB2', 'Gene', (106, 111))	('carcinogenesis', 'Disease', 'MESH:D063646', (13, 27))	('p42', 'Gene', '2038', (113, 116))	('carcinogenesis', 'Disease', (13, 27))	('ErbB2', 'Gene', '2064', (106, 111))	('chromosomal aneuploidy', 'Disease', (59, 81))	('activates', 'PosReg', (3, 12))	('chromosomal aneuploidy', 'Disease', 'MESH:D000782', (59, 81))	('mutation', 'Var', (36, 44))
131316	28669153	MMP breaks down extracellular matrix and results in tumor spread.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('MMP', 'Var', (0, 3))	('tumor', 'Disease', (52, 57))	('breaks down', 'Phenotype', 'HP:0001061', (4, 15))	('extracellular', 'MPA', (16, 29))	('results in', 'Reg', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('breaks down', 'NegReg', (4, 15))
131328	28669153	Deoxycholic acid, a bile acid component, activates EGRF via TGFalpha and induces COX-2 expression via p42/44 and p38MAPK.	('p38MAPK', 'Var', (113, 120))	('EGRF', 'Protein', (51, 55))	('bile acid', 'Chemical', 'MESH:D001647', (20, 29))	('Deoxycholic acid', 'Chemical', 'MESH:D003840', (0, 16))	('induces', 'PosReg', (73, 80))	('TGFalpha', 'Protein', (60, 68))	('COX-2', 'Gene', '4513', (81, 86))	('p42', 'Gene', (102, 105))	('expression', 'MPA', (87, 97))	('COX-2', 'Gene', (81, 86))	('p42', 'Gene', '2038', (102, 105))	('activates', 'PosReg', (41, 50))
131377	29246025	Furthermore, the abnormal expression of certain long non-coding RNAs has roused people's interest in the role of long non-coding RNAs in tumorigenesis.	('people', 'Species', '9606', (80, 86))	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('long', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('abnormal', 'Var', (17, 25))
131379	29246025	This review takes a retrospect at the latest researches on the link between microRNA/long non-coding RNA and cholangiocarcinoma and the potential of microRNA/long non-coding RNA serving as distinctive biomarkers for CCA in clinical practice.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (109, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('microRNA/long non-coding', 'Var', (149, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('CCA', 'Gene', (216, 219))	('CCA', 'Gene', '2201', (216, 219))	('cholangiocarcinoma', 'Disease', (109, 127))
131386	29246025	MicroRNAs (miRNAs) refer to a subgroup of small, noncoding RNA that mediate a series of biological events from controlling the growth of insects to deactivating X chromosome in mammals.	('miR', 'Gene', (11, 14))	('deactivating', 'Var', (148, 160))	('miR', 'Gene', '220972', (11, 14))
131392	29246025	Although previous studies have confirmed that dysregulated miRNAs have a crucial role in tumors, the underlying mechanisms remain largely unknown.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('miR', 'Gene', '220972', (59, 62))	('dysregulated', 'Var', (46, 58))	('miR', 'Gene', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
131435	29246025	It is found that miRNA-122 deficiency may be closely associated with bad prognosis of CCA patients.	('miRNA-122', 'Gene', (17, 26))	('CCA', 'Gene', (86, 89))	('deficiency', 'Var', (27, 37))	('associated', 'Reg', (53, 63))	('CCA', 'Gene', '2201', (86, 89))	('patients', 'Species', '9606', (90, 98))	('miRNA-122', 'Gene', '406906', (17, 26))
131439	29246025	Further researches confirmed miRNA-200a deficiency is correlated with the progression of certain types of cancers.	('deficiency', 'Var', (40, 50))	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('correlated', 'Reg', (54, 64))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
131445	29246025	Furthermore, the overall survival rate is much lower in miRNA-203 underexpression group than miRNA-203 overexpression group.	('lower', 'NegReg', (47, 52))	('miRNA-203', 'Gene', '406986', (56, 65))	('underexpression', 'Var', (66, 81))	('miRNA-203', 'Gene', '406986', (93, 102))	('miRNA-203', 'Gene', (56, 65))	('miRNA-203', 'Gene', (93, 102))
131485	29246025	Moreover, a close connection between dysregulated lncRNA expression and the prognosis of tumor patients has been discovered.	('lncRNA', 'Protein', (50, 56))	('patients', 'Species', '9606', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('dysregulated', 'Var', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
131498	29246025	However, low BAP1 expressing CCA cell lines exhibit higher sensitivity to gemcitabine and cisplatin with lower IC50.	('CCA', 'Gene', (29, 32))	('lower', 'NegReg', (105, 110))	('low', 'Var', (9, 12))	('BAP1', 'Gene', (13, 17))	('CCA', 'Gene', '2201', (29, 32))	('gemcitabine', 'Chemical', 'MESH:C056507', (74, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('IC50', 'MPA', (111, 115))	('higher', 'PosReg', (52, 58))	('BAP1', 'Gene', '8314', (13, 17))	('sensitivity to gemcitabine', 'MPA', (59, 85))
131500	29246025	In NEAT-1 knock-down CCA cell lines, the cytotoxicity of gemcitabine is significantly higher than control group which implies lncRNA NEAT-1 might serve as a chemosensitivity tissue biomarker for CCA.	('CCA', 'Gene', '2201', (21, 24))	('CCA', 'Gene', (21, 24))	('CCA', 'Gene', '2201', (195, 198))	('NEAT-1', 'Gene', (133, 139))	('CCA', 'Gene', (195, 198))	('NEAT-1', 'Gene', (3, 9))	('knock-down', 'Var', (10, 20))	('cytotoxicity', 'Disease', (41, 53))	('higher', 'PosReg', (86, 92))	('NEAT-1', 'Gene', '283131', (133, 139))	('gemcitabine', 'Chemical', 'MESH:C056507', (57, 68))	('NEAT-1', 'Gene', '283131', (3, 9))	('cytotoxicity', 'Disease', 'MESH:D064420', (41, 53))
131551	25855031	Sections of formalin-fixed paraffin-embedded liver tissue were stained with anti-CD1d or an isotype control and co-stained with an anti-CK19 antibody.	('paraffin', 'Chemical', 'MESH:D010232', (27, 35))	('anti-CD1d', 'Var', (76, 85))	('CK19', 'Gene', (136, 140))	('CK19', 'Gene', '3880', (136, 140))	('formalin', 'Chemical', 'MESH:D005557', (12, 20))
131574	25855031	In line with the experiments performed in the murine and human cholangiocyte cell lines, we evaluated CD1d expression in eight cholangiocarcinoma cell lines by Western blotting which demonstrated that all cell lines expressed CD1d (Fig.	('cholangiocarcinoma', 'Disease', (127, 145))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (127, 145))	('murine', 'Species', '10090', (46, 52))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (127, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('CD1d', 'Var', (226, 230))	('human', 'Species', '9606', (57, 62))
131595	25855031	IECs and their CD1d expression play an important role in intestinal inflammation, as intestinal epithelial CD1d appears to protect from intestinal inflammation through its ability to induce secretion of IL-10 when ligated by iNKT cells, while iNKT cells activated by bone-marrow-derived antigen presenting cells (APCs) contribute to inflammation.	('intestinal inflammation', 'Disease', 'MESH:D007249', (57, 80))	('intestinal inflammation', 'Disease', (57, 80))	('intestinal inflammation', 'Disease', 'MESH:D007249', (136, 159))	('IL-10', 'Gene', '3586', (203, 208))	('inflammation', 'Disease', 'MESH:D007249', (333, 345))	('intestinal inflammation', 'Disease', (136, 159))	('inflammation', 'Disease', 'MESH:D007249', (68, 80))	('inflammation', 'Disease', (333, 345))	('intestinal epithelial CD1d', 'Var', (85, 111))	('APC', 'Disease', 'MESH:D011125', (313, 316))	('IL-10', 'Gene', (203, 208))	('inflammation', 'Disease', 'MESH:D007249', (147, 159))	('inflammation', 'Disease', (68, 80))	('secretion', 'MPA', (190, 199))	('inflammation', 'Disease', (147, 159))	('induce', 'PosReg', (183, 189))	('APC', 'Disease', (313, 316))
131613	21483830	siRNA targeted knockdown of XIAP mimics sensitization to mitochondria-independent TRAIL killing achieved by Hedgehog inhibition.	('sensitization', 'Reg', (40, 53))	('XIAP', 'Gene', (28, 32))	('knockdown', 'Var', (15, 24))	('XIAP', 'Gene', '331', (28, 32))	('TRAIL', 'Gene', '8743', (82, 87))	('TRAIL', 'Gene', (82, 87))
131617	21483830	TRAIL-induced clustering and oligomerization of DR4 and DR5 results in conformational changes of the death domains within their cytoplasmic tails, facilitating recruitment and activation of caspases 8 and 10 within a death inducing signaling complex (DISC).	('conformational changes', 'MPA', (71, 93))	('caspases', 'Gene', (190, 198))	('caspases', 'Gene', '841', (190, 198))	('DR4', 'Gene', (48, 51))	('TRAIL', 'Gene', (0, 5))	('DR5', 'Gene', (56, 59))	('recruitment', 'MPA', (160, 171))	('DR5', 'Gene', '8795', (56, 59))	('oligomerization', 'Var', (29, 44))	('DR4', 'Gene', '8797', (48, 51))	('activation', 'PosReg', (176, 186))	('TRAIL', 'Gene', '8743', (0, 5))
131624	21483830	Herein, we demonstrate that inhibition of the oncogenic Hedgehog pathway represses the expression of XIAP and sensitizes cancer cells to TRAIL cytotoxicity, using cholangiocarcinoma cells as a model to study TRAIL resistance.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('XIAP', 'Gene', (101, 105))	('cholangiocarcinoma', 'Disease', (163, 181))	('TRAIL', 'Gene', '8743', (208, 213))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (163, 181))	('TRAIL', 'Gene', '8743', (137, 142))	('oncogenic Hedgehog pathway', 'Pathway', (46, 72))	('cytotoxicity', 'Disease', (143, 155))	('cytotoxicity', 'Disease', 'MESH:D064420', (143, 155))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('TRAIL', 'Gene', (208, 213))	('sensitizes', 'Reg', (110, 120))	('represses', 'NegReg', (73, 82))	('TRAIL', 'Gene', (137, 142))	('XIAP', 'Gene', '331', (101, 105))	('expression', 'MPA', (87, 97))	('inhibition', 'Var', (28, 38))	('cancer', 'Disease', (121, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (163, 181))
131661	21483830	Given a pivotal mechanistic role for inhibitor of apoptosis proteins (IAPs) in death receptor signaling and the role Hedgehog in cellular survival, we first ascertained if inhibiting Smoothened (SMO), the signaling component of the Hedgehog receptor complex, modulates expression of IAPs.	('inhibiting', 'Var', (172, 182))	('IAP', 'Gene', '961', (70, 73))	('SMO', 'Gene', (195, 198))	('Smoothened', 'Gene', '6608', (183, 193))	('IAP', 'Gene', (70, 73))	('expression', 'MPA', (269, 279))	('IAP', 'Gene', '961', (283, 286))	('IAP', 'Gene', (283, 286))	('modulates', 'Reg', (259, 268))	('Smoothened', 'Gene', (183, 193))	('SMO', 'Gene', '6608', (195, 198))
131664	21483830	The pharmacological effect of cyclopamine was validated by using shRNA targeted knockdown of SMO, a signaling component of the Hedgehog receptor, which also decreased both cIAP-1 and XIAP cellular protein levels, but not cIAP-2 (Fig.	('knockdown', 'Var', (80, 89))	('cIAP-1', 'Gene', '329', (172, 178))	('XIAP', 'Gene', (183, 187))	('SMO', 'Gene', '6608', (93, 96))	('cIAP-1', 'Gene', (172, 178))	('cyclopamine', 'Chemical', 'MESH:C000541', (30, 41))	('XIAP', 'Gene', '331', (183, 187))	('cIAP-2', 'Gene', '330', (221, 227))	('SMO', 'Gene', (93, 96))	('cIAP-2', 'Gene', (221, 227))	('decreased', 'NegReg', (157, 166))
131676	21483830	2A) were identified upstream of the XIAP transcription start site (NM_001167) at positions -2820/-2807 (Site I) and -1594/-1581 (Site II).	('NM_001167', 'Var', (67, 76))	('XIAP', 'Gene', '331', (36, 40))	('XIAP', 'Gene', (36, 40))
131680	21483830	Of the three GLI family members, siRNA to GLI2 caused a significant decrease in XIAP protein expression while siRNA to GLI1 or GLI3 did not alter XIAP levels (Fig.	('GLI2', 'Gene', (42, 46))	('GLI2', 'Gene', '2736', (42, 46))	('GLI3', 'Gene', '2737', (127, 131))	('GLI', 'Gene', (42, 45))	('GLI1', 'Gene', (119, 123))	('GLI3', 'Gene', (127, 131))	('decrease', 'NegReg', (68, 76))	('GLI', 'Gene', (119, 122))	('XIAP', 'Gene', (146, 150))	('XIAP', 'Gene', '331', (80, 84))	('GLI', 'Gene', (127, 130))	('GLI', 'Gene', '2735', (42, 45))	('GLI', 'Gene', (13, 16))	('GLI1', 'Gene', '2735', (119, 123))	('GLI', 'Gene', '2735', (119, 122))	('GLI', 'Gene', '2735', (127, 130))	('siRNA', 'Var', (33, 38))	('XIAP', 'Gene', '331', (146, 150))	('XIAP', 'Gene', (80, 84))	('GLI', 'Gene', '2735', (13, 16))
131685	21483830	XIAP is a key discriminator for converting Type II to Type I death receptor signaling, thus, we considered loss of XIAP protein as a mechanism by which Hedgehog inhibition sensitized cholangiocarcinoma cells to TRAIL-induced apoptosis.	('TRAIL', 'Gene', (211, 216))	('XIAP', 'Gene', (0, 4))	('XIAP', 'Gene', '331', (0, 4))	('Type II to Type I death', 'Disease', (43, 66))	('loss', 'Var', (107, 111))	('Type II to Type I death', 'Disease', 'MESH:D005776', (43, 66))	('XIAP', 'Gene', (115, 119))	('XIAP', 'Gene', '331', (115, 119))	('cholangiocarcinoma', 'Disease', (183, 201))	('TRAIL', 'Gene', '8743', (211, 216))	('inhibition', 'NegReg', (161, 171))	('Hedgehog', 'Gene', (152, 160))	('sensitized', 'PosReg', (172, 182))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (183, 201))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (183, 201))
131690	21483830	Indeed, Bid or Bim knockdown was sufficient to inhibit Fas-induced cell death by the agonistic antibody CH-11 (Fig.	('Bim', 'Gene', (15, 18))	('knockdown', 'Var', (19, 28))	('inhibit', 'NegReg', (47, 54))	('Fas', 'Chemical', 'MESH:C038178', (55, 58))	('Fas-induced', 'Disease', (55, 66))	('CH-11', 'Chemical', 'MESH:C418965', (104, 109))	('Bid', 'Gene', (8, 11))	('Bim', 'Gene', '10018', (15, 18))	('Bid', 'Gene', '637', (8, 11))
131698	21483830	The independence of Bid or Bim suggested the intriguing possibility that cyclopamine may sensitize cholangiocarcinoma cells to TRAIL by converting apoptotic signaling from a Type II to a Type I death receptor pathway.	('TRAIL', 'Gene', '8743', (127, 132))	('converting', 'Reg', (136, 146))	('Type I death', 'Disease', 'MESH:D003643', (187, 199))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (99, 117))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (99, 117))	('Bim', 'Gene', (27, 30))	('TRAIL', 'Gene', (127, 132))	('apoptotic signaling', 'MPA', (147, 166))	('Bim', 'Gene', '10018', (27, 30))	('Bid', 'Gene', (20, 23))	('Bid', 'Gene', '637', (20, 23))	('sensitize', 'Reg', (89, 98))	('cyclopamine', 'Var', (73, 84))	('cyclopamine', 'Chemical', 'MESH:C000541', (73, 84))	('cholangiocarcinoma', 'Disease', (99, 117))	('Type I death', 'Disease', (187, 199))
131699	21483830	To test this hypothesis, we next determined whether Hedgehog inhibition converts Type II death receptor signaling to Type I signaling.	('Type II death', 'Disease', 'MESH:D003643', (81, 94))	('Type II death', 'Disease', (81, 94))	('Type I signaling', 'MPA', (117, 133))	('converts', 'Reg', (72, 80))	('inhibition', 'Var', (61, 71))
131704	21483830	However, TRAIL-induced apoptosis was dramatically increased by cyclopamine (Fig.	('TRAIL', 'Gene', '8743', (9, 14))	('increased', 'PosReg', (50, 59))	('cyclopamine', 'Var', (63, 74))	('cyclopamine', 'Chemical', 'MESH:C000541', (63, 74))	('TRAIL', 'Gene', (9, 14))
131706	21483830	These data suggest that Hedgehog inhibition circumvents mitochondrial resistance to TRAIL cytotoxicity by converting a Type II signaling to a Type I signaling pathway.	('inhibition', 'Var', (33, 43))	('cytotoxicity', 'Disease', 'MESH:D064420', (90, 102))	('Hedgehog', 'Gene', (24, 32))	('converting', 'Reg', (106, 116))	('TRAIL', 'Gene', '8743', (84, 89))	('circumvents', 'NegReg', (44, 55))	('Type I signaling pathway', 'Pathway', (142, 166))	('cytotoxicity', 'Disease', (90, 102))	('TRAIL', 'Gene', (84, 89))	('Type II signaling', 'MPA', (119, 136))
131707	21483830	Next, we determined the functional relevance of XIAP expression in these cancer cells using siRNA-targeted knockdown of cIAP-1 or XIAP.	('knockdown', 'Var', (107, 116))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('XIAP', 'Gene', (48, 52))	('cIAP-1', 'Gene', (120, 126))	('XIAP', 'Gene', '331', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('XIAP', 'Gene', '331', (130, 134))	('XIAP', 'Gene', (130, 134))	('cIAP-1', 'Gene', '329', (120, 126))
131709	21483830	Consistent with previous reports, knockdown of XIAP significantly sensitized the cells to TRAIL cytotoxicity, while knockdown of cIAP-1 only modestly sensitized the cells to TRAIL-induced cell death, measured either morphologically (Fig.	('TRAIL', 'Gene', '8743', (174, 179))	('cIAP-1', 'Gene', (129, 135))	('sensitized', 'Reg', (66, 76))	('TRAIL', 'Gene', (174, 179))	('TRAIL', 'Gene', '8743', (90, 95))	('knockdown', 'Var', (116, 125))	('cytotoxicity', 'Disease', (96, 108))	('XIAP', 'Gene', (47, 51))	('TRAIL', 'Gene', (90, 95))	('knockdown', 'Var', (34, 43))	('cIAP-1', 'Gene', '329', (129, 135))	('XIAP', 'Gene', '331', (47, 51))	('cytotoxicity', 'Disease', 'MESH:D064420', (96, 108))
131712	21483830	To test this interpretation of the data, we designed experiments to ascertain if knockdown of XIAP protein was sufficient to convert TRAIL signaling to a mitochondria-independent, Type I pathway.	('TRAIL', 'Gene', (133, 138))	('mitochondria-independent', 'Pathway', (154, 178))	('convert', 'Reg', (125, 132))	('XIAP', 'Gene', (94, 98))	('XIAP', 'Gene', '331', (94, 98))	('knockdown', 'Var', (81, 90))	('TRAIL', 'Gene', '8743', (133, 138))	('protein', 'Protein', (99, 106))
131714	21483830	First, to confirm that BI-6C9 functionally inhibited cell death in this system, KMCH cells were pre-treated with BI-6C9 or vehicle (DMSO), followed by Fas agonistic antibody.	('inhibited', 'NegReg', (43, 52))	('BI-6C9', 'Chemical', '-', (23, 29))	('BI-6C9', 'Chemical', '-', (113, 119))	('Fas', 'Chemical', 'MESH:C038178', (151, 154))	('DMSO', 'Chemical', 'MESH:D004121', (132, 136))	('BI-6C9', 'Var', (23, 29))	('BI-6C9', 'Var', (113, 119))	('cell death', 'CPA', (53, 63))
131715	21483830	Indeed, pharmacologic inhibition of Bid by BI-6C9 was sufficient to repress Fas-induced apoptosis.	('Fas', 'Chemical', 'MESH:C038178', (76, 79))	('Bid', 'Gene', (36, 39))	('BI-6C9', 'Chemical', '-', (43, 49))	('Fas-induced apoptosis', 'CPA', (76, 97))	('BI-6C9', 'Var', (43, 49))	('repress', 'NegReg', (68, 75))	('Bid', 'Gene', '637', (36, 39))
131717	21483830	In contrast, BI-6C9 did not functionally inhibit TRAIL-induced cell death in cyclopamine-treated cells (Fig.	('BI-6C9', 'Var', (13, 19))	('TRAIL', 'Gene', '8743', (49, 54))	('cyclopamine', 'Chemical', 'MESH:C000541', (77, 88))	('TRAIL', 'Gene', (49, 54))	('inhibit', 'NegReg', (41, 48))	('BI-6C9', 'Chemical', '-', (13, 19))
131721	21483830	The results demonstrate that in human cholangiocarcinoma cells, (i) Hedgehog pathway inhibition sensitizes human cholangiocarcinoma cells to TRAIL-mediated apoptosis, in part, by down-regulating XIAP protein; (ii) XIAP repression by SMO inhibition occurs at the mRNA level as well, consistent with GLI-mediated enhancement of XIAP transcription; and (iii) inhibition of Hedgehog promotes TRAIL cytotoxicity independent of Bid, Bim, Bax, and Bak.	('Bax', 'Gene', '581', (432, 435))	('Bak', 'Gene', '578', (441, 444))	('GLI', 'Gene', '2735', (298, 301))	('XIAP', 'Gene', (195, 199))	('Bim', 'Gene', (427, 430))	('promotes', 'PosReg', (379, 387))	('XIAP', 'Gene', '331', (326, 330))	('SMO', 'Gene', '6608', (233, 236))	('down-regulating', 'NegReg', (179, 194))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (113, 131))	('Bid', 'Gene', (422, 425))	('XIAP', 'Gene', '331', (214, 218))	('human', 'Species', '9606', (32, 37))	('SMO', 'Gene', (233, 236))	('cholangiocarcinoma', 'Disease', (113, 131))	('TRAIL', 'Gene', '8743', (388, 393))	('inhibition', 'Var', (356, 366))	('Hedgehog', 'Gene', (370, 378))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (113, 131))	('TRAIL', 'Gene', '8743', (141, 146))	('Bak', 'Gene', (441, 444))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (38, 56))	('XIAP', 'Gene', (326, 330))	('cholangiocarcinoma', 'Disease', (38, 56))	('XIAP', 'Gene', '331', (195, 199))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (38, 56))	('TRAIL', 'Gene', (388, 393))	('GLI', 'Gene', (298, 301))	('human', 'Species', '9606', (107, 112))	('cytotoxicity', 'Disease', (394, 406))	('Bid', 'Gene', '637', (422, 425))	('TRAIL', 'Gene', (141, 146))	('Bax', 'Gene', (432, 435))	('XIAP', 'Gene', (214, 218))	('cytotoxicity', 'Disease', 'MESH:D064420', (394, 406))	('Bim', 'Gene', '10018', (427, 430))
131722	21483830	These data suggest inhibition of Hedgehog signaling modulates TRAIL cytotoxicity in human cholangiocarcinoma cells by regulating XIAP expression and converting TRAIL signaling from Type II to Type I apoptotic signaling.	('TRAIL', 'Gene', (160, 165))	('inhibition', 'Var', (19, 29))	('TRAIL', 'Gene', '8743', (62, 67))	('cytotoxicity', 'Disease', (68, 80))	('cholangiocarcinoma', 'Disease', (90, 108))	('modulates', 'Reg', (52, 61))	('XIAP', 'Gene', (129, 133))	('TRAIL', 'Gene', (62, 67))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (90, 108))	('TRAIL', 'Gene', '8743', (160, 165))	('human', 'Species', '9606', (84, 89))	('converting', 'Reg', (149, 159))	('XIAP', 'Gene', '331', (129, 133))	('cytotoxicity', 'Disease', 'MESH:D064420', (68, 80))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))	('regulating', 'Reg', (118, 128))
131724	21483830	Indeed, this pathway is active in human cholangiocarcinoma cell lines in an autocrine and/or paracrine manner as cyclopamine suppresses the growth of cholangiocarcinoma cells both in vitro and in vivo  and imparts survival signals.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (40, 58))	('human', 'Species', '9606', (34, 39))	('cyclopamine', 'Var', (113, 124))	('cyclopamine', 'Chemical', 'MESH:C000541', (113, 124))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (40, 58))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (150, 168))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (150, 168))	('growth', 'MPA', (140, 146))	('survival signals', 'CPA', (214, 230))	('cholangiocarcinoma', 'Disease', (40, 58))	('cholangiocarcinoma', 'Disease', (150, 168))	('suppresses', 'NegReg', (125, 135))
131729	21483830	Finally, genetic inhibition of XIAP not only sensitized cholangiocarcinoma cells to TRAIL killing, but did so independently of mitochondrial involvement (i.e.	('XIAP', 'Gene', (31, 35))	('sensitized', 'Reg', (45, 55))	('cholangiocarcinoma', 'Disease', (56, 74))	('XIAP', 'Gene', '331', (31, 35))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (56, 74))	('TRAIL', 'Gene', '8743', (84, 89))	('genetic inhibition', 'Var', (9, 27))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (56, 74))	('TRAIL', 'Gene', (84, 89))
131740	21483830	We speculate that Fas signaling and TRAIL signaling are affected differently by Hedgehog inhibition.	('TRAIL', 'Gene', (36, 41))	('inhibition', 'Var', (89, 99))	('Fas', 'CPA', (18, 21))	('TRAIL', 'Gene', '8743', (36, 41))	('affected', 'Reg', (56, 64))	('Fas', 'Chemical', 'MESH:C038178', (18, 21))
131742	21483830	Further, Hedgehog inhibition did not alter Fas protein expression, but increased DR4 at both the mRNA and protein levels.	('DR4', 'Gene', '8797', (81, 84))	('DR4', 'Gene', (81, 84))	('Fas', 'Chemical', 'MESH:C038178', (43, 46))	('increased', 'PosReg', (71, 80))	('inhibition', 'Var', (18, 28))	('Hedgehog', 'Gene', (9, 17))
131745	21483830	As these cancers express TRAIL in vivo, pharmacologic inhibition of Hedgehog signaling may promote autocrine and/or paracrine cholangiocarcinoma-autonomous cytotoxicity.	('cytotoxicity', 'Disease', (156, 168))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('promote', 'PosReg', (91, 98))	('TRAIL', 'Gene', '8743', (25, 30))	('pharmacologic', 'Var', (40, 53))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('Hedgehog signaling', 'Gene', (68, 86))	('cholangiocarcinoma-autonomous', 'Disease', 'MESH:D018281', (126, 155))	('cytotoxicity', 'Disease', 'MESH:D064420', (156, 168))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (126, 144))	('TRAIL', 'Gene', (25, 30))	('cholangiocarcinoma-autonomous', 'Disease', (126, 155))	('autocrine and/or', 'CPA', (99, 115))
131792	30959757	For clinical use, two cut-off points of the preoperative bilirubin level were established: >=6.00 mg/dL and >=2.50 mg/dL.	('>=2.50 mg/dL', 'Var', (108, 120))	('bilirubin', 'Chemical', 'MESH:D001663', (57, 66))	('bilirubin level', 'MPA', (57, 72))	('>=6.00', 'Var', (91, 97))
131798	30959757	In the present study, the optimal bilirubin concentration cut-off to predict postoperative mortality was >=6.20 mg/dL with a positive predictive value of 29.6% and high sensitivity level of 87.5%, which are already valuable parameters to predict postoperative mortality.	('>=6.20', 'Var', (105, 111))	('bilirubin', 'Chemical', 'MESH:D001663', (34, 43))	('postoperative mortality', 'Disease', (77, 100))
131805	30959757	In the present analysis, the optimal bilirubin concentration cut-off to predict severe postoperative complications was >=2.48 mg/dL in the whole group, with a positive predictive value of 42.5% and sensitivity of 73.9%.	('bilirubin', 'Chemical', 'MESH:D001663', (37, 46))	('>=2.48', 'Var', (119, 125))	('severe', 'Disease', (80, 86))
131824	30959757	analyzed data from three hospitals and concluded that patients with a creatinine concentration >=1.8 mg/dL are at a risk of developing severe postoperative complications, including respiratory insufficiency and renal failure.	('renal failure', 'Disease', 'MESH:D051437', (211, 224))	('respiratory insufficiency', 'Phenotype', 'HP:0002093', (181, 206))	('creatinine', 'MPA', (70, 80))	('renal failure', 'Disease', (211, 224))	('patients', 'Species', '9606', (54, 62))	('creatinine', 'Chemical', 'MESH:D003404', (70, 80))	('>=1.8', 'Var', (95, 100))	('respiratory insufficiency', 'Disease', 'MESH:D012131', (181, 206))	('renal failure', 'Phenotype', 'HP:0000083', (211, 224))	('respiratory insufficiency', 'Disease', (181, 206))
131851	30959757	The results indicate that preoperative biliary drainage should be performed in all patients with hilar cholangiocarcinoma with a bilirubin concentration >=6.00 mg/dL, whereas it should be considered in patients with a bilirubin concentration <6.00 mg/dL and >=2.50 mg/dL, especially in patients with preoperative hypoalbuminemia, anemia, or renal dysfunction, those who are scheduled to undergo right or extended right hemihepatectomy, and those with ineffective biliary drainage.	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (97, 121))	('anemia', 'Disease', 'MESH:D000740', (330, 336))	('bilirubin', 'Chemical', 'MESH:D001663', (218, 227))	('anemia', 'Phenotype', 'HP:0001903', (330, 336))	('hilar cholangiocarcinoma', 'Disease', (97, 121))	('renal dysfunction', 'Disease', (341, 358))	('>=6.00', 'Var', (153, 159))	('patients', 'Species', '9606', (83, 91))	('renal dysfunction', 'Phenotype', 'HP:0000083', (341, 358))	('patients', 'Species', '9606', (202, 210))	('hypoalbuminemia', 'Disease', 'MESH:D034141', (313, 328))	('renal dysfunction', 'Disease', 'MESH:D007674', (341, 358))	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (313, 328))	('bilirubin', 'Chemical', 'MESH:D001663', (129, 138))	('hypoalbuminemia', 'Disease', (313, 328))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (103, 121))	('anemia', 'Disease', (330, 336))	('patients', 'Species', '9606', (286, 294))
131890	27177447	By generating tandem minigene (TMG) constructs of each of the mutations and co-culturing with expanded populations of isolated tumor infiltrating lymphocytes (TIL), they identified a reactive population of CD4+ cells.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('CD4', 'Gene', (206, 209))	('tumor', 'Disease', (127, 132))	('CD4', 'Gene', '920', (206, 209))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('mutations', 'Var', (62, 71))
131895	27177447	In 239 cases of BTC in whom whole-exome sequencing was performed the median numbers of mutations across the intrahepatic (ICC), extrahepatic (ECC) and gallbladder cancer subtypes were 39, 35 and 64, respectively.	('gallbladder cancer', 'Disease', 'MESH:D005706', (151, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('BTC', 'Chemical', '-', (16, 19))	('mutations', 'Var', (87, 96))	('gallbladder cancer', 'Disease', (151, 169))
132054	31565366	After soaking in PBS for 14 days, the doublet peaks of V2p3/2 (517.6 eV) and V2p1/2 (524.8 eV) in V2O5 were the major peaks detected on the surface.25 Therefore, the zeta potential and XPS analysis results were consistent.	('eta', 'Gene', '1909', (167, 170))	('V2O5', 'Chemical', 'MESH:C066075', (98, 102))	('eta', 'Gene', (167, 170))	('V2p1/2', 'Var', (77, 83))
132062	31565366	According to the results, the presence of a VO2 nanocoating on quartz glass could cause severe cytotoxicity to tumor cells.	('VO2', 'Gene', (44, 47))	('O2', 'Chemical', 'MESH:D013481', (45, 47))	('cytotoxicity to tumor', 'Disease', 'MESH:D064420', (95, 116))	('cause', 'Reg', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('presence', 'Var', (30, 38))	('cytotoxicity to tumor', 'Disease', (95, 116))
132065	31565366	On the contrary, the number of tumor cells was significantly reduced on the VO2 nanocoating, and most of them maintained a spherical or spindle morphology (Figure 3e1,f1,g1).	('nanocoating', 'Var', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('spherical or spindle morphology', 'CPA', (123, 154))	('tumor', 'Disease', (31, 36))	('O2', 'Chemical', 'MESH:D013481', (77, 79))	('VO2', 'Gene', (76, 79))	('reduced', 'NegReg', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
132069	31565366	Meanwhile, visualization of the tumor cell viability in Figure 3h shows the live/dead fluorescence staining results, which reveal that the number of live cells (stained in green fluorescence) reduced sharply on the VO2 nanocoating at day four of culture.	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('VO2', 'Var', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('reduced', 'NegReg', (192, 199))	('tumor', 'Disease', (32, 37))	('O2', 'Chemical', 'MESH:D013481', (216, 218))
132070	31565366	Moreover, increasing number of dead cells (stained in red fluorescence) were observed, further demonstrating that exposure to the VO2 nanocoating caused a severe decrease in the viability of tumor cells, especially in the VO-2 and VO-3 samples.	('viability', 'CPA', (178, 187))	('VO2', 'Gene', (130, 133))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('rat', 'Species', '10116', (102, 105))	('nanocoating', 'Var', (134, 145))	('decrease', 'NegReg', (162, 170))	('O2', 'Chemical', 'MESH:D013481', (131, 133))
132074	31565366	Quantitatively, exposure to the VO2 nanocoating could obviously elevate the intracellular ROS levels of tumor cells, and the order of DCF/DAPI intensity ratios was as follows: VO-3 (1.6 +- 0.1)   VO-2 (1.7 +- 0.03) > VO-1 (0.6 +- 0.1) > VO-0 (0.1 +- 0.01).	('elevate', 'PosReg', (64, 71))	('DCF', 'Chemical', 'MESH:C037631', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('intracellular ROS levels', 'MPA', (76, 100))	('rat', 'Species', '10116', (153, 156))	('O2', 'Chemical', 'MESH:D013481', (33, 35))	('tumor', 'Disease', (104, 109))	('elevate the intracellular ROS level', 'Phenotype', 'HP:0025464', (64, 99))	('elevate the intracellular ROS levels', 'Phenotype', 'HP:0025464', (64, 100))	('nanocoating', 'Var', (36, 47))	('VO2', 'Var', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
132096	31565366	According to the conversion equation for the standard hydrogen electrode (E SHE, V) and absolute potential level (E, eV),34 E SHE = -4.44 -E, the mitochondria-associated redox potentials are in the range of the biological redox potential (-4.12 to -4.84 eV).32 H2VO4 - anions are the most common intracellular form in biological systems, and they can be actively transported into mammalian cells.35 The most common forms of vanadium oxidation states are +3, +4, and +5 valences.36 The redox potential for the H2VO4 -/VO2+ redox couple is -0.34 V at pH = 7.37 According to the redox potentials of redox couples in the electron transport chain (Table 1), the +5 valent vanadate (H2VO4 -) tends to be reduced to the +4 valent VO2+ (vanadyl) by the nicotinamide adenine dinucleotide phosphate/reduced nicotinamide adenine dinucleotide phosphate (NADP+/NADPH), nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide (NAD+/NADH), flavin adenine dinucleotide/reduced flavin adenine dinucleotide (FAD2+/FADH2), and flavin mononucleotide/reduced flavin mononucleotide (FMN2+/FMNH2) redox couples,38 according to the following equation: H2VO4 - + 4H+ + e-   VO2+ + 3H2O.39  Based on the above analysis, by destructive extraction of electrons from the mitochondrial membrane, the bioreduction of vanadate tends to interrupt the electron transport chain and impair mitochondrial function.	('nicotinamide adenine dinucleotide', 'Chemical', 'MESH:D009243', (797, 830))	('hydrogen', 'Chemical', 'MESH:D006859', (54, 62))	('flavin adenine dinucleotide', 'Chemical', 'MESH:D005182', (981, 1008))	('H2VO4', 'Chemical', 'MESH:C581824', (677, 682))	('Ta', 'Chemical', 'MESH:D013635', (643, 645))	('bioreduction', 'Var', (1290, 1302))	('mammalian', 'Species', '9606', (380, 389))	('vanadate', 'Chemical', 'MESH:D014638', (1306, 1314))	('electron transport chain', 'MPA', (1338, 1362))	('nicotinamide adenine dinucleotide', 'Chemical', 'MESH:D009243', (898, 931))	('NAD', 'Chemical', 'MESH:D009243', (848, 851))	('NADP', 'Chemical', 'MESH:D009249', (842, 846))	('VO2+', 'Chemical', 'MESH:C581824', (1169, 1173))	('mitochondrial function', 'MPA', (1374, 1396))	('H2VO4', 'Chemical', 'MESH:C581824', (509, 514))	('nicotinamide adenine dinucleotide', 'Chemical', 'MESH:D009243', (745, 778))	('NAD', 'Chemical', 'MESH:D009243', (933, 936))	('VO2+', 'Chemical', 'MESH:C581824', (517, 521))	('VO2+', 'Chemical', 'MESH:C581824', (723, 727))	('NADPH', 'Chemical', 'MESH:D009249', (848, 853))	('nicotinamide adenine dinucleotide', 'Chemical', 'MESH:D009243', (856, 889))	('NADH', 'Chemical', 'MESH:D009243', (938, 942))	('flavin mononucleotide', 'Chemical', 'MESH:D005486', (1028, 1049))	('impair', 'NegReg', (1367, 1373))	('4H+', 'Chemical', 'MESH:D006859', (1158, 1161))	('H2VO4', 'Chemical', 'MESH:C581824', (261, 266))	('nicotinamide adenine dinucleotide phosphate', 'Chemical', 'MESH:D009249', (745, 788))	('flavin adenine dinucleotide', 'Chemical', 'MESH:D005182', (945, 972))	('FAD2', 'Chemical', 'MESH:D005182', (1010, 1014))	('flavin mononucleotide', 'Chemical', 'MESH:D005486', (1058, 1079))	('NADP', 'Chemical', 'MESH:D009249', (848, 852))	('vanadyl', 'Chemical', 'MESH:D014638', (729, 736))	('3H2O', 'Chemical', 'MESH:D014867', (1176, 1180))	('FMN2', 'Chemical', 'MESH:D005486', (1081, 1085))	('NAD', 'Chemical', 'MESH:D009243', (938, 941))	('FADH2', 'Chemical', 'MESH:C058805', (1016, 1021))	('NAD', 'Chemical', 'MESH:D009243', (842, 845))	('vanadium', 'Chemical', 'MESH:D014639', (424, 432))	('nicotinamide adenine dinucleotide phosphate', 'Chemical', 'MESH:D009249', (797, 840))	('interrupt', 'NegReg', (1324, 1333))	('H2VO4', 'Chemical', 'MESH:C581824', (1148, 1153))	('vanadate', 'Chemical', 'MESH:D014638', (667, 675))
132140	31565366	"[qv: 62] The current study suggests that the deposition of VO2 nanocoating on biomaterial/implant surfaces could induce the death of cancer cells.	('death', 'CPA', (125, 130))	('O2', 'Chemical', 'MESH:D013481', (61, 63))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('induce', 'PosReg', (114, 120))	('nanocoating', 'Var', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('VO2', 'Gene', (60, 63))
132145	31565366	The dysfunction of the mitochondria ultimately induces the apoptosis of the cancer cells.	('mitochondria', 'Enzyme', (23, 35))	('induces', 'Reg', (47, 54))	('dysfunction', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('apoptosis', 'CPA', (59, 68))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
132260	27653566	In humans, genetic variants of fucosyl transferase 2, a molecule expressed in gut and cholangiocytes, participate in the synthesis of the H antigen oligosaccharide, which serves as a binding moiety for some intestinal bacteria.	('oligosaccharide', 'Chemical', 'MESH:D009844', (148, 163))	('synthesis', 'MPA', (121, 130))	('participate', 'Reg', (102, 113))	('humans', 'Species', '9606', (3, 9))	('fucosyl transferase', 'Enzyme', (31, 50))	('genetic variants', 'Var', (11, 27))
132262	27653566	Such a scenario assumes that intestinal T cells are stimulated within intestine-associated lymphoid tissue, express the cell-surface receptors integrin alpha4beta7 and CCR9, and then are recruited to the hepatic tissue as a result of abnormal expression in the liver of their associated ligands such as the adhesion protein mucosal addressin-cell adhesion molecule 1 (MAdCAM-1) and the chemotactic protein CCL25, which are typically limited to the gut.	('abnormal', 'Var', (234, 242))	('CCL25', 'Gene', '6370', (406, 411))	('MAdCAM-1', 'Gene', (368, 376))	('mucosal addressin-cell adhesion molecule 1', 'Gene', '8174', (324, 366))	('MAdCAM-1', 'Gene', '8174', (368, 376))	('CCL25', 'Gene', (406, 411))	('CCR9', 'Gene', '10803', (168, 172))	('mucosal addressin-cell adhesion molecule 1', 'Gene', (324, 366))	('CCR9', 'Gene', (168, 172))
132266	27653566	Dysregulation of such "activated cholangiocytes," particularly in genetically susceptible persons, may confer a predisposition to the development and progression of primary sclerosing cholangitis.	('Dysregulation', 'Var', (0, 13))	('primary sclerosing cholangitis', 'Disease', 'MESH:D015209', (165, 195))	('persons', 'Species', '9606', (90, 97))	('primary sclerosing cholangitis', 'Disease', (165, 195))	('cholangitis', 'Phenotype', 'HP:0030151', (184, 195))	('predisposition', 'Reg', (112, 126))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (173, 195))
132279	27653566	In one randomized, double-blind, placebo-controlled trial, patients who received ursodeoxycholic acid had decreased levels of serum liver enzymes, but they did not have higher rates of survival than the rates among patients who received placebo.	('decreased', 'NegReg', (106, 115))	('patients', 'Species', '9606', (215, 223))	('levels of serum liver enzymes', 'MPA', (116, 145))	('patients', 'Species', '9606', (59, 67))	('ursodeoxycholic acid', 'Var', (81, 101))	('ursodeoxycholic acid', 'Chemical', 'MESH:D014580', (81, 101))
132280	27653566	In a randomized, double-blind, placebo-controlled trial, the risk of the primary end point (death, liver transplantation, minimal listing criteria for liver transplantation, cirrhosis, esophageal or gastric varices, and cholangiocarcinoma) was 2.3 times higher among patients who received high-dose ursodeoxycholic acid (at a dose of 25 mg per kilogram of body weight) than among those who received placebo (P < 0.01).	('death', 'Disease', 'MESH:D003643', (92, 97))	('death', 'Disease', (92, 97))	('patients', 'Species', '9606', (267, 275))	('cholangiocarcinoma', 'Disease', (220, 238))	('cirrhosis', 'Phenotype', 'HP:0001394', (174, 183))	('higher', 'PosReg', (254, 260))	('liver transplantation', 'Disease', (99, 120))	('esophageal', 'Disease', (185, 195))	('ursodeoxycholic acid', 'Chemical', 'MESH:D014580', (299, 319))	('esophageal', 'Disease', 'MESH:D004941', (185, 195))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (220, 238))	('cirrhosis', 'Disease', 'MESH:D005355', (174, 183))	('high-dose', 'Var', (289, 298))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (220, 238))	('cirrhosis', 'Disease', (174, 183))	('gastric varices', 'Phenotype', 'HP:0030169', (199, 214))
132313	24382987	The DNA damage can cause mutations and has been implicated in the initiation and/or promotion of inflammation-mediated carcinogenesis.	('cause', 'Reg', (19, 24))	('inflammation-mediated carcinogenesis', 'Disease', (97, 133))	('inflammation-mediated carcinogenesis', 'Disease', 'MESH:D007249', (97, 133))	('mutations', 'MPA', (25, 34))	('implicated', 'Reg', (48, 58))	('DNA', 'Var', (4, 7))
132325	24382987	ROS and RNS are capable of causing damage to various cellular constituents, such as nucleic acids, proteins, and lipids.	('ROS', 'Var', (0, 3))	('proteins', 'Protein', (99, 107))	('lipids', 'MPA', (113, 119))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('causing', 'Reg', (27, 34))	('damage', 'MPA', (35, 41))	('RNS', 'Chemical', 'MESH:D026361', (8, 11))	('RNS', 'Var', (8, 11))	('lipids', 'Chemical', 'MESH:D008055', (113, 119))	('nucleic acids', 'MPA', (84, 97))
132327	24382987	ROS can induce the formation of oxidative DNA lesion products, including 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), which is considered to be mutagenic.	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('8-oxodG', 'Chemical', 'MESH:C067134', (110, 117))	('oxidative DNA lesion products', 'MPA', (32, 61))	("8-oxo-7,8-dihydro-2'-deoxyguanosine", 'Chemical', 'MESH:C067134', (73, 108))	('formation', 'MPA', (19, 28))
132343	24382987	In the ONOO--treated supF shuttle vector, which was replicated in host Escherichia coli cells, the majority of mutations occurred at G:C base pairs, predominantly involving G:C to T:A transversions.	('mutations', 'Var', (111, 120))	('occurred', 'Reg', (121, 129))	('ONOO-', 'Chemical', '-', (7, 12))	('Escherichia coli', 'Species', '562', (71, 87))	('G:C to T:A transversions', 'Var', (173, 197))	('G:C base pairs', 'Var', (133, 147))	('shuttle vector', 'Species', '45197', (26, 40))	('involving', 'Reg', (163, 172))
132362	24382987	Importantly, experimental evidence has suggested that 8-nitroguanine can lead to mutations, preferentially G:C to T:A transversions, in addition to 8-oxodG.	('8-oxodG', 'Chemical', 'MESH:C067134', (148, 155))	('mutations', 'Var', (81, 90))	('lead to', 'Reg', (73, 80))	('8-nitroguanine', 'Chemical', 'MESH:C095838', (54, 68))	('8-nitroguanine', 'Var', (54, 68))
132363	24382987	Indeed, G:C to T:A transversions have been observed in vivo in the ras gene and the p53 tumor suppressor gene in lung and liver cancer.	('liver cancer', 'Phenotype', 'HP:0002896', (122, 134))	('liver cancer', 'Disease', 'MESH:D006528', (122, 134))	('transversions', 'Var', (19, 32))	('liver cancer', 'Disease', (122, 134))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('ras gene', 'Gene', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('lung', 'Disease', (113, 117))	('tumor', 'Disease', (88, 93))
132364	24382987	We also revealed that 8-nitroguanine and 8-oxodG were apparently formed in adenocarcinoma caused by mutated K-ras, by using conditional transgenic mice with K- rasval12.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('mutated', 'Var', (100, 107))	('K-ras', 'Gene', (108, 113))	('caused', 'Reg', (90, 96))	('adenocarcinoma', 'Disease', 'MESH:D000230', (75, 89))	('8-oxodG', 'Chemical', 'MESH:C067134', (41, 48))	('transgenic mice', 'Species', '10090', (136, 151))	('8-nitroguanine', 'Chemical', 'MESH:C095838', (22, 36))	('formed', 'Reg', (65, 71))	('adenocarcinoma', 'Disease', (75, 89))
132365	24382987	8-Nitroguanine was colocalized with iNOS, NF-kappaB, IKK, MAPK, MEK, and mutated K-ras, suggesting that oncogenic K-ras causes additional DNA damage via signaling pathways involving these molecules.	('DNA damage', 'MPA', (138, 148))	('MEK', 'Gene', (64, 67))	('causes', 'Reg', (120, 126))	('8-Nitroguanine', 'Chemical', 'MESH:C095838', (0, 14))	('oncogenic K-ras', 'Var', (104, 119))	('MEK', 'Gene', '17242', (64, 67))	('signaling pathways', 'Pathway', (153, 171))	('K-ras', 'Var', (114, 119))
132366	24382987	It is noteworthy that K-ras mutation mediates not only cell overproliferation but also the accumulation of mutagenic DNA lesions, leading to carcinogenesis.	('mutagenic DNA lesions', 'MPA', (107, 128))	('leading to', 'Reg', (130, 140))	('cell overproliferation', 'CPA', (55, 77))	('carcinogenesis', 'Disease', 'MESH:D063646', (141, 155))	('mutation', 'Var', (28, 36))	('accumulation', 'PosReg', (91, 103))	('K-ras', 'Protein', (22, 27))	('carcinogenesis', 'Disease', (141, 155))
132369	24382987	Several studies have revealed that cancer cells show accumulation of mutations, genetic instability, and epigenetic change suggesting that cancer is also a disease of genes.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('mutations', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('genetic instability', 'Var', (80, 99))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('epigenetic change', 'Var', (105, 122))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', (139, 145))
132375	24382987	On the basis of our recent studies, it is considered that chronic inflammation can increase mutagenic DNA lesions through ROS/RNS generation and can promote proliferation via stem cells activation for tissue regeneration.	('increase', 'PosReg', (83, 91))	('inflammation', 'Disease', (66, 78))	('promote', 'PosReg', (149, 156))	('ROS', 'Chemical', 'MESH:D017382', (122, 125))	('RNS', 'Chemical', 'MESH:D026361', (126, 129))	('tissue regeneration', 'CPA', (201, 220))	('mutagenic', 'Var', (92, 101))	('ROS/RNS', 'MPA', (122, 129))	('proliferation', 'CPA', (157, 170))	('inflammation', 'Disease', 'MESH:D007249', (66, 78))	('stem cells activation', 'CPA', (175, 196))
132393	24382987	SH-induced urinary bladder cancer correlates with the expression of Oct3/4, while urinary bladder cancer without the infection correlates with the expression of CD44v6.	('Oct3/4', 'Gene', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (11, 33))	('SH', 'Species', '6185', (0, 2))	('CD44', 'Gene', '960', (161, 165))	('bladder cancer', 'Phenotype', 'HP:0009725', (19, 33))	('infection', 'Disease', (117, 126))	('SH-induced', 'Var', (0, 10))	('CD44', 'Gene', (161, 165))	('infection', 'Disease', 'MESH:D007239', (117, 126))	('urinary bladder cancer', 'Disease', (82, 104))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('urinary bladder cancer', 'Disease', (11, 33))	('Oct3/4', 'Gene', '5460', (68, 74))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (82, 104))
132403	24382987	We have proposed that carbonylations of serotransferrin and HSP70.1 may induce oxidative stress by iron-accumulation and dysfunction of antioxidative property, leading to increased oxidative DNA damage and progression of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (221, 239))	('oxidative DNA damage', 'MPA', (181, 201))	('carbonylations', 'Var', (22, 36))	('oxidative stress', 'MPA', (79, 95))	('serotransferrin', 'Gene', (40, 55))	('serotransferrin', 'Gene', '7018', (40, 55))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (221, 239))	('dysfunction', 'MPA', (121, 132))	('HSP70.1', 'Gene', '3303', (60, 67))	('induce', 'PosReg', (72, 78))	('cholangiocarcinoma', 'Disease', (221, 239))	('oxidative stress', 'Phenotype', 'HP:0025464', (79, 95))	('iron-accumulation', 'MPA', (99, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('HSP70.1', 'Gene', (60, 67))	('increased', 'PosReg', (171, 180))	('iron', 'Chemical', 'MESH:D007501', (99, 103))
132407	24382987	These findings suggest that CD133 and Oct3/4 in cholangiocarcinoma are highly associated with formation of DNA lesions, which may be involved in genetic instability and lead to tumor development with aggressive clinical features.	('involved', 'Reg', (133, 141))	('Oct3/4', 'Gene', (38, 44))	('associated', 'Reg', (78, 88))	('cholangiocarcinoma', 'Disease', (48, 66))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('CD133', 'Var', (28, 33))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (48, 66))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (48, 66))	('lead to', 'Reg', (169, 176))	('tumor', 'Disease', (177, 182))	('Oct3/4', 'Gene', '5460', (38, 44))
132409	24382987	Inflammation by OV infection may increase the number of mutant stem cell, in which oxidative stresses, such as carbonylation of proteins and oxidative DNA damage, and cell proliferation are promoted, leading to progression of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (226, 244))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (226, 244))	('oxidative stresses', 'Phenotype', 'HP:0025464', (83, 101))	('mutant', 'Var', (56, 62))	('oxidative DNA damage', 'MPA', (141, 161))	('oxidative stresses', 'MPA', (83, 101))	('proteins', 'Protein', (128, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('increase', 'PosReg', (33, 41))	('OV infection', 'Disease', 'MESH:D007239', (16, 28))	('carbonylation', 'MPA', (111, 124))	('oxidative stress', 'Phenotype', 'HP:0025464', (83, 99))	('OV infection', 'Disease', (16, 28))	('promoted', 'PosReg', (190, 198))	('cholangiocarcinoma', 'Disease', (226, 244))	('cell proliferation', 'CPA', (167, 185))
132414	24382987	In these cells, ROS/RNS from inflammation can cause multiple mutations, which may generate mutant stem cells and cancer stem cells, leading to carcinogenesis.	('leading to', 'Reg', (132, 142))	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('inflammation', 'Disease', 'MESH:D007249', (29, 41))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('mutations', 'Var', (61, 70))	('RNS', 'Chemical', 'MESH:D026361', (20, 23))	('cancer', 'Disease', (113, 119))	('inflammation', 'Disease', (29, 41))	('carcinogenesis', 'Disease', (143, 157))	('ROS', 'Chemical', 'MESH:D017382', (16, 19))	('mutant', 'Var', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
132505	23658488	The weight loss of the PCL was accelerated at 0.01 N NaOH (Figure 2A(c)) rather than PBS (Figure 2A(a)) or artificial bile (Figure 2A(b)).	('0.01 N NaOH', 'Var', (46, 57))	('NaOH', 'Var', (53, 57))	('PCL', 'Gene', '2324', (23, 26))	('PBS', 'Chemical', '-', (85, 88))	('NaOH', 'Chemical', '-', (53, 57))	('weight loss', 'Phenotype', 'HP:0001824', (4, 15))	('accelerated', 'PosReg', (31, 42))	('PCL', 'Gene', (23, 26))
132595	23658488	Since the metastatic invasion and angiogenesis potential of cholangiocarcinoma cells are regarded as causes of poor prognosis after chemotherapy or radiotherapy, inhibition of these factors in vitro may enhance the therapeutic potential of sorafenib-eluting stents.	('cholangiocarcinoma', 'Disease', (60, 78))	('therapeutic potential', 'CPA', (215, 236))	('sorafenib', 'Chemical', 'MESH:D000077157', (240, 249))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (60, 78))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (60, 78))	('enhance', 'PosReg', (203, 210))	('inhibition', 'Var', (162, 172))	('angiogenesis potential', 'CPA', (34, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('metastatic invasion', 'CPA', (10, 29))
132599	23658488	Furthermore, a defect or crack on the polymer film surface is known to affect the potential of DESs.	('crack', 'Var', (25, 30))	('potential', 'MPA', (82, 91))	('affect', 'Reg', (71, 77))	('defect', 'Var', (15, 21))	('polymer', 'Chemical', 'MESH:D011108', (38, 45))
132733	21837735	By contrast, our results suggest caution in providing exception points for these patients, and that if physicians are referring patients with PSC for living donor transplantation to prevent them from developing cholangiocarcinoma, such choices may erode access for other patients and/or lead to more living donations than is truly necessary to promote acceptable outcomes for patients with PSC, thereby causing unnecessary risks to donors.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (211, 229))	('PSC', 'Gene', '100653366', (390, 393))	('cholangiocarcinoma', 'Disease', (211, 229))	('donor', 'Species', '9606', (432, 437))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (211, 229))	('PSC', 'Gene', '100653366', (142, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('patients', 'Species', '9606', (376, 384))	('PSC', 'Gene', (390, 393))	('access', 'MPA', (254, 260))	('donor', 'Species', '9606', (157, 162))	('PSC', 'Gene', (142, 145))	('patients', 'Species', '9606', (271, 279))	('patients', 'Species', '9606', (128, 136))	('choices', 'Var', (236, 243))	('lead to', 'Reg', (287, 294))	('patients', 'Species', '9606', (81, 89))	('living donations', 'CPA', (300, 316))	('erode', 'NegReg', (248, 253))	('promote', 'PosReg', (344, 351))
132778	31916422	In univariate analyses, factors associated with survival included age >= 65 years (p = 0.005), albumin >= 3.5 g/dL (p = 0.025), CA 19-9 >= 100 ng/mL (p < 0.001), T stage (T1-T3) at diagnosis (p < 0.001), presence of lymph node invasion (p < 0.001), presence of metastases at diagnosis (p < 0.001), adjuvant chemotherapy after surgery (p = 0.004) and curative surgery (p < 0.001).	('metastases', 'Disease', (261, 271))	('CA 19-9 >= 100 ng/mL', 'Var', (128, 148))	('metastases', 'Disease', 'MESH:D009362', (261, 271))	('lymph node invasion', 'CPA', (216, 235))	('albumin', 'Gene', (95, 102))	('albumin', 'Gene', '213', (95, 102))
132802	31916422	Better survival was observed in patients with CA 19-9 < 100 ng/mL, with T stage 1 to 3 at diagnosis, and without lymph node invasion.	('CA 19-9 < 100 ng/mL', 'Var', (46, 65))	('patients', 'Species', '9606', (32, 40))	('Better', 'PosReg', (0, 6))
132833	32168787	The prevalence of PSC is increased by genetic factors (11-fold risk for a sibling with first-degree relatives with PSC), nonsmoking (probably associated with ulcerative colitis), and other autoimmune diseases (25% of patients with PSC).	('PSC', 'Gene', (231, 234))	('colitis', 'Phenotype', 'HP:0002583', (169, 176))	('autoimmune diseases', 'Disease', 'MESH:D001327', (189, 208))	('PSC', 'Gene', '100653366', (18, 21))	('ulcerative colitis', 'Disease', (158, 176))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (158, 176))	('PSC', 'Gene', '100653366', (231, 234))	('autoimmune diseases', 'Disease', (189, 208))	('nonsmoking', 'Var', (121, 131))	('associated', 'Reg', (142, 152))	('PSC', 'Gene', '100653366', (115, 118))	('PSC', 'Gene', (18, 21))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (189, 208))	('patients', 'Species', '9606', (217, 225))	('PSC', 'Gene', (115, 118))	('ulcerative colitis', 'Disease', 'MESH:D003093', (158, 176))
132839	32168787	In PSC, multiple disturbances in the bile homeostasis appear, such as mutations in CFTR.	('CFTR', 'Gene', '1080', (83, 87))	('mutations', 'Var', (70, 79))	('PSC', 'Gene', '100653366', (3, 6))	('PSC', 'Gene', (3, 6))	('bile homeostasis', 'MPA', (37, 53))	('CFTR', 'Gene', (83, 87))
132849	32168787	Other immunological alterations are serum elevation of IL-8 and IL-10 (exaggerated humoral immunity), abnormal antigen expression of bile duct epithelial cells, cross-reacting with colonic epithelial cells, aberrant expression of human leukocyte antigen (HLA) class II antigens and intercellular adhesion molecule (ICAM)-1 on ductal epithelial cells, and mutation in the gene encoding CTFR.	('colonic', 'Disease', 'MESH:D003110', (181, 188))	('immunological alterations', 'Phenotype', 'HP:0002715', (6, 31))	('IL-10', 'Gene', (64, 69))	('aberrant', 'Var', (207, 215))	('CTFR', 'Gene', (385, 389))	('colonic', 'Disease', (181, 188))	('exaggerated humoral immunity', 'Phenotype', 'HP:0005368', (71, 99))	('IL-8', 'Gene', '3576', (55, 59))	('IL-8', 'Gene', (55, 59))	('mutation', 'Var', (355, 363))	('IL-10', 'Gene', '3586', (64, 69))
132853	32168787	Recent studies show that NKG2D polymorphism is a risk factor for oncogenesis.	('oncogenesis', 'Disease', (65, 76))	('polymorphism', 'Var', (31, 43))	('NKG2D', 'Gene', '22914', (25, 30))	('risk factor', 'Reg', (49, 60))	('NKG2D', 'Gene', (25, 30))
132867	32168787	Low albumin can show decompensated disease with hepatic synthetic dysfunction, malnutrition, or active IBD.	('hepatic synthetic dysfunction', 'Disease', (48, 77))	('albumin', 'Gene', (4, 11))	('IBD', 'Disease', (103, 106))	('malnutrition', 'Disease', (79, 91))	('malnutrition', 'Disease', 'MESH:D044342', (79, 91))	('albumin', 'Gene', '213', (4, 11))	('hepatic synthetic dysfunction', 'Disease', 'MESH:D008107', (48, 77))	('IBD', 'Disease', 'MESH:D015212', (103, 106))	('Low albumin', 'Phenotype', 'HP:0003073', (0, 11))	('decompensated disease', 'Disease', (21, 42))	('malnutrition', 'Phenotype', 'HP:0004395', (79, 91))	('Low', 'Var', (0, 3))
132868	32168787	Immunological and serological markers can be present, such as hypergammaglobulinemia (encountered in almost 30% of patients), increased serum immunoglobulin M (40-50% of patients with PSC), HLA DRx52a, and positive perinuclear anti-neutrophil cytoplasmic antibodies (pANCA).	('patients', 'Species', '9606', (170, 178))	('PSC', 'Gene', (184, 187))	('patients', 'Species', '9606', (115, 123))	('hypergammaglobulinemia', 'Disease', 'MESH:D006942', (62, 84))	('increased serum immunoglobulin', 'Phenotype', 'HP:0010702', (126, 156))	('serum immunoglobulin M', 'MPA', (136, 158))	('hypergammaglobulinemia', 'Disease', (62, 84))	('HLA DRx52a', 'Var', (190, 200))	('anti-neutrophil cytoplasmic antibodies', 'Phenotype', 'HP:0032230', (227, 265))	('PSC', 'Gene', '100653366', (184, 187))	('hypergammaglobulinemia', 'Phenotype', 'HP:0010702', (62, 84))	('increased', 'PosReg', (126, 135))
132874	32168787	However, this is dependent on the expression of Lewis antigen (10% of the population lacks Lewis antigen) and on the genotypic variants of fucosyltransferase 2 and 3 (improves tumor marker sensitivity).	('variants', 'Var', (127, 135))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('Lewis', 'MPA', (91, 96))	('lacks', 'NegReg', (85, 90))	('tumor', 'Disease', (176, 181))	('fucosyltransferase 2 and 3', 'Gene', '2524', (139, 165))	('improves', 'PosReg', (167, 175))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
132927	32168787	FISH uses labelled DNA probes to detect abnormal loss or gain of selected chromosomes or chromosome foci in individual cells, and the presence of serial or multifocal polysomy represent increased risk of cholangiocarcinoma.	('abnormal loss', 'Disease', (40, 53))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (204, 222))	('abnormal loss', 'Disease', 'MESH:D025063', (40, 53))	('cholangiocarcinoma', 'Disease', (204, 222))	('increased risk of cholangiocarcinoma', 'Phenotype', 'HP:0001402', (186, 222))	('presence', 'Var', (134, 142))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (204, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('gain', 'PosReg', (57, 61))
132934	32168787	Gene alterations might affect pathways such as P13K/AKT/mTOR, RAS/RAF/MEK/ERK (KRAS and BRAF), and tyrosine kinase receptor signaling (ERBB2 and FGFR2).	('RAF', 'Gene', (66, 69))	('RAF', 'Gene', '673', (66, 69))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('alterations', 'Var', (5, 16))	('affect', 'Reg', (23, 29))	('MEK', 'Gene', '5609', (70, 73))	('RAF', 'Gene', (89, 92))	('ERBB2', 'Gene', (135, 140))	('RAF', 'Gene', '673', (89, 92))	('FGFR2', 'Gene', (145, 150))	('tyrosine kinase receptor', 'MPA', (99, 123))	('MEK', 'Gene', (70, 73))	('ERK', 'Gene', (74, 77))	('ERBB2', 'Gene', '2064', (135, 140))	('mTOR', 'Gene', (56, 60))	('P13K', 'SUBSTITUTION', 'None', (47, 51))	('KRAS', 'Gene', '3845', (79, 83))	('ERK', 'Gene', '2048', (74, 77))	('AKT', 'Gene', (52, 55))	('FGFR2', 'Gene', '2263', (145, 150))	('KRAS', 'Gene', (79, 83))	('mTOR', 'Gene', '2475', (56, 60))	('P13K', 'Var', (47, 51))	('AKT', 'Gene', '207', (52, 55))
132989	32168787	However, due to the increased risk of cholangiocarcinoma under TGR5 agonists (stimulating the same pathway), all clinical trials were abandoned.	('cholangiocarcinoma', 'Disease', (38, 56))	('TGR5', 'Gene', (63, 67))	('increased risk of cholangiocarcinoma', 'Phenotype', 'HP:0001402', (20, 56))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (38, 56))	('TGR5', 'Gene', '151306', (63, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (38, 56))	('agonists', 'Var', (68, 76))
132997	32168787	Moreover, variations of MELD scores might appear, and the indication for liver transplant might be reevaluated, especially in suspected cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (136, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('MELD scores', 'MPA', (24, 35))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (136, 154))	('variations', 'Var', (10, 20))	('cholangiocarcinoma', 'Disease', (136, 154))
133027	24089088	Aberrant DNA methylation at genes associated with a stem cell-like phenotype in cholangiocarcinoma tumours Genetic abnormalities of cholangiocarcinoma have been widely studied; however, epigenomic changes related to cholangiocarcinogenesis have been less well characterised.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('Aberrant', 'Var', (0, 8))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (80, 98))	('cholangiocarcinogenesis', 'Disease', 'None', (216, 239))	('Genetic abnormalities of cholangiocarcinoma', 'Disease', (107, 150))	('cholangiocarcinoma tumours', 'Disease', 'MESH:D018281', (80, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('cholangiocarcinoma tumours', 'Disease', (80, 106))	('Genetic abnormalities of cholangiocarcinoma', 'Disease', 'MESH:D030342', (107, 150))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (132, 150))	('cholangiocarcinogenesis', 'Disease', (216, 239))
133030	24089088	Gene ontology and gene set enrichment analyses identified gene sets significantly associated with hypermethylation at linked CpG sites in cholangiocarcinoma including homeobox genes and target genes of PRC2, EED, SUZ12 and histone H3 trimethylation at lysine 27.	('associated', 'Reg', (82, 92))	('SUZ12', 'Gene', (213, 218))	('cholangiocarcinoma', 'Disease', (138, 156))	('lysine', 'Chemical', 'MESH:D008239', (252, 258))	('EED', 'Gene', '8726', (208, 211))	('SUZ12', 'Gene', '23512', (213, 218))	('homeobox genes', 'Gene', (167, 181))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (138, 156))	('PRC2', 'Gene', (202, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (138, 156))	('hypermethylation', 'Var', (98, 114))	('EED', 'Gene', (208, 211))
133031	24089088	We confirmed frequent hypermethylation at the homeobox genes HOXA9 and HOXD9 by bisulfite pyrosequencing in a larger cohort of cholangiocarcinoma (n = 102).	('cholangiocarcinoma', 'Disease', (127, 145))	('HOXA9', 'Gene', (61, 66))	('HOXD9', 'Gene', (71, 76))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (127, 145))	('HOXD9', 'Gene', '3235', (71, 76))	('hypermethylation', 'Var', (22, 38))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (127, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('bisulfite', 'Chemical', 'MESH:C042345', (80, 89))	('HOXA9', 'Gene', '3205', (61, 66))
133032	24089088	Our findings indicate a key role for hypermethylation of multiple CpG sites at genes associated with a stem cell-like phenotype as a common molecular aberration in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (164, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (164, 182))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (164, 182))	('hypermethylation', 'Var', (37, 53))
133040	24089088	Epigenetic changes in tumours are associated with cancer development and progression.	('associated', 'Reg', (34, 44))	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('tumours', 'Disease', (22, 29))	('progression', 'CPA', (73, 84))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('Epigenetic changes', 'Var', (0, 18))
133041	24089088	Aberrant DNA methylation occurs very early during carcinogenesis before the onset of malignancy and is thought to interact with genetic aberrations in driving the tumourigenic phenotype of cancer cells.	('malignancy', 'Disease', (85, 95))	('genetic aberrations', 'Disease', (128, 147))	('Aberrant', 'Var', (0, 8))	('methylation', 'Var', (13, 24))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('carcinogenesis', 'Disease', (50, 64))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('DNA', 'Protein', (9, 12))	('genetic aberrations', 'Disease', 'MESH:D030342', (128, 147))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('carcinogenesis', 'Disease', 'MESH:D063646', (50, 64))	('malignancy', 'Disease', 'MESH:D009369', (85, 95))	('tumour', 'Disease', (163, 169))	('cancer', 'Disease', (189, 195))
133042	24089088	Epigenetic silencing at CpG islands, in particular, is observed in many solid tumour types.	('solid tumour', 'Disease', 'MESH:D009369', (72, 84))	('solid tumour', 'Disease', (72, 84))	('Epigenetic silencing', 'Var', (0, 20))	('observed', 'Reg', (55, 63))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
133063	24089088	Adjacent normal tissues, on the other hand, clustered tightly together with only two tumours (P055T and U030T) co-clustering with this subgroup of tissues.	('U030T', 'Var', (104, 109))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('P055T', 'Var', (94, 99))	('tumours', 'Disease', 'MESH:D009369', (85, 92))	('P055T', 'Mutation', 'p.P055T', (94, 99))	('tumours', 'Disease', (85, 92))	('U030T', 'CellLine', 'CVCL:C028', (104, 109))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
133067	24089088	Among the methylation changes identified in the group comparison, 781/809 hypermethylated CpG sites (associated with 585 genes) and 748/801 hypomethylated CpG sites (associated with 665 genes) remained significant (FDR <= 0.05 and  Deltabeta  >= 15%) when comparing the six pairs of matched tumours and adjacent normal samples (Supplementary Tables S5 and S6).	('tumours', 'Phenotype', 'HP:0002664', (291, 298))	('hypermethylated', 'Var', (74, 89))	('tumours', 'Disease', 'MESH:D009369', (291, 298))	('tumours', 'Disease', (291, 298))	('tumour', 'Phenotype', 'HP:0002664', (291, 297))
133069	24089088	Hypermethylation of HOXA9 and HOXD9 was found in 86.3% (88/102) and 89.2% (91/102) of primary CCA, respectively.	('HOXA9', 'Gene', '3205', (20, 25))	('primary CCA', 'Disease', (86, 97))	('HOXD9', 'Gene', (30, 35))	('Hypermethylation', 'Var', (0, 16))	('HOXD9', 'Gene', '3235', (30, 35))	('HOXA9', 'Gene', (20, 25))	('found', 'Reg', (40, 45))	('CCA', 'Phenotype', 'HP:0030153', (94, 97))
133073	24089088	Overall, the observed enrichment of differential methylation in CCA at embryonic gene sets, particularly those associated with the PRC2 and its components indicates aberrant DNA methylation of genes associated with a more stem cell-like phenotype in CCA tumours as compared to adjacent normal tissue.	('aberrant', 'Var', (165, 173))	('tumours', 'Phenotype', 'HP:0002664', (254, 261))	('CCA tumours', 'Disease', (250, 261))	('CCA tumours', 'Disease', 'MESH:C536211', (250, 261))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))	('CCA', 'Phenotype', 'HP:0030153', (250, 253))	('CCA', 'Phenotype', 'HP:0030153', (64, 67))
133074	24089088	Aberrant DNA methylomes are one of the key features of cancer.	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('Aberrant DNA', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (55, 61))
133075	24089088	Recent advances in DNA methylation technology have allowed for genome-wide profiling of cancer tissues providing a vast amount of previously unknown methylation changes which further our understanding of the underlying pathways associated with tumourigenesis.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Phenotype', 'HP:0002664', (244, 250))	('changes', 'Var', (161, 168))	('methylation', 'Var', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumour', 'Disease', 'MESH:D009369', (244, 250))	('tumour', 'Disease', (244, 250))
133079	24089088	More specifically, we examined methylation states of gene sets associated with a stem-cell like phenotype and identified hypermethylation at specific target genes of the PcG complexes including PRC2 targets, homeobox genes, EED targets, SUZ12 targets and H3K27me3 target genes.	('SUZ12', 'Gene', '23512', (237, 242))	('hypermethylation', 'Var', (121, 137))	('SUZ12', 'Gene', (237, 242))	('EED', 'Gene', '8726', (224, 227))	('EED', 'Gene', (224, 227))	('PRC2', 'Gene', (194, 198))
133080	24089088	More than 55% of homeobox genes are also the target genes of PRC2, EED, SUZ12 and H3K27me3 indicating that the overlap of these gene sets might be the main target of hypermethylation in CCA.	('homeobox genes', 'Gene', (17, 31))	('SUZ12', 'Gene', '23512', (72, 77))	('CCA', 'Phenotype', 'HP:0030153', (186, 189))	('CCA', 'Disease', (186, 189))	('H3K27me3', 'Var', (82, 90))	('SUZ12', 'Gene', (72, 77))	('EED', 'Gene', '8726', (67, 70))	('EED', 'Gene', (67, 70))	('PRC2', 'Gene', (61, 65))
133084	24089088	Aberrant levels of EZH2 have previously been linked to tumour development and have been observed in a variety of tumours including prostate, breast and melanoma.	('tumour', 'Disease', (55, 61))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('prostate', 'Disease', (131, 139))	('linked', 'Reg', (45, 51))	('Aberrant levels', 'Var', (0, 15))	('observed', 'Reg', (88, 96))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('tumours', 'Disease', 'MESH:D009369', (113, 120))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', (113, 119))	('tumours', 'Disease', (113, 120))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('EZH2', 'Gene', '2146', (19, 23))	('EZH2', 'Gene', (19, 23))	('breast and melanoma', 'Disease', 'MESH:D008545', (141, 160))
133085	24089088	Moreover, high EZH2 levels have been associated with poor prognosis in these tumours types.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('tumours', 'Disease', (77, 84))	('high', 'Var', (10, 14))	('EZH2', 'Gene', (15, 19))	('EZH2', 'Gene', '2146', (15, 19))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
133091	24089088	In glioblastoma multiform, an aggressive type of brain tumour, pharmacologic EZH2 inhibitors such as DZNep have been shown to strongly impair cancer stem cell self-renewal in vitro and tumour-initiating capacity in vivo.	('tumour', 'Disease', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('aggressive type of brain tumour', 'Disease', (30, 61))	('DZNep', 'Chemical', '-', (101, 106))	('inhibitors', 'Var', (82, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('brain tumour', 'Phenotype', 'HP:0030692', (49, 61))	('cancer', 'Disease', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('glioblastoma', 'Disease', (3, 15))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('EZH2', 'Gene', '2146', (77, 81))	('tumour', 'Disease', (185, 191))	('EZH2', 'Gene', (77, 81))	('aggressive type of brain tumour', 'Disease', 'MESH:D001927', (30, 61))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('impair', 'NegReg', (135, 141))
133115	24960829	There is no clear etiology of the disease in adults but an anomalous junction between the bile duct and pancreatic duct is a common finding.	('anomalous', 'Var', (59, 68))	('pancreatic duct', 'Disease', (104, 119))	('pancreatic duct', 'Disease', 'MESH:D021441', (104, 119))
133147	21103345	Patients with X-linked hyper IgM syndrome have a mutation in the CD154 gene, which is associated with enhanced susceptibility to Pneumocystis Carinii, Cryptosporidosis and development of biliary tract, liver and pancreatic tumours.	('enhanced', 'PosReg', (102, 110))	('X-linked hyper IgM syndrome', 'Disease', (14, 41))	('liver and pancreatic tumours', 'Disease', 'MESH:D008113', (202, 230))	('Pneumocystis Carinii, Cryptosporidosis', 'Disease', 'MESH:D016720', (129, 167))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('CD154', 'Gene', (65, 70))	('mutation', 'Var', (49, 57))	('Patients', 'Species', '9606', (0, 8))	('susceptibility', 'Reg', (111, 125))	('hyper IgM', 'Phenotype', 'HP:0003496', (23, 32))	('tumours', 'Phenotype', 'HP:0002664', (223, 230))	('X-linked hyper IgM syndrome', 'Disease', 'MESH:D053307', (14, 41))
133151	21103345	Our subsequent work demonstrated that CD40 and Fas are expressed by cholangiocytes (biliary epithelial cells) in inflamed portal tracts and ligation of cholangiocyte CD40 by CD154 leads to autocrine or paracrine amplification of Fas mediated apoptosis mediated through sustained activation of AP-1 (JNK/ERK) and JAK2 dependent activation of STAT-3.	('JAK2', 'Gene', (312, 316))	('AP-1', 'Gene', '2353', (293, 297))	('CD154', 'Var', (174, 179))	('ligation', 'Var', (140, 148))	('autocrine', 'MPA', (189, 198))	('STAT-3', 'Gene', (341, 347))	('ERK', 'Gene', '5594', (303, 306))	('Fas mediated apoptosis', 'CPA', (229, 251))	('STAT-3', 'Gene', '6774', (341, 347))	('AP-1', 'Gene', (293, 297))	('JNK', 'Gene', (299, 302))	('activation', 'PosReg', (279, 289))	('ERK', 'Gene', (303, 306))	('JNK', 'Gene', '5599', (299, 302))	('activation', 'PosReg', (327, 337))	('CD40', 'Gene', (166, 170))	('rat', 'Species', '10116', (27, 30))	('CD40', 'Gene', (38, 42))	('JAK2', 'Gene', '3717', (312, 316))	('CD40', 'Gene', '958', (166, 170))	('Fas', 'Chemical', 'MESH:C038178', (229, 232))	('Fas', 'Chemical', 'MESH:C038178', (47, 50))	('CD40', 'Gene', '958', (38, 42))
133198	21103345	pSTAT-3, c-Fos and c-Jun increased in all cells following stimulation with CD154 compared to unstimulated cells or those stimulated with FasL or TNFalpha.	('STAT-3', 'Gene', '6774', (1, 7))	('FasL', 'Gene', '356', (137, 141))	('increased', 'PosReg', (25, 34))	('STAT-3', 'Gene', (1, 7))	('CD154', 'Var', (75, 80))	('c-Fos', 'Gene', '2353', (9, 14))	('Jun increased', 'Phenotype', 'HP:0003138', (21, 34))	('c-Jun', 'Gene', (19, 24))	('TNFalpha', 'Gene', (145, 153))	('TNFalpha', 'Gene', '7124', (145, 153))	('c-Fos', 'Gene', (9, 14))	('c-Jun', 'Gene', '3725', (19, 24))	('FasL', 'Gene', (137, 141))
133199	21103345	Activation of cell-surface CD40 with srh CD154 induced similar high levels of apoptosis in primary and malignant cells after 24 hours; whereas only the CC-SW-1 cholangiocarcinoma cell line underwent apoptosis when stimulated with FasL for 24 hours despite all cell lines and primary cells expressing high levels of cell surface Fas.	('CD40', 'Gene', (27, 31))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (160, 178))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (160, 178))	('FasL', 'Gene', '356', (230, 234))	('FasL', 'Gene', (230, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('srh CD154', 'Var', (37, 46))	('CD40', 'Gene', '958', (27, 31))	('Fas', 'Chemical', 'MESH:C038178', (328, 331))	('CC-SW-1', 'CellLine', 'CVCL:A429', (152, 159))	('Fas', 'Chemical', 'MESH:C038178', (230, 233))	('srh', 'Chemical', '-', (37, 40))	('cholangiocarcinoma', 'Disease', (160, 178))
133202	21103345	After stimulation with CD154 there was a sustained upregulation of FasL and induction of apoptosis was accompanied by activation of the AP-1 (c-Fos/c-Jun) and pSTAT-3 signalling pathways as previously reported in primary cholangiocytes.	('upregulation', 'PosReg', (51, 63))	('STAT-3', 'Gene', '6774', (160, 166))	('CD154', 'Var', (23, 28))	('activation', 'PosReg', (118, 128))	('c-Jun', 'Gene', (148, 153))	('STAT-3', 'Gene', (160, 166))	('AP-1', 'Gene', (136, 140))	('apoptosis', 'CPA', (89, 98))	('AP-1', 'Gene', '2353', (136, 140))	('c-Fos', 'Gene', (142, 147))	('c-Jun', 'Gene', '3725', (148, 153))	('FasL', 'Gene', '356', (67, 71))	('FasL', 'Gene', (67, 71))	('c-Fos', 'Gene', '2353', (142, 147))
133223	21103345	CD40 ligation can also cause the activation of the transcription factor complex AP-1, which consists of two heterodimer subunits c-Fos and c-Jun and these have been found to be pro-apoptotic because they form dimers capable of binding to promoter regions of genes involved in apoptosis such as caspase 3.	('c-Fos', 'Gene', (129, 134))	('CD40', 'Gene', (0, 4))	('activation', 'PosReg', (33, 43))	('ligation', 'Var', (5, 13))	('c-Jun', 'Gene', (139, 144))	('c-Fos', 'Gene', '2353', (129, 134))	('binding', 'Interaction', (227, 234))	('AP-1', 'Gene', '2353', (80, 84))	('AP-1', 'Gene', (80, 84))	('CD40', 'Gene', '958', (0, 4))	('c-Jun', 'Gene', '3725', (139, 144))
133224	21103345	Consistent with this we found increased levels of c-Fos and c-Jun in cells undergoing apoptosis at 24 hours in response to CD154 but not FasL.	('FasL', 'Gene', '356', (137, 141))	('c-Fos', 'Gene', (50, 55))	('c-Jun', 'Gene', '3725', (60, 65))	('CD154', 'Var', (123, 128))	('c-Fos', 'Gene', '2353', (50, 55))	('levels', 'MPA', (40, 46))	('c-Jun', 'Gene', (60, 65))	('increased', 'PosReg', (30, 39))	('FasL', 'Gene', (137, 141))
133231	21103345	Fas resistance is well-reported in several cancers and may provide an important survival advantage to the tumour.	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('survival advantage', 'CPA', (80, 98))	('cancers', 'Disease', (43, 50))	('Fas', 'Chemical', 'MESH:C038178', (0, 3))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('tumour', 'Disease', (106, 112))	('Fas resistance', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
133238	21103345	While some studies showed that stimulating the CD40 receptor inhibits Fas-induced apoptosis in normal and neoplastic cells, many more have shown that CD40 and Fas can synergize to enhance the apoptosis signal to increase cell death and that receptor levels on the cell surface may determine the outcome.	('cell death', 'CPA', (221, 231))	('CD40', 'Gene', (150, 154))	('apoptosis', 'CPA', (82, 91))	('stimulating', 'Var', (31, 42))	('apoptosis signal', 'MPA', (192, 208))	('CD40', 'Gene', '958', (47, 51))	('Fas', 'Chemical', 'MESH:C038178', (159, 162))	('Fas', 'Chemical', 'MESH:C038178', (70, 73))	('increase', 'PosReg', (212, 220))	('enhance', 'PosReg', (180, 187))	('CD40', 'Gene', '958', (150, 154))	('CD40', 'Gene', (47, 51))	('inhibits', 'NegReg', (61, 69))
133240	21103345	Chu and colleagues reported that CD40 ligation on CLL B cells induced a programme of events in which shifts in the balance of anti-apoptotic and pro-apoptotic FLIP and FADD were associated with initial resistance to Fas-mediated killing followed by subsequent sensitization.	('associated', 'Reg', (178, 188))	('FADD', 'Gene', (168, 172))	('shifts', 'Reg', (101, 107))	('resistance', 'CPA', (202, 212))	('CD40', 'Gene', '958', (33, 37))	('FADD', 'Gene', '8772', (168, 172))	('CD40', 'Gene', (33, 37))	('Fas', 'Chemical', 'MESH:C038178', (216, 219))	('balance of anti-apoptotic and', 'MPA', (115, 144))	('ligation', 'Var', (38, 46))
133256	21103345	In this study we have shown that cholangiocarcinoma cells lines are resistant to Fas-mediated killing but show sensitivity to CD40 mediated apoptosis suggesting that CD154 therapy might be effective in the treatment and management of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (234, 252))	('Fas', 'Chemical', 'MESH:C038178', (81, 84))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (33, 51))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (234, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (234, 252))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (33, 51))	('cholangiocarcinoma', 'Disease', (33, 51))	('CD40', 'Gene', '958', (126, 130))	('CD154', 'Var', (166, 171))	('CD40', 'Gene', (126, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
133259	29029475	The prognostic potential and carcinogenesis of long non-coding RNA TUG1 in human cholangiocarcinoma Cholangiocarcinoma (CCA) is a fatal disease with increasing worldwide incidence and is characterized by poor prognosis due to its poor response to conventional chemotherapy or radiotherapy.	('carcinogenesis', 'Disease', (29, 43))	('si', 'Chemical', 'MESH:D012825', (155, 157))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (81, 99))	('CCA', 'Phenotype', 'HP:0030153', (120, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (81, 99))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (100, 118))	('Cholangiocarcinoma', 'Disease', (100, 118))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))	('si', 'Chemical', 'MESH:D012825', (215, 217))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('TUG1', 'Gene', '55000', (67, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('TUG1', 'Gene', (67, 71))	('human', 'Species', '9606', (75, 80))	('carcinogenesis', 'Disease', 'MESH:D063646', (29, 43))	('cholangiocarcinoma', 'Disease', (81, 99))	('long non-coding', 'Var', (47, 62))
133263	29029475	In addition, the functional roles of TUG1 including cell proliferation, apoptosis, migration, invasion and epithelial-mesenchymal transition (EMT), were evaluated after TUG1 silencing.	('invasion', 'CPA', (94, 102))	('si', 'Chemical', 'MESH:D012825', (134, 136))	('si', 'Chemical', 'MESH:D012825', (174, 176))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('epithelial-mesenchymal transition', 'CPA', (107, 140))	('apoptosis', 'CPA', (72, 81))	('TUG1', 'Gene', (169, 173))	('silencing', 'Var', (174, 183))	('migration', 'CPA', (83, 92))
133276	29029475	Furthermore, evidence suggests that aberrant lncRNA expression can function as a tumor suppressor or oncogene.	('lncRNA expression', 'Protein', (45, 62))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('aberrant', 'Var', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('tumor', 'Disease', (81, 86))
133280	29029475	Inhibition of TUG1 expression can prevent proliferation of retinal cells, which suggests a moderating effect of TUG1 on cell growth and its participation in human tumor progression.	('TUG1', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('proliferation of retinal cells', 'CPA', (42, 72))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('prevent', 'NegReg', (34, 41))	('tumor', 'Disease', (163, 168))	('Inhibition', 'Var', (0, 10))	('si', 'Chemical', 'MESH:D012825', (25, 27))	('si', 'Chemical', 'MESH:D012825', (176, 178))	('human', 'Species', '9606', (157, 162))
133283	29029475	On the other hand, TUG1 seems to be silenced in glioma and non-small cell lung cancer (NSCLC), and thus, TUG1 may suppress the growth of some types of tumors.	('NSCLC', 'Disease', (87, 92))	('suppress', 'NegReg', (114, 122))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (59, 85))	('tumors', 'Disease', (151, 157))	('silenced', 'NegReg', (36, 44))	('TUG1', 'Var', (105, 109))	('TUG1', 'Gene', (19, 23))	('glioma', 'Disease', (48, 54))	('growth', 'CPA', (127, 133))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (59, 85))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (63, 85))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('non-small cell lung cancer', 'Disease', (59, 85))
133286	29029475	In addition, we analyzed CCA cell growth, apoptosis, migration, invasion and epithelial-mesenchymal transition (EMT) after knockdown of TUG1 in vitro.	('epithelial-mesenchymal transition', 'CPA', (77, 110))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('CCA', 'Phenotype', 'HP:0030153', (25, 28))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('analyzed', 'Reg', (16, 24))	('knockdown', 'Var', (123, 132))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('TUG1', 'Gene', (136, 140))
133293	29029475	Furthermore, Kaplan-Meier survival analysis and the log-rank test applied based on postoperative survival time and TUG1 expression clearly showed that TUG1 expression was associated with a reduced overall survival time of patients after surgery (p=0.010; Figure 1C).	('TUG1', 'Gene', (151, 155))	('si', 'Chemical', 'MESH:D012825', (162, 164))	('expression', 'Var', (156, 166))	('reduced', 'NegReg', (189, 196))	('patients', 'Species', '9606', (222, 230))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('si', 'Chemical', 'MESH:D012825', (40, 42))
133298	29029475	Si-TUG1-2 and -3 were the most effective siRNAs targeting TUG1 compared to scrambled siRNA, and therefore were used in subsequent experiments.	('Si-TUG1-2', 'Var', (0, 9))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('TUG1', 'Gene', (58, 62))	('si', 'Chemical', 'MESH:D012825', (41, 43))
133299	29029475	Consist with these data, after transfection with si-TUG1-2 or si-TUG1-3, clonogenic ability was remarkedly weakened as shown by the colony formation assay (Figure 2F).	('si-TUG1-3', 'Var', (62, 71))	('si-TUG1-2', 'Var', (49, 58))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('weakened', 'NegReg', (107, 115))	('clonogenic ability', 'CPA', (73, 91))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('colony formation assay', 'CPA', (132, 154))	('si', 'Chemical', 'MESH:D012825', (49, 51))
133300	29029475	Moreover, PCNA was down-regulated after knockdown of TUG1 proved by Western blot assay (Figure 2G).	('knockdown', 'Var', (40, 49))	('PCNA', 'Gene', (10, 14))	('PCNA', 'Gene', '5111', (10, 14))	('TUG1', 'Gene', (53, 57))	('down-regulated', 'NegReg', (19, 33))
133302	29029475	A multitude of cells transfected with si-NC were alive and did not stain positive for Annexin-V and PI in both QBC939 and RBE cells, whereas in the si-TUG1 counterpart groups, early and late apoptotic cells increased dramatically (Figure 3A).	('Annexin-V', 'Gene', '308', (86, 95))	('Annexin-V', 'Gene', (86, 95))	('si', 'Chemical', 'MESH:D012825', (148, 150))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('si-NC', 'Var', (38, 43))	('increased', 'PosReg', (207, 216))	('si-NC', 'Chemical', 'MESH:C052464', (38, 43))	('si', 'Chemical', 'MESH:D012825', (38, 40))
133305	29029475	Similarly, relative activities of caspase-3 and -9 were significantly increased in si-TUG1 treatment groups compared to si-NC group (Figure 4A).	('si-TUG1', 'Var', (83, 90))	('increased', 'PosReg', (70, 79))	('caspase-3 and -9', 'Gene', '836;842', (34, 50))	('si-NC', 'Chemical', 'MESH:C052464', (120, 125))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('activities', 'MPA', (20, 30))	('si', 'Chemical', 'MESH:D012825', (83, 85))
133306	29029475	The Western blot results demonstrated that silenced TUG1 activated Bax protein expression and restrained the protein level of Bcl-2 compared to negative control group (Figure 4B).	('activated', 'PosReg', (57, 66))	('restrained', 'NegReg', (94, 104))	('TUG1', 'Gene', (52, 56))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('Bcl-2', 'Gene', (126, 131))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('Bax', 'Gene', '581', (67, 70))	('silenced', 'Var', (43, 51))	('Bcl-2', 'Gene', '596', (126, 131))	('Bax', 'Gene', (67, 70))
133307	29029475	To evaluate the extent of TUG1 function in other aspects of CCA, such as migration and invasion, a wound healing assay and Transwell assay were conducted in QBC939 and RBE cells transfected with si-NC or selected siRNAs specifically targeting TUG1.	('si-NC', 'Var', (195, 200))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('si-NC', 'Chemical', 'MESH:C052464', (195, 200))	('si', 'Chemical', 'MESH:D012825', (195, 197))	('si', 'Chemical', 'MESH:D012825', (213, 215))	('TUG1', 'Gene', (243, 247))	('CCA', 'Phenotype', 'HP:0030153', (60, 63))
133308	29029475	Interestingly, TUG1 depletion leads to prolonged healing times compared with si-NC groups (Figure 5A).	('si-NC', 'Chemical', 'MESH:C052464', (77, 82))	('healing times', 'CPA', (49, 62))	('prolonged healing times', 'Phenotype', 'HP:0001058', (39, 62))	('depletion', 'Var', (20, 29))	('TUG1', 'Gene', (15, 19))	('prolonged', 'PosReg', (39, 48))
133309	29029475	Furthermore, the migratory ability as well as invasion potential of selected cells obviously decreased due to TUG1 depletion (Figure 5B and 5C).	('TUG1', 'Gene', (110, 114))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('decreased', 'NegReg', (93, 102))	('migratory ability', 'CPA', (17, 34))	('invasion potential of', 'CPA', (46, 67))	('depletion', 'Var', (115, 124))
133312	29029475	Therefore, to assess the relationship between dysregulation of TUG1 and EMT, EMT markers including E-cadherin, N-cadherin and Vimentin were analyzed by Western blot.	('Vimentin', 'Gene', '7431', (126, 134))	('N-cadherin', 'Gene', (111, 121))	('E-cadherin', 'Gene', (99, 109))	('E-cadherin', 'Gene', '999', (99, 109))	('dysregulation', 'Var', (46, 59))	('N-cadherin', 'Gene', '1000', (111, 121))	('Vimentin', 'Gene', (126, 134))
133320	29029475	Aberrant upregulated TUG1 has been detected in various types of carcinomas, such as osteosarcoma, ovarian cancer, colon cancer, bladder carcinoma, esophageal squamous cell cancer and kidney cancer.	('bladder carcinoma', 'Phenotype', 'HP:0002862', (128, 145))	('carcinomas', 'Disease', (64, 74))	('TUG1', 'Gene', (21, 25))	('ovarian cancer', 'Disease', 'MESH:D010051', (98, 112))	('bladder carcinoma', 'Disease', 'MESH:D001749', (128, 145))	('osteosarcoma', 'Disease', (84, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('colon cancer', 'Disease', 'MESH:D015179', (114, 126))	('osteosarcoma', 'Disease', 'MESH:D012516', (84, 96))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (158, 178))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Aberrant', 'Var', (0, 8))	('ovarian cancer', 'Disease', (98, 112))	('kidney cancer', 'Disease', 'MESH:D007680', (183, 196))	('bladder carcinoma', 'Disease', (128, 145))	('esophageal squamous cell cancer', 'Disease', (147, 178))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (98, 112))	('carcinomas', 'Disease', 'MESH:D002277', (64, 74))	('colon cancer', 'Disease', (114, 126))	('kidney cancer', 'Phenotype', 'HP:0009726', (183, 196))	('osteosarcoma', 'Phenotype', 'HP:0002669', (84, 96))	('kidney cancer', 'Disease', (183, 196))	('upregulated', 'PosReg', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('colon cancer', 'Phenotype', 'HP:0003003', (114, 126))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (147, 178))
133328	29029475	Additionally, high expression of TUG1 was closely associated with tumor size, TNM stage, postoperative relapse and overall survival of CCA patients.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('patients', 'Species', '9606', (139, 147))	('CCA', 'Disease', (135, 138))	('tumor', 'Disease', (66, 71))	('TNM', 'Gene', (78, 81))	('postoperative relapse', 'CPA', (89, 110))	('high', 'Var', (14, 18))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('CCA', 'Phenotype', 'HP:0030153', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('TUG1', 'Gene', (33, 37))	('si', 'Chemical', 'MESH:D012825', (25, 27))	('associated', 'Reg', (50, 60))	('TNM', 'Gene', '10178', (78, 81))
133331	29029475	In our study, CCA cell proliferation was remarkedly inhibited along with the loss of PCNA and Ki67 followed by silencing of TUG1, indicating that TUG1 promotes tumor development and progression in CCA.	('si', 'Chemical', 'MESH:D012825', (111, 113))	('silencing', 'Var', (111, 120))	('CCA', 'Disease', (197, 200))	('promotes', 'PosReg', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('PCNA', 'Gene', (85, 89))	('CCA', 'Phenotype', 'HP:0030153', (14, 17))	('TUG1', 'Gene', (146, 150))	('progression', 'CPA', (182, 193))	('TUG1', 'Gene', (124, 128))	('CCA', 'Phenotype', 'HP:0030153', (197, 200))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('loss', 'NegReg', (77, 81))	('inhibited', 'NegReg', (52, 61))	('PCNA', 'Gene', '5111', (85, 89))	('tumor', 'Disease', (160, 165))	('si', 'Chemical', 'MESH:D012825', (189, 191))
133345	29029475	Therefore, a Western blot assay was carried out and revealed that silenced TUG1 could impair migratory and invasive potential of QBC939 and RBE cells by reversing EMT progress.	('EMT progress', 'CPA', (163, 175))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('silenced', 'Var', (66, 74))	('impair', 'NegReg', (86, 92))	('si', 'Chemical', 'MESH:D012825', (158, 160))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('reversing', 'NegReg', (153, 162))	('TUG1', 'Gene', (75, 79))
133375	29029475	Cells transfected with si-TUG1 or si-NC in the exponential growth phase were cultured in an incubator of 5% CO2 at 37 C, followed by staining with prepared AO/EB mixing solution for 5 min (Solarbio, Beijing, China).	('CO2', 'Chemical', '-', (108, 111))	('si-TUG1', 'Var', (23, 30))	('si-NC', 'Var', (34, 39))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('si-NC', 'Chemical', 'MESH:C052464', (34, 39))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('EB', 'Chemical', 'MESH:C004912', (159, 161))
133404	29075134	As this process is driven by a panel of experts, often quite remote from the patients and their families, it has the potential to give rise to weaknesses in approach to patient communication, one which has the potential not only to cause emotional distress and anxiety to those undergoing diagnosis and treatment, but which threatens to exclude the patient as a "conscious" and involved participant in their own care and recovery.	('cause', 'Reg', (232, 237))	('anxiety', 'Disease', (261, 268))	('patient', 'Species', '9606', (349, 356))	('anxiety', 'Phenotype', 'HP:0000739', (261, 268))	('emotional distress', 'MPA', (238, 256))	('patients', 'Species', '9606', (77, 85))	('patient', 'Species', '9606', (169, 176))	('anxiety', 'Disease', 'MESH:D001008', (261, 268))	('weaknesses', 'Var', (143, 153))	('emotional distress', 'Phenotype', 'HP:0000712', (238, 256))	('patient', 'Species', '9606', (77, 84))	('participant', 'Species', '9606', (387, 398))
133448	33520692	This study aimed to investigate the action mechanism of miR-144-5p and miR-451a in cholangiocarcinoma.	('-144-5p', 'Chemical', '-', (59, 66))	('cholangiocarcinoma', 'Disease', (83, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('miR-451a', 'Var', (71, 79))	('miR-144-5p', 'Var', (56, 66))
133449	33520692	We found that miR-144-5p and miR-451a were significantly decreased in cholangiocarcinoma patient samples compared to the adjacent normal bile duct samples.	('patient', 'Species', '9606', (89, 96))	('-144-5p', 'Chemical', '-', (17, 24))	('cholangiocarcinoma', 'Disease', (70, 88))	('miR-451a', 'Var', (29, 37))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (70, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))	('decreased', 'NegReg', (57, 66))	('miR-144-5p', 'Var', (14, 24))
133451	33520692	Overexpression of miR-144-5p and miR-451a suppressed the proliferation, invasion and migration of cholangiocarcinoma cells in vitro and inhibited xenograft tumor growth.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('-144-5p', 'Chemical', '-', (21, 28))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (98, 116))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (98, 116))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('invasion', 'CPA', (72, 80))	('inhibited', 'NegReg', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('suppressed', 'NegReg', (42, 52))	('tumor', 'Disease', (156, 161))	('miR-451a', 'Var', (33, 41))	('migration', 'CPA', (85, 94))	('cholangiocarcinoma', 'Disease', (98, 116))	('proliferation', 'CPA', (57, 70))	('miR-144-5p', 'Var', (18, 28))
133452	33520692	miR-144-5p and miR-451a regulated the expression of ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 4 (ST8SIA4), and presented a correlation with ST8SIA4 in patient samples.	('ST8SIA4', 'Gene', (157, 164))	('correlation', 'Interaction', (140, 151))	('expression', 'MPA', (38, 48))	('ST8SIA4', 'Gene', (114, 121))	('ST8SIA4', 'Gene', '7903', (114, 121))	('patient', 'Species', '9606', (168, 175))	('ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 4', 'Gene', '7903', (52, 112))	('miR-451a', 'Gene', (15, 23))	('regulated', 'Reg', (24, 33))	('miR-144-5p', 'Var', (0, 10))	('ST8SIA4', 'Gene', '7903', (157, 164))	('-144-5p', 'Chemical', '-', (3, 10))
133453	33520692	Overexpression of ST8SIA4 promoted the proliferation, invasion and migration of cholangiocarcinoma cells, and the changes were reversed by upregulating the expression of miR-144-5p and miR-451a.	('invasion', 'CPA', (54, 62))	('miR-144-5p', 'Var', (170, 180))	('ST8SIA4', 'Gene', (18, 25))	('ST8SIA4', 'Gene', '7903', (18, 25))	('-144-5p', 'Chemical', '-', (173, 180))	('promoted', 'PosReg', (26, 34))	('cholangiocarcinoma', 'Disease', (80, 98))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (80, 98))	('migration', 'CPA', (67, 76))	('proliferation', 'CPA', (39, 52))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (80, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('upregulating', 'PosReg', (139, 151))	('miR-451a', 'Var', (185, 193))
133454	33520692	Our findings indicated that miR-144-5p and miR-451a displayed a tumor suppressor role through decreasing the expression of ST8SIA4 in cholangiocarcinoma.	('decreasing', 'NegReg', (94, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('tumor', 'Disease', (64, 69))	('expression', 'MPA', (109, 119))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (134, 152))	('-144-5p', 'Chemical', '-', (31, 38))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (134, 152))	('miR-451a', 'Var', (43, 51))	('miR-144-5p', 'Var', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('ST8SIA4', 'Gene', (123, 130))	('ST8SIA4', 'Gene', '7903', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('cholangiocarcinoma', 'Disease', (134, 152))
133461	33520692	In recent years, the function of non-coding RNAs in the occurrence and development of cancers has been increasingly recognized.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('non-coding RNAs', 'Var', (33, 48))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
133466	33520692	It has been reported that clustered miRNAs, such as miR-144-5p and miR-451a, inhibited the proliferation of bladder carcinoma cells by reducing the expression of their oncogenic target genes.	('reducing', 'NegReg', (135, 143))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (108, 125))	('inhibited', 'NegReg', (77, 86))	('proliferation', 'CPA', (91, 104))	('-144-5p', 'Chemical', '-', (55, 62))	('bladder carcinoma', 'Disease', 'MESH:D001749', (108, 125))	('miR-451a', 'Var', (67, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('miR-144-5p', 'Var', (52, 62))	('bladder carcinoma', 'Disease', (108, 125))	('expression', 'MPA', (148, 158))
133467	33520692	miR-144/451, a double cis-trans miRNA loci, locates on chromosome 17 which could encode miR-144-5p and miR-451a.	('miR-144-5p', 'Var', (88, 98))	('miR-144/451', 'Gene', '406936;574411', (0, 11))	('miR-451a', 'Var', (103, 111))	('-144-5p', 'Chemical', '-', (91, 98))	('miR-144/451', 'Gene', (0, 11))
133471	33520692	However, whether and how miR-144-5p and miR-451a take part in the development and progression of cholangiocarcinoma is unclear and requires further investigation.	('-144-5p', 'Chemical', '-', (28, 35))	('miR-451a', 'Var', (40, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('cholangiocarcinoma', 'Disease', (97, 115))	('miR-144-5p', 'Var', (25, 35))	('take', 'Reg', (49, 53))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (97, 115))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))
133472	33520692	Sialylation is a glycosyl modification pattern that affects the development and progression of cancer.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('development', 'CPA', (64, 75))	('cancer', 'Disease', (95, 101))	('Sialylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('affects', 'Reg', (52, 59))
133482	33520692	In the present study, we demonstrated that miR-144-5p and miR-451a were downregulated in cholangiocarcinoma patient samples.	('cholangiocarcinoma', 'Disease', (89, 107))	('miR-144-5p', 'Var', (43, 53))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (89, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (89, 107))	('-144-5p', 'Chemical', '-', (46, 53))	('patient', 'Species', '9606', (108, 115))	('downregulated', 'NegReg', (72, 85))	('miR-451a', 'Var', (58, 66))
133483	33520692	miR-144-5p and miR-451a overexpression inhibited proliferation, invasion and migration of cholangiocarcinoma cells by down-regulating ST8SIA4.	('inhibited', 'NegReg', (39, 48))	('down-regulating', 'NegReg', (118, 133))	('invasion', 'CPA', (64, 72))	('proliferation', 'CPA', (49, 62))	('cholangiocarcinoma', 'Disease', (90, 108))	('migration', 'CPA', (77, 86))	('ST8SIA4', 'Gene', '7903', (134, 141))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (90, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('miR-451a', 'Gene', (15, 23))	('ST8SIA4', 'Gene', (134, 141))	('miR-144-5p', 'Var', (0, 10))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))	('-144-5p', 'Chemical', '-', (3, 10))
133484	33520692	ST8SIA4 reversed the miR-144-5p- and miR-451a- induced the growth defect of cholangiocarcinoma cells, and presented a correlation with the expression of these two microRNAs in patient samples.	('growth defect of cholangiocarcinoma', 'Disease', 'MESH:D018281', (59, 94))	('-144-5p', 'Chemical', '-', (24, 31))	('miR-451a-', 'Gene', (37, 46))	('ST8SIA4', 'Gene', (0, 7))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (76, 94))	('miR-144-5p-', 'Var', (21, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('patient', 'Species', '9606', (176, 183))	('growth defect of cholangiocarcinoma', 'Disease', (59, 94))	('ST8SIA4', 'Gene', '7903', (0, 7))
133486	33520692	Twenty-three cholangiocarcinoma tissues and paired normal bile duct tissues were collected (from December 2016 to December 2017) for qRT-PCR analysis of miR-144-5p, miR-451a and ST8SIA4, and western blot analysis of ST8SIA4.	('cholangiocarcinoma', 'Disease', (13, 31))	('ST8SIA4', 'Gene', (216, 223))	('ST8SIA4', 'Gene', '7903', (216, 223))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (13, 31))	('miR-451a', 'Var', (165, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('-144-5p', 'Chemical', '-', (156, 163))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (13, 31))	('ST8SIA4', 'Gene', '7903', (178, 185))	('ST8SIA4', 'Gene', (178, 185))	('miR-144-5p', 'Var', (153, 163))
133500	33520692	Cells were cultured in six-well plates and transfected with miR-144-5p and miR-451a mimic/inhibitor or negative control (NC) (RiboBio, Guangzhou, China) at a final concentration of 50nm/100nm using Lipofectamine 2000 (Thermo Fisher Scientific) according to the manufacturer's instructions.	('miR-144-5p', 'Var', (60, 70))	('-144-5p', 'Chemical', '-', (63, 70))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (198, 216))	('miR-451a', 'Gene', (75, 83))
133504	33520692	HCCC-9810 cells transfected with miR-144-5p, miR-451a mimics or inhibitors or controls were subcutaneously injected into the left flank of mice (1x107 cells for mimics group; 5x106 cells for inhibitor group).	('HCCC-9810', 'CellLine', 'CVCL:6908', (0, 9))	('miR-144-5p', 'Var', (33, 43))	('miR-451a', 'Gene', (45, 53))	('HCC', 'Phenotype', 'HP:0001402', (0, 3))	('mice', 'Species', '10090', (139, 143))	('-144-5p', 'Chemical', '-', (36, 43))
133510	33520692	Cholangiocarcinoma cells were transfected with psicheck-2-ST8SIA4 and miR-144-5p, miR-451a or NC mimics using Lipofectamine 2000 (Invitrogen).	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (110, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (0, 18))	('-144-5p', 'Chemical', '-', (73, 80))	('miR-451a', 'Var', (82, 90))	('miR-144-5p', 'Var', (70, 80))	('ST8SIA4', 'Gene', (58, 65))	('ST8SIA4', 'Gene', '7903', (58, 65))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 18))	('Cholangiocarcinoma', 'Disease', (0, 18))
133519	33520692	The membranes were incubated with antibodies against GAPDH (1: 10000; Abcam, UK) and ST8SIA4 (1:1000; ABclonal, USA) at 4 C overnight.	('1: 10000', 'Var', (60, 68))	('GAPDH', 'Gene', '2597', (53, 58))	('ST8SIA4', 'Gene', (85, 92))	('ST8SIA4', 'Gene', '7903', (85, 92))	('GAPDH', 'Gene', (53, 58))
133521	33520692	The Spearman correlation analysis was performed to analyze the association between miR-144-5p or miR-451a and ST8SIA4 expression.	('-144-5p', 'Chemical', '-', (86, 93))	('ST8SIA4', 'Gene', (110, 117))	('ST8SIA4', 'Gene', '7903', (110, 117))	('association', 'Interaction', (63, 74))	('miR-451a', 'Gene', (97, 105))	('miR-144-5p', 'Var', (83, 93))
133522	33520692	Relationship between miR-144-5p, miR-451a or ST8SIA4 expression and the clinicopathological characteristics was evaluated using chi2 test.	('ST8SIA4', 'Gene', (45, 52))	('-144-5p', 'Chemical', '-', (24, 31))	('miR-451a', 'Var', (33, 41))	('miR-144-5p', 'Var', (21, 31))	('ST8SIA4', 'Gene', '7903', (45, 52))
133525	33520692	The association between miR-144-5p, miR-451a expression and the clinicopathological features of cholangiocarcinoma was assessed in 98 patient samples (Table 1).	('-144-5p', 'Chemical', '-', (27, 34))	('cholangiocarcinoma', 'Disease', (96, 114))	('miR-451a', 'Var', (36, 44))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('miR-144-5p', 'Var', (24, 34))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))	('patient', 'Species', '9606', (134, 141))
133528	33520692	The downregulated expression of miR-144-5p and miR-451a suggested that they may play a tumor suppressor role in cholangiocarcinoma, and additional work will be required to confirm the expression and the association between expression and the clinicopathological features in more cholangiocarcinoma tissues.	('miR-451a', 'Gene', (47, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 130))	('miR-144-5p', 'Var', (32, 42))	('downregulated', 'NegReg', (4, 17))	('cholangiocarcinoma', 'Disease', (279, 297))	('-144-5p', 'Chemical', '-', (35, 42))	('tumor', 'Disease', (87, 92))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('expression', 'MPA', (18, 28))	('cholangiocarcinoma', 'Disease', (112, 130))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (279, 297))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (279, 297))
133529	33520692	The endogenous expression of miR-144-5p and miR-451a was then examined in four cholangiocarcinoma cell lines.	('miR-144-5p', 'Var', (29, 39))	('cholangiocarcinoma', 'Disease', (79, 97))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (79, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (79, 97))	('miR-451a', 'Var', (44, 52))	('-144-5p', 'Chemical', '-', (32, 39))
133532	33520692	Overexpression of miR-144-5p or miR-451a significantly reduced cell proliferation, invasion and migration abilities in HCCC-9810 (Figures 2B, C) and TFK1 cells (Supplementary Figures S1B, C).	('-144-5p', 'Chemical', '-', (21, 28))	('HCCC-9810', 'CellLine', 'CVCL:6908', (119, 128))	('reduced', 'NegReg', (55, 62))	('miR-451a', 'Var', (32, 40))	('cell proliferation', 'CPA', (63, 81))	('HCC', 'Phenotype', 'HP:0001402', (119, 122))	('invasion', 'CPA', (83, 91))	('miR-144-5p', 'Var', (18, 28))
133534	33520692	We next evaluated whether miR-144-5p and miR-451a mediated tumorigenesis in vivo.	('tumor', 'Disease', (59, 64))	('miR-144-5p', 'Var', (26, 36))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('-144-5p', 'Chemical', '-', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('miR-451a', 'Var', (41, 49))
133535	33520692	Because TFK1, HuCCT1, and RBE cells cannot form subcutaneous tumors, HCCC-9810 cells with overexpression or downregulation of miR-144-5p or miR-451a were subcutaneously injected into nude mice, respectively (Figure 3A).	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('nude mice', 'Species', '10090', (183, 192))	('HCC', 'Phenotype', 'HP:0001402', (69, 72))	('miR-144-5p', 'Var', (126, 136))	('HCCC-9810', 'CellLine', 'CVCL:6908', (69, 78))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (48, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('downregulation', 'NegReg', (108, 122))	('-144-5p', 'Chemical', '-', (129, 136))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('miR-451a', 'Var', (140, 148))	('overexpression', 'PosReg', (90, 104))
133537	33520692	Both the average weight and volume of tumor xenografts were markedly suppressed by the overexpression of miR-144-5p or miR-451a compared with the control groups.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('miR-144-5p', 'Var', (105, 115))	('-144-5p', 'Chemical', '-', (108, 115))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('suppressed', 'NegReg', (69, 79))	('overexpression', 'PosReg', (87, 101))	('miR-451a', 'Var', (119, 127))
133538	33520692	Knockdown of miR-144-5p or miR-451a had the opposite effects (Figures 3B-D).	('-144-5p', 'Chemical', '-', (16, 23))	('miR-451a', 'Var', (27, 35))	('miR-144-5p', 'Var', (13, 23))
133540	33520692	Tumors with miR-144-5p or miR-451a overexpression had lower Ki-67-positive cells.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Ki-67-positive cells', 'CPA', (60, 80))	('miR-144-5p', 'Var', (12, 22))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('-144-5p', 'Chemical', '-', (15, 22))	('miR-451a', 'Var', (26, 34))	('lower', 'NegReg', (54, 59))
133542	33520692	The miRDB, PicTar TargetScan, and miRanda algorithms were chosen to predict the potential targets of miR-144-5p and miR-451a.	('-144-5p', 'Chemical', '-', (104, 111))	('miR-144-5p', 'Var', (101, 111))	('miRanda algorithms', 'Disease', (34, 52))	('miRanda algorithms', 'Disease', 'MESH:C537402', (34, 52))	('miR-451a', 'Var', (116, 124))
133543	33520692	There were 148 and 22 predictive targets of miR-144-5p and miR-451a, respectively, and only one common candidate target, which is the Homo sapiens ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 4 gene (ST8SIA4, Figure 4A).	('miR-451a', 'Var', (59, 67))	('miR-144-5p', 'Var', (44, 54))	('ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 4', 'Gene', '7903', (147, 207))	('ST8SIA4', 'Gene', (214, 221))	('Homo sapiens', 'Species', '9606', (134, 146))	('ST8SIA4', 'Gene', '7903', (214, 221))	('-144-5p', 'Chemical', '-', (47, 54))
133544	33520692	ST8SIA4 has four transcripts and the potential binding sequences of miR-144-5p and miR-451a are located in the 3' UTR of transcripts 1 and 2 (abbreviated as T1 and T2, Figure 4B).	('miR-144-5p', 'Var', (68, 78))	('-144-5p', 'Chemical', '-', (71, 78))	('ST8SIA4', 'Gene', (0, 7))	('ST8SIA4', 'Gene', '7903', (0, 7))	('miR-451a', 'Var', (83, 91))
133545	33520692	Luciferase reporter assay was performed to validate whether ST8SIA4 was a direct target of miR-144-5p and miR-451a.	('miR-144-5p', 'Var', (91, 101))	('-144-5p', 'Chemical', '-', (94, 101))	('ST8SIA4', 'Gene', (60, 67))	('ST8SIA4', 'Gene', '7903', (60, 67))	('miR-451a', 'Var', (106, 114))
133546	33520692	The miR-144-5p and miR-451a mimics significantly downregulated the luciferase activity of reporter vectors containing wild-type binding sequences.	('miR-451a', 'Gene', (19, 27))	('-144-5p', 'Chemical', '-', (7, 14))	('luciferase', 'Enzyme', (67, 77))	('miR-144-5p', 'Var', (4, 14))	('downregulated', 'NegReg', (49, 62))	('activity', 'MPA', (78, 86))
133558	33520692	Cholangiocarcinoma cells were transfected with miR-144-5p, miR-451a mimics or inhibitors together with ST8SIA4 expression plasmids or siRNA-3# to further assess whether miR-144-5p and miR-451a can restrain the cholangiocarcinoma cell proliferation, invasion, and migration by regulating ST8SIA4.	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('ST8SIA4', 'Gene', '7903', (103, 110))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (210, 228))	('-144-5p', 'Chemical', '-', (172, 179))	('invasion', 'CPA', (249, 257))	('cholangiocarcinoma', 'Disease', (210, 228))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (210, 228))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (0, 18))	('miR-451a', 'Var', (184, 192))	('restrain', 'NegReg', (197, 205))	('ST8SIA4', 'Gene', (287, 294))	('-144-5p', 'Chemical', '-', (50, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 18))	('Cholangiocarcinoma', 'Disease', (0, 18))	('miR-144-5p', 'Var', (169, 179))	('ST8SIA4', 'Gene', (103, 110))	('migration', 'CPA', (263, 272))	('ST8SIA4', 'Gene', '7903', (287, 294))
133561	33520692	Moreover, ST8SIA4 rescued the miR-144-5p- and miR-451a-induced the growth defect of cholangiocarcinoma cells (Figure 7; Supplementary Figure S5).	('ST8SIA4', 'Gene', (10, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('ST8SIA4', 'Gene', '7903', (10, 17))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('growth defect of cholangiocarcinoma', 'Disease', (67, 102))	('miR-144-5p-', 'Var', (30, 41))	('growth defect of cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 102))	('miR-451a-induced', 'Gene', (46, 62))	('-144-5p', 'Chemical', '-', (33, 40))
133566	33520692	indicated that miR-144-5p accelerated the proliferation, migration and invasion of nasopharyngeal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('miR-144-5p', 'Var', (15, 25))	('accelerated', 'PosReg', (26, 37))	('proliferation', 'CPA', (42, 55))	('invasion', 'CPA', (71, 79))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('migration', 'CPA', (57, 66))	('-144-5p', 'Chemical', '-', (18, 25))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (83, 104))	('cancer', 'Disease', (98, 104))
133571	33520692	We identified the expression of miR-144-5p and miR-451a was lower in cholangiocarcinoma tissues compared with normal tissues, and their expression levels were significantly correlated with HBsAg as well as tumor size, easier vascular invasion (Figures 1A, B and Table 1).	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('HBsAg', 'Disease', (189, 194))	('miR-144-5p', 'Var', (32, 42))	('-144-5p', 'Chemical', '-', (35, 42))	('tumor', 'Disease', (206, 211))	('correlated', 'Reg', (173, 183))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('cholangiocarcinoma', 'Disease', (69, 87))	('expression', 'MPA', (18, 28))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (69, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (69, 87))	('miR-451a', 'Var', (47, 55))	('easier vascular invasion', 'CPA', (218, 242))	('expression levels', 'MPA', (136, 153))	('lower', 'NegReg', (60, 65))
133574	33520692	Our results demonstrated that miR-144-5p and miR-451a suppressed the proliferation, migration and invasion of cholangiocarcinoma cells (Figure 2; Supplementary Figure S1), which shed new light on the effect of non-coding RNA on cholangiocarcinoma development.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (110, 128))	('miR-451a', 'Var', (45, 53))	('suppressed', 'NegReg', (54, 64))	('proliferation', 'CPA', (69, 82))	('invasion of', 'CPA', (98, 109))	('miR-144-5p', 'Var', (30, 40))	('migration', 'CPA', (84, 93))	('cholangiocarcinoma', 'Disease', (110, 128))	('cholangiocarcinoma', 'Disease', (228, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('-144-5p', 'Chemical', '-', (33, 40))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (110, 128))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (228, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (228, 246))
133578	33520692	Abnormal changes of Sts could lead to aberrant glycosylation, which is one of the significant hallmarks of carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('Sts', 'Gene', (20, 23))	('lead to', 'Reg', (30, 37))	('glycosylation', 'MPA', (47, 60))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (38, 60))	('hallmarks of carcinoma', 'Disease', (94, 116))	('aberrant', 'Var', (38, 46))	('Abnormal changes', 'Var', (0, 16))	('hallmarks of carcinoma', 'Disease', 'MESH:D009369', (94, 116))
133582	33520692	In the present study, bioinformatics analysis revealed that ST8SIA4 was a potential target gene of both miR-144-5p and miR-451a (Figures 4A, B).	('-144-5p', 'Chemical', '-', (107, 114))	('ST8SIA4', 'Gene', (60, 67))	('ST8SIA4', 'Gene', '7903', (60, 67))	('miR-451a', 'Var', (119, 127))	('miR-144-5p', 'Var', (104, 114))
133583	33520692	Luciferase activity assays confirmed that miR-144-5p and miR-451a bound to the 3' UTR of the ST8SIA4 mRNA (Figures 4C, D; Supplementary Figure S2).	('ST8SIA4', 'Gene', (93, 100))	('-144-5p', 'Chemical', '-', (45, 52))	('ST8SIA4', 'Gene', '7903', (93, 100))	('bound', 'Interaction', (66, 71))	('miR-144-5p', 'Var', (42, 52))	('miR-451a', 'Var', (57, 65))
133584	33520692	We also demonstrated that miR-144-5p and miR-451a inhibited the progression of cholangiocarcinoma through targeting ST8SIA4 (Figure 6; Supplementary Figure S4).	('cholangiocarcinoma', 'Disease', (79, 97))	('progression', 'CPA', (64, 75))	('targeting', 'Reg', (106, 115))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (79, 97))	('miR-144-5p', 'Var', (26, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (79, 97))	('ST8SIA4', 'Gene', (116, 123))	('-144-5p', 'Chemical', '-', (29, 36))	('ST8SIA4', 'Gene', '7903', (116, 123))	('inhibited', 'NegReg', (50, 59))	('miR-451a', 'Var', (41, 49))
133589	33520692	Our data showed that ST8SIA4 was a direct target of miR-144-5p and miR-451a.	('-144-5p', 'Chemical', '-', (55, 62))	('miR-451a', 'Var', (67, 75))	('miR-144-5p', 'Var', (52, 62))	('ST8SIA4', 'Gene', (21, 28))	('ST8SIA4', 'Gene', '7903', (21, 28))
133590	33520692	The increased expression of miR-144-5p and miR-451a prevented proliferation, migration and invasion of cholangiocarcinoma cells through suppressing the expression of ST8SIA4.	('suppressing', 'NegReg', (136, 147))	('-144-5p', 'Chemical', '-', (31, 38))	('invasion', 'CPA', (91, 99))	('proliferation', 'CPA', (62, 75))	('cholangiocarcinoma', 'Disease', (103, 121))	('ST8SIA4', 'Gene', '7903', (166, 173))	('ST8SIA4', 'Gene', (166, 173))	('migration', 'CPA', (77, 86))	('prevented', 'NegReg', (52, 61))	('miR-144-5p', 'Var', (28, 38))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (103, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('miR-451a', 'Var', (43, 51))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (103, 121))	('expression', 'MPA', (152, 162))	('increased', 'PosReg', (4, 13))
133591	33520692	These findings demonstrated that miR-144-5p, miR-451a, and ST8SIA4 are functionally important components of cholangiocarcinoma, and may be promising targets in the future development of cholangiocarcinoma therapy.	('miR-451a', 'Var', (45, 53))	('ST8SIA4', 'Gene', (59, 66))	('miR-144-5p', 'Var', (33, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('cholangiocarcinoma', 'Disease', (186, 204))	('cholangiocarcinoma', 'Disease', (108, 126))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (108, 126))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (186, 204))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (186, 204))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (108, 126))	('-144-5p', 'Chemical', '-', (36, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('ST8SIA4', 'Gene', '7903', (59, 66))
133735	29141394	The univariate analysis revealed that resection margin status (MST, 33 months vs. 21 months; p=0.011), proximal RM positivity (MST, 33 months vs. 19 months; p=0.002), lymph node involvement (MST, 32 months vs. 15 months; p < 0.001), adjuvant therapy (MST, 33 months vs. 21 months; p=0.01), and CA 19-9 level (MST, 32 months vs. 21 months; p=0.022) were significantly associated with patient survival.	('men', 'Species', '9606', (185, 188))	('associated', 'Reg', (367, 377))	('lymph node involvement', 'CPA', (167, 189))	('positivity', 'Var', (115, 125))	('patient', 'Species', '9606', (383, 390))	('patient survival', 'CPA', (383, 399))
133736	29141394	A multivariate analysis confirmed that proximal RM positivity (hazard ratio [HR], 2.688; p=0.007) and lymph node involvement (HR, 3.293; p < 0.001) remained independently associated with survival.	('proximal RM', 'CPA', (39, 50))	('positivity', 'Var', (51, 61))	('lymph node involvement', 'CPA', (102, 124))	('associated', 'Reg', (171, 181))	('men', 'Species', '9606', (120, 123))
133750	29141394	evaluated negative margin lengths in 28 cholangiocarcinoma patients who underwent R0 resection and found similar rates of recurrence among patients with margins <= 5 mm and > 5 mm (p=0.930).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (40, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('patients', 'Species', '9606', (139, 147))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (40, 58))	('patients', 'Species', '9606', (59, 67))	('cholangiocarcinoma', 'Disease', (40, 58))	('<= 5 mm', 'Var', (161, 168))
133818	26517522	After knockdown of LKB1 gene (Figure 2C), we found decreased expression of TGFbeta1, COX2, and ICAM-1 (Figure 2D).	('LKB1', 'Gene', '6794', (19, 23))	('TGFbeta1', 'Gene', '7040', (75, 83))	('TGFbeta1', 'Gene', (75, 83))	('decreased', 'NegReg', (51, 60))	('COX2', 'Gene', (85, 89))	('ICAM-1', 'Gene', (95, 101))	('ICAM-1', 'Gene', '3383', (95, 101))	('COX2', 'Gene', '4513', (85, 89))	('knockdown', 'Var', (6, 15))	('LKB1', 'Gene', (19, 23))	('expression', 'MPA', (61, 71))
133845	26517522	Because exposure to MbetaCD and lovastatin induced similar results (Figure 5D), cholesterol depletion by MbetaCD causes anoikis-like apoptosis, which in A431 cells involved decreased raft levels, Bcl-xL downregulation, caspase-3 activation, and Akt inactivation regardless of epidermal growth factor receptor activation.	('MbetaCD', 'Chemical', '-', (20, 27))	('Bcl-xL', 'Gene', '598', (196, 202))	('Akt', 'Gene', (245, 248))	('anoikis-like apoptosis', 'Disease', (120, 142))	('MbetaCD', 'Chemical', '-', (105, 112))	('lovastatin', 'Chemical', 'MESH:D008148', (32, 42))	('raft levels', 'MPA', (183, 194))	('inactivation', 'NegReg', (249, 261))	('epidermal growth factor receptor', 'Gene', (276, 308))	('cholesterol', 'Chemical', 'MESH:D002784', (80, 91))	('epidermal growth factor receptor', 'Gene', '1956', (276, 308))	('Akt', 'Gene', '207', (245, 248))	('downregulation', 'NegReg', (203, 217))	('cholesterol', 'MPA', (80, 91))	('A431', 'CellLine', 'CVCL:0037', (153, 157))	('caspase-3', 'Gene', '836', (219, 228))	('decreased', 'NegReg', (173, 182))	('caspase-3', 'Gene', (219, 228))	('activation', 'PosReg', (229, 239))	('Bcl-xL', 'Gene', (196, 202))	('MbetaCD', 'Var', (105, 112))
133852	26517522	After knockdown of LKB1 gene expression, lovastatin-induced inhibitory effects on the expressions of TGFbeta1, COX2, and ICAM-1 were reduced (Figure 2D).	('LKB1', 'Gene', '6794', (19, 23))	('TGFbeta1', 'Gene', (101, 109))	('COX2', 'Gene', '4513', (111, 115))	('lovastatin', 'Chemical', 'MESH:D008148', (41, 51))	('ICAM-1', 'Gene', (121, 127))	('reduced', 'NegReg', (133, 140))	('expressions', 'MPA', (86, 97))	('knockdown', 'Var', (6, 15))	('TGFbeta1', 'Gene', '7040', (101, 109))	('lovastatin-induced inhibitory effects', 'MPA', (41, 78))	('LKB1', 'Gene', (19, 23))	('ICAM-1', 'Gene', '3383', (121, 127))	('COX2', 'Gene', (111, 115))
133915	25557794	MSCs may contribute to tumour propagation or dissemination by preventing recognition of the tumour cells by the immune system or by promoting tumour cell invasiveness.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('preventing', 'NegReg', (62, 72))	('tumour', 'Disease', (142, 148))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('recognition', 'MPA', (73, 84))	('tumour', 'Disease', (92, 98))	('promoting', 'PosReg', (132, 141))	('tumour', 'Disease', (23, 29))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('MSCs', 'Var', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('tumour cell invasiveness', 'Disease', (142, 166))	('contribute', 'Reg', (9, 19))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('tumour cell invasiveness', 'Disease', 'MESH:D009361', (142, 166))
133927	25557794	We have recently shown that tumour cells can transfer genetic information by release of EVs that can modulate recipient cell behaviour.	('modulate', 'Reg', (101, 109))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('tumour', 'Disease', (28, 34))	('genetic', 'Var', (54, 61))
133960	25557794	The expression of alpha-SMA and FAP mRNA was significantly increased in MSCs incubated with either KMBC-EVs or HuCCT1-EVs compared to controls incubated in medium without EVs after 48 hours (Fig.	('FAP', 'Gene', (32, 35))	('KMBC-EVs', 'Chemical', '-', (99, 107))	('expression', 'MPA', (4, 14))	('KMBC-EVs', 'Var', (99, 107))	('FAP', 'Gene', '2191', (32, 35))	('alpha-SMA', 'Protein', (18, 27))	('increased', 'PosReg', (59, 68))
133962	25557794	KMBC-CM increased the most expression of alpha-SMA and FAP mRNA on MSCs.	('KMBC', 'Chemical', '-', (0, 4))	('FAP', 'Gene', '2191', (55, 58))	('expression', 'MPA', (27, 37))	('increased', 'PosReg', (8, 17))	('FAP', 'Gene', (55, 58))	('KMBC-CM', 'Var', (0, 7))	('alpha-SMA', 'Protein', (41, 50))
133965	25557794	Similar observations were made on immunofluorescence microscopy for expression in long-term 28-day cultures of MSCs with KMBC-EVs; however, an increase in vimentin was not detected (Fig.	('KMBC-EVs', 'Chemical', '-', (121, 129))	('KMBC-EVs', 'Var', (121, 129))	('vimentin', 'Gene', (155, 163))	('vimentin', 'Gene', '7431', (155, 163))
133969	25557794	Incubation of MSCs with KMBC-EVs resulted in increased cell migration after 12 hours compared to control MSCs that were not exposed to KMBC-EVs (Fig.	('increased', 'PosReg', (45, 54))	('KMBC-EVs', 'Chemical', '-', (24, 32))	('cell migration', 'CPA', (55, 69))	('KMBC-EVs', 'Chemical', '-', (135, 143))	('KMBC-EVs', 'Var', (24, 32))
133970	25557794	Moreover, migration of MSCs cultured with CM from KMBC pre-incubated with GW4869 was decreased compared to migration of MSCs cultured with CM from KMBC.	('GW4869', 'Var', (74, 80))	('decreased', 'NegReg', (85, 94))	('KMBC', 'Chemical', '-', (50, 54))	('GW4869', 'Chemical', 'MESH:C468773', (74, 80))	('KMBC', 'Chemical', '-', (147, 151))	('migration', 'CPA', (10, 19))
133978	25557794	Furthermore, the expression of IL-6, CXCL1 and CCL2 mRNA was also significantly increased in MSCs treated with KMBC-EVs by quantitative RT-PCR analyses compared to control (Fig.	('IL-6', 'Gene', (31, 35))	('CXCL1', 'Gene', (37, 42))	('IL-6', 'Gene', '3569', (31, 35))	('CXCL1', 'Gene', '2919', (37, 42))	('increased', 'PosReg', (80, 89))	('expression', 'MPA', (17, 27))	('KMBC-EVs', 'Chemical', '-', (111, 119))	('CCL2', 'Gene', '6347', (47, 51))	('CCL2', 'Gene', (47, 51))	('KMBC-EVs', 'Var', (111, 119))
134021	25557794	These observations may be important in other conditions that are characterized by aberrant IL-6 release, such as tissue injury, or other cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('IL-6', 'Gene', (91, 95))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('release', 'MPA', (96, 103))	('cancers', 'Disease', (137, 144))	('IL-6', 'Gene', '3569', (91, 95))	('tissue injury', 'Disease', 'MESH:D017695', (113, 126))	('aberrant', 'Var', (82, 90))	('tissue injury', 'Disease', (113, 126))
134057	24934314	Laboratory studies on admission yield normal blood biochemistry and mild thrombocytopenia (127000 per cubic millimeter).	('thrombocytopenia', 'Disease', 'MESH:D013921', (73, 89))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (73, 89))	('127000', 'Var', (91, 97))	('blood biochemistry', 'MPA', (45, 63))	('thrombocytopenia', 'Disease', (73, 89))
134085	24934314	Therefore, it is reasonable to deduce that pathological insults to these glands may instigate a variety of disorders including cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('pathological', 'Var', (43, 55))	('instigate', 'Reg', (84, 93))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))
134133	19795457	In addition, modulation of dopamine receptors is being proposed as a possible treatment of pituitary tumors due to the suppressive effects of dopamine on prolactin secretion.	('pituitary tumors', 'Disease', (91, 107))	('dopamine', 'Chemical', 'MESH:D004298', (27, 35))	('dopamine', 'Chemical', 'MESH:D004298', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('pituitary tumors', 'Disease', 'MESH:D010911', (91, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('modulation', 'Var', (13, 23))	('prolactin secretion', 'MPA', (154, 173))	('suppressive effects', 'MPA', (119, 138))
134134	19795457	It may also have a role in the treatment of neuroblastoma cells, where D1DR agonists have a toxic effect on cell proliferation which appears to be neuronal specific.	('D1DR', 'Gene', (71, 75))	('agonists', 'Var', (76, 84))	('neuroblastoma', 'Disease', 'MESH:D009447', (44, 57))	('neuroblastoma', 'Disease', (44, 57))	('cell proliferation', 'CPA', (108, 126))	('neuroblastoma', 'Phenotype', 'HP:0003006', (44, 57))
134136	19795457	In the present study, we show a dysregulation of the cellular machinery responsible for the metabolism of dopamine in cholangiocarcinoma cell lines and human samples, which results in an increased production and secretion of dopamine from cholangiocarcinoma.	('dopamine', 'Chemical', 'MESH:D004298', (106, 114))	('dysregulation', 'Var', (32, 45))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (118, 136))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (239, 257))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (239, 257))	('cholangiocarcinoma cell', 'Disease', (118, 141))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (118, 141))	('cholangiocarcinoma', 'Disease', (118, 136))	('human', 'Species', '9606', (152, 157))	('increased', 'PosReg', (187, 196))	('dopamine', 'Chemical', 'MESH:D004298', (225, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('secretion of dopamine', 'MPA', (212, 233))	('cholangiocarcinoma', 'Disease', (239, 257))	('production', 'MPA', (197, 207))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (118, 136))
134137	19795457	Furthermore, we show that the increased secretion of dopamine has growth-promoting effects on cholangiocarcinoma cells and that inhibiting dopamine synthesis significantly blocks cholangiocarcinoma cell proliferation in vitro and in vivo.	('cholangiocarcinoma cell', 'Disease', (179, 202))	('cholangiocarcinoma cell', 'Disease', (94, 117))	('blocks', 'NegReg', (172, 178))	('inhibiting', 'Var', (128, 138))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (179, 202))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (94, 117))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (179, 197))	('secretion of dopamine', 'MPA', (40, 61))	('dopamine', 'Chemical', 'MESH:D004298', (139, 147))	('dopamine', 'Chemical', 'MESH:D004298', (53, 61))	('increased', 'PosReg', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('growth-promoting effects', 'CPA', (66, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (94, 112))
134142	19795457	Cells were serum-starved for 24 hr prior to stimulation with dopamine (10-9 M to 10-5 M) or L-(-)-alpha-methyldopa (a specific DDC inhibitor; 10-6 M to 10-8 M; Ki = 39.3 muM) for 48 hours.	('DDC', 'Gene', '1644', (127, 130))	('L-(-)-alpha-methyldopa', 'Chemical', 'MESH:D008750', (92, 114))	('DDC', 'Gene', (127, 130))	('muM', 'Gene', '56925', (170, 173))	('dopamine', 'Chemical', 'MESH:D004298', (61, 69))	('L-(-)-alpha-methyldopa', 'Var', (92, 114))	('muM', 'Gene', (170, 173))
134175	19795457	In addition, the latency of tumor growth (i.e., time taken for tumor volume to increase to 150% of the original size) was increased after alpha-Methyl dopa treatment compared to vehicle treatment (Figure 6B).	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (28, 33))	('alpha-Methyl dopa', 'Chemical', 'MESH:D008750', (138, 155))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('increased', 'PosReg', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('alpha-Methyl dopa', 'Var', (138, 155))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('latency', 'MPA', (17, 24))
134177	19795457	Histological analysis of the excised tumors revealed that all cells within tumors from alpha-Methyl dopa-treated and vehicle-treated animals were CK-19 positive, indicating cholangiocyte phenotype (Figure 7).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('cholangiocyte', 'Disease', (173, 186))	('alpha-Methyl dopa', 'Chemical', 'MESH:D008750', (87, 104))	('CK-19', 'Gene', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('alpha-Methyl dopa-treated', 'Var', (87, 112))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('CK-19', 'Gene', '3880', (146, 151))
134190	19795457	Treatment of cholangiocarcinoma cell lines with dopamine increased cell proliferation in vitro, and inhibition of dopamine synthesis decreased cell proliferation in vitro and in an in vivo xenograft model of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (13, 31))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (13, 36))	('dopamine', 'Chemical', 'MESH:D004298', (114, 122))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (13, 31))	('dopamine synthesis decreased', 'Phenotype', 'HP:0012656', (114, 142))	('dopamine increased', 'Phenotype', 'HP:0012655', (48, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (208, 226))	('cholangiocarcinoma cell', 'Disease', (13, 36))	('cholangiocarcinoma', 'Disease', (208, 226))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (208, 226))	('decreased', 'NegReg', (133, 142))	('cell proliferation', 'CPA', (143, 161))	('dopamine', 'Chemical', 'MESH:D004298', (48, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('increased', 'PosReg', (57, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (13, 31))	('inhibition', 'Var', (100, 110))	('cell proliferation', 'CPA', (67, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
134196	19795457	Conversely, dopamine levels are depleted in malignant colon tissue and gastric cancer tissues, whereas dopamine treatement slows tumor growth, presumably by decreasing the expression of vascular epithelial growth factor and subsequent angiogenesis.	('dopamine', 'Var', (103, 111))	('slows', 'NegReg', (123, 128))	('gastric cancer', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('dopamine', 'Chemical', 'MESH:D004298', (103, 111))	('malignant colon', 'Disease', (44, 59))	('vascular epithelial growth factor', 'Protein', (186, 219))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('angiogenesis', 'CPA', (235, 247))	('malignant colon', 'Disease', 'MESH:D009369', (44, 59))	('gastric cancer', 'Disease', 'MESH:D013274', (71, 85))	('expression', 'MPA', (172, 182))	('decreasing', 'NegReg', (157, 167))	('dopamine', 'Chemical', 'MESH:D004298', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))	('dopamine levels', 'MPA', (12, 27))	('tumor', 'Disease', (129, 134))
134226	33105816	In principle such modifications aim at taking advantage of pathological features of tumors where permeation into the tumor is enhanced due to fenestrated tumor vasculature and nanoparticles are retained inside tumors due to a lack of a functional lymphatic drainage; a mechanism known as enhanced permeation and retention (EPR) effect, and so far EPR-based passive targeting was the central paradigm in cancer nanomedicine.	('modifications', 'Var', (18, 31))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('p', 'Chemical', 'MESH:D010758', (357, 358))	('p', 'Chemical', 'MESH:D010758', (180, 181))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('p', 'Chemical', 'MESH:D010758', (59, 60))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumors', 'Disease', (84, 90))	('p', 'Chemical', 'MESH:D010758', (297, 298))	('p', 'Chemical', 'MESH:D010758', (250, 251))	('p', 'Chemical', 'MESH:D010758', (391, 392))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('cancer', 'Disease', (403, 409))	('p', 'Chemical', 'MESH:D010758', (3, 4))	('enhanced', 'PosReg', (126, 134))	('p', 'Chemical', 'MESH:D010758', (97, 98))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (403, 409))	('p', 'Chemical', 'MESH:D010758', (9, 10))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('permeation', 'MPA', (97, 107))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (117, 122))	('tumors', 'Disease', (210, 216))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('cancer', 'Disease', 'MESH:D009369', (403, 409))
134236	33105816	Therefore, manipulating the tumor microenvironment to increase perfusion, permeability, and extravasation, or even normalization of tumor vasculatures, were found to enhance drug delivery in tumors.	('tumor', 'Disease', (28, 33))	('increase', 'PosReg', (54, 62))	('enhance', 'PosReg', (166, 173))	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumors', 'Disease', (191, 197))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor vasculatures', 'Disease', (132, 150))	('perfusion', 'MPA', (63, 72))	('manipulating', 'Var', (11, 23))	('p', 'Chemical', 'MESH:D010758', (74, 75))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('extravasation', 'CPA', (92, 105))	('permeability', 'MPA', (74, 86))	('tumor vasculatures', 'Disease', 'MESH:C565633', (132, 150))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (191, 196))	('p', 'Chemical', 'MESH:D010758', (63, 64))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('drug delivery', 'MPA', (174, 187))	('p', 'Chemical', 'MESH:D010758', (15, 16))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))
134257	33105816	Despite ligand-modification of nanoparticles enhances internalization into cells, it has been shown that cellular level of drugs delivered into cells does not necessarily imply the availability of free drug molecules to affect the subcellular targets.	('p', 'Chemical', 'MESH:D010758', (3, 4))	('internalization into cells', 'MPA', (54, 80))	('p', 'Chemical', 'MESH:D010758', (35, 36))	('p', 'Chemical', 'MESH:D010758', (173, 174))	('enhances', 'PosReg', (45, 53))	('ligand-modification', 'Var', (8, 27))
134259	33105816	In addition, ligand modification negatively impacts on pharmacokinetics and distribution of nanoparticles; while ligand modification reduces circulation lifetime of nanoparticles, because of augmented clearance rate, which in turn decreases tumor accumulation, addition of an avidity to nanoparticles results in a prompt interaction with tumor cells soon after extravasation, limiting distribution and penetration of nanoparticles deeper into the tumor.	('distribution', 'MPA', (385, 397))	('tumor', 'Disease', (338, 343))	('circulation lifetime of nanoparticles', 'MPA', (141, 178))	('p', 'Chemical', 'MESH:D010758', (434, 435))	('p', 'Chemical', 'MESH:D010758', (55, 56))	('p', 'Chemical', 'MESH:D010758', (46, 47))	('clearance', 'MPA', (201, 210))	('p', 'Chemical', 'MESH:D010758', (291, 292))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('tumor', 'Disease', (447, 452))	('tumor', 'Disease', (241, 246))	('decreases tumor', 'Disease', (231, 246))	('p', 'Chemical', 'MESH:D010758', (402, 403))	('p', 'Chemical', 'MESH:D010758', (314, 315))	('prompt', 'MPA', (314, 320))	('augmented', 'PosReg', (191, 200))	('interaction', 'Interaction', (321, 332))	('tumor', 'Disease', 'MESH:D009369', (447, 452))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('modification', 'Var', (120, 132))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('decreases tumor', 'Disease', 'MESH:D002303', (231, 246))	('p', 'Chemical', 'MESH:D010758', (318, 319))	('p', 'Chemical', 'MESH:D010758', (169, 170))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (447, 452))	('reduces', 'NegReg', (133, 140))	('p', 'Chemical', 'MESH:D010758', (96, 97))	('p', 'Chemical', 'MESH:D010758', (421, 422))
134279	33105816	In addition to these effects mild hyperthermia also increases the permeability of tumor vasculature by enlarging pore size in the endothelial lining, facilitating nanoparticle extravasation, which, alongside increased perfusion, improves accumulation of liposomes or free drug inside the tumor interstitium (Figure 1).	('improves', 'PosReg', (229, 237))	('increases', 'PosReg', (52, 61))	('pore size', 'MPA', (113, 122))	('enlarging', 'PosReg', (103, 112))	('liposomes', 'MPA', (254, 263))	('tumor', 'Disease', (82, 87))	('mild', 'Var', (29, 33))	('hyperthermia', 'Phenotype', 'HP:0001945', (34, 46))	('free drug', 'MPA', (267, 276))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('p', 'Chemical', 'MESH:D010758', (36, 37))	('p', 'Chemical', 'MESH:D010758', (218, 219))	('tumor', 'Disease', (288, 293))	('hyperthermia', 'Disease', (34, 46))	('p', 'Chemical', 'MESH:D010758', (66, 67))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('p', 'Chemical', 'MESH:D010758', (231, 232))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('permeability', 'MPA', (66, 78))	('p', 'Chemical', 'MESH:D010758', (113, 114))	('p', 'Chemical', 'MESH:D010758', (256, 257))	('p', 'Chemical', 'MESH:D010758', (167, 168))	('nanoparticle extravasation', 'MPA', (163, 189))	('hyperthermia', 'Disease', 'MESH:D005334', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('accumulation', 'MPA', (238, 250))
134309	33105816	The therapeutic benefit of TSLs containing cis-Dichlorodiammineplatinum(ll) was then evaluated in mice bearing sarcoma 180 tumors.	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('p', 'Chemical', 'MESH:D010758', (63, 64))	('cis-Dichlorodiammineplatinum', 'Var', (43, 71))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('cis-Dichlorodiammineplatinum', 'Chemical', 'MESH:D002945', (43, 71))	('sarcoma', 'Disease', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('p', 'Chemical', 'MESH:D010758', (9, 10))	('mice', 'Species', '10090', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('TSL', 'Chemical', '-', (27, 30))
134324	33105816	We have shown that for thermoresponsive liposomes a concentration of 5 mol% mPEG2000-DSPE is an optimal concentration, which not only prolongs circulation time of TSLs in blood but also it is believed that the PEG molecules stabilize grain boundaries and facilitate DXR release.	('p', 'Chemical', 'MESH:D010758', (134, 135))	('mPEG2000-DSPE', 'Var', (76, 89))	('facilitate', 'PosReg', (255, 265))	('p', 'Chemical', 'MESH:D010758', (42, 43))	('TSL', 'Chemical', '-', (163, 166))	('grain boundaries', 'CPA', (234, 250))	('p', 'Chemical', 'MESH:D010758', (97, 98))	('DXR release', 'MPA', (266, 277))	('DSPE', 'Chemical', 'MESH:C038089', (85, 89))	('DXR', 'Chemical', 'MESH:D004317', (266, 269))	('PEG', 'Chemical', 'MESH:D011092', (77, 80))	('mPEG2000', 'Chemical', '-', (76, 84))	('circulation time', 'MPA', (143, 159))	('p', 'Chemical', 'MESH:D010758', (32, 33))	('prolongs', 'PosReg', (134, 142))	('PEG', 'Chemical', 'MESH:D011092', (210, 213))
134332	33105816	Uptake of the cytotoxic drug, e.g., DXR, by endothelial cells results in vascular damage and indirectly boosts the treatment efficacy by depriving tumor cells from oxygen and nutrition supply and, in part, contribute to the enhanced antitumor efficacy of TSLs plus hyperthermia.	('treatment efficacy', 'CPA', (115, 133))	('hyperthermia', 'Phenotype', 'HP:0001945', (265, 277))	('enhanced', 'PosReg', (224, 232))	('TSLs plus hyperthermia', 'Disease', 'MESH:D005334', (255, 277))	('boosts', 'PosReg', (104, 110))	('vascular damage', 'Disease', 'MESH:D000783', (73, 88))	('p', 'Chemical', 'MESH:D010758', (267, 268))	('p', 'Chemical', 'MESH:D010758', (260, 261))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('vascular damage', 'Disease', (73, 88))	('tumor', 'Disease', (147, 152))	('p', 'Chemical', 'MESH:D010758', (188, 189))	('oxygen', 'Chemical', 'MESH:D010100', (164, 170))	('DXR', 'Var', (36, 39))	('depriving', 'NegReg', (137, 146))	('p', 'Chemical', 'MESH:D010758', (139, 140))	('p', 'Chemical', 'MESH:D010758', (187, 188))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('p', 'Chemical', 'MESH:D010758', (200, 201))	('p', 'Chemical', 'MESH:D010758', (1, 2))	('results in', 'Reg', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (237, 242))	('DXR', 'Chemical', 'MESH:D004317', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('TSLs plus hyperthermia', 'Disease', (255, 277))
134341	33105816	Brij78 not only provides pore formation at grain boundaries to enhance release, the PEG moiety provides steric stabilization.	('p', 'Chemical', 'MESH:D010758', (25, 26))	('release', 'MPA', (71, 78))	('enhance', 'PosReg', (63, 70))	('PEG', 'Chemical', 'MESH:D011092', (84, 87))	('p', 'Chemical', 'MESH:D010758', (16, 17))	('p', 'Chemical', 'MESH:D010758', (95, 96))	('Brij78', 'Var', (0, 6))
134342	33105816	Compared to LTSLs composed of DPPC:MSPC:mPEG2000-DSPE (86:10:4 mol%), liposomes of DPPC:Brij78 (96:4 mol%) exhibited similar pharmacokinetics but appeared more effective in an EMT-6 tumor model after a dose of 3 mg DXR/kg and 1 h hyperthermia of 43  C. Later the loading method was changed from pH gradient to Cu2+ gradient, which improves the pharmacokinetics by a 2.5-times slower clearance rate and 2-times more DXR delivery to the heated tumor compared to LTSLs.	('p', 'Chemical', 'MESH:D010758', (333, 334))	('tumor', 'Disease', 'MESH:D009369', (442, 447))	('p', 'Chemical', 'MESH:D010758', (125, 126))	('Brij78', 'Var', (88, 94))	('DPPC:Brij78', 'Var', (83, 94))	('hyperthermia', 'Disease', 'MESH:D005334', (230, 242))	('DXR', 'Chemical', 'MESH:D004317', (415, 418))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('DPPC', 'Chemical', 'MESH:D015060', (30, 34))	('LTSL', 'Chemical', '-', (12, 16))	('pharmacokinetics', 'MPA', (344, 360))	('DPPC', 'Chemical', 'MESH:D015060', (83, 87))	('DXR', 'Chemical', 'MESH:D004317', (215, 218))	('p', 'Chemical', 'MESH:D010758', (21, 22))	('tumor', 'Phenotype', 'HP:0002664', (442, 447))	('p', 'Chemical', 'MESH:D010758', (148, 149))	('DSPE', 'Chemical', 'MESH:C038089', (49, 53))	('hyperthermia', 'Phenotype', 'HP:0001945', (230, 242))	('slower', 'NegReg', (376, 382))	('p', 'Chemical', 'MESH:D010758', (147, 148))	('p', 'Chemical', 'MESH:D010758', (3, 4))	('p', 'Chemical', 'MESH:D010758', (344, 345))	('LTSL', 'Chemical', '-', (460, 464))	('DXR delivery', 'MPA', (415, 427))	('p', 'Chemical', 'MESH:D010758', (232, 233))	('mPEG2000', 'Chemical', '-', (40, 48))	('hyperthermia', 'Disease', (230, 242))	('p', 'Chemical', 'MESH:D010758', (295, 296))	('more', 'PosReg', (410, 414))	('tumor', 'Disease', (182, 187))	('p', 'Chemical', 'MESH:D010758', (72, 73))	('p', 'Chemical', 'MESH:D010758', (451, 452))	('h hyperthermia', 'Phenotype', 'HP:0001945', (228, 242))	('tumor', 'Disease', (442, 447))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('clearance rate', 'MPA', (383, 397))
134344	33105816	Therefore, the lower DXR delivery of LTSLs compared to Brij-TSLs could partly be attributed to overheating of the tumor at 43  C in these experiments.	('p', 'Chemical', 'MESH:D010758', (140, 141))	('LTSLs', 'Var', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('TSL', 'Chemical', '-', (38, 41))	('LTSL', 'Chemical', '-', (37, 41))	('DXR delivery', 'MPA', (21, 33))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('DXR', 'Chemical', 'MESH:D004317', (21, 24))	('p', 'Chemical', 'MESH:D010758', (46, 47))	('TSL', 'Chemical', '-', (60, 63))	('lower', 'NegReg', (15, 20))	('p', 'Chemical', 'MESH:D010758', (71, 72))
134346	33105816	They found that addition of 1.2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPGOG or DPPG2, transition temperature 39.7  C), a derivative of the naturally occurring DPPG, into TSLs composed of DPPC:DSPC:DPPGOG (50:20:30 mol%) results in prolongation of the circulation time of TSLs (t1/2 9.6 h in hamsters and t1/2 5.0 h in rats) and greatly increases the release rate of CF from TSLs in response to mild hyperthermia of 42  C, which was comparable to the fast release from LTSL composed of DPPC:MPPC:mPEG2000-DSPE (90:10:4 mol ratio).	('mPEG2000', 'Chemical', '-', (507, 515))	('DPPG', 'Chemical', 'MESH:C030345', (171, 175))	('p', 'Chemical', 'MESH:D010758', (61, 62))	('DPPC', 'Chemical', 'MESH:D015060', (497, 501))	('release', 'MPA', (362, 369))	('DPPGOG', 'Chemical', '-', (209, 215))	('TSL', 'Chemical', '-', (481, 484))	('DPPG', 'Chemical', 'MESH:C030345', (91, 95))	('glycerol', 'Chemical', 'MESH:D005990', (71, 79))	('DPPG', 'Chemical', 'MESH:C030345', (209, 213))	('p', 'Chemical', 'MESH:D010758', (488, 489))	('LTSL', 'Chemical', '-', (480, 484))	('prolongation', 'PosReg', (243, 255))	('TSL', 'Chemical', '-', (386, 389))	('hyperthermia', 'Disease', 'MESH:D005334', (411, 423))	('TSL', 'Chemical', '-', (283, 286))	('DPPGOG', 'Chemical', '-', (81, 87))	('MPPC', 'Chemical', 'MESH:C086029', (502, 506))	('p', 'Chemical', 'MESH:D010758', (34, 35))	('p', 'Chemical', 'MESH:D010758', (243, 244))	('p', 'Chemical', 'MESH:D010758', (447, 448))	('DPPG', 'Chemical', 'MESH:C030345', (81, 85))	('DPPG', 'Var', (171, 175))	('circulation', 'MPA', (263, 274))	('p', 'Chemical', 'MESH:D010758', (57, 58))	('DSPE', 'Chemical', 'MESH:C038089', (516, 520))	('p', 'Chemical', 'MESH:D010758', (112, 113))	('hyperthermia', 'Phenotype', 'HP:0001945', (411, 423))	('DSPC', 'Chemical', 'MESH:C010942', (204, 208))	('DPPC', 'Chemical', 'MESH:D015060', (199, 203))	('rats', 'Species', '10116', (330, 334))	('increases', 'PosReg', (348, 357))	('p', 'Chemical', 'MESH:D010758', (190, 191))	('p', 'Chemical', 'MESH:D010758', (413, 414))	('p', 'Chemical', 'MESH:D010758', (397, 398))	('TSL', 'Chemical', '-', (182, 185))	('hyperthermia', 'Disease', (411, 423))
134397	33105816	It was found that copolymers of NIPAM with octadecyl acrylate (ODA) can sensitize non-TSLs to heat or increase the sensitivity and response of TSLs at elevated temperature.	('p', 'Chemical', 'MESH:D010758', (134, 135))	('p', 'Chemical', 'MESH:D010758', (20, 21))	('sensitize non-TSLs to heat', 'MPA', (72, 98))	('elevate', 'Disease', 'MESH:D006973', (151, 158))	('copolymers', 'Chemical', '-', (18, 28))	('TSL', 'Chemical', '-', (86, 89))	('response', 'MPA', (131, 139))	('p', 'Chemical', 'MESH:D010758', (163, 164))	('elevate', 'Disease', (151, 158))	('octadecyl acrylate', 'Chemical', '-', (43, 61))	('NIPAM', 'Chemical', '-', (32, 37))	('increase', 'PosReg', (102, 110))	('sensitivity', 'MPA', (115, 126))	('copolymers', 'Var', (18, 28))	('TSL', 'Chemical', '-', (143, 146))	('ODA', 'Chemical', '-', (63, 66))
134412	33105816	Such changes in hydrophilicity and conformational changes have been shown to increase liposomes permeability for the encapsulated drug or may also lead to disintegration of the liposome.	('p', 'Chemical', 'MESH:D010758', (179, 180))	('p', 'Chemical', 'MESH:D010758', (96, 97))	('changes', 'Reg', (5, 12))	('p', 'Chemical', 'MESH:D010758', (21, 22))	('p', 'Chemical', 'MESH:D010758', (121, 122))	('increase liposomes', 'Phenotype', 'HP:0012240', (77, 95))	('disintegration', 'MPA', (155, 169))	('lead to', 'Reg', (147, 154))	('conformational changes', 'Var', (35, 57))	('increase', 'PosReg', (77, 85))	('p', 'Chemical', 'MESH:D010758', (88, 89))	('liposomes permeability for the encapsulated drug', 'MPA', (86, 134))	('hydrophilicity', 'MPA', (16, 30))
134425	33105816	Meanwhile, the PEGylated TSPL exhibited about 55% drug release at 37  C at a pH of 5 mimicking lysosomal condition.	('PEGylated', 'Var', (15, 24))	('PEG', 'Chemical', 'MESH:D011092', (15, 18))	('p', 'Chemical', 'MESH:D010758', (77, 78))	('drug release', 'MPA', (50, 62))
134442	33105816	synthesized a peptide composed of three repeats of VPGVG amino acids, conjugated to a stearyl group (C18) at N-terminus, and amidized the C-terminal (SA-ELP3-NH2).	('amidized', 'Var', (125, 133))	('p', 'Chemical', 'MESH:D010758', (25, 26))	('p', 'Chemical', 'MESH:D010758', (14, 15))	('p', 'Chemical', 'MESH:D010758', (42, 43))	('ELP3', 'Gene', '55140', (153, 157))	('VPGVG', 'Gene', (51, 56))	('C18', 'Chemical', 'MESH:C109760', (101, 104))	('p', 'Chemical', 'MESH:D010758', (16, 17))	('p', 'Chemical', 'MESH:D010758', (98, 99))	('ELP3', 'Gene', (153, 157))
134443	33105816	Incorporation of 1 mol% of this lipopeptide into liposomes composed of DPPC:Chol:mPEG2000-DSPE (76:21:3 mol%) and loaded with DXR resulted in a fast drug release at mild hyperthermia of 42  C with >=95% release within 10 s in the presence of 20% serum, comparable to what was observed with LTSL composed of DPPC:DMPC:mPEG2000-DSPE (90:10:4 mol%).	('p', 'Chemical', 'MESH:D010758', (38, 39))	('LTSL', 'Chemical', '-', (290, 294))	('p', 'Chemical', 'MESH:D010758', (62, 63))	('hyperthermia', 'Phenotype', 'HP:0001945', (170, 182))	('DPPC', 'Chemical', 'MESH:D015060', (307, 311))	('Chol', 'Chemical', '-', (76, 80))	('p', 'Chemical', 'MESH:D010758', (172, 173))	('hyperthermia', 'Disease', (170, 182))	('release', 'MPA', (203, 210))	('p', 'Chemical', 'MESH:D010758', (36, 37))	('DSPE', 'Chemical', 'MESH:C038089', (90, 94))	('p', 'Chemical', 'MESH:D010758', (5, 6))	('p', 'Chemical', 'MESH:D010758', (298, 299))	('p', 'Chemical', 'MESH:D010758', (34, 35))	('Incorporation', 'Var', (0, 13))	('DSPE', 'Chemical', 'MESH:C038089', (326, 330))	('DMPC', 'Chemical', 'MESH:D004134', (312, 316))	('p', 'Chemical', 'MESH:D010758', (51, 52))	('DXR', 'Chemical', 'MESH:D004317', (126, 129))	('p', 'Chemical', 'MESH:D010758', (256, 257))	('mPEG2000', 'Chemical', '-', (81, 89))	('p', 'Chemical', 'MESH:D010758', (230, 231))	('hyperthermia', 'Disease', 'MESH:D005334', (170, 182))	('mPEG2000', 'Chemical', '-', (317, 325))	('mPEG2000-DSPE', 'Var', (81, 94))	('DPPC', 'Chemical', 'MESH:D015060', (71, 75))
134476	29169115	The results showed that CD133, Oct3/4 and TFF1 expression levels, wound healing, and cell migration of EBF1 knockdown-MMNK1 cells were significantly increased.	('cell migration', 'CPA', (85, 99))	('EBF1', 'Gene', '1879', (103, 107))	('Oct3/4', 'Gene', '5460', (31, 37))	('Oct3/4', 'Gene', (31, 37))	('wound healing', 'CPA', (66, 79))	('knockdown-MMNK1', 'Var', (108, 123))	('increased', 'PosReg', (149, 158))	('TFF1', 'Gene', '7031', (42, 46))	('EBF1', 'Gene', (103, 107))	('TFF1', 'Gene', (42, 46))	('CD133', 'Gene', (24, 29))	('expression levels', 'MPA', (47, 64))	('CD133', 'Gene', '8842', (24, 29))
134482	29169115	EBF1 silencing increases stem cell and tumorigenic properties in cholangiocyte cells.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('silencing', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('increases', 'PosReg', (15, 24))	('tumor', 'Disease', (39, 44))	('EBF1', 'Gene', (0, 4))	('EBF1', 'Gene', '1879', (0, 4))
134483	29169115	EBF1 silencing increases oxidative stress resistance in cholangiocyte cells.	('silencing', 'Var', (5, 14))	('oxidative stress', 'Phenotype', 'HP:0025464', (25, 41))	('increases', 'PosReg', (15, 24))	('oxidative stress resistance', 'MPA', (25, 52))	('EBF1', 'Gene', (0, 4))	('EBF1', 'Gene', '1879', (0, 4))
134499	29169115	Moreover, mono-allelic deletions of EBF1 may contribute to block differentiation of mature B cells which lead to leukaemogenesis via increasing of immature B cells that are hallmarks of ALL.	('leukaemogenesis', 'Disease', (113, 128))	('ALL', 'Phenotype', 'HP:0006721', (186, 189))	('immature B cells', 'CPA', (147, 163))	('lead to', 'Reg', (105, 112))	('EBF1', 'Gene', (36, 40))	('increasing', 'PosReg', (133, 143))	('mono-allelic deletions', 'Var', (10, 32))	('EBF1', 'Gene', '1879', (36, 40))	('block differentiation of mature B cells', 'Phenotype', 'HP:0030252', (59, 98))	('block differentiation', 'CPA', (59, 80))
134500	29169115	EBF1 was also found to be suppressed in solid cancers of which EBF1 suppression could be achieved in different ways, such as the genomic loss of 5q32 which encodes for EBF1 in breast cancer.	('EBF1', 'Gene', '1879', (63, 67))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('breast cancer', 'Disease', (176, 189))	('EBF1', 'Gene', '1879', (168, 172))	('EBF1', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('loss', 'Var', (137, 141))	('EBF1', 'Gene', (168, 172))	('EBF1', 'Gene', (63, 67))	('EBF1', 'Gene', '1879', (0, 4))	('5q32', 'Gene', (145, 149))
134501	29169115	In addition, somatic missense mutation that causes the amino acid substitution of arginine for glutamine at position 242 located on DNA binding domain of EBF1 contributes to the EBF1 suppression in pancreatic ductal adenocarcinoma.	('arginine for glutamine at position 242', 'Mutation', 'rs768597902', (82, 120))	('EBF1', 'Gene', '1879', (178, 182))	('amino acid substitution', 'Var', (55, 78))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (198, 230))	('missense mutation', 'Var', (21, 38))	('suppression', 'NegReg', (183, 194))	('pancreatic ductal adenocarcinoma', 'Disease', (198, 230))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (198, 230))	('EBF1', 'Gene', (154, 158))	('EBF1', 'Gene', (178, 182))	('EBF1', 'Gene', '1879', (154, 158))
134502	29169115	Interestingly, EBF1 had been proposed to be the negative regulator of estrogen receptors (ERs), and ERs were reported to promote carcinogenesis including CCA.	('EBF1', 'Gene', (15, 19))	('carcinogenesis', 'Disease', 'MESH:D063646', (129, 143))	('CCA', 'Disease', (154, 157))	('carcinogenesis', 'Disease', (129, 143))	('EBF1', 'Gene', '1879', (15, 19))	('ERs', 'Var', (100, 103))	('promote', 'PosReg', (121, 128))	('CCA', 'Phenotype', 'HP:0030153', (154, 157))
134534	29169115	EBF1, CD133, Oct3/4, TFF1 and beta-actin mRNA expression levels were analyzed with Taqman gene expression assay using Taqman probes (EBF1, Hs00395513_m1, CD133, Hs01009257_m1, Oct3/4, Hs04260367_gH, TFF1, Hs00907239_m1 and beta-actin, Hs99999903_m1) on an ABI-7500 real time PCR system (Applied Biosystems, CA, USA).	('TFF1', 'Gene', '7031', (21, 25))	('EBF1', 'Gene', (133, 137))	('beta-actin', 'Gene', (30, 40))	('TFF1', 'Gene', (21, 25))	('beta-actin', 'Gene', '728378', (223, 233))	('Hs00907239_m1', 'Var', (205, 218))	('Oct3/4', 'Gene', '5460', (13, 19))	('CD133', 'Gene', (6, 11))	('CD133', 'Gene', '8842', (6, 11))	('Hs99999903_m1', 'Var', (235, 248))	('Oct3/4', 'Gene', (13, 19))	('beta-actin', 'Gene', '728378', (30, 40))	('beta-actin', 'Gene', (223, 233))	('Hs04260367_gH', 'Var', (184, 197))	('EBF1', 'Gene', '1879', (0, 4))	('Oct3/4', 'Gene', '5460', (176, 182))	('TFF1', 'Gene', '7031', (199, 203))	('Oct3/4', 'Gene', (176, 182))	('TFF1', 'Gene', (199, 203))	('EBF1', 'Gene', '1879', (133, 137))	('EBF1', 'Gene', (0, 4))	('CD133', 'Gene', (154, 159))	('CD133', 'Gene', '8842', (154, 159))
134542	29169115	To confirm whether EBF1 down-regulation is involved in oxidative stress-resistant property; 1 x 104 cells at 48 h after EBF1 knockdown treatment (media, lipofectamine and siEBF1) were plated into 96 well plates in triplicate.	('knockdown', 'Var', (125, 134))	('EBF1', 'Gene', (19, 23))	('EBF1', 'Gene', (173, 177))	('EBF1', 'Gene', '1879', (19, 23))	('EBF1', 'Gene', '1879', (173, 177))	('EBF1', 'Gene', (120, 124))	('lipofectamine', 'Chemical', 'MESH:C086724', (153, 166))	('oxidative stress', 'Phenotype', 'HP:0025464', (55, 71))	('EBF1', 'Gene', '1879', (120, 124))	('down-regulation', 'NegReg', (24, 39))
134562	29169115	4 shows the effect of EBF1 knockdown on stem cell markers expression.	('knockdown', 'Var', (27, 36))	('expression', 'MPA', (58, 68))	('EBF1', 'Gene', (22, 26))	('EBF1', 'Gene', '1879', (22, 26))	('stem cell markers', 'CPA', (40, 57))
134564	29169115	Following 48 h of transfection, the EBF1 mRNA was significantly decreased, whereas CD133 and Oct3/4 mRNA levels were significantly increased when compared with the control sets as shown in Figs.	('CD133', 'Gene', (83, 88))	('increased', 'PosReg', (131, 140))	('CD133', 'Gene', '8842', (83, 88))	('Oct3/4', 'Gene', '5460', (93, 99))	('EBF1', 'Gene', (36, 40))	('Oct3/4', 'Gene', (93, 99))	('EBF1', 'Gene', '1879', (36, 40))	('transfection', 'Var', (18, 30))	('mRNA', 'MPA', (41, 45))	('decreased', 'NegReg', (64, 73))
134566	29169115	EBF1 protein was slightly expressed, whereas CD133 was highly expressed in EBF1 knockdown-MMNK1 cells when compared to the control, suggesting that suppression of EBF1 associates with stem cell properties.	('suppression', 'Var', (148, 159))	('CD133', 'Gene', (45, 50))	('EBF1', 'Gene', (163, 167))	('CD133', 'Gene', '8842', (45, 50))	('stem cell properties', 'CPA', (184, 204))	('EBF1', 'Gene', '1879', (75, 79))	('EBF1', 'Gene', '1879', (163, 167))	('knockdown-MMNK1', 'Var', (80, 95))	('EBF1', 'Gene', (75, 79))	('EBF1', 'Gene', (0, 4))	('EBF1', 'Gene', '1879', (0, 4))
134572	29169115	Additionally, we also confirmed the ability of EBF1 knockdown-MMNK1 cell in cell migration using a Boyden chamber transwell consisting of a membrane filter insert in 24-well plate with 8-mum pore size.	('mum', 'Gene', (187, 190))	('cell migration', 'CPA', (76, 90))	('knockdown-MMNK1', 'Var', (52, 67))	('EBF1', 'Gene', (47, 51))	('EBF1', 'Gene', '1879', (47, 51))	('mum', 'Gene', '56925', (187, 190))
134573	29169115	The result showed that EBF1 knockdown in MMNK1 cell was significantly increased in cell migration numbers when compared with the controls (P < 0.001) (Figs.	('increased', 'PosReg', (70, 79))	('EBF1', 'Gene', (23, 27))	('knockdown', 'Var', (28, 37))	('EBF1', 'Gene', '1879', (23, 27))	('cell migration numbers', 'CPA', (83, 105))
134576	29169115	We also explored the migration of cholangiocyte cells after EBF1 knockdown and treated with 17beta-estradiol.	('knockdown', 'Var', (65, 74))	('EBF1', 'Gene', '1879', (60, 64))	('17beta-estradiol', 'Chemical', 'MESH:D004958', (92, 108))	('EBF1', 'Gene', (60, 64))
134577	29169115	Our results showed that a significant increase in the number of migrated cells was observed in EBF1 knockdown-MMNK1 cells after being treated with estradiol for 12 h when compared to the EBF1 knockdown-MMNK1cells alone (P < 0.001) as shown in Figs.	('increase', 'PosReg', (38, 46))	('EBF1', 'Gene', (187, 191))	('estradiol', 'Chemical', 'MESH:D004958', (147, 156))	('knockdown-MMNK1', 'Var', (100, 115))	('EBF1', 'Gene', '1879', (187, 191))	('EBF1', 'Gene', (95, 99))	('EBF1', 'Gene', '1879', (95, 99))
134604	29169115	On the other hand, the number of migrated cells significantly increased in the EBF1 knockdown-MMNK1 cells after being treated with 17beta-estradiol.	('increased', 'PosReg', (62, 71))	('EBF1', 'Gene', '1879', (79, 83))	('17beta-estradiol', 'Chemical', 'MESH:D004958', (131, 147))	('knockdown-MMNK1', 'Var', (84, 99))	('EBF1', 'Gene', (79, 83))
134608	29169115	Suppression of EBF1 can induce stem cell and migration properties of the cholangiocytes leading to CCA promotion and progression resulting in CCA development with aggressive clinical outcomes such as short survival time.	('promotion', 'PosReg', (103, 112))	('EBF1', 'Gene', (15, 19))	('induce', 'PosReg', (24, 30))	('Suppression', 'Var', (0, 11))	('CCA', 'Disease', (99, 102))	('EBF1', 'Gene', '1879', (15, 19))	('CCA', 'Phenotype', 'HP:0030153', (142, 145))	('CCA', 'Phenotype', 'HP:0030153', (99, 102))	('CCA', 'Disease', (142, 145))
134658	20202214	Moreover, high MMC V expression showed a statistically significant inverse correlation with the number of lymph node metastases (Pearson's correlation coefficient of -0.314, 2 tailed significance of p < 0.001).	('inverse', 'NegReg', (67, 74))	('MMC', 'Protein', (15, 18))	('expression', 'MPA', (21, 31))	('lymph node metastases', 'Disease', 'MESH:D009362', (106, 127))	('lymph node metastases', 'Disease', (106, 127))	('high', 'Var', (10, 14))
134662	20202214	There was a tendency to better survival in patients who showed high expression of MMC I in their cancer compared with those who had no or low expression of MMC I, although this did not reach statistical significance (Kaplan Meier, Mantel Cox p = 0.08).	('cancer', 'Disease', (97, 103))	('better', 'PosReg', (24, 30))	('patients', 'Species', '9606', (43, 51))	('survival', 'CPA', (31, 39))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('high expression', 'Var', (63, 78))	('MMC I', 'Gene', (82, 87))
134665	20202214	In addition, high expression of MMC V showed inverse correlation with lymph node metastases (r = -0.314, p < 0.001) and high VCMI (r = -0.231, p = 0.018).	('lymph node metastases', 'Disease', 'MESH:D009362', (70, 91))	('lymph node metastases', 'Disease', (70, 91))	('high', 'Var', (13, 17))	('high VCMI', 'CPA', (120, 129))	('inverse', 'NegReg', (45, 52))	('MMC V', 'Gene', (32, 37))
134685	20202214	Moreover, high expression of some of these MMCs (I and V) may be associated with better survival, by suppressing tumour biological factors like proliferative capacity and lymph node metastasis.	('MMCs', 'Gene', (43, 47))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('better', 'PosReg', (81, 87))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('lymph node metastasis', 'CPA', (171, 192))	('tumour', 'Disease', (113, 119))	('high expression', 'Var', (10, 25))	('suppressing', 'NegReg', (101, 112))
134968	29404524	P0708S; New England BioLabs, Inc., Ipswich, MA) to hydrolyze N-glycan chains from Msln.	('P0708S', 'Var', (0, 6))	('N-glycan', 'Chemical', '-', (61, 69))	('P0708S', 'Mutation', 'p.P0708S', (0, 6))	('hydrolyze N-glycan chains', 'MPA', (51, 76))
135002	29404524	6A); in contrast but similar to the BDEneu liver tumor, the BDEneu and BDEneu-Met cell lines each predominantly expressed the 40-kDa Msln band.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('neu', 'Gene', '2064', (74, 77))	('neu', 'Gene', '2064', (39, 42))	('40-kDa Msln', 'Var', (126, 137))	('neu', 'Gene', (74, 77))	('liver tumor', 'Disease', 'MESH:D008113', (43, 54))	('liver tumor', 'Disease', (43, 54))	('neu', 'Gene', (39, 42))	('liver tumor', 'Phenotype', 'HP:0002896', (43, 54))	('neu', 'Gene', '2064', (63, 66))	('expressed', 'Reg', (112, 121))	('neu', 'Gene', (63, 66))
135008	29404524	6A for cultured BDEneu and BDEneu-Met cells compared with TDECC cells; taken together, the data associate loss of luminal Msln immunoreactivity combined with increased expression of 40-kDa Msln to a higher cholangiocarcinoma cell grade and conversely higher 50-kDa Msln expression with strong luminal immunostaining to a lower malignant grade.	('expression', 'MPA', (168, 178))	('luminal Msln', 'Protein', (114, 126))	('cholangiocarcinoma', 'Disease', (206, 224))	('neu', 'Gene', '2064', (30, 33))	('neu', 'Gene', '2064', (19, 22))	('expression', 'MPA', (270, 280))	('higher', 'PosReg', (251, 257))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (206, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('neu', 'Gene', (19, 22))	('neu', 'Gene', (30, 33))	('loss', 'NegReg', (106, 110))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (206, 224))	('40-kDa Msln', 'Var', (182, 193))	('increased', 'PosReg', (158, 167))
135025	29404524	Similar to the western blot findings of others9 for human ICCs and cholangiocarcinoma cell lines, we observed the 40-kDa Msln to be the predominant form being expressed in the BDEneu tumors and cultured BDEneu cholangiocarcinoma cell line as well as in the two cultured human cholangiocarcinoma cell lines that we analyzed.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cholangiocarcinoma', 'Disease', (67, 85))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (210, 228))	('tumors', 'Disease', (183, 189))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))	('cholangiocarcinoma', 'Disease', (210, 228))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (210, 228))	('human', 'Species', '9606', (270, 275))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('40-kDa', 'Var', (114, 120))	('neu', 'Gene', '2064', (206, 209))	('neu', 'Gene', (179, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (285, 294))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (276, 294))	('human', 'Species', '9606', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('neu', 'Gene', '2064', (179, 182))	('cholangiocarcinoma', 'Disease', (276, 294))	('neu', 'Gene', (206, 209))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (276, 294))
135038	29404524	Even more compelling is our finding that the 50-kDa form of Msln was expressed at significantly higher levels compared to the 40-kDa form in the less aggressive BDEsp and TDECC cholangiocarcinomas in situ and polarized TDECC structures formed in 3-D culture that express apical/luminal Msln cell-surface immunoreactivity; the highly tumorigenic and more malignantly aggressive orthotopic BDEneu liver tumors and associated peritoneal metastases and the corresponding BDEneu and BDEneu-Met cell lines, characterized by cytoplasmic Msln immunostaining, loss of cell polarity, and increased anaplasia, significantly overexpressed 40-kDa Msln compared to the 50-kDa form.	('tumor', 'Disease', 'MESH:D009369', (401, 406))	('increased', 'PosReg', (578, 587))	('neu', 'Gene', '2064', (391, 394))	('neu', 'Gene', '2064', (470, 473))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('tumors', 'Phenotype', 'HP:0002664', (401, 407))	('neu', 'Gene', (481, 484))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (177, 195))	('liver tumors', 'Phenotype', 'HP:0002896', (395, 407))	('overexpressed', 'PosReg', (613, 626))	('tumor', 'Phenotype', 'HP:0002664', (401, 406))	('anaplasia', 'Disease', 'MESH:D000708', (588, 597))	('anaplasia', 'Disease', (588, 597))	('Msln', 'Var', (634, 638))	('metastases', 'Disease', 'MESH:D009362', (434, 444))	('malignantly aggressive orthotopic BDEneu liver tumors', 'Disease', 'MESH:D008113', (354, 407))	('neu', 'Gene', (391, 394))	('neu', 'Gene', '2064', (481, 484))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (177, 196))	('neu', 'Gene', (470, 473))	('tumor', 'Disease', (333, 338))	('metastases', 'Disease', (434, 444))	('cholangiocarcinomas', 'Disease', (177, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('liver tumor', 'Phenotype', 'HP:0002896', (395, 406))	('tumor', 'Disease', (401, 406))
135118	26911245	On day 3, Tbil levels were decreased significantly in patients with 3D reconstruction compared with those without, which might be caused by the shorter operation time and milder liver damage.	('Tbil levels', 'MPA', (10, 21))	('liver damage', 'Disease', (178, 190))	('patients', 'Species', '9606', (54, 62))	('decreased', 'NegReg', (27, 36))	('liver damage', 'Disease', 'MESH:D056486', (178, 190))	('Tbil', 'Chemical', '-', (10, 14))	('3D reconstruction', 'Var', (68, 85))
135123	26911245	ALB albumin ALT alanine aminotransferase CT computed tomography LPV left portal vein MPV main portal vein MRI magnetic resonance imaging RAPV right anterior portal vein RPPV right posterior portal vein	('ALB', 'Gene', (0, 3))	('albumin', 'Gene', (4, 11))	('albumin', 'Gene', '213', (4, 11))	('LPV', 'Chemical', '-', (64, 67))	('alanine aminotransferase', 'Gene', (16, 40))	('ALB', 'Gene', '213', (0, 3))	('LPV', 'Var', (64, 67))	('alanine aminotransferase', 'Gene', '2875', (16, 40))
135278	22943044	Strangely, much epidemiologic evidence has suggested a negative association between the presence of mast cells and tumor progression in lung, colon and breast cancers.	('colon and breast cancers', 'Disease', 'MESH:D001943', (142, 166))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('presence', 'Var', (88, 96))	('negative', 'NegReg', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancers', 'Phenotype', 'HP:0003002', (152, 166))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('lung', 'Disease', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
135318	22943044	Inhibiting HDC and antagonizing HlHR decreased histamine synthesis.	('Inhibiting', 'Var', (0, 10))	('histamine synthesis', 'MPA', (47, 66))	('HDC', 'Protein', (11, 14))	('decreased', 'NegReg', (37, 46))	('histamine', 'Chemical', 'MESH:D006632', (47, 56))	('antagonizing', 'Var', (19, 31))
135319	22943044	In vivo methods using a xenograft tumor model were utilized to measure tumor volume after treatment with histamine or inhibition of histamine synthesis by manipulation of HDC.	('histamine', 'Chemical', 'MESH:D006632', (105, 114))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('HDC', 'Gene', (171, 174))	('manipulation', 'Var', (155, 167))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('histamine', 'Chemical', 'MESH:D006632', (132, 141))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
135338	22943044	MCs were positively correlated to serum alanine aminotransferase, a liver enzyme that is an inflammatory marker for hepatic parenchymal damage.	('MCs', 'Var', (0, 3))	('hepatic parenchymal damage', 'Disease', (116, 142))	('alanine aminotransferase', 'Gene', '2875', (40, 64))	('correlated', 'Reg', (20, 30))	('hepatic parenchymal damage', 'Disease', 'MESH:D056486', (116, 142))	('alanine aminotransferase', 'Gene', (40, 64))
135470	28117886	Assuming that HCV infection is causally associated with the cancers, elimination of HCV infection would reduce the risk of the cancers of liver, intrahepatic bile ducts, extrahepatic bile ducts, pancreas, and MDS and DLBCL by 16.14%, 1.15%, 0.50%, 0.13%, 0.41%, and 0.28% respectively.	('extrahepatic bile ducts', 'Disease', (170, 193))	('HCV infection', 'Disease', (84, 97))	('elimination', 'Var', (69, 80))	('MDS', 'Disease', (209, 212))	('intrahepatic bile duct', 'Disease', (145, 167))	('pancreas', 'Disease', (195, 203))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('liver', 'Disease', (138, 143))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('intrahepatic bile duct', 'Disease', 'MESH:D002780', (145, 167))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('pancreas', 'Disease', 'MESH:D010190', (195, 203))	('MDS', 'Phenotype', 'HP:0002863', (209, 212))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('HCV infection', 'Disease', 'MESH:D006526', (14, 27))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('HCV infection', 'Disease', 'MESH:D006526', (84, 97))	('reduce', 'NegReg', (104, 110))	('MDS', 'Disease', 'MESH:D009190', (209, 212))	('HCV infection', 'Disease', (14, 27))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
135528	28601826	Mutations in the genes IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma.	('IDH2', 'Gene', (32, 36))	('isocitrate', 'Chemical', 'MESH:C034219', (38, 48))	('II-IV glioma', 'Disease', 'MESH:D005910', (121, 133))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (145, 176))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (158, 176))	('IDH1', 'Gene', (23, 27))	('occur', 'Reg', (72, 77))	('intrahepatic cholangiocarcinoma', 'Disease', (145, 176))	('IDH2', 'Gene', '3418', (32, 36))	('chondrosarcoma', 'Disease', 'MESH:D002813', (88, 102))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('IDH1', 'Gene', '3417', (23, 27))	('chondrosarcoma', 'Disease', (88, 102))	('II-IV glioma', 'Disease', (121, 133))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (88, 102))
135539	28601826	In addition, IDH1/2 mutations occur in varying percentages of acute lymphocytic leukaemia (10%), acute myeloid leukaemia (AML; 20%), angioimmunoblastic T cell lymphoma (40%), colorectal cancer (5%) and melanoma (12%).	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (103, 120))	('AML', 'Disease', 'MESH:D015470', (122, 125))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (152, 167))	('angioimmunoblastic T cell lymphoma', 'Disease', (133, 167))	('lymphoma', 'Phenotype', 'HP:0002665', (159, 167))	('AML', 'Phenotype', 'HP:0004808', (122, 125))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('AML', 'Disease', (122, 125))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (97, 120))	('acute lymphocytic leukaemia', 'Disease', 'MESH:D054198', (62, 89))	('colorectal cancer', 'Disease', (175, 192))	('IDH1/2', 'Gene', (13, 19))	('acute lymphocytic leukaemia', 'Disease', (62, 89))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (97, 120))	('cell lymphoma', 'Phenotype', 'HP:0012191', (154, 167))	('acute lymphocytic leukaemia', 'Phenotype', 'HP:0006721', (62, 89))	('angioimmunoblastic T cell lymphoma', 'Disease', 'MESH:D016399', (133, 167))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', (202, 210))	('acute myeloid leukaemia', 'Disease', (97, 120))	('mutations', 'Var', (20, 29))	('occur', 'Reg', (30, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))
135540	28601826	In chondrosarcoma and glioma, IDH1/2 mutations are considered very early or even inaugural genetic defects, and are thus present in a large fraction of, or even all, cancer cells.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('chondrosarcoma', 'Disease', (3, 17))	('inaugural genetic defects', 'Disease', 'MESH:D030342', (81, 106))	('inaugural genetic defects', 'Disease', (81, 106))	('IDH1/2', 'Gene', (30, 36))	('glioma', 'Disease', (22, 28))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (3, 17))	('mutations', 'Var', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('glioma', 'Disease', 'MESH:D005910', (22, 28))	('chondrosarcoma', 'Disease', 'MESH:D002813', (3, 17))
135541	28601826	This renders IDH1/2 mutations an interesting target for anticancer treatment because such tumour homogeneity decreases the risk of therapy resistance.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', (60, 66))	('IDH1/2', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('decreases', 'NegReg', (109, 118))	('mutations', 'Var', (20, 29))	('tumour', 'Disease', (90, 96))	('therapy resistance', 'MPA', (131, 149))
135542	28601826	Recently, inhibitors of mutant IDH1 and IDH2 were developed that may be effective in stalling malignant progression of early-stage IDH1/2-mutated cancers.	('mutant', 'Var', (24, 30))	('cancers', 'Disease', (146, 153))	('IDH2', 'Gene', (40, 44))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('IDH1', 'Gene', (131, 135))	('stalling', 'NegReg', (85, 93))	('IDH1', 'Gene', '3417', (31, 35))	('IDH1', 'Gene', '3417', (131, 135))	('IDH2', 'Gene', '3418', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('malignant progression', 'CPA', (94, 115))	('IDH1', 'Gene', (31, 35))
135543	28601826	The prognosis of solid tumours with frequent occurrence of IDH1/2 mutations remains poor.	('mutations', 'Var', (66, 75))	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('solid tumours', 'Disease', 'MESH:D009369', (17, 30))	('IDH1/2', 'Gene', (59, 65))	('solid tumours', 'Disease', (17, 30))
135552	28601826	D-2HG is chemically very similar to alphaKG and inhibits over 60 alphaKG-dependent enzymes, resulting in global DNA/histone hypermethylation, decreased hypoxia-inducible factor 1a expression and perturbed collagen maturation.	('inhibits', 'NegReg', (48, 56))	('D-2HG', 'Var', (0, 5))	('DNA/histone hypermethylation', 'MPA', (112, 140))	('decreased', 'NegReg', (142, 151))	('expression', 'MPA', (180, 190))	('perturbed', 'Reg', (195, 204))	('collagen maturation', 'CPA', (205, 224))	('hypoxia', 'Disease', 'MESH:D000860', (152, 159))	('hypoxia', 'Disease', (152, 159))
135556	28601826	IDH1/2 mutations downregulate alphaKG levels by consuming alphaKG and by inhibition of alphaKG production via direct effects, that is, by disabling IDH1/2 wild-type kinetics, and indirect effects, for example, by decreasing TCA cycle activity.	('disabling', 'NegReg', (138, 147))	('inhibition', 'NegReg', (73, 83))	('downregulate', 'NegReg', (17, 29))	('IDH1/2 wild-type kinetics', 'MPA', (148, 173))	('decreasing', 'NegReg', (213, 223))	('TCA', 'Chemical', 'MESH:D014233', (224, 227))	('TCA cycle activity', 'MPA', (224, 242))	('IDH1/2', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
135560	28601826	Autophagy is inhibited by chloroquine and the anticancer properties of chloroquine may thus be selective for IDH1/2-mutated cells because it inhibits glutaminolysis and autophagy on which the cells are dependent.	('chloroquine', 'Var', (71, 82))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('inhibited', 'NegReg', (13, 22))	('inhibits', 'NegReg', (141, 149))	('autophagy', 'CPA', (169, 178))	('IDH1/2-mutated', 'Gene', (109, 123))	('glutaminolysis', 'MPA', (150, 164))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('Autophagy', 'CPA', (0, 9))	('chloroquine', 'Chemical', 'MESH:D002738', (26, 37))	('chloroquine', 'Chemical', 'MESH:D002738', (71, 82))
135561	28601826	IDH1/2 mutations induce further metabolic stress in IDH1/2-mutated cancer cells via inhibition of the TCA cycle and electron transport chain (ETC) by D-2HG.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('inhibition', 'NegReg', (84, 94))	('TCA', 'Enzyme', (102, 105))	('cancer', 'Disease', (67, 73))	('TCA', 'Chemical', 'MESH:D014233', (102, 105))	('electron transport chain', 'MPA', (116, 140))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('metabolic stress', 'MPA', (32, 48))	('IDH1/2', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
135562	28601826	More specifically, D-2HG inhibits enzymatic activity of complex IV (cytochrome C oxidase) of the ETC and the TCA(-like) enzymes IDH1/2 and alphaKG dehydrogenase.	('TCA', 'Chemical', 'MESH:D014233', (109, 112))	('D-2HG', 'Var', (19, 24))	('inhibits', 'NegReg', (25, 33))	('alphaKG dehydrogenase', 'Enzyme', (139, 160))	('enzymatic activity', 'MPA', (34, 52))
135569	28601826	We and others have shown that IDH1/2 mutations sensitise glioma and colorectal carcinoma cells to therapies that involve oxidative stress, such as radiotherapy, cisplatin and carmustine.	('colorectal carcinoma cells', 'Disease', (68, 94))	('oxidative stress', 'Phenotype', 'HP:0025464', (121, 137))	('glioma', 'Disease', (57, 63))	('IDH1/2', 'Gene', (30, 36))	('mutations', 'Var', (37, 46))	('colorectal carcinoma cells', 'Disease', 'MESH:D015179', (68, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (161, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('sensitise', 'Reg', (47, 56))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('carmustine', 'Chemical', 'MESH:D002330', (175, 185))
135570	28601826	Combined, these data suggest that at least some types of cancer with IDH1/2 mutations should be targeted by compounds that exploit this presumed metabolic vulnerability rather than compounds that decrease metabolic stress (ie, IDH1/2-mutant inhibitors).	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('mutations', 'Var', (76, 85))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('IDH1/2', 'Gene', (69, 75))
135571	28601826	Accordingly, we hypothesised that the difference in survival of patients with IDH1/2-mutated glioma or intrahepatic cholangiocarcinoma versus IDH1/2 wild-type counterparts is caused by dysregulation of cellular defence mechanisms by IDH1/2 mutations against anticancer therapy.	('cancer', 'Disease', (262, 268))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (103, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('glioma', 'Disease', (93, 99))	('patients', 'Species', '9606', (64, 72))	('cellular defence mechanisms', 'CPA', (202, 229))	('dysregulation', 'Reg', (185, 198))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))	('intrahepatic cholangiocarcinoma', 'Disease', (103, 134))	('IDH1/2', 'Gene', (233, 239))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('IDH1/2-mutated', 'Gene', (78, 92))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('mutations', 'Var', (240, 249))
135572	28601826	Little is known about the role of IDH1/2 mutations in late-stage cancer.	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('IDH1/2', 'Gene', (34, 40))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
135573	28601826	It is plausible that with increasing mutational burden, the dependence of late-stage malignant tumours on IDH1/2 mutations decreases, diminishing the therapeutic index of IDH1/2-mutant inhibitors.	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('decreases', 'NegReg', (123, 132))	('therapeutic index', 'MPA', (150, 167))	('mutational', 'Var', (37, 47))	('dependence', 'MPA', (60, 70))	('mutations', 'Var', (113, 122))	('IDH1/2', 'Gene', (106, 112))	('malignant tumours', 'Disease', 'MESH:D009369', (85, 102))	('diminishing', 'NegReg', (134, 145))	('malignant tumours', 'Disease', (85, 102))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
135574	28601826	On the other hand, metabolic stress that results from IDH1/2 mutations persists, and this metabolic vulnerability provides an excellent target for therapy irrespective of the tumour stage.	('tumour', 'Disease', 'MESH:D009369', (175, 181))	('IDH1/2', 'Gene', (54, 60))	('tumour', 'Disease', (175, 181))	('mutations', 'Var', (61, 70))	('metabolic stress', 'MPA', (19, 35))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))
135579	28601826	The potential of metformin and chloroquine as adjuvant drugs was recently demonstrated in vivo, where metformin or chloroquine had a sensitising and/or synergistic antitumour effect in combination with temozolomide, cisplatin and gemcitabine in xenograft models or proof-of-concept clinical trials of various types of human cancer, including glioma.	('chloroquine', 'Chemical', 'MESH:D002738', (115, 126))	('human', 'Species', '9606', (318, 323))	('glioma', 'Disease', (342, 348))	('glioma', 'Disease', 'MESH:D005910', (342, 348))	('cancer', 'Disease', (324, 330))	('gemcitabine', 'Chemical', 'MESH:C056507', (230, 241))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('chloroquine', 'Chemical', 'MESH:D002738', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('metformin', 'Chemical', 'MESH:D008687', (17, 26))	('tumour', 'Disease', (168, 174))	('glioma', 'Phenotype', 'HP:0009733', (342, 348))	('metformin', 'Var', (102, 111))	('sensitising', 'MPA', (133, 144))	('temozolomide', 'Chemical', 'MESH:D000077204', (202, 214))	('metformin', 'Chemical', 'MESH:D008687', (102, 111))	('cancer', 'Disease', 'MESH:D009369', (324, 330))	('cisplatin', 'Chemical', 'MESH:D002945', (216, 225))
135580	28601826	Metformin, but not chloroquine, sensitised xenograft models of various types of human cancer to ionising radiation.	('sensitised', 'Reg', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Metformin', 'Var', (0, 9))	('human', 'Species', '9606', (80, 85))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('chloroquine', 'Chemical', 'MESH:D002738', (19, 30))	('cancer', 'Disease', (86, 92))
135587	28601826	However, phenformin has a less favourable safety compared with metformin because it carries an increased risk of inducing lactic acidosis.	('lactic acidosis', 'Phenotype', 'HP:0003128', (122, 137))	('lactic acidosis', 'Disease', (122, 137))	('phenformin', 'Chemical', 'MESH:D010629', (9, 19))	('metformin', 'Chemical', 'MESH:D008687', (63, 72))	('lactic acidosis', 'Disease', 'MESH:D000140', (122, 137))	('phenformin', 'Var', (9, 19))	('acidosis', 'Phenotype', 'HP:0001941', (129, 137))	('inducing', 'Reg', (113, 121))
135595	28601826	The gold standard of IDH1/2 mutation detection is genetic analysis of tumour DNA.	('IDH1/2', 'Gene', (21, 27))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('mutation', 'Var', (28, 36))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('tumour', 'Disease', (70, 76))
135596	28601826	In glioma, 90% of all IDH1/2 mutations are IDH1R132H and its presence can be reliably detected using a immunohistochemistry of glioma tissue with an IDH1R132H-specific antibody.	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('IDH1', 'Gene', (149, 153))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('mutations', 'Var', (29, 38))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('IDH1', 'Gene', (43, 47))	('IDH1', 'Gene', '3417', (149, 153))	('IDH1', 'Gene', (22, 26))	('glioma', 'Disease', (3, 9))	('IDH1', 'Gene', '3417', (43, 47))	('IDH1', 'Gene', '3417', (22, 26))	('glioma', 'Disease', (127, 133))
135597	28601826	The presence of IDH1/2 mutations in AML and intrahepatic cholangiocarcinoma can be easily, reliably and non-invasively detected via determination of 2HG levels or D-2HG levels in serum or urine by mass spectrometry (MS).	('AML', 'Disease', 'MESH:D015470', (36, 39))	('intrahepatic cholangiocarcinoma', 'Disease', (44, 75))	('D-2HG', 'MPA', (163, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('IDH1/2', 'Gene', (16, 22))	('AML', 'Disease', (36, 39))	('AML', 'Phenotype', 'HP:0004808', (36, 39))	('mutations', 'Var', (23, 32))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (44, 75))	('2HG levels', 'MPA', (149, 159))
135599	28601826	In a previous study investigating intrahepatic cholangiocarcinoma, total 2HG levels in serum predicted the presence of an IDH1/2 mutation (as determined using targeted DNA sequencing) with a sensitivity of 83% and a specificity of 90%.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (47, 65))	('mutation', 'Var', (129, 137))	('intrahepatic cholangiocarcinoma', 'Disease', (34, 65))	('IDH1/2', 'Gene', (122, 128))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (34, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
135600	28601826	Whereas no non-invasive detection methods of IDH1/2 mutations have been described to be effective in chondrosarcoma yet, the presence of IDH1/2 mutations in glioma can be determined using magnetic resonance spectroscopy (MRS) of the brain, which detects intratumoural 2HG levels.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (101, 115))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('MRS', 'Disease', (221, 224))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('chondrosarcoma', 'Disease', 'MESH:D002813', (101, 115))	('IDH1/2', 'Gene', (137, 143))	('tumoural', 'Disease', 'MESH:D009369', (259, 267))	('tumoural', 'Disease', (259, 267))	('chondrosarcoma', 'Disease', (101, 115))	('MRS', 'Disease', 'MESH:D008556', (221, 224))	('tumour', 'Phenotype', 'HP:0002664', (259, 265))	('glioma', 'Disease', (157, 163))	('mutations', 'Var', (144, 153))
135601	28601826	Conversely, serum 2HG levels correlate poorly with the IDH1/2 mutational status in glioma due to a limited BBB passage of D-2HG.	('glioma', 'Disease', (83, 89))	('mutational status', 'Var', (62, 79))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('IDH1/2', 'Gene', (55, 61))
135603	28601826	Most aforementioned measurements determined total 2HG levels and thus did not discriminate between the D-enantiomer of 2HG (which is specific for IDH1/2 mutations) and the L-enantiomer of 2HG (which is unspecific and is generated during hypoxia).	('determined', 'Reg', (33, 43))	('IDH1/2', 'Gene', (146, 152))	('2HG levels', 'MPA', (50, 60))	('mutations', 'Var', (153, 162))	('hypoxia', 'Disease', (237, 244))	('hypoxia', 'Disease', 'MESH:D000860', (237, 244))
135604	28601826	Besides methods that detect D-2HG accumulation, IDH1/2 mutations may also be detected via next-generation sequencing (NGS) of circulating tumour DNA (ctDNA) that is isolated from serum as liquid biopsies.	('mutations', 'Var', (55, 64))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('IDH1/2', 'Gene', (48, 54))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('tumour', 'Disease', (138, 144))
135607	28601826	In liquid biopsies, variant allelic frequencies can be used as biomarkers for tumour load and dynamic clonal hierarchies within the tumour.	('tumour', 'Disease', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('tumour', 'Disease', (78, 84))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('variant', 'Var', (20, 27))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
135608	28601826	To summarise, fundamental and translational research by us and others revealed that IDH1/2 mutations impart therapeutically targetable metabolic vulnerabilities to cells from several types of cancer.	('IDH1/2', 'Gene', (84, 90))	('cancer', 'Disease', (192, 198))	('mutations', 'Var', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('metabolic vulnerabilities', 'MPA', (135, 160))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
135610	28601826	Furthermore, we aim to specifically inhibit the metabolic processes that are essential to IDH1/2-mutated tumours using metformin and chloroquine, which specifically target the metabolic vulnerabilities that are caused by IDH1/2 mutations.	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('IDH1/2', 'Gene', (221, 227))	('chloroquine', 'Chemical', 'MESH:D002738', (133, 144))	('metabolic', 'MPA', (48, 57))	('IDH1/2-mutated', 'Gene', (90, 104))	('inhibit', 'NegReg', (36, 43))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('tumours', 'Disease', (105, 112))	('mutations', 'Var', (228, 237))	('metformin', 'Chemical', 'MESH:D008687', (119, 128))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
135617	28601826	to describe the toxic effects and pharmacokinetics of metformin plus chloroquine in patients with IDH1/2-mutated chondrosarcoma, glioma or intrahepatic cholangiocarcinoma; to provide evidence of complete or partial tumour regression in patients with IDH1/2-mutated chondrosarcoma, glioma or intrahepatic cholangiocarcinoma after treatment with metformin plus chloroquine; to provide evidence that the IDH1/2 mutational status of chondrosarcoma, glioma and intrahepatic cholangiocarcinoma can be assessed using enantiomer-specific measurements that determine the separate D-2HG and L-2HG levels in serum, urine or bile (with better sensitivity and specificity than with measurements that determine total 2HG concentrations); to provide evidence that the IDH1/2 mutational status of patients with chondrosarcoma and intrahepatic cholangiocarcinoma can be determined by MRS-facilitated detection of intratumoural 2HG levels or liquid biopsies; to provide evidence of activity of metformin plus chloroquine related to D-2HG levels in the serum, urine, bile and/or tumoural mass of patients with IDH1/2-mutated chondrosarcoma, glioma or intrahepatic cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (478, 487))	('tumour', 'Phenotype', 'HP:0002664', (1060, 1066))	('intrahepatic cholangiocarcinoma', 'Disease', (814, 845))	('chondrosarcoma', 'Disease', (429, 443))	('carcinoma', 'Phenotype', 'HP:0030731', (1154, 1163))	('carcinoma', 'Phenotype', 'HP:0030731', (836, 845))	('tumour regression', 'Disease', (215, 232))	('glioma', 'Disease', (281, 287))	('tumoural mass', 'Disease', 'MESH:C536030', (1060, 1073))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (139, 170))	('tumoural', 'Disease', 'MESH:D009369', (901, 909))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (1106, 1120))	('chondrosarcoma', 'Disease', (795, 809))	('intrahepatic cholangiocarcinoma', 'Disease', (139, 170))	('chondrosarcoma', 'Disease', 'MESH:D002813', (795, 809))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (265, 279))	('tumoural', 'Disease', 'MESH:D009369', (1060, 1068))	('tumour', 'Phenotype', 'HP:0002664', (901, 907))	('glioma', 'Disease', 'MESH:D005910', (281, 287))	('patients', 'Species', '9606', (1077, 1085))	('patients', 'Species', '9606', (84, 92))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (456, 487))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (304, 322))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (113, 127))	('IDH1/2-mutated', 'Var', (1091, 1105))	('patients', 'Species', '9606', (236, 244))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (429, 443))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (1145, 1163))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (827, 845))	('intrahepatic cholangiocarcinoma', 'Disease', (456, 487))	('glioma', 'Disease', (1122, 1128))	('tumoural', 'Disease', (901, 909))	('glioma', 'Disease', (129, 135))	('chloroquine', 'Chemical', 'MESH:D002738', (359, 370))	('MRS', 'Disease', 'MESH:D008556', (867, 870))	('patients', 'Species', '9606', (781, 789))	('metformin', 'Chemical', 'MESH:D008687', (344, 353))	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (281, 287))	('tumoural', 'Disease', (1060, 1068))	('glioma', 'Disease', 'MESH:D005910', (1122, 1128))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (795, 809))	('D-2HG levels', 'MPA', (1014, 1026))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (152, 170))	('MRS', 'Disease', (867, 870))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (469, 487))	('glioma', 'Disease', (445, 451))	('tumoural mass', 'Disease', (1060, 1073))	('activity', 'MPA', (964, 972))	('tumour regression', 'Disease', 'MESH:D009365', (215, 232))	('tumour', 'Phenotype', 'HP:0002664', (215, 221))	('glioma', 'Disease', 'MESH:D005910', (445, 451))	('metformin', 'Chemical', 'MESH:D008687', (976, 985))	('chondrosarcoma', 'Disease', 'MESH:D002813', (1106, 1120))	('glioma', 'Phenotype', 'HP:0009733', (1122, 1128))	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('chloroquine', 'Chemical', 'MESH:D002738', (991, 1002))	('metformin', 'Chemical', 'MESH:D008687', (54, 63))	('chondrosarcoma', 'Disease', (1106, 1120))	('chondrosarcoma', 'Disease', 'MESH:D002813', (265, 279))	('chondrosarcoma', 'Disease', 'MESH:D002813', (429, 443))	('chondrosarcoma', 'Disease', (265, 279))	('glioma', 'Phenotype', 'HP:0009733', (445, 451))	('chloroquine', 'Chemical', 'MESH:D002738', (69, 80))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (1132, 1163))	('chondrosarcoma', 'Disease', 'MESH:D002813', (113, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('intrahepatic cholangiocarcinoma', 'Disease', (1132, 1163))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (291, 322))	('chondrosarcoma', 'Disease', (113, 127))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (814, 845))	('intrahepatic cholangiocarcinoma', 'Disease', (291, 322))
135624	28601826	The variant allelic frequency of IDH1 mutations or IDH2 mutations will be measured using NGS on liquid biopsies at the start and end of the treatment and every 4 weeks during treatment to determine the effects of metformin plus chloroquine on the variant allelic frequency and mutational load of these mutations.	('IDH2', 'Gene', '3418', (51, 55))	('mutations', 'Var', (56, 65))	('IDH1', 'Gene', (33, 37))	('IDH1', 'Gene', '3417', (33, 37))	('metformin', 'Chemical', 'MESH:D008687', (213, 222))	('IDH2', 'Gene', (51, 55))	('chloroquine', 'Chemical', 'MESH:D002738', (228, 239))
135634	28601826	Tumour carries a D-2HG-generating mutation in IDH1 or IDH2 as determined by sequencing of primary tumour DNA, immunohistochemistry of primary tumour tissue with an IDH1/2 mutant-specific antibody, or MRS imaging of the tumour (for patients with glioma).	('tumour', 'Disease', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (219, 225))	('IDH2', 'Gene', (54, 58))	('IDH2', 'Gene', '3418', (54, 58))	('tumour', 'Disease', 'MESH:D009369', (219, 225))	('tumour', 'Disease', (219, 225))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (245, 251))	('IDH1', 'Gene', (46, 50))	('mutation', 'Var', (34, 42))	('D-2HG-generating', 'Reg', (17, 33))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Disease', (98, 104))	('MRS', 'Disease', 'MESH:D008556', (200, 203))	('IDH1', 'Gene', '3417', (46, 50))	('IDH1', 'Gene', (164, 168))	('glioma', 'Disease', 'MESH:D005910', (245, 251))	('MRS', 'Disease', (200, 203))	('patients', 'Species', '9606', (231, 239))	('glioma', 'Disease', (245, 251))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('IDH1', 'Gene', '3417', (164, 168))
135671	28601826	In a patient with glioma, the presence of an IDH1/2 mutation can also be established using MRS to detect intratumoural 2HG levels.	('patient', 'Species', '9606', (5, 12))	('glioma', 'Disease', (18, 24))	('tumoural', 'Disease', 'MESH:D009369', (110, 118))	('tumoural', 'Disease', (110, 118))	('MRS', 'Disease', (91, 94))	('glioma', 'Disease', 'MESH:D005910', (18, 24))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('IDH1/2', 'Gene', (45, 51))	('mutation', 'Var', (52, 60))	('MRS', 'Disease', 'MESH:D008556', (91, 94))
135699	28601826	Tumour volumes (from CT/MRI scans), serum metformin, chloroquine and D-2HG concentrations (from MRS/MS measurements), and IDH1/2 mutational loads (from NGS) from before, during and after treatment time points will be compared using the paired samples t-test.	('MRS', 'Disease', 'MESH:D008556', (96, 99))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('IDH1/2', 'Gene', (122, 128))	('mutational', 'Var', (129, 139))	('MRS', 'Disease', (96, 99))	('metformin', 'Chemical', 'MESH:D008687', (42, 51))	('chloroquine', 'Chemical', 'MESH:D002738', (53, 64))
135741	26470769	Accordingly, modulation of IGF-1R signaling could represent a strategy for the management of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (93, 111))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('IGF-1R', 'Gene', (27, 33))	('modulation', 'Var', (13, 23))	('IGF-1R', 'Gene', '3480', (27, 33))
135780	26470769	Caspase-3 activity, which plays a central role in the execution-phase of cell apoptosis, was also significantly and dose-dependently increased by simvastatin (Fig.	('Caspase-3', 'Gene', (0, 9))	('activity', 'MPA', (10, 18))	('simvastatin', 'Var', (146, 157))	('simvastatin', 'Chemical', 'MESH:D019821', (146, 157))	('increased', 'PosReg', (133, 142))	('Caspase-3', 'Gene', '836', (0, 9))
135797	26470769	A study demonstrated that lipophilic, but not hydrophilic, statins induce cell death in melanoma cells via inhibition of hypoxia-inducible factor 1alpha expression, nonenzymatic antioxidant levels, and superoxide dismutase activity.	('nonenzymatic antioxidant levels', 'MPA', (165, 196))	('cell death', 'CPA', (74, 84))	('activity', 'MPA', (223, 231))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('lipophilic', 'Var', (26, 36))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('superoxide dismutase', 'Enzyme', (202, 222))	('hypoxia-inducible factor 1alpha', 'Gene', '3091', (121, 152))	('hypoxia-inducible factor 1alpha', 'Gene', (121, 152))	('expression', 'MPA', (153, 163))	('inhibition', 'NegReg', (107, 117))
135811	26470769	Therefore, modulation of IGF-1R may be an important strategy for the management of cholangiocarcinoma.	('modulation', 'Var', (11, 21))	('cholangiocarcinoma', 'Disease', (83, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('IGF-1R', 'Gene', '3480', (25, 31))	('IGF-1R', 'Gene', (25, 31))
135819	26470769	In some epidemiological studies, statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes, and a small to considerable reduction in the risk of colon cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('hepatocellular carcinoma', 'Disease', (79, 103))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (79, 103))	('reduced', 'NegReg', (63, 70))	('reduction', 'NegReg', (177, 186))	('statins', 'Var', (33, 40))	('colon cancer', 'Phenotype', 'HP:0003003', (202, 214))	('colon cancer', 'Disease', 'MESH:D015179', (202, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('diabetes', 'Disease', (139, 147))	('diabetes', 'Disease', 'MESH:D003920', (139, 147))	('colon cancer', 'Disease', (202, 214))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (79, 103))	('patients', 'Species', '9606', (125, 133))
135914	24699315	We observed that inhibition of miR-21 significantly decreased cell growth (p<0.01) and reduced colonogenic efficiency (p<0.01) (Figure 2C and 2D).	('decreased', 'NegReg', (52, 61))	('miR-21', 'Gene', (31, 37))	('inhibition', 'Var', (17, 27))	('reduced colonogenic efficiency', 'Disease', (87, 117))	('reduced colonogenic efficiency', 'Disease', 'MESH:D015354', (87, 117))	('cell growth', 'CPA', (62, 73))
135923	24699315	To document the role of the putative miR-21 binding site for regulation of 15-PGDH in cholangiocarcinoma cells, we co-transfected miR-21 mimic with 15-PGDH wild type or mutant 3'UTR reporter plasmid.	('15-PGDH', 'Gene', (75, 82))	('15-PGDH', 'Gene', '873', (75, 82))	('cholangiocarcinoma cells', 'Disease', 'MESH:D018281', (86, 110))	('15-PGDH', 'Gene', '873', (148, 155))	('mutant', 'Var', (169, 175))	('cholangiocarcinoma cells', 'Disease', (86, 110))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (86, 104))	('miR-21', 'Gene', (130, 136))	('15-PGDH', 'Gene', (148, 155))
135926	24699315	As cyclooxygenase-2 (COX-2) is a rate-limiting key enzyme that mediates PGE2 synthesis, we also examined the level of COX-2 protein and found that miR-21 did not alter the expression of COX-2 (data not shown).	('COX-2', 'Gene', '5743', (21, 26))	('COX-2', 'Gene', (186, 191))	('COX-2', 'Gene', '5743', (186, 191))	('miR-21', 'Var', (147, 153))	('COX-2', 'Gene', (118, 123))	('COX-2', 'Gene', '5743', (118, 123))	('PGE2', 'Chemical', 'MESH:D015232', (72, 76))	('cyclooxygenase-2', 'Gene', '5743', (3, 19))	('cyclooxygenase-2', 'Gene', (3, 19))	('COX-2', 'Gene', (21, 26))
135933	24699315	Thus, miR-21 reduces 15-PGDH level and enhances cholangiocarcinoma growth, both in vitro and in vivo.	('reduces', 'NegReg', (13, 20))	('15-PGDH', 'Gene', '873', (21, 28))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (48, 73))	('enhances', 'PosReg', (39, 47))	('15-PGDH', 'Gene', (21, 28))	('miR-21', 'Var', (6, 12))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (48, 66))	('cholangiocarcinoma growth', 'Disease', (48, 73))
135936	24699315	COX-2 overexpression also increased miR-21 level in H69 cells (Supplemental Figure S4).	('H69', 'CellLine', 'CVCL:8121', (52, 55))	('overexpression', 'Var', (6, 20))	('miR-21 level', 'MPA', (36, 48))	('increased', 'PosReg', (26, 35))	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (0, 5))
135953	24699315	This conclusion is based on the following findings: (1) miR-21 binding site was identified in the 3'UTR of 15-PGDH mRNA by sequence alignment analysis; (2) miR-21 overexpression decreased 15-PGDH mRNA and protein levels; and (3) transfection of miR-21 mimic decreased 15-PGDH 3'UTR luciferase reporter activity and the effect was abolished by miR-21 seed binding site mutation.	('15-PGDH', 'Gene', (107, 114))	('15-PGDH', 'Gene', '873', (188, 195))	('decreased', 'NegReg', (178, 187))	('decreased', 'NegReg', (258, 267))	('15-PGDH', 'Gene', (188, 195))	('15-PGDH', 'Gene', '873', (268, 275))	('mutation', 'Var', (368, 376))	('15-PGDH', 'Gene', '873', (107, 114))	('miR-21', 'Gene', (156, 162))	('15-PGDH', 'Gene', (268, 275))
135964	24699315	Thus, blocking COX2/PGE2 signaling in combination with targeting miR-21 may represent a promising therapeutic strategy for the treatment of human cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (146, 164))	('human', 'Species', '9606', (140, 145))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (146, 164))	('PGE2', 'Chemical', 'MESH:D015232', (20, 24))	('miR-21', 'Gene', (65, 71))	('cholangiocarcinoma', 'Disease', (146, 164))	('COX2/PGE2 signaling', 'MPA', (15, 34))	('targeting', 'Var', (55, 64))	('blocking', 'NegReg', (6, 14))
136023	23637956	Consistent with the above results, the pU6-NGF-beta-shRNA transfection caused tumor growth inhibition and decreased the size of the colonies (P<0.05; Figure 2B and D).	('decreased', 'NegReg', (106, 115))	('NGF-beta', 'Gene', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('size of the colonies', 'CPA', (120, 140))	('NGF-beta', 'Gene', '4803', (43, 51))	('transfection', 'Var', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
136029	23637956	The corresponding percentages of the cells transfected with pU6-NC and pU6-NGF-beta-shRNA were 15.95+-0.72% and 10.07+-1.01%, respectively (Figure 3B).	('NGF-beta', 'Gene', '4803', (75, 83))	('NGF-beta', 'Gene', (75, 83))	('pU6-NC', 'Var', (60, 66))
136033	23637956	We have previously demonstrated that the expression of NGF-beta was associated with lymph node metastasis in human hilar cholangiocarcinoma.	('human', 'Species', '9606', (109, 114))	('associated', 'Reg', (68, 78))	('lymph node metastasis', 'CPA', (84, 105))	('cholangiocarcinoma', 'Disease', (121, 139))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (121, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('NGF-beta', 'Gene', (55, 63))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))	('expression', 'Var', (41, 51))	('NGF-beta', 'Gene', '4803', (55, 63))
136039	23637956	In contrast, co-culture with QBC939 stable cell lines with silenced NGF-beta reduced the proliferation and migration of LECs (Figure 4B and D; Figure S3).	('proliferation', 'CPA', (89, 102))	('migration', 'CPA', (107, 116))	('LEC', 'Gene', (120, 123))	('LEC', 'Gene', '6360', (120, 123))	('silenced', 'Var', (59, 67))	('NGF-beta', 'Gene', '4803', (68, 76))	('NGF-beta', 'Gene', (68, 76))	('reduced', 'NegReg', (77, 84))	('QBC939', 'CellLine', 'CVCL:6942', (29, 35))
136078	21490883	Polycystic liver disease (PLD) is a genetic inherited entity associated with polycystic renal disease due to mutations in PKD1 or PKD2 genes.	('liver disease', 'Phenotype', 'HP:0001392', (11, 24))	('PKD2', 'Gene', (130, 134))	('PKD1', 'Gene', (122, 126))	('renal disease', 'Phenotype', 'HP:0000112', (88, 101))	('Polycystic liver disease', 'Phenotype', 'HP:0006557', (0, 24))	('PLD', 'Phenotype', 'HP:0006557', (26, 29))	('polycystic renal disease', 'Disease', (77, 101))	('polycystic renal disease', 'Disease', 'MESH:D007690', (77, 101))	('PKD2', 'Gene', '5311', (130, 134))	('polycystic renal disease', 'Phenotype', 'HP:0000113', (77, 101))	('Polycystic liver disease', 'Disease', (0, 24))	('mutations', 'Var', (109, 118))	('PKD1', 'Gene', '5310', (122, 126))	('Polycystic liver disease', 'Disease', 'MESH:C536330', (0, 24))
136079	21490883	A rarer PRKCSH gene mutation exists and is associated with isolated multiple liver cysts.	('associated with', 'Reg', (43, 58))	('multiple liver cysts', 'Disease', (68, 88))	('mutation', 'Var', (20, 28))	('PRKCSH', 'Gene', '5589', (8, 14))	('multiple liver cysts', 'Disease', 'MESH:D008113', (68, 88))	('PRKCSH', 'Gene', (8, 14))	('liver cysts', 'Phenotype', 'HP:0001407', (77, 88))	('liver cyst', 'Phenotype', 'HP:0001407', (77, 87))
136087	21490883	Liver function tests were compatible with obstructive jaundice, with total bilirubin 8.07 mg/dl (normal range <1 mg/dl), with direct predominance (7.51 mg/dl) and elevation of alkaline phosphatase (337 U/l, normal range 50-136U/l) and gamma-GT (404 U/l, normal range 15-85 U/l).	('elevation', 'PosReg', (163, 172))	('obstructive jaundice', 'Disease', (42, 62))	('bilirubin', 'Chemical', 'MESH:D001663', (75, 84))	('337 U/l', 'Var', (198, 205))	('jaundice', 'Phenotype', 'HP:0000952', (54, 62))	('alkaline phosphatase', 'MPA', (176, 196))	('gamma-GT', 'MPA', (235, 243))	('obstructive jaundice', 'Disease', 'MESH:D041781', (42, 62))	('elevation of alkaline phosphatase', 'Phenotype', 'HP:0003155', (163, 196))	('total bilirubin', 'MPA', (69, 84))
136098	21490883	Autosomal dominant polycystic disease is genetically heterogeneous, with mutations in two distinct genes predisposing to the combination of renal and liver cysts (AD-PKD1 and AD-PKD2).	('liver cyst', 'Phenotype', 'HP:0001407', (150, 160))	('AD-PKD1 and AD-PKD2', 'Disease', 'MESH:D000544', (163, 182))	('predisposing', 'Reg', (105, 117))	('Autosomal dominant polycystic disease', 'Disease', (0, 37))	('renal and liver cysts', 'Disease', 'MESH:C536330', (140, 161))	('Autosomal dominant polycystic disease', 'Disease', 'MESH:C536324', (0, 37))	('liver cysts', 'Phenotype', 'HP:0001407', (150, 161))	('mutations', 'Var', (73, 82))
136173	33363768	Immunohistochemistry showed positivity for CK7 (biliary origin marker) (Figure 3B).	('CK7', 'Gene', '3855', (43, 46))	('positivity', 'Var', (28, 38))	('CK7', 'Gene', (43, 46))
136240	31258745	When silencing UCA1, Vimentin and N-cadherin were decreased with enhanced expression of E-cadherin.	('expression', 'MPA', (74, 84))	('E-cadherin', 'Gene', (88, 98))	('N-cadherin', 'Gene', (34, 44))	('Vimentin', 'Gene', '7431', (21, 29))	('E-cadherin', 'Gene', '999', (88, 98))	('UCA1', 'Gene', '652995', (15, 19))	('silencing', 'Var', (5, 14))	('N-cadherin', 'Gene', '1000', (34, 44))	('UCA1', 'Gene', (15, 19))	('enhanced', 'PosReg', (65, 73))	('decreased', 'NegReg', (50, 59))	('Vimentin', 'Gene', (21, 29))
136250	31258745	Inhibition of Wnt signaling in animal models can markedly reduce cancer cell proliferation and increase apoptosis, resulting in tumor regression.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Wnt', 'Gene', '114487', (14, 17))	('rat', 'Species', '10116', (84, 87))	('increase', 'PosReg', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('reduce', 'NegReg', (58, 64))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (128, 133))	('Wnt', 'Gene', (14, 17))	('apoptosis', 'CPA', (104, 113))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
136254	31258745	After treating with Wnt inhibitors ICG-001 and C-59 in rat CCA models, uc.158- (an intergenic 224nt T-UCR located at chromosome 5) was reduced and cancer cell growth was depressed.	('rat', 'Species', '10116', (55, 58))	('depressed', 'Disease', 'MESH:D000275', (170, 179))	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('ICG', 'Chemical', 'MESH:D007208', (35, 38))	('CCA', 'Phenotype', 'HP:0030153', (59, 62))	('Wnt', 'Gene', (20, 23))	('reduced', 'NegReg', (135, 142))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('CCA', 'Disease', (59, 62))	('depressed', 'Disease', (170, 179))	('Wnt', 'Gene', '114487', (20, 23))	('uc.158-', 'Var', (71, 78))
136256	31258745	It is well known that abnormal glutamine is characteristic in tumor tissues and related to tumorigenesis and development.	('glutamine', 'Protein', (31, 40))	('related', 'Reg', (80, 87))	('glutamine', 'Chemical', 'MESH:D005973', (31, 40))	('development', 'CPA', (109, 120))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('abnormal', 'Var', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
136266	31258745	Moreover, CPS1 was depressed by silencing CPS1-IT1, resulting in reduced cell proliferation and enhanced apoptosis.	('reduced', 'NegReg', (65, 72))	('CPS1-IT1', 'Gene', '29034;1373;79441', (42, 50))	('depressed', 'Disease', 'MESH:D000275', (19, 28))	('enhanced', 'PosReg', (96, 104))	('CPS1-IT1', 'Gene', (42, 50))	('apoptosis', 'CPA', (105, 114))	('rat', 'Species', '10116', (85, 88))	('CPS1', 'Gene', (10, 14))	('silencing', 'Var', (32, 41))	('CPS1', 'Gene', (42, 46))	('cell proliferation', 'CPA', (73, 91))	('CPS1', 'Gene', '1373', (10, 14))	('depressed', 'Disease', (19, 28))	('CPS1', 'Gene', '1373', (42, 46))
136278	31258745	It directly binds with EZH2, then epigenetically silencing targeting genes by regulating H3K27me3.	('regulating', 'Reg', (78, 88))	('epigenetically', 'Var', (34, 48))	('targeting genes', 'Gene', (59, 74))	('H3K27me3', 'Protein', (89, 97))	('binds', 'Interaction', (12, 17))	('EZH2', 'Gene', '2146', (23, 27))	('EZH2', 'Gene', (23, 27))
136281	31258745	Silencing SNHG1 leads to high expression of CDKN1A with lower tumor proliferation and higher apoptosis in CCA cell lines.	('expression', 'MPA', (30, 40))	('SNHG1', 'Gene', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('CCA', 'Phenotype', 'HP:0030153', (106, 109))	('rat', 'Species', '10116', (75, 78))	('CDKN1A', 'Gene', (44, 50))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', (62, 67))	('lower', 'NegReg', (56, 61))	('CDKN1A', 'Gene', '1026', (44, 50))	('higher', 'PosReg', (86, 92))	('apoptosis', 'CPA', (93, 102))	('SNHG1', 'Gene', '23642', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
136300	31258745	The high expression of lncRNA CCAT1 could be an independent unfavorable prognostic biomarker for CCA.	('CCA', 'Disease', (97, 100))	('CCAT1', 'Gene', '100507056', (30, 35))	('CCA', 'Phenotype', 'HP:0030153', (97, 100))	('high', 'Var', (4, 8))	('CCAT1', 'Gene', (30, 35))	('CCA', 'Phenotype', 'HP:0030153', (30, 33))
136305	31258745	Knocking down or silencing lncRNA in CCA decreases cell proliferation, migration and invasion and promotes cell apoptosis in vitro.	('rat', 'Species', '10116', (63, 66))	('promotes', 'PosReg', (98, 106))	('decreases', 'NegReg', (41, 50))	('lncRNA', 'Gene', (27, 33))	('CCA', 'Disease', (37, 40))	('rat', 'Species', '10116', (74, 77))	('migration', 'CPA', (71, 80))	('invasion', 'CPA', (85, 93))	('cell proliferation', 'CPA', (51, 69))	('CCA', 'Phenotype', 'HP:0030153', (37, 40))	('silencing', 'Var', (17, 26))	('cell apoptosis', 'CPA', (107, 121))
136386	30197484	The results of the subanalysis in the validation set based on the tumor size demonstrated that the diagnostic performance of the CEUS score nomogram (AUC = 0.929) was far superior to that of the LI-RADS nomogram (AUC = 0.835) in differentiating a <= 5.0 cm ICC from HCC (P = 0.008).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('HCC', 'Gene', '619501', (266, 269))	('HCC', 'Phenotype', 'HP:0001402', (266, 269))	('ICC', 'Disease', (257, 260))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('<= 5.0 cm', 'Var', (247, 256))	('HCC', 'Gene', (266, 269))
136412	30197484	We performed subgroup analysis according to the tumor size and found that the CEUS score significantly improved the discriminative performance in the <= 5.0 cm subgroup compared to the LI-RADS.	('tumor', 'Disease', (48, 53))	('discriminative performance', 'MPA', (116, 142))	('improved', 'PosReg', (103, 111))	('<= 5.0 cm', 'Var', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
136414	30197484	Since the NRI and IDI were decreased in the <= 3.0 cm lesions, the LI-RADS nomogram was superior to the CEUS score nomogram for small lesions, while the CEUS score nomogram was recommended for lesions larger than 3.0 cm.	('decreased', 'NegReg', (27, 36))	('<= 3.0 cm', 'Var', (44, 53))	('men', 'Species', '9606', (182, 185))
136542	28970730	The demand for more cases to reach significance is also based on the fact that only a portion of the dysplasias, or even CCAs, presented with aneuploid DNA.	('aneuploid', 'Var', (142, 151))	('dysplasias', 'Disease', (101, 111))	('CCA', 'Phenotype', 'HP:0030153', (121, 124))	('presented', 'Reg', (127, 136))	('dysplasias', 'Disease', 'MESH:D004476', (101, 111))	('CCA', 'Gene', (121, 124))	('CCA', 'Gene', '2201', (121, 124))
136551	28970730	These findings suggest that CA19-9 and CEA are late markers, and they cannot be used for the detection of premalignant lesions.	('CA19-9', 'Var', (28, 34))	('CEA', 'Gene', '1084', (39, 42))	('CA19-9', 'Chemical', 'MESH:C086528', (28, 34))	('CEA', 'Gene', (39, 42))
136554	28970730	ALP is generally elevated at PSC diagnosis, and normalisation of ALP is associated with a better prognosis.	('PSC', 'Gene', (29, 32))	('PSC', 'Gene', '100653366', (29, 32))	('ALP', 'Gene', '250', (0, 3))	('ALP', 'Gene', '250', (65, 68))	('normalisation', 'Var', (48, 61))	('elevated', 'PosReg', (17, 25))	('ALP', 'Gene', (0, 3))	('ALP', 'Gene', (65, 68))
136600	23091390	Moreover, loss of E-cadherin was retained as an independent prognostic factor for patients with intrahepatic cholangiocarcinoma in multivariate analysis.	('loss', 'Var', (10, 14))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('patients', 'Species', '9606', (82, 90))	('intrahepatic cholangiocarcinoma', 'Disease', (96, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('E-cadherin', 'Gene', (18, 28))	('E-cadherin', 'Gene', '999', (18, 28))
136657	23091390	Furthermore, loss of E-cadherin had an independent prognostic value in predicting outcomes in patients with primary intrahepatic cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('patients', 'Species', '9606', (94, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (129, 147))	('primary intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (108, 147))	('E-cadherin', 'Gene', (21, 31))	('E-cadherin', 'Gene', '999', (21, 31))	('loss', 'Var', (13, 17))	('primary intrahepatic cholangiocarcinoma', 'Disease', (108, 147))
136668	23091390	We propose that EMT markers would have clinical implications for clinical classification; furthermore, inhibition of EMT might offer a novel promising target for the treatment of patients with intrahepatic cholangiocarcinoma.	('EMT', 'Gene', (117, 120))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (193, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('inhibition', 'Var', (103, 113))	('patients', 'Species', '9606', (179, 187))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (206, 224))	('intrahepatic cholangiocarcinoma', 'Disease', (193, 224))
136805	32164049	Univariate analysis identified the following predictors of survival: posthepatectomy liver failure (PHLF; International Study Group of Liver Surgery grade B or C, p < 0.001), histologic differentiation (poorly differentiated, moderate differentiated vs. well differentiated, p=0.005), T category (T3, p=0.001 and T4, p=0.004), N category (N1 and N2, p < 0.001), distant metastasis (p < 0.001), intraoperative transfusion (p=0.001), resection margin (R1 vs. R0, p < 0.001), and lymphovascular invasion (p < 0.001).	('poorly', 'Var', (203, 209))	('distant metastasis', 'CPA', (362, 380))	('liver failure', 'Phenotype', 'HP:0001399', (85, 98))	('liver failure', 'Disease', 'MESH:D017093', (85, 98))	('liver failure', 'Disease', (85, 98))	('lymphovascular invasion', 'CPA', (477, 500))
136841	30228815	SHMT2 knockdown in hepatocellular cancer cell lines was found to reduce cell growth and tumorigenicity in vitro and in vivo.	('cell growth', 'CPA', (72, 83))	('hepatocellular cancer', 'Disease', (19, 40))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (19, 40))	('tumorigenicity', 'CPA', (88, 102))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('reduce', 'NegReg', (65, 71))	('knockdown', 'Var', (6, 15))	('SHMT2', 'Gene', (0, 5))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (19, 40))
136861	30228815	found that glycine decarboxylase (GLDC) was upregulated in SHMT2 overexpressed 3T3 cells and whether or not GLDC is responsible for the cell proliferation induced by SHMT2 remains to be explored.	('overexpressed', 'Var', (65, 78))	('GLDC', 'Gene', '104174', (108, 112))	('upregulated', 'PosReg', (44, 55))	('glycine decarboxylase', 'Gene', '104174', (11, 32))	('GLDC', 'Gene', (34, 38))	('glycine decarboxylase', 'Gene', (11, 32))	('GLDC', 'Gene', (108, 112))	('GLDC', 'Gene', '104174', (34, 38))	('SHMT2', 'Gene', (59, 64))
136866	30006612	Genomic analyses of tumors confirmed known and identified new (gains in 19q) copy number alterations (CNA).	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumors', 'Disease', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('copy number alterations', 'Var', (77, 100))
136867	30006612	Tumors with LNM (N1) had more alterations and exclusive gains (3p, 4q, 5p, 13q) and losses (17p and 20p).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('losses', 'NegReg', (84, 90))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('LNM', 'Var', (12, 15))	('gains', 'PosReg', (56, 61))
136868	30006612	LNM shared most alterations with their matched tumors (86%), but 79% acquired new isolated gains [12q14 (36%); 1p13, 2p23, 7p22, 7q11, 11q12, 13q13 and 14q12 (>20%)].	('tumors', 'Disease', (47, 53))	('1p13', 'Var', (111, 115))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('2p23', 'Var', (117, 121))	('7p22', 'Var', (123, 127))	('7q11', 'Var', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
136870	30006612	TP53 and KRAS mutations occurred in 19% of tumors and 6% of metastases.	('TP53', 'Gene', (0, 4))	('KRAS', 'Gene', (9, 13))	('metastases', 'Disease', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('metastases', 'Disease', 'MESH:D009362', (60, 70))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('mutations', 'Var', (14, 23))	('occurred', 'Reg', (24, 32))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
136883	30006612	Therefore the aim of our study was (1) to analyze copy number alterations in intrahepatic cholangiocarcinomas and their corresponding lymph node metastases and (2) to analyze and correlate clinical and histopathological factors.	('metastases', 'Disease', (145, 155))	('intrahepatic cholangiocarcinomas', 'Disease', (77, 109))	('metastases', 'Disease', 'MESH:D009362', (145, 155))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (77, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('copy number alterations', 'Var', (50, 73))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))
136892	30006612	Patients with LNM developed significantly more (11 vs. 5, p = 0.012, Supplementary Table 3) and earlier distant metastases than those with N0 tumors (8 vs. 17 months).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('N0 tumors', 'Disease', 'MESH:D009369', (139, 148))	('N0 tumors', 'Disease', (139, 148))	('LNM', 'Var', (14, 17))	('metastases', 'Disease', (112, 122))	('Patients', 'Species', '9606', (0, 8))	('more', 'PosReg', (42, 46))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))
136895	30006612	In addition, the maximum amount of CNAs was higher in N1 (3-161 CNAs) compared to N0 tumors (4-137 CNAs) (Supplementary Fig.	('N1 (3-161 CNAs', 'Var', (54, 68))	('N0 tumors', 'Disease', 'MESH:D009369', (82, 91))	('higher', 'PosReg', (44, 50))	('N0 tumors', 'Disease', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
136897	30006612	Nodal positive primary tumors showed significant additional gains and losses compared to N0 tumors.	('Nodal', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('N0 tumors', 'Disease', 'MESH:D009369', (89, 98))	('gains', 'PosReg', (60, 65))	('primary tumors', 'Disease', (15, 29))	('N0 tumors', 'Disease', (89, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('losses', 'NegReg', (70, 76))	('primary tumors', 'Disease', 'MESH:D009369', (15, 29))
136911	30006612	We performed mutational analyses for the common and cancer-relevant mutations in the genes KRAS and TP53.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('TP53', 'Gene', (100, 104))	('cancer', 'Disease', (52, 58))	('mutations', 'Var', (68, 77))	('KRAS', 'Gene', (91, 95))
136912	30006612	Mutational analysis (18 N1 primary tumors and 18 matched lymph node metastases) revealed mutations of TP53 in six samples (19%) and mutations of KRAS in two samples (6%).	('TP53', 'Gene', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('primary tumors', 'Disease', (27, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('primary tumors', 'Disease', 'MESH:D009369', (27, 41))	('mutations', 'Var', (89, 98))	('metastases', 'Disease', (68, 78))	('metastases', 'Disease', 'MESH:D009362', (68, 78))
136913	30006612	Of the six TP53 mutations, four were detected for Exon 7 (11%) and two for Exon 5 (six %) (4 mutations were found in primary tumors, 2 in LNM).	('primary tumors', 'Disease', (117, 131))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('TP53', 'Gene', (11, 15))	('primary tumors', 'Disease', 'MESH:D009369', (117, 131))	('mutations', 'Var', (16, 25))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))
136914	30006612	The KRAS mutations were detected for Exon 2 (both were found in primary tumors).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('primary tumors', 'Disease', 'MESH:D009369', (64, 78))	('KRAS', 'Var', (4, 8))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('primary tumors', 'Disease', (64, 78))
136915	30006612	Mutations in the primary tumor were also detected in the corresponding lymph node metastasis, except for one sample.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('lymph node metastasis', 'CPA', (71, 92))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
136917	30006612	Interestingly, the amount of CNAs did not differ between tumors with TP53 inactivating mutations and those without.	('TP53', 'Gene', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('inactivating mutations', 'Var', (74, 96))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
136925	30006612	LNM have been identified as an important prognostic factor therefore, we aimed to analyze copy number alterations in primary tumors along with their matched LNM and together with important clinical factors.	('primary tumors', 'Disease', (117, 131))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('primary tumors', 'Disease', 'MESH:D009369', (117, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('copy', 'Var', (90, 94))
136930	30006612	Accordingly, the in silico pathway analyses revealed that chromosomal gains of N1 tumors harbor genes involved in pathways important for tumor progression and metastasis, such as the MAPK-, Wnt-, JAK-STAT-, PPAR-, TGF-beta-, p53-, VEGF- and mTOR-signaling pathways.	('p53', 'Gene', (225, 228))	('PPAR-', 'Pathway', (207, 212))	('N1 tumors', 'Disease', (79, 88))	('VEGF-', 'Gene', (231, 236))	('tumor', 'Disease', (82, 87))	('gains', 'PosReg', (70, 75))	('mTOR', 'Gene', (241, 245))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('mTOR', 'Gene', '2475', (241, 245))	('tumor', 'Disease', (137, 142))	('N1 tumors', 'Disease', 'MESH:D009369', (79, 88))	('VEGF-', 'Gene', '7422', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('chromosomal', 'Var', (58, 69))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('Wnt-', 'Pathway', (190, 194))	('TGF-beta-', 'Pathway', (214, 223))	('p53', 'Gene', '7157', (225, 228))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
136932	30006612	In addition, gains on 13q have been reported to play an important role for esophagus and bladder cancer, gliomas and glioblastomas, but not yet for iCCA.	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('gains', 'Var', (13, 18))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('13q', 'Gene', (22, 25))	('gliomas', 'Disease', (105, 112))	('bladder cancer', 'Disease', (89, 103))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('glioblastomas', 'Phenotype', 'HP:0012174', (117, 130))	('esophagus', 'Disease', (75, 84))	('glioblastomas', 'Disease', 'MESH:D005909', (117, 130))	('glioblastomas', 'Disease', (117, 130))
136934	30006612	Overexpression of the latter was also significantly associated with poor survival in cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (85, 103))	('poor', 'NegReg', (68, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('Overexpression', 'Var', (0, 14))	('cholangiocarcinoma', 'Disease', (85, 103))
136937	30006612	It could recently be shown, that the metastatic potential of cholangiocarcinoma cells can be increased by the deletion of TP53, underscoring its role for the development of metastasis.	('TP53', 'Gene', (122, 126))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('increased', 'PosReg', (93, 102))	('metastatic potential of', 'CPA', (37, 60))	('deletion', 'Var', (110, 118))	('cholangiocarcinoma', 'Disease', (61, 79))
136938	30006612	We also detected mutations for TP53 in four N1 tumors and two matched LNM.	('N1 tumors', 'Disease', 'MESH:D009369', (44, 53))	('detected', 'Reg', (8, 16))	('TP53', 'Gene', (31, 35))	('N1 tumors', 'Disease', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (17, 26))
136945	30006612	TBK1 was successfully targeted in oral squamous cell carcinoma and osteosarcoma leading to a decrease in tumor activity and MDM2 amplifications are known to be involved in tumorigenesis of liposarcoma.	('amplifications', 'Var', (129, 143))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (34, 62))	('tumor', 'Disease', (172, 177))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('oral squamous cell carcinoma', 'Disease', (34, 62))	('decrease', 'NegReg', (93, 101))	('MDM2', 'Gene', '4193', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('TBK1', 'Gene', '29110', (0, 4))	('involved', 'Reg', (160, 168))	('liposarcoma', 'Phenotype', 'HP:0012034', (189, 200))	('TBK1', 'Gene', (0, 4))	('tumor', 'Disease', (105, 110))	('osteosarcoma', 'Disease', (67, 79))	('liposarcoma', 'Disease', 'MESH:D008080', (189, 200))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('osteosarcoma', 'Disease', 'MESH:D012516', (67, 79))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('targeted', 'Var', (22, 30))	('liposarcoma', 'Disease', (189, 200))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('MDM2', 'Gene', (124, 128))	('osteosarcoma', 'Phenotype', 'HP:0002669', (67, 79))
136949	30006612	This poor prognosis group harbored significantly more CNAs including chromosomal alterations at 7p, 9p and 17q that have previously been described to be related to poor tumor differentiation and worse survival in iCCA.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('iCCA', 'Disease', (213, 217))	('chromosomal alterations', 'Var', (69, 92))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('CNAs', 'Disease', (54, 58))	('tumor', 'Disease', (169, 174))
136959	30006612	For the first time, a matched analysis of primary iCCA tumors and their corresponding LNM was performed showing highly similar CNAs with very specific novel alterations in the LNM.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('alterations', 'Var', (157, 168))
136990	30006612	Regions with isolated amplifications in lymph node metastases compared to their corresponding primary tumors were further analyzed for known genes and matched against the Therapeutic Targets Database (TTD).	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('metastases', 'Disease', 'MESH:D009362', (51, 61))	('primary tumors', 'Disease', (94, 108))	('primary tumors', 'Disease', 'MESH:D009369', (94, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('amplifications', 'Var', (22, 36))	('metastases', 'Disease', (51, 61))
137003	29084594	Further, the administration of miR-200b induced a remarkably tumor regression in vivo and reduced the effect of TGF-beta-related EMT in AP-2alpha and MAPK7-dependent manner.	('reduced', 'NegReg', (90, 97))	('AP-2alpha', 'Gene', (136, 145))	('MAPK7', 'Gene', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('TGF-beta', 'Gene', '7040', (112, 120))	('miR-200b', 'Var', (31, 39))	('effect', 'MPA', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('AP-2alpha', 'Gene', '7020', (136, 145))	('TGF-beta', 'Gene', (112, 120))	('tumor', 'Disease', (61, 66))	('MAPK7', 'Gene', '5598', (150, 155))
137010	29084594	Mounting evidences indicated that tumor microenvironment harbored aberrant TGF-beta expression activated the expression of transcription factor Slug/Snail2, ZEB1, and ZEB2, and contributed to the initiation of EMT.	('Snail2', 'Gene', '6591', (149, 155))	('Slug', 'Gene', (144, 148))	('ZEB1', 'Gene', (157, 161))	('aberrant', 'Var', (66, 74))	('TGF-beta', 'Gene', '7040', (75, 83))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('TGF-beta', 'Gene', (75, 83))	('Slug', 'Gene', '6591', (144, 148))	('EMT', 'CPA', (210, 213))	('initiation', 'PosReg', (196, 206))	('contributed', 'Reg', (177, 188))	('ZEB1', 'Gene', '6935', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('expression', 'MPA', (109, 119))	('activated', 'PosReg', (95, 104))	('ZEB2', 'Gene', (167, 171))	('Snail2', 'Gene', (149, 155))	('ZEB2', 'Gene', '9839', (167, 171))
137014	29084594	The miR-200 family, including miR-200a, miR-200b, miR-200c, miR-141, and miR-429, suppresses metastasis in EMT by targeting and reciprocally repressing ZEB1 to regulate EMT and invasion in cancer cells.	('miR-141', 'Gene', (60, 67))	('miR-200b', 'Var', (40, 48))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('miR-200', 'Chemical', '-', (30, 37))	('ZEB1', 'Gene', '6935', (152, 156))	('miR-200a', 'Gene', (30, 38))	('miR-200c', 'Gene', '406985', (50, 58))	('suppresses', 'NegReg', (82, 92))	('miR-429', 'Gene', (73, 80))	('invasion', 'CPA', (177, 185))	('miR-200c', 'Gene', (50, 58))	('miR-200', 'Gene', (4, 11))	('EMT', 'CPA', (169, 172))	('miR-200', 'Chemical', '-', (4, 11))	('miR-200', 'Chemical', '-', (50, 57))	('cancer', 'Disease', (189, 195))	('ZEB1', 'Gene', (152, 156))	('miR-200a', 'Gene', '406983', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('miR-429', 'Gene', '554210', (73, 80))	('miR-141', 'Gene', '406933', (60, 67))	('miR-200', 'Chemical', '-', (40, 47))	('metastasis in EMT', 'CPA', (93, 110))
137022	29084594	Several studies have demonstrated an association between aberrant activator protein-2 (AP-2) and protein kinase MAPK7, which is critical for the malignant transformation in EMT.	('MAPK7', 'Gene', (112, 117))	('AP-2', 'Gene', (87, 91))	('protein', 'Protein', (97, 104))	('activator protein-2', 'Gene', (66, 85))	('activator protein-2', 'Gene', '7020', (66, 85))	('AP-2', 'Gene', '7020', (87, 91))	('MAPK7', 'Gene', '5598', (112, 117))	('aberrant', 'Var', (57, 65))
137024	29084594	The anti-tumor ability of miR-200b in vivo indicated its efficiency as potential treatment strategy in the treatment of CCA.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('CCA', 'Phenotype', 'HP:0030153', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('miR-200b', 'Var', (26, 34))	('tumor', 'Disease', (9, 14))	('CCA', 'Disease', (120, 123))
137030	29084594	Reporter plasmid of full-length 3'-UTR (wild-type or mutant) of TFAP2A and MAPK7 mRNA and pGL-3-TGFB1 was conducted by GenePharma (Shanghai, China).	('MAPK7', 'Gene', (75, 80))	('TFAP2A', 'Gene', (64, 70))	('pGL-3', 'Gene', '6391', (90, 95))	('TGFB1', 'Gene', '7040', (96, 101))	('pGL-3', 'Gene', (90, 95))	('TFAP2A', 'Gene', '7020', (64, 70))	('TGFB1', 'Gene', (96, 101))	('mutant', 'Var', (53, 59))	('MAPK7', 'Gene', '5598', (75, 80))
137032	29084594	The HCCC and RBE cells were cultured to about 80% confluence in 6-well plates and, using Lipofectamine 2000 (Invitrogen, USA), the cells were transfected with miR-200b, pcDNA3.0-TFAP2A, and MAPK7 and pGL-3-TGFB1 according to the manufacturer's instructions.	('TGFB1', 'Gene', '7040', (206, 211))	('pGL-3', 'Gene', '6391', (200, 205))	('TFAP2A', 'Gene', (178, 184))	('TGFB1', 'Gene', (206, 211))	('MAPK7', 'Gene', '5598', (190, 195))	('pGL-3', 'Gene', (200, 205))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (89, 107))	('TFAP2A', 'Gene', '7020', (178, 184))	('MAPK7', 'Gene', (190, 195))	('miR-200b', 'Var', (159, 167))
137033	29084594	After the transfection for indicated time, HCCC and RBE cells were harvested and washed with PBS and cell counting kit-8 (Kumamoto, Japan) mixed with DMEM was used for cell viability assay.	('DMEM', 'Chemical', '-', (150, 154))	('transfection', 'Var', (10, 22))	('PBS', 'Disease', 'MESH:D011535', (93, 96))	('PBS', 'Disease', (93, 96))
137058	29084594	Overexpression of miR-200b in two cells was demonstrated to abrogate the switch to fibroblastic-like cell phenotype by repressing the expression of fibronectin and alpha-SMA induced by TGF-beta (Fig.	('TGF-beta', 'Gene', (185, 193))	('expression', 'MPA', (134, 144))	('a-SMA', 'Gene', '58', (168, 173))	('abrogate', 'NegReg', (60, 68))	('fibronectin', 'Gene', (148, 159))	('repressing', 'NegReg', (119, 129))	('TGF-beta', 'Gene', '7040', (185, 193))	('a-SMA', 'Gene', (168, 173))	('fibronectin', 'Gene', '2335', (148, 159))	('miR-200b', 'Var', (18, 26))
137059	29084594	Besides, overexpression of miR-200b inhibit the TGF-beta-induced upregulation of migration and invasion (Fig.	('overexpression', 'PosReg', (9, 23))	('TGF-beta', 'Gene', (48, 56))	('inhibit', 'NegReg', (36, 43))	('miR-200b', 'Var', (27, 35))	('upregulation', 'PosReg', (65, 77))	('TGF-beta', 'Gene', '7040', (48, 56))
137061	29084594	2e), despite the treatment of TGF-beta, which suggested that miR-200b could not only inhibit the EMT of tumor cell, but also impair the cell proliferation in CCA.	('CCA', 'Phenotype', 'HP:0030153', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('miR-200b', 'Var', (61, 69))	('tumor', 'Disease', (104, 109))	('inhibit', 'NegReg', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('impair', 'NegReg', (125, 131))	('TGF-beta', 'Gene', '7040', (30, 38))	('CCA', 'Disease', (158, 161))	('TGF-beta', 'Gene', (30, 38))	('cell proliferation', 'CPA', (136, 154))
137064	29084594	To conform this, a luciferase reporter vector, with full-length 3'-UTR (wild-type or mutant) of TFAP2A, was transfected into HCCC cell-line.	('TFAP2A', 'Gene', (96, 102))	('mutant', 'Var', (85, 91))	('TFAP2A', 'Gene', '7020', (96, 102))
137071	29084594	The results showed that, while miR-200b could prevent the EMT, overexpression of AP-2alpha significantly increased the level of TGF-beta to restore the EMT phenotype of HCCC cell (Fig.	('TGF-beta', 'Gene', '7040', (128, 136))	('level', 'MPA', (119, 124))	('TGF-beta', 'Gene', (128, 136))	('AP-2alpha', 'Gene', (81, 90))	('restore', 'PosReg', (140, 147))	('EMT', 'MPA', (152, 155))	('miR-200b', 'Var', (31, 39))	('increased', 'PosReg', (105, 114))	('AP-2alpha', 'Gene', '7020', (81, 90))	('EMT', 'CPA', (58, 61))
137074	29084594	Upon analyzing the 3'-UTR of MAPK7, it was observed that MAPK7 harbored a binding site of miR-200b.	('miR-200b', 'Var', (90, 98))	('MAPK7', 'Gene', (29, 34))	('MAPK7', 'Gene', '5598', (57, 62))	('MAPK7', 'Gene', '5598', (29, 34))	('MAPK7', 'Gene', (57, 62))	('binding', 'Interaction', (74, 81))
137075	29084594	Luciferase reporter assays indicated that miR-200b mimics could significantly decrease the luciferase activity of wild-type MAPK7-3'UTR, but not the mutant-type (Fig.	('decrease', 'NegReg', (78, 86))	('luciferase', 'Enzyme', (91, 101))	('MAPK7', 'Gene', '5598', (124, 129))	('mimics', 'Var', (51, 57))	('activity', 'MPA', (102, 110))	('MAPK7', 'Gene', (124, 129))	('miR-200b', 'Gene', (42, 50))
137077	29084594	Further, overexpression of MAPK7 in HCCC cells could upregulate the TGF-beta expression, repress the expression of E-cadherin and TTF-1, and promote the expression of fibronectin and alpha-SMA in order to re-activate the miR-200b-induced inhibition of EMT (Fig.	('inhibition', 'NegReg', (238, 248))	('a-SMA', 'Gene', '58', (187, 192))	('expression', 'MPA', (153, 163))	('fibronectin', 'Gene', (167, 178))	('TGF-beta', 'Gene', (68, 76))	('E-cadherin', 'Gene', (115, 125))	('E-cadherin', 'Gene', '999', (115, 125))	('upregulate', 'PosReg', (53, 63))	('overexpression', 'Var', (9, 23))	('promote', 'PosReg', (141, 148))	('repress', 'NegReg', (89, 96))	('a-SMA', 'Gene', (187, 192))	('re-activate', 'PosReg', (205, 216))	('MAPK7', 'Gene', (27, 32))	('fibronectin', 'Gene', '2335', (167, 178))	('TTF-1', 'Gene', '7080', (130, 135))	('TTF-1', 'Gene', (130, 135))	('expression', 'MPA', (77, 87))	('MAPK7', 'Gene', '5598', (27, 32))	('TGF-beta', 'Gene', '7040', (68, 76))	('expression', 'MPA', (101, 111))
137082	29084594	Mechanistically, overexpression of miR-200b in HCCC cells decreased the expression of cyclin D1 and Cdk2 in order to induce cell cycle arrest and was able restore their expression for the growth of tumor cells (Fig.	('cyclin D1', 'Gene', (86, 95))	('Cdk2', 'Gene', (100, 104))	('arrest', 'Disease', 'MESH:D006323', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('decreased', 'NegReg', (58, 67))	('restore', 'PosReg', (155, 162))	('expression', 'MPA', (72, 82))	('induce', 'PosReg', (117, 123))	('arrest', 'Disease', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('overexpression', 'PosReg', (17, 31))	('expression', 'MPA', (169, 179))	('miR-200b', 'Var', (35, 43))	('tumor', 'Disease', (198, 203))	('Cdk2', 'Gene', '1017', (100, 104))	('cyclin D1', 'Gene', '595', (86, 95))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (124, 141))
137085	29084594	The results showed that the mice treated with miR-200b mimics showed a delayed tumor growth, with less tumor weight and volume, than those treated with PBS or negative control (Fig.	('miR-200b', 'Gene', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (79, 84))	('PBS', 'Disease', (152, 155))	('PBS', 'Disease', 'MESH:D011535', (152, 155))	('tumor', 'Disease', (103, 108))	('mice', 'Species', '10090', (28, 32))	('less', 'NegReg', (98, 102))	('mimics', 'Var', (55, 61))	('delayed', 'NegReg', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
137087	29084594	It was observed that the treatment of miR-200b significantly abrogated the AP-2alpha/MAPK7/TGF-beta expression (Fig.	('AP-2alpha', 'Gene', (75, 84))	('MAPK7', 'Gene', (85, 90))	('TGF-beta', 'Gene', '7040', (91, 99))	('expression', 'MPA', (100, 110))	('TGF-beta', 'Gene', (91, 99))	('abrogated', 'NegReg', (61, 70))	('miR-200b', 'Var', (38, 46))	('AP-2alpha', 'Gene', '7020', (75, 84))	('MAPK7', 'Gene', '5598', (85, 90))
137101	29084594	In addition, ectopic expression of miR-200b could abrogate the switch to fibroblastic-like cell phenotype by repressing the expression of fibronectin and alpha-SMA induced by TGF-beta, and could inhibit the tumor cell vitality and proliferation.	('switch to fibroblastic-like cell phenotype', 'CPA', (63, 105))	('inhibit', 'NegReg', (195, 202))	('abrogate', 'NegReg', (50, 58))	('fibronectin', 'Gene', (138, 149))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('miR-200b', 'Var', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('TGF-beta', 'Gene', '7040', (175, 183))	('expression', 'MPA', (124, 134))	('a-SMA', 'Gene', (158, 163))	('repressing', 'NegReg', (109, 119))	('ectopic expression', 'Var', (13, 31))	('tumor', 'Disease', (207, 212))	('a-SMA', 'Gene', '58', (158, 163))	('fibronectin', 'Gene', '2335', (138, 149))	('TGF-beta', 'Gene', (175, 183))
137107	29084594	Since TFAP2A (encode AP-2alpha) could be directly targeted by miR-200b, decreased miR-200b enhanced AP-2alpha/ TGF-beta signals in CCA for tumor metastasis.	('TGF-beta', 'Gene', '7040', (111, 119))	('tumor metastasis', 'Disease', (139, 155))	('CCA', 'Disease', (131, 134))	('AP-2alpha', 'Gene', '7020', (100, 109))	('CCA', 'Phenotype', 'HP:0030153', (131, 134))	('AP-2alpha', 'Gene', (21, 30))	('decreased', 'NegReg', (72, 81))	('TGF-beta', 'Gene', (111, 119))	('TFAP2A', 'Gene', (6, 12))	('miR-200b', 'Var', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('AP-2alpha', 'Gene', (100, 109))	('TFAP2A', 'Gene', '7020', (6, 12))	('tumor metastasis', 'Disease', 'MESH:D009362', (139, 155))	('AP-2alpha', 'Gene', '7020', (21, 30))	('enhanced', 'PosReg', (91, 99))
137109	29084594	Inhibition of MAPK7 blocked the TGF-beta1 signal for Smad3 transcriptional activity via acetylation and regulated TGF-beta1-induced pulmonary fibrosis.	('MAPK7', 'Gene', '5598', (14, 19))	('Smad3', 'Gene', (53, 58))	('pulmonary fibrosis', 'Disease', (132, 150))	('Smad3', 'Gene', '4088', (53, 58))	('transcriptional activity', 'MPA', (59, 83))	('acetylation', 'MPA', (88, 99))	('MAPK7', 'Gene', (14, 19))	('TGF-beta1', 'Gene', '7040', (114, 123))	('TGF-beta1', 'Gene', (114, 123))	('Inhibition', 'Var', (0, 10))	('blocked', 'NegReg', (20, 27))	('TGF-beta1', 'Gene', '7040', (32, 41))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (132, 150))	('TGF-beta1', 'Gene', (32, 41))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (132, 150))
137110	29084594	In human glioma, MAPK7 was found to be a direct target gene of miR-200b and was essential to the miR-200b-induced inhibition of glioma tumor growth, invasion and EMT.	('glioma tumor', 'Disease', (128, 140))	('glioma', 'Disease', (9, 15))	('inhibition', 'NegReg', (114, 124))	('MAPK7', 'Gene', '5598', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('glioma', 'Disease', (128, 134))	('glioma tumor', 'Disease', 'MESH:D005910', (128, 140))	('human', 'Species', '9606', (3, 8))	('EMT', 'CPA', (162, 165))	('MAPK7', 'Gene', (17, 22))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Disease', 'MESH:D005910', (9, 15))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('miR-200b', 'Gene', (63, 71))	('miR-200b-induced', 'Var', (97, 113))	('invasion', 'CPA', (149, 157))
137120	29084594	These findings showed that the miR-200b-based gene therapy could be conducive in the treatment of CCA patients.	('miR-200b-based', 'Var', (31, 45))	('CCA', 'Disease', (98, 101))	('CCA', 'Phenotype', 'HP:0030153', (98, 101))	('patients', 'Species', '9606', (102, 110))
137171	27342988	Vascular endothelial growth factor (VEGF) is expressed in approximately 50 % of intrahepatic cholangiocarcinomas, and anti-VEGF treatments result in pruning of the tumor vasculature and reductions in vessel tortuosity.	('tumor', 'Disease', (164, 169))	('reductions', 'NegReg', (186, 196))	('intrahepatic cholangiocarcinomas', 'Disease', (80, 112))	('VEGF', 'Gene', '7422', (123, 127))	('VEGF', 'Gene', (36, 40))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (80, 112))	('Vascular endothelial growth factor', 'Gene', '7422', (0, 34))	('VEGF', 'Gene', (123, 127))	('vessel tortuosity', 'Phenotype', 'HP:0004948', (200, 217))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('vessel tortuosity', 'CPA', (200, 217))	('pruning', 'CPA', (149, 156))	('VEGF', 'Gene', '7422', (36, 40))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('Vascular endothelial growth factor', 'Gene', (0, 34))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('treatments', 'Var', (128, 138))
137185	23391555	Mutational analysis revealed mutation in the KRAS oncogene in 2 of 11 patients (18%).	('KRAS', 'Gene', '3845', (45, 49))	('mutation', 'Var', (29, 37))	('patients', 'Species', '9606', (70, 78))	('revealed', 'Reg', (20, 28))	('KRAS', 'Gene', (45, 49))
137251	23391555	Testing for mutations in KRAS, NRAS, BRAF, cKIT, EGFR, PIK3CA, TP53, as well as immunohistochemistry for PTEN loss and HER-2/neu FISH amplification was completed on patients with adequate available tissue in the MD Anderson CLIA-certified laboratory.	('loss', 'NegReg', (110, 114))	('BRAF', 'Gene', '673', (37, 41))	('TP53', 'Gene', (63, 67))	('HER-2/neu', 'Gene', (119, 128))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (12, 21))	('BRAF', 'Gene', (37, 41))	('HER-2/neu', 'Gene', '2064', (119, 128))	('PIK3CA', 'Gene', (55, 61))	('patients', 'Species', '9606', (165, 173))	('PIK3CA', 'Gene', '5290', (55, 61))	('KRAS', 'Gene', (25, 29))	('NRAS', 'Gene', (31, 35))	('KRAS', 'Gene', '3845', (25, 29))
137253	23391555	Of 11 tested patients, a KRAS mutation was detected in the tumor of two patients with cholangiocarcinoma, one in codon 12 and another in codon 13.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('cholangiocarcinoma', 'Disease', (86, 104))	('KRAS', 'Gene', '3845', (25, 29))	('mutation', 'Var', (30, 38))	('patients', 'Species', '9606', (13, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('detected', 'Reg', (43, 51))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (86, 104))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (86, 104))	('KRAS', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('patients', 'Species', '9606', (72, 80))
137263	23391555	Although KRAS mutations may sensitize a tumor to MEK inhibitors, the KRAS status of our patient with prolonged stable disease on a novel MEK inhibitor was unknown due to lack of tissue available for molecular analysis.	('KRAS', 'Gene', (69, 73))	('patient', 'Species', '9606', (88, 95))	('MEK', 'Gene', (137, 140))	('KRAS', 'Gene', '3845', (69, 73))	('MEK', 'Gene', '5609', (137, 140))	('prolonged stable disease', 'Disease', 'MESH:D060050', (101, 125))	('KRAS', 'Gene', (9, 13))	('prolonged stable disease', 'Disease', (101, 125))	('MEK', 'Gene', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('MEK', 'Gene', '5609', (49, 52))	('KRAS', 'Gene', '3845', (9, 13))	('sensitize', 'Reg', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('mutations', 'Var', (14, 23))
137264	23391555	Somatic mutations of KRAS, most commonly G12D and G13D, and PIK3CA, most commonly E545K, along with deletion of p53 have been reported in CCs; activating mutations in PIK3CA have also been reported in 12.5% of patients with GC, highlighting the therapeutic targeting potential of the RAS/RAF/MEK/ERK pathway and PI3K/AKT/MTOR pathway.	('PIK3CA', 'Gene', '5290', (167, 173))	('MEK', 'Gene', (292, 295))	('G13D', 'Var', (50, 54))	('AKT', 'Gene', (317, 320))	('G12D', 'Var', (41, 45))	('MTOR', 'Gene', (321, 325))	('RAF', 'Gene', (288, 291))	('G12D', 'Mutation', 'rs121913529', (41, 45))	('MTOR', 'Gene', '2475', (321, 325))	('ERK', 'Gene', (296, 299))	('p53', 'Gene', '7157', (112, 115))	('activating', 'PosReg', (143, 153))	('PIK3CA', 'Gene', (60, 66))	('p53', 'Gene', (112, 115))	('patients', 'Species', '9606', (210, 218))	('PIK3CA', 'Gene', (167, 173))	('E545K', 'Mutation', 'rs104886003', (82, 87))	('CCs', 'Disease', (138, 141))	('AKT', 'Gene', '207', (317, 320))	('CC', 'Phenotype', 'HP:0030153', (138, 140))	('KRAS', 'Gene', '3845', (21, 25))	('E545K', 'Var', (82, 87))	('MEK', 'Gene', '5609', (292, 295))	('PIK3CA', 'Gene', '5290', (60, 66))	('G13D', 'Mutation', 'rs112445441', (50, 54))	('RAF', 'Gene', '22882', (288, 291))	('KRAS', 'Gene', (21, 25))	('ERK', 'Gene', '5594', (296, 299))
137265	23391555	It is conceivable that the responses to MEK inhibitors seen in CC are due to the frequency of KRAS mutations among these patients (13%).	('MEK', 'Gene', '5609', (40, 43))	('CC', 'Phenotype', 'HP:0030153', (63, 65))	('responses', 'MPA', (27, 36))	('KRAS', 'Gene', (94, 98))	('KRAS', 'Gene', '3845', (94, 98))	('mutations', 'Var', (99, 108))	('patients', 'Species', '9606', (121, 129))	('MEK', 'Gene', (40, 43))
137266	23391555	Most recently, tissue from 9 of 40 patients (23%) with intrahepatic CC was shown to harbor mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1).	('intrahepatic', 'Disease', (55, 67))	('isocitrate dehydrogenase 1', 'Gene', (122, 148))	('isocitrate dehydrogenase 1', 'Gene', '3417', (122, 148))	('intrahepatic', 'Disease', 'MESH:D002780', (55, 67))	('mutations', 'Var', (91, 100))	('CC', 'Phenotype', 'HP:0030153', (68, 70))	('IDH1', 'Gene', (150, 154))	('patients', 'Species', '9606', (35, 43))	('IDH1', 'Gene', '3417', (150, 154))
137267	23391555	The clinical significance of this is not known, but one proposed mechanism demonstrates that a heterozygous IDH1 mutation leads to elevated levels of hypoxia-inducible factor subunit HIF-1alpha, thereby promoting tumor development and suggesting that IDH1 may be a tumor suppressor.	('tumor', 'Disease', (213, 218))	('elevated', 'PosReg', (131, 139))	('mutation', 'Var', (113, 121))	('IDH1', 'Gene', '3417', (251, 255))	('IDH1', 'Gene', '3417', (108, 112))	('promoting', 'PosReg', (203, 212))	('hypoxia', 'Disease', (150, 157))	('hypoxia', 'Disease', 'MESH:D000860', (150, 157))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('HIF-1alpha', 'Gene', (183, 193))	('tumor', 'Disease', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('IDH1', 'Gene', (251, 255))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('HIF-1alpha', 'Gene', '3091', (183, 193))	('IDH1', 'Gene', (108, 112))	('men', 'Species', '9606', (226, 229))
137280	33068050	Although frequent KRAS mutations and epigenetic changes at the INK4A/ARF locus have been identified, the molecular pathogenesis of BTC is unclear and the development of corresponding anticancer agents remains inadequate.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('epigenetic changes', 'Var', (37, 55))	('BTC', 'Phenotype', 'HP:0100574', (131, 134))	('KRAS', 'Gene', (18, 22))	('cancer', 'Disease', (187, 193))	('mutations', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('INK4A/ARF', 'Gene', (63, 72))
137292	33068050	4  The tumor suppressor gene INK4A, which encodes the cyclin-dependent kinase inhibitor p16, was found to be inactivated in up to 80% of cholangiocarcinomas, with the most frequent mechanism of inactivation being the loss of transcription as a result of DNA methylation at a CpG island in the promoter region.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('DNA methylation', 'Var', (254, 269))	('INK4A', 'Gene', '1029', (29, 34))	('tumor', 'Disease', (7, 12))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (137, 156))	('INK4A', 'Gene', (29, 34))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (137, 155))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('transcription', 'MPA', (225, 238))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('cholangiocarcinomas', 'Disease', (137, 156))	('inactivated', 'NegReg', (109, 120))	('loss', 'NegReg', (217, 221))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
137317	33068050	The cells were then labeled in the presence of the ROCK inhibitor Y-27632 (10 mumol/L; Miltenyi Biotec) with allophycocyanin (APC)-conjugated rat monoclonal antibodies to mouse EpCAM (#118214; Biolegend, San Diego, CA, USA) and FITC-conjugated rat monoclonal antibodies to mouse CD45 and CD31 (#102108 and #102406, respectively, Biolegend) for FACS with a MoFlo XDP Cell Sorter (Beckman Coulter).	('CD45', 'Gene', (279, 283))	('CD31', 'Gene', '18613', (288, 292))	('CD45', 'Gene', '19264', (279, 283))	('CD31', 'Gene', (288, 292))	('FITC', 'Chemical', 'MESH:D016650', (228, 232))	('#102406', 'Var', (306, 313))	('FACS', 'Gene', (344, 348))	('Y-27632', 'Chemical', 'MESH:C108830', (66, 73))	('#102108', 'Var', (294, 301))	('Biotec', 'Chemical', '-', (96, 102))	('EpCAM', 'Gene', (177, 182))	('FACS', 'Gene', '14081', (344, 348))	('mouse', 'Species', '10090', (273, 278))	('EpCAM', 'Gene', '17075', (177, 182))	('mouse', 'Species', '10090', (171, 176))
137322	33068050	Plat-E packaging cells were transfected with pMXs-IRES-GFP-KRAS(G12V) or pMXs-IRES-GFP (control plasmid) with the use of the FugeneHD reagent (Promega), and the culture supernatants were subsequently collected, passed through a 0.45-mum cellulose acetate filter (Iwaki), and centrifuged at 23 000 x g for 4 hours at 4 C. The virus pellets were suspended in EM and added to BECs in organoid culture.	('pMXs-IRES-GFP', 'Var', (73, 86))	('FugeneHD', 'Disease', 'None', (125, 133))	('FugeneHD', 'Disease', (125, 133))	('G12V', 'Mutation', 'rs121913529', (64, 68))
137347	33068050	IHC analysis of mouse liver (IHBD), GB, and EHBD confirmed that the corresponding BECs express EpCAM and CK19 (Figure 1A,B).	('EpCAM', 'Gene', '17075', (95, 100))	('CK19', 'Var', (105, 109))	('EpCAM', 'Gene', (95, 100))	('mouse', 'Species', '10090', (16, 21))
137355	33068050	We next infected the organoid cultures for each type of BEC from WT and Ink4a/Arf -/- mice either with a retrovirus encoding the oncogenic mutant KRAS(G12V)-GFP or with a control virus encoding GFP alone.	('Ink4a/Arf', 'Gene', '12578', (72, 81))	('KRAS(G12V)-GFP', 'Var', (146, 160))	('mice', 'Species', '10090', (86, 90))	('infected', 'Disease', 'MESH:D007239', (8, 16))	('Ink4a/Arf', 'Gene', (72, 81))	('G12V', 'Mutation', 'rs121913529', (151, 155))	('infected', 'Disease', (8, 16))
137357	33068050	However, those infected with the virus for KRAS(G12V)-GFP did not proliferate, possibly as a result of oncogene-induced senescence dependent on Ink4a/Arf.	('infected', 'Disease', (15, 23))	('Ink4a/Arf', 'Gene', '12578', (144, 153))	('Ink4a/Arf', 'Gene', (144, 153))	('infected', 'Disease', 'MESH:D007239', (15, 23))	('senescence', 'CPA', (120, 130))	('KRAS(G12V)-GFP', 'Var', (43, 57))	('G12V', 'Mutation', 'rs121913529', (48, 52))
137362	33068050	Immunoblot analysis also showed that the extent of ERK or Akt phosphorylation was not substantially affected by expression of KRAS(G12V).	('ERK', 'Gene', (51, 54))	('ERK', 'Gene', '26413', (51, 54))	('G12V', 'Mutation', 'rs121913529', (131, 135))	('Akt', 'Gene', '11651', (58, 61))	('KRAS(G12V', 'Var', (126, 135))	('Akt', 'Gene', (58, 61))
137363	33068050	Microarray analysis revealed that the expression of 205 genes was increased >2-fold in Ink4a/Arf -/- BECs infected with the KRAS(G12V)-GFP virus compared with those infected with the control virus, but gene ontology analysis did not detect significant changes for any functional category among these genes (data not shown).	('increased', 'PosReg', (66, 75))	('infected', 'Disease', 'MESH:D007239', (106, 114))	('infected', 'Disease', 'MESH:D007239', (165, 173))	('KRAS(G12V)-GFP virus', 'Var', (124, 144))	('expression', 'MPA', (38, 48))	('G12V', 'Mutation', 'rs121913529', (129, 133))	('Ink4a/Arf', 'Gene', '12578', (87, 96))	('infected', 'Disease', (106, 114))	('infected', 'Disease', (165, 173))	('Ink4a/Arf', 'Gene', (87, 96))
137366	33068050	The phosphorylation of ERK was detected in the developed tumors (Figure 3A), suggesting that ERK signaling was activated by KRAS(G12V) and was associated with tumorigenesis.	('ERK', 'Gene', (93, 96))	('KRAS(G12V', 'Var', (124, 133))	('associated with', 'Reg', (143, 158))	('ERK', 'Gene', '26413', (93, 96))	('G12V', 'Mutation', 'rs121913529', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('ERK', 'Gene', (23, 26))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('ERK', 'Gene', '26413', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('activated', 'PosReg', (111, 120))
137367	33068050	Given that ERK phosphorylation was not induced by KRAS(G12V) in the corresponding BECs in culture, the activation of ERK signaling downstream of KRAS(G12V) in the tumors was likely either dependent on the tumor microenvironment or due to the selection of cells with activated ERK signaling.	('ERK', 'Gene', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('ERK', 'Gene', '26413', (276, 279))	('tumor', 'Disease', (163, 168))	('ERK', 'Gene', (11, 14))	('ERK', 'Gene', '26413', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('activation', 'PosReg', (103, 113))	('ERK', 'Gene', '26413', (11, 14))	('KRAS(G12V', 'Var', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('G12V', 'Mutation', 'rs121913529', (55, 59))	('ERK', 'Gene', (276, 279))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumor', 'Disease', (205, 210))	('G12V', 'Mutation', 'rs121913529', (150, 154))
137385	33068050	Limiting dilution analysis revealed that, in contrast with BECs expressing only GFP, which did not form tumors, those expressing KRAS(G12V) had a high tumor-initiating ability, with as few as 100 KRAS(G12V)-expressing BECs being sufficient for tumor formation (Figure 5D).	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('G12V', 'Mutation', 'rs121913529', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (244, 249))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('KRAS(G12V', 'Var', (129, 138))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('G12V', 'Mutation', 'rs121913529', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
137416	33068050	34 ,  35  Similar to normal stem cells, we obtained cultures of KRAS(G12V)-expressing EpCAM+ BECs (IHBD, GB, and EHBD cells) as organoids in serum-free medium supplemented with growth factors.	('EpCAM', 'Gene', (86, 91))	('G12V', 'Mutation', 'rs121913529', (69, 73))	('EpCAM', 'Gene', '17075', (86, 91))	('KRAS(G12V)-expressing', 'Var', (64, 85))
137433	33068050	Analysis of 36 such patients revealed an association between high expression of both KRT19 and ZEB1 and poor survival, suggesting that intratumoral heterogeneity characterized by the presence of both epithelial-type and mesenchymal-type tumor cells may contribute to a poor clinical outcome.	('high expression', 'Var', (61, 76))	('KRT19', 'Gene', (85, 90))	('tumor', 'Disease', (237, 242))	('KRT19', 'Gene', '3880', (85, 90))	('ZEB1', 'Gene', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('patients', 'Species', '9606', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', (140, 145))
137442	33068050	Gene amplification for mutant KRAS has been detected in a substantial fraction of lung 52  and prostate 53  cancers, and it is apparent in many cases of pancreatic cancer in The Cancer Genome Atlas (TCGA).	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (153, 170))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('Cancer', 'Disease', (178, 184))	('cancers', 'Disease', (108, 115))	('lung 52', 'Disease', (82, 89))	('pancreatic cancer', 'Disease', (153, 170))	('Cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Cancer', 'Phenotype', 'HP:0002664', (178, 184))	('pancreatic cancer', 'Disease', 'MESH:D010190', (153, 170))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('KRAS', 'Gene', (30, 34))	('mutant', 'Var', (23, 29))
137443	33068050	Although limited information is available for biliary carcinomas, a tumor with high expression of mutant KRAS as a result of gene amplification is present in the TCGA database (Figure S6).	('tumor', 'Disease', (68, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('KRAS', 'Gene', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (54, 64))	('biliary carcinomas', 'Disease', 'MESH:D001661', (46, 64))	('biliary carcinomas', 'Disease', (46, 64))	('expression', 'MPA', (84, 94))	('mutant', 'Var', (98, 104))
137444	33068050	Furthermore, a previous study identified 2 of 182 cases of biliary tract cholangiocarcinoma in Taiwan as being positive for both KRAS mutation and gene amplification.	('biliary tract cholangiocarcinoma', 'Disease', (59, 91))	('gene amplification', 'Var', (147, 165))	('mutation', 'Var', (134, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('KRAS', 'Gene', (129, 133))	('positive', 'Reg', (111, 119))	('biliary tract cholangiocarcinoma', 'Disease', 'MESH:D001660', (59, 91))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (73, 91))
137445	33068050	55  The BTC-initiating cells established in the present study by KRAS(G12V) overexpression possess CSC properties and therefore generate aggressive tumors characterized by a high tumorigenic activity and metastatic ability in mice.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('metastatic ability', 'CPA', (204, 222))	('G12V', 'Mutation', 'rs121913529', (70, 74))	('mice', 'Species', '10090', (226, 230))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('overexpression', 'Var', (76, 90))	('tumor', 'Disease', (148, 153))	('aggressive tumors', 'Disease', 'MESH:D001523', (137, 154))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('KRAS(G12V', 'Gene', (65, 74))	('aggressive tumors', 'Disease', (137, 154))	('BTC', 'Phenotype', 'HP:0100574', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', (179, 184))
137446	33068050	In conclusion, we have established novel organoids and syngeneic mouse models of IHCC, GC, and EHCC based on KRAS activation and homozygous Ink4a/Arf deletion in corresponding EpCAM+ BECs.	('EpCAM', 'Gene', (176, 181))	('Ink4a/Arf', 'Gene', '12578', (140, 149))	('mouse', 'Species', '10090', (65, 70))	('IHCC', 'Disease', (81, 85))	('EpCAM', 'Gene', '17075', (176, 181))	('Ink4a/Arf', 'Gene', (140, 149))	('deletion', 'Var', (150, 158))
137565	27087417	Remarkably, the biliary/hepatic levels of most of GS-DCPs in EHBRs were much lower than those in SD rats (Supplementary Fig.	('lower', 'NegReg', (77, 82))	('EHBRs', 'Var', (61, 66))	('GS-DCPs', 'Chemical', '-', (50, 57))	('biliary/hepatic levels', 'MPA', (16, 38))	('rats', 'Species', '10116', (100, 104))	('men', 'Species', '9606', (112, 115))	('EHBRs', 'Chemical', '-', (61, 66))
137603	27087417	In general, glutathione conjugation (a Phase II reaction) and the subsequent export of conjugated metabolites mediated by the GS-X pump (a Phase III reaction) play a pivotal role in the biological inactivation of xenobiotics and their elimination.	('biological', 'MPA', (186, 196))	('elimination', 'MPA', (235, 246))	('xenobiotics', 'Var', (213, 224))	('glutathione conjugation', 'MPA', (12, 35))	('GS', 'Disease', 'MESH:D011125', (126, 128))	('glutathione', 'Chemical', 'MESH:D005978', (12, 23))	('export of conjugated metabolites mediated by the', 'MPA', (77, 125))
137637	27087417	Interestingly, accumulating evidence suggests the influence of GST polymorphisms in cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('GS', 'Disease', 'MESH:D011125', (63, 65))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('influence', 'Reg', (50, 59))	('polymorphisms', 'Var', (67, 80))
137640	27087417	In addition, an association of genetic variation in ABCC2 with susceptibility to bile duct cancer has been pointed out, which would warrant further investigations for cholangiocarcinoma risk focusing on biliary excretion system as well as hepatic metabolizing system.	('bile duct cancer', 'Disease', (81, 97))	('genetic variation', 'Var', (31, 48))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (167, 185))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (167, 185))	('association', 'Reg', (16, 27))	('bile duct cancer', 'Disease', 'MESH:D001650', (81, 97))	('bile duct cancer', 'Phenotype', 'HP:0030153', (81, 97))	('cholangiocarcinoma', 'Disease', (167, 185))	('ABCC2', 'Gene', (52, 57))	('susceptibility', 'Reg', (63, 77))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
137716	27212785	In conclusion, anti-VEGFR-3 autoantibodies are early produced during BDL-induced cholestatic injury, and they are closely related to cholestasis, suggesting the potential of anti-VEGFR-3 autoantibodies as NIBMs of cholestasis in CCLDs and justifying the need for further investigations in patients with CCLD.	('anti-VEGFR-3', 'Gene', (15, 27))	('BDL-induced', 'Disease', (69, 80))	('anti-VEGFR-3', 'Var', (174, 186))	('CCLD', 'Disease', (303, 307))	('cholestasis', 'Disease', (214, 225))	('CCLD', 'Disease', 'None', (229, 233))	('cholestasis', 'Disease', 'MESH:D002779', (133, 144))	('cholestasis', 'Disease', 'MESH:D002779', (214, 225))	('CCLDs', 'Phenotype', 'HP:0002611', (229, 234))	('cholestatic injury', 'Disease', (81, 99))	('cholestasis', 'Disease', (133, 144))	('CCLD', 'Disease', (229, 233))	('cholestatic injury', 'Disease', 'MESH:D002779', (81, 99))	('cholestasis', 'Phenotype', 'HP:0001396', (214, 225))	('cholestasis', 'Phenotype', 'HP:0001396', (133, 144))	('CCLD', 'Disease', 'None', (303, 307))	('patients', 'Species', '9606', (289, 297))
137728	27212785	The mechanism that triggers the autoantibody response against TAA has still not been elucidated but could be consequent to abnormal self-antigen expression by tumor cells, through chemical alteration, mutation, posttranslational modification, misfolding, aberrant cleavage or localization, and overexposure and/or exposure or spillage of new TAA, in conjunction with the development of an inflammatory reaction within the tumor microenvironment.	('tumor', 'Disease', (422, 427))	('aberrant', 'Var', (255, 263))	('rat', 'Species', '10116', (193, 196))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('misfolding', 'Var', (243, 253))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (422, 427))	('tumor', 'Phenotype', 'HP:0002664', (422, 427))	('mutation', 'Var', (201, 209))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
137772	27212785	Another explanation is that, during the earliest stage of tumorigenesis, proteins are likely mutated, overexpressed, posttranslationally modified, misfolded, aberrantly cleaved, or aberrantly localized in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('proteins', 'Protein', (73, 81))	('mutated', 'Var', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('aberrantly', 'Var', (181, 191))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))
137786	27212785	We found that absorbances associated with the serum levels of autoantibodies to VEGFR-3 in BDL groups were systematically higher than control rats.	('autoantibodies', 'MPA', (62, 76))	('serum levels', 'MPA', (46, 58))	('higher', 'PosReg', (122, 128))	('BDL', 'Var', (91, 94))	('rats', 'Species', '10116', (142, 146))	('absorbances', 'MPA', (14, 25))	('VEGFR-3', 'Gene', (80, 87))
137788	27212785	This may offer the opportunity of using autoantibodies to VEGFR-3 to early diagnose BDL-induced chronic cholestatic liver injury.	('VEGFR-3', 'Gene', (58, 65))	('cholestatic liver injury', 'Disease', (104, 128))	('cholestatic liver injury', 'Phenotype', 'HP:0002611', (104, 128))	('autoantibodies', 'Var', (40, 54))	('cholestatic liver injury', 'Disease', 'MESH:D056486', (104, 128))
137806	27212785	This finding, in parallel to the observation that the mean value of absorbances associated with the serum levels of autoantibodies to VEGFR-3 is increased directly after BDL and stays high without enabling the distinction between one, three, and five weeks of BDL, a common tendency to TB but not to the relative fibrotic area, suggests that levels of autoantibodies to VEGFR-3 may be better associated with cholestasis than fibrosis.	('cholestasis', 'Phenotype', 'HP:0001396', (408, 419))	('cholestasis', 'Disease', 'MESH:D002779', (408, 419))	('associated', 'Reg', (392, 402))	('fibrosis', 'Disease', (425, 433))	('increased', 'PosReg', (145, 154))	('fibrosis', 'Disease', 'MESH:D005355', (425, 433))	('cholestasis', 'Disease', (408, 419))	('BDL', 'Var', (170, 173))	('TB', 'Chemical', 'MESH:D001663', (286, 288))
137807	27212785	This provides the first evidence on the potential application of autoantibodies to VEGFR-3 as NIBMs of cholestasis in CCLDs.	('autoantibodies', 'Var', (65, 79))	('CCLD', 'Disease', 'None', (118, 122))	('cholestasis', 'Phenotype', 'HP:0001396', (103, 114))	('CCLDs', 'Phenotype', 'HP:0002611', (118, 123))	('VEGFR-3', 'Gene', (83, 90))	('CCLD', 'Disease', (118, 122))	('cholestasis', 'Disease', 'MESH:D002779', (103, 114))	('cholestasis', 'Disease', (103, 114))
137814	18948067	Activation of microOR, but not deltaOR, increases cholangiocarcinoma cell growth.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (50, 68))	('deltaOR', 'Chemical', '-', (31, 38))	('increases cholangiocarcinoma', 'Disease', 'MESH:D018281', (40, 68))	('microOR', 'Var', (14, 21))	('increases cholangiocarcinoma', 'Disease', (40, 68))
137817	18948067	The anti-apoptotic effect of microOR was PI3K dependent.	('PI3', 'Gene', (41, 44))	('PI3', 'Gene', '5266', (41, 44))	('microOR', 'Var', (29, 36))	('anti-apoptotic effect', 'CPA', (4, 25))
137848	18948067	To define the intracellular pathways that mediate the effect of DAMGO on cholangiocarcinoma cell survival, the above experiments were also performed in the absence or presence of a 30 min pre-incubation with either, PD98059 (50 micromol/L), wortmannin (100 nmol/L) or KN62 [10 micromol/L, a CamKII inhibitor].	('CamKII', 'Gene', '818', (291, 297))	('CamKII', 'Gene', (291, 297))	('PD98059', 'Var', (216, 223))	('cholangiocarcinoma', 'Disease', (73, 91))	('KN62', 'Chemical', 'MESH:C063302', (268, 272))	('PD98059', 'Chemical', 'MESH:C093973', (216, 223))	('wortmannin', 'Chemical', 'MESH:D000077191', (241, 251))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (73, 91))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (73, 91))
137850	18948067	PD98059, Rp-cAMPs, KN62, Ro-32-0432, BAPTA/AM were purchased from Calbiochem (Milan, Italy).	('cAMP', 'Gene', (12, 16))	('cAMP', 'Gene', '820', (12, 16))	('PD98059', 'Var', (0, 7))	('PD98059', 'Chemical', 'MESH:C093973', (0, 7))	('BAPTA', 'Chemical', 'MESH:C025603', (37, 42))	('KN62', 'Chemical', 'MESH:C063302', (19, 23))
137857	18948067	2D), thus confirming that activation of deltaOR does not affect cholangiocarcinoma cell proliferation.	('deltaOR', 'Gene', (40, 47))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (64, 82))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('deltaOR', 'Chemical', '-', (40, 47))	('cholangiocarcinoma', 'Disease', (64, 82))	('activation', 'Var', (26, 36))
137867	18948067	The blockage of the MAPK or CamKII pathways (by PD98059 and KN62, respectively) did not affect the ability of DAMGO to inhibit the GCDCA-induced increase in caspase 3 activity (Fig.	('caspase 3', 'Gene', (157, 166))	('MAPK', 'Gene', '5595;5594;5595', (20, 24))	('GCDCA', 'Chemical', 'MESH:D005999', (131, 136))	('MAPK', 'Gene', (20, 24))	('CamKII', 'Gene', '818', (28, 34))	('CamKII', 'Gene', (28, 34))	('inhibit', 'NegReg', (119, 126))	('KN62', 'Var', (60, 64))	('PD98059', 'Var', (48, 55))	('activity', 'MPA', (167, 175))	('caspase 3', 'Gene', '836', (157, 166))	('KN62', 'Chemical', 'MESH:C063302', (60, 64))	('PD98059', 'Chemical', 'MESH:C093973', (48, 55))
137869	18948067	In particular, this study shows that: (i) human cholangiocarcinoma cells express both deltaOR and microOR; (ii) human cholangiocarcinoma cell growth cannot be inhibited by OR activation; microOR, but not deltaOR, activation results in significant increase in cholangiocarcinoma cell proliferation; (iii) microOR signal is mediated by ERK1/2, PI3K and Ca2+/CamKIIalpha pathways; (iv) microOR enhances cholangiocarcinoma cell migration and escape from apoptosis.	('microOR', 'Var', (383, 390))	('human', 'Species', '9606', (42, 47))	('cholangiocarcinoma', 'Disease', (400, 418))	('enhances', 'PosReg', (391, 399))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (400, 418))	('human', 'Species', '9606', (112, 117))	('CamKII', 'Gene', '818', (356, 362))	('PI3', 'Gene', '5266', (342, 345))	('ERK1/2', 'Gene', (334, 340))	('ERK1/2', 'Gene', '5595;5594', (334, 340))	('Ca2+', 'Chemical', 'MESH:D000069285', (351, 355))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (48, 66))	('escape', 'CPA', (438, 444))	('cholangiocarcinoma', 'Disease', (48, 66))	('cholangiocarcinoma cell migration', 'Disease', (400, 433))	('deltaOR', 'Chemical', '-', (86, 93))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (48, 66))	('PI3', 'Gene', (342, 345))	('cholangiocarcinoma cell migration', 'Disease', 'MESH:D018281', (400, 433))	('increase', 'PosReg', (247, 255))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (259, 277))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (118, 136))	('CamKII', 'Gene', (356, 362))	('cholangiocarcinoma', 'Disease', (259, 277))	('cholangiocarcinoma', 'Disease', (118, 136))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (400, 418))	('deltaOR', 'Chemical', '-', (204, 211))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (118, 136))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (259, 277))
137889	18948067	In addition, microOR stimulates cell growth through the PI3K/ERK1/2 cascade, but without affecting the Ca2+ signalling at all.	('PI3', 'Gene', (56, 59))	('cell growth', 'CPA', (32, 43))	('Ca2+', 'Chemical', 'MESH:D000069285', (103, 107))	('stimulates', 'PosReg', (21, 31))	('ERK1/2', 'Gene', '5595;5594', (61, 67))	('microOR', 'Var', (13, 20))	('ERK1/2', 'Gene', (61, 67))	('PI3', 'Gene', '5266', (56, 59))
137890	18948067	In contrast, in malignant cholangiocytes we found that microOR activates Ca2+/CamKIIalpha cascade that elicits, instead of inhibiting, cell growth (Fig.	('microOR', 'Var', (55, 62))	('CamKII', 'Gene', '818', (78, 84))	('CamKII', 'Gene', (78, 84))	('Ca2+', 'Chemical', 'MESH:D000069285', (73, 77))	('cell growth', 'CPA', (135, 146))	('elicits', 'Reg', (103, 110))
137905	18948067	It can be conceived that a genetic or acquired disruption of opioidergic regulation of cholangiocyte biology may confer to a subset of patients a higher risk of developing such a malignancy.	('malignancy', 'Disease', 'MESH:D009369', (179, 189))	('patients', 'Species', '9606', (135, 143))	('malignancy', 'Disease', (179, 189))	('disruption', 'Var', (47, 57))
137928	33093444	Moreover, MNX1-AS1 was proved to be highly expressed in gastric cancer, and the ectopic expression of MNX1-AS1 was associated with poor prognosis for gastric cancer patients.	('MNX1-AS1', 'Gene', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('MNX1-AS1', 'Gene', '5729', (102, 110))	('gastric cancer', 'Disease', (150, 164))	('associated', 'Reg', (115, 125))	('MNX1-AS1', 'Gene', '5729', (10, 18))	('gastric cancer', 'Disease', 'MESH:D013274', (150, 164))	('patients', 'Species', '9606', (165, 173))	('gastric cancer', 'Disease', (56, 70))	('gastric cancer', 'Disease', 'MESH:D013274', (56, 70))	('MNX1-AS1', 'Gene', (102, 110))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))	('ectopic', 'Var', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
137933	33093444	Several researchers have demonstrated that aberrantly expressed MNX1 had a vital role in infant acute myeloid leukemia.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (96, 118))	('MNX1', 'Gene', (64, 68))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (102, 118))	('aberrantly expressed', 'Var', (43, 63))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (96, 118))	('leukemia', 'Phenotype', 'HP:0001909', (110, 118))	('acute myeloid leukemia', 'Disease', (96, 118))	('role', 'Reg', (81, 85))
137936	33093444	Abnormal expression of MNX1 was responsible for cell proliferation and tumorigenicity of bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('responsible', 'Reg', (32, 43))	('MNX1', 'Gene', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cell proliferation', 'CPA', (48, 66))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('bladder cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Abnormal', 'Var', (0, 8))	('tumor', 'Disease', (71, 76))
137938	33093444	MNX1-AS1 knockdown markedly reduced MNX1 expression in breast cancer, while overexpression of MNX1-AS1 elicited an increased expression of MNX1.	('MNX1', 'Gene', (36, 40))	('reduced', 'NegReg', (28, 35))	('knockdown', 'Var', (9, 18))	('MNX1-AS1', 'Gene', '5729', (94, 102))	('expression', 'MPA', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('MNX1-AS1', 'Gene', '5729', (0, 8))	('expression', 'MPA', (125, 135))	('MNX1-AS1', 'Gene', (94, 102))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('MNX1-AS1', 'Gene', (0, 8))
137941	33093444	However, the mechanisms behind MNX1-AS1 and MNX1 dysregulation in ICC are not clear until now, and whether the expression of MNX1-AS1 and MNX1 is correlated in ICC has not yet been determined.	('MNX1', 'Gene', (44, 48))	('MNX1-AS1', 'Gene', '5729', (125, 133))	('MNX1-AS1', 'Gene', (125, 133))	('MNX1-AS1', 'Gene', '5729', (31, 39))	('dysregulation', 'Var', (49, 62))	('ICC', 'Disease', (66, 69))	('MNX1-AS1', 'Gene', (31, 39))
137945	33093444	MNX1-AS1 facilitated the transcription of MNX1 by recruiting TFs c-Myc and MAZ, and then MNX1 repressed Hippo signaling pathway by upregulating the expression of Ajuba protein.	('recruiting', 'PosReg', (50, 60))	('MAZ', 'Gene', '4150', (75, 78))	('Ajuba', 'Gene', '84962', (162, 167))	('c-Myc', 'Gene', (65, 70))	('repressed', 'NegReg', (94, 103))	('transcription', 'MPA', (25, 38))	('facilitated', 'PosReg', (9, 20))	('MNX1-AS1', 'Gene', '5729', (0, 8))	('Ajuba', 'Gene', (162, 167))	('MNX1', 'Gene', (42, 46))	('MNX1', 'Var', (89, 93))	('expression', 'MPA', (148, 158))	('upregulating', 'PosReg', (131, 143))	('c-Myc', 'Gene', '4609', (65, 70))	('Hippo signaling pathway', 'Pathway', (104, 127))	('MAZ', 'Gene', (75, 78))	('MNX1-AS1', 'Gene', (0, 8))
138020	33093444	To further verified the effects of TFs c-Myc and MAZ on the expression of MNX1, loss-of-function assay was performed, and found that the expression of MNX1 was significantly decreased in c-Myc or MAZ knockdown FRH0201 cells (Fig.	('decreased', 'NegReg', (174, 183))	('knockdown', 'Var', (200, 209))	('MAZ', 'Gene', (196, 199))	('expression', 'MPA', (137, 147))	('MNX1', 'Gene', (74, 78))	('MAZ', 'Gene', '4150', (196, 199))	('c-Myc', 'Gene', '4609', (39, 44))	('MAZ', 'Gene', (49, 52))	('c-Myc', 'Gene', '4609', (187, 192))	('MAZ', 'Gene', '4150', (49, 52))	('MNX1', 'Gene', (151, 155))	('c-Myc', 'Gene', (187, 192))	('c-Myc', 'Gene', (39, 44))
138036	33093444	The expression of MNX1 was significantly decreased after MNX1-AS1 knockdown (Supplementary Fig.	('MNX1-AS1', 'Gene', '5729', (57, 65))	('decreased', 'NegReg', (41, 50))	('expression', 'MPA', (4, 14))	('MNX1-AS1', 'Gene', (57, 65))	('MNX1', 'Gene', (18, 22))	('knockdown', 'Var', (66, 75))
138038	33093444	4a, The size and weight of tumors in the sh-MNX1-AS1 group were significantly smaller than those in the nc-MNX1-AS1 group (4-week volume: 0.86 +- 0.16 vs. 1.92 +- 0.16 cm3; weight: 0.33 +- 0.08 vs. 0.81 +- 0.11 g, P < 0.05), which indicated that the proliferation ability of tumor in vivo was markedly decreased after knockdown of MNX1-AS1.	('tumor', 'Disease', (275, 280))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('proliferation ability', 'CPA', (250, 271))	('MNX1-AS1', 'Gene', '5729', (331, 339))	('smaller', 'NegReg', (78, 85))	('MNX1-AS1', 'Gene', '5729', (44, 52))	('tumor', 'Disease', (27, 32))	('decreased', 'NegReg', (302, 311))	('MNX1-AS1', 'Gene', '5729', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('knockdown', 'Var', (318, 327))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('MNX1-AS1', 'Gene', (331, 339))	('MNX1-AS1', 'Gene', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('MNX1-AS1', 'Gene', (107, 115))	('tumors', 'Disease', (27, 33))
138041	33093444	Then, immunohistochemical staining for Ki-67 was conducted, the results demonstrated that the expression of Ki-67 in the sh-MNX1-AS1 group was remarkably decreased (IHC score: sh-MNX1-AS1 vs. nc-MNX1-AS1: 3.33 +- 0.33 vs. 7.33 +- 0.33, P = 0.001), indicating that cell proliferation ability in pulmonary metastases was considerably decreased after MNX1-AS1 knockdown (Fig.	('pulmonary metastases', 'Disease', (294, 314))	('decreased', 'NegReg', (332, 341))	('decreased', 'NegReg', (154, 163))	('MNX1-AS1', 'Gene', (179, 187))	('MNX1-AS1', 'Gene', (124, 132))	('MNX1-AS1', 'Gene', (348, 356))	('Ki-67', 'Gene', (108, 113))	('MNX1-AS1', 'Gene', '5729', (179, 187))	('MNX1-AS1', 'Gene', '5729', (195, 203))	('expression', 'MPA', (94, 104))	('MNX1-AS1', 'Gene', '5729', (124, 132))	('knockdown', 'Var', (357, 366))	('MNX1-AS1', 'Gene', '5729', (348, 356))	('MNX1-AS1', 'Gene', (195, 203))	('pulmonary metastases', 'Disease', 'MESH:D009362', (294, 314))
138042	33093444	Taken together, these findings illuminated that inhibition of MNX1-AS1 might suppress ICC tumorigenesis in vivo.	('MNX1-AS1', 'Gene', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('inhibition', 'Var', (48, 58))	('MNX1-AS1', 'Gene', '5729', (62, 70))	('suppress', 'NegReg', (77, 85))	('ICC tumor', 'Disease', (86, 95))	('ICC tumor', 'Disease', 'MESH:C566123', (86, 95))
138055	33093444	Finally, the inactivity of the Hippo pathway leads to an increasing YAP1 protein in the nucleus, which will prompt the tumorigenesis and progression of ICC (Fig.	('prompt', 'PosReg', (108, 114))	('tumor', 'Disease', (119, 124))	('increasing', 'PosReg', (57, 67))	('ICC', 'Disease', (152, 155))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('YAP1', 'Gene', '10413', (68, 72))	('inactivity', 'Var', (13, 23))	('Hippo pathway', 'Pathway', (31, 44))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('YAP1', 'Gene', (68, 72))
138077	33093444	Dysregulation of c-Myc may contribute to the progression of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (60, 78))	('c-Myc', 'Gene', (17, 22))	('Dysregulation', 'Var', (0, 13))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (60, 78))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (60, 78))	('contribute', 'Reg', (27, 37))	('c-Myc', 'Gene', '4609', (17, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
138088	33093444	Inactivity of the Hippo pathway may facilitate the progression of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (66, 84))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (66, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('Hippo pathway', 'Pathway', (18, 31))	('progression', 'CPA', (51, 62))	('facilitate', 'PosReg', (36, 46))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (66, 84))	('Inactivity', 'Var', (0, 10))
138096	33093444	What's more, a recent study about oral squamous cell carcinoma revealed that knockdown of YAP prohibited the expression of c-Myc, while overexpression of YAP showed the opposite effects, suggesting that YAP could regulate c-Myc transcriptional activity.	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (34, 62))	('c-Myc', 'Gene', (123, 128))	('knockdown', 'Var', (77, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('regulate', 'Reg', (213, 221))	('oral squamous cell carcinoma', 'Disease', (34, 62))	('c-Myc', 'Gene', '4609', (123, 128))	('c-Myc', 'Gene', (222, 227))	('YAP', 'Gene', (154, 157))	('prohibited', 'NegReg', (94, 104))	('YAP', 'Gene', (203, 206))	('YAP', 'Gene', (90, 93))	('c-Myc', 'Gene', '4609', (222, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('expression', 'MPA', (109, 119))	('YAP', 'Gene', '10413', (154, 157))	('transcriptional activity', 'MPA', (228, 252))	('YAP', 'Gene', '10413', (203, 206))	('YAP', 'Gene', '10413', (90, 93))
138103	31798275	Current status of associating liver partition with portal vein ligation for staged hepatectomy: Comparison with two-stage hepatectomy and strategies for better outcomes Since its introduction in 2012, associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) has significantly expanded the pool of candidates for liver resection.	('liver', 'Var', (213, 218))	('portal vein ligation', 'Phenotype', 'HP:0030242', (234, 254))	('ALPPS', 'Disease', 'None', (279, 284))	('portal vein ligation', 'Phenotype', 'HP:0030242', (51, 71))	('ALPPS', 'Disease', (279, 284))
138114	31798275	In patients with challenging anatomy, partial ALPPS potentially reduces morbidity, but remnant hypertrophy may compare unfavorably to a complete split.	('morbidity', 'MPA', (72, 81))	('hypertrophy', 'Disease', 'MESH:D006984', (95, 106))	('partial', 'Var', (38, 45))	('patients', 'Species', '9606', (3, 11))	('ALPPS', 'Disease', 'None', (46, 51))	('reduces', 'NegReg', (64, 71))	('hypertrophy', 'Disease', (95, 106))	('ALPPS', 'Disease', (46, 51))
138121	31798275	In patients with challenging anatomy, partial ALPPS reduces morbidity, but remnant hypertrophy may compare unfavorably to a complete split.	('hypertrophy', 'Disease', (83, 94))	('partial', 'Var', (38, 45))	('hypertrophy', 'Disease', 'MESH:D006984', (83, 94))	('patients', 'Species', '9606', (3, 11))	('ALPPS', 'Disease', 'None', (46, 51))	('morbidity', 'MPA', (60, 69))	('ALPPS', 'Disease', (46, 51))
138125	31798275	Redistribution of portal flow constitutes a stimulus to hypertrophy.	('hypertrophy', 'Disease', 'MESH:D006984', (56, 67))	('Redistribution', 'Var', (0, 14))	('hypertrophy', 'Disease', (56, 67))
138185	31798275	Kinetic growth rate >= 6%/d and FLR > 30% at 1 wk after ALPPS stage I were associated with no PHLF.	('ALPPS', 'Disease', 'None', (56, 61))	('ALPPS', 'Disease', (56, 61))	('> 30', 'Var', (36, 40))	('Kinetic', 'MPA', (0, 7))
138263	31798275	Patients with low grade fibrosis are better candidates for the procedure, and a longer inter-stage interval is desirable to allow sufficient liver hypertrophy.	('low grade', 'Var', (14, 23))	('liver hypertrophy', 'Disease', (141, 158))	('liver hypertrophy', 'Phenotype', 'HP:0002240', (141, 158))	('fibrosis', 'Disease', 'MESH:D005355', (24, 32))	('fibrosis', 'Disease', (24, 32))	('Patients', 'Species', '9606', (0, 8))	('liver hypertrophy', 'Disease', 'MESH:D006984', (141, 158))
138296	31798275	Partial ALPPS effectively induced the same degree of FLR hypertrophy as a complete split (median hypertrophy 60% vs 61% in 7 d).	('ALPPS', 'Disease', (8, 13))	('FLR', 'MPA', (53, 56))	('hypertrophy', 'Disease', (97, 108))	('ALPPS', 'Disease', 'None', (8, 13))	('hypertrophy', 'Disease', 'MESH:D006984', (97, 108))	('hypertrophy', 'Disease', (57, 68))	('hypertrophy', 'Disease', 'MESH:D006984', (57, 68))	('Partial', 'Var', (0, 7))
138298	31798275	However, the effectiveness of partial split appeared to be limited in chronic hepatitis.	('hepatitis', 'Disease', 'MESH:D056486', (78, 87))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (70, 87))	('hepatitis', 'Phenotype', 'HP:0012115', (78, 87))	('hepatitis', 'Disease', (78, 87))	('partial', 'Var', (30, 37))
138304	31798275	Partial ALPPS potentially reduced bleeding and subsequent complications.	('ALPPS potentially reduced bleeding', 'Disease', 'MESH:D006470', (8, 42))	('ALPPS potentially reduced bleeding', 'Disease', (8, 42))	('Partial', 'Var', (0, 7))
138312	31798275	In patients with challenging anatomy, partial ALPPS potentially reduces morbidity but remnant hypertrophy may compare unfavorably to a complete split.	('morbidity', 'MPA', (72, 81))	('hypertrophy', 'Disease', (94, 105))	('partial', 'Var', (38, 45))	('hypertrophy', 'Disease', 'MESH:D006984', (94, 105))	('patients', 'Species', '9606', (3, 11))	('ALPPS', 'Disease', 'None', (46, 51))	('reduces', 'NegReg', (64, 71))	('ALPPS', 'Disease', (46, 51))
138375	26931063	Finally, multi-b-value technology prolongs scanning time, which is onerous for patients.	('multi-b-value', 'Var', (9, 22))	('scanning time', 'MPA', (43, 56))	('patients', 'Species', '9606', (79, 87))	('prolongs', 'NegReg', (34, 42))
138389	26695839	The ABC-02 phase 3 trial established the current standard of systemic chemotherapy (SYS) in advanced biliary cancer but showed only a modest survival benefit in patients treated with gemcitabine-cisplatin compared to gemcitabine monotherapy (11.7 months vs 8.1 months, respectively).	('gemcitabine', 'Chemical', 'MESH:C056507', (217, 228))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('biliary cancer', 'Disease', 'MESH:D001661', (101, 115))	('gemcitabine-cisplatin', 'Var', (183, 204))	('patients', 'Species', '9606', (161, 169))	('gemcitabine', 'Chemical', 'MESH:C056507', (183, 194))	('cisplatin', 'Chemical', 'MESH:D002945', (195, 204))	('biliary cancer', 'Disease', (101, 115))	('SYS', 'Chemical', '-', (84, 87))
138411	26695839	Exclusion criteria included prior hepatic radiation or treatment with FUDR, Karnofsky performance status <60, first-degree sclerosing cholangitis, Gilbert's disease, portal hypertension, severe hepatic parenchymal dysfunction (encephalopathy, serum albumin <2.5 g/dl, serum bilirubin >=1.8 mg/dl, or international normalized ration (INR) >1.5), portal inflow occlusion, WBC <3500 cells/mm3, concurrent malignancy (except localized basal or squamous cell skin cancers), active infection, and concurrent pregnancy or lactation (females).	('hypertension', 'Disease', (173, 185))	("Gilbert's disease", 'Disease', (147, 164))	('cholangitis', 'Disease', 'MESH:D002761', (134, 145))	('portal inflow occlusion', 'Disease', (345, 368))	('hepatic radiation', 'Disease', (34, 51))	('squamous cell skin cancers', 'Disease', (440, 466))	('encephalopathy', 'Disease', 'MESH:D001927', (227, 241))	('cholangitis', 'Disease', (134, 145))	('hypertension', 'Phenotype', 'HP:0000822', (173, 185))	('malignancy', 'Disease', 'MESH:D009369', (402, 412))	('hepatic parenchymal dysfunction', 'Disease', 'MESH:D002543', (194, 225))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (123, 145))	('international normalized ration', 'MPA', (300, 331))	('lactation', 'Disease', (515, 524))	('hepatic radiation', 'Disease', 'MESH:D004194', (34, 51))	('first-degree', 'Disease', (110, 122))	('lactation', 'Disease', 'MESH:D007775', (515, 524))	("Gilbert's disease", 'Disease', 'MESH:D005878', (147, 164))	('encephalopathy', 'Phenotype', 'HP:0001298', (227, 241))	('cholangitis', 'Phenotype', 'HP:0030151', (134, 145))	('cancers', 'Phenotype', 'HP:0002664', (459, 466))	('portal hypertension', 'Phenotype', 'HP:0001409', (166, 185))	('malignancy', 'Disease', (402, 412))	('FUDR', 'Chemical', 'MESH:D005467', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (459, 465))	('active infection', 'Disease', (469, 485))	('active infection', 'Disease', 'MESH:D006505', (469, 485))	('bilirubin', 'Chemical', 'MESH:D001663', (274, 283))	('hepatic parenchymal dysfunction', 'Disease', (194, 225))	('encephalopathy', 'Disease', (227, 241))	('>=1.8', 'Var', (284, 289))	('squamous cell skin cancers', 'Disease', 'MESH:D002294', (440, 466))	('skin cancers', 'Phenotype', 'HP:0008069', (454, 466))	('hypertension', 'Disease', 'MESH:D006973', (173, 185))
138460	26695839	Based on available chemotherapy response data, (HAI: 78 and SYS: 18), the response rate for patients who received HAI and SYS was better than for those who received SYS alone.	('SYS', 'Var', (122, 125))	('SYS', 'Chemical', '-', (60, 63))	('response', 'CPA', (74, 82))	('SYS', 'Chemical', '-', (122, 125))	('SYS', 'Chemical', '-', (165, 168))	('patients', 'Species', '9606', (92, 100))	('HAI', 'Var', (114, 117))
138461	26695839	A partial response according to RECIST was observed in 47 of 79 (59%) after HAI and SYS, versus 7 of 18 (39%) for patients with SYS (p=0.11) (figure 3).	('SYS', 'Chemical', '-', (128, 131))	('SYS', 'Var', (84, 87))	('patients', 'Species', '9606', (114, 122))	('HAI', 'Var', (76, 79))	('SYS', 'Chemical', '-', (84, 87))
138462	26695839	Progression-free survival was better for the HAI and SYS group, although this did not reach statistical significance (12 months vs 7 months, p=0.2).	('better', 'PosReg', (30, 36))	('HAI', 'Var', (45, 48))	('SYS', 'Var', (53, 56))	('Progression-free survival', 'CPA', (0, 25))	('SYS', 'Chemical', '-', (53, 56))
138463	26695839	The combination of both HAI and SYS was associated with an improved overall survival compared to patients who received only SYS (30.8 months vs 18.4 months, respectively; p<0.001) (figure 4).	('improved', 'PosReg', (59, 67))	('HAI', 'Var', (24, 27))	('overall survival', 'MPA', (68, 84))	('SYS', 'Chemical', '-', (124, 127))	('SYS', 'Chemical', '-', (32, 35))	('patients', 'Species', '9606', (97, 105))
138482	26695839	Recent advancements in knowledge of the biology of these tumors and identification of novel mutations are expected to aid in the identification of new, targeted therapies that could potentially lead to improvements in survival.	('aid', 'Gene', '57379', (118, 121))	('survival', 'MPA', (218, 226))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('aid', 'Gene', (118, 121))	('improvements', 'PosReg', (202, 214))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
138490	26695839	Patients with liver confined disease who were treated with both HAI and SYS experienced better response rates and improved survival compared to patients who received only SYS (30.8 months vs 18.4 months, respectively), a survival benefit that was maintained when patients with nodal disease were included in the survival analysis (29.6 months vs 15.9 months, respectively).	('response rates', 'MPA', (95, 109))	('HAI', 'Var', (64, 67))	('SYS', 'Chemical', '-', (171, 174))	('liver confined disease', 'Disease', (14, 36))	('patients', 'Species', '9606', (263, 271))	('improved', 'PosReg', (114, 122))	('nodal disease', 'Disease', 'MESH:D013611', (277, 290))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (144, 152))	('survival', 'MPA', (123, 131))	('SYS', 'Chemical', '-', (72, 75))	('nodal disease', 'Disease', (277, 290))	('better', 'PosReg', (88, 94))
138499	26695839	Additionally, recent studies of ICC have suggested a number of potentially exploitable mutations in known cancer-related genes; continued efforts to characterize these mutations may not only help identify patients most likely to benefit from this treatment approach, but may also open up other therapeutic avenues.	('patients', 'Species', '9606', (205, 213))	('open up', 'Reg', (280, 287))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('mutations', 'Var', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
138500	26695839	In conclusion, in this retrospective review, the use of HAI chemotherapy offered a partial response in 59% of patients and was associated with a higher overall survival when compared to the use of systemic chemotherapy alone for unresectable intrahepatic cholangiocarcinoma confined to the liver and/or the portal nodes (30.8 months vs 18.4 months).	('overall survival', 'MPA', (152, 168))	('intrahepatic cholangiocarcinoma', 'Disease', (242, 273))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (242, 273))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (255, 273))	('HAI', 'Var', (56, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('patients', 'Species', '9606', (110, 118))	('higher', 'PosReg', (145, 151))
138507	33649266	The extent of the tumor was pT4N2M0 (stage IVB), thus concurrent chemoradiation therapy and adjuvant chemotherapy were performed.	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('pT4N2M0', 'Var', (28, 35))	('tumor', 'Disease', (18, 23))
138510	33649266	The extent of the bile duct tumor was pT4N1M0 (stage IVA) and that of gallbladder tumor was pT2N0M0 (stage II).	('pT4N1M0', 'Var', (38, 45))	('bile duct tumor', 'Phenotype', 'HP:0030153', (18, 33))	('bile duct tumor', 'Disease', 'MESH:D001650', (18, 33))	('bile duct tumor', 'Disease', (18, 33))	('gallbladder tumor', 'Disease', (70, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('gallbladder tumor', 'Phenotype', 'HP:0100575', (70, 87))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('pT2N0M0', 'Var', (92, 99))	('gallbladder tumor', 'Disease', 'MESH:D005706', (70, 87))
138527	33649266	The extent of the tumor was pT4N2M0, thus regarded as stage IVB.	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('pT4N2M0', 'Var', (28, 35))	('tumor', 'Disease', (18, 23))
138539	33649266	The extent of the bile duct tumor was pT4N1M0, thus regarded as stage IVA.	('pT4N1M0', 'Var', (38, 45))	('bile duct tumor', 'Phenotype', 'HP:0030153', (18, 33))	('bile duct tumor', 'Disease', 'MESH:D001650', (18, 33))	('bile duct tumor', 'Disease', (18, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
138542	33649266	The extent of the gallbladder tumor was pT2N0M0, thus regarded as stage II.	('gallbladder tumor', 'Disease', (18, 35))	('gallbladder tumor', 'Phenotype', 'HP:0100575', (18, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('pT2N0M0', 'Var', (40, 47))	('gallbladder tumor', 'Disease', 'MESH:D005706', (18, 35))
138647	33362387	Prior studies have demonstrated that the combination of AFP and CA19-9 with radiologic characteristics may aid the diagnosis of CHC.	('CHC', 'Disease', 'MESH:D019698', (128, 131))	('AFP', 'Gene', '174', (56, 59))	('combination', 'Var', (41, 52))	('CA19-9', 'Gene', (64, 70))	('CHC', 'Disease', (128, 131))	('CA19-9', 'Chemical', 'MESH:C086528', (64, 70))	('aid', 'PosReg', (107, 110))	('AFP', 'Gene', (56, 59))
138719	25999659	As shown in Table 1, the expression of S100A2 is notably higher in KKU-M213 than in KKU-100.	('S100A2', 'Gene', (39, 45))	('higher', 'PosReg', (57, 63))	('expression', 'MPA', (25, 35))	('KKU-M213', 'Var', (67, 75))	('S100A2', 'Gene', '6273', (39, 45))
138775	33142831	To determine whether E3 targets other cancer types aside from prostate cancer, we incubated a panel of 11 different cancer cell lines with increasing concentrations of DL650-E3.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('prostate cancer', 'Phenotype', 'HP:0012125', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('DL650', 'Chemical', '-', (168, 173))	('DL650-E3', 'Var', (168, 176))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('prostate cancer', 'Disease', (62, 77))	('E3', 'Chemical', '-', (21, 23))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (38, 44))	('E3', 'Chemical', '-', (174, 176))	('prostate cancer', 'Disease', 'MESH:D011471', (62, 77))
138785	33142831	DL650-E3 targeted all 3 of these breast cancer subtypes with apparent binding affinities (Kds) ranging from 172-231 nM (Figure 1a).	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('binding', 'Interaction', (70, 77))	('E3', 'Chemical', '-', (6, 8))	('DL650', 'Chemical', '-', (0, 5))	('DL650-E3', 'Var', (0, 8))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
138790	33142831	DL650-E3 targeted all 3 of these PDAC cell lines with apparent binding affinities (Kds) ranging from 196:301 nM (Figure 1c).	('PDAC', 'Phenotype', 'HP:0006725', (33, 37))	('E3', 'Chemical', '-', (6, 8))	('binding', 'Interaction', (63, 70))	('DL650', 'Chemical', '-', (0, 5))	('DL650-E3', 'Var', (0, 8))
138793	33142831	DL650-E3 targeted both cell lines, with higher affinity binding to the SK-N-AS neuroblastoma cells (Kd = 230nM) compared to the U-118MG glioblastoma cells (Kd = 486nM) (Figure 1e).	('neuroblastoma', 'Phenotype', 'HP:0003006', (79, 92))	('higher', 'PosReg', (40, 46))	('glioblastoma', 'Disease', (136, 148))	('E3', 'Chemical', '-', (6, 8))	('glioblastoma', 'Disease', 'MESH:D005909', (136, 148))	('DL650', 'Chemical', '-', (0, 5))	('DL650-E3', 'Var', (0, 8))	('SK-N-AS neuroblastoma', 'Disease', 'MESH:D009447', (71, 92))	('glioblastoma', 'Phenotype', 'HP:0012174', (136, 148))	('binding', 'Interaction', (56, 63))	('SK-N-AS neuroblastoma', 'Disease', (71, 92))
138814	33142831	Confocal microscopy revealed extensive E3 internalization into both the CRC240XIa and CRC119x colorectal PDX-derived cell lines, with punctate aptamer staining throughout the cytoplasm of both cell types, which contrasts to staining with the control aptamer C36 (Figure 3).	('CRC240XIa', 'Var', (72, 81))	('internalization', 'MPA', (42, 57))	('aptamer', 'Protein', (143, 150))	('E3', 'Chemical', '-', (39, 41))	('colorectal PDX', 'Phenotype', 'HP:0200063', (94, 108))	('CRC119x', 'Var', (86, 93))
138825	33142831	However, at 37  C, DL650-E3 internalized into the cells and was not accessible to the RNase treatment (Figure S6b).	('DL650-E3', 'Var', (19, 27))	('E3', 'Chemical', '-', (25, 27))	('DL650', 'Chemical', '-', (19, 24))	('internalized', 'MPA', (28, 40))
138827	33142831	Consistent with the E3 aptamer's ability to target a variety of different cancer cells, both the MMAE-E3 and MMAF-E3 conjugates caused cell killing across a range of different cancer cell types (Figure 4, Table S2).	('MMAE-E3', 'Chemical', '-', (97, 104))	('MMAF-E3', 'Chemical', '-', (109, 116))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('conjugates', 'Var', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('caused', 'Reg', (128, 134))	('E3', 'Chemical', '-', (114, 116))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cell killing', 'CPA', (135, 147))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('E3', 'Chemical', '-', (20, 22))	('MMAF-E3', 'Gene', (109, 116))	('E3', 'Chemical', '-', (102, 104))
138831	33142831	Regardless, the MMAE-E3 conjugate was always at least ~3-fold more potent than the control C36 conjugate and, in the case of the Jurkat cells, was over 25 times as potent.	('MMAE-E3', 'Var', (16, 23))	('more', 'PosReg', (62, 66))	('potent', 'MPA', (67, 73))	('Jurkat', 'CellLine', 'CVCL:0065', (129, 135))	('MMAE-E3', 'Chemical', '-', (16, 23))
138833	33142831	As with the MMAE conjugate, Jurkat cells were particularly sensitive to MMAF-E3, with an IC50 of only 5 nM.	('MMAF-E3', 'Var', (72, 79))	('sensitive', 'MPA', (59, 68))	('MMAF-E3', 'Chemical', '-', (72, 79))	('MMAE', 'Chemical', 'MESH:C495575', (12, 16))	('Jurkat', 'CellLine', 'CVCL:0065', (28, 34))
138834	33142831	Interestingly, while MMAF-E3 had a similar IC50 value as MMAE-E3 on the MIA PaCa-2 cells, both the PANC-1 and BxPC3 cells were more sensitive to MMAE-E3 treatment than to MMAF-E3 treatment.	('MMAE-E3', 'Var', (145, 152))	('sensitive', 'MPA', (132, 141))	('MMAF-E3', 'Chemical', '-', (171, 178))	('MMAF-E3', 'Chemical', '-', (21, 28))	('MMAE-E3', 'Chemical', '-', (57, 64))	('PANC-1', 'CellLine', 'CVCL:0480', (99, 105))	('BxPC3', 'CellLine', 'CVCL:0186', (110, 115))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (72, 82))	('MMAE-E3', 'Chemical', '-', (145, 152))
138853	33142831	While the renal cancer cell line 13-789 was not more sensitive to MMAE-E3 than to the control MMAE-C36 conjugate, MMAF-E3 engendered 13-789 cell death more effectively than the MMAF control conjugate (Figure 5a, Table S2).	('renal cancer', 'Disease', (10, 22))	('cell death', 'CPA', (140, 150))	('MMAF-E3', 'Var', (114, 121))	('renal cancer', 'Phenotype', 'HP:0009726', (10, 22))	('MMAE-E3', 'Chemical', '-', (66, 73))	('MMAE', 'Chemical', 'MESH:C495575', (66, 70))	('renal cancer', 'Disease', 'MESH:D007680', (10, 22))	('MMAF', 'Chemical', 'MESH:C513576', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('MMAF-E3', 'Chemical', '-', (114, 121))	('MMAF', 'Chemical', 'MESH:C513576', (177, 181))	('MMAE', 'Chemical', 'MESH:C495575', (94, 98))
138863	33142831	As shown in Figure 6, AF750-E3 targets and accumulates in PDX tumors, while the control aptamer AF750-C36 does not.	('PDX tumors', 'Disease', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('E3', 'Chemical', '-', (28, 30))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('AF750', 'Chemical', 'MESH:C502599', (96, 101))	('accumulates', 'PosReg', (43, 54))	('PDX tumors', 'Disease', 'MESH:D009369', (58, 68))	('AF750', 'Chemical', 'MESH:C502599', (22, 27))	('AF750-E3', 'Var', (22, 30))
138873	33142831	Most significantly, AF750-E3 localized to prostate xenografts in mice and treatment with MMAF-E3 significantly inhibited prostate tumor growth and prolonged survival in mice.	('AF750-E3', 'Var', (20, 28))	('MMAF-E3', 'Gene', (89, 96))	('survival', 'CPA', (157, 165))	('MMAF-E3', 'Chemical', '-', (89, 96))	('prolonged', 'PosReg', (147, 156))	('mice', 'Species', '10090', (65, 69))	('E3', 'Chemical', '-', (94, 96))	('prostate tumor', 'Disease', 'MESH:D011471', (121, 135))	('AF750', 'Chemical', 'MESH:C502599', (20, 25))	('E3', 'Chemical', '-', (26, 28))	('mice', 'Species', '10090', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('inhibited', 'NegReg', (111, 120))	('prostate tumor', 'Phenotype', 'HP:0100787', (121, 135))	('prostate tumor', 'Disease', (121, 135))
138878	33142831	E3 targeting to PDX cell lines extends to the E3 drug conjugates, with both MMAE-E3 and MMAF-E3 efficiently inducing cell death in certain PDX cell lines.	('MMAF-E3', 'Gene', (88, 95))	('MMAF-E3', 'Chemical', '-', (88, 95))	('E3', 'Chemical', '-', (0, 2))	('MMAE-E3', 'Chemical', '-', (76, 83))	('inducing', 'Reg', (108, 116))	('MMAE-E3', 'Var', (76, 83))	('cell death', 'CPA', (117, 127))	('E3', 'Chemical', '-', (93, 95))	('E3', 'Chemical', '-', (46, 48))	('E3', 'Chemical', '-', (81, 83))
138885	33142831	While the E3 MMAE/F drug conjugates do not elicit efficient or specific cell death in every cancer cell line tested (Figure 4c), this result is not surprising given the extensive heterogeneity of cancer cells as well as the extensive number of steps necessary for aptamer-mediated targeting to deliver the drug to its site of action in the cytosol.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('E3', 'Chemical', '-', (10, 12))	('MMAE', 'Chemical', 'MESH:C495575', (13, 17))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('E3 MMAE/F', 'Var', (10, 19))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
138897	33142831	Thus, the ability to quickly inactivate E3 targeting serves as a promising control mechanism should the issue of toxicity in normal tissue arise.	('toxicity', 'Disease', 'MESH:D064420', (113, 121))	('toxicity', 'Disease', (113, 121))	('E3 targeting', 'Protein', (40, 52))	('E3', 'Chemical', '-', (40, 42))	('inactivate', 'Var', (29, 39))
138917	33142831	Cells were then treated for 1 h with 1 or 10 muM of AF488 or DL650-labeled E3 or C36 in complete media with 1 mg/mL ssDNA.	('DL650', 'Chemical', '-', (61, 66))	('C36', 'Var', (81, 84))	('DL650-labeled E3', 'Var', (61, 77))	('AF488', 'Chemical', '-', (52, 57))	('E3', 'Chemical', '-', (75, 77))
138918	33142831	Mice bearing CRC119x PDX tumors were established as previously described.	('PDX tumors', 'Disease', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('CRC119x', 'Var', (13, 20))	('Mice', 'Species', '10090', (0, 4))	('PDX tumors', 'Disease', 'MESH:D009369', (21, 31))
138919	33142831	Mice bearing CRC119x tumors in the right flank were injected via tail vein with 2 nmol AF750-E3 or AF750-C36 and imaged at different time points up to 48 h post-aptamer injection on an IVIS Lumina XR (PerkinElmer, Waltham, MA, USA).	('AF750', 'Chemical', 'MESH:C502599', (99, 104))	('AF750-E3', 'Var', (87, 95))	('AF750-C36', 'Var', (99, 108))	('tumors', 'Disease', (21, 27))	('CRC119x', 'Var', (13, 20))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('AF750', 'Chemical', 'MESH:C502599', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('E3', 'Chemical', '-', (93, 95))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
138925	33142831	); and National Cancer Institute (NCI) Grants R21CA182330 (to M.L.)	('Cancer', 'Disease', 'MESH:D009369', (16, 22))	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Cancer', 'Disease', (16, 22))	('R21CA182330', 'Var', (46, 57))
138956	30238077	They proposed that surgeons do not need to persist in their attempts to achieve negative ductal resection margins when a diagnosis of residual carcinoma in situ is made on intraoperative examination of frozen sections.29 In 2011, Wakai et al58 reported that after stratification based on pN and pM classification, the ductal resection margin status in patients with extrahepatic cholangiocarcinoma significantly influenced long-term survival following resection in those with pN0pM0 disease but not in those with pN1 and/or pM1 disease.	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (366, 397))	('long-term', 'CPA', (423, 432))	('patients', 'Species', '9606', (352, 360))	('carcinoma in situ', 'Disease', 'MESH:D002278', (143, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (388, 397))	('extrahepatic cholangiocarcinoma', 'Disease', (366, 397))	('pN0pM0', 'Var', (476, 482))	('influenced', 'Reg', (412, 422))	('carcinoma in situ', 'Disease', (143, 160))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (143, 160))	('pN1', 'Gene', '5270', (513, 516))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (379, 397))	('pM1', 'Gene', '8834', (524, 527))	('pM1', 'Gene', (524, 527))	('pN1', 'Gene', (513, 516))
139051	28415824	ICCs were defined by topography code C22.0 for liver and morphology codes 8160 and 8161, or by topography code C22.1 (intrahepatic bile duct) and morphology codes 8010, 8020, 8140, 8160 and 8161, as previously reported.	('C22.1', 'Var', (111, 116))	('8161', 'Var', (190, 194))	('intrahepatic bile duct', 'Disease', (118, 140))	('intrahepatic bile duct', 'Disease', 'MESH:D002780', (118, 140))	('8140', 'Var', (175, 179))	('8161', 'Var', (83, 87))
139061	26497197	Patients with high density of TAMs in tumor invasive front (TIF) showed significantly higher local and overall tumor recurrence (both rho < 0.05).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('TAMs', 'Chemical', '-', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('higher', 'PosReg', (86, 92))	('high density', 'Var', (14, 26))
139062	26497197	Furthermore, high density of TAMs was associated with decreased overall (one-year 83.6 % vs. 75.1 %; three-year 61.3 % vs. 42.4 %; both rho < 0.05) and recurrence-free survival (one-year 93.9 % vs. 57.4 %; three-year 59.8 % vs. 26.2 %; both rho < 0.05).	('TAMs', 'Protein', (29, 33))	('high density', 'Var', (13, 25))	('decreased', 'NegReg', (54, 63))	('TAMs', 'Chemical', '-', (29, 33))	('recurrence-free survival', 'CPA', (152, 176))
139064	26497197	Overall survival and recurrence free survival of patients with hilar cholangiocarcinoma significantly improved in patients with low levels of TAMs in the area of TIF, when compared to those with a high density of TAMs.	('low', 'Var', (128, 131))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (69, 87))	('TAMs', 'Chemical', '-', (213, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('TAMs', 'Chemical', '-', (142, 146))	('Overall survival', 'CPA', (0, 16))	('patients', 'Species', '9606', (49, 57))	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (63, 87))	('hilar cholangiocarcinoma', 'Disease', (63, 87))	('recurrence free survival', 'CPA', (21, 45))	('improved', 'PosReg', (102, 110))	('patients', 'Species', '9606', (114, 122))
139116	26497197	18 (69.2 %) of 26 patients in high TIF CD68 group displayed tumor recurrence (rho = 0.015).	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('CD68', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('patients', 'Species', '9606', (18, 26))	('CD68', 'Gene', '968', (39, 43))	('tumor', 'Disease', (60, 65))	('high TIF', 'Var', (30, 38))
139118	26497197	Moreover, patients with high levels of macrophages in TIF showed a significantly enhanced incidence of local tumor recurrence (rho = 0.0001).	('local tumor', 'Disease', (103, 114))	('local tumor', 'Disease', 'MESH:D009364', (103, 114))	('enhanced', 'PosReg', (81, 89))	('high levels', 'Var', (24, 35))	('macrophages', 'Var', (39, 50))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('patients', 'Species', '9606', (10, 18))
139121	26497197	11 (68.8 %) and 15 (93.8 %) patients in the low CD68 TIF group did not develop overall or local tumor recurrence following R0 surgery (rho = 0.064 and rho = 0.001, respectively).	('local tumor', 'Disease', 'MESH:D009364', (90, 101))	('CD68', 'Gene', (48, 52))	('CD68', 'Gene', '968', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('low', 'Var', (44, 47))	('local tumor', 'Disease', (90, 101))	('patients', 'Species', '9606', (28, 36))
139124	26497197	Related to angioinvasion, 8 (30.8 %) of 26 and 7 (33.3 %) of 21 patients in the high or low CD68 TIF group, respectively, showed a microscopic angioinvasion (rho = 0.549).	('patients', 'Species', '9606', (64, 72))	('low', 'NegReg', (88, 91))	('CD68', 'Gene', (92, 96))	('CD68', 'Gene', '968', (92, 96))	('high', 'Var', (80, 84))
139125	26497197	18 (69.2 %) of 26 and 13 (61.9 %) of 21 patients in the high or low CD68 TIF group, respectively, showed a more advanced T stage (rho = 0.413).	('patients', 'Species', '9606', (40, 48))	('low', 'NegReg', (64, 67))	('CD68', 'Gene', (68, 72))	('CD68', 'Gene', '968', (68, 72))	('T stage', 'CPA', (121, 128))	('high', 'Var', (56, 60))
139126	26497197	Related to perineural sheet infiltration, 3 (11.5 %) of 26 and 1 (4.8 %) of 21 patients in the high or low CD68 TIF group, respectively, showed an absence of perineural sheet infiltration (rho = 0.390).	('CD68', 'Gene', (107, 111))	('absence', 'NegReg', (147, 154))	('high', 'Var', (95, 99))	('CD68', 'Gene', '968', (107, 111))	('perineural sheet infiltration', 'CPA', (158, 187))	('patients', 'Species', '9606', (79, 87))	('low', 'NegReg', (103, 106))
139128	26497197	In the univariate analysis R category, overall and local tumor recurrence, and low density of macrophages in TIF were associated with a statistically significant improvement of patient survival after resection (rho = 0.039, rho = 0.001, rho = 0.001 and rho = 0.036, respectively).	('local tumor', 'Disease', 'MESH:D009364', (51, 62))	('improvement', 'PosReg', (162, 173))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('low', 'Var', (79, 82))	('local tumor', 'Disease', (51, 62))	('patient survival', 'CPA', (177, 193))	('patient', 'Species', '9606', (177, 184))
139129	26497197	In multivariate analysis presence of TAMs in TIF (related to recurrence-free survival for all patients, as well for R0 status only) and tumor recurrence were identified as independent prognostic factors for survival (all rho < 0.05; Table 3).	('patients', 'Species', '9606', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('presence', 'Var', (25, 33))	('TAMs', 'Chemical', '-', (37, 41))
139131	26497197	The presence of TAMs in TIF affected patients' survival after resection for hilar cholangiocarcinoma.	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (76, 100))	('hilar cholangiocarcinoma', 'Disease', (76, 100))	('patients', 'Species', '9606', (37, 45))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (82, 100))	('affected', 'Reg', (28, 36))	('survival', 'MPA', (47, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('presence', 'Var', (4, 12))	('TAMs', 'Chemical', '-', (16, 20))
139132	26497197	Univariate analysis revealed a significantly better survival in the low TIF CD68 group (rho = 0.013).	('low TIF', 'Var', (68, 75))	('better', 'PosReg', (45, 51))	('CD68', 'Gene', (76, 80))	('CD68', 'Gene', '968', (76, 80))	('survival', 'CPA', (52, 60))
139137	26497197	Overall survival and recurrence free survival of patients with hilar cholangiocarcinoma were significantly better in patients with low levels of TAMs in the area of TIF when compared to those with a high density of TAMs.	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (63, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (69, 87))	('TAMs', 'Chemical', '-', (145, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('better', 'PosReg', (107, 113))	('low levels', 'Var', (131, 141))	('patients', 'Species', '9606', (117, 125))	('Overall survival', 'CPA', (0, 16))	('patients', 'Species', '9606', (49, 57))	('TAMs', 'Chemical', '-', (215, 219))	('hilar cholangiocarcinoma', 'Disease', (63, 87))	('recurrence free survival', 'CPA', (21, 45))
139140	26497197	High density of TAMs in TIF was an independent negative prognostic factor for recurrence-free survival.	('High density', 'Var', (0, 12))	('recurrence-free survival', 'CPA', (78, 102))	('TAMs', 'Chemical', '-', (16, 20))	('negative', 'NegReg', (47, 55))
139156	26497197	To date, tumor progression is successfully treated by depletion of TAMs in preclinical animal models.	('depletion', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('TAMs', 'Chemical', '-', (67, 71))
139167	26497197	In conclusion, in the current study we demonstrate for the first time that presence of CD68-positive TAMs in tumor invasive front correlates with tumor recurrence and serves as an independent prognostic factor for survival in hilar cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('CD68', 'Gene', (87, 91))	('CD68', 'Gene', '968', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (232, 250))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('TAMs', 'Chemical', '-', (101, 105))	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (226, 250))	('hilar cholangiocarcinoma', 'Disease', (226, 250))	('presence', 'Var', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
139230	25132998	In biliary tract cancers, carcinoma cases expressing MHC class II but lacking costimulatory molecules (CD80 and CD86) are found in 54% (Figure 4(a)).	('CD86', 'Gene', '942', (112, 116))	('CD86', 'Gene', (112, 116))	('biliary tract cancers', 'Disease', 'MESH:D001661', (3, 24))	('biliary tract cancers', 'Disease', (3, 24))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('CD80', 'Gene', (103, 107))	('carcinoma', 'Disease', 'MESH:D002277', (26, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('CD80', 'Gene', '941', (103, 107))	('carcinoma', 'Disease', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (3, 23))	('MHC class II', 'Var', (53, 65))
139241	25132998	Further examination of cholangiocarcinoma cells with four primer sets revealed a Foxp3 splice variant lacking exon 3 that caused a frameshift at the C-terminus creating a novel amino acid, which has been reported in a melanoma cell line.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (23, 41))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (23, 41))	('frameshift', 'Var', (131, 141))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('melanoma', 'Disease', (218, 226))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('Foxp3', 'Gene', '50943', (81, 86))	('cholangiocarcinoma', 'Disease', (23, 41))	('caused', 'Reg', (122, 128))	('Foxp3', 'Gene', (81, 86))
139262	25132998	In the IgG4-SC case, moreover, the BilIN lesion expressed a mutated form of the p53 tumor suppressor protein, suggesting that cholangiocarcinoma is possibly associated with IgG4-SC as precursors of malignancy.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (126, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('p53', 'Gene', (80, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (126, 144))	('tumor', 'Disease', (84, 89))	('malignancy', 'Disease', 'MESH:D009369', (198, 208))	('p53', 'Gene', '7157', (80, 83))	('mutated', 'Var', (60, 67))	('malignancy', 'Disease', (198, 208))	('cholangiocarcinoma', 'Disease', (126, 144))
139492	31795085	For in silico meta-analysis, we integrated three GEO datasets (GSE31370, GSE32879 and 32225) including 18 normal and 171 CCA patients by using Limma R package.	('CCA', 'Disease', (121, 124))	('GSE32879 and 32225', 'Var', (73, 91))	('rat', 'Species', '10116', (37, 40))	('GSE31370', 'Var', (63, 71))	('patients', 'Species', '9606', (125, 133))
139503	31795085	Analyzing the mRNA data for 19 DEGs, DBH, and FOS expression were found to be significantly overexpressed (p < 0.05) with the altered group.	('altered', 'Var', (126, 133))	('DBH', 'Gene', '1621', (37, 40))	('FOS', 'Gene', (46, 49))	('DBH', 'Gene', (37, 40))	('overexpressed', 'PosReg', (92, 105))	('FOS', 'Gene', '2353', (46, 49))
139528	31795085	In addition, the transcriptomics alterations presented some genes that were related to clinical data with CCA.	('genes', 'Gene', (60, 65))	('rat', 'Species', '10116', (37, 40))	('alterations', 'Var', (33, 44))	('CCA', 'Disease', (106, 109))	('related', 'Reg', (76, 83))
139551	31795085	Aberrant expression of CCND-1 may cause an imbalance of the cell cycle, resulting in tumorigenesis.	('resulting', 'Reg', (72, 81))	('tumor', 'Disease', (85, 90))	('Aberrant expression', 'Var', (0, 19))	('imbalance of the cell cycle', 'Phenotype', 'HP:0011018', (43, 70))	('cause', 'Reg', (34, 39))	('CCND-1', 'Gene', (23, 29))	('imbalance', 'Phenotype', 'HP:0002172', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('imbalance of the', 'MPA', (43, 59))	('CCND-1', 'Gene', '595', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
139565	31795085	Interestingly, EGR-1 alterations may have a key role in responsive alcohol exposure mechanisms, which provides an important strategy for the development of a new molecular therapy for the treatment of CCA.	('alcohol', 'Chemical', 'MESH:D000438', (67, 74))	('CCA', 'Disease', (201, 204))	('EGR-1', 'Gene', (15, 20))	('rat', 'Species', '10116', (25, 28))	('EGR-1', 'Gene', '1958', (15, 20))	('rat', 'Species', '10116', (126, 129))	('alterations', 'Var', (21, 32))
139652	30299561	nucleotides detection, acts as a mechanism for tumor suppression by regulating cell growth, migration and invasion.	('rat', 'Species', '10116', (95, 98))	('suppression', 'NegReg', (53, 64))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('invasion', 'CPA', (106, 114))	('migration', 'CPA', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('nucleotides detection', 'Var', (0, 21))	('cell growth', 'CPA', (79, 90))	('tumor', 'Disease', (47, 52))
139690	30299561	First, lncuCyte live cell imaging showed that ATP inhibited migration in normal ciliated cholangiocytes but, in contrast, induced migration in normal deciliated and iCCA cells (Supplemental Figure 2A,B).	('ATP', 'Var', (46, 49))	('induced', 'Reg', (122, 129))	('rat', 'Species', '10116', (133, 136))	('migration', 'CPA', (60, 69))	('migration', 'CPA', (130, 139))	('CCA', 'Phenotype', 'HP:0030153', (166, 169))	('rat', 'Species', '10116', (63, 66))	('ATP', 'Chemical', 'MESH:D000255', (46, 49))	('inhibited', 'NegReg', (50, 59))
139701	30299561	Additionally, we tested the effects of ATP on the phosphorylation of LKB1 at S428, which is required for activation of LKB1.	('tested', 'Reg', (17, 23))	('ATP', 'Chemical', 'MESH:D000255', (39, 42))	('LKB1', 'Gene', (69, 73))	('S428', 'Var', (77, 81))
139709	30299561	The results showed that knockdown of LKB1 abolished the inhibition of migration normally observed in control cholangiocytes (Figure 2E and Supplemental Figure 3B).	('inhibition', 'NegReg', (56, 66))	('abolished', 'NegReg', (42, 51))	('rat', 'Species', '10116', (73, 76))	('knockdown', 'Var', (24, 33))	('LKB1', 'Gene', (37, 41))
139713	30299561	Therefore, we generated the stable transfected normal cell lines NHC P2Y1 (NHC shRNA-P2Y1) and NHC P2Y11 (NHC shRNA-P2Y11) knockdowns (Figure 3A).	('rat', 'Species', '10116', (18, 21))	('P2Y11', 'Gene', '5032', (116, 121))	('P2Y1', 'Gene', '5028', (116, 120))	('P2Y1', 'Gene', (69, 73))	('P2Y11', 'Gene', (116, 121))	('P2Y11', 'Gene', '5032', (99, 104))	('P2Y1', 'Gene', '5028', (85, 89))	('P2Y1', 'Gene', '5028', (99, 103))	('P2Y11', 'Gene', (99, 104))	('P2Y1', 'Gene', (99, 103))	('knockdowns', 'Var', (123, 133))	('P2Y1', 'Gene', '5028', (69, 73))	('P2Y1', 'Gene', (85, 89))	('P2Y1', 'Gene', (116, 120))
139714	30299561	We found that the ATP-induced activation of LKB1 was abolished by P2Y11 knockdown but not by P2Y1, suggesting that this regulation is mediated by P2Y11 (Figure 3B).	('abolished', 'NegReg', (53, 62))	('P2Y1', 'Gene', (146, 150))	('P2Y1', 'Gene', (93, 97))	('P2Y1', 'Gene', (66, 70))	('activation', 'PosReg', (30, 40))	('P2Y11', 'Gene', '5032', (66, 71))	('P2Y1', 'Gene', '5028', (66, 70))	('P2Y11', 'Gene', (66, 71))	('P2Y11', 'Gene', '5032', (146, 151))	('P2Y1', 'Gene', '5028', (93, 97))	('P2Y1', 'Gene', '5028', (146, 150))	('ATP', 'Chemical', 'MESH:D000255', (18, 21))	('P2Y11', 'Gene', (146, 151))	('LKB1', 'Gene', (44, 48))	('knockdown', 'Var', (72, 81))
139716	30299561	In addition, we evaluated the effect of P2Y11 knockdown on cell proliferation and no significant difference was found compared with NHC SCR (Figure 3D).	('P2Y11', 'Gene', '5032', (40, 45))	('P2Y11', 'Gene', (40, 45))	('rat', 'Species', '10116', (71, 74))	('knockdown', 'Var', (46, 55))	('cell proliferation', 'CPA', (59, 77))
139721	30299561	To elucidate the mechanism by which the ciliary-dependent detection of ATP induces inhibition of migration and invasion in normal cholangiocytes, we evaluated the possibility that activated LKB1 inhibits AKT, which is a key regulator of several cellular pathways involved in metabolism, cell survival, migration and invasion among others.	('migration', 'CPA', (97, 106))	('inhibits', 'NegReg', (195, 203))	('rat', 'Species', '10116', (305, 308))	('AKT', 'Gene', '207', (204, 207))	('activated', 'Var', (180, 189))	('AKT', 'Gene', (204, 207))	('LKB1', 'Gene', (190, 194))	('ATP', 'Chemical', 'MESH:D000255', (71, 74))	('rat', 'Species', '10116', (100, 103))
139726	30299561	Moreover, phosphorylation of PTEN induced a significant increment of the total PTEN (Figure 4B).	('PTEN', 'Gene', (29, 33))	('PTEN', 'Gene', '5728', (29, 33))	('increment', 'PosReg', (56, 65))	('PTEN', 'Gene', (79, 83))	('phosphorylation', 'Var', (10, 25))	('PTEN', 'Gene', '5728', (79, 83))
139731	30299561	Moreover, we found that NYK80 abolished the inhibition of migration induced by ATP in normal ciliated cholangiocytes (Figure 5B).	('NYK80', 'Var', (24, 29))	('ATP', 'Chemical', 'MESH:D000255', (79, 82))	('rat', 'Species', '10116', (61, 64))	('inhibition', 'NegReg', (44, 54))	('abolished', 'NegReg', (30, 39))	('migration', 'CPA', (58, 67))
139747	30299561	The results showed that HMC induced apoptosis in normal and deciliated cholangiocytes and iCCA cells, but has no effect on LKB1-shRNA normal cholangiocytes (Figure 7E and Supplemental Figure 5).	('HMC', 'Var', (24, 27))	('apoptosis', 'CPA', (36, 45))	('CCA', 'Phenotype', 'HP:0030153', (91, 94))	('HMC', 'Chemical', 'MESH:C033022', (24, 27))
139750	30299561	Furthermore, consistently with the in vitro experiments, HMC induced significant apoptosis compared to controls (Figure 7G).	('HMC', 'Var', (57, 60))	('apoptosis', 'CPA', (81, 90))	('HMC', 'Chemical', 'MESH:C033022', (57, 60))
139760	30299561	While the activation of Galpha0 leads to activation of RhoA, activation of Galpha12 leads to activation of Rac, which participates in the cytoskeleton rearrangement involved in migration.	('RhoA', 'Gene', (55, 59))	('Galpha', 'Gene', '8802', (75, 81))	('activation', 'PosReg', (93, 103))	('Galpha', 'Gene', '8802', (24, 30))	('Galpha12', 'Gene', (75, 83))	('Rac', 'Protein', (107, 110))	('Galpha', 'Gene', (24, 30))	('RhoA', 'Gene', '387', (55, 59))	('rat', 'Species', '10116', (180, 183))	('Galpha12', 'Gene', '2768', (75, 83))	('activation', 'PosReg', (41, 51))	('activation', 'Var', (61, 71))	('Galpha', 'Gene', (75, 81))
139773	30299561	The fact that ciliated cholangiocytes with LKB1 shRNA knockdown migrate at the same rate as scramble controls when treated with ATP highlights the importance of LKB1 activation in this process.	('rat', 'Species', '10116', (67, 70))	('knockdown', 'Var', (54, 63))	('rat', 'Species', '10116', (84, 87))	('ATP', 'Chemical', 'MESH:D000255', (128, 131))	('LKB1', 'Gene', (43, 47))
139774	30299561	Recently, Zhang et al showed that LKB1 loss in melanoma cell lines does not promote migration and invasion, however, loss of LKB1 cooperates with other genetic alterations to induce migration and invasion.	('migration', 'CPA', (182, 191))	('induce', 'PosReg', (175, 181))	('LKB1', 'Gene', (34, 38))	('rat', 'Species', '10116', (135, 138))	('loss', 'Var', (117, 121))	('invasion', 'CPA', (196, 204))	('LKB1', 'Gene', (125, 129))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('loss', 'NegReg', (39, 43))	('rat', 'Species', '10116', (164, 167))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('rat', 'Species', '10116', (185, 188))	('rat', 'Species', '10116', (87, 90))
139777	30299561	There is a cluster of PTEN phosphorylations (Ser380/Thr382/Thr383) reported to be phosphorylated by LKB1, which induce a conformational change that stabilizes the protein but decreases its functionality.	('decreases', 'NegReg', (175, 184))	('LKB1', 'Gene', (100, 104))	('Ser380/Thr382/Thr383', 'Var', (45, 65))	('protein', 'Protein', (163, 170))	('Thr382', 'Chemical', '-', (52, 58))	('conformational change', 'MPA', (121, 142))	('Ser380', 'Chemical', '-', (45, 51))	('Thr383', 'Chemical', '-', (59, 65))	('PTEN', 'Gene', (22, 26))	('stabilizes', 'MPA', (148, 158))	('functionality', 'MPA', (189, 202))	('PTEN', 'Gene', '5728', (22, 26))
139779	30299561	However, LKB1-induced phosphorylation and stabilization of PTEN results in dephosphorylation of AKT, suggesting that phosphorylation in this cluster induces stabilization and activation of PTEN that leads to inhibition of the PI3K-AKT pathway in normal cholangiocytes.	('PTEN', 'Gene', (189, 193))	('phosphorylation', 'Var', (117, 132))	('inhibition', 'NegReg', (208, 218))	('AKT', 'Gene', (96, 99))	('PTEN', 'Gene', '5728', (189, 193))	('AKT', 'Gene', '207', (231, 234))	('activation', 'PosReg', (175, 185))	('stabilization', 'MPA', (157, 170))	('AKT', 'Gene', (231, 234))	('AKT', 'Gene', '207', (96, 99))	('dephosphorylation', 'MPA', (75, 92))	('PTEN', 'Gene', (59, 63))	('PTEN', 'Gene', '5728', (59, 63))
139788	30299561	Since filopodia is associated with the malignant phenotype of cancer cells and tumor cell transformation, migration and invasion, dysfunction of the cell chemosensory function caused by ciliary loss may contribute to increased filopodial activity and motility that is associated with increased metastatic and invasive potential of the cell.	('motility', 'CPA', (251, 259))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('loss', 'NegReg', (194, 198))	('rat', 'Species', '10116', (109, 112))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('dysfunction', 'Var', (130, 141))	('filopodial activity', 'CPA', (227, 246))	('increased', 'PosReg', (217, 226))
139789	30299561	Therefore, our data, showing that LKB1 is activated by a ciliary-dependent mechanism that regulates migration and invasion in normal cholangiocytes, suggest the loss of primary cilia in iCCA may contribute not only to cholangiocarcinoma development as we previously described, but also to metastasis and progression of the disease.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (218, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('rat', 'Species', '10116', (103, 106))	('metastasis', 'CPA', (289, 299))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (218, 236))	('contribute', 'Reg', (195, 205))	('primary cilia', 'CPA', (169, 182))	('CCA', 'Phenotype', 'HP:0030153', (187, 190))	('cholangiocarcinoma', 'Disease', (218, 236))	('loss', 'Var', (161, 165))	('iCCA', 'Gene', (186, 190))
139791	30299561	In line with this, a recent publication shows that patients with iCCA and low levels of LKB1 protein in tumors have worse prognoses compared to patients with higher LKB1 expression, suggesting that LKB1 is involved, at least, in the progression of the disease; even more, the activation of LKB1 by phosphorylation at S428 mediates the cell cycle arrest induced by the combined lovastatin and gefitinib treatment in HuH-28 cells.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('lovastatin', 'Chemical', 'MESH:D008148', (377, 387))	('activation', 'PosReg', (276, 286))	('phosphorylation at S428', 'Var', (298, 321))	('CCA', 'Phenotype', 'HP:0030153', (66, 69))	('gefitinib', 'Chemical', 'MESH:D000077156', (392, 401))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('arrest', 'Disease', 'MESH:D006323', (346, 352))	('patients', 'Species', '9606', (144, 152))	('patients', 'Species', '9606', (51, 59))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (335, 352))	('HuH-28', 'CellLine', 'CVCL:2955', (415, 421))	('arrest', 'Disease', (346, 352))	('LKB1', 'Gene', (290, 294))
139814	30736852	Previously, literatures have demonstrated that gammadelta T cells are the "first line of defense" as an antitumor effector cell, for instance, gammadelta T cells provide an early source of IFN-gamma in the tumor microenvironment.	('IFN-gamma', 'Gene', '3458', (189, 198))	('IFN-gamma', 'Gene', (189, 198))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (206, 211))	('gammadelta T', 'Var', (143, 155))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
139826	30736852	The MRI scan performed on Feb. 24th, 2015 showed a lesion in patient's liver, therefore, he received lymph node resection on Apr.	('Apr', 'Gene', '5366', (125, 128))	('patient', 'Species', '9606', (61, 68))	('Apr', 'Gene', (125, 128))	('lesion', 'Var', (51, 57))
139834	30736852	Following this procedure, a cell culture formula, which we developed (patent pending) that included zoledronic acid and a variety of interleukin was applied specifically to expand Vgamma9Vdelta2 T cells in vitro (culture media components and mechanism will be discussed in detail in our preparing article).	('Vgamma9Vdelta2 T', 'Var', (180, 196))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (100, 115))	('expand', 'PosReg', (173, 179))	('Vdelta2 T', 'CellLine', 'CVCL:0042', (187, 196))
139843	30736852	The results showed that gammadelta T cell therapy could greatly improve immunity by regulating the immunological functions of these immune cells, as the administration of gammadelta T cells was associated with an increase of the functional CD3 + CD4 + CD28+ T cells and CD3 + CD8 + CD28+ T cells, and decrease of CD3 + CD4 + CD28- T cells and CD3 + CD4 + CD28-CD57+ T cells.	('CD28', 'Gene', '940', (355, 359))	('decrease', 'NegReg', (301, 309))	('CD57', 'Gene', '27087', (360, 364))	('CD28', 'Gene', '940', (252, 256))	('gammadelta', 'Var', (171, 181))	('increase', 'PosReg', (213, 221))	('CD8', 'Gene', '925', (276, 279))	('CD28', 'Gene', '940', (282, 286))	('CD57', 'Gene', (360, 364))	('CD4', 'Gene', '920', (319, 322))	('CD28', 'Gene', (325, 329))	('CD28', 'Gene', (355, 359))	('CD4', 'Gene', '920', (246, 249))	('CD8', 'Gene', (276, 279))	('CD4', 'Gene', '920', (349, 352))	('CD4', 'Gene', (319, 322))	('CD28', 'Gene', (252, 256))	('CD4', 'Gene', (246, 249))	('CD28', 'Gene', '940', (325, 329))	('CD28', 'Gene', (282, 286))	('CD4', 'Gene', (349, 352))
139850	30736852	In this report, we evaluated the safety and efficacy of allogenic Vgamma9Vdelta2 T cells for the first time as a new type of immunotherapy to treat a patient (stage IV Cholangiocarcinoma and liver transplanted) with recurrent mediastinal lymph node metastasis.	('Vgamma9Vdelta2', 'Var', (66, 80))	('stage IV Cholangiocarcinoma', 'Disease', (159, 186))	('patient', 'Species', '9606', (150, 157))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (168, 186))	('Vdelta2 T', 'CellLine', 'CVCL:0042', (73, 82))	('mediastinal lymph node metastasis', 'Phenotype', 'HP:0100721', (226, 259))	('stage IV Cholangiocarcinoma', 'Disease', 'MESH:D018281', (159, 186))
139858	30736852	As a further step, our work here revealed that Vdelta2 subpopulation transfer therapy can affect alphabeta T cell differentiation and NK maturation, particularly, for example, by reducing exhausted and aged alphabeta T cells and elevating functional alphabeta T cells.	('affect', 'Reg', (90, 96))	('functional alphabeta', 'Disease', (239, 259))	('alphabeta T', 'Disease', 'MESH:D001260', (250, 261))	('alphabeta T', 'Disease', (97, 108))	('reducing', 'NegReg', (179, 187))	('alphabeta T', 'Disease', (207, 218))	('elevating', 'PosReg', (229, 238))	('alphabeta T', 'Disease', (250, 261))	('NK maturation', 'CPA', (134, 147))	('alphabeta T', 'Disease', 'MESH:D001260', (97, 108))	('functional alphabeta', 'Disease', 'OMIM:608852', (239, 259))	('alphabeta T', 'Disease', 'MESH:D001260', (207, 218))	('Vdelta2', 'Var', (47, 54))
139880	27516528	Colonization with liver flukes Opisthorchis viverrini (Thailand, Laos PDR and Vietnam) and Clonorchis sinensis (China, Taiwan, eastern Russia, Korea and Vietnam) causes chronic inflammation and is a risk factor for the development of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (234, 252))	('Opisthorchis viverrini', 'Species', '6198', (31, 53))	('Clonorchis sinensis', 'Var', (91, 110))	('liver flukes', 'Species', '6192', (18, 30))	('Clonorchis sinensis', 'Species', '79923', (91, 110))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (234, 252))	('causes', 'Reg', (162, 168))
139903	22025972	studied the relationship among dietary and supplementary vitamin D, physical activity, body mass index, and sunlight exposure in 47,800 individuals and found a strong association between low levels of vitamin D3 and increased cancer incidence, particularly for cancers of the digestive system.	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('vitamin D', 'Chemical', 'MESH:D014807', (201, 210))	('cancers', 'Disease', 'MESH:D009369', (261, 268))	('low levels', 'Var', (187, 197))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('vitamin D', 'Chemical', 'MESH:D014807', (57, 66))	('sunlight exposure', 'Phenotype', 'HP:0000992', (108, 125))	('cancer', 'Disease', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('vitamin D3', 'Chemical', 'MESH:D002762', (201, 211))	('low levels of vitamin D3', 'Phenotype', 'HP:0100512', (187, 211))	('increased', 'PosReg', (216, 225))	('cancers', 'Disease', (261, 268))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
139906	22025972	Amplification of 20q13.2, which harbors the CYP24 gene, has been reported in gastric and breast cancers.	('CYP24', 'Gene', (44, 49))	('Amplification', 'Var', (0, 13))	('breast cancers', 'Disease', 'MESH:D001943', (89, 103))	('breast cancers', 'Disease', (89, 103))	('reported', 'Reg', (65, 73))	('CYP24', 'Gene', '1591', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('gastric', 'Disease', (77, 84))	('breast cancers', 'Phenotype', 'HP:0003002', (89, 103))
139942	22025972	To investigate the underlying mechanism involved in the regulation of viability by vitamin D3, we examined Hh signaling because cyclopamine, a specific inhibitor of the Hh signaling pathway, almost completely suppressed cancer cell viability (Fig.	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('suppressed', 'NegReg', (209, 219))	('cyclopamine', 'Var', (128, 139))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('vitamin D3', 'Chemical', 'MESH:D002762', (83, 93))	('cancer', 'Disease', (220, 226))	('cyclopamine', 'Chemical', 'MESH:C000541', (128, 139))
139949	22025972	In particular, we have shown previously that inhibiting Hh signaling reduces bcl2 expression in gastric cancer cells.	('inhibiting', 'Var', (45, 55))	('expression', 'MPA', (82, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('bcl2', 'Gene', (77, 81))	('reduces', 'NegReg', (69, 76))	('Hh signaling', 'Protein', (56, 68))	('bcl2', 'Gene', '596', (77, 81))	('gastric cancer', 'Disease', (96, 110))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))
139968	22025972	reported that vitamin D3 inhibits pancreatic cancer cell viability in the presence of 0.5% serum; however, it does not inhibit the pancreatic cancer cell viability in the presence of 10% serum.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('inhibits', 'NegReg', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('pancreatic cancer', 'Disease', 'MESH:D010190', (131, 148))	('pancreatic cancer', 'Disease', (131, 148))	('vitamin D3', 'Chemical', 'MESH:D002762', (14, 24))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('pancreatic cancer', 'Disease', (34, 51))	('vitamin', 'Var', (14, 21))
139981	21731504	We also identified post-transcriptional protein variants for six collagens and lysine hydroxylation modifications for 14 collagens.	('lysine', 'Chemical', 'MESH:D008239', (79, 85))	('lysine hydroxylation modifications', 'MPA', (79, 113))	('variants', 'Var', (48, 56))
139982	21731504	Tumor-associated collagen proteomes were similar in both models with increased expression of collagens type IV, VI, VII, X, XIV, XV, XVI, and XVIII.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('increased', 'PosReg', (69, 78))	('expression', 'MPA', (79, 89))	('XIV', 'Var', (124, 127))	('VI', 'Gene', '12835', (116, 118))	('VI', 'Gene', '12835', (134, 136))	('VI', 'Gene', '12835', (112, 114))	('VI', 'Gene', '12835', (143, 145))	('increased expression of collagens type IV', 'Phenotype', 'HP:0030095', (69, 110))	('collagens', 'Protein', (93, 102))
139997	21731504	Another relevant model is mice with liver specific deletion of the phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (Pten).	('phosphoinositide 3-kinase', 'Gene', (67, 92))	('Pten', 'Gene', (132, 136))	('phosphoinositide 3-kinase', 'Gene', '18708', (67, 92))	('deletion', 'Var', (51, 59))	('mice', 'Species', '10090', (26, 30))
140009	21731504	Steatosis is also particularly pronounced in the Pten null liver as shown by the accumulation of lipid droplets (Figure 1A).	('Steatosis', 'Phenotype', 'HP:0001397', (0, 9))	('lipid', 'Chemical', 'MESH:D008055', (97, 102))	('Steatosis', 'Disease', 'MESH:D005234', (0, 9))	('Pten', 'Var', (49, 53))	('Steatosis', 'Disease', (0, 9))	('accumulation', 'PosReg', (81, 93))
140023	21731504	Col4a2 mRNA was strongly up-regulated in tumors of both models with 10.8-fold increase (p = 0.008) in PDGFC Tg mice (Figure 4A) and 4.8-fold increase (p = 0.002) in Pten null mice (Figure 4B).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('up-regulated', 'PosReg', (25, 37))	('mice', 'Species', '10090', (175, 179))	('Col4a2', 'Gene', '12827', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('PDGFC Tg', 'Var', (102, 110))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('mice', 'Species', '10090', (111, 115))	('increase', 'PosReg', (78, 86))	('Col4a2', 'Gene', (0, 6))	('mRNA', 'MPA', (7, 11))
140026	21731504	Its expression was significantly increased in tumors in both models with 6.8-fold increase (p = 0.009) in PDGFC Tg mice (Figure 4C) and 6.3-fold increase (p = 0.003) in Pten null mice (Figure 4D).	('mice', 'Species', '10090', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('increase', 'PosReg', (145, 153))	('expression', 'MPA', (4, 14))	('PDGFC Tg', 'Var', (106, 114))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('increased', 'PosReg', (33, 42))	('increase', 'PosReg', (82, 90))	('tumors', 'Disease', (46, 52))	('mice', 'Species', '10090', (115, 119))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
140028	21731504	Peptides specific to post-transcriptional variants were identified for Col1a1, Col6a2, Col6a3 and Col18a1 (Figure 5).	('Col6a3', 'Gene', (87, 93))	('Col1a1', 'Gene', '12842', (71, 77))	('Col18a1', 'Gene', '12822', (98, 105))	('variants', 'Var', (42, 50))	('Col6a2', 'Gene', (79, 85))	('Col6a2', 'Gene', '12834', (79, 85))	('Col18a1', 'Gene', (98, 105))	('Col6a3', 'Gene', '12835', (87, 93))	('Col1a1', 'Gene', (71, 77))
140031	21731504	Col6a2 canonical mRNA was strongly up-regulated in tissue adjacent to tumors in both models with 23.4-fold increase (p = 0.01) in PDGFC Tg mice (Figure 6A) and 6.0-fold increase (p = 0.02) in Pten null mice (Figure 6B).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('increase', 'PosReg', (107, 115))	('mice', 'Species', '10090', (202, 206))	('Col6a2', 'Gene', (0, 6))	('Col6a2', 'Gene', '12834', (0, 6))	('PDGFC Tg', 'Var', (130, 138))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('mRNA', 'MPA', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mice', 'Species', '10090', (139, 143))	('up-regulated', 'PosReg', (35, 47))
140032	21731504	A correlated up-regulation was observed for Col6a2 splice variant with 8.5-fold increase (p = 0.01) in PDGFC Tg mice (Figure 6C) and 3.4-fold increase (p = 0.02) in Pten null mice (Figure 6D).	('Col6a2', 'Gene', '12834', (44, 50))	('mice', 'Species', '10090', (175, 179))	('increase', 'PosReg', (80, 88))	('PDGFC Tg', 'Var', (103, 111))	('up-regulation', 'PosReg', (13, 26))	('Col6a2', 'Gene', (44, 50))	('mice', 'Species', '10090', (112, 116))
140033	21731504	Col18a1 canonical mRNA also called NC1-764, was unchanged in liver tissue and tumors of PDGFC Tg mice (Figure 7A) and decreased in tumors of Pten null mice (5.5-fold, p = 0.002) (Figure 7B).	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('PDGFC Tg', 'Var', (88, 96))	('mice', 'Species', '10090', (151, 155))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('mice', 'Species', '10090', (97, 101))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('decreased', 'NegReg', (118, 127))	('tumors', 'Disease', (131, 137))	('Col18a1', 'Gene', '12822', (0, 7))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('Col18a1', 'Gene', (0, 7))
140034	21731504	In contrast, Col18a1 variant NC1-301 strongly increased in tumors in both models with 32.8-fold increase (p = 0.01) in PDGFC Tg mice (Figure 7C) and 118.7-fold increase (p = 0.0006) in Pten null mice (Figure 7D).	('mice', 'Species', '10090', (195, 199))	('increased', 'PosReg', (46, 55))	('increase', 'PosReg', (160, 168))	('tumors', 'Disease', (59, 65))	('mice', 'Species', '10090', (128, 132))	('variant', 'Var', (21, 28))	('Col18a1', 'Gene', '12822', (13, 20))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('Col18a1', 'Gene', (13, 20))	('NC1-301', 'Gene', (29, 36))	('increase', 'PosReg', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
140035	21731504	Col18a1 variant NC1-301 also strongly increased in adjacent tissue in both models with 16.9-fold increase (p = 0.01) in PDGFC Tg mice (Figure 7C) and 50.7-fold increase (p = 0.001) in Pten null mice (Figure 7D).	('variant', 'Var', (8, 15))	('increase', 'PosReg', (97, 105))	('Col18a1', 'Gene', (0, 7))	('increase', 'PosReg', (160, 168))	('NC1-301', 'Gene', (16, 23))	('Col18a1', 'Gene', '12822', (0, 7))	('mice', 'Species', '10090', (129, 133))	('adjacent tissue', 'CPA', (51, 66))	('mice', 'Species', '10090', (194, 198))	('increased', 'PosReg', (38, 47))
140036	21731504	Lysine hydroxylation is a well-known post-translational modification of type I, III and V collagens and contributes to matrix remodeling and stiffening.	('matrix remodeling', 'CPA', (119, 136))	('Lysine hydroxylation', 'Var', (0, 20))	('contributes', 'Reg', (104, 115))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))	('stiffening', 'CPA', (141, 151))
140039	21731504	Other collagens with modified lysine residues included all six type IV collagens, COL6A2, COL16A1 and COL27A1 (Table 2).	('COL6A2', 'Gene', '12834', (82, 88))	('COL16A1', 'Gene', (90, 97))	('COL6A2', 'Gene', (82, 88))	('lysine', 'Chemical', 'MESH:D008239', (30, 36))	('modified lysine residues', 'Var', (21, 45))	('COL16A1', 'Gene', '107581', (90, 97))	('COL27A1', 'Gene', '373864', (102, 109))	('COL27A1', 'Gene', (102, 109))
140042	21731504	Inversely, the lysyl hydroxylation status of COL6A2 slightly decreased in the tumors compared to the fibrotic and steatotic livers in both models decreasing from 29% to 17% in PDGFC Tg mice and from 15% to 13% in Pten null mice (Figure 8).	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('decreasing', 'NegReg', (146, 156))	('steatotic livers', 'Phenotype', 'HP:0001397', (114, 130))	('lysyl hydroxylation status', 'MPA', (15, 41))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('mice', 'Species', '10090', (223, 227))	('steatotic liver', 'Phenotype', 'HP:0001397', (114, 129))	('mice', 'Species', '10090', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('COL6A2', 'Gene', (45, 51))	('COL6A2', 'Gene', '12834', (45, 51))	('decreased', 'NegReg', (61, 70))	('PDGFC Tg', 'Var', (176, 184))
140048	21731504	Laminin alpha5 mRNA was only weakly expressed in fibrotic and steatotic liver in both models but was significantly up-regulated in tumors in both models (6.4-fold (p = 0.01) in PDGFC Tg mice and 10.5-fold (p = 0.0002) in Pten null mice) (Figure 10).	('Laminin alpha5', 'Gene', (0, 14))	('steatotic liver', 'Phenotype', 'HP:0001397', (62, 77))	('PDGFC Tg', 'Var', (177, 185))	('Laminin alpha5', 'Gene', '16776', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('up-regulated', 'PosReg', (115, 127))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('mice', 'Species', '10090', (186, 190))	('tumors', 'Disease', (131, 137))	('mice', 'Species', '10090', (231, 235))	('tumors', 'Disease', 'MESH:D009369', (131, 137))
140050	21731504	Nidogen 1 mRNA was increased by 7.2-fold (p = 0.008) and by 8.9-fold (p = 0.0003) in tumors from PDGFC Tg and Pten null mice, respectively (Figure 11A, 11B).	('Nidogen 1', 'Gene', (0, 9))	('mice', 'Species', '10090', (120, 124))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('PDGFC', 'Var', (97, 102))	('Nidogen 1', 'Gene', '18073', (0, 9))	('increased', 'PosReg', (19, 28))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mRNA', 'MPA', (10, 14))	('tumors', 'Disease', (85, 91))
140051	21731504	Similarly, nidogen 1 protein was increased by 6.1-fold (p = 0.01) and by 15.3-fold (p = 0.001) in tumors from PDGFC Tg and Pten null mice, respectively (Figure 11C, 11D).	('mice', 'Species', '10090', (133, 137))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('nidogen 1', 'Gene', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('increased', 'PosReg', (33, 42))	('nidogen 1', 'Gene', '18073', (11, 20))	('PDGFC Tg', 'Var', (110, 118))
140059	21731504	Integrin alpha8 mRNA was increased in PDGFC Tg liver tissue at all disease stages by 16.2- to 24.0-fold (Figure 14C) but remained unchanged in Pten null liver (Figure 14D).	('increased', 'PosReg', (25, 34))	('Integrin alpha8', 'Gene', (0, 15))	('mRNA', 'MPA', (16, 20))	('PDGFC Tg', 'Var', (38, 46))	('Integrin alpha8', 'Gene', '241226', (0, 15))
140062	21731504	High ratios of COL18A1 variant NC1-301 over COL18A1 variant NC1-764, high ratios of integrin alpha6 over integrin alpha8 and high levels of integrin alpha3 were specifically observed in the Pten null tumors.	('variant', 'Var', (52, 59))	('observed', 'Reg', (174, 182))	('integrin alpha6', 'Gene', '16403', (84, 99))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('integrin alpha3', 'Gene', (140, 155))	('COL18A1', 'Gene', (15, 22))	('COL18A1', 'Gene', (44, 51))	('COL18A1', 'Gene', '12822', (15, 22))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('Pten null', 'Disease', (190, 199))	('rat', 'Species', '10116', (5, 8))	('integrin alpha6', 'Gene', (84, 99))	('NC1-301', 'Var', (31, 38))	('integrin alpha8', 'Gene', '241226', (105, 120))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('COL18A1', 'Gene', '12822', (44, 51))	('variant NC1-301', 'Var', (23, 38))	('rat', 'Species', '10116', (74, 77))	('tumors', 'Disease', (200, 206))	('integrin alpha3', 'Gene', '16400', (140, 155))	('integrin alpha8', 'Gene', (105, 120))
140070	21731504	Collagens type V (COL5A1, COL5A2 and COL5A3) and type II (COL2A1), the other fibril-forming collagens, were also up-regulated in the fibrotic liver of the PDGFC Tg mice.	('PDGFC', 'Var', (155, 160))	('COL5A2', 'Gene', '12832', (26, 32))	('COL2A1', 'Gene', (58, 64))	('COL5A3', 'Gene', '53867', (37, 43))	('mice', 'Species', '10090', (164, 168))	('COL2A1', 'Gene', '12824', (58, 64))	('up-regulated', 'PosReg', (113, 125))	('COL5A1', 'Gene', (18, 24))	('COL5A1', 'Gene', '12831', (18, 24))	('COL5A3', 'Gene', (37, 43))	('fibrotic liver', 'Phenotype', 'HP:0001395', (133, 147))	('COL5A2', 'Gene', (26, 32))
140086	21731504	It was previously reported that NC1-764 mRNA expression decreases in advanced HCCs and that cholangiocarcinoma cells expressed NC1-301 which was deposited in tumor basement membrane.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (92, 110))	('tumor', 'Disease', (158, 163))	('mRNA expression', 'MPA', (40, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('decreases', 'NegReg', (56, 65))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (92, 110))	('HCC', 'Phenotype', 'HP:0001402', (78, 81))	('NC1-301', 'Var', (127, 134))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('cholangiocarcinoma', 'Disease', (92, 110))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('NC1-764', 'Gene', (32, 39))	('advanced HCCs', 'Disease', (69, 82))
140087	21731504	This is in good agreement with the changes we observed in both COL18A1 isoforms in the mice tumors, with a greater ratio NC1-301/NC1-764 in Pten null tumors compared to PDGFC Tg tumors.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('COL18A1', 'Gene', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (150, 156))	('Tg tumors', 'Disease', (175, 184))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('COL18A1', 'Gene', '12822', (63, 70))	('tumors', 'Disease', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('Tg tumors', 'Disease', 'MESH:D009369', (175, 184))	('greater', 'PosReg', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('NC1-301/NC1-764', 'Var', (121, 136))	('rat', 'Species', '10116', (115, 118))	('tumors', 'Disease', (178, 184))	('mice', 'Species', '10090', (87, 91))
140108	21731504	Altogether, these results suggest that laminin 332/integrin alpha3-induced HCC growth and that laminin 511-integrin alpha6beta1 interaction is specific to Pten null tumors.	('Pten', 'Gene', (155, 159))	('integrin alpha3', 'Gene', '16400', (51, 66))	('integrin alpha3', 'Gene', (51, 66))	('integrin alpha6', 'Gene', '16403', (107, 122))	('HCC growth', 'CPA', (75, 85))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('integrin alpha6', 'Gene', (107, 122))	('interaction', 'Interaction', (128, 139))	('HCC', 'Phenotype', 'HP:0001402', (75, 78))	('laminin 511', 'Gene', (95, 106))	('laminin 511', 'Gene', '16776', (95, 106))	('null', 'Var', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))
140115	21731504	Mice carrying Pten conditional knockout alleles were crossed with an Albumin (Alb)-Cre-transgenic mouse.	('Alb', 'Gene', (78, 81))	('Alb', 'Gene', '11657', (69, 72))	('Albumin', 'Gene', '11657', (69, 76))	('mouse', 'Species', '10090', (98, 103))	('Alb', 'Gene', (69, 72))	('Pten', 'Gene', (14, 18))	('Mice', 'Species', '10090', (0, 4))	('alleles', 'Var', (40, 47))	('Albumin', 'Gene', (69, 76))	('Alb', 'Gene', '11657', (78, 81))
140244	33381458	For patients diagnosed with eCCA, the presence of postoperative CA19-9 (HR 2.26) and presence of lymph node infiltration (HR 2.33) were associated with worse outcomes.	('CCA', 'Gene', (29, 32))	('presence', 'Var', (38, 46))	('CCA', 'Gene', '2201', (29, 32))	('CA19-9', 'Var', (64, 70))	('patients', 'Species', '9606', (4, 12))
140245	33381458	Patients with resected eCCA with high pre-and post-operative CA19-9 were shown to have a higher distant metastasis rate and shorter disease-free interval.	('high', 'Var', (33, 37))	('met', 'Gene', '79811', (104, 107))	('CA19-9', 'Gene', (61, 67))	('shorter', 'NegReg', (124, 131))	('met', 'Gene', (104, 107))	('disease-free interval', 'CPA', (132, 153))	('higher', 'PosReg', (89, 95))	('CCA', 'Gene', '2201', (24, 27))	('Patients', 'Species', '9606', (0, 8))	('CCA', 'Gene', (24, 27))
140249	33381458	Prognostic nomograms have been designed for patients with resected iCCA including serum carcinoembryonic antigen (CEA), CA199), tumor diameter and number, vascular invasion, lymph node metastasis, direct invasion, and local extra-hepatic metastasis, showing a superiority in prognostic discrimination compared to five other staging systems for iCCA (p < 0.001).	('met', 'Gene', '79811', (185, 188))	('met', 'Gene', (137, 140))	('CCA', 'Gene', (68, 71))	('met', 'Gene', (185, 188))	('met', 'Gene', '79811', (238, 241))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('met', 'Gene', (238, 241))	('CCA', 'Gene', (345, 348))	('CEA', 'Gene', (114, 117))	('carcinoembryonic antigen', 'Gene', '1084', (88, 112))	('patients', 'Species', '9606', (44, 52))	('vascular invasion', 'CPA', (155, 172))	('direct invasion', 'CPA', (197, 212))	('CEA', 'Gene', '1084', (114, 117))	('CA199', 'Var', (120, 125))	('CCA', 'Gene', '2201', (68, 71))	('tumor', 'Disease', (128, 133))	('CCA', 'Gene', '2201', (345, 348))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('carcinoembryonic antigen', 'Gene', (88, 112))	('met', 'Gene', '79811', (137, 140))
140251	33381458	For GBM, higher recurrence rates are associated with R1-resection, depth of mural invasion, lymph node metastasis, extramural extension, and perineural invasion.	('depth of mural invasion', 'CPA', (67, 90))	('met', 'Gene', '79811', (103, 106))	('extramural extension', 'CPA', (115, 135))	('met', 'Gene', (103, 106))	('R1-resection', 'Var', (53, 65))	('GBM', 'Gene', (4, 7))	('perineural invasion', 'CPA', (141, 160))
140268	33381458	RT was associated with a trend toward improved survival for R1/R2 lymph node negative patients (39.5 vs. 21.1 months; p = 0.052).	('R1/R2', 'Var', (60, 65))	('survival', 'MPA', (47, 55))	('improved', 'PosReg', (38, 46))	('patients', 'Species', '9606', (86, 94))
140270	33381458	In an additional NCD analysis, from 2004-2012, evaluating the role of surgery and adjuvant therapy in lymph node positive GBC and iCCA, adjuvant treatment, including radiation, was associated with a lower risk of death relative to surgery alone for patients with GBC regardless of margin status (margin-negative resection: HR, 0.66; 95% CI, 0.52-0.84; margin-positive resection: HR, 0.54; 95% CI, 0.39-0.75), while adjuvant chemotherapy alone was not.	('lower', 'NegReg', (199, 204))	('patients', 'Species', '9606', (249, 257))	('death', 'Disease', 'MESH:D003643', (213, 218))	('death', 'Disease', (213, 218))	('margin-positive', 'Var', (352, 367))	('CCA', 'Gene', '2201', (131, 134))	('CCA', 'Gene', (131, 134))
140274	33381458	A SEER database comprising patients with EHCC (n = 1569) treated between 1973 and 2005 suggest an early survival advantage for adjuvant radiotherapy (25 vs. 21 months after R1 resection with versus without adjuvant radiotherapy, p < 0.001) whereas survival was almost identical for patients after R0-resection (26 vs. 25 months).	('adjuvant', 'Var', (127, 135))	('patients', 'Species', '9606', (27, 35))	('EHCC', 'Disease', (41, 45))	('patients', 'Species', '9606', (282, 290))
140303	33381458	Emerging therapies that hold considerable promise include FGFR inhibitors such as pemigatinib and IDH1 and/or IDH2 inhibitors, whereas the inhibition of other molecular pathways, including the RAS/RAF/MEK/ERK, the MET, the PI3K/AKT/mTOR and angiogenetic pathways, is unclear.	('IDH2', 'Gene', '3418', (110, 114))	('AKT', 'Gene', '207', (228, 231))	('ERK', 'Gene', (205, 208))	('ERK', 'Gene', '2048', (205, 208))	('FGFR', 'Gene', (58, 62))	('MET', 'Gene', '79811', (214, 217))	('MEK', 'Gene', (201, 204))	('pemigatinib', 'Chemical', '-', (82, 93))	('IDH1', 'Gene', (98, 102))	('mTOR', 'Gene', (232, 236))	('AKT', 'Gene', (228, 231))	('mTOR', 'Gene', '2475', (232, 236))	('inhibitors', 'Var', (63, 73))	('MEK', 'Gene', '5609', (201, 204))	('IDH1', 'Gene', '3417', (98, 102))	('MET', 'Gene', (214, 217))	('IDH2', 'Gene', (110, 114))
140305	33381458	In some studies, it was indicated that tumors with DNA mismatch repair deficiency (dMMR) are sensitive to PD-1 blockade, so that for tumors with microsatellite instability (MSI-high) or dMMR tumors progressing after prior treatment, pembrolizumab is a possible treatment option.	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('microsatellite', 'MPA', (145, 159))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('tumors', 'Disease', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('PD-1 blockade', 'Disease', (106, 119))	('PD-1 blockade', 'Disease', 'MESH:D010300', (106, 119))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('deficiency', 'Disease', 'MESH:D007153', (71, 81))	('tumors', 'Disease', (133, 139))	('dMMR', 'Var', (186, 190))	('deficiency', 'Disease', (71, 81))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('pembrolizumab', 'Chemical', 'MESH:C582435', (233, 246))
140327	33381458	Intraluminal brachytherapy might increase the risk of cholangitis, pain, duodenopathy, and bleeding.	('cholangitis', 'Phenotype', 'HP:0030151', (54, 65))	('bleeding', 'Disease', 'MESH:D006470', (91, 99))	('duodenopathy', 'Disease', (73, 85))	('bleeding', 'Disease', (91, 99))	('Intraluminal brachytherapy', 'Var', (0, 26))	('cholangitis', 'Disease', 'MESH:D002761', (54, 65))	('duodenopathy', 'Disease', 'None', (73, 85))	('pain', 'Phenotype', 'HP:0012531', (67, 71))	('pain', 'Disease', 'MESH:D010146', (67, 71))	('pain', 'Disease', (67, 71))	('cholangitis', 'Disease', (54, 65))
140343	33381458	In the phase III ACTICCA-1 trial adjuvant chemotherapy with gemcitabine and cisplatin compared to standard of care after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma has recently embedded a radiotherapy sub-study (NCT02170090 randomizing between adjuvant CRT vs. chemotherapy in EHCC and GBC (NCT02798510).	('gemcitabine', 'Chemical', 'MESH:C056507', (60, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('muscle invasive gallbladder carcinoma', 'Disease', 'MESH:D005706', (173, 210))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (150, 168))	('EHCC', 'Disease', (324, 328))	('CCA', 'Gene', '2201', (21, 24))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (150, 168))	('CCA', 'Gene', (21, 24))	('muscle invasive gallbladder carcinoma', 'Disease', (173, 210))	('cholangiocarcinoma', 'Disease', (150, 168))	('NCT02798510', 'Var', (338, 349))
140350	33381458	Moreover, ionizing radiation, beside cytotoxicity, has been shown to additionally induce immune-modulatory effects, which trigger anti-tumor immune responses.	('cytotoxicity', 'Disease', (37, 49))	('induce', 'Reg', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('cytotoxicity', 'Disease', 'MESH:D064420', (37, 49))	('trigger', 'Reg', (122, 129))	('immune-modulatory effects', 'MPA', (89, 114))	('ionizing radiation', 'Var', (10, 28))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
140390	33028805	Abnormality of HER2 with gene overexpression and/or activated mutations has been reported in multiple cancers, such as breast cancer, colon cancer, lung cancer, stomach cancer, and BTC.	('multiple cancers', 'Disease', (93, 109))	('stomach cancer', 'Phenotype', 'HP:0012126', (161, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('overexpression', 'PosReg', (30, 44))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('activated', 'PosReg', (52, 61))	('colon cancer', 'Disease', (134, 146))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('breast cancer', 'Disease', (119, 132))	('HER2', 'Protein', (15, 19))	('lung cancer', 'Disease', (148, 159))	('BTC', 'Phenotype', 'HP:0030153', (181, 184))	('BTC', 'Disease', (181, 184))	('mutations', 'Var', (62, 71))	('reported', 'Reg', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('stomach cancer', 'Disease', (161, 175))	('colon cancer', 'Phenotype', 'HP:0003003', (134, 146))	('multiple cancers', 'Disease', 'MESH:D009369', (93, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('colon cancer', 'Disease', 'MESH:D015179', (134, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('stomach cancer', 'Disease', 'MESH:D013274', (161, 175))
140394	33028805	Frequency of mutations of HER2 and HER3 was found to be 9.8% and 11.8%, respectively, which accounted for ErbB signaling pathway activations in GBC.	('HER3', 'Gene', (35, 39))	('ErbB', 'Gene', '1956', (106, 110))	('HER3', 'Gene', '2065', (35, 39))	('ErbB', 'Gene', (106, 110))	('mutations', 'Var', (13, 22))	('activations', 'PosReg', (129, 140))	('HER2', 'Protein', (26, 30))
140395	33028805	Supporting the evidence, these activated mutations of HER2/3 in GBC cell lines resulted in a significant increase in cell proliferation and tumor development in animals, underscoring the essential role of HER2/3 mutations in the development of GBC.	('mutations', 'Var', (41, 50))	('cell proliferation', 'CPA', (117, 135))	('increase', 'PosReg', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('HER2/3', 'Protein', (54, 60))	('tumor', 'Disease', (140, 145))
140396	33028805	Ah-Rong and co-workers found that HER2+ SNU-2670 and SNU-2773 GBC cell lines were more sensitive to trastuzumab, dacomitinib, and afatinib than HER2- BTC cell lines.	('HER2+ SNU-2670', 'Var', (34, 48))	('more', 'PosReg', (82, 86))	('dacomitinib', 'Chemical', 'MESH:C525726', (113, 124))	('SNU-2670', 'Chemical', '-', (40, 48))	('trastuzumab', 'Chemical', 'MESH:D000068878', (100, 111))	('SNU-2773', 'Var', (53, 61))	('SNU', 'Chemical', '-', (53, 56))	('SNU', 'Chemical', '-', (40, 43))	('BTC', 'Phenotype', 'HP:0030153', (150, 153))	('sensitive to trastuzumab', 'MPA', (87, 111))	('afatinib', 'Chemical', 'MESH:D000077716', (130, 138))
140400	33028805	reported that a GBC case harboring HER2 mutation on the primary and metastatic site underwent HER2-targeted treatment with lapatinib and capecitabin.	('lapatinib', 'Chemical', 'MESH:D000077341', (123, 132))	('mutation', 'Var', (40, 48))	('HER2', 'Gene', (35, 39))	('capecitabin', 'Chemical', 'MESH:D000069287', (137, 148))
140406	33028805	operated another phase II SUMMIT "basket" trial, a multi-histology, open-label, phase II "basket" study for patients who harbored somatic HER2 mutations and received neratinib (ClinicalTrial.gov NCT01953926; EudraCT 2013-002872-42).	('patients', 'Species', '9606', (108, 116))	('neratinib', 'Chemical', 'MESH:C487932', (166, 175))	('mutations', 'Var', (143, 152))	('HER2', 'Gene', (138, 142))
140421	33028805	Activated VEGFR3 induces the RAS/MAPK/ERK pathway and the PI3K-AKT/PKB pathway, leading to increased differentiation, migration, proliferation, and survival of lymphatic endothelial cells.	('induces', 'Reg', (17, 24))	('PKB', 'Gene', '207', (67, 70))	('migration', 'CPA', (118, 127))	('differentiation', 'CPA', (101, 116))	('VEGFR3', 'Gene', (10, 16))	('Activated', 'Var', (0, 9))	('PKB', 'Gene', (67, 70))	('proliferation', 'CPA', (129, 142))	('survival', 'CPA', (148, 156))	('increased', 'PosReg', (91, 100))	('ERK', 'Gene', '5594', (38, 41))	('ERK', 'Gene', (38, 41))	('VEGFR3', 'Gene', '2324', (10, 16))
140422	33028805	Intriguingly, VEGFR3 was also documented to fenestrate VEGF-A/VEGFR2 signaling, participating in angiogenesis.	('VEGFR2', 'Gene', '3791', (62, 68))	('VEGFR3', 'Gene', '2324', (14, 20))	('angiogenesis', 'CPA', (97, 109))	('VEGFR2', 'Gene', (62, 68))	('VEGF-A', 'Gene', '7422', (55, 61))	('VEGF-A', 'Gene', (55, 61))	('participating', 'Reg', (80, 93))	('VEGFR3', 'Gene', (14, 20))	('fenestrate', 'Var', (44, 54))
140436	33028805	In a large cohort study with 195 GBC patients and 300 healthy serum samples, polymorphisms of c.*237C > T and g.43737830A > G of VEGF gene were associated with the disease development, indicating that VEGF polymorphisms may offer a valuable marker to predict the susceptibility of carcinogenesis.	('associated with', 'Reg', (144, 159))	('carcinogenesis', 'Disease', 'MESH:D063646', (281, 295))	('patients', 'Species', '9606', (37, 45))	('polymorphisms', 'Var', (77, 90))	('g.43737830A > G', 'Var', (110, 125))	('carcinogenesis', 'Disease', (281, 295))	('g.43737830A > G', 'Mutation', 'rs1570360', (110, 125))	('disease development', 'CPA', (164, 183))	('VEGF', 'Gene', (129, 133))	('c.*237C > T', 'Mutation', 'rs3025039', (94, 105))	('c.*237C > T', 'Var', (94, 105))
140438	33028805	found that inhibition of VEGF-D led to the suppression of lymphangiogenesis and lymphatic metastasis.	('lymphangiogenesis', 'CPA', (58, 75))	('VEGF-D', 'Gene', '2277', (25, 31))	('inhibition', 'Var', (11, 21))	('lymphatic metastasis', 'CPA', (80, 100))	('suppression', 'NegReg', (43, 54))	('VEGF-D', 'Gene', (25, 31))
140451	33028805	In addition, the divergent expression levels of VEGF/VEGFR and/or polymorphisms in GBC should be evaluated with respect to susceptibility to specific blockers.	('VEGFR', 'Gene', '3791', (53, 58))	('GBC', 'Gene', (83, 86))	('VEGFR', 'Gene', (53, 58))	('polymorphisms', 'Var', (66, 79))
140455	33028805	In addition, constitutively activated mutations of EGFR existed in multiple cancers, thereby EGFR serves as a diagnostic and prognostic cancer biomarker, and also a potential target for cancer treatment.	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('EGFR', 'Gene', (51, 55))	('multiple cancers', 'Disease', (67, 83))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (136, 142))	('activated', 'PosReg', (28, 37))	('multiple cancers', 'Disease', 'MESH:D009369', (67, 83))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
140460	33028805	As point mutation of EGFR T790M developed during the treatment of NSCLC patients with the first-generation EGFR TKIs, drug resistance emerged.	('EGFR', 'Gene', (21, 25))	('point mutation', 'Var', (3, 17))	('NSCLC', 'Disease', (66, 71))	('T790M', 'Mutation', 'rs121434569', (26, 31))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('emerged', 'Reg', (134, 141))	('T790M', 'Var', (26, 31))	('drug resistance', 'Phenotype', 'HP:0020174', (118, 133))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('drug resistance', 'MPA', (118, 133))	('patients', 'Species', '9606', (72, 80))
140462	33028805	In some of the clinical trials with afatinib, the drug failed to reach a level by which it effectively abolishes activity of T790M mutant EGFR.	('EGFR', 'Gene', (138, 142))	('afatinib', 'Chemical', 'MESH:D000077716', (36, 44))	('abolishes', 'NegReg', (103, 112))	('activity', 'MPA', (113, 121))	('T790M', 'Mutation', 'rs121434569', (125, 130))	('T790M', 'Var', (125, 130))
140464	33028805	Both drugs exhibited robust inhibition on the mutation activities of EGFR, as a favorable responses to osimertinib and olmutinib were achieved in 50-60% of patients with the T790M mutations.	('patients', 'Species', '9606', (156, 164))	('osimertinib', 'Chemical', 'MESH:C000596361', (103, 114))	('olmutinib', 'Chemical', 'MESH:C000617753', (119, 128))	('responses', 'MPA', (90, 99))	('EGFR', 'Gene', (69, 73))	('mutation activities', 'MPA', (46, 65))	('T790M', 'Mutation', 'rs121434569', (174, 179))	('T790M', 'Var', (174, 179))
140488	33028805	Approximately 40% of all human cancers involve altered MAPK pathway, including mutations of BRAF (~10%) and RAS (~30%).	('BRAF', 'Gene', '673', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('RAS', 'Gene', (108, 111))	('BRAF', 'Gene', (92, 96))	('mutations', 'Var', (79, 88))	('human', 'Species', '9606', (25, 30))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('altered', 'Reg', (47, 54))	('cancers', 'Disease', (31, 38))	('cancers', 'Disease', 'MESH:D009369', (31, 38))	('MAPK pathway', 'Pathway', (55, 67))
140490	33028805	There was ample convincing evidence demonstrating that KRAS mutations mediate carcinogenesis of BTC by multiple research groups.	('KRAS', 'Gene', (55, 59))	('carcinogenesis', 'Disease', 'MESH:D063646', (78, 92))	('KRAS', 'Gene', '3845', (55, 59))	('carcinogenesis', 'Disease', (78, 92))	('mediate', 'Reg', (70, 77))	('BTC', 'Disease', (96, 99))	('mutations', 'Var', (60, 69))	('BTC', 'Phenotype', 'HP:0030153', (96, 99))
140491	33028805	Gln25His polymorphism of KRAS gene was identified to connect with GBC pathogenesis.	('GBC', 'Disease', (66, 69))	('Gln25His', 'SUBSTITUTION', 'None', (0, 8))	('KRAS', 'Gene', (25, 29))	('Gln25His', 'Var', (0, 8))	('connect', 'Reg', (53, 60))	('KRAS', 'Gene', '3845', (25, 29))
140503	33028805	Interestingly, a phase II study of GEMOX in combination with EGFR inhibitor cetuximab declared that KRAS mutations did not affect the difference in ORR and PFS between GEMOX and combination with EGFR inhibitor (NCT01308840, NCT01389414) in GBC, suggesting that the addition of cetuximab to gemcitabine and oxaliplatin did not seem to enhance the activity of chemotherapy in patients with GBC.	('KRAS', 'Gene', (100, 104))	('GEMOX', 'Chemical', '-', (35, 40))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (306, 317))	('KRAS', 'Gene', '3845', (100, 104))	('cetuximab', 'Chemical', 'MESH:D000068818', (76, 85))	('mutations', 'Var', (105, 114))	('cetuximab', 'Chemical', 'MESH:D000068818', (277, 286))	('patients', 'Species', '9606', (374, 382))	('GEMOX', 'Chemical', '-', (168, 173))	('gemcitabine', 'Chemical', 'MESH:C056507', (290, 301))
140513	33028805	Transmembrane growth factor receptors VEGFR, EGFR, insulin growth factor receptor 1, G protein-coupled receptors, and RAS proteins are capable of activating PI3K that phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3).	('VEGFR', 'Gene', '3791', (38, 43))	('EGFR', 'Gene', (45, 49))	('PI3K', 'Var', (157, 161))	('PIP2', 'Chemical', 'MESH:D019269', (221, 225))	('PIP3', 'Chemical', '-', (281, 285))	('VEGFR', 'Gene', (38, 43))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:D019269', (182, 219))	('activating', 'PosReg', (146, 156))	('phosphatidylinositol-3,4,5-trisphosphate', 'Chemical', 'MESH:C060974', (239, 279))
140523	33028805	While no PIK3CA mutations were found in Brazil patients, 12.5%, 16.9%, and 21.4% of GBC with PIK3CA mutations were identified in USA, Japan, and Chile, respectively.	('mutations', 'Var', (100, 109))	('PIK3CA', 'Gene', '5290', (93, 99))	('patients', 'Species', '9606', (47, 55))	('PIK3CA', 'Gene', (9, 15))	('PIK3CA', 'Gene', (93, 99))	('PIK3CA', 'Gene', '5290', (9, 15))
140524	33028805	We previously found that PIK3CA mutations E545K occurred in ~5.9% of GBC, and that these patients exhibited a worse prognosis.	('GBC', 'Disease', (69, 72))	('E545K', 'Mutation', 'rs104886003', (42, 47))	('E545K', 'Var', (42, 47))	('PIK3CA', 'Gene', (25, 31))	('PIK3CA', 'Gene', '5290', (25, 31))	('patients', 'Species', '9606', (89, 97))	('mutations E545K', 'Var', (32, 47))
140525	33028805	Epigenetic alteration of PTEN also contributes to the development of GBC as 30% GBCs exhibited PTEN promoter hypermethylated.	('GBC', 'Disease', (69, 72))	('contributes', 'Reg', (35, 46))	('PTEN', 'Gene', (95, 99))	('PTEN', 'Gene', '5728', (25, 29))	('promoter hypermethylated', 'PosReg', (100, 124))	('PTEN', 'Gene', '5728', (95, 99))	('PTEN', 'Gene', (25, 29))	('Epigenetic alteration', 'Var', (0, 21))
140533	33028805	Specificity protein 1-induced lncRNA LINC00152 up-regulates PI3K/AKT pathway and contributes to GBC cell growth and tumor metastasis.	('LINC00152', 'Gene', (37, 46))	('tumor metastasis', 'Disease', 'MESH:D009362', (116, 132))	('contributes', 'PosReg', (81, 92))	('Specificity protein 1', 'Gene', '6667', (0, 21))	('tumor metastasis', 'Disease', (116, 132))	('LINC00152', 'Gene', '112597', (37, 46))	('lncRNA', 'Var', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('Specificity protein 1', 'Gene', (0, 21))	('up-regulates', 'PosReg', (47, 59))	('PI3K/AKT pathway', 'Pathway', (60, 76))	('GBC', 'Disease', (96, 99))
140535	33028805	Several inhibitors targeting the PI3K/AKT/mTOR pathway, including A66, Wortmannin, and LY294002, have been demonstrated to inhibit GBC cell proliferation, migration, and invasion both in vitro and in vivo.	('mTOR', 'Gene', '2475', (42, 46))	('migration', 'CPA', (155, 164))	('A66', 'Var', (66, 69))	('mTOR', 'Gene', (42, 46))	('LY294002', 'Var', (87, 95))	('A66', 'Chemical', '-', (66, 69))	('inhibit', 'NegReg', (123, 130))	('GBC cell proliferation', 'CPA', (131, 153))	('Wortmannin', 'Chemical', 'MESH:D000077191', (71, 81))	('invasion', 'CPA', (170, 178))	('LY294002', 'Chemical', 'MESH:C085911', (87, 95))
140546	33028805	In the recent few years, intense research evidence focusing on antitumor immunity has established the proof of concept that blockade of the interaction between tumor-derived checkpoint ligands and their corresponding binding receptors expressed by T cells elicits T cell immunity against tumors.	('tumor', 'Disease', (288, 293))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('blockade', 'Var', (124, 132))	('interaction', 'Interaction', (140, 151))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('elicits', 'Reg', (256, 263))	('tumor', 'Disease', (160, 165))	('tumors', 'Disease', (288, 294))
140549	33028805	While the aberrant expression of PD-L1 in multiple cancers enables tumor cells to escape the host immune surveillance and drive tumor metastasis, little is known regarding mechanistic regulation of PD-L1 and PD-1 underlying GBC development.	('multiple cancers', 'Disease', (42, 58))	('tumor', 'Disease', (128, 133))	('PD-L1', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('drive', 'PosReg', (122, 127))	('aberrant', 'Var', (10, 18))	('multiple cancers', 'Disease', 'MESH:D009369', (42, 58))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor metastasis', 'Disease', 'MESH:D009362', (128, 144))	('tumor metastasis', 'Disease', (128, 144))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('tumor', 'Disease', (67, 72))
140550	33028805	We are the first group, to our knowledge, to report that ectopic expression of ErbB2/ErbB3 mutants in GBC cells upregulated PD-L1 expression, which suppressed T cell-mediated cytotoxicity and drove tumor growth and metastasis.	('PD-L1', 'Gene', (124, 129))	('expression', 'MPA', (130, 140))	('ErbB3', 'Gene', (85, 90))	('ErbB3', 'Gene', '2065', (85, 90))	('upregulated', 'PosReg', (112, 123))	('drove', 'PosReg', (192, 197))	('cytotoxicity', 'Disease', (175, 187))	('metastasis', 'CPA', (215, 225))	('ErbB2', 'Gene', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('cytotoxicity', 'Disease', 'MESH:D064420', (175, 187))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('mutants', 'Var', (91, 98))	('tumor', 'Disease', (198, 203))	('ErbB2', 'Gene', '2064', (79, 84))	('suppressed', 'NegReg', (148, 158))
140552	33028805	The results demonstrated that acquired ERBB2/ERBB3 mutations by tumor cells are essential to induce checkpoint PD-L1, rendering tumor cells evasive from cytotoxic T cell immunity against tumor.	('ERBB2', 'Gene', '2064', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', (64, 69))	('mutations', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('ERBB3', 'Gene', '2065', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('ERBB3', 'Gene', (45, 50))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('evasive', 'PosReg', (140, 147))	('ERBB2', 'Gene', (39, 44))
140556	33028805	found that 12% patients with tumor cell-expressing PD-L1 and 55% patients with tumor-infiltrating lymphocyte (TIL)-expressing PD-1 in a total of 203 GBC patients were associated with corresponding genetic aberrations and tumor mutational burden (TMB) status.	('PD-L1', 'Var', (51, 56))	('patients', 'Species', '9606', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', (79, 84))	('patients', 'Species', '9606', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('genetic aberrations', 'Var', (197, 216))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('patients', 'Species', '9606', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('associated', 'Reg', (167, 177))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
140578	33028805	Unlike KEYNOTE-028 study, the trail (NCT02443324) recruited both PD-L1+ and PD-L1- patients, in which 46.2% of PD-L1 patients underwent tumor recurrence or metastasis.	('metastasis', 'CPA', (156, 166))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (117, 125))	('tumor', 'Disease', (136, 141))	('PD-L1', 'Var', (111, 116))
140580	33028805	PD-L1+ patients had improved OS compared with PD-L1- cases (11.3 vs. 6.1 months), but there is no difference in mPFS (1.5 vs. 1.6 months).	('PD-L1+', 'Var', (0, 6))	('improved', 'PosReg', (20, 28))	('OS', 'Gene', '17451', (29, 31))	('patients', 'Species', '9606', (7, 15))
140584	33028805	mOS was 8.1 (95% CI 5.6-10.1) months and 10.1 (95% CI 6.2-11.4) months for the single and dual treatment, respectively, suggesting that conjunction of anti-PD-L1/PD-1 with anti-CTLA-4 therapies may hold promising efficacy for patients with GBC.	('mOS', 'Gene', (0, 3))	('CTLA-4', 'Gene', '1493', (177, 183))	('GBC', 'Disease', (240, 243))	('anti-PD-L1/PD-1', 'Var', (151, 166))	('mOS', 'Gene', '17451', (0, 3))	('CTLA-4', 'Gene', (177, 183))	('patients', 'Species', '9606', (226, 234))
140593	33028805	BRCA-associated BTC is uncommon as BRCA1/2 mutations were detected in 4.0% of 353 GBC samples by Spizzo.	('BTC', 'Phenotype', 'HP:0030153', (16, 19))	('detected', 'Reg', (58, 66))	('BRCA', 'Gene', (0, 4))	('BRCA1/2', 'Gene', '672;675', (35, 42))	('BRCA', 'Gene', (35, 39))	('BRCA', 'Gene', '672', (35, 39))	('mutations', 'Var', (43, 52))	('BRCA', 'Gene', '672', (0, 4))	('Spizzo', 'Chemical', '-', (97, 103))	('BRCA1/2', 'Gene', (35, 42))
140595	33028805	identified 7.8% BRCA2 or ATM mutations in 623 advanced GBC patients.	('mutations', 'Var', (29, 38))	('BRCA2', 'Gene', (16, 21))	('ATM', 'Gene', (25, 28))	('patients', 'Species', '9606', (59, 67))	('BRCA2', 'Gene', '675', (16, 21))	('advanced GBC', 'Disease', (46, 58))	('ATM', 'Gene', '472', (25, 28))
140596	33028805	The alterations of DDR genes increase the sensitivity of anti-cancer chemotherapy and radiation treatments.	('alterations', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('increase', 'PosReg', (29, 37))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('DDR genes', 'Gene', (19, 28))
140597	33028805	The recent researches suggest that specific DDR gene mutation or expression may have an impact on response to platinum-based chemotherapy in patients diagnosed with BTC.	('platinum', 'Chemical', 'MESH:D010984', (110, 118))	('impact', 'Reg', (88, 94))	('mutation', 'Var', (53, 61))	('response', 'MPA', (98, 106))	('DDR gene', 'Gene', (44, 52))	('BTC', 'Phenotype', 'HP:0030153', (165, 168))	('patients', 'Species', '9606', (141, 149))
140600	33028805	revealed that DDR gene mutations were found in 62.5% of BTC patients (including 20.2% GBC patients), and that DDR gene mutations associated with longer mPFS (6.9 vs. 5.7 months; P = 0.013) and mOS (21.0 vs. 13.3 months; P = 0.009) in patients with BTC treated with first-line platinum-based chemotherapy for unresectable or metastatic disease.	('DDR gene', 'Gene', (110, 118))	('mPFS', 'CPA', (152, 156))	('platinum', 'Chemical', 'MESH:D010984', (276, 284))	('BTC', 'Phenotype', 'HP:0030153', (56, 59))	('mOS', 'Gene', (193, 196))	('patients', 'Species', '9606', (60, 68))	('DDR gene', 'Gene', (14, 22))	('mutations', 'Var', (23, 32))	('patients', 'Species', '9606', (234, 242))	('mOS', 'Gene', '17451', (193, 196))	('longer', 'PosReg', (145, 151))	('mutations', 'Var', (119, 128))	('patients', 'Species', '9606', (90, 98))	('BTC', 'Phenotype', 'HP:0030153', (248, 251))	('BTC', 'Disease', (56, 59))
140601	33028805	These results indicate that mutations in DDR genes may serve as predictive biomarkers for the response to platinum-based chemotherapy in patients with BTC.	('patients', 'Species', '9606', (137, 145))	('BTC', 'Phenotype', 'HP:0030153', (151, 154))	('DDR genes', 'Gene', (41, 50))	('platinum', 'Chemical', 'MESH:D010984', (106, 114))	('mutations', 'Var', (28, 37))
140617	33028805	The TP53 mutations in Greek GBC patients were lower than those in Japan and Chile GBC patients.	('patients', 'Species', '9606', (32, 40))	('TP53', 'Gene', (4, 8))	('mutations', 'Var', (9, 18))	('lower', 'NegReg', (46, 51))	('TP53', 'Gene', '7157', (4, 8))	('patients', 'Species', '9606', (86, 94))
140618	33028805	One-third of the north Indian patients with GBC have mutations in exons 5-8 of p53 gene.	('p53', 'Gene', '7157', (79, 82))	('p53', 'Gene', (79, 82))	('patients', 'Species', '9606', (30, 38))	('mutations in exons', 'Var', (53, 71))
140619	33028805	Moreover, different types of TP53 mutations in GBC were defined in Japan, Chile, and Hungary.	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))
140620	33028805	Overexpression and high mutation frequency of p53 protein, which has tumor-promoting signature rather than cell apoptotic activity, were correlated with a poor survival of a broad type of cancers, including GBC, thus serving as a cancer biomarker.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('tumor', 'Disease', (69, 74))	('p53', 'Gene', (46, 49))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancers', 'Disease', (188, 195))	('p53', 'Gene', '7157', (46, 49))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('high mutation', 'Var', (19, 32))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('protein', 'Protein', (50, 57))	('cancer', 'Disease', (188, 194))	('cancer', 'Disease', (230, 236))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('poor', 'NegReg', (155, 159))
140623	33028805	Supporting this notion, a variety of studies also pointed to the mutated p53 as a prognostic marker of GBC.	('p53', 'Gene', (73, 76))	('GBC', 'Disease', (103, 106))	('p53', 'Gene', '7157', (73, 76))	('mutated', 'Var', (65, 72))
140625	33028805	One hundred and three (44.8%) of 230 GBC cases expressed mutant p53 protein that was not correlated with clinical parameters such as tumor growth.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('mutant', 'Var', (57, 63))	('tumor', 'Disease', (133, 138))	('p53', 'Gene', (64, 67))	('protein', 'Protein', (68, 75))	('p53', 'Gene', '7157', (64, 67))
140627	33028805	Although these distinct conclusions are still controversial, mechanistic insights should be in parallel taken into account, as a variety of p53 mutation forms together with multiple phosphorylation sites coexist, implicating dissimilar roles played by p53 in tumor development, such as tumor-promoting effects and loss of tumor suppressor activity.	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Disease', (286, 291))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('loss', 'NegReg', (314, 318))	('p53', 'Gene', (140, 143))	('tumor', 'Disease', 'MESH:D009369', (322, 327))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('p53', 'Gene', (252, 255))	('mutation', 'Var', (144, 152))	('p53', 'Gene', '7157', (252, 255))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('tumor', 'Disease', (259, 264))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('tumor', 'Disease', (322, 327))	('p53', 'Gene', '7157', (140, 143))
140628	33028805	Although TP53 has the highest mutation rate in GBC, very limited clinical trials targeting mutated p53 were reported to evaluate potential therapeutic benefit.	('p53', 'Gene', (99, 102))	('mutation', 'Var', (30, 38))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('p53', 'Gene', '7157', (99, 102))
140629	33028805	led to a phase II clinical trial of oncolytic adenovirus ONYX-015(dl1520, CI-1042), which intervenes the p53 pathway in 19 patients with hepatobiliary tumors, in which 15 cases expressed p53 mutations, and 5 patients had GBCs.	('patients', 'Species', '9606', (208, 216))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('p53', 'Gene', (187, 190))	('intervenes', 'Reg', (90, 100))	('tumors', 'Disease', (151, 157))	('adenovirus', 'Species', '10508', (46, 56))	('mutations', 'Var', (191, 200))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('patients', 'Species', '9606', (123, 131))	('p53', 'Gene', '7157', (187, 190))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('expressed', 'Reg', (177, 186))
140631	33028805	CDKN2A/B, a cyclin-dependent kinase inhibitor 2A/B, inhibits CDK4 and CDK6, and also prevents pRB phosphorylation, thus leading to cell cycle arrest at the G1/S phase.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (131, 148))	('CDKN2A/B', 'Gene', (0, 8))	('arrest', 'Disease', 'MESH:D006323', (142, 148))	('pRB', 'Gene', '5925', (94, 97))	('2A/B', 'SUBSTITUTION', 'None', (4, 8))	('2A/B', 'Var', (4, 8))	('CDK4', 'Gene', (61, 65))	('leading to', 'Reg', (120, 130))	('pRB', 'Gene', (94, 97))	('inhibits', 'NegReg', (52, 60))	('prevents', 'NegReg', (85, 93))	('arrest', 'Disease', (142, 148))	('CDK4', 'Gene', '1019', (61, 65))	('2A/B', 'SUBSTITUTION', 'None', (46, 50))	('CDKN2A/B', 'Gene', '1029;1030', (0, 8))	('2A/B', 'Var', (46, 50))	('CDK6', 'Gene', (70, 74))	('CDK6', 'Gene', '1021', (70, 74))
140634	33028805	More interestingly, the coincidence of ERBB2 genetic mutations with CDKN2A/B variations in US patients was stronger (odds ratio 10.8, P = 0.0001) than those in Chinese cohort (odds ratio 5.4, P = 0.0014), which suggests that CDKN2A/B alterations were significantly associated with distant metastases.	('ERBB2', 'Gene', '2064', (39, 44))	('patients', 'Species', '9606', (94, 102))	('metastases', 'Disease', (289, 299))	('CDKN2A/B', 'Gene', '1029;1030', (225, 233))	('metastases', 'Disease', 'MESH:D009362', (289, 299))	('CDKN2A/B', 'Gene', '1029;1030', (68, 76))	('mutations', 'Var', (53, 62))	('associated', 'Reg', (265, 275))	('CDKN2A/B', 'Gene', (225, 233))	('CDKN2A/B', 'Gene', (68, 76))	('ERBB2', 'Gene', (39, 44))
140635	33028805	Our previous study showed that CDKN2A/B mutation rate was ~5.9% in GBC.	('mutation', 'Var', (40, 48))	('GBC', 'Disease', (67, 70))	('CDKN2A/B', 'Gene', (31, 39))	('CDKN2A/B', 'Gene', '1029;1030', (31, 39))
140636	33028805	There were other reports supporting the notion that CDKN2A/B mutations mediate the pathogenesis of GBC.	('CDKN2A/B', 'Gene', '1029;1030', (52, 60))	('mutations', 'Var', (61, 70))	('CDKN2A/B', 'Gene', (52, 60))	('GBC', 'Disease', (99, 102))	('mediate', 'Reg', (71, 78))
140689	31772721	Because of the abnormally located junction, the sphincter of Oddi does not work effectively.	('sphincter of Oddi', 'Disease', 'MESH:D046628', (48, 65))	('abnormally', 'Var', (15, 25))	('sphincter of Oddi', 'Disease', (48, 65))
140692	31772721	The anomaly can also cause chronic cholangitis and chronic bacterbilia.	('anomaly', 'Var', (4, 11))	('chronic bacterbilia', 'Disease', (51, 70))	('cholangitis', 'Phenotype', 'HP:0030151', (35, 46))	('cholangitis', 'Disease', (35, 46))	('cause', 'Reg', (21, 26))	('cholangitis', 'Disease', 'MESH:D002761', (35, 46))
140816	30273859	The utilization of anti-CD20 antibody had previously demonstrated reduction in LT rates for ovarian carcinoma PDX models.	('anti-CD20', 'Gene', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (92, 109))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (92, 109))	('ovarian carcinoma', 'Disease', (92, 109))	('anti-CD20', 'Var', (19, 28))	('LT rates', 'CPA', (79, 87))	('LT', 'Chemical', '-', (79, 81))	('reduction', 'NegReg', (66, 75))
140834	28356940	Imbalanced adaptive responses associated with microsatellite instability in cholangiocarcinoma The adaptive response of the genome protection mechanism occurs in cells when exposed to genotoxic stress due to the overproduction of free radicals via inflammation and infection.	('inflammation', 'Disease', (248, 260))	('overproduction', 'PosReg', (212, 226))	('infection', 'Disease', (265, 274))	('cholangiocarcinoma', 'Disease', (76, 94))	('microsatellite instability', 'Var', (46, 72))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (76, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('infection', 'Disease', 'MESH:D007239', (265, 274))	('free radicals', 'Chemical', 'MESH:D005609', (230, 243))	('inflammation', 'Disease', 'MESH:D007249', (248, 260))	('Imbalance', 'Phenotype', 'HP:0002172', (0, 9))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (76, 94))
140844	28356940	In the patients, a MSI-high was correlated with poor prognosis, indicated by a shorter survival rate.	('survival rate', 'CPA', (87, 100))	('shorter', 'NegReg', (79, 86))	('rat', 'Species', '10116', (96, 99))	('MSI-high', 'Var', (19, 27))	('patients', 'Species', '9606', (7, 15))
140904	28356940	The DNA extracted from tumor tissues, non-tumor tissues of the adjacent area and WBCs of the same patient were analyzed for MSI using five microsatellite markers: BAT25, BAT26, D5S346, D2S123 and D17S250.	('tumor', 'Disease', (42, 47))	('patient', 'Species', '9606', (98, 105))	('D5S346', 'Var', (177, 183))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('BAT26', 'Var', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('D17S250', 'Var', (196, 203))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('D2S123', 'Var', (185, 191))
140932	28356940	In comparing the patients with MSI-low and patients with MSI-high, the 5-year survival rate of the patients in the MSI-low (n=4) group was 31%, whereas that of the patients in the MSI-high (n=9) group was 69%, indicating that the survival rate was higher in the MSI-low group, as shown in Fig.	('patients', 'Species', '9606', (43, 51))	('survival', 'CPA', (230, 238))	('rat', 'Species', '10116', (239, 242))	('patients', 'Species', '9606', (99, 107))	('MSI-low', 'Var', (115, 122))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (164, 172))	('rat', 'Species', '10116', (87, 90))	('higher', 'PosReg', (248, 254))
140934	28356940	Impairment of the antioxidant system may favor the accumulation of free radicals, as it has been found that low levels of essential antioxidants are associated with an increased risk of cancer.	('low', 'Var', (108, 111))	('favor', 'PosReg', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('free radicals', 'Chemical', 'MESH:D005609', (67, 80))	('free radicals', 'MPA', (67, 80))	('associated', 'Reg', (149, 159))	('accumulation', 'MPA', (51, 63))	('Impairment', 'Var', (0, 10))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
140952	28356940	These etheno modified DNA bases are miscoding lesions, which are considered to contribute to the initiation of carcinogenesis through the induction of specific point mutations in DNA.	('DNA', 'Gene', (179, 182))	('initiation of carcinogenesis', 'Disease', (97, 125))	('initiation of carcinogenesis', 'Disease', 'MESH:D063646', (97, 125))	('point mutations', 'Var', (160, 175))
140954	28356940	The present study also found MSI-low (31%) and MSI-high (69%) in human CCA tissues.	('MSI-low', 'Var', (29, 36))	('human', 'Species', '9606', (65, 70))	('CCA', 'Disease', (71, 74))
140955	28356940	MSI-high was correlated with poor prognosis in patients, as indicated by shorter survival rates, compared with the group of MSI-low patients; however, this was not statistically significant, which may be due to the small sample size.	('MSI-high', 'Var', (0, 8))	('patients', 'Species', '9606', (47, 55))	('shorter', 'NegReg', (73, 80))	('survival', 'MPA', (81, 89))	('patients', 'Species', '9606', (132, 140))	('rat', 'Species', '10116', (90, 93))
140956	28356940	Liengswangwong et al reported MSI-low and MSS in liver fluke infection-associated intrahepatic CCA.	('liver fluke infection', 'Disease', (49, 70))	('MSI-low', 'Var', (30, 37))	('liver fluke infection', 'Disease', 'MESH:D017093', (49, 70))
140958	28356940	Previously, it was demonstrated the generation of a mutator phenotype in yeast was caused by imbalanced BER.	('imbalance', 'Phenotype', 'HP:0002172', (93, 102))	('rat', 'Species', '10116', (26, 29))	('caused by', 'Reg', (83, 92))	('rat', 'Species', '10116', (40, 43))	('mutator', 'Var', (52, 59))	('yeast', 'Species', '4932', (73, 78))
140960	28356940	An imbalance between apurinic/apyrimidinic (AP) endonuclease and one particular DNA glycosylase produced a mutator phenotype in yeast.	('yeast', 'Species', '4932', (128, 133))	('produced', 'Reg', (96, 104))	('imbalance', 'Phenotype', 'HP:0002172', (3, 12))	('apurinic/apyrimidinic', 'MPA', (21, 42))	('mutator phenotype', 'MPA', (107, 124))	('imbalance', 'Var', (3, 12))
140961	28356940	Imbalance in the glycosylase to AP endonuclease ratio may arise by promoter mutations, which affect the expression of DNA repair genes.	('mutations', 'Var', (76, 85))	('affect', 'Reg', (93, 99))	('arise', 'Reg', (58, 63))	('glycosylase to AP', 'MPA', (17, 34))	('DNA repair genes', 'Gene', (118, 134))	('expression', 'MPA', (104, 114))	('Imbalance', 'Phenotype', 'HP:0002172', (0, 9))	('rat', 'Species', '10116', (48, 51))
140962	28356940	Imbalances in BER enzymes may represent a previously unrecognized source of increased cancer risk.	('BER enzymes', 'Enzyme', (14, 25))	('Imbalances', 'Phenotype', 'HP:0002172', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Imbalances', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('Imbalance', 'Phenotype', 'HP:0002172', (0, 9))	('cancer', 'Disease', (86, 92))
140963	28356940	Furthermore, imbalanced BER increases spontaneous mutation and alkylation sensitivity in Escherichia coli.	('increases', 'PosReg', (28, 37))	('alkylation sensitivity', 'MPA', (63, 85))	('Escherichia coli', 'Species', '562', (89, 105))	('spontaneous mutation', 'MPA', (38, 58))	('imbalanced', 'Var', (13, 23))	('imbalance', 'Phenotype', 'HP:0002172', (13, 22))
140964	28356940	In a previous study of human colon adenoma showing dysregulation of BER, a correlation was found between the expression of AAG and iNOS.	('AAG', 'Gene', (123, 126))	('colon adenoma', 'Disease', (29, 42))	('correlation', 'Reg', (75, 86))	('iNOS', 'Gene', '4843', (131, 135))	('AAG', 'Gene', '4350', (123, 126))	('iNOS', 'Gene', (131, 135))	('colon adenoma', 'Disease', 'MESH:D000236', (29, 42))	('dysregulation', 'Var', (51, 64))	('human', 'Species', '9606', (23, 28))
140965	28356940	Nitration in the AAG active site of tyrosine 162 in vitro was found to impair epsilonA-excision activity, whereas nitrosation of cysteine 167 increased epsilonA-excision activity.	('AAG', 'Gene', (17, 20))	('tyrosine', 'Chemical', 'MESH:D014443', (36, 44))	('cysteine', 'Chemical', 'MESH:D003545', (129, 137))	('epsilonA-excision activity', 'MPA', (78, 104))	('tyrosine 162', 'Var', (36, 48))	('Nitration', 'Var', (0, 9))	('AAG', 'Gene', '4350', (17, 20))	('rat', 'Species', '10116', (3, 6))	('impair', 'NegReg', (71, 77))
140966	28356940	Therefore, the post-translational modification of AAG by reactive nitrogen species via the overproduction of NO appears to be one mechanism of BER dysregulation leading to malignancy.	('AAG', 'Gene', (50, 53))	('malignancy', 'Disease', 'MESH:D009369', (172, 182))	('malignancy', 'Disease', (172, 182))	('AAG', 'Gene', '4350', (50, 53))	('reactive nitrogen species', 'Chemical', 'MESH:D026361', (57, 82))	('overproduction', 'PosReg', (91, 105))	('post-translational modification', 'Var', (15, 46))
140967	28356940	In ulcerative colitis, it has been shown that the adaptive imbalance in BER enzymes generates MSI in chronic inflammation.	('ulcerative colitis', 'Disease', 'MESH:D003093', (3, 21))	('BER enzymes', 'Enzyme', (72, 83))	('MSI', 'MPA', (94, 97))	('rat', 'Species', '10116', (88, 91))	('inflammation', 'Disease', 'MESH:D007249', (109, 121))	('rat', 'Species', '10116', (7, 10))	('colitis', 'Phenotype', 'HP:0002583', (14, 21))	('inflammation', 'Disease', (109, 121))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (3, 21))	('imbalance', 'Var', (59, 68))	('ulcerative colitis', 'Disease', (3, 21))	('imbalance', 'Phenotype', 'HP:0002172', (59, 68))
140968	28356940	Mechanistic studies using yeast and human cell models overexpressing AAG and/or APE1 were associated with frameshift mutations and MSI, indicating that the adaptive imbalanced increase in BER enzymes may have DNA-damaging effects and may contribute to carcinogenesis in chronic inflammation.	('contribute', 'Reg', (238, 248))	('carcinogenesis', 'Disease', 'MESH:D063646', (252, 266))	('APE1', 'Gene', (80, 84))	('increase', 'PosReg', (176, 184))	('inflammation', 'Disease', (278, 290))	('carcinogenesis', 'Disease', (252, 266))	('yeast', 'Species', '4932', (26, 31))	('APE1', 'Gene', '328', (80, 84))	('imbalanced increase', 'Phenotype', 'HP:0002172', (165, 184))	('AAG', 'Gene', (69, 72))	('DNA-damaging', 'MPA', (209, 221))	('human', 'Species', '9606', (36, 41))	('frameshift mutations', 'Var', (106, 126))	('imbalance', 'Phenotype', 'HP:0002172', (165, 174))	('inflammation', 'Disease', 'MESH:D007249', (278, 290))	('AAG', 'Gene', '4350', (69, 72))
140972	28356940	Yamada and Farber reported the induction of a low level of MSI by the overexpression of DNA pol beta, and a mechanism was identified for the induction of microsatellite mutations by using a selection-based cell culture system with high sensitivity to relatively small increases in mutation rates.	('DNA pol beta', 'Gene', '5423', (88, 100))	('MSI', 'MPA', (59, 62))	('rat', 'Species', '10116', (290, 293))	('overexpression', 'PosReg', (70, 84))	('microsatellite', 'Var', (154, 168))	('DNA pol beta', 'Gene', (88, 100))
141017	24281176	Of the five peaks, the 3,400, 4,502 and 7,598 Da peptides appeared to be down-regulated, and the 5,680 and 11,242 Da peptide were up-regulated in sera samples from BTCs compared with those from controls, as shown in Figure 1B, in which randomly selected protein mass spectra for two BTC cases and controls were presented as an example.	('down-regulated', 'NegReg', (73, 87))	('up-regulated', 'PosReg', (130, 142))	('BTCs', 'Var', (164, 168))	('peptides', 'Chemical', 'MESH:D010455', (49, 57))
141074	23118872	Pooled bile and tissue proteins (40 microg) or crude bile (2 microl) from individual patients were resolved on SDS-PAGE gels, transferred onto PVDF membranes (Millipore, Bedford, MA, USA) and incubated overnight with primary antibodies against PGAM1 (1:1000; Abnova, Taibei, Jhouzih St, Taiwan), HSPD1 (1:1,000; Abcam, Cambridge, MA, USA), SSP411 (1:1,000; Abgent, San Diego, CA, USA), APOM (1:100; Santa Cruz Biotechnology, Santa Cruz, CA, USA), Pdia3 (1:500; Abcam) and GAPDH (1:5,000; Abcam).	('APOM', 'Gene', (386, 390))	('APOM', 'Gene', '55937', (386, 390))	('Pdia3', 'Gene', '2923', (447, 452))	('SSP411', 'Gene', (340, 346))	('PGAM1', 'Gene', '5223', (244, 249))	('SSP411', 'Gene', '64847', (340, 346))	('HSPD1', 'Gene', (296, 301))	('patients', 'Species', '9606', (85, 93))	('HSPD1', 'Gene', '3329', (296, 301))	('GAPDH', 'Gene', '2597', (472, 477))	('GAPDH', 'Gene', (472, 477))	('1:100;', 'Var', (392, 398))	('Pdia3', 'Gene', (447, 452))	('PGAM1', 'Gene', (244, 249))
141130	23118872	PGAM1 is overexpressed in breast cancer, and suppression of PGAM1 can inhibit breast cancer cell proliferation.	('breast cancer', 'Disease', (26, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('PGAM1', 'Gene', '5223', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('PGAM1', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('suppression', 'Var', (45, 56))	('inhibit', 'NegReg', (70, 77))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('PGAM1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))	('PGAM1', 'Gene', '5223', (60, 65))
141199	34017024	Pro-oncogenic processes resulting from chronic biliary inflammation and cholestasis with accumulation of bile acids is suspected to contribute to the development of CCA, possibly through induction of nitric oxide synthase and nitric oxide generation, which promotes oxidative DNA damage and inhibits DNA repair and could result in oncogenic mutations.	('result', 'Reg', (321, 327))	('cholestasis', 'Phenotype', 'HP:0001396', (72, 83))	('mutations', 'Var', (341, 350))	('CCA', 'Phenotype', 'HP:0030153', (165, 168))	('nitric oxide', 'Chemical', 'MESH:D009569', (200, 212))	('promotes', 'PosReg', (257, 265))	('biliary inflammation', 'Disease', 'MESH:D007249', (47, 67))	('DNA repair', 'MPA', (300, 310))	('biliary inflammation', 'Disease', (47, 67))	('oxidative DNA damage', 'MPA', (266, 286))	('cholestasis', 'Disease', 'MESH:D002779', (72, 83))	('cholestasis', 'Disease', (72, 83))	('nitric oxide', 'Chemical', 'MESH:D009569', (226, 238))	('CCA', 'Disease', (165, 168))	('bile acids', 'Chemical', 'MESH:D001647', (105, 115))	('inhibits', 'NegReg', (291, 299))
141200	34017024	Some reports have shown mutations in loci with tumor suppressor function, such as p16INK4a, both in PSC cases without cholangiocarcinoma and PSC cases with cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (156, 174))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cholangiocarcinoma', 'Disease', (156, 174))	('mutations', 'Var', (24, 33))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (156, 174))	('cholangiocarcinoma and PSC', 'Disease', 'MESH:D015209', (118, 144))	('PSC', 'Gene', '100653366', (141, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('PSC', 'Gene', '100653366', (100, 103))	('p16INK4a', 'Gene', (82, 90))	('PSC', 'Gene', (141, 144))	('tumor', 'Disease', (47, 52))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (118, 136))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('p16INK4a', 'Gene', '1029', (82, 90))	('cholangiocarcinoma', 'Disease', (118, 136))	('PSC', 'Gene', (100, 103))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (118, 136))
141201	34017024	Mutations, homozygous deletions or inactivation by methylation in p16INK4a have also been observed across several cancers, e.g., pancreatic, esophageal, bladder and liver cancer and familial melanoma, homozygous deletions in bladder, kidney, pancreas and ovary tumors, and inactivation through methylation in cancers of the breast, prostate, head and neck, and hepatocellular carcinomas.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('liver cancer', 'Phenotype', 'HP:0002896', (165, 177))	('cancers', 'Disease', (114, 121))	('p16INK4a', 'Gene', '1029', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('methylation', 'Var', (294, 305))	('breast', 'Disease', (324, 330))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (361, 386))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('carcinomas', 'Phenotype', 'HP:0030731', (376, 386))	('esophageal', 'Disease', (141, 151))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('homozygous deletions', 'Var', (11, 31))	('hepatocellular carcinomas', 'Disease', (361, 386))	('homozygous deletions', 'Var', (201, 221))	('ovary tumors', 'Phenotype', 'HP:0100615', (255, 267))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('inactivation', 'Var', (35, 47))	('prostate', 'Disease', (332, 340))	('pancreatic', 'Disease', 'MESH:D010195', (129, 139))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (309, 316))	('cancers', 'Disease', (309, 316))	('familial melanoma', 'Disease', (182, 199))	('inactivation', 'Var', (273, 285))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('bladder', 'Disease', (225, 232))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('pancreatic', 'Disease', (129, 139))	('bladder and liver cancer', 'Disease', 'MESH:D001749', (153, 177))	('pancreas and ovary tumors', 'Disease', 'MESH:D010051', (242, 267))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('p16INK4a', 'Gene', (66, 74))	('familial melanoma', 'Disease', 'MESH:C562393', (182, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (376, 385))	('kidney', 'Disease', (234, 240))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (361, 386))	('cancers', 'Disease', 'MESH:D009369', (309, 316))	('observed', 'Reg', (90, 98))
141216	32280473	Furthermore, elevated AFP and/or CA19-9 were independent unfavorable prognostic factors in various subgroups of cHCC-CC, including patients aged <60 years, positive hepatitis B surface antigen, cirrhosis, single tumor, tumor size >=5 cm, no vascular invasion, no LNM, and no local extra-hepatic invasion (all P < 0.05).	('cHCC-CC', 'Chemical', '-', (112, 119))	('tumor', 'Disease', (219, 224))	('cHCC-CC', 'Disease', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('hepatitis B', 'Disease', 'MESH:D006509', (165, 176))	('patients', 'Species', '9606', (131, 139))	('hepatitis', 'Phenotype', 'HP:0012115', (165, 174))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('cirrhosis', 'Disease', 'MESH:D005355', (194, 203))	('positive hepatitis B surface antigen', 'Phenotype', 'HP:0410369', (156, 192))	('positive', 'Var', (156, 164))	('tumor', 'Disease', (212, 217))	('cirrhosis', 'Phenotype', 'HP:0001394', (194, 203))	('CA19-9', 'Gene', (33, 39))	('AFP', 'Gene', (22, 25))	('AFP', 'Gene', '174', (22, 25))	('elevated', 'PosReg', (13, 21))	('HCC', 'Phenotype', 'HP:0001402', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('CA19-9', 'Chemical', 'MESH:C086528', (33, 39))	('hepatitis B', 'Disease', (165, 176))	('cirrhosis', 'Disease', (194, 203))
141217	32280473	Elevated AFP and/or CA19-9, vascular invasion, local extra-hepatic invasion, and LNM were independent unfavorable prognostic factors for long-term survival of cHCC-CC undergoing curative resections.	('vascular invasion', 'CPA', (28, 45))	('AFP', 'Gene', '174', (9, 12))	('CA19-9', 'Var', (20, 26))	('HCC', 'Phenotype', 'HP:0001402', (160, 163))	('CA19-9', 'Chemical', 'MESH:C086528', (20, 26))	('cHCC-CC', 'Chemical', '-', (159, 166))	('cHCC-CC', 'Disease', (159, 166))	('AFP', 'Gene', (9, 12))
141249	32280473	However, OS (P = 0.320) and RFS (P = 0.899) were not significantly different between patients with both elevated AFP and CA19-9 and those with elevated AFP or CA19-9.	('AFP', 'Gene', (152, 155))	('CA19-9', 'Chemical', 'MESH:C086528', (121, 127))	('AFP', 'Gene', '174', (152, 155))	('AFP', 'Gene', (113, 116))	('elevated', 'Var', (104, 112))	('CA19-9', 'Chemical', 'MESH:C086528', (159, 165))	('AFP', 'Gene', '174', (113, 116))	('patients', 'Species', '9606', (85, 93))	('CA19-9', 'Var', (121, 127))
141256	32280473	Clinically, the detection of AFP and CA19-9 is widely used for post-operative surveillance of HCC and ICC, respectively.	('HCC', 'Phenotype', 'HP:0001402', (94, 97))	('AFP', 'Gene', (29, 32))	('CA19-9', 'Var', (37, 43))	('AFP', 'Gene', '174', (29, 32))	('ICC', 'Disease', (102, 105))	('CA19-9', 'Chemical', 'MESH:C086528', (37, 43))	('HCC', 'Disease', (94, 97))
141273	32280473	Second, in order to detect recurrence at an early stage, for patients with elevated AFP and/or CA19-9, the interval of post-operative follow-up should be shortened, since its recurrence rate was higher than for those with normal AFP and CA19-9.	('CA19-9', 'Gene', (95, 101))	('AFP', 'Gene', (84, 87))	('AFP', 'Gene', '174', (229, 232))	('AFP', 'Gene', (229, 232))	('AFP', 'Gene', '174', (84, 87))	('patients', 'Species', '9606', (61, 69))	('elevated', 'Var', (75, 83))	('CA19-9', 'Chemical', 'MESH:C086528', (95, 101))	('CA19-9', 'Chemical', 'MESH:C086528', (237, 243))
141325	32127742	There was no difference in bilirubin reduction between the unilateral and bilateral stent groups when patients were stratified according to whether their decrease in bilirubin was >=75%, >50 to <75%, or <=50% from the level before stent placement (P=0.06) (Table 2).	('bilirubin', 'MPA', (27, 36))	('>50 to <75', 'Var', (187, 197))	('bilirubin', 'MPA', (166, 175))	('bilirubin', 'Chemical', 'MESH:D001663', (27, 36))	('reduction', 'NegReg', (37, 46))	('patients', 'Species', '9606', (102, 110))	('decrease in bilirubin', 'Phenotype', 'HP:0003573', (154, 175))	('bilirubin', 'Chemical', 'MESH:D001663', (166, 175))	('decrease', 'NegReg', (154, 162))
141386	24359879	Although neutropenia was significantly more frequent in the XP-CCRT than in the XP group (48% vs. 9%, p < 0.001), the rates of other toxicities and > grade 3 toxicities did not differ.	('neutropenia', 'Disease', 'MESH:D009503', (9, 20))	('toxicities', 'Disease', 'MESH:D064420', (133, 143))	('toxicities', 'Disease', 'MESH:D064420', (158, 168))	('neutropenia', 'Disease', (9, 20))	('toxicities', 'Disease', (133, 143))	('XP-CCRT', 'Var', (60, 67))	('toxicities', 'Disease', (158, 168))	('neutropenia', 'Phenotype', 'HP:0001875', (9, 20))
141423	24359879	The mean maximum tumor size was 7.3 cm, and the mean serum concentrations of carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) were 2675.4 U/mL and 107.7 ng/mL, respectively.	('carbohydrate', 'Chemical', 'MESH:D002241', (77, 89))	('tumor', 'Disease', (17, 22))	('CEA', 'Gene', '1084', (138, 141))	('carcinoembryonic antigen', 'Gene', '1084', (112, 136))	('2675.4', 'Var', (148, 154))	('carcinoembryonic antigen', 'Gene', (112, 136))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('serum concentrations', 'MPA', (53, 73))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('CEA', 'Gene', (138, 141))
141430	24359879	Disease control rate (DCR), which accounted for patients with complete response (CR), PR, and SD, was higher in the XP-CCRT than in the XP group, although the difference was not statistically significant (56.0% vs. 41.5%, p = 0.217) (Table  2).	('XP-CCRT', 'Var', (116, 123))	('patients', 'Species', '9606', (48, 56))	('higher', 'PosReg', (102, 108))	('Disease control rate', 'CPA', (0, 20))
141434	24359879	Neutropenia and hand-foot syndrome were more frequent in the XP-CCRT than in the XP group.	('XP-CCRT', 'Var', (61, 68))	('Neutropenia', 'Disease', 'MESH:D009503', (0, 11))	('hand-foot syndrome', 'Disease', (16, 34))	('hand-foot syndrome', 'Disease', 'MESH:D060831', (16, 34))	('Neutropenia', 'Phenotype', 'HP:0001875', (0, 11))	('Neutropenia', 'Disease', (0, 11))
141453	24359879	Moreover, except for neutropenia, the frequencies of treatment-related toxicity and >3 grade toxicity (24% vs. 10.4%, p = 0.174) were not significantly higher in the XP-CCRT than in the XP group, despite the former group receiving more cycles of chemotherapy as well as RT.	('toxicity', 'Disease', (71, 79))	('neutropenia', 'Disease', 'MESH:D009503', (21, 32))	('neutropenia', 'Phenotype', 'HP:0001875', (21, 32))	('toxicity', 'Disease', 'MESH:D064420', (93, 101))	('toxicity', 'Disease', (93, 101))	('XP-CCRT', 'Var', (166, 173))	('neutropenia', 'Disease', (21, 32))	('toxicity', 'Disease', 'MESH:D064420', (71, 79))
141498	22799744	found that HCC derived-HCV core variants alleviate TGF-beta cytostatic responses and increase TGF-beta-mediated epithelial to mesenchymal transition (EMT) in mouse or human primary hepatocytes.	('mouse', 'Species', '10090', (158, 163))	('increase TGF-beta', 'Phenotype', 'HP:0030269', (85, 102))	('variants', 'Var', (32, 40))	('alleviate', 'NegReg', (41, 50))	('TGF-beta cytostatic responses', 'MPA', (51, 80))	('HCV', 'Species', '11103', (23, 26))	('human', 'Species', '9606', (167, 172))	('increase', 'PosReg', (85, 93))
141501	22799744	There are reports providing evidence that HBx gene transfection can upregulate the transcriptional expression of human telomerase reverse transcriptase mRNA both in HCC and cholangiocarcinoma cell lines.	('telomerase reverse transcriptase', 'Gene', '7015', (119, 151))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (173, 191))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (173, 191))	('HBx', 'Gene', '944566', (42, 45))	('HBx', 'Gene', (42, 45))	('transcriptional expression', 'MPA', (83, 109))	('transfection', 'Var', (51, 63))	('upregulate', 'PosReg', (68, 78))	('cholangiocarcinoma', 'Disease', (173, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('telomerase reverse transcriptase', 'Gene', (119, 151))	('human', 'Species', '9606', (113, 118))	('human', 'Protein', (113, 118))
141576	31881895	Other factors that were associated with significantly improved survival were Child-Pugh A liver function (P = 0.004), absence of jaundice (P = 0.002), and undergoing maintenance chemotherapy (P = 0.000).	('absence of jaundice', 'Disease', 'MESH:D007565', (118, 137))	('absence of jaundice', 'Disease', (118, 137))	('jaundice', 'Phenotype', 'HP:0000952', (129, 137))	('Child-Pugh', 'Var', (77, 87))	('improved', 'PosReg', (54, 62))	('Child', 'Species', '9606', (77, 82))	('liver', 'Disease', (90, 95))	('survival', 'MPA', (63, 71))
141788	27694951	Further, high NLR predicted a poor prognosis in patients treated with both surgical (HR = 1.353, 95% CI: 1.099-1.607) and mixed (surgical and non-surgical) interventions (HR = 1.424, 95% CI: 1.217-1.691).	('patients', 'Species', '9606', (48, 56))	('NLR', 'Gene', (14, 17))	('high', 'Var', (9, 13))
141790	27694951	Subgroup analysis by the NOS score of the studies showed that a high NLR indicated poorer OS in CCA patients for studies with both NOS score >=7 (HR = 1.396, 95% CI: 1.235-1.556) and NOS score < 7 (HR = 1.311, 95% CI: 1.078-1.544).	('CCA', 'Phenotype', 'HP:0030153', (96, 99))	('poorer', 'NegReg', (83, 89))	('patients', 'Species', '9606', (100, 108))	('NOS score >=7', 'Var', (131, 144))	('CCA', 'Disease', (96, 99))	('NOS score < 7', 'Var', (183, 196))
141798	27694951	The infiltration of CD4+ T cells triggers the immune activation of CD8+ T cells, and activated CD8+ T cells cause apoptosis of cancer cells by releasing cytotoxic factors.	('immune activation', 'CPA', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('releasing', 'PosReg', (143, 152))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cytotoxic factors', 'MPA', (153, 170))	('CD8+', 'Var', (95, 99))	('cancer', 'Disease', (127, 133))	('cause', 'Reg', (108, 113))	('apoptosis', 'CPA', (114, 123))
141844	24891967	The tumor cells are positive for cytokeratin 7, cytokeratin 20, and CA19-9, and they are negative for TTF-1, CA125, thrombomodulin, and mammaglobin.	('tumor', 'Disease', (4, 9))	('cytokeratin 7', 'Gene', '3855', (33, 46))	('cytokeratin 20', 'Gene', '54474', (48, 62))	('TTF-1', 'Gene', '7270', (102, 107))	('CA125', 'Gene', '94025', (109, 114))	('positive', 'Reg', (20, 28))	('cytokeratin 7', 'Gene', (33, 46))	('CA19-9', 'Var', (68, 74))	('CA125', 'Gene', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('TTF-1', 'Gene', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('cytokeratin 20', 'Gene', (48, 62))
141908	23964337	Numerous studies, including two randomized clinical trials, have found that PDT is superior to biliary stenting alone in the treatment of unresectable cholangiocarcinoma, improving both survival as well as quality of life.	('cholangiocarcinoma', 'Disease', (151, 169))	('survival', 'MPA', (186, 194))	('improving', 'PosReg', (171, 180))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (151, 169))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (151, 169))	('PDT', 'Var', (76, 79))	('quality of life', 'CPA', (206, 221))
141913	23964337	However, despite its benefit, PDT was also associated with a substantial incidence of cholangitis requiring stent revision, occurring in just over 50% of our patients.	('PDT', 'Var', (30, 33))	('cholangitis', 'Disease', 'MESH:D002761', (86, 97))	('cholangitis', 'Disease', (86, 97))	('cholangitis', 'Phenotype', 'HP:0030151', (86, 97))	('patients', 'Species', '9606', (158, 166))
141953	33180184	The human embryonic cell line 911 was used for the amplification of the E1- and E3-deleted adenoviral vectors.	('E1-', 'Var', (72, 75))	('human', 'Species', '9606', (4, 9))	('E3-deleted', 'Var', (80, 90))
141999	33180184	To investigate the transduction efficiency and transgene expression of DC, hDC were transduced with Ad-GFP and with Ad-hCD40L.	('hCD40L', 'Gene', '959', (119, 125))	('hDC', 'Gene', '3067', (75, 78))	('DC', 'Gene', '3067', (71, 73))	('Ad-GFP', 'Var', (100, 106))	('DC', 'Gene', '3067', (76, 78))	('hDC', 'Gene', (75, 78))	('hCD40L', 'Gene', (119, 125))
142007	33180184	For CD80, the number of positive Ad-hCD40L-transduced DC was significantly (p = 0.0198) higher (90.1 +- 2.9%) compared to the number of positive CD80 + Ad-Mock DC (50.3 +- 11.3%).	('CD80', 'Var', (4, 8))	('higher', 'PosReg', (88, 94))	('CD', 'Chemical', 'MESH:D002104', (145, 147))	('DC', 'Gene', '3067', (54, 56))	('DC', 'Gene', '3067', (160, 162))	('CD', 'Chemical', 'MESH:D002104', (37, 39))	('hCD40L', 'Gene', (36, 42))	('hCD40L', 'Gene', '959', (36, 42))	('CD', 'Chemical', 'MESH:D002104', (4, 6))
142024	33180184	The reduced levels of IL-12 in the supernatant of transduced DC were dependent on the concentration of the blocking antibody; whereas, the IL-12 secretion of DC incubated with the control antibody remains unaffected (Fig.	('transduced', 'Var', (50, 60))	('DC', 'Gene', '3067', (158, 160))	('levels', 'MPA', (12, 18))	('DC', 'Gene', '3067', (61, 63))
142025	33180184	The blocking of CD40L led to a reduced IL-12 expression.	('reduced', 'NegReg', (31, 38))	('blocking', 'Var', (4, 12))	('CD40L', 'Gene', '959', (16, 21))	('IL-12', 'Protein', (39, 44))	('CD40L', 'Gene', (16, 21))
142033	33180184	The number of CD80+ and CD83+ cells was significantly higher compared to Ad-Mock DC incubated with the supernatant of Ad-Mock DC (p = 0.0024, p = 0.0003, respectively).	('higher', 'PosReg', (54, 60))	('DC', 'Gene', '3067', (81, 83))	('DC', 'Gene', '3067', (126, 128))	('CD', 'Chemical', 'MESH:D002104', (14, 16))	('CD83+', 'Var', (24, 29))	('CD80+', 'Var', (14, 19))	('CD', 'Chemical', 'MESH:D002104', (24, 26))
142116	32721879	The genes involved in RNA splicing and protein degradation processes and miR-144-3p may play fundamental roles in the pathogenesis of CHOL.	('CHOL', 'Phenotype', 'HP:0030153', (134, 138))	('play', 'Reg', (88, 92))	('CHOL', 'Disease', (134, 138))	('miR-144-3p', 'Chemical', '-', (73, 83))	('miR-144-3p', 'Var', (73, 83))
142124	32721879	Competing endogenous RNAs (ceRNAs), natural decoys that compete for a common pool of microRNAs (miRNA, miR), represent a novel layer of gene regulation by systematically functionalizing miRNA response element (MRE)-harboring non-coding RNAs, such as long non-coding RNAs (lncRNAs), pseudogenes, and circular RNAs (circRNAs), and forming complex miRNA-mediated ceRNA networks.	('miR', 'Gene', '220972', (186, 189))	('miR', 'Gene', (186, 189))	('functionalizing', 'Reg', (170, 185))	('pseudogenes', 'Var', (282, 293))	('miR', 'Gene', '220972', (96, 99))	('miR', 'Gene', (96, 99))	('miR', 'Gene', '220972', (103, 106))	('miR', 'Gene', (103, 106))	('miR', 'Gene', '220972', (345, 348))	('miR', 'Gene', (345, 348))
142125	32721879	The perturbation of ceRNA crosstalk will disrupt the balance of cellular processes and functions, leading to development of diseases such as cancer.	('disrupt', 'NegReg', (41, 48))	('leading to', 'Reg', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('perturbation', 'Var', (4, 16))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
142139	32721879	The genes in moduleA were significantly involved in GO:0006614~SRP-dependent cotranslational protein targeting to membrane, GO:0019083~viral transcription, and GO:0000184~nuclear-transcribed mRNA catabolic process, nonsense-mediated decay; genes in moduleB were significantly associated with GO:0000398~mRNA splicing, via spliceosome and GO:0000387~spliceosomal small nuclear ribonucleoprotein particle (snRNP) assembly.	('snRNP', 'Gene', '57819', (404, 409))	('moduleB', 'Gene', (249, 256))	('GO:0000398~mRNA', 'Var', (292, 307))	('GO:0000387~spliceosomal', 'Var', (338, 361))	('associated', 'Reg', (276, 286))	('snRNP', 'Gene', (404, 409))
142140	32721879	Genes in moduleC were concerned with GO:0006521~regulation of the cellular amino acid metabolic process and GO:0038061~NIK/nuclear factor-kappa B (NF-kappaB) signaling.	('NIK', 'Gene', '9020', (119, 122))	('GO:0006521~regulation', 'MPA', (37, 58))	('cellular amino acid metabolic process', 'MPA', (66, 103))	('NF-kappaB', 'Gene', '4790', (147, 156))	('NIK', 'Gene', (119, 122))	('NF-kappaB', 'Gene', (147, 156))	('GO:0006521~regulation', 'Var', (37, 58))
142173	32721879	Plausibly, miR-144-3p may play an important role in the pathogenesis of CHOL.	('miR-144-3p', 'Var', (11, 21))	('CHOL', 'Phenotype', 'HP:0030153', (72, 76))	('miR-144-3p', 'Chemical', '-', (11, 21))	('CHOL', 'Disease', (72, 76))
142174	32721879	Future mechanistic studies are warranted to determine the role of miR-144-3p in CHOL.	('miR-144-3p', 'Chemical', '-', (66, 76))	('CHOL', 'Phenotype', 'HP:0030153', (80, 84))	('CHOL', 'Disease', (80, 84))	('miR-144-3p', 'Var', (66, 76))
142176	32721879	miR-144-3p may play an important role in the pathogenesis of CHOL.	('miR-144-3p', 'Var', (0, 10))	('CHOL', 'Disease', (61, 65))	('miR-144-3p', 'Chemical', '-', (0, 10))	('CHOL', 'Phenotype', 'HP:0030153', (61, 65))
142214	31173252	Kaplan-Meier survival analysis revealed that ICC patients with positive CHD1L expression had shorter overall and disease-free survival than those with negative CHD1L expression.	('positive', 'Var', (63, 71))	('shorter', 'NegReg', (93, 100))	('CHD1L', 'Gene', (72, 77))	('patients', 'Species', '9606', (49, 57))	('ICC', 'Disease', (45, 48))
142226	31173252	More interestingly, a number of studies have found that amplification of CHD1L is extremely common in many solid tumors, including breast, gastric and nasopharyngeal carcinoma.	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (151, 175))	('nasopharyngeal carcinoma', 'Disease', (151, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (151, 175))	('common', 'Reg', (92, 98))	('solid tumors', 'Disease', (107, 119))	('breast', 'Disease', (131, 137))	('CHD1L', 'Gene', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('gastric', 'Disease', (139, 146))	('amplification', 'Var', (56, 69))	('solid tumors', 'Disease', 'MESH:D009369', (107, 119))
142277	31173252	Kaplan-Meier analysis showed that ICC patients with positive CHD1L expression had reduced overall and disease-free survival than those with negative CHD1L expression (log rank, 7.117; P=0.0076; Fig.	('CHD1L', 'Gene', (61, 66))	('disease-free survival', 'CPA', (102, 123))	('expression', 'Var', (67, 77))	('patients', 'Species', '9606', (38, 46))	('ICC', 'Disease', (34, 37))	('positive', 'Var', (52, 60))	('reduced', 'NegReg', (82, 89))
142306	31173252	Recently, CHD1L expression was found to increase tumor progression in pancreatic cancer.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('expression', 'Var', (16, 26))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('pancreatic cancer', 'Disease', (70, 87))	('CHD1L', 'Gene', (10, 15))	('increase', 'PosReg', (40, 48))	('tumor', 'Disease', (49, 54))	('pancreatic cancer', 'Disease', 'MESH:D010190', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (70, 87))
142311	31173252	In addition, Cox regression statistical analysis further indicated that high CHD1L expression was an independent predictor for poor prognosis in ICC patients.	('patients', 'Species', '9606', (149, 157))	('Cox', 'Gene', (13, 16))	('expression', 'MPA', (83, 93))	('ICC', 'Disease', (145, 148))	('high', 'Var', (72, 76))	('CHD1L', 'Gene', (77, 82))	('Cox', 'Gene', '1351', (13, 16))
142318	31173252	This evidence suggested that the dysregulation of the P53/cyclin D1/CDK2 pathway maybe involved in CHD1L-induced G1/S transition in ICC.	('dysregulation', 'Var', (33, 46))	('P53', 'Gene', (54, 57))	('ICC', 'Disease', (132, 135))	('CDK2', 'Gene', '1017', (68, 72))	('P53', 'Gene', '7157', (54, 57))	('involved', 'Reg', (87, 95))	('cyclin D1', 'Gene', '595', (58, 67))	('cyclin D1', 'Gene', (58, 67))	('CDK2', 'Gene', (68, 72))
142325	31173252	Furthermore, silencing of CHD1L expression inhibited MET phenotype, which involved decreased expression of E-cadherin and increased expression of N-cadherin in nude mice by IHC.	('E-cadherin', 'Protein', (107, 117))	('CHD1L', 'Gene', (26, 31))	('nude mice', 'Species', '10090', (160, 169))	('MET', 'CPA', (53, 56))	('inhibited', 'NegReg', (43, 52))	('decreased', 'NegReg', (83, 92))	('expression', 'MPA', (93, 103))	('increased', 'PosReg', (122, 131))	('expression', 'MPA', (132, 142))	('N-cadherin', 'Protein', (146, 156))	('silencing', 'Var', (13, 22))
142328	31173252	We hypothesize that the dysregulation of the P53/cyclin D1/CDK2 pathway maybe involved in CHD1L-induced G1/S transition and that CHD1L may drive EMT and MET in ICC cells, resulting in metastasis.	('involved', 'Reg', (78, 86))	('resulting in', 'Reg', (171, 183))	('CDK2', 'Gene', (59, 63))	('cyclin D1', 'Gene', '595', (49, 58))	('metastasis', 'CPA', (184, 194))	('MET', 'CPA', (153, 156))	('cyclin D1', 'Gene', (49, 58))	('dysregulation', 'Var', (24, 37))	('EMT', 'Gene', (145, 148))	('CHD1L', 'Var', (129, 134))	('EMT', 'Gene', '3702', (145, 148))	('P53', 'Gene', (45, 48))	('CDK2', 'Gene', '1017', (59, 63))	('P53', 'Gene', '7157', (45, 48))	('drive', 'PosReg', (139, 144))
142439	28394406	PBRM1 loss is a late event during the development of cholangiocarcinoma Somatic mutations in genes encoding chromatin remodelers have been recently reported in several cancer types, including approximately half of cholangiocarcinomas.	('loss', 'NegReg', (6, 10))	('cholangiocarcinomas', 'Disease', (214, 233))	('PBRM1', 'Gene', '55193', (0, 5))	('cancer', 'Disease', (168, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('carcinomas', 'Phenotype', 'HP:0030731', (223, 233))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (80, 89))	('PBRM1', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (214, 232))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cholangiocarcinoma', 'Disease', (214, 232))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (214, 232))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (53, 71))	('reported', 'Reg', (148, 156))	('cholangiocarcinoma', 'Disease', (53, 71))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (53, 71))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (214, 233))
142441	28394406	In order to determine the timing of PBRM1 mutations in biliary carcinogenesis, we used immunohistochemistry to assess PBRM1 protein expression in a series of precursor lesions and invasive biliary carcinomas.	('PBRM1', 'Gene', '55193', (118, 123))	('PBRM1', 'Gene', (36, 41))	('PBRM1', 'Gene', '55193', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('carcinomas', 'Phenotype', 'HP:0030731', (197, 207))	('invasive biliary carcinomas', 'Disease', 'MESH:D001661', (180, 207))	('invasive biliary carcinomas', 'Disease', (180, 207))	('PBRM1', 'Gene', (118, 123))	('mutations', 'Var', (42, 51))
142442	28394406	Previous studies have correlated loss of protein expression on immunohistochemistry with inactivating mutations in this tumor suppressor gene.	('protein', 'Protein', (41, 48))	('loss', 'NegReg', (33, 37))	('tumor suppressor', 'Gene', (120, 136))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor suppressor', 'Gene', '7248', (120, 136))	('inactivating mutations', 'Var', (89, 111))
142444	28394406	These findings indicate that PBRM1 mutation (and resultant loss of expression) is a late event during biliary carcinogenesis.	('PBRM1', 'Gene', '55193', (29, 34))	('loss of', 'NegReg', (59, 66))	('biliary carcinogenesis', 'Disease', (102, 124))	('mutation', 'Var', (35, 43))	('PBRM1', 'Gene', (29, 34))
142446	28394406	The genes involved in the establishment of chromatin structure, such as those coding for members of the Switch/Sucrose Non Fermentable (SWI/SNF) complex, are frequently mutated in a number of human cancers.	('human', 'Species', '9606', (192, 197))	('mutated', 'Var', (169, 176))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', (198, 205))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('Sucrose', 'Chemical', 'MESH:D013395', (111, 118))
142450	28394406	first reported that PBRM1 is frequently mutated in biliary carcinoma, describing somatic mutations of this gene in 17% of intrahepatic cholangiocarcinomas (ICCs) and in 25% of gallbladder carcinomas.	('PBRM1', 'Gene', (20, 25))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (135, 153))	('PBRM1', 'Gene', '55193', (20, 25))	('biliary carcinoma', 'Disease', (51, 68))	('intrahepatic cholangiocarcinomas', 'Disease', (122, 154))	('gallbladder carcinomas', 'Disease', (176, 198))	('mutations', 'Var', (89, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (122, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('biliary carcinoma', 'Disease', 'MESH:D001661', (51, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('gallbladder carcinomas', 'Disease', 'MESH:D005706', (176, 198))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))
142451	28394406	An independent study identified PBRM1 mutations in about 10% of cholangiocarcinomas, with enrichment in ICC, while a more recent study investigating mutational status of PBRM1 with immunohistochemistry reported that 23% of ICCs lack PBRM1 expression.	('PBRM1', 'Gene', (32, 37))	('expression', 'MPA', (239, 249))	('PBRM1', 'Gene', '55193', (170, 175))	('PBRM1', 'Gene', '55193', (32, 37))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (64, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('mutations', 'Var', (38, 47))	('PBRM1', 'Gene', (233, 238))	('cholangiocarcinomas', 'Disease', (64, 83))	('PBRM1', 'Gene', '55193', (233, 238))	('lack', 'NegReg', (228, 232))	('PBRM1', 'Gene', (170, 175))	('ICC', 'Disease', (104, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
142452	28394406	Interestingly, in addition to PBRM1, mutations in other genes influencing chromatin organization, including ARID1A, BAP1 and SMARCB1, have been identified in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (158, 176))	('SMARCB1', 'Gene', '6598', (125, 132))	('BAP1', 'Gene', (116, 120))	('PBRM1', 'Gene', (30, 35))	('SMARCB1', 'Gene', (125, 132))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (158, 176))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (158, 176))	('PBRM1', 'Gene', '55193', (30, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('mutations', 'Var', (37, 46))	('ARID1A', 'Gene', '8289', (108, 114))	('ARID1A', 'Gene', (108, 114))	('BAP1', 'Gene', '8314', (116, 120))	('identified', 'Reg', (144, 154))
142453	28394406	documented mutations in at least one chromatin-remodeling gene in 47% of cholangiocarcinomas, highlighting aberrant chromatin remodeling as a crucial step in biliary carcinogenesis.	('mutations', 'Var', (11, 20))	('cholangiocarcinomas', 'Disease', (73, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (73, 92))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (73, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))
142454	28394406	Although the presence of somatic PBRM1 mutations is already well-established in biliary carcinoma, little is known about the timing of PBRM1 mutations during biliary carcinogenesis.	('PBRM1', 'Gene', '55193', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('mutations', 'Var', (39, 48))	('biliary carcinoma', 'Disease', 'MESH:D001661', (80, 97))	('PBRM1', 'Gene', '55193', (135, 140))	('biliary carcinoma', 'Disease', (80, 97))	('PBRM1', 'Gene', (135, 140))	('PBRM1', 'Gene', (33, 38))
142456	28394406	PBRM1 mutations are inactivating and result in a loss of protein expression, and previous studies have demonstrated that loss of protein expression on immunohistochemistry strongly correlates with mutational status of PBRM1, as well as for other chromatin remodeling genes.	('PBRM1', 'Gene', (218, 223))	('protein expression', 'MPA', (129, 147))	('loss', 'NegReg', (49, 53))	('PBRM1', 'Gene', '55193', (218, 223))	('loss', 'NegReg', (121, 125))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('mutational', 'Var', (197, 207))	('protein expression', 'MPA', (57, 75))	('mutations', 'Var', (6, 15))
142457	28394406	In order to determine the timing of PBRM1 mutations, we have assayed PBRM1 protein expression in a series of precursor lesions and invasive carcinomas, including both intrahepatic and gallbladder lesions, representing a broad sample of the spectrum of biliary neoplasia.	('assayed', 'Reg', (61, 68))	('PBRM1', 'Gene', (36, 41))	('PBRM1', 'Gene', '55193', (36, 41))	('neoplasia', 'Phenotype', 'HP:0002664', (260, 269))	('invasive carcinomas', 'Disease', (131, 150))	('invasive carcinomas', 'Disease', 'MESH:D009361', (131, 150))	('biliary neoplasia', 'Disease', (252, 269))	('PBRM1', 'Gene', (69, 74))	('protein', 'Protein', (75, 82))	('biliary neoplasia', 'Phenotype', 'HP:0100574', (252, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('PBRM1', 'Gene', '55193', (69, 74))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))	('mutations', 'Var', (42, 51))	('intrahepatic and gallbladder lesions', 'Disease', 'MESH:D005705', (167, 203))	('biliary neoplasia', 'Disease', 'MESH:D009369', (252, 269))
142472	28394406	Because PBRM1 mutations result in a loss of protein expression, we used an immunohistochemical approach to study PBRM1 mutational status.	('protein expression', 'MPA', (44, 62))	('PBRM1', 'Gene', '55193', (8, 13))	('PBRM1', 'Gene', (113, 118))	('loss', 'NegReg', (36, 40))	('PBRM1', 'Gene', '55193', (113, 118))	('mutations', 'Var', (14, 23))	('PBRM1', 'Gene', (8, 13))
142495	28394406	Importantly, in our ICC cases with known PBRM1 mutation status, there was a perfect correlation between immunohistochemical staining and PBRM1 mutation status: the 2 cases with PBRM1 mutations showed loss of PBRM1 protein expression, and the 4 wild-type cases retained PBRM1 expression.	('PBRM1', 'Gene', (177, 182))	('PBRM1', 'Gene', '55193', (177, 182))	('mutations', 'Var', (183, 192))	('PBRM1', 'Gene', '55193', (208, 213))	('loss', 'NegReg', (200, 204))	('PBRM1', 'Gene', (137, 142))	('PBRM1', 'Gene', '55193', (137, 142))	('PBRM1', 'Gene', (269, 274))	('PBRM1', 'Gene', (41, 46))	('PBRM1', 'Gene', '55193', (41, 46))	('protein', 'Protein', (214, 221))	('PBRM1', 'Gene', (208, 213))	('PBRM1', 'Gene', '55193', (269, 274))
142505	28394406	With a multivariate analysis, the loss of PBRM1 was not associated with any increased risk of mortality (HR=1.19; 95%CI: 0.06-22.31; p=0.59), as also shown in the Kaplan-Meier curve (Figure 4).	('PBRM1', 'Gene', '55193', (42, 47))	('PBRM1', 'Gene', (42, 47))	('loss', 'Var', (34, 38))
142507	28394406	Overall, our results suggest that PBRM1 mutation is a late event during biliary carcinogenesis in the liver and gallbladder.	('mutation', 'Var', (40, 48))	('biliary carcinogenesis', 'Disease', (72, 94))	('PBRM1', 'Gene', (34, 39))	('PBRM1', 'Gene', '55193', (34, 39))
142508	28394406	reported that PBRM1 mutations occurred at similar prevalence in both subtypes (42% in type 1 and 53% in type 2), suggesting molecular similarities between the subtypes.	('PBRM1', 'Gene', '55193', (14, 19))	('PBRM1', 'Gene', (14, 19))	('mutations', 'Var', (20, 29))
142512	28394406	Notably, in contrast to ICC, PBRM1 expression has been shown to significantly impact survival in other solid malignancies with PBRM1 mutations.	('malignancies', 'Disease', 'MESH:D009369', (109, 121))	('PBRM1', 'Gene', '55193', (29, 34))	('malignancies', 'Disease', (109, 121))	('impact', 'Reg', (78, 84))	('PBRM1', 'Gene', (127, 132))	('PBRM1', 'Gene', '55193', (127, 132))	('mutations', 'Var', (133, 142))	('survival', 'MPA', (85, 93))	('PBRM1', 'Gene', (29, 34))	('expression', 'Var', (35, 45))
142516	28394406	We hypothesize that this is because the alterations assayed to date are late events in biliary carcinogenesis, but an alternative explanation for the lack of driver alterations is that BilINs are not in fact precursors to cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (222, 240))	('biliary carcinogenesis', 'Disease', (87, 109))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (222, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('BilINs', 'Chemical', 'MESH:D001654', (185, 191))	('alterations', 'Var', (40, 51))	('cholangiocarcinoma', 'Disease', (222, 240))
142517	28394406	BilINs have been proposed as a precursor for only type 1 ICC, but PBRM1 mutations occur at similar frequency in both subtypes of ICC.	('PBRM1', 'Gene', (66, 71))	('mutations', 'Var', (72, 81))	('PBRM1', 'Gene', '55193', (66, 71))	('BilINs', 'Chemical', 'MESH:D001654', (0, 6))
142518	28394406	The lack of PBRM1 loss in BilINs suggest that alterations in this gene are a late event, at least in the tumorigenesis of type 1 ICC.	('PBRM1', 'Gene', (12, 17))	('PBRM1', 'Gene', '55193', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('alterations', 'Var', (46, 57))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('BilINs', 'Chemical', 'MESH:D001654', (26, 32))	('type 1 ICC', 'Disease', (122, 132))	('tumor', 'Disease', (105, 110))
142523	28394406	In keeping with our results, this study further highlights that mutations in chromatin remodeling genes are late events in biliary carcinogenesis, occurring predominantly in invasive carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('invasive carcinoma', 'Disease', 'MESH:D009361', (174, 192))	('occurring', 'Reg', (147, 156))	('mutations', 'Var', (64, 73))	('biliary carcinogenesis', 'Disease', (123, 145))	('invasive carcinoma', 'Disease', (174, 192))
142524	28394406	In contrast, in other organs mutations in chromatin remodelers have been suggested as an early event during carcinogenesis; this has been previously reported for esophageal cancer, as well as ovarian and endometrial cancers.	('esophageal cancer', 'Disease', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('mutations', 'Var', (29, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (162, 179))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('reported', 'Reg', (149, 157))	('ovarian and endometrial cancers', 'Disease', 'MESH:D016889', (192, 223))
142528	28394406	Still, the true prevalence of these early mutations in intracystic papillary neoplasms remains to be determined, as we have only four cases in our cohort.	('intracystic papillary neoplasms', 'Disease', (55, 86))	('intracystic papillary neoplasms', 'Disease', 'MESH:D002291', (55, 86))	('neoplasms', 'Phenotype', 'HP:0002664', (77, 86))	('neoplasm', 'Phenotype', 'HP:0002664', (77, 85))	('mutations', 'Var', (42, 51))
142536	28394406	Such inaccurate categorization could contribute to the low prevalence of PBRM1 alterations demonstrated in our study.	('PBRM1', 'Gene', '55193', (73, 78))	('alterations', 'Var', (79, 90))	('PBRM1', 'Gene', (73, 78))
142538	28394406	Moreover, although it is possible that cases diagnosed as BilIN-1 might truly represent reactive atypia, this is far less likely for higher grades of dysplasia.	('reactive atypia', 'Disease', (88, 103))	('BilIN-1', 'Var', (58, 65))	('BilIN-1', 'Chemical', '-', (58, 65))	('dysplasia', 'Disease', (150, 159))	('dysplasia', 'Disease', 'MESH:D004476', (150, 159))
142540	28394406	In conclusion, based on immunohistochemical analysis of PBRM1 expression in BilIN lesions, we found that PBRM1 mutations are a late event during cholangiocarcinogenesis.	('mutations', 'Var', (111, 120))	('PBRM1', 'Gene', (105, 110))	('PBRM1', 'Gene', '55193', (105, 110))	('BilIN', 'Chemical', '-', (76, 81))	('cholangiocarcinogenesis', 'Disease', (145, 168))	('PBRM1', 'Gene', (56, 61))	('PBRM1', 'Gene', '55193', (56, 61))
142590	18805651	Patients with negative resection margins (R0 vs. R1 or R2) had a significantly improved local control rate at 5 years (82% vs. 60%, respectively, p = 0.02), but this did not convey a survival benefit (5-year OS rate, 36% vs. 32%, respectively, p = 0.7).	('local control', 'CPA', (88, 101))	('improved', 'PosReg', (79, 87))	('R2', 'Var', (55, 57))	('Patients', 'Species', '9606', (0, 8))
142691	23049491	In contrast, the vascular enhancement with Gd-EOB is less pronounced and has a short duration.	('vascular', 'CPA', (17, 25))	('enhancement', 'PosReg', (26, 37))	('Gd-EOB', 'Chemical', '-', (43, 49))	('Gd-EOB', 'Var', (43, 49))	('men', 'Species', '9606', (33, 36))
142693	23049491	The hepatobiliary phase is usually sufficient at 20 min after Gd-EOB and 1-2 hours after Gd-BOPTA administration.	('hepatobiliary', 'Disease', 'MESH:D004066', (4, 17))	('Gd-BOPTA', 'Chemical', 'MESH:C064572', (89, 97))	('hepatobiliary', 'Disease', (4, 17))	('Gd-EOB', 'Chemical', '-', (62, 68))	('Gd-EOB', 'Var', (62, 68))
142734	23049491	Those with male hormone administration, familial polyposis and mutated b-catenin has enhanced risk.	('mutated', 'Var', (63, 70))	('b-catenin', 'Gene', (71, 80))	('familial polyposis', 'Disease', 'MESH:D011125', (40, 58))	('familial polyposis', 'Disease', (40, 58))	('b-catenin', 'Gene', '1499', (71, 80))
142775	23049491	In a recent study, in the hepatobiliary phase, 95% of HCC were hypointense on T1, whereas 94% of the pseudolesions were isointense.	('hepatobiliary', 'Disease', 'MESH:D004066', (26, 39))	('HCC', 'Gene', '619501', (54, 57))	('hypointense', 'Var', (63, 74))	('HCC', 'Phenotype', 'HP:0001402', (54, 57))	('hepatobiliary', 'Disease', (26, 39))	('HCC', 'Gene', (54, 57))
142777	23049491	In another study on HCC <=2 cm, it was shown that by adding DWI to conventional dynamic Gd-MRI, the sensitivity was significantly increased from 85% to 98%.	('HCC', 'Gene', (20, 23))	('sensitivity', 'MPA', (100, 111))	('HCC', 'Gene', '619501', (20, 23))	('Gd', 'Chemical', 'MESH:D005682', (88, 90))	('increased', 'PosReg', (130, 139))	('DWI', 'Var', (60, 63))	('HCC', 'Phenotype', 'HP:0001402', (20, 23))
142807	23049491	Hepatic metastases show higher SI on DWI than on T2-weighted fast SE images, whereas the signal from vessels and cysts are suppressed with DWI.	('metastases', 'Disease', (8, 18))	('SI', 'Disease', 'None', (31, 33))	('metastases', 'Disease', 'MESH:D009362', (8, 18))	('higher', 'PosReg', (24, 30))	('DWI', 'Var', (37, 40))
142815	23049491	Lymphoma is isointense to the spleen and hypointense on T1 and hyperintense on T2 compared to surrounding liver tissue.	('Lymphoma', 'Phenotype', 'HP:0002665', (0, 8))	('hyperintense', 'Var', (63, 75))	('Lymphoma', 'Disease', (0, 8))	('Lymphoma', 'Disease', 'MESH:D008223', (0, 8))
142933	33805461	In microsatellite-stable, pre-treated biliary tract cancers, single-agent immune checkpoint blockade has a limited albeit often long-lasting clinical activity in a still ill-defined subgroup of patients.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('patients', 'Species', '9606', (194, 202))	('microsatellite-stable', 'Var', (3, 24))	('biliary tract cancers', 'Disease', 'MESH:D001661', (38, 59))	('biliary tract cancers', 'Disease', (38, 59))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
142951	33805461	Besides cancers with prevalent oncogenic mutations (e.g., BRAF mutation in melanoma, c-kit or PDGFR mutations in gastrointestinal stromal tumors), BTCs are now known to present one of the highest frequencies of targetable molecular alterations across cancer types.	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (113, 144))	('c-kit', 'Gene', (85, 90))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (113, 144))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('gastrointestinal stromal tumors', 'Disease', (113, 144))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('c-kit', 'Gene', '3815', (85, 90))	('PDGFR', 'Gene', (94, 99))	('PDGFR', 'Gene', '5159', (94, 99))	('BTCs', 'Chemical', '-', (147, 151))	('mutation', 'Var', (63, 71))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', (251, 257))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('mutations', 'Var', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('BRAF', 'Gene', '673', (58, 62))	('BRAF', 'Gene', (58, 62))
142953	33805461	Isocitrate dehydrogenase gene (IDH) mutations and fibroblast growth factor receptor 2 (FGFR2) fusions are found almost exclusively in intrahepatic cholangiocarcinomas, with frequencies of approximately 15% and 20% respectively, whereas human epidermal growth factor receptor-2 gene (HER2) aberrations are observed in approximately 15% of cases of extrahepatic cholangiocarcinomas and gallbladder carcinomas.	('fibroblast growth factor receptor 2', 'Gene', (50, 85))	('gallbladder carcinomas', 'Disease', (384, 406))	('HER2', 'Gene', (283, 287))	('intrahepatic cholangiocarcinomas', 'Disease', (134, 166))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (360, 378))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (147, 165))	('IDH', 'Gene', (31, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (396, 405))	('gallbladder carcinomas', 'Disease', 'MESH:D005706', (384, 406))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (134, 166))	('fusions', 'Var', (94, 101))	('extrahepatic cholangiocarcinomas', 'Disease', (347, 379))	('FGFR2', 'Gene', (87, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('epidermal growth factor receptor-2', 'Gene', (242, 276))	('IDH', 'Gene', '3417', (31, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (396, 406))	('HER2', 'Gene', '2064', (283, 287))	('epidermal growth factor receptor-2', 'Gene', '2064', (242, 276))	('human', 'Species', '9606', (236, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (369, 378))	('FGFR2', 'Gene', '2263', (87, 92))	('extrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (347, 379))	('mutations', 'Var', (36, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (369, 379))	('carcinomas', 'Phenotype', 'HP:0030731', (156, 166))	('fibroblast growth factor receptor 2', 'Gene', '2263', (50, 85))
142954	33805461	Several targeted therapies have been or are currently tested in BTCs, leading notably to the FDA accelerated approval of pemigatinib, an oral and selective inhibitor of FGFR1, 2 and 3, for the treatment of patients with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma that exhibits a FGFR2 rearrangement or fusion.	('locally advanced', 'Disease', (254, 270))	('fusion', 'Var', (343, 349))	('cholangiocarcinoma', 'Disease', (285, 303))	('FGFR2', 'Gene', (320, 325))	('FGFR2', 'Gene', '2263', (320, 325))	('patients', 'Species', '9606', (206, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('pemigatinib', 'Chemical', '-', (121, 132))	('FGFR1, 2 and 3', 'Gene', '2260;2263;2261', (169, 183))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (285, 303))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (285, 303))	('BTCs', 'Chemical', '-', (64, 68))	('rearrangement', 'Var', (326, 339))
142961	33805461	Almost 40% of patients were classified in Cluster 4 with higher mutation load and higher expression of immune checkpoint genes (LAG3, CTLA4, PDCD1, TNFRSF9, BTLA, IDO1, HAVCR2, and TNFRSF4).	('IDO1', 'Gene', '3620', (163, 167))	('HAVCR2', 'Gene', '84868', (169, 175))	('TNFRSF9', 'Gene', (148, 155))	('PDCD1', 'Gene', (141, 146))	('TNFRSF9', 'Gene', '3604', (148, 155))	('PDCD1', 'Gene', '5133', (141, 146))	('patients', 'Species', '9606', (14, 22))	('CTLA4', 'Gene', (134, 139))	('expression', 'MPA', (89, 99))	('BTLA', 'Gene', '151888', (157, 161))	('IDO1', 'Gene', (163, 167))	('TNFRSF4', 'Gene', '7293', (181, 188))	('LAG3', 'Gene', '3902', (128, 132))	('HAVCR2', 'Gene', (169, 175))	('BTLA', 'Gene', (157, 161))	('LAG3', 'Gene', (128, 132))	('higher', 'PosReg', (57, 63))	('higher', 'PosReg', (82, 88))	('TNFRSF4', 'Gene', (181, 188))	('CTLA4', 'Gene', '1493', (134, 139))	('mutation load', 'Var', (64, 77))
142992	33805461	Bintrafusp alpha (M7824), a bifunctional fusion protein that targets PD-L1 and transforming growth factor beta (TGF-beta), gave interesting results in 30 pre-treated BTC patients (53% PD-L1 > 1%).	('patients', 'Species', '9606', (170, 178))	('transforming growth factor beta', 'Gene', '7124', (79, 110))	('TGF-beta', 'Gene', '7039', (112, 120))	('M7824', 'Var', (18, 23))	('transforming growth factor beta', 'Gene', (79, 110))	('TGF-beta', 'Gene', (112, 120))	('PD-L1', 'Gene', (69, 74))
143048	33805461	Genomic instability provides one mechanism for creating unique antigenicity for a cancer cell.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('Genomic instability', 'Var', (0, 19))	('antigenicity', 'MPA', (63, 75))
143049	33805461	Consequently, tumors with high TMB respond favorably to immune checkpoint inhibitors.	('TMB', 'Gene', (31, 34))	('high', 'Var', (26, 30))	('TMB', 'Chemical', '-', (31, 34))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
143050	33805461	In the KEYNOTE-158 study, ORR were significantly improved in patients with a TMB >10 mutations per megabase (Mut/Mb) compared to those with a lower TMB.	('improved', 'PosReg', (49, 57))	('patients', 'Species', '9606', (61, 69))	('TMB', 'Gene', (77, 80))	('>10 mutations', 'Var', (81, 94))	('TMB', 'Chemical', '-', (148, 151))	('mutations', 'Var', (85, 94))	('TMB', 'Chemical', '-', (77, 80))	('ORR', 'MPA', (26, 29))
143075	33805461	In the KEYNOTE-158 study, 58% of patients had PD-L1 expression >1% while only 6% of patients had a response.	('patients', 'Species', '9606', (33, 41))	('patients', 'Species', '9606', (84, 92))	('PD-L1', 'Protein', (46, 51))	('expression', 'MPA', (52, 62))	('>1%', 'Var', (63, 66))
143077	33805461	Another exploratory strategy in BTCs could be the use of mutations in DNA damage repair (DDR) genes (germline or somatic).	('mutations', 'Var', (57, 66))	('BTCs', 'Chemical', '-', (32, 36))	('DDR) genes', 'Gene', (89, 99))	('DNA', 'Gene', (70, 73))
143080	33805461	This is of importance since alterations in DDR genes can increase sensitivity to anti-cancer chemotherapy and radiation treatments.	('sensitivity to', 'MPA', (66, 80))	('alterations', 'Var', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('increase', 'PosReg', (57, 65))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('DDR genes', 'Gene', (43, 52))	('cancer', 'Disease', (86, 92))
143081	33805461	Since DDR defects induce genomic instability, increasing tumor immunogenicity, a sensitization to immune therapies could be obtained by inducing DNA damage (with chemotherapy or radiotherapy), by inhibiting DDR pathways or directly by using immune therapies in patients with a known DDR deficiency.	('increasing', 'PosReg', (46, 56))	('inducing', 'Reg', (136, 144))	('DDR', 'Gene', (6, 9))	('inhibiting', 'NegReg', (196, 206))	('DDR pathways', 'Pathway', (207, 219))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('induce', 'Reg', (18, 24))	('DDR deficiency', 'Disease', (283, 297))	('genomic instability', 'MPA', (25, 44))	('DDR deficiency', 'Disease', 'MESH:D007153', (283, 297))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('patients', 'Species', '9606', (261, 269))	('tumor', 'Disease', (57, 62))	('DNA damage', 'MPA', (145, 155))	('defects', 'Var', (10, 17))
143083	33805461	They arise from germline mutations in MMR genes (i.e., MLH1, MSH2, MSH6 or PMS2), called Lynch syndrome, or following silencing of the MLH1 promoter by hypermethylation, mostly due to aging.	('MLH1', 'Gene', (135, 139))	('arise from', 'Reg', (5, 15))	('silencing', 'NegReg', (118, 127))	('MSH2', 'Gene', (61, 65))	('PMS2', 'Gene', '5395', (75, 79))	('MSH2', 'Gene', '4436', (61, 65))	('hypermethylation', 'Var', (152, 168))	('MLH1', 'Gene', '4292', (55, 59))	('MMR genes', 'Gene', (38, 47))	('Lynch syndrome', 'Disease', (89, 103))	('MLH1', 'Gene', (55, 59))	('MSH6', 'Gene', (67, 71))	('Lynch syndrome', 'Disease', 'MESH:D003123', (89, 103))	('PMS2', 'Gene', (75, 79))	('MLH1', 'Gene', '4292', (135, 139))	('MSH6', 'Gene', '2956', (67, 71))
143091	33805461	As previously said, BTCs are known to harbor one of the highest frequencies of targetable molecular alterations across cancer types, including FGFR2 fusions or IDH1/2 mutations.	('FGFR2', 'Gene', (143, 148))	('IDH1/2', 'Gene', (160, 166))	('fusions', 'Var', (149, 156))	('FGFR2', 'Gene', '2263', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('BTCs', 'Chemical', '-', (20, 24))	('mutations', 'Var', (167, 176))	('cancer', 'Disease', (119, 125))	('IDH1/2', 'Gene', '3417;3418', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
143093	33805461	Moreover, FGFR inhibitors could also modulate tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('FGFR', 'Gene', (10, 14))	('tumor', 'Disease', (46, 51))	('modulate', 'Reg', (37, 45))	('inhibitors', 'Var', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
143114	33805461	Among those, some are tumor-intrinsic factors, such as a lack of neoantigens, epigenetic changes in cancer cells (that can alter the expression of immune-related genes), alteration of signaling pathways, and regulation of interferon-gamma pathway.	('expression', 'MPA', (133, 143))	('epigenetic changes', 'Var', (78, 96))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('interferon-gamma', 'Gene', '3458', (222, 238))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('regulation', 'Reg', (208, 218))	('neoantigens', 'Protein', (65, 76))	('alter', 'Reg', (123, 128))	('immune-related genes', 'Gene', (147, 167))	('signaling pathways', 'Pathway', (184, 202))	('alteration', 'Reg', (170, 180))	('interferon-gamma', 'Gene', (222, 238))	('tumor', 'Disease', (22, 27))	('cancer', 'Disease', (100, 106))	('lack', 'NegReg', (57, 61))
143117	33805461	Moreover, some patients may present a targetable alteration (e.g., FGFR2 fusion, IDH1/2 mutation, etc.)	('patients', 'Species', '9606', (15, 23))	('mutation', 'Var', (88, 96))	('IDH1/2', 'Gene', (81, 87))	('FGFR2', 'Gene', (67, 72))	('FGFR2', 'Gene', '2263', (67, 72))	('fusion', 'Var', (73, 79))	('IDH1/2', 'Gene', '3417;3418', (81, 87))
143207	32128221	Two recent meta-analyses and systematic reviews comparing SEMS and plastic stents (11 retrospective and prospective studies, n = 947 and 20 randomised controlled trials, n = 1713, respectively) found SEMS to be associated with longer stent patency, lower re-intervention rates and lower rates of cholangitis.	('lower', 'NegReg', (281, 286))	('re-intervention rates', 'CPA', (255, 276))	('SEMS', 'Var', (200, 204))	('cholangitis', 'Phenotype', 'HP:0030151', (296, 307))	('cholangitis', 'Disease', (296, 307))	('longer', 'PosReg', (227, 233))	('lower', 'NegReg', (249, 254))	('cholangitis', 'Disease', 'MESH:D002761', (296, 307))
143275	31638221	Besides, according to RT-qPCR, the relative expression levels of miR-132-3p were higher in the CCA group (2.4634+-1.59019) compared with in non-tumor control tissues (1.0190+-0.83004; P<0.001; Fig.	('non-tumor', 'Disease', 'MESH:C580335', (140, 149))	('miR-132-3p', 'Gene', '100302255', (65, 75))	('CCA', 'Disease', 'MESH:D018281', (95, 98))	('CCA', 'Disease', (95, 98))	('higher', 'PosReg', (81, 87))	('miR-132-3p', 'Gene', (65, 75))	('CCA', 'Phenotype', 'HP:0030153', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('non-tumor', 'Disease', (140, 149))	('expression levels', 'MPA', (44, 61))	('2.4634+-1.59019', 'Var', (106, 121))
143277	31638221	Regarding the SMD of miR-132-3p in CCA, heterogeneity existed with an I2 of 78.5%, and GSE53870 had the greatest impact on the results of the meta-analysis based on the sensitivity analysis conducted (Fig.	('CCA', 'Phenotype', 'HP:0030153', (35, 38))	('miR-132-3p', 'Gene', (21, 31))	('CCA', 'Disease', 'MESH:D018281', (35, 38))	('GSE53870', 'Var', (87, 95))	('CCA', 'Disease', (35, 38))	('miR-132-3p', 'Gene', '100302255', (21, 31))
143313	31638221	A previous study reported that the single nucleotide polymorphism rs1599795 in CD80 3'-UTR contributed to the occurrence of gastric cancer through disrupting the regulatory role of miR-132-3p, miR-212-3p and miR-361-5p in CD80 expression.	('miR-132-3p', 'Gene', (181, 191))	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('rs1599795', 'Var', (66, 75))	('miR-361-5p', 'Gene', (208, 218))	('single nucleotide polymorphism rs1599795', 'Var', (35, 75))	('CD80', 'Gene', '941', (79, 83))	('miR-361-5p', 'Gene', '100500847', (208, 218))	('gastric cancer', 'Disease', (124, 138))	('CD80', 'Gene', '941', (222, 226))	('CD80', 'Gene', (79, 83))	('rs1599795', 'Mutation', 'rs1599795', (66, 75))	('regulatory', 'MPA', (162, 172))	('miR-132-3p', 'Gene', '100302255', (181, 191))	('miR-212-3p', 'Var', (193, 203))	('CD80', 'Gene', (222, 226))	('gastric cancer', 'Disease', 'MESH:D013274', (124, 138))	('expression', 'MPA', (227, 237))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('disrupting', 'NegReg', (147, 157))	('212-3p', 'Chemical', 'MESH:C014896', (197, 203))
143325	31638221	Focal adhesion has been reported to be involved in CCA progression and metastasis, whereas the PI3K-Akt-mTOR signaling pathway serves an essential role in regulating cell survival and proliferation in unresectable and liver metastases of pancreatic cancer; notably, inhibition of the PI3K/Akt/mTOR signaling pathway may serve as a promising therapeutic strategy in the treatment of intrahepatic cholangiocarcinoma.	('CCA', 'Disease', (51, 54))	('inhibition', 'Var', (266, 276))	('rat', 'Species', '10116', (191, 194))	('metastases of pancreatic cancer', 'Disease', 'MESH:D010190', (224, 255))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('mTOR', 'Gene', (104, 108))	('Akt', 'Gene', (100, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (404, 413))	('Akt', 'Gene', '207', (100, 103))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:C535533', (382, 413))	('metastases of pancreatic cancer', 'Disease', (224, 255))	('involved', 'Reg', (39, 47))	('mTOR', 'Gene', '2475', (104, 108))	('mTOR', 'Gene', (293, 297))	('Akt', 'Gene', (289, 292))	('rat', 'Species', '10116', (355, 358))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (238, 255))	('intrahepatic cholangiocarcinoma', 'Disease', (382, 413))	('Akt', 'Gene', '207', (289, 292))	('mTOR', 'Gene', '2475', (293, 297))	('CCA', 'Phenotype', 'HP:0030153', (51, 54))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (395, 413))	('CCA', 'Disease', 'MESH:D018281', (51, 54))
143355	30511939	The cirrhotic liver gives way to HCC via hepatocarcinogenesis, an anaplastic complex process characterized by stepwise accumulation of epigenetic and genetic alterations at the molecular and cellular level, and changes in the hepatic architecture seen at the histologic level.	('epigenetic', 'Var', (135, 145))	('changes', 'Reg', (211, 218))	('HCC via hepatocarcinogenesis', 'Disease', (33, 61))	('HCC', 'Phenotype', 'HP:0001402', (33, 36))	('HCC via hepatocarcinogenesis', 'Disease', 'MESH:D006528', (33, 61))	('cirrhotic liver', 'Phenotype', 'HP:0001394', (4, 19))	('accumulation', 'PosReg', (119, 131))
143413	30511939	Transient arterial enhancement due to focal obstruction of a distal parenchymal portal vein or nontumorous arterioportal shunts, for example, is often seen in the cirrhotic liver.	('cirrhotic liver', 'Phenotype', 'HP:0001394', (163, 178))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('enhancement', 'PosReg', (19, 30))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('men', 'Species', '9606', (26, 29))	('tumor', 'Disease', (98, 103))	('focal obstruction', 'Var', (38, 55))	('arterial', 'MPA', (10, 18))
143440	30511939	Several radiotracers have been used to achieve this objective, including 18F-fluorodeoxyglucose (18F-FDG) to estimate glucose consumption and choline labelled with either 11C (Cho) or 18F (FCho) to reflect cell-membrane metabolism and tumor proliferation., 18F-FDG is the most widely used radiotracer in oncology and has great sensitivity for detecting metastases from most cancers.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('Cho', 'Chemical', 'MESH:C034482', (176, 179))	('choline', 'Chemical', 'MESH:D002794', (142, 149))	('18F-fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (73, 95))	('metastases', 'Disease', (353, 363))	('11C', 'Chemical', 'MESH:C000615233', (171, 174))	('oncology', 'Phenotype', 'HP:0002664', (304, 312))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('18F-FDG', 'Var', (257, 264))	('FDG', 'Chemical', 'MESH:D019788', (261, 264))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('Cho', 'Chemical', 'MESH:C034482', (190, 193))	('cancers', 'Phenotype', 'HP:0002664', (374, 381))	('cancers', 'Disease', (374, 381))	('FDG', 'Chemical', 'MESH:D019788', (101, 104))	('glucose consumption', 'Disease', (118, 137))	('glucose consumption', 'Disease', 'MESH:D014397', (118, 137))	('tumor', 'Disease', (235, 240))	('cancers', 'Disease', 'MESH:D009369', (374, 381))	('metastases', 'Disease', 'MESH:D009362', (353, 363))
143452	30026852	To test this hypothesis, here, we estimated the associations between DNA methylation and BMI through two different methods across 15 cancer types, at approximately 485,000 CpG sites and 2415 samples using data from The Cancer Genome Atlas.	('associations', 'Interaction', (48, 60))	('Cancer', 'Disease', 'MESH:D009369', (219, 225))	('Cancer', 'Disease', (219, 225))	('Cancer', 'Phenotype', 'HP:0002664', (219, 225))	('methylation', 'Var', (73, 84))	('BMI', 'Disease', (89, 92))	('15 cancer', 'Disease', (130, 139))	('15 cancer', 'Disease', 'MESH:C567447', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
143454	30026852	The DMSs of COAD or UCEC were enriched in several obesity-induced and cancer-related pathways.	('DMSs', 'Var', (4, 8))	('obesity-induced', 'Disease', (50, 65))	('DMSs', 'Chemical', '-', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('COAD', 'Disease', 'MESH:D029424', (12, 16))	('obesity-induced', 'Disease', 'MESH:D009765', (50, 65))	('obesity', 'Phenotype', 'HP:0001513', (50, 57))	('COAD', 'Disease', (12, 16))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
143455	30026852	Next, when BMI was used as a continuous variable, we identified BMI-associated methylated CpG sites (BMS) (P (Bonferroni) < 0.05) in CHOL (BMS = 1), COAD (BMS = 1), and UCEC (BMS = 4) using multivariable linear regression.	('BMS = 1', 'Gene', (155, 162))	('COAD', 'Disease', 'MESH:D029424', (149, 153))	('methylated', 'Var', (79, 89))	('BMS = 1', 'Gene', '9790', (155, 162))	('BMS = 1', 'Gene', (139, 146))	('COAD', 'Disease', (149, 153))	('CHOL', 'Phenotype', 'HP:0030153', (133, 137))	('BMS = 1', 'Gene', '9790', (139, 146))
143457	30026852	Overall, we observed associations between DNA methylation and high BMI in CHOL, COAD, and UCEC.	('CHOL', 'Disease', (74, 78))	('methylation', 'Var', (46, 57))	('UCEC', 'Disease', (90, 94))	('DNA', 'Protein', (42, 45))	('COAD', 'Disease', 'MESH:D029424', (80, 84))	('high', 'Disease', (62, 66))	('COAD', 'Disease', (80, 84))	('CHOL', 'Phenotype', 'HP:0030153', (74, 78))	('associations', 'Interaction', (21, 33))
143465	30026852	Another study revealed that 7 BMI-associated SNPs located in 8 obesity-related genes were significantly associated with a risk for endometrial cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('endometrial cancer', 'Disease', (131, 149))	('obesity', 'Phenotype', 'HP:0001513', (63, 70))	('associated', 'Reg', (104, 114))	('SNPs', 'Var', (45, 49))	('endometrial cancer', 'Phenotype', 'HP:0012114', (131, 149))	('obesity', 'Disease', 'MESH:D009765', (63, 70))	('endometrial cancer', 'Disease', 'MESH:D016889', (131, 149))	('obesity', 'Disease', (63, 70))
143466	30026852	Similarly, SNPs in genes known to be associated with metabolism and obesity are relevant to prostate cancer.	('obesity', 'Phenotype', 'HP:0001513', (68, 75))	('prostate cancer', 'Phenotype', 'HP:0012125', (92, 107))	('obesity', 'Disease', 'MESH:D009765', (68, 75))	('prostate cancer', 'Disease', (92, 107))	('obesity', 'Disease', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('prostate cancer', 'Disease', 'MESH:D011471', (92, 107))	('SNPs', 'Var', (11, 15))
143467	30026852	These findings suggest that high BMI associated with multiple genes and can influence various biological pathways, thus contributing to the susceptibility of complex human cancers.	('contributing', 'Reg', (120, 132))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('human', 'Species', '9606', (166, 171))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('associated', 'Reg', (37, 47))	('biological pathways', 'Pathway', (94, 113))	('cancers', 'Disease', (172, 179))	('high BMI', 'Var', (28, 36))	('influence', 'Reg', (76, 85))
143469	30026852	Changes in DNA methylation can indeed be implicated in the initiation and progression of neoplasm.	('methylation', 'Var', (15, 26))	('neoplasm', 'Disease', (89, 97))	('DNA', 'Protein', (11, 14))	('neoplasm', 'Disease', 'MESH:D009369', (89, 97))	('neoplasm', 'Phenotype', 'HP:0002664', (89, 97))	('implicated', 'Reg', (41, 51))	('Changes', 'Reg', (0, 7))
143470	30026852	Sirtuin 1, a gene related to epigenetic silencing, links obesity to cancer, and also plays a role in colorectal cancer development, suggesting that obesity-related epigenetic changes may be an important determinant in colorectal cancer.	('obesity', 'Disease', (148, 155))	('colorectal cancer', 'Disease', (218, 235))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Sirtuin 1', 'Gene', (0, 9))	('links obesity to cancer', 'Disease', (51, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('obesity', 'Disease', 'MESH:D009765', (148, 155))	('obesity', 'Phenotype', 'HP:0001513', (57, 64))	('role', 'Reg', (93, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (218, 235))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('obesity', 'Disease', (57, 64))	('links obesity to cancer', 'Disease', 'MESH:D009765', (51, 74))	('obesity', 'Phenotype', 'HP:0001513', (148, 155))	('Sirtuin 1', 'Gene', '23411', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('colorectal cancer', 'Disease', (101, 118))	('epigenetic', 'Var', (29, 39))	('obesity', 'Disease', 'MESH:D009765', (57, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (218, 235))
143472	30026852	Furthermore, a previous study that analyzed 345 breast tumor samples has also shown an association between BMI and DNA methylation in tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('breast tumor', 'Disease', (48, 60))	('methylation', 'Var', (119, 130))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('BMI', 'Gene', (107, 110))	('breast tumor', 'Disease', 'MESH:D001943', (48, 60))	('association', 'Interaction', (87, 98))	('breast tumor', 'Phenotype', 'HP:0100013', (48, 60))	('DNA', 'Gene', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
143479	30026852	For adults, BMI was classified according to World Health Organization (WHO) definitions as underweight (BMI < 18.5), normal weight (18.5 <= BMI < 25), overweight (25 <= BMI < 30), and obese (BMI >= 30).	('obese', 'Disease', (184, 189))	('18.5 <=', 'Var', (132, 139))	('obese', 'Disease', 'MESH:D009765', (184, 189))	('overweight', 'Phenotype', 'HP:0025502', (151, 161))	('25 <= BMI <', 'Var', (163, 174))
143487	30026852	High BMI has an increased risk for cancers.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('High BMI', 'Var', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))
143489	30026852	In COAD, the average global DNA methylation levels in high BMI cases (beta value = 0.46) were significantly lower than the control cases (beta value = 0.47) (P = 0.0024).	('global DNA methylation levels', 'MPA', (21, 50))	('COAD', 'Disease', (3, 7))	('high BMI', 'Var', (54, 62))	('lower', 'NegReg', (108, 113))	('COAD', 'Disease', 'MESH:D029424', (3, 7))
143491	30026852	Using limma method and a FDR value of < 0.05 as the significance cut-off value for downstream analyses, we identified 3, 1169, and 394 DMSs in CHOL, COAD (Table S2), and UCEC (Table S3), respectively.	('CHOL', 'Phenotype', 'HP:0030153', (143, 147))	('COAD', 'Disease', 'MESH:D029424', (149, 153))	('DMSs', 'Var', (135, 139))	('COAD', 'Disease', (149, 153))	('DMSs', 'Chemical', '-', (135, 139))
143493	30026852	3 DMSs in CHOL included cg26987376 that was located at an intergenic region, cg21515384 that was located at 200 bp upstream of the transcription start site (TSS200) of the 3-oxoacid CoA-transferase 1 (OXCT1), and cg02725055 that was located at 1500 bp upstream of the transcriptional start site (TSS1500) of the transcription factor 4 (TCF4).	('OXCT1', 'Gene', '5019', (201, 206))	('DMSs', 'Chemical', '-', (2, 6))	('TCF4', 'Gene', '6925', (336, 340))	('cg26987376', 'Var', (24, 34))	('CHOL', 'Phenotype', 'HP:0030153', (10, 14))	('cg02725055', 'Var', (213, 223))	('transcription factor 4', 'Gene', '6925', (312, 334))	('3-oxoacid CoA-transferase 1', 'Gene', (172, 199))	('cg26987376', 'Chemical', '-', (24, 34))	('3-oxoacid CoA-transferase 1', 'Gene', '5019', (172, 199))	('cg21515384', 'Var', (77, 87))	('OXCT1', 'Gene', (201, 206))	('TCF4', 'Gene', (336, 340))	('transcription factor 4', 'Gene', (312, 334))
143498	30026852	Regarding the CpG context, the 1169 DMSs were significantly overrepresented in the CpG islands and DNA regions within 2 kb of the CpG islands (North Shore and South Shore).	('DMSs', 'Chemical', '-', (36, 40))	('overrepresented', 'PosReg', (60, 75))	('1169 DMSs', 'Var', (31, 40))
143501	30026852	2c), suggesting that altered methylated regions for high BMI are clearly tumor- or tissue-specific.	('high BMI', 'Var', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('methylated regions', 'MPA', (29, 47))
143513	30026852	Among them, 4 DMSs (cg01222719, cg17307474, cg22187246, cg11209289) in gene body regions and 4 DMSs (cg00130530, cg23410129, cg12726213, cg26033529) in promoter regions, were negatively correlated with their corresponding genes (Table S5).	('cg22187246', 'Var', (44, 54))	('cg17307474', 'Var', (32, 42))	('DMSs', 'Chemical', '-', (95, 99))	('cg01222719', 'Chemical', '-', (20, 30))	('cg01222719', 'Var', (20, 30))	('cg12726213', 'Var', (125, 135))	('DMSs', 'Chemical', '-', (14, 18))	('cg00130530', 'Var', (101, 111))	('cg11209289', 'Var', (56, 66))	('negatively', 'NegReg', (175, 185))	('cg26033529', 'Var', (137, 147))	('cg23410129', 'Var', (113, 123))
143517	30026852	The identified BMSs included cg04545963 (beta = 0.680, FDR = 0.024) located in NF-kappaB inhibitor alpha (NFKBIA) in CHOL and cg15542880 (beta = -0.082, FDR = 0.020) located in dual serine/threonine and tyrosine protein kinase (DSTYK) in COAD.	('DSTYK', 'Gene', '25778', (228, 233))	('NF-kappaB inhibitor alpha', 'Gene', (79, 104))	('DSTYK', 'Gene', (228, 233))	('NFKBIA', 'Gene', '4792', (106, 112))	('NF-kappaB inhibitor alpha', 'Gene', '4792', (79, 104))	('cg04545963', 'Chemical', '-', (29, 39))	('COAD', 'Disease', 'MESH:D029424', (238, 242))	('cg15542880', 'Var', (126, 136))	('cg04545963', 'Var', (29, 39))	('dual serine/threonine and tyrosine protein kinase', 'Gene', '25778', (177, 226))	('cg15542880', 'Chemical', '-', (126, 136))	('CHOL', 'Phenotype', 'HP:0030153', (117, 121))	('COAD', 'Disease', (238, 242))	('NFKBIA', 'Gene', (106, 112))
143520	30026852	Meanwhile, a SNP in SOX6 gene, rs297325, located 0.22 Mb downstream of cg21992400 (beta = -0.088, FDR < 0.05), has been identified to associate with the risk of both BMI and endometrial cancer.	('rs297325', 'Var', (31, 39))	('endometrial cancer', 'Phenotype', 'HP:0012114', (174, 192))	('SOX6', 'Gene', '55553', (20, 24))	('cg21992400', 'Gene', (71, 81))	('BMI', 'Disease', (166, 169))	('endometrial cancer', 'Disease', 'MESH:D016889', (174, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('endometrial cancer', 'Disease', (174, 192))	('associate with', 'Reg', (134, 148))	('rs297325', 'Mutation', 'rs297325', (31, 39))	('SOX6', 'Gene', (20, 24))
143523	30026852	Using the more stringent Bonferroni correction for multiple testing (Bonferroni-corrected P < 0.05) in the analyses of multivariable linear regression models, cg04545963 in CHOL and cg15542880 in COAD were still significantly associated with BMI.	('cg04545963', 'Var', (159, 169))	('associated', 'Reg', (226, 236))	('BMI', 'Disease', (242, 245))	('cg15542880', 'Var', (182, 192))	('COAD', 'Disease', 'MESH:D029424', (196, 200))	('cg15542880', 'Chemical', '-', (182, 192))	('CHOL', 'Phenotype', 'HP:0030153', (173, 177))	('cg04545963', 'Chemical', '-', (159, 169))	('COAD', 'Disease', (196, 200))
143524	30026852	However, in UCEC, the number of significant BMSs was markedly reduced, and only 4 BMSs remained, including cg12645852 (beta = -0.107, Bonferroni-corrected P = 5.85E-04) located in an intergenic region, cg09621472 (beta = -0.107, Bonferroni-corrected P = 0.018) located in NatE catalytic subunit of N (alpha)-acetyltransferase 50 (NAA50), cg27131667 (beta = -0.198, Bonferroni-corrected P = 0.028) located in spastic paraplegia 7 (SPG7), and cg14044785 (beta = -0.116, Bonferroni-corrected P = 0.041) located in thyroid adenoma associated (THADA).	('spastic paraplegia', 'Phenotype', 'HP:0001258', (408, 426))	('THADA', 'Gene', '63892', (539, 544))	('thyroid adenoma', 'Phenotype', 'HP:0000854', (511, 526))	('paraplegia', 'Phenotype', 'HP:0010550', (416, 426))	('cg14044785', 'Chemical', '-', (441, 451))	('cg12645852', 'Chemical', '-', (107, 117))	('SPG7', 'Gene', (430, 434))	('SPG7', 'Gene', '6687', (430, 434))	('NAA50', 'Gene', '80218', (330, 335))	('cg09621472', 'Var', (202, 212))	('cg12645852', 'Var', (107, 117))	('spastic paraplegia 7', 'Gene', '6687', (408, 428))	('cg27131667', 'Var', (338, 348))	('spastic paraplegia 7', 'Gene', (408, 428))	('THADA', 'Gene', (539, 544))	('cg09621472', 'Chemical', '-', (202, 212))	('NAA50', 'Gene', (330, 335))	('cg14044785', 'Var', (441, 451))	('thyroid adenoma', 'Disease', 'MESH:D013964', (511, 526))	('thyroid adenoma', 'Disease', (511, 526))	('cg27131667', 'Chemical', '-', (338, 348))
143525	30026852	Of these 4 BMSs, cg12645852, cg09621472, and cg14044785 in patients with high BMI in UCEC had significant hypomethylation when compared to controls.	('cg14044785', 'Var', (45, 55))	('cg12645852', 'Var', (17, 27))	('hypomethylation', 'MPA', (106, 121))	('cg09621472', 'Chemical', '-', (29, 39))	('patients', 'Species', '9606', (59, 67))	('cg14044785', 'Chemical', '-', (45, 55))	('cg09621472', 'Var', (29, 39))	('cg12645852', 'Chemical', '-', (17, 27))
143530	30026852	With regards to methylation status, cg04545963 in CHOL, cg15542880 in COAD, and cg12645852 in UCEC did not significantly affect the patient survival rates (Fig.	('COAD', 'Disease', 'MESH:D029424', (70, 74))	('cg15542880', 'Chemical', '-', (56, 66))	('CHOL', 'Phenotype', 'HP:0030153', (50, 54))	('cg04545963', 'Chemical', '-', (36, 46))	('COAD', 'Disease', (70, 74))	('cg12645852', 'Var', (80, 90))	('cg04545963', 'Var', (36, 46))	('cg15542880', 'Var', (56, 66))	('patient', 'Species', '9606', (132, 139))	('cg12645852', 'Chemical', '-', (80, 90))
143531	30026852	For cg09621472, cg27131667, cg14044785, patients with UCEC with low methylated levels had improved survival rates when compared with those who had high methylated levels (P = 0.0008, 0.0248, 0.0109, respectively, Fig.	('cg27131667', 'Var', (16, 26))	('cg09621472', 'Chemical', '-', (4, 14))	('cg09621472', 'Var', (4, 14))	('low', 'NegReg', (64, 67))	('patients', 'Species', '9606', (40, 48))	('cg14044785', 'Chemical', '-', (28, 38))	('improved', 'PosReg', (90, 98))	('survival rates', 'CPA', (99, 113))	('cg14044785', 'Var', (28, 38))	('cg27131667', 'Chemical', '-', (16, 26))
143532	30026852	5a), suggesting that cg09621472, cg27131667, and cg14044785 could be used as potential biomarkers for predicting survival outcomes of patients with UCEC.	('UCEC', 'Disease', (148, 152))	('cg27131667', 'Var', (33, 43))	('cg09621472', 'Var', (21, 31))	('cg09621472', 'Chemical', '-', (21, 31))	('patients', 'Species', '9606', (134, 142))	('cg14044785', 'Chemical', '-', (49, 59))	('cg14044785', 'Var', (49, 59))	('cg27131667', 'Chemical', '-', (33, 43))
143534	30026852	The methylation status of cg04545963 was not significantly associated with the initiation and grade of CHOL, and neither was cg15542880 in COAD (Fig.	('cg15542880', 'Var', (125, 135))	('cg15542880', 'Chemical', '-', (125, 135))	('COAD', 'Disease', 'MESH:D029424', (139, 143))	('cg04545963', 'Chemical', '-', (26, 36))	('CHOL', 'Phenotype', 'HP:0030153', (103, 107))	('cg04545963', 'Var', (26, 36))	('COAD', 'Disease', (139, 143))
143535	30026852	We found that, in adjacent tissue, the methylation levels of cg12645852 and cg27131667 were significantly higher than tumor tissue of the early stages (grade 1) from UCEC.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('cg12645852', 'Chemical', '-', (61, 71))	('higher', 'PosReg', (106, 112))	('tumor', 'Disease', (118, 123))	('cg27131667', 'Chemical', '-', (76, 86))	('cg12645852', 'Var', (61, 71))	('cg27131667', 'Var', (76, 86))	('methylation levels', 'MPA', (39, 57))
143536	30026852	However, for cg09621472, cg27131667, and cg14044785, the methylation levels in adjacent tissues were lower than those of tumor tissues (Fig.	('methylation levels', 'MPA', (57, 75))	('cg09621472', 'Var', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cg14044785', 'Chemical', '-', (41, 51))	('tumor', 'Disease', (121, 126))	('lower', 'NegReg', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('cg27131667', 'Chemical', '-', (25, 35))	('cg27131667', 'Var', (25, 35))	('cg09621472', 'Chemical', '-', (13, 23))	('cg14044785', 'Var', (41, 51))
143539	30026852	The dataset of GSE67116 from the GEO database showed higher methylation levels of cg09621472 (P < 0.001) and cg27131667 (P = 0.014) in 33 patients with endometrial metastasis cancer relative to 53 patients with endometrial primary cancer.	('cg09621472', 'Var', (82, 92))	('higher', 'PosReg', (53, 59))	('patients', 'Species', '9606', (197, 205))	('endometrial primary cancer', 'Disease', (211, 237))	('methylation levels', 'MPA', (60, 78))	('cg27131667', 'Chemical', '-', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cg27131667', 'Var', (109, 119))	('endometrial metastasis cancer', 'Disease', 'MESH:D009362', (152, 181))	('endometrial metastasis cancer', 'Disease', (152, 181))	('endometrial primary cancer', 'Disease', 'MESH:D016889', (211, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('patients', 'Species', '9606', (138, 146))	('cg09621472', 'Chemical', '-', (82, 92))
143540	30026852	These data suggested that cg12645852, cg09621472, cg27131667, and cg14044785 may be associated with the effect of BMI on UCEC advancement.	('cg27131667', 'Chemical', '-', (50, 60))	('cg27131667', 'Var', (50, 60))	('cg09621472', 'Var', (38, 48))	('cg09621472', 'Chemical', '-', (38, 48))	('cg12645852', 'Chemical', '-', (26, 36))	('cg14044785', 'Chemical', '-', (66, 76))	('associated', 'Reg', (84, 94))	('UCEC advancement', 'CPA', (121, 137))	('cg12645852', 'Var', (26, 36))	('cg14044785', 'Var', (66, 76))
143542	30026852	The two analyses consistently showed that the dynamic features of DNA methylation in the three known obesity-related cancers (CHOL, COAD, and UCEC) associated with BMI, but not in the other 12 major cancers.	('obesity', 'Disease', 'MESH:D009765', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('obesity', 'Disease', (101, 108))	('CHOL', 'Phenotype', 'HP:0030153', (126, 130))	('COAD', 'Disease', (132, 136))	('DNA', 'Gene', (66, 69))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('methylation', 'Var', (70, 81))	('obesity', 'Phenotype', 'HP:0001513', (101, 108))	('BMI', 'Disease', (164, 167))	('associated', 'Reg', (148, 158))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (199, 206))	('COAD', 'Disease', 'MESH:D029424', (132, 136))	('cancers', 'Disease', (117, 124))
143549	30026852	Alterations in DNA methylation also respond to adiposity, therefore, in COAD, high BMI inhibits methylation of PI3K-AKT signaling pathway genes, which in turn may activate the pathway and the development of COAD.	('COAD', 'Disease', 'MESH:D029424', (72, 76))	('COAD', 'Disease', 'MESH:D029424', (207, 211))	('high', 'Var', (78, 82))	('methylation', 'MPA', (96, 107))	('inhibits', 'NegReg', (87, 95))	('COAD', 'Disease', (72, 76))	('AKT', 'Gene', (116, 119))	('COAD', 'Disease', (207, 211))	('AKT', 'Gene', '207', (116, 119))	('activate', 'PosReg', (163, 171))	('pathway', 'Pathway', (176, 183))
143555	30026852	Even though the other 18 biological pathways in COAD linking obesity to cancer have not been reported, these pathways allow us to examine whether DNA methylation alterations due to high BMI have effects on colon cancer, particularly in case of cancer-related pathways such as the Hippo signaling pathway and cAMP signaling pathway and in ECM-receptor interaction.	('COAD linking obesity to cancer', 'Disease', 'MESH:D029424', (48, 78))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('cancer', 'Disease', (72, 78))	('alterations', 'Var', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('colon cancer', 'Phenotype', 'HP:0003003', (206, 218))	('interaction', 'Interaction', (351, 362))	('cancer', 'Disease', (212, 218))	('colon cancer', 'Disease', 'MESH:D015179', (206, 218))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('obesity', 'Phenotype', 'HP:0001513', (61, 68))	('cancer', 'Disease', (244, 250))	('COAD linking obesity to cancer', 'Disease', (48, 78))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('effects', 'Reg', (195, 202))	('cAMP signaling pathway', 'Pathway', (308, 330))	('cAMP', 'Chemical', '-', (308, 312))	('Hippo signaling pathway', 'Pathway', (280, 303))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('colon cancer', 'Disease', (206, 218))
143563	30026852	Additionally, BMI-associated CpGs located in NAA50, SPG7, and THADA among UCEC tumor tissues are significantly associated with the survival time and tumor progression of this cancer, indicating that BMI may encourage the role of tumor mechanism through controlling DNA methylation.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('SPG7', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('cancer', 'Disease', (175, 181))	('SPG7', 'Gene', '6687', (52, 56))	('THADA', 'Gene', '63892', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('NAA50', 'Gene', '80218', (45, 50))	('CpGs', 'Var', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('survival time', 'CPA', (131, 144))	('tumor', 'Disease', (79, 84))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('NAA50', 'Gene', (45, 50))	('THADA', 'Gene', (62, 67))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('associated with', 'Reg', (111, 126))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
143565	30026852	This deduction is consistent with previous reports showing that DNA methylation in HIF3A was associated with BMI in white blood cells and adipose tissue, but not in breast tumor tissue.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('breast tumor', 'Disease', (165, 177))	('breast tumor', 'Phenotype', 'HP:0100013', (165, 177))	('associated', 'Reg', (93, 103))	('BMI', 'Disease', (109, 112))	('DNA methylation', 'Var', (64, 79))	('HIF3A', 'Gene', '64344', (83, 88))	('breast tumor', 'Disease', 'MESH:D001943', (165, 177))	('HIF3A', 'Gene', (83, 88))
143568	30026852	Thus, we demonstrated that high BMI may induce metabolic perturbations, leading to alterations in DNA methylation in cancer development-related and obesity-induced pathways in primary tumor tissues of CHOL, COAD, and UCEC.	('obesity-induced', 'Disease', (148, 163))	('DNA', 'Gene', (98, 101))	('COAD', 'Disease', 'MESH:D029424', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('obesity-induced', 'Disease', 'MESH:D009765', (148, 163))	('primary tumor', 'Disease', (176, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('primary tumor', 'Disease', 'MESH:D009369', (176, 189))	('COAD', 'Disease', (207, 211))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('high BMI', 'Var', (27, 35))	('obesity', 'Phenotype', 'HP:0001513', (148, 155))	('CHOL', 'Phenotype', 'HP:0030153', (201, 205))	('cancer', 'Disease', (117, 123))	('alterations', 'Reg', (83, 94))
143575	30026852	This study supports the view that changes in DNA methylation represent an intermediate step between the BMI and CHOL, COAD, or UCEC, which may in turn provide information for guiding treatment options for patients with CHOL, COAD, and UCEC with high BMIs.	('CHOL', 'Phenotype', 'HP:0030153', (112, 116))	('patients', 'Species', '9606', (205, 213))	('COAD', 'Disease', 'MESH:D029424', (225, 229))	('COAD', 'Disease', 'MESH:D029424', (118, 122))	('CHOL', 'Phenotype', 'HP:0030153', (219, 223))	('COAD', 'Disease', (225, 229))	('changes', 'Var', (34, 41))	('COAD', 'Disease', (118, 122))
143670	28120434	S1PR2 deficiency significantly reduced BDL-induced cholangiocyte proliferation and cholestatic injury as indicated by significant reduction of inflammation and liver fibrosis in S1PR2-/- mice.	('liver fibrosis', 'Disease', (160, 174))	('rat', 'Species', '10116', (72, 75))	('reduced', 'NegReg', (31, 38))	('BDL', 'Chemical', '-', (39, 42))	('reduction of inflammation', 'Disease', (130, 155))	('deficiency', 'Var', (6, 16))	('liver fibrosis', 'Disease', 'MESH:D008103', (160, 174))	('reduction of inflammation', 'Disease', 'MESH:D007249', (130, 155))	('cholestatic injury', 'Disease', (83, 101))	('mice', 'Species', '10090', (187, 191))	('liver fibrosis', 'Phenotype', 'HP:0001395', (160, 174))	('S1PR2', 'Gene', (0, 5))	('cholestatic injury', 'Disease', 'MESH:D002779', (83, 101))
143674	28120434	Impaired bile formation or bile flow results in hepatic injury, fibrosis and eventually cirrhosis.	('fibrosis', 'Disease', 'MESH:D005355', (64, 72))	('hepatic injury', 'Disease', (48, 62))	('results in', 'Reg', (37, 47))	('cirrhosis', 'Disease', 'MESH:D005355', (88, 97))	('hepatic injury', 'Disease', 'MESH:D056486', (48, 62))	('Impaired', 'Var', (0, 8))	('cirrhosis', 'Disease', (88, 97))	('bile', 'CPA', (27, 31))	('fibrosis', 'Disease', (64, 72))	('cirrhosis', 'Phenotype', 'HP:0001394', (88, 97))
143688	28120434	In addition, antagonism of S1PR2 selectively reduces portal vein pressure in BDL rodents.	('S1PR2', 'Gene', (27, 32))	('BDL', 'Chemical', '-', (77, 80))	('reduces', 'NegReg', (45, 52))	('antagonism', 'Var', (13, 23))	('portal vein pressure', 'MPA', (53, 73))
143692	28120434	Furthermore, we also showed that S1PR2 is responsible for CBA-mediated invasive growth, bile duct proliferation and upregulation of cyclooxygenase 2 (COX-2) in cholangiocarcinoma cells.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (160, 178))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (160, 178))	('bile duct proliferation', 'CPA', (88, 111))	('rat', 'Species', '10116', (105, 108))	('CBA', 'Chemical', '-', (58, 61))	('S1PR2', 'Var', (33, 38))	('COX-2', 'Gene', '19225', (150, 155))	('cyclooxygenase 2', 'Gene', '19225', (132, 148))	('upregulation', 'PosReg', (116, 128))	('COX-2', 'Gene', (150, 155))	('cholangiocarcinoma', 'Disease', (160, 178))	('bile duct proliferation', 'Phenotype', 'HP:0001408', (88, 111))	('cyclooxygenase 2', 'Gene', (132, 148))	('invasive growth', 'CPA', (71, 86))
143694	28120434	Inhibition of S1PR2 activation using a specific chemical antagonist or knock down of S1PR2 expression using a gene-specific shRNA significantly inhibited TCA-induced cholangiocyte proliferation and migration.	('rat', 'Species', '10116', (201, 204))	('rat', 'Species', '10116', (187, 190))	('knock down', 'Var', (71, 81))	('inhibited', 'NegReg', (144, 153))	('TCA', 'Chemical', 'MESH:D013656', (154, 157))	('S1PR2', 'Gene', (85, 90))
143729	28120434	Furthermore, 2-week BDL not only markedly increased S1PR2 mRNA level, but also increased S1PR2 protein level in the liver (Fig.	('increased', 'PosReg', (42, 51))	('increased', 'PosReg', (79, 88))	('BDL', 'Var', (20, 23))	('S1PR2 mRNA level', 'MPA', (52, 68))	('S1PR2 protein level', 'MPA', (89, 108))	('BDL', 'Chemical', '-', (20, 23))
143742	28120434	2, both TCA- and S1P-induced cell proliferation was blocked by U0126 or MK2206 in MLE cells.	('blocked', 'NegReg', (52, 59))	('S1P', 'Gene', '13609', (17, 20))	('MK2206', 'Chemical', 'MESH:C548887', (72, 78))	('TCA', 'Chemical', 'MESH:D013656', (8, 11))	('U0126', 'Var', (63, 68))	('rat', 'Species', '10116', (41, 44))	('cell proliferation', 'CPA', (29, 47))	('S1P', 'Gene', (17, 20))	('U0126', 'Chemical', 'MESH:C113580', (63, 68))	('MK2206', 'Var', (72, 78))
143745	28120434	Previous studies have shown that BDL markedly increased the bile acid levels in serum and liver.	('BDL', 'Chemical', '-', (33, 36))	('increased', 'PosReg', (46, 55))	('bile acid levels in', 'MPA', (60, 79))	('BDL', 'Var', (33, 36))	('bile acid', 'Chemical', 'MESH:D001647', (60, 69))
143750	28120434	4A, BDL dramatically increased serum total bile acid levels as compared to sham control wild type mice.	('increased', 'PosReg', (21, 30))	('BDL', 'Var', (4, 7))	('serum total bile acid levels', 'MPA', (31, 59))	('BDL', 'Chemical', '-', (4, 7))	('bile acid', 'Chemical', 'MESH:D001647', (43, 52))	('mice', 'Species', '10090', (98, 102))
143754	28120434	S1PR2 deficiency prevented bile acid accumulation in the liver and serum after a two-week BDL.	('bile acid', 'Chemical', 'MESH:D001647', (27, 36))	('bile acid accumulation in', 'MPA', (27, 52))	('prevented', 'NegReg', (17, 26))	('deficiency', 'Var', (6, 16))	('S1PR2', 'Gene', (0, 5))	('BDL', 'Chemical', '-', (90, 93))
143758	28120434	S1PR2 deficiency markedly reduced BDL-induced increase of ALP (Fig.	('increase of ALP', 'Phenotype', 'HP:0003155', (46, 61))	('ALP', 'Disease', (58, 61))	('deficiency', 'Var', (6, 16))	('reduced', 'NegReg', (26, 33))	('ALP', 'Disease', 'MESH:D050197', (58, 61))	('BDL', 'Chemical', '-', (34, 37))	('S1PR2', 'Gene', (0, 5))
143759	28120434	In addition, liver weight and spleen weight were increased by BDL, but not significantly different between wild type and S1PR2-/- mice (Supplementary Fig.4).	('mice', 'Species', '10090', (130, 134))	('spleen weight', 'CPA', (30, 43))	('BDL', 'Var', (62, 65))	('increased', 'PosReg', (49, 58))	('BDL', 'Chemical', '-', (62, 65))
143761	28120434	As shown in Fig.4F, the hepatic hydroxyproline level was increased in wild type mice after BDL, but not in S1PR2-/- mice, indicating that S1PR2 deficiency prevented BDL-induced liver fibrosis.	('BDL-induced', 'Disease', (165, 176))	('mice', 'Species', '10090', (116, 120))	('liver fibrosis', 'Disease', (177, 191))	('BDL', 'Chemical', '-', (91, 94))	('deficiency', 'Var', (144, 154))	('liver fibrosis', 'Disease', 'MESH:D008103', (177, 191))	('hepatic hydroxyproline level', 'MPA', (24, 52))	('prevented', 'NegReg', (155, 164))	('mice', 'Species', '10090', (80, 84))	('increased', 'PosReg', (57, 66))	('BDL', 'Chemical', '-', (165, 168))	('liver fibrosis', 'Phenotype', 'HP:0001395', (177, 191))	('hydroxyproline', 'Chemical', 'MESH:D006909', (32, 46))	('S1PR2', 'Gene', (138, 143))
143764	28120434	Consistently, real-time RT-PCR results showed that BDL significantly increased mRNA expression levels of collagen type I and alpha-smooth actin (alpha-SMA) in the liver of wild type mice, but not in that of S1PR2-/- mice (Fig.	('increased', 'PosReg', (69, 78))	('mice', 'Species', '10090', (216, 220))	('alpha-SMA', 'Gene', (145, 154))	('BDL', 'Var', (51, 54))	('mice', 'Species', '10090', (182, 186))	('mRNA expression levels of collagen type I', 'MPA', (79, 120))	('alpha-SMA', 'Gene', '11475', (145, 154))	('alpha-smooth actin', 'Gene', (125, 143))	('BDL', 'Chemical', '-', (51, 54))	('alpha-smooth actin', 'Gene', '11475', (125, 143))
143770	28120434	In addition, JTE-013 also reduced BDL-induced CK-19, Ki67 and collagen I expression (Supplementary Fig.9).	('Ki67', 'Gene', (53, 57))	('CK-19', 'Gene', (46, 51))	('JTE-013', 'Var', (13, 20))	('reduced', 'NegReg', (26, 33))	('JTE-013', 'Chemical', 'MESH:C471998', (13, 20))	('CK-19', 'Gene', '16669', (46, 51))	('BDL', 'Chemical', '-', (34, 37))	('Ki67', 'Gene', '17345', (53, 57))	('collagen I expression', 'MPA', (62, 83))
143775	28120434	7, BDL significantly upregulated COX-2 expression in the liver and cholangiocytes of the wild type mice, but not in those of S1PR2-/- mice.	('mice', 'Species', '10090', (99, 103))	('BDL', 'Var', (3, 6))	('mice', 'Species', '10090', (134, 138))	('COX-2', 'Gene', (33, 38))	('upregulated', 'PosReg', (21, 32))	('COX-2', 'Gene', '19225', (33, 38))	('BDL', 'Chemical', '-', (3, 6))	('expression', 'MPA', (39, 49))
143793	28120434	BDL-induced cholestatic liver injury was significantly reduced in S1PR2-/- mice compared to wild type mice as assessed by ALP level, hepatic hydroxyproline level and liver histology (Fig.4 & 5).	('mice', 'Species', '10090', (102, 106))	('mice', 'Species', '10090', (75, 79))	('reduced', 'NegReg', (55, 62))	('S1PR2-/-', 'Var', (66, 74))	('hepatic hydroxyproline level', 'MPA', (133, 161))	('ALP', 'Disease', (122, 125))	('BDL', 'Chemical', '-', (0, 3))	('ALP', 'Disease', 'MESH:D050197', (122, 125))	('hydroxyproline', 'Chemical', 'MESH:D006909', (141, 155))	('cholestatic liver injury', 'Phenotype', 'HP:0002611', (12, 36))	('cholestatic liver injury', 'Disease', (12, 36))	('cholestatic liver injury', 'Disease', 'MESH:D056486', (12, 36))	('BDL-induced', 'Disease', (0, 11))
143797	28120434	Moreover, BDL significantly induced COX-2 expression in the liver and cholangiocytes of wild type mice, but not in those of S1PR2-/- mice (Fig.7).	('mice', 'Species', '10090', (133, 137))	('BDL', 'Var', (10, 13))	('expression', 'MPA', (42, 52))	('COX-2', 'Gene', (36, 41))	('BDL', 'Chemical', '-', (10, 13))	('COX-2', 'Gene', '19225', (36, 41))	('induced', 'Reg', (28, 35))	('mice', 'Species', '10090', (98, 102))
143812	28120434	In our studies, we found that TGR5 expression was not affected by BDL or TCA, but S1PR2 expression is induced by BDL and TCA (Fig.	('TCA', 'Chemical', 'MESH:D013656', (73, 76))	('TCA', 'Chemical', 'MESH:D013656', (121, 124))	('BDL', 'Chemical', '-', (113, 116))	('induced', 'Reg', (102, 109))	('S1PR2', 'Gene', (82, 87))	('BDL', 'Chemical', '-', (66, 69))	('expression', 'MPA', (88, 98))	('TCA', 'Var', (121, 124))
143813	28120434	A recent study reported that activation of TGR5 attenuated inflammation and renal fibrosis in diabetic nephropathy via inhibiting S1PR2 expression and promoting S1PR2 internalization in glomerular mesangial cells.	('expression', 'MPA', (136, 146))	('attenuated', 'NegReg', (48, 58))	('promoting', 'PosReg', (151, 160))	('inhibiting', 'NegReg', (119, 129))	('renal fibrosis', 'Disease', 'MESH:D005355', (76, 90))	('diabetic nephropathy', 'Disease', (94, 114))	('renal fibrosis', 'Phenotype', 'HP:0030760', (76, 90))	('nephropathy', 'Phenotype', 'HP:0000112', (103, 114))	('TGR5', 'Gene', (43, 47))	('S1PR2', 'Gene', (130, 135))	('renal fibrosis', 'Disease', (76, 90))	('diabetic nephropathy', 'Disease', 'MESH:D003928', (94, 114))	('activation', 'Var', (29, 39))	('S1PR2 internalization', 'MPA', (161, 182))	('inflammation', 'Disease', 'MESH:D007249', (59, 71))	('inflammation', 'Disease', (59, 71))
143852	24587347	A recent report indicates that inhibiting JNK enhances TGF-beta-induced apoptosis of CCA cells, which suggests the link between JNK and CCA.	('JNK', 'Gene', (42, 45))	('enhances', 'PosReg', (46, 54))	('JNK', 'Gene', '5599', (42, 45))	('TGF-beta', 'Gene', (55, 63))	('CCA', 'Phenotype', 'HP:0030153', (136, 139))	('JNK', 'Gene', '5599', (128, 131))	('inhibiting', 'Var', (31, 41))	('CCA', 'Disease', (85, 88))	('TGF-beta', 'Gene', '7040', (55, 63))	('CCA', 'Phenotype', 'HP:0030153', (85, 88))	('JNK', 'Gene', (128, 131))
143863	24587347	p70S6K inhibitor PF-4708671 (PF) was purchased from Selleck Chemicals (Houston, TX, USA).	('p70S6K', 'Gene', (0, 6))	('PF-4708671', 'Var', (17, 27))	('p70S6K', 'Gene', '6198', (0, 6))
143866	24587347	Antibodies against phospho-eIF2alpha (Ser-51), phospho-p70S6K (Thr-389), phospho-mTOR (Ser-2448), phospho-Raptor (Ser-863), phospho-c-Jun (Ser-73), phospho-JNK (Thr-183/Tyr-185), phospho-4E-BP1 (Thr-37/46), p70S6K, mTOR, Raptor, c-Jun, JNK, 4E-BP1 and ATF4 were purchased from Cell Signaling Technology (Danvers, MA, USA).	('Raptor', 'Gene', (221, 227))	('ATF4', 'Gene', (252, 256))	('Raptor', 'Gene', '57521', (106, 112))	('ATF4', 'Gene', '468', (252, 256))	('p70S6K', 'Gene', (207, 213))	('c-Jun', 'Gene', '3725', (229, 234))	('Thr-183/Tyr', 'SUBSTITUTION', 'None', (161, 172))	('JNK', 'Gene', (236, 239))	('mTOR', 'Gene', (215, 219))	('c-Jun', 'Gene', (229, 234))	('JNK', 'Gene', '5599', (236, 239))	('p70S6K', 'Gene', (55, 61))	('4E-BP1', 'Gene', '1978', (187, 193))	('mTOR', 'Gene', (81, 85))	('Raptor', 'Gene', '57521', (221, 227))	('JNK', 'Gene', (156, 159))	('Raptor', 'Gene', (106, 112))	('4E-BP1', 'Gene', '1978', (241, 247))	('mTOR', 'Gene', '2475', (215, 219))	('Thr-183/Tyr', 'Var', (161, 172))	('JNK', 'Gene', '5599', (156, 159))	('mTOR', 'Gene', '2475', (81, 85))	('c-Jun', 'Gene', '3725', (132, 137))	('p70S6K', 'Gene', '6198', (207, 213))	('4E-BP1', 'Gene', (187, 193))	('eIF2alpha', 'Gene', (27, 36))	('c-Jun', 'Gene', (132, 137))	('eIF2alpha', 'Gene', '83939', (27, 36))	('p70S6K', 'Gene', '6198', (55, 61))	('4E-BP1', 'Gene', (241, 247))
143868	24587347	QBC939, RBE and HCCC-9810 cells were cultured in RPMI-1640 medium, and HepG2 cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin in a humidified incubator containing 5% CO2 and 95% ambient air at 37 C. The protocol used for GRP78, JNK, ATF4 and mTOR knockdown has been previously described.	('HCCC-9810', 'CellLine', 'CVCL:6908', (16, 25))	('ATF4', 'Gene', (314, 318))	('JNK', 'Gene', '5599', (309, 312))	('Dulbecco', 'Chemical', '-', (100, 108))	('GRP78', 'Gene', (302, 307))	('mTOR', 'Gene', (323, 327))	('mTOR', 'Gene', '2475', (323, 327))	('GRP78', 'Gene', '3309', (302, 307))	('streptomycin', 'Chemical', 'MESH:D013307', (194, 206))	('HepG2', 'CellLine', 'CVCL:0027', (71, 76))	('knockdown', 'Var', (328, 337))	('ATF4', 'Gene', '468', (314, 318))	('CO2', 'Chemical', '-', (247, 250))	('bovine', 'Species', '9913', (163, 169))	('JNK', 'Gene', (309, 312))	('RPMI-1640 medium', 'Chemical', '-', (49, 65))	('penicillin', 'Chemical', 'MESH:D010406', (183, 193))
143879	24587347	SP600125, a selective inhibitor of JNK, inhibited the phosphorylation of c-Jun in a dose-dependent manner in QBC939, RBE and HCCC-9810 cells (Figure 1B), indicating that SP600125 can effetely inhibit the activity of JNK in human CCA cells.	('JNK', 'Gene', '5599', (216, 219))	('SP600125', 'Chemical', 'MESH:C432165', (170, 178))	('inhibited', 'NegReg', (40, 49))	('c-Jun', 'Gene', (73, 78))	('JNK', 'Gene', '5599', (35, 38))	('SP600125', 'Var', (170, 178))	('human', 'Species', '9606', (223, 228))	('activity', 'MPA', (204, 212))	('inhibit', 'NegReg', (192, 199))	('HCCC-9810', 'CellLine', 'CVCL:6908', (125, 134))	('JNK', 'Gene', (216, 219))	('SP600125', 'Chemical', 'MESH:C432165', (0, 8))	('c-Jun', 'Gene', '3725', (73, 78))	('CCA', 'Phenotype', 'HP:0030153', (229, 232))	('JNK', 'Gene', (35, 38))
143881	24587347	SP600125 inhibited the proliferation of human CCA cells in a dose- and time-dependent manner (Figure 1C).	('inhibited', 'NegReg', (9, 18))	('proliferation', 'CPA', (23, 36))	('SP600125', 'Var', (0, 8))	('SP600125', 'Chemical', 'MESH:C432165', (0, 8))	('CCA', 'Phenotype', 'HP:0030153', (46, 49))	('human', 'Species', '9606', (40, 45))
143882	24587347	Furthermore, migration (Figure 1D) and invasion (Figure 1E) of human CCA cells were significantly suppressed by SP600125.	('suppressed', 'NegReg', (98, 108))	('human', 'Species', '9606', (63, 68))	('invasion', 'CPA', (39, 47))	('SP600125', 'Chemical', 'MESH:C432165', (112, 120))	('CCA', 'Phenotype', 'HP:0030153', (69, 72))	('SP600125', 'Var', (112, 120))	('migration', 'CPA', (13, 22))
143883	24587347	These data indicate that aberrant activation of JNK signaling plays an important role in the pathogenesis of CCA.	('CCA', 'Phenotype', 'HP:0030153', (109, 112))	('JNK', 'Gene', (48, 51))	('JNK', 'Gene', '5599', (48, 51))	('aberrant', 'Var', (25, 33))	('CCA', 'Disease', (109, 112))	('activation', 'PosReg', (34, 44))
143890	24587347	As the phosphorylation of eIF2alpha can induce GRP78 expression through activating transcription factor 4 (ATF4) independent of UPR elements, the eIF2alpha/ATF4 pathway was investigated in human CCA cells.	('eIF2alpha', 'Gene', '83939', (26, 35))	('ATF4', 'Gene', (156, 160))	('CCA', 'Phenotype', 'HP:0030153', (195, 198))	('eIF2alpha', 'Gene', (146, 155))	('ATF4', 'Gene', (107, 111))	('ATF4', 'Gene', '468', (107, 111))	('human', 'Species', '9606', (189, 194))	('ATF4', 'Gene', '468', (156, 160))	('GRP78', 'Gene', '3309', (47, 52))	('GRP78', 'Gene', (47, 52))	('activating transcription factor 4', 'Gene', '468', (72, 105))	('phosphorylation', 'Var', (7, 22))	('expression', 'MPA', (53, 63))	('activating transcription factor 4', 'Gene', (72, 105))	('eIF2alpha', 'Gene', '83939', (146, 155))	('eIF2alpha', 'Gene', (26, 35))	('induce', 'PosReg', (40, 46))
143893	24587347	Furthermore, ATF4 knockdown decreased the levels of GRP78 in human CCA cells (Figure 2D).	('levels', 'MPA', (42, 48))	('knockdown', 'Var', (18, 27))	('GRP78', 'Gene', (52, 57))	('decreased', 'NegReg', (28, 37))	('GRP78', 'Gene', '3309', (52, 57))	('ATF4', 'Gene', (13, 17))	('CCA', 'Phenotype', 'HP:0030153', (67, 70))	('ATF4', 'Gene', '468', (13, 17))	('human', 'Species', '9606', (61, 66))
143897	24587347	Furthermore, migration (Figure 3B) and invasion (Figure 3C) of QBC939, RBE and HCCC-9810 cells were significantly suppressed by GRP78 knockdown.	('RBE', 'CPA', (71, 74))	('invasion', 'CPA', (39, 47))	('HCCC-9810', 'CellLine', 'CVCL:6908', (79, 88))	('GRP78', 'Gene', (128, 133))	('knockdown', 'Var', (134, 143))	('QBC939', 'Gene', (63, 69))	('GRP78', 'Gene', '3309', (128, 133))	('suppressed', 'NegReg', (114, 124))	('migration', 'CPA', (13, 22))
143902	24587347	It is notable that JNK inhibitor SP600125 treatment decreased the levels of GRP78 in a time-dependent manner in QBC939, RBE and HCCC-9810 cells (Figure 4A).	('SP600125', 'Chemical', 'MESH:C432165', (33, 41))	('decreased', 'NegReg', (52, 61))	('JNK', 'Gene', (19, 22))	('GRP78', 'Gene', (76, 81))	('GRP78', 'Gene', '3309', (76, 81))	('SP600125', 'Var', (33, 41))	('levels of', 'MPA', (66, 75))	('JNK', 'Gene', '5599', (19, 22))	('HCCC-9810', 'CellLine', 'CVCL:6908', (128, 137))
143906	24587347	As shown in Figure 4C, SP600125 pretreatment inhibited eIF2alpha phosphatase enzymes inhibitor, salubrinal-induced GRP78 expression in HepG2 cells.	('GRP78', 'Gene', (115, 120))	('salubrinal', 'Chemical', 'MESH:C496827', (96, 106))	('SP600125', 'Chemical', 'MESH:C432165', (23, 31))	('expression', 'MPA', (121, 131))	('GRP78', 'Gene', '3309', (115, 120))	('eIF2alpha', 'Gene', (55, 64))	('HepG2', 'CellLine', 'CVCL:0027', (135, 140))	('SP600125', 'Var', (23, 31))	('eIF2alpha', 'Gene', '83939', (55, 64))	('inhibited', 'NegReg', (45, 54))	('salubrinal-induced', 'MPA', (96, 114))
143910	24587347	The data showed that JNK inhibitor SP600125 pretreatment had no demonstrable effects on tunicamycin-mediated GRP78 induction in HepG2 cells (Figure 4D).	('JNK', 'Gene', '5599', (21, 24))	('SP600125', 'Var', (35, 43))	('tunicamycin', 'Chemical', 'MESH:D014415', (88, 99))	('HepG2', 'CellLine', 'CVCL:0027', (128, 133))	('tunicamycin-mediated', 'MPA', (88, 108))	('JNK', 'Gene', (21, 24))	('GRP78', 'Gene', '3309', (109, 114))	('SP600125', 'Chemical', 'MESH:C432165', (35, 43))	('GRP78', 'Gene', (109, 114))
143914	24587347	We found that JNK inhibitor SP600125 decreased the levels of phosphorylated ribosomal protein kinase S6 (p70S6K) (Figure 5A).	('JNK', 'Gene', (14, 17))	('p70S6K', 'Gene', (105, 111))	('SP600125', 'Chemical', 'MESH:C432165', (28, 36))	('p70S6K', 'Gene', '6198', (105, 111))	('JNK', 'Gene', '5599', (14, 17))	('levels of phosphorylated', 'MPA', (51, 75))	('decreased', 'NegReg', (37, 46))	('SP600125', 'Var', (28, 36))
143920	24587347	Interestingly, JNK inhibitor SP600125 decreased the levels of phosphorylated Raptor in QBC939, RBE and HCCC-9810 cells (Figure 5D).	('decreased', 'NegReg', (38, 47))	('Raptor', 'Gene', (77, 83))	('Raptor', 'Gene', '57521', (77, 83))	('SP600125', 'Chemical', 'MESH:C432165', (29, 37))	('JNK', 'Gene', (15, 18))	('SP600125', 'Var', (29, 37))	('HCCC-9810', 'CellLine', 'CVCL:6908', (103, 112))	('JNK', 'Gene', '5599', (15, 18))
143939	24587347	It is notable that p70S6K inhibitor PF-4708671, which had no demonstrable effects on ATF4 and GRP78 accumulation, enhanced the decreasing of ATF4 and GRP78 in 4EGI-1-treated QBC939, RBE and HCCC-9810 cells (Figure 7D).	('ATF4', 'Gene', (141, 145))	('p70S6K', 'Gene', (19, 25))	('p70S6K', 'Gene', '6198', (19, 25))	('ATF4', 'Gene', '468', (141, 145))	('GRP78', 'Gene', '3309', (94, 99))	('PF-4708671', 'Var', (36, 46))	('ATF4', 'Gene', (85, 89))	('GRP78', 'Gene', (94, 99))	('decreasing', 'NegReg', (127, 137))	('enhanced', 'PosReg', (114, 122))	('HCCC-9810', 'CellLine', 'CVCL:6908', (190, 199))	('GRP78', 'Gene', (150, 155))	('ATF4', 'Gene', '468', (85, 89))	('GRP78', 'Gene', '3309', (150, 155))
143941	24587347	Conversely, mTOR inhibition obviously decreased the mRNA levels of GRP78 (Figure 7E).	('mRNA levels of', 'MPA', (52, 66))	('decreased', 'NegReg', (38, 47))	('inhibition', 'Var', (17, 27))	('mTOR', 'Gene', '2475', (12, 16))	('mTOR', 'Gene', (12, 16))	('GRP78', 'Gene', (67, 72))	('GRP78', 'Gene', '3309', (67, 72))
143944	24587347	As shown in Figure S2, PI3K inhibitor LY2940012 not only blocked the activity of mTOR but also inhibited the expression of ATF4 and GRP78 without affecting the phosphorylation of eIF2alpha in human CCA cells.	('eIF2alpha', 'Gene', (179, 188))	('mTOR', 'Gene', '2475', (81, 85))	('CCA', 'Phenotype', 'HP:0030153', (198, 201))	('activity', 'MPA', (69, 77))	('expression', 'MPA', (109, 119))	('human', 'Species', '9606', (192, 197))	('eIF2alpha', 'Gene', '83939', (179, 188))	('ATF4', 'Gene', (123, 127))	('inhibited', 'NegReg', (95, 104))	('blocked', 'NegReg', (57, 64))	('GRP78', 'Gene', '3309', (132, 137))	('GRP78', 'Gene', (132, 137))	('LY2940012', 'Var', (38, 47))	('LY2940012', 'Chemical', '-', (38, 47))	('mTOR', 'Gene', (81, 85))	('ATF4', 'Gene', '468', (123, 127))
143960	24587347	This speculation is supported by our data which demonstrated that ATF4 knockdown obviously decreased the accumulation of GRP78 in human CCA cells.	('ATF4', 'Gene', '468', (66, 70))	('CCA', 'Phenotype', 'HP:0030153', (136, 139))	('GRP78', 'Gene', '3309', (121, 126))	('GRP78', 'Gene', (121, 126))	('ATF4', 'Gene', (66, 70))	('knockdown', 'Var', (71, 80))	('accumulation', 'MPA', (105, 117))	('decreased', 'NegReg', (91, 100))	('human', 'Species', '9606', (130, 135))
143962	24587347	Based on the data that blocking JNK by SP600125 inhibited the proliferation and invasion of human CCA cells, we suggest that JNK promotes the carcinogenesis and progression of CCA.	('carcinogenesis', 'Disease', (142, 156))	('invasion', 'CPA', (80, 88))	('CCA', 'Phenotype', 'HP:0030153', (98, 101))	('JNK', 'Gene', (125, 128))	('CCA', 'Disease', (176, 179))	('promotes', 'PosReg', (129, 137))	('JNK', 'Gene', (32, 35))	('SP600125', 'Chemical', 'MESH:C432165', (39, 47))	('progression', 'CPA', (161, 172))	('JNK', 'Gene', '5599', (125, 128))	('SP600125', 'Var', (39, 47))	('inhibited', 'NegReg', (48, 57))	('JNK', 'Gene', '5599', (32, 35))	('CCA', 'Phenotype', 'HP:0030153', (176, 179))	('carcinogenesis', 'Disease', 'MESH:D063646', (142, 156))	('human', 'Species', '9606', (92, 97))
143973	24587347	This hypothesis was supported by the data that JNK inhibition decreased the activity of mTOR, and mTOR inhibition suppressed eIF2alpha-initiated ATF4 and GRP78 induction.	('ATF4', 'Gene', (145, 149))	('activity', 'MPA', (76, 84))	('decreased', 'NegReg', (62, 71))	('eIF2alpha', 'Gene', (125, 134))	('ATF4', 'Gene', '468', (145, 149))	('mTOR', 'Gene', (88, 92))	('GRP78', 'Gene', '3309', (154, 159))	('mTOR', 'Gene', '2475', (88, 92))	('JNK', 'Gene', (47, 50))	('eIF2alpha', 'Gene', '83939', (125, 134))	('inhibition', 'Var', (103, 113))	('suppressed', 'NegReg', (114, 124))	('GRP78', 'Gene', (154, 159))	('mTOR', 'Gene', '2475', (98, 102))	('mTOR', 'Gene', (98, 102))	('induction', 'MPA', (160, 169))	('JNK', 'Gene', '5599', (47, 50))
143979	24587347	Inhibiting eIF4E/eIF4G interaction substantially decreased ATF4 and GRP78 accumulation.	('accumulation', 'MPA', (74, 86))	('ATF4', 'Gene', '468', (59, 63))	('eIF4E', 'Gene', (11, 16))	('GRP78', 'Gene', '3309', (68, 73))	('Inhibiting', 'Var', (0, 10))	('eIF4G', 'Gene', (17, 22))	('eIF4G', 'Gene', '1981', (17, 22))	('decreased', 'NegReg', (49, 58))	('ATF4', 'Gene', (59, 63))	('eIF4E', 'Gene', '1977', (11, 16))	('interaction', 'Interaction', (23, 34))	('GRP78', 'Gene', (68, 73))
143982	24587347	This notion is supported by the data that mTOR inhibition suppressed ATF4 expression without affecting its mRNA levels.	('mTOR', 'Gene', '2475', (42, 46))	('expression', 'MPA', (74, 84))	('ATF4', 'Gene', '468', (69, 73))	('mTOR', 'Gene', (42, 46))	('inhibition', 'Var', (47, 57))	('suppressed', 'NegReg', (58, 68))	('ATF4', 'Gene', (69, 73))
143988	24587347	More detailed studies on the mechanism of JNK aberrant activation and GRP78 aberrant accumulation in CCA will contribute to the understanding of molecular mechanism of cholangiocarcinogenesis and the development of new therapeutic strategies against CCA.	('JNK', 'Gene', (42, 45))	('JNK', 'Gene', '5599', (42, 45))	('carcinogenesis', 'Disease', (177, 191))	('CCA', 'Disease', (101, 104))	('GRP78', 'Gene', '3309', (70, 75))	('GRP78', 'Gene', (70, 75))	('aberrant', 'Var', (76, 84))	('CCA', 'Phenotype', 'HP:0030153', (101, 104))	('CCA', 'Phenotype', 'HP:0030153', (250, 253))	('aberrant', 'Var', (46, 54))	('carcinogenesis', 'Disease', 'MESH:D063646', (177, 191))	('activation', 'PosReg', (55, 65))
143996	22707408	Inactivation of miR-200c resulted in an induction of EMT while activation of miR-200c led to a reduction of EMT including a reduced cell migration and invasion in ICC cells.	('induction', 'PosReg', (40, 49))	('reduced', 'NegReg', (124, 131))	('miR-200c', 'Gene', (16, 24))	('miR-200c', 'Gene', '406985', (16, 24))	('miR-200c', 'Gene', (77, 85))	('EMT', 'CPA', (53, 56))	('cell migration', 'CPA', (132, 146))	('reduction', 'NegReg', (95, 104))	('invasion in ICC cells', 'CPA', (151, 172))	('miR-200c', 'Gene', '406985', (77, 85))	('Inactivation', 'Var', (0, 12))	('activation', 'PosReg', (63, 73))
144028	22707408	Probes used for the analyses were as follows: ZEB1, Hs00232783_m1; ZEB2, Hs00207691_m1 ; VIM, Hs00185584_m1; CDH1, Hs01023894_m1; CDH2, Hs00983056_m1; MYC, Hs00905030_m1; Hsa-miR-200c, 002300 ; Hsa-miR-141, 000463 (Applied Biosystems).	('ZEB1', 'Gene', (46, 50))	('CDH2', 'Gene', (130, 134))	('CDH1', 'Gene', (109, 113))	('VIM', 'Gene', '7431', (89, 92))	('Hs00983056_m1', 'Var', (136, 149))	('Hs01023894_m1', 'Var', (115, 128))	('CDH2', 'Gene', '1000', (130, 134))	('Hs00905030_m1', 'Var', (156, 169))	('VIM', 'Gene', (89, 92))	('MYC', 'Gene', (151, 154))	('ZEB1', 'Gene', '6935', (46, 50))	('ZEB2', 'Gene', (67, 71))	('miR-200c', 'Gene', '406985', (175, 183))	('miR-141', 'Gene', '406933', (198, 205))	('ZEB2', 'Gene', '9839', (67, 71))	('miR-141', 'Gene', (198, 205))	('Hs00232783_m1', 'Var', (52, 65))	('MYC', 'Gene', '4609', (151, 154))	('miR-200c', 'Gene', (175, 183))	('Hs00185584_m1', 'Var', (94, 107))	('CDH1', 'Gene', '999', (109, 113))
144091	22707408	Consistently, ICC cases with high levels of NCAM1 had a worse survival compared to those with low NCAM1 expression (Figure 7F).	('NCAM1', 'Gene', (44, 49))	('NCAM1', 'Gene', '4684', (98, 103))	('NCAM1', 'Gene', '4684', (44, 49))	('high levels', 'Var', (29, 40))	('ICC', 'Disease', (14, 17))	('NCAM1', 'Gene', (98, 103))
144114	22707408	Interestingly, abnormal regulation of EMT-related genes has been reported to be linked to HCC development.	('linked', 'Reg', (80, 86))	('men', 'Species', '9606', (101, 104))	('HCC', 'Gene', (90, 93))	('abnormal', 'Var', (15, 23))	('HCC', 'Gene', '619501', (90, 93))	('EMT-related genes', 'Gene', (38, 55))
144130	22707408	These subtypes include type-A (collision or double cancer, which is referred to as separate HCC and ICC arising in the same liver), type-B (contiguous mass, which is referred to as admixed HCC/ICC such as fibrolamellar tumors) and type-C (transitional tumors, which is referred to as a tumor mass with cellular features of both HCC and ICC).	('HCC', 'Gene', (328, 331))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('type-B', 'Var', (132, 138))	('tumor', 'Disease', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('collision', 'Disease', (31, 40))	('HCC', 'Gene', '619501', (189, 192))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Disease', (252, 258))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('type-C', 'Var', (231, 237))	('tumors', 'Disease', (219, 225))	('tumor', 'Disease', (286, 291))	('HCC', 'Gene', '619501', (92, 95))	('HCC', 'Gene', (189, 192))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('tumors', 'Disease', 'MESH:D009369', (252, 258))	('HCC', 'Gene', (92, 95))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('fibrolamellar tumors', 'Disease', 'MESH:C537258', (205, 225))	('HCC', 'Gene', '619501', (328, 331))	('tumor', 'Disease', (252, 257))	('cancer', 'Disease', (51, 57))	('fibrolamellar tumors', 'Disease', (205, 225))
144150	31088529	Aside from therapeutically relevant ctDNA alterations, they also noted that one or a number of other molecular alterations could be identified in the circulating DNA of these patients and Andersen and Jakobsen demonstrated that driver mutations in RAS and RAF seen in the tumors can typically be identified in cfDNA.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumors', 'Disease', (272, 278))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('RAS', 'Gene', (248, 251))	('mutations', 'Var', (235, 244))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('patients', 'Species', '9606', (175, 183))	('cfDNA', 'Disease', (310, 315))	('RAF', 'Gene', '22882', (256, 259))	('RAF', 'Gene', (256, 259))
144153	31088529	However, aside from being derived from a carcinoma from a different tissue of origin, there are tumor suppressor gene alterations described in cholangiocarcinomas which if found in cfDNA could very infrequently be related to a nonmalignant source.	('carcinoma', 'Disease', 'MESH:D002277', (152, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (143, 162))	('alterations', 'Var', (118, 129))	('carcinoma', 'Disease', (41, 50))	('tumor', 'Disease', (96, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (143, 161))	('carcinoma', 'Disease', (152, 161))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('carcinoma', 'Disease', 'MESH:D002277', (41, 50))	('cholangiocarcinomas', 'Disease', (143, 162))
144154	31088529	For example, identification of circulating BRCA mutated DNA might imply a germline BRCA mutation without an underlying related malignancy (particularly if the mutation allelic frequency is low) and circulating mutated TP53 might be related to clonal hematopoietic cells of indeterminate potential (CHIPs).	('malignancy', 'Disease', 'MESH:D009369', (127, 137))	('BRCA', 'Gene', '672', (83, 87))	('mutated', 'Var', (48, 55))	('imply', 'Reg', (66, 71))	('malignancy', 'Disease', (127, 137))	('BRCA', 'Gene', (83, 87))	('TP53', 'Gene', '7157', (218, 222))	('BRCA', 'Gene', '672', (43, 47))	('TP53', 'Gene', (218, 222))	('BRCA', 'Gene', (43, 47))
144156	31088529	demonstrated that "no significance difference in tumor size, stage, and survival time were observed between low and high methylation group".	('low', 'Var', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('high methylation', 'Var', (116, 132))	('tumor', 'Disease', (49, 54))
144158	31088529	Next-generation circulating cfDNA sequencing in patients suspected of having an underlying cholangiocarcinoma appears to be a promising and also minimally invasive tool as well to aid in diagnosing early-stage cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('aid', 'Gene', '57379', (180, 183))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('cholangiocarcinoma', 'Disease', (210, 228))	('patients', 'Species', '9606', (48, 56))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (210, 228))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (210, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('sequencing', 'Var', (34, 44))	('cholangiocarcinoma', 'Disease', (91, 109))	('aid', 'Gene', (180, 183))	('cfDNA', 'Gene', (28, 33))
144173	19637356	Included cases of extrahepatic cholangiocarcinoma were identified by topography codes representing extrahepatic bile ducts (C24.0) and histology codes representative of cholangiocarcinoma (histology codes 8010, 8020, 8041, 8070, 8140, 8144, 8160, 8162, 8260, 8310, 8490, and 8560).	('8140', 'Var', (229, 233))	('extrahepatic cholangiocarcinoma', 'Disease', (18, 49))	('8041', 'Var', (217, 221))	('8260', 'Var', (253, 257))	('8310', 'Var', (259, 263))	('8490', 'Var', (265, 269))	('cholangiocarcinoma', 'Disease', (31, 49))	('cholangiocarcinoma', 'Disease', (169, 187))	('8070', 'Var', (223, 227))	('8160', 'Var', (241, 245))	('8162', 'Var', (247, 251))	('8144', 'Var', (235, 239))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (31, 49))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (31, 49))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (18, 49))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (169, 187))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (169, 187))	('8560', 'Var', (275, 279))
144174	19637356	Perihilar cholangiocarcinomas, or Klatskin's tumors, were specifically identified by topography codes C24.0 and specific histology code 8162/3; since these tumors cannot be reliably differentiated from EHCC, in accordance with previously described identification analysis of cases in SEER datasets, they therefore were included in this analysis.	('cholangiocarcinomas', 'Disease', (10, 29))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('C24.0', 'Var', (102, 107))	("Klatskin's tumors", 'Disease', (34, 51))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (10, 29))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (10, 28))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	("Klatskin's tumors", 'Disease', 'MESH:D018285', (34, 51))	('tumors', 'Disease', (156, 162))
144189	19637356	The addition of radiotherapy was associated with improved survival probability for subtotal resection patients up to 21 months of follow-up, with a higher cumulative hazard rate thereafter compared to subtotal resection alone.	('patients', 'Species', '9606', (102, 110))	('improved', 'PosReg', (49, 57))	('subtotal', 'Var', (83, 91))	('survival', 'MPA', (58, 66))
144217	31687002	In particular, we focused on the effects of the overexpression of collagen type III alpha 1 chain (COL3A1) in iCCA, thus providing evidences that COL3A1 promotes iCCA cells migration and is a component of tumor-associated aligned collagen.	('COL3A1', 'Var', (146, 152))	('iCCA', 'Disease', 'MESH:C535533', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('iCCA', 'Disease', 'MESH:C535533', (162, 166))	('iCCA', 'Disease', (110, 114))	('iCCA', 'Disease', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('(COL3A1', 'Gene', '1281', (98, 105))	('promotes', 'PosReg', (153, 161))	('COL3A1', 'Gene', (99, 105))
144230	31687002	Knockdown of the POSTN receptor was able to reduce the POSTN-mediated tumor proliferation and invasion.	('invasion', 'CPA', (94, 102))	('POSTN', 'Chemical', 'MESH:C512835', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('reduce', 'NegReg', (44, 50))	('Knockdown', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('POSTN', 'Chemical', 'MESH:C512835', (17, 22))
144234	31687002	Dysregulations of these ECM regulators are usually associated with primary liver tumors.	('liver tumors', 'Disease', (75, 87))	('liver tumors', 'Phenotype', 'HP:0002896', (75, 87))	('Dysregulations', 'Var', (0, 14))	('associated', 'Reg', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('liver tumors', 'Disease', 'MESH:D008113', (75, 87))
144251	31687002	Calibration was performed using default calibration originated by five standard spots (Mass Standards kit for Calibration P/N 4333604).	('Sta', 'Gene', (92, 95))	('P/N 4333604', 'Var', (122, 133))	('Sta', 'Gene', '2656', (92, 95))	('P/N 4333604', 'SUBSTITUTION', 'None', (122, 133))
144315	31687002	: POSTN, COL3A1, COL12A1), the overexpression of periostin has been extensively demonstrated to promote cholangiocarcinogenesis.	('cholangiocarcinogenesis', 'Disease', (104, 127))	('COL12A1', 'Var', (17, 24))	('promote', 'PosReg', (96, 103))	('POSTN', 'Chemical', 'MESH:C512835', (2, 7))	('cholangiocarcinogenesis', 'Disease', 'None', (104, 127))	('overexpression', 'PosReg', (31, 45))
144372	29740198	Statistical analysis showed mutations in TP53 and ARID1A genes and amplification of MET gene as independent predictors of poor prognosis (TP53, p = 0.0031, ARID1A, p = 0.0007, MET, p = 0.0003 in Cox analysis).	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('TP53', 'Gene', '7157', (138, 142))	('Cox', 'Gene', '1351', (195, 198))	('amplification', 'Var', (67, 80))	('TP53', 'Gene', (138, 142))	('Cox', 'Gene', (195, 198))	('ARID1A', 'Gene', '8289', (156, 162))	('ARID1A', 'Gene', '8289', (50, 56))	('mutations', 'Var', (28, 37))	('ARID1A', 'Gene', (50, 56))	('ARID1A', 'Gene', (156, 162))
144393	29740198	More specifically, HCTS yielded an average coverage of 1347x (40-3874x) in normal samples and 3728x (259-24725X) in tumour samples.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('tumour', 'Disease', (116, 122))	('3728x', 'Var', (94, 99))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
144394	29740198	FISH validation of representative cases affected by loss of heterozygosity (LOH) and rearrangement of FGFR2 are illustrated in Supplementary Figures S1 and S2 respectively.	('FGFR2', 'Gene', '2263', (102, 107))	('rearrangement', 'Var', (85, 98))	('loss', 'NegReg', (52, 56))	('Supplementary Figures S1', 'Disease', 'MESH:D017034', (127, 151))	('Supplementary Figures S1', 'Disease', (127, 151))	('FGFR2', 'Gene', (102, 107))	('heterozygosity', 'MPA', (60, 74))
144396	29740198	CNV analysis showed that loss of heterozygosis (LOH) or homozygous deletion (HD) of CDKN2A was most frequent event (24 cases; 36.4%), followed by LOH at the FHIT locus (19 cases; 28.8%) and copy gain of SRC (18 cases; 27.3%).	('CDKN2A', 'Gene', (84, 90))	('CDKN2A', 'Gene', '1029', (84, 90))	('copy gain', 'Var', (190, 199))	('loss of heterozygosis', 'Disease', 'MESH:D015431', (25, 46))	('HD', 'Disease', 'MESH:D006816', (77, 79))	('FHIT', 'Gene', (157, 161))	('FHIT', 'Gene', '2272', (157, 161))	('SRC', 'Gene', '6714', (203, 206))	('LOH', 'Var', (146, 149))	('loss of heterozygosis', 'Disease', (25, 46))	('SRC', 'Gene', (203, 206))
144397	29740198	To further complement mutation and CNV analysis, all cases were screened through break-apart FISH probe to detect rearrangement of FGFR2, FGFR3 and ROS1 genes.	('FGFR3', 'Gene', '2261', (138, 143))	('FGFR2', 'Gene', (131, 136))	('FGFR2', 'Gene', '2263', (131, 136))	('FGFR3', 'Gene', (138, 143))	('ROS1', 'Gene', (148, 152))	('rearrangement', 'Var', (114, 127))	('ROS1', 'Gene', '6098', (148, 152))
144398	29740198	Only one case showed rearrangement at the FGFR2 gene locus (Supplementary Figure S2).	('FGFR2', 'Gene', (42, 47))	('rearrangement', 'Var', (21, 34))	('FGFR2', 'Gene', '2263', (42, 47))
144401	29740198	Furthermore, one hyper-mutated sample was identified in the PP group, that is a sample characterized by a gross excess of point mutations relative to the same tumour type as analysed here and reported in current literature.	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumour type', 'Disease', (159, 170))	('tumour type', 'Disease', 'MESH:D009369', (159, 170))	('point mutations', 'Var', (122, 137))
144407	29740198	Of note, mutations of TGFBR2 (3 cases; 9.1%), BRAF and IGF2R (2 cases each; 9.1%) were present exclusively in the PP group, albeit at low rates.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('IGF2R', 'Gene', (55, 60))	('TGFBR2', 'Gene', '7048', (22, 28))	('mutations', 'Var', (9, 18))	('TGFBR2', 'Gene', (22, 28))	('IGF2R', 'Gene', '3482', (55, 60))
144408	29740198	As for CNVs (Table 3), loss of one or both copies of CDKN2A and copy gain of MET (12 cases; 36.4%) were the most frequent events followed by copy gains in MYC (10 cases; 30.3%).	('copy', 'Var', (64, 68))	('CDKN2A', 'Gene', (53, 59))	('MYC', 'Gene', (155, 158))	('MET', 'MPA', (77, 80))	('CDKN2A', 'Gene', '1029', (53, 59))	('loss', 'NegReg', (23, 27))	('MYC', 'Gene', '4609', (155, 158))
144409	29740198	LOH of TP53 was particularly enriched in this group (7 cases; 21.2%; p = 0.024) and associated to mutation at the same locus.	('TP53', 'Gene', (7, 11))	('TP53', 'Gene', '7157', (7, 11))	('LOH', 'Var', (0, 3))
144410	29740198	The 33 patients included in GP group had exclusive mutations in IDH2 (2cases; 3.0%), APC, ARAF, POLQ and RASA (1 case each; 1.5%), while it shared mutations in KRAS, IDH1, BAP1 and PIK3CA (5 cases each; 15.2%) with the PP group.	('mutations', 'Var', (51, 60))	('RASA', 'Gene', '5921', (105, 109))	('PIK3CA', 'Gene', (181, 187))	('GP', 'Chemical', '-', (28, 30))	('patients', 'Species', '9606', (7, 15))	('POLQ', 'Gene', (96, 100))	('APC', 'Disease', 'MESH:D011125', (85, 88))	('IDH1', 'Gene', (166, 170))	('APC', 'Disease', (85, 88))	('ARAF', 'Gene', '369', (90, 94))	('ARAF', 'Gene', (90, 94))	('BAP1', 'Gene', '8314', (172, 176))	('IDH1', 'Gene', '3417', (166, 170))	('KRAS', 'Gene', (160, 164))	('PIK3CA', 'Gene', '5290', (181, 187))	('RASA', 'Gene', (105, 109))	('POLQ', 'Gene', '10721', (96, 100))	('IDH2', 'Gene', (64, 68))	('BAP1', 'Gene', (172, 176))	('IDH2', 'Gene', '3418', (64, 68))
144414	29740198	Considering the whole cohort, we assessed the prognostic impact of principal differently distributed molecular alterations between GP and PP groups: mutations in TP53; mutations in ARID1A; copy gains in MET; copy gains in MYC.	('mutations', 'Var', (149, 158))	('ARID1A', 'Gene', '8289', (181, 187))	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('MET', 'Gene', (203, 206))	('ARID1A', 'Gene', (181, 187))	('copy gains', 'Var', (189, 199))	('MYC', 'Gene', '4609', (222, 225))	('copy gains', 'Var', (208, 218))	('GP', 'Chemical', '-', (131, 133))	('MYC', 'Gene', (222, 225))	('mutations', 'Var', (168, 177))
144416	29740198	3, alterations in TP53 (p = 0.0004), ARID1A (p = 0.009) and MET (p = 0.03) genes but not gain in MYC gene (p = 0.065) were predictors of poorer prognosis at univariate analysis.	('TP53', 'Gene', '7157', (18, 22))	('alterations', 'Var', (3, 14))	('MYC', 'Gene', (97, 100))	('TP53', 'Gene', (18, 22))	('ARID1A', 'Gene', '8289', (37, 43))	('ARID1A', 'Gene', (37, 43))	('MYC', 'Gene', '4609', (97, 100))	('MET', 'Gene', (60, 63))
144420	29740198	For clinical outcome, we tested the association of overall survival to mutation in TP53 and ARID1A, gains affecting MET and MYC loci, tumour stage, grade and resection margins status.	('TP53', 'Gene', '7157', (83, 87))	('mutation', 'Var', (71, 79))	('TP53', 'Gene', (83, 87))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('MYC', 'Gene', (124, 127))	('tumour', 'Disease', (134, 140))	('tested', 'Reg', (25, 31))	('MYC', 'Gene', '4609', (124, 127))	('ARID1A', 'Gene', '8289', (92, 98))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))	('ARID1A', 'Gene', (92, 98))
144421	29740198	Results are summarized in Table 4 and show that the resulting independent molecular predictors of poor outcome were mutation of TP53 (p = 0.0031) and ARID1A (p = 0.0007), and copy gain of MET (p = 0.0003).	('ARID1A', 'Gene', '8289', (150, 156))	('ARID1A', 'Gene', (150, 156))	('TP53', 'Gene', '7157', (128, 132))	('copy', 'Var', (175, 179))	('TP53', 'Gene', (128, 132))	('mutation', 'Var', (116, 124))
144422	29740198	We observed positive stain for p53 in all samples affected by missense mutation, while the case affected by a nonsense mutation showed no protein expression (Supplementary Figure S3A).	('p53', 'Gene', '7157', (31, 34))	('p53', 'Gene', (31, 34))	('positive', 'Reg', (12, 20))	('missense mutation', 'Var', (62, 79))
144423	29740198	Similarly, arid1a immunolabelling was negative in presence of nonsense and frameshift mutations but not when samples were unaffected or affected by missense mutations (Supplementary Figure S3B).	('arid1a', 'Gene', '8289', (11, 17))	('nonsense', 'Var', (62, 70))	('arid1a', 'Gene', (11, 17))	('frameshift mutations', 'Var', (75, 95))
144424	29740198	As for pten protein, we observed a generally low or negative immunolabelling irrespective of the presence of LOH, mutation, or no alteration at all.	('immunolabelling', 'MPA', (61, 76))	('pten', 'Gene', '5728', (7, 11))	('negative', 'NegReg', (52, 60))	('mutation', 'Var', (114, 122))	('pten', 'Gene', (7, 11))
144425	29740198	Finally, we observed positive immunolabelling for c-met protein in those cases which had the MET locus affected by copy gain (Supplementary Figure S3C).	('copy gain', 'Var', (115, 124))	('c-met', 'Gene', (50, 55))	('c-met', 'Gene', '4233', (50, 55))
144433	29740198	In these, aside from mutations in TP53, other different molecular alterations were identified as poor prognosis markers as IDH1, RNF43, KRAS and ARID2.	('ARID2', 'Gene', '196528', (145, 150))	('TP53', 'Gene', (34, 38))	('RNF43', 'Gene', '54894', (129, 134))	('ARID2', 'Gene', (145, 150))	('RNF43', 'Gene', (129, 134))	('IDH1', 'Gene', (123, 127))	('KRAS', 'Disease', (136, 140))	('IDH1', 'Gene', '3417', (123, 127))	('TP53', 'Gene', '7157', (34, 38))	('mutations', 'Var', (21, 30))
144437	29740198	Of note, coding sequence mutations of TP53 were found only in poor prognostic performers in our study, with a significant discrepancy (p = 0.011) between groups.	('TP53', 'Gene', (38, 42))	('coding sequence mutations', 'Var', (9, 34))	('TP53', 'Gene', '7157', (38, 42))
144438	29740198	Similarly, we found mutations of ARID1A only in this prognostic group (p = 0.024).	('ARID1A', 'Gene', '8289', (33, 39))	('mutations', 'Var', (20, 29))	('ARID1A', 'Gene', (33, 39))
144439	29740198	The association between mutations in TP53 and poor prognosis is not novel for intrahepatic cholangiocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('intrahepatic cholangiocarcinomas', 'Disease', (78, 110))	('mutations', 'Var', (24, 33))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (78, 110))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))
144440	29740198	showed similar results in a large unbiased group of 224 ICCs where TP53 resulted mutated in 24% of cases.	('mutated', 'Var', (81, 88))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))
144443	29740198	showed as mutation or low expression of ARID1A is a predictor of shorter disease specific survival and time to disease recurrence in cancer patients, but a direct correlation to ICC was not evident.	('expression', 'MPA', (26, 36))	('ARID1A', 'Gene', (40, 46))	('low', 'NegReg', (22, 25))	('shorter', 'NegReg', (65, 72))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('mutation', 'Var', (10, 18))	('cancer', 'Disease', (133, 139))	('patients', 'Species', '9606', (140, 148))	('disease specific survival', 'CPA', (73, 98))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('ARID1A', 'Gene', '8289', (40, 46))
144444	29740198	Copy number variation analysis identified LOH in CDKN2A as the most frequent event, in keeping with previous studies, with no difference in alteration rates between the two groups.	('CDKN2A', 'Gene', '1029', (49, 55))	('CDKN2A', 'Gene', (49, 55))	('LOH', 'Var', (42, 45))
144445	29740198	Conversely, a higher proportion of cases affected by copy gain in MET and in MYC genes was observed in the PP group.	('MET', 'Gene', (66, 69))	('MYC', 'Gene', (77, 80))	('copy gain', 'Var', (53, 62))	('MYC', 'Gene', '4609', (77, 80))
144448	29740198	Recently, heterozygous and homozygous deletion of PTEN locus in presence of KRAS activation was demonstrated to induce intrahepatic cholangiocarcinoma in cholangiocytes of a new mouse model showing an important role of PTEN in the development of this tumour type.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('mouse', 'Species', '10090', (178, 183))	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('intrahepatic cholangiocarcinoma', 'Disease', (119, 150))	('PTEN', 'Gene', (50, 54))	('tumour type', 'Disease', (251, 262))	('tumour type', 'Disease', 'MESH:D009369', (251, 262))	('deletion', 'Var', (38, 46))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (119, 150))	('induce', 'Reg', (112, 118))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (132, 150))
144450	29740198	TP53 mutation), while providing several interesting evidences about independent poor prognostic markers for intrahepatic cholangiocarcinomas.	('TP53', 'Gene', '7157', (0, 4))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (108, 140))	('TP53', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))	('mutation', 'Var', (5, 13))	('intrahepatic cholangiocarcinomas', 'Disease', (108, 140))
144469	29740198	The following assays were used: CCND1 (Hs03772544), FHIT (Hs03491211), MET (Hs04951661), SRC (Hs07169853) and RNaseP (part number 4403326).	('Hs07169853', 'Var', (94, 104))	('Hs04951661', 'Var', (76, 86))	('Hs03772544', 'Var', (39, 49))	('CCND1', 'Gene', (32, 37))	('SRC', 'Gene', '6714', (89, 92))	('SRC', 'Gene', (89, 92))	('Hs03491211', 'Var', (58, 68))	('CCND1', 'Gene', '595', (32, 37))	('FHIT', 'Gene', (52, 56))	('FHIT', 'Gene', '2272', (52, 56))
144473	29740198	Representative cases of PTEN and TP53 monosomy and CDKN2A homozygous deletion are illustrated in Supplementary Figure S1, while the only case with confirmed FGFR2 rearrangement is shown in Supplementary Figure S2.	('CDKN2A', 'Gene', '1029', (51, 57))	('TP53', 'Gene', '7157', (33, 37))	('Supplementary Figure S1', 'Disease', 'MESH:D017034', (97, 120))	('monosomy', 'Var', (38, 46))	('Supplementary Figure S1', 'Disease', (97, 120))	('FGFR2', 'Gene', (157, 162))	('TP53', 'Gene', (33, 37))	('deletion', 'Var', (69, 77))	('CDKN2A', 'Gene', (51, 57))	('FGFR2', 'Gene', '2263', (157, 162))	('PTEN', 'Gene', (24, 28))
144534	28178656	The protein level of Stathminin RBE cells was reduced by approximately 70% when Stathmin was knocked down (Figure 4A).	('protein level', 'MPA', (4, 17))	('Stathmin', 'Gene', '3925', (80, 88))	('reduced', 'NegReg', (46, 53))	('knocked down', 'Var', (93, 105))	('Stathmin', 'Gene', (80, 88))	('Stathmin', 'Gene', '3925', (21, 29))	('Stathmin', 'Gene', (21, 29))
144549	28178656	The fact that the proliferation of the cells decreased with Stathmin knockdown suggests that Stathmin could promote cellular proliferation.	('Stathmin', 'Gene', '3925', (93, 101))	('Stathmin', 'Gene', (93, 101))	('cellular proliferation', 'CPA', (116, 138))	('decreased', 'NegReg', (45, 54))	('Stathmin', 'Gene', '3925', (60, 68))	('promote', 'PosReg', (108, 115))	('Stathmin', 'Gene', (60, 68))	('knockdown', 'Var', (69, 78))
144551	28178656	When Stathmin was knocked down in RBE, AKT phosphorylation was downregulated in the RBE-siNS cells, despite the fact that no significant changes in total AKT levels were observed in these cells (Figure 5D).	('AKT', 'Gene', '207', (154, 157))	('Stathmin', 'Gene', '3925', (5, 13))	('knocked down', 'Var', (18, 30))	('AKT', 'Gene', '207', (39, 42))	('downregulated', 'NegReg', (63, 76))	('Stathmin', 'Gene', (5, 13))	('AKT', 'Gene', (154, 157))	('AKT', 'Gene', (39, 42))
144559	28178656	When Stathmin was knocked down in RBE, integrin alpha5 and beta1were markedly decreased in the RBE cells(Figure 6A).	('Stathmin', 'Gene', '3925', (5, 13))	('knocked down', 'Var', (18, 30))	('integrin alpha5', 'Gene', (39, 54))	('integrin alpha5', 'Gene', '3678', (39, 54))	('Stathmin', 'Gene', (5, 13))	('beta1', 'Gene', '146712', (59, 64))	('beta1', 'Gene', (59, 64))	('decreased', 'NegReg', (78, 87))
144579	28178656	When Stathmin was knocked down, Stathmin and integrin beta1 were dispersed in the cytoplasm of the RBE cells (Figure 6C).	('Stathmin', 'Gene', '3925', (32, 40))	('Stathmin', 'Gene', '3925', (5, 13))	('knocked down', 'Var', (18, 30))	('Stathmin', 'Gene', (32, 40))	('Stathmin', 'Gene', (5, 13))	('integrin beta1', 'Gene', (45, 59))	('integrin beta1', 'Gene', '3688', (45, 59))
144583	28178656	Stathmin knockdown inhibited both Thr308-P-Akt and Ser473-P-Akt.	('Thr308', 'Chemical', '-', (34, 40))	('Stathmin', 'Gene', (0, 8))	('inhibited', 'NegReg', (19, 28))	('knockdown', 'Var', (9, 18))	('Ser473', 'Chemical', '-', (51, 57))	('Akt', 'Gene', '207', (43, 46))	('Akt', 'Gene', '207', (60, 63))	('Akt', 'Gene', (43, 46))	('Akt', 'Gene', (60, 63))	('Stathmin', 'Gene', '3925', (0, 8))
144584	28178656	When Stathmin was knocked down, RBE showed significantly decreased expression of p-Stathmin and p-ERK, compared to that in the RBE-siNS cells, even though the RBE cells were treated with Akt activator, dbcAMP.	('Stathmin', 'Gene', '3925', (83, 91))	('p-ERK', 'Gene', '9451', (96, 101))	('dbcAMP', 'Chemical', 'MESH:D003994', (202, 208))	('Stathmin', 'Gene', (83, 91))	('Akt', 'Gene', (187, 190))	('p-ERK', 'Gene', (96, 101))	('Stathmin', 'Gene', '3925', (5, 13))	('knocked down', 'Var', (18, 30))	('Stathmin', 'Gene', (5, 13))	('expression', 'MPA', (67, 77))	('Akt', 'Gene', '207', (187, 190))	('decreased', 'NegReg', (57, 66))
144586	28178656	As a result of the presence of TIC10 and STS, a significant decrease in the phosphorylated ERK and Akt level in the RBE-siStathmin cells (Figure 5G).	('Stathmin', 'Gene', (122, 130))	('decrease', 'NegReg', (60, 68))	('Akt', 'Gene', '207', (99, 102))	('ERK', 'Gene', '5594', (91, 94))	('STS', 'Gene', (41, 44))	('presence', 'Var', (19, 27))	('ERK', 'Gene', (91, 94))	('Akt', 'Gene', (99, 102))	('TIC10', 'Var', (31, 36))	('STS', 'Chemical', 'MESH:D019311', (41, 44))	('Stathmin', 'Gene', '3925', (122, 130))
144591	28178656	The current work was performed to evaluate if high Stathmin expression would regulate anti-apoptotic signaling by enhancing the Bax/Bcl-2 ratio; critical to cholangiocarcinoma cell survival (Figure 4).	('high', 'Var', (46, 50))	('Stathmin', 'Gene', (51, 59))	('cholangiocarcinoma', 'Disease', (157, 175))	('regulate', 'Reg', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('expression', 'Var', (60, 70))	('Bax', 'Gene', '581', (128, 131))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (157, 175))	('Bcl-2', 'Gene', (132, 137))	('anti-apoptotic signaling', 'MPA', (86, 110))	('Bcl-2', 'Gene', '596', (132, 137))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (157, 175))	('enhancing', 'PosReg', (114, 123))	('Stathmin', 'Gene', '3925', (51, 59))	('Bax', 'Gene', (128, 131))
144684	27357928	Defective biliary clearance in the transition area between tumor and normal liver tissue and in primary liver tumors results in ICG retention, which can be visualized using a near-infrared (NIR) fluorescence imaging system.	('ICG', 'Disease', (128, 131))	('liver tumor', 'Phenotype', 'HP:0002896', (104, 115))	('tumor', 'Disease', (59, 64))	('ICG', 'Chemical', 'MESH:D007208', (128, 131))	('tumor', 'Disease', (110, 115))	('liver tumors', 'Disease', 'MESH:D008113', (104, 116))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('biliary clearance', 'CPA', (10, 27))	('liver tumors', 'Phenotype', 'HP:0002896', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('liver tumors', 'Disease', (104, 116))	('Defective', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('results in', 'Reg', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
144823	27843429	Pathologic examination revealed a R0 resected pT3N0M0 distal cholangiocarcinoma (UICC, 7th edition, 2009) originating from the common bile duct.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('pT3N0M0', 'Var', (46, 53))	('cholangiocarcinoma', 'Disease', (61, 79))
144869	27583880	For inclusion in our analysis, studies (cohorts) had to meet the following 4 inclusion criteria: ICC (confirmed by pathological examination) patients primarily undergoing potentially curative resections; inclusion of surgical margins as a variable in the outcome analysis; stratification of negative surgical margins into less than 10 mm (with or without additional subgroups) and 10 mm or more groups; and a survival hazard ratio (HR) for a less than 10 mm group compared with a 10 mm or more group, either directly available in the article or possible to calculate.	('ICC', 'Disease', (97, 100))	('patients', 'Species', '9606', (141, 149))	('less than 10 mm', 'Var', (442, 457))
144881	27583880	Based on the available data from 5 studies (7 cohorts), the tumor size and the proportions of solitary lesions and MF subtypes were similar between the 2 groups (>=10 mm margin group and <10 mm margin group).	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('>=10 mm', 'Var', (162, 169))	('tumor', 'Disease', 'MESH:D009369', (60, 65))
144882	27583880	A statistically significant survival benefit was identified in patients with negative margins 10 mm or more relative to those with negative margins less than 10 mm.	('survival', 'MPA', (28, 36))	('benefit', 'PosReg', (37, 44))	('negative margins 10', 'Var', (77, 96))	('patients', 'Species', '9606', (63, 71))
145017	25903557	Despite the limitations imposed by this control sample, it is clear that the miRNA profiles of D-NT tissue were more similar to ICC tumor tissue than to normal liver tissue N-NT.	('D', 'Chemical', 'MESH:D003903', (0, 1))	('ICC tumor', 'Disease', 'MESH:C566123', (128, 137))	('miRNA profiles', 'MPA', (77, 91))	('N-NT', 'Chemical', '-', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('D-NT', 'Chemical', '-', (95, 99))	('D', 'Chemical', 'MESH:D003903', (95, 96))	('D-NT', 'Var', (95, 99))	('ICC tumor', 'Disease', (128, 137))
145022	25903557	Another miRNA identified in our analysis, miR210, has been repeatedly implicated in the establishment of hypoxia.	('miR210', 'Var', (42, 48))	('implicated', 'Reg', (70, 80))	('hypoxia', 'Disease', (105, 112))	('hypoxia', 'Disease', 'MESH:D000860', (105, 112))
145038	18087285	Among potential therapeutic targets, several studies have revealed overexpression of epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) protein, amplification, and mutation of these genes (Ito et al, 2001; Aishima et al, 2002; Ukita et al, 2002; Altimari et al, 2003; Gwak et al, 2005; Nakazawa et al, 2005; Leone et al, 2006) as well as overexpression of vascular endothelial growth factor (VEGF) protein (Hida et al, 1999; Tang et al, 2006) in cholangiocarcinoma.	('mutation', 'Var', (204, 212))	('VEGF', 'Gene', '7422', (432, 436))	('epidermal growth factor receptor', 'Gene', '1956', (134, 166))	('vascular endothelial growth factor', 'Gene', (396, 430))	('overexpression', 'PosReg', (378, 392))	('VEGF', 'Gene', (432, 436))	('epidermal growth factor receptor', 'Gene', (85, 117))	('HER2', 'Gene', (170, 174))	('overexpression', 'PosReg', (67, 81))	('epidermal growth factor receptor', 'Gene', '1956', (85, 117))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (486, 504))	('human', 'Species', '9606', (128, 133))	('cholangiocarcinoma', 'Disease', (486, 504))	('EGFR', 'Gene', (119, 123))	('epidermal growth factor receptor 2', 'Gene', '2064', (134, 168))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (486, 504))	('epidermal growth factor receptor 2', 'Gene', (134, 168))	('HER2', 'Gene', '2064', (170, 174))	('EGFR', 'Gene', '1956', (119, 123))	('vascular endothelial growth factor', 'Gene', '7422', (396, 430))
145106	18087285	Our study revealed that VEGF expression was significantly associated with intrahepatic metastasis in IHCC.	('expression', 'Var', (29, 39))	('associated with', 'Reg', (58, 73))	('intrahepatic metastasis', 'Disease', 'MESH:D009362', (74, 97))	('intrahepatic metastasis', 'Disease', (74, 97))	('VEGF', 'Gene', '7422', (24, 28))	('IHCC', 'Disease', (101, 105))	('VEGF', 'Gene', (24, 28))
145109	18087285	It has also been reported that high MVD is an independent prognostic factor in node-negative IHCC (Shirabe et al, 2004) and is associated with VEGF expression in IHCC (Tang et al, 2006), although no study has clarified the involvement of angiogenesis in the process of metastasis in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (283, 301))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (283, 301))	('associated', 'Reg', (127, 137))	('VEGF', 'Gene', '7422', (143, 147))	('MVD', 'Disease', (36, 39))	('VEGF', 'Gene', (143, 147))	('cholangiocarcinoma', 'Disease', (283, 301))	('MVD', 'Disease', 'None', (36, 39))	('IHCC', 'Disease', (93, 97))	('high', 'Var', (31, 35))
145113	18087285	In contrast to EGFR expression, HER2 expression was associated with more favourable clinical features, such as a polypoid macroscopic type and absence of other organ involvement.	('expression', 'Var', (37, 47))	('HER2', 'Gene', (32, 36))	('HER2', 'Gene', '2064', (32, 36))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))
145122	18087285	In summary, we have shown that EGFR and VEGF expression is relatively common in cholangiocarcinoma.	('common', 'Reg', (70, 76))	('EGFR', 'Gene', '1956', (31, 35))	('VEGF', 'Gene', (40, 44))	('EGFR', 'Gene', (31, 35))	('cholangiocarcinoma', 'Disease', (80, 98))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (80, 98))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (80, 98))	('VEGF', 'Gene', '7422', (40, 44))	('expression', 'Var', (45, 55))
145255	24459639	Approximately 50% of the injected dose of Gd-EOB-DTPA is taken up by hepatocytes and eliminated through the hepatobiliary system.	('hepatobiliary system', 'Disease', 'MESH:D004066', (108, 128))	('Gd-EOB-DTPA', 'Var', (42, 53))	('hepatobiliary system', 'Disease', (108, 128))	('Gd-EOB-DTPA', 'Chemical', 'MESH:C073590', (42, 53))
145262	24459639	Moreover, Gd-EOB-DTPA has higher relaxivity compared with other gadolinium agents.	('Gd-EOB-DTPA', 'Var', (10, 21))	('relaxivity', 'MPA', (33, 43))	('gadolinium', 'Chemical', 'MESH:D005682', (64, 74))	('higher', 'PosReg', (26, 32))	('Gd-EOB-DTPA', 'Chemical', 'MESH:C073590', (10, 21))
145267	24459639	As noted above, hepatobiliary phase images are generally acquired 20-40 minutes after Gd-EOB-DTPA injection, or 1-2 hours after Gd-BOPTA injection because the contrast agent should be distributed into hepatocytes.	('Gd-BOPTA', 'Chemical', 'MESH:C064572', (128, 136))	('hepatobiliary', 'Disease', 'MESH:D004066', (16, 29))	('hepatobiliary', 'Disease', (16, 29))	('Gd-EOB-DTPA', 'Chemical', 'MESH:C073590', (86, 97))	('Gd-EOB-DTPA', 'Var', (86, 97))
145277	24459639	However, malformed bile duct in FNH, abnormal biliary excretion by decreased MRP2 expression, and pseudoglandular type of HCC lead to an accumulation of contrast agent in the lesion, and hepatobiliary phase imaging shows hyper-intense.	('accumulation', 'PosReg', (137, 149))	('FNH', 'Disease', (32, 35))	('hepatobiliary', 'Disease', 'MESH:D004066', (187, 200))	('HCC', 'Gene', (122, 125))	('expression', 'MPA', (82, 92))	('hepatobiliary', 'Disease', (187, 200))	('MRP2', 'Gene', (77, 81))	('abnormal biliary excretion', 'Phenotype', 'HP:0011036', (37, 63))	('malformed bile duct', 'Phenotype', 'HP:0007993', (9, 28))	('MRP2', 'Gene', '1244', (77, 81))	('HCC', 'Gene', '619501', (122, 125))	('abnormal biliary excretion', 'MPA', (37, 63))	('HCC', 'Phenotype', 'HP:0001402', (122, 125))	('decreased', 'NegReg', (67, 76))	('malformed', 'Var', (9, 18))	('contrast agent', 'MPA', (153, 167))
145299	24459639	However, as with other malignant focal hepatic diseases, specificity of metastasis characterization remained to be undetermined because benign hepatic lesions such as cysts and hemangioma also appear hypointense on hepatobiliary phase image.	('hemangioma', 'Phenotype', 'HP:0001028', (177, 187))	('hepatic lesions', 'Disease', 'MESH:D056486', (143, 158))	('hepatobiliary', 'Disease', 'MESH:D004066', (215, 228))	('hepatobiliary', 'Disease', (215, 228))	('hepatic diseases', 'Disease', 'MESH:D056486', (39, 55))	('hypointense', 'Var', (200, 211))	('cysts and hemangioma', 'Disease', 'MESH:D006391', (167, 187))	('hepatic lesions', 'Disease', (143, 158))	('hepatic diseases', 'Disease', (39, 55))
145326	20564213	Mutagenesis analysis and gel shift data are consistent with a direct binding of Gli to the mir-29 promoter.	('mir', 'Gene', (91, 94))	('Mutagenesis', 'Var', (0, 11))	('Gli', 'Gene', (80, 83))	('binding', 'Interaction', (69, 76))	('Gli', 'Gene', '2735', (80, 83))	('mir', 'Gene', '220972', (91, 94))
145327	20564213	Finally, activation of NF-kappaB signaling, via ligation of Toll-like receptors, also repressed mir-29b expression and promoter function.	('repressed', 'NegReg', (86, 95))	('activation', 'PosReg', (9, 19))	('NF-kappaB', 'Gene', (23, 32))	('mir-29b', 'Gene', '407024', (96, 103))	('mir-29b', 'Gene', (96, 103))	('promoter function', 'MPA', (119, 136))	('expression', 'MPA', (104, 114))	('NF-kappaB', 'Gene', '4790', (23, 32))	('ligation', 'Var', (48, 56))
145330	20564213	Altered expression levels of microRNAs have been described in many cancers and result in aberrant expression of proteins that influence malignant behavior, such as resistance to apoptosis, proliferation, and metastasis.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('expression of', 'MPA', (98, 111))	('proliferation', 'CPA', (189, 202))	('cancers', 'Disease', (67, 74))	('aberrant', 'Var', (89, 97))	('described', 'Reg', (49, 58))	('metastasis', 'CPA', (208, 218))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('malignant behavior', 'CPA', (136, 154))	('Altered', 'Reg', (0, 7))	('influence', 'Reg', (126, 135))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('expression levels', 'MPA', (8, 25))	('resistance to apoptosis', 'CPA', (164, 187))	('proteins', 'Protein', (112, 120))
145342	20564213	Reactivation of the developmental hedgehog signaling pathway is a feature of many cancers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('developmental hedgehog signaling pathway', 'Pathway', (20, 60))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('Reactivation', 'Var', (0, 12))	('cancers', 'Disease', 'MESH:D009369', (82, 89))
145410	20564213	Luciferase activity increased significantly when cells were treated overnight with cyclopamine, but not when the putative Gli-binding site was disrupted (Gli-mut) by site-directed mutagenesis (Figure 3A).	('Gli', 'Gene', '2735', (154, 157))	('increased', 'PosReg', (20, 29))	('Gli', 'Gene', '2735', (122, 125))	('activity', 'MPA', (11, 19))	('cyclopamine', 'Var', (83, 94))	('Gli', 'Gene', (154, 157))	('cyclopamine', 'Chemical', 'MESH:C000541', (83, 94))	('Luciferase', 'Enzyme', (0, 10))	('Gli', 'Gene', (122, 125))
145429	20564213	Double stranded oligonucleotide probes designed from each of the three predicted NF-kappaB sites, (-561, -110, and +134) exhibited a gel shift in the presence of nuclear extract from LPS-treated H69 cells (Figure 4E).	('NF-kappaB', 'Gene', '4790', (81, 90))	('gel', 'MPA', (133, 136))	('NF-kappaB', 'Gene', (81, 90))	('oligonucleotide', 'Chemical', 'MESH:D009841', (16, 31))	('-561', 'Var', (99, 103))	('H69', 'CellLine', 'CVCL:8121', (195, 198))
145448	20564213	Recent data have indicated that cholangiocarcinoma cells express signaling factors comprising the hedgehog pathway, and that inhibition by cyclopamine could limit cell survival and promote regression of xenografted cholangiocarcinoma cells.	('hedgehog pathway', 'Pathway', (98, 114))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (32, 50))	('cyclopamine', 'Chemical', 'MESH:C000541', (139, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (32, 50))	('limit', 'NegReg', (157, 162))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (215, 233))	('regression', 'CPA', (189, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (215, 233))	('cell survival', 'CPA', (163, 176))	('promote', 'PosReg', (181, 188))	('cholangiocarcinoma', 'Disease', (215, 233))	('cholangiocarcinoma', 'Disease', (32, 50))	('inhibition', 'Var', (125, 135))
145450	20564213	Indeed, activity of the mir-29b-1/mir-29a promoter fragment (-1530/+165) was increased 3-4 fold in cells treated with cyclopamine, an effect that was prevented by mutagenesis of the Gli binding site.	('mir-29b-1', 'Gene', (24, 33))	('Gli', 'Gene', '2735', (182, 185))	('cyclopamine', 'Chemical', 'MESH:C000541', (118, 129))	('mir-29a', 'Gene', (34, 41))	('activity', 'MPA', (8, 16))	('mir-29a', 'Gene', '407021', (34, 41))	('mir-29b-1', 'Gene', '407024', (24, 33))	('increased', 'PosReg', (77, 86))	('-1530/+165', 'Var', (61, 71))	('Gli', 'Gene', (182, 185))
145472	20564213	As loss of mir-29 contributes to apoptosis, metastasis/invasion, and epigenetic signaling, approaches to increase endogenous mir-29b-1/mir-29a expression may have a beneficial effect on cancer treatment through multiple inter-related pathways.	('mir', 'Gene', (125, 128))	('mir-29b-1', 'Gene', (125, 134))	('mir', 'Gene', (11, 14))	('mir-29b-1', 'Gene', '407024', (125, 134))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('dog', 'Species', '9615', (116, 119))	('mir', 'Gene', '220972', (135, 138))	('mir-29a', 'Gene', '407021', (135, 142))	('mir-29a', 'Gene', (135, 142))	('mir', 'Gene', '220972', (125, 128))	('beneficial', 'PosReg', (165, 175))	('cancer', 'Disease', (186, 192))	('epigenetic signaling', 'MPA', (69, 89))	('apoptosis', 'CPA', (33, 42))	('loss', 'Var', (3, 7))	('mir', 'Gene', '220972', (11, 14))	('mir', 'Gene', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('metastasis/invasion', 'CPA', (44, 63))
145497	33541011	Studies were excluded if any of the following criteria were met: (1) non-human studies; (2) non-observational studies or observational studies without an analytical epidemiologic approach; (3) irrelevant exposure or outcome variables (hepatolithiasis or intrahepatic cholangiocarcinoma); (4) duplication or unobtainable abstract/full-text; (5) the absence of a risk estimate that was either reported or could be calculated by the given information.	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (267, 285))	('human', 'Species', '9606', (73, 78))	('duplication', 'Var', (292, 303))	('hepatolithiasis or intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (235, 285))	('hepatolithiasis or intrahepatic cholangiocarcinoma', 'Disease', (235, 285))
145506	33541011	A total of 26 studies presented associations between the presence of gallstones and the risk of BTC (Figure 2).	('associations', 'Interaction', (32, 44))	('presence', 'Var', (57, 65))	('gallstones', 'Disease', (69, 79))	('BTC', 'Disease', (96, 99))	('gallstones', 'Phenotype', 'HP:0001081', (69, 79))	('gallstone', 'Phenotype', 'HP:0001081', (69, 78))	('BTC', 'Phenotype', 'HP:0100574', (96, 99))	('gallstones', 'Disease', 'MESH:D042882', (69, 79))
145512	33541011	A total of 17 studies presented associations between the presence of gallstones and the risk of EBDC in its broadest sense (a concept embracing EBDC, EHC, CCA, and BDC), as shown in Supplementary Material 1B.	('EBDC', 'Phenotype', 'HP:0005242', (96, 100))	('CCA', 'Phenotype', 'HP:0030153', (155, 158))	('associations', 'Interaction', (32, 44))	('EBDC', 'Disease', (96, 100))	('BDC', 'Phenotype', 'HP:0030153', (164, 167))	('EBDC', 'Phenotype', 'HP:0005242', (144, 148))	('presence', 'Var', (57, 65))	('gallstones', 'Disease', (69, 79))	('gallstones', 'Phenotype', 'HP:0001081', (69, 79))	('gallstone', 'Phenotype', 'HP:0001081', (69, 78))	('BDC', 'Phenotype', 'HP:0030153', (97, 100))	('BDC', 'Phenotype', 'HP:0030153', (145, 148))	('gallstones', 'Disease', 'MESH:D042882', (69, 79))
145513	33541011	We identified 4 cohort studies and 13 casecontrol studies that presented associations between the presence of gallstones and the risk of EBDC.	('gallstones', 'Disease', 'MESH:D042882', (110, 120))	('EBDC', 'Disease', (137, 141))	('gallstones', 'Phenotype', 'HP:0001081', (110, 120))	('associations', 'Interaction', (73, 85))	('EBDC', 'Phenotype', 'HP:0005242', (137, 141))	('gallstones', 'Disease', (110, 120))	('presence', 'Var', (98, 106))	('BDC', 'Phenotype', 'HP:0030153', (138, 141))	('gallstone', 'Phenotype', 'HP:0001081', (110, 119))
145518	33541011	The result still showed a significant association between the presence of gallstones and the risk of AOVC (OR, 3.28; 95% CI, 1.33 to 8.11; I2=93.3%; p<0.001).	('gallstone', 'Phenotype', 'HP:0001081', (74, 83))	('AOVC', 'Phenotype', 'HP:0031524', (101, 105))	('gallstones', 'Disease', (74, 84))	('gallstones', 'Phenotype', 'HP:0001081', (74, 84))	('gallstones', 'Disease', 'MESH:D042882', (74, 84))	('AOVC', 'Disease', (101, 105))	('presence', 'Var', (62, 70))
145528	33541011	A gallbladder carrying larger gallstones or crammed with multiple gallstones is already known to increase the risk of GBC, and this finding was also verified through our meta-analyses (Supplementary Material 7).	('increase', 'PosReg', (97, 105))	('gallstones', 'Phenotype', 'HP:0001081', (30, 40))	('gallstones', 'Disease', (30, 40))	('gallstone', 'Phenotype', 'HP:0001081', (30, 39))	('crammed', 'Var', (44, 51))	('GBC', 'Disease', (118, 121))	('gallstones', 'Disease', 'MESH:D042882', (30, 40))	('gallstones', 'Disease', (66, 76))	('gallstone', 'Phenotype', 'HP:0001081', (66, 75))	('gallstones', 'Disease', 'MESH:D042882', (66, 76))	('gallstones', 'Phenotype', 'HP:0001081', (66, 76))
145558	33067881	The panoramic picture of pepsinogen gene family with pan-cancer The panoramic picture of pepsinogen gene family with pan-cancer It is well known that pepsinogen (PGs), as an important precursor of pepsin performing digestive function, has a good correlation with the occurrence and development of gastric cancer and it is also known that ectopic PGs expression is related to the prognosis of some cancers.	('correlation', 'Reg', (246, 257))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (57, 63))	('related', 'Reg', (364, 371))	('gastric cancer', 'Phenotype', 'HP:0012126', (297, 311))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (397, 404))	('cancers', 'Disease', (397, 404))	('cancer', 'Disease', (397, 403))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('PGs', 'Chemical', 'MESH:D010715', (346, 349))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('PGs', 'Chemical', 'MESH:D010715', (162, 165))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('gastric cancer', 'Disease', (297, 311))	('ectopic', 'Var', (338, 345))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('cancers', 'Disease', 'MESH:D009369', (397, 404))	('cancer', 'Disease', (305, 311))	('gastric cancer', 'Disease', 'MESH:D013274', (297, 311))	('cancer', 'Disease', (121, 127))
145560	33067881	This study focused on elucidating the expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their potential role in human cancer.	('human', 'Species', '9606', (175, 180))	('copy number variation', 'Var', (118, 139))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('PGs', 'Chemical', 'MESH:D010715', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('PGs', 'Gene', (143, 146))	('cancer', 'Disease', (181, 187))
145561	33067881	Based on the next generation sequence data from TCGA, Oncomine, and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically by R language, including the expression, mutation, and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration, and prognostic potential in different cancers.	('CCLE', 'Chemical', '-', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('copy number variation', 'Var', (230, 251))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('Oncomine', 'Chemical', '-', (54, 62))	('tumor', 'Disease', (134, 139))	('PGs', 'Chemical', 'MESH:D010715', (255, 258))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cancers', 'Disease', 'MESH:D009369', (394, 401))	('cancer', 'Disease', 'MESH:D009369', (394, 400))	('cancers', 'Phenotype', 'HP:0002664', (394, 401))	('PGs', 'Chemical', 'MESH:D010715', (124, 127))	('PGs', 'Gene', (255, 258))	('cancer', 'Disease', (394, 400))	('cancers', 'Disease', (394, 401))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Disease', (286, 292))	('cancer', 'Disease', 'MESH:D009369', (286, 292))
145566	33067881	PGs expression was significantly related to the activation or inhibition of many signal transduction pathways, in which PGC and PGA5 are more likely to be associated with cancer-related pathways.	('PGC', 'Gene', (120, 123))	('signal transduction pathways', 'Pathway', (81, 109))	('PGA5', 'Gene', (128, 132))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('PGs', 'Chemical', 'MESH:D010715', (0, 3))	('associated', 'Reg', (155, 165))	('cancer', 'Disease', (171, 177))	('PGA5', 'Gene', '5222', (128, 132))	('activation', 'PosReg', (48, 58))	('inhibition', 'NegReg', (62, 72))	('PGC', 'Gene', '5225', (120, 123))	('PGs', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
145572	33067881	Genetic variation analysis showed that PGC gene often mutated in uterine corpus endometrial carcinoma and stomach adenocarcinoma had extensive copy number amplification in various tumor types.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('tumor', 'Disease', (180, 185))	('PGC', 'Gene', '5225', (39, 42))	('mutated', 'Var', (54, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (80, 101))	('copy number amplification', 'MPA', (143, 168))	('endometrial carcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D016889', (80, 128))	('PGC', 'Gene', (39, 42))
145573	33067881	PGC expression was upregulated with the increase of copy number in cholangiocarcinoma, esophageal carcinoma, and kidney renal papillary cell carcinoma, while in stomach adenocarcinoma, PGC was upregulated regardless of whether the copy number was increased or decreased.	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (120, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('expression', 'MPA', (4, 14))	('esophageal carcinoma', 'Disease', (87, 107))	('cholangiocarcinoma', 'Disease', (67, 85))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))	('PGC', 'Gene', (185, 188))	('kidney renal papillary cell carcinoma', 'Disease', (113, 150))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (87, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (161, 183))	('upregulated', 'PosReg', (193, 204))	('upregulated', 'PosReg', (19, 30))	('PGC', 'Gene', (0, 3))	('PGC', 'Gene', '5225', (185, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('stomach adenocarcinoma', 'Disease', (161, 183))	('PGC', 'Gene', '5225', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('increase', 'PosReg', (40, 48))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (87, 107))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (113, 150))	('copy number', 'Var', (52, 63))
145577	33067881	The variation of copy number of PGC gene could affect the PGC expression.	('PGC', 'Gene', (58, 61))	('variation', 'Var', (4, 13))	('copy number', 'Var', (17, 28))	('expression', 'MPA', (62, 72))	('PGC', 'Gene', '5225', (32, 35))	('PGC', 'Gene', (32, 35))	('affect', 'Reg', (47, 53))	('PGC', 'Gene', '5225', (58, 61))
145579	33067881	Based on the next generation sequence data from TCGA and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically including the expression profiles, mutation and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration and prognostic potential in different cancers.	('cancers', 'Phenotype', 'HP:0002664', (375, 382))	('cancer', 'Disease', (268, 274))	('cancers', 'Disease', (375, 382))	('PGs', 'Chemical', 'MESH:D010715', (113, 116))	('tumor', 'Disease', (123, 128))	('PGs', 'Chemical', 'MESH:D010715', (237, 240))	('copy number variation', 'Var', (212, 233))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('CCLE', 'Chemical', '-', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancers', 'Disease', 'MESH:D009369', (375, 382))	('correlation', 'Reg', (251, 262))	('PGs', 'Gene', (237, 240))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('cancer', 'Disease', (375, 381))	('cancer', 'Disease', 'MESH:D009369', (375, 381))
145599	33067881	In this study, by using the multilevel data from TCGA based Pan-Cancer Atlas, Oncomine and Cancer Cell Line Encyclopedia (CCLE), we focused on the elucidating expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their prediction/diagnosis/prognosis potential in pan-cancer.	('Cancer', 'Disease', (91, 97))	('Cancer', 'Disease', (64, 70))	('CCLE', 'Chemical', '-', (122, 126))	('Cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('-cancer', 'Disease', 'MESH:D009369', (325, 332))	('-cancer', 'Disease', (325, 332))	('Oncomine', 'Chemical', '-', (78, 86))	('PGs', 'Chemical', 'MESH:D010715', (264, 267))	('copy number variation', 'Var', (239, 260))	('PGs', 'Gene', (264, 267))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
145600	33067881	We totally collected the information of 33 different kinds of tumors in TCGA database (http://cancergenome.nih.gov/), including the information of TPM (Transcripts Per Kilobase Million) expression, mutation, and copy number variation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('copy number variation', 'Var', (212, 233))	('TPM', 'Gene', (147, 150))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Disease', (94, 100))	('mutation', 'Var', (198, 206))
145605	33067881	CCLE database(https://portals.broadinstitute.org/ccle)was used to identify the PGs expression, mutation, and copy number variation in different cancer cell lines, including all 431 cell lines from six cancer types.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('CCLE', 'Chemical', '-', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('PGs', 'Chemical', 'MESH:D010715', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('PGs', 'Gene', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('mutation', 'Var', (95, 103))
145618	33067881	The frequency of CNV in each cancer type and cell lines was calculated as the proportion of CNV amplification and deletion.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('deletion', 'Var', (114, 122))
145630	33067881	The results showed that in stomach adenocarcinoma and lung squamous cell carcinoma, high expression of PG is a protective factor, and high expression can reduce the risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('reduce', 'NegReg', (154, 160))	('high expression', 'Var', (134, 149))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (27, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (54, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('stomach adenocarcinoma', 'Disease', (27, 49))	('lung squamous cell carcinoma', 'Disease', (54, 82))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 82))
145641	33067881	The results show that PGs expression was significantly related to the activation or inhibition of many carcinogenic pathways (Figure 7A), in which PGC and PGA5 are more likely to be associated with carcinogenic processes.	('PGC', 'Gene', (147, 150))	('carcinogenic', 'Disease', 'MESH:D063646', (198, 210))	('associated', 'Reg', (182, 192))	('inhibition', 'NegReg', (84, 94))	('carcinogenic', 'Disease', (198, 210))	('expression', 'Var', (26, 36))	('PGA5', 'Gene', (155, 159))	('PGs', 'Gene', (22, 25))	('PGA5', 'Gene', '5222', (155, 159))	('carcinogenic', 'Disease', 'MESH:D063646', (103, 115))	('carcinogenic', 'Disease', (103, 115))	('activation', 'PosReg', (70, 80))	('related', 'Reg', (55, 62))	('PGs', 'Chemical', 'MESH:D010715', (22, 25))	('PGC', 'Gene', '5225', (147, 150))
145665	33067881	The results showed that PGC gene mutations frequently occurred in uterine corpus endometrial carcinoma and stomach adenocarcinoma (Figure 10A).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('PGC', 'Gene', '5225', (24, 27))	('PGC', 'Gene', (24, 27))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (81, 102))	('endometrial carcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D016889', (81, 129))	('mutations', 'Var', (33, 42))	('occurred', 'Reg', (54, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))
145668	33067881	PGA3, PGA4, and PGA5 showed more copy number amplification in lung adenocarcinoma, esophageal carcinoma, kidney chromophobe, and copy number reduction in bladder urothelial carcinoma, lung squamous cell carcinoma, rectum adenocarcinoma, and cholangiocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('copy number', 'Var', (129, 140))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (184, 212))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('PGA4', 'Gene', '643847', (6, 10))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (241, 259))	('PGA5', 'Gene', (16, 20))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (214, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('cholangiocarcinoma', 'Disease', (241, 259))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (241, 259))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (83, 103))	('copy', 'MPA', (33, 37))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (184, 212))	('lung squamous cell carcinoma', 'Disease', (184, 212))	('kidney chromophobe', 'Disease', 'MESH:D000238', (105, 123))	('PGA5', 'Gene', '5222', (16, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('esophageal carcinoma', 'Disease', (83, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('kidney chromophobe', 'Disease', (105, 123))	('PGA3', 'Chemical', '-', (0, 4))	('rectum adenocarcinoma', 'Disease', (214, 235))	('bladder urothelial carcinoma', 'Disease', (154, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('lung adenocarcinoma', 'Disease', (62, 81))	('PGA4', 'Gene', (6, 10))	('PGA3', 'Gene', (0, 4))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (83, 103))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (154, 182))
145669	33067881	In addition, CCLE database analysis revealed the mutation status of PGs in different human cancer cell lines, which showed that there were frequent mutations of PGs in colorectal cancer and gastric cancer cell lines (Figure 11).	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))	('gastric cancer', 'Disease', 'MESH:D013274', (190, 204))	('cancer', 'Disease', (198, 204))	('PGs', 'Chemical', 'MESH:D010715', (68, 71))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('colorectal cancer', 'Disease', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('PGs', 'Gene', (161, 164))	('CCLE', 'Chemical', '-', (13, 17))	('mutations', 'Var', (148, 157))	('PGs', 'Chemical', 'MESH:D010715', (161, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (190, 204))	('rectal cancer', 'Phenotype', 'HP:0100743', (172, 185))	('human', 'Species', '9606', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (179, 185))	('gastric cancer', 'Disease', (190, 204))
145670	33067881	In order to explore whether PGC self-variation affects its expression, we analyzed the correlation between PGs mutation, CNV, and PGs expression.	('PGs', 'Gene', (107, 110))	('PGC', 'Gene', '5225', (28, 31))	('PGC', 'Gene', (28, 31))	('PGs', 'Chemical', 'MESH:D010715', (130, 133))	('expression', 'MPA', (59, 69))	('PGs', 'Chemical', 'MESH:D010715', (107, 110))	('mutation', 'Var', (111, 119))
145671	33067881	The results showed that PGs mutations did not affect the PGs expression in all cancers.	('cancers', 'Disease', (79, 86))	('PGs', 'Chemical', 'MESH:D010715', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PGs', 'Chemical', 'MESH:D010715', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('PGs', 'Gene', (24, 27))	('mutations', 'Var', (28, 37))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
145674	33067881	In this study, we used the multilevel data of TCGA, Oncomine, and CCLE to reveal the expression and activated pathways, mutation, and copy number variation, prognostic potential of PGs in all 33 types of tumors and 431 cell lines, aiming to clarify the important role of PGs in tumorigenesis and development of cancers.	('Oncomine', 'Chemical', '-', (52, 60))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('copy number variation', 'Var', (134, 155))	('tumor', 'Disease', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('CCLE', 'Chemical', '-', (66, 70))	('PGs', 'Chemical', 'MESH:D010715', (271, 274))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('cancers', 'Disease', (311, 318))	('tumor', 'Disease', (204, 209))	('PGs', 'Chemical', 'MESH:D010715', (181, 184))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
145675	33067881	The results suggest that there was differential expression of PGs between many kinds of cancer tissues and corresponding normal tissues, which is related to the prognosis of patients; PGs expression was closely associated with the activation of cancer-related pathways and immune cell infiltration; the copy number variation of PGC could affect the gene expression.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('gene expression', 'MPA', (349, 364))	('PGC', 'Gene', (328, 331))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('affect', 'Reg', (338, 344))	('immune cell infiltration', 'CPA', (273, 297))	('activation', 'PosReg', (231, 241))	('cancer', 'Disease', (245, 251))	('PGs', 'Chemical', 'MESH:D010715', (62, 65))	('copy number variation', 'Var', (303, 324))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PGC', 'Gene', '5225', (328, 331))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('associated', 'Reg', (211, 221))	('PGs', 'Chemical', 'MESH:D010715', (184, 187))
145694	33067881	The loss of pepsinogen in advanced esophageal squamous cell carcinoma indicates that pepsin is involved in the process of protein synthesis in the esophagus and causes esophageal carcinogenesis.	('pepsin', 'Var', (85, 91))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (168, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (35, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('causes', 'Reg', (161, 167))	('esophageal carcinogenesis', 'Disease', (168, 193))	('esophageal squamous cell carcinoma', 'Disease', (35, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('loss', 'NegReg', (4, 8))	('pepsinogen', 'Protein', (12, 22))
145696	33067881	Both lung tissue and gastric mucosa have the same function of producing pepsinogen molecules, 11  and the injury of normal lung tissue could increase the synthesis of pepsinogen C. 22  Some studies have also suggested that the existence of pepsin in respiratory biological samples was caused by gastroesophageal reflux associated lung inhalation.	('increase', 'PosReg', (141, 149))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (295, 318))	('pepsinogen C', 'Gene', '5225', (167, 179))	('injury', 'Var', (106, 112))	('pepsinogen C', 'Gene', (167, 179))	('gastroesophageal reflux', 'Disease', (295, 318))	('pepsin', 'Gene', (240, 246))	('synthesis', 'MPA', (154, 163))	('caused by', 'Reg', (285, 294))
145717	33067881	The results showed that the overall average mutation rate of PGs was 0%-5.3%, and the mutation rate of PGC was higher in stomach adenocarcinoma and endometrial carcinoma.	('higher', 'Reg', (111, 117))	('PGC', 'Gene', '5225', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('PGs', 'Chemical', 'MESH:D010715', (61, 64))	('PGC', 'Gene', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (148, 169))	('mutation', 'Var', (86, 94))	('stomach adenocarcinoma and endometrial carcinoma', 'Disease', 'MESH:D016889', (121, 169))
145718	33067881	It is worth noticed that all PGC, PGA3, and PGA5 genes had a certain degree of mutation in endometrial carcinoma, which is a tumor with high global mutation rate.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('PGA3', 'Gene', (34, 38))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (91, 112))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('PGA3', 'Chemical', '-', (34, 38))	('PGA5', 'Gene', (44, 48))	('mutation', 'Var', (79, 87))	('PGC', 'Gene', '5225', (29, 32))	('PGC', 'Gene', (29, 32))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (91, 112))	('endometrial carcinoma', 'Disease', (91, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('PGA5', 'Gene', '5222', (44, 48))
145719	33067881	31  In addition, CCLE-based analysis of human cancer cell lines showed that most of the PGs mutations were found in colorectal adenocarcinoma and stomach adenocarcinoma cell lines, suggesting PGs mutation may be the key events in tumorigenesis and development of both gastric cancer and colorectal adenocarcinoma.	('CCLE', 'Chemical', '-', (17, 21))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('gastric cancer', 'Disease', (268, 282))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (287, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (268, 282))	('colorectal adenocarcinoma', 'Disease', (116, 141))	('human', 'Species', '9606', (40, 45))	('tumor', 'Disease', (230, 235))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', (46, 52))	('PGs', 'Chemical', 'MESH:D010715', (192, 195))	('mutations', 'Var', (92, 101))	('PGs', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PGs', 'Chemical', 'MESH:D010715', (88, 91))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (116, 141))	('gastric cancer', 'Phenotype', 'HP:0012126', (268, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('colorectal adenocarcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D000230', (116, 168))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('found', 'Reg', (107, 112))	('colorectal adenocarcinoma', 'Disease', (287, 312))
145720	33067881	In this study, we also found that there was extensive copy number amplification in various tumor types, which may be related to its widespread expression in various tissues.	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('copy number amplification', 'Var', (54, 79))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
145722	33067881	The results showed that there was no correlation between PGs mutation and PGs expression in cancer cells.	('PGs', 'Chemical', 'MESH:D010715', (74, 77))	('cancer', 'Disease', (92, 98))	('PGs', 'Chemical', 'MESH:D010715', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutation', 'Var', (61, 69))	('PGs', 'Gene', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
145723	33067881	However, previous studies in our lab have found that PGC gene insertion-deletion fragment polymorphism and single nucleotide polymorphism from human germline cells can affect PGC expression.	('PGC', 'Gene', (175, 178))	('human', 'Species', '9606', (143, 148))	('expression', 'MPA', (179, 189))	('insertion-deletion fragment polymorphism', 'Var', (62, 102))	('single nucleotide polymorphism', 'Var', (107, 137))	('PGC', 'Gene', '5225', (53, 56))	('PGC', 'Gene', (53, 56))	('affect', 'Reg', (168, 174))	('PGC', 'Gene', '5225', (175, 178))
145725	33067881	In cholangiocarcinoma, esophageal cancer, and kidney renal papillary cell carcinoma, PGC expression was upregulated with the increase of copy number, but in stomach adenocarcinoma, both increase and deletion of PGC copy number could lead to the up-regulation of PGC expression.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('expression', 'MPA', (266, 276))	('PGC', 'Gene', '5225', (211, 214))	('stomach adenocarcinoma', 'Disease', (157, 179))	('deletion', 'Var', (199, 207))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('cholangiocarcinoma', 'Disease', (3, 21))	('copy number', 'Var', (215, 226))	('up-regulation', 'PosReg', (245, 258))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (46, 83))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (53, 83))	('PGC', 'Gene', (262, 265))	('upregulated', 'PosReg', (104, 115))	('PGC', 'Gene', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('PGC', 'Gene', '5225', (262, 265))	('kidney renal papillary cell carcinoma', 'Disease', (46, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('PGC', 'Gene', (211, 214))	('cancer', 'Disease', (34, 40))	('PGC', 'Gene', '5225', (85, 88))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (157, 179))
145794	31417643	The search parameters included iTRAQ labeling at N-terminus and lysine residues, cysteine modification by methyl methanethiosulfonate (MMTS), and digestion by trypsin.	('cysteine modification', 'MPA', (81, 102))	('iTRAQ labeling', 'MPA', (31, 45))	('iTRAQ', 'Chemical', '-', (31, 36))	('lysine', 'Chemical', 'MESH:D008239', (64, 70))	('cysteine', 'Chemical', 'MESH:D003545', (81, 89))	('digestion', 'Var', (146, 155))	('MMTS', 'Chemical', 'MESH:C014674', (135, 139))	('methyl methanethiosulfonate', 'Chemical', 'MESH:C014674', (106, 133))
145928	31417920	The histopathology-based differential diagnosis of iCCA with hepatocarcinoma or metas-tasis requires a panel of immunohistochemistry markers and a cytokeratin profile (CK7+, CK19+, CK20-).	('CCA', 'Gene', '2201', (52, 55))	('CK19', 'Gene', '3880', (174, 178))	('hepatocarcinoma', 'Disease', 'None', (61, 76))	('hepatocarcinoma', 'Disease', (61, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('CCA', 'Gene', (52, 55))	('CK20', 'Gene', (181, 185))	('CK19', 'Gene', (174, 178))	('CK20', 'Gene', '54474', (181, 185))	('CK7+', 'Var', (168, 172))
145940	31417920	Serum levels of CA19.9 > 130 U/mL in PSC had a sensitivity of 79% and specificity of 98% for detection of CCA.	('PSC', 'Gene', (37, 40))	('CA19.9', 'Var', (16, 22))	('CCA', 'Gene', (106, 109))	('CCA', 'Gene', '2201', (106, 109))	('PSC', 'Gene', '100653366', (37, 40))
145941	31417920	However, the serum level of CA19.9 is skewed by high secondary elevation in cholangitis and cholestasis.	('cholestasis', 'Disease', 'MESH:D002779', (92, 103))	('serum level', 'MPA', (13, 24))	('cholestasis', 'Disease', (92, 103))	('cholangitis', 'Disease', (76, 87))	('CA19.9', 'Var', (28, 34))	('cholangitis', 'Phenotype', 'HP:0030151', (76, 87))	('elevation', 'PosReg', (63, 72))	('cholestasis', 'Phenotype', 'HP:0001396', (92, 103))	('cholangitis', 'Disease', 'MESH:D002761', (76, 87))
145955	31417920	The accuracy for differentiating between malignant and benign strictures (e.g., PSC) based on cholangiographic morphology (e.g., irregularity, asymmetry, and extension) is unsatisfactory, even in the hands of expert endoscopists (accuracy ranges from 72% to 80%), thus highlighting the need for tissue samples to ensure an appropriate diagnosis.	('PSC', 'Gene', '100653366', (80, 83))	('asymmetry', 'Var', (143, 152))	('PSC', 'Gene', (80, 83))	('irregularity', 'Var', (129, 141))
146012	31417920	In patients who are candidates for surgery but have a relative criterion, ipsilateral portal vein embolization can lead to compensatory hypertrophy of the healthy remnant liver.	('portal vein embolization', 'Phenotype', 'HP:0030242', (86, 110))	('lead to', 'Reg', (115, 122))	('patients', 'Species', '9606', (3, 11))	('ipsilateral', 'Var', (74, 85))	('hypertrophy', 'Disease', (136, 147))	('hypertrophy', 'Disease', 'MESH:D006984', (136, 147))	('compensatory', 'MPA', (123, 135))
146074	31417920	Another retrospective cohort study included 1335 patients with T1-3 N1 M0 gallbladder cancer and 1009 patients with intrahepatic CCA from the National Cancer Database.	('intrahepatic CCA', 'Disease', (116, 132))	('patients', 'Species', '9606', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Cancer', 'Disease', 'MESH:D009369', (151, 157))	('Cancer', 'Disease', (151, 157))	('Cancer', 'Phenotype', 'HP:0002664', (151, 157))	('gallbladder cancer', 'Disease', (74, 92))	('gallbladder cancer', 'Disease', 'MESH:D005706', (74, 92))	('patients', 'Species', '9606', (49, 57))	('T1-3 N1 M0', 'Var', (63, 73))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (116, 132))
146082	31417920	Finally, a meta-analysis that included 20 studies and more than 6000 patients suggested that patients with high-risk features such as those with node or margin positivity appeared to derive the clearest benefit from adjuvant strategies.	('margin positivity', 'Var', (153, 170))	('patients', 'Species', '9606', (93, 101))	('patients', 'Species', '9606', (69, 77))	('node', 'Var', (145, 149))
146103	31417920	Alterations in genes encoding fibroblast growth factor receptors (FGFRs) can promote aberrant FGF pathway activation and the development of tumorigenesis.	('FGF pathway', 'Pathway', (94, 105))	('promote', 'PosReg', (77, 84))	('FGFRs', 'Gene', (66, 71))	('Alterations', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('activation', 'PosReg', (106, 116))	('tumor', 'Disease', (140, 145))
146104	31417920	FGFR fusions and translocations constitute driver mutations in CCA and are present in 13% to 17% of intrahepatic CCAs.	('CCA', 'Gene', (113, 116))	('CCA', 'Gene', '2201', (113, 116))	('FGFR', 'Gene', (0, 4))	('fusions', 'Var', (5, 12))	('CCA', 'Gene', (63, 66))	('intrahepatic CCAs', 'Disease', 'MESH:D002780', (100, 117))	('CCA', 'Gene', '2201', (63, 66))	('translocations', 'Var', (17, 31))	('intrahepatic CCAs', 'Disease', (100, 117))
146105	31417920	BGJ398 is an oral selective pan-FGFR inhibitor with activity in tumor models harboring FGFR alterations.	('BGJ398', 'Chemical', 'MESH:C568950', (0, 6))	('tumor', 'Disease', (64, 69))	('BGJ398', 'Gene', (0, 6))	('activity', 'MPA', (52, 60))	('alterations', 'Var', (92, 103))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
146108	31417920	Other agents against FGFR2 resistance mutations have shown activity in patients with advanced CCA.	('activity', 'MPA', (59, 67))	('FGFR2', 'Gene', (21, 26))	('FGFR2', 'Gene', '2263', (21, 26))	('patients', 'Species', '9606', (71, 79))	('CCA', 'Gene', (94, 97))	('mutations', 'Var', (38, 47))	('CCA', 'Gene', '2201', (94, 97))
146109	31417920	The phase I/II basket trial evaluated the novel FGFR inhibitor TAS-120 in 23 patients with FGFR2 fusion and other FGFR-altered CCAs.	('FGFR2', 'Gene', '2263', (91, 96))	('CCA', 'Gene', (127, 130))	('CCA', 'Gene', '2201', (127, 130))	('patients', 'Species', '9606', (77, 85))	('TAS-120', 'Chemical', '-', (63, 70))	('fusion', 'Var', (97, 103))	('FGFR2', 'Gene', (91, 96))
146112	31417920	Mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2, which occur in about 20% of intrahepatic CCAs, constitute promising targets for patients with BTC.	('IDH', 'Gene', '3417', (43, 46))	('IDH2', 'Gene', '3418', (63, 67))	('patients', 'Species', '9606', (149, 157))	('intrahepatic CCAs', 'Disease', (97, 114))	('IDH', 'Gene', (63, 66))	('IDH1', 'Gene', (54, 58))	('IDH', 'Gene', '3417', (54, 57))	('IDH', 'Gene', '3417', (63, 66))	('isocitrate dehydrogenase', 'Gene', (17, 41))	('Mutations', 'Var', (0, 9))	('IDH', 'Gene', (54, 57))	('IDH1', 'Gene', '3417', (54, 58))	('isocitrate dehydrogenase', 'Gene', '3417', (17, 41))	('intrahepatic CCAs', 'Disease', 'MESH:D002780', (97, 114))	('IDH2', 'Gene', (63, 67))	('IDH', 'Gene', (43, 46))	('occur', 'Reg', (75, 80))	('BTC', 'Phenotype', 'HP:0100574', (163, 166))
146113	31417920	Ivosidenib (AG-120) is an oral, selective, reversible inhibitor of mutant IDH1 that is currently being evaluated in phase III studies of CCA and acute myeloid leukemia.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (145, 167))	('IDH1', 'Gene', (74, 78))	('CCA', 'Gene', '2201', (137, 140))	('CCA', 'Gene', (137, 140))	('leukemia', 'Phenotype', 'HP:0001909', (159, 167))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (151, 167))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (145, 167))	('AG-120', 'Chemical', 'MESH:C000627630', (12, 18))	('mutant', 'Var', (67, 73))	('IDH1', 'Gene', '3417', (74, 78))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))	('acute myeloid leukemia', 'Disease', (145, 167))
146114	31417920	Studies of melanoma and colorectal cancer have suggested that tumors with BRAF-activating mutations are sensitive to MEK inhibition.	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('mutations', 'Var', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (24, 41))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('MEK', 'Gene', (117, 120))	('colorectal cancer', 'Disease', (24, 41))	('MEK', 'Gene', '5609', (117, 120))	('colorectal cancer', 'Disease', 'MESH:D015179', (24, 41))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
146117	31417920	The combination of dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) in patients with BRAF V600E- mutant metastatic BTC was recently reported to be active.	('V600E', 'Mutation', 'rs113488022', (104, 109))	('BRAF', 'Gene', '673', (33, 37))	('BTC', 'Phenotype', 'HP:0100574', (129, 132))	('BRAF', 'Gene', (33, 37))	('V600E- mutant', 'Var', (104, 117))	('BRAF', 'Gene', (99, 103))	('dabrafenib', 'Chemical', 'MESH:C561627', (19, 29))	('BRAF', 'Gene', '673', (99, 103))	('patients', 'Species', '9606', (85, 93))	('MEK', 'Gene', (67, 70))	('MEK', 'Gene', '5609', (67, 70))	('trametinib', 'Chemical', 'MESH:C560077', (53, 63))	('metastatic BTC', 'Disease', (118, 132))
146125	31417920	The biologic footprint of mismatch repair-deficient tumors is microsatellite instability (MSI).	('mismatch', 'Var', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('microsatellite instability', 'MPA', (62, 88))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('MSI', 'Disease', 'None', (90, 93))	('deficient tumors', 'Disease', (42, 58))	('deficient tumors', 'Disease', 'MESH:D009369', (42, 58))	('MSI', 'Disease', (90, 93))
146126	31417920	About 3% of CCAs are mismatch repair-deficient/ MSI-high, which makes them susceptible to programmed cell death protein 1 (PD-1) inhibitors.	('PD-1', 'Gene', (123, 127))	('PD-1', 'Gene', '5133', (123, 127))	('MSI', 'Disease', 'None', (48, 51))	('programmed cell death protein 1', 'Gene', '5133', (90, 121))	('MSI', 'Disease', (48, 51))	('CCA', 'Gene', '2201', (12, 15))	('CCA', 'Gene', (12, 15))	('programmed cell death protein 1', 'Gene', (90, 121))	('mismatch repair-deficient/', 'Var', (21, 47))
146167	29208940	Besides, CA19-9 has also been suggested as a prognostic marker for CCA patients undergoing tumor resection and patients receiving chemotherapy.	('CCA', 'Disease', (67, 70))	('patients', 'Species', '9606', (71, 79))	('CA19-9', 'Chemical', 'MESH:C086528', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('CA19-9', 'Var', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('patients', 'Species', '9606', (111, 119))
146191	29208940	Figure 1a, b and d), patients with a more advanced local tumor stage (T2, T3 and T4) had significantly higher CRP levels compared to T1-stage patients (Suppl.	('CRP', 'Gene', (110, 113))	('CRP', 'Gene', '1401', (110, 113))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('T4', 'Var', (81, 83))	('higher', 'PosReg', (103, 109))	('patients', 'Species', '9606', (142, 150))	('tumor', 'Disease', (57, 62))
146215	29208940	For this, we first performed ROC curve analyses which revealed AUC values of 0.649 (CA19-9), 0.602 (CEA), 0.666 (CRP) and 0.534 (leucocyte count) for the differentiation between patient that died during the follow-up period and patients that were still alive (Suppl.	('CEA', 'Gene', '1084', (100, 103))	('0.534', 'Var', (122, 127))	('patient', 'Species', '9606', (178, 185))	('CA19-9', 'Chemical', 'MESH:C086528', (84, 90))	('patients', 'Species', '9606', (228, 236))	('CRP', 'Gene', (113, 116))	('CRP', 'Gene', '1401', (113, 116))	('CEA', 'Gene', (100, 103))	('patient', 'Species', '9606', (228, 235))
146217	29208940	Using these respective cut-off levels, only CA19-9 and CRP but not CEA and the leucocyte showed a significantly impaired long-term survival in patients with serum levels above the respective 50th percentile (Suppl.	('CRP', 'Gene', '1401', (55, 58))	('CA19-9', 'Var', (44, 50))	('CEA', 'Gene', (67, 70))	('CEA', 'Gene', '1084', (67, 70))	('patients', 'Species', '9606', (143, 151))	('long-term survival', 'CPA', (121, 139))	('impaired', 'NegReg', (112, 120))	('CA19-9', 'Chemical', 'MESH:C086528', (44, 50))	('CRP', 'Gene', (55, 58))
146219	29208940	The optimal cut-off values for CA19-9 and CRP were 324.15 U/ml and 7.7 mg/L, respectively which further increased the prognostic potential of these markers (Fig.	('324.15 U/ml', 'Var', (51, 62))	('CA19-9', 'Chemical', 'MESH:C086528', (31, 37))	('CRP', 'Gene', '1401', (42, 45))	('increased', 'PosReg', (104, 113))	('CA19-9', 'Gene', (31, 37))	('prognostic potential', 'MPA', (118, 138))	('CRP', 'Gene', (42, 45))
146259	29208940	In line, in the subgroup of PSC patients analysed in this study, CA19-9 but not CEA significantly correlated with CRP (Suppl.	('patients', 'Species', '9606', (32, 40))	('CRP', 'Gene', '1401', (114, 117))	('CA19-9', 'Chemical', 'MESH:C086528', (65, 71))	('CEA', 'Gene', (80, 83))	('correlated', 'Reg', (98, 108))	('CEA', 'Gene', '1084', (80, 83))	('CA19-9', 'Var', (65, 71))	('PSC', 'Disease', (28, 31))	('CRP', 'Gene', (114, 117))
146261	29208940	As another limitation of CA19-9, it should also be kept in mind that patients with Lewis negative blood type are unable to express CA19-9 and might therefore be diagnosed as "false-negative".	('CA19-9', 'Chemical', 'MESH:C086528', (25, 31))	('CA19-9', 'Chemical', 'MESH:C086528', (131, 137))	('patients', 'Species', '9606', (69, 77))	('unable', 'NegReg', (113, 119))	('CA19-9', 'Var', (131, 137))
146281	29029413	Deletion of the N-SH2 domain (dN1) or point mutation (D61A) of SHP-1 counteracted the effect of SC-43-induced SHP-1 phosphatase activation and antiproliferation ability in CCA cells.	('activation', 'PosReg', (128, 138))	('SHP-1', 'Gene', '15170', (63, 68))	('point mutation', 'Var', (38, 52))	('CCA', 'Phenotype', 'HP:0030153', (172, 175))	('dN1', 'Gene', (30, 33))	('SC-43', 'Chemical', '-', (96, 101))	('SHP-1', 'Gene', '15170', (110, 115))	('SHP-1', 'Gene', (63, 68))	('D61A', 'Mutation', 'p.D61A', (54, 58))	('dN1', 'Gene', '249423', (30, 33))	('SHP-1', 'Gene', (110, 115))	('antiproliferation ability', 'CPA', (143, 168))	('Deletion', 'Var', (0, 8))
146299	29029413	STAT3 is activated by the cytokine IL-6 as well as other growth factors, including epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR) through tyrosine phosphorylation.	('tyrosine phosphorylation', 'Var', (226, 250))	('activated', 'PosReg', (9, 18))	('IL-6', 'Gene', (35, 39))	('tyrosine', 'Chemical', 'MESH:D014443', (226, 234))	('IL-6', 'Gene', '3569', (35, 39))	('EGFR', 'Gene', '1956', (117, 121))	('epidermal growth factor receptor', 'Gene', (83, 115))	('EGFR', 'Gene', (117, 121))	('PDGFR', 'Gene', (211, 216))	('PDGFR', 'Gene', '5159', (211, 216))	('STAT3', 'Gene', '6774', (0, 5))	('platelet-derived growth factor receptor', 'Gene', '5159', (170, 209))	('epidermal growth factor receptor', 'Gene', '1956', (83, 115))	('STAT3', 'Gene', (0, 5))	('platelet-derived growth factor receptor', 'Gene', (170, 209))
146304	29029413	Because of the role of STAT3 in inflammation and cancer development, targeting STAT3 is a rational treatment strategy for CCA.	('inflammation', 'Disease', 'MESH:D007249', (32, 44))	('men', 'Species', '9606', (63, 66))	('CCA', 'Phenotype', 'HP:0030153', (122, 125))	('STAT3', 'Gene', '6774', (23, 28))	('men', 'Species', '9606', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('inflammation', 'Disease', (32, 44))	('STAT3', 'Gene', (23, 28))	('STAT3', 'Gene', '6774', (79, 84))	('targeting', 'Var', (69, 78))	('CCA', 'Disease', (122, 125))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('STAT3', 'Gene', (79, 84))	('cancer', 'Disease', (49, 55))
146309	29029413	Among these derivatives, SC-43 was found to be a more potent SHP-1 agonist than sorafenib.	('SHP-1', 'Gene', (61, 66))	('sorafenib', 'Chemical', 'MESH:D000077157', (80, 89))	('SC-43', 'Chemical', '-', (25, 30))	('SHP-1', 'Gene', '15170', (61, 66))	('SC-43', 'Var', (25, 30))	('agonist', 'PosReg', (67, 74))
146324	29029413	Furthermore, SC-43-induced downregulation of the p-STAT3 signaling pathway in KKU-100 was time-dependent (Figure 2B), as well as in HuCCT-1 and CGCCA (Supplementary Figure 1).	('HuCCT-1', 'CellLine', 'CVCL:0324', (132, 139))	('SC-43', 'Chemical', '-', (13, 18))	('KKU-100', 'Var', (78, 85))	('CCA', 'Phenotype', 'HP:0030153', (146, 149))	('p-STAT3', 'Gene', '6774', (49, 56))	('downregulation', 'NegReg', (27, 41))	('men', 'Species', '9606', (157, 160))	('p-STAT3', 'Gene', (49, 56))
146330	29029413	In summary, we hypothesized that SC-43 had an antiproliferative effect on CCA cells through inhibiting the STAT3 pathway, as well as G2-M arrest by inhibiting cyclin B1 and Cdc2 In our previous study, we found that SC-43 induced cancer cell apoptosis through upregulation of SHP-1 and downregulation of p-STAT3, suggesting that SHP-1 is a target of SC-43.	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('SHP-1', 'Gene', (275, 280))	('downregulation', 'NegReg', (285, 299))	('inhibiting', 'NegReg', (148, 158))	('SC-43', 'Chemical', '-', (215, 220))	('SHP-1', 'Gene', '15170', (328, 333))	('SHP-1', 'Gene', (328, 333))	('SC-43', 'Chemical', '-', (349, 354))	('Cdc2', 'Gene', '983', (173, 177))	('STAT3', 'Gene', (107, 112))	('SC-43', 'Var', (33, 38))	('cancer', 'Disease', (229, 235))	('upregulation', 'PosReg', (259, 271))	('STAT3', 'Gene', (305, 310))	('STAT3', 'Gene', '6774', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('Cdc2', 'Gene', (173, 177))	('p-STAT3', 'Gene', (303, 310))	('SHP-1', 'Gene', '15170', (275, 280))	('cyclin B1', 'Gene', (159, 168))	('cyclin B1', 'Gene', '891', (159, 168))	('STAT3', 'Gene', '6774', (305, 310))	('p-STAT3', 'Gene', '6774', (303, 310))	('SC-43', 'Chemical', '-', (33, 38))	('SC-43', 'Gene', (215, 220))	('CCA', 'Phenotype', 'HP:0030153', (74, 77))	('inhibiting', 'NegReg', (92, 102))
146334	29029413	Furthermore, SC-43 increased the phosphatase activity of SHP-1 in IP-SHP-1 cell lysate from HuCCT-1 cells, suggesting that SC-43 activates SHP-1 through direct interaction with SHP-1 proteins (Figure 3B).	('SHP-1', 'Gene', (139, 144))	('SHP-1', 'Gene', (177, 182))	('SHP-1', 'Gene', '15170', (69, 74))	('SC-43', 'Chemical', '-', (123, 128))	('activates', 'PosReg', (129, 138))	('proteins', 'Protein', (183, 191))	('SHP-1', 'Gene', (57, 62))	('SC-43', 'Chemical', '-', (13, 18))	('SHP-1', 'Gene', '15170', (177, 182))	('HuCCT-1', 'CellLine', 'CVCL:0324', (92, 99))	('SHP-1', 'Gene', (69, 74))	('SHP-1', 'Gene', '15170', (139, 144))	('SC-43', 'Var', (123, 128))	('SHP-1', 'Gene', '15170', (57, 62))	('interaction', 'Interaction', (160, 171))	('phosphatase activity', 'MPA', (33, 53))
146341	29029413	As the activity of SHP-1 was strongly regulated by the auto-inhibited 3D structure, we constructed wild-type, deletion of N-SH2 (dN1), and D61 single mutant (D61A) of SHP-1 to investigate the effect of SC-43 on different SHP-1 statuses (Figure 4A).	('D61A', 'Mutation', 'p.D61A', (158, 162))	('dN1', 'Gene', '249423', (129, 132))	('SHP-1', 'Gene', (167, 172))	('D61', 'Var', (139, 142))	('SHP-1', 'Gene', '15170', (221, 226))	('dN1', 'Gene', (129, 132))	('SC-43', 'Chemical', '-', (202, 207))	('SHP-1', 'Gene', '15170', (19, 24))	('deletion', 'Var', (110, 118))	('N-SH2', 'Gene', (122, 127))	('SHP-1', 'Gene', '15170', (167, 172))	('SHP-1', 'Gene', (221, 226))	('SHP-1', 'Gene', (19, 24))
146342	29029413	The dN1 and D61A mutants resemble open (non-autoinhibition) forms.	('D61A', 'Mutation', 'p.D61A', (12, 16))	('dN1', 'Gene', (4, 7))	('dN1', 'Gene', '249423', (4, 7))	('D61A', 'Var', (12, 16))
146343	29029413	As demonstrated in Figure 4B, SC-43 induced significantly less p-STAT3 downregulation and apoptosis in HuCCT-1 cells expressing the dN1 and D61A mutants than in the wild-type control, suggesting that N-SH2 and PTPase catalytic domain are important for SC-43 induced effects.	('HuCCT-1', 'CellLine', 'CVCL:0324', (103, 110))	('downregulation', 'NegReg', (71, 85))	('mutants', 'Var', (145, 152))	('dN1', 'Gene', (132, 135))	('SC-43', 'Chemical', '-', (252, 257))	('SC-43', 'Chemical', '-', (30, 35))	('D61A', 'Mutation', 'p.D61A', (140, 144))	('PTP', 'Gene', (210, 213))	('p-STAT3', 'Gene', '6774', (63, 70))	('dN1', 'Gene', '249423', (132, 135))	('apoptosis', 'CPA', (90, 99))	('PTP', 'Gene', '26191', (210, 213))	('D61A mutants', 'Var', (140, 152))	('less', 'NegReg', (58, 62))	('p-STAT3', 'Gene', (63, 70))
146344	29029413	The conformational change of SHP-1 induced by dN1 and D61A counteracted the SC-43 effect.	('SHP-1', 'Gene', (29, 34))	('conformational change', 'MPA', (4, 25))	('dN1', 'Gene', (46, 49))	('D61A', 'Var', (54, 58))	('SHP-1', 'Gene', '15170', (29, 34))	('D61A', 'Mutation', 'p.D61A', (54, 58))	('SC-43', 'Chemical', '-', (76, 81))	('dN1', 'Gene', '249423', (46, 49))
146345	29029413	Furthermore, dose-escalation study of transfection of dN1 and D61A suppressed the expression of p-STAT3 and decreased SC-43-induced p-STAT3 inhibition (Figure 4C).	('D61A', 'Var', (62, 66))	('p-STAT3', 'Gene', (132, 139))	('D61A', 'Mutation', 'p.D61A', (62, 66))	('expression', 'MPA', (82, 92))	('dN1', 'Gene', (54, 57))	('decreased', 'NegReg', (108, 117))	('SC-43', 'Chemical', '-', (118, 123))	('p-STAT3', 'Gene', '6774', (96, 103))	('p-STAT3', 'Gene', '6774', (132, 139))	('suppressed', 'NegReg', (67, 77))	('dN1', 'Gene', '249423', (54, 57))	('p-STAT3', 'Gene', (96, 103))
146371	29029413	Furthermore, expression of STAT3 is associated with poor histological differentiation and adverse prognosis in patients with cholangiocarcinoma.	('STAT3', 'Gene', (27, 32))	('cholangiocarcinoma', 'Disease', (125, 143))	('expression', 'Var', (13, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (125, 143))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (125, 143))	('associated', 'Reg', (36, 46))	('STAT3', 'Gene', '6774', (27, 32))	('patients', 'Species', '9606', (111, 119))
146380	29029413	In current study, the hypothesized mechanism of SC-43 was supported by using dN1 (deleted N-SH2) and D61A mutant SHP-1- overexpressing cells; SC-43 exerted less p-STAT3 downregulation and apoptosis-inducing effects in these mutant SHP-1 over-expressing cells, compared to wild-type SHP-1-expressing cells.	('SHP-1', 'Gene', '15170', (231, 236))	('SC-43', 'Chemical', '-', (48, 53))	('SC-43', 'Chemical', '-', (142, 147))	('SHP-1', 'Gene', (282, 287))	('SHP-1', 'Gene', '15170', (113, 118))	('mutant', 'Var', (224, 230))	('apoptosis-inducing effects', 'CPA', (188, 214))	('over-expressing', 'PosReg', (237, 252))	('SHP-1', 'Gene', (231, 236))	('D61A', 'Var', (101, 105))	('SHP-1', 'Gene', (113, 118))	('dN1', 'Gene', (77, 80))	('p-STAT3', 'Gene', (161, 168))	('downregulation', 'NegReg', (169, 183))	('less', 'NegReg', (156, 160))	('SHP-1', 'Gene', '15170', (282, 287))	('D61A', 'Mutation', 'p.D61A', (101, 105))	('p-STAT3', 'Gene', '6774', (161, 168))	('dN1', 'Gene', '249423', (77, 80))
146427	29029413	Smart-pool siRNAs, including control (D-001810-10), SHP-1 (PTPN6, L-009778- 00-0005), and STAT3 were all purchased from Dharmacon (Chicago, IL, USA).	('STAT3', 'Gene', '6774', (90, 95))	('STAT3', 'Gene', (90, 95))	('SHP-1', 'Gene', '15170', (52, 57))	('D-001810-10', 'Var', (38, 49))	('SHP-1', 'Gene', (52, 57))	('PTPN6', 'Gene', (59, 64))	('PTPN6', 'Gene', '5777', (59, 64))
146429	29029413	For mutant-type SHP-1 expression, we generated two plasmids, designated dN1 and D61A, with a truncated N-SH2/PTP domain and aspartic acid at 61 changed to an alanine residue, respectively.	('mutant-type', 'Var', (4, 15))	('SHP-1', 'Gene', (16, 21))	('dN1', 'Gene', (72, 75))	('PTP', 'Gene', (109, 112))	('PTP', 'Gene', '26191', (109, 112))	('D61A', 'Mutation', 'p.D61A', (80, 84))	('dN1', 'Gene', '249423', (72, 75))	('aspartic acid at 61 changed to an alanine', 'Mutation', 'p.D61A', (124, 165))	('SHP-1', 'Gene', '15170', (16, 21))
146453	29029413	This study reinforced the hypothesis that targeting STAT3 in this inflammatory malignancy may be a useful therapeutic strategy, and provides an innovative approach to CCA management.	('malignancy', 'Disease', 'MESH:D009369', (79, 89))	('STAT3', 'Gene', (52, 57))	('malignancy', 'Disease', (79, 89))	('CCA', 'Phenotype', 'HP:0030153', (167, 170))	('men', 'Species', '9606', (177, 180))	('CCA', 'Disease', (167, 170))	('targeting', 'Var', (42, 51))	('STAT3', 'Gene', '6774', (52, 57))
146539	27439662	The National Cancer Data Base (NCDB-2010-2012) was reviewed for patients with ICCA and reported CA19-9.	('patients', 'Species', '9606', (64, 72))	('Cancer', 'Disease', (13, 19))	('Cancer', 'Disease', 'MESH:D009369', (13, 19))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('ICCA', 'Disease', (78, 82))	('CA19-9', 'Var', (96, 102))
146559	27439662	CA19-9 is a readily available and inexpensive measure of tumor biology, quantifiable in the pre-operative setting without invasive tests:making it an ideal parameter for use in a staging system.	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('CA19-9', 'Var', (0, 6))
146569	27439662	CA19-9 is reported in the biliary NCDB PUF as site-specific-factor 12 and is the highest value documented in the medical record prior to treatment.	('PUF', 'Gene', '4831', (39, 42))	('PUF', 'Gene', (39, 42))	('CA19-9', 'Var', (0, 6))
146587	27439662	Patients with elevated CA19-9 were equally likely to receive chemotherapy and radiation but less likely to undergo surgery (83.0% vs. 67.0% having no surgery, P < 0.001 Table I).	('Patients', 'Species', '9606', (0, 8))	('CA19-9', 'Gene', (23, 29))	('less', 'NegReg', (92, 96))	('elevated', 'Var', (14, 22))
146596	27439662	The negative impact of high CA19-9 on prognosis is similar in magnitude to nodal metastases and positive margin resection:both of which are accepted predictors of poor outcome.	('CA19-9', 'Gene', (28, 34))	('metastases', 'Disease', 'MESH:D009362', (81, 91))	('high', 'Var', (23, 27))	('metastases', 'Disease', (81, 91))
146626	29862278	Interestingly, high expression of Pontin was significantly associated with lymph node metastasis (p = 0.011) and tumor node metastasis (TNM) stage (p = 0.005).	('high', 'Var', (15, 19))	('tumor node metastasis', 'Disease', (113, 134))	('Pontin', 'Gene', '8607', (34, 40))	('lymph node metastasis', 'CPA', (75, 96))	('associated', 'Reg', (59, 69))	('tumor node metastasis', 'Disease', 'MESH:D009362', (113, 134))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Pontin', 'Gene', (34, 40))
146643	29862278	Aberrant Pontin expression has been reported in liver cancer, colon carcinoma, renal cell carcinoma (RCC), and acute myeloid leukemia (AML).	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('RCC', 'Disease', (101, 104))	('Pontin', 'Gene', '8607', (9, 15))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (111, 133))	('Aberrant', 'Var', (0, 8))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (79, 99))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('colon carcinoma', 'Disease', (62, 77))	('leukemia', 'Phenotype', 'HP:0001909', (125, 133))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (111, 133))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (117, 133))	('AML', 'Disease', 'MESH:D015470', (135, 138))	('colon carcinoma', 'Disease', 'MESH:D015179', (62, 77))	('AML', 'Phenotype', 'HP:0004808', (135, 138))	('AML', 'Disease', (135, 138))	('liver cancer', 'Disease', 'MESH:D006528', (48, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('renal cell carcinoma', 'Disease', (79, 99))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (79, 99))	('liver cancer', 'Phenotype', 'HP:0002896', (48, 60))	('Pontin', 'Gene', (9, 15))	('reported', 'Reg', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('liver cancer', 'Disease', (48, 60))	('acute myeloid leukemia', 'Disease', (111, 133))
146699	29862278	Multivariate analyses showed that only high Pontin expression (p = 0.001) and lymph node metastasis (p = 0.005) were confirmed as independent prognostic indicators for HC patients, suggesting that high Pontin expression is a high-risk factor for poor prognosis (Table 3).	('Pontin', 'Gene', '8607', (44, 50))	('high', 'Var', (197, 201))	('Pontin', 'Gene', '8607', (202, 208))	('patients', 'Species', '9606', (171, 179))	('Pontin', 'Gene', (44, 50))	('Pontin', 'Gene', (202, 208))
146707	29862278	Invading cells was quantified by staining, and the results revealed that Pontin depletion in RBE and QBC939 cells significantly restrained the invasive ability of cells (Figures 4(c) and 4(d)).	('QBC939', 'Gene', (101, 107))	('restrained', 'NegReg', (128, 138))	('invasive ability of cells', 'CPA', (143, 168))	('Pontin', 'Gene', (73, 79))	('Pontin', 'Gene', '8607', (73, 79))	('QBC939', 'CellLine', 'CVCL:6942', (101, 107))	('depletion', 'Var', (80, 89))
146710	29862278	In addition, the presence of tumor markers is related to disease progression and OS.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('related', 'Reg', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('disease', 'Disease', (57, 64))	('presence', 'Var', (17, 25))
146720	29862278	A previous study showed that two single-nucleotide polymorphisms were identified in the Pontin gene that were related to an increased risk of ovarian carcinoma.	('ovarian carcinoma', 'Disease', (142, 159))	('single-nucleotide polymorphisms', 'Var', (33, 64))	('related to', 'Reg', (110, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('Pontin', 'Gene', (88, 94))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (142, 159))	('Pontin', 'Gene', '8607', (88, 94))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (142, 159))
146721	29862278	These polymorphisms may be the cause of the variations in the expression of Pontin.	('expression', 'MPA', (62, 72))	('Pontin', 'Gene', '8607', (76, 82))	('Pontin', 'Gene', (76, 82))	('polymorphisms', 'Var', (6, 19))
146731	29862278	Therefore, high expression of Pontin was correlated significantly with disease progression, including tumor invasion and lymph node metastasis.	('lymph node metastasis', 'CPA', (121, 142))	('Pontin', 'Gene', '8607', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('disease progression', 'CPA', (71, 90))	('Pontin', 'Gene', (30, 36))	('high', 'Var', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('correlated', 'Reg', (41, 51))
146733	29862278	Moreover, high Pontin expression was an independent prognostic indicator for poor survival outcomes of HC, which was confirmed by the multivariate Cox proportional hazards model.	('Pontin', 'Gene', (15, 21))	('Pontin', 'Gene', '8607', (15, 21))	('poor', 'NegReg', (77, 81))	('high', 'Var', (10, 14))
146743	29862278	A previous study reported that the nuclear colocalization of Pontin and beta-catenin was involved in the progression of colon cancer, and Pontin depletion was found to significantly decrease nuclear beta-catenin in renal cell carcinoma cell lines.	('decrease', 'NegReg', (182, 190))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (215, 235))	('Pontin', 'Gene', '8607', (138, 144))	('beta-catenin', 'Gene', (199, 211))	('beta-catenin', 'Gene', '1499', (199, 211))	('beta-catenin', 'Gene', (72, 84))	('involved', 'Reg', (89, 97))	('beta-catenin', 'Gene', '1499', (72, 84))	('colon cancer', 'Phenotype', 'HP:0003003', (120, 132))	('Pontin', 'Gene', (61, 67))	('depletion', 'Var', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('renal cell carcinoma', 'Disease', (215, 235))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (215, 235))	('colon cancer', 'Disease', 'MESH:D015179', (120, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('nuclear colocalization', 'MPA', (35, 57))	('Pontin', 'Gene', '8607', (61, 67))	('Pontin', 'Gene', (138, 144))	('colon cancer', 'Disease', (120, 132))
146747	29862278	In our study, we showed that high Pontin expression had a significant prognostic value for patients with HC.	('high', 'Var', (29, 33))	('patients', 'Species', '9606', (91, 99))	('Pontin', 'Gene', (34, 40))	('Pontin', 'Gene', '8607', (34, 40))
146749	29862278	reported that p53 mutation was also associated with poor survival in HC.	('p53', 'Gene', '7157', (14, 17))	('mutation', 'Var', (18, 26))	('p53', 'Gene', (14, 17))
146758	29862278	In this respect, antagonizing the ATPase activity of Pontin appears to be an attractive option and could be feasible, and a small molecule antagonizing the ATPase activity of Pontin has been discovered.	('Pontin', 'Gene', '8607', (175, 181))	('antagonizing', 'Var', (17, 29))	('ATP', 'Chemical', 'MESH:D000255', (34, 37))	('Pontin', 'Gene', (53, 59))	('ATP', 'Chemical', 'MESH:D000255', (156, 159))	('Pontin', 'Gene', (175, 181))	('ATPase', 'Protein', (34, 40))	('activity', 'MPA', (41, 49))	('Pontin', 'Gene', '8607', (53, 59))
146760	29862278	In conclusion, the present study suggested that high Pontin expression was related to unfavorable clinicopathological factors and decreased survival in human HC.	('survival', 'CPA', (140, 148))	('human', 'Species', '9606', (152, 157))	('Pontin', 'Gene', (53, 59))	('high', 'Var', (48, 52))	('decreased', 'NegReg', (130, 139))	('Pontin', 'Gene', '8607', (53, 59))
146769	29732001	High PD-L1 expression was associated with poor histopathological classification (P = 0.034), and low E-cadherin (P = 0.001), high N-cadherin (P = 0.044), high vimentin (P < 0.001) and high ZEB1 (P = 0.036) expression.	('vimentin', 'Gene', '7431', (159, 167))	('N-cadherin', 'Gene', (130, 140))	('E-cadherin', 'Gene', (101, 111))	('high', 'Protein', (184, 188))	('High', 'Var', (0, 4))	('poor histopathological classification', 'CPA', (42, 79))	('vimentin', 'Gene', (159, 167))	('expression', 'MPA', (11, 21))	('expression', 'MPA', (206, 216))	('PD-L1', 'Gene', (5, 10))	('PD-L1', 'Gene', '29126', (5, 10))	('E-cadherin', 'Gene', '999', (101, 111))	('N-cadherin', 'Gene', '1000', (130, 140))	('ZEB1', 'Gene', (189, 193))	('low', 'NegReg', (97, 100))	('ZEB1', 'Gene', '6935', (189, 193))
146798	29732001	We immunohistochemically analyzed PD-L1 expression on tumor cells utilizing 2 types of monoclonal antibodies against PD-L1: SP142 and E1L3N (Figure 2).	('PD-L1', 'Gene', '29126', (117, 122))	('E1L3N', 'Var', (134, 139))	('SP142', 'Chemical', '-', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('PD-L1', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('PD-L1', 'Gene', (117, 122))	('tumor', 'Disease', (54, 59))	('PD-L1', 'Gene', '29126', (34, 39))
146799	29732001	SP142 detected PD-L1 expression in 42 patients (36%), but did not detect any PD-L1 expression in the tumor cells of 75 patients (64%) (Supplementary Figure 1A).	('detected', 'Reg', (6, 14))	('PD-L1', 'Gene', (15, 20))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('PD-L1', 'Gene', (77, 82))	('expression', 'MPA', (21, 31))	('PD-L1', 'Gene', '29126', (15, 20))	('PD-L1', 'Gene', '29126', (77, 82))	('SP142', 'Chemical', '-', (0, 5))	('patients', 'Species', '9606', (38, 46))	('SP142', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
146822	29732001	reported that tumors with somatic mutations due to mismatch-repair defects including cholangiocarcinoma, may be susceptible to immune checkpoint blockade.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (85, 103))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('tumors', 'Disease', (14, 20))	('mismatch-repair defects', 'Var', (51, 74))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('cholangiocarcinoma', 'Disease', (85, 103))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
146825	29732001	The use of the optimal antibody in IHC analyses, demonstrated that high PD-L1 expression in eCCA was an independent poor prognostic factor.	('expression', 'MPA', (78, 88))	('high', 'Var', (67, 71))	('PD-L1', 'Gene', (72, 77))	('PD-L1', 'Gene', '29126', (72, 77))
146832	29732001	This difference in the specificity of PD-L1 membranous staining may be the reason why SP142 staining reflected patient prognosis better than E1L3N staining.	('SP142', 'Var', (86, 91))	('PD-L1', 'Gene', '29126', (38, 43))	('PD-L1', 'Gene', (38, 43))	('patient', 'Species', '9606', (111, 118))	('SP142', 'Chemical', '-', (86, 91))
146838	29732001	demonstrated the regression of metastatic cholangiocarcinoma following the infusion of CD4+ T cells specific to a neo-antigen (mutated ERBB2IP).	('cholangiocarcinoma', 'Disease', (42, 60))	('ERBB2IP', 'Gene', (135, 142))	('CD4', 'Gene', (87, 90))	('CD4', 'Gene', '920', (87, 90))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (42, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (42, 60))	('mutated', 'Var', (127, 134))	('ERBB2IP', 'Gene', '55914', (135, 142))
146845	29732001	reported significantly better prognosis in the group with high HLA class I expression and low PD-L1 expression in iCCA.	('PD-L1', 'Gene', (94, 99))	('better', 'PosReg', (23, 29))	('HLA class I', 'Protein', (63, 74))	('PD-L1', 'Gene', '29126', (94, 99))	('expression', 'MPA', (100, 110))	('high', 'Var', (58, 62))	('low', 'NegReg', (90, 93))	('expression', 'MPA', (75, 85))
146846	29732001	reported that patients with high HLA class I expression had a higher overall survival probability and that HLA class I expression correlated with the number of TILs in biliary tract cancers.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (168, 188))	('HLA class I', 'Gene', (107, 118))	('biliary tract cancers', 'Disease', 'MESH:D001661', (168, 189))	('biliary tract cancers', 'Disease', (168, 189))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('higher', 'PosReg', (62, 68))	('expression', 'MPA', (45, 55))	('correlated', 'Reg', (130, 140))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (14, 22))	('HLA class I', 'Protein', (33, 44))
146904	29023935	Last, we identified mRNA targets for miR-335 that are down-regulated following treatments with EV-miR-335-5p.	('EV-miR-335-5p', 'Var', (95, 108))	('5p', 'Chemical', '-', (106, 108))	('miR-335', 'Gene', (37, 44))	('down-regulated', 'NegReg', (54, 68))
146921	29023935	We concluded that disrupting the cross-talk between liver fibroblasts/activated stellate cells/CAFs and cancer cells may potentially open a novel avenue to improve clinical outcomes.	('CAF', 'Gene', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CAF', 'Gene', '8850', (95, 98))	('disrupting', 'Var', (18, 28))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', (104, 110))	('improve', 'PosReg', (156, 163))
146923	29023935	Here, we demonstrated that EVs loaded with miR-335-5p (EV-miR-335) can decrease cancer growth and invasion in vitro and in vivo.	('rat', 'Species', '10116', (16, 19))	('decrease', 'NegReg', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('miR-335-5p', 'Var', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('5p', 'Chemical', '-', (51, 53))	('cancer', 'Disease', (80, 86))
146924	29023935	We have also shown that EV-miR-335-5p can be utilized successfully in vivo to induce HCC shrinking.	('induce', 'PosReg', (78, 84))	('HCC', 'Gene', '619501', (85, 88))	('EV-miR-335-5p', 'Var', (24, 37))	('5p', 'Chemical', '-', (35, 37))	('HCC', 'Gene', (85, 88))
146936	29023935	Real time PCR with miR-335-5p primers identified in excess of 6,000 fold more miR-335-5p when EVs were present, suggesting that all miR-335-5p is associated with EVs and almost nothing exists outside of EVs (Supplementary Figure S1).	('miR-335-5p', 'Var', (132, 142))	('5p', 'Chemical', '-', (140, 142))	('associated', 'Reg', (146, 156))	('EVs', 'Disease', (162, 165))	('5p', 'Chemical', '-', (27, 29))	('5p', 'Chemical', '-', (86, 88))
146944	29023935	The successful packaging of Cre into EVs by LX2 cells, followed by the successful uptake of these exosomes by MHCC97L and finally utilization of Cre by these cancer cells would result in a deletion event between the 2 loxp sites of MHCC97L.	('HCC', 'Gene', '619501', (111, 114))	('HCC', 'Gene', (233, 236))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('result in', 'Reg', (177, 186))	('cancer', 'Disease', (158, 164))	('deletion event', 'Var', (189, 203))	('HCC', 'Gene', '619501', (233, 236))	('HCC', 'Gene', (111, 114))	('LX2', 'CellLine', 'CVCL:5792', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
146955	29023935	MHCC97H and MHCC97L cells were transfected with miR-335-5p mimic or.	('HCC', 'Gene', (13, 16))	('HCC', 'Gene', '619501', (1, 4))	('HCC', 'Gene', '619501', (13, 16))	('miR-335-5p mimic', 'Var', (48, 64))	('5p', 'Chemical', '-', (56, 58))	('HCC', 'Gene', (1, 4))
146957	29023935	In addition, RNA was extracted from mouse tumors treated with miR-335 or NSM, respectively.	('miR-335', 'Var', (62, 69))	('tumors', 'Disease', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('mouse', 'Species', '10090', (36, 41))
146967	29023935	We have chosen to study miR-335-5p due to these its reported cancer suppressing and anti-fibrotic effects.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('5p', 'Chemical', '-', (32, 34))	('cancer', 'Disease', (61, 67))	('anti-fibrotic effects', 'CPA', (84, 105))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('miR-335-5p', 'Var', (24, 34))
146968	29023935	In the current study, we focused on the delivery of miR-335-5p to HCC cells by utilizing EVs.	('miR-335-5p', 'Var', (52, 62))	('HCC', 'Gene', (66, 69))	('HCC', 'Gene', '619501', (66, 69))	('5p', 'Chemical', '-', (60, 62))
146969	29023935	First, we assessed baseline levels of miR-335 in LX2, as well as in several HCC cell lines when cultured individually.	('HCC', 'Gene', '619501', (76, 79))	('LX2', 'CellLine', 'CVCL:5792', (49, 52))	('miR-335', 'Var', (38, 45))	('HCC', 'Gene', (76, 79))
146970	29023935	We found that the level of miR-335 was higher in LX2 cultured by themselves vs. HepG2, MHCC97L, MHCC97H and Huh7 liver cancer cells cultured by themselves, respectively (Figure 1A).	('HepG2', 'CellLine', 'CVCL:0027', (80, 85))	('higher', 'PosReg', (39, 45))	('liver cancer', 'Disease', (113, 125))	('HCC', 'Gene', '619501', (88, 91))	('Huh7', 'Gene', (108, 112))	('LX2', 'CellLine', 'CVCL:5792', (49, 52))	('level', 'MPA', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('Huh7', 'Gene', '284424', (108, 112))	('HCC', 'Gene', (97, 100))	('liver cancer', 'Phenotype', 'HP:0002896', (113, 125))	('liver cancer', 'Disease', 'MESH:D006528', (113, 125))	('HCC', 'Gene', '619501', (97, 100))	('HCC', 'Gene', (88, 91))	('miR-335', 'Var', (27, 34))
146977	29023935	We hypothesized that an etiologic role for miR-335-5p in HCC development (in particular in a background of fibrosis) might be accompanied by simultaneous downregulation both in cancer cells and stromal cells.	('cancer', 'Disease', (177, 183))	('HCC', 'Gene', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('miR-335-5p', 'Var', (43, 53))	('downregulation', 'NegReg', (154, 168))	('HCC', 'Gene', '619501', (57, 60))	('fibrosis', 'Disease', 'MESH:D005355', (107, 115))	('fibrosis', 'Disease', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('5p', 'Chemical', '-', (51, 53))
146983	29023935	In order to investigate the potential role of miR-335-5p in HCC growth and metastasis, HepG2, MHCC97H, MHCC97L and Huh7 cells were transfected with miR-335-5p mimics and negative control (NSM).	('HCC', 'Gene', '619501', (95, 98))	('HCC', 'Gene', '619501', (60, 63))	('miR-335-5p', 'Var', (148, 158))	('HCC', 'Gene', '619501', (104, 107))	('5p', 'Chemical', '-', (156, 158))	('HepG2', 'CellLine', 'CVCL:0027', (87, 92))	('5p', 'Chemical', '-', (54, 56))	('HCC', 'Gene', (104, 107))	('Huh7', 'Gene', (115, 119))	('Huh7', 'Gene', '284424', (115, 119))	('HCC', 'Gene', (95, 98))	('HCC', 'Gene', (60, 63))
146985	29023935	The proliferation assays showed that miR-335-5p restoration markedly inhibited cell growth in each of the 4 HCC cell lines tested (Figure 2A) when compared with control NSM transfected cells.	('cell growth in', 'CPA', (79, 93))	('miR-335-5p', 'Var', (37, 47))	('rat', 'Species', '10116', (53, 56))	('HCC', 'Gene', (108, 111))	('rat', 'Species', '10116', (11, 14))	('inhibited', 'NegReg', (69, 78))	('5p', 'Chemical', '-', (45, 47))	('HCC', 'Gene', '619501', (108, 111))
146986	29023935	The transwell assay demonstrated significant cell invasion inhibition in the miR-335-5p transfected cells compared with their control counterparts (Figure 2B, C).	('cell invasion inhibition', 'CPA', (45, 69))	('rat', 'Species', '10116', (27, 30))	('miR-335-5p transfected', 'Var', (77, 99))	('5p', 'Chemical', '-', (85, 87))
146987	29023935	We conclude that miR-335-5p exerts its anti-cancer effects through inhibiting the growth as well as the invasion of HCC cells.	('HCC', 'Gene', (116, 119))	('growth', 'CPA', (82, 88))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('HCC', 'Gene', '619501', (116, 119))	('miR-335-5p', 'Var', (17, 27))	('5p', 'Chemical', '-', (25, 27))	('inhibiting', 'NegReg', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
146988	29023935	We transfected LX2 cells with miR-335-5p or NSM, respectively, then co-cultured these cells with each of the following 4 HCC cell lines: HepG2, MHCC97H, MHCC97L and Huh7.	('HCC', 'Gene', '619501', (121, 124))	('Huh7', 'Gene', (165, 169))	('HCC', 'Gene', (154, 157))	('Huh7', 'Gene', '284424', (165, 169))	('HCC', 'Gene', '619501', (154, 157))	('HCC', 'Gene', (145, 148))	('miR-335-5p', 'Var', (30, 40))	('HCC', 'Gene', (121, 124))	('LX2', 'CellLine', 'CVCL:5792', (15, 18))	('5p', 'Chemical', '-', (38, 40))	('HepG2', 'CellLine', 'CVCL:0027', (137, 142))	('HCC', 'Gene', '619501', (145, 148))
146990	29023935	We found that each of the 4 cancer cell lines proliferated less when co-cultured with LX2 cells over-expressing miR-335 vs. control (Figure 3A).	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('proliferated', 'CPA', (46, 58))	('LX2', 'CellLine', 'CVCL:5792', (86, 89))	('rat', 'Species', '10116', (53, 56))	('less', 'NegReg', (59, 63))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('miR-335', 'Var', (112, 119))	('over-expressing', 'PosReg', (96, 111))	('cancer', 'Disease', (28, 34))
146991	29023935	We further explored the invasion ability of cancer cells when co-cultured with LX2-miR-335-5p or LX2-NSM.	('5p', 'Chemical', '-', (91, 93))	('cancer', 'Disease', (44, 50))	('LX2', 'CellLine', 'CVCL:5792', (79, 82))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('LX2', 'CellLine', 'CVCL:5792', (97, 100))	('LX2-miR-335-5p', 'Var', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
146992	29023935	We found that co-culturing with LX2 cells transfected with miR-335-5p, cancer cells invaded less vs. control.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('less', 'NegReg', (92, 96))	('5p', 'Chemical', '-', (67, 69))	('LX2', 'CellLine', 'CVCL:5792', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('invaded', 'CPA', (84, 91))	('miR-335-5p', 'Var', (59, 69))
146994	29023935	We concluded that up-regulation of miR-335-5p in fibroblasts is sufficient to inhibit growth and invasion in neighboring cancer cells.	('miR-335-5p', 'Var', (35, 45))	('up-regulation', 'PosReg', (18, 31))	('5p', 'Chemical', '-', (43, 45))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('inhibit', 'NegReg', (78, 85))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
146996	29023935	Data presented above suggested that miR-335-5p might be actively shuttled between fibroblasts and cancer cells in our co-culture system.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('miR-335-5p', 'Var', (36, 46))	('5p', 'Chemical', '-', (44, 46))	('cancer', 'Disease', (98, 104))
147007	29023935	To study the intercellular EV exchange in vivo, we first established xenograft subcutaneous tumors in NOD Scid Gamma (NSG) mice with HepG2-loxp-dsRed-loxp-Stop-eGFP, MHCC97H-loxp-dsRed-loxp-Stop-eGFP and MHCC97L-loxp-dsRed-loxp-Stop-eGFP cells, respectively.	('HepG2-loxp-dsRed-loxp-Stop-eGFP', 'Var', (133, 164))	('HCC', 'Gene', '619501', (205, 208))	('HCC', 'Gene', (167, 170))	('subcutaneous tumors', 'Disease', (79, 98))	('HepG2', 'CellLine', 'CVCL:0027', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('HCC', 'Gene', '619501', (167, 170))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (79, 98))	('HCC', 'Gene', (205, 208))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (79, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('mice', 'Species', '10090', (123, 127))
147013	29023935	As shown in Figure 5D, dsRed was detected in lysate from all tumors, while GFP was detected only in lysates from mouse tumors treated with EV-Cre.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('EV-Cre', 'Chemical', '-', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('dsRed', 'Var', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('mouse', 'Species', '10090', (113, 118))
147020	29023935	We noted MHCC97H spheroids treated with EV-miR-335-5p invaded the surrounding Matrigel significantly less vs. spheroids treated with the control EV-NSM (Figure 6A, B).	('less', 'NegReg', (101, 105))	('EV-NSM', 'Chemical', '-', (145, 151))	('HCC', 'Gene', (10, 13))	('EV-miR-335-5p', 'Var', (40, 53))	('HCC', 'Gene', '619501', (10, 13))	('5p', 'Chemical', '-', (51, 53))
147021	29023935	To further delineate whether EV transfer of fibroblast-derived miR-335-5p could impact HCC growth in vivo, MHCC97H cells (2x106) were injected subcutaneously into 6-week old female NSG mice.	('miR-335-5p', 'Var', (63, 73))	('HCC', 'Gene', '619501', (87, 90))	('5p', 'Chemical', '-', (71, 73))	('mice', 'Species', '10090', (185, 189))	('HCC', 'Gene', (87, 90))	('HCC', 'Gene', (108, 111))	('impact', 'Reg', (80, 86))	('HCC', 'Gene', '619501', (108, 111))
147022	29023935	When tumors reached 5mm in diameter, EVs that were transiently transfected with miR-335-5p or negative control were quantified.	('tumors', 'Disease', (5, 11))	('miR-335-5p', 'Var', (80, 90))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('5p', 'Chemical', '-', (88, 90))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
147026	29023935	To verify that, indeed, the levels of miR-335-5p are higher in tumors that grew less vs. control tumors, we quantified its levels by RT-PCR.	('levels', 'MPA', (28, 34))	('grew less', 'CPA', (75, 84))	('5p', 'Chemical', '-', (46, 48))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('miR-335-5p', 'Var', (38, 48))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
147027	29023935	We found that levels of miR-335-5p were approximately 30 fold higher in tumors that were treated with EV-miR-335 vs. control (Figure 6F).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('levels', 'MPA', (14, 20))	('5p', 'Chemical', '-', (32, 34))	('miR-335-5p', 'MPA', (24, 34))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('higher', 'PosReg', (62, 68))	('EV-miR-335', 'Var', (102, 112))
147028	29023935	To investigate the mechanism of miR-335-5p meditated tumor inhibition, we assayed for ki67 and caspase-3 in slides prepared from the tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('ki67', 'Gene', '17345', (86, 90))	('caspase-3', 'Gene', '836', (95, 104))	('tumors', 'Disease', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('miR-335-5p', 'Var', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('5p', 'Chemical', '-', (40, 42))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('caspase-3', 'Gene', (95, 104))	('ki67', 'Gene', (86, 90))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', (53, 58))
147030	29023935	These data suggest that EV-miR-335-5p inhibits tumor growth in vivo through decreased proliferation as well as increased apoptosis.	('increased', 'PosReg', (111, 120))	('inhibits', 'NegReg', (38, 46))	('decreased', 'NegReg', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('EV-miR-335-5p', 'Var', (24, 37))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('apoptosis', 'CPA', (121, 130))	('5p', 'Chemical', '-', (35, 37))	('tumor', 'Disease', (47, 52))	('rat', 'Species', '10116', (93, 96))
147032	29023935	In addition, mouse xenograft tumors from mice treated with EV-miR-335-5p as well as control, respectively, were collected.	('5p', 'Chemical', '-', (70, 72))	('mouse', 'Species', '10090', (13, 18))	('mice', 'Species', '10090', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('EV-miR-335-5p', 'Var', (59, 72))	('tumors', 'Disease', (29, 35))
147037	29023935	Similarly, one mouse tumor was treated with EV-NSM and the other with EV-miR-335-5p.	('EV-miR-335-5p', 'Var', (70, 83))	('tumor', 'Disease', (21, 26))	('EV-NSM', 'Chemical', '-', (44, 50))	('5p', 'Chemical', '-', (81, 83))	('mouse', 'Species', '10090', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
147038	29023935	Intra tumoral injections with EV-NSM or EV-miR-335-5p were performed twice a week for duration of 4 weeks.	('rat', 'Species', '10116', (88, 91))	('tumoral', 'Disease', (6, 13))	('tumoral', 'Disease', 'MESH:D009369', (6, 13))	('EV-miR-335-5p', 'Var', (40, 53))	('EV-NSM', 'Chemical', '-', (30, 36))	('5p', 'Chemical', '-', (51, 53))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
147039	29023935	RNA from cell lines (a total of 4 samples) and from mouse tumors (a total of 4 samples) were used to identify differentially expressed mRNA species between NSM and miR-335-5p treated samples.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('mouse', 'Species', '10090', (52, 57))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('miR-335-5p', 'Var', (164, 174))	('5p', 'Chemical', '-', (172, 174))	('mRNA species', 'MPA', (135, 147))
147041	29023935	Bioinformatics analyses identified 13 genes which were consistently and uniformly down-regulated in the 4 RNA samples treated with miR-335-5p.	('miR-335-5p', 'Var', (131, 141))	('5p', 'Chemical', '-', (139, 141))	('down-regulated', 'NegReg', (82, 96))
147042	29023935	Given how strict the determination of these putative targets was (in vitro - Figure 8 A and B, as well as in vivo -Figure 8 C and D, each on 2 separate cell lines), it is likely that these targets are indeed down-regulated by miR-335-5p and involved in its downstream effects.	('rat', 'Species', '10116', (147, 150))	('down-regulated', 'NegReg', (208, 222))	('miR-335-5p', 'Var', (226, 236))	('5p', 'Chemical', '-', (234, 236))
147050	29023935	Conversely, up-regulation of miR-335-5p in cancer cells, or in neighboring fibroblasts, should result in cancer repression.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('miR-335-5p', 'Var', (29, 39))	('5p', 'Chemical', '-', (37, 39))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('result in', 'Reg', (95, 104))	('up-regulation', 'PosReg', (12, 25))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
147051	29023935	We have noted such cancer repression (invasion as well as growth) when miR-335-5p has been up-regulated either in cancer cells or in fibroblasts.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('5p', 'Chemical', '-', (79, 81))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('miR-335-5p', 'Var', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('up-regulated', 'PosReg', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Disease', (114, 120))
147054	29023935	Previously published work showed that that miR-335-5p is 1) downregulated in liver cancer cells; and 2) downregulated in activated, collagen producing stellate cells vs. inactive cells.	('liver cancer', 'Disease', 'MESH:D006528', (77, 89))	('liver cancer', 'Disease', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('miR-335-5p', 'Var', (43, 53))	('downregulated', 'NegReg', (104, 117))	('5p', 'Chemical', '-', (51, 53))	('downregulated', 'NegReg', (60, 73))	('liver cancer', 'Phenotype', 'HP:0002896', (77, 89))
147057	29023935	Furthermore, it is formally possible that, through a yet to be discovered mechanism, the symbiotic cancer cell-stromal cell environment requires low levels of miR-335-5p for successful cancer genesis and development.	('miR-335-5p', 'Var', (159, 169))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('5p', 'Chemical', '-', (167, 169))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('development', 'CPA', (204, 215))	('cancer', 'Disease', (185, 191))
147058	29023935	In strong support of this hypothesis are our findings that upregulation of miR-335-5p in either cancer cells, or in stromal cells, is sufficient to inhibit HCC growth and/or invasion (Figures 2, 3, 4 and 6).	('inhibit', 'NegReg', (148, 155))	('HCC', 'Gene', '619501', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('invasion', 'CPA', (174, 182))	('miR-335-5p', 'Var', (75, 85))	('HCC', 'Gene', (156, 159))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('upregulation', 'PosReg', (59, 71))	('cancer', 'Disease', (96, 102))	('5p', 'Chemical', '-', (83, 85))
147060	29023935	Indeed, when miR-335-5p was directly up-regulated in EVs and delivered to cancer cells, a similar effect was noted.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('up-regulated', 'PosReg', (37, 49))	('cancer', 'Disease', (74, 80))	('miR-335-5p', 'Var', (13, 23))	('5p', 'Chemical', '-', (21, 23))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
147061	29023935	Building on these observations, we verified that EVs can be utilized as vehicles to deliver miR-335-5p in vivo to cancer cells, as it has been reported previously by our group in cholangiocarcinoma.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (179, 197))	('miR-335-5p', 'Var', (92, 102))	('5p', 'Chemical', '-', (100, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (179, 197))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('cholangiocarcinoma', 'Disease', (179, 197))	('cancer', 'Disease', (114, 120))
147077	29023935	While we took first steps towards finding miR-335-5p targets in an unbiased fashion, further work is necessary should miR-335-5p be considered as a potential HCC therapeutics.	('miR-335-5p', 'Var', (118, 128))	('HCC', 'Gene', (158, 161))	('5p', 'Chemical', '-', (50, 52))	('5p', 'Chemical', '-', (126, 128))	('HCC', 'Gene', '619501', (158, 161))
147152	30783369	MRE has been shown to predict liver decompensation in a large single-centre retrospective study involving 266 PSC patients with median follow-up of 2 years.	('predict', 'Reg', (22, 29))	('liver decompensation', 'Disease', (30, 50))	('PSC', 'Gene', '100653366', (110, 113))	('PSC', 'Gene', (110, 113))	('patients', 'Species', '9606', (114, 122))	('MRE', 'Var', (0, 3))
147178	30783369	ERCP: Craig et al retrospectively reviewed ERCP cholangiograms of a cohort of 174 PSC patients with relatively advanced disease and found that both high-grade intrahepatic duct strictures and diffuse intrahepatic duct strictures were associated with a lower 3-year survival.	('PSC', 'Gene', (82, 85))	('patients', 'Species', '9606', (86, 94))	('intrahepatic duct', 'Phenotype', 'HP:0006571', (159, 176))	('high-grade', 'Var', (148, 158))	('3-year survival', 'MPA', (258, 273))	('intrahepatic duct', 'Phenotype', 'HP:0006571', (200, 217))	('PSC', 'Gene', '100653366', (82, 85))	('lower', 'NegReg', (252, 257))
147247	29091291	Moreover, antisense inhibition or genetic deletion of miR-21 in two independently generated knockout mice did not alter HSC activation or liver fibrosis in models of toxic and biliary liver injury.	('liver fibrosis', 'Disease', 'MESH:D008103', (138, 152))	('antisense inhibition', 'Var', (10, 30))	('genetic deletion', 'Var', (34, 50))	('biliary liver injury', 'Disease', (176, 196))	('biliary liver injury', 'Disease', 'MESH:D008105', (176, 196))	('liver fibrosis', 'Phenotype', 'HP:0001395', (138, 152))	('mice', 'Species', '10090', (101, 105))	('HSC', 'MPA', (120, 123))	('miR-21', 'Gene', (54, 60))	('liver fibrosis', 'Disease', (138, 152))
147248	29091291	Despite a strong upregulation of miR-21 in injury-associated hepatocellular carcinoma and in cholangiocarcinoma, miR-21 deletion or antisense inhibition did not reduce the development of liver tumors.	('miR-21', 'Gene', (113, 119))	('upregulation', 'PosReg', (17, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('cholangiocarcinoma', 'Disease', (93, 111))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('liver tumors', 'Disease', (187, 199))	('deletion', 'Var', (120, 128))	('liver tumors', 'Disease', 'MESH:D008113', (187, 199))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (61, 85))	('liver tumors', 'Phenotype', 'HP:0002896', (187, 199))	('miR-21', 'Gene', (33, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('hepatocellular carcinoma', 'Disease', (61, 85))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (61, 85))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))
147250	29091291	Although Dicer deletion decreased microRNA expression in HSC and altered the expression of select genes, it only exerted negligible effects on HSC activation and liver fibrosis.	('altered', 'Reg', (65, 72))	('decreased', 'NegReg', (24, 33))	('expression', 'MPA', (77, 87))	('liver fibrosis', 'Disease', 'MESH:D008103', (162, 176))	('deletion', 'Var', (15, 23))	('Dicer', 'Gene', (9, 14))	('liver fibrosis', 'Phenotype', 'HP:0001395', (162, 176))	('microRNA expression', 'MPA', (34, 53))	('liver fibrosis', 'Disease', (162, 176))	('select genes', 'Gene', (91, 103))
147255	29091291	One particular microRNA, miR-21, has been shown to contribute to the development of fibrosis in multiple organs, including lung, kidney and heart.	('miR-21', 'Var', (25, 31))	('contribute', 'Reg', (51, 61))	('fibrosis', 'Disease', 'MESH:D005355', (84, 92))	('fibrosis', 'Disease', (84, 92))
147256	29091291	However, the role of miR-21 in fibrogenesis has been controversial, with some studies demonstrating a promotion of fibrosis by miR-21 but others demonstrating no influence.	('fibrosis', 'Disease', (115, 123))	('miR-21', 'Var', (127, 133))	('promotion', 'PosReg', (102, 111))	('fibrosis', 'Disease', 'MESH:D005355', (115, 123))
147261	29091291	Moreover, HSC-specific deletion of Dicer1, an RNAse that is required for the generation of mature microRNAs, had no effect on HSC activation and only minimally affected liver fibrosis, suggesting that microRNAs do not play a crucial role in driving HSC activation or maintaining their activated phenotype.	('deletion', 'Var', (23, 31))	('liver fibrosis', 'Disease', 'MESH:D008103', (169, 183))	('liver fibrosis', 'Disease', (169, 183))	('Dicer1', 'Gene', (35, 41))	('liver fibrosis', 'Phenotype', 'HP:0001395', (169, 183))	('activated', 'MPA', (285, 294))	('Dicer1', 'Gene', '192119', (35, 41))
147264	29091291	Mice expressing Alb-Cre (Jax#003574) and a second line of miR-21KO mice (Jax#016856) were from Jackson.	('Jax#003574', 'Var', (25, 35))	('Alb', 'Gene', '11657', (16, 19))	('Mice', 'Species', '10090', (0, 4))	('Alb', 'Gene', (16, 19))	('mice', 'Species', '10090', (67, 71))
147265	29091291	For HSC-specific ablation of Dicer, floxed Dicer1 mice were crossed with LRAT-Cre mice.	('mice', 'Species', '10090', (82, 86))	('Dicer1', 'Gene', '192119', (43, 49))	('LRAT', 'Gene', (73, 77))	('ablation', 'Var', (17, 25))	('mice', 'Species', '10090', (50, 54))	('Dicer1', 'Gene', (43, 49))	('LRAT', 'Gene', '79235', (73, 77))
147278	29091291	Mice with Alb-Cre-mediated deletion of Pten and Tgfbr2 were used as model of cholangiocarcinoma, using a floxed miR-21 allele to simultaneously delete miR-21 in cells from which cholangiocarcinomas originate.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (77, 95))	('miR-21', 'Gene', (151, 157))	('delete', 'NegReg', (144, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (178, 196))	('Mice', 'Species', '10090', (0, 4))	('cholangiocarcinoma', 'Disease', (178, 196))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (178, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (178, 197))	('Tgfbr2', 'Gene', '21813', (48, 54))	('deletion', 'Var', (27, 35))	('cholangiocarcinomas', 'Disease', (178, 197))	('Alb', 'Gene', '11657', (10, 13))	('Pten', 'Gene', (39, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (77, 95))	('Alb', 'Gene', (10, 13))	('cholangiocarcinoma', 'Disease', (77, 95))	('Tgfbr2', 'Gene', (48, 54))
147279	29091291	In a second model, cholangiocarcinoma was induced by hydrodynamic tail vein injection of plasmids encoding sleeping beauty, pT3-myrAKT and pT3-YapS127A as described.	('AKT', 'Gene', '11651', (131, 134))	('pT3-YapS127A', 'Var', (139, 151))	('AKT', 'Gene', (131, 134))	('cholangiocarcinoma', 'Disease', (19, 37))	('induced', 'Reg', (42, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('YapS127A', 'Mutation', 'rs762471803', (143, 151))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (19, 37))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (19, 37))
147287	29091291	Following treatment of miR-21 null (miR-21KO) and wild-type (WT) controls with eight injections of CCl4, we did not observe significant differences in Sirius red staining (Fig.	('CCl4', 'Gene', (99, 103))	('miR-21', 'Gene', (23, 29))	('Sirius red', 'Chemical', '-', (151, 161))	('miR-21KO', 'Var', (36, 44))	('CCl4', 'Gene', '20303', (99, 103))
147289	29091291	Moreover, markers of HSC activation, including alpha-SMA protein and of Acta2, Col1a1, Lox, and Timp1 mRNA, increased in CCl4-treated livers but were similar between miR-21KO mice and WT controls (Fig.	('mice', 'Species', '10090', (175, 179))	('Lox', 'Gene', (87, 90))	('Acta2', 'Gene', '11475', (72, 77))	('Acta2', 'Gene', (72, 77))	('Timp1', 'Gene', '21857', (96, 101))	('Lox', 'Gene', '16948', (87, 90))	('increased', 'PosReg', (108, 117))	('Timp1', 'Gene', (96, 101))	('CCl4', 'Gene', (121, 125))	('alpha-SMA', 'Gene', (47, 56))	('Col1a1', 'Gene', (79, 85))	('CCl4', 'Gene', '20303', (121, 125))	('alpha-SMA', 'Gene', '11475', (47, 56))	('Col1a1', 'Gene', '12842', (79, 85))	('miR-21KO', 'Var', (166, 174))
147290	29091291	mRNA and protein expression of HSC marker desmin increased in livers from CCl4-treated mice, indicating that HSC expanded to similar degree in miR-21KO and WT mice during fibrogenesis (Fig.	('CCl4', 'Gene', '20303', (74, 78))	('desmin', 'Gene', '13346', (42, 48))	('desmin', 'Gene', (42, 48))	('increased', 'PosReg', (49, 58))	('mice', 'Species', '10090', (87, 91))	('miR-21KO', 'Var', (143, 151))	('CCl4', 'Gene', (74, 78))	('mice', 'Species', '10090', (159, 163))	('desmin increased', 'Phenotype', 'HP:0100300', (42, 58))
147293	29091291	Treatment of mice with miR-21KD antimirs decreased miR-21 levels by 94% and 85% in non-fibrotic and fibrotic livers, respectively, when compared to mice treated with scrambled control oligonucleotides (Suppl.	('oligonucleotides', 'Chemical', 'MESH:D009841', (184, 200))	('mice', 'Species', '10090', (13, 17))	('miR-21KD antimirs', 'Var', (23, 40))	('decreased', 'NegReg', (41, 50))	('fibrotic liver', 'Phenotype', 'HP:0001395', (100, 114))	('mice', 'Species', '10090', (148, 152))	('miR-21 levels', 'MPA', (51, 64))
147295	29091291	To determine whether our antimir strategy decreased miR-21 in HSC, we isolated HSC from mice treated with miR-21KD antimir or scrambled control oligos.	('miR-21KD antimir', 'Var', (106, 122))	('mice', 'Species', '10090', (88, 92))	('miR-21', 'MPA', (52, 58))
147296	29091291	qPCR demonstrated an 80% decrease of miR-21 levels in HSC from miR-21KD-treated mice (Suppl.	('miR-21 levels', 'MPA', (37, 50))	('decrease', 'NegReg', (25, 33))	('miR-21KD-treated', 'Var', (63, 79))	('mice', 'Species', '10090', (80, 84))
147297	29091291	However, similar to the results in mirR-21KO mice, acute inhibition of miR-21 by miR-21KD antimirs did not reduce the development of liver fibrosis, as determined by Sirius red staining and hepatic hydroxyproline measurement (Suppl.	('hydroxyproline', 'Chemical', 'MESH:D006909', (198, 212))	('mice', 'Species', '10090', (45, 49))	('liver fibrosis', 'Phenotype', 'HP:0001395', (133, 147))	('hepatic hydroxyproline measurement', 'MPA', (190, 224))	('inhibition', 'NegReg', (57, 67))	('Sirius red', 'Chemical', '-', (166, 176))	('liver fibrosis', 'Disease', (133, 147))	('miR-21KD', 'Var', (81, 89))	('miR-21', 'Gene', (71, 77))	('reduce', 'NegReg', (107, 113))	('liver fibrosis', 'Disease', 'MESH:D008103', (133, 147))
147299	29091291	Moreover, miR-21KD antimirs did not reduce proliferation, as determined by qPCR for Mki67 mRNA (Suppl.	('Mki67', 'Gene', (84, 89))	('miR-21KD antimirs', 'Var', (10, 27))	('Mki67', 'Gene', '17345', (84, 89))
147307	29091291	In addition, liver injury was not different between miR-21KO and WT mice, as measured by plasma ALT levels (Fig 3B).	('mice', 'Species', '10090', (68, 72))	('ALT', 'Gene', (96, 99))	('liver injury', 'Disease', (13, 25))	('liver injury', 'Disease', 'MESH:D056486', (13, 25))	('miR-21KO', 'Var', (52, 60))	('ALT', 'Gene', '76282', (96, 99))
147310	29091291	We additionally investigated the effect of miR-21 deletion in biliary fibrosis induced by DDC.	('biliary fibrosis', 'Disease', 'MESH:D005355', (62, 78))	('deletion', 'Var', (50, 58))	('miR-21', 'Gene', (43, 49))	('biliary fibrosis', 'Disease', (62, 78))	('DDC', 'Chemical', 'MESH:C530773', (90, 93))
147312	29091291	Similar to our findings in miR-21KO mice, treatment with miR-21KD antimir did not prevent the development of DDC-induced liver fibrosis (Suppl.	('liver fibrosis', 'Phenotype', 'HP:0001395', (121, 135))	('miR-21KD', 'Var', (57, 65))	('DDC', 'Chemical', 'MESH:C530773', (109, 112))	('liver fibrosis', 'Disease', (121, 135))	('mice', 'Species', '10090', (36, 40))	('liver fibrosis', 'Disease', 'MESH:D008103', (121, 135))
147314	29091291	Treatment with miR-21KD antimir did not significantly inhibit BDL-induced liver fibrosis or injury, as assessed by Sirius red staining, hepatic hydroxyproline content, hepatic fibrogenic gene mRNA expression, and ALT levels (Suppl.	('hepatic', 'MPA', (168, 175))	('BDL-induced', 'Disease', (62, 73))	('ALT', 'Gene', (213, 216))	('inhibit', 'NegReg', (54, 61))	('hepatic hydroxyproline content', 'MPA', (136, 166))	('Sirius red', 'Chemical', '-', (115, 125))	('hydroxyproline', 'Chemical', 'MESH:D006909', (144, 158))	('liver fibrosis or injury', 'Disease', (74, 98))	('miR-21KD antimir', 'Var', (15, 31))	('ALT', 'Gene', '76282', (213, 216))	('liver fibrosis or injury', 'Disease', 'MESH:D008103', (74, 98))	('liver fibrosis', 'Phenotype', 'HP:0001395', (74, 88))
147315	29091291	As a third approach, in addition to miR-21KO mice and miR-21KD antimir, we determined the effect of miR-21 deletion on liver fibrosis in a second miR-21KO mouse line.	('mice', 'Species', '10090', (45, 49))	('liver fibrosis', 'Disease', (119, 133))	('miR-21', 'Gene', (100, 106))	('mouse', 'Species', '10090', (155, 160))	('liver fibrosis', 'Disease', 'MESH:D008103', (119, 133))	('deletion', 'Var', (107, 115))	('liver fibrosis', 'Phenotype', 'HP:0001395', (119, 133))
147318	29091291	Treatment of HSC with miR-21KD antimirs decreased miR-21 in cultured HSC in a dose-dependent manner (up to 99% at the highest dose) in comparison to scrambled control oligonucleotides, without affecting its precursor primir-21 (Fig.	('miR-21KD', 'Var', (22, 30))	('miR-21', 'MPA', (50, 56))	('decreased', 'NegReg', (40, 49))	('oligonucleotides', 'Chemical', 'MESH:D009841', (167, 183))
147321	29091291	Treatment of human HSC with miR-21KD antimir decreased miR-21 in a dose-dependent manner, achieving up to 99% reduction of miR-21 expression (Fig.	('miR-21', 'Gene', (123, 129))	('expression', 'MPA', (130, 140))	('reduction', 'NegReg', (110, 119))	('human', 'Species', '9606', (13, 18))	('miR-21KD', 'Var', (28, 36))
147322	29091291	However, similarly to our data in murine HSC, miR-21 knockdown did not affect HSC activation status as determined by alpha-SMA protein expression and qPCR for ACTA2, COL1A1, and TIMP1 mRNA (Fig.	('COL1A1', 'Gene', '12842', (166, 172))	('ACTA2', 'Gene', (159, 164))	('alpha-SMA', 'Gene', (117, 126))	('alpha-SMA', 'Gene', '11475', (117, 126))	('COL1A1', 'Gene', (166, 172))	('knockdown', 'Var', (53, 62))	('TIMP1', 'Gene', '21857', (178, 183))	('ACTA2', 'Gene', '11475', (159, 164))	('murine', 'Species', '10090', (34, 40))	('TIMP1', 'Gene', (178, 183))	('miR-21', 'Gene', (46, 52))
147325	29091291	Dicer1 deletion blocks the generation of microRNAs and causes important alterations in organ development and function.	('generation', 'MPA', (27, 37))	('alterations', 'Reg', (72, 83))	('Dicer1', 'Gene', (0, 6))	('organ development', 'CPA', (87, 104))	('Dicer1', 'Gene', '192119', (0, 6))	('microRNAs', 'MPA', (41, 50))	('function', 'CPA', (109, 117))	('deletion', 'Var', (7, 15))	('blocks', 'NegReg', (16, 22))
147326	29091291	To further evaluate the importance of microRNAs in HSC activation and liver fibrosis, we generated mice with a HSC-specific deletion of Dicer1 (DicerDeltaHSC) by crossing Dicerf/f mice with Lrat-Cre mice.	('mice', 'Species', '10090', (99, 103))	('Lrat', 'Gene', '79235', (190, 194))	('Dicer1', 'Gene', (136, 142))	('liver fibrosis', 'Disease', 'MESH:D008103', (70, 84))	('mice', 'Species', '10090', (199, 203))	('Dicer1', 'Gene', '192119', (136, 142))	('liver fibrosis', 'Phenotype', 'HP:0001395', (70, 84))	('mice', 'Species', '10090', (180, 184))	('Lrat', 'Gene', (190, 194))	('liver fibrosis', 'Disease', (70, 84))	('deletion', 'Var', (124, 132))
147327	29091291	This approach resulted in efficient deletion of Dicer1 in HSC with a 94% decrease in Dicer1 mRNA and decreases in the levels of miR-21, miR-199a-3p and let-7i of at least 50% (Fig.	('Dicer1', 'Gene', (85, 91))	('Dicer1', 'Gene', (48, 54))	('deletion', 'Var', (36, 44))	('let-7i', 'Gene', (152, 158))	('Dicer1', 'Gene', '192119', (85, 91))	('mRNA', 'MPA', (92, 96))	('decreases', 'NegReg', (101, 110))	('let-7i', 'Gene', '387251', (152, 158))	('miR', 'Gene', '735281', (136, 139))	('miR', 'Gene', (136, 139))	('decrease', 'NegReg', (73, 81))	('Dicer1', 'Gene', '192119', (48, 54))	('miR', 'Gene', (128, 131))	('miR', 'Gene', '735281', (128, 131))
147328	29091291	To determine the role of microRNA modulation by Dicer1 deletion, we first needed to exclude that Dicer1 deletion resulted in spontaneous activation of HSC or that it severely disturbed the phenotype of HSC.	('deletion', 'Var', (104, 112))	('Dicer1', 'Gene', (48, 54))	('phenotype', 'MPA', (189, 198))	('Dicer1', 'Gene', '192119', (48, 54))	('activation', 'PosReg', (137, 147))	('Dicer1', 'Gene', (97, 103))	('HSC', 'Disease', (151, 154))	('disturbed', 'Reg', (175, 184))	('HSC', 'Disease', (202, 205))	('Dicer1', 'Gene', '192119', (97, 103))
147329	29091291	For this purpose, we isolated HSCs from DicerDeltaHSC and Dicer+/+ Lrat-Cre control mice.	('Dicer+/+', 'Var', (58, 66))	('Lrat', 'Gene', (67, 71))	('Lrat', 'Gene', '79235', (67, 71))	('DicerDeltaHSC', 'Var', (40, 53))	('mice', 'Species', '10090', (84, 88))
147335	29091291	To evaluate the effect of Dicer1 deletion in HSC on liver fibrosis, we treated DicerDeltaHSC mice and control mice with CCl4.	('liver fibrosis', 'Disease', 'MESH:D008103', (52, 66))	('CCl4', 'Gene', '20303', (120, 124))	('Dicer1', 'Gene', '192119', (26, 32))	('deletion', 'Var', (33, 41))	('liver fibrosis', 'Phenotype', 'HP:0001395', (52, 66))	('mice', 'Species', '10090', (110, 114))	('mice', 'Species', '10090', (93, 97))	('liver fibrosis', 'Disease', (52, 66))	('Dicer1', 'Gene', (26, 32))	('CCl4', 'Gene', (120, 124))
147337	29091291	We detected a small but statistically significant reduction in some but not all fibrosis markers in DicerDeltaHSC mice.	('reduction', 'NegReg', (50, 59))	('DicerDeltaHSC', 'Var', (100, 113))	('mice', 'Species', '10090', (114, 118))	('fibrosis', 'Disease', 'MESH:D005355', (80, 88))	('fibrosis', 'Disease', (80, 88))
147338	29091291	DicerDeltaHSC livers had modestly decreased Sirius red staining, but there was not difference in hepatic hydroxyproline content (Fig.	('hydroxyproline', 'Chemical', 'MESH:D006909', (105, 119))	('decreased', 'NegReg', (34, 43))	('Sirius red staining', 'MPA', (44, 63))	('Sirius red', 'Chemical', '-', (44, 54))	('DicerDeltaHSC', 'Var', (0, 13))
147339	29091291	Likewise, DicerDeltaHSC livers displayed a decrease in Col1a1 mRNA expression, but no differences in the expression of other fibrogenesic genes including Acta2, Lox or Timp1 (Fig.	('DicerDeltaHSC', 'Var', (10, 23))	('decrease', 'NegReg', (43, 51))	('Timp1', 'Gene', '21857', (168, 173))	('Timp1', 'Gene', (168, 173))	('Acta2', 'Gene', (154, 159))	('mRNA expression', 'MPA', (62, 77))	('Col1a1', 'Gene', (55, 61))	('Lox', 'Gene', (161, 164))	('Acta2', 'Gene', '11475', (154, 159))	('Lox', 'Gene', '16948', (161, 164))	('Col1a1', 'Gene', '12842', (55, 61))
147340	29091291	However, as DicerDeltaHSC mice were significantly smaller than their Dicerf/f control mice (Suppl.	('mice', 'Species', '10090', (86, 90))	('DicerDeltaHSC', 'Var', (12, 25))	('mice', 'Species', '10090', (26, 30))	('smaller', 'NegReg', (50, 57))
147341	29091291	7F) - most likely due to extrahepatic deletion of Dicer1 related to the high expression of Lrat-Cre in several organs during development - it cannot be excluded that the observed minor role of Dicer in HSC activation and liver fibrosis was either exaggerated or masked by differences in body weight.	('liver fibrosis', 'Disease', (221, 235))	('Dicer1', 'Gene', '192119', (50, 56))	('Lrat', 'Gene', (91, 95))	('liver fibrosis', 'Disease', 'MESH:D008103', (221, 235))	('Lrat', 'Gene', '79235', (91, 95))	('Dicer1', 'Gene', (50, 56))	('deletion', 'Var', (38, 46))	('liver fibrosis', 'Phenotype', 'HP:0001395', (221, 235))	('HSC activation', 'CPA', (202, 216))
147342	29091291	To further investigate the effect of Dicer deletion in the absence of such a confounder, we deleted Dicer1 in HSC in vitro and studied the effect on culture-activation.	('Dicer1', 'Gene', '192119', (100, 106))	('deleted', 'Var', (92, 99))	('Dicer1', 'Gene', (100, 106))
147345	29091291	Moreover, Dicer1 mRNA was already 98% reduced 72h hours after infection with Ad5-CMVCre, demonstrating that reduced Dicer1 expression was present for most of the culture activation period in these experiments.	('Ad5-CMVCre', 'Var', (77, 87))	('expression', 'MPA', (123, 133))	('reduced', 'NegReg', (38, 45))	('Dicer1', 'Gene', '192119', (116, 122))	('Dicer1', 'Gene', (10, 16))	('Dicer1', 'Gene', '192119', (10, 16))	('Dicer1', 'Gene', (116, 122))
147346	29091291	However, Dicer1 deletion had minimal effects on HSC activation with no changes in alpha-SMA protein expression, similar levels of Acta2, Lox and Timp1, and only a moderate increase in Col1a1 mRNA (Fig.	('increase', 'PosReg', (172, 180))	('deletion', 'Var', (16, 24))	('alpha-SMA', 'Gene', (82, 91))	('Acta2', 'Gene', (130, 135))	('HSC activation', 'MPA', (48, 62))	('Timp1', 'Gene', '21857', (145, 150))	('alpha-SMA', 'Gene', '11475', (82, 91))	('expression', 'MPA', (100, 110))	('Timp1', 'Gene', (145, 150))	('Dicer1', 'Gene', (9, 15))	('Col1a1', 'Gene', (184, 190))	('Lox', 'Gene', (137, 140))	('Acta2', 'Gene', '11475', (130, 135))	('Dicer1', 'Gene', '192119', (9, 15))	('Lox', 'Gene', '16948', (137, 140))	('Col1a1', 'Gene', '12842', (184, 190))
147350	29091291	Upregulation of miR-21 has been reported in a large number of malignancies, including HCC and cholangiocarcinoma and miR-21 has been termed an "oncomir" based on functional studies.	('Upregulation', 'PosReg', (0, 12))	('miR-21', 'Var', (117, 123))	('cholangiocarcinoma', 'Disease', (94, 112))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('miR-21', 'Gene', (16, 22))	('HCC', 'Disease', (86, 89))	('malignancies', 'Disease', (62, 74))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (94, 112))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (94, 112))
147351	29091291	Similarly to previous studies, we observed increased miR-21 expression in liver cancer, including HCC induced by DEN+CCl4, HCC induced by liver parenchymal cell (LPC)-specific Pten deficiency and cholangiocarcinoma induced by LPC-specific deletion of Pten and Tgfbr2 (Fig.	('expression', 'MPA', (60, 70))	('cholangiocarcinoma', 'Disease', (196, 214))	('CCl4', 'Gene', (117, 121))	('deletion', 'Var', (239, 247))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (196, 214))	('CCl4', 'Gene', '20303', (117, 121))	('liver cancer', 'Disease', 'MESH:D006528', (74, 86))	('miR-21', 'Gene', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Tgfbr2', 'Gene', (260, 266))	('increased', 'PosReg', (43, 52))	('liver cancer', 'Phenotype', 'HP:0002896', (74, 86))	('Pten deficiency', 'Disease', 'MESH:C566636', (176, 191))	('liver cancer', 'Disease', (74, 86))	('Pten deficiency', 'Disease', (176, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('HCC', 'Phenotype', 'HP:0001402', (123, 126))	('HCC', 'Disease', (98, 101))	('Pten', 'Gene', (251, 255))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (196, 214))	('HCC', 'Phenotype', 'HP:0001402', (98, 101))	('DEN', 'Chemical', 'MESH:D004052', (113, 116))	('Tgfbr2', 'Gene', '21813', (260, 266))
147353	29091291	There were no differences in tumor development between miR-21KO and WT mice, with similar liver-to-body weight ratio, tumor number, and size in both groups (Fig.	('mice', 'Species', '10090', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', (29, 34))	('miR-21KO', 'Var', (55, 63))
147354	29091291	In a complementary approach, we determined effects of miR-21KD antimirs on DEN+CCl4-induced HCC.	('CCl4', 'Gene', (79, 83))	('miR-21KD', 'Var', (54, 62))	('CCl4', 'Gene', '20303', (79, 83))	('HCC', 'Phenotype', 'HP:0001402', (92, 95))	('DEN', 'Chemical', 'MESH:D004052', (75, 78))
147357	29091291	Treatment with miR-21KD antimir efficiently decreased miR-21 in tumors and surrounding non-tumor tissue (Fig.	('tumors', 'Disease', (64, 70))	('non-tumor', 'Disease', (87, 96))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('miR-21', 'MPA', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('miR-21KD', 'Var', (15, 23))	('non-tumor', 'Disease', 'MESH:D009369', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('decreased', 'NegReg', (44, 53))
147358	29091291	Consistent with our studies in knockout mice, miR-21 knockdown did not alter tumor development (Fig.	('knockdown', 'Var', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('miR-21', 'Gene', (46, 52))	('mice', 'Species', '10090', (40, 44))	('tumor', 'Disease', (77, 82))
147361	29091291	First, we used a model of CCA driven by deletion of PTEN and TGFBR2.	('PTEN', 'Gene', (52, 56))	('driven by', 'Reg', (30, 39))	('deletion', 'Var', (40, 48))	('CCA', 'Disease', (26, 29))	('TGFBR2', 'Gene', (61, 67))	('TGFBR2', 'Gene', '21813', (61, 67))
147362	29091291	In this model, co- deletion of miR-21 increased the tumor number and liver-to-body weight ratio but not tumor size (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (104, 109))	('liver-to-body weight ratio', 'CPA', (69, 95))	('miR-21', 'Gene', (31, 37))	('co-', 'Var', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('increased', 'PosReg', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
147365	29091291	These results are in agreement with the lack of any effect of miR-21KD on the hepatic expression of cancer-related target genes (Suppl.	('miR-21KD', 'Var', (62, 70))	('hepatic expression', 'MPA', (78, 96))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
147367	29091291	In HepG2 and PLC/PRF/5, transfection with miR-21KD decreased miR-21 levels 97% and 99%.	('PLC', 'Gene', (13, 16))	('PLC', 'Gene', '15530', (13, 16))	('decreased', 'NegReg', (51, 60))	('HepG2', 'CellLine', 'CVCL:0027', (3, 8))	('miR-21 levels', 'MPA', (61, 74))	('miR-21KD', 'Var', (42, 50))
147368	29091291	Similarly, miR-21KD decreased miR-21 in HuCCT-1 and KMCH cells but did not affect those cancer properties (Suppl.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('decreased', 'NegReg', (20, 29))	('miR-21', 'MPA', (30, 36))	('HuCCT-1', 'CellLine', 'CVCL:0324', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('miR-21KD', 'Var', (11, 19))
147378	29091291	Despite efficient knockdown of miR-21, we only observed a moderate increase in the expression of recognized miR-21 target Timp3 mRNA (Suppl.	('knockdown', 'Var', (18, 27))	('Timp3', 'Gene', (122, 127))	('miR-21', 'Gene', (31, 37))	('increase', 'PosReg', (67, 75))	('expression', 'MPA', (83, 93))	('Timp3', 'Gene', '21859', (122, 127))
147380	29091291	These variable and mostly absent effects are consistent with our finding of unaltered PDCD4 and SPRY1 protein in livers of miR-21KO mice (data not shown) in our studies as well as previous studies in hearts of miR-21KO mice.	('PDCD4', 'Gene', '18569', (86, 91))	('mice', 'Species', '10090', (219, 223))	('miR-21KO', 'Var', (123, 131))	('SPRY1', 'Gene', '24063', (96, 101))	('mice', 'Species', '10090', (132, 136))	('PDCD4', 'Gene', (86, 91))	('SPRY1', 'Gene', (96, 101))
147381	29091291	These findings support the notion that miR-21 exerts little influence on gene expression in the liver as previously shown by others, whereas its role in other organs such as the skin may be more potent as evidenced by moderately upregulated target gene expression in keratinocytes of the miR-21KO mouse, employed in our study.	('gene expression', 'MPA', (73, 88))	('miR-21', 'Var', (39, 45))	('upregulated', 'PosReg', (229, 240))	('mouse', 'Species', '10090', (297, 302))
147382	29091291	While genetic knockouts are the cleanest strategy to study the role of miR-21 in fibrosis and cancer, it has been suggested by some but refuted by others that miR-21 knockout may trigger compensatory mechanisms.	('fibrosis', 'Disease', 'MESH:D005355', (81, 89))	('fibrosis', 'Disease', (81, 89))	('miR-21', 'Gene', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('trigger', 'Reg', (179, 186))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Disease', (94, 100))	('knockout', 'Var', (166, 174))
147385	29091291	Our results differ from two previous publications, which have reported that miR-21 promotes liver fibrosis.	('liver fibrosis', 'Disease', (92, 106))	('promotes', 'PosReg', (83, 91))	('miR-21', 'Var', (76, 82))	('liver fibrosis', 'Disease', 'MESH:D008103', (92, 106))	('liver fibrosis', 'Phenotype', 'HP:0001395', (92, 106))
147390	29091291	To further understand the overall role of microRNAs in HSC biology and liver fibrosis, we deleted Dicer1 in HSC in vitro and in vivo.	('liver fibrosis', 'Disease', (71, 85))	('Dicer1', 'Gene', (98, 104))	('liver fibrosis', 'Disease', 'MESH:D008103', (71, 85))	('deleted', 'Var', (90, 97))	('Dicer1', 'Gene', '192119', (98, 104))	('liver fibrosis', 'Phenotype', 'HP:0001395', (71, 85))	('HSC', 'Disease', (108, 111))
147402	28733220	Pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma induced in mice by AKT and Yap co-expression Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy without effective treatment options.	('mTOR', 'Gene', '56717', (4, 8))	('mice', 'Species', '10090', (91, 95))	('malignancy', 'Disease', (175, 185))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (138, 156))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (48, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('Intrahepatic cholangiocarcinoma', 'Disease', (125, 156))	('Intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (125, 156))	('intrahepatic cholangiocarcinoma', 'Disease', (48, 79))	('AKT', 'Gene', '11651', (99, 102))	('MLN0128', 'Var', (19, 26))	('malignancy', 'Disease', 'MESH:D009369', (175, 185))	('AKT', 'Gene', (99, 102))	('mTOR', 'Gene', (4, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('MLN0128', 'Chemical', 'MESH:C572449', (19, 26))
147403	28733220	MLN0128, a second-generation pan-mTOR inhibitor, shows efficacy for multiple tumor types.	('MLN0128', 'Var', (0, 7))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('efficacy', 'MPA', (55, 63))	('tumor', 'Disease', (77, 82))
147406	28733220	Gemcitabine/Oxaliplatin and MLN0128 were administered in AKT/YapS127A tumor-bearing mice to study their antitumor efficacy in vivo.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Gemcitabine', 'Chemical', 'MESH:C056507', (0, 11))	('MLN0128', 'Var', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (108, 113))	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (12, 23))	('MLN0128', 'Chemical', 'MESH:C572449', (28, 35))	('S127A', 'Mutation', 'p.S127A', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('mice', 'Species', '10090', (84, 88))
147409	28733220	Co-expression of myr-AKT and YapS127A promoted ICC development in mice.	('ICC development', 'CPA', (47, 62))	('myr-AKT', 'Gene', (17, 24))	('S127A', 'Mutation', 'p.S127A', (32, 37))	('mice', 'Species', '10090', (66, 70))	('promoted', 'PosReg', (38, 46))	('myr-AKT', 'Gene', '11651', (17, 24))	('YapS127A', 'Var', (29, 37))
147412	28733220	In contrast, partial tumor regression was achieved when MLN0128 was applied in the late stage of AKT/YapS127A cholangiocarcinogenesis.	('S127A', 'Mutation', 'p.S127A', (104, 109))	('tumor', 'Disease', (21, 26))	('cholangiocarcinogenesis', 'Disease', (110, 133))	('MLN0128', 'Var', (56, 63))	('MLN0128', 'Chemical', 'MESH:C572449', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('cholangiocarcinogenesis', 'Disease', 'None', (110, 133))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
147413	28733220	Furthermore, when MLN0128 was administered in the early stage of AKT/YapS127A carcinogenesis, it led to disease stabilization.	('S127A', 'Mutation', 'p.S127A', (72, 77))	('MLN0128', 'Var', (18, 25))	('MLN0128', 'Chemical', 'MESH:C572449', (18, 25))	('AKT/YapS127A', 'Disease', (65, 77))	('disease stabilization', 'CPA', (104, 125))
147414	28733220	Mechanistically, MLN0128 efficiently inhibited AKT/mTOR signaling both in vivo and in vitro, inducing strong ICC cell apoptosis and only marginally affecting proliferation.	('MLN0128', 'Chemical', 'MESH:C572449', (17, 24))	('inhibited', 'NegReg', (37, 46))	('inducing', 'NegReg', (93, 101))	('ICC', 'Disease', (109, 112))	('AKT/mTOR signaling', 'Pathway', (47, 65))	('MLN0128', 'Var', (17, 24))
147418	28733220	Our study shows the anti-neoplastic potential of MLN0128, suggesting that it may be superior to Gemcitabine/Oxaliplatin based chemotherapy for the treatment of ICC, especially in the tumors exhibiting activated AKT/mTOR cascade.	('MLN0128', 'Var', (49, 56))	('Gemcitabine', 'Chemical', 'MESH:C056507', (96, 107))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('anti-neoplastic potential', 'CPA', (20, 45))	('ICC', 'Disease', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('MLN0128', 'Chemical', 'MESH:C572449', (49, 56))	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (108, 119))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Disease', (183, 189))
147431	28733220	MLN0128 has already entered many phase I and II clinical trials as a single agent or in combined therapy, mostly for solid tumors.	('MLN0128', 'Var', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('solid tumors', 'Disease', (117, 129))	('solid tumors', 'Disease', 'MESH:D009369', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
147433	28733220	Compared to allosteric inhibitors such as rapamycin, MLN0128 suppresses mTORC1 activity more completely, as indicated by robust and lasting inhibition of 4EBP1, and it also targets mTORC2 to inhibit AKT signaling, thus leading to superior therapeutic effect.	('activity', 'MPA', (79, 87))	('AKT signaling', 'Pathway', (199, 212))	('inhibit', 'NegReg', (191, 198))	('suppresses', 'NegReg', (61, 71))	('mTORC1', 'Gene', '382056', (72, 78))	('mTORC2', 'Gene', (181, 187))	('therapeutic effect', 'CPA', (239, 257))	('superior', 'PosReg', (230, 238))	('MLN0128', 'Var', (53, 60))	('inhibition', 'NegReg', (140, 150))	('mTORC2', 'Gene', '74343', (181, 187))	('4EBP1', 'Gene', '13685', (154, 159))	('rapamycin', 'Chemical', 'MESH:D020123', (42, 51))	('4EBP1', 'Gene', (154, 159))	('MLN0128', 'Chemical', 'MESH:C572449', (53, 60))	('mTORC1', 'Gene', (72, 78))
147441	28733220	To inhibit mTORC2 signaling, we injected 60mug pT3-EF1 alpha-Cre or 60mug pT3-EF1alpha (empty vector control) together with 20mug pT3-EF1alpha-HA-myr-AKT and 30mug pT3-EF1alpha-YapS127A to delete Rictor while co-expressing AKT and YapS127A in Rictorflox/flox mice.	('EF1alpha', 'Gene', (168, 176))	('EF1alpha', 'Gene', (78, 86))	('YapS127A', 'Var', (231, 239))	('mice', 'Species', '10090', (259, 263))	('Rictor', 'Gene', '78757', (243, 249))	('mTORC2', 'Gene', '74343', (11, 17))	('EF1alpha', 'Gene', (134, 142))	('S127A', 'Mutation', 'p.S127A', (180, 185))	('myr-AKT', 'Gene', (146, 153))	('Rictor', 'Gene', (196, 202))	('S127A', 'Mutation', 'p.S127A', (234, 239))	('EF1alpha', 'Gene', '13664', (168, 176))	('myr-AKT', 'Gene', '11651', (146, 153))	('inhibit', 'NegReg', (3, 10))	('Rictor', 'Gene', (243, 249))	('EF1alpha', 'Gene', '13664', (78, 86))	('EF1alpha', 'Gene', '13664', (134, 142))	('delete', 'NegReg', (189, 195))	('mTORC2', 'Gene', (11, 17))	('Rictor', 'Gene', '78757', (196, 202))
147454	28733220	Overexpression of YapS127A did not result in any liver abnormality.	('liver abnormality', 'Disease', 'MESH:D056486', (49, 66))	('YapS127A', 'Var', (18, 26))	('liver abnormality', 'Disease', (49, 66))	('liver abnormality', 'Phenotype', 'HP:0001392', (49, 66))	('S127A', 'Mutation', 'p.S127A', (21, 26))
147460	28733220	Furthermore, AKT/YapS127A tumors exhibited positive staining for markers of tissue desmoplasia, such as vimentin and smooth muscle actin (alpha -SMA) in the stromal cells, a prominent feature of human ICC, which was further proven by Sirius Red staining (Supplementary Fig.	('AKT/YapS127A', 'Var', (13, 25))	('human', 'Species', '9606', (195, 200))	('vimentin', 'Gene', '7431', (104, 112))	('desmoplasia', 'Disease', (83, 94))	('positive', 'PosReg', (43, 51))	('vimentin', 'Gene', (104, 112))	('Sirius Red', 'Chemical', '-', (234, 244))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('desmoplasia', 'Disease', 'None', (83, 94))	('S127A', 'Mutation', 'p.S127A', (20, 25))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
147461	28733220	Western blotting was performed to determine the activation of AKT and Yap signaling in wild-type livers and AKT/YapS127A ICC lesions.	('S127A', 'Mutation', 'p.S127A', (115, 120))	('AKT/YapS127A', 'Var', (108, 120))	('Yap', 'MPA', (70, 73))	('AKT', 'Pathway', (62, 65))	('activation', 'PosReg', (48, 58))	('lesions', 'Var', (125, 132))
147462	28733220	As expected, total AKT and phosphorylated AKT at S473 and T308 sites as well as key downstream components of mTORC1 and mTORC2 signaling (p-mTOR, p-PRS6, p-4E-BP1, p-PRAS40 and p-NDRG1) were elevated in AKT/YapS127A mouse cancer tissues.	('PRAS40', 'Gene', '67605', (166, 172))	('mouse', 'Species', '10090', (216, 221))	('elevated', 'PosReg', (191, 199))	('p-PRS6', 'Var', (146, 152))	('p-mTOR', 'Var', (138, 144))	('S127A', 'Mutation', 'p.S127A', (210, 215))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', (222, 228))	('4E-BP1', 'Gene', '13685', (156, 162))	('4E-BP1', 'Gene', (156, 162))	('mTORC1', 'Gene', (109, 115))	('mTORC2', 'Gene', (120, 126))	('p-NDRG1', 'Var', (177, 184))	('AKT', 'Protein', (19, 22))	('mTORC2', 'Gene', '74343', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('mTORC1', 'Gene', '382056', (109, 115))	('PRAS40', 'Gene', (166, 172))
147466	28733220	In summary, co-expression of activated AKT and Yap induces ICC development in mice.	('Yap', 'Gene', (47, 50))	('induces', 'PosReg', (51, 58))	('ICC development', 'CPA', (59, 74))	('mice', 'Species', '10090', (78, 82))	('activated', 'Protein', (29, 38))	('co-expression', 'Var', (12, 25))
147468	28733220	Silencing of Raptor by shRNA substantially delayed the development of ICC by AKT/YapS127A expression in mice.	('development of', 'CPA', (55, 69))	('ICC', 'Disease', (70, 73))	('delayed', 'NegReg', (43, 50))	('Raptor', 'Gene', (13, 19))	('S127A', 'Mutation', 'p.S127A', (84, 89))	('mice', 'Species', '10090', (104, 108))	('Silencing', 'Var', (0, 9))
147482	28733220	Western blotting showed that, compared with AKT/YapS127A/pT3 mice, Rictor was effectively knocked down and p-AKT expression was suppressed in AKT/YapS127A/Cre mice (Fig.	('expression', 'MPA', (113, 123))	('mice', 'Species', '10090', (61, 65))	('knocked down', 'NegReg', (90, 102))	('S127A', 'Mutation', 'p.S127A', (51, 56))	('Rictor', 'Gene', (67, 73))	('S127A', 'Mutation', 'p.S127A', (149, 154))	('Rictor', 'Gene', '78757', (67, 73))	('AKT/YapS127A/Cre', 'Var', (142, 158))	('p-AKT', 'Protein', (107, 112))	('suppressed', 'NegReg', (128, 138))	('mice', 'Species', '10090', (159, 163))
147483	28733220	Consistently, clonogenic capacity of HuCCT1 and KMCH human ICC cells was impaired after inhibiting Rictor via lentivirus transfection of shRictor (Supplementary Fig.	('impaired', 'NegReg', (73, 81))	('Rictor', 'Gene', (139, 145))	('Rictor', 'Gene', '78757', (139, 145))	('HuCCT1', 'CellLine', 'CVCL:0324', (37, 43))	('Rictor', 'Gene', (99, 105))	('human', 'Species', '9606', (53, 58))	('clonogenic capacity', 'CPA', (14, 33))	('Rictor', 'Gene', '78757', (99, 105))	('transfection', 'Var', (121, 133))	('inhibiting', 'NegReg', (88, 98))
147495	28733220	3 and 4), we investigated the therapeutic effect of the second generation mTOR inhibitor MLN0128 in antagonizing ICC development.	('MLN0128', 'Var', (89, 96))	('ICC', 'Disease', (113, 116))	('MLN0128', 'Chemical', 'MESH:C572449', (89, 96))
147497	28733220	Next, we determined the in vitro effect of MLN0128 and treated CCA cells with MLN0128 for 48 hours.	('MLN0128', 'Chemical', 'MESH:C572449', (43, 50))	('MLN0128', 'Var', (78, 85))	('MLN0128', 'Chemical', 'MESH:C572449', (78, 85))	('MLN0128', 'Var', (43, 50))
147498	28733220	MLN0128 inhibited the growth of all 6 cell lines at nanomolar concentrations (Fig.	('MLN0128', 'Var', (0, 7))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('growth', 'CPA', (22, 28))	('inhibited', 'NegReg', (8, 17))
147499	28733220	At the biochemical level, as fast as 2 hours after MLN0128 treatment, AKT/mTOR signaling was suppressed, as indicated by decreased expression of p-AKT, p-mTOR, p-RPS6 and p-4E-BP1 in ICC cells (Fig.	('MLN0128', 'Var', (51, 58))	('4E-BP1', 'Gene', (173, 179))	('4E-BP1', 'Gene', '13685', (173, 179))	('MLN0128', 'Chemical', 'MESH:C572449', (51, 58))	('AKT/mTOR signaling', 'Pathway', (70, 88))	('decreased', 'NegReg', (121, 130))	('expression', 'MPA', (131, 141))	('p-AKT', 'Protein', (145, 150))	('p-mTOR', 'MPA', (152, 158))	('p-RPS6', 'Var', (160, 166))	('suppressed', 'NegReg', (93, 103))
147500	28733220	While MLN0128 could suppress the expression of Cyclin D1/E in the KMCH cell line, it had no effect on the expression of other proliferation-associated proteins, including PCNA and Cyclin A/B1/D1/E, in HuCCT1 cells.	('MLN0128', 'Var', (6, 13))	('HuCCT1', 'CellLine', 'CVCL:0324', (201, 207))	('A/B1', 'Var', (187, 191))	('expression', 'MPA', (106, 116))	('PCNA', 'Gene', (171, 175))	('MLN0128', 'Chemical', 'MESH:C572449', (6, 13))	('Cyclin D1', 'Gene', (47, 56))	('expression', 'MPA', (33, 43))	('Cyclin D1', 'Gene', '12443', (47, 56))	('A/B1', 'SUBSTITUTION', 'None', (187, 191))	('suppress', 'NegReg', (20, 28))	('PCNA', 'Gene', '18538', (171, 175))
147501	28733220	However, the expression of cleaved caspase-3/7 and PARP, well known markers of apoptosis induction, were elevated in both cell lines starting 24 hours after MLN0128 treatment (Fig.	('elevated', 'PosReg', (105, 113))	('MLN0128', 'Chemical', 'MESH:C572449', (157, 164))	('expression', 'MPA', (13, 23))	('PARP', 'Gene', (51, 55))	('caspase-3/7', 'Protein', (35, 46))	('PARP', 'Gene', '11545', (51, 55))	('cleaved', 'MPA', (27, 34))	('MLN0128', 'Var', (157, 164))
147502	28733220	Pretreatment of the cells with the pan-Caspase inhibitor V-ZAD-FMK blunted MLN0128 induced apoptosis (Supplementary Fig.	('blunted', 'NegReg', (67, 74))	('V-ZAD-FMK', 'Chemical', '-', (57, 66))	('apoptosis', 'CPA', (91, 100))	('MLN0128', 'Var', (75, 82))	('MLN0128', 'Chemical', 'MESH:C572449', (75, 82))
147503	28733220	Altogether, our data suggest that MLN0128 effectively inhibits ICC cell growth, mainly due to induction of apoptosis.	('MLN0128', 'Var', (34, 41))	('ICC', 'Disease', (63, 66))	('MLN0128', 'Chemical', 'MESH:C572449', (34, 41))	('inhibits', 'NegReg', (54, 62))
147506	28733220	Our experiment confirmed that mTOR signaling was effectively suppressed after 5 days of MLN0128 administration, with no obvious toxicity (Supplementary Fig.	('suppressed', 'NegReg', (61, 71))	('MLN0128', 'Chemical', 'MESH:C572449', (88, 95))	('toxicity', 'Disease', 'MESH:D064420', (128, 136))	('toxicity', 'Disease', (128, 136))	('MLN0128', 'Var', (88, 95))	('mTOR signaling', 'MPA', (30, 44))
147509	28733220	Lethal tumor burden occurred 6.5 weeks post injection in vehicle-treated mice, when MLN0128-treated mice appeared instead healthy with normal abdominal size (Fig.	('tumor', 'Disease', (7, 12))	('MLN0128-treated', 'Var', (84, 99))	('mice', 'Species', '10090', (100, 104))	('mice', 'Species', '10090', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('MLN0128', 'Chemical', 'MESH:C572449', (84, 91))
147510	28733220	ICC burden in MLN0128-treated mice was significantly smaller than that in vehicle-treated mice as shown by gross and histological evidence, and by liver weight (Fig.	('mice', 'Species', '10090', (30, 34))	('liver weight', 'CPA', (147, 159))	('ICC burden', 'CPA', (0, 10))	('mice', 'Species', '10090', (90, 94))	('MLN0128', 'Chemical', 'MESH:C572449', (14, 21))	('smaller', 'NegReg', (53, 60))	('MLN0128-treated', 'Var', (14, 29))
147511	28733220	MLN0128 administration significantly improved AKT/YapS127A mouse survival (Fig.	('MLN0128 administration', 'Var', (0, 22))	('mouse', 'Species', '10090', (59, 64))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('S127A', 'Mutation', 'p.S127A', (53, 58))	('improved', 'PosReg', (37, 45))	('AKT/YapS127A mouse survival', 'CPA', (46, 73))
147513	28733220	Importantly, MLN0128 showed significantly superior efficacy to that of Gemcitabine/Oxaliplatin in early stage AKT/YapS127A ICC when comparing liver weight data, as the measurement of tumor burden (Supplementary Fig.	('S127A', 'Mutation', 'p.S127A', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('MLN0128', 'Chemical', 'MESH:C572449', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (83, 94))	('Gemcitabine', 'Chemical', 'MESH:C056507', (71, 82))	('tumor', 'Disease', (183, 188))	('MLN0128', 'Var', (13, 20))	('superior', 'PosReg', (42, 50))
147514	28733220	Histological analysis revealed that AKT/YapS127A mice after MLN0128 treatment for 3 weeks had a similar tumor burden to AKT/YapS127A mice at 3.5 weeks post injection, the time point when MLN0128 therapy started.	('MLN0128', 'Chemical', 'MESH:C572449', (60, 67))	('mice', 'Species', '10090', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('mice', 'Species', '10090', (49, 53))	('S127A', 'Mutation', 'p.S127A', (43, 48))	('S127A', 'Mutation', 'p.S127A', (127, 132))	('MLN0128', 'Var', (60, 67))	('MLN0128', 'Chemical', 'MESH:C572449', (187, 194))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
147515	28733220	8), indicating that MLN0128 treatment leads to stable disease when applied to early stage tumors.	('stable disease', 'MPA', (47, 61))	('stage tumors', 'Disease', 'MESH:D062706', (84, 96))	('MLN0128 treatment', 'Var', (20, 37))	('MLN0128', 'Chemical', 'MESH:C572449', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('stage tumors', 'Disease', (84, 96))
147516	28733220	Unexpectedly, tumor cells still were highly proliferative upon MLN0128 treatment, as shown by Ki-67 staining, with only mild decrease of proliferation index from vehicle treated tumors (Fig.	('tumor', 'Disease', (178, 183))	('MLN0128', 'Var', (63, 70))	('tumor', 'Disease', (14, 19))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('MLN0128', 'Chemical', 'MESH:C572449', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('Ki-67', 'Chemical', '-', (94, 99))
147517	28733220	In striking contrast, MLN0128 administration induced massive apoptosis in AKT/YapS127A ICC cells, as detected by TUNEL assay.	('S127A', 'Mutation', 'p.S127A', (81, 86))	('apoptosis', 'CPA', (61, 70))	('MLN0128', 'Var', (22, 29))	('MLN0128', 'Chemical', 'MESH:C572449', (22, 29))
147518	28733220	Specifically, apoptosis index was ~5 times higher in MLN0128 treated tumor samples when compared with the vehicle treated group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('higher', 'PosReg', (43, 49))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('MLN0128 treated', 'Var', (53, 68))	('apoptosis index', 'CPA', (14, 29))	('MLN0128', 'Chemical', 'MESH:C572449', (53, 60))
147519	28733220	To further investigate the molecular mechanisms underlying therapeutic efficacy of MLN0128, we evaluated the protein expression of major signaling pathways in vehicle or MLN0128 treated tumor samples.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('MLN0128', 'Var', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('protein', 'MPA', (109, 116))	('tumor', 'Disease', (186, 191))	('MLN0128', 'Chemical', 'MESH:C572449', (83, 90))	('MLN0128', 'Var', (170, 177))	('MLN0128', 'Chemical', 'MESH:C572449', (170, 177))	('evaluated', 'Reg', (95, 104))
147520	28733220	We first used tumor samples treated with vehicle or MLN0128 harvested after 3 weeks of treatment.	('tumor', 'Disease', (14, 19))	('MLN0128', 'Var', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('MLN0128', 'Chemical', 'MESH:C572449', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
147523	28733220	We therefore chose to use ICC tumor samples from mice at 3.5 weeks post injection and compare them with tumor harvested after 3 weeks of MLN0128 therapy, as we have shown that tumor burdens are similar in the pre-treatment and MLN0128 treated cohorts (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('MLN0128', 'Chemical', 'MESH:C572449', (137, 144))	('ICC tumor', 'Disease', (26, 35))	('MLN0128', 'Var', (227, 234))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', (104, 109))	('ICC tumor', 'Disease', 'MESH:C566123', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('mice', 'Species', '10090', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('MLN0128', 'Chemical', 'MESH:C572449', (227, 234))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
147525	28733220	We found that MLN0128 could effectively inhibit AKT/mTOR signaling, while had no influence on Yap and Jag1 expression.	('inhibit', 'NegReg', (40, 47))	('MLN0128', 'Var', (14, 21))	('AKT/mTOR signaling', 'Pathway', (48, 66))	('MLN0128', 'Chemical', 'MESH:C572449', (14, 21))	('Jag1', 'Gene', (102, 106))	('Jag1', 'Gene', '16449', (102, 106))
147526	28733220	There was no difference in p-ERK expression between the two groups, suggesting that no feedback activation of the Ras/MAPK pathway occurs after AKT signaling inhibition by MLN0128 (Fig.	('AKT signaling', 'Pathway', (144, 157))	('p-ERK', 'Gene', (27, 32))	('p-ERK', 'Gene', '13666', (27, 32))	('MLN0128', 'Chemical', 'MESH:C572449', (172, 179))	('inhibition', 'NegReg', (158, 168))	('MAPK', 'Gene', (118, 122))	('MAPK', 'Gene', '26413;26417', (118, 122))	('MLN0128', 'Var', (172, 179))
147527	28733220	Consistent with in vitro findings, MLN0128 treatment had no effects on cell proliferation as indicated by equal expression level of PCNA and Cyclin A/B1/D1/E in tissues from the two groups (Fig.	('A/B1', 'Var', (148, 152))	('PCNA', 'Gene', '18538', (132, 136))	('MLN0128', 'Chemical', 'MESH:C572449', (35, 42))	('A/B1', 'SUBSTITUTION', 'None', (148, 152))	('MLN0128 treatment', 'Var', (35, 52))	('expression level', 'MPA', (112, 128))	('PCNA', 'Gene', (132, 136))	('cell proliferation', 'CPA', (71, 89))
147528	28733220	The expressions of cleaved caspase-3/7 increased in ICC after MLN0128 treatment, indicating induction of apoptosis by MLN0128 (Fig.	('MLN0128', 'Var', (62, 69))	('MLN0128', 'Var', (118, 125))	('expressions', 'MPA', (4, 15))	('MLN0128', 'Chemical', 'MESH:C572449', (62, 69))	('increased', 'PosReg', (39, 48))	('MLN0128', 'Chemical', 'MESH:C572449', (118, 125))
147529	28733220	The expression of major survival and apoptosis related genes, including Survivin, MCL-1, BCL-XL, BIM and BCL-2 did not show significant difference in control and MLN0128 treated tumor samples (Fig.	('tumor', 'Disease', (178, 183))	('BCL-XL', 'Gene', (89, 95))	('BCL-2', 'Gene', (105, 110))	('BIM', 'Gene', (97, 100))	('MLN0128', 'Var', (162, 169))	('BCL-XL', 'Gene', '12048', (89, 95))	('BIM', 'Gene', '12125', (97, 100))	('MCL-1', 'Gene', (82, 87))	('Survivin', 'Gene', '11799', (72, 80))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('MLN0128', 'Chemical', 'MESH:C572449', (162, 169))	('Survivin', 'Gene', (72, 80))	('MCL-1', 'Gene', '17210', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('BCL-2', 'Gene', '12043', (105, 110))
147530	28733220	BAD proapoptotic protein was mildly upregulated in MLN0128 samples (Fig.	('upregulated', 'PosReg', (36, 47))	('MLN0128', 'Var', (51, 58))	('BAD proapoptotic protein', 'MPA', (0, 24))	('MLN0128', 'Chemical', 'MESH:C572449', (51, 58))
147531	28733220	Importantly, ER stress markers, including Bip and CHOP, were highly upregulated in MLN0128 treated ICC tumor samples (Fig.	('Bip', 'Gene', '14828', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('upregulated', 'PosReg', (68, 79))	('CHOP', 'Gene', (50, 54))	('ICC tumor', 'Disease', (99, 108))	('ICC tumor', 'Disease', 'MESH:C566123', (99, 108))	('MLN0128', 'Chemical', 'MESH:C572449', (83, 90))	('MLN0128 treated', 'Var', (83, 98))	('ER stress markers', 'MPA', (13, 30))	('CHOP', 'Gene', '13198', (50, 54))	('Bip', 'Gene', (42, 45))
147532	28733220	Overall, the data suggest that MLN0128 achieves disease control in early stage AKT/YapS127A ICC by triggering apoptosis, most likely via inducing ER stress.	('MLN0128', 'Var', (31, 38))	('S127A', 'Mutation', 'p.S127A', (86, 91))	('achieves', 'PosReg', (39, 47))	('triggering', 'Reg', (99, 109))	('MLN0128', 'Chemical', 'MESH:C572449', (31, 38))	('AKT/YapS127A ICC', 'Disease', (79, 95))	('apoptosis', 'CPA', (110, 119))	('inducing', 'Reg', (137, 145))
147537	28733220	The liver burden and liver weight gradually reduced after 1, 2 or 3 weeks of MLN0128 therapy (Fig.	('MLN0128', 'Var', (77, 84))	('liver burden', 'MPA', (4, 16))	('reduced', 'NegReg', (44, 51))	('liver weight', 'CPA', (21, 33))	('MLN0128', 'Chemical', 'MESH:C572449', (77, 84))
147538	28733220	MLN0128 treatment greatly improved survival, with mice at 8.5 weeks post injection being in good conditions (Fig.	('MLN0128 treatment', 'Var', (0, 17))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('survival', 'CPA', (35, 43))	('mice', 'Species', '10090', (50, 54))	('improved', 'PosReg', (26, 34))
147540	28733220	Consistent with the observation in early stage ICC treatment, MLN0128 had limited influence on cancer cell proliferation as indicated by Ki-67 staining, but promoted massive apoptosis, as shown by TUNEL assay (Fig.	('MLN0128', 'Var', (62, 69))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('Ki-67', 'Chemical', '-', (137, 142))	('MLN0128', 'Chemical', 'MESH:C572449', (62, 69))	('promoted', 'PosReg', (157, 165))	('apoptosis', 'CPA', (174, 183))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
147541	28733220	Overall, the data demonstrate that MLN0128 induces cancer cell apoptosis and leads to partial tumor regression in late stage AKT/YapS127A ICC mice.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('MLN0128', 'Var', (35, 42))	('partial', 'NegReg', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('S127A', 'Mutation', 'p.S127A', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', (94, 99))	('MLN0128', 'Chemical', 'MESH:C572449', (35, 42))	('mice', 'Species', '10090', (142, 146))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('induces', 'PosReg', (43, 50))
147547	28733220	We performed microarray analysis of AKT/YapS127A ICC and normal liver, and identified 1320 and 799 mRNAs that were upregulated and downregulated, respectively, in AKT/YapS127A ICC.	('S127A', 'Mutation', 'p.S127A', (170, 175))	('AKT/YapS127A', 'Var', (163, 175))	('S127A', 'Mutation', 'p.S127A', (43, 48))	('downregulated', 'NegReg', (131, 144))	('upregulated', 'PosReg', (115, 126))
147555	28733220	We hypothesize that YapS127A induces the de-differentiation of hepatocytes towards biliary cell lineage, and AKT/mTOR signaling promotes malignant transformation to eventually form ICC.	('induces', 'Reg', (29, 36))	('YapS127A', 'Var', (20, 28))	('ICC', 'Disease', (181, 184))	('de-differentiation', 'MPA', (41, 59))	('S127A', 'Mutation', 'p.S127A', (23, 28))	('promotes', 'PosReg', (128, 136))	('malignant transformation', 'CPA', (137, 161))
147558	28733220	As mTORC1 is a major cascade downstream of AKT, as expected, silencing of mTORC1 strongly inhibited AKT/YapS127A induced tumorigenesis.	('mTORC1', 'Gene', '382056', (74, 80))	('mTORC1', 'Gene', '382056', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('mTORC1', 'Gene', (74, 80))	('silencing', 'Var', (61, 70))	('mTORC1', 'Gene', (3, 9))	('inhibited', 'NegReg', (90, 99))	('S127A', 'Mutation', 'p.S127A', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
147559	28733220	Interestingly, ablation of mTORC2 inhibited AKT/S127A ICC development, leading instead to HCC formation in the Rictor KO genetic background.	('AKT/S127A ICC development', 'CPA', (44, 69))	('Rictor', 'Gene', '78757', (111, 117))	('ablation', 'Var', (15, 23))	('HCC formation', 'CPA', (90, 103))	('inhibited', 'NegReg', (34, 43))	('leading', 'Reg', (71, 78))	('S127A', 'Mutation', 'p.S127A', (48, 53))	('mTORC2', 'Gene', '74343', (27, 33))	('mTORC2', 'Gene', (27, 33))	('Rictor', 'Gene', (111, 117))
147560	28733220	Our preliminary data suggest that Notch signaling, a key determinant of ICC development, is suppressed by the loss of mTORC2 (Xu M, unpublished data).	('mTORC2', 'Gene', '74343', (118, 124))	('suppressed', 'NegReg', (92, 102))	('loss', 'Var', (110, 114))	('Notch signaling', 'MPA', (34, 49))	('mTORC2', 'Gene', (118, 124))
147562	28733220	Using AKT/YapS127A mice as preclinical model, we tested the therapeutic efficacy of multiple drugs, including Gemcitabine/Oxaliplatin, MLN0128, and Everolimus.	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (122, 133))	('Everolimus', 'Chemical', 'MESH:D000068338', (148, 158))	('Gemcitabine', 'Chemical', 'MESH:C056507', (110, 121))	('MLN0128', 'Var', (135, 142))	('tested', 'Reg', (49, 55))	('S127A', 'Mutation', 'p.S127A', (13, 18))	('MLN0128', 'Chemical', 'MESH:C572449', (135, 142))	('mice', 'Species', '10090', (19, 23))
147567	28733220	Because our genetic studies suggest that both mTORC1 and mTORC2 are required for cholangiocarcinogenesis, we chose to test the therapeutic efficacy of the dual mTOR inhibitor MLN0128, which has not been tested in ICC.	('mTORC2', 'Gene', (57, 63))	('cholangiocarcinogenesis', 'Disease', 'None', (81, 104))	('mTORC1', 'Gene', (46, 52))	('MLN0128', 'Chemical', 'MESH:C572449', (175, 182))	('mTORC2', 'Gene', '74343', (57, 63))	('cholangiocarcinogenesis', 'Disease', (81, 104))	('mTORC1', 'Gene', '382056', (46, 52))	('MLN0128', 'Var', (175, 182))
147568	28733220	Here, we show that MLN0128 efficiently inhibits the growth of a panel of human ICC cells with high AKT/mTOR activity, mainly via inducing apoptosis.	('growth', 'CPA', (52, 58))	('human', 'Species', '9606', (73, 78))	('MLN0128', 'Var', (19, 26))	('apoptosis', 'CPA', (138, 147))	('inducing', 'Reg', (129, 137))	('inhibits', 'NegReg', (39, 47))	('MLN0128', 'Chemical', 'MESH:C572449', (19, 26))
147569	28733220	Furthermore, we found that MLN0128 leads to stable disease in AKT/YapS127A mice when administered in early stage of tumorigenesis and partial regression when given at late stage.	('S127A', 'Mutation', 'p.S127A', (69, 74))	('mice', 'Species', '10090', (75, 79))	('MLN0128', 'Var', (27, 34))	('stable disease', 'Disease', (44, 58))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('MLN0128', 'Chemical', 'MESH:C572449', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
147571	28733220	Mechanistically, we demonstrated that the in vivo anti-tumor activity of MLN0128 is mainly due to apoptosis induction.	('apoptosis induction', 'CPA', (98, 117))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('MLN0128', 'Var', (73, 80))	('tumor', 'Disease', (55, 60))	('MLN0128', 'Chemical', 'MESH:C572449', (73, 80))
147572	28733220	Further evidence indicates that MLN0128 promotes ER stress in AKT/YapS127A ICC cells, resulting in the expression of the pro-apoptotic gene CHOP.	('ER stress', 'MPA', (49, 58))	('S127A', 'Mutation', 'p.S127A', (69, 74))	('CHOP', 'Gene', '13198', (140, 144))	('expression', 'MPA', (103, 113))	('MLN0128', 'Var', (32, 39))	('CHOP', 'Gene', (140, 144))	('MLN0128', 'Chemical', 'MESH:C572449', (32, 39))	('promotes', 'PosReg', (40, 48))
147574	28733220	Differently from this study, however, no changes in DR5 mRNA expression were detected in MLN0128 treated AKT/YapS127A ICC (Supplementary Fig.	('DR5', 'Gene', '21933', (52, 55))	('MLN0128', 'Chemical', 'MESH:C572449', (89, 96))	('DR5', 'Gene', (52, 55))	('MLN0128 treated', 'Var', (89, 104))	('S127A', 'Mutation', 'p.S127A', (112, 117))
147576	28733220	It would be important to identify the arm of ER Stress/UPR modulated by MLN0128 in ICC tumor cells and mechanisms contributing to MLN0128 induced apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('MLN0128', 'Var', (72, 79))	('Stress', 'Disease', (48, 54))	('MLN0128', 'Var', (130, 137))	('ICC tumor', 'Disease', (83, 92))	('MLN0128', 'Chemical', 'MESH:C572449', (72, 79))	('ICC tumor', 'Disease', 'MESH:C566123', (83, 92))	('Stress', 'Disease', 'MESH:D004194', (48, 54))	('MLN0128', 'Chemical', 'MESH:C572449', (130, 137))
147577	28733220	Altogether, our in vitro and in vivo data support further investigation on MLN0128 and other pan-mTOR inhibitors for ICC treatment.	('ICC', 'Disease', (117, 120))	('MLN0128', 'Var', (75, 82))	('MLN0128', 'Chemical', 'MESH:C572449', (75, 82))
147582	28733220	The anti-neoplastic potential of MLN0128 may be superior to Gemcitabine/Oxaliplatin based chemotherapy for the treatment of ICC, especially in the ICCs exhibiting activated AKT/mTOR cascade.	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (72, 83))	('anti-neoplastic potential', 'CPA', (4, 29))	('MLN0128', 'Var', (33, 40))	('Gemcitabine', 'Chemical', 'MESH:C056507', (60, 71))	('MLN0128', 'Chemical', 'MESH:C572449', (33, 40))	('ICC', 'Disease', (124, 127))
147623	29278425	Intriguingly, patients lacking all 3 mutations ('undetermined') harbored the most extensive structural alterations while IDH mutant tumors displayed the most extensive DNA methylome dysregulation, consistent with previous findings.	('mutant', 'Var', (125, 131))	('structural alterations', 'MPA', (92, 114))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('IDH', 'Gene', (121, 124))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('IDH', 'Gene', '3417', (121, 124))	('tumors', 'Disease', (132, 138))	('DNA methylome dysregulation', 'MPA', (168, 195))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('patients', 'Species', '9606', (14, 22))
147624	29278425	Stratification of iCCA patients based on occurrence of mutations in three classifier genes (IDH, KRAS, TP53) revealed unique oncogenic programs (mutational, structural, epi-mutational) that influence pharmacologic response in drug repositioning protocols.	('epi-mutational', 'Var', (169, 183))	('TP53', 'Gene', '7157', (103, 107))	('KRAS', 'Gene', (97, 101))	('mutations', 'Var', (55, 64))	('patients', 'Species', '9606', (23, 31))	('TP53', 'Gene', (103, 107))	('iCCA', 'Disease', (18, 22))	('IDH', 'Gene', (92, 95))	('IDH', 'Gene', '3417', (92, 95))	('influence', 'Reg', (190, 199))
147631	29278425	While no targeted therapy has been approved to date, FGFR2 inhibitors (e.g.	('FGFR2', 'Gene', '2263', (53, 58))	('FGFR2', 'Gene', (53, 58))	('inhibitors', 'Var', (59, 69))
147636	29278425	As such, mutations in IDH1 and IDH2 have already been associated with unique genomic features (DNA hypermethylation, altered chromatin remodeler expression, increased copy number and expression of mitochondrial genes), as well as sensitivity to dasatinib and PARP inhibitors.	('IDH2', 'Gene', '3418', (31, 35))	('altered', 'Reg', (117, 124))	('chromatin remodeler expression', 'MPA', (125, 155))	('mutations', 'Var', (9, 18))	('IDH1', 'Gene', (22, 26))	('PARP', 'Gene', '1302', (259, 263))	('PARP', 'Gene', (259, 263))	('expression', 'MPA', (183, 193))	('increased', 'PosReg', (157, 166))	('mitochondrial', 'Gene', (197, 210))	('IDH1', 'Gene', '3417', (22, 26))	('dasatinib', 'Chemical', 'MESH:D000069439', (245, 254))	('copy', 'MPA', (167, 171))	('IDH2', 'Gene', (31, 35))	('associated', 'Reg', (54, 64))
147637	29278425	The potential for individual driver mutations to influence diverse tumor networks is intriguing and remains to be evaluated for other recurrently mutated genes in iCCA, such as KRAS, TP53 and chromatin remodeling enzymes (e.g., ARID1A and BAP1).	('tumor', 'Disease', (67, 72))	('TP53', 'Gene', '7157', (183, 187))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('mutations', 'Var', (36, 45))	('TP53', 'Gene', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('BAP1', 'Gene', '8314', (239, 243))	('ARID1A', 'Gene', '8289', (228, 234))	('iCCA', 'Disease', (163, 167))	('ARID1A', 'Gene', (228, 234))	('influence', 'Reg', (49, 58))	('BAP1', 'Gene', (239, 243))
147638	29278425	Accordingly, we aimed to deconstruct the molecular programs of iCCA tumors associated with specific individual mutations.	('mutations', 'Var', (111, 120))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
147639	29278425	To this end, we grouped 496 patients into four subgroups where three were classified based on the most recurrent somatic mutations (IDH, KRAS and TP53) and the remaining based on wild-type status for these genes (referred to as 'undetermined group').	('TP53', 'Gene', '7157', (146, 150))	('IDH', 'Gene', (132, 135))	('TP53', 'Gene', (146, 150))	('IDH', 'Gene', '3417', (132, 135))	('KRAS', 'Var', (137, 141))	('patients', 'Species', '9606', (28, 36))
147640	29278425	This stratification approach unveiled distinct mutational signatures and co-mutations, pathway-enrichment and pharmacologic response profiles between subgroups, as well as suggesting an enhanced role of structural and epigenomic alterations in undetermined group tumors.	('epigenomic alterations', 'Var', (218, 240))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('mutational', 'Var', (47, 57))	('enhanced', 'PosReg', (186, 194))	('tumors', 'Disease', (263, 269))
147641	29278425	These findings uncover the potential of individual mutations to induce substantial downstream molecular heterogeneity which could facilitate prediction of therapeutic sensitivities for iCCA patients using standard targeted genotyping.	('induce', 'Reg', (64, 70))	('iCCA', 'Disease', (185, 189))	('mutations', 'Var', (51, 60))	('patients', 'Species', '9606', (190, 198))
147657	29278425	FGFR2 fusions were predicted using BreakDancer.	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (6, 13))	('FGFR2', 'Gene', '2263', (0, 5))
147661	29278425	Subsequent analysis of WES-cohort (Table S2-3) corroborated our TES-cohort findings where TP53 (n=57/277; 20%), KRAS (n=44/277; 16%) and IDH1/IDH2 (n=31/277; 11%) were most prevalent (Fig.	('TES', 'Chemical', '-', (64, 67))	('IDH2', 'Gene', '3418', (142, 146))	('TP53', 'Gene', '7157', (90, 94))	('IDH1', 'Gene', '3417', (137, 141))	('IDH1', 'Gene', (137, 141))	('prevalent', 'Reg', (173, 182))	('TP53', 'Gene', (90, 94))	('KRAS', 'Var', (112, 116))	('IDH2', 'Gene', (142, 146))
147662	29278425	Mutations in IDH1 (R132C/G/L) and KRAS (G12A/C/D) were recurrent hotspots, while TP53 mutations were distributed throughout its entire gene body (Fig.	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('G12A', 'Mutation', 'rs121913529', (40, 44))	('TP53', 'Gene', '7157', (81, 85))	('R132C', 'Var', (19, 24))	('TP53', 'Gene', (81, 85))	('R132C', 'SUBSTITUTION', 'None', (19, 24))
147664	29278425	Importantly, co-occurrence of IDH1/KRAS mutations (TES-cohort: n=1/150; 0.7%; WES-cohort: n=1/277; 0.4%) and IDH1/TP53 (TES-cohort: n=3/150, 2%; WES-cohort: n=1/277, 0.4%) was rare, suggesting mutual exclusivity (Fig.	('TES', 'Chemical', '-', (120, 123))	('IDH1', 'Gene', (109, 113))	('TP53', 'Gene', '7157', (114, 118))	('IDH1', 'Gene', (30, 34))	('mutations', 'Var', (40, 49))	('TES', 'Chemical', '-', (51, 54))	('IDH1', 'Gene', '3417', (109, 113))	('TP53', 'Gene', (114, 118))	('IDH1', 'Gene', '3417', (30, 34))
147670	29278425	Clinically, FGFR2 fusion-positive status was associated with shorter overall survival (P<0.0001; Supporting Fig.	('shorter', 'NegReg', (61, 68))	('overall survival', 'MPA', (69, 85))	('FGFR2', 'Gene', (12, 17))	('FGFR2', 'Gene', '2263', (12, 17))	('fusion-positive', 'Var', (18, 33))
147671	29278425	Similarly, in previously reported FGFR2 fusions from RNAseq data (n=117/277; 42.2%; Japanese patients), FGFR2 fusions are predominant in Udt-gr (n=3/4; 75%) (Supporting Fig.	('FGFR2', 'Gene', (34, 39))	('FGFR2', 'Gene', '2263', (34, 39))	('FGFR2', 'Gene', (104, 109))	('FGFR2', 'Gene', '2263', (104, 109))	('patients', 'Species', '9606', (93, 101))	('fusions', 'Var', (110, 117))
147677	29278425	IDH-gr displayed a specific enrichment of C>A transversions (67%, P=7.01x10-132) (signature 18, 28) (Fig.	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (0, 3))	('C>A transversions', 'Var', (42, 59))
147678	29278425	As such, C>A transversions have been associated with oxidative stress, complementing previous studies characterizing the physiological role of wild type IDH1 in protecting hepatocytes from oxidative stress.	('oxidative stress', 'Phenotype', 'HP:0025464', (53, 69))	('C>A transversions', 'Var', (9, 26))	('IDH1', 'Gene', (153, 157))	('IDH1', 'Gene', '3417', (153, 157))	('oxidative stress', 'Phenotype', 'HP:0025464', (189, 205))	('oxidative stress', 'MPA', (53, 69))	('associated', 'Reg', (37, 47))
147680	29278425	Also, promoters of genes mutated in KRAS-gr were enriched for FOSL2 motif binding sites (Supporting Fig.	('FOSL2', 'Gene', (62, 67))	('KRAS-gr', 'Gene', (36, 43))	('FOSL2', 'Gene', '2355', (62, 67))	('mutated', 'Var', (25, 32))	('binding', 'Interaction', (74, 81))
147683	29278425	Although, a significant enrichment of R249S mutations were detected in TP53-gr (Fig.	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('R249S', 'Mutation', 'rs28934571', (38, 43))	('R249S', 'Var', (38, 43))
147685	29278425	Also, R249S did not display a significant relationship with HBV status (P=0.48, Fisher's exact test) or overall survival (P=0.917) when comparing with patients manifesting other TP53-specific mutations.	('TP53', 'Gene', '7157', (178, 182))	('TP53', 'Gene', (178, 182))	('patients', 'Species', '9606', (151, 159))	('R249S', 'Mutation', 'rs28934571', (6, 11))	('HBV status', 'Disease', (60, 70))	('R249S', 'Var', (6, 11))	('HBV', 'Species', '10407', (60, 63))
147693	29278425	Among the previously reported chromatin modifier genes, ARID1A mutations were present in IDH-gr, KRAS-gr and Udt-gr but only significantly enriched with Udt-gr tumors (P=8.86x10-8), while BAP1 was preferentially associated with IDH-gr (P=2.57x10-8).	('mutations', 'Var', (63, 72))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('BAP1', 'Gene', (188, 192))	('Udt-gr', 'Disease', (153, 159))	('IDH', 'Gene', (228, 231))	('ARID1A', 'Gene', '8289', (56, 62))	('BAP1', 'Gene', '8314', (188, 192))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('ARID1A', 'Gene', (56, 62))	('IDH', 'Gene', (89, 92))	('IDH', 'Gene', '3417', (228, 231))	('tumors', 'Disease', (160, 166))	('IDH', 'Gene', '3417', (89, 92))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
147695	29278425	In the WES-cohort of 142 tumor/normal patient samples, KRAS-gr and TP53-gr were significantly associated with poor overall survival (P=0.003; Fig.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('overall survival', 'MPA', (115, 131))	('tumor', 'Disease', (25, 30))	('patient', 'Species', '9606', (38, 45))	('amp', 'Chemical', 'MESH:D000249', (47, 50))	('KRAS-gr', 'Var', (55, 62))	('TP53', 'Gene', '7157', (67, 71))	('poor', 'NegReg', (110, 114))	('TP53', 'Gene', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
147696	29278425	These findings were confirmed in two independent cohorts whereby KRAS-gr was associated with worse overall survival in TES-cohort (N=150) (P=0.0004; Fig.	('KRAS-gr', 'Var', (65, 72))	('worse', 'NegReg', (93, 98))	('overall survival', 'MPA', (99, 115))	('TES', 'Chemical', '-', (119, 122))
147697	29278425	3G) and both KRAS-gr and TP53-gr were correlated with worse overall survival (P=0.0001; Fig.	('TP53', 'Gene', (25, 29))	('KRAS-gr', 'Var', (13, 20))	('overall survival', 'MPA', (60, 76))	('TP53', 'Gene', '7157', (25, 29))	('worse', 'NegReg', (54, 59))
147699	29278425	KRAS-gr was highly enriched for various immune-related pathways, including ErbB (P=4.39x10-17), VEGF (P=2.49x10-16) and actin cytoskeleton rearrangement (P=4.7x10-10).	('KRAS-gr', 'Var', (0, 7))	('VEGF', 'Gene', '7422', (96, 100))	('ErbB', 'Gene', '1956', (75, 79))	('ErbB', 'Gene', (75, 79))	('actin', 'CPA', (120, 125))	('VEGF', 'Gene', (96, 100))
147701	29278425	Since mutations in KRAS and TP53 occur in a small subset of patients, pathway enrichment in dual mutants was independently assessed.	('TP53', 'Gene', '7157', (28, 32))	('patients', 'Species', '9606', (60, 68))	('TP53', 'Gene', (28, 32))	('KRAS', 'Gene', (19, 23))	('mutations', 'Var', (6, 15))
147715	29278425	As such, KRAS- and IDH-grs have few recurrent focal SCNAs, while TP53- and Udt-gr tumors have comparably higher frequency of recurrent structural variants (and encoded genes) (Supporting Fig.	('TP53', 'Gene', '7157', (65, 69))	('tumors', 'Disease', (82, 88))	('TP53', 'Gene', (65, 69))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('structural variants', 'Var', (135, 154))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('IDH', 'Gene', (19, 22))	('IDH', 'Gene', '3417', (19, 22))	('focal SCNAs', 'Disease', (46, 57))
147716	29278425	Recurrent deletions were significant across all four groups, while recurrent amplifications were only significant in TP53- and Udt-gr (Fig.	('amp', 'Chemical', 'MESH:D000249', (77, 80))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('deletions', 'Var', (10, 19))	('Udt-gr', 'Gene', (127, 133))
147718	29278425	We then examined whether recurrent SCNA segments were correlated with transposons, microsatellite instability (MSI) or HBV integrations but found no significant correlation (Supporting Fig.	('HBV', 'Species', '10407', (119, 122))	('transposons', 'Var', (70, 81))	('microsatellite', 'MPA', (83, 97))	('correlated', 'Reg', (54, 64))	('MSI', 'Disease', 'None', (111, 114))	('MSI', 'Disease', (111, 114))
147721	29278425	In contrast, KRAS-gr showed enrichment of multiple immune-related processes (NK cytotoxicity, JAK/STAT and cytokine signaling), complementing our findings from SNVs of widespread immune pathway subversion in these patients (Fig.	('patients', 'Species', '9606', (214, 222))	('KRAS-gr', 'Var', (13, 20))	('cytotoxicity', 'Disease', 'MESH:D064420', (80, 92))	('STAT', 'Disease', 'None', (98, 102))	('STAT', 'Disease', (98, 102))	('cytotoxicity', 'Disease', (80, 92))
147727	29278425	Given the fact that the copy number status has been reported to have little effect on DNA methylation alterations, here we demonstrate an additional independent molecular patho-mechanism that may positively affect iCCA subtypes and influence tumor behavior as well as therapeutic response.	('influence', 'Reg', (232, 241))	('tumor behavior', 'Disease', 'MESH:D001523', (242, 256))	('copy', 'Var', (24, 28))	('therapeutic response', 'CPA', (268, 288))	('affect', 'Reg', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('iCCA', 'Disease', (214, 218))	('tumor behavior', 'Disease', (242, 256))	('positively', 'PosReg', (196, 206))
147731	29278425	Patients harboring METTL13 amplification display greater overall survival (P=0.00033; Fig.	('greater', 'PosReg', (49, 56))	('METTL13', 'Gene', (19, 26))	('Patients', 'Species', '9606', (0, 8))	('METTL13', 'Gene', '51603', (19, 26))	('overall survival', 'MPA', (57, 73))	('amp', 'Chemical', 'MESH:D000249', (27, 30))	('amplification', 'Var', (27, 40))
147732	29278425	KEGG pathway analysis of METTL13 amplification-unique DMRs revealed enrichment of transcriptional control and kinase signaling pathways (Fig 6F).	('amplification-unique', 'Var', (33, 53))	('DM', 'Disease', 'MESH:D009223', (54, 56))	('kinase signaling pathways', 'Pathway', (110, 135))	('amp', 'Chemical', 'MESH:D000249', (33, 36))	('METTL13', 'Gene', '51603', (25, 32))	('transcriptional control', 'Pathway', (82, 105))	('METTL13', 'Gene', (25, 32))
147733	29278425	As such, METTL13 amplification could potentially contribute to the elusive pathogenicity of Udt-gr tumors (Supporting Fig.	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('amplification', 'Var', (17, 30))	('amp', 'Chemical', 'MESH:D000249', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('contribute', 'Reg', (49, 59))	('METTL13', 'Gene', '51603', (9, 16))	('tumors', 'Disease', (99, 105))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('METTL13', 'Gene', (9, 16))
147735	29278425	Previous efforts have identified individual genomic events responsible for specific therapeutic sensitivities (e.g., IDH mutations and FGFR2 fusions) and broad clusters of patients with diverse characteristic pathobiological properties.	('IDH', 'Gene', (117, 120))	('FGFR2', 'Gene', (135, 140))	('FGFR2', 'Gene', '2263', (135, 140))	('IDH', 'Gene', '3417', (117, 120))	('patients', 'Species', '9606', (172, 180))	('fusions', 'Var', (141, 148))
147739	29278425	Hotspot mutations in KRAS (G12A/C/D) play a significant role in iCCA initiation in mouse models and are associated with a proliferation subgroup of patients with poor prognosis.	('iCCA', 'Disease', (64, 68))	('patients', 'Species', '9606', (148, 156))	('G12A', 'Mutation', 'rs121913529', (27, 31))	('mouse', 'Species', '10090', (83, 88))	('mutations', 'Var', (8, 17))	('associated with', 'Reg', (104, 119))
147740	29278425	Mutational inactivation of tumor suppressor TP53 contributes to this tumor formation in vivo and was previously correlated with hypermutated patient tumors.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Mutational inactivation', 'Var', (0, 23))	('patient', 'Species', '9606', (141, 148))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumor', 'Disease', (149, 154))	('TP53', 'Gene', '7157', (44, 48))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('TP53', 'Gene', (44, 48))
147741	29278425	Unlike KRAS, no mutational hotspot exists in TP53 and different mutations in this gene have been shown to generate diverse neomorphic mutants with varied cellular effects (reviewed in), indicating the potential for additional network heterogeneity within this subgroup.	('TP53', 'Gene', (45, 49))	('mutations', 'Var', (64, 73))	('generate', 'Reg', (106, 114))	('mutants', 'Var', (134, 141))	('TP53', 'Gene', '7157', (45, 49))
147742	29278425	Functionally nonsynonymous hotspot mutations in IDH1 (R132) and IDH2 (R172) promote cholangiocarcinogenesis through repression of hepatocyte differentiation.	('promote', 'PosReg', (76, 83))	('IDH2', 'Gene', (64, 68))	('IDH1', 'Gene', '3417', (48, 52))	('IDH2', 'Gene', '3418', (64, 68))	('cholangiocarcinogenesis', 'Disease', (84, 107))	('R172', 'Var', (70, 74))	('IDH1', 'Gene', (48, 52))	('mutations', 'Var', (35, 44))
147743	29278425	Prediction of sufficiency of 3 mutations to induce invasive carcinoma, however, reinforces the missing molecular pathogenicity garnered through use of single-gene dissection of tumors.	('mutations', 'Var', (31, 40))	('sufficiency', 'Disease', 'None', (14, 25))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('sufficiency', 'Disease', (14, 25))	('invasive carcinoma', 'Disease', (51, 69))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('tumors', 'Disease', (177, 183))	('invasive carcinoma', 'Disease', 'MESH:D009361', (51, 69))	('induce', 'Reg', (44, 50))
147745	29278425	Such mutations may be complimentary in a minority of patients given their opposing nature as oncogenes and tumor suppressors, or potentially if they arise at different times during cellular transformation.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('patients', 'Species', '9606', (53, 61))	('tumor', 'Disease', (107, 112))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
147746	29278425	Indeed, KRAS- and TP53-gr tumors share the greatest similarity in altered pathways.	('KRAS-', 'Var', (8, 13))	('TP53', 'Gene', '7157', (18, 22))	('altered pathways', 'Pathway', (66, 82))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('TP53', 'Gene', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
147750	29278425	Conversely, KRAS mutations are highly recurrent in pancreatic cancer and perihilar CCA (pCCA), potentially suggesting a more likely origin from peribiliary glands.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('pancreatic cancer', 'Disease', (51, 68))	('KRAS', 'Gene', (12, 16))	('pancreatic cancer', 'Disease', 'MESH:D010190', (51, 68))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (51, 68))	('perihilar CCA', 'Disease', (73, 86))	('mutations', 'Var', (17, 26))
147755	29278425	This agrees with pan-cancer studies that have identified trade-offs between mutational ('M-class') and structural/copy number ('C-class'), as well as large-scale pan-cancer pharmacogenomics studies that identify different contributions from diverse 'cancer functional events' (including mutation, structural alteration and DNA methylation).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('mutation', 'Var', (287, 295))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('structural alteration', 'Var', (297, 318))	("'cancer", 'Disease', (249, 256))	('cancer', 'Disease', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	("'cancer", 'Disease', 'MESH:D009369', (249, 256))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
147756	29278425	Specifically, METTL13 amplification was detected in more than 70% of the Udt-gr tumors with pan-cancer analysis revealing it to be most recurrent in cholangiocarcinoma.	('amp', 'Chemical', 'MESH:D000249', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Udt-gr', 'Gene', (73, 79))	('cholangiocarcinoma', 'Disease', (149, 167))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('amplification', 'Var', (22, 35))	('METTL13', 'Gene', '51603', (14, 21))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('METTL13', 'Gene', (14, 21))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (149, 167))	('cancer', 'Disease', (96, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (149, 167))
147757	29278425	Previous studies have reported METTL13 amplification in HCV-associated hepatocellular carcinoma, conflicting with its downregulation in bladder cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('amp', 'Chemical', 'MESH:D000249', (39, 42))	('amplification', 'Var', (39, 52))	('METTL13', 'Gene', '51603', (31, 38))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (71, 95))	('bladder cancer', 'Disease', 'MESH:D001749', (136, 150))	('bladder cancer', 'Disease', (136, 150))	('hepatocellular carcinoma', 'Disease', (71, 95))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (71, 95))	('METTL13', 'Gene', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
147762	29278425	Importantly, lack of specific mutations did not dictate a complete absence of therapeutic response and similarly, co-mutations appeared to be capable of influencing therapeutic benefit (as evident in the dual KRAS and IDH1 mutant RBE cell line).	('therapeutic', 'MPA', (165, 176))	('influencing', 'Reg', (153, 164))	('IDH1', 'Gene', (218, 222))	('IDH1', 'Gene', '3417', (218, 222))	('co-mutations', 'Var', (114, 126))
147775	28120369	Results: BDL-induced liver damage was reduced in the BDL KitW-sh mice, whereas injection of MCs did not mimic BDL-induced damage.	('BDL', 'Chemical', '-', (9, 12))	('BDL', 'Chemical', '-', (53, 56))	('reduced', 'NegReg', (38, 45))	('liver damage', 'Disease', (21, 33))	('mice', 'Species', '10090', (65, 69))	('liver damage', 'Disease', 'MESH:D056486', (21, 33))	('BDL-induced', 'Disease', (9, 20))	('BDL', 'Var', (53, 56))	('BDL', 'Chemical', '-', (110, 113))
147782	28120369	Knockout of MCs decreases BDL-induced damage.	('BDL', 'Chemical', '-', (26, 29))	('MCs', 'Gene', (12, 15))	('decreases BDL', 'Phenotype', 'HP:0003563', (16, 29))	('Knockout', 'Var', (0, 8))	('BDL-induced', 'Disease', (26, 37))	('decreases', 'NegReg', (16, 25))
147783	28120369	Modulation of MCs may be important in developing therapeutics for cholangiopathies.	('Modulation', 'Var', (0, 10))	('cholangiopathies', 'Disease', (66, 82))	('cholangiopathies', 'Disease', 'None', (66, 82))	('MCs', 'Gene', (14, 17))
147799	28120369	Different white spotting (W) locus (c-kit) mutant rodents have been developed and investigated as models for the analysis of mast cell function, including KitW/W-v and KitW-f/W-f mice and KitW-s/W-s rats.	('mice', 'Species', '10090', (179, 183))	('rats', 'Species', '10116', (199, 203))	('mutant', 'Var', (43, 49))	('c-kit', 'Gene', '16590', (36, 41))	('c-kit', 'Gene', (36, 41))
147847	28120369	In BDL KitW-sh mice there is an overall reduction of biliary mass compared to BDL WT mice (Figure 2A).	('mice', 'Species', '10090', (85, 89))	('biliary mass', 'MPA', (53, 65))	('BDL', 'Var', (3, 6))	('BDL', 'Chemical', '-', (3, 6))	('BDL', 'Chemical', '-', (78, 81))	('reduction', 'NegReg', (40, 49))	('mice', 'Species', '10090', (15, 19))
147848	28120369	As expected, biliary proliferation (indicated by red arrows) was significantly decreased in BDL KitW-sh mice compared to BDL WT (Figure 2C).	('biliary proliferation', 'CPA', (13, 34))	('BDL', 'Chemical', '-', (121, 124))	('decreased', 'NegReg', (79, 88))	('mice', 'Species', '10090', (104, 108))	('BDL', 'Chemical', '-', (92, 95))	('BDL KitW-sh', 'Var', (92, 103))	('rat', 'Species', '10116', (28, 31))
147850	28120369	Collagen deposition is dramatically reduced in BDL KitW-sh mice compared to BDL WT mice as shown by Masson's Trichrome and Fast Green/Sirius Red staining (Figure 3A and 3B, respectively).	('mice', 'Species', '10090', (59, 63))	('BDL', 'Chemical', '-', (47, 50))	('Collagen deposition', 'CPA', (0, 19))	('mice', 'Species', '10090', (83, 87))	('reduced', 'NegReg', (36, 43))	('BDL KitW-sh', 'Var', (47, 58))	('KitW-sh', 'Var', (51, 58))	('BDL', 'Chemical', '-', (76, 79))	('Sirius Red', 'Chemical', '-', (134, 144))
147851	28120369	Semi-quantification of Fast Green/Sirius Red staining shows a significant decrease in collagen deposition in BDL KitW-sh mice compared to BDL WT (Figure 3C).	('decrease', 'NegReg', (74, 82))	('Sirius Red', 'Chemical', '-', (34, 44))	('BDL', 'Chemical', '-', (109, 112))	('collagen deposition', 'CPA', (86, 105))	('BDL KitW-sh', 'Var', (109, 120))	('mice', 'Species', '10090', (121, 125))	('BDL', 'Chemical', '-', (138, 141))
147852	28120369	Hydroxyproline content was significantly reduced in BDL KitW-sh mice compared to BDL WT (Figure 3D).	('reduced', 'NegReg', (41, 48))	('Hydroxyproline content', 'MPA', (0, 22))	('BDL KitW-sh', 'Var', (52, 63))	('BDL', 'Chemical', '-', (81, 84))	('Hydroxyproline', 'Chemical', 'MESH:D006909', (0, 14))	('mice', 'Species', '10090', (64, 68))	('BDL', 'Chemical', '-', (52, 55))
147853	28120369	The expression of alpha-SMA, fibronectin-1 and collagen type-1a increased in BDL WT mice compared to sham WT; whereas, these markers were decreased in BDL KitW-sh mice compared to BDL WT mice (Supplemental Figure 2).	('BDL', 'Chemical', '-', (77, 80))	('alpha-SMA', 'Protein', (18, 27))	('expression', 'MPA', (4, 14))	('BDL', 'Chemical', '-', (151, 154))	('mice', 'Species', '10090', (187, 191))	('BDL', 'Var', (77, 80))	('BDL', 'Chemical', '-', (180, 183))	('mice', 'Species', '10090', (163, 167))	('increased', 'PosReg', (64, 73))	('fibronectin-1 and collagen type-1a', 'Gene', '14268', (29, 63))	('mice', 'Species', '10090', (84, 88))
147857	28120369	Similarly, histamine serum release was increased in BDL WT mice compared to sham WT; whereas, histamine release decreased in BDL KitW-sh mice compared to BDL WT (Supplemental Figure 3C).	('BDL', 'Chemical', '-', (125, 128))	('BDL', 'Chemical', '-', (52, 55))	('mice', 'Species', '10090', (59, 63))	('BDL', 'Chemical', '-', (154, 157))	('BDL', 'Var', (52, 55))	('histamine', 'Chemical', 'MESH:D006632', (94, 103))	('histamine', 'Chemical', 'MESH:D006632', (11, 20))	('increased', 'PosReg', (39, 48))	('histamine release', 'MPA', (94, 111))	('decreased', 'NegReg', (112, 121))	('mice', 'Species', '10090', (137, 141))	('histamine serum release', 'MPA', (11, 34))
147869	28120369	Taken together these data strongly suggest that the reintroduction of mast cells alters the proliferative capacity of cholangiocytes and the vascular bed in mast cell deficient mice.	('alters', 'Reg', (81, 87))	('rat', 'Species', '10116', (99, 102))	('proliferative capacity of', 'CPA', (92, 117))	('mice', 'Species', '10090', (177, 181))	('reintroduction', 'Var', (52, 66))
147873	28120369	It should be noted that this data, coupled with the H&E and ALT levels (Figure 1C and 1D), which showed no visible alterations in liver morphology and function, suggest that mast cell injection increases proliferation and fibrosis, but does not mimic the damage induced by BDL.	('ALT', 'Gene', (60, 63))	('fibrosis', 'Disease', (222, 230))	('fibrosis', 'Disease', 'MESH:D005355', (222, 230))	('BDL', 'Chemical', '-', (273, 276))	('rat', 'Species', '10116', (211, 214))	('injection', 'PosReg', (184, 193))	('rat', 'Species', '10116', (119, 122))	('ALT', 'Gene', '76282', (60, 63))	('H&E', 'Chemical', 'MESH:D006371', (52, 55))	('increases', 'CPA', (194, 203))	('cell', 'Var', (179, 183))	('and', 'CPA', (218, 221))
147882	28120369	Biliary hyperplasia following BDL is the livers first attempt to repair the injured bile duct and our data suggests that mast cells are also critical to this event as there is a dramatic decrease in biliary mass and proliferation in BDL KitW-sh mice compared to BDL WT mice.	('BDL', 'Var', (233, 236))	('biliary mass', 'CPA', (199, 211))	('BDL', 'Chemical', '-', (30, 33))	('Biliary hyperplasia', 'Disease', (0, 19))	('Biliary hyperplasia', 'Disease', 'MESH:D006965', (0, 19))	('Biliary hyperplasia', 'Phenotype', 'HP:0006560', (0, 19))	('BDL', 'Chemical', '-', (233, 236))	('rat', 'Species', '10116', (223, 226))	('mice', 'Species', '10090', (269, 273))	('mice', 'Species', '10090', (245, 249))	('decrease', 'NegReg', (187, 195))	('BDL', 'Chemical', '-', (262, 265))	('proliferation', 'CPA', (216, 229))
147883	28120369	In addition, the reintroduction of mast cells into mast cell deficient mice resulted in large increases in both IBDM and cholangiocyte proliferation suggesting that mast cells are essential during these events.	('mice', 'Species', '10090', (71, 75))	('cholangiocyte proliferation', 'CPA', (121, 148))	('increases', 'PosReg', (94, 103))	('reintroduction', 'Var', (17, 31))	('rat', 'Species', '10116', (142, 145))
147887	28120369	Studies have demonstrated that (i) mast cells promote tissue fibrosis; (ii) loss of mast cells induces fibrosis leading to a worsening condition and (iii) mast cells play no real role in tissue fibrosis.	('fibrosis', 'Disease', 'MESH:D005355', (61, 69))	('promote', 'PosReg', (46, 53))	('fibrosis', 'Disease', (61, 69))	('loss', 'Var', (76, 80))	('fibrosis', 'Disease', (103, 111))	('worsening condition', 'MPA', (125, 144))	('fibrosis', 'Disease', 'MESH:D005355', (103, 111))	('rat', 'Species', '10116', (20, 23))	('fibrosis', 'Disease', 'MESH:D005355', (194, 202))	('fibrosis', 'Disease', (194, 202))	('mast cells', 'Gene', (84, 94))	('induces', 'Reg', (95, 102))
147890	28120369	In contrast to our current work, an early study by Sugihara, et al., demonstrated that mast cells have no consequence on the development of liver fibrosis in rats and mice; whereas, our present studies indicate that mast cell introduction (shown by mast cell injection into deficient mice) induces robust hepatic fibrosis and there is decreased fibrotic progression in BDL KitW-sh compared to the BDL WT.	('decreased', 'NegReg', (335, 344))	('liver fibrosis', 'Phenotype', 'HP:0001395', (140, 154))	('BDL', 'Chemical', '-', (369, 372))	('rat', 'Species', '10116', (76, 79))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (305, 321))	('rats', 'Species', '10116', (158, 162))	('fibrotic progression', 'CPA', (345, 365))	('liver fibrosis', 'Disease', (140, 154))	('BDL KitW-sh', 'Var', (369, 380))	('hepatic fibrosis', 'Disease', (305, 321))	('rat', 'Species', '10116', (158, 161))	('liver fibrosis', 'Disease', 'MESH:D008103', (140, 154))	('hepatic fibrosis', 'Disease', 'MESH:D008103', (305, 321))	('mice', 'Species', '10090', (167, 171))	('mice', 'Species', '10090', (284, 288))	('BDL', 'Chemical', '-', (397, 400))
147896	28120369	We found that ablation of mast cells significantly reduces BDL-induced TGF-beta1 expression and secretion.	('expression', 'MPA', (81, 91))	('reduces', 'NegReg', (51, 58))	('TGF-beta1', 'Gene', '21803', (71, 80))	('secretion', 'MPA', (96, 105))	('TGF-beta1', 'Gene', (71, 80))	('BDL', 'Chemical', '-', (59, 62))	('ablation', 'Var', (14, 22))
147904	28120369	Stabilization of mast cells using cromolyn sodium has demonstrated that inhibition of mast cell-derived histamine decreases biliary hyperplasia, fibrosis and cholangiocarcinoma growth, pinpointing mast cell-derived histamine as a culprit in various cholangiopathies.	('decreases biliary hyperplasia', 'Disease', 'MESH:D006965', (114, 143))	('biliary hyperplasia', 'Phenotype', 'HP:0006560', (124, 143))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (158, 176))	('cromolyn sodium', 'Chemical', 'MESH:D004205', (34, 49))	('rat', 'Species', '10116', (61, 64))	('histamine', 'Chemical', 'MESH:D006632', (104, 113))	('inhibition', 'Var', (72, 82))	('cholangiopathies', 'Disease', (249, 265))	('fibrosis', 'Disease', 'MESH:D005355', (145, 153))	('fibrosis', 'Disease', (145, 153))	('cholangiopathies', 'Disease', 'None', (249, 265))	('cholangiocarcinoma growth', 'Disease', (158, 183))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (158, 183))	('decreases biliary hyperplasia', 'Disease', (114, 143))	('histamine', 'Chemical', 'MESH:D006632', (215, 224))
147912	28120369	In our study we found that BDL KitW-sh mice have lower levels of VEGF-C and further, the vascular bed is altered in BDL KitW-sh mice as shown by the diminished presence of peribiliary glands and decreased expression of vWF.	('BDL', 'Var', (116, 119))	('levels', 'MPA', (55, 61))	('vWF', 'Gene', (219, 222))	('VEGF-C', 'Gene', (65, 71))	('diminished', 'NegReg', (149, 159))	('mice', 'Species', '10090', (128, 132))	('BDL', 'Chemical', '-', (116, 119))	('lower', 'NegReg', (49, 54))	('BDL', 'Chemical', '-', (27, 30))	('vWF', 'Gene', '22371', (219, 222))	('altered', 'Reg', (105, 112))	('vascular bed', 'CPA', (89, 101))	('VEGF-C', 'Gene', '22341', (65, 71))	('expression', 'MPA', (205, 215))	('mice', 'Species', '10090', (39, 43))	('decreased', 'NegReg', (195, 204))
147918	28120369	found no difference in angiogenic signaling in mast cell deficient mice, WBB6F1-W/W(V) compared to controls following implantation of cotton threading to induce granulation tissue formation; however, HDC knockout mice displayed marked alterations in angiogenic signaling.	('mice', 'Species', '10090', (213, 217))	('WBB6F1-W/W', 'Var', (73, 83))	('HDC', 'Gene', (200, 203))	('rat', 'Species', '10116', (239, 242))	('alterations', 'Reg', (235, 246))	('angiogenic signaling', 'MPA', (250, 270))	('HDC', 'Gene', '15186', (200, 203))	('mice', 'Species', '10090', (67, 71))
147931	28120369	Since mast cells that infiltrate the liver following damage are not resident liver cells, inhibition or knockdown of mast cells or mast cell components are likely to be excellent therapeutics for patients suffering from cholangiopathies.	('cholangiopathies', 'Disease', (220, 236))	('cholangiopathies', 'Disease', 'None', (220, 236))	('patients', 'Species', '9606', (196, 204))	('rat', 'Species', '10116', (28, 31))	('knockdown', 'Var', (104, 113))
147947	33135073	Examples of such serum glycans include CA19-9, sialyl Tn, sialyl Lewis X and Du-Pan-2, which can be detected using monoclonal antibodies.	('sialyl', 'Var', (47, 53))	('CA19-9', 'Var', (39, 45))	('sialyl', 'Var', (58, 64))	('sialyl', 'Chemical', '-', (58, 64))	('Pan-2', 'Gene', (80, 85))	('CA19-9', 'Chemical', 'MESH:C086528', (39, 45))	('glycans', 'Chemical', 'MESH:D011134', (23, 30))	('Pan-2', 'Gene', '9924', (80, 85))	('sialyl', 'Chemical', '-', (47, 53))
148004	33135073	The product was detected as an ion at m/z 692 [M + H + TEA]+ (Hex2dHex1Sulfate1-PA +2 x 2H -2 x CH2O), and the MS2 spectrum of the ion contained ions at m/z 259 and 339 corresponding to protonated forms of intact Hex-PA and sulfate-Hex-PA, respectively (Figure 5A).	('m/z 259', 'Var', (153, 160))	('Hex', 'Gene', '3087', (62, 65))	('PA', 'Chemical', 'MESH:D011478', (80, 82))	('2H', 'Chemical', 'MESH:D003903', (88, 90))	('Hex', 'Gene', (213, 216))	('MS2', 'Species', '2710868', (111, 114))	('Hex', 'Gene', '3087', (67, 70))	('Hex', 'Gene', '3087', (232, 235))	('Hex', 'Gene', (62, 65))	('PA', 'Chemical', 'MESH:D011478', (236, 238))	('Hex', 'Gene', '3087', (213, 216))	('sulfate', 'Chemical', 'MESH:D013431', (224, 231))	('PA', 'Chemical', 'MESH:D011478', (217, 219))	('Hex', 'Gene', (67, 70))	('CH2O', 'Chemical', '-', (96, 100))	('Hex', 'Gene', (232, 235))	('dHex', 'Chemical', '-', (66, 70))
148015	33135073	Based on these results, we concluded that glycan #47 and glycan #51 were likely to contain blood group B- and A-antigens, respectively, and were consistent with sulfated forms of previously reported blood group-related free-pentasaccharides in urine (data not shown).	('pentasaccharides', 'Chemical', '-', (224, 240))	('blood group B-', 'Protein', (91, 105))	('glycan', 'Chemical', 'MESH:D011134', (42, 48))	('contain', 'Reg', (83, 90))	('sulfate', 'Chemical', 'MESH:D013431', (161, 168))	('A-antigens', 'Protein', (110, 120))	('glycan #51', 'Var', (57, 67))	('glycan #47', 'Var', (42, 52))	('glycan', 'Chemical', 'MESH:D011134', (57, 63))
148032	33135073	Among them, #115 and #118 contained Lewis X on the beta1,6-arm (Figure 4C).	('Lewis', 'Var', (36, 41))	('C', 'Chemical', 'MESH:D002244', (72, 73))	('contained', 'Reg', (26, 35))
148067	33135073	Furthermore, ions at m/z 760 and 626 were consistent with products of cleavage at the beta4-Man residue and at the alpha6-Man residue with the antenna at the C-6 position, respectively.	('alpha6', 'Gene', (115, 121))	('beta4', 'Gene', '28898', (86, 91))	('alpha6', 'Gene', '28873', (115, 121))	('beta4', 'Gene', (86, 91))	('m/z 760', 'Var', (21, 28))	('C', 'Chemical', 'MESH:D002244', (158, 159))
148072	33135073	After de-sulfation, the glycan was digested by alpha3/4-fucosidase resulting in an alpha6-Man-arm structure with one type-II LacNAc antenna (data not shown).	('alpha6', 'Gene', (83, 89))	('alpha6', 'Gene', '28873', (83, 89))	('glycan', 'Chemical', 'MESH:D011134', (24, 30))	('LacNAc', 'Chemical', '-', (125, 131))	('de-sulfation', 'Var', (6, 18))	('alpha3', 'Gene', (47, 53))	('alpha3', 'Gene', '28883', (47, 53))
148074	33135073	These results indicated that glycan #76 possess a unique Lewis X antenna containing a 4-sulfo-Fuc residue.	('glycan #76', 'Var', (29, 39))	('glycan', 'Chemical', 'MESH:D011134', (29, 35))	('Lewis', 'MPA', (57, 62))	('4-sulfo-Fuc', 'Chemical', '-', (86, 97))
148086	33135073	Glycan #50, which comprises Hex2Pen1NeuAc1-PA at m/z 844 [M + H]+, was observed in all cases (Figure 3, line Fr4).	('Glycan', 'Chemical', 'MESH:D011134', (0, 6))	('Hex2Pen1NeuAc1-PA', 'Chemical', '-', (28, 45))	('m/z', 'Var', (49, 52))	('Hex2Pen1NeuAc1-PA', 'Var', (28, 45))
148092	33135073	The base peak ion of the MS2 spectrum at m/z 495 corresponded to the de-sialylated Y-ion, and was subjected to further fragmentation (Figure 5C).	('MS2', 'Gene', (25, 28))	('sialyl', 'Chemical', '-', (72, 78))	('m/z 495', 'Var', (41, 48))	('MS2', 'Species', '2710868', (25, 28))	('C', 'Chemical', 'MESH:D002244', (142, 143))
148094	33135073	In addition, an ion at m/z 241 was detected, which corresponded to the PA-tetrose with additional C2-fragment (42 Da), indicating periodate-cleavage between C-2 and C-3 with free hydroxyl groups of the internal Pen-residue (Figure 5D).	('C2', 'Chemical', 'MESH:C023714', (98, 100))	('m/z 241', 'Var', (23, 30))	('Pen', 'Gene', (211, 214))	('C', 'Chemical', 'MESH:D002244', (98, 99))	('C', 'Chemical', 'MESH:D002244', (157, 158))	('Pen', 'Gene', '340348', (211, 214))	('periodate', 'Chemical', 'MESH:C009288', (130, 139))	('PA-tetrose', 'Chemical', '-', (71, 81))	('C', 'Chemical', 'MESH:D002244', (165, 166))
148105	33135073	PA-glycan #73 was a sialyl Lewis A attached via C-3 of Gal, which corresponded to a peeling product of mucin type glycans previously identified in serum O-glycan analysis.	('Gal', 'Chemical', 'MESH:C101993', (55, 58))	('O-glycan', 'Chemical', '-', (153, 161))	('C', 'Chemical', 'MESH:D002244', (48, 49))	('mucin', 'Gene', '100508689', (103, 108))	('PA-glycan', 'Var', (0, 9))	('sialyl', 'Chemical', '-', (20, 26))	('glycans', 'Chemical', 'MESH:D011134', (114, 121))	('mucin', 'Gene', (103, 108))	('PA-glycan', 'Chemical', '-', (0, 9))
148113	33135073	In addition, urine showed a variety of HexA-containing structures, including a Pen-capped structure, a glucuronyl maltotriose, a free-form of a protein-linkage structure of glycosaminoglycan, a B-blood group related structure and hyaluronan hexasaccharide (#49, #57, #74, #82 and #95).	('Pen', 'Gene', (79, 82))	('glucuronyl maltotriose', 'Chemical', '-', (103, 125))	('Pen', 'Gene', '340348', (79, 82))	('HexA-containing structures', 'MPA', (39, 65))	('#49', 'Var', (257, 260))	('glycosaminoglycan', 'Chemical', 'MESH:D006025', (173, 190))	('HexA', 'Chemical', 'MESH:D006603', (39, 43))	('hyaluronan hexasaccharide', 'Chemical', '-', (230, 255))
148114	33135073	We noticed that some glycans possessed an additional nonreducing terminal HexNAc attached to the sub-terminal GlcA (#31, #34, #36, #44 and #74).	('#31', 'Var', (116, 119))	('glycans', 'Chemical', 'MESH:D011134', (21, 28))	('nonreducing', 'MPA', (53, 64))	('GlcA', 'Chemical', '-', (110, 114))	('HexNAc', 'Chemical', '-', (74, 80))
148131	33135073	Backbone structures and modifications of glycans seemed to influence the cancer-related increase in the level of these compounds.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('glycans', 'Chemical', 'MESH:D011134', (41, 48))	('level of', 'MPA', (104, 112))	('glycans', 'Protein', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('increase', 'PosReg', (88, 96))	('influence', 'Reg', (59, 68))	('modifications', 'Var', (24, 37))
148132	33135073	The simple sialyllactoses (#24 and #35) showed elevated levels in cancer patients (Figure 6A).	('levels', 'MPA', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('elevated', 'PosReg', (47, 55))	('#24', 'Var', (27, 30))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('patients', 'Species', '9606', (73, 81))	('sialyllactose', 'Chemical', 'MESH:C000020', (11, 24))	('cancer', 'Disease', (66, 72))
148138	33135073	By contrast, glycans containing sialylation and Lewis X showed a pronounced increase in cancer patients (#84 and #118 in Figure 6A; #96 and #115 in Supplementary Figure S9A).	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('increase', 'PosReg', (76, 84))	('Lewis X', 'Var', (48, 55))	('patients', 'Species', '9606', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('glycans', 'Chemical', 'MESH:D011134', (13, 20))	('sialyl', 'Chemical', '-', (32, 38))	('sialylation', 'Var', (32, 43))
148149	33135073	The level of glycans containing alpha2,6-sialylated antenna and Man2GlcNAc1- or bisecting GlcNAc-Man3GlcNAc1-core (#91 and #102 in Figure 6C; #119 and #121 in Supplementary Figure S9C) increased in cancer patients, particularly in some gastric cancer patients (G2 and G12).	('patients', 'Species', '9606', (205, 213))	('sialyl', 'Chemical', '-', (41, 47))	('C', 'Chemical', 'MESH:D002244', (139, 140))	('patients', 'Species', '9606', (251, 259))	('GlcNAc', 'Chemical', 'MESH:D000117', (101, 107))	('GlcNAc', 'Chemical', 'MESH:D000117', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('cancer', 'Disease', (198, 204))	('gastric cancer', 'Disease', (236, 250))	('GlcNAc', 'Chemical', 'MESH:D000117', (90, 96))	('Man3GlcNAc1', 'Chemical', '-', (97, 108))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('increased', 'PosReg', (185, 194))	('gastric cancer', 'Disease', 'MESH:D013274', (236, 250))	('glycans', 'Chemical', 'MESH:D011134', (13, 20))	('C', 'Chemical', 'MESH:D002244', (182, 183))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('#91', 'Var', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('gastric cancer', 'Phenotype', 'HP:0012126', (236, 250))	('Man2GlcNAc1', 'Chemical', '-', (64, 75))
148158	33135073	The Man3GlcNAc1-core glycan (#131) was elevated in gastric cancer and cholangiocar-cinoma patients.	('cholangiocar-cinoma', 'Disease', (70, 89))	('Man3GlcNAc1', 'Chemical', '-', (4, 15))	('cholangiocar-cinoma', 'Disease', 'None', (70, 89))	('glycan', 'Chemical', 'MESH:D011134', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('elevated', 'PosReg', (39, 47))	('#131', 'Var', (29, 33))	('gastric cancer', 'Phenotype', 'HP:0012126', (51, 65))	('Man3GlcNAc1-core glycan', 'Protein', (4, 27))	('patients', 'Species', '9606', (90, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (51, 65))	('gastric cancer', 'Disease', (51, 65))
148169	33135073	In score plots of PC1-PC2 and PC1-PC3, the distributions of cancer patients and normal controls were partially segregated (Supplementary Figure S11A and C).	('C', 'Chemical', 'MESH:D002244', (31, 32))	('PC1', 'Gene', (18, 21))	('PC1', 'Gene', '3868', (30, 33))	('PC3', 'Gene', '3853', (34, 37))	('S11A', 'Var', (144, 148))	('patients', 'Species', '9606', (67, 75))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('S11A', 'SUBSTITUTION', 'None', (144, 148))	('C', 'Chemical', 'MESH:D002244', (153, 154))	('C', 'Chemical', 'MESH:D002244', (23, 24))	('cancer', 'Disease', (60, 66))	('PC1', 'Gene', (30, 33))	('C', 'Chemical', 'MESH:D002244', (19, 20))	('PC3', 'Gene', (34, 37))	('PC1', 'Gene', '3868', (18, 21))	('PC1-PC2', 'CellLine', 'CVCL:0152', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
148172	33135073	The PC2 axis (13.8%) seemed to reflect modifications on the glycans (Supplementary Figure S11A and B).	('S11A', 'Var', (90, 94))	('glycans', 'Chemical', 'MESH:D011134', (60, 67))	('PC2', 'Gene', '3854', (4, 7))	('modifications', 'Reg', (39, 52))	('S11A', 'SUBSTITUTION', 'None', (90, 94))	('glycans', 'Protein', (60, 67))	('PC2', 'Gene', (4, 7))
148180	33135073	The PC3 axis (8.3%) appeared to reflect the core structures in addition to the modifications of the glycans, referring to the PC1-PC3 loading plot (Supplementary Figure S11D).	('S11D', 'SUBSTITUTION', 'None', (169, 173))	('PC3', 'Gene', '3853', (4, 7))	('glycans', 'Chemical', 'MESH:D011134', (100, 107))	('PC1', 'Gene', '3868', (126, 129))	('PC3', 'Gene', (130, 133))	('PC3', 'Gene', (4, 7))	('PC1', 'Gene', (126, 129))	('PC3', 'Gene', '3853', (130, 133))	('S11D', 'Var', (169, 173))
148182	33135073	This assoc-iated was related to the location of several gastric cancer patients distributed in the lower area, which was different from several pancreatic cancer patients on the PC1-PC3 score plot(Supplementary Figure S11C).	('S11C', 'SUBSTITUTION', 'None', (218, 222))	('patients', 'Species', '9606', (162, 170))	('pancreatic cancer', 'Disease', (144, 161))	('PC3', 'Gene', '3853', (182, 185))	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('pancreatic cancer', 'Disease', 'MESH:D010190', (144, 161))	('patients', 'Species', '9606', (71, 79))	('PC1', 'Gene', '3868', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('PC3', 'Gene', (182, 185))	('S11C', 'Var', (218, 222))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (144, 161))	('gastric cancer', 'Disease', (56, 70))	('PC1', 'Gene', (178, 181))	('gastric cancer', 'Disease', 'MESH:D013274', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
148185	33135073	PCA score plots using these selected glycans showed a tendency to improve segregations of distribution between cancer patients and normal controls (Supplementary Figure S12B, E and H) compared to PCA using total quantified glycans (Supplementary Figure S12A, D and G).	('glycans', 'Chemical', 'MESH:D011134', (223, 230))	('S12A', 'SUBSTITUTION', 'None', (253, 257))	('S12A', 'Var', (253, 257))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('segregations', 'MPA', (74, 86))	('improve', 'PosReg', (66, 73))	('S12B', 'Var', (169, 173))	('distribution', 'MPA', (90, 102))	('C', 'Chemical', 'MESH:D002244', (197, 198))	('C', 'Chemical', 'MESH:D002244', (1, 2))	('glycans', 'Chemical', 'MESH:D011134', (37, 44))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('patients', 'Species', '9606', (118, 126))	('S12B', 'SUBSTITUTION', 'None', (169, 173))
148191	33135073	In this study, we further identified a number of lactose- and LacNAc-core glycans with modifications of LacNAc-extension, fucose, sulfate and/or sialic acid.	('sialic acid', 'Chemical', 'MESH:D019158', (145, 156))	('LacNAc', 'Chemical', '-', (62, 68))	('LacNAc-core glycans', 'Protein', (62, 81))	('modifications', 'Var', (87, 100))	('LacNAc', 'Chemical', '-', (104, 110))	('fucose', 'Chemical', 'MESH:D005643', (122, 128))	('LacNAc-extension', 'Protein', (104, 120))	('sulfate', 'Chemical', 'MESH:D013431', (130, 137))	('sulfate', 'MPA', (130, 137))	('lactose', 'Chemical', 'MESH:D007785', (49, 56))	('fucose', 'Protein', (122, 128))	('glycans', 'Chemical', 'MESH:D011134', (74, 81))	('lactose-', 'Protein', (49, 57))	('sialic acid', 'Protein', (145, 156))
148197	33135073	Some glycans with a combination of fucosylation and sulfation showed elevated levels, although only in a few pancreatic cancer and cholangiocarcinoma patients.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('sulfation', 'Var', (52, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (109, 126))	('glycans', 'Chemical', 'MESH:D011134', (5, 12))	('cholangiocarcinoma', 'Disease', (131, 149))	('levels', 'MPA', (78, 84))	('patients', 'Species', '9606', (150, 158))	('pancreatic cancer', 'Disease', 'MESH:D010190', (109, 126))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (131, 149))	('pancreatic cancer', 'Disease', (109, 126))	('elevated', 'PosReg', (69, 77))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))	('fucosylation', 'Var', (35, 47))
148201	33135073	This observed cancer-specificity may be caused by not only the sialyl Lewis A, but also combined type-I and type-II LacNAc backbone (Galbeta1-3GlcNAcbeta1-3Galbeta1-4GlcNAc).	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('sialyl', 'Chemical', '-', (63, 69))	('Galbeta1-3GlcNAcbeta1-3Galbeta1-4GlcNAc', 'Var', (133, 172))	('caused', 'Reg', (40, 46))	('LacNAc', 'Chemical', '-', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
148205	33135073	For glycans with the same mono-antennary structure, Man3GlcNAc1-core show a less dramatic increase in cancer patients than Man2GlcNAc1-core (#108).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('patients', 'Species', '9606', (109, 117))	('Man3GlcNAc1', 'Chemical', '-', (52, 63))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Man2GlcNAc1', 'Chemical', '-', (123, 134))	('Man3GlcNAc1-core', 'Var', (52, 68))	('glycans', 'Chemical', 'MESH:D011134', (4, 11))
148229	33135073	The sequence of NeuAcalpha2-3Galbeta1-4(Fucalpha1-3) Xyl is structurally similar to sialyl Lewis X and 3'-sialyl-3-fucosyllactose and was presumably formed by upregulation of Lewis-related alpha1,3-fucosyltransferases in cancer.	('Fucalpha1-3', 'Gene', (40, 51))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('Xyl', 'Chemical', '-', (53, 56))	('sialyl', 'Chemical', '-', (106, 112))	('lactose', 'Chemical', 'MESH:D007785', (122, 129))	('cancer', 'Disease', (221, 227))	('Fucalpha1-3', 'Gene', '2517;2519', (40, 51))	('NeuAcalpha2-3Galbeta1-4', 'Var', (16, 39))	('NeuAc', 'Chemical', 'MESH:D009438', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('sialyl', 'Chemical', '-', (84, 90))	('upregulation', 'PosReg', (159, 171))
148239	33135073	However, the levels of #60 in the urine from three patients were clearly elevated and the levels of #50 (Figure 6E), #24, #35, #84, and #118 (Figure 6A) were moderately elevated compared with normal controls.	('#35', 'Var', (122, 125))	('#118', 'Var', (136, 140))	('#84', 'Var', (127, 130))	('patients', 'Species', '9606', (51, 59))	('levels', 'MPA', (13, 19))	('#24', 'Var', (117, 120))	('elevated', 'PosReg', (73, 81))
148259	33135073	The patients were numbered G1-G13 for gastric cancer patients, P1-P10 for pancreatic cancer patients and C1-C4 for cholangiocarcinoma patients.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('C', 'Chemical', 'MESH:D002244', (108, 109))	('patients', 'Species', '9606', (134, 142))	('cholangiocarcinoma', 'Disease', (115, 133))	('gastric cancer', 'Disease', (38, 52))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (115, 133))	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (92, 100))	('patients', 'Species', '9606', (4, 12))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('pancreatic cancer', 'Disease', 'MESH:D010190', (74, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (38, 52))	('P1-P10', 'Var', (63, 69))	('C1-C4', 'Var', (105, 110))	('pancreatic cancer', 'Disease', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (38, 52))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (115, 133))	('G1-G13', 'Var', (27, 33))
148368	30953499	Proteins satisfying the following conditions were candidates for the study: RSC > 1 or < - 1, SpI > 0.6 or < - 0.6, and P <  0.01 by the non-parametric G-test.	('SpI > 0.6', 'Var', (94, 103))	('RSC > 1', 'Var', (76, 83))	('RSC', 'Chemical', '-', (76, 79))	('P <  0.01', 'Var', (120, 129))
148470	29743818	Furthermore, we found that high CXCL5 expression was associated with reduced OS in intrahepatic cholangiocarcinoma (HR 1.91; 95% CI 1.31-2.78) and hepatocellular carcinoma (HR 1.87; 95% CI 1.55-2.27).	('hepatocellular carcinoma', 'Disease', (147, 171))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (147, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('CXCL5', 'Gene', '6374', (32, 37))	('reduced', 'NegReg', (69, 76))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 114))	('high', 'Var', (27, 31))	('intrahepatic cholangiocarcinoma', 'Disease', (83, 114))	('OS', 'Chemical', '-', (77, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (147, 171))	('reduced OS in intrahepatic cholangiocarcinoma', 'Phenotype', 'HP:0006571', (69, 114))	('CXCL5', 'Gene', (32, 37))
148481	29743818	Given the important roles of chemokines in cancer, abnormal expression of chemokines has been detected in many tumors, and several chemokines have been proven to be associated with poor prognosis of cancer patients.	('expression', 'MPA', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('abnormal expression of chemokines', 'Phenotype', 'HP:0011115', (51, 84))	('abnormal', 'Var', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('associated', 'Reg', (165, 175))	('detected', 'Reg', (94, 102))	('cancer', 'Disease', (43, 49))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (206, 214))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', (199, 205))
148510	29743818	Fourteen studies including seventeen cohorts reported the relationship between abnormal expression levels of CXCL5 with OS in a total of 4952 cancer patients.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('patients', 'Species', '9606', (149, 157))	('abnormal', 'Var', (79, 87))	('CXCL5', 'Gene', (109, 114))	('CXCL5', 'Gene', '6374', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('OS', 'Chemical', '-', (120, 122))	('cancer', 'Disease', (142, 148))
148516	29743818	Through systematic analysis, our results demonstrated that high CXCL5 expression was associated with reduced OS in intrahepatic cholangiocarcinoma (HR 1.91; 95% CI 1.31-2.78, p = 0.001) (Fig.	('reduced OS in intrahepatic cholangiocarcinoma', 'Phenotype', 'HP:0006571', (101, 146))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (128, 146))	('CXCL5', 'Gene', (64, 69))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (115, 146))	('CXCL5', 'Gene', '6374', (64, 69))	('intrahepatic cholangiocarcinoma', 'Disease', (115, 146))	('reduced', 'NegReg', (101, 108))	('high', 'Var', (59, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('OS', 'Chemical', '-', (109, 111))
148541	29743818	We found that high CXCL5 expression was associated with reduced OS in intrahepatic cholangiocarcinoma and hepatocellular carcinoma, which was consistent with previous studies.	('intrahepatic cholangiocarcinoma and hepatocellular carcinoma', 'Disease', 'MESH:D018281', (70, 130))	('CXCL5', 'Gene', (19, 24))	('CXCL5', 'Gene', '6374', (19, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('reduced', 'NegReg', (56, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('high', 'Var', (14, 18))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('OS', 'Chemical', '-', (64, 66))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (106, 130))	('reduced OS in intrahepatic cholangiocarcinoma', 'Phenotype', 'HP:0006571', (56, 101))
148663	27276221	Only lymph node status was found to be of significant influence on 5-year survival rate (43% in patients with pN0 disease versus 16% in patients with pN1 disease, P = 0.002).	('pN1', 'Gene', '5270', (150, 153))	('pN0 disease', 'Var', (110, 121))	('pN1', 'Gene', (150, 153))	('patients', 'Species', '9606', (136, 144))	('patients', 'Species', '9606', (96, 104))
148676	27276221	Therefore, the Mayo Clinic group also accepts patients with a malignant-appearing stricture on percutaneous or endoscopic cholangiography and at least one of the three following criteria: polysomy on fluorescent in situ hybridization; or CA-19.9 > 100 U/mL; or a mass on cross-sectional imaging at the site of the stricture.	('patients', 'Species', '9606', (46, 54))	('stricture', 'Disease', (82, 91))	('CA-19.9 > 100 U/mL', 'Var', (238, 256))	('Mayo', 'Species', '162683', (15, 19))	('polysomy', 'Var', (188, 196))
148739	26579437	This is of particular interest because of the association of defects in the MAPK pathway with a variety of cancers.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('MAPK', 'Gene', (76, 80))	('defects', 'Var', (61, 68))	('association', 'Interaction', (46, 57))	('MAPK', 'Gene', '5595;5594;5595', (76, 80))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
148742	26579437	Binding to this G protein leads to an increase in cAMP signaling, suggesting that there is a stimulatory relationship between TGR5 and non-ciliated cholangiocyte cells.	('increase', 'PosReg', (38, 46))	('cAMP', 'Chemical', '-', (50, 54))	('cAMP signaling', 'MPA', (50, 64))	('Binding', 'Var', (0, 7))	('TGR5', 'Gene', (126, 130))
148750	26579437	It was also noted that the lack of TGR5 activation increased inflammatory hepatic infiltrates, but decreased the incidence of cholesterol gallstones.	('decreased', 'NegReg', (99, 108))	('TGR5', 'Gene', (35, 39))	('increased', 'PosReg', (51, 60))	('cholesterol gallstones', 'Disease', (126, 148))	('lack', 'Var', (27, 31))	('cholesterol gallstones', 'Disease', 'MESH:D042882', (126, 148))	('inflammatory hepatic infiltrates', 'MPA', (61, 93))	('gallstone', 'Phenotype', 'HP:0001081', (138, 147))	('gallstones', 'Phenotype', 'HP:0001081', (138, 148))	('cholesterol gallstones', 'Phenotype', 'HP:0011980', (126, 148))	('hepatic infiltrates', 'Phenotype', 'HP:0002113', (74, 93))
148751	26579437	Mutations in the coding region of TGR5, such as 2q35, have been found in patients with PSC and ulcerative colitis, but have not been found to enhance one s susceptibility to these diseases.	('ulcerative colitis', 'Disease', (95, 113))	('colitis', 'Phenotype', 'HP:0002583', (106, 113))	('PSC', 'Gene', '100653366', (87, 90))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (95, 113))	('Mutations', 'Var', (0, 9))	('PSC', 'Gene', (87, 90))	('found', 'Reg', (64, 69))	('ulcerative colitis', 'Disease', 'MESH:D003093', (95, 113))	('patients', 'Species', '9606', (73, 81))	('TGR5', 'Gene', (34, 38))
148765	26579437	Inhibition of CYP27 prevents the basolateral cholesterol efflux mediated by liver X receptor and 27-hydrocholesterol, the product of Cyp27, in the cholangiocyte.	('Cyp27', 'Gene', (133, 138))	('Cyp27', 'Gene', '1593', (133, 138))	('basolateral cholesterol efflux', 'MPA', (33, 63))	('X receptor', 'Gene', '9213', (82, 92))	('cholesterol', 'Chemical', 'MESH:D002784', (105, 116))	('27-hydrocholesterol', 'Chemical', '-', (97, 116))	('prevents', 'NegReg', (20, 28))	('Inhibition', 'Var', (0, 10))	('CYP27', 'Gene', (14, 19))	('cholesterol', 'Chemical', 'MESH:D002784', (45, 56))	('CYP27', 'Gene', '1593', (14, 19))	('X receptor', 'Gene', (82, 92))	('27-hydrocholesterol', 'MPA', (97, 116))
148768	26579437	Studies have shown that defects in FXR, and its associated factors, are linked to gallstone disease.	('gallstone', 'Phenotype', 'HP:0001081', (82, 91))	('linked', 'Reg', (72, 78))	('gallstone disease', 'Disease', (82, 99))	('gallstone disease', 'Disease', 'MESH:D042882', (82, 99))	('FXR', 'Gene', (35, 38))	('defects', 'Var', (24, 31))
148830	26579437	It has been hypothesized that conjugated bile acids exert the aforementioned effects without ever actually entering the cholangiocyte, and this, if true, could explain dysregulation of FXR expression in the setting of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (218, 236))	('bile acids', 'Chemical', 'MESH:D001647', (41, 51))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (218, 236))	('dysregulation', 'Var', (168, 181))	('cholangiocarcinoma', 'Disease', (218, 236))
148880	22703944	However there have been a few case reports where very high levels of CA19-9 along with other suggestive radiological findings have been thought of as cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('CA19-9', 'Chemical', 'MESH:C086528', (69, 75))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (150, 168))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (150, 168))	('cholangiocarcinoma', 'Disease', (150, 168))	('CA19-9', 'Var', (69, 75))
148967	20002305	The HBV gene has been detected in cholangiocarcinoma tissue in some studies, and its presence has been associated with the potential of carcinogenesis in human cholangiocytes.	('human', 'Species', '9606', (154, 159))	('carcinogenesis', 'Disease', 'MESH:D063646', (136, 150))	('associated', 'Reg', (103, 113))	('HBV', 'Gene', (4, 7))	('HBV', 'Species', '10407', (4, 7))	('carcinogenesis', 'Disease', (136, 150))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (34, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (34, 52))	('detected', 'Reg', (22, 30))	('presence', 'Var', (85, 93))	('cholangiocarcinoma', 'Disease', (34, 52))
148970	20002305	In the multi-centre survey in Japan, the prevalence of anti-HCV among ICC cases (20-30%) has consistently been high since 1990.	('anti-HCV', 'Var', (55, 63))	('ICC', 'Disease', (70, 73))	('HCV', 'Species', '11103', (60, 63))
148997	33161814	The diagnosis of S-iCCA is based on histopathological and immunohistochemical examinations, and S-iCCA often has a poorer prognosis than that of ordinary iCCA.	('S-iCCA', 'Var', (96, 102))	('S-iCCA', 'Disease', (17, 23))	('S-iCCA', 'Chemical', '-', (17, 23))	('S-iCCA', 'Chemical', '-', (96, 102))
149047	33161814	Several studies have shown that cisplatin, doxorubicin, cyclophosphamide, and taxol as adjuvant chemotherapy after surgery may prolong survival in patients with sarcomatoid carcinomas.	('sarcomatoid carcinomas', 'Phenotype', 'HP:0100242', (161, 183))	('sarcomatoid carcinomas', 'Disease', 'MESH:C538614', (161, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('cisplatin', 'Var', (32, 41))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (56, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('doxorubicin', 'Chemical', 'MESH:D004317', (43, 54))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('sarcomatoid carcinomas', 'Disease', (161, 183))	('taxol', 'Chemical', 'MESH:D017239', (78, 83))	('patients', 'Species', '9606', (147, 155))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('prolong', 'PosReg', (127, 134))	('survival', 'CPA', (135, 143))
149084	30588526	More 3a complications such as wound dehiscence, intra-abdominal fluid collection, ascites and ileus were seen with type IIIa than type IIIb HC (p=0.002).	('wound', 'Disease', (30, 35))	('type IIIa', 'Var', (115, 124))	('ascites', 'Disease', (82, 89))	('ascites', 'Phenotype', 'HP:0001541', (82, 89))	('ascites', 'Disease', 'MESH:D001201', (82, 89))	('intra-abdominal fluid collection', 'Disease', (48, 80))	('wound dehiscence', 'Phenotype', 'HP:0032156', (30, 46))	('ileus', 'Disease', (94, 99))	('ileus', 'Phenotype', 'HP:0002595', (94, 99))
149165	25632932	Liver specific dicer1 knockout illustrates the regulatory role of miRNA in liver function.	('rat', 'Species', '10116', (37, 40))	('miR', 'Gene', (66, 69))	('knockout', 'Var', (22, 30))	('dicer1', 'Gene', '23405', (15, 21))	('miR', 'Gene', '220972', (66, 69))	('dicer1', 'Gene', (15, 21))
149166	25632932	Even though the hepatic function is preserved in the absence of mature miRNAs, disruption of dicer1 affects proper liver zonation and promotes hepatocarcinogenesis.	('miR', 'Gene', (71, 74))	('hepatocarcinogenesis', 'Disease', (143, 163))	('promotes', 'PosReg', (134, 142))	('dicer1', 'Gene', '23405', (93, 99))	('dicer1', 'Gene', (93, 99))	('disruption', 'Var', (79, 89))	('affects', 'Reg', (100, 107))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (143, 163))	('miR', 'Gene', '220972', (71, 74))
149171	25632932	Formation of hepatic cysts is initiated by mutations in disease-related genes: (1) SEC63 and PRKCSH (ADPLD), (2) PKD1 and PKD2 (ADPKD), and (3) PKHD1 (ARPKD).	('AD', 'Disease', (128, 130))	('ARPKD', 'Gene', '5314', (151, 156))	('PRKCSH', 'Gene', '5589', (93, 99))	('PRKCSH', 'Gene', (93, 99))	('SEC63', 'Gene', (83, 88))	('AD', 'Disease', 'MESH:D000544', (128, 130))	('PKD2', 'Gene', (122, 126))	('hepatic cysts', 'Disease', (13, 26))	('SEC63', 'Gene', '11231', (83, 88))	('PKD1', 'Gene', '5310', (113, 117))	('PKD2', 'Gene', '5311', (122, 126))	('hepatic cysts', 'Phenotype', 'HP:0001407', (13, 26))	('PKHD1', 'Gene', '5314', (144, 149))	('initiated', 'Reg', (30, 39))	('AD', 'Disease', (101, 103))	('PKHD1', 'Gene', (144, 149))	('hepatic cysts', 'Disease', 'MESH:D056486', (13, 26))	('PLD', 'Phenotype', 'HP:0006557', (103, 106))	('AD', 'Disease', 'MESH:D000544', (101, 103))	('mutations', 'Var', (43, 52))	('ARPKD', 'Gene', (151, 156))	('PKD1', 'Gene', (113, 117))
149198	25632932	Whether manipulation of miR-29 in the RRV model of BA modifies disease course has yet to be determined.	('modifies', 'Reg', (54, 62))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', (24, 27))	('BA', 'Phenotype', 'HP:0005912', (51, 53))	('manipulation', 'Var', (8, 20))
149207	25632932	There are several seminal studies profiling miRNAs expression in CCA; the dysregulation of miR-NAs, as in other tumors, has been linked to the repression of tumor suppressor genes (oncomiRs) and the upregulation of oncogenes (tumor suppressor miRs).	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', '220972', (243, 246))	('CCA', 'Phenotype', 'HP:0030153', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('CCA', 'Disease', (65, 68))	('upregulation', 'PosReg', (199, 211))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('dysregulation', 'Var', (74, 87))	('miR', 'Gene', (91, 94))	('miR', 'Gene', (44, 47))	('miR', 'Gene', (243, 246))	('tumor suppressor', 'Gene', (157, 173))	('miR', 'Gene', '220972', (185, 188))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('oncogenes', 'Gene', (215, 224))	('tumor suppressor', 'Gene', (226, 242))	('miR', 'Gene', (185, 188))	('tumor suppressor', 'Gene', '7248', (157, 173))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('repression', 'NegReg', (143, 153))	('tumor suppressor', 'Gene', '7248', (226, 242))	('tumors', 'Disease', (112, 118))	('miR', 'Gene', '220972', (91, 94))
149217	25632932	Furthermore, in vitro manipulations of miR-138 regulate cell proliferation, likely through RhoC and its downstream effector ERK, but no evidence has been provided beyond the direct binding of miR-138 to the 3'UTR region of RhoC messenger.	('RhoC', 'Gene', (91, 95))	('ERK', 'Gene', (124, 127))	('RhoC', 'Gene', '389', (223, 227))	('RhoC', 'Gene', (223, 227))	('regulate', 'Reg', (47, 55))	('manipulations', 'Var', (22, 35))	('miR-1', 'Gene', (39, 44))	('miR-1', 'Gene', '79187', (192, 197))	('rat', 'Species', '10116', (68, 71))	('cell proliferation', 'CPA', (56, 74))	('ERK', 'Gene', '5594', (124, 127))	('miR-1', 'Gene', (192, 197))	('RhoC', 'Gene', '389', (91, 95))	('miR-1', 'Gene', '79187', (39, 44))
149224	25632932	For example, we found by miRNA micro-array that the majority of miRNAs are downregulated in cystic cholangiocytes from the PCK (polycystic kidney) rat (an animal model of ARPKD) compared with normal rats, and experimentally proved that manipulations with one of the most downregulated miRNAs, miR-15a, affect hepatic cystogenesis in vitro.	('downregulated', 'NegReg', (75, 88))	('ARPKD', 'Gene', (171, 176))	('polycystic kidney', 'Phenotype', 'HP:0000113', (128, 145))	('rat', 'Species', '10116', (199, 202))	('ARPKD', 'Gene', '5314', (171, 176))	('miR', 'Gene', '220972', (25, 28))	('polycystic kidney', 'Disease', (128, 145))	('miR', 'Gene', '220972', (64, 67))	('rats', 'Species', '10116', (199, 203))	('manipulations', 'Var', (236, 249))	('miR', 'Gene', (25, 28))	('miR', 'Gene', '220972', (285, 288))	('rat', 'Species', '10116', (147, 150))	('miR', 'Gene', '220972', (293, 296))	('hepatic cystogenesis', 'Disease', 'MESH:D056486', (309, 329))	('miR-15a', 'Gene', '104795671', (293, 300))	('affect', 'Reg', (302, 308))	('polycystic kidney', 'Disease', 'MESH:D007690', (128, 145))	('miR-15a', 'Gene', (293, 300))	('miR', 'Gene', (64, 67))	('hepatic cystogenesis', 'Disease', (309, 329))	('miR', 'Gene', (285, 288))	('miR', 'Gene', (293, 296))
149243	25632932	Collectively, these studies suggest that miRNAs are involved in the maintenance of bile duct integrity, and aberrant miRNA expression contributes to cyst formation and cyst growth.	('contributes', 'Reg', (134, 145))	('miR', 'Gene', '220972', (41, 44))	('aberrant', 'Var', (108, 116))	('miR', 'Gene', (41, 44))	('miR', 'Gene', '220972', (117, 120))	('cyst formation', 'CPA', (149, 163))	('miR', 'Gene', (117, 120))	('cyst growth', 'CPA', (168, 179))
149244	25632932	Disturbances in apoptotic pathways may lead to uncontrolled cell proliferation or abnormal cell death.	('abnormal cell death', 'Disease', 'MESH:D003643', (82, 101))	('rat', 'Species', '10116', (72, 75))	('lead to', 'Reg', (39, 46))	('abnormal cell death', 'Disease', (82, 101))	('Disturbances', 'Var', (0, 12))	('uncontrolled cell proliferation', 'CPA', (47, 78))	('apoptotic pathways', 'Pathway', (16, 34))
149489	31179237	Compared with HCC patients, CHC patients had higher proportions of CA19-9 seropositivity, NLR (>3.3), and PLR (>117).	('CA19-9', 'Gene', (67, 73))	('CHC', 'Disease', (28, 31))	('patients', 'Species', '9606', (32, 40))	('CHC', 'Phenotype', 'HP:0030153', (28, 31))	('seropositivity', 'Var', (74, 88))	('HCC', 'Gene', (14, 17))	('PLR', 'Disease', (106, 109))	('patients', 'Species', '9606', (18, 26))	('HCC', 'Gene', '619501', (14, 17))	('NLR', 'Disease', (90, 93))	('CHC', 'Disease', 'MESH:D019698', (28, 31))	('HCC', 'Phenotype', 'HP:0001402', (14, 17))
149491	31179237	Compared with HCC patients without HBV infection, HCC patients with HBV infection were 10 years younger and had higher proportions of positive AFP (>=20 ng/ml), positive CA19-9 (>=37 U/ml), the presence of liver cirrhosis, high direct bilirubin (>7 mumol/L), advanced BCLC stage, and the presence of MVI and lower proportions of NLR (>3.3) and PLR (>117; Table 1).	('patients', 'Species', '9606', (54, 62))	('positive', 'Var', (161, 169))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (206, 221))	('high direct bilirubin', 'MPA', (223, 244))	('cirrhosis', 'Phenotype', 'HP:0001394', (212, 221))	('bilirubin', 'Chemical', 'MESH:D001663', (235, 244))	('HCC', 'Gene', '619501', (14, 17))	('HCC', 'Phenotype', 'HP:0001402', (14, 17))	('liver cirrhosis', 'Disease', 'MESH:D008103', (206, 221))	('AFP', 'Gene', (143, 146))	('HCC', 'Gene', (14, 17))	('HBV infection', 'Disease', (68, 81))	('AFP', 'Gene', '174', (143, 146))	('HBV infection', 'Disease', (35, 48))	('patients', 'Species', '9606', (18, 26))	('high direct bilirubin', 'Phenotype', 'HP:0003573', (223, 244))	('CA19-9', 'Gene', (170, 176))	('higher', 'PosReg', (112, 118))	('HCC', 'Gene', '619501', (50, 53))	('HCC', 'Phenotype', 'HP:0001402', (50, 53))	('HBV infection', 'Disease', 'MESH:D006509', (68, 81))	('liver cirrhosis', 'Disease', (206, 221))	('HCC', 'Gene', (50, 53))	('MVI', 'Disease', (300, 303))	('HBV infection', 'Disease', 'MESH:D006509', (35, 48))
149493	31179237	Similarly, CHC patients with HBV infection were 9 years younger and had higher proportions of AFP positivity and cirrhosis, and lower proportions of NLR (>3.3) and PLR (>117) than those without HBV infection (Supplementary Table 2).	('patients', 'Species', '9606', (15, 23))	('CHC', 'Disease', (11, 14))	('HBV infection', 'Disease', 'MESH:D006509', (29, 42))	('HBV infection', 'Disease', 'MESH:D006509', (194, 207))	('cirrhosis', 'Phenotype', 'HP:0001394', (113, 122))	('cirrhosis', 'Disease', 'MESH:D005355', (113, 122))	('AFP', 'Gene', '174', (94, 97))	('men', 'Species', '9606', (215, 218))	('CHC', 'Disease', 'MESH:D019698', (11, 14))	('lower', 'NegReg', (128, 133))	('higher', 'PosReg', (72, 78))	('cirrhosis', 'Disease', (113, 122))	('CHC', 'Phenotype', 'HP:0030153', (11, 14))	('HBV infection', 'Disease', (29, 42))	('AFP', 'Gene', (94, 97))	('HBV infection', 'Disease', (194, 207))	('positivity', 'Var', (98, 108))
149501	31179237	CA19-9 (>37U/ml), multiple tumor nodules, and BCLC were significantly associated with shorter OS in univariate Cox analysis, while CA19-9 and more advanced BCLC stage were independently associated with OS in ICC (Supplementary Table 5).	('CA19-9', 'Var', (0, 6))	('OS', 'Chemical', '-', (202, 204))	('men', 'Species', '9606', (219, 222))	('multiple tumor nodules', 'Disease', 'MESH:D055613', (18, 40))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('OS', 'Chemical', '-', (94, 96))	('ICC', 'Disease', (208, 211))	('Cox', 'Gene', '1351', (111, 114))	('multiple tumor nodules', 'Disease', (18, 40))	('associated with', 'Reg', (186, 201))	('Cox', 'Gene', (111, 114))	('CA19-9', 'Var', (131, 137))
149510	31179237	The C-index was 0.644, 0.638, 0.597, and 0.546 by tumor size, AFP, MVI, and incomplete tumor capsule, respectively, which were significantly lower than that by the nomogram (P < 0.001 for each comparison).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('0.597', 'Var', (30, 35))	('MVI', 'Var', (67, 70))	('tumor', 'Disease', (87, 92))	('C-index', 'MPA', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('0.546', 'Var', (41, 46))	('AFP', 'Gene', (62, 65))	('AFP', 'Gene', '174', (62, 65))	('lower', 'NegReg', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (50, 55))
149535	31179237	The genotypes and/or allele of HLA-DQ, HLA-DP, and NFKBIA single-nucleotide polymorphisms (SNPs) that significantly increased the risk of chronic HBV infection are more frequent in Chinese population than in European population (http://www.hapmap.org/).	('chronic HBV infection', 'Disease', (138, 159))	('NFKBIA', 'Gene', (51, 57))	('chronic HBV infection', 'Disease', 'MESH:D006509', (138, 159))	('increased', 'PosReg', (116, 125))	('single-nucleotide polymorphisms', 'Var', (58, 89))
149538	31179237	Instead, the C/C genotype of a SNP (rs12979860) of the IL28B gene, which is strongly associated with spontaneous clearance of HCV, is more frequent in Chinese population than in African or European population (http://www.hapmap.org/).	('rs12979860', 'Mutation', 'rs12979860', (36, 46))	('rs12979860', 'Var', (36, 46))	('associated with', 'Reg', (85, 100))	('C/C', 'Var', (13, 16))	('IL28B', 'Gene', (55, 60))	('HCV', 'Species', '11103', (126, 129))
149556	29069029	PTBD was associated with lower risk of cholangitis (risk ratio [RR] = 0.49, 95% confidence interval [CI]: 0.36-0.67; P < .00001), particularly in patients with Bismuth-Corlette type II, III, IV KT (RR = 0.50, 95% CI: 0.33-0.77; P = .05).	('PTBD', 'Chemical', '-', (0, 4))	('cholangitis', 'Phenotype', 'HP:0030151', (39, 50))	('PTBD', 'Var', (0, 4))	('lower', 'NegReg', (25, 30))	('cholangitis', 'Disease', 'MESH:D002761', (39, 50))	('patients', 'Species', '9606', (146, 154))	('cholangitis', 'Disease', (39, 50))
149569	29069029	However, ENBD has demonstrated that associated with a lower incidence of ascending cholangitis than EBS, whereas, ENBD catheter may cause discomfort because of nasopharyngeal irritation.	('cholangitis', 'Disease', 'MESH:D002761', (83, 94))	('EBS', 'Chemical', '-', (100, 103))	('ENBD', 'Var', (114, 118))	('cholangitis', 'Phenotype', 'HP:0030151', (83, 94))	('cholangitis', 'Disease', (83, 94))	('nasopharyngeal irritation', 'Disease', 'MESH:D009304', (160, 185))	('nasopharyngeal irritation', 'Disease', (160, 185))	('lower', 'NegReg', (54, 59))
149610	29069029	The primary outcome showed that PTBD is closely associated with lower risk of cholangitis in patients with KT compared with that of EBD (Fig.	('cholangitis', 'Phenotype', 'HP:0030151', (78, 89))	('lower', 'NegReg', (64, 69))	('EBD', 'Chemical', '-', (132, 135))	('cholangitis', 'Disease', 'MESH:D002761', (78, 89))	('PTBD', 'Chemical', '-', (32, 36))	('PTBD', 'Var', (32, 36))	('patients', 'Species', '9606', (93, 101))	('cholangitis', 'Disease', (78, 89))
149613	29069029	2) shows that there are also significant differences in the incidence of cholangitis between the PTBD and EBD groups, but the type II-IV KT accounts for significant proportion of a total number of patients compared to type I (up to 80%).	('type II-IV', 'Var', (126, 136))	('cholangitis', 'Disease', 'MESH:D002761', (73, 84))	('patients', 'Species', '9606', (197, 205))	('cholangitis', 'Disease', (73, 84))	('PTBD', 'Chemical', '-', (97, 101))	('cholangitis', 'Phenotype', 'HP:0030151', (73, 84))	('EBD', 'Chemical', '-', (106, 109))
149615	29069029	The overall incidence of cholangitis was 16.67% (69/414) of patients in PTBD groups compared to 30.52% (152/498) in the EBD.	('patients', 'Species', '9606', (60, 68))	('cholangitis', 'Phenotype', 'HP:0030151', (25, 36))	('cholangitis', 'Disease', (25, 36))	('PTBD', 'Chemical', '-', (72, 76))	('PTBD', 'Var', (72, 76))	('EBD', 'Chemical', '-', (120, 123))	('cholangitis', 'Disease', 'MESH:D002761', (25, 36))
149616	29069029	The second outcomes showed that PTBD is associated with lower risk of pancreatitis and with a higher success rate of palliative relief of cholestasis compared with that of EBD.	('cholestasis', 'Disease', (138, 149))	('pancreatitis', 'Phenotype', 'HP:0001733', (70, 82))	('cholestasis', 'Phenotype', 'HP:0001396', (138, 149))	('lower', 'NegReg', (56, 61))	('pancreatitis', 'Disease', (70, 82))	('PTBD', 'Chemical', '-', (32, 36))	('EBD', 'Chemical', '-', (172, 175))	('cholestasis', 'Disease', 'MESH:D002779', (138, 149))	('PTBD', 'Var', (32, 36))	('pancreatitis', 'Disease', 'MESH:D010195', (70, 82))
149763	26774260	Cysteine reduction was performed with 10 mmol/L DTT-100 mmol/L NH4HCO3 for 45 min at 56  C, and protein alkylation was carried out with 55 mmol/L iodoacetamide-100 mmol/L NH4HCO3 for 30 min in the dark at room temperature, the gel pieces being washed successively with 100 mmol/L NH4HCO3, a 1:1 (by volume) mixture of 100 mmol/L NH4HCO3 and acetonitrile, and acetonitrile, before being dried again.	('NH4HCO3', 'Chemical', '-', (280, 287))	('a 1', 'Gene', (289, 292))	('DTT', 'Chemical', 'MESH:D004229', (48, 51))	('C', 'Chemical', 'MESH:D002244', (89, 90))	('acetonitrile', 'Chemical', 'MESH:C032159', (341, 353))	('acetonitrile', 'Chemical', 'MESH:C032159', (359, 371))	('NH4HCO3', 'Gene', (329, 336))	('NH4HCO3', 'Chemical', '-', (329, 336))	('NH4HCO3', 'Chemical', '-', (171, 178))	('a 1', 'Gene', '28881', (289, 292))	('C', 'Chemical', 'MESH:D002244', (67, 68))	('DTT-100', 'Var', (48, 55))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (175, 176))	('C', 'Chemical', 'MESH:D002244', (284, 285))	('NH4HCO3', 'Chemical', '-', (63, 70))	('C', 'Chemical', 'MESH:D002244', (333, 334))
149808	26774260	It is postulated that autoantibodies in cancer are induced by a breakdown in self-tolerance resulting from over-expression, mutations, changes to post-translational modifications or the truncation of proteins in a cancer cell.	('changes', 'Reg', (135, 142))	('breakdown', 'NegReg', (64, 73))	('truncation', 'Var', (186, 196))	('cancer', 'Disease', (214, 220))	('mutations', 'Var', (124, 133))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('proteins', 'Protein', (200, 208))	('over-expression', 'PosReg', (107, 122))	('post-translational modifications', 'MPA', (146, 178))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('self-tolerance', 'CPA', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
149833	26774260	The over-expression or post-translational modification of annexin A2 has been reported in various cancers, such as colorectal, oral and lung cancers.	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', (98, 105))	('colorectal', 'Disease', 'MESH:D015179', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('over-expression', 'PosReg', (4, 19))	('lung cancers', 'Disease', 'MESH:D008175', (136, 148))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', (141, 148))	('lung cancers', 'Disease', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('lung cancers', 'Phenotype', 'HP:0100526', (136, 148))	('annexin A2', 'Gene', '302', (58, 68))	('reported', 'Reg', (78, 86))	('colorectal', 'Disease', (115, 125))	('annexin A2', 'Gene', (58, 68))	('oral', 'Disease', (127, 131))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('post-translational modification', 'Var', (23, 54))
149834	26774260	However, AAbs to annexin A2 have also been reported in the context of anti-phospholipid syndrome, sometimes in association with cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('annexin A2', 'Gene', (17, 27))	('AAb', 'Chemical', '-', (9, 12))	('anti-phospholipid syndrome', 'Disease', (70, 96))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('AAbs', 'Var', (9, 13))	('reported', 'Reg', (43, 51))	('annexin A2', 'Gene', '302', (17, 27))	('cancer', 'Disease', (128, 134))
149836	26774260	Serotansferrin carries iron from its absorption sites and delivers the metal to cells, and may also contribute to stimulating cell proliferation.	('cell proliferation', 'CPA', (126, 144))	('delivers', 'MPA', (58, 66))	('Serotansferrin', 'Var', (0, 14))	('stimulating', 'PosReg', (114, 125))	('metal', 'Chemical', 'MESH:D008670', (71, 76))	('iron', 'Chemical', 'MESH:D007501', (23, 27))
149849	26296968	LIF effect on chemotherapy-induced apoptosis was evaluated after LIFR silencing and Mcl-1 inactivation.	('silencing', 'NegReg', (70, 79))	('LIF', 'Gene', '3976', (0, 3))	('LIF', 'Gene', (0, 3))	('LIF', 'Gene', (65, 68))	('LIF', 'Gene', '3976', (65, 68))	('Mcl-1', 'Gene', '4170', (84, 89))	('inactivation', 'Var', (90, 102))	('LIFR', 'Gene', '3977', (65, 69))	('LIFR', 'Gene', (65, 69))	('Mcl-1', 'Gene', (84, 89))
149853	26296968	LIFR silencing and Mcl-1 blockade restored drug-induced apoptosis.	('Mcl-1', 'Gene', (19, 24))	('silencing', 'Var', (5, 14))	('Mcl-1', 'Gene', '4170', (19, 24))	('LIFR', 'Gene', '3977', (0, 4))	('LIFR', 'Gene', (0, 4))
149890	26296968	To understand whether lack of LIF's proliferating effects was affected by autocrine LIF production by CCA cells, possibly inducing a constitutive activation of cell proliferation which precludes further activation upon ligand stimulation, we evaluated MTS assay in CCA cells with genetic inactivation of LIFR.	('inducing', 'Reg', (122, 130))	('genetic inactivation', 'Var', (280, 300))	('LIFR', 'Gene', '3977', (304, 308))	('LIFR', 'Gene', (304, 308))	('LIF', 'Gene', '3976', (84, 87))	('LIF', 'Gene', '3976', (30, 33))	('LIF', 'Gene', '3976', (304, 307))	('LIF', 'Gene', (30, 33))	('cell', 'CPA', (160, 164))	('LIF', 'Gene', (84, 87))	('LIF', 'Gene', (304, 307))
149901	26296968	Following treatment with GEM+CDDP, genetic inactivation of LIFR in cells exposed to rhLIF led to an increased activation of caspases 3/7 of an extent comparable to scrambled cells and to cells without rhLIF pre-treatment (Figure 3C, 3D).	('activation', 'PosReg', (110, 120))	('LIF', 'Gene', (203, 206))	('LIF', 'Gene', (86, 89))	('LIF', 'Gene', (59, 62))	('LIF', 'Gene', '3976', (203, 206))	('caspases', 'Enzyme', (124, 132))	('LIF', 'Gene', '3976', (86, 89))	('LIF', 'Gene', '3976', (59, 62))	('LIFR', 'Gene', (59, 63))	('LIFR', 'Gene', '3977', (59, 63))	('genetic inactivation', 'Var', (35, 55))	('GEM+CDDP', 'Chemical', '-', (25, 33))
149911	26296968	At our given dosage (10 muM), UMI-77 did not induce any change in cell viability (data not shown), nor affect Mcl-1 expression in both cell lines (data not shown).	('expression', 'MPA', (116, 126))	('UMI-77', 'Chemical', 'MESH:C000592878', (30, 36))	('Mcl-1', 'Gene', '4170', (110, 115))	('muM', 'Gene', '56925', (24, 27))	('muM', 'Gene', (24, 27))	('Mcl-1', 'Gene', (110, 115))	('UMI-77', 'Var', (30, 36))	('affect', 'Reg', (103, 109))
149915	26296968	We demonstrate that in CCA: 1) LIF is expressed both in the bile ducts, particularly in the 'ductular-like' rather than 'mucin-producing' subtype, and the stromal cell compartment, including CAF and TAM; 2) its cognate receptor LIFR is selectively up-regulated in neoplastic cholangiocytes; 3) LIF primarily aids tumoral cholangiocytes to resist apoptosis induced by the chemotherapeutic agents GEM and CDDP, without affecting cell proliferation, invasion or the gain of stemness signatures; 4) anti-apoptotic mechanisms are mediated by Mcl-1, through activation of the PI3K/AKT pathway without involving the conventional LIF downstream effector STAT3 or MAPK/ERK; 5) in vitro inactivation of Mcl-1 prevents cytoprotective effects exerted by LIF from GEM+CDDP-induced apoptosis in CCA cells.	('LIF', 'Gene', '3976', (622, 625))	('AKT', 'Gene', '207', (575, 578))	('GEM', 'Chemical', 'MESH:C056507', (395, 398))	('LIFR', 'Gene', '3977', (228, 232))	('ERK; 5', 'Gene', (660, 666))	('LIFR', 'Gene', (228, 232))	('LIF', 'Gene', '3976', (742, 745))	('GEM+CDDP', 'Chemical', '-', (751, 759))	('GEM', 'Chemical', 'MESH:C056507', (751, 754))	('LIF', 'Gene', (622, 625))	('Mcl-1', 'Gene', '4170', (537, 542))	('LIF', 'Gene', (742, 745))	('Mcl-1', 'Gene', '4170', (693, 698))	('ERK; 5', 'Gene', '5598', (660, 666))	('CDDP', 'Chemical', 'MESH:D002945', (403, 407))	('cytoprotective effects', 'MPA', (708, 730))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('LIF', 'Gene', '3976', (294, 297))	('gain of stemness', 'Disease', 'MESH:D015430', (463, 479))	('gain of stemness', 'Disease', (463, 479))	('CAF', 'Gene', '8850', (191, 194))	('PI3', 'Gene', '5266', (570, 573))	('LIF', 'Gene', '3976', (31, 34))	('inactivation', 'Var', (677, 689))	('AKT', 'Gene', (575, 578))	('LIF', 'Gene', '3976', (228, 231))	('tumoral', 'Disease', (313, 320))	('Mcl-1', 'Gene', (537, 542))	('tumoral', 'Disease', 'MESH:D009369', (313, 320))	('CAF', 'Gene', (191, 194))	('Mcl-1', 'Gene', (693, 698))	('LIF', 'Gene', (294, 297))	('prevents', 'NegReg', (699, 707))	('LIF', 'Gene', (31, 34))	('TAM; 2', 'Gene', (199, 205))	('TAM; 2', 'Gene', '84876', (199, 205))	('LIF', 'Gene', (228, 231))	('PI3', 'Gene', (570, 573))	('CDDP', 'Chemical', 'MESH:D002945', (755, 759))
149928	26296968	also suggested that an autocrine LIF/LIFR axis is active in reactive ductules of cirrhotic livers based on their intense neoexpression compared with bile ducts in normal liver, likely acting as an important signal for ductular reaction.	('cirrhotic livers', 'Phenotype', 'HP:0001394', (81, 97))	('neoexpression', 'MPA', (121, 134))	('LIFR', 'Gene', '3977', (37, 41))	('LIFR', 'Gene', (37, 41))	('LIF', 'Gene', '3976', (33, 36))	('LIF', 'Gene', '3976', (37, 40))	('LIF', 'Gene', (33, 36))	('cirrhotic', 'Var', (81, 90))	('LIF', 'Gene', (37, 40))
149937	26296968	In accordance with these findings, LIF was able to hamper the increase of active caspases 3/7 induced by GEM+CDDP by 22-24% in both CCA cells, a fundamental step initiating the cascade of events ultimately leading to apoptosis.	('hamper', 'NegReg', (51, 57))	('LIF', 'Gene', '3976', (35, 38))	('GEM+CDDP', 'Chemical', '-', (105, 113))	('LIF', 'Gene', (35, 38))	('GEM+CDDP', 'Var', (105, 113))	('active', 'MPA', (74, 80))	('increase', 'PosReg', (62, 70))
149950	26296968	On the other hand, LIF stimulation up-regulated pAKT in both CCA cell lines, while their treatment with LY294002, a specific PI3K inhibitor, reduced the LIF induced up-regulation of Mcl-1.	('Mcl-1', 'Gene', '4170', (182, 187))	('AKT', 'Gene', (49, 52))	('PI3', 'Gene', (125, 128))	('LY294002', 'Var', (104, 112))	('PI3', 'Gene', '5266', (125, 128))	('Mcl-1', 'Gene', (182, 187))	('LY294002', 'Chemical', 'MESH:C085911', (104, 112))	('LIF', 'Gene', '3976', (153, 156))	('up-regulation', 'PosReg', (165, 178))	('AKT', 'Gene', '207', (49, 52))	('LIF', 'Gene', (19, 22))	('LIF', 'Gene', (153, 156))	('LIF', 'Gene', '3976', (19, 22))	('up-regulated', 'PosReg', (35, 47))
149982	26296968	Gene silencing was performed using commercially available siRNAs against LIFR, and scramble RNA was used as a control (Life Technologies).	('Gene', 'Var', (0, 4))	('LIFR', 'Gene', '3977', (73, 77))	('LIFR', 'Gene', (73, 77))
150078	31702638	Patients suffering from cholangiocarcinoma with dMMR status and a high tumor mutation burden (TMB) may have a consistent eutherapeutic effect with anti-PD-1-directed treatment.	('cholangiocarcinoma', 'Disease', (24, 42))	('dMMR status', 'Var', (48, 59))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (24, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Patients', 'Species', '9606', (0, 8))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (24, 42))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
150088	31702638	Tumor DNA mismatch repair (MMR) deficiency and/or microsatellite instability (MSI) are examples of genetic aberrations that are associated with high rates and durability of responses to immune-checkpoint inhibitors across some tumor types, including melanoma, NSCLC, and urothelial carcinoma.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumor', 'Disease', (227, 232))	('urothelial carcinoma', 'Disease', (271, 291))	('NSCLC', 'Disease', 'MESH:D002289', (260, 265))	('melanoma', 'Disease', 'MESH:D008545', (250, 258))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('melanoma', 'Disease', (250, 258))	('MMR', 'Gene', (27, 30))	('NSCLC', 'Disease', (260, 265))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('deficiency', 'Var', (32, 42))	('microsatellite', 'MPA', (50, 64))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (271, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))
150091	31702638	These data predict that PD-1 or PD-L1 inhibitors might provide a new therapeutic option for a substantial proportion of cholangiocarcinoma patients.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (120, 138))	('PD-L1', 'Gene', (32, 37))	('patients', 'Species', '9606', (139, 147))	('PD-1', 'Gene', (24, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (120, 138))	('inhibitors', 'Var', (38, 48))	('cholangiocarcinoma', 'Disease', (120, 138))
150094	31702638	Lenvatinib (E7080) is another multitargeted kinase inhibitor of FGFR1-4, VEGFR1-3, KIT, RET, as well as PDGFR-beta.	('PDGFR', 'Gene', (104, 109))	('PDGFR', 'Gene', '5159', (104, 109))	('RET', 'Gene', (88, 91))	('KIT', 'Gene', (83, 86))	('VEGFR1', 'Gene', '2321', (73, 79))	('FGFR1-4', 'Gene', '2260;2263;2261;2264', (64, 71))	('E7080', 'Chemical', 'MESH:C531958', (12, 17))	('RET', 'Gene', '5979', (88, 91))	('Lenvatinib', 'Chemical', 'MESH:C531958', (0, 10))	('VEGFR1', 'Gene', (73, 79))	('E7080', 'Var', (12, 17))	('FGFR1-4', 'Gene', (64, 71))	('KIT', 'Gene', '3815', (83, 86))
150151	31702638	Deficiency in the DNA MMR pathway due to qualitative or quantitative abnormalities of the key proteins MLH1, MSH2, MSH6, and PMS2 leads to accelerated accumulation of genetic errors (i.e., mutations) at microsatellites, leading to diffuse high levels of microsatellite instability (MSI-H).	('abnormalities', 'Var', (69, 82))	('DNA MMR pathway', 'Pathway', (18, 33))	('microsatellite instability', 'MPA', (254, 280))	('accelerated accumulation', 'PosReg', (139, 163))	('MSH6', 'Gene', (115, 119))	('PMS2', 'Gene', (125, 129))	('MSH6', 'Gene', '2956', (115, 119))	('MLH1', 'Gene', '4292', (103, 107))	('genetic errors', 'MPA', (167, 181))	('PMS2', 'Gene', '5395', (125, 129))	('MLH1', 'Gene', (103, 107))	('Deficiency', 'NegReg', (0, 10))	('mutations', 'Var', (189, 198))	('MSH2', 'Gene', (109, 113))	('MSH2', 'Gene', '4436', (109, 113))
150164	31702638	Phase II clinical trials (NCT02923934 and NCT02829918) of nivolumab as PD-1 immune checkpoint inhibitor for BTCs are in preparation.	('NCT02923934', 'Chemical', 'MESH:C079985', (26, 37))	('BTC', 'Disease', (108, 111))	('BTC', 'Phenotype', 'HP:0100574', (108, 111))	('BTC', 'Disease', 'MESH:D001661', (108, 111))	('NCT02829918', 'Var', (42, 53))
150209	31702638	Methodology: Weixun Chen, Peng Zhu, Bi-xiang Zhang, Ze-yang Ding.	('Ze', 'Chemical', 'MESH:C510722', (52, 54))	('Ding', 'Gene', (60, 64))	('Bi', 'Chemical', 'MESH:D001729', (36, 38))	('Bi-xiang', 'Var', (36, 44))	('Ding', 'Gene', '6045', (60, 64))
150256	30956914	In the past, ICC would be misdiagnosed as metastatic disease from another primary or CUP due to the fact that ICC share many of the same immunohistochemistry (IHC) with other cancers, such as staining positive for cytokeratin (CK) seven and CK19 and negative staining for CK20 .	('CK19', 'Gene', (241, 245))	('CK20', 'Gene', (272, 276))	('CK20', 'Gene', '54474', (272, 276))	('cancers', 'Disease', (175, 182))	('CK19', 'Gene', '3880', (241, 245))	('metastatic disease', 'Disease', (42, 60))	('ICC', 'Disease', (13, 16))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('staining', 'Var', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
150260	30956914	Moreover, in the USA, along with PSC, which is likely the most common risk factor for cholangiocarcinoma, rates of obesity, diabetes, alcohol use are all rising and likely are all significantly impacting the incidence of cholangiocarcinoma .	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (221, 239))	('obesity', 'Disease', (115, 122))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (221, 239))	('impacting', 'Reg', (194, 203))	('alcohol', 'Chemical', 'MESH:D000438', (134, 141))	('cholangiocarcinoma', 'Disease', (86, 104))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (86, 104))	('diabetes', 'Disease', (124, 132))	('diabetes', 'Disease', 'MESH:D003920', (124, 132))	('cholangiocarcinoma', 'Disease', (221, 239))	('obesity', 'Phenotype', 'HP:0001513', (115, 122))	('alcohol use', 'Var', (134, 145))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (86, 104))	('PSC', 'Gene', '100653366', (33, 36))	('alcohol use', 'Phenotype', 'HP:0030955', (134, 145))	('obesity', 'Disease', 'MESH:D009765', (115, 122))	('PSC', 'Gene', (33, 36))
150411	29859128	The overall impact of a positive lymph node on the extent of the disease is emphasized by the seventh edition, such that involvement of any lymph node results in tumor stage IV which has been a tumor stage III in the sixth edition.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Disease', (162, 167))	('involvement', 'Var', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('results in', 'Reg', (151, 161))
150521	28441703	Treatment with alpha-mangostin induced G1-phase cell-cycle arrest (Figure 6); this was due to inhibition of entry into the S phase and G2/M phase of cell-cycle arrest (Matsumoto et al., 2005), which was completed by 48 h. alpha-mangostin has a powerful antiproliferative effect by inducing apoptosis.	('apoptosis', 'CPA', (290, 299))	('alpha-mangostin', 'Var', (222, 237))	('antiproliferative', 'CPA', (253, 270))	('inducing', 'PosReg', (281, 289))	('alpha-mangostin', 'Chemical', 'MESH:C021053', (15, 30))	('alpha-mangostin', 'Chemical', 'MESH:C021053', (222, 237))
150523	28441703	As shown in Figure 7, the percentage of annexin V-positive cells (right quadrants) increased to 22.6%, 54.7%, 50%, 55.1% and 75.4% after treatment with 1, 1.5, 2, 4 and 8 microg/ml of alpha-mangostin, respectively, compared with only 11.13% of the control cells; this is in accordance with previous results showing that alpha-mangostin induces apoptosis in SK-Hep-1 cells, i.e.	('apoptosis', 'CPA', (344, 353))	('SK-Hep-1', 'CellLine', 'CVCL:0525', (357, 365))	('annexin V', 'Gene', '308', (40, 49))	('alpha-mangostin', 'Chemical', 'MESH:C021053', (320, 335))	('annexin V', 'Gene', (40, 49))	('alpha-mangostin', 'Chemical', 'MESH:C021053', (184, 199))	('alpha-mangostin', 'Var', (320, 335))
150589	24750423	Perhaps most strikingly, patients with moderate or marked hilar IgG4+ infiltration were significantly more likely to have a dominant biliary stricture than those with lesser degrees of IgG4+ infiltration (43.3% and 52.6% vs. 24.3%; P = 0.04 and P = 0.01 respectively) and required biliary stenting more commonly (43.3% and 57.9% vs. 21.3%; P = 0.02 and P = 0.001 respectively).	('IgG4+ infiltration', 'Var', (64, 82))	('dominant biliary stricture', 'Disease', (124, 150))	('patients', 'Species', '9606', (25, 33))
150618	24750423	Such patients, particularly those with marked hilar IgG4+ staining, were more likely to have dominant strictures and need for biliary intervention.	('dominant strictures', 'Disease', (93, 112))	('IgG4+ staining', 'Var', (52, 66))	('patients', 'Species', '9606', (5, 13))
150688	32232655	The aim of this study was to compare the prognostic value of CA 19-9 changes versus response determined by imaging in patients with ICC undergoing chemotherapy.	('changes', 'Var', (69, 76))	('CA 19-9', 'Gene', (61, 68))	('patients', 'Species', '9606', (118, 126))
150708	32232655	The aim of this study was to compare the discriminatory power of CA 19-9 changes versus response determined by imaging to identify patients at risk while receiving palliative chemotherapy.	('patients', 'Species', '9606', (131, 139))	('CA 19-9', 'Gene', (65, 72))	('changes', 'Var', (73, 80))
150758	32232655	Moreover, false-positive CA 19-9 values when diagnosing patients with cholangiocarcinoma have been reported in over 15% of cases (Qin et al.)	('patients', 'Species', '9606', (56, 64))	('cholangiocarcinoma', 'Disease', (70, 88))	('Qin', 'Gene', '2290', (130, 133))	('false-positive', 'Var', (10, 24))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (70, 88))	('Qin', 'Gene', (130, 133))	('CA 19-9 values', 'MPA', (25, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))
150763	32232655	However, changes in serum CA 19-9 levels have the potential to identify patients who are at risk for progressive disease and likely to benefit from closer imaging evaluation.	('progressive disease', 'Disease', (101, 120))	('changes', 'Var', (9, 16))	('patients', 'Species', '9606', (72, 80))
150785	28098904	Hybridizations of miRNA and mRNA were performed on GPL14732 Nanostring nCounter Human microRNA Expression Platform (NanoString Technologies, Inc., Seattle, WA, USA) and GPL6244 [HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array [transcript (gene) version; Affymetrix, Inc., Santa Clara, CA, USA], respectively.	('GPL6244', 'Var', (169, 176))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('Human', 'Species', '9606', (80, 85))	('Human', 'Species', '9606', (204, 209))
150794	28098904	Functional enrichment analysis indicated that the DEGs were primarily involved in the biological processes associated with cell activity, including cell adhesion and regulation of cell proliferation, which have previously been demonstrated to be associated with cancer progression.	('cancer', 'Disease', (262, 268))	('cell activity', 'CPA', (123, 136))	('DEGs', 'Var', (50, 54))	('cell adhesion', 'CPA', (148, 161))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('involved', 'Reg', (70, 78))	('associated', 'Reg', (246, 256))	('cancer', 'Disease', 'MESH:D009369', (262, 268))
150803	28098904	The dysregulation of miRNA may result in numerous diseases, including ICC.	('ICC', 'Disease', (70, 73))	('numerous diseases', 'Disease', 'MESH:D004194', (41, 58))	('dysregulation', 'Var', (4, 17))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('result in', 'Reg', (31, 40))	('numerous diseases', 'Disease', (41, 58))
150807	28098904	Furthermore, the dysregulation of hsa-miR-96 was revealed to contribute to the progression of ICC.	('ICC', 'Disease', (94, 97))	('hsa-miR-96', 'Gene', '407053', (34, 44))	('contribute', 'Reg', (61, 71))	('dysregulation', 'Var', (17, 30))	('hsa-miR-96', 'Gene', (34, 44))
150820	26206664	AKT/beta-catenin-transfected livers displayed increased expression of LTbeta and LTbetaR, with antagonism of LTbetaR signalling reducing tumour progression and enhancing survival.	('increased expression of LTbeta', 'Phenotype', 'HP:0003141', (46, 76))	('antagonism', 'Var', (95, 105))	('increased', 'PosReg', (46, 55))	('LTbeta', 'Gene', (70, 76))	('LTbeta', 'Gene', '4050', (70, 76))	('LTbeta', 'Gene', '4050', (81, 87))	('reducing', 'NegReg', (128, 136))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('LTbeta', 'Gene', (109, 115))	('tumour', 'Disease', (137, 143))	('expression', 'MPA', (56, 66))	('survival', 'CPA', (170, 178))	('enhancing', 'PosReg', (160, 169))	('LTbeta', 'Gene', '4050', (109, 115))	('LTbeta', 'Gene', (81, 87))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
150822	26206664	LTbetaR-activation also rapidly accelerated ICC progression initiated by AKT/Notch, but not Notch alone.	('accelerated', 'PosReg', (32, 43))	('rat', 'Species', '10116', (38, 41))	('AKT/Notch', 'Var', (73, 82))	('ICC', 'Disease', (44, 47))
150837	26206664	Aetiology-driven liver damage, compensatory proliferation and chronic inflammation culminates in genetic and epigenetic instability, oncogene/tumour suppressor dysregulation  and liver cancer formation.	('inflammation', 'Disease', 'MESH:D007249', (70, 82))	('epigenetic instability', 'Var', (109, 131))	('tumour', 'Disease', (142, 148))	('liver cancer', 'Phenotype', 'HP:0002896', (179, 191))	('liver cancer', 'Disease', 'MESH:D006528', (179, 191))	('inflammation', 'Disease', (70, 82))	('liver damage', 'Disease', (17, 29))	('liver cancer', 'Disease', (179, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('liver damage', 'Disease', 'MESH:D056486', (17, 29))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('culminates', 'Reg', (83, 93))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('rat', 'Species', '10116', (51, 54))
150844	26206664	It has also been demonstrated that aberrant expression of LTalphabeta in hepatocytes is capable of inducing hepatitis and initiating HCC formation in mice through canonical nuclear factor kappa-light-chain-enhancer of activated B cells(NF-kappaB)-dependent mechanisms.	('mice', 'Species', '10090', (150, 154))	('LTalphabeta', 'Disease', 'None', (58, 69))	('hepatitis', 'Phenotype', 'HP:0012115', (108, 117))	('expression', 'Var', (44, 54))	('hepatitis', 'Disease', (108, 117))	('aberrant expression', 'Var', (35, 54))	('HCC formation', 'Disease', (133, 146))	('rat', 'Species', '10116', (24, 27))	('hepatitis', 'Disease', 'MESH:D056486', (108, 117))	('inducing', 'PosReg', (99, 107))	('LTalphabeta', 'Disease', (58, 69))
150863	26206664	The following ABI primers (ABI identifier) were used: LTbetaR (Mm00440235_m1) and Gapdh (Mm99999915_g1).	('Gapdh', 'Gene', '2597', (82, 87))	('Gapdh', 'Gene', (82, 87))	('Mm00440235_m1', 'Var', (63, 76))	('Mm99999915_g1', 'Var', (89, 102))
150869	26206664	IHC staining for LTbetaR and LTbeta of liver sections obtained 40 days after transfection of AKT/CAT showed increased levels of staining when compared with single oncogenes (figure 1A, B), with expression primarily restricted to regions of hepatic dysplasia.	('LTbeta', 'Gene', (17, 23))	('LTbeta', 'Gene', '4050', (17, 23))	('CAT', 'Gene', (97, 100))	('hepatic dysplasia', 'Disease', 'MESH:D056486', (240, 257))	('transfection', 'Var', (77, 89))	('increased', 'PosReg', (108, 117))	('LTbeta', 'Gene', (29, 35))	('LTbeta', 'Gene', '4050', (29, 35))	('hepatic dysplasia', 'Disease', (240, 257))	('CAT', 'Gene', '847', (97, 100))
150870	26206664	Isolated liver RNA obtained 40 days after AKT/CAT transfection displayed a modest increase in LTbeta, while in contrast, LTbetaR ligand LIGHT (TNFSF14) and the LTalpha mRNA levels were not significantly changed relative to empty vector (pT3) control (see online supplementary figure S1A).	('CAT', 'Gene', '847', (46, 49))	('LTbeta', 'Gene', '4050', (121, 127))	('CAT', 'Gene', (46, 49))	('LTbeta', 'Gene', (121, 127))	('LTbeta', 'Gene', (94, 100))	('LTalpha', 'Gene', (160, 167))	('LTbeta', 'Gene', '4050', (94, 100))	('increase', 'PosReg', (82, 90))	('TNFSF14', 'Gene', '8740', (143, 150))	('transfection', 'Var', (50, 62))	('LTalpha', 'Gene', '4049', (160, 167))	('TNFSF14', 'Gene', (143, 150))
150874	26206664	Administration was initiated day 10 post oncogene transfection to circumvent potential complications associated with hydrodynamic injection-induced acute liver injury and/or oncogene integration, and continued for 8 weeks.	('cat', 'Gene', (93, 96))	('rat', 'Species', '10116', (8, 11))	('acute liver injury', 'Disease', 'MESH:D056486', (148, 166))	('acute liver injury', 'Disease', (148, 166))	('cat', 'Gene', '847', (93, 96))	('rat', 'Species', '10116', (188, 191))	('transfection', 'Var', (50, 62))
150875	26206664	LTbetaR-Fc significantly extended median survival to 206 days versus 157 days in Ig-treated control mice (figure 1C).	('mice', 'Species', '10090', (100, 104))	('Ig', 'Gene', '16059', (81, 83))	('LTbetaR-Fc', 'Var', (0, 10))	('extended', 'PosReg', (25, 33))	('median survival', 'CPA', (34, 49))
150879	26206664	Quantitative analysis of liver IHC staining for pAKTser473, CAT and the proliferation marker Ki-67 demonstrated significantly reduced levels of oncogenes and the number of proliferating hepatocytes (figure 1F), but failed to significantly alter serum liver aspartate transaminase (AST)/alanine transaminase (ALT) enzyme and total bilirubin levels (see online supplementary figure S2A).	('ALT', 'Gene', (308, 311))	('oncogenes', 'MPA', (144, 153))	('CAT', 'Gene', (60, 63))	('CAT', 'Gene', '847', (60, 63))	('bilirubin', 'Chemical', 'MESH:D001663', (330, 339))	('rat', 'Species', '10116', (79, 82))	('ALT', 'Gene', '76282', (308, 311))	('levels', 'MPA', (134, 140))	('rat', 'Species', '10116', (106, 109))	('rat', 'Species', '10116', (179, 182))	('pAKTser473', 'Var', (48, 58))	('total bilirubin levels', 'MPA', (324, 346))	('reduced', 'NegReg', (126, 133))
150882	26206664	Malignant transformation of hepatic adenoma to carcinoma is frequently accompanied by mutation of the beta-catenin pathway.	('beta-catenin pathway', 'Pathway', (102, 122))	('hepatic adenoma to carcinoma', 'Disease', 'MESH:C564190', (28, 56))	('accompanied by', 'Reg', (71, 85))	('hepatic adenoma', 'Phenotype', 'HP:0012028', (28, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('Malignant transformation', 'CPA', (0, 24))	('mutation', 'Var', (86, 94))	('hepatic adenoma to carcinoma', 'Disease', (28, 56))
150884	26206664	Survival was significantly reduced with chronic anti-LTbetaR treatment (figure 2A), and dramatically different tumour frequencies were observed between livers from control and anti-LTbetaR-treated mice at day 40 (figure 2B).	('reduced', 'NegReg', (27, 34))	('Survival', 'CPA', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('anti-LTbetaR', 'Var', (48, 60))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Disease', (111, 117))	('mice', 'Species', '10090', (197, 201))
150886	26206664	Additionally, serum liver enzymes ALT and AST were significantly elevated at day 40 following anti-LTbetaR treatment (figure 2C).	('AST', 'MPA', (42, 45))	('serum liver enzyme', 'Phenotype', 'HP:0002910', (14, 32))	('ALT', 'Gene', (34, 37))	('serum liver enzymes ALT', 'Phenotype', 'HP:0002910', (14, 37))	('elevated', 'PosReg', (65, 73))	('ALT', 'Gene', '76282', (34, 37))	('anti-LTbetaR', 'Var', (94, 106))
150890	26206664	These data suggest that LTbetaR-activation accelerates AKT/CAT-initiated tumour formation and progression.	('tumour', 'Disease', (73, 79))	('rat', 'Species', '10116', (49, 52))	('accelerates', 'PosReg', (43, 54))	('progression', 'CPA', (94, 105))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('CAT', 'Gene', '847', (59, 62))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('LTbetaR-activation', 'Var', (24, 42))	('CAT', 'Gene', (59, 62))
150891	26206664	It should be noted that in the absence of AKT/CAT oncogene expression, anti-LTbetaR failed to significantly alter proliferation, endogenous oncogene expression (see online supplementary figure S3A), and serum liver enzyme levels (see online supplementary figure S3B).	('endogenous oncogene expression', 'MPA', (129, 159))	('anti-LTbetaR', 'Var', (71, 83))	('CAT', 'Gene', '847', (46, 49))	('serum liver enzyme', 'Phenotype', 'HP:0002910', (203, 221))	('CAT', 'Gene', (46, 49))	('serum liver enzyme levels', 'MPA', (203, 228))	('alter', 'Reg', (108, 113))	('rat', 'Species', '10116', (121, 124))
150903	26206664	Moribund livers following 8 weeks of anti-LTbetaR or Ig treatment displayed a preponderance of lipogenic foci with mean histological scores of 3.7 for anti-LTbetaR and 3.5 for Ig (figure 3E) and similar incidence of hepatoblastoma/HCC-like tumours following agonism (figure 3E).	('lipogenic foci', 'MPA', (95, 109))	('Ig', 'Gene', '16059', (53, 55))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (216, 230))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))	('anti-LTbetaR', 'Var', (151, 163))	('tumours', 'Phenotype', 'HP:0002664', (240, 247))	('hepatoblastoma/HCC-like tumours', 'Disease', 'MESH:D006528', (216, 247))	('hepatoblastoma/HCC-like tumours', 'Disease', (216, 247))	('Ig', 'Gene', '16059', (176, 178))
150907	26206664	Hydrodynamic transfection of AKT/NICD, combined with chronic administration of anti-LTbetaR, dramatically increased liver weight (VC=1.1 g to anti-LTbetaR=2.2 g) and levels of cotransfected oncogenic reporter, Gaussia luciferase increased twofold (figure 4A).	('increased liver', 'Phenotype', 'HP:0002240', (106, 121))	('transfection', 'Var', (13, 25))	('levels', 'MPA', (166, 172))	('increased', 'PosReg', (229, 238))	('ICD', 'Disease', 'OMIM:252500', (34, 37))	('liver', 'MPA', (116, 121))	('increased', 'PosReg', (106, 115))	('rat', 'Species', '10116', (69, 72))	('ICD', 'Disease', (34, 37))
150908	26206664	Gross examination of these livers suggests LTbetaR-activation rapidly accelerates progression and pathogenesis of ICC (figure 4C).	('rat', 'Species', '10116', (76, 79))	('LTbetaR-activation', 'Var', (43, 61))	('accelerates', 'PosReg', (70, 81))	('ICC', 'Disease', (114, 117))
150911	26206664	Likewise, anti-LTbetaR livers displayed increased staining of transfected Notch1, mediator Hes1 and oncogenic drivers NF-kappaB p65, pSTAT3 and c-MYC observed in ICC nodules (figure 4D).	('Notch1', 'Gene', '4851', (74, 80))	('NF-kappaB', 'Gene', (118, 127))	('staining', 'MPA', (50, 58))	('transfected', 'Var', (62, 73))	('c-MYC', 'Gene', '4609', (144, 149))	('pSTAT3', 'Gene', (133, 139))	('anti-LTbetaR', 'Var', (10, 22))	('increased', 'PosReg', (40, 49))	('Notch1', 'Gene', (74, 80))	('c-MYC', 'Gene', (144, 149))
150912	26206664	LTbetaR-accelerated tumour burden was further documented by increased levels of the transfected oncogenes NICD, with increased levels of AKT, activated pAKTThr308, pAKTSer473, NICD and Hes1 observed at day 40 (figure 4E) by western blot with liver lysates derived from AKT/NICD/anti-LTbetaR treated mice.	('levels', 'MPA', (70, 76))	('ICD', 'Disease', 'OMIM:252500', (107, 110))	('tumour burden', 'Disease', (20, 33))	('tumour burden', 'Disease', 'MESH:D009369', (20, 33))	('ICD', 'Disease', 'OMIM:252500', (177, 180))	('ICD', 'Disease', (107, 110))	('increased', 'PosReg', (117, 126))	('AKT', 'Gene', (137, 140))	('mice', 'Species', '10090', (299, 303))	('ICD', 'Disease', 'OMIM:252500', (274, 277))	('ICD', 'Disease', (177, 180))	('rat', 'Species', '10116', (14, 17))	('ICD', 'Disease', (274, 277))	('pAKTSer473', 'Var', (164, 174))	('increased', 'PosReg', (60, 69))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
150914	26206664	Increased levels of CAT, c-MYC, and pSTAT3Tyr705 were detected in AKT/NICD/anti-LTbetaR livers (figure 4E).	('c-MYC', 'Gene', (25, 30))	('ICD', 'Disease', 'OMIM:252500', (71, 74))	('ICD', 'Disease', (71, 74))	('c-MYC', 'Gene', '4609', (25, 30))	('CAT', 'Gene', '847', (20, 23))	('pSTAT3Tyr705', 'Var', (36, 48))	('CAT', 'Gene', (20, 23))
150919	26206664	Sequential serum analyses of Guassia Luciferase, AST, ALT and total bilirubin levels suggest that anti-LTbetaR treatments selectively promote AKT-initiated tumour progression (figure 5A), which was consistent with significantly increased liver weights at day 90 (figure 5B) and survival observed in AKT/anti-LTbetaR-treated mice (figure 5C).	('promote', 'PosReg', (134, 141))	('anti-LTbetaR', 'Var', (98, 110))	('tumour', 'Disease', (156, 162))	('bilirubin', 'Chemical', 'MESH:D001663', (68, 77))	('increased liver', 'Phenotype', 'HP:0002240', (228, 243))	('ALT', 'Gene', '76282', (54, 57))	('increased', 'PosReg', (228, 237))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('mice', 'Species', '10090', (324, 328))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('ALT', 'Gene', (54, 57))
150922	26206664	Similar to AKT/CAT/anti-LTbetaR, AKT and AKT/anti-LTbetaR tumours were predominantly lipogenic hepatic foci, with LTbetaR agonism inducing the appearance of ICC-like nodules/regions by day 90 (figure 5B) and increasing frequency in moribund mice.	('CAT', 'Gene', '847', (15, 18))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('CAT', 'Gene', (15, 18))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('mice', 'Species', '10090', (241, 245))	('lipogenic hepatic', 'MPA', (85, 102))	('tumours', 'Disease', 'MESH:D009369', (58, 65))	('tumours', 'Disease', (58, 65))	('inducing', 'PosReg', (130, 138))	('LTbetaR agonism', 'Var', (114, 129))
150924	26206664	Transfection of CAT results in the formation of distinct hepatoblastoma and HCC-like nodules at day 90 and day 400 (figure 5D, E), while NICD transfected livers were similar in morphology to AKT/NICD-initiated livers; solely ICC at day 90 and time of morbidity (Fig 5D, E).	('ICD', 'Disease', (196, 199))	('ICD', 'Disease', 'OMIM:252500', (138, 141))	('CAT', 'Gene', (16, 19))	('HCC-like nodules', 'CPA', (76, 92))	('CAT', 'Gene', '847', (16, 19))	('ICD', 'Disease', (138, 141))	('hepatoblastoma', 'Disease', 'MESH:D018197', (57, 71))	('Transfection', 'Var', (0, 12))	('ICD', 'Disease', 'OMIM:252500', (196, 199))	('hepatoblastoma', 'Disease', (57, 71))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (57, 71))
150926	26206664	Noteworthy changes were observed in biliary proliferation (H&E) following AKT or AKT/CAT/anti-LTbetaR, but not observed in pT3 or CAT/anti-LTbetaR livers at day 40 following 4 weeks of treatment (see online supplementary figure S8A, arrows).	('following', 'Var', (64, 73))	('CAT', 'Gene', '847', (85, 88))	('CAT', 'Gene', (85, 88))	('CAT', 'Gene', '847', (130, 133))	('biliary proliferation', 'CPA', (36, 57))	('CAT', 'Gene', (130, 133))	('H&E', 'Chemical', 'MESH:D006371', (59, 62))	('rat', 'Species', '10116', (51, 54))
150931	26206664	Knockdown of LTbetaR in Huh1 and Oz cells with targeting siRNA resulted in decreased protein expression/activation of pAKTser473, CAT, NICD and Hes1 levels at 48 h post transfection (figure 6B), suggesting that LTbetaR signalling may be important for maintaining the activity of these oncogenes in human liver cancer cells.	('liver cancer', 'Phenotype', 'HP:0002896', (304, 316))	('protein expression/activation', 'MPA', (85, 114))	('siRNA', 'Gene', (57, 62))	('human liver cancer', 'Disease', (298, 316))	('targeting', 'Var', (47, 56))	('Hes1 levels', 'MPA', (144, 155))	('human liver cancer', 'Disease', 'MESH:D006528', (298, 316))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('Huh1', 'Gene', '25932', (24, 28))	('CAT', 'Gene', '847', (130, 133))	('ICD', 'Disease', 'OMIM:252500', (136, 139))	('CAT', 'Gene', (130, 133))	('pAKTser473', 'MPA', (118, 128))	('Huh1', 'Gene', (24, 28))	('ICD', 'Disease', (136, 139))	('decreased', 'NegReg', (75, 84))
150935	26206664	Furthermore, an ICC cohort of Thai patients obtained for study through the TIGER-LC consortium (Chaisaingmongkol et al, manuscript in preparation) stratified LTbetaR high (n=43) expression with significantly worse survival as compared with ICC cases with LTbetaR low (n=42) expression (figure 6E).	('rat', 'Species', '10116', (149, 152))	('rat', 'Species', '10116', (139, 142))	('LTbetaR high', 'Var', (158, 170))	('survival', 'MPA', (214, 222))	('TIGER', 'Species', '9694', (75, 80))	('patients', 'Species', '9606', (35, 43))	('worse', 'NegReg', (208, 213))
150948	26206664	Similarly, we detected increased LTbeta expression in AKT/NICD and cMET/CAT-hydrodynamically transfected livers (see online supplementary figure S10A, B).	('expression', 'MPA', (40, 50))	('S10A', 'SUBSTITUTION', 'None', (145, 149))	('CAT', 'Gene', (72, 75))	('S10A', 'Var', (145, 149))	('LTbeta', 'Gene', (33, 39))	('increased', 'PosReg', (23, 32))	('LTbeta', 'Gene', '4050', (33, 39))	('ICD', 'Disease', 'OMIM:252500', (59, 62))	('increased LTbeta', 'Phenotype', 'HP:0003141', (23, 39))	('ICD', 'Disease', (59, 62))	('CAT', 'Gene', '847', (72, 75))
150954	26206664	We expanded on this observation and demonstrate that LTbetaR agonism+AKT and to a greater extent LTbetaR agonism + AKT/CAT, results in tumour pathology characterised by lipogenic hepatic foci with interspersed regions of ICC.	('LTbetaR agonism+AKT', 'Var', (53, 72))	('CAT', 'Gene', '847', (119, 122))	('rat', 'Species', '10116', (43, 46))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('lipogenic hepatic foci', 'MPA', (169, 191))	('CAT', 'Gene', (119, 122))	('tumour pathology', 'Disease', (135, 151))	('tumour pathology', 'Disease', 'MESH:D005598', (135, 151))	('results in', 'Reg', (124, 134))
150967	26206664	It is therefore intriguing to speculate that the reduction in AKT/CAT-initiated tumour development by LTbetaR-Fc is mediated in part through a normalisation of metabolic functions.	('tumour', 'Disease', (80, 86))	('metabolic functions', 'MPA', (160, 179))	('reduction', 'NegReg', (49, 58))	('LTbetaR-Fc', 'Var', (102, 112))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('CAT', 'Gene', (66, 69))	('CAT', 'Gene', '847', (66, 69))
151016	26870353	The development of IPNB was reported to follow an adenoma-to-carcinoma sequence, which correlated with the stepwise activation of common oncogenic pathways, including mutated Kirsten rat sarcoma viral oncogene homolog, the overexpression of tumor protein 53 and loss of p16.	('rat', 'Species', '10116', (183, 186))	('sarcoma viral', 'Disease', 'MESH:D001102', (187, 200))	('p16', 'Gene', '25163', (270, 273))	('sarcoma viral', 'Disease', (187, 200))	('tumor', 'Disease', (241, 246))	('adenoma-to-carcinoma', 'Disease', (50, 70))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('p16', 'Gene', (270, 273))	('IPNB', 'Chemical', '-', (19, 23))	('oncogenic pathways', 'Pathway', (137, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('overexpression', 'PosReg', (223, 237))	('IPNB', 'Disease', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('loss', 'NegReg', (262, 266))	('adenoma-to-carcinoma', 'Disease', 'MESH:D000236', (50, 70))	('activation', 'PosReg', (116, 126))	('mutated', 'Var', (167, 174))
151032	26870353	Several previous studies reported that false-negative results obtained in cases of 18F-FDG PET were due to the morphology of extrahepatic cholangiocarcinoma.	('extrahepatic cholangiocarcinoma', 'Disease', (125, 156))	('18F-FDG', 'Var', (83, 90))	('18F-FDG', 'Chemical', 'MESH:D019788', (83, 90))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (125, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (138, 156))
151071	26230769	Both fibrotic and neoplastic transformation have been linked to increased levels of OS by several mechanisms, including DNA damage, genomic instability, and cellular proliferation, The DNA base modifications caused by OS also result in oxidation of guanine residues to 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), which are excised into bodily fluids, such as urine, blood and saliva.	('guanine residues', 'MPA', (249, 265))	('result in', 'Reg', (226, 235))	('modifications', 'Var', (194, 207))	('DNA base', 'MPA', (185, 193))	('guanine', 'Chemical', 'MESH:D006147', (249, 256))	("8-oxo-7,8-dihydro-2'-deoxyguanosine", 'Chemical', 'MESH:C067134', (269, 304))	('oxidation', 'MPA', (236, 245))	('OS', 'Phenotype', 'HP:0025464', (84, 86))	('OS', 'Phenotype', 'HP:0025464', (218, 220))
78092	26230769	HE450525 and HE531061).	('HE531061', 'Var', (13, 21))	('HE531061', 'CellLine', 'CVCL:2922', (13, 21))	('HE450525', 'Var', (0, 8))
151122	24212831	For example, high expression levels of TNF-alpha in the liver tissues of patients with chronic viral hepatitis activate the NF-kappaB classical pathway, which is associated with cell proliferation and suppression of apoptosis, leading to hepatocarcinogenesis.	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (238, 258))	('viral hepatitis', 'Phenotype', 'HP:0006562', (95, 110))	('high', 'Var', (13, 17))	('chronic viral hepatitis', 'Disease', (87, 110))	('hepatitis', 'Phenotype', 'HP:0012115', (101, 110))	('patients', 'Species', '9606', (73, 81))	('activate', 'PosReg', (111, 119))	('hepatocarcinogenesis', 'Disease', (238, 258))	('expression', 'MPA', (18, 28))	('NF-kappaB', 'Gene', '4790', (124, 133))	('leading to', 'Reg', (227, 237))	('TNF-alpha', 'Gene', '7124', (39, 48))	('NF-kappaB', 'Gene', (124, 133))	('TNF-alpha', 'Gene', (39, 48))	('chronic viral hepatitis', 'Disease', 'MESH:D006525', (87, 110))
151126	24212831	Genetic changes, such as nucleotide alterations and chromosomal translocation occurred in oncogenes and tumor-suppressor genes, have an important role in cancer development.	('oncogenes', 'Gene', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('cancer', 'Disease', (154, 160))	('chromosomal translocation', 'Var', (52, 77))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('nucleotide alterations', 'Var', (25, 47))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
151128	24212831	Use of these technologies to analyze the whole genomes of various cancer tissues, such as acute myeloid leukemia, lung cancer, breast cancer, and pancreatic cancer has led to the detection of a variety of nucleotide alterations, gene amplifications, and chromosomal translocations.	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (90, 112))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (90, 112))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('chromosomal translocations', 'Var', (254, 280))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('cancer', 'Disease', (134, 140))	('breast cancer', 'Disease', (127, 140))	('cancer', 'Disease', (119, 125))	('pancreatic cancer', 'Disease', 'MESH:D010190', (146, 163))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('gene amplifications', 'Var', (229, 248))	('pancreatic cancer', 'Disease', (146, 163))	('lung cancer', 'Disease', (114, 125))	('cancer', 'Disease', (157, 163))	('acute myeloid leukemia', 'Disease', (90, 112))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('nucleotide alterations', 'Var', (205, 227))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (96, 112))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (146, 163))	('cancer', 'Disease', (66, 72))
151129	24212831	In addition, almost all of the nucleotide alterations are "passenger mutations", which are not involved in carcinogenesis, in contrast to the small percentage of "driver mutations", which directly contribute to oncogenesis.	('carcinogenesis', 'Disease', (107, 121))	('carcinogenesis', 'Disease', 'MESH:D063646', (107, 121))	('nucleotide alterations', 'Var', (31, 53))
151130	24212831	On the other hand, organ-specific profiles of copy number variations have been reported in the genome of various cancer tissues, including HCC and lung cancer, based on the traditional comparative genomic hybridization array analysis.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('copy number variations', 'Var', (46, 68))	('lung cancer', 'Disease', (147, 158))	('HCC', 'Gene', '619501', (139, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('HCC', 'Phenotype', 'HP:0001402', (139, 142))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('HCC', 'Gene', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
151131	24212831	In some diseases, such as hereditary non-polyposis colorectal cancer, abnormalities in DNA mismatch repair genes lead to the accumulation of nucleotide alterations in various genes and colon carcinogenesis.	('abnormalities', 'Var', (70, 83))	('hereditary non-polyposis colorectal cancer', 'Phenotype', 'HP:0006716', (26, 68))	('lead to', 'Reg', (113, 120))	('hereditary non-polyposis colorectal cancer', 'Disease', (26, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('genes', 'Gene', (175, 180))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (185, 205))	('accumulation', 'PosReg', (125, 137))	('nucleotide alterations', 'MPA', (141, 163))	('colon carcinogenesis', 'Disease', (185, 205))	('hereditary non-polyposis colorectal cancer', 'Disease', 'MESH:D015179', (26, 68))	('DNA mismatch repair genes', 'Gene', (87, 112))
151132	24212831	Genetic aberrations in DNA repair systems, however, have been reported in only a few cancers and the molecular mechanism for acquiring the genetic abnormalities remains unclear for most cancers.	('genetic abnormalities', 'Disease', (139, 160))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('reported', 'Reg', (62, 70))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('Genetic aberrations', 'Var', (0, 19))	('genetic abnormalities', 'Disease', 'MESH:D030342', (139, 160))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
151138	24212831	U-guanine (G) mismatch created by AID is resolved by several pathways that may compete with one another (Figure 1).	('U-guanine', 'Var', (0, 9))	('mismatch', 'Var', (14, 22))	('U-guanine', 'Chemical', '-', (0, 9))
151140	24212831	Alternatively, removal of the U nucleotide by uracil-DNA glycosylase creates an abasic site, which gives rise to both transition and transversion mutations at C-G base pairs when a short-patch base-excision repair can fill the gap with error-prone polymerases.	('mutations', 'Var', (146, 155))	('gives rise to', 'Reg', (99, 112))	('uracil-DNA glycosylase', 'Gene', (46, 68))	('removal', 'Var', (15, 22))	('uracil-DNA glycosylase', 'Gene', '7374', (46, 68))
151141	24212831	On the other hand, the mismatch repair heterodimer Msh2/Msh6 is thought to trigger the excision and error-prone resynthesis of DNA sequences, leading to mutations at the A-T base pairs near the initiating U-G mismatch.	('Msh6', 'Gene', (56, 60))	('mutations at', 'Var', (153, 165))	('Msh2', 'Gene', (51, 55))	('Msh2', 'Gene', '4436', (51, 55))	('Msh6', 'Gene', '2956', (56, 60))
151144	24212831	Sequence analysis in 83 transcribed non-Ig genes extracted from Ung/Msh2 double-knockout germinal center B cells revealed that more than half of the genes exhibited a strong bias for C:G to T:A transition mutations and enrichment for mutations in AID hotspots.	('Ung', 'Gene', '7374', (64, 67))	('C:G to T:A transition mutations', 'Var', (183, 214))	('Msh2', 'Gene', '4436', (68, 72))	('Ung', 'Gene', (64, 67))	('Msh2', 'Gene', (68, 72))
151146	24212831	These results indicate that a number of non-Ig genes are targeted by AID but some are protected from substantial mutation accumulation by high-fidelity repair through the combined action of Ung and Msh2, although some other genes are repaired in an error prone manner, frequently leading to accumulation of mutations like Ig gene.	('Ung', 'Gene', '7374', (190, 193))	('accumulation', 'PosReg', (291, 303))	('Msh2', 'Gene', '4436', (198, 202))	('mutations', 'Var', (307, 316))	('leading to', 'Reg', (280, 290))	('Ung', 'Gene', (190, 193))	('Msh2', 'Gene', (198, 202))	('Ig gene', 'Gene', (322, 329))
151149	24212831	They also reported that point mutations are massively introduced in various non-Ig genes, including the proto-oncogene c-myc and T cell receptor gene, in lymphoma cells.	('lymphoma', 'Disease', (154, 162))	('lymphoma', 'Disease', 'MESH:D008223', (154, 162))	('proto-oncogene c-myc', 'Gene', '4609', (104, 124))	('lymphoma', 'Phenotype', 'HP:0002665', (154, 162))	('non-Ig genes', 'Gene', (76, 88))	('point mutations', 'Var', (24, 39))	('proto-oncogene c-myc', 'Gene', (104, 124))
151151	24212831	Notably, organ-specific preferences for nucleotide alterations are observed in some of the tumor-related genes in each epithelial tissue of the AID Tg mice.	('mice', 'Species', '10090', (151, 155))	('nucleotide alterations', 'Var', (40, 62))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
151153	24212831	In contrast, nucleotide alterations in the Trp53 and Ctnnb1 genes are commonly induced during the development of lung, liver, and gastric cancers.	('gastric cancers', 'Disease', (130, 145))	('gastric cancers', 'Phenotype', 'HP:0012126', (130, 145))	('liver', 'Disease', (119, 124))	('nucleotide alterations', 'Var', (13, 35))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Ctnnb1', 'Gene', (53, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (130, 144))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('induced', 'Reg', (79, 86))	('lung', 'Disease', (113, 117))	('Ctnnb1', 'Gene', '1499', (53, 59))	('Trp53', 'Gene', (43, 48))	('gastric cancers', 'Disease', 'MESH:D013274', (130, 145))
151154	24212831	These findings suggest that inappropriate or deregulated AID expression increases the mutation rate of genes that are not normally attacked by AID and contribute to tumor development in both lymphoid and non-lymphoid organs, and that AID might be involved in the generation of organ-specific genetic diversity in oncogenic pathways during cancer development.	('mutation', 'MPA', (86, 94))	('increases', 'PosReg', (72, 81))	('cancer', 'Disease', (339, 345))	('genes', 'Gene', (103, 108))	('deregulated', 'Var', (45, 56))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('cancer', 'Disease', 'MESH:D009369', (339, 345))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('AID', 'Gene', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('tumor', 'Disease', (165, 170))
151155	24212831	A number of studies demonstrated high AID expression in various neoplasms of B lymphocytic lineage and determined that AID expression levels are associated with unfavorable gene mutations and chromosomal translocations.	('neoplasms', 'Disease', (64, 73))	('associated', 'Reg', (145, 155))	('neoplasms', 'Phenotype', 'HP:0002664', (64, 73))	('AID expression levels', 'MPA', (119, 140))	('AID expression', 'MPA', (38, 52))	('chromosomal translocations', 'Var', (192, 218))	('neoplasms', 'Disease', 'MESH:D009369', (64, 73))
151167	24212831	On the other hand, nucleotide alterations frequently occur in tumor-related genes, such as TP53 in HCC tissues.	('TP53', 'Gene', (91, 95))	('nucleotide alterations', 'Var', (19, 41))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('HCC', 'Gene', '619501', (99, 102))	('HCC', 'Phenotype', 'HP:0001402', (99, 102))	('TP53', 'Gene', '7157', (91, 95))	('occur', 'Reg', (53, 58))	('HCC', 'Gene', (99, 102))
151168	24212831	In addition, various genetic alterations accumulate in various genes in the chronic hepatitis tissues before HCC develops.	('HCC', 'Gene', (109, 112))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (76, 93))	('HCC', 'Gene', '619501', (109, 112))	('chronic hepatitis', 'Disease', 'MESH:D056487', (76, 93))	('hepatitis', 'Phenotype', 'HP:0012115', (84, 93))	('HCC', 'Phenotype', 'HP:0001402', (109, 112))	('chronic hepatitis', 'Disease', (76, 93))	('genetic alterations', 'Var', (21, 40))
151185	24212831	Furthermore, a high incidence of mutation accumulation in the Trp53 gene is observed in both HCC tissues and non-cancerous liver tissues in TNAP-AID mice.	('HCC', 'Gene', '619501', (93, 96))	('HCC', 'Phenotype', 'HP:0001402', (93, 96))	('non-cancerous liver', 'Disease', 'MESH:D006528', (109, 128))	('mutation', 'Var', (33, 41))	('Trp53', 'Gene', (62, 67))	('non-cancerous liver', 'Disease', (109, 128))	('TNAP', 'Gene', (140, 144))	('HCC', 'Gene', (93, 96))	('mice', 'Species', '10090', (149, 153))	('TNAP', 'Gene', '11647', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancerous liver', 'Phenotype', 'HP:0002896', (113, 128))
151188	24212831	detected that the ectopic AID production in both gastric cancer tissues and chronic gastritis tissues infected with H. pylori, although no AID expression was observed in normal gastric mucosa or in gastric tissues after eradicating the H. pylori.	('chronic gastritis', 'Phenotype', 'HP:0005231', (76, 93))	('gastritis tissues infected', 'Disease', (84, 110))	('gastric mucosa', 'Disease', (177, 191))	('H. pylori', 'Species', '210', (116, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('gastritis tissues infected', 'Disease', 'MESH:D005756', (84, 110))	('ectopic AID production', 'MPA', (18, 40))	('H. pylori', 'Var', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('gastric cancer', 'Disease', (49, 63))	('gastric mucosa', 'Disease', 'MESH:D013274', (177, 191))	('gastritis', 'Phenotype', 'HP:0005263', (84, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (49, 63))	('H. pylori', 'Species', '210', (236, 245))
151194	24212831	Intriguingly, cagPAI-positive H. pylori infection induces aberrant AID expression in gastric epithelial cells via NF-kappaB activation.	('infection', 'Disease', (40, 49))	('infection', 'Disease', 'MESH:D007239', (40, 49))	('activation', 'PosReg', (124, 134))	('NF-kappaB', 'Gene', (114, 123))	('H. pylori', 'Species', '210', (30, 39))	('H. pylori', 'Disease', (30, 39))	('AID expression', 'MPA', (67, 81))	('aberrant', 'Var', (58, 66))	('NF-kappaB', 'Gene', '4790', (114, 123))	('induces', 'Reg', (50, 57))	('H. pylori infection', 'Phenotype', 'HP:0005202', (30, 49))
151196	24212831	In in vitro-cultured gastric epithelial cells, cagPAI-positive H. pylori infection led to somatic mutations in the tumor-suppressor TP53 gene.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('led to', 'Reg', (83, 89))	('H. pylori', 'Species', '210', (63, 72))	('infection', 'Disease', (73, 82))	('tumor', 'Disease', (115, 120))	('TP53', 'Gene', (132, 136))	('infection', 'Disease', 'MESH:D007239', (73, 82))	('mutations', 'Var', (98, 107))	('TP53', 'Gene', '7157', (132, 136))	('H. pylori infection', 'Phenotype', 'HP:0005202', (63, 82))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
151197	24212831	The number of nucleotide alterations observed in H. pylori-infected cells was significantly reduced by knockdown of endogenous AID, indicating that the somatic mutations in the TP53 gene in cagPAI-positive H. pylori infected cells were due to the induction of endogenous AID expression in gastric cells.	('mutations', 'Var', (160, 169))	('TP53', 'Gene', '7157', (177, 181))	('H. pylori', 'Species', '210', (206, 215))	('H. pylori', 'Species', '210', (49, 58))	('TP53', 'Gene', (177, 181))
151198	24212831	These findings indicate that cagPAI-positive H. pylori infection causes accumulation of somatic mutations in tumor-related genes such as TP53 through aberrant AID upregulation in gastric epithelial cells.	('upregulation', 'PosReg', (163, 175))	('tumor', 'Disease', (109, 114))	('H. pylori', 'Species', '210', (45, 54))	('H. pylori infection', 'Phenotype', 'HP:0005202', (45, 64))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('accumulation', 'PosReg', (72, 84))	('infection', 'Disease', (55, 64))	('H. pylori', 'Disease', (45, 54))	('TP53', 'Gene', '7157', (137, 141))	('infection', 'Disease', 'MESH:D007239', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mutations', 'Var', (96, 105))	('TP53', 'Gene', (137, 141))
151204	24212831	In sporadic colorectal cancer, colorectal adenoma first develops through the occurrence of an APC gene mutation, and other genetic alterations such as KRAS activation and TP53 inactivation occur during carcinogenesis.	('TP53', 'Gene', (171, 175))	('colorectal cancer', 'Disease', (12, 29))	('colorectal adenoma', 'Disease', (31, 49))	('KRAS', 'Gene', '3845', (151, 155))	('colorectal adenoma', 'Disease', 'MESH:D015179', (31, 49))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('carcinogenesis', 'Disease', 'MESH:D063646', (202, 216))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('APC', 'Disease', 'MESH:D011125', (94, 97))	('carcinogenesis', 'Disease', (202, 216))	('mutation', 'Var', (103, 111))	('APC', 'Disease', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('KRAS', 'Gene', (151, 155))	('TP53', 'Gene', '7157', (171, 175))
151205	24212831	In contrast, mutations in the TP53 gene appear to be an early event and already present in the colonic mucosa of patients with UC before CAC onset.	('TP53', 'Gene', (30, 34))	('UC', 'Phenotype', 'HP:0100279', (127, 129))	('patients', 'Species', '9606', (113, 121))	('CAC', 'Phenotype', 'HP:0002664', (137, 140))	('mutations', 'Var', (13, 22))	('TP53', 'Gene', '7157', (30, 34))
151206	24212831	Interestingly, aberrant endogenous AID protein is detected both in the inflamed colonic mucosa and CAC tissues of UC patients.	('inflamed colonic mucosa', 'Disease', 'MESH:C531841', (71, 94))	('CAC', 'Phenotype', 'HP:0002664', (99, 102))	('UC', 'Phenotype', 'HP:0100279', (114, 116))	('aberrant', 'Var', (15, 23))	('patients', 'Species', '9606', (117, 125))	('inflamed colonic mucosa', 'Disease', (71, 94))
151216	24212831	These results suggest that the proinflammatory cytokine-mediated aberrant AID expression in colonic epithelial cells is a genotoxic factor linking inflammation, TP53 mutation and CAC development (Figure 2c).	('colonic epithelia', 'Disease', 'MESH:D015179', (92, 109))	('TP53', 'Gene', (161, 165))	('aberrant', 'Var', (65, 73))	('inflammation', 'Disease', 'MESH:D007249', (147, 159))	('CAC', 'Phenotype', 'HP:0002664', (179, 182))	('CAC', 'Disease', (179, 182))	('inflammation', 'Disease', (147, 159))	('TP53', 'Gene', '7157', (161, 165))	('mutation', 'Var', (166, 174))	('colonic epithelia', 'Disease', (92, 109))
151223	24212831	Furthermore, the aberrant AID expression in biliary cells results in the generation of mutations in tumor-related genes including TP53 and INK4A/p16, both of which are frequently mutated in human cholangiocarcinoma tissues underlying PSC.	('aberrant', 'Var', (17, 25))	('INK4A', 'Gene', '1029', (139, 144))	('cholangiocarcinoma', 'Disease', (196, 214))	('tumor', 'Disease', (100, 105))	('PSC', 'Gene', (234, 237))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (196, 214))	('p16', 'Gene', (145, 148))	('results in', 'Reg', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mutations', 'Var', (87, 96))	('p16', 'Gene', '1029', (145, 148))	('INK4A', 'Gene', (139, 144))	('human', 'Species', '9606', (190, 195))	('TP53', 'Gene', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('PSC', 'Gene', '100653366', (234, 237))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (196, 214))	('TP53', 'Gene', '7157', (130, 134))
151226	24212831	Recent studies indicate the possibility that the mutagenic activity of AID causes inflammation-associated carcinogenesis in various tissues.	('causes', 'Reg', (75, 81))	('carcinogenesis', 'Disease', 'MESH:D063646', (106, 120))	('carcinogenesis', 'Disease', (106, 120))	('inflammation', 'Disease', 'MESH:D007249', (82, 94))	('mutagenic activity', 'Var', (49, 67))	('inflammation', 'Disease', (82, 94))
151235	21873469	A xenograft tumour model was used to measure tumour volume after treatment with histamine or inhibition of histamine synthesis by manipulation of HDC.	('inhibition', 'NegReg', (93, 103))	('HDC', 'Gene', (146, 149))	('tumour', 'Disease', (12, 18))	('histamine', 'Chemical', 'MESH:D006632', (107, 116))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('manipulation', 'Var', (130, 142))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('histamine', 'Chemical', 'MESH:D006632', (80, 89))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumour', 'Disease', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (12, 18))
151238	21873469	Inhibition of HDC and antagonising H1HR decreased histamine secretion in Mz-ChA-1 cells.	('H1HR', 'Protein', (35, 39))	('antagonising', 'Var', (22, 34))	('decreased', 'NegReg', (40, 49))	('Inhibition', 'Var', (0, 10))	('histamine secretion', 'MPA', (50, 69))	('histamine', 'Chemical', 'MESH:D006632', (50, 59))	('HDC', 'Protein', (14, 17))
151244	21873469	Cholangiocarcinoma arises from aberrant cholangiocyte hyperplasia caused by obstruction and inflammation of bile ducts.	('obstruction', 'Disease', (76, 87))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (0, 18))	('aberrant', 'Var', (31, 39))	('hyperplasia', 'Disease', 'MESH:D006965', (54, 65))	('inflammation', 'Disease', 'MESH:D007249', (92, 104))	('inflammation of bile', 'Phenotype', 'HP:0030151', (92, 112))	('hyperplasia', 'Disease', (54, 65))	('inflammation', 'Disease', (92, 104))	('obstruction', 'Disease', 'MESH:D000402', (76, 87))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 18))	('Cholangiocarcinoma', 'Disease', (0, 18))
151255	21873469	For example, H3HR inhibits cholangiocarcinoma growth both in vitro and in vivo by downregulation of vascular endothelial growth factor (VEGF)-A/C expression, growth factors which modulate biliary function.	('cholangiocarcinoma growth', 'Disease', (27, 52))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (27, 52))	('H3HR', 'Var', (13, 17))	('inhibits', 'NegReg', (18, 26))	('downregulation', 'NegReg', (82, 96))	('vascular endothelial growth factor', 'Gene', (100, 134))	('H3HR', 'Chemical', '-', (13, 17))	('vascular endothelial growth factor', 'Gene', '7422', (100, 134))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (27, 45))
151338	21873469	The decrease in the expression of the stimulatory HRs H1-H2 (Alpini, unpublished observations, 2011) following genetic loss of HDC probably depends on the lack of histamine secretion in cholangiocarcinoma.	('genetic loss', 'Var', (111, 123))	('expression', 'MPA', (20, 30))	('cholangiocarcinoma', 'Disease', (186, 204))	('decrease', 'NegReg', (4, 12))	('histamine', 'Chemical', 'MESH:D006632', (163, 172))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (186, 204))	('HDC', 'Gene', (127, 130))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (186, 204))
151341	21873469	By real-time PCR and immunoblots we found a significant decrease in HDC and PCNA expression in tumours from Mz-HDC mice compared with Mz-neg tumours (figure 7B,C).	('tumours', 'Disease', (141, 148))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('Mz-HDC', 'Var', (108, 114))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumours', 'Disease', (95, 102))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('HDC', 'Gene', (68, 71))	('tumours', 'Disease', 'MESH:D009369', (141, 148))	('PCNA', 'Gene', (76, 80))	('mice', 'Species', '10090', (115, 119))	('decrease', 'NegReg', (56, 64))	('expression', 'MPA', (81, 91))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
151342	21873469	There was decreased VEGF-A/C expression in RNA of tumours from Mz-HDC mice compared with samples from Mz-neg tumours (see figure 5 in online supplement).	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('decreased', 'NegReg', (10, 19))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('Mz-HDC', 'Var', (63, 69))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('VEGF-A/C', 'Gene', (20, 28))	('tumours', 'Disease', (50, 57))	('tumours', 'Disease', (109, 116))	('mice', 'Species', '10090', (70, 74))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('expression', 'MPA', (29, 39))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
151346	21873469	The over-secretion of histamine increased tumour growth and expression of VEGF-A/C by enhanced HDC expression.	('over-secretion', 'PosReg', (4, 18))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('tumour growth', 'Disease', (42, 55))	('expression', 'Var', (60, 70))	('tumour growth', 'Disease', 'MESH:D006130', (42, 55))	('VEGF-A/C', 'Gene', (74, 82))	('enhanced', 'PosReg', (86, 94))	('increased', 'PosReg', (32, 41))	('HDC expression', 'CPA', (95, 109))	('histamine', 'Chemical', 'MESH:D006632', (22, 31))
151347	21873469	Inhibition of HDC decreased cholangiocarcinoma proliferation and VEGF expression both in vivo and in vitro.	('decreased cholangiocarcinoma proliferation', 'Disease', (18, 60))	('decreased cholangiocarcinoma proliferation', 'Disease', 'MESH:D018281', (18, 60))	('expression', 'MPA', (70, 80))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (28, 46))	('Inhibition', 'Var', (0, 10))	('HDC decreased', 'Phenotype', 'HP:0031851', (14, 27))	('HDC', 'Protein', (14, 17))	('VEGF', 'Gene', (65, 69))
151348	21873469	Increased cholangiocarcinoma growth (induced by enhanced HDC expression and histamine secretion) is ablated by the H1HR but not the H2HR antagonist.	('H1HR', 'Var', (115, 119))	('H2HR', 'Chemical', '-', (132, 136))	('enhanced', 'PosReg', (48, 56))	('HDC', 'Protein', (57, 60))	('histamine', 'Chemical', 'MESH:D006632', (76, 85))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (10, 28))	('cholangiocarcinoma growth', 'Disease', (10, 35))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (10, 35))
151351	21873469	Supporting our findings, the synthesis of dopamine and serotonin is dysregulated in cholangiocarcinoma, and blocking the rate-limiting enzymes responsible for the production of these amines decreases cholangiocarcinoma growth.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('amines', 'Chemical', 'MESH:D000588', (183, 189))	('dopamine', 'Chemical', 'MESH:D004298', (42, 50))	('serotonin', 'Chemical', 'MESH:D012701', (55, 64))	('cholangiocarcinoma', 'Disease', (200, 218))	('cholangiocarcinoma', 'Disease', (84, 102))	('blocking', 'Var', (108, 116))	('synthesis', 'MPA', (29, 38))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (200, 218))	('decreases cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (190, 225))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (200, 218))	('decreases cholangiocarcinoma growth', 'Disease', (190, 225))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
151352	21873469	In support of the expression pattern of H1-H4 HRs in cholangiocarcinoma, H3HRs are expressed by cholangiocytes and inhibit biliary hyperplasia whereas H1HRs increase the proliferation of cholangiocytes.	('biliary hyperplasia', 'Disease', (123, 142))	('H3HRs', 'Var', (73, 78))	('inhibit', 'NegReg', (115, 122))	('increase', 'PosReg', (157, 165))	('biliary hyperplasia', 'Disease', 'MESH:D006965', (123, 142))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (53, 71))	('cholangiocarcinoma', 'Disease', (53, 71))	('proliferation of cholangiocytes', 'CPA', (170, 201))	('biliary hyperplasia', 'Phenotype', 'HP:0006560', (123, 142))	('H3HR', 'Chemical', '-', (73, 77))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (53, 71))
151353	21873469	In breast cancer cells, HDC is upregulated and identified as a key player in the progression of mammary carcinogenesis whereas the H4HR decreased breast cancer growth via cell cycle arrest and induction of cell death.	('mammary carcinogenesis', 'Disease', (96, 118))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('arrest', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('upregulated', 'PosReg', (31, 42))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (171, 188))	('cell death', 'CPA', (206, 216))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('arrest', 'Disease', 'MESH:D006323', (182, 188))	('decreased', 'NegReg', (136, 145))	('H4HR', 'Var', (131, 135))
151364	21873469	In vivo, we demonstrated that the loss of HDC by pharmacological or genetic modification inhibits tumour growth compared with histamine-treated mice or mice with normal levels of HDC.	('loss', 'Var', (34, 38))	('histamine', 'Chemical', 'MESH:D006632', (126, 135))	('inhibits', 'NegReg', (89, 97))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('mice', 'Species', '10090', (144, 148))	('tumour growth', 'Disease', 'MESH:D006130', (98, 111))	('mice', 'Species', '10090', (152, 156))	('HDC', 'Protein', (42, 45))	('tumour growth', 'Disease', (98, 111))
151372	21873469	After knockdown of HDC, tumour volume did not increase as aggressively as the tumours induced by the mock-transformed line but remained similar throughout most of the measurement time after an initial fall in tumour volume.	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('fall', 'Phenotype', 'HP:0002527', (201, 205))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('tumour', 'Disease', 'MESH:D009369', (209, 215))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('tumour', 'Disease', (78, 84))	('tumours', 'Disease', (78, 85))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('tumour', 'Disease', (24, 30))	('HDC', 'Gene', (19, 22))	('tumour', 'Disease', (209, 215))	('knockdown', 'Var', (6, 15))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
151375	21873469	We propose that increased histamine release increases tumour growth whereas blocking HDC or inhibition of the H1HR decreases cholangiocarcinoma growth (figure 8).	('inhibition', 'Var', (92, 102))	('H1HR', 'Gene', (110, 114))	('histamine release', 'MPA', (26, 43))	('HDC', 'Protein', (85, 88))	('decreases cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (115, 150))	('increased', 'PosReg', (16, 25))	('blocking', 'Var', (76, 84))	('tumour growth', 'Disease', (54, 67))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (125, 143))	('increases', 'PosReg', (44, 53))	('tumour growth', 'Disease', 'MESH:D006130', (54, 67))	('decreases cholangiocarcinoma growth', 'Disease', (115, 150))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('histamine', 'Chemical', 'MESH:D006632', (26, 35))
151380	21873469	Inhibition of the H1HR decreases cholangiocarcinoma growth.	('decreases cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (23, 58))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (33, 51))	('decreases cholangiocarcinoma growth', 'Disease', (23, 58))	('H1HR', 'Protein', (18, 22))	('Inhibition', 'Var', (0, 10))
151396	19228732	Overexpression of c-FLIP inhibited tamoxifen-induced apoptosis and enhanced tumorigenesis of cholangiocarcinoma cells in nude mice, whereas deletion of the calmodulin-binding domain on c-FLIP restored the sensitivity to tamoxifen and inhibited tumorigenesis.	('restored', 'PosReg', (192, 200))	('c-FLIP', 'Gene', (185, 191))	('c-FLIP', 'Gene', (18, 24))	('tumor', 'Disease', (76, 81))	('inhibited', 'NegReg', (234, 243))	('enhanced', 'PosReg', (67, 75))	('sensitivity to tamoxifen', 'MPA', (205, 229))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tamoxifen', 'Chemical', 'MESH:D013629', (220, 229))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('deletion', 'Var', (140, 148))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('inhibited', 'NegReg', (25, 34))	('tumor', 'Disease', (244, 249))	('c-FLIP', 'Gene', '12633', (185, 191))	('c-FLIP', 'Gene', '12633', (18, 24))	('cholangiocarcinoma', 'Disease', (93, 111))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('tamoxifen', 'Chemical', 'MESH:D013629', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('nude mice', 'Species', '10090', (121, 130))
151430	19228732	Stable cholangiocarcinoma clones overexpressing wild-type and mutant FLIP with deletion of the calmodulin-binding domain (DeltaFLIP) were generated using lentiviral FLIPL expression vector as described previously.	('mutant', 'Var', (62, 68))	('cholangiocarcinoma', 'Disease', (7, 25))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (7, 25))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (7, 25))	('deletion', 'Var', (79, 87))
151433	19228732	Antibodies include anti-FLIP, NF6 (Alexis Corp.), anti-caspase-8, anti-caspase-10, anti-caspase-3, anti-caspase-9, anti-AKT, anti-phospho-AKT (Cell Signaling), and anti-glyceraldehyde-3-phosphate dehydrogenase (Research Diag., Inc.).	('anti-caspase-9', 'Var', (99, 113))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (169, 209))	('caspase-10', 'Gene', '843', (71, 81))	('caspase-3', 'Gene', (88, 97))	('anti-FLIP', 'Var', (19, 28))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '14433', (169, 209))	('caspase-10', 'Gene', (71, 81))	('NF6', 'Gene', (30, 33))	('anti-caspase-8', 'Var', (50, 64))	('caspase-3', 'Gene', '12367', (88, 97))
151498	19228732	Taken together, our observations showed that the expression of pAKT and FLIP regulates cholangiocarcinoma cell survival and tamoxifen executes its apoptotic effect on cholangiocarcinoma cells through the calmodulin/FLIP axis and activation of caspases.	('caspases', 'Gene', (243, 251))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (167, 185))	('regulates', 'Reg', (77, 86))	('apoptotic effect', 'CPA', (147, 163))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (167, 185))	('cholangiocarcinoma', 'Disease', (87, 105))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (87, 105))	('cholangiocarcinoma', 'Disease', (167, 185))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('pAKT', 'Gene', (63, 67))	('caspases', 'Gene', '12362;841;12370;842;12371;843', (243, 251))	('tamoxifen', 'Chemical', 'MESH:D013629', (124, 133))	('expression', 'Var', (49, 59))
151502	19228732	4B and D, shows that caspase-8 and caspase-10 inhibitors effectively blocked tamoxifen-induced activation of the respective caspases.	('tamoxifen', 'Chemical', 'MESH:D013629', (77, 86))	('inhibitors', 'Var', (46, 56))	('caspase-10', 'Gene', (35, 45))	('caspases', 'Gene', '12362;841;12370;842;12371;843', (124, 132))	('caspases', 'Gene', (124, 132))	('blocked', 'NegReg', (69, 76))	('caspase-10', 'Gene', '843', (35, 45))
151509	19228732	Cholangiocarcinoma cells stably overexpressing wild-type (WT) FLIPL, DeltaFLIPL (mutant with deletion of calmodulin-binding domain) or LacZ (control) proteins were generated as described previously and the effects of tamoxifen on apoptosis of these cells were determined by Annexin/propidium iodide staining.	('propidium iodide', 'Chemical', 'MESH:D011419', (282, 298))	('Annexin', 'Gene', (274, 281))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (0, 18))	('Annexin', 'Gene', '105245705', (274, 281))	('tamoxifen', 'Chemical', 'MESH:D013629', (217, 226))	('deletion', 'Var', (93, 101))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 18))	('Cholangiocarcinoma', 'Disease', (0, 18))
151510	19228732	5A, FLIP over-expression decreased the sensitivity of cholangiocarcinoma cells to tamoxifen, which was restored by deletion of calmodulin-binding domain from overexpressed FLIPL.	('deletion', 'Var', (115, 123))	('sensitivity', 'MPA', (39, 50))	('tamoxifen', 'Chemical', 'MESH:D013629', (82, 91))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (54, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('decreased', 'NegReg', (25, 34))	('over-expression', 'PosReg', (9, 24))	('cholangiocarcinoma', 'Disease', (54, 72))
151512	19228732	Thus, WT FLIP overexpression decreased W-7-induced apoptosis, which was restored after deletion of the calmodulin-binding region from FLIPL.	('FLIPL', 'Gene', (134, 139))	('deletion', 'Var', (87, 95))	('W-7', 'Chemical', 'MESH:C017967', (39, 42))	('decreased', 'NegReg', (29, 38))
151514	19228732	5C, disruption of calmodulin-FLIP binding also resulted in decreased cell proliferation compared with WT FLIP-expressing cholangiocarcinoma cells in which calmodulin-FLIP binding is intact.	('binding', 'Interaction', (34, 41))	('decreased', 'NegReg', (59, 68))	('cholangiocarcinoma', 'Disease', (121, 139))	('calmodulin-FLIP', 'Protein', (18, 33))	('cell proliferation', 'CPA', (69, 87))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (121, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))	('disruption', 'Var', (4, 14))
151517	19228732	Cholangiocarcinoma cells expressing LacZ, WT FLIP, and DeltaFLIP were injected in the flanks of 6- to 7-week-old athymic nude mice.	('to 7', 'Species', '1214577', (99, 103))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (0, 18))	('Cholangiocarcinoma', 'Disease', (0, 18))	('LacZ', 'Gene', (36, 40))	('DeltaFLIP', 'Var', (55, 64))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 18))	('nude mice', 'Species', '10090', (121, 130))
151520	19228732	WT FLIP cells formed significantly bigger tumors than control LacZ and DeltaFLIP cells, whereas DeltaFLIP cells formed the smallest tumors at day 18 (tumor volumes in mm3, control LacZ = 124 +- 12, WT FLIP = 170 +- 25, DeltaFLIP = 82 +- 15).	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('DeltaFLIP', 'Var', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumors', 'Disease', (132, 138))	('tumor', 'Disease', (150, 155))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
151521	19228732	At day 14, DeltaFLIP cells grew significantly smaller tumors than both LacZ and WT FLIP cells (LacZ = 99 +- 9, WT FLIP = 101 +- 16, DeltaFLIP = 62 +- 11), supporting the concept that the interaction between calmodulin and FLIP is important in cholangiocarcinoma pathogenesis.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (243, 261))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (243, 261))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('DeltaFLIP', 'Var', (11, 20))	('cholangiocarcinoma', 'Disease', (243, 261))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('smaller', 'NegReg', (46, 53))	('tumors', 'Disease', (54, 60))
151534	19228732	Mutants of calmodulin with disabled Ca2+-binding domains and calmodulin antagonists were shown to inhibit activation of AKT and significantly decreased long-term cell survival, suggesting a pivotal role for calmodulin in AKT-mediated cell survival.	('activation', 'MPA', (106, 116))	('long-term cell survival', 'CPA', (152, 175))	('decreased', 'NegReg', (142, 151))	('AKT', 'Pathway', (120, 123))	('inhibit', 'NegReg', (98, 105))	('calmodulin', 'Gene', (11, 21))	('Ca2+', 'Chemical', 'MESH:D000069285', (36, 40))	('Mutants', 'Var', (0, 7))
151542	19228732	We recently showed that AKT is activated in cholangiocarcinoma cells that are resistant to Fas-induced apoptosis and inhibition of AKT using dominant-negative AKT enhances the sensitivity of these cells to Fas-mediated apoptosis.	('enhances', 'PosReg', (163, 171))	('AKT', 'Gene', (159, 162))	('Fas', 'Chemical', 'MESH:C038178', (91, 94))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (44, 62))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (44, 62))	('dominant-negative', 'Var', (141, 158))	('sensitivity', 'MPA', (176, 187))	('AKT', 'Pathway', (24, 27))	('Fas', 'Chemical', 'MESH:C038178', (206, 209))	('inhibition', 'NegReg', (117, 127))	('activated', 'PosReg', (31, 40))	('cholangiocarcinoma', 'Disease', (44, 62))
151543	19228732	Inhibition of pAKT has been linked to FLIP down-regulation in several cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('down-regulation', 'NegReg', (43, 58))	('FLIP', 'MPA', (38, 42))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
151552	19228732	Further, disrupted calmodulin-FLIP binding decreased cell survival and decreased tumorigenicity in nude mice compared with WT FLIP-overexpressing cells with intact calmodulin-FLIP binding (Fig.	('disrupted', 'Var', (9, 18))	('calmodulin-FLIP binding', 'Protein', (19, 42))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('nude mice', 'Species', '10090', (99, 108))	('cell survival', 'CPA', (53, 66))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('decreased', 'NegReg', (43, 52))	('decreased', 'NegReg', (71, 80))	('tumor', 'Disease', (81, 86))
151591	33912461	Programmed cell death protein 1 or ligand 1 (PD-1/L1) blockades are relatively novel therapeutics which have been tested for a variety of tumors and have found to have robust, durable antitumor activity.	('tumor', 'Disease', (188, 193))	('PD-1/L1', 'Gene', '5133;3897', (45, 52))	('tumor', 'Disease', (138, 143))	('PD-1/L1', 'Gene', (45, 52))	('blockades', 'Var', (54, 63))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('Programmed cell death protein 1 or ligand 1', 'Gene', '5133', (0, 43))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('Programmed cell death protein 1 or ligand 1', 'Gene', (0, 43))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
151704	33327311	To identify the candidate genes between LIHC and CHOL, three data series including GSE31370, GSE15765 and GSE40367 were downloaded from Gene Expression Omnibus (GEO) database.	('GSE15765', 'Var', (93, 101))	('GSE40367', 'Var', (106, 114))	('CHOL', 'Phenotype', 'HP:0030153', (49, 53))	('LIHC', 'Chemical', '-', (40, 44))	('GSE31370', 'Var', (83, 91))
151726	33327311	GSE31370 was retrieved from platform GPL10558 (Illumina HumanHT-12 V4.0 expression beadchip), while GSE15765 and GSE40367 were obtained from GPL571 ([HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array) and GPL570 ([HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array) respectively.	('GSE40367', 'Var', (113, 121))	('Human', 'Species', '9606', (243, 248))	('Human', 'Species', '9606', (56, 61))	('Human', 'Species', '9606', (173, 178))	('GSE15765', 'Var', (100, 108))
151751	33327311	The results are consistent with experimental results reported by Chen, whose hypothesis indicated that the aberrant lipid metabolic pathway play a significant role in LIHC, while high serum level of bile acids founded in patients with CHOL.	('bile acids', 'Chemical', 'MESH:D001647', (199, 209))	('patients', 'Species', '9606', (221, 229))	('LIHC', 'Chemical', '-', (167, 171))	('lipid', 'Chemical', 'MESH:D008055', (116, 121))	('serum level of bile acids', 'MPA', (184, 209))	('LIHC', 'Disease', (167, 171))	('aberrant', 'Var', (107, 115))	('lipid metabolic pathway', 'Pathway', (116, 139))	('CHOL', 'Phenotype', 'HP:0030153', (235, 239))
151798	32539768	The multivariate Cox regression results showed that a high fibrosis score was an independent risk factor of OS.	('Cox', 'Gene', '1351', (17, 20))	('high', 'Var', (54, 58))	('fibrosis', 'Disease', (59, 67))	('Cox', 'Gene', (17, 20))	('fibrosis', 'Disease', 'MESH:D005355', (59, 67))
151806	32539768	In fact, more than 80% of HCC cases are known to have developed in the setting of fibrosis or cirrhosis, with chronic inflammation, tissue regeneration, and other molecular events resulting in the production of reactive oxygen species, chromosomal mutations, and, eventually, the malignant transformation of proliferating hepatocytes.	('inflammation', 'Disease', 'MESH:D007249', (118, 130))	('fibrosis', 'Disease', 'MESH:D005355', (82, 90))	('fibrosis', 'Disease', (82, 90))	('HCC', 'Gene', '619501', (26, 29))	('HCC', 'Gene', (26, 29))	('inflammation', 'Disease', (118, 130))	('cirrhosis', 'Disease', (94, 103))	('oxygen', 'Chemical', 'MESH:D010100', (220, 226))	('reactive oxygen species', 'MPA', (211, 234))	('HCC', 'Phenotype', 'HP:0001402', (26, 29))	('malignant transformation', 'CPA', (280, 304))	('cirrhosis', 'Phenotype', 'HP:0001394', (94, 103))	('resulting in', 'Reg', (180, 192))	('chromosomal mutations', 'Var', (236, 257))	('cirrhosis', 'Disease', 'MESH:D005355', (94, 103))	('production', 'MPA', (197, 207))
151828	32539768	3a) showed that a high-Fb score was a significant risk factor of OS in ICC patients (HR 95%CI = 1.371 [1.154-1.628], P < 0.001).	('high-Fb', 'Var', (18, 25))	('patients', 'Species', '9606', (75, 83))	('ICC', 'Disease', (71, 74))
151830	32539768	We found that a high-Fb score was an independent risk factor of OS in ICC patients (HR 95%CI = 1.282 [1.067-1.541], P = 0.008).	('patients', 'Species', '9606', (74, 82))	('high-Fb', 'Var', (16, 23))	('ICC', 'Disease', (70, 73))
151835	32539768	The 6th AJCC stage III was more inclined to occur in patients with high-Fb scores than in their counterparts.	('patients', 'Species', '9606', (53, 61))	('high-Fb scores', 'Var', (67, 81))	('stage III', 'Disease', (13, 22))
151850	32539768	Using the stratification analysis, we found that a high liver Fb score was significant in the poor prognostic outcomes of patients with records of common clinical treatments (surgery, radiation, and systemic chemotherapy).	('patients', 'Species', '9606', (122, 130))	('high', 'Var', (51, 55))	('liver Fb', 'Gene', (56, 64))	('high liver', 'Phenotype', 'HP:0002240', (51, 61))
151851	32539768	In addition, patients characterized as male and single and having AFP > 15 ng/mL, tumor size <=3 cm, multiple tumors, and stage III of the 6th AJCC stage were likely to have high-Fb scores.	('patients', 'Species', '9606', (13, 21))	('high-Fb', 'Var', (174, 181))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('AFP', 'Gene', (66, 69))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('AFP', 'Gene', '174', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
151853	32539768	The results of our study demonstrated that relative to low-Fb scores, high-Fb scores impaired patients' survival outcomes, which were independent of the treatment methods.	('survival outcomes', 'CPA', (104, 121))	('impaired', 'NegReg', (85, 93))	('high-Fb scores', 'Var', (70, 84))	('patients', 'Species', '9606', (94, 102))
151854	32539768	Moreover, ICC patients with low-Fb scores could obtain more survival benefits than those with high-Fb scores.	('survival benefits', 'CPA', (60, 77))	('patients', 'Species', '9606', (14, 22))	('low-Fb scores', 'Var', (28, 41))	('ICC', 'Disease', (10, 13))
151867	32539768	The aforementioned research might explain why patients with high-Fb scores are prone to having nonideal survival outcomes.	('patients', 'Species', '9606', (46, 54))	('nonideal', 'MPA', (95, 103))	('high-Fb', 'Var', (60, 67))
151883	32539768	Patients with low-Fb scores could benefit greatly from ICC treatments.	('ICC', 'Disease', (55, 58))	('low-Fb', 'Var', (14, 20))	('Patients', 'Species', '9606', (0, 8))
151892	31692584	Furthermore, iNOS was high expression in ICC cell lines (QBC-939, ICC-9810, SSP-25) compare with human normal biliary epithelium cell line (HIBEpic); both iNOS knockdown and iNOS inhibitor (1400 W) suppressed cell proliferation, invasion, and migration though nitric oxide production in ICC cells.	('cell proliferation', 'CPA', (209, 227))	('human', 'Species', '9606', (97, 102))	('nitric oxide', 'Chemical', 'MESH:D009569', (260, 272))	('iNOS', 'Gene', (13, 17))	('ICC', 'Disease', (41, 44))	('suppressed', 'NegReg', (198, 208))	('ICC', 'Disease', 'MESH:C535533', (66, 69))	('iNOS', 'Gene', (174, 178))	('ICC', 'Disease', (287, 290))	('migration', 'CPA', (243, 252))	('iNOS', 'Gene', '4843', (13, 17))	('iNOS', 'Gene', '4843', (174, 178))	('ICC', 'Disease', 'MESH:C535533', (41, 44))	('knockdown', 'Var', (160, 169))	('iNOS', 'Gene', (155, 159))	('ICC', 'Disease', 'MESH:C535533', (287, 290))	('invasion', 'CPA', (229, 237))	('iNOS', 'Gene', '4843', (155, 159))	('ICC', 'Disease', (66, 69))
151894	31692584	Moreover, iNOS knockdown treatment significantly decreased Wip1, MMP-9, and MMP-2 gene expression.	('MMP-9', 'Gene', '4318', (65, 70))	('MMP-2', 'Gene', '4313', (76, 81))	('iNOS', 'Gene', '4843', (10, 14))	('knockdown', 'Var', (15, 24))	('iNOS', 'Gene', (10, 14))	('MMP-9', 'Gene', (65, 70))	('decreased', 'NegReg', (49, 58))	('Wip1', 'Gene', (59, 63))	('Wip1', 'Gene', '8493', (59, 63))	('MMP-2', 'Gene', (76, 81))
151896	31692584	Our data show targeted inhibition of iNOS in ICC may have therapeutic value.	('ICC', 'Disease', 'MESH:C535533', (45, 48))	('inhibition', 'Var', (23, 33))	('iNOS', 'Gene', '4843', (37, 41))	('iNOS', 'Gene', (37, 41))	('ICC', 'Disease', (45, 48))
151961	31692584	Furthermore, these data also demonstrated that high iNOS expression was dramatically associated with pathology T (p=0.002) and pathology M (p=0.029), which serve as important prognostic markers for patients with ICC.	('expression', 'MPA', (57, 67))	('ICC', 'Disease', 'MESH:C535533', (212, 215))	('iNOS', 'Gene', '4843', (52, 56))	('iNOS', 'Gene', (52, 56))	('patients', 'Species', '9606', (198, 206))	('high', 'Var', (47, 51))	('pathology T', 'Disease', (101, 112))	('ICC', 'Disease', (212, 215))	('pathology T', 'Disease', 'MESH:D004108', (101, 112))	('associated', 'Reg', (85, 95))
151972	31692584	The efficiency of iNOS knockdown was confirmed by qPCR (Figure 2.1A) and immunoblot (Figure 2.1B and C) analyses.	('iNOS', 'Gene', '4843', (18, 22))	('knockdown', 'Var', (23, 32))	('iNOS', 'Gene', (18, 22))
151973	31692584	We observed a significant decrease in cell proliferation upon transient knockdown of iNOS compared with control cells transfected with non-T siRNA (Figure 2.2D).	('iNOS', 'Gene', (85, 89))	('cell proliferation', 'CPA', (38, 56))	('decrease', 'NegReg', (26, 34))	('knockdown', 'Var', (72, 81))	('iNOS', 'Gene', '4843', (85, 89))
151975	31692584	Additionally, iNOS knockdown in ICC-9810 and QBC939 reduced the invasive potential of these cells, as assessed by the Boyden chamber Matrigel invasion assay (Figure 2.2E).	('iNOS', 'Gene', '4843', (14, 18))	('iNOS', 'Gene', (14, 18))	('ICC', 'Disease', (32, 35))	('reduced', 'NegReg', (52, 59))	('knockdown', 'Var', (19, 28))	('QBC939', 'CellLine', 'CVCL:6942', (45, 51))	('QBC939', 'Gene', (45, 51))	('ICC', 'Disease', 'MESH:C535533', (32, 35))	('invasive potential of these cells', 'CPA', (64, 97))	('Boyden chamber Matrigel invasion assay', 'CPA', (118, 156))
151976	31692584	NO production was also decreased in QBC939 cells when iNOS was knocked down with siRNA; however, the cell viability showed no significant change in these cells (Figure 2.2F).	('knocked down', 'Var', (63, 75))	('iNOS', 'Gene', '4843', (54, 58))	('QBC939', 'CellLine', 'CVCL:6942', (36, 42))	('iNOS', 'Gene', (54, 58))	('decreased', 'NegReg', (23, 32))
151984	31692584	Therefore, knockdown of iNOS dramatically induced G0/G1 cell cycle arrest and apoptosis of QBC939 and ICC-9810 cells in vitro.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (56, 73))	('apoptosis', 'CPA', (78, 87))	('iNOS', 'Gene', (24, 28))	('arrest', 'Disease', 'MESH:D006323', (67, 73))	('QBC939', 'CellLine', 'CVCL:6942', (91, 97))	('ICC', 'Disease', (102, 105))	('ICC', 'Disease', 'MESH:C535533', (102, 105))	('arrest', 'Disease', (67, 73))	('knockdown', 'Var', (11, 20))	('iNOS', 'Gene', '4843', (24, 28))
152015	31692584	iNOS positivity has consistently been reported in human cancers at a variety of sites, including the prostate, lung, bladder, breast, pancreas, gastric, oral cavity, esophagus, and colon.	('cancers', 'Disease', (56, 63))	('iNOS', 'Gene', '4843', (0, 4))	('positivity', 'Var', (5, 15))	('iNOS', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('pancreas', 'Disease', (134, 142))	('gastric', 'Disease', (144, 151))	('oral cavity', 'Disease', (153, 164))	('colon', 'Disease', (181, 186))	('reported', 'Reg', (38, 46))	('esophagus', 'Disease', (166, 175))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung', 'Disease', (111, 115))	('human', 'Species', '9606', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('bladder', 'Disease', (117, 124))	('breast', 'Disease', (126, 132))	('prostate', 'Disease', (101, 109))
152032	31692584	Furthermore, we demonstrated that knockdown of iNOS and the iNOS inhibitor 1400 W could suppress ICC cell migration and invasion through NO in vitro.	('ICC', 'Disease', (97, 100))	('iNOS', 'Gene', '4843', (60, 64))	('ICC', 'Disease', 'MESH:C535533', (97, 100))	('iNOS', 'Gene', '4843', (47, 51))	('suppress', 'NegReg', (88, 96))	('knockdown', 'Var', (34, 43))	('iNOS', 'Gene', (60, 64))	('iNOS', 'Gene', (47, 51))	('invasion through NO', 'CPA', (120, 139))
152045	31692584	In the present study, the data show that high expression of iNOS was correlated with poor prognosis in ICC patients after radical resection.	('ICC', 'Disease', (103, 106))	('ICC', 'Disease', 'MESH:C535533', (103, 106))	('high', 'Var', (41, 45))	('iNOS', 'Gene', '4843', (60, 64))	('iNOS', 'Gene', (60, 64))	('patients', 'Species', '9606', (107, 115))
152049	31692584	In other clinical studies of gastric carcinoma, patients with intermediate or high iNOS expression had much poorer prognosis according to the 5-year survival analysis.	('gastric carcinoma', 'Disease', (29, 46))	('high', 'Var', (78, 82))	('iNOS', 'Gene', '4843', (83, 87))	('iNOS', 'Gene', (83, 87))	('clinical', 'Species', '191496', (9, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (29, 46))	('gastric carcinoma', 'Disease', 'MESH:D013274', (29, 46))	('patients', 'Species', '9606', (48, 56))
152051	31692584	Overexpression of iNOS is correlated with tumor recurrence and promotes tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (42, 47))	('iNOS', 'Gene', '4843', (18, 22))	('tumor', 'Disease', (72, 77))	('promotes', 'PosReg', (63, 71))	('iNOS', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
152067	30866966	Downregulated pyruvate levels decreased the inhibition to HDAC3 and consequently protected CCA cells from apoptosis.	('Downregulated', 'Var', (0, 13))	('HDAC3', 'Gene', (58, 63))	('inhibition', 'MPA', (44, 54))	('apoptosis', 'CPA', (106, 115))	('pyruvate', 'Chemical', 'MESH:D019289', (14, 22))	('pyruvate levels', 'MPA', (14, 29))	('protected', 'Reg', (81, 90))	('CCA', 'Phenotype', 'HP:0030153', (91, 94))	('HDAC3', 'Gene', '8841', (58, 63))	('decreased', 'NegReg', (30, 39))
152089	30866966	There are various mechanism of MYC-induced tumorigenesis, including increased Warburg effect, and many studies have found that MYC increased metabolic proteins, such as LDH and PKM2.	('MYC', 'Var', (127, 130))	('PKM2', 'Gene', '5315', (177, 181))	('increased', 'PosReg', (131, 140))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('Warburg', 'MPA', (78, 85))	('metabolic proteins', 'MPA', (141, 159))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PKM2', 'Gene', (177, 181))	('tumor', 'Disease', (43, 48))	('increased', 'PosReg', (68, 77))	('LDH', 'Disease', (169, 172))
152096	30866966	Genetic or epigenetic alterations, which disrupt proliferation and cell death pathways, are the fundamental event for initiation and progression of cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('proliferation', 'CPA', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Genetic', 'Var', (0, 7))	('epigenetic alterations', 'Var', (11, 33))	('cell death', 'CPA', (67, 77))
152097	30866966	Imbalanced epigenetic networks have been identified in all types of cancers and involve multiple metabolic changes.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Imbalanced', 'Var', (0, 10))	('identified', 'Reg', (41, 51))	('involve', 'Reg', (80, 87))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))
152103	30866966	HDACs inhibitors have been noted for their ability to induce cell cycle arrest and apoptosis of a broad spectrum of cancer cells.	('HDAC', 'Gene', (0, 4))	('HDAC', 'Gene', '9734', (0, 4))	('arrest', 'Disease', 'MESH:D006323', (72, 78))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('arrest', 'Disease', (72, 78))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (61, 78))	('inhibitors', 'Var', (6, 16))	('apoptosis', 'CPA', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('induce', 'PosReg', (54, 60))
152107	30866966	Thus, the question of whether cMyc acetylation is beneficial for its induced-tumorigenesis still remains unanswered.	('cMyc', 'Gene', (30, 34))	('cMyc', 'Gene', '4609', (30, 34))	('acetylation', 'Var', (35, 46))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('acetyl', 'Chemical', 'MESH:D003545', (35, 41))
152123	30866966	Primary antibodies were as follows: HDAC1 (Abcam, Cambridge, UK), HDAC2 (Abcam), HDAC3 (Abcam), cleaved caspase-3 (CST, Danvers, MA, USA), cleaved PARP (CST), PARP (CST), PKM2 (Abcam), LDHA (Abcam), cMYC (Abcam), beta-actin (Sigma), FLAG (Abcam), and HA (provided by the Zhao lab of Fudan University).	('beta-actin (Sigma)', 'Gene', '728378', (213, 231))	('LDHA', 'Gene', (185, 189))	('CST', 'Gene', '106478911', (153, 156))	('cleaved', 'Var', (139, 146))	('beta-actin (Sigma', 'Gene', (213, 230))	('CST', 'Gene', (115, 118))	('HDAC3', 'Gene', '8841', (81, 86))	('PARP', 'Gene', '142', (147, 151))	('PARP', 'Gene', (147, 151))	('CST', 'Gene', '106478911', (165, 168))	('CST', 'Gene', (153, 156))	('cMYC', 'Gene', (199, 203))	('PKM2', 'Gene', (171, 175))	('HDAC1', 'Gene', (36, 41))	('PKM2', 'Gene', '5315', (171, 175))	('LDHA', 'Gene', '3939', (185, 189))	('HDAC2', 'Gene', '3066', (66, 71))	('HDAC2', 'Gene', (66, 71))	('HDAC3', 'Gene', (81, 86))	('CST', 'Gene', '106478911', (115, 118))	('PARP', 'Gene', '142', (159, 163))	('CST', 'Gene', (165, 168))	('cMYC', 'Gene', '4609', (199, 203))	('HDAC1', 'Gene', '3065', (36, 41))	('PARP', 'Gene', (159, 163))
152160	30866966	The splice variant PKM2 is expressed specifically in cancer cells in the dimeric form with low catalytic activity, and predicts a poor prognosis in CCA patients.	('PKM2', 'Gene', '5315', (19, 23))	('CCA', 'Disease', (148, 151))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('splice variant', 'Var', (4, 18))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('CCA', 'Phenotype', 'HP:0030153', (148, 151))	('PKM2', 'Gene', (19, 23))	('patients', 'Species', '9606', (152, 160))
152166	30866966	We found that LDHA knockdown increased oxygen consumption, and that both LDHA inhibition and LDHA knockdown did not significantly promote apoptosis of CCA cells (Fig.	('oxygen consumption', 'MPA', (39, 57))	('LDHA', 'Gene', (14, 18))	('CCA', 'Phenotype', 'HP:0030153', (151, 154))	('knockdown', 'Var', (19, 28))	('LDHA', 'Gene', '3939', (14, 18))	('LDHA', 'Gene', (73, 77))	('LDHA', 'Gene', (93, 97))	('LDHA', 'Gene', '3939', (73, 77))	('increased', 'PosReg', (29, 38))	('LDHA', 'Gene', '3939', (93, 97))	('oxygen', 'Chemical', 'MESH:D010100', (39, 45))
152175	30866966	There are various mechanisms for cMYC-induced tumorigenesis, including an increased Warburg effect, and many studies have found that MYC increases metabolic proteins, such as LDHA and PKM2.	('LDHA', 'Gene', (175, 179))	('Warburg effect', 'CPA', (84, 98))	('LDHA', 'Gene', '3939', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('metabolic proteins', 'MPA', (147, 165))	('tumor', 'Disease', (46, 51))	('increased', 'PosReg', (74, 83))	('cMYC', 'Gene', (33, 37))	('PKM2', 'Gene', (184, 188))	('increases', 'PosReg', (137, 146))	('MYC', 'Var', (133, 136))	('PKM2', 'Gene', '5315', (184, 188))	('cMYC', 'Gene', '4609', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
152184	30866966	We found cMYC knockdown simultaneously decreased the levels of PKM2 and LDHA, resulting in high intracellular pyruvate levels, as well as that cMYC overexpression could reversed it (Fig.	('cMYC', 'Gene', '4609', (143, 147))	('levels', 'MPA', (53, 59))	('PKM2', 'Gene', (63, 67))	('high', 'PosReg', (91, 95))	('LDHA', 'Gene', (72, 76))	('cMYC', 'Gene', (9, 13))	('pyruvate', 'Chemical', 'MESH:D019289', (110, 118))	('PKM2', 'Gene', '5315', (63, 67))	('cMYC', 'Gene', (143, 147))	('knockdown', 'Var', (14, 23))	('LDHA', 'Gene', '3939', (72, 76))	('decreased', 'NegReg', (39, 48))	('intracellular pyruvate levels', 'MPA', (96, 125))	('cMYC', 'Gene', '4609', (9, 13))
152185	30866966	Moreover, the mutant type of cMYC had no effect on the levels of PKM2 and LDHA (Fig.	('cMYC', 'Gene', '4609', (29, 33))	('mutant', 'Var', (14, 20))	('PKM2', 'Gene', (65, 69))	('LDHA', 'Gene', '3939', (74, 78))	('cMYC', 'Gene', (29, 33))	('PKM2', 'Gene', '5315', (65, 69))	('LDHA', 'Gene', (74, 78))
152192	30866966	Collectively, these results revealed that cMYC-induced metabolic enzyme changes contribute to a poor prognosis in CCA patients.	('cMYC', 'Gene', (42, 46))	('CCA', 'Disease', (114, 117))	('cMYC', 'Gene', '4609', (42, 46))	('CCA', 'Phenotype', 'HP:0030153', (114, 117))	('changes', 'Var', (72, 79))	('metabolic enzyme', 'MPA', (55, 71))	('patients', 'Species', '9606', (118, 126))
152200	30866966	To elucidate the direct target of HDAC3, we used an in vitro deacetylation system and found that both RGFP966 and pyruvate treatment inhibited HDAC3 deacetylation at the K323 site of cMYC (Fig.	('HDAC3', 'Gene', '8841', (34, 39))	('HDAC3', 'Gene', '8841', (143, 148))	('HDAC3', 'Gene', (34, 39))	('cMYC', 'Gene', (183, 187))	('HDAC3', 'Gene', (143, 148))	('inhibited', 'NegReg', (133, 142))	('pyruvate', 'Chemical', 'MESH:D019289', (114, 122))	('RGFP966', 'Var', (102, 109))	('acetyl', 'Chemical', 'MESH:D003545', (151, 157))	('cMYC', 'Gene', '4609', (183, 187))	('K323', 'Chemical', '-', (170, 174))	('acetyl', 'Chemical', 'MESH:D003545', (63, 69))
152201	30866966	Consistent with MS results, HDAC3 inhibition enhanced acetylation of wildtype cMYC but resulting in marginal acetylation change after the lysine (K) of the K323 acetylation site was mutated to arginine (R) in CCA cells (Fig.	('mutated', 'Var', (182, 189))	('K323', 'Chemical', '-', (156, 160))	('HDAC3', 'Gene', (28, 33))	('cMYC', 'Gene', '4609', (78, 82))	('acetylation', 'MPA', (109, 120))	('lysine', 'Chemical', 'MESH:D008239', (138, 144))	('acetylation', 'MPA', (54, 65))	('acetyl', 'Chemical', 'MESH:D003545', (54, 60))	('enhanced', 'PosReg', (45, 53))	('acetyl', 'Chemical', 'MESH:D003545', (109, 115))	('inhibition', 'NegReg', (34, 44))	('cMYC', 'Gene', (78, 82))	('CCA', 'Phenotype', 'HP:0030153', (209, 212))	('arginine', 'Chemical', 'MESH:D001120', (193, 201))	('acetyl', 'Chemical', 'MESH:D003545', (161, 167))	('HDAC3', 'Gene', '8841', (28, 33))
152204	30866966	Together, these results suggest that HDAC3 inhibition enhanced the acetylation-promoted degradation of cMYC in CCA cells.	('inhibition', 'Var', (43, 53))	('cMYC', 'Gene', (103, 107))	('acetyl', 'Chemical', 'MESH:D003545', (67, 73))	('HDAC3', 'Gene', '8841', (37, 42))	('cMYC', 'Gene', '4609', (103, 107))	('HDAC3', 'Gene', (37, 42))	('CCA', 'Phenotype', 'HP:0030153', (111, 114))	('acetylation-promoted degradation', 'MPA', (67, 99))	('enhanced', 'PosReg', (54, 62))
152205	30866966	Previous data confirmed that the accumulated pyruvate induced by cMYC inhibition promoted apoptosis in CCA cells, so we further inquired whether promoting cMYC degradation by HDAC3 inhibition could also induce CCA apoptosis.	('cMYC', 'Gene', (65, 69))	('HDAC3', 'Gene', (175, 180))	('CCA', 'Phenotype', 'HP:0030153', (210, 213))	('induce', 'PosReg', (203, 209))	('promoted', 'PosReg', (81, 89))	('cMYC', 'Gene', (155, 159))	('pyruvate', 'Chemical', 'MESH:D019289', (45, 53))	('CCA', 'Phenotype', 'HP:0030153', (103, 106))	('cMYC', 'Gene', '4609', (65, 69))	('cMYC', 'Gene', '4609', (155, 159))	('inhibition', 'Var', (70, 80))	('apoptosis', 'CPA', (90, 99))	('HDAC3', 'Gene', '8841', (175, 180))
152206	30866966	Both RGFP966 treatment and HDAC3 knockdown significantly decreased cMYC and increased caspase substrate (polyADP ribose polymerase (PARP) and caspase 3) cleavage; this effect was reversed by HDAC3 overexpression (Fig.	('RGFP966', 'Gene', (5, 12))	('caspase 3', 'Gene', (142, 151))	('HDAC3', 'Gene', '8841', (27, 32))	('cMYC', 'Gene', '4609', (67, 71))	('PARP', 'Gene', '142', (132, 136))	('increased', 'PosReg', (76, 85))	('HDAC3', 'Gene', (27, 32))	('knockdown', 'Var', (33, 42))	('caspase 3', 'Gene', '836', (142, 151))	('HDAC3', 'Gene', '8841', (191, 196))	('PARP', 'Gene', (132, 136))	('polyADP ribose polymerase', 'Gene', '142', (105, 130))	('cMYC', 'Gene', (67, 71))	('HDAC3', 'Gene', (191, 196))	('decreased', 'NegReg', (57, 66))	('polyADP ribose polymerase', 'Gene', (105, 130))
152207	30866966	Besides, oxygen consumption was extremely low after the treatment of RGFP966, which indicated that cells were on their way to apoptosis (Fig.	('oxygen consumption', 'MPA', (9, 27))	('oxygen', 'Chemical', 'MESH:D010100', (9, 15))	('RGFP966', 'Var', (69, 76))	('low', 'NegReg', (42, 45))
152208	30866966	Furthermore, HDAC3 knockdown significantly inhibited xenografts (Fig.	('xenografts', 'CPA', (53, 63))	('HDAC3', 'Gene', (13, 18))	('inhibited', 'NegReg', (43, 52))	('knockdown', 'Var', (19, 28))	('HDAC3', 'Gene', '8841', (13, 18))
152210	30866966	Importantly, HDAC3 knockdown induced high levels of pyruvate, which contributed to xenograft apoptosis (Fig.	('HDAC3', 'Gene', (13, 18))	('knockdown', 'Var', (19, 28))	('pyruvate', 'Chemical', 'MESH:D019289', (52, 60))	('levels of pyruvate', 'MPA', (42, 60))	('contributed to', 'Reg', (68, 82))	('HDAC3', 'Gene', '8841', (13, 18))	('xenograft apoptosis', 'CPA', (83, 102))
152227	30866966	Interestingly, inhibition of any one of these targets could neither induce tumor proliferation, nor reverse CCA metabolic type.	('induce', 'Reg', (68, 74))	('reverse', 'Reg', (100, 107))	('neither', 'NegReg', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('CCA', 'Phenotype', 'HP:0030153', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('CCA', 'Disease', (108, 111))	('inhibition', 'Var', (15, 25))	('tumor', 'Disease', (75, 80))
152233	30866966	Many studies have also found that MYC increased metabolic proteins, such as LDHA and PKM2.	('MYC', 'Var', (34, 37))	('PKM2', 'Gene', (85, 89))	('metabolic proteins', 'MPA', (48, 66))	('LDHA', 'Gene', (76, 80))	('PKM2', 'Gene', '5315', (85, 89))	('LDHA', 'Gene', '3939', (76, 80))	('increased', 'PosReg', (38, 47))
152237	30866966	The stability of c-Myc protein is related to its acetylation at K323, and HDACi treatment, but not SIRTi treatment, induced c-Myc K323 acetylation as well as tumorigenesis inhibition.	('stability', 'MPA', (4, 13))	('tumor', 'Disease', (158, 163))	('acetylation', 'MPA', (135, 146))	('c-Myc', 'Gene', (17, 22))	('K323', 'Chemical', '-', (64, 68))	('c-Myc', 'Gene', '4609', (124, 129))	('K323', 'Chemical', '-', (130, 134))	('c-Myc', 'Gene', (124, 129))	('HDAC', 'Gene', (74, 78))	('K323', 'Var', (130, 134))	('HDAC', 'Gene', '9734', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('c-Myc', 'Gene', '4609', (17, 22))	('acetylation', 'MPA', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('acetyl', 'Chemical', 'MESH:D003545', (135, 141))	('acetyl', 'Chemical', 'MESH:D003545', (49, 55))
152238	30866966	Employing immunoprecipitation, we further inquired as to which HDAC interacted with cMYC, and found that HDAC3 deacetylated cMYC at K323 and further protected cMYC from ubiquitinated degradation.	('protected', 'Reg', (149, 158))	('cMYC', 'Gene', (124, 128))	('HDAC', 'Gene', (63, 67))	('HDAC', 'Gene', '9734', (63, 67))	('ubiquitinated degradation', 'MPA', (169, 194))	('deacetylated', 'NegReg', (111, 123))	('cMYC', 'Gene', (159, 163))	('cMYC', 'Gene', '4609', (84, 88))	('HDAC', 'Gene', (105, 109))	('acetyl', 'Chemical', 'MESH:D003545', (113, 119))	('K323', 'Chemical', '-', (132, 136))	('cMYC', 'Gene', '4609', (124, 128))	('cMYC', 'Gene', (84, 88))	('HDAC3', 'Gene', '8841', (105, 110))	('cMYC', 'Gene', '4609', (159, 163))	('HDAC', 'Gene', '9734', (105, 109))	('HDAC3', 'Gene', (105, 110))	('K323', 'Var', (132, 136))
152241	30866966	Previous studies have concluded that the tumor suppressive function of pyruvate is related to its ability to inhibit HDACs; pyruvate is an HDAC inhibitor and a tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('pyruvate', 'Chemical', 'MESH:D019289', (71, 79))	('HDAC', 'Gene', (117, 121))	('tumor', 'Disease', (41, 46))	('HDAC', 'Gene', '9734', (117, 121))	('inhibit', 'NegReg', (109, 116))	('HDAC', 'Gene', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('pyruvate', 'Chemical', 'MESH:D019289', (124, 132))	('HDAC', 'Gene', '9734', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('pyruvate', 'Var', (124, 132))	('tumor', 'Disease', (160, 165))
152324	27890867	High resistin is risk of breast cancer in pre- and post-menopausal females and promotes growth and aggressiveness of tumor cells through STAT3 activation in breast cancer.	('STAT3', 'Gene', (137, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', (25, 38))	('STAT3', 'Gene', '6774', (137, 142))	('aggressiveness', 'Phenotype', 'HP:0000718', (99, 113))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('High', 'Var', (0, 4))	('aggressiveness of tumor', 'Disease', (99, 122))	('breast cancer', 'Disease', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('resistin', 'Gene', (5, 13))	('men', 'Species', '9606', (56, 59))	('activation', 'PosReg', (143, 153))	('aggressiveness of tumor', 'Disease', 'MESH:D001523', (99, 122))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('promotes', 'PosReg', (79, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('resistin', 'Gene', '56729', (5, 13))
152345	27890867	A large study using 8,571 Korean men, who underwent comprehensive screening and endoscopy, demonstrated that high BMI increased the risk of reflux esophagitis with dose-dependent pattern.	('esophagitis', 'Phenotype', 'HP:0100633', (147, 158))	('high BMI', 'Var', (109, 117))	('reflux esophagitis', 'Disease', 'MESH:D005764', (140, 158))	('reflux esophagitis', 'Disease', (140, 158))	('BMI increased', 'Phenotype', 'HP:0031418', (114, 127))	('men', 'Species', '9606', (33, 36))
152353	27890867	Additionally, alterations in the secretion of adiponectin and leptin from adipocytes is a proposed link between obesity and Barrett's esophagus and EAC.	('alterations', 'Var', (14, 25))	('EAC', 'Disease', (148, 151))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (124, 143))	('EAC', 'Phenotype', 'HP:0011459', (148, 151))	('adiponectin', 'Gene', '9370', (46, 57))	('obesity', 'Disease', 'MESH:D009765', (112, 119))	('link', 'Reg', (99, 103))	('obesity', 'Disease', (112, 119))	('adiponectin', 'Gene', (46, 57))	('leptin', 'Gene', '3952', (62, 68))	('leptin', 'Gene', (62, 68))	('esophagus', 'Disease', (134, 143))	('secretion', 'MPA', (33, 42))	('obesity', 'Phenotype', 'HP:0001513', (112, 119))
152361	27890867	It is known that GERD can lead to erosive esophagitis, progressing to a metaplastic, specialized intestinal epithelium (Barrett's esophagus).	('lead to', 'Reg', (26, 33))	('esophagitis', 'Disease', (42, 53))	('esophagitis', 'Phenotype', 'HP:0100633', (42, 53))	('GERD', 'Var', (17, 21))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (120, 139))	('esophagitis', 'Disease', 'MESH:D004941', (42, 53))
152371	27890867	A polymorphism in IGF-I gene is associated with BE, and a polymorphism in IGF-I receptor modifies the effect of obesity on the risk of BE and EAC.	('BE', 'Phenotype', 'HP:0100580', (135, 137))	('IGF-I', 'Gene', (74, 79))	('polymorphism', 'Var', (58, 70))	('obesity', 'Disease', 'MESH:D009765', (112, 119))	('obesity', 'Disease', (112, 119))	('IGF-I', 'Gene', '3479', (18, 23))	('IGF-I receptor', 'Gene', '3480', (74, 88))	('modifies', 'Reg', (89, 97))	('IGF-I receptor', 'Gene', (74, 88))	('EAC', 'Phenotype', 'HP:0011459', (142, 145))	('associated', 'Reg', (32, 42))	('IGF-I', 'Gene', (18, 23))	('polymorphism', 'Var', (2, 14))	('IGF-I', 'Gene', '3479', (74, 79))	('BE', 'Phenotype', 'HP:0100580', (48, 50))	('obesity', 'Phenotype', 'HP:0001513', (112, 119))
152380	27890867	However, a large cross sectional study using 3,922 screening persons demonstrated colorectal adenoma had a positive association with VAT and high waist circumference when they were considered separately but only VAT contributed to colorectal adenoma when both were considered simultaneously.	('colorectal adenoma', 'Disease', 'MESH:D015179', (231, 249))	('high waist circumference', 'Phenotype', 'HP:0031819', (141, 165))	('persons', 'Species', '9606', (61, 68))	('VAT', 'Disease', 'None', (133, 136))	('colorectal adenoma', 'Disease', 'MESH:D015179', (82, 100))	('VAT', 'Disease', 'None', (212, 215))	('VAT', 'Disease', (133, 136))	('colorectal adenoma', 'Disease', (231, 249))	('high', 'Var', (141, 145))	('VAT', 'Disease', (212, 215))	('colorectal adenoma', 'Disease', (82, 100))
152389	27890867	In summary, BMI appears to increase the risk of CRC in men, but less in women.	('CRC', 'Disease', (48, 51))	('men', 'Species', '9606', (55, 58))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('men', 'Species', '9606', (74, 77))	('BMI', 'Var', (12, 15))	('women', 'Species', '9606', (72, 77))
152397	27890867	The first "hit" includes accumulation of fat in hepatocytes, which is associated with insulin resistance, and fatty acid metabolism dysregulation that leads to steatosis.	('leads to', 'Reg', (151, 159))	('fatty acid', 'Chemical', 'MESH:D005227', (110, 120))	('accumulation', 'PosReg', (25, 37))	('insulin', 'Gene', '3630', (86, 93))	('steatosis', 'Phenotype', 'HP:0001397', (160, 169))	('steatosis', 'Disease', 'MESH:D005234', (160, 169))	('insulin', 'Gene', (86, 93))	('steatosis', 'Disease', (160, 169))	('fatty acid metabolism', 'MPA', (110, 131))	('dysregulation', 'Var', (132, 145))	('insulin resistance', 'Phenotype', 'HP:0000855', (86, 104))
152408	27890867	It seems that NAFLD causes HCC via cirrhosis, even if the exact pathogenesis is unclear.	('cirrhosis', 'Phenotype', 'HP:0001394', (35, 44))	('causes', 'Reg', (20, 26))	('HCC', 'Gene', (27, 30))	('cirrhosis', 'Disease', (35, 44))	('HCC', 'Gene', '619501', (27, 30))	('HCC', 'Phenotype', 'HP:0001402', (27, 30))	('NAFLD', 'Var', (14, 19))	('cirrhosis', 'Disease', 'MESH:D005355', (35, 44))
152420	27890867	High BMI (BMI of >=30 kg/m2) was associated with an increased risk of pancreatic cancer compared with normal (BMI of <23 kg/m2).	('pancreatic cancer', 'Phenotype', 'HP:0002894', (70, 87))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (52, 87))	('pancreatic cancer', 'Disease', (70, 87))	('pancreatic cancer', 'Disease', 'MESH:D010190', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('High BMI', 'Var', (0, 8))
152422	27890867	Furthermore, high BMI is associated with decreased survival in patients with pancreatic cancer.	('BMI', 'MPA', (18, 21))	('high', 'Var', (13, 17))	('decreased', 'NegReg', (41, 50))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('patients', 'Species', '9606', (63, 71))	('pancreatic cancer', 'Disease', (77, 94))	('survival', 'MPA', (51, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))
152426	27890867	In stratified analysis, obesity (BMI>25) was associated with an increased risk of cardia gastric cancer (OR, 1.55) and gastric cancer among non-Asians (OR, 1.24) but had no association with noncardia gastric cancer and Asian gastric cancers.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('gastric cancer', 'Disease', 'MESH:D013274', (200, 214))	('gastric cancer', 'Disease', 'MESH:D013274', (225, 239))	('gastric cancer', 'Disease', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('gastric cancers', 'Disease', (225, 240))	('gastric cancers', 'Disease', 'MESH:D013274', (225, 240))	('gastric cancers', 'Phenotype', 'HP:0012126', (225, 240))	('obesity', 'Phenotype', 'HP:0001513', (24, 31))	('gastric cancer', 'Phenotype', 'HP:0012126', (200, 214))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('gastric cancer', 'Phenotype', 'HP:0012126', (225, 239))	('BMI>25', 'Var', (33, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cardia gastric cancer', 'Disease', 'MESH:D013274', (82, 103))	('cardia gastric cancer', 'Disease', (82, 103))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('obesity', 'Disease', (24, 31))	('cardia gastric cancer', 'Disease', 'MESH:D013274', (193, 214))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('noncardia gastric cancer', 'Disease', (190, 214))	('noncardia gastric cancer', 'Disease', 'MESH:D013274', (190, 214))	('obesity', 'Disease', 'MESH:D009765', (24, 31))
152447	27890867	In one cohort study of 25,291 colon cancer patients who received treatment in adjuvant chemotherapy trials, obesity and underweight status were associated independently with inferior outcomes.	('underweight status', 'Var', (120, 138))	('patients', 'Species', '9606', (43, 51))	('obesity', 'Phenotype', 'HP:0001513', (108, 115))	('colon cancer', 'Phenotype', 'HP:0003003', (30, 42))	('colon cancer', 'Disease', 'MESH:D015179', (30, 42))	('men', 'Species', '9606', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('colon cancer', 'Disease', (30, 42))	('obesity', 'Disease', 'MESH:D009765', (108, 115))	('obesity', 'Disease', (108, 115))
152508	25197535	Focal fat accumulation in the liver may present as a mass on imaging, which may be misinterpreted as neoplasia.	('neoplasia', 'Disease', (101, 110))	('fat accumulation in the liver', 'Phenotype', 'HP:0001397', (6, 35))	('neoplasia', 'Disease', 'MESH:D009369', (101, 110))	('neoplasia', 'Phenotype', 'HP:0002664', (101, 110))	('Focal', 'Var', (0, 5))	('present', 'Reg', (40, 47))
152578	33572913	OCT increases the sensitivity and accuracy of malignancy detection when compared to brush cytology alone.	('increases', 'PosReg', (4, 13))	('sensitivity', 'MPA', (18, 29))	('malignancy', 'Disease', 'MESH:D009369', (46, 56))	('OCT', 'Var', (0, 3))	('malignancy', 'Disease', (46, 56))
152620	33572913	reported that patients undergoing PTBD have lower overall survival and a higher risk for seeding metastasis when compared with ERCP.	('lower', 'NegReg', (44, 49))	('overall survival', 'MPA', (50, 66))	('PTBD', 'Var', (34, 38))	('seeding metastasis', 'CPA', (89, 107))	('patients', 'Species', '9606', (14, 22))
152668	33572913	In cholangiocarcinoma, PDT has been shown to reduce malignant biliary stenosis and to be an option in post-surgical recurrence.	('biliary stenosis', 'Phenotype', 'HP:0007678', (62, 78))	('cholangiocarcinoma', 'Disease', (3, 21))	('malignant biliary stenosis', 'Disease', 'MESH:D009369', (52, 78))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('reduce', 'NegReg', (45, 51))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('PDT', 'Var', (23, 26))	('malignant biliary stenosis', 'Disease', (52, 78))
152678	33572913	reported a significant longer stent patency and overall survival in patients receiving RFA when compared with those treated only with stent placement.	('overall survival', 'CPA', (48, 64))	('longer', 'PosReg', (23, 29))	('RFA', 'Var', (87, 90))	('patients', 'Species', '9606', (68, 76))	('stent patency', 'CPA', (30, 43))
152710	32181423	in a systematic review demonstrated NAT with FOLFIRINOX for locally advanced pancreatic cancers had a median overall survival (OS) ranging between 10 and 33 months and resection rates of up to 43%.	('FOLFIRINOX', 'Var', (45, 55))	('pancreatic cancers', 'Disease', 'MESH:D010190', (77, 95))	('pancreatic cancers', 'Disease', (77, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('resection', 'CPA', (168, 177))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (45, 55))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (77, 95))
152741	32181423	OS was significantly longer in patients receiving NAT with resection (median, 36 months; range, 18-37 months) compared to NAT alone (median, 12 months; range, 5-43 months, p=0.02).	('resection', 'Var', (59, 68))	('patients', 'Species', '9606', (31, 39))	('NAT', 'Var', (50, 53))
152805	31707480	Skeletonization of the extrahepatic bile duct may induce ischemia then delayed stricture formation.	('ischemia', 'Disease', (57, 65))	('Skeletonization', 'Var', (0, 15))	('ischemia', 'Disease', 'MESH:D007511', (57, 65))	('induce', 'Reg', (50, 56))	('stricture formation', 'CPA', (79, 98))
152817	30791227	Dysregulation, functional implications, and prognostic ability of the circadian clock across cancers It has been proposed that the circadian rhythm generally plays important roles in tumor suppression, but there is also evidence that disruption of the canonical circadian pathway has anticancer effects.	('cancers', 'Disease', (93, 100))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('canonical circadian pathway', 'Pathway', (252, 279))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', (288, 294))	('disruption', 'Var', (234, 244))	('tumor', 'Disease', (183, 188))	('clock', 'Gene', '9575', (80, 85))	('clock', 'Gene', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
152826	30791227	The 2017 Nobel Prize in Physiology or Medicine was awarded to Jeffrey C. Hall, Michael Rosbash and Michael W. Young for their leading discoveries of the molecular mechanisms controlling the circadian rhythm.1, 2 The circadian clock is critical for the normal physiological functions of cells, and disruption of the circadian system has been proposed to pose an important cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (371, 377))	('clock', 'Gene', '9575', (226, 231))	('clock', 'Gene', (226, 231))	('cancer', 'Disease', (371, 377))	('cancer', 'Disease', 'MESH:D009369', (371, 377))	('disruption', 'Var', (297, 307))
152831	30791227	The results revealed that the circadian clock genes were most often dysregulated through DNA hypermethylation-based disruption of expression rather than mutations or copy number alterations.	('expression', 'MPA', (130, 140))	('DNA hypermethylation-based', 'Var', (89, 115))	('clock', 'Gene', (40, 45))	('clock', 'Gene', '9575', (40, 45))	('dysregulated', 'Reg', (68, 80))	('disruption', 'NegReg', (116, 126))	('hypermethylation-based', 'Var', (93, 115))
152841	30791227	The correlation between mutations of 375 driver genes40 and the CCI was analyzed by regression method, while cancer types and tumor mutation burden were adjusted.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('CCI', 'Disease', (64, 67))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (24, 33))	('CCI', 'Chemical', '-', (64, 67))	('tumor', 'Disease', (126, 131))
152845	30791227	To test whether the mutational status of the driver genes40, 43 was significantly associated with the CCI, rank-transformed CCI was modeled via linear regression as a function of the gene's mutational status, and the rank-transformed mutation burden was used to diminish confounding effects.	('associated', 'Reg', (82, 92))	('CCI', 'Chemical', '-', (124, 127))	('genes40', 'Var', (52, 59))	('CCI', 'Chemical', '-', (102, 105))	('CCI', 'Disease', (102, 105))
152848	30791227	As shown in Figure 1A, the mutation frequencies of core clock genes varied notably among cancers.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('varied', 'Reg', (68, 74))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('mutation', 'Var', (27, 35))	('cancers', 'Disease', (89, 96))	('clock', 'Gene', '9575', (56, 61))	('clock', 'Gene', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
152850	30791227	Thus, since the mutation rates of core clock genes were found to be low, the circadian rhythm system might not be disrupted by mutation in cancers.	('clock', 'Gene', '9575', (39, 44))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('mutation', 'Var', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('mutation', 'MPA', (16, 24))	('clock', 'Gene', (39, 44))
152851	30791227	In general, PER1/2/3 exhibited the highest mutation frequencies among the core clock genes.	('PER1/2/3', 'Gene', '5187;8864;8863', (12, 20))	('PER1/2/3', 'Gene', (12, 20))	('mutation', 'Var', (43, 51))	('clock', 'Gene', (79, 84))	('clock', 'Gene', '9575', (79, 84))
152853	30791227	Furthermore, the mutation rates of other CCMCCs in cancer were also low (Figure S1 and S8).	('mutation', 'Var', (17, 25))	('low', 'NegReg', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
152854	30791227	To further dissect the genomic alterations of circadian rhythm, the copy number variations of core clock genes were also analyzed (Figure 1B), and the results showed that the copy number alterations of core clock genes were limited, although both amplifications and deletions of core clock genes were observed.	('clock', 'Gene', (284, 289))	('deletions', 'Var', (266, 275))	('clock', 'Gene', '9575', (207, 212))	('clock', 'Gene', (99, 104))	('clock', 'Gene', '9575', (284, 289))	('clock', 'Gene', '9575', (99, 104))	('clock', 'Gene', (207, 212))
152857	30791227	To investigate aberrances in rhythmic genes across cancers, the mutations in the 1350 experimentally identified rhythmic genes curated from the CGDB were systematically analyzed in various cancers.	('CGDB', 'Gene', (144, 148))	('various cancers', 'Disease', 'MESH:D009369', (181, 196))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('various cancers', 'Disease', (181, 196))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('analyzed', 'Reg', (169, 177))	('mutations', 'Var', (64, 73))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('cancers', 'Disease', (189, 196))
152881	30791227	As the results shown in Figure 2D, the CCI was negatively correlated with mutations of driver genes including TP53 in BRCA, LIHC, and LUAD, XIRP2 in STAD, MUC4 in KIRC and FAM46C in HNSC, while negatively correlations were observed for RNF43 in CESC, PIK3CA in BRCA, FRG1 in HNSC, and EGFR in BLCA.	('EGFR', 'Gene', '1956', (285, 289))	('FAM46C', 'Gene', '54855', (172, 178))	('LUAD', 'Gene', (134, 138))	('PIK3CA', 'Gene', (251, 257))	('BRCA', 'Gene', '672', (261, 265))	('BRCA', 'Gene', '672', (118, 122))	('TP53', 'Gene', '7157', (110, 114))	('MUC4', 'Gene', '4585', (155, 159))	('RNF43', 'Gene', '54894', (236, 241))	('XIRP2', 'Gene', (140, 145))	('BRCA', 'Gene', (261, 265))	('MUC4', 'Gene', (155, 159))	('FRG1', 'Gene', '2483', (267, 271))	('BRCA', 'Gene', (118, 122))	('CCI', 'Chemical', '-', (39, 42))	('FRG1', 'Gene', (267, 271))	('LUAD', 'Phenotype', 'HP:0030078', (134, 138))	('EGFR', 'Gene', (285, 289))	('RNF43', 'Gene', (236, 241))	('PIK3CA', 'Gene', '5290', (251, 257))	('FAM46C', 'Gene', (172, 178))	('CCI', 'Disease', (39, 42))	('negatively', 'NegReg', (47, 57))	('TP53', 'Gene', (110, 114))	('BRCA', 'Phenotype', 'HP:0003002', (261, 265))	('mutations', 'Var', (74, 83))	('BRCA', 'Phenotype', 'HP:0003002', (118, 122))	('HNSC', 'Phenotype', 'HP:0012288', (275, 279))	('HNSC', 'Phenotype', 'HP:0012288', (182, 186))	('XIRP2', 'Gene', '129446', (140, 145))
152882	30791227	Furthermore, the expression and methylation of CCMCCs were analyzed, and the results presented in Figure S8 show that the expression of CCMCCs was disrupted in tumors and that hypermethylation contributed substantially to this disruption.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('expression', 'MPA', (122, 132))	('hypermethylation', 'Var', (176, 192))	('CCMCCs', 'Gene', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('disrupted', 'NegReg', (147, 156))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
152883	30791227	In tumor tissues, dysregulated circadian rhythm would disrupt the oscillatory expression of circadian genes; therefore, it was necessary to investigate the differential expression of rhythmic genes.	('dysregulated', 'Var', (18, 30))	('tumor', 'Disease', (3, 8))	('oscillatory expression', 'MPA', (66, 88))	('circadian genes', 'Gene', (92, 107))	('disrupt', 'NegReg', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('circadian', 'MPA', (31, 40))
152885	30791227	Enrichment analyses of DEGs in rhythmic genes across cancers were based on using a hypergeometric test.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('DEGs', 'Var', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
152893	30791227	Furthermore, CCI was positively correlated with a large number of metabolic pathways in LIHC (Figure S4A), which was consistent with the findings of previous studies.46, 47, 48, 49, 50  The circadian rhythm recently emerged as an important regulator of the immune system.51, 52 The GSEA results showed that a number of immune pathways were differentially activated in high- and low-CCI tumor tissues (Figure 3B).	('GSEA', 'Chemical', '-', (282, 286))	('high-', 'Var', (368, 373))	('low-CCI tumor', 'Disease', 'MESH:D009800', (378, 391))	('CCI', 'Chemical', '-', (382, 385))	('tumor', 'Phenotype', 'HP:0002664', (386, 391))	('low-CCI tumor', 'Disease', (378, 391))	('immune pathways', 'Pathway', (319, 334))	('CCI', 'Chemical', '-', (13, 16))	('activated', 'PosReg', (355, 364))
152895	30791227	Various pathways, including natural killer cell-mediated cytotoxicity, T- and B-cell receptor signaling pathways, Toll-like receptor signaling pathway, and primary immunodeficiency, were upregulated in high-CCI tumor tissues compared with low-CCI tumor tissues in BLCA and CESC.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('Toll-like receptor signaling pathway', 'Pathway', (114, 150))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('primary immunodeficiency', 'Disease', (156, 180))	('low-CCI tumor', 'Disease', (239, 252))	('tumor', 'Disease', (247, 252))	('cytotoxicity', 'Disease', (57, 69))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('immunodeficiency', 'Phenotype', 'HP:0002721', (164, 180))	('CCI', 'Chemical', '-', (207, 210))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('cytotoxicity', 'Disease', 'MESH:D064420', (57, 69))	('CCI', 'Chemical', '-', (243, 246))	('high-CCI', 'Var', (202, 210))	('low-CCI tumor', 'Disease', 'MESH:D009800', (239, 252))	('primary immunodeficiency', 'Disease', 'MESH:D007153', (156, 180))	('upregulated', 'PosReg', (187, 198))
152896	30791227	Fc gamma R-mediated phagocytosis was upregulated in high-CCI tumor tissues compared with low-CCI tumor tissues in BLCA and STAD.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('upregulated', 'PosReg', (37, 48))	('high-CCI', 'Var', (52, 60))	('low-CCI tumor', 'Disease', 'MESH:D009800', (89, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CCI', 'Chemical', '-', (93, 96))	('low-CCI tumor', 'Disease', (89, 102))	('Fc gamma R-mediated', 'Protein', (0, 19))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('CCI', 'Chemical', '-', (57, 60))	('tumor', 'Disease', (61, 66))
152897	30791227	The NOD-like receptor signaling pathway was upregulated in high-CCI tumor tissues compared with low-CCI tumor tissues in BLCA.	('tumor', 'Disease', (68, 73))	('CCI', 'Chemical', '-', (100, 103))	('NOD-like receptor signaling pathway', 'Pathway', (4, 39))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('upregulated', 'PosReg', (44, 55))	('tumor', 'Disease', (104, 109))	('low-CCI tumor', 'Disease', 'MESH:D009800', (96, 109))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('low-CCI tumor', 'Disease', (96, 109))	('CCI', 'Chemical', '-', (64, 67))	('high-CCI', 'Var', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
152898	30791227	In BLCA and THCA, antigen processing and presentation were upregulated and downregulated in high-CCI tumor tissues compared with low-CCI tumor tissues, respectively.	('CCI', 'Chemical', '-', (133, 136))	('THCA', 'Phenotype', 'HP:0002890', (12, 16))	('downregulated', 'NegReg', (75, 88))	('tumor', 'Disease', (137, 142))	('low-CCI tumor', 'Disease', (129, 142))	('tumor', 'Disease', (101, 106))	('presentation', 'MPA', (41, 53))	('CCI', 'Chemical', '-', (97, 100))	('high-CCI', 'Var', (92, 100))	('upregulated', 'PosReg', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('antigen processing', 'MPA', (18, 36))	('low-CCI tumor', 'Disease', 'MESH:D009800', (129, 142))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
152911	30791227	A previous study found that the circadian rhythm is associated with survival in colorectal cancer patients.8 For circadian rhythm is crucial to cell physiology and the core clock genes were dysregulated at mutation, SCNA, DNA methylation and expression levels, the prognostic ability of the circadian system in cancers should be investigated.	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('patients', 'Species', '9606', (98, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('cancers', 'Disease', (311, 318))	('mutation', 'Var', (206, 214))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Disease', (80, 97))	('clock', 'Gene', '9575', (173, 178))	('clock', 'Gene', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
152917	30791227	The survival analysis with the best cutoff value showed that a high CCI predicted better survival in BRCA, CESC, KIRP, and LIHC (Figure 4B-E).	('CESC', 'Disease', (107, 111))	('high CCI', 'Var', (63, 71))	('better', 'PosReg', (82, 88))	('BRCA', 'Phenotype', 'HP:0003002', (101, 105))	('CCI', 'Var', (68, 71))	('BRCA', 'Gene', '672', (101, 105))	('KIRP', 'Disease', (113, 117))	('BRCA', 'Gene', (101, 105))	('CCI', 'Chemical', '-', (68, 71))
152924	30791227	For example, in KIRC, high expression level of FBXL3 predicted better survival, while RORB, CSNK1D, and CSNK1E significantly predicted poor survival (Figure S7).	('RORB', 'Gene', (86, 90))	('CSNK1E', 'Gene', (104, 110))	('high', 'Var', (22, 26))	('CSNK1E', 'Gene', '1454', (104, 110))	('better', 'PosReg', (63, 69))	('RORB', 'Gene', '6096', (86, 90))	('survival', 'CPA', (70, 78))	('FBXL3', 'Gene', (47, 52))	('CSNK1D', 'Gene', (92, 98))	('expression level', 'MPA', (27, 43))	('CSNK1D', 'Gene', '1453', (92, 98))	('FBXL3', 'Gene', '26224', (47, 52))
152925	30791227	However, high expression of FBXL3 was related to poor survival in STAD (Figure S7).	('FBXL3', 'Gene', (28, 33))	('STAD', 'Disease', (66, 70))	('FBXL3', 'Gene', '26224', (28, 33))	('poor', 'NegReg', (49, 53))	('high', 'Var', (9, 13))
152931	30791227	reported that in hematologic malignancies ARNTL was transcriptionally silenced by the hypermethylation of its promoter CpG island.30 TCGA data showed that the expression of ARNTL was significantly lower in most solid tumors than in nontumor tissues; in addition, hypermethylation of ARNTL was also observed in PRAD (Figure 2A) and STAD, while the methylation status of ARNTL in other cancers was not available.	('lower', 'NegReg', (197, 202))	('ARNTL', 'Gene', '406', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('hypermethylation', 'Var', (263, 279))	('solid tumors', 'Disease', (211, 223))	('tumor', 'Disease', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('cancers', 'Disease', 'MESH:D009369', (384, 391))	('expression', 'MPA', (159, 169))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('solid tumors', 'Disease', 'MESH:D009369', (211, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('ARNTL', 'Gene', (283, 288))	('ARNTL', 'Gene', '406', (173, 178))	('ARNTL', 'Gene', (173, 178))	('ARNTL', 'Gene', '406', (283, 288))	('hematologic malignancies', 'Disease', (17, 41))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('ARNTL', 'Gene', '406', (369, 374))	('ARNTL', 'Gene', (369, 374))	('STAD', 'Disease', (331, 335))	('cancers', 'Phenotype', 'HP:0002664', (384, 391))	('cancers', 'Disease', (384, 391))	('tumor', 'Disease', (235, 240))	('hematologic malignancies', 'Disease', 'MESH:D019337', (17, 41))	('ARNTL', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (384, 390))
152933	30791227	Thus, the main cause of the lower expression levels of circadian clock genes might be hypermethylation of ARNTL and PER1/PER2/PER3, while the mechanisms for CLOCK and CRY1/CRY2 require further investigation.	('PER3', 'Gene', '8863', (126, 130))	('hypermethylation', 'Var', (86, 102))	('PER2', 'Gene', (121, 125))	('CRY2', 'Gene', (172, 176))	('lower', 'NegReg', (28, 33))	('clock', 'Gene', (65, 70))	('CRY2', 'Gene', '1408', (172, 176))	('CRY1', 'Gene', (167, 171))	('PER2', 'Gene', '8864', (121, 125))	('PER3', 'Gene', (126, 130))	('clock', 'Gene', '9575', (65, 70))	('CLOCK', 'Gene', '9575', (157, 162))	('ARNTL', 'Gene', (106, 111))	('CRY1', 'Gene', '1407', (167, 171))	('ARNTL', 'Gene', '406', (106, 111))	('CLOCK', 'Gene', (157, 162))	('expression levels', 'MPA', (34, 51))
152940	30791227	Thus, further detailed investigations should be performed to determine the mechanisms and functions of the dysregulation of the circadian clock in different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('clock', 'Gene', '9575', (138, 143))	('clock', 'Gene', (138, 143))	('cancer', 'Disease', (157, 163))	('dysregulation', 'Var', (107, 120))
153001	29286615	Various thresholds have been used in studies examining the predictive performance of CTC in different cancers, for example studies have put values of 3CTC/7.5 ml for metastatic colorectal cancer (Cohen et al.,2008), 5CTC/7.5 ml for breast and prostate cancers (Liu et al., 2009; de Bono et al., 2008), which may be related to the variation or loss in the expression of EpCAM.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('colorectal cancer', 'Disease', (177, 194))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast and prostate cancers', 'Disease', 'MESH:D011471', (232, 259))	('prostate cancers', 'Phenotype', 'HP:0012125', (243, 259))	('cancers', 'Disease', (252, 259))	('5CTC/7.5 ml', 'Var', (216, 227))	('EpCAM', 'Gene', (369, 374))	('colorectal cancer', 'Disease', 'MESH:D015179', (177, 194))	('cancers', 'Disease', 'MESH:D009369', (252, 259))	('3CTC/7.5', 'Var', (150, 158))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('EpCAM', 'Gene', '4072', (369, 374))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancers', 'Disease', (102, 109))	('colorectal cancer', 'Phenotype', 'HP:0003003', (177, 194))
153012	29286615	We have observed a significant difference of CTC level between T stage (T1andT2 vs. T3andT4), systemic metastasis (M0 vs. M1), tumor stage (IandII vs. IIIandIV) and nodal metastasis viz N0 vs. N1 +N2.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('T1andT2', 'Var', (72, 79))	('tumor', 'Disease', (127, 132))	('CTC level', 'MPA', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
153039	29286615	The circulating tumor DNA and DNA from CTC can also be utilized for specific molecular tests like p53 mutation detection thereby increasing the specificity of diagnosis.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('increasing', 'PosReg', (129, 139))	('mutation', 'Var', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('p53', 'Gene', (98, 101))	('tumor', 'Disease', (16, 21))	('p53', 'Gene', '7157', (98, 101))
153078	22197937	The majority of cases are caused by mutations in the PKHD1 gene, which encodes for fibrocystin/polycystin.	('fibrocystin', 'Gene', (83, 94))	('fibrocystin', 'Gene', '5314', (83, 94))	('caused by', 'Reg', (26, 35))	('mutations', 'Var', (36, 45))	('PKHD1', 'Gene', (53, 58))	('PKHD1', 'Gene', '5314', (53, 58))
153249	23900219	Activating BRAF gene mutations in the Raf/MEK/ERK pathway have been implicated in the development of biliary cancers and could represent a potential therapeutic target.	('Activating', 'PosReg', (0, 10))	('biliary cancers', 'Disease', 'MESH:D001661', (101, 116))	('Raf', 'Gene', '22882', (38, 41))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('ERK', 'Gene', (46, 49))	('ERK', 'Gene', '2048', (46, 49))	('MEK', 'Gene', (42, 45))	('MEK', 'Gene', '5609', (42, 45))	('biliary cancers', 'Disease', (101, 116))	('Raf', 'Gene', (38, 41))	('implicated', 'Reg', (68, 78))	('BRAF', 'Gene', '673', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('BRAF', 'Gene', (11, 15))	('mutations', 'Var', (21, 30))
153250	23900219	Cholangiocarcinoma cells are reported to become more susceptible to apoptosis with Raf-1 inhibitor BAY 37-9751, which is a close structural analogue of sorafenib, by blocking Mcl-1, an antiapoptotic protein.	('Mcl-1', 'Gene', '4170', (175, 180))	('inhibitor', 'Var', (89, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (0, 18))	('Raf-1', 'Gene', '5894', (83, 88))	('sorafenib', 'Chemical', 'MESH:D000077157', (152, 161))	('Mcl-1', 'Gene', (175, 180))	('blocking', 'NegReg', (166, 174))	('BAY 37-9751', 'Chemical', '-', (99, 110))	('Raf-1', 'Gene', (83, 88))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 18))	('Cholangiocarcinoma', 'Disease', (0, 18))
153262	23900219	Patients were required to have a Karnofsky performance status of >=80% and adequate organ function, including a haemoglobin level of >=8 g dl-1, ANC >=1.5 x 103 mul-1, platelet count >=100 x 103 mul-1, serum creatinine <=2 mg dl-1 or calculated creatinine clearance >=60 ml min-1, total bilirubin <=2 mg dl-1, and ALT and AST <=3 times the upper limit of normal (<=5 times if liver metastases present).	('min-1', 'Gene', (274, 279))	('ALT', 'CPA', (314, 317))	('>=100', 'Var', (183, 188))	('mul-1', 'Gene', '79594', (161, 166))	('min-1', 'Gene', '966', (274, 279))	('mul-1', 'Gene', (161, 166))	('mul-1', 'Gene', '79594', (195, 200))	('liver metastases', 'Disease', (376, 392))	('haemoglobin', 'MPA', (112, 123))	('total bilirubin', 'MPA', (281, 296))	('Patients', 'Species', '9606', (0, 8))	('mul-1', 'Gene', (195, 200))	('bilirubin', 'Chemical', 'MESH:D001663', (287, 296))	('<=2', 'NegReg', (297, 300))	('liver metastases', 'Disease', 'MESH:D009362', (376, 392))	('serum creatinine', 'MPA', (202, 218))	('creatinine clearance', 'MPA', (245, 265))
153285	23900219	Using an exact single-stage binomial design with a desirable PFS6 of 77% and an undesirable PFS6 of 57%, the study called for enrolment of 39 patients to give a 90% power to detect the hypothesised improvement in the PFS6 rate for gemcitabine, cisplatin and sorafenib, with a type I error of 10%.	('sorafenib', 'Chemical', 'MESH:D000077157', (258, 267))	('gemcitabine', 'Chemical', 'MESH:C056507', (231, 242))	('improvement', 'PosReg', (198, 209))	('patients', 'Species', '9606', (142, 150))	('PFS6', 'Var', (217, 221))	('cisplatin', 'Chemical', 'MESH:D002945', (244, 253))
153363	32872053	However, ID-RFA in perihilar applications has the potential to cause bile duct perforation and vascular injuries, such as hemobilia and liver infarction, because the hilar bile duct is located near the hepatic artery and portal vein complexes.	('bile duct perforation', 'Disease', (69, 90))	('hepatic artery', 'Disease', (202, 216))	('liver infarction', 'Disease', (136, 152))	('vascular injuries', 'Disease', 'MESH:D057772', (95, 112))	('hepatic artery', 'Disease', 'MESH:D056486', (202, 216))	('hemobilia', 'Phenotype', 'HP:0100762', (122, 131))	('ID-RFA', 'Var', (9, 15))	('cause', 'Reg', (63, 68))	('vascular injuries', 'Disease', (95, 112))	('bile duct perforation', 'Phenotype', 'HP:0030154', (69, 90))	('hemobilia', 'Disease', (122, 131))	('liver infarction', 'Disease', 'MESH:D000081011', (136, 152))	('hemobilia', 'Disease', 'MESH:D006431', (122, 131))
153424	32872053	We observed a tendency to maintain longer stent patency in the patients with an intraductal growth pattern than that in the patients without an intraductal growth pattern, but the difference was not statistically significant.	('intraductal growth pattern', 'Var', (80, 106))	('longer', 'PosReg', (35, 41))	('patients', 'Species', '9606', (63, 71))	('stent patency', 'CPA', (42, 55))	('patients', 'Species', '9606', (124, 132))
153448	31964941	Long-term PPI use is an effective treatment for gastroesophageal disorders and Helicobacter pylori infection, and are taken without prescription to relieve heartburn.	('gastroesophageal disorders', 'Disease', (48, 74))	('Helicobacter pylori infection', 'Disease', 'MESH:D016481', (79, 108))	('heartburn', 'Disease', (156, 165))	('gastroesophageal disorders', 'Disease', 'MESH:D005764', (48, 74))	('PPI', 'Var', (10, 13))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (79, 108))	('gastroesophageal disorders', 'Phenotype', 'HP:0011024', (48, 74))	('Helicobacter pylori infection', 'Disease', (79, 108))	('heartburn', 'Phenotype', 'HP:0002020', (156, 165))
153452	31964941	PPI users tend to have a less healthy gut microbiome than non-users, with significant increase of Enterococcus, Streptococcus, Staphylococcus and Escherichia coli.	('Escherichia coli', 'Species', '562', (146, 162))	('increase', 'PosReg', (86, 94))	('Escherichia coli', 'MPA', (146, 162))	('Streptococcus', 'MPA', (112, 125))	('Enterococcus', 'MPA', (98, 110))	('PPI', 'Var', (0, 3))	('Staphylococcus', 'MPA', (127, 141))	('gut microbiome', 'Species', '749906', (38, 52))
153453	31964941	PPIs have been shown to cause changes in bile salt composition in Barrett's esophagus patient.	('changes', 'Reg', (30, 37))	('bile salt composition', 'MPA', (41, 62))	('patient', 'Species', '9606', (86, 93))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (66, 85))	("Barrett's esophagus", 'Disease', (66, 85))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (66, 85))	('PPIs', 'Var', (0, 4))
153496	31964941	alpha-tocopherol is a fat-soluble vitamin E with potent antioxidant activity and is involved lipid metabolism, and L-phenylalanine and L-tyrosine are aromatic amino acids and have been shown to decrease in high-fat diet mouse model.	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (0, 16))	('vitamin E', 'Chemical', 'MESH:D014810', (34, 43))	('aromatic amino acids', 'Chemical', 'MESH:D065105', (150, 170))	('L-tyrosine', 'Chemical', 'None', (135, 145))	('mouse', 'Species', '10090', (220, 225))	('L-phenylalanine', 'Chemical', 'MESH:C119108', (115, 130))	('antioxidant activity', 'MPA', (56, 76))	('L-tyrosine', 'Var', (135, 145))	('L-phenylalanine', 'Var', (115, 130))	('decrease', 'NegReg', (194, 202))
153507	31964941	Microbiome analysis revealed significant imbalances in the fecal flora of rats exposed to PPIs compared to control.	('imbalances', 'MPA', (41, 51))	('PPIs', 'Var', (90, 94))	('imbalances', 'Phenotype', 'HP:0002172', (41, 51))	('fecal flora', 'MPA', (59, 70))	('rats', 'Species', '10116', (74, 78))
153512	31964941	Interestingly, loss of FXR protects diabetic mice against diet-induced or genetic obesity and accelerates liver carcinogenesis.	('obesity', 'Phenotype', 'HP:0001513', (82, 89))	('mice', 'Species', '10090', (45, 49))	('obesity', 'Disease', 'MESH:D009765', (82, 89))	('FXR', 'Gene', (23, 26))	('liver carcinogenesis', 'Disease', 'MESH:D063646', (106, 126))	('obesity', 'Disease', (82, 89))	('loss', 'Var', (15, 19))	('diabetic', 'Disease', 'MESH:D003920', (36, 44))	('accelerates', 'PosReg', (94, 105))	('liver carcinogenesis', 'Disease', (106, 126))	('rat', 'Species', '10116', (100, 103))	('diabetic', 'Disease', (36, 44))
153513	31964941	In our animal models, the body weights of PPI-treated rats also remained unchanged compared with controls (Supplementary Fig.	('PPI-treated', 'Var', (42, 53))	('rats', 'Species', '10116', (54, 58))	('body weights', 'CPA', (26, 38))
153520	31964941	We wish to emphasize that PPI should be use following proper treatment and deprescribing guidelines, and our work highlights the need for increase awareness of physicians, patients and general public potential risks associating with PPI misuse and overuse.	('patients', 'Species', '9606', (172, 180))	('misuse', 'Var', (237, 243))	('overuse', 'PosReg', (248, 255))
153556	31775892	The growth rate of human ICC cell lines treated with MFAP5 or MFAP5 shRNAs was examined by CCK8 and colony formation assays.	('ICC', 'Disease', 'MESH:C535533', (25, 28))	('MFAP5', 'Var', (62, 67))	('ICC', 'Disease', (25, 28))	('human', 'Species', '9606', (19, 24))	('MFAP5', 'Var', (53, 58))
153581	31775892	Loss function of MFAP5 inhibits bone loss in mice, whereas MFAP5 mutation is associated with the pathology of thoracic aortic aneurysms and dissections in human.	('thoracic aortic aneurysms', 'Phenotype', 'HP:0012727', (110, 135))	('dissections', 'Disease', (140, 151))	('Loss function', 'NegReg', (0, 13))	('bone loss', 'Disease', 'MESH:D016301', (32, 41))	('mice', 'Species', '10090', (45, 49))	('aneurysms', 'Phenotype', 'HP:0002617', (126, 135))	('human', 'Species', '9606', (155, 160))	('thoracic aortic aneurysms', 'Disease', 'MESH:D017545', (110, 135))	('thoracic aortic aneurysms', 'Disease', (110, 135))	('aortic aneurysms', 'Phenotype', 'HP:0004942', (119, 135))	('mutation', 'Var', (65, 73))	('bone loss', 'Phenotype', 'HP:0002797', (32, 41))	('MFAP5', 'Gene', (17, 22))	('MFAP5', 'Gene', (59, 64))	('inhibits', 'NegReg', (23, 31))	('bone loss', 'Disease', (32, 41))	('associated', 'Reg', (77, 87))
153599	31775892	The array data of GSE76297 included 92 CCA tissue samples and 92 non-cancerous tissue samples.	('GSE76297', 'Var', (18, 26))	('CCA', 'Disease', 'MESH:D018281', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('CCA', 'Disease', (39, 42))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('CCA', 'Phenotype', 'HP:0030153', (39, 42))
153605	31775892	The anti-beta-actin (#4970), anti-rabbit IgG, HRP-linked antibody (#7071) and Notch activated targets antibody sample kit (#68309) were obtained from Cell Signaling Technology.	('#4970', 'Var', (21, 26))	('rabbit', 'Species', '9986', (34, 40))	('Notch', 'Gene', '4851;4853', (78, 83))	('Notch', 'Gene', (78, 83))
153606	31775892	The anti-CCND1 (60186-1-Ig), anti-CDK4 (11026-1-AP), anti-CDK6 (14052-1-AP), anti-CDKN1A (10355-1-AP) and anti-CDC25A (55031-1-AP) antibodies were purchased from Maygene Co.	('CCND1', 'Gene', (9, 14))	('14052-1-AP', 'Chemical', 'None', (64, 74))	('10355-1-AP', 'Var', (90, 100))	('CCND1', 'Gene', '595', (9, 14))	('10355-1-AP', 'Chemical', 'None', (90, 100))	('CDKN1A', 'Gene', (82, 88))	('CDK6', 'Gene', (58, 62))	('CDKN1A', 'Gene', '1026', (82, 88))	('CDK6', 'Gene', '1021', (58, 62))	('CDK4', 'Gene', (34, 38))	('CDC25A', 'Gene', (111, 117))	('CDC25A', 'Gene', '993', (111, 117))	('CDK4', 'Gene', '1019', (34, 38))	('55031-1-AP', 'Chemical', 'None', (119, 129))
153610	31775892	To determine the functional and clinical relevance of ECM-related genes in ICC, we first analyzed all the differentially expressed protein-coding genes within two microarray datasets (GSE76297 and GSE26566) from the GEO database.	('ICC', 'Disease', (75, 78))	('GSE76297', 'Var', (184, 192))	('ICC', 'Disease', 'MESH:C535533', (75, 78))	('GSE26566', 'Var', (197, 205))
153636	31775892	The results demonstrated that exogenous recMFAP5 increased ICC cells' proliferation in a dose-dependent manner (Fig.	('ICC', 'Disease', 'MESH:C535533', (59, 62))	('increased', 'PosReg', (49, 58))	('exogenous', 'Var', (30, 39))	('recMFAP5', 'Gene', (40, 48))	('ICC', 'Disease', (59, 62))
153642	31775892	Furthermore, IHC staining revealed that the expression of MFAP5 and Ki-67 were markedly downregulated in MFAP5 knockdown tumors (Figs.	('expression', 'MPA', (44, 54))	('knockdown', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Ki-67', 'Gene', (68, 73))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('MFAP5', 'Gene', (105, 110))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('downregulated', 'NegReg', (88, 101))	('MFAP5', 'Gene', (58, 63))
153645	31775892	These results indicate that the ICC cells could be arrested at the G0/G1 phase via silencing of MFAP5.	('ICC', 'Disease', 'MESH:C535533', (32, 35))	('MFAP5', 'Gene', (96, 101))	('ICC', 'Disease', (32, 35))	('silencing', 'Var', (83, 92))
153648	31775892	In addition, CCND1/CDK4/6/CDC25A protein and mRNA levels were significantly attenuated by MFAP5 knockdown, whereas p21 expression was increased (Fig.	('knockdown', 'Var', (96, 105))	('mRNA levels', 'MPA', (45, 56))	('expression', 'MPA', (119, 129))	('CDC25A', 'Gene', (26, 32))	('CCND1', 'Gene', '595', (13, 18))	('CDK4/6', 'Gene', '1019;1021', (19, 25))	('MFAP5', 'Gene', (90, 95))	('p21', 'Gene', '1026', (115, 118))	('CDC25A', 'Gene', '993', (26, 32))	('CDK4/6', 'Gene', (19, 25))	('attenuated', 'NegReg', (76, 86))	('p21', 'Gene', (115, 118))	('CCND1', 'Gene', (13, 18))	('increased', 'PosReg', (134, 143))
153653	31775892	Western blot and qPCR analysis showed that several Notch signaling pathway components, as well as Notch signaling targets, were reduced in MFAP5 knockdown cells compared to shControl cells (Fig.	('knockdown', 'Var', (145, 154))	('reduced', 'NegReg', (128, 135))	('MFAP5', 'Gene', (139, 144))	('Notch', 'Gene', '4851;4853', (51, 56))	('Notch', 'Gene', (51, 56))	('Notch', 'Gene', '4851;4853', (98, 103))	('Notch', 'Gene', (98, 103))
153657	31775892	Strong positive correlations were observed between recMFAP5 dosage and the expression of Notch1 signaling factors (Figs.	('dosage', 'Var', (60, 66))	('Notch1', 'Gene', (89, 95))	('Notch1', 'Gene', '4851', (89, 95))	('recMFAP5', 'Gene', (51, 59))	('expression', 'MPA', (75, 85))
153672	31775892	The ECM regulates tissue homeostasis, and ECM dysregulation contributes to tumor progression.	('contributes', 'Reg', (60, 71))	('tissue homeostasis', 'MPA', (18, 36))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('dysregulation', 'Var', (46, 59))	('tumor', 'Disease', (75, 80))
153682	31775892	identified DNA methylation of CDO1, CNRIP1, SEPT9, and VIM displaying frequencies of 45-77% in biliary brushes from CCA patients.	('methylation', 'Var', (15, 26))	('SEPT9', 'Gene', '10801', (44, 49))	('CCA', 'Phenotype', 'HP:0030153', (116, 119))	('CNRIP1', 'Gene', (36, 42))	('CDO1', 'Gene', '1036', (30, 34))	('CDO1', 'Gene', (30, 34))	('SEPT9', 'Gene', (44, 49))	('CNRIP1', 'Gene', '25927', (36, 42))	('CCA', 'Disease', 'MESH:D018281', (116, 119))	('VIM', 'Gene', '7431', (55, 58))	('patients', 'Species', '9606', (120, 128))	('CCA', 'Disease', (116, 119))	('VIM', 'Gene', (55, 58))
153694	31775892	In our study, we showed that a NOTCH1 inhibitor phenocopied MFAP5 knockdown and abolished MFAP5-induced ICC outgrowth, strongly suggesting that MFAP5 acts upstream of Notch signaling in ICC.	('Notch', 'Gene', '4851;4853', (167, 172))	('MFAP5-induced', 'Gene', (90, 103))	('ICC', 'Disease', (186, 189))	('ICC', 'Disease', 'MESH:C535533', (104, 107))	('abolished', 'NegReg', (80, 89))	('ICC', 'Disease', 'MESH:C535533', (186, 189))	('MFAP5', 'Gene', (60, 65))	('NOTCH1', 'Gene', '4851', (31, 37))	('NOTCH1', 'Gene', (31, 37))	('knockdown', 'Var', (66, 75))	('Notch', 'Gene', (167, 172))	('ICC', 'Disease', (104, 107))
153698	31775892	Previous studies showed that MFAP5 inhibition induces G2/M phase arrest, decreases the expression of Cyclin B1, Cyclin D1, and CDK4, and enhances p21 and p53 levels in cervical cancer.	('enhances', 'PosReg', (137, 145))	('Cyclin D1', 'Gene', '595', (112, 121))	('Cyclin D1', 'Gene', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('inhibition', 'Var', (35, 45))	('induces', 'Reg', (46, 53))	('MFAP5', 'Gene', (29, 34))	('p21', 'Gene', '1026', (146, 149))	('G2/M phase arrest', 'CPA', (54, 71))	('decreases', 'NegReg', (73, 82))	('CDK4', 'Gene', (127, 131))	('Cyclin B1', 'Gene', (101, 110))	('expression', 'MPA', (87, 97))	('p53', 'Gene', '7157', (154, 157))	('Cyclin B1', 'Gene', '891', (101, 110))	('p21', 'Gene', (146, 149))	('cervical cancer', 'Disease', 'MESH:D002583', (168, 183))	('CDK4', 'Gene', '1019', (127, 131))	('cervical cancer', 'Disease', (168, 183))	('p53', 'Gene', (154, 157))
153699	31775892	Inhibition of cell growth by MFAP5 knockdown is dependent on reactive oxygen species (ROS) production.	('knockdown', 'Var', (35, 44))	('Inhibition', 'NegReg', (0, 10))	('MFAP5', 'Gene', (29, 34))	('oxygen', 'Chemical', 'MESH:D010100', (70, 76))	('cell growth', 'CPA', (14, 25))
153706	31775892	The mode and mechanism of the suppression of tumor aggressiveness by MFAP5 depletion are potentially important.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor aggressiveness', 'Disease', (45, 65))	('depletion', 'Var', (75, 84))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (45, 65))	('aggressiveness', 'Phenotype', 'HP:0000718', (51, 65))	('MFAP5', 'Gene', (69, 74))
153709	31775892	This study was supported by grants from the National Natural Science Foundation of China (81772522, 81472261, 81572766, and 31771630), the Natural Science Foundation of Guangdong Province (2016A030313238, 2017A030312009, 2019A1515010686), the Science and Technology Development Projects of Guangzhou, Guangdong, China (201604020044), the Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06S029) and the China Postdoctoral Science Foundation (2016 M602588, 2108 M643325, 2108 M643327), and Shenzhen Science Foundation (KY20160309) .	('2108 M643325', 'Chemical', 'MESH:C479717', (477, 489))	('2016 M602588', 'Var', (463, 475))	('M602588', 'Chemical', 'MESH:D008775', (468, 475))	('2108 M643327', 'Chemical', 'MESH:C479717', (491, 503))	('2016ZT06S029', 'Var', (402, 414))	('201604020044', 'Var', (319, 331))
153714	30665289	Use of radiofrequency ablation and photodynamic therapy in malignant biliary obstruction has been shown to improve the survival rates as well as the patency of biliary stents.	('biliary obstruction', 'Phenotype', 'HP:0005230', (69, 88))	('patency', 'MPA', (149, 156))	('malignant biliary obstruction', 'Disease', 'MESH:D009369', (59, 88))	('malignant biliary obstruction', 'Disease', (59, 88))	('survival rates', 'CPA', (119, 133))	('improve', 'PosReg', (107, 114))	('radiofrequency', 'Var', (7, 21))	('biliary', 'Disease', (160, 167))
153744	30665289	In a systematic review and metanalysis including nine studies (505 patients), the pooled weighted mean difference in the stent patency was 50.6 days in favor of RFA.	('RFA', 'Var', (161, 164))	('patients', 'Species', '9606', (67, 75))	('stent', 'MPA', (121, 126))
153745	30665289	Overall survival was also better in patients treated with RFA (hazard ratio, 1.395; 95% confidence interval, 1.145-1.7; p<0.001).	('RFA', 'Var', (58, 61))	('better', 'PosReg', (26, 32))	('patients', 'Species', '9606', (36, 44))	('Overall', 'MPA', (0, 7))
153747	30665289	In addition to local ablation, RFA also incites an immune response towards malignant cells and could be the possible reason for improved survival in these patients.	('RFA', 'Var', (31, 34))	('immune response towards malignant cells', 'MPA', (51, 90))	('improved', 'PosReg', (128, 136))	('patients', 'Species', '9606', (155, 163))	('incites', 'Reg', (40, 47))
153749	30665289	In addition, serious adverse events like partial liver infarction due to vascular injury have been reported after RFA.	('liver infarction', 'Disease', 'MESH:D000081011', (49, 65))	('RFA', 'Var', (114, 117))	('vascular injury', 'Disease', (73, 88))	('liver infarction', 'Disease', (49, 65))	('vascular injury', 'Disease', 'MESH:D057772', (73, 88))
153754	30665289	In an early randomized trial by Ortner and colleagues, PDT resulted in better biliary drainage and improved survival in patients with non-resectable cholangiocarcinoma (493 days vs. 98 days, p<0.0001).	('improved', 'PosReg', (99, 107))	('biliary', 'Disease', (78, 85))	('cholangiocarcinoma', 'Disease', (149, 167))	('PDT', 'Var', (55, 58))	('patients', 'Species', '9606', (120, 128))	('non-resectable', 'Disease', (134, 148))	('better', 'PosReg', (71, 77))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (149, 167))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (149, 167))	('survival', 'MPA', (108, 116))
153755	30665289	In a systematic review and meta-analysis, PDT was superior to biliary stenting alone with regard to successful biliary drainage (>50% reduction in bilirubin at day 7) and survival.	('bilirubin', 'Chemical', 'MESH:D001663', (147, 156))	('reduction', 'NegReg', (134, 143))	('PDT', 'Var', (42, 45))
153771	30665289	Hyperechoic foci measuring about 1 cm and representing the area of coagulation necrosis were observed after RFA.	('coagulation necrosis', 'Disease', (67, 87))	('coagulation necrosis', 'Disease', 'MESH:D009336', (67, 87))	('RFA', 'Var', (108, 111))	('coagulation necrosis', 'Phenotype', 'HP:0010885', (67, 87))
153927	30103720	In contrast series with higher rates of cancer positive resection margins identified R1/2 resections as an independent significant negative prognostic factor on survival in multivariable analysis.	('R1/2 resections', 'Var', (85, 100))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('negative', 'NegReg', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
153952	29042681	Moreover, three potential biomarker genes were hypomethylated in the tumorigenesis of ICC: ehf, epha4 and itgb6.	('epha4', 'Gene', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('itgb6', 'Gene', '100499533', (106, 111))	('itgb6', 'Gene', (106, 111))	('tumor', 'Disease', (69, 74))	('epha4', 'Gene', '64270', (96, 101))	('hypomethylated', 'Var', (47, 61))	('ehf', 'Disease', (91, 94))	('ICC', 'Disease', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
153960	29042681	Another model developed by Wu's laboratory conditionally coexpressed hepatitis B virus X (HBx) and hepatitis C virus core (HCP) in zebrafish livers, which caused the formation of ICC.	('HB', 'Phenotype', 'HP:0002884', (90, 92))	('hepatitis', 'Phenotype', 'HP:0012115', (69, 78))	('hepatitis B virus X', 'Gene', '944566', (69, 88))	('caused', 'Reg', (155, 161))	('zebrafish', 'Species', '7955', (131, 140))	('hepatitis B virus X', 'Gene', (69, 88))	('hepatitis C virus', 'Var', (99, 116))	('HBx', 'Gene', '944566', (90, 93))	('hepatitis C virus', 'Species', '11103', (99, 116))	('HBx', 'Gene', (90, 93))	('hepatitis', 'Phenotype', 'HP:0012115', (99, 108))
153961	29042681	Aberrant activation of the RAS pathway is ubiquitous in most human tumours, whether due to mutations of the RAS genes themselves or to alterations in the upstream or downstream signalling components, such as the Raf-MEK-ERK and PI3K-AKT-mTOR pathways.	('activation', 'PosReg', (9, 19))	('Raf', 'Gene', '22882', (212, 215))	('MEK', 'Gene', (216, 219))	('ERK', 'Gene', '2048', (220, 223))	('MEK', 'Gene', '5609', (216, 219))	('tumours', 'Disease', 'MESH:D009369', (67, 74))	('tumours', 'Disease', (67, 74))	('alterations', 'Reg', (135, 146))	('Raf', 'Gene', (212, 215))	('mutations', 'Var', (91, 100))	('RAS pathway', 'Pathway', (27, 38))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('ERK', 'Gene', (220, 223))	('human', 'Species', '9606', (61, 66))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))	('RAS genes', 'Gene', (108, 117))
153967	29042681	Aberrations in DNA methylation often lead to harmful alterations in gene expression, which is a major hallmark of tumor progression.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('lead to', 'Reg', (37, 44))	('gene expression', 'MPA', (68, 83))	('alterations', 'Reg', (53, 64))	('tumor', 'Disease', (114, 119))	('DNA', 'Gene', (15, 18))	('Aberrations', 'Var', (0, 11))
153968	29042681	For example, hypermethylation in promoter regions of tumor suppressor genes often results in transcriptional silencing of those genes, which then drives the cancer initiation.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('drives', 'Reg', (146, 152))	('transcriptional', 'MPA', (93, 108))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer initiation', 'Disease', 'MESH:D009369', (157, 174))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('results in', 'Reg', (82, 92))	('cancer initiation', 'Disease', (157, 174))	('tumor', 'Disease', (53, 58))	('hypermethylation', 'Var', (13, 29))
153969	29042681	In addition, DNA methylation changes in other gene body regions in oncogenes may also contribute to the pathogenesis of cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('contribute', 'Reg', (86, 96))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('DNA', 'Var', (13, 16))
153970	29042681	Abnormal DNA methylation frequently appears in various cancers.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('appears', 'Reg', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Abnormal DNA methylation', 'Var', (0, 24))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancers', 'Disease', (55, 62))
153971	29042681	With regards to the liver cancer research, studies revealed massive epigenetic alternations in HCC, indicating that deregulation of DNA methylation plays an important role in tumorigenesis and metastasis.	('liver cancer', 'Phenotype', 'HP:0002896', (20, 32))	('tumor', 'Disease', (175, 180))	('liver cancer', 'Disease', 'MESH:D006528', (20, 32))	('HCC', 'Gene', '619501', (95, 98))	('liver cancer', 'Disease', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('HCC', 'Phenotype', 'HP:0001402', (95, 98))	('metastasis', 'CPA', (193, 203))	('epigenetic alternations', 'Var', (68, 91))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('HCC', 'Gene', (95, 98))	('deregulation', 'Var', (116, 128))
153981	29042681	Obviously enlarged bellies (compared to the control) of Tg(fabp10:nras 61K) transgenic zebrafish were observed starting in 12 months old juveniles.	('transgenic', 'Var', (76, 86))	('zebrafish', 'Species', '7955', (87, 96))	('enlarged', 'PosReg', (10, 18))	('bellies', 'CPA', (19, 26))	('Tg(fabp10', 'Gene', '171481', (56, 65))
153994	29042681	In addition, previous studies showed that 25 significantly mutated genes and top 42 up-regulated genes in ICC patients are likely to be good candidates for ICC markers.	('ICC', 'Disease', (156, 159))	('up-regulated', 'PosReg', (84, 96))	('ICC', 'Disease', (106, 109))	('patients', 'Species', '9606', (110, 118))	('mutated', 'Var', (59, 66))
153998	29042681	The overall CG methylation level of transgenic zebrafish was lower than that in WT zebrafish (75.82%), but it was still considered to be relatively high.	('lower', 'NegReg', (61, 66))	('CG methylation level', 'MPA', (12, 32))	('zebrafish', 'Species', '7955', (83, 92))	('transgenic', 'Var', (36, 46))	('CG', 'Chemical', 'MESH:C028505', (12, 14))	('zebrafish', 'Species', '7955', (47, 56))
154003	29042681	Our result indicate that two discrete switch over zones, upstream of the TSS and the exon 1, demarcate the transition from hypo- to hypermethylation in the inverse relationship between promoter and gene-body methylation and expression both in liver samples of Tg(fabp10:nras 61K) transgenic and WT zebrafish (data not shown).	('Tg(fabp10', 'Gene', '171481', (260, 269))	('expression', 'MPA', (224, 234))	('transgenic', 'Var', (280, 290))	('zebrafish', 'Species', '7955', (298, 307))
154006	29042681	We compared the methylome and transcriptomic profiles with the finding that when the CG methylation up-regulated, there were 72 genes up-regulated and 44 genes down-regulated at transcription level, while 924 genes remained unchanged.	('down-regulated', 'NegReg', (160, 174))	('up-regulated', 'PosReg', (100, 112))	('methylation', 'Var', (88, 99))	('up-regulated', 'PosReg', (134, 146))	('CG', 'Chemical', 'MESH:C028505', (85, 87))
154018	29042681	One explanation for the phenotypic differences between kras V12 and nras 61K is that they are expressed at different levels within specific cell types.	('V12', 'Gene', '28817', (60, 63))	('V12', 'Gene', (60, 63))	('nras 61K', 'Var', (68, 76))
154019	29042681	However, further studies are necessary to determine whether nras 61K is responsible for the conversion of hepatocytes to the biliary lineage cells, and next, to induce the malignant transformation to the intrahepatic cholangiocarcinoma.	('induce', 'Reg', (161, 167))	('malignant transformation', 'CPA', (172, 196))	('nras 61K', 'Var', (60, 68))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (204, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (217, 235))	('intrahepatic cholangiocarcinoma', 'Disease', (204, 235))
154024	29042681	Moreover, our data uncovered that 11 of these potential ICC marker genes (Table 3) were obviously up-regulated in the Tg(fabp10:nras 61K) transgenic zebrafish, indicating that these genes may play critical roles in the nras 61K liver tumorigenesis and that our model provides a good platform for ICC studies.	('tumor', 'Disease', (234, 239))	('transgenic', 'Var', (138, 148))	('Tg(fabp10', 'Gene', '171481', (118, 127))	('zebrafish', 'Species', '7955', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('nras 61K', 'Var', (219, 227))	('up-regulated', 'PosReg', (98, 110))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
154025	29042681	Deregulation of developmental genes by hypomethylation of CG islands appears to be one of the major factors driving tumorigenesis.	('CG', 'Chemical', 'MESH:C028505', (58, 60))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('Deregulation', 'MPA', (0, 12))	('CG islands', 'Protein', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('developmental genes', 'Gene', (16, 35))	('hypomethylation', 'Var', (39, 54))
154027	29042681	found that DNA demethylation together with specific nras mutations drives the early steps of oxidative damage colorectal tumourigenesis.	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('damage colorectal tumourigenesis', 'Disease', 'MESH:D015179', (103, 135))	('mutations', 'Var', (57, 66))	('nras', 'Gene', (52, 56))	('DNA demethylation', 'MPA', (11, 28))	('damage colorectal tumourigenesis', 'Disease', (103, 135))
154028	29042681	Another study reported that the hypomethylated genes may play important roles in the pathogenesis of nras 61K-mutated melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('play', 'Reg', (57, 61))	('nras 61K-mutated', 'Var', (101, 117))
154033	29042681	Our results showed that three potential ICC marker genes were hypomethylated in liver samples of the 12 months post fertilization (mpf) Tg(fabp10:nras 61K) transgenic fish.	('Tg(fabp10', 'Gene', '171481', (136, 145))	('transgenic', 'Var', (156, 166))	('hypomethylated', 'Var', (62, 76))
154038	29042681	Moreover, hypomethylated loci featured prominently in gene bodies (mainly in introns) but not promoter regions, which is similar to the previous report of the nras 61K-mutated melanoma.	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('hypomethylated', 'Var', (10, 24))	('melanoma', 'Disease', (176, 184))
154042	29042681	The liver-driver construction was made by the insertion of zebrafish liver-specific fatty acid-binding protein (fabp10) promotor at the Apal I and Nhe I sites into the vector pAcGFP1-N1 (Clontech, Mountain View, CA, 632469).	('zebrafish', 'Species', '7955', (59, 68))	('fabp10', 'Gene', (112, 118))	('fabp10', 'Gene', '171481', (112, 118))	('insertion', 'Var', (46, 55))	('pAc', 'Phenotype', 'HP:0006699', (175, 178))
154047	29042681	Liver tumor in transgenic fish was defined as GFP-marked liver which was enlarged to at least twice the size of a WT normal liver.	('transgenic', 'Var', (15, 25))	('Liver tumor', 'Phenotype', 'HP:0002896', (0, 11))	('Liver tumor', 'Disease', (0, 11))	('Liver tumor', 'Disease', 'MESH:D008113', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
154125	26351206	Abnormal DNA content is a common characteristic of several malignancy neoplasms.	('malignancy neoplasms', 'Disease', 'MESH:D009369', (59, 79))	('Abnormal', 'Var', (0, 8))	('malignancy neoplasms', 'Disease', (59, 79))	('neoplasms', 'Phenotype', 'HP:0002664', (70, 79))
154132	26351206	As with most cancers, development of CCA is believed to be a multistep accumulation of genetic and epigenetic alterations in regulatory genes, leading to the activation of oncogenes and inactivation or loss of tumor suppressor genes.	('oncogenes', 'Protein', (172, 181))	('loss of tumor', 'Disease', (202, 215))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('CCA', 'Disease', (37, 40))	('activation', 'PosReg', (158, 168))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('loss of tumor', 'Disease', 'MESH:D009369', (202, 215))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('cancers', 'Disease', (13, 20))	('inactivation', 'Var', (186, 198))	('CCA', 'Phenotype', 'HP:0030153', (37, 40))
154133	26351206	Mutations of the K-ras gene in CCA have been reported by several investigators.	('K-ras', 'Gene', '3845', (17, 22))	('CCA', 'Phenotype', 'HP:0030153', (31, 34))	('Mutations', 'Var', (0, 9))	('K-ras', 'Gene', (17, 22))	('CCA', 'Disease', (31, 34))
154134	26351206	detected two cases of a point mutation in codon 12 of K-ras among three cases of stool samples of CCA.	('CCA', 'Phenotype', 'HP:0030153', (98, 101))	('K-ras', 'Gene', (54, 59))	('K-ras', 'Gene', '3845', (54, 59))	('point mutation in codon', 'Var', (24, 47))
154136	26351206	These findings indicate that detecting the K-ras gene mutation could provide useful information for the early diagnosis of CCA.	('CCA', 'Phenotype', 'HP:0030153', (123, 126))	('mutation', 'Var', (54, 62))	('CCA', 'Disease', (123, 126))	('K-ras', 'Gene', (43, 48))	('K-ras', 'Gene', '3845', (43, 48))
154141	26351206	Overexpression of the Bcl-2 gene has also been related to the invasiveness of the cholangiocarcinoma.	('invasiveness', 'CPA', (62, 74))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (82, 100))	('related', 'Reg', (47, 54))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (82, 100))	('Bcl-2', 'Gene', (22, 27))	('Bcl-2', 'Gene', '596', (22, 27))	('Overexpression', 'Var', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('cholangiocarcinoma', 'Disease', (82, 100))
154144	26351206	These data demonstrate that mutations of the p53 gene in CCA are very common; therefore, detecting the mutations of p53 would be a useful molecular tool for early diagnosis.	('p53', 'Gene', (45, 48))	('p53', 'Gene', (116, 119))	('p53', 'Gene', '7157', (45, 48))	('CCA', 'Phenotype', 'HP:0030153', (57, 60))	('CCA', 'Disease', (57, 60))	('mutations', 'Var', (28, 37))	('p53', 'Gene', '7157', (116, 119))
154149	26351206	Mammalian cells possess the capacity to epigenetically modify their genomes via the covalent addition of a methyl group to the five-position of the cytosine ring within the context of the CpG dinucleotide.	('epigenetically modify', 'Var', (40, 61))	('Mammalian', 'Species', '9606', (0, 9))	('genomes', 'MPA', (68, 75))	('cytosine', 'Chemical', 'MESH:D003596', (148, 156))
154150	26351206	However, hypermethylation of CpG islands can cause inactivation of genes and relate to tumorigenesis and progress.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('relate', 'Reg', (77, 83))	('tumor', 'Disease', (87, 92))	('hypermethylation', 'Var', (9, 25))	('cause', 'Reg', (45, 50))	('inactivation of genes', 'MPA', (51, 72))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('progress', 'CPA', (105, 113))
154152	26351206	The frequency of tumor-suppressor gene methylation in CCA was P14 (24%), DAPK (30.6%), TMS1/ASC (36.1%).	('ASC', 'Gene', '29108', (92, 95))	('methylation', 'Var', (39, 50))	('tumor-suppressor', 'Gene', '7248', (17, 33))	('P14', 'Gene', (62, 65))	('CCA', 'Disease', (54, 57))	('TMS1', 'Gene', (87, 91))	('DAPK', 'Gene', (73, 77))	('DAPK', 'Gene', '1612', (73, 77))	('TMS1', 'Gene', '29108', (87, 91))	('tumor-suppressor', 'Gene', (17, 33))	('P14', 'Gene', '11102', (62, 65))	('ASC', 'Gene', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('CCA', 'Phenotype', 'HP:0030153', (54, 57))
154154	26351206	Our study indicates that methylation of the p53-Bax mitochondrial apoptosis pathway in CCA is a common epigenetic event and may be significant for early diagnosis.	('Bax', 'Gene', '581', (48, 51))	('CCA', 'Phenotype', 'HP:0030153', (87, 90))	('p53', 'Gene', (44, 47))	('methylation', 'Var', (25, 36))	('p53', 'Gene', '7157', (44, 47))	('Bax', 'Gene', (48, 51))	('CCA', 'Disease', (87, 90))
154156	26351206	Mechanistic understanding suggests that these changes in miRNA expression increase CCA proliferation and survival: for example, miR-141 decreases CLOCK expression, which disinhibits cell proliferation.	('CLOCK', 'Gene', '9575', (146, 151))	('CCA', 'Disease', (83, 86))	('miR-141', 'Gene', (128, 135))	('changes', 'Var', (46, 53))	('cell proliferation', 'CPA', (182, 200))	('miR-141', 'Gene', '406933', (128, 135))	('increase', 'PosReg', (74, 82))	('CLOCK', 'Gene', (146, 151))	('CCA', 'Phenotype', 'HP:0030153', (83, 86))	('disinhibits', 'NegReg', (170, 181))	('survival', 'CPA', (105, 113))	('decreases', 'NegReg', (136, 145))
154168	26351206	Wnt-inducible signaling pathway protein 1v is overexpressed in stroma nests around CCA, and levels of WISP 1v are associated with reduced survival times of patients.	('patients', 'Species', '9606', (156, 164))	('survival times', 'CPA', (138, 152))	('overexpressed', 'PosReg', (46, 59))	('CCA', 'Phenotype', 'HP:0030153', (83, 86))	('reduced', 'NegReg', (130, 137))	('levels', 'Var', (92, 98))
53071	26351206	Inhibition of hedgehog signaling with cyclopamine impedes CCA cell migration, proliferation, and invasion.	('impedes', 'NegReg', (50, 57))	('CCA', 'Phenotype', 'HP:0030153', (58, 61))	('hedgehog', 'Protein', (14, 22))	('cyclopamine', 'Chemical', 'MESH:C000541', (38, 49))	('proliferation', 'CPA', (78, 91))	('Inhibition', 'Var', (0, 10))	('CCA', 'Disease', (58, 61))	('invasion', 'CPA', (97, 105))
154186	33194743	However, in in vitro studies, metformin does inhibit the proliferation and viability of BTC and promote the apoptosis of BTC through various mechanisms.	('metformin', 'Var', (30, 39))	('viability', 'CPA', (75, 84))	('BTC', 'CPA', (88, 91))	('metformin', 'Chemical', 'MESH:D008687', (30, 39))	('promote', 'PosReg', (96, 103))	('inhibit', 'NegReg', (45, 52))	('apoptosis', 'CPA', (108, 117))
154202	33194743	The ICD-9-CM codes for the related diagnoses are provided below: hypertension (401-405), dyslipidemia (272.0-272.4), obesity (278), nephropathy (580-589), eye disease (250.5: diabetes with ophthalmic manifestations, 362.0: diabetic retinopathy, 369: blindness and low vision, 366.41: diabetic cataract, and 365.44: glaucoma associated with systemic syndromes), stroke (430-438), ischemic heart disease (410-414), peripheral arterial disease (250.7, 785.4, 443.81, and 440-448), chronic obstructive pulmonary disease (a surrogate for smoking; 490-496), tobacco abuse (305.1, 649.0, and 989.84), alcohol-related diagnoses (291, 303, 535.3, 571.0-571.3, and 980.0), gallstone (574.00, 574.01, 574.10, 574.11, 574.20, 574.21, and A348), diagnoses related to Epstein-Barr virus infection (075, 710.3, and 710.4), hepatitis B virus infection (070.22, 070.23, 070.32, 070.33, and V02.61), hepatitis C virus infection (070.41, 070.44, 070.51, 070.54, and V02.62), and disease of pancreas (577).	('blindness', 'Phenotype', 'HP:0000618', (250, 259))	('hepatitis C virus infection', 'Phenotype', 'HP:0410371', (882, 909))	('gallstone', 'Disease', 'MESH:D042882', (663, 672))	('chronic obstructive pulmonary disease', 'Disease', (478, 515))	('tobacco abuse', 'Disease', (552, 565))	('peripheral arterial disease', 'Disease', 'MESH:D058729', (413, 440))	('dyslipidemia', 'Phenotype', 'HP:0003119', (89, 101))	('nephropathy', 'Phenotype', 'HP:0000112', (132, 143))	('glaucoma', 'Phenotype', 'HP:0000501', (315, 323))	('stroke', 'Disease', (361, 367))	('obesity', 'Disease', 'MESH:D009765', (117, 124))	('glaucoma', 'Disease', (315, 323))	('hepatitis C virus infection', 'Disease', 'MESH:D006526', (882, 909))	('disease of pancreas', 'Phenotype', 'HP:0001732', (960, 979))	('diabetes', 'Disease', (175, 183))	('low vision', 'Disease', (264, 274))	('dyslipidemia', 'Disease', (89, 101))	('low vision', 'Disease', 'MESH:D015354', (264, 274))	('diabetic cataract', 'Disease', 'MESH:D003920', (284, 301))	('Epstein-Barr virus infection', 'Disease', 'MESH:D020031', (754, 782))	('glaucoma', 'Disease', 'MESH:D005901', (315, 323))	('hepatitis B virus infection', 'Phenotype', 'HP:0410369', (808, 835))	('V02.62', 'Var', (947, 953))	('hypertension', 'Disease', 'MESH:D006973', (65, 77))	('hepatitis', 'Phenotype', 'HP:0012115', (882, 891))	('blindness', 'Disease', (250, 259))	('alcohol', 'Chemical', 'MESH:D000438', (594, 601))	('hypertension', 'Disease', (65, 77))	('diabetic retinopathy', 'Disease', (223, 243))	('diabetic cataract', 'Disease', (284, 301))	('cataract', 'Phenotype', 'HP:0000518', (293, 301))	('ischemic heart disease', 'Disease', (379, 401))	('070.41', 'Var', (911, 917))	('stroke', 'Disease', 'MESH:D020521', (361, 367))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (486, 515))	('pancreas', 'Disease', (971, 979))	('obesity', 'Phenotype', 'HP:0001513', (117, 124))	('ischemic heart disease', 'Disease', 'MESH:D003324', (379, 401))	('gallstone', 'Disease', (663, 672))	('tobacco abuse', 'Disease', 'MESH:D014029', (552, 565))	('gallstone', 'Phenotype', 'HP:0001081', (663, 672))	('hepatitis', 'Phenotype', 'HP:0012115', (808, 817))	('nephropathy', 'Disease', (132, 143))	('eye disease', 'Disease', 'MESH:D000853', (155, 166))	('hepatitis C virus infection', 'Disease', (882, 909))	('hypertension', 'Phenotype', 'HP:0000822', (65, 77))	('hepatitis B virus infection', 'Disease', 'MESH:D006509', (808, 835))	('hepatitis B virus infection', 'Disease', (808, 835))	('nephropathy', 'Disease', 'MESH:D007674', (132, 143))	('Epstein-Barr virus infection', 'Disease', (754, 782))	('diabetic retinopathy', 'Disease', 'MESH:D003920', (223, 243))	('diabetes', 'Disease', 'MESH:D003920', (175, 183))	('eye disease', 'Disease', (155, 166))	('dyslipidemia', 'Disease', 'MESH:D050171', (89, 101))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (478, 515))	('eye disease', 'Phenotype', 'HP:0000478', (155, 166))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (478, 515))	('stroke', 'Phenotype', 'HP:0001297', (361, 367))	('pancreas', 'Disease', 'MESH:D010190', (971, 979))	('blindness', 'Disease', 'MESH:D001766', (250, 259))	('retinopathy', 'Phenotype', 'HP:0000488', (232, 243))	('peripheral arterial disease', 'Phenotype', 'HP:0004950', (413, 440))	('peripheral arterial disease', 'Disease', (413, 440))	('obesity', 'Disease', (117, 124))
154232	33194743	The findings supported that metformin use in patients with type 2 diabetes mellitus was associated with a significantly lower risk of BTC in a dose-response pattern, which could be demonstrated in different regression models in either the main analyses ( Table 2 ) or the sensitivity analyses ( Table 3 ).	('lower', 'NegReg', (120, 125))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (66, 83))	('type 2 diabetes mellitus', 'Disease', 'MESH:D003924', (59, 83))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (59, 74))	('metformin', 'Var', (28, 37))	('BTC', 'Disease', (134, 137))	('patients', 'Species', '9606', (45, 53))	('metformin', 'Chemical', 'MESH:D008687', (28, 37))	('type 2 diabetes mellitus', 'Disease', (59, 83))
154235	33194743	In our previous studies, metformin use was also associated with a lower risk of other types of cancer and the overall hazard ratios in well-matched cohorts were 0.72 (0.58-0.88) for lung cancer, 0.62 (0.53-0.74) for colorectal cancer, and 0.52 (0.31-0.89) for cervical cancer.	('lung cancer', 'Disease', (182, 193))	('colorectal cancer', 'Disease', (216, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('lower', 'NegReg', (66, 71))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('cancer', 'Disease', (269, 275))	('colorectal cancer', 'Phenotype', 'HP:0003003', (216, 233))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('metformin', 'Var', (25, 34))	('cancer', 'Disease', (227, 233))	('metformin', 'Chemical', 'MESH:D008687', (25, 34))	('cancer', 'Disease', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('colorectal cancer', 'Disease', 'MESH:D015179', (216, 233))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
154246	33194743	suggested that metformin may alter cholangiocarcinoma cancer cell metabolism and reverse the Warburg effect by reducing the expression of lactate dehydrogenase A. Metformin inhibits the mammalian target of rapamycin (mTOR) through an AMPK-dependent or an AMPK-independent pathway and upregulation of mTOR is always observed in BTC.	('mTOR', 'Gene', '2475', (300, 304))	('AMPK', 'Gene', '5563', (255, 259))	('lactate dehydrogenase A', 'Gene', '3939', (138, 161))	('cholangiocarcinoma cancer', 'Disease', 'MESH:D009369', (35, 60))	('AMPK', 'Gene', (234, 238))	('cholangiocarcinoma cancer', 'Disease', (35, 60))	('mTOR', 'Gene', (217, 221))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (35, 53))	('lactate dehydrogenase A', 'Gene', (138, 161))	('AMPK', 'Gene', (255, 259))	('inhibits', 'NegReg', (173, 181))	('mTOR', 'Gene', '2475', (217, 221))	('mammalian target of rapamycin', 'Gene', '2475', (186, 215))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mammalian target of rapamycin', 'Gene', (186, 215))	('AMPK', 'Gene', '5563', (234, 238))	('metformin', 'Chemical', 'MESH:D008687', (15, 24))	('Metformin', 'Chemical', 'MESH:D008687', (163, 172))	('Metformin', 'Var', (163, 172))	('mTOR', 'Gene', (300, 304))
154247	33194743	Metformin may also reduce inflammation, another feature of BTC, through the improvement of metabolic disturbances such as hyperglycemia, insulin resistance and dyslipidemia.	('dyslipidemia', 'Disease', 'MESH:D050171', (160, 172))	('dyslipidemia', 'Phenotype', 'HP:0003119', (160, 172))	('reduce', 'NegReg', (19, 25))	('improvement', 'PosReg', (76, 87))	('hyperglycemia', 'Disease', 'MESH:D006943', (122, 135))	('men', 'Species', '9606', (83, 86))	('insulin', 'Gene', (137, 144))	('dyslipidemia', 'Disease', (160, 172))	('Metformin', 'Var', (0, 9))	('hyperglycemia', 'Disease', (122, 135))	('metabolic disturbances', 'MPA', (91, 113))	('inflammation', 'Disease', 'MESH:D007249', (26, 38))	('insulin', 'Gene', '3630', (137, 144))	('insulin resistance', 'Phenotype', 'HP:0000855', (137, 155))	('inflammation', 'Disease', (26, 38))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('hyperglycemia', 'Phenotype', 'HP:0003074', (122, 135))
154249	33194743	Inactivation of tumor suppression function of FoxO3 is related to human development of BTC and metformin activates the AMPK-FoxO3 pathway resulting in a reduction of intracellular reactive oxygen species.	('men', 'Species', '9606', (79, 82))	('reduction', 'NegReg', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('FoxO3', 'Gene', (124, 129))	('FoxO3', 'Gene', (46, 51))	('FoxO3', 'Gene', '2309', (46, 51))	('FoxO3', 'Gene', '2309', (124, 129))	('human', 'Species', '9606', (66, 71))	('AMPK', 'Gene', (119, 123))	('metformin', 'Chemical', 'MESH:D008687', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('activates', 'PosReg', (105, 114))	('oxygen', 'Chemical', 'MESH:D010100', (189, 195))	('tumor', 'Disease', (16, 21))	('Inactivation', 'Var', (0, 12))	('AMPK', 'Gene', '5563', (119, 123))	('intracellular reactive oxygen species', 'MPA', (166, 203))
154250	33194743	Lysophosphatidylcholine may cause cholangiocyte senescence which is potentially related to the development of BTC.	('cause', 'Reg', (28, 33))	('cholangiocyte senescence', 'Disease', (34, 58))	('Lysophosphatidylcholine', 'Chemical', 'MESH:D008244', (0, 23))	('Lysophosphatidylcholine', 'Var', (0, 23))	('men', 'Species', '9606', (102, 105))
154251	33194743	It is interesting that metformin reduces lysophosphatidylcholine levels in human hepatocytes, which is related to the reduced secretion of Apo B.	('Apo B', 'Gene', (139, 144))	('lysophosphatidylcholine levels', 'MPA', (41, 71))	('lysophosphatidylcholine', 'Chemical', 'MESH:D008244', (41, 64))	('metformin', 'Chemical', 'MESH:D008687', (23, 32))	('Apo B', 'Gene', '338', (139, 144))	('reduced', 'NegReg', (118, 125))	('secretion', 'MPA', (126, 135))	('human', 'Species', '9606', (75, 80))	('reduces', 'NegReg', (33, 40))	('metformin', 'Var', (23, 32))
154253	33194743	However, because metformin has been consistently shown to reduce the risk of various types of cancer in the Taiwanese population, including cancers of the gastrointestinal system, gynecology-related cancers, prostate cancer, cancers of the urinary system, thyroid cancer, nasopharyngeal cancer, lung cancer, skin cancer, and non-Hodgkin lymphoma, it is possible that the anticancer effects of metformin may involve some common pathophysiological mechanisms relating to the development of various cancers.	('cancers', 'Phenotype', 'HP:0002664', (225, 232))	('cancers of the gastrointestinal system', 'Phenotype', 'HP:0007378', (140, 178))	('lung cancer', 'Disease', (295, 306))	('cancer', 'Disease', (287, 293))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (325, 345))	('cancers', 'Disease', (225, 232))	('cancer', 'Disease', (225, 231))	('prostate cancer', 'Disease', 'MESH:D011471', (208, 223))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('prostate cancer', 'Phenotype', 'HP:0012125', (208, 223))	('cancer', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('lymphoma', 'Phenotype', 'HP:0002665', (337, 345))	('prostate cancer', 'Disease', (208, 223))	('cancer', 'Disease', (264, 270))	('metformin', 'Chemical', 'MESH:D008687', (393, 402))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (496, 502))	('cancers', 'Disease', 'MESH:D009369', (496, 503))	('skin cancer', 'Disease', 'MESH:D012878', (308, 319))	('thyroid cancer', 'Disease', (256, 270))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('gastrointestinal system', 'Disease', (155, 178))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('lung cancer', 'Disease', 'MESH:D008175', (295, 306))	('cancers', 'Disease', (199, 206))	('cancer', 'Disease', 'MESH:D009369', (313, 319))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', (300, 306))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('lung cancer', 'Phenotype', 'HP:0100526', (295, 306))	('metformin', 'Var', (17, 26))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('reduce', 'NegReg', (58, 64))	('metformin', 'Chemical', 'MESH:D008687', (17, 26))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (325, 345))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('thyroid cancer', 'Disease', 'MESH:D013964', (256, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('skin cancer', 'Disease', (308, 319))	('cancer', 'Disease', (496, 502))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (329, 345))	('cancers', 'Phenotype', 'HP:0002664', (496, 503))	('cancers', 'Disease', (496, 503))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('thyroid cancer', 'Phenotype', 'HP:0002890', (256, 270))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (272, 293))	('cancer', 'Disease', (217, 223))	('non-Hodgkin lymphoma', 'Disease', (325, 345))	('cancers', 'Disease', (140, 147))	('men', 'Species', '9606', (480, 483))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('cancer', 'Disease', (313, 319))	('skin cancer', 'Phenotype', 'HP:0008069', (308, 319))	('cancer', 'Disease', (375, 381))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
154256	33194743	Specifically, metformin inhibits cancer stem cells formation, inhibits epithelial-to-mesenchymal transition which is associated with cancer metastasis, influences the expressions of many microRNAs that may exert epigenetic effects on cancer development, blocks the Warburg effect in energy metabolism that usually exists in cancer cells and inhibits cellular senescence.	('expressions', 'MPA', (167, 178))	('cancer', 'Disease', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('inhibits', 'NegReg', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('inhibits', 'NegReg', (341, 349))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('influences', 'Reg', (152, 162))	('Warburg effect', 'CPA', (265, 279))	('men', 'Species', '9606', (248, 251))	('inhibits', 'NegReg', (62, 70))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (324, 330))	('blocks', 'NegReg', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('cancer', 'Disease', (133, 139))	('epithelial-to-mesenchymal transition', 'CPA', (71, 107))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('energy', 'MPA', (283, 289))	('metformin', 'Var', (14, 23))	('cellular senescence', 'CPA', (350, 369))	('metformin', 'Chemical', 'MESH:D008687', (14, 23))	('cancer', 'Disease', (234, 240))	('cancer', 'Disease', 'MESH:D009369', (324, 330))
154269	33194743	Consistent findings in all regression models ( Tables 2  -  4 ) strengthened the beneficial effect of metformin on BTC risk.	('BTC', 'Disease', (115, 118))	('metformin', 'Var', (102, 111))	('metformin', 'Chemical', 'MESH:D008687', (102, 111))	('beneficial', 'PosReg', (81, 91))	('strengthened', 'PosReg', (64, 76))
154304	28975827	They found significantly longer operative times with robotic procedures but no significant differences in blood loss, hospital stay, morbidity, mortality, or surgical margins.	('longer', 'PosReg', (25, 31))	('blood loss', 'Disease', 'MESH:D006473', (106, 116))	('robotic', 'Var', (53, 60))	('blood loss', 'Disease', (106, 116))
154333	28975827	Another small Korean study looked specifically at patients with T stage T2b or lower cholangiocarcinomas undergoing open resection, 26 cases, versus laparoscopic resection, 11 cases, and showed no differences in resection margins, operative times, transfusions, mortality, or length of hospital stay.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (85, 104))	('patients', 'Species', '9606', (50, 58))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('T stage T2b', 'Var', (64, 75))	('cholangiocarcinomas', 'Disease', (85, 104))
154365	27681524	However, fascioliasis caused by F. hepatica or F. gigantica has not been clearly associated with cancer to date.	('F. gigantica', 'Var', (47, 59))	('cancer', 'Disease', (97, 103))	('fascioliasis', 'Disease', (9, 21))	('fascioliasis', 'Disease', 'MESH:D005211', (9, 21))	('F. hepatica', 'Species', '6192', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('F. gigantica', 'Species', '46835', (47, 59))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
154380	27681524	For basic research studies, articles were selected considering any evidence of fascioliasis and genetic alteration events, either in vivo or in vitro.	('genetic alteration', 'Var', (96, 114))	('fascioliasis', 'Disease', 'MESH:D005211', (79, 91))	('fascioliasis', 'Disease', (79, 91))
154425	27681524	Some studies conducted by Motorna (2011) and Gentile (1998) used the lambda/lacI Big Blue transgenic mouse model to investigate if genetic damage, as a measure of lacI mutations, could result in liver tissue from infection by F. hepatica.	('lacI', 'Gene', (76, 80))	('lacI', 'Gene', (163, 167))	('transgenic', 'Species', '10090', (90, 100))	('infection', 'Disease', (213, 222))	('infection', 'Disease', 'MESH:D007239', (213, 222))	('mouse', 'Species', '10090', (101, 106))	('result in', 'Reg', (185, 194))	('lacI', 'Gene', '21788', (76, 80))	('lacI', 'Gene', '21788', (163, 167))	('genetic damage', 'Disease', 'MESH:D030342', (131, 145))	('liver', 'MPA', (195, 200))	('F. hepatica', 'Species', '6192', (226, 237))	('mutations', 'Var', (168, 177))	('genetic damage', 'Disease', (131, 145))
154426	27681524	There was an increase of lacI mutations in mice with fascioliasis suggesting that the infection increases the risk for complex hepatic cell mutations rather than mutations stemming from more definable oxygen radical-associated events.	('mice', 'Species', '10090', (43, 47))	('lacI', 'Gene', '21788', (25, 29))	('oxygen radical', 'Chemical', 'MESH:D017382', (201, 215))	('infection', 'Disease', (86, 95))	('lacI', 'Gene', (25, 29))	('mutations', 'Var', (30, 39))	('increase', 'PosReg', (13, 21))	('fascioliasis', 'Disease', (53, 65))	('infection', 'Disease', 'MESH:D007239', (86, 95))	('fascioliasis', 'Disease', 'MESH:D005211', (53, 65))
154439	27681524	To further justify the plausibility that F. hepatica is associated with fibrosis, there are reports of fibrosis triggered by related organisms.	('F. hepatica', 'Species', '6192', (41, 52))	('associated', 'Reg', (56, 66))	('fibrosis', 'Disease', (103, 111))	('fibrosis', 'Disease', 'MESH:D005355', (72, 80))	('F. hepatica', 'Var', (41, 52))	('fibrosis', 'Disease', (72, 80))	('fibrosis', 'Disease', 'MESH:D005355', (103, 111))
154450	27681524	A recent study on HCC patients in Peru showed that all four K-RAS-mutated HCCs were unusual I21M mutants, uncommon K-RAS mutations different from codon 12 mutations have been associated with cholangiocarcinoma produced by viral infections or fluke infestations.	('associated', 'Reg', (175, 185))	('K-RAS', 'Gene', (60, 65))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (191, 209))	('fluke infestations', 'Disease', (242, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (191, 209))	('patients', 'Species', '9606', (22, 30))	('viral infections', 'Disease', (222, 238))	('viral infections', 'Disease', 'MESH:D001102', (222, 238))	('K-RAS', 'Gene', '3845', (115, 120))	('I21M', 'Mutation', 'p.I21M', (92, 96))	('cholangiocarcinoma', 'Disease', (191, 209))	('K-RAS', 'Gene', (115, 120))	('I21M', 'Var', (92, 96))	('K-RAS', 'Gene', '3845', (60, 65))	('fluke infestations', 'Disease', 'MESH:D007239', (242, 260))
154457	27681524	For example, alcohol consumption can exacerbate cholangiofibrosis in hamsters infected by Opisthorchis, another liver fluke infecting bile ducts, but no studies in Fasciola have been performed.	('liver fluke', 'Species', '6192', (112, 123))	('cholangiofibrosis', 'Disease', 'None', (48, 65))	('alcohol', 'Chemical', 'MESH:D000438', (13, 20))	('cholangiofibrosis', 'Disease', (48, 65))	('Fasciola', 'Species', '46835', (164, 172))	('alcohol consumption', 'Var', (13, 32))	('exacerbate', 'PosReg', (37, 47))	('Opisthorchis', 'Species', '147828', (90, 102))
154522	26956050	Previous studies have shown that Tyr705-phosphorylation of STAT3 is required for its nuclear accumulation, and consequently its transcriptional activation of anti-apoptotic proteins.	('transcriptional', 'MPA', (128, 143))	('anti-apoptotic proteins', 'MPA', (158, 181))	('Tyr705-phosphorylation', 'Var', (33, 55))	('Tyr705', 'Chemical', '-', (33, 39))	('activation', 'PosReg', (144, 154))	('STAT3', 'Gene', '6774', (59, 64))	('STAT3', 'Gene', (59, 64))
154553	26956050	Altogether, these results suggest that autophagy functions as a survival mechanism during ABC294640 treatment and that inhibition of autophagy enhances the anticancer effect of ABC294640 in CCA cells.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('ABC294640', 'Gene', '10058', (177, 186))	('cancer', 'Disease', (160, 166))	('CCA', 'Disease', (190, 193))	('inhibition', 'Var', (119, 129))	('ABC294640', 'Gene', (90, 99))	('autophagy', 'CPA', (39, 48))	('enhances', 'PosReg', (143, 151))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ABC294640', 'Gene', (177, 186))	('autophagy', 'CPA', (133, 142))	('CCA', 'Phenotype', 'HP:0030153', (190, 193))	('ABC294640', 'Gene', '10058', (90, 99))
154567	26956050	Inhibition of Sphk2 is observed to suppress colitis-driven colon cancer in mice.	('mice', 'Species', '10090', (75, 79))	('colitis', 'Phenotype', 'HP:0002583', (44, 51))	('colitis-driven colon cancer', 'Disease', (44, 71))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('colitis-driven colon cancer', 'Disease', 'MESH:D015179', (44, 71))	('Inhibition', 'Var', (0, 10))	('Sphk2', 'Gene', (14, 19))	('suppress', 'NegReg', (35, 43))
154578	26956050	S1P generated from Sphk1 has been shown to promote STAT3 phosphorylation either through its receptor or through inducing IL-6, the main activator of STAT3.	('STAT3', 'Gene', '6774', (51, 56))	('Sphk1', 'Gene', (19, 24))	('STAT3', 'Gene', '6774', (149, 154))	('IL-6', 'Gene', '3569', (121, 125))	('promote', 'PosReg', (43, 50))	('STAT3', 'Gene', (149, 154))	('STAT3', 'Gene', (51, 56))	('Sphk1', 'Gene', '8877', (19, 24))	('inducing', 'PosReg', (112, 120))	('S1P', 'Var', (0, 3))	('IL-6', 'Gene', (121, 125))	('S1P', 'Chemical', 'MESH:C060506', (0, 3))
154588	26956050	We also show that inhibition of autophagy enhances the sensitivity of CCA cells to ABC294640 and promotes its anticancer effect.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('enhances', 'PosReg', (42, 50))	('ABC294640', 'Gene', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('CCA', 'Phenotype', 'HP:0030153', (70, 73))	('sensitivity', 'CPA', (55, 66))	('promotes', 'PosReg', (97, 105))	('autophagy', 'CPA', (32, 41))	('inhibition', 'Var', (18, 28))	('ABC294640', 'Gene', '10058', (83, 92))	('cancer', 'Disease', (114, 120))
154591	26956050	Inhibition of Sphk2 has been shown to synergize with chemotherapeutic agents in breast cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('Inhibition', 'Var', (0, 10))	('breast cancer', 'Disease', (80, 93))	('Sphk2', 'Gene', (14, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
154595	26956050	In conclusion, we show that inhibition of Sphk2 by a novel highly specific inhibitor ABC294640 inhibits proliferation and induces apoptosis in cholangiocarcinoma cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('proliferation', 'CPA', (104, 117))	('apoptosis', 'CPA', (130, 139))	('induces', 'Reg', (122, 129))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (143, 161))	('inhibition', 'Var', (28, 38))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (143, 161))	('ABC294640', 'Gene', '10058', (85, 94))	('Sphk2', 'Gene', (42, 47))	('inhibits', 'NegReg', (95, 103))	('ABC294640', 'Gene', (85, 94))	('cholangiocarcinoma', 'Disease', (143, 161))
154603	26956050	Antibodies against human caspase 3 (#9662), caspase 8 (#9746), caspase 9 (#9502), PARP (#9542), LC3B (#2775), p-STAT3 (#9145) and STAT3 (#4904) were purchased from Cell Signaling (Beverly, MA).	('STAT3', 'Gene', '6774', (112, 117))	('#9502', 'Var', (74, 79))	('#9542', 'Var', (88, 93))	('PARP', 'Gene', '1302', (82, 86))	('caspase 3', 'Gene', (25, 34))	('LC3B', 'Gene', (96, 100))	('caspase 3', 'Gene', '836', (25, 34))	('caspase 9', 'Gene', (63, 72))	('LC3B', 'Gene', '81631', (96, 100))	('caspase 8', 'Gene', (44, 53))	('#9145', 'Var', (119, 124))	('PARP', 'Gene', (82, 86))	('#4904', 'Var', (137, 142))	('STAT3', 'Gene', (130, 135))	('caspase 9', 'Gene', '842', (63, 72))	('#9746', 'Var', (55, 60))	('#9662', 'Var', (36, 41))	('#2775', 'Var', (102, 107))	('STAT3', 'Gene', '6774', (130, 135))	('STAT3', 'Gene', (112, 117))	('caspase 8', 'Gene', '841', (44, 53))	('human', 'Species', '9606', (19, 24))
154705	27280413	Cytoplasmic expression of SOX9 has already been observed in pancreatic adenocarcinoma affected with p53 mutation, in breast cancer cells and in biliary tract cancers, suggesting that the location of SOX9 may depend on the mutational status of the cells.	('SOX9', 'Gene', '6662', (26, 30))	('SOX9', 'Gene', '6662', (199, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('observed', 'Reg', (48, 56))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (60, 85))	('biliary tract cancers', 'Disease', 'MESH:D001661', (144, 165))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('breast cancer', 'Disease', (117, 130))	('mutation', 'Var', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('p53', 'Gene', '7157', (100, 103))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (60, 85))	('SOX9', 'Gene', (26, 30))	('pancreatic adenocarcinoma', 'Disease', (60, 85))	('p53', 'Gene', (100, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('SOX9', 'Gene', (199, 203))	('biliary tract cancers', 'Disease', (144, 165))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
154720	22629477	Elevated Plasma IL-6 Associates with Increased Risk of Advanced Fibrosis and Cholangiocarcinoma in Individuals Infected by Opisthorchis viverrini Opisthorchis viverrini is considered among the most important of the food-borne trematodes due to its strong association with advanced periductal fibrosis and bile duct cancer (cholangiocarcinoma).	('Opisthorchis viverrini', 'Species', '6198', (123, 145))	('IL-6', 'Gene', (16, 20))	('Elevated Plasma IL-6', 'Phenotype', 'HP:0030783', (0, 20))	('Opisthorchis viverrini', 'Species', '6198', (146, 168))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (77, 95))	('Cholangiocarcinoma', 'Disease', (77, 95))	('food-borne trematodes', 'Disease', (215, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (332, 341))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('food-borne trematodes', 'Disease', 'MESH:D005517', (215, 236))	('Opisthorchis', 'Var', (146, 158))	('Opisthorchis', 'Species', '6198', (123, 135))	('bile duct cancer', 'Phenotype', 'HP:0030153', (305, 321))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (323, 341))	('bile duct cancer', 'Disease', (305, 321))	('Opisthorchis', 'Species', '6198', (146, 158))	('bile duct cancer', 'Disease', 'MESH:D001650', (305, 321))	('cholangiocarcinoma', 'Disease', (323, 341))	('association', 'Interaction', (255, 266))	('food-borne trematode', 'Disease', 'MESH:D005517', (215, 235))	('fibrosis', 'Disease', (292, 300))	('fibrosis', 'Disease', 'MESH:D005355', (292, 300))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (323, 341))	('Fibrosis and Cholangiocarcinoma', 'Disease', 'MESH:D005355', (64, 95))	('IL-6', 'Gene', '3569', (16, 20))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (77, 95))
154760	31799781	Immunohistochemical analyses revealed that high CXCL9 expression was closely correlated with prolonged postoperative survival and a large number of tumor-infiltrating natural killer (NK) cells.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('high', 'Var', (43, 47))	('tumor', 'Disease', (148, 153))	('prolonged', 'PosReg', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('CXCL9 expression', 'MPA', (48, 64))
154763	31799781	Our findings also suggested that CXCL9 upregulation might offer a therapeutic strategy for treating CXCL9-expressing iCCA by augmenting anti-tumor immune surveillance.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('CXCL9-expressing', 'Var', (100, 116))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('augmenting', 'NegReg', (125, 135))	('iCCA', 'Disease', 'MESH:C535533', (117, 121))	('tumor', 'Disease', (141, 146))	('iCCA', 'Disease', (117, 121))
154809	31799781	We anesthetized the mice with intraperitoneal injections of midazolam, medetomidine and butorphanol, and then randomly inoculated 100-muL suspensions of 1-1a cells transduced with empty shRNA, sh-CXCL9 1 or sh-CXCL9 2 (1.5 x 106 cells per mouse) into mouse spleens, followed by splenectomy to induce liver tumor formation.	('liver tumor', 'Phenotype', 'HP:0002896', (300, 311))	('mouse', 'Species', '10090', (251, 256))	('medetomidine', 'Chemical', 'MESH:D020926', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('mice', 'Species', '10090', (20, 24))	('sh-CXCL9', 'Var', (193, 201))	('midazolam', 'Chemical', 'MESH:D008874', (60, 69))	('induce', 'Reg', (293, 299))	('mouse', 'Species', '10090', (239, 244))	('butorphanol', 'Chemical', 'MESH:D002077', (88, 99))	('liver tumor', 'Disease', 'MESH:D008113', (300, 311))	('liver tumor', 'Disease', (300, 311))
154819	31799781	Patients with CXCL9high showed favorable postoperative overall survival (OS; P = 0.0035; Figure 1B) and recurrence-free survival (RFS; P < 0.0001; Figure 1C) compared to those with CXCL9low.	('recurrence-free survival', 'CPA', (104, 128))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'CPA', (55, 71))	('CXCL9high', 'Var', (14, 23))
154822	31799781	Although the number of T-bet+ Th1 cells was significantly higher in patients with CXCL9high and a trend toward significance was detected with the number of CD8+ cytotoxic T cells in all iCCA stages, the difference was not statistically significant when early (stages <=II) and advanced (stages >=III) cancer stages were considered separately (Figure 2E,F).	('T-bet', 'Gene', '30009', (23, 28))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('T-bet', 'Gene', (23, 28))	('cancer', 'Disease', (301, 307))	('patients', 'Species', '9606', (68, 76))	('iCCA', 'Disease', 'MESH:C535533', (186, 190))	('higher', 'PosReg', (58, 64))	('iCCA', 'Disease', (186, 190))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('CD8', 'Gene', (156, 159))	('CXCL9high', 'Var', (82, 91))	('CD8', 'Gene', '925', (156, 159))
154823	31799781	NCR+ NK cells were significantly enriched in patients with CXCL9high compared to those with CXCL9low, in both early and advanced cancer stages (Figure 2G).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('CXCL9high', 'Var', (59, 68))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('patients', 'Species', '9606', (45, 53))
154824	31799781	FOXP3+ Treg cells were comparable between patients with CXCL9high and CXCL9low (Figure 2H).	('patients', 'Species', '9606', (42, 50))	('FOXP3', 'Gene', '50943', (0, 5))	('FOXP3', 'Gene', (0, 5))	('CXCL9high', 'Var', (56, 65))
154825	31799781	To validate the impact of endogenous CXCL9 expression on tumor burden, we compared tumor volumes between murine iCCA 1-1a cells that expressed CXCL9 (empty shRNA) and 1-1a cells with knocked-down CXCL9 (sh-CXCL9 1 or sh-CXCL9-2) (Figure S1A,B).	('iCCA', 'Disease', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('sh-CXCL9-2', 'Gene', (217, 227))	('murine', 'Species', '10090', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('sh-CXCL9-2', 'Gene', '17329', (217, 227))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('iCCA', 'Disease', 'MESH:C535533', (112, 116))	('knocked-down', 'Var', (183, 195))
154839	31799781	We found that the NK depletion eliminated the volume differences between CXCL9-sufficient and CXCL9-deficient tumors (Figure 3K).	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('depletion', 'Var', (21, 30))	('CXCL9-deficient tumors', 'Disease', (94, 116))	('eliminated', 'NegReg', (31, 41))	('volume differences', 'MPA', (46, 64))	('CXCL9-deficient tumors', 'Disease', 'MESH:D009369', (94, 116))
154859	31799781	It has been demonstrated that tumor-derived CXCL9 is a tumor suppressor12; hence, CXCL9 was implicated in a favorable prognosis19, 20, 28 and good responsiveness to chemotherapy.29 CXCL9 stimulated lymphocyte trafficking into the tumor and enhanced anti-cancer immune surveillance, even though the targeted lymphocyte phenotypes differed, depending on the cancer type.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('lymphocyte trafficking into the', 'CPA', (198, 229))	('enhanced', 'PosReg', (240, 248))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('cancer', 'Disease', (254, 260))	('chemotherapy.29 CXCL9', 'Var', (165, 186))	('CXCL9', 'Var', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('stimulated', 'PosReg', (187, 197))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancer', 'Disease', (356, 362))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('tumor', 'Disease', (230, 235))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('cancer', 'Disease', 'MESH:D009369', (356, 362))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', (30, 35))
154861	31799781	In addition, Walser et al30 showed that NK cells and CD4+ T cells were critical to the mechanism by which CXCL9 limited metastasis and local growth in a murine breast cancer model.	('murine', 'Species', '10090', (153, 159))	('local growth', 'CPA', (135, 147))	('CXCL9', 'Var', (106, 111))	('metastasis', 'CPA', (120, 130))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('limited', 'NegReg', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))
154863	31799781	In this model, we showed that tumors with CXCL9-sufficient cells were associated with high frequencies of all tumor-infiltrating NK cells and of CXCR3+ NK cells.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('CXCL9-sufficient', 'Var', (42, 58))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
154887	31611977	However, CCA progression is affected by mRNA precursors that modify gene expression levels and protein structures through alternative splicing (AS) events, which create molecular indicators that may potentially be used to predict CCA outcomes.	('CCA', 'Disease', 'MESH:D018281', (9, 12))	('CCA', 'Disease', (9, 12))	('modify', 'Reg', (61, 67))	('CCA', 'Disease', 'MESH:D018281', (230, 233))	('gene expression levels', 'MPA', (68, 90))	('affected', 'Reg', (28, 36))	('CCA', 'Disease', (230, 233))	('protein structures', 'MPA', (95, 113))	('alternative splicing', 'Var', (122, 142))	('N', 'Chemical', 'MESH:D009584', (42, 43))
154903	31611977	CCA involves a high frequency of gene mutations and abnormal epigenetic changes, including DNA methylation, and histone and RNA modifications, all of which may lead to the occurrence of AS events.	('lead to', 'Reg', (160, 167))	('DNA methylation', 'MPA', (91, 106))	('epigenetic changes', 'Var', (61, 79))	('RNA', 'MPA', (124, 127))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('CCA', 'Disease', 'MESH:D018281', (0, 3))	('CCA', 'Disease', (0, 3))	('N', 'Chemical', 'MESH:D009584', (125, 126))	('histone', 'MPA', (112, 119))
154904	31611977	For example, the widely reported tumor suppressor genes tumor protein p53, AT-rich interaction domain 1A, PTEN and PI3K, as well as the proto-oncogenes NOTCH1 and MET proto-oncogene, receptor tyrosine kinase, cause variations in gene function through AS events, thus affecting cancer development.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('NOTCH1', 'Gene', (152, 158))	('PI3K', 'Var', (115, 119))	('NOTCH1', 'Gene', '4851', (152, 158))	('affecting', 'Reg', (267, 276))	('cancer', 'Disease', (277, 283))	('PTEN', 'Gene', (106, 110))	('tumor', 'Disease', (33, 38))	('gene function', 'MPA', (229, 242))	('MET proto-oncogene, receptor tyrosine kinase', 'Gene', '4233', (163, 207))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('variations', 'Var', (215, 225))	('p53', 'Gene', '7157', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', (56, 61))	('PTEN', 'Gene', '5728', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('p53', 'Gene', (70, 73))	('cause', 'Reg', (209, 214))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))
154967	31611977	Carcinoembryonic antigens (CEAs) and carbohydrate antigen (CA) 199, CA 125, CA 50 and CA 242 are currently used as CCA tumor markers, but these biomarkers have disadvantages in clinical application.	('CCA', 'Disease', 'MESH:D018281', (115, 118))	('tumor', 'Disease', (119, 124))	('CA 242', 'Var', (86, 92))	('CCA', 'Disease', (115, 118))	('CA 50', 'Var', (76, 81))	('clinical', 'Species', '191496', (177, 185))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('carbohydrate', 'Chemical', 'MESH:D002241', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('CA 125', 'Var', (68, 74))
154974	31611977	For example, the abnormal expression of genes such as transforming growth factor beta1, SMAD4, c-MET, matrix metallopeptidase 7, vascular endothelial growth factor (VEGF)-A, VEGF-B, VEGF-C and VEGF-D are associated with poor prognosis.	('beta1', 'Gene', '3779', (81, 86))	('matrix metallopeptidase 7', 'Gene', '4316', (102, 127))	('VEGF-D', 'Gene', '2277', (193, 199))	('VEGF-C', 'Gene', '7424', (182, 188))	('VEGF-B', 'Gene', (174, 180))	('VEGF', 'Gene', '7422', (193, 197))	('SMAD4', 'Gene', '4089', (88, 93))	('expression', 'MPA', (26, 36))	('VEGF', 'Gene', (193, 197))	('c-MET', 'Gene', '4233', (95, 100))	('c-MET', 'Gene', (95, 100))	('matrix metallopeptidase 7', 'Gene', (102, 127))	('vascular endothelial growth factor', 'Gene', '7422', (129, 163))	('abnormal', 'Var', (17, 25))	('vascular endothelial growth factor', 'Gene', (129, 163))	('VEGF', 'Gene', '7422', (165, 169))	('VEGF', 'Gene', '7422', (174, 178))	('VEGF-B', 'Gene', '7423', (174, 180))	('VEGF-D', 'Gene', (193, 199))	('SMAD4', 'Gene', (88, 93))	('VEGF', 'Gene', '7422', (182, 186))	('beta1', 'Gene', (81, 86))	('VEGF', 'Gene', (165, 169))	('VEGF', 'Gene', (174, 178))	('VEGF-C', 'Gene', (182, 188))	('VEGF', 'Gene', (182, 186))
154975	31611977	Mutations in genes such as human epidermal growth factor receptor 2, TP53, KRAS, cytosolic NADP-dependent isocitrate dehydrogenase and mitochondrial NADP-dependent isocitrate dehydrogenase can also affect the prognosis of patients with CCA, but the prognostic value of these genes remains controversial and has not been applied clinically.	('TP53', 'Gene', '7157', (69, 73))	('CCA', 'Disease', (236, 239))	('TP53', 'Gene', (69, 73))	('isocitrate', 'Chemical', 'MESH:D007523', (164, 174))	('isocitrate', 'Chemical', 'MESH:D007523', (106, 116))	('affect', 'Reg', (198, 204))	('patients', 'Species', '9606', (222, 230))	('human', 'Species', '9606', (27, 32))	('NADP', 'Chemical', 'MESH:D009249', (149, 153))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (75, 79))	('clinical', 'Species', '191496', (328, 336))	('epidermal growth factor receptor 2', 'Gene', (33, 67))	('epidermal growth factor receptor 2', 'Gene', '2064', (33, 67))	('NADP', 'Chemical', 'MESH:D009249', (91, 95))	('CCA', 'Disease', 'MESH:D018281', (236, 239))	('KRAS', 'Gene', '3845', (75, 79))
154980	31611977	For instance, the first AS event reported to be associated with CCA prognosis was exon 2 skipping of the trefoil factor 2 (TFF2) gene.	('trefoil factor 2', 'Gene', '7032', (105, 121))	('trefoil factor 2', 'Gene', (105, 121))	('CCA', 'Disease', 'MESH:D018281', (64, 67))	('TFF2', 'Gene', '7032', (123, 127))	('CCA', 'Disease', (64, 67))	('TFF2', 'Gene', (123, 127))	('exon 2 skipping', 'Var', (82, 97))
154982	31611977	Exon 2 skipping AS events lead to the loss of exon 2, resulting in a decrease in wild-type TFF2 proteins.	('skipping', 'Var', (7, 15))	('TFF2', 'Gene', '7032', (91, 95))	('exon 2', 'MPA', (46, 52))	('decrease', 'NegReg', (69, 77))	('TFF2', 'Gene', (91, 95))	('loss', 'NegReg', (38, 42))
154984	31611977	Another example is P53, as alterations in the N-terminus of this protein by AS has been demonstrated to worsen the prognosis in patients with CCA.	('N-terminus', 'MPA', (46, 56))	('prognosis', 'CPA', (115, 124))	('N', 'Chemical', 'MESH:D009584', (46, 47))	('P53', 'Gene', (19, 22))	('P53', 'Gene', '7157', (19, 22))	('worsen', 'Reg', (104, 110))	('CCA', 'Disease', 'MESH:D018281', (142, 145))	('patients', 'Species', '9606', (128, 136))	('CCA', 'Disease', (142, 145))	('alterations in', 'Var', (27, 41))
154989	31611977	Yosudjai et al also demonstrated that aberrant AS of anterior gradient protein 2 homolog promoted cell proliferation, migration, invasion and adhesive potential in CCA; however, there has been a lack of research on its association with patient prognoses.	('cell proliferation', 'CPA', (98, 116))	('aberrant AS', 'Var', (38, 49))	('invasion', 'CPA', (129, 137))	('CCA', 'Disease', 'MESH:D018281', (164, 167))	('migration', 'CPA', (118, 127))	('promoted', 'PosReg', (89, 97))	('CCA', 'Disease', (164, 167))	('adhesive potential', 'CPA', (142, 160))	('patient', 'Species', '9606', (236, 243))
154992	31611977	CHEK1 is a cell cycle monitoring-related protein, abnormalities of which result in DNA damage and the bypassing of the cell cycle checkpoints.	('N', 'Chemical', 'MESH:D009584', (84, 85))	('DNA damage', 'MPA', (83, 93))	('abnormalities', 'Var', (50, 63))	('bypassing', 'CPA', (102, 111))	('CHEK1', 'Gene', (0, 5))	('CHEK1', 'Gene', '1111', (0, 5))	('result in', 'Reg', (73, 82))
154993	31611977	FOXA1 is a transcription factor, the aberrant expression of which is closely associated with hepatocellular carcinoma; however, its association with CCA has not been previously reported.	('CCA', 'Disease', (149, 152))	('FOXA1', 'Gene', (0, 5))	('aberrant expression', 'Var', (37, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (93, 117))	('hepatocellular carcinoma', 'Disease', (93, 117))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (93, 117))	('FOXA1', 'Gene', '3169', (0, 5))	('CCA', 'Disease', 'MESH:D018281', (149, 152))	('associated', 'Reg', (77, 87))
155010	31611977	Therefore, in CCA, splicing factors may affect the structure of their own proteins by creating their own AS event and then subsequently affecting the AS events of other genes.	('AS event', 'MPA', (105, 113))	('affecting', 'Reg', (136, 145))	('splicing factors', 'Var', (19, 35))	('structure', 'MPA', (51, 60))	('proteins', 'Protein', (74, 82))	('affect', 'Reg', (40, 46))	('creating', 'Reg', (86, 94))	('CCA', 'Disease', 'MESH:D018281', (14, 17))	('CCA', 'Disease', (14, 17))
155147	27651736	A lesion was considered malignant by CECT if it demonstrated any combination of two or more of the following characteristics: The lesion was hypoattenuating, demonstrated enhancement on portal venous or delayed phase scans, caused distortion of normal anatomic architecture, caused obstruction or dilatation of the biliary tree, or was associated with adenopathy FDG.	('obstruction', 'Disease', (282, 293))	('caused', 'Reg', (224, 230))	('adenopathy FDG', 'Disease', 'MESH:D000072281', (352, 366))	('caused', 'Reg', (275, 281))	('associated with', 'Reg', (336, 351))	('obstruction', 'Disease', 'MESH:D000402', (282, 293))	('adenopathy FDG', 'Disease', (352, 366))	('dilatation', 'Phenotype', 'HP:0002617', (297, 307))	('enhancement', 'PosReg', (171, 182))	('lesion', 'Var', (130, 136))	('dilatation', 'CPA', (297, 307))
155177	27651736	In terms of lesion-based diagnostic performance [Table 2], FDG PET/CT has significantly higher sensitivity of 96.5% (138/143) compared to that of CECT (62.2%) (89/92) (P < 0.0001).	('higher', 'PosReg', (88, 94))	('FDG', 'Chemical', 'MESH:D019788', (59, 62))	('FDG PET/CT', 'Var', (59, 69))
155186	27651736	As NCCN Guidelines are widely recognized and used as the standard for clinical policy in oncology by clinicians and insurance payers, we set to add the database of FDG PET/CT in evaluation of CCA, through summarizing our institutional experience in a lesion-based comparison between FDG PET/CT and NCCN-recommended CECT.	('FDG', 'Var', (283, 286))	('CCA', 'Phenotype', 'HP:0030153', (192, 195))	('oncology', 'Phenotype', 'HP:0002664', (89, 97))	('CCA', 'Disease', (192, 195))	('FDG', 'Chemical', 'MESH:D019788', (283, 286))	('FDG', 'Chemical', 'MESH:D019788', (164, 167))
155198	27651736	Thus, FDG PET/CT has an overall significant better diagnostic performance than CECT in our patient cohort with cholangiocarcinoma.	('better', 'PosReg', (44, 50))	('FDG', 'Chemical', 'MESH:D019788', (6, 9))	('cholangiocarcinoma', 'Disease', (111, 129))	('diagnostic performance', 'MPA', (51, 73))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 129))	('FDG PET/CT', 'Var', (6, 16))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))	('patient', 'Species', '9606', (91, 98))
155203	27651736	Although our study is limited by the small number of patients with FDG PET/CT prior to treatment, our data indicate that FDG PET/CT directly influenced management decisions in three out of six patients who were evaluated prior to initiation of treatment.	('influenced', 'Reg', (141, 151))	('patients', 'Species', '9606', (193, 201))	('patients', 'Species', '9606', (53, 61))	('FDG', 'Chemical', 'MESH:D019788', (121, 124))	('management', 'MPA', (152, 162))	('FDG', 'Chemical', 'MESH:D019788', (67, 70))	('FDG PET/CT', 'Var', (121, 131))
155286	32616770	Photodynamic therapy and local tumor ablation could improve bile drainage and keep biliary patency and have been proposed to prolong a patient's survival.	('patient', 'Species', '9606', (135, 142))	('biliary patency', 'MPA', (83, 98))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('keep', 'PosReg', (78, 82))	('tumor', 'Disease', (31, 36))	('ablation', 'Var', (37, 45))	('prolong', 'PosReg', (125, 132))	('improve', 'PosReg', (52, 59))	('bile drainage', 'MPA', (60, 73))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
155328	31914150	When the survival pathway is inhibited, such as via depletion of cIAP1/2, TNF-alpha induces the formation of complex IIa, consisting of TRADD, FADD (Fas-associated death domain-containing protein), RIPK1, and procaspase-8, which leads to the activation of caspase-8 and apoptosis.	('inhibited', 'NegReg', (29, 38))	('caspase-8', 'Gene', '841', (256, 265))	('FADD', 'Gene', (143, 147))	('activation', 'PosReg', (242, 252))	('survival pathway', 'Pathway', (9, 25))	('apoptosis', 'CPA', (270, 279))	('depletion', 'Var', (52, 61))	('caspase-8', 'Gene', '841', (212, 221))	('Fas-associated death domain-containing protein', 'Gene', (149, 195))	('TNF-alpha', 'Gene', '7124', (74, 83))	('caspase-8', 'Gene', (256, 265))	('TNF-alpha', 'Gene', (74, 83))	('induces', 'Reg', (84, 91))	('FADD', 'Gene', '8772', (143, 147))	('cIAP1/2', 'Gene', (65, 72))	('RIPK1', 'Gene', (198, 203))	('caspase-8', 'Gene', (212, 221))	('cIAP1/2', 'Gene', '329;330', (65, 72))	('RIPK1', 'Gene', '8737', (198, 203))	('Fas-associated death domain-containing protein', 'Gene', '8772', (149, 195))
155342	31914150	The depletion of cIAP1 and cIAP2 also facilitates the stabilization of nuclear factor kappaB (NF-kB)-inducing kinase (NIK) and activation of noncanonical NF-kappaB signaling, resulting in autocrine secretion of TNF-alpha.	('NF-kappaB', 'Gene', '4790', (154, 163))	('depletion', 'Var', (4, 13))	('autocrine secretion', 'MPA', (188, 207))	('N', 'Chemical', 'MESH:D009584', (212, 213))	('NIK', 'Gene', (118, 121))	('stabilization', 'MPA', (54, 67))	('cIAP1', 'Gene', (17, 22))	('N', 'Chemical', 'MESH:D009584', (154, 155))	('TNF-alpha', 'Gene', '7124', (211, 220))	('cIAP2', 'Gene', (27, 32))	('TNF-alpha', 'Gene', (211, 220))	('NIK', 'Gene', '9020', (118, 121))	('cIAP1', 'Gene', '329', (17, 22))	('cIAP2', 'Gene', '330', (27, 32))	('activation', 'PosReg', (127, 137))	('facilitates', 'PosReg', (38, 49))	('NF-kappaB', 'Gene', (154, 163))	('N', 'Chemical', 'MESH:D009584', (118, 119))	('N', 'Chemical', 'MESH:D009584', (94, 95))
155343	31914150	Overexpression of IAPs has been commonly reported in many human malignancies and frequently contributes to drug resistance by promoting evasion of cell death.	('promoting', 'PosReg', (126, 135))	('malignancies', 'Disease', 'MESH:D009369', (64, 76))	('IAP', 'Gene', '961', (18, 21))	('malignancies', 'Disease', (64, 76))	('evasion of cell death', 'MPA', (136, 157))	('IAP', 'Gene', (18, 21))	('human', 'Species', '9606', (58, 63))	('drug resistance', 'Phenotype', 'HP:0020174', (107, 122))	('contributes to', 'Reg', (92, 106))	('Overexpression', 'Var', (0, 14))	('drug resistance', 'MPA', (107, 122))
155364	31914150	CRISPR plasmids targeting human RIPK1 (NM_003804) and human RIPK3 (NM_006871) were generated according to Zhang's protocol.	('human', 'Species', '9606', (54, 59))	('N', 'Chemical', 'MESH:D009584', (67, 68))	('RIPK3', 'Gene', '11035', (60, 65))	('NM_003804', 'Var', (39, 48))	('N', 'Chemical', 'MESH:D009584', (39, 40))	('NM_006871', 'Var', (67, 76))	('RIPK1', 'Gene', '8737', (32, 37))	('RIPK3', 'Gene', (60, 65))	('RIPK1', 'Gene', (32, 37))	('human', 'Species', '9606', (26, 31))
155367	31914150	To generate lentiviral particles, HEK293T were co-transfected with packaging plasmid (pCMV-VSV-G) and envelope plasmid (pCMV-dr8.2-dvpr) and either shRNA-non-targeting (shNT; pLKO.1puro) or shRNA-MLKL (shMLKL) or CRISPR-V2 or CRISPR-RIPK1 or CRISPR-RIPK3 plasmids.	('CRISPR-RIPK1', 'Gene', '8737', (226, 238))	('N', 'Chemical', 'MESH:D009584', (193, 194))	('MLKL', 'Gene', (196, 200))	('CRISPR-RIPK3', 'Gene', '11035', (242, 254))	('N', 'Chemical', 'MESH:D009584', (171, 172))	('CRISPR-RIPK3', 'Gene', (242, 254))	('MLKL', 'Gene', (204, 208))	('CRISPR-RIPK1', 'Gene', (226, 238))	('N', 'Chemical', 'MESH:D009584', (151, 152))	('MLKL', 'Gene', '197259', (204, 208))	('HEK293T', 'Var', (34, 41))	('HEK293T', 'CellLine', 'CVCL:0063', (34, 41))	('MLKL', 'Gene', '197259', (196, 200))
155373	31914150	Necroptosis was induced by TNF-alpha (10 ng/ml), Smac mimetic, SM-164 (10 nM) and zVAD-fmk (20 muM).	('induced', 'Reg', (16, 23))	('TNF-alpha', 'Gene', '7124', (27, 36))	('TNF-alpha', 'Gene', (27, 36))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('SM-164', 'Var', (63, 69))	('muM', 'Gene', '56925', (95, 98))	('N', 'Chemical', 'MESH:D009584', (28, 29))	('Necroptosis', 'CPA', (0, 11))	('muM', 'Gene', (95, 98))
155382	31914150	Briefly, cells were fixed with 70% ethanol, after washing the cells were resuspended in PBS with 0.25% Triton X, containing RNase A (100 mug/ml) and PI (50 mug/ml) for 30 min.	('100 mug/ml', 'Var', (133, 143))	('ethanol', 'Chemical', 'MESH:D000431', (35, 42))	('RNase A', 'Gene', (124, 131))	('Triton', 'Chemical', 'MESH:D011092', (103, 109))	('RNase A', 'Gene', '6035', (124, 131))
155414	31914150	The phosphorylation of MLKL was lower at 16 h when compared to the level at 8 h, probably due to the translocation of phosphorylated MLKL into the RIPA-insoluble pellet fraction.	('MLKL', 'Gene', (133, 137))	('phosphorylated', 'Var', (118, 132))	('phosphorylation', 'MPA', (4, 19))	('MLKL', 'Gene', '197259', (23, 27))	('translocation', 'MPA', (101, 114))	('MLKL', 'Gene', '197259', (133, 137))	('MLKL', 'Gene', (23, 27))	('lower', 'NegReg', (32, 37))
155417	31914150	RIPK1 (necrostatin-1, Nec-1), RIPK3 (GSK'872) and MLKL (necrosulfonamide, NSA) inhibitors significantly reduced TNF-alpha/Smac mimetic/zVAD-fmk-induced cell death (Fig 3B).	('N', 'Chemical', 'MESH:D009584', (74, 75))	('reduced', 'NegReg', (104, 111))	('RIPK1', 'Gene', (0, 5))	('RIPK3', 'Gene', '11035', (30, 35))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('necrosulfonamide', 'Chemical', 'MESH:C570695', (56, 72))	('inhibitors', 'Var', (79, 89))	('MLKL', 'Gene', (50, 54))	('RIPK3', 'Gene', (30, 35))	('MLKL', 'Gene', '197259', (50, 54))	('TNF-alpha', 'Gene', '7124', (112, 121))	('RIPK1', 'Gene', '8737', (0, 5))	('TNF-alpha', 'Gene', (112, 121))
155419	31914150	In addition to pharmacological inhibitors, CRISPR/cas9-mediated deletion of RIPK1 and RIPK3 and short hairpin RNA (shRNA) silencing of MLKL by two distinct shRNA sequences were used to create genetic knockout and knockdown models in KKU213 and RMCCA-1 cells.	('RIPK3', 'Gene', (86, 91))	('RIPK1', 'Gene', '8737', (76, 81))	('deletion', 'Var', (64, 72))	('MLKL', 'Gene', '197259', (135, 139))	('RIPK3', 'Gene', '11035', (86, 91))	('silencing', 'NegReg', (122, 131))	('RIPK1', 'Gene', (76, 81))	('MLKL', 'Gene', (135, 139))	('N', 'Chemical', 'MESH:D009584', (111, 112))	('N', 'Chemical', 'MESH:D009584', (159, 160))	('N', 'Chemical', 'MESH:D009584', (118, 119))
155421	31914150	Similarly, knockdown of MLKL almost completely reduced MLKL levels (Fig 3D).	('MLKL', 'Gene', '197259', (24, 28))	('MLKL', 'Gene', '197259', (55, 59))	('MLKL', 'Gene', (24, 28))	('MLKL', 'Gene', (55, 59))	('reduced', 'NegReg', (47, 54))	('knockdown', 'Var', (11, 20))
155422	31914150	Consistent with the results with pharmacological inhibitors, knockout of RIPK1 and RIPK3 or knockdown of MLKL rendered the cells resistant to TNF-alpha/Smac mimetic/zVAD-fmk-induced cell death (Fig 3C and 3D).	('RIPK3', 'Gene', (83, 88))	('TNF-alpha', 'Gene', '7124', (142, 151))	('RIPK1', 'Gene', '8737', (73, 78))	('knockdown', 'Var', (92, 101))	('RIPK3', 'Gene', '11035', (83, 88))	('resistant', 'CPA', (129, 138))	('knockout', 'Var', (61, 69))	('TNF-alpha', 'Gene', (142, 151))	('cell death', 'CPA', (182, 192))	('MLKL', 'Gene', '197259', (105, 109))	('RIPK1', 'Gene', (73, 78))	('MLKL', 'Gene', (105, 109))
155426	31914150	Accumulating evidence shows that small molecules that antagonize IAPs, Smac mimetics, greatly increase chemotherapy response to both apoptosis and necroptosis in cancer cells, although necroptosis has been far less examined.	('IAP', 'Gene', '961', (65, 68))	('chemotherapy', 'MPA', (103, 115))	('antagonize', 'Var', (54, 64))	('increase', 'PosReg', (94, 102))	('necroptosis in cancer', 'Disease', (147, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('necroptosis in cancer', 'Disease', 'MESH:D009369', (147, 168))	('IAP', 'Gene', (65, 68))
155434	31914150	Although key necroptotic proteins were dispensable for gemcitabine-induced cell death (S7 Fig), knockout of RIPK1 and RIPK3 and knockdown of MLKL reduced gemcitabine and Smac mimetic-induced cell death when caspases were inhibited to the level of cell death seen with single-agent gemcitabine treatment (Fig 4B and 4C).	('gemcitabine', 'Chemical', 'MESH:C056507', (281, 292))	('RIPK1', 'Gene', '8737', (108, 113))	('knockdown', 'Var', (128, 137))	('MLKL', 'Gene', '197259', (141, 145))	('reduced', 'NegReg', (146, 153))	('gemcitabine', 'Chemical', 'MESH:C056507', (55, 66))	('RIPK3', 'Gene', '11035', (118, 123))	('RIPK3', 'Gene', (118, 123))	('MLKL', 'Gene', (141, 145))	('gemcitabine', 'Chemical', 'MESH:C056507', (154, 165))	('RIPK1', 'Gene', (108, 113))	('knockout', 'Var', (96, 104))	('caspases', 'Gene', (207, 215))	('caspases', 'Gene', '841', (207, 215))
155469	31914150	Via in vivo deletion of RIPK3, the researchers of the study in PDA further indicated that necroptosis was a driver of PDA oncogenesis and progression.	('deletion', 'Var', (12, 20))	('RIPK3', 'Gene', (24, 29))	('RIPK3', 'Gene', '11035', (24, 29))	('PDA', 'Disease', (118, 121))
155471	31914150	Targeting necroptosis as a novel therapeutic approach to overcome therapeutic failure in cancers has become very important, as growing evidence suggests that targeting this novel cell death pathway, so-called immunogenic cell death (ICD), has the dual benefits of killing tumor cells and inducing antitumor immunity, as demonstrated in colon cancer and melanoma models.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('colon cancer', 'Phenotype', 'HP:0003003', (336, 348))	('inducing', 'PosReg', (288, 296))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('failure', 'Disease', 'MESH:D017093', (78, 85))	('cancers', 'Disease', (89, 96))	('melanoma', 'Disease', 'MESH:D008545', (353, 361))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', (272, 277))	('colon cancer', 'Disease', 'MESH:D015179', (336, 348))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('ICD', 'Disease', (233, 236))	('failure', 'Disease', (78, 85))	('targeting', 'Var', (158, 167))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('melanoma', 'Phenotype', 'HP:0002861', (353, 361))	('melanoma', 'Disease', (353, 361))	('ICD', 'Disease', 'OMIM:252500', (233, 236))	('colon cancer', 'Disease', (336, 348))	('tumor', 'Disease', (301, 306))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (301, 306))
155501	31914150	Because Smac mimetics such as LCL161 and DEBIO1143 are currently being investigated in clinical trials as monotherapy or in combination with chemotherapeutic drugs, our findings could lead to a novel potential therapeutic approach to improve the efficacy and decrease the side effects of gemcitabine for CCA patients.	('DEBIO1143', 'Var', (41, 50))	('clinical', 'Species', '191496', (87, 95))	('efficacy', 'MPA', (246, 254))	('gemcitabine', 'Chemical', 'MESH:C056507', (288, 299))	('patients', 'Species', '9606', (308, 316))	('CCA', 'Disease', (304, 307))	('improve', 'PosReg', (234, 241))	('LCL161', 'Var', (30, 36))	('DEBIO1143', 'Chemical', 'MESH:C559144', (41, 50))	('side effects', 'MPA', (272, 284))	('decrease', 'NegReg', (259, 267))
155538	31914150	More citations are added in result section, line 325 and in discussion section, line 449 (Ref 56, 57, 58, 59) Reviewer #2 (Remarks to the Author): This manuscript presents data demonstrating that necroptosis can be induced to kill CCA cell lines providing they have not silenced the expression of RIPK3, and that concurrent addition of Smac mimetic can produce additional cell death to that induced by conventional CCA chemotherapeutic gemcitabine.	('necroptosis', 'MPA', (196, 207))	('gemcitabine', 'Chemical', 'MESH:C056507', (436, 447))	('RIPK3', 'Gene', (297, 302))	('silenced', 'Var', (270, 278))	('cell death', 'CPA', (372, 382))	('RIPK3', 'Gene', '11035', (297, 302))
155556	31251815	Deletion of ITPR3 from CCA cells impaired proliferation and cell migration.	('cell migration', 'CPA', (60, 74))	('proliferation', 'CPA', (42, 55))	('impaired', 'NegReg', (33, 41))	('ITPR3', 'Gene', '3710', (12, 17))	('ITPR3', 'Gene', (12, 17))	('Deletion', 'Var', (0, 8))
155559	31251815	Deletion of ITPR3 from these cells impaired mitochondrial Ca2+ signaling and led to cell death.	('death', 'Disease', 'MESH:D003643', (89, 94))	('death', 'Disease', (89, 94))	('Ca2', 'Gene', '760', (58, 61))	('ITPR3', 'Gene', '3710', (12, 17))	('led to', 'Reg', (77, 83))	('ITPR3', 'Gene', (12, 17))	('impaired', 'NegReg', (35, 43))	('Ca2', 'Gene', (58, 61))	('Deletion', 'Var', (0, 8))
155568	31251815	A mutation in the ITPR3 gene was identified in the genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (97, 134))	('ITPR3', 'Gene', (18, 23))	('mutation', 'Var', (2, 10))	('neck squamous cell carcinoma', 'Disease', (106, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (106, 134))	('ITPR3', 'Gene', '3710', (18, 23))
155591	31251815	Consistent with the histological and quantitative immunofluorescence findings in CCA patients, ITPR3 expression was higher in MzCha1 and HuCCA1 cells than in cells derived from normal cholangiocytes (Figures 1D and 1E), although ITPR3 expression was more variable in HuCCT1 and TFK-1 cells (Supporting Figure S2).	('MzCha1', 'Var', (126, 132))	('higher', 'PosReg', (116, 122))	('CCA', 'Disease', (81, 84))	('ITPR3', 'Gene', (229, 234))	('ITPR3', 'Gene', '3710', (229, 234))	('patients', 'Species', '9606', (85, 93))	('expression', 'MPA', (101, 111))	('ITPR3', 'Gene', '3710', (95, 100))	('ITPR3', 'Gene', (95, 100))	('HuCCA1', 'CellLine', 'CVCL:M255', (137, 143))
155595	31251815	To examine the role of ITPR3 in proliferation and migration of CCA cells, the CRISPR/Cas9 system was used to knockout ITPR3 in both MzCha1 and HuCCA1 cells (Figure 2A and Supporting Figure S3A).	('HuCCA1', 'CellLine', 'CVCL:M255', (143, 149))	('knockout', 'Var', (109, 117))	('ITPR3', 'Gene', '3710', (118, 123))	('ITPR3', 'Gene', (118, 123))	('ITPR3', 'Gene', '3710', (23, 28))	('ITPR3', 'Gene', (23, 28))
155615	31251815	Calcium signals may be increased not only as a result of increased ITPR expression but also because of increased channel activity, and O-linked glycosylation enhances calcium release from ITPR3.	('increased', 'PosReg', (103, 112))	('ITPR3', 'Gene', '3710', (188, 193))	('expression', 'MPA', (72, 82))	('O-linked glycosylation', 'Var', (135, 157))	('Calcium signals', 'MPA', (0, 15))	('channel activity', 'MPA', (113, 129))	('calcium', 'Chemical', 'MESH:D002118', (167, 174))	('enhances', 'PosReg', (158, 166))	('increased', 'PosReg', (23, 32))	('increased', 'PosReg', (57, 66))	('Calcium', 'Chemical', 'MESH:D002118', (0, 7))	('ITPR3', 'Gene', (188, 193))	('ITPR', 'Gene', (67, 71))	('calcium release', 'MPA', (167, 182))
155621	31251815	Bioinformatic analysis identified six genes from the TCGA cholangiocarcinoma dataset that were significantly affected by loss of ITPR3 in NHC cells (Supporting Table 1).	('NHC', 'Gene', '10473', (138, 141))	('cholangiocarcinoma', 'Disease', (58, 76))	('loss', 'Var', (121, 125))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 76))	('ITPR3', 'Gene', '3710', (129, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('ITPR3', 'Gene', (129, 134))	('NHC', 'Gene', (138, 141))	('affected', 'Reg', (109, 117))
155644	31251815	Mitochondria Ca2+ stimulates aerobic metabolism, so the effects of ITPR3 on mitochondrial metabolic state also were examined.	('aerobic metabolism', 'MPA', (29, 47))	('ITPR3', 'Gene', '3710', (67, 72))	('Ca2', 'Gene', '760', (13, 16))	('ITPR3', 'Gene', (67, 72))	('Mitochondria', 'Var', (0, 12))	('stimulates', 'PosReg', (18, 28))	('Ca2', 'Gene', (13, 16))
155645	31251815	There was no difference in mitochondrial membrane potential between control and ITPR3-KO-MzCha1 cells, as measured by the fluorescent indicator dye JC-1 (Supporting Figure S10A).	('mitochondrial membrane potential', 'MPA', (27, 59))	('ITPR3', 'Gene', '3710', (80, 85))	('ITPR3', 'Gene', (80, 85))	('S10A', 'Var', (172, 176))	('S10A', 'SUBSTITUTION', 'None', (172, 176))
155646	31251815	However, there was a small but significant increase in basal respiratory rate in control cells relative to ITPR3-KO-MzCha1 cells (Supporting Figure S10B), which likely is driven by the increased mitochondrial calcium transmitted by ITPR3.	('ITPR3', 'Gene', (107, 112))	('ITPR3', 'Gene', '3710', (107, 112))	('S10B', 'SUBSTITUTION', 'None', (148, 152))	('calcium', 'Chemical', 'MESH:D002118', (209, 216))	('ITPR3', 'Gene', '3710', (232, 237))	('basal respiratory rate', 'MPA', (55, 77))	('increase', 'PosReg', (43, 51))	('ITPR3', 'Gene', (232, 237))	('mitochondrial', 'MPA', (195, 208))	('S10B', 'Var', (148, 152))
155649	31251815	Cytosolic calcium signals were detected in the majority of MzCha1 cells stimulated with ATP, but this was blocked in nearly all cells pre-treated with the ITPR inhibitor Xestospongin C (P < 0.05; Supporting Figure S11A), confirming that ATP-induced calcium signals are mediated by IP3/ITPR.	('S11A', 'SUBSTITUTION', 'None', (214, 218))	('ATP', 'Chemical', 'MESH:D000255', (88, 91))	('Xestospongin C', 'Chemical', 'MESH:C511704', (170, 184))	('calcium', 'Chemical', 'MESH:D002118', (249, 256))	('ATP', 'Chemical', 'MESH:D000255', (237, 240))	('Cytosolic calcium signals', 'MPA', (0, 25))	('MzCha1', 'Gene', (59, 65))	('IP3', 'Chemical', 'MESH:D015544', (281, 284))	('S11A', 'Var', (214, 218))	('calcium', 'Chemical', 'MESH:D002118', (10, 17))
155650	31251815	MzCha1 control cells were slightly more sensitive than ITPR3-KO cells to ATP, but there was no difference in the amplitude of calcium signals among responding cells (Supporting Figure S11B).	('ITPR3', 'Gene', '3710', (55, 60))	('ITPR3', 'Gene', (55, 60))	('ATP', 'Chemical', 'MESH:D000255', (73, 76))	('calcium', 'Chemical', 'MESH:D002118', (126, 133))	('S11B', 'SUBSTITUTION', 'None', (184, 188))	('S11B', 'Var', (184, 188))
155651	31251815	There also was no difference in expression levels of other calcium-dependent proteins (NFATc1-4, calcineurins A-C, SERCA2, and calmodulin 1) between control and ITPR3-KO cells (Supporting Figure S11C).	('SERCA2', 'Gene', '488', (115, 121))	('S11C', 'SUBSTITUTION', 'None', (195, 199))	('calmodulin 1', 'Gene', (127, 139))	('ITPR3', 'Gene', '3710', (161, 166))	('ITPR3', 'Gene', (161, 166))	('expression', 'MPA', (32, 42))	('calcium', 'Chemical', 'MESH:D002118', (59, 66))	('S11C', 'Var', (195, 199))	('SERCA2', 'Gene', (115, 121))	('calmodulin 1', 'Gene', '801', (127, 139))
155659	31251815	Similarly, loss of ITPR3 decreased the percentage of healthy HuCCA1 cells from 92.0 +- 1.0% in controls to 68.0 +- 1.6% in ITPR3-KO cells (P < 0.0001).	('ITPR3', 'Gene', (123, 128))	('loss', 'Var', (11, 15))	('decreased', 'NegReg', (25, 34))	('ITPR3', 'Gene', '3710', (19, 24))	('ITPR3', 'Gene', (19, 24))	('HuCCA1', 'CellLine', 'CVCL:M255', (61, 67))	('ITPR3', 'Gene', '3710', (123, 128))
155660	31251815	In these cells, deletion of ITPR3 increased the percentage in both late apoptosis (6.1 +- 0.5% in control HuCCA1 cells versus 9.9 +- 1.4% in ITPR3-KO-HuCCA1, P < 0.05) and necrosis (0.6 +- 0.1% in control HuCCA1 versus 19.0 +- 1.1% in ITPR3-KO-HuCCA1, P < 0.0001) (Figures 6C and 6D).	('necrosis', 'Disease', (172, 180))	('ITPR3', 'Gene', '3710', (141, 146))	('ITPR3', 'Gene', '3710', (28, 33))	('ITPR3', 'Gene', (141, 146))	('deletion', 'Var', (16, 24))	('HuCCA1', 'CellLine', 'CVCL:M255', (244, 250))	('ITPR3', 'Gene', (235, 240))	('necrosis', 'Disease', 'MESH:D009336', (172, 180))	('ITPR3', 'Gene', '3710', (235, 240))	('HuCCA1', 'CellLine', 'CVCL:M255', (205, 211))	('late apoptosis', 'CPA', (67, 81))	('increased', 'PosReg', (34, 43))	('HuCCA1', 'CellLine', 'CVCL:M255', (150, 156))	('HuCCA1', 'CellLine', 'CVCL:M255', (106, 112))	('ITPR3', 'Gene', (28, 33))
155674	31251815	Loss of ITPR3 then leads to cell death largely due to necrosis, with lesser contributions from autophagy, senescence and apoptosis.	('death', 'Disease', (33, 38))	('necrosis', 'Disease', 'MESH:D009336', (54, 62))	('ITPR3', 'Gene', '3710', (8, 13))	('ITPR3', 'Gene', (8, 13))	('necrosis', 'Disease', (54, 62))	('Loss', 'Var', (0, 4))	('death', 'Disease', 'MESH:D003643', (33, 38))
155684	31251815	Second, epigenetic factors such as demethylation play a well-known role in expression of a variety of oncogenes, but it is not yet known if this contributes to increased expression of ITPR3.	('demethylation', 'Var', (35, 48))	('ITPR3', 'Gene', '3710', (184, 189))	('increased', 'PosReg', (160, 169))	('ITPR3', 'Gene', (184, 189))	('expression', 'MPA', (75, 85))	('expression', 'MPA', (170, 180))
155687	31251815	Finally, ITPR3 is degraded in part by ubiquitination, so modulation of this pathway could also contribute to altered cellular ITPR3 expression.	('ubiquitination', 'MPA', (38, 52))	('contribute', 'Reg', (95, 105))	('ITPR3', 'Gene', '3710', (9, 14))	('ITPR3', 'Gene', (9, 14))	('expression', 'MPA', (132, 142))	('modulation', 'Var', (57, 67))	('altered', 'Reg', (109, 116))	('ITPR3', 'Gene', '3710', (126, 131))	('ITPR3', 'Gene', (126, 131))
155688	31251815	Indeed, abnormal expression of tumor suppressors that modify this degradation pathway, including BAP1 and PTEN, has been linked to altered ITPR3 and resulting tumor development in several types of malignancies.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('BAP1', 'Gene', '8314', (97, 101))	('linked', 'Reg', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('ITPR3', 'Gene', (139, 144))	('tumor', 'Disease', (31, 36))	('expression', 'MPA', (17, 27))	('ITPR3', 'Gene', '3710', (139, 144))	('abnormal', 'Var', (8, 16))	('BAP1', 'Gene', (97, 101))	('altered', 'Var', (131, 138))	('tumor', 'Disease', (159, 164))	('PTEN', 'Gene', (106, 110))	('PTEN', 'Gene', '5728', (106, 110))	('malignancies', 'Disease', 'MESH:D009369', (197, 209))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('malignancies', 'Disease', (197, 209))
155690	31251815	In each of these cases, however, a decrease rather than an increase in ITPR3 or its activity is thought to contribute to neoplasia, because loss of ITPR3 from MAMs can sometimes decrease apoptosis of cancer cells.	('MAM', 'Gene', '6445', (159, 162))	('ITPR3', 'Gene', '3710', (148, 153))	('ITPR3', 'Gene', (148, 153))	('neoplasia', 'Phenotype', 'HP:0002664', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('decrease', 'NegReg', (178, 186))	('neoplasia', 'Disease', 'MESH:D009369', (121, 130))	('ITPR3', 'Gene', '3710', (71, 76))	('MAM', 'Gene', (159, 162))	('ITPR3', 'Gene', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))	('neoplasia', 'Disease', (121, 130))	('loss', 'Var', (140, 144))
155693	31251815	The current findings that ITPR3 localizes to MAMs and is responsible for mitochondrial calcium signals, and loss of ITPR3 results in necrotic cell death, suggests that this mechanism may occur in CCA as well.	('necrotic cell death', 'Disease', (133, 152))	('calcium', 'Chemical', 'MESH:D002118', (87, 94))	('loss', 'Var', (108, 112))	('mitochondrial calcium signals', 'MPA', (73, 102))	('results in', 'Reg', (122, 132))	('necrotic cell death', 'Disease', 'MESH:D003643', (133, 152))	('ITPR3', 'Gene', '3710', (116, 121))	('MAM', 'Gene', (45, 48))	('ITPR3', 'Gene', (26, 31))	('ITPR3', 'Gene', (116, 121))	('ITPR3', 'Gene', '3710', (26, 31))	('CCA', 'Disease', (196, 199))	('MAM', 'Gene', '6445', (45, 48))
155695	31251815	Although loss of ITPR2 contributes to canalicular cholestasis, mis-localization of ITPR2 can contribute as well, and occurs in clinical conditions such as estrogen- or endotoxin-induced cholestasis, or in situations in which lipid rafts in the apical membrane are disrupted.	('cholestasis', 'Disease', (186, 197))	('ITPR2', 'Gene', '3709', (83, 88))	('ITPR2', 'Gene', '3709', (17, 22))	('cholestasis', 'Disease', 'MESH:D002779', (186, 197))	('cholestasis', 'Disease', (50, 61))	('ITPR2', 'Gene', (17, 22))	('cholestasis', 'Phenotype', 'HP:0001396', (186, 197))	('cholestasis', 'Phenotype', 'HP:0001396', (50, 61))	('ITPR2', 'Gene', (83, 88))	('loss', 'Var', (9, 13))	('lipid', 'Chemical', 'MESH:D008055', (225, 230))	('estrogen-', 'Disease', (155, 164))	('occurs', 'Reg', (117, 123))	('mis-localization', 'Var', (63, 79))	('cholestasis', 'Disease', 'MESH:D002779', (50, 61))
155748	31921856	These bipotent epithelial liver organoids could be differentiated into mature and functional hepatocytes in vitro and could rescue liver failure in the fumarylacetoacetate hydrolase (Fah-/-) mutant mouse, a model for tyrosinemia type I liver disease, after transplantation.	('tyrosinemia type I liver disease', 'Disease', (217, 249))	('fumarylacetoacetate hydrolase', 'Gene', (152, 181))	('liver failure', 'Phenotype', 'HP:0001399', (131, 144))	('liver failure', 'Disease', 'MESH:D017093', (131, 144))	('liver failure', 'Disease', (131, 144))	('liver disease', 'Phenotype', 'HP:0001392', (236, 249))	('tyrosinemia', 'Phenotype', 'HP:0003231', (217, 228))	('tyrosinemia type I liver disease', 'Disease', 'MESH:D020176', (217, 249))	('mutant', 'Var', (191, 197))	('Fah', 'Gene', '14085', (183, 186))	('fumarylacetoacetate hydrolase', 'Gene', '14085', (152, 181))	('mouse', 'Species', '10090', (198, 203))	('Fah', 'Gene', (183, 186))
155752	31921856	Although Huch's model elegantly demonstrated that the ductal progenitors had the capacity to generate hepatocytes under defined culture conditions and Raven and collaborators have more recently shown that impaired hepatocellular regeneration during liver injury could trigger ductular reaction and the generation of hepatocytes of non-hepatocyte origin, there is an ongoing controversy surrounding studies that demonstrated that the majority of regenerative response following hepatic damage rely primarily on hepatocytes rather than stem cells.	('Raven', 'Species', '56781', (151, 156))	('liver injury', 'Disease', (249, 261))	('hepatic damage', 'Disease', (477, 491))	('liver injury', 'Disease', 'MESH:D056486', (249, 261))	('ductular reaction', 'CPA', (276, 293))	('hepatic damage', 'Disease', 'MESH:D056486', (477, 491))	('impaired', 'Var', (205, 213))	('trigger', 'Reg', (268, 275))
155756	31921856	Likewise, periportal and hybrid hepatocytes with low levels of SOX9 expression replenished the liver mass after chronic injury.	('liver mass', 'MPA', (95, 105))	('SOX9', 'Gene', (63, 67))	('low levels', 'Var', (49, 59))	('chronic injury', 'Disease', (112, 126))	('SOX9', 'Gene', '6662', (63, 67))	('chronic injury', 'Disease', 'MESH:D020208', (112, 126))	('replenished', 'PosReg', (79, 90))
155782	31921856	The most common genetic missense mutation in A1ATD is the PiZ allele (Glu342Lys) of the SERPINA1 gene, which results in the agglomeration of misfolded proteins in hepatocytes.	('missense', 'Var', (24, 32))	('Glu342Lys', 'Mutation', 'rs28929474', (70, 79))	('SERPINA1', 'Gene', (88, 96))	('A1AT', 'Gene', '5265', (45, 49))	('results in', 'Reg', (109, 119))	('Glu342Lys', 'Var', (70, 79))	('A1AT', 'Gene', (45, 49))	('A1ATD', 'Phenotype', 'HP:0032025', (45, 50))	('agglomeration of misfolded proteins', 'MPA', (124, 159))	('SERPINA1', 'Gene', '5265', (88, 96))
155786	31921856	Of note, ALGS has autosomal dominant inheritance and is predominantly caused by heterozygous mutations in the JAG1 gene, which codes for the Jagged1 protein, a transmembrane ligand in the Notch signaling pathway.	('mutations', 'Var', (93, 102))	('caused', 'Reg', (70, 76))	('JAG1', 'Gene', (110, 114))	('ALGS', 'Disease', 'MESH:D016738', (9, 13))	('Jagged1', 'Gene', '182', (141, 148))	('ALGS', 'Disease', (9, 13))	('Jagged1', 'Gene', (141, 148))
155791	31921856	In addition, using a reverse approach employing CRISPR-Cas9 technology, ALGS-causing JAG1 mutation C829X was introduced into iPSCs prepared from healthy human fibroblasts.	('JAG1', 'Gene', (85, 89))	('C829X', 'Var', (99, 104))	('C829X', 'Mutation', 'p.C829X', (99, 104))	('ALGS', 'Disease', 'MESH:D016738', (72, 76))	('human', 'Species', '9606', (153, 158))	('ALGS', 'Disease', (72, 76))
155793	31921856	Citrullinemia type I (CTLN1) is an inherited urea cycle disorder of the liver arising from a deficiency in the enzyme Argininosuccinate Synthase 1 (ASS1).	('ASS1', 'Gene', (148, 152))	('Citrullinemia type I', 'Disease', 'MESH:D020159', (0, 20))	('ASS1', 'Gene', '445', (148, 152))	('Argininosuccinate Synthase 1', 'Gene', '445', (118, 146))	('CTLN1', 'Gene', '445', (22, 27))	('urea cycle disorder', 'Disease', 'MESH:D056806', (45, 64))	('urea cycle disorder', 'Disease', (45, 64))	('Argininosuccinate Synthase 1', 'Gene', (118, 146))	('urea cycle disorder', 'Phenotype', 'HP:0000816', (45, 64))	('Citrullinemia type I', 'Disease', (0, 20))	('deficiency', 'Var', (93, 103))	('CTLN1', 'Gene', (22, 27))	('disorder of the liver', 'Phenotype', 'HP:0001392', (56, 77))
155796	31921856	Recently, iPSCs derived from Citrullinemia type I patients with homozygous G390R mutations in the ASS1 gene have been used to develop a disease-specific model.	('G390R', 'Var', (75, 80))	('patients', 'Species', '9606', (50, 58))	('Citrullinemia type I', 'Disease', (29, 49))	('ASS1', 'Gene', (98, 102))	('G390R', 'Mutation', 'rs121908641', (75, 80))	('Citrullinemia type I', 'Disease', 'MESH:D020159', (29, 49))	('ASS1', 'Gene', '445', (98, 102))
155800	31921856	Moreover, these phenotypes could be rescued by ectopic expression of the wild-type ASS1 gene in patient-derived organoids.	('ASS1', 'Gene', (83, 87))	('ectopic expression', 'Var', (47, 65))	('ASS1', 'Gene', '445', (83, 87))	('patient', 'Species', '9606', (96, 103))
155803	31921856	CF is a life-threatening rare autosomal recessive disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene.	('CF', 'Disease', 'MESH:D003550', (139, 141))	('mutations', 'Var', (69, 78))	('autosomal recessive disorder', 'Disease', (30, 58))	('CFTR', 'Gene', '1080', (139, 143))	('Cystic Fibrosis Transmembrane Conductance Regulator', 'Gene', '1080', (86, 137))	('CF', 'Disease', 'MESH:D003550', (0, 2))	('caused by', 'Reg', (59, 68))	('CFTR', 'Gene', (139, 143))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (30, 58))
155804	31921856	Mutations in the CFTR gene disrupt the function of the chloride ion channel, causing dysregulation of ion flux and epithelial fluid transport in the lung, pancreas, colon, and liver.	('epithelial fluid transport', 'MPA', (115, 141))	('chloride ion channel', 'MPA', (55, 75))	('chloride', 'Chemical', 'MESH:D002712', (55, 63))	('disrupt', 'NegReg', (27, 34))	('CFTR', 'Gene', (17, 21))	('dysregulation', 'MPA', (85, 98))	('Mutations', 'Var', (0, 9))	('causing', 'Reg', (77, 84))	('CFTR', 'Gene', '1080', (17, 21))	('function', 'MPA', (39, 47))
155805	31921856	In this study, Chol-org derived from iPSCs displayed misfolded CFTR proteins, impaired cyst formation, and loss of chloride channel function, reflecting the disease phenotype of the patients.	('CFTR', 'Gene', '1080', (63, 67))	('cyst', 'MPA', (87, 91))	('loss', 'NegReg', (107, 111))	('chloride', 'Chemical', 'MESH:D002712', (115, 123))	('misfolded', 'Var', (53, 62))	('CFTR', 'Gene', (63, 67))	('impaired', 'NegReg', (78, 86))	('chloride channel function', 'MPA', (115, 140))	('patients', 'Species', '9606', (182, 190))
155806	31921856	Furthermore, they showed that exposure of the organoids to a small-molecule CFTR potentiator drug VX-770 (Ivacaftor) along with forskolin and IBMX corrected the misfolding defect and led to the functional restoration of the mutant CFTR protein.	('mutant', 'Var', (224, 230))	('CFTR', 'Gene', '1080', (76, 80))	('CFTR', 'Gene', '1080', (231, 235))	('restoration', 'PosReg', (205, 216))	('protein', 'Protein', (236, 243))	('CFTR', 'Gene', (76, 80))	('functional', 'MPA', (194, 204))	('forskolin', 'Chemical', 'MESH:D005576', (128, 137))	('misfolding defect', 'MPA', (161, 178))	('CFTR', 'Gene', (231, 235))
155814	31921856	For instance, when passaged for long periods in 2D culture, the cancer cell lines accumulate mutations and undergo clonal selection, which results in loss of original genetic and phenotypic heterogeneity.	('mutations', 'Var', (93, 102))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('loss', 'NegReg', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
155832	31921856	Organoids derived from normal tissues can also be used to model cancer by sequential introduction of cancer driver gene mutations.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
155833	31921856	To this end, different laboratories have independently engineered mutant colon organoids by incorporating mutations for at least four of the most commonly altered genes in colorectal carcinoma, namely KRAS, APC, TP53, SMAD4, and PIK3CA.	('incorporating', 'Reg', (92, 105))	('APC', 'Disease', (207, 210))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (172, 192))	('KRAS', 'Gene', (201, 205))	('SMAD4', 'Gene', (218, 223))	('PIK3CA', 'Gene', '5290', (229, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('KRAS', 'Gene', '3845', (201, 205))	('mutations', 'Var', (106, 115))	('SMAD4', 'Gene', '4089', (218, 223))	('APC', 'Disease', 'MESH:D011125', (207, 210))	('colorectal carcinoma', 'Disease', (172, 192))	('TP53', 'Gene', '7157', (212, 216))	('PIK3CA', 'Gene', (229, 235))	('TP53', 'Gene', (212, 216))
155834	31921856	These mutant organoids developed adenocarcinomas when transplanted into the kidney capsule of recipient mice, modeling the progression of colon cancer.	('colon cancer', 'Disease', (138, 150))	('mutant', 'Var', (6, 12))	('adenocarcinomas', 'Disease', (33, 48))	('mice', 'Species', '10090', (104, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('colon cancer', 'Phenotype', 'HP:0003003', (138, 150))	('colon cancer', 'Disease', 'MESH:D015179', (138, 150))	('adenocarcinomas', 'Disease', 'MESH:D000230', (33, 48))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
155845	31921856	Notably, HBV infection resulted in severe hepatic dysfunction of organoids, characterized by elevated hepatic injury markers and an altered hepatic ultrastructure.	('hepatic dysfunction', 'Phenotype', 'HP:0001410', (42, 61))	('hepatic dysfunction', 'Disease', 'MESH:D008107', (42, 61))	('hepatic ultrastructure', 'MPA', (140, 162))	('HBV', 'Disease', (9, 12))	('altered', 'Reg', (132, 139))	('HBV', 'Disease', 'MESH:D006509', (9, 12))	('infection', 'Var', (13, 22))	('elevated hepatic injury', 'Disease', 'MESH:D056486', (93, 116))	('hepatic dysfunction', 'Disease', (42, 61))	('elevated hepatic injury', 'Disease', (93, 116))
155848	31921856	Recently, Huch's team has predicted novel drug targets for liver cancer patients by studying the omic profiles of tumoroids and showed that ERK inhibitors could decrease tumor formation in patient-derived xenograft models.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('liver cancer', 'Phenotype', 'HP:0002896', (59, 71))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('liver cancer', 'Disease', 'MESH:D006528', (59, 71))	('decrease', 'NegReg', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('liver cancer', 'Disease', (59, 71))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', (170, 175))	('inhibitors', 'Var', (144, 154))	('ERK', 'Gene', '5594', (140, 143))	('patient', 'Species', '9606', (72, 79))	('patient', 'Species', '9606', (189, 196))	('ERK', 'Gene', (140, 143))	('patients', 'Species', '9606', (72, 80))
155873	31921856	Targeted gene therapy has been used with great success to repair or inactivate mutations of genetic diseases in animal or in vitro cell culture models.	('inactivate', 'NegReg', (68, 78))	('genetic diseases', 'Disease', 'MESH:D030342', (92, 108))	('genetic diseases', 'Disease', (92, 108))	('mutations', 'Var', (79, 88))
155876	31921856	As an example, a disease-causing mutation has recently been reverted to wild-type via CRISPR-Cas9 in patient-derived organoids from Alagille syndrome, and the phenotype of the disease was successfully rescued in vitro.	('CRISPR-Cas9', 'Gene', (86, 97))	('mutation', 'Var', (33, 41))	('Alagille syndrome', 'Disease', (132, 149))	('Alagille syndrome', 'Disease', 'MESH:D016738', (132, 149))	('patient', 'Species', '9606', (101, 108))
155898	27729636	Related genetic alterations are polycystic kidney disease (PKD)1 and PKD2 mutations in ADPKD and protein kinase C substrate 80K-H (PRKCSH) or the SEC63 mutation in 20% of PCLD cases.	('PKD', 'Disease', (89, 92))	('PRKCSH', 'Gene', '5589', (131, 137))	('PKD', 'Disease', 'MESH:C537180', (89, 92))	('PRKCSH', 'Gene', (131, 137))	('SEC63', 'Gene', (146, 151))	('PCLD', 'Disease', (171, 175))	('SEC63', 'Gene', '11231', (146, 151))	('ADPKD', 'Disease', 'MESH:D007690', (87, 92))	('PCLD', 'Disease', 'None', (171, 175))	('protein kinase C substrate 80K-H', 'Gene', (97, 129))	('polycystic kidney disease', 'Disease', 'MESH:D007690', (32, 57))	('kidney disease', 'Phenotype', 'HP:0000112', (43, 57))	('polycystic kidney', 'Phenotype', 'HP:0000113', (32, 49))	('PKD', 'Disease', (69, 72))	('protein kinase C substrate 80K-H', 'Gene', '5589', (97, 129))	('PKD', 'Disease', 'MESH:C537180', (69, 72))	('PKD2', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('PKD', 'Disease', 'MESH:C537180', (59, 62))	('PKD', 'Disease', (59, 62))	('ADPKD', 'Disease', (87, 92))	('polycystic kidney disease', 'Disease', (32, 57))	('PKD2', 'Gene', '5311', (69, 73))
155903	27729636	The potential role of VMC as a preneoplastic lesion for ICC are based on several studies that have reported ICC arising from VMCs, suggesting malignant transformation from VMC to ICC, ICC having histopathologic similarities with VMC or DPM, and histologic similarity of ICC and VMC in K-ras and p53 mutated animal models inducing ICC.	('p53', 'Gene', '7157', (295, 298))	('K-ras', 'Gene', (285, 290))	('mutated', 'Var', (299, 306))	('K-ras', 'Gene', '3845', (285, 290))	('inducing', 'Reg', (321, 329))	('p53', 'Gene', (295, 298))	('ICC', 'Disease', (330, 333))
155930	27729636	Histologic features implying an invasive phenotype or high proliferative activity in cells, such as an irregularity of the glandular border, fusion of glands, stratification of epithelial cells, pleomorphisms of cholangiocytes, hyperchomasia of nuclei, or necrotic debri in the glandular lumen, are also identified in exaggerated VMCs, ductular reactions, or bile duct adenomas.	('hyperchomasia', 'Disease', (228, 241))	('necrotic debri', 'Disease', (256, 270))	('pleomorphisms', 'Var', (195, 208))	('bile duct adenomas', 'Disease', 'MESH:D002759', (359, 377))	('necrotic debri', 'Disease', 'MESH:C536356', (256, 270))	('bile duct adenomas', 'Disease', (359, 377))	('exaggerated VMCs', 'Disease', (318, 334))	('hyperchomasia', 'Disease', 'None', (228, 241))	('ductular reactions', 'Disease', (336, 354))	('bile duct adenoma', 'Phenotype', 'HP:0012028', (359, 376))
155995	31443224	Interestingly, the two targets of miR-877 reported in Table S2 included K-RAS, which plays a major role in both CCA and PDAC carcinogenesis (though K-RAS mutations are present in 90% of early stage PDACs, 61% of the ampullary cancers, but only in 15.2% of bile duct cancers).	('PDAC', 'Phenotype', 'HP:0006725', (198, 202))	('miR-877', 'Gene', (34, 41))	('carcinogenesis', 'Disease', 'MESH:D063646', (125, 139))	('miR-877', 'Gene', '100126314', (34, 41))	('CCA', 'Phenotype', 'HP:0030153', (112, 115))	('cancers', 'Disease', 'MESH:D009369', (266, 273))	('K-RAS', 'Gene', (72, 77))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('early stage PDACs', 'Disease', (186, 203))	('bile duct cancers', 'Disease', 'MESH:D001650', (256, 273))	('K-RAS', 'Gene', '3845', (72, 77))	('K-RAS', 'Gene', (148, 153))	('PDAC', 'Chemical', '-', (198, 202))	('PDAC', 'Chemical', '-', (120, 124))	('bile duct cancers', 'Disease', (256, 273))	('bile duct cancers', 'Phenotype', 'HP:0030153', (256, 273))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('cancers', 'Disease', (266, 273))	('K-RAS', 'Gene', '3845', (148, 153))	('PDAC', 'Phenotype', 'HP:0006725', (120, 124))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('cancers', 'Disease', (226, 233))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('mutations', 'Var', (154, 163))	('carcinogenesis', 'Disease', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
156027	31443224	Combining CA19-9 with the two-miRNA panel did not improve the diagnostic power, presumably since expression of CA19-9 was less discriminative between distal CCA and BD, resulting in no additive effect on the diagnostic capacity of the two-miRNA panel.	('miR', 'Gene', '220972', (30, 33))	('CA19-9', 'Chemical', 'MESH:C086528', (10, 16))	('miR', 'Gene', (30, 33))	('miR', 'Gene', (239, 242))	('CA19-9', 'Chemical', 'MESH:C086528', (111, 117))	('CCA', 'Phenotype', 'HP:0030153', (157, 160))	('miR', 'Gene', '220972', (239, 242))	('distal CCA', 'Disease', (150, 160))	('less', 'NegReg', (122, 126))	('CA19-9', 'Var', (111, 117))	('expression', 'MPA', (97, 107))
156098	30314525	Four patients with T3-T4 staging died from recurrence and metastasis between 2 and 5 months, and three patients with T1 staging did not have any recurrence between 16 and 24 months.	('metastasis', 'CPA', (58, 68))	('patients', 'Species', '9606', (103, 111))	('patients', 'Species', '9606', (5, 13))	('T3-T4', 'Var', (19, 24))
156143	30314525	All of the five tumors with MR examinations were mainly hypointense on T1WI and hyperintense relative to liver parenchyma on T2WI and DWI.	('liver parenchyma', 'Disease', (105, 121))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('T1WI', 'Var', (71, 75))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('hypointense', 'Var', (56, 67))	('tumors', 'Disease', (16, 22))	('liver parenchyma', 'Disease', 'MESH:D010195', (105, 121))
156145	30314525	The signal with hyperintensity on T1WI and hypointensity on T2WI indicating hemorrhage was found not only inside the center of the tumor but also the subcapsular space (Fig.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('hypointensity', 'Var', (43, 56))	('hemorrhage', 'Disease', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('hemorrhage', 'Disease', 'MESH:D006470', (76, 86))
156165	30314525	As reported in some previous studies, S-HCC was characterized by lower serum AFP level.	('AFP', 'Gene', (77, 80))	('lower', 'NegReg', (65, 70))	('S-HCC', 'Var', (38, 43))	('AFP', 'Gene', '174', (77, 80))
156179	30314525	On the MR imaging of five patients, bright signal intensity similar to that of cyst or hemangioma on T2WI might be explained by necrosis and the signal might be attributed to hemorrhage seen as hypointensity or hyperintensity on T1WI and hypointensity on T2WI not only inside the center of the tumor but also in the subcapsular area.	('tumor', 'Disease', (294, 299))	('hemangioma', 'Disease', (87, 97))	('hemorrhage', 'Disease', 'MESH:D006470', (175, 185))	('hypointensity', 'Var', (238, 251))	('necrosis', 'Disease', (128, 136))	('hemangioma', 'Disease', 'MESH:D006391', (87, 97))	('hyperintensity', 'Var', (211, 225))	('patients', 'Species', '9606', (26, 34))	('cyst', 'Disease', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('hemorrhage', 'Disease', (175, 185))	('necrosis', 'Disease', 'MESH:D009336', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('hemangioma', 'Phenotype', 'HP:0001028', (87, 97))	('hypointensity', 'Var', (194, 207))
156180	30314525	The other S-HCCs showed inhomogeneous high signals on DWI and T2WI, similar to the "normal" type.	('HCCs', 'Gene', '3052', (12, 16))	('HCCs', 'Gene', (12, 16))	('T2WI', 'Var', (62, 66))
156275	23420090	More specifically, inhibition occurs through upregulation of mito-inhibitors including p15, p21 and p27, and through downregulation of mito-activators including cyclins and cyclin dependent kinases (cdks).	('mito-inhibitors', 'Gene', (61, 76))	('cyclins', 'Protein', (161, 168))	('mito', 'Species', '262676', (135, 139))	('cdks', 'Gene', '1019', (199, 203))	('p27', 'Gene', (100, 103))	('p27', 'Gene', '3429', (100, 103))	('cdks', 'Gene', (199, 203))	('downregulation', 'NegReg', (117, 131))	('p15', 'Var', (87, 90))	('p21', 'Var', (92, 95))	('upregulation', 'PosReg', (45, 57))	('mito', 'Species', '262676', (61, 65))	('cyclin', 'Enzyme', (173, 179))
156293	23420090	The AGS cancer cell line treated with 0.5 ng/ml TGF-beta1 displayed a higher absorbance value of 0.724.	('TGF-beta1', 'Gene', '7040', (48, 57))	('TGF-beta1', 'Gene', (48, 57))	('AGS cancer', 'Disease', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('0.5 ng/ml', 'Var', (38, 47))	('AGS cancer', 'Disease', 'MESH:C535607', (4, 14))	('higher', 'PosReg', (70, 76))	('absorbance value', 'MPA', (77, 93))
156319	23420090	According to the cell proliferation assay results for AGS cancer cell lines, the absorbance values of AGS cells treated with 0, 0.5 and 5 ng/ml TGF-beta1 consistently increased.	('TGF-beta1', 'Gene', '7040', (144, 153))	('TGF-beta1', 'Gene', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('AGS cancer', 'Disease', 'MESH:C535607', (54, 64))	('0.5', 'Var', (128, 131))	('AGS cancer', 'Disease', (54, 64))	('increased', 'PosReg', (167, 176))	('absorbance values', 'MPA', (81, 98))
156427	32212786	Abnormality of apoptosis pathways have been shown to link with cancers (Gobe et al., 2002; Han et al., 2002) as well as several other pathological conditions including Alzheimer (Nikolaev et al., 2009), Parkinson (da Costa and Checler, 2010), rheumatoid arthritis (Eguchi, 2001) and ischemia (Lopez-Neblina et al., 2005).	('Abnormality', 'Var', (0, 11))	('Alzheimer', 'Disease', 'MESH:D000544', (168, 177))	('ischemia', 'Disease', (283, 291))	('arthritis', 'Phenotype', 'HP:0001369', (254, 263))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (243, 263))	('link', 'Reg', (53, 57))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('Alzheimer', 'Disease', (168, 177))	('ischemia', 'Disease', 'MESH:D007511', (283, 291))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Parkinson', 'Disease', (203, 212))	('rheumatoid arthritis', 'Disease', (243, 263))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (243, 263))	('Parkinson', 'Disease', 'MESH:D010302', (203, 212))	('apoptosis pathways', 'Pathway', (15, 33))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
156442	32212786	For the last checkpoint at M phase, the mistake of this process can lead to several conditions including Down's syndrome (Herault and Delabar, 2017), turner's syndrome (Culen et al., 2017) and acute myeloid leukemia (addition copy of chromosome 8) (Nucifora and Rowley, 1995).	("Down's syndrome", 'Disease', (105, 120))	('acute myeloid leukemia', 'Disease', (193, 215))	('lead to', 'Reg', (68, 75))	("turner's syndrome", 'Disease', 'MESH:D014424', (150, 167))	("turner's syndrome", 'Disease', (150, 167))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (193, 215))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (199, 215))	('leukemia', 'Phenotype', 'HP:0001909', (207, 215))	('mistake', 'Var', (40, 47))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (193, 215))
156450	32212786	For cholangiocarcinoma, garlicin the active ingredient of garlic was shown to inhibit cancer cell invasion and migration via PI3K/AKT signaling pathway (Xie et al., 2015).	('migration', 'CPA', (111, 120))	('garlic', 'Species', '4682', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (4, 22))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (4, 22))	('inhibit', 'NegReg', (78, 85))	('garlicin', 'Var', (24, 32))	('PI3K/AKT signaling pathway', 'Pathway', (125, 151))	('cholangiocarcinoma', 'Disease', (4, 22))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('garlicin', 'Chemical', 'MESH:C028009', (24, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('garlic', 'Species', '4682', (24, 30))	('cancer', 'Disease', (86, 92))
156473	32801339	Pemigatinib has recently been approved for 9-14% of CCA patients harboring a fusion or rearrangement of growth factor receptor 2 gene, and ivosidenib has been shown to significantly improve the progression-free survival of patients with isocitrate dehydrogenase-1 mutant advanced CCA in a phase 3 clinical trial.	('patients', 'Species', '9606', (56, 64))	('fusion', 'Var', (77, 83))	('Pemigatinib', 'Chemical', '-', (0, 11))	('improve', 'PosReg', (182, 189))	('rearrangement', 'Var', (87, 100))	('mutant', 'Var', (264, 270))	('CCA', 'Phenotype', 'HP:0030153', (52, 55))	('ivosidenib', 'Chemical', 'MESH:C000627630', (139, 149))	('progression-free survival', 'CPA', (194, 219))	('patients', 'Species', '9606', (223, 231))	('CCA', 'Phenotype', 'HP:0030153', (280, 283))
156504	32801339	For examining the regulatory effects between TTN-AS1 and miR-320a, we first showed that transfection of miR-320a mimics had little effect on TTN-AS1 expression, but depletion of TTN-AS1 significantly increased the expression of miR-320a in RBE and HCCC9810 cells (Supplementary Fig.	('miR-320a', 'Gene', (104, 112))	('TTN-AS1', 'Gene', '100506866', (178, 185))	('miR-320a', 'Gene', '407037', (104, 112))	('HCCC9810', 'CellLine', 'CVCL:6908', (248, 256))	('TTN-AS1', 'Gene', '100506866', (45, 52))	('TTN-AS1', 'Gene', (178, 185))	('increased', 'PosReg', (200, 209))	('depletion', 'Var', (165, 174))	('TTN-AS1', 'Gene', '100506866', (141, 148))	('expression', 'Species', '29278', (149, 159))	('miR-320a', 'Gene', (228, 236))	('TTN-AS1', 'Gene', (45, 52))	('TTN-AS1', 'Gene', (141, 148))	('miR-320a', 'Gene', (57, 65))	('miR-320a', 'Gene', '407037', (228, 236))	('miR-320a', 'Gene', '407037', (57, 65))	('expression', 'Species', '29278', (214, 224))	('expression', 'MPA', (214, 224))
156515	32801339	In addition, the expression of miR-320a was downregulated by TTN-AS1 overexpression and upregulated by TTN-AS1 knockdown, and these effects could be abolished by miR-320a mimics and antagomiR-320a, respectively (Supplementary Fig.	('TTN-AS1', 'Gene', '100506866', (61, 68))	('knockdown', 'Var', (111, 120))	('downregulated', 'NegReg', (44, 57))	('expression', 'Species', '29278', (17, 27))	('miR-320a', 'Gene', (162, 170))	('upregulated', 'PosReg', (88, 99))	('miR-320a', 'Gene', '407037', (188, 196))	('TTN-AS1', 'Gene', (61, 68))	('expression', 'MPA', (17, 27))	('miR-320a', 'Gene', '407037', (162, 170))	('overexpression', 'Var', (69, 83))	('expression', 'Species', '29278', (73, 83))	('TTN-AS1', 'Gene', '100506866', (103, 110))	('miR-320a', 'Gene', (188, 196))	('TTN-AS1', 'Gene', (103, 110))	('miR-320a', 'Gene', (31, 39))	('miR-320a', 'Gene', '407037', (31, 39))
156518	32801339	We have previously reported that NRP-1 depletion and ectopic expression of miR-320a inhibited the proliferation of CCA cells.	('depletion', 'Var', (39, 48))	('CCA', 'Disease', (115, 118))	('CCA', 'Phenotype', 'HP:0030153', (115, 118))	('expression', 'Species', '29278', (61, 71))	('NRP-1', 'Gene', (33, 38))	('proliferation', 'CPA', (98, 111))	('miR-320a', 'Gene', '407037', (75, 83))	('miR-320a', 'Gene', (75, 83))	('inhibited', 'NegReg', (84, 93))
156520	32801339	We could further show that knockdown of TTN-AS1 significantly reduced cell viability while antagomiR-320a partially restored cell viability (Supplementary Fig.	('knockdown', 'Var', (27, 36))	('miR-320a', 'Gene', (97, 105))	('TTN-AS1', 'Gene', (40, 47))	('miR-320a', 'Gene', '407037', (97, 105))	('cell viability', 'CPA', (70, 84))	('TTN-AS1', 'Gene', '100506866', (40, 47))	('reduced', 'NegReg', (62, 69))
156521	32801339	Mechanistically, TTN-AS1 knockdown led to a significant downregulation of NRP-1, cyclin-dependent kinase 2 (CDK2) and cyclin E, a significant upregulation of p27, but had little effect on the expression of cyclin D1 and p21.	('p27', 'Protein', (158, 161))	('TTN-AS1', 'Gene', '100506866', (17, 24))	('upregulation', 'PosReg', (142, 154))	('expression', 'Species', '29278', (192, 202))	('cyclin E', 'Protein', (118, 126))	('CDK2', 'Gene', (108, 112))	('NRP-1', 'Protein', (74, 79))	('TTN-AS1', 'Gene', (17, 24))	('downregulation', 'NegReg', (56, 70))	('cyclin-dependent', 'Protein', (81, 97))	('knockdown', 'Var', (25, 34))
156522	32801339	AntagomiR-320a counteracted the effect of TTN-AS1 knockdown (Fig.	('miR-320a', 'Gene', (6, 14))	('miR-320a', 'Gene', '407037', (6, 14))	('TTN-AS1', 'Gene', '100506866', (42, 49))	('knockdown', 'Var', (50, 59))	('TTN-AS1', 'Gene', (42, 49))
156523	32801339	Cell cycle distribution assays showed that knockdown of TTN-AS1 led to more cells arrested at the G0/G1 phase, while antagomiR-320a partially abolished this effect of TTN-AS1 knockdown (Supplementary Fig.	('TTN-AS1', 'Gene', '100506866', (167, 174))	('arrest', 'Disease', (82, 88))	('TTN-AS1', 'Gene', (167, 174))	('knockdown', 'Var', (43, 52))	('TTN-AS1', 'Gene', '100506866', (56, 63))	('miR-320a', 'Gene', (123, 131))	('miR-320a', 'Gene', '407037', (123, 131))	('arrest', 'Disease', 'MESH:D006323', (82, 88))	('TTN-AS1', 'Gene', (56, 63))
156527	32801339	Therefore, we examined the effects of TTN-AS1 knockdown on the expression of decisive factors involved in the process of EMT.	('TTN-AS1', 'Gene', '100506866', (38, 45))	('knockdown', 'Var', (46, 55))	('expression', 'Species', '29278', (63, 73))	('examined', 'Reg', (14, 22))	('TTN-AS1', 'Gene', (38, 45))
156528	32801339	TTN-AS1 knockdown significantly downregulated the expression of NRP-1, Snail, N-cadherin, matrix metalloproteinase (MMP)-2, and MMP-9, and upregulated the expression of E-cadherin (Fig.	('TTN-AS1', 'Gene', '100506866', (0, 7))	('downregulated', 'NegReg', (32, 45))	('Snail', 'Gene', (71, 76))	('upregulated', 'PosReg', (139, 150))	('NRP-1', 'Gene', (64, 69))	('E-cadherin', 'Protein', (169, 179))	('knockdown', 'Var', (8, 17))	('expression', 'Species', '29278', (155, 165))	('expression', 'MPA', (155, 165))	('N-cadherin', 'Protein', (78, 88))	('TTN-AS1', 'Gene', (0, 7))	('MMP-9', 'Gene', (128, 133))	('expression', 'Species', '29278', (50, 60))	('expression', 'MPA', (50, 60))
156529	32801339	The results were supported by gelatin zymography assays, which showed that TTN-AS1 knockdown significantly reduced activities of MMP-2 and MMP-9, while antagomiR-320a partially counteracted this effect (Fig.	('miR-320a', 'Gene', '407037', (158, 166))	('MMP-2', 'MPA', (129, 134))	('TTN-AS1', 'Gene', (75, 82))	('activities', 'MPA', (115, 125))	('MMP-9', 'MPA', (139, 144))	('reduced', 'NegReg', (107, 114))	('TTN-AS1', 'Gene', '100506866', (75, 82))	('knockdown', 'Var', (83, 92))	('miR-320a', 'Gene', (158, 166))
156548	32801339	Control and shRNA-TTN-AS1-transfected RBE cells were incubated with recombinant human TGF-beta protein or/and LY2157299, a specific TGF-beta receptor (TGF-betaR) inhibitor.	('TGF-beta', 'Gene', (151, 159))	('TGF-beta', 'Gene', '7039', (151, 159))	('TGF-beta', 'Gene', (86, 94))	('TTN-AS1', 'Gene', '100506866', (18, 25))	('TGF-beta', 'Gene', (132, 140))	('LY2157299', 'Var', (110, 119))	('LY2157299', 'Chemical', 'MESH:C557799', (110, 119))	('human', 'Species', '9606', (80, 85))	('TGF-beta', 'Gene', '7039', (132, 140))	('TGF-beta', 'Gene', '7039', (86, 94))	('TTN-AS1', 'Gene', (18, 25))
156549	32801339	Incubation of TGF-beta protein or LY2157299 did not affect the expression of NRP-1 or TGF-betaRI (Fig.	('LY2157299', 'Chemical', 'MESH:C557799', (34, 43))	('TGF-beta', 'Gene', (14, 22))	('LY2157299', 'Var', (34, 43))	('expression', 'Species', '29278', (63, 73))	('TGF-beta', 'Gene', (86, 94))	('TGF-beta', 'Gene', '7039', (14, 22))	('TGF-beta', 'Gene', '7039', (86, 94))	('NRP-1', 'Gene', (77, 82))
156550	32801339	However, TGF-beta induced the upregulation, while LY2157299 reduced the expression, of p-TGF-betaRI.	('expression', 'Species', '29278', (72, 82))	('TGF-beta', 'Gene', (9, 17))	('TGF-beta', 'Gene', '7039', (89, 97))	('expression', 'MPA', (72, 82))	('LY2157299', 'Var', (50, 59))	('reduced', 'NegReg', (60, 67))	('LY2157299', 'Chemical', 'MESH:C557799', (50, 59))	('upregulation', 'PosReg', (30, 42))	('TGF-beta', 'Gene', '7039', (9, 17))	('TGF-beta', 'Gene', (89, 97))
156551	32801339	TTN-AS1 knockdown had little effect on TGF-betaRI expression, but significantly inhibited its phosphorylation (Fig.	('TGF-beta', 'Gene', '7039', (39, 47))	('TTN-AS1', 'Gene', '100506866', (0, 7))	('inhibited', 'NegReg', (80, 89))	('knockdown', 'Var', (8, 17))	('TTN-AS1', 'Gene', (0, 7))	('phosphorylation', 'MPA', (94, 109))	('expression', 'Species', '29278', (50, 60))	('TGF-beta', 'Gene', (39, 47))	('expression', 'MPA', (50, 60))
156572	32801339	However, LY2157299, a specific TGF-betaR inhibitor, can block NRP-1-induced activation of the TGF-beta/TGF-betaRI pathway (Fig.	('TGF-beta', 'Gene', (31, 39))	('NRP-1-induced', 'Protein', (62, 75))	('block', 'NegReg', (56, 61))	('TGF-beta', 'Gene', (103, 111))	('TGF-beta', 'Gene', '7039', (31, 39))	('TGF-beta', 'Gene', (94, 102))	('TGF-beta', 'Gene', '7039', (103, 111))	('LY2157299', 'Var', (9, 18))	('LY2157299', 'Chemical', 'MESH:C557799', (9, 18))	('TGF-beta', 'Gene', '7039', (94, 102))
156593	31450023	In this study, we found that knockout of zebrafish Irx1 gene induced hyperplasia and tumorigenesis in the multiple organs where the gene was expressed.	('hyperplasia and tumor', 'Disease', 'MESH:D006965', (69, 90))	('knockout', 'Var', (29, 37))	('zebrafish', 'Species', '7955', (41, 50))	('induced', 'Reg', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Irx1', 'Gene', (51, 55))
156603	31450023	Other study showed that IRX1 was found to be frequently methylated in head and neck squamous cell carcinoma, suggesting silencing of the malignancy.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (70, 107))	('malignancy', 'Disease', (137, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('neck squamous cell carcinoma', 'Disease', (79, 107))	('methylated', 'Var', (56, 66))	('silencing', 'NegReg', (120, 129))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (79, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('IRX1', 'Gene', (24, 28))	('malignancy', 'Disease', 'MESH:D009369', (137, 147))
156610	31450023	Thus, in this study, we used the two different knockout strategies to establish homozygous knockout mutants of the two zebrafish genes, and the homozygous knockout mutants showed aberrant phenotype of hyperplasia and tumor development in multiple organs where the genes are expressed.	('hyperplasia and tumor', 'Disease', 'MESH:D006965', (201, 222))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('zebrafish', 'Species', '7955', (119, 128))	('mutants', 'Var', (100, 107))	('mutants', 'Var', (164, 171))
156615	31450023	For targeted mutation of these Irx1 genes in zebrafish, each gene was separately designed to induce frameshift mutation by using TALEN technology and CRISPR/Cas9 technology for Irx1a and Irx1b, respectively (Figure 1).	('Irx1', 'Gene', (31, 35))	('Irx1a', 'Gene', (177, 182))	('TAL', 'Gene', '324556', (129, 132))	('TAL', 'Gene', (129, 132))	('Irx1b', 'Gene', '114430', (187, 192))	('Irx1b', 'Gene', (187, 192))	('frameshift mutation', 'Var', (100, 119))	('Irx1a', 'Gene', '403019', (177, 182))	('zebrafish', 'Species', '7955', (45, 54))	('induce', 'Reg', (93, 99))
156620	31450023	CRISPR/Cas9 technology was applied for Irx1b knockout mutation by using pT7gRNA (Addgene) and pRGEN-Cas9-CMV (Toolgen).	('Irx1b', 'Gene', '114430', (39, 44))	('mutation', 'Var', (54, 62))	('Irx1b', 'Gene', (39, 44))
156652	31450023	In order to obtain knockout mutants of target genes, each gene was separately designed to induce frameshift mutation by using TALEN and CRISPR/Cas9 technologies for Irx1a and Irx1b, respectively (Figure 1).	('TAL', 'Gene', '324556', (126, 129))	('TAL', 'Gene', (126, 129))	('frameshift mutation', 'Var', (97, 116))	('Irx1a', 'Gene', (165, 170))	('Irx1a', 'Gene', '403019', (165, 170))	('induce', 'Reg', (90, 96))	('Irx1b', 'Gene', '114430', (175, 180))	('Irx1b', 'Gene', (175, 180))
156654	31450023	Genomic DNA sequencing of the progenies from F0 founder zebrafish revealed that single nucleotide C insertion and two nucleotides (CG) deletion with three nucleotides insertion (TTT) occurred, respectively, in the Irx1a and Irx1b regions, resulting in frameshift mutation (Figure 1, A and B).	('Irx1b', 'Gene', (224, 229))	('deletion', 'Var', (135, 143))	('Irx1a', 'Gene', (214, 219))	('nucleotide C', 'Chemical', '-', (87, 99))	('Irx1a', 'Gene', '403019', (214, 219))	('frameshift mutation', 'MPA', (252, 271))	('zebrafish', 'Species', '7955', (56, 65))	('Irx1b', 'Gene', '114430', (224, 229))
156656	31450023	The homozygous mutants for Irx1a (Irx1a-/-) and Irx1b (Irx1b-/-) were vital without showing morphological abnormality at embryogenic stage and survived long enough to cause abnormal phenotypes later.	('Irx1b', 'Gene', (55, 60))	('cause', 'Reg', (167, 172))	('abnormality at embryogenic stage', 'Phenotype', 'HP:0012862', (106, 138))	('mutants', 'Var', (15, 22))	('Irx1a', 'Gene', (34, 39))	('Irx1a', 'Gene', '403019', (34, 39))	('Irx1a', 'Gene', '403019', (27, 32))	('Irx1a', 'Gene', (27, 32))	('Irx1b', 'Gene', '114430', (48, 53))	('Irx1b', 'Gene', (48, 53))	('Irx1b', 'Gene', '114430', (55, 60))
156657	31450023	However, homozygous mutants for both Irx1a and Irx1b (Irx1a-/-/b-/-) were severely malformed (Figure 1C).	('Irx1a', 'Gene', (37, 42))	('mutants', 'Var', (20, 27))	('Irx1a', 'Gene', '403019', (54, 59))	('Irx1a', 'Gene', (54, 59))	('Irx1b', 'Gene', '114430', (47, 52))	('Irx1b', 'Gene', (47, 52))	('malformed', 'Reg', (83, 92))	('Irx1a', 'Gene', '403019', (37, 42))
156670	31450023	Interestingly, although the abnormal phenotypes were observed basically to be identical in both Irx1a and Irx1b knockout mutants, we found that the abnormal phenotypes were prominently induced by Irx1a gene knockout than induced by Irx1b gene knockout (Table 1).	('Irx1b', 'Gene', '114430', (232, 237))	('Irx1b', 'Gene', '114430', (106, 111))	('mutants', 'Var', (121, 128))	('Irx1b', 'Gene', (232, 237))	('induced', 'Reg', (185, 192))	('Irx1b', 'Gene', (106, 111))	('Irx1a', 'Gene', (96, 101))	('Irx1a', 'Gene', (196, 201))	('Irx1a', 'Gene', '403019', (96, 101))	('Irx1a', 'Gene', '403019', (196, 201))
156676	31450023	Because majority of the homozygote mutants of both Irx1 genes did not survive, repetitive genotyping was required to find Irx1a-/-/b-/-.	('Irx1a', 'Gene', '403019', (122, 127))	('Irx1a', 'Gene', (122, 127))	('Irx1', 'Gene', (51, 55))	('mutants', 'Var', (35, 42))
156678	31450023	Of them, five top canonical pathways changed by Irx1 knockout were found to include cyclins and cell cycle regulation, mitotic roles of polo-like kinase, farnesoid X / retinoid X receptor (FXR/RXR) activation, estrogen-mediated S-phase entry, and cell cycle control of chromosomal replication (Supplementary Table 2).	('Irx1', 'Gene', (48, 52))	('RXR', 'Gene', '793011', (193, 196))	('knockout', 'Var', (53, 61))	('FXR', 'Gene', '30614', (189, 192))	('RXR', 'Gene', (193, 196))	('cell cycle regulation', 'CPA', (96, 117))	('FXR', 'Gene', (189, 192))	('cyclins', 'Protein', (84, 91))
156681	31450023	As the tumorigenesis in bile duct was found to be the predominant phenotype in the Irx1 knockout zebrafish (Figure 4), we decided to further evaluate the role of Irx1 by performing transduction of human IRX1 gene into cholangiocarcinoma cell lines.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (218, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('knockout', 'Var', (88, 96))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (218, 236))	('zebrafish', 'Species', '7955', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('human', 'Species', '9606', (197, 202))	('cholangiocarcinoma', 'Disease', (218, 236))	('IRX1', 'Gene', (203, 207))	('Irx1', 'Gene', (83, 87))
156687	31450023	On flow cytometry analyses of the released cells from their arrested point (i.e., 0 hour in the Figure 7, A and B), the results showed that IRX1 expression actually delayed each progression of the cell cycle in the two different cholangiocarcinoma cell lines.	('expression', 'Var', (145, 155))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (229, 247))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (229, 247))	('delayed', 'NegReg', (165, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('IRX1', 'Gene', (140, 144))	('cholangiocarcinoma', 'Disease', (229, 247))	('progression of the cell cycle', 'CPA', (178, 207))
156690	31450023	Taken together, the results suggested that tumor suppression of the gene is mediated by repressing cell cycle progression.	('suppression', 'NegReg', (49, 60))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('repressing', 'NegReg', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('gene', 'Var', (68, 72))	('tumor', 'Disease', (43, 48))	('cell cycle progression', 'CPA', (99, 121))
156693	31450023	Not only for the tumor suppressor, IRX1 also acts an oncogene, especially when the gene undergoes allelic deletion or promoter methylation.	('IRX1', 'Gene', (35, 39))	('tumor', 'Disease', (17, 22))	('promoter methylation', 'Var', (118, 138))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
156694	31450023	For instance, in osteosarcoma, IRX1 was identified as a metastatic oncogene that is activated by hypomethylation, whereas the gene was reported as a tumor suppressor in other cancer types.	('osteosarcoma', 'Disease', (17, 29))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('activated', 'PosReg', (84, 93))	('osteosarcoma', 'Disease', 'MESH:D012516', (17, 29))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('hypomethylation', 'Var', (97, 112))	('tumor', 'Disease', (149, 154))	('IRX1', 'Gene', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('osteosarcoma', 'Phenotype', 'HP:0002669', (17, 29))
156698	31450023	In this study of functional analysis of Irx1 gene, we generated each of homozygous Irx1a and Irx1b mutants that were vital and fertile to generate descendants (Figure 1).	('Irx1b', 'Gene', '114430', (93, 98))	('Irx1a', 'Gene', '403019', (83, 88))	('Irx1a', 'Gene', (83, 88))	('mutants', 'Var', (99, 106))	('Irx1b', 'Gene', (93, 98))
156704	31450023	Observation of abnormal phenotypes caused by the gene knockout in the zebrafish mutants revealed that the mutants contained tumor development where the gene was expressed (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('zebrafish', 'Species', '7955', (70, 79))	('tumor', 'Disease', (124, 129))	('mutants', 'Var', (80, 87))	('contained', 'Reg', (114, 123))	('mutants', 'Var', (106, 113))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
156707	31450023	The same redundancy was phenotypically observed from both Irx1a and Irx1b knockout mutants, although the abnormal phenotype was found to be more prominent in the Irx1a mutant than appeared on Irx1b mutants.	('mutant', 'Var', (168, 174))	('mutants', 'Var', (83, 90))	('Irx1b', 'Gene', '114430', (68, 73))	('Irx1a', 'Gene', '403019', (58, 63))	('Irx1a', 'Gene', (58, 63))	('Irx1b', 'Gene', '114430', (192, 197))	('Irx1a', 'Gene', '403019', (162, 167))	('Irx1b', 'Gene', (68, 73))	('Irx1b', 'Gene', (192, 197))	('Irx1a', 'Gene', (162, 167))
156709	31450023	Unlike in other mammalian studies with homozygous mutants, we believe that because of this functional redundancy, the zebrafish homozygous mutants were able to survive long enough to show the phenotypic abnormality of tumorigenesis in the multiple organs, although the Irx1a/b knockout mutants did not survive longer than 6 months.	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('mammalian', 'Species', '9606', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('zebrafish', 'Species', '7955', (118, 127))	('mutants', 'Var', (139, 146))	('tumor', 'Disease', (218, 223))	('Irx1a', 'Gene', '403019', (269, 274))	('Irx1a', 'Gene', (269, 274))
156712	31450023	Histological analysis with the serial sections obtained from the internal organs well revealed how the tumor masses were severely formed in the organs of the knockout mutants (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('knockout mutants', 'Var', (158, 174))	('formed', 'PosReg', (130, 136))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
156718	31450023	In an attempt of identifying the genes regulated by the transcription factor Irx1 during antitumorigenesis, we performed cRNA microarray assay using the cRNA obtained from the knockout mutants (Figure 5).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('mutants', 'Var', (185, 192))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
156719	31450023	Especially, we noticed that the highest fold change occurred in CDKN2ab (homolog for CDKN2A in mammals), a cyclin-dependent kinase inhibitor, which codes for two proteins: p16INK4a and p14arf.	('p14arf', 'Var', (185, 191))	('p16INK4a', 'Var', (172, 180))	('CDKN2ab', 'Gene', (64, 71))	('mammal', 'Species', '9606', (95, 101))
156722	31450023	In a previous study with gastric cancer, protein arginine methyltransferase 5 (PRMT5, an enzyme responsible for symmetric demethylation of histone) has been introduced as an upstream regulator of IRX1, suggesting that methylation of the gene is involved in tumorigenic process.	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', (257, 262))	('PRMT5', 'Gene', '368664', (79, 84))	('methylation', 'Var', (218, 229))	('protein arginine methyltransferase 5', 'Gene', '368664', (41, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('PRMT5', 'Gene', (79, 84))	('gastric cancer', 'Disease', 'MESH:D013274', (25, 39))	('involved', 'Reg', (245, 253))	('gastric cancer', 'Disease', (25, 39))	('protein arginine methyltransferase 5', 'Gene', (41, 77))
156723	31450023	Further study with PRMT5 has revealed that knockout of IRX1 gene induces cell cycle arrest and growth inhibition.	('PRMT5', 'Gene', (19, 24))	('knockout', 'Var', (43, 51))	('cell cycle arrest', 'CPA', (73, 90))	('growth inhibition', 'CPA', (95, 112))	('induces', 'Reg', (65, 72))	('PRMT5', 'Gene', '368664', (19, 24))	('IRX1', 'Gene', (55, 59))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (73, 90))
156724	31450023	Also, a study with head and neck squamous cell carcinoma has suggested that methylation of IRX1 gene induces tumorigenesis by causing decrease of the gene expression.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (19, 56))	('gene expression', 'MPA', (150, 165))	('neck squamous cell carcinoma', 'Disease', (28, 56))	('decrease', 'NegReg', (134, 142))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (28, 56))	('induces', 'PosReg', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('IRX1', 'Gene', (91, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('methylation', 'Var', (76, 87))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
156726	31450023	Taken together, these results suggest that the IRX1 gene expression is suppressed by hypermethylation during tumorigenesis and that restoring the gene expression inhibits tumorigenesis in cancer cells.	('hypermethylation', 'Var', (85, 101))	('expression', 'MPA', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('restoring', 'PosReg', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('expression', 'MPA', (151, 161))	('inhibits', 'NegReg', (162, 170))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('IRX1 gene', 'Gene', (47, 56))	('tumor', 'Disease', (109, 114))	('suppressed', 'NegReg', (71, 81))
156727	31450023	In our study with the cholangiocarcinoma cell lines, IRX1 overexpression also resulted in delayed progression of the tumor cell cycle along with decrease of cyclin expression, and the most prominent changes were delayed mitotic exit and reentry into G1 phase (Figure 7).	('overexpression', 'Var', (58, 72))	('delayed mitotic exit', 'CPA', (212, 232))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (22, 40))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (22, 40))	('progression', 'CPA', (98, 109))	('tumor', 'Disease', (117, 122))	('IRX1', 'Gene', (53, 57))	('cyclin expression', 'MPA', (157, 174))	('reentry', 'CPA', (237, 244))	('cholangiocarcinoma', 'Disease', (22, 40))	('decrease', 'NegReg', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
156728	31450023	Although it necessitates to further clarify how IRX1 controls the progression of mitotic phase, these results indicate that regulation of cell cycle is an important mechanism of IRX1 function leading to tumor suppression.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('function', 'Var', (183, 191))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('IRX1', 'Gene', (178, 182))
156729	31450023	In this study with homozygous knockout mutants of Irx1 in zebrafish, the results have demonstrated that the gene functions as a true tumor suppressor.	('Irx1', 'Gene', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('zebrafish', 'Species', '7955', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('mutants', 'Var', (39, 46))
156929	32883228	Survival analysis of patients with stage T2a and T2b perihilar cholangiocarcinoma treated with radical resection Both the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging system for perihilar cholangiocarcinoma (pCCA) had the same definition for T2a and T2b.	('T2b', 'Var', (49, 52))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (221, 239))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (221, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('Cancer', 'Disease', (178, 184))	('cholangiocarcinoma', 'Disease', (63, 81))	('Cancer', 'Disease', 'MESH:D009369', (178, 184))	('patients', 'Species', '9606', (21, 29))	('cholangiocarcinoma', 'Disease', (221, 239))	('Cancer', 'Phenotype', 'HP:0002664', (178, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (63, 81))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (63, 81))	('CCA', 'Phenotype', 'HP:0030153', (242, 245))
156930	32883228	178 patients with stage T2a or T2b who underwent curative intent resection for pCCA between Jan 2010 and Dec 2018 were enrolled.	('pCCA', 'Disease', (79, 83))	('T2b', 'Var', (31, 34))	('patients', 'Species', '9606', (4, 12))	('CCA', 'Phenotype', 'HP:0030153', (80, 83))
156944	32883228	Currently, both the T2aN0M0 and T2bN0M0 are classified as TNM stage II in the 7th and 8th edition of AJCC staging system.	('TNM', 'Gene', '10178', (58, 61))	('T2aN0M0', 'Var', (20, 27))	('T2bN0M0', 'Var', (32, 39))	('TNM', 'Gene', (58, 61))
156975	32883228	For final pathology of the resected tumor, tumor grade were classified as well- (n = 14, 7.9%), moderate- (n = 133, 74.7%) or poor- (n = 31, 17.4%) differentiated.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (36, 41))	('poor-', 'Var', (126, 131))
156984	32883228	In the univariate analysis (Table S1), TBIL, AST, CA19-9, vascular resection, postoperative complication, perineural invasion, positive resection margin, pathological differentiation, N-staging and total stage were associated with poor survival.	('vascular resection', 'CPA', (58, 76))	('TBIL', 'Chemical', 'MESH:D001663', (39, 43))	('AST', 'Gene', (45, 48))	('pathological differentiation', 'CPA', (154, 182))	('positive', 'Var', (127, 135))	('TBIL', 'Disease', (39, 43))	('AST', 'Gene', '26503', (45, 48))	('CA19-9', 'Chemical', 'MESH:C086528', (50, 56))	('N-staging', 'CPA', (184, 193))	('perineural invasion', 'CPA', (106, 125))
156986	32883228	The median survival of patients with high level of AST (>=85.0 IU/L) was 31 months, whereas that of patients with low level of AST (< 85.0 IU/L) was 41 months (P = 0.047).	('patients', 'Species', '9606', (23, 31))	('AST', 'Gene', (51, 54))	('>=85.0 IU/L', 'Var', (56, 67))	('AST', 'Gene', '26503', (127, 130))	('AST', 'Gene', '26503', (51, 54))	('patients', 'Species', '9606', (100, 108))	('low level of AST', 'Phenotype', 'HP:0032198', (114, 130))	('AST', 'Gene', (127, 130))
156992	32883228	The median survival for the patients with well-, moderate- and poor- differentiation tumors were 51, 37, 21 months, respectively (P = 0.001).	('poor- differentiation', 'Var', (63, 84))	('moderate-', 'Var', (49, 58))	('tumors', 'Disease', (85, 91))	('patients', 'Species', '9606', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
156998	32883228	Similarly, patients with high level of CA19-9 were associated with a significantly worse long-term outcome, with a 1-, 3- and 5-year OS rates of 85.4, 32.4 and 15.8%.	('patients', 'Species', '9606', (11, 19))	('CA19-9', 'Chemical', 'MESH:C086528', (39, 45))	('CA19-9', 'Var', (39, 45))	('high level', 'Var', (25, 35))
157022	32883228	We found that the current AJCC T staging systems poorly stratified the prognosis of patients with T2a and T2b after curative intent resection and several clinicopathological factors of the tumor were the independent predictors for poor survival.	('tumor', 'Disease', (189, 194))	('patients', 'Species', '9606', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('T2b', 'Var', (106, 109))
157025	32883228	In the current study, high level of preoperative AST (>=85.0 IU/L), high level of preoperative CA19-9 (>=1000 U/mL), vascular resection and poor differentiation of the tumor remained as independent predictors for poor survival, which were in line with previous researches.	('AST', 'Gene', (49, 52))	('tumor', 'Disease', (168, 173))	('poor', 'Var', (140, 144))	('AST', 'Gene', '26503', (49, 52))	('vascular', 'CPA', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('CA19-9', 'Chemical', 'MESH:C086528', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
157027	32883228	In the present research, N-staging was associated with survival in the univariate analysis, while did not remain as independent predictors of poor survival in multivariate analysis, which maybe attribute to the confounding effect of tumor differentiation.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (233, 238))	('N-staging', 'Var', (25, 34))	('associated', 'Reg', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
157088	32503466	High expression of TRIM44 protein in malignant tissues was found to be strongly associated with poor OS (HR = 1.94, 95% CI: 1.60-2.35, p < 0.0001), and the heterogeneity test revealed a mild heterogeneity (I2 = 32.6%; PQ = 0.139).	('High', 'Var', (0, 4))	('poor OS', 'Disease', (96, 103))	('TRIM44', 'Gene', '54765', (19, 25))	('associated', 'Reg', (80, 90))	('TRIM44', 'Gene', (19, 25))	('PQ', 'Chemical', '-', (218, 220))	('protein', 'Protein', (26, 33))
157102	32503466	When combined with all data from 33 different types of malignant tumors in GEPIA, the Kaplan-Meier analysis suggested that cancer patients with a high expression level of TRIM44 exhibited poorer OS, compared with cases expressing a low level of TRIM44 (Fig.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TRIM44', 'Gene', '54765', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('TRIM44', 'Gene', '54765', (171, 177))	('patients', 'Species', '9606', (130, 138))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (123, 129))	('TRIM44', 'Gene', (245, 251))	('malignant tumors', 'Disease', (55, 71))	('TRIM44', 'Gene', (171, 177))	('malignant tumors', 'Disease', 'MESH:D009369', (55, 71))	('high expression', 'Var', (146, 161))
157110	32503466	TRIM44 amplification is correlated with unfavorable prognosis and advanced clinicopathological parameters of malignancies.	('TRIM44', 'Gene', (0, 6))	('malignancies', 'Disease', (109, 121))	('TRIM44', 'Gene', '54765', (0, 6))	('amplification', 'Var', (7, 20))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))
157120	32503466	Overexpression of TRIM44 has been shown to induce a similar change in hallmark characteristics of EMT in other cancers, such as ICC and HEC.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('ICC', 'Disease', (128, 131))	('HEC', 'CellLine', 'CVCL:N814', (136, 139))	('TRIM44', 'Gene', '54765', (18, 24))	('cancers', 'Disease', (111, 118))	('change', 'Reg', (60, 66))	('hallmark characteristics of', 'MPA', (70, 97))	('HEC', 'Disease', (136, 139))	('TRIM44', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Overexpression', 'Var', (0, 14))
157122	32503466	TRIM44 expression positively affects the expression of cyclins and CDKs, suggesting that TRIM44 is involved in the regulation of cell cycle G1/s transformation.	('TRIM44', 'Gene', (0, 6))	('affects', 'Reg', (29, 36))	('expression', 'MPA', (41, 51))	('involved', 'Reg', (99, 107))	('TRIM44', 'Gene', '54765', (0, 6))	('TRIM44', 'Gene', '54765', (89, 95))	('cyclin', 'Gene', '5111', (55, 61))	('expression', 'Var', (7, 17))	('CDKs', 'Gene', '23097', (67, 71))	('TRIM44', 'Gene', (89, 95))	('cyclin', 'Gene', (55, 61))	('CDKs', 'Gene', (67, 71))
157124	32503466	Indeed, ectopic expression of TRIM44 promotes cell proliferation by accelerating the G1/S-phase transition in HCC.	('accelerating', 'PosReg', (68, 80))	('HCC', 'Gene', '619501', (110, 113))	('ectopic expression', 'Var', (8, 26))	('G1/S-phase transition', 'CPA', (85, 106))	('HCC', 'Gene', (110, 113))	('TRIM44', 'Gene', '54765', (30, 36))	('TRIM44', 'Gene', (30, 36))	('cell proliferation', 'CPA', (46, 64))	('promotes', 'PosReg', (37, 45))
157125	32503466	In colony formation assays, knockdown of TRIM44 in Huh7 cells significantly decreased the expression levels of cyclin D1 and cyclin E, which have been shown to play a crucial role in accelerating the G1/S-phase transition.	('G1/S-phase transition', 'CPA', (200, 221))	('cyclin D1', 'Gene', (111, 120))	('TRIM44', 'Gene', (41, 47))	('Huh7', 'CellLine', 'CVCL:0336', (51, 55))	('expression levels', 'MPA', (90, 107))	('decreased', 'NegReg', (76, 85))	('cyclin D1', 'Gene', '595', (111, 120))	('cyclin', 'Gene', '5111', (111, 117))	('cyclin', 'Gene', '5111', (125, 131))	('knockdown', 'Var', (28, 37))	('accelerating', 'PosReg', (183, 195))	('cyclin', 'Gene', (125, 131))	('TRIM44', 'Gene', '54765', (41, 47))	('cyclin', 'Gene', (111, 117))
157127	32503466	Knock-down of TRIM44 in glioma cells induces an increase in p21/p27 expression,and then it inhibited cell division.	('p27', 'Gene', '10671', (64, 67))	('TRIM44', 'Gene', '54765', (14, 20))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('cell division', 'CPA', (101, 114))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('p21', 'Gene', '644914', (60, 63))	('expression', 'MPA', (68, 78))	('p27', 'Gene', (64, 67))	('TRIM44', 'Gene', (14, 20))	('inhibited', 'NegReg', (91, 100))	('Knock-down', 'Var', (0, 10))	('glioma', 'Disease', (24, 30))	('p21', 'Gene', (60, 63))	('increase', 'PosReg', (48, 56))
157128	32503466	Further, the critical p21/p27 regulator AKT is inactivated after TRIM44 is knocked down, but it is activated in glioma cells that overexpress TRIM44.	('inactivated', 'NegReg', (47, 58))	('TRIM44', 'Gene', '54765', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('TRIM44', 'Gene', '54765', (142, 148))	('knocked', 'Var', (75, 82))	('AKT', 'Gene', '207', (40, 43))	('TRIM44', 'Gene', (65, 71))	('TRIM44', 'Gene', (142, 148))	('glioma', 'Disease', (112, 118))	('p21', 'Gene', (22, 25))	('activated', 'PosReg', (99, 108))	('p27', 'Gene', '10671', (26, 29))	('AKT', 'Gene', (40, 43))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('p21', 'Gene', '644914', (22, 25))	('p27', 'Gene', (26, 29))	('overexpress', 'PosReg', (130, 141))
157129	32503466	TRIM44 overexpression leads to high mTOR activity, which is consistent with observations of reduced mTOR signaling in cancer cell lines after siRNA knockdown of TRIM44.	('TRIM44', 'Gene', (161, 167))	('cancer', 'Disease', (118, 124))	('TRIM44', 'Gene', (0, 6))	('overexpression', 'Var', (7, 21))	('mTOR', 'Gene', (36, 40))	('mTOR', 'Gene', '2475', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('reduced', 'NegReg', (92, 99))	('TRIM44', 'Gene', '54765', (161, 167))	('TRIM44', 'Gene', '54765', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mTOR', 'Gene', (100, 104))	('mTOR', 'Gene', '2475', (100, 104))
157130	32503466	The phosphorylation of downstream mTOR substrates, including p-Akt (Ser473) and p-p70S6K (Thr389), in TRIM44-knockdown cells was markedly inhibited, indicating that TRIM44 functions upstream of the mTOR signaling pathway by phosphorylating mTOR.	('TRIM44', 'Gene', (102, 108))	('TRIM44', 'Gene', (165, 171))	('p70S6K', 'Gene', (82, 88))	('Ser473', 'Var', (68, 74))	('inhibited', 'NegReg', (138, 147))	('Akt', 'Gene', '207', (63, 66))	('Ser473', 'Chemical', '-', (68, 74))	('mTOR', 'Gene', (34, 38))	('mTOR', 'Gene', (240, 244))	('mTOR', 'Gene', '2475', (34, 38))	('mTOR', 'Gene', '2475', (240, 244))	('Thr389', 'Var', (90, 96))	('p70S6K', 'Gene', '6198', (82, 88))	('mTOR', 'Gene', (198, 202))	('Thr389', 'Chemical', '-', (90, 96))	('phosphorylation', 'MPA', (4, 19))	('mTOR', 'Gene', '2475', (198, 202))	('TRIM44', 'Gene', '54765', (102, 108))	('TRIM44', 'Gene', '54765', (165, 171))	('Akt', 'Gene', (63, 66))
157141	32503466	Microarray analysis showed that TRIM44 knockdown is associated with the dysregulation of NUPR1, CDK19, CADM1, INHBA, TNFSF10, and DDIT4, which could normally activate the apoptotic cell pathways.	('TNFSF10', 'Gene', (117, 124))	('apoptotic cell pathways', 'Pathway', (171, 194))	('INHBA', 'Gene', (110, 115))	('activate', 'PosReg', (158, 166))	('CADM1', 'Gene', (103, 108))	('DDIT4', 'Gene', (130, 135))	('knockdown', 'Var', (39, 48))	('NUPR1', 'Gene', (89, 94))	('CADM1', 'Gene', '23705', (103, 108))	('TRIM44', 'Gene', '54765', (32, 38))	('TNFSF10', 'Gene', '8743', (117, 124))	('TRIM44', 'Gene', (32, 38))	('CDK19', 'Gene', (96, 101))	('INHBA', 'Gene', '3624', (110, 115))	('NUPR1', 'Gene', '26471', (89, 94))	('DDIT4', 'Gene', '54541', (130, 135))	('CDK19', 'Gene', '23097', (96, 101))	('dysregulation', 'MPA', (72, 85))
157150	32503466	A previous report has shown that the silencing of TRIM44 could decrease the c-IAP1, c-IAP2, and XIAP expression levels, especially in the presence of doxorubicin.	('c-IAP1', 'Gene', (76, 82))	('XIAP', 'Gene', '331', (96, 100))	('c-IAP1', 'Gene', '329', (76, 82))	('doxorubicin', 'Chemical', 'MESH:D004317', (150, 161))	('TRIM44', 'Gene', '54765', (50, 56))	('silencing', 'Var', (37, 46))	('decrease', 'NegReg', (63, 71))	('c-IAP2', 'Gene', (84, 90))	('c-IAP2', 'Gene', '330', (84, 90))	('TRIM44', 'Gene', (50, 56))	('XIAP', 'Gene', (96, 100))
157157	32503466	Moreover, miR-26b-5p is the upstream regulatory gene of TRIM44, which acts as a suppressor.	('miR-26b-5p', 'Var', (10, 20))	('TRIM44', 'Gene', '54765', (56, 62))	('TRIM44', 'Gene', (56, 62))
157300	28561948	3C) and fucosylated hemopexin (data not shown) but to a lesser extent.	('hemopexin', 'Gene', '3263', (20, 29))	('fucosylated', 'Var', (8, 19))	('hemopexin', 'Gene', (20, 29))
157309	28561948	Using just these samples, CA-19-9 had a median level of 55.6 U/mL (+-60.21) in patients with PSC and 9289 U/mL (+-54 459) in patients with cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (139, 157))	('CA-19-9', 'Var', (26, 33))	('9289 U/mL', 'Var', (101, 110))	('cholangiocarcinoma', 'Disease', (139, 157))	('PSC', 'Gene', '100653366', (93, 96))	('patients', 'Species', '9606', (79, 87))	('PSC', 'Gene', (93, 96))	('CA-19-9', 'Chemical', 'MESH:C086528', (26, 33))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (139, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('patients', 'Species', '9606', (125, 133))
157337	28561948	The work presented here highlights the potential role of fucosylated fetuin-A as a biomarker of cholangiocarcinoma and may help in the early detection of this deadly cancer.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('fetuin-A', 'Gene', '197', (69, 77))	('fucosylated', 'Var', (57, 68))	('help', 'Reg', (123, 127))	('cholangiocarcinoma', 'Disease', (96, 114))	('fetuin-A', 'Gene', (69, 77))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))
157363	29093624	CCA cases: All patients diagnosed with CCA who were admitted to affiliated hospitals during the January 2008 to December 2013 study period were identified in the NHAD registry using the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) codes of C22.1 (intrahepatic cholangiocarcinoma), C24.0 (extrahepatic cholangiocarcinoma), C24.1 (cancer of the ampulla of Vater), C24.8 (cholangiocarcinoma whose subtype cannot be classified), and C24.9 (cholangiocarcinoma, unspecified subtype).	('patients', 'Species', '9606', (15, 23))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (306, 337))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (360, 378))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (347, 378))	('intrahepatic cholangiocarcinoma', 'Disease', (306, 337))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (495, 513))	('cholangiocarcinoma', 'Disease', (360, 378))	('CCA', 'Phenotype', 'HP:0030153', (0, 3))	('C24.1', 'Var', (381, 386))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (360, 378))	('cholangiocarcinoma', 'Disease', (495, 513))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (319, 337))	('cancer', 'Disease', (388, 394))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (495, 513))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (428, 446))	('CCA', 'Phenotype', 'HP:0030153', (39, 42))	('cholangiocarcinoma', 'Disease', (319, 337))	('C22.1', 'Var', (299, 304))	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (319, 337))	('NHAD', 'Disease', (162, 166))	('cholangiocarcinoma', 'Disease', (428, 446))	('NHAD', 'Disease', 'None', (162, 166))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (428, 446))	('C24.8', 'Var', (421, 426))	('extrahepatic cholangiocarcinoma', 'Disease', (347, 378))	('C24.0', 'Var', (340, 345))	('C22.1', 'CellLine', 'CVCL:F277', (299, 304))	('unspecified', 'Species', '32644', (515, 526))	('cancer', 'Disease', 'MESH:D009369', (388, 394))	('C24.9', 'Var', (488, 493))
157364	29093624	Potential risk factors for CCA, including cirrhosis, diabetes, and chronic viral hepatitis B and C infection, were collected using the corresponding ICD-10 codes, as follows: HBV infection: B18.0 and B18.1; HCV infection: B18.2; cirrhosis: K74, K74.0, K74.1, K74.2, K74.6, K70.2, K70.3, and K70.9; and diabetes mellitus type 2: E11.	('cirrhosis', 'Disease', (42, 51))	('cirrhosis', 'Disease', 'MESH:D005355', (229, 238))	('diabetes mellitus type 2', 'Disease', (302, 326))	('K70.9', 'Var', (291, 296))	('HBV infection', 'Disease', 'MESH:D006509', (175, 188))	('chronic viral hepatitis B', 'Disease', 'MESH:D019694', (67, 92))	('hepatitis', 'Phenotype', 'HP:0012115', (81, 90))	('cirrhosis', 'Phenotype', 'HP:0001394', (229, 238))	('diabetes', 'Disease', 'MESH:D003920', (53, 61))	('C infection', 'Disease', (97, 108))	('HCV infection', 'Disease', 'MESH:D006526', (207, 220))	('diabetes', 'Disease', (302, 310))	('K74.0', 'Var', (245, 250))	('K74.6', 'Var', (266, 271))	('cirrhosis', 'Disease', (229, 238))	('chronic viral hepatitis B', 'Disease', (67, 92))	('K74', 'Var', (240, 243))	('HCV infection', 'Disease', (207, 220))	('K74.1', 'Var', (252, 257))	('diabetes mellitus type 2', 'Phenotype', 'HP:0005978', (302, 326))	('K70.3', 'Var', (280, 285))	('cirrhosis', 'Disease', 'MESH:D005355', (42, 51))	('diabetes', 'Disease', (53, 61))	('B18.2', 'Var', (222, 227))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (302, 319))	('K70.2', 'Var', (273, 278))	('viral hepatitis', 'Phenotype', 'HP:0006562', (75, 90))	('HBV infection', 'Disease', (175, 188))	('CCA', 'Phenotype', 'HP:0030153', (27, 30))	('cirrhosis', 'Phenotype', 'HP:0001394', (42, 51))	('diabetes mellitus type 2', 'Disease', 'MESH:D003924', (302, 326))	('K74.2', 'Var', (259, 264))	('CCA', 'Disease', (27, 30))	('diabetes', 'Disease', 'MESH:D003920', (302, 310))	('C infection', 'Disease', 'MESH:D019698', (97, 108))
157380	29093624	In a comparison of the proportion of individuals with underlying diabetes and chronic liver diseases between CCA vs non-CCA patients, we found that a greater proportion of CCA patients had diabetes than non-CCA patients, i.e., 4502/39421 (11.42%) vs 977973/18508448 (5.28%), P < 0.001, respectively.	('CCA', 'Phenotype', 'HP:0030153', (109, 112))	('patients', 'Species', '9606', (176, 184))	('diabetes', 'Disease', (65, 73))	('liver disease', 'Phenotype', 'HP:0001392', (86, 99))	('4502/39421', 'Var', (227, 237))	('patients', 'Species', '9606', (211, 219))	('diabetes', 'Disease', (189, 197))	('CCA', 'Phenotype', 'HP:0030153', (120, 123))	('diabetes', 'Disease', 'MESH:D003920', (189, 197))	('CCA', 'Phenotype', 'HP:0030153', (172, 175))	('diabetes', 'Disease', 'MESH:D003920', (65, 73))	('liver diseases', 'Phenotype', 'HP:0001392', (86, 100))	('liver diseases', 'Disease', (86, 100))	('liver diseases', 'Disease', 'MESH:D008107', (86, 100))	('CCA', 'Phenotype', 'HP:0030153', (207, 210))	('CCA', 'Disease', (172, 175))	('977973/18508448', 'Var', (250, 265))	('patients', 'Species', '9606', (124, 132))
157381	29093624	Similarly, a significantly greater proportion of CCA patients had viral hepatitis B and C infection and cirrhosis, i.e., 291/39421 (0.74%) vs 21797/18508448 (0.12%), 196/39421 (0.50%) vs 18339/18508448 (0.10%), and 1896/39421 (4.81%) vs 170255/18508448 (0.92%) for viral hepatitis B, viral hepatitis C and cirrhosis, respectively; P < 0.001 for all comparisons (Table 3).	('C infection', 'Disease', 'MESH:D019698', (88, 99))	('CCA', 'Phenotype', 'HP:0030153', (49, 52))	('18339/18508448', 'Var', (187, 201))	('cirrhosis', 'Phenotype', 'HP:0001394', (104, 113))	('viral hepatitis C', 'Disease', (284, 301))	('CCA', 'Disease', (49, 52))	('hepatitis', 'Phenotype', 'HP:0012115', (290, 299))	('hepatitis', 'Phenotype', 'HP:0012115', (72, 81))	('C infection', 'Disease', (88, 99))	('patients', 'Species', '9606', (53, 61))	('hepatitis', 'Phenotype', 'HP:0012115', (271, 280))	('cirrhosis', 'Disease', (104, 113))	('viral hepatitis B', 'Disease', (66, 83))	('viral hepatitis B', 'Disease', (265, 282))	('viral hepatitis C', 'Disease', 'MESH:D006526', (284, 301))	('cirrhosis', 'Disease', 'MESH:D005355', (306, 315))	('greater', 'PosReg', (27, 34))	('viral hepatitis', 'Phenotype', 'HP:0006562', (284, 299))	('viral hepatitis', 'Phenotype', 'HP:0006562', (66, 81))	('cirrhosis', 'Phenotype', 'HP:0001394', (306, 315))	('21797/18508448', 'Var', (142, 156))	('viral hepatitis', 'Phenotype', 'HP:0006562', (265, 280))	('cirrhosis', 'Disease', (306, 315))	('viral hepatitis B', 'Disease', 'MESH:D006509', (66, 83))	('viral hepatitis B', 'Disease', 'MESH:D006509', (265, 282))	('cirrhosis', 'Disease', 'MESH:D005355', (104, 113))
157392	29093624	Accordingly, the eradication of OV infection could potentially reduce the incidence of CCA in Thailand.	('eradication', 'Var', (17, 28))	('CCA', 'Phenotype', 'HP:0030153', (87, 90))	('OV infection', 'Disease', 'MESH:D007239', (32, 44))	('OV infection', 'Disease', (32, 44))	('reduce', 'NegReg', (63, 69))	('CCA', 'Disease', (87, 90))
157446	27798773	Furthermore, the results of published studies and case reports demonstrated that CS-PHP with melphalan resulted in favorable tumor response rates in a range of tumor histologies (ocular or cutaneous melanoma, colorectal cancer, and hepatobiliary tumors).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('CS-PHP', 'Var', (81, 87))	('colorectal cancer', 'Disease', (209, 226))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('melphalan', 'Chemical', 'MESH:D008558', (93, 102))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('cutaneous melanoma', 'Disease', (189, 207))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (189, 207))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (189, 207))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('CS-PHP', 'Chemical', '-', (81, 87))	('hepatobiliary tumors', 'Disease', (232, 252))	('colorectal cancer', 'Phenotype', 'HP:0003003', (209, 226))	('tumor', 'Disease', (246, 251))	('tumor', 'Disease', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', (125, 130))	('colorectal cancer', 'Disease', 'MESH:D015179', (209, 226))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('hepatobiliary tumors', 'Disease', 'MESH:D004066', (232, 252))
157448	27798773	Taken together, these findings indicate that CS-PHP is a promising locoregional therapy for patients with primary and secondary liver tumors and has a acceptable safety profile.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('liver tumor', 'Phenotype', 'HP:0002896', (128, 139))	('patients', 'Species', '9606', (92, 100))	('primary', 'Disease', (106, 113))	('liver tumors', 'Disease', 'MESH:D008113', (128, 140))	('CS-PHP', 'Var', (45, 51))	('liver tumors', 'Phenotype', 'HP:0002896', (128, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('liver tumors', 'Disease', (128, 140))	('CS-PHP', 'Chemical', '-', (45, 51))
157503	27798773	Intravenous (IV) hydration is started to ensure an adequate fluid preload before the procedure; however, this is not consistently done at all institutions, as some centers believe that a fluid preload increases the risk of edema, particularly of the neck, airways, and pulmonary interstitium.	('fluid preload', 'Phenotype', 'HP:0011105', (187, 200))	('pulmonary interstitium', 'Phenotype', 'HP:0006530', (269, 291))	('edema', 'Disease', (223, 228))	('edema', 'Phenotype', 'HP:0000969', (223, 228))	('fluid preload', 'Var', (187, 200))	('edema', 'Disease', 'MESH:D004487', (223, 228))	('fluid preload', 'Phenotype', 'HP:0011105', (60, 73))
157540	27798773	A clinically meaningful and statistically significant improvement in hPFS was observed in the CS-PHP group compared to the BAC group.	('BAC', 'Chemical', '-', (123, 126))	('hPFS', 'CPA', (69, 73))	('improvement', 'PosReg', (54, 65))	('CS-PHP', 'Var', (94, 100))	('CS-PHP', 'Chemical', '-', (94, 100))
157542	27798773	Additionally, there was a statistically significant (P < 0.0001) improvement in the hOR rate with PHP (36.4%) compared to BAC (2.0%).	('PHP', 'Var', (98, 101))	('improvement', 'PosReg', (65, 76))	('BAC', 'Chemical', '-', (122, 125))	('hOR rate', 'CPA', (84, 92))
157569	27798773	The ECOG score trended lower in the CS-PHP group (P = 0.051) compared with the yttrium and chemoembolization groups.	('CS-PHP', 'Var', (36, 42))	('CS-PHP', 'Chemical', '-', (36, 42))	('ECOG score', 'MPA', (4, 14))	('yttrium', 'Chemical', 'MESH:D015019', (79, 86))	('lower', 'NegReg', (23, 28))
157570	27798773	Median hPFS was significantly (P = 0.002) longer with CS-PHP (310 days) than with yttrium (54 days) and chemoembolization (80 days).	('CS-PHP', 'Var', (54, 60))	('CS-PHP', 'Chemical', '-', (54, 60))	('longer', 'PosReg', (42, 48))	('hPFS', 'MPA', (7, 11))	('yttrium', 'Chemical', 'MESH:D015019', (82, 89))
157571	27798773	Median hPFS was also significantly longer with CS-PHP versus yttrium (P < 0.001) and CS-PHP versus chemoembolization (P = 0.008), but not yttrium versus chemoembolization (P = 0.44).	('yttrium', 'Chemical', 'MESH:D015019', (61, 68))	('CS-PHP', 'Var', (47, 53))	('CS-PHP', 'Var', (85, 91))	('CS-PHP', 'Chemical', '-', (85, 91))	('yttrium', 'Chemical', 'MESH:D015019', (138, 145))	('CS-PHP', 'Chemical', '-', (47, 53))	('hPFS', 'MPA', (7, 11))	('longer', 'PosReg', (35, 41))
157597	27798773	In the clinical trial program (specifically, the randomized, controlled phase 3 study), CS-PHP with melphalan resulted in a clinically meaningful and statistically significant improvement in hPFS in patients with unresectable hepatic metastases from ocular or cutaneous melanoma.	('CS-PHP', 'Chemical', '-', (88, 94))	('hepatic metastases', 'Disease', (226, 244))	('improvement', 'PosReg', (176, 187))	('ocular', 'Disease', (250, 256))	('melanoma', 'Phenotype', 'HP:0002861', (270, 278))	('hepatic metastases', 'Disease', 'MESH:D009362', (226, 244))	('melphalan', 'Chemical', 'MESH:D008558', (100, 109))	('patients', 'Species', '9606', (199, 207))	('hPFS', 'MPA', (191, 195))	('cutaneous melanoma', 'Disease', (260, 278))	('CS-PHP', 'Var', (88, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (260, 278))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (260, 278))
157602	33800328	Identification and In-Depth Analysis of the Novel FGFR2-NDC80 Fusion in a Cholangiocarcinoma Patient: Implication for Therapy Fibroblast growth factor receptor 2 (FGFR2) fusions have emerged as a new therapeutic target for cholangiocarcinoma in clinical practice following the United States Food and Drug Administration (FDA) approval of Pemigatinib in May 2020.	('cholangiocarcinoma', 'Disease', (223, 241))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (74, 92))	('Patient', 'Species', '9606', (93, 100))	('fusions', 'Var', (170, 177))	('Fibroblast growth factor receptor 2', 'Gene', (126, 161))	('NDC80', 'Gene', (56, 61))	('Pemigatinib', 'Chemical', '-', (338, 349))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (223, 241))	('FGFR2', 'Gene', (163, 168))	('FGFR2', 'Gene', '2263', (50, 55))	('FGFR2', 'Gene', '2263', (163, 168))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (223, 241))	('NDC80', 'Gene', '10403', (56, 61))	('FGFR2', 'Gene', (50, 55))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (74, 92))	('Cholangiocarcinoma', 'Disease', (74, 92))	('Fibroblast growth factor receptor 2', 'Gene', '2263', (126, 161))
157603	33800328	FGFR2 fusions can result in a ligand-independent constitutive activation of FGFR2 signaling with a downstream activation of multiple pathways, including the mitogen-activated protein (MAPK) cascade.	('signaling', 'MPA', (82, 91))	('activation', 'PosReg', (110, 120))	('FGFR2', 'Gene', (76, 81))	('FGFR2', 'Gene', '2263', (76, 81))	('FGFR2', 'Gene', '2263', (0, 5))	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (6, 13))	('activation', 'PosReg', (62, 72))
157604	33800328	Until today, only a limited number of fusion partners have been reported, of which the most prevalent is BicC Family RNA Binding Protein (BICC1), representing one-third of all detected FGFR2 fusions.	('BICC1', 'Gene', '80114', (138, 143))	('fusions', 'Var', (191, 198))	('prevalent', 'Reg', (92, 101))	('BICC1', 'Gene', (138, 143))	('FGFR2', 'Gene', '2263', (185, 190))	('FGFR2', 'Gene', (185, 190))
157605	33800328	Here, we present the case of a metastasized intrahepatic cholangiocarcinoma harboring a novel FGFR2-NDC80 fusion, which was discussed in our molecular tumor board.	('metastasized intrahepatic cholangiocarcinoma', 'Disease', (31, 75))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('NDC80', 'Gene', (100, 105))	('fusion', 'Var', (106, 112))	('tumor', 'Disease', (151, 156))	('FGFR2', 'Gene', (94, 99))	('metastasized intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D009362', (31, 75))	('FGFR2', 'Gene', '2263', (94, 99))	('NDC80', 'Gene', '10403', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
157608	33800328	The FGFR2-NDC80 fusion resulted in strong activation of the FGFR2 signaling pathway.	('NDC80', 'Gene', (10, 15))	('fusion', 'Var', (16, 22))	('FGFR2', 'Gene', '2263', (4, 9))	('NDC80', 'Gene', '10403', (10, 15))	('activation', 'PosReg', (42, 52))	('FGFR2', 'Gene', (60, 65))	('FGFR2', 'Gene', '2263', (60, 65))	('FGFR2', 'Gene', (4, 9))
157613	33800328	Therefore, the approval of Pemigatinib in May 2020 by the FDA based on the results of the FIGHT-202 study for CCAs harboring a Fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement represents a significant milestone both in the treatment of this cancer entity as well as in the field of personalized medicine.	('CCAs', 'Disease', (110, 114))	('fusion', 'Var', (171, 177))	('Pemigatinib', 'Chemical', '-', (27, 38))	('rearrangement', 'Var', (181, 194))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('Fibroblast growth factor receptor 2', 'Gene', (127, 162))	('cancer', 'Disease', (260, 266))	('CCA', 'Phenotype', 'HP:0030153', (110, 113))	('FGFR2', 'Gene', '2263', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('Fibroblast growth factor receptor 2', 'Gene', '2263', (127, 162))	('FGFR2', 'Gene', (164, 169))
157614	33800328	Fibroblast growth factor receptor (FGFR) fusions can be found in various cancers, including rearrangements of FGFR2 in 14 percent of CCAs.	('cancers', 'Disease', (73, 80))	('rearrangements', 'Var', (92, 106))	('FGFR2', 'Gene', (110, 115))	('FGFR2', 'Gene', '2263', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('CCAs', 'Disease', (133, 137))	('fusions', 'Var', (41, 48))	('FGFR', 'Gene', (35, 39))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('found', 'Reg', (56, 61))	('CCA', 'Phenotype', 'HP:0030153', (133, 136))
157622	33800328	It is noteworthy that NDC80 mutations have been described in CCA, suggesting a role in cholangiocarcinogenesis.	('role', 'Reg', (79, 83))	('NDC80', 'Gene', '10403', (22, 27))	('CCA', 'Phenotype', 'HP:0030153', (61, 64))	('cholangiocarcinogenesis', 'Disease', (87, 110))	('CCA', 'Disease', (61, 64))	('NDC80', 'Gene', (22, 27))	('cholangiocarcinogenesis', 'Disease', 'None', (87, 110))	('mutations', 'Var', (28, 37))
157671	33800328	Thirdly, downstream effectors such as pFRS2, pPLC, and p4EB-P1 displayed significantly elevated levels when compared to normal liver tissue and tissue microarrays of cholangiocarcinoma specimens.	('levels', 'MPA', (96, 102))	('FRS2', 'Gene', '10818', (39, 43))	('cholangiocarcinoma', 'Disease', (166, 184))	('p4EB-P1', 'Var', (55, 62))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (166, 184))	('FRS2', 'Gene', (39, 43))	('elevated', 'PosReg', (87, 95))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (166, 184))
157679	33800328	In this case report, we described a CCA harboring a novel FGFR2-NDC80 fusion.	('NDC80', 'Gene', (64, 69))	('FGFR2', 'Gene', '2263', (58, 63))	('CCA', 'Disease', (36, 39))	('NDC80', 'Gene', '10403', (64, 69))	('fusion', 'Var', (70, 76))	('CCA', 'Phenotype', 'HP:0030153', (36, 39))	('FGFR2', 'Gene', (58, 63))
157720	32590784	The staging of the distal cholangiocarcinoma is T3N0M0, and the histologic grading revealed a moderately differentiated adenocarcinoma.	('adenocarcinoma', 'Disease', (120, 134))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (26, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (26, 44))	('T3N0M0', 'Var', (48, 54))	('adenocarcinoma', 'Disease', 'MESH:D000230', (120, 134))	('moderately differentiated', 'CPA', (94, 119))	('cholangiocarcinoma', 'Disease', (26, 44))
157748	32590784	Chen et al found that pathological classification of grade 3, high expression of Ki-67 positive index (PI), abnormal elevation of CA125, abnormalities of ALT and AST, anemia and lack of radical operation indicated a poor prognosis.	('anemia', 'Disease', (167, 173))	('CA125', 'Gene', '94025', (130, 135))	('anemia', 'Disease', 'MESH:D000740', (167, 173))	('elevation', 'PosReg', (117, 126))	('abnormalities of ALT', 'Phenotype', 'HP:0031964', (137, 157))	('AST', 'Gene', (162, 165))	('CA125', 'Gene', (130, 135))	('abnormalities', 'Var', (137, 150))	('expression', 'MPA', (67, 77))	('high', 'PosReg', (62, 66))	('AST', 'Gene', '26503', (162, 165))	('anemia', 'Phenotype', 'HP:0001903', (167, 173))	('Ki-67', 'Gene', (81, 86))
158013	30062820	As the representative staining results shown in Figure 3B, it was demonstrated that compared to control cells treated with NFs-CM and 10% FBS medium, the migration ability of cholangiocarcinoma cells cultured in CAFs-CM were significantly promoted (P < 0.0001 for HuCCT-1 and P < 0.001 for RBE).	('promoted', 'PosReg', (239, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('migration ability', 'CPA', (154, 171))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (175, 193))	('CAFs-CM', 'Var', (212, 219))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (175, 193))	('cholangiocarcinoma', 'Disease', (175, 193))
158014	30062820	In addition, a significant increase was also observed in invading cholangiocarcinoma cells cultured with CAFs-CM compared with NFs-CM and 10% FBS medium (Figure 3C; P < 0.001 for HuCCT-1 and P < 0.0001 for RBE).	('CAFs-CM', 'Var', (105, 112))	('cholangiocarcinoma', 'Disease', (66, 84))	('invading', 'CPA', (57, 65))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (66, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (66, 84))	('increase', 'PosReg', (27, 35))
158039	30062820	Furthermore, CAFs remarkably boosted tumor growth in xenograft model.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('boosted', 'PosReg', (29, 36))	('CAFs', 'Var', (13, 17))
158076	29849596	The degree of lymphatic invasion, venous invasion, perineural invasion, pancreatic invasion, and duodenal invasion was classified in detail as follows: ly0, v0, pn0, panc0, and du0 = no evidence of invasion; ly1, v1, pn1, panc1, and du1 = mild invasion; ly2, v2, pn2, panc2, and du2 = moderate invasion; and ly3, v3, pn3, panc3, and du3 = severe invasion, respectively.	('pn2', 'Gene', (263, 266))	('pn1', 'Gene', '5270', (217, 220))	('pn3', 'Gene', (317, 320))	('ly2', 'Var', (254, 257))	('ly3', 'Var', (308, 311))	('pn1', 'Gene', (217, 220))	('pn3', 'Gene', '6336', (317, 320))	('pn2', 'Gene', '351', (263, 266))	('ly1', 'Var', (208, 211))
158080	29849596	A previous study reported that fluorodeoxyglucose positron emission tomography (FDG-PET) was useful for predicting lymph node metastasis, and lymph node metastasis detected on 18F-FDG PET/CT had a positive correlation with 1-year recurrence after surgical resection in patients with peripheral intrahepatic cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (307, 325))	('18F-FDG', 'Var', (176, 183))	('peripheral intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (283, 325))	('fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (31, 49))	('peripheral intrahepatic cholangiocarcinoma', 'Disease', (283, 325))
158090	28535665	L1 Cell Adhesion Molecule Promotes Migration and Invasion via JNK Activation in Extrahepatic Cholangiocarcinoma Cells with Activating KRAS Mutation Extrahepatic cholangiocarcinoma (ECC), a malignant tumor of biliary origin, has a poor prognosis with limited treatment options.	('Promotes', 'PosReg', (26, 34))	('L1 Cell Adhesion Molecule', 'Gene', (0, 25))	('tumor of biliary', 'Phenotype', 'HP:0100574', (199, 215))	('Extrahepatic Cholangiocarcinoma Cells', 'Disease', 'MESH:D018281', (80, 117))	('Extrahepatic cholangiocarcinoma', 'Disease', (148, 179))	('Extrahepatic Cholangiocarcinoma Cells', 'Disease', (80, 117))	('JNK', 'Gene', (62, 65))	('Activation', 'PosReg', (66, 76))	('JNK', 'Gene', '5599', (62, 65))	('malignant tumor', 'Disease', (189, 204))	('malignant tumor', 'Disease', 'MESH:D018198', (189, 204))	('Invasion', 'CPA', (49, 57))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (161, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('Activating', 'PosReg', (123, 133))	('Mutation', 'Var', (139, 147))	('KRAS', 'Gene', '3845', (134, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('Migration', 'CPA', (35, 44))	('Extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (148, 179))	('L1 Cell Adhesion Molecule', 'Gene', '3897', (0, 25))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('KRAS', 'Gene', (134, 138))
158093	28535665	In this study we investigate the functional significance of L1CAM in ECC cells with activating KRAS mutation.	('activating', 'PosReg', (84, 94))	('mutation', 'Var', (100, 108))	('KRAS', 'Gene', '3845', (95, 99))	('KRAS', 'Gene', (95, 99))
158094	28535665	We selected an ECC cell line, EGI-1, with activating KRAS mutation, and then confirmed its expression of L1CAM by RT-PCR, western blot analysis, and flow cytometry.	('mutation', 'Var', (58, 66))	('KRAS', 'Gene', '3845', (53, 57))	('activating', 'PosReg', (42, 52))	('KRAS', 'Gene', (53, 57))
158096	28535665	Further, exposure to a JNK inhibitor (SP600125) decreased migration and invasion of EGI-1 cells.	('SP600125', 'Var', (38, 46))	('decreased', 'NegReg', (48, 57))	('JNK', 'Gene', (23, 26))	('JNK', 'Gene', '5599', (23, 26))	('SP600125', 'Chemical', 'MESH:C432165', (38, 46))
158098	28535665	Our study is the first to demonstrate a functional role for L1CAM in ECC carrying the activating KRAS mutation.	('KRAS', 'Gene', (97, 101))	('mutation', 'Var', (102, 110))	('KRAS', 'Gene', '3845', (97, 101))	('activating', 'Reg', (86, 96))	('L1CAM', 'Gene', (60, 65))	('ECC', 'Disease', (69, 72))
158099	28535665	Given that KRAS is the most commonly mutated oncogene in ECC, L1CAM may serve as an attractive therapeutic target for ECC cells with activating KRAS mutation.	('KRAS', 'Gene', (11, 15))	('activating', 'PosReg', (133, 143))	('KRAS', 'Gene', '3845', (144, 148))	('KRAS', 'Gene', '3845', (11, 15))	('KRAS', 'Gene', (144, 148))	('mutation', 'Var', (149, 157))
158113	28535665	Mutations in codons 12, 13, 61, or 146 of one of the three RAS genes (HRAS, KRAS, and NRAS) are sufficient to convert these into oncogenes.	('convert', 'Reg', (110, 117))	('NRAS', 'Gene', (86, 90))	('NRAS', 'Gene', '4893', (86, 90))	('HRAS', 'Gene', '3265', (70, 74))	('KRAS', 'Gene', (76, 80))	('KRAS', 'Gene', '3845', (76, 80))	('HRAS', 'Gene', (70, 74))	('Mutations', 'Var', (0, 9))
158118	28535665	High L1CAM expression is an independent poor prognostic factor in predicting the overall survival of patients with ECC.	('patients', 'Species', '9606', (101, 109))	('L1CAM', 'Protein', (5, 10))	('ECC', 'Disease', (115, 118))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))
158120	28535665	In this study, we modulated L1CAM expression in an ECC (EGI-1) cell line with activating KRAS mutation, and investigated its functional significance.	('activating', 'PosReg', (78, 88))	('expression', 'MPA', (34, 44))	('L1CAM', 'Gene', (28, 33))	('KRAS', 'Gene', (89, 93))	('mutation', 'Var', (94, 102))	('modulated', 'Reg', (18, 27))	('KRAS', 'Gene', '3845', (89, 93))
158123	28535665	The ERK (U0126) and JNK inhibitors (SP600125) were purchased from Sigma Aldrich and AbMole BioScience (USA), respectively.	('SP600125', 'Chemical', 'MESH:C432165', (36, 44))	('JNK', 'Gene', '5599', (20, 23))	('SP600125', 'Var', (36, 44))	('U0126', 'Chemical', 'MESH:C113580', (9, 14))	('ERK', 'Gene', '5594', (4, 7))	('JNK', 'Gene', (20, 23))	('ERK', 'Gene', (4, 7))
158144	28535665	For inhibitor studies, 10 muM of either the JNK (SP600125) or ERK inhibitor (U0126) were added prior to scratching the monolayers.	('JNK', 'Gene', (44, 47))	('ERK', 'Gene', '5594', (62, 65))	('JNK', 'Gene', '5599', (44, 47))	('U0126', 'Chemical', 'MESH:C113580', (77, 82))	('SP600125', 'Var', (49, 57))	('ERK', 'Gene', (62, 65))	('SP600125', 'Chemical', 'MESH:C432165', (49, 57))
158148	28535665	DNA sequencing of PCR-amplified KRAS allowed us to confirm that EGI-1 cells carry the G12D mutation, vs. wild-type KRAS in TFK-1 cells (Fig.	('G12D', 'Mutation', 'rs121913529', (86, 90))	('KRAS', 'Gene', (115, 119))	('KRAS', 'Gene', (32, 36))	('KRAS', 'Gene', '3845', (115, 119))	('KRAS', 'Gene', '3845', (32, 36))	('G12D', 'Var', (86, 90))
158153	28535665	However, L1CAM knockdown in EGI-1 cells neither affected cell proliferation nor survival following exposure to chemotherapeutic drugs such as gemcitabine or cisplatin (Figs.	('knockdown', 'Var', (15, 24))	('gemcitabine', 'Chemical', 'MESH:C056507', (142, 153))	('affected', 'Reg', (48, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (157, 166))	('cell proliferation', 'CPA', (57, 75))	('L1CAM', 'Gene', (9, 14))
158154	28535665	To investigate whether L1CAM knockdown in EGI-1 cells influences Ras activation, or it's downstream signaling pathway effectors (Raf-ERK, MEKK-JNK, or PI3K-AKT), we compared protein levels of Ras-GTP, P-ERK, P-JNK, and P-AKT between L1CAM-depleted and control cells.	('Raf', 'Gene', (129, 132))	('knockdown', 'Var', (29, 38))	('AKT', 'Gene', (221, 224))	('P-ERK', 'Gene', (201, 206))	('JNK', 'Gene', (143, 146))	('ERK', 'Gene', (203, 206))	('JNK', 'Gene', '5599', (143, 146))	('AKT', 'Gene', (156, 159))	('Raf', 'Gene', '22882', (129, 132))	('influences', 'Reg', (54, 64))	('AKT', 'Gene', '207', (221, 224))	('P-ERK', 'Gene', '9451', (201, 206))	('L1CAM', 'Gene', (23, 28))	('ERK', 'Gene', '5594', (133, 136))	('JNK', 'Gene', (210, 213))	('AKT', 'Gene', '207', (156, 159))	('JNK', 'Gene', '5599', (210, 213))	('Ras', 'Protein', (65, 68))	('ERK', 'Gene', (133, 136))	('MEKK', 'Gene', (138, 142))	('ERK', 'Gene', '5594', (203, 206))	('Ras-GTP', 'Chemical', '-', (192, 199))	('MEKK', 'Gene', '4214', (138, 142))
158159	28535665	L1CAM knockdown decreased the levels of both phosphorylated MKK4 and total MKK4 protein, but not MKK7 phosphorylation (Figs.	('MKK4', 'Gene', (60, 64))	('MKK4', 'Gene', (75, 79))	('MKK4', 'Gene', '6416', (60, 64))	('MKK4', 'Gene', '6416', (75, 79))	('phosphorylated', 'MPA', (45, 59))	('L1CAM', 'Gene', (0, 5))	('MKK7', 'Gene', '5609', (97, 101))	('knockdown', 'Var', (6, 15))	('levels', 'MPA', (30, 36))	('MKK7', 'Gene', (97, 101))	('decreased', 'NegReg', (16, 25))
158160	28535665	To examine whether JNK signaling contributes to the migration and invasion of EGI-1 cells, cells were exposed to a specific JNK inhibitor (SP600125) and then subjected to the cell proliferation, migration, and invasion assays.	('JNK', 'Gene', '5599', (124, 127))	('SP600125', 'Chemical', 'MESH:C432165', (139, 147))	('JNK', 'Gene', (19, 22))	('SP600125', 'Var', (139, 147))	('JNK', 'Gene', '5599', (19, 22))	('migration', 'CPA', (195, 204))	('JNK', 'Gene', (124, 127))
158164	28535665	Given that KRAS is the most commonly mutated gene in ECC, with this mutation correlating with a poor prognosis and low survival rate, we opted to assess the functional significance of L1CAM in ECC cells on a background of elevated RAS signaling.	('mutation', 'Var', (68, 76))	('KRAS', 'Gene', (11, 15))	('KRAS', 'Gene', '3845', (11, 15))
158165	28535665	To achieve this, we analyzed the L1CAM-positive ECC cell line (EGI-1) containing the KRAS activating mutation.	('KRAS', 'Gene', (85, 89))	('mutation', 'Var', (101, 109))	('KRAS', 'Gene', '3845', (85, 89))
158172	28535665	Regarding the role of JNK in the tumor progression of cholangiocarcinoma, two recent studies showed that JNK promotes proliferation and invasion by cholangiocarcinoma cells via induction of the mTOR-regulated, glucose-regulated protein 78 (GRP78), whereas a JNK inhibitor (SP600125) enhanced TGF-beta1-induced apoptosis of RBE (ICC) cells via a SMAD-dependent caspase activation.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (148, 166))	('glucose-regulated protein 78', 'Gene', (210, 238))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (54, 72))	('mTOR', 'Gene', (194, 198))	('cholangiocarcinoma', 'Disease', (148, 166))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (148, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('glucose-regulated protein 78', 'Gene', '3309', (210, 238))	('JNK', 'Gene', (22, 25))	('proliferation', 'CPA', (118, 131))	('SP600125', 'Var', (273, 281))	('mTOR', 'Gene', '2475', (194, 198))	('JNK', 'Gene', '5599', (22, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('tumor', 'Disease', (33, 38))	('GRP78', 'Gene', '3309', (240, 245))	('GRP78', 'Gene', (240, 245))	('TGF-beta1', 'Gene', (292, 301))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('invasion', 'CPA', (136, 144))	('enhanced', 'PosReg', (283, 291))	('JNK', 'Gene', (258, 261))	('TGF-beta1', 'Gene', '7040', (292, 301))	('JNK', 'Gene', '5599', (258, 261))	('SP600125', 'Chemical', 'MESH:C432165', (273, 281))	('JNK', 'Gene', (105, 108))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('JNK', 'Gene', '5599', (105, 108))	('cholangiocarcinoma', 'Disease', (54, 72))	('promotes', 'PosReg', (109, 117))
158174	28535665	In the present study, we found that L1CAM induced MKK4 and JNK activation, which, in turn, promotes the migration and invasion of EGI-1 cells.	('promotes', 'PosReg', (91, 99))	('JNK', 'Gene', '5599', (59, 62))	('migration', 'CPA', (104, 113))	('L1CAM', 'Var', (36, 41))	('invasion', 'CPA', (118, 126))	('MKK4', 'Gene', '6416', (50, 54))	('JNK', 'Gene', (59, 62))	('MKK4', 'Gene', (50, 54))	('activation', 'PosReg', (63, 73))
158178	28535665	However, its functional role in cells with activating KRAS mutation has not yet been clearly shown.	('KRAS', 'Gene', (54, 58))	('activating', 'PosReg', (43, 53))	('mutation', 'Var', (59, 67))	('KRAS', 'Gene', '3845', (54, 58))
158179	28535665	In this study, we found that L1CAM contributes to the migration and invasion of ECC cells with a KRAS activating mutation.	('mutation', 'Var', (113, 121))	('KRAS', 'Gene', (97, 101))	('KRAS', 'Gene', '3845', (97, 101))	('invasion', 'CPA', (68, 76))	('migration', 'CPA', (54, 63))
158280	25120647	The default search parameters were applied as follows: Enzyme, trypsin; taxonomy, Homo sapiens (human); maximum missed cleavages, 1; fixed modifications, carbamidomethyl (C); variable modifications, oxidation (M); peptide tolerance, +-1.2 Da; MS/MS tolerance, +-0.6 Da; peptide charge, 1+, 2+ and 3+; and instrument, ESI-QUAD-TOF.	('ESI-QUAD-TOF', 'Disease', (317, 329))	('human', 'Species', '9606', (96, 101))	('+-1.2', 'Var', (233, 238))	('Homo sapiens', 'Species', '9606', (82, 94))	('+-0.6', 'Var', (260, 265))	('ESI-QUAD-TOF', 'Disease', 'MESH:D013771', (317, 329))
158284	25120647	L-plastin siRNA (Santa Cruz Biotechnology) was used to knock down L-plastin gene expression.	('L-plastin', 'Gene', '3936', (66, 75))	('L-plastin', 'Gene', (0, 9))	('L-plastin', 'Gene', '3936', (0, 9))	('knock', 'Var', (55, 60))	('L-plastin', 'Gene', (66, 75))	('expression', 'MPA', (81, 91))
158311	25120647	To determine whether the expression of L-plastin is associated with cholangiocarcinoma cell invasion, we knocked down the expression of L-plastin using L-plastin siRNA.	('L-plastin', 'Gene', (152, 161))	('knocked', 'Var', (105, 112))	('L-plastin', 'Gene', '3936', (152, 161))	('L-plastin', 'Gene', (39, 48))	('associated', 'Reg', (52, 62))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (68, 86))	('L-plastin', 'Gene', (136, 145))	('L-plastin', 'Gene', '3936', (39, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (68, 86))	('L-plastin', 'Gene', '3936', (136, 145))	('cholangiocarcinoma', 'Disease', (68, 86))
158368	34012920	Acceptable function of vital organs: absolute neutrophil count (ANC) >=1.5 x 109/L; platelet count >=75 x 109/L; hemoglobin >=8 g/dl; serum proteins >=2.8 g/dl; serum total bilirubin <=3 times upper limit of normal value (ULN), and ALT and AST <=2.5 times ULN (if liver metastasis is present, ALT and AST <=5 times ULN); creatinine clearance >=50 ml/min; 7.	('>=2.8', 'Var', (149, 154))	('bilirubin', 'Chemical', 'MESH:D001663', (173, 182))	('AST', 'Gene', (240, 243))	('AST', 'Gene', '26503', (240, 243))	('>=8', 'Var', (124, 127))	('AST', 'Gene', (301, 304))	('>=75', 'Var', (99, 103))	('serum proteins', 'MPA', (134, 148))	('ALT', 'MPA', (232, 235))	('creatinine', 'Chemical', 'MESH:D003404', (321, 331))	('AST', 'Gene', '26503', (301, 304))	('creatinine clearance', 'MPA', (321, 341))
158456	34012920	The advent of genome-wide analyses using next-generation sequencing technologies have demonstrated the landscape of molecular mutations and identified several driver genetic alterations in bile duct cancer; for example, intracholangiocarcinoma have the highest of mutations in isocitrate dehydrogenase 1 (IDH1), and fibroblast growth factor receptor (FGFR) fusions which are of special interest, because they are not detectable in other liver malignancies, whereas the most prominent mutated gene extracholangiocarcinoma is BRAF.	('mutations', 'Var', (264, 273))	('BRAF', 'Gene', '673', (524, 528))	('BRAF', 'Gene', (524, 528))	('extracholangiocarcinoma', 'Disease', 'None', (497, 520))	('IDH1', 'Gene', '3417', (305, 309))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (502, 520))	('bile duct cancer', 'Phenotype', 'HP:0030153', (189, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('bile duct cancer', 'Disease', (189, 205))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (225, 243))	('bile duct cancer', 'Disease', 'MESH:D001650', (189, 205))	('liver malignancies', 'Phenotype', 'HP:0002896', (437, 455))	('extracholangiocarcinoma', 'Disease', (497, 520))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('liver malignancies', 'Disease', 'MESH:D017093', (437, 455))	('intracholangiocarcinoma', 'Disease', (220, 243))	('highest', 'Reg', (253, 260))	('isocitrate dehydrogenase 1', 'Gene', (277, 303))	('isocitrate dehydrogenase 1', 'Gene', '3417', (277, 303))	('liver malignancies', 'Disease', (437, 455))	('intracholangiocarcinoma', 'Disease', 'None', (220, 243))	('IDH1', 'Gene', (305, 309))	('carcinoma', 'Phenotype', 'HP:0030731', (511, 520))	('FGFR', 'Gene', (351, 355))
158458	34012920	The inhibition of the IDH1 mutation through its inhibitor ivosidenib represents a recent breakthrough in second-line therapy for cholangiocarcinoma, dramatically improved median PFS (2.7 months vs 1.4 months, HR = 0.37, one-sided p < 0.0001) compared with placebo.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('PFS', 'MPA', (178, 181))	('ivosidenib', 'Chemical', 'MESH:C000627630', (58, 68))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (129, 147))	('improved', 'PosReg', (162, 170))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (129, 147))	('mutation', 'Var', (27, 35))	('IDH1', 'Gene', (22, 26))	('IDH1', 'Gene', '3417', (22, 26))	('inhibition', 'NegReg', (4, 14))	('cholangiocarcinoma', 'Disease', (129, 147))
158498	34012920	Subgroup analysis indicated that both mOS (14.0 months versus 6.5 months, P = 0.001, chi2 = 10.085) and mPFS (10.3 months versus 4.5 months, P = 0.003, chi2 = 8.835) were prolonged in the apatinib plus TACE group compared with the apatinib alone, and further univariate Cox's regression analysis yielded that apatinib plus cTACE (vs. apatinib) were associated with increased mPFS (HR = 0.196, P = 0.004) and mOS (HR = 0.013, P < 0.001).	('mOS', 'Gene', '17451', (408, 411))	('mPFS', 'CPA', (375, 379))	('apatinib plus cTACE', 'Var', (309, 328))	('mOS', 'Gene', (38, 41))	('TACE', 'Chemical', '-', (202, 206))	('apatinib', 'Chemical', 'MESH:C553458', (231, 239))	('increased', 'PosReg', (365, 374))	('mOS', 'Gene', '17451', (38, 41))	('apatinib', 'Chemical', 'MESH:C553458', (334, 342))	('mPFS', 'CPA', (104, 108))	('apatinib', 'Chemical', 'MESH:C553458', (188, 196))	('mOS', 'Gene', (408, 411))	('TACE', 'Chemical', '-', (324, 328))	('apatinib', 'Chemical', 'MESH:C553458', (309, 317))
158579	33962620	P-Group H and p-Group U patients had tumor infiltration into bile ducts significantly more frequently than those in p-Group P. Figure 2a shows that the overall survival of patients in p-Group P was better than that of those in p-Group H and p-Group U (p = 0.098, < 0.05, respectively).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('better', 'PosReg', (198, 204))	('p-Group P', 'Var', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (172, 180))
158580	33962620	2b shows that disease-free survival of patients in p-Group P was significantly better than that of those in p-Group H and p-Group U (p < 0.05).	('better', 'PosReg', (79, 85))	('disease-free survival', 'CPA', (14, 35))	('patients', 'Species', '9606', (39, 47))	('p-Group', 'Var', (51, 58))
158651	32726292	Laboratory investigations comprehend serum tumour markers including CA19-9 and CEA.	('CEA', 'Gene', '5670', (79, 82))	('tumour', 'Disease', (43, 49))	('CA19-9', 'Var', (68, 74))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('CEA', 'Gene', (79, 82))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
158724	32726292	Several genetic modifications, epigenetic alterations, gene fusions products (including FGFR2 gene fusion), hormone influences (including evaluation of tumour estrogen sensitivity) and growth factors effects have been assessed and are still under continuous evaluation.	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('tumour', 'Disease', (152, 158))	('gene fusion', 'Var', (94, 105))	('FGFR2', 'Gene', (88, 93))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('FGFR2', 'Gene', '2263', (88, 93))
158727	32726292	For example, while KRAS mutation has been found in patients experiencing recurrence, FGFR gene fusion seems related with an indolent disease.	('FGFR', 'Gene', (85, 89))	('gene fusion', 'Var', (90, 101))	('KRAS', 'Gene', (19, 23))	('indolent disease', 'Disease', (124, 140))	('KRAS', 'Gene', '3845', (19, 23))	('patients', 'Species', '9606', (51, 59))	('related', 'Reg', (108, 115))
158759	30984349	Univariate and multivariate analyses revealed both decreased overall survival [hazard ratio (HR): 2.88, 95%CI: 1.19-5.78] and recurrence-free survival (HR: 2.31, 95%CI: 1.40-3.29) in patients with AAPR < 0.41 compared to those with AAPR >= 0.41.	('AAPR < 0.41', 'Var', (197, 208))	('decreased', 'NegReg', (51, 60))	('recurrence-free survival', 'CPA', (126, 150))	('overall survival', 'CPA', (61, 77))	('patients', 'Species', '9606', (183, 191))
158762	30984349	Moreover, it is necessary to investigate the mechanisms concerning the correlation of low AAPR with poor post-operative survival in CCA patients.	('CCA', 'Disease', (132, 135))	('patients', 'Species', '9606', (136, 144))	('CCA', 'Phenotype', 'HP:0030153', (132, 135))	('AAPR', 'Gene', (90, 94))	('low', 'Var', (86, 89))
158786	30984349	The RFS was significantly prolonged in the high AAPR group compared to the low AAPR group (P = 0.017) (Figure 1B).	('prolonged', 'PosReg', (26, 35))	('high AAPR', 'Var', (43, 52))	('RFS', 'MPA', (4, 7))	('RFS', 'Chemical', '-', (4, 7))
158879	27871980	Based upon these considerations, doses of 0, 0.02, 0.044, 0.092, 0.2, 0.44, 0.92 and 2.0 mg furan/kg BW were selected for the 2-year bioassay (Table 1).	('0.044', 'Var', (51, 56))	('0.2', 'Var', (65, 68))	('0.02', 'Var', (45, 49))	('0.92', 'Var', (76, 80))	('furan', 'Chemical', 'MESH:C039281', (92, 97))	('0.44', 'Var', (70, 74))	('rat', 'Species', '10116', (24, 27))	('0.092', 'Var', (58, 63))
158886	27871980	While the NCTR sub-strain differs from the Charles River sub-strain used in the previous furan bioassay, the NCTR F344/N sub-strain has given tumorigenic responses comparable to those of other F344/N sub-strains in previously reported carcinogenicity bioassays (e.g., acrylamide).	('carcinogenic', 'Disease', (235, 247))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('F344/N', 'Var', (114, 120))	('C', 'Chemical', 'MESH:D002244', (110, 111))	('tumor', 'Disease', (142, 147))	('C', 'Chemical', 'MESH:D002244', (43, 44))	('furan', 'Chemical', 'MESH:C039281', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('carcinogenic', 'Disease', 'MESH:D063646', (235, 247))	('acrylamide', 'Chemical', 'MESH:D020106', (268, 278))	('C', 'Chemical', 'MESH:D002244', (11, 12))
158913	27871980	Male F344/N Nctr rats were administered 0, 0.02, 0.044, 0.092, 0.2, 0.44, 0.92, and 2.0 mg furan/kg BW by gavage in corn oil 5 days/week for 2 years (104 weeks), with interim sacrifices conducted at 9 (36 weeks) and 15 (60 weeks) months (Table 1).	('0.044', 'Var', (49, 54))	('0.092', 'Var', (56, 61))	('rats', 'Species', '10116', (17, 21))	('0.2', 'Var', (63, 66))	('furan', 'Chemical', 'MESH:C039281', (91, 96))	('corn', 'Species', '4577', (116, 120))	('0.44', 'Var', (68, 72))
158925	27871980	Male F344/N Nctr rats had dose-related increases in the incidence of mononuclear cell leukemia, with the increase in incidence being significant at 0.092, 0.2, 0.92, and 2 mg furan/kg BW (Table 2).	('rats', 'Species', '10116', (17, 21))	('0.2', 'Var', (155, 158))	('furan', 'Chemical', 'MESH:C039281', (175, 180))	('0.092', 'Var', (148, 153))	('0.92', 'Var', (160, 164))	('leukemia', 'Disease', (86, 94))	('leukemia', 'Phenotype', 'HP:0001909', (86, 94))	('leukemia', 'Disease', 'MESH:D007938', (86, 94))	('increases', 'PosReg', (39, 48))
158930	27871980	Significant increases in cholangiofibrosis, bile duct subcapsular hyperplasia, and subcapsular fibrosis, chronic inflammation, and pigmentation were observed at 0.44 mg furan/kg BW.	('cholangiofibrosis', 'Disease', 'None', (25, 42))	('0.44 mg', 'Var', (161, 168))	('hyperplasia', 'Disease', 'MESH:D006965', (66, 77))	('inflammation', 'Disease', 'MESH:D007249', (113, 125))	('fibrosis', 'Disease', (34, 42))	('furan', 'Chemical', 'MESH:C039281', (169, 174))	('pigmentation', 'Disease', 'MESH:D010859', (131, 143))	('fibrosis', 'Disease', 'MESH:D005355', (34, 42))	('bile duct subcapsular hyperplasia', 'Phenotype', 'HP:0006560', (44, 77))	('cholangiofibrosis', 'Disease', (25, 42))	('subcapsular fibrosis', 'Phenotype', 'HP:0000523', (83, 103))	('inflammation', 'Disease', (113, 125))	('increases', 'PosReg', (12, 21))	('pigmentation', 'Disease', (131, 143))	('hyperplasia', 'Disease', (66, 77))	('fibrosis', 'Disease', 'MESH:D005355', (95, 103))	('fibrosis', 'Disease', (95, 103))	('subcapsular hyperplasia', 'Phenotype', 'HP:0000523', (54, 77))
158935	27871980	For example, in the 60-week rats, the incidence of subcapsular fibrosis, chronic inflammation, and pigmentation became significant at 0.2 mg furan/kg BW (as compared to 0.44 mg furan/kg BW at 36 weeks).	('furan', 'Chemical', 'MESH:C039281', (141, 146))	('fibrosis', 'Disease', 'MESH:D005355', (63, 71))	('rats', 'Species', '10116', (28, 32))	('fibrosis', 'Disease', (63, 71))	('furan', 'Chemical', 'MESH:C039281', (177, 182))	('inflammation', 'Disease', 'MESH:D007249', (81, 93))	('inflammation', 'Disease', (81, 93))	('subcapsular fibrosis', 'Phenotype', 'HP:0000523', (51, 71))	('pigmentation', 'Disease', 'MESH:D010859', (99, 111))	('0.2 mg', 'Var', (134, 140))	('pigmentation', 'Disease', (99, 111))
158937	27871980	The incidence of cholangiofibrosis was significantly increased at 0.2 mg furan/kg BW, and a single occurrence was observed at 0.092 mg furan/kg BW.	('furan', 'Chemical', 'MESH:C039281', (73, 78))	('cholangiofibrosis', 'Disease', 'None', (17, 34))	('0.2 mg', 'Var', (66, 72))	('furan', 'Chemical', 'MESH:C039281', (135, 140))	('cholangiofibrosis', 'Disease', (17, 34))	('increased', 'PosReg', (53, 62))
159002	27871980	Promoter region hypermethylation was observed in the tumor suppressor genes p16IKN4a and Rassf1a, and this was accompanied by a decreased expression of Rassf1a.	('Rassf1a', 'Gene', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('hypermethylation', 'Var', (16, 32))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('p16IKN4a', 'Gene', (76, 84))	('Rassf1a', 'Gene', (152, 159))	('expression', 'MPA', (138, 148))	('decreased', 'NegReg', (128, 137))	('tumor', 'Disease', (53, 58))
159009	27871980	In contrast to Areg and Jag 1, hypermethylation of the promoter region and decreased gene expression was found with Foxe1, which encodes a thyroid-specific forkhead transcription factor that represses transcription of several rat genes, including fibrogenesis-associated Duox2 and Adamts1 genes.	('Adamts1', 'Gene', (281, 288))	('Foxe1', 'Gene', (116, 121))	('fibrogenesis-associated', 'Disease', (247, 270))	('hypermethylation', 'Var', (31, 47))	('Areg', 'Gene', (15, 19))	('Foxe1', 'Gene', '192274', (116, 121))	('Duox2', 'Gene', '79107', (271, 276))	('Adamts1', 'Gene', '79252', (281, 288))	('Jag 1', 'Gene', '29146', (24, 29))	('transcription', 'MPA', (201, 214))	('represses', 'NegReg', (191, 200))	('Duox2', 'Gene', (271, 276))	('rat', 'Species', '10116', (226, 229))	('Areg', 'Gene', '29183', (15, 19))	('Jag 1', 'Gene', (24, 29))
159010	27871980	Therefore, hypermethylation-associated inhibition of Foxe1 expression may cause activation of these genes and stimulation of liver fibrogenesis.	('liver fibrogenesis', 'CPA', (125, 143))	('inhibition', 'NegReg', (39, 49))	('liver fibrogenesis', 'Phenotype', 'HP:0001395', (125, 143))	('expression', 'MPA', (59, 69))	('stimulation', 'PosReg', (110, 121))	('hypermethylation-associated', 'Var', (11, 38))	('Foxe1', 'Gene', '192274', (53, 58))	('Foxe1', 'Gene', (53, 58))	('activation', 'PosReg', (80, 90))
159011	27871980	These results indicate that gene-specific changes in DNA methylation have functional consequences that may be important for the induction of cholangiofibrosis and subsequently cholangiocarcinoma.	('methylation', 'Var', (57, 68))	('cholangiocarcinoma', 'Disease', (176, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('cholangiofibrosis', 'Disease', 'None', (141, 158))	('DNA', 'Protein', (53, 56))	('changes', 'Var', (42, 49))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (176, 194))	('cholangiofibrosis', 'Disease', (141, 158))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (176, 194))
159062	28293379	Another clue that should raise suspicion for CHC pre-operatively is discordant tumor markers.	('CHC', 'Disease', (45, 48))	('tumor', 'Disease', (79, 84))	('discordant', 'Var', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('CHC', 'Disease', 'MESH:D019698', (45, 48))	('CHC', 'Phenotype', 'HP:0030153', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
159066	28293379	Although histogenesis of the CHC has been a topic of debate, three types of tumor origins have been hypothesized: (1) collision tumors; (2) de-differentiation or re-differentiation of a primary HCC into a biliary phenotype or vice versa; (3) derivation from bipotent HPC.	('de-differentiation', 'Var', (140, 158))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CHC', 'Phenotype', 'HP:0030153', (29, 32))	('collision tumors', 'Disease', 'MESH:D009369', (118, 134))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('re-differentiation', 'CPA', (162, 180))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('CHC', 'Disease', (29, 32))	('tumor', 'Disease', (128, 133))	('bipotent HPC', 'Disease', 'MESH:C537262', (258, 270))	('collision tumors', 'Disease', (118, 134))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('HCC', 'Gene', '619501', (194, 197))	('CHC', 'Disease', 'MESH:D019698', (29, 32))	('HCC', 'Phenotype', 'HP:0001402', (194, 197))	('bipotent HPC', 'Disease', (258, 270))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('HCC', 'Gene', (194, 197))
159086	28293379	Analysis of copy number changes in CC and HCC components of CHC showed concordance in the overall trend of gain or loss for several target genes although magnitude of copy number change differed.	('copy number', 'Var', (12, 23))	('loss', 'NegReg', (115, 119))	('CHC', 'Disease', 'MESH:D019698', (60, 63))	('HCC', 'Gene', (42, 45))	('CHC', 'Disease', (60, 63))	('CHC', 'Phenotype', 'HP:0030153', (60, 63))	('HCC', 'Gene', '619501', (42, 45))	('gain', 'Disease', (107, 111))	('gain', 'Disease', 'MESH:D015430', (107, 111))	('HCC', 'Phenotype', 'HP:0001402', (42, 45))
159087	28293379	The copy number gains in the CC component were likely to be paired with a similar but not identical copy number gain in the HCC component of the tumor, with the same holding true for copy number losses.	('HCC', 'Phenotype', 'HP:0001402', (124, 127))	('HCC component of the tumor', 'Disease', (124, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('gain', 'Disease', (16, 20))	('gain', 'Disease', 'MESH:D015430', (16, 20))	('gain', 'Disease', (112, 116))	('HCC component of the tumor', 'Disease', 'MESH:D006528', (124, 150))	('gain', 'Disease', 'MESH:D015430', (112, 116))	('copy number', 'Var', (100, 111))
159094	28293379	A recent whole genome sequencing analysis showed that genome-wide substitution patterns in liver cancers of biliary phenotype (both CC and CHC) overlapped with those of HCC in cases associated with chronic viral hepatitis, while biliary cancers (mostly CC in this study) unrelated to chronic hepatitis differed from HCC.	('liver cancers', 'Disease', 'MESH:D006528', (91, 104))	('CHC', 'Disease', 'MESH:D019698', (139, 142))	('chronic viral hepatitis', 'Disease', 'MESH:D006525', (198, 221))	('liver cancer', 'Phenotype', 'HP:0002896', (91, 103))	('HCC', 'Gene', '619501', (316, 319))	('liver cancers', 'Phenotype', 'HP:0002896', (91, 104))	('HCC', 'Phenotype', 'HP:0001402', (316, 319))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('biliary cancers', 'Disease', 'MESH:D001661', (229, 244))	('HCC', 'Gene', (316, 319))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (284, 301))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('CHC', 'Phenotype', 'HP:0030153', (139, 142))	('biliary cancers', 'Disease', (229, 244))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('hepatitis', 'Phenotype', 'HP:0012115', (212, 221))	('viral hepatitis', 'Phenotype', 'HP:0006562', (206, 221))	('hepatitis', 'Phenotype', 'HP:0012115', (292, 301))	('liver cancers', 'Disease', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('hepatitis', 'Disease', 'MESH:D056486', (212, 221))	('biliary', 'Disease', (108, 115))	('hepatitis', 'Disease', 'MESH:D056486', (292, 301))	('substitution', 'Var', (66, 78))	('hepatitis', 'Disease', (212, 221))	('HCC', 'Gene', '619501', (169, 172))	('HCC', 'Phenotype', 'HP:0001402', (169, 172))	('hepatitis', 'Disease', (292, 301))	('HCC', 'Gene', (169, 172))	('CHC', 'Disease', (139, 142))	('chronic viral hepatitis', 'Disease', (198, 221))
159132	28293379	CAM 5.2 and AE1 can also be useful to differentiate between HCC and CC component; HCC will be positive for CAM5.2 while AE1 will be positive in CC component.	('AE1', 'Gene', (120, 123))	('HCC', 'Gene', (82, 85))	('AE1', 'Gene', '6521', (120, 123))	('HCC', 'Gene', '619501', (60, 63))	('HCC', 'Gene', '619501', (82, 85))	('HCC', 'Phenotype', 'HP:0001402', (60, 63))	('AE1', 'Gene', '6521', (12, 15))	('HCC', 'Phenotype', 'HP:0001402', (82, 85))	('AE1', 'Gene', (12, 15))	('positive', 'Reg', (94, 102))	('CAM5.2', 'Var', (107, 113))	('HCC', 'Gene', (60, 63))
159138	28293379	Survival of patients with high expression of DLK1 is worse suggesting that patients with CHC with stem cell features do worse in comparison to classical type CHC.	('patients', 'Species', '9606', (12, 20))	('DLK1', 'Gene', '8788', (45, 49))	('high expression', 'Var', (26, 41))	('DLK1', 'Gene', (45, 49))	('patients', 'Species', '9606', (75, 83))	('CHC', 'Disease', 'MESH:D019698', (89, 92))	('CHC', 'Disease', 'MESH:D019698', (158, 161))	('CHC', 'Phenotype', 'HP:0030153', (158, 161))	('CHC', 'Disease', (89, 92))	('CHC', 'Phenotype', 'HP:0030153', (89, 92))	('CHC', 'Disease', (158, 161))
159161	28293379	Adverse clinicopathologic prognostic factors associated with increased tumor recurrence and worse survival in various studies include large tumor size (> 5 cm), presence of satellite nodules, lymph node involvement, multifocality, vascular invasion, portal vein invasion, high tumor stage, high levels of CA 19-9, decreased capsule formation, free surgical resection margins < 2 cm, and GGT levels > 60 U/L.	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('increased', 'PosReg', (61, 70))	('lymph node involvement', 'CPA', (192, 214))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('GGT', 'Gene', (387, 390))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('portal vein invasion', 'CPA', (250, 270))	('high', 'Var', (290, 294))	('multifocality', 'Var', (216, 229))	('vascular invasion', 'CPA', (231, 248))	('tumor', 'Disease', (277, 282))	('tumor', 'Disease', (71, 76))	('capsule formation', 'CPA', (324, 341))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('GGT', 'Gene', '653590', (387, 390))	('decreased', 'NegReg', (314, 323))	('tumor', 'Disease', (140, 145))
159187	26486326	The karyotype is highly complex, with a hypotriploid to hypertriploid modal number (3n+/-) (52 to 77 chromosomes); low level of HER2 gene amplification, TP53 deletion, gain of AURKA were identified; K-RAS G12D mutation were maintained from primary tumor to MT-CHC01 cells.	('HER2', 'Gene', (128, 132))	('K-RAS', 'Gene', '3845', (199, 204))	('primary tumor', 'Disease', (240, 253))	('AURKA', 'Gene', '6790', (176, 181))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (257, 265))	('HER2', 'Gene', '2064', (128, 132))	('gain', 'PosReg', (168, 172))	('K-RAS', 'Gene', (199, 204))	('primary tumor', 'Disease', 'MESH:D009369', (240, 253))	('G12D', 'Mutation', 'rs121913529', (205, 209))	('AURKA', 'Gene', (176, 181))	('TP53', 'Gene', (153, 157))	('TP53', 'Gene', '7157', (153, 157))	('hypotriploid to hypertriploid modal number', 'Disease', (40, 82))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('deletion', 'Var', (158, 166))	('hypotriploid to hypertriploid modal number', 'Disease', 'MESH:D007674', (40, 82))	('G12D', 'Var', (205, 209))
159256	26486326	After the quantification with NanoDrop, 2 mug of genomic DNA of both tumor DNA and control DNA from Promega (Human Genomic DNA Female N 30742202/male N 30993901) were labeled with CY5-dCTPs and CY3-dCTP, respectively, and hybridized on glass array 2 X105 K at 65  C for 40 h at 20 rpm.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Human', 'Species', '9606', (109, 114))	('CY5-dCTPs', 'Var', (180, 189))	('X105 K', 'Mutation', 'p.X105K', (250, 256))	('CY3-dCTP', 'Chemical', '-', (194, 202))	('tumor', 'Disease', (69, 74))	('CY5-dCTPs', 'Chemical', 'MESH:C544355', (180, 189))	('P', 'Chemical', 'MESH:D010758', (201, 202))	('P', 'Chemical', 'MESH:D010758', (100, 101))	('CY3-dCTP', 'Var', (194, 202))	('P', 'Chemical', 'MESH:D010758', (187, 188))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
159258	26486326	FISH analysis was performed using the following probes: ALK (2p23) Break Apart Rearrangement probe (Vysis, Downers Grove, IL, USA), dual color AURKA (20q13)/CEN20 probe (Kreatech Diagnostics, Amsterdam, Netherlands), dual color EGFR (7p12)/CEP7 probe (Vysis), dual color HER2 (17q11.2)/CEP17 (DAKO, Glostrup, Denmark), dual color MET (7q31.2)/CEP7 probe (Vysis) and dual color TP53 (17p13.1)/CEP17 (Vysis) and Del(5q) Deletion probe (Cytocell, Cambridge, UK).	('S', 'Chemical', 'MESH:D013455', (127, 128))	('P', 'Chemical', 'MESH:D010758', (394, 395))	('P', 'Chemical', 'MESH:D010758', (378, 379))	('P', 'Chemical', 'MESH:D010758', (345, 346))	('P', 'Chemical', 'MESH:D010758', (242, 243))	('TP53', 'Gene', (377, 381))	('EGFR', 'Gene', '1956', (228, 232))	('HER2', 'Gene', (271, 275))	('P', 'Chemical', 'MESH:D010758', (288, 289))	('Break Apart', 'Phenotype', 'HP:0001061', (67, 78))	('S', 'Chemical', 'MESH:D013455', (2, 3))	('AURKA', 'Gene', '6790', (143, 148))	('TP53', 'Gene', '7157', (377, 381))	('Del(5q) Deletion probe', 'Var', (410, 432))	('AURKA', 'Gene', (143, 148))	('ALK', 'Gene', '238', (56, 59))	('EGFR', 'Gene', (228, 232))	('ALK', 'Gene', (56, 59))	('HER2', 'Gene', '2064', (271, 275))
159282	26486326	Figure 4a-d shows that the wound in MT-CHC01 cells was significantly closed at 24, 48, and 72 h after the wound; the migration potential of MT-CHC01 is lower if compared to other commercial cell lines such as HuH28 (Fig.	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (140, 148))	('HuH28', 'CellLine', 'CVCL:2955', (209, 214))	('MT-CHC01', 'Var', (140, 148))	('migration potential', 'CPA', (117, 136))	('lower', 'NegReg', (152, 157))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (36, 44))
159283	26486326	4f-i), in which we observed that MT-CHC01 cells had a lower migration potential rate (Fig.	('MT-CHC01', 'Var', (33, 41))	('migration potential rate', 'CPA', (60, 84))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (33, 41))	('lower', 'NegReg', (54, 59))
159286	26486326	In three independent experiments of ten mice each, MT-CHC01 cells were able to develop tumor in all animals.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('MT-CHC01', 'Var', (51, 59))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (51, 59))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mice', 'Species', '10090', (40, 44))
159315	26486326	In soft agar medium, MT-CHC01 cells revealed the ability to grow in anchorage-independent manner as cellular aggregates; in low attachment and serum-free culture conditions in stem cell medium, MT-CHC01 originated spheroid structures.	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (21, 29))	('MT-CHC01', 'Var', (194, 202))	('spheroid structures', 'CPA', (214, 233))	('agar', 'Chemical', 'MESH:D000362', (8, 12))	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (194, 202))
159327	26486326	The complex karyotype of MT-CHC01 was further confirmed by aCGH analysis; it revealed a huge number of chromosomic aberrations; in particular, there is the gain of chr 2q, 3q, 12p, and the loss of 3p, 5q, 6p, 8p, 9p, 18q, already described in BTC by Rijken and collaborators.	('MT-CHC01', 'CellLine', 'CVCL:4Z41', (25, 33))	('12p', 'Var', (176, 179))	('gain', 'PosReg', (156, 160))	('chr 2q', 'Var', (164, 170))	('loss', 'NegReg', (189, 193))
159335	22007315	Fibrocystin/polyductin, the gene product responsible for ARPKD, is normally localized to primary cilia, and defects in the fibrocystin from primary cilia are observed in PCK cholangiocytes.	('defects', 'Var', (108, 115))	('ARPKD', 'Gene', (57, 62))	('ARPKD', 'Gene', '5314', (57, 62))	('PCK', 'Phenotype', 'HP:0000113', (170, 173))
159336	22007315	Ciliopathies involving PCK cholangiocytes (cholangiociliopathies) appear to be associated with decreased intracellular calcium levels and increased cAMP concentrations, causing cholangiocyte hyperproliferation, abnormal cell matrix interactions, and altered fluid secretion, which ultimately result in bile duct dilatation.	('rat', 'Species', '10116', (160, 163))	('cholangiocyte hyperproliferation', 'Disease', (177, 209))	('cAMP', 'Gene', (148, 152))	('intracellular calcium levels', 'MPA', (105, 133))	('increased', 'PosReg', (138, 147))	('cAMP', 'Gene', '316010', (148, 152))	('PCK', 'Phenotype', 'HP:0000113', (23, 26))	('Ciliopathies', 'Disease', (0, 12))	('fluid secretion', 'MPA', (258, 273))	('abnormal', 'Reg', (211, 219))	('decreased', 'NegReg', (95, 104))	('causing', 'Reg', (169, 176))	('altered', 'Reg', (250, 257))	('calcium', 'Chemical', 'MESH:D002118', (119, 126))	('bile duct dilatation', 'Phenotype', 'HP:0006560', (302, 322))	('rat', 'Species', '10116', (203, 206))	('cell matrix interactions', 'CPA', (220, 244))	('bile duct dilatation', 'Disease', (302, 322))	('PCK', 'Var', (23, 26))	('abnormal cell matrix', 'Phenotype', 'HP:0031377', (211, 231))	('result in', 'Reg', (292, 301))	('dilatation', 'Phenotype', 'HP:0002617', (312, 322))
159413	22007315	ARPKD is caused by mutations in a single gene, PKHD1, which has been localized to chromosome 6p21.1-p12.	('caused by', 'Reg', (9, 18))	('ARPKD', 'Gene', (0, 5))	('mutations', 'Var', (19, 28))	('PKHD1', 'Gene', (47, 52))	('ARPKD', 'Gene', '5314', (0, 5))
159416	22007315	Mutations in PKHD1 have also been identified in patients with Caroli's disease.	('PKHD1', 'Gene', (13, 18))	("Caroli's disease", 'Disease', 'MESH:D016767', (62, 78))	("Caroli's disease", 'Disease', (62, 78))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (34, 44))	('patients', 'Species', '9606', (48, 56))
159428	22007315	The polycystic disease it suffers from is inherited in an autosomal recessive manner, and this model has a spontaneous mutation in its Pkhd1 gene, an ortholog of human PKHD1.	('mutation', 'Var', (119, 127))	('Pkhd1', 'Gene', (135, 140))	('human', 'Species', '9606', (162, 167))	('polycystic disease', 'Disease', (4, 22))	('polycystic disease', 'Disease', 'MESH:D007690', (4, 22))
159443	22007315	Hyperproliferation of the PCK cholangiocytes in response to PKA stimulation is associated with decreased intracellular calcium levels, and the restoration of calcium levels blocks PKA-dependent proliferation via the PI3K/AKT pathway.	('decreased', 'NegReg', (95, 104))	('PKA', 'Gene', (60, 63))	('intracellular calcium levels', 'MPA', (105, 133))	('rat', 'Species', '10116', (148, 151))	('rat', 'Species', '10116', (201, 204))	('rat', 'Species', '10116', (12, 15))	('AKT', 'Gene', (221, 224))	('PKA', 'Gene', '25636', (180, 183))	('calcium', 'Chemical', 'MESH:D002118', (158, 165))	('calcium', 'Chemical', 'MESH:D002118', (119, 126))	('PKA', 'Gene', '25636', (60, 63))	('AKT', 'Gene', '24185', (221, 224))	('PCK', 'Phenotype', 'HP:0000113', (26, 29))	('restoration', 'Var', (143, 154))	('blocks', 'NegReg', (173, 179))	('PKA', 'Gene', (180, 183))
159448	22007315	Thus, dysregulated cell kinetics may be involved in the biliary abnormalities associated with PCK rats.	('dysregulated', 'Var', (6, 18))	('rats', 'Species', '10116', (98, 102))	('PCK', 'Phenotype', 'HP:0000113', (94, 97))	('biliary abnormalities', 'Disease', (56, 77))	('biliary abnormalities', 'Phenotype', 'HP:0001080', (56, 77))	('cell kinetics', 'MPA', (19, 32))	('biliary abnormalities', 'Disease', 'MESH:D001657', (56, 77))	('involved', 'Reg', (40, 48))
159450	22007315	Indeed, bile secretion is increased in the PCK rats compared with that in age-matched normal rats.	('PCK', 'Var', (43, 46))	('increased', 'PosReg', (26, 35))	('rats', 'Species', '10116', (93, 97))	('PCK', 'Phenotype', 'HP:0000113', (43, 46))	('bile secretion', 'MPA', (8, 22))	('rats', 'Species', '10116', (47, 51))
159457	22007315	In PCK rats, a splicing mutation in Pkhd1 results in structural and functional ciliary abnormalities.	('functional ciliary abnormalities', 'Disease', (68, 100))	('splicing mutation', 'Var', (15, 32))	('rats', 'Species', '10116', (7, 11))	('functional ciliary abnormalities', 'Disease', 'MESH:D002925', (68, 100))	('ciliary abnormalities', 'Phenotype', 'HP:0012776', (79, 100))	('Pkhd1', 'Gene', (36, 41))	('results in', 'Reg', (42, 52))	('PCK', 'Phenotype', 'HP:0000113', (3, 6))
159459	22007315	Other calcium channels such as Trpv4 are present in cholangiocyte cilia, and the activation of Trpv4 leads to increased intracellular calcium levels and reduces the hyperproliferative phenotype of PCK cholangiocytes.	('intracellular calcium levels', 'MPA', (120, 148))	('rat', 'Species', '10116', (177, 180))	('increased', 'PosReg', (110, 119))	('Trpv4', 'Gene', '66026', (31, 36))	('Trpv4', 'Gene', (95, 100))	('reduces', 'NegReg', (153, 160))	('calcium', 'Chemical', 'MESH:D002118', (6, 13))	('calcium', 'Chemical', 'MESH:D002118', (134, 141))	('PCK', 'Phenotype', 'HP:0000113', (197, 200))	('increased intracellular calcium', 'Phenotype', 'HP:0003575', (110, 141))	('activation', 'Var', (81, 91))	('Trpv4', 'Gene', (31, 36))	('hyperproliferative phenotype', 'CPA', (165, 193))	('Trpv4', 'Gene', '66026', (95, 100))
159489	22007315	The activation of calcium-sensing receptors with R-568 reduces the interstitial fibrosis, but not the cystogenesis, of the PCK kidney.	('calcium', 'Chemical', 'MESH:D002118', (18, 25))	('interstitial fibrosis', 'Phenotype', 'HP:0005576', (67, 88))	('R-568', 'Var', (49, 54))	('reduces', 'NegReg', (55, 62))	('interstitial', 'MPA', (67, 79))	('R-568', 'Chemical', 'MESH:C107873', (49, 54))	('PCK', 'Phenotype', 'HP:0000113', (123, 126))	('fibrosis', 'Disease', 'MESH:D005355', (80, 88))	('fibrosis', 'Disease', (80, 88))
159498	21738807	Developmental Transcriptomic Features of the Carcinogenic Liver Fluke, Clonorchis sinensis Clonorchis sinensis is the causative agent of the life-threatening disease endemic to China, Korea, and Vietnam.	('Clonorchis sinensis', 'Var', (91, 110))	('Clonorchis sinensis', 'Species', '79923', (71, 90))	('Clonorchis sinensis', 'Species', '79923', (91, 110))	('Carcinogenic Liver Fluke', 'Disease', (45, 69))	('Carcinogenic Liver Fluke', 'Disease', 'MESH:D008107', (45, 69))
159500	21738807	C. sinensis provokes inflammation, epithelial hyperplasia, and periductal fibrosis in bile ducts, and may cause cholangiocarcinoma in chronically infected individuals.	('fibrosis', 'Disease', (74, 82))	('C. sinensis', 'Var', (0, 11))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 130))	('cause', 'Reg', (106, 111))	('cholangiocarcinoma', 'Disease', (112, 130))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('C. sinensis', 'Species', '79923', (0, 11))	('chronically infected', 'Disease', (134, 154))	('inflammation', 'Disease', 'MESH:D007249', (21, 33))	('inflammation', 'Disease', (21, 33))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (35, 57))	('provokes', 'Reg', (12, 20))	('chronically infected', 'Disease', 'MESH:D006505', (134, 154))	('epithelial hyperplasia', 'Disease', (35, 57))	('fibrosis', 'Disease', 'MESH:D005355', (74, 82))
159516	21738807	Approval for animal experiments was obtained from Korea FDA animal facility (NIH-06-15, NIH-07-16 and NIH-08-19).	('NIH-08-19', 'CellLine', 'CVCL:0601', (102, 111))	('NIH-07-16', 'CellLine', 'CVCL:J978', (88, 97))	('NIH-06-15', 'CellLine', 'CVCL:0601', (77, 86))	('NIH-07-16', 'Var', (88, 97))	('NIH-08-19', 'Var', (102, 111))
159526	21738807	To gain insight into the evolutionary history of C. sinensis and to investigate parasitism-related genes, the global similarity of C. sinensis whole ESTs at the amino acid sequence level were compared to those of other parasites and free-living platyhelminthes using the SimiTri program (cut-off score: 50).	('C. sinensis', 'Var', (131, 142))	('parasitism', 'Disease', 'MESH:D010272', (80, 90))	('parasitism', 'Disease', (80, 90))
159527	21738807	The others are as follow: K+-channel, CL3811; Ca+2-channels, CL6309, CSM01492; Na+-Channel, CSA10278; Cl- channel, CL2019; Sodium transporters, CL5256, CL25, CL6319, CL420, CSA00901, CSA10105, CSA10217, CSA19634; Na+/K+-ATPases, CL2552, CSA23629; Glucose transporters, CL272, CL25; Amino acid transporters, CL1075, CL1111; Zinc transporter, CL1482; Phosphate transporters, CL5278, CSA12737; Fatty acid transporter, CL384.	('Fatty acid transporter', 'MPA', (391, 413))	('Amino acid transporters', 'MPA', (282, 305))	('CL1111', 'Var', (315, 321))	('Glucose', 'Chemical', 'MESH:D005947', (247, 254))	('CL5278', 'Var', (373, 379))	('CSA23629', 'Var', (237, 245))	('CSA12737', 'Var', (381, 389))	('ATP', 'Chemical', 'MESH:D000255', (220, 223))	('CL1075', 'Var', (307, 313))	('CSA10217', 'Var', (193, 201))	('CL272', 'Var', (269, 274))	('CSA19634', 'Var', (203, 211))	('CL1482', 'Var', (341, 347))	('Glucose transporters', 'MPA', (247, 267))
159552	19319137	We therefore examined whether inhibition of VEGFR and EGFR could be a potential therapeutic target for cholangiocarcinoma.	('VEGFR', 'Gene', '3791', (44, 49))	('inhibition', 'Var', (30, 40))	('cholangiocarcinoma', 'Disease', (103, 121))	('VEGFR', 'Gene', (44, 49))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (103, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (103, 121))	('EGFR', 'Gene', (54, 58))
159555	19319137	In vitro, two cell lines (OZ and HuCCT1), both of which harboured KRAS mutation, were refractory to vandetanib, one cell line (TGBC24TKB) was somewhat resistant, and another cell line (TKKK) was sensitive.	('mutation', 'Var', (71, 79))	('KRAS', 'Gene', '3845', (66, 70))	('vandetanib', 'Chemical', 'MESH:C452423', (100, 110))	('KRAS', 'Gene', (66, 70))
159558	19319137	Inhibiting both VEGFR and EGFR signalling appears a promising therapeutic approach for cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('Inhibiting', 'Var', (0, 10))	('VEGFR', 'Gene', (16, 21))	('cholangiocarcinoma', 'Disease', (87, 105))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (87, 105))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('VEGFR', 'Gene', '3791', (16, 21))	('EGFR', 'Protein', (26, 30))
159559	19319137	The absence of KRAS mutation and the presence of EGFR amplification may be potential predictive molecular marker of sensitivity to EGFR-targeted therapy in cholangiocarcinoma.	('amplification', 'Var', (54, 67))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (156, 174))	('EGFR', 'Gene', (49, 53))	('KRAS', 'Gene', (15, 19))	('KRAS', 'Gene', '3845', (15, 19))	('cholangiocarcinoma', 'Disease', (156, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (156, 174))
159565	19319137	Several studies have shown overexpression of EGFR, amplification and mutation of EGFR genes (Gwak et al, 2005; Nakazawa et al, 2005; Leone et al, 2006), and overexpression of VEGF protein (Tang et al, 2006) in cholangiocarcinoma.	('EGFR genes', 'Gene', (81, 91))	('cholangiocarcinoma', 'Disease', (210, 228))	('mutation', 'Var', (69, 77))	('overexpression', 'PosReg', (157, 171))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (210, 228))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (210, 228))	('overexpression', 'PosReg', (27, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('VEGF', 'Protein', (175, 179))	('amplification', 'Var', (51, 64))
159604	19319137	Evaluation of IHC for CD34 and Ki67 and for TUNEL was conducted by DY and two pathologists (HO and TS), using standard light microscopy without knowledge of any therapeutic intervention.	('CD34', 'Gene', '947', (22, 26))	('HO', 'CellLine', 'CVCL:M698', (92, 94))	('Ki67', 'Var', (31, 35))	('CD34', 'Gene', (22, 26))
159606	19319137	Ki67 proliferation index (PI) and apoptotic index (AI) were defined as the percentage of positive cells among 1000 tumour cells or over at the hotspot.	('apoptotic index', 'CPA', (34, 49))	('rat', 'Species', '10116', (12, 15))	('Ki67', 'Var', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('tumour', 'Disease', (115, 121))
159630	19319137	Phosphorylation of EGFR was inhibited by vandetanib treatment in all cell lines, and it can be noted that phosphorylation of MAPK was inhibited in TKKK and TGBC24TKB (not refractory to vandetanib) cell lines but not in OZ and HuCCT1 (refractory to vandetanib) cell lines.	('vandetanib', 'Chemical', 'MESH:C452423', (185, 195))	('phosphorylation', 'MPA', (106, 121))	('inhibited', 'NegReg', (134, 143))	('vandetanib', 'Chemical', 'MESH:C452423', (41, 51))	('Phosphorylation', 'MPA', (0, 15))	('inhibited', 'NegReg', (28, 37))	('TKKK', 'Var', (147, 151))	('TGBC24TKB', 'Var', (156, 165))	('MAPK', 'Gene', (125, 129))	('EGFR', 'Gene', (19, 23))	('vandetanib', 'Chemical', 'MESH:C452423', (248, 258))
159654	19319137	We have reported earlier that both EGFR and VEGF overexpressions are associated with progression of cholangiocarcinoma (Yoshikawa et al, 2008), and hypothesised that simultaneously blocking the EGFR and VEGF pathways might have synergistic therapeutic effects against cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (268, 286))	('overexpressions', 'Var', (49, 64))	('VEGF pathways', 'Pathway', (203, 216))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))	('cholangiocarcinoma', 'Disease', (100, 118))	('associated', 'Reg', (69, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('VEGF', 'Gene', (44, 48))	('EGFR', 'Gene', (35, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (268, 286))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (268, 286))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (100, 118))	('EGFR', 'Pathway', (194, 198))
159655	19319137	In this study, we investigated the efficacy of vandetanib in cholangiocarcinoma cell lines and in xenograft models, and report here that vandetanib strongly inhibits tumour progression in vivo.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('inhibits', 'NegReg', (157, 165))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 79))	('tumour', 'Disease', (166, 172))	('vandetanib', 'Chemical', 'MESH:C452423', (47, 57))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('vandetanib', 'Var', (137, 147))	('vandetanib', 'Chemical', 'MESH:C452423', (137, 147))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('cholangiocarcinoma', 'Disease', (61, 79))
159660	19319137	It is interesting that KRAS mutations were found in both cell lines (HuCCT1 and OZ) considered refractory to vandetanib in this study, and KRAS mutation has been reported as a mechanism of resistance to EGFR inhibitors in lung and colorectal cancers (Pao et al, 2005; Lievre et al, 2006).	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('colorectal cancers', 'Disease', (231, 249))	('vandetanib', 'Chemical', 'MESH:C452423', (109, 119))	('KRAS', 'Gene', '3845', (23, 27))	('EGFR', 'Gene', (203, 207))	('KRAS', 'Gene', (139, 143))	('KRAS', 'Gene', (23, 27))	('mutation', 'Var', (144, 152))	('KRAS', 'Gene', '3845', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('resistance', 'MPA', (189, 199))	('lung', 'Disease', (222, 226))	('colorectal cancers', 'Disease', 'MESH:D015179', (231, 249))
159662	19319137	These in vitro results suggest that in cholangiocarcinoma cells, upregulation of the RAS/RAF/MAPK pathway by mutant KRAS might counteract the anti-growth effect of vandetanib by EGFR inhibition.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (39, 57))	('vandetanib', 'Chemical', 'MESH:C452423', (164, 174))	('KRAS', 'Gene', (116, 120))	('mutant', 'Var', (109, 115))	('cholangiocarcinoma', 'Disease', (39, 57))	('RAF', 'Gene', (89, 92))	('upregulation', 'PosReg', (65, 77))	('RAF', 'Gene', '22882', (89, 92))	('KRAS', 'Gene', '3845', (116, 120))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (39, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
159663	19319137	The incidence of KRAS mutation in cholangiocarcinoma is estimated to be 54-67% (Tada et al, 1990; Tannapfel et al, 2000), and therefore it may be important to examine the KRAS status when evaluating the activity of EGFR inhibitors in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (234, 252))	('mutation', 'Var', (22, 30))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (234, 252))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (34, 52))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (234, 252))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (34, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('KRAS', 'Gene', (17, 21))	('KRAS', 'Gene', (171, 175))	('KRAS', 'Gene', '3845', (17, 21))	('KRAS', 'Gene', '3845', (171, 175))	('cholangiocarcinoma', 'Disease', (34, 52))
159664	19319137	In non-small-cell lung cancer, EGFR mutation and/or amplification have been reported as possible predictive factors of sensitivity to EGFR tyrosine kinase inhibitors (Lynch et al, 2004; Paez et al, 2004; Pao et al, 2004; Cappuzzo et al, 2005).	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('EGFR', 'Gene', (31, 35))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('lung cancer', 'Disease', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('mutation', 'Var', (36, 44))	('sensitivity', 'MPA', (119, 130))
159666	19319137	The incidence of EGFR mutations in cholangiocarcinoma is reported as 13.6-15.0% (Gwak et al, 2005; Leone et al, 2006).	('cholangiocarcinoma', 'Disease', (35, 53))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (35, 53))	('mutations', 'Var', (22, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (35, 53))	('EGFR', 'Gene', (17, 21))
159668	19319137	In this study, our FISH analysis of clinical samples revealed that EGFR gene amplification was present in 42% (8 out of 19) of samples with EGFR overexpression, but absent in samples lacking EGFR overexpression.	('EGFR', 'Gene', (67, 71))	('overexpression', 'Var', (145, 159))	('clinical samples', 'Species', '191496', (36, 52))	('EGFR', 'Gene', (140, 144))
159669	19319137	This result is consistent with an earlier report that EGFR amplification was found in 6.8% of cholangiocarcinomas (Nakazawa et al, 2005).	('cholangiocarcinomas', 'Disease', (94, 113))	('found', 'Reg', (77, 82))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (94, 113))	('amplification', 'Var', (59, 72))	('EGFR', 'Gene', (54, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (94, 112))
159689	19319137	Indeed, VEGF expression is associated with intrahepatic metastasis in IHCC (Yoshikawa et al, 2008).	('intrahepatic metastasis', 'Disease', (43, 66))	('associated with', 'Reg', (27, 42))	('VEGF', 'Gene', (8, 12))	('intrahepatic metastasis', 'Disease', 'MESH:D009362', (43, 66))	('expression', 'Var', (13, 23))	('IHCC', 'Disease', (70, 74))
159693	19319137	Moreover, both the absence of KRAS mutation and the presence of EGFR amplification appear promising biomarkers for predicting the response of cholangiocarcinoma to agents that inhibit EGFR (such as vandetanib).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (142, 160))	('absence', 'Var', (19, 26))	('KRAS', 'Gene', '3845', (30, 34))	('cholangiocarcinoma', 'Disease', (142, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('EGFR', 'Gene', (184, 188))	('mutation', 'Var', (35, 43))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (142, 160))	('EGFR', 'Gene', (64, 68))	('KRAS', 'Gene', (30, 34))	('inhibit', 'NegReg', (176, 183))	('vandetanib', 'Chemical', 'MESH:C452423', (198, 208))
159818	31900160	Silencing of KLK6 expression in cell cultures resulted in molecular features resembling EMT, whereas in the case of KLK4 high expression transduces EMT-like effects.	('KLK4', 'Gene', (116, 120))	('resulted in', 'Reg', (46, 57))	('EMT', 'Disease', (88, 91))	('KLK6', 'Gene', '5653', (13, 17))	('KLK6', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))	('KLK4', 'Gene', '9622', (116, 120))
159822	31900160	However, peptide fragments of these adhesion receptors were observed in urine and not in bile, indicating a systemic rather than a local feature of CCA.	('peptide fragments', 'Var', (9, 26))	('CCA', 'Disease', 'MESH:D018281', (148, 151))	('CCA', 'Disease', (148, 151))
159887	31519967	Mutations that impair DNA mismatch repair like Lynch syndrome are a strong risk factor for both tumor types (IHCC and EHCC).	('IHCC', 'Disease', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('IHCC', 'Disease', 'MESH:C535533', (109, 113))	('EHCC', 'Disease', (118, 122))	('risk', 'Reg', (75, 79))	('tumor', 'Disease', (96, 101))	('Mutations', 'Var', (0, 9))	('Lynch syndrome', 'Disease', (47, 61))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('Lynch syndrome', 'Disease', 'MESH:D003123', (47, 61))	('EHCC', 'Disease', 'MESH:D018281', (118, 122))
159888	31519967	TP53 and KRAS mutations were significantly associated with a worse survival and are more frequent in EHCC, while mutations and fusions in FGFR1-3, IDH1/2 and ARID1A were more frequent in IHCC.	('EHCC', 'Disease', (101, 105))	('EHCC', 'Disease', 'MESH:D018281', (101, 105))	('mutations', 'Var', (113, 122))	('FGFR1', 'Gene', '2260', (138, 143))	('IHCC', 'Disease', (187, 191))	('TP53', 'Gene', '7157', (0, 4))	('KRAS', 'Gene', '3845', (9, 13))	('frequent', 'Reg', (89, 97))	('mutations', 'Var', (14, 23))	('ARID1A', 'Gene', (158, 164))	('IDH1/2', 'Gene', '3417;3418', (147, 153))	('KRAS', 'Gene', (9, 13))	('FGFR1', 'Gene', (138, 143))	('IDH1/2', 'Gene', (147, 153))	('associated', 'Reg', (43, 53))	('ARID1A', 'Gene', '8289', (158, 164))	('TP53', 'Gene', (0, 4))	('fusions', 'Var', (127, 134))	('IHCC', 'Disease', 'MESH:C535533', (187, 191))
159889	31519967	These specific differences in the mutational landscape open for separate therapeutic targeting for example with the dual BCR/ABL and Src family tyrosine kinase inhibitor dasatinib (NCT02428855) or AG120 and IDH1-inhibitors (NCT02073994).	('IDH1', 'Gene', (207, 211))	('Src', 'Gene', (133, 136))	('Src', 'Gene', '6714', (133, 136))	('ABL', 'Disease', (125, 128))	('ABL', 'Disease', 'MESH:D000012', (125, 128))	('IDH1', 'Gene', '3417', (207, 211))	('dasatinib', 'Chemical', 'MESH:C488369', (170, 179))	('NCT02428855', 'Chemical', 'MESH:C079985', (181, 192))	('tyrosine', 'Chemical', 'None', (144, 152))	('NCT02073994', 'Var', (224, 235))	('NCT02428855', 'Var', (181, 192))
159906	31519967	ctDNA sampled during 1st line palliative treatment was available from 11 patients and used for tracking of tumor-specific mutations in ctDNA under therapy.	('ctDNA', 'Gene', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('mutations', 'Var', (122, 131))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('patients', 'Species', '9606', (73, 81))
159910	31519967	In our cohort 61% of patients (IHCC: 58%; EHCC: 64%) had at least one mutation in tumor driver genes.	('EHCC', 'Disease', (42, 46))	('IHCC', 'Disease', 'MESH:C535533', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('EHCC', 'Disease', 'MESH:D018281', (42, 46))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('IHCC', 'Disease', (31, 35))	('mutation', 'Var', (70, 78))	('tumor', 'Disease', (82, 87))
159917	31519967	The largest number of unique variants was detected in the TP53 gene (Fig.	('TP53', 'Gene', (58, 62))	('variants', 'Var', (29, 37))	('TP53', 'Gene', '7157', (58, 62))
159918	31519967	Overall, 67% of all mutations were concordant between tumor tissue and ctDNA.	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mutations', 'Var', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))
159922	31519967	Mean sequencing depth across the analyzed genes was significantly higher for ctDNA samples (1010x) than for tumor tissue samples (465x, p < 0.0001) (Fig.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('ctDNA', 'Disease', (77, 82))	('1010x', 'Var', (92, 97))	('higher', 'PosReg', (66, 72))	('sequencing', 'MPA', (5, 15))
159925	31519967	Three of them had a TP53 mutation that was no more detectable after treatment.	('mutation', 'Var', (25, 33))	('TP53', 'Gene', '7157', (20, 24))	('TP53', 'Gene', (20, 24))
159926	31519967	The fourth patient had a PBRM1 mutation, which was not seen any more at the "progression" time point.	('patient', 'Species', '9606', (11, 18))	('PBRM1', 'Gene', (25, 30))	('PBRM1', 'Gene', '55193', (25, 30))	('mutation', 'Var', (31, 39))
159937	31519967	Baseline CA19-9 levels did not correlate with tumor load (P = 0.1341, r = -0.3148), variant allele frequency (P = 0.7851, r = -0.0550) or PFS (P = 0.8614, r = -0.03854).	('variant', 'Var', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
159939	31519967	The most frequently mutated genes among these were ERBB2, KMT2C and MUC1, which were each mutated in 75% of patients, followed by ARID1A, CBLB, FOXE1, GATA6 and MAP3K4 which were each mutated in 62.5% of patients.	('ARID1A', 'Gene', (130, 136))	('CBLB', 'Gene', (138, 142))	('KMT2C', 'Gene', '58508', (58, 63))	('KMT2C', 'Gene', (58, 63))	('ERBB2', 'Gene', '2064', (51, 56))	('GATA6', 'Gene', '2627', (151, 156))	('patients', 'Species', '9606', (108, 116))	('ARID1A', 'Gene', '8289', (130, 136))	('patients', 'Species', '9606', (204, 212))	('FOXE1', 'Gene', (144, 149))	('MUC1', 'Gene', (68, 72))	('MUC1', 'Gene', '4582', (68, 72))	('MAP3K4', 'Gene', '4216', (161, 167))	('mutated', 'Var', (90, 97))	('FOXE1', 'Gene', '2304', (144, 149))	('mutated', 'Reg', (20, 27))	('GATA6', 'Gene', (151, 156))	('MAP3K4', 'Gene', (161, 167))	('ERBB2', 'Gene', (51, 56))	('CBLB', 'Gene', '868', (138, 142))
159946	31519967	Mutations in BAP1 and PBRM1, KRAS and TP53 were previously reported to be associated with poor overall survival, even in the curative disease stage.	('poor', 'NegReg', (90, 94))	('BAP1', 'Gene', (13, 17))	('PBRM1', 'Gene', '55193', (22, 27))	('TP53', 'Gene', (38, 42))	('KRAS', 'Gene', (29, 33))	('associated', 'Reg', (74, 84))	('overall survival', 'MPA', (95, 111))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', '3845', (29, 33))	('BAP1', 'Gene', '8314', (13, 17))	('PBRM1', 'Gene', (22, 27))	('TP53', 'Gene', '7157', (38, 42))
159947	31519967	Our data show a trend towards shorter PFS in patients with a mutation in either of the genes mentioned above compared to patients without any mutation in these genes (Supplementary Fig.	('mutation', 'Var', (61, 69))	('PFS', 'MPA', (38, 41))	('patients', 'Species', '9606', (45, 53))	('shorter', 'NegReg', (30, 37))	('patients', 'Species', '9606', (121, 129))
159950	31519967	In addition, the mutational status of CDKN2A, TP53 and ARID1A was reported to influence treatment response and PFS in CCA.	('influence', 'Reg', (78, 87))	('treatment response', 'CPA', (88, 106))	('CCA', 'Disease', (118, 121))	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('CDKN2A', 'Gene', (38, 44))	('ARID1A', 'Gene', '8289', (55, 61))	('ARID1A', 'Gene', (55, 61))	('mutational', 'Var', (17, 27))	('CCA', 'Disease', 'MESH:D018281', (118, 121))	('CDKN2A', 'Gene', '1029', (38, 44))	('PFS', 'CPA', (111, 114))
159952	31519967	One of our patients (#15) had a potentially actionable mutation in IDH1 in the baseline blood sample.	('IDH1', 'Gene', (67, 71))	('actionable', 'Reg', (44, 54))	('IDH1', 'Gene', '3417', (67, 71))	('mutation', 'Var', (55, 63))	('patients', 'Species', '9606', (11, 19))
159953	31519967	The biological role of IDH1 mutations in CCA is currently unclear.	('IDH1', 'Gene', (23, 27))	('CCA', 'Disease', 'MESH:D018281', (41, 44))	('IDH1', 'Gene', '3417', (23, 27))	('CCA', 'Disease', (41, 44))	('mutations', 'Var', (28, 37))
159955	31519967	Moreover, Ivosidenib, an inhibitor of mutated IDH1 has shown encouraging results in a phase I trial including patients with CCA and is evaluated in a phase III trial in advanced cholangiocarcinoma (ClinicalTrials.gov identifier: NCT02989857).	('mutated', 'Var', (38, 45))	('cholangiocarcinoma', 'Disease', (178, 196))	('CCA', 'Disease', (124, 127))	('IDH1', 'Gene', (46, 50))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (178, 196))	('IDH1', 'Gene', '3417', (46, 50))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (178, 196))	('CCA', 'Disease', 'MESH:D018281', (124, 127))	('patients', 'Species', '9606', (110, 118))	('Ivosidenib', 'Chemical', 'None', (10, 20))
159956	31519967	Thus, screening ctDNA for IDH1 mutations under therapy could indeed help to personalize first line treatment.	('IDH1', 'Gene', '3417', (26, 30))	('mutations', 'Var', (31, 40))	('IDH1', 'Gene', (26, 30))	('help', 'Reg', (68, 72))
159958	31519967	Considering the data presented here and the confined number of relevant mutations in CCA previously identified by whole exome sequencing, the targeted approach chosen may be clinically valuable for diagnosis of suspicious findings and estimation of prognosis.	('mutations', 'Var', (72, 81))	('CCA', 'Disease', 'MESH:D018281', (85, 88))	('CCA', 'Disease', (85, 88))
159962	31519967	We identified a set of 149 out of 710 cancer-related genes that show mutations in CCA before and throughout chemotherapeutic treatment and a subset of 76 genes with variants absent at baseline but emerging under chemotherapy that are probably driving disease progression, suggesting that tumor progress in CCA is a rather heterogenous process and large-scale panels are needed to monitor treatment-induced tumor evolution in this disease.	('tumor', 'Disease', (288, 293))	('mutations', 'Var', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (406, 411))	('CCA', 'Disease', (306, 309))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('CCA', 'Disease', 'MESH:D018281', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (406, 411))	('tumor', 'Disease', (406, 411))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('CCA', 'Disease', (82, 85))	('cancer', 'Disease', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('CCA', 'Disease', 'MESH:D018281', (306, 309))
159965	31519967	ERBB2 mutations were reported to be druggable.	('ERBB2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('ERBB2', 'Gene', '2064', (0, 5))
159966	31519967	KMTC2 mutations were not correlated with CCA so far.	('CCA', 'Disease', 'MESH:D018281', (41, 44))	('KMTC2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('CCA', 'Disease', (41, 44))
159968	31519967	In liver cancer, MUC1 was described as a prognostic biomarker and MAP3K4 deficiency leads to invasive growth and epithelial-mesenchymal transition, namely in IHCC.	('IHCC', 'Disease', 'MESH:C535533', (158, 162))	('leads to', 'Reg', (84, 92))	('liver cancer', 'Phenotype', 'HP:0002896', (3, 15))	('MAP3K4', 'Gene', '4216', (66, 72))	('liver cancer', 'Disease', 'MESH:D006528', (3, 15))	('IHCC', 'Disease', (158, 162))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('liver cancer', 'Disease', (3, 15))	('MAP3K4', 'Gene', (66, 72))	('MUC1', 'Gene', (17, 21))	('MUC1', 'Gene', '4582', (17, 21))	('deficiency', 'Var', (73, 83))	('invasive growth', 'CPA', (93, 108))	('epithelial-mesenchymal transition', 'CPA', (113, 146))
159969	31519967	Reports about FOXE1 and CBLB mutations in CCA are lacking so far but FOXE1 was described as a new susceptibility locus in thyroid cancer and CBLB gene mutations were reported to be associated with multi-chemoresistance in breast cancer cell-lines.	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('CCA', 'Disease', 'MESH:D018281', (42, 45))	('thyroid cancer', 'Disease', (122, 136))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))	('CCA', 'Disease', (42, 45))	('multi-chemoresistance', 'CPA', (197, 218))	('breast cancer', 'Disease', (222, 235))	('CBLB', 'Gene', '868', (24, 28))	('mutations', 'Var', (151, 160))	('thyroid cancer', 'Disease', 'MESH:D013964', (122, 136))	('CBLB', 'Gene', (24, 28))	('FOXE1', 'Gene', (14, 19))	('FOXE1', 'Gene', (69, 74))	('thyroid cancer', 'Phenotype', 'HP:0002890', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('CBLB', 'Gene', '868', (141, 145))	('associated with', 'Reg', (181, 196))	('FOXE1', 'Gene', '2304', (14, 19))	('FOXE1', 'Gene', '2304', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('CBLB', 'Gene', (141, 145))
159971	31519967	showed that an aberrant expression of GATA binding protein 6 correlates with poor prognosis and promotes metastasis in CCA.	('expression', 'MPA', (24, 34))	('CCA', 'Disease', 'MESH:D018281', (119, 122))	('promotes', 'PosReg', (96, 104))	('GATA binding protein 6', 'Gene', '2627', (38, 60))	('CCA', 'Disease', (119, 122))	('metastasis', 'CPA', (105, 115))	('aberrant', 'Var', (15, 23))	('GATA binding protein 6', 'Gene', (38, 60))
159974	31519967	A number of epigenetic alterations, such as promoter hypermethylation and microRNA dysregulation have been associated with development, biological and clinical behavior of CCA.	('microRNA', 'MPA', (74, 82))	('associated', 'Reg', (107, 117))	('epigenetic alterations', 'Var', (12, 34))	('CCA', 'Disease', 'MESH:D018281', (172, 175))	('promoter', 'MPA', (44, 52))	('CCA', 'Disease', (172, 175))
159977	31519967	Mutations detected in ctDNA are representative for the respective tumor tissue (especially for IHCC), paving the way to a non-invasive molecular diagnosis and therapy stratification.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('IHCC', 'Disease', (95, 99))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('IHCC', 'Disease', 'MESH:C535533', (95, 99))
159999	29654067	We sought to catalog these mutations in rare tumors and to assess their clinical utility.	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('rare tumors', 'Disease', (40, 51))	('rare tumors', 'Disease', 'MESH:D035583', (40, 51))
160002	29654067	To index potentially actionable alterations, patients' reports were reviewed for mutations in cancer associated genes and pathways.	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('patients', 'Species', '9606', (45, 53))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
160005	29654067	The most common identifiable mutations were in TP53 (23%), KRAS (10%), PIK3CA (9%), CDKN2A/B (8%), BRAF (7%), MLL (7%), and ARID1A (6%).	('KRAS', 'Gene', '3845', (59, 63))	('PIK3CA', 'Gene', '5290', (71, 77))	('mutations', 'Var', (29, 38))	('CDKN2A/B', 'Gene', '1029;1030', (84, 92))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('MLL', 'Gene', (110, 113))	('ARID1A', 'Gene', '8289', (124, 130))	('MLL', 'Gene', '4297', (110, 113))	('ARID1A', 'Gene', (124, 130))	('TP53', 'Gene', '7157', (47, 51))	('CDKN2A/B', 'Gene', (84, 92))	('KRAS', 'Gene', (59, 63))	('TP53', 'Gene', (47, 51))	('PIK3CA', 'Gene', (71, 77))
160009	29654067	In our analysis, tumors with a BRAF alteration responded well to BRAF inhibitors.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('alteration', 'Var', (36, 46))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('BRAF', 'Gene', '673', (65, 69))	('BRAF', 'Gene', '673', (31, 35))	('BRAF', 'Gene', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('BRAF', 'Gene', (31, 35))
160022	29654067	There is currently a paucity of data on targetable mutations in rare tumors and a blossoming numbering of targeted therapies in development.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mutations', 'Var', (51, 60))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('rare tumors', 'Disease', (64, 75))	('rare tumors', 'Disease', 'MESH:D035583', (64, 75))
160024	29654067	The recent histology-agnostic approval of immune checkpoint inhibitor pembrolizumab across all cancers that express high levels of microsatellite instability is a landmark event.	('microsatellite instability', 'Var', (131, 157))	('pembrolizumab', 'Chemical', 'MESH:C582435', (70, 83))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
160026	29654067	This development, along with the recent discovery of NTRK fusions across tumor types and rapid clinical translation of an effective drug targeting these fusions, are all fueling rare cancer research and the search for new drug targets.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cancer', 'Disease', (183, 189))	('NTRK', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('fusions', 'Var', (58, 65))	('tumor', 'Disease', (73, 78))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
160028	29654067	The purpose of this study was to further the understanding of molecular mechanisms underlying various rare cancers, identify potentially actionable mutations, and evaluate the response of patients to therapies chosen based on these mutations.	('mutations', 'Var', (148, 157))	('rare cancers', 'Disease', 'MESH:D035583', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('patients', 'Species', '9606', (188, 196))	('rare cancers', 'Disease', (102, 114))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
160030	29654067	We identified potentially actionable genomic alterations in with the aid of the MD Anderson Knowledge Base for Precision Medicine and defined their responses to therapy using Response Evaluation Criteria in Solid Tumors.	('Tumor', 'Phenotype', 'HP:0002664', (213, 218))	('Tumors', 'Phenotype', 'HP:0002664', (213, 219))	('genomic alterations', 'Var', (37, 56))	('Solid Tumors', 'Disease', 'MESH:D009369', (207, 219))	('Solid Tumors', 'Disease', (207, 219))
160048	29654067	The most frequently identified mutations were in TP53 (23%), KRAS (10%), PIK3CA (9%), CDKN2A/B (8%), BRAF (7%), MLL (7%), and ARID1A (6%) (Figure 1).	('BRAF', 'Gene', (101, 105))	('PIK3CA', 'Gene', '5290', (73, 79))	('mutations', 'Var', (31, 40))	('MLL', 'Gene', (112, 115))	('CDKN2A/B', 'Gene', '1029;1030', (86, 94))	('MLL', 'Gene', '4297', (112, 115))	('ARID1A', 'Gene', (126, 132))	('TP53', 'Gene', (49, 53))	('TP53', 'Gene', '7157', (49, 53))	('ARID1A', 'Gene', '8289', (126, 132))	('CDKN2A/B', 'Gene', (86, 94))	('KRAS', 'Gene', (61, 65))	('PIK3CA', 'Gene', (73, 79))	('BRAF', 'Gene', '673', (101, 105))	('KRAS', 'Gene', '3845', (61, 65))
160051	29654067	MAP kinase pathway alterations were seen in the form of BRAFV600E mutations in Erdheim-Chester disease, acinic cell tumor, cholangiocarcinoma, glioblastoma, and anaplastic thyroid carcinomas.	('BRAFV600E', 'Mutation', 'rs113488022', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (123, 141))	('cholangiocarcinoma', 'Disease', (123, 141))	('Erdheim-Chester disease', 'Disease', 'MESH:D031249', (79, 102))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (123, 141))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('anaplastic thyroid carcinomas', 'Disease', (161, 190))	('anaplastic thyroid carcinomas', 'Disease', 'MESH:D065646', (161, 190))	('Erdheim-Chester disease', 'Disease', (79, 102))	('MAP kinase pathway', 'Pathway', (0, 18))	('BRAFV600E', 'Var', (56, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('alterations', 'Reg', (19, 30))	('glioblastoma', 'Disease', 'MESH:D005909', (143, 155))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (172, 190))	('anaplastic thyroid carcinomas', 'Phenotype', 'HP:0011779', (161, 190))	('glioblastoma', 'Disease', (143, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('glioblastoma', 'Phenotype', 'HP:0012174', (143, 155))	('tumor', 'Disease', (116, 121))
160052	29654067	KRAS mutations were seen predominantly in tumors of gastrointestinal or biliary origin.	('seen', 'Reg', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mutations', 'Var', (5, 14))	('tumors of gastrointestinal', 'Disease', (42, 68))	('KRAS', 'Gene', (0, 4))	('tumors of gastrointestinal', 'Disease', 'MESH:D004067', (42, 68))	('tumors of gastrointestinal', 'Phenotype', 'HP:0007378', (42, 68))	('KRAS', 'Gene', '3845', (0, 4))
160053	29654067	Amplifications dominated the landscape of FGFR alterations, which were seen in cholangiocarinoma, vaginal, metaplastic breast, rectal, ovarian serous, gallbladder, mixed mullerian, and lung large cell carcinomas and carcinoid.	('cholangiocarinoma', 'Disease', (79, 96))	('carcinoid', 'Phenotype', 'HP:0100570', (216, 225))	('rectal', 'Disease', (127, 133))	('gallbladder', 'Disease', (151, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('metaplastic breast', 'Disease', (107, 125))	('carcinoid', 'Disease', (216, 225))	('carcinoid', 'Disease', 'MESH:D002276', (216, 225))	('carcinomas', 'Phenotype', 'HP:0030731', (201, 211))	('FGFR', 'Gene', (42, 46))	('lung large cell carcinomas', 'Disease', 'MESH:D018287', (185, 211))	('ovarian serous', 'Disease', 'MESH:D010051', (135, 149))	('ovarian serous', 'Disease', (135, 149))	('cholangiocarinoma', 'Disease', 'None', (79, 96))	('lung large cell carcinomas', 'Disease', (185, 211))	('alterations', 'Var', (47, 58))	('vaginal', 'Disease', (98, 105))	('lung large cell carcinomas', 'Phenotype', 'HP:0030360', (185, 211))
160055	29654067	NTRK alterations were identified in a salivary gland carcinoma.	('salivary gland carcinoma', 'Phenotype', 'HP:0100684', (38, 62))	('salivary gland carcinoma', 'Disease', (38, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('alterations', 'Var', (5, 16))	('salivary gland carcinoma', 'Disease', 'MESH:D012468', (38, 62))	('NTRK', 'Gene', (0, 4))
160056	29654067	SOX2 amplification was identified in anal, lung large cell, serous ovarian, testicular, and bladder adenocarcinomas and glioblastoma.	('SOX2', 'Gene', '6657', (0, 4))	('serous ovarian', 'Disease', (60, 74))	('testicular', 'Disease', (76, 86))	('amplification', 'Var', (5, 18))	('anal', 'Disease', (37, 41))	('bladder adenocarcinomas and glioblastoma', 'Disease', 'MESH:D005909', (92, 132))	('lung large cell', 'Disease', (43, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('serous ovarian', 'Disease', 'MESH:D010051', (60, 74))	('SOX2', 'Gene', (0, 4))
160057	29654067	Mutations in germ-line associated genes (VHL, TSC2, NF1, NF2) were reported in anaplastic thyroid, appendiceal, lung large cell, and urachal carcinomas; carcinoid; mesothelioma.	('NF2', 'Gene', '4771', (57, 60))	('TSC2', 'Gene', (46, 50))	('reported', 'Reg', (67, 75))	('NF2', 'Gene', (57, 60))	('urachal carcinomas', 'Phenotype', 'HP:0012618', (133, 151))	('VHL', 'Disease', (41, 44))	('Mutations', 'Var', (0, 9))	('carcinoid', 'Phenotype', 'HP:0100570', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('anaplastic thyroid', 'Disease', (79, 97))	('NF1', 'Gene', '4763', (52, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('lung large cell', 'Disease', (112, 127))	('urachal carcinomas; carcinoid; mesothelioma', 'Disease', 'MESH:C536475', (133, 176))	('NF1', 'Gene', (52, 55))	('VHL', 'Disease', 'MESH:D006623', (41, 44))	('appendiceal', 'Disease', (99, 110))	('urachal carcinomas; carcinoid; mesothelioma', 'Disease', (133, 176))	('TSC2', 'Gene', '7249', (46, 50))	('appendiceal', 'Disease', 'MESH:D001063', (99, 110))
160062	29654067	We were able to identify 2 (3%) patients (one with a nasopharyngeal carcinoma and one with a rectal squamous cell carcinoma) that had high mutational burden.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('carcinoma', 'Disease', (68, 77))	('patients', 'Species', '9606', (32, 40))	('rectal squamous cell carcinoma', 'Disease', 'MESH:D002294', (93, 123))	('carcinoma', 'Disease', 'MESH:D002277', (114, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('mutational', 'Var', (139, 149))	('carcinoma', 'Disease', (114, 123))	('rectal squamous cell carcinoma', 'Disease', (93, 123))	('carcinoma', 'Disease', 'MESH:D002277', (68, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (53, 77))
160080	29654067	Our experience was colored by a preponderance of patients with BRAF V600E mutations, some of whom had remarkable responses to BRAF-directed therapy.	('V600E', 'Var', (68, 73))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('BRAF', 'Gene', '673', (63, 67))	('V600E', 'Mutation', 'rs113488022', (68, 73))	('patients', 'Species', '9606', (49, 57))	('BRAF', 'Gene', (63, 67))
160082	29654067	This selection bias is also likely the reason that BRAF inhibition led to the strongest clinical responses and is consistent with several prior reports of BRAF inhibitor activity.	('BRAF', 'Gene', (155, 159))	('BRAF', 'Gene', '673', (51, 55))	('inhibition', 'Var', (56, 66))	('clinical responses', 'CPA', (88, 106))	('BRAF', 'Gene', (51, 55))	('BRAF', 'Gene', '673', (155, 159))
160092	29654067	Showing a survival advantage in a rare tumor with an even rarer mutation is an almost unrealistic expectation as the numbers required to show benefit may be unattainable in a single institution or in a timeframe meaningful to current patients.	('mutation', 'Var', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('patients', 'Species', '9606', (234, 242))	('tumor', 'Disease', (39, 44))
160093	29654067	Intuitively, finding an actionable mutation on a backdrop of many other mutations makes it unlikely that this mutation is driving the cancer.	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (134, 140))	('mutation', 'Var', (35, 43))
160094	29654067	Alternatively, a single potentially actionable mutation on a backdrop of a quiescent tumor genome is more likely to yield therapeutic success.	('tumor', 'Disease', (85, 90))	('mutation', 'Var', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
160097	29654067	The availability of the VE-Basket trial had an important effect on patients harboring the BRAF alteration.	('alteration', 'Var', (95, 105))	('BRAF', 'Gene', '673', (90, 94))	('BRAF', 'Gene', (90, 94))	('patients', 'Species', '9606', (67, 75))
160107	29654067	Recently, the MyPathway trial used four currently approved targeted therapies to treat patients with advanced solid tumors harboring alterations in HER-2, EGFR, BRAF, or Hedgehog pathway.	('HER-2', 'Gene', (148, 153))	('solid tumors', 'Disease', 'MESH:D009369', (110, 122))	('EGFR', 'Gene', '1956', (155, 159))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('EGFR', 'Gene', (155, 159))	('Hedgehog pathway', 'Pathway', (170, 186))	('solid tumors', 'Disease', (110, 122))	('BRAF', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('alterations', 'Var', (133, 144))	('HER-2', 'Gene', '2064', (148, 153))	('patients', 'Species', '9606', (87, 95))
160117	29654067	KIT inhibitors have activity in caners with KIT and PDGFRA alterations other than gastrointestinal stromal tumors.	('activity', 'MPA', (20, 28))	('alterations', 'Var', (59, 70))	('PDGFRA', 'Gene', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (82, 113))	('PDGFRA', 'Gene', '5156', (52, 58))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (82, 113))	('caners', 'Disease', (32, 38))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (82, 112))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('KIT', 'Gene', (44, 47))	('gastrointestinal stromal tumors', 'Disease', (82, 113))
160129	24239776	In vivo, genetic inhibition of the Hedgehog signaling pathway employing BDEDeltaLoop2 cells or pharmacological inhibition with a small-molecule antagonist of Smoothened, vismodegib, was tumor and metastasis suppressive.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('BDEDeltaLoop2', 'CellLine', 'CVCL:4317', (72, 85))	('genetic inhibition', 'Var', (9, 27))	('Hedgehog signaling pathway', 'Pathway', (35, 61))
160134	24239776	In mammalian cells, Hh signaling comprises complex relationships between the Hh ligands [Sonic Hh (Shh), Indian Hh, and Desert Hh] and two plasma membrane proteins, Patched-1 (Ptch1) and Smoothened (Smo) Canonically, binding of the Hh ligand to Ptch1 leads to derepression and translocation of Smo to cilia resulting in activation of the glioma-associated transcriptional factors (Gli1, Gli2, and Gli3).	('activation', 'PosReg', (320, 330))	('Ptch1', 'Gene', (245, 250))	('glioma', 'Disease', (338, 344))	('translocation', 'MPA', (277, 290))	('Gli2', 'Gene', (387, 391))	('Gli3', 'Gene', '2737', (397, 401))	('glioma', 'Disease', 'MESH:D005910', (338, 344))	('Gli3', 'Gene', (397, 401))	('Smo', 'Protein', (294, 297))	('binding', 'Var', (217, 224))	('glioma', 'Phenotype', 'HP:0009733', (338, 344))	('derepression', 'MPA', (260, 272))	('Gli1', 'Gene', (381, 385))	('mammalian', 'Species', '9606', (3, 12))
160135	24239776	Aberrant activation of Hh pathway signaling is a characteristic of many malignancies, and tumor progression is often Hh signaling responsive despite the lack of cilia expression by many cancers.	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('Hh pathway signaling', 'Pathway', (23, 43))	('malignancies', 'Disease', 'MESH:D009369', (72, 84))	('malignancies', 'Disease', (72, 84))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
160157	24239776	Details regarding the assays for generation of the BDEneu cell line expressing dominant-negative Ptch1, quantitative real time PCR (qRT-PCR), cell proliferation assay, cell surface protein biotinylation, animal experiments, and statistical analysis are described in detail within the Supplementary materials and methods section.	('rat', 'Species', '10116', (154, 157))	('dominant-negative', 'Var', (79, 96))	('Ptch1', 'Gene', (97, 102))	('rat', 'Species', '10116', (37, 40))
160168	24239776	To investigate this signaling pathway via a loss of function paradigm, we used a genetic approach and generated a BDEneu cell line expressing dominant-negative Ptch1 (BDEDeltaLoop2 cells).	('rat', 'Species', '10116', (106, 109))	('BDEDeltaLoop2', 'CellLine', 'CVCL:4317', (167, 180))	('Ptch1', 'Gene', (160, 165))	('dominant-negative', 'Var', (142, 159))
160176	24239776	This chemotaxic response to purmorphamine stimulation was abrogated by PTX (Fig.	('abrogated', 'NegReg', (58, 67))	('chemotaxic response to purmorphamine stimulation', 'MPA', (5, 53))	('purmorphamine', 'Chemical', 'MESH:C470893', (28, 41))	('PTX', 'Var', (71, 74))
160189	24239776	The tumor burden measured by tumor to liver weight ratio was also lower in animals treated with vismodegib as compared with animals treated with vehicle (3.2% vs. 0.7%, p = 0.15; Fig.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('lower', 'NegReg', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('vismodegib', 'Var', (96, 106))	('tumor', 'Disease', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('rat', 'Species', '10116', (51, 54))
160192	24239776	After 14 days of treatment we observed that animals treated with vismodegib had the significantly lower tumor to liver weight ratio (54% vs. 25%, p <0.05; Fig.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('vismodegib', 'Var', (65, 75))	('rat', 'Species', '10116', (126, 129))	('lower', 'NegReg', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
160204	24239776	Inhibition of the Hh signaling pathway was found to be tumor suppressive for several solid organs and hematological malignancies in experimental and clinical settings.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('hematological malignancies', 'Disease', (102, 128))	('Hh signaling pathway', 'Pathway', (18, 38))	('hematological malignancies', 'Disease', 'MESH:D019337', (102, 128))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('hematological malignancies', 'Phenotype', 'HP:0004377', (102, 128))	('Inhibition', 'Var', (0, 10))
160207	24239776	Finally, vismodegib also reduced the tumor burden in an advanced stage of CCA in this rodent model.	('reduced', 'NegReg', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('CCA', 'Disease', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('vismodegib', 'Var', (9, 19))	('CCA', 'Phenotype', 'HP:0030153', (74, 77))
160211	24239776	It also demonstrates that genetic and pharmacological inhibition of the Hh pathway is tumor suppressive in a preclinical model of CCA.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('CCA', 'Phenotype', 'HP:0030153', (130, 133))	('rat', 'Species', '10116', (15, 18))	('tumor', 'Disease', (86, 91))	('Hh pathway', 'Pathway', (72, 82))	('CCA', 'Disease', (130, 133))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('genetic', 'Var', (26, 33))
160219	24587299	In a xenograft nude mouse model, PTK7 siRNA resulted in a reduction of the tumor size, compared with scrambled siRNA injection.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('PTK7 siRNA', 'Var', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('reduction', 'NegReg', (58, 67))	('tumor', 'Disease', (75, 80))	('mouse', 'Species', '10090', (20, 25))
160224	24587299	Biliary epithelial cells undergo genetic and epigenetic alterations in various regulatory genes, which accumulate and lead to the activation of oncogenes and the dysregulation of tumor suppressor genes, generating irreversible changes in the physiology of the cholangiocytes.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('alterations', 'Var', (56, 67))	('activation', 'PosReg', (130, 140))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('physiology of', 'MPA', (242, 255))	('oncogenes', 'Gene', (144, 153))	('changes', 'Reg', (227, 234))	('epigenetic alterations', 'Var', (45, 67))	('tumor', 'Disease', (179, 184))
160230	24587299	Previously, we have found that PTK7 was associated with a poor prognosis in patients with intrahepatic cholangiocarcinoma using cDNA mediated annealing, selection, extension and ligation CHiP study (unpublished data).	('patients', 'Species', '9606', (76, 84))	('PTK7', 'Var', (31, 35))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (90, 121))	('intrahepatic cholangiocarcinoma', 'Disease', (90, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (103, 121))
160268	24587299	DNA synthesis rate was also higher in HuCCT1 and JCK cells (Figure 1C, P <0.01).	('JCK', 'Gene', (49, 52))	('higher', 'PosReg', (28, 34))	('HuCCT1', 'Var', (38, 44))	('DNA synthesis rate', 'MPA', (0, 18))	('HuCCT1', 'CellLine', 'CVCL:0324', (38, 44))	('JCK', 'Gene', '284086', (49, 52))
160281	24587299	The data showed that PTK7 does not influence the canonical Wnt/beta-catenin pathway (Figure 5B, lower panel), which was further confirmed by the immunohistochemical staining of beta-catenin, showing no nuclear translocation (Figure 5B, upper panel).	('beta-catenin', 'Gene', (63, 75))	('beta-catenin', 'Gene', '1499', (63, 75))	('beta-catenin', 'Gene', (177, 189))	('PTK7', 'Var', (21, 25))	('beta-catenin', 'Gene', '1499', (177, 189))
160284	24587299	Silencing of PTK7 dramatically suppressed tumor formation in the xenografts of the nude mice (Figure 6A, right panel, P <0.01).	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('suppressed', 'NegReg', (31, 41))	('Silencing', 'Var', (0, 9))	('nude mice', 'Species', '10090', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('PTK7', 'Gene', (13, 17))
160286	24587299	The group treated with the PTK7 siRNA tended to have more TUNEL positive and less Ki67 positive cells than the scrambled siRNA group (Figure 6D).	('Ki67', 'Chemical', '-', (82, 86))	('less', 'NegReg', (77, 81))	('PTK7 siRNA', 'Var', (27, 37))	('TUNEL positive', 'CPA', (58, 72))	('Ki67 positive cells', 'CPA', (82, 101))
160288	24587299	Multivariate Cox proportional hazards regression analysis revealed that patients with a high PTK7 expression had a 2.3-fold greater risk of disease recurrence and a 1.8-fold greater risk of disease-related death (P = 0.015 and 0.036, respectively, Table 2).	('high', 'Var', (88, 92))	('disease recurrence', 'CPA', (140, 158))	('Cox', 'Gene', (13, 16))	('Cox', 'Gene', '1351', (13, 16))	('PTK7', 'Gene', (93, 97))	('patients', 'Species', '9606', (72, 80))
160292	24587299	A previous study proved that the silencing of PTK7 can lead to the inhibition of cell proliferation and apoptosis in colon cancer cells.	('cell proliferation', 'CPA', (81, 99))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('inhibition', 'NegReg', (67, 77))	('colon cancer', 'Disease', (117, 129))	('silencing', 'Var', (33, 42))	('colon cancer', 'Phenotype', 'HP:0003003', (117, 129))	('PTK7', 'Gene', (46, 50))	('apoptosis', 'CPA', (104, 113))	('colon cancer', 'Disease', 'MESH:D015179', (117, 129))
160293	24587299	In this study, we first demonstrated that silencing of PTK7 slightly decreased Cdk2, Cdk4, Cdk6, and cyclin D1 and increased p16, p21, and p27 expression.	('p21', 'Gene', (130, 133))	('p21', 'Gene', '644914', (130, 133))	('PTK7', 'Gene', (55, 59))	('p16', 'Gene', '1029', (125, 128))	('increased', 'PosReg', (115, 124))	('Cdk6', 'Gene', (91, 95))	('Cdk4', 'Gene', (85, 89))	('Cdk6', 'Gene', '1021', (91, 95))	('expression', 'MPA', (143, 153))	('cyclin D1', 'Gene', (101, 110))	('decreased', 'NegReg', (69, 78))	('p27', 'Gene', '3429', (139, 142))	('Cdk4', 'Gene', '1019', (85, 89))	('Cdk2', 'Gene', '1017', (79, 83))	('silencing', 'Var', (42, 51))	('p27', 'Gene', (139, 142))	('cyclin D1', 'Gene', '595', (101, 110))	('Cdk2', 'Gene', (79, 83))	('p16', 'Gene', (125, 128))
160294	24587299	Our results showed that silencing of PTK7 did not have an effect on FADD and cleaved caspase-8, suggesting no effect in the extrinsic apoptotic pathway.	('cleaved', 'MPA', (77, 84))	('caspase-8', 'Gene', '841', (85, 94))	('FADD', 'Chemical', '-', (68, 72))	('caspase-8', 'Gene', (85, 94))	('PTK7', 'Gene', (37, 41))	('silencing', 'Var', (24, 33))	('extrinsic apoptotic pathway', 'Pathway', (124, 151))
160295	24587299	In contrast, pro-apoptotic BAX was increased by PTK7 silencing, followed by a decrease of anti-apoptotic BCL-2.	('increased', 'PosReg', (35, 44))	('decrease', 'NegReg', (78, 86))	('BCL-2', 'Gene', (105, 110))	('BAX', 'Gene', '581', (27, 30))	('BAX', 'Gene', (27, 30))	('PTK7', 'Gene', (48, 52))	('silencing', 'Var', (53, 62))	('BCL-2', 'Gene', '596', (105, 110))
160296	24587299	The apoptotic cascade was also activated by PTK7-specific siRNA, with an increase of cleaved caspase-3 and caspase-9.	('caspase-9', 'Gene', (107, 116))	('increase', 'PosReg', (73, 81))	('apoptotic', 'CPA', (4, 13))	('caspase-9', 'Gene', '842', (107, 116))	('PTK7-specific', 'Var', (44, 57))	('cleaved caspase-3', 'MPA', (85, 102))
160297	24587299	These results demonstrated that PTK7 silencing leads to apoptosis in HuCCT1 cells via the intrinsic mitochondrial pathway.	('HuCCT1', 'CellLine', 'CVCL:0324', (69, 75))	('silencing', 'Var', (37, 46))	('PTK7', 'Gene', (32, 36))	('apoptosis', 'CPA', (56, 65))	('intrinsic mitochondrial pathway', 'Pathway', (90, 121))
160301	24587299	In addition, the tumor suppressor genes p53 and RB were also increased by the knockdown of PTK7.	('tumor', 'Disease', (17, 22))	('PTK7', 'Gene', (91, 95))	('knockdown', 'Var', (78, 87))	('p53', 'Gene', (40, 43))	('increased', 'PosReg', (61, 70))	('p53', 'Gene', '7157', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
160313	24587299	In the present study, phospho-JNK expression was increased by PTK7 silencing.	('increased', 'PosReg', (49, 58))	('JNK', 'Gene', (30, 33))	('PTK7', 'Gene', (62, 66))	('silencing', 'Var', (67, 76))	('JNK', 'Gene', '5599', (30, 33))
160314	24587299	In addition to the result that PTK7-specific siRNA can induce cell apoptosis, we hypothesized that the action may be partially related to JNK activation, since the role of the JNK in apoptosis is both cell-type- and stimulus-dependent.	('JNK', 'Gene', (176, 179))	('PTK7-specific', 'Var', (31, 44))	('JNK', 'Gene', '5599', (138, 141))	('JNK', 'Gene', '5599', (176, 179))	('cell apoptosis', 'CPA', (62, 76))	('induce', 'PosReg', (55, 61))	('JNK', 'Gene', (138, 141))
160318	24587299	We found that PTK7 silencing impaired the migration and invasion abilities with a downregulation of activated phospho-RhoA, which is in agreement with the results from other studies.	('impaired', 'NegReg', (29, 37))	('PTK7', 'Gene', (14, 18))	('RhoA', 'Gene', (118, 122))	('silencing', 'Var', (19, 28))	('downregulation', 'NegReg', (82, 96))	('RhoA', 'Gene', '387', (118, 122))
160320	24587299	In contrast, PTK7-CTF2 is able to be effectively concentrated in the nucleus, and thus activate signaling pathways that promote tumorigenesis and metastasis.	('PTK7-CTF2', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('promote', 'PosReg', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('signaling pathways', 'Pathway', (96, 114))	('activate', 'PosReg', (87, 95))	('tumor', 'Disease', (128, 133))
160417	22653260	Of the patients considered for surgical resection, all were excluded due to presence of advanced PSC, peritoneal metastases at staging laparoscopy, Bismuth III or IV strictures considered unsuitable for curative surgery, or being medically unfit for surgery.	('strictures', 'Var', (166, 176))	('Bismuth', 'Gene', (148, 155))	('metastases', 'Disease', (113, 123))	('PSC', 'Gene', '100653366', (97, 100))	('PSC', 'Gene', (97, 100))	('patients', 'Species', '9606', (7, 15))	('metastases', 'Disease', 'MESH:D009362', (113, 123))
160511	22802838	Nowadays, there are several different approaches to find the best treatment for patients with unresectable metastatic liver malignancies: systemic chemotherapy, biological therapy, traditional transcatheter chemoembolization TACE and DEM TACE, Yttrium-90 radioembolization, radiofrequency ablationon RFA, microwave ablation and irreversible electroporation IRE.	('patients', 'Species', '9606', (80, 88))	('liver malignancies', 'Disease', (118, 136))	('liver malignancies', 'Phenotype', 'HP:0002896', (118, 136))	('men', 'Species', '9606', (71, 74))	('radiofrequency', 'Var', (274, 288))	('liver malignancies', 'Disease', 'MESH:D009369', (118, 136))	('TACE', 'Chemical', '-', (225, 229))	('TACE', 'Chemical', '-', (238, 242))
160545	33228682	The density of CD68+ PD-L1+ significantly and positively correlated with the density of CD8+ PD-1High (P < 0.0001, r = 0.5927).	('CD8', 'Gene', '925', (88, 91))	('CD68+ PD-L1+', 'Var', (15, 27))	('CD8', 'Gene', (88, 91))
160560	33228682	Furthermore, CD68+ macrophages can affect the progression of tumors with conflicting results.	('tumors', 'Disease', (61, 67))	('affect', 'Reg', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('CD68+', 'Var', (13, 18))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
160564	33228682	Furthermore, the expression of PD-1 in TAMs inhibits phagocytosis and tumor immunity has been reported.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('TAMs inhibits phagocytosis', 'Disease', 'MESH:C565433', (39, 65))	('expression', 'Var', (17, 27))	('PD-1', 'Gene', (31, 35))	('TAMs inhibits phagocytosis', 'Disease', (39, 65))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
160586	33228682	We found that ICC patients with high expression of PD-1 has better OS (logrank test: P < 0.0001) and prolonged TTR (logrank test: P < 0.0001).	('better', 'PosReg', (60, 66))	('PD-1', 'Gene', (51, 55))	('prolonged', 'PosReg', (101, 110))	('TTR', 'MPA', (111, 114))	('patients', 'Species', '9606', (18, 26))	('ICC', 'Disease', (14, 17))	('high expression', 'Var', (32, 47))
160611	33228682	High proportion of CD68+ PD-L1+ cells within CD68+ macrophages in ICC patients had shorter OS (logrank test: P = 0.0344) and worse TTR (logrank test: P = 0.0380) (Fig.	('patients', 'Species', '9606', (70, 78))	('ICC', 'Disease', (66, 69))	('shorter', 'NegReg', (83, 90))	('worse', 'NegReg', (125, 130))	('TTR', 'MPA', (131, 134))	('CD68+ PD-L1+ cells', 'Var', (19, 37))
160612	33228682	In the multivariate analyses, the proportion of CD68+ PD-L1+ cells within CD68+ macrophages in ICC failed to be an independent prognostic factor for OS and TTR in ICC patients (Table 2, Supplementary Table 2).	('TTR', 'Disease', (156, 159))	('patients', 'Species', '9606', (167, 175))	('CD68+', 'Var', (48, 53))
160618	33228682	Furthermore, high expression of PD-1 was positively correlated with lower CA19-9 level, smaller tumor size, and HBsAg in our research, and it has been shown that CA19-9 could predict postoperative survival for ICC patients in a previous study.	('predict', 'Reg', (175, 182))	('lower', 'NegReg', (68, 73))	('patients', 'Species', '9606', (214, 222))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('high', 'Var', (13, 17))	('CA19-9', 'Chemical', 'MESH:C086528', (162, 168))	('tumor', 'Disease', (96, 101))	('expression', 'MPA', (18, 28))	('CA19-9', 'Chemical', 'MESH:C086528', (74, 80))	('PD-1', 'Gene', (32, 36))	('ICC', 'Disease', (210, 213))	('CA19-9 level', 'MPA', (74, 86))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
160627	33228682	This may be due to PD-1High expression indicating CD8+ T cells are highly activated, but exhibit a severe dysfunction phenotype and impaired IFN-gamma secretion and negatively affect clinical outcomes.	('impaired', 'NegReg', (132, 140))	('CD8', 'Gene', (50, 53))	('CD8', 'Gene', '925', (50, 53))	('IFN-gamma', 'Gene', (141, 150))	('affect', 'Reg', (176, 182))	('IFN-gamma', 'Gene', '396991', (141, 150))	('PD-1High expression', 'Var', (19, 38))
160635	33228682	One study in oral squamous cell carcinoma showed that PD-L1 expression on TAMs suppressed the anti-tumor immunity, which is in line with our study.	('tumor', 'Disease', (99, 104))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (13, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (18, 41))	('expression', 'Var', (60, 70))	('suppressed', 'NegReg', (79, 89))	('PD-L1', 'Gene', (54, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('oral squamous cell carcinoma', 'Disease', (13, 41))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('TAMs', 'Chemical', '-', (74, 78))
160637	33228682	More interestingly, we found that the expression of CD68+ PD-L1+ was correlated with the expression of CD8+ PD-1High, and both CD68+ PD-L1+ cells and CD8+ PD-1High cells had unfavorable prognosis.	('CD68+', 'Var', (127, 132))	('CD8', 'Gene', (150, 153))	('correlated', 'Reg', (69, 79))	('CD8', 'Gene', '925', (150, 153))	('CD68+ PD-L1+', 'Var', (52, 64))	('CD8', 'Gene', (103, 106))	('CD8', 'Gene', '925', (103, 106))
160639	33228682	Thus, we speculate that the interaction of the CD68+ PD-L1+ cells and CD8+ PD-1High cells plays a role in inhibiting the anti-cancer response.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('inhibiting', 'NegReg', (106, 116))	('cancer', 'Disease', (126, 132))	('interaction', 'Interaction', (28, 39))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('CD68+', 'Var', (47, 52))	('CD8', 'Gene', (70, 73))	('CD8', 'Gene', '925', (70, 73))
160642	33228682	High expression of CD8+ PD-1High is associated with CD68+ PD-L1+, suggesting that CD68+ PD-L1+ could cooperate with CD8+ PD-1High to cause the suppression of anti-cancer immunity.	('CD8', 'Gene', (19, 22))	('CD8', 'Gene', '925', (19, 22))	('CD8', 'Gene', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('CD8', 'Gene', '925', (116, 119))	('CD68+ PD-L1+', 'Var', (82, 94))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
160686	33200010	Several mutations in IL-6, ErbB2, K-ras, BRAF, and COX-2, p53, P16, cyclin D1, and DNA repair enzymes have all been linked to ICC and provide a basis for targeted therapies.	('K-ras', 'Gene', '3845', (34, 39))	('cyclin D1', 'Gene', '595', (68, 77))	('IL-6', 'Gene', (21, 25))	('P16', 'Gene', '1029', (63, 66))	('mutations', 'Var', (8, 17))	('P16', 'Gene', (63, 66))	('ErbB2', 'Gene', (27, 32))	('K-ras', 'Gene', (34, 39))	('linked', 'Reg', (116, 122))	('ICC', 'Disease', (126, 129))	('p53', 'Gene', '7157', (58, 61))	('COX-2', 'Gene', (51, 56))	('BRAF', 'Gene', '673', (41, 45))	('BRAF', 'Gene', (41, 45))	('p53', 'Gene', (58, 61))	('IL-6', 'Gene', '3569', (21, 25))	('cyclin D1', 'Gene', (68, 77))	('ErbB2', 'Gene', '2064', (27, 32))	('COX-2', 'Gene', '4513', (51, 56))
160745	33200010	In addition, patients who received SIRT as part of their downstaging NT were more likely to undergo an R0 resection.	('patients', 'Species', '9606', (13, 21))	('SIRT', 'Var', (35, 39))	('R0 resection', 'CPA', (103, 115))
160757	33200010	Although there was no significant difference in tumor response by RECIST criteria, patients who received HAI plus systemic chemotherapy had better overall survival (30.8 mo) compared with patients who received systemic therapy alone (18.4 mo).	('overall', 'MPA', (147, 154))	('better', 'PosReg', (140, 146))	('tumor', 'Disease', (48, 53))	('patients', 'Species', '9606', (188, 196))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('patients', 'Species', '9606', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('HAI', 'Var', (105, 108))
160764	33200010	For example, mutations in KRAS have been identified and are an independent predictor of worse survival after hepatectomy.	('mutations', 'Var', (13, 22))	('KRAS', 'Gene', '3845', (26, 30))	('KRAS', 'Gene', (26, 30))
160765	33200010	Mutations in BRAF, EGFR, PI3K, and TP53 have also been reported with varying percentages.	('BRAF', 'Gene', '673', (13, 17))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('BRAF', 'Gene', (13, 17))	('PI3K', 'Gene', (25, 29))	('EGFR', 'Gene', '1956', (19, 23))	('Mutations', 'Var', (0, 9))	('EGFR', 'Gene', (19, 23))
160766	33200010	In addition, there are novel antitumor therapies directed at the fibroblast growth factor receptor 2 fusion protein (FGFR), isocitrate dehydrogenase-1 (IDH1), and IDH2, BAP1, BRAF V600, and Her2/neu mutations.	('IDH1', 'Gene', (152, 156))	('Her2', 'Gene', '2064', (190, 194))	('fibroblast growth factor receptor 2', 'Gene', (65, 100))	('BRAF', 'Gene', (175, 179))	('BRAF', 'Gene', '673', (175, 179))	('fibroblast growth factor receptor 2', 'Gene', '2263', (65, 100))	('BAP1', 'Gene', (169, 173))	('mutations', 'Var', (199, 208))	('Her2', 'Gene', (190, 194))	('IDH1', 'Gene', '3417', (152, 156))	('isocitrate dehydrogenase-1', 'Gene', '3417', (124, 150))	('isocitrate dehydrogenase-1', 'Gene', (124, 150))	('FGFR', 'Gene', (117, 121))	('tumor', 'Disease', (33, 38))	('neu', 'Gene', (195, 198))	('IDH2', 'Gene', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('IDH2', 'Gene', '3418', (163, 167))	('BAP1', 'Gene', '8314', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('neu', 'Gene', '2064', (195, 198))
160783	33200010	For example, KRAS mutations, one of the most frequently seen mutations in ICC, is also associated with worse survival after resection in some studies.	('worse', 'NegReg', (103, 108))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))	('mutations', 'Var', (18, 27))
160795	31121195	Distinct histomorphological features are associated with IDH1 Mutation in Intrahepatic Cholangiocarcinoma Intrahepatic cholangiocarcinoma has known histological heterogeneity.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('Intrahepatic cholangiocarcinoma', 'Disease', (106, 137))	('Intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (106, 137))	('Intrahepatic Cholangiocarcinoma', 'Disease', 'MESH:D018281', (74, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('Intrahepatic Cholangiocarcinoma', 'Disease', (74, 105))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (119, 137))	('IDH1', 'Gene', (57, 61))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('Mutation', 'Var', (62, 70))	('IDH1', 'Gene', '3417', (57, 61))
160796	31121195	Mutations in IDH1 (mIDH1) define a molecular subclass of intrahepatic cholangiocarcinoma and IDH-targeted therapies are in development.	('IDH1', 'Gene', '3417', (20, 24))	('IDH1', 'Gene', (13, 17))	('mIDH1', 'Gene', '15926', (19, 24))	('Mutations', 'Var', (0, 9))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (57, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('IDH1', 'Gene', '3417', (13, 17))	('IDH1', 'Gene', (20, 24))	('mIDH1', 'Gene', (19, 24))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))	('intrahepatic cholangiocarcinoma', 'Disease', (57, 88))
160801	31121195	In the examined cohort (113 ICC: 29 mIDH1 and 84 IDH wild type), all IDH1 mutant tumors were of small duct type histology, thus analysis was limited to 101 small duct type tumors.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mIDH1', 'Gene', (36, 41))	('tumors', 'Disease', (81, 87))	('IDH1', 'Gene', '3417', (69, 73))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('IDH1', 'Gene', (37, 41))	('IDH1', 'Gene', '3417', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mIDH1', 'Gene', '15926', (36, 41))	('mutant', 'Var', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('IDH1', 'Gene', (69, 73))	('small duct type', 'Disease', (96, 111))
160803	31121195	Plump cuboidal/polygonal cell shape and a geographic-type pattern of intra-tumoral fibrosis are more often seen in mIDH1compared to IDH wild type tumors, however IDH1 mutation is not associated with a distinct histoarchitectural pattern.	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('IDH1', 'Gene', '3417', (162, 166))	('mutation', 'Var', (167, 175))	('mIDH1', 'Gene', '15926', (115, 120))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('IDH1', 'Gene', (116, 120))	('mIDH1', 'Gene', (115, 120))	('intra-tumoral fibrosis', 'Disease', 'MESH:D005355', (69, 91))	('IDH1', 'Gene', '3417', (116, 120))	('intra-tumoral fibrosis', 'Disease', (69, 91))	('tumors', 'Disease', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('IDH1', 'Gene', (162, 166))
160806	31121195	Recent genomic studies have shown that neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) in cholangiocarcinoma is highly associated with intrahepatic origin, with a prevalence of approximately 20% in North American studies.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (100, 118))	('associated', 'Reg', (129, 139))	('intrahepatic origin', 'Disease', (145, 164))	('cholangiocarcinoma', 'Disease', (100, 118))	('IDH1', 'Gene', (91, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('isocitrate dehydrogenase 1', 'Gene', (63, 89))	('IDH1', 'Gene', '3417', (91, 95))	('isocitrate dehydrogenase 1', 'Gene', '3417', (63, 89))	('neomorphic mutations', 'Var', (39, 59))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))
160808	31121195	Neomorphic mutations in this enzyme, which also occur in acute myeloid leukemia, gliomas, and chondrosarcoma, typically lead to altered activity that results in the increased production of (R)-2-hydroxyglutarate, which interferes with histone and DNA demethylases, as well as several other alpha-ketoglutarate-consuming processes.	('mutations', 'Var', (11, 20))	('production', 'MPA', (175, 185))	('altered', 'Reg', (128, 135))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (63, 79))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (57, 79))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (57, 79))	('activity', 'MPA', (136, 144))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('(R)-2-hydroxyglutarate', 'Chemical', '-', (189, 211))	('chondrosarcoma', 'Disease', (94, 108))	('chondrosarcoma', 'Disease', 'MESH:D002813', (94, 108))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (290, 309))	('gliomas', 'Disease', (81, 88))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (94, 108))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('lead', 'Reg', (120, 124))	('acute myeloid leukemia', 'Disease', (57, 79))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('increased', 'PosReg', (165, 174))
160809	31121195	An additional consequence of this mutation in myeloid neoplasms and glioma is interference with tumor differentiation.	('neoplasms', 'Phenotype', 'HP:0002664', (54, 63))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (46, 63))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('interference', 'NegReg', (78, 90))	('mutation', 'Var', (34, 42))	('tumor', 'Disease', (96, 101))	('myeloid neoplasms', 'Disease', (46, 63))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (46, 63))	('glioma', 'Disease', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
160810	31121195	Mutations in IDH1 tend to occur in hotspots such as R132, and in ICC the most common mutations are R132C, R132G, and R132L, which are distinct from the R132H mutation found in gliomas and not detected by commercially available immunohistochemical stains.	('R132L', 'Var', (117, 122))	('R132C', 'Var', (99, 104))	('gliomas', 'Disease', 'MESH:D005910', (176, 183))	('R132C', 'Mutation', 'rs121913499', (99, 104))	('R132G', 'Mutation', 'rs121913499', (106, 111))	('gliomas', 'Disease', (176, 183))	('gliomas', 'Phenotype', 'HP:0009733', (176, 183))	('R132L', 'Mutation', 'rs121913500', (117, 122))	('R132H', 'Mutation', 'rs121913500', (152, 157))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('IDH1', 'Gene', (13, 17))	('R132G', 'Var', (106, 111))	('IDH1', 'Gene', '3417', (13, 17))	('ICC', 'Disease', (65, 68))
160811	31121195	Nonetheless, these activating mutations have been shown to increase the serum level of (R)-2-hydroxyglutarate in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (113, 131))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (113, 131))	('(R)-2-hydroxyglutarate', 'Chemical', '-', (87, 109))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (113, 131))	('mutations', 'Var', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('increase', 'PosReg', (59, 67))
160817	31121195	While the prognostic relevance of IDH1 mutation is uncertain, it is expected to be of therapeutic relevance.	('IDH1', 'Gene', '3417', (34, 38))	('IDH1', 'Gene', (34, 38))	('mutation', 'Var', (39, 47))
160818	31121195	Nonetheless, mutant IDH1 represents a promising actionable target for small molecule therapy in leukemia, glioma, and cholangiocarcinoma and clinical trials are in progress.	('mutant', 'Var', (13, 19))	('IDH1', 'Gene', '3417', (20, 24))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (118, 136))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('leukemia', 'Disease', (96, 104))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('leukemia', 'Disease', 'MESH:D007938', (96, 104))	('cholangiocarcinoma', 'Disease', (118, 136))	('glioma', 'Disease', (106, 112))	('IDH1', 'Gene', (20, 24))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (118, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
160819	31121195	This study aims to comprehensively evaluate the cytological and architectural features of IDH1 mutated (mIDH1) ICC in comparison to ICC lacking hotspot mutations in IDH1 and IDH2 which could aid in the identification of IDH1 mutant tumors.	('IDH1', 'Gene', (90, 94))	('IDH1', 'Gene', '3417', (90, 94))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('IDH1', 'Gene', (105, 109))	('mIDH1', 'Gene', '15926', (104, 109))	('IDH2', 'Gene', (174, 178))	('mutated', 'Var', (95, 102))	('mIDH1', 'Gene', (104, 109))	('IDH1', 'Gene', (165, 169))	('IDH1', 'Gene', '3417', (105, 109))	('IDH2', 'Gene', '3418', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('IDH1', 'Gene', (220, 224))	('IDH1', 'Gene', '3417', (165, 169))	('tumors', 'Disease', (232, 238))	('IDH1', 'Gene', '3417', (220, 224))
160822	31121195	MSK-IMPACT was clinically validated for the detection of mutations of IDH1 exon 4 (41-138) and IDH2 exon 4 (125-178) inclusive of hotspot mutations observed in intrahepatic cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (173, 191))	('intrahepatic cholangiocarcinoma', 'Disease', (160, 191))	('IDH1', 'Gene', '3417', (70, 74))	('IDH2', 'Gene', (95, 99))	('mutations', 'Var', (57, 66))	('IDH2', 'Gene', '3418', (95, 99))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (160, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('IDH1', 'Gene', (70, 74))
160823	31121195	Cases were stratified by the mutation status of IDH1.	('IDH1', 'Gene', (48, 52))	('mutation', 'Var', (29, 37))	('IDH1', 'Gene', '3417', (48, 52))
160824	31121195	Tumors with IDH2 mutations were excluded, therefore the wild type IDH (wtIDH) was defined by lacking alterations in IDH1 and IDH2 as detected by MSK-IMPACT.	('IDH2', 'Gene', (12, 16))	('IDH2', 'Gene', '3418', (125, 129))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('IDH2', 'Gene', '3418', (12, 16))	('IDH1', 'Gene', (116, 120))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('IDH1', 'Gene', '3417', (116, 120))	('IDH2', 'Gene', (125, 129))	('mutations', 'Var', (17, 26))
160839	31121195	The somatic alterations in IDH1 exon 4 consisted of p.R132C in n=23 (79.3%), p.R132L in n=3 (10.3%), and p.R132G in n=3 (10.3%).	('p.R132G', 'Var', (105, 112))	('p.R132C', 'Mutation', 'rs121913499', (52, 59))	('p.R132C', 'Var', (52, 59))	('p.R132G', 'Mutation', 'rs121913499', (105, 112))	('IDH1', 'Gene', (27, 31))	('IDH1', 'Gene', '3417', (27, 31))	('p.R132L', 'Var', (77, 84))	('p.R132L', 'Mutation', 'rs121913500', (77, 84))
160846	31121195	The presence of plump cuboidal/polygonal shape had a sensitivity of 60% and specificity of 71% for identifying IDH1 mutation.	('mutation', 'Var', (116, 124))	('IDH1', 'Gene', '3417', (111, 115))	('IDH1', 'Gene', (111, 115))
160847	31121195	Geographic-type fibrosis had a sensivitity 44% and specificity of 86% for identifying IDH1 mutation.	('fibrosis', 'Disease', 'MESH:D005355', (16, 24))	('fibrosis', 'Disease', (16, 24))	('mutation', 'Var', (91, 99))	('IDH1', 'Gene', (86, 90))	('IDH1', 'Gene', '3417', (86, 90))
160848	31121195	The presence of both features (plump cuboidal/polygonal shape and geographic fibrosis) had a sensitivity of 72% and specificity of 60% for identifying IDH1 mutation.	('fibrosis', 'Disease', 'MESH:D005355', (77, 85))	('fibrosis', 'Disease', (77, 85))	('IDH1', 'Gene', (151, 155))	('IDH1', 'Gene', '3417', (151, 155))	('geographic fibrosis', 'Phenotype', 'HP:0031609', (66, 85))	('mutation', 'Var', (156, 164))
160849	31121195	Examples of IDH1 mutant histology are shown in Figure 2.	('IDH1', 'Gene', '3417', (12, 16))	('mutant', 'Var', (17, 23))	('IDH1', 'Gene', (12, 16))
160855	31121195	FGFR2 rearrangements, and the corresponding signaling pathway (MAPK), were the only two significant other genomic differences between the wtIDH and mIDH1 groups (Table 3).	('mIDH1', 'Gene', '15926', (148, 153))	('rearrangements', 'Var', (6, 20))	('mIDH1', 'Gene', (148, 153))	('signaling pathway', 'Pathway', (44, 61))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))
160856	31121195	IDH1 mutated intrahepatic cholangiocarcinoma has uniquely altered cellular biology known to affect cellular differentiation on a molecular level.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (13, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('IDH1', 'Gene', '3417', (0, 4))	('intrahepatic cholangiocarcinoma', 'Disease', (13, 44))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (26, 44))	('cellular biology', 'MPA', (66, 82))	('affect', 'Reg', (92, 98))	('mutated', 'Var', (5, 12))	('IDH1', 'Gene', (0, 4))	('cellular differentiation', 'CPA', (99, 123))	('altered', 'Reg', (58, 65))
160862	31121195	Since complexity of histoarchitecture is a component of most criteria of tumor differentiation at various anatomic sites, another aim of this study was to determine whether mIDH1-related altered cellular differentiation would have an observable histoarchitectural association.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cellular differentiation', 'CPA', (195, 219))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('altered', 'Var', (187, 194))	('mIDH1', 'Gene', '15926', (173, 178))	('mIDH1', 'Gene', (173, 178))
160864	31121195	Recently, for example, the ductal plate malformation pattern was shown to have an association with ARID1A mutation.	('association', 'Interaction', (82, 93))	('ARID1A', 'Gene', (99, 105))	('mutation', 'Var', (106, 114))	('ARID1A', 'Gene', '8289', (99, 105))
160867	31121195	IDH1 mutants accumulate the metabolite (R)-2-hydroxyglutarate, show high expression of mitochondrial genes by integrative genomic analysis, and high mitochondrial DNA copy number.	('mitochondrial', 'Gene', (87, 100))	('expression', 'MPA', (73, 83))	('mutants', 'Var', (5, 12))	('(R)-2-hydroxyglutarate', 'Chemical', '-', (39, 61))	('IDH1', 'Gene', (0, 4))	('accumulate', 'PosReg', (13, 23))	('IDH1', 'Gene', '3417', (0, 4))
160868	31121195	In vitro models and mouse studies have also shown that mutant IDH blocks hepatocyte differentiation and IDH mutant ICC express a liver progenitor cell gene signature..	('IDH', 'Gene', (104, 107))	('mutant', 'Var', (55, 61))	('mutant', 'Var', (108, 114))	('blocks', 'NegReg', (66, 72))	('hepatocyte differentiation', 'CPA', (73, 99))	('IDH', 'Gene', (62, 65))	('mouse', 'Species', '10090', (20, 25))
160869	31121195	Among the clinical variables we assessed, only autoimmune disease had a significant association with IDH1 mutation status.	('IDH1', 'Gene', (101, 105))	('autoimmune disease', 'Disease', (47, 65))	('IDH1', 'Gene', '3417', (101, 105))	('autoimmune disease', 'Phenotype', 'HP:0002960', (47, 65))	('autoimmune disease', 'Disease', 'MESH:D001327', (47, 65))	('mutation status', 'Var', (106, 121))
160874	31121195	Analysis that compared the detected mutations by grouping into signaling pathway only showed a significant difference in the MAPK pathway that includes FGFR2 rearrangements.	('rearrangements', 'Var', (158, 172))	('FGFR2', 'Gene', '2263', (152, 157))	('FGFR2', 'Gene', (152, 157))	('MAPK pathway', 'Pathway', (125, 137))	('difference', 'Reg', (107, 117))
160877	31121195	IDH1 mutant intrahepatic cholangiocarcinomas are small duct histologic type IDH1 mutant intrahepatic cholangiocarcinomas tend to have plump cuboidal/polygonal cell shape and geographic fibrosis IDH1 and IDH wild type intrahepatic cholangiocarcinomas are predominantly architecturally heterogeneous with no significant difference in the distribution of tubular, anastomosing, compact tubular, and solid architectural patterns	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (217, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('intrahepatic cholangiocarcinomas', 'Disease', (88, 120))	('IDH1', 'Gene', '3417', (76, 80))	('IDH1', 'Gene', '3417', (194, 198))	('mutant', 'Var', (81, 87))	('IDH1', 'Gene', (0, 4))	('fibrosis', 'Disease', 'MESH:D005355', (185, 193))	('fibrosis', 'Disease', (185, 193))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (88, 120))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (230, 248))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (25, 43))	('IDH1', 'Gene', '3417', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('intrahepatic cholangiocarcinomas', 'Disease', (12, 44))	('intrahepatic cholangiocarcinomas', 'Disease', (217, 249))	('IDH1', 'Gene', (76, 80))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (12, 44))	('IDH1', 'Gene', (194, 198))	('geographic fibrosis', 'Phenotype', 'HP:0031609', (174, 193))	('mutant', 'Var', (5, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))
160878	31173267	Bile cell-free DNA as a novel and powerful liquid biopsy for detecting somatic variants in biliary tract cancer Tissue sampling of biliary tract carcinomas (BTCs) for molecular characterization is challenging.	('biliary tract cancer', 'Disease', 'MESH:D001661', (91, 111))	('biliary tract cancer', 'Disease', (91, 111))	('biliary tract carcinomas', 'Disease', (131, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (145, 155))	('BTC', 'Gene', '685', (157, 160))	('variants', 'Var', (79, 87))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (91, 111))	('BTC', 'Gene', (157, 160))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('biliary tract carcinomas', 'Disease', 'MESH:D001661', (131, 155))
160882	31173267	When comparing bile cfDNA and tumor DNA for single nucleotide variation (SNV)/insertion and deletion (Indel), the results using targeted deep sequencing revealed high sensitivity (94.7%) and specificity (99.9%).	('Indel', 'Chemical', '-', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('single nucleotide variation', 'Var', (44, 71))	('tumor', 'Disease', (30, 35))
160885	31173267	The present study revealed that targeted deep sequencing can reliably detect mutational variants within bile cfDNA obtained from BTC patients.	('mutational variants', 'Var', (77, 96))	('BTC', 'Gene', '685', (129, 132))	('detect', 'Reg', (70, 76))	('patients', 'Species', '9606', (133, 141))	('BTC', 'Gene', (129, 132))
160890	31173267	Thus, appropriate biopsies and technologies are required to identify relevant biomarkers, such as single nucleotide variations (SNVs), insertion and deletions (Indels), gene fusions, copy number variations (CNVs), or aberrant expression.	('single nucleotide variations', 'Var', (98, 126))	('copy number variations', 'Var', (183, 205))	('Indel', 'Chemical', '-', (160, 165))	('aberrant expression', 'Var', (217, 236))	('gene fusions', 'Var', (169, 181))	('insertion', 'Var', (135, 144))
160897	31173267	Previous studies have revealed that cfDNA can be utilized to identify actionable mutations and predict therapeutic responses in non-small cell lung cancer (NSCLC).	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (128, 154))	('non-small cell lung cancer', 'Disease', (128, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (132, 154))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (128, 154))	('mutations', 'Var', (81, 90))	('NSCLC', 'Disease', (156, 161))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))
160918	31173267	To explore the mutational landscape, the obtained bile cfDNA was sequenced using targeted deep sequencing, which is able to detect SNVs, Indels and CNVs concurrently, and a panel of 150 tumor-related genes was examined.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('CNVs', 'Var', (148, 152))	('SNVs', 'Var', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('Indels', 'Var', (137, 143))	('Indel', 'Chemical', '-', (137, 142))
160920	31173267	A total of 71 unique somatic mutations, including SNVs (48%), Indels (9%), CNVs (35%), and deep deletions (8%), were revealed (Fig.	('SNVs', 'Var', (50, 54))	('deep deletions', 'Var', (91, 105))	('CNVs', 'Var', (75, 79))	('Indels', 'Var', (62, 68))	('Indel', 'Chemical', '-', (62, 67))
160921	31173267	Further analysis of the gene mutational profiles revealed that in six of the patients, SNVs and Indels accounted for more than half of the mutations.	('accounted', 'Reg', (103, 112))	('patients', 'Species', '9606', (77, 85))	('Indel', 'Chemical', '-', (96, 101))	('Indels', 'Var', (96, 102))	('SNVs', 'Var', (87, 91))
160923	31173267	Furthermore, the mutational profiles revealed that of the SNV/Indel mutations, the highest variation was observed in TP53 (70%), followed by KRAS (30%), NOTCH1 (20%), NOTCH2 (20%), and KMT2A (20%).	('NOTCH2', 'Gene', '4853', (167, 173))	('NOTCH1', 'Gene', (153, 159))	('KRAS', 'Gene', (141, 145))	('NOTCH1', 'Gene', '4851', (153, 159))	('TP53', 'Gene', '7157', (117, 121))	('KRAS', 'Gene', '3845', (141, 145))	('TP53', 'Gene', (117, 121))	('SNV/Indel mutations', 'Var', (58, 77))	('KMT2A', 'Gene', (185, 190))	('NOTCH2', 'Gene', (167, 173))	('KMT2A', 'Gene', '4297', (185, 190))	('Indel', 'Chemical', '-', (62, 67))
160924	31173267	Among the CNV mutations, low recurrent amplified genes, such as CCNE1, ERBB2, CDKN1B, ZNF217 and CDK6 were identified; with CDKN2A revealing a deep deletion (Fig.	('CDKN2A', 'Gene', (124, 130))	('CDK6', 'Gene', '1021', (97, 101))	('ZNF217', 'Gene', (86, 92))	('ERBB2', 'Gene', '2064', (71, 76))	('ZNF217', 'Gene', '7764', (86, 92))	('CDKN2A', 'Gene', '1029', (124, 130))	('ERBB2', 'Gene', (71, 76))	('CCNE1', 'Gene', '898', (64, 69))	('CCNE1', 'Gene', (64, 69))	('CDKN1B', 'Gene', '1027', (78, 84))	('CNV', 'Gene', (10, 13))	('CDK6', 'Gene', (97, 101))	('mutations', 'Var', (14, 23))	('CDKN1B', 'Gene', (78, 84))
160926	31173267	To assess the performance of the targeted deep sequencing in detecting mutations in the bile cfDNA samples, the findings were compared to the paired tumor tissue DNA findings.	('mutations', 'Var', (71, 80))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))
160927	31173267	In the tumor tissues, a total of 19 SNVs/Indels and 20 CNVs were identified as a reference (Table III).	('SNVs/Indels', 'Var', (36, 47))	('tumor', 'Disease', (7, 12))	('Indel', 'Chemical', '-', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
160930	31173267	In seven patients (70%, 7/10), >50% mutational concordance between the bile cfDNA and tumor tissue DNA was revealed (Fig.	('patients', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('mutational', 'Var', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
160932	31173267	Of the 19 variants detected in the tumor samples, 18 were also detected in bile cfDNA (Fig.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('detected', 'Reg', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('bile cfDNA', 'Disease', (75, 85))	('variants', 'Var', (10, 18))	('tumor', 'Disease', (35, 40))
160949	31173267	The examination of these bile cfDNA samples with targeted deep sequencing revealed a high sensitivity and specificity in detecting SNVs/Indels (94.7 and 99.9%, respectively) and CNVs (75.0 and 98.9%, respectively).	('SNVs/Indels', 'Var', (131, 142))	('Indel', 'Chemical', '-', (136, 141))	('CNVs', 'Var', (178, 182))
160956	31173267	In the present study, similar to previous research of tumor tissue, mutated TP53, KRAS, CDKN2A, PIK3CA, and ERBB2 were also detected in bile cfDNA.	('CDKN2A', 'Gene', (88, 94))	('detected', 'Reg', (124, 132))	('CDKN2A', 'Gene', '1029', (88, 94))	('TP53', 'Gene', '7157', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('bile cfDNA', 'Disease', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('PIK3CA', 'Gene', (96, 102))	('TP53', 'Gene', (76, 80))	('ERBB2', 'Gene', '2064', (108, 113))	('PIK3CA', 'Gene', '5290', (96, 102))	('KRAS', 'Gene', (82, 86))	('tumor', 'Disease', (54, 59))	('mutated', 'Var', (68, 75))	('KRAS', 'Gene', '3845', (82, 86))	('ERBB2', 'Gene', (108, 113))
160957	31173267	NOTCH1, and NOTCH2 mutations were recurrent in bile cfDNA from BTC patients, which was not observed in previous studies.	('patients', 'Species', '9606', (67, 75))	('bile cfDNA', 'Disease', (47, 57))	('BTC', 'Gene', (63, 66))	('mutations', 'Var', (19, 28))	('BTC', 'Gene', '685', (63, 66))	('NOTCH2', 'Gene', (12, 18))	('recurrent', 'Reg', (34, 43))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('NOTCH2', 'Gene', '4853', (12, 18))
160961	31173267	This study found a high concordance between bile cfDNA and tumor tissues when examining SNVs/Indels, but a high concordance was also found when identifying CNVs, which has not been previously reported.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('SNVs/Indels', 'Var', (88, 99))	('CNVs', 'Var', (156, 160))	('Indel', 'Chemical', '-', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
160969	31173267	Notably, several clinical features have been revealed to have a marked influence on variant detection sensitivity in bile cfDNA when compared with tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('influence', 'Reg', (71, 80))	('variant', 'Var', (84, 91))	('bile cfDNA', 'Disease', (117, 127))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
160970	31173267	In our previous study, lung cancer patients with different tumor stages exhibited a significant difference in mutational concordance between plasma cfDNA and tumor tissues.	('lung cancer', 'Disease', (23, 34))	('tumor', 'Disease', (158, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('tumor', 'Disease', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutational', 'Var', (110, 120))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('patients', 'Species', '9606', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
160975	31173267	Thus, these findings demonstrated that tumor stage and incidence site can impact variant detection sensitivity in bile cfDNA samples.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('impact', 'Reg', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('variant', 'Var', (81, 88))	('tumor', 'Disease', (39, 44))	('bile', 'Disease', (114, 118))
160976	31173267	In conclusion, the present study revealed that long DNA fragments are prevalent in bile cfDNA samples and that targeted deep sequencing can reproducibly identify somatic variants in BTC bile cfDNA samples.	('prevalent', 'Reg', (70, 79))	('BTC', 'Gene', '685', (182, 185))	('BTC', 'Gene', (182, 185))	('long DNA', 'Var', (47, 55))	('bile cfDNA', 'Disease', (83, 93))
160992	31173267	BTC biliary tract cancer GBC gallbladder carcinoma cfDNA cell-free DNA SNV single nucleotide variations Indel insertion and deletion CNV copy number variation FFPE formalin-fixed paraffin-embedded PTCD percutaneous transhepatic cholangial drainage	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('gallbladder carcinoma', 'Disease', (29, 50))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('paraffin', 'Chemical', 'MESH:D010232', (179, 187))	('copy number variation', 'Var', (137, 158))	('single nucleotide variations Indel insertion', 'Var', (75, 119))	('transhepatic cholangial drainage', 'Disease', (215, 247))	('BTC', 'Gene', '685', (0, 3))	('transhepatic cholangial drainage', 'Disease', 'MESH:D015209', (215, 247))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('deletion', 'Var', (124, 132))	('BTC', 'Gene', (0, 3))	('formalin', 'Chemical', 'MESH:D005557', (164, 172))	('PTCD', 'Chemical', '-', (197, 201))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (29, 50))	('cancer', 'Disease', (18, 24))	('Indel', 'Chemical', '-', (104, 109))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (4, 24))
161035	29916092	Thus, there were indeterminate imaging features, some imaging findings pointing to intrahepatic cholangiocarcinoma, metastatic liver cancer, or scirrhous hepatocellular carcinoma (ring enhancement, hyperintensity on T2 with hypointensity on T1 imaging).	('liver cancer', 'Disease', 'MESH:D006528', (127, 139))	('liver cancer', 'Disease', (127, 139))	('hyperintensity', 'Var', (198, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 114))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (154, 178))	('scirrhous hepatocellular carcinoma', 'Disease', 'MESH:D002293', (144, 178))	('intrahepatic cholangiocarcinoma', 'Disease', (83, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))	('scirrhous hepatocellular carcinoma', 'Disease', (144, 178))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('liver cancer', 'Phenotype', 'HP:0002896', (127, 139))
161266	26060333	In "Polymorphisms in C-Reactive Protein and Glypican-5 Are Associated with Lung Cancer Risk and Gartrokine-1 Influences Cisplatin-Based Chemotherapy Response in a Chinese Han Population," S. Zhang et al.	('Glypican-5', 'Gene', (44, 54))	('C-Reactive Protein', 'Gene', '1401', (21, 39))	('C-Reactive Protein', 'Gene', (21, 39))	('Polymorphisms', 'Var', (4, 17))	('Associated', 'Reg', (59, 69))	('Lung Cancer', 'Disease', (75, 86))	('Lung Cancer', 'Phenotype', 'HP:0100526', (75, 86))	('Cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('Influences', 'Reg', (109, 119))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Glypican-5', 'Gene', '2262', (44, 54))	('Cisplatin-Based Chemotherapy Response', 'MPA', (120, 157))	('Lung Cancer', 'Disease', 'MESH:D008175', (75, 86))
161267	26060333	investigated polymorphic variations in seven genes including CRP, GPC5, ACTA2, AGPHD1, SEC14L5, RBMS3, and GKN1, which have previously been associated with lung cancer.	('GKN1', 'Gene', '56287', (107, 111))	('GPC5', 'Gene', (66, 70))	('ACTA2', 'Gene', (72, 77))	('RBMS3', 'Gene', '27303', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ACTA2', 'Gene', '59', (72, 77))	('CRP', 'Gene', (61, 64))	('RBMS3', 'Gene', (96, 101))	('lung cancer', 'Disease', (156, 167))	('AGPHD1', 'Gene', (79, 85))	('associated', 'Reg', (140, 150))	('GPC5', 'Gene', '2262', (66, 70))	('AGPHD1', 'Gene', '123688', (79, 85))	('SEC14L5', 'Gene', '9717', (87, 94))	('polymorphic variations', 'Var', (13, 35))	('GKN1', 'Gene', (107, 111))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('CRP', 'Gene', '1401', (61, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('SEC14L5', 'Gene', (87, 94))
161302	33578971	Hepatobiliary injury markers normalized after restoration of hepatic bile flow under continued OCA treatment, suggesting that OCA mainly aggravates biliary injury during obstructive cholestasis.	('cholestasis', 'Phenotype', 'HP:0001396', (182, 193))	('OCA', 'Chemical', 'MESH:C464660', (126, 129))	('biliary injury', 'Disease', (148, 162))	('obstructive cholestasis', 'Disease', (170, 193))	('OCA', 'Var', (126, 129))	('rat', 'Species', '10116', (51, 54))	('normalized', 'MPA', (29, 39))	('OCA', 'Chemical', 'MESH:C464660', (95, 98))	('biliary injury', 'Disease', 'MESH:D001660', (6, 20))	('obstructive cholestasis', 'Disease', 'MESH:D002779', (170, 193))	('biliary injury', 'Disease', (6, 20))	('biliary injury', 'Disease', 'MESH:D001660', (148, 162))	('aggravates', 'PosReg', (137, 147))
161376	33578971	Moreover, a dramatic increase in serum bilirubin was seen in BDL rats on t = -1 day, which normalized after restoration of intestinal bile flow (t = 0-5 days, Figure 2C).	('BDL', 'Var', (61, 64))	('rat', 'Species', '10116', (113, 116))	('rats', 'Species', '10116', (65, 69))	('serum bilirubin', 'MPA', (33, 48))	('bilirubin', 'Chemical', 'MESH:D001663', (39, 48))	('increase in serum bilirubin', 'Phenotype', 'HP:0003573', (21, 48))	('increase', 'PosReg', (21, 29))	('rat', 'Species', '10116', (65, 68))
161381	33578971	As expected, gross (wet) liver mass was higher in cholestatic rats than in control animals (Sham) 6 days after rBDL and 1 day before PHx (t = -1 day) (Figure 3A).	('higher', 'PosReg', (40, 46))	('cholestatic', 'Disease', (50, 61))	('rats', 'Species', '10116', (62, 66))	('rBDL', 'Var', (111, 115))	('PHx', 'Chemical', '-', (133, 136))	('cholestatic', 'Disease', 'MESH:D002779', (50, 61))
161388	33578971	Expression of basolateral importer Slco1a1/OATP1A1 was significantly downregulated in BDL rats compared to their control counterparts, whereas the basolateral exporter Slc51b/OSTbeta was upregulated (Figure 3C, Table S4).	('OATP', 'Chemical', 'MESH:C004282', (43, 47))	('OSTbeta', 'Gene', (175, 182))	('BDL', 'Var', (86, 89))	('Expression', 'MPA', (0, 10))	('Slc51b', 'Gene', '300790', (168, 174))	('basolateral importer', 'MPA', (14, 34))	('Slco1a1', 'Gene', (35, 42))	('downregulated', 'NegReg', (69, 82))	('OSTbeta', 'Gene', '303879', (175, 182))	('Slco1a1', 'Gene', '50572', (35, 42))	('rats', 'Species', '10116', (90, 94))	('Slc51b', 'Gene', (168, 174))	('upregulated', 'PosReg', (187, 198))
161419	33578971	These results are contradictory to previous findings where ALP levels remained higher in rBDL-OCA rats compared to rBDL only from t = 0 days onward.	('rats', 'Species', '10116', (98, 102))	('OCA', 'Chemical', 'MESH:C464660', (94, 97))	('ALP', 'Gene', '250', (59, 62))	('rBDL-OCA', 'Var', (89, 97))	('higher', 'PosReg', (79, 85))	('ALP', 'Gene', (59, 62))
161424	33578971	At the time of PHx (t = 0 days) and after PHx (t = 1, 3, and 5 days), livers of post-obstructive (BDL) rats exhibited high portal and lobular inflammation and predominantly showed bridging fibrosis, in contrast to livers of sham-operated animals which only revealed mild periportal fibrosis (Figures S5 and S7).	('rat', 'Species', '10116', (103, 106))	('PHx', 'Chemical', '-', (42, 45))	('rat', 'Species', '10116', (232, 235))	('inflammation', 'Disease', 'MESH:D007249', (142, 154))	('inflammation', 'Disease', (142, 154))	('rats', 'Species', '10116', (103, 107))	('fibrosis', 'Disease', 'MESH:D005355', (189, 197))	('fibrosis', 'Disease', (189, 197))	('fibrosis', 'Disease', (282, 290))	('periportal fibrosis', 'Phenotype', 'HP:0001405', (271, 290))	('PHx', 'Chemical', '-', (15, 18))	('fibrosis', 'Disease', 'MESH:D005355', (282, 290))	('showed', 'Reg', (173, 179))	('post-obstructive', 'Var', (80, 96))
161498	33578971	However, differential BA composition on t = 0 days was only noted in the BDL groups but not the sham-operated animals.	('not', 'Gene', '208624', (60, 63))	('BDL', 'Var', (73, 76))	('not', 'Gene', (88, 91))	('not', 'Gene', (60, 63))	('BA', 'Chemical', 'MESH:D001647', (22, 24))	('not', 'Gene', '208624', (88, 91))	('rat', 'Species', '10116', (104, 107))
161510	33578971	The fact that hepatic Slc51b (encoding OSTbeta) expression was higher in BDL-OCA rats than in the BDL-Veh group on t = 1 day may stem from induced Slc51b/OSTbeta transcription by OCA-activated hepatic FXR.	('OCA', 'Chemical', 'MESH:C464660', (179, 182))	('BDL-OCA', 'Var', (73, 80))	('hepatic', 'MPA', (14, 21))	('OSTbeta', 'Gene', '303879', (39, 46))	('rats', 'Species', '10116', (81, 85))	('OSTbeta', 'Gene', '303879', (154, 161))	('Slc51b', 'Gene', '300790', (147, 153))	('Slc51b', 'Gene', (22, 28))	('expression', 'MPA', (48, 58))	('OCA', 'Chemical', 'MESH:C464660', (77, 80))	('OSTbeta', 'Gene', (39, 46))	('Slc51b', 'Gene', '300790', (22, 28))	('higher', 'PosReg', (63, 69))	('OSTbeta', 'Gene', (154, 161))	('Slc51b', 'Gene', (147, 153))
161530	33578971	Given that OCA was administered during obstructive cholestasis, OCA aggravated biliary injury most likely due to BSEP induction and consequently forced pumping of BAs into an obstructed biliary tree.	('obstructive cholestasis', 'Disease', (39, 62))	('cholestasis', 'Phenotype', 'HP:0001396', (51, 62))	('OCA', 'Chemical', 'MESH:C464660', (64, 67))	('OCA', 'Var', (64, 67))	('BSEP', 'Gene', '83569', (113, 117))	('BAs', 'Chemical', 'MESH:D001647', (163, 166))	('biliary injury', 'Disease', 'MESH:D001660', (79, 93))	('obstructive cholestasis', 'Disease', 'MESH:D002779', (39, 62))	('aggravated', 'PosReg', (68, 78))	('biliary injury', 'Disease', (79, 93))	('BSEP', 'Gene', (113, 117))	('OCA', 'Chemical', 'MESH:C464660', (11, 14))
161571	29123259	The initiation of solid tumours is thought to be governed by genetic and epigenetic alterations of neoplastic cells during a multi-step tumour pathogenesis.	('multi-step tumour', 'Disease', 'MESH:D015140', (125, 142))	('epigenetic alterations', 'Var', (73, 95))	('multi-step tumour', 'Disease', (125, 142))	('initiation of solid tumours', 'Disease', 'MESH:D009369', (4, 31))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('initiation of solid tumours', 'Disease', (4, 31))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
161620	29123259	High TANs (HR, 2.20; 95% CI, 1.22-4.29; P=0.01) (Figure 3A), low CD8+ T cells (HR, 2.03; 95% CI, 1.13-3.99; P=0.02) (Figure 3C), and high Tregs (HR,1.78; 95% CI, 1.03-3.26; P=0.04) (Figure 3D) were significantly associated with worse OS; however, high TAMs were not (HR, 1.42; 95% CI, 0.84-2.53; P=0.21) (Figure 3B).	('TAMs', 'Chemical', '-', (252, 256))	('low CD8+ T cells', 'Phenotype', 'HP:0005415', (61, 77))	('OS', 'Chemical', '-', (234, 236))	('low', 'Var', (61, 64))	('CD8', 'Gene', (65, 68))	('low CD8+ T cell', 'Phenotype', 'HP:0005415', (61, 76))	('CD8', 'Gene', '925', (65, 68))	('worse OS', 'Disease', (228, 236))	('TANs', 'Chemical', '-', (5, 9))
161628	29123259	Univariate analysis for RFS revealed that low albumin (<3.8 g dl-l), high CA19-9 (>74 U ml-1), large tumour size (>25 mm), presence of lymph node metastasis, and high-risk signature were significantly associated with poor RFS.	('tumour', 'Disease', (101, 107))	('lymph node metastasis', 'CPA', (135, 156))	('CA19-9', 'MPA', (74, 80))	('low albumin', 'Phenotype', 'HP:0003073', (42, 53))	('high', 'Var', (69, 73))	('low', 'NegReg', (42, 45))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
161630	29123259	Univariate analysis found that high CA19-9, presence of lymph node metastasis, and high-risk signature were significantly associated with poor OS.	('lymph node metastasis', 'CPA', (56, 77))	('poor OS', 'Disease', (138, 145))	('high', 'Var', (31, 35))	('CA19-9', 'Protein', (36, 42))	('OS', 'Chemical', '-', (143, 145))
161647	29123259	High TAN, low CD8+ T cell, and high Treg populations were also significantly associated with worse OS in this series of ECC patients with surgical resection.	('CD8', 'Gene', (14, 17))	('ECC', 'Disease', (120, 123))	('low', 'Var', (10, 13))	('CD8', 'Gene', '925', (14, 17))	('OS', 'Chemical', '-', (99, 101))	('low CD8+ T cell', 'Phenotype', 'HP:0005415', (10, 25))	('patients', 'Species', '9606', (124, 132))
161740	28399849	Inasmuch as cholestatic hepatopathology is amplified as a result of I/R, the pharmacodynamic efficacy of ATV was examined in a dose finding setting at 6 h reperfusion following 30 min of ischemia.	('cholestatic hepatopathology', 'Disease', 'MESH:D002779', (12, 39))	('I/R', 'Var', (68, 71))	('ischemia', 'Disease', 'MESH:D007511', (187, 195))	('cholestatic hepatopathology', 'Disease', (12, 39))	('ATV', 'Chemical', 'MESH:D000069059', (105, 108))	('ischemia', 'Disease', (187, 195))
161751	28399849	Nevertheless, this treatment regimen neither resulted in reduced liver damage at 24 h of reperfusion, as measured in terms of ALT levels (1491 +- 1094 U/L for control vs. 1396 +- 986 U/L for ATV; P = .91; Fig.	('ALT levels', 'MPA', (126, 136))	('reduced liver damage', 'Disease', (57, 77))	('ATV', 'Chemical', 'MESH:D000069059', (191, 194))	('1491 +- 1094 U/L', 'Var', (138, 154))	('reduced liver damage', 'Disease', 'MESH:D056486', (57, 77))
161840	25505711	The median biliary IgG4 levels were markedly elevated in patients with IgG4-SC (5.5 mg/dL) compared to patients with other diseases such as PSC (1.2 mg/dL) and cholangiocarcinoma (0.9 mg/dL).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (160, 178))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (160, 178))	('patients', 'Species', '9606', (57, 65))	('biliary IgG4 levels', 'MPA', (11, 30))	('IgG4-SC', 'Var', (71, 78))	('elevated', 'PosReg', (45, 53))	('PSC', 'Disease', (140, 143))	('patients', 'Species', '9606', (103, 111))	('cholangiocarcinoma', 'Disease', (160, 178))
161846	23221385	Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma Cancer associated fibroblasts (CAF) are abundant in the stroma of desmoplastic cancers where they promote tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('stroma of desmoplastic cancers', 'Disease', 'MESH:D009369', (140, 170))	('Cancer', 'Disease', 'MESH:D009369', (84, 90))	('CAF', 'Gene', '8850', (115, 118))	('deleting', 'Var', (23, 31))	('cancer', 'Disease', (32, 38))	('promote', 'PosReg', (182, 189))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('CAF', 'Gene', (115, 118))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))	('stroma of desmoplastic cancers', 'Disease', (140, 170))	('cholangiocarcinoma', 'Disease', (65, 83))	('tumor', 'Disease', (190, 195))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (65, 83))	('desmoplastic cancer', 'Phenotype', 'HP:0100245', (150, 169))	('cancer', 'Disease', (163, 169))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Cancer', 'Disease', (84, 90))
161863	23221385	By analogy, one may predict that CAF may also be uniquely sensitive to pro-apoptotic stimuli, suggesting that selective deletion of CAF with pro-apoptotic therapies could potentially abrogate their support of cancer cells.	('abrogate', 'NegReg', (183, 191))	('CAF', 'Gene', (33, 36))	('CAF', 'Gene', '8850', (132, 135))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('CAF', 'Gene', '8850', (33, 36))	('deletion', 'Var', (120, 128))	('cancer', 'Disease', (209, 215))	('CAF', 'Gene', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
161903	23221385	Cell lysates were prepared from shBax and shBak cells to confirm knockdown of Bax or Bak protein by Western blot.	('Bax', 'Gene', '581', (34, 37))	('Bax', 'Gene', (78, 81))	('Bak', 'Gene', (85, 88))	('Bak', 'Gene', (44, 47))	('Bak', 'Gene', '578', (44, 47))	('Bax', 'Gene', (34, 37))	('Bak', 'Gene', '578', (85, 88))	('knockdown', 'Var', (65, 74))	('Bax', 'Gene', '581', (78, 81))
161905	23221385	LX-2 cells were stably transfected with an S-peptide tagged Mcl-1 construct as previously described for HuH-7 cells.	('S-peptide tagged', 'Var', (43, 59))	('Mcl-1', 'Gene', (60, 65))	('HuH-7', 'CellLine', 'CVCL:0336', (104, 109))	('LX-2', 'CellLine', 'CVCL:5792', (0, 4))	('Mcl-1', 'Gene', '4170', (60, 65))
161906	23221385	The S-tag results in a slight increase in molecular weight for Mcl-1 which can readily be identified by immunoblot analysis to verify stable expression of the protein.	('Mcl-1', 'Gene', (63, 68))	('molecular weight', 'MPA', (42, 58))	('increase', 'PosReg', (30, 38))	('S-tag', 'Var', (4, 9))	('Mcl-1', 'Gene', '4170', (63, 68))
161935	23221385	Finally, shRNA targeted knockdown of Bax but not Bak reduced navitoclax-induced cytotoxicity of myofibroblastic LX-2 cells (Fig.	('Bak', 'Gene', '578', (49, 52))	('Bax', 'Gene', (37, 40))	('LX-2', 'CellLine', 'CVCL:5792', (112, 116))	('cytotoxicity', 'Disease', 'MESH:D064420', (80, 92))	('reduced', 'NegReg', (53, 60))	('navitoclax', 'Chemical', 'MESH:C528561', (61, 71))	('Bak', 'Gene', (49, 52))	('Bax', 'Gene', '581', (37, 40))	('knockdown', 'Var', (24, 33))	('cytotoxicity', 'Disease', (80, 92))
161937	23221385	shRNA knockdown of Mcl-1 in KMCH cells sensitized the cancer cells to navitoclax-mediated apoptosis.	('Mcl-1', 'Gene', (19, 24))	('navitoclax', 'Chemical', 'MESH:C528561', (70, 80))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('Mcl-1', 'Gene', '4170', (19, 24))	('navitoclax-mediated apoptosis', 'CPA', (70, 99))	('sensitized', 'Reg', (39, 49))	('knockdown', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
162061	29904468	Studies have described high positive predictive values in diagnosing primary pulmonary adenocarcinoma with individual positivity of either TTF-1 (72%) or napsin A (83%) and higher specificity when positivity was demonstrated with both markers.	('napsin A', 'Gene', '9476', (154, 162))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 101))	('primary pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (69, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('TTF-1', 'Gene', '7080', (139, 144))	('primary pulmonary adenocarcinoma', 'Disease', (69, 101))	('TTF-1', 'Gene', (139, 144))	('napsin A', 'Gene', (154, 162))	('positivity', 'Var', (118, 128))
162282	27278629	In Bismuth type IIIb patients with supraportal posterior branches, the risk of intraoperative arterial injury during left-sided hepatectomy is increased.	('intraoperative arterial injury', 'Disease', (79, 109))	('patients', 'Species', '9606', (21, 29))	('supraportal posterior branches', 'Var', (35, 65))	('intraoperative arterial injury', 'Disease', 'MESH:D007431', (79, 109))
162284	27278629	Misidentification of the supraportal posterior branches can result in severe postoperative complications, such as hepatic infarction and hepatic failure.	('hepatic failure', 'Disease', (137, 152))	('Misidentification', 'Var', (0, 17))	('hepatic failure', 'Phenotype', 'HP:0001399', (137, 152))	('result in', 'Reg', (60, 69))	('hepatic infarction', 'Disease', (114, 132))	('hepatic infarction', 'Disease', 'MESH:D000081011', (114, 132))	('hepatic failure', 'Disease', 'MESH:D017093', (137, 152))
162431	33239315	PD-1+ and PD-1- was statistically significant in pathological differentiation (OR 2.45; 95% CI 0.76 to 7.86), capsular retraction (OR 0.72; 95% CI 0.2 to 2.62), imaging classification (IC) (OR 0.32; 95% CI 0.07 to 1.59), intratumour vascularity (OR 4.11; 95% CI 0.69 to 24.3) and enhancement patterns (OR 0.18; 95% CI 0.04 to 0.96) based on multivariable analysis.	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('PD-1+', 'Var', (0, 5))	('tumour', 'Disease', 'MESH:D009369', (226, 232))	('capsular retraction', 'CPA', (110, 129))	('tumour', 'Disease', (226, 232))	('imaging classification', 'CPA', (161, 183))	('pathological differentiation', 'CPA', (49, 77))	('PD-1-', 'Var', (10, 15))	('enhancement patterns', 'CPA', (280, 300))
162433	33239315	PD-1+ or PD-L1+ in ICC patients was more often associated with poor outcomes than PD-1- or PD-L1-, and the difference was statistically significant (p<0.05) (online supplemental figure 7).	('PD-1+', 'Var', (0, 5))	('patients', 'Species', '9606', (23, 31))	('ICC', 'Disease', (19, 22))	('PD-L1+', 'Var', (9, 15))	('associated', 'Reg', (47, 57))
162449	33239315	In this study, we found that PD-1+ or PD-L1+ expression was linked to poor outcomes in ICC patients.	('ICC', 'Disease', (87, 90))	('patients', 'Species', '9606', (91, 99))	('PD-L1+ expression', 'Var', (38, 55))	('linked', 'Reg', (60, 66))	('PD-1+', 'Var', (29, 34))
162458	33239315	Moreover, a meta-analysis showed that PD-L1+ expression is not associated with outcomes in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('cholangiocarcinoma', 'Disease', (91, 109))	('PD-L1+ expression', 'Var', (38, 55))
162483	31523056	In addition, COMMD6 may modulate the ubiquitination and degradation of NF-kappaB subunits and regulate ribonucleoprotein and spliceosome complex biogenesis in tumours.	('regulate', 'Reg', (94, 102))	('tumours', 'Disease', (159, 166))	('degradation', 'MPA', (56, 67))	('NF-kappaB', 'Gene', (71, 80))	('COMMD6', 'Var', (13, 19))	('NF-kappaB', 'Gene', '4790', (71, 80))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('tumours', 'Disease', 'MESH:D009369', (159, 166))	('ubiquitination', 'MPA', (37, 51))	('modulate', 'Reg', (24, 32))
162497	31523056	It is also found that nuclear expression of COMMD1 sensitises ovarian cancer to cisplatin, and downregulation COMMD1 promotes tumour development by modulating a positive feedback loop that amplifies inflammatory- and stemness-associated properties of cancer cells.	('positive feedback loop', 'MPA', (161, 183))	('sensitises ovarian cancer', 'Disease', (51, 76))	('ovarian cancer', 'Phenotype', 'HP:0100615', (62, 76))	('COMMD1', 'Gene', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('promotes', 'PosReg', (117, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('cancer', 'Disease', (70, 76))	('downregulation', 'Var', (95, 109))	('COMMD1', 'Gene', '150684', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('amplifies', 'PosReg', (189, 198))	('cancer', 'Disease', (251, 257))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('COMMD1', 'Gene', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('sensitises ovarian cancer', 'Disease', 'MESH:D010051', (51, 76))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))	('modulating', 'Reg', (148, 158))	('COMMD1', 'Gene', '150684', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
162498	31523056	In addition, COMMD5 inhibits renal cell carcinoma by promoting de-phosphorylation of ErbB2/HER2 and epigenetic gene silencing of EGFR and ErbB3 via promoter methylation.	('de-phosphorylation', 'MPA', (63, 81))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (29, 49))	('inhibits', 'NegReg', (20, 28))	('epigenetic gene silencing', 'Var', (100, 125))	('ErbB2', 'Gene', (85, 90))	('renal cell carcinoma', 'Disease', (29, 49))	('COMMD5', 'Gene', (13, 19))	('COMMD5', 'Gene', '28991', (13, 19))	('ErbB3', 'Gene', (138, 143))	('ErbB3', 'Gene', '2065', (138, 143))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (29, 49))	('EGFR', 'Gene', '1956', (129, 133))	('promoting', 'PosReg', (53, 62))	('HER2', 'Gene', (91, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('ErbB2', 'Gene', '2064', (85, 90))	('HER2', 'Gene', '2064', (91, 95))	('EGFR', 'Gene', (129, 133))
162500	31523056	It has also been found that inhibition of COMMD7 suppresses invasion of pancreatic ductal adenocarcinoma by decreasing MMP2 secretion.	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (72, 104))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (72, 104))	('invasion', 'CPA', (60, 68))	('MMP2', 'Gene', '4313', (119, 123))	('inhibition', 'Var', (28, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('COMMD7', 'Gene', '149951', (42, 48))	('COMMD7', 'Gene', (42, 48))	('pancreatic ductal adenocarcinoma', 'Disease', (72, 104))	('decreasing', 'NegReg', (108, 118))	('MMP2', 'Gene', (119, 123))	('suppresses', 'NegReg', (49, 59))
162504	31523056	Moreover, COMMD6 has also been reported to be involved in the inhibition of NF-kappaB pathway activity in HEK-293 cells.	('NF-kappaB', 'Gene', (76, 85))	('activity', 'MPA', (94, 102))	('NF-kappaB', 'Gene', '4790', (76, 85))	('COMMD6', 'Var', (10, 16))	('inhibition', 'NegReg', (62, 72))	('HEK-293', 'CellLine', 'CVCL:0045', (106, 113))
162505	31523056	The activation of NF-kappaB could be completely abolished by the mutation of the amino acid residues Trp24 and Pro41 in the COMM domain of COMMD6.	('Trp24', 'Gene', (101, 106))	('abolished', 'NegReg', (48, 57))	('NF-kappaB', 'Gene', '4790', (18, 27))	('mutation', 'Var', (65, 73))	('NF-kappaB', 'Gene', (18, 27))	('Trp24', 'Chemical', 'MESH:C509690', (101, 106))	('activation', 'PosReg', (4, 14))
162529	31523056	The mutation of COMMD6 in human tumour cell lines evaluated by COSMIC database (https://cancer.sanger.ac.uk/cosmic).	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('COMMD6', 'Gene', (16, 22))	('tumour', 'Disease', (32, 38))	('mutation', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('human', 'Species', '9606', (26, 31))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
162561	31523056	High expression of COMMD6 was associated with shorter overall survival (OS) and disease free survival (DFS) in patients with head and neck squamous cell carcinoma (HNSC, P = 0.0084 and HR = 1.7 for OS; P = 0.0056 and HR = 2.0 for DFS), cholangiocarcinoma (CHOL, P = 0.05 and HR = 2.7 for OS; P = 0.029 and HR = 2.8 for DFS) and adrenocortical carcinoma (ACC, P = 0.0077 and HR = 2.9 for OS; P = 0.0053 and HR = 2.6 for DFS) (Fig.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (125, 162))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (236, 254))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (328, 352))	('High', 'Var', (0, 4))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (125, 162))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (236, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('disease free survival', 'CPA', (80, 101))	('adrenocortical carcinoma', 'Disease', (328, 352))	('overall survival', 'CPA', (54, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (343, 352))	('COMMD6', 'Gene', (19, 25))	('shorter', 'NegReg', (46, 53))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (328, 352))	('cholangiocarcinoma', 'Disease', (236, 254))	('patients', 'Species', '9606', (111, 119))
162562	31523056	In contrast, high expression of COMMD6 was associated with longer OS and DFS in patients with brain lower grade glioma (LGG, P = 0.0016 and HR = 0.56 for OS; P = 0.0096 and HR = 0.66 for DFS) and uveal melanoma (UVM, P = 0.0085 and HR = 0.30 for OS; P = 0.028 and HR = 0.35 for DFS) (Fig.	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('patients', 'Species', '9606', (80, 88))	('high expression', 'Var', (13, 28))	('glioma', 'Disease', (112, 118))	('COMMD6', 'Gene', (32, 38))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('uveal melanoma', 'Disease', 'MESH:C536494', (196, 210))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('DFS', 'MPA', (73, 76))	('uveal melanoma', 'Phenotype', 'HP:0007716', (196, 210))	('uveal melanoma', 'Disease', (196, 210))
162563	31523056	In addition, high expression of COMMD6 was associated with longer OS in patients with testicular germ cell tumours (TGCT, P = 0.05, HR = 1.7E-09), longer DFS in patients with thyroid carcinoma (THCA, P = 0.017, HR = 0.48) and uterine corpus endometrial carcinoma (UCEC, P = 0.029, HR = 0.47) (Fig.	('TGCT', 'Disease', (116, 120))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('THCA', 'Disease', 'MESH:D013964', (194, 198))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('THCA', 'Disease', (194, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('endometrial carcinoma', 'Disease', (241, 262))	('longer', 'PosReg', (147, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('DFS', 'MPA', (154, 157))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (175, 192))	('patients', 'Species', '9606', (161, 169))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (241, 262))	('thyroid carcinoma', 'Disease', (175, 192))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (241, 262))	('high expression', 'Var', (13, 28))	('TGCT', 'Disease', 'MESH:C563236', (116, 120))	('COMMD6', 'Gene', (32, 38))	('testicular germ cell tumours', 'Disease', 'MESH:C563236', (86, 114))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (175, 192))	('testicular germ cell tumours', 'Disease', (86, 114))	('patients', 'Species', '9606', (72, 80))
162586	31523056	COMMD6 has been reported to completely abolish NF-kappaB pathway activity by the mutation of the amino acid residues Trp24 and Pro41 in the COMM domain in HEK293 cells, indicating that COMMD6 may also play a vital role in the tumorigenesis and malignant progression.	('Trp24', 'Gene', (117, 122))	('activity', 'MPA', (65, 73))	('NF-kappaB', 'Gene', (47, 56))	('mutation', 'Var', (81, 89))	('Trp24', 'Chemical', 'MESH:C509690', (117, 122))	('abolish', 'NegReg', (39, 46))	('HEK293', 'CellLine', 'CVCL:0045', (155, 161))	('NF-kappaB', 'Gene', '4790', (47, 56))
162590	31523056	Phylogenetic analysis results showed that COMMD6 was clustered with COMMD7, COMMD8 and COMMD10 rather than other COMMD family members, indicating that these four COMMD members might play familiar roles during evolution.	('COMMD10', 'Gene', '51397', (87, 94))	('COMMD7', 'Gene', '149951', (68, 74))	('COMMD7', 'Gene', (68, 74))	('COMMD8', 'Gene', (76, 82))	('COMMD6', 'Var', (42, 48))	('COMMD10', 'Gene', (87, 94))	('COMMD8', 'Gene', '54951', (76, 82))
162635	31523056	Mutations of ribosome genes have been detected in various tumours, such as endometrial cancer, colorectal cancer and glioma.	('detected', 'Reg', (38, 46))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('tumours', 'Disease', 'MESH:D009369', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('ribosome genes', 'Gene', (13, 27))	('Mutations', 'Var', (0, 9))	('endometrial cancer', 'Phenotype', 'HP:0012114', (75, 93))	('colorectal cancer', 'Disease', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('endometrial cancer', 'Disease', (75, 93))	('glioma', 'Disease', (117, 123))	('endometrial cancer', 'Disease', 'MESH:D016889', (75, 93))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('rectal cancer', 'Phenotype', 'HP:0100743', (99, 112))	('tumours', 'Disease', (58, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))
162637	31523056	Inhibition of the spliceosome impairs survival, tumorigenicity and metastasis of MYC-dependent breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumorigenicity', 'CPA', (48, 62))	('breast cancer', 'Disease', (95, 108))	('impairs', 'NegReg', (30, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('metastasis', 'CPA', (67, 77))	('survival', 'CPA', (38, 46))	('Inhibition', 'Var', (0, 10))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
162639	31523056	More importantly, the expression of COMMD6 could predict the survival of cancer patients, indicating the significant role of COMMD6 in tumour development and progression.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('patients', 'Species', '9606', (80, 88))	('expression', 'Var', (22, 32))	('COMMD6', 'Gene', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('tumour', 'Disease', (135, 141))	('predict', 'Reg', (49, 56))
162641	31523056	In addition, we found that COMMD6 may modulate the ubiquitination and degradation of NF-kappaB subunits and regulate ribonucleoprotein and spliceosome complex biogenesis in tumours.	('degradation', 'MPA', (70, 81))	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('tumours', 'Disease', (173, 180))	('NF-kappaB', 'Gene', '4790', (85, 94))	('ubiquitination', 'MPA', (51, 65))	('NF-kappaB', 'Gene', (85, 94))	('COMMD6', 'Var', (27, 33))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('regulate', 'Reg', (108, 116))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('modulate', 'Reg', (38, 46))
162652	26475437	ROS-expressing tumors were associated with better disease-free survival (30.1 months for ROS1 expression (+) tumors vs. 9.0 months for ROS1 (-) tumors, p = 0.006).	('tumors', 'Disease', (144, 150))	('ROS', 'Chemical', '-', (0, 3))	('ROS1', 'Gene', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('ROS', 'Chemical', '-', (135, 138))	('ROS-expressing', 'Var', (0, 14))	('ROS1', 'Gene', (135, 139))	('better', 'PosReg', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('tumors', 'Disease', (15, 21))	('ROS1', 'Gene', '6098', (89, 93))	('disease-free survival', 'CPA', (50, 71))	('ROS1', 'Gene', '6098', (135, 139))	('ROS', 'Chemical', '-', (89, 92))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
162653	26475437	Moreover, ROS1 expression was an independent predictor of better disease-free survival in a multivariate analysis (HR 0.607, 95 % CI 0.377-0.976; p = 0.039).	('expression', 'Var', (15, 25))	('better', 'PosReg', (58, 64))	('ROS1', 'Gene', (10, 14))	('disease-free survival', 'CPA', (65, 86))	('ROS1', 'Gene', '6098', (10, 14))
162664	26475437	Moreover, gene rearrangement of ROS1 has been found in nonsmall cell lung cancer (NSCLC), glioblastoma multiforme, gastric cancer, and colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (55, 80))	('colon cancer', 'Disease', (135, 147))	('gene rearrangement', 'Var', (10, 28))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (58, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('colon cancer', 'Phenotype', 'HP:0003003', (135, 147))	('ROS1', 'Gene', '6098', (32, 36))	('found', 'Reg', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))	('gastric cancer', 'Disease', (115, 129))	('nonsmall cell lung cancer', 'Disease', (55, 80))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('NSCLC', 'Disease', (82, 87))	('glioblastoma multiforme', 'Disease', (90, 113))	('colon cancer', 'Disease', 'MESH:D015179', (135, 147))	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (90, 113))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('ROS1', 'Gene', (32, 36))
162665	26475437	These rearrangements create fusion proteins in which the kinase domain of ROS1 becomes constitutively active and drives cellular proliferation.	('ROS1', 'Gene', '6098', (74, 78))	('drives', 'PosReg', (113, 119))	('rearrangements', 'Var', (6, 20))	('cellular proliferation', 'CPA', (120, 142))	('ROS1', 'Gene', (74, 78))
162666	26475437	Crizotinib, an oral MET/anaplastic lymphoma kinase (ALK) inhibitor, has shown encouraging clinical activity in ROS1-rearranged NSCLC, indicating that ROS1 rearrangement is a driver mutation in NSCLC.	('NSCLC', 'Disease', (127, 132))	('MET/anaplastic lymphoma kinase', 'Gene', (20, 50))	('ROS1', 'Gene', (150, 154))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('ALK', 'Gene', '238', (52, 55))	('ROS1', 'Gene', '6098', (150, 154))	('MET/anaplastic lymphoma kinase', 'Gene', '238', (20, 50))	('ROS1', 'Gene', (111, 115))	('ROS1', 'Gene', '6098', (111, 115))	('rearrangement', 'Var', (155, 168))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (24, 43))	('lymphoma', 'Phenotype', 'HP:0002665', (35, 43))	('NSCLC', 'Disease', (193, 198))	('ALK', 'Gene', (52, 55))	('NSCLC', 'Disease', 'MESH:D002289', (193, 198))
162668	26475437	found a fusion of the ROS1 gene with the FIG gene in 2 out of 23 patients (8.7 %) with cholangiocarcinoma; the authors suggested that this could be a driver mutation, because it confers transforming activity to bile duct cells and can be effectively blocked with an ROS1 tyrosine kinase inhibitor.	('ROS1', 'Gene', (22, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('ROS1', 'Gene', '6098', (22, 26))	('cholangiocarcinoma', 'Disease', (87, 105))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (87, 105))	('transforming activity', 'MPA', (186, 207))	('patients', 'Species', '9606', (65, 73))	('fusion', 'Var', (8, 14))	('ROS1', 'Gene', (266, 270))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('ROS1', 'Gene', '6098', (266, 270))
162684	26475437	one combined signal and one separate red and green signal, and (c) deletion of the distal portion of ROS1 as indicated by one combined signal and a single green signal found in >15 % of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('deletion', 'Var', (67, 75))	('tumor', 'Disease', (186, 191))	('ROS1', 'Gene', (101, 105))	('ROS1', 'Gene', '6098', (101, 105))
162705	26475437	Microscopic features of tumors with ROS1 expression were significantly related to well differentiated histology, papillary or mucinous tumors, and intestinal type.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mucinous tumors', 'Disease', 'MESH:D002288', (126, 141))	('intestinal type', 'Disease', (147, 162))	('tumors', 'Disease', (24, 30))	('related', 'Reg', (71, 78))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('expression', 'Var', (41, 51))	('ROS1', 'Gene', (36, 40))	('mucinous tumors', 'Disease', (126, 141))	('well', 'Disease', (82, 86))	('ROS1', 'Gene', '6098', (36, 40))
162714	26475437	As rearrangement of ROS1 gene was reported in cholangiocarcinoma recently, and ROS1 inhibitors such as crizotinib or foretinib (GSK1363089) have shown remarkable activity in ROS1-driven tumors, the actual incidence of protein expression and gene rearrangements of ROS1, as well as its clinical significance in BTC, were pursued in the present study.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (46, 64))	('ROS1', 'Gene', '6098', (20, 24))	('ROS1', 'Gene', (79, 83))	('ROS1', 'Gene', (174, 178))	('rearrangement', 'Var', (3, 16))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('ROS1', 'Gene', '6098', (264, 268))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('ROS1', 'Gene', (20, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('tumors', 'Disease', (186, 192))	('crizotinib', 'Chemical', 'MESH:D000077547', (103, 113))	('ROS1', 'Gene', '6098', (79, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (46, 64))	('foretinib', 'Chemical', 'MESH:C544831', (117, 126))	('activity', 'MPA', (162, 170))	('ROS1', 'Gene', '6098', (174, 178))	('GSK1363089', 'Chemical', 'MESH:C544831', (128, 138))	('ROS1', 'Gene', (264, 268))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('cholangiocarcinoma', 'Disease', (46, 64))
162718	26475437	Importantly, fusion proteins created by the rearrangements also have the kinase domain of ROS1 and it becomes constitutively active and drives cellular proliferation.	('drives', 'PosReg', (136, 142))	('kinase domain', 'MPA', (73, 86))	('ROS1', 'Gene', (90, 94))	('cellular proliferation', 'CPA', (143, 165))	('ROS1', 'Gene', '6098', (90, 94))	('rearrangements', 'Var', (44, 58))
162719	26475437	Both wild-type and rearranged ROS1 have transformative activity attributable to its kinase domain.	('rearranged', 'Var', (19, 29))	('ROS1', 'Gene', '6098', (30, 34))	('ROS1', 'Gene', (30, 34))	('transformative activity', 'MPA', (40, 63))
162720	26475437	Fusion of ROS1 gene was first found in 2 out of 23 BTCs (8.7 %), but there have been scarce reports following the original study.	('ROS1', 'Gene', '6098', (10, 14))	('ROS1', 'Gene', (10, 14))	('Fusion', 'Var', (0, 6))
162721	26475437	Recently, ROS1 alterations were found in 1 out of 100 (1 %) patients with intrahepatic cholangiocarcioma.	('intrahepatic cholangiocarcioma', 'Disease', 'MESH:D002780', (74, 104))	('patients', 'Species', '9606', (60, 68))	('found', 'Reg', (32, 37))	('ROS1', 'Gene', (10, 14))	('alterations', 'Var', (15, 26))	('ROS1', 'Gene', '6098', (10, 14))	('intrahepatic cholangiocarcioma', 'Disease', (74, 104))
162724	26475437	The actual incidence of ROS1 rearrangement in intrahepatic cholangiocarcinoma is expected to be lower than that previously reported due to ethnic and environmental differences.	('lower', 'NegReg', (96, 101))	('ROS1', 'Gene', (24, 28))	('ROS1', 'Gene', '6098', (24, 28))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (46, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('intrahepatic cholangiocarcinoma', 'Disease', (46, 77))	('rearrangement', 'Var', (29, 42))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (59, 77))
162731	26475437	In general, ROS1 expression is related to less aggressive tumors, well differentiated features, and better survival in BTC.	('ROS1', 'Gene', '6098', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('aggressive tumors', 'Disease', 'MESH:D001523', (47, 64))	('better', 'PosReg', (100, 106))	('survival', 'CPA', (107, 115))	('expression', 'Var', (17, 27))	('aggressive tumors', 'Disease', (47, 64))	('ROS1', 'Gene', (12, 16))
162733	26475437	In a large cohort of 1478 NSCLCs, ROS1 expression was correlated with better survival and specific features such as low T stages, TTF1 and napsin expression, and certain histomorphological adenocarcinoma patterns (lepidic, acinar, and solid), although there is also a contradictory data.	('acinar', 'Disease', (223, 229))	('TTF1', 'Gene', (130, 134))	('expression', 'Var', (39, 49))	('survival', 'CPA', (77, 85))	('ROS1', 'Gene', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('TTF1', 'Gene', '7270', (130, 134))	('adenocarcinoma', 'Disease', (189, 203))	('ROS1', 'Gene', '6098', (34, 38))	('better', 'PosReg', (70, 76))	('lepidic', 'Disease', (214, 221))	('expression', 'MPA', (146, 156))	('NSCLC', 'Disease', (26, 31))	('adenocarcinoma', 'Disease', 'MESH:D000230', (189, 203))	('napsin', 'Gene', (139, 145))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))
162742	26475437	Therefore, we conclude that ROS1 IHC cannot be used as a screening tool for ROS1 rearrangement in BTC.	('ROS1', 'Gene', (28, 32))	('ROS1', 'Gene', '6098', (28, 32))	('ROS1', 'Gene', (76, 80))	('ROS1', 'Gene', '6098', (76, 80))	('rearrangement', 'Var', (81, 94))
162856	33143318	However, perturbations of the virome steady-state may, both directly and indirectly, ignite/sustain oncogenic mechanisms contributing to the initiation of a dysplastic process and/or cancer progression.	('perturbations', 'Var', (9, 22))	('cancer', 'Disease', (183, 189))	('dysplastic', 'Disease', (157, 167))	('oncogenic mechanisms', 'CPA', (100, 120))	('dysplastic', 'Disease', 'MESH:D004416', (157, 167))	('ignite/sustain', 'Reg', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
162860	33143318	Nowadays, the microbiota is considered to be crucial for our immune, hormonal, and metabolic homeostasis, and perturbations in its composition contribute to the emergence of various diseases, such as inflammatory bowel diseases, obesity, and metabolic syndrome.	('obesity', 'Disease', 'MESH:D009765', (229, 236))	('inflammatory bowel diseases', 'Disease', 'MESH:D015212', (200, 227))	('inflammatory bowel diseases', 'Phenotype', 'HP:0002037', (200, 227))	('obesity', 'Disease', (229, 236))	('inflammatory bowel diseases', 'Disease', (200, 227))	('metabolic syndrome', 'Disease', (242, 260))	('contribute', 'Reg', (143, 153))	('obesity', 'Phenotype', 'HP:0001513', (229, 236))	('metabolic syndrome', 'Disease', 'MESH:D024821', (242, 260))	('perturbations', 'Var', (110, 123))
162871	33143318	Moreover, the pretreatment of mice with antiviral drugs resulted in more severe colitis in a mouse model of dextran sulphate sodium-induced colitis.	('mice', 'Species', '10090', (30, 34))	('colitis', 'Disease', (140, 147))	('antiviral', 'Var', (40, 49))	('mouse', 'Species', '10090', (93, 98))	('dextran sulphate sodium', 'Chemical', '-', (108, 131))	('colitis', 'Phenotype', 'HP:0002583', (140, 147))	('colitis', 'Disease', 'MESH:D003092', (80, 87))	('men', 'Species', '9606', (22, 25))	('colitis', 'Disease', (80, 87))	('colitis', 'Disease', 'MESH:D003092', (140, 147))	('colitis', 'Phenotype', 'HP:0002583', (80, 87))
162872	33143318	On the other hand, some members of the gut virome may contribute, either directly or indirectly, such as via increasing the frequency of mutations, chromosomal rearrangements, and insertional mutagenesis, to the emergence and development of cancers.	('age', 'Gene', '5973', (195, 198))	('increasing', 'PosReg', (109, 119))	('chromosomal rearrangements', 'Var', (148, 174))	('contribute', 'Reg', (54, 64))	('men', 'Species', '9606', (169, 172))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancers', 'Phenotype', 'HP:0002664', (241, 248))	('age', 'Gene', (195, 198))	('mutations', 'Var', (137, 146))	('cancers', 'Disease', 'MESH:D009369', (241, 248))	('men', 'Species', '9606', (233, 236))	('cancers', 'Disease', (241, 248))
162883	33143318	In this context, protein-protein interaction between GP24 of T4 and HAP1 phages and integrin beta3 or the HSP90 receptor of cancer cells was shown to inhibit metastasis in melanoma and lung cancer in murine (B16 and LLC) and human (HS294T and A549) cell lines.	('protein-protein', 'Protein', (17, 32))	('inhibit', 'NegReg', (150, 157))	('integrin beta3', 'Gene', (84, 98))	('metastasis', 'CPA', (158, 168))	('age', 'Gene', (75, 78))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Disease', (190, 196))	('integrin beta3', 'Gene', '16416', (84, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('age', 'Gene', '5973', (75, 78))	('GP24', 'Var', (53, 57))	('A549', 'CellLine', 'CVCL:0023', (243, 247))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('HAP1', 'Gene', (68, 72))	('murine', 'Species', '10090', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Disease', (124, 130))	('melanoma and lung cancer', 'Disease', 'MESH:D008175', (172, 196))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('human', 'Species', '9606', (225, 230))	('HAP1', 'Gene', '15114', (68, 72))	('HS294', 'CellLine', 'CVCL:0331', (232, 237))
162916	33143318	Subsequently, a meta-analysis performed in India reported HPV positivity in almost 40% of patients bearing OC:with an odds ratio of 2.82:thus indicating a significantly higher risk of developing OC for HPV-positive patients compared with the general population.	('HPV', 'Species', '10566', (202, 205))	('patients', 'Species', '9606', (215, 223))	('HPV', 'Gene', (58, 61))	('positivity', 'Var', (62, 72))	('patients', 'Species', '9606', (90, 98))	('HPV', 'Species', '10566', (58, 61))
162917	33143318	None of the standard clinicopathological variables (e.g., age, sex, smoking and oral tobacco history, grade, or site) were predictive for HPV positivity.	('age', 'Gene', (58, 61))	('tobacco', 'Species', '4097', (85, 92))	('HPV', 'Species', '10566', (138, 141))	('HPV', 'Gene', (138, 141))	('age', 'Gene', '5973', (58, 61))	('positivity', 'Var', (142, 152))
162920	33143318	Several reports have highlighted the importance of p53 in HPV infections with regards to p53 mutations or the p53 expression status, or as an association with poor patient survival.	('p53', 'Gene', (51, 54))	('p53', 'Gene', (110, 113))	('p53', 'Gene', '7157', (51, 54))	('mutations', 'Var', (93, 102))	('patient', 'Species', '9606', (164, 171))	('HPV infections', 'Disease', 'MESH:D030361', (58, 72))	('p53', 'Gene', '7157', (110, 113))	('association', 'Interaction', (142, 153))	('p53', 'Gene', (89, 92))	('HPV infections', 'Disease', (58, 72))	('p53', 'Gene', '7157', (89, 92))
162924	33143318	However, there is no clear evidence to date indicating that the presence of HPV represents a risk factor for the development of EC, as reports are controversial.	('presence', 'Var', (64, 72))	('men', 'Species', '9606', (120, 123))	('HPV', 'Species', '10566', (76, 79))	('HPV', 'Gene', (76, 79))
162945	33143318	Furthermore, in combination with HPV16 seropositivity, two p53 single nucleotide polymorphisms Arg/Arg and Arg/Pro increased the risk for ESCC.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('Pro', 'Chemical', 'MESH:D011392', (111, 114))	('HPV16', 'Species', '333760', (33, 38))	('Arg/Arg', 'Var', (95, 102))	('increased', 'PosReg', (115, 124))	('Arg', 'Chemical', 'MESH:D001120', (107, 110))	('Arg/Pro', 'Var', (107, 114))	('Arg', 'Chemical', 'MESH:D001120', (95, 98))	('Arg', 'Chemical', 'MESH:D001120', (99, 102))	('ESCC', 'Disease', (138, 142))
162958	33143318	In contrast, Martinez-Lopez and co-workers revealed the presence of EBV in GC specimens and proposed that EBV may exert carcinogenic actions, either directly, by infecting epithelial cells, or indirectly, by inducing inflammation.	('inflammation', 'Disease', (217, 229))	('EBV', 'Var', (106, 109))	('carcinogenic', 'Disease', 'MESH:D063646', (120, 132))	('men', 'Species', '9606', (83, 86))	('infecting', 'Reg', (162, 171))	('carcinogenic', 'Disease', (120, 132))	('EBV', 'Species', '10376', (68, 71))	('inducing', 'Reg', (208, 216))	('GC', 'Phenotype', 'HP:0012126', (75, 77))	('inflammation', 'Disease', 'MESH:D007249', (217, 229))	('epithelial cells', 'CPA', (172, 188))	('EBV', 'Species', '10376', (106, 109))
162966	33143318	Besides proteins, EBV encodes many miRNAs and, among these, EBV-miR-BART3-3p was reported to promote the growth of GC cells, both in vitro and in vivo, by inhibiting their senescence induced by an oncogene (RASG12V) or chemotherapy (irinotecan).	('RASG12V', 'Chemical', '-', (207, 214))	('senescence', 'MPA', (172, 182))	('growth', 'MPA', (105, 111))	('irinotecan', 'Chemical', 'MESH:D000077146', (233, 243))	('GC', 'Phenotype', 'HP:0012126', (115, 117))	('EBV', 'Species', '10376', (60, 63))	('inhibiting', 'NegReg', (155, 165))	('EBV-miR-BART3-3p', 'Var', (60, 76))	('promote', 'PosReg', (93, 100))	('RASG12V', 'Var', (207, 214))	('EBV', 'Species', '10376', (18, 21))
162967	33143318	In conclusion, although EBV positivity seems to confer some sort of protection against GC, it is important to point out that the sole presence or absence of EBV in GC samples does not imply a direct causality or a role of EBV in this neoplasia.	('EBV', 'Species', '10376', (24, 27))	('GC', 'Phenotype', 'HP:0012126', (164, 166))	('neoplasia', 'Disease', 'MESH:D009369', (234, 243))	('positivity', 'Var', (28, 38))	('GC', 'Phenotype', 'HP:0012126', (87, 89))	('neoplasia', 'Disease', (234, 243))	('EBV', 'Species', '10376', (222, 225))	('EBV', 'Species', '10376', (157, 160))	('neoplasia', 'Phenotype', 'HP:0002664', (234, 243))
162986	33143318	indicated a high TTV load as an independent risk factor for HCC.	('high', 'Var', (12, 16))	('HCC', 'Disease', (60, 63))	('HCC', 'Phenotype', 'HP:0001402', (60, 63))	('TTV load', 'MPA', (17, 25))	('TTV', 'Chemical', '-', (17, 20))
162988	33143318	To date, the evidence produced does not seem to support an association between the presence of TTV and an increased risk of developing HCC.	('presence', 'Var', (83, 91))	('HCC', 'Disease', (135, 138))	('TTV', 'Gene', (95, 98))	('HCC', 'Phenotype', 'HP:0001402', (135, 138))	('TTV', 'Chemical', '-', (95, 98))
163046	33143318	observed that 56% of HPV-positive CRC samples carried mutations in the protooncogene K-Ras.	('HPV', 'Species', '10566', (21, 24))	('CRC', 'Phenotype', 'HP:0003003', (34, 37))	('K-Ras', 'Gene', '3845', (85, 90))	('mutations', 'Var', (54, 63))	('K-Ras', 'Gene', (85, 90))	('carried', 'Reg', (46, 53))	('CRC', 'Disease', (34, 37))	('HPV-positive', 'Gene', (21, 33))
163047	33143318	Although it remains inconclusive, research has also been conducted to determine a possible association between HPV infection and p53 mutation.	('mutation', 'Var', (133, 141))	('HPV infection', 'Disease', 'MESH:D030361', (111, 124))	('p53', 'Gene', '7157', (129, 132))	('p53', 'Gene', (129, 132))	('HPV infection', 'Disease', (111, 124))
163066	33143318	Chen and colleagues revealed that the presence of CMV in CRC tumors was associated with a worse outcome and an increased expression of interleukin-17 in elder patients, whereas a more favorable disease-free survival rate was reported in CMV-positive non-elderly (aged < 65 years) CRC patients, suggesting that there may be a possible age-dependent effect.	('CRC', 'Phenotype', 'HP:0003003', (280, 283))	('presence', 'Var', (38, 46))	('CRC', 'Phenotype', 'HP:0003003', (57, 60))	('increased', 'PosReg', (111, 120))	('patients', 'Species', '9606', (284, 292))	('age', 'Gene', '5973', (263, 266))	('expression', 'MPA', (121, 131))	('CRC tumors', 'Disease', (57, 67))	('CRC tumors', 'Disease', 'MESH:D015179', (57, 67))	('CMV', 'Disease', (50, 53))	('age', 'Gene', (334, 337))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('patients', 'Species', '9606', (159, 167))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('age', 'Gene', '5973', (334, 337))	('age', 'Gene', (263, 266))
163082	33143318	However, whether CMV can cause cell transformation by itself or should be viewed as a factor contributing to CRC development remains to be elucidated.	('cell transformation', 'CPA', (31, 50))	('CMV', 'Var', (17, 20))	('CRC', 'Disease', (109, 112))	('cause', 'Reg', (25, 30))	('CRC', 'Phenotype', 'HP:0003003', (109, 112))	('men', 'Species', '9606', (120, 123))
163088	33143318	In this regard, the hypermethylation of hMLH1 was associated with tumor JCV positivity and this suggested that the virus was capable of inducing aberrant methylation, as well as chromosomal instability.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('inducing', 'Reg', (136, 144))	('hypermethylation', 'Var', (20, 36))	('chromosomal instability', 'Phenotype', 'HP:0040012', (178, 201))	('tumor', 'Disease', (66, 71))	('hMLH1', 'Gene', '4292', (40, 45))	('chromosomal instability', 'CPA', (178, 201))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('associated', 'Reg', (50, 60))	('hMLH1', 'Gene', (40, 45))	('methylation', 'MPA', (154, 165))
163092	33143318	The highly conserved central region of p53 is responsible for such inhibition and this means that mutations in this region may affect the protection conferred by p53.	('protection', 'MPA', (138, 148))	('p53', 'Gene', (162, 165))	('p53', 'Gene', '7157', (162, 165))	('mutations', 'Var', (98, 107))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('affect', 'Reg', (127, 133))
163093	33143318	After infecting with JCV the CRC cell lines HCT116 and SW837, cells expressing T-ag showed a two- to three-fold increase in migration and invasion compared to controls.	('HCT116', 'CellLine', 'CVCL:0291', (44, 50))	('SW837', 'CellLine', 'CVCL:1729', (55, 60))	('migration', 'CPA', (124, 133))	('T-ag', 'Var', (79, 83))	('increase', 'PosReg', (112, 120))	('CRC', 'Phenotype', 'HP:0003003', (29, 32))	('invasion', 'CPA', (138, 146))
163094	33143318	Treatment with inhibitors of PI3K/AKT and MAPK pathways reduced both cell migration and invasion, thus underlining a possible involvement of such pathways in the JCV-driven increase of CRC metastasis.	('AKT', 'Gene', (34, 37))	('invasion', 'CPA', (88, 96))	('CRC', 'Phenotype', 'HP:0003003', (185, 188))	('reduced', 'NegReg', (56, 63))	('MAPK pathways', 'Pathway', (42, 55))	('cell migration', 'CPA', (69, 83))	('AKT', 'Gene', '207', (34, 37))	('men', 'Species', '9606', (133, 136))	('men', 'Species', '9606', (5, 8))	('CRC', 'Disease', (185, 188))	('inhibitors', 'Var', (15, 25))
163097	33143318	Subsequently, the expression of TCF-4, which is a component of Wnt/beta-catenin signaling, has been reported to decrease JCV DNA replication.	('decrease', 'NegReg', (112, 120))	('beta-catenin', 'Gene', (67, 79))	('JCV', 'CPA', (121, 124))	('TCF-4', 'Gene', '6925', (32, 37))	('beta-catenin', 'Gene', '1499', (67, 79))	('expression', 'Var', (18, 28))	('TCF-4', 'Gene', (32, 37))
163113	33143318	Surprisingly, in patients with HPV-positive advanced AC, the overall survival was better compared to HPV-negative patients with an equal disease stage.	('HPV-positive', 'Var', (31, 43))	('HPV', 'Species', '10566', (31, 34))	('better', 'PosReg', (82, 88))	('age', 'Gene', (147, 150))	('HPV', 'Species', '10566', (101, 104))	('patients', 'Species', '9606', (17, 25))	('age', 'Gene', '5973', (147, 150))	('AC', 'Phenotype', 'HP:0032186', (53, 55))	('patients', 'Species', '9606', (114, 122))
163135	33143318	Even though a study dated to 2013 showed that the recurrence rate of AC was associated with HIV positivity, but not with HPV/p16, Liu and colleagues recently reported an association between HPV-16 positivity and the presence of high-grade lesions in AC patients.	('HIV positivity', 'Var', (92, 106))	('HPV-16', 'Species', '333760', (190, 196))	('p16', 'Gene', '1029', (125, 128))	('HPV', 'Species', '10566', (121, 124))	('high-grade lesions', 'CPA', (228, 246))	('patients', 'Species', '9606', (253, 261))	('AC', 'Phenotype', 'HP:0032186', (69, 71))	('HPV', 'Species', '10566', (190, 193))	('HIV', 'Species', '12721', (92, 95))	('AC', 'Phenotype', 'HP:0032186', (250, 252))	('p16', 'Gene', (125, 128))
163435	32295646	Appearance of tumor recurrence was not affected by suspLN (p = 0.289).	('suspLN', 'Var', (51, 57))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
163452	32295646	Presence of suspLN had significant influence on nodal status for lymph nodes of the hepatoduodenal ligament (p < 0.001), retropancreatic (p = 0.011) and the lower curvature (p = 0.001), while interaortocaval lymph nodes had not (p = 0.540).	('nodal status', 'MPA', (48, 60))	('suspLN', 'Gene', (12, 18))	('Presence', 'Var', (0, 8))	('retropancreatic', 'Disease', 'None', (121, 136))	('influence', 'Reg', (35, 44))	('retropancreatic', 'Disease', (121, 136))
163471	32295646	Park and colleagues showed a higher sensitivity (80%) and specificity (92.3%) in predicting lymph node metastases with preoperative PET-CT, while Yoh and colleagues were able to show that patients with a low CA19-9 value (< 37 IU/ml), peripheral ICC and no suspicious lymph nodes in preoperative imaging were likely to have no lymph node metastases (false negative rate 2.3%).	('< 37 IU/ml', 'Var', (222, 232))	('metastases', 'Disease', (338, 348))	('low', 'NegReg', (204, 207))	('metastases', 'Disease', 'MESH:D009362', (103, 113))	('metastases', 'Disease', 'MESH:D009362', (338, 348))	('CA19-9', 'Chemical', 'MESH:C086528', (208, 214))	('CA19-9', 'Gene', (208, 214))	('metastases', 'Disease', (103, 113))
163488	27870574	Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study This two-part, first-in-human study was initiated in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor.	('tumor', 'Disease', 'MESH:D009369', (578, 583))	('BGJ398', 'Gene', (601, 607))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('tumors', 'Phenotype', 'HP:0002664', (340, 346))	('tumor', 'Phenotype', 'HP:0002664', (578, 583))	('FGFR1', 'Gene', '2260', (621, 626))	('tyrosine', 'Chemical', 'None', (629, 637))	('Advanced Solid Tumors Harboring', 'Disease', 'MESH:C537062', (97, 128))	('solid tumors', 'Disease', (334, 346))	('Advanced Solid Tumors Harboring', 'Disease', (97, 128))	('tumor', 'Disease', (340, 345))	('Tumors', 'Phenotype', 'HP:0002664', (112, 118))	('human', 'Species', '9606', (282, 287))	('FGFR1', 'Gene', (621, 626))	('alterations', 'Var', (365, 376))	('tumor', 'Disease', 'MESH:D009369', (340, 345))	('patients', 'Species', '9606', (311, 319))	('tumor', 'Disease', (578, 583))	('Patients', 'Species', '9606', (83, 91))	('Tumor', 'Phenotype', 'HP:0002664', (112, 117))	('solid tumors', 'Disease', 'MESH:D009369', (334, 346))
163490	27870574	During expansion at the MTD, patients with FGFR1-amplified squamous cell non-small-cell lung cancer (sqNSCLC; arm 1) or other solid tumors with FGFR genetic alterations (mutations/amplifications/fusions) received BGJ398 daily on a continuous schedule (arm 2), or on a 3-weeks-on/1-week-off schedule (arm 3).	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (77, 99))	('patients', 'Species', '9606', (29, 37))	('FGFR1', 'Gene', (43, 48))	('lung cancer', 'Disease', (88, 99))	('genetic alterations', 'Var', (149, 168))	('solid tumors', 'Disease', (126, 138))	('FGFR1', 'Gene', '2260', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('FGFR', 'Gene', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (73, 99))	('solid tumors', 'Disease', 'MESH:D009369', (126, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
163499	27870574	Genomic alterations in FGFR1-3 (eg, gene amplifications, gain-of-function mutations, and chromosomal translocations) that trigger pathway activation have been identified in bladder cancer, squamous cell non-small-cell lung cancer (sqNSCLC), squamous cell cancer of the head and neck, endometrial cancer, cholangiocarcinoma, and breast cancer.	('squamous cell cancer of the head', 'Phenotype', 'HP:0030413', (241, 273))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (207, 229))	('endometrial cancer', 'Phenotype', 'HP:0012114', (284, 302))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('FGFR1', 'Gene', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('lung cancer', 'Phenotype', 'HP:0100526', (218, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (304, 322))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (203, 229))	('endometrial cancer', 'Disease', (284, 302))	('cholangiocarcinoma', 'Disease', (304, 322))	('bladder cancer', 'Disease', 'MESH:D001749', (173, 187))	('bladder cancer', 'Disease', (173, 187))	('endometrial cancer', 'Disease', 'MESH:D016889', (284, 302))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (304, 322))	('breast cancer', 'Phenotype', 'HP:0003002', (328, 341))	('squamous cell non-small-cell lung cancer (sqNSCLC), squamous cell cancer of the head', 'Disease', 'MESH:D018307', (189, 273))	('cancer of the head and neck', 'Phenotype', 'HP:0012288', (255, 282))	('bladder cancer', 'Phenotype', 'HP:0009725', (173, 187))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (241, 261))	('breast cancer', 'Disease', 'MESH:D001943', (328, 341))	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('breast cancer', 'Disease', (328, 341))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('gain-of-function', 'PosReg', (57, 73))	('FGFR1', 'Gene', '2260', (23, 28))	('mutations', 'Var', (74, 83))
163501	27870574	BGJ398, an orally bioavailable, selective FGFR1 to 3 inhibitor (half maximal inhibitory concentration values range from 0.9 to 1.4 nM for FGFR1-3 to 60 nM for FGFR4), inhibits proliferation and tumor growth in preclinical cancer models bearing FGFR1-3 genetic alterations.	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('FGFR4', 'Gene', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('BGJ398', 'Gene', (0, 6))	('cancer', 'Disease', (222, 228))	('FGFR4', 'Gene', '2264', (159, 164))	('FGFR1', 'Gene', (42, 47))	('genetic alterations', 'Var', (252, 271))	('proliferation', 'CPA', (176, 189))	('FGFR1', 'Gene', (138, 143))	('FGFR1', 'Gene', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('FGFR1', 'Gene', '2260', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('FGFR1', 'Gene', '2260', (138, 143))	('FGFR1', 'Gene', '2260', (244, 249))	('inhibits', 'NegReg', (167, 175))
163502	27870574	On the basis of these preclinical data, we conducted a global, personalized phase I single-agent study to determine the maximum tolerated dose (MTD), recommended phase II dose (RP2D), schedule, safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of BGJ398 in patients with solid tumors bearing FGFR alterations (ClinicalTrials.gov identifier NCT01004224).	('solid tumors', 'Disease', (298, 310))	('BGJ398', 'Gene', (274, 280))	('patients', 'Species', '9606', (284, 292))	('alterations', 'Var', (324, 335))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('PD', 'Disease', 'MESH:D010300', (243, 245))	('FGFR', 'Gene', (319, 323))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('solid tumors', 'Disease', 'MESH:D009369', (298, 310))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Disease', (304, 309))	('tumors', 'Phenotype', 'HP:0002664', (304, 310))	('tumor', 'Disease', (256, 261))
163503	27870574	Adults with solid tumors harboring FGFR alterations (eg, amplification, mutation, fusion) for whom no effective standard therapy exists were enrolled.	('solid tumors', 'Disease', 'MESH:D009369', (12, 24))	('fusion', 'Var', (82, 88))	('alterations', 'Var', (40, 51))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('solid tumors', 'Disease', (12, 24))	('mutation', 'Var', (72, 80))	('FGFR', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
163504	27870574	Patient selection criteria relative to FGFR genetic alterations are defined in the Appendix (online only).	('FGFR', 'Gene', (39, 43))	('Patient', 'Species', '9606', (0, 7))	('genetic alterations', 'Var', (44, 63))
163505	27870574	FGFR genetic alterations not specified in the protocol were compared with those in public databases (eg, COSMIC and dbSNP) and were adjudicated to determine suitability for enrollment, allowing for continual review and enrollment of patients with newly reported FGFR alterations suggestive of potential sensitivity to FGFR inhibition (Appendix Table A1, online only).	('FGFR', 'Gene', (0, 4))	('FGFR', 'Gene', (262, 266))	('alterations', 'Var', (267, 278))	('not specified', 'Species', '32644', (25, 38))	('patients', 'Species', '9606', (233, 241))
163559	27870574	Of 26 patients with breast cancer (FGFR1/2 amplified [n = 25]; FGFR3 mutant [n = 1]) with pre-and post-treatment target lesion measurements, four (15.4%) had reduced tumor burden.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('FGFR3', 'Gene', '2261', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('mutant', 'Var', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('breast cancer', 'Disease', (20, 33))	('tumor', 'Disease', (166, 171))	('FGFR3', 'Gene', (63, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('patients', 'Species', '9606', (6, 14))	('FGFR1', 'Gene', (35, 40))	('reduced', 'NegReg', (158, 165))	('FGFR1', 'Gene', '2260', (35, 40))
163560	27870574	In addition, all three patients with FGFR2-altered (fusion [n = 2] or mutation [n = 1]) cholangiocarcinoma with pre-and post-treatment target lesion assessments had reduced tumor burden (Fig 3).	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('patients', 'Species', '9606', (23, 31))	('FGFR2', 'Gene', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('cholangiocarcinoma', 'Disease', (88, 106))	('FGFR2', 'Gene', '2263', (37, 42))	('mutation', 'Var', (70, 78))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 106))	('reduced', 'NegReg', (165, 172))
163563	27870574	This global first-in-human study of the FGFR1-3 inhibitor BGJ398 demonstrated a tolerable safety profile in patients with advancedsolid tumors bearing FGFR amplifications, mutations, or fusions.	('advancedsolid tumors', 'Disease', (122, 142))	('mutations', 'Var', (172, 181))	('advancedsolid tumors', 'Disease', 'MESH:D009369', (122, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('fusions', 'Var', (186, 193))	('FGFR1', 'Gene', (40, 45))	('FGFR', 'Gene', (151, 155))	('BGJ398', 'Gene', (58, 64))	('FGFR1', 'Gene', '2260', (40, 45))	('human', 'Species', '9606', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('patients', 'Species', '9606', (108, 116))	('amplifications', 'Var', (156, 170))
163578	27870574	Despite preselecting for FGFR1 amplification, the response rate was lower than expected on the basis of preclinical data, suggesting that FGFR1 amplification may not function as a sole biomarker predicting clinical benefit.	('lower', 'NegReg', (68, 73))	('response', 'MPA', (50, 58))	('FGFR1', 'Gene', (138, 143))	('FGFR1', 'Gene', (25, 30))	('FGFR1', 'Gene', '2260', (138, 143))	('FGFR1', 'Gene', '2260', (25, 30))	('amplification', 'Var', (31, 44))
163580	27870574	Responses observed in FGFR3-mutant bladder/urothelial cancer after failure of platinum-based chemotherapy (38% overall response rate, 75% DCR) strongly support a role for FGFR3 mutations as driver alterations in this molecular subgroup and the potent inhibitory function of BGJ398.	('bladder/urothelial cancer', 'Disease', (35, 60))	('FGFR3', 'Gene', (22, 27))	('FGFR3', 'Gene', (171, 176))	('mutations', 'Var', (177, 186))	('platinum', 'Chemical', 'MESH:D010984', (78, 86))	('bladder/urothelial cancer', 'Disease', 'MESH:D001749', (35, 60))	('FGFR3', 'Gene', '2261', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('DCR', 'Gene', (138, 141))	('FGFR3', 'Gene', '2261', (171, 176))	('DCR', 'Gene', '1637', (138, 141))
163582	27870574	To this end, a fourth expansion arm was opened to further evaluate BGJ398 activity in patients with urothelial cancer harboring an FGFR3 mutation or fusion.	('mutation', 'Var', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('FGFR3', 'Gene', '2261', (131, 136))	('activity', 'MPA', (74, 82))	('urothelial cancer', 'Disease', (100, 117))	('fusion', 'Var', (149, 155))	('BGJ398', 'Gene', (67, 73))	('FGFR3', 'Gene', (131, 136))	('urothelial cancer', 'Disease', 'MESH:D014523', (100, 117))	('patients', 'Species', '9606', (86, 94))
163583	27870574	SD with reduced tumor burden was also observed in patients with cholangiocarcinoma (FGFR2 fusions [n = 2], FGFR2 mutation [n = 1]) and FGFR1-amplified squamous head and neck cancer.	('FGFR2', 'Gene', (107, 112))	('FGFR2', 'Gene', '2263', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('FGFR1', 'Gene', (135, 140))	('mutation', 'Var', (113, 121))	('FGFR2', 'Gene', '2263', (107, 112))	('reduced', 'NegReg', (8, 15))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('fusions', 'Var', (90, 97))	('patients', 'Species', '9606', (50, 58))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('head and neck cancer', 'Phenotype', 'HP:0012288', (160, 180))	('tumor', 'Disease', (16, 21))	('cholangiocarcinoma', 'Disease', (64, 82))	('FGFR1', 'Gene', '2260', (135, 140))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (64, 82))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('FGFR2', 'Gene', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
163585	27870574	Of interest, another patient with cholangiocarcinoma who was enrolled with a presumed FGFR3 mutation progressed rapidly and was later identified to be wild type for FGFR but as having a mutation in KRAS, a negative predictor (preclinically) for BGJ398 sensitivity.	('mutation', 'Var', (92, 100))	('patient', 'Species', '9606', (21, 28))	('FGFR3', 'Gene', '2261', (86, 91))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (34, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (34, 52))	('KRAS', 'Gene', (198, 202))	('KRAS', 'Gene', '3845', (198, 202))	('FGFR3', 'Gene', (86, 91))	('mutation', 'Var', (186, 194))	('cholangiocarcinoma', 'Disease', (34, 52))	('progressed', 'PosReg', (101, 111))
163587	27870574	The lack of objective responses and the limited disease control observed with BGJ398 in patients with breast cancer challenge the idea of FGFR amplification as a sole oncogenic driver in this disease; however, BGJ398 may prove more effective against advanced breast cancer when combined with other endocrine or targeted agents.	('breast cancer', 'Disease', (102, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('BGJ398', 'Var', (210, 216))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('breast cancer', 'Disease', 'MESH:D001943', (259, 272))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (259, 272))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('breast cancer', 'Disease', (259, 272))
163588	27870574	Certain FGFR alterations (eg, FGFR3 mutations/gene fusions in bladder/urothelial carcinoma and FGFR2 gene fusions in cholangiocarcinoma) are dominant oncogenic drivers and confer sensitivity to BGJ398-mediated FGFR inhibition, whereas FGFR1 amplification, observed in a number of tumor types including sqNSCLC and breast cancer, may not be sufficient to identify a BGJ398-sensitive population.	('FGFR1', 'Gene', '2260', (235, 240))	('bladder/urothelial carcinoma', 'Disease', 'MESH:D001749', (62, 90))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('FGFR', 'Gene', (8, 12))	('FGFR3', 'Gene', (30, 35))	('bladder/urothelial carcinoma', 'Disease', (62, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (314, 327))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('tumor', 'Disease', (280, 285))	('FGFR3', 'Gene', '2261', (30, 35))	('FGFR1', 'Gene', (235, 240))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('mutations/gene', 'Var', (36, 50))	('FGFR2', 'Gene', (95, 100))	('sqNSCLC and breast cancer', 'Disease', 'MESH:D001943', (302, 327))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (117, 135))	('cholangiocarcinoma', 'Disease', (117, 135))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (117, 135))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('alterations', 'Var', (13, 24))	('FGFR2', 'Gene', '2263', (95, 100))
163590	27870574	As the knowledge of FGFR biology and driver genetic alterations increased and assays for patient selection became available over the 6-year enrollment period, patient inclusion criteria were amended accordingly (Appendix Table A1).	('patient', 'Species', '9606', (159, 166))	('FGFR', 'Gene', (20, 24))	('patient', 'Species', '9606', (89, 96))	('genetic alterations', 'Var', (44, 63))
163592	27870574	Taken together, treatment with BGJ398 in patients with advanced solid tumors bearing FGFR alterations was tolerable, with manageable toxicity.	('solid tumors', 'Disease', (64, 76))	('toxicity', 'Disease', 'MESH:D064420', (133, 141))	('alterations', 'Var', (90, 101))	('toxicity', 'Disease', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('FGFR', 'Gene', (85, 89))	('BGJ398', 'Gene', (31, 37))	('solid tumors', 'Disease', 'MESH:D009369', (64, 76))	('patients', 'Species', '9606', (41, 49))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))
163594	27870574	BGJ398 clinical development is ongoing, including adding a fourth expansion arm to this study for patients with urothelial carcinoma and FGFR3 mutation/gene fusion and a phase II study in cholangiocarcinoma with FGFR2 gene fusion/other FGFR genetic alterations.	('FGFR3', 'Gene', '2261', (137, 142))	('FGFR2', 'Gene', '2263', (212, 217))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (188, 206))	('gene fusion/other', 'Var', (218, 235))	('FGFR3', 'Gene', (137, 142))	('patients', 'Species', '9606', (98, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('urothelial carcinoma', 'Disease', (112, 132))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (188, 206))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (112, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('FGFR2', 'Gene', (212, 217))	('mutation/gene', 'Var', (143, 156))	('cholangiocarcinoma', 'Disease', (188, 206))
163595	27870574	Patient eligibility was determined on the basis of FGFR alteration status as assessed centrally or locally using fresh and/or archival tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('FGFR', 'Gene', (51, 55))	('tumor', 'Disease', (135, 140))	('alteration', 'Var', (56, 66))	('Patient', 'Species', '9606', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
163597	27870574	Patients were eligible for enrollment if one of the following genetic alteration criteria was met: (1) FGFR1 or FGFR2 amplification was identified using fluorescence in situ hybridization (defined as a ratio of the respective FGFR to chromosome enumeration probe 8 [FGFR1] or chromosome enumeration probe 10 [FGFR2] of >= 2.2 or an average FGFR copy number of six or more signals/nucleus in >= 20 contiguous cells from two tumor areas); chromogenic or silver-enhanced in situ hybridization (defined as an average respective FGFR copy number of six or more signals/nucleus or a large gene cluster in >= 30% of tumor cells from >= 100 contiguous cells from two tumor areas); or quantitative polymerase chain reaction (defined as a respective FGFR copy number of at least six); (2) FGFR3 mutations were detected in exon 7 (R248C, S249C), exon 10 (G372C, A393E, Y375C), or exon 15 (K652M/T, K652E/Q); or (3) other FGFR genetic alterations, including gene fusions, were identified.	('tumor', 'Disease', 'MESH:D009369', (609, 614))	('S249C', 'Mutation', 'rs121913483', (827, 832))	('A393E', 'Mutation', 'rs28931615', (851, 856))	('FGFR1', 'Gene', (103, 108))	('A393E', 'Var', (851, 856))	('K652E', 'Var', (887, 892))	('K652M', 'SUBSTITUTION', 'None', (878, 883))	('R248C', 'Var', (820, 825))	('R248C', 'Mutation', 'rs121913482', (820, 825))	('Y375C', 'SUBSTITUTION', 'None', (858, 863))	('tumor', 'Disease', (423, 428))	('FGFR1', 'Gene', '2260', (266, 271))	('FGFR', 'Gene', (910, 914))	('tumor', 'Phenotype', 'HP:0002664', (609, 614))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (785, 794))	('FGFR2', 'Gene', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (423, 428))	('FGFR2', 'Gene', (309, 314))	('tumor', 'Disease', (659, 664))	('tumor', 'Disease', 'MESH:D009369', (659, 664))	('Y375C', 'Var', (858, 863))	('G372C', 'Var', (844, 849))	('FGFR2', 'Gene', '2263', (112, 117))	('FGFR1', 'Gene', '2260', (103, 108))	('FGFR2', 'Gene', '2263', (309, 314))	('tumor', 'Phenotype', 'HP:0002664', (423, 428))	('FGFR1', 'Gene', (266, 271))	('K652E', 'SUBSTITUTION', 'None', (887, 892))	('FGFR3', 'Gene', (779, 784))	('K652M', 'Var', (878, 883))	('silver', 'Chemical', 'MESH:D012834', (452, 458))	('tumor', 'Disease', (609, 614))	('tumor', 'Phenotype', 'HP:0002664', (659, 664))	('G372C', 'Mutation', 'rs121913479', (844, 849))	('FGFR3', 'Gene', '2261', (779, 784))
163598	27870574	The intent of including unspecified FGFR alterations, such as fusions, in the prescreening evaluation was to adapt to the rapidly evolving understanding of the role of FGFR in various cancer types and to allow the enrollment of patients with previously unknown activating FGFR alterations (Appendix Table A1).	('cancer', 'Disease', (184, 190))	('unspecified', 'Species', '32644', (24, 35))	('patients', 'Species', '9606', (228, 236))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('activating', 'PosReg', (261, 271))	('FGFR', 'Gene', (272, 276))	('alterations', 'Var', (277, 288))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('alterations', 'Var', (41, 52))
163618	27870574	It was recognized that many patients required dose reduction over the course of their therapy for the management of chronic toxicities; however, given the fact that patients with FGFR alterations are rare and are not easily identified, we chose to initiate treatment with a dose most likely to provide clinical benefit.	('toxicities', 'Disease', (124, 134))	('FGFR', 'Gene', (179, 183))	('alterations', 'Var', (184, 195))	('patients', 'Species', '9606', (165, 173))	('toxicities', 'Disease', 'MESH:D064420', (124, 134))	('patients', 'Species', '9606', (28, 36))
163632	30868740	The curative resectability rate was reported as low as 18%-42% and the majority of patients are only eligible for palliative therapy.2, 3, 4 Witzigmann et al5 reported an R0 resection rate of 23% in 184 HCCA patients, while Hu et al6 reported an R0 resection rate of 37.0% in 814 HCCA patients.	('Witzigmann', 'Var', (141, 151))	('patients', 'Species', '9606', (208, 216))	('HCCA', 'Disease', (203, 207))	('R0 resection', 'CPA', (171, 183))	('patients', 'Species', '9606', (285, 293))	('patients', 'Species', '9606', (83, 91))
163659	30868740	It indicated that lymph node metastasis (OR = 2.756, 95% CI 1.409-5.393; P = 0.003), poor differentiation (OR = 1.653; 95% CI 1.040-2.632; P = 0.034), increased postoperative CA 19-9 levels (OR = 1.965, 95% CI 1.282-3.013; P = 0.002), NLR > 3.41 (OR = 5.125, 95% CI 2.419-10.857; P < 0.001) and age > 60 years (OR = 2.018, 95% CI 1.032-3.947; P = 0.040) were independent determinants of early recurrence in patients with R0 resection of HCCA.	('increased', 'PosReg', (151, 160))	('poor', 'Var', (85, 89))	('patients', 'Species', '9606', (407, 415))	('CA 19-9', 'Chemical', 'MESH:C086528', (175, 182))	('CA 19-9 levels', 'MPA', (175, 189))	('lymph node metastasis', 'CPA', (18, 39))	('HCCA', 'Disease', (437, 441))
163661	30868740	The univariate analysis demonstrated patients with tumor size > 3 cm (P = 0.018), Bismuth classification type III and IV (P = 0.018; Figure 2), perineural invasion (P = 0.003; Figure 3), poor differentiation (P = 0.006; Figure 4), CA 125 > 35 U/mL (P = 0.034) had poorer overall survival outcomes.	('Bismuth', 'Chemical', 'MESH:D001729', (82, 89))	('poor differentiation', 'CPA', (187, 207))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('patients', 'Species', '9606', (37, 45))	('CA 125 > 35 U/mL', 'Var', (231, 247))	('tumor', 'Disease', (51, 56))	('poorer', 'NegReg', (264, 270))	('perineural invasion', 'CPA', (144, 163))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
163724	29510695	After cooling, the sections were incubated in peroxidase blocking reagent (Dako) for 1 h and then incubated with the following primary antibodies at 4  C for overnight: anti-CK19 (Dako, Hamburg, Germany), 1:200; anti-CD133 (R&D Biotechnology, USA), 1:200; anti-TGF-beta1 (Santa Cruz Biotechnology, USA), 1:200; anti-p-Smad2 (Santa Cruz Biotechnology, USA), 1:100; and anti-S100A4 (Sigma-Aldrich Biotechnology, Germany), 1:200; anti-E-Cadherin (1:200; Abcam) and anti-Vimentin (1:200; Abcam).	('CD133', 'Gene', '8842', (217, 222))	('and', 'Protein', (458, 461))	('CK19', 'Gene', '3880', (174, 178))	('Vimentin', 'Gene', (467, 475))	('Smad2', 'Gene', '4087', (318, 323))	('TGF-beta1', 'Gene', '7040', (261, 270))	('E-Cadherin', 'Gene', '999', (432, 442))	('TGF-beta1', 'Gene', (261, 270))	('Smad2', 'Gene', (318, 323))	('S100A4', 'Gene', (373, 379))	('Vimentin', 'Gene', '7431', (467, 475))	('S100A4', 'Gene', '6275', (373, 379))	('E-Cadherin', 'Gene', (432, 442))	('and', 'Var', (364, 367))	('CK19', 'Gene', (174, 178))	('CD133', 'Gene', (217, 222))
163804	30832707	In cancer patients, cfDNA is mainly derived from apoptotic and necrotic tumor cells which contain genetic abnormalities and epigenetic aberrations such as point mutations, loss of heterozygosity (LOH), microsatellite instability (MSI), and DNA methylation.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('necrotic tumor', 'Disease', (63, 77))	('microsatellite', 'MPA', (202, 216))	('genetic abnormalities', 'Disease', (98, 119))	('necrotic tumor', 'Disease', 'MESH:D009369', (63, 77))	('loss of heterozygosity', 'Var', (172, 194))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('point mutations', 'Var', (155, 170))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('patients', 'Species', '9606', (10, 18))	('DNA methylation', 'Var', (240, 255))	('genetic abnormalities', 'Disease', 'MESH:D030342', (98, 119))
163806	30832707	Aberrant DNA methylation has been evidenced as an early event which supports genetic alterations during tumorigenesis and remained existed in advanced stage, in which altered DNA methylation accelerated tumor progression leading to poor clinical outcomes.	('accelerated', 'PosReg', (191, 202))	('tumor', 'Disease', (203, 208))	('clinical', 'Species', '191496', (237, 245))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('DNA', 'Gene', (175, 178))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('altered', 'Var', (167, 174))
163808	30832707	Our previous study demonstrated that hypermethylation of OPCML was highly frequent in CCA tissues but not in normal adjacent (72% vs 0%).	('frequent', 'Reg', (74, 82))	('CCA', 'Phenotype', 'HP:0030153', (86, 89))	('OPCML', 'Gene', (57, 62))	('OPCML', 'Gene', '4978', (57, 62))	('hypermethylation', 'Var', (37, 53))	('CCA', 'Disease', (86, 89))
163809	30832707	Hypermethylation of OPCML was also observed in many cancers such as ovarian cancer, non-small-cell lung carcinoma, brain tumor, bladder cancer, and colorectal cancer.	('cancers', 'Disease', (52, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (148, 165))	('Hypermethylation', 'Var', (0, 16))	('ovarian cancer', 'Disease', 'MESH:D010051', (68, 82))	('brain tumor', 'Phenotype', 'HP:0030692', (115, 126))	('brain tumor', 'Disease', 'MESH:D001932', (115, 126))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('brain tumor', 'Disease', (115, 126))	('bladder cancer', 'Disease', 'MESH:D001749', (128, 142))	('bladder cancer', 'Disease', (128, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ovarian cancer', 'Disease', (68, 82))	('bladder cancer', 'Phenotype', 'HP:0009725', (128, 142))	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('ovarian cancer', 'Phenotype', 'HP:0100615', (68, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (148, 165))	('OPCML', 'Gene', (20, 25))	('colorectal cancer', 'Disease', (148, 165))	('observed', 'Reg', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('non-small-cell lung carcinoma', 'Disease', (84, 113))	('non-small-cell lung carcinoma', 'Disease', 'MESH:D002289', (84, 113))	('OPCML', 'Gene', '4978', (20, 25))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
163812	30832707	Low expression of OPCML due to promoter hypermethylation promotes cell proliferation and short survival in gastric cancer.	('OPCML', 'Gene', '4978', (18, 23))	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('cell proliferation', 'CPA', (66, 84))	('OPCML', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('short survival', 'CPA', (89, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))	('gastric cancer', 'Disease', (107, 121))	('Low', 'NegReg', (0, 3))	('promoter hypermethylation', 'Var', (31, 56))	('promotes', 'PosReg', (57, 65))
163813	30832707	Methylation array data showed that hypermethylation of HOXA9 and HOXD9 was observed in 86.3% (88/102) and 89.2% (91/102) of CCA tissue samples, respectively, but not in normal adjacent.	('hypermethylation', 'Var', (35, 51))	('CCA', 'Disease', (124, 127))	('HOXD9', 'Gene', (65, 70))	('HOXA9', 'Gene', '3205', (55, 60))	('observed', 'Reg', (75, 83))	('CCA', 'Phenotype', 'HP:0030153', (124, 127))	('HOXD9', 'Gene', '3235', (65, 70))	('HOXA9', 'Gene', (55, 60))
163816	30832707	Promoter hypermethylation of HOXA9 was found in oral, breast, ovarian, bladder, and non-small cell lung cancer in which HOXA9 functions as a tumor suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('HOXA9', 'Gene', (120, 125))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (84, 110))	('breast', 'Disease', (54, 60))	('HOXA9', 'Gene', '3205', (120, 125))	('Promoter hypermethylation', 'Var', (0, 25))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (88, 110))	('HOXA9', 'Gene', (29, 34))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (84, 110))	('found', 'Reg', (39, 44))	('HOXA9', 'Gene', '3205', (29, 34))	('ovarian', 'Disease', (62, 69))	('bladder', 'Disease', (71, 78))	('non-small cell lung cancer', 'Disease', (84, 110))	('tumor', 'Disease', (141, 146))	('oral', 'Disease', (48, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
163817	30832707	Low expression of HOXA9 as a result of promoter hypermethylation could promote cell proliferation, invasion, and metastasis in breast cancer.	('promote', 'PosReg', (71, 78))	('HOXA9', 'Gene', '3205', (18, 23))	('cell proliferation', 'CPA', (79, 97))	('metastasis in breast cancer', 'Disease', (113, 140))	('promoter hypermethylation', 'Var', (39, 64))	('expression', 'MPA', (4, 14))	('HOXA9', 'Gene', (18, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('invasion', 'CPA', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('Low', 'NegReg', (0, 3))	('metastasis in breast cancer', 'Disease', 'MESH:D009362', (113, 140))
163822	30832707	By contrast, low expression of HOXD9 transcript and protein due to promoter hypermethylation was noticed in melanoma brain metastasis by which DNA methylation of HOXD9 was significantly higher than that in early stages.	('promoter hypermethylation', 'Var', (67, 92))	('DNA methylation', 'MPA', (143, 158))	('melanoma brain metastasis', 'Disease', (108, 133))	('expression', 'MPA', (17, 27))	('HOXD9', 'Gene', (162, 167))	('HOXD9', 'Gene', (31, 36))	('melanoma brain metastasis', 'Disease', 'MESH:D009362', (108, 133))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('HOXD9', 'Gene', '3235', (162, 167))	('higher', 'PosReg', (186, 192))	('HOXD9', 'Gene', '3235', (31, 36))
163823	30832707	Besides, melanoma patients with hypermethylated HOXD9 in lymph node metastasis showed poorer disease-free and overall survival.	('hypermethylated', 'Var', (32, 47))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma', 'Disease', (9, 17))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('poorer', 'NegReg', (86, 92))	('HOXD9', 'Gene', (48, 53))	('HOXD9', 'Gene', '3235', (48, 53))	('patients', 'Species', '9606', (18, 26))
163824	30832707	Promoter hypermethylation of HOXD9 was also found in astrocytomas.	('astrocytomas', 'Disease', (53, 65))	('HOXD9', 'Gene', '3235', (29, 34))	('found', 'Reg', (44, 49))	('astrocytomas', 'Disease', 'MESH:D001254', (53, 65))	('HOXD9', 'Gene', (29, 34))	('Promoter hypermethylation', 'Var', (0, 25))
163825	30832707	According to hypermethylation of OPCML, HOXA9, and HOXD9 frequently found in CCA tissues, we raised the questions whether this phenomenon could be found in serum cfDNA of CCA and other biliary diseases, and could be used to differentiate CCA from other biliary diseases.	('CCA', 'Disease', (238, 241))	('CCA', 'Phenotype', 'HP:0030153', (171, 174))	('biliary disease', 'Phenotype', 'HP:0001080', (185, 200))	('OPCML', 'Gene', (33, 38))	('HOXA9', 'Gene', (40, 45))	('CCA', 'Phenotype', 'HP:0030153', (238, 241))	('found', 'Reg', (68, 73))	('biliary disease', 'Phenotype', 'HP:0001080', (253, 268))	('CCA', 'Disease', (171, 174))	('OPCML', 'Gene', '4978', (33, 38))	('HOXD9', 'Gene', (51, 56))	('hypermethylation', 'Var', (13, 29))	('CCA', 'Phenotype', 'HP:0030153', (77, 80))	('HOXD9', 'Gene', '3235', (51, 56))	('HOXA9', 'Gene', '3205', (40, 45))
163847	30832707	The frequency of OPCML methylation in serum cfDNA of CCA was 87.5% (35/40), whereas other biliary disease group was 30% (12/40).	('OPCML', 'Gene', '4978', (17, 22))	('biliary disease', 'Phenotype', 'HP:0001080', (90, 105))	('methylation', 'Var', (23, 34))	('CCA', 'Disease', (53, 56))	('OPCML', 'Gene', (17, 22))	('CCA', 'Phenotype', 'HP:0030153', (53, 56))
163848	30832707	Moreover, the methylation of HOXD9 in serum cfDNA of CCA was also frequently detected in 67.5% (27/40) while in other biliary disease group was found only in 10% (4/40).	('biliary disease', 'Phenotype', 'HP:0001080', (118, 133))	('HOXD9', 'Gene', '3235', (29, 34))	('CCA', 'Disease', (53, 56))	('methylation', 'Var', (14, 25))	('detected', 'Reg', (77, 85))	('HOXD9', 'Gene', (29, 34))	('CCA', 'Phenotype', 'HP:0030153', (53, 56))
163872	30832707	For example, the detection of serum DNA methylation in intrauterine growth retardation infants, in pregnant women, and in nasopharyngeal carcinoma patients.	('intrauterine growth retardation', 'Disease', (55, 86))	('methylation', 'Var', (40, 51))	('nasopharyngeal carcinoma', 'Disease', (122, 146))	('women', 'Species', '9606', (108, 113))	('intrauterine growth retardation', 'Phenotype', 'HP:0001511', (55, 86))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (122, 146))	('DNA', 'Protein', (36, 39))	('intrauterine growth retardation', 'Disease', 'MESH:D005317', (55, 86))	('patients', 'Species', '9606', (147, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('detection', 'Reg', (17, 26))	('infants', 'Species', '9606', (87, 94))	('growth retardation', 'Phenotype', 'HP:0001510', (68, 86))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (122, 146))
163884	30832707	Previous study in melanoma patients with lymph node metastasis showed the association of hypermethylated HOXD9 with poor prognosis.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('HOXD9', 'Gene', '3235', (105, 110))	('hypermethylated', 'Var', (89, 104))	('patients', 'Species', '9606', (27, 35))	('HOXD9', 'Gene', (105, 110))	('association', 'Interaction', (74, 85))	('melanoma', 'Disease', (18, 26))
163887	30832707	Interestingly, the combined OPCML and HOXD9 methylation increased the specificity and PPV of the test to 100%, potentially supporting differential diagnosis between CCA and other biliary diseases.	('OPCML', 'Gene', '4978', (28, 33))	('biliary disease', 'Phenotype', 'HP:0001080', (179, 194))	('methylation', 'Var', (44, 55))	('increased', 'PosReg', (56, 65))	('HOXD9', 'Gene', '3235', (38, 43))	('CCA', 'Phenotype', 'HP:0030153', (165, 168))	('HOXD9', 'Gene', (38, 43))	('specificity', 'MPA', (70, 81))	('biliary diseases', 'Disease', (179, 195))	('OPCML', 'Gene', (28, 33))	('CCA', 'Disease', (165, 168))
163893	30832707	We analyzed DNA methylation of OPCML at the same area from - 60 to + 41 bp of the TSS which contains ten overlapped CpG sites with the previous studies implicating that promoter DNA methylation of OPCML in our study may affect gene silencing in CCA.	('affect', 'Reg', (220, 226))	('OPCML', 'Gene', '4978', (31, 36))	('OPCML', 'Gene', (197, 202))	('CCA', 'Disease', (245, 248))	('gene silencing', 'MPA', (227, 241))	('promoter DNA methylation', 'Var', (169, 193))	('OPCML', 'Gene', '4978', (197, 202))	('CCA', 'Phenotype', 'HP:0030153', (245, 248))	('OPCML', 'Gene', (31, 36))
163897	30832707	Promoter DNA methylation of HOXD9 at a region from - 753 to + 193 bp of the TSS decreased its expression in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('methylation', 'Var', (13, 24))	('HOXD9', 'Gene', (28, 33))	('decreased', 'NegReg', (80, 89))	('expression', 'MPA', (94, 104))	('TSS', 'Gene', (76, 79))	('HOXD9', 'Gene', '3235', (28, 33))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))
163899	30832707	Loss of HOXD9 may promote dedifferentiation of cholangiocyte leading to CCA development.	('HOXD9', 'Gene', (8, 13))	('CCA', 'Disease', (72, 75))	('HOXD9', 'Gene', '3235', (8, 13))	('dedifferentiation', 'CPA', (26, 43))	('CCA', 'Phenotype', 'HP:0030153', (72, 75))	('Loss', 'Var', (0, 4))	('promote', 'PosReg', (18, 25))
163901	30832707	Further study in early stage CCA should be warranted for the application of serum cfDNA methylation of OPCML and HOXD9 as an early differential biomarker in CCA.	('CCA', 'Phenotype', 'HP:0030153', (157, 160))	('methylation', 'Var', (88, 99))	('HOXD9', 'Gene', (113, 118))	('OPCML', 'Gene', '4978', (103, 108))	('HOXD9', 'Gene', '3235', (113, 118))	('CCA', 'Disease', (157, 160))	('OPCML', 'Gene', (103, 108))	('CCA', 'Phenotype', 'HP:0030153', (29, 32))
163912	30652045	Rare Anomaly of Common Bile Duct in Association with Distal Cholangiocarcinoma Duplication of common bile duct is a rare entity and its association with distal cholangiocarcinoma is extremely rare.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (160, 178))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (160, 178))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (60, 78))	('Distal', 'Disease', (53, 59))	('Anomaly', 'Disease', 'MESH:D000014', (5, 12))	('Anomaly of Common Bile Duct', 'Phenotype', 'HP:0100889', (5, 32))	('cholangiocarcinoma', 'Disease', (160, 178))	('Duplication', 'Var', (79, 90))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (60, 78))	('Cholangiocarcinoma', 'Disease', (60, 78))	('Anomaly', 'Disease', (5, 12))
124260	30652045	Duplication of the extrahepatic bile duct is a rare anomaly of the biliary system.	('anomaly of the biliary system', 'Phenotype', 'HP:0004297', (52, 81))	('anomaly of the biliary system', 'Disease', 'MESH:D001656', (52, 81))	('anomaly of the biliary', 'Phenotype', 'HP:0012440', (52, 74))	('Duplication', 'Var', (0, 11))	('anomaly of the biliary system', 'Disease', (52, 81))
163922	30652045	On detailed evaluation of the resected specimen, a septum extending from the hilum with cystic duct opening on the right side (Figure 1(a)) to the distal end of the bile duct was appreciated, suggesting duplication of the common bile duct.	('cystic duct opening', 'Disease', 'MESH:D005597', (88, 107))	('cystic duct opening', 'Disease', (88, 107))	('duplication', 'Var', (203, 214))
163931	30652045	Although biliary tree anomalies are quite common, duplication of common bile duct is a rare entity and its association with distal cholangiocarcinoma is extremely rare.	('duplication', 'Var', (50, 61))	('biliary tree anomalies', 'Disease', (9, 31))	('cholangiocarcinoma', 'Disease', (131, 149))	('biliary tree anomalies', 'Disease', 'MESH:C531647', (9, 31))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (131, 149))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))
163934	28808500	Recent large scale molecular characterisation studies have identified recurrent genetic alterations in CCA which may be amenable to therapeutic targeting.	('CCA', 'Phenotype', 'HP:0030153', (103, 106))	('genetic alterations', 'Var', (80, 99))	('CCA', 'Disease', (103, 106))	('men', 'Species', '9606', (121, 124))
163973	28808500	There are clear differences in the prevalence of known oncogenic driver mutations between ICC and ECC, implicating distinct processes of oncogenesis for these tumour subtypes (Table 1).	('mutations', 'Var', (72, 81))	('tumour', 'Disease', (159, 165))	('ECC', 'Disease', (98, 101))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('ICC', 'Disease', (90, 93))
163975	28808500	In one of the first studies to sequence CCA, 8 liver fluke CCA were analysed, revealing novel mutations in SMAD4 (17%), MLL3 (15%), ROBO2, GNAS and RNF (9%) each and CKDN2A and PEG3 (5%) each.	('liver fluke', 'Species', '6192', (47, 58))	('CKDN2A', 'Gene', (166, 172))	('RNF', 'Gene', (148, 151))	('mutations', 'Var', (94, 103))	('MLL3', 'Gene', (120, 124))	('ROBO2', 'Gene', (132, 137))	('SMAD4', 'Gene', '4089', (107, 112))	('CCA', 'Phenotype', 'HP:0030153', (59, 62))	('GNAS', 'Gene', (139, 143))	('CCA', 'Phenotype', 'HP:0030153', (40, 43))	('SMAD4', 'Gene', (107, 112))
163976	28808500	In a subsequent follow up study of 208 CCA cases (108 caused by liver fluke O. viverinni), TP53 mutations were more often seen in fluke related CCA, whilst IDH1/2 and BAP1 mutations were more common in non-fluke CCA.	('TP53', 'Gene', (91, 95))	('liver fluke', 'Species', '6192', (64, 75))	('CCA', 'Phenotype', 'HP:0030153', (212, 215))	('CCA', 'Phenotype', 'HP:0030153', (144, 147))	('seen', 'Reg', (122, 126))	('BAP1', 'Gene', '8314', (167, 171))	('fluke related CCA', 'Disease', (130, 147))	('TP53', 'Gene', '7157', (91, 95))	('mutations', 'Var', (96, 105))	('BAP1', 'Gene', (167, 171))	('CCA', 'Phenotype', 'HP:0030153', (39, 42))
163978	28808500	Interestingly IDH1/2 (Isocitrate dehydrogenase) mutations are seen almost exclusively in ICC.	('seen', 'Reg', (62, 66))	('IDH1/2 (Isocitrate dehydrogenase', 'Gene', '3417;3418', (14, 46))	('mutations', 'Var', (48, 57))	('ICC', 'Disease', (89, 92))
163979	28808500	The IDH mutation results in reduced normal function of this enzyme and leads to increased production of 2-hydroxyglutarate (2-HG) from alpha-ketoglutarate.	('function', 'MPA', (43, 51))	('reduced', 'NegReg', (28, 35))	('IDH', 'Gene', '3417', (4, 7))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (104, 122))	('increased', 'PosReg', (80, 89))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (135, 154))	('mutation', 'Var', (8, 16))	('IDH', 'Gene', (4, 7))
163980	28808500	2-HG is considered an oncometabolite and causes epigenetic changes, including histone and DNA methylation, which promotes tumour development.	('promotes', 'PosReg', (113, 121))	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('tumour', 'Disease', (122, 128))	('DNA methylation', 'MPA', (90, 105))	('epigenetic changes', 'MPA', (48, 66))	('2-HG', 'Var', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('men', 'Species', '9606', (136, 139))	('histone', 'MPA', (78, 85))
163981	28808500	In one study of 326 patients with resected ICC, IDH1/2 mutations were associated with improved overall survival, however another whole exome sequencing study (n = 32) suggested worse overall survival for patients with these aberrations (3 year OS 33% mutant vs 81% wildtype, P = 0.003), however in this study a higher proportion of patients with IDH mutations had advanced disease (50% vs 15%).	('patients', 'Species', '9606', (204, 212))	('IDH', 'Gene', (48, 51))	('IDH', 'Gene', '3417', (346, 349))	('mutations', 'Var', (55, 64))	('advanced disease', 'Disease', (364, 380))	('OS', 'Gene', '17451', (244, 246))	('IDH', 'Gene', '3417', (48, 51))	('improved', 'PosReg', (86, 94))	('patients', 'Species', '9606', (332, 340))	('overall survival', 'MPA', (95, 111))	('advanced disease', 'Disease', 'MESH:D020178', (364, 380))	('patients', 'Species', '9606', (20, 28))	('IDH', 'Gene', (346, 349))
163982	28808500	Two other studies examining the effect of IDH mutations in patients with resected and advanced ICC demonstrated no significant association with prognosis.	('IDH', 'Gene', (42, 45))	('mutations', 'Var', (46, 55))	('ICC', 'Disease', (95, 98))	('IDH', 'Gene', '3417', (42, 45))	('patients', 'Species', '9606', (59, 67))
163983	28808500	Pre-clinical data suggesting oncogenic addiction to IDH signalling can be pharmacologically abrogated resulting in control of cancer cell growth has been demonstrated in IDH mutant glioma lines.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('IDH', 'Gene', (52, 55))	('cancer', 'Disease', (126, 132))	('IDH', 'Gene', (170, 173))	('IDH', 'Gene', '3417', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('IDH', 'Gene', '3417', (170, 173))	('glioma', 'Disease', (181, 187))	('mutant', 'Var', (174, 180))
163984	28808500	Inhibitors of mutant IDH1 and IDH2 are currently in clinical trials (Table 2); early results for AG-120 which is an IDH1 inhibitor demonstrated tolerable toxicity with evidence of pharmacodynamic endpoint modulation with reduced circulating levels of 2-hydroxyglulatrate were observed in most patients.	('toxicity', 'Disease', 'MESH:D064420', (154, 162))	('toxicity', 'Disease', (154, 162))	('mutant', 'Var', (14, 20))	('circulating levels of 2-hydroxyglulatrate', 'MPA', (229, 270))	('IDH2', 'Gene', (30, 34))	('IDH1', 'Gene', (116, 120))	('AG-120', 'Chemical', 'MESH:C000627630', (97, 103))	('reduced', 'NegReg', (221, 228))	('AG-120', 'Gene', (97, 103))	('IDH1', 'Gene', (21, 25))	('IDH1', 'Gene', '3417', (116, 120))	('IDH2', 'Gene', '3418', (30, 34))	('2-hydroxyglulatrate', 'Chemical', '-', (251, 270))	('patients', 'Species', '9606', (293, 301))	('IDH1', 'Gene', '3417', (21, 25))
163986	28808500	The genes BAP1, ARID1A and PBRM1, which are involved in chromatin remodelling, have been found to be frequently mutated in ICC and in one study had inactivating mutations in just under half (n = 15/32) of ICC cases.	('ICC', 'Disease', (205, 208))	('BAP1', 'Gene', (10, 14))	('ICC', 'Disease', (123, 126))	('PBRM1', 'Gene', (27, 32))	('mutated', 'Var', (112, 119))	('PBRM1', 'Gene', '55193', (27, 32))	('ARID1A', 'Gene', '8289', (16, 22))	('ARID1A', 'Gene', (16, 22))	('BAP1', 'Gene', '8314', (10, 14))
163991	28808500	In NSCLC EGFR gene mutation, predicts response to EGFR inhibition.	('NSCLC', 'Disease', (3, 8))	('mutation', 'Var', (19, 27))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('predicts', 'Reg', (29, 37))	('EGFR', 'Gene', '1956', (50, 54))	('response to', 'MPA', (38, 49))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('EGFR', 'Gene', (50, 54))
163992	28808500	Both activating mutations and amplifications of the EGFR gene have been observed in CCA.	('amplifications', 'Var', (30, 44))	('activating', 'PosReg', (5, 15))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('CCA', 'Disease', (84, 87))	('CCA', 'Phenotype', 'HP:0030153', (84, 87))
163993	28808500	EGFR mutations have been observed in 10%-15% of CCA, however due to small sample numbers data are conflicting regarding whether prevalence is higher in ICC or ECC.	('EGFR', 'Gene', (0, 4))	('ICC', 'Disease', (152, 155))	('CCA', 'Phenotype', 'HP:0030153', (48, 51))	('mutations', 'Var', (5, 14))	('EGFR', 'Gene', '1956', (0, 4))	('ECC', 'Disease', (159, 162))	('CCA', 'Disease', (48, 51))
164005	28808500	However the objective response rate (CR + PR) was higher in the erlotinib group (40 vs 21 patients, P = 0.005) and in the subgroup of patients with CCA, PFS was longer in the erlotinib group (5.9 mo vs 3.0 mo, HR = 0.73, 95%CI: 0.53-1.0, P = 0.049).	('higher', 'PosReg', (50, 56))	('erlotinib', 'Chemical', 'MESH:D000069347', (64, 73))	('CCA', 'Disease', (148, 151))	('erlotinib', 'Var', (64, 73))	('patients', 'Species', '9606', (134, 142))	('CCA', 'Phenotype', 'HP:0030153', (148, 151))	('erlotinib', 'Chemical', 'MESH:D000069347', (175, 184))	('objective response', 'MPA', (12, 30))	('patients', 'Species', '9606', (90, 98))
164028	28808500	Abnormalities of this pathway have been implicated as driver events in carcinogenesis.	('carcinogenesis', 'Disease', (71, 85))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))	('Abnormalities', 'Var', (0, 13))
164030	28808500	Sia et al demonstrated in a cohort of 107 ICC patients that FGFR2 translocations represented the most common actionable target detected; these occurred in 16% of patients screened; this prevalence has been confirmed in other series.	('patients', 'Species', '9606', (162, 170))	('translocations', 'Var', (66, 80))	('patients', 'Species', '9606', (46, 54))	('FGFR2', 'Gene', '2263', (60, 65))	('FGFR2', 'Gene', (60, 65))
164031	28808500	One United States study has suggested that FGFR2 fusion in ICC is more common in females, and a Japanese study has implicated viral hepatitis infection in this pathway, however these findings require validation.	('hepatitis', 'Phenotype', 'HP:0012115', (132, 141))	('viral hepatitis infection', 'Disease', (126, 151))	('common', 'Reg', (71, 77))	('fusion', 'Var', (49, 55))	('FGFR2', 'Gene', (43, 48))	('FGFR2', 'Gene', '2263', (43, 48))	('viral hepatitis', 'Phenotype', 'HP:0006562', (126, 141))	('viral hepatitis infection', 'Disease', 'MESH:D006525', (126, 151))	('ICC', 'Disease', (59, 62))
164032	28808500	FGFR2 translocation in CCA may confer a prognostic benefit.	('translocation', 'Var', (6, 19))	('CCA', 'Disease', (23, 26))	('FGFR2', 'Gene', (0, 5))	('CCA', 'Phenotype', 'HP:0030153', (23, 26))	('FGFR2', 'Gene', '2263', (0, 5))
164033	28808500	Cancer specific survival in one dataset for patients harbouring FGFR2 translocations was superior to non-translocated tumours (123 mo vs 37 mo respectively).	('FGFR2', 'Gene', '2263', (64, 69))	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('tumours', 'Disease', (118, 125))	('translocations', 'Var', (70, 84))	('patients', 'Species', '9606', (44, 52))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('superior', 'PosReg', (89, 97))	('FGFR2', 'Gene', (64, 69))
164034	28808500	Preclinical work in cell lines and patient derived xenografts supports blockade of FGFR2 signalling in CCA as a potential effective therapy and early anecdotal reports of FGFR inhibitor therapy in FGFR2 translocated CCA patients have been encouraging.	('FGFR2', 'Gene', (83, 88))	('FGFR2', 'Gene', '2263', (83, 88))	('CCA', 'Phenotype', 'HP:0030153', (216, 219))	('translocated', 'Var', (203, 215))	('patient', 'Species', '9606', (35, 42))	('FGFR2', 'Gene', (197, 202))	('patient', 'Species', '9606', (220, 227))	('patients', 'Species', '9606', (220, 228))	('CCA', 'Phenotype', 'HP:0030153', (103, 106))	('FGFR2', 'Gene', '2263', (197, 202))	('CCA', 'Disease', (216, 219))
164037	28808500	ROS1 gene rearrangements are seen in a number of cancers and result in a fusion protein with a constitutively activated kinase domain that promotes oncogenesis.	('ROS1', 'Gene', (0, 4))	('rearrangements', 'Var', (10, 24))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ROS1', 'Gene', '6098', (0, 4))	('result in', 'Reg', (61, 70))	('men', 'Species', '9606', (19, 22))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('oncogenesis', 'CPA', (148, 159))	('promotes', 'PosReg', (139, 147))	('cancers', 'Disease', (49, 56))	('fusion', 'Interaction', (73, 79))
164039	28808500	In CCA the prevalence of ROS1 rearrangement is reported to be around 8%-9%.	('rearrangement', 'Var', (30, 43))	('CCA', 'Phenotype', 'HP:0030153', (3, 6))	('ROS1', 'Gene', (25, 29))	('ROS1', 'Gene', '6098', (25, 29))	('men', 'Species', '9606', (39, 42))	('CCA', 'Disease', (3, 6))
164040	28808500	Larger series are needed to determine whether prevalence is higher in ICC or ECC, however Neia et al found that in a cohort of 65 biliary tract cancer patients FIG-ROS1 fusions were found in 4/25 ECC, 2/14 gallbladder carcinoma, 0/26 ICC.	('fusions', 'Var', (169, 176))	('biliary tract cancer', 'Disease', 'MESH:D001661', (130, 150))	('biliary tract cancer', 'Disease', (130, 150))	('carcinoma', 'Disease', 'MESH:D002277', (218, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('ROS1', 'Gene', (164, 168))	('patients', 'Species', '9606', (151, 159))	('ECC', 'Disease', (196, 199))	('ROS1', 'Gene', '6098', (164, 168))	('found', 'Reg', (182, 187))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (130, 150))	('carcinoma', 'Disease', (218, 227))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
164042	28808500	Clinical trials are in progress to assess the efficacy of targeting ROS1 rearrangement in CCA (NCT02374489, NCT02034981).	('CCA', 'Disease', (90, 93))	('ROS1', 'Gene', '6098', (68, 72))	('NCT02034981', 'Var', (108, 119))	('rearrangement', 'Var', (73, 86))	('CCA', 'Phenotype', 'HP:0030153', (90, 93))	('NCT02374489', 'Var', (95, 106))	('men', 'Species', '9606', (82, 85))	('ROS1', 'Gene', (68, 72))
164047	28808500	BRAF mutations in CCA are reported to occur at a rate of 0-22%.	('CCA', 'Disease', (18, 21))	('mutations', 'Var', (5, 14))	('CCA', 'Phenotype', 'HP:0030153', (18, 21))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))
164048	28808500	In one large study, BRAF V600E mutation was detected in 3% (5/159) of ICC cases but in no (0/149) ECC cases.	('ICC', 'Disease', (70, 73))	('V600E', 'Var', (25, 30))	('BRAF', 'Gene', (20, 24))	('BRAF', 'Gene', '673', (20, 24))	('V600E', 'Mutation', 'rs113488022', (25, 30))
164049	28808500	BRAF mutation showed no correlation with prognosis in this study.	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('mutation', 'Var', (5, 13))
164050	28808500	Due to the infrequent occurrence of BRAF mutation in CC, molecularly targeted clinical trials are difficult to conduct, however a phase II trial of combination BRAF and MEK inhibition in rare cancers is in progress (NCT02034110).	('BRAF', 'Gene', (160, 164))	('BRAF', 'Gene', '673', (160, 164))	('BRAF', 'Gene', (36, 40))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('mutation', 'Var', (41, 49))	('cancers', 'Disease', (192, 199))	('MEK', 'Gene', (169, 172))	('MEK', 'Gene', '5609', (169, 172))	('BRAF', 'Gene', '673', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
164052	28808500	In one of the first reported studies on this topic Meng et al demonstrated that miR-21, miR-141, and miR-200b were highly over-expressed in malignant CCA cells, and whereas inhibition of miR-21 and miR-200b increased sensitivity to gemcitabine, inhibition of miR-141 decreased cell growth.	('miR-21', 'Gene', '406991', (187, 193))	('miR-141', 'Gene', (259, 266))	('gemcitabine', 'Chemical', 'MESH:C056507', (232, 243))	('over-expressed', 'PosReg', (122, 136))	('CCA', 'Phenotype', 'HP:0030153', (150, 153))	('miR-200b', 'Gene', (198, 206))	('miR-21', 'Gene', (187, 193))	('miR-141', 'Gene', '406933', (88, 95))	('inhibition', 'Var', (245, 255))	('miR-21', 'Gene', '406991', (80, 86))	('miR-200b', 'Gene', (101, 109))	('miR-141', 'Gene', (88, 95))	('cell growth', 'CPA', (277, 288))	('decreased', 'NegReg', (267, 276))	('inhibition', 'Var', (173, 183))	('miR-200b', 'Gene', '406984', (198, 206))	('sensitivity to gemcitabine', 'MPA', (217, 243))	('increased', 'PosReg', (207, 216))	('miR-21', 'Gene', (80, 86))	('miR-141', 'Gene', '406933', (259, 266))	('miR-200b', 'Gene', '406984', (101, 109))
164054	28808500	The inflammatory cytokine, IL-6 has been identified as a driver of cholangiocarcinogenesis and has been shown to alter the expression of a number of miRNAs including miRNA 7a, 370, 148a and 152.	('expression', 'MPA', (123, 133))	('alter', 'Reg', (113, 118))	('cholangiocarcinogenesis', 'Disease', (67, 90))	('370', 'Var', (176, 179))	('IL-6', 'Gene', (27, 31))	('148a', 'Var', (181, 185))	('miRNA 7a', 'Var', (166, 174))	('IL-6', 'Gene', '3569', (27, 31))	('cholangiocarcinogenesis', 'Disease', 'None', (67, 90))
164055	28808500	IL-6 signalling is associated with increased expression of DNA methyltransferase (DNMT), which promotes silencing of tumour suppressor genes through DNA hypermethylation.	('increased', 'PosReg', (35, 44))	('DNA methyltransferase', 'Gene', (59, 80))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('DNMT', 'Gene', '1786', (82, 86))	('hypermethylation', 'Var', (153, 169))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('DNA methyltransferase', 'Gene', '1786', (59, 80))	('DNMT', 'Gene', (82, 86))	('expression', 'MPA', (45, 55))	('IL-6', 'Gene', (0, 4))	('silencing', 'MPA', (104, 113))	('tumour', 'Disease', (117, 123))	('IL-6', 'Gene', '3569', (0, 4))
164057	28808500	Crucially in cells transfected with these miRNAs DNMT levels were shown to decrease leading to reduced cellular proliferation.	('DNMT', 'Gene', (49, 53))	('decrease', 'NegReg', (75, 83))	('reduced', 'NegReg', (95, 102))	('miRNAs', 'Var', (42, 48))	('cellular proliferation', 'CPA', (103, 125))	('DNMT', 'Gene', '1786', (49, 53))
164058	28808500	In another study, in a cell culture model, miRNA 29b was under-expressed in CCA cell lines compared to normal cholangiocytes, resulting in up-regulation of the anti-apoptotic protein MCL-1 and allowing tumour cells to evade apoptosis.	('allowing tumour', 'Disease', (193, 208))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('up-regulation', 'PosReg', (139, 152))	('evade apoptosis', 'CPA', (218, 233))	('MCL-1', 'Gene', (183, 188))	('allowing tumour', 'Disease', 'MESH:D009369', (193, 208))	('MCL-1', 'Gene', '4170', (183, 188))	('CCA', 'Phenotype', 'HP:0030153', (76, 79))	('miRNA 29b', 'Var', (43, 52))
164059	28808500	In a further study, miRNA 494 was shown to induce G1/S transition cell cycle arrest, through downregulation of cyclin dependent kinase 6.	('cyclin dependent kinase 6', 'Gene', '1021', (111, 136))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (66, 83))	('miRNA 494', 'Var', (20, 29))	('cyclin dependent kinase 6', 'Gene', (111, 136))	('G1/S transition cell cycle arrest', 'CPA', (50, 83))	('induce', 'PosReg', (43, 49))	('downregulation', 'NegReg', (93, 107))
164060	28808500	miRNA 26a was shown to promote proliferation of CCA cells by lowering levels of glycogen synthase kinase 3beta (GSK-3beta) and preventing the degradation of beta-catenin, leading to upregulation of transcription of target genes involved in carcinogenesis.	('beta-catenin', 'Gene', '1499', (157, 169))	('degradation', 'MPA', (142, 153))	('proliferation', 'CPA', (31, 44))	('promote', 'PosReg', (23, 30))	('lowering', 'NegReg', (61, 69))	('transcription of', 'MPA', (198, 214))	('CCA', 'Phenotype', 'HP:0030153', (48, 51))	('lowering levels of glycogen synthase', 'Phenotype', 'HP:0003524', (61, 97))	('carcinogenesis', 'Disease', 'MESH:D063646', (240, 254))	('GSK-3beta', 'Gene', (112, 121))	('glycogen synthase kinase 3beta', 'Gene', '2932', (80, 110))	('miRNA', 'Var', (0, 5))	('beta-catenin', 'Gene', (157, 169))	('glycogen synthase kinase 3beta', 'Gene', (80, 110))	('upregulation', 'PosReg', (182, 194))	('carcinogenesis', 'Disease', (240, 254))	('GSK-3beta', 'Gene', '2932', (112, 121))	('preventing', 'NegReg', (127, 137))
164069	28808500	The panel consisted of miR-191, miR-486-3p, miR-16, and miR-484, of which the last is the most sensitive for CCA.	('CCA', 'Phenotype', 'HP:0030153', (109, 112))	('miR-191', 'Gene', (23, 30))	('miR-16', 'Gene', '51573', (44, 50))	('CCA', 'Disease', (109, 112))	('miR-486-3p', 'Var', (32, 42))	('miR-484', 'Gene', '619553', (56, 63))	('miR-484', 'Gene', (56, 63))	('miR-191', 'Gene', '406966', (23, 30))	('miR-16', 'Gene', (44, 50))	('sensitive', 'Reg', (95, 104))
164084	28808500	Le et al also reported data from a phase II trial of 17 patients with mismatch repair deficient non-colorectal gastrointestinal cancers treated with the PD-1 inhibitor pembrolizumab.	('patients', 'Species', '9606', (56, 64))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('mismatch', 'Var', (70, 78))	('deficient non-colorectal gastrointestinal cancers', 'Disease', 'MESH:D015179', (86, 135))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('deficient non-colorectal gastrointestinal cancers', 'Disease', (86, 135))	('pembrolizumab', 'Chemical', 'MESH:C582435', (168, 181))
164090	28808500	Tran et al treated a female patient with metastatic CCA who had progressed on multiple lines of chemotherapy, with autologous TH1 tumour infiltrating lymphocytes (TILs) specific to a mutated antigen expressed by the patient's cancer.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('Tran', 'Gene', '7154', (0, 4))	('mutated', 'Var', (183, 190))	('Tran', 'Gene', (0, 4))	('TH1', 'Gene', '51497', (126, 129))	('tumour', 'Disease', (130, 136))	('patient', 'Species', '9606', (216, 223))	('CCA', 'Phenotype', 'HP:0030153', (52, 55))	('patient', 'Species', '9606', (28, 35))	('cancer', 'Disease', (226, 232))	('TH1', 'Gene', (126, 129))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
164092	28808500	Further testing revealed that CD4+ TH1 TILs recognised mutated erbb2 interacting protein (ERBB2IP) in the tumour tissue.	('ERBB2IP', 'Gene', (90, 97))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('mutated', 'Var', (55, 62))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('erbb2 interacting protein', 'Gene', (63, 88))	('erbb2 interacting protein', 'Gene', '55914', (63, 88))	('ERBB2IP', 'Gene', '55914', (90, 97))	('TH1', 'Gene', '51497', (35, 38))	('tumour', 'Disease', (106, 112))	('CD4', 'Gene', (30, 33))	('CD4', 'Gene', '920', (30, 33))	('TH1', 'Gene', (35, 38))
164097	28808500	Genomic profiling studies have highlighted differing patterns of mutation signatures between ICC and ECC, helping to stratify patients for targeted therapies.	('ECC', 'Disease', (101, 104))	('mutation', 'Var', (65, 73))	('ICC', 'Disease', (93, 96))	('patients', 'Species', '9606', (126, 134))
164098	28808500	FGFR fusions and IDH mutations appear to be frequently mutated in ICC and hold promise as therapeutic targets.	('IDH', 'Gene', '3417', (17, 20))	('FGFR', 'Gene', (0, 4))	('fusions', 'Var', (5, 12))	('ICC', 'Disease', (66, 69))	('IDH', 'Gene', (17, 20))
164177	30042823	High Ang-1 expression was associated with less lymphangiosis carcinomatosa and better histological grading (all p < 0.05).	('Ang-1', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('Ang-1', 'Gene', '284', (5, 10))	('histological grading', 'CPA', (86, 106))	('lymphangiosis carcinomatosa', 'Disease', 'None', (47, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('lymphangiosis carcinomatosa', 'Disease', (47, 74))	('less', 'NegReg', (42, 46))
164179	30042823	High miR-126, low miR-128 and TEMs were independent prognostic factors for recurrence-free and overall survival (all p < 0.05).	('miR-126', 'Gene', (5, 12))	('low miR-128', 'Var', (14, 25))	('overall survival', 'CPA', (95, 111))	('miR-128', 'Chemical', '-', (18, 25))	('miR-126', 'Gene', '406913', (5, 12))	('recurrence-free', 'CPA', (75, 90))
164198	30042823	However, as is already apparent for TAMs, data also imply that TEMs have a beneficial impact in human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (102, 114))	('human', 'Species', '9606', (96, 101))	('malignancies', 'Disease', (102, 114))	('TAMs', 'Chemical', '-', (36, 40))	('TEMs', 'Var', (63, 67))
164209	30042823	MiR-126, miR-145, miR-128 and miR-107 were detected in all CCA samples.	('MiR-126', 'Gene', (0, 7))	('miR-145', 'Gene', (9, 16))	('miR-107', 'Gene', '406901', (30, 37))	('miR-145', 'Gene', '406937', (9, 16))	('MiR-126', 'Gene', '406913', (0, 7))	('miR-107', 'Gene', (30, 37))	('detected', 'Reg', (43, 51))	('miR-128', 'Chemical', '-', (18, 25))	('CCA', 'Disease', (59, 62))	('miR-128', 'Var', (18, 25))
164216	30042823	In HC, high miR-126 relative expression was associated with a smaller tumour mass (largest tumour diameter < 50 mm) (Table 1).	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('tumour mass', 'Disease', 'MESH:C536030', (70, 81))	('smaller', 'NegReg', (62, 69))	('tumour mass', 'Disease', (70, 81))	('tumour', 'Disease', (91, 97))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('high', 'Var', (7, 11))	('miR-126', 'Gene', '406913', (12, 19))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('tumour', 'Disease', (70, 76))	('miR-126', 'Gene', (12, 19))
164224	30042823	In iCC, the high density of Ang-1 in tumour tissue was associated with reduced lymphangiosis carcinomatosa.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('high density', 'Var', (12, 24))	('reduced lymphangiosis carcinomatosa', 'Disease', (71, 106))	('tumour', 'Disease', (37, 43))	('reduced lymphangiosis carcinomatosa', 'Disease', 'MESH:D015354', (71, 106))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('Ang-1', 'Gene', (28, 33))	('Ang-1', 'Gene', '284', (28, 33))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
164232	30042823	The absence of TEMs in the tumour-infiltrating front was associated with pathological CA19-9 levels.	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('TEMs', 'Protein', (15, 19))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('CA19-9 levels', 'MPA', (86, 99))	('absence', 'Var', (4, 11))	('tumour', 'Disease', (27, 33))
164235	30042823	In iCC, survival was significantly decreased in patients with high relative miR-128 expression in the tumour in comparison to those with low miR-128 expression (p = 0.018; Figure 3A).	('miR-128', 'Gene', (76, 83))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('decreased', 'NegReg', (35, 44))	('miR-128', 'Chemical', '-', (76, 83))	('tumour', 'Disease', (102, 108))	('iCC', 'Disease', (3, 6))	('miR-128', 'Chemical', '-', (141, 148))	('survival', 'CPA', (8, 16))	('expression', 'MPA', (84, 94))	('high', 'Var', (62, 66))	('patients', 'Species', '9606', (48, 56))
164236	30042823	The overall survival rates at 1-year postsurgery were 75.2% and 42.3% for patients with low and high miR-128 tumour expression, respectively.	('miR-128', 'Gene', (101, 108))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('patients', 'Species', '9606', (74, 82))	('tumour', 'Disease', (109, 115))	('high', 'Var', (96, 100))	('miR-128', 'Chemical', '-', (101, 108))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
164237	30042823	In HC, survival was significantly better in patients with high relative miR-126 expression in the tumour in comparison to those with low miR-126 expression (Figure 3B).	('better', 'PosReg', (34, 40))	('survival', 'MPA', (7, 15))	('patients', 'Species', '9606', (44, 52))	('miR-126', 'Gene', '406913', (137, 144))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('high relative', 'Var', (58, 71))	('miR-126', 'Gene', (137, 144))	('miR-126', 'Gene', '406913', (72, 79))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('miR-126', 'Gene', (72, 79))	('tumour', 'Disease', (98, 104))	('expression', 'MPA', (80, 90))
164238	30042823	No survival for longer than 3 years after resection was observed in patients with high miR-128 or low miR-126 expression in the tumour.	('tumour', 'Disease', (128, 134))	('miR-126', 'Gene', '406913', (102, 109))	('high', 'Var', (82, 86))	('low', 'NegReg', (98, 101))	('miR-126', 'Gene', (102, 109))	('patients', 'Species', '9606', (68, 76))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('expression', 'MPA', (110, 120))	('miR-128', 'Chemical', '-', (87, 94))	('miR-128', 'Gene', (87, 94))	('tumour', 'Disease', 'MESH:D009369', (128, 134))
164240	30042823	The overall survival rates were 67.8%, 32.4% and 27.6% at 1-, 3- and 5-years postsurgery, respectively, in patients with TEMs in the tumour-infiltrating front.	('TEMs', 'Var', (121, 125))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('tumour', 'Disease', (133, 139))	('patients', 'Species', '9606', (107, 115))
164245	30042823	Using multivariate analysis, the presence of TEMs in tumorous tissue, miR-126 and miR-128 were all identified as independent prognostic factors for survival (p = 0.040, p = 0.013 and p = 0.004, respectively; Table 2).	('miR-128', 'Chemical', '-', (82, 89))	('miR-128', 'Gene', (82, 89))	('miR-126', 'Gene', '406913', (70, 77))	('presence', 'Var', (33, 41))	('miR-126', 'Gene', (70, 77))	('tumorous', 'Disease', 'MESH:D009369', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumorous', 'Disease', (53, 61))
164246	30042823	With regards to recurrence-free survival, the presence of TEMs in the tumour-infiltrating front proved to be an independent prognostic variable in the multivariate analysis (P = 0.047; Table 2).	('tumour', 'Disease', (70, 76))	('presence', 'Var', (46, 54))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumour', 'Disease', 'MESH:D009369', (70, 76))
164248	30042823	The main findings were five-fold: (1) a high Ang-1 density was associated with reduced lymphangiosis carcinomatosa and improved histological grading in iCC; (2) angiogenic TEMs and miRNAs were differentially expressed in iCC and HC; (3) associated with established tumour markers, tumour growth and lymph node involvement; (4) served as independent prognosticators and (5) impacted on survival rates.	('Ang-1', 'Gene', (45, 50))	('high', 'Var', (40, 44))	('Ang-1', 'Gene', '284', (45, 50))	('reduced lymphangiosis carcinomatosa', 'Disease', 'MESH:D015354', (79, 114))	('improved', 'PosReg', (119, 127))	('tumour', 'Phenotype', 'HP:0002664', (281, 287))	('tumour', 'Disease', 'MESH:D009369', (281, 287))	('impacted', 'Reg', (373, 381))	('tumour growth', 'Disease', 'MESH:D006130', (281, 294))	('associated', 'Reg', (237, 247))	('tumour', 'Phenotype', 'HP:0002664', (265, 271))	('tumour', 'Disease', (281, 287))	('tumour', 'Disease', 'MESH:D009369', (265, 271))	('reduced lymphangiosis carcinomatosa', 'Disease', (79, 114))	('tumour', 'Disease', (265, 271))	('iCC', 'Disease', (152, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('histological grading', 'CPA', (128, 148))	('tumour growth', 'Disease', (281, 294))
164267	30042823	Recent results are inconsistent; however, they do suggest that miR-128 is involved in malignant diseases, either as a tumour suppressor or oncogene.	('involved', 'Reg', (74, 82))	('tumour', 'Disease', (118, 124))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('miR-128', 'Chemical', '-', (63, 70))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('malignant diseases', 'Disease', 'MESH:D009369', (86, 104))	('malignant diseases', 'Disease', (86, 104))	('miR-128', 'Var', (63, 70))
164268	30042823	A tumour suppressive role of miR-128 was documented for glioma, neuroblastoma, prostate and nonsmall cell lung cancer, where abnormal miR-128 expression may impact the malignant phenotypes of cancer cells (i.e.	('neuroblastoma', 'Disease', (64, 77))	('cancer', 'Disease', (192, 198))	('neuroblastoma', 'Phenotype', 'HP:0003006', (64, 77))	('cancer', 'Disease', (111, 117))	('prostate', 'Disease', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('miR-128', 'Chemical', '-', (29, 36))	('neuroblastoma', 'Disease', 'MESH:D009447', (64, 77))	('miR-128', 'Gene', (134, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('abnormal', 'Var', (125, 133))	('tumour', 'Phenotype', 'HP:0002664', (2, 8))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (92, 117))	('tumour', 'Disease', 'MESH:D009369', (2, 8))	('glioma', 'Disease', (56, 62))	('tumour', 'Disease', (2, 8))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('expression', 'MPA', (142, 152))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('miR-128', 'Chemical', '-', (134, 141))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('nonsmall cell lung cancer', 'Disease', (92, 117))	('impact', 'Reg', (157, 163))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (92, 117))
164276	30042823	One possible explanation for these contradictory results is that in CCA dysregulation of miR-128 impacts tumour progression via mechanisms different from tumour related angiogenesis.	('impacts tumour', 'Disease', (97, 111))	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('miR-128', 'Chemical', '-', (89, 96))	('tumour', 'Disease', (105, 111))	('miR-128', 'Gene', (89, 96))	('tumour', 'Disease', (154, 160))	('impacts tumour', 'Disease', 'MESH:D004834', (97, 111))	('CCA', 'Disease', (68, 71))	('dysregulation', 'Var', (72, 85))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
164279	30042823	Conversely, novel scientific data has linked TEMs to enhanced liver regeneration and a positive influence on patient outcome.	('enhanced', 'PosReg', (53, 61))	('TEMs', 'Var', (45, 49))	('patient', 'Species', '9606', (109, 116))	('liver regeneration', 'CPA', (62, 80))
164289	30042823	In summary, angiogenic miRNAs, the related Ang-1 axis and corresponding TEMs were associated with beneficial tumour profiles and improved outcomes in human CCA.	('human', 'Species', '9606', (150, 155))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('CCA', 'Disease', (156, 159))	('angiogenic', 'CPA', (12, 22))	('miRNAs', 'Var', (23, 29))	('tumour', 'Disease', (109, 115))	('Ang-1', 'Gene', (43, 48))	('beneficial', 'PosReg', (98, 108))	('Ang-1', 'Gene', '284', (43, 48))	('improved', 'PosReg', (129, 137))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
164309	30042823	Samples were snap frozen, and the relative expression of angiogenic miRNAs (hsa-miR-107 (MS00031255), which regulates VEGF-D signalling; hsa-miR-126 (MS00003430), which regulates Ang-1 signalling; hsa-miR-128 (MS00008582), which regulates VEGF-C signalling and hsa-miR-145 (MS00003528), which regulates Ang-2 signalling) was assessed by quantitative reverse transcriptase PCR.	('hsa-miR-145', 'Gene', '406937', (261, 272))	('VEGF-D', 'Gene', (118, 124))	('miR-107', 'Gene', '406901', (80, 87))	('VEGF-D', 'Gene', '2277', (118, 124))	('VEGF-C', 'Gene', '7424', (239, 245))	('MS00003528', 'Var', (274, 284))	('miR-107', 'Gene', (80, 87))	('hsa-miR-145', 'Gene', (261, 272))	('miR-126', 'Gene', '406913', (141, 148))	('miR-126', 'Gene', (141, 148))	('Ang-1', 'Gene', (179, 184))	('MS00003430', 'Var', (150, 160))	('Ang-1', 'Gene', '284', (179, 184))	('Ang-2', 'Gene', '285', (303, 308))	('Ang-2', 'Gene', (303, 308))	('VEGF-C', 'Gene', (239, 245))	('miR-128', 'Chemical', '-', (201, 208))	('regulates', 'Reg', (169, 178))
164352	28652654	Bcl-2 degradation is an additional pro-apoptotic effect of polo-like kinase inhibition in cholangiocarcinoma cells To examine the influence on apoptotic mechanisms following inhibition of polo-like kinases as therapeutically approach for cholangiocellular cancer treatment.	('polo-like kinase', 'Gene', (188, 204))	('cholangiocellular cancer', 'Phenotype', 'HP:0030153', (238, 262))	('polo-like kinase', 'Gene', '5347', (59, 75))	('cholangiocarcinoma', 'Disease', (90, 108))	('polo-like kinase', 'Gene', (59, 75))	('cholangiocellular cancer', 'Disease', 'MESH:D018281', (238, 262))	('cholangiocellular cancer', 'Disease', (238, 262))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (90, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('inhibition', 'Var', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('Bcl-2', 'Gene', (0, 5))	('Bcl-2', 'Gene', '596', (0, 5))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))	('polo-like kinase', 'Gene', '5347', (188, 204))
164355	28652654	Here, cells were treated with PLK inhibitor BI6727 (Volasertib), Cisplatin, and in combination of both compounds.	('PLK', 'Gene', (30, 33))	('BI6727', 'Chemical', 'MESH:C541363', (44, 50))	('PLK', 'Gene', '5347', (30, 33))	('Volasertib', 'Chemical', 'MESH:C541363', (52, 62))	('BI6727', 'Var', (44, 50))	('Cisplatin', 'Chemical', 'MESH:D002945', (65, 74))
164359	28652654	Co-treatment with BI6727 and cisplatin could even enhance the cytotoxic effect of cisplatin single treatment.	('BI6727', 'Var', (18, 24))	('cytotoxic effect', 'CPA', (62, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('BI6727', 'Chemical', 'MESH:C541363', (18, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('enhance', 'PosReg', (50, 57))
164360	28652654	Thus, co-treatment of cisplatin with BI6727 could slightly enhance the cytotoxic effect of the cisplatin in both cell lines whereas there was evidence of increased apoptosis induction solely in Mz-Ch-1 as compared to KMCH-1.	('enhance', 'PosReg', (59, 66))	('KMCH-1', 'CellLine', 'CVCL:7970', (217, 223))	('apoptosis', 'CPA', (164, 173))	('BI6727', 'Var', (37, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (22, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('BI6727', 'Chemical', 'MESH:C541363', (37, 43))	('cytotoxic effect', 'CPA', (71, 87))
164362	28652654	In contrast, protein levels of Bax were not found to be altered by PLK inhibition.	('inhibition', 'Var', (71, 81))	('Bax', 'Gene', '581', (31, 34))	('PLK', 'Gene', '5347', (67, 70))	('PLK', 'Gene', (67, 70))	('Bax', 'Gene', (31, 34))
164363	28652654	These findings indicate that cytotoxic effects of Cisplatin in Mz-Ch-1 cells can be enhanced by cotreatment with BI6727.	('Cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('BI6727', 'Chemical', 'MESH:C541363', (113, 119))	('cytotoxic effects', 'CPA', (29, 46))	('enhanced', 'PosReg', (84, 92))	('BI6727', 'Var', (113, 119))
164364	28652654	In conclusion, BI6727 treatment can sensitize CCA cells to cisplatin-induced apoptosis with proteasomal Bcl-2 degradation as an additional pro-apoptotic effect.	('BI6727', 'Chemical', 'MESH:C541363', (15, 21))	('CCA', 'Disease', (46, 49))	('Bcl-2', 'Gene', (104, 109))	('Bcl-2', 'Gene', '596', (104, 109))	('sensitize', 'Reg', (36, 45))	('BI6727', 'Var', (15, 21))	('CCA', 'Phenotype', 'HP:0030731', (46, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))
164366	28652654	These data suggest that polo-like kinases -Inhibition by BI6727 (volasertib) sensitizes some cholangiocarcinoma cell lines to cisplatin-induced apoptosis.	('cholangiocarcinoma cell', 'Disease', (93, 116))	('polo-like kinase', 'Gene', '5347', (24, 40))	('polo-like kinase', 'Gene', (24, 40))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (93, 116))	('sensitizes', 'Reg', (77, 87))	('BI6727', 'Var', (57, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('cisplatin-induced', 'MPA', (126, 143))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('BI6727', 'Chemical', 'MESH:C541363', (57, 63))
164367	28652654	Our findings include an enhanced cytotoxic effect of cisplatin by co-treatment with BI6727 (volasertib) and results in decreased protein expression levels of the anti-apoptotic molecule Bcl-2, which appears to be mediated via proteasomal degradation.	('decreased', 'NegReg', (119, 128))	('protein expression levels', 'MPA', (129, 154))	('BI6727', 'Var', (84, 90))	('Bcl-2', 'Gene', (186, 191))	('Bcl-2', 'Gene', '596', (186, 191))	('enhanced', 'PosReg', (24, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('cytotoxic effect', 'CPA', (33, 49))	('BI6727', 'Chemical', 'MESH:C541363', (84, 90))
164378	28652654	In this context, PLK inhibition is discussed as a new potential therapeutical approach for the treatment of different cancers and has been described to decrease myeloid cell leukemia-1 (Mcl-1) - an anti-apoptotic member of the Bcl2 protein family that has been identified as an important survival factor in CCA.	('cancers', 'Disease', (118, 125))	('leukemia', 'Phenotype', 'HP:0001909', (174, 182))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('Bcl2', 'Gene', (227, 231))	('PLK', 'Gene', (17, 20))	('Mcl-1', 'Gene', '4170', (186, 191))	('myeloid cell leukemia-1', 'Gene', '4170', (161, 184))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('CCA', 'Phenotype', 'HP:0030731', (307, 310))	('inhibition', 'Var', (21, 31))	('myeloid cell leukemia-1', 'Gene', (161, 184))	('Bcl2', 'Gene', '596', (227, 231))	('Mcl-1', 'Gene', (186, 191))	('PLK', 'Gene', '5347', (17, 20))	('decrease', 'NegReg', (152, 160))	('myeloid cell leukemia', 'Phenotype', 'HP:0012324', (161, 182))	('CCA', 'Disease', (307, 310))
164381	28652654	We have recently shown that PLK2 inhibition can decrease Mcl-1 levels by proteasomal degradation inducing apoptosis in CCA cells, which finally results in tumor suppression in vivo.	('inhibition', 'Var', (33, 43))	('results', 'Reg', (144, 151))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('PLK2', 'Gene', '10769', (28, 32))	('Mcl-1', 'Gene', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('decrease Mcl', 'Phenotype', 'HP:0025066', (48, 60))	('apoptosis', 'MPA', (106, 115))	('proteasomal degradation', 'MPA', (73, 96))	('PLK2', 'Gene', (28, 32))	('tumor', 'Disease', (155, 160))	('decrease', 'NegReg', (48, 56))	('Mcl-1', 'Gene', '4170', (57, 62))	('CCA', 'Phenotype', 'HP:0030731', (119, 122))
164396	28652654	In previous studies, we demonstrated that the PLK inhibitor BI6727 had a pro-apoptotic effect in CCA cell lines and could exacerbate TRAIL-induced cell death.	('TRAIL', 'Gene', (133, 138))	('CCA', 'Disease', (97, 100))	('BI6727', 'Chemical', 'MESH:C541363', (60, 66))	('PLK', 'Gene', '5347', (46, 49))	('pro-apoptotic effect', 'CPA', (73, 93))	('CCA', 'Phenotype', 'HP:0030731', (97, 100))	('BI6727', 'Var', (60, 66))	('TRAIL', 'Gene', '8743', (133, 138))	('PLK', 'Gene', (46, 49))	('exacerbate', 'PosReg', (122, 132))
164398	28652654	Here, we aimed to further investigate the effect of the PLK inhibitor BI6727 on cell death in CCA cell lines in the presence or absence of cisplatin.	('BI6727', 'Var', (70, 76))	('PLK', 'Gene', '5347', (56, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('CCA', 'Phenotype', 'HP:0030731', (94, 97))	('BI6727', 'Chemical', 'MESH:C541363', (70, 76))	('PLK', 'Gene', (56, 59))
164403	28652654	In KMCH-1 cells treated with BI6727, cisplatin and the combination of BI6727 and cisplatin, some apoptotic nuclei were found (Figure 1B).	('apoptotic nuclei', 'CPA', (97, 113))	('BI6727', 'Var', (70, 76))	('cisplatin', 'Var', (37, 46))	('cisplatin', 'Var', (81, 90))	('BI6727', 'Var', (29, 35))	('KMCH-1', 'CellLine', 'CVCL:7970', (3, 9))	('BI6727', 'Chemical', 'MESH:C541363', (70, 76))	('BI6727', 'Chemical', 'MESH:C541363', (29, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))
164404	28652654	Moreover, caspase-3/-7 activity was slightly induced in BI6727-treated KMCH-1 cells (Figure 1C).	('caspase-3/-7', 'Gene', (10, 22))	('induced', 'PosReg', (45, 52))	('caspase-3/-7', 'Gene', '836;840', (10, 22))	('BI6727', 'Chemical', 'MESH:C541363', (56, 62))	('activity', 'MPA', (23, 31))	('BI6727-treated', 'Var', (56, 70))	('KMCH-1', 'CellLine', 'CVCL:7970', (71, 77))
164405	28652654	In KMCH-1 cells treated with the cytotoxic drug cisplatin, caspase-3/-7 activity was reduced compared to vehicle-treated cells whereas co-treatment with BI6727 and cisplatin induced caspase -3/-7 activitiy as compared to cisplatin only-treated cells.	('activitiy', 'MPA', (196, 205))	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('caspase-3/-7', 'Gene', (59, 71))	('cisplatin', 'Chemical', 'MESH:D002945', (221, 230))	('cisplatin', 'Chemical', 'MESH:D002945', (164, 173))	('BI6727', 'Var', (153, 159))	('activity', 'MPA', (72, 80))	('caspase-3/-7', 'Gene', '836;840', (59, 71))	('KMCH-1', 'CellLine', 'CVCL:7970', (3, 9))	('caspase', 'Gene', (59, 66))	('caspase', 'Gene', (182, 189))	('BI6727', 'Chemical', 'MESH:C541363', (153, 159))	('reduced', 'NegReg', (85, 92))	('caspase', 'Gene', '841', (59, 66))	('caspase', 'Gene', '841', (182, 189))
164406	28652654	In KMCH-1 cells, viability was reduced by treatment with BI6727 or cisplatin and the combination of BI6727 with cisplatin could even exacerbate this effect (which does not appear to be mediated by apoptosis induction).	('BI6727', 'Var', (100, 106))	('reduced', 'NegReg', (31, 38))	('KMCH-1', 'CellLine', 'CVCL:7970', (3, 9))	('BI6727', 'Chemical', 'MESH:C541363', (100, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('BI6727', 'Var', (57, 63))	('viability', 'MPA', (17, 26))	('BI6727', 'Chemical', 'MESH:C541363', (57, 63))	('exacerbate', 'PosReg', (133, 143))
164407	28652654	In Mz-Ch-1 cells, we could observe a similar effect as cotreatment of BI6727 and cisplatin could slightly enhance the cytotoxic effect of both single agents (Figure 1D).	('enhance', 'PosReg', (106, 113))	('BI6727', 'Var', (70, 76))	('cisplatin', 'Var', (81, 90))	('BI6727', 'Chemical', 'MESH:C541363', (70, 76))	('cytotoxic effect', 'CPA', (118, 134))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))
164408	28652654	Quantification of apoptotic nuclei demonstrated that BI6727 or cisplatin treatment increased the number of apoptotic nuclei.	('BI6727', 'Chemical', 'MESH:C541363', (53, 59))	('BI6727', 'Var', (53, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('increased', 'PosReg', (83, 92))
164409	28652654	The number of apoptotic nuclei was increased in BI6727-treated cells as compared to cisplatin-treated cells while the combination of these substances enhanced the apoptotic effect of cisplatin single treatment (Figure 1E).	('combination', 'Interaction', (118, 129))	('increased', 'PosReg', (35, 44))	('enhanced', 'PosReg', (150, 158))	('apoptotic effect', 'CPA', (163, 179))	('cisplatin', 'Chemical', 'MESH:D002945', (183, 192))	('BI6727', 'Chemical', 'MESH:C541363', (48, 54))	('BI6727-treated', 'Var', (48, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))
164410	28652654	Caspase-3/-7 activity was induced in BI6727-treated as compared to vehicle-treated cells whereas cisplatin treatment did not enhance caspase activity (Figure 1F).	('Caspase-3/-7', 'Gene', '836;840', (0, 12))	('BI6727-treated', 'Var', (37, 51))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('caspase', 'Gene', (133, 140))	('Caspase-3/-7', 'Gene', (0, 12))	('caspase', 'Gene', '841', (133, 140))	('activity', 'MPA', (13, 21))	('induced', 'PosReg', (26, 33))	('BI6727', 'Chemical', 'MESH:C541363', (37, 43))
164411	28652654	Under co-treatment conditions with BI6727 and cisplatin, caspase-3/-7 activity could be stronger induced as compared to cisplatin single treatment.	('activity', 'MPA', (70, 78))	('caspase-3/-7', 'Gene', '836;840', (57, 69))	('BI6727', 'Var', (35, 41))	('BI6727', 'Chemical', 'MESH:C541363', (35, 41))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('caspase-3/-7', 'Gene', (57, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('stronger', 'PosReg', (88, 96))
164413	28652654	PARP is involved in DNA repair and replication but PARP cleavage has been described to be an early event during apoptosis while cleavage may diminish DNA-repair and replication processes.	('diminish', 'NegReg', (141, 149))	('PARP', 'Gene', (0, 4))	('PARP', 'Gene', (51, 55))	('cleavage', 'Var', (128, 136))	('PARP', 'Gene', '142', (0, 4))	('DNA-repair', 'CPA', (150, 160))	('PARP', 'Gene', '142', (51, 55))
164414	28652654	In KMCH-1 cells PARP cleavage was not detected (data not shown) while in Mz-Ch-1 cells, protein levels of cleaved PARP were slightly induced after BI6727 single treatment and cisplatin/BI6727 combination treatment (Figure 2A and B).	('PARP', 'Gene', (16, 20))	('induced', 'PosReg', (133, 140))	('BI6727', 'Var', (147, 153))	('protein levels of cleaved', 'MPA', (88, 113))	('PARP', 'Gene', '142', (114, 118))	('BI6727', 'Chemical', 'MESH:C541363', (147, 153))	('BI6727', 'Chemical', 'MESH:C541363', (185, 191))	('KMCH-1', 'CellLine', 'CVCL:7970', (3, 9))	('PARP', 'Gene', '142', (16, 20))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('PARP', 'Gene', (114, 118))
164415	28652654	Thus, co-treatment of cisplatin with the PLK-inhibitor BI6727 could (slightly) enhance the cytotoxic effect of the cytostatic drug cisplatin in both cell lines whereas there was evidence of increased apoptosis induction solely in Mz-Ch-1 cells as compared to KMCH-1 cells.	('cisplatin', 'Chemical', 'MESH:D002945', (131, 140))	('PLK', 'Gene', (41, 44))	('BI6727', 'Var', (55, 61))	('enhance', 'PosReg', (79, 86))	('BI6727', 'Chemical', 'MESH:C541363', (55, 61))	('PLK', 'Gene', '5347', (41, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (22, 31))	('KMCH-1', 'CellLine', 'CVCL:7970', (259, 265))	('apoptosis', 'CPA', (200, 209))	('cytotoxic effect', 'CPA', (91, 107))
164416	28652654	As shown previously, pro-apoptotic effects of BI6727 treatment are in part mediated by Mcl-1 down regulation.	('Mcl-1', 'Gene', '4170', (87, 92))	('down regulation', 'NegReg', (93, 108))	('BI6727', 'Var', (46, 52))	('Mcl-1', 'Gene', (87, 92))	('BI6727', 'Chemical', 'MESH:C541363', (46, 52))
164417	28652654	As other important regulators of apoptosis, we here aimed to investigate the effect of BI6727 on the anti-apoptotic protein Bcl-2 as well as the pro-apoptotic Bcl-2 family member Bax.	('Bcl-2', 'Gene', (159, 164))	('Bax', 'Gene', '581', (179, 182))	('Bcl-2', 'Gene', '596', (159, 164))	('Bcl-2', 'Gene', (124, 129))	('Bcl-2', 'Gene', '596', (124, 129))	('BI6727', 'Var', (87, 93))	('Bax', 'Gene', (179, 182))	('anti-apoptotic protein', 'MPA', (101, 123))	('BI6727', 'Chemical', 'MESH:C541363', (87, 93))
164418	28652654	We determined Bax mRNA expression levels in KMCH-1 and Mz-Ch-1 cells by qRT-PCR treated with BI6727, cisplatin or both substances.	('KMCH-1', 'CellLine', 'CVCL:7970', (44, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('Bax', 'Gene', '581', (14, 17))	('BI6727', 'Var', (93, 99))	('Bax', 'Gene', (14, 17))	('BI6727', 'Chemical', 'MESH:C541363', (93, 99))
164419	28652654	In KMCH-1 cells, BI6727 treatment induced Bax expression and this effect was also present in cells co-treated with BI6727 and cisplatin.	('BI6727', 'Chemical', 'MESH:C541363', (17, 23))	('Bax', 'Gene', '581', (42, 45))	('KMCH-1', 'CellLine', 'CVCL:7970', (3, 9))	('BI6727', 'Chemical', 'MESH:C541363', (115, 121))	('Bax', 'Gene', (42, 45))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('BI6727', 'Var', (17, 23))
164421	28652654	In contrast, Bax protein levels, determined via western blot analysis and quantified by densitometric measurement, were not changed in KMCH-1 cells treated with BI6727 and/or cisplatin (Figure 3B and C).	('BI6727', 'Var', (161, 167))	('BI6727', 'Chemical', 'MESH:C541363', (161, 167))	('Bax', 'Gene', (13, 16))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('KMCH-1', 'CellLine', 'CVCL:7970', (135, 141))	('Bax', 'Gene', '581', (13, 16))
164422	28652654	In Mz-Ch-1 cells, Bax expression was significantly induced by cisplatin treatment whereas BI6727 treatment had no effect on Bax.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('Bax', 'Gene', (18, 21))	('Bax', 'Gene', '581', (18, 21))	('Bax', 'Gene', '581', (124, 127))	('cisplatin', 'Var', (62, 71))	('BI6727', 'Chemical', 'MESH:C541363', (90, 96))	('induced', 'Reg', (51, 58))	('Bax', 'Gene', (124, 127))	('expression', 'MPA', (22, 32))
164423	28652654	Following combination treatment of BI6727 with cisplatin, Bax was not further induced (Figure 3D).	('Bax', 'Gene', '581', (58, 61))	('BI6727', 'Var', (35, 41))	('BI6727', 'Chemical', 'MESH:C541363', (35, 41))	('Bax', 'Gene', (58, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('combination', 'Interaction', (10, 21))
164425	28652654	In Mz-Ch-1 cells, protein levels of Bcl-2 were reduced after treatment with cisplatin single treatment, cisplatin/BI6727 combination treatment, and especially BI6727 single treatment (Figure 3G and H).	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('BI6727', 'Var', (159, 165))	('cisplatin/BI6727', 'Var', (104, 120))	('Bcl-2', 'Gene', (36, 41))	('BI6727', 'Chemical', 'MESH:C541363', (159, 165))	('Bcl-2', 'Gene', '596', (36, 41))	('BI6727', 'Chemical', 'MESH:C541363', (114, 120))	('reduced', 'NegReg', (47, 54))
164427	28652654	Indeed, inhibition of proteasomal degradation by co-treatment of BI6727 with MG-132 restored Bcl-2 to normal levels similar to the vehicle control.	('Bcl-2', 'Gene', (93, 98))	('inhibition', 'NegReg', (8, 18))	('Bcl-2', 'Gene', '596', (93, 98))	('BI6727', 'Var', (65, 71))	('MG-132', 'Chemical', 'MESH:C072553', (77, 83))	('BI6727', 'Chemical', 'MESH:C541363', (65, 71))	('restored', 'PosReg', (84, 92))	('proteasomal degradation', 'MPA', (22, 45))	('MG-132', 'Gene', (77, 83))
164430	28652654	The findings indicate that the cytotoxic effect of cisplatin can be enhanced by co-treatment with the PLK inhibitor BI6727 and that PLK inhibition (beside Mcl-1) decreases Bcl-2 via its proteasomal degradation.	('Bcl-2', 'Gene', '596', (172, 177))	('enhanced', 'PosReg', (68, 76))	('BI6727', 'Chemical', 'MESH:C541363', (116, 122))	('Bcl-2', 'Gene', (172, 177))	('inhibition', 'Var', (136, 146))	('cytotoxic effect', 'CPA', (31, 47))	('PLK', 'Gene', (102, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('decreases', 'NegReg', (162, 171))	('proteasomal degradation', 'MPA', (186, 209))	('PLK', 'Gene', '5347', (132, 135))	('PLK', 'Gene', '5347', (102, 105))	('Mcl-1', 'Gene', '4170', (155, 160))	('Mcl-1', 'Gene', (155, 160))	('PLK', 'Gene', (132, 135))
164436	28652654	The potent PLK inhibitor BI6727 (volasertib) has been identified as a promising candidate for cancer therapy as PLK are upregulated in many different cancers.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('PLK', 'Gene', (112, 115))	('BI6727', 'Var', (25, 31))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('upregulated', 'PosReg', (120, 131))	('PLK', 'Gene', (11, 14))	('cancers', 'Disease', (150, 157))	('BI6727', 'Chemical', 'MESH:C541363', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (150, 156))	('PLK', 'Gene', '5347', (112, 115))	('PLK', 'Gene', '5347', (11, 14))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
164438	28652654	Using KMCH-1 and Mz-Ch-1 CCA cancer cells, we here could demonstrate increased overall cell death and enhanced apoptosis induction following treatment with the PLK-inhibitor BI6727.	('PLK', 'Gene', (160, 163))	('enhanced', 'PosReg', (102, 110))	('CCA', 'Phenotype', 'HP:0030731', (25, 28))	('BI6727', 'Chemical', 'MESH:C541363', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('PLK', 'Gene', '5347', (160, 163))	('CCA cancer', 'Disease', (25, 35))	('KMCH-1', 'CellLine', 'CVCL:7970', (6, 12))	('apoptosis induction', 'CPA', (111, 130))	('cell death', 'CPA', (87, 97))	('BI6727', 'Var', (174, 180))	('CCA cancer', 'Disease', 'MESH:C536211', (25, 35))
164439	28652654	In combination with the conventional chemotherapeutic drug cisplatin, BI6727 could even (slightly) enhance cell death in KMCH-1 and Mz-Ch-1 cells whereas the pro-apoptotic effect was more potent in MzCh1 as compared to KMCH-1 cells.	('BI6727', 'Var', (70, 76))	('KMCH-1', 'CellLine', 'CVCL:7970', (219, 225))	('BI6727', 'Chemical', 'MESH:C541363', (70, 76))	('cell death', 'CPA', (107, 117))	('KMCH-1', 'CellLine', 'CVCL:7970', (121, 127))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('enhance', 'PosReg', (99, 106))
164441	28652654	Here, we focused on the effect of BI6727 on the pro-apoptotic protein Bax and the anti-apoptotic molecule Bcl-2.	('Bax', 'Gene', (70, 73))	('BI6727', 'Chemical', 'MESH:C541363', (34, 40))	('Bax', 'Gene', '581', (70, 73))	('BI6727', 'Var', (34, 40))	('Bcl-2', 'Gene', (106, 111))	('Bcl-2', 'Gene', '596', (106, 111))
164442	28652654	Bax mRNA levels were slightly induced in KMCH-1 and Mz-Ch-1 cells treated with BI6727 and cisplatin, whereas Bax protein levels were not found to be changed in both cell lines.	('Bax', 'Gene', '581', (0, 3))	('BI6727', 'Var', (79, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('Bax', 'Gene', (109, 112))	('Bax', 'Gene', (0, 3))	('KMCH-1', 'CellLine', 'CVCL:7970', (41, 47))	('BI6727', 'Chemical', 'MESH:C541363', (79, 85))	('Bax', 'Gene', '581', (109, 112))	('induced', 'PosReg', (30, 37))	('cisplatin', 'Var', (90, 99))
164443	28652654	Moreover, Bcl-2 levels were decreased in Mz-Ch-1 cells treated with BI6727 (and cisplatin).	('decreased', 'NegReg', (28, 37))	('BI6727', 'Chemical', 'MESH:C541363', (68, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('BI6727', 'Var', (68, 74))	('Bcl-2', 'Gene', (10, 15))	('Bcl-2', 'Gene', '596', (10, 15))
164444	28652654	In a previous study we could demonstrate that BI6727 treatment reduced Mcl-1 levels but not Bcl-2 levels after 8 h of incubation.	('Mcl-1', 'Gene', (71, 76))	('reduced', 'NegReg', (63, 70))	('Bcl-2', 'Gene', (92, 97))	('BI6727', 'Var', (46, 52))	('Bcl-2', 'Gene', '596', (92, 97))	('Mcl-1', 'Gene', '4170', (71, 76))	('reduced Mcl', 'Phenotype', 'HP:0025066', (63, 74))	('BI6727', 'Chemical', 'MESH:C541363', (46, 52))
164445	28652654	In the present study we observed a significant reduction of Bcl-2 protein levels due to a longer incubation period with BI6727 of 24 h. Thus, the pro-apoptotic effect of BI6727 treatment appears to be mediated by proteasomal degradation not only of Mcl-1 but also of the anti-apoptotic protein Bcl-2 (without affecting Bax protein levels).	('Bcl-2', 'Gene', (294, 299))	('proteasomal degradation', 'MPA', (213, 236))	('BI6727', 'Chemical', 'MESH:C541363', (120, 126))	('pro-apoptotic', 'CPA', (146, 159))	('Bax', 'Gene', (319, 322))	('Mcl-1', 'Gene', '4170', (249, 254))	('BI6727', 'Var', (170, 176))	('Bcl-2', 'Gene', (60, 65))	('Bcl-2', 'Gene', '596', (60, 65))	('BI6727', 'Chemical', 'MESH:C541363', (170, 176))	('Bax', 'Gene', '581', (319, 322))	('Mcl-1', 'Gene', (249, 254))	('Bcl-2', 'Gene', '596', (294, 299))
164446	28652654	Overexpression of Bcl-2 is common in many types of human cancer and has been correlated with decreased susceptibility to chemotherapeutical drugs.	('Bcl-2', 'Gene', (18, 23))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('decreased', 'NegReg', (93, 102))	('human', 'Species', '9606', (51, 56))	('Overexpression', 'Var', (0, 14))	('susceptibility to', 'MPA', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Bcl-2', 'Gene', '596', (18, 23))
164448	28652654	Treatment of CCA cells with the PLK inhibitor BI6727 beside Mcl-1 decreases Bcl-2 protein levels thereby reducing cell viability and enhancing apoptosis.	('Mcl-1', 'Gene', (60, 65))	('decreases', 'NegReg', (66, 75))	('Bcl-2', 'Gene', (76, 81))	('Bcl-2', 'Gene', '596', (76, 81))	('PLK', 'Gene', '5347', (32, 35))	('cell viability', 'CPA', (114, 128))	('apoptosis', 'CPA', (143, 152))	('BI6727', 'Var', (46, 52))	('Mcl-1', 'Gene', '4170', (60, 65))	('reducing', 'NegReg', (105, 113))	('PLK', 'Gene', (32, 35))	('BI6727', 'Chemical', 'MESH:C541363', (46, 52))	('CCA', 'Phenotype', 'HP:0030731', (13, 16))	('enhancing', 'PosReg', (133, 142))
164449	28652654	In combination with the chemotherapeutical drug cisplatin, BI6727 treatment could even enhance the cytotoxic effect of cisplatin single treatment.	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('enhance', 'PosReg', (87, 94))	('BI6727', 'Chemical', 'MESH:C541363', (59, 65))	('BI6727 treatment', 'Var', (59, 75))	('cytotoxic effect', 'CPA', (99, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))
164450	28652654	In conclusion, BI6727 treatment sensitizes some CCA cell lines to cisplatin-induced apoptosis with proteasomal Bcl-2 degradation as an additional pro-apoptotic effect.	('BI6727', 'Chemical', 'MESH:C541363', (15, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('Bcl-2', 'Gene', (111, 116))	('Bcl-2', 'Gene', '596', (111, 116))	('sensitizes', 'Reg', (32, 42))	('CCA', 'Phenotype', 'HP:0030731', (48, 51))	('BI6727', 'Var', (15, 21))
164457	28652654	It was already known that polo-like kinase inhibition could decrease expression levels of the anti-apoptotic molecule Mcl-1 in cholangiocarcinoma cells.	('cholangiocarcinoma cell', 'Disease', (127, 150))	('decrease', 'NegReg', (60, 68))	('inhibition', 'Var', (43, 53))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (127, 150))	('Mcl-1', 'Gene', '4170', (118, 123))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (127, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('polo-like kinase', 'Gene', '5347', (26, 42))	('polo-like kinase', 'Gene', (26, 42))	('Mcl-1', 'Gene', (118, 123))
164459	28652654	Polo-like kinase inhibition by BI6727 (volasertib) could enhance cytotoxic effect of cisplatin in cholangiocarcinoma cell lines by reducing expression of the anti-apoptotic molecule Bcl-2 that seems to be mediated via proteasomal degradation.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('Bcl-2', 'Gene', (182, 187))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (98, 121))	('Bcl-2', 'Gene', '596', (182, 187))	('BI6727', 'Var', (31, 37))	('expression', 'MPA', (140, 150))	('Polo-like kinase', 'Gene', '5347', (0, 16))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (98, 116))	('BI6727', 'Chemical', 'MESH:C541363', (31, 37))	('cytotoxic effect', 'CPA', (65, 81))	('reducing', 'NegReg', (131, 139))	('Polo-like kinase', 'Gene', (0, 16))	('inhibition', 'NegReg', (17, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))	('enhance', 'PosReg', (57, 64))	('cholangiocarcinoma cell', 'Disease', (98, 121))
164478	24040621	For example, a loss- of-function mutation in PGRN has been associated with the onset of frontotemporal lobar degeneration.	('frontotemporal lobar degeneration', 'Disease', (88, 121))	('PGRN', 'Gene', '2896', (45, 49))	('mutation', 'Var', (33, 41))	('loss- of-function', 'NegReg', (15, 32))	('PGRN', 'Gene', (45, 49))	('frontotemporal lobar degeneration', 'Phenotype', 'HP:0006892', (88, 121))
164480	24040621	However, how the dysregulation of PGRN function leads to these pathogenic states is largely unknown.	('dysregulation', 'Var', (17, 30))	('PGRN', 'Gene', '2896', (34, 38))	('leads', 'Reg', (48, 53))	('PGRN', 'Gene', (34, 38))
164485	24040621	Complete cleavage of full length PGRN results in granulin peptides (GRN A-G and paragranulin) that are approximately 6 kDa in size, though intermediary cleavage products have also been identified.	('GRN', 'Gene', (34, 37))	('granulin', 'Gene', '2896', (84, 92))	('granulin', 'Gene', (49, 57))	('GRN', 'Gene', '2896', (68, 71))	('GRN', 'Gene', '2896', (34, 37))	('cleavage', 'Var', (9, 17))	('PGRN', 'Gene', '2896', (33, 37))	('granulin', 'Gene', '2896', (49, 57))	('granulin', 'Gene', (84, 92))	('GRN', 'Gene', (68, 71))	('PGRN', 'Gene', (33, 37))
164498	24040621	The malignancy of highly tumorigenic PGRN-expressing cell lines depends on the expression level, since attenuating PGRN mRNA levels greatly inhibits tumor progression.	('malignancy', 'Disease', 'MESH:D009369', (4, 14))	('inhibits', 'NegReg', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('PGRN', 'Gene', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('PGRN', 'Gene', (37, 41))	('tumor', 'Disease', (25, 30))	('malignancy', 'Disease', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('PGRN', 'Gene', '2896', (115, 119))	('mRNA levels', 'MPA', (120, 131))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('PGRN', 'Gene', '2896', (37, 41))	('attenuating', 'Var', (103, 114))
164538	24040621	To identify the soluble factors released from the chemoresistant CRCs, proteomic analysis of the conditioned media was performed, demonstrating that PGRN levels (among other factors) were significantly higher in the media from chemoresistant CRCs than the chemonaive cells.	('chemoresistant', 'Var', (227, 241))	('PGRN', 'Gene', '2896', (149, 153))	('higher', 'PosReg', (202, 208))	('levels', 'MPA', (154, 160))	('PGRN', 'Gene', (149, 153))
164555	21988803	We also found that FXR agonist GW4064 effectively blocked the stimulatory effect of GDCA on tumor growth.	('stimulatory effect', 'MPA', (62, 80))	('GW4064', 'Var', (31, 37))	('GW4064', 'Chemical', 'MESH:C412815', (31, 37))	('GDCA', 'Gene', (84, 88))	('blocked', 'NegReg', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('GDCA', 'Chemical', 'MESH:D005999', (84, 88))
164558	21988803	The imbalance of ratio of free and conjugated bile acids may play an important role in tumorigenesis of cholangiocarcinoma.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cholangiocarcinoma', 'Disease', (104, 122))	('tumor', 'Disease', (87, 92))	('imbalance', 'Var', (4, 13))	('play', 'Reg', (61, 65))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (104, 122))	('free', 'Chemical', '-', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('bile acids', 'Chemical', 'MESH:D001647', (46, 56))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (104, 122))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
164566	21988803	Several epidemiologic studies have implicated that the alterations of the composition of bile acids increased the incidence of colorectal adenocarcinoma.	('colorectal adenocarcinoma', 'Disease', (127, 152))	('alterations', 'Var', (55, 66))	('increased', 'PosReg', (100, 109))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (127, 152))	('composition', 'MPA', (74, 85))	('bile acids increased', 'Phenotype', 'HP:0012202', (89, 109))	('bile acids', 'Chemical', 'MESH:D001647', (89, 99))
164568	21988803	According to Muhlbauer's report, conjugated bile acid could stimulate NF-kappaB pathway and regulate the expression of inflammatory factors, leading to abnormal proliferation of epithelial cells in the colon.	('stimulate', 'PosReg', (60, 69))	('regulate', 'Reg', (92, 100))	('conjugated', 'Var', (33, 43))	('bile acid', 'Chemical', 'MESH:D001647', (44, 53))	('expression', 'MPA', (105, 115))	('leading to', 'Reg', (141, 151))	('NF-kappaB pathway', 'Pathway', (70, 87))
164571	21988803	1) Do changes in the human bile acid composition affect the activation of nuclear receptors and cell signaling pathways in the cholangiocarcinoma in a physiologically significant way?	('cholangiocarcinoma', 'Disease', (127, 145))	('affect', 'Reg', (49, 55))	('bile acid', 'Chemical', 'MESH:D001647', (27, 36))	('cell signaling pathways', 'Pathway', (96, 119))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (127, 145))	('human', 'Species', '9606', (21, 26))	('nuclear receptors', 'Pathway', (74, 91))	('changes', 'Var', (6, 13))	('activation', 'PosReg', (60, 70))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (127, 145))
164585	21988803	Next day, six different bile acids (CA 200 mumol/L; DCA 200 mumol/L; CDCA 200 mumol/L; GCA 800 mumol/L; GDCA 400 mumol/L; GCDCA 400 mumol/L) were added to the cell culture for 48 hours.	('CDCA', 'Chemical', 'MESH:D002635', (123, 127))	('bile acids', 'Chemical', 'MESH:D001647', (24, 34))	('GDCA', 'Chemical', 'MESH:D005999', (104, 108))	('DCA', 'Chemical', 'MESH:D003840', (124, 127))	('CDCA', 'Chemical', 'MESH:D002635', (69, 73))	('DCA', 'Chemical', 'MESH:D003840', (52, 55))	('GCA', 'Chemical', '-', (87, 90))	('DCA', 'Chemical', 'MESH:D003840', (70, 73))	('DCA', 'Chemical', 'MESH:D003840', (105, 108))	('GCDCA', 'Chemical', 'MESH:D005999', (122, 127))	('GDCA 400 mumol/L', 'Var', (104, 120))	('CA', 'Var', (36, 38))
164620	21988803	This is consistent with previous study findings that deficiency of FXR could lead to cell oxidative stress injury and hyperplasia.	('lead to', 'Reg', (77, 84))	('hyperplasia', 'Disease', (118, 129))	('FXR', 'Gene', (67, 70))	('cell', 'CPA', (85, 89))	('stress injury', 'Disease', (100, 113))	('stress injury', 'Disease', 'MESH:D015775', (100, 113))	('oxidative stress', 'Phenotype', 'HP:0025464', (90, 106))	('hyperplasia', 'Disease', 'MESH:D006965', (118, 129))	('deficiency', 'Var', (53, 63))
164623	21988803	When combined with GW4064, the inhibitory effect of the free bile acids on cell growth was even more pronounced (inhibition rate: 91.8%, 93.1% and 92.3%, respectively).	('GW4064', 'Var', (19, 25))	('free', 'Chemical', '-', (56, 60))	('cell growth', 'CPA', (75, 86))	('inhibition', 'NegReg', (113, 123))	('GW4064', 'Chemical', 'MESH:C412815', (19, 25))	('bile acids', 'Chemical', 'MESH:D001647', (61, 71))
164628	21988803	When the conjugated bile acids were combined with GW4064, cell viability was significantly decreased (inhibition rate: 65.7%, 65.6% and 64.1%, p < 0.05).	('cell viability', 'CPA', (58, 72))	('GW4064', 'Var', (50, 56))	('GW4064', 'Chemical', 'MESH:C412815', (50, 56))	('decreased', 'NegReg', (91, 100))	('bile acids', 'Chemical', 'MESH:D001647', (20, 30))
164636	21988803	Tumor volume at the end of the experiment was 0.279 +- 0.068 cm3 and 0.228 +- 0.116 cm3 (n = 6) in animals receiving CDCA and GW 4064, respectively.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CDCA', 'Var', (117, 121))	('CDCA', 'Chemical', 'MESH:D002635', (117, 121))	('GW 4064', 'Var', (126, 133))	('GW', 'Chemical', 'MESH:C032120', (126, 128))
164637	21988803	Administration of CDCA and GW 4064 resulted in a significant (P < 0.05) inhibition of tumor growth in both sets of animals compared with control group (tumor volume: 0.609 +- 0.089 cm3).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('GW', 'Chemical', 'MESH:C032120', (27, 29))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', (152, 157))	('CDCA', 'Chemical', 'MESH:D002635', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('inhibition', 'NegReg', (72, 82))	('GW 4064', 'Var', (27, 34))
164640	21988803	In addition, we found that FXR agonist GW4064 effectively blocked the stimulatory effect of GDCA on tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('stimulatory effect', 'MPA', (70, 88))	('tumor', 'Disease', (100, 105))	('GDCA', 'Gene', (92, 96))	('blocked', 'NegReg', (58, 65))	('GW4064', 'Var', (39, 45))	('GW4064', 'Chemical', 'MESH:C412815', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('GDCA', 'Chemical', 'MESH:D005999', (92, 96))
164641	21988803	The volumes of tumor xenografts in the combination of GDCA and GW4064 group were similar to data in the control group (Table 1).	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('GW4064', 'Var', (63, 69))	('GW4064', 'Chemical', 'MESH:C412815', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('GDCA', 'Chemical', 'MESH:D005999', (54, 58))
164645	21988803	The results also revealed that GDCA reduced the expression of FXR to 8.80%, but GW4064 reversed the effect (the positive rate was 23.00%).	('GW4064', 'Var', (80, 86))	('GW4064', 'Chemical', 'MESH:C412815', (80, 86))	('expression', 'MPA', (48, 58))	('GDCA', 'Chemical', 'MESH:D005999', (31, 35))	('reduced', 'NegReg', (36, 43))	('FXR', 'MPA', (62, 65))
164654	21988803	Because the level of p-IkB can reflect indirectly the activation of NF-kappa B pathway, we therefore propose that the effect of bile acids on tumor growth is related to NF-kappa B pathway.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('NF-kappa B', 'Gene', (68, 78))	('NF-kappa B', 'Gene', '4790', (169, 179))	('p-IkB', 'Var', (21, 26))	('tumor', 'Disease', (142, 147))	('NF-kappa B', 'Gene', '4790', (68, 78))	('bile acids', 'Chemical', 'MESH:D001647', (128, 138))	('NF-kappa B', 'Gene', (169, 179))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
164659	21988803	Regulating the balance of free/conjugated bile acids as well as activating/inhibiting FXR might provide promising therapeutic approaches to treating cholangiocarcinoma patients.	('FXR', 'Enzyme', (86, 89))	('balance', 'MPA', (15, 22))	('bile acids', 'Chemical', 'MESH:D001647', (42, 52))	('activating/inhibiting', 'NegReg', (64, 85))	('cholangiocarcinoma', 'Disease', (149, 167))	('patients', 'Species', '9606', (168, 176))	('free', 'Chemical', '-', (26, 30))	('free/conjugated bile acids', 'MPA', (26, 52))	('activating/inhibiting', 'Var', (64, 85))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (149, 167))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (149, 167))
164665	32767862	The sensitivity of FDG PET-CT for detecting primary tumor and regional lymph node metastases was lower than that of MDCT or MRI (p < 0.001), whereas the specificity and positive predictive value for detecting regional lymph nodes metastases was significantly better in FDG PET-CT compared to MDCT and MRI (all p < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('FDG', 'Var', (19, 22))	('metastases', 'Disease', 'MESH:D009362', (230, 240))	('tumor', 'Disease', (52, 57))	('metastases', 'Disease', (230, 240))	('FDG', 'Var', (269, 272))	('lower', 'NegReg', (97, 102))	('better', 'PosReg', (259, 265))	('FDG', 'Chemical', '-', (19, 22))	('metastases', 'Disease', (82, 92))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('metastases', 'Disease', 'MESH:D009362', (82, 92))	('FDG', 'Chemical', '-', (269, 272))
164731	32767862	In the current study of 234 patients with confirmed extrahepatic cholangiocarcinoma (including CBD cancer and hilar cholangiocarcinoma), we found that the diagnostic performance of FDG PET-CT for the detection of primary tumors is inadequate compared to MDCT and MRI.	('extrahepatic cholangiocarcinoma', 'Disease', (52, 83))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (116, 134))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cholangiocarcinoma', 'Disease', (65, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))	('cancer', 'Disease', (99, 105))	('FDG', 'Var', (181, 184))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (65, 83))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (52, 83))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (221, 227))	('cholangiocarcinoma', 'Disease', (116, 134))	('FDG', 'Chemical', '-', (181, 184))	('patients', 'Species', '9606', (28, 36))
164750	32767862	We set the cutoff value of SUVmax to 5.0, and found that patients with an SUVmax above the cutoff value in the primary tumor, regional lymph node, and metastatic lesions had a significantly poorer survival rate than those with an SUVmax below the cutoff value.	('tumor', 'Disease', (119, 124))	('SUVmax', 'Var', (74, 80))	('patients', 'Species', '9606', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('poorer', 'NegReg', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('survival rate', 'CPA', (197, 210))
164771	32708604	Additionally, the constitutive activation of cellular signaling by the overexpression and somatic mutation-mediated alterations conferred by the ErBb family on cholangiocarcinoma and other cancers enhances tumor aggressiveness and chemoresistance by contributing to the tumor microenvironment.	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (206, 226))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('rat', 'Species', '10116', (120, 123))	('alterations', 'Var', (116, 127))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('cellular signaling', 'MPA', (45, 63))	('ErBb', 'Gene', '1956', (145, 149))	('enhances', 'PosReg', (197, 205))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (160, 178))	('ErBb', 'Gene', (145, 149))	('cholangiocarcinoma', 'Disease', (160, 178))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('activation', 'PosReg', (31, 41))	('tumor', 'Disease', (270, 275))	('cancers', 'Disease', (189, 196))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (160, 178))	('overexpression', 'PosReg', (71, 85))	('tumor aggressiveness', 'Disease', (206, 226))	('chemoresistance', 'CPA', (231, 246))	('tumor', 'Disease', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('contributing', 'Reg', (250, 262))	('aggressiveness', 'Phenotype', 'HP:0000718', (212, 226))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
164772	32708604	This review summarizes the recent findings on the molecular functions of the ErBb family and their mutations during the progression of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (135, 153))	('ErBb', 'Gene', '1956', (77, 81))	('ErBb', 'Gene', (77, 81))	('mutations', 'Var', (99, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (135, 153))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (135, 153))
164782	32708604	EGF and its receptor EGFR are highly upregulated in 59.5% (22/37), and 32.4 (12/37) of patients with ICC, and these expressions showed no correlation with metastases of ICC.. Another report revealed that EGFR is highly expressed in 44.7% (17/38) of ICC patients, and its upregulation is closely correlated with poor differentiation, lymph node metastasis, and aberrant p53 expression.	('aberrant', 'Var', (360, 368))	('ICC', 'Disease', (249, 252))	('patients', 'Species', '9606', (253, 261))	('EGF', 'Gene', '1950', (204, 207))	('p53', 'Gene', (369, 372))	('poor differentiation', 'CPA', (311, 331))	('EGF', 'Gene', (0, 3))	('CC', 'Phenotype', 'HP:0030153', (102, 104))	('CC', 'Phenotype', 'HP:0030153', (250, 252))	('EGF', 'Gene', (21, 24))	('lymph node metastasis', 'CPA', (333, 354))	('EGF', 'Gene', (204, 207))	('expression', 'MPA', (373, 383))	('CC', 'Phenotype', 'HP:0030153', (170, 172))	('EGF', 'Gene', '1950', (0, 3))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('upregulation', 'PosReg', (271, 283))	('patients', 'Species', '9606', (87, 95))	('EGF', 'Gene', '1950', (21, 24))	('metastases', 'Disease', (155, 165))
164810	32708604	E-cadherin is preferentially localized in the cytoplasm of patients with CC relative to localization at the plasma membrane of bile duct epithelial cells, and its localization is significantly correlated with EGFR expression in patients with CC, such that loss of EGFR activity leads to restoration of membrane expression of E-cadherin.	('CC', 'Phenotype', 'HP:0030153', (73, 75))	('EGFR', 'Gene', (209, 213))	('preferentially', 'PosReg', (14, 28))	('restoration', 'MPA', (287, 298))	('activity', 'MPA', (269, 277))	('CC', 'Phenotype', 'HP:0030153', (242, 244))	('localization', 'MPA', (163, 175))	('correlated', 'Reg', (193, 203))	('patients', 'Species', '9606', (228, 236))	('rat', 'Species', '10116', (292, 295))	('patients', 'Species', '9606', (59, 67))	('E-cadherin', 'Protein', (325, 335))	('loss', 'Var', (256, 260))	('membrane expression', 'MPA', (302, 321))
164816	32708604	Tyrphostin AG1517 and tyrphostin AG879 as inhibitors of EGFR and ERBB2, respectively, effectively suppress the growth of CC cells, and combination treatment has shown a synergistic effect on the inhibition of CC cell growth by inhibiting cyclin D1 and activating caspase-3.	('growth', 'CPA', (111, 117))	('caspase-3', 'Gene', (263, 272))	('tyrphostin', 'Var', (22, 32))	('cyclin D1', 'Gene', '595', (238, 247))	('inhibiting', 'NegReg', (227, 237))	('cyclin D1', 'Gene', (238, 247))	('ERBB2', 'Gene', (65, 70))	('CC', 'Phenotype', 'HP:0030153', (209, 211))	('EGFR', 'Gene', (56, 60))	('suppress', 'NegReg', (98, 106))	('caspase-3', 'Gene', '836', (263, 272))	('activating', 'PosReg', (252, 262))	('CC', 'Phenotype', 'HP:0030153', (121, 123))
164820	32708604	Genome-wide microarray analysis revealed that the expression of EGFR and mitogen-activated protein kinase (MAPK) kinase 2 is regulated by IL-6 and 5-aza-CdR.	('IL-6', 'Gene', '3569', (138, 142))	('5-aza-CdR', 'Chemical', '-', (147, 156))	('mitogen-activated protein kinase (MAPK) kinase 2', 'Gene', '5605', (73, 121))	('5-aza-CdR', 'Var', (147, 156))	('EGFR', 'Gene', (64, 68))	('IL-6', 'Gene', (138, 142))	('regulated', 'Reg', (125, 134))
164824	32708604	High NTS expression was closely correlated with reduced progression-free survival (PFS) and OS of patients with CC, and loss of NTS led to suppression of CC cell invasion through inhibition of the EGFR/AKT signaling pathway by reducing EGFR expression.	('NTS', 'Gene', '4922', (5, 8))	('reduced', 'NegReg', (48, 55))	('progression-free survival', 'CPA', (56, 81))	('expression', 'MPA', (241, 251))	('patients', 'Species', '9606', (98, 106))	('CC', 'Phenotype', 'HP:0030153', (112, 114))	('reducing', 'NegReg', (227, 235))	('NTS', 'Gene', (128, 131))	('suppression', 'NegReg', (139, 150))	('expression', 'MPA', (9, 19))	('CC cell invasion', 'CPA', (154, 170))	('inhibition', 'NegReg', (179, 189))	('EGFR', 'Protein', (236, 240))	('CC', 'Phenotype', 'HP:0030153', (154, 156))	('EGFR/AKT signaling pathway', 'Pathway', (197, 223))	('loss', 'Var', (120, 124))	('NTS', 'Gene', (5, 8))	('NTS', 'Gene', '4922', (128, 131))
164830	32708604	ERBB2 expression significantly increased tumor formation in vivo by increasing bile duct obstruction and gross peritoneal metastases.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('increased', 'PosReg', (31, 40))	('tumor', 'Disease', (41, 46))	('ERBB2', 'Gene', (0, 5))	('increasing', 'PosReg', (68, 78))	('bile duct obstruction', 'Phenotype', 'HP:0005230', (79, 100))	('bile duct obstruction', 'Disease', (79, 100))	('metastases', 'Disease', (122, 132))	('bile duct obstruction', 'Disease', 'MESH:D002779', (79, 100))	('duct obstruction', 'Phenotype', 'HP:0000579', (84, 100))	('metastases', 'Disease', 'MESH:D009362', (122, 132))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('expression', 'Var', (6, 16))
164841	32708604	Furthermore, loss of NRP-1 induces cell cycle arrest at phase G1/S by suppressing cyclin E and cyclin-dependent kinase (CDK)2 and inducing p27, and it inhibits tumor metastasis and growth in vivo and in vitro by inhibiting activation of the VEGF/VEGFR, EGF/EGFR, and HGF/c-Met pathways.	('inhibits', 'NegReg', (151, 159))	('inducing', 'Reg', (130, 138))	('cyclin-dependent kinase (CDK)2', 'Gene', (95, 125))	('VEGFR', 'Gene', (246, 251))	('EGF', 'Gene', '1950', (242, 245))	('inhibiting', 'NegReg', (212, 222))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('arrest', 'Disease', (46, 52))	('loss', 'Var', (13, 17))	('EGF', 'Gene', '1950', (257, 260))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (35, 52))	('EGF', 'Gene', (253, 256))	('NRP-1', 'Gene', (21, 26))	('VEGF', 'Gene', '7422', (241, 245))	('EGF', 'Gene', '1950', (247, 250))	('EGF', 'Gene', (242, 245))	('VEGF', 'Gene', (241, 245))	('EGF', 'Gene', (257, 260))	('HGF/c-Met pathways', 'Pathway', (267, 285))	('arrest', 'Disease', 'MESH:D006323', (46, 52))	('induces', 'Reg', (27, 34))	('NRP-1', 'Gene', '8829', (21, 26))	('p27', 'Gene', '3429', (139, 142))	('tumor', 'Disease', (160, 165))	('VEGF', 'Gene', '7422', (246, 250))	('growth', 'CPA', (181, 187))	('p27', 'Gene', (139, 142))	('cyclin-dependent kinase (CDK)2', 'Gene', '1017', (95, 125))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('suppressing', 'NegReg', (70, 81))	('VEGF', 'Gene', (246, 250))	('EGF', 'Gene', (247, 250))	('EGF', 'Gene', '1950', (253, 256))	('VEGFR', 'Gene', '3791', (246, 251))
164843	32708604	L1CAM is a transmembrane glycoprotein that has been reported as highly expressed in 40.5% (17/42) of patients with poorly differentiated ICC, and loss of L1CAM markedly reduces the tumor growth and metastatic ability of CC cells in vivo and in vitro by inhibiting focal adhesion kinase (FAK) and AKT activation.	('inhibiting', 'NegReg', (253, 263))	('metastatic ability of', 'CPA', (198, 219))	('focal adhesion kinase', 'Gene', '5747', (264, 285))	('reduces', 'NegReg', (169, 176))	('L1CAM', 'Gene', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('CC', 'Phenotype', 'HP:0030153', (220, 222))	('patients', 'Species', '9606', (101, 109))	('L1CAM', 'Gene', (0, 5))	('focal adhesion kinase', 'Gene', (264, 285))	('CC', 'Phenotype', 'HP:0030153', (138, 140))	('FAK', 'Gene', (287, 290))	('loss', 'Var', (146, 150))	('AKT activation', 'Pathway', (296, 310))	('L1CAM', 'Gene', '3897', (154, 159))	('tumor', 'Disease', (181, 186))	('FAK', 'Gene', '5747', (287, 290))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('L1CAM', 'Gene', '3897', (0, 5))
164846	32708604	Inhibition of PGE2 synthesis or loss of the EP1 receptor suppresses EGFR activation.	('suppresses', 'NegReg', (57, 67))	('EP1 receptor', 'Protein', (44, 56))	('PGE2', 'Chemical', '-', (14, 18))	('loss', 'Var', (32, 36))	('activation', 'MPA', (73, 83))	('Inhibition', 'Var', (0, 10))	('EGFR', 'Protein', (68, 72))	('PGE2', 'Protein', (14, 18))
164869	32708604	Additionally, EP1 receptor-induced intracellular calcium concentration induces EGFR activation and subsequently leads to PGE2-mediated ERK activation.	('ERK', 'Gene', '5594', (135, 138))	('EGFR', 'Protein', (79, 83))	('activation', 'PosReg', (139, 149))	('activation', 'PosReg', (84, 94))	('ERK', 'Gene', (135, 138))	('rat', 'Species', '10116', (64, 67))	('EP1', 'Var', (14, 17))	('PGE2', 'Chemical', '-', (121, 125))	('leads to', 'Reg', (112, 120))	('calcium', 'Chemical', 'MESH:D002118', (49, 56))
164874	32708604	Fucosylation, which is the most common modification of glycoproteins and glycolipids, induces the biosynthesis of glycan branches of proteins via the addition of fucose to the reducing end of N- and O-linked glycan structures in glycoproteins and glycolipids by fucosyltransferases (FUTs).	('induces', 'PosReg', (86, 93))	('glycan', 'Chemical', 'MESH:D011134', (208, 214))	('glycan', 'Chemical', 'MESH:D011134', (114, 120))	('biosynthesis of glycan branches of', 'MPA', (98, 132))	('Fucosylation', 'Var', (0, 12))	('N- and O-linked glycan', 'Chemical', '-', (192, 214))	('fucose', 'Chemical', 'MESH:D005643', (162, 168))
164877	32708604	Loss of FUT1 reduces the metastatic ability of CC cells by inhibiting EMT through suppression of EGFR-mediated activation of the AKT/ERK pathway.	('reduces', 'NegReg', (13, 20))	('metastatic ability of CC cells', 'CPA', (25, 55))	('EMT', 'CPA', (70, 73))	('FUT1', 'Gene', '2523', (8, 12))	('ERK', 'Gene', '5594', (133, 136))	('ERK', 'Gene', (133, 136))	('inhibiting', 'NegReg', (59, 69))	('CC', 'Phenotype', 'HP:0030153', (47, 49))	('FUT1', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))	('suppression', 'NegReg', (82, 93))	('EGFR-mediated', 'Protein', (97, 110))
164883	32708604	Loss of SOX4 in CC cells markedly reduced the migration and EMT of CC cells by suppressing EGFR expression.	('EGFR', 'Gene', (91, 95))	('reduced', 'NegReg', (34, 41))	('SOX4', 'Gene', (8, 12))	('migration', 'CPA', (46, 55))	('CC', 'Phenotype', 'HP:0030153', (16, 18))	('CC', 'Phenotype', 'HP:0030153', (67, 69))	('expression', 'MPA', (96, 106))	('SOX4', 'Gene', '6659', (8, 12))	('suppressing', 'NegReg', (79, 90))	('rat', 'Species', '10116', (49, 52))	('Loss', 'Var', (0, 4))
164892	32708604	Loss of EBP50 enhances cell motility and migration through induction CC cell EMT by increasing activation of EGFR and its signaling pathways such as ERK1/2 and STAT3.	('CC', 'Phenotype', 'HP:0030153', (69, 71))	('signaling pathways', 'Pathway', (122, 140))	('induction', 'PosReg', (59, 68))	('ERK1/2', 'Gene', (149, 155))	('EBP50', 'Gene', (8, 13))	('rat', 'Species', '10116', (44, 47))	('ERK1/2', 'Gene', '5595;5594', (149, 155))	('EBP50', 'Gene', '9368', (8, 13))	('enhances', 'PosReg', (14, 22))	('Loss', 'Var', (0, 4))	('EGFR', 'Pathway', (109, 113))	('increasing activation', 'PosReg', (84, 105))
164893	32708604	Identification of mutations in various types of cancers by next-generation sequencing technology has demonstrated that somatic mutations as activating mutations are significantly correlated with metastases and poor outcomes in targeted therapy via constitutive activation of downstream signaling pathways, eventually leading to new strategies for mutation-driven drug resistance.	('cancers', 'Disease', (48, 55))	('rat', 'Species', '10116', (108, 111))	('metastases', 'Disease', 'MESH:D009362', (195, 205))	('drug resistance', 'Phenotype', 'HP:0020174', (363, 378))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('rat', 'Species', '10116', (334, 337))	('activation', 'PosReg', (261, 271))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('rat', 'Species', '10116', (68, 71))	('metastases', 'Disease', (195, 205))	('downstream signaling pathways', 'Pathway', (275, 304))	('mutations', 'Var', (127, 136))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('leading to', 'Reg', (317, 327))
164895	32708604	All identified EGFR mutations were in-frame deletions in exon 19 (K745_E749 del) of patients with ICC and exon 19 (E746_A750 del) of one patient with ECC.	('E746_A750 del', 'Var', (115, 128))	('patient', 'Species', '9606', (137, 144))	('patients', 'Species', '9606', (84, 92))	('K745_E749 del', 'Var', (66, 79))	('E746_A750 del', 'Mutation', 'p.746,750delA', (115, 128))	('CC', 'Phenotype', 'HP:0030153', (99, 101))	('ICC', 'Disease', (98, 101))	('EGFR', 'Gene', (15, 19))	('patient', 'Species', '9606', (84, 91))	('CC', 'Phenotype', 'HP:0030153', (151, 153))	('K745_E749 del', 'Mutation', 'p.745,749delE', (66, 79))
164897	32708604	It was also shown that 15% (6/40) of patients with CC had point mutations in the tyrosine kinase domain of the EGFR of patients with ICC (K575R, E872K, T790M), ECC (C775Y, G882S, V843I, L858R), and GBC (A864T).	('V843I', 'Var', (179, 184))	('V843I', 'Mutation', 'rs146795390', (179, 184))	('K575R', 'Var', (138, 143))	('L858R', 'Mutation', 'rs121434568', (186, 191))	('patients', 'Species', '9606', (37, 45))	('T790M', 'Mutation', 'rs121434569', (152, 157))	('C775Y', 'Mutation', 'p.C775Y', (165, 170))	('CC', 'Phenotype', 'HP:0030153', (51, 53))	('K575R', 'Mutation', 'rs1282253805', (138, 143))	('G882S', 'Var', (172, 177))	('G882S', 'Mutation', 'p.G882S', (172, 177))	('EGFR', 'Gene', (111, 115))	('L858R', 'Var', (186, 191))	('CC', 'Phenotype', 'HP:0030153', (161, 163))	('E872K', 'Var', (145, 150))	('T790M', 'Var', (152, 157))	('patients', 'Species', '9606', (119, 127))	('CC', 'Phenotype', 'HP:0030153', (134, 136))	('C775Y', 'Var', (165, 170))	('E872K', 'Mutation', 'rs776347334', (145, 150))	('point mutations in', 'Var', (58, 76))	('A864T', 'Mutation', 'rs1171287261', (203, 208))
164898	32708604	Additionally, 90% (36/40) of CC patients showed a silent mutation at codon 787 in exon 20, and 83.3% of patients with EGFR mutations showed increased MAPK and AKT phosphorylation.	('patients', 'Species', '9606', (32, 40))	('CC', 'Phenotype', 'HP:0030153', (29, 31))	('MAPK', 'Protein', (150, 154))	('EGFR', 'Gene', (118, 122))	('AKT', 'Pathway', (159, 162))	('phosphorylation', 'MPA', (163, 178))	('increased', 'PosReg', (140, 149))	('patients', 'Species', '9606', (104, 112))	('mutations', 'Var', (123, 132))
164899	32708604	Another study demonstrated that 5% (1/20) of patients with CC had a mutation (E804K) in the tyrosine kinase domain located in exon 20 of EGFR, but its function is unknown.	('EGFR', 'Gene', (137, 141))	('E804K) in', 'Var', (78, 87))	('E804K', 'Mutation', 'rs552733360', (78, 83))	('rat', 'Species', '10116', (21, 24))	('patients', 'Species', '9606', (45, 53))	('CC', 'Phenotype', 'HP:0030153', (59, 61))
164901	32708604	The patient that harbored this mutation had pulmonary metastasis after undergoing curative surgical resection.	('pulmonary metastasis', 'Disease', 'MESH:D009362', (44, 64))	('rat', 'Species', '10116', (84, 87))	('mutation', 'Var', (31, 39))	('patient', 'Species', '9606', (4, 11))	('pulmonary metastasis', 'Disease', (44, 64))
164902	32708604	Moreover, EGFR mutations (E709K, L747-P753 delins, V786M) were identified in 7.4% (6/81) of patients with ICC, and a higher EGFR mutation rate (5/38, 13.2%) was detected in patients with ICC who had chronic advanced liver disease relative to those with normal livers (1/43, 2.3%).	('rat', 'Species', '10116', (138, 141))	('chronic advanced liver disease', 'Phenotype', 'HP:0100626', (199, 229))	('CC', 'Phenotype', 'HP:0030153', (107, 109))	('ICC', 'Disease', (187, 190))	('chronic advanced liver disease', 'Disease', 'MESH:D058625', (199, 229))	('patients', 'Species', '9606', (173, 181))	('liver disease', 'Phenotype', 'HP:0001392', (216, 229))	('EGFR', 'Gene', (10, 14))	('E709K', 'Var', (26, 31))	('L747-P753 delins', 'Mutation', 'p.747,753delinsP', (33, 49))	('patients', 'Species', '9606', (92, 100))	('V786M', 'Var', (51, 56))	('ICC', 'Disease', (106, 109))	('chronic advanced liver disease', 'Disease', (199, 229))	('CC', 'Phenotype', 'HP:0030153', (188, 190))	('V786M', 'Mutation', 'rs762672864', (51, 56))	('E709K', 'Mutation', 'rs727504256', (26, 31))	('L747-P753 delins', 'Var', (33, 49))
164903	32708604	Another report exhibits that mutations of EGFR (G719X, S768I, and L861Q) were identified in 21% (17/81) of patients with CC.	('identified', 'Reg', (78, 88))	('patients', 'Species', '9606', (107, 115))	('L861Q', 'Var', (66, 71))	('G719X', 'Mutation', 'p.G719X', (48, 53))	('EGFR', 'Gene', (42, 46))	('S768I', 'Var', (55, 60))	('G719X', 'Var', (48, 53))	('CC', 'Phenotype', 'HP:0030153', (121, 123))	('L861Q', 'Mutation', 'rs121913444', (66, 71))	('S768I', 'Mutation', 'rs121913465', (55, 60))
164904	32708604	Additionally, 9.5% (13/137) of biliary tract cancer (BTC) patients including those with CC have mutations in exon 20 and exon 21 in patients with ICC (T783I, S784F, D837N), ECC (D800G, C818R, V819M, Q820R, D837N, V851I, G873E, G874D), or GBC (A837N, T785I), which correspond with the kinase domain of EGFR.	('V819M', 'Var', (192, 197))	('G874D', 'Var', (227, 232))	('ICC', 'Disease', (146, 149))	('BTC', 'Phenotype', 'HP:0100574', (53, 56))	('S784F', 'Var', (158, 163))	('D800G', 'Var', (178, 183))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('V851I', 'Mutation', 'rs538497054', (213, 218))	('patients', 'Species', '9606', (132, 140))	('ECC', 'Disease', (173, 176))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (31, 51))	('T785I', 'Mutation', 'p.T785I', (250, 255))	('D837N', 'Var', (165, 170))	('C818R', 'Mutation', 'p.C818R', (185, 190))	('Q820R', 'Mutation', 'rs1381875722', (199, 204))	('D837N', 'Var', (206, 211))	('A837N', 'Mutation', 'p.A837N', (243, 248))	('G873E', 'Var', (220, 225))	('CC', 'Phenotype', 'HP:0030153', (147, 149))	('V819M', 'Mutation', 'p.V819M', (192, 197))	('mutations', 'Reg', (96, 105))	('Q820R', 'Var', (199, 204))	('C818R', 'Var', (185, 190))	('T783I', 'Var', (151, 156))	('G873E', 'Mutation', 'p.G873E', (220, 225))	('S784F', 'Mutation', 'rs1424329195', (158, 163))	('patients', 'Species', '9606', (58, 66))	('D800G', 'Mutation', 'p.D800G', (178, 183))	('cancer', 'Disease', (45, 51))	('D837N', 'Mutation', 'rs761920220', (165, 170))	('D837N', 'Mutation', 'rs761920220', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('G874D', 'Mutation', 'p.G874D', (227, 232))	('V851I', 'Var', (213, 218))	('CC', 'Phenotype', 'HP:0030153', (88, 90))	('T783I', 'Mutation', 'rs529174941', (151, 156))	('CC', 'Phenotype', 'HP:0030153', (174, 176))	('A837N', 'Var', (243, 248))
164905	32708604	Also, 10.5% (6/57) and 12.3% (7/57) of BTC patients have an identified mutation in the extracellular domain (ECD) of EGFR (L443Q, S464P, K467stop, N468D, G482E, G482R, L469S) as new mutations and in the tyrosine kinase domain (TKD) of EGFR (L707S, V786M, L788H, G810S, G824S, D837N T854I, D855N), respectively; 50%, 16.7%, and 33.3% of mutated BTC were detected in patients with ICC, ECC, and GBC, respectively.	('patients', 'Species', '9606', (365, 373))	('G482E', 'Var', (154, 159))	('L707S', 'Var', (241, 246))	('V786M', 'Var', (248, 253))	('N468D', 'Mutation', 'rs571837012', (147, 152))	('detected', 'Reg', (353, 361))	('BTC', 'Phenotype', 'HP:0100574', (344, 347))	('G824S', 'Var', (269, 274))	('L707S', 'Mutation', 'p.L707S', (241, 246))	('K467stop', 'Mutation', 'p.K467X', (137, 145))	('K467stop', 'Var', (137, 145))	('G482R', 'Var', (161, 166))	('D855N', 'Var', (289, 294))	('L443Q', 'Mutation', 'p.L443Q', (123, 128))	('CC', 'Phenotype', 'HP:0030153', (385, 387))	('T854I', 'Var', (282, 287))	('G482E', 'Mutation', 'p.G482E', (154, 159))	('ICC', 'Disease', (379, 382))	('L788H', 'Mutation', 'p.L788H', (255, 260))	('D837N', 'Mutation', 'rs761920220', (276, 281))	('patients', 'Species', '9606', (43, 51))	('L469S', 'Mutation', 'p.L469S', (168, 173))	('ECC', 'Disease', (384, 387))	('D855N', 'Mutation', 'p.D855N', (289, 294))	('S464P', 'Mutation', 'p.S464P', (130, 135))	('S464P', 'Var', (130, 135))	('BTC', 'Gene', (344, 347))	('L788H', 'Var', (255, 260))	('BTC', 'Phenotype', 'HP:0100574', (39, 42))	('T854I', 'SUBSTITUTION', 'None', (282, 287))	('EGFR', 'Gene', (117, 121))	('G824S', 'Mutation', 'p.G824S', (269, 274))	('L443Q', 'Var', (123, 128))	('CC', 'Phenotype', 'HP:0030153', (380, 382))	('G482R', 'Mutation', 'rs768627073', (161, 166))	('V786M', 'Mutation', 'rs762672864', (248, 253))	('N468D', 'Var', (147, 152))	('G810S', 'Mutation', 'rs121913230', (262, 267))
164906	32708604	Also, patients with a mutation of the ECD of EGFR revealed a worse OS, and those with maturation at the TKD of EGFR had shorter PFS and OS.	('shorter', 'NegReg', (120, 127))	('mutation', 'Var', (22, 30))	('EGFR', 'Gene', (45, 49))	('patients', 'Species', '9606', (6, 14))	('PFS', 'CPA', (128, 131))	('rat', 'Species', '10116', (90, 93))
164907	32708604	Moreover, new mutations of EGFR were identified in patients with BTCs, including CC (E114K, Y1069C, I425L, C818F, G203R, R669Qfs*36, V524Sfs*44).	('E114K', 'Var', (85, 90))	('EGFR', 'Gene', (27, 31))	('BTCs', 'Disease', (65, 69))	('G203R', 'Var', (114, 119))	('I425L', 'Mutation', 'p.I425L', (100, 105))	('C818F', 'Var', (107, 112))	('R669Qfs*36', 'Mutation', 'p.R669QfsX36', (121, 131))	('Y1069C', 'Var', (92, 98))	('V524Sfs*44', 'Mutation', 'p.V524SfsX44', (133, 143))	('E114K', 'Mutation', 'rs1219568637', (85, 90))	('patients', 'Species', '9606', (51, 59))	('BTC', 'Phenotype', 'HP:0100574', (65, 68))	('V524Sfs*44', 'Var', (133, 143))	('G203R', 'Mutation', 'p.G203R', (114, 119))	('Y1069C', 'Mutation', 'p.Y1069C', (92, 98))	('CC', 'Phenotype', 'HP:0030153', (81, 83))	('I425L', 'Var', (100, 105))	('R669Qfs*36', 'Var', (121, 131))	('C818F', 'Mutation', 'p.C818F', (107, 112))
164908	32708604	ERBB2 mutations were identified in 25% (5/20) of patients with ECC, wherein ERBB2 was mutated in the kinase domain (V777L) and extracellular domain (S310F).	('S310F', 'Mutation', 'rs1057519816', (149, 154))	('ECC', 'Disease', (63, 66))	('V777L', 'Mutation', 'rs121913471', (116, 121))	('ERBB2', 'Gene', (0, 5))	('CC', 'Phenotype', 'HP:0030153', (64, 66))	('patients', 'Species', '9606', (49, 57))	('V777L', 'Var', (116, 121))	('S310F', 'Var', (149, 154))	('ERBB2', 'Gene', (76, 81))
164909	32708604	Also, ERBB2 activating mutations (S310F/Y, G292R, T862A, D769H, L869R, V842I, R678Q, G776V, S653C, R897W, and G660D) were detected in 2% (9/459) of patients with CC.	('G292R', 'Var', (43, 48))	('R678Q', 'Var', (78, 83))	('G660D', 'Mutation', 'rs1196929947', (110, 115))	('S653C', 'Var', (92, 97))	('L869R', 'Var', (64, 69))	('S653C', 'Mutation', 'p.S653C', (92, 97))	('D769H', 'Var', (57, 62))	('G660D', 'Var', (110, 115))	('patients', 'Species', '9606', (148, 156))	('T862A', 'Var', (50, 55))	('ERBB2', 'Gene', (6, 11))	('R897W', 'Var', (99, 104))	('G776V', 'Var', (85, 90))	('CC', 'Phenotype', 'HP:0030153', (162, 164))	('D769H', 'Mutation', 'rs121913468', (57, 62))	('S310F/Y', 'Var', (34, 41))	('activating', 'PosReg', (12, 22))	('G292R', 'Mutation', 'p.G292R', (43, 48))	('V842I', 'Mutation', 'rs1057519738', (71, 76))	('L869R', 'Mutation', 'rs1131692237', (64, 69))	('G776V', 'Mutation', 'rs144434331', (85, 90))	('V842I', 'Var', (71, 76))	('R897W', 'Mutation', 'rs375135008', (99, 104))	('S310F', 'Mutation', 'rs1057519816', (34, 39))	('T862A', 'Mutation', 'c.862T>A', (50, 55))	('R678Q', 'Mutation', 'rs1057519862', (78, 83))
164910	32708604	Although mutations of ERBB4 have been identified in patients with CC (S79Y, R106C, D376Y, C580*, K682N, F682L, E835D, R847C, R938C, Y950H, D960G, R992H, Y1066H, P1092S, Q1126K, Q1270K), its function remains unknown.	('R847C', 'Var', (118, 123))	('C580*', 'Var', (90, 95))	('R938C', 'Mutation', 'p.R938C', (125, 130))	('Q1126K', 'Var', (169, 175))	('R106C', 'Var', (76, 81))	('D376Y', 'Mutation', 'p.D376Y', (83, 88))	('F682L', 'Mutation', 'p.F682L', (104, 109))	('Y1066H', 'Mutation', 'rs878936823', (153, 159))	('K682N', 'Mutation', 'p.K682N', (97, 102))	('R106C', 'Mutation', 'rs751175543', (76, 81))	('D376Y', 'Var', (83, 88))	('ERBB4', 'Gene', '2066', (22, 27))	('R992H', 'Var', (146, 151))	('CC', 'Phenotype', 'HP:0030153', (66, 68))	('patients', 'Species', '9606', (52, 60))	('D960G', 'Mutation', 'p.D960G', (139, 144))	('identified', 'Reg', (38, 48))	('ERBB4', 'Gene', (22, 27))	('R847C', 'Mutation', 'rs754127388', (118, 123))	('C580*', 'SUBSTITUTION', 'None', (90, 95))	('R938C', 'Var', (125, 130))	('E835D', 'Mutation', 'p.E835D', (111, 116))	('Y950H', 'Mutation', 'p.Y950H', (132, 137))	('Q1270K', 'Var', (177, 183))	('Q1270K', 'Mutation', 'p.Q1270K', (177, 183))	('E835D', 'Var', (111, 116))	('F682L', 'Var', (104, 109))	('D960G', 'Var', (139, 144))	('Q1126K', 'Mutation', 'p.Q1126K', (169, 175))	('P1092S', 'Var', (161, 167))	('K682N', 'Var', (97, 102))	('Y1066H', 'Var', (153, 159))	('P1092S', 'Mutation', 'p.P1092S', (161, 167))	('R992H', 'Mutation', 'rs1390491269', (146, 151))	('Y950H', 'Var', (132, 137))	('S79Y', 'Mutation', 'p.S79Y', (70, 74))
164911	32708604	Moreover, new mutations of ERBB2 have been identified in patients with BTC, including CC (L755P/S, E265K, L994V, L1098M) (TCGA dataset).	('E265K', 'Mutation', 'p.E265K', (99, 104))	('L994V', 'Mutation', 'p.L994V', (106, 111))	('BTC', 'Phenotype', 'HP:0100574', (71, 74))	('BTC', 'Disease', (71, 74))	('patients', 'Species', '9606', (57, 65))	('L994V', 'Var', (106, 111))	('L755P', 'SUBSTITUTION', 'None', (90, 95))	('L1098M', 'Var', (113, 119))	('E265K', 'Var', (99, 104))	('L1098M', 'Mutation', 'p.L1098M', (113, 119))	('ERBB2', 'Gene', (27, 32))	('L755P', 'Var', (90, 95))	('CC', 'Phenotype', 'HP:0030153', (86, 88))
164912	32708604	ERBB3 mutations (G284R, V104M, A232V, E928G, G284R, V104L, D297Y, T355I) were detected in patients with BTC including CC, as activating mutants.	('G284R', 'Mutation', 'rs1057519803', (17, 22))	('A232V', 'Var', (31, 36))	('CC', 'Phenotype', 'HP:0030153', (118, 120))	('V104L', 'Mutation', 'rs1057519893', (52, 57))	('D297Y', 'Var', (59, 64))	('A232V', 'Mutation', 'p.A232V', (31, 36))	('G284R', 'Var', (17, 22))	('E928G', 'Var', (38, 43))	('ERBB3', 'Gene', (0, 5))	('T355I', 'Var', (66, 71))	('E928G', 'Mutation', 'p.E928G', (38, 43))	('V104M', 'Mutation', 'rs1057519893', (24, 29))	('BTC', 'Phenotype', 'HP:0100574', (104, 107))	('V104L', 'Var', (52, 57))	('V104M', 'Var', (24, 29))	('T355I', 'Mutation', 'rs993665271', (66, 71))	('G284R', 'Mutation', 'rs1057519803', (45, 50))	('patients', 'Species', '9606', (90, 98))	('ERBB3', 'Gene', '2065', (0, 5))	('G284R', 'Var', (45, 50))	('D297Y', 'Mutation', 'rs1057519891', (59, 64))	('BTC', 'Disease', (104, 107))
164913	32708604	Other mutants of EBBB3 (V1035D, G508R, G582W, A1252S, D581N, R444Q, V586M, G994D, N222Tfs*47, E230Dfs*39, D73Tfs*11, D296Ifs*16, D297Ifs*16) and ERBB4 (R103C, I68N, L432M, S602C, P1158H, T475A, S1286Lfs*5, F356Sfs*2) were identified in patients with BTC, including CC, but their function is unknown (TCGA dataset).	('E230Dfs*39', 'Mutation', 'p.E230DfsX39', (94, 104))	('BTC', 'Phenotype', 'HP:0100574', (250, 253))	('R444Q', 'Var', (61, 66))	('N222Tfs*47', 'Var', (82, 92))	('P1158H', 'Mutation', 'p.P1158H', (179, 185))	('G994D', 'Mutation', 'rs1195904336', (75, 80))	('V1035D', 'Mutation', 'p.V1035D', (24, 30))	('D297Ifs*16', 'Mutation', 'p.D297IfsX16', (129, 139))	('R103C', 'Mutation', 'rs201152419', (152, 157))	('L432M', 'Var', (165, 170))	('G582W', 'Var', (39, 44))	('D296Ifs*16', 'Var', (117, 127))	('T475A', 'Mutation', 'rs755541652', (187, 192))	('D581N', 'Mutation', 'p.D581N', (54, 59))	('G508R', 'Var', (32, 37))	('P1158H', 'Var', (179, 185))	('E230Dfs*39', 'Var', (94, 104))	('S1286Lfs*5', 'Var', (194, 204))	('patients', 'Species', '9606', (236, 244))	('S602C', 'Var', (172, 177))	('G994D', 'Var', (75, 80))	('V586M', 'Var', (68, 73))	('CC', 'Phenotype', 'HP:0030153', (265, 267))	('F356Sfs*2', 'Var', (206, 215))	('N222Tfs*47', 'Mutation', 'p.N222TfsX47', (82, 92))	('D73Tfs*11', 'Mutation', 'p.D73TfsX11', (106, 115))	('D581N', 'Var', (54, 59))	('BTC', 'Disease', (250, 253))	('V586M', 'Mutation', 'p.V586M', (68, 73))	('G582W', 'Mutation', 'p.G582W', (39, 44))	('D73Tfs*11', 'Var', (106, 115))	('A1252S', 'Mutation', 'p.A1252S', (46, 52))	('V1035D', 'Var', (24, 30))	('D297Ifs*16', 'Var', (129, 139))	('EBBB3', 'Gene', (17, 22))	('A1252S', 'Var', (46, 52))	('D296Ifs*16', 'Mutation', 'p.D296IfsX16', (117, 127))	('G508R', 'Mutation', 'rs770129304', (32, 37))	('I68N', 'Mutation', 'p.I68N', (159, 163))	('ERBB4', 'Gene', '2066', (145, 150))	('S602C', 'Mutation', 'p.S602C', (172, 177))	('L432M', 'Mutation', 'p.L432M', (165, 170))	('R444Q', 'Mutation', 'rs777498890', (61, 66))	('ERBB4', 'Gene', (145, 150))	('T475A', 'Var', (187, 192))
164914	32708604	EGFR inhibitors and their efficacy in cholangiocarcinoma summarized in Table 2.	('cholangiocarcinoma', 'Disease', (38, 56))	('EGFR', 'Gene', (0, 4))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (38, 56))	('inhibitors', 'Var', (5, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (38, 56))
164921	32708604	The FDA approved gefitinib is an EGFR inhibitor for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations, which has exon 19 deletions or exon 21 (L858R).	('lung cancer', 'Disease', (84, 95))	('gefitinib', 'Chemical', 'MESH:D000077156', (17, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (73, 95))	('NSCLC', 'Disease', (97, 102))	('mutations', 'Var', (114, 123))	('L858R', 'Mutation', 'rs121434568', (165, 170))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (69, 95))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('EGFR', 'Gene', (109, 113))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
164922	32708604	CC cells showed resistance to gefitinib or CI-1040, an inhibitor of MEK1/2, alone.	('gefitinib', 'Chemical', 'MESH:D000077156', (30, 39))	('resistance', 'MPA', (16, 26))	('CI-1040', 'Var', (43, 50))	('CI-1040', 'Chemical', 'MESH:C120227', (43, 50))	('CC', 'Phenotype', 'HP:0030153', (0, 2))	('MEK1/2', 'Gene', '5604;5605', (68, 74))	('MEK1/2', 'Gene', (68, 74))
164926	32708604	Gemcitabine, a pyrimidine analog, also inhibits the growth of CC cells in a concentration-dependent manner, and the combination of gefitinib and gemcitabine showed a synergistic effect in suppressing the tumor growth of CC cells in vivo and in vitro through significant inhibition of EGFR/ERK1/2 activation relative to treatment with either gefitinib or gemcitabine alone.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('suppressing', 'NegReg', (188, 199))	('gefitinib', 'Chemical', 'MESH:D000077156', (341, 350))	('ERK1/2', 'Gene', (289, 295))	('inhibition', 'NegReg', (270, 280))	('ERK1/2', 'Gene', '5595;5594', (289, 295))	('gemcitabine', 'Chemical', 'MESH:C056507', (145, 156))	('inhibits', 'NegReg', (39, 47))	('activation', 'PosReg', (296, 306))	('CC', 'Phenotype', 'HP:0030153', (220, 222))	('combination', 'Var', (116, 127))	('Gemcitabine', 'Chemical', 'MESH:C056507', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('gefitinib', 'Chemical', 'MESH:D000077156', (131, 140))	('pyrimidine', 'Chemical', 'MESH:C030986', (15, 25))	('rat', 'Species', '10116', (83, 86))	('growth', 'CPA', (52, 58))	('gemcitabine', 'Chemical', 'MESH:C056507', (354, 365))	('tumor', 'Disease', (204, 209))	('CC', 'Phenotype', 'HP:0030153', (62, 64))
164936	32708604	Cetuximab combined with target agents for the treatment of CC, and solid tumors are currently under evaluation in phase 1 or 2 clinical trials (ClinicalTrials.gov Identifier: NCT03829436, NCT03768375, NCT02836847, and NCT03693807).	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('NCT03829436', 'Var', (175, 186))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('NCT03693807', 'Var', (218, 229))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('Cetuximab', 'Chemical', 'MESH:D000068818', (0, 9))	('tumors', 'Disease', (73, 79))	('NCT02836847', 'Var', (201, 212))	('CC', 'Phenotype', 'HP:0030153', (59, 61))	('NCT03768375', 'Var', (188, 199))
164953	32708604	FDA-approved erlotinib is an EFGR inhibitor for first-line treatment of NSCLC patients with EGFR mutations.	('mutations', 'Var', (97, 106))	('NSCLC', 'Disease', (72, 77))	('patients', 'Species', '9606', (78, 86))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('EGFR', 'Gene', (92, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))	('erlotinib', 'Chemical', 'MESH:D000069347', (13, 22))
164959	32708604	The treatment of erlotinib for a patient with hepatocholangiocellular carcinoma with the EGFR R521K mutation had an SD with no metastases and showed a response duration of more than one year.	('patient', 'Species', '9606', (33, 40))	('rat', 'Species', '10116', (162, 165))	('metastases', 'Disease', 'MESH:D009362', (127, 137))	('EGFR', 'Gene', (89, 93))	('hepatocholangiocellular carcinoma', 'Disease', (46, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('R521K', 'Mutation', 'rs2227983', (94, 99))	('hepatocholangiocellular carcinoma', 'Disease', 'MESH:D009369', (46, 79))	('erlotinib', 'Chemical', 'MESH:D000069347', (17, 26))	('metastases', 'Disease', (127, 137))	('R521K', 'Var', (94, 99))
164968	32708604	T-DM1 treatment significantly increased invasive disease-free survival and showed a 50% lower risk of recurrence relative to the trastuzumab group (ClinicalTrials.gov Identifier: NCT01772472).	('trastuzumab', 'Chemical', 'MESH:D000068878', (129, 140))	('T-DM1', 'Var', (0, 5))	('T-DM1', 'Chemical', 'MESH:C550911', (0, 5))	('invasive disease-free survival', 'CPA', (40, 70))	('increased', 'PosReg', (30, 39))	('lower', 'NegReg', (88, 93))
164969	32708604	T-DM1 showed preclinical activity for inhibiting the progression of BTC, including CC.	('CC', 'Phenotype', 'HP:0030153', (83, 85))	('T-DM1', 'Var', (0, 5))	('T-DM1', 'Chemical', 'MESH:C550911', (0, 5))	('BTC', 'Phenotype', 'HP:0100574', (68, 71))	('inhibiting', 'NegReg', (38, 48))	('BTC', 'Disease', (68, 71))
164970	32708604	The growth inhibitory activity of BTC cells in vivo and in vitro by T-DM1 treatment was closely dependent on ERBB2 expression so that T-DM1 treatment has significant antitumor efficacy for ERBB2-expressing BTC cells but not for ERBB2-negative BTC cells in BTC xenograft models.	('T-DM1', 'Chemical', 'MESH:C550911', (134, 139))	('T-DM1', 'Chemical', 'MESH:C550911', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('T-DM1', 'Var', (134, 139))	('BTC', 'Phenotype', 'HP:0100574', (256, 259))	('BTC', 'Phenotype', 'HP:0100574', (243, 246))	('ERBB2-expressing', 'Var', (189, 205))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('BTC', 'Phenotype', 'HP:0100574', (206, 209))	('BTC', 'Phenotype', 'HP:0100574', (34, 37))	('growth inhibitory activity', 'MPA', (4, 30))
164971	32708604	Also, T-DM1 induces cell cycle arrest at the G2/M phase by inhibiting the activation of both ERBB2 and EGBB3.	('T-DM1', 'Var', (6, 11))	('arrest', 'Disease', (31, 37))	('T-DM1', 'Chemical', 'MESH:C550911', (6, 11))	('ERBB2', 'Protein', (93, 98))	('inhibiting', 'NegReg', (59, 69))	('EGBB3', 'Gene', (103, 108))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (20, 37))	('activation', 'MPA', (74, 84))	('arrest', 'Disease', 'MESH:D006323', (31, 37))
164972	32708604	Pertuzumab, in combination with trastuzumab for ERBB2 positive one CC patient, showed an excellent, ongoing, durable response by reduction of dominant TP53 mutation and significant tumor regression.	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('TP53', 'Gene', (151, 155))	('reduction', 'NegReg', (129, 138))	('patient', 'Species', '9606', (70, 77))	('CC', 'Phenotype', 'HP:0030153', (67, 69))	('ERBB2', 'Gene', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('Pertuzumab', 'Chemical', 'MESH:C485206', (0, 10))	('trastuzumab', 'Chemical', 'MESH:D000068878', (32, 43))	('TP53', 'Gene', '7157', (151, 155))	('mutation', 'Var', (156, 164))
164981	32708604	Afatinib is an inhibitor for EGFR and ERBBs (HER2, HER4) and was approved by the FDA for metastatic NSCLC with non-resistant EGFR mutations (EGFR S768I, L861Q, and G719X).	('EGFR', 'Var', (141, 145))	('ERBB', 'Gene', '1956', (38, 42))	('L861Q', 'Mutation', 'rs121913444', (153, 158))	('NSCLC', 'Disease', (100, 105))	('G719X', 'Mutation', 'p.G719X', (164, 169))	('HER4', 'Gene', '2066', (51, 55))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('HER4', 'Gene', (51, 55))	('ERBB', 'Gene', (38, 42))	('EGFR', 'Gene', (125, 129))	('L861Q', 'Var', (153, 158))	('HER2', 'Gene', (45, 49))	('G719X', 'Var', (164, 169))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('HER2', 'Gene', '2064', (45, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('S768I', 'Mutation', 'rs121913465', (146, 151))
164989	32708604	Various EGFR-and ERBB2-CAR-T clinical trials are also under evaluation for patients with various cancer types (ClinicalTrials.gov Identifier: NCT03618381, NCT03638167, NCT03696030, NCT03198052, etc.).	('NCT03618381', 'Var', (142, 153))	('CAR-T', 'Gene', (23, 28))	('NCT03638167', 'Var', (155, 166))	('NCT03198052', 'Var', (181, 192))	('cancer', 'Disease', (97, 103))	('patients', 'Species', '9606', (75, 83))	('CAR-T', 'Gene', '9607', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('NCT03696030', 'Var', (168, 179))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
165008	32708604	Recently, tucatinib has been under evaluation for patients with breast cancer and CRC in combination with trastuzumab and capecitabine or palbociclib and letrozole (ClinicalTrials.gov Identifier: NCT03054363, NCT03501979, NCT03043313).	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('CRC', 'Disease', 'MESH:D015179', (82, 85))	('capecitabine', 'Chemical', 'MESH:D000069287', (122, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('patients', 'Species', '9606', (50, 58))	('letrozole', 'Chemical', 'MESH:D000077289', (154, 163))	('trastuzumab', 'Chemical', 'MESH:D000068878', (106, 117))	('palbociclib', 'Chemical', 'MESH:C500026', (138, 149))	('tucatinib', 'Chemical', '-', (10, 19))	('CRC', 'Disease', (82, 85))	('NCT03043313', 'Var', (222, 233))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
165014	32708604	Recently, mutations of EGFR and ERBBs were identified, but the functional role of the newly identified mutations of EGFR and ERBBs has remained unclear.	('ERBB', 'Gene', (32, 36))	('ERBB', 'Gene', '1956', (125, 129))	('ERBB', 'Gene', '1956', (32, 36))	('mutations', 'Var', (10, 19))	('ERBB', 'Gene', (125, 129))	('EGFR', 'Gene', (23, 27))	('EGFR', 'Gene', (116, 120))
165015	32708604	However, these mutations seem to affect the survival, invasion, metastasis, and chemoresistance of CC through changes in the expression or activation of EGFR and ERBBs.	('chemoresistance', 'CPA', (80, 95))	('survival', 'CPA', (44, 52))	('invasion', 'CPA', (54, 62))	('activation', 'PosReg', (139, 149))	('ERBB', 'Gene', '1956', (162, 166))	('affect', 'Reg', (33, 39))	('mutations', 'Var', (15, 24))	('CC', 'Phenotype', 'HP:0030153', (99, 101))	('expression', 'MPA', (125, 135))	('EGFR', 'Gene', (153, 157))	('metastasis', 'CPA', (64, 74))	('changes', 'Reg', (110, 117))	('ERBB', 'Gene', (162, 166))
165016	32708604	Overexpression and activation by mutation of EGFR and ERBBs have been linked to the development and progression of CC and acquisition of chemoresistance against chemotherapeutic agents.	('ERBB', 'Gene', (54, 58))	('mutation', 'Var', (33, 41))	('linked', 'Reg', (70, 76))	('EGFR', 'Gene', (45, 49))	('CC', 'Phenotype', 'HP:0030153', (115, 117))	('activation', 'PosReg', (19, 29))	('ERBB', 'Gene', '1956', (54, 58))
165026	30105289	We conducted this retrospective single-center study to examine the effectiveness of m-ENBD compared with c-ENBD among patients with preoperative suspected perihilar cholangiocarcinoma, many of whom met the Bismuth-Corlette criteria (B-C) for type III-IV tumours  , using a propensity score matching analysis.	('III-IV tumours', 'Disease', 'MESH:D009369', (247, 261))	('m-ENBD', 'Var', (84, 90))	('perihilar cholangiocarcinoma', 'Disease', (155, 183))	('III-IV tumours', 'Disease', (247, 261))	('tumours', 'Phenotype', 'HP:0002664', (254, 261))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (165, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))
165040	28913712	Complications may lead to an associated immune-modulatory effect that inhibits the body's response to cancer surveillance.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Complications', 'Var', (0, 13))	('immune-modulatory effect', 'MPA', (40, 64))	('inhibits', 'NegReg', (70, 78))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('lead', 'Reg', (18, 22))
165047	28913712	Among 279 patients who had EHBM that had no associated lymph node metastases, well-to-moderate tumor differentiation, as well as an R0 resection margin, SSI remained associated with worse RFS (HR 1.84, 95% CI 1.03-3.29; p=0.038), as well as overall survival (HR 1.87, 95% CI 1.18-2.97; p=0.008).	('overall survival', 'MPA', (241, 257))	('metastases', 'Disease', (66, 76))	('metastases', 'Disease', 'MESH:D009362', (66, 76))	('worse', 'NegReg', (182, 187))	('EHBM', 'Phenotype', 'HP:0005242', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('patients', 'Species', '9606', (10, 18))	('SSI', 'Var', (153, 156))	('RFS', 'MPA', (188, 191))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
165055	28913712	Specifically, complications may lead to an associated immune-modulatory effect that inhibits the body's response to cancer surveillance.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('immune-modulatory effect', 'MPA', (54, 78))	('complications', 'Var', (14, 27))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('inhibits', 'NegReg', (84, 92))	('lead', 'Reg', (32, 36))
165089	28913712	In addition, SSI was associated with long-term survival as patients who experienced an SSI had a median RFS of 19.5 months compared with 30.5 months for those patients who did not have an SSI (HR 1.40, 95% CI 1.08-1.80; p=0.01; Figure 1).	('patients', 'Species', '9606', (159, 167))	('RFS', 'MPA', (104, 107))	('patients', 'Species', '9606', (59, 67))	('SSI', 'Var', (87, 90))
165095	28913712	Of note, even among patients with a good prognosis, SSI impacted survival.	('impacted', 'Reg', (56, 64))	('patients', 'Species', '9606', (20, 28))	('survival', 'MPA', (65, 73))	('SSI', 'Var', (52, 55))
165106	28913712	For example, lymph node metastases, poor tumor differentiation, and positive resection margins have been previously associated with EHBM prognosis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('metastases', 'Disease', 'MESH:D009362', (24, 34))	('tumor', 'Disease', (41, 46))	('EHBM', 'Disease', (132, 136))	('EHBM', 'Phenotype', 'HP:0005242', (132, 136))	('metastases', 'Disease', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('poor', 'Var', (36, 40))	('associated', 'Reg', (116, 126))
165119	28913712	While the reason for this may be multifactorial, SSI may induce inflammation and thereby alter systemic inflammatory cytokines and chemokines.	('SSI', 'Var', (49, 52))	('chemokines', 'MPA', (131, 141))	('inflammation', 'Disease', 'MESH:D007249', (64, 76))	('alter', 'Reg', (89, 94))	('inflammation', 'Disease', (64, 76))	('induce', 'PosReg', (57, 63))
165154	24204165	Previously, approaches for genotyping tumors were limited to single gene mutations or a select group of predefined mutations (ie, polymerase chain reaction, Sanger sequencing, and mass spectrometry-based assays).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('mutations', 'Var', (115, 124))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))
165160	24204165	Within this panel of tumors, 206 somatic mutations were identified in 187 genes using Sanger sequencing.	('mutations', 'Var', (41, 50))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
165163	24204165	Previous efforts analyzing the frequency of mutations in cholangiocarcinoma have established a wide range of alterations contributing to the heterogeneity of tumor pathogenesis.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (57, 75))	('tumor', 'Disease', (158, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('mutations', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('cholangiocarcinoma', 'Disease', (57, 75))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
165165	24204165	Reported rates of KRAS mutations range from 9%-54% in intrahepatic tumors and 10%-22% in extrahepatic samples.	('intrahepatic tumors', 'Disease', (54, 73))	('intrahepatic tumors', 'Disease', 'MESH:D002780', (54, 73))	('KRAS', 'Gene', (18, 22))	('KRAS', 'Gene', '3845', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mutations', 'Var', (23, 32))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))
165166	24204165	Mutations in gallbladder carcinoma tend to be less frequent at 3%-38%.	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (13, 34))	('Mutations', 'Var', (0, 9))	('gallbladder carcinoma', 'Disease', (13, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
165167	24204165	Directly downstream from RAS, B-RAF mutations have changed the scope of metastatic melanoma.	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('B-RAF', 'Gene', (30, 35))	('mutations', 'Var', (36, 45))	('B-RAF', 'Gene', '673', (30, 35))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))	('changed', 'Reg', (51, 58))
165168	24204165	One particular series found BRAF to be mutated in approximately 20% of patients in both gallbladder and intrahepatic carcinomas.	('BRAF', 'Gene', '673', (28, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('patients', 'Species', '9606', (71, 79))	('mutated', 'Var', (39, 46))	('intrahepatic carcinomas', 'Disease', (104, 127))	('intrahepatic carcinomas', 'Disease', 'MESH:D002780', (104, 127))	('BRAF', 'Gene', (28, 32))	('gallbladder', 'Disease', (88, 99))
165169	24204165	It should be noted that these particular mutations were found to be mutually exclusive of KRAS mutations.	('mutations', 'Var', (41, 50))	('KRAS', 'Gene', (90, 94))	('KRAS', 'Gene', '3845', (90, 94))
165172	24204165	EGFR mutations of the tyrosine kinase domain have been found in intrahepatic and extrahepatic tumors (5%-15%) and in gallbladder carcinoma (9%-38%).	('found', 'Reg', (55, 60))	('EGFR', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('mutations', 'Var', (5, 14))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (117, 138))	('gallbladder carcinoma', 'Disease', (117, 138))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('intrahepatic and extrahepatic tumors', 'Disease', 'MESH:D001651', (64, 100))	('EGFR', 'Gene', '1956', (0, 4))
165174	24204165	Mutations of the PIK3CA/mammalian target of rapamycin signaling pathway have also been found in varying percentages of BTC samples, with frequencies ranging from 0%-33%.	('PIK3CA', 'Gene', (17, 23))	('BTC', 'Phenotype', 'HP:0100574', (119, 122))	('PIK3CA', 'Gene', '5290', (17, 23))	('mammalian target of rapamycin', 'Gene', '2475', (24, 53))	('Mutations', 'Var', (0, 9))	('mammalian target of rapamycin', 'Gene', (24, 53))	('found', 'Reg', (87, 92))
165176	24204165	These somatic mutations lead to disruptive enzyme activity, allowing alpha-ketoglutarate to be more effectively converted to 2-hydroxyglutarate.	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (69, 88))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (125, 143))	('alpha-ketoglutarate', 'MPA', (69, 88))	('activity', 'MPA', (50, 58))	('mutations', 'Var', (14, 23))
165178	24204165	Emerging data have identified that these mutations also occur in BTC; in one series of 87 patients with BTC, IDH mutations were found in 23% of intrahepatic cholangiocarcinoma samples.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (144, 175))	('intrahepatic cholangiocarcinoma', 'Disease', (144, 175))	('found', 'Reg', (128, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('mutations', 'Var', (113, 122))	('BTC', 'Phenotype', 'HP:0100574', (104, 107))	('IDH', 'Gene', (109, 112))	('BTC', 'Phenotype', 'HP:0100574', (65, 68))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (157, 175))	('patients', 'Species', '9606', (90, 98))	('IDH', 'Gene', '3417', (109, 112))
165179	24204165	In another analysis of 94 tumors, mutations of IDH1 and IDH2 were found in 28% of intrahepatic samples, but only in 7% of extrahepatic tumors.	('found', 'Reg', (66, 71))	('IDH2', 'Gene', '3418', (56, 60))	('extrahepatic tumors', 'Disease', (122, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('IDH1', 'Gene', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('extrahepatic tumors', 'Disease', 'MESH:D001651', (122, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('IDH1', 'Gene', '3417', (47, 51))	('IDH2', 'Gene', (56, 60))	('mutations', 'Var', (34, 43))	('tumors', 'Disease', (26, 32))
165180	24204165	One could postulate that the anatomic location of the tumor correlates to the genetic subtype; intrahepatic tumors have higher rates of IDH1/IDH2 mutations.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('intrahepatic tumors', 'Disease', (95, 114))	('mutations', 'Var', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('intrahepatic tumors', 'Disease', 'MESH:D002780', (95, 114))	('IDH2', 'Gene', '3418', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (108, 113))	('IDH1', 'Gene', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('IDH1', 'Gene', '3417', (136, 140))	('tumor', 'Disease', (54, 59))	('IDH2', 'Gene', (141, 145))
165195	24204165	Analysis of KRAS mutational status has just been completed; in the 91 patient samples adequate for deoxyribonucleic acid analysis, KRAS and BRAF mutations were found in 19% and 5% of patients, respectively.	('KRAS', 'Gene', (131, 135))	('mutations', 'Var', (145, 154))	('found', 'Reg', (160, 165))	('patient', 'Species', '9606', (70, 77))	('BRAF', 'Gene', '673', (140, 144))	('KRAS', 'Gene', (12, 16))	('BRAF', 'Gene', (140, 144))	('KRAS', 'Gene', '3845', (131, 135))	('patient', 'Species', '9606', (183, 190))	('KRAS', 'Gene', '3845', (12, 16))	('patients', 'Species', '9606', (183, 191))
165200	24204165	Analysis of the tumors sample revealed KRAS mutations in 3/30 (10%); two of these patients had a partial response and the third had stable disease.	('tumors', 'Disease', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutations', 'Var', (44, 53))	('KRAS', 'Gene', (39, 43))	('KRAS', 'Gene', '3845', (39, 43))	('tumors', 'Disease', 'MESH:D009369', (16, 22))
165203	24204165	Interestingly, subgroup analysis suggested that patients with KRAS mutated tumors derived benefit from cetuximab with increased PFS and OS of 7.0 months versus 1.9 months, and 10.3 months versus 6.6 months, respectively.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('KRAS', 'Gene', (62, 66))	('cetuximab', 'Gene', (103, 112))	('cetuximab', 'Chemical', 'MESH:D000068818', (103, 112))	('KRAS', 'Gene', '3845', (62, 66))	('benefit', 'PosReg', (90, 97))	('PFS', 'MPA', (128, 131))	('increased', 'PosReg', (118, 127))	('mutated', 'Var', (67, 74))	('patients', 'Species', '9606', (48, 56))	('OS', 'Gene', '17451', (136, 138))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))
165204	24204165	This is surprising given the known and well established paradigms of KRAS mutation and its effect on EGFR therapy in colorectal cancer.	('KRAS', 'Gene', (69, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (117, 134))	('mutation', 'Var', (74, 82))	('KRAS', 'Gene', '3845', (69, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('colorectal cancer', 'Disease', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))
165297	33363208	reported that KLHL5 knockdown inhibited proliferation in ovarian adenocarcinoma and renal carcinoma cell lines, and sensitized tumor cells to anticancer agents.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('sensitized', 'Reg', (116, 126))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('ovarian adenocarcinoma and renal carcinoma', 'Disease', 'MESH:C538614', (57, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('tumor', 'Disease', (127, 132))	('KLHL5', 'Gene', '51088', (14, 19))	('inhibited', 'NegReg', (30, 39))	('KLHL5', 'Gene', (14, 19))	('renal carcinoma', 'Phenotype', 'HP:0005584', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (57, 79))	('knockdown', 'Var', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('proliferation', 'CPA', (40, 53))
165331	33363208	What is more, KLHL5 expression was associated with the immunocyte level of B cell in 21 types, CD8+ T cell in 27 types, CD4+ T cell in 25 types, macrophage in 33 types, dendritic cell in 31 types, and neutrophil in 33 cancer types (Supplementary Figures 2A-2AK).	('CD4', 'Gene', (120, 123))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('CD8', 'Gene', '925', (95, 98))	('cancer', 'Disease', (218, 224))	('CD4', 'Gene', '920', (120, 123))	('KLHL5', 'Gene', '51088', (14, 19))	('KLHL5', 'Gene', (14, 19))	('associated', 'Reg', (35, 45))	('expression', 'Var', (20, 30))	('immunocyte level of B cell', 'MPA', (55, 81))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('CD8', 'Gene', (95, 98))
165349	33363208	Although its full functions remain uncertain, it is clear that KLHL5 knockdown inhibits cell proliferation in certain cancer cell lines (Schleifer et al.,).	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('KLHL5', 'Gene', '51088', (63, 68))	('KLHL5', 'Gene', (63, 68))	('inhibits', 'NegReg', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cell proliferation in', 'CPA', (88, 109))	('knockdown', 'Var', (69, 78))
165415	31517963	On multivariable Cox regression, LDLT was again associated with improved overall survival (adjusted HR, 0.60; 95% CI, 0.45-0.79; P < .001).	('Cox', 'Gene', '1351', (17, 20))	('LDLT', 'Var', (33, 37))	('Cox', 'Gene', (17, 20))	('improved', 'PosReg', (64, 72))	('overall survival', 'MPA', (73, 89))
165418	31517963	After multiple imputation, LDLT remained associated with improved overall survival using multivariable Cox regression on the imputed data set (HR, 0.60; 95% CI, 0.48-0.74; P < .001) (Table 2).	('overall survival', 'MPA', (66, 82))	('Cox', 'Gene', '1351', (103, 106))	('LDLT', 'Var', (27, 31))	('improved', 'PosReg', (57, 65))	('Cox', 'Gene', (103, 106))
165426	31517963	When selecting only those patients who received LDLT within 30 days of chemotherapy initiation, LDLT continued to be associated with improved overall survival when compared with chemotherapy alone (HR, 0.67; 95% CI, 0.48-0.93; P = .02).	('improved', 'PosReg', (133, 141))	('overall survival', 'MPA', (142, 158))	('LDLT', 'Var', (96, 100))	('patients', 'Species', '9606', (26, 34))
165535	29731637	Some studies indicate that NETs are linked with cholelithiasis and congenital malformation of the biliary tract, both of which lead to chronic inflammation.	('cholelithiasis', 'Disease', 'MESH:D002769', (48, 62))	('lead', 'Reg', (127, 131))	('NETs', 'Var', (27, 31))	('NETs', 'Phenotype', 'HP:0100634', (27, 31))	('congenital malformation', 'Disease', (67, 90))	('cholelithiasis', 'Phenotype', 'HP:0001081', (48, 62))	('NET', 'Phenotype', 'HP:0100634', (27, 30))	('inflammation', 'Disease', 'MESH:D007249', (143, 155))	('inflammation', 'Disease', (143, 155))	('linked', 'Reg', (36, 42))	('malformation of the biliary tract', 'Phenotype', 'HP:0012440', (78, 111))	('cholelithiasis', 'Disease', (48, 62))
165565	29731637	Patients with non-functional NETs in the CBD often have the symptom of jaundice first, with or without the symptom of fever and abdominal discomfort.	('jaundice', 'Disease', 'MESH:D007565', (71, 79))	('NETs', 'Phenotype', 'HP:0100634', (29, 33))	('fever', 'Disease', 'MESH:D005334', (118, 123))	('fever', 'Disease', (118, 123))	('fever', 'Phenotype', 'HP:0001945', (118, 123))	('jaundice', 'Disease', (71, 79))	('jaundice', 'Phenotype', 'HP:0000952', (71, 79))	('NET', 'Phenotype', 'HP:0100634', (29, 32))	('non-functional', 'Var', (14, 28))	('Patients', 'Species', '9606', (0, 8))	('abdominal discomfort', 'Phenotype', 'HP:0002027', (128, 148))
165667	26155274	According to our experience and the literature, the presence of LSGB is often associated with serious combined anomalies of the hepatic vascular and biliary systems.	('associated', 'Reg', (78, 88))	('presence', 'Var', (52, 60))	('LSGB', 'Gene', (64, 68))	('anomalies of the hepatic vascular', 'Disease', (111, 144))	('anomalies of the hepatic vascular', 'Disease', 'MESH:D056486', (111, 144))
165672	26155274	Based on our experience of 4,000 living donor hepatectomies, the rarer the type of the portal vein variation was, the more common the combined bile duct variation became.	('combined bile duct variation', 'Disease', (134, 162))	('donor', 'Species', '9606', (40, 45))	('variation', 'Var', (99, 108))
165675	26155274	In fact, the anomalous anatomy in LSGB might be helpful for resecting the tumor because it might displace the location of the tumor towards the peripheral side of the left hepatic duct.	('location', 'MPA', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', (74, 79))	('anomalous', 'Var', (13, 22))	('displace', 'NegReg', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
165690	25548748	Additional gadoxetic acid-enhanced magnetic resonance images (MRI) showed a T1 hypointense and T2 hyperintense focal lesion adjacent to the cystic lesion and dilated intrahepatic ducts in the left lateral section of the liver, corresponding to the hypodense nodular lesion noted on CT (Fig.	('cystic lesion', 'Disease', 'MESH:D052177', (140, 153))	('hypodense nodular lesion', 'Disease', (248, 272))	('cystic lesion', 'Disease', (140, 153))	('dilated intrahepatic ducts', 'Phenotype', 'HP:0006571', (158, 184))	('dilated intrahepatic', 'Disease', (158, 178))	('dilated intrahepatic', 'Disease', 'MESH:C531647', (158, 178))	('T2 hyperintense', 'Var', (95, 110))	('hypodense nodular lesion', 'Disease', 'MESH:D020518', (248, 272))	('gadoxetic acid', 'Chemical', 'MESH:C073590', (11, 25))
165782	24169343	It has been demonstrated that the ectopic expression of miR-200 suppresses the multidrug resistance and metastasis of cancer.	('metastasis of cancer', 'Disease', 'MESH:D009362', (104, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('suppresses', 'NegReg', (64, 74))	('miR', 'Gene', '220972', (56, 59))	('ectopic expression', 'Var', (34, 52))	('miR', 'Gene', (56, 59))	('drug resistance', 'Phenotype', 'HP:0020174', (84, 99))	('metastasis of cancer', 'Disease', (104, 124))
165788	24169343	We found that miR-200b/c influenced the tumourigenesis of cholangiocarcinoma cells including their tumour-initiating capacity, sphere formation, and drug resistance.	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('cholangiocarcinoma', 'Disease', (58, 76))	('tumour', 'Disease', (40, 46))	('tumour', 'Disease', (99, 105))	('drug resistance', 'CPA', (149, 164))	('sphere formation', 'CPA', (127, 143))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 76))	('drug resistance', 'Phenotype', 'HP:0020174', (149, 164))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('miR-200b/c', 'Var', (14, 24))	('influenced', 'Reg', (25, 35))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
165790	24169343	Our study shows that miR-200b/c has a critical role in the regulation of the tumorigenic and metastatic capacity of cholangiocarcinoma and reveals the probable underlying mechanisms.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (116, 134))	('miR-200b/c', 'Var', (21, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))	('cholangiocarcinoma', 'Disease', (116, 134))	('tumorigenic', 'CPA', (77, 88))
165793	24169343	The development of cholangiocarcinoma is a multistep process, with an accumulation of genetic and epigenetic alterations.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (19, 37))	('epigenetic', 'Var', (98, 108))	('cholangiocarcinoma', 'Disease', (19, 37))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (19, 37))
165802	24169343	Here, we demonstrate that miR-200b/c regulates the metastatic capacity and tumorigenic properties of cholangiocarcinoma, including tumour-initiating capacity, sphere formation, and drug resistance.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (101, 119))	('tumour', 'Disease', (131, 137))	('regulates', 'Reg', (37, 46))	('miR-200b/c', 'Var', (26, 36))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('tumorigenic properties', 'CPA', (75, 97))	('drug resistance', 'CPA', (181, 196))	('drug resistance', 'Phenotype', 'HP:0020174', (181, 196))	('cholangiocarcinoma', 'Disease', (101, 119))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('metastatic capacity', 'CPA', (51, 70))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('sphere formation', 'CPA', (159, 175))
165804	24169343	Moreover, miR-200b/c influences cholangiocarcinoma tumourigenesis by silencing SUZ12 (a subunit of a polycomb repressor complex).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (32, 50))	('SUZ12', 'Gene', '23512', (79, 84))	('SUZ12', 'Gene', (79, 84))	('influences', 'Reg', (21, 31))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('cholangiocarcinoma tumourigenesis', 'Disease', 'MESH:D018281', (32, 65))	('miR-200b/c', 'Var', (10, 20))	('cholangiocarcinoma tumourigenesis', 'Disease', (32, 65))	('silencing', 'NegReg', (69, 78))
165821	24169343	After 24 h of transfection, the cell layer was scratched with a sterile plastic tip, washed with PBS two times, and then cultured for 24 h with medium containing 1% FBS.	('transfection', 'Var', (14, 26))	('plastic tip', 'Disease', (72, 83))	('plastic tip', 'Disease', 'MESH:D060725', (72, 83))
165834	24169343	The mutant SUZ12/ROCK2 3'-UTR construct was designed to mutate three intermittent nucleotides complementary to the miR-200b/c/429 seed region.	('SUZ12', 'Gene', '23512', (11, 16))	('SUZ12', 'Gene', (11, 16))	('mutate', 'Var', (56, 62))	('ROCK2', 'Gene', (17, 22))	('ROCK2', 'Gene', '9475', (17, 22))
165843	24169343	The data analysis showed that miR-200b, miR-200c, and miR-429 were underexpressed in the cholangiocarcinoma group compared with the controls (Figure 1B and Supplementary Figure 7A).	('miR-429', 'Gene', (54, 61))	('cholangiocarcinoma', 'Disease', (89, 107))	('miR-200c', 'Gene', (40, 48))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (89, 107))	('miR-200c', 'Gene', '406985', (40, 48))	('underexpressed', 'NegReg', (67, 81))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (89, 107))	('miR-200b', 'Var', (30, 38))	('miR-429', 'Gene', '554210', (54, 61))
165844	24169343	The data showed that the reduced expression of miR-200b and miR-200c was significant (Figure 1C, P=0.038 and P=0.019, respectively), whereas that of miR-429 was not (Figure 1C, P=0.057).	('reduced', 'NegReg', (25, 32))	('miR-200c', 'Gene', (60, 68))	('miR-200b', 'Var', (47, 55))	('miR-200c', 'Gene', '406985', (60, 68))	('miR-429', 'Gene', '554210', (149, 156))	('expression', 'MPA', (33, 43))	('miR-429', 'Gene', (149, 156))
165845	24169343	Therefore, miR-200b and miR-200c were selected for further study.	('miR-200c', 'Gene', (24, 32))	('miR-200b', 'Var', (11, 19))	('miR-200c', 'Gene', '406985', (24, 32))
165846	24169343	We determined whether miR-200b/c can alter the migration and invasion capacities of cholangiocarcinoma cells.	('miR-200b/c', 'Var', (22, 32))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('alter', 'Reg', (37, 42))	('cholangiocarcinoma', 'Disease', (84, 102))	('migration', 'CPA', (47, 56))	('invasion capacities', 'CPA', (61, 80))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
165848	24169343	In contrast, the knockdown of miR-200b/c promoted the invasion of the cholangiocarcinoma cells (Figure 2C): miR-200b/c knockdown in TFK-1 cells resulted in significant gap closure in the wound healing assay (Figure 2D, 0.69+-0.01- and 0.65+-0.03-fold, respectively, P<0.001) and a increase in cell invasion compared with that of the antagomir-NC group (Figure 2B, 1.96+-0.10- and 3.07+-0.19-fold, respectively, P<0.001).	('miR-200b/c knockdown', 'Var', (108, 128))	('invasion', 'CPA', (54, 62))	('increase', 'PosReg', (281, 289))	('cholangiocarcinoma', 'Disease', (70, 88))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (70, 88))	('cell invasion', 'CPA', (293, 306))	('knockdown', 'Var', (119, 128))	('gap closure in the wound healing assay', 'CPA', (168, 206))	('knockdown', 'Var', (17, 26))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))
165849	24169343	Moreover, we confirmed an effect of miR-200b/c on cholangiocarcinoma's metastatic capacity in vivo.	('miR-200b/c', 'Var', (36, 46))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (50, 68))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (50, 68))	('cholangiocarcinoma', 'Disease', (50, 68))	('effect', 'Reg', (26, 32))	('metastatic capacity', 'CPA', (71, 90))
165854	24169343	In conclusion, these data show that miR-200b/c is an important participant in the regulation of the migration and invasion potentials of cholangiocarcinoma cells.	('miR-200b/c', 'Var', (36, 46))	('participant', 'Species', '9606', (63, 74))	('migration', 'CPA', (100, 109))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (137, 155))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (137, 155))	('invasion potentials', 'CPA', (114, 133))	('cholangiocarcinoma', 'Disease', (137, 155))
165856	24169343	The expression level of miR-200b/c in the 5-fluorouracil-pretreated TFK-1 cells was lower than that in the untreated controls (Supplementary Figure 3C).	('expression level', 'MPA', (4, 20))	('miR-200b/c', 'Var', (24, 34))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (42, 56))	('lower', 'NegReg', (84, 89))
165858	24169343	The IC50 values for the pre-miR-200b mimics+5-fluorouracil and pre-miR-200c mimics+5-fluorouracil groups at various time points are shown in Supplementary Table 3, with the IC50 value for the miR-200b/c mimics+5-fluorouracil group being significantly lower than that of the NC group.	('lower', 'NegReg', (251, 256))	('miR-200c', 'Gene', '406985', (67, 75))	('miR-200b/c', 'Var', (192, 202))	('miR-200c', 'Gene', (67, 75))	('IC50', 'MPA', (173, 177))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (44, 58))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (83, 97))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (210, 224))
165859	24169343	Conversely, the knockdown of miR-200b/c by an antagomir aggravated the chemoresistance against 5-fluorouracil.	('aggravated', 'PosReg', (56, 66))	('miR-200b/c', 'Gene', (29, 39))	('chemoresistance', 'CPA', (71, 86))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (95, 109))	('knockdown', 'Var', (16, 25))
165860	24169343	As shown in Supplementary Table 3, the IC50 values for the pre-miR-200b antagomir+5-fluorouracil and pre-miR-200c antagomir+5-fluorouracil groups at various time points were significantly higher than those of the NC+5-fluorouracil.	('pre-miR-200b', 'Var', (59, 71))	('miR-200c', 'Gene', (105, 113))	('miR-200c', 'Gene', '406985', (105, 113))	('higher', 'PosReg', (188, 194))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (82, 96))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (216, 230))	('IC50', 'MPA', (39, 43))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (124, 138))
165861	24169343	These data illustrate that miR-200b/c significantly enhances the cytotoxic effect of 5-fluorouracil on cholangiocarcinoma cells.	('cytotoxic', 'CPA', (65, 74))	('cholangiocarcinoma', 'Disease', (103, 121))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (85, 99))	('miR-200b/c', 'Var', (27, 37))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (103, 121))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (103, 121))	('enhances', 'PosReg', (52, 60))
165865	24169343	Strikingly, even after 3 weeks, injection of 1 x 105 miR-200b/c-knockdown cells resulted in large tumours, whereas the miR-200b/c-overexpressing cells formed smaller tumours in five out of five mice compared with the control groups (Figure 3B, P<0.001).	('miR-200b/c-knockdown', 'Gene', (53, 73))	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('tumours', 'Disease', (166, 173))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumours', 'Disease', 'MESH:D009369', (98, 105))	('tumours', 'Disease', (98, 105))	('miR-200b/c-overexpressing', 'Var', (119, 144))	('large tumours', 'Disease', (92, 105))	('large tumours', 'Disease', 'MESH:D009369', (92, 105))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('tumours', 'Phenotype', 'HP:0002664', (166, 173))	('mice', 'Species', '10090', (194, 198))	('tumours', 'Disease', 'MESH:D009369', (166, 173))
165866	24169343	The tumour size was also dramatically altered, as shown in Figure 3D, the miR-200b/c-overexpressing cells formed tumours at a much slower rate than the NC group.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumours', 'Disease', 'MESH:D009369', (113, 120))	('miR-200b/c-overexpressing', 'Var', (74, 99))	('tumour', 'Disease', (113, 119))	('tumours', 'Disease', (113, 120))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('slower', 'NegReg', (131, 137))
165877	24169343	As our above results confirmed that miR-200b/c expression might be associated with the self-renewal capacity of cholangiocarcinoma, miR-200b/c may have a potential effect on stem-like cholangiocarcinoma cells.	('effect', 'Reg', (164, 170))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 130))	('self-renewal capacity of', 'CPA', (87, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('cholangiocarcinoma', 'Disease', (184, 202))	('associated', 'Reg', (67, 77))	('cholangiocarcinoma', 'Disease', (112, 130))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (184, 202))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (184, 202))	('miR-200b/c', 'Var', (132, 142))
165882	24169343	Collectively, these data show that CD133 is a potential CSC marker of cholangiocarcinoma, which can be inhibited by miR-200b/c.	('CD133', 'Gene', (35, 40))	('miR-200b/c', 'Var', (116, 126))	('cholangiocarcinoma', 'Disease', (70, 88))	('CD133', 'Gene', '8842', (35, 40))	('inhibited', 'NegReg', (103, 112))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (70, 88))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))
165883	24169343	According to our results, miR-200b/c affects migration, invasion, chemoresistance, tumour growth, and self-renewal capacities.	('miR-200b/c', 'Var', (26, 36))	('tumour growth', 'Disease', (83, 96))	('migration', 'CPA', (45, 54))	('affects', 'Reg', (37, 44))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour growth', 'Disease', 'MESH:D006130', (83, 96))	('self-renewal capacities', 'CPA', (102, 125))	('chemoresistance', 'CPA', (66, 81))	('invasion', 'CPA', (56, 64))
165887	24169343	The ectopic expression of miR-200b/c in TFK-1 cells resulted in a reduction in SUZ12 and ROCK2 expression, whereas miR-200b/c inhibition led to increased expression (Figure 5C).	('miR-200b/c', 'Var', (26, 36))	('SUZ12', 'Gene', '23512', (79, 84))	('SUZ12', 'Gene', (79, 84))	('ROCK2', 'Gene', (89, 94))	('ROCK2', 'Gene', '9475', (89, 94))	('reduction', 'NegReg', (66, 75))
165888	24169343	To further confirm whether SUZ12 and ROCK2 are direct targets of miR-200b/c, we detected the expression of the SUZ12 and ROCK2 proteins in 12 cholangiocarcinoma samples and the corresponding normal bile duct tissues using western blotting and immunohistochemistry.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (142, 160))	('ROCK2', 'Gene', (37, 42))	('ROCK2', 'Gene', '9475', (37, 42))	('SUZ12', 'Gene', '23512', (27, 32))	('SUZ12', 'Gene', (27, 32))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (142, 160))	('SUZ12', 'Gene', '23512', (111, 116))	('cholangiocarcinoma', 'Disease', (142, 160))	('SUZ12', 'Gene', (111, 116))	('detected', 'Reg', (80, 88))	('miR-200b/c', 'Var', (65, 75))	('ROCK2', 'Gene', (121, 126))	('proteins', 'Protein', (127, 135))	('ROCK2', 'Gene', '9475', (121, 126))
165891	24169343	Regardless, there was little significant difference in the mRNA expression levels of SUZ12/ROCK2 between the cholangiocarcinoma and normal bile duct groups (Supplementary Figure 7B), suggesting that miR-200b/c might silence these two target only in a post-transcriptional manner.	('SUZ12', 'Gene', (85, 90))	('ROCK2', 'Gene', (91, 96))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (109, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('miR-200b/c', 'Var', (199, 209))	('ROCK2', 'Gene', '9475', (91, 96))	('mRNA expression levels', 'MPA', (59, 81))	('cholangiocarcinoma', 'Disease', (109, 127))	('SUZ12', 'Gene', '23512', (85, 90))
165894	24169343	Similar data were observed for ROCK2, showing that the forced expression of miR-200b/c in TFK-1 cells results in a decrease in luciferase activity using conserved wild-type binding sites compared with a mutant sequence (Figures 6A and B) and also indicating that the conserved predicted binding sites of miR-200b/c in the 3'-UTR of ROCK2 were functional.	('activity', 'MPA', (138, 146))	('ROCK2', 'Gene', (332, 337))	('ROCK2', 'Gene', '9475', (332, 337))	('binding', 'Interaction', (173, 180))	('ROCK2', 'Gene', (31, 36))	('miR-200b/c', 'Var', (76, 86))	('luciferase', 'Enzyme', (127, 137))	('decrease', 'NegReg', (115, 123))	('ROCK2', 'Gene', '9475', (31, 36))
165897	24169343	To determine whether SUZ12 and ROCK2 are related to these capacities, we transfected TFK-1 cells with SUZ12 and ROCK2 siRNAs to knockdown their expression and then detected the invasion capacity using a Transwell assay.	('ROCK2', 'Gene', (112, 117))	('SUZ12', 'Gene', (102, 107))	('SUZ12', 'Gene', '23512', (21, 26))	('SUZ12', 'Gene', (21, 26))	('expression', 'MPA', (144, 154))	('knockdown', 'Var', (128, 137))	('ROCK2', 'Gene', '9475', (112, 117))	('ROCK2', 'Gene', (31, 36))	('SUZ12', 'Gene', '23512', (102, 107))	('ROCK2', 'Gene', '9475', (31, 36))	('detected', 'Reg', (164, 172))
165899	24169343	In contrast, ROCK2 knockdown reduced the number of invasive cells compared with the controls (Figures 2B and C).	('knockdown', 'Var', (19, 28))	('ROCK2', 'Gene', (13, 18))	('ROCK2', 'Gene', '9475', (13, 18))	('reduced', 'NegReg', (29, 36))
165901	24169343	However, the silencing of neither ROCK2 nor ZEB1/2 in the miR-200b/c-knockdown cells could recover the invasive capacity compared with that of the controls.	('ZEB1/2', 'Gene', '6935;9839', (44, 50))	('invasive capacity', 'CPA', (103, 120))	('recover', 'PosReg', (91, 98))	('ROCK2', 'Gene', (34, 39))	('miR-200b/c-knockdown', 'Gene', (58, 78))	('ZEB1/2', 'Gene', (44, 50))	('ROCK2', 'Gene', '9475', (34, 39))	('silencing', 'Var', (13, 22))
165902	24169343	In addition, the silencing of both ROCK2 and ZEB1/2 resulted in the lowest number of invasive cells (Supplementary Figures 6A and D).	('ROCK2', 'Gene', '9475', (35, 40))	('ZEB1/2', 'Gene', '6935;9839', (45, 51))	('lowest', 'NegReg', (68, 74))	('ROCK2', 'Gene', (35, 40))	('silencing', 'Var', (17, 26))	('ZEB1/2', 'Gene', (45, 51))
165903	24169343	Collectively, the results showed that the effect of miR-200b/c on the invasion capacities of cholangiocarcinoma cells is mediated by both the Zeb1/2-E-cadherin axis and also the ROCK2 pathway, whereas SUZ12 is not associated with the migration and invasion capacities of cholangiocarcinoma cells.	('cholangiocarcinoma', 'Disease', (271, 289))	('invasion capacities', 'CPA', (70, 89))	('E-cadherin', 'Gene', '999', (149, 159))	('ROCK2', 'Gene', (178, 183))	('cholangiocarcinoma', 'Disease', (93, 111))	('miR-200b/c', 'Var', (52, 62))	('Zeb1/2', 'Gene', (142, 148))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (271, 289))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('ROCK2', 'Gene', '9475', (178, 183))	('Zeb1/2', 'Gene', '6935', (142, 148))	('SUZ12', 'Gene', '23512', (201, 206))	('SUZ12', 'Gene', (201, 206))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (271, 289))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('E-cadherin', 'Gene', (149, 159))	('mediated', 'Reg', (121, 129))
165904	24169343	Furthermore, we transfected TFK-1 cells with miR-200b/c mimics/antagomir and detected selected downstream genes of the ROCK2 pathway.	('ROCK2', 'Gene', (119, 124))	('ROCK2', 'Gene', '9475', (119, 124))	('miR-200b/c', 'Var', (45, 55))
165905	24169343	As shown in Figures 5C and 6G, the overexpression of miR-200b/c decreased the protein expression level of ROCK2 and then increased the expression level of LIMK2.	('ROCK2', 'Gene', (106, 111))	('LIMK2', 'Gene', (155, 160))	('increased', 'PosReg', (121, 130))	('expression level', 'MPA', (135, 151))	('miR-200b/c', 'Var', (53, 63))	('ROCK2', 'Gene', '9475', (106, 111))	('overexpression', 'PosReg', (35, 49))	('protein expression level', 'MPA', (78, 102))	('LIMK2', 'Gene', '3985', (155, 160))	('decreased', 'NegReg', (64, 73))
165916	24169343	Here, we investigated the dysregulation of miR-200b/c as a possible cause of the invasion and metastasis capacities and tumorigenic properties of cholangiocarcinoma, and we clarify a novel downstream mechanism.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (146, 164))	('dysregulation', 'Var', (26, 39))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (146, 164))	('cause', 'Reg', (68, 73))	('miR-200b/c', 'Gene', (43, 53))	('tumorigenic properties', 'CPA', (120, 142))	('cholangiocarcinoma', 'Disease', (146, 164))
165921	24169343	Thus, in our study, we demonstrated that miR-200b/c is downregulated in cholangiocarcinoma and that the knockdown of miR-200b/c promotes the invasion and metastasis capacities of cholangiocarcinoma cells.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (179, 197))	('cholangiocarcinoma', 'Disease', (72, 90))	('miR-200b/c', 'Var', (117, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (179, 197))	('promotes', 'PosReg', (128, 136))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 90))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))	('cholangiocarcinoma', 'Disease', (179, 197))	('knockdown', 'Var', (104, 113))
165922	24169343	Similarly, we demonstrated that inhibiting the expression of ROCK2 reduces the invasion of cholangiocarcinoma cells (although the inhibition of SUZ12 had no effect).	('SUZ12', 'Gene', '23512', (144, 149))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('ROCK2', 'Gene', (61, 66))	('SUZ12', 'Gene', (144, 149))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('invasion of', 'CPA', (79, 90))	('ROCK2', 'Gene', '9475', (61, 66))	('inhibiting', 'Var', (32, 42))	('reduces', 'NegReg', (67, 74))	('cholangiocarcinoma', 'Disease', (91, 109))
165923	24169343	Both the overexpression of miR-200b/c and inhibition of ROCK2 can reduce the invasion of cholangiocarcinoma cells, yet ROCK2-knockdown cholangiocarcinoma cells may retain a stronger invasion capacity.	('stronger', 'PosReg', (173, 181))	('cholangiocarcinoma', 'Disease', (89, 107))	('overexpression', 'PosReg', (9, 23))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (135, 153))	('invasion capacity', 'CPA', (182, 199))	('ROCK2', 'Gene', (119, 124))	('cholangiocarcinoma', 'Disease', (135, 153))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (89, 107))	('ROCK2', 'Gene', '9475', (56, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (89, 107))	('miR-200b/c', 'Var', (27, 37))	('ROCK2', 'Gene', (56, 61))	('ROCK2', 'Gene', '9475', (119, 124))	('reduce', 'NegReg', (66, 72))	('inhibition', 'NegReg', (42, 52))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (135, 153))	('invasion of', 'CPA', (77, 88))
165926	24169343	Therefore, both ZEB1/2 and ROCK2 are crucial regulatory proteins of the invasion capacity of cholangiocarcinoma cells and are silenced by miR-200b/c.	('cholangiocarcinoma', 'Disease', (93, 111))	('ZEB1/2', 'Gene', (16, 22))	('ROCK2', 'Gene', (27, 32))	('invasion capacity', 'CPA', (72, 89))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('miR-200b/c', 'Var', (138, 148))	('silenced', 'NegReg', (126, 134))	('ROCK2', 'Gene', '9475', (27, 32))	('ZEB1/2', 'Gene', '6935;9839', (16, 22))
165928	24169343	Indeed, our experiments examining sphere formation, drug resistance, and tumour-initiating capacity addressed CSC-like properties, suggesting a possible link between miR-200b/c and cholangiocarcinoma stem-like cells.	('link', 'Interaction', (153, 157))	('tumour', 'Disease', (73, 79))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (181, 199))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (181, 199))	('drug resistance', 'Phenotype', 'HP:0020174', (52, 67))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('cholangiocarcinoma', 'Disease', (181, 199))	('miR-200b/c', 'Var', (166, 176))
165936	24169343	Our results establish that miR-200b/c influences the drug resistance, tumour-initiating capacity, sphere formation, and CD133 expression level, a potential CSC marker, of cholangiocarcinoma cells.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (171, 189))	('influences', 'Reg', (38, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (171, 189))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('expression level', 'MPA', (126, 142))	('miR-200b/c', 'Var', (27, 37))	('sphere formation', 'CPA', (98, 114))	('drug resistance', 'CPA', (53, 68))	('drug resistance', 'Phenotype', 'HP:0020174', (53, 68))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('CD133', 'Gene', (120, 125))	('CD133', 'Gene', '8842', (120, 125))	('tumour', 'Disease', (70, 76))	('cholangiocarcinoma', 'Disease', (171, 189))
165937	24169343	SUZ12 has been reported to be a direct target of miR-200b in breast CSCs, and the direct targeting of SUZ12 by miR-200c was demonstrated in our study.	('miR-200c', 'Gene', (111, 119))	('SUZ12', 'Gene', (102, 107))	('miR-200c', 'Gene', '406985', (111, 119))	('SUZ12', 'Gene', (0, 5))	('breast CSCs', 'Disease', (61, 72))	('miR-200b', 'Var', (49, 57))	('SUZ12', 'Gene', '23512', (102, 107))	('SUZ12', 'Gene', '23512', (0, 5))
165938	24169343	The direct knockdown of SUZ12 by shRNA achieved a similar suppressive effect on the sphere formation and tumour-initiating capacities of cholangiocarcinoma as that of miR-200b/c.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('cholangiocarcinoma', 'Disease', (137, 155))	('SUZ12', 'Gene', (24, 29))	('tumour', 'Disease', (105, 111))	('sphere formation', 'CPA', (84, 100))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (137, 155))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (137, 155))	('suppressive', 'NegReg', (58, 69))	('shRNA', 'Gene', (33, 38))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('knockdown', 'Var', (11, 20))	('SUZ12', 'Gene', '23512', (24, 29))
165939	24169343	This result confirms that SUZ12 is important in tumourigenesis and that related genes may be directly regulated by miR-200b/c.	('SUZ12', 'Gene', (26, 31))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('regulated', 'Reg', (102, 111))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('SUZ12', 'Gene', '23512', (26, 31))	('tumour', 'Disease', (48, 54))	('miR-200b/c', 'Var', (115, 125))
165941	24169343	Interestingly, the expression of miR-200b/c was decreased during low-differentiation cell enrichment and increased upon differentiation, indicating that there may be negative feedback between miR-200b/c and cholangiocarcinoma stem-like cells.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (207, 225))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (207, 225))	('expression', 'MPA', (19, 29))	('low-differentiation cell enrichment', 'CPA', (65, 100))	('miR-200b/c', 'Gene', (33, 43))	('miR-200b/c', 'Var', (192, 202))	('cholangiocarcinoma', 'Disease', (207, 225))	('increased', 'PosReg', (105, 114))
165942	24169343	In conclusion, our findings demonstrate that miR-200b/c inhibits the invasion and metastasis capacities, and tumorigenic capacity (or the so-called CSC-like properties), including drug resistance, tumour-initiating capacity, sphere formation, and CD133 expression level, of cholangiocarcinoma cells.	('tumour', 'Disease', 'MESH:D009369', (197, 203))	('tumorigenic capacity', 'CPA', (109, 129))	('CD133', 'Gene', '8842', (247, 252))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (274, 292))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (274, 292))	('sphere formation', 'CPA', (225, 241))	('inhibits', 'NegReg', (56, 64))	('tumour', 'Disease', (197, 203))	('miR-200b/c', 'Var', (45, 55))	('drug resistance', 'CPA', (180, 195))	('drug resistance', 'Phenotype', 'HP:0020174', (180, 195))	('CD133', 'Gene', (247, 252))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))	('cholangiocarcinoma', 'Disease', (274, 292))
165943	24169343	Such a suppression of these properties can be imitated by directly repressing ROCK2 and SUZ12, two direct targets of miR-200b/c.	('ROCK2', 'Gene', (78, 83))	('ROCK2', 'Gene', '9475', (78, 83))	('miR-200b/c', 'Var', (117, 127))	('SUZ12', 'Gene', '23512', (88, 93))	('SUZ12', 'Gene', (88, 93))
165953	20108122	Potential predictors of decreased survival on univariate analysis included site of origin, preoperative jaundice, microscopic positive margin, nodal metastasis, lymphovascular invasion, neural invasion, and poor differentiation.	('lymphovascular', 'Disease', (161, 175))	('decreased', 'NegReg', (24, 33))	('poor differentiation', 'CPA', (207, 227))	('microscopic', 'Var', (114, 125))	('jaundice', 'Disease', 'MESH:D007565', (104, 112))	('neural invasion', 'CPA', (186, 201))	('nodal metastasis', 'CPA', (143, 159))	('preoperative', 'Disease', (91, 103))	('preoperative jaundice', 'Phenotype', 'HP:0006579', (91, 112))	('jaundice', 'Disease', (104, 112))	('jaundice', 'Phenotype', 'HP:0000952', (104, 112))
166019	20108122	However, positive margin was a predictor of poor survival in ampullary cancers.	('ampullary cancers', 'Disease', 'MESH:D009369', (61, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('ampullary cancers', 'Disease', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('positive margin', 'Var', (9, 24))
166024	20108122	Patients who underwent R1 resection had median overall survival of 21.5 months, compared with 27.8 months in patients who underwent R0 resection (P = 0.027).	('R1 resection', 'Var', (23, 35))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (47, 63))	('patients', 'Species', '9606', (109, 117))
166039	33021006	The identification of FGFR fusions and other alterations in a wide range of solid tumors, including cholangiocarcinoma and bladder cancer, has resulted in the development of several selective FGFR inhibitors for use in these indications, for example, infigratinib, erdafitinib, derazantinib, pemigatinib, and futibatinib.	('infigratinib', 'Chemical', 'MESH:C568950', (251, 263))	('alterations', 'Var', (45, 56))	('FGFR', 'Gene', (22, 26))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('futibatinib', 'Chemical', '-', (309, 320))	('FGFR', 'Gene', (192, 196))	('cholangiocarcinoma and bladder cancer', 'Disease', 'MESH:D001749', (100, 137))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('bladder cancer', 'Phenotype', 'HP:0009725', (123, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('men', 'Species', '9606', (166, 169))	('erdafitinib', 'Chemical', 'MESH:C000604580', (265, 276))	('pemigatinib', 'Chemical', '-', (292, 303))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('fusions', 'Var', (27, 34))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))	('derazantinib', 'Chemical', 'MESH:C000621805', (278, 290))
166043	33021006	Identification of fibroblast growth factor receptor (FGFR) aberrations in cholangiocarcinoma and bladder cancer led to development of selective FGFR inhibitors for these indications, based on clinical benefit and safety profiles.	('men', 'Species', '9606', (126, 129))	('FGFR', 'Gene', (53, 57))	('aberrations', 'Var', (59, 70))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (74, 92))	('FGFR', 'Gene', (144, 148))	('inhibitors', 'NegReg', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))	('cholangiocarcinoma and bladder cancer', 'Disease', 'MESH:D001749', (74, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
166044	33021006	This work reviewed skin AEs reported with FGFR inhibitors and provides management guidelines for physicians, aiming to increase awareness of skin events and provide effective treatment strategies.	('skin AEs', 'Disease', 'MESH:D012871', (19, 27))	('inhibitors', 'Var', (47, 57))	('men', 'Species', '9606', (77, 80))	('FGFR', 'Gene', (42, 46))	('skin AEs', 'Disease', (19, 27))	('men', 'Species', '9606', (180, 183))
166046	33021006	This review provides oncologists with an understanding of dermatologic adverse events related to the use of FGFR inhibitors and proposes guidelines for treatment.	('inhibitors', 'Var', (113, 123))	('FGFR', 'Gene', (108, 112))	('men', 'Species', '9606', (157, 160))
166049	33021006	FGFR fusions and other alterations have been reported in a wide range of solid tumors, including cholangiocarcinoma [4], bladder cancer [5], lung cancer [6], and glioblastoma [7].	('bladder cancer', 'Disease', (121, 135))	('FGFR', 'Gene', (0, 4))	('bladder cancer', 'Phenotype', 'HP:0009725', (121, 135))	('lung cancer', 'Disease', (141, 152))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('glioblastoma', 'Disease', 'MESH:D005909', (162, 174))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('fusions', 'Var', (5, 12))	('tumors', 'Disease', (79, 85))	('glioblastoma', 'Disease', (162, 174))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))	('glioblastoma', 'Phenotype', 'HP:0012174', (162, 174))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cholangiocarcinoma', 'Disease', (97, 115))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (97, 115))	('reported', 'Reg', (45, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('alterations', 'Var', (23, 34))	('bladder cancer', 'Disease', 'MESH:D001749', (121, 135))
166050	33021006	Identification of targetable genomic alterations has resulted in the development of several FGF/FGFR-directed therapies, primarily small-molecule tyrosine kinase inhibitors (TKIs) or multikinase inhibitors, with differing profiles (Table 1).	('FGF/FGFR-directed', 'Gene', (92, 109))	('alterations', 'Var', (37, 48))	('men', 'Species', '9606', (76, 79))
166052	33021006	As FGFs act with other signaling molecules to orchestrate processes such as tissue regeneration and healing, inhibition of FGFR signaling has the potential to lead to on-target adverse events such as hyperphosphatemia, which is believed to result from inhibition of FGFR signaling in the proximal renal tubule, as well as others associated with off-target effects, including alopecia, dry mouth/xerostomia, nail changes, and other dermatologic events [8, 9].	('nail changes', 'Disease', (407, 419))	('FGFR', 'Gene', (123, 127))	('dry mouth/xerostomia', 'Disease', (385, 405))	('xerostomia', 'Phenotype', 'HP:0000217', (395, 405))	('inhibition', 'Var', (109, 119))	('inhibition', 'NegReg', (252, 262))	('hyperphosphatemia', 'Phenotype', 'HP:0002905', (200, 217))	('hyperphosphatemia', 'Disease', 'MESH:D054559', (200, 217))	('alopecia', 'Disease', (375, 383))	('dry mouth/xerostomia', 'Disease', 'MESH:D014987', (385, 405))	('alopecia', 'Phenotype', 'HP:0001596', (375, 383))	('dry mouth', 'Phenotype', 'HP:0000217', (385, 394))	('lead to', 'Reg', (159, 166))	('hyperphosphatemia', 'Disease', (200, 217))
166053	33021006	Depending on the breadth of their inhibitory targets, adverse events associated with anti-FGFR TKIs can also include those related to vascular endothelial growth factor receptor (VEGFR) inhibition (e.g., hypertension, cardiovascular events, and proteinuria), as seen with earlier-generation multikinase inhibitors, and others commonly reported with TKIs (e.g., gastrointestinal disorders, such as vomiting and diarrhea, skin reactions, and ocular effects, such as dry eye and retinal pigment epithelium detachment).	('hypertension', 'Disease', (204, 216))	('vomiting', 'Disease', 'MESH:D014839', (397, 405))	('hypertension', 'Disease', 'MESH:D006973', (204, 216))	('dry eye', 'Disease', (464, 471))	('diarrhea', 'Disease', (410, 418))	('vomiting', 'Phenotype', 'HP:0002013', (397, 405))	('gastrointestinal disorders', 'Phenotype', 'HP:0011024', (361, 387))	('vomiting', 'Disease', (397, 405))	('VEGFR', 'Gene', '3791', (179, 184))	('hypertension', 'Phenotype', 'HP:0000822', (204, 216))	('VEGFR', 'Gene', (179, 184))	('gastrointestinal disorders', 'Disease', 'MESH:D005767', (361, 387))	('cardiovascular events', 'Disease', (218, 239))	('diarrhea', 'Disease', 'MESH:D003967', (410, 418))	('inhibition', 'NegReg', (186, 196))	('dry eye', 'Disease', 'MESH:D015352', (464, 471))	('cardiovascular events', 'Phenotype', 'HP:0001626', (218, 239))	('epithelium detachment', 'Phenotype', 'HP:0032156', (492, 513))	('proteinuria', 'Disease', (245, 256))	('TKIs', 'Gene', (95, 99))	('ocular effects', 'Disease', (440, 454))	('skin reactions', 'Phenotype', 'HP:0011123', (420, 434))	('proteinuria', 'Disease', 'MESH:D011507', (245, 256))	('dry eye', 'Phenotype', 'HP:0001097', (464, 471))	('skin reaction', 'Phenotype', 'HP:0011123', (420, 433))	('vascular endothelial growth factor receptor', 'Gene', '3791', (134, 177))	('vascular endothelial growth factor receptor', 'Gene', (134, 177))	('skin reactions', 'Disease', (420, 434))	('proteinuria', 'Phenotype', 'HP:0000093', (245, 256))	('gastrointestinal disorders', 'Disease', (361, 387))	('diarrhea', 'Phenotype', 'HP:0002014', (410, 418))	('retinal pigment epithelium detachment', 'Disease', (476, 513))	('anti-FGFR', 'Var', (85, 94))	('retinal pigment epithelium detachment', 'Disease', 'MESH:D012163', (476, 513))
166054	33021006	The aim of this review is to provide oncologists with an understanding of the dermatologic events associated with FGFR inhibitors currently in clinical development or approved by regulatory agencies for the treatment of cholangiocarcinoma and urothelial cancers.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('men', 'Species', '9606', (159, 162))	('inhibitors', 'Var', (119, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('cholangiocarcinoma and urothelial cancers', 'Disease', 'MESH:D014523', (220, 261))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (220, 238))	('FGFR', 'Gene', (114, 118))	('men', 'Species', '9606', (212, 215))
166064	33021006	Alterations in genes encoding FGFRs are common in patients with cholangiocarcinoma, the most common being FGFR2 fusions, FGFR19 amplifications, and FGFR2 mutations [20].	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (64, 82))	('patients', 'Species', '9606', (50, 58))	('FGFR2', 'Gene', (148, 153))	('FGFR2', 'Gene', '2263', (148, 153))	('Alterations', 'Var', (0, 11))	('FGFR2', 'Gene', '2263', (106, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('fusions', 'Var', (112, 119))	('common', 'Reg', (40, 46))	('FGFR1', 'Gene', '2260', (121, 126))	('FGFR1', 'Gene', (121, 126))	('mutations', 'Var', (154, 163))	('amplifications', 'Var', (128, 142))	('FGFR2', 'Gene', (106, 111))	('cholangiocarcinoma', 'Disease', (64, 82))	('FGFRs', 'Gene', (30, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
166065	33021006	FGFR2 fusions are present in 13%-25% of patients with cholangiocarcinoma [20, 21] and therefore represent a promising target for therapy in enriched patient populations.	('patient', 'Species', '9606', (40, 47))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (54, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('patients', 'Species', '9606', (40, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('patient', 'Species', '9606', (149, 156))	('cholangiocarcinoma', 'Disease', (54, 72))	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (6, 13))	('FGFR2', 'Gene', '2263', (0, 5))
166067	33021006	Pemigatinib was approved for use in patients with FGFR2 fusion or rearrangement in April 2020, based on the results of the phase II FIGHT-202 study [22].	('Pemigatinib', 'Chemical', '-', (0, 11))	('patients', 'Species', '9606', (36, 44))	('FGFR2', 'Gene', (50, 55))	('rearrangement', 'Var', (66, 79))	('men', 'Species', '9606', (75, 78))	('fusion', 'Var', (56, 62))	('FGFR2', 'Gene', '2263', (50, 55))
166077	33021006	Several possible mechanisms have been proposed, including inhibition of FGFR in keratinocytes, inducing dysregulation of hair-follicle homeostasis and epidermal proliferation and/or differentiation with downregulation of tight junction gene expression, as demonstrated in FGFR-deficient mice [29] and by inhibiting hormonal (nonpathological) FGF signaling by FGF19, FGF21, and FGF23 [30].	('epidermal proliferation', 'CPA', (151, 174))	('inhibiting', 'NegReg', (304, 314))	('FGF21', 'Gene', '56636', (366, 371))	('inhibition', 'Var', (58, 68))	('FGF19', 'Gene', '14170', (359, 364))	('expression', 'MPA', (241, 251))	('FGF23', 'Gene', '64654', (377, 382))	('hormonal', 'MPA', (315, 323))	('downregulation', 'NegReg', (203, 217))	('inducing', 'PosReg', (95, 103))	('FGFR', 'Gene', (72, 76))	('FGF19', 'Gene', (359, 364))	('hair-follicle', 'CPA', (121, 134))	('FGF23', 'Gene', (377, 382))	('tight junction gene', 'Gene', (221, 240))	('FGF21', 'Gene', (366, 371))	('mice', 'Species', '10090', (287, 291))	('dysregulation', 'MPA', (104, 117))
166089	33021006	Other body hair can also be adversely affected in patients undergoing treatment with FGFR inhibitors (e.g., eyelash trichomegaly has been reported with infigratinib) [33].	('eyelash trichomegaly', 'Disease', (108, 128))	('FGFR', 'Gene', (85, 89))	('patients', 'Species', '9606', (50, 58))	('infigratinib', 'Chemical', 'MESH:C568950', (152, 164))	('men', 'Species', '9606', (75, 78))	('eyelash trichomegaly', 'Phenotype', 'HP:0000527', (108, 128))	('eyelash trichomegaly', 'Disease', 'MESH:C536554', (108, 128))	('inhibitors', 'Var', (90, 100))
166096	33021006	Conversely, with FGFR inhibitors, the ventral aspect of the distal digits and lateral aspects of the palms and soles are affected by erythema and pain, accompanied by onycholysis and secondary paronychia, reminiscent of changes observed with microtubule inhibitors (i.e., taxanes).	('pain', 'Phenotype', 'HP:0012531', (146, 150))	('FGFR', 'Gene', (17, 21))	('taxanes', 'Chemical', 'MESH:D043823', (272, 279))	('inhibitors', 'Var', (22, 32))	('pain', 'Disease', 'MESH:D010146', (146, 150))	('pain', 'Disease', (146, 150))	('erythema', 'Phenotype', 'HP:0010783', (133, 141))	('erythema', 'Disease', 'MESH:D004890', (133, 141))	('ventral aspect of the distal digits', 'CPA', (38, 73))	('onycholysis', 'Phenotype', 'HP:0001806', (167, 178))	('affected', 'Reg', (121, 129))	('secondary paronychia', 'Disease', (183, 203))	('erythema', 'Disease', (133, 141))	('paronychia', 'Phenotype', 'HP:0001818', (193, 203))	('onycholysis', 'Disease', (167, 178))
166097	33021006	PPES often presents as a mild to moderate cutaneous edema, erythema, and hyperkeratosis with FGFR inhibitors; this evolves into painful digits that can impact patients' quality of life [46, 47] and can ultimately limit daily functioning and lead to a reduction of the duration and intensity of treatment or its discontinuation [48].	('quality of life', 'CPA', (169, 184))	('painful', 'Disease', 'MESH:D010146', (128, 135))	('reduction', 'NegReg', (251, 260))	('limit daily functioning', 'Phenotype', 'HP:0031058', (213, 236))	('edema', 'Phenotype', 'HP:0000969', (52, 57))	('cutaneous edema', 'Disease', 'MESH:D004487', (42, 57))	('erythema', 'Disease', (59, 67))	('pain', 'Phenotype', 'HP:0012531', (128, 132))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (73, 87))	('erythema', 'Phenotype', 'HP:0010783', (59, 67))	('erythema', 'Disease', 'MESH:D004890', (59, 67))	('painful', 'Disease', (128, 135))	('FGFR', 'Gene', (93, 97))	('daily functioning', 'CPA', (219, 236))	('hyperkeratosis', 'Disease', (73, 87))	('impact', 'Reg', (152, 158))	('PPES', 'Disease', (0, 4))	('hyperkeratosis', 'Disease', 'MESH:D017488', (73, 87))	('patients', 'Species', '9606', (159, 167))	('limit', 'NegReg', (213, 218))	('men', 'Species', '9606', (299, 302))	('inhibitors', 'Var', (98, 108))	('cutaneous edema', 'Disease', (42, 57))
166098	33021006	Stomatitis is one of the most commonly observed adverse events in patients treated with FGFR inhibitors, with lesions appearing rapidly after treatment initiation.	('Stomatitis', 'Disease', (0, 10))	('Stomatitis', 'Phenotype', 'HP:0010280', (0, 10))	('Stomatitis', 'Disease', 'MESH:D013280', (0, 10))	('inhibitors', 'Var', (93, 103))	('men', 'Species', '9606', (147, 150))	('patients', 'Species', '9606', (66, 74))	('FGFR', 'Gene', (88, 92))
166101	33021006	Among patients with urothelial carcinoma, the incidence of stomatitis ranged from 12% with rogaratinib [49] to 58% with erdafitinib [28].	('erdafitinib', 'Chemical', 'MESH:C000604580', (120, 131))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (20, 40))	('stomatitis', 'Disease', 'MESH:D013280', (59, 69))	('stomatitis', 'Disease', (59, 69))	('patients', 'Species', '9606', (6, 14))	('stomatitis', 'Phenotype', 'HP:0010280', (59, 69))	('urothelial carcinoma', 'Disease', (20, 40))	('rogaratinib', 'Var', (91, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
166106	33021006	Although severe or life-threatening complications are uncommon, low-grade xerosis can result in dose delays or discontinuations, potentially impacting the overall efficacy of treatment.	('impacting', 'NegReg', (141, 150))	('xerosis', 'Disease', (74, 81))	('xerosis', 'Phenotype', 'HP:0000958', (74, 81))	('xerosis', 'Disease', 'None', (74, 81))	('men', 'Species', '9606', (180, 183))	('discontinuations', 'MPA', (111, 127))	('low-grade', 'Var', (64, 73))	('dose', 'MPA', (96, 100))
166107	33021006	The incidence of dry skin in patients with cholangiocarcinoma treated with the FGFR inhibitors ranged from 10% in derazantinib-treated patients [39] to 35% in erdafitinib-treated patients [42], whereas for those with urothelial cancer, dry skin was reported in 12% of infigratinib-treated patients [40] and 32% of erdafitinib-treated patients [34].	('patients', 'Species', '9606', (135, 143))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (43, 61))	('dry skin', 'Disease', (17, 25))	('dry skin', 'Disease', 'MESH:D012871', (236, 244))	('infigratinib', 'Chemical', 'MESH:C568950', (268, 280))	('erdafitinib', 'Chemical', 'MESH:C000604580', (159, 170))	('FGFR', 'Gene', (79, 83))	('cholangiocarcinoma', 'Disease', (43, 61))	('dry skin', 'Phenotype', 'HP:0000958', (236, 244))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (43, 61))	('patients', 'Species', '9606', (29, 37))	('dry skin', 'Disease', 'MESH:D012871', (17, 25))	('patients', 'Species', '9606', (179, 187))	('urothelial cancer', 'Disease', 'MESH:D014523', (217, 234))	('patients', 'Species', '9606', (289, 297))	('derazantinib', 'Chemical', 'MESH:C000621805', (114, 126))	('inhibitors', 'Var', (84, 94))	('dry skin', 'Phenotype', 'HP:0000958', (17, 25))	('urothelial cancer', 'Disease', (217, 234))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('patients', 'Species', '9606', (334, 342))	('dry skin', 'Disease', (236, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('erdafitinib', 'Chemical', 'MESH:C000604580', (314, 325))
166111	33021006	Dry mouth, generally grade 1 or 2, was common in patients treated with FGFR inhibitors, occurring in 23%-59% of patients with cholangiocarcinoma and 31%-46% of patients with urothelial cancers (Tables 3, 4).	('Dry mouth', 'Disease', (0, 9))	('Dry mouth', 'Disease', 'MESH:D014987', (0, 9))	('patients', 'Species', '9606', (160, 168))	('Dry mouth', 'Phenotype', 'HP:0000217', (0, 9))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (126, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('patients', 'Species', '9606', (112, 120))	('FGFR', 'Gene', (71, 75))	('urothelial cancers', 'Disease', (174, 192))	('urothelial cancers', 'Disease', 'MESH:D014523', (174, 192))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (126, 144))	('inhibitors', 'Var', (76, 86))	('patients', 'Species', '9606', (49, 57))	('cholangiocarcinoma', 'Disease', (126, 144))
166112	33021006	A rare skin/soft tissue reaction that has been observed in patients undergoing treatment with FGFR inhibitors is calcinosis cutis, a condition in which calcium salts are deposited in the skin and subcutaneous tissues.	('calcinosis cutis', 'Phenotype', 'HP:0025520', (113, 129))	('calcium', 'Chemical', 'MESH:D002118', (152, 159))	('inhibitors', 'Var', (99, 109))	('calcinosis cutis', 'Disease', 'MESH:D002114', (113, 129))	('men', 'Species', '9606', (84, 87))	('patients', 'Species', '9606', (59, 67))	('calcinosis cutis', 'Disease', (113, 129))	('FGFR', 'Gene', (94, 98))	('calcinosis', 'Phenotype', 'HP:0003761', (113, 123))
166119	33021006	Prevention and early treatment of dermatologic adverse events are key to maximizing adherence to therapy and optimizing outcomes in patients undergoing treatment with FGFR inhibitors; however, data specific to preventive therapies for use with FGFR-targeted therapy are scarce.	('FGFR', 'Gene', (167, 171))	('inhibitors', 'Var', (172, 182))	('men', 'Species', '9606', (26, 29))	('men', 'Species', '9606', (157, 160))	('patients', 'Species', '9606', (132, 140))
166123	33021006	Counseling and education on the potential for nail changes are essential before initiation of treatment with FGFR inhibitors.	('inhibitors', 'Var', (114, 124))	('FGFR', 'Gene', (109, 113))	('men', 'Species', '9606', (99, 102))
166131	33021006	Preventive measures normally considered for patients undergoing traditional chemotherapy regimens, for example, scalp compression, scalp cooling, and medications, are not applicable to patients receiving FGFR inhibitors, and the health care provider's attention should be focused on early identification and management of symptoms.	('patients', 'Species', '9606', (44, 52))	('men', 'Species', '9606', (93, 96))	('inhibitors', 'Var', (209, 219))	('men', 'Species', '9606', (314, 317))	('patients', 'Species', '9606', (185, 193))	('FGFR', 'Gene', (204, 208))
166268	30310318	Patients with narrow-margin hepatectomy were recommended to receive postoperative radiotherapy by the Multidisciplinary Liver Cancer Team in our institute.	('Cancer', 'Phenotype', 'HP:0002664', (126, 132))	('narrow-margin', 'Var', (14, 27))	('Patients', 'Species', '9606', (0, 8))	('Multidisciplinary Liver Cancer', 'Disease', (102, 132))	('Liver Cancer', 'Phenotype', 'HP:0002896', (120, 132))	('Multidisciplinary Liver Cancer', 'Disease', 'MESH:D006528', (102, 132))
166288	30310318	Patients in Group A tend to have received more nonanatomical resection compared to Group B (61.5%vs 34.8% P=0.062), with 15% more null-margin resections (P=0.303).	('Patients', 'Species', '9606', (0, 8))	('null-margin', 'Var', (130, 141))	('nonanatomical resection', 'CPA', (47, 70))
166308	30310318	Shimada et al found that, while not statistically significant, patients with narrow-margin resection tended to experience more intrahepatic recurrence.	('intrahepatic recurrence', 'MPA', (127, 150))	('narrow-margin', 'Var', (77, 90))	('patients', 'Species', '9606', (63, 71))
166534	33798493	The study met its primary endpoint and confirmed that patients who received FOLFOX chemotherapy had a longer overall survival, with a clinically meaningful increase in 6-month and 12-month overall survival rates, than those who received active symptom control alone.	('FOLFOX', 'Var', (76, 82))	('longer', 'PosReg', (102, 108))	('patients', 'Species', '9606', (54, 62))	('FOLFOX', 'Chemical', '-', (76, 82))	('increase', 'PosReg', (156, 164))	('overall survival', 'MPA', (189, 205))
166550	33798493	Novel molecular targets such as fibroblast growth factor receptor-2 (FGFR2) fusions and isocitrate dehydrogenase-1 (IDH1) mutations have been identified as promising within phase 2 and phase 3 trials, respectively, showing benefit in the second-line setting for a selected population of patients harbouring such aberrations (mainly those with intrahepatic cholangiocarcinoma, with approximately 15% prevalence of each).	('intrahepatic cholangiocarcinoma', 'Disease', (343, 374))	('carcinoma', 'Phenotype', 'HP:0030731', (365, 374))	('FGFR2', 'Gene', (69, 74))	('FGFR2', 'Gene', '2263', (69, 74))	('fusions', 'Var', (76, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (356, 374))	('patients', 'Species', '9606', (287, 295))	('IDH1', 'Gene', (116, 120))	('fibroblast growth factor receptor-2', 'Gene', '2263', (32, 67))	('mutations', 'Var', (122, 131))	('isocitrate dehydrogenase-1', 'Gene', '3417', (88, 114))	('IDH1', 'Gene', '3417', (116, 120))	('isocitrate dehydrogenase-1', 'Gene', (88, 114))	('fibroblast growth factor receptor-2', 'Gene', (32, 67))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (343, 374))
166614	33798493	The other factors included in the multivariable analyses for overall survival were platinum sensitivity (adjusted HR 0 71, 0 49-1 00; p=0 050), high albumin at baseline (0 54, 0 37-0 78; p=0 0010), and metastatic disease (1 33, 0 85-2 09; p=0 21).	('platinum sensitivity', 'CPA', (83, 103))	('high albumin', 'Phenotype', 'HP:0012117', (144, 156))	('high', 'Var', (144, 148))	('metastatic disease', 'CPA', (202, 220))	('albumin', 'Gene', (149, 156))	('albumin', 'Gene', '213', (149, 156))	('platinum', 'Chemical', 'MESH:D010984', (83, 91))
166642	33798493	Nevertheless, this study supports the position that even when anticancer strategies are not being pursued, ASC (a proactive supportive care) rather than reactive management of symptoms is of benefit and might improve survival.	('improve', 'PosReg', (209, 216))	('ASC', 'Chemical', '-', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('survival', 'CPA', (217, 225))	('benefit', 'PosReg', (191, 198))	('ASC', 'Var', (107, 110))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
166649	33798493	Patients harbouring such alterations would be suitable for precision medicine strategies and their outcome might be difficult to compare with other advanced biliary tract cancers without such alterations.	('alterations', 'Var', (25, 36))	('biliary tract cancers', 'Disease', 'MESH:D001661', (157, 178))	('biliary tract cancers', 'Disease', (157, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (157, 177))
166698	31385048	Subsequently published studies have emphasised the increased sensitivity with limited loss of specificity if hypointensity on the HBP is included for diagnosing HCC.	('hypointensity', 'Var', (109, 122))	('HCC', 'Gene', '619501', (161, 164))	('HCC', 'Gene', (161, 164))
166716	31385048	[74/89 (83.2%) agreement] Using multiparametric MRI (including T2-weighted [T2W] and diffusion-weighted imaging [DWI]), high specificity (> 90%) for the diagnosis of HCC can be achieved when hypointensity in the HBP is associated with solid arterial enhancement, regardless of venous washout, in patients with liver cirrhosis.	('liver cirrhosis', 'Phenotype', 'HP:0001394', (310, 325))	('solid arterial enhancement', 'Disease', (235, 261))	('HCC', 'Gene', '619501', (166, 169))	('hypointensity', 'Var', (191, 204))	('associated', 'Reg', (219, 229))	('liver cirrhosis', 'Disease', 'MESH:D008103', (310, 325))	('cirrhosis', 'Phenotype', 'HP:0001394', (316, 325))	('HCC', 'Gene', (166, 169))	('patients', 'Species', '9606', (296, 304))	('liver cirrhosis', 'Disease', (310, 325))
166719	31385048	[80/88 (90.9%) agreement] Macrovascular invasion is a characteristic feature of advanced HCC, indicating high risk for metastasis, recurrence, liver functional impairment, and poor prognosis (Barcelona Clinic Liver Cancer [BCLC] stage C).	('HCC', 'Gene', (89, 92))	('Cancer', 'Phenotype', 'HP:0002664', (215, 221))	('Barcelona Clinic Liver Cancer', 'Disease', 'MESH:D006528', (192, 221))	('Barcelona Clinic Liver Cancer', 'Disease', (192, 221))	('HCC', 'Gene', '619501', (89, 92))	('Liver Cancer', 'Phenotype', 'HP:0002896', (209, 221))	('liver functional impairment', 'Disease', 'MESH:D017093', (143, 170))	('liver functional impairment', 'Disease', (143, 170))	('Macrovascular', 'Var', (26, 39))
166725	31385048	[39/43 (90.7%) agreement] The key imaging findings of HCC (1-2 cm) in LI-RADS v2018 are arterial phase hyperenhancement (APHE, washin), PVP or delayed phase washout, capsular appearance, and threshold growth.	('v2018', 'Var', (78, 83))	('LI-RADS', 'Chemical', '-', (70, 77))	('threshold growth', 'CPA', (191, 207))	('arterial', 'MPA', (88, 96))	('HCC (1-2', 'Gene', '6358;6359', (54, 62))	('PVP', 'MPA', (136, 139))
166762	31385048	Another meta-analysis concluded that MRI with an ECCM or gadoxetic acid has a significantly higher sensitivity (82% vs. 66%) and lower negative likelihood ratio (0.20 vs. 0.37) versus CT, with no differences between the techniques in specificities and positive likelihood ratios.	('higher', 'PosReg', (92, 98))	('gadoxetic acid', 'Chemical', 'MESH:C073590', (57, 71))	('sensitivity', 'MPA', (99, 110))	('lower', 'NegReg', (129, 134))	('gadoxetic acid', 'Var', (57, 71))
166776	31385048	Concomitantly, there were cases of image quality being severely degraded by patient respiratory motion during the AP, which were more frequent in the gadoxetic acid than in the gadobenate dimeglumine group, both for all patients (17 vs. 2%, p = 0.0007) and for the cirrhotic subpopulation (19 vs. 3%, p = 0.02).	('gadoxetic acid', 'Var', (150, 164))	('image', 'MPA', (35, 40))	('gadoxetic acid', 'Chemical', 'MESH:C073590', (150, 164))	('patient', 'Species', '9606', (220, 227))	('gadobenate dimeglumine', 'Chemical', 'MESH:C064572', (177, 199))	('patients', 'Species', '9606', (220, 228))	('patient', 'Species', '9606', (76, 83))	('degraded', 'NegReg', (64, 72))
166809	28166242	Regarding the mechanism of action, Ab417 was internalized into the tumor cells and thereby down-regulated membrane L1CAM, and inhibited tumor growth by reducing tumor cell proliferation in vivo.	('Ab417', 'Chemical', '-', (35, 40))	('down-regulated', 'NegReg', (91, 105))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('inhibited', 'NegReg', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (67, 72))	('reducing', 'NegReg', (152, 160))	('membrane L1CAM', 'Protein', (106, 120))	('tumor', 'Disease', (136, 141))	('Ab417', 'Var', (35, 40))
166812	28166242	Combined treatment with Ab417 and gemcitabine or cisplatin exerted enhanced tumor growth inhibition compared to treatment with antibody or drug alone.	('gemcitabine', 'Chemical', 'MESH:C056507', (34, 45))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('Ab417', 'Var', (24, 29))	('Ab417', 'Chemical', '-', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('enhanced', 'PosReg', (67, 75))
166813	28166242	The results suggest that Ab417 in combination with chemotherapy may have potential as a new therapeutic regimen for cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (116, 134))	('Ab417', 'Chemical', '-', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))	('Ab417', 'Var', (25, 30))	('cholangiocarcinoma', 'Disease', (116, 134))
166831	28166242	Also, L1CAM acts as an independent poor prognostic factor predicting patient survival in ECC and GBC.	('GBC', 'Disease', (97, 100))	('ECC', 'Disease', (89, 92))	('L1CAM', 'Var', (6, 11))	('patient', 'Species', '9606', (69, 76))
166835	28166242	We previously developed a fully human anti-L1CAM mAb (Ab417, IgG1) that cross-reacts with mouse L1CAM, and validated that Ab417 inhibits tumor growth in a Choi-CK xenograft nude mouse model.	('mouse', 'Species', '10090', (178, 183))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('inhibits', 'NegReg', (128, 136))	('IgG1', 'Gene', '16017', (61, 65))	('mouse', 'Species', '10090', (90, 95))	('Ab417', 'Var', (122, 127))	('Ab417', 'Chemical', '-', (54, 59))	('Ab417', 'Chemical', '-', (122, 127))	('human', 'Species', '9606', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('IgG1', 'Gene', (61, 65))
166846	28166242	The animal studies to evaluate anti-tumor efficacy of Ab417, drug (gemcitabine or cisplatin), or combination of Ab417 and drug (gemcitabine or cisplatin) were approved prior to beginning studies from the committee (B13698, B13933, or B13934, respectively).	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('B13934', 'Var', (234, 240))	('B13933', 'Var', (223, 229))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('gemcitabine', 'Chemical', 'MESH:C056507', (128, 139))	('Ab417', 'Chemical', '-', (112, 117))	('Ab417', 'Chemical', '-', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('gemcitabine', 'Chemical', 'MESH:C056507', (67, 78))	('tumor', 'Disease', (36, 41))
166897	28166242	At 22 days post-injection, Ab417 resulted in 68.6% tumor growth inhibition compared to recombinant human Fc (hFc) as an isotype control, based on mean tumor weight, while it did not affect body weight or induce other adverse effects in the mice.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mice', 'Species', '10090', (240, 244))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('Ab417', 'Var', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('Ab417', 'Chemical', '-', (27, 32))	('human', 'Species', '9606', (99, 104))
166901	28166242	Thus, the tumor growth inhibition of an Ab417-treated group was 35.6% compared to hFc, based on mean tumor weight.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('Ab417-treated', 'Var', (40, 53))	('tumor', 'Disease', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('Ab417', 'Chemical', '-', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
166903	28166242	To investigate whether the tumor growth inhibition by Ab417 was the result of inhibition of tumor cell proliferation in vivo, Choi-CK cells were injected into nude mice to establish tumors.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('nude mice', 'Species', '10090', (159, 168))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('Ab417', 'Var', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('inhibition', 'NegReg', (78, 88))	('Ab417', 'Chemical', '-', (54, 59))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
166906	28166242	Ab417 treatment resulted in 30% tumor growth inhibition compared to the control, based on mean tumor volume (data not shown), and the Ab417-treated tumors showed a lower Ki-67 index compared to the control tumors, indicating that Ab417 inhibits tumor growth by inhibiting tumor cell proliferation in vivo (Fig 1D and S1 Fig).	('lower', 'NegReg', (164, 169))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (272, 277))	('tumors', 'Disease', (206, 212))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('inhibits', 'NegReg', (236, 244))	('Ki-67', 'Gene', '17345', (170, 175))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('Ab417', 'Var', (230, 235))	('Ab417', 'Chemical', '-', (230, 235))	('tumors', 'Disease', (148, 154))	('tumor', 'Disease', (245, 250))	('Ab417', 'Chemical', '-', (0, 5))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('Ki-67', 'Gene', (170, 175))	('Ab417', 'Chemical', '-', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('inhibiting', 'NegReg', (261, 271))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
166908	28166242	To investigate whether inhibition of tumor cell proliferation by Ab417 was due to decreased membrane L1CAM level, we performed an antibody internalization assay using SCK-L1 cells.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('membrane L1CAM level', 'MPA', (92, 112))	('SCK', 'Gene', (167, 170))	('SCK', 'Gene', '25759', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('Ab417', 'Var', (65, 70))	('Ab417', 'Chemical', '-', (65, 70))	('decreased', 'NegReg', (82, 91))
166910	28166242	Therefore, to examine whether membrane L1CAM level is reduced by internalization of Ab417, Choi-CK cells were incubated with the antibody for the indicated times (1, 2, 4, 6 h), and the membrane protein fractions of the treated cells were subjected to western blot analysis using a murine anti-L1CAM mAb (A10-A3) that binds to the Ig1 domain of human L1CAM.	('Ab417', 'Var', (84, 89))	('Ab417', 'Chemical', '-', (84, 89))	('membrane', 'MPA', (30, 38))	('human', 'Species', '9606', (345, 350))	('reduced', 'NegReg', (54, 61))	('murine', 'Species', '10090', (282, 288))
166912	28166242	In addition, immunofluorescence staining of the Choi-CK tumors with a murine mAb specific for the N-terminal region of human L1CAM showed that the Ab417 treated tumors had significantly reduced L1CAM level compared with the hFc treated tumors (Fig 2C and 2D).	('Choi-CK tumors', 'Disease', (48, 62))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (161, 167))	('reduced', 'NegReg', (186, 193))	('L1CAM level', 'MPA', (194, 205))	('tumors', 'Disease', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('murine', 'Species', '10090', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('Choi-CK tumors', 'Disease', 'OMIM:300831', (48, 62))	('Ab417', 'Var', (147, 152))	('tumors', 'Disease', (236, 242))	('Ab417', 'Chemical', '-', (147, 152))	('human', 'Species', '9606', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
166913	28166242	To validate tumor targeting ability of Ab417, we performed biodistribution study of Ab417 in the Choi-CK xenograft model using 64Cu-NOTA-Ab417 and 125I-Ab417, because internalization, metabolism, and retention of radiolabeled mAbs are different based on radioisotope and radiolabeling methods: internalized 125I-labeled antibody is rapidly degraded in lysosomes and I-125 is excreted from the cells, whereas internalized antibody conjugated with radiometals is retained intracellularly, even after trafficking to lysosomes.	('Ab417', 'Chemical', '-', (152, 157))	('64Cu-NOTA-Ab417', 'Chemical', '-', (127, 142))	('125I-labeled', 'Var', (307, 319))	('Ab417', 'Chemical', '-', (39, 44))	('Ab417', 'Chemical', '-', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('125I-Ab417', 'Chemical', '-', (147, 157))	('Ab417', 'Chemical', '-', (137, 142))	('tumor', 'Disease', (12, 17))	('excreted', 'MPA', (375, 383))
166916	28166242	The radiolabeling yield and radiochemical purity of 125I-Ab417 and 64Cu-NOTA-Ab417 were all above 99% (C and D in S2 Fig).	('radiolabeling yield', 'MPA', (4, 23))	('125I-Ab417', 'Chemical', '-', (52, 62))	('64Cu-NOTA-Ab417', 'Chemical', '-', (67, 82))	('125I-Ab417', 'Var', (52, 62))
166919	28166242	As shown in Fig 3A, 64Cu-NOTA-Ab417 was localized in Choi-CK tumors.	('Choi-CK tumors', 'Disease', 'OMIM:300831', (53, 67))	('64Cu-NOTA-Ab417', 'Var', (20, 35))	('64Cu-NOTA-Ab417', 'Chemical', '-', (20, 35))	('localized', 'Reg', (40, 49))	('Choi-CK tumors', 'Disease', (53, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
166921	28166242	Tumor-to-blood ratios of 64Cu-Ab417 increased with time: 0.3 +- 0.1 at 2 h; 1.8 +- 0.1 at 24 h; and 4.9 +- 0.4 at 48 h. Tumor-to-muscle ratios of 64Cu-Ab417 were 7.1 +- 0.3 at 2 h; 6.7 +- 0.9 at 24 h; 13.0 +- 2.2 at 48 h. In contrast, the uptake of 125I-labeled Ab417 was rapidly decreased in the tumor and other mouse tissues, which may be due to that 125I-labeled Ab417 was internalized into cells and rapidly degraded and deiodinated in the lysosome (Fig 3B).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('64Cu', 'Chemical', 'MESH:C000615411', (25, 29))	('degraded', 'NegReg', (412, 420))	('mouse', 'Species', '10090', (313, 318))	('64Cu', 'Chemical', 'MESH:C000615411', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('Ab417', 'Var', (366, 371))	('uptake', 'MPA', (239, 245))	('Ab417', 'Chemical', '-', (366, 371))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('deiodinated', 'MPA', (425, 436))	('Ab417', 'Chemical', '-', (30, 35))	('decreased', 'NegReg', (280, 289))	('tumor', 'Disease', (297, 302))	('Tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Ab417', 'Chemical', '-', (262, 267))	('Ab417', 'Chemical', '-', (151, 156))
166927	28166242	Flow cytometry analysis revealed that the cell cycle was arrested at the G2/M phase after Choi-CK cells were treated with gemcitabine or cisplatin at IC50, while the cell cycle arrest was more increased in the cells treated with cisplatin compared to gemcitabine (B and C in S4 Fig).	('cisplatin', 'Var', (229, 238))	('gemcitabine', 'Chemical', 'MESH:C056507', (122, 133))	('cell cycle', 'CPA', (42, 52))	('G2/M phase', 'CPA', (73, 83))	('gemcitabine', 'Chemical', 'MESH:C056507', (251, 262))	('cell cycle arrest', 'CPA', (166, 183))	('cisplatin', 'Chemical', 'MESH:D002945', (229, 238))	('cisplatin', 'Chemical', 'MESH:D002945', (137, 146))	('increased', 'PosReg', (193, 202))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (166, 183))
166933	28166242	Based on the results of previous experiments, sub-maximal doses of Ab417 and gemcitabine or cisplatin were injected into the Choi-CK xenograft model to examine whether combined treatment with Ab417 and the drug exerts greater tumor growth inhibition compared to antibody or drug alone.	('Ab417', 'Gene', (67, 72))	('Ab417', 'Chemical', '-', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('Ab417', 'Var', (192, 197))	('cisplatin', 'Chemical', 'MESH:D002945', (92, 101))	('Ab417', 'Chemical', '-', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('gemcitabine', 'Chemical', 'MESH:C056507', (77, 88))	('tumor', 'Disease', (226, 231))
166935	28166242	Combined treatment with Ab417 and gemcitabine completely inhibited tumor growth, resulting in 88.8% tumor growth inhibition compared to the control, while Ab417 or gemcitabine treatment resulted in 35.3% or 44.4% tumor growth inhibition, respectively, based on mean tumor weight (Fig 5A and 5B).	('tumor', 'Disease', (213, 218))	('Ab417', 'Chemical', '-', (155, 160))	('gemcitabine', 'Chemical', 'MESH:C056507', (164, 175))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (67, 72))	('gemcitabine', 'Chemical', 'MESH:C056507', (34, 45))	('inhibited', 'NegReg', (57, 66))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('Ab417', 'Var', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', (266, 271))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('Ab417', 'Chemical', '-', (24, 29))
166936	28166242	Combined treatment with Ab417 and cisplatin resulted in 79.2% (p < 0.01) tumor growth inhibition compared to the control, based on mean tumor weight, while treatment with Ab417 or cisplatin resulted in 39.7% or 51.2% inhibition, respectively (Fig 5C and 5D).	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (180, 189))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', (73, 78))	('Ab417', 'Chemical', '-', (171, 176))	('cisplatin', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('Ab417', 'Var', (24, 29))	('Ab417', 'Chemical', '-', (24, 29))	('tumor', 'Disease', (136, 141))
166937	28166242	The results indicate that combined treatment with Ab417 and cisplatin or gemcitabine exerted enhanced tumor growth inhibition compared to treatment with antibody or drug alone.	('Ab417', 'Var', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Ab417', 'Chemical', '-', (50, 55))	('gemcitabine', 'Chemical', 'MESH:C056507', (73, 84))	('enhanced', 'PosReg', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))
166939	28166242	In the present study, we elucidated the mode of action of Ab417 and showed that combined treatment with Ab417 and a chemotherapeutic drug for cholangiocarcinoma exerts greater tumor growth inhibition compared to antibody or drug alone.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (142, 160))	('Ab417', 'Var', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('greater', 'PosReg', (168, 175))	('Ab417', 'Chemical', '-', (104, 109))	('tumor', 'Disease', (176, 181))	('cholangiocarcinoma', 'Disease', (142, 160))	('combined', 'Interaction', (80, 88))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (142, 160))	('Ab417', 'Chemical', '-', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
166940	28166242	Our study is the first to show a therapeutic effect of anti-L1CAM mAb in combination with chemotherapy in cholangiocarcinoma model.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (106, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (106, 124))	('anti-L1CAM', 'Var', (55, 65))	('cholangiocarcinoma', 'Disease', (106, 124))
166942	28166242	Regarding mechanism of action, in this study we observed that Ab417 was internalized into L1CAM-expressing cells and decreased membrane L1CAM level in vitro and in vivo, while it inhibited tumor cell proliferation in vivo.	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('membrane L1CAM level', 'MPA', (127, 147))	('decreased', 'NegReg', (117, 126))	('inhibited', 'NegReg', (179, 188))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('Ab417', 'Var', (62, 67))	('Ab417', 'Chemical', '-', (62, 67))
166944	28166242	Therefore, it may be likely that Ab417 exerted tumor growth inhibition in vivo by inducing down-regulation of L1CAM on the cell surface and thereby resulting in reduced tumor cell proliferation by a cytostatic effect.	('reduced', 'NegReg', (161, 168))	('Ab417', 'Var', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('Ab417', 'Chemical', '-', (33, 38))	('down-regulation', 'NegReg', (91, 106))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('L1CAM', 'Protein', (110, 115))	('tumor', 'Disease', (47, 52))
166946	28166242	Generally, it is known that gemcitabine causes cell cycle arrest, resulting in a cytostatic effect, whereas cisplatin, which induces DNA crosslinks, can cause cell cycle arrest and apoptosis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (159, 176))	('cell cycle arrest', 'CPA', (47, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (47, 64))	('gemcitabine', 'Chemical', 'MESH:C056507', (28, 39))	('apoptosis', 'CPA', (181, 190))	('cell cycle arrest', 'CPA', (159, 176))	('cytostatic effect', 'MPA', (81, 98))	('cisplatin', 'Var', (108, 117))
166950	28166242	Combined treatment with Ab417 and gemcitabine or cisplatin exerted greater tumor growth inhibition compared to treatment with antibody or drug alone.	('gemcitabine', 'Chemical', 'MESH:C056507', (34, 45))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Ab417', 'Var', (24, 29))	('Ab417', 'Chemical', '-', (24, 29))	('tumor', 'Disease', (75, 80))
166951	28166242	The possible mechanisms may be likely that combined treatment with Ab417 and gemcitabine additively inhibited the growth of Choi-CK tumors by combined cytostatic effects, while combined treatment with Ab417 and cisplatin additively inhibited the growth of the tumors by cytostatic and cytotoxic effects.	('inhibited', 'NegReg', (100, 109))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('Ab417', 'Var', (67, 72))	('Ab417', 'Chemical', '-', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('tumors', 'Disease', (260, 266))	('growth', 'MPA', (114, 120))	('Ab417', 'Var', (201, 206))	('inhibited', 'NegReg', (232, 241))	('Choi-CK tumors', 'Disease', (124, 138))	('Ab417', 'Chemical', '-', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Disease', (132, 138))	('gemcitabine', 'Chemical', 'MESH:C056507', (77, 88))	('growth', 'MPA', (246, 252))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('cisplatin', 'Chemical', 'MESH:D002945', (211, 220))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('Choi-CK tumors', 'Disease', 'OMIM:300831', (124, 138))
166952	28166242	We previously observed that L1CAM conferred cisplatin resistance, while down-regulation of L1CAM expression sensitized ICC cells to cisplatin.	('down-regulation', 'NegReg', (72, 87))	('sensitized', 'Reg', (108, 118))	('L1CAM', 'Gene', (91, 96))	('cisplatin', 'Chemical', 'MESH:D002945', (132, 141))	('conferred', 'Reg', (34, 43))	('L1CAM', 'Var', (28, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('expression', 'MPA', (97, 107))	('cisplatin resistance', 'MPA', (44, 64))
166953	28166242	Therefore, combined treatment with Ab417 and cisplatin may have sensitized the Choi-CK cells to cisplatin, which also additively contributed to tumor growth inhibition.	('Ab417', 'Chemical', '-', (35, 40))	('tumor', 'Disease', (144, 149))	('sensitized', 'Reg', (64, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('Ab417', 'Var', (35, 40))
166954	28166242	Whether Ab417 in combination with gemcitabine and cisplatin would improve the therapeutic response of cholangiocarcinoma compared to the combined chemotherapy remains to be established.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (102, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('gemcitabine', 'Chemical', 'MESH:C056507', (34, 45))	('Ab417', 'Var', (8, 13))	('Ab417', 'Chemical', '-', (8, 13))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (102, 120))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('improve', 'PosReg', (66, 73))	('cholangiocarcinoma', 'Disease', (102, 120))	('therapeutic', 'MPA', (78, 89))
166962	23797727	Compared with minor duct involvement and 51 controls without intrabiliary growth, major duct involvement was more likely to produce obstructive liver chemistries (P=0.004), radiographic evidence of biliary disease (P<0.0001), and sclerosing cholangitis in non-neoplastic liver (P<0.0001).	('produce', 'Reg', (124, 131))	('men', 'Species', '9606', (100, 103))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (230, 252))	('cholangitis', 'Disease', (241, 252))	('neoplastic liver', 'Phenotype', 'HP:0002896', (260, 276))	('men', 'Species', '9606', (32, 35))	('cholangitis', 'Disease', 'MESH:D002761', (241, 252))	('cholangitis', 'Phenotype', 'HP:0030151', (241, 252))	('biliary disease', 'Disease', 'MESH:D001660', (198, 213))	('biliary disease', 'Phenotype', 'HP:0001080', (198, 213))	('obstructive liver chemistries', 'Disease', (132, 161))	('biliary disease', 'Disease', (198, 213))	('major duct involvement', 'Var', (82, 104))
166980	23797727	Cases were also prospectively evaluated for intrabiliary tumor growth by 4 of the authors (J.S.E., M.W.T., S.R.H., and S.C.A.	('M.W.T.', 'Var', (99, 105))	('intrabiliary tumor', 'Disease', (44, 62))	('S.R.H.', 'Var', (107, 113))	('biliary tumor', 'Phenotype', 'HP:0100574', (49, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('intrabiliary tumor', 'Disease', 'MESH:D009369', (44, 62))
166995	23797727	Therefore, the prevalence of intrabiliary growth by metastatic CRC ranges from 3.6% to 10.6%:and with other metastatic tumor types, it ranges from 0.7% to 1.9%:depending upon whether this feature is evaluated retrospectively or prospectively.	('tumor', 'Disease', (119, 124))	('metastatic CRC', 'Var', (52, 66))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('intrabiliary', 'Disease', (29, 41))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('CRC', 'Phenotype', 'HP:0030731', (63, 66))
167060	23797727	Institutions with a strong surgical tradition, for example, might be more willing to operate on patients with large duct involvement or multifocal involvement, whereas other institutions might deem some of these patients as unresectable or better candidates for systemic chemotherapy.	('large duct involvement', 'Disease', (110, 132))	('multifocal', 'Var', (136, 146))	('men', 'Species', '9606', (128, 131))	('patients', 'Species', '9606', (212, 220))	('men', 'Species', '9606', (154, 157))	('patients', 'Species', '9606', (96, 104))
167176	33562535	A cholangioscope was inserted into the bile duct over a 0.025-inch hydrophilic guidewire (G-260-2545A; Olympus Corp., Tokyo, Japan; MTA0025N48S; Medico's Hirata Inc, Osaka, Japan; M00556700; Boston Scientific Corporation, Marlborough, MA, USA), and M00546270 (SpyBite Biopsy Forceps; Boston Scientific, Marlborough, MA, USA) was used for POCS-FMB under direct vision.	('M00546270', 'Var', (249, 258))	('G-260-2545A', 'Var', (90, 101))	('POCS-FMB', 'Chemical', '-', (338, 346))	('G-260-2545A', 'SUBSTITUTION', 'None', (90, 101))
167268	33436545	Long intergenic non-protein coding RNA 665 (LINC00665) were found to rank the top 10 upregulated lncRNAs in our study, and high LINC00665 expression was closely associated with poor prognosis and chemoresistance of CCA patients.	('LINC00665', 'Gene', '100506930', (44, 53))	('LINC00665', 'Gene', (128, 137))	('associated with', 'Reg', (161, 176))	('upregulated', 'PosReg', (85, 96))	('CCA', 'Disease', (215, 218))	('high', 'Var', (123, 127))	('LINC00665', 'Gene', (44, 53))	('poor prognosis', 'CPA', (177, 191))	('LINC00665', 'Gene', '100506930', (128, 137))	('patients', 'Species', '9606', (219, 227))	('chemoresistance', 'CPA', (196, 211))	('CCA', 'Phenotype', 'HP:0030153', (215, 218))
167269	33436545	Silencing LINC00665 in gemcitabine resistant CCA cells impaired gemcitabine tolerance, while enforced LINC00665 expression increased gemcitabine resistance of sensitive CCA cells.	('gemcitabine', 'Chemical', 'MESH:C056507', (133, 144))	('gemcitabine tolerance', 'MPA', (64, 85))	('LINC00665', 'Gene', '100506930', (10, 19))	('gemcitabine resistance', 'MPA', (133, 155))	('CCA', 'Phenotype', 'HP:0030153', (45, 48))	('LINC00665', 'Gene', (102, 111))	('CCA', 'Phenotype', 'HP:0030153', (169, 172))	('LINC00665', 'Gene', (10, 19))	('Silencing', 'Var', (0, 9))	('gemcitabine', 'Chemical', 'MESH:C056507', (64, 75))	('impaired', 'NegReg', (55, 63))	('gemcitabine', 'Chemical', 'MESH:C056507', (23, 34))	('LINC00665', 'Gene', '100506930', (102, 111))
167270	33436545	The gemcitabine resistant CCA cells showed increased EMT and stemness properties, and silencing LINC00665 suppressed sphere formation, migration, invasion and expression of EMT and stemness markers.	('silencing', 'Var', (86, 95))	('migration', 'CPA', (135, 144))	('LINC00665', 'Gene', '100506930', (96, 105))	('gemcitabine', 'Chemical', 'MESH:C056507', (4, 15))	('suppressed', 'NegReg', (106, 116))	('expression', 'MPA', (159, 169))	('increased EMT', 'Phenotype', 'HP:0008151', (43, 56))	('increased', 'PosReg', (43, 52))	('LINC00665', 'Gene', (96, 105))	('CCA', 'Phenotype', 'HP:0030153', (26, 29))	('sphere formation', 'CPA', (117, 133))	('invasion', 'CPA', (146, 154))
167271	33436545	In addition, Wnt/beta-Catenin signaling was activated in gemcitabine resistant CCA cells, but LINC00665 knockdown suppressed Wnt/beta-Catenin activation.	('LINC00665', 'Gene', (94, 103))	('Wnt/beta-Catenin activation', 'MPA', (125, 152))	('CCA', 'Phenotype', 'HP:0030153', (79, 82))	('Wnt/beta-Catenin signaling', 'MPA', (13, 39))	('activated', 'PosReg', (44, 53))	('LINC00665', 'Gene', '100506930', (94, 103))	('suppressed', 'NegReg', (114, 124))	('gemcitabine', 'Chemical', 'MESH:C056507', (57, 68))	('knockdown', 'Var', (104, 113))
167274	33436545	Moreover, silencing BCL9L or miR-424-5p overexpression suppressed gemcitabine resistance, EMT, stemness and Wnt/beta-Catenin activation in resistant CCA cells.	('gemcitabine', 'Chemical', 'MESH:C056507', (66, 77))	('EMT', 'CPA', (90, 93))	('gemcitabine resistance', 'MPA', (66, 88))	('stemness', 'CPA', (95, 103))	('CCA', 'Phenotype', 'HP:0030153', (149, 152))	('suppressed', 'NegReg', (55, 65))	('BCL9L', 'Protein', (20, 25))	('miR-424', 'Gene', (29, 36))	('Wnt/beta-Catenin activation', 'CPA', (108, 135))	('miR-424', 'Gene', '494336', (29, 36))	('silencing', 'Var', (10, 19))
167289	33436545	For example, Low BAP1 expression is proved to be closely associated with increased gemcitabine sensitivity in cholangiocarcinoma, and exogenous modulation of a BAP1 dependent lncRNA NEAT-1 evidently influence gemcitabine sensitivity and tumor cell phenotype.	('gemcitabine', 'Chemical', 'MESH:C056507', (209, 220))	('gemcitabine sensitivity', 'MPA', (209, 232))	('gemcitabine', 'Chemical', 'MESH:C056507', (83, 94))	('influence', 'Reg', (199, 208))	('BAP1', 'Gene', (160, 164))	('NEAT-1', 'Gene', (182, 188))	('NEAT-1', 'Gene', '283131', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('gemcitabine sensitivity', 'MPA', (83, 106))	('Low', 'NegReg', (13, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('increased', 'PosReg', (73, 82))	('modulation', 'Var', (144, 154))	('BAP1', 'Gene', '8314', (17, 21))	('expression', 'MPA', (22, 32))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (110, 128))	('tumor', 'Disease', (237, 242))	('BAP1', 'Gene', '8314', (160, 164))	('cholangiocarcinoma', 'Disease', (110, 128))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (110, 128))	('associated', 'Reg', (57, 67))	('BAP1', 'Gene', (17, 21))
167294	33436545	Silencing LINC00665 impaired gemcitabine tolerance of resistant CCA cells, while LINC00665 overexpression increased gemcitabine resistance in sensitive CCA cells.	('gemcitabine', 'MPA', (116, 127))	('gemcitabine', 'Chemical', 'MESH:C056507', (116, 127))	('LINC00665', 'Gene', '100506930', (81, 90))	('LINC00665', 'Gene', '100506930', (10, 19))	('LINC00665', 'Gene', (81, 90))	('LINC00665', 'Gene', (10, 19))	('CCA', 'Phenotype', 'HP:0030153', (152, 155))	('gemcitabine tolerance', 'MPA', (29, 50))	('gemcitabine', 'Chemical', 'MESH:C056507', (29, 40))	('impaired', 'NegReg', (20, 28))	('Silencing', 'Var', (0, 9))	('CCA', 'Phenotype', 'HP:0030153', (64, 67))
167295	33436545	Silencing LINC00665 also suppressed gemcitabine-induced EMT, stemness, and Wnt/beta-Catenin activation.	('LINC00665', 'Gene', '100506930', (10, 19))	('Wnt/beta-Catenin activation', 'CPA', (75, 102))	('stemness', 'CPA', (61, 69))	('gemcitabine-induced EMT', 'CPA', (36, 59))	('suppressed', 'NegReg', (25, 35))	('LINC00665', 'Gene', (10, 19))	('gemcitabine', 'Chemical', 'MESH:C056507', (36, 47))	('Silencing', 'Var', (0, 9))
167296	33436545	Moreover, LINC00665 regulated BCL9L expression by acting as a molecular sponge for miR-424-5p, while enforced miR-424-5p expression or silencing BCL9L abolished the effects mediated by LINC00665 in resistant CCA cells.	('BCL9L', 'Gene', (145, 150))	('LINC00665', 'Gene', '100506930', (185, 194))	('miR-424', 'Gene', (83, 90))	('LINC00665', 'Gene', '100506930', (10, 19))	('silencing', 'Var', (135, 144))	('BCL9L', 'Gene', (30, 35))	('miR-424', 'Gene', (110, 117))	('miR-424', 'Gene', '494336', (110, 117))	('miR-424', 'Gene', '494336', (83, 90))	('LINC00665', 'Gene', (185, 194))	('LINC00665', 'Gene', (10, 19))	('CCA', 'Phenotype', 'HP:0030153', (208, 211))	('expression', 'MPA', (36, 46))
167316	33436545	We found that high expression of LINC00665 was positively associated with a higher TNM stage, lymph node metastasis, and distant metastasis in CCA patients (Table 1).	('CCA', 'Phenotype', 'HP:0030153', (143, 146))	('lymph node metastasis', 'CPA', (94, 115))	('LINC00665', 'Gene', (33, 42))	('TNM', 'Gene', '10178', (83, 86))	('high', 'Var', (14, 18))	('patients', 'Species', '9606', (147, 155))	('CCA', 'Disease', (143, 146))	('TNM', 'Gene', (83, 86))	('higher', 'PosReg', (76, 82))	('LINC00665', 'Gene', '100506930', (33, 42))	('distant metastasis', 'CPA', (121, 139))
167317	33436545	In Kaplan-Meier survival analysis, CCA patients with high LINC00665 expression had significantly shorter overall survival time and recurrence-free survival time (Fig.	('high', 'Var', (53, 57))	('patients', 'Species', '9606', (39, 47))	('overall survival time', 'CPA', (105, 126))	('CCA', 'Phenotype', 'HP:0030153', (35, 38))	('LINC00665', 'Gene', '100506930', (58, 67))	('recurrence-free survival time', 'CPA', (131, 160))	('shorter', 'NegReg', (97, 104))	('CCA', 'Disease', (35, 38))	('LINC00665', 'Gene', (58, 67))
167323	33436545	To disclose the potential role of LINC00665 in gemcitabine resistant CCA cells, we knocked down LINC00665 expression using two small hairpin RNA (shRNA) specifically targeting LINC00665 (sh-LINC0065-1 and sh-LINC00665-2).	('LINC00665', 'Gene', '100506930', (208, 217))	('gemcitabine', 'Chemical', 'MESH:C056507', (47, 58))	('NC', 'Disease', 'OMIM:617025', (36, 38))	('NC', 'Disease', 'OMIM:617025', (98, 100))	('LINC00665', 'Gene', (208, 217))	('LINC00665', 'Gene', '100506930', (34, 43))	('LINC00665', 'Gene', '100506930', (96, 105))	('CCA', 'Phenotype', 'HP:0030153', (69, 72))	('NC', 'Disease', 'OMIM:617025', (178, 180))	('NC', 'Disease', 'OMIM:617025', (192, 194))	('LINC00665', 'Gene', '100506930', (176, 185))	('sh-LINC00665-2', 'Gene', '100506930', (205, 219))	('sh-LINC00665-2', 'Gene', (205, 219))	('NC', 'Disease', 'OMIM:617025', (210, 212))	('LINC00665', 'Gene', (34, 43))	('LINC00665', 'Gene', (96, 105))	('knocked', 'Var', (83, 90))	('LINC00665', 'Gene', (176, 185))
167326	33436545	As we expected, silencing LINC00665 significantly decreased the gemcitabine IC50 in HuCCT1-Gem and SNU-245-Gem cells, suggesting that LINC00665 knockdown impaired gemcitabine tolerance (Fig.	('LINC00665', 'Gene', '100506930', (134, 143))	('gemcitabine', 'Chemical', 'MESH:C056507', (163, 174))	('LINC00665', 'Gene', (26, 35))	('LINC00665', 'Gene', (134, 143))	('silencing', 'Var', (16, 25))	('impaired', 'NegReg', (154, 162))	('decreased', 'NegReg', (50, 59))	('gemcitabine IC50', 'MPA', (64, 80))	('gemcitabine tolerance', 'MPA', (163, 184))	('SNU-245-Gem', 'Chemical', '-', (99, 110))	('gemcitabine', 'Chemical', 'MESH:C056507', (64, 75))	('LINC00665', 'Gene', '100506930', (26, 35))
167327	33436545	This was further evaluated in soft agar assay, and we found that silencing LINC00665 or treated with low dose gemcitabine (10 nM) slightly suppressed colony formation of HuCCT1-Gem and SNU-245-Gem cells, but the combination of them had strengthened repression on colony formation, indicating the LINC00665 knockdown had additional effects on gemcitabine cytotoxicity (Fig.	('cytotoxicity', 'Disease', 'MESH:D064420', (354, 366))	('LINC00665', 'Gene', '100506930', (75, 84))	('gemcitabine', 'Chemical', 'MESH:C056507', (342, 353))	('silencing', 'Var', (65, 74))	('SNU-245-Gem', 'Chemical', '-', (185, 196))	('LINC00665', 'Gene', '100506930', (296, 305))	('colony formation', 'CPA', (150, 166))	('gemcitabine', 'Chemical', 'MESH:C056507', (110, 121))	('effects', 'Reg', (331, 338))	('LINC00665', 'Gene', (75, 84))	('cytotoxicity', 'Disease', (354, 366))	('agar', 'Chemical', 'MESH:D000362', (35, 39))	('LINC00665', 'Gene', (296, 305))	('suppressed', 'NegReg', (139, 149))
167330	33436545	Our results revealed that silencing LINC00665 alone had little impact on cell apoptosis and growth of HuCCT1-Gem and SNU-245-Gem cells, with no obvious increase in PI and Annexin-V double-positive subsets (Fig.	('cell apoptosis', 'CPA', (73, 87))	('LINC00665', 'Gene', (36, 45))	('SNU-245-Gem', 'Chemical', '-', (117, 128))	('Annexin-V', 'Gene', '308', (171, 180))	('Annexin-V', 'Gene', (171, 180))	('growth', 'CPA', (92, 98))	('silencing', 'Var', (26, 35))	('LINC00665', 'Gene', '100506930', (36, 45))
167332	33436545	However, LINC00665 knockdown significantly increased the cytotoxicity of gemcitabine, with apparently enlarged PI and Annexin-V double-positive subsets (Fig.	('Annexin-V', 'Gene', (118, 127))	('enlarged', 'PosReg', (102, 110))	('LINC00665', 'Gene', (9, 18))	('cytotoxicity', 'Disease', (57, 69))	('knockdown', 'Var', (19, 28))	('Annexin-V', 'Gene', '308', (118, 127))	('gemcitabine', 'Chemical', 'MESH:C056507', (73, 84))	('PI and', 'CPA', (111, 117))	('increased', 'PosReg', (43, 52))	('cytotoxicity', 'Disease', 'MESH:D064420', (57, 69))	('LINC00665', 'Gene', '100506930', (9, 18))
167335	33436545	The protein expression of cleaved Caspase-3 and PCNA was evaluated by western blot, and we found that gemcitabine treatment increased cleaved Caspase-3 expression and decreased PCNA level, and this effect was further strengthened by silencing LINC00665 (Fig.	('PCNA', 'Gene', (177, 181))	('gemcitabine', 'Chemical', 'MESH:C056507', (102, 113))	('Caspase-3', 'Gene', (34, 43))	('Caspase-3', 'Gene', (142, 151))	('Caspase-3', 'Gene', '836', (34, 43))	('increased', 'PosReg', (124, 133))	('PCNA', 'Gene', '5111', (177, 181))	('Caspase-3', 'Gene', '836', (142, 151))	('LINC00665', 'Gene', (243, 252))	('PCNA', 'Gene', (48, 52))	('expression', 'MPA', (152, 162))	('PCNA', 'Gene', '5111', (48, 52))	('LINC00665', 'Gene', '100506930', (243, 252))	('silencing', 'Var', (233, 242))	('decreased', 'NegReg', (167, 176))
167336	33436545	In tumor formation assay, gemcitabine group showed a moderate suppression on tumor growth of HuCCT1-Gem cells in nude mice, but this was significantly enforced by silencing LINC00665 (Fig.	('suppression', 'NegReg', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', (3, 8))	('silencing', 'Var', (163, 172))	('LINC00665', 'Gene', (173, 182))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('nude mice', 'Species', '10090', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('enforced', 'PosReg', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('gemcitabine', 'Chemical', 'MESH:C056507', (26, 37))	('tumor', 'Disease', (77, 82))	('LINC00665', 'Gene', '100506930', (173, 182))
167337	33436545	Taken together, our results suggested that LINC00665 knockdown increased the cytotoxic activity of gemcitabine on cell apoptosis and growth, thus impaired gemcitabine tolerance of resistant CCA cells.	('impaired', 'NegReg', (146, 154))	('increased', 'PosReg', (63, 72))	('cytotoxic activity of gemcitabine', 'MPA', (77, 110))	('knockdown', 'Var', (53, 62))	('LINC00665', 'Gene', '100506930', (43, 52))	('gemcitabine', 'Chemical', 'MESH:C056507', (155, 166))	('LINC00665', 'Gene', (43, 52))	('gemcitabine tolerance', 'MPA', (155, 176))	('gemcitabine', 'Chemical', 'MESH:C056507', (99, 110))	('CCA', 'Phenotype', 'HP:0030153', (190, 193))	('cell apoptosis', 'CPA', (114, 128))	('growth', 'CPA', (133, 139))
167343	33436545	We found that the percentage of BrdU positive cells was increased in LINC00665 overexpressed cells (Fig.	('overexpressed', 'Var', (79, 92))	('increased', 'PosReg', (56, 65))	('LINC00665', 'Gene', '100506930', (69, 78))	('BrdU positive cells', 'CPA', (32, 51))	('BrdU', 'Chemical', 'MESH:D001973', (32, 36))	('LINC00665', 'Gene', (69, 78))
167356	33436545	To explore the potential function of LINC00665 upregulation in gemcitabine-induced EMT phenotype and stemness properties, we silenced LINC00665 in HuCCT1-Gem and SNU-245-Gem cells and evaluated the changes in sphere formation, transwell cell migration and invasion, and expression of EMT and CSC makers.	('LINC00665', 'Gene', '100506930', (134, 143))	('transwell cell migration', 'CPA', (227, 251))	('LINC00665', 'Gene', (37, 46))	('gemcitabine', 'Chemical', 'MESH:C056507', (63, 74))	('invasion', 'CPA', (256, 264))	('silenced', 'Var', (125, 133))	('LINC00665', 'Gene', (134, 143))	('sphere formation', 'CPA', (209, 225))	('SNU-245-Gem', 'Chemical', '-', (162, 173))	('LINC00665', 'Gene', '100506930', (37, 46))
167357	33436545	Silencing LINC00665 evidently decreased the sphere formation of HuCCT1-Gem and SNU-245-Gem cells (Fig.	('LINC00665', 'Gene', '100506930', (10, 19))	('SNU-245-Gem', 'Chemical', '-', (79, 90))	('sphere formation of HuCCT1-Gem', 'CPA', (44, 74))	('LINC00665', 'Gene', (10, 19))	('Silencing', 'Var', (0, 9))	('decreased', 'NegReg', (30, 39))
167358	33436545	In addition, transwell migration and invasion cells were dramatically reduced after LINC00665 knockdown (Fig.	('knockdown', 'Var', (94, 103))	('reduced', 'NegReg', (70, 77))	('transwell migration', 'CPA', (13, 32))	('LINC00665', 'Gene', (84, 93))	('invasion cells', 'CPA', (37, 51))	('LINC00665', 'Gene', '100506930', (84, 93))
167361	33436545	We found that LINC00665 overexpression facilitated sphere formation, transwell migration, and invasion of HuCCT1 and SNU-245 cells (Figure S4F-J).	('invasion', 'CPA', (94, 102))	('LINC00665', 'Gene', '100506930', (14, 23))	('facilitated', 'PosReg', (39, 50))	('SNU', 'Chemical', '-', (117, 120))	('LINC00665', 'Gene', (14, 23))	('transwell migration', 'CPA', (69, 88))	('sphere formation', 'CPA', (51, 67))	('overexpression', 'Var', (24, 38))
167362	33436545	Above all, these results indicated that silencing LINC00665 suppressed gemcitabine-induced EMT and stemness properties in resistant CCA cells.	('LINC00665', 'Gene', (50, 59))	('suppressed', 'NegReg', (60, 70))	('LINC00665', 'Gene', '100506930', (50, 59))	('CCA', 'Phenotype', 'HP:0030153', (132, 135))	('silencing', 'Var', (40, 49))	('gemcitabine', 'Chemical', 'MESH:C056507', (71, 82))	('gemcitabine-induced', 'MPA', (71, 90))
167365	33436545	Moreover, the conventional downstream genes of Wnt/beta-Catenin signaling were upregulated in HuCCT1-Gem and SNU-245-Gem cells (Fig.	('HuCCT1-Gem', 'Var', (94, 104))	('Wnt/beta-Catenin signaling', 'MPA', (47, 73))	('SNU-245-Gem', 'Var', (109, 120))	('SNU-245-Gem', 'Chemical', '-', (109, 120))	('upregulated', 'PosReg', (79, 90))
167366	33436545	To disclose the connection between LINC00665 and Wnt/beta-Catenin signaling, we knocked down LINC00665 in HuCCT1-Gem and SNU-245-Gem cells and evaluated the variation of Wnt/beta-Catenin pathway.	('LINC00665', 'Gene', (93, 102))	('knocked', 'Var', (80, 87))	('SNU-245-Gem', 'Chemical', '-', (121, 132))	('LINC00665', 'Gene', '100506930', (35, 44))	('LINC00665', 'Gene', '100506930', (93, 102))	('LINC00665', 'Gene', (35, 44))
167367	33436545	Indeed, LINC00665 knockdown suppressed nucleus translocation of beta-Catenin and phosphorylation of GSK-3beta, and increased phosphorylation of beta-Catenin (Fig.	('knockdown', 'Var', (18, 27))	('GSK-3beta', 'Gene', '2931', (100, 109))	('phosphorylation', 'MPA', (81, 96))	('beta-Catenin', 'Protein', (64, 76))	('GSK-3beta', 'Gene', (100, 109))	('increased', 'PosReg', (115, 124))	('LINC00665', 'Gene', (8, 17))	('beta-Catenin', 'Protein', (144, 156))	('suppressed', 'NegReg', (28, 38))	('nucleus translocation', 'MPA', (39, 60))	('phosphorylation', 'MPA', (125, 140))	('LINC00665', 'Gene', '100506930', (8, 17))
167371	33436545	5D, HuCCT1-Gem and SNU-245-Gem cells had more nucleus accumulation of beta-Catenin, but this was abolished by LINC00665 knockdown, suggesting that silencing LINC00665 repressed the nucleus translocation of beta-Catenin, and subsequently suppressed Wnt/beta-Catenin activation.	('LINC00665', 'Gene', (110, 119))	('Wnt/beta-Catenin', 'CPA', (248, 264))	('nucleus accumulation', 'MPA', (46, 66))	('LINC00665', 'Gene', (157, 166))	('suppressed', 'NegReg', (237, 247))	('beta-Catenin', 'Protein', (206, 218))	('LINC00665', 'Gene', '100506930', (110, 119))	('SNU-245-Gem', 'Chemical', '-', (19, 30))	('nucleus translocation', 'MPA', (181, 202))	('LINC00665', 'Gene', '100506930', (157, 166))	('silencing', 'Var', (147, 156))
167373	33436545	As silencing LINC00665 suppressed the activation of Wnt/beta-Catenin signaling in resistant CCA cells, we supposed that some genes involved in regulating Wnt/beta-Catenin signaling pathway might be influenced by LINC00665 knockdown.	('silencing', 'Var', (3, 12))	('LINC00665', 'Gene', '100506930', (212, 221))	('suppressed', 'NegReg', (23, 33))	('LINC00665', 'Gene', '100506930', (13, 22))	('activation', 'MPA', (38, 48))	('LINC00665', 'Gene', (212, 221))	('LINC00665', 'Gene', (13, 22))	('Wnt/beta-Catenin signaling', 'MPA', (52, 78))	('CCA', 'Phenotype', 'HP:0030153', (92, 95))
167374	33436545	Though some genes were slightly downregulated by LINC00665 knockdown, we were surprised to find that the expression of BCL9L was dramatically decreased (Fig.	('downregulated', 'NegReg', (32, 45))	('LINC00665', 'Gene', (49, 58))	('decreased', 'NegReg', (142, 151))	('BCL9L', 'Gene', (119, 124))	('LINC00665', 'Gene', '100506930', (49, 58))	('knockdown', 'Var', (59, 68))	('expression', 'MPA', (105, 115))
167375	33436545	This was further confirmed by western blot, as LINC00665 knockdown decreased protein expression of BCL9L (Fig.	('LINC00665', 'Gene', (47, 56))	('knockdown', 'Var', (57, 66))	('decreased', 'NegReg', (67, 76))	('LINC00665', 'Gene', '100506930', (47, 56))	('protein expression', 'MPA', (77, 95))
167378	33436545	Therefore, we supposed that silencing LINC00665 might suppress Wnt/beta-Catenin activation by downregulating BCL9L.	('Wnt/beta-Catenin activation', 'MPA', (63, 90))	('LINC00665', 'Gene', '100506930', (38, 47))	('BCL9L', 'MPA', (109, 114))	('downregulating', 'NegReg', (94, 108))	('suppress', 'NegReg', (54, 62))	('LINC00665', 'Gene', (38, 47))	('silencing', 'Var', (28, 37))
167390	33436545	On the contrary, silencing LINC00665 in HuCCT1-Gem and SNU-245-Gem cells enhanced miR-424-5p expression (Fig.	('miR-424', 'Gene', '494336', (82, 89))	('LINC00665', 'Gene', '100506930', (27, 36))	('SNU-245-Gem', 'Chemical', '-', (55, 66))	('enhanced', 'PosReg', (73, 81))	('miR-424', 'Gene', (82, 89))	('silencing', 'Var', (17, 26))	('LINC00665', 'Gene', (27, 36))
167405	33436545	Thus, we overexpressed miR-424-5p or knocked down BCL9L in gemcitabine-resistant CCA cells, then evaluated for gemcitabine tolerance, cell apoptosis, sphere formation, transwell cell migration and invasion, and Wnt/beta-Catenin activation.	('invasion', 'CPA', (197, 205))	('sphere formation', 'CPA', (150, 166))	('knocked', 'Var', (37, 44))	('BCL9L', 'Gene', (50, 55))	('gemcitabine', 'Chemical', 'MESH:C056507', (59, 70))	('miR-424', 'Gene', (23, 30))	('gemcitabine', 'Chemical', 'MESH:C056507', (111, 122))	('transwell cell migration', 'CPA', (168, 192))	('CCA', 'Phenotype', 'HP:0030153', (81, 84))	('miR-424', 'Gene', '494336', (23, 30))
167407	33436545	In our study, we found that miR-424-5p overexpression or silencing BCL9L increased gemcitabine sensitivity of resistant CCA cells, with decreased gemcitabine IC50 (Fig.	('increased', 'PosReg', (73, 82))	('BCL9L', 'Gene', (67, 72))	('miR-424', 'Gene', (28, 35))	('CCA', 'Phenotype', 'HP:0030153', (120, 123))	('gemcitabine IC50', 'MPA', (146, 162))	('miR-424', 'Gene', '494336', (28, 35))	('gemcitabine', 'Chemical', 'MESH:C056507', (83, 94))	('silencing', 'Var', (57, 66))	('gemcitabine', 'Chemical', 'MESH:C056507', (146, 157))	('decreased', 'NegReg', (136, 145))	('gemcitabine sensitivity', 'MPA', (83, 106))
167408	33436545	Moreover, miR-424-5p overexpression or silencing BCL9L evidently increased apoptosis of HuCCT1-Gem and SNU-245-Gem cells under gemcitabine treatment (Figure S7A and S7B).	('gemcitabine', 'Chemical', 'MESH:C056507', (127, 138))	('increased', 'PosReg', (65, 74))	('miR-424', 'Gene', (10, 17))	('apoptosis', 'CPA', (75, 84))	('miR-424', 'Gene', '494336', (10, 17))	('SNU-245-Gem', 'Chemical', '-', (103, 114))	('overexpression', 'PosReg', (21, 35))	('silencing', 'Var', (39, 48))	('BCL9L', 'Gene', (49, 54))
167409	33436545	Furthermore, miR-424-5p overexpression or silencing BCL9L reduced sphere formation (Fig.	('silencing', 'Var', (42, 51))	('miR-424', 'Gene', '494336', (13, 20))	('overexpression', 'PosReg', (24, 38))	('BCL9L', 'Gene', (52, 57))	('reduced', 'NegReg', (58, 65))	('sphere formation', 'CPA', (66, 82))	('miR-424', 'Gene', (13, 20))
167411	33436545	In tumor xenograft formation assay, we found that miR-424-5p overexpression or silencing BCL9L alone slightly suppressed tumor formation of HuCCT1-Gem cells, but dramatically increased gemcitabine sensitivity and reduced tumor growth when treated with gemcitabine (Figure S7C-E).	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (3, 8))	('gemcitabine', 'Chemical', 'MESH:C056507', (185, 196))	('tumor', 'Disease', (121, 126))	('BCL9L', 'Gene', (89, 94))	('miR-424', 'Gene', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('suppressed', 'NegReg', (110, 120))	('miR-424', 'Gene', '494336', (50, 57))	('gemcitabine sensitivity', 'MPA', (185, 208))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('reduced', 'NegReg', (213, 220))	('tumor', 'Disease', (221, 226))	('increased', 'PosReg', (175, 184))	('gemcitabine', 'Chemical', 'MESH:C056507', (252, 263))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('silencing', 'Var', (79, 88))
167412	33436545	The activation of Wnt/beta-Catenin signaling was evaluated by western blot, and we found that miR-424-5p overexpression or silencing BCL9L suppressed nucleus translocation of beta-Catenin and phosphorylation of GSK-3beta, and increased phosphorylation of beta-Catenin (Fig.	('miR-424', 'Gene', (94, 101))	('phosphorylation', 'MPA', (192, 207))	('BCL9L', 'Gene', (133, 138))	('beta-Catenin', 'Protein', (255, 267))	('GSK-3beta', 'Gene', '2931', (211, 220))	('beta-Catenin', 'Protein', (175, 187))	('GSK-3beta', 'Gene', (211, 220))	('silencing', 'Var', (123, 132))	('miR-424', 'Gene', '494336', (94, 101))	('nucleus translocation', 'MPA', (150, 171))	('increased', 'PosReg', (226, 235))	('phosphorylation', 'MPA', (236, 251))	('suppressed', 'NegReg', (139, 149))
167413	33436545	Besides, the well-recognized downstream target genes c-Myc and Survivin were downregulated by miR-424-5p overexpression or silencing BCL9L.	('downregulated', 'NegReg', (77, 90))	('miR-424', 'Gene', (94, 101))	('BCL9L', 'Gene', (133, 138))	('overexpression', 'PosReg', (105, 119))	('c-Myc', 'Gene', '4609', (53, 58))	('Survivin', 'Protein', (63, 71))	('miR-424', 'Gene', '494336', (94, 101))	('c-Myc', 'Gene', (53, 58))	('silencing', 'Var', (123, 132))
167419	33436545	Upregulation of LINC00665 are also demonstrated in prostate and gastric patients, and LINC00665 overexpression accelerates tumorigenesis and progression.	('LINC00665', 'Gene', '100506930', (16, 25))	('gastric', 'Disease', (64, 71))	('accelerates', 'PosReg', (111, 122))	('overexpression', 'Var', (96, 110))	('tumor', 'Disease', (123, 128))	('LINC00665', 'Gene', (16, 25))	('LINC00665', 'Gene', '100506930', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('progression', 'CPA', (141, 152))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('prostate', 'Disease', (51, 59))	('LINC00665', 'Gene', (86, 95))	('patients', 'Species', '9606', (72, 80))
167420	33436545	In our study, we found that LINC00665 was upregulated and predicted poor prognosis in CCA patients, and silencing LINC00665 impaired gemcitabine tolerance, repressed EMT and stemness, and inactived Wnt/beta-Catenin signaling through miR-424-5p/BCL9L axis.	('gemcitabine tolerance', 'MPA', (133, 154))	('gemcitabine', 'Chemical', 'MESH:C056507', (133, 144))	('impaired', 'NegReg', (124, 132))	('LINC00665', 'Gene', (114, 123))	('miR-424', 'Gene', '494336', (233, 240))	('LINC00665', 'Gene', '100506930', (28, 37))	('silencing', 'Var', (104, 113))	('repressed', 'NegReg', (156, 165))	('CCA', 'Phenotype', 'HP:0030153', (86, 89))	('LINC00665', 'Gene', '100506930', (114, 123))	('Wnt/beta-Catenin signaling', 'Pathway', (198, 224))	('upregulated', 'PosReg', (42, 53))	('inactived', 'NegReg', (188, 197))	('LINC00665', 'Gene', (28, 37))	('patients', 'Species', '9606', (90, 98))	('CCA', 'Disease', (86, 89))	('miR-424', 'Gene', (233, 240))
167425	33436545	In our study, we found that silencing LINC00665 suppressed BCL9L expression, and subsequently decreased nucleus translocation of beta-Catenin and Wnt signaling activation, therefore impaired gemcitabine-induced EMT and stemness of resistant CCA cells.	('nucleus translocation of beta-Catenin', 'MPA', (104, 141))	('LINC00665', 'Gene', '100506930', (38, 47))	('CCA', 'Phenotype', 'HP:0030153', (241, 244))	('activation', 'PosReg', (160, 170))	('stemness of resistant CCA cells', 'CPA', (219, 250))	('silencing', 'Var', (28, 37))	('Wnt', 'MPA', (146, 149))	('suppressed', 'NegReg', (48, 58))	('decreased', 'NegReg', (94, 103))	('expression', 'MPA', (65, 75))	('gemcitabine', 'Chemical', 'MESH:C056507', (191, 202))	('LINC00665', 'Gene', (38, 47))	('impaired', 'NegReg', (182, 190))	('BCL9L', 'Protein', (59, 64))
167427	33436545	For example, silencing BCL9L suppresses EMT and nucleus translocation of beta-Catenin in carcinoma cells, while forced expression of BCL9L induces EMT of nontransformed cells.	('suppresses', 'NegReg', (29, 39))	('nucleus translocation of beta-Catenin', 'MPA', (48, 85))	('BCL9L', 'Gene', (23, 28))	('carcinoma', 'Disease', 'MESH:D009369', (89, 98))	('EMT', 'CPA', (40, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('silencing', 'Var', (13, 22))	('carcinoma', 'Disease', (89, 98))
167428	33436545	In colon cancer, conditional ablation of BCL9/BCL9L suppresses the expression of stem cell markers and generation of ulcerated colon epithelium in intestinal epithelium, and transcriptional profiles indicates that BCL9/BCL9L regulates a subset of Wnt/beta-Catenin target genes controlling EMT and stemness.	('regulates', 'Reg', (225, 234))	('ablation', 'Var', (29, 37))	('ulcerated colon epithelium', 'Disease', 'MESH:D014456', (117, 143))	('stem cell', 'CPA', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('BCL9/BCL9L', 'Gene', (41, 51))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('expression', 'MPA', (67, 77))	('ulcerated colon epithelium', 'Disease', (117, 143))	('suppresses', 'NegReg', (52, 62))	('colon cancer', 'Disease', (3, 15))
167430	33436545	BCL9L overexpression is positively correlated with poor overall survival in hepatocellular carcinoma patients, and silencing BCL9L, but not BCL9, reduced Wnt signaling, and suppressed cell growth and induced apoptosis of Wnt-inactive hepatocellular carcinoma cells.	('Wnt signaling', 'MPA', (154, 167))	('apoptosis', 'CPA', (208, 217))	('induced', 'Reg', (200, 207))	('patients', 'Species', '9606', (101, 109))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (234, 258))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (234, 258))	('cell growth', 'CPA', (184, 195))	('hepatocellular carcinoma', 'Disease', (234, 258))	('silencing', 'Var', (115, 124))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (76, 100))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (76, 100))	('reduced', 'NegReg', (146, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('hepatocellular carcinoma', 'Disease', (76, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('suppressed', 'NegReg', (173, 183))	('BCL9L', 'Gene', (125, 130))
167431	33436545	In pancreatic cancer, BCL9L knockdown decreases cell proliferation, migration, invasion, and liver metastasis, and increases E-cadherin expression even in the presence of TGF-beta, suggesting a role of BCL9L in regulating EMT.	('decreases', 'NegReg', (38, 47))	('E-cadherin', 'Gene', '999', (125, 135))	('expression', 'MPA', (136, 146))	('pancreatic cancer', 'Disease', (3, 20))	('BCL9L', 'Gene', (22, 27))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('TGF-beta', 'Gene', '7039', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('increases', 'PosReg', (115, 124))	('cell proliferation', 'CPA', (48, 66))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('liver metastasis', 'Disease', 'MESH:D009362', (93, 109))	('liver metastasis', 'Disease', (93, 109))	('knockdown', 'Var', (28, 37))	('invasion', 'CPA', (79, 87))	('E-cadherin', 'Gene', (125, 135))	('TGF-beta', 'Gene', (171, 179))	('migration', 'CPA', (68, 77))
167436	33436545	Silencing LINC00665 suppressed EMT, stemness and Wnt/beta-Catenin signaling, thus impaired gemcitabine tolerance of these resistant CCA cells.	('EMT', 'CPA', (31, 34))	('gemcitabine', 'Chemical', 'MESH:C056507', (91, 102))	('LINC00665', 'Gene', '100506930', (10, 19))	('suppressed', 'NegReg', (20, 30))	('impaired', 'NegReg', (82, 90))	('LINC00665', 'Gene', (10, 19))	('CCA', 'Phenotype', 'HP:0030153', (132, 135))	('Silencing', 'Var', (0, 9))	('Wnt/beta-Catenin signaling', 'MPA', (49, 75))	('stemness', 'CPA', (36, 44))	('gemcitabine tolerance', 'MPA', (91, 112))
167439	33436545	For example, Wnt/beta-Catenin signaling regulates ZEB1 expression in mantle cell lymphoma, and silencing ZEB1 suppresses cell proliferation and xenograft growth, and increases gemcitabine sensitivity of mantle cell lymphoma cells.	('ZEB1', 'Gene', '6935', (50, 54))	('mantle cell lymphoma', 'Disease', (203, 223))	('ZEB1', 'Gene', '6935', (105, 109))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (203, 223))	('cell proliferation', 'CPA', (121, 139))	('silencing', 'Var', (95, 104))	('gemcitabine sensitivity', 'MPA', (176, 199))	('lymphoma', 'Phenotype', 'HP:0002665', (215, 223))	('lymphoma', 'Phenotype', 'HP:0002665', (81, 89))	('cell lymphoma', 'Phenotype', 'HP:0012191', (76, 89))	('gemcitabine', 'Chemical', 'MESH:C056507', (176, 187))	('xenograft growth', 'CPA', (144, 160))	('ZEB1', 'Gene', (105, 109))	('ZEB1', 'Gene', (50, 54))	('cell lymphoma', 'Phenotype', 'HP:0012191', (210, 223))	('increases', 'PosReg', (166, 175))	('suppresses', 'NegReg', (110, 120))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (69, 89))	('mantle cell lymphoma', 'Disease', (69, 89))
167441	33436545	In genetic engineered mouse models of pancreatic cancer, restrain EMT by depletion of Snail or Twist does not affect metastasis, but enhanced gemcitabine sensitivity and increases overall survival of mice, highlights the importance of EMT in gemcitabine resistance.	('gemcitabine sensitivity', 'MPA', (142, 165))	('pancreatic cancer', 'Disease', (38, 55))	('pancreatic cancer', 'Disease', 'MESH:D010190', (38, 55))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Twist', 'Gene', (95, 100))	('increases', 'PosReg', (170, 179))	('gemcitabine', 'Chemical', 'MESH:C056507', (142, 153))	('depletion', 'Var', (73, 82))	('Snail', 'Gene', (86, 91))	('Snail', 'Gene', '20613', (86, 91))	('mice', 'Species', '10090', (200, 204))	('gemcitabine', 'Chemical', 'MESH:C056507', (242, 253))	('mouse', 'Species', '10090', (22, 27))	('Twist', 'Gene', '22160', (95, 100))	('enhanced', 'PosReg', (133, 141))
167469	33436545	Quickchange site-directed mutagenesis kit (Agilent Technologies, USA) was used to generate mutations at the predicted binding sites in LINC00665 and BCL9L.	('kit', 'Gene', (38, 41))	('LINC00665', 'Gene', (135, 144))	('kit', 'Gene', '3815', (38, 41))	('mutations', 'Var', (91, 100))	('LINC00665', 'Gene', '100506930', (135, 144))
167488	33436545	Cells were transfected with biotinylated wild-type or mutant miR-424-5p, or miR-ctrl.	('miR-424', 'Gene', '494336', (61, 68))	('miR', 'Gene', '220972', (61, 64))	('miR', 'Gene', (61, 64))	('biotin', 'Chemical', 'MESH:D001710', (28, 34))	('miR', 'Gene', '220972', (76, 79))	('mutant', 'Var', (54, 60))	('miR-424', 'Gene', (61, 68))	('miR', 'Gene', (76, 79))
167502	33436545	132102310187, 122102310137, and 172102310517), and the "23456" Talent Support Project of Henan people's hospital.	('people', 'Species', '9606', (95, 101))	('172102310517', 'Var', (32, 44))	('132102310187', 'Var', (0, 12))	('122102310137', 'Var', (14, 26))
167572	30206411	The Role of a Monoclonal Antibody 11C8B1 as a Diagnostic Marker of IDH2-Mutated Sinonasal Undifferentiated Carcinoma IDH2 R172 mutations occur in >80% sinonasal undifferentiated carcinomas ("SNUC") and ~80% of these are R172S and R172T variants.	('IDH2', 'Gene', (117, 121))	('undifferentiated carcinomas', 'Disease', (161, 188))	('IDH2', 'Gene', '3418', (117, 121))	('occur', 'Reg', (137, 142))	('Sinonasal Undifferentiated Carcinoma', 'Disease', 'MESH:C537344', (80, 116))	('Carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('undifferentiated carcinomas', 'Disease', 'MESH:D002277', (161, 188))	('mutations', 'Var', (127, 136))	('S', 'Chemical', 'MESH:D012694', (224, 225))	('IDH2', 'Gene', (67, 71))	('Sinonasal Undifferentiated Carcinoma', 'Disease', (80, 116))	('S', 'Chemical', 'MESH:D012694', (191, 192))	('S', 'Chemical', 'MESH:D012694', (80, 81))	('sinonasal undifferentiated carcinoma', 'Disease', 'MESH:C537344', (151, 187))	('IDH2', 'Gene', '3418', (67, 71))	('R172T', 'Mutation', 'p.R172T', (230, 235))	('sinonasal undifferentiated carcinoma', 'Disease', (151, 187))	('R172S', 'Mutation', 'rs1057519736', (220, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('carcinomas', 'Phenotype', 'HP:0030731', (178, 188))
167576	30206411	Interestingly, monoclonal antibody 11C8B1 was reactive with all IDH2 R172S (N = 15) mutated tumors including 12 sinonasal carcinomas, 2 high-grade sarcomas and one intrahepatic cholangiocarci- noma, and with all R172T (N = 3) mutated sinonasal carcinomas displaying a distinct granular cytoplasmic labeling in all R172S/T mutated malignancies.	('intrahepatic cholangiocarci- noma', 'Disease', (164, 197))	('R172S', 'Var', (314, 319))	('R172S', 'SUBSTITUTION', 'None', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('intrahepatic cholangiocarci- noma', 'Disease', 'MESH:D009625', (164, 197))	('carcinomas', 'Disease', (244, 254))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mutated', 'Var', (84, 91))	('sarcomas', 'Disease', 'MESH:D012509', (147, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('tumors', 'Disease', (92, 98))	('sarcomas', 'Phenotype', 'HP:0100242', (147, 155))	('R172S', 'SUBSTITUTION', 'None', (314, 319))	('carcinomas', 'Disease', (122, 132))	('sarcomas', 'Disease', (147, 155))	('malignancies', 'Disease', 'MESH:D009369', (330, 342))	('R172S', 'Mutation', 'rs1057519736', (69, 74))	('malignancies', 'Disease', (330, 342))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('carcinomas', 'Disease', 'MESH:D009369', (244, 254))	('IDH2', 'Gene', (64, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (244, 254))	('R172S', 'Var', (69, 74))	('R172T', 'Mutation', 'p.R172T', (212, 217))	('IDH2', 'Gene', '3418', (64, 68))	('carcinomas', 'Disease', 'MESH:D009369', (122, 132))	('R172S', 'Mutation', 'rs1057519736', (314, 319))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))
167577	30206411	11C8B1 immunohistochemistry was also positive in 2 of 6 IDH1 R132S-mutated tumors, including one intrahepatic cholangiocarcinoma and one chondrosarcoma showing a smooth homogeneous cytoplasmic staining pattern.	('chondrosarcoma', 'Disease', 'MESH:D002813', (137, 151))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('R132S', 'Mutation', 'rs121913499', (61, 66))	('R132S-mutated', 'Var', (61, 74))	('IDH1', 'Gene', '3417', (56, 60))	('intrahepatic cholangiocarcinoma', 'Disease', (97, 128))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (137, 151))	('tumors', 'Disease', (75, 81))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (97, 128))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('chondrosarcoma', 'Disease', (137, 151))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (110, 128))	('IDH1', 'Gene', (56, 60))
167578	30206411	All IDH2 R172G/K/M/W (N = 22) and IDH1 132H/C/G/L (N = 15) mutated tumors, and all IDH1/2-wild- type tumors (N=25), including a histologic variety of 23 sinonasal tumors, were immunonegative.	('R172G', 'Var', (9, 14))	('IDH1', 'Gene', '3417', (83, 87))	('132H/C', 'SUBSTITUTION', 'None', (39, 45))	('R172G', 'SUBSTITUTION', 'None', (9, 14))	('IDH1', 'Gene', '3417', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('IDH2', 'Gene', (4, 8))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('sinonasal tumors', 'Phenotype', 'HP:0030072', (153, 169))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('IDH2', 'Gene', '3418', (4, 8))	('mutated', 'Var', (59, 66))	('IDH1/2', 'Gene', '3417;3418', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('132H/C', 'Var', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Disease', (163, 169))	('sinonasal tumor', 'Phenotype', 'HP:0030072', (153, 168))	('tumors', 'Disease', (67, 73))	('IDH1', 'Gene', (83, 87))	('tumors', 'Disease', (101, 107))	('IDH1/2', 'Gene', (83, 89))	('L', 'Chemical', 'MESH:D007930', (48, 49))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('IDH1', 'Gene', (34, 38))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
167580	30206411	Literature search revealed a virtual absence of IDH2 R172 and IDH1 R132S mutations in >1000 cases of 8 different malignancies included in the differential diagnosis of sinonasal undifferentiated carcinoma.	('sinonasal undifferentiated carcinoma', 'Disease', (168, 204))	('absence', 'NegReg', (37, 44))	('IDH1', 'Gene', '3417', (62, 66))	('IDH2', 'Gene', '3418', (48, 52))	('malignancies', 'Disease', (113, 125))	('sinonasal undifferentiated carcinoma', 'Disease', 'MESH:C537344', (168, 204))	('IDH1', 'Gene', (62, 66))	('L', 'Chemical', 'MESH:D007930', (0, 1))	('IDH2', 'Gene', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('R132S', 'Var', (67, 72))	('malignancies', 'Disease', 'MESH:D009369', (113, 125))	('R132S', 'Mutation', 'rs121913499', (67, 72))
167581	30206411	Our study suggests that positive IDH2 11C8B1 immunohistochemistry in sinonasal carcinomas would be highly predictive of the presence of IDH2 R172S/T mutations and could serve as a reliable adjunct diagnostic marker of sinonasal undifferentiated carcinomas in >70% cases.	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))	('sinonasal undifferentiated carcinoma', 'Disease', 'MESH:C537344', (218, 254))	('carcinomas', 'Disease', (79, 89))	('carcinomas', 'Disease', 'MESH:D009369', (245, 255))	('IDH2', 'Gene', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('IDH2', 'Gene', (136, 140))	('undifferentiated carcinomas', 'Disease', 'MESH:D002277', (228, 255))	('carcinomas', 'Disease', (245, 255))	('undifferentiated carcinomas', 'Disease', (228, 255))	('R172S', 'Var', (141, 146))	('IDH2', 'Gene', '3418', (33, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (245, 255))	('IDH2', 'Gene', '3418', (136, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('carcinomas', 'Disease', 'MESH:D009369', (79, 89))	('sinonasal undifferentiated carcinoma', 'Disease', (218, 254))	('R172S', 'SUBSTITUTION', 'None', (141, 146))
167583	30206411	The IDH2 R172 mutant protein gains a neo- morphic ability to produce the "oncometabolite" 2- hydroxyglutarate, which results in histone and DNA hypermethylation, and ultimately leads to block in cellular differentiation.	('neo- morphic ability', 'MPA', (37, 57))	('cellular differentiation', 'CPA', (195, 219))	('leads to', 'Reg', (177, 185))	('mutant', 'Var', (14, 20))	('DNA hypermethylation', 'MPA', (140, 160))	('block', 'NegReg', (186, 191))	('gains', 'PosReg', (29, 34))	('2- hydroxyglutarate', 'Chemical', 'MESH:C019417', (90, 109))	('histone', 'MPA', (128, 135))	('IDH2', 'Gene', (4, 8))	('produce the "oncometabolite" 2- hydroxyglutarate', 'MPA', (61, 109))	('IDH2', 'Gene', '3418', (4, 8))	('R172 mutant', 'Var', (9, 20))	('protein', 'Protein', (21, 28))
167584	30206411	Over the past decade, activating somatic hotspot IDH1/2 mutations have been identified at variable proportions in various cancer types, including gliomas, chondrosarcomas, intrahepatic cholangiocarcinoma, acute myeloid leukemia, angioimmunoblastic T-cell lymphoma, and solid papillary carcinoma with reverse polarity, a rare breast carcinoma subtype.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (172, 203))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (155, 170))	('intrahepatic cholangiocarcinoma', 'Disease', (172, 203))	('lymphoma', 'Phenotype', 'HP:0002665', (255, 263))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (185, 203))	('chondrosarcomas', 'Disease', 'MESH:D002813', (155, 170))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (248, 263))	('solid papillary carcinoma', 'Disease', (269, 294))	('breast carcinoma', 'Disease', 'MESH:D001943', (325, 341))	('mutations', 'Var', (56, 65))	('angioimmunoblastic T-cell lymphoma', 'Disease', 'MESH:D016399', (229, 263))	('acute myeloid leukemia', 'Disease', (205, 227))	('gliomas', 'Disease', (146, 153))	('solid papillary carcinoma', 'Disease', 'MESH:D002291', (269, 294))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (332, 341))	('cell lymphoma', 'Phenotype', 'HP:0012191', (250, 263))	('chondrosarcomas', 'Disease', (155, 170))	('activating', 'PosReg', (22, 32))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (211, 227))	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (285, 294))	('leukemia', 'Phenotype', 'HP:0001909', (219, 227))	('breast carcinoma', 'Phenotype', 'HP:0003002', (325, 341))	('sarcomas', 'Phenotype', 'HP:0100242', (162, 170))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (205, 227))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (205, 227))	('breast carcinoma', 'Disease', (325, 341))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('cancer', 'Disease', (122, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('IDH1/2', 'Gene', '3417;3418', (49, 55))	('angioimmunoblastic T-cell lymphoma', 'Disease', (229, 263))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (155, 169))	('IDH1/2', 'Gene', (49, 55))
167585	30206411	Given the relatively higher frequency, and the diagnostic and prognostic significance of IDH1 mutations in gliomas for example, the immunohistochemical detection of IDH1 R132H has been well- established and widely used in surgical pathology.	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('mutations', 'Var', (94, 103))	('gliomas', 'Disease', (107, 114))	('R132H', 'Var', (170, 175))	('R132H', 'Mutation', 'rs121913500', (170, 175))	('IDH1', 'Gene', (165, 169))	('IDH1', 'Gene', (89, 93))	('IDH1', 'Gene', '3417', (165, 169))	('IDH1', 'Gene', '3417', (89, 93))
167586	30206411	In contrast, IDH2 mutations are less common, which may explain the lack of an established IDH2 immunohistochemistry protocols.	('IDH2', 'Gene', '3418', (90, 94))	('IDH2', 'Gene', (13, 17))	('IDH2', 'Gene', '3418', (13, 17))	('IDH2', 'Gene', (90, 94))	('mutations', 'Var', (18, 27))
167587	30206411	Recently, we showed that the vast majority of sinonasal undifferentiated carcinomas ("SNUC", 82%), and a variable proportion of other high- grade sinonasal epithelial malignancies, such as high- grade neuroendocrine carcinomas, large cell type, and poorly differentiated carcinomas with glandular/acinar differentiation, harbor somatic IDH2 R172 mutations with about 80% being either R172S or R172T variants.	('neuroendocrine carcinomas', 'Disease', (201, 226))	('R172S', 'Mutation', 'rs1057519736', (384, 389))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (201, 226))	('carcinomas', 'Disease', 'MESH:D009369', (271, 281))	('carcinomas', 'Disease', 'MESH:D009369', (216, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	('malignancies', 'Disease', 'MESH:D009369', (167, 179))	('carcinomas', 'Phenotype', 'HP:0030731', (271, 281))	('R172T', 'Mutation', 'p.R172T', (393, 398))	('carcinomas', 'Phenotype', 'HP:0030731', (216, 226))	('undifferentiated carcinomas', 'Disease', (56, 83))	('carcinomas', 'Disease', 'MESH:D009369', (73, 83))	('malignancies', 'Disease', (167, 179))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (201, 225))	('undifferentiated carcinomas', 'Disease', 'MESH:D002277', (56, 83))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (201, 226))	('IDH2', 'Gene', (336, 340))	('mutations', 'Var', (346, 355))	('IDH2', 'Gene', '3418', (336, 340))	('sinonasal undifferentiated carcinoma', 'Disease', 'MESH:C537344', (46, 82))	('S', 'Chemical', 'MESH:D012694', (388, 389))	('carcinomas', 'Disease', (271, 281))	('carcinomas', 'Disease', (216, 226))	('S', 'Chemical', 'MESH:D012694', (86, 87))	('carcinomas', 'Disease', (73, 83))	('sinonasal undifferentiated carcinoma', 'Disease', (46, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (156, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
167589	30206411	; although, the frequency of IDH2 mutant sinonasal undifferentiated carcinomas in their cohort of 11 cases was lower.	('undifferentiated carcinomas', 'Disease', 'MESH:D002277', (51, 78))	('IDH2', 'Gene', (29, 33))	('undifferentiated carcinomas', 'Disease', (51, 78))	('sinonasal undifferentiated carcinoma', 'Disease', (41, 77))	('sinonasal undifferentiated carcinoma', 'Disease', 'MESH:C537344', (41, 77))	('IDH2', 'Gene', '3418', (29, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))	('mutant', 'Var', (34, 40))
167590	30206411	IDH2 single nucleotide variants are typically detected by DNA-based sequencing assays, which may be costly, time-consuming or simply unavailable in a pathology practice.	('single nucleotide variants', 'Var', (5, 31))	('IDH2', 'Gene', (0, 4))	('IDH2', 'Gene', '3418', (0, 4))
167591	30206411	An implementation of immunohistochemical assays targeting specifically IDH2 mutant proteins may provide a rapid, inexpensive alternate and/or corroborating method for mutant protein detection and help select cases amenable for further IDH2 mutation confirmation.	('IDH2', 'Gene', (235, 239))	('proteins', 'Protein', (83, 91))	('IDH2', 'Gene', (71, 75))	('mutant', 'Var', (76, 82))	('IDH2', 'Gene', '3418', (235, 239))	('IDH2', 'Gene', '3418', (71, 75))
167592	30206411	Except for a single study exploring the utility of a multispecific antibody against IDH1/IDH2 mutant proteins in sinonasal tumors, monoclonal antibodies for specific detection of IDH2 R172S mutant protein have not been evaluated in formalin-fixed surgical specimens.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('sinonasal tumor', 'Phenotype', 'HP:0030072', (113, 128))	('sinonasal tumors', 'Phenotype', 'HP:0030072', (113, 129))	('IDH1', 'Gene', (84, 88))	('proteins', 'Protein', (101, 109))	('mutant', 'Var', (94, 100))	('IDH2', 'Gene', (179, 183))	('formalin', 'Chemical', 'MESH:D005557', (232, 240))	('R172S', 'Var', (184, 189))	('IDH2', 'Gene', (89, 93))	('IDH1', 'Gene', '3417', (84, 88))	('R172S', 'Mutation', 'rs1057519736', (184, 189))	('IDH2', 'Gene', '3418', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('IDH2', 'Gene', '3418', (89, 93))
167594	30206411	In view of the very high recurrence rate of these mutations in sinonasal undifferentiated carcinomas in particular, we sought to explore potential advantages of IDH2 R172S immunohistochemistry as an adjunct diagnostic marker in this tumor type.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('undifferentiated carcinomas', 'Disease', 'MESH:D002277', (73, 100))	('sinonasal undifferentiated carcinoma', 'Disease', (63, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('tumor', 'Disease', (233, 238))	('mutations', 'Var', (50, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('undifferentiated carcinomas', 'Disease', (73, 100))	('IDH2', 'Gene', (161, 165))	('sinonasal undifferentiated carcinoma', 'Disease', 'MESH:C537344', (63, 99))	('R172S', 'Mutation', 'rs1057519736', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('IDH2', 'Gene', '3418', (161, 165))
167604	30206411	For the original assessment of the immunohistochemical properties, we employed chondrosarcoma cell line SW1353, known to harbor IDH2 R172S mutation.	('SW1353', 'CellLine', 'CVCL:0543', (104, 110))	('chondrosarcoma', 'Disease', 'MESH:D002813', (79, 93))	('IDH2', 'Gene', '3418', (128, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('chondrosarcoma', 'Disease', (79, 93))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (79, 93))	('IDH2', 'Gene', (128, 132))	('R172S', 'Mutation', 'rs1057519736', (133, 138))	('R172S', 'Var', (133, 138))
167605	30206411	The authenticity of SW1353 was confirmed by short tandem repeats (STR) analysis (data not shown) and the presence of the mutation was confirmed by Sanger sequencing (data not shown).	('short tandem repeats', 'Var', (44, 64))	('S', 'Chemical', 'MESH:D012694', (147, 148))	('SW1353', 'Gene', (20, 26))	('S', 'Chemical', 'MESH:D012694', (66, 67))	('SW1353', 'CellLine', 'CVCL:0543', (20, 26))	('S', 'Chemical', 'MESH:D012694', (20, 21))
167606	30206411	Cell pellets of SW1353 displayed consistent strong immunopositivity and sections thereof proved to be valuable positive controls and were also used for monoclonal antibody optimization.	('SW1353', 'Var', (16, 22))	('SW1353', 'CellLine', 'CVCL:0543', (16, 22))	('immunopositivity', 'MPA', (51, 67))
167610	30206411	Once the conditions were optimized we used this protocol to test a pre-genotyped cohort of IDH1/2 mutated and IDH1/2 wild- type tumors as outlined above for immunoreactivity with 11C8B1.	('IDH1/2', 'Gene', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('IDH1/2', 'Gene', '3417;3418', (110, 116))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('mutated', 'Var', (98, 105))	('IDH1/2', 'Gene', (110, 116))	('IDH1/2', 'Gene', '3417;3418', (91, 97))
167612	30206411	Among the tumors with known IDH1/2 mutations status all IDH2 R172S mutant tumors (15/15, 100%), including 12 sinonasal carcinomas (Fig.	('carcinomas', 'Disease', (119, 129))	('IDH2', 'Gene', '3418', (56, 60))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('IDH1/2', 'Gene', '3417;3418', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('IDH1/2', 'Gene', (28, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('carcinomas', 'Disease', 'MESH:D009369', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('R172S mutant', 'Var', (61, 73))	('R172S', 'Mutation', 'rs1057519736', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('mutant', 'Var', (67, 73))	('IDH2', 'Gene', (56, 60))	('tumors', 'Disease', (74, 80))
167615	30206411	In addition, all three IDH2 R172T-mutated sinonasal carcinomas (3/3, 100%) were immunopositive for 11C8B1.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('IDH2', 'Gene', (23, 27))	('carcinomas', 'Disease', (52, 62))	('R172T-mutated', 'Var', (28, 41))	('IDH2', 'Gene', '3418', (23, 27))	('R172T', 'Mutation', 'p.R172T', (28, 33))	('carcinomas', 'Disease', 'MESH:D009369', (52, 62))
167616	30206411	Interestingly, two out of six IDH1 R132S cases, including one intrahepatic cholangiocarcinoma, and one chondrosarcoma were also immunopositive although dis- played a staining pattern distinct from that observed in IDH2 R172S/T mutant tumors (Fig.	('chondrosarcoma', 'Disease', (103, 117))	('chondrosarcoma', 'Disease', 'MESH:D002813', (103, 117))	('IDH2', 'Gene', (214, 218))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (75, 93))	('R172S', 'Var', (219, 224))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('IDH2', 'Gene', '3418', (214, 218))	('R132S', 'Mutation', 'rs121913499', (35, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (103, 117))	('R172S', 'SUBSTITUTION', 'None', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('IDH1', 'Gene', (30, 34))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (62, 93))	('intrahepatic cholangiocarcinoma', 'Disease', (62, 93))	('tumors', 'Disease', (234, 240))	('IDH1', 'Gene', '3417', (30, 34))
167617	30206411	All tumors harboring either IDH2 R172K/G/W/M (N = 22) or IDH1 132 H/G/C/L (N = 15) mutations, and all IDH1/2 wild-type tumors (N = 25), including a histologic variety of 23 sinonasal tumors, were negative for 11C8B1 immuno- histochemistry.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('IDH1', 'Gene', (57, 61))	('tumors', 'Disease', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('IDH1/2', 'Gene', '3417;3418', (102, 108))	('tumors', 'Disease', (119, 125))	('R172K', 'Var', (33, 38))	('IDH1', 'Gene', (102, 106))	('IDH1/2', 'Gene', (102, 108))	('IDH2', 'Gene', (28, 32))	('IDH1', 'Gene', '3417', (57, 61))	('132 H/G', 'Var', (62, 69))	('sinonasal tumor', 'Phenotype', 'HP:0030072', (173, 188))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('R172K', 'SUBSTITUTION', 'None', (33, 38))	('IDH2', 'Gene', '3418', (28, 32))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('132 H/G', 'SUBSTITUTION', 'None', (62, 69))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('sinonasal tumors', 'Phenotype', 'HP:0030072', (173, 189))	('IDH1', 'Gene', '3417', (102, 106))	('mutations', 'Var', (83, 92))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('L', 'Chemical', 'MESH:D007930', (72, 73))
167619	30206411	Notably, among all sinonasal undifferentiated carcinomas irrespective of their IDH1/2 mutation status, 11 (N = 14, 79%) cases were positive for 11C8B1 immunohistochemistry, as well as all three IDH2 R172S/T-mutated high-grade neuroendocrine carcinomas, large cell type.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('carcinomas', 'Phenotype', 'HP:0030731', (241, 251))	('IDH1/2', 'Gene', '3417;3418', (79, 85))	('positive', 'Reg', (131, 139))	('IDH1/2', 'Gene', (79, 85))	('11C8B1', 'Gene', (144, 150))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (226, 250))	('sinonasal undifferentiated carcinoma', 'Disease', 'MESH:C537344', (19, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (226, 251))	('sinonasal undifferentiated carcinoma', 'Disease', (19, 55))	('IDH2', 'Gene', (194, 198))	('R172S', 'Var', (199, 204))	('undifferentiated carcinomas', 'Disease', (29, 56))	('IDH2', 'Gene', '3418', (194, 198))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('undifferentiated carcinomas', 'Disease', 'MESH:D002277', (29, 56))	('R172S', 'SUBSTITUTION', 'None', (199, 204))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (226, 251))	('neuroendocrine carcinomas', 'Disease', (226, 251))
167620	30206411	The immunohistochemical stain in all IDH2 R172S/T mutated cases was diffuse and moderate to strong in all cases except for one IDH2 R172T-mutated high-grade neuroendocrine carcinomas, large cell type (Fig.	('R172T-mutated', 'Var', (132, 145))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (157, 181))	('R172T', 'Mutation', 'p.R172T', (132, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (172, 182))	('IDH2', 'Gene', (37, 41))	('IDH2', 'Gene', (127, 131))	('R172S', 'Var', (42, 47))	('IDH2', 'Gene', '3418', (37, 41))	('IDH2', 'Gene', '3418', (127, 131))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (157, 182))	('R172S', 'SUBSTITUTION', 'None', (42, 47))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (157, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('neuroendocrine carcinomas', 'Disease', (157, 182))
167622	30206411	Importantly, all IDH2 R172S/T-mutated malignancies showed strong granular cytoplasmic labeling, including sinonasal carcinomas (Fig.	('carcinomas', 'Disease', (116, 126))	('R172S', 'SUBSTITUTION', 'None', (22, 27))	('malignancies', 'Disease', 'MESH:D009369', (38, 50))	('IDH2', 'Gene', (17, 21))	('granular cytoplasmic labeling', 'MPA', (65, 94))	('carcinomas', 'Disease', 'MESH:D009369', (116, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('malignancies', 'Disease', (38, 50))	('IDH2', 'Gene', '3418', (17, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('R172S', 'Var', (22, 27))
167624	30206411	In contrast, the two IDH1 R132S-mutated tumors showed a homogeneous diffuse cytoplasmic staining lacking the distinct granularity observed in IDH2 R172S/T-mutated cases (Fig.	('R132S-mutated', 'Var', (26, 39))	('IDH2', 'Gene', '3418', (142, 146))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('R132S', 'Mutation', 'rs121913499', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('R172S', 'Var', (147, 152))	('R172S', 'SUBSTITUTION', 'None', (147, 152))	('IDH1', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('IDH2', 'Gene', (142, 146))	('IDH1', 'Gene', '3417', (21, 25))	('tumors', 'Disease', (40, 46))
167625	30206411	Our immunohistochemistry results suggested that finding a positive immunostaining with monoclonal antibody 11C8B1 immunohistochemistry in a tumor without IDH2 R172S/T or IDH1 R132S mutation would be very unlikely.	('IDH1', 'Gene', (170, 174))	('R132S', 'Mutation', 'rs121913499', (175, 180))	('IDH1', 'Gene', '3417', (170, 174))	('IDH2', 'Gene', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('R172S', 'Var', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('IDH2', 'Gene', '3418', (154, 158))	('R172S', 'SUBSTITUTION', 'None', (159, 164))	('R132S', 'Var', (175, 180))	('tumor', 'Disease', (140, 145))
167626	30206411	This prompted us to search the literature to determine the frequency of these mutations in other tumors with emphasis on entities arising in the head and neck.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutations', 'Var', (78, 87))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
167627	30206411	Next-generation sequencing studies failed to reveal any IDH2 mutation in >1000 cases among 8 relatively common entities that would be considered in the differential diagnosis of sinonasal undifferentiated carcinoma (Table 2), while an IDH1 R132C variant occurred in a single case of adenoid cystic carcinoma.	('sinonasal undifferentiated carcinoma', 'Disease', (178, 214))	('IDH2', 'Gene', '3418', (56, 60))	('adenoid cystic carcinoma', 'Disease', (283, 307))	('IDH1', 'Gene', (235, 239))	('sinonasal undifferentiated carcinoma', 'Disease', 'MESH:C537344', (178, 214))	('mutation', 'Var', (61, 69))	('R132C', 'Mutation', 'rs121913499', (240, 245))	('IDH1', 'Gene', '3417', (235, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (283, 307))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))	('IDH2', 'Gene', (56, 60))
167628	30206411	In addition, based on our own institutional experience reported in a pan-cancer study on >10,000 various predominantly solid malignancies profiled by MSK- IMPACT  IDH2 hotspot variants occurred in only 0.3% cases with R172S/T mutations being detected in total 4 (0.04%) cases including one of each; chondrosarcoma, angioimmunoblastic T-cell lymphoma, intrahepatic cholangiocarcinoma, and sinonasal undifferentiated carcinoma.	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (334, 349))	('R172S', 'Var', (218, 223))	('cancer', 'Disease', (73, 79))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (351, 382))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('intrahepatic cholangiocarcinoma', 'Disease', (351, 382))	('variants', 'Var', (176, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (373, 382))	('IDH2', 'Gene', (163, 167))	('cell lymphoma', 'Phenotype', 'HP:0012191', (336, 349))	('lymphoma', 'Phenotype', 'HP:0002665', (341, 349))	('R172S', 'SUBSTITUTION', 'None', (218, 223))	('sinonasal undifferentiated carcinoma', 'Disease', 'MESH:C537344', (388, 424))	('IDH2', 'Gene', '3418', (163, 167))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (364, 382))	('malignancies', 'Disease', 'MESH:D009369', (125, 137))	('chondrosarcoma, angioimmunoblastic T-cell lymphoma', 'Disease', 'MESH:D016399', (299, 349))	('S', 'Chemical', 'MESH:D012694', (222, 223))	('sinonasal undifferentiated carcinoma', 'Disease', (388, 424))	('malignancies', 'Disease', (125, 137))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('S', 'Chemical', 'MESH:D012694', (151, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (306, 313))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (299, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (415, 424))
167629	30206411	IDH1 hotspot mutations occurred in 2.5% cases including only 4 (0.04%) R132S variants detected in the tumors outside of the sinonasal tract (Table 2).	('R132S', 'Mutation', 'rs121913499', (71, 76))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('R132S', 'Var', (71, 76))	('IDH1', 'Gene', '3417', (0, 4))
167630	30206411	Prompted by previous findings of highly recurrent IDH2 hotspot alterations, namely R172S/T variants in sinonasal undifferentiated carcinoma, in the present study, we explored the feasibility and utility of an immunohistochemical assay in detecting the mutated IDH2 protein in standard archival surgical pathology specimens with a particular emphasis on potential diagnostic application of this immunostain in carcinomas of the sinonasal tract.	('IDH2', 'Gene', (50, 54))	('carcinomas', 'Disease', (409, 419))	('alterations', 'Var', (63, 74))	('R172S', 'SUBSTITUTION', 'None', (83, 88))	('protein', 'Protein', (265, 272))	('IDH2', 'Gene', '3418', (50, 54))	('R172S', 'Var', (83, 88))	('sinonasal undifferentiated carcinoma', 'Disease', (103, 139))	('IDH2', 'Gene', (260, 264))	('carcinomas', 'Phenotype', 'HP:0030731', (409, 419))	('variants', 'Var', (91, 99))	('mutated', 'Var', (252, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (409, 418))	('carcinomas', 'Disease', 'MESH:D009369', (409, 419))	('IDH2', 'Gene', '3418', (260, 264))	('sinonasal undifferentiated carcinoma', 'Disease', 'MESH:C537344', (103, 139))
167632	30206411	Due to the high homology in the protein structure between the IDH2 and IDH1 mutation hotspot regions R172 and R132 respectively, testing of a variety of IDH1 R132 mutants such as those having argi- nine (R) substituted by cysteine (C), histidine (H), leucine (L), glycine (G), or serine (S) was essential to explore potential cross-reactivity of the IDH2 11C8B1 antibody with IDH1 R132-mutated proteins.	('IDH1', 'Gene', (153, 157))	('argi', 'Chemical', '-', (192, 196))	('IDH1', 'Gene', '3417', (376, 380))	('mutants', 'Var', (163, 170))	('histidine', 'Chemical', 'MESH:D006639', (236, 245))	('IDH2', 'Gene', (62, 66))	('IDH2', 'Gene', '3418', (62, 66))	('leucine', 'Chemical', 'MESH:D007930', (251, 258))	('IDH1', 'Gene', '3417', (153, 157))	('L', 'Chemical', 'MESH:D007930', (260, 261))	('IDH1', 'Gene', (71, 75))	('glycine', 'Chemical', 'MESH:D005998', (264, 271))	('cysteine', 'Chemical', 'MESH:D003545', (222, 230))	('S', 'Chemical', 'MESH:D012694', (288, 289))	('serine', 'Chemical', 'MESH:D012694', (280, 286))	('IDH1', 'Gene', '3417', (71, 75))	('IDH1', 'Gene', (376, 380))	('IDH2', 'Gene', (350, 354))	('IDH2', 'Gene', '3418', (350, 354))
167633	30206411	11C8B1 showed consistent and strong granular cytoplasmic immunoreactivity with IDH2 R172S and IDH2 R172T mutant proteins consistent with mitochondrial localization of IDH2 protein.	('IDH2', 'Gene', '3418', (79, 83))	('granular cytoplasmic immunoreactivity', 'MPA', (36, 73))	('IDH2', 'Gene', '3418', (94, 98))	('IDH2', 'Gene', (167, 171))	('R172T', 'Var', (99, 104))	('R172T', 'Mutation', 'p.R172T', (99, 104))	('IDH2', 'Gene', (79, 83))	('IDH2', 'Gene', '3418', (167, 171))	('R172S', 'Mutation', 'rs1057519736', (84, 89))	('proteins', 'Protein', (112, 120))	('R172S', 'Var', (84, 89))	('IDH2', 'Gene', (94, 98))
167634	30206411	It also showed weak to moderately strong homogeneous cytoplasmic immunoreactivity in the minority of IDH1 R132S-mutated cases despite the manufacturer's designation this being a mono- clonal antibody raised specifically against the IDH2 R172S protein.	('IDH1', 'Gene', (101, 105))	('R132S', 'Mutation', 'rs121913499', (106, 111))	('IDH1', 'Gene', '3417', (101, 105))	('R132S-mutated', 'Var', (106, 119))	('IDH2', 'Gene', (232, 236))	('R172S', 'Mutation', 'rs1057519736', (237, 242))	('homogeneous cytoplasmic immunoreactivity', 'MPA', (41, 81))	('IDH2', 'Gene', '3418', (232, 236))
167635	30206411	The cross-reactivity of the monoclonal antibody 11C8B1 between the R172S antibody and R172T mutant protein may be explained by a remarkable similarity in the chemical structure and properties between serine and threonine, which are both polar and neutral amino acids.	('R172T', 'Var', (86, 91))	('R172S', 'Var', (67, 72))	('serine', 'Chemical', 'MESH:D012694', (200, 206))	('threonine', 'Chemical', 'MESH:D013912', (211, 220))	('R172T', 'Mutation', 'p.R172T', (86, 91))	('R172S', 'Mutation', 'rs1057519736', (67, 72))
167636	30206411	However, from a practical perspective this relative lack in specificity has proven to be useful as we were able to detect all R172S/T variants by a single IDH2 monoclonal antibody.	('R172S', 'Var', (126, 131))	('IDH2', 'Gene', '3418', (155, 159))	('detect', 'Reg', (115, 121))	('R172S', 'SUBSTITUTION', 'None', (126, 131))	('IDH2', 'Gene', (155, 159))
167637	30206411	Similarly, given the high homology in the protein sequence between the IDH2 R172S and IDH1 R132S, the immunoreactivity of monoclonal antibody 11C8B1 observed in some IDH1 R132S mutants would not be unusual.	('IDH1', 'Gene', (166, 170))	('R132S', 'Mutation', 'rs121913499', (91, 96))	('IDH1', 'Gene', (86, 90))	('S', 'Chemical', 'MESH:D012694', (95, 96))	('R132S', 'Mutation', 'rs121913499', (171, 176))	('IDH1', 'Gene', '3417', (166, 170))	('IDH2', 'Gene', (71, 75))	('IDH1', 'Gene', '3417', (86, 90))	('mutants', 'Var', (177, 184))	('S', 'Chemical', 'MESH:D012694', (80, 81))	('R172S', 'Mutation', 'rs1057519736', (76, 81))	('IDH2', 'Gene', '3418', (71, 75))	('R172S', 'Var', (76, 81))	('R132S mutants', 'Var', (171, 184))	('S', 'Chemical', 'MESH:D012694', (175, 176))	('S', 'Chemical', 'MESH:D012694', (0, 1))
167638	30206411	The reasons for the lack of detection in other IDH1 R132S-mutated cases remain unclear.	('IDH1', 'Gene', '3417', (47, 51))	('R132S-mutated', 'Var', (52, 65))	('IDH1', 'Gene', (47, 51))	('R132S', 'Mutation', 'rs121913499', (52, 57))
167639	30206411	Importantly, along with IDH2 R172K/G/W/M all remaining IDH1 variants such as R132G/C/H/L were immunohistochemically negative for 11C8B1.	('IDH1', 'Gene', '3417', (55, 59))	('R172K', 'Var', (29, 34))	('R132G', 'SUBSTITUTION', 'None', (77, 82))	('R132G', 'Var', (77, 82))	('IDH2', 'Gene', (24, 28))	('R172K', 'SUBSTITUTION', 'None', (29, 34))	('IDH1', 'Gene', (55, 59))	('IDH2', 'Gene', '3418', (24, 28))
167640	30206411	We also showed that the IDH2 R172S-mutated SW1353 chondrosarcoma cell line pellets may serve as an inexhaustible positive control for IDH2 R172S immunohistochemistry, thus representing a suitable alternative to often limited clinical biopsy specimens.	('R172S', 'Mutation', 'rs1057519736', (139, 144))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (50, 64))	('SW1353', 'CellLine', 'CVCL:0543', (43, 49))	('R172S-mutated', 'Var', (29, 42))	('IDH2', 'Gene', (134, 138))	('IDH2', 'Gene', (24, 28))	('chondrosarcoma', 'Disease', 'MESH:D002813', (50, 64))	('chondrosarcoma', 'Disease', (50, 64))	('IDH2', 'Gene', '3418', (134, 138))	('R172S', 'Mutation', 'rs1057519736', (29, 34))	('SW1353', 'Gene', (43, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('IDH2', 'Gene', '3418', (24, 28))
167641	30206411	Massively parallel sequencing studies have shown that, except for a single IDH1 R132C-mutated adenoid cystic carcinoma, other IDH1 and IDH2 hotspot mutations are virtually absent in multiple tumor types that would typically be included in the differential diagnosis of sinonasal undifferentiated carcinoma.	('IDH1', 'Gene', '3417', (126, 130))	('IDH2', 'Gene', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (94, 118))	('sinonasal undifferentiated carcinoma', 'Disease', (269, 305))	('IDH2', 'Gene', '3418', (135, 139))	('IDH1', 'Gene', (75, 79))	('sinonasal undifferentiated carcinoma', 'Disease', 'MESH:C537344', (269, 305))	('R132C-mutated', 'Var', (80, 93))	('tumor', 'Disease', (191, 196))	('IDH1', 'Gene', (126, 130))	('R132C', 'Mutation', 'rs121913499', (80, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('IDH1', 'Gene', '3417', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('adenoid cystic carcinoma', 'Disease', (94, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))
167643	30206411	In addition, based on our limited experience, none of the 10 next-generation sequencing-profiled SMARCB1-deficient sinonasal carcinomas were found with a co-existing IDH2 or IDH1 variant [, including unpublished experience].	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('SMARCB1-deficient sinonasal carcinomas', 'Disease', (97, 135))	('IDH2', 'Gene', '3418', (166, 170))	('SMARCB1-deficient sinonasal carcinomas', 'Disease', 'MESH:C537344', (97, 135))	('IDH1', 'Gene', (174, 178))	('variant', 'Var', (179, 186))	('IDH1', 'Gene', '3417', (174, 178))	('IDH2', 'Gene', (166, 170))
167645	30206411	Aside from sinonasal undifferentiated carcinoma, IDH2 R172S/T mutations may be highly recurrent in high-grade neuroendocrine carcinomas, large cell type as well.	('R172S', 'Var', (54, 59))	('sinonasal undifferentiated carcinoma', 'Disease', (11, 47))	('IDH2', 'Gene', '3418', (49, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (110, 135))	('R172S', 'SUBSTITUTION', 'None', (54, 59))	('sinonasal undifferentiated carcinoma', 'Disease', 'MESH:C537344', (11, 47))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (110, 135))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (110, 134))	('neuroendocrine carcinomas', 'Disease', (110, 135))	('IDH2', 'Gene', (49, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('large cell type', 'Disease', (137, 152))
167646	30206411	Taking into account one IDH2-wild-type case we reported previously, in our experience, 3 of 4 (75%) high-grade neuroendocrine carcinomas, large cell type harbored IDH2 R172S/T variants.	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (111, 135))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (111, 136))	('neuroendocrine carcinomas', 'Disease', (111, 136))	('R172S', 'Var', (168, 173))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (111, 136))	('IDH2', 'Gene', '3418', (163, 167))	('IDH2', 'Gene', (24, 28))	('R172S', 'SUBSTITUTION', 'None', (168, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('IDH2', 'Gene', '3418', (24, 28))	('IDH2', 'Gene', (163, 167))
167649	30206411	Although such a small number of tested samples precludes any definitive conclusions, we speculate that the IDH2 variants in sino- nasal small cell neuroendocrine carcinoma might be as uncommon as in pulmonary small cell carcinomas.	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (147, 171))	('neuroendocrine carcinoma', 'Disease', (147, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('carcinomas', 'Phenotype', 'HP:0030731', (220, 230))	('IDH2', 'Gene', '3418', (107, 111))	('pulmonary small cell carcinomas', 'Disease', 'MESH:D018288', (199, 230))	('small cell carcinomas', 'Phenotype', 'HP:0030357', (209, 230))	('- nasal small', 'Phenotype', 'HP:0009924', (128, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (147, 171))	('pulmonary small cell carcinomas', 'Disease', (199, 230))	('IDH2', 'Gene', (107, 111))	('variants', 'Var', (112, 120))
167650	30206411	IDH2 mutations were not detected in any of 282 lung small cell carcinomas examined by a massive parallel sequencing.	('lung small cell carcinomas', 'Disease', 'MESH:D055752', (47, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('lung small', 'Phenotype', 'HP:0002089', (47, 57))	('mutations', 'Var', (5, 14))	('IDH2', 'Gene', (0, 4))	('small cell carcinomas', 'Phenotype', 'HP:0030357', (52, 73))	('lung small cell carcinomas', 'Disease', (47, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('IDH2', 'Gene', '3418', (0, 4))
167655	30206411	A more extensive diagnostic work-up, including costly ancillary studies such as in situ hybridization studies and/or molecular assays, may be considered only in IDH2 11C8B1 negative cases to rule out other entities, and/or to identify cases harboring less common variants such as IDH2 R172G or R172M.	('R172M', 'Mutation', 'rs121913503', (294, 299))	('R172M', 'Var', (294, 299))	('IDH2', 'Gene', (280, 284))	('IDH2', 'Gene', (161, 165))	('IDH2', 'Gene', '3418', (280, 284))	('R172G', 'Mutation', 'rs1057519906', (285, 290))	('R172G', 'Var', (285, 290))	('IDH2', 'Gene', '3418', (161, 165))
167656	30206411	In carcinomas outside of the sinonasal tract, a high frequency of IDH2 R172 variants was found in 77% solid papillary breast carcinomas with reverse polarity, a rare subtype characterized by a distinct histologic appearance resembling tall cell variant of papillary thyroid carcinoma.	('carcinomas', 'Phenotype', 'HP:0030731', (3, 13))	('breast carcinomas', 'Phenotype', 'HP:0003002', (118, 135))	('papillary thyroid carcinoma', 'Disease', (256, 283))	('carcinomas', 'Disease', (125, 135))	('variants', 'Var', (76, 84))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (256, 283))	('papillary breast carcinomas', 'Disease', 'MESH:D001943', (108, 135))	('found', 'Reg', (89, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Disease', 'MESH:D009369', (125, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('carcinomas', 'Disease', (3, 13))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (266, 283))	('tall cell variant', 'Disease', (235, 252))	('IDH2', 'Gene', (66, 70))	('papillary breast carcinomas', 'Disease', (108, 135))	('IDH2', 'Gene', '3418', (66, 70))	('breast carcinoma', 'Phenotype', 'HP:0003002', (118, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('carcinomas', 'Disease', 'MESH:D009369', (3, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (3, 12))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (256, 283))
167657	30206411	In intrahepatic cholangiocarcinoma, IDH1 and IDH2 hotspot mutations occur in about 10% and 5% cases, respectively, and minority of those are R132S or R172S variants.	('mutations', 'Var', (58, 67))	('R172S', 'Mutation', 'rs1057519736', (150, 155))	('IDH1', 'Gene', (36, 40))	('R172S', 'Var', (150, 155))	('occur', 'Reg', (68, 73))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 34))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (16, 34))	('intrahepatic cholangiocarcinoma', 'Disease', (3, 34))	('R132S', 'Var', (141, 146))	('IDH1', 'Gene', '3417', (36, 40))	('IDH2', 'Gene', (45, 49))	('R132S', 'Mutation', 'rs121913499', (141, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('IDH2', 'Gene', '3418', (45, 49))
167660	30206411	Although IDH1 R132S and IDH2 R172S/T-mutated tumors cannot be distinguished based on the presence of 11C8B1 immunopositivity alone, a homogeneous cytoplasmic dis- tribution i.e., a lack-of-distinct granularity in labeling may suggest IDH1 R132S over IDH2 R172S/T mutant.	('IDH1', 'Gene', (9, 13))	('R132S', 'Mutation', 'rs121913499', (239, 244))	('R172S', 'SUBSTITUTION', 'None', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('IDH1', 'Gene', '3417', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('IDH2', 'Gene', (250, 254))	('R132S', 'Mutation', 'rs121913499', (14, 19))	('R172S', 'Var', (255, 260))	('IDH2', 'Gene', '3418', (250, 254))	('IDH1', 'Gene', (234, 238))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('IDH2', 'Gene', (24, 28))	('R172S', 'SUBSTITUTION', 'None', (255, 260))	('11C8B1', 'Gene', (101, 107))	('IDH2', 'Gene', '3418', (24, 28))	('R172S', 'Var', (29, 34))	('IDH1', 'Gene', '3417', (234, 238))
167661	30206411	Further on, IDH2 11C8B1 immunohistochemistry may have therapeutic implications in clinical practice since mutant IDH2 proteins represent an attractive therapeutic target.	('IDH2', 'Gene', (12, 16))	('mutant', 'Var', (106, 112))	('IDH2', 'Gene', (113, 117))	('proteins', 'Protein', (118, 126))	('IDH2', 'Gene', '3418', (12, 16))	('IDH2', 'Gene', '3418', (113, 117))
167663	30206411	These findings suggest that a similar treatment approach may eventually be explored in other tumors harboring IDH2 mutations, including sinonasal carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('IDH2', 'Gene', '3418', (110, 114))	('mutations', 'Var', (115, 124))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('carcinomas', 'Disease', 'MESH:D009369', (146, 156))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('carcinomas', 'Disease', (146, 156))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('IDH2', 'Gene', (110, 114))	('tumors', 'Disease', (93, 99))
167664	30206411	In such cases, an addition of IDH2 immunohistochemistry in a diagnostic work-up could easily identify the cases amenable for further molecular IDH2 mutation confirmation and help select patients for clinical IDH2-inhibitors trials.	('IDH2', 'Gene', (208, 212))	('IDH2', 'Gene', (143, 147))	('IDH2', 'Gene', (30, 34))	('IDH2', 'Gene', '3418', (208, 212))	('IDH2', 'Gene', '3418', (143, 147))	('IDH2', 'Gene', '3418', (30, 34))	('mutation', 'Var', (148, 156))	('patients', 'Species', '9606', (186, 194))
167665	30206411	In conclusion, here we provide a first established immunohistochemical protocol for detection of mutant IDH2 using monoclonal antibody 11C8B1 in formalin-fixed paraffin-embedded surgical specimens.	('IDH2', 'Gene', '3418', (104, 108))	('formalin', 'Chemical', 'MESH:D005557', (145, 153))	('mutant', 'Var', (97, 103))	('paraffin', 'Chemical', 'MESH:D010232', (160, 168))	('IDH2', 'Gene', (104, 108))
167666	30206411	This monoclonal antibody detects IDH2 R172S/T proteins with optimal sensitivity irrespective of the tumor type.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('IDH2', 'Gene', (33, 37))	('tumor', 'Disease', (100, 105))	('R172S', 'Var', (38, 43))	('proteins', 'Protein', (46, 54))	('IDH2', 'Gene', '3418', (33, 37))	('R172S', 'SUBSTITUTION', 'None', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
167667	30206411	In view of the molecular epidemiology of the IDH2 R172 variants across human malignancies and their notable predominance among high-grade sinonasal carcinomas, especially sinonasal undifferentiated carcinoma, we suggest that IDH2 11C8B1 immunohistochemistry could be used as a reliable surrogate marker for the presence of IDH2 R172S/T mutations in carcinomas in this location.	('sinonasal undifferentiated carcinoma', 'Disease', 'MESH:C537344', (171, 207))	('IDH2', 'Gene', (45, 49))	('IDH2', 'Gene', (323, 327))	('R172S', 'Var', (328, 333))	('IDH2', 'Gene', '3418', (45, 49))	('IDH2', 'Gene', '3418', (323, 327))	('sinonasal undifferentiated carcinoma', 'Disease', (171, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('carcinomas', 'Disease', 'MESH:D009369', (349, 359))	('carcinomas', 'Disease', (148, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (349, 358))	('carcinomas', 'Phenotype', 'HP:0030731', (349, 359))	('human', 'Species', '9606', (71, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('IDH2', 'Gene', (225, 229))	('R172S', 'SUBSTITUTION', 'None', (328, 333))	('variants', 'Var', (55, 63))	('IDH2', 'Gene', '3418', (225, 229))	('malignancies', 'Disease', 'MESH:D009369', (77, 89))	('malignancies', 'Disease', (77, 89))	('carcinomas', 'Disease', 'MESH:D009369', (148, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('carcinomas', 'Disease', (349, 359))
167679	30607140	Despite the fact that tremendous somatic mutations in a variety of cancer types can give chances for personalized treatment targeting at patients' specific mutations, these mutations can eventually translate into new antigens for possible anti-tumor immune response.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('translate', 'Reg', (198, 207))	('cancer', 'Disease', (67, 73))	('tumor', 'Disease', (244, 249))	('mutations', 'Var', (156, 165))	('patients', 'Species', '9606', (137, 145))	('mutations', 'Var', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
167685	30607140	Thus, monoclonal antibodies blocking PD-1 have arisen as an impressive treatment strategy for cancer patients and have been approved by the U.S. Food and Drug Administration (FDA) for human use.	('patients', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (184, 189))	('monoclonal', 'Var', (6, 16))	('PD-1', 'Gene', (37, 41))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
167754	30607140	The combination of PD-1 and CTLA-4 blockade has demonstrated higher response rates in advanced melanoma, while combination with LAG3 blockade are still carrying on clinical trials (NCT03250832, NCT02658981, NCT01968109, NCT03005782).	('advanced melanoma', 'Disease', 'MESH:D008545', (86, 103))	('LAG3', 'Gene', '3902', (128, 132))	('higher', 'PosReg', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('advanced melanoma', 'Disease', (86, 103))	('NCT03250832', 'Var', (181, 192))	('CTLA-4', 'Gene', '1493', (28, 34))	('PD-1', 'Gene', (19, 23))	('LAG3', 'Gene', (128, 132))	('CTLA-4', 'Gene', (28, 34))
167758	30607140	Therefore, we can infer that the high expression of LFA-1 may improve the efficacy of T cells that have been released from the "brake" of PD-1 by PD-1 blockade.	('LFA-1', 'Gene', (52, 57))	('high expression', 'Var', (33, 48))	('improve', 'PosReg', (62, 69))	('efficacy', 'CPA', (74, 82))	('LFA-1', 'Gene', '3689', (52, 57))
167796	30568968	Computed tomography, magnetic resonance cholangiopancreatography, and EUS imaging all confirmed a defect in the proximal common hepatic duct that was separate from the pancreatic head mass, ruling out a tumor growth extension.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('pancreatic', 'Disease', 'MESH:D010195', (168, 178))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('pancreatic', 'Disease', (168, 178))	('defect', 'Var', (98, 104))
168016	24949206	v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are indicated to be an early event in IPNBs, as shown by several reports.	('rat', 'Species', '10116', (18, 21))	('IPNBs', 'Chemical', '-', (108, 113))	('sarcoma', 'Disease', 'MESH:D012509', (22, 29))	('KRAS', 'Gene', '24525', (54, 58))	('KRAS', 'Gene', (54, 58))	('IPNBs', 'Disease', (108, 113))	('sarcoma', 'Disease', (22, 29))	('mutations', 'Var', (60, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))
168017	24949206	The occurrence of these mutations was more common in IPNBs (17.6 to 46.2% of cases) than in BilINs.	('IPNBs', 'Chemical', '-', (53, 58))	('common', 'Reg', (43, 49))	('IPNBs', 'Disease', (53, 58))	('BilINs', 'Chemical', 'MESH:D001654', (92, 98))	('mutations', 'Var', (24, 33))
168018	24949206	In contrast, with regard to guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) codon 201 mutations, which have been exclusively detected in approximately two-thirds of IPMNs of the pancreas but not pancreatic ductal adenocarcinoma, there are some conflicting data among the studies.	('GNAS', 'Gene', '2778', (104, 108))	('pancreatic ductal adenocarcinoma', 'Disease', (229, 261))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (229, 261))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (229, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('GNAS', 'Gene', (104, 108))	('mutations', 'Var', (120, 129))	('IPMNs', 'Disease', (199, 204))
168019	24949206	showed that GNAS mutation was detected in 15 of 30 IPNBs, whereas Schlitter et al.	('IPNBs', 'Chemical', '-', (51, 56))	('GNAS', 'Gene', (12, 16))	('mutation', 'Var', (17, 25))	('GNAS', 'Gene', '2778', (12, 16))	('detected', 'Reg', (30, 38))
168020	24949206	found GNAS mutation only in one of 44 IPNBs and one of 23 IPNBs, respectively.	('GNAS', 'Gene', (6, 10))	('IPNBs', 'Chemical', '-', (38, 43))	('IPNBs', 'Chemical', '-', (58, 63))	('mutation', 'Var', (11, 19))	('GNAS', 'Gene', '2778', (6, 10))
168023	24949206	Similarly, all IPNBs with GNAS mutation only showed high-mucin production in the study by Sasaki et al., whereas GNAS mutation was detected in the intestinal subtype in both studies by Schlitter et al.	('mucin', 'Gene', (57, 62))	('GNAS', 'Gene', (26, 30))	('IPNBs', 'Chemical', '-', (15, 20))	('mutation', 'Var', (31, 39))	('mucin', 'Gene', '100508689', (57, 62))	('GNAS', 'Gene', '2778', (113, 117))	('GNAS', 'Gene', '2778', (26, 30))	('GNAS', 'Gene', (113, 117))
168031	24949206	Another report revealed that frequency of p53 aberrant expression progressively increased from low-grade intraepithelial neoplasia to invasive carcinoma.	('p53', 'Gene', (42, 45))	('p53', 'Gene', '7157', (42, 45))	('neoplasia', 'Phenotype', 'HP:0002664', (121, 130))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (105, 130))	('increased', 'PosReg', (80, 89))	('intraepithelial neoplasia to invasive carcinoma', 'Disease', (105, 152))	('intraepithelial neoplasia to invasive carcinoma', 'Disease', 'MESH:D019048', (105, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('aberrant expression', 'Var', (46, 65))
168034	24949206	This frequency was higher than that previously reported for extrahepatic and intrahepatic cholangiocarcinoma, indicating that impaired DNA mismatch repair might play a role in the pathogenesis of a subset of IPNBs.	('role', 'Reg', (168, 172))	('intrahepatic cholangiocarcinoma', 'Disease', (77, 108))	('IPNBs', 'Chemical', '-', (208, 213))	('DNA mismatch repair', 'MPA', (135, 154))	('impaired', 'Var', (126, 134))	('play', 'Reg', (161, 165))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (77, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('IPNBs', 'Disease', (208, 213))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))
168102	33413162	Significant intergroup differences were observed regarding factors such as sex, alcohol use, tumor size >= 5 cm, AFP level >= 200 ng/mL, operative margin > 1 cm, major hepatectomy, microvascular invasion, macrovascular invasion, AJCC stage I-II, recurrence, recurrence per 100 person-years, mortality, mortality per 100 person-years, and median follow-up time.	('alcohol use', 'Phenotype', 'HP:0030955', (80, 91))	('> 1', 'Var', (154, 157))	('mortality', 'Disease', (291, 300))	('recurrence', 'Disease', (246, 256))	('mortality', 'Disease', 'MESH:D003643', (302, 311))	('recurrence', 'CPA', (258, 268))	('alcohol', 'Chemical', 'MESH:D000438', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('AFP', 'Gene', (113, 116))	('AFP', 'Gene', '174', (113, 116))	('mortality', 'Disease', 'MESH:D003643', (291, 300))	('microvascular invasion', 'CPA', (181, 203))	('>= 200', 'Var', (123, 129))	('mortality', 'Disease', (302, 311))	('macrovascular invasion', 'CPA', (205, 227))	('CC', 'Phenotype', 'HP:0030153', (231, 233))	('major hepatectomy', 'Disease', (162, 179))	('tumor', 'Disease', (93, 98))	('AJCC', 'Disease', (229, 233))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
168103	33413162	The cHCC-CC group had the highest proportion of patients with hypertension, smoking, alcohol use, CP class A, tumor size >= 5 cm, microvascular invasion, lymph node metastasis, AJCC stage I-II, recurrence per 100 person-years, and mortality per 100 person-years.	('microvascular invasion', 'CPA', (130, 152))	('hypertension', 'Phenotype', 'HP:0000822', (62, 74))	('CC', 'Phenotype', 'HP:0030153', (6, 8))	('recurrence', 'CPA', (194, 204))	('alcohol', 'Chemical', 'MESH:D000438', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('alcohol use', 'Var', (85, 96))	('CC', 'Phenotype', 'HP:0030153', (179, 181))	('alcohol use', 'Phenotype', 'HP:0030955', (85, 96))	('mortality', 'Disease', (231, 240))	('cHCC-CC', 'Disease', (4, 11))	('HCC', 'Phenotype', 'HP:0001402', (5, 8))	('CP class A', 'Disease', (98, 108))	('cHCC-CC', 'Chemical', '-', (4, 11))	('>= 5', 'Var', (121, 125))	('AJCC', 'Gene', (177, 181))	('hypertension', 'Disease', 'MESH:D006973', (62, 74))	('tumor', 'Disease', (110, 115))	('CC', 'Phenotype', 'HP:0030153', (9, 11))	('lymph node metastasis', 'CPA', (154, 175))	('patients', 'Species', '9606', (48, 56))	('hypertension', 'Disease', (62, 74))	('mortality', 'Disease', 'MESH:D003643', (231, 240))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
168104	33413162	By contrast, the HCC group had more patients with old age, male, cirrhosis, Edmondson-Steiner grades I-II, tumor number, AFP level >= 200 ng/mL, ICG%, operative margin > 1 cm, macrovascular invasion, and antiviral therapy.	('CC', 'Phenotype', 'HP:0030153', (18, 20))	('cirrhosis', 'Disease', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('patients', 'Species', '9606', (36, 44))	('HCC', 'Gene', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('>= 200', 'Var', (131, 137))	('cirrhosis', 'Phenotype', 'HP:0001394', (65, 74))	('HCC', 'Gene', '619501', (17, 20))	('cirrhosis', 'Disease', 'MESH:D005355', (65, 74))	('AFP', 'Gene', (121, 124))	('HCC', 'Phenotype', 'HP:0001402', (17, 20))	('macrovascular invasion', 'CPA', (176, 198))	('ICG%', 'Var', (145, 149))	('AFP', 'Gene', '174', (121, 124))
168107	33413162	Furthermore, significant differences were observed between cHCC-CC and CC groups in terms of diabetes mellitus, alcohol use, cirrhosis, AFP level >= 200 ng/mL, operative margin > 1 cm, major hepatectomy, microvascular invasion, and macrovascular invasion.	('alcohol', 'Chemical', 'MESH:D000438', (112, 119))	('CC', 'Phenotype', 'HP:0030153', (61, 63))	('differences', 'Reg', (25, 36))	('cirrhosis', 'Disease', 'MESH:D005355', (125, 134))	('alcohol use', 'Phenotype', 'HP:0030955', (112, 123))	('macrovascular invasion', 'CPA', (232, 254))	('cirrhosis', 'Phenotype', 'HP:0001394', (125, 134))	('diabetes mellitus', 'Disease', (93, 110))	('cirrhosis', 'Disease', (125, 134))	('AFP', 'Gene', (136, 139))	('HCC', 'Phenotype', 'HP:0001402', (60, 63))	('cHCC-CC', 'Chemical', '-', (59, 66))	('AFP', 'Gene', '174', (136, 139))	('microvascular invasion', 'CPA', (204, 226))	('CC', 'Phenotype', 'HP:0030153', (71, 73))	('diabetes mellitus', 'Disease', 'MESH:D003920', (93, 110))	('major', 'Disease', (185, 190))	('alcohol use', 'Disease', (112, 123))	('>= 200', 'Var', (146, 152))	('CC', 'Phenotype', 'HP:0030153', (64, 66))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (93, 110))
168108	33413162	In addition, significant differences were noted between HCC and CC groups in terms of sex, hypertension, cirrhosis, Edmondson-Steiner Grades I-II, tumor size >= 5 cm, AFP level >= 200 ng/mL, operative margin > 1 cm, major hepatectomy, microvascular invasion, macrovascular invasion, lymph node metastasis, AJCC stage I-II, recurrence, recurrence per 100 person-years, mortality, mortality per 100 person-years, and median follow-up time.	('major hepatectomy', 'Disease', (216, 233))	('hypertension', 'Disease', (91, 103))	('mortality', 'Disease', (379, 388))	('cirrhosis', 'Phenotype', 'HP:0001394', (105, 114))	('microvascular invasion', 'CPA', (235, 257))	('CC', 'Phenotype', 'HP:0030153', (308, 310))	('cirrhosis', 'Disease', (105, 114))	('recurrence', 'CPA', (323, 333))	('HCC', 'Gene', '619501', (56, 59))	('mortality', 'Disease', (368, 377))	('tumor', 'Disease', (147, 152))	('HCC', 'Phenotype', 'HP:0001402', (56, 59))	('hypertension', 'Phenotype', 'HP:0000822', (91, 103))	('AJCC', 'Disease', (306, 310))	('>= 5 cm', 'Var', (158, 165))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('HCC', 'Gene', (56, 59))	('mortality', 'Disease', 'MESH:D003643', (379, 388))	('>= 200 ng/mL', 'Var', (177, 189))	('> 1', 'Var', (208, 211))	('recurrence', 'CPA', (335, 345))	('AFP', 'Gene', (167, 170))	('AFP', 'Gene', '174', (167, 170))	('lymph node metastasis', 'CPA', (283, 304))	('mortality', 'Disease', 'MESH:D003643', (368, 377))	('CC', 'Phenotype', 'HP:0030153', (57, 59))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('macrovascular invasion', 'CPA', (259, 281))	('cirrhosis', 'Disease', 'MESH:D005355', (105, 114))	('CC', 'Phenotype', 'HP:0030153', (64, 66))	('hypertension', 'Disease', 'MESH:D006973', (91, 103))
168147	33413162	When cHCC-CC and CC groups were compared, significant differences were noted regarding diabetes mellitus, alcohol use, cirrhosis, AFP level >= 200 ng/mL, operative margin > 1 cm, major hepatectomy, microvascular invasion, and macrovascular invasion.	('cirrhosis', 'Disease', 'MESH:D005355', (119, 128))	('diabetes mellitus', 'Disease', (87, 104))	('cirrhosis', 'Phenotype', 'HP:0001394', (119, 128))	('AFP', 'Gene', (130, 133))	('AFP', 'Gene', '174', (130, 133))	('HCC', 'Phenotype', 'HP:0001402', (6, 9))	('>= 200', 'Var', (140, 146))	('cirrhosis', 'Disease', (119, 128))	('microvascular invasion', 'CPA', (198, 220))	('cHCC-CC', 'Chemical', '-', (5, 12))	('diabetes mellitus', 'Disease', 'MESH:D003920', (87, 104))	('alcohol use', 'Disease', (106, 117))	('CC', 'Phenotype', 'HP:0030153', (17, 19))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (87, 104))	('CC', 'Phenotype', 'HP:0030153', (10, 12))	('major hepatectomy', 'Disease', (179, 196))	('macrovascular invasion', 'CPA', (226, 248))	('alcohol', 'Chemical', 'MESH:D000438', (106, 113))	('CC', 'Phenotype', 'HP:0030153', (7, 9))	('alcohol use', 'Phenotype', 'HP:0030955', (106, 117))
168166	33413162	This study was supported by grants to Chih-Wen Lin from MOST (108-2314-B-214-006-MY2), the E-Da Hospital-National Taiwan University Hospital Joint Research Program (108-EDN11), and the E-Da Hospital (EDAHP109044, EDAHP109045, and EDAHP109053).	('E-Da', 'Gene', '1896', (185, 189))	('EDAHP109044', 'Var', (200, 211))	('EDAHP109045', 'Var', (213, 224))	('E-Da', 'Gene', (91, 95))	('E-Da', 'Gene', (185, 189))	('EDAHP109053', 'Var', (230, 241))	('E-Da', 'Gene', '1896', (91, 95))
168178	30142851	Diagnosis of preoperative cholangitis has traditionally been made by following the criteria: Temperature: body temperature is higher than 38 C. Liver function: abnormalities in liver function test results and exception of jaundice.	('cholangitis', 'Phenotype', 'HP:0030151', (26, 37))	('jaundice', 'Disease', 'MESH:D007565', (222, 230))	('cholangitis', 'Disease', 'MESH:D002761', (26, 37))	('abnormalities', 'Var', (160, 173))	('jaundice', 'Disease', (222, 230))	('jaundice', 'Phenotype', 'HP:0000952', (222, 230))	('abnormalities in liver', 'Phenotype', 'HP:0001392', (160, 182))	('abnormalities in liver function test', 'Phenotype', 'HP:0002910', (160, 196))	('cholangitis', 'Disease', (26, 37))	('liver function test', 'MPA', (177, 196))
168205	30142851	But most of these operations will induce cholangitis.	('induce', 'Reg', (34, 40))	('cholangitis', 'Phenotype', 'HP:0030151', (41, 52))	('cholangitis', 'Disease', (41, 52))	('operations', 'Var', (18, 28))	('cholangitis', 'Disease', 'MESH:D002761', (41, 52))
168240	29209530	CCA is the most common liver cancer in northeast Thailand where the highest incidence worldwide is significantly correlated with the presence of the liver fluke Opisthorchis viverrini, which is classified as a group 1 carcinogen.	('liver cancer', 'Disease', (23, 35))	('CCA', 'Phenotype', 'HP:0030153', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('correlated', 'Reg', (113, 123))	('presence', 'Var', (133, 141))	('liver cancer', 'Disease', 'MESH:D006528', (23, 35))	('CCA', 'Disease', (0, 3))	('liver fluke', 'Species', '6192', (149, 160))	('fluke Opisthorchis', 'Phenotype', 'HP:0002179', (155, 173))	('liver cancer', 'Phenotype', 'HP:0002896', (23, 35))	('Opisthorchis viverrini', 'Species', '6198', (161, 183))
168252	29209530	Combinations of these types are possible as the growth of PI-CCA may lead to invasion of the liver parenchyma.	('CCA', 'Phenotype', 'HP:0030153', (61, 64))	('PI-CCA', 'Var', (58, 64))	('liver parenchyma', 'Disease', 'MESH:D010195', (93, 109))	('lead to', 'Reg', (69, 76))	('liver parenchyma', 'Disease', (93, 109))
168309	26176256	Although bile duct obstruction could have been attributed to the occurrence of a biliary metastasis from renal cell carcinoma, immunohistochemical analysis confirmed the biliary epithelial origin in this case (positivity for CK19, CK07, CAM 5.2 and AE1+AE3).	('biliary', 'Disease', (81, 88))	('duct obstruction', 'Phenotype', 'HP:0000579', (14, 30))	('bile duct obstruction', 'Phenotype', 'HP:0005230', (9, 30))	('renal cell carcinoma', 'Disease', (105, 125))	('CK19', 'Gene', (225, 229))	('CK07', 'Var', (231, 235))	('CAM', 'Gene', '808', (237, 240))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (105, 125))	('CAM', 'Gene', (237, 240))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (105, 125))	('CK19', 'Gene', '3880', (225, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('biliary', 'Disease', (170, 177))	('bile duct obstruction', 'Disease', (9, 30))
168384	23868055	5) was used to calculate an area under the curve of 0.894 (95 % CI = 0.825-0.962) for S100A9 and 0.860 (95 % CI = 0.779-0.942) for CCTgamma.	('S100A9', 'Gene', '6280', (86, 92))	('0.860', 'Var', (97, 102))	('CCTgamma', 'Gene', (131, 139))	('S100A9', 'Gene', (86, 92))	('CCTgamma', 'Gene', '7203', (131, 139))
168417	22178589	We analyzed mutations in KRAS, epidermal growth factor receptor (EGFR), and BRAF in samples from 69 tumors.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('EGFR', 'Gene', '1956', (65, 69))	('epidermal growth factor receptor', 'Gene', (31, 63))	('EGFR', 'Gene', (65, 69))	('mutations', 'Var', (12, 21))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('epidermal growth factor receptor', 'Gene', '1956', (31, 63))	('KRAS', 'Gene', (25, 29))	('KRAS', 'Gene', '3845', (25, 29))
168420	22178589	Class comparison identified 4 survival subgroups (SGI-IV; chi2 = 8.34; P < .03); SGIII was characterized by genes associated with proteasomal activity and the worst prognosis.	('SGIII', 'Gene', '29106', (81, 86))	('genes', 'Var', (108, 113))	('SGI', 'Gene', '6406', (50, 53))	('SGI', 'Gene', '6406', (81, 84))	('associated', 'Reg', (114, 124))	('SGIII', 'Gene', (81, 86))	('SGI', 'Gene', (50, 53))	('SGI', 'Gene', (81, 84))	('proteasomal activity', 'MPA', (130, 150))
168423	22178589	We provide insight into the pathogenesis of cholangiocarcinoma and identify previously unrecognized subclasses of patients, based on KRAS mutations and increased levels of EGFR and HER2 signaling, who might benefit from dual-target tyrosine kinase inhibitors.	('EGFR', 'Gene', '1956', (172, 176))	('tyrosine kinase', 'Gene', (232, 247))	('HER2', 'Gene', '2064', (181, 185))	('EGFR', 'Gene', (172, 176))	('increased', 'PosReg', (152, 161))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (44, 62))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (44, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('KRAS', 'Gene', (133, 137))	('HER2', 'Gene', (181, 185))	('tyrosine kinase', 'Gene', '7294', (232, 247))	('KRAS', 'Gene', '3845', (133, 137))	('patients', 'Species', '9606', (114, 122))	('cholangiocarcinoma', 'Disease', (44, 62))	('mutations', 'Var', (138, 147))
168437	22178589	A subgroup of patients with poor overall survival and early recurrence was characterized by the presence of KRAS mutations and multiple aberrantly regulated oncogenic pathways, including activation of HER2 and epidermal growth factor receptor (EGFR) signaling, as compared with patients with a good clinical outcome.	('KRAS', 'Gene', (108, 112))	('EGFR', 'Gene', '1956', (244, 248))	('HER2', 'Gene', (201, 205))	('HER2', 'Gene', '2064', (201, 205))	('epidermal growth factor receptor', 'Gene', (210, 242))	('EGFR', 'Gene', (244, 248))	('presence', 'Reg', (96, 104))	('activation', 'PosReg', (187, 197))	('KRAS', 'Gene', '3845', (108, 112))	('oncogenic pathways', 'Pathway', (157, 175))	('mutations', 'Var', (113, 122))	('epidermal growth factor receptor', 'Gene', '1956', (210, 242))	('patients', 'Species', '9606', (278, 286))	('patients', 'Species', '9606', (14, 22))
168477	22178589	To extend the molecular characterization, all CCAs (n = 69) with available genomic DNA were analyzed for 11 somatic mutations in KRAS, 1 in BRAF, and 28 in EGFR.	('KRAS, 1', 'Gene', '3845', (129, 136))	('EGFR', 'Gene', '1956', (156, 160))	('BRAF', 'Gene', '673', (140, 144))	('EGFR', 'Gene', (156, 160))	('mutations', 'Var', (116, 125))	('BRAF', 'Gene', (140, 144))	('CCA', 'Phenotype', 'HP:0030153', (46, 49))
168478	22178589	KRAS mutations were identified in 17 of 69 patients, whereas only one tested positive for BRAFV600E.	('patients', 'Species', '9606', (43, 51))	('BRAFV600E', 'Mutation', 'rs113488022', (90, 99))	('mutations', 'Var', (5, 14))	('identified', 'Reg', (20, 30))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
168481	22178589	Mutations in KRAS were previously detected in 21%-100% of CCAs as compared with 24.6% (17/69) in our cohort (Figure 5A).	('detected', 'Reg', (34, 42))	('CCAs', 'Disease', (58, 62))	('CCA', 'Phenotype', 'HP:0030153', (58, 61))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))
168482	22178589	When classified by tumor site, 53.3% (8/15) of hilar versus 16.7% (9/54) of peripheral-type CCAs had mutations in KRAS.	('mutations', 'Var', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('hilar', 'Disease', (47, 52))	('KRAS', 'Gene', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('KRAS', 'Gene', '3845', (114, 118))	('tumor', 'Disease', (19, 24))	('CCA', 'Phenotype', 'HP:0030153', (92, 95))
168486	22178589	Although we were unable to establish KRAS as an independent prognostic factor within our cohort, integrating the KRAS mutational status and the 238-gene classifier grouped all patients with mutated KRAS/BRAF in cluster 2 (patients with poor prognosis) (P < .01) (Figure 5B).	('patients', 'Species', '9606', (176, 184))	('patients', 'Species', '9606', (222, 230))	('KRAS', 'Gene', (198, 202))	('KRAS', 'Gene', (37, 41))	('BRAF', 'Gene', '673', (203, 207))	('KRAS', 'Gene', (113, 117))	('mutated', 'Var', (190, 197))	('KRAS', 'Gene', '3845', (198, 202))	('KRAS', 'Gene', '3845', (113, 117))	('BRAF', 'Gene', (203, 207))	('KRAS', 'Gene', '3845', (37, 41))
168495	22178589	Selected tumors (n = 48) were additionally analyzed for EGFR, HER2, and MET copy number variations.	('HER2', 'Gene', '2064', (62, 66))	('EGFR', 'Gene', '1956', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('EGFR', 'Gene', (56, 60))	('tumors', 'Disease', (9, 15))	('analyzed', 'Reg', (43, 51))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('HER2', 'Gene', (62, 66))	('copy number variations', 'Var', (76, 98))
168502	22178589	It is noteworthy that 2 of the TKI-resistant cell lines (HuCCT1 and WITT) that integrated with the poor prognosis subclass (Figure 6A) had mutations in KRAS codon 12, supporting a link between resistance to EGFR-based therapies and activation of KRAS, a downstream effector of RTKs.	('RTK', 'Gene', '5979', (277, 280))	('mutations', 'Var', (139, 148))	('EGFR', 'Gene', '1956', (207, 211))	('KRAS', 'Gene', (152, 156))	('KRAS', 'Gene', (246, 250))	('KRAS', 'Gene', '3845', (152, 156))	('EGFR', 'Gene', (207, 211))	('RTK', 'Gene', (277, 280))	('KRAS', 'Gene', '3845', (246, 250))
168513	22178589	Aberrant HER2 expression has been described in many cancers (eg, ovarian, gastric) and most prominently in breast cancer, where it has a significant role in malignant transformation and choice of therapy.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('Aberrant', 'Var', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('ovarian', 'Disease', (65, 72))	('HER2', 'Gene', (9, 13))	('HER2', 'Gene', '2064', (9, 13))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('expression', 'MPA', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('described', 'Reg', (34, 43))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
168520	22178589	Indeed, we found a significant association of activating KRAS mutations (24.6%) in the cohort with outcome when integrated with the classifier.	('KRAS', 'Gene', (57, 61))	('activating', 'PosReg', (46, 56))	('mutations', 'Var', (62, 71))	('KRAS', 'Gene', '3845', (57, 61))
168521	22178589	The presence of KRAS mutations is predictive of resistance to EGFR therapy in colorectal cancer.	('mutations', 'Var', (21, 30))	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', (62, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('KRAS', 'Gene', (16, 20))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('KRAS', 'Gene', '3845', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('colorectal cancer', 'Disease', (78, 95))
168523	22178589	Although a low frequency of EGFR mutations (13.6%) was described in CCA, we found no EGFR-specific mutations or amplification of EGFR in our cohort.	('EGFR', 'Gene', (85, 89))	('EGFR', 'Gene', '1956', (28, 32))	('CCA', 'Phenotype', 'HP:0030153', (68, 71))	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('EGFR', 'Gene', '1956', (129, 133))	('CCA', 'Disease', (68, 71))	('EGFR', 'Gene', '1956', (85, 89))	('EGFR', 'Gene', (129, 133))
168557	32395602	In this case, immunohistochemical staining for breast cancer markers was negative, and positive CK-7 and negative CK-20 were more consistent with a malignancy of hepatic or biliopancreatic origin.	('CK-20', 'Gene', '54474', (114, 119))	('CK-20', 'Gene', (114, 119))	('breast cancer', 'Disease', (47, 60))	('malignancy of hepatic', 'Disease', 'MESH:D056486', (148, 169))	('malignancy of hepatic', 'Disease', (148, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('positive', 'Var', (87, 95))	('CK-7', 'Gene', '3855', (96, 100))	('CK-7', 'Gene', (96, 100))	('negative', 'NegReg', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
168572	28192597	One patient with 3+ MET expression in the tumor stayed on treatment for 278 days, but MET expression did not correlate with outcomes in the overall study population.	('tumor', 'Disease', (42, 47))	('3+ MET expression', 'Var', (17, 34))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
168589	28192597	For example, over time VEGFR2 inhibition may cause an increase in tumor hypoxia, which can upregulate MET and enhance cancer cell invasion and promote treatment resistance.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cancer', 'Disease', (118, 124))	('upregulate', 'PosReg', (91, 101))	('VEGFR2', 'Gene', (23, 29))	('inhibition', 'Var', (30, 40))	('MET', 'CPA', (102, 105))	('enhance', 'PosReg', (110, 117))	('increase', 'PosReg', (54, 62))	('promote', 'PosReg', (143, 150))	('tumor hypoxia', 'Disease', 'MESH:D000860', (66, 79))	('treatment resistance', 'CPA', (151, 171))	('tumor hypoxia', 'Disease', (66, 79))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('VEGFR2', 'Gene', '3791', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
168627	28192597	Following withdrawal for progression, 6 of 16 (38%) patients received further systemic therapy including 5-fluorouracil (5-FU)/leucovorin (n=1), 5-FU/leucovorin/oxaliplatin (n=2), erlotinib (n=1), the PD-L1 inhibitor MPDL280A on a clinical trial (n=1), and the stem cell kinase inhibitor BBI503 on a clinical trial (n=1).	('leucovorin', 'Chemical', 'MESH:D002955', (150, 160))	('erlotinib', 'Chemical', 'MESH:D000069347', (180, 189))	('PD-L1', 'Gene', (201, 206))	('leucovorin', 'Chemical', 'MESH:D002955', (127, 137))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (105, 119))	('BBI503', 'Chemical', '-', (288, 294))	('PD-L1', 'Gene', '29126', (201, 206))	('patients', 'Species', '9606', (52, 60))	('5-FU', 'Chemical', 'MESH:D005472', (121, 125))	('5-FU', 'Chemical', 'MESH:D005472', (145, 149))	('MPDL280A', 'Chemical', '-', (217, 225))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (161, 172))	('5-FU/leucovorin/oxaliplatin', 'Var', (145, 172))
168744	24921218	The clinical criteria required the presence of a malignant-appearing stricture on percutaneous or endoscopic retrograde cholangiopancreatography, combined with 1 of the 4 following criteria: positive findings on brushing or biopsy; polysomy on fluorescence in situ hybridization testing; cancer antigen (CA) 19-9 level higher than 100 U/mL in the absence of cholangitis; or mass on axial imaging at the level of the stricture.	('cholangitis', 'Disease', 'MESH:D002761', (358, 369))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cholangitis', 'Disease', (358, 369))	('cancer', 'Disease', (288, 294))	('cholangitis', 'Phenotype', 'HP:0030151', (358, 369))	('polysomy', 'Var', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))
168841	21674559	Further, the presence of IgG4 positive plasma cell infiltrates was associated with a more aggressive clinical course including a significantly shorter time to transplant, a lower likelihood of cirrhosis at the time of transplant, and a greater than 3-fold higher risk of PSC recurrence after transplant.	('cirrhosis', 'Phenotype', 'HP:0001394', (193, 202))	('cirrhosis', 'Disease', 'MESH:D005355', (193, 202))	('shorter', 'NegReg', (143, 150))	('PSC', 'Gene', '100653366', (271, 274))	('PSC', 'Gene', (271, 274))	('presence', 'Var', (13, 21))	('IgG4 positive', 'Phenotype', 'HP:0032300', (25, 38))	('cirrhosis', 'Disease', (193, 202))	('IgG4', 'Gene', (25, 29))
168878	21674559	Median survival of CCA patients with elevated IgG4 > ULN was compared to that of CCA patients with normal sIgG4 levels by the Kaplan Meier method.	('IgG4 > ULN', 'Var', (46, 56))	('patients', 'Species', '9606', (23, 31))	('sIgG4', 'Chemical', '-', (106, 111))	('CCA', 'Disease', (19, 22))	('patients', 'Species', '9606', (85, 93))
168910	21674559	The mean CA 19-9 levels were not significantly different between those with sIgG4 >1xULN and those with normal sIgG4 levels in both cohorts.	('sIgG4', 'Chemical', '-', (111, 116))	('sIgG4', 'Chemical', '-', (76, 81))	('>1xULN', 'Var', (82, 88))	('sIgG4', 'Gene', (76, 81))	('CA 19-9 levels', 'MPA', (9, 23))
168912	21674559	The median survival of all CCA patients with elevated sIgG4 over 1xULN was longer than for patients with normal sIgG4 levels, however, the difference did not reach statistical significance (97.1 vs 27.1 months, p=0.43, 19.8 vs 28.1 months, p=0.93 and 97.1 vs 27.6 months, p=0.53, for the test, validation and combined cohorts, respectively).	('longer', 'PosReg', (75, 81))	('patients', 'Species', '9606', (91, 99))	('sIgG4', 'Chemical', '-', (112, 117))	('sIgG4', 'Chemical', '-', (54, 59))	('patients', 'Species', '9606', (31, 39))	('CCA', 'Disease', (27, 30))	('sIgG4', 'Gene', (54, 59))	('elevated', 'Var', (45, 53))
168942	21674559	This potential association of PSC with high serum and tissue IgG4 in CCA patients suggests that PSC patients with high IgG4 may be at increased risk of developing CCA.	('CCA', 'Disease', (163, 166))	('high', 'Var', (114, 118))	('PSC', 'Gene', '100653366', (96, 99))	('PSC', 'Gene', (96, 99))	('patients', 'Species', '9606', (100, 108))	('IgG4', 'Gene', (119, 123))	('PSC', 'Gene', '100653366', (30, 33))	('patients', 'Species', '9606', (73, 81))	('PSC', 'Gene', (30, 33))
168943	21674559	Considered together with the finding that PSC patients with elevated sIgG4 tend to have more severe liver disease and a shorter time to liver transplantation, our study suggests the possibility that IgG4 immunoreactivity may be one of the driving forces behind the malignant transformation from PSC to CCA or perhaps to other neoplastic processes such as non-Hodgkin lymphoma.	('patients', 'Species', '9606', (46, 54))	('sIgG4', 'Gene', (69, 74))	('PSC', 'Gene', '100653366', (42, 45))	('lymphoma', 'Phenotype', 'HP:0002665', (367, 375))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (359, 375))	('PSC', 'Gene', '100653366', (295, 298))	('liver disease', 'Phenotype', 'HP:0001392', (100, 113))	('non-Hodgkin lymphoma', 'Disease', (355, 375))	('liver disease', 'Disease', 'MESH:D008107', (100, 113))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (355, 375))	('PSC', 'Gene', (42, 45))	('sIgG4', 'Chemical', '-', (69, 74))	('CCA', 'Disease', (302, 305))	('liver disease', 'Disease', (100, 113))	('PSC', 'Gene', (295, 298))	('IgG4', 'Protein', (199, 203))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (355, 375))	('elevated', 'Var', (60, 68))	('elevated sIgG4 tend', 'Phenotype', 'HP:0032300', (60, 79))	('neoplastic processes', 'Phenotype', 'HP:0002664', (326, 346))
169004	21798073	Log-rank test showed that the CD133 positive patients had a significantly better survival than negative ones (P = 0.001) and the negative expression of CD133 was a worse prognostic indicator for patients with CC (Figure 3).	('better', 'PosReg', (74, 80))	('CD133', 'Gene', (152, 157))	('CD133', 'Gene', '8842', (152, 157))	('CC', 'Phenotype', 'HP:0030153', (209, 211))	('patients', 'Species', '9606', (195, 203))	('survival', 'MPA', (81, 89))	('patients', 'Species', '9606', (45, 53))	('CD133', 'Gene', (30, 35))	('positive', 'Var', (36, 44))	('CD133', 'Gene', '8842', (30, 35))	('negative', 'NegReg', (129, 137))
169027	21798073	Recently, several studies have reported that the presence of CD133 in various tumors is correlated with poor prognosis.	('presence', 'Var', (49, 57))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('CD133', 'Gene', (61, 66))	('CD133', 'Gene', '8842', (61, 66))
169030	21798073	Furthermore, the high expression of CD133 is correlated with the increased tumor grade, advanced disease stage, elevated serum alpha-fetoprotein levels and poor survival of the patients with hepatocellular carcinoma.	('poor', 'NegReg', (156, 160))	('increased', 'PosReg', (65, 74))	('alpha-fetoprotein', 'Gene', '174', (127, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('patients', 'Species', '9606', (177, 185))	('high', 'Var', (17, 21))	('alpha-fetoprotein', 'Gene', (127, 144))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (191, 215))	('elevated', 'PosReg', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('CD133', 'Gene', (36, 41))	('hepatocellular carcinoma', 'Disease', (191, 215))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (191, 215))	('expression', 'MPA', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('elevated serum alpha-fetoprotein', 'Phenotype', 'HP:0006254', (112, 144))	('CD133', 'Gene', '8842', (36, 41))	('tumor', 'Disease', (75, 80))
169032	21798073	Firstly, the patients of CC with positive CD133 expression had significantly better prognosis than those negative ones.	('CD133', 'Gene', '8842', (42, 47))	('better', 'PosReg', (77, 83))	('patients', 'Species', '9606', (13, 21))	('CC', 'Phenotype', 'HP:0030153', (25, 27))	('positive', 'Var', (33, 41))	('CD133', 'Gene', (42, 47))
169046	21798073	Moreover, the patients of CC with positive CD133 expression had a significantly better prognosis than those negative ones.	('positive', 'Var', (34, 42))	('CC', 'Phenotype', 'HP:0030153', (26, 28))	('CD133', 'Gene', (43, 48))	('CD133', 'Gene', '8842', (43, 48))	('patients', 'Species', '9606', (14, 22))
169090	33440754	Mutations in the genes isocitrate dehydrogenases (IDH1 and 2) and fusions of the fibroblast growth factor receptor 2 (FGFR2) were found exclusively in iCCA, whereas Kirsten rat sarcoma viral oncogene homolog (KRAS) were more common in eCCA.	('fibroblast growth factor receptor 2', 'Gene', (81, 116))	('rat', 'Species', '10116', (173, 176))	('sarcoma', 'Disease', 'MESH:D012509', (177, 184))	('iCCA', 'Disease', (151, 155))	('sarcoma', 'Disease', (177, 184))	('rat', 'Species', '10116', (29, 32))	('FGFR2', 'Gene', (118, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('Mutations', 'Var', (0, 9))	('found', 'Reg', (130, 135))	('IDH1 and 2', 'Gene', '24479;361596', (50, 60))	('CCA', 'Phenotype', 'HP:0030153', (152, 155))	('CCA', 'Phenotype', 'HP:0030153', (236, 239))	('fusions', 'Var', (66, 73))	('KRAS', 'Gene', '24525', (209, 213))	('fibroblast growth factor receptor 2', 'Gene', '25022', (81, 116))	('KRAS', 'Gene', (209, 213))	('eCCA', 'Disease', (235, 239))
169093	33440754	Currently, inhibitors of IDH and FGFR are being investigated in clinical trials following encouraging preliminary results for specific cohorts of patients containing IDH mutations [NCT02989857] and FGFR2 fusions [NCT03656536, NCT03773302].	('NCT03773302]', 'Var', (226, 238))	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('mutations [NCT02989857]', 'Var', (170, 193))	('[NCT03656536', 'Var', (212, 224))	('IDH', 'Gene', (166, 169))	('[NCT02989857]', 'Var', (180, 193))	('FGFR2', 'Gene', (198, 203))	('IDH', 'Gene', '3417', (166, 169))	('patients', 'Species', '9606', (146, 154))
169095	33440754	Several such clinical trials fail to recruit the patients conforming to the study designs, for example, studies investigating the effect of ceritinib in ROS, ALK mutations positive CCA patients were prematurely terminated due to insufficient recruitment of patients [NCT02374489, NCT02638909].	('ROS', 'Gene', (153, 156))	('mutations', 'Var', (162, 171))	('ALK', 'Gene', (158, 161))	('CCA', 'Phenotype', 'HP:0030153', (181, 184))	('ceritinib', 'Chemical', 'MESH:C586847', (140, 149))	('patients', 'Species', '9606', (257, 265))	('patients', 'Species', '9606', (185, 193))	('CCA', 'Disease', (181, 184))	('patients', 'Species', '9606', (49, 57))	('NCT02638909]', 'Var', (280, 292))	('ROS', 'Chemical', '-', (153, 156))
169103	33440754	Evidently, infigratinib (BGJ398), a selective FGFR inhibitor, has exhibited promising outcomes in a CCA patient cohort containing the FGFR2 fusions.	('BGJ398', 'Chemical', 'MESH:C568950', (25, 31))	('CCA', 'Phenotype', 'HP:0030153', (100, 103))	('infigratinib', 'Chemical', 'MESH:C568950', (11, 23))	('patient', 'Species', '9606', (104, 111))	('fusions', 'Var', (140, 147))	('FGFR2', 'Gene', (134, 139))	('CCA', 'Disease', (100, 103))
169107	33440754	Therefore, it is noteworthy that the FDA granted accelerated approval for pemigatinib, a novel FGFR inhibitor, to be used in treatment of CCA patients that are positive for FGFR2 fusions and have failed first line chemotherapy based on outcomes from a multi-cohort Phase II clinical trial [NCT04096417].	('CCA', 'Disease', (138, 141))	('pemigatinib', 'Chemical', '-', (74, 85))	('FGFR2', 'Gene', (173, 178))	('CCA', 'Phenotype', 'HP:0030153', (138, 141))	('fusions', 'Var', (179, 186))	('patients', 'Species', '9606', (142, 150))	('rat', 'Species', '10116', (55, 58))
169108	33440754	Currently, pemigatinib is in Phase III clinical trials as first-line treatment for CCA patients with FGFR2 fusions.	('CCA', 'Disease', (83, 86))	('fusions', 'Var', (107, 114))	('FGFR2', 'Gene', (101, 106))	('CCA', 'Phenotype', 'HP:0030153', (83, 86))	('pemigatinib', 'Chemical', '-', (11, 22))	('patients', 'Species', '9606', (87, 95))
169154	33440754	Moreover, researchers are using GEMMs to understand the biology of cancer driven by specific mutations.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (93, 102))	('cancer', 'Disease', (67, 73))
169156	33440754	While treatment with FGFR inhibitors is effective in terms of tumor response, the patients ultimately develop drug resistance, possibly due to acquired secondary mutations.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('inhibitors', 'Var', (26, 36))	('patients', 'Species', '9606', (82, 90))	('develop', 'Reg', (102, 109))	('tumor', 'Disease', (62, 67))	('FGFR', 'Gene', (21, 25))	('drug resistance', 'Phenotype', 'HP:0020174', (110, 125))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('drug resistance', 'MPA', (110, 125))
169194	33440754	There are currently a number of different targeted therapies investigated against ERBB2 [NCT03602079, NCT04466891], FGFR [NCT03773302, NCT02150967, NCT03656536, NCT02150967, NCT03230318], IDH [NCT03212274, NCT03878095, NCT03991832, NCT04521686], and ROS1/ALK [NCT02568267] as either monotherapies or in combination with chemotherapy in clinical trials in CCA.	('NCT02150967', 'Var', (135, 146))	('IDH', 'Gene', '3417', (188, 191))	('NCT03991832', 'Var', (219, 230))	('NCT03230318]', 'Var', (174, 186))	('ERBB2', 'Gene', '2064', (82, 87))	('CCA', 'Disease', (355, 358))	('NCT03878095', 'Var', (206, 217))	('ERBB2', 'Gene', (82, 87))	('ROS1', 'Gene', '6098', (250, 254))	('NCT02150967', 'Var', (161, 172))	('NCT03656536', 'Var', (148, 159))	('NCT04521686]', 'Var', (232, 244))	('CCA', 'Phenotype', 'HP:0030153', (355, 358))	('IDH', 'Gene', (188, 191))	('ROS1', 'Gene', (250, 254))
169290	32510820	Further analysis demonstrated that patients without a cancer-associated factor had a higher rate of >= T3 (72.6% vs 55.1%: P = .029), N1 (57.8% vs 36.5%: P = .010), and M1 (31.6% vs 15.6%: P = .023) in ICC.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('>= T3', 'Var', (100, 105))	('patients', 'Species', '9606', (35, 43))	('ICC', 'Disease', (202, 205))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
92504	28658632	More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA.	('liver tumors', 'Disease', 'MESH:D008113', (99, 111))	('liver tumors', 'Disease', (99, 111))	('IDH', 'Gene', (28, 31))	('liver tumors', 'Phenotype', 'HP:0002896', (99, 111))	('IDH', 'Gene', '3417', (28, 31))	('liver tumor', 'Phenotype', 'HP:0002896', (99, 110))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('associated with', 'Reg', (46, 61))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('CCA', 'Disease', (155, 158))
92517	28658632	Prior studies indicate that iCCAs are unusual among epithelial cancers in having a relatively high rate of missense mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) genes, which encode metabolic enzymes that interconvert isocitrate and alpha-ketoglutarate in central carbon metabolism.	('IDH', 'Gene', (172, 175))	('IDH', 'Gene', '3417', (167, 170))	('epithelial cancers', 'Disease', 'MESH:D000077216', (52, 70))	('IDH', 'Gene', '3417', (172, 175))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (249, 268))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('IDH1', 'Gene', (167, 171))	('missense mutations', 'Var', (107, 125))	('carbon', 'Chemical', 'MESH:D002244', (280, 286))	('IDH1', 'Gene', '3417', (167, 171))	('epithelial cancers', 'Disease', (52, 70))	('IDH', 'Gene', (167, 170))
169363	28658632	These mutations, which are also common in acute myeloid leukemia, low grade glioma and glioblastoma, and chondrosarcoma, occur at defined hotspots and result in neomorphic enzyme activity, leading to production of high levels of the metabolite (R)-2-hydroxyglutarate (2HG).	('glioma', 'Disease', (76, 82))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (42, 64))	('leukemia', 'Phenotype', 'HP:0001909', (56, 64))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (48, 64))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (105, 119))	('(R)-2-hydroxyglutarate', 'Chemical', '-', (244, 266))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('neomorphic', 'MPA', (161, 171))	('mutations', 'Var', (6, 15))	('acute myeloid leukemia', 'Disease', (42, 64))	('glioblastoma', 'Disease', 'MESH:D005909', (87, 99))	('activity', 'MPA', (179, 187))	('glioblastoma', 'Disease', (87, 99))	('chondrosarcoma', 'Disease', 'MESH:D002813', (105, 119))	('production', 'MPA', (200, 210))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('chondrosarcoma', 'Disease', (105, 119))	('result in', 'Reg', (151, 160))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (42, 64))
92519	28658632	2HG does not participate in normal metabolic processes but instead interferes with the function of enzymes that utilize alpha-ketoglutarate as a co-enzyme, including histone and DNA demethylases, and inhibits the mitochondrial electron transport chain .	('interferes', 'NegReg', (67, 77))	('histone', 'Enzyme', (166, 173))	('inhibits', 'NegReg', (200, 208))	('function', 'MPA', (87, 95))	('2HG', 'Var', (0, 3))	('DNA demethylases', 'Enzyme', (178, 194))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (120, 139))	('enzymes', 'Enzyme', (99, 106))	('mitochondrial', 'MPA', (213, 226))
92520	28658632	Additional recurrent mutations and fusions have been reported in CCAs involving the fibroblast growth factor receptor 2 (FGFR2) gene, as well as in KRAS, BRAF, TP53, and in genes encoding chromatin-modifying enzymes .	('CCAs', 'Disease', (65, 69))	('FGFR2', 'Gene', (121, 126))	('FGFR2', 'Gene', '2263', (121, 126))	('fusions', 'Var', (35, 42))	('mutations', 'Var', (21, 30))
169366	28658632	Consistent with previous studies, we identified inactivating mutations in the tumor suppressor genes ARID1A, ARID1B, BAP1, PBRM1, TP53, STK11, and PTEN, and hotspot gain-of-function mutations in the oncogenes IDH1, IDH2, KRAS, BRAF, and PIK3CA (Figure 1A, Figure S1A, and Table S1 and 3).	('ARID1A', 'Gene', (101, 107))	('PBRM1', 'Gene', (123, 128))	('gain-of-function', 'PosReg', (165, 181))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('IDH', 'Gene', (215, 218))	('PTEN', 'Gene', (147, 151))	('IDH1', 'Gene', '3417', (209, 213))	('IDH', 'Gene', '3417', (215, 218))	('ARID1B', 'Gene', (109, 115))	('TP53', 'Gene', (130, 134))	('mutations', 'Var', (182, 191))	('STK11', 'Gene', (136, 141))	('inactivating mutations', 'Var', (48, 70))	('BAP1', 'Gene', (117, 121))	('tumor', 'Disease', (78, 83))	('IDH', 'Gene', (209, 212))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('IDH1', 'Gene', (209, 213))	('IDH', 'Gene', '3417', (209, 212))
169368	28658632	In two tumors, we identified a recurrent P216L mutation in the regulatory domain of ARAF adjacent to the functionally validated N217I mutation , which suggests an activated state.	('N217I', 'Mutation', 'p.N217I', (128, 133))	('ARAF', 'Gene', (84, 88))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('P216L', 'Var', (41, 46))	('P216L', 'Mutation', 'p.P216L', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
169369	28658632	We also identified two frameshift deletions and one missense mutation S217F in the albumin gene (ALB), one of the most significantly mutated genes in HCC.	('frameshift deletions', 'Var', (23, 43))	('S217F', 'Mutation', 'p.S217F', (70, 75))	('S217F', 'Var', (70, 75))	('ALB', 'Gene', (97, 100))
92531	28658632	Although analyzed separately, these additional samples corroborated the mutations above and highlighted additional recurrent mutations in the BRCA2, MLL3, APC, NF1, and ELF3 tumor-suppressor genes.	('tumor', 'Disease', (174, 179))	('mutations', 'Var', (125, 134))	('BRCA2', 'Gene', (142, 147))	('NF1', 'Gene', (160, 163))	('APC', 'Disease', 'MESH:D011125', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('APC', 'Disease', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('MLL3', 'Gene', (149, 153))
169370	28658632	An analysis of gene fusions from RNA-seq data identified 5 samples (13%) that expressed FGFR2 fusion transcripts; this prevalence is consistent with other studies .	('FGFR2', 'Gene', (88, 93))	('fusion transcripts', 'Var', (94, 112))	('FGFR2', 'Gene', '2263', (88, 93))
92533	28658632	Other than the FGFR2-FRK fusion, which resulted in loss of the FGFR2 kinase domain and retention of the FRK kinase domain, the rest of the fusions retained the kinase domain, consisting of FGFR2 exons 1-17 spliced in frame with the partner gene.	('kinase domain', 'MPA', (69, 82))	('FGFR2', 'Gene', '2263', (189, 194))	('kinase', 'MPA', (160, 166))	('fusions', 'Var', (139, 146))	('FGFR2', 'Gene', (15, 20))	('FGFR2', 'Gene', '2263', (15, 20))	('FRK kinase domain', 'MPA', (104, 121))	('FGFR2', 'Gene', '2263', (63, 68))	('loss', 'NegReg', (51, 55))	('FGFR2', 'Gene', (63, 68))	('FGFR2', 'Gene', (189, 194))
169371	28658632	We also observed 2 missense mutations and 1 in-frame insertion in FGFR2.	('FGFR2', 'Gene', (66, 71))	('missense mutations', 'Var', (19, 37))	('FGFR2', 'Gene', '2263', (66, 71))
169372	28658632	We further identified low-prevalence cases of focal SCNAs that have been reported in other cancers, including amplification of CDK4/MDM2 and homozygous focal deletion of QKI and SAV1 (Table S1 and Figure S1B).	('QKI', 'Gene', (170, 173))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('amplification', 'Var', (110, 123))	('CDK4/MDM2', 'Gene', (127, 136))	('cancers', 'Disease', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('focal SCNAs', 'Disease', (46, 57))
92538	28658632	Collectively, CDKN2A was mutated, deleted, or silenced in 47% of cancers, a higher rate than previously appreciated with single platform analyses.	('silenced', 'NegReg', (46, 54))	('deleted', 'Var', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('mutated', 'Var', (25, 32))	('CDKN2A', 'Gene', (14, 20))
92539	28658632	Next, cross-comparing sequencing and copy number data, we found that all mutations in BAP1 and PBRM1 (both located on 3p21) were detected in tumors with 3p loss of heterozygosity, suggesting biallelic inactivation of these genes in near-diploid tumors.	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('PBRM1', 'Gene', (95, 100))	('diploid tumors', 'Disease', (237, 251))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('loss', 'NegReg', (156, 160))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('BAP1', 'Gene', (86, 90))	('detected', 'Reg', (129, 137))	('tumors', 'Disease', (245, 251))	('diploid tumors', 'Disease', 'MESH:C548012', (237, 251))	('mutations', 'Var', (73, 82))
169373	28658632	Cancer cell fractions were higher for the broad or arm-level loss of chromosome 3 than for BAP1 mutations, followed by PBRM1 mutations, suggesting that these events occur chronologically (3p loss, BAP1, PBRM1) in CCA development (Figure S1F-G).	('mutations', 'Var', (125, 134))	('BAP1', 'Gene', (91, 95))	('PBRM1', 'Gene', (119, 124))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('CCA', 'Disease', (213, 216))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('loss', 'NegReg', (61, 65))	('mutations', 'Var', (96, 105))
169374	28658632	As observed across 31 tumor types analyzed to date , the most common signature was C>T/G>A substitutions at CpG islands (signature #6), followed by signature #1, characterized by AC>AN, AT>AN (Figure 1).	('C>T/G>A substitutions', 'Var', (83, 104))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('substitutions', 'Var', (91, 104))	('tumor', 'Disease', (22, 27))	('AT', 'Disease', 'None', (186, 188))
169376	28658632	Intriguingly, Cluster 1 included all 7 cases with an IDH1 or IDH2 hotspot mutation, while Cluster 2 was enriched in extrahepatic or perihilar CCA and Cluster 3 contained all 5 FGFR2 fusions.	('mutation', 'Var', (74, 82))	('IDH', 'Gene', '3417', (61, 64))	('FGFR2', 'Gene', (176, 181))	('FGFR2', 'Gene', '2263', (176, 181))	('IDH1', 'Gene', (53, 57))	('IDH1', 'Gene', '3417', (53, 57))	('IDH', 'Gene', (53, 56))	('IDH', 'Gene', (61, 64))	('IDH', 'Gene', '3417', (53, 56))
169377	28658632	Notably, most IDH1/2 mutations (8/10) were located in the cluster that most strongly resembled the IDH mutant-enriched TCGA cluster 1.	('IDH', 'Gene', '3417', (99, 102))	('IDH1', 'Gene', '3417', (14, 18))	('IDH', 'Gene', (14, 17))	('IDH', 'Gene', '3417', (14, 17))	('IDH1', 'Gene', (14, 18))	('IDH', 'Gene', (99, 102))	('mutations', 'Var', (21, 30))
92551	28658632	Examination of the GSE26566 dataset provided an external validation of these findings, again identifying an enrichment of IDH mutants among the tumors with high expression of the mitochondrial gene signature (Figure 3C).	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('IDH', 'Gene', '3417', (122, 125))	('IDH', 'Gene', (122, 125))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('mutants', 'Var', (126, 133))
169382	28658632	This association between this signature and IDH mutations appears to be particular to CCA, since it was not observed upon analysis of TCGA datasets for glioblastoma, low grade glioma, melanoma, or acute myeloid leukemia TCGA datasets (Figure S3C).	('glioma', 'Disease', (176, 182))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('glioblastoma', 'Phenotype', 'HP:0012174', (152, 164))	('melanoma', 'Disease', (184, 192))	('acute myeloid leukemia', 'Disease', (197, 219))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (197, 219))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (203, 219))	('IDH', 'Gene', (44, 47))	('leukemia', 'Phenotype', 'HP:0001909', (211, 219))	('CCA', 'Disease', (86, 89))	('IDH', 'Gene', '3417', (44, 47))	('glioblastoma', 'Disease', (152, 164))	('glioblastoma', 'Disease', 'MESH:D005909', (152, 164))	('mutations', 'Var', (48, 57))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (197, 219))
92556	28658632	These results suggest that mitochondrial activity and chromatin modification are linked basic biological events that are also regulated by IDH hotspot mutations in CCA.	('regulated', 'Reg', (126, 135))	('IDH', 'Gene', (139, 142))	('CCA', 'Disease', (164, 167))	('mitochondrial', 'MPA', (27, 40))	('mutations', 'Var', (151, 160))	('IDH', 'Gene', '3417', (139, 142))
169387	28658632	One group (cluster 4) consisted entirely of tumors with high-level amplification of CCND1.	('tumors', 'Disease', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('CCND1', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('high-level amplification', 'Var', (56, 80))
169389	28658632	Lastly, cluster 1 consisted of molecularly atypical tumors, including two genomically silent cases that were completely devoid of copy number alterations or recurrent CCA driver mutations (the low-purity extrahepatic W5-AAH2 and the 0.61-purity intrahepatic ZH-A8Y6).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('CCA', 'Disease', (167, 170))	('mutations', 'Var', (178, 187))
169390	28658632	Next, unsupervised clustering of samples using CpG sites that show cancer-specific DNA methylation changes identified 4 subgroups in our CCA cohort (Figure 4B).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('changes', 'Var', (99, 106))	('CCA', 'Disease', (137, 140))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
169394	28658632	Lastly, we note that tumors in clusters 2 and 3 had frequent mutation of genes encoding chromatin regulators, including PBRM1 and ARID1A (10/20).	('ARID1A', 'Gene', (130, 136))	('PBRM1', 'Gene', (120, 125))	('mutation', 'Var', (61, 69))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
169397	28658632	IDH hotspot mutations were present exclusively in COCA2 (p=0.0004; "IDH COCA"), reflecting the mRNA and methylation specificity noted earlier, and identifying a correlation with copy number cluster 2 ("genomically unstable").	('IDH', 'Gene', '3417', (68, 71))	('IDH', 'Gene', (0, 3))	('mutations', 'Var', (12, 21))	('IDH', 'Gene', '3417', (0, 3))	('COCA2', 'Gene', (50, 55))	('COCA', 'Species', '289672', (72, 76))	('IDH', 'Gene', (68, 71))	('COCA', 'Species', '289672', (50, 54))
92573	28658632	Patients with IDH COCA tumors were typically nonsmokers, and the tumors exhibited a lower frequency of lymphatic invasion and chromosome arm 8p gains (Figure 4C).	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('IDH COCA tumors', 'Disease', 'MESH:D009369', (14, 29))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('chromosome', 'Var', (126, 136))	('lower', 'NegReg', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('IDH COCA tumors', 'Disease', (14, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('lymphatic invasion', 'CPA', (103, 121))
169399	28658632	COCA4 ("METH3 COCA" contained 8 of 12 cases with BAP1 mutations (p=0.01) and all 5 FGFR2 fusion cases (p=0.004).	('FGFR2', 'Gene', '2263', (83, 88))	('FGFR2', 'Gene', (83, 88))	('BAP1', 'Gene', (49, 53))	('COCA', 'Species', '289672', (0, 4))	('mutations', 'Var', (54, 63))	('COCA', 'Species', '289672', (14, 18))
92580	28658632	Nevertheless, these results clearly highlight the molecular distinctness of IDH mutants and the power of integrated multiplatform analyses.	('IDH', 'Gene', '3417', (76, 79))	('IDH', 'Gene', (76, 79))	('mutants', 'Var', (80, 87))
92588	28658632	Collectively, these data suggest that IDH mutations result in hypermethylation and silencing of ARID1A, and that impingement of ARID1A is a convergent feature of IDH COCA tumors.	('IDH COCA tumors', 'Disease', (162, 177))	('IDH', 'Gene', (38, 41))	('silencing', 'MPA', (83, 92))	('IDH', 'Gene', (162, 165))	('IDH COCA tumors', 'Disease', 'MESH:D009369', (162, 177))	('ARID1A', 'Gene', (96, 102))	('IDH', 'Gene', '3417', (38, 41))	('IDH', 'Gene', '3417', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('hypermethylation', 'MPA', (62, 78))	('mutations', 'Var', (42, 51))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
169408	28658632	For miRNAs, we note that miRNA-194-5p is significantly upregulated in the IDH COCA subtype and negatively correlated with the CM signature (Figure 4 and Figure S5D-H).	('correlated', 'Interaction', (106, 116))	('CM signature', 'MPA', (126, 138))	('IDH', 'Gene', (74, 77))	('upregulated', 'PosReg', (55, 66))	('miRNA-194-5p', 'Var', (25, 37))	('negatively', 'NegReg', (95, 105))	('IDH', 'Gene', '3417', (74, 77))	('COCA', 'Species', '289672', (78, 82))
92598	28658632	These tumors shared several molecular features with CCA, including mRNA and miRNA expression patterns, DNA methylation, and to a lesser extent copy number (Figure 6B).	('CCA', 'Disease', (52, 55))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('copy number', 'Var', (143, 154))	('miRNA expression patterns', 'MPA', (76, 101))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('DNA', 'MPA', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
169410	28658632	Strikingly, 5 of those 7 samples harbored either hotspot IDH1/2 mutations (n=4) or an FGFR2 fusion (n=1), and they were the only cases in the HCC dataset with these mutations.	('FGFR2', 'Gene', (86, 91))	('FGFR2', 'Gene', '2263', (86, 91))	('IDH1', 'Gene', (57, 61))	('hotspot', 'PosReg', (49, 56))	('IDH1', 'Gene', '3417', (57, 61))	('mutations', 'Var', (64, 73))
169411	28658632	Re-examination of their histology revealed that although regions of these 7 cases fall within the spectrum of HCC, each of the 5 tumors with IDH1 or FGFR2 lesions had some features that have also been described in iCCA, including focal to diffuse glandular differentiation, abundant fibrotic stroma (desmoplasia), and in some areas, an anastomosing architecture (Figure S6G-L).	('IDH1', 'Gene', (141, 145))	('tumors', 'Disease', (129, 135))	('desmoplasia', 'Disease', (300, 311))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('fall', 'Phenotype', 'HP:0002527', (82, 86))	('IDH1', 'Gene', '3417', (141, 145))	('anastomosing architecture', 'CPA', (336, 361))	('FGFR2', 'Gene', (149, 154))	('desmoplasia', 'Disease', 'None', (300, 311))	('FGFR2', 'Gene', '2263', (149, 154))	('lesions', 'Var', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('fibrotic stroma', 'Disease', (283, 298))	('fibrotic stroma', 'Disease', 'None', (283, 298))	('iCCA', 'Disease', (214, 218))	('focal to', 'CPA', (230, 238))	('HCC', 'Disease', (110, 113))
92604	28658632	The prominent enrichment of IDH mutations in molecularly CCA-like HCCs is consistent with previous findings that IDH mutations block liver progenitor cells from undergoing hepatocyte differentiation and shift them toward a cholangiocellular fate.	('IDH', 'Gene', '3417', (113, 116))	('mutations', 'Var', (117, 126))	('IDH', 'Gene', (28, 31))	('block', 'NegReg', (127, 132))	('hepatocyte differentiation', 'CPA', (172, 198))	('IDH', 'Gene', '3417', (28, 31))	('HCCs', 'Disease', (66, 70))	('mutations', 'Var', (32, 41))	('shift', 'Reg', (203, 208))	('IDH', 'Gene', (113, 116))	('liver progenitor cells', 'CPA', (133, 155))
92608	28658632	Relevantly, IDH mutants hypermethylate and putatively silence the ARID1A promoter, which may contribute to the lowered chromatin modifier signature expression.	('lowered', 'NegReg', (111, 118))	('ARID1A', 'Gene', (66, 72))	('IDH', 'Gene', (12, 15))	('chromatin modifier signature expression', 'MPA', (119, 158))	('IDH', 'Gene', '3417', (12, 15))	('mutants hypermethylate', 'Var', (16, 38))	('silence', 'NegReg', (54, 61))	('hypermethylate', 'Var', (24, 38))
92609	28658632	Moreover, we identify a group of liver tumors with an atypical histopathology and a highly CCA-like molecular profile that is enriched for IDH mutations, consistent with the emerging view that liver tumors comprise a continuous spectrum .	('liver tumors', 'Phenotype', 'HP:0002896', (33, 45))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('liver tumor', 'Phenotype', 'HP:0002896', (193, 204))	('liver tumor', 'Phenotype', 'HP:0002896', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('liver tumors', 'Disease', 'MESH:D008113', (193, 205))	('IDH', 'Gene', '3417', (139, 142))	('IDH', 'Gene', (139, 142))	('liver tumors', 'Disease', 'MESH:D008113', (33, 45))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('liver tumors', 'Disease', (193, 205))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('liver tumors', 'Disease', (33, 45))	('mutations', 'Var', (143, 152))	('liver tumors', 'Phenotype', 'HP:0002896', (193, 205))
92610	28658632	Furthermore, the complete lack of IDH mutations in otherwise standard HCC from the TCGA set (0/172) has implications about specific functions of mutant IDH in modulating liver cell identity and also underscores the benefit of combined molecular and histopathological diagnosis.	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('liver', 'MPA', (170, 175))	('mutant', 'Var', (145, 151))	('modulating', 'Reg', (159, 169))	('IDH', 'Gene', (152, 155))	('IDH', 'Gene', '3417', (152, 155))
92611	28658632	Although previous studies also identified transcriptionally CCA-like HCC, our results identify IDH and FGFR2 perturbations as associated drivers linked to methylation, miRNA, and copy number similarities.	('FGFR2', 'Gene', (103, 108))	('methylation', 'MPA', (155, 166))	('perturbations', 'Var', (109, 122))	('FGFR2', 'Gene', '2263', (103, 108))	('miRNA', 'MPA', (168, 173))	('IDH', 'Gene', (95, 98))	('IDH', 'Gene', '3417', (95, 98))
169414	28658632	As examples, i) extrahepatic CCAs have more SMAD4 mutations than iCCAs; ii) a Chinese study found a much lower incidence of IDH (5%), PBRM1 (1%), and BAP1 (1%) mutations in iCCAs; and iii) liver fluke- and/or viral hepatitis-positive cancers have a higher incidence of TP53 mutations and lower incidence of IDH mutations.	('mutations', 'Var', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('extrahepatic CCAs', 'Disease', (16, 33))	('TP53', 'Gene', (269, 273))	('viral hepatitis-positive cancers', 'Disease', 'MESH:D006525', (209, 241))	('liver fluke', 'Species', '6192', (189, 200))	('viral hepatitis-positive cancers', 'Disease', (209, 241))	('hepatitis', 'Phenotype', 'HP:0012115', (215, 224))	('lower', 'NegReg', (105, 110))	('BAP1', 'Gene', (150, 154))	('IDH', 'Gene', (124, 127))	('PBRM1', 'Gene', (134, 139))	('IDH', 'Gene', (307, 310))	('SMAD4', 'Gene', (44, 49))	('liver fluke- and/or', 'Disease', (189, 208))	('mutations', 'Var', (50, 59))	('IDH', 'Gene', '3417', (124, 127))	('viral hepatitis', 'Phenotype', 'HP:0006562', (209, 224))	('IDH', 'Gene', '3417', (307, 310))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))	('mutations', 'Var', (274, 283))
92622	28658632	Notably, prior work has suggested that BAP1, PBRM1, and ARID1A deficiency all result in sensitivity to EZH2 inhibition across cancer types; the association of ARID1A methylation with IDH mutation opens the question of whether EZH2 inhibition might also be effective in this subtype.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('ARID1A deficiency', 'Disease', (56, 73))	('association', 'Interaction', (144, 155))	('IDH', 'Gene', (183, 186))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('ARID1A', 'Gene', (159, 165))	('IDH', 'Gene', '3417', (183, 186))	('mutation', 'Var', (187, 195))	('methylation', 'Var', (166, 177))	('ARID1A deficiency', 'Disease', 'MESH:D007153', (56, 73))
169456	22977829	Thickening of long segments of the pancreatic duct wall, or the presence of a hypoechoic halo around the duct, may be suggestive of autoimmune pancreatitis.	('pancreatic duct', 'Disease', (35, 50))	('autoimmune pancreatitis', 'Disease', 'MESH:D000081012', (132, 155))	('Thickening', 'Var', (0, 10))	('autoimmune pancreatitis', 'Disease', (132, 155))	('pancreatic duct', 'Disease', 'MESH:D021441', (35, 50))	('pancreatitis', 'Phenotype', 'HP:0001733', (143, 155))
169497	22240785	Outcome measures were estimated by calculating SIRs for intrahepatic cholangiocarcinoma (ICD7 code 155.0; histopathology code 076) and extrahepatic cholangiocarcinoma (ICD7 codes 155.2, 155.3, 155.8, 155.9; histopathology code 096), and their 95% confidence intervals (CI), assuming that the number of cases followed a Poisson distribution.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (148, 166))	('intrahepatic cholangiocarcinoma ', 'Gene', (56, 88))	('ICD7', 'Var', (168, 172))	('extrahepatic cholangiocarcinoma', 'Disease', (135, 166))	('SIRs', 'Disease', (47, 51))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (69, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('intrahepatic cholangiocarcinoma ', 'Gene', '128360', (56, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('SIRs', 'Disease', 'None', (47, 51))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (135, 166))
169560	32085654	Mice lacking even a single VEGF-A allele exhibit impaired development of early vasculature and die at E11-E12.	('development of early vasculature', 'CPA', (58, 90))	('men', 'Species', '9606', (65, 68))	('E11-E12', 'Var', (102, 109))	('VEGF-A', 'Gene', (27, 33))	('Mice', 'Species', '10090', (0, 4))	('impaired', 'NegReg', (49, 57))
169594	32085654	As expected, VEGF-A overexpression frequently correlates not only with enhanced cancer invasiveness, but also with a high risk of tumor recurrence and unfavorable prognosis.	('enhanced', 'PosReg', (71, 79))	('overexpression', 'Var', (20, 34))	('cancer invasiveness', 'Disease', 'MESH:D009362', (80, 99))	('cancer invasiveness', 'Disease', (80, 99))	('VEGF-A', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
169595	32085654	On this basis, inhibition of the VEGF-A/VEGFRs signaling represents a widely used approach for cancer treatment through the use of the anti-VEGF-A and anti-VEGFR-2 monoclonal antibodies (mAbs) bevacizumab and ramucirumab, respectively; the chimeric molecule ziv-aflibercept; or a number of multi-targeted small-molecule TK inhibitors.	('bevacizumab', 'Chemical', 'MESH:D000068258', (193, 204))	('ramucirumab', 'Chemical', 'MESH:C543333', (209, 220))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('men', 'Species', '9606', (107, 110))	('VEGFR', 'Gene', (156, 161))	('anti-VEGF-A', 'Var', (135, 146))	('VEGFR', 'Gene', (40, 45))	('cancer', 'Disease', (95, 101))	(')', 'Gene', '7424', (191, 192))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('VEGFR', 'Gene', '3791', (156, 161))	('VEGFR', 'Gene', '3791', (40, 45))
169600	32085654	In regard to VEGF-B, ectopic expression of the growth factor in pancreatic beta-cells of transgenic mice prevented the formation of neuroendocrine tumors likely displacing VEGF-A or PlGF from VEGFR-1.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('prevented', 'NegReg', (105, 114))	('displacing', 'NegReg', (161, 171))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('formation', 'CPA', (119, 128))	('pancreatic', 'Disease', 'MESH:D010195', (64, 74))	('transgenic mice', 'Species', '10090', (89, 104))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (132, 153))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (132, 153))	('pancreatic', 'Disease', (64, 74))	('ectopic expression', 'Var', (21, 39))	('neuroendocrine tumors', 'Disease', (132, 153))
169613	32085654	The anti-VEGF-A bevacizumab is the standard regimen for advanced/metastatic non-squamous NSCLC in the first-line setting, in combination with platinum-based chemotherapy.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('platinum', 'Chemical', 'MESH:D010984', (142, 150))	('men', 'Species', '9606', (48, 51))	('bevacizumab', 'Chemical', 'MESH:D000068258', (16, 27))	('SCLC', 'Phenotype', 'HP:0030357', (90, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('NSCLC', 'Disease', (89, 94))	('anti-VEGF-A', 'Var', (4, 15))
169616	32085654	NSCLC is often associated with a hypoxic environment leading to HIF-1alpha overexpression, and HIF-1alpha knockdown in the NCI-H157 lung carcinoma cell line has been shown to reduce VEGF-A expression and cell invasiveness.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('HIF-1alpha', 'Gene', '3091', (95, 105))	('men', 'Species', '9606', (48, 51))	('overexpression', 'PosReg', (75, 89))	('HIF-1alpha', 'Gene', '3091', (64, 74))	('reduce', 'NegReg', (175, 181))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('expression', 'MPA', (189, 199))	('knockdown', 'Var', (106, 115))	('VEGF-A', 'Protein', (182, 188))	('HIF-1alpha', 'Gene', (95, 105))	('NCI-H157 lung carcinoma', 'Disease', (123, 146))	('NCI-H157 lung carcinoma', 'Disease', 'MESH:D008175', (123, 146))	('SCLC', 'Phenotype', 'HP:0030357', (1, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('HIF-1alpha', 'Gene', (64, 74))	('cell invasiveness', 'CPA', (204, 221))	('NSCLC', 'Disease', (0, 5))
169623	32085654	The sVEGFR-1-i13 splice variant was reported to increase during treatment with antiangiogenic therapies and to contribute to the progression of squamous lung carcinoma.	('splice variant', 'Var', (17, 31))	('men', 'Species', '9606', (69, 72))	('squamous lung carcinoma', 'Disease', (144, 167))	('sVEGFR-1-i13', 'Gene', (4, 16))	('squamous lung carcinoma', 'Phenotype', 'HP:0030359', (144, 167))	('squamous lung carcinoma', 'Disease', 'MESH:D002294', (144, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('contribute', 'Reg', (111, 121))	('increase', 'PosReg', (48, 56))
169624	32085654	In fact, besides acting as inhibitor of angiogenesis, this sVEGFR-1 variant is a component of the ECM that binds to the alpha5beta1 integrin and stimulates the adhesion and migration of endothelial cells.	('binds', 'Interaction', (107, 112))	('rat', 'Species', '10116', (176, 179))	('sVEGFR-1', 'Gene', (59, 67))	('adhesion', 'CPA', (160, 168))	('variant', 'Var', (68, 75))	('beta1 integrin', 'Gene', '3688', (126, 140))	('stimulates', 'PosReg', (145, 155))	('beta1 integrin', 'Gene', (126, 140))
169634	32085654	Furthermore, the VEGFR-1 relevance to NSCLC aggressiveness was confirmed by the observation that patients with squamous cell carcinoma and high VEGF-B expression showed poorer survival compared to those with low VEGF-B expression.	('NSCLC', 'Disease', (38, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('aggressiveness', 'Disease', (44, 58))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('survival', 'MPA', (176, 184))	('aggressiveness', 'Phenotype', 'HP:0000718', (44, 58))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (111, 134))	('VEGF-B', 'Gene', (144, 150))	('squamous cell carcinoma', 'Disease', (111, 134))	('patients', 'Species', '9606', (97, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('poorer', 'NegReg', (169, 175))	('SCLC', 'Phenotype', 'HP:0030357', (39, 43))	('high', 'Var', (139, 143))	('aggressiveness', 'Disease', 'MESH:D001523', (44, 58))
169648	32085654	Nevertheless, after metastatic nodule formation, VEGFR-1 blockade led to a decrease of BMDCs infiltration inside and around the metastatic nodules.	('decrease', 'NegReg', (75, 83))	('blockade', 'Var', (57, 65))	('VEGFR-1', 'Gene', (49, 56))	('rat', 'Species', '10116', (99, 102))	('BMDCs infiltration', 'CPA', (87, 105))
169653	32085654	Hepatocellular carcinoma is a hypervascularized cancer type, and dysregulation of several angiogenic pathways, including those activated by the VEGF family members, has been involved in the development and progression of this tumor.	('involved', 'Reg', (174, 182))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (0, 24))	('VEGF', 'Gene', '7422', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('dysregulation', 'Var', (65, 78))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('men', 'Species', '9606', (197, 200))	('hypervascularized cancer', 'Disease', 'MESH:D009369', (30, 54))	('Hepatocellular carcinoma', 'Disease', (0, 24))	('hypervascularized cancer', 'Disease', (30, 54))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('VEGF', 'Gene', (144, 148))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (0, 24))	('angiogenic pathways', 'Pathway', (90, 109))	('tumor', 'Disease', (226, 231))
169660	32085654	PlGF blockade resulted in normalization of tumor-associated vessels, reduced tumor nodule formation in the liver, and increased animal survival.	('blockade', 'Var', (5, 13))	('reduced', 'NegReg', (69, 76))	('animal survival', 'CPA', (128, 143))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('increased', 'PosReg', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PlGF', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (77, 82))	('normalization', 'NegReg', (26, 39))
169661	32085654	Similar findings were obtained in chemically-induced hepatocellular and cholangiocarcinoma in vivo models, where treatment with the 5D11D4 mAb decreased tumor burden and infiltration by protumoral M2 cells.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (189, 194))	('rat', 'Species', '10116', (176, 179))	('cholangiocarcinoma', 'Disease', (72, 90))	('decreased', 'NegReg', (143, 152))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))	('men', 'Species', '9606', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('tumoral', 'Disease', (189, 196))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 90))	('5D11D4', 'Var', (132, 138))	('tumoral', 'Disease', 'MESH:D009369', (189, 196))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('hepatocellular', 'Disease', (53, 67))
169670	32085654	Consistently, patients with high PlGF and miR-19a levels in the tumor showed a shorter overall survival (OS) than patients with low expression.	('tumor', 'Disease', (64, 69))	('miR-19a', 'Gene', (42, 49))	(')', 'Gene', '7424', (107, 108))	('shorter', 'NegReg', (79, 86))	('miR-19a', 'Gene', '406979', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('PlGF', 'MPA', (33, 37))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('overall survival', 'MPA', (87, 103))
169673	32085654	In fact, blockade of VEGFR-1 by the MF-1 mAb in syngeneic murine RCC models induced 31% reduction in the growth of liver metastases, whereas blockade of VEGFR-2 had minimal effects.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('RCC', 'Disease', (65, 68))	('MF-1', 'Gene', (36, 40))	('VEGFR-1', 'Gene', (21, 28))	('reduction', 'NegReg', (88, 97))	('liver metastases', 'Disease', (115, 131))	('murine', 'Species', '10090', (58, 64))	('MF-1', 'Gene', '17300', (36, 40))	('liver metastases', 'Disease', 'MESH:D009362', (115, 131))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('blockade', 'Var', (9, 17))
169674	32085654	In the case of metastases from colon carcinoma, only the neutralization of both VEGFR-1 and VEGFR-2 was able to decrease the size of liver metastasis.	('liver metastasis', 'Disease', (133, 149))	('VEGFR-2', 'Gene', (92, 99))	('metastases', 'Disease', (15, 25))	('decrease', 'NegReg', (112, 120))	('neutralization', 'Var', (57, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('colon carcinoma', 'Disease', 'MESH:D015179', (31, 46))	('metastases', 'Disease', 'MESH:D009362', (15, 25))	('size of liver', 'Phenotype', 'HP:0002240', (125, 138))	('colon carcinoma', 'Disease', (31, 46))	('VEGFR-1', 'Gene', (80, 87))	('liver metastasis', 'Disease', 'MESH:D009362', (133, 149))
169683	32085654	The ccRCC is characterized by mutations or epigenetic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, which are considered to play a key role in VEGF-A overexpression.	('epigenetic inactivation', 'Var', (43, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (74, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ccRCC', 'Disease', (4, 9))	('ccRCC', 'Disease', 'MESH:C538614', (4, 9))	('mutations', 'Var', (30, 39))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))
169686	32085654	Thus, in the presence of low expression or dysfunctional VHL, the HIF-1alpha accumulates and activates a number of hypoxia-driven genes, including VEGF-A.	('hypoxia', 'Disease', 'MESH:D000860', (115, 122))	('dysfunctional', 'Var', (43, 56))	('HIF-1alpha', 'Gene', (66, 76))	('activates', 'PosReg', (93, 102))	('low expression', 'Var', (25, 39))	('accumulates', 'PosReg', (77, 88))	('VHL', 'Gene', (57, 60))	('HIF-1alpha', 'Gene', '3091', (66, 76))	('VHL', 'Gene', '7428', (57, 60))	('hypoxia', 'Disease', (115, 122))
169687	32085654	Several single nucleotide polymorphisms identified in the VEGF gene have been reported to be associated with RCC risk, tumor growth, and metastases.	('VEGF', 'Gene', (58, 62))	('tumor', 'Disease', (119, 124))	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('VEGF', 'Gene', '7422', (58, 62))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('associated', 'Reg', (93, 103))	('RCC', 'Disease', (109, 112))	('single nucleotide polymorphisms', 'Var', (8, 39))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('metastases', 'Disease', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
169688	32085654	In particular, two meta-analysis studies indicated that the VEGF -2578C/A, +936C/T, and +405G/C polymorphisms correlated with elevated risk of RCC, especially in the Asian populations.	('VEGF', 'Gene', '7422', (60, 64))	('+405G/C', 'Mutation', 'rs2010963', (88, 95))	('VEGF', 'Gene', (60, 64))	('-2578C/A', 'Mutation', 'rs699947', (65, 73))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('+936C/T', 'Mutation', 'rs3025039', (75, 82))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))	('+405G/C', 'Var', (88, 95))
169703	32085654	However, PlGF neutralization by the TB403 mAb did not inhibit the growth of sunitinib-resistant ccRCC xenografts, which did not express VEGFR-1.	('TB403', 'Var', (36, 41))	('TB', 'Chemical', 'MESH:D013725', (36, 38))	('inhibit', 'NegReg', (54, 61))	('sunitinib', 'Chemical', 'MESH:D000077210', (76, 85))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('ccRCC', 'Disease', (96, 101))	('ccRCC', 'Disease', 'MESH:C538614', (96, 101))
169710	32085654	demonstrated that VEGFR-1 overexpression increases in vitro and in vivo glioma growth via modulation of the Sonic Hedgehog Homolog (SHH) signaling pathway.	('glioma', 'Disease', (72, 78))	('increases', 'PosReg', (41, 50))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('VEGFR-1', 'Gene', (18, 25))	('rat', 'Species', '10116', (7, 10))	('overexpression', 'Var', (26, 40))	('Sonic Hedgehog Homolog', 'Gene', '6469', (108, 130))	('Sonic Hedgehog Homolog', 'Gene', (108, 130))	('modulation', 'Reg', (90, 100))
169713	32085654	In vitro treatment with the anti-VEGFR-1 D16F7 mAb markedly inhibited receptor autophosphorylation and ERK1/2 activation and reduced glioblastoma cell invasive behavior.	('glioblastoma', 'Disease', (133, 145))	('anti-VEGFR-1', 'Gene', (28, 40))	('men', 'Species', '9606', (14, 17))	('ERK1/2', 'Gene', (103, 109))	('ERK1/2', 'Gene', '5595;5594', (103, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (133, 145))	('receptor autophosphorylation', 'MPA', (70, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('reduced', 'NegReg', (125, 132))	('activation', 'MPA', (110, 120))	('inhibited', 'NegReg', (60, 69))	('D16F7', 'Var', (41, 46))	('D16F7', 'Chemical', 'MESH:C000627505', (41, 46))
169714	32085654	In vivo studies in glioblastoma murine models indicated that D16F7 was well-tolerated and confirmed its promising therapeutic potential, as the mAb induced a decrease in glioma growth and angiogenesis, as well as an increase in mice survival.	('glioblastoma', 'Disease', (19, 31))	('D16F7', 'Var', (61, 66))	('decrease in glioma growth', 'Disease', (158, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (19, 31))	('rat', 'Species', '10116', (80, 83))	('D16F7', 'Chemical', 'MESH:C000627505', (61, 66))	('murine', 'Species', '10090', (32, 38))	('glioblastoma', 'Phenotype', 'HP:0012174', (19, 31))	('angiogenesis', 'CPA', (188, 200))	('decrease in glioma growth', 'Disease', 'MESH:D005910', (158, 183))	('mice survival', 'CPA', (228, 241))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('increase', 'PosReg', (216, 224))	('mice', 'Species', '10090', (228, 232))
169715	32085654	In particular, the efficacy of D16F7 mAb was tested in heterotopic (intramuscular) and orthotopic (intracranial) models using rat C6 glioma sublines, transfected to overexpress VEGFR-1.	('C6 glioma sublines', 'Disease', 'MESH:C567307', (130, 148))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('overexpress', 'PosReg', (165, 176))	(')', 'Gene', '7424', (111, 112))	('rat', 'Species', '10116', (126, 129))	('tested', 'Reg', (45, 51))	('C6 glioma sublines', 'Disease', (130, 148))	('D16F7', 'Var', (31, 36))	('VEGFR-1', 'Gene', (177, 184))	(')', 'Gene', '7424', (81, 82))	('D16F7', 'Chemical', 'MESH:C000627505', (31, 36))
169716	32085654	In the heterotopic intramuscular model, treatment with D16F7 reduced tumor growth and in the orthotopic intracranial model the mAb increased animal survival by 40% and 65% at 10 and 20 mg/kg, respectively, with a remarkable percentage (46%) of long-term survivors at the higher dose.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('increased', 'PosReg', (131, 140))	('men', 'Species', '9606', (45, 48))	('animal survival', 'CPA', (141, 156))	('tumor', 'Disease', (69, 74))	('D16F7', 'Var', (55, 60))	(')', 'Gene', '7424', (239, 240))	('D16F7', 'Chemical', 'MESH:C000627505', (55, 60))	('reduced', 'NegReg', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
169717	32085654	Additionally, immunohistochemical analysis of tumor sections from D16F7-treated animals showed a higher number of apoptotic cells and fewer blood vessels compared to untreated mice.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('apoptotic cells', 'CPA', (114, 129))	('mice', 'Species', '10090', (176, 180))	('fewer', 'NegReg', (134, 139))	('D16F7', 'Chemical', 'MESH:C000627505', (66, 71))	('D16F7-treated', 'Var', (66, 79))	('blood vessels', 'CPA', (140, 153))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
169739	32085654	Treatment of human (CR-Mel) and murine (B16F10) melanoma cells with the anti-VEGFR-1 D16F7 mAb strongly down-modulated the migration triggered by PlGF.	('human', 'Species', '9606', (13, 18))	('melanoma cells', 'Disease', 'MESH:D008545', (48, 62))	('murine', 'Species', '10090', (32, 38))	('anti-VEGFR-1', 'Var', (72, 84))	(')', 'Gene', '7424', (26, 27))	('D16F7', 'Chemical', 'MESH:C000627505', (85, 90))	(')', 'Gene', '7424', (46, 47))	('men', 'Species', '9606', (5, 8))	('rat', 'Species', '10116', (126, 129))	('down-modulated', 'NegReg', (104, 118))	('melanoma cells', 'Disease', (48, 62))	('migration', 'CPA', (123, 132))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
169740	32085654	Moreover, D16F7 inhibited vasculogenic mimicry (i.e., the formation of tube-like structures, resembling blood vessels) by melanoma cells in response to VEGF-A.	('inhibited', 'NegReg', (16, 25))	(')', 'Gene', '7424', (117, 118))	('D16F7', 'Var', (10, 15))	('melanoma cells', 'Disease', 'MESH:D008545', (122, 136))	('melanoma cells', 'Disease', (122, 136))	('vasculogenic mimicry', 'CPA', (26, 46))	('D16F7', 'Chemical', 'MESH:C000627505', (10, 15))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('formation of tube-like structures', 'CPA', (58, 91))
169741	32085654	In vivo studies performed in a syngeneic murine melanoma model (B16F10 cells injected in B6D2F1 mice) confirmed the efficacy of VEGFR-1 blockade by D16F7 and the good tolerability of the treatment.	('melanoma', 'Disease', (48, 56))	('blockade', 'NegReg', (136, 144))	('D16F7', 'Chemical', 'MESH:C000627505', (148, 153))	('murine', 'Species', '10090', (41, 47))	('VEGFR-1', 'Gene', (128, 135))	('men', 'Species', '9606', (192, 195))	('D16F7', 'Var', (148, 153))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
169743	32085654	Furthermore, immunohistochemical analysis of melanoma sections from D16F7-treated animals showed a reduction of tumor infiltration by monocytes/macrophages and a marked decrease of bone invasion by melanoma cells.	('rat', 'Species', '10116', (124, 127))	('decrease', 'NegReg', (169, 177))	('melanoma cells', 'Disease', 'MESH:D008545', (198, 212))	('melanoma cells', 'Disease', (198, 212))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('D16F7-treated', 'Var', (68, 81))	('reduction', 'NegReg', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('D16F7', 'Chemical', 'MESH:C000627505', (68, 73))	('tumor', 'Disease', (112, 117))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
169745	32085654	In fact, the expression of VEGFR-1 in melanoma cells resistant to the BRAFi vemurafenib was higher than in their BRAFi-sensitive counterparts, whereas the transient silencing of VEGFR-1 in resistant cells increased BRAFi sensitivity and in susceptible cells delayed resistance development.	('BRAF', 'Gene', (215, 219))	('VEGFR-1', 'Gene', (178, 185))	('delayed', 'NegReg', (258, 265))	('VEGFR-1', 'Gene', (27, 34))	('increased', 'PosReg', (205, 214))	('BRAFi vemurafenib', 'Chemical', '-', (70, 87))	('silencing', 'Var', (165, 174))	('higher', 'PosReg', (92, 98))	('melanoma cells', 'Disease', 'MESH:D008545', (38, 52))	('BRAF', 'Gene', '673', (70, 74))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('BRAF', 'Gene', (70, 74))	('men', 'Species', '9606', (284, 287))	('BRAF', 'Gene', '673', (113, 117))	('expression', 'MPA', (13, 23))	('BRAF', 'Gene', (113, 117))	('melanoma cells', 'Disease', (38, 52))	('resistance development', 'CPA', (266, 288))	('BRAF', 'Gene', '673', (215, 219))
169746	32085654	Furthermore, vemurafenib-resistant melanoma cells expressing VEGFR-1 showed a higher invasive behavior, compared to melanoma cells susceptible to the BRAFi.	('vemurafenib', 'Chemical', 'MESH:D000077484', (13, 24))	('VEGFR-1', 'Var', (61, 68))	('higher', 'PosReg', (78, 84))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('BRAF', 'Gene', (150, 154))	('BRAF', 'Gene', '673', (150, 154))	('melanoma cells', 'Disease', (116, 130))	('melanoma cells', 'Disease', 'MESH:D008545', (116, 130))	('invasive behavior', 'CPA', (85, 102))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma cells', 'Disease', 'MESH:D008545', (35, 49))	('melanoma cells', 'Disease', (35, 49))
169747	32085654	Accordingly, treatment with D16F7 markedly reduced ECM invasion by resistant cells in response to VEGF-A and PlGF, suggesting that VEGFR-1 blockade in combination with the BRAFi might delay the acquisition of a resistance phenotype.	('D16F7', 'Chemical', 'MESH:C000627505', (28, 33))	('resistance phenotype', 'CPA', (211, 231))	('men', 'Species', '9606', (18, 21))	('D16F7', 'Var', (28, 33))	('delay', 'NegReg', (184, 189))	('ECM invasion', 'CPA', (51, 63))	('BRAF', 'Gene', '673', (172, 176))	('reduced', 'NegReg', (43, 50))	('VEGFR-1', 'Gene', (131, 138))	('BRAF', 'Gene', (172, 176))
169750	32085654	Indeed, PlGF silencing or inhibition of NF-kappaB restored melanoma cell sensitivity to the chemotherapeutic agent Finally, VEGF-B transcript levels in the tumor measured in a large cohort of melanoma patients inversely correlated with survival.	('patients', 'Species', '9606', (201, 209))	('PlGF', 'Gene', (8, 12))	('transcript levels', 'MPA', (131, 148))	('NF-kappaB', 'Gene', (40, 49))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('inhibition', 'NegReg', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanoma', 'Disease', (192, 200))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('tumor', 'Disease', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('VEGF-B', 'Gene', (124, 130))	('restored', 'PosReg', (50, 58))	('correlated', 'Reg', (220, 230))	('silencing', 'Var', (13, 22))
169761	32085654	Moreover, a meta-analysis study performed in a Chinese population reported a link between VEGF-A gene polymorphisms (VEGF +936C/T and -634 G/C) and the risk of developing osteosarcoma.	('+936C/T', 'Mutation', 'rs3025039', (122, 129))	('VEGF', 'Gene', (117, 121))	('osteosarcoma', 'Phenotype', 'HP:0002669', (171, 183))	('VEGF', 'Gene', (90, 94))	('osteosarcoma', 'Disease', 'MESH:D012516', (171, 183))	('-634 G/C', 'Var', (134, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('VEGF', 'Gene', '7422', (117, 121))	('-634 G/C', 'SUBSTITUTION', 'None', (134, 142))	('VEGF', 'Gene', '7422', (90, 94))	('osteosarcoma', 'Disease', (171, 183))
169763	32085654	Indeed, HIF-1alpha and VEGF-A knockdown decreased the invasive potential of Saos-2 and U2-OS osteosarcoma cell lines.	('VEGF-A', 'Gene', (23, 29))	('HIF-1alpha', 'Gene', '3091', (8, 18))	('HIF-1alpha', 'Gene', (8, 18))	('osteosarcoma', 'Phenotype', 'HP:0002669', (93, 105))	('invasive potential of Saos-2', 'CPA', (54, 82))	('osteosarcoma', 'Disease', (93, 105))	('osteosarcoma', 'Disease', 'MESH:D012516', (93, 105))	('knockdown', 'Var', (30, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('decreased', 'NegReg', (40, 49))
169770	32085654	Consistently with the in vitro data, tumors originated from high-VEGFR-1 K7M3 cells produced more VEGF-A than low-VEGFR-1 cells.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('high-VEGFR-1 K7M3', 'Var', (60, 77))	('K7M3', 'Var', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('VEGF-A', 'MPA', (98, 104))
169794	32085654	Increased levels of PlGF were reported in obesity-associated pancreatic cancer patients and ablation of the VEGFR-1 signaling in pancreatic ductal adenocarcinoma murine models prevented obesity-induced tumor progression.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('ablation', 'Var', (92, 100))	('obesity', 'Phenotype', 'HP:0001513', (42, 49))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (129, 161))	('pancreatic cancer', 'Disease', 'MESH:D010190', (61, 78))	('obesity', 'Disease', (186, 193))	('tumor', 'Disease', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('pancreatic ductal adenocarcinoma', 'Disease', (129, 161))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('obesity', 'Disease', (42, 49))	('pancreatic cancer', 'Disease', (61, 78))	('obesity', 'Disease', 'MESH:D009765', (186, 193))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (129, 161))	('obesity', 'Disease', 'MESH:D009765', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('murine', 'Species', '10090', (162, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('prevented', 'NegReg', (176, 185))	('VEGFR-1', 'Gene', (108, 115))	('patients', 'Species', '9606', (79, 87))	('obesity', 'Phenotype', 'HP:0001513', (186, 193))
169811	32085654	Patients with VEGF-A overexpression have a significantly increased risk (2-fold) of disease progression, with the development of distant metastases and shorter OS.	(')', 'Gene', '7424', (79, 80))	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('overexpression', 'Var', (21, 35))	('men', 'Species', '9606', (121, 124))	('Patients', 'Species', '9606', (0, 8))	('disease', 'Disease', (84, 91))	('VEGF-A', 'Gene', (14, 20))	('metastases', 'Disease', (137, 147))
169813	32085654	Furthermore, a clinical study enrolling 334 patients with advanced esophageal squamous cell carcinoma revealed that the genetic polymorphism rs2010963 in VEGF-A gene independently correlated with worse OS, although this genotype was not associated with high pretreatment VEGF-A levels in the serum.	('patients', 'Species', '9606', (44, 52))	('VEGF-A', 'Gene', (154, 160))	('rs2010963', 'Mutation', 'rs2010963', (141, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (67, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('rs2010963', 'Var', (141, 150))	('men', 'Species', '9606', (266, 269))	('worse OS', 'Disease', (196, 204))	('correlated with', 'Reg', (180, 195))	('esophageal squamous cell carcinoma', 'Disease', (67, 101))
169827	32085654	These effects were only mediated by activation of VEGFR-1 and not by other receptors, as they were specifically inhibited by treatment with the anti-VEGFR-1 neutralizing IMC-18F1 mAb.	('anti-VEGFR-1', 'Var', (144, 156))	('inhibited', 'NegReg', (112, 121))	('IMC-18F1', 'Chemical', 'MESH:C548516', (170, 178))	('VEGFR-1', 'Gene', (50, 57))	('men', 'Species', '9606', (130, 133))
169856	32085654	Overexpression of CSE also increased the levels of MMP2 and MMP9 in early metastatic breast cancer cells, allowing the degradation of the ECM and consequently the entering of tumor cells into the blood circulation.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('tumor', 'Disease', (175, 180))	('MMP2', 'Gene', (51, 55))	('increased', 'PosReg', (27, 36))	('breast cancer', 'Disease', (85, 98))	('entering', 'MPA', (163, 171))	('CSE', 'Gene', '1491', (18, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('degradation', 'MPA', (119, 130))	('MMP2', 'Gene', '4313', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('allowing', 'Reg', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('MMP9', 'Var', (60, 64))	('CSE', 'Gene', (18, 21))
169862	32085654	The addition of the anti-VEGFR-1 KM1732 mAb and a VEGFR-1 trap (sFlt-1-Fc) to CD34+ cultures, pretreated with the MDA-MB-231-conditioned medium or PlGF, prevented the generation of CD11b+ cells with sprouting-inducing ability.	('CD11b', 'Gene', (181, 186))	('CD34', 'Gene', (78, 82))	('CD34', 'Gene', '947', (78, 82))	('Flt-1', 'Gene', '2321', (65, 70))	('rat', 'Species', '10116', (171, 174))	(')', 'Gene', '7424', (73, 74))	('prevented', 'NegReg', (153, 162))	('Flt-1', 'Gene', (65, 70))	('CD11b', 'Gene', '3684', (181, 186))	('anti-VEGFR-1', 'Var', (20, 32))
169863	32085654	Furthermore, CD11b+ cells induced a significant angiogenic response in the murine corneal angiogenesis in vivo assay and PlGF silencing reduced the proangiogenic activity of circulating CD11b+ myelomonocytic cells in a breast cancer murine model.	('CD11b', 'Gene', (13, 18))	('corneal angiogenesis', 'Phenotype', 'HP:0011496', (82, 102))	('CD11b', 'Gene', '3684', (13, 18))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('murine', 'Species', '10090', (75, 81))	('CD11b', 'Gene', (186, 191))	('breast cancer', 'Disease', (219, 232))	('angiogenic response', 'CPA', (48, 67))	('murine', 'Species', '10090', (233, 239))	('CD11b', 'Gene', '3684', (186, 191))	('reduced', 'NegReg', (136, 143))	('silencing', 'Var', (126, 135))	('proangiogenic activity', 'CPA', (148, 170))	('PlGF', 'Gene', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
169867	32085654	Furthermore, while obesity promoted IL-6 and MMP9 expression in tumors, deletion of VEGFR-1 TK domain decreased the expression of these pro-M2 markers only in obese mice.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('mice', 'Species', '10090', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('expression', 'MPA', (50, 60))	('deletion', 'Var', (72, 80))	('tumors', 'Disease', (64, 70))	('obese', 'Disease', (159, 164))	('IL-6', 'Gene', (36, 40))	('obesity', 'Disease', (19, 26))	('obese', 'Disease', 'MESH:D009765', (159, 164))	('decreased', 'NegReg', (102, 111))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('obesity', 'Disease', 'MESH:D009765', (19, 26))	('IL-6', 'Gene', '16193', (36, 40))	('promoted', 'PosReg', (27, 35))	('expression', 'MPA', (116, 126))	('MMP9', 'Protein', (45, 49))	('VEGFR-1', 'Gene', (84, 91))	('obesity', 'Phenotype', 'HP:0001513', (19, 26))
169868	32085654	PlGF was identified as the VEGFR-1 ligand responsible for such effects since its plasma levels were elevated in diet-induced obese mice, and its deletion induced similar effects to those observed in VEGFR-1-TK-null obese mice.	('obese', 'Disease', (125, 130))	('obese', 'Disease', 'MESH:D009765', (215, 220))	('obese', 'Disease', (215, 220))	('mice', 'Species', '10090', (221, 225))	('PlGF', 'Gene', (0, 4))	('plasma levels', 'MPA', (81, 94))	('obese', 'Disease', 'MESH:D009765', (125, 130))	('mice', 'Species', '10090', (131, 135))	('elevated', 'PosReg', (100, 108))	('deletion', 'Var', (145, 153))
169876	32085654	Also ZEB2 expression, a transcription factor with a crucial role in EMT, strongly correlated with PlGF levels in ovarian cancer tissues: PlGF overexpression significantly increased ZEB2 levels and cell invasiveness, conversely PlGF depletion was associated with a decline of ZEB2 levels and cell invasiveness.	('cell invasiveness', 'CPA', (291, 308))	('ovarian cancer', 'Phenotype', 'HP:0100615', (113, 127))	('cell invasiveness', 'CPA', (197, 214))	('ovarian cancer', 'Disease', 'MESH:D010051', (113, 127))	('ZEB2', 'Gene', '9839', (181, 185))	('PlGF', 'Gene', (137, 141))	('ZEB2', 'Gene', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ZEB2', 'Gene', '9839', (275, 279))	('overexpression', 'Var', (142, 156))	('ZEB2', 'Gene', (181, 185))	('ovarian cancer', 'Disease', (113, 127))	('ZEB2', 'Gene', (275, 279))	('ZEB2', 'Gene', '9839', (5, 9))	('increased', 'PosReg', (171, 180))
169879	32085654	Mice transplanted with human ovarian adenocarcinoma SKOV3 cells transfected with pLV-sFLT1 or exogenously (intraperitoneally) treated with recombinant sVEGFR-1, confirmed the antitumor effect of sVEGFR-1 also in vivo, in terms of reduced tumor size compared to control animals.	('reduced', 'NegReg', (230, 237))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('ovarian adenocarcinoma', 'Disease', 'MESH:D010051', (29, 51))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('sVEGFR-1', 'Var', (195, 203))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (29, 51))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('ovarian adenocarcinoma', 'Disease', (29, 51))	(')', 'Gene', '7424', (124, 125))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Disease', (238, 243))	('human', 'Species', '9606', (23, 28))	('Mice', 'Species', '10090', (0, 4))	('SKOV3', 'CellLine', 'CVCL:0532;0.04086655203281981', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('tumor', 'Disease', (179, 184))
169881	32085654	VEGFR-1 as well VEGFR-2 expression levels in biopsy specimens have been recognized as prognostic factors for patients with cervical cancer: high VEGFR-1 expression was linked to distant metastases, together with poor OS and PFS, whereas high VEGFR-2 expression correlated with increased tumor size and reduced OS.	('metastases', 'Disease', (186, 196))	('patients', 'Species', '9606', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('cervical cancer', 'Disease', (123, 138))	('high', 'Var', (140, 144))	('cervical cancer', 'Disease', 'MESH:D002583', (123, 138))	('metastases', 'Disease', 'MESH:D009362', (186, 196))	('VEGFR-1', 'Gene', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('increased', 'PosReg', (277, 286))	('tumor', 'Disease', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('men', 'Species', '9606', (57, 60))	('linked to', 'Reg', (168, 177))
169883	32085654	On the other hand, a recent study reported that patients with high serum levels of both VEGF-A and VEGFR-2 presented bulky tumors, pelvic lymph node involvement, parametrial infiltration, and significantly lower OS than patients with low VEGF-A and VEGFR-2 expression.	('VEGFR-2', 'Gene', (99, 106))	('parametrial infiltration', 'CPA', (162, 186))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('rat', 'Species', '10116', (180, 183))	('pelvic lymph node involvement', 'CPA', (131, 160))	('men', 'Species', '9606', (156, 159))	('lower', 'NegReg', (206, 211))	('serum levels', 'MPA', (67, 79))	('patients', 'Species', '9606', (220, 228))	('high', 'Var', (62, 66))	('patients', 'Species', '9606', (48, 56))	('VEGF-A', 'Gene', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
169887	32085654	Deregulation of cellular energetic metabolism has been recognized as another feature of cancer, aimed at increasing the production of lactate, whose efflux in the ECM induces angiogenesis.	('cellular energetic metabolism', 'MPA', (16, 45))	('increasing', 'PosReg', (105, 115))	('cancer', 'Disease', (88, 94))	('induces', 'Reg', (167, 174))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('Deregulation', 'Var', (0, 12))	('lactate', 'Chemical', 'MESH:D019344', (134, 141))	('angiogenesis', 'CPA', (175, 187))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('efflux', 'MPA', (149, 155))	('production of lactate', 'MPA', (120, 141))
169909	32085654	Consistently, ectopic VEGF-A expression decreased miR-130b level and abrogated its antiangiogenic effect, thus promoting the angiogenic response.	('abrogated', 'NegReg', (69, 78))	('antiangiogenic effect', 'CPA', (83, 104))	('promoting', 'PosReg', (111, 120))	('miR-130b', 'Gene', '406920', (50, 58))	('miR-130b', 'Gene', (50, 58))	('ectopic', 'Var', (14, 21))	('angiogenic response', 'CPA', (125, 144))	('decreased', 'NegReg', (40, 49))	('VEGF-A', 'Gene', (22, 28))
169932	32085654	Thus, the authors suggested that blockade of VEGFR-1 by a selective therapeutic agent might counteract leukemia cell movement within the bone marrow, delaying the extra-medullary tumor growth.	('blockade', 'Var', (33, 41))	('men', 'Species', '9606', (121, 124))	('delaying', 'NegReg', (150, 158))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('leukemia', 'Disease', 'MESH:D007938', (103, 111))	('VEGFR-1', 'Gene', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('leukemia', 'Disease', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
169938	32085654	Other approved agents that are endowed with antiangiogenic effects but do not directly target the VEGFRs or their ligands include (i) the mammalian target of rapamycin (mTOR) inhibitors temsirolimus (approved for RCC and mantle cell lymphoma) and everolimus (approved for advanced kidney and breast cancers, subependymal giant cell astrocytoma, pancreatic neuroendocrine tumors, neuroendocrine tumors of gastrointestinal or lung origin), and the (ii) the immunomodulatory drugs (IMiDs) thalidomide, lenalidomide and pomalidomide, approved for the treatment of multiple myeloma (lenalidomide also for relapsed or refractory mantle cell lymphoma and myelodysplastic syndromes with deletion of the long arm of chromosome 5).	('men', 'Species', '9606', (552, 555))	('multiple myeloma', 'Phenotype', 'HP:0006775', (560, 576))	('breast cancers', 'Phenotype', 'HP:0003002', (292, 306))	(')', 'Gene', '7424', (484, 485))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (356, 377))	('subependymal giant cell astrocytoma', 'Disease', (308, 343))	('pancreatic neuroendocrine tumors', 'Disease', (345, 377))	('cell lymphoma', 'Phenotype', 'HP:0012191', (228, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (292, 305))	('lymphoma', 'Phenotype', 'HP:0002665', (233, 241))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (379, 400))	('mantle cell lymphoma', 'Disease', (623, 643))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (623, 643))	('multiple myeloma', 'Disease', 'MESH:D009101', (560, 576))	('tumors', 'Phenotype', 'HP:0002664', (394, 400))	('subependymal giant cell astrocytoma', 'Phenotype', 'HP:0009718', (308, 343))	('myelodysplastic syndromes', 'Disease', (648, 673))	('tumors', 'Phenotype', 'HP:0002664', (371, 377))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (648, 673))	('cell lymphoma', 'Phenotype', 'HP:0012191', (630, 643))	('lymphoma', 'Phenotype', 'HP:0002665', (635, 643))	(')', 'Gene', '7424', (173, 174))	('subependymal giant cell astrocytoma', 'Disease', 'MESH:D001254', (308, 343))	('mammalian target of rapamycin', 'Gene', '2475', (138, 167))	(')', 'Gene', '7424', (435, 436))	('VEGFR', 'Gene', '3791', (98, 103))	('everolimus', 'Chemical', 'MESH:D000068338', (247, 257))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('tumor', 'Phenotype', 'HP:0002664', (394, 399))	('multiple myeloma', 'Disease', (560, 576))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (648, 673))	('deletion', 'Var', (679, 687))	('VEGFR', 'Gene', (98, 103))	('RCC', 'Disease', (213, 216))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (221, 241))	(')', 'Gene', '7424', (719, 720))	(')', 'Gene', '7424', (132, 133))	('mammalian target of rapamycin', 'Gene', (138, 167))	('mantle cell lymphoma', 'Disease', (221, 241))	(')', 'Gene', '7424', (449, 450))	('cancers', 'Phenotype', 'HP:0002664', (299, 306))	('astrocytoma', 'Phenotype', 'HP:0009592', (332, 343))	(')', 'Gene', '7424', (241, 242))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('breast cancers', 'Disease', 'MESH:D001943', (292, 306))	('breast cancers', 'Disease', (292, 306))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('neuroendocrine tumors of gastrointestinal', 'Disease', (379, 420))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (345, 377))	('tumors of gastrointestinal', 'Phenotype', 'HP:0007378', (394, 420))	('neuroendocrine tumors of gastrointestinal', 'Disease', 'MESH:D018358', (379, 420))
169942	32085654	Most of these mAbs prevent the interaction of VEGFR-1 ligands with the receptor (competitive inhibitors), whereas only D16F7 blocks receptor signal transduction without inhibiting ligand binding (non-competitive inhibitor).	('prevent', 'NegReg', (19, 26))	('D16F7', 'Var', (119, 124))	('interaction', 'Interaction', (31, 42))	(')', 'Gene', '7424', (103, 104))	('D16F7', 'Chemical', 'MESH:C000627505', (119, 124))	(')', 'Gene', '7424', (221, 222))	('blocks', 'NegReg', (125, 131))	('receptor signal transduction', 'MPA', (132, 160))	('VEGFR-1', 'Gene', (46, 53))
169947	32085654	Moreover, immunohistochemical analysis of tumor xenografts collected from treated mice showed an increase of tumor cell apoptosis and a decrease in MAPK and AKT activation and cell proliferation; (ii) The murine anti-human VEGFR-1 D16F7 mAb (mouse IgG1), which has a novel mechanism of action, as it interacts with a receptor site distinct from that involved in VEGF-A or PlGF binding and downregulates the signaling through the membrane receptor without affecting ligand binding.	(')', 'Gene', '7424', (199, 200))	('human', 'Species', '9606', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (42, 47))	('murine', 'Species', '10090', (205, 211))	('rat', 'Species', '10116', (188, 191))	('signaling through the membrane receptor', 'MPA', (407, 446))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	(')', 'Gene', '7424', (252, 253))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('D16F7', 'Var', (231, 236))	('mice', 'Species', '10090', (82, 86))	('MAPK', 'Pathway', (148, 152))	('mouse', 'Species', '10090', (242, 247))	('downregulates', 'NegReg', (389, 402))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('interacts', 'Interaction', (300, 309))	('D16F7', 'Chemical', 'MESH:C000627505', (231, 236))	('decrease', 'NegReg', (136, 144))	('tumor', 'Disease', (109, 114))
169949	32085654	Moreover, D16F7 leaves unaffected the sVEGFR-1 decoy function, as it neither affects sVEGFR-1 interaction with its ligands nor hampers the sVEGFR-1/VEGFR-2 inhibitory heterodimer formation.	('interaction', 'Interaction', (94, 105))	('D16F7', 'Var', (10, 15))	('D16F7', 'Chemical', 'MESH:C000627505', (10, 15))	('hampers', 'NegReg', (127, 134))	('sVEGFR-1/VEGFR-2 inhibitory heterodimer formation', 'MPA', (139, 188))
169950	32085654	D16F7 has shown antitumor efficacy in preclinical in vivo models against highly aggressive tumor types, such as glioblastoma and melanoma (see also Section 2.4 and Section 2.5).	('D16F7', 'Var', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('D16F7', 'Chemical', 'MESH:C000627505', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('aggressive tumor', 'Disease', 'MESH:D001523', (80, 96))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('glioblastoma and melanoma', 'Disease', 'MESH:D005909', (112, 137))	('aggressive tumor', 'Disease', (80, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (20, 25))	(')', 'Gene', '7424', (175, 176))
169951	32085654	Its ability to recognize not only the human form of the VEGFR-1 but also the murine receptor has allowed the analysis of the effects of VEGFR-1 inhibition on tumor-associated microenvironment; (iii) The anti-human VEGFR-1 KM1730 and KM1732 mAbs (mouse IgG1), which recognize different epitopes of the second Ig-like domain.	(')', 'Gene', '7424', (256, 257))	('tumor', 'Disease', (158, 163))	('human', 'Species', '9606', (38, 43))	('murine', 'Species', '10090', (77, 83))	('KM1732', 'Var', (233, 239))	('men', 'Species', '9606', (187, 190))	('mouse', 'Species', '10090', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	(')', 'Gene', '7424', (197, 198))	('human', 'Species', '9606', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('KM1730', 'Var', (222, 228))
169953	32085654	Moreover, treatment with KM1732 mAb of primary cell cultures derived from bone marrow samples collected from patients with AML resulted in significant inhibition of cell growth.	('patients', 'Species', '9606', (109, 117))	('AML', 'Disease', 'MESH:D015470', (123, 126))	('men', 'Species', '9606', (15, 18))	('AML', 'Phenotype', 'HP:0004808', (123, 126))	('KM1732 mAb', 'Var', (25, 35))	('inhibition', 'NegReg', (151, 161))	('cell growth', 'CPA', (165, 176))	('AML', 'Disease', (123, 126))
169960	32085654	The anti-PlGF mAb 5D11D4 is directed against the murine PlGF of which inhibits the interaction with VEGFR-1 and with NRP-1.	('VEGFR-1', 'Protein', (100, 107))	('interaction', 'Interaction', (83, 94))	('inhibits', 'NegReg', (70, 78))	('5D11D4', 'Var', (18, 24))	('murine', 'Species', '10090', (49, 55))
169961	32085654	The 5D11D4 mAb inhibited tumor growth and metastasis formation in melanoma, cholangiocarcinoma, pancreatic, hepatocellular, and colon cancer in vivo models.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('melanoma', 'Disease', (66, 74))	('cholangiocarcinoma', 'Disease', (76, 94))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (76, 94))	('hepatocellular', 'Disease', (108, 122))	('colon cancer', 'Phenotype', 'HP:0003003', (128, 140))	('5D11D4', 'Var', (4, 10))	('pancreatic', 'Disease', 'MESH:D010195', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('colon cancer', 'Disease', 'MESH:D015179', (128, 140))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('tumor', 'Disease', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('pancreatic', 'Disease', (96, 106))	('inhibited', 'NegReg', (15, 24))	('colon cancer', 'Disease', (128, 140))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (76, 94))
169978	32085654	AEE788 is instead a dual inhibitor of epidermal growth factor and VEGF receptors and is currently under investigation in patients with recurrent glioblastoma, as single agent or in combination with everolimus.	('VEGF', 'Gene', (66, 70))	('AEE788', 'Var', (0, 6))	('glioblastoma', 'Phenotype', 'HP:0012174', (145, 157))	('everolimus', 'Chemical', 'MESH:D000068338', (198, 208))	('AEE788', 'Chemical', 'MESH:C489254', (0, 6))	('VEGF', 'Gene', '7422', (66, 70))	('glioblastoma', 'Disease', (145, 157))	('epidermal growth factor', 'Protein', (38, 61))	('patients', 'Species', '9606', (121, 129))	('glioblastoma', 'Disease', 'MESH:D005909', (145, 157))
169980	32085654	A total of thirty-two trials can be found in  where lucitanib is tested for solid tumors, breast cancer, NSCLC, SCLC, gastroesophageal reflux disease, and functional dyspepsia, with two of them including tumors with genetic alterations of the FGF receptor.	('gastroesophageal reflux disease', 'Disease', (118, 149))	('tumors', 'Disease', (82, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (118, 149))	('SCLC', 'Disease', 'MESH:D055752', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('genetic alterations', 'Var', (216, 235))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('rat', 'Species', '10116', (228, 231))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('SCLC', 'Disease', 'MESH:D055752', (112, 116))	('SCLC', 'Disease', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('solid tumors', 'Disease', (76, 88))	('dyspepsia', 'Phenotype', 'HP:0410281', (166, 175))	('tumors', 'Disease', (204, 210))	('SCLC', 'Phenotype', 'HP:0030357', (106, 110))	('FGF receptor', 'Gene', (243, 255))	('SCLC', 'Disease', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('functional dyspepsia', 'Disease', 'MESH:D004415', (155, 175))	('SCLC', 'Phenotype', 'HP:0030357', (112, 116))	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (118, 141))	('solid tumors', 'Disease', 'MESH:D009369', (76, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('functional dyspepsia', 'Disease', (155, 175))	('breast cancer', 'Disease', (90, 103))	('lucitanib', 'Chemical', 'MESH:C000595232', (52, 61))	('NSCLC', 'Disease', (105, 110))	('tested', 'Reg', (65, 71))
169988	32085654	Inhibition of VEGF-A and its signaling through VEGFR-2, a receptor also involved in physiological angiogenesis, causes important adverse effects such as hypertension, proteinuria, bleeding, thromboembolism, delay in wound healing, and gastrointestinal perforation.	('bleeding', 'Disease', (180, 188))	('gastrointestinal', 'Disease', (235, 251))	('thromboembolism', 'Disease', 'MESH:D013923', (190, 205))	('thromboembolism', 'Phenotype', 'HP:0001907', (190, 205))	('VEGFR-2', 'Gene', (47, 54))	('hypertension', 'Disease', 'MESH:D006973', (153, 165))	('delay', 'CPA', (207, 212))	('proteinuria', 'Disease', (167, 178))	('hypertension', 'Disease', (153, 165))	('proteinuria', 'Disease', 'MESH:D011507', (167, 178))	('Inhibition', 'Var', (0, 10))	('rat', 'Species', '10116', (257, 260))	('thromboembolism', 'Disease', (190, 205))	('bleeding', 'Disease', 'MESH:D006470', (180, 188))	('proteinuria', 'Phenotype', 'HP:0000093', (167, 178))	('wound healing', 'CPA', (216, 229))	('hypertension', 'Phenotype', 'HP:0000822', (153, 165))	('VEGF-A', 'Gene', (14, 20))	('delay in wound healing', 'Phenotype', 'HP:0001058', (207, 229))
169991	32085654	Conversely, the neutralization of VEGFR-1 specific ligands, i.e., VEGF-B and PlGF, and the selective blockade of VEGFR-1 activation, represents a promising strategy to specifically counteract tumor-associated angiogenesis as well as malignant processes not directly related to new blood vessels formation.	('tumor', 'Disease', (192, 197))	('neutralization', 'Var', (16, 30))	('VEGFR-1', 'Gene', (34, 41))	('rat', 'Species', '10116', (158, 161))	('VEGF-B', 'Gene', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('VEGFR-1', 'Gene', (113, 120))
169992	32085654	Indeed, inhibition of VEGFR-1 signaling also reduces tumor cell survival and invasiveness, counteracts the mobilization of myeloid progenitors and prevents tumor infiltration by M2 protumoral macrophages.	('VEGFR-1', 'Gene', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumoral', 'Disease', 'MESH:D009369', (184, 191))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('reduces', 'NegReg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('prevents', 'NegReg', (147, 155))	('tumor', 'Disease', (184, 189))	('invasiveness', 'CPA', (77, 89))	('tumor', 'Disease', (53, 58))	('rat', 'Species', '10116', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('inhibition', 'Var', (8, 18))	('tumoral', 'Disease', (184, 191))
169993	32085654	In this context, the D16F7 mAb is a promising tool to specifically and non-competitively interfere with VEGFR-1 signaling in the tumor.	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('interfere', 'NegReg', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('D16F7', 'Chemical', 'MESH:C000627505', (21, 26))	('D16F7', 'Var', (21, 26))	('tumor', 'Disease', (129, 134))	('VEGFR-1 signaling', 'MPA', (104, 121))
169994	32085654	Conversely, other experimental mAbs designed to inhibit human VEGFR-1 signaling, like IMC-18F1/icrucumab, KM1730, or KM1732, possess a competitive mechanism of action, by inhibiting VEGF-A, VEGF-B, or PlGF binding to VEGFR-1.	('men', 'Species', '9606', (24, 27))	('PlGF', 'Protein', (201, 205))	('inhibiting', 'NegReg', (171, 181))	('binding', 'Interaction', (206, 213))	('icrucumab', 'Chemical', 'MESH:C000626257', (95, 104))	('IMC-18F1', 'Chemical', 'MESH:C548516', (86, 94))	('KM1730', 'Var', (106, 112))	('human', 'Species', '9606', (56, 61))	('VEGF-A', 'Protein', (182, 188))	('KM1732', 'Var', (117, 123))	('VEGF-B', 'Protein', (190, 196))	('inhibit', 'NegReg', (48, 55))
169995	32085654	Competitive VEGFR-1 inhibitors, by antagonizing ligand binding, may increase in the ECM the free VEGF-A available for VEGFR-2 activation and this may reduce the overall efficacy of the treatment.	('free VEGF-A', 'MPA', (92, 103))	('ligand binding', 'Interaction', (48, 62))	('reduce', 'NegReg', (150, 156))	('inhibitors', 'Var', (20, 30))	('antagonizing', 'Reg', (35, 47))	('men', 'Species', '9606', (190, 193))	('increase', 'PosReg', (68, 76))	('ECM', 'MPA', (84, 87))	('VEGFR-1', 'Gene', (12, 19))	('efficacy of the treatment', 'CPA', (169, 194))
169997	32085654	D16F7 mAb efficacy in monotherapy has already been demonstrated in in vivo preclinical models of highly aggressive tumors, showing significant inhibition of glioblastoma and melanoma growth, invasiveness and migration, impairment of endothelial cells chemotaxis and tumor-associated angiogenesis, as well as reduced myeloid progenitor mobilization and tumor infiltration by monocytes/macrophages.	('impairment', 'NegReg', (219, 229))	('aggressive tumors', 'Disease', 'MESH:D001523', (104, 121))	('tumor', 'Disease', (115, 120))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('men', 'Species', '9606', (225, 228))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('tumor', 'Disease', (266, 271))	('inhibition', 'NegReg', (143, 153))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('invasiveness', 'CPA', (191, 203))	('melanoma growth', 'Disease', 'MESH:D008545', (174, 189))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', (352, 357))	('myeloid progenitor mobilization', 'CPA', (316, 347))	('rat', 'Species', '10116', (364, 367))	('glioblastoma and melanoma', 'Disease', 'MESH:D005909', (157, 182))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('endothelial cells chemotaxis', 'CPA', (233, 261))	('rat', 'Species', '10116', (211, 214))	('D16F7', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('rat', 'Species', '10116', (58, 61))	('reduced', 'NegReg', (308, 315))	('melanoma growth', 'Disease', (174, 189))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('aggressive tumors', 'Disease', (104, 121))	('D16F7', 'Chemical', 'MESH:C000627505', (0, 5))	('migration', 'CPA', (208, 217))
170078	33557774	The knockdown of MT1JP led to opposite results.	('knockdown', 'Var', (4, 13))	('MT1JP', 'Gene', '4498', (17, 22))	('MT1JP', 'Gene', (17, 22))
170135	33557774	The MT1JP sequence containing miR-18a-5p-bound region or mutant sequence was cloned into pmirGLO vector with NheI and XhoI sites, and cotransfected into 293 T cells with miR-18a-5p mimics.	('miR-18a', 'Gene', '406953', (30, 37))	('miR-18a', 'Gene', (170, 177))	('MT1JP', 'Gene', (4, 9))	('mutant', 'Var', (57, 63))	('miR-18a', 'Gene', (30, 37))	('MT1JP', 'Gene', '4498', (4, 9))	('293 T', 'CellLine', 'CVCL:0063', (153, 158))	('miR-18a', 'Gene', '406953', (170, 177))
170175	33557774	The expression level of PCNA was decreased after MT1JP overexpression and increased after MT1JP knockdown (Fig.	('knockdown', 'Var', (96, 105))	('MT1JP', 'Gene', (49, 54))	('expression level', 'MPA', (4, 20))	('MT1JP', 'Gene', (90, 95))	('MT1JP', 'Gene', '4498', (49, 54))	('MT1JP', 'Gene', '4498', (90, 95))	('PCNA', 'Gene', (24, 28))	('increased', 'PosReg', (74, 83))	('PCNA', 'Gene', '5111', (24, 28))	('decreased', 'NegReg', (33, 42))
170176	33557774	The flow cytometry results revealed that MT1JP delayed G1/S and S/G2 transition in HCCC-9810 cells, and the silencing of MT1JP accelerated cell cycle transition in HUCCT1 cells (Fig.	('MT1JP', 'Gene', (121, 126))	('delayed', 'NegReg', (47, 54))	('MT1JP', 'Gene', (41, 46))	('silencing', 'Var', (108, 117))	('MT1JP', 'Gene', '4498', (121, 126))	('MT1JP', 'Gene', '4498', (41, 46))	('HCCC-9810', 'CellLine', 'CVCL:6908', (83, 92))	('accelerated', 'PosReg', (127, 138))	('S/G2', 'Var', (64, 68))	('S/G2', 'SUBSTITUTION', 'None', (64, 68))	('G1/S', 'CPA', (55, 59))	('HUCCT1', 'CellLine', 'CVCL:0324', (164, 170))	('cell cycle transition', 'CPA', (139, 160))
170179	33557774	The knockdown slightly inhibited the apoptosis in HUCCT1 cells (Fig.	('knockdown', 'Var', (4, 13))	('HUCCT1', 'CellLine', 'CVCL:0324', (50, 56))	('apoptosis', 'CPA', (37, 46))	('inhibited', 'NegReg', (23, 32))
170182	33557774	3, the overexpression of MT1JP suppressed migration and invasion in HCCC-9810 cells, and the silencing of MT1JP enhanced migration and invasion in HUCCT1 cells.	('enhanced', 'PosReg', (112, 120))	('invasion', 'CPA', (56, 64))	('migration', 'CPA', (42, 51))	('silencing', 'Var', (93, 102))	('migration', 'CPA', (121, 130))	('HCCC-9810', 'CellLine', 'CVCL:6908', (68, 77))	('MT1JP', 'Gene', '4498', (25, 30))	('MT1JP', 'Gene', '4498', (106, 111))	('MT1JP', 'Gene', (106, 111))	('suppressed', 'NegReg', (31, 41))	('HUCCT1', 'CellLine', 'CVCL:0324', (147, 153))	('MT1JP', 'Gene', (25, 30))	('invasion', 'CPA', (135, 143))
170233	33557774	Migratory and invasive abilities were also reduced after ectopic expression of MT1JP.	('MT1JP', 'Gene', (79, 84))	('ectopic expression', 'Var', (57, 75))	('reduced', 'NegReg', (43, 50))	('MT1JP', 'Gene', '4498', (79, 84))
170256	32475354	As the results shown, the pooled OR values of the risk of colorectal cancer and adenomas in patients with NAFLD were 1.72 (95%CI: 1.40-2.11) and 1.37 (95%CI: 1.29-1.46), respectively.	('adenomas', 'Disease', 'MESH:D000236', (80, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('adenomas', 'Disease', (80, 88))	('patients', 'Species', '9606', (92, 100))	('colorectal cancer', 'Disease', (58, 75))	('NAFLD', 'Var', (106, 111))	('colorectal cancer', 'Disease', 'MESH:D015179', (58, 75))
170258	32475354	The pooled OR value of the risk of breast cancer in patients with NAFLD was 1.69 (95%CI: 1.44-1.99).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', (35, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('NAFLD', 'Var', (66, 71))	('patients', 'Species', '9606', (52, 60))
170259	32475354	In addition, NAFLD was also tightly associatied with the risk of gastric cancer, pancreatic cancer, prostate cancer, and esophageal cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('esophageal cancer', 'Disease', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('NAFLD', 'Var', (13, 18))	('prostate cancer', 'Disease', (100, 115))	('gastric cancer', 'Disease', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))	('pancreatic cancer', 'Disease', (81, 98))
170260	32475354	NAFLD could significantly increase the development risk of colorectal adenomas and cancer, intrahepatic and extrahepatic cholangiocarcinoma, breast, gastric, pancreatic, prostate, and esophageal cancer.	('breast', 'Disease', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (184, 201))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('intrahepatic and extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 139))	('colorectal adenomas', 'Disease', 'MESH:D015179', (59, 78))	('cancer', 'Disease', (195, 201))	('esophageal cancer', 'Disease', (184, 201))	('men', 'Species', '9606', (46, 49))	('NAFLD', 'Var', (0, 5))	('gastric', 'Disease', (149, 156))	('pancreatic', 'Disease', 'MESH:D010195', (158, 168))	('prostate', 'Disease', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('colorectal adenomas', 'Disease', (59, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('increase', 'PosReg', (26, 34))	('pancreatic', 'Disease', (158, 168))	('cancer', 'Disease', (83, 89))
170267	32475354	Accumulated evidence have shown that cardiovascular disease is the leading cause of death in patients with NAFLD, and malignancies at both gastrointestinal (liver, colon, esophagus, stomach, and pancreas) and extra-intestinal site (kidney in men, and breast in women) were also significant contributors to the mainly death of patients with NAFLD.	('colon', 'Disease', 'MESH:D003110', (164, 169))	('cardiovascular disease', 'Disease', 'MESH:D002318', (37, 59))	('patients', 'Species', '9606', (93, 101))	('colon', 'Disease', (164, 169))	('patients', 'Species', '9606', (326, 334))	('malignancies', 'Disease', 'MESH:D009369', (118, 130))	('men', 'Species', '9606', (242, 245))	('death', 'Disease', 'MESH:D003643', (317, 322))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (37, 59))	('death', 'Disease', (317, 322))	('cardiovascular disease', 'Disease', (37, 59))	('men', 'Species', '9606', (263, 266))	('women', 'Species', '9606', (261, 266))	('NAFLD', 'Var', (107, 112))	('esophagus', 'Disease', (171, 180))	('malignancies', 'Disease', (118, 130))	('death', 'Disease', 'MESH:D003643', (84, 89))	('death', 'Disease', (84, 89))
170269	32475354	In their study, they found that NAFLD potentially contributes to the risk of developing cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('NAFLD', 'Var', (32, 37))	('cholangiocarcinoma', 'Disease', (88, 106))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 106))
170288	32475354	The results indicated that patients with NAFLD have a significant risk of developing colorectal cancer (OR = 1.72, 95% CI: 1.40-2.11) (Fig.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Disease', (85, 102))	('patients', 'Species', '9606', (27, 35))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('NAFLD', 'Var', (41, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
170291	32475354	The results indicated a significant developmental risk of colorectal adenoma in patients with NAFLD (OR = 1.37, 95% CI: 1.29-1.46) (Fig.	('colorectal adenoma', 'Disease', (58, 76))	('NAFLD', 'Var', (94, 99))	('patients', 'Species', '9606', (80, 88))	('developmental risk', 'Phenotype', 'HP:0001263', (36, 54))	('colorectal adenoma', 'Disease', 'MESH:D015179', (58, 76))	('men', 'Species', '9606', (43, 46))
170293	32475354	These results suggest that patients with NAFLD have a higher risk of developing colorectal cancer and colorectal adenoma than patients without NAFLD.	('colorectal adenoma', 'Disease', 'MESH:D015179', (102, 120))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('patients', 'Species', '9606', (27, 35))	('colorectal adenoma', 'Disease', (102, 120))	('patients', 'Species', '9606', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Disease', (80, 97))	('NAFLD', 'Var', (41, 46))
170296	32475354	The results showed a significant risk of developing ICC in patients with NAFLD (OR = 2.46, 95% CI: 1.77-3.44) (Fig.	('ICC', 'Disease', (52, 55))	('patients', 'Species', '9606', (59, 67))	('NAFLD', 'Var', (73, 78))
170297	32475354	The results showed that the risk of developing ECC was significantly higher in patients with NAFLD (OR = 2.24, 95% CI: 1.58-3.17) than in patients without NAFLD (Table 1, Fig.	('ECC', 'Disease', (47, 50))	('patients', 'Species', '9606', (79, 87))	('NAFLD', 'Var', (93, 98))	('higher', 'PosReg', (69, 75))	('patients', 'Species', '9606', (138, 146))
170301	32475354	Three of the included studies evaluated the association between NAFLD and the risk of developing gastric cancer (Supplementary Table 1).	('gastric cancer', 'Disease', (97, 111))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('NAFLD', 'Var', (64, 69))	('men', 'Species', '9606', (119, 122))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('association', 'Interaction', (44, 55))
170302	32475354	The pooled OR of gastric cancer was 1.74 (95% CI: 1.03-2.95) (Table 1), which suggests that patients with NAFLD have a high risk of developing gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (143, 157))	('gastric cancer', 'Phenotype', 'HP:0012126', (17, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('patients', 'Species', '9606', (92, 100))	('NAFLD', 'Var', (106, 111))	('gastric cancer', 'Disease', (143, 157))	('gastric cancer', 'Disease', 'MESH:D013274', (143, 157))	('gastric cancer', 'Disease', (17, 31))	('gastric cancer', 'Disease', 'MESH:D013274', (17, 31))
170304	32475354	The pooled OR of pancreatic cancer was 2.12 (95% CI: 1.58-2.83) (Table 1), which suggests that patients with NAFLD have a high risk of developing pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('pancreatic cancer', 'Disease', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('patients', 'Species', '9606', (95, 103))	('pancreatic cancer', 'Disease', 'MESH:D010190', (17, 34))	('pancreatic cancer', 'Disease', (146, 163))	('pancreatic cancer', 'Disease', 'MESH:D010190', (146, 163))	('NAFLD', 'Var', (109, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (146, 163))
170305	32475354	In addition, it was observed that patients with NAFLD have a high risk of developing prostate cancer (OR = 1.36, 95% CI: 1.03-1.79) (Tables 1 and Supplementary Table 1).	('men', 'Species', '9606', (152, 155))	('prostate cancer', 'Disease', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('patients', 'Species', '9606', (34, 42))	('NAFLD', 'Var', (48, 53))	('prostate cancer', 'Disease', 'MESH:D011471', (85, 100))	('prostate cancer', 'Phenotype', 'HP:0012125', (85, 100))
170306	32475354	Furthermore, two of the studies reported an association between NAFLD and a risk of developing esophageal cancer, with the OR value of esophageal cancer being 1.77 (95% CI: 1.19-2.62) (Tables 1 and Supplementary Table 1).	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('esophageal cancer', 'Disease', (135, 152))	('NAFLD', 'Var', (64, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('men', 'Species', '9606', (204, 207))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('esophageal cancer', 'Disease', (95, 112))	('association', 'Interaction', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
170317	32475354	In a previous meta-analysis which investigated the association of incident and recurrent colorectal cancer and adenoma with NAFLD, it was observed that the presence and severity of NAFLD were associated with an increased risk of incident colorectal cancer or adenomas.	('adenomas', 'Disease', 'MESH:D000236', (259, 267))	('colorectal cancer', 'Disease', (238, 255))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('adenoma', 'Disease', (259, 266))	('presence', 'Var', (156, 164))	('colorectal cancer', 'Disease', 'MESH:D015179', (238, 255))	('colorectal cancer', 'Disease', (89, 106))	('adenomas', 'Disease', (259, 267))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('NAFLD', 'Gene', (181, 186))	('adenoma', 'Disease', 'MESH:D000236', (111, 118))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (238, 255))	('adenoma', 'Disease', 'MESH:D000236', (259, 266))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('adenoma', 'Disease', (111, 118))
170318	32475354	examined the association between NAFLD and colorectal tumors in asymptomatic adults who underwent a screening colonoscopy, they found that NAFLD was associated with a moderate increase in the risk of colorectal cancer and adenoma.	('NAFLD', 'Var', (139, 144))	('colorectal cancer', 'Disease', 'MESH:D015179', (200, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('adenoma', 'Disease', (222, 229))	('colon', 'Disease', 'MESH:D003110', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('colorectal tumors', 'Disease', 'MESH:D015179', (43, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (200, 217))	('colorectal cancer', 'Disease', (200, 217))	('colorectal tumors', 'Disease', (43, 60))	('colon', 'Disease', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('adenoma', 'Disease', 'MESH:D000236', (222, 229))
170320	32475354	The results show that NAFLD significantly increases the risk of colorectal cancer (OR = 1.72, 95% CI: 1.40-2.11) and the risk of colorectal adenoma (OR = 1.37, 95% CI: 1.29-1.46) compared to healthy controls.	('increases', 'PosReg', (42, 51))	('colorectal cancer', 'Disease', (64, 81))	('NAFLD', 'Var', (22, 27))	('colorectal adenoma', 'Disease', 'MESH:D015179', (129, 147))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('colorectal adenoma', 'Disease', (129, 147))
170323	32475354	conducted a meta-analysis to investigate a possible relationship between NAFLD and cholangiocarcinoma, they found that NAFLD was associated with both ICC (OR = 2.22, 95% CI: 1.52-3.24) and ECC (OR = 1.55, 95% CI: 1.03-2.33).	('associated', 'Reg', (129, 139))	('cholangiocarcinoma', 'Disease', (83, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('ICC', 'Disease', (150, 153))	('NAFLD', 'Var', (119, 124))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('ECC', 'Disease', (189, 192))
170327	32475354	have verified that NAFLD may be associated with more severe renal cell carcinoma and shorter overall survival in Japanese populations.	('shorter', 'NegReg', (85, 92))	('overall survival', 'MPA', (93, 109))	('NAFLD', 'Var', (19, 24))	('renal cell carcinoma', 'Disease', (60, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (60, 80))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (60, 80))
170330	32475354	reported that patients with NAFLD possess the higher susceptibility to colorectal cancer in males, and breast cancer in females, whether there is the gender-related difference in the association of NAFLD and extrahepatic cancers remains unclear.	('susceptibility', 'Reg', (53, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('colorectal cancer', 'Disease', (71, 88))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('extrahepatic cancers', 'Disease', (208, 228))	('extrahepatic cancers', 'Disease', 'MESH:D009369', (208, 228))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('NAFLD', 'Var', (28, 33))	('patients', 'Species', '9606', (14, 22))
170331	32475354	A recent study demonstrated that patients with NAFLD are more likely to exhibit chronic inflammation with insulin resistance, which may generate a microenvironment conducive for cancer development.	('exhibit', 'Reg', (72, 79))	('patients', 'Species', '9606', (33, 41))	('men', 'Species', '9606', (159, 162))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('inflammation', 'Disease', 'MESH:D007249', (88, 100))	('NAFLD', 'Var', (47, 52))	('insulin resistance', 'Phenotype', 'HP:0000855', (106, 124))	('insulin', 'Gene', (106, 113))	('inflammation', 'Disease', (88, 100))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('insulin', 'Gene', '3630', (106, 113))	('men', 'Species', '9606', (192, 195))	('chronic', 'Disease', (80, 87))
170332	32475354	Emerging translational and epidemiologic data support that local ectopic fat may also affect functional factors, and in turn the paracrine pathway, to induce cancer development in the liver, pancreas, and breast.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('affect', 'Reg', (86, 92))	('ectopic fat', 'Var', (65, 76))	('induce', 'PosReg', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('paracrine pathway', 'Pathway', (129, 146))	('functional factors', 'MPA', (93, 111))	('men', 'Species', '9606', (172, 175))
170333	32475354	Therefore, the results of the present study are consistent with those of previous studies and they indicate that NAFLD is a risk factor for various extrahepatic cancers.	('extrahepatic cancers', 'Disease', 'MESH:D009369', (148, 168))	('extrahepatic cancers', 'Disease', (148, 168))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('NAFLD', 'Var', (113, 118))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('risk', 'Reg', (124, 128))
170340	32475354	The results indicate that NAFLD can significantly increase the risk of developing colorectal cancer and colorectal adenoma, ICC and ECC, and breast, gastric, pancreatic, prostate, and esophageal cancers.	('colorectal cancer', 'Disease', (82, 99))	('colorectal adenoma', 'Disease', (104, 122))	('breast', 'Disease', (141, 147))	('NAFLD', 'Var', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('esophageal cancers', 'Disease', (184, 202))	('ECC', 'Disease', (132, 135))	('gastric', 'Disease', (149, 156))	('pancreatic', 'Disease', 'MESH:D010195', (158, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('esophageal cancers', 'Disease', 'MESH:D004938', (184, 202))	('colorectal adenoma', 'Disease', 'MESH:D015179', (104, 122))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('pancreatic', 'Disease', (158, 168))	('prostate', 'Disease', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('ICC', 'Disease', (124, 127))
170344	30469416	The present study addressed the underlying role of agalactosylated IgG beyond tumorigenesis.	('agalactosylated', 'Var', (51, 66))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('IgG', 'Gene', '668542', (67, 70))	('IgG', 'Gene', (67, 70))	('tumor', 'Disease', (78, 83))
170361	30469416	Much more attentions on aberrant N-glycoproteome in chronic diseases and cancers have been drawn over the last decade owing to an advancement and application of high-throughput approaches, such as mass spectrometry, in clinical glycoresearches.	('cancers', 'Disease', (73, 80))	('N', 'Chemical', 'MESH:D009584', (33, 34))	('aberrant', 'Var', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('men', 'Species', '9606', (137, 140))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('chronic diseases', 'Disease', 'MESH:D002908', (52, 68))	('chronic diseases', 'Disease', (52, 68))
170366	30469416	Agalactosylated IgG has been shown to elicit inflammation and mannan-binding lectin-mediated complement cascade because of a high binding tendency to activating FcgammaRs.	('inflammation', 'Disease', (45, 57))	('Agalactosylated', 'Var', (0, 15))	('elicit', 'Reg', (38, 44))	('IgG', 'Gene', '668542', (16, 19))	('IgG', 'Gene', (16, 19))	('men', 'Species', '9606', (99, 102))	('FcgammaRs', 'Protein', (161, 170))	('mannan-binding lectin', 'Gene', '4153', (62, 83))	('mannan-binding lectin', 'Gene', (62, 83))	('inflammation', 'Disease', 'MESH:D007249', (45, 57))	('activating', 'MPA', (150, 160))	('binding', 'Interaction', (130, 137))
170368	30469416	Based on our previous studies reporting a clinical relevance of aberrant serum IgG N-glycome in chronic hepatitis, we hypothesize a similar pathophysiological characteristic of IgG in bile duct diseases.	('chronic hepatitis', 'Phenotype', 'HP:0200123', (96, 113))	('IgG', 'Gene', '668542', (79, 82))	('IgG', 'Gene', (79, 82))	('chronic hepatitis', 'Disease', 'MESH:D056487', (96, 113))	('hepatitis', 'Phenotype', 'HP:0012115', (104, 113))	('chronic hepatitis', 'Disease', (96, 113))	('IgG', 'Gene', '668542', (177, 180))	('bile duct diseases', 'Disease', (184, 202))	('IgG', 'Gene', (177, 180))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('aberrant', 'Var', (64, 72))
170370	30469416	In this study, we report that agalactosylated IgG was able to activate tumor-associated macrophages, thereby leading to tumor metastasis and recurrence of cholangiocarcinoma.	('tumor metastasis', 'Disease', 'MESH:D009362', (120, 136))	('tumor metastasis', 'Disease', (120, 136))	('activate', 'PosReg', (62, 70))	('cholangiocarcinoma', 'Disease', (155, 173))	('leading to', 'Reg', (109, 119))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('agalactosylated', 'Var', (30, 45))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (155, 173))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (155, 173))	('IgG', 'Gene', '668542', (46, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('IgG', 'Gene', (46, 49))	('tumor', 'Disease', (71, 76))	('recurrence', 'CPA', (141, 151))	('tumor', 'Disease', (120, 125))
170398	30469416	After blocking in 5% (w/v) dry milk in Tris-buffered saline with 0.1% Tween 20, the membranes were incubated with anti-CD68 (ab125212, Abcam, Cambridge, UK), anti-CD163 (ab182422, Abcam), anti-CD204 (ab123946, Abcam), anti-CD64 (PA5-24855, Thermo Fisher Scientific), anti-CD16 (MA1-19006, Thermo Fisher Scientific), or anti-beta-actin (ab8227, Abcam) primary antibody at room temperature for one hour.	('CD16', 'Gene', (272, 276))	('CD16', 'Gene', '2214', (163, 167))	('CD64', 'Gene', '2209', (223, 227))	('CD16', 'Gene', (163, 167))	('CD204', 'Gene', (193, 198))	('CD204', 'Gene', '4481', (193, 198))	('ab125212', 'Var', (125, 133))	('CD163', 'Gene', '9332', (163, 168))	('CD68', 'Gene', (119, 123))	('CD16', 'Gene', '2214', (272, 276))	('CD64', 'Gene', (223, 227))	('CD68', 'Gene', '968', (119, 123))	('CD163', 'Gene', (163, 168))
170428	30469416	Patients had higher proportions of FN, Man3FN, G0F, G0N, G0FN, G1N, and G2FN glycoforms in IgG1 and Man3FN, G0, G0F, and G1 glycoforms in IgG2 than did healthy controls (Table 2).	('IgG', 'Gene', '668542', (138, 141))	('G0F', 'Var', (47, 50))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('IgG', 'Gene', (138, 141))	('G0N', 'Var', (52, 55))	('Man3FN', 'Var', (39, 45))	('IgG1', 'Gene', (91, 95))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('Man', 'Species', '9606', (39, 42))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('N', 'Chemical', 'MESH:D009584', (44, 45))	('G1N', 'Var', (63, 66))	('higher', 'PosReg', (13, 19))	('Patients', 'Species', '9606', (0, 8))	('Man', 'Species', '9606', (100, 103))	('N', 'Chemical', 'MESH:D009584', (105, 106))	('Man3FN', 'Var', (100, 106))	('G0FN', 'Var', (57, 61))	('N', 'Chemical', 'MESH:D009584', (65, 66))	('G2FN', 'Var', (72, 76))	('G0F', 'Var', (112, 115))	('IgG1', 'Gene', '16017', (91, 95))	('IgG', 'Gene', '668542', (91, 94))	('IgG', 'Gene', (91, 94))
170429	30469416	Moreover, patients had decreased proportions of G1F and G2F glycoforms on IgG1 and G1F and G2FS glycoforms on IgG2.	('IgG1', 'Gene', '16017', (74, 78))	('IgG', 'Gene', '668542', (110, 113))	('G1F', 'Var', (48, 51))	('G2FS', 'Var', (91, 95))	('G1F', 'Var', (83, 86))	('G2F', 'Var', (56, 59))	('IgG', 'Gene', (110, 113))	('IgG1', 'Gene', (74, 78))	('IgG', 'Gene', '668542', (74, 77))	('patients', 'Species', '9606', (10, 18))	('IgG', 'Gene', (74, 77))	('decreased', 'NegReg', (23, 32))
170432	30469416	Interestingly, only six glycoforms including G0FN, G1F, G1F2, G1FS, G2F, and G2FS between IgG1-Fc and IgG2-Fc were correlated (Supplementary Table S4).	('IgG', 'Gene', (102, 105))	('G2FS', 'Var', (77, 81))	('IgG', 'Gene', '668542', (90, 93))	('IgG1', 'Gene', (90, 94))	('IgG', 'Gene', (90, 93))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('men', 'Species', '9606', (133, 136))	('IgG1', 'Gene', '16017', (90, 94))	('IgG', 'Gene', '668542', (102, 105))
170448	30469416	According to these clues, we assessed whether agalactosylated IgG connected to an activation of tumor-associated macrophages.	('IgG', 'Gene', '668542', (62, 65))	('IgG', 'Gene', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('agalactosylated', 'Var', (46, 61))	('activation', 'PosReg', (82, 92))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
170463	30469416	Aberrant serum total N-glycome is a prominently serological marker of chronic and end-stage liver diseases.	('Aberrant', 'Var', (0, 8))	('serum total N-glycome', 'MPA', (9, 30))	('end-stage liver diseases', 'Disease', (82, 106))	('N', 'Chemical', 'MESH:D009584', (21, 22))	('end-stage liver diseases', 'Disease', 'MESH:D058625', (82, 106))	('liver diseases', 'Phenotype', 'HP:0001392', (92, 106))
170469	30469416	Here we report for the first time about the pathological role of agalactosylated IgG on the activation of tumor-associated macrophages, which links to tumor metastasis and early recurrence of cholangiocarcinoma.	('agalactosylated', 'Var', (65, 80))	('cholangiocarcinoma', 'Disease', (192, 210))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('tumor metastasis', 'Disease', 'MESH:D009362', (151, 167))	('links to', 'Reg', (142, 150))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (192, 210))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor metastasis', 'Disease', (151, 167))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (192, 210))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('IgG', 'Gene', '668542', (81, 84))	('IgG', 'Gene', (81, 84))	('tumor', 'Disease', (106, 111))
170473	30469416	Interestingly, even if glycan distributions between IgG1 and IgG2 were not synchronized, a unique glycoform G0F in both IgG subclasses were identified to be associated with the early recurrence of cholangiocarcinoma.	('IgG', 'Gene', '668542', (120, 123))	('IgG', 'Gene', (61, 64))	('IgG', 'Gene', (120, 123))	('glycan', 'Chemical', 'MESH:D011134', (23, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (197, 215))	('associated with', 'Reg', (157, 172))	('IgG1', 'Gene', (52, 56))	('IgG', 'Gene', '668542', (52, 55))	('cholangiocarcinoma', 'Disease', (197, 215))	('IgG', 'Gene', (52, 55))	('G0F', 'Var', (108, 111))	('IgG1', 'Gene', '16017', (52, 56))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (197, 215))	('IgG', 'Gene', '668542', (61, 64))
170479	30469416	In regard to the associations of IgG-G0F with proinflammatory cytokines, tumor metastasis, and tumor recurrence, our results imply that agalactosylated IgG does not restrain but facilitate the expansion of biliary tumor cells, which stand for a theory of invalid inflammation on driving cancer cells proliferation and metastasis.	('cancer', 'Disease', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('biliary tumor', 'Phenotype', 'HP:0100574', (206, 219))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('biliary tumor', 'Disease', (206, 219))	('facilitate', 'PosReg', (178, 188))	('tumor metastasis', 'Disease', 'MESH:D009362', (73, 89))	('agalactosylated', 'Var', (136, 151))	('IgG', 'Gene', '668542', (152, 155))	('IgG', 'Gene', (152, 155))	('IgG', 'Gene', '668542', (33, 36))	('IgG', 'Gene', (33, 36))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('inflammation', 'Disease', 'MESH:D007249', (263, 275))	('expansion', 'CPA', (193, 202))	('tumor', 'Disease', (73, 78))	('tumor metastasis', 'Disease', (73, 89))	('tumor', 'Disease', (214, 219))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('inflammation', 'Disease', (263, 275))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('biliary tumor', 'Disease', 'MESH:D001661', (206, 219))
170480	30469416	In vitro assays plus validations in tumor sections implicated agalactosylated IgG in the activation of tumor-associated macrophages.	('IgG', 'Gene', '668542', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('IgG', 'Gene', (78, 81))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('activation', 'PosReg', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('agalactosylated', 'Var', (62, 77))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (36, 41))
170512	26797527	Infection can cause recurrent inflammation, especially of the bile ducts, leading to disorders of the biliary system, including cholangitis, obstructive jaundice, hepatomegaly, fibrosis of the periportal system, cholecystitis, and cholelithiasis.	('cholangitis, obstructive jaundice', 'Disease', 'MESH:D041781', (128, 161))	('cholelithiasis', 'Disease', (231, 245))	('leading to', 'Reg', (74, 84))	('inflammation', 'Disease', 'MESH:D007249', (30, 42))	('Infection', 'Var', (0, 9))	('cholecystitis', 'Disease', 'MESH:D002764', (212, 225))	('cause', 'Reg', (14, 19))	('disorders', 'Disease', (85, 94))	('biliary system', 'Disease', (102, 116))	('cholangitis', 'Phenotype', 'HP:0030151', (128, 139))	('inflammation', 'Disease', (30, 42))	('fibrosis', 'Disease', 'MESH:D005355', (177, 185))	('fibrosis', 'Disease', (177, 185))	('hepatomegaly', 'Disease', (163, 175))	('jaundice', 'Phenotype', 'HP:0000952', (153, 161))	('cholelithiasis', 'Phenotype', 'HP:0001081', (231, 245))	('cholecystitis', 'Phenotype', 'HP:0001082', (212, 225))	('disorders of the biliary system', 'Phenotype', 'HP:0004297', (85, 116))	('cholelithiasis', 'Disease', 'MESH:D002769', (231, 245))	('hepatomegaly', 'Disease', 'MESH:D006529', (163, 175))	('cholecystitis', 'Disease', (212, 225))	('hepatomegaly', 'Phenotype', 'HP:0002240', (163, 175))
170628	32222826	Gut-derived antigens presented by PSC-associated human leukocyte antigen (HLA) variants to the T cell receptor (TCR) may also contribute to adaptive immune responses in the portal areas by means of molecular mimicry.	('PSC', 'Gene', '100653366', (34, 37))	('adaptive immune responses', 'CPA', (140, 165))	('human', 'Species', '9606', (49, 54))	('HLA', 'Gene', (74, 77))	('variants', 'Var', (79, 87))	('PSC', 'Gene', (34, 37))	('contribute', 'Reg', (126, 136))	('TCR', 'Gene', (112, 115))
170642	32222826	Under the "toxic bile hypothesis"-model for PSC, it may also be argued that bile acids serve as initiating factors for the inflammation and fibro-obliterative changes to the bile ducts, either because of changes to bile composition, or to deficiencies in protective or compensatory mechanisms, the so-called "biliary bicarbonate umbrella" included.	('changes', 'Reg', (204, 211))	('bile', 'MPA', (215, 219))	('fibro-obliterative', 'CPA', (140, 158))	('bile acids', 'Chemical', 'MESH:D001647', (76, 86))	('inflammation', 'Disease', 'MESH:D007249', (123, 135))	('inflammation', 'Disease', (123, 135))	('PSC', 'Gene', '100653366', (44, 47))	('bicarbonate', 'Chemical', 'MESH:D001639', (317, 328))	('deficiencies', 'Var', (239, 251))	('PSC', 'Gene', (44, 47))
170644	32222826	The bicarbonate is concentrated at the apical surface of the biliary epithelium, presumed to form a protective layer above the cholangiocytes, whereby deficient protection might lead to or aggravate biliary disease.	('biliary disease', 'Phenotype', 'HP:0001080', (199, 214))	('aggravate', 'PosReg', (189, 198))	('biliary disease', 'Disease', (199, 214))	('lead to', 'Reg', (178, 185))	('bicarbonate', 'Chemical', 'MESH:D001639', (4, 15))	('deficient', 'Var', (151, 160))	('biliary disease', 'Disease', 'MESH:D001660', (199, 214))
170695	32222826	Exemplified, two pairs of siblings with homozygous FXR truncation or deletion variants were reported, of which all four children suffered from severe, early-onset PFIC and liver failure before the age of two.	('FXR', 'Gene', '9971', (51, 54))	('deletion variants', 'Var', (69, 86))	('liver failure', 'Phenotype', 'HP:0001399', (172, 185))	('children', 'Species', '9606', (120, 128))	('suffered from', 'Reg', (129, 142))	('FXR', 'Gene', (51, 54))	('PFIC and liver failure', 'Disease', 'MESH:D017093', (163, 185))	('truncation', 'Var', (55, 65))
170720	32222826	It inhibits bile acid synthesis via downregulation of CYP7A1 but as a note of caution may also stimulate cell proliferation in the liver and gut through pathways mediated by activation of IL6/STAT3 signaling, and has been implicated in the development of hepatocellular carcinoma in mouse models.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (255, 279))	('downregulation', 'NegReg', (36, 50))	('IL6', 'Gene', (188, 191))	('hepatocellular carcinoma', 'Disease', (255, 279))	('stimulate', 'PosReg', (95, 104))	('inhibits', 'NegReg', (3, 11))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (255, 279))	('implicated', 'Reg', (222, 232))	('bile acid synthesis', 'MPA', (12, 31))	('CYP7A1', 'Var', (54, 60))	('bile acid', 'Chemical', 'MESH:D001647', (12, 21))	('IL6', 'Gene', '16193', (188, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('STAT3', 'Gene', '20848', (192, 197))	('mouse', 'Species', '10090', (283, 288))	('cell proliferation', 'CPA', (105, 123))	('STAT3', 'Gene', (192, 197))
170721	32222826	NGM282 is a synthetic analogue of FGF-19, which may provide beneficial effects in cholestatic liver disease through prolonged inhibition of bile acid synthesis.	('FGF-19', 'Gene', '9965', (34, 40))	('NGM282', 'Var', (0, 6))	('liver disease', 'Phenotype', 'HP:0001392', (94, 107))	('FGF-19', 'Gene', (34, 40))	('cholestatic liver disease', 'Phenotype', 'HP:0002611', (82, 107))	('cholestatic liver disease', 'Disease', 'MESH:D008107', (82, 107))	('inhibition', 'NegReg', (126, 136))	('NGM282', 'Chemical', '-', (0, 6))	('beneficial effects', 'PosReg', (60, 78))	('bile acid synthesis', 'MPA', (140, 159))	('cholestatic liver disease', 'Disease', (82, 107))	('bile acid', 'Chemical', 'MESH:D001647', (140, 149))
170729	32222826	Inhibition of ASBT is associated with improved liver histology in animal models of cholestatic liver disease and was hypothesized to bring therapeutic benefit in PSC.	('cholestatic liver disease', 'Disease', 'MESH:D008107', (83, 108))	('cholestatic liver disease', 'Disease', (83, 108))	('improved', 'PosReg', (38, 46))	('ASBT', 'Gene', (14, 18))	('ASBT', 'Gene', '6555', (14, 18))	('liver', 'MPA', (47, 52))	('PSC', 'Gene', '100653366', (162, 165))	('Inhibition', 'Var', (0, 10))	('liver disease', 'Phenotype', 'HP:0001392', (95, 108))	('cholestatic liver disease', 'Phenotype', 'HP:0002611', (83, 108))	('PSC', 'Gene', (162, 165))
170735	32222826	In a small pilot study (n = 15), combination therapy with UDCA (15-23 mg/day) and ATRA for 12 weeks did not meet the primary endpoint of 30% serum ALP reduction [median DeltaALP - 34 (reduced from 277 to 243), - 12.3%, P = 0.09]; however, DeltaALT - 39% (median ALT 76 vs 46, P = 0.001) (Table 2).	('ALP', 'Gene', '250', (147, 150))	('serum ALP reduction', 'Phenotype', 'HP:0003282', (141, 160))	('ATRA', 'Chemical', 'MESH:D014212', (82, 86))	('DeltaALT', 'Var', (239, 247))	('ALP', 'Gene', (174, 177))	('UDCA', 'Chemical', 'MESH:D014580', (58, 62))	('ALP', 'Gene', (147, 150))	('ALP', 'Gene', '250', (174, 177))	('reduction', 'NegReg', (151, 160))
170748	32222826	In a small study of eight PSC patients only published as an abstract, fenofibrate was reported to induce significant reduction in ALP and ALT but no change in Mayo risk score at 6 months.	('reduction', 'NegReg', (117, 126))	('PSC', 'Gene', (26, 29))	('ALP', 'Gene', '250', (130, 133))	('fenofibrate', 'Var', (70, 81))	('Mayo', 'Species', '162683', (159, 163))	('ALT', 'MPA', (138, 141))	('fenofibrate', 'Chemical', 'MESH:D011345', (70, 81))	('ALP', 'Gene', (130, 133))	('patients', 'Species', '9606', (30, 38))	('PSC', 'Gene', '100653366', (26, 29))
170791	32222826	Minocycline has several properties in addition to being antibiotic, potentially contributing to its therapeutic effects in PSC, including anti-inflammatory (e.g.	('PSC', 'Gene', '100653366', (123, 126))	('Minocycline', 'Chemical', 'MESH:D008911', (0, 11))	('PSC', 'Gene', (123, 126))	('Minocycline', 'Var', (0, 11))	('anti-inflammatory', 'MPA', (138, 155))	('contributing', 'Reg', (80, 92))
170861	32222826	Stratification of patients by baseline ALP demonstrated a stepwise increase in risk of clinical events at week 96 (risk 6%, 19% and 34% in patients with baseline ALP < 158, 158-324 and > 324 U/L), supporting previous reports of an association between ALP > 1.5 x ULN with clinical outcomes in PSC.	('ALP', 'Gene', (162, 165))	('patients', 'Species', '9606', (139, 147))	('clinical events', 'MPA', (87, 102))	('ALP', 'Gene', '250', (162, 165))	('ALP', 'Gene', (39, 42))	('PSC', 'Gene', '100653366', (293, 296))	('> 324 U/L', 'Var', (185, 194))	('ALP', 'Gene', (251, 254))	('PSC', 'Gene', (293, 296))	('patients', 'Species', '9606', (18, 26))	('ALP', 'Gene', '250', (39, 42))	('ALP', 'Gene', '250', (251, 254))
170922	32020235	Enhancement was shown to occur through interactions with membrane receptor integrin (ITG)alphavbeta3 or alphavbeta5 in ovarian cancer, ITGalpha6beta4 in pancreatic cancer, and ITGalpha5beta1 in CCA.	('Enhancement', 'PosReg', (0, 11))	('CCA', 'Disease', 'MESH:D018281', (194, 197))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ovarian cancer', 'Disease', 'MESH:D010051', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (153, 170))	('CCA', 'Disease', (194, 197))	('ovarian cancer', 'Phenotype', 'HP:0100615', (119, 133))	('ITG', 'Gene', (85, 88))	('alphavbeta5', 'Gene', (104, 115))	('pancreatic cancer', 'Disease', (153, 170))	('ovarian cancer', 'Disease', (119, 133))	('pancreatic cancer', 'Disease', 'MESH:D010190', (153, 170))	('CCA', 'Phenotype', 'HP:0030153', (194, 197))	('ITGalpha6beta4', 'Var', (135, 149))	('ITGalpha5beta1', 'Var', (176, 190))	('interactions', 'Interaction', (39, 51))
170974	32020235	Based on the fact that the ITGalpha5 subunit can bind only to the ITGb1 subunit, changes in ITGalpha5 were taken as equivalent to changes in ITGalpha5beta1.	('bind', 'Interaction', (49, 53))	('ITGb1', 'Gene', (66, 71))	('changes', 'Var', (81, 88))	('ITGb1', 'Gene', '3688', (66, 71))
171009	32020235	Moreover, the siITGalpha5-transfected cells had a significantly lower response rate in the PN-induced cell migration assay compared to the scrambled-siRNA-treated cells (Fig.	('lower', 'NegReg', (64, 69))	('PN', 'Gene', '10631', (91, 93))	('siITGalpha5-transfected', 'Var', (14, 37))	('response', 'CPA', (70, 78))
171016	32020235	Interestingly, CCA patients with high TWIST-2 had shorter mean survival times (211+-14 days) compared to those with low TWIST-2 (637+-503 days).	('CCA', 'Disease', 'MESH:D018281', (15, 18))	('patients', 'Species', '9606', (19, 27))	('CCA', 'Disease', (15, 18))	('high TWIST-2', 'Var', (33, 45))	('shorter', 'NegReg', (50, 57))	('CCA', 'Phenotype', 'HP:0030153', (15, 18))
171017	32020235	The overall survival analysis by Kaplan-Meier test showed, with statistical significance, that patients exhibiting high TWIST-2 levels had shorter survival times than those with low TWIST-2 using both 3-year and 5-year survival as the cut-off values (Fig.	('high', 'Var', (115, 119))	('survival', 'MPA', (147, 155))	('shorter', 'NegReg', (139, 146))	('patients', 'Species', '9606', (95, 103))
171020	32020235	The aberration of secretomes in ASMA-positive stromal fibroblasts led to the discovery of periostin (PN) as a major protein having a tumorigenic impact in intrahepatic CCA, and a variety of EMT markers have been proposed as indicators for the poor patient prognosis.	('CCA', 'Phenotype', 'HP:0030153', (168, 171))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('PN', 'Gene', '10631', (101, 103))	('aberration', 'Var', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('patient', 'Species', '9606', (248, 255))	('intrahepatic CCA', 'Disease', (155, 171))	('tumor', 'Disease', (133, 138))	('intrahepatic CCA', 'Disease', 'MESH:D018281', (155, 171))	('periostin', 'Gene', (90, 99))	('periostin', 'Gene', '10631', (90, 99))
171044	32020235	The involvement of ITGalpha5beta1 in the regulation of the PN-activated EMT pathway was confirmed here by the finding that cells silenced for ITGalpha5beta1 had both less migration ability induced by PN treatment and reduced MMP production.	('less', 'NegReg', (166, 170))	('PN', 'Gene', '10631', (59, 61))	('migration ability', 'CPA', (171, 188))	('PN', 'Gene', '10631', (200, 202))	('MMP production', 'MPA', (225, 239))	('ITGalpha5beta1', 'Gene', (142, 156))	('silenced', 'Var', (129, 137))	('reduced', 'NegReg', (217, 224))
171055	32020235	This is similar to the findings of the present study; those patients with high levels of TWIST-2 had significantly shorter survival times compared to those with low TWIST-2.	('high levels', 'Var', (74, 85))	('patients', 'Species', '9606', (60, 68))	('shorter', 'NegReg', (115, 122))	('TWIST-2', 'Gene', (89, 96))	('survival times', 'CPA', (123, 137))
171077	31186313	Reduction in tumor diameter negatively correlated with p-ERK change in tumor (Spearman rho = -0.71; P = 0.05).	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('Reduction', 'NegReg', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', (71, 76))	('negatively', 'NegReg', (28, 38))	('p-ERK', 'Var', (55, 60))
171078	31186313	NRAS mutation was associated with response (Fisher exact P = 0.008).	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))	('mutation', 'Var', (5, 13))	('response', 'Disease', (34, 42))
171086	31186313	Mutations in BRAF and RAS genes, along with rearrangements in RET, TRK, and ALK genes and others have been found in the majority (70%) of patients.	('patients', 'Species', '9606', (138, 146))	('ALK', 'Gene', '238', (76, 79))	('BRAF', 'Gene', '673', (13, 17))	('RET', 'Gene', (62, 65))	('RAS genes', 'Gene', (22, 31))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('ALK', 'Gene', (76, 79))	('RET', 'Gene', '5979', (62, 65))	('TRK', 'Gene', (67, 70))	('found', 'Reg', (107, 112))	('TRK', 'Gene', '4914', (67, 70))
171093	31186313	We hypothesized that inhibition of receptor tyrosine kinases VEGFR and PDGFR with the addition of MEK inhibitor trametinib could improve clinical benefit for patients with DTC compared with pazopanib alone.	('MEK', 'Gene', (98, 101))	('clinical', 'MPA', (137, 145))	('improve', 'PosReg', (129, 136))	('MEK', 'Gene', '5609', (98, 101))	('VEGFR', 'Gene', (61, 66))	('PDGFR', 'Gene', (71, 76))	('inhibition', 'Var', (21, 31))	('pazopanib', 'Chemical', 'MESH:C516667', (190, 199))	('PDGFR', 'Gene', '5159', (71, 76))	('DTC', 'Chemical', '-', (172, 175))	('patients', 'Species', '9606', (158, 166))	('VEGFR', 'Gene', '3791', (61, 66))	('DTC', 'Disease', (172, 175))	('trametinib', 'Chemical', 'MESH:C560077', (112, 122))
171135	31186313	IHC with pERK was performed using anti-phospho-p44/42 MAPK (ERK1/2; Thr202/Tyr204; 20G11; 4376S, Cell Signaling Technology) rabbit mAb.	('Tyr204', 'Chemical', '-', (75, 81))	('Thr202', 'Chemical', '-', (68, 74))	('rabbit', 'Species', '9986', (124, 130))	('ERK', 'Gene', (60, 63))	('anti-phospho-p44/42', 'Var', (34, 53))	('ERK', 'Gene', '2048', (60, 63))	('ERK', 'Gene', '2048', (10, 13))	('pERK', 'Gene', (9, 13))	('pERK', 'Gene', '9451', (9, 13))	('ERK', 'Gene', (10, 13))
171140	31186313	DTC cohort patients had hotspot mutational sequencing on tumor DNA from fresh biopsy specimens or archival tissue (if fresh biopsy tissue was not available) performed by nextgeneration sequencing using AmpliSeq Cancer Hotspot Panel (v2) for targeted multigene amplification, as described previously.	('Cancer', 'Phenotype', 'HP:0002664', (211, 217))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('mutational', 'Var', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('DTC', 'Chemical', '-', (0, 3))	('patients', 'Species', '9606', (11, 19))	('tumor', 'Disease', (57, 62))
171208	31186313	Three of 11 patients with available tissue had NRAS mutations, slightly higher than expected possibly due to the patients enrolled being more advanced cases, as RAS mutations have been suggested to represent a more aggressive phenotype.	('mutations', 'Var', (52, 61))	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (113, 121))	('NRAS', 'Gene', (47, 51))	('NRAS', 'Gene', '4893', (47, 51))
171209	31186313	All three patients with NRAS mutations had PRs (with the final PR patient not having available tissue for sequencing).	('NRAS', 'Gene', '4893', (24, 28))	('PRs', 'Disease', (43, 46))	('mutations', 'Var', (29, 38))	('patient', 'Species', '9606', (10, 17))	('patient', 'Species', '9606', (66, 73))	('patients', 'Species', '9606', (10, 18))	('NRAS', 'Gene', (24, 28))
171212	31186313	Lenvatinib, another VEGFR/FGFR tyrosine kinase inhibitor, is approved in DTC, and a phase II study suggested that RAS-mutated patients had more benefit from lenvatinib than wild-type tumors, although this finding was not substantiated in the subsequent phase III study.	('VEGFR', 'Gene', '3791', (20, 25))	('benefit', 'PosReg', (144, 151))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('lenvatinib', 'Var', (157, 167))	('RAS-mutated', 'Var', (114, 125))	('lenvatinib', 'Chemical', 'MESH:C531958', (157, 167))	('VEGFR', 'Gene', (20, 25))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('Lenvatinib', 'Chemical', 'MESH:C531958', (0, 10))	('patients', 'Species', '9606', (126, 134))	('tumors', 'Disease', (183, 189))	('DTC', 'Chemical', '-', (73, 76))
171224	29353494	Mutations in catenin beta 1 (CTNBB1) and tumor protein 53 (P53) are the main genetic alterations in HCC.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('catenin beta 1', 'Gene', (13, 27))	('HCC', 'Gene', '619501', (100, 103))	('tumor protein 53', 'Gene', '7157', (41, 57))	('CTNBB1', 'Gene', (29, 35))	('HCC', 'Gene', (100, 103))	('Mutations', 'Var', (0, 9))	('P53', 'Gene', (59, 62))	('catenin beta 1', 'Gene', '1499', (13, 27))	('P53', 'Gene', '7157', (59, 62))	('HCC', 'Phenotype', 'HP:0001402', (100, 103))	('tumor protein 53', 'Gene', (41, 57))
171256	29353494	Aflatoxin B1 is directly mutagenic and is associated with a specific P53 mutation and mutational activation of oncogenes such as Harvey Rat Sarcoma Viral Oncogene Homolog, HRAS.	('Aflatoxin B1', 'Chemical', 'MESH:D016604', (0, 12))	('activation', 'PosReg', (97, 107))	('Harvey Rat Sarcoma Viral', 'Disease', 'MESH:D001102', (129, 153))	('associated', 'Reg', (42, 52))	('HRAS', 'Gene', (172, 176))	('Sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('Aflatoxin', 'Gene', (0, 9))	('P53', 'Gene', (69, 72))	('HRAS', 'Gene', '293621', (172, 176))	('mutation', 'Var', (73, 81))	('P53', 'Gene', '7157', (69, 72))	('Harvey Rat Sarcoma Viral', 'Disease', (129, 153))	('mutational', 'Var', (86, 96))
171261	29353494	These include hereditary hemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency, tyrosinemia, glycogen storage diseases type I and II, and porphyrias.	('Wilson disease', 'Disease', 'MESH:D006527', (42, 56))	('porphyrias', 'Disease', (148, 158))	('deficiency', 'Var', (78, 88))	('alpha-1 antitrypsin deficiency', 'Phenotype', 'HP:0032025', (58, 88))	('hereditary hemochromatosis', 'Disease', (14, 40))	('tyrosinemia', 'Disease', (90, 101))	('Wilson disease', 'Disease', (42, 56))	('tyrosinemia', 'Disease', 'MESH:D020176', (90, 101))	('diseases type I', 'Disease', 'MESH:D005776', (120, 135))	('hereditary hemochromatosis', 'Disease', 'MESH:D006432', (14, 40))	('alpha-1 antitrypsin', 'Gene', '5265', (58, 77))	('Wilson disease', 'Phenotype', 'HP:0032102', (42, 56))	('tyrosinemia', 'Phenotype', 'HP:0003231', (90, 101))	('alpha-1 antitrypsin', 'Gene', (58, 77))	('diseases type I', 'Disease', (120, 135))
171263	29353494	A clear distinction among the various etiologies is that in contrast to HBV and aflatoxin-B1, which affect the genome via viral integration and generation of mutations, respectively, HCV and alcohol induce changes in the liver microenvironment through the development of cirrhosis.	('HCV', 'Gene', (183, 186))	('cirrhosis', 'Disease', (271, 280))	('men', 'Species', '9606', (239, 242))	('changes', 'Reg', (206, 213))	('liver microenvironment', 'MPA', (221, 243))	('men', 'Species', '9606', (263, 266))	('cirrhosis', 'Phenotype', 'HP:0001394', (271, 280))	('cirrhosis', 'Disease', 'MESH:D005355', (271, 280))	('mutations', 'Var', (158, 167))	('alcohol', 'Chemical', 'MESH:D000438', (191, 198))
171265	29353494	Research studying signaling genes or HCC pathways in cell lines and patient tissue studies have identified multiple key mutations and pathway alterations that occur during hepatocellular carcinogenesis.	('alterations', 'Reg', (142, 153))	('patient', 'Species', '9606', (68, 75))	('HCC', 'Gene', '619501', (37, 40))	('hepatocellular carcinogenesis', 'Disease', (172, 201))	('HCC', 'Phenotype', 'HP:0001402', (37, 40))	('hepatocellular carcinogenesis', 'Disease', 'MESH:D063646', (172, 201))	('mutations', 'Var', (120, 129))	('HCC', 'Gene', (37, 40))
171266	29353494	The most frequent are the Wnt/beta-catenin pathway and mutations in tumor protein 53 (TP53), Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Protein kinase B (AKT), suppressor of cytokine signaling-3 (SOCS3), NF-kappaB, NF-kappaB essential-modulator (NEMO)/Inhibitor of nuclear factor kappa-B kinase subunit gamma (IKK-gamma) , P16, Myelocytomatosis Viral Oncogene Homolog (MYC), and human hemochromatosis (HFE).	('Protein kinase B', 'Gene', (147, 163))	('suppressor of cytokine signaling-3', 'Gene', (171, 205))	('Protein kinase B', 'Gene', '2185', (147, 163))	('NEMO', 'Gene', (257, 261))	('P16', 'Gene', (334, 337))	('IKK-gamma', 'Gene', '8517', (321, 330))	('AKT', 'Gene', (165, 168))	('SOCS3', 'Gene', (207, 212))	('frequent', 'Reg', (9, 17))	('NF-kappaB', 'Gene', (215, 224))	('SOCS3', 'Gene', '9021', (207, 212))	('MYC', 'Gene', (380, 383))	('NF-kappaB essential-modulator', 'Gene', (226, 255))	('Phosphatidylinositol-4,5-bisphosphate 3-kinase', 'Gene', '5294', (93, 139))	('HFE', 'Gene', '3077', (413, 416))	('human', 'Species', '9606', (390, 395))	('NF-kappaB', 'Gene', '4790', (215, 224))	('mutations', 'Var', (55, 64))	('NF-kappaB', 'Gene', (226, 235))	('tumor protein 53', 'Gene', (68, 84))	('NEMO', 'Gene', '8517', (257, 261))	('AKT', 'Gene', '207', (165, 168))	('Inhibitor of nuclear factor kappa-B kinase subunit gamma', 'Gene', '8517', (263, 319))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('beta-catenin', 'Gene', (30, 42))	('hemochromatosis', 'Disease', (396, 411))	('NF-kappaB essential-modulator', 'Gene', '8517', (226, 255))	('beta-catenin', 'Gene', '1499', (30, 42))	('HFE', 'Gene', (413, 416))	('tumor protein 53', 'Gene', '7157', (68, 84))	('NF-kappaB', 'Gene', '4790', (226, 235))	('hemochromatosis', 'Disease', 'MESH:D006432', (396, 411))	('MYC', 'Gene', '4609', (380, 383))	('Myelocytomatosis Viral Oncogene Homolog', 'Gene', (339, 378))	('IKK-gamma', 'Gene', (321, 330))	('P16', 'Gene', '1029', (334, 337))	('Myelocytomatosis Viral Oncogene Homolog', 'Gene', '4609', (339, 378))	('suppressor of cytokine signaling-3', 'Gene', '9021', (171, 205))
171267	29353494	Abnormally activated Wnt-beta-catenin and Hedgehog pathways are causes of altered cellular proliferation in HCC, with aberrant accumulation of beta-catenin in HCC cell nuclei.	('accumulation', 'PosReg', (127, 139))	('beta-catenin', 'Gene', '1499', (143, 155))	('HCC', 'Gene', '619501', (159, 162))	('causes', 'Reg', (64, 70))	('HCC', 'Phenotype', 'HP:0001402', (108, 111))	('beta-catenin', 'Gene', '1499', (25, 37))	('activated', 'PosReg', (11, 20))	('HCC', 'Gene', (159, 162))	('cellular proliferation', 'CPA', (82, 104))	('Hedgehog pathways', 'Pathway', (42, 59))	('HCC', 'Gene', (108, 111))	('beta-catenin', 'Gene', (143, 155))	('Abnormally', 'Var', (0, 10))	('beta-catenin', 'Gene', (25, 37))	('HCC', 'Gene', '619501', (108, 111))	('HCC', 'Phenotype', 'HP:0001402', (159, 162))
171268	29353494	Furthermore, aberrant Wnt signaling has been implicated in the malignant transformation of preneoplastic hepatic adenomas.	('implicated', 'Reg', (45, 55))	('preneoplastic hepatic adenomas', 'Disease', 'MESH:C564190', (91, 121))	('hepatic adenomas', 'Phenotype', 'HP:0012028', (105, 121))	('preneoplastic hepatic adenomas', 'Disease', (91, 121))	('aberrant', 'Var', (13, 21))
171270	29353494	In particular, P53 protein accumulation, with a GTTval   GCTala mutation at codon 274, and a silent mutation (ACCthr   ACTthr) at codon 140 of the P53 gene were highlighted by these findings.	('P53', 'Gene', (15, 18))	('accumulation', 'PosReg', (27, 39))	('mutation', 'Var', (64, 72))	('P53', 'Gene', '7157', (15, 18))	('P53', 'Gene', (147, 150))	('P53', 'Gene', '7157', (147, 150))	('protein', 'Protein', (19, 26))
171273	29353494	Deletion or silencing of the SOCS3 gene in the hepatocytes protects against hepatocellular apoptosis and promotes the activation of Signal transducer and activator of transcription 3 (STAT3), contributing to enhanced hepatitis-induced carcinogenesis.	('promotes', 'PosReg', (105, 113))	('SOCS3', 'Gene', (29, 34))	('STAT3', 'Gene', '6774', (184, 189))	('hepatitis', 'Phenotype', 'HP:0012115', (217, 226))	('STAT3', 'Gene', (184, 189))	('hepatitis-induced carcinogenesis', 'Disease', (217, 249))	('silencing', 'Var', (12, 21))	('SOCS3', 'Gene', '9021', (29, 34))	('hepatocellular apoptosis', 'MPA', (76, 100))	('enhanced', 'PosReg', (208, 216))	('hepatitis-induced carcinogenesis', 'Disease', 'MESH:D056486', (217, 249))	('Deletion', 'Var', (0, 8))
171278	29353494	For example, mutations in CTNBB1 occur more frequently in HCV-associated HCC and nonviral-related HCC compared to HBV-related HCC.	('HCC', 'Gene', '619501', (73, 76))	('HCC', 'Phenotype', 'HP:0001402', (73, 76))	('HCC', 'Gene', (98, 101))	('HCC', 'Gene', (126, 129))	('HCC', 'Gene', '619501', (98, 101))	('CTNBB1', 'Gene', (26, 32))	('HCC', 'Gene', '619501', (126, 129))	('HCC', 'Phenotype', 'HP:0001402', (98, 101))	('HCC', 'Gene', (73, 76))	('mutations', 'Var', (13, 22))	('HCC', 'Phenotype', 'HP:0001402', (126, 129))
171279	29353494	In contrast, P53 mutations occur more frequently in HBV-associated HCC compared to HCV and in viral-associated HCC.	('HCC', 'Gene', '619501', (111, 114))	('HCC', 'Gene', '619501', (67, 70))	('HCC', 'Phenotype', 'HP:0001402', (67, 70))	('HCC', 'Phenotype', 'HP:0001402', (111, 114))	('P53', 'Gene', (13, 16))	('P53', 'Gene', '7157', (13, 16))	('HCC', 'Gene', (67, 70))	('HCC', 'Gene', (111, 114))	('mutations', 'Var', (17, 26))
171280	29353494	Other driver mutations include Kelch-like ECH-associated protein 1 (KEAP1), Homo sapiens chromosome 16 open reading frame 62 (C16orf62), (MLL4), and A signaling GTPase of the Rho family GTPase (RAC2).	('C16orf62', 'Gene', '57020', (126, 134))	('C16orf62', 'Gene', (126, 134))	('KEAP1', 'Gene', (68, 73))	('Homo sapiens', 'Species', '9606', (76, 88))	('Kelch-like ECH-associated protein 1', 'Gene', (31, 66))	('MLL4', 'Gene', (138, 142))	('RAC2', 'Gene', '5880', (194, 198))	('MLL4', 'Gene', '9757', (138, 142))	('mutations', 'Var', (13, 22))	('Kelch-like ECH-associated protein 1', 'Gene', '9817', (31, 66))	('RAC2', 'Gene', (194, 198))	('KEAP1', 'Gene', '9817', (68, 73))
171281	29353494	As a result of NGS studies, inactivating mutations in genes encoding proteins in chromatin remodeling have been identified as being frequent in HCC.	('inactivating mutations', 'Var', (28, 50))	('HCC', 'Gene', (144, 147))	('HCC', 'Gene', '619501', (144, 147))	('HCC', 'Phenotype', 'HP:0001402', (144, 147))	('frequent', 'Reg', (132, 140))
171284	29353494	Genetic alterations in chromatin remodelers were observed in 50% of HCC, making these very common mutations.	('Genetic alterations', 'Var', (0, 19))	('HCC', 'Gene', (68, 71))	('HCC', 'Phenotype', 'HP:0001402', (68, 71))	('HCC', 'Gene', '619501', (68, 71))
171290	29353494	Integration into CCNE1 drives aberrant cell cycle control in HCC.	('Integration', 'Var', (0, 11))	('HCC', 'Gene', (61, 64))	('CCNE1', 'Gene', '898', (17, 22))	('HCC', 'Gene', '619501', (61, 64))	('aberrant cell cycle', 'Phenotype', 'HP:0011018', (30, 49))	('HCC', 'Phenotype', 'HP:0001402', (61, 64))	('CCNE1', 'Gene', (17, 22))	('cell cycle control', 'CPA', (39, 57))
171292	29353494	Alterations in telomere maintenance are the most frequent, either due to mutations in the TERT gene or insertion of the HBV viral DNA into the TERT gene loci.	('TERT', 'Gene', '7015', (90, 94))	('TERT', 'Gene', (143, 147))	('Alterations', 'Reg', (0, 11))	('HBV', 'Gene', (120, 123))	('TERT', 'Gene', '7015', (143, 147))	('due', 'Reg', (66, 69))	('TERT', 'Gene', (90, 94))	('telomere maintenance', 'CPA', (15, 35))	('mutations', 'Var', (73, 82))
171295	29353494	Mutations in genes controlling cell cycle regulation including P53, CKDN2A, Axis inhibition protein (ATM), and Interferon Regulatory Factor 2 (IRF2) have been identified.	('ATM', 'Gene', (101, 104))	('ATM', 'Gene', '472', (101, 104))	('Interferon Regulatory Factor 2', 'Gene', '3660', (111, 141))	('CKDN2A', 'Gene', (68, 74))	('Mutations', 'Var', (0, 9))	('IRF2', 'Gene', '3660', (143, 147))	('P53', 'Gene', '7157', (63, 66))	('P53', 'Gene', (63, 66))	('Interferon Regulatory Factor 2', 'Gene', (111, 141))	('IRF2', 'Gene', (143, 147))
171299	29353494	Finally, activating mutations of PI3K, Fibroblast growth factor 19 (FGF19) amplification, and inactivating mutations of RPS6KA3 are also recurrent genetic alterations in HCC, leading to a constitutive activation of PI3K/Akt/mTOR and Ras/Raf/MAP kinase pathways.	('mTOR', 'Gene', (224, 228))	('activation', 'PosReg', (201, 211))	('HCC', 'Gene', (170, 173))	('Raf', 'Gene', '22882', (237, 240))	('FGF19', 'Gene', (68, 73))	('HCC', 'Gene', '619501', (170, 173))	('FGF19', 'Gene', '9965', (68, 73))	('HCC', 'Phenotype', 'HP:0001402', (170, 173))	('RPS6KA3', 'Gene', (120, 127))	('inactivating mutations', 'Var', (94, 116))	('Raf', 'Gene', (237, 240))	('activating', 'PosReg', (9, 19))	('Akt', 'Gene', '207', (220, 223))	('Fibroblast growth factor 19', 'Gene', (39, 66))	('RPS6KA3', 'Gene', '6197', (120, 127))	('Akt', 'Gene', (220, 223))	('mTOR', 'Gene', '2475', (224, 228))	('Fibroblast growth factor 19', 'Gene', '9965', (39, 66))
171300	29353494	Figure 1 illustrates the pathways involved in HCC carcinogenesis and the corresponding mutations and associated frequencies.	('HCC carcinogenesis', 'Disease', (46, 64))	('HCC carcinogenesis', 'Disease', 'MESH:D006528', (46, 64))	('mutations', 'Var', (87, 96))	('HCC', 'Phenotype', 'HP:0001402', (46, 49))
171323	29353494	In addition, studies have associated variants of genes that regulate DNA repair, inflammation, and carcinogen metabolism with ICC development.	('ICC development', 'Disease', (126, 141))	('inflammation', 'Disease', 'MESH:D007249', (81, 93))	('inflammation', 'Disease', (81, 93))	('variants', 'Var', (37, 45))	('men', 'Species', '9606', (137, 140))
171326	29353494	Genetic and epigenetic alterations cause the activation of these oncogenes and/or loss of these tumor suppressor gene functions.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('epigenetic alterations', 'Var', (12, 34))	('tumor', 'Disease', (96, 101))	('Genetic', 'Var', (0, 7))	('loss', 'NegReg', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('activation', 'PosReg', (45, 55))	('oncogenes', 'Protein', (65, 74))
171329	29353494	The most frequently identified mutation has been KRAS with hotspot mutations at codon 12.	('KRAS', 'Gene', '3845', (49, 53))	('mutations', 'Var', (67, 76))	('KRAS', 'Gene', (49, 53))
171330	29353494	Mutations in P53 were reported in up to 21% of cholangiocarcinomas (CCA) in a review of 10 studies, comprising 229 patients with CCA from Europe, Asia, and the United States.	('patients', 'Species', '9606', (115, 123))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (47, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (47, 65))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('P53', 'Gene', (13, 16))	('P53', 'Gene', '7157', (13, 16))	('Mutations', 'Var', (0, 9))	('cholangiocarcinomas', 'Disease', (47, 66))	('reported', 'Reg', (22, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
171331	29353494	Mutations in IDH1 have been detected more frequently in ICC than in extrahepatic cholangiocarcinoma (ECC), occurring in 28% of ICC compared to cholangiocarcinomas at other locations (7%).	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('ICC', 'Disease', (56, 59))	('detected', 'Reg', (28, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (143, 162))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (81, 99))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (68, 99))	('IDH1', 'Gene', (13, 17))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (143, 161))	('Mutations', 'Var', (0, 9))	('ICC', 'Disease', (127, 130))	('extrahepatic cholangiocarcinoma', 'Disease', (68, 99))	('IDH1', 'Gene', '3417', (13, 17))	('occurring', 'Reg', (107, 116))	('cholangiocarcinomas', 'Disease', (143, 162))
171332	29353494	A subsequent analysis of 62 cholangiocarcinomas detected Isocitrate dehydrogenases 1 (IDH1) mutations in only ICC.	('Isocitrate dehydrogenases 1', 'Gene', '3417', (57, 84))	('IDH1', 'Gene', (86, 90))	('Isocitrate dehydrogenases 1', 'Gene', (57, 84))	('IDH1', 'Gene', '3417', (86, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('mutations', 'Var', (92, 101))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (28, 47))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (28, 46))	('cholangiocarcinomas', 'Disease', (28, 47))
171333	29353494	Zhu et al analyzed the incidence and prognostic significance of mutations associated with ICC using nucleic acids extracted from 200 resected ICC tumor specimens using a mutational profiling panel that queried 150 hotspot mutations of 15 known cancer genes.	('ICC', 'Disease', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('ICC tumor', 'Disease', (142, 151))	('mutations', 'Var', (64, 73))	('men', 'Species', '9606', (157, 160))	('ICC tumor', 'Disease', 'MESH:C566123', (142, 151))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
171338	29353494	Putra et al compared ICC to ECC and found that ICC harbored IDH1 and NRAS mutations, whereas KRAS, P53, and BRAF mutations were found in ECC, confirming a difference in the mutational landscape according to location of the cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (223, 241))	('KRAS', 'Gene', (93, 97))	('IDH1', 'Gene', (60, 64))	('P53', 'Gene', (99, 102))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (223, 241))	('mutations', 'Var', (74, 83))	('P53', 'Gene', '7157', (99, 102))	('KRAS', 'Gene', '3845', (93, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (223, 241))	('IDH1', 'Gene', '3417', (60, 64))	('NRAS', 'Gene', (69, 73))
171345	29353494	Interestingly, ICCs with chronic advanced liver disease showed significantly higher EGFR mutation rates (5/38, 13.2% vs 1/43, 2.3%) and lower mutation rates of KRAS (3/38, 7.9% vs 8/43, 18.6%), MLH1 (2/38, 5.3% vs 5/43, 11.6%), and gnas (1/38, 2.6% vs 5/43, 11.6%), compared with those in ICCs with normal liver.	('liver disease', 'Disease', (42, 55))	('MLH1', 'Gene', (194, 198))	('lower', 'NegReg', (136, 141))	('chronic advanced liver disease', 'Phenotype', 'HP:0100626', (25, 55))	('higher', 'PosReg', (77, 83))	('liver disease', 'Disease', 'MESH:D008107', (42, 55))	('mutation', 'Var', (89, 97))	('KRAS', 'Gene', (160, 164))	('mutation rates', 'MPA', (142, 156))	('KRAS', 'Gene', '3845', (160, 164))	('EGFR', 'Gene', '1956', (84, 88))	('gnas', 'Gene', (232, 236))	('EGFR', 'Gene', (84, 88))	('liver disease', 'Phenotype', 'HP:0001392', (42, 55))	('MLH1', 'Gene', '4292', (194, 198))	('gnas', 'Gene', '2778', (232, 236))
171346	29353494	Mutations in PI3K, PTEN, CDKN2A, and P53 were harbored only in ICCs with normal liver, whereas KRAS (P = .0075) or GNAS mutations (P = .0256) were associated with poor overall survival in all patients with ICC.	('KRAS', 'Gene', '3845', (95, 99))	('poor', 'NegReg', (163, 167))	('PI3K', 'Gene', (13, 17))	('P53', 'Gene', (37, 40))	('P53', 'Gene', '7157', (37, 40))	('PTEN', 'Gene', (19, 23))	('patients', 'Species', '9606', (192, 200))	('GNAS', 'Gene', '2778', (115, 119))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (95, 99))	('CDKN2A', 'Gene', (25, 31))	('GNAS', 'Gene', (115, 119))	('CDKN2A', 'Gene', '1029', (25, 31))	('overall survival', 'MPA', (168, 184))
171348	29353494	One important signaling involved in carcinogenesis of cholangiocarcinoma is PI3K/AKT/PTEN pathway, where PI3K functions under the modulation by its upstream regulators especially RAS oncogene.	('carcinogenesis of cholangiocarcinoma', 'Disease', (36, 72))	('AKT', 'Gene', '207', (81, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('carcinogenesis of cholangiocarcinoma', 'Disease', 'MESH:D063646', (36, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('AKT', 'Gene', (81, 84))	('PI3K', 'Var', (105, 109))
171349	29353494	Loss of phosphatase function of PTEN due to either protein loss or its suppression by the upper stream molecules will lead to constitutive activation of the PI3K/Protein kinase B (AKT) signaling in cholangiocarcinoma, including downstream the mechanistic target of rapamycin (mTOR), heralding a worsened prognosis for the patients; inhibition of PI3K/AKT signaling effectively suppressed proliferation and invasive behavior of cholangiocarcinoma tumor cells, indicative of the potential therapeutic value of PI3K and/or AKT inhibitor(s).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (427, 445))	('invasive behavior', 'CPA', (406, 423))	('cholangiocarcinoma tumor', 'Disease', 'MESH:D018281', (427, 451))	('AKT', 'Gene', '207', (520, 523))	('Protein kinase B', 'Gene', (162, 178))	('Protein kinase B', 'Gene', '2185', (162, 178))	('AKT', 'Gene', '207', (351, 354))	('proliferation', 'CPA', (388, 401))	('patients', 'Species', '9606', (322, 330))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('AKT', 'Gene', (180, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (436, 445))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (198, 216))	('mechanistic target of rapamycin', 'Gene', (243, 274))	('mechanistic target of rapamycin', 'Gene', '2475', (243, 274))	('protein loss', 'Disease', 'MESH:D011488', (51, 63))	('mTOR', 'Gene', (276, 280))	('cholangiocarcinoma', 'Disease', (198, 216))	('AKT', 'Gene', (520, 523))	('cholangiocarcinoma tumor', 'Disease', (427, 451))	('tumor', 'Phenotype', 'HP:0002664', (446, 451))	('AKT', 'Gene', '207', (180, 183))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (198, 216))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (427, 445))	('suppressed', 'NegReg', (377, 387))	('AKT', 'Gene', (351, 354))	('mTOR', 'Gene', '2475', (276, 280))	('inhibition', 'Var', (332, 342))	('cholangiocarcinoma', 'Disease', (427, 445))	('protein loss', 'Disease', (51, 63))
171353	29353494	Activation of Wnt signaling pathway, together with inactivation of P53, led to more aggressive ICC behavior in animal models comparable to human ICC progression.	('P53', 'Gene', '7157', (67, 70))	('inactivation', 'Var', (51, 63))	('aggressive', 'CPA', (84, 94))	('Wnt signaling pathway', 'Pathway', (14, 35))	('aggressive ICC behavior', 'Phenotype', 'HP:0000718', (84, 107))	('Activation', 'PosReg', (0, 10))	('more', 'PosReg', (79, 83))	('human', 'Species', '9606', (139, 144))	('P53', 'Gene', (67, 70))
171354	29353494	Importantly, aberrant activation of this signaling pathway has been associated with both carcinogenesis in HCC and ICC.	('HCC', 'Gene', '619501', (107, 110))	('HCC', 'Phenotype', 'HP:0001402', (107, 110))	('associated', 'Reg', (68, 78))	('ICC', 'Disease', (115, 118))	('carcinogenesis', 'Disease', 'MESH:D063646', (89, 103))	('activation', 'PosReg', (22, 32))	('carcinogenesis', 'Disease', (89, 103))	('HCC', 'Gene', (107, 110))	('aberrant', 'Var', (13, 21))
171355	29353494	Variations in the tumor suppressor P53 and murine double minute 2 (MDM2) antioncogenes are closely connected to genetic susceptibility to biliary neoplasms.	('MDM2', 'Gene', (67, 71))	('connected', 'Reg', (99, 108))	('murine', 'Species', '10090', (43, 49))	('tumor suppressor P53', 'Gene', (18, 38))	('biliary neoplasms', 'Disease', 'MESH:D001661', (138, 155))	('Variations', 'Var', (0, 10))	('biliary neoplasms', 'Phenotype', 'HP:0100574', (138, 155))	('tumor suppressor P53', 'Gene', '22059', (18, 38))	('biliary neoplasms', 'Disease', (138, 155))	('neoplasms', 'Phenotype', 'HP:0002664', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
171356	29353494	P53 and its negative regulator MDM2 cooperate in modulating basic cell functions such as cell cycle control and apoptosis; the errors in their expressions and functions contribute to biliary carcinogenesis, displayed by cholangiocarcinoma formation in animal models carrying germline P53 mutants.	('biliary carcinogenesis', 'Disease', 'MESH:D063646', (183, 205))	('errors', 'Var', (127, 133))	('P53', 'Gene', (284, 287))	('expressions', 'MPA', (143, 154))	('contribute to', 'Reg', (169, 182))	('cholangiocarcinoma', 'Disease', (220, 238))	('P53', 'Gene', '7157', (284, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('biliary carcinogenesis', 'Disease', (183, 205))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (220, 238))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('mutants', 'Var', (288, 295))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (220, 238))
171357	29353494	A convincing association between functional variation in P53 and MDM2 and susceptibility to ICC in human has not been completely established.	('variation', 'Var', (44, 53))	('P53', 'Gene', (57, 60))	('P53', 'Gene', '7157', (57, 60))	('ICC', 'Disease', (92, 95))	('MDM2', 'Gene', (65, 69))	('human', 'Species', '9606', (99, 104))
171358	29353494	Hypermethylation of genes tightly modulates cellular fate by controlling proliferation, migration, cell cycle, DNA repair, angiogenesis, and apoptosis and is involved in carcinogenesis.	('carcinogenesis', 'Disease', (170, 184))	('cell cycle', 'CPA', (99, 109))	('controlling', 'Reg', (61, 72))	('modulates', 'Reg', (34, 43))	('proliferation', 'CPA', (73, 86))	('Hypermethylation', 'Var', (0, 16))	('cellular fate', 'CPA', (44, 57))	('involved', 'Reg', (158, 166))	('migration', 'CPA', (88, 97))	('angiogenesis', 'CPA', (123, 135))	('DNA repair', 'CPA', (111, 121))	('carcinogenesis', 'Disease', 'MESH:D063646', (170, 184))	('apoptosis', 'CPA', (141, 150))
171359	29353494	It has been accepted that there is a complex interplay of genetic and epigenetic alterations that accumulate in precancerous tissues and culminate in the development of full-blown carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (180, 189))	('culminate in', 'Reg', (137, 149))	('cancer', 'Disease', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('carcinoma', 'Disease', (180, 189))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('accumulate', 'PosReg', (98, 108))	('epigenetic alterations', 'Var', (70, 92))	('men', 'Species', '9606', (161, 164))
171360	29353494	Not surprisingly, methylation of P16 and its inactivation has been detected as an early event in near 90% of cholangiocarcinoma, and loss of P16 expression has been correlated with poor patient outcomes.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (109, 127))	('P16', 'Gene', '1029', (33, 36))	('P16', 'Gene', '1029', (141, 144))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('P16', 'Gene', (141, 144))	('expression', 'MPA', (145, 155))	('detected', 'Reg', (67, 75))	('methylation', 'Var', (18, 29))	('patient', 'Species', '9606', (186, 193))	('loss', 'Var', (133, 137))	('P16', 'Gene', (33, 36))	('cholangiocarcinoma', 'Disease', (109, 127))	('inactivation', 'MPA', (45, 57))
171369	29353494	Silencing of suppressor of cytokine signaling 3, which controls the IL-6/STAT-3 signaling, further contributes to sustained IL-6/STAT-3 signaling and enhanced Mcl-1 expression in cholangiocarcinoma.	('IL-6', 'Gene', '3569', (124, 128))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (179, 197))	('STAT-3', 'Gene', (129, 135))	('IL-6', 'Gene', '3569', (68, 72))	('suppressor of cytokine signaling 3', 'Gene', '9021', (13, 47))	('Silencing', 'Var', (0, 9))	('Mcl-1', 'Gene', (159, 164))	('IL-6', 'Gene', (124, 128))	('STAT-3', 'Gene', (73, 79))	('STAT-3', 'Gene', '6774', (129, 135))	('IL-6', 'Gene', (68, 72))	('STAT-3', 'Gene', '6774', (73, 79))	('suppressor of cytokine signaling 3', 'Gene', (13, 47))	('enhanced', 'PosReg', (150, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('Mcl-1', 'Gene', '4170', (159, 164))	('expression', 'MPA', (165, 175))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (179, 197))	('cholangiocarcinoma', 'Disease', (179, 197))
171370	29353494	Epigenetic regulation by IL-6 contributes to cholangiocarcinoma progression via affecting promoter methylation and gene expression in growth regulatory pathways, including that of EGFR.	('growth regulatory pathways', 'Pathway', (134, 160))	('promoter methylation', 'MPA', (90, 110))	('contributes', 'Reg', (30, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('cholangiocarcinoma', 'Disease', (45, 63))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('Epigenetic regulation', 'Var', (0, 21))	('IL-6', 'Gene', (25, 29))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (45, 63))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (45, 63))	('affecting', 'Reg', (80, 89))	('IL-6', 'Gene', '3569', (25, 29))	('gene expression', 'MPA', (115, 130))
171377	29353494	Mutations of KRAS have been confirmed in more than 30% of BilIN lesions, occurring as an early signaling event during the progression of BilIN to cholangiocarcinoma, including those BilIN arising from large bile ducts, whereas P53 overexpression has been proved to happen afterward.	('P53', 'Gene', '7157', (227, 230))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (146, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (146, 164))	('KRAS', 'Gene', '3845', (13, 17))	('large bile ducts', 'Phenotype', 'HP:0006560', (201, 217))	('BilIN', 'Disease', (137, 142))	('BilIN', 'Chemical', '-', (137, 142))	('Mutations', 'Var', (0, 9))	('cholangiocarcinoma', 'Disease', (146, 164))	('P53', 'Gene', (227, 230))	('KRAS', 'Gene', (13, 17))	('BilIN', 'Chemical', '-', (182, 187))	('BilIN', 'Chemical', '-', (58, 63))
171378	29353494	Of notice, KRAS mutation and that of BRAF are identified to be mutually exclusive; however, both are associated with a higher cholangiocarcinoma stage at the time of surgical resection and show an increased risk of lymph node metastasis, as well as associated shortened patient survival.	('KRAS', 'Gene', (11, 15))	('mutation', 'Var', (16, 24))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (126, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('lymph node metastasis', 'CPA', (215, 236))	('shortened', 'NegReg', (260, 269))	('KRAS', 'Gene', '3845', (11, 15))	('higher', 'PosReg', (119, 125))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (126, 144))	('patient', 'Species', '9606', (270, 277))	('cholangiocarcinoma', 'Disease', (126, 144))	('increased risk of lymph node', 'Phenotype', 'HP:0032536', (197, 225))
171382	29353494	Among those identified or discovered risk factors, mutations in CTNBB1 and P53 have been proven to be the main genetic alterations in HCC; in parallel, primary genetic alterations involving IDH1/2, KRAS, NAS, and P53 genes have been implicated in cholangiocarcinogenesis.	('IDH1/2', 'Gene', (190, 196))	('mutations', 'Var', (51, 60))	('HCC', 'Gene', (134, 137))	('P53', 'Gene', (213, 216))	('NAS', 'Gene', (204, 207))	('P53', 'Gene', '7157', (75, 78))	('P53', 'Gene', '7157', (213, 216))	('carcinogenesis', 'Disease', (256, 270))	('KRAS', 'Gene', (198, 202))	('HCC', 'Gene', '619501', (134, 137))	('KRAS', 'Gene', '3845', (198, 202))	('CTNBB1', 'Gene', (64, 70))	('IDH1/2', 'Gene', '3417;3418', (190, 196))	('implicated', 'Reg', (233, 243))	('HCC', 'Phenotype', 'HP:0001402', (134, 137))	('alterations', 'Var', (168, 179))	('P53', 'Gene', (75, 78))	('carcinogenesis', 'Disease', 'MESH:D063646', (256, 270))
171383	29353494	The mutational profiles are closely related to the underlying etiologies in both HCC and ICC, and they also impact the disease progression; some of these affected molecules could potentially serve as therapeutic targets in the future in our combat against these lethal neoplasms.	('neoplasms', 'Phenotype', 'HP:0002664', (269, 278))	('HCC', 'Gene', '619501', (81, 84))	('HCC', 'Phenotype', 'HP:0001402', (81, 84))	('ICC', 'Disease', (89, 92))	('neoplasms', 'Disease', 'MESH:D009369', (269, 278))	('neoplasms', 'Disease', (269, 278))	('disease progression', 'CPA', (119, 138))	('HCC', 'Gene', (81, 84))	('mutational', 'Var', (4, 14))	('impact', 'Reg', (108, 114))
171423	28906410	The following steps were performed with the assistance of the video-based AR navigation system and ultrasonography: incising the liver parenchyma along the left side of the middle HV; severing the right PV; estimating the boundary of the tumor with regard to the HAs and biliary ducts; determining the drainage basins of the PTBD tubes, and incising 1.5-cm tumor margins in the adjacent parenchyma.	('tumor', 'Disease', (357, 362))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('incising', 'Var', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Disease', (238, 243))	('tumor', 'Disease', 'MESH:D009369', (357, 362))	('severing', 'Var', (184, 192))	('incising', 'Reg', (341, 349))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('AR', 'Chemical', '-', (74, 76))
171509	26974538	By using the area under of the curve (AUC) as a determinant of overall performance of the test, we found that biliary CEACAM6 could differentiate any cholangiocarcinoma (AUC = 0.738) or extrahepatic cholangiocarcinoma (AUC = 0.791) from benign disease.	('CEACAM6', 'Gene', (118, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('extrahepatic cholangiocarcinoma', 'Disease', (186, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (150, 168))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (150, 168))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (199, 217))	('CEACAM6', 'Gene', '4680', (118, 125))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (199, 217))	('benign disease', 'Disease', (237, 251))	('benign disease', 'Disease', 'MESH:D009369', (237, 251))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (186, 217))	('cholangiocarcinoma', 'Disease', (150, 168))	('biliary', 'Var', (110, 117))	('cholangiocarcinoma', 'Disease', (199, 217))
171564	26474277	Furthermore, MSCs greatly increased the colony formation and invasion of cholangiocarcinoma cells QBC939 and Mz-ChA-1.	('colony formation', 'CPA', (40, 56))	('cholangiocarcinoma', 'Disease', (73, 91))	('MSCs', 'Var', (13, 17))	('invasion', 'CPA', (61, 69))	('increased', 'PosReg', (26, 35))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (73, 91))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (73, 91))
171566	26474277	We further demonstrated that MSCs and MSCs-CM could promote proliferation and migration of cholangiocarcinoma cells through targeting the Wnt/beta-catenin signaling pathway.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('Wnt/beta-catenin signaling pathway', 'Pathway', (138, 172))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('cholangiocarcinoma', 'Disease', (91, 109))	('migration', 'CPA', (78, 87))	('proliferation', 'CPA', (60, 73))	('targeting', 'Reg', (124, 133))	('MSCs-CM', 'Var', (38, 45))	('promote', 'PosReg', (52, 59))
171583	26474277	On one hand, MSCs may affect cancer progression through secreted factors triggering activation of various cell signaling pathways.	('cancer', 'Disease', (29, 35))	('cell signaling pathways', 'Pathway', (106, 129))	('MSCs', 'Var', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('affect', 'Reg', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
171596	26474277	Here, using multiple in vitro and in vivo models, we examined the roles of hUC-MSCs in the progression of cholangiocarcinoma development, and revealed the cellular and molecular mechanisms by which MSCs promote cholangiocarcinoma development.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (211, 229))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (106, 124))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (211, 229))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (106, 124))	('MSCs', 'Var', (198, 202))	('promote', 'PosReg', (203, 210))	('cholangiocarcinoma', 'Disease', (211, 229))	('cholangiocarcinoma', 'Disease', (106, 124))
171597	26474277	Our study first demonstrated that MSCs or their CM significantly increased cholangiocarcinoma cells proliferation, metastatic potency and chemoresistance both in vitro and in vivo.	('chemoresistance', 'CPA', (138, 153))	('increased', 'PosReg', (65, 74))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (75, 93))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (75, 93))	('metastatic potency', 'CPA', (115, 133))	('MSCs', 'Var', (34, 38))	('cholangiocarcinoma', 'Disease', (75, 93))
171614	26474277	From in vivo study, mice bearing the mixed QBC939+MSCs tumors display a marked increase in the number of macroscopic liver metastases (Figure 2B).	('increase', 'PosReg', (79, 87))	('macroscopic liver', 'Phenotype', 'HP:0002240', (105, 122))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('mice', 'Species', '10090', (20, 24))	('liver metastases', 'Disease', (117, 133))	('MSCs tumors', 'Disease', (50, 61))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('liver metastases', 'Disease', 'MESH:D009362', (117, 133))	('MSCs tumors', 'Disease', 'MESH:D009369', (50, 61))	('mixed', 'Var', (37, 42))
171633	26474277	What's more, compared the inhibit ratio about MSCs group with control group, we found that in MSCs group CK inhibit ratio is lower than the control group (p < 0.05) (Figure 3F).	('MSCs', 'Var', (94, 98))	('CK', 'Chemical', 'MESH:C112772', (105, 107))	('lower', 'NegReg', (125, 130))	('CK inhibit ratio', 'MPA', (105, 121))
171636	26474277	Aberrant activation of the Wnt signaling pathway may lead to malignancy.	('activation', 'PosReg', (9, 19))	('lead to', 'Reg', (53, 60))	('Aberrant', 'Var', (0, 8))	('Wnt signaling pathway', 'Pathway', (27, 48))	('malignancy', 'Disease', 'MESH:D009369', (61, 71))	('malignancy', 'Disease', (61, 71))
171642	26474277	As shown in Figure 4A, MSCs-CM promotes the activation of Wnt signaling significantly (p < 0.01), meanwhile CK inhibited Wnt activation (p < 0.05).	('Wnt', 'MPA', (121, 124))	('MSCs-CM', 'Var', (23, 30))	('activation', 'PosReg', (44, 54))	('CK', 'Chemical', 'MESH:C112772', (108, 110))	('Wnt signaling', 'Pathway', (58, 71))	('inhibited', 'NegReg', (111, 120))
171643	26474277	Western blotting results showed that MSCs-CM significantly up-regulated beta-catenin expression, as well as the downstream proteins including c-Myc, MMP2 and cyclin D1, compared with control group (p < 0.05) (Figure 4B, 4C).	('up-regulated', 'PosReg', (59, 71))	('MMP2', 'Gene', '4313', (149, 153))	('c-Myc', 'Gene', (142, 147))	('cyclin D1', 'Gene', '595', (158, 167))	('MMP2', 'Gene', (149, 153))	('MSCs-CM', 'Var', (37, 44))	('cyclin D1', 'Gene', (158, 167))	('beta-catenin expression', 'MPA', (72, 95))	('c-Myc', 'Gene', '4609', (142, 147))
171644	26474277	Nuclear beta-catenin accumulated when treated with MSCs-CM, at the same time, beta-catenin expression level was decreased after CK treatment (Figure 4D, 4E).	('beta-catenin expression level', 'MPA', (78, 107))	('CK', 'Chemical', 'MESH:C112772', (128, 130))	('decreased', 'NegReg', (112, 121))	('accumulated', 'PosReg', (21, 32))	('MSCs-CM', 'Var', (51, 58))
171647	26474277	From Figure 5A, beta-catenin expression level was unregulated by MSCs-CM and LiCl, and remarkably inhibited by XAV939.	('LiCl', 'Chemical', 'MESH:D018021', (77, 81))	('MSCs-CM', 'Var', (65, 72))	('inhibited', 'NegReg', (98, 107))	('beta-catenin expression level', 'MPA', (16, 45))
171652	26474277	Recent studies revealed that MSCs exert multiple effects on tumor development and progression, by increasing stemness of tumor cells, mediating migration, promoting angiogenesis, suppressing immune response and inducing drug resistance.	('immune response', 'CPA', (191, 206))	('drug resistance', 'CPA', (220, 235))	('MSCs', 'Var', (29, 33))	('drug resistance', 'Phenotype', 'HP:0020174', (220, 235))	('increasing', 'PosReg', (98, 108))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('promoting', 'PosReg', (155, 164))	('suppressing immune response', 'Phenotype', 'HP:0002721', (179, 206))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (121, 126))	('mediating migration', 'CPA', (134, 153))	('suppressing', 'NegReg', (179, 190))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('inducing', 'Reg', (211, 219))	('angiogenesis', 'CPA', (165, 177))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
171655	26474277	Some studies showed that MSCs could promote tumor progression and metastasis.	('promote', 'PosReg', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('MSCs', 'Var', (25, 29))	('tumor', 'Disease', (44, 49))
171656	26474277	While some investigators reported that MSCs could inhibit cancer growth and or inhibit cancer cell metastasis.	('inhibit', 'NegReg', (79, 86))	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('MSCs', 'Var', (39, 43))	('inhibit', 'NegReg', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
171673	26474277	Abnormal regulation of Wnt/beta-catenin signaling is linked to a variety of human diseases, such as malignancy.	('malignancy', 'Disease', 'MESH:D009369', (100, 110))	('malignancy', 'Disease', (100, 110))	('human', 'Species', '9606', (76, 81))	('linked', 'Reg', (53, 59))	('Abnormal', 'Var', (0, 8))
171676	26474277	According to Keishi Sugimachi et al, no beta-catenin mutations have been reported for intrahepatic cholangiocarcinoma, and reduced membranous expression and nuclear translocation of beta-catenin are involved in cholangiocarcinogenesis, progression and invasion.	('cholangiocarcinogenesis', 'Disease', 'None', (211, 234))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (86, 117))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (99, 117))	('beta-catenin', 'Protein', (40, 52))	('membranous expression', 'MPA', (131, 152))	('intrahepatic cholangiocarcinoma', 'Disease', (86, 117))	('mutations', 'Var', (53, 62))	('cholangiocarcinogenesis', 'Disease', (211, 234))	('beta-catenin', 'Protein', (182, 194))	('nuclear translocation', 'MPA', (157, 178))	('reduced', 'NegReg', (123, 130))
171678	26474277	These results suggest that MSCs may promote cholangiocarcinoma cell metastasis through Wnt/beta-catenin pathway.	('promote', 'PosReg', (36, 43))	('cholangiocarcinoma cell metastasis', 'Disease', (44, 78))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (44, 62))	('MSCs', 'Var', (27, 31))	('cholangiocarcinoma cell metastasis', 'Disease', 'MESH:D009362', (44, 78))
171685	26474277	That means the anti-tumor effect of CK was decreased at the presence of MSCs-CM.	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('decreased', 'NegReg', (43, 52))	('MSCs-CM', 'Var', (72, 79))	('tumor', 'Disease', (20, 25))	('CK', 'Chemical', 'MESH:C112772', (36, 38))
171686	26474277	From in vivo study, on the condition of MSCs, the tumor inhibition rate of CK was also decreased.	('MSCs', 'Var', (40, 44))	('decreased', 'NegReg', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('CK', 'Chemical', 'MESH:C112772', (75, 77))
171687	26474277	These results showed that MSCs promote the chemoresistance of cholangiocarcinoma, and suggested that soluble factors, such as cytokines, chemokines and growth factors secreted, may be the main aspect inducing the drug resistance.	('drug resistance', 'Phenotype', 'HP:0020174', (213, 228))	('cholangiocarcinoma', 'Disease', (62, 80))	('MSCs', 'Var', (26, 30))	('promote', 'PosReg', (31, 38))	('chemoresistance', 'CPA', (43, 58))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (62, 80))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (62, 80))
171690	26474277	The elucidation of the mechanism of MSCs promoting tumor cell growth and metastasis provides evidence of MSCs on cancer progression.	('MSCs', 'Var', (36, 40))	('promoting', 'PosReg', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('metastasis', 'CPA', (73, 83))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Disease', (51, 56))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
171722	26474277	The slides were rinsed in phosphate-buffered saline and incubated overnight at 4 C with diluted anti-cyclinD1, anti-c-Myc, anti-ki67 or anti-beta-catenin antibodies.	('phosphate-buffered saline', 'Chemical', '-', (26, 51))	('anti-ki67', 'Var', (123, 132))	('anti-beta-catenin', 'Protein', (136, 153))	('cyclinD1', 'Gene', (101, 109))	('cyclinD1', 'Gene', '595', (101, 109))	('c-Myc', 'Gene', '4609', (116, 121))	('c-Myc', 'Gene', (116, 121))
171737	18250017	Most patients have no predisposing risk factors, but the presence of the following risk factors may lead to development of the tumor at a younger age: primary sclerosing cholangitis (PSC) (5-15% lifetime risk); choledochal cysts (5% will transform and risk increases with age); Caroli disease (7% lifetime risk); hepatolithiasis; chronic intraductal stones; bile duct adenoma; biliary papillomatosis; Clonorchis sinensis infection; and Thorotrast (thorium dioxide) exposure.	('Caroli disease', 'Disease', 'MESH:D016767', (278, 292))	('biliary papillomatosis', 'Disease', 'MESH:D010212', (377, 399))	('men', 'Species', '9606', (115, 118))	('adenoma', 'Disease', 'MESH:D000236', (368, 375))	('PSC', 'Gene', '100653366', (183, 186))	('presence', 'Var', (57, 65))	('lead to', 'Reg', (100, 107))	('cholangitis', 'Phenotype', 'HP:0030151', (170, 181))	('bile duct adenoma', 'Phenotype', 'HP:0012028', (358, 375))	('choledochal cysts', 'Disease', (211, 228))	('hepatolithiasis', 'Disease', (313, 328))	('Caroli disease', 'Disease', (278, 292))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('patients', 'Species', '9606', (5, 13))	('choledochal cysts', 'Phenotype', 'HP:0100890', (211, 228))	('PSC', 'Gene', (183, 186))	('biliary papillomatosis', 'Disease', (377, 399))	('Clonorchis sinensis infection', 'Disease', (401, 430))	('Clonorchis sinensis infection', 'Disease', 'MESH:D003003', (401, 430))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (159, 181))	('tumor', 'Disease', (127, 132))	('cholangitis', 'Disease', 'MESH:D002761', (170, 181))	('hepatolithiasis', 'Disease', 'None', (313, 328))	('chronic intraductal stones', 'Disease', (330, 356))	('cholangitis', 'Disease', (170, 181))	('adenoma', 'Disease', (368, 375))
171857	18250017	Enlarged lymph nodes are best seen on T2W fat suppressed, and T1W fat suppressed gadolinium-enhanced images.	('gadolinium', 'Chemical', 'MESH:D005682', (81, 91))	('gadolinium-enhanced', 'MPA', (81, 100))	('suppressed', 'NegReg', (70, 80))	('T1W fat', 'Var', (62, 69))	('T2W fat suppressed', 'Var', (38, 56))	('Enlarged lymph nodes', 'Phenotype', 'HP:0002716', (0, 20))
171869	18250017	Encasement of the portal vein or its branches results in an autoregulatory increase in the hepatic arterial supply, which causes a transient increased enhancement of the affected segment or lobe in the hepatic arterial-dominant phase, also known as "transient hepatic intensity difference, THID".	('hepatic arterial supply', 'MPA', (91, 114))	('autoregulatory', 'MPA', (60, 74))	('Encasement', 'Var', (0, 10))	('men', 'Species', '9606', (158, 161))	('increase', 'PosReg', (75, 83))	('increased enhancement', 'PosReg', (141, 162))	('men', 'Species', '9606', (182, 185))	('THID', 'Chemical', '-', (290, 294))	('men', 'Species', '9606', (6, 9))
172035	32493242	Previous studies have shown that the combination of 5-Fluorouracil, leucovorin, oxaliplatin and irinotecan (FOLFIRINOX) or the combination of gemcitabine and nab-paclitaxel are associated with improved survival compared with gemcitabine alone in patients with metastatic pancreatic ductal adenocarcinoma.	('5-Fluorouracil', 'Var', (52, 66))	('leucovorin', 'Chemical', 'MESH:D002955', (68, 78))	('paclitaxel', 'Chemical', 'MESH:D017239', (162, 172))	('5-Fluorouracil', 'Chemical', 'MESH:D005472', (52, 66))	('patients', 'Species', '9606', (246, 254))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (80, 91))	('nab', 'Chemical', '-', (158, 161))	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (108, 118))	('improved', 'PosReg', (193, 201))	('gemcitabine', 'Chemical', 'MESH:C056507', (142, 153))	('irinotecan', 'Chemical', 'MESH:D000077146', (96, 106))	('pancreatic ductal adenocarcinoma', 'Disease', (271, 303))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (271, 303))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (271, 303))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('gemcitabine', 'Chemical', 'MESH:C056507', (225, 236))	('survival', 'MPA', (202, 210))
172044	32493242	FOLFIRINOX regimen consisted in the intravenous administration of irinotecan (180 mg/m2), oxaliplatin (85 mg/m2), leucovorin (400 mg/m2) and 5FU (2800 mg/m2, including the bolus injection and the 46-h constant infusion).	('5FU', 'Chemical', 'MESH:D005472', (141, 144))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (90, 101))	('leucovorin', 'Chemical', 'MESH:D002955', (114, 124))	('irinotecan', 'Chemical', 'MESH:D000077146', (66, 76))	('400 mg/m2', 'Var', (126, 135))	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (0, 10))	('85 mg/m2', 'Var', (103, 111))
172088	32493242	Conversely, nano-albumin-bound paclitaxel added to gemcitabine and cisplatin seemed to provide encouraging efficacy, albeit with more frequent severe toxicity.	('paclitaxel', 'Chemical', 'MESH:D017239', (31, 41))	('nano-albumin-bound', 'Var', (12, 30))	('toxicity', 'Disease', 'MESH:D064420', (150, 158))	('toxicity', 'Disease', (150, 158))	('gemcitabine', 'Chemical', 'MESH:C056507', (51, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))
172186	28981082	Previously, several papers suggested that high serum CRP level was associated with high risk of myocardial infarction, angina pectoris, heart failure, coronary death, and stroke.	('myocardial infarction', 'Disease', (96, 117))	('high serum CRP', 'Phenotype', 'HP:0011227', (42, 56))	('stroke', 'Disease', (171, 177))	('heart failure', 'Disease', (136, 149))	('angina pectoris', 'Disease', 'MESH:D000787', (119, 134))	('myocardial infarction', 'Phenotype', 'HP:0001658', (96, 117))	('coronary death', 'Disease', (151, 165))	('myocardial infarction', 'Disease', 'MESH:D009203', (96, 117))	('CRP', 'Gene', (53, 56))	('associated', 'Reg', (67, 77))	('heart failure', 'Phenotype', 'HP:0001635', (136, 149))	('heart failure', 'Disease', 'MESH:D006333', (136, 149))	('stroke', 'Phenotype', 'HP:0001297', (171, 177))	('serum', 'MPA', (47, 52))	('angina pectoris', 'Disease', (119, 134))	('coronary death', 'Disease', 'MESH:D003324', (151, 165))	('CRP', 'Gene', '1401', (53, 56))	('stroke', 'Disease', 'MESH:D020521', (171, 177))	('high', 'Var', (42, 46))	('angina pectoris', 'Phenotype', 'HP:0001681', (119, 134))
172223	28981082	For patients with TNM stage I, high CRP level was significantly associated with lower OS in the training cohort (median OS (95% CI) for low CRP (n=74) vs. high CRP (n=30): 39 (34.7-44.4) vs. 25 (16.7-33.6) months; P=0.0003; Figure 1a).	('CRP', 'Gene', (36, 39))	('CRP', 'Gene', (160, 163))	('OS', 'Chemical', '-', (86, 88))	('CRP', 'Gene', '1401', (36, 39))	('TNM', 'Gene', '10178', (18, 21))	('CRP', 'Gene', '1401', (160, 163))	('high CRP level', 'Phenotype', 'HP:0011227', (31, 45))	('CRP', 'Gene', (140, 143))	('low', 'Var', (136, 139))	('lower', 'NegReg', (80, 85))	('patients', 'Species', '9606', (4, 12))	('OS', 'Chemical', '-', (120, 122))	('CRP', 'Gene', '1401', (140, 143))	('TNM', 'Gene', (18, 21))
172224	28981082	Moreover, the same was true in the validation cohort (median OS (95% CI) for low CRP (n=38) vs. high CRP (n=18): 37(30.4-43.3) vs. 22 (14.9-30.0) months; P=0.002; Figure 1b).	('low', 'Var', (77, 80))	('CRP', 'Gene', (101, 104))	('CRP', 'Gene', (81, 84))	('CRP', 'Gene', '1401', (101, 104))	('CRP', 'Gene', '1401', (81, 84))	('OS', 'Chemical', '-', (61, 63))
172225	28981082	For patients in TNM II and III stages, high CRP level was significantly associated with lower OS in the training cohort (median OS (95% CI) for low CRP (n=74) vs. high CRP (n=30): 24 (16.7-31.3) vs. 9 (3.5-14.5) months; P=0.0304; Figure 1c).	('TNM', 'Gene', (16, 19))	('high', 'Var', (39, 43))	('CRP', 'Gene', (148, 151))	('CRP', 'Gene', '1401', (148, 151))	('OS', 'Chemical', '-', (94, 96))	('CRP', 'Gene', (44, 47))	('OS', 'Chemical', '-', (128, 130))	('CRP', 'Gene', '1401', (44, 47))	('CRP', 'Gene', (168, 171))	('TNM', 'Gene', '10178', (16, 19))	('patients', 'Species', '9606', (4, 12))	('low', 'Var', (144, 147))	('CRP', 'Gene', '1401', (168, 171))	('high CRP level', 'Phenotype', 'HP:0011227', (39, 53))
172231	28981082	In the training cohort, patients with high CRP level were significantly associated with lower OS (median OS (95% CI) for low CRP (n=96) vs. high CRP (n=47): 37 (32.4-41.5) vs. 28 (21.4-35.6) months; P=0.0018; Figure 2a) among those patients with vascular invasion.	('CRP', 'Gene', (125, 128))	('CRP', 'Gene', '1401', (145, 148))	('OS', 'Chemical', '-', (94, 96))	('patients', 'Species', '9606', (232, 240))	('CRP', 'Gene', '1401', (125, 128))	('CRP', 'Gene', (43, 46))	('high', 'Var', (38, 42))	('high CRP level', 'Phenotype', 'HP:0011227', (38, 52))	('CRP', 'Gene', '1401', (43, 46))	('OS', 'Chemical', '-', (105, 107))	('patients', 'Species', '9606', (24, 32))	('lower', 'NegReg', (88, 93))	('CRP', 'Gene', (145, 148))
172233	28981082	In patients without vascular invasion, patients with high CRP level were also significantly associated with lower OS in both the training cohort (median OS (95% CI) for low CRP (n=9) vs. high CRP (n=12): 24(13.0-35.0) vs. 6 (4.3-7.7) months; P=0.0006; Figure 2c) and the validation cohort (median OS (95% CI) for low CRP (n=11) vs. high CRP (n=4): 33 (22.0-43.9) vs. 7 (5.5-8.0) months; P=0.002; Figure 2d).	('CRP', 'Gene', '1401', (317, 320))	('high', 'Var', (53, 57))	('CRP', 'Gene', (173, 176))	('CRP', 'Gene', '1401', (192, 195))	('patients', 'Species', '9606', (39, 47))	('CRP', 'Gene', '1401', (337, 340))	('OS', 'Chemical', '-', (153, 155))	('OS', 'Chemical', '-', (114, 116))	('CRP', 'Gene', '1401', (173, 176))	('high CRP level', 'Phenotype', 'HP:0011227', (53, 67))	('CRP', 'Gene', (192, 195))	('patients', 'Species', '9606', (3, 11))	('lower', 'NegReg', (108, 113))	('OS', 'Chemical', '-', (297, 299))	('CRP', 'Gene', (58, 61))	('CRP', 'Gene', '1401', (58, 61))	('CRP', 'Gene', (317, 320))	('CRP', 'Gene', (337, 340))
172243	28981082	In the training cohort, patients with high PPS value were significantly associated with dismal OS (median OS (95% CI) for PPS 0 (n=84): 39 (34.5-43.9); median OS (95% CI) for PPS 1 (n=52): 25 (5.3-44.6); median OS for PPS 2 (n=18): 7(2.8-11.2); 0 vs. 1, P=0.001; 0 vs. 2, P<0.0001; 1 vs. 2, P=0.006; Figure 3a).	('PPS 2', 'Gene', (218, 223))	('PPS', 'Var', (43, 46))	('PPS', 'Chemical', '-', (218, 221))	('PPS', 'Chemical', '-', (43, 46))	('OS', 'Chemical', '-', (159, 161))	('associated', 'Reg', (72, 82))	('PPS 1', 'Gene', (175, 180))	('OS', 'Chemical', '-', (211, 213))	('high PPS', 'Var', (38, 46))	('PPS', 'Chemical', '-', (175, 178))	('PPS', 'Chemical', '-', (122, 125))	('patients', 'Species', '9606', (24, 32))	('OS', 'Chemical', '-', (95, 97))	('PPS 1', 'Gene', '3664', (175, 180))	('PPS 2', 'Gene', '54101', (218, 223))	('OS', 'Chemical', '-', (106, 108))	('dismal OS', 'Disease', (88, 97))
172260	28981082	If chronic inflammation, as measured by the CRP level, contributes to aggravating cancer, the survival of ICC patients with high CRP level may potentially be improved by intervening against chronic inflammation, such as COX inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('chronic inflammation', 'Disease', (190, 210))	('improved', 'PosReg', (158, 166))	('chronic inflammation', 'Disease', 'MESH:D007249', (190, 210))	('COX', 'Gene', (220, 223))	('CRP', 'Gene', (44, 47))	('patients', 'Species', '9606', (110, 118))	('CRP', 'Gene', (129, 132))	('chronic inflammation', 'Disease', 'MESH:D007249', (3, 23))	('cancer', 'Disease', (82, 88))	('CRP', 'Gene', '1401', (44, 47))	('chronic inflammation', 'Disease', (3, 23))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CRP', 'Gene', '1401', (129, 132))	('COX', 'Gene', '1351', (220, 223))	('high CRP level', 'Phenotype', 'HP:0011227', (124, 138))	('high', 'Var', (124, 128))	('aggravating', 'PosReg', (70, 81))
172292	19414358	During carcinogenesis, aberrant cytokine stimuli alter cholangiocyte intracellular signaling, which contributes to the development and growth of biliary tract carcinomas.	('growth of biliary tract carcinomas', 'Disease', 'MESH:D001661', (135, 169))	('carcinomas', 'Phenotype', 'HP:0030731', (159, 169))	('contributes to', 'Reg', (100, 114))	('carcinogenesis', 'Disease', 'MESH:D063646', (7, 21))	('growth of biliary tract carcinomas', 'Disease', (135, 169))	('carcinogenesis', 'Disease', (7, 21))	('alter', 'Reg', (49, 54))	('cholangiocyte intracellular signaling', 'MPA', (55, 92))	('aberrant', 'Var', (23, 31))
172299	19414358	PTGS2 is up-regulated in murine and rat models of biliary adenocarcinoma, while the antisense depletion of PTGS2 has been observed to inhibit tumor cell proliferation.	('biliary adenocarcinoma', 'Disease', 'MESH:D000230', (50, 72))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('PTGS2', 'Gene', (0, 5))	('rat', 'Species', '10116', (160, 163))	('biliary adenocarcinoma', 'Disease', (50, 72))	('antisense depletion', 'Var', (84, 103))	('rat', 'Species', '10116', (36, 39))	('tumor', 'Disease', (142, 147))	('inhibit', 'NegReg', (134, 141))	('PTGS2', 'Gene', (107, 112))	('up-regulated', 'PosReg', (9, 21))	('murine', 'Species', '10090', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
172313	19414358	However, mutations in TGFBR1 (TGF beta receptor 1) and SMAD4 (alias DPC4) alter TGFB1 signaling in cholangiocarcinoma cells, allowing them to escape from TGFB1 tumor suppression.	('alter', 'Reg', (74, 79))	('mutations', 'Var', (9, 18))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (99, 117))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cholangiocarcinoma', 'Disease', (99, 117))	('TGF beta receptor 1', 'Gene', '7046', (30, 49))	('SMAD4', 'Gene', (55, 60))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (99, 117))	('TGFBR1', 'Gene', '7046', (22, 28))	('TGFBR1', 'Gene', (22, 28))	('alias', 'Disease', 'None', (62, 67))	('TGFB1', 'Gene', '7040', (154, 159))	('TGFB1', 'Gene', (154, 159))	('signaling', 'MPA', (86, 95))	('DPC4', 'Gene', (68, 72))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('alias', 'Disease', (62, 67))	('TGFB1', 'Gene', '7040', (80, 85))	('TGF beta receptor 1', 'Gene', (30, 49))	('TGFB1', 'Gene', (80, 85))	('escape', 'MPA', (142, 148))	('DPC4', 'Gene', '4089', (68, 72))
172314	19414358	SMAD4 is an important component of the TGFB1 pathway, and mutations causing loss of its expression have been described in biliary malignancies, particularly extrahepatic cholangiocarcinoma.	('mutations', 'Var', (58, 67))	('loss', 'NegReg', (76, 80))	('biliary malignancies', 'Disease', (122, 142))	('extrahepatic cholangiocarcinoma', 'Disease', (157, 188))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (157, 188))	('biliary malignancies', 'Disease', 'MESH:D009369', (122, 142))	('TGFB1', 'Gene', '7040', (39, 44))	('described', 'Reg', (109, 118))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (170, 188))	('expression', 'MPA', (88, 98))	('TGFB1', 'Gene', (39, 44))
172315	19414358	SMAD4 and PTEN are tumor suppressor genes that function synergistically in cholangiocarcinogenesis, and their disruption in a mouse model resulted in the development of biliary malignancies.	('mouse', 'Species', '10090', (126, 131))	('carcinogenesis', 'Disease', (84, 98))	('biliary malignancies', 'Disease', (169, 189))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('SMAD4', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('biliary malignancies', 'Disease', 'MESH:D009369', (169, 189))	('PTEN', 'Gene', (10, 14))	('PTEN', 'Gene', '19211', (10, 14))	('carcinogenesis', 'Disease', 'MESH:D063646', (84, 98))	('resulted in', 'Reg', (138, 149))	('disruption', 'Var', (110, 120))
172320	19414358	Abnormalities of this mechanism promote tumorigenesis because mutated cholangiocytes may subsequently result in malignancy.	('Abnormalities', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('result in', 'Reg', (102, 111))	('malignancy', 'Disease', 'MESH:D009369', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('promote', 'PosReg', (32, 39))	('malignancy', 'Disease', (112, 122))	('mutated', 'Var', (62, 69))
172321	19414358	The inhibition of apoptosis in cholangiocarcinoma has been linked to increased BCL2 expression, KRAS mutation, and/or TP53 deregulation.	('deregulation', 'Var', (123, 135))	('BCL2', 'Gene', '596', (79, 83))	('KRAS', 'Gene', '3845', (96, 100))	('increased', 'PosReg', (69, 78))	('cholangiocarcinoma', 'Disease', (31, 49))	('BCL2', 'Gene', (79, 83))	('TP53', 'Gene', '7157', (118, 122))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (31, 49))	('TP53', 'Gene', (118, 122))	('apoptosis', 'CPA', (18, 27))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (31, 49))	('expression', 'MPA', (84, 94))	('mutation', 'Var', (101, 109))	('inhibition', 'NegReg', (4, 14))	('KRAS', 'Gene', (96, 100))
172323	19414358	Point mutations of the KRAS proto-oncogene are frequently present in cholangiocarcinoma specimens arising near the hepatic hilum, especially when there is lymph node metastasis.	('present', 'Reg', (58, 65))	('cholangiocarcinoma', 'Disease', (69, 87))	('KRAS', 'Gene', (23, 27))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (69, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (69, 87))	('Point mutations', 'Var', (0, 15))	('KRAS', 'Gene', '3845', (23, 27))
172324	19414358	Mutations of the tumor suppressor TP53 have also been described in intrahepatic cholangiocarcinomas.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('TP53', 'Gene', (34, 38))	('intrahepatic cholangiocarcinomas', 'Disease', (67, 99))	('described', 'Reg', (54, 63))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (67, 99))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (80, 98))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('TP53', 'Gene', '7157', (34, 38))
172325	19414358	In addition to initiating tumor formation via mutagenesis, NO inhibits apoptosis in human cholangiocarcinoma cell lines through the nitrosylation of caspase 9.	('apoptosis', 'CPA', (71, 80))	('inhibits', 'NegReg', (62, 70))	('cholangiocarcinoma', 'Disease', (90, 108))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('nitrosylation', 'MPA', (132, 145))	('mutagenesis', 'Var', (46, 57))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (90, 108))	('human', 'Species', '9606', (84, 89))	('initiating', 'Reg', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('caspase 9', 'Gene', (149, 158))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))	('caspase 9', 'Gene', '842', (149, 158))
172327	19414358	Administration of the selective PTGS2 inhibitor celecoxib enhances apoptosis in rat cholangiocarcinoma cells, suggesting that PTGS2 deregulation may promote carcinogenesis.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('rat', 'Species', '10116', (8, 11))	('apoptosis', 'CPA', (67, 76))	('promote', 'PosReg', (149, 156))	('carcinogenesis', 'Disease', 'MESH:D063646', (157, 171))	('rat', 'Species', '10116', (80, 83))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))	('deregulation', 'Var', (132, 144))	('cholangiocarcinoma', 'Disease', (84, 102))	('celecoxib', 'Chemical', 'MESH:D000068579', (48, 57))	('carcinogenesis', 'Disease', (157, 171))	('enhances', 'PosReg', (58, 66))	('PTGS2', 'Gene', (126, 131))
172329	19414358	Mutations of either KRAS or BRAF are frequently encountered in cholangiocarcinogenesis.	('KRAS', 'Gene', '3845', (20, 24))	('BRAF', 'Gene', '673', (28, 32))	('encountered', 'Reg', (48, 59))	('Mutations', 'Var', (0, 9))	('carcinogenesis', 'Disease', 'MESH:D063646', (72, 86))	('BRAF', 'Gene', (28, 32))	('carcinogenesis', 'Disease', (72, 86))	('KRAS', 'Gene', (20, 24))
172359	19414358	Putative molecular targets such as PTGS2 and NOS2 inhibitors can potentially affect the incidence and growth of cholangiocarcinoma when used as prophylactic and therapeutic options, respectively.	('inhibitors', 'Var', (50, 60))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 130))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('PTGS2', 'Gene', (35, 40))	('incidence', 'MPA', (88, 97))	('growth', 'MPA', (102, 108))	('affect', 'Reg', (77, 83))	('cholangiocarcinoma', 'Disease', (112, 130))	('NOS2', 'Gene', (45, 49))
172427	31859916	The presence of extrahepatic stones is classified as type E, with normal sphincter of Oddi (Ea), relaxation of the sphincter of Oddi (Eb), or stricture of the sphincter of Oddi (Ec).	('stricture of the sphincter of Oddi', 'Phenotype', 'HP:0012441', (142, 176))	('sphincter of Oddi', 'Disease', (159, 176))	('sphincter of Oddi', 'Disease', 'MESH:D046628', (73, 90))	('sphincter of Oddi', 'Disease', (115, 132))	('stricture', 'Var', (142, 151))	('sphincter of Oddi', 'Disease', 'MESH:D046628', (159, 176))	('sphincter of Oddi', 'Disease', 'MESH:D046628', (115, 132))	('extrahepatic stones', 'Disease', 'MESH:D001651', (16, 35))	('extrahepatic stones', 'Disease', (16, 35))	('stricture of the sphincter', 'Phenotype', 'HP:0002839', (142, 168))	('sphincter of Oddi', 'Disease', (73, 90))
172476	29784024	According to the seventh edition of the TNM staging system of the Union for International Cancer Control, the patient's disease was diagnosed as distal cholangiocarcinoma, T3N1M0, stage IIB.	('T3N1M0', 'Var', (172, 178))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (152, 170))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (152, 170))	('cholangiocarcinoma', 'Disease', (152, 170))	('patient', 'Species', '9606', (110, 117))	('Cancer', 'Phenotype', 'HP:0002664', (90, 96))
172520	27267998	An average of 44.8 somatic mutations was detected per Mb in the genome of the printing workers' cholangiocarcinoma tissues, approximately 30-fold higher than that found in control common cholangiocarcinoma tissues.	('mutations', 'Var', (27, 36))	('higher', 'PosReg', (146, 152))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (187, 205))	('cholangiocarcinoma', 'Disease', (96, 114))	('cholangiocarcinoma', 'Disease', (187, 205))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (187, 205))
172521	27267998	Furthermore, C:G-to-T:A transitions with substantial strand bias as well as unique trinucleotide mutational changes of GpCpY to GpTpY and NpCpY to NpTpY or NpApY were predominant in all of the printing workers' cholangiocarcinoma genomes.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (211, 229))	('NpCpY', 'Var', (138, 143))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (211, 229))	('trinucleotide', 'Chemical', '-', (83, 96))	('GpCpY', 'Gene', (119, 124))	('C:G-to-T', 'Var', (13, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('changes', 'Var', (108, 115))	('cholangiocarcinoma', 'Disease', (211, 229))
172581	27267998	Notably, the number of INDELs was significantly smaller than the number of SNVs in the printing worker cholangiocarcinoma cases.	('cholangiocarcinoma', 'Disease', (103, 121))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (103, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('INDELs', 'Var', (23, 29))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (103, 121))
172584	27267998	Each of the printing workers' cholangiocarcinoma had amino acid-altering mutations in two to six genes (Table 3).	('amino acid-altering mutations', 'Var', (53, 82))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (30, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (30, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('cholangiocarcinoma', 'Disease', (30, 48))
172585	27267998	Among the mutations detected in case 1, we confirmed mutations in ARID1A, BRAF, CDKN2A and MLL3 by Sanger sequencing (Supplementary Table 1 and Supplementary Figure 1, available at Carcinogenesis Online).	('CDKN2A', 'Gene', '1029', (80, 86))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('MLL3', 'Gene', (91, 95))	('ARID1A', 'Gene', '8289', (66, 72))	('mutations', 'Var', (53, 62))	('ARID1A', 'Gene', (66, 72))	('MLL3', 'Gene', '58508', (91, 95))	('CDKN2A', 'Gene', (80, 86))
172586	27267998	We next analyzed the single-nucleotide substitution patterns in the printing worker cholangiocarcinoma cases and found that C:G-to-T:A transitions were predominant, among the somatic SNVs, followed by C:G to A:T transversion.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('cholangiocarcinoma', 'Disease', (84, 102))	('C:G-to-T:A', 'Var', (124, 134))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
172588	27267998	In all of the printing workers' cholangiocarcinomas, a substantial difference in the prevalence of mutations between the sense and antisense strands was observed for the C:G-to-T:A transition, whereas no significant difference was detected in the control cholangiocarcinoma cases (Figure 1C).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (32, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (32, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('cholangiocarcinoma', 'Disease', (255, 273))	('cholangiocarcinomas', 'Disease', (32, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (255, 273))	('mutations', 'Var', (99, 108))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (255, 273))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (32, 51))	('cholangiocarcinoma', 'Disease', (32, 50))	('C:G-to-T:A', 'Var', (170, 180))
172598	27267998	In contrast, the average mutation rate of clones exposed to 3500 ppm of DCM (n = 47) was 0.5/Mb, which is significantly higher than that for the non-exposed control (P < 0.01, Student's t-test), and C:G to A:T transversions were predominant (46.6% of total SNVs), followed by C:G-to-T:A transitions (44.1% of total SNVs) (Figure 3A and B).	('DCM', 'Chemical', 'MESH:D008752', (72, 75))	('higher', 'PosReg', (120, 126))	('C:G-to-T:A', 'Var', (276, 286))	('C:G to A:T', 'Var', (199, 209))
172600	27267998	Clones exposed to 1,2-DCP harbored NpCpC to NpTpC changes (Figure 3C, indicated by the asterisks), and these changes were more remarkable at 6000 ppm than at 3000 ppm (Supplementary Figure 2, available at Carcinogenesis Online).	('6000 ppm', 'Var', (141, 149))	('1,2-DCP', 'Chemical', 'MESH:C004765', (18, 25))	('NpTpC', 'Gene', (44, 49))
172602	27267998	With DCM exposure, the clones harbored broad changes in C:G to A:T and C:G to T:A mutations, and no specific trinucleotide mutational patterns were observed (Figure 3C).	('trinucleotide', 'Chemical', '-', (109, 122))	('C:G', 'Var', (71, 74))	('changes', 'Reg', (45, 52))	('DCM', 'Chemical', 'MESH:D008752', (5, 8))	('C:G', 'MPA', (56, 59))
172609	27267998	Similarly, in NCC-CC1 cells, C:G to T:A transitions and C:G to A:T transversions were observed to predominate (59.6% of total SNVs) (Supplementary Figure 4B, available at Carcinogenesis Online), and the trinucleotide signatures observed in the printing workers' cholangiocarcinomas were not recapitulated (Supplementary Figure 4C, available at Carcinogenesis Online).	('carcinomas', 'Phenotype', 'HP:0030731', (271, 281))	('cholangiocarcinomas', 'Disease', (262, 281))	('trinucleotide', 'Chemical', '-', (203, 216))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (262, 281))	('C:G to T', 'Var', (29, 37))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (262, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))
172610	27267998	The representative characteristic mutational profile, including a high somatic mutation burden, substantial strand bias in C:G to T:A mutations and unique trinucleotide mutational changes (GpCpY to GpTpY and NpCpY to NpTpY or NpApY), shared in all of the investigated printing workers' cholangiocarcinomas suggests that the patients might have been exposed to a common strong mutagen and that these conditions might increase the chance for mutations in cholangiocarcinoma driver genes.	('mutations', 'Var', (440, 449))	('patients', 'Species', '9606', (324, 332))	('cholangiocarcinoma', 'Disease', (453, 471))	('cholangiocarcinomas', 'Disease', (286, 305))	('cholangiocarcinoma', 'Disease', (286, 304))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (453, 471))	('trinucleotide', 'Chemical', '-', (155, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (295, 304))	('carcinomas', 'Phenotype', 'HP:0030731', (295, 305))	('carcinoma', 'Phenotype', 'HP:0030731', (462, 471))	('mutations', 'Var', (134, 143))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (286, 305))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (286, 304))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (453, 471))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (286, 304))	('C:G to T', 'Gene', (123, 131))
172611	27267998	Mutations with transcriptional strand bias are known to occur in cancer genomes as a result of exposure to abundant mutagens and the formation of bulky DNA adducts, such as in smoking-related lung cancer and ultraviolet-associated melanoma.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('lung cancer', 'Disease', (192, 203))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('cancer', 'Disease', (197, 203))	('melanoma', 'Disease', (231, 239))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung cancer', 'Disease', 'MESH:D008175', (192, 203))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
172615	27267998	recently reported that co-exposure to 1,2-DCP and DCM induced an increase in mutations in a mouse gpt mutation model.	('increase', 'PosReg', (65, 73))	('mutations', 'MPA', (77, 86))	('mutation', 'Var', (102, 110))	('gpt', 'Gene', '76282', (98, 101))	('DCM', 'Var', (50, 53))	('gpt', 'Gene', (98, 101))	('DCM', 'Chemical', 'MESH:D008752', (50, 53))	('mouse', 'Species', '10090', (92, 97))	('1,2-DCP', 'Chemical', 'MESH:C004765', (38, 45))
172616	27267998	However, they detected mutations predominantly at A:T pairs rather than C:G pairs, in contrast to the mutations observed in the printing workers' cholangiocarcinomas in this study.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (146, 164))	('detected', 'Reg', (14, 22))	('cholangiocarcinomas', 'Disease', (146, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('mutations', 'Var', (23, 32))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (146, 165))	('A:T pairs', 'Var', (50, 59))
172626	27267998	S-(chloromethyl)glutathione from DCM is involved in mutagenesis by forming guanine adducts, inducing C:G to A:T and C:G to T:A substitutions, in bacteria and mammalian cells.	('C:G to A:T', 'Var', (101, 111))	('C:G to T:A', 'Var', (116, 126))	('S-(chloromethyl)glutathione', 'Chemical', '-', (0, 27))	('guanine', 'Chemical', 'MESH:D006147', (75, 82))	('DCM', 'Chemical', 'MESH:D008752', (33, 36))	('inducing', 'Reg', (92, 100))	('mammalian', 'Species', '9606', (158, 167))
172636	27267998	They reported that acquired mutations caused by overexpression of activation-induced cytidine deaminase (AID) in immortalized human TP53 knock-in mouse fibroblasts were predominantly C:G to T:A substitutions with a GpCp(A/C/T) to GpTp(A/C/T) trinucleotide signature.	('human', 'Species', '9606', (126, 131))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('AID', 'Gene', (105, 108))	('mouse', 'Species', '10090', (146, 151))	('AID', 'Gene', '57379', (105, 108))	('overexpression', 'PosReg', (48, 62))	('activation-induced cytidine deaminase', 'Gene', (66, 103))	('activation-induced cytidine deaminase', 'Gene', '57379', (66, 103))	('C:G to T:A', 'Var', (183, 193))	('trinucleotide', 'Chemical', '-', (242, 255))
172638	27267998	In addition, the aberrant expression of AID induces lymphoid and nonlymphoid malignancies with accumulated mutations in known cancer-related genes in animal models.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutations', 'Var', (107, 116))	('lymphoid and nonlymphoid malignancies', 'Disease', 'MESH:D008223', (52, 89))	('aberrant expression', 'Var', (17, 36))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('AID', 'Gene', '57379', (40, 43))	('AID', 'Gene', (40, 43))	('induces', 'Reg', (44, 51))
172650	27267998	1,2-DCP 1,2-dichloropropane AID activation-induced cytidine deaminase COSMIC Catalogue of Somatic Mutations in Cancer DCM dichloromethane GSTT1 glutathione S-transferase theta 1 HEK293 human embryonic kidney 293 IARC The International Agency for Research on Cancer ICGC The International Cancer Genome Consortium INDELs insertions and deletions SNVs single-nucleotide variants	('AID', 'Gene', '57379', (28, 31))	('AID', 'Gene', (28, 31))	('activation-induced cytidine deaminase', 'Gene', (32, 69))	('dichloromethane', 'Chemical', 'MESH:D008752', (122, 137))	('human', 'Species', '9606', (185, 190))	('activation-induced cytidine deaminase', 'Gene', '57379', (32, 69))	('Cancer', 'Phenotype', 'HP:0002664', (288, 294))	('HEK293', 'CellLine', 'CVCL:0045', (178, 184))	('DCM', 'Chemical', 'MESH:D008752', (118, 121))	('1,2-dichloropropane', 'Chemical', 'MESH:C004765', (8, 27))	('Cancer', 'Phenotype', 'HP:0002664', (258, 264))	('GSTT1', 'Gene', (138, 143))	('embryonic kidney', 'Disease', (191, 207))	('GSTT1', 'Gene', '2952', (138, 143))	('INDELs insertions', 'Var', (313, 330))	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('1,2-DCP', 'Chemical', 'MESH:C004765', (0, 7))	('embryonic kidney', 'Disease', 'MESH:D007674', (191, 207))
172659	21087480	EGFR or its signal transducers are mutated in 26.5% of cases: 4 samples bear mutations of PI3K (8.2%), 3 cases (6.1%) in K-RAS, 4 (8.2%) in B-RAF, and 2 cases (4.1%) in PTEN, but no loss of PTEN expression is detected.	('B-RAF', 'Gene', '673', (140, 145))	('EGFR', 'Gene', (0, 4))	('K-RAS', 'Gene', '3845', (121, 126))	('PTEN', 'Gene', (190, 194))	('PTEN', 'Gene', (169, 173))	('PTEN', 'Gene', '5728', (190, 194))	('B-RAF', 'Gene', (140, 145))	('K-RAS', 'Gene', (121, 126))	('PTEN', 'Gene', '5728', (169, 173))	('mutations', 'Var', (77, 86))	('EGFR', 'Gene', '1956', (0, 4))	('PI3K', 'Gene', (90, 94))
172661	21087480	In EGI-1 cells, combination with gefitinib further increases the antiproliferative effect of gemcitabine.	('antiproliferative effect', 'CPA', (65, 89))	('increases', 'PosReg', (51, 60))	('gemcitabine', 'Chemical', 'MESH:C056507', (93, 104))	('gefitinib', 'Chemical', 'MESH:D000077156', (33, 42))	('combination', 'Var', (16, 27))
172671	21087480	More recently a multicenter, randomized phase III trial (the UK ABC-02 trial) recruiting 410 patients with advanced BTCs demonstrated that the median progression free survival was greater with the association of Gem with cisplatin than Gem alone (8 vs. 5 months).	('progression free survival', 'CPA', (150, 175))	('Gem', 'Chemical', 'MESH:C056507', (212, 215))	('cisplatin', 'Chemical', 'MESH:D002945', (221, 230))	('BTC', 'Gene', '685', (116, 119))	('BTC', 'Gene', (116, 119))	('greater', 'PosReg', (180, 187))	('Gem', 'Var', (212, 215))	('association', 'Interaction', (197, 208))	('patients', 'Species', '9606', (93, 101))	('Gem', 'Chemical', 'MESH:C056507', (236, 239))
172678	21087480	On these bases, several lines of evidence may point to the usefulness of EGFR targeting as an adjuvant therapy in cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (114, 132))	('targeting', 'Var', (78, 87))	('EGFR', 'Gene', '1956', (73, 77))	('EGFR', 'Gene', (73, 77))	('cholangiocarcinoma', 'Disease', (114, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (114, 132))
172679	21087480	We previously reported that 15% of biliary tree and gallbladder carcinomas had EGFR gene mutations in the tyrosine kinase (TK) domain and that the mutations led to activation of one or both of the EGFR signal transduction pathways.	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('biliary tree', 'Disease', (35, 47))	('gallbladder carcinomas', 'Disease', (52, 74))	('activation', 'PosReg', (164, 174))	('mutations in', 'Var', (89, 101))	('EGFR', 'Gene', '1956', (197, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('tyrosine', 'Chemical', 'MESH:D014443', (106, 114))	('gallbladder carcinomas', 'Disease', 'MESH:D005706', (52, 74))	('EGFR', 'Gene', (197, 201))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))
172680	21087480	Some of these mutations are identical to those previously reported to confer sensitivity to some TK inhibitors like erlotinib and gefitinib in non small cell lung cancer (NSCLC).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (147, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('small cell lung cancer', 'Disease', (147, 169))	('erlotinib', 'Chemical', 'MESH:D000069347', (116, 125))	('gefitinib', 'Chemical', 'MESH:D000077156', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('NSCLC', 'Disease', (171, 176))	('small cell lung cancer', 'Disease', 'MESH:D055752', (147, 169))	('mutations', 'Var', (14, 23))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
172681	21087480	However, these inhibitors are ineffective if used in the presence of mutations in EGFR downstream transducers, such as K-RAS, B-RAF, PI3K or phosphatase and tensin homolog deleted on chromosome 10 (PTEN).	('mutations', 'Var', (69, 78))	('EGFR', 'Gene', (82, 86))	('B-RAF', 'Gene', '673', (126, 131))	('K-RAS', 'Gene', (119, 124))	('PTEN', 'Gene', (198, 202))	('B-RAF', 'Gene', (126, 131))	('PTEN', 'Gene', '5728', (198, 202))	('EGFR', 'Gene', '1956', (82, 86))	('K-RAS', 'Gene', '3845', (119, 124))
172682	21087480	In NSCLC, increased copy number of the HER2 gene is associated with gefitinib sensitivity in EGFR-positive patients, thus supporting the use of HER2 FISH analysis for selection of patients for TK inhibitor (TKI) therapies.	('NSCLC', 'Disease', (3, 8))	('gefitinib', 'Chemical', 'MESH:D000077156', (68, 77))	('EGFR', 'Gene', '1956', (93, 97))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('associated', 'Reg', (52, 62))	('HER2', 'Gene', (39, 43))	('EGFR', 'Gene', (93, 97))	('gefitinib sensitivity', 'MPA', (68, 89))	('patients', 'Species', '9606', (180, 188))	('copy number', 'Var', (20, 31))	('HER2', 'Gene', (144, 148))	('HER2', 'Gene', '2064', (39, 43))	('HER2', 'Gene', '2064', (144, 148))	('patients', 'Species', '9606', (107, 115))	('increased', 'PosReg', (10, 19))
172684	21087480	In addition, in vitro experiments have demonstrated that PI3K oncogenic mutations promote sustained PI3K signaling, conferring resistance to gefitinib-induced apoptosis.	('mutations', 'Var', (72, 81))	('PI3K', 'Gene', (57, 61))	('promote', 'PosReg', (82, 89))	('resistance to gefitinib-induced apoptosis', 'MPA', (127, 168))	('gefitinib', 'Chemical', 'MESH:D000077156', (141, 150))	('PI3K signaling', 'Pathway', (100, 114))	('sustained', 'MPA', (90, 99))
172685	21087480	The tumor suppressor gene PTEN, that counteracts the activity of PI3K, was frequently mutated in high-grade glioblastoma, melanoma, prostate, and endometrium cancers.	('prostate', 'Disease', (132, 140))	('tumor', 'Disease', (4, 9))	('mutated', 'Var', (86, 93))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('glioblastoma', 'Disease', (108, 120))	('PTEN', 'Gene', (26, 30))	('glioblastoma', 'Disease', 'MESH:D005909', (108, 120))	('melanoma', 'Disease', (122, 130))	('PTEN', 'Gene', '5728', (26, 30))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))
172687	21087480	In vitro models demonstrated that the re-establishment of PTEN expression restores sensitivity to gefitinib.	('PTEN', 'Gene', '5728', (58, 62))	('restores', 'PosReg', (74, 82))	('sensitivity to gefitinib', 'MPA', (83, 107))	('gefitinib', 'Chemical', 'MESH:D000077156', (98, 107))	('expression', 'Var', (63, 73))	('PTEN', 'Gene', (58, 62))
172703	21087480	Sorafenib is a multikinase inhibitor that blocks tumor cell proliferation and angiogenesis by inhibiting serine/threonine kinases (c-RAF, mutant and wild-type B-RAF) as well as the receptor tyrosine kinases vascular endothelial growth factor receptor 2 (VEGFR2), VEGFR3, platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-KIT.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('VEGFR3', 'Gene', '2324', (263, 269))	('c-RAF', 'Gene', (131, 136))	('mutant', 'Var', (138, 144))	('tyrosine', 'Chemical', 'MESH:D014443', (190, 198))	('platelet-derived growth factor receptor', 'Gene', '5159', (271, 310))	('platelet-derived growth factor receptor', 'Gene', (271, 310))	('Ret', 'Gene', (326, 329))	('vascular endothelial growth factor receptor 2', 'Gene', (207, 252))	('blocks', 'NegReg', (42, 48))	('VEGFR2', 'Gene', (254, 260))	('B-RAF', 'Gene', '673', (159, 164))	('VEGFR2', 'Gene', '3791', (254, 260))	('serine/threonine kinases', 'MPA', (105, 129))	('c-RAF', 'Gene', '5894', (131, 136))	('Ret', 'Gene', '5979', (326, 329))	('FLT3', 'Gene', (320, 324))	('angiogenesis', 'CPA', (78, 90))	('tumor', 'Disease', (49, 54))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('FLT3', 'Gene', '2322', (320, 324))	('VEGFR3', 'Gene', (263, 269))	('B-RAF', 'Gene', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('c-KIT', 'Gene', (335, 340))	('vascular endothelial growth factor receptor 2', 'Gene', '3791', (207, 252))	('c-KIT', 'Gene', '3815', (335, 340))	('PDGFR', 'Gene', (312, 317))	('PDGFR', 'Gene', '5159', (312, 317))	('inhibiting', 'NegReg', (94, 104))
172720	21087480	Positive immunostaining was scored + when present in more than 40% of cells and attributed to nuclear staining for p-MAPK and cytoplasmatic with a faint membranous staining for p-Akt.	('Akt', 'Gene', '207', (179, 182))	('p-MAPK', 'Var', (115, 121))	('Akt', 'Gene', (179, 182))
172731	21087480	The R statistical language adaptation of Fisher exact test for non 2 x 2 contingency tables was performed in order to detect any significant association between histotype and the categorical variables describing the presence of mutations in EGFR or in specific signal transducers, the expression of EGFR, HER2, TGF-alpha, p-MAPK, p-Akt and PTEN.	('p-MAPK', 'Gene', (322, 328))	('TGF-alpha', 'Gene', '7039', (311, 320))	('EGFR', 'Gene', '1956', (299, 303))	('EGFR', 'Gene', '1956', (241, 245))	('EGFR', 'Gene', (299, 303))	('Akt', 'Gene', '207', (332, 335))	('mutations', 'Var', (228, 237))	('TGF-alpha', 'Gene', (311, 320))	('EGFR', 'Gene', (241, 245))	('HER2', 'Gene', (305, 309))	('Akt', 'Gene', (332, 335))	('HER2', 'Gene', '2064', (305, 309))	('PTEN', 'Gene', (340, 344))	('PTEN', 'Gene', '5728', (340, 344))
172764	21087480	Sample number 39 showed a novel EGFR mutation (TGG to TAG) consistent with a nonsense substitution (W817Stop), leading to the production of a truncated protein lacking the intracytoplasmatic tail, which contains the interaction sites with the signal transducer PI3K.	('W817Stop', 'Mutation', 'p.W817X', (100, 108))	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'Gene', (32, 36))	('mutation', 'Var', (37, 45))
172766	21087480	The mutational analysis of the EGFR/HER2 intracellular effectors identified mutations in K-RAS, PI3K, B-RAF and PTEN (table 4).	('EGFR', 'Gene', '1956', (31, 35))	('mutations', 'Var', (76, 85))	('B-RAF', 'Gene', '673', (102, 107))	('K-RAS', 'Gene', (89, 94))	('HER2', 'Gene', (36, 40))	('B-RAF', 'Gene', (102, 107))	('EGFR', 'Gene', (31, 35))	('HER2', 'Gene', '2064', (36, 40))	('PI3K', 'Gene', (96, 100))	('PTEN', 'Gene', (112, 116))	('PTEN', 'Gene', '5728', (112, 116))	('K-RAS', 'Gene', '3845', (89, 94))
172767	21087480	Three samples (6.1%) had point mutations of K-RAS (2 were the previously described G13 D substitution, ID 532, the third was a novel mutation, I24F) and 4 (8.2%) had the V600E mutation (ID 476) of B-RAF.	('V600E', 'Mutation', 'rs113488022', (170, 175))	('G13 D', 'Mutation', 'rs112445441', (83, 88))	('B-RAF', 'Gene', (197, 202))	('ID 476', 'Var', (186, 192))	('I24F', 'Mutation', 'p.I24F', (143, 147))	('point mutations', 'Var', (25, 40))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('V600E', 'Var', (170, 175))	('K-RAS', 'Gene', '3845', (44, 49))	('K-RAS', 'Gene', (44, 49))	('B-RAF', 'Gene', '673', (197, 202))
172769	21087480	Namely, sample 23 had Thr to Ile substitution at codon 202 of exon 6 and Glu to Gly substitution at codon 235 of the exon 7; sample 29 had Phe to Leu substitution at codon 271 of exon 8.	('Phe to Leu substitution at codon 271', 'Mutation', 'p.F271L', (139, 175))	('Glu to Gly substitution at codon 235', 'Mutation', 'p.E235G', (73, 109))	('Thr', 'Var', (22, 25))	('Thr to Ile substitution at codon 202', 'Mutation', 'rs1085308053', (22, 58))	('Phe to Leu substitution', 'Var', (139, 162))
172770	21087480	All PTEN mutations involved codons previously found in other tumors as bearing single base deletions or mutations (ID 5856, ID 5292 and ID 5821).	('PTEN', 'Gene', '5728', (4, 8))	('involved', 'Reg', (19, 27))	('ID 5821', 'Var', (136, 143))	('tumors', 'Disease', (61, 67))	('ID 5856', 'Var', (115, 122))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('ID 5292', 'Var', (124, 131))	('mutations', 'Var', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('PTEN', 'Gene', (4, 8))
172771	21087480	In 4 cases, mutations of multiple transducers were present simultaneously: sample 22 had mutated B-RAF and K-RAS; sample 23 had mutated K-RAS, PI3K and PTEN; sample 29 had mutated EGFR, PI3K and PTEN; sample 31 had mutated EGFR, PI3K and B-RAF (table 4).	('EGFR', 'Gene', '1956', (223, 227))	('K-RAS', 'Gene', '3845', (107, 112))	('B-RAF', 'Gene', '673', (97, 102))	('PTEN', 'Gene', (195, 199))	('mutated', 'Var', (172, 179))	('K-RAS', 'Gene', (136, 141))	('EGFR', 'Gene', '1956', (180, 184))	('K-RAS', 'Gene', '3845', (136, 141))	('PTEN', 'Gene', '5728', (195, 199))	('PI3K', 'Var', (143, 147))	('B-RAF', 'Gene', '673', (238, 243))	('B-RAF', 'Gene', (97, 102))	('PTEN', 'Gene', (152, 156))	('EGFR', 'Gene', (223, 227))	('mutated', 'Var', (89, 96))	('B-RAF', 'Gene', (238, 243))	('mutated', 'Var', (128, 135))	('PTEN', 'Gene', '5728', (152, 156))	('K-RAS', 'Gene', (107, 112))	('EGFR', 'Gene', (180, 184))	('mutated', 'Var', (215, 222))
172772	21087480	The percentage of PTEN labeled nuclei in tumor samples with activating EGFR or PI3K mutations was higher than in tissues with EGFR and PI3K wild type displaying 62%+31 (score 3+) vs 39%+26 (score 2+) respectively (p = 0.032).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('activating', 'PosReg', (60, 70))	('PTEN', 'Gene', (18, 22))	('EGFR', 'Gene', (126, 130))	('tumor', 'Disease', (41, 46))	('PTEN', 'Gene', '5728', (18, 22))	('mutations', 'Var', (84, 93))	('higher', 'PosReg', (98, 104))	('PI3K', 'Gene', (79, 83))	('EGFR', 'Gene', '1956', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('EGFR', 'Gene', (71, 75))	('EGFR', 'Gene', '1956', (126, 130))
172773	21087480	In particular, in the cases with activating mutations involving EGFR and/or PI3K and not PTEN, the mean of PTEN+ cells was 80+19 (score 3+) (p = 0.002 vs wild type), suggesting that a compensatory change in the level of the phosphatase might counteract EGFR pathway activation.	('PTEN', 'Gene', (107, 111))	('PTEN', 'Gene', '5728', (107, 111))	('mutations', 'Var', (44, 53))	('EGFR', 'Gene', '1956', (253, 257))	('activating', 'PosReg', (33, 43))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('PTEN', 'Gene', (89, 93))	('PTEN', 'Gene', '5728', (89, 93))	('EGFR', 'Gene', (253, 257))	('PI3K', 'Gene', (76, 80))
172774	21087480	In agreement, the sample 39 harboring the EGFR stop codon mutation and, presumably, associated with an inactive pathway, had low PTEN expression (9% or score 0).	('EGFR', 'Gene', '1956', (42, 46))	('stop codon mutation', 'Var', (47, 66))	('EGFR', 'Gene', (42, 46))	('PTEN', 'Gene', (129, 133))	('PTEN', 'Gene', '5728', (129, 133))	('low', 'NegReg', (125, 128))
172778	21087480	EGFR mutations were more frequently observed in female gender (p = 0.04).	('observed', 'Reg', (36, 44))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
172798	21087480	In other cell lines, the best result was obtained with the chemotherapeutic agent and everolimus, highly efficient on extrahepatic cell lines, (Dm = 0.13 nM for TFK-1 and Dm = 0.57 nM for EGI-1) and gallbladder cell line (Dm = 1 nM).	('Dm = 0.57', 'Var', (171, 180))	('Dm = 0.13', 'Var', (144, 153))	('everolimus', 'Chemical', 'MESH:D000068338', (86, 96))
172802	21087480	Mutations in the EGFR TK domain were present in 15% of cases.	('Mutations', 'Var', (0, 9))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (17, 21))
172803	21087480	Furthermore, the incidence of K-RAS mutation was particularly low (6.1%).	('mutation', 'Var', (36, 44))	('K-RAS', 'Gene', '3845', (30, 35))	('K-RAS', 'Gene', (30, 35))
172805	21087480	Previous studies of K-RAS mutations in cholangiocarcinoma revealed divergent results.	('K-RAS', 'Gene', (20, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (39, 57))	('mutations', 'Var', (26, 35))	('cholangiocarcinoma', 'Disease', (39, 57))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (39, 57))	('K-RAS', 'Gene', '3845', (20, 25))
172806	21087480	A higher occurrence of K-RAS mutations was found in Japan and Germany (ranging from 39% to 54%) relative to other areas such as Thailand (from 0% to 8%) in which this tumor occurred with high frequency.	('mutations', 'Var', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('K-RAS', 'Gene', '3845', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('K-RAS', 'Gene', (23, 28))	('tumor', 'Disease', (167, 172))
172808	21087480	We observed a lower incidence of B-RAF mutations compared to that reported by Tannapfel and coworkers (8% vs. 21% respectively).	('lower', 'NegReg', (14, 19))	('B-RAF', 'Gene', '673', (33, 38))	('B-RAF', 'Gene', (33, 38))	('mutations', 'Var', (39, 48))
172809	21087480	We identified PI3K mutations in 4 cases (8.2%) and PTEN mutations in 2 cases (4.1%).	('mutations', 'Var', (56, 65))	('mutations', 'Var', (19, 28))	('PI3K', 'Gene', (14, 18))	('PTEN', 'Gene', (51, 55))	('PTEN', 'Gene', '5728', (51, 55))
172811	21087480	Namely, a total of 14 mutations were found in 8 tumor samples and only 3 samples had a single point mutation.	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mutations', 'Var', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
172814	21087480	We observed a rare frequency of PTEN mutations and we did not find any loss of PTEN protein expression in comparison with normal cholangiocytes; rather a stronger labeling intensity and a high percentage of labeled cells were significantly present in tumor cells compared to normal counterparts.	('labeling intensity', 'MPA', (163, 181))	('tumor', 'Disease', (251, 256))	('PTEN', 'Gene', (32, 36))	('stronger', 'PosReg', (154, 162))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('PTEN', 'Gene', '5728', (32, 36))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('PTEN', 'Gene', (79, 83))	('PTEN', 'Gene', '5728', (79, 83))
172815	21087480	In particular, samples displaying EGFR pathway activation due to transducer mutations had the highest percentage of PTEN-labeled cells suggesting that a preserved PTEN function might counteract the EGFR downstream pathway activation.	('mutations', 'Var', (76, 85))	('EGFR', 'Gene', (34, 38))	('PTEN', 'Gene', (163, 167))	('transducer', 'Gene', (65, 75))	('activation', 'PosReg', (47, 57))	('PTEN', 'Gene', '5728', (163, 167))	('EGFR', 'Gene', '1956', (198, 202))	('PTEN', 'Gene', (116, 120))	('EGFR', 'Gene', (198, 202))	('PTEN', 'Gene', '5728', (116, 120))	('EGFR', 'Gene', '1956', (34, 38))
172819	21087480	Furthermore, the presence of PI3K mutation and PTEN deletion in the HuH28 and TGBC1-TKB cells respectively could probably explain the resistance to these treatments.	('mutation', 'Var', (34, 42))	('PTEN', 'Gene', (47, 51))	('PTEN', 'Gene', '5728', (47, 51))	('deletion', 'Var', (52, 60))	('PI3K', 'Gene', (29, 33))
172836	21087480	Moreover, EGFR/HER2 pathway inhibitors had synergistic effect with gemcitabine treatment.	('EGFR', 'Gene', '1956', (10, 14))	('EGFR', 'Gene', (10, 14))	('HER2', 'Gene', (15, 19))	('HER2', 'Gene', '2064', (15, 19))	('inhibitors', 'Var', (28, 38))	('gemcitabine', 'Chemical', 'MESH:C056507', (67, 78))	('synergistic', 'MPA', (43, 54))
172856	29137600	However, transfusions may cause short or severe complications including allergic reactions, hemolytic reactions, and immunosuppression.	('hemolytic reaction', 'Disease', 'MESH:D004342', (92, 110))	('hemolytic reaction', 'Disease', (92, 110))	('immunosuppression', 'Disease', (117, 134))	('transfusions', 'Var', (9, 21))	('allergic reaction', 'Phenotype', 'HP:0012393', (72, 89))	('allergic reactions', 'Phenotype', 'HP:0012393', (72, 90))	('allergic reactions', 'Disease', (72, 90))	('allergic reactions', 'Disease', 'MESH:D004342', (72, 90))
172947	26155212	Portal vein embolization induces shrinkage of the embolized lobe and compensatory enlargement of the non-embolized lobe, but it does not always induce sufficient liver regeneration.	('enlargement', 'PosReg', (82, 93))	('embolized lobe', 'Disease', 'MESH:D020766', (50, 64))	('Portal vein embolization', 'Phenotype', 'HP:0030242', (0, 24))	('embolized lobe', 'Disease', 'MESH:D020766', (105, 119))	('embolized lobe', 'Disease', (50, 64))	('embolized lobe', 'Disease', (105, 119))	('shrinkage', 'NegReg', (33, 42))	('embolization', 'Var', (12, 24))
172968	21334995	Inhibition of HMG-CoA reductase results in the depletion of several important cholesterol pathway intermediates, including mevalonate, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP).	('cholesterol', 'Chemical', 'MESH:D002784', (78, 89))	('geranylgeranyl pyrophosphate', 'MPA', (168, 196))	('HMG-CoA reductase', 'Gene', '3156', (14, 31))	('mevalonate', 'Chemical', 'MESH:D008798', (123, 133))	('GGPP', 'Chemical', 'MESH:C002963', (198, 202))	('farnesyl pyrophosphate', 'MPA', (135, 157))	('geranylgeranyl pyrophosphate', 'Chemical', 'MESH:C002963', (168, 196))	('depletion of several important cholesterol', 'MPA', (47, 89))	('Inhibition', 'Var', (0, 10))	('FPP', 'Chemical', 'MESH:C004808', (159, 162))	('mevalonate', 'MPA', (123, 133))	('HMG-CoA reductase', 'Gene', (14, 31))	('farnesyl pyrophosphate', 'Chemical', 'MESH:C004808', (135, 157))
172970	21334995	Inhibition of mevalonate synthesis prevents the covalent attachment of farnesyl residues on small GTP binding proteins preventing their attachment to the cell membrane and subsequently blocks cell growth.	('farnesyl', 'Chemical', '-', (71, 79))	('attachment', 'MPA', (136, 146))	('GTP', 'Chemical', 'MESH:D006160', (98, 101))	('covalent', 'MPA', (48, 56))	('cell growth', 'CPA', (192, 203))	('farnesyl residues', 'Var', (71, 88))	('prevents', 'NegReg', (35, 43))	('blocks', 'NegReg', (185, 191))	('preventing', 'NegReg', (119, 129))	('Inhibition', 'Var', (0, 10))	('mevalonate', 'Chemical', 'MESH:D008798', (14, 24))
173054	21334995	In the present study, we demonstrate that simvastatin stimulates cholangiocarcinoma apoptosis and that this activity was closely associated with (i) decreased total cellular cholesterol, (ii) disruption of Rac1 co-localization in lipid rafts, (iii) the down regulation of Rac1 activity, and (iv) along with increased apoptosis characterized by increased numbers of annexin V-positive cholangiocytes and increased caspase activity.	('activity', 'MPA', (421, 429))	('increased', 'PosReg', (403, 412))	('annexin V', 'Gene', (365, 374))	('Rac1', 'Gene', '5879', (272, 276))	('co-localization', 'MPA', (211, 226))	('cholangiocarcinoma apoptosis', 'Disease', (65, 93))	('cholesterol', 'Chemical', 'MESH:D002784', (174, 185))	('annexin V', 'Gene', '308', (365, 374))	('Rac1', 'Gene', '5879', (206, 210))	('activity', 'MPA', (277, 285))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))	('cholangiocarcinoma apoptosis', 'Disease', 'MESH:D018281', (65, 93))	('lipid', 'Chemical', 'MESH:D008055', (230, 235))	('increased', 'PosReg', (344, 353))	('decreased', 'NegReg', (149, 158))	('Rac1', 'Gene', (272, 276))	('simvastatin', 'Chemical', 'MESH:D019821', (42, 53))	('caspase', 'CPA', (413, 420))	('stimulates', 'PosReg', (54, 64))	('disruption', 'Var', (192, 202))	('simvastatin', 'Var', (42, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('Rac1', 'Gene', (206, 210))	('down regulation', 'NegReg', (253, 268))
173058	21334995	Overall risk of developing colorectal cancer was associated with expression of HMG-CoA reductase lacking exon 13, which suggested that patients expressing this isoform would not benefit as greatly from the protective benefits of statin utilization.	('HMG-CoA reductase', 'Gene', '3156', (79, 96))	('patients', 'Species', '9606', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('colorectal cancer', 'Disease', (27, 44))	('HMG-CoA reductase', 'Gene', (79, 96))	('expression', 'Var', (65, 75))	('colorectal cancer', 'Disease', 'MESH:D015179', (27, 44))
173064	21334995	However, simvastatin did not stimulate apoptosis in HiBEpiC suggesting that simvastatin triggers a cell death mechanism in cholangiocarcinoma cells while simply inhibiting the proliferation of HiBEpiC.	('cholangiocarcinoma', 'Disease', (123, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('cell', 'CPA', (99, 103))	('triggers', 'Reg', (88, 96))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (123, 141))	('proliferation', 'CPA', (176, 189))	('inhibiting', 'NegReg', (161, 171))	('simvastatin', 'Var', (76, 87))	('simvastatin', 'Chemical', 'MESH:D019821', (76, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (123, 141))	('simvastatin', 'Chemical', 'MESH:D019821', (9, 20))
173074	21334995	In support of this concept, we found that inhibitors of GGTase (GGTI-298) and FTase (FTI-277) also reduce the number of viable Mz-ChA-1 cells.	('GGTase', 'Gene', (56, 62))	('GGTI', 'Gene', '5229', (64, 68))	('reduce', 'NegReg', (99, 105))	('GGTI', 'Gene', (64, 68))	('FTI-277', 'Chemical', 'MESH:C096856', (85, 92))	('inhibitors', 'Var', (42, 52))
173081	21334995	In support of the role of Rac1 in the regulation of Mz-ChA-1 cell viability, treatment with simvastatin significantly depresses Rac1 activity, which was blocked by pre-treatment with cholesterol.	('cholesterol', 'Chemical', 'MESH:D002784', (183, 194))	('simvastatin', 'Chemical', 'MESH:D019821', (92, 103))	('Rac1', 'Gene', (26, 30))	('Rac1', 'Gene', '5879', (26, 30))	('Rac1', 'Gene', '5879', (128, 132))	('activity', 'MPA', (133, 141))	('Rac1', 'Gene', (128, 132))	('simvastatin', 'Var', (92, 103))	('depresses', 'NegReg', (118, 127))
173086	21334995	We demonstrated that simvastatin-induced apoptosis in cholangiocarcinoma cells was dependent upon dysregulation of the cholesterol biosynthetic pathway resulting in disruption of Rac1 activity.	('disruption', 'NegReg', (165, 175))	('dysregulation', 'Var', (98, 111))	('cholesterol biosynthetic pathway', 'Pathway', (119, 151))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (54, 72))	('Rac1', 'Gene', '5879', (179, 183))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('activity', 'MPA', (184, 192))	('cholesterol', 'Chemical', 'MESH:D002784', (119, 130))	('Rac1', 'Gene', (179, 183))	('simvastatin', 'Chemical', 'MESH:D019821', (21, 32))	('cholangiocarcinoma', 'Disease', (54, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
173089	21334995	A recent study has implicated dysregulation of the mevalonate pathway in the promotion of transformation and suggests that HMG Co-A reductase may have oncogenic potential and suggests that studies are needed to provide knowledge of HMG-CoA reductase expression in situ in cholangiocarcinoma tumors and in disease states such as primary sclerosing cholangitis, which is a risk factor for the development of cholangiocarcinoma.	('dysregulation', 'Var', (30, 43))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (272, 290))	('tumors', 'Phenotype', 'HP:0002664', (291, 297))	('cholangitis', 'Disease', 'MESH:D002761', (347, 358))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (406, 424))	('cholangiocarcinoma', 'Disease', (272, 290))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (336, 358))	('cholangitis', 'Disease', (347, 358))	('cholangiocarcinoma tumors', 'Disease', (272, 297))	('oncogenic potential', 'CPA', (151, 170))	('cholangiocarcinoma', 'Disease', (406, 424))	('HMG-CoA reductase', 'Gene', (232, 249))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (272, 290))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (406, 424))	('cholangitis', 'Phenotype', 'HP:0030151', (347, 358))	('mevalonate', 'Chemical', 'MESH:D008798', (51, 61))	('cholangiocarcinoma tumors', 'Disease', 'MESH:D018281', (272, 297))	('HMG-CoA reductase', 'Gene', '3156', (232, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (415, 424))
173128	33756162	Liver function tests demonstrated high levels of serum aspartate aminotransferase (771 IU/L), serum alanine aminotransferase (135 IU/L), serum alkaline phosphatase (5912 IU/L), serum gamma-glutamyl transpeptidase (584 IU/L), and serum total bilirubin (8 mg/dL) and low levels of serum total protein (6.1 mg/dL) and albumin (2.5 mg/dL) at readmission.	('high levels of serum aspartate', 'Phenotype', 'HP:0500159', (34, 64))	('serum alkaline phosphatase', 'MPA', (137, 163))	('albumin', 'MPA', (315, 322))	('serum total bilirubin', 'MPA', (229, 250))	('bilirubin', 'Chemical', 'MESH:D001663', (241, 250))	('high levels of serum aspartate aminotransferase', 'Phenotype', 'HP:0031956', (34, 81))	('5912 IU/L', 'Var', (165, 174))	('serum aspartate aminotransferase', 'Phenotype', 'HP:0031956', (49, 81))	('serum aspartate aminotransferase', 'MPA', (49, 81))	('alanine aminotransferase', 'Gene', (100, 124))	('alanine aminotransferase', 'Gene', '2875', (100, 124))
173302	32731493	As we can see in the figure, there is a dramatic increase in the HepG2 cell line after stretching compared to in other cells.	('HepG2', 'CellLine', 'CVCL:0027', (65, 70))	('stretching', 'Var', (87, 97))	('increase', 'PosReg', (49, 57))	('HepG2 cell line', 'CPA', (65, 80))
173360	32110489	The main inclusion criteria were as follows: age 0 to 104 years, liver cancer with cholangiocarcinoma as the main malignant cancer diagnosis, pathological types of Klatskin tumors (based on ICD-O-3 8162/3), ICCA (based on ICD-O-3 8160/3), and HCC (based on ICD-O-3 8170/3).	('Klatskin tumors', 'Disease', 'MESH:D018285', (164, 179))	('cholangiocarcinoma', 'Disease', (83, 101))	('HCC', 'Disease', 'MESH:D006528', (243, 246))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('CCA', 'Phenotype', 'HP:0030153', (208, 211))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Disease', (71, 77))	('liver cancer', 'Disease', 'MESH:D006528', (65, 77))	('ICCA', 'Disease', (207, 211))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('liver cancer', 'Phenotype', 'HP:0002896', (65, 77))	('HCC', 'Disease', (243, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('HCC', 'Phenotype', 'HP:0001402', (243, 246))	('liver cancer', 'Disease', (65, 77))	('based', 'Var', (213, 218))	('ICCA', 'Disease', 'MESH:C535533', (207, 211))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('Klatskin tumors', 'Disease', (164, 179))
173589	30288116	In accordance with the National Cholesterol Education Program, the definition of dyslipidemia was high-density lipoprotein cholesterol (HDL-C) <40 mg/dL as well as Total cholesterol, low-density lipoprotein cholesterol (LDL-C) and TG levels of >=200, >=130 and >=130 mg/dL, respectively.	('>=200', 'Var', (244, 249))	('cholesterol', 'Chemical', 'MESH:D002784', (170, 181))	('>=130', 'Var', (251, 256))	('cholesterol', 'Chemical', 'MESH:D002784', (123, 134))	('TG levels', 'MPA', (231, 240))	('high-density lipoprotein cholesterol', 'MPA', (98, 134))	('dyslipidemia', 'Disease', 'MESH:D050171', (81, 93))	('dyslipidemia', 'Phenotype', 'HP:0003119', (81, 93))	('TG', 'Chemical', '-', (231, 233))	('HDL-C', 'Chemical', '-', (136, 141))	('low-density lipoprotein cholesterol', 'MPA', (183, 218))	('>=130 mg/dL', 'Var', (261, 272))	('dyslipidemia', 'Disease', (81, 93))	('Cholesterol', 'Chemical', 'MESH:D002784', (32, 43))	('cholesterol', 'Chemical', 'MESH:D002784', (207, 218))	('Total cholesterol', 'MPA', (164, 181))
173612	30288116	The integration of HBV DNA into human chromosomes and the sustained expression of viral proteins, such as HBx proteins and large proteins (LHBs), can activate oncogenes, induce oxidative stress and cause genetic instability.	('HBV', 'Species', '10407', (19, 22))	('integration', 'Var', (4, 15))	('activate', 'PosReg', (150, 158))	('cause', 'Reg', (198, 203))	('oncogenes', 'CPA', (159, 168))	('LHBs', 'Chemical', 'MESH:D037101', (139, 143))	('HBx', 'Gene', (106, 109))	('oxidative stress', 'MPA', (177, 193))	('genetic', 'CPA', (204, 211))	('induce', 'Reg', (170, 176))	('human', 'Species', '9606', (32, 37))	('oxidative stress', 'Phenotype', 'HP:0025464', (177, 193))
173613	30288116	In addition, viruses can cause continuous hepatocyte destruction-regeneration in the inflammatory environments created by the host immune response to infection, thereby creating an environment favorable for genetic mutations leading to hepatocyte transformation.	('genetic mutations', 'Var', (207, 224))	('viruses', 'Var', (13, 20))	('infection', 'Disease', (150, 159))	('infection', 'Disease', 'MESH:D007239', (150, 159))	('hepatocyte destruction', 'Phenotype', 'HP:0001404', (42, 64))	('hepatocyte', 'MPA', (42, 52))	('leading to', 'Reg', (225, 235))	('hepatocyte', 'Disease', (236, 246))
173622	30288116	NAFLD is closely related to HCC and can sequentially promote the development of liver fibrosis, cirrhosis, end-stage liver disease and eventually HCC.	('liver disease', 'Phenotype', 'HP:0001392', (117, 130))	('cirrhosis', 'Disease', (96, 105))	('liver fibrosis', 'Disease', 'MESH:D008103', (80, 94))	('HCC', 'Phenotype', 'HP:0001402', (146, 149))	('cirrhosis', 'Phenotype', 'HP:0001394', (96, 105))	('NAFLD', 'Var', (0, 5))	('liver fibrosis', 'Phenotype', 'HP:0001395', (80, 94))	('end-stage liver disease', 'Disease', 'MESH:D058625', (107, 130))	('HCC', 'Phenotype', 'HP:0001402', (28, 31))	('cirrhosis', 'Disease', 'MESH:D005355', (96, 105))	('end-stage liver disease', 'Disease', (107, 130))	('HCC', 'Disease', (146, 149))	('liver fibrosis', 'Disease', (80, 94))	('promote', 'PosReg', (53, 60))
173625	30288116	However, in consideration of the same progenitor cells of cholangiocytes and hepatocytes, NAFLD may trigger carcinogenesis in cholangiocytes via the same mechanism.	('NAFLD', 'Var', (90, 95))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('trigger', 'Reg', (100, 107))	('carcinogenesis', 'Disease', (108, 122))
173660	29350068	This type of dysplasia is considered precancerous, since it harbors molecular alterations involved in carcinogenesis, including chromosomal gains and losses, telomere shortening, and inactivation of cyclin Dependent Kinase Inhibitor 1A (CDKN1A).	('dysplasia', 'Disease', 'MESH:D004476', (13, 22))	('carcinogenesis', 'Disease', 'MESH:D063646', (102, 116))	('cyclin Dependent Kinase Inhibitor 1A', 'Gene', (199, 235))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cyclin Dependent Kinase Inhibitor 1A', 'Gene', '1026', (199, 235))	('carcinogenesis', 'Disease', (102, 116))	('telomere shortening', 'Phenotype', 'HP:0031413', (158, 177))	('cancer', 'Disease', (40, 46))	('CDKN1A', 'Gene', (237, 243))	('telomere shortening', 'CPA', (158, 177))	('inactivation', 'Var', (183, 195))	('losses', 'NegReg', (150, 156))	('CDKN1A', 'Gene', '1026', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('dysplasia', 'Disease', (13, 22))
173707	29350068	Cytokeratins 7 and 19 are also recognized as stemness-related markers in HCC, and expression of these proteins in an HCC predicts a worse outcome for the patient.	('HCC', 'Gene', '619501', (73, 76))	('HCC', 'Gene', '619501', (117, 120))	('patient', 'Species', '9606', (154, 161))	('expression', 'Var', (82, 92))	('HCC', 'Gene', (117, 120))	('HCC', 'Gene', (73, 76))	('predicts', 'Reg', (121, 129))
173845	29350068	Furthermore, extra caution is needed for interpreting unexpected glypican 3 positivity associated with significantly inflamed benign hepatocytes, macroregenerative nodules, and DNs.	('DNs', 'Disease', (177, 180))	('positivity', 'Var', (76, 86))	('glypican 3', 'Gene', '2719', (65, 75))	('associated', 'Reg', (87, 97))	('macroregenerative nodules', 'Disease', (146, 171))	('glypican 3', 'Gene', (65, 75))
173895	29350068	The established HA subtypes are (1) HAs with mutated, inactive HNF1A, (HA-H), (2) HAs with activating mutations in the CTNNB1 gene encoding beta-catenin (HA-B), (3) HA without mutations of HNF1A or beta-catenin genes but with inflammatory features (HA-I, formerly called telangiectatic FNH), and lastly (4) unclassified HAs that have neither known gene mutations nor a unique histomorphology (HA-U, the histological features of these adenomas are shown in Figure 10A-D, respectively).	('beta-catenin', 'Gene', '1499', (140, 152))	('CTNNB1', 'Gene', (119, 125))	('HNF1A', 'Gene', '6927', (63, 68))	('HNF1A', 'Gene', '6927', (189, 194))	('telangiectatic FNH', 'Disease', 'MESH:D001816', (271, 289))	('adenomas', 'Disease', 'MESH:D000236', (434, 442))	('adenomas', 'Disease', (434, 442))	('HA-I', 'Gene', '6692', (249, 253))	('telangiectatic FNH', 'Disease', (271, 289))	('beta-catenin', 'Gene', (198, 210))	('CTNNB1', 'Gene', '1499', (119, 125))	('mutations', 'Var', (102, 111))	('HNF1A', 'Gene', (63, 68))	('HNF1A', 'Gene', (189, 194))	('HA-I', 'Gene', (249, 253))	('beta-catenin', 'Gene', '1499', (198, 210))	('beta-catenin', 'Gene', (140, 152))
173896	29350068	Hepatic adenoma with HNF1A mutations account for approximately 30% of HAs.	('mutations', 'Var', (27, 36))	('HNF1A', 'Gene', '6927', (21, 26))	('Hepatic adenoma', 'Disease', (0, 15))	('Hepatic adenoma', 'Disease', 'MESH:C564190', (0, 15))	('Hepatic adenoma', 'Phenotype', 'HP:0012028', (0, 15))	('HNF1A', 'Gene', (21, 26))
173898	29350068	Hepatic adenoma with HNF1A mutation with somatic mutations occur mostly in females with a history of oral contraceptive use.	('HNF1A', 'Gene', '6927', (21, 26))	('Hepatic adenoma', 'Disease', (0, 15))	('mutation', 'Var', (27, 35))	('Hepatic adenoma', 'Disease', 'MESH:C564190', (0, 15))	('Hepatic adenoma', 'Phenotype', 'HP:0012028', (0, 15))	('HNF1A', 'Gene', (21, 26))
173899	29350068	Hepatic adenoma with HNF1A mutation with germ line mutations also present mostly in females but occur at an earlier age and patients do not typically have a history of oral contraceptive use.	('HNF1A', 'Gene', '6927', (21, 26))	('Hepatic adenoma', 'Disease', (0, 15))	('mutation', 'Var', (27, 35))	('Hepatic adenoma', 'Disease', 'MESH:C564190', (0, 15))	('Hepatic adenoma', 'Phenotype', 'HP:0012028', (0, 15))	('patients', 'Species', '9606', (124, 132))	('HNF1A', 'Gene', (21, 26))
173901	29350068	Familial hepatic adenomatosis has been well-documented in patients with germ line mutations of HNF1A and it is also associated with maturity-onset diabetes mellitus of youth, type 3.	('diabetes mellitus', 'Disease', 'MESH:D003920', (147, 164))	('Familial hepatic adenomatosis', 'Disease', (0, 29))	('HNF1A', 'Gene', '6927', (95, 100))	('men', 'Species', '9606', (48, 51))	('maturity-onset diabetes mellitus of youth', 'Phenotype', 'HP:0004904', (132, 173))	('Familial hepatic adenomatosis', 'Disease', 'MESH:D009377', (0, 29))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (147, 164))	('mutations', 'Var', (82, 91))	('HNF1A', 'Gene', (95, 100))	('hepatic adenomatosis', 'Phenotype', 'HP:0012028', (9, 29))	('patients', 'Species', '9606', (58, 66))	('diabetes mellitus', 'Disease', (147, 164))	('maturity-onset diabetes mellitus', 'Phenotype', 'HP:0100651', (132, 164))	('hepatic adenoma', 'Phenotype', 'HP:0012028', (9, 24))	('associated', 'Reg', (116, 126))
173902	29350068	Detection of germ line mutations of HNF1A in family members of patients with hepatic adenomatosis has been established to identify familial predisposition for the disease.	('hepatic adenomatosis', 'Phenotype', 'HP:0012028', (77, 97))	('hepatic adenoma', 'Phenotype', 'HP:0012028', (77, 92))	('HNF1A', 'Gene', '6927', (36, 41))	('mutations', 'Var', (23, 32))	('HNF1A', 'Gene', (36, 41))	('hepatic adenomatosis', 'Disease', (77, 97))	('patients', 'Species', '9606', (63, 71))	('hepatic adenomatosis', 'Disease', 'MESH:D056486', (77, 97))
173904	29350068	Expression of liver fatty acid-binding protein (LFABP) is downregulated in HA-H as a consequence of the HNF1A mutation, therefore, immunohistochemistry for LFABP serves as a translational marker to identify this subtype of HA, since expression will be lost in HA-H compared to normal liver, in which it is normally expressed.	('liver fatty acid-binding protein', 'Gene', '2168', (14, 46))	('HNF1A', 'Gene', (104, 109))	('LFABP', 'Gene', (48, 53))	('LFABP', 'Gene', '2168', (48, 53))	('expression', 'MPA', (233, 243))	('Expression', 'MPA', (0, 10))	('liver fatty acid-binding protein', 'Gene', (14, 46))	('downregulated', 'NegReg', (58, 71))	('HNF1A', 'Gene', '6927', (104, 109))	('mutation', 'Var', (110, 118))	('LFABP', 'Gene', '2168', (156, 161))	('LFABP', 'Gene', (156, 161))	('lost', 'NegReg', (252, 256))
173906	29350068	Mutations in this gene are exclusive of HNF1A mutations.	('HNF1A', 'Gene', (40, 45))	('Mutations', 'Var', (0, 9))	('HNF1A', 'Gene', '6927', (40, 45))
173912	29350068	HAs with activating mutations in the CTNNB1 gene encoding beta-catenin with mutations in exon 3 of the CTNNB1 gene encoding beta-catenin (HA-Bex3) are associated with a high risk of malignant transformation.	('CTNNB1', 'Gene', '1499', (103, 109))	('beta-catenin', 'Gene', (58, 70))	('mutations in', 'Var', (76, 88))	('beta-catenin', 'Gene', (124, 136))	('associated', 'Reg', (151, 161))	('beta-catenin', 'Gene', '1499', (124, 136))	('CTNNB1', 'Gene', (37, 43))	('CTNNB1', 'Gene', (103, 109))	('beta-catenin', 'Gene', '1499', (58, 70))	('CTNNB1', 'Gene', '1499', (37, 43))	('activating', 'PosReg', (9, 19))	('mutations', 'Var', (20, 29))	('malignant transformation', 'CPA', (182, 206))
173919	29350068	This pathway is activated through mutations in IL6ST (most common), Fyn Related Src Family Tyrosine Kinase (FRK), JAK1, STAT3, and Guanine nucleotide-binding protein (G9s) subunit alpha isoforms short (GNAS).	('Src', 'Gene', '6714', (80, 83))	('JAK1', 'Gene', (114, 118))	('Fyn', 'Gene', '2534', (68, 71))	('Tyrosine Kinase', 'Gene', '7294', (91, 106))	('Fyn', 'Gene', (68, 71))	('IL6ST', 'Gene', '3572', (47, 52))	('JAK1', 'Gene', '3716', (114, 118))	('GNAS', 'Gene', (202, 206))	('activated', 'PosReg', (16, 25))	('FRK', 'Gene', '2444', (108, 111))	('STAT3', 'Gene', '6774', (120, 125))	('Tyrosine Kinase', 'Gene', (91, 106))	('FRK', 'Gene', (108, 111))	('Src', 'Gene', (80, 83))	('STAT3', 'Gene', (120, 125))	('GNAS', 'Gene', '2778', (202, 206))	('IL6ST', 'Gene', (47, 52))	('mutations', 'Var', (34, 43))
173922	29350068	A subset of HA-I may also have mutations in the CTNNB1 gene encoding beta-catenin, either exon 3 or exons 7 and 8 (HA-IBex3 and HA-IBex7,8, respectively).	('mutations', 'Var', (31, 40))	('HA-I', 'Gene', '6692', (128, 132))	('beta-catenin', 'Gene', (69, 81))	('HA-I', 'Gene', '6692', (12, 16))	('HA-I', 'Gene', '6692', (115, 119))	('beta-catenin', 'Gene', '1499', (69, 81))	('CTNNB1', 'Gene', (48, 54))	('HA-I', 'Gene', (128, 132))	('HA-I', 'Gene', (115, 119))	('HA-I', 'Gene', (12, 16))	('CTNNB1', 'Gene', '1499', (48, 54))
173928	29350068	This pathway is driven by structural rearrangements of Inhibin Beta E Subunit (INHBE) producing a highly expressed INHBE_Glioma-associated oncogene family zinc finger 1 (GLI1) fusion protein leading to the constitutive activation of the sonic hedgehog pathway.	('sonic hedgehog pathway', 'Pathway', (237, 259))	('GLI1', 'Gene', '2735', (170, 174))	('INHBE', 'Gene', (115, 120))	('Glioma', 'Disease', 'MESH:D005910', (121, 127))	('GLI1', 'Gene', (170, 174))	('INHBE', 'Gene', '83729', (79, 84))	('activation', 'PosReg', (219, 229))	('Glioma', 'Disease', (121, 127))	('men', 'Species', '9606', (46, 49))	('Inhibin Beta E Subunit', 'Gene', '83729', (55, 77))	('Inhibin Beta E Subunit', 'Gene', (55, 77))	('INHBE', 'Gene', (79, 84))	('rearrangements', 'Var', (37, 51))	('INHBE', 'Gene', '83729', (115, 120))
173935	29350068	The frequency of histological hemorrhage was higher in HA-IBex7,8 and SA-SH.	('hemorrhage', 'Disease', 'MESH:D006470', (30, 40))	('HA-I', 'Gene', '6692', (55, 59))	('HA-I', 'Gene', (55, 59))	('SA-SH', 'Var', (70, 75))	('hemorrhage', 'Disease', (30, 40))
173936	29350068	Features associated with malignant transformation included TERT promoter mutations, CTNNB1 exon 3 mutations, a unique nodule at imaging, high alcohol intake, fibrosis in nontumoral liver, and diabetes type 2.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('CTNNB1', 'Gene', '1499', (84, 90))	('TERT', 'Gene', (59, 63))	('diabetes type 2', 'Disease', 'MESH:D003924', (192, 207))	('fibrosis', 'Disease', 'MESH:D005355', (158, 166))	('fibrosis', 'Disease', (158, 166))	('associated', 'Reg', (9, 19))	('mutations', 'Var', (98, 107))	('tumor', 'Disease', (173, 178))	('diabetes type 2', 'Disease', (192, 207))	('TERT', 'Gene', '7015', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('alcohol', 'Chemical', 'MESH:D000438', (142, 149))	('CTNNB1', 'Gene', (84, 90))
173937	29350068	In patients with multiple HA, the largest HA tended to be associated with CTNNB1 exon 3 mutations; thus, image-guided biopsies in patients with adenomatosis can be directed at the largest nodule.	('adenomatosis', 'Disease', (144, 156))	('CTNNB1', 'Gene', (74, 80))	('associated', 'Reg', (58, 68))	('mutations', 'Var', (88, 97))	('adenomatosis', 'Disease', 'MESH:D018255', (144, 156))	('CTNNB1', 'Gene', '1499', (74, 80))	('patients', 'Species', '9606', (130, 138))	('patients', 'Species', '9606', (3, 11))
173979	29350068	Precursor lesions leading to cholangiocarcinoma include high-grade BilIN, discussed earlier in this review.	('high-grade', 'Var', (56, 66))	('leading', 'Reg', (18, 25))	('BilIN', 'Chemical', '-', (67, 72))	('cholangiocarcinoma', 'Disease', (29, 47))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (29, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (29, 47))
174003	29350068	In comparison, HCCs, including all the variants, are predominantly positive in the described pattern for the immunostain markers introduced earlier, including arginase, HepPar-1, glypican 3, CD34, CD10, and p-CEA; HCCs are also positive for AE1/3 and CAM5.2 in almost all cases but remain negative mostly for CK-7 and CK-20.	('CK-20', 'Gene', '54474', (318, 323))	('HepPar-1, glypican 3', 'Gene', '2719', (169, 189))	('CD10', 'Gene', (197, 201))	('CEA', 'Gene', (209, 212))	('CD34', 'Gene', (191, 195))	('positive', 'Reg', (67, 75))	('HCCs', 'Gene', (15, 19))	('HCCs', 'Gene', (214, 218))	('CK-20', 'Gene', (318, 323))	('CEA', 'Gene', '1048', (209, 212))	('CK-7', 'Gene', '3855', (309, 313))	('variants', 'Var', (39, 47))	('CD34', 'Gene', '947', (191, 195))	('HCCs', 'Gene', '3052', (15, 19))	('AE1/3', 'Gene', '6521;6508', (241, 246))	('HCCs', 'Gene', '3052', (214, 218))	('CD10', 'Gene', '4311', (197, 201))	('AE1/3', 'Gene', (241, 246))	('CK-7', 'Gene', (309, 313))
174037	29350068	Molecular wise, in recent years, it has been recognized that a spectrum of genetic alterations are responsible for the initiation, progression, and prognosis of cholangiocarcinoma; the main culprits include Kirsten rat sarcoma virus oncogene (KRAS), tumor protein p53 (TP53), a tumor suppressor gene, mothers Against DPP Homolog 1 gene (SMAD) mutation, BRAF, and INK4a, the gene encoding the p16 protein, while genetic and epigenetic alterations both cause the activation of oncogenes and/or loss of tumor suppressor functions.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('p53', 'Gene', '7157', (264, 267))	('KRAS', 'Gene', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (500, 505))	('Kirsten rat sarcoma virus oncogene', 'Gene', (207, 241))	('tumor', 'Disease', (250, 255))	('oncogenes', 'Protein', (475, 484))	('mutation', 'Var', (343, 351))	('p53', 'Gene', (264, 267))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (161, 179))	('activation', 'PosReg', (461, 471))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('cholangiocarcinoma', 'Disease', (161, 179))	('tumor', 'Disease', (278, 283))	('BRAF', 'Gene', '673', (353, 357))	('BRAF', 'Gene', (353, 357))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (161, 179))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Disease', (500, 505))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('loss', 'NegReg', (492, 496))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('tumor', 'Disease', 'MESH:D009369', (500, 505))	('Kirsten rat sarcoma virus oncogene', 'Gene', '3845', (207, 241))	('KRAS', 'Gene', '3845', (243, 247))
174039	29350068	For example, KRAS mutation is also a frequent event observed in gastrointestinal adenocarcinomas, especially those from colorectal regions.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('gastrointestinal adenocarcinomas', 'Disease', 'MESH:D004067', (64, 96))	('colorectal', 'Disease', (120, 130))	('mutation', 'Var', (18, 26))	('gastrointestinal adenocarcinomas', 'Disease', (64, 96))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))
174152	28795594	But because we do not have past-life memories and cannot know all of the past causes of an event, believing in kamma appears to invoke some kind of fatalism or predestination.	('believing', 'Var', (98, 107))	('fatalism', 'Disease', 'MESH:D034062', (148, 156))	('fatalism', 'Disease', (148, 156))
174166	28795594	This very act of forgiving confirmed that local villagers believed Boonsong's suffering before death was due to the complex working of kamma, and that forgiveness might exhaust the kammic effect somehow.	('death', 'Disease', 'MESH:D003643', (95, 100))	('death', 'Disease', (95, 100))	('forgiveness', 'Var', (151, 162))	('kammic effect', 'MPA', (181, 194))	('exhaust', 'NegReg', (169, 176))
174181	28795594	Opisthorchis viverrini causes liver and bile duct damage, which causes cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (71, 89))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (71, 89))	('causes', 'Reg', (64, 70))	('causes', 'Reg', (23, 29))	('Opisthorchis viverrini', 'Var', (0, 22))	('cholangiocarcinoma', 'Disease', (71, 89))	('Opisthorchis viverrini', 'Species', '6198', (0, 22))
174225	26589730	The proliferative rate estimated with immunohistochemical analysis for Ki67 (MIB-1, DAKO, M0701, 1:100) was up to 8 % and up to three mitotic figures were present in 50 HPF (Fig.	('MIB-1', 'Gene', (77, 82))	('Ki67', 'Var', (71, 75))	('proliferative rate', 'CPA', (4, 22))	('MIB-1', 'Gene', '57534', (77, 82))
174240	26589730	Blood or bile testing for tumour markers such as CA19-9 and carcinoembryonic antigen (CEA), are often of limited diagnostic utility in isolation as both markers lack sensitivity and specificity, as was evident in this case.	('lack', 'NegReg', (161, 165))	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('carcinoembryonic antigen', 'Gene', '1048', (60, 84))	('tumour', 'Disease', (26, 32))	('carcinoembryonic antigen', 'Gene', (60, 84))	('CEA', 'Gene', (86, 89))	('sensitivity', 'MPA', (166, 177))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('CA19-9', 'Var', (49, 55))	('CEA', 'Gene', '1048', (86, 89))
174359	33538186	17  In patients with liver cirrhosis, SOLs 10 mm or larger have a substantial likelihood of being malignancies.	('liver cirrhosis', 'Disease', 'MESH:D008103', (21, 36))	('malignancies', 'Disease', (98, 110))	('SOLs 10 mm', 'Var', (38, 48))	('liver cirrhosis', 'Disease', (21, 36))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (21, 36))	('malignancies', 'Disease', 'MESH:D009369', (98, 110))	('patients', 'Species', '9606', (7, 15))
174438	28623758	Detectable TSG mutational change was restricted to the neuroendocrine growth pattern, thereby affirming its increased biological aggressiveness and responsibility for metastatic spread (Table 1).	('aggressiveness', 'Disease', (129, 143))	('aggressiveness', 'Phenotype', 'HP:0000718', (129, 143))	('TSG', 'Gene', (11, 14))	('aggressiveness', 'Disease', 'MESH:D001523', (129, 143))	('mutational change', 'Var', (15, 32))
174439	28623758	Intratumoral molecular heterogeneity was prominently displayed in the neuroendocrine component with varying degrees of further mutation acquisition across individual targets including development of new alleles reflecting microsatellite instability (Table 1).	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('neuroendocrine component', 'Disease', (70, 94))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('microsatellite instability', 'Var', (222, 248))	('neuroendocrine component', 'Disease', 'MESH:D018358', (70, 94))	('tumor', 'Disease', (5, 10))
174441	28623758	Lack of detectable neuroendocrine-associated mutations in the HCC-like component supports that the neuroendocrine component likely was not derived from the HCC-like cancer cells.	('mutations', 'Var', (45, 54))	('CC', 'Phenotype', 'HP:0030153', (63, 65))	('HCC', 'Phenotype', 'HP:0001402', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('neuroendocrine component', 'Disease', (99, 123))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('CC', 'Phenotype', 'HP:0030153', (157, 159))	('HCC', 'Phenotype', 'HP:0001402', (62, 65))	('neuroendocrine component', 'Disease', 'MESH:D018358', (99, 123))
174466	28623758	When compared to contemporary patients with HCC and ICC, tumor recurrence rates did not differ (p = 0.43) but survival for MHCC patients was significantly worse (p = 0.000).	('CC', 'Phenotype', 'HP:0030153', (45, 47))	('HCC', 'Phenotype', 'HP:0001402', (124, 127))	('survival', 'MPA', (110, 118))	('MHCC', 'Chemical', '-', (123, 127))	('worse', 'NegReg', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('CC', 'Phenotype', 'HP:0030153', (53, 55))	('HCC', 'Phenotype', 'HP:0001402', (44, 47))	('patients', 'Species', '9606', (30, 38))	('MHCC', 'Var', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('patients', 'Species', '9606', (128, 136))	('tumor', 'Disease', (57, 62))	('CC', 'Phenotype', 'HP:0030153', (125, 127))
174474	28623758	Mutational profiling findings were striking between the different growth patterns with detectable mutational change confined to the neuroendocrine component in keeping with its greater apparent biological aggressiveness.	('aggressiveness', 'Phenotype', 'HP:0000718', (205, 219))	('neuroendocrine component', 'Disease', (132, 156))	('mutational', 'Var', (98, 108))	('aggressiveness', 'Disease', 'MESH:D001523', (205, 219))	('neuroendocrine component', 'Disease', 'MESH:D018358', (132, 156))	('aggressiveness', 'Disease', (205, 219))
174476	28623758	Genomic instability in the neuroendocrine component was further evidenced by emergence of new microsatellite alleles consistent with a degree of microsatellite instability inherent within this growth component.	('neuroendocrine component', 'Disease', (27, 51))	('neuroendocrine component', 'Disease', 'MESH:D018358', (27, 51))	('microsatellite', 'Var', (94, 108))
174477	28623758	These are common sites for tumor suppressor gene loss and/or oncogene amplification, which in this patient were consistently present in all primary and metastatic deposits of neuroendocrine tumor.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('patient', 'Species', '9606', (99, 106))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (175, 195))	('loss', 'NegReg', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('neuroendocrine tumor', 'Disease', (175, 195))	('tumor', 'Disease', (190, 195))	('oncogene', 'Gene', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (175, 195))	('amplification', 'Var', (70, 83))
174497	33207685	In addition, a higher level of CA50 was associated with poor clinical outcome and shorter survival in iCCA patients.	('survival', 'MPA', (90, 98))	('patients', 'Species', '9606', (107, 115))	('CA50', 'Var', (31, 35))	('shorter', 'NegReg', (82, 89))
174508	33207685	In fact, both CA19-9 and CA50 are valuable markers for the differentiation of pancreatic cancer from benign diseases of the pancreatobiliary tract.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('benign diseases', 'Disease', (101, 116))	('pancreatic cancer', 'Disease', (78, 95))	('benign diseases', 'Disease', 'MESH:D009369', (101, 116))	('pancreatic cancer', 'Disease', 'MESH:D010190', (78, 95))	('CA19-9', 'Var', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
174532	33207685	Univariate Cox proportional hazard analysis revealed that the iCCA patients with high CA50 have 3.629 times higher hazard ratio compared with those with low CA50 (Table 3, p < 0.05).	('high CA50', 'Var', (81, 90))	('higher', 'PosReg', (108, 114))	('patients', 'Species', '9606', (67, 75))
174534	33207685	As shown in Figure 2H, Kaplan-Meier plot and log-rank analysis showed that the patients with a high level of CA50 had the shortest survival (127.0 days, 95% CI of 35.5-128.5 days), compared with those with medium CA50 (172.0 days, 95% CI of 91.6-252.4 days) and low CA50 (227.0 days, 95% CI of 161.5-292.5 days) (p < 0.001).	('CA50', 'Var', (109, 113))	('shortest', 'NegReg', (122, 130))	('patients', 'Species', '9606', (79, 87))	('survival', 'MPA', (131, 139))
174536	33207685	Altered glycosylation is seen in CCA, and aberrant expression of glycans plays significant roles in CCA progression, leading to poor survival of patients.	('glycosylation', 'MPA', (8, 21))	('poor', 'NegReg', (128, 132))	('patients', 'Species', '9606', (145, 153))	('aberrant', 'Var', (42, 50))	('glycans', 'Protein', (65, 72))	('CCA', 'Disease', (33, 36))	('expression', 'MPA', (51, 61))	('Altered', 'Reg', (0, 7))	('CCA', 'Disease', (100, 103))	('glycans', 'Chemical', 'MESH:D011134', (65, 72))
174542	33207685	When the cut-off value was set at 85.3 U/mL, the CA50 could exclude 82% (19/23) of BBD, 84% (28/33) of OCA, and 100% (110/110) of HE cases, suggesting that the patients with high CA50 have high possibility of having iCCA.	('CA50', 'Var', (179, 183))	('iCCA', 'Disease', (216, 220))	('patients', 'Species', '9606', (160, 168))	('OCA', 'Disease', (103, 106))	('BBD', 'Chemical', '-', (83, 86))	('high CA50', 'Var', (174, 183))
174547	33207685	High level of CA50 in the serum was associated with the advanced tumor stage and shorter survival of iCCA patients.	('CA50', 'Var', (14, 18))	('tumor', 'Disease', (65, 70))	('survival', 'CPA', (89, 97))	('patients', 'Species', '9606', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('associated', 'Reg', (36, 46))	('shorter', 'NegReg', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
174548	33207685	Previous studies on CA50 expression in gastric and pancreatic cancer patients showed that the high level of CA50 is significantly associated with shorter survival of the patients.	('patients', 'Species', '9606', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('high level', 'Var', (94, 104))	('pancreatic cancer', 'Disease', (51, 68))	('patients', 'Species', '9606', (69, 77))	('pancreatic cancer', 'Disease', 'MESH:D010190', (51, 68))	('shorter', 'NegReg', (146, 153))	('CA50', 'Gene', (20, 24))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (51, 68))	('CA50', 'Gene', (108, 112))	('gastric', 'Disease', (39, 46))
174559	31911531	Targeted sequencing of tumor DNA after disease progression revealed the FGFR2 kinase domain p.E565A and p.L617M single nucleotide variants (SNVs) hypothesized to drive acquired resistance to infigratinib.	('FGFR2', 'Gene', (72, 77))	('FGFR2', 'Gene', '2263', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (23, 28))	('drive', 'Reg', (162, 167))	('p.E565A', 'Var', (92, 99))	('p.E565A', 'Mutation', 'rs121918506', (92, 99))	('infigratinib', 'Chemical', 'MESH:C568950', (191, 203))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('p.L617M', 'Var', (104, 111))	('p.L617M', 'Mutation', 'rs1057519796', (104, 111))	('acquired resistance', 'MPA', (168, 187))
174560	31911531	The sensitivities of these FGFR2 SNVs, which were detected post-infigratinib therapy, were extended to include clinically relevant FGFR inhibitors including AZD4547, erdafitinib (JNJ-42756493), dovitinib, ponatinib, and TAS120, and were evaluated in vitro.	('AZD4547', 'Chemical', 'MESH:C572463', (157, 164))	('TAS120', 'Chemical', '-', (220, 226))	('ponatinib', 'Chemical', 'MESH:C545373', (205, 214))	('FGFR2', 'Gene', (27, 32))	('FGFR2', 'Gene', '2263', (27, 32))	('FGFR', 'Gene', (131, 135))	('dovitinib', 'Chemical', 'MESH:C500007', (194, 203))	('infigratinib', 'Chemical', 'MESH:C568950', (64, 76))	('erdafitinib', 'Chemical', 'MESH:C000604580', (166, 177))	('AZD4547', 'Var', (157, 164))
174561	31911531	Through a proteomics approach, we identified upregulation of the PI3K/AKT/mTOR signaling pathway in cells harboring the FGFR2 p.E565A mutation and demonstrated that combination therapy strategies with FGFR and mTOR inhibitors may be used to overcome resistance to FGFR inhibition, specific to infigratinib.	('FGFR2', 'Gene', '2263', (120, 125))	('PI3K/AKT/mTOR signaling pathway', 'Pathway', (65, 96))	('infigratinib', 'Chemical', 'MESH:C568950', (293, 305))	('p.E565A', 'Var', (126, 133))	('upregulation', 'PosReg', (45, 57))	('p.E565A', 'Mutation', 'rs121918506', (126, 133))	('FGFR2', 'Gene', (120, 125))
174571	31911531	Multiple FGFR tyrosine kinase inhibitors (TKIs) have demonstrated clinical efficacy in patients with advanced FGFR-mutant cancers.	('FGFR-mutant', 'Var', (110, 121))	('FGFR-mutant', 'Gene', (110, 121))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('patients', 'Species', '9606', (87, 95))
174574	31911531	Recent studies have identified the emergence of recurrent secondary single nucleotide variants (SNVs) in FGFR following FGFR inhibition that desensitize tumor cells to these therapies.	('FGFR', 'Gene', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('desensitize', 'NegReg', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('single nucleotide variants', 'Var', (68, 94))	('inhibition', 'NegReg', (125, 135))
174577	31911531	From tumor sequencing at the time of progression, we identified two acquired secondary FGFR2 kinase domain mutations, p.E565A and p.L617M, which were hypothesized to drive acquired resistance to infigratinib.	('FGFR2', 'Gene', (87, 92))	('p.L617M', 'Var', (130, 137))	('infigratinib', 'Chemical', 'MESH:C568950', (195, 207))	('p.E565A', 'Mutation', 'rs121918506', (118, 125))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('FGFR2', 'Gene', '2263', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('drive', 'Reg', (166, 171))	('tumor', 'Disease', (5, 10))	('p.L617M', 'Mutation', 'rs1057519796', (130, 137))	('p.E565A', 'Var', (118, 125))
174578	31911531	Moreover, we confirmed this hypothesis through in vitro drug sensitivity studies utilizing cell lines transduced to stably express these FGFR2 mutants.	('FGFR2', 'Gene', (137, 142))	('drug sensitivity', 'Phenotype', 'HP:0020174', (56, 72))	('FGFR2', 'Gene', '2263', (137, 142))	('mutants', 'Var', (143, 150))
174579	31911531	Through a proteomics approach, we identified upregulation of the PI3K/AKT/mTOR signaling pathway in cells expressing FGFR2 p.E565A and further tested the effects of mTOR inhibitors, which re-sensitized these cells to FGFR inhibition.	('FGFR2', 'Gene', (117, 122))	('FGFR2', 'Gene', '2263', (117, 122))	('PI3K/AKT/mTOR signaling pathway', 'Pathway', (65, 96))	('p.E565A', 'Var', (123, 130))	('tested', 'Reg', (143, 149))	('upregulation', 'PosReg', (45, 57))	('p.E565A', 'Mutation', 'rs121918506', (123, 130))
174580	31911531	In summary, understanding how secondary mutations in FGFR affect sensitivity to different FGFR inhibitors and developing rational combination therapies will both be critical to improving the clinical outcome of patients with FGFR-altered cancers.	('FGFR', 'Gene', (53, 57))	('FGFR-altered cancers', 'Disease', 'MESH:D009369', (225, 245))	('patients', 'Species', '9606', (211, 219))	('FGFR-altered cancers', 'Disease', (225, 245))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('sensitivity', 'MPA', (65, 76))	('mutations', 'Var', (40, 49))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))	('affect', 'Reg', (58, 64))
174590	31911531	GenScript used site directed mutagenesis to introduce the FGFR2 p.E565A and FGFR2 p.L617M SNVs into the fusion.	('p.L617M', 'Var', (82, 89))	('p.L617M', 'Mutation', 'rs1057519796', (82, 89))	('FGFR2', 'Gene', (76, 81))	('FGFR2', 'Gene', '2263', (58, 63))	('FGFR2', 'Gene', '2263', (76, 81))	('p.E565A', 'Var', (64, 71))	('p.E565A', 'Mutation', 'rs121918506', (64, 71))	('FGFR2', 'Gene', (58, 63))
174591	31911531	NIH3T3, 293T, and MMNK-1 cells were stably transduced with either empty, FGFR2-KIAA1598 WT or FGFR2-KIAA1598 p.E565A, or FGFR2-KIAA1598 p.L617M lentiviral vectors and were subsequently selected and maintained in 1 ug/mL puromycin (Sigma) containing media prior to downstream applications.	('p.L617M', 'Mutation', 'rs1057519796', (136, 143))	('MMNK-1', 'CellLine', 'CVCL:M266', (18, 24))	('KIAA1598', 'Gene', (100, 108))	('FGFR2', 'Gene', '2263', (94, 99))	('FGFR2', 'Gene', (121, 126))	('p.E565A', 'Var', (109, 116))	('KIAA1598', 'Gene', '57698', (127, 135))	('p.E565A', 'Mutation', 'rs121918506', (109, 116))	('KIAA1598', 'Gene', '57698', (79, 87))	('FGFR2', 'Gene', '2263', (121, 126))	('NIH3T3', 'CellLine', 'CVCL:0594', (0, 6))	('FGFR2', 'Gene', (73, 78))	('KIAA1598', 'Gene', '57698', (100, 108))	('puromycin', 'Chemical', 'MESH:D011691', (220, 229))	('KIAA1598', 'Gene', (127, 135))	('FGFR2', 'Gene', (94, 99))	('KIAA1598', 'Gene', (79, 87))	('FGFR2', 'Gene', '2263', (73, 78))	('293T', 'CellLine', 'CVCL:0063', (8, 12))
174592	31911531	The presence of the fusion and mutations was confirmed by PCR and Sanger Sequencing as previously described (The Ohio State University Comprehensive Cancer Center Genomics Shared Resource, Columbus, OH).	('Cancer', 'Phenotype', 'HP:0002664', (149, 155))	('Cancer', 'Disease', 'MESH:D009369', (149, 155))	('Cancer', 'Disease', (149, 155))	('mutations', 'Var', (31, 40))
174611	31911531	She was subsequently enrolled on the Phase II Multicenter, Single Arm Study of Oral Infigratinib in Adult Patients with Advanced or Metastatic Cholangiocarcinoma with FGFR2 Gene Fusions or Other FGFR Genetic Alterations Who Failed or Are Intolerant to Platinum-based Chemotherapy (NCT02150967).	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('Metastatic Cholangiocarcinoma', 'Disease', (132, 161))	('FGFR', 'Gene', (195, 199))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (143, 161))	('Patients', 'Species', '9606', (106, 114))	('FGFR2', 'Gene', '2263', (167, 172))	('Gene Fusions', 'Var', (173, 185))	('Platinum', 'Chemical', 'MESH:D010984', (252, 260))	('FGFR2', 'Gene', (167, 172))	('Infigratinib', 'Chemical', 'MESH:C568950', (84, 96))	('Metastatic Cholangiocarcinoma', 'Disease', 'MESH:D018281', (132, 161))
174613	31911531	Over the course of treatment, she underwent two dose reductions of infigratinib due to hyperphosphatemia (100 mg and 75 mg, respectively).	('hyperphosphatemia', 'Disease', 'MESH:D054559', (87, 104))	('hyperphosphatemia', 'Disease', (87, 104))	('100', 'Var', (106, 109))	('infigratinib', 'Chemical', 'MESH:C568950', (67, 79))	('hyperphosphatemia', 'Phenotype', 'HP:0002905', (87, 104))
174615	31911531	A repeat biopsy of progressive tumor revealed the same FGFR2-KIAA1598 gene fusion; however, a single nucleotide variant (SNV) p.E565A was detected in the FGFR2 kinase domain (Figure 1A and 1C).	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('KIAA1598', 'Gene', (61, 69))	('tumor', 'Disease', (31, 36))	('FGFR2', 'Gene', (55, 60))	('FGFR2', 'Gene', '2263', (55, 60))	('KIAA1598', 'Gene', '57698', (61, 69))	('p.E565A', 'Var', (126, 133))	('p.E565A', 'Mutation', 'rs121918506', (126, 133))	('FGFR2', 'Gene', (154, 159))	('FGFR2', 'Gene', '2263', (154, 159))
174620	31911531	Analysis of the post-progression ctDNA sample revealed a p.L617M mutation in addition to the p.E565A mutation that was present in the biopsy.	('p.L617M', 'Var', (57, 64))	('p.L617M', 'Mutation', 'rs1057519796', (57, 64))	('p.E565A', 'Mutation', 'rs121918506', (93, 100))	('p.E565A', 'Var', (93, 100))
174621	31911531	The p.L617M mutation was not detected in the post-progression tumor biopsy sample demonstrating the limitations of tumor biopsies in capturing tumor heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (115, 120))	('p.L617M', 'Var', (4, 11))	('p.L617M', 'Mutation', 'rs1057519796', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
174622	31911531	We next sought to characterize the fusion and the secondary SNVs (p.E565A and p.L617M) through in vitro assays.	('p.L617M', 'Mutation', 'rs1057519796', (78, 85))	('p.E565A', 'Var', (66, 73))	('p.E565A', 'Mutation', 'rs121918506', (66, 73))	('p.L617M', 'Var', (78, 85))
174623	31911531	We generated NIH3T3, 293T, and MMNK-1 cells expressing the control vector (empty), the wild type FGFR2-KIAA1598 fusion protein (FK WT), and the fusion protein containing either the p.E565A (FK p.E565A) or p.L617M (FK p.L617M) mutation.	('293T', 'CellLine', 'CVCL:0063', (21, 25))	('NIH3T3', 'CellLine', 'CVCL:0594', (13, 19))	('p.L617M', 'Mutation', 'rs1057519796', (205, 212))	('FGFR2', 'Gene', (97, 102))	('p.L617M', 'Mutation', 'rs1057519796', (217, 224))	('p.E565A', 'Mutation', 'rs121918506', (193, 200))	('FGFR2', 'Gene', '2263', (97, 102))	('KIAA1598', 'Gene', (103, 111))	('p.E565A', 'Var', (181, 188))	('KIAA1598', 'Gene', '57698', (103, 111))	('p.E565A', 'Mutation', 'rs121918506', (181, 188))	('MMNK-1', 'CellLine', 'CVCL:M266', (31, 37))	('p.L617M', 'Var', (205, 212))
174627	31911531	Sanger sequencing also confirmed the fusion sequence and the p.E565A and p.L617M mutations (Supplemental Figure 1B).	('p.E565A', 'Mutation', 'rs121918506', (61, 68))	('p.L617M', 'Var', (73, 80))	('p.L617M', 'Mutation', 'rs1057519796', (73, 80))	('p.E565A', 'Var', (61, 68))
174629	31911531	We stained empty, FK WT, FK p.E565A, FK p.L617M containing NIH3T3, 293T, and MMMK-1 cells for actin, cortactin, and DAPI in order to visualize the cell cytoskeleton, including actin-based cell extensions and lamellipodia (Figure 2).	('cortactin', 'Gene', (101, 110))	('p.L617M', 'Mutation', 'rs1057519796', (40, 47))	('cortactin', 'Gene', '2017', (101, 110))	('NIH3T3', 'CellLine', 'CVCL:0594', (59, 65))	('MMMK-1', 'CellLine', 'CVCL:B526', (77, 83))	('293T', 'CellLine', 'CVCL:0063', (67, 71))	('p.E565A', 'Var', (28, 35))	('p.E565A', 'Mutation', 'rs121918506', (28, 35))	('DAPI', 'Chemical', 'MESH:C007293', (116, 120))
174630	31911531	Interestingly, all of the cell lines containing the fusion (FK WT) and the fusion plus mutations (FK p.E565A and FK p.L617M) demonstrated dramatically different morphologies at baseline (Figure 2).	('p.L617M', 'Mutation', 'rs1057519796', (116, 123))	('different', 'Reg', (151, 160))	('p.E565A', 'Mutation', 'rs121918506', (101, 108))	('FK p.E565A', 'Var', (98, 108))
174632	31911531	To evaluate the underlying mechanism of acquired resistance to FGFR inhibition in our patient, we evaluated the in vitro sensitivity of NIH3T3, 293T, and MMNK-1 cells expressing empty control, FK WT, FK p.E565A, and FK p.L617M cells to infigratinib.	('293T', 'CellLine', 'CVCL:0063', (144, 148))	('p.L617M', 'Mutation', 'rs1057519796', (219, 226))	('p.L617M', 'Var', (219, 226))	('patient', 'Species', '9606', (86, 93))	('MMNK-1', 'CellLine', 'CVCL:M266', (154, 160))	('NIH3T3', 'CellLine', 'CVCL:0594', (136, 142))	('p.E565A', 'Var', (203, 210))	('p.E565A', 'Mutation', 'rs121918506', (203, 210))	('infigratinib', 'Chemical', 'MESH:C568950', (236, 248))
174634	31911531	The FK cells were particularly sensitive to infigratinib with an IC50 value of 18.24 nM, whereas the FK p.E565A and FK p.L617M cells were resistant to infigratinib with IC50 values of 490.91 nM and 2296.15 nM, respectively (Table 1, Supplemental Figure 2).	('p.E565A', 'Mutation', 'rs121918506', (104, 111))	('p.L617M', 'Var', (119, 126))	('p.L617M', 'Mutation', 'rs1057519796', (119, 126))	('IC50', 'MPA', (65, 69))	('infigratinib', 'Chemical', 'MESH:C568950', (151, 163))	('sensitive', 'Reg', (31, 40))	('infigratinib', 'Chemical', 'MESH:C568950', (44, 56))	('p.E565A', 'Var', (104, 111))
174635	31911531	The presence of the p.E565A and p.L617M mutations decreased the respective sensitivity to infigratinib by 27 and 126 fold (Table 1, Supplemental Figure 2).	('sensitivity to infigratinib', 'MPA', (75, 102))	('decreased', 'NegReg', (50, 59))	('infigratinib', 'Chemical', 'MESH:C568950', (90, 102))	('p.E565A', 'Var', (20, 27))	('p.L617M', 'Var', (32, 39))	('p.L617M', 'Mutation', 'rs1057519796', (32, 39))	('p.E565A', 'Mutation', 'rs121918506', (20, 27))
174637	31911531	Collectively, these in vitro findings support the clinical findings seen in this patient in that the FGFR2-KIAA1598 fusion is sensitive to infigratinib and that acquisition of the secondary kinase mutations, p.E565A and p.L617M, in part drive resistance to infigratinib.	('infigratinib', 'Chemical', 'MESH:C568950', (257, 269))	('patient', 'Species', '9606', (81, 88))	('p.E565A', 'Var', (208, 215))	('FGFR2', 'Gene', (101, 106))	('FGFR2', 'Gene', '2263', (101, 106))	('drive', 'Reg', (237, 242))	('resistance', 'MPA', (243, 253))	('p.E565A', 'Mutation', 'rs121918506', (208, 215))	('p.L617M', 'Var', (220, 227))	('KIAA1598', 'Gene', (107, 115))	('p.L617M', 'Mutation', 'rs1057519796', (220, 227))	('sensitive to infigratinib', 'MPA', (126, 151))	('infigratinib', 'Chemical', 'MESH:C568950', (139, 151))	('KIAA1598', 'Gene', '57698', (107, 115))
174639	31911531	These inhibitors that are currently being evaluated clinically and have shown early efficacy in patients with FGFR-mutant cancers.	('FGFR-mutant', 'Var', (110, 121))	('FGFR-mutant', 'Gene', (110, 121))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))
174641	31911531	However, cells harboring either secondary mutation (FK p.E565A or FK p.L617M), were less sensitive to AZD-4547, erdafitinib, and TAS120, thus confirming the acquisition of these mutations as drivers of resistance to FGFR inhibition (Table 1, Supplemental Figure 2).	('erdafitinib', 'Chemical', 'MESH:C000604580', (112, 123))	('p.E565A', 'Mutation', 'rs121918506', (55, 62))	('less', 'NegReg', (84, 88))	('sensitive', 'MPA', (89, 98))	('AZD-4547', 'Chemical', 'MESH:C572463', (102, 110))	('p.L617M', 'Var', (69, 76))	('p.L617M', 'Mutation', 'rs1057519796', (69, 76))	('FK p.E565A', 'Var', (52, 62))	('p.E565A', 'Var', (55, 62))	('TAS120', 'Chemical', '-', (129, 135))
174643	31911531	Interestingly, the FK expressing cells and cells expressing FK p.E565A or FK p.L617M demonstrated equal sensitivity to the nonselective FGFR inhibitor ponatinib.	('p.E565A', 'Mutation', 'rs121918506', (63, 70))	('sensitivity', 'MPA', (104, 115))	('p.L617M', 'Mutation', 'rs1057519796', (77, 84))	('p.E565A', 'Var', (63, 70))	('ponatinib', 'Chemical', 'MESH:C545373', (151, 160))	('p.L617M', 'Var', (77, 84))
174645	31911531	The presence of the FGFR p.E565A and p.L617M SNVs decreased sensitivity to FGFR inhibition, anywhere from 2- to 1000- fold.	('FGFR', 'Gene', (20, 24))	('p.L617M', 'Var', (37, 44))	('p.L617M', 'Mutation', 'rs1057519796', (37, 44))	('sensitivity to FGFR inhibition', 'MPA', (60, 90))	('decreased', 'NegReg', (50, 59))	('p.E565A', 'Var', (25, 32))	('p.E565A', 'Mutation', 'rs121918506', (25, 32))
174646	31911531	Specifically, the p.L617M mutation demonstrated varying degrees of resistance depending on both the inhibitor and cell line used.	('resistance', 'MPA', (67, 77))	('p.L617M', 'Mutation', 'rs1057519796', (18, 25))	('p.L617M', 'Var', (18, 25))
174647	31911531	The p.E565A mutation conferred the greatest degree of resistance across all cell lines and inhibitors tested.	('p.E565A', 'Var', (4, 11))	('resistance', 'MPA', (54, 64))	('p.E565A', 'Mutation', 'rs121918506', (4, 11))
174648	31911531	Furthermore, FGFR2 p.E565A has been previously described as a recurrent acquired secondary resistance mutation in response to infigratinib therapy.	('infigratinib', 'Chemical', 'MESH:C568950', (126, 138))	('acquired secondary resistance', 'Disease', (72, 101))	('p.E565A', 'Var', (19, 26))	('p.E565A', 'Mutation', 'rs121918506', (19, 26))	('FGFR2', 'Gene', '2263', (13, 18))	('FGFR2', 'Gene', (13, 18))
174649	31911531	In order to characterize the signal transduction pathways involved in resistance to FGFR inhibition, we performed Reverse Phase Protein Array (RPPA) analysis on NIH3T3 empty, FK WT, and FK p.E565A cells.	('NIH3T3', 'CellLine', 'CVCL:0594', (161, 167))	('p.E565A', 'Mutation', 'rs121918506', (189, 196))	('p.E565A', 'Var', (189, 196))	('NIH3T3', 'Gene', (161, 167))
174650	31911531	Using a false discovery rate (FDR) of 0.05, we identified proteins differentially expressed in FK WT compared to control cells and FK p.E565A compared to control cells (Figure 3A and 3B).	('p.E565A', 'Var', (134, 141))	('proteins', 'Protein', (58, 66))	('p.E565A', 'Mutation', 'rs121918506', (134, 141))
174651	31911531	We identified that phosphorylated ribosomal protein S6 (RPS6) involved in PI3K/AKT/mTOR signaling was the most upregulated protein in FK WT (Figure 3A) and FK p.E565A (Figure 3B) cells relative to empty control.	('ribosomal protein S6', 'Gene', '6194', (34, 54))	('p.E565A', 'Mutation', 'rs121918506', (159, 166))	('RPS6', 'Gene', (56, 60))	('ribosomal protein S6', 'Gene', (34, 54))	('RPS6', 'Gene', '20104', (56, 60))	('upregulated', 'PosReg', (111, 122))	('p.E565A', 'Var', (159, 166))	('FK p.E565A', 'Var', (156, 166))
174652	31911531	In FK p.E565A cells there was further potentiation of the PI3K/AKT pathway with an FDR of 1.96e-19 along with activation of the mTOR pathway with an FDR of 1.08e-17 (Figure 3D).	('activation', 'PosReg', (110, 120))	('PI3K/AKT pathway', 'Pathway', (58, 74))	('potentiation', 'PosReg', (38, 50))	('mTOR pathway', 'Pathway', (128, 140))	('p.E565A', 'Var', (6, 13))	('p.E565A', 'Mutation', 'rs121918506', (6, 13))
174653	31911531	These findings were subsequently confirmed with Western blot analysis in NIH3T3 cells revealing upregulation of phospho-RPS6, phospho-AKT, and phospho-mTOR in both FK WT and FK p.E565A cells (Figure 3E).	('RPS6', 'Gene', (120, 124))	('p.E565A', 'Var', (177, 184))	('p.E565A', 'Mutation', 'rs121918506', (177, 184))	('RPS6', 'Gene', '20104', (120, 124))	('NIH3T3', 'CellLine', 'CVCL:0594', (73, 79))	('phospho-mTOR', 'MPA', (143, 155))	('upregulation', 'PosReg', (96, 108))	('phospho-AKT', 'MPA', (126, 137))
174654	31911531	Having demonstrated upregulation of the PI3K/AKT/mTOR signaling pathway in FGFR-inhibitor resistant FK p.E565A cells, we next sought to determine if treatment with an mTOR inhibitor would enhance sensitivity to FGFR inhibitors.	('PI3K/AKT/mTOR signaling pathway', 'Pathway', (40, 71))	('p.E565A', 'Mutation', 'rs121918506', (103, 110))	('sensitivity to FGFR', 'MPA', (196, 215))	('upregulation', 'PosReg', (20, 32))	('p.E565A', 'Var', (103, 110))	('enhance', 'PosReg', (188, 195))
174655	31911531	Sapanisertib (INK128, MLN0128, or TAK-228), is a highly potent, orally active mTOR kinase inhibitor that is currently in phase I and phase II clinical trials for solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('TAK-228', 'Chemical', 'MESH:C572449', (34, 41))	('MLN0128', 'Var', (22, 29))	('INK128', 'Chemical', 'MESH:C572449', (14, 20))	('MLN0128', 'Chemical', 'MESH:C572449', (22, 29))
174658	31911531	We next extended these studies to cells harboring the second resistance mutation of interest, p.L617M, and found that combination of INK128 and FGFR inhibition yielded mildly synergistic effects (Figure 4B).	('inhibition', 'NegReg', (149, 159))	('INK128', 'Chemical', 'MESH:C572449', (133, 139))	('FGFR', 'Gene', (144, 148))	('p.L617M', 'Var', (94, 101))	('p.L617M', 'Mutation', 'rs1057519796', (94, 101))	('INK128', 'Gene', (133, 139))
174659	31911531	Through our case study of a patient with intrahepatic cholangiocarcinoma, we identified two FGFR2 kinase domain mutations, p.E565A and p.L617M, associated with acquired resistance to the selective FGFR inhibitor infigratinib.	('infigratinib', 'Chemical', 'MESH:C568950', (212, 224))	('associated with', 'Reg', (144, 159))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (41, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('intrahepatic cholangiocarcinoma', 'Disease', (41, 72))	('acquired resistance', 'MPA', (160, 179))	('p.E565A', 'Var', (123, 130))	('patient', 'Species', '9606', (28, 35))	('FGFR2', 'Gene', (92, 97))	('FGFR2', 'Gene', '2263', (92, 97))	('p.E565A', 'Mutation', 'rs121918506', (123, 130))	('p.L617M', 'Mutation', 'rs1057519796', (135, 142))	('p.L617M', 'Var', (135, 142))
174660	31911531	Interestingly, only one of these mutations, FGFR2 p.E565A, was identified through sequencing of a tumor biopsy collected from a progressing liver lesion; however, ctDNA captured this mutation as well as a second mutation, FGFR2 p.L617M.	('p.L617M', 'Mutation', 'rs1057519796', (228, 235))	('p.E565A', 'Var', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('p.E565A', 'Mutation', 'rs121918506', (50, 57))	('liver lesion', 'Disease', 'MESH:D017093', (140, 152))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('FGFR2', 'Gene', (222, 227))	('FGFR2', 'Gene', (44, 49))	('FGFR2', 'Gene', '2263', (222, 227))	('liver lesion', 'Disease', (140, 152))	('FGFR2', 'Gene', '2263', (44, 49))	('tumor', 'Disease', (98, 103))	('p.L617M', 'Var', (228, 235))
174663	31911531	Taken collectively, our findings suggest that these mutations confer resistance to FGFR inhibition, but remain sensitive to the non-selective FGFR inhibitor ponatinib.	('resistance', 'MPA', (69, 79))	('mutations', 'Var', (52, 61))	('ponatinib', 'Chemical', 'MESH:C545373', (157, 166))
174669	31911531	Cell-free circulating tumor DNA (ctDNA) has the potential to fully capture tumor heterogeneity including the presence of acquired secondary resistance mutations in patients receiving targeted therapies and therefore has the potential to overcome limitations associated with tumor biopsies.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('acquired secondary resistance', 'MPA', (121, 150))	('patients', 'Species', '9606', (164, 172))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('mutations', 'Var', (151, 160))	('tumor', 'Disease', (75, 80))
174672	31911531	the authors demonstrated that ctDNA can identify FGFR2 mutations that were not present in the tumor biopsies from the same patient.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('patient', 'Species', '9606', (123, 130))	('mutations', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('FGFR2', 'Gene', (49, 54))	('FGFR2', 'Gene', '2263', (49, 54))	('tumor', 'Disease', (94, 99))
174673	31911531	Furthermore, in the patient presented in this manuscript, the FGFR2 p.L617M mutation was identified in ctDNA but was not detected in the tissue biopsy specimen.	('FGFR2', 'Gene', (62, 67))	('p.L617M', 'Mutation', 'rs1057519796', (68, 75))	('FGFR2', 'Gene', '2263', (62, 67))	('p.L617M', 'Var', (68, 75))	('patient', 'Species', '9606', (20, 27))	('ctDNA', 'Disease', (103, 108))
174675	31911531	ctDNA is less invasive, can be collected serially, and thus may be a clinically useful method to track tumor heterogeneity with respect to acquired FGFR resistance mutations in patients.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('patients', 'Species', '9606', (177, 185))	('FGFR', 'Gene', (148, 152))	('mutations', 'Var', (164, 173))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
174676	31911531	Moving forward, upon progression we propose a combination of tumor biopsy and ctDNA for patients with FGFR-mutant cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('FGFR-mutant', 'Gene', (102, 113))	('cancers', 'Disease', (114, 121))	('patients', 'Species', '9606', (88, 96))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('FGFR-mutant', 'Var', (102, 113))	('tumor', 'Disease', (61, 66))
174679	31911531	Interestingly, our in vitro studies support the use of ponatinib following acquisition of both the p.E565A and p.L617M secondary mutations as they retained sensitivity to ponatinib at nanomolar concentrations.	('p.L617M', 'Mutation', 'rs1057519796', (111, 118))	('p.E565A', 'Var', (99, 106))	('ponatinib', 'Chemical', 'MESH:C545373', (171, 180))	('sensitivity', 'MPA', (156, 167))	('p.E565A', 'Mutation', 'rs121918506', (99, 106))	('p.L617M', 'Var', (111, 118))	('ponatinib', 'Chemical', 'MESH:C545373', (55, 64))
174681	31911531	Currently, numerous selective ATP-competitive FGFR inhibitors are being assessed clinically including AZD4547, infigratinib, erdafitinib, pemigatinib (INCB054828), and LY2874455, among others.	('AZD4547', 'Chemical', 'MESH:C572463', (102, 109))	('ATP', 'Chemical', 'MESH:D000255', (30, 33))	('infigratinib', 'Chemical', 'MESH:C568950', (111, 123))	('erdafitinib', 'Chemical', 'MESH:C000604580', (125, 136))	('LY2874455', 'Var', (168, 177))	('AZD4547', 'Var', (102, 109))	('FGFR', 'Gene', (46, 50))	('pemigatinib', 'Chemical', '-', (138, 149))	('LY2874455', 'Chemical', 'MESH:C570663', (168, 177))
174682	31911531	While these inhibitors have shown promising activity in early clinical trials, they are largely ineffective at overcoming the commonly acquired FGFR gatekeeper mutations (FGFR1 V561M, FGFR2 V564F, FGFR3 V555M).	('gatekeeper', 'Species', '111938', (149, 159))	('V564F', 'Mutation', 'p.V564F', (190, 195))	('V561M', 'Var', (177, 182))	('FGFR3', 'Gene', (197, 202))	('FGFR1', 'Gene', (171, 176))	('FGFR1', 'Gene', '2260', (171, 176))	('FGFR', 'Gene', (144, 148))	('FGFR2', 'Gene', (184, 189))	('FGFR2', 'Gene', '2263', (184, 189))	('V561M', 'Mutation', 'p.V561M', (177, 182))	('V555M', 'Mutation', 'rs199544087', (203, 208))	('V564F', 'Var', (190, 195))	('ineffective', 'NegReg', (96, 107))	('V555M', 'Var', (203, 208))
174683	31911531	While not considered gatekeeper mutations, the FGFR2 p.E565A and FGFR2 p.L617M mutations we observed are located near the ATP-binding pocket and are hypothesized to also be resistant to these selective inhibitors.	('FGFR2', 'Gene', (65, 70))	('p.E565A', 'Var', (53, 60))	('FGFR2', 'Gene', '2263', (65, 70))	('ATP', 'Chemical', 'MESH:D000255', (122, 125))	('p.E565A', 'Mutation', 'rs121918506', (53, 60))	('FGFR2', 'Gene', '2263', (47, 52))	('p.L617M', 'Mutation', 'rs1057519796', (71, 78))	('FGFR2', 'Gene', (47, 52))	('gatekeeper', 'Species', '111938', (21, 31))	('p.L617M', 'Var', (71, 78))
174686	31911531	In addition to acquired FGFR2 mutations, numerous studies have identified activation of the PI3K/AKT/mTOR pathway following acquired resistance to FGFR inhibition.	('FGFR2', 'Gene', '2263', (24, 29))	('activation', 'PosReg', (74, 84))	('mutations', 'Var', (30, 39))	('PI3K/AKT/mTOR pathway', 'Pathway', (92, 113))	('FGFR2', 'Gene', (24, 29))
174687	31911531	Through RPPA analysis we also identified increased PI3K/AKT/mTOR activation in an FGFR inhibitor resistant cell line and determined that combination therapy using an FGFR inhibitor with the mTOR inhibitor, INK128, was able to induce synergistic effects that may be able to overcome the therapeutic limitations posed by current mechanisms of resistance.	('inhibitor', 'Var', (171, 180))	('increased', 'PosReg', (41, 50))	('PI3K/AKT/mTOR', 'Pathway', (51, 64))	('combination', 'Interaction', (137, 148))	('INK128', 'Chemical', 'MESH:C572449', (206, 212))	('FGFR', 'Gene', (166, 170))	('activation', 'PosReg', (65, 75))
174716	31500433	Whole genome sequencing performed by the International Cancer Genome Consortium revealed distinct mutations that affect prognosis.	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (98, 107))	('Cancer', 'Disease', (55, 61))	('affect', 'Reg', (113, 119))	('Cancer', 'Disease', 'MESH:D009369', (55, 61))	('prognosis', 'MPA', (120, 129))
174717	31500433	Broadly, BTCs have clusters of mutations in known oncogenes (KRAS, p53, ERBB2/HER2/NEU) and tumor suppressor genes (SMAD-4, BCL-2, p16, and p53).	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('KRAS', 'Gene', (61, 65))	('ERBB2', 'Gene', (72, 77))	('p16', 'Gene', (131, 134))	('NEU', 'Gene', '2064', (83, 86))	('p16', 'Gene', '1029', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('SMAD-4', 'Gene', (116, 122))	('ERBB2', 'Gene', '2064', (72, 77))	('HER2', 'Gene', '2064', (78, 82))	('mutations', 'Var', (31, 40))	('NEU', 'Gene', (83, 86))	('p53', 'Gene', '7157', (67, 70))	('p53', 'Gene', '7157', (140, 143))	('SMAD-4', 'Gene', '4089', (116, 122))	('p53', 'Gene', (67, 70))	('HER2', 'Gene', (78, 82))	('BCL-2', 'Gene', '596', (124, 129))	('tumor', 'Disease', (92, 97))	('BCL-2', 'Gene', (124, 129))	('p53', 'Gene', (140, 143))	('KRAS', 'Gene', '3845', (61, 65))
174718	31500433	IHCC uniquely has FGFR1-3 fusion gene mutation rates of 11-17% and IDH1/2 mutation rates of 5-36%.	('FGFR1-3', 'Gene', (18, 25))	('FGFR1-3', 'Gene', '2260;2263;2261', (18, 25))	('IDH1/2', 'Gene', (67, 73))	('IDH1/2', 'Gene', '3417;3418', (67, 73))	('fusion gene mutation', 'Var', (26, 46))
174719	31500433	The frequency of KRAS and p53 mutations is 40-50% and 2.4-44.4%, respectively.	('p53', 'Gene', (26, 29))	('mutations', 'Var', (30, 39))	('KRAS', 'Gene', (17, 21))	('p53', 'Gene', '7157', (26, 29))	('KRAS', 'Gene', '3845', (17, 21))
174720	31500433	EHCC have ERBB2/ HER2/NEU overexpression frequencies of 5-10%, KRAS mutation rates of 8.3-42%, SMAD4 mutation rates 21%, and PIK3CA mutation rates of 7%.	('KRAS', 'Gene', '3845', (63, 67))	('overexpression', 'PosReg', (26, 40))	('NEU', 'Gene', (22, 25))	('SMAD4', 'Gene', (95, 100))	('PIK3CA', 'Gene', (125, 131))	('ERBB2', 'Gene', (10, 15))	('HER2', 'Gene', (17, 21))	('ERBB2', 'Gene', '2064', (10, 15))	('NEU', 'Gene', '2064', (22, 25))	('HER2', 'Gene', '2064', (17, 21))	('PIK3CA', 'Gene', '5290', (125, 131))	('mutation', 'Var', (101, 109))	('SMAD4', 'Gene', '4089', (95, 100))	('KRAS', 'Gene', (63, 67))
174721	31500433	IDH1/2 mutations are seen at much lower rates of 0-7% compared to IHCC.	('IDH1/2', 'Gene', (0, 6))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('mutations', 'Var', (7, 16))
174724	31500433	Ongoing clinical trials are evaluating the use of FGFR kinase inhibitors (NCT02924376, NCT02150967), IDH1 inhibitors (NCT02989857), and PDL1 immune checkpoint inhibitors (NCT02628067).	('IDH1', 'Gene', (101, 105))	('IDH1', 'Gene', '3417', (101, 105))	('PDL1', 'Gene', (136, 140))	('NCT02924376', 'Var', (74, 85))	('NCT02989857', 'Var', (118, 129))	('NCT02150967', 'Var', (87, 98))	('FGFR', 'Gene', (50, 54))	('PDL1', 'Gene', '29126', (136, 140))
174748	31500433	PVE has been shown to increase the FLR volume an average of 12% and allow 60% of patients previously deemed unresectable due to liver capacity limitations to proceed with surgery.	('PVE', 'Phenotype', 'HP:0030242', (0, 3))	('PVE', 'Var', (0, 3))	('patients', 'Species', '9606', (81, 89))	('FLR volume', 'MPA', (35, 45))	('increase', 'PosReg', (22, 30))
174798	31500433	Despite negative margin resections, however, there was no statistically significant difference in median DFS or OS (P=0.91, P=0.26, respectively).	('resections', 'Var', (24, 34))	('DFS', 'Disease', 'None', (105, 108))	('DFS', 'Disease', (105, 108))
174843	32040444	For example, miR-21 may be oncogenic by inhibiting PDCD4 and TIMP3 in CCA, and miR-204 and miR-320 can regulate Bcl-2 and Mcl-1, respectively.	('miR-21', 'Gene', (13, 19))	('CCA', 'Disease', (70, 73))	('Mcl-1', 'Gene', (122, 127))	('miR-320', 'Var', (91, 98))	('Mcl-1', 'Gene', '4170', (122, 127))	('TIMP3', 'Gene', (61, 66))	('TIMP3', 'Gene', '7078', (61, 66))	('miR-204', 'Gene', '406987', (79, 86))	('miR-21', 'Gene', '406991', (13, 19))	('CCA', 'Phenotype', 'HP:0030153', (70, 73))	('Bcl-2', 'Gene', (112, 117))	('miR-204', 'Gene', (79, 86))	('regulate', 'Reg', (103, 111))	('PDCD4', 'Gene', (51, 56))	('Bcl-2', 'Gene', '596', (112, 117))	('CCA', 'Disease', 'MESH:D018281', (70, 73))	('PDCD4', 'Gene', '27250', (51, 56))	('inhibiting', 'NegReg', (40, 50))
174885	32040444	We analyzed the mutation profile of these screened genes across 33 cancer types, and identified mutated sites in many cancers (Figure 4A and 4B).	('mutated', 'Var', (96, 103))	('cancers', 'Disease', (118, 125))	('cancer type', 'Disease', 'MESH:D009369', (67, 78))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer type', 'Disease', (67, 78))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
174887	32040444	However, in patients with CCA, mutations were identified in only four genes: MKI67, ASPM, TOP2A, and RECQL4 (Figure 4B).	('patients', 'Species', '9606', (12, 20))	('mutations', 'Var', (31, 40))	('MKI67', 'Gene', (77, 82))	('TOP2A', 'Gene', '7153', (90, 95))	('MKI67', 'Gene', '4288', (77, 82))	('CCA', 'Disease', 'MESH:D018281', (26, 29))	('ASPM', 'Gene', (84, 88))	('RECQL4', 'Gene', '9401', (101, 107))	('CCA', 'Disease', (26, 29))	('TOP2A', 'Gene', (90, 95))	('RECQL4', 'Gene', (101, 107))	('CCA', 'Phenotype', 'HP:0030153', (26, 29))	('ASPM', 'Gene', '259266', (84, 88))
174894	32040444	Four genes with mutations identified in patients with CCA, RECQL4, TOP2A, MKI67, and ASPM, were found to have complex interactions with other genes, some of which showed significantly positive expression correlations (Figure 4D).	('CCA', 'Disease', 'MESH:D018281', (54, 57))	('MKI67', 'Gene', '4288', (74, 79))	('ASPM', 'Gene', '259266', (85, 89))	('RECQL4', 'Gene', (59, 65))	('TOP2A', 'Gene', (67, 72))	('patients', 'Species', '9606', (40, 48))	('CCA', 'Disease', (54, 57))	('mutations', 'Var', (16, 25))	('TOP2A', 'Gene', '7153', (67, 72))	('ASPM', 'Gene', (85, 89))	('interactions', 'Interaction', (118, 130))	('RECQL4', 'Gene', '9401', (59, 65))	('expression', 'MPA', (193, 203))	('positive', 'Reg', (184, 192))	('CCA', 'Phenotype', 'HP:0030153', (54, 57))	('MKI67', 'Gene', (74, 79))
174906	32040444	For example, TPX2 is associated with poor survival in gastric cancer, targeting TPX2 can suppress tumor cell growth in prostate cancer, and TPX2 is a potential therapeutic target and a prognostic indicator in clear cell renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('tumor', 'Disease', (98, 103))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (209, 240))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('gastric cancer', 'Disease', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('suppress', 'NegReg', (89, 97))	('prostate cancer', 'Disease', 'MESH:D011471', (119, 134))	('prostate cancer', 'Phenotype', 'HP:0012125', (119, 134))	('TPX2', 'Gene', (80, 84))	('TPX2', 'Gene', '22974', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('TPX2', 'Gene', (13, 17))	('prostate cancer', 'Disease', (119, 134))	('gastric cancer', 'Disease', 'MESH:D013274', (54, 68))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('TPX2', 'Gene', '22974', (13, 17))	('targeting', 'Var', (70, 79))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (209, 240))	('TPX2', 'Gene', (140, 144))	('clear cell renal cell carcinoma', 'Disease', (209, 240))	('gastric cancer', 'Phenotype', 'HP:0012126', (54, 68))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (220, 240))	('TPX2', 'Gene', '22974', (140, 144))
174913	32040444	Overexpression of CENPF may correlate with poor prognosis in breast cancer, CENPF may be a new prognostic biomarker in nonmuscle invasive bladder cancer, and the HnRNPR-CCNB1/CENPF axis contributes to gastric cancer proliferation and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('gastric cancer', 'Disease', 'MESH:D013274', (201, 215))	('bladder cancer', 'Phenotype', 'HP:0009725', (138, 152))	('CCNB1', 'Gene', '891', (169, 174))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('contributes', 'Reg', (186, 197))	('HnRNPR', 'Gene', (162, 168))	('invasive bladder', 'Phenotype', 'HP:0100645', (129, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('CENPF', 'Gene', (76, 81))	('gastric cancer', 'Phenotype', 'HP:0012126', (201, 215))	('CENPF', 'Gene', '1063', (76, 81))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('HnRNPR', 'Gene', '10236', (162, 168))	('CCNB1', 'Gene', (169, 174))	('breast cancer', 'Disease', (61, 74))	('nonmuscle invasive bladder', 'Phenotype', 'HP:0000011', (119, 145))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (129, 152))	('CENPF', 'Gene', (18, 23))	('CENPF', 'Gene', '1063', (18, 23))	('metastasis', 'CPA', (234, 244))	('CENPF', 'Gene', (175, 180))	('invasive bladder cancer', 'Disease', (129, 152))	('gastric cancer', 'Disease', (201, 215))	('CENPF', 'Gene', '1063', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
174914	32040444	FOXM1 and CENPF co-expression could be a potential robust prognostic indicator of poor survival and metastasis in prostate cancer, and these two genes may contribute to driving prostate cancer.	('co-expression', 'Var', (16, 29))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('prostate cancer', 'Disease', (177, 192))	('metastasis in prostate cancer', 'Disease', (100, 129))	('CENPF', 'Gene', (10, 15))	('prostate cancer', 'Disease', 'MESH:D011471', (114, 129))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('prostate cancer', 'Disease', 'MESH:D011471', (177, 192))	('prostate cancer', 'Phenotype', 'HP:0012125', (114, 129))	('CENPF', 'Gene', '1063', (10, 15))	('FOXM1', 'Gene', '2305', (0, 5))	('prostate cancer', 'Phenotype', 'HP:0012125', (177, 192))	('FOXM1', 'Gene', (0, 5))	('metastasis in prostate cancer', 'Disease', 'MESH:D011471', (100, 129))	('contribute', 'Reg', (155, 165))
174976	32093644	The results showed that high expression of protein in this pathway was mostly involved in the worse clinical outcome of CCA patients.	('involved', 'Reg', (78, 86))	('CCA', 'Phenotype', 'HP:0030153', (120, 123))	('CCA', 'Disease', 'MESH:D018281', (120, 123))	('high', 'Var', (24, 28))	('CCA', 'Disease', (120, 123))	('expression', 'MPA', (29, 39))	('patients', 'Species', '9606', (124, 132))	('protein', 'Protein', (43, 50))
174977	32093644	Moreover, targeting of this pathway using NVP-BEZ235 could inhibit tumor growth and metastasis through reduced protein kinase activation.	('NVP-BEZ235', 'Var', (42, 52))	('reduced', 'NegReg', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('reduced protein kinase activation', 'Phenotype', 'HP:0012175', (103, 136))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('protein kinase activation', 'MPA', (111, 136))	('tumor', 'Disease', (67, 72))	('inhibit', 'NegReg', (59, 66))
174979	32093644	The result showed the alteration of Wnt proteins was associated with poor prognosis of CCA patients, and inhibition of beta-catenin expression could inhibit CCA cell growth.	('alteration', 'Var', (22, 32))	('inhibit', 'NegReg', (149, 156))	('beta-catenin', 'Gene', '1499', (119, 131))	('CCA', 'Phenotype', 'HP:0030153', (157, 160))	('patients', 'Species', '9606', (91, 99))	('inhibition', 'Var', (105, 115))	('CCA', 'Phenotype', 'HP:0030153', (87, 90))	('CCA', 'Disease', 'MESH:D018281', (157, 160))	('CCA', 'Disease', (157, 160))	('beta-catenin', 'Gene', (119, 131))	('associated', 'Reg', (53, 63))	('Wnt proteins', 'Protein', (36, 48))	('CCA', 'Disease', 'MESH:D018281', (87, 90))	('CCA', 'Disease', (87, 90))
174983	32093644	ERBB2 amplification was reported for 3.9-8.5% of CCAs.	('ERBB2', 'Gene', '2064', (0, 5))	('CCA', 'Phenotype', 'HP:0030153', (49, 52))	('ERBB2', 'Gene', (0, 5))	('CCA', 'Disease', 'MESH:D018281', (49, 52))	('amplification', 'Var', (6, 19))	('CCA', 'Disease', (49, 52))
174986	32093644	Single-nucleotide variations (SNVs) and insertion-deletions (indels) were found in ERBB3 gene in BTCs (5%).	('BTC', 'Phenotype', 'HP:0100574', (97, 100))	('Single-nucleotide variations', 'Var', (0, 28))	('BTC', 'Disease', 'MESH:D001661', (97, 100))	('ERBB3', 'Gene', '2065', (83, 88))	('insertion-deletions', 'Var', (40, 59))	('ERBB3', 'Gene', (83, 88))	('BTC', 'Disease', (97, 100))
174988	32093644	reported that the mutation of ERBB4 gene was also found in intrahepatic CCA (iCCA).	('ERBB4', 'Gene', '2066', (30, 35))	('ERBB4', 'Gene', (30, 35))	('found', 'Reg', (50, 55))	('intrahepatic CCA', 'Disease', (59, 75))	('CCA', 'Phenotype', 'HP:0030153', (72, 75))	('mutation', 'Var', (18, 26))	('intrahepatic CCA', 'Disease', 'MESH:C535533', (59, 75))	('iCCA', 'Disease', 'MESH:C535533', (77, 81))	('iCCA', 'Disease', (77, 81))	('CCA', 'Phenotype', 'HP:0030153', (78, 81))
174990	32093644	They found that the patients who have KRAS mutation were enriched for immune-related pathways, ErbB and VEGF pathways.	('KRAS', 'Gene', '3845', (38, 42))	('immune-related pathways', 'Pathway', (70, 93))	('mutation', 'Var', (43, 51))	('VEGF', 'Gene', '7422', (104, 108))	('ErbB', 'Gene', '1956', (95, 99))	('ErbB', 'Gene', (95, 99))	('patients', 'Species', '9606', (20, 28))	('VEGF', 'Gene', (104, 108))	('KRAS', 'Gene', (38, 42))
174991	32093644	On the other hand, WNT pathway was enriched in patients with TP53 gene mutation.	('mutation', 'Var', (71, 79))	('patients', 'Species', '9606', (47, 55))	('WNT pathway', 'Pathway', (19, 30))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
174993	32093644	In the current study, we hypothesized that the alteration of these protein kinases including EGFR family, VEGFR3 and its ligand, Eph receptor and its ligand, Akt1 and its activated form, Wnt, and beta-catenin may be used as the predicting markers for post-operative CCA recurrence.	('CCA', 'Disease', 'MESH:D018281', (266, 269))	('beta-catenin', 'Gene', '1499', (196, 208))	('EGFR', 'Gene', '1956', (93, 97))	('Akt1', 'Gene', (158, 162))	('alteration', 'Var', (47, 57))	('VEGFR3', 'Gene', (106, 112))	('EGFR', 'Gene', '1956', (107, 111))	('CCA', 'Phenotype', 'HP:0030153', (266, 269))	('Akt1', 'Gene', '207', (158, 162))	('CCA', 'Disease', (266, 269))	('EGFR', 'Gene', (107, 111))	('EGFR', 'Gene', (93, 97))	('VEGFR3', 'Gene', '2324', (106, 112))	('Eph receptor', 'Gene', (129, 141))	('beta-catenin', 'Gene', (196, 208))
175004	32093644	The antibodies used in this study were as follows: EGFR (1:50; # ab52894), HER3 (1:25; # ab5470), HER4 (1:150; # ab19391), VEGFR3 (1:100; # ab27278), VEGF-C (1:50; # ab135506), Wnt5a (1:100; # ab72583), Beta-Catenin (1:100; # ab32572), p-Akt1 (1:100; # ab32505), Akt1 (1:50; #ab59380) were purchased from Abcam company, UK.	('Wnt5a', 'Gene', '7474', (177, 182))	('EGFR', 'Gene', (51, 55))	('VEGF-C', 'Gene', '7424', (150, 156))	('1:100; # ab72583', 'Var', (184, 200))	('Akt1', 'Gene', (263, 267))	('HER3', 'Gene', (75, 79))	('Wnt5a', 'Gene', (177, 182))	('EGFR', 'Gene', '1956', (124, 128))	('HER4', 'Gene', (98, 102))	('Beta-Catenin', 'Gene', (203, 215))	('Akt1', 'Gene', (238, 242))	('1:100; # ab32572', 'Var', (217, 233))	('EGFR', 'Gene', '1956', (51, 55))	('Akt1', 'Gene', '207', (263, 267))	('VEGFR3', 'Gene', (123, 129))	('Akt1', 'Gene', '207', (238, 242))	('HER3', 'Gene', '2065', (75, 79))	('HER4', 'Gene', '2066', (98, 102))	('EGFR', 'Gene', (124, 128))	('1:100; # ab32505', 'Var', (244, 260))	('Beta-Catenin', 'Gene', '1499', (203, 215))	('VEGFR3', 'Gene', '2324', (123, 129))	('VEGF-C', 'Gene', (150, 156))
175057	32093644	The above results demonstrate that the expression of EGFR, HER2, HER4, EphA3 and p-Akt1 was significantly associated with post-operative recurrence.	('Akt1', 'Gene', (83, 87))	('associated with', 'Reg', (106, 121))	('expression', 'Var', (39, 49))	('EphA3', 'Gene', (71, 76))	('post-operative recurrence', 'CPA', (122, 147))	('HER4', 'Gene', (65, 69))	('HER4', 'Gene', '2066', (65, 69))	('HER2', 'Gene', (59, 63))	('EGFR', 'Gene', '1956', (53, 57))	('Akt1', 'Gene', '207', (83, 87))	('EGFR', 'Gene', (53, 57))	('HER2', 'Gene', '2064', (59, 63))	('EphA3', 'Gene', '2042', (71, 76))
175058	32093644	Patients with high expression of EGFR, HER4 or EphA3 have shorter RFS (p = 0.003: p = 0.001: 0.010; Fig.	('HER4', 'Gene', (39, 43))	('shorter', 'NegReg', (58, 65))	('EphA3', 'Gene', '2042', (47, 52))	('HER4', 'Gene', '2066', (39, 43))	('EphA3', 'Gene', (47, 52))	('EGFR', 'Gene', '1956', (33, 37))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('EGFR', 'Gene', (33, 37))	('RFS', 'MPA', (66, 69))
175090	32093644	Moreover, knockdown of EGFR expression could reduce the colony formation, migration and proliferation of colorectal cancer (CRC).	('CRC', 'Disease', (124, 127))	('colorectal cancer', 'Disease', 'MESH:D015179', (105, 122))	('colony formation', 'CPA', (56, 72))	('CRC', 'Phenotype', 'HP:0003003', (124, 127))	('CRC', 'Disease', 'MESH:D015179', (124, 127))	('migration', 'CPA', (74, 83))	('EGFR', 'Gene', '1956', (23, 27))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('reduce', 'NegReg', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('proliferation', 'CPA', (88, 101))	('EGFR', 'Gene', (23, 27))	('knockdown', 'Var', (10, 19))	('colorectal cancer', 'Disease', (105, 122))
175101	32093644	The previous study, exploring the mechanism underlying Eph receptor induce cancer recurrence demonstrated that co-expression of EphA2 and EphA3 led to the high clonogenicity and tumorigenic potential in recurrence of glioblastoma which has been shown in both in vitro and in vivo models.	('tumor', 'Disease', (178, 183))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('EphA2', 'Gene', (128, 133))	('EphA3', 'Gene', '2042', (138, 143))	('cancer', 'Disease', (75, 81))	('glioblastoma', 'Disease', (217, 229))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('recurrence', 'CPA', (203, 213))	('EphA2', 'Gene', '1969', (128, 133))	('co-expression', 'Var', (111, 124))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('EphA3', 'Gene', (138, 143))	('glioblastoma', 'Phenotype', 'HP:0012174', (217, 229))	('glioblastoma', 'Disease', 'MESH:D005909', (217, 229))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
175102	32093644	Moreover, co-targeting of EphA2 and EphA3 could also reduce clonogenic ability and tumorigenesis.	('reduce', 'NegReg', (53, 59))	('EphA3', 'Gene', '2042', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('co-targeting', 'Var', (10, 22))	('clonogenic ability', 'CPA', (60, 78))	('EphA3', 'Gene', (36, 41))	('EphA2', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('EphA2', 'Gene', '1969', (26, 31))
175136	29152142	Notch enhances proliferation in many different cancers such as bladder, retinoblastoma, and gastric cancer.	('retinoblastoma', 'Disease', (72, 86))	('bladder', 'Disease', (63, 70))	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('proliferation', 'CPA', (15, 28))	('retinoblastoma', 'Phenotype', 'HP:0009919', (72, 86))	('enhances', 'PosReg', (6, 14))	('cancers', 'Disease', (47, 54))	('bladder', 'Disease', 'MESH:D001745', (63, 70))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Notch', 'Var', (0, 5))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('retinoblastoma', 'Disease', 'MESH:D012175', (72, 86))
175139	29152142	Inhibition of Notch induces cell cycle arrest and apoptosis in CCA.	('Notch', 'Gene', (14, 19))	('arrest', 'Disease', 'MESH:D006323', (39, 45))	('Inhibition', 'Var', (0, 10))	('arrest', 'Disease', (39, 45))	('CCA', 'Disease', (63, 66))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (28, 45))	('apoptosis', 'CPA', (50, 59))
175173	29152142	Furthermore, Notch reduction was associated with reduction in phosphorylation of AKT, a key downstream mediator of the PI3-K/AKT pathway (Figure 3A).	('AKT', 'Gene', '207', (125, 128))	('P', 'Chemical', 'MESH:D010758', (119, 120))	('reduction', 'NegReg', (49, 58))	('reduction', 'NegReg', (19, 28))	('AKT', 'Gene', '207', (81, 84))	('phosphorylation', 'MPA', (62, 77))	('AKT', 'Gene', (125, 128))	('AKT', 'Gene', (81, 84))	('Notch', 'Var', (13, 18))
175195	29152142	Recently, Notch1 inhibition has shown to deplete the cancer stem cell population in gastric, breast, and glioma cancers through inhibiting angiogenesis and sensitizing the tumors to chemotherapy.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('angiogenesis', 'CPA', (139, 151))	('glioma cancers', 'Disease', 'MESH:D005910', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Notch1', 'Gene', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('Notch1', 'Gene', '4851', (10, 16))	('inhibition', 'Var', (17, 27))	('breast', 'Disease', (93, 99))	('deplete', 'NegReg', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Disease', (53, 59))	('tumors', 'Disease', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('glioma cancers', 'Disease', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('inhibiting', 'NegReg', (128, 138))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('sensitizing', 'Reg', (156, 167))	('gastric', 'Disease', (84, 91))
175203	29152142	Furthermore, Notch inhibition elicited the reduction in phosphorylation of AKT at the serine 473 residue without changing the levels of total AKT.	('AKT', 'Gene', '207', (75, 78))	('reduction', 'NegReg', (43, 52))	('serine', 'Chemical', 'MESH:D012694', (86, 92))	('AKT', 'Gene', (142, 145))	('inhibition', 'NegReg', (19, 29))	('AKT', 'Gene', (75, 78))	('phosphorylation', 'MPA', (56, 71))	('AKT', 'Gene', '207', (142, 145))	('Notch', 'Var', (13, 18))
175205	29152142	Furthermore, inhibition of AKT by LY294002 significantly suppressed human-growth factor-stimulated invasion in CCA by stabilization of E-cadherin.	('LY294002', 'Var', (34, 42))	('CCA', 'Disease', (111, 114))	('human', 'Species', '9606', (68, 73))	('AKT', 'Gene', (27, 30))	('E-cadherin', 'Gene', '999', (135, 145))	('suppressed', 'NegReg', (57, 67))	('LY294002', 'Chemical', 'MESH:C085911', (34, 42))	('AKT', 'Gene', '207', (27, 30))	('stabilization', 'NegReg', (118, 131))	('inhibition', 'NegReg', (13, 23))	('E-cadherin', 'Gene', (135, 145))	('human-growth', 'CPA', (68, 80))
175206	29152142	Recently, we have shown that inhibition of the AKT pathway by MK-2206, AKT inhibitor, resulted in growth suppression.Therefore, we speculate that inhibition of both Notch and AKT pathways should be synergistic and more efficacious than inhibition of either pathway alone.	('AKT', 'Gene', (47, 50))	('MK-2206', 'Chemical', 'MESH:C548887', (62, 69))	('AKT', 'Gene', '207', (71, 74))	('AKT', 'Gene', '207', (47, 50))	('AKT', 'Gene', '207', (175, 178))	('AKT', 'Gene', (71, 74))	('Notch', 'Pathway', (165, 170))	('inhibition', 'Var', (146, 156))	('AKT', 'Gene', (175, 178))
175209	29152142	Reduction in phosphorylation of AKT at 3 days suggested that Notch signaling precedes and may initiate cross-talk with the PI3K/AKT signaling pathway.	('AKT', 'Gene', '207', (32, 35))	('phosphorylation', 'MPA', (13, 28))	('P', 'Chemical', 'MESH:D010758', (123, 124))	('Notch signaling', 'Var', (61, 76))	('initiate', 'Reg', (94, 102))	('AKT', 'Gene', (128, 131))	('AKT', 'Gene', (32, 35))	('cross-talk', 'Interaction', (103, 113))	('Reduction', 'NegReg', (0, 9))	('AKT', 'Gene', '207', (128, 131))
175259	27999794	Even, some patients could achieve serological conversion of HBsAg (HBsAg-/HBcAb+) whereas, for patients with curative resection of HBV-related HCC, positive HBcAb is associated with higher risk of early recurrence and poorer survival and hepatitis B reactivation in HBsAg-/HBcAb+ patients receiving rituximab for lymphoma.	('HBcAb', 'Gene', (157, 162))	('early recurrence', 'CPA', (197, 213))	('hepatitis', 'Phenotype', 'HP:0012115', (238, 247))	('lymphoma', 'Disease', (313, 321))	('rituximab', 'Chemical', 'MESH:D000069283', (299, 308))	('hepatitis B reactivation', 'MPA', (238, 262))	('HCC', 'Phenotype', 'HP:0001402', (143, 146))	('lymphoma', 'Disease', 'MESH:D008223', (313, 321))	('positive', 'Var', (148, 156))	('lymphoma', 'Phenotype', 'HP:0002665', (313, 321))
175264	27999794	Patients with HBsAg+/HBcAb+ showed a high risk of ICC (OR = 6.857, 95% CI 4.421-10.633) with calculating in a fix-effects model (P = 0.447, I 2 = 0%, Figure 5(a)).	('ICC', 'Disease', (50, 53))	('Patients', 'Species', '9606', (0, 8))	('HBsAg+/HBcAb+', 'Var', (14, 27))
175296	23416860	In addition, patients with node-positive disease or R1 resection appeared to benefit from adjuvant therapy.	('node-positive disease', 'Disease', (27, 48))	('R1 resection', 'Var', (52, 64))	('patients', 'Species', '9606', (13, 21))	('adjuvant therapy', 'CPA', (90, 106))	('benefit', 'PosReg', (77, 84))	('node-positive disease', 'Disease', 'MESH:D012804', (27, 48))
175331	23416860	Related to EGFR, KRAS mutations are also seen in biliary tract cancers, but their frequency is unclear.	('biliary tract cancer', 'Phenotype', 'HP:0100574', (49, 69))	('biliary tract cancers', 'Disease', 'MESH:D001661', (49, 70))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('biliary tract cancers', 'Disease', (49, 70))	('KRAS', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('KRAS', 'Gene', '3845', (17, 21))	('seen', 'Reg', (41, 45))
175346	23416860	VEGF expression in BTC is associated with poor survival, metastasis and disease recurrence; therefore, anti-VEGF therapies have been studied in this disease.	('VEGF', 'Gene', (108, 112))	('VEGF', 'Gene', '7422', (0, 4))	('poor survival', 'CPA', (42, 55))	('expression', 'Var', (5, 15))	('VEGF', 'Gene', '7422', (108, 112))	('metastasis', 'Disease', 'MESH:D009362', (57, 67))	('metastasis', 'Disease', (57, 67))	('VEGF', 'Gene', (0, 4))
175355	23416860	Mitogen-activated ERK (extracellular signal regulated kinase) kinase, or MEK, inhibition is a very promising therapy currently under investigation for multiple solid tumor types, including biliary tract cancers.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (189, 209))	('ERK', 'Gene', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('extracellular signal regulated kinase', 'Gene', (23, 60))	('biliary tract cancers', 'Disease', 'MESH:D001661', (189, 210))	('biliary tract cancers', 'Disease', (189, 210))	('tumor', 'Disease', (166, 171))	('inhibition', 'Var', (78, 88))	('MEK', 'Gene', (73, 76))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('MEK', 'Gene', '5609', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('ERK', 'Gene', '5594', (18, 21))	('extracellular signal regulated kinase', 'Gene', '5594', (23, 60))
175360	23416860	Correlative analysis demonstrated that patients with short-lived stable disease had KRAS mutations, and absence of pERK staining was associated with lack of response, but predicting which patients will respond to MEK inhibitors will require analysis of larger studies with these drugs.	('patients', 'Species', '9606', (39, 47))	('MEK', 'Gene', '5609', (213, 216))	('ERK', 'Gene', '5594', (116, 119))	('KRAS', 'Gene', (84, 88))	('patients', 'Species', '9606', (188, 196))	('KRAS', 'Gene', '3845', (84, 88))	('mutations', 'Var', (89, 98))	('ERK', 'Gene', (116, 119))	('rat', 'Species', '10116', (28, 31))	('MEK', 'Gene', (213, 216))
175363	23416860	Molecular characterizations of BTCs have revealed mutations in target genes such as KRAS, PIK3CA, BRAF, NRAS, IDH1 and IDH2.	('IDH1', 'Gene', '3417', (110, 114))	('NRAS', 'Gene', '4893', (104, 108))	('mutations', 'Var', (50, 59))	('IDH2', 'Gene', (119, 123))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))	('KRAS', 'Gene', (84, 88))	('PIK3CA', 'Gene', (90, 96))	('KRAS', 'Gene', '3845', (84, 88))	('IDH2', 'Gene', '3418', (119, 123))	('NRAS', 'Gene', (104, 108))	('IDH1', 'Gene', (110, 114))	('PIK3CA', 'Gene', '5290', (90, 96))
175445	31307551	found that ICC with positive VEGFR expression represented aggressive malignancy owing to the mechanism that inhibition of VEGFR-2 expression increased apoptosis and decreased cell proliferation.	('VEGFR', 'Gene', '3791', (122, 127))	('decreased', 'NegReg', (165, 174))	('cell proliferation', 'CPA', (175, 193))	('VEGFR', 'Gene', (29, 34))	('VEGFR-2', 'Gene', (122, 129))	('malignancy', 'Disease', 'MESH:D009369', (69, 79))	('increased', 'PosReg', (141, 150))	('malignancy', 'Disease', (69, 79))	('VEGFR', 'Gene', (122, 127))	('ICC', 'Disease', (11, 14))	('VEGFR', 'Gene', '3791', (29, 34))	('apoptosis', 'CPA', (151, 160))	('VEGFR-2', 'Gene', '3791', (122, 129))	('inhibition', 'Var', (108, 118))
175450	31307551	Similarly, a few previous studies found CA199 to be a preoperative predictor of prognosis, while others removed CA199 as an independent prognostic factor of ER.	('removed', 'NegReg', (104, 111))	('CA199', 'Var', (112, 117))	('CA199', 'Var', (40, 45))	('CA199', 'Chemical', '-', (112, 117))	('CA199', 'Chemical', '-', (40, 45))
175461	28670887	PD-L1 positivity was associated with worse overall survival compared with those with a PD-L1 negative tumor but did not reach a level of significance (7.2 vs. 7.9 months, p=0.32).	('positivity', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('PD-L1', 'Gene', (0, 5))	('overall survival', 'MPA', (43, 59))	('worse', 'NegReg', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
175470	28670887	With growing evidence, it is becoming clear that blocking the PD-1/ PD-L1 pathway could benefit in a durable response and prolong overall survival in many cancers, including melanoma, lung, and kidney cancer (Motzer et al., 2015; Robert et al., 2015; Reck et al., 2016).	('lung', 'Disease', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('kidney cancer', 'Phenotype', 'HP:0009726', (194, 207))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Disease', (174, 182))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('kidney cancer', 'Disease', (194, 207))	('benefit', 'PosReg', (88, 95))	('prolong', 'NegReg', (122, 129))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('durable', 'MPA', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', (155, 162))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('PD-1', 'Gene', (62, 66))	('blocking', 'Var', (49, 57))	('kidney cancer', 'Disease', 'MESH:D007680', (194, 207))	('PD-1', 'Gene', '5133', (62, 66))	('overall', 'MPA', (130, 137))
175488	28670887	The Cox regression model was used to assess the association of PD-L1 positivity with OS.	('Cox', 'Gene', '1351', (4, 7))	('Cox', 'Gene', (4, 7))	('association', 'Interaction', (48, 59))	('positivity', 'Var', (69, 79))	('PD-L1', 'Gene', (63, 68))	('OS', 'Chemical', '-', (85, 87))
175499	28670887	There was a significant association of high NLR (>3) and PD-L1 expression (OR=5.36, p=0.018) and stage IV disease (OR=3.98, p=0.046).	('stage IV disease', 'Disease', 'MESH:D058625', (97, 113))	('high', 'Var', (39, 43))	('PD-L1', 'Gene', (57, 62))	('expression', 'MPA', (63, 73))	('stage IV disease', 'Disease', (97, 113))
175500	28670887	PD-L1 positivity was not significantly associated with patients' age, gender, pathological lymph node status, tumor grade, serum albumin, or serum tumor markers that were found as shown in Table 2.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('positivity', 'Var', (6, 16))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('PD-L1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
175518	28670887	In summary, PD-L1 expression in tumors was observed in 70% of cholangiocarcinomas and PD-L1 positivity was associated with high neutrophil/lymphocyte ratio and a higher tumor stage.	('PD-L1', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('associated', 'Reg', (107, 117))	('observed', 'Reg', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (62, 81))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (169, 174))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (62, 80))	('tumors', 'Disease', (32, 38))	('tumor', 'Disease', (32, 37))	('PD-L1', 'Gene', (86, 91))	('positivity', 'Var', (92, 102))	('cholangiocarcinomas', 'Disease', (62, 81))
175625	28864693	Dislocation, migration or clogging of stents causes cholangitis with or without a rise in plasma bilirubin, requiring reintervention.	('bilirubin', 'Chemical', 'MESH:D001663', (97, 106))	('cholangitis', 'Disease', (52, 63))	('clogging', 'Var', (26, 34))	('cholangitis', 'Phenotype', 'HP:0030151', (52, 63))	('Dislocation', 'Var', (0, 11))	('cholangitis', 'Disease', 'MESH:D002761', (52, 63))
175633	28851390	Tumoral LINE-1 hypomethylation is associated with poor survival of patients with intrahepatic cholangiocarcinoma DNA methylation changes occurring in cancer cells are featured with both promoter CpG island hypermethylation and diffuse genomic hypomethylation.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('patients', 'Species', '9606', (67, 75))	('changes', 'Var', (129, 136))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (81, 112))	('intrahepatic cholangiocarcinoma', 'Disease', (81, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (94, 112))
175634	28851390	LINE-1 has its CpG sites of the 5' untranslated region methylated heavily in normal cells and undergoes demethylation in association with cancerization.	('demethylation', 'MPA', (104, 117))	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('methylated', 'Var', (55, 65))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
175635	28851390	However, little information is available regarding LINE-1 hypomethylation and its prognostic implication in intrahepatic cholangiocarcinomas.	('hypomethylation', 'Var', (58, 73))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (108, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))	('intrahepatic cholangiocarcinomas', 'Disease', (108, 140))
175638	28851390	LINE-1 hypomethylation was significantly linked with lower cancer-specific survival in patients with intrahepatic cholangiocarcinoma and was found to be an independent prognostic parameter.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (114, 132))	('hypomethylation', 'Var', (7, 22))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (101, 132))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('intrahepatic cholangiocarcinoma', 'Disease', (101, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('cancer', 'Disease', (59, 65))	('patients', 'Species', '9606', (87, 95))	('lower', 'NegReg', (53, 58))	('LINE-1', 'Gene', (0, 6))
175640	28851390	DNA methylation changes occurring in cancer cells are featured with regional promoter CpG island hypermethylation and generalized genomic hypomethylation.	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('hypermethylation', 'Var', (97, 113))
175641	28851390	Promoter CpG island hypermethylation contributes to inactivation of tumor suppressor genes or tumor-related genes, whereas diffuse genomic hypomethylation is associated with chromosomal instability.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('hypermethylation', 'Var', (20, 36))	('chromosomal instability', 'Phenotype', 'HP:0040012', (174, 197))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('inactivation', 'NegReg', (52, 64))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
175664	28851390	With fixation of tissue samples in formalin solution, formaldehyde induces protein-DNA crosslinks and interstrand DNA crosslinks which may cause some difficulty in thermal and alkaline denaturation.	('formaldehyde', 'Var', (54, 66))	('induces', 'Reg', (67, 74))	('formalin', 'Chemical', 'MESH:D005557', (35, 43))	('formaldehyde', 'Chemical', 'MESH:D005557', (54, 66))	('protein-DNA crosslinks', 'Protein', (75, 97))	('thermal', 'MPA', (164, 171))
175679	28851390	Low LINE-1 methylation status was associated with worse cancer-specific survival in Kaplan-Meier survival analysis.	('methylation status', 'Var', (11, 29))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('LINE-1', 'Gene', (4, 10))	('cancer', 'Disease', (56, 62))	('worse', 'NegReg', (50, 55))	('Low', 'Var', (0, 3))
175680	28851390	In addition to low LINE-1 methylation status, T staging, N staging, lymphatic emboli, perineural invasion, and histological differentiation were included into a multivariate analysis which revealed that a low LINE-1 methylation status was independently associated with worse cancer-specific survival in patients with ICC (Tables 2 and 3).	('ICC', 'Disease', (317, 320))	('low', 'Var', (205, 208))	('methylation status', 'Var', (216, 234))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('lymphatic emboli', 'Phenotype', 'HP:0001004', (68, 84))	('worse', 'NegReg', (269, 274))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('LINE-1', 'Gene', (209, 215))	('cancer', 'Disease', (275, 281))	('patients', 'Species', '9606', (303, 311))
175694	28851390	ICCs belonging to a cluster with a high frequency of mutations in BAP1, IDH1, or NRAS tended to exhibit better clinical outcomes compared with ICCs belonging to two clusters with a high frequency of mutations in TP53, KRAS, or SMAD4.	('IDH1', 'Gene', (72, 76))	('BAP1', 'Gene', '8314', (66, 70))	('SMAD4', 'Gene', '4089', (227, 232))	('IDH1', 'Gene', '3417', (72, 76))	('mutations', 'Var', (53, 62))	('BAP1', 'Gene', (66, 70))	('KRAS', 'Gene', (218, 222))	('better', 'PosReg', (104, 110))	('NRAS', 'Gene', (81, 85))	('KRAS', 'Gene', '3845', (218, 222))	('clinical outcomes', 'CPA', (111, 128))	('SMAD4', 'Gene', (227, 232))	('TP53', 'Gene', '7157', (212, 216))	('NRAS', 'Gene', '4893', (81, 85))	('TP53', 'Gene', (212, 216))
175758	28796833	Our comparisons indicate that there is a statistically significant difference between early and advanced stage patients in the abundances of genus Streptococcus (Fig 3A) and one Streptococcus OTU (Otu00020), and between advanced disease patients and patients with dysplasia/carcinoma in two Streptococcus OTUs (Otu00035 and Otu00061).	('Otu00061', 'Var', (324, 332))	('Otu00035', 'Var', (311, 319))	('patients', 'Species', '9606', (250, 258))	('dysplasia/carcinoma', 'Disease', 'MESH:D002277', (264, 283))	('abundances', 'MPA', (127, 137))	('patients', 'Species', '9606', (111, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('dysplasia/carcinoma', 'Disease', (264, 283))	('significant', 'Reg', (55, 66))	('patients', 'Species', '9606', (237, 245))
175770	28796833	Otu0008, Otu00045, Otu00089, Otu00213, and Otu00188 are all less abundant in the early stage PSC group than in controls, which argues against an etiological role in PSC.	('Otu0008', 'Var', (0, 7))	('PSC', 'Gene', '100653366', (165, 168))	('less', 'NegReg', (60, 64))	('Otu00045', 'Var', (9, 17))	('PSC', 'Gene', (165, 168))	('PSC', 'Gene', '100653366', (93, 96))	('PSC', 'Gene', (93, 96))	('Otu00089', 'Var', (19, 27))	('Otu00188', 'Var', (43, 51))	('Otu00213', 'Var', (29, 37))
175802	26160843	15% of the EGFR gene mutations in the kinase domain are in biliary cancer.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (21, 30))
175803	26160843	K-ras mutation and aberrant expression of p53 are present in one-third of the intrahepatic cholangiocarcinomas.	('p53', 'Gene', (42, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('p53', 'Gene', '7157', (42, 45))	('expression', 'MPA', (28, 38))	('mutation', 'Var', (6, 14))	('intrahepatic cholangiocarcinomas', 'Disease', (78, 110))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (78, 110))	('K-ras', 'Gene', (0, 5))	('K-ras', 'Gene', '3845', (0, 5))	('aberrant', 'Var', (19, 27))	('present', 'Reg', (50, 57))
175804	26160843	These mutations lead to the resistance to many chemotherapeutic agents in cholangiocarcinomas but there is no standard therapy in this situation.	('lead to', 'Reg', (16, 23))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (74, 93))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (74, 92))	('resistance', 'MPA', (28, 38))	('cholangiocarcinomas', 'Disease', (74, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('mutations', 'Var', (6, 15))
175805	26160843	LKB1 (also known as serine-threonine kinase 11, STK11) is a tumor suppressor, which is mutated in various cancers including cholangiocarcinomas.	('cholangiocarcinomas', 'Disease', (124, 143))	('mutated', 'Var', (87, 94))	('LKB1', 'Gene', (0, 4))	('STK11', 'Gene', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('LKB1', 'Gene', '6794', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (124, 143))	('STK11', 'Gene', '6794', (48, 53))	('tumor', 'Disease', (60, 65))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (124, 142))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
175810	26160843	Mutation or loss of LKB1 drives tumorigenesis in several types of tumors.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('LKB1', 'Gene', (20, 24))	('tumor', 'Disease', (66, 71))	('Mutation', 'Var', (0, 8))	('tumors', 'Disease', (66, 72))	('loss', 'NegReg', (12, 16))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('LKB1', 'Gene', '6794', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (32, 37))
175815	26160843	Mutant K-ras renders the constitutively GTP-bound protein, eventually resulting in the activation of the MEK-ERK and the PI3K-AKT antiapoptotic pathways.	('activation', 'PosReg', (87, 97))	('AKT', 'Gene', (126, 129))	('K-ras', 'Gene', '3845', (7, 12))	('ERK', 'Gene', '5594', (109, 112))	('P', 'Chemical', 'MESH:D010758', (42, 43))	('P', 'Chemical', 'MESH:D010758', (121, 122))	('ERK', 'Gene', (109, 112))	('AKT', 'Gene', '207', (126, 129))	('Mutant', 'Var', (0, 6))	('GTP', 'Chemical', 'MESH:D006160', (40, 43))	('K-ras', 'Gene', (7, 12))
175817	26160843	Administering IGF1R-TKI decreases AKT signaling and restores gefitinib sensitivity in mutant K-ras cells.	('K-ras', 'Gene', (93, 98))	('decreases', 'NegReg', (24, 33))	('AKT', 'Gene', (34, 37))	('K-ras', 'Gene', '3845', (93, 98))	('mutant', 'Var', (86, 92))	('gefitinib sensitivity', 'MPA', (61, 82))	('IGF1R-TKI', 'Gene', (14, 23))	('AKT', 'Gene', '207', (34, 37))	('gefitinib', 'Chemical', 'MESH:D000077156', (61, 70))	('restores', 'PosReg', (52, 60))
175819	26160843	Lovastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor; its inhibitory action on HMG-CoA reductase leads to the depletion of isoprenoids, which inhibits posttranslational modification of K-ras.	('3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase', 'Gene', '3156', (16, 73))	('Lovastatin', 'Chemical', 'MESH:D008148', (0, 10))	('inhibitory action', 'Var', (89, 106))	('depletion of isoprenoids', 'MPA', (141, 165))	('K-ras', 'Gene', (216, 221))	('posttranslational modification', 'MPA', (182, 212))	('isoprenoids', 'Chemical', 'MESH:D013729', (154, 165))	('inhibits', 'NegReg', (173, 181))	('K-ras', 'Gene', '3845', (216, 221))
175820	26160843	The effect of the combination of lovastatin with gefitinib on gefitinib-resistant human nonsmall-cell lung cancer (NSCLC) A549 and NCI-H460 cell lines with K-ras mutations has shown to effectively downregulate K-ras protein and suppress the Raf, ERK1/2, AKT, and EGFR phosphorylation in both cell lines.	('downregulate', 'NegReg', (197, 209))	('AKT', 'Gene', (254, 257))	('K-ras', 'Gene', '3845', (210, 215))	('gefitinib', 'Chemical', 'MESH:D000077156', (49, 58))	('S', 'Chemical', 'MESH:D013455', (116, 117))	('nonsmall-cell lung cancer', 'Disease', (88, 113))	('NCI-H460', 'CellLine', 'CVCL:0459', (131, 139))	('Raf', 'Gene', '22882', (241, 244))	('gefitinib', 'Chemical', 'MESH:D000077156', (62, 71))	('K-ras', 'Gene', (156, 161))	('ERK1/2', 'Gene', (246, 252))	('ERK1/2', 'Gene', '5595;5594', (246, 252))	('EGFR', 'Gene', (263, 267))	('AKT', 'Gene', '207', (254, 257))	('K-ras', 'Gene', (210, 215))	('nonsmall-cell lung cancer', 'Disease', 'MESH:D002289', (88, 113))	('mutations', 'Var', (162, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Raf', 'Gene', (241, 244))	('suppress', 'NegReg', (228, 236))	('K-ras', 'Gene', '3845', (156, 161))	('EGFR', 'Gene', '1956', (263, 267))	('lovastatin', 'Chemical', 'MESH:D008148', (33, 43))	('A549', 'CellLine', 'CVCL:0023', (122, 126))	('human', 'Species', '9606', (82, 87))
175822	26160843	Similar results are observed in the combined treatment of lovastatin (1 muM) and gefitinib inhibits proliferation, which promotes cell apoptosis, and reduces the AKT activity in K-ras mutant NSCLC cells compared with gefitinib alone.	('gefitinib', 'Chemical', 'MESH:D000077156', (217, 226))	('S', 'Chemical', 'MESH:D013455', (192, 193))	('AKT', 'Gene', '207', (162, 165))	('lovastatin', 'Chemical', 'MESH:D008148', (58, 68))	('mutant', 'Var', (184, 190))	('cell apoptosis', 'CPA', (130, 144))	('muM', 'Gene', '56925', (72, 75))	('proliferation', 'CPA', (100, 113))	('AKT', 'Gene', (162, 165))	('gefitinib', 'Chemical', 'MESH:D000077156', (81, 90))	('promotes', 'PosReg', (121, 129))	('muM', 'Gene', (72, 75))	('inhibits', 'NegReg', (91, 99))	('reduces', 'NegReg', (150, 157))	('K-ras', 'Gene', (178, 183))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('K-ras', 'Gene', '3845', (178, 183))
175825	26160843	On the other hand, gefitinib induced autophagy and lovastatin induced apoptosis in SSP-25 cells.	('gefitinib', 'Var', (19, 28))	('lovastatin', 'Chemical', 'MESH:D008148', (51, 61))	('gefitinib', 'Chemical', 'MESH:D000077156', (19, 28))	('autophagy', 'CPA', (37, 46))	('apoptosis', 'CPA', (70, 79))
175830	26160843	1A, SSP-25 and HuH-28 cells were resistant to gefitinib; however, the combined treatment of gefitinib and lovastatin significantly decreased viability in a concentration-dependent manner.	('lovastatin', 'Chemical', 'MESH:D008148', (106, 116))	('gefitinib', 'Var', (92, 101))	('combined', 'Interaction', (70, 78))	('HuH-28', 'CellLine', 'CVCL:2955', (15, 21))	('decreased', 'NegReg', (131, 140))	('viability', 'CPA', (141, 150))	('gefitinib', 'Chemical', 'MESH:D000077156', (46, 55))	('gefitinib', 'Chemical', 'MESH:D000077156', (92, 101))
175842	26160843	This suggests that although there are different gene statuses in these two cholangiocarcinoma cell lines, gefitinib can potentiate lovastatin-induced antiproliferation through enhancing TNF-alpha expression.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (75, 93))	('potentiate', 'PosReg', (120, 130))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (75, 93))	('lovastatin', 'Chemical', 'MESH:D008148', (131, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('gefitinib', 'Var', (106, 115))	('lovastatin-induced', 'MPA', (131, 149))	('expression', 'MPA', (196, 206))	('TNF-alpha', 'Gene', '7124', (186, 195))	('TNF-alpha', 'Gene', (186, 195))	('enhancing', 'PosReg', (176, 185))	('gefitinib', 'Chemical', 'MESH:D000077156', (106, 115))	('cholangiocarcinoma', 'Disease', (75, 93))
175851	26160843	However, knockdown of LKB1 did not affect the gefitinib and lovastatin-induced anti-proliferation (data not show).	('LKB1', 'Gene', '6794', (22, 26))	('knockdown', 'Var', (9, 18))	('gefitinib', 'Chemical', 'MESH:D000077156', (46, 55))	('lovastatin', 'Chemical', 'MESH:D008148', (60, 70))	('anti-proliferation', 'CPA', (79, 97))	('LKB1', 'Gene', (22, 26))
175855	26160843	The results indicated that blockage of the autophagic process enhanced lovastatin-induced cytotoxicity (Fig.	('cytotoxicity', 'Disease', 'MESH:D064420', (90, 102))	('enhanced', 'PosReg', (62, 70))	('blockage', 'Var', (27, 35))	('autophagic process', 'CPA', (43, 61))	('lovastatin', 'Chemical', 'MESH:D008148', (71, 81))	('cytotoxicity', 'Disease', (90, 102))
175878	26160843	In this study, the knockdown of ATG5 and the treatment with 3-MA to inhibit autophagy process enhanced the cytotoxicity induced by the combined treatment of gefitinib and lovastatin in SSP-25 cells (Fig.	('cytotoxicity', 'Disease', 'MESH:D064420', (107, 119))	('lovastatin', 'Chemical', 'MESH:D008148', (171, 181))	('knockdown', 'Var', (19, 28))	('ATG5', 'Gene', '9474', (32, 36))	('inhibit', 'NegReg', (68, 75))	('autophagy process', 'CPA', (76, 93))	('3-MA', 'Chemical', '-', (60, 64))	('combined', 'Interaction', (135, 143))	('cytotoxicity', 'Disease', (107, 119))	('enhanced', 'PosReg', (94, 102))	('ATG5', 'Gene', (32, 36))	('gefitinib', 'Chemical', 'MESH:D000077156', (157, 166))
175936	25580681	IL-33 Facilitates Oncogene Induced Cholangiocarcinoma in Mice by an IL-6 Sensitive Mechanism Cholangiocarcinoma (CCA) is a lethal hepatobiliary neoplasm originating from the biliary apparatus.	('Cholangiocarcinoma', 'Disease', (93, 111))	('Mice', 'Species', '10090', (57, 61))	('hepatobiliary neoplasm', 'Disease', 'MESH:D004066', (130, 152))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('IL-33', 'Gene', '77125', (0, 5))	('IL-33', 'Gene', (0, 5))	('IL-6', 'Gene', (68, 72))	('Facilitates', 'PosReg', (6, 17))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (35, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('neoplasm originating from the biliary apparatus', 'Phenotype', 'HP:0100574', (144, 191))	('IL-6', 'Gene', '16193', (68, 72))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (35, 53))	('Cholangiocarcinoma', 'Disease', (35, 53))	('Oncogene', 'Var', (18, 26))	('neoplasm', 'Phenotype', 'HP:0002664', (144, 152))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('hepatobiliary neoplasm', 'Disease', (130, 152))
176011	25580681	Additionally, it has recently been demonstrated that YAP activates the Notch pathway by upregulating jagged 1 (JAG1) in human hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('human', 'Species', '9606', (120, 125))	('hepatocellular carcinoma', 'Disease', (126, 150))	('jagged 1', 'Gene', '182', (101, 109))	('JAG1', 'Gene', '182', (111, 115))	('Notch pathway', 'Pathway', (71, 84))	('YAP', 'Var', (53, 56))	('activates', 'PosReg', (57, 66))	('JAG1', 'Gene', (111, 115))	('jagged 1', 'Gene', (101, 109))	('upregulating', 'PosReg', (88, 100))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (126, 150))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (126, 150))
176016	25580681	As exogenous IL-33 facilitated tumorigenesis in our murine model, we therefore examined expression of its cognate receptor, ST2.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('facilitated', 'PosReg', (19, 30))	('murine', 'Species', '10090', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('exogenous', 'Var', (3, 12))
176038	25580681	Indeed, transduction of the liver with active Notch plus AKT signaling oncogenes results in the development of intrahepatic cholangiocarcinoma.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 142))	('results in', 'Reg', (81, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('intrahepatic cholangiocarcinoma', 'Disease', (111, 142))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (124, 142))	('transduction', 'Var', (8, 20))	('AKT', 'Gene', (57, 60))
176044	25580681	The importance of this pathway in CCA oncogenesis was substantiated by demonstrating that IL-6 can substitute for IL-33 in facilitating tumorigenesis in this model, and by the observation that a significant reduction in CCA development occurs in Il-6 -/- mice.	('mice', 'Species', '10090', (255, 259))	('reduction', 'NegReg', (207, 216))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('Il-6', 'Var', (246, 250))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('CCA', 'Disease', (220, 223))	('tumor', 'Disease', (136, 141))
176059	25580681	For example, the role of IDH mutations or FGFR2 fusion genes described in human CCA can now be readily examined in our model.	('FGFR2', 'Gene', (42, 47))	('FGFR2', 'Gene', '2263', (42, 47))	('IDH', 'Gene', (25, 28))	('CCA', 'Disease', (80, 83))	('fusion genes', 'Var', (48, 60))	('human', 'Species', '9606', (74, 79))
176061	24204826	Activation of Notch Signaling Is Required for Cholangiocarcinoma Progression and Is Enhanced by Inactivation of p53 In Vivo Cholangiocacinoma (CC) is a cancer disease with rising incidence.	('Inactivation', 'Var', (96, 108))	('cancer disease', 'Disease', 'MESH:D009369', (152, 166))	('Cholangiocacinoma', 'Disease', 'None', (124, 141))	('Cholangiocacinoma', 'Disease', (124, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (46, 64))	('Enhanced', 'PosReg', (84, 92))	('p53', 'Gene', (112, 115))	('Cholangiocarcinoma', 'Disease', (46, 64))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer disease', 'Disease', (152, 166))	('p53', 'Gene', '7157', (112, 115))	('Notch Signaling', 'MPA', (14, 29))
176064	24204826	In this study, we investigated the effects of Notch inhibition by gamma-secretase inhibitor IX (GSI IX) in cultured human CC cell lines and we established a transgenic mouse model with liver specific expression of the intracellular domain of Notch (Notch-ICD) and inactivation of tumor suppressor p53.	('GSI IX', 'Chemical', '-', (96, 102))	('mouse', 'Species', '10090', (168, 173))	('inactivation', 'Var', (264, 276))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumor', 'Disease', (280, 285))	('ICD', 'Disease', 'OMIM:252500', (255, 258))	('ICD', 'Disease', (255, 258))	('human', 'Species', '9606', (116, 121))
176066	24204826	In vivo overexpression of Notch-ICD together with an inactivation of p53 significantly increased tumor burden and showed CC characteristics.	('overexpression', 'PosReg', (8, 22))	('increased', 'PosReg', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('p53', 'Gene', (69, 72))	('ICD', 'Disease', 'OMIM:252500', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('ICD', 'Disease', (32, 35))	('CC characteristics', 'CPA', (121, 139))	('tumor', 'Disease', (97, 102))	('inactivation', 'Var', (53, 65))
176067	24204826	Conclusion: Our study highlights the importance of Notch signaling in the tumorigenesis of CC and demonstrates that additional inactivation of p53 in vivo.	('inactivation', 'Var', (127, 139))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('p53', 'Gene', (143, 146))
176074	24204826	Furthermore, losses of the Notch ligand Jagged1 or the Notch 2 gene result in congenital hypoplasia of the biliary system, the Alagille syndrome.	('Notch 2', 'Gene', (55, 62))	('Notch 2', 'Gene', '4853', (55, 62))	('congenital hypoplasia', 'Phenotype', 'HP:0011451', (78, 99))	('Jagged1', 'Gene', (40, 47))	('congenital hypoplasia', 'Disease', (78, 99))	('Alagille syndrome', 'Disease', 'MESH:D016738', (127, 144))	('result in', 'Reg', (68, 77))	('congenital hypoplasia', 'Disease', 'MESH:D000013', (78, 99))	('losses', 'Var', (13, 19))	('Jagged1', 'Gene', '182', (40, 47))	('Alagille syndrome', 'Disease', (127, 144))
176075	24204826	Analysis of mice after liver-specific inactivation of RBP-Jkappa, a common transcriptional mediator of Notch signaling, revealed a reduced number of biliary cells differentiating from hepatoblasts.	('RBP-Jkappa', 'Gene', '19664', (54, 64))	('inactivation', 'Var', (38, 50))	('reduced', 'NegReg', (131, 138))	('biliary cells', 'MPA', (149, 162))	('mice', 'Species', '10090', (12, 16))	('RBP-Jkappa', 'Gene', (54, 64))
176077	24204826	It was also reported that liver-specific expression of the intracellular domain of Notch2 in mice caused biliary hyperplasia.	('biliary hyperplasia', 'Phenotype', 'HP:0006560', (105, 124))	('biliary hyperplasia', 'Disease', (105, 124))	('Notch2', 'Gene', (83, 89))	('mice', 'Species', '10090', (93, 97))	('biliary hyperplasia', 'Disease', 'MESH:D006965', (105, 124))	('expression of the intracellular domain', 'Var', (41, 79))	('Notch2', 'Gene', '18129', (83, 89))	('caused', 'Reg', (98, 104))
176080	24204826	In the present study, we sought to further examine the potential benefit of targeting Notch in CC by studying in detail the impact of gamma-secretase inhibitor IX (GSI) in human CC cell lines and by establishing a transgenic mouse model with liver specific expression of the intracellular domain of Notch (Notch-ICD) and inactivation of p53.	('p53', 'Gene', (337, 340))	('human', 'Species', '9606', (172, 177))	('GSI', 'Chemical', '-', (164, 167))	('mouse', 'Species', '10090', (225, 230))	('ICD', 'Disease', 'OMIM:252500', (312, 315))	('inactivation', 'Var', (321, 333))	('ICD', 'Disease', (312, 315))
176081	24204826	Our work reveals that GSI can impair cell proliferation, EMT, migration and invasion in human CC cell lines.	('migration', 'CPA', (62, 71))	('GSI', 'Chemical', '-', (22, 25))	('impair', 'NegReg', (30, 36))	('GSI', 'Var', (22, 25))	('EMT', 'CPA', (57, 60))	('human', 'Species', '9606', (88, 93))	('cell proliferation', 'CPA', (37, 55))	('invasion', 'CPA', (76, 84))
176082	24204826	Notch activation and loss of p53 together is showing a increased tumor burden in vivo, showing the underlying role of Notch in CC pathogenesis.	('loss', 'Var', (21, 25))	('tumor', 'Disease', (65, 70))	('increased', 'PosReg', (55, 64))	('p53', 'Gene', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('activation', 'PosReg', (6, 16))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
176108	24204826	ROSA26 NICD mice were crossed with AlbCre and p53lox/lox mice to generate mice with a liver specific over expression of the activated form of the Notch1 receptor and inactivation of the tumor suppressor gene p53.	('lox', 'Gene', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('mice', 'Species', '10090', (57, 61))	('ICD', 'Disease', 'OMIM:252500', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('ICD', 'Disease', (8, 11))	('lox', 'Gene', '16948', (53, 56))	('tumor', 'Disease', (186, 191))	('lox', 'Gene', (49, 52))	('p53', 'Gene', (208, 211))	('inactivation', 'Var', (166, 178))	('ROSA26', 'Gene', '14910', (0, 6))	('lox', 'Gene', '16948', (49, 52))	('mice', 'Species', '10090', (12, 16))	('mice', 'Species', '10090', (74, 78))	('ROSA26', 'Gene', (0, 6))	('over expression', 'PosReg', (101, 116))
176136	24204826	We hypothesized that the overexpression of the activated form of the Notch1 receptor together with an inactivation of the tumor suppressor gene p53 will enhance tumor development.	('inactivation', 'Var', (102, 114))	('Notch1', 'Gene', (69, 75))	('enhance', 'PosReg', (153, 160))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('overexpression', 'PosReg', (25, 39))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', (122, 127))	('p53', 'Gene', (144, 147))
176159	24204826	GSI leads to an increase in the number of cells in the subG1 phase of the cell cycle, which correlates with the increase in the number of apoptotic cells.	('increase', 'PosReg', (16, 24))	('GSI', 'Chemical', '-', (0, 3))	('cells in the subG1 phase of the cell cycle', 'CPA', (42, 84))	('increase', 'PosReg', (112, 120))	('GSI', 'Var', (0, 3))
176164	24204826	p53 is the most commonly mutated tumour suppressor gene associated with the development of human cancer and has been implicated in cholangiocarcinoma development by various studies, including immunohistochemical and molecular epidemiological investigations.	('p53', 'Gene', (0, 3))	('cancer', 'Disease', (97, 103))	('tumour', 'Disease', (33, 39))	('human', 'Species', '9606', (91, 96))	('associated', 'Reg', (56, 66))	('cholangiocarcinoma', 'Disease', (131, 149))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (131, 149))	('implicated', 'Reg', (117, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))	('tumour', 'Disease', 'MESH:D009369', (33, 39))	('mutated', 'Var', (25, 32))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
176166	24204826	We hypothesized that overexpression of Notch-ICD together with an inactivation of p53 in a mouse model would accelerate tumor development.	('accelerate', 'PosReg', (109, 119))	('ICD', 'Disease', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('overexpression', 'PosReg', (21, 35))	('inactivation', 'Var', (66, 78))	('p53', 'Gene', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('ICD', 'Disease', 'OMIM:252500', (45, 48))	('mouse', 'Species', '10090', (91, 96))	('tumor', 'Disease', (120, 125))
176167	24204826	In comparison to data from our own working party and a group of control ROSA26/AlbCre mice only, we saw that the additional inactivation of p53 indeed enhanced CC development in our animals, starting with an age of 6 month.	('ROSA26', 'Gene', (72, 78))	('enhanced', 'PosReg', (151, 159))	('mice', 'Species', '10090', (86, 90))	('inactivation', 'Var', (124, 136))	('CC development', 'CPA', (160, 174))	('ROSA26', 'Gene', '14910', (72, 78))	('p53', 'Gene', (140, 143))
176309	30561756	Recent studies uncovered spectra of genetic alterations of BTC that included potential therapy targets.	('genetic alterations', 'Var', (36, 55))	('BTC', 'Disease', (59, 62))	('BTC', 'Disease', 'MESH:D001661', (59, 62))	('BTC', 'Phenotype', 'HP:0100574', (59, 62))
176311	30561756	FGFR2 fusion; IDH1/2, EPHAE, and BAP1mutations are more prevalent in ICC; PRKACA or PRKACB fusion, ELF3, and ARID1B mutations in ECC; EGFR, ERBB3, PTEN, ARID2, MLL2, MLL3, and TERT promoter mutatiosn in GBC).	('ARID2', 'Gene', '196528', (153, 158))	('ICC', 'Disease', 'MESH:C535533', (69, 72))	('MLL2', 'Gene', (160, 164))	('BAP1', 'Gene', (33, 37))	('MLL3', 'Gene', (166, 170))	('PTEN', 'Gene', (147, 151))	('ELF3', 'Gene', (99, 103))	('EGFR', 'Gene', '1956', (134, 138))	('ERBB3', 'Gene', '2065', (140, 145))	('prevalent', 'Reg', (56, 65))	('PRKACA', 'Gene', '5566', (74, 80))	('ARID2', 'Gene', (153, 158))	('IDH1/2', 'Gene', '3417;3418', (14, 20))	('FGFR2', 'Gene', (0, 5))	('ARID1B', 'Gene', (109, 115))	('IDH1/2', 'Gene', (14, 20))	('PTEN', 'Gene', '5728', (147, 151))	('GBC', 'Disease', (203, 206))	('ARID1B', 'Gene', '57492', (109, 115))	('mutations', 'Var', (116, 125))	('TERT', 'Gene', (176, 180))	('FGFR2', 'Gene', '2263', (0, 5))	('ICC', 'Disease', (69, 72))	('MLL2', 'Gene', '9757', (160, 164))	('TERT', 'Gene', '7015', (176, 180))	('PRKACA', 'Gene', (74, 80))	('GBC', 'Disease', 'MESH:D005706', (203, 206))	('ERBB3', 'Gene', (140, 145))	('EGFR', 'Gene', (134, 138))	('ECC', 'Disease', 'MESH:D018281', (129, 132))	('ECC', 'Disease', (129, 132))	('BAP1', 'Gene', '8314', (33, 37))	('MLL3', 'Gene', '58508', (166, 170))	('ELF3', 'Gene', '1999', (99, 103))
176312	30561756	Studies found nearly 40% of BTC cases harbored genetic alterations in potential therapeutic targets, and the repertoire of driver genes diverged across anatomical locations.	('BTC', 'Disease', (28, 31))	('BTC', 'Phenotype', 'HP:0100574', (28, 31))	('genetic alterations', 'Var', (47, 66))	('BTC', 'Disease', 'MESH:D001661', (28, 31))
176313	30561756	Among these significantly altered genes, KRAS, TP53 and ARID2 mutations are high in BTCs and their mutation status of them was significantly associated with poorer patient prognosis.	('KRAS', 'Gene', '3845', (41, 45))	('BTC', 'Disease', (84, 87))	('ARID2', 'Gene', (56, 61))	('TP53', 'Gene', (47, 51))	('patient', 'Species', '9606', (164, 171))	('BTC', 'Phenotype', 'HP:0100574', (84, 87))	('BTC', 'Disease', 'MESH:D001661', (84, 87))	('associated', 'Reg', (141, 151))	('ARID2', 'Gene', '196528', (56, 61))	('TP53', 'Gene', '7157', (47, 51))	('KRAS', 'Gene', (41, 45))	('mutations', 'Var', (62, 71))
176423	29169904	Patients who underwent HAR were significantly more likely to have received neoadjuvant chemotherapy than those who did not undergo VR and those who underwent PVR (3/12 versus 6/170 and 1/19, respectively, p=0.002).	('neoadjuvant chemotherapy', 'CPA', (75, 99))	('Patients', 'Species', '9606', (0, 8))	('HAR', 'Var', (23, 26))
176433	29169904	Patients who received vascular resection also tended to have lower ASA class, although this did not reach statistical significance.	('lower', 'NegReg', (61, 66))	('vascular resection', 'Var', (22, 40))	('Patients', 'Species', '9606', (0, 8))	('ASA', 'Chemical', '-', (67, 70))	('ASA class', 'Disease', (67, 76))
176437	29169904	While some prior series have argued that PVR is a safer operation while HAR should be regarded with caution, the present data show that PVR yielded slightly worse perioperative outcomes, although the number of patients analyzed may be too small to detect true differences.	('PVR', 'Var', (136, 139))	('perioperative outcomes', 'MPA', (163, 185))	('patients', 'Species', '9606', (210, 218))	('worse', 'NegReg', (157, 162))
176550	26087784	Hypertension was significantly more common in the PTBD group than in the EBD group (40.3% vs 20.5%, p=0.031).	('Hypertension', 'Phenotype', 'HP:0000822', (0, 12))	('Hypertension', 'Disease', 'MESH:D006973', (0, 12))	('common', 'Reg', (36, 42))	('PTBD', 'Var', (50, 54))	('Hypertension', 'Disease', (0, 12))	('EBD', 'Chemical', '-', (73, 76))
176559	26087784	Median period of biliary decompression in patients who underwent PTBD was 20 days (range, 3 to 56 days) compared to 18 days (range, 2 to 68 days) for patients who underwent EBD.	('biliary decompression', 'Disease', (17, 38))	('EBD', 'Chemical', '-', (173, 176))	('PTBD', 'Var', (65, 69))	('patients', 'Species', '9606', (150, 158))	('patients', 'Species', '9606', (42, 50))
176618	26087784	In the present study, although we found that ERBD was associated with a higher rate of procedure-related cholangitis than ENBD (44.4% vs 34.3%), the difference was not statistically significant (p=0.702).	('cholangitis', 'Phenotype', 'HP:0030151', (105, 116))	('cholangitis', 'Disease', 'MESH:D002761', (105, 116))	('cholangitis', 'Disease', (105, 116))	('ERBD', 'Var', (45, 49))
176671	22456038	Patients with pancreaticobiliary cancers coded by the International Classification of Diseases for Oncology (ICD-O-3) system as arising from the pancreas (C25.x), gallbladder (C23.9), or biliary tract (C22.1, C22.x) were selected for inclusion in this study.	('C22.1', 'Var', (202, 207))	('pancreas', 'Disease', 'MESH:D010190', (145, 153))	('pancreaticobiliary cancers', 'Disease', (14, 40))	('pancreaticobiliary cancers', 'Disease', 'MESH:D000080222', (14, 40))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('Oncology', 'Phenotype', 'HP:0002664', (99, 107))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('arising', 'Reg', (128, 135))	('pancreas', 'Disease', (145, 153))	('C25.x', 'Var', (155, 160))	('C23.9', 'Var', (176, 181))
176747	22456038	In a large case-control study in Korean patients, a significant association was seen with seropositivity for hepatitis B, but not hepatitis C, and intrahepatic cholangiocarcinoma.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (147, 178))	('hepatitis B', 'Disease', 'MESH:D006509', (109, 120))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (160, 178))	('intrahepatic cholangiocarcinoma', 'Disease', (147, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('patients', 'Species', '9606', (40, 48))	('hepatitis B', 'Disease', (109, 120))	('hepatitis C', 'Species', '11103', (130, 141))	('hepatitis', 'Phenotype', 'HP:0012115', (130, 139))	('hepatitis', 'Phenotype', 'HP:0012115', (109, 118))	('seropositivity', 'Var', (90, 104))
176769	22456038	As a substudy assessing gallbladder disease, a multivariate logistic regression analysis was performed, which showed that age, AI heritage and waist circumference were associated with gallbladder disease among men; and age, AI heritage, diabetes and parity were associated with gallbladder disease among women.	('AI heritage', 'Var', (127, 138))	('men', 'Species', '9606', (210, 213))	('gallbladder disease', 'Phenotype', 'HP:0005264', (184, 203))	('associated', 'Reg', (168, 178))	('gallbladder disease', 'Disease', (24, 43))	('gallbladder disease', 'Disease', (278, 297))	('diabetes', 'Disease', (237, 245))	('associated', 'Reg', (262, 272))	('gallbladder disease', 'Disease', 'MESH:D005705', (184, 203))	('women', 'Species', '9606', (304, 309))	('men', 'Species', '9606', (306, 309))	('diabetes', 'Disease', 'MESH:D003920', (237, 245))	('gallbladder disease', 'Phenotype', 'HP:0005264', (24, 43))	('gallbladder disease', 'Disease', (184, 203))	('gallbladder disease', 'Phenotype', 'HP:0005264', (278, 297))	('gallbladder disease', 'Disease', 'MESH:D005705', (278, 297))	('gallbladder disease', 'Disease', 'MESH:D005705', (24, 43))
176814	33369464	Endogenous peroxidase was blocked with 0.3% H2O2 in methanol for 30 min, followed by incubation with G-Block (Genostaff, Tokyo, Japan) and the avidin/biotin blocking kit (Vector, Burlingame, USA).	('methanol', 'Chemical', 'MESH:D000432', (52, 60))	('biotin', 'Chemical', 'MESH:D001710', (150, 156))	('Endogenous peroxidase', 'Enzyme', (0, 21))	('H2O2', 'Chemical', 'MESH:D006861', (44, 48))	('H2O2', 'Var', (44, 48))
176815	33369464	The sections were incubated with the anti-S100P or gamma-H2AX rabbit monoclonal antibody overnight at 4oC, followed by a biotin-conjugated anti-rabbit IgG (Dako, Santa Clara, USA) for 30 min at room temperature and the addition of peroxidase-conjugated streptavidin (Nichirei, Tokyo, Japan) for 5 min at room temperature.	('S100P', 'Gene', (42, 47))	('biotin', 'Chemical', 'MESH:D001710', (121, 127))	('gamma-H2AX', 'Chemical', '-', (51, 61))	('S100P', 'Gene', '6286', (42, 47))	('gamma-H2AX', 'Var', (51, 61))
176818	33369464	Multiple fields in sections were observed under x200 magnification, and areas with strongest nuclear staining for gamma-H2AX and S100P were selected to determine the proportions of cells that were positive and negative for gamma-H2AX and S100P.	('S100P', 'Gene', '6286', (129, 134))	('S100P', 'Gene', '6286', (238, 243))	('gamma-H2AX', 'Chemical', '-', (223, 233))	('gamma-H2AX', 'Chemical', '-', (114, 124))	('S100P', 'Gene', (129, 134))	('S100P', 'Gene', (238, 243))	('gamma-H2AX', 'Var', (223, 233))
176867	33369464	The positive expression of gamma-H2AX, the phosphorylated form of a histone 2A variant which indicates the presence of DNA double-stranded breaks, i.e., DNA injury, is observed in various cancers (Bartkova et al., 2005).	('gamma-H2AX', 'Chemical', '-', (27, 37))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('positive', 'PosReg', (4, 12))	('cancers', 'Disease', (188, 195))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('gamma-H2AX', 'Var', (27, 37))
176873	33369464	On the other hand, patients without gamma-H2AX or S100P expressions did not develop postoperative carcinogenesis.	('patients', 'Species', '9606', (19, 27))	('postoperative carcinogenesis', 'Disease', 'MESH:D063646', (84, 112))	('S100P', 'Gene', '6286', (50, 55))	('gamma-H2AX', 'Var', (36, 46))	('postoperative carcinogenesis', 'Disease', (84, 112))	('S100P', 'Gene', (50, 55))	('gamma-H2AX', 'Chemical', '-', (36, 46))
176930	33572744	The study was based on all cases of primary liver cancer (International Classification of Disease, Tenth Revision (ICD-10) C220 and C221) reported to the Registry during 1998-2015.	('primary liver cancer', 'Disease', 'MESH:D006528', (36, 56))	('C221', 'Var', (132, 136))	('Classification of Disease', 'Disease', (72, 97))	('liver cancer', 'Phenotype', 'HP:0002896', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('primary liver cancer', 'Disease', (36, 56))	('Classification of Disease', 'Disease', 'MESH:D008310', (72, 97))
176933	33572744	The histology codes were grouped into the following categories: hepatocellular carcinoma (ICDO-3 codes: 8170-8175), cholangiocarcinoma (ICDO-3 codes: 8032-8033, 8041, 8050, 8070-8071, 8140-8141, 8160, 8260, 8480, 8481, 8490, and 8560), other, and unspecified.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (116, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('hepatocellular carcinoma', 'Disease', (64, 88))	('8070-8071', 'Var', (173, 182))	('8041', 'Var', (161, 165))	('8032-8033', 'Var', (150, 159))	('8160', 'Var', (195, 199))	('8560', 'Var', (229, 233))	('8490', 'Var', (219, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('unspecified', 'Species', '32644', (247, 258))	('8050', 'Var', (167, 171))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (64, 88))	('8140-8141', 'Var', (184, 193))	('8481', 'Var', (213, 217))	('8260', 'Var', (201, 205))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))	('cholangiocarcinoma', 'Disease', (116, 134))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (64, 88))	('8480', 'Var', (207, 211))
177000	33572744	Before initiating screening of blood donors, anti-HCV was found in 7.9% of commercial blood donors, 13.9% of commercial blood plasma donors, 48.3% of hemodialysis patients, and 29.4% of prisoners.	('found', 'Reg', (58, 63))	('patients', 'Species', '9606', (163, 171))	('anti-HCV', 'Var', (45, 53))	('HCV', 'Species', '11103', (50, 53))
177011	33572744	Lack of achieving SVR is a strong independent predictor of the development of HCC early after the treatment of hepatitis C with DAA.	('hepatitis', 'Disease', (111, 120))	('Lack', 'Var', (0, 4))	('men', 'Species', '9606', (103, 106))	('men', 'Species', '9606', (70, 73))	('HCC', 'Disease', (78, 81))	('hepatitis', 'Phenotype', 'HP:0012115', (111, 120))	('DAA', 'Chemical', '-', (128, 131))	('hepatitis', 'Disease', 'MESH:D056486', (111, 120))
177012	33572744	Eradication of HCV reduces, but does not eliminate, the risk of HCC development, especially when the advanced hepatic fibrosis already originated.	('HCC development', 'Disease', (64, 79))	('fibrosis', 'Disease', 'MESH:D005355', (118, 126))	('Eradication', 'Var', (0, 11))	('fibrosis', 'Disease', (118, 126))	('men', 'Species', '9606', (75, 78))	('HCV', 'Species', '11103', (15, 18))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (110, 126))
177053	26627606	TGFB signaling in liver epithelial cells was inhibited by albumin-Cre-, K19-CreERT-, Prom1-CreERT2-, or AAV8-TBG-Cre-mediated deletion of the floxed TGFB receptor II gene (Tgfbr2).	('TBG', 'Gene', '331535', (109, 112))	('TGFB', 'Gene', '21803', (0, 4))	('Prom1', 'Gene', (85, 90))	('inhibited', 'NegReg', (45, 54))	('albumin', 'Gene', (58, 65))	('TGFB', 'Gene', (0, 4))	('Tgfbr2', 'Gene', '21813', (172, 178))	('TGFB', 'Gene', '21803', (149, 153))	('TBG', 'Gene', (109, 112))	('albumin', 'Gene', '11657', (58, 65))	('Prom1', 'Gene', '19126', (85, 90))	('deletion', 'Var', (126, 134))	('K19', 'Gene', '16669', (72, 75))	('TGFB', 'Gene', (149, 153))	('K19', 'Gene', (72, 75))	('Tgfbr2', 'Gene', (172, 178))
177054	26627606	Liver fibrosis was induced by carbon tetrachloride, bile duct ligation, or disruption of the multidrug-resistance transporter 2 gene (Mdr2).	('carbon tetrachloride', 'Chemical', 'MESH:D002251', (30, 50))	('Liver fibrosis', 'Phenotype', 'HP:0001395', (0, 14))	('disruption', 'Var', (75, 85))	('induced', 'Reg', (19, 26))	('Mdr2', 'Gene', (134, 138))	('bile duct', 'Disease', (52, 61))	('Liver fibrosis', 'Disease', 'MESH:D008103', (0, 14))	('Liver fibrosis', 'Disease', (0, 14))
177056	26627606	Deletion of Tgfbr2 from liver epithelial cells did not alter liver injury, toxin-induced or biliary fibrosis, or diethylnitrosamine-induced hepatocarcinogenesis.	('hepatocarcinogenesis', 'Disease', (140, 160))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (113, 131))	('Tgfbr2', 'Gene', (12, 18))	('liver injury', 'Disease', (61, 73))	('fibrosis', 'Disease', (100, 108))	('fibrosis', 'Disease', 'MESH:D005355', (100, 108))	('liver injury', 'Disease', 'MESH:D056486', (61, 73))	('Tgfbr2', 'Gene', '21813', (12, 18))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (140, 160))	('Deletion', 'Var', (0, 8))
177057	26627606	In contrast, epithelial deletion of Tgfbr2 promoted tumorigenesis and reduced survival of mice with concomitant hepatic deletion of Pten, accompanied by an increase in tumor number and a shift from hepatocellular carcinoma to cholangiocarcinoma.	('Pten', 'Gene', '19211', (132, 136))	('tumor', 'Disease', (52, 57))	('tumor number', 'Disease', (168, 180))	('deletion', 'Var', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('Tgfbr2', 'Gene', '21813', (36, 42))	('survival', 'CPA', (78, 86))	('increase', 'PosReg', (156, 164))	('hepatocellular carcinoma to cholangiocarcinoma', 'Disease', 'MESH:D006528', (198, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('hepatocellular carcinoma to cholangiocarcinoma', 'Disease', (198, 244))	('reduced', 'NegReg', (70, 77))	('tumor', 'Disease', (168, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('Tgfbr2', 'Gene', (36, 42))	('tumor number', 'Disease', 'MESH:D009369', (168, 180))	('mice', 'Species', '10090', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('shift', 'Reg', (187, 192))	('promoted', 'PosReg', (43, 51))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (226, 244))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (198, 222))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('Pten', 'Gene', (132, 136))
177058	26627606	Surprisingly, both hepatocyte-and cholangiocyte-specific deletion of Pten and Tgfbr2 promoted the development of cholangiocarcinoma, but with different latencies.	('cholangiocarcinoma', 'Disease', (113, 131))	('Tgfbr2', 'Gene', '21813', (78, 84))	('chol', 'Chemical', '-', (113, 117))	('deletion', 'Var', (57, 65))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (113, 131))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (113, 131))	('promoted', 'PosReg', (85, 93))	('Tgfbr2', 'Gene', (78, 84))	('chol', 'Chemical', '-', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('Pten', 'Gene', (69, 73))	('Pten', 'Gene', '19211', (69, 73))
177059	26627606	The prolonged latency and the presence of hepatocyte-derived cholangiocytes after AAV8-TBG-Cre-mediated deletion of Tgfbr2 and Pten indicated that cholangiocarcinoma might arise from hepatocyte-derived cholangiocytes in this model.	('TBG', 'Gene', (87, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('cholangiocarcinoma', 'Disease', (147, 165))	('chol', 'Chemical', '-', (61, 65))	('Tgfbr2', 'Gene', (116, 122))	('Pten', 'Gene', (127, 131))	('Pten', 'Gene', '19211', (127, 131))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (147, 165))	('chol', 'Chemical', '-', (147, 151))	('chol', 'Chemical', '-', (202, 206))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (147, 165))	('TBG', 'Gene', '331535', (87, 90))	('Tgfbr2', 'Gene', '21813', (116, 122))	('deletion', 'Var', (104, 112))
177060	26627606	Pten deletion resulted in upregulation of Tgfbr2, and deletion of Tgfbr2 increased cholangiocyte but not hepatocyte proliferation, indicating that the main function of epithelial TGFBR2 is to restrict cholangiocyte proliferation.	('upregulation', 'PosReg', (26, 38))	('chol', 'Chemical', '-', (83, 87))	('chol', 'Chemical', '-', (201, 205))	('deletion', 'Var', (54, 62))	('TGFBR2', 'Gene', (179, 185))	('Tgfbr2', 'Gene', '21813', (42, 48))	('TGFBR2', 'Gene', '21813', (179, 185))	('rat', 'Species', '10116', (222, 225))	('Tgfbr2', 'Gene', '21813', (66, 72))	('cholangiocyte', 'MPA', (83, 96))	('restrict', 'NegReg', (192, 200))	('increased', 'PosReg', (73, 82))	('deletion', 'Var', (5, 13))	('rat', 'Species', '10116', (123, 126))	('Pten', 'Gene', (0, 4))	('Pten', 'Gene', '19211', (0, 4))	('cholangiocyte proliferation', 'CPA', (201, 228))	('Tgfbr2', 'Gene', (42, 48))	('Tgfbr2', 'Gene', (66, 72))
177068	26627606	In another study, ablation of TGFbeta receptor II (TBR2) or SMAD4 reduced the development of liver fibrosis induced by the hepatocyte-specific ablation of TAK1.	('reduced', 'NegReg', (66, 73))	('TAK1', 'Gene', '26409', (155, 159))	('TBR2', 'Gene', (51, 55))	('liver fibrosis', 'Disease', 'MESH:D008103', (93, 107))	('TGFbeta receptor II', 'Gene', (30, 49))	('TGFbeta receptor II', 'Gene', '21813', (30, 49))	('SMAD4', 'Gene', (60, 65))	('TAK1', 'Gene', (155, 159))	('liver fibrosis', 'Phenotype', 'HP:0001395', (93, 107))	('SMAD4', 'Gene', '17128', (60, 65))	('ablation', 'Var', (18, 26))	('liver fibrosis', 'Disease', (93, 107))
177070	26627606	Ablation of TBR2 in this model may modulate the phenotype of hepatic TAK1 deficiency rather than instructing about the role of TBR2 in epithelial responses to injury.	('Ablation', 'Var', (0, 8))	('hepatic TAK1 deficiency', 'Disease', 'MESH:D056486', (61, 84))	('rat', 'Species', '10116', (85, 88))	('TBR2', 'Gene', (12, 16))	('hepatic TAK1 deficiency', 'Disease', (61, 84))	('modulate', 'Reg', (35, 43))
177073	26627606	Loss of Smad4 is common in cholangiocarcinoma, but loss of TGFbeta receptor II (TBR2) has also been described.	('cholangiocarcinoma', 'Disease', (27, 45))	('TBR2', 'Gene', (80, 84))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (27, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('Smad4', 'Gene', (8, 13))	('TGFbeta receptor II', 'Gene', (59, 78))	('TGFbeta receptor II', 'Gene', '21813', (59, 78))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (27, 45))	('loss', 'NegReg', (51, 55))	('Loss', 'Var', (0, 4))
177078	26627606	Using multiple cell-specific Cre deleters to delete floxed TBR2 in hepatocytes, cholangiocytes or both populations, we demonstrate that epithelial TGFbeta signaling does not affect liver fibrosis but that it suppresses the development of cholangiocarcinoma arising from hepatocytes and cholangiocytes by restricting cholangiocyte proliferation.	('delete', 'Var', (45, 51))	('development', 'CPA', (223, 234))	('cholangiocyte proliferation', 'CPA', (316, 343))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('liver fibrosis', 'Phenotype', 'HP:0001395', (181, 195))	('suppresses', 'NegReg', (208, 218))	('rat', 'Species', '10116', (126, 129))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (238, 256))	('liver fibrosis', 'Disease', (181, 195))	('cholangiocarcinoma', 'Disease', (238, 256))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (238, 256))	('TBR2', 'Gene', (59, 63))	('chol', 'Chemical', '-', (286, 290))	('chol', 'Chemical', '-', (80, 84))	('chol', 'Chemical', '-', (238, 242))	('rat', 'Species', '10116', (337, 340))	('restricting', 'NegReg', (304, 315))	('liver fibrosis', 'Disease', 'MESH:D008103', (181, 195))	('chol', 'Chemical', '-', (316, 320))
177079	26627606	For liver-specific deletion of PTEN and TBR2, Albumin-Cre mice were crossed with floxed PTEN mice (both from Jackson, in C57Bl/6 background), floxed TBR2 mice (a gift from Hal Moses, Vanderbilt University, Nashville, TN; in C57Bl/6 background) or both.	('PTEN', 'Gene', (31, 35))	('mice', 'Species', '10090', (154, 158))	('Albumin', 'Gene', (46, 53))	('deletion', 'Var', (19, 27))	('mice', 'Species', '10090', (58, 62))	('Albumin', 'Gene', '11657', (46, 53))	('mice', 'Species', '10090', (93, 97))
177090	26627606	Liver-specific (via Albumin-Cre) or hepatocyte-specific (via AAV8-TBG-Cre) ablation of PTEN or PTEN and TBR2 were employed as genetic carcinogenesis models.	('TBG', 'Gene', (66, 69))	('PTEN', 'Gene', (87, 91))	('TBR2', 'Gene', (104, 108))	('Albumin', 'Gene', '11657', (20, 27))	('TBG', 'Gene', '331535', (66, 69))	('ablation', 'Var', (75, 83))	('genetic carcinogenesis', 'Disease', 'MESH:D030342', (126, 148))	('PTEN', 'Gene', (95, 99))	('Albumin', 'Gene', (20, 27))	('genetic carcinogenesis', 'Disease', (126, 148))
177091	26627606	For some induction of cholangiocarcinoma, mice with cholangiocyte-specific PTEN and TBR2 ablation were fed a 0.1% 3,5-diethoxycarbonyl-1,4-dihydro-collidin (DDC)-containing diet for 6-8 weeks.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (22, 40))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (22, 40))	('mice', 'Species', '10090', (42, 46))	('chol', 'Chemical', '-', (22, 26))	('3,5-diethoxycarbonyl-1,4-dihydro-collidin', 'Chemical', '-', (114, 155))	('DDC', 'Chemical', '-', (157, 160))	('TBR2', 'Gene', (84, 88))	('cholangiocarcinoma', 'Disease', (22, 40))	('chol', 'Chemical', '-', (52, 56))	('ablation', 'Var', (89, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
177104	26627606	In CCl4-, BDL-and Mdr2ko-induced liver injury we observed a similar pattern of pSmad3 expression (Suppl.Fig.1A).	('CCl4', 'Gene', (3, 7))	('Mdr2ko-induced', 'Var', (18, 32))	('liver injury', 'Disease', (33, 45))	('CCl4', 'Gene', '20303', (3, 7))	('liver injury', 'Disease', 'MESH:D056486', (33, 45))	('expression', 'MPA', (86, 96))	('BDL-and', 'Var', (10, 17))	('pSmad3', 'Gene', (79, 85))
177107	26627606	To determine whether epithelial TGFbeta signaling affects the development of liver fibrosis, we generated double transgenic mice co-expressing floxed TBR2 and Albumin-Cre (TBR2lko) leading to the deletion of TBR2 in hepatocytes and cholangiocytes.	('liver fibrosis', 'Disease', (77, 91))	('chol', 'Chemical', '-', (232, 236))	('Albumin', 'Gene', '11657', (159, 166))	('liver fibrosis', 'Disease', 'MESH:D008103', (77, 91))	('transgenic mice', 'Species', '10090', (113, 128))	('deletion', 'Var', (196, 204))	('TBR2', 'Gene', (208, 212))	('liver fibrosis', 'Phenotype', 'HP:0001395', (77, 91))	('Albumin', 'Gene', (159, 166))	('rat', 'Species', '10116', (100, 103))
177113	26627606	To address the possibility that epithelial TBR2 might play a role in cholangiocytes rather than in hepatocytes, we additionally investigated biliary liver fibrosis induced by bile duct ligation (BDL) or by knockout of Mdr2, a model of progressive cholestatic liver disease that closely resembles human disease.	('Mdr2', 'Gene', (218, 222))	('cholestatic liver', 'Phenotype', 'HP:0002611', (247, 264))	('liver disease', 'Phenotype', 'HP:0001392', (259, 272))	('human', 'Species', '9606', (296, 301))	('chol', 'Chemical', '-', (247, 251))	('rat', 'Species', '10116', (84, 87))	('cholestatic liver disease', 'Phenotype', 'HP:0002611', (247, 272))	('investigated', 'Reg', (128, 140))	('liver fibrosis', 'Phenotype', 'HP:0001395', (149, 163))	('cholestatic liver disease', 'Disease', 'MESH:D008107', (247, 272))	('knockout', 'Var', (206, 214))	('chol', 'Chemical', '-', (69, 73))	('cholestatic liver disease', 'Disease', (247, 272))	('biliary liver fibrosis', 'Disease', (141, 163))	('biliary liver fibrosis', 'Disease', 'MESH:D008103', (141, 163))
177118	26627606	To test this hypothesis, TBR2lko and floxed littermate controls were subjected to diethylnitrosamine (DEN) at day 15 postpartum, and sacrificed 10 months later.	('TBR2lko', 'Var', (25, 32))	('DEN', 'Chemical', 'MESH:D004052', (102, 105))	('subjected', 'Reg', (69, 78))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (82, 100))
177122	26627606	We chose this model as PTEN deletion led to a significant upregulation of Tgfbr2 mRNA and protein (Supp.Fig.3A-C), suggesting that TBR2 provides a protective signal that restricts the proliferation of PTEN-deleted cells.	('Tgfbr2', 'Gene', '21813', (74, 80))	('rat', 'Species', '10116', (191, 194))	('PTEN', 'Gene', (23, 27))	('Tgfbr2', 'Gene', (74, 80))	('restricts', 'NegReg', (170, 179))	('deletion', 'Var', (28, 36))	('upregulation', 'PosReg', (58, 70))
177123	26627606	Hepatic deletion of PTEN and TBR2 was at the expected rate of  80%, representing the percentage of hepatocytes and cholangiocytes in the total liver (Suppl.Fig.3A-B).	('chol', 'Chemical', '-', (115, 119))	('Hep', 'Gene', '109838', (0, 3))	('rat', 'Species', '10116', (54, 57))	('TBR2', 'Gene', (29, 33))	('Hep', 'Gene', (0, 3))	('PTEN', 'Gene', (20, 24))	('deletion', 'Var', (8, 16))
177128	26627606	Together, these data suggest that the loss of TBR2 in the epithelial compartment promotes a shift from hepatocellular carcinoma to cholangiocarcinoma when there is loss of PTEN expression, a common event in human hepatocarcinogenesis.	('loss', 'Var', (38, 42))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (103, 127))	('hepatocellular carcinoma to cholangiocarcinoma', 'Disease', 'MESH:D006528', (103, 149))	('TBR2', 'Gene', (46, 50))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (213, 233))	('hepatocarcinogenesis', 'Disease', (213, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('human', 'Species', '9606', (207, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))	('hepatocellular carcinoma to cholangiocarcinoma', 'Disease', (103, 149))	('shift', 'MPA', (92, 97))
177129	26627606	These relevance of these findings is emphasized by the high percentage of mutations in the TGFbeta signaling pathway, in particular Smad4, in most studies of human cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (164, 182))	('TGFbeta', 'Gene', (91, 98))	('human', 'Species', '9606', (158, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('mutations', 'Var', (74, 83))	('Smad4', 'Gene', (132, 137))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (164, 182))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (164, 182))
177130	26627606	Our findings therefore suggest that TGFbeta-mediated activated of Smad4 represents a mechanism that protects from cholangiocarcinoma development, and that loss of this protective pathway promotes cancer development.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (114, 132))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('Smad4', 'Gene', (66, 71))	('protects', 'NegReg', (100, 108))	('loss', 'Var', (155, 159))	('cholangiocarcinoma', 'Disease', (114, 132))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('promotes', 'PosReg', (187, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (114, 132))
177135	26627606	Together with our finding that epithelial TBR2 deletion results in expansion of keratin-positive cells in biliary fibrosis (Suppl.Fig.2C), these findings indicate that TBR2 restricts proliferation in cholangiocytes, suggesting that loss of this restriction after TBR2 deletion may promote the development of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (308, 326))	('TBR2', 'Gene', (42, 46))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (308, 326))	('chol', 'Chemical', '-', (308, 312))	('promote', 'PosReg', (281, 288))	('rat', 'Species', '10116', (190, 193))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (308, 326))	('fibrosis', 'Disease', (114, 122))	('TBR2', 'Gene', (263, 267))	('proliferation', 'CPA', (183, 196))	('deletion', 'Var', (47, 55))	('rat', 'Species', '10116', (82, 85))	('fibrosis', 'Disease', 'MESH:D005355', (114, 122))	('loss', 'Var', (232, 236))	('deletion', 'Var', (268, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (317, 326))	('restricts', 'NegReg', (173, 182))	('chol', 'Chemical', '-', (200, 204))
177139	26627606	These approaches permitted to delete PTEN and TBR2 in cholangiocytes without affecting hepatocytes as demonstrated in Prom1-CreERT2 mice with fluorescent Cre reporters (Suppl.	('chol', 'Chemical', '-', (54, 58))	('TBR2', 'Gene', (46, 50))	('Prom1', 'Gene', (118, 123))	('Prom1', 'Gene', '19126', (118, 123))	('PTEN', 'Gene', (37, 41))	('rat', 'Species', '10116', (109, 112))	('mice', 'Species', '10090', (132, 136))	('delete', 'Var', (30, 36))
177146	26627606	Together these data not only suggest that cholangiocytes are the cellular origin of cholangiocarcinomas in this model, but that the loss of TGFbeta-mediated growth restriction in cholangiocytes promotes cancer development.	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (84, 103))	('promotes', 'PosReg', (194, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('chol', 'Chemical', '-', (84, 88))	('cholangiocarcinomas', 'Disease', (84, 103))	('loss', 'Var', (132, 136))	('chol', 'Chemical', '-', (179, 183))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('growth restriction', 'Phenotype', 'HP:0001510', (157, 175))	('chol', 'Chemical', '-', (42, 46))	('TGFbeta-mediated', 'Gene', (140, 156))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
177147	26627606	To determine whether the combined deletion of TBR2 and PTEN in hepatocytes was responsible for cholangiocarcinoma development, we employed AAV8-TBG-Cre, allowing for selective ablation of TBR2 and PTEN in hepatocytes (Fig.5A).	('TBG', 'Gene', (144, 147))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (95, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (95, 113))	('TBR2', 'Gene', (46, 50))	('TBG', 'Gene', '331535', (144, 147))	('deletion', 'Var', (34, 42))	('TBR2', 'Gene', (188, 192))	('cholangiocarcinoma', 'Disease', (95, 113))	('PTEN', 'Gene', (55, 59))
177148	26627606	As previously reported, AAV8-TBG-Cre-mediated deletion was highly efficient with a 94.4% and 71.3% reduction of Pten and Tgfbr2 mRNA expression, respectively, in whole liver (Suppl.Fig.5A).	('deletion', 'Var', (46, 54))	('Pten', 'Gene', (112, 116))	('Tgfbr2', 'Gene', '21813', (121, 127))	('Pten', 'Gene', '19211', (112, 116))	('reduction', 'NegReg', (99, 108))	('TBG', 'Gene', (29, 32))	('TBG', 'Gene', '331535', (29, 32))	('mRNA expression', 'MPA', (128, 143))	('Tgfbr2', 'Gene', (121, 127))
177150	26627606	In constrat to mice with liver-specific TBR2 and PTEN deletion via Albumin-Cre, all mice with hepatocyte-specific AAV8-TBG-Cre-mediated deletion of TBR2 and PTEN survived for one year.	('Albumin', 'Gene', (67, 74))	('rat', 'Species', '10116', (8, 11))	('TBG', 'Gene', '331535', (119, 122))	('mice', 'Species', '10090', (84, 88))	('deletion', 'Var', (54, 62))	('TBR2', 'Gene', (148, 152))	('TBR2', 'Gene', (40, 44))	('deletion', 'Var', (136, 144))	('Albumin', 'Gene', '11657', (67, 74))	('TBG', 'Gene', (119, 122))	('PTEN', 'Gene', (157, 161))	('mice', 'Species', '10090', (15, 19))	('PTEN', 'Gene', (49, 53))
177154	26627606	Of note, keratin-positive cholangiocarcinoma cells in mice with hepatocyte-specific AAV8-TBG-Cre-mediated deletion of TBR2 and PTEN co-labeled with Cre reporter GFP, demonstrating hepatocyte origin (Suppl.Fig.5B-C).	('TBG', 'Gene', '331535', (89, 92))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (26, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('rat', 'Species', '10116', (173, 176))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (26, 44))	('TBR2', 'Gene', (118, 122))	('deletion', 'Var', (106, 114))	('TBG', 'Gene', (89, 92))	('rat', 'Species', '10116', (11, 14))	('cholangiocarcinoma', 'Disease', (26, 44))	('mice', 'Species', '10090', (54, 58))
177159	26627606	To fit these results with the seemingly contrasting results from cholangiocyte-specific deletion of PTEN and TBR2, we determined whether cholangiocytes or progenitors in the AAV8-TBG-Cre-deleted mice were derived from hepatocytes as suggested by recent studies.	('PTEN', 'Gene', (100, 104))	('mice', 'Species', '10090', (195, 199))	('TBG', 'Gene', '331535', (179, 182))	('deletion', 'Var', (88, 96))	('TBR2', 'Gene', (109, 113))	('chol', 'Chemical', '-', (137, 141))	('chol', 'Chemical', '-', (65, 69))	('TBG', 'Gene', (179, 182))
177161	26627606	Moreover, we also detected intermediate hepatocyte-derived progenitors in both PTEN Hep and TBR2 PTEN Hep mice 8 weeks after AAV8-TBG-Cre-mediated deletion (Suppl.Fig.7).	('Hep', 'Gene', '109838', (102, 105))	('mice', 'Species', '10090', (106, 110))	('TBG', 'Gene', '331535', (130, 133))	('Hep', 'Gene', (84, 87))	('Hep', 'Gene', (102, 105))	('deletion', 'Var', (147, 155))	('TBR2', 'Gene', (92, 96))	('Hep', 'Gene', '109838', (84, 87))	('TBG', 'Gene', (130, 133))
177162	26627606	Together, these data suggest that loss of TBR2 in hepatocyte-derived cholangiocytes results in cholangiocarcinoma development through an increase in hepatocyte-derived cholangiocyte proliferation (rather than an increase of transdifferentiation).	('TBR2', 'Gene', (42, 46))	('loss', 'Var', (34, 38))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (95, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (95, 113))	('rat', 'Species', '10116', (197, 200))	('rat', 'Species', '10116', (189, 192))	('chol', 'Chemical', '-', (95, 99))	('increase', 'PosReg', (137, 145))	('chol', 'Chemical', '-', (168, 172))	('chol', 'Chemical', '-', (69, 73))	('hepatocyte-derived cholangiocyte proliferation', 'CPA', (149, 195))	('cholangiocarcinoma', 'Disease', (95, 113))
177166	26627606	Importantly, we did not find a role for epithelial TGFbeta signaling in the development of liver fibrosis, as determined in three different fibrosis models, suggesting that TGFbeta signals in HSCs represent the key mechanism through which TGFbeta promotes liver fibrosis.	('liver fibrosis', 'Disease', (91, 105))	('liver fibrosis', 'Disease', (256, 270))	('TGFbeta', 'Var', (239, 246))	('promotes', 'PosReg', (247, 255))	('fibrosis', 'Disease', 'MESH:D005355', (140, 148))	('fibrosis', 'Disease', (140, 148))	('liver fibrosis', 'Disease', 'MESH:D008103', (91, 105))	('fibrosis', 'Disease', 'MESH:D005355', (262, 270))	('fibrosis', 'Disease', (262, 270))	('liver fibrosis', 'Disease', 'MESH:D008103', (256, 270))	('fibrosis', 'Disease', 'MESH:D005355', (97, 105))	('fibrosis', 'Disease', (97, 105))	('liver fibrosis', 'Phenotype', 'HP:0001395', (91, 105))	('liver fibrosis', 'Phenotype', 'HP:0001395', (256, 270))
177170	26627606	Nonetheless, as TAK1 deletion is not a component of normal liver fibrosis, it can be concluded that epithelial TGFbeta signaling does not contribute to the development of toxic or biliary liver fibrosis.	('toxic', 'Disease', (171, 176))	('liver fibrosis', 'Phenotype', 'HP:0001395', (188, 202))	('liver fibrosis', 'Phenotype', 'HP:0001395', (59, 73))	('biliary liver fibrosis', 'Disease', 'MESH:D008103', (180, 202))	('deletion', 'Var', (21, 29))	('TAK1', 'Gene', '26409', (16, 20))	('liver fibrosis', 'Disease', (59, 73))	('biliary liver fibrosis', 'Disease', (180, 202))	('liver fibrosis', 'Disease', 'MESH:D008103', (188, 202))	('liver fibrosis', 'Disease', 'MESH:D008103', (59, 73))	('TAK1', 'Gene', (16, 20))
177172	26627606	However, we did not observe a role for epithelial TGFbeta signaling in hepatocarcinogenesis as evidenced by unaltered HCC development by TBR2 deletion in two different models.	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (71, 91))	('HCC development', 'CPA', (118, 133))	('TBR2', 'Gene', (137, 141))	('deletion', 'Var', (142, 150))	('hepatocarcinogenesis', 'Disease', (71, 91))
177173	26627606	Again, these data are in contrast to the study of Yang et al, in which HCC development in TAK1-deleted livers was reduced by TBR2 deletion.	('HCC development', 'CPA', (71, 86))	('TBR2', 'Gene', (125, 129))	('reduced', 'NegReg', (114, 121))	('TAK1', 'Gene', (90, 94))	('deletion', 'Var', (130, 138))	('TAK1', 'Gene', '26409', (90, 94))
177175	26627606	In contrast to our data on HCC, we observed a key role of the TGFbeta pathway in the development of cholangiocarcinoma in mice with liver-specific ablation of TBR2 and PTEN.	('mice', 'Species', '10090', (122, 126))	('cholangiocarcinoma', 'Disease', (100, 118))	('TBR2', 'Gene', (159, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('ablation', 'Var', (147, 155))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (100, 118))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))
177176	26627606	Of note, recent exome sequencing studies have revealed a high prevalence of mutations in Smad4, a key downstream mediator of TGFbeta signals, in human cholangiocarcinoma.	('mutations', 'Var', (76, 85))	('cholangiocarcinoma', 'Disease', (151, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('human', 'Species', '9606', (145, 150))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (151, 169))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (151, 169))	('Smad4', 'Gene', (89, 94))
177177	26627606	In contrast, human HCC is dominated by mutations in the beta-catenin, p53 and chromatin remodeling pathways.	('human', 'Species', '9606', (13, 18))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('beta-catenin', 'Gene', (56, 68))	('mutations', 'Var', (39, 48))	('beta-catenin', 'Gene', '1499', (56, 68))	('chromatin remodeling pathways', 'Pathway', (78, 107))	('human HCC', 'Disease', (13, 22))
177180	26627606	It should be noted that TGFbeta ablation also affected cholangiocyte expansion in Mdr2ko model of cholestatic fibrosis.	('cholestatic fibrosis', 'Disease', 'MESH:D005355', (98, 118))	('ablation', 'Var', (32, 40))	('cholestatic fibrosis', 'Disease', (98, 118))	('chol', 'Chemical', '-', (98, 102))	('Mdr2ko', 'Var', (82, 88))	('TGFbeta', 'Gene', (24, 31))	('chol', 'Chemical', '-', (55, 59))	('affected', 'Reg', (46, 54))	('cholangiocyte', 'MPA', (55, 68))
177181	26627606	Accordingly, cholangiocyte-specific combined ablation of PTEN and TBR2 by two different approaches resulted in cholangiocarcinoma formation as well as increased cholangiocyte proliferation.	('increased', 'PosReg', (151, 160))	('TBR2', 'Gene', (66, 70))	('cholangiocarcinoma', 'Disease', (111, 129))	('cholangiocyte proliferation', 'CPA', (161, 188))	('chol', 'Chemical', '-', (13, 17))	('PTEN', 'Gene', (57, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('chol', 'Chemical', '-', (161, 165))	('rat', 'Species', '10116', (182, 185))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 129))	('ablation', 'Var', (45, 53))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))	('chol', 'Chemical', '-', (111, 115))
177183	26627606	The deleterious effect of combined PTEN and TBR2 deletion has been found in a wide range of cancers including prostate, pancreas and stomach.	('pancreas', 'Disease', 'MESH:D010190', (120, 128))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('PTEN', 'Gene', (35, 39))	('pancreas', 'Disease', (120, 128))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('found', 'Reg', (67, 72))	('cancers', 'Disease', (92, 99))	('TBR2', 'Gene', (44, 48))	('deletion', 'Var', (49, 57))	('stomach', 'Disease', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('prostate', 'Disease', (110, 118))
177184	26627606	Xu et al reported that combined deletion of PTEN and Smad4 by Albumin-Cre results in increased cholangiocarcinoma formation.	('deletion', 'Var', (32, 40))	('Albumin', 'Gene', '11657', (62, 69))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (95, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (95, 113))	('PTEN', 'Gene', (44, 48))	('Smad4', 'Gene', (53, 58))	('increased', 'PosReg', (85, 94))	('Albumin', 'Gene', (62, 69))	('cholangiocarcinoma', 'Disease', (95, 113))
177187	26627606	A recent study found a similar phenotype in mice with dual deletion of TBR2 and PTEN in the liver, but did not further investigate the involved cell types.	('dual deletion', 'Var', (54, 67))	('mice', 'Species', '10090', (44, 48))	('PTEN', 'Gene', (80, 84))	('TBR2', 'Gene', (71, 75))
177190	26627606	We clearly show the key role of this pathway in cholangiocytes, as demonstrated by cholangiocarcinoma induction in mice with cholangiocyte-specific ablation of PTEN and TBR2 but not PTEN alone.	('cholangiocarcinoma', 'Disease', (83, 101))	('PTEN', 'Gene', (160, 164))	('TBR2', 'Gene', (169, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('rat', 'Species', '10116', (74, 77))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('chol', 'Chemical', '-', (83, 87))	('mice', 'Species', '10090', (115, 119))	('chol', 'Chemical', '-', (48, 52))	('ablation', 'Var', (148, 156))	('chol', 'Chemical', '-', (125, 129))
177193	26627606	Our data also show that concomitant and selective PTEN and TBR2 ablation in hepatocytes (mediated by AAV8-TBG-Cre) can result in cholangiocarcioma formation.	('TBG', 'Gene', '331535', (106, 109))	('ablation', 'Var', (64, 72))	('PTEN', 'Gene', (50, 54))	('result in', 'Reg', (119, 128))	('cholangiocarcioma', 'Disease', (129, 146))	('cholangiocarcioma', 'Disease', 'None', (129, 146))	('TBR2', 'Gene', (59, 63))	('TBG', 'Gene', (106, 109))
177195	26627606	similar to the development of cholangiocarcinoma by cholangiocyte-specific deletion of TBR2 and PTEN, albeit much slower.	('TBR2', 'Gene', (87, 91))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (30, 48))	('deletion', 'Var', (75, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (30, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('chol', 'Chemical', '-', (30, 34))	('chol', 'Chemical', '-', (52, 56))	('cholangiocarcinoma', 'Disease', (30, 48))	('PTEN', 'Gene', (96, 100))
177196	26627606	TGFbeta is a key pathway in the promotion of liver fibrosis and targeting TGFbeta may inhibit the development of this significant clinical problem.	('liver fibrosis', 'Disease', 'MESH:D008103', (45, 59))	('liver fibrosis', 'Phenotype', 'HP:0001395', (45, 59))	('targeting', 'Var', (64, 73))	('TGFbeta', 'Gene', (74, 81))	('inhibit', 'NegReg', (86, 93))	('liver fibrosis', 'Disease', (45, 59))
177197	26627606	However, our results suggest that non-targeted inhibition of TGFbeta signaling may adversely affect cholangiocytes and increase the risk for cholangiocarcinoma development.	('affect', 'Reg', (93, 99))	('non-targeted inhibition', 'Var', (34, 57))	('cholangiocarcinoma', 'Disease', (141, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('TGFbeta signaling', 'Gene', (61, 78))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (141, 159))	('increase', 'PosReg', (119, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (141, 159))	('chol', 'Chemical', '-', (100, 104))	('chol', 'Chemical', '-', (141, 145))	('cholangiocytes', 'CPA', (100, 114))
177198	26627606	Further studies are required to understand why loss of TGFbeta affects cholangiocytes and cholangiocarcinoma formation so profoundly whereas it has little effect on hepatocytes and HCC development.	('cholangiocytes', 'Disease', (71, 85))	('chol', 'Chemical', '-', (90, 94))	('chol', 'Chemical', '-', (71, 75))	('cholangiocarcinoma', 'Disease', (90, 108))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (90, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('loss', 'Var', (47, 51))	('TGFbeta', 'Gene', (55, 62))	('affects', 'Reg', (63, 70))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))
177199	26627606	Similar differences exist probably in other organs as TBR2 deletion results in increased tumor formation only in some cell types.	('increased', 'PosReg', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('TBR2', 'Gene', (54, 58))	('deletion', 'Var', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
177200	26627606	TGFbeta transforming growth factor beta TBR2 TGFbeta receptor II DEN diethylnitrosamine CCl4 carbon tetrachloride DDC 3,5-diethoxycarbonyl-1,4-dihydro-collidin BDL bile duct ligation ALT alanine transaminase HCC hepatocellular carcinoma ICC intrahepatic cholangiocarcinoma FDR false discovery rate qPCR quantitative real-time PCR CAF cancer -associated fibroblasts TBR2 PTENldko Albumin-Cre, floxed PTEN and floxed TBR2 PTENldko Albumin-Cre, floxed PTEN TBR2 PTEN chol(Prom1) Prom1-CreERT2, floxed PTEN and floxed TBR2 PTEN chol(Prom1) Prom1-CreERT2, floxed PTEN TBR2 PTEN chol(K19) K19-CreERT, floxed PTEN and floxed TBR2 PTEN chol(K19) K19-CreERT, floxed PTEN TBR2 PTEN Hep AAV8-TBG-Cre-mediated deletion of floxed PTEN and floxed TBR2 PTEN Hep AAV8-TBG-Cre-mediated deletion of floxed PTEN	('Prom1', 'Gene', (529, 534))	('Prom1', 'Gene', '19126', (536, 541))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('DEN', 'Chemical', 'MESH:D004052', (65, 68))	('CAF', 'Gene', (330, 333))	('chol', 'Chemical', '-', (464, 468))	('Albumin', 'Gene', (429, 436))	('3,5-diethoxycarbonyl-1,4-dihydro-collidin', 'Chemical', '-', (118, 159))	('TGFbeta receptor II', 'Gene', (45, 64))	('TBG', 'Gene', (752, 755))	('Albumin', 'Gene', (379, 386))	('CAF', 'Gene', '104272', (330, 333))	('cancer', 'Disease', (334, 340))	('rat', 'Species', '10116', (293, 296))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (212, 236))	('Prom1', 'Gene', (536, 541))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (241, 272))	('K19', 'Gene', (638, 641))	('K19', 'Gene', (583, 586))	('Prom1', 'Gene', '19126', (469, 474))	('intrahepatic cholangiocarcinoma', 'Disease', (241, 272))	('TBG', 'Gene', (681, 684))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (254, 272))	('deletion', 'Var', (769, 777))	('K19', 'Gene', '16669', (633, 636))	('K19', 'Gene', '16669', (578, 581))	('ALT', 'Gene', (183, 186))	('DDC', 'Chemical', '-', (114, 117))	('hepatocellular carcinoma', 'Disease', (212, 236))	('ALT', 'Gene', '76282', (183, 186))	('carbon tetrachloride', 'Chemical', 'MESH:D002251', (93, 113))	('chol', 'Chemical', '-', (524, 528))	('Prom1', 'Gene', (469, 474))	('Prom1', 'Gene', '19126', (476, 481))	('factor beta', 'Gene', (28, 39))	('chol', 'Chemical', '-', (573, 577))	('CCl4', 'Gene', (88, 92))	('chol', 'Chemical', '-', (254, 258))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (69, 87))	('chol', 'Chemical', '-', (628, 632))	('CCl4', 'Gene', '20303', (88, 92))	('cancer', 'Disease', 'MESH:D009369', (334, 340))	('Prom1', 'Gene', '19126', (529, 534))	('Hep', 'Gene', (743, 746))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (212, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('Albumin', 'Gene', '11657', (429, 436))	('K19', 'Gene', '16669', (638, 641))	('K19', 'Gene', '16669', (583, 586))	('Albumin', 'Gene', '11657', (379, 386))	('Hep', 'Gene', (672, 675))	('Prom1', 'Gene', (476, 481))	('TBG', 'Gene', '331535', (752, 755))	('Hep', 'Gene', '109838', (743, 746))	('K19', 'Gene', (633, 636))	('TBG', 'Gene', '331535', (681, 684))	('K19', 'Gene', (578, 581))	('TGFbeta receptor II', 'Gene', '21813', (45, 64))	('Hep', 'Gene', '109838', (672, 675))	('factor beta', 'Gene', '14962', (28, 39))
177210	29871612	Deep sequencing performed in one patient confirmed the IDH1 mutation in REC.	('mutation', 'Var', (60, 68))	('patient', 'Species', '9606', (33, 40))	('IDH1', 'Gene', '3417', (55, 59))	('IDH1', 'Gene', (55, 59))
177211	29871612	IDH1 is mutated in 30% of RECs, becoming both a marker of progression and a target for therapy.	('IDH1', 'Gene', (0, 4))	('mutated', 'Var', (8, 15))	('RECs', 'Disease', (26, 30))	('IDH1', 'Gene', '3417', (0, 4))
177221	29871612	The most commonly observed alterations were within TP53, KRAS, PI3K, BRAF, SMAD4, IDH1, IDH2, NRAS, ARID1A, PTEN, CDKN2A, CDK6, ERBB3, MET, BRCA1, BRCA2, NF1, PTCH1, and TSC, with variable percentages due to the heterogeneity of the case studies.	('BRCA1', 'Gene', (140, 145))	('PTEN', 'Gene', (108, 112))	('CDK6', 'Gene', (122, 126))	('ARID1A', 'Gene', '8289', (100, 106))	('PTCH1', 'Gene', (159, 164))	('IDH1', 'Gene', '3417', (82, 86))	('CDKN2A', 'Gene', (114, 120))	('alterations', 'Var', (27, 38))	('BRCA2', 'Gene', '675', (147, 152))	('TP53', 'Gene', (51, 55))	('PTEN', 'Gene', '5728', (108, 112))	('NRAS', 'Gene', '4893', (94, 98))	('NF1', 'Gene', '4763', (154, 157))	('KRAS', 'Gene', '3845', (57, 61))	('BRAF', 'Gene', '673', (69, 73))	('ERBB3', 'Gene', (128, 133))	('BRAF', 'Gene', (69, 73))	('TSC', 'Gene', (170, 173))	('CDKN2A', 'Gene', '1029', (114, 120))	('NF1', 'Gene', (154, 157))	('SMAD4', 'Gene', (75, 80))	('KRAS', 'Gene', (57, 61))	('TP53', 'Gene', '7157', (51, 55))	('NRAS', 'Gene', (94, 98))	('PTCH1', 'Gene', '5727', (159, 164))	('IDH2', 'Gene', (88, 92))	('IDH1', 'Gene', (82, 86))	('IDH2', 'Gene', '3418', (88, 92))	('CDK6', 'Gene', '1021', (122, 126))	('ARID1A', 'Gene', (100, 106))	('TSC', 'Gene', '54997', (170, 173))	('ERBB3', 'Gene', '2065', (128, 133))	('BRCA2', 'Gene', (147, 152))	('BRCA1', 'Gene', '672', (140, 145))	('SMAD4', 'Gene', '4089', (75, 80))
177222	29871612	A key role in tumorigenesis seems to be played by mutant IDH1.	('tumor', 'Disease', (14, 19))	('IDH1', 'Gene', (57, 61))	('IDH1', 'Gene', '3417', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('mutant', 'Var', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
177223	29871612	IDH1 mutation causes an impaired production of alpha-KG in favour of the oncometabolite 2-HG; in particular, it acts as a competitor of alpha-KG, causing a hypermethylation of histones and of DNA and promoting epigenetic alterations, all phenomena typically found during progression and metastatic processes.	('histones', 'Protein', (176, 184))	('hypermethylation', 'MPA', (156, 172))	('epigenetic alterations', 'MPA', (210, 232))	('promoting', 'PosReg', (200, 209))	('causing', 'Reg', (146, 153))	('alpha-KG', 'Chemical', '-', (47, 55))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('alpha-KG', 'Chemical', '-', (136, 144))	('IDH1', 'Gene', '3417', (0, 4))
177224	29871612	The role of IDH1 as prognostic marker is controversial; literature data demonstrated that IDH1 mutations correlated with good prognosis in brain tumors, such as glioma, glioblastoma and anaplastic astrocytoma.	('IDH1', 'Gene', (90, 94))	('brain tumors', 'Disease', 'MESH:D001932', (139, 151))	('brain tumors', 'Phenotype', 'HP:0030692', (139, 151))	('IDH1', 'Gene', '3417', (12, 16))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (186, 208))	('IDH1', 'Gene', '3417', (90, 94))	('brain tumors', 'Disease', (139, 151))	('mutations', 'Var', (95, 104))	('glioma', 'Disease', (161, 167))	('glioblastoma', 'Disease', 'MESH:D005909', (169, 181))	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('astrocytoma', 'Phenotype', 'HP:0009592', (197, 208))	('anaplastic astrocytoma', 'Disease', (186, 208))	('glioblastoma', 'Disease', (169, 181))	('IDH1', 'Gene', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('glioblastoma', 'Phenotype', 'HP:0012174', (169, 181))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))
177226	29871612	It has been demonstrated that ICC patients are frequently mutated (about 25%) in IDH1 hot-spots.	('ICC', 'Disease', (30, 33))	('IDH1', 'Gene', (81, 85))	('patients', 'Species', '9606', (34, 42))	('IDH1', 'Gene', '3417', (81, 85))	('mutated', 'Var', (58, 65))
177227	29871612	A recent work of Saha and collaborators demonstrated that IDH1 mutations promoted ICC by blocking hepatocyte differentiation with an increased number of hepatic progenitors susceptible to other mutations.	('mutations', 'Var', (63, 72))	('IDH1', 'Gene', '3417', (58, 62))	('ICC', 'Disease', (82, 85))	('IDH1', 'Gene', (58, 62))	('promoted', 'PosReg', (73, 81))	('hepatocyte', 'MPA', (98, 108))	('blocking', 'NegReg', (89, 97))
177228	29871612	Further, patients harboring IDH1 mutations had a distinct transcriptional signature enriched for hepatic stem cell genes, identifying a particular subclass of ICC patients.	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (163, 171))	('IDH1', 'Gene', '3417', (28, 32))	('mutations', 'Var', (33, 42))	('ICC', 'Disease', (159, 162))	('IDH1', 'Gene', (28, 32))
177229	29871612	In preclinical models, IDH1 mutated cell lines were highly responsive to Src inhibitors, such as Dasatinib and Saracatinib, suggesting potential targeted therapies.	('mutated', 'Var', (28, 35))	('Dasatinib', 'Chemical', 'MESH:D000069439', (97, 106))	('IDH1', 'Gene', (23, 27))	('Saracatinib', 'Chemical', 'MESH:C515233', (111, 122))	('IDH1', 'Gene', '3417', (23, 27))	('Src', 'Gene', '6714', (73, 76))	('Src', 'Gene', (73, 76))
177231	29871612	Further, phase I, II and III clinical trials were planned and are ongoing to test the safety and efficacy of IDH1 inhibitors in different malignancies, such as glioma, cholangiocarcinoma, AML (NCT02074839, NCT02073994, NCT02719574, NCT02989857).	('NCT02074839', 'Var', (193, 204))	('glioma', 'Disease', 'MESH:D005910', (160, 166))	('cholangiocarcinoma', 'Disease', (168, 186))	('NCT02719574', 'Var', (219, 230))	('malignancies', 'Disease', 'MESH:D009369', (138, 150))	('glioma', 'Disease', (160, 166))	('IDH1', 'Gene', (109, 113))	('AML', 'Disease', 'MESH:D015470', (188, 191))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (168, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('IDH1', 'Gene', '3417', (109, 113))	('NCT02989857', 'Var', (232, 243))	('NCT02073994', 'Var', (206, 217))	('malignancies', 'Disease', (138, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (168, 186))	('AML', 'Disease', (188, 191))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))
177255	29871612	They were associated to Epithelial to Mesenchymal Transition (EMT) mediated by Rho alpha, PI3K and ILK mediated by TGF beta, cytoskeleton remodeling by GTPase, anti-apoptotic process mediated by BAD phosphorylation, and in general cell cycle, cytoskeleton remodeling and EMT networks.	('Rho alpha', 'Gene', '387', (79, 88))	('TGF beta', 'Gene', (115, 123))	('Epithelial to Mesenchymal Transition', 'CPA', (24, 60))	('anti-apoptotic process', 'CPA', (160, 182))	('ILK', 'Gene', (99, 102))	('cytoskeleton remodeling', 'CPA', (125, 148))	('ILK', 'Gene', '3611', (99, 102))	('Rho alpha', 'Gene', (79, 88))	('PI3K', 'Var', (90, 94))	('TGF beta', 'Gene', '7040', (115, 123))	('cell cycle', 'CPA', (231, 241))
177265	29871612	As shown in Additional file 12: Table S9, five patients (#3, #6, #11, #15 and #18) harbored an IDH1 R132x mutation in the REC counterpart (31.3%); only in patient #6 (6.25%) the mutation was already present in PR.	('patient', 'Species', '9606', (47, 54))	('R132x', 'Var', (100, 105))	('patients', 'Species', '9606', (47, 55))	('patient', 'Species', '9606', (155, 162))	('IDH1', 'Gene', (95, 99))	('IDH1', 'Gene', '3417', (95, 99))
177266	29871612	In order to confirm the naive IDH1 mutation identified by Sanger sequencing in REC tumor, patient #3 was analyzed by NGS using the AmpliSeq technology on Ion Torrent device.	('Amp', 'Chemical', 'MESH:D000249', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('IDH1', 'Gene', (30, 34))	('patient', 'Species', '9606', (90, 97))	('REC tumor', 'Disease', (79, 88))	('REC tumor', 'Disease', 'MESH:D009369', (79, 88))	('mutation', 'Var', (35, 43))	('IDH1', 'Gene', '3417', (30, 34))
177267	29871612	In patient #3, the IDH1 mutation in codon 132 was confirmed in REC tumor, with a 17.37% of frequency (p = 0.0001) and PR counterpart resulted WT.	('IDH1', 'Gene', (19, 23))	('patient', 'Species', '9606', (3, 10))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('REC tumor', 'Disease', (63, 72))	('IDH1', 'Gene', '3417', (19, 23))	('mutation in', 'Var', (24, 35))	('REC tumor', 'Disease', 'MESH:D009369', (63, 72))
177271	29871612	Further, mutated IDH1 hotspot (codon 132) emerged in about 30% of REC tumors suggesting that it could be a putative marker of progression.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('REC tumors', 'Disease', 'MESH:D009369', (66, 76))	('mutated', 'Var', (9, 16))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('IDH1', 'Gene', (17, 21))	('REC tumors', 'Disease', (66, 76))	('IDH1', 'Gene', '3417', (17, 21))
177273	29871612	Mutational analysis by Sanger revealed that 4 patients harbored IDH1 R132x mutations in RECs, but not in the PRs; NGS analysis performed in a PR-REC pair showed that IDH1 mutation was gained in REC, confirming our direct sequencing results.	('IDH1', 'Gene', (166, 170))	('patients', 'Species', '9606', (46, 54))	('R132x mutations', 'Var', (69, 84))	('IDH1', 'Gene', '3417', (166, 170))	('IDH1', 'Gene', (64, 68))	('IDH1', 'Gene', '3417', (64, 68))
177292	29871612	In fact, it has been demonstrated that IDH1 mutation promoted sensitivity to the multitarget inhibitor Dasatinib.	('promoted', 'PosReg', (53, 61))	('mutation', 'Var', (44, 52))	('IDH1', 'Gene', (39, 43))	('sensitivity to the multitarget inhibitor Dasatinib', 'MPA', (62, 112))	('IDH1', 'Gene', '3417', (39, 43))	('Dasatinib', 'Chemical', 'MESH:D000069439', (103, 112))
177294	29871612	As an example, BAY1436032 targeting the hot-spot mutation R132x is now tested in patients with advanced solid tumors enrolled in one open-label, non-randomized, multicenter phase I-II clinical trial (NCT02746081).	('BAY1436032', 'Var', (15, 25))	('R132x', 'Var', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('patients', 'Species', '9606', (81, 89))	('solid tumors', 'Disease', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))
177295	29871612	Of main interest, the effect of AG-120 is now compared to placebo in the phase III, multicenter, randomized double-blind ClarIDHy trial on non-resectable/metastatic cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (165, 183))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (165, 183))	('AG-120', 'Chemical', 'MESH:C000627630', (32, 38))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (165, 183))	('AG-120', 'Var', (32, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))
177342	22328884	demonstrated that ADAM12 cleaves various extracellular matrix protein molecules including gelatin, type IV collagen and fibronectin, suggesting that the role of ADAM12 in cancer development and metastasis may be linked to their proteinase activity.	('fibronectin', 'Gene', (120, 131))	('ADAM12', 'Gene', (161, 167))	('ADAM12', 'Gene', '8038', (18, 24))	('ADAM12', 'Gene', (18, 24))	('cleaves', 'Var', (25, 32))	('metastasis', 'CPA', (194, 204))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('fibronectin', 'Gene', '2335', (120, 131))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('ADAM12', 'Gene', '8038', (161, 167))
177388	33606753	The acquisition was separated in blocks (b0, b10), (b0, b25), (b0, b50)...(b0, b800), each acquired in a single breath-hold in expiration (TA = 24 s) to avoid motion artefacts.	('b10', 'Gene', '5169', (45, 48))	('b10', 'Gene', (45, 48))	('b50', 'Gene', '2596', (67, 70))	('b50', 'Gene', (67, 70))	('b0', 'Var', (75, 77))
177397	33606753	Quantitative ADC maps were calculated on voxel-by-voxel basis using commercial workstation for combination of b = 0 and b1 = 800 using the equation:  where S0 and S1 correspond to signal intensities for b values 0 and b = 800 s/mm2.	('ADC ', 'Gene', '113451', (13, 17))	('b = 800 s/mm2', 'Var', (218, 231))	('ADC ', 'Gene', (13, 17))
177398	33606753	The final values of f, D, D* and ADC for b = 800 s/mm2 were calculated by averaging the three measurements.	('D', 'Chemical', 'MESH:D003903', (34, 35))	('b = 800 s/mm2', 'Var', (41, 54))	('ADC ', 'Gene', '113451', (33, 37))	('ADC ', 'Gene', (33, 37))	('D', 'Chemical', 'MESH:D003903', (23, 24))	('D', 'Chemical', 'MESH:D003903', (26, 27))
177444	30042074	Median OS from radioembolization was significantly longer in patients with Eastern Cooperative Oncology Group (ECOG) scores of 0 and 1 than patients with an ECOG score of 2 (18.5 vs 5.5 months, P =.0012), and median OS from radioembolization was significantly longer in patients with well-differentiated histology than patients with poorly differentiated histology (18.6 vs 9.7 months, P = .012).	('Oncology', 'Phenotype', 'HP:0002664', (95, 103))	('patients', 'Species', '9606', (270, 278))	('patients', 'Species', '9606', (61, 69))	('patients', 'Species', '9606', (319, 327))	('scores', 'Var', (117, 123))	('longer', 'PosReg', (51, 57))	('patients', 'Species', '9606', (140, 148))	('well-differentiated histology', 'Disease', (284, 313))
177487	30042074	Similarly, on univariate analysis, the absence of extrahepatic metastasis was associated with significantly increased median OS from the radioembolization treatment compared to the presence of extrahepatic metastasis (15.2 months vs 6.8 months, P = .003), but this was not significant on multivariate analysis (P = .26) (Table 2).	('absence', 'Var', (39, 46))	('increased', 'PosReg', (108, 117))	('extrahepatic', 'CPA', (50, 62))	('men', 'Species', '9606', (160, 163))
177489	30042074	On multivariate analysis, preprocedural low INR, low albumin, and elevated aspartate aminotransferase level showed a statistically significant association with decreased OS from the first radioembolization treatment (Table 3).	('low INR', 'Phenotype', 'HP:0032198', (40, 47))	('aspartate aminotransferase level', 'MPA', (75, 107))	('low', 'Var', (40, 43))	('elevated aspartate', 'Phenotype', 'HP:0500159', (66, 84))	('men', 'Species', '9606', (211, 214))	('elevated aspartate aminotransferase', 'Phenotype', 'HP:0031956', (66, 101))	('low', 'NegReg', (49, 52))	('low albumin', 'Phenotype', 'HP:0003073', (49, 60))	('decreased', 'NegReg', (160, 169))	('albumin', 'Gene', '213', (53, 60))	('albumin', 'Gene', (53, 60))	('elevated', 'PosReg', (66, 74))
177530	30042074	This study found that low pretreatment albumin was associated with decreased survival.	('low', 'Var', (22, 25))	('survival', 'MPA', (77, 85))	('decreased', 'NegReg', (67, 76))	('albumin', 'Gene', (39, 46))	('albumin', 'Gene', '213', (39, 46))	('men', 'Species', '9606', (34, 37))
177603	32008331	Several molecular targets have been identified in recent years for cholangiocarcinoma, including tumors with fibroblast growth factor receptor genetic alterations (FGFR GAs), isocitrate dehydrogenase-1 (IDH1) mutations, and high microsatellite instability.	('isocitrate dehydrogenase-1', 'Gene', (175, 201))	('isocitrate dehydrogenase-1', 'Gene', '3417', (175, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('FGFR', 'Gene', (164, 168))	('microsatellite instability', 'Var', (229, 255))	('tumors', 'Disease', (97, 103))	('mutations', 'Var', (209, 218))	('cholangiocarcinoma', 'Disease', (67, 85))	('IDH1', 'Gene', (203, 207))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('IDH1', 'Gene', '3417', (203, 207))
177605	32008331	Javle and associates studied an orally bioavailable, selective pan-FGFR kinase inhibitor BGJ398 (infigratinib) in patients with FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy.	('BGJ398', 'Gene', (89, 95))	('FGFR2', 'Gene', (128, 133))	('fusions', 'Var', (134, 141))	('infigratinib', 'Chemical', 'MESH:C568950', (97, 109))	('FGFR2', 'Gene', '2263', (128, 133))	('patients', 'Species', '9606', (114, 122))	('BGJ398', 'Chemical', 'MESH:C568950', (89, 95))
177607	32008331	Other FGFR inhibitors, including TAS-120, JNJ-42756493, AZD4547 are similarly being tested in clinical trials.	('FGFR', 'Gene', (6, 10))	('AZD4547', 'Chemical', 'MESH:C572463', (56, 63))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (42, 54))	('AZD4547', 'Var', (56, 63))
177611	32008331	Silencing of FGFR4 radiosensitized the HT29 cells by attenuation of double strand break repair by homologous recombination.	('attenuation', 'NegReg', (53, 64))	('double strand break repair', 'MPA', (68, 94))	('HT29', 'CellLine', 'CVCL:0320', (39, 43))	('Silencing', 'Var', (0, 9))	('FGFR4', 'Gene', '2264', (13, 18))	('FGFR4', 'Gene', (13, 18))
177612	32008331	investigated the ability of FGFR inhibition with JNJ-42756493 to radiosensitize colorectal xenograft models with wild type FGFR and FGFR2 amplification, but did not observe a radiosensitizing effect.	('colorectal', 'Disease', (80, 90))	('JNJ-42756493', 'Var', (49, 61))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (49, 61))	('FGFR2', 'Gene', '2263', (132, 137))	('FGFR2', 'Gene', (132, 137))
177614	32008331	In a cohort of patients with mutated IDH1 cholangiocarcinoma, the partial response rate was 5% (4 out of 73 patients).	('patients', 'Species', '9606', (15, 23))	('cholangiocarcinoma', 'Disease', (42, 60))	('IDH1', 'Gene', (37, 41))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (42, 60))	('mutated', 'Var', (29, 36))	('IDH1', 'Gene', '3417', (37, 41))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (42, 60))	('patients', 'Species', '9606', (108, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
177616	32008331	Mutations in IDH1/2 occur in a hotspot of the catalytically active site of action for these enzymes, resulting in production of D-2-hydroxyglutarate (D-2HG).	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (128, 148))	('D-2-hydroxyglutarate', 'MPA', (128, 148))	('IDH1/2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('D-2HG', 'Chemical', 'MESH:C019417', (150, 155))	('production', 'MPA', (114, 124))
177617	32008331	D-2HG competitively binds alpha-ketoglutarate, causing alterations in multiple downstream cellular processes like cell metabolism, DNA repair, redox states, and epigenetic regulation.	('alterations', 'Reg', (55, 66))	('D-2HG', 'Var', (0, 5))	('redox states', 'MPA', (143, 155))	('epigenetic regulation', 'MPA', (161, 182))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (26, 45))	('cell metabolism', 'MPA', (114, 129))	('D-2HG', 'Chemical', 'MESH:C019417', (0, 5))	('DNA repair', 'MPA', (131, 141))
177618	32008331	Patients with IDH1/2 mutations have been shown to have improved responses to radiation in glioma.	('glioma', 'Disease', (90, 96))	('improved', 'PosReg', (55, 63))	('IDH1/2', 'Gene', '3417;3418', (14, 20))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('Patients', 'Species', '9606', (0, 8))	('responses to radiation', 'MPA', (64, 86))	('IDH1/2', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
177619	32008331	In preclinical studies, the silencing of wild type IDH1 has shown sensitization of cancer cells to chemotherapy and radiation, indicating that the targeting of wild type IDH1/2 cancers with pharmacologic inhibition may confer the same therapy responses seen in mutant IDH1/2 cancers.	('IDH1', 'Gene', '3417', (51, 55))	('cancer', 'Disease', (177, 183))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('IDH1', 'Gene', '3417', (170, 174))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancers', 'Disease', 'MESH:D009369', (275, 282))	('IDH1/2', 'Gene', '3417;3418', (268, 274))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('silencing', 'Var', (28, 37))	('IDH1/2', 'Gene', (268, 274))	('IDH1', 'Gene', (268, 272))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('mutant', 'Var', (261, 267))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('IDH1', 'Gene', (51, 55))	('IDH1/2', 'Gene', '3417;3418', (170, 176))	('cancers', 'Disease', (275, 282))	('cancer', 'Disease', (275, 281))	('IDH1', 'Gene', (170, 174))	('IDH1/2', 'Gene', (170, 176))	('IDH1', 'Gene', '3417', (268, 272))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('therapy responses', 'CPA', (235, 252))	('cancer', 'Disease', (83, 89))
177620	32008331	In the mutant IDH1/2 population, targeted therapies may also be rationally combined with radiation or chemotherapy to further sensitize the cancers to treatment.	('mutant', 'Var', (7, 13))	('IDH1/2', 'Gene', '3417;3418', (14, 20))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('IDH1/2', 'Gene', (14, 20))
177621	32008331	For example, mutated IDH1/2 cancers can have a "BRCAness" phenotype due to impaired homologous recombination DNA repair, that is partly attributed to inhibition of the alpha-ketoglutarate-dependent dioxygenases [DNA damage response proteins lysine-specific demethylase 4A/B (KDM4A/B)], which induces the DNA repair defect.	('cancers', 'Disease', (28, 35))	('inhibition', 'NegReg', (150, 160))	('mutated', 'Var', (13, 20))	('4A/B', 'Var', (278, 282))	('IDH1/2', 'Gene', '3417;3418', (21, 27))	('KDM4A', 'Gene', '9682', (275, 280))	('impaired', 'NegReg', (75, 83))	('4A/B', 'SUBSTITUTION', 'None', (278, 282))	('KDM4A', 'Gene', (275, 280))	('IDH1/2', 'Gene', (21, 27))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('4A/B', 'Var', (269, 273))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (168, 187))	('homologous recombination DNA repair', 'MPA', (84, 119))	('4A/B', 'SUBSTITUTION', 'None', (269, 273))	('BRCAness', 'Disease', (48, 56))	('BRCAness', 'Disease', 'None', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))
177625	32008331	Around 1% of cholangiocarcinomas are thought to have high level microsatellite instability.	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (13, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (13, 31))	('cholangiocarcinomas', 'Disease', (13, 32))	('microsatellite instability', 'Var', (64, 90))
177640	32008331	Improved outcomes for patients in terms of LC will thus require new strategies, and targeted agents, particularly for FGFR gene aberrations, IDH1/2 mutations, and MSI-high, offer multiple avenues for clinical research with radiation therapy.	('mutations', 'Var', (148, 157))	('MSI', 'Gene', '5928', (163, 166))	('aberrations', 'Var', (128, 139))	('IDH1/2', 'Gene', '3417;3418', (141, 147))	('patients', 'Species', '9606', (22, 30))	('IDH1/2', 'Gene', (141, 147))	('FGFR', 'Gene', (118, 122))	('MSI', 'Gene', (163, 166))
177664	31582774	Once ingestion occurs, O. viverrini commonly invade the bile ducts and cause pathological changes to the bile ducts, liver and gall bladder.	('invade', 'Reg', (45, 51))	('cause', 'Reg', (71, 76))	('gall bladder', 'Disease', (127, 139))	('bile duct', 'Disease', 'MESH:D002779', (105, 114))	('bile duct', 'Disease', (105, 114))	('O. viverrini', 'Species', '6198', (23, 35))	('O. viverrini', 'Var', (23, 35))	('gall bladder', 'Disease', 'MESH:D005705', (127, 139))	('bile duct', 'Disease', 'MESH:D002779', (56, 65))	('bile duct', 'Disease', (56, 65))
177786	30720001	Compared with PTBD, EBD yields a significant benefit to OS (HR = 0.70, 95% CI 0.59-0.84, P = 0.0002, Figure 2).	('benefit', 'PosReg', (45, 52))	('EBD', 'Var', (20, 23))	('OS', 'Chemical', '-', (56, 58))
177809	27267833	The most common molecular alterations were in TP53 (8/19, 42.1%), including missense mutations such as C242Y, E285K, G112S, P19T, R148T, R248Q, and R273L.	('P19T', 'Mutation', 'rs28934874', (124, 128))	('R273L', 'Mutation', 'rs28934576', (148, 153))	('C242Y', 'Var', (103, 108))	('R248Q', 'Var', (137, 142))	('G112S', 'Mutation', 'rs1057519989', (117, 122))	('E285K', 'Mutation', 'rs112431538', (110, 115))	('TP53', 'Gene', '7157', (46, 50))	('G112S', 'Var', (117, 122))	('R248Q', 'Mutation', 'rs11540652', (137, 142))	('TP53', 'Gene', (46, 50))	('C242Y', 'Mutation', 'rs121912655', (103, 108))	('R148T', 'Mutation', 'rs121912660', (130, 135))	('P19T', 'Var', (124, 128))	('E285K', 'Var', (110, 115))	('R148T', 'Var', (130, 135))	('R273L', 'Var', (148, 153))
177810	27267833	We also detected two NRAS mutations (G12C and Q61L), two KRAS mutations (G12A and G12S), two ERBB2 mutations (V777L and pM774delinsMA) and amplification, and three PIK3CA mutations (N345K, E545K, and E521K).	('G12C', 'Mutation', 'rs121913250', (37, 41))	('E545K', 'Mutation', 'rs104886003', (189, 194))	('PIK3CA', 'Gene', (164, 170))	('Q61L', 'Mutation', 'rs121913240', (46, 50))	('V777L', 'Mutation', 'rs121913471', (110, 115))	('NRAS', 'Gene', '4893', (21, 25))	('G12S', 'Mutation', 'rs121913530', (82, 86))	('V777L', 'Var', (110, 115))	('E545K', 'Var', (189, 194))	('E521K', 'Var', (200, 205))	('pM774delinsMA', 'Var', (120, 133))	('G12A', 'Var', (73, 77))	('ERBB2', 'Gene', (93, 98))	('KRAS', 'Gene', '3845', (57, 61))	('N345K', 'Var', (182, 187))	('KRAS', 'Gene', (57, 61))	('NRAS', 'Gene', (21, 25))	('PIK3CA', 'Gene', '5290', (164, 170))	('E521K', 'Mutation', 'p.E521K', (200, 205))	('ERBB2', 'Gene', '2064', (93, 98))	('N345K', 'Mutation', 'rs121913284', (182, 187))	('G12S', 'Var', (82, 86))	('G12A', 'Mutation', 'rs121913529', (73, 77))	('Q61L', 'Var', (46, 50))	('G12C', 'Var', (37, 41))
177840	27267833	In case 1, we identified CCND1 amplification, TP53 (C242Y), and CDKN2A (A128V) mutations as well.	('CCND1', 'Gene', (25, 30))	('CDKN2A', 'Gene', (64, 70))	('A128V', 'Mutation', 'rs104894104', (72, 77))	('CCND1', 'Gene', '595', (25, 30))	('TP53', 'Gene', '7157', (46, 50))	('CDKN2A', 'Gene', '1029', (64, 70))	('TP53', 'Gene', (46, 50))	('C242Y', 'Mutation', 'rs121912655', (52, 57))	('C242Y', 'Var', (52, 57))	('A128V', 'Var', (72, 77))
177841	27267833	FGFR3 amplification with TP53 (E285K), ERBB2 (V777L), and PIK3CA (E545K) mutations was detected in case 3 (hilar cholangiocarcinoma).	('cholangiocarcinoma', 'Disease', (113, 131))	('ERBB2', 'Gene', '2064', (39, 44))	('TP53', 'Gene', (25, 29))	('FGFR3', 'Gene', '2261', (0, 5))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (113, 131))	('V777L', 'Var', (46, 51))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (113, 131))	('FGFR3', 'Gene', (0, 5))	('PIK3CA', 'Gene', (58, 64))	('TP53', 'Gene', '7157', (25, 29))	('E545K', 'Mutation', 'rs104886003', (66, 71))	('PIK3CA', 'Gene', '5290', (58, 64))	('E545K', 'Var', (66, 71))	('E285K', 'Mutation', 'rs112431538', (31, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('E285K', 'Var', (31, 36))	('V777L', 'Mutation', 'rs121913471', (46, 51))	('ERBB2', 'Gene', (39, 44))
177842	27267833	In cases 12 and 16, amplifications of ERBB2 and CCNE1 were identified, respectively, without any notable somatic mutations, and both showed strong HER2 protein overexpression (data not shown).	('overexpression', 'PosReg', (160, 174))	('amplifications', 'Var', (20, 34))	('CCNE1', 'Gene', '898', (48, 53))	('ERBB2', 'Gene', (38, 43))	('ERBB2', 'Gene', '2064', (38, 43))	('HER2', 'Gene', (147, 151))	('CCNE1', 'Gene', (48, 53))	('HER2', 'Gene', '2064', (147, 151))
177843	27267833	Additionally, mutations of IDH1 (R132C), RB1 (S576L), and CTNBB1 (S45F) were accompanied by TP53 mutation.	('S45F', 'Mutation', 'p.S45F', (66, 70))	('CTNBB1', 'Gene', (58, 64))	('RB1', 'Gene', '5925', (41, 44))	('mutation', 'Var', (97, 105))	('S576L', 'Var', (46, 51))	('S576L', 'Mutation', 'p.S576L', (46, 51))	('R132C', 'Mutation', 'rs121913499', (33, 38))	('accompanied', 'Reg', (77, 88))	('IDH1', 'Gene', (27, 31))	('TP53', 'Gene', (92, 96))	('TP53', 'Gene', '7157', (92, 96))	('IDH1', 'Gene', '3417', (27, 31))	('mutations', 'Var', (14, 23))	('R132C', 'Var', (33, 38))	('RB1', 'Gene', (41, 44))
177856	27267833	The most commonly detected genomic alterations were in TP53 (C242Y, E285K, G112S, P19T, R148T, R248Q, and R273L), NRAS (G12C and Q61L), KRAS (G12A and G12S), ERBB2 (V777L and pM774delinsMA), and PIK3CA (N345K, E545K, and E521K).	('N345K', 'Mutation', 'rs121913284', (203, 208))	('PIK3CA', 'Gene', (195, 201))	('G12S', 'Var', (151, 155))	('E285K', 'Mutation', 'rs112431538', (68, 73))	('P19T', 'Var', (82, 86))	('V777L', 'Mutation', 'rs121913471', (165, 170))	('G12A', 'Mutation', 'rs121913529', (142, 146))	('C242Y', 'Var', (61, 66))	('V777L', 'Var', (165, 170))	('TP53', 'Gene', '7157', (55, 59))	('NRAS', 'Gene', (114, 118))	('pM774delinsMA', 'Var', (175, 188))	('Q61L', 'Var', (129, 133))	('ERBB2', 'Gene', (158, 163))	('R148T', 'Var', (88, 93))	('G112S', 'Mutation', 'rs1057519989', (75, 80))	('KRAS', 'Gene', '3845', (136, 140))	('G12C', 'Mutation', 'rs121913250', (120, 124))	('C242Y', 'Mutation', 'rs121912655', (61, 66))	('E521K', 'Var', (221, 226))	('R248Q', 'Mutation', 'rs11540652', (95, 100))	('ERBB2', 'Gene', '2064', (158, 163))	('E545K', 'Mutation', 'rs104886003', (210, 215))	('Q61L', 'Mutation', 'rs121913240', (129, 133))	('G12S', 'Mutation', 'rs121913530', (151, 155))	('PIK3CA', 'Gene', '5290', (195, 201))	('KRAS', 'Gene', (136, 140))	('R273L', 'Mutation', 'rs28934576', (106, 111))	('R148T', 'Mutation', 'rs121912660', (88, 93))	('R248Q', 'Var', (95, 100))	('G112S', 'Var', (75, 80))	('N345K', 'Var', (203, 208))	('TP53', 'Gene', (55, 59))	('R273L', 'Var', (106, 111))	('E285K', 'Var', (68, 73))	('NRAS', 'Gene', '4893', (114, 118))	('E521K', 'Mutation', 'p.E521K', (221, 226))	('P19T', 'Mutation', 'rs28934874', (82, 86))	('E545K', 'Var', (210, 215))
177857	27267833	We also identified CCND1 amplification and concomitant TP53 (C242Y) and CDKN2A (A128V) mutations.	('A128V', 'Var', (80, 85))	('CCND1', 'Gene', (19, 24))	('C242Y', 'Mutation', 'rs121912655', (61, 66))	('CDKN2A', 'Gene', '1029', (72, 78))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (55, 59))	('A128V', 'Mutation', 'rs104894104', (80, 85))	('C242Y', 'Var', (61, 66))	('amplification', 'Var', (25, 38))	('CCND1', 'Gene', '595', (19, 24))	('CDKN2A', 'Gene', (72, 78))
177865	33106918	Molecular detection and clinicopathological characteristics of advanced/recurrent biliary tract carcinomas harboring the FGFR2 rearrangements: a prospective observational study (PRELUDE Study) Fibroblast growth factor receptor 2 (FGFR2) rearrangement is expected to be a novel therapeutic target in advanced/recurrent biliary tract cancer (BTC).	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinomas', 'Disease', 'MESH:D009369', (96, 106))	('rearrangements', 'Var', (127, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('biliary tract cancer', 'Disease', (318, 338))	('FGFR2', 'Gene', (121, 126))	('FGFR2', 'Gene', '2263', (121, 126))	('carcinomas', 'Disease', (96, 106))	('rearrangement', 'Var', (237, 250))	('BTC', 'Phenotype', 'HP:0100574', (340, 343))	('FGFR2', 'Gene', '2263', (230, 235))	('Fibroblast growth factor receptor 2', 'Gene', '2263', (193, 228))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (318, 338))	('Fibroblast growth factor receptor 2', 'Gene', (193, 228))	('FGFR2', 'Gene', (230, 235))	('biliary tract cancer', 'Disease', 'MESH:D001661', (318, 338))
177866	33106918	However, efficient detection and the exact frequency of FGFR2 rearrangements among patients with advanced/recurrent BTC have not been determined, and the clinical characteristics of FGFR2 rearrangement-positive patients have not been fully elucidated.	('FGFR2', 'Gene', '2263', (182, 187))	('FGFR2', 'Gene', (182, 187))	('patients', 'Species', '9606', (211, 219))	('rearrangements', 'Var', (62, 76))	('FGFR2', 'Gene', '2263', (56, 61))	('FGFR2', 'Gene', (56, 61))	('BTC', 'Phenotype', 'HP:0100574', (116, 119))	('patients', 'Species', '9606', (83, 91))
177867	33106918	We aimed to determine the frequency of FGFR2 rearrangement-positive patients among those with advanced/recurrent BTC and elucidate their clinicopathological characteristics.	('rearrangement-positive', 'Var', (45, 67))	('BTC', 'Phenotype', 'HP:0100574', (113, 116))	('patients', 'Species', '9606', (68, 76))	('FGFR2', 'Gene', (39, 44))	('FGFR2', 'Gene', '2263', (39, 44))
177868	33106918	Paraffin-embedded tumor samples from formalin-fixed surgical or biopsy specimens of patients with advanced/recurrent BTC were analyzed for positivity of FGFR2 rearrangement by fluorescent in situ hybridization (FISH).	('Paraffin', 'Chemical', 'MESH:D010232', (0, 8))	('patients', 'Species', '9606', (84, 92))	('tumor', 'Disease', (18, 23))	('FGFR2', 'Gene', (153, 158))	('formalin', 'Chemical', 'MESH:D005557', (37, 45))	('FGFR2', 'Gene', '2263', (153, 158))	('rearrangement', 'Var', (159, 172))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('BTC', 'Phenotype', 'HP:0100574', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
177873	33106918	Twenty-three of the 25 FISH-positive patients (20 ICC and 3 PCC) were recognized as FGFR2 rearrangement positive by targeted RNA sequencing.	('patients', 'Species', '9606', (37, 45))	('rearrangement', 'Var', (90, 103))	('FGFR2', 'Gene', (84, 89))	('FGFR2', 'Gene', '2263', (84, 89))
177874	33106918	Younger age (<= 65 years; p = 0.018) and HCV Ab- and/or HBs Ag-positivity (p = 0.037) were significantly associated with the presence of FGFR2 rearrangement (logistic regression).	('rearrangement', 'Var', (143, 156))	('FGFR2', 'Gene', (137, 142))	('FGFR2', 'Gene', '2263', (137, 142))
177875	33106918	FGFR2 rearrangement was identified in ICC and PCC patients, and was associated with younger age and history of hepatitis viral infection.	('ICC', 'Disease', (38, 41))	('associated', 'Reg', (68, 78))	('rearrangement', 'Var', (6, 19))	('patients', 'Species', '9606', (50, 58))	('PCC', 'Disease', (46, 49))	('hepatitis viral infection', 'Disease', (111, 136))	('hepatitis', 'Phenotype', 'HP:0012115', (111, 120))	('FGFR2', 'Gene', (0, 5))	('hepatitis viral infection', 'Disease', 'MESH:D006509', (111, 136))	('FGFR2', 'Gene', '2263', (0, 5))
177879	33106918	Especially, isocitrate dehydrogenase (IDH) mutations and fibroblast growth factor receptor 2 (FGFR2) fusion genes in ICC have been identified as important driver alterations and are promising therapeutic targets.	('ICC', 'Disease', (117, 120))	('isocitrate dehydrogenase', 'Gene', '3417', (12, 36))	('IDH', 'Gene', (38, 41))	('FGFR2', 'Gene', (94, 99))	('FGFR2', 'Gene', '2263', (94, 99))	('IDH', 'Gene', '3417', (38, 41))	('mutations', 'Var', (43, 52))	('fusion genes', 'Var', (101, 113))	('fibroblast growth factor receptor 2', 'Gene', '2263', (57, 92))	('fibroblast growth factor receptor 2', 'Gene', (57, 92))	('isocitrate dehydrogenase', 'Gene', (12, 36))
177880	33106918	Actually, the US Food and Drug Administration (FDA) granted accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion in April 2020 based on the favorable results of a clinical trial.	('fusion', 'Var', (150, 156))	('FGFR2', 'Gene', '2263', (127, 132))	('pemigatinib', 'Chemical', '-', (84, 95))	('cholangiocarcinoma', 'Disease', (100, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (100, 118))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))	('rearrangement', 'Var', (133, 146))	('FGFR2', 'Gene', (127, 132))
177881	33106918	FGFR rearrangements (fusions/truncations) autonomously activate the FGF signaling pathway and are involved in breast cancer, lung cancer, gastric cancer, and hematological tumors.	('hematological tumors', 'Disease', 'MESH:D019337', (158, 178))	('involved', 'Reg', (98, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (138, 152))	('FGFR', 'Gene', (0, 4))	('FGF signaling pathway', 'Pathway', (68, 89))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('gastric cancer', 'Phenotype', 'HP:0012126', (138, 152))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('lung cancer', 'Disease', (125, 136))	('hematological tumors', 'Disease', (158, 178))	('breast cancer', 'Disease', (110, 123))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('rearrangements', 'Var', (5, 19))	('gastric cancer', 'Disease', (138, 152))	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('activate', 'PosReg', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))
177882	33106918	FGFR2 rearrangements are considered to be one of the important driver genes in ICC, with 9-14% of ICC cases reported as positive for FGFR2 rearrangements.	('rearrangements', 'Var', (6, 20))	('positive', 'Reg', (120, 128))	('ICC', 'Disease', (98, 101))	('FGFR2', 'Gene', (133, 138))	('rearrangements', 'Var', (139, 153))	('FGFR2', 'Gene', '2263', (133, 138))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))	('ICC', 'Disease', (79, 82))
177883	33106918	Several clinical trials targeting FGFR2 rearrangements have already been conducted, but there is only limited information of its positivity rate and the related clinical features in advanced/recurrent cases.	('FGFR2', 'Gene', (34, 39))	('rearrangements', 'Var', (40, 54))	('FGFR2', 'Gene', '2263', (34, 39))
177884	33106918	In addition, although the positive rate of FGFR2 rearrangements has been reported in ICC, data are not available for the other BTCs.	('rearrangements', 'Var', (49, 63))	('BTC', 'Phenotype', 'HP:0100574', (127, 130))	('ICC', 'Disease', (85, 88))	('FGFR2', 'Gene', '2263', (43, 48))	('FGFR2', 'Gene', (43, 48))
177885	33106918	Thus, to verify whether, in addition to ICC, other BTCs are also associated with FGFR2 rearrangements, investigations should be extended to all advanced/recurrent BTCs, including those outside of ICC.	('rearrangements', 'Var', (87, 101))	('FGFR2', 'Gene', (81, 86))	('BTC', 'Phenotype', 'HP:0100574', (51, 54))	('FGFR2', 'Gene', '2263', (81, 86))	('BTC', 'Phenotype', 'HP:0100574', (163, 166))
177888	33106918	Among those candidates, we adopted FISH assay for screening FGFR2 rearrangements in this prospective study, because the majority of our cases were expected not to have archival surgical tissue and it is frequently difficult to obtain enough volume of tumor tissue for many tests including next-generation sequencing (NGS).	('tumor', 'Disease', (251, 256))	('rearrangements', 'Var', (66, 80))	('FGFR2', 'Gene', '2263', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('FGFR2', 'Gene', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
177893	33106918	For efficient and prospective diagnosis of the status of FGFR2 rearrangement, we performed the break-apart FISH assays using paraffin-embedded tumor samples from formalin-fixed surgical or biopsy specimens as described below.	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('rearrangement', 'Var', (63, 76))	('paraffin', 'Chemical', 'MESH:D010232', (125, 133))	('FGFR2', 'Gene', (57, 62))	('FGFR2', 'Gene', '2263', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('formalin', 'Chemical', 'MESH:D005557', (162, 170))
177901	33106918	In the second period, the survival of FGFR2 rearrangement-positive patients and the use of FGFR inhibitors were also investigated.	('rearrangement-positive', 'Var', (44, 66))	('FGFR2', 'Gene', '2263', (38, 43))	('FGFR2', 'Gene', (38, 43))	('patients', 'Species', '9606', (67, 75))
177902	33106918	The primary end point was the frequency of FGFR2 rearrangement-positive patients among those with BTC.	('BTC', 'Phenotype', 'HP:0100574', (98, 101))	('rearrangement-positive', 'Var', (49, 71))	('FGFR2', 'Gene', '2263', (43, 48))	('FGFR2', 'Gene', (43, 48))	('patients', 'Species', '9606', (72, 80))
177903	33106918	The secondary end point was the correlation between the presence of FGFR2 rearrangement and the clinical characteristics of the patients.	('presence', 'Var', (56, 64))	('FGFR2', 'Gene', '2263', (68, 73))	('patients', 'Species', '9606', (128, 136))	('rearrangement', 'Var', (74, 87))	('FGFR2', 'Gene', (68, 73))
177913	33106918	The primary objective was to estimate the rate of FGFR2 rearrangement-positive patients.	('rearrangement-positive', 'Var', (56, 78))	('FGFR2', 'Gene', (50, 55))	('FGFR2', 'Gene', '2263', (50, 55))	('patients', 'Species', '9606', (79, 87))
177914	33106918	With an expected positive FGFR2 rearrangement rate of 20-40%, a total of 100 patients were planned for achieving a target width of less than 10% for the two-sided 95% confidence interval.	('patients', 'Species', '9606', (77, 85))	('rearrangement', 'Var', (32, 45))	('FGFR2', 'Gene', '2263', (26, 31))	('FGFR2', 'Gene', (26, 31))
177915	33106918	The correlations between the presence of FGFR2 rearrangement and the clinical characteristics of the patients were analyzed using the Fisher's exact test and logistic regression.	('patients', 'Species', '9606', (101, 109))	('FGFR2', 'Gene', '2263', (41, 46))	('rearrangement', 'Var', (47, 60))	('FGFR2', 'Gene', (41, 46))	('presence', 'Var', (29, 37))
177917	33106918	The FGFR2 rearrangement-positive patients enrolled in the second period were included in the survival analysis.	('FGFR2', 'Gene', '2263', (4, 9))	('FGFR2', 'Gene', (4, 9))	('patients', 'Species', '9606', (33, 41))	('rearrangement-positive', 'Var', (10, 32))
177934	33106918	Discrimination of FGFR2 fusion transcript positive or negative was validated in six cases (cases 2, 3, 4, 5, 24 and 25) by another RNA sequencing method, AMP-FGFR, targeting FGFR1, FGFR2 and FGFR3 genes, and the results of the identified FGFR2 fusion transcripts or no FGFR2 fusion transcripts were coincident completely with the prior ones.	('FGFR2', 'Gene', (181, 186))	('FGFR2', 'Gene', '2263', (181, 186))	('FGFR3', 'Gene', (191, 196))	('FGFR2', 'Gene', (18, 23))	('FGFR2', 'Gene', '2263', (18, 23))	('FGFR2', 'Gene', (269, 274))	('FGFR2', 'Gene', '2263', (269, 274))	('FGFR2', 'Gene', (238, 243))	('FGFR1', 'Gene', (174, 179))	('FGFR2', 'Gene', '2263', (238, 243))	('FGFR1', 'Gene', '2260', (174, 179))	('fusion', 'Var', (244, 250))	('FGFR3', 'Gene', '2261', (191, 196))
177937	33106918	This implies no false negative cases in the FISH assay for FGFR2 rearrangement.	('FGFR2', 'Gene', (59, 64))	('FGFR2', 'Gene', '2263', (59, 64))	('rearrangement', 'Var', (65, 78))
177938	33106918	Taken together, 23 patients were identified as FGFR2 rearrangement positive including 20 (7.4%) ICC cases and three (3.6%) PCC cases.	('positive', 'Reg', (67, 75))	('patients', 'Species', '9606', (19, 27))	('ICC', 'Disease', (96, 99))	('FGFR2', 'Gene', (47, 52))	('FGFR2', 'Gene', '2263', (47, 52))	('rearrangement', 'Var', (53, 66))
177939	33106918	The clinical characteristics were evaluated in the 23 cases with FGFR2 rearrangements.	('FGFR2', 'Gene', (65, 70))	('rearrangements', 'Var', (71, 85))	('FGFR2', 'Gene', '2263', (65, 70))
177940	33106918	The macroscopic type of FGFR2 rearrangement-positive ICC was invariably the mass forming type (Table 3).	('rearrangement-positive', 'Var', (30, 52))	('FGFR2', 'Gene', '2263', (24, 29))	('FGFR2', 'Gene', (24, 29))	('ICC', 'Disease', (53, 56))
177941	33106918	Univariate analysis unveiled associations between the presence of FGFR2 rearrangement and two factors, i.e., younger age (<= 65 years; p = 0.0085), and HCV Ab- and/or HBs Ag-positivity (p = 0.02).	('FGFR2', 'Gene', (66, 71))	('FGFR2', 'Gene', '2263', (66, 71))	('presence', 'Var', (54, 62))	('rearrangement', 'Var', (72, 85))	('associations', 'Interaction', (29, 41))
177942	33106918	Although a history of heavy drinking (ethanol >= 60 g/day) also tended to be associated with positivity for FGFR2 rearrangement, no statistically significant difference was achieved (p = 0.06).	('ethanol', 'Chemical', 'MESH:D000431', (38, 45))	('FGFR2', 'Gene', '2263', (108, 113))	('FGFR2', 'Gene', (108, 113))	('positivity', 'Var', (93, 103))	('rearrangement', 'Var', (114, 127))
177943	33106918	Furthermore, multivariate analysis of these three factors identified younger age (<= 65 years) and HCV Ab- and/or HBs Ag-positivity as associated with FGFR2 rearrangement (Table 4).	('FGFR2', 'Gene', (151, 156))	('associated', 'Reg', (135, 145))	('rearrangement', 'Var', (157, 170))	('FGFR2', 'Gene', '2263', (151, 156))
177944	33106918	The median age of FGFR2 rearrangement positive/negative patients was 60 years old (range 40-75)/67 years old (range 25-91), respectively.	('rearrangement', 'Var', (24, 37))	('patients', 'Species', '9606', (56, 64))	('FGFR2', 'Gene', '2263', (18, 23))	('FGFR2', 'Gene', (18, 23))
177945	33106918	Thus, 10.3% (17/165) of younger patients and 16.6% (6/36) of hepatitis virus-positive patients were FGFR2 rearrangement positive.	('hepatitis', 'Disease', 'MESH:D056486', (61, 70))	('patients', 'Species', '9606', (32, 40))	('FGFR2', 'Gene', (100, 105))	('FGFR2', 'Gene', '2263', (100, 105))	('hepatitis', 'Phenotype', 'HP:0012115', (61, 70))	('hepatitis', 'Disease', (61, 70))	('rearrangement', 'Var', (106, 119))	('patients', 'Species', '9606', (86, 94))
177946	33106918	Of the patients who were positive for both factors, 26% showed FGFR2 rearrangements.	('FGFR2', 'Gene', '2263', (63, 68))	('rearrangements', 'Var', (69, 83))	('patients', 'Species', '9606', (7, 15))	('FGFR2', 'Gene', (63, 68))
177947	33106918	In the second period, we investigated the details and clinical responses of first-line chemotherapy regimens for cases positive for FGFR2 rearrangements.	('FGFR2', 'Gene', '2263', (132, 137))	('FGFR2', 'Gene', (132, 137))	('rearrangements', 'Var', (138, 152))
177949	33106918	The overall survival (OS), from the initiation of first-line chemotherapy, of FGFR2 rearrangement-positive patients is shown in Fig.	('FGFR2', 'Gene', (78, 83))	('patients', 'Species', '9606', (107, 115))	('rearrangement-positive', 'Var', (84, 106))	('FGFR2', 'Gene', '2263', (78, 83))
177950	33106918	The median OS was 38.8 months for the 18 FGFR2 rearrangement-positive patients, 13 of whom received molecular targeting therapy with FGFR inhibitors.	('FGFR2', 'Gene', '2263', (41, 46))	('patients', 'Species', '9606', (70, 78))	('rearrangement-positive', 'Var', (47, 69))	('FGFR2', 'Gene', (41, 46))
177951	33106918	FGFR2 gene alterations were reported to be associated with early stages; however, no study has selectively examined advanced cases.	('alterations', 'Var', (11, 22))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))	('associated', 'Reg', (43, 53))
177952	33106918	In this study, the frequency of FGFR2 rearrangement-positive cases was 7.4% among patients with advanced/recurrent ICC, which was lower than those of previous reports (13-14%) that analyzed surgically resected cases.	('ICC', 'Disease', (115, 118))	('patients', 'Species', '9606', (82, 90))	('FGFR2', 'Gene', (32, 37))	('FGFR2', 'Gene', '2263', (32, 37))	('rearrangement-positive', 'Var', (38, 60))
177956	33106918	The different frequency of FGFR2 rearrangements between patients undergoing resection, and those with advanced cancer, could be due to the preferential occurrence of FGFR2 rearrangements in patients with peripheral and mass forming type, which progress slowly and are frequently treated by surgical resection.	('patients', 'Species', '9606', (56, 64))	('FGFR2', 'Gene', (27, 32))	('FGFR2', 'Gene', '2263', (27, 32))	('patients', 'Species', '9606', (190, 198))	('FGFR2', 'Gene', (166, 171))	('rearrangements', 'Var', (172, 186))	('FGFR2', 'Gene', '2263', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rearrangements', 'Var', (33, 47))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('occurrence', 'Reg', (152, 162))
177957	33106918	This study also revealed that 3.6% of patients with PCC had FGFR2 rearrangements.	('PCC', 'Disease', (52, 55))	('rearrangements', 'Var', (66, 80))	('patients', 'Species', '9606', (38, 46))	('FGFR2', 'Gene', '2263', (60, 65))	('FGFR2', 'Gene', (60, 65))
177958	33106918	Additionally, in the current study, three PCC patients were found to be FGFR2 rearrangement positive, two of which had intrahepatic extension.	('PCC', 'Disease', (42, 45))	('intrahepatic extension', 'Disease', (119, 141))	('positive', 'Reg', (92, 100))	('patients', 'Species', '9606', (46, 54))	('intrahepatic extension', 'Disease', 'MESH:D000079822', (119, 141))	('FGFR2', 'Gene', (72, 77))	('FGFR2', 'Gene', '2263', (72, 77))	('rearrangement', 'Var', (78, 91))
177960	33106918	Our results indicate that PCC could also be screened for FGFR2 rearrangements as a potential target category of FGFR inhibitors.	('rearrangements', 'Var', (63, 77))	('FGFR2', 'Gene', '2263', (57, 62))	('FGFR2', 'Gene', (57, 62))
177961	33106918	According to the post hoc targeted RNA sequencing using FFPE specimens, the sensitivity and specificity of the FISH assay to detect FGFR2 rearrangements was 100% and 99.0%, respectively, indicating that FISH is a reliable diagnostic assay method.	('FGFR2', 'Gene', '2263', (132, 137))	('FGFR2', 'Gene', (132, 137))	('rearrangements', 'Var', (138, 152))
177965	33106918	ICC patients with 3'-UTR truncated FGFR2 transcripts exhibited higher RNA expression compared to wild-type FGFR2 transcripts.	('FGFR2', 'Gene', (107, 112))	('FGFR2', 'Gene', '2263', (107, 112))	('FGFR2', 'Gene', (35, 40))	("3'-UTR truncated", 'Var', (18, 34))	('FGFR2', 'Gene', '2263', (35, 40))	('transcripts', 'Var', (41, 52))	('ICC', 'Disease', (0, 3))	('patients', 'Species', '9606', (4, 12))	('higher', 'PosReg', (63, 69))	('RNA expression', 'MPA', (70, 84))
177966	33106918	Meanwhile, C-terminal truncation of FGFR2 showed transforming ability in gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('gastric cancer', 'Disease', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('FGFR2', 'Gene', '2263', (36, 41))	('FGFR2', 'Gene', (36, 41))	('C-terminal truncation', 'Var', (11, 32))	('transforming', 'MPA', (49, 61))
177970	33106918	Although break-apart FISH assays cannot identify the fusion partner gene, it can clarify the presence/absence of FGFR2 rearrangements (fusions/truncations) including those involved with unknown partners.	('FGFR2', 'Gene', '2263', (113, 118))	('FGFR2', 'Gene', (113, 118))	('rearrangements', 'Var', (119, 133))
177975	33106918	Break-apart ALK FISH assay was approved by the FDA as a companion diagnostic for detecting ALK rearrangements in lung cancer patients who may benefit from treatment of ALK tyrosine kinase inhibitor therapy using >= 15% as a cutoff value.	('rearrangements', 'Var', (95, 109))	('ALK', 'Gene', (12, 15))	('ALK', 'Gene', (91, 94))	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('ALK', 'Gene', (168, 171))	('ALK', 'Gene', '238', (12, 15))	('ALK', 'Gene', '238', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('ALK', 'Gene', '238', (168, 171))	('patients', 'Species', '9606', (125, 133))
177976	33106918	In meta-analysis of ALK rearrangement-positive non-small lung cancer, higher percentage of ALK rearrangement-positive cells tend to respond better to the crizotinib therapy.	('ALK', 'Gene', '238', (20, 23))	('ALK', 'Gene', (91, 94))	('small lung', 'Phenotype', 'HP:0002089', (51, 61))	('better', 'PosReg', (140, 146))	('rearrangement-positive', 'Var', (24, 46))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('crizotinib', 'Chemical', 'MESH:D000077547', (154, 164))	('respond', 'MPA', (132, 139))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('ALK', 'Gene', '238', (91, 94))	('ALK', 'Gene', (20, 23))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
177978	33106918	FGFR2 rearrangement was more frequently detected in younger and hepatitis virus-positive patients.	('rearrangement', 'Var', (6, 19))	('hepatitis', 'Disease', 'MESH:D056486', (64, 73))	('hepatitis', 'Phenotype', 'HP:0012115', (64, 73))	('detected', 'Reg', (40, 48))	('patients', 'Species', '9606', (89, 97))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))	('hepatitis', 'Disease', (64, 73))
177979	33106918	A previous study analyzing somatic mutations related to ICC with cirrhotic liver reported higher frequencies of either IDH mutations or FGFR2 alterations.	('IDH', 'Gene', '3417', (119, 122))	('cirrhotic liver', 'Phenotype', 'HP:0001394', (65, 80))	('alterations', 'Var', (142, 153))	('cirrhotic liver', 'Disease', 'MESH:D017093', (65, 80))	('FGFR2', 'Gene', '2263', (136, 141))	('cirrhotic liver', 'Disease', (65, 80))	('FGFR2', 'Gene', (136, 141))	('IDH', 'Gene', (119, 122))	('mutations', 'Var', (123, 132))
177980	33106918	Both that report and our study suggest a possible association with a background of continuous damage to hepatocytes, such as those related to virus infection and the presence of FGFR2 rearrangements.	('virus infection', 'Disease', 'MESH:D001102', (142, 157))	('presence', 'Var', (166, 174))	('virus infection', 'Disease', (142, 157))	('rearrangements', 'Var', (184, 198))	('FGFR2', 'Gene', '2263', (178, 183))	('association', 'Interaction', (50, 61))	('FGFR2', 'Gene', (178, 183))
177981	33106918	In FGFR2 rearrangement-positive 18 patients, the median OS was 38.8 months, and they have good prognosis as survival in advanced/recurrent ICC/PCC.	('FGFR2', 'Gene', (3, 8))	('FGFR2', 'Gene', '2263', (3, 8))	('ICC/PCC', 'Disease', (139, 146))	('rearrangement-positive', 'Var', (9, 31))	('patients', 'Species', '9606', (35, 43))
177982	33106918	It may be due to the clinical feature of FGFR2 fusion/rearrangement ICC/PCC patients and therapeutic intervention of FGFR inhibitors.	('patients', 'Species', '9606', (76, 84))	('FGFR2', 'Gene', '2263', (41, 46))	('FGFR2', 'Gene', (41, 46))	('ICC/PCC', 'Disease', (68, 75))	('fusion/rearrangement', 'Var', (47, 67))
177987	33106918	First, since the number of positive patients was small, the prognostic significance of FGFR2 rearrangement positivity must be confirmed in larger studies.	('FGFR2', 'Gene', '2263', (87, 92))	('FGFR2', 'Gene', (87, 92))	('rearrangement', 'Var', (93, 106))	('patients', 'Species', '9606', (36, 44))
177988	33106918	In conclusion, this study demonstrated the feasibility of FGFR2-FISH assay using biopsy specimens of BTC, and showed that 7.4% of cases in advanced/recurrent ICC retained FGFR2 rearrangements, and 3.6% cases in advanced/recurrent PCC also carried the alterations.	('BTC', 'Phenotype', 'HP:0100574', (101, 104))	('FGFR2', 'Gene', '2263', (58, 63))	('ICC', 'Disease', (158, 161))	('FGFR2', 'Gene', (171, 176))	('rearrangements', 'Var', (177, 191))	('FGFR2', 'Gene', '2263', (171, 176))	('FGFR2', 'Gene', (58, 63))
177989	33106918	Moreover, younger age and a history of hepatitis viral infection are associated with the presence of FGFR2 rearrangements.	('FGFR2', 'Gene', (101, 106))	('FGFR2', 'Gene', '2263', (101, 106))	('hepatitis viral infection', 'Disease', 'MESH:D006509', (39, 64))	('rearrangements', 'Var', (107, 121))	('hepatitis viral infection', 'Disease', (39, 64))	('hepatitis', 'Phenotype', 'HP:0012115', (39, 48))	('presence', 'Var', (89, 97))
177990	33106918	These findings have important implications for elucidating the pathophysiology of FGFR2 rearrangements, and will be useful in developing targeted therapy for ICC and PCC.	('PCC', 'Disease', (166, 169))	('ICC', 'Disease', (158, 161))	('FGFR2', 'Gene', '2263', (82, 87))	('rearrangements', 'Var', (88, 102))	('FGFR2', 'Gene', (82, 87))
178072	31824996	However, in cases of lymph node metastases or R1 resections, the prognosis was poor and not different between patients with HLC or CBDC.	('HLC', 'Disease', (124, 127))	('metastases', 'Disease', (32, 42))	('R1 resections', 'Var', (46, 59))	('HLC', 'Disease', 'MESH:D018281', (124, 127))	('metastases', 'Disease', 'MESH:D009362', (32, 42))	('patients', 'Species', '9606', (110, 118))
178095	33579265	Several risk factors, i.e, bile duct disorders, liver diseases, digestive disorders, metabolic and endocrine disorders, and parasitic infections (Opisthorchis viverrine and Clonorchis sinensis) cause chronic biliary inflammation and cholestasis, resulting in uncontrolled proliferation, genetic and epigenetic mutations and eventually malignant transformation and tumor formation.	('genetic', 'Var', (287, 294))	('biliary inflammation', 'Disease', 'MESH:D007249', (208, 228))	('bile duct disorders', 'Phenotype', 'HP:0001080', (27, 46))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('bile duct disorders', 'Disease', 'MESH:D001649', (27, 46))	('cholestasis', 'Disease', 'MESH:D002779', (233, 244))	('Clonorchis sinensis', 'Species', '79923', (173, 192))	('liver diseases', 'Phenotype', 'HP:0001392', (48, 62))	('uncontrolled', 'MPA', (259, 271))	('malignant transformation', 'CPA', (335, 359))	('digestive disorders', 'Phenotype', 'HP:0011024', (64, 83))	('epigenetic mutations', 'Var', (299, 319))	('parasitic infections', 'Phenotype', 'HP:0030885', (124, 144))	('biliary inflammation', 'Disease', (208, 228))	('liver diseases', 'Disease', 'MESH:D008107', (48, 62))	('endocrine disorders', 'Disease', 'MESH:D004700', (99, 118))	('cause', 'Reg', (194, 199))	('tumor', 'Disease', (364, 369))	('Opisthorchis', 'Species', '6198', (146, 158))	('endocrine disorders', 'Disease', (99, 118))	('parasitic infections', 'Disease', (124, 144))	('liver diseases', 'Disease', (48, 62))	('metabolic and endocrine disorders', 'Phenotype', 'HP:0000818', (85, 118))	('cholestasis', 'Disease', (233, 244))	('bile duct disorders', 'Disease', (27, 46))	('tumor', 'Disease', 'MESH:D009369', (364, 369))	('parasitic infections', 'Disease', 'MESH:D010272', (124, 144))	('cholestasis', 'Phenotype', 'HP:0001396', (233, 244))
178144	33579265	The delta-delta Ct calculation for the relative quantification of the target gene was as follow:  Where DeltaCt (1) = delta Ct of unknown sample, DeltaCt (2) = delta Ct of control, IL-6 or TNF-alpha = target gene, and GAPDH = housekeeping gene.	('TNF-alpha', 'Gene', '7124', (189, 198))	('C', 'Chemical', 'MESH:D002244', (151, 152))	('TNF-alpha', 'Gene', (189, 198))	('DeltaCt (2', 'Var', (146, 156))	('C', 'Chemical', 'MESH:D002244', (166, 167))	('C', 'Chemical', 'MESH:D002244', (124, 125))	('C', 'Chemical', 'MESH:D002244', (16, 17))	('IL-6', 'Gene', (181, 185))	('C', 'Chemical', 'MESH:D002244', (109, 110))	('delta Ct', 'Var', (160, 168))	('GAPDH', 'Gene', '2597', (218, 223))	('IL-6', 'Gene', '3569', (181, 185))	('GAPDH', 'Gene', (218, 223))
178260	33579265	Notably, among the CCA cell lines, ex vivo expanded human NK cells showed a higher cytolytic activity to HuCCT1 and SNU308, but lower activity in SNU1196 and SNU478 cells.	('cytolytic activity', 'MPA', (83, 101))	('activity', 'MPA', (134, 142))	('human', 'Species', '9606', (52, 57))	('lower', 'NegReg', (128, 133))	('higher', 'PosReg', (76, 82))	('HuCCT1', 'Protein', (105, 111))	('SNU308', 'Var', (116, 122))	('CCA', 'Phenotype', 'HP:0030153', (19, 22))
178330	30439965	The primary endpoint was the surgical feasibility of EB-RFA and technical difficulty, including immediate adverse events, such as perforation or massive hemobilia, and delayed adverse events including cholangitis, abscess formation, and severe adhesion, which can be obstacles for surgery.	('EB-RFA', 'Chemical', '-', (53, 59))	('hemobilia', 'Disease', (153, 162))	('cholangitis', 'Disease', 'MESH:D002761', (201, 212))	('EB-RFA', 'Var', (53, 59))	('hemobilia', 'Disease', 'MESH:D006431', (153, 162))	('abscess', 'Disease', (214, 221))	('abscess', 'Phenotype', 'HP:0025615', (214, 221))	('severe adhesion', 'CPA', (237, 252))	('cholangitis', 'Disease', (201, 212))	('cholangitis', 'Phenotype', 'HP:0030151', (201, 212))	('perforation', 'CPA', (130, 141))	('hemobilia', 'Phenotype', 'HP:0100762', (153, 162))
178371	30439965	Secondly, because there is concern about severe EB-RFA related adverse events such as hepatic infarction and hemobilia following EB-RFA for hilar bile duct which is a complex portion of the blood vessels structure, our study only included the distal extrahepatic cholangiocarcinoma.	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (250, 281))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (263, 281))	('hemobilia', 'Phenotype', 'HP:0100762', (109, 118))	('EB-RFA', 'Chemical', '-', (129, 135))	('extrahepatic cholangiocarcinoma', 'Disease', (250, 281))	('hepatic infarction', 'Disease', (86, 104))	('hemobilia', 'Disease', (109, 118))	('EB-RFA', 'Chemical', '-', (48, 54))	('EB-RFA', 'Var', (129, 135))	('hemobilia', 'Disease', 'MESH:D006431', (109, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('hepatic infarction', 'Disease', 'MESH:D000081011', (86, 104))
178375	30439965	In conclusion, EB-RFA with a temperature-controlled RFA catheter could result in coagulation necrosis of human cancer tissue.	('coagulation necrosis', 'Disease', 'MESH:D009336', (81, 101))	('human', 'Species', '9606', (105, 110))	('EB-RFA', 'Chemical', '-', (15, 21))	('coagulation necrosis', 'Disease', (81, 101))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('EB-RFA', 'Var', (15, 21))	('result in', 'Reg', (71, 80))	('coagulation necrosis', 'Phenotype', 'HP:0010885', (81, 101))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
178381	30160357	With silencing SPRY2 expression, we demonstrated that SPRY2 could suppress FGFR2-induced ERK phosphorylation, migration, invasion and epithelial-mesenchymal transition (EMT) under FGF1 stimulation.	('suppress', 'NegReg', (66, 74))	('FGFR2-induced', 'Gene', (75, 88))	('SPRY2', 'Gene', (15, 20))	('epithelial-mesenchymal transition', 'CPA', (134, 167))	('migration', 'CPA', (110, 119))	('ERK', 'Gene', '5594', (89, 92))	('silencing', 'Var', (5, 14))	('SPRY2', 'Gene', (54, 59))	('FGF1', 'Gene', (180, 184))	('SPRY2', 'Gene', '10253', (15, 20))	('ERK', 'Gene', (89, 92))	('invasion', 'CPA', (121, 129))	('SPRY2', 'Gene', '10253', (54, 59))	('FGF1', 'Gene', '2246', (180, 184))
178382	30160357	By overexpressing SPRY2-wide type or SPRY2-Y55F, the tyrosine-55 of SPRY2 was demonstrated to be essential in suppressing ERK phosphorylation, tumour invasion and EMT of ICC cells.	('SPRY2', 'Gene', '10253', (18, 23))	('tyrosine-55', 'Var', (53, 64))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('EMT of ICC cells', 'CPA', (163, 179))	('SPRY2', 'Gene', (37, 42))	('tumour invasion', 'Disease', 'MESH:D009361', (143, 158))	('suppressing', 'NegReg', (110, 121))	('tyrosine', 'Chemical', 'MESH:D014443', (53, 61))	('SPRY2', 'Gene', (68, 73))	('SPRY2', 'Gene', '10253', (37, 42))	('ERK', 'Gene', '5594', (122, 125))	('tumour invasion', 'Disease', (143, 158))	('ERK', 'Gene', (122, 125))	('SPRY2', 'Gene', (18, 23))	('SPRY2', 'Gene', '10253', (68, 73))	('Y55F', 'Mutation', 'p.Y55F', (43, 47))
178399	30160357	Human recombinant FGF1 was purchased from PeproTech Company, and the inhibitor AP24534 was purchased from Selleck, the primary antibodies of SPRY1-4, pan-phospho-Tyr, and beta-actin were bought from Santa Cruz Biotechnology (Santa Cruz, CA), antibodies of FGFR2, Grb2, pFRS2-Tyr436, p-ERK-Tyr202/204 and the EMT antibody sampler kit were purchased from the Cell Signaling Technology (Danvers, MA), antibody of p-FGFR2-Tyr769 was from Biorbyt Company (Cambridge, UK).	('Human', 'Species', '9606', (0, 5))	('beta-actin', 'Gene', (171, 181))	('Grb2', 'Gene', '2885', (263, 267))	('Tyr', 'Chemical', 'MESH:D014443', (289, 292))	('Tyr', 'Chemical', 'MESH:D014443', (162, 165))	('FRS2', 'Gene', (270, 274))	('SPRY1-4', 'Gene', (141, 148))	('ERK', 'Gene', '5594', (285, 288))	('SPRY1-4', 'Gene', '10252;10253;10251;81848', (141, 148))	('FGF1', 'Gene', (18, 22))	('AP24534', 'Chemical', 'MESH:C545373', (79, 86))	('beta-actin', 'Gene', '728378', (171, 181))	('FGF1', 'Gene', '2246', (18, 22))	('Grb2', 'Gene', (263, 267))	('FRS2', 'Gene', '10818', (270, 274))	('ERK', 'Gene', (285, 288))	('p-FGFR2-Tyr769', 'Var', (410, 424))	('Tyr', 'Chemical', 'MESH:D014443', (418, 421))	('Tyr', 'Chemical', 'MESH:D014443', (275, 278))
178409	30160357	Cells were passaged into the matrigel invasion chambers and cultured for 6 hours for adherence, and then incubated in 1%-serum-containing medium with 100 ng/mL FGF1 for 12 hours.	('FGF1', 'Gene', '2246', (160, 164))	('FGF1', 'Gene', (160, 164))	('100 ng/mL', 'Var', (150, 159))
178433	30160357	With the incubation of 10 ng/mL FGF1 and/or 1 mumol/L FGFR2 inhibitor AP24534, we demonstrated that FGFR2 phosphorylation could induce the phosphorylation of FRS2 and ERK of RBE cells (Figure 4B).	('phosphorylation', 'MPA', (139, 154))	('FGF1', 'Gene', '2246', (32, 36))	('FGFR2', 'Gene', (100, 105))	('AP24534', 'Chemical', 'MESH:C545373', (70, 77))	('FGF1', 'Gene', (32, 36))	('ERK', 'Gene', '5594', (167, 170))	('FRS2', 'Gene', '10818', (158, 162))	('induce', 'PosReg', (128, 134))	('ERK', 'Gene', (167, 170))	('phosphorylation', 'Var', (106, 121))	('FRS2', 'Gene', (158, 162))
178434	30160357	With silencing FGFR2 or SPRY2 expression with siRNA, FGFR2 was demonstrated to be required in FGF1-induced ERK phosphorylation in RBE cells (Figure 4C), and SPRY2 could suppress the FGFR2-mediated ERK phosphorylation (Figure 4D).	('ERK', 'Gene', '5594', (107, 110))	('ERK', 'Gene', (107, 110))	('ERK', 'Gene', '5594', (197, 200))	('SPRY2', 'Gene', '10253', (24, 29))	('suppress', 'NegReg', (169, 177))	('ERK', 'Gene', (197, 200))	('silencing', 'Var', (5, 14))	('FGF1', 'Gene', (94, 98))	('FGFR2', 'Gene', (15, 20))	('SPRY2', 'Gene', (157, 162))	('SPRY2', 'Gene', '10253', (157, 162))	('SPRY2', 'Gene', (24, 29))	('FGF1', 'Gene', '2246', (94, 98))
178437	30160357	With wound healing assay, we proved that FGFR2 knockdown notably impaired the tumour cell migration while silencing SPRY2 could promote migration of RBE or HuCCT-1 cells (Figure 5A,B).	('migration', 'CPA', (136, 145))	('impaired the tumour', 'Disease', 'MESH:D001523', (65, 84))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('FGFR2', 'Gene', (41, 46))	('SPRY2', 'Gene', (116, 121))	('knockdown', 'Var', (47, 56))	('impaired the tumour', 'Disease', (65, 84))	('silencing', 'Var', (106, 115))	('promote', 'PosReg', (128, 135))	('SPRY2', 'Gene', '10253', (116, 121))
178438	30160357	FGF1 stimulation could remarkably increase tumour invasion with normal FGFR2 expression, but the invasion of RBE or HuCCT-1 was decreased when FGFR2 was knocked down and increased when SPRY2 was knocked down (Figure 5C,D).	('FGFR2', 'Gene', (143, 148))	('FGF1', 'Gene', (0, 4))	('SPRY2', 'Gene', '10253', (185, 190))	('tumour invasion', 'Disease', 'MESH:D009361', (43, 58))	('increased', 'PosReg', (170, 179))	('tumour invasion', 'Disease', (43, 58))	('decreased', 'NegReg', (128, 137))	('increase', 'PosReg', (34, 42))	('SPRY2', 'Gene', (185, 190))	('FGF1', 'Gene', '2246', (0, 4))	('invasion of', 'CPA', (97, 108))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('knocked down', 'Var', (153, 165))
178441	30160357	FGFR inhibitor AP24534 could suppress FGF1-induced expression of Slug and Snail, and rescue the decrease in E-cadherin, indicating AP24534 could attenuate the FGF1-induced EMT process of ICC (Figure 5E).	('FGF1', 'Gene', (38, 42))	('E-cadherin', 'Gene', (108, 118))	('E-cadherin', 'Gene', '999', (108, 118))	('FGF1', 'Gene', '2246', (159, 163))	('suppress', 'NegReg', (29, 37))	('Slug', 'Gene', '6591', (65, 69))	('FGF1', 'Gene', '2246', (38, 42))	('decrease', 'NegReg', (96, 104))	('AP24534', 'Var', (131, 138))	('FGF1', 'Gene', (159, 163))	('Slug', 'Gene', (65, 69))	('expression', 'MPA', (51, 61))	('AP24534', 'Chemical', 'MESH:C545373', (131, 138))	('AP24534', 'Chemical', 'MESH:C545373', (15, 22))	('attenuate', 'NegReg', (145, 154))	('AP24534', 'Var', (15, 22))	('Snail', 'Gene', '6615', (74, 79))	('Snail', 'Gene', (74, 79))
178442	30160357	With knocking down FGFR2 or SPRY2, we demonstrated that FGFR2 was necessary for the FGF1-induced EMT and SPRY2 could repress the FGFR2-mediated EMT process (Figure 5F,G).	('SPRY2', 'Gene', '10253', (28, 33))	('FGF1', 'Gene', '2246', (84, 88))	('repress', 'NegReg', (117, 124))	('SPRY2', 'Gene', (105, 110))	('FGF1', 'Gene', (84, 88))	('knocking', 'Var', (5, 13))	('FGFR2', 'Gene', (19, 24))	('SPRY2', 'Gene', '10253', (105, 110))	('SPRY2', 'Gene', (28, 33))
178443	30160357	According to previous studies, The tyrosine55 of SPRY2 is considered to be responsible for binding with Grb2 and recognizing FGF-specific ERK-activating pathway,25 so the function of SPRY2-Tyr55 in RBE cells was further investigated.	('SPRY2', 'Gene', (49, 54))	('ERK', 'Gene', (138, 141))	('ERK', 'Gene', '5594', (138, 141))	('Grb2', 'Gene', (104, 108))	('SPRY2', 'Gene', (183, 188))	('SPRY2', 'Gene', '10253', (49, 54))	('SPRY2', 'Gene', '10253', (183, 188))	('Grb2', 'Gene', '2885', (104, 108))	('Tyr55', 'Chemical', '-', (189, 194))	('binding', 'Interaction', (91, 98))	('tyrosine55', 'Var', (35, 45))	('tyrosine55', 'Chemical', '-', (35, 45))
178446	30160357	To verify the function of SPRY2 Tyr55, the plasmids carrying wild-type SPRY2 (SPRY2-WT) or mutated SPRY2 (SPRY2-Y55F) were transfected into RBE cells.	('Y55F', 'Mutation', 'p.Y55F', (112, 116))	('Tyr55', 'Chemical', '-', (32, 37))	('SPRY2', 'Gene', (78, 83))	('SPRY2', 'Gene', (71, 76))	('mutated', 'Var', (91, 98))	('SPRY2', 'Gene', (106, 111))	('SPRY2', 'Gene', '10253', (78, 83))	('SPRY2', 'Gene', (26, 31))	('SPRY2', 'Gene', (99, 104))	('SPRY2', 'Gene', '10253', (71, 76))	('SPRY2', 'Gene', '10253', (106, 111))	('SPRY2', 'Gene', '10253', (26, 31))	('SPRY2', 'Gene', '10253', (99, 104))
178448	30160357	Moreover, the mutation of SPRY2 Tyr-55 also impaired its function of suppressing EMT (Figure 6C).	('Tyr-55', 'Var', (32, 38))	('impaired', 'NegReg', (44, 52))	('Tyr', 'Chemical', 'MESH:D014443', (32, 35))	('suppressing', 'NegReg', (69, 80))	('SPRY2', 'Gene', (26, 31))	('SPRY2', 'Gene', '10253', (26, 31))
178449	30160357	With wound healing assay and transwell assay, cells with SPRY2-Y55F overexpression had significantly more aggressive migration and invasion than cells overexpressing SPRY2-WT(Figure 6D,E), indicating Tyr-55 was required in ICC migration and invasion.	('SPRY2', 'Gene', (166, 171))	('invasion', 'CPA', (131, 139))	('SPRY2', 'Gene', '10253', (166, 171))	('Y55F', 'Mutation', 'p.Y55F', (63, 67))	('SPRY2', 'Gene', (57, 62))	('Tyr', 'Chemical', 'MESH:D014443', (200, 203))	('aggressive migration', 'CPA', (106, 126))	('SPRY2', 'Gene', '10253', (57, 62))	('more', 'PosReg', (101, 105))	('overexpression', 'Var', (68, 82))
178453	30160357	In our study, high expression of SPRY2 was demonstrated to indicate favourable prognosis via antagonizing FGF-FGFR2 signalling.	('SPRY2', 'Gene', (33, 38))	('FGF-FGFR2 signalling', 'MPA', (106, 126))	('SPRY2', 'Gene', '10253', (33, 38))	('antagonizing', 'NegReg', (93, 105))	('high expression', 'Var', (14, 29))
178467	28008139	The clonal origin of these samples was tested using two platforms: next-generation sequencing (NGS) of 390 key genes harboring cancer-relevant actionable mutations and whole-genome copy number variation (CNV) chip analysis.	('mutations', 'Var', (154, 163))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (127, 133))
178483	28008139	The cancer cell population is characterized by a high incidence of somatic mutations, aberrant ploidies of chromosomes, and copy number variations (CNVs).	('copy number variations', 'Var', (124, 146))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('aberrant', 'Var', (86, 94))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))
178485	28008139	For example, screening mutations of the consensus key cancer genes (http://cancer.sanger.ac.uk/census) provides a means to examine not only the clonal evolution theory of tumor cells, but also their metastasis and origin.	('consensus key cancer', 'Disease', 'MESH:D009369', (40, 60))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('consensus key cancer', 'Disease', (40, 60))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', (54, 60))	('mutations', 'Var', (23, 32))	('examine', 'Reg', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Disease', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
178488	28008139	Indeed, performing sample-wise clustering in 12 different malignancies to derive subtypes based on 6 different data types from the TCGA showed that the patterns of copy number change varied across tissue type, and subtyping of the tumors based on CNVs revealed a significant correlation with tissue type.	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('copy number', 'Var', (164, 175))	('malignancies', 'Disease', 'MESH:D009369', (58, 70))	('malignancies', 'Disease', (58, 70))	('tumors', 'Disease', (231, 237))
178493	28008139	We found the same TP53 mutation (chr17 7577538 exon7 C = >T), with mutation frequencies of 0.156, 0.084, and 0.06 in the bile duct, omentum, and pancreas, respectively.	('chr17 7577538 exon7 C = >T', 'Var', (33, 59))	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))
178496	28008139	Intriguingly, although KRAS mutations are reported for 99% of PanIN-1s37, no more than 95% of pancreatic cancers have a KRAS or BRAF mutation, supporting the notion that a KRAS mutation is not strictly required for the development of pancreatic cancer.	('KRAS', 'Gene', '3845', (172, 176))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (94, 112))	('pancreatic cancer', 'Disease', 'MESH:D010190', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('pancreatic cancers', 'Disease', (94, 112))	('KRAS', 'Gene', (172, 176))	('pancreatic cancer', 'Disease', 'MESH:D010190', (234, 251))	('KRAS', 'Gene', '3845', (120, 124))	('pancreatic cancer', 'Disease', (234, 251))	('pancreatic cancers', 'Disease', 'MESH:D010190', (94, 112))	('KRAS', 'Gene', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('KRAS', 'Gene', '3845', (23, 27))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (94, 111))	('mutation', 'Var', (133, 141))	('KRAS', 'Gene', (23, 27))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (234, 251))	('BRAF', 'Gene', '673', (128, 132))	('BRAF', 'Gene', (128, 132))
178526	28008139	Both in somatic mutations and CNVs (whether in the 390 key genes tested or at the chromosomal level), we observed a greater number of biological events in cancer cells from the biliary duct.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (155, 161))	('mutations', 'Var', (16, 25))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
178534	28008139	Given the relatively distinct mutation signatures between the biliary duct and the pancreas, it seems that cancer cells in the pancreas migrated into the bile duct at a relative early stage according to the moderate number of shared mutations and CNVs.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('mutations', 'Var', (233, 242))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))
178562	28008139	A total of 390 key cancer-relevant genes were deep sequenced for potential mutations, which were called only on single base substitutions or small indel substitutions.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('mutations', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
178564	28008139	The probes were used to capture the alleles of over 220,000 single nucleotide polymorphisms (SNPs) at carefully selected genomic locations, both those evenly distributed across the genome and those with increased density, within nearly 900 cancer-relevant genes.	('single nucleotide', 'Var', (60, 77))	('cancer', 'Disease', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))
178574	28256614	In this study, we demonstrated that both the 1alpha,25(OH)2D3 analog, MART-10, and 1alpha,25(OH)2D3 possessed anti-growth effect on human CCA cells with MART-10 much more potent than 1alpha,25(OH)2D3.	('anti-growth effect', 'CPA', (110, 128))	('MART', 'Gene', (153, 157))	('1alpha', 'Chemical', '-', (45, 51))	('1alpha', 'Chemical', '-', (83, 89))	('MART', 'Gene', '5414', (70, 74))	('1alpha', 'Chemical', '-', (183, 189))	('25(OH)2D3', 'Chemical', '-', (190, 199))	('MART', 'Gene', '5414', (153, 157))	('25(OH)2D3', 'Chemical', '-', (52, 61))	('rat', 'Species', '10116', (25, 28))	('human', 'Species', '9606', (132, 137))	('25(OH)2D3', 'Chemical', '-', (90, 99))	('1alpha,25(OH)2D3', 'Var', (83, 99))	('MART', 'Gene', (70, 74))
178576	28256614	Human neutrophil gelatinase associated lipocalin (NGAL) was found to be involved in 1alpha,25(OH)2D3 and MART-10 meditated growth inhibition for CCA as knockdown of NGAL decreased Ki-67 expression in SNU308 cells and rendered SNU308 cells less responsive to 1alpha,25(OH)2D3 and MART-10 treatment.	('Human', 'Species', '9606', (0, 5))	('MART', 'Gene', (105, 109))	('MART', 'Gene', '5414', (279, 283))	('neutrophil gelatinase associated lipocalin', 'Gene', (6, 48))	('MART', 'Gene', (279, 283))	('NGAL', 'Gene', (165, 169))	('NGAL', 'Gene', '3934', (50, 54))	('neutrophil gelatinase associated lipocalin', 'Gene', '3934', (6, 48))	('knockdown', 'Var', (152, 161))	('NGAL', 'Gene', '3934', (165, 169))	('Ki-67', 'Gene', (180, 185))	('1alpha', 'Chemical', '-', (84, 90))	('NGAL', 'Gene', (50, 54))	('1alpha', 'Chemical', '-', (258, 264))	('25(OH)2D3', 'Chemical', '-', (91, 100))	('decreased', 'NegReg', (170, 179))	('expression', 'MPA', (186, 196))	('25(OH)2D3', 'Chemical', '-', (265, 274))	('MART', 'Gene', '5414', (105, 109))
178577	28256614	Vitamin D receptor (VDR) knockdown partly abolished MART-10-induced inhibition of NGAL and cell growth in SNU308 cells.	('NGAL', 'Gene', '3934', (82, 86))	('VDR', 'Gene', '7421', (20, 23))	('Vitamin D receptor', 'Gene', (0, 18))	('abolished', 'NegReg', (42, 51))	('MART', 'Gene', '5414', (52, 56))	('NGAL', 'Gene', (82, 86))	('inhibition', 'NegReg', (68, 78))	('Vitamin D receptor', 'Gene', '7421', (0, 18))	('VDR', 'Gene', (20, 23))	('MART', 'Gene', (52, 56))	('knockdown', 'Var', (25, 34))
178591	28256614	Since VDR has been found to exist in a variety of cancer cell lines, it is not surprising that a lot of cancer cells growth are inhibited by 1alpha,25(OH)2D3.	('1alpha,25(OH)2D3', 'Var', (141, 157))	('1alpha', 'Chemical', '-', (141, 147))	('cancer', 'Disease', (50, 56))	('VDR', 'Gene', '7421', (6, 9))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('25(OH)2D3', 'Chemical', '-', (148, 157))	('VDR', 'Gene', (6, 9))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('inhibited', 'NegReg', (128, 137))
178616	28256614	Previously, we have shown NGAL expression in CCA cells and knockdown of NGAL in CCA cells was able to increase CCA cells doubling time, indicating NGAL role as an oncogene in human CCA.	('NGAL', 'Gene', '3934', (26, 30))	('human', 'Species', '9606', (175, 180))	('CCA', 'Disease', (111, 114))	('NGAL', 'Gene', '3934', (147, 151))	('NGAL', 'Gene', '3934', (72, 76))	('NGAL', 'Gene', (72, 76))	('increase', 'PosReg', (102, 110))	('knockdown', 'Var', (59, 68))	('NGAL', 'Gene', (26, 30))	('NGAL', 'Gene', (147, 151))
178630	28256614	NGAL expression in SNU308 cells was not influenced significantly by MART-10 after VDR knockdown (Fig.	('VDR', 'Gene', '7421', (82, 85))	('knockdown', 'Var', (86, 95))	('NGAL', 'Gene', '3934', (0, 4))	('NGAL', 'Gene', (0, 4))	('MART', 'Gene', (68, 72))	('VDR', 'Gene', (82, 85))	('MART', 'Gene', '5414', (68, 72))
178632	28256614	7d) and NGAL reporter activity was less inhibited by MART-10 as VDR knockdown (Fig.	('MART', 'Gene', (53, 57))	('VDR', 'Gene', (64, 67))	('knockdown', 'Var', (68, 77))	('NGAL', 'Gene', '3934', (8, 12))	('NGAL', 'Gene', (8, 12))	('MART', 'Gene', '5414', (53, 57))	('VDR', 'Gene', '7421', (64, 67))
178668	28256614	Regarding CCA, knockdown o NGAL has been shown to increase CCA cells invasiveness and doubling time.	('invasiveness', 'CPA', (69, 81))	('NGAL', 'Gene', (27, 31))	('knockdown', 'Var', (15, 24))	('NGAL', 'Gene', '3934', (27, 31))	('increase', 'PosReg', (50, 58))	('CCA', 'Disease', (59, 62))	('doubling time', 'CPA', (86, 99))	('CCA', 'Disease', (10, 13))
178678	28256614	The western blot and reporter assay demonstrated that the reporter activity and protein expression of NGAL in SNU308 cells were less influenced by MART-10 as VDR knockdown (Fig.	('NGAL', 'Gene', '3934', (102, 106))	('VDR', 'Gene', '7421', (158, 161))	('MART', 'Gene', '5414', (147, 151))	('rat', 'Species', '10116', (43, 46))	('MART', 'Gene', (147, 151))	('protein expression', 'MPA', (80, 98))	('VDR', 'Gene', (158, 161))	('reporter activity', 'MPA', (58, 75))	('NGAL', 'Gene', (102, 106))	('knockdown', 'Var', (162, 171))
178683	28256614	Regarding OS, after multivariate Cox proportional hazard analysis, only low VDR staining intensity was identified as independent predictors for an inferior OS rate (Supplemental Table 2 and Fig.	('low', 'Var', (72, 75))	('VDR', 'Gene', (76, 79))	('inferior OS rate', 'MPA', (147, 163))	('VDR', 'Gene', '7421', (76, 79))	('rat', 'Species', '10116', (159, 162))
178685	28256614	The finding that high expression of VDR is linked with better OS of CCA patients further implies the feasibility of application of vitamin D in CCA treatment.	('VDR', 'Gene', (36, 39))	('vitamin D', 'Chemical', 'MESH:D014807', (131, 140))	('high', 'Var', (17, 21))	('patients', 'Species', '9606', (72, 80))	('CCA', 'Disease', (68, 71))	('VDR', 'Gene', '7421', (36, 39))	('expression', 'MPA', (22, 32))	('better OS', 'Disease', (55, 64))
178696	28256614	The primary antibodies used in this study were monoclonal antibodies against p21 (#2946, Cell Signal, Beverly, MA, USA,), p27 (#3698, Cell Signal), CDK4 (cell signal, #2906, Beverly, MA, USA), CDK6 (cell signal, #3136, Beverly, MA, USA), cyclin D3 (cell signal, #2936, Beverly, MA, USA), NGAL(#PAB9543, Abnova Corporation, Taipei, Taiwan).	('cyclin D3', 'Gene', '896', (238, 247))	('CDK4', 'Gene', '1019', (148, 152))	('p27', 'Gene', '3429', (122, 125))	('cyclin D3', 'Gene', (238, 247))	('#2946', 'Var', (82, 87))	('p27', 'Gene', (122, 125))	('rat', 'Species', '10116', (315, 318))	('p21', 'Gene', '644914', (77, 80))	('NGAL', 'Gene', (288, 292))	('p21', 'Gene', (77, 80))	('CDK6', 'Gene', (193, 197))	('NGAL', 'Gene', '3934', (288, 292))	('CDK4', 'Gene', (148, 152))	('CDK6', 'Gene', '1021', (193, 197))
178699	28256614	The procedures of knockdown of NGAL or VDR in SNU308 cells to obtain SNU308-NGALsi or SNU308-VDRsi cells were described previously.	('knockdown', 'Var', (18, 27))	('NGAL', 'Gene', (31, 35))	('NGAL', 'Gene', (76, 80))	('VDR', 'Gene', '7421', (93, 96))	('VDR', 'Gene', (39, 42))	('NGAL', 'Gene', '3934', (31, 35))	('NGAL', 'Gene', '3934', (76, 80))	('VDR', 'Gene', '7421', (39, 42))	('VDR', 'Gene', (93, 96))
178702	28256614	The DNA fragment containing the enhancer/promoter of the NGAL gene (-5450 to +4) was synthesized with primers (T7 and 5'-CCATGGAGTGAGAGGCTCACCTGGGTGG-3') by PCR using the pGEM3_LCN2 as target DNA, and was digested and cloned into the luciferase reporter vector (pGL3-Basic; Promega Biosciences) at the Sac I and Nco I sites.	('pGL3', 'Gene', (262, 266))	('NGAL', 'Gene', '3934', (57, 61))	('LCN2', 'Gene', '3934', (177, 181))	('LCN2', 'Gene', (177, 181))	('pGL3', 'Gene', '6391', (262, 266))	('NGAL', 'Gene', (57, 61))	('-5450 to +4', 'Var', (68, 79))
178710	28256614	The study was approved by the local institutional review board of Chang Gung Memorial Hospital (clinical study numbers 99-2886B, 99-3810B and 102-5813B), and written informed consent for immunohistochemical tumor analysis was obtained from each patient.	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('102-5813B', 'Var', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('99-3810B', 'Var', (129, 137))	('tumor', 'Disease', (207, 212))	('patient', 'Species', '9606', (245, 252))
178752	33832503	Analyses of public data revealed somatic GNAS alterations in 2.1% hepatobiliary tumors and relation with parasite infection.	('biliary tumors', 'Disease', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('parasite infection', 'Disease', (105, 123))	('GNAS', 'Gene', (41, 45))	('biliary tumors', 'Phenotype', 'HP:0100574', (72, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('alterations', 'Var', (46, 57))	('biliary tumors', 'Disease', 'MESH:D001661', (72, 86))	('parasite infection', 'Disease', 'MESH:D010272', (105, 123))	('GNAS', 'Gene', '2778', (41, 45))
178755	33832503	Here we provide the first evidence of the molecular etiology of a rare HMEC associated with germline Fanconi's anemia gene mutations and somatic GNAS R201H mutation.	('anemia', 'Phenotype', 'HP:0001903', (111, 117))	("Fanconi's anemia", 'Phenotype', 'HP:0001994', (101, 117))	('GNAS', 'Gene', '2778', (145, 149))	('associated', 'Reg', (76, 86))	('R201H', 'Mutation', 'rs121913495', (150, 155))	("germline Fanconi's anemia", 'Phenotype', 'HP:0001994', (92, 117))	("Fanconi's anemia", 'Disease', 'MESH:D005199', (101, 117))	("Fanconi's anemia", 'Disease', (101, 117))	('GNAS', 'Gene', (145, 149))	('mutations', 'Var', (123, 132))
178757	33832503	Over 50-60% of salivary MEC (SMEC) cases are associated with a fusion gene, CRTC1/CRTC3-MAML2, which results from the chromosomal translocation t(11;19)(q21;p13).	('CRTC3', 'Gene', (82, 87))	('t(11;19)(q21;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (144, 161))	('CRTC3', 'Gene', '64784', (82, 87))	('t(11;19)(q21;p13', 'Var', (144, 160))	('associated', 'Reg', (45, 55))	('MAML2', 'Gene', (88, 93))	('CRTC1', 'Gene', (76, 81))	('CRTC1', 'Gene', '23373', (76, 81))	('MAML2', 'Gene', '84441', (88, 93))
178776	33832503	Primary antibodies included antibodies against MUC1 (1:200), MUC5AC (1:200), CK7 (1:250), CK19 (1:150), p63 (1:150) and CEA (1:250) (all from Leica, Wetzlar,Germany).	('MUC5AC', 'Gene', '4586', (61, 67))	('CK7', 'Gene', (77, 80))	('CK19', 'Gene', (90, 94))	('1:150', 'Var', (96, 101))	('CK19', 'Gene', '3880', (90, 94))	('1:250', 'Var', (82, 87))	('p63', 'Gene', (104, 107))	('MUC1', 'Gene', (47, 51))	('MUC1', 'Gene', '4582', (47, 51))	('CK7', 'Gene', '3855', (77, 80))	('MUC5AC', 'Gene', (61, 67))	('CEA', 'Gene', (120, 123))	('1:200', 'Var', (69, 74))	('p63', 'Gene', '8626', (104, 107))	('CEA', 'Gene', '1084', (120, 123))	('1:150', 'Var', (109, 114))
178780	33832503	FISH was performed for the CRTC1/MECT1-MAML2 fusion gene and 200 interphase tumor cells were examined in at least two visual fields.	('MECT1', 'Gene', '23373', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('CRTC1', 'Gene', (27, 32))	('CRTC1', 'Gene', '23373', (27, 32))	('MAML2', 'Gene', '84441', (39, 44))	('MAML2', 'Gene', (39, 44))	('fusion gene', 'Var', (45, 56))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('MECT1', 'Gene', (33, 38))
178784	33832503	Using the paired samples of tumor tissue and corresponding non-tumor tissues, somatic SNVs were detected by MuTect, somatic InDels by Strelka and somatic CNVs by Control-FREEC.	('tumor', 'Disease', (63, 68))	('InDels', 'Var', (124, 130))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
178803	33832503	GNAS mutation (NM_000516:exon8:c.G602A:p.R201H) was detected in both the tumor tissue and corresponding non-tumor tissue by WES, but the wild-type gene was determined in the corresponding non-tumor tissue by Sanger sequencing.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('c.G602A:p.R201H', 'SUBSTITUTION', 'None', (31, 46))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('GNAS', 'Gene', (0, 4))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('c.G602A:p.R201H', 'Var', (31, 46))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('GNAS', 'Gene', '2778', (0, 4))
178804	33832503	In addition, protein-truncating genetic variants included a frameshift indel mutation in ELF3 (c.909dupC:p.F303fs), and nonsense mutations in DOCK3 (c.C2483A:p.S828X) and KMT2C (c.C1519T:p.Q507X) were detected in tumor samples by Sanger sequencing (Fig.	('tumor', 'Disease', (213, 218))	('c.909dupC', 'Var', (95, 104))	('c.C2483A:p.S828X', 'SUBSTITUTION', 'None', (149, 165))	('DOCK3', 'Gene', '1795', (142, 147))	('ELF3', 'Gene', '1999', (89, 93))	('KMT2C', 'Gene', '58508', (171, 176))	('KMT2C', 'Gene', (171, 176))	('c.909dupC', 'Mutation', 'c.909dupC', (95, 104))	('c.C1519T:p.Q507X', 'SUBSTITUTION', 'None', (178, 194))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('DOCK3', 'Gene', (142, 147))	('frameshift indel', 'Var', (60, 76))	('p.F303fs', 'Mutation', 'p.F303fsX', (105, 113))	('protein-truncating', 'NegReg', (13, 31))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('c.C2483A:p.S828X', 'Var', (149, 165))	('c.C1519T:p.Q507X', 'Var', (178, 194))	('ELF3', 'Gene', (89, 93))
178805	33832503	A total of 1004 significant mutated genes (source: Onco KB) in SNVs from 8 studies containing 1487 HCC patients (Supplementary Fig.	('mutated genes', 'Var', (28, 41))	('HCC', 'Phenotype', 'HP:0001402', (99, 102))	('HCC', 'Gene', '619501', (99, 102))	('patients', 'Species', '9606', (103, 111))	('HCC', 'Gene', (99, 102))
178806	33832503	2A) and 654 significant mutated genes (source: Onco KB) in SNVs from 7 studies containing 445 CHL patients were downloaded (Supplementary Fig.	('mutated', 'Var', (24, 31))	('CHL', 'Disease', (94, 97))	('CHL', 'Disease', 'MESH:D006689', (94, 97))	('patients', 'Species', '9606', (98, 106))	('CHL', 'Phenotype', 'HP:0030153', (94, 97))
178809	33832503	Somatic GNAS gene alterations (including missense mutation, amplification and truncating mutation) were detected in 2.1% (9/445) patients with primary hepatobiliary tumors including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and perihilar cholangiocarcinoma (Fig.	('biliary tumors', 'Disease', (157, 171))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (215, 246))	('biliary tumors', 'Phenotype', 'HP:0100574', (157, 171))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (195, 213))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('missense mutation', 'Var', (41, 58))	('GNAS', 'Gene', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('GNAS', 'Gene', '2778', (8, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('detected', 'Reg', (104, 112))	('alterations', 'Var', (18, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('patients', 'Species', '9606', (129, 137))	('extrahepatic cholangiocarcinoma', 'Disease', (215, 246))	('truncating', 'MPA', (78, 88))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (261, 279))	('amplification', 'MPA', (60, 73))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (228, 246))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (182, 213))	('cholangiocarcinoma', 'Disease', (261, 279))	('biliary tumors', 'Disease', 'MESH:D001661', (157, 171))	('intrahepatic cholangiocarcinoma', 'Disease', (182, 213))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (195, 213))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (261, 279))	('cholangiocarcinoma', 'Disease', (228, 246))	('cholangiocarcinoma', 'Disease', (195, 213))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (228, 246))
178810	33832503	Three patients showed GNAS (p.R201H/C) missense mutation (a putative driver) in exon 8.	('GNAS', 'Gene', (22, 26))	('p.R201H', 'Var', (28, 35))	('patients', 'Species', '9606', (6, 14))	('GNAS', 'Gene', '2778', (22, 26))	('p.R201H', 'SUBSTITUTION', 'None', (28, 35))
178812	33832503	The 56 germline variants in 20 Fanconi's anemia pathway genes included 19 missense variants, 25 synonymous variants and 12 UTR3 and UTR5 in the proband corresponding non-tumor tissue detected by WES (Supplementary Table 2).	('tumor', 'Disease', 'MESH:D009369', (170, 175))	("Fanconi's anemia", 'Phenotype', 'HP:0001994', (31, 47))	("Fanconi's anemia", 'Disease', 'MESH:D005199', (31, 47))	('anemia', 'Phenotype', 'HP:0001903', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	("Fanconi's anemia", 'Disease', (31, 47))	('tumor', 'Disease', (170, 175))	('variants', 'Var', (16, 24))
178818	33832503	Heterozygous variants in FANCA (c.G1501A:p.G501S), FANCA (c.A796G:p.T266A) and FANCJ/BRIP1 (c.T2755C:p.S919P) were detected in the proband, but homozygous mutations were shown in the other family members.	('FANCA', 'Gene', (25, 30))	('BRIP1', 'Gene', '83990', (85, 90))	('c.A796G:p.T266A', 'Var', (58, 73))	('c.T2755C:p.S919P', 'SUBSTITUTION', 'None', (92, 108))	('c.T2755C:p.S919P', 'Var', (92, 108))	('c.A796G:p.T266A', 'SUBSTITUTION', 'None', (58, 73))	('FANCJ', 'Gene', '83990', (79, 84))	('BRIP1', 'Gene', (85, 90))	('FANCJ', 'Gene', (79, 84))	('c.G1501A:p.G501S', 'Var', (32, 48))	('c.G1501A:p.G501S', 'SUBSTITUTION', 'None', (32, 48))
178819	33832503	Only heterozygous FANCI variants (c.C257T:p.A86V and c.G2225C:p.C742S) were unique in the proband (Table 2, Fig.	('c.G2225C:p.C742S', 'SUBSTITUTION', 'None', (53, 69))	('c.C257T:p.A86V', 'Var', (34, 48))	('c.C257T:p.A86V', 'SUBSTITUTION', 'None', (34, 48))	('c.G2225C:p.C742S', 'Var', (53, 69))	('FANCI', 'Gene', '55215', (18, 23))	('FANCI', 'Gene', (18, 23))
178829	33832503	FANCA variants (c.G1501A:p.G501S and c.A796G:p.T266A) were shown to confer an increased risk for cervical squamous carcinoma.	('c.A796G:p.T266A', 'SUBSTITUTION', 'None', (37, 52))	('squamous carcinoma', 'Disease', (106, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (106, 124))	('c.G1501A:p.G501S', 'Var', (16, 32))	('c.A796G:p.T266A', 'Var', (37, 52))	('squamous carcinoma', 'Disease', 'MESH:D002294', (106, 124))	('c.G1501A:p.G501S', 'SUBSTITUTION', 'None', (16, 32))
178830	33832503	An association with both progression-free and overall survival probabilities was found with the FANCD1/BRCA2 V2466A variant in breast cancer.	('V2466A', 'Mutation', 'rs169547', (109, 115))	('BRCA2', 'Gene', '675', (103, 108))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('breast cancer', 'Disease', (127, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('FANCD1', 'Gene', (96, 102))	('V2466A', 'Var', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('BRCA2', 'Gene', (103, 108))	('FANCD1', 'Gene', '675', (96, 102))
178832	33832503	showed that FAN1 defects can cause cancers in knock-in mice, and the FAN1 variant in high-risk pancreatic cancers abolishes recruitment by Ub-FANCD2, resulting in genetic instability without affecting interstrand crosslink repair.	('FANCD2', 'Gene', '211651', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('variant', 'Var', (74, 81))	('pancreatic cancers', 'Disease', (95, 113))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('FAN1', 'Gene', (12, 16))	('cancers', 'Disease', (106, 113))	('defects', 'Var', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('recruitment', 'MPA', (124, 135))	('pancreatic cancers', 'Disease', 'MESH:D010190', (95, 113))	('Ub', 'Chemical', '-', (139, 141))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cause', 'Reg', (29, 34))	('genetic instability', 'MPA', (163, 182))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('FAN1', 'Gene', (69, 73))	('abolishes', 'NegReg', (114, 123))	('FANCD2', 'Gene', (142, 148))	('mice', 'Species', '10090', (55, 59))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (95, 113))
178833	33832503	Germline FAN1 mutations occur frequently in high-risk pancreatic cancers and hereditary susceptibility to familial colorectal cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('familial colorectal cancers', 'Disease', 'MESH:D015179', (106, 133))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('pancreatic cancers', 'Disease', 'MESH:D010190', (54, 72))	('pancreatic cancers', 'Disease', (54, 72))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('familial colorectal cancers', 'Disease', (106, 133))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (54, 72))	('mutations', 'Var', (14, 23))
178834	33832503	Therefore, we propose that germline Fanconi's anemia gene mutations are likely predisposing factors to the occurrence of HMEC.	('mutations', 'Var', (58, 67))	("germline Fanconi's anemia", 'Phenotype', 'HP:0001994', (27, 52))	("Fanconi's anemia", 'Phenotype', 'HP:0001994', (36, 52))	('anemia', 'Phenotype', 'HP:0001903', (46, 52))	("Fanconi's anemia", 'Disease', 'MESH:D005199', (36, 52))	("Fanconi's anemia", 'Disease', (36, 52))
178835	33832503	Mutations in the GNAS gene typically occur at exon 8, in which Arg201 is converted to either a cysteine (R201C) or a histidine (R201H), leading to activation of the Galphas subunit.	('GNAS', 'Gene', (17, 21))	('Galphas', 'Gene', (165, 172))	('Galphas', 'Gene', '2778', (165, 172))	('R201H', 'Mutation', 'rs121913495', (128, 133))	('Arg201', 'Var', (63, 69))	('Mutations', 'Var', (0, 9))	('R201C', 'Var', (105, 110))	('GNAS', 'Gene', '2778', (17, 21))	('activation', 'PosReg', (147, 157))	('Arg201 is converted to either a cysteine', 'Mutation', 'rs11554273', (63, 103))	('histidine', 'Chemical', 'MESH:D006639', (117, 126))	('R201H', 'Var', (128, 133))
178837	33832503	The GNAS R201H/C missense mutation have been showed a cross-communication between JAK/STAT and cyclic-AMP pathways in rare subtypes of liver inflammatory tumorigenesis.	('GNAS', 'Gene', '2778', (4, 8))	('STAT', 'Gene', (86, 90))	('cyclic-AMP pathways', 'Pathway', (95, 114))	('R201H', 'SUBSTITUTION', 'None', (9, 14))	('cyclic-AMP', 'Chemical', 'MESH:D000242', (95, 105))	('GNAS', 'Gene', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('R201H', 'Var', (9, 14))	('cross-communication', 'Reg', (54, 73))	('STAT', 'Gene', '6772;6774', (86, 90))	('tumor', 'Disease', (154, 159))
178838	33832503	also described an adult male patient with inflammatory hepatic adenoma associated with Fanconi's anemia and somatic GNAS mutation who developed malignant transformation of HCC.	('patient', 'Species', '9606', (29, 36))	("Fanconi's anemia", 'Phenotype', 'HP:0001994', (87, 103))	('inflammatory hepatic adenoma', 'Disease', 'MESH:D000236', (42, 70))	('GNAS', 'Gene', (116, 120))	('inflammatory hepatic adenoma', 'Disease', (42, 70))	('HCC', 'Gene', (172, 175))	("Fanconi's anemia", 'Disease', 'MESH:D005199', (87, 103))	('hepatic adenoma', 'Phenotype', 'HP:0012028', (55, 70))	('anemia', 'Phenotype', 'HP:0001903', (97, 103))	("Fanconi's anemia", 'Disease', (87, 103))	('HCC', 'Phenotype', 'HP:0001402', (172, 175))	('mutation', 'Var', (121, 129))	('HCC', 'Gene', '619501', (172, 175))	('GNAS', 'Gene', '2778', (116, 120))	('associated', 'Reg', (71, 81))
178840	33832503	The somatic GNAS R201H/C mutation occurs frequently in secreting-mucous tumors like pancreatic intraductal papillary mucinous neoplasms (IPMN) as a bona fide precursor to carcinogenesis.	('R201H', 'SUBSTITUTION', 'None', (17, 22))	('carcinogenesis', 'Disease', 'MESH:D063646', (171, 185))	('GNAS', 'Gene', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mucinous neoplasms', 'Phenotype', 'HP:0031495', (117, 135))	('neoplasm', 'Phenotype', 'HP:0002664', (126, 134))	('carcinogenesis', 'Disease', (171, 185))	('R201H', 'Var', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('GNAS', 'Gene', '2778', (12, 16))	('neoplasms', 'Phenotype', 'HP:0002664', (126, 135))	('tumors like pancreatic intraductal papillary mucinous neoplasms', 'Disease', 'MESH:D000077779', (72, 135))
178842	33832503	The mucus production and carcinogenesis of the intestinal subtype of intraductal papillary neoplasm of the biliary ducts, a counterpart of pancreatic IPMN, have also been connected with gain-of-function mutations of GNAS R201.	('mucus', 'CPA', (4, 9))	('GNAS', 'Gene', (216, 220))	('papillary neoplasm', 'Disease', 'MESH:D002291', (81, 99))	('pancreatic IPMN', 'Disease', (139, 154))	('carcinogenesis', 'Disease', 'MESH:D063646', (25, 39))	('pancreatic IPMN', 'Disease', 'MESH:D000077779', (139, 154))	('neoplasm', 'Phenotype', 'HP:0002664', (91, 99))	('GNAS', 'Gene', '2778', (216, 220))	('carcinogenesis', 'Disease', (25, 39))	('mutations', 'Var', (203, 212))	('papillary neoplasm', 'Disease', (81, 99))	('gain-of-function', 'PosReg', (186, 202))
178843	33832503	The protein-truncating genetic variants in the present case included a frameshift insertion in ELF3 and nonsense mutation in KMT2C, and both genes were also reported in biliary tumors as tumor suppressors.	('KMT2C', 'Gene', '58508', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', (187, 192))	('biliary tumors', 'Disease', (169, 183))	('protein-truncating', 'MPA', (4, 22))	('ELF3', 'Gene', '1999', (95, 99))	('biliary tumors', 'Phenotype', 'HP:0100574', (169, 183))	('biliary tumors', 'Disease', 'MESH:D001661', (169, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('ELF3', 'Gene', (95, 99))	('frameshift insertion', 'Var', (71, 91))	('tumor', 'Disease', (177, 182))	('KMT2C', 'Gene', (125, 130))	('nonsense mutation', 'Var', (104, 121))
178845	33832503	Moreover, GNAS and KMT2C were almost only mutated in Opisthorchis viverrini-induced CHL compared non-O.	('GNAS', 'Gene', '2778', (10, 14))	('mutated', 'Var', (42, 49))	('CHL', 'Phenotype', 'HP:0030153', (84, 87))	('KMT2C', 'Gene', '58508', (19, 24))	('KMT2C', 'Gene', (19, 24))	('CHL', 'Disease', (84, 87))	('GNAS', 'Gene', (10, 14))	('Opisthorchis viverrini', 'Species', '6198', (53, 75))	('CHL', 'Disease', 'MESH:D006689', (84, 87))
178853	33832503	We present here for the first time the etiology of HMEC associated with germline Fanconi's anemia mutations and somatic GNAS R201 mutation.	("Fanconi's anemia", 'Disease', 'MESH:D005199', (81, 97))	('HMEC', 'Disease', (51, 55))	('GNAS', 'Gene', (120, 124))	("Fanconi's anemia", 'Disease', (81, 97))	('mutation', 'Var', (130, 138))	("germline Fanconi's anemia", 'Phenotype', 'HP:0001994', (72, 97))	('associated', 'Reg', (56, 66))	('mutations', 'Var', (98, 107))	("Fanconi's anemia", 'Phenotype', 'HP:0001994', (81, 97))	('GNAS', 'Gene', '2778', (120, 124))	('anemia', 'Phenotype', 'HP:0001903', (91, 97))
178854	33832503	MEC Mucoepidermoid carcinoma HMEC Hepatic mucoepidermoid carcinoma SMEC Salivary mucoepidermoid carcinoma HCC Hepatocellular carcinoma CHL Cholangiocarcinoma WES Whole exome-sequencing FISH Fluorescence in situ hybridization CT Computer tomography SNV Single-nucleotide variant This study was designed by Ping Hou, Wenjun Liao and Linquan Wu.	('Hepatocellular carcinoma', 'Disease', (110, 134))	('Hepatic mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (34, 66))	('HCC', 'Gene', (106, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (110, 134))	('CHL', 'Disease', 'MESH:D006689', (135, 138))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (139, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (110, 134))	('CHL', 'Disease', (135, 138))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (139, 157))	('Cholangiocarcinoma', 'Disease', (139, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('CHL', 'Phenotype', 'HP:0030153', (135, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('Hepatic mucoepidermoid carcinoma', 'Disease', (34, 66))	('Single-nucleotide', 'Chemical', '-', (252, 269))	('Salivary mucoepidermoid carcinoma', 'Disease', (72, 105))	('Mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (4, 28))	('Salivary mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (72, 105))	('Mucoepidermoid carcinoma', 'Disease', (4, 28))	('Single-nucleotide', 'Var', (252, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('HCC', 'Gene', '619501', (106, 109))	('HCC', 'Phenotype', 'HP:0001402', (106, 109))
178963	30335866	Dimerization leads to the activation of different downstream signaling cascades, including the mitogen-activated protein kinase (MAPK) proliferation pathway and phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (PKB or Akt) pro-survival pathway.	('Akt', 'Gene', (223, 226))	('Protein kinase B', 'Gene', '2185', (198, 214))	('PKB', 'Gene', '207', (216, 219))	('Dimerization', 'Var', (0, 12))	('PKB', 'Gene', (216, 219))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (161, 190))	('activation', 'PosReg', (26, 36))	('Protein kinase B', 'Gene', (198, 214))	('phosphatidylinositol 3-kinase', 'Gene', (161, 190))	('Akt', 'Gene', '207', (223, 226))
178966	30335866	Several trials treating patients with BTC with inhibitors of the HER pathway (when HER2 overexpression was identified) have yielded disappointing results [for example lapatinib, and erlotinib ].	('inhibitors', 'Var', (47, 57))	('patients', 'Species', '9606', (24, 32))	('lapatinib', 'Chemical', 'MESH:D000077341', (167, 176))	('HER2', 'Gene', (83, 87))	('erlotinib', 'Chemical', 'MESH:D000069347', (182, 191))	('HER2', 'Gene', '2064', (83, 87))
178971	30335866	This study investigated the prevalence of overexpression and amplification of HER2 and HER3 in patients with BTC, using a standardised approach for IHC and FISH methodology and interpretation.	('HER3', 'Gene', (87, 91))	('HER3', 'Gene', '2065', (87, 91))	('patients', 'Species', '9606', (95, 103))	('HER2', 'Gene', (78, 82))	('amplification', 'Var', (61, 74))	('HER2', 'Gene', '2064', (78, 82))	('overexpression', 'PosReg', (42, 56))
178986	30335866	Cases scoring IHC2+ were considered borderline, equivocal and referred for confirmation of both HER2 and HER3 status by FISH, as per previous groups.	('IHC2+', 'Var', (14, 19))	('HER3', 'Gene', (105, 109))	('HER3', 'Gene', '2065', (105, 109))	('HER2', 'Gene', (96, 100))	('HER2', 'Gene', '2064', (96, 100))
179010	30335866	Of the five patients with HER2 IHC2+ who underwent FISH analysis (Fig 2B), HER2 amplification was confirmed in only one patient (a second patient was classified as "borderline").	('patients', 'Species', '9606', (12, 20))	('IHC2+', 'Var', (31, 36))	('patient', 'Species', '9606', (120, 127))	('HER2', 'Gene', (75, 79))	('HER2', 'Gene', (26, 30))	('HER2', 'Gene', '2064', (75, 79))	('patient', 'Species', '9606', (138, 145))	('HER2', 'Gene', '2064', (26, 30))	('patient', 'Species', '9606', (12, 19))
179036	30335866	HER2 and HER3 mutations were widely spread through the whole exome of both genes (Fig 3C and 3D); two of the HER2 mutations are located in the kinase domain (one patient with intrahepatic cholangiocarcinoma and a second patient with gallbladder cancer) (Fig 3C); none of the HER3 mutations were located in kinase domain; two were located in the receptor L domain (site of ligand binding) (Fig 3D).	('intrahepatic cholangiocarcinoma', 'Disease', (175, 206))	('HER3', 'Gene', '2065', (275, 279))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('HER2', 'Gene', (109, 113))	('mutations', 'Var', (114, 123))	('HER2', 'Gene', '2064', (109, 113))	('HER3', 'Gene', (9, 13))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (188, 206))	('patient', 'Species', '9606', (220, 227))	('HER3', 'Gene', '2065', (9, 13))	('HER2', 'Gene', (0, 4))	('patient', 'Species', '9606', (162, 169))	('HER2', 'Gene', '2064', (0, 4))	('gallbladder cancer', 'Disease', (233, 251))	('mutations', 'Var', (14, 23))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (175, 206))	('HER3', 'Gene', (275, 279))	('gallbladder cancer', 'Disease', 'MESH:D005706', (233, 251))
179051	30335866	Because mutations identified in HER3 are usually not located in the kinase domain, it may be that overexpression/amplification rather than mutation could be targeted in BTC using an antibody approach.	('HER3', 'Gene', (32, 36))	('HER3', 'Gene', '2065', (32, 36))	('mutations', 'Var', (8, 17))
179054	30335866	The link between aberrations in the HER pathway especially in liver-fluke related BTC (more frequent in Asian countries) could also support this hypothesis.	('liver-fluke', 'Species', '6192', (62, 73))	('HER pathway', 'Pathway', (36, 47))	('liver-fluke related BTC', 'Disease', (62, 85))	('link', 'Reg', (4, 8))	('aberrations', 'Var', (17, 28))
179059	30335866	This suggests that mutations located in the HER2 kinase domain rather than amplification may be worth targeting in BTC.	('BTC', 'Disease', (115, 118))	('HER2', 'Gene', '2064', (44, 48))	('HER2', 'Gene', (44, 48))	('mutations', 'Var', (19, 28))
179090	30142881	CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism Cholangiocarcinoma is a disease with a poor prognosis and increasing incidence and hence there is a pressing unmet clinical need for new adjuvant treatments.	('Induces', 'Reg', (8, 15))	('Methuosis in Cholangiocarcinoma Cell', 'Disease', 'MESH:D018281', (16, 52))	('CX-4945', 'Chemical', 'MESH:C555142', (0, 7))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (90, 108))	('Cholangiocarcinoma', 'Disease', (90, 108))	('Cholangiocarcinoma', 'Disease', (29, 47))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('Methuosis in Cholangiocarcinoma Cell', 'Disease', (16, 52))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (29, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (29, 47))	('CX-4945', 'Var', (0, 7))
179093	30142881	Here, we show that CX-4945 inhibited the proliferation of cholangiocarcinoma cell lines in vitro.	('CX-4945', 'Chemical', 'MESH:C555142', (19, 26))	('cholangiocarcinoma cell lines', 'Disease', 'MESH:D018281', (58, 87))	('cholangiocarcinoma cell lines', 'Disease', (58, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('CX-4945', 'Var', (19, 26))	('inhibited', 'NegReg', (27, 36))	('proliferation of', 'CPA', (41, 57))
179094	30142881	Moreover, CX-4945 treatment induced the formation of cytosolic vacuoles in cholangiocarcinoma cell lines and other cancer cell lines.	('cholangiocarcinoma cell lines', 'Disease', (75, 104))	('cancer', 'Disease', (115, 121))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (75, 93))	('CX-4945', 'Chemical', 'MESH:C555142', (10, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('formation of cytosolic vacuoles', 'MPA', (40, 71))	('cholangiocarcinoma cell lines', 'Disease', 'MESH:D018281', (75, 104))	('CX-4945', 'Var', (10, 17))
179098	30142881	Our data suggest that CX-4945 inhibits cell proliferation and induces cell death via CK2-independent pathways.	('CK2-independent pathways', 'Pathway', (85, 109))	('induces', 'Reg', (62, 69))	('CX-4945', 'Var', (22, 29))	('cell death', 'CPA', (70, 80))	('cell proliferation', 'CPA', (39, 57))	('CX-4945', 'Chemical', 'MESH:C555142', (22, 29))	('inhibits', 'NegReg', (30, 38))
179099	30142881	Moreover, the increase in cell invasion brought about by CX-4945 treatment suggests that this drug might increase tumor invasion in clinical settings.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('CX-4945', 'Chemical', 'MESH:C555142', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('increase', 'PosReg', (105, 113))	('tumor', 'Disease', (114, 119))	('CX-4945', 'Var', (57, 64))	('cell invasion', 'CPA', (26, 39))	('increase', 'PosReg', (14, 22))
179111	30142881	Downregulation of CK2 with small interfering (siRNA) or by using CX-4945 induced apoptosis in non-small cell lung cancer cell lines by downregulation of Akt and its downstream signals.	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('Akt', 'Gene', '207', (153, 156))	('non-small cell lung cancer', 'Disease', (94, 120))	('Downregulation', 'NegReg', (0, 14))	('CX-4945', 'Chemical', 'MESH:C555142', (65, 72))	('apoptosis', 'CPA', (81, 90))	('Akt', 'Gene', (153, 156))	('downregulation', 'NegReg', (135, 149))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (98, 120))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (94, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('small interfering', 'Var', (27, 44))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (94, 120))	('CK2', 'Protein', (18, 21))
179112	30142881	Similarly, apoptosis was observed in acute myeloid leukemia cells by a p53-dependent mechanism after CK2 knockdown or CX-4945 application.	('myeloid leukemia', 'Disease', 'MESH:D007951', (43, 59))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (43, 59))	('leukemia', 'Phenotype', 'HP:0001909', (51, 59))	('knockdown', 'Var', (105, 114))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('CX-4945', 'Chemical', 'MESH:C555142', (118, 125))	('myeloid leukemia', 'Disease', (43, 59))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (37, 59))
179113	30142881	Furthermore, stable knockdown of CK2 sensitized HEp-2 laryngeal carcinoma cells to cisplatin-induced apoptosis.	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('HEp-2', 'CellLine', 'CVCL:1906', (48, 53))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (54, 73))	('laryngeal carcinoma', 'Disease', (54, 73))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (54, 73))	('cisplatin-induced apoptosis', 'MPA', (83, 110))	('CK2', 'Gene', (33, 36))	('sensitized', 'Reg', (37, 47))	('knockdown', 'Var', (20, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
179116	30142881	CX-4945 has also been shown to decrease the survival of many cancer cell types including bladder, hematological, prostate, and breast cancer cells.	('survival', 'CPA', (44, 52))	('hematological', 'Disease', (98, 111))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('prostate', 'Disease', (113, 121))	('CX-4945', 'Chemical', 'MESH:C555142', (0, 7))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('cancer', 'Disease', (61, 67))	('decrease', 'NegReg', (31, 39))	('cancer', 'Disease', (134, 140))	('breast cancer', 'Disease', (127, 140))	('bladder', 'Disease', (89, 96))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('CX-4945', 'Var', (0, 7))
179119	30142881	An in vivo study showed that CX-4045 up to 75 mg/kg was safe in mice and inhibited PC3 tumor xenograft growth.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('inhibited', 'NegReg', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mice', 'Species', '10090', (64, 68))	('CX-4045', 'Var', (29, 36))
179120	30142881	In primary human mucin- and mixed-intrahepatic CCA, CX-4945 up to 50 microM significantly decreased the viability of primary human cell cultures and induced apoptosis at 10 microM, whereas Cytokeratin 19 (CK19)-positive cells required a higher dose at 30 microM.	('Cytokeratin 19', 'Gene', '3880', (189, 203))	('mucin', 'Gene', '100508689', (17, 22))	('CX-4945', 'Var', (52, 59))	('apoptosis', 'CPA', (157, 166))	('human', 'Species', '9606', (11, 16))	('CCA', 'Phenotype', 'HP:0030153', (47, 50))	('CK19', 'Gene', (205, 209))	('mucin', 'Gene', (17, 22))	('human', 'Species', '9606', (125, 130))	('decreased', 'NegReg', (90, 99))	('CK19', 'Gene', '3880', (205, 209))	('CX-4945', 'Chemical', 'MESH:C555142', (52, 59))	('viability', 'CPA', (104, 113))	('induced', 'Reg', (149, 156))	('Cytokeratin 19', 'Gene', (189, 203))
179121	30142881	CX-4945 increased the number of gamma-H2AX positive cells that are a marker for DNA double-strand breaks.	('increased', 'PosReg', (8, 17))	('CX-4945', 'Var', (0, 7))	('gamma-H2AX', 'Protein', (32, 42))	('CX-4945', 'Chemical', 'MESH:C555142', (0, 7))
179122	30142881	However, inhibition of DNA-PK (DNA-dependent protein kinase), previously reported as downstream of CK2 in glioblastoma cells, unexpectedly reduced gamma-H2AX positive cells in primary human intrahepatic CCA cells.	('DNA-dependent protein kinase', 'Gene', '5591', (31, 59))	('DNA-PK', 'Gene', '5591', (23, 29))	('glioblastoma', 'Disease', (106, 118))	('gamma-H2AX', 'Protein', (147, 157))	('glioblastoma', 'Disease', 'MESH:D005909', (106, 118))	('CCA', 'Phenotype', 'HP:0030153', (203, 206))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('DNA-dependent protein kinase', 'Gene', (31, 59))	('human', 'Species', '9606', (184, 189))	('reduced', 'NegReg', (139, 146))	('DNA-PK', 'Gene', (23, 29))	('inhibition', 'Var', (9, 19))
179126	30142881	In addition, CX-4945 has been shown to affect alternative splicing of a wide range of genes, including CK2 itself, in a CK2-independent manner in the HEK293T cell line.	('CK2', 'Gene', (103, 106))	('CX-4945', 'Chemical', 'MESH:C555142', (13, 20))	('HEK293T', 'CellLine', 'CVCL:0063', (150, 157))	('alternative splicing', 'MPA', (46, 66))	('affect', 'Reg', (39, 45))	('CX-4945', 'Var', (13, 20))
179131	30142881	Herein, we report for the first time that CX-4945 at low doses stimulated CCA cell invasion due to an upregulation of matrix metallopeptidase 7 (MMP-7) and matrix metallopeptidase 9 (MMP-9).	('CX-4945', 'Var', (42, 49))	('MMP-7', 'Gene', '4316', (145, 150))	('matrix metallopeptidase 9', 'Gene', '4318', (156, 181))	('CX-4945', 'Chemical', 'MESH:C555142', (42, 49))	('MMP-9', 'Gene', (183, 188))	('CCA cell invasion', 'CPA', (74, 91))	('matrix metallopeptidase 7', 'Gene', (118, 143))	('MMP-9', 'Gene', '4318', (183, 188))	('CCA', 'Phenotype', 'HP:0030153', (74, 77))	('upregulation', 'PosReg', (102, 114))	('MMP-7', 'Gene', (145, 150))	('stimulated', 'PosReg', (63, 73))	('matrix metallopeptidase 9', 'Gene', (156, 181))	('matrix metallopeptidase 7', 'Gene', '4316', (118, 143))
179132	30142881	Also, CX-4945 induced cytosolic vacuolization, which met the criteria of methuosis, via a CK2-independent mechanism in a dose- and time-dependent manner.	('methuosis', 'Chemical', '-', (73, 82))	('CX-4945', 'Chemical', 'MESH:C555142', (6, 13))	('cytosolic vacuolization', 'MPA', (22, 45))	('CX-4945', 'Var', (6, 13))
179134	30142881	CX-4945 reduced CK2 activity in a dose-dependent manner 4 h post-treatment as determined using Western blotting with an antibody that recognizes phosphorylated CK2 sites in multiple proteins (Figure 1a).	('activity', 'MPA', (20, 28))	('CX-4945', 'Chemical', 'MESH:C555142', (0, 7))	('reduced', 'NegReg', (8, 15))	('CK2', 'Enzyme', (16, 19))	('CX-4945', 'Var', (0, 7))
179136	30142881	After 5 days of treatment, CX-4945 at 5 microM or higher doses reduced CCA cell number in all of the cell lines (Figure 1b).	('CX-4945', 'Var', (27, 34))	('reduced', 'NegReg', (63, 70))	('CCA', 'Disease', (71, 74))	('CX-4945', 'Chemical', 'MESH:C555142', (27, 34))	('CCA', 'Phenotype', 'HP:0030153', (71, 74))
179137	30142881	CX-4945 at 5 microM reduced CCA cell number to approximately 50% of the vehicle control in HuCCA-1, KKU-M213 cells and in CCLP-1 approximately to 70% as compared to vehicle control group at 5-days post-treatment.	('reduced', 'NegReg', (20, 27))	('CX-4945', 'Chemical', 'MESH:C555142', (0, 7))	('CCA cell number', 'CPA', (28, 43))	('CCA', 'Phenotype', 'HP:0030153', (28, 31))	('CCA', 'Phenotype', 'HP:0030153', (93, 96))	('CCLP-1', 'Gene', (122, 128))	('CX-4945', 'Var', (0, 7))	('CCLP-1', 'Gene', '8495', (122, 128))
179145	30142881	CX-4945 at 10 microM significantly inhibited cell invasion through Matrigel in the three CCA cell lines tested (Figure 1d).	('cell invasion through Matrigel', 'CPA', (45, 75))	('CX-4945', 'Chemical', 'MESH:C555142', (0, 7))	('inhibited', 'NegReg', (35, 44))	('CX-4945', 'Var', (0, 7))	('CCA', 'Phenotype', 'HP:0030153', (89, 92))
179150	30142881	The decrease in cell invasion at 10 microM of CX-4945 was at least in part due to a decrease in MMP-9 and MMP-7 levels in HuCCA-1 and to MMP-7 levels in KKU-M213.	('decrease', 'NegReg', (84, 92))	('MMP-9', 'Gene', '4318', (96, 101))	('MMP-9', 'Gene', (96, 101))	('MMP-7', 'Gene', (106, 111))	('CX-4945', 'Var', (46, 53))	('decrease', 'NegReg', (4, 12))	('MMP-7', 'Gene', '4316', (106, 111))	('MMP-7', 'Gene', (137, 142))	('CCA', 'Phenotype', 'HP:0030153', (124, 127))	('MMP-7', 'Gene', '4316', (137, 142))	('CX-4945', 'Chemical', 'MESH:C555142', (46, 53))	('cell invasion', 'CPA', (16, 29))
179155	30142881	The number of vacuoles also increased in a time-dependent manner until 4 h post-treatment in HuCCA-1 (Figure 2e) or 2 h after treatment in CCLP-1 and KKU-M213 (Figure 2i,m) before declining at later time points.	('CCLP-1', 'Gene', (139, 145))	('CCA', 'Phenotype', 'HP:0030153', (95, 98))	('KKU-M213', 'Var', (150, 158))	('CCLP-1', 'Gene', '8495', (139, 145))
179159	30142881	Furthermore, 50 microM CX-4945 treatment at 4 h also induced intensive vacuolization in immortalized cholangiocytes (MMNK-1 and AKN-1 cells), as well as breast cancer cell lines (MDA-MB-231 and T47D), prostate cancer cell line DU145, and human embryonic kidney cells (HEK293T).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (179, 189))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('prostate cancer', 'Disease', 'MESH:D011471', (201, 216))	('prostate cancer', 'Phenotype', 'HP:0012125', (201, 216))	('embryonic kidney', 'Disease', 'MESH:D007674', (244, 260))	('DU145', 'CellLine', 'CVCL:0105', (227, 232))	('vacuolization', 'MPA', (71, 84))	('CX-4945', 'Chemical', 'MESH:C555142', (23, 30))	('prostate cancer', 'Disease', (201, 216))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('human', 'Species', '9606', (238, 243))	('HEK293T', 'CellLine', 'CVCL:0063', (268, 275))	('induced', 'Reg', (53, 60))	('CX-4945', 'Var', (23, 30))	('T47D', 'CellLine', 'CVCL:0553', (194, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('embryonic kidney', 'Disease', (244, 260))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('breast cancer', 'Disease', (153, 166))
179163	30142881	However, CX-4945 at 25 and 50 microM significantly induced cell death in HuCCA-1 cells (Figure 4b) and KKU-M213 cells (Figure 4f) at 48 h post-treatment.	('CCA', 'Phenotype', 'HP:0030153', (75, 78))	('CX-4945', 'Var', (9, 16))	('cell death', 'CPA', (59, 69))	('CX-4945', 'Chemical', 'MESH:C555142', (9, 16))
179164	30142881	Although there was no significant increase in the number of dead CCLP-1 cells following treatment with CX-4945, the total number of cells 48 h post-treatment was clearly reduced (Figure 4d, calcein panels).	('CCLP-1', 'Gene', (65, 71))	('CX-4945', 'Var', (103, 110))	('calcein', 'Chemical', 'MESH:C007740', (190, 197))	('CX-4945', 'Chemical', 'MESH:C555142', (103, 110))	('CCLP-1', 'Gene', '8495', (65, 71))	('reduced', 'NegReg', (170, 177))
179168	30142881	Furthermore, the vacuoles that presented after CX-4945 treatment do not appear to be autophagosomes since levels of the autophagosomal marker LC3B-II decreased (Figure 5a) while the number and size of the vacuoles increased (Figure 2).	('CX-4945', 'Chemical', 'MESH:C555142', (47, 54))	('LC3B', 'Gene', '81631', (142, 146))	('LC3B', 'Gene', (142, 146))	('increased', 'PosReg', (214, 223))	('CX-4945', 'Var', (47, 54))	('levels of the autophagosomal', 'MPA', (106, 134))	('decreased', 'NegReg', (150, 159))
179169	30142881	Although HuCCA-1 treated with 10 and 25 microM CX-4945 showed an increased level of LC3B-II, the cells treated with 50 microM, which is the concentration where the highest number of vacuoles was observed, showed a decreased level of LC3B-II.	('CX-4945', 'Chemical', 'MESH:C555142', (47, 54))	('CCA', 'Phenotype', 'HP:0030153', (11, 14))	('LC3B', 'Gene', '81631', (84, 88))	('LC3B', 'Gene', (233, 237))	('CX-4945', 'Var', (47, 54))	('LC3B', 'Gene', '81631', (233, 237))	('decreased', 'NegReg', (214, 223))	('LC3B', 'Gene', (84, 88))
179174	30142881	We conclude that CX-4945 is likely to induce non-canonical cell death in these cell lines.	('CX-4945', 'Chemical', 'MESH:C555142', (17, 24))	('non-canonical cell death', 'CPA', (45, 69))	('CX-4945', 'Var', (17, 24))
179178	30142881	Second, KKU-M213, which are cells that are most sensitive to CX-4945 in terms of vacuole formation, were incubated for 72 h with CellLight  ER-GFP BacMam 2.0 (C10590, Fisher Scientific, Hampton, NH, USA).	('CX-4945', 'Chemical', 'MESH:C555142', (61, 68))	('C10590', 'Var', (159, 165))	('vacuole', 'MPA', (81, 88))
179188	30142881	In all three cell lines, knockdown of CK2 alpha and CK2 alpha' decreased the levels of multiple phospho-CK2 substrates (Figure 7b).	('CK2 alpha', 'Gene', '1459', (52, 61))	('CK2 alpha', 'Gene', (38, 47))	('decreased', 'NegReg', (63, 72))	('CK2 alpha', 'Gene', (52, 61))	('levels of multiple phospho-CK2 substrates', 'MPA', (77, 118))	('knockdown', 'Var', (25, 34))	('CK2 alpha', 'Gene', '1459', (38, 47))
179189	30142881	However, CK2 alpha and CK2 alpha' knockdown failed to induce vacuolization in any of the CCA cell lines (Figure 7c).	('CK2 alpha', 'Gene', (23, 32))	('CK2 alpha', 'Gene', '1459', (9, 18))	('CK2 alpha', 'Gene', '1459', (23, 32))	('knockdown', 'Var', (34, 43))	('CK2 alpha', 'Gene', (9, 18))	('CCA', 'Phenotype', 'HP:0030153', (89, 92))
179194	30142881	Combined CK2 alpha and CK2 alpha' knockdown had no effect on HUCCA-1 cell number over 5 days in culture and only a modest effect on the number of CCLP-1 and KKU-M213 cells (Figure 8a).	('CK2 alpha', 'Gene', (23, 32))	('HUCCA-1 cell number', 'CPA', (61, 80))	('CK2 alpha', 'Gene', '1459', (9, 18))	('CCA', 'Phenotype', 'HP:0030153', (63, 66))	('CK2 alpha', 'Gene', '1459', (23, 32))	('CCLP-1', 'Gene', (146, 152))	('knockdown', 'Var', (34, 43))	('CK2 alpha', 'Gene', (9, 18))	('CCLP-1', 'Gene', '8495', (146, 152))
179196	30142881	In contrast to the biphasic effects of CX-4945 treatment on CCA cell invasion, combined CK2 alpha and CK2 alpha' knockdown inhibited CCA cell invasion in HuCCA-1 and KKU-M213 cells.	('CK2 alpha', 'Gene', (102, 111))	('CCA', 'Disease', (133, 136))	('CK2 alpha', 'Gene', '1459', (88, 97))	('CCA', 'Phenotype', 'HP:0030153', (156, 159))	('inhibited', 'NegReg', (123, 132))	('knockdown', 'Var', (113, 122))	('CK2 alpha', 'Gene', '1459', (102, 111))	('CX-4945', 'Chemical', 'MESH:C555142', (39, 46))	('CK2 alpha', 'Gene', (88, 97))	('CCA', 'Phenotype', 'HP:0030153', (60, 63))	('CCA', 'Phenotype', 'HP:0030153', (133, 136))
179197	30142881	Moreover, CK2 alpha and CK2 alpha' knockdown had no effect on invasion of CCLP-1 cells.	('knockdown', 'Var', (35, 44))	('CCLP-1', 'Gene', '8495', (74, 80))	('CK2 alpha', 'Gene', (10, 19))	('CK2 alpha', 'Gene', (24, 33))	('CK2 alpha', 'Gene', '1459', (24, 33))	('CCLP-1', 'Gene', (74, 80))	('CK2 alpha', 'Gene', '1459', (10, 19))
179201	30142881	Herein, CX-4945, at 10 muM and above, was shown to decrease protein kinase CK2 activity when delivered to CCA cells and to inhibit CCA cell proliferation (Figure 1).	('activity', 'MPA', (79, 87))	('CCA', 'Disease', (131, 134))	('CCA', 'Phenotype', 'HP:0030153', (106, 109))	('CX-4945', 'Var', (8, 15))	('protein kinase CK2', 'Gene', '1457', (60, 78))	('inhibit', 'NegReg', (123, 130))	('CX-4945', 'Chemical', 'MESH:C555142', (8, 15))	('decrease', 'NegReg', (51, 59))	('protein kinase CK2', 'Gene', (60, 78))	('CCA', 'Phenotype', 'HP:0030153', (131, 134))
179203	30142881	At 10 microM, CX-4945 inhibited CCA cell invasion through a reduction of MMP-9 and MMP-7 levels plus an inhibitory effect on cell proliferation.	('CX-4945', 'Var', (14, 21))	('inhibited', 'NegReg', (22, 31))	('CCA', 'Disease', (32, 35))	('MMP-9', 'Gene', '4318', (73, 78))	('CX-4945', 'Chemical', 'MESH:C555142', (14, 21))	('reduction', 'NegReg', (60, 69))	('cell proliferation', 'CPA', (125, 143))	('MMP-9', 'Gene', (73, 78))	('MMP-7', 'Gene', (83, 88))	('CCA', 'Phenotype', 'HP:0030153', (32, 35))	('MMP-7', 'Gene', '4316', (83, 88))
179204	30142881	Interestingly, lower doses of CX-4945 (1 and 5 microM) increased the levels of MMP-9, MMP-7, and MMP-2 (Figure 1e,f).	('MMP-9', 'Gene', (79, 84))	('MMP-9', 'Gene', '4318', (79, 84))	('MMP-2', 'Gene', '4313', (97, 102))	('increased', 'PosReg', (55, 64))	('MMP-2', 'Gene', (97, 102))	('CX-4945', 'Var', (30, 37))	('MMP-7', 'Gene', (86, 91))	('CX-4945', 'Chemical', 'MESH:C555142', (30, 37))	('MMP-7', 'Gene', '4316', (86, 91))
179205	30142881	A biphasic effect of CX-4945 on cell proliferation has been reported previously in s22Rv1 prostate cancer cells, UM-SCC1 head and neck cancer cells, and A549 lung cancer cells.	('SCC1', 'Gene', '5885', (116, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (90, 105))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('A549 lung cancer', 'Disease', 'MESH:D008175', (153, 169))	('prostate cancer', 'Disease', (90, 105))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('A549 lung cancer', 'Disease', (153, 169))	('cancer', 'Disease', (135, 141))	('CX-4945', 'Chemical', 'MESH:C555142', (21, 28))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cell proliferation', 'CPA', (32, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('head and neck cancer', 'Phenotype', 'HP:0012288', (121, 141))	('Rv1', 'CellLine', 'CVCL:1045', (86, 89))	('CX-4945', 'Var', (21, 28))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (99, 105))	('SCC1', 'Gene', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
179206	30142881	CX-4945 at 0.5, 0.1, and 0.01 microM slightly stimulated cell proliferation in the aforementioned cell lines, whereas higher doses inhibited cell proliferation.	('stimulated', 'PosReg', (46, 56))	('CX-4945', 'Chemical', 'MESH:C555142', (0, 7))	('cell proliferation', 'CPA', (141, 159))	('inhibited', 'NegReg', (131, 140))	('CX-4945', 'Var', (0, 7))	('cell proliferation in', 'CPA', (57, 78))
179207	30142881	Knockdown of the alpha and alpha' catalytic subunits of CK2 simultaneously also significantly reduced the phosphorylation of multiple CK2 substrates indicating that CK2 knockdown and CX-4945 treatment both inhibited CK2 activity.	('CK2', 'Enzyme', (216, 219))	('CK2', 'Gene', (56, 59))	('activity', 'MPA', (220, 228))	('reduced', 'NegReg', (94, 101))	('knockdown', 'Var', (169, 178))	('phosphorylation', 'MPA', (106, 121))	('CX-4945', 'Chemical', 'MESH:C555142', (183, 190))	('inhibited', 'NegReg', (206, 215))	('CK2', 'Gene', (165, 168))	('CK2', 'Enzyme', (134, 137))
179209	30142881	Both CK2 knockdown and CX-4945 treatment inhibited the proliferation of CCA cells.	('CCA', 'Disease', (72, 75))	('knockdown', 'Var', (9, 18))	('proliferation', 'CPA', (55, 68))	('CK2', 'Gene', (5, 8))	('CCA', 'Phenotype', 'HP:0030153', (72, 75))	('inhibited', 'NegReg', (41, 50))	('CX-4945', 'Chemical', 'MESH:C555142', (23, 30))
179210	30142881	However, in contrast to the biphasic effects of CX-4945 on CCA cell invasion, CK2 knockdown only inhibited CCA cell invasion.	('CCA', 'Disease', (107, 110))	('knockdown', 'Var', (82, 91))	('CCA', 'Phenotype', 'HP:0030153', (59, 62))	('CX-4945', 'Chemical', 'MESH:C555142', (48, 55))	('CCA', 'Phenotype', 'HP:0030153', (107, 110))	('CK2', 'Gene', (78, 81))	('inhibited', 'NegReg', (97, 106))	('CCA', 'Disease', (59, 62))
179212	30142881	In addition, intensive vacuolization and cell death was observed following CX-4945 treatment (Figure 2 and Figure 3), but vacuolization was absent following CK2alpha and CK2alpha' knockdown (Figure 7c) and following treatment with another CK2 inhibitor (Figure 7e-g).	('knockdown', 'Var', (180, 189))	('CK2alpha', 'Gene', (170, 178))	('CK2alpha', 'Gene', '1459', (157, 165))	('cell death', 'CPA', (41, 51))	('CK2alpha', 'Gene', (157, 165))	('vacuolization', 'MPA', (23, 36))	('CX-4945', 'Chemical', 'MESH:C555142', (75, 82))	('CK2alpha', 'Gene', '1459', (170, 178))
179215	30142881	CX-4945 was reported to inhibit the Cdc2-like kinases (Clks) resulting in a suppression of phosphorylation of serine/arginine (S/R) rich proteins in mammalian cells.	('CX-4945', 'Chemical', 'MESH:C555142', (0, 7))	('mammalian', 'Species', '9606', (149, 158))	('suppression', 'NegReg', (76, 87))	('CX-4945', 'Var', (0, 7))	('Cdc2-like kinases', 'Enzyme', (36, 53))	('serine', 'Chemical', 'MESH:D012694', (110, 116))	('inhibit', 'NegReg', (24, 31))	('arginine', 'Chemical', 'MESH:D001120', (117, 125))
179216	30142881	In addition, CX-4945 has been shown to affect alternative splicing of a wide range of genes in a CK2-independent manner.	('CX-4945', 'Var', (13, 20))	('alternative splicing of', 'MPA', (46, 69))	('affect', 'Reg', (39, 45))	('CX-4945', 'Chemical', 'MESH:C555142', (13, 20))
179217	30142881	It has been reported that CX-4945 induces apoptosis via caspase-3 activity in lung cancer cells and in primary CCA tumor lines.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('caspase-3', 'Gene', '836', (56, 65))	('activity', 'MPA', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CCA tumor', 'Disease', (111, 120))	('apoptosis', 'CPA', (42, 51))	('CX-4945', 'Var', (26, 33))	('CCA tumor', 'Disease', 'MESH:C536211', (111, 120))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('CCA', 'Phenotype', 'HP:0030153', (111, 114))	('CX-4945', 'Chemical', 'MESH:C555142', (26, 33))	('caspase-3', 'Gene', (56, 65))
179218	30142881	Autophagy was induced by CX-4945 in pancreatic and lung cancer cell lines.	('CX-4945', 'Var', (25, 32))	('CX-4945', 'Chemical', 'MESH:C555142', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('induced', 'Reg', (14, 21))	('pancreatic and lung cancer', 'Disease', 'MESH:D010190', (36, 62))	('Autophagy', 'CPA', (0, 9))
179219	30142881	Surprisingly, we have shown that CX-4945-induced cell death in CCA cell lines was not accompanied by caspase-3 cleavage and did not appear to involve autophagy (Figure 5a,b) despite the involvement of intensive cytoplasmic vacuolization.	('CCA', 'Phenotype', 'HP:0030153', (63, 66))	('CX-4945-induced', 'Var', (33, 48))	('caspase-3', 'Gene', '836', (101, 110))	('CX-4945', 'Chemical', 'MESH:C555142', (33, 40))	('caspase-3', 'Gene', (101, 110))
179223	30142881	We propose that the non-apoptotic, non-autophagic cell death mechanism induced by CX-4945 is not oncosis, paraptosis, or necroptosis according to the following criteria.	('CX-4945', 'Chemical', 'MESH:C555142', (82, 89))	('non-autophagic cell death', 'CPA', (35, 60))	('oncosis, paraptosis', 'Disease', 'None', (97, 116))	('non-apoptotic', 'CPA', (20, 33))	('CX-4945', 'Var', (82, 89))
179224	30142881	All of the aforementioned data fit the criteria of methuosis, therefore, we propose that CX-4945 induces methuosis at least in the CCA cell line KKU-M213.	('CX-4945', 'Chemical', 'MESH:C555142', (89, 96))	('methuosis', 'MPA', (105, 114))	('methuosis', 'Chemical', '-', (51, 60))	('CX-4945', 'Var', (89, 96))	('induces', 'Reg', (97, 104))	('CCA', 'Phenotype', 'HP:0030153', (131, 134))	('methuosis', 'Chemical', '-', (105, 114))
179227	30142881	It seems likely that CX-4945 activity and its effects on cell death are cell-type specific, that is, dependent on, for example, whether tumor suppressors such as TP53 are wild type or mutant in the cell line being tested.	('cell death', 'CPA', (57, 67))	('CX-4945', 'Chemical', 'MESH:C555142', (21, 28))	('mutant', 'Var', (184, 190))	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('CX-4945', 'Enzyme', (21, 28))	('activity', 'MPA', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
179229	30142881	Further investigation of the molecular mechanisms underlying CX-4945-induced vacuolization and cell death might lead to a better understanding of possible combinations of this treatment with other current chemotherapeutic drugs to optimize treatment outcomes in patients.	('CX-4945-induced', 'Var', (61, 76))	('combinations', 'Interaction', (155, 167))	('patients', 'Species', '9606', (262, 270))	('CX-4945', 'Chemical', 'MESH:C555142', (61, 68))
179254	30142881	Primary antibodies included 1:1500 MMP-9 (2270, Cell Signaling Technology, Danvers, MA, USA), 1:1000 MMP-7 (ab5706, Abcam), 1:1500 MMP-2 (4022, Cell Signaling Technology), 1:1500 cleaved caspase-3 (9664, Cell Signaling Technology), 1:1500 phospho-CK2 substrate (motif pS/pTDXE) (8738, Cell Signaling Technology), 1:1500 LC3B (3868, Cell Signaling Technology), and 1:5000 beta-actin (A2066, Sigma Aldrich, St. Louis, MO, USA).	('MMP-2', 'Gene', '4313', (131, 136))	('MMP-7', 'Gene', '4316', (101, 106))	('1:1500', 'Var', (172, 178))	('MMP-9', 'Gene', '4318', (35, 40))	('caspase-3', 'Gene', (187, 196))	('MMP-9', 'Gene', (35, 40))	('MMP-2', 'Gene', (131, 136))	('LC3B', 'Gene', (320, 324))	('caspase-3', 'Gene', '836', (187, 196))	('MMP-7', 'Gene', (101, 106))	('LC3B', 'Gene', '81631', (320, 324))
179263	30142881	Our data suggest that CX-4945 inhibits cell proliferation and induces methuosis via CK2-independent pathways.	('induces', 'Reg', (62, 69))	('CX-4945', 'Var', (22, 29))	('methuosis', 'Chemical', '-', (70, 79))	('CK2-independent pathways', 'Pathway', (84, 108))	('methuosis', 'MPA', (70, 79))	('cell proliferation', 'CPA', (39, 57))	('CX-4945', 'Chemical', 'MESH:C555142', (22, 29))	('inhibits', 'NegReg', (30, 38))
179264	30142881	A biphasic effect of CX-4945 on CCA cell invasion was, at least in part, due to an alteration of MMP-2, MMP-7, and MMP-9.	('MMP-2', 'Gene', '4313', (97, 102))	('CX-4945', 'Var', (21, 28))	('CX-4945', 'Chemical', 'MESH:C555142', (21, 28))	('MMP-9', 'Gene', '4318', (115, 120))	('alteration', 'Reg', (83, 93))	('MMP-9', 'Gene', (115, 120))	('MMP-2', 'Gene', (97, 102))	('CCA', 'Phenotype', 'HP:0030153', (32, 35))	('CCA cell invasion', 'CPA', (32, 49))	('MMP-7', 'Gene', (104, 109))	('MMP-7', 'Gene', '4316', (104, 109))
179267	23905013	A simulation result demonstrated an improved accuracy and robustness by S-score method comparing with other scoring methods.	('robustness', 'MPA', (58, 68))	('accuracy', 'MPA', (45, 53))	('rat', 'Species', '10116', (27, 30))	('S-score', 'Var', (72, 79))	('improved', 'PosReg', (36, 44))
179286	23905013	While genetic alterations in KRAS, TP53, BRAF and EGFR have been reported for CAC, there has been a relative lack of systematic exploration.	('rat', 'Species', '10116', (18, 21))	('reported', 'Reg', (65, 73))	('KRAS', 'Gene', (29, 33))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('CAC', 'Disease', (78, 81))	('rat', 'Species', '10116', (133, 136))	('BRAF', 'Gene', '673', (41, 45))	('EGFR', 'Gene', '1956', (50, 54))	('KRAS', 'Gene', '3845', (29, 33))	('BRAF', 'Gene', (41, 45))	('EGFR', 'Gene', (50, 54))	('CAC', 'Phenotype', 'HP:0030153', (78, 81))	('genetic alterations', 'Var', (6, 25))
179316	23905013	The result showed that (see Figure S1), among 4 methods, S-score and correlation-based method have the capacity to integrate up- and down-regulated gene sets.	('down-regulated', 'NegReg', (133, 147))	('up-', 'PosReg', (125, 128))	('S-score', 'Var', (57, 64))	('rat', 'Species', '10116', (120, 123))
179324	23905013	Combining these two observations from simulations, S-score and Z-score have the best robustness (mean shift close to zero) against noises in the test samples, while S-score has the ability of suppressing non-performing genes in a GSS.	('robustness', 'MPA', (85, 95))	('GSS', 'Chemical', '-', (230, 233))	('S-score', 'Var', (165, 172))	('suppressing', 'NegReg', (192, 203))
179345	23905013	Also other terms of cell functions, such as mRNA metabolic, translation, and telomere maintenance via recombination, possessed positive correlation with signature cluster A.	('mRNA metabolic', 'MPA', (44, 58))	('telomere maintenance', 'CPA', (77, 97))	('N', 'Chemical', 'MESH:D009584', (46, 47))	('signature cluster A', 'Var', (153, 172))	('translation', 'MPA', (60, 71))
179360	23905013	For example, the results of the signatures p63, AKT, and PR, were excluded in the analysis of GSE26566 after filtering by L0.01 to avoid the situation of small variance of S-score, causing instable t-test significance.	('p63', 'Gene', '8626', (43, 46))	('AKT', 'Gene', (48, 51))	('AKT', 'Gene', '207', (48, 51))	('p63', 'Gene', (43, 46))	('GSE26566', 'Var', (94, 102))
179364	23905013	Mutation of SMAD4, which was a downstream gene of TGFbeta pathway, also has been identified in a proportion of CAC patients.	('patients', 'Species', '9606', (115, 123))	('CAC', 'Disease', (111, 114))	('SMAD4', 'Gene', (12, 17))	('Mutation', 'Var', (0, 8))	('CAC', 'Phenotype', 'HP:0030153', (111, 114))	('SMAD4', 'Gene', '4089', (12, 17))	('identified', 'Reg', (81, 91))
179395	23905013	The progression of cancer can be reasoned from different kinds of alteration in the genome, such like mutations, copy number variations, and epigenetic modifications.	('rat', 'Species', '10116', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('epigenetic modifications', 'Var', (141, 165))	('copy number variations', 'Var', (113, 135))	('mutations', 'Var', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
179396	23905013	The consequences of these alterations will induce changes of gene expression and then to the protein expression level in their pathways.	('gene expression', 'MPA', (61, 76))	('changes', 'Reg', (50, 57))	('rat', 'Species', '10116', (30, 33))	('alterations', 'Var', (26, 37))
179449	32039381	Moreover, tumor necrosis factor (TNF) derived from KCs promotes JNK-mediated CCA proliferation and oncogenic transformation, depletion of KCs has been shown to reduce pre-malignant CCA lesions.	('reduce', 'NegReg', (160, 166))	('rat', 'Species', '10116', (88, 91))	('JNK', 'Gene', (64, 67))	('JNK', 'Gene', '5599', (64, 67))	('oncogenic transformation', 'CPA', (99, 123))	('tumor necrosis factor', 'Gene', (10, 31))	('TNF', 'Gene', (33, 36))	('CCA', 'Phenotype', 'HP:0030153', (77, 80))	('CCA', 'Disease', 'MESH:D018281', (77, 80))	('CCA', 'Disease', (77, 80))	('CCA', 'Phenotype', 'HP:0030153', (181, 184))	('CCA', 'Disease', 'MESH:D018281', (181, 184))	('CCA', 'Disease', (181, 184))	('pre-malignant', 'CPA', (167, 180))	('TNF', 'Gene', '7124', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor necrosis factor', 'Gene', '7124', (10, 31))	('promotes', 'PosReg', (55, 63))	('depletion', 'Var', (125, 134))
179452	32039381	Macrophage depletion in preclinical models results in inhibition of WNT signalling, and reduction in tumour growth.	('tumour', 'Disease', (101, 107))	('reduction', 'NegReg', (88, 97))	('WNT signalling', 'Pathway', (68, 82))	('inhibition', 'NegReg', (54, 64))	('depletion', 'Var', (11, 20))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
179465	32039381	Murine models of HCC suggest that depletion of PMN-MDSC may increase sensitivity to PD-L1 checkpoint inhibitor therapy.	('increase', 'PosReg', (60, 68))	('HCC', 'Disease', 'MESH:D006528', (17, 20))	('depletion', 'Var', (34, 43))	('Murine', 'Species', '10090', (0, 6))	('HCC', 'Disease', (17, 20))	('sensitivity to PD-L1 checkpoint inhibitor therapy', 'MPA', (69, 118))	('HCC', 'Phenotype', 'HP:0001402', (17, 20))	('PMN-MDSC', 'Gene', (47, 55))
179469	32039381	Preclinical and clinical studies have demonstrated that NK cell deficiency or impaired NK cell function is linked to increased incidence of a variety of malignancies.	('impaired NK cell', 'Phenotype', 'HP:0012176', (78, 94))	('malignancies', 'Disease', (153, 165))	('deficiency', 'Var', (64, 74))	('NK cell deficiency', 'Phenotype', 'HP:0040218', (56, 74))	('impaired', 'NegReg', (78, 86))	('NK cell', 'Protein', (56, 63))	('NK cell function', 'CPA', (87, 103))	('malignancies', 'Disease', 'MESH:D009369', (153, 165))	('rat', 'Species', '10116', (45, 48))
179476	32039381	Accordingly, NKG2D receptor variants have been linked to CCA development in patients with primary sclerosing cholangitis.	('cholangitis', 'Disease', (109, 120))	('patients', 'Species', '9606', (76, 84))	('CCA', 'Phenotype', 'HP:0030153', (57, 60))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (98, 120))	('CCA', 'Disease', 'MESH:D018281', (57, 60))	('variants', 'Var', (28, 36))	('linked to', 'Reg', (47, 56))	('cholangitis', 'Disease', 'MESH:D002761', (109, 120))	('NKG2D receptor', 'Gene', (13, 27))	('CCA', 'Disease', (57, 60))	('cholangitis', 'Phenotype', 'HP:0030151', (109, 120))	('NKG2D receptor', 'Gene', '22914', (13, 27))
179487	32039381	As the presence of DCs confers a better patient outcome, the therapeutic potential of DC-based immunotherapies has been explored in limited preclinical and clinical studies of CCA.	('presence', 'Var', (7, 15))	('DCs', 'Gene', (19, 22))	('patient', 'Species', '9606', (40, 47))	('CCA', 'Disease', (176, 179))	('patient outcome', 'MPA', (40, 55))	('CCA', 'Phenotype', 'HP:0030153', (176, 179))	('CCA', 'Disease', 'MESH:D018281', (176, 179))	('better', 'PosReg', (33, 39))
179502	32039381	Interplay between components of the innate immune system and TILs can impact the antitumour immune response.	('Interplay', 'Var', (0, 9))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumour', 'Disease', (85, 91))	('impact', 'Reg', (70, 76))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
179516	32039381	This regimen modestly increased survival, with a median OS of 11.7 months in patients treated with gemcitabine/cisplatin, compared to 8.1 months for those treated with gemcitabine alone in a phase III trial.	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('gemcitabine', 'Chemical', 'MESH:C056507', (168, 179))	('survival', 'MPA', (32, 40))	('gemcitabine/cisplatin', 'Var', (99, 120))	('patients', 'Species', '9606', (77, 85))	('increased', 'PosReg', (22, 31))	('gemcitabine', 'Chemical', 'MESH:C056507', (99, 110))
179518	32039381	An open-label, single-arm, phase II clinical trial demonstrated prolonged median progression free survival (PFS) (11.8 months) and median OS (19.2 months) in patients with advanced BTC (n = 62) treated with nab-paclitaxel plus gemcitabine-cisplatin compared to historical controls treated with gemcitabine-cisplatin alone.	('gemcitabine-cisplatin', 'Chemical', 'MESH:C056507', (227, 248))	('prolonged', 'PosReg', (64, 73))	('progression free survival', 'CPA', (81, 106))	('nab-paclitaxel', 'Var', (207, 221))	('gemcitabine-cisplatin', 'Chemical', 'MESH:C056507', (294, 315))	('paclitaxel', 'Chemical', 'MESH:D017239', (211, 221))	('rat', 'Species', '10116', (58, 61))	('patients', 'Species', '9606', (158, 166))
179547	32039381	Although ORR was slightly higher in the PDL-1 positive group (6.6% vs. 2.9%), there were no significant differences in median PFS (1.9 vs. 2.1 months) or OS (7.2 vs. 9.6 months).	('PDL-1', 'Gene', '29126', (40, 45))	('higher', 'PosReg', (26, 32))	('PDL-1', 'Gene', (40, 45))	('PFS', 'MPA', (126, 129))	('ORR', 'MPA', (9, 12))	('positive', 'Var', (46, 54))
179553	32039381	At least 2 early phase trials of dual CTLA-4 and PD-1 blockade are ongoing in advanced solid tumours, including CCAs (NCT02834013 and NCT01938612).	('CCA', 'Phenotype', 'HP:0030153', (112, 115))	('CCA', 'Disease', 'MESH:D018281', (112, 115))	('PD-1', 'Gene', (49, 53))	('advanced solid tumours', 'Disease', (78, 100))	('PD-1', 'Gene', '5133', (49, 53))	('CTLA-4', 'Gene', '1493', (38, 44))	('CCA', 'Disease', (112, 115))	('NCT01938612', 'Var', (134, 145))	('advanced solid tumours', 'Disease', 'MESH:D020178', (78, 100))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('CTLA-4', 'Gene', (38, 44))	('NCT02834013', 'Var', (118, 129))
179558	32039381	Preclinical and clinical data regarding these checkpoints are far less mature, but there is early data from melanoma and renal cell carcinoma suggesting some clinical effect of LAG-3 inhibitors.	('renal cell carcinoma', 'Disease', 'MESH:D002292', (121, 141))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('renal cell carcinoma', 'Disease', (121, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (121, 141))	('LAG-3', 'Gene', (177, 182))	('LAG-3', 'Gene', '3902', (177, 182))	('inhibitors', 'Var', (183, 193))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))
179559	32039381	Clinical trials are currently underway targeting CD40 (NCT03329950) and OX40 (NCT03071757) as single agent or combination therapies in advanced cancers including CCA.	('CCA', 'Disease', 'MESH:D018281', (162, 165))	('CCA', 'Disease', (162, 165))	('CD40', 'Gene', (49, 53))	('NCT03071757', 'Var', (78, 89))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('OX40', 'Gene', '7293', (72, 76))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('CCA', 'Phenotype', 'HP:0030153', (162, 165))	('NCT03071757', 'Chemical', 'MESH:C079985', (78, 89))	('cancers', 'Disease', (144, 151))	('OX40', 'Gene', (72, 76))	('CD40', 'Gene', '958', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('NCT03329950', 'Var', (55, 66))
179567	32039381	Other ongoing trials in CCA featuring immunomodulators include a fusion protein designed to inhibit PD-L1 and TGF-beta, an immunosuppressive cytokine (NCT03825705), and recombinant IL-12, a pro-inflammatory cytokine, combined with HER2 targeted therapy (NCT00004074; Table 2).	('NCT03825705', 'Var', (151, 162))	('PD-L1', 'Protein', (100, 105))	('HER2', 'Gene', (231, 235))	('TGF-beta', 'Gene', (110, 118))	('CCA', 'Phenotype', 'HP:0030153', (24, 27))	('HER2', 'Gene', '2064', (231, 235))	('TGF-beta', 'Gene', '7039', (110, 118))	('inhibit', 'NegReg', (92, 99))	('CCA', 'Disease', 'MESH:D018281', (24, 27))	('CCA', 'Disease', (24, 27))
179570	32039381	VEGF receptor (VEGFR) inhibitors are approved for treatment of multiple cancers, including HCC, but have shown limited activity as monotherapy in CCA.	('HCC', 'Disease', 'MESH:D006528', (91, 94))	('VEGF receptor', 'Gene', '3791', (0, 13))	('HCC', 'Disease', (91, 94))	('inhibitors', 'Var', (22, 32))	('VEGFR', 'Gene', (15, 20))	('CCA', 'Disease', (146, 149))	('HCC', 'Phenotype', 'HP:0001402', (91, 94))	('VEGF receptor', 'Gene', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('CCA', 'Phenotype', 'HP:0030153', (146, 149))	('VEGFR', 'Gene', '3791', (15, 20))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('CCA', 'Disease', 'MESH:D018281', (146, 149))
179580	32039381	A tantalizing rationale for combining targeted therapies and immunotherapies is that molecular targeted therapies can produce significant but often short-lived responses in susceptible tumours, which could theoretically be prolonged with induction of an effective antitumour immune response.	('tumour', 'Disease', (268, 274))	('responses', 'MPA', (160, 169))	('tumours', 'Phenotype', 'HP:0002664', (185, 192))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('tumour', 'Phenotype', 'HP:0002664', (268, 274))	('tumours', 'Disease', 'MESH:D009369', (185, 192))	('tumour', 'Disease', 'MESH:D009369', (268, 274))	('tumours', 'Disease', (185, 192))	('molecular targeted therapies', 'Var', (85, 113))	('rat', 'Species', '10116', (14, 17))	('tumour', 'Disease', (185, 191))
179581	32039381	A pan-cancer analysis of tumour mutational burden and specific targetable mutations in The Cancer Genome Atlas dataset suggested that 9% of cancers could be amenable to combined molecular and immune-targeting therapy.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (74, 83))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (6, 12))	('tumour', 'Disease', (25, 31))
179582	32039381	There are several ongoing human clinical trials evaluating the combination of ICB with a variety of targeted therapies including inhibitors of FGFR, mutant IDH, MEK, PARP, PPAR-alpha, and HSP90 (summarized in Table 1).	('FGFR', 'Gene', (143, 147))	('PPAR-alpha', 'Gene', '5465', (172, 182))	('MEK', 'Gene', (161, 164))	('HSP90', 'Gene', (188, 193))	('HSP90', 'Gene', '3320', (188, 193))	('MEK', 'Gene', '5609', (161, 164))	('mutant', 'Var', (149, 155))	('PARP', 'Gene', '1302', (166, 170))	('IDH', 'Gene', (156, 159))	('PPAR-alpha', 'Gene', (172, 182))	('IDH', 'Gene', '3417', (156, 159))	('PARP', 'Gene', (166, 170))	('human', 'Species', '9606', (26, 31))
179592	32039381	Inhibition of the CSF1/CSF1R axis leads to TAM depletion, enhanced CTL function and improved tumour response to chemotherapy or ICB in multiple preclinical models, although this has not been investigated in CCA specifically.	('TAM', 'Chemical', 'MESH:C419191', (43, 46))	('CCA', 'Disease', 'MESH:D018281', (207, 210))	('tumour', 'Disease', (93, 99))	('CCA', 'Disease', (207, 210))	('CSF1', 'Gene', '1435', (23, 27))	('CSF1R', 'Gene', (23, 28))	('enhanced', 'PosReg', (58, 66))	('CSF1', 'Gene', (23, 27))	('improved', 'PosReg', (84, 92))	('Inhibition', 'Var', (0, 10))	('CTL', 'MPA', (67, 70))	('CSF1', 'Gene', '1435', (18, 22))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('CSF1', 'Gene', (18, 22))	('CSF1R', 'Gene', '1436', (23, 28))	('CCA', 'Phenotype', 'HP:0030153', (207, 210))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('TAM depletion', 'MPA', (43, 56))
179604	32039381	In a single patient with metastatic CCA, adoptive transfer of TILs enriched for a CD4+ T helper 1 population of cells that recognized a tumour-specific mutation resulted in PR lasting 13 months.	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('CCA', 'Disease', (36, 39))	('tumour', 'Disease', (136, 142))	('CCA', 'Disease', 'MESH:D018281', (36, 39))	('CD4', 'Gene', (82, 85))	('CCA', 'Phenotype', 'HP:0030153', (36, 39))	('patient', 'Species', '9606', (12, 19))	('mutation', 'Var', (152, 160))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('CD4', 'Gene', '920', (82, 85))
179607	32039381	Patients who received autologous tumour lysate pulsed DCs plus ex vivo activated T cell transfer following surgery had improved median PFS and OS (18.3 and 31.9 months, respectively) compared to patients who underwent surgery alone (7.7 and 17.4 months, respectively).	('pulsed DCs', 'Var', (47, 57))	('tumour', 'Disease', (33, 39))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (195, 203))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('improved', 'PosReg', (119, 127))	('PFS', 'MPA', (135, 138))	('tumour', 'Disease', 'MESH:D009369', (33, 39))
179616	32039381	A retrospective analysis of 65 patients with BTC treated with DCs pulsed with peptides from WT1, MUC1 or both, showed adequate safety and a median survival of 7.2 months following vaccination.	('WT1', 'Gene', (92, 95))	('MUC1', 'Gene', (97, 101))	('MUC1', 'Gene', '4582', (97, 101))	('peptides', 'Var', (78, 86))	('patients', 'Species', '9606', (31, 39))	('WT1', 'Gene', '7490', (92, 95))
179659	29465558	Therefore, more than a third of patients suffer from delayed diagnosis or misdiagnosis, even erroneous and extensive hepatobiliary surgery before they are confirmed as IAC.	('hepatobiliary', 'Disease', (117, 130))	('patients', 'Species', '9606', (32, 40))	('erroneous', 'Var', (93, 102))	('hepatobiliary', 'Disease', 'MESH:D004066', (117, 130))
179749	25155229	The risk of malignancy in IgG4-RD has received recent attention, but it remains largely undefined.	('malignancy', 'Disease', (12, 22))	('malignancy', 'Disease', 'MESH:D009369', (12, 22))	('IgG4-RD', 'Var', (26, 33))
179834	25155229	One patient, with biopsy-proven multiorgan IgG4-RD, developed a rapidly progressive encephalitic illness, and a diagnosis of autoimmune encephalitis was made on the basis of characteristic features of encephalitis on imaging (gadolinium magnetic resonance imaging) and cerebrospinal fluid analysis.	('autoimmune encephalitis', 'Disease', (125, 148))	('encephalitic illness', 'Disease', 'MESH:D010301', (84, 104))	('encephalitic illness', 'Disease', (84, 104))	('encephalitis', 'Disease', 'MESH:D004660', (201, 213))	('encephalitis', 'Disease', (201, 213))	('gadolinium', 'Chemical', 'MESH:D005682', (226, 236))	('patient', 'Species', '9606', (4, 11))	('encephalitis', 'Phenotype', 'HP:0002383', (136, 148))	('IgG4-RD', 'Var', (43, 50))	('encephalitic illness', 'Phenotype', 'HP:0002383', (84, 104))	('autoimmune encephalitis', 'Disease', 'MESH:C535841', (125, 148))	('encephalitis', 'Phenotype', 'HP:0002383', (201, 213))	('encephalitis', 'Disease', 'MESH:D004660', (136, 148))	('encephalitis', 'Disease', (136, 148))
179845	25155229	We found that pretreatment serum IgG4 level, or its change with treatment, did not predict relapse, but that patients with IgG4-SC were more likely to relapse and had a more complicated course.	('relapse', 'CPA', (151, 158))	('patients', 'Species', '9606', (109, 117))	('IgG4-SC', 'Var', (123, 130))
179860	25155229	The fundamental question of whether IgG4-RD is associated with cancer, and an overall reduced life expectancy, remains unanswered.	('reduced', 'NegReg', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('life expectancy', 'CPA', (94, 109))	('IgG4-RD', 'Var', (36, 43))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('associated', 'Reg', (47, 57))	('cancer', 'Disease', (63, 69))
179899	25155229	There may be an increased risk of malignancy in IgG4-RD, but this risk is largely undefined.	('malignancy', 'Disease', 'MESH:D009369', (34, 44))	('malignancy', 'Disease', (34, 44))	('IgG4-RD', 'Var', (48, 55))
179911	24757411	Treatment with LY294002 further decreased the expression of survivin and Bcl-2 and increased caspase-3 levels.	('caspase-3', 'Gene', (93, 102))	('LY294002', 'Chemical', 'MESH:C085911', (15, 23))	('increased', 'PosReg', (83, 92))	('Bcl-2', 'Gene', (73, 78))	('Bcl-2', 'Gene', '596', (73, 78))	('LY294002', 'Var', (15, 23))	('caspase-3', 'Gene', '836', (93, 102))	('survivin', 'Protein', (60, 68))	('expression', 'MPA', (46, 56))	('decreased', 'NegReg', (32, 41))
179920	24757411	Specifically, deletions within both FHIT alleles result in the loss of exons with a concomitant absence of full-length FHIT transcript and protein.	('FHIT', 'Gene', '2272', (36, 40))	('FHIT', 'Gene', (119, 123))	('exons', 'MPA', (71, 76))	('absence', 'NegReg', (96, 103))	('FHIT', 'Gene', '2272', (119, 123))	('deletions', 'Var', (14, 23))	('loss', 'NegReg', (63, 67))	('FHIT', 'Gene', (36, 40))
179923	24757411	Our previous studies showed that the loss of FHIT protein may play an important role in the carcinogenesis and prognosis of cholangiocarcinoma.	('carcinogenesis', 'Disease', 'MESH:D063646', (92, 106))	('carcinogenesis', 'Disease', (92, 106))	('cholangiocarcinoma', 'Disease', (124, 142))	('FHIT', 'Gene', (45, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('FHIT', 'Gene', '2272', (45, 49))	('loss', 'Var', (37, 41))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (124, 142))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (124, 142))
179951	24757411	The mRNA expression of FHIT was increased 7.945-fold after transfection (Figure 1(a)), and the protein levels were also increased (Figure 1(b)).	('FHIT', 'Gene', (23, 27))	('FHIT', 'Gene', '2272', (23, 27))	('transfection', 'Var', (59, 71))	('mRNA expression', 'MPA', (4, 19))	('protein levels', 'MPA', (95, 109))	('increased', 'PosReg', (32, 41))	('increased', 'PosReg', (120, 129))
179955	24757411	Western blotting revealed that the levels of p-Akt were suppressed in QBC939 cells treated with LY294002 (the PI3K inhibitor) or transfected with FHIT (Figure 2).	('LY294002', 'Var', (96, 104))	('levels', 'MPA', (35, 41))	('Akt', 'Gene', '207', (47, 50))	('QBC939', 'CellLine', 'CVCL:6942', (70, 76))	('suppressed', 'NegReg', (56, 66))	('LY294002', 'Chemical', 'MESH:C085911', (96, 104))	('Akt', 'Gene', (47, 50))	('FHIT', 'Gene', (146, 150))	('FHIT', 'Gene', '2272', (146, 150))
179962	24757411	The expression of survivin, Bcl-2, and caspase-3 was also assessed in cells treated with LY294002 as a positive control.	('LY294002', 'Var', (89, 97))	('Bcl-2', 'Gene', (28, 33))	('Bcl-2', 'Gene', '596', (28, 33))	('caspase-3', 'Gene', (39, 48))	('LY294002', 'Chemical', 'MESH:C085911', (89, 97))	('caspase-3', 'Gene', '836', (39, 48))
179964	24757411	The mRNA and protein expression levels of survivin and Bcl-2 mRNA were downregulated, and caspase-3 was upregulated in LY294002-treated cells.	('LY294002-treated', 'Var', (119, 135))	('downregulated', 'NegReg', (71, 84))	('Bcl-2', 'Gene', (55, 60))	('caspase-3', 'Gene', (90, 99))	('survivin', 'Protein', (42, 50))	('Bcl-2', 'Gene', '596', (55, 60))	('LY294002', 'Chemical', 'MESH:C085911', (119, 127))	('caspase-3', 'Gene', '836', (90, 99))	('upregulated', 'PosReg', (104, 115))
179966	24757411	MTT assay revealed that cell proliferation was reduced in cells overexpressing FHIT or treated with LY294002 compared with the NC group (Figure 4).	('LY294002', 'Var', (100, 108))	('cell proliferation', 'CPA', (24, 42))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('overexpressing', 'PosReg', (64, 78))	('FHIT', 'Gene', (79, 83))	('LY294002', 'Chemical', 'MESH:C085911', (100, 108))	('FHIT', 'Gene', '2272', (79, 83))	('reduced', 'NegReg', (47, 54))
179967	24757411	Consistent with this, cellular apoptosis was increased in the FHIT-overexpressing and LY294002 treatment groups (Figure 5).	('cellular apoptosis', 'CPA', (22, 40))	('increased', 'PosReg', (45, 54))	('LY294002', 'Var', (86, 94))	('FHIT', 'Gene', (62, 66))	('LY294002', 'Chemical', 'MESH:C085911', (86, 94))	('FHIT', 'Gene', '2272', (62, 66))
179968	24757411	These data suggest that both FHIT and LY294002 could inhibit growth and promote apoptosis in QBC939 cells.	('FHIT', 'Gene', (29, 33))	('FHIT', 'Gene', '2272', (29, 33))	('inhibit', 'NegReg', (53, 60))	('LY294002', 'Var', (38, 46))	('promote', 'PosReg', (72, 79))	('QBC939', 'CellLine', 'CVCL:6942', (93, 99))	('LY294002', 'Chemical', 'MESH:C085911', (38, 46))	('growth', 'CPA', (61, 67))	('apoptosis', 'CPA', (80, 89))
179984	24757411	The results of our study showed that the expression of survivin and bcl-2 was decreased and the expression of caspase-3 was increased after FHIT transfection.	('caspase-3', 'Gene', (110, 119))	('survivin', 'Protein', (55, 63))	('bcl-2', 'Gene', (68, 73))	('expression', 'MPA', (41, 51))	('increased', 'PosReg', (124, 133))	('expression', 'MPA', (96, 106))	('FHIT', 'Gene', (140, 144))	('caspase-3', 'Gene', '836', (110, 119))	('bcl-2', 'Gene', '596', (68, 73))	('FHIT', 'Gene', '2272', (140, 144))	('decreased', 'NegReg', (78, 87))	('transfection', 'Var', (145, 157))
179985	24757411	Importantly, the effects of FHIT overexpression were similar to the LY294002.	('LY294002', 'Chemical', 'MESH:C085911', (68, 76))	('FHIT', 'Gene', (28, 32))	('LY294002', 'Var', (68, 76))	('FHIT', 'Gene', '2272', (28, 32))
179987	24757411	Data revealed that the overexpression of FHIT andthe addition of LY294002 could suppress cholangiocarcinoma cell growth and induce apoptosis in QBC939 cells.	('LY294002', 'Var', (65, 73))	('cholangiocarcinoma', 'Disease', (89, 107))	('overexpression', 'PosReg', (23, 37))	('QBC939', 'CellLine', 'CVCL:6942', (144, 150))	('suppress', 'NegReg', (80, 88))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (89, 107))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (89, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('FHIT', 'Gene', (41, 45))	('FHIT', 'Gene', '2272', (41, 45))	('induce', 'PosReg', (124, 130))	('apoptosis', 'CPA', (131, 140))	('LY294002', 'Chemical', 'MESH:C085911', (65, 73))
180003	18855901	The opening session of the conference elucidated the role of the Notch signaling pathway on intrahepatic bile duct development and proliferation, profiling various Notch pathway mutant mouse models that recapitulate clinically relevant features of Alagille syndrome.	('rat', 'Species', '10116', (138, 141))	('mouse', 'Species', '10090', (185, 190))	('mutant', 'Var', (178, 184))	('Alagille syndrome', 'Disease', (248, 265))	('Notch', 'Gene', (65, 70))	('Notch', 'Gene', (164, 169))	('intrahepatic bile duct', 'Disease', (92, 114))	('intrahepatic bile duct', 'Disease', 'MESH:D002780', (92, 114))	('Alagille syndrome', 'Disease', 'MESH:D016738', (248, 265))	('Notch', 'Gene', '4853', (164, 169))	('Notch', 'Gene', '4853', (65, 70))
180039	18855901	Aberrant expression and activation of growth factor receptor tyrosine kinases, such as epidermal growth factor receptor B (ErbB) family receptor tyrosine kinases, hepatocyte growth factor (HGF)-Met, and interleukin-6 (IL-6) signaling, have each been linked to autonomous proliferation, apoptosis resistance, and progression of cholangiocarcinoma cells (Fig.	('progression', 'CPA', (312, 323))	('epidermal growth factor receptor', 'Gene', (87, 119))	('interleukin-6', 'Gene', (203, 216))	('apoptosis resistance', 'CPA', (286, 306))	('epidermal growth factor receptor', 'Gene', '1956', (87, 119))	('rat', 'Species', '10116', (278, 281))	('Aberrant', 'Var', (0, 8))	('IL-6', 'Gene', '3569', (218, 222))	('autonomous proliferation', 'CPA', (260, 284))	('ErbB', 'Gene', '1956;2064', (123, 127))	('activation', 'PosReg', (24, 34))	('cholangiocarcinoma cells', 'Disease', 'MESH:D018281', (327, 351))	('cholangiocarcinoma cells', 'Disease', (327, 351))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (327, 345))	('IL-6', 'Gene', (218, 222))	('HGF', 'Gene', '3082', (189, 192))	('ErbB', 'Gene', (123, 127))	('HGF', 'Gene', (189, 192))	('interleukin-6', 'Gene', '3569', (203, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (336, 345))	('linked', 'Reg', (250, 256))
180044	18855901	Of further interest, aberrantly expressed microRNAs are providing mechanistic insight into hepatic cystogenesis and tumorigenesis, cholangiocarcinoma cell proliferation and chemoresistance, and may serve as potential targets for cholangiocarcinoma therapy.	('chemoresistance', 'CPA', (173, 188))	('hepatic cystogenesis', 'Disease', (91, 111))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (229, 247))	('rat', 'Species', '10116', (162, 165))	('hepatic cyst', 'Phenotype', 'HP:0001407', (91, 103))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (229, 247))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('cholangiocarcinoma', 'Disease', (131, 149))	('aberrantly expressed', 'Var', (21, 41))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cholangiocarcinoma', 'Disease', (229, 247))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (131, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))	('tumor', 'Disease', (116, 121))
180054	18855901	In addition, factors such as intratumoral heterogeneity, varied mechanisms of acquired resistance, constitutive overexpression of autocrine and/or paracrine growth factor ligands, coactivation of multiple receptor tyrosine kinases resulting in signaling redundancy, cross-talk and interplay, tumor hypovascularization limiting bioavailability, and impaired liver function can all act to circumvent the efficacy of target-based therapies.	('coactivation', 'Var', (180, 192))	('cross-talk', 'MPA', (266, 276))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('impaired liver function', 'Disease', (348, 371))	('tumor', 'Disease', (34, 39))	('rat', 'Species', '10116', (32, 35))	('impaired liver function', 'Disease', 'MESH:D008107', (348, 371))	('interplay', 'Interaction', (281, 290))	('tumor', 'Disease', (292, 297))	('signaling redundancy', 'MPA', (244, 264))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('bioavailability', 'MPA', (327, 342))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('impaired liver function', 'Phenotype', 'HP:0001410', (348, 371))
180117	33430887	CRP > 10 mg/dL (p = 0.001), modified Glasgow Prognostic Score 2 (p = 0.002), albumin < 35 g/L (p = 0.05), CA 19-9 > 230 U/mL (p = 0.001), and Wirsung diameter > 3 mm (p < 0.001) were significant at univariate logistic analysis.	('CA 19-9 > 230 U/mL', 'Var', (106, 124))	('CRP', 'Gene', '1401', (0, 3))	('CRP', 'Gene', (0, 3))
180145	33430887	Univariate analysis identified 5 parameters as diagnostic for primary pancreatic adenocarcinoma (PDAC), including modified Glasgow Prognostic Score > 1, CRP > 10 mg/dL, Wirsung duct > 3 mm, CA 19-9 > 230 U/mL, and albuminemia < 35 g/L.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('PDAC', 'Phenotype', 'HP:0006725', (97, 101))	('> 3', 'Var', (182, 185))	('Wirsung duct', 'Disease', (169, 181))	('CRP', 'Gene', (153, 156))	('albuminemia', 'Disease', (214, 225))	('PDAC', 'Chemical', '-', (97, 101))	('CRP', 'Gene', '1401', (153, 156))	('primary pancreatic adenocarcinoma', 'Disease', (62, 95))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (70, 95))	('primary pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (62, 95))	('albuminemia', 'Disease', 'None', (214, 225))
180160	33430887	The correlation between pancreatic histologic origin and high value of CA 19-9, mostly related to risk of recurrence and to locally advanced tumors, reflects the PDAC malignant potential.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('high value', 'Var', (57, 67))	('PDAC', 'Chemical', '-', (162, 166))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('CA 19-9', 'Gene', (71, 78))	('pancreatic histologic origin', 'Disease', (24, 52))	('PDAC', 'Phenotype', 'HP:0006725', (162, 166))
180175	32236578	A high ZEB1-AS1 expression was associated with clinical progression and a poor survival of patients with IHCC, and was identified as an independent risk factor for a poor prognosis.	('patients', 'Species', '9606', (91, 99))	('ZEB1-AS1', 'Gene', (7, 15))	('high', 'Var', (2, 6))	('poor', 'NegReg', (74, 78))	('associated with', 'Reg', (31, 46))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (7, 15))	('expression', 'MPA', (16, 26))
180236	32236578	The QuikChange Site-directed Mutagenesis kit (Stratagene, Agilent Technologies, Inc.) was used to generate mutations in potential miR-200a-binding sites.	('miR-200a', 'Gene', (130, 138))	('miR-200a', 'Gene', '406983', (130, 138))	('mutations', 'Var', (107, 116))
180247	32236578	Of note, a high ZEB1-AS1 expression was identified to be associated with microvascular invasion (P=0.020), lymphatic metastasis (P=0.036) and an advanced TNM stage (P=0.037) (Table I).	('ZEB1-AS1', 'Gene', '220930;6935;5729', (16, 24))	('expression', 'MPA', (25, 35))	('lymphatic metastasis', 'CPA', (107, 127))	('high', 'Var', (11, 15))	('ZEB1-AS1', 'Gene', (16, 24))	('microvascular invasion', 'CPA', (73, 95))	('associated', 'Reg', (57, 67))
180250	32236578	Patients with a high ZEB1-AS1 expression had substantially lower OS and PFS rates than patients with a low ZEB1-AS1 expression (Fig.	('ZEB1-AS1', 'Gene', (21, 29))	('high', 'Var', (16, 20))	('lower', 'NegReg', (59, 64))	('expression', 'Var', (30, 40))	('ZEB1-AS1', 'Gene', (107, 115))	('PFS rates', 'CPA', (72, 81))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (21, 29))	('Patients', 'Species', '9606', (0, 8))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (107, 115))	('patients', 'Species', '9606', (87, 95))
180251	32236578	A high ZEB1-AS1 expression was revealed to be an independent risk factor for poor OS (HR, 1.157; 95% CI, 1.059-1.265; P=0.001) and PFS (HR, 1.131; 95% CI, 1.038-1.232; P=0.005) (Table III).	('ZEB1-AS1', 'Gene', (7, 15))	('high', 'Var', (2, 6))	('PFS', 'Disease', (131, 134))	('poor OS', 'Disease', (77, 84))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (7, 15))	('expression', 'MPA', (16, 26))
180255	32236578	2A) Notably, the HuCCT1 cells with ZEB1-AS1 deficiency exhibited a substantially reduced proliferative ability in the colony formation and CCK-8 assays (Fig.	('colony formation', 'CPA', (118, 134))	('deficiency', 'Var', (44, 54))	('HuCCT1', 'CellLine', 'CVCL:0324', (17, 23))	('ZEB1-AS1', 'Gene', (35, 43))	('CCK-8', 'Chemical', 'MESH:D012844', (139, 144))	('proliferative ability in', 'CPA', (89, 113))	('reduced', 'NegReg', (81, 88))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (35, 43))
180256	32236578	Consistently, the ectopic expression of ZEB1-AS1 significantly increased the proliferative ability of the RBE cells (Fig.	('ZEB1-AS1', 'Gene', '220930;6935;5729', (40, 48))	('increased', 'PosReg', (63, 72))	('ectopic expression', 'Var', (18, 36))	('proliferative ability of the RBE cells', 'CPA', (77, 115))	('ZEB1-AS1', 'Gene', (40, 48))
180257	32236578	In the wound healing assay, the knockdown of ZEB1-AS1 inhibited the migration of the HuCCT1 cells and the overexpression of ZEB1-AS1 promoted the migration of RBE cells (Fig.	('inhibited', 'NegReg', (54, 63))	('migration', 'CPA', (146, 155))	('ZEB1-AS1', 'Gene', (45, 53))	('ZEB1-AS1', 'Gene', (124, 132))	('migration of the HuCCT1 cells', 'CPA', (68, 97))	('promoted', 'PosReg', (133, 141))	('knockdown', 'Var', (32, 41))	('HuCCT1', 'CellLine', 'CVCL:0324', (85, 91))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (45, 53))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (124, 132))
180262	32236578	Moreover, the metastatic ability of the HuCCT1 cells was significantly inhibited when ZEB1-AS1 was knocked down (Fig.	('knocked down', 'Var', (99, 111))	('inhibited', 'NegReg', (71, 80))	('metastatic ability of the HuCCT1 cells', 'CPA', (14, 52))	('HuCCT1', 'CellLine', 'CVCL:0324', (40, 46))	('ZEB1-AS1', 'Gene', (86, 94))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (86, 94))
180263	32236578	4B), and ectopic expression of ZEB1-AS1 increased the number of metastatic foci in liver and lungs (Fig.	('ectopic expression', 'Var', (9, 27))	('ZEB1-AS1', 'Gene', (31, 39))	('increased', 'PosReg', (40, 49))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (31, 39))
180264	32236578	Additionally, a decreased tumor size and weight were observed when ZEB1-AS1 was knocked down (Fig.	('ZEB1-AS1', 'Gene', '220930;6935;5729', (67, 75))	('decreased tumor', 'Disease', (16, 31))	('ZEB1-AS1', 'Gene', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('decreased tumor', 'Disease', 'MESH:D002303', (16, 31))	('knocked down', 'Var', (80, 92))
180271	32236578	Moreover, the HuCCT1 cells in which ZEB1-AS1 was silenced displayed an epithelial morphology and formed colonies with increased intercellular contacts (Fig.	('ZEB1-AS1', 'Gene', '220930;6935;5729', (36, 44))	('HuCCT1', 'CellLine', 'CVCL:0324', (14, 20))	('silenced', 'Var', (49, 57))	('colonies', 'CPA', (104, 112))	('increased', 'PosReg', (118, 127))	('epithelial morphology', 'CPA', (71, 92))	('ZEB1-AS1', 'Gene', (36, 44))	('intercellular contacts', 'CPA', (128, 150))
180281	32236578	Moreover, miR-200a expression was increased in the HuCCT1 cells in which ZEB1-AS1 was knocked down and decreased in the RBE cells in which ZEB1-AS1 was overexpressed (Fig.	('ZEB1-AS1', 'Gene', '220930;6935;5729', (139, 147))	('expression', 'MPA', (19, 29))	('miR-200a', 'Gene', (10, 18))	('decreased', 'NegReg', (103, 112))	('ZEB1-AS1', 'Gene', (73, 81))	('miR-200a', 'Gene', '406983', (10, 18))	('ZEB1-AS1', 'Gene', (139, 147))	('knocked down', 'Var', (86, 98))	('increased', 'PosReg', (34, 43))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (73, 81))	('HuCCT1', 'CellLine', 'CVCL:0324', (51, 57))
180286	32236578	Consistently, transfection with miR-200a inhibitor blocked the increased expression of E-cadherin and the decreased expression of vimentin in the HuCCT1 cells in which ZEB1-AS1 was knocked down (Fig.	('decreased', 'NegReg', (106, 115))	('expression', 'MPA', (116, 126))	('E-cadherin', 'Gene', (87, 97))	('increased', 'PosReg', (63, 72))	('ZEB1-AS1', 'Gene', (168, 176))	('E-cadherin', 'Gene', '999', (87, 97))	('HuCCT1', 'CellLine', 'CVCL:0324', (146, 152))	('knocked down', 'Var', (181, 193))	('expression', 'MPA', (73, 83))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (168, 176))	('miR-200a', 'Gene', (32, 40))	('vimentin', 'Gene', '7431', (130, 138))	('blocked', 'NegReg', (51, 58))	('miR-200a', 'Gene', '406983', (32, 40))	('vimentin', 'Gene', (130, 138))
180297	32236578	The log-rank test revealed that patients with a high ZEB1-AS1 expression had considerably lower OS and PFS rates than patients with a low ZEB1-AS1 expression.	('patients', 'Species', '9606', (32, 40))	('ZEB1-AS1', 'Gene', (138, 146))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (53, 61))	('patients', 'Species', '9606', (118, 126))	('lower', 'NegReg', (90, 95))	('ZEB1-AS1', 'Gene', (53, 61))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (138, 146))	('high', 'Var', (48, 52))	('expression', 'Var', (62, 72))
180298	32236578	Additionally, a high ZEB1-AS1 expression was identified as an independent risk factor for low OS and PFS.	('ZEB1-AS1', 'Gene', (21, 29))	('expression', 'MPA', (30, 40))	('high', 'Var', (16, 20))	('PFS', 'Disease', (101, 104))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (21, 29))	('low OS', 'Disease', (90, 96))
180299	32236578	A previous meta-analysis aimed at discovering the prognostic value of ZEB1-AS1 in cancer, which included 11 studies representing 891 cancer patients, indicated that a high ZEB1-AS1 expression was an unfavorable predictor of cancer prognosis in terms of OS, disease-free survival and recurrence-free survival.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('expression', 'MPA', (181, 191))	('recurrence-free survival', 'CPA', (283, 307))	('ZEB1-AS1', 'Gene', (172, 180))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('ZEB1-AS1', 'Gene', (70, 78))	('high', 'Var', (167, 171))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', (133, 139))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (172, 180))	('disease-free survival', 'CPA', (257, 278))	('patients', 'Species', '9606', (140, 148))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (70, 78))	('cancer', 'Disease', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
180305	32236578	As presented in the current study, no statistically significant differences were observed between the expression of ZEB1-AS1 and the number of tumors and tumor size in the clinical specimens; however, ZEB-AS1 accelerated cell proliferation in colony formation and CCK-8 assays.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Disease', (143, 148))	('tumors', 'Disease', (143, 149))	('ZEB-AS1', 'Var', (201, 208))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (116, 124))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('accelerated', 'PosReg', (209, 220))	('cell proliferation in colony formation', 'CPA', (221, 259))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('ZEB1-AS1', 'Gene', (116, 124))	('CCK-8', 'Chemical', 'MESH:D012844', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', (154, 159))
180318	32236578	Moreover, high ZEB1-AS1 expression indicates poor OS and PFS rates, and serves as an independent risk factor for poor OS and PFS.	('ZEB1-AS1', 'Gene', '220930;6935;5729', (15, 23))	('expression', 'MPA', (24, 34))	('ZEB1-AS1', 'Gene', (15, 23))	('poor', 'NegReg', (45, 49))	('high', 'Var', (10, 14))	('PFS rates', 'CPA', (57, 66))
180352	31920396	Furthermore, this study concluded that the patients who had high-risk features, including high level of CA19-9, T4 stage, lymph node involvement, and R1 margin, were more likely to get benefits from adjuvant chemotherapy.	('patients', 'Species', '9606', (43, 51))	('CA19-9', 'Protein', (104, 110))	('lymph node involvement', 'CPA', (122, 144))	('benefits', 'PosReg', (185, 193))	('T4 stage', 'CPA', (112, 120))	('high', 'Var', (90, 94))	('adjuvant chemotherapy', 'CPA', (199, 220))
180427	31920396	The 2-year DFS and 2-year OS for R1+RT group was significantly lower than both R0+S group (2-year DFS: 9.6% vs 62.6%, respectively, P=0.002; 2-year OS: 15.4% vs 61.5%, respectively, P<0.001) and R1+CCRT group (2-year DFS: P=0.005; 2-year OS: P=0.017).	('R0+S', 'Chemical', 'MESH:D013455', (79, 83))	('CC', 'Phenotype', 'HP:0030153', (198, 200))	('R1+RT', 'Var', (33, 38))	('lower', 'NegReg', (63, 68))
180452	31920396	Negative histologic margins, concomitant partial hepatectomy and portal vein resection, and well-differentiated tumor histology are associated with improved outcome after surgery, while increasing T-stage significantly correlated with reduced R0 resection rate, higher distant metastasis rate, and lower median survival.	('lower', 'NegReg', (298, 303))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('improved', 'PosReg', (148, 156))	('distant metastasis rate', 'CPA', (269, 292))	('partial', 'Var', (41, 48))	('reduced', 'NegReg', (235, 242))	('median survival', 'CPA', (304, 319))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('R0 resection', 'CPA', (243, 255))	('tumor', 'Disease', (112, 117))	('higher', 'PosReg', (262, 268))
180520	29731848	Finally, cell viability in the different treated groups (0, 2, 4, 6, 8, 10, 12 and 14 microM solamargine) was calculated as a proportion, using the formula: Cell viability (%)=(OD570 nm-OD630 nm)treated/(OD570 nm-OD630 nm)untreatedx100%.	('solamargine', 'Chemical', 'MESH:C026609', (93, 104))	('OD570 nm-OD630 nm', 'Var', (204, 221))	('OD570 nm-OD630 nm', 'Var', (177, 194))
180540	29731848	As the concentration of solamargine increased (0, 2, 4, 6, 8 and 10 microM), the morphology of cholangiocarcinoma cells changed markedly at 24 h. Solamargine may cause shrinkage, irregularity and inhibit the viability of cells (Fig.	('Solamargine', 'Var', (146, 157))	('viability of cells', 'CPA', (208, 226))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (95, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (95, 113))	('shrinkage', 'CPA', (168, 177))	('Solamargine', 'Chemical', 'MESH:C026609', (146, 157))	('solamargine', 'Chemical', 'MESH:C026609', (24, 35))	('irregularity', 'CPA', (179, 191))	('inhibit', 'NegReg', (196, 203))	('cholangiocarcinoma', 'Disease', (95, 113))
180560	29731848	5B, solamargine increased the protein expression of Bax, caspase 3, cleaved-caspase 3, caspase 7 and cleaved PARP, but decreased the protein expression of Bcl-2, XIAP and PARP.	('protein expression', 'MPA', (133, 151))	('Bax', 'Gene', '581', (52, 55))	('caspase 3', 'Gene', (57, 66))	('caspase 7', 'Gene', '840', (87, 96))	('PARP', 'Gene', '142', (171, 175))	('caspase 3', 'Gene', '836', (57, 66))	('Bcl-2', 'Gene', (155, 160))	('XIAP', 'Gene', (162, 166))	('PARP', 'Gene', (171, 175))	('decreased', 'NegReg', (119, 128))	('Bcl-2', 'Gene', '596', (155, 160))	('PARP', 'Gene', '142', (109, 113))	('XIAP', 'Gene', '331', (162, 166))	('caspase 3', 'Gene', (76, 85))	('caspase 3', 'Gene', '836', (76, 85))	('cleaved', 'Var', (101, 108))	('solamargine', 'Chemical', 'MESH:C026609', (4, 15))	('increased', 'PosReg', (16, 25))	('caspase 7', 'Gene', (87, 96))	('PARP', 'Gene', (109, 113))	('Bax', 'Gene', (52, 55))	('protein expression', 'MPA', (30, 48))
180572	29731848	A previous study revealed that the alteration in MMP is an early event of pro-apoptosis and may result in the release of cytochrome c in mitochondria, which may induce the activation of caspase 9.	('alteration', 'Var', (35, 45))	('induce', 'Reg', (161, 167))	('MMP', 'Gene', (49, 52))	('cytochrome c', 'Gene', (121, 133))	('cytochrome c', 'Gene', '54205', (121, 133))	('caspase 9', 'Gene', (186, 195))	('result in', 'Reg', (96, 105))	('caspase 9', 'Gene', '842', (186, 195))
180576	29731848	The results indicated that solamargine increased the expression of Bax, caspase 3, cleaved caspase 3, caspase 7 and cleaved PARP and decreased the expression of Bcl-2, Bcl-xL, XIAP and PARP.	('expression', 'MPA', (147, 157))	('caspase 7', 'Gene', (102, 111))	('cleaved', 'Var', (83, 90))	('XIAP', 'Gene', '331', (176, 180))	('PARP', 'Gene', (124, 128))	('caspase 3', 'Gene', (72, 81))	('caspase 3', 'Gene', '836', (72, 81))	('caspase 7', 'Gene', '840', (102, 111))	('Bcl-xL', 'Gene', (168, 174))	('Bcl-2', 'Gene', (161, 166))	('decreased', 'NegReg', (133, 142))	('PARP', 'Gene', '142', (185, 189))	('Bcl-xL', 'Gene', '598', (168, 174))	('XIAP', 'Gene', (176, 180))	('PARP', 'Gene', (185, 189))	('expression', 'MPA', (53, 63))	('Bcl-2', 'Gene', '596', (161, 166))	('Bax', 'Gene', (67, 70))	('solamargine', 'Chemical', 'MESH:C026609', (27, 38))	('Bax', 'Gene', '581', (67, 70))	('increased', 'PosReg', (39, 48))	('caspase 3', 'Gene', (91, 100))	('caspase 3', 'Gene', '836', (91, 100))	('cleaved', 'Var', (116, 123))	('PARP', 'Gene', '142', (124, 128))
180582	29445149	Deregulated microRNAs (miRNAs) are implicated in several cancer types including CCA.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('Deregulated', 'Var', (0, 11))	('CCA', 'Disease', (80, 83))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('CCA', 'Phenotype', 'HP:0030153', (80, 83))	('implicated', 'Reg', (35, 45))	('microRNAs', 'MPA', (12, 21))
180584	29445149	In our translational study we show that microRNA let-7c expression was significantly downregulated in human cholangiocarcinoma tissues when compared to adjacent tissues of the same patient.	('downregulated', 'NegReg', (85, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('cholangiocarcinoma tissues', 'Disease', 'MESH:D018281', (108, 134))	('microRNA', 'Var', (40, 48))	('cholangiocarcinoma tissues', 'Disease', (108, 134))	('let-7c', 'Gene', (49, 55))	('let-7c', 'Gene', '406885', (49, 55))	('patient', 'Species', '9606', (181, 188))	('expression', 'MPA', (56, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (108, 126))	('human', 'Species', '9606', (102, 107))
180588	29445149	The miRNA let-7c thus plays an important dual role in regulating tumorigenic and metastatic abilities of human cholangiocarcinoma through mechanisms involving EZH2 protein and the DVL3/beta-catenin axis.	('let-7c', 'Gene', (10, 16))	('human', 'Species', '9606', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('cholangiocarcinoma', 'Disease', (111, 129))	('let-7c', 'Gene', '406885', (10, 16))	('metastatic abilities', 'CPA', (81, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('EZH2 protein', 'Protein', (159, 171))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 129))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))	('miRNA', 'Var', (4, 9))
180591	29445149	The progression of cholangiocarcinoma involves multiple genetic and epigenetic alterations.	('cholangiocarcinoma', 'Disease', (19, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('epigenetic alterations', 'Var', (68, 90))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (19, 37))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (19, 37))
180618	29445149	In contrast, the spheres with low let-7c expression showed a greater ability for sphere formation, thereby revealing a higher self-renewal capacity.	('let-7c', 'Gene', '406885', (34, 40))	('greater', 'PosReg', (61, 68))	('low', 'Var', (30, 33))	('higher', 'PosReg', (119, 125))	('sphere formation', 'CPA', (81, 97))	('let-7c', 'Gene', (34, 40))	('self-renewal capacity', 'CPA', (126, 147))
180632	29445149	To determine whether let-7c affects metastasis ability of cholangiocarcinoma in vivo, we injected the stable TFK-1 cells with high let-7c expression (and respective parental control cells) and HUCCT-1 cells with low let-7c expression (and respective parental control cells) into the tail vein of BALB/c nude mice in order to establish a distant metastasis mouse model.	('let-7c', 'Gene', (216, 222))	('let-7c', 'Gene', (21, 27))	('let-7c', 'Gene', '406885', (21, 27))	('let-7c', 'Gene', (131, 137))	('cholangiocarcinoma', 'Disease', (58, 76))	('let-7c', 'Gene', '406885', (216, 222))	('let-7c', 'Gene', '406885', (131, 137))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('high', 'Var', (126, 130))	('HUCCT-1', 'CellLine', 'CVCL:0324', (193, 200))	('nude mice', 'Species', '10090', (303, 312))	('mouse', 'Species', '10090', (356, 361))
180637	29445149	To additionally determine whether the other two miRNAs, miR-99a and miR-125b-2, that occur in the cluster with let-7c contribute to our observations, we generated a distant metastasis mouse model with miR-99a overexpressed cells or miR-125b-2 or let-7c overexpressed cells.	('let-7c', 'Gene', (111, 117))	('let-7c', 'Gene', (246, 252))	('let-7c', 'Gene', '406885', (111, 117))	('mouse', 'Species', '10090', (184, 189))	('miR-99a', 'Var', (201, 208))	('let-7c', 'Gene', '406885', (246, 252))	('distant metastasis', 'CPA', (165, 183))
180652	29445149	When the wild-type sequence of EZH2 was transfected into TFK-1 cells, we discovered that aberrant expression of let-7c lead to a reduction in luciferase activity.	('luciferase', 'Enzyme', (142, 152))	('aberrant', 'Var', (89, 97))	('reduction', 'NegReg', (129, 138))	('let-7c', 'Gene', (112, 118))	('activity', 'MPA', (153, 161))	('let-7c', 'Gene', '406885', (112, 118))
180657	29445149	7d and Supplementary Figure 3A); furthermore, silencing of EZH2 in let-7c downregulated cells could recover the invasive capacity compared with negative control group (Fig.	('silencing', 'Var', (46, 55))	('EZH2', 'Gene', (59, 63))	('let-7c', 'Gene', (67, 73))	('let-7c', 'Gene', '406885', (67, 73))	('invasive capacity', 'CPA', (112, 129))	('recover', 'PosReg', (100, 107))
180659	29445149	Compared with the negative control group, we found that there were more distant metastasized foci only in the group with knockdown of DVL3 but not in the group with knockdown of EZH2 (Supplementary Figure 3D), in addition, the number of distant metastasized foci in the group with downregulated let-7c plus siDVL3 were as similar to the negative control group (Supplementary Figure 3E).	('knockdown', 'Var', (121, 130))	('downregulated', 'NegReg', (281, 294))	('more', 'PosReg', (67, 71))	('distant metastasized foci', 'CPA', (237, 262))	('let-7c', 'Gene', (295, 301))	('let-7c', 'Gene', '406885', (295, 301))	('distant metastasized foci', 'CPA', (72, 97))
180660	29445149	Further, there was a significant weight reduction in mice from the DVL3 knockdown group compared with the negative control group from the fourth week on (Fig.	('weight reduction', 'Disease', (33, 49))	('DVL3', 'Gene', (67, 71))	('mice', 'Species', '10090', (53, 57))	('knockdown', 'Var', (72, 81))	('weight reduction', 'Disease', 'MESH:D015431', (33, 49))
180670	29445149	The decrease in weights of BalB/c nude mice and tumor diameter were significantly different between the EZH2 knockdown group and NC group (Fig.	('nude mice', 'Species', '10090', (34, 43))	('tumor', 'Disease', (48, 53))	('weights of BalB/c nude mice', 'CPA', (16, 43))	('EZH2', 'Gene', (104, 108))	('decrease', 'NegReg', (4, 12))	('knockdown', 'Var', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
180677	29445149	MiRNAs were not only recognized to regulate tumor growth but have also been recognized to play a role in other cancer-related processes such as metastasis.	('MiRNAs', 'Var', (0, 6))	('play', 'Reg', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('tumor', 'Disease', (44, 49))
180685	29445149	ShRNA mediated knockdown of DVL3 or EZH2 showed that only knockdown of expression of DVL3 promoted the pro-invasive activity of in vivo tail vein injected cholangiocarcinoma cells similar to let-7c overexpression.	('DVL3', 'Gene', (85, 89))	('let-7c', 'Gene', (191, 197))	('cholangiocarcinoma', 'Disease', (155, 173))	('let-7c', 'Gene', '406885', (191, 197))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (155, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('pro-invasive activity', 'CPA', (103, 124))	('promoted', 'PosReg', (90, 98))	('knockdown', 'Var', (58, 67))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (155, 173))
180687	29445149	A previous study demonstrated that reversion of EMT can promote proliferation and colonization of cancer cells in distant sites.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('EMT', 'Gene', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('proliferation', 'CPA', (64, 77))	('cancer', 'Disease', (98, 104))	('promote', 'PosReg', (56, 63))	('reversion', 'Var', (35, 44))
180727	29445149	We mutated three nucleotides in each of the EZH2/DVL3/beta-catenin 3'-UTRs complementary to the let-7c seed region.	('EZH2/DVL3/beta-catenin', 'Gene', (44, 66))	('let-7c', 'Gene', '406885', (96, 102))	('mutated', 'Var', (3, 10))	('let-7c', 'Gene', (96, 102))
180748	24046106	MicroRNAs may also function as oncogenes or tumor suppressor genes.	('MicroRNAs', 'Var', (0, 9))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
180766	24046106	Comparison of the miR expression profiles established from cholangiocarcinoma and pancreatic adenocarcinoma versus their adjacent normal tissue revealed 15 miRs that were commonly dysregulated between tumor types (miRs -221, -10a, -135b, -21, -151-3p, -181a, -106b, -139-5p, -100, -145, -125b, -127-3p, -30e, -96, and miR-30b).	('cholangiocarcinoma and pancreatic adenocarcinoma', 'Disease', 'MESH:D018281', (59, 107))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (82, 107))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('miRs -221', 'Var', (214, 223))	('miR-30b', 'Gene', '407030', (318, 325))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))	('miR-30b', 'Gene', (318, 325))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (59, 77))
180797	24900154	The CRP level (p < 0.001) and white blood cell count (p = 0.023) were significantly higher in the group of patients with diffuse splenic FDG uptake.	('white blood', 'CPA', (30, 41))	('patients', 'Species', '9606', (107, 115))	('CRP', 'Gene', '1401', (4, 7))	('diffuse', 'Var', (121, 128))	('CRP', 'Gene', (4, 7))	('FDG', 'Chemical', 'MESH:D019788', (137, 140))	('higher', 'PosReg', (84, 90))
180798	24900154	The hemoglobin (p < 0.001) and the hematocrit (p < 0.001) were significantly lower in patients with diffuse splenic FDG uptake.	('lower', 'NegReg', (77, 82))	('diffuse splenic', 'Var', (100, 115))	('patients', 'Species', '9606', (86, 94))	('hematocrit', 'MPA', (35, 45))	('hemoglobin', 'MPA', (4, 14))	('FDG', 'Chemical', 'MESH:D019788', (116, 119))
180841	24900154	BM glucose metabolism was higher in the diffusely increased splenic uptake group; however, there was no statistical significance.	('higher', 'PosReg', (26, 32))	('increased', 'PosReg', (50, 59))	('diffusely', 'Var', (40, 49))	('glucose', 'Chemical', 'MESH:D005947', (3, 10))	('splenic uptake', 'MPA', (60, 74))	('BM glucose metabolism', 'MPA', (0, 21))
180845	24900154	In contrast, almost all patients (82.6 %) in the spleen group underwent ERCP before F-18 FDG PET-CT, while two-thirds of patients in the control group did not receive ERCP before F-18 FDG PET-CT.	('F-18', 'Gene', '10046', (84, 88))	('-18 FDG', 'Chemical', 'MESH:D019788', (180, 187))	('underwent', 'Reg', (62, 71))	('F-18', 'Gene', '10046', (179, 183))	('ERCP', 'Var', (72, 76))	('-18 FDG', 'Chemical', 'MESH:D019788', (85, 92))	('patients', 'Species', '9606', (24, 32))	('F-18', 'Gene', (84, 88))	('patients', 'Species', '9606', (121, 129))	('F-18', 'Gene', (179, 183))
180850	24900154	It has been demonstrated that diffuse splenic F-18 FDG uptake can be associated with various infections: varicella, HIV, and malaria.	('diffuse', 'Var', (30, 37))	('malaria', 'Disease', (125, 132))	('associated', 'Reg', (69, 79))	('infection', 'Disease', (93, 102))	('varicella', 'Disease', (105, 114))	('infection', 'Disease', 'MESH:D007239', (93, 102))	('-18 FDG', 'Chemical', 'MESH:D019788', (47, 54))	('F-18', 'Gene', (46, 50))	('HIV', 'Disease', (116, 119))	('malaria', 'Disease', 'MESH:D008288', (125, 132))	('F-18', 'Gene', '10046', (46, 50))
180865	24900154	Although no clinically significant complication was noticed, CRP level was elevated and leukocytosis was found after ERCP.	('ERCP', 'Var', (117, 121))	('found', 'Reg', (105, 110))	('elevated', 'PosReg', (75, 83))	('leukocytosis', 'Disease', 'MESH:D007964', (88, 100))	('leukocytosis', 'Phenotype', 'HP:0001974', (88, 100))	('CRP', 'Gene', (61, 64))	('leukocytosis', 'Disease', (88, 100))	('CRP', 'Gene', '1401', (61, 64))
180868	24900154	It is known that leukotriene B4 has a strong chemotactic activity for leukocytes and the spleen is a reservoir of several kinds of immune cells, including leukocytes.	('leukotriene', 'Var', (17, 28))	('chemotactic activity', 'MPA', (45, 65))	('leukotriene B4', 'Chemical', 'MESH:D007975', (17, 31))
180879	23959098	Clonal expansion of such apoptosis-resistant cells may contribute to the genesis of cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('Clonal', 'Var', (0, 6))	('cholangiocarcinoma', 'Disease', (84, 102))	('contribute', 'Reg', (55, 65))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
180889	23959098	Triol and 3K4 induced DNA damage and apoptosis in the human cholangiocyte MMNK-1 cell line.	('Triol', 'Chemical', '-', (0, 5))	('3K4', 'Var', (10, 13))	('apoptosis', 'CPA', (37, 46))	('DNA damage', 'MPA', (22, 32))	('MMNK-1', 'CellLine', 'CVCL:M266', (74, 80))	('human', 'Species', '9606', (54, 59))
180897	23959098	Such resistance, was stable after at least 4 weeks growth in the absence of the oxysterol, and thus must have been due to somatically inherited changes in the cells, such as epigenetic or mutational alterations.	('mutational alterations', 'Var', (188, 210))	('oxysterol', 'Chemical', 'MESH:D000072376', (80, 89))	('due', 'Reg', (115, 118))	('epigenetic', 'Var', (174, 184))	('rat', 'Species', '10116', (203, 206))
180939	23959098	To confirm the phosphorylation status of kinase proteins and expression of apoptosis-related proteins in Triol-exposed cells, we examined the protein levels of key-targeted proteins that included total-ERK1/2, phospho-ERK1/2, total-p38MAPK, phospho-p38MAPK, Bcl-2 and Bax.	('Triol', 'Chemical', '-', (105, 110))	('Bax', 'Gene', (268, 271))	('p38', 'Gene', '5594', (249, 252))	('p38', 'Gene', '5594', (232, 235))	('p38', 'Gene', (232, 235))	('phospho-ERK1/2', 'Var', (210, 224))	('Bax', 'Gene', '581', (268, 271))	('p38', 'Gene', (249, 252))	('total-ERK1/2', 'Var', (196, 208))	('Bcl-2', 'Gene', (258, 263))	('Bcl-2', 'Gene', '596', (258, 263))
180944	23959098	Both Triol and 3K4 induced DNA damage and apoptosis via a mitochondria-dependent mechanism.	('apoptosis', 'CPA', (42, 51))	('Triol', 'Chemical', '-', (5, 10))	('DNA damage', 'MPA', (27, 37))	('3K4', 'Var', (15, 18))
180975	23959098	Long term chronic inflammation due to Ov infection would allow the generation of reactive oxygen and nitrogen species, DNA damage, selection for apoptosis resistance, and increased mutation leading to carcinogenesis.	('inflammation', 'Disease', (18, 30))	('rat', 'Species', '10116', (71, 74))	('carcinogenesis', 'Disease', (201, 215))	('infection', 'Disease', (41, 50))	('reactive oxygen and nitrogen species', 'Chemical', '-', (81, 117))	('mutation', 'Var', (181, 189))	('infection', 'Disease', 'MESH:D007239', (41, 50))	('Ov', 'Species', '6198', (38, 40))	('carcinogenesis', 'Disease', 'MESH:D063646', (201, 215))	('inflammation', 'Disease', 'MESH:D007249', (18, 30))
180996	19147772	AKT is activated by phosphorylation at Thr308 by PIP3 and at Ser473 by mammalian target of rapamycin (mTOR) as a part of the mTOR complex (mTORC; ref.).	('mammalian target of rapamycin', 'Gene', '2475', (71, 100))	('mammalian target of rapamycin', 'Gene', (71, 100))	('Thr308', 'Chemical', '-', (39, 45))	('Ser473', 'Chemical', '-', (61, 67))	('AKT', 'Pathway', (0, 3))	('activated', 'PosReg', (7, 16))	('PIP3', 'Chemical', '-', (49, 53))	('phosphorylation', 'Var', (20, 35))
181042	19147772	Although patients with high p-AKT expression group had shorter 1-, 3-, and 5-year survival rates (79.7%, 46.1%, and 36.3%, respectively) than those with low p-AKT expression (83.3%, 83.3%, and 83.3%, respectively), the difference was not statistically significant (P = 0.06).	('patients', 'Species', '9606', (9, 17))	('high p-AKT expression', 'Var', (23, 44))	('shorter', 'NegReg', (55, 62))
181050	19147772	Patients with low PTEN/p-mTOR expression (<0.33 of PTEN/p-mTOR; median survival, 18 months) had a significantly worse patients' survival time than those with high PTEN/p-mTOR expression (>0.33; median survival, 39 months; log-rank test, P = 0.009).	('<0.33', 'Var', (42, 47))	('PTEN/p-mTOR', 'Gene', (51, 62))	('PTEN/p-mTOR', 'Gene', (18, 29))	('Patients', 'Species', '9606', (0, 8))	('low', 'NegReg', (14, 17))	('survival time', 'CPA', (128, 141))	('patients', 'Species', '9606', (118, 126))	('worse', 'NegReg', (112, 117))
181053	19147772	In a murine model of intrahepatic cholangiocarcinoma, the disruption of the PTEN gene was associated with increased level of p-AKT, GSK-3beta, mTOR, and ERK, suggesting that PTEN may involve in cholangiocarcinogenesis by affecting its downstream genes.	('level', 'MPA', (116, 121))	('intrahepatic cholangiocarcinoma', 'Disease', (21, 52))	('GSK-3beta', 'Gene', '606496', (132, 141))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (34, 52))	('mTOR', 'MPA', (143, 147))	('cholangiocarcinogenesis', 'Disease', 'None', (194, 217))	('GSK-3beta', 'Gene', (132, 141))	('increased', 'PosReg', (106, 115))	('involve', 'Reg', (183, 190))	('PTEN gene', 'Gene', (76, 85))	('p-AKT', 'MPA', (125, 130))	('ERK', 'Gene', (153, 156))	('murine', 'Species', '10090', (5, 11))	('disruption', 'Var', (58, 68))	('cholangiocarcinogenesis', 'Disease', (194, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('ERK', 'Gene', '26413', (153, 156))	('affecting', 'Reg', (221, 230))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (21, 52))
181057	19147772	A previous study showed that AKT and p-AKT expression was associated with improved prognosis in cholangiocarcinoma.	('p-AKT', 'Protein', (37, 42))	('expression', 'Var', (43, 53))	('cholangiocarcinoma', 'Disease', (96, 114))	('AKT', 'Protein', (29, 32))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))	('improved', 'PosReg', (74, 82))
181071	19147772	Several studies showed that loss of PTEN protein expression could be used as a prognostic factor in other malignancies, including breast, endometrial, hepatocellular, and gastric carcinomas.	('endometrial', 'Disease', (138, 149))	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('loss', 'Var', (28, 32))	('protein', 'Protein', (41, 48))	('hepatocellular', 'Disease', (151, 165))	('malignancies', 'Disease', (106, 118))	('expression', 'MPA', (49, 59))	('PTEN', 'Gene', (36, 40))	('gastric carcinomas', 'Disease', (171, 189))	('gastric carcinomas', 'Disease', 'MESH:D013274', (171, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('breast', 'Disease', (130, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (179, 189))
181092	30863466	In 50 patients with radical surgeries, the levels of preoperative serums CEA, CA125, and CA19-9 were 5.0 +- 13.9 ng/mL, 15.3 +- 11.8 U/mL, and 257.5 +- 325.6 U/mL, respectively, which were lower than those in patients with unresectable tumor.	('CA125', 'Gene', '94025', (78, 83))	('CEA', 'Gene', (73, 76))	('CEA', 'Gene', '1084', (73, 76))	('CA19-9', 'Var', (89, 95))	('CA125', 'Gene', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('patients', 'Species', '9606', (209, 217))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', (236, 241))	('CA19-9', 'Chemical', 'MESH:C086528', (89, 95))
181137	30863466	Multivariate logistic regression analysis for predicting the resectability of cholangiocarcinoma showed that the serum levels of CEA, CA125, and CA19-9 had a better predictive value in radical resection.	('CA125', 'Gene', '94025', (134, 139))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 96))	('CA19-9', 'Chemical', 'MESH:C086528', (145, 151))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (78, 96))	('serum levels', 'MPA', (113, 125))	('CEA', 'Gene', (129, 132))	('CA125', 'Gene', (134, 139))	('CEA', 'Gene', '1084', (129, 132))	('cholangiocarcinoma', 'Disease', (78, 96))	('radical resection', 'Disease', (185, 202))	('CA19-9', 'Var', (145, 151))
181271	29879137	Other predictors related to short TTPlocal were multiple recurrences and maximum tumor diameter (HRs 5.13 and 1.04, respectively; P < 0.05 for each).	('tumor', 'Disease', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('short', 'Var', (28, 33))
181326	29776401	A decrease in the expression of ADAM-17 by silencing FoxM1 led to an inhibition of cell proliferation, tumor growth, and the production of tumor necrosis factor alpha.	('tumor necrosis factor alpha', 'Gene', '7124', (139, 166))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor necrosis factor alpha', 'Gene', (139, 166))	('FoxM1', 'Gene', (53, 58))	('decrease', 'NegReg', (2, 10))	('ADAM-17', 'Gene', (32, 39))	('tumor', 'Disease', (103, 108))	('cell proliferation', 'CPA', (83, 101))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('silencing', 'Var', (43, 52))	('expression', 'MPA', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('inhibition', 'NegReg', (69, 79))
181343	29776401	Tissue microarrays containing HC (n = 49) and matched non-cancerous bile duct tissues and the fresh tissues (n = 5) were immunostained with antibodies against ADAM-10 (1:100), ADAM-17 (1:100), ADAM-28 (1:100, H102, Santa Cruz Biotechnology), and FoxM1 (1:150) according standard protocols.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ADAM-17', 'Gene', (176, 183))	('ADAM-28', 'Gene', (193, 200))	('FoxM1', 'Gene', (246, 251))	('cancerous bile duct', 'Phenotype', 'HP:0030153', (58, 77))	('ADAM-10', 'Gene', (159, 166))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('ADAM-10', 'Gene', '102', (159, 166))	('cancer', 'Disease', (58, 64))	('1:100', 'Var', (202, 207))	('ADAM-28', 'Gene', '10863', (193, 200))
181381	29776401	Furthermore, silencing of FoxM1 decreased the expression of ADAM-17, as well as the expression and secretion of TNFa (Fig.	('TNFa', 'Gene', (112, 116))	('secretion', 'MPA', (99, 108))	('TNFa', 'Gene', '7124', (112, 116))	('FoxM1', 'Gene', (26, 31))	('ADAM-17', 'Gene', (60, 67))	('expression', 'MPA', (84, 94))	('expression', 'MPA', (46, 56))	('decreased', 'NegReg', (32, 41))	('silencing', 'Var', (13, 22))
181387	29776401	Consistent with this implication, increasing evidences have suggested that specific ADAMs, including ADAM-9, ADAM-12, ADAM-17, ADAM-28, ADAM-33, were upregulated in various human solid cancers and correlated to the malignant behaviors of these tumors.	('ADAM-12', 'Gene', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('ADAM-28', 'Gene', '10863', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('ADAM-12', 'Gene', '8038', (109, 116))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('solid cancers', 'Disease', 'MESH:D009369', (179, 192))	('ADAM-9', 'Gene', (101, 107))	('ADAM-9', 'Gene', '8754', (101, 107))	('tumors', 'Disease', (244, 250))	('solid cancers', 'Disease', (179, 192))	('human', 'Species', '9606', (173, 178))	('malignant behaviors', 'CPA', (215, 234))	('upregulated', 'PosReg', (150, 161))	('ADAM-17', 'Var', (118, 125))	('correlated', 'Reg', (197, 207))	('ADAM-33', 'Gene', (136, 143))	('ADAM-33', 'Gene', '80332', (136, 143))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('ADAM-28', 'Gene', (127, 134))
181394	29776401	ADAM activities can be activated by TGF-ss, TPA, PKCdelta, and MMPs and inactivated by TIMPs.	('TPA', 'Chemical', '-', (44, 47))	('PKCdelta', 'Gene', '5580', (49, 57))	('activated', 'PosReg', (23, 32))	('TGF-ss', 'Var', (36, 42))	('ADAM', 'Enzyme', (0, 4))	('activities', 'MPA', (5, 15))	('PKCdelta', 'Gene', (49, 57))
181513	28578306	In regard to D-dimer levels, several groups have studied D-dimer as a marker of a cancer-associated hypercoagulable state and in some cases high levels of D-dimer have been correlated with an increased risk of early recurrent events in patients with cancer after an initial acute ischaemic stroke.	('ischaemic stroke', 'Phenotype', 'HP:0002140', (280, 296))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('acute ischaemic stroke', 'Disease', (274, 296))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('hypercoagulable state', 'Phenotype', 'HP:0100724', (100, 121))	('early recurrent', 'CPA', (210, 225))	('high', 'Var', (140, 144))	('cancer', 'Disease', (250, 256))	('acute ischaemic stroke', 'Disease', 'MESH:D020521', (274, 296))	('cancer', 'Disease', (82, 88))	('D-dimer', 'MPA', (155, 162))	('patients', 'Species', '9606', (236, 244))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('correlated with', 'Reg', (173, 188))	('stroke', 'Phenotype', 'HP:0001297', (290, 296))
181669	32368289	Apolipoprotein E is involved in DNA synthesis, cell proliferation, angiogenesis, and metastasis, and changes of these functions might induce tumorigenesis or progression.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('induce', 'Reg', (134, 140))	('DNA', 'MPA', (32, 35))	('progression', 'CPA', (158, 169))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('Apolipoprotein E', 'Gene', '348', (0, 16))	('involved', 'Reg', (20, 28))	('angiogenesis', 'CPA', (67, 79))	('Apolipoprotein E', 'Gene', (0, 16))	('tumor', 'Disease', (141, 146))	('metastasis', 'CPA', (85, 95))	('changes', 'Var', (101, 108))	('cell proliferation', 'CPA', (47, 65))
181697	32368289	It was founded that the neonatal Fc Receptor is required for delivery of synthesized albumin to the blood stream and absence of this receptor results in increased albumin levels in the bile.	('albumin', 'Gene', (85, 92))	('albumin', 'Gene', '213', (85, 92))	('increased albumin', 'Phenotype', 'HP:0012117', (153, 170))	('increased', 'PosReg', (153, 162))	('albumin', 'Gene', (163, 170))	('albumin', 'Gene', '213', (163, 170))	('neonatal Fc Receptor', 'Gene', '2217', (24, 44))	('neonatal Fc Receptor', 'Gene', (24, 44))	('absence', 'Var', (117, 124))
181698	32368289	Cholangiocyte is differentiated from liver progenitor cells and alterations in bile secretion and abnormal bile composition can result in hepatocellular and/or bile duct injury.	('bile duct injury', 'Disease', 'MESH:D002779', (160, 176))	('result in', 'Reg', (128, 137))	('bile duct injury', 'Disease', (160, 176))	('bile composition', 'MPA', (107, 123))	('bile secretion', 'MPA', (79, 93))	('alterations', 'Var', (64, 75))	('hepatocellular and/or', 'MPA', (138, 159))
181724	31632083	Several kinds of methylation, such as promoter methylation and CpG island methylation, are strongly associated with CCA.	('methylation', 'Var', (74, 85))	('CCA', 'Phenotype', 'HP:0030153', (116, 119))	('promoter', 'MPA', (38, 46))	('associated', 'Reg', (100, 110))	('CCA', 'Disease', 'MESH:D018281', (116, 119))	('CCA', 'Disease', (116, 119))
181736	31632083	Then, we selected three separate gene expression profiles (GSE107943, GSE26566, and GSE119337) for our study, about 228 human cholangiocarcinoma samples information were retrieved from these profiles.	('human', 'Species', '9606', (120, 125))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (126, 144))	('GSE119337', 'Var', (84, 93))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (126, 144))	('GSE107943', 'Var', (59, 68))	('GSE26566', 'Var', (70, 78))	('cholangiocarcinoma', 'Disease', (126, 144))
181743	31632083	MEXPRESS is a web tool which could offer the visualized analysis of clinical data, the expression (normalized RNASeqV2 value), and methylation TCGA and detect the relationship between them for one single gene in the specific tumor type.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Disease', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('methylation', 'Var', (131, 142))
181744	31632083	As shown in Table 1, GSE107943 contained 31 CCA specimens and 30 normal specimens, GSE26566 contained 104 CCA specimens and 65 normal liver specimens, and GSE119337 included 30 CCA samples and 30 normal liver samples.	('GSE119337', 'Var', (155, 164))	('CCA', 'Disease', 'MESH:D018281', (44, 47))	('CCA', 'Phenotype', 'HP:0030153', (106, 109))	('CCA', 'Disease', (177, 180))	('CCA', 'Disease', 'MESH:D018281', (106, 109))	('CCA', 'Disease', (44, 47))	('GSE26566', 'Var', (83, 91))	('GSE107943', 'Var', (21, 30))	('CCA', 'Phenotype', 'HP:0030153', (177, 180))	('CCA', 'Disease', (106, 109))	('CCA', 'Disease', 'MESH:D018281', (177, 180))	('CCA', 'Phenotype', 'HP:0030153', (44, 47))
181786	31632083	Epigenetics is the main factor which causes the reduction of tumor suppressor gene expression in tumor, and DNA methylation plays an important role in the epigenetic modification.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Epigenetics', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('reduction', 'NegReg', (48, 57))	('tumor', 'Disease', (61, 66))
181799	29923988	Duplication of gallbladder is an extremely rare congenital abnormality, which is easy to be ignored in ultrasonography, posing a great risk for surgical removal of gallbladder stones, which might lead to complications such as bile duct injury or leakage.	('Duplication of gallbladder', 'Phenotype', 'HP:0005608', (0, 26))	('leakage', 'Disease', (246, 253))	('lead to', 'Reg', (196, 203))	('bile duct injury', 'Disease', (226, 242))	('congenital abnormality', 'Disease', 'MESH:D000013', (48, 70))	('bile duct injury', 'Disease', 'MESH:D002779', (226, 242))	('Duplication', 'Var', (0, 11))	('congenital abnormality', 'Disease', (48, 70))
181801	29923988	Here, we report the first case with coexistence of duplication of gallbladder and cholangiocarcinoma, which was diagnosed by ultrasound, CT, MRCP, as well as surgery and pathology.	('gallbladder', 'Disease', (66, 77))	('duplication of gallbladder', 'Phenotype', 'HP:0005608', (51, 77))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (82, 100))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (82, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('duplication', 'Var', (51, 62))	('cholangiocarcinoma', 'Disease', (82, 100))
181935	28102343	We developed patient-specific ctDNA assays based on multiplexed detection of somatic mutations identified from patient primary tumours, and applied them to detect ctDNA in 44 CRC patients, analysing a total of 260 plasma samples.	('tumours', 'Phenotype', 'HP:0002664', (127, 134))	('patient', 'Species', '9606', (13, 20))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('patient', 'Species', '9606', (179, 186))	('tumours', 'Disease', 'MESH:D009369', (127, 134))	('mutations', 'Var', (85, 94))	('tumours', 'Disease', (127, 134))	('patients', 'Species', '9606', (179, 187))	('patient', 'Species', '9606', (111, 118))
181953	28102343	However, we and others showed that there is a large degree of genomic concordance amongst somatic mutations (about 80%) in each patient's primary tumour and corresponding metastatic lesion.	('tumour', 'Disease', (146, 152))	('mutations', 'Var', (98, 107))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('patient', 'Species', '9606', (128, 135))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
181955	28102343	To address these issues, we developed an approach to detect ctDNA based on multiplex-PCR amplicon sequencing of patient-specific primary somatic mutations in plasma (Fig.	('mutations', 'Var', (145, 154))	('patient', 'Species', '9606', (112, 119))	('ctDNA', 'Disease', (60, 65))
181959	28102343	One patient had a DNA polymerase epsilon mutation leading to an "ultramutation" phenotype.	('mutation', 'Var', (41, 49))	('patient', 'Species', '9606', (4, 11))	('leading to', 'Reg', (50, 60))
181963	28102343	Re-sequencing patient tumour tissue samples with these multiplex PPS assays verified the presence of nearly all of the somatic mutations (402 of 407 amplicons with at least 100X read depth), and the tumour mutation allele fraction estimated from the PPS multiplex amplicon sequencing assays was concordant with the estimates from the initial target-capture sequencing (Pearson: r2 = 0.88, Supplementary Fig.	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('PPS', 'Chemical', '-', (250, 253))	('tumour', 'Disease', (22, 28))	('tumour', 'Disease', 'MESH:D009369', (199, 205))	('tumour', 'Disease', (199, 205))	('patient', 'Species', '9606', (14, 21))	('PPS', 'Chemical', '-', (65, 68))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('mutations', 'Var', (127, 136))
181972	28102343	149 plasma samples of the remaining (58%) were positive for at least one PPS mutation and 38 patients had at least one positive sample.	('positive', 'Reg', (47, 55))	('mutation', 'Var', (77, 85))	('PPS', 'Gene', (73, 76))	('PPS', 'Chemical', '-', (73, 76))	('patients', 'Species', '9606', (93, 101))
181985	28102343	25 of these patients (96%) had detectable PPS-ctDNA, providing support that because of sufficient genomic similarity between primary and metastatic disease, the same mutations present in a patient's primary tumour can later be detected in the plasma when recurrent CRC develops.	('patients', 'Species', '9606', (12, 20))	('tumour', 'Disease', (207, 213))	('mutations', 'Var', (166, 175))	('patient', 'Species', '9606', (12, 19))	('patient', 'Species', '9606', (189, 196))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('PPS', 'Chemical', '-', (42, 45))	('CRC', 'Disease', (265, 268))	('tumour', 'Disease', 'MESH:D009369', (207, 213))
182009	28102343	Instead, mutations corresponding to the cholangiocarcinoma were detected, up to 2 months before clinical detection of the liver lesion.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (40, 58))	('liver lesion', 'Disease', 'MESH:D017093', (122, 134))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (40, 58))	('mutations', 'Var', (9, 18))	('liver lesion', 'Disease', (122, 134))	('cholangiocarcinoma', 'Disease', (40, 58))
182017	28102343	Here, we sought to describe a more general assay based on standard PCR techniques and sequencing to detect multiple somatic mutations per patient, and its general applicability across various CRC patients at differing stages with plasma samples obtained at varied time points after initial primary surgery.	('mutations', 'Var', (124, 133))	('patient', 'Species', '9606', (196, 203))	('patients', 'Species', '9606', (196, 204))	('CRC', 'Disease', (192, 195))	('patient', 'Species', '9606', (138, 145))
182021	28102343	This could affect our ability to reliably identify somatic mutations, initially found in one random sector of a primary tumour, in plasma ctDNA from the patient at a later time.	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('tumour', 'Disease', (120, 126))	('mutations', 'Var', (59, 68))	('patient', 'Species', '9606', (153, 160))	('affect', 'Reg', (11, 17))
182025	28102343	Also, recent studies by us - using targeted capture sequencing with the same 799-gene panel used here - as well as others, have further demonstrated that there is a high level of concordance of mutations present across different sectors of patients' primary colorectal tumours.	('mutations', 'Var', (194, 203))	('tumour', 'Phenotype', 'HP:0002664', (269, 275))	('tumours', 'Phenotype', 'HP:0002664', (269, 276))	('patients', 'Species', '9606', (240, 248))	('colorectal tumours', 'Disease', (258, 276))	('colorectal tumours', 'Disease', 'MESH:D015179', (258, 276))
182045	28102343	For each patient, up to 15 somatic variants were selected for amplicon design, with priority given to: a) variants at a site amplified by a previously tested primer pair, b) variants in genes associated with colorectal cancer, c) missense variants and short insertions or deletions (indels), d) splice-site variants, e) synonymous variants, f) variants in untranslated regions or introns.	('variants', 'Var', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('variants', 'Var', (106, 114))	('colorectal cancer', 'Disease', 'MESH:D015179', (208, 225))	('missense variants', 'Var', (230, 247))	('variants', 'Reg', (344, 352))	('colorectal cancer', 'Phenotype', 'HP:0003003', (208, 225))	('patient', 'Species', '9606', (9, 16))	('colorectal cancer', 'Disease', (208, 225))
182052	28102343	Linearity and sensitivity of the assay was assessed using serially diluted tumour DNA, where tumour DNA was mixed with corresponding normal DNA at the following ratios: 1:10, 1:20, 1:40, 1:80, 1:160, 1:320, 1:640, 1:1280 and 1:2560.	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('tumour', 'Disease', (93, 99))	('tumour', 'Disease', (75, 81))	('1:320', 'Var', (200, 205))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('1:640', 'Var', (207, 212))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
182262	25797574	Anti-SRP antibodies are detected in ~5% of patients with idiopathic inflammatory myopathy, and the presence of anti-SRP antibodies is frequently associated with acute onset severe myopathy.	('myopathy', 'Phenotype', 'HP:0003198', (81, 89))	('myopathy', 'Disease', (81, 89))	('myopathy', 'Disease', 'MESH:D009135', (180, 188))	('patients', 'Species', '9606', (43, 51))	('Anti-SRP antibodies', 'Protein', (0, 19))	('inflammatory myopathy', 'Phenotype', 'HP:0009071', (68, 89))	('associated with', 'Reg', (145, 160))	('myopathy', 'Disease', (180, 188))	('myopathy', 'Disease', 'MESH:D009135', (81, 89))	('myopathy', 'Phenotype', 'HP:0003198', (180, 188))	('presence', 'Var', (99, 107))	('anti-SRP', 'Var', (111, 119))
182275	23646150	The proliferation inhibition rate increased from 6.21% to 49.86%, whereas the apoptosis rate increased from 9.3% to 48.1% when HCCC-9810 cells were cultured with 50% hUC-MSC conditioned media for 24 h. Immunoblot analysis showed that the expression of phosphor-PDK1 (Ser241), phosphor-Akt (Ser 437 and Thr308), phosphorylated glycogen synthase kinase 3beta (phospho-GSK-3betaSer9), beta-catenin, cyclin-D1, and c-myc were down-regulated.	('Akt', 'Gene', (285, 288))	('beta-catenin', 'Gene', (382, 394))	('down-regulated', 'NegReg', (422, 436))	('beta-catenin', 'Gene', '1499', (382, 394))	('Akt', 'Gene', '207', (285, 288))	('Ser', 'Chemical', 'MESH:D012694', (290, 293))	('PDK1', 'Gene', (261, 265))	('Ser', 'Chemical', 'MESH:D012694', (267, 270))	('Thr308', 'Var', (302, 308))	('c-myc', 'Gene', (411, 416))	('Ser', 'Chemical', 'MESH:D012694', (375, 378))	('expression', 'MPA', (238, 248))	('cyclin-D1', 'Gene', '595', (396, 405))	('cyclin-D1', 'Gene', (396, 405))	('Ser 437', 'Var', (290, 297))	('HCCC-9810', 'CellLine', 'CVCL:6908', (127, 136))	('Thr308', 'Chemical', '-', (302, 308))	('PDK1', 'Gene', '5163', (261, 265))	('c-myc', 'Gene', '4609', (411, 416))
182276	23646150	We further demonstrated that CHIR99021, a GSK-3beta inhibitor reversed the suppressive effects of hUC-MSCs on HCCC-9810 cells and increased the expression of beta-catenin.	('GSK-3beta', 'Gene', '2932', (42, 51))	('beta-catenin', 'Gene', (158, 170))	('GSK-3beta', 'Gene', (42, 51))	('beta-catenin', 'Gene', '1499', (158, 170))	('expression', 'MPA', (144, 154))	('CHIR99021', 'Var', (29, 38))	('HCCC-9810', 'CellLine', 'CVCL:6908', (110, 119))	('increased', 'PosReg', (130, 139))
182335	23646150	Flow-cytometric analysis of cell surface antigens showed that the cells were positive for CD44, CD29, and CD105, but were negative for CD34 and CD45 (Fig.	('CD44', 'Gene', (90, 94))	('positive', 'Reg', (77, 85))	('CD34', 'Gene', (135, 139))	('CD45', 'Gene', '5788', (144, 148))	('CD29', 'Gene', '3688', (96, 100))	('CD29', 'Gene', (96, 100))	('CD105', 'Var', (106, 111))	('CD44', 'Gene', '960', (90, 94))	('CD45', 'Gene', (144, 148))	('CD34', 'Gene', '947', (135, 139))
182346	23646150	Results showed that on the 50th day after injection, the mice injected with HCCC-9810 cells and hUC-MSCs had a lower tumor incidence than the control groups, and the mean volume of tumors of the mice injected with tumor cells and MSCs was dramatically lower than that of control groups: 7 mice developed detectable tumors on day 35-40 (average tumor volume = 1.3 cm3 on day 50), and 3 mice had not developed any tumors when they were killed on day 50.	('tumors', 'Phenotype', 'HP:0002664', (412, 418))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('HCCC-9810 cells', 'Var', (76, 91))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mice', 'Species', '10090', (195, 199))	('tumors', 'Disease', (412, 418))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('mice', 'Species', '10090', (385, 389))	('tumor', 'Disease', (344, 349))	('mice', 'Species', '10090', (289, 293))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('tumor', 'Disease', 'MESH:D009369', (344, 349))	('tumors', 'Disease', (315, 321))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (412, 418))	('tumor', 'Disease', 'MESH:D009369', (412, 417))	('lower', 'NegReg', (111, 116))	('tumor', 'Disease', (214, 219))	('mice', 'Species', '10090', (57, 61))	('tumors', 'Disease', 'MESH:D009369', (315, 321))	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (412, 417))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('HCCC-9810', 'CellLine', 'CVCL:6908', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', (315, 320))	('lower', 'NegReg', (252, 257))
182347	23646150	In contrast, mice injected with HCCC-9810 only, or a mixture of HCCC-9810 and HUVEV, formed detectable tumors (average tumor volumes were 2.6 cm3 and 2.5 cm3, respectively on day 50) (P<0.01, Table 1).	('HCCC-9810', 'Var', (64, 73))	('mice', 'Species', '10090', (13, 17))	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('HCCC-9810', 'CellLine', 'CVCL:6908', (64, 73))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('HCCC-9810', 'CellLine', 'CVCL:6908', (32, 41))
182349	23646150	The mean tumor volume in the hUC-MSCs group was significantly smaller compared with that of the control.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('smaller', 'NegReg', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('hUC-MSCs', 'Var', (29, 37))
182350	23646150	The average tumor volume decreased to 1.4 cm3 in the MSCs group, whereas it continued to increase to 3.5 cm3 in the HUVEC control group by day 70 (P<0.01, Fig.	('MSCs', 'Var', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('decreased', 'NegReg', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
182355	23646150	Immunoblot analysis showed that, compared with control groups, treatment of HCCC-9810 cells with hUC-MSC conditioned media resulted in reduced phosphorylation of PI3KY458, PDK1Ser241, AktThr308, and AktSer473, while the total Akt level did not change.	('Akt', 'Gene', '207', (184, 187))	('phosphorylation', 'MPA', (143, 158))	('Akt', 'Gene', (184, 187))	('PDK1Ser241', 'Var', (172, 182))	('Akt', 'Gene', '207', (226, 229))	('reduced', 'NegReg', (135, 142))	('HCCC-9810', 'CellLine', 'CVCL:6908', (76, 85))	('Akt', 'Gene', '207', (199, 202))	('PI3KY458', 'Enzyme', (162, 170))	('Akt', 'Gene', (226, 229))	('Akt', 'Gene', (199, 202))
182376	23646150	6A, the GSK-3beta inhibitors CHIR99021 significantly rescued HCCC-9810 cells from the inhibitory effects of hUC-MSCs conditioned media (P<0.001), whereas the GSK-3beta activator SNP significantly increased the inhibitory effects of hUC-MSCs conditioned media (P<0.001).	('HCCC-9810', 'CellLine', 'CVCL:6908', (61, 70))	('CHIR99021', 'Var', (29, 38))	('GSK-3beta', 'Gene', '2932', (8, 17))	('GSK-3beta', 'Gene', (8, 17))	('inhibitory effects', 'MPA', (86, 104))	('GSK-3beta', 'Gene', '2932', (158, 167))	('GSK-3beta', 'Gene', (158, 167))
182377	23646150	Treatment with CHIR99021 increased beta-catenin protein levels in the conditioned media-treated group, while SNP treatment resulted in decreased beta-catenin protein levels (Fig.	('beta-catenin', 'Gene', (35, 47))	('increased', 'PosReg', (25, 34))	('beta-catenin', 'Gene', (145, 157))	('beta-catenin', 'Gene', '1499', (35, 47))	('CHIR99021', 'Var', (15, 24))	('beta-catenin', 'Gene', '1499', (145, 157))	('decreased', 'NegReg', (135, 144))
182393	23646150	Dysregulation of beta-catenin and other Wnt components lead to nuclear localization of beta-catenin, activation of Wnt target genes, including c-Myc, cyclin D1, cyclooxygenase-2, matrix metalloproteinase-7, gastrin, and ITF-2 and enhance tumor formation.	('nuclear localization', 'MPA', (63, 83))	('beta-catenin', 'Gene', '1499', (17, 29))	('enhance', 'PosReg', (230, 237))	('Dysregulation', 'Var', (0, 13))	('activation', 'PosReg', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('cyclooxygenase-2, matrix metalloproteinase-7', 'Gene', '5743;4316', (161, 205))	('ITF-2', 'Gene', '6925', (220, 225))	('beta-catenin', 'Gene', (87, 99))	('ITF-2', 'Gene', (220, 225))	('beta-catenin', 'Gene', '1499', (87, 99))	('gastrin', 'Gene', '2520', (207, 214))	('cyclin D1', 'Gene', (150, 159))	('c-Myc', 'Gene', (143, 148))	('cyclin D1', 'Gene', '595', (150, 159))	('tumor', 'Disease', (238, 243))	('c-Myc', 'Gene', '4609', (143, 148))	('gastrin', 'Gene', (207, 214))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('beta-catenin', 'Gene', (17, 29))
182399	23646150	It has been shown that in response to certain growth stimuli, PI3K-activated AKT can phosphorylate GSK-3beta at Ser9, leading to inactivation of GSK-3beta and augmentation of beta-catenin-TCF4 transcriptional activity.	('AKT', 'Gene', (77, 80))	('AKT', 'Gene', '207', (77, 80))	('beta-catenin', 'Gene', '1499', (175, 187))	('augmentation', 'PosReg', (159, 171))	('TCF4', 'Gene', '6925', (188, 192))	('GSK-3beta', 'Gene', '2932', (145, 154))	('GSK-3beta', 'Gene', (145, 154))	('Ser9', 'Chemical', '-', (112, 116))	('PI3K-activated', 'Var', (62, 76))	('GSK-3beta', 'Gene', (99, 108))	('inactivation', 'NegReg', (129, 141))	('beta-catenin', 'Gene', (175, 187))	('TCF4', 'Gene', (188, 192))	('GSK-3beta', 'Gene', '2932', (99, 108))
182405	23646150	We treated HCCC-9810 cells with IGF-1 in combination with hUC-MSC conditioned media, and found an increase in the expression of phosphor-Akt (Ser 437 and Thr308).	('Thr308', 'Chemical', '-', (154, 160))	('IGF-1', 'Gene', '3479', (32, 37))	('IGF-1', 'Gene', (32, 37))	('Akt', 'Gene', '207', (137, 140))	('HCCC-9810', 'CellLine', 'CVCL:6908', (11, 20))	('Ser', 'Chemical', 'MESH:D012694', (142, 145))	('increase', 'PosReg', (98, 106))	('Akt', 'Gene', (137, 140))	('expression', 'MPA', (114, 124))	('Ser 437', 'Var', (142, 149))
182475	32884228	The tumor markers Ca-19-9 is often elevated in cases of benign biliary obstruction or cholangitis, and higher levels may mislead the correct diagnosis.	('tumor', 'Disease', (4, 9))	('cholangitis', 'Disease', 'MESH:D002761', (86, 97))	('biliary obstruction', 'Phenotype', 'HP:0005230', (63, 82))	('cholangitis', 'Disease', (86, 97))	('Ca-19-9', 'Var', (18, 25))	('mislead', 'Reg', (121, 128))	('cholangitis', 'Phenotype', 'HP:0030151', (86, 97))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('benign biliary obstruction', 'Disease', 'MESH:D001657', (56, 82))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('benign biliary obstruction', 'Disease', (56, 82))	('elevated', 'PosReg', (35, 43))
182596	31943574	Expression of THBS2 was able to accurately discriminate HDs from both PDAC (AUC = 0.822), as well as HDs from dCCA (AUC = 0.906; supplemental online Fig.	('PDAC', 'Phenotype', 'HP:0006725', (70, 74))	('HDs', 'Disease', (56, 59))	('THBS2', 'Gene', (14, 19))	('Expression', 'Var', (0, 10))	('HDs', 'Disease', 'None', (56, 59))	('HDs', 'Disease', 'None', (101, 104))	('HDs', 'Disease', (101, 104))	('PDAC', 'Chemical', '-', (70, 74))	('dCCA', 'Chemical', '-', (110, 114))
182599	31943574	The combination of THBS2 and CA19-9 resulted in an enhanced AUC of 0.952 (95% CI, 0.921-0.984; p < .001; Fig.	('CA19-9', 'Var', (29, 35))	('AUC', 'MPA', (60, 63))	('CA19-9', 'Chemical', 'MESH:C086528', (29, 35))	('enhanced', 'PosReg', (51, 59))	('THBS2', 'Gene', (19, 24))
182604	31943574	The combination of the optimal cutoff of THBS2 (40.9 ng/mL) and CA19-9 (7.2 U/mL) demonstrated an AUC of 0.906 (95% CI, 0.860-0.953) and classified correctly 96/111 (86%) of the patients with PDAC or dCCA and 44/50 (88%) of the HDs.	('dCCA', 'Chemical', '-', (200, 204))	('PDAC', 'Phenotype', 'HP:0006725', (192, 196))	('HDs', 'Disease', (228, 231))	('patients', 'Species', '9606', (178, 186))	('THBS2', 'Gene', (41, 46))	('PDAC', 'Disease', (192, 196))	('PDAC', 'Chemical', '-', (192, 196))	('HDs', 'Disease', 'None', (228, 231))	('CA19-9', 'Chemical', 'MESH:C086528', (64, 70))	('dCCA', 'Disease', (200, 204))	('40.9 ng/mL', 'Var', (48, 58))
182608	31943574	The diagnostic performance of THBS2 in this cohort demonstrated an AUC of 0.614 (95% CI, 0.498-0.730; p = .055) and CA19-9 an AUC of 0.779 (95% CI, 0.695-0.862; p < .001).	('CA19-9', 'Var', (116, 122))	('THBS2', 'Gene', (30, 35))	('CA19-9', 'Chemical', 'MESH:C086528', (116, 122))
182657	24185509	We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas.	('IDH2', 'Gene', (86, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('IDH2', 'Gene', '3418', (86, 90))	('IDH1', 'Gene', (77, 81))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (140, 158))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (127, 159))	('IDH1', 'Gene', '3417', (77, 81))	('intrahepatic cholangiocarcinomas', 'Disease', (127, 159))	('mutations', 'Var', (28, 37))
182666	24185509	Somatic alterations in the KRAS, TP53, CDKN2A and SMAD4 (DPC4) genes have been reported in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('CDKN2A', 'Gene', (39, 45))	('KRAS', 'Gene', '3845', (27, 31))	('reported', 'Reg', (79, 87))	('CDKN2A', 'Gene', '1029', (39, 45))	('alterations', 'Var', (8, 19))	('SMAD4', 'Gene', (50, 55))	('TP53', 'Gene', '7157', (33, 37))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('TP53', 'Gene', (33, 37))	('DPC4', 'Gene', (57, 61))	('KRAS', 'Gene', (27, 31))	('cholangiocarcinoma', 'Disease', (91, 109))	('SMAD4', 'Gene', '4089', (50, 55))	('DPC4', 'Gene', '4089', (57, 61))
182668	24185509	Mutations in genes coding for components of the phosphatidylinositide 3-kinase (PI3K) cell signaling pathway, including PIK3CA, PTEN and AKT1, have also been reported in cholangiocarcinoma, as have mutations in previously identified hotspots in IDH1 and IDH2 (encoding isocitrate dehydrogenase 1 and 2, respectively).	('phosphatidylinositide 3-kinase', 'Gene', (48, 78))	('PIK3CA', 'Gene', '5290', (120, 126))	('cholangiocarcinoma', 'Disease', (170, 188))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (170, 188))	('IDH1', 'Gene', (245, 249))	('mutations', 'Var', (198, 207))	('Mutations', 'Var', (0, 9))	('AKT1', 'Gene', '207', (137, 141))	('PIK3CA', 'Gene', (120, 126))	('phosphatidylinositide 3-kinase', 'Gene', '5290', (48, 78))	('PTEN', 'Gene', (128, 132))	('IDH1', 'Gene', '3417', (245, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('AKT1', 'Gene', (137, 141))	('reported', 'Reg', (158, 166))	('PTEN', 'Gene', '5728', (128, 132))	('IDH2', 'Gene', (254, 258))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (170, 188))	('IDH2', 'Gene', '3418', (254, 258))
182669	24185509	Interestingly, mutations in these latter genes encoding metabolic enzymes occur frequently in tumors of the central nervous system and in leukemias but have not been identified in any other gastrointestinal malignancy studied so far.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (94, 130))	('mutations', 'Var', (15, 24))	('leukemias', 'Disease', 'MESH:D007938', (138, 147))	('tumors of the central nervous system', 'Disease', 'MESH:D016543', (94, 130))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors of the central nervous system', 'Disease', (94, 130))	('gastrointestinal malignancy', 'Disease', (190, 217))	('leukemias', 'Phenotype', 'HP:0001909', (138, 147))	('gastrointestinal malignancy', 'Disease', 'MESH:D005767', (190, 217))	('leukemias', 'Disease', (138, 147))
182672	24185509	Rare mutations in CTNNB1 (the gene encoding beta-catenin) and PIK3CA have also been reported in gallbladder carcinomas.	('bladder carcinoma', 'Phenotype', 'HP:0002862', (100, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('CTNNB1', 'Gene', '1499', (18, 24))	('PIK3CA', 'Gene', (62, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('gallbladder carcinomas', 'Disease', (96, 118))	('mutations', 'Var', (5, 14))	('beta-catenin', 'Gene', (44, 56))	('PIK3CA', 'Gene', '5290', (62, 68))	('CTNNB1', 'Gene', (18, 24))	('beta-catenin', 'Gene', '1499', (44, 56))	('reported', 'Reg', (84, 92))	('gallbladder carcinomas', 'Disease', 'MESH:D005706', (96, 118))
182682	24185509	Several chromatin-remodeling genes, including BAP1, ARID1A and PBRM1, frequently harbored inactivating mutations in the discovery screen intrahepatic cholangiocarcinomas (Table 1).	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (159, 169))	('BAP1', 'Gene', '8314', (46, 50))	('inactivating mutations', 'Var', (90, 112))	('ARID1A', 'Gene', '8289', (52, 58))	('intrahepatic cholangiocarcinomas', 'Disease', (137, 169))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (150, 168))	('ARID1A', 'Gene', (52, 58))	('PBRM1', 'Gene', (63, 68))	('chromatin-remodeling genes', 'Gene', (8, 34))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (137, 169))	('PBRM1', 'Gene', '55193', (63, 68))	('BAP1', 'Gene', (46, 50))
182683	24185509	Somatic mutations in BAP1, which encodes a nuclear deubiquitinase involved in chromatin remodeling, occurred in 8 of 32 intrahepatic cholangiocarcinomas (25%).	('BAP1', 'Gene', (21, 25))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (133, 151))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('mutations', 'Var', (8, 17))	('intrahepatic cholangiocarcinomas', 'Disease', (120, 152))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (120, 152))	('occurred', 'Reg', (100, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('BAP1', 'Gene', '8314', (21, 25))
182685	24185509	We also identified somatic ARID1A mutations in 6 of 32 intrahepatic cholangiocarcinomas (19%).	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (55, 87))	('ARID1A', 'Gene', '8289', (27, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('ARID1A', 'Gene', (27, 33))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (68, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('mutations', 'Var', (34, 43))	('intrahepatic cholangiocarcinomas', 'Disease', (55, 87))
182686	24185509	ARID1A encodes a subunit of the SWI/SNF chromatin-remodeling complexes, and mutations in ARID1A have been reported in several tumor types, including ovarian, colorectal and gastric carcinomas, although they have not been reported in cholangiocarcinomas.	('colorectal and gastric carcinomas', 'Disease', 'MESH:D013274', (158, 191))	('ARID1A', 'Gene', '8289', (89, 95))	('mutations', 'Var', (76, 85))	('ARID1A', 'Gene', (89, 95))	('reported', 'Reg', (106, 114))	('ARID1A', 'Gene', '8289', (0, 6))	('ovarian', 'Disease', (149, 156))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (233, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('ARID1A', 'Gene', (0, 6))	('carcinomas', 'Phenotype', 'HP:0030731', (242, 252))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (233, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('cholangiocarcinomas', 'Disease', (233, 252))	('tumor', 'Disease', (126, 131))
182687	24185509	Somatic PBRM1 mutations were identified in 5 of 32 intrahepatic cholangiocarcinomas (17%).	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (51, 83))	('intrahepatic cholangiocarcinomas', 'Disease', (51, 83))	('PBRM1', 'Gene', '55193', (8, 13))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('identified', 'Reg', (29, 39))	('mutations', 'Var', (14, 23))	('PBRM1', 'Gene', (8, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
182688	24185509	As with ARID1A, PBRM1 encodes a subunit of the ATP-dependent SWI/SNF chromatin-remodeling complexes, and mutations in PBRM1 have previously been reported in approximately 40% of clear-cell renal cell carcinomas but have not yet been described in biliary cancers.	('ATP', 'Chemical', 'MESH:D000255', (47, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('carcinomas', 'Phenotype', 'HP:0030731', (200, 210))	('biliary cancers', 'Disease', (246, 261))	('mutations', 'Var', (105, 114))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (189, 210))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('PBRM1', 'Gene', '55193', (16, 21))	('clear-cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (178, 210))	('reported', 'Reg', (145, 153))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('clear-cell renal cell carcinomas', 'Disease', 'MESH:C538614', (178, 210))	('ARID1A', 'Gene', (8, 14))	('PBRM1', 'Gene', (16, 21))	('PBRM1', 'Gene', '55193', (118, 123))	('ARID1A', 'Gene', '8289', (8, 14))	('clear-cell renal cell carcinomas', 'Disease', (178, 210))	('PBRM1', 'Gene', (118, 123))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (189, 209))	('biliary cancers', 'Disease', 'MESH:D001661', (246, 261))
182691	24185509	However, these mutations were not mutually exclusive: three tumors contained mutations in multiple chromatin-remodeling genes, suggesting a lack of overlap in function and an additive effect in epigenetic changes in the cancer cell.	('contained', 'Reg', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('chromatin-remodeling genes', 'Gene', (99, 125))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', (220, 226))	('tumors', 'Disease', (60, 66))
182692	24185509	When considered together, subjects with a mutation in any one of the three chromatin-remodeling genes (BAP1, ARID1A or PBRM1) trended toward worse survival compared to subjects in whom all three genes were wild type (3-year survival of 47.1% for subjects with mutations compared to 93.3% for subjects without mutations), but these results were not statistically significant (P = 0.1672 by log-rank test).	('BAP1', 'Gene', '8314', (103, 107))	('PBRM1', 'Gene', (119, 124))	('BAP1', 'Gene', (103, 107))	('worse', 'NegReg', (141, 146))	('PBRM1', 'Gene', '55193', (119, 124))	('mutation', 'Var', (42, 50))	('survival', 'MPA', (147, 155))	('ARID1A', 'Gene', '8289', (109, 115))	('ARID1A', 'Gene', (109, 115))
182693	24185509	Notably, these mutations may identify additional therapies for cholangiocarcinomas, as the mutations may cause sensitivity to drugs targeting chromatin remodeling, such as histone deacetylase (HDAC) inhibitors, which are already in use or being developed for individuals with cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('cause', 'Reg', (105, 110))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('mutations', 'Var', (15, 24))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (63, 82))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('sensitivity', 'MPA', (111, 122))	('mutations', 'Var', (91, 100))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (63, 81))	('cholangiocarcinomas', 'Disease', (63, 82))
182695	24185509	In addition to identifying inactivating mutations in chromatin-remodeling genes, we also confirmed many of the previous genetic observations in this tumor type.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('inactivating mutations', 'Var', (27, 49))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('chromatin-remodeling', 'Gene', (53, 73))
182696	24185509	We found somatic mutations in IDH1 in four tumors and in IDH2 in two tumors (19% of the intrahepatic cholangiocarcinomas in total), and these mutations clustered in previously identified hotspots (codons 132 and 172, respectively).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('IDH2', 'Gene', (57, 61))	('intrahepatic cholangiocarcinomas', 'Disease', (88, 120))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (88, 120))	('IDH1', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (69, 75))	('IDH2', 'Gene', '3418', (57, 61))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('mutations', 'Var', (17, 26))	('IDH1', 'Gene', '3417', (30, 34))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
182697	24185509	The clustering of somatic alterations in mutational hotspots has important implications for early detection: detection of these hotspot IDH gene mutations in plasma could be employed as a screening strategy for populations at high risk.	('mutations', 'Var', (145, 154))	('IDH', 'Gene', (136, 139))	('IDH', 'Gene', '3417', (136, 139))
182698	24185509	The mutational status of IDH genes was noted to be significantly associated with prognosis:subjects with IDH1 or IDH2 mutations had 3-year survival of 33% compared with 3-year survival of 81% for subjects with wild-type IDH genes (P = 0.0034) (Supplementary Fig.	('IDH', 'Gene', '3417', (113, 116))	('IDH', 'Gene', (220, 223))	('IDH', 'Gene', (25, 28))	('IDH2', 'Gene', (113, 117))	('IDH', 'Gene', '3417', (25, 28))	('IDH1', 'Gene', (105, 109))	('IDH', 'Gene', '3417', (220, 223))	('mutations', 'Var', (118, 127))	('IDH2', 'Gene', '3418', (113, 117))	('IDH1', 'Gene', '3417', (105, 109))	('IDH', 'Gene', (105, 108))	('IDH', 'Gene', (113, 116))	('IDH', 'Gene', '3417', (105, 108))
182699	24185509	Although subjects with IDH gene mutations were somewhat older and had higher tumor stage (both non-significant; Supplementary Table 5), worse survival persisted, even after adjusting for stage, age and sex using a Cox proportional hazards model (hazards ratio (HR) = 7.37, 95% confidence interval (CI) = 1.13-48.29, P = 0.037).	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('higher', 'PosReg', (70, 76))	('IDH', 'Gene', (23, 26))	('tumor', 'Disease', (77, 82))	('IDH', 'Gene', '3417', (23, 26))
182700	24185509	This effect on survival is opposite to the one previously reported for IDH gene mutations in cholangiocarcinoma.	('mutations', 'Var', (80, 89))	('cholangiocarcinoma', 'Disease', (93, 111))	('IDH', 'Gene', (71, 74))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('IDH', 'Gene', '3417', (71, 74))
182701	24185509	As our sample size was much smaller than that used in the previous study that showed improved survival for cholangiocarcinomas with IDH gene mutation, this discrepancy should be assessed using another independent sample of individuals with intrahepatic cholangiocarcinoma.	('improved', 'PosReg', (85, 93))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (253, 271))	('cholangiocarcinomas', 'Disease', (107, 126))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (240, 271))	('IDH', 'Gene', (132, 135))	('intrahepatic cholangiocarcinoma', 'Disease', (240, 271))	('IDH', 'Gene', '3417', (132, 135))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (107, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (107, 125))	('mutation', 'Var', (141, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))
182705	24185509	Moreover, FGFR2 gene fusions were recently reported in cholangiocarcinoma, further highlighting the possible importance of this gene in biliary tumorigenesis.	('tumor', 'Disease', (144, 149))	('FGFR2', 'Gene', '2263', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cholangiocarcinoma', 'Disease', (55, 73))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (55, 73))	('fusions', 'Var', (21, 28))	('reported', 'Reg', (43, 51))	('FGFR2', 'Gene', (10, 15))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (55, 73))
182706	24185509	Notably, these FGFR2 alterations represent possible therapeutic targets, with multiple FGFR inhibitors currently in clinical trials.	('FGFR2', 'Gene', '2263', (15, 20))	('clinical', 'Species', '191496', (116, 124))	('alterations', 'Var', (21, 32))	('FGFR2', 'Gene', (15, 20))
182707	24185509	Mutations were also identified in several other well-known cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (20, 30))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
182708	24185509	Somatic mutations were identified in several components of the PI3K pathway, including two mutations in PIK3CA, two mutations in PTEN, two mutations in PIK3C2G and one mutation in PIK3C2A (22% of cholangiocarcinomas in total).	('PIK3C2A', 'Gene', '5286', (180, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('PTEN', 'Gene', (129, 133))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (196, 215))	('PIK3CA', 'Gene', (104, 110))	('PIK3C2G', 'Gene', (152, 159))	('mutations', 'Var', (91, 100))	('PTEN', 'Gene', '5728', (129, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (205, 215))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (196, 214))	('PI3K pathway', 'Pathway', (63, 75))	('cholangiocarcinomas', 'Disease', (196, 215))	('PIK3CA', 'Gene', '5290', (104, 110))	('PIK3C2A', 'Gene', (180, 187))	('PIK3C2G', 'Gene', '5288', (152, 159))
182711	24185509	No mutations in SMAD4 (DPC4) were identified in intrahepatic cholangiocarcinomas, although a single tumor harbored a mutation in TGFBR2.	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (48, 80))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('intrahepatic cholangiocarcinomas', 'Disease', (48, 80))	('SMAD4', 'Gene', (16, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('tumor', 'Disease', (100, 105))	('TGFBR2', 'Gene', '7048', (129, 135))	('SMAD4', 'Gene', '4089', (16, 21))	('DPC4', 'Gene', (23, 27))	('mutation', 'Var', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('DPC4', 'Gene', '4089', (23, 27))	('TGFBR2', 'Gene', (129, 135))
182712	24185509	To objectively analyze the significance of the mutations identified in the 32 intrahepatic cholangiocarcinomas in the discovery screen, we calculated a combined P value for the mutations in each gene based on three distinct measures of mutation significance: the count of single-base substitutions, the count of insertion-deletion mutations and the relative count of nonsynonymous single-base substitutions.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('intrahepatic cholangiocarcinomas', 'Disease', (78, 110))	('single-base substitutions', 'Var', (272, 297))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (78, 110))	('insertion-deletion mutations', 'Var', (312, 340))
182716	24185509	As was observed in the discovery screen, multiple mutations were identified in chromatin-remodeling genes: BAP1 was mutated in 5 of 32 cholangiocarcinomas (16%), ARID1A was mutated in 3 of 32 cholangiocarcinomas (9%), and PBRM1 was mutated in 3 of 32 cholangiocarcinomas (9%) (Table 1 and Supplementary Table 7a).	('cholangiocarcinomas', 'Disease', (135, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (201, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('ARID1A', 'Gene', (162, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('PBRM1', 'Gene', '55193', (222, 227))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (251, 270))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (192, 210))	('ARID1A', 'Gene', '8289', (162, 168))	('cholangiocarcinomas', 'Disease', (251, 270))	('mutated', 'Var', (116, 123))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (135, 153))	('BAP1', 'Gene', '8314', (107, 111))	('PBRM1', 'Gene', (222, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('carcinomas', 'Phenotype', 'HP:0030731', (260, 270))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (192, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('BAP1', 'Gene', (107, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (251, 269))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (135, 154))	('cholangiocarcinomas', 'Disease', (192, 211))
182717	24185509	In the prevalence screen, mutations in these genes were mutually exclusive, and mutation in one of these genes occurred in 11 of 32 cholangiocarcinomas (34%).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (132, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('occurred', 'Reg', (111, 119))	('cholangiocarcinomas', 'Disease', (132, 151))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (132, 151))	('mutation', 'Var', (80, 88))
182718	24185509	Combining the discovery and prevalence screens, BAP1 was mutated in 13 of 64 tumors (20%), ARID1A was mutated in 9 of 64 tumors (14%), and PBRM1 was mutated in 8 of 64 tumors (13%), adding up to 26 cholangiocarcinomas with mutations in chromatin-remodeling genes out of 64 total cholangiocarcinomas (41%).	('cholangiocarcinomas', 'Disease', (279, 298))	('BAP1', 'Gene', '8314', (48, 52))	('ARID1A', 'Gene', (91, 97))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('carcinomas', 'Phenotype', 'HP:0030731', (288, 298))	('mutations', 'Var', (223, 232))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (198, 217))	('ARID1A', 'Gene', '8289', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('BAP1', 'Gene', (48, 52))	('cholangiocarcinomas', 'Disease', (198, 217))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('carcinomas', 'Phenotype', 'HP:0030731', (207, 217))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (279, 297))	('tumors', 'Disease', (77, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (198, 216))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('PBRM1', 'Gene', '55193', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (279, 298))	('mutated', 'Var', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('PBRM1', 'Gene', (139, 144))
182719	24185509	Frequent mutations in IDH1 and IDH2 hotspots were also identified in this prevalence screen, as mutations in these genes were identified in 7 of 32 cholangiocarcinomas (22%; overall prevalence of 20% when both the discovery and prevalence screens were combined).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (148, 166))	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('IDH2', 'Gene', '3418', (31, 35))	('cholangiocarcinomas', 'Disease', (148, 167))	('IDH1', 'Gene', (22, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('IDH1', 'Gene', '3417', (22, 26))	('identified', 'Reg', (126, 136))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (148, 167))	('IDH2', 'Gene', (31, 35))	('mutations', 'Var', (96, 105))
182720	24185509	The prevalence screen identified additional mutations in KRAS, NRAS and components of the PI3K pathway (PIK3CA and PI3KC2G), confirming the key role of RAS and PI3K signaling in this tumor type.	('NRAS', 'Gene', '4893', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('PI3K pathway', 'Pathway', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('KRAS', 'Gene', (57, 61))	('PIK3CA', 'Gene', (104, 110))	('mutations', 'Var', (44, 53))	('tumor', 'Disease', (183, 188))	('KRAS', 'Gene', '3845', (57, 61))	('NRAS', 'Gene', (63, 67))	('PIK3CA', 'Gene', '5290', (104, 110))
182721	24185509	Overall, these data on somatic mutations in intrahepatic cholangiocarcinomas highlight the genetic heterogeneity of the disease.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('mutations', 'Var', (31, 40))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('intrahepatic cholangiocarcinomas', 'Disease', (44, 76))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (44, 76))
182731	24185509	Intriguingly, we identified not only two additional mutations in PBRM1 (25%) but also one mutation each in BAP1 (13%) and ARID1A (13%) (Supplementary Table 7b).	('mutations', 'Var', (52, 61))	('ARID1A', 'Gene', '8289', (122, 128))	('BAP1', 'Gene', '8314', (107, 111))	('ARID1A', 'Gene', (122, 128))	('BAP1', 'Gene', (107, 111))	('PBRM1', 'Gene', (65, 70))	('PBRM1', 'Gene', '55193', (65, 70))
182732	24185509	When both the discovery and prevalence screens were combined, the overall mutation prevalence in gallbladder carcinoma for BAP1, ARID1A and PBRM1 was 6%, 6% and 25%, respectively.	('BAP1', 'Gene', (123, 127))	('mutation', 'Var', (74, 82))	('ARID1A', 'Gene', '8289', (129, 135))	('ARID1A', 'Gene', (129, 135))	('PBRM1', 'Gene', (140, 145))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (101, 118))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (97, 118))	('PBRM1', 'Gene', '55193', (140, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('BAP1', 'Gene', '8314', (123, 127))	('gallbladder carcinoma', 'Disease', (97, 118))
182734	24185509	In addition, the prevalence screen confirmed the key role of TP53 mutations in gallbladder carcinoma, with mutations identified in two of eight tumors (25%; overall prevalence of 44% when both the discovery and prevalence screens were combined).	('tumors', 'Disease', (144, 150))	('mutations', 'Var', (66, 75))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (83, 100))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (79, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('gallbladder carcinoma', 'Disease', (79, 100))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
182737	24185509	These data highlight the key role of mutations in chromatin-remodeling genes in cholangiocarcinoma: frequent inactivating mutations occur in three different genes, affecting almost half of the tumors sequenced.	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('inactivating', 'NegReg', (109, 121))	('tumors', 'Disease', (193, 199))	('cholangiocarcinoma', 'Disease', (80, 98))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (80, 98))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (80, 98))
182746	24185509	For A-tailing, 42 mul of end-repaired DNA was mixed with 5 mul of 10x dA Tailing Reaction Buffer and 3 mul of Klenow (exo-, E6053, NEB).	('E6053', 'Var', (124, 129))	('NEB', 'Gene', (131, 134))	('mix', 'Gene', (46, 49))	('NEB', 'Gene', '4703', (131, 134))	('mix', 'Gene', '83881', (46, 49))
182748	24185509	Purified DNA was eluted with 25 mul of elution buffer warmed to 70  C. For adaptor ligation, 25 mul of A-tailed DNA was mixed with 10 mul of PE adaptor (Illumina), 10 mul of 5x Ligation buffer and 5 mul of Quick T4 DNA ligase (E6056, NEB).	('NEB', 'Gene', '4703', (234, 237))	('mix', 'Gene', '83881', (120, 123))	('mix', 'Gene', (120, 123))	('NEB', 'Gene', (234, 237))	('E6056', 'Var', (227, 232))
182769	24185509	Cox proportional hazards regression was used to adjust for confounding by subject and tumor characteristics in the analysis of IDH gene mutations.	('IDH', 'Gene', '3417', (127, 130))	('IDH', 'Gene', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('mutations', 'Var', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
182772	24185509	Subsequently, we identified the dinucleotide context for all single-base substitution (SBS) somatic mutations identified in each sample cohort and derived the counts of mutations in each context over all coding sequence (protein-coding sequence) (ni).	('single-base substitution', 'Var', (61, 85))	('dinucleotide', 'Chemical', 'MESH:D015226', (32, 44))	('SBS', 'Disease', 'MESH:C536611', (87, 90))	('SBS', 'Disease', (87, 90))
182774	24185509	To capture the impact of mutations on protein, we applied an extension of the tests above that examines enrichment for nonsynonymous mutations in the set of SBS mutations identified in a gene of interest.	('SBS', 'Disease', (157, 160))	('mutations', 'Var', (161, 170))	('SBS', 'Disease', 'MESH:C536611', (157, 160))
182838	18615198	In general, cholangiocarcinoma development is based possibly upon the cytotoxicity of bile constituents, that is, cytotoxic bile acids and lysolecithins.	('cytotoxic', 'Var', (114, 123))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (12, 30))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (12, 30))	('cytotoxicity', 'Disease', 'MESH:D064420', (70, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('lysolecithins', 'Chemical', 'MESH:D008244', (139, 152))	('bile acids', 'Chemical', 'MESH:D001647', (124, 134))	('cholangiocarcinoma', 'Disease', (12, 30))	('cytotoxicity', 'Disease', (70, 82))
182852	18615198	Other lipid-related proteins, such as lipoprotein lipase (LPL) and fatty acid binding proteins (FABPs), are positively regulated by the PPARgamma ligand GW1929.	('LPL', 'Gene', (58, 61))	('lipoprotein lipase', 'Gene', (38, 56))	('fatty acid binding protein', 'Gene', '2806', (67, 93))	('positively', 'PosReg', (108, 118))	('lipid', 'Chemical', 'MESH:D008055', (6, 11))	('PPARgamma', 'Gene', (136, 145))	('fatty acid binding protein', 'Gene', (67, 93))	('lipoprotein lipase', 'Gene', '4023', (38, 56))	('PPARgamma', 'Gene', '5468', (136, 145))	('regulated', 'Reg', (119, 128))	('LPL', 'Gene', '4023', (58, 61))	('GW1929', 'Var', (153, 159))
182862	18615198	Moreover, it was reported that patients receiving pioglitazone may develop serious liver injury and should be monitored for evidence of hepatitis.	('liver injury', 'Disease', 'MESH:D056486', (83, 95))	('liver injury', 'Disease', (83, 95))	('pioglitazone', 'Chemical', 'MESH:D000077205', (50, 62))	('hepatitis', 'Disease', 'MESH:D056486', (136, 145))	('pioglitazone', 'Var', (50, 62))	('patients', 'Species', '9606', (31, 39))	('develop', 'PosReg', (67, 74))	('hepatitis', 'Phenotype', 'HP:0012115', (136, 145))	('hepatitis', 'Disease', (136, 145))
182870	33562094	However, a comprehensive analysis of tumour cells using The Cancer Genome Atlas (TCGA) project has led to the identification of various driver mutations.	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', (60, 66))	('tumour', 'Disease', (37, 43))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('mutations', 'Var', (143, 152))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
182871	33562094	Such basket trials not only focus on the gate keeper-type oncogene mutations, such as HER2 and BRAF, but also focus on the caretaker-type tumour suppressor genes, such as BRCA1/2, mismatch repair-related genes, which cause hereditary cancer syndrome.	('HER2', 'Gene', (86, 90))	('BRCA1/2', 'Gene', '672;675', (171, 178))	('hereditary cancer syndrome', 'Disease', 'MESH:D061325', (223, 249))	('HER2', 'Gene', '2064', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('hereditary cancer syndrome', 'Disease', (223, 249))	('BRAF', 'Gene', '673', (95, 99))	('cause', 'Reg', (217, 222))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (67, 76))	('BRAF', 'Gene', (95, 99))	('BRCA1/2', 'Gene', (171, 178))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('tumour', 'Disease', (138, 144))
182883	33562094	The cancer panel test introduced in clinical practice has led to the identification of druggable mutations in approximately 10% of the pancreatic cancers and 40% of the biliary tract cancers.	('mutations', 'Var', (97, 106))	('cancer', 'Disease', (146, 152))	('pancreatic cancers', 'Disease', (135, 153))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('biliary tract cancers', 'Disease', 'MESH:D001661', (169, 190))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('pancreatic cancers', 'Disease', 'MESH:D010190', (135, 153))	('cancer', 'Disease', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (135, 152))	('biliary tract cancers', 'Disease', (169, 190))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (169, 189))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (135, 153))	('cancer', 'Disease', (4, 10))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
182886	33562094	A considerable number of the gene mutations reported in pancreatic cancer are attributed to KRAS, tumour protein p53 (TP53), SMAD4, and cyclin-dependent kinase inhibitor 2A (CDKN2A), and KRAS mutations account for approximately 90% of the pancreatic cancers.	('KRAS', 'Gene', (187, 191))	('pancreatic cancer', 'Disease', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('KRAS', 'Gene', (92, 96))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (136, 172))	('pancreatic cancers', 'Disease', (239, 257))	('TP53', 'Gene', (118, 122))	('p53', 'Gene', (113, 116))	('SMAD4', 'Gene', (125, 130))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (239, 256))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (136, 172))	('pancreatic cancers', 'Disease', 'MESH:D010190', (239, 257))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (56, 73))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (239, 257))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('CDKN2A', 'Gene', (174, 180))	('tumour', 'Disease', (98, 104))	('SMAD4', 'Gene', '4089', (125, 130))	('TP53', 'Gene', '7157', (118, 122))	('pancreatic cancer', 'Disease', 'MESH:D010190', (239, 256))	('cancers', 'Phenotype', 'HP:0002664', (250, 257))	('KRAS', 'Gene', '3845', (187, 191))	('pancreatic cancer', 'Disease', 'MESH:D010190', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('CDKN2A', 'Gene', '1029', (174, 180))	('p53', 'Gene', '7157', (113, 116))	('KRAS', 'Gene', '3845', (92, 96))	('mutations', 'Var', (34, 43))
182887	33562094	The results of all exon analyses and single-nucleotide polymorphism (SNP) arrays using samples obtained from 24 pancreatic cancer patient indicate that pancreatic cancer exhibits an average of 63 genetic changes, most of which are point mutations and such gene mutations are concentrated in 12 cellular signalling pathways.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('point mutations', 'Var', (231, 246))	('patient', 'Species', '9606', (130, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('pancreatic cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('pancreatic cancer', 'Disease', 'MESH:D010190', (152, 169))	('pancreatic cancer', 'Disease', (112, 129))	('pancreatic cancer', 'Disease', 'MESH:D010190', (112, 129))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (152, 169))
182888	33562094	performed copy number variation (CNV) analysis using exome sequences and arrays of 142 cases of early pancreatic cancer and reported gene mutations in the molecules of the Axon Guidance signal during the embryonic period in addition to the abovementioned 12 cellular signals (slit guidance ligand 2 (SLIT2), roundabout homolog 2 (ROBO2) gene mutation, ROBO1 and SLIT2 copy number decrease, semaphorin 3A (SEMA3A), and plexin-A2 (PLXNA2) copy number increase).	('ROBO1', 'Gene', (352, 357))	('PLXNA2', 'Gene', (429, 435))	('decrease', 'NegReg', (380, 388))	('semaphorin 3A', 'Gene', (390, 403))	('SEMA3A', 'Gene', '10371', (405, 411))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('ROBO1', 'Gene', '6091', (352, 357))	('SLIT2', 'Gene', (300, 305))	('copy', 'MPA', (437, 441))	('increase', 'PosReg', (449, 457))	('ROBO2', 'Gene', '6092', (330, 335))	('plexin-A2', 'Gene', '5362', (418, 427))	('SEMA3A', 'Gene', (405, 411))	('mutation', 'Var', (342, 350))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('SLIT2', 'Gene', '9353', (300, 305))	('SLIT2', 'Gene', (362, 367))	('semaphorin 3A', 'Gene', '10371', (390, 403))	('mutations', 'Var', (138, 147))	('ROBO2', 'Gene', (330, 335))	('roundabout homolog 2', 'Gene', '6092', (308, 328))	('PLXNA2', 'Gene', '5362', (429, 435))	('plexin-A2', 'Gene', (418, 427))	('roundabout homolog 2', 'Gene', (308, 328))	('copy number', 'Var', (368, 379))	('SLIT2', 'Gene', '9353', (362, 367))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
182892	33562094	Furthermore, it was reported that cases with abnormalities in these genes were sensitive to platinum-based drugs.	('abnormalities', 'Var', (45, 58))	('sensitive', 'Reg', (79, 88))	('platinum', 'Chemical', 'MESH:D010984', (92, 100))
182894	33562094	They reported that abnormalities in genes of the RAS pathway other than KRAS were observed in approximately 60% of the KRAS wild-type pancreatic cancers.	('KRAS', 'Gene', (72, 76))	('KRAS', 'Gene', '3845', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('abnormalities', 'Var', (19, 32))	('pancreatic cancers', 'Disease', (134, 152))	('pancreatic cancers', 'Disease', 'MESH:D010190', (134, 152))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (134, 151))	('KRAS', 'Gene', (119, 123))	('KRAS', 'Gene', '3845', (119, 123))	('RAS pathway', 'Pathway', (49, 60))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (134, 152))
182896	33562094	Based on the abovementioned findings, it can be implied that pancreatic cancer is dominated by KRAS mutations or RAS pathway genes, but other gene mutations have also been observed that may be targeted for treatment.	('KRAS', 'Gene', '3845', (95, 99))	('mutations', 'Var', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('RAS pathway', 'Pathway', (113, 124))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('KRAS', 'Gene', (95, 99))	('pancreatic cancer', 'Disease', 'MESH:D010190', (61, 78))	('pancreatic cancer', 'Disease', (61, 78))
182898	33562094	Based on the results of comprehensive genetic analysis of biliary tract cancer, the mutant genes of biliary tract cancer constitute a heterogeneous population consisting of common genetic abnormalities and unique genetic abnormalities in gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (258, 289))	('intrahepatic cholangiocarcinoma', 'Disease', (258, 289))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (58, 78))	('gallbladder cancer', 'Disease', 'MESH:D005706', (238, 256))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('biliary tract cancer', 'Disease', 'MESH:D001661', (58, 78))	('biliary tract cancer', 'Disease', (100, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (317, 326))	('genetic abnormalities', 'Disease', 'MESH:D030342', (213, 234))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('extrahepatic cholangiocarcinoma', 'Disease', (295, 326))	('genetic abnormalities', 'Disease', 'MESH:D030342', (180, 201))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (271, 289))	('mutant genes', 'Var', (84, 96))	('genetic abnormalities', 'Disease', (180, 201))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (100, 120))	('gallbladder cancer', 'Disease', (238, 256))	('unique genetic abnormalities', 'Disease', 'MESH:D030342', (206, 234))	('biliary tract cancer', 'Disease', 'MESH:D001661', (100, 120))	('biliary tract cancer', 'Disease', (58, 78))	('unique genetic abnormalities', 'Disease', (206, 234))	('abnormalities in gallbladder', 'Phenotype', 'HP:0005264', (221, 249))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (295, 326))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (308, 326))	('bladder cancer', 'Phenotype', 'HP:0009725', (242, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))
182899	33562094	performed a paired analysis with normal specimens of 57 cases of gallbladder cancer and found that gene mutations such as TP53 (47.1%), KRAS (7.8%), and ERBB3 (11.8%) were frequently observed, and patients with ERBB pathway mutations, which comprised 36.8% of the cohort, had a worse outcome.	('ERBB', 'Gene', (153, 157))	('TP53', 'Gene', (122, 126))	('mutations', 'Var', (104, 113))	('patients', 'Species', '9606', (197, 205))	('gallbladder cancer', 'Disease', (65, 83))	('ERBB', 'Gene', (211, 215))	('gallbladder cancer', 'Disease', 'MESH:D005706', (65, 83))	('bladder cancer', 'Phenotype', 'HP:0009725', (69, 83))	('ERBB', 'Gene', '1956', (211, 215))	('KRAS', 'Gene', (136, 140))	('ERBB', 'Gene', '1956', (153, 157))	('ERBB3', 'Gene', (153, 158))	('ERBB3', 'Gene', '2065', (153, 158))	('mutations', 'Var', (224, 233))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('TP53', 'Gene', '7157', (122, 126))	('KRAS', 'Gene', '3845', (136, 140))
182902	33562094	Structural abnormalities in AT-rich interaction domain 1A (ARID1A; 36%), isocitrate dehydrogenase 1/2 (IDH1/2; 36%), TP53 (36%), and induced myeloid leukaemia cell differentiation protein (MCL1; 21%) were observed frequently, and fusion genes of FGFR2 and neurotrophic tyrosine kinase (NTRK) were also reported.	('Structural abnormalities', 'Disease', (0, 24))	('TP53', 'Gene', (117, 121))	('tyrosine kinase', 'Gene', '7294', (269, 284))	('MCL1', 'Gene', '4170', (189, 193))	('ARID1A', 'Gene', (59, 65))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (141, 158))	('ARID1A', 'Gene', '8289', (59, 65))	('myeloid leukaemia', 'Disease', (141, 158))	('Structural abnormalities', 'Disease', 'MESH:C566527', (0, 24))	('isocitrate dehydrogenase', 'Gene', '3417', (73, 97))	('myeloid leukaemia', 'Disease', 'MESH:C580075', (141, 158))	('TP53', 'Gene', '7157', (117, 121))	('FGFR2', 'Gene', (246, 251))	('AT-rich interaction domain 1A', 'Gene', (28, 57))	('IDH1/2', 'Gene', '3417;3418', (103, 109))	('fusion', 'Var', (230, 236))	('AT-rich interaction domain 1A', 'Gene', '8289', (28, 57))	('FGFR2', 'Gene', '2263', (246, 251))	('MCL1', 'Gene', (189, 193))	('tyrosine kinase', 'Gene', (269, 284))	('IDH1/2', 'Gene', (103, 109))	('isocitrate dehydrogenase', 'Gene', (73, 97))
182904	33562094	Compared to the intrahepatic cholangiocarcinoma cases, gallbladder cancer and extrahepatic cholangiocarcinoma cases exhibit a higher frequency of gene mutations and an apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signature.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 109))	('gallbladder cancer', 'Disease', (55, 73))	('gallbladder cancer', 'Disease', 'MESH:D005706', (55, 73))	('gene mutations', 'Var', (146, 160))	('bladder cancer', 'Phenotype', 'HP:0009725', (59, 73))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('APOBEC', 'Gene', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (16, 47))	('extrahepatic cholangiocarcinoma', 'Disease', (78, 109))	('intrahepatic cholangiocarcinoma', 'Disease', (16, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (29, 47))	('apolipoprotein B mRNA editing', 'Protein', (168, 197))
182905	33562094	Significant mutations occurred in 32 genes, including KRAS, PIK3CA, IDH1, NRAS, guanine nucleotide binding protein, alpha stimulating activity polypeptide (GNAS), and ERBB2.	('ERBB2', 'Gene', (167, 172))	('PIK3CA', 'Gene', (60, 66))	('ERBB2', 'Gene', '2064', (167, 172))	('mutations', 'Var', (12, 21))	('PIK3CA', 'Gene', '5290', (60, 66))	('NRAS', 'Gene', (74, 78))	('guanine', 'MPA', (80, 87))	('IDH1', 'Gene', (68, 72))	('GNAS', 'Gene', '2778', (156, 160))	('KRAS', 'Gene', (54, 58))	('occurred', 'Reg', (22, 30))	('NRAS', 'Gene', '4893', (74, 78))	('KRAS', 'Gene', '3845', (54, 58))	('IDH1', 'Gene', '3417', (68, 72))	('GNAS', 'Gene', (156, 160))
182907	33562094	Site-specific gene abnormalities of EGFR, ERBB3, phosphatase, and tensin homolog (PTEN), ARID2, mixed-lineage leukaemia protein 2 (MLL2), MLL3, telomerase reverse transcriptase (TERT) promoter mutations were found in gallbladder cancer, PRKACA or PRKACB fusion, ELF3, ARID1B in extrahepatic bile duct cancer, and FGFR2 fusion, IDH1/2, EPHA2, and BRCA1 associated protein-1 (BAP1) in intrahepatic bile duct cancer.	('FGFR2', 'Gene', (313, 318))	('IDH1/2', 'Gene', (327, 333))	('bile duct cancer', 'Phenotype', 'HP:0030153', (396, 412))	('ERBB3', 'Gene', (42, 47))	('PRKACA', 'Gene', (237, 243))	('extrahepatic bile duct cancer', 'Disease', 'MESH:D001650', (278, 307))	('mutations', 'Var', (193, 202))	('BRCA1 associated protein-1', 'Gene', '8314', (346, 372))	('ARID2', 'Gene', '196528', (89, 94))	('EPHA2', 'Gene', '1969', (335, 340))	('mixed-lineage leukaemia protein 2', 'Gene', '9757', (96, 129))	('gallbladder cancer', 'Disease', (217, 235))	('ELF3', 'Gene', '1999', (262, 266))	('PRKACB', 'Gene', '5567', (247, 253))	('FGFR2', 'Gene', '2263', (313, 318))	('found', 'Reg', (208, 213))	('BAP1', 'Gene', (374, 378))	('MLL3', 'Gene', '58508', (138, 142))	('EGFR', 'Gene', '1956', (36, 40))	('phosphatase, and tensin homolog', 'Gene', '5728', (49, 80))	('PTEN', 'Gene', (82, 86))	('mixed-lineage leukaemia protein 2', 'Gene', (96, 129))	('bile duct cancer', 'Phenotype', 'HP:0030153', (291, 307))	('ARID2', 'Gene', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('cancer', 'Phenotype', 'HP:0002664', (406, 412))	('MLL2', 'Gene', '9757', (131, 135))	('extrahepatic bile duct cancer', 'Phenotype', 'HP:0005242', (278, 307))	('ERBB3', 'Gene', '2065', (42, 47))	('telomerase reverse transcriptase', 'Gene', (144, 176))	('ELF3', 'Gene', (262, 266))	('fusion', 'Var', (319, 325))	('ARID1B', 'Gene', (268, 274))	('TERT', 'Gene', (178, 182))	('PRKACA', 'Gene', '5566', (237, 243))	('intrahepatic bile duct cancer', 'Disease', (383, 412))	('ARID1B', 'Gene', '57492', (268, 274))	('MLL3', 'Gene', (138, 142))	('PTEN', 'Gene', '5728', (82, 86))	('TERT', 'Gene', '7015', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('bladder cancer', 'Phenotype', 'HP:0009725', (221, 235))	('gallbladder cancer', 'Disease', 'MESH:D005706', (217, 235))	('BRCA1 associated protein-1', 'Gene', (346, 372))	('MLL2', 'Gene', (131, 135))	('EPHA2', 'Gene', (335, 340))	('intrahepatic bile duct cancer', 'Disease', 'MESH:D001650', (383, 412))	('telomerase reverse transcriptase', 'Gene', '7015', (144, 176))	('extrahepatic bile duct cancer', 'Disease', (278, 307))	('PRKACB', 'Gene', (247, 253))	('IDH1/2', 'Gene', '3417;3418', (327, 333))	('EGFR', 'Gene', (36, 40))	('BAP1', 'Gene', '8314', (374, 378))
182908	33562094	KRAS, SMAD4, ARID1A, and GNAS mutations were commonly observed in intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.	('SMAD4', 'Gene', '4089', (6, 11))	('ARID1A', 'Gene', '8289', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('ARID1A', 'Gene', (13, 19))	('observed', 'Reg', (54, 62))	('SMAD4', 'Gene', (6, 11))	('GNAS', 'Gene', (25, 29))	('intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (66, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (79, 97))	('mutations', 'Var', (30, 39))	('KRAS', 'Gene', (0, 4))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (115, 133))	('GNAS', 'Gene', '2778', (25, 29))	('KRAS', 'Gene', '3845', (0, 4))
182911	33562094	Genetic structural mutations associated with the poor prognosis include deletions of CDKN2A/B, ERBB2, TP53, KRAS, ARID1A, and deletion of 7q22.1.	('CDKN2A/B', 'Gene', (85, 93))	('KRAS', 'Gene', (108, 112))	('TP53', 'Gene', (102, 106))	('ERBB2', 'Gene', '2064', (95, 100))	('KRAS', 'Gene', '3845', (108, 112))	('ERBB2', 'Gene', (95, 100))	('2.1', 'Gene', (141, 144))	('deletion', 'Var', (126, 134))	('CDKN2A/B', 'Gene', '1029;1030', (85, 93))	('2.1', 'Gene', '6700', (141, 144))	('deletions', 'Var', (72, 81))	('ARID1A', 'Gene', (114, 120))	('TP53', 'Gene', '7157', (102, 106))	('ARID1A', 'Gene', '8289', (114, 120))
182917	33562094	It has been reported that 25% of the patients with BRCA1/2 gene germline mutations are at risk of developing pancreatic cancer, and the lifetime risk of developing pancreatic cancer in patients with BRCA1/2 gene germline mutations is estimated to be 3-8%.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('pancreatic cancer', 'Disease', (164, 181))	('pancreatic cancer', 'Disease', 'MESH:D010190', (164, 181))	('patients', 'Species', '9606', (37, 45))	('BRCA1/2', 'Gene', (51, 58))	('BRCA1/2', 'Gene', '672;675', (199, 206))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (109, 126))	('BRCA1/2', 'Gene', '672;675', (51, 58))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (164, 181))	('pancreatic cancer', 'Disease', 'MESH:D010190', (109, 126))	('patients', 'Species', '9606', (185, 193))	('pancreatic cancer', 'Disease', (109, 126))	('mutations', 'Var', (73, 82))	('BRCA1/2', 'Gene', (199, 206))
182918	33562094	Additionally, germline or somatic BRCA1/2 mutations are associated with 5-9% of the unselected cases of pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (104, 121))	('BRCA1/2', 'Gene', (34, 41))	('BRCA1/2', 'Gene', '672;675', (34, 41))	('pancreatic cancer', 'Disease', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('associated', 'Reg', (56, 66))	('pancreatic cancer', 'Disease', 'MESH:D010190', (104, 121))	('mutations', 'Var', (42, 51))
182919	33562094	Since abnormalities in the homologous recombination deficiency (HRD)-related genes are observed in pancreatic cancer, clinical trials to verify the efficacy of the poly (ADP-ribose) polymerase (PARP) inhibitors have been conducted in pancreatic cancer patients with germline mutations in BRCA1/2.	('deficiency', 'Disease', (52, 62))	('poly (ADP-ribose) polymerase', 'Gene', '142', (164, 192))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (99, 116))	('BRCA1/2', 'Gene', (288, 295))	('poly (ADP-ribose) polymerase', 'Gene', (164, 192))	('HRD', 'Disease', (64, 67))	('HRD', 'Disease', 'None', (64, 67))	('pancreatic cancer', 'Disease', 'MESH:D010190', (234, 251))	('patients', 'Species', '9606', (252, 260))	('PARP', 'Gene', '142', (194, 198))	('BRCA1/2', 'Gene', '672;675', (288, 295))	('pancreatic cancer', 'Disease', (234, 251))	('pancreatic cancer', 'Disease', 'MESH:D010190', (99, 116))	('PARP', 'Gene', (194, 198))	('germline mutations', 'Var', (266, 284))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('pancreatic cancer', 'Disease', (99, 116))	('deficiency', 'Disease', 'MESH:D007153', (52, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (234, 251))
182924	33562094	The effectiveness of PARP inhibitors for biliary tract cancer remains unclear, as fewer patients with BRCA1/2 germline mutations present with biliary tract cancer compared to those presenting with pancreatic cancer.	('biliary tract cancer', 'Phenotype', 'HP:0100574', (41, 61))	('BRCA1/2', 'Gene', '672;675', (102, 109))	('PARP', 'Gene', (21, 25))	('biliary tract cancer', 'Disease', 'MESH:D001661', (41, 61))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('pancreatic cancer', 'Disease', 'MESH:D010190', (197, 214))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (142, 162))	('fewer', 'NegReg', (82, 87))	('pancreatic cancer', 'Disease', (197, 214))	('biliary tract cancer', 'Disease', 'MESH:D001661', (142, 162))	('mutations', 'Var', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('biliary tract cancer', 'Disease', (41, 61))	('BRCA1/2', 'Gene', (102, 109))	('patients', 'Species', '9606', (88, 96))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (197, 214))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('biliary tract cancer', 'Disease', (142, 162))	('PARP', 'Gene', '142', (21, 25))
182926	33562094	also reported that HRD scores tended to increase for BRCA mutation-associated tumours compared to those for non-BRCA mutation-associated types.	('BRCA', 'Gene', (112, 116))	('BRCA', 'Gene', '672', (53, 57))	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('HRD', 'Disease', (19, 22))	('increase', 'PosReg', (40, 48))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('tumours', 'Disease', (78, 85))	('BRCA', 'Gene', (53, 57))	('BRCA', 'Gene', '672', (112, 116))	('mutation-associated', 'Var', (58, 77))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('HRD', 'Disease', 'None', (19, 22))
182929	33562094	Among the MMR genes, mutL homolog 1(MLH1), mutS homolog 2 (MSH2), MSH6, and PMS2 are reportedly involved in germline pathogenic mutations in Lynch syndrome.	('MLH1', 'Gene', '4292', (36, 40))	('MLH1', 'Gene', (36, 40))	('Lynch syndrome', 'Disease', (141, 155))	('MSH6', 'Gene', (66, 70))	('MMR', 'Gene', (10, 13))	('MSH2', 'Gene', (59, 63))	('mutations', 'Var', (128, 137))	('involved', 'Reg', (96, 104))	('mutS homolog 2', 'Gene', (43, 57))	('MSH2', 'Gene', '4436', (59, 63))	('Lynch syndrome', 'Disease', 'MESH:D003123', (141, 155))	('mutS homolog 2', 'Gene', '4436', (43, 57))	('MSH6', 'Gene', '2956', (66, 70))	('PMS2', 'Gene', (76, 80))	('PMS2', 'Gene', '5395', (76, 80))	('mutL homolog 1', 'Gene', '4292', (21, 35))	('mutL homolog 1', 'Gene', (21, 35))
182930	33562094	Additionally, since epithelial cell adhesion molecule (EPCAM) is located adjacent and upstream to MSH2 and deletion of EPCAM causes decreased expression of MSH2, deletion of the germline EPCAM leads to the development of Lynch syndrome.	('MSH2', 'Gene', '4436', (98, 102))	('EPCAM', 'Gene', '4072', (187, 192))	('EPCAM', 'Gene', (119, 124))	('Lynch syndrome', 'Disease', (221, 235))	('EPCAM', 'Gene', (55, 60))	('MSH2', 'Gene', (156, 160))	('Lynch syndrome', 'Disease', 'MESH:D003123', (221, 235))	('EPCAM', 'Gene', (187, 192))	('expression', 'MPA', (142, 152))	('EPCAM', 'Gene', '4072', (119, 124))	('deletion', 'Var', (107, 115))	('MSH2', 'Gene', '4436', (156, 160))	('deletion', 'Var', (162, 170))	('epithelial cell adhesion molecule', 'Gene', (20, 53))	('MSH2', 'Gene', (98, 102))	('EPCAM', 'Gene', '4072', (55, 60))	('epithelial cell adhesion molecule', 'Gene', '4072', (20, 53))	('leads to', 'Reg', (193, 201))	('decreased', 'NegReg', (132, 141))
182931	33562094	Furthermore, abnormalities in the functions of MMR-related genes other than those of the abovementioned genes may also result in Lynch syndrome.	('functions', 'MPA', (34, 43))	('MMR-related genes', 'Gene', (47, 64))	('result in', 'Reg', (119, 128))	('Lynch syndrome', 'Disease', (129, 143))	('Lynch syndrome', 'Disease', 'MESH:D003123', (129, 143))	('abnormalities', 'Var', (13, 26))
182932	33562094	It has been reported that the patients with germline mutations of the MMR gene demonstrate a cumulative risk of 1.31% of developing pancreatic cancer by the age of 50 years and a cumulative risk of 3.68% of developing pancreatic cancer by the age of 70 years, and the risk is estimated to be 8.6 times more that of the general population.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('MMR', 'Gene', (70, 73))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (218, 235))	('pancreatic cancer', 'Disease', (132, 149))	('germline mutations', 'Var', (44, 62))	('pancreatic cancer', 'Disease', 'MESH:D010190', (132, 149))	('patients', 'Species', '9606', (30, 38))	('pancreatic cancer', 'Disease', 'MESH:D010190', (218, 235))	('pancreatic cancer', 'Disease', (218, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (132, 149))
182933	33562094	Other reports also suggest that MMR gene germline mutations are a risk factor for pancreatic cancer development; however, mutations in the MMR genes in hereditary pancreatic cancer are relatively rare.	('hereditary pancreatic cancer', 'Disease', 'MESH:D010190', (152, 180))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (163, 180))	('hereditary pancreatic cancer', 'Disease', (152, 180))	('MMR', 'Gene', (32, 35))	('germline', 'Var', (41, 49))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (82, 99))	('MMR', 'Gene', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('pancreatic cancer', 'Disease', 'MESH:D010190', (163, 180))	('risk', 'Reg', (66, 70))	('pancreatic cancer', 'Disease', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('pancreatic cancer', 'Disease', 'MESH:D010190', (82, 99))
182943	33562094	also reported that tumours with MS-stable/high-TMB phenotypes exhibit better reactivity to PD-1 antibody than tumours with MS-stable/low or intermediate TMB phenotypes.	('TMB', 'Chemical', '-', (47, 50))	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('MS-stable/high-TMB', 'Var', (32, 50))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('better', 'PosReg', (70, 76))	('tumours', 'Phenotype', 'HP:0002664', (110, 117))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('PD-1 antibody than tumours', 'Disease', (91, 117))	('PD-1 antibody than tumours', 'Disease', 'MESH:D010300', (91, 117))	('reactivity', 'MPA', (77, 87))	('TMB', 'Chemical', '-', (153, 156))	('tumours', 'Disease', 'MESH:D009369', (110, 117))	('tumours', 'Disease', (110, 117))
182948	33562094	In a pathway basket trial, nine pancreatic cancer patients showing HER2 overexpression or gene amplification by using fluorescence in situ hybridization (FISH) were treated with the combination therapy of trastuzumab and pertuzumab, which is an HER dimerization inhibitor, and a 22.2% objective response rate was obtained.	('patients', 'Species', '9606', (50, 58))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (32, 49))	('gene amplification', 'Var', (90, 108))	('HER2', 'Gene', (67, 71))	('pertuzumab', 'Chemical', 'MESH:C485206', (221, 231))	('pancreatic cancer', 'Disease', (32, 49))	('HER2', 'Gene', '2064', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('trastuzumab', 'Chemical', 'MESH:D000068878', (205, 216))	('pancreatic cancer', 'Disease', 'MESH:D010190', (32, 49))	('overexpression', 'PosReg', (72, 86))
182949	33562094	In the same study, eight patients with biliary tract cancer overexpressing HER2 and three patients with ERBB2 structural abnormalities (D277Y, S310F, and A775-G776ins YVMA) were treated with pertuzumab plus trastuzumab, and the response rates were 37.5 and 33.3%, respectively.	('structural abnormalities', 'Disease', (110, 134))	('S310F', 'Var', (143, 148))	('biliary tract cancer', 'Disease', (39, 59))	('structural abnormalities', 'Disease', 'MESH:C566527', (110, 134))	('S310F', 'SUBSTITUTION', 'None', (143, 148))	('ERBB2', 'Gene', (104, 109))	('HER2', 'Gene', (75, 79))	('ERBB2', 'Gene', '2064', (104, 109))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (39, 59))	('biliary tract cancer', 'Disease', 'MESH:D001661', (39, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('pertuzumab plus trastuzumab', 'Disease', 'MESH:D007625', (191, 218))	('patients', 'Species', '9606', (25, 33))	('D277Y', 'Var', (136, 141))	('overexpressing', 'PosReg', (60, 74))	('patients', 'Species', '9606', (90, 98))	('D277Y', 'SUBSTITUTION', 'None', (136, 141))	('HER2', 'Gene', '2064', (75, 79))	('A775-G776ins', 'Var', (154, 166))	('pertuzumab plus trastuzumab', 'Disease', (191, 218))
182950	33562094	Furthermore, DS-8201 is currently expected to be a new anti-HER2 therapy.	('HER2', 'Gene', '2064', (60, 64))	('DS-8201', 'Var', (13, 20))	('HER2', 'Gene', (60, 64))	('DS-8201', 'Chemical', 'MESH:C000614160', (13, 20))
182955	33562094	Among these subtypes, point mutations in IDH1 and IDH2 have been reported in gliomas of grade II and III developed from low-grade glioma.	('IDH2', 'Gene', (50, 54))	('point mutations', 'Var', (22, 37))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('reported', 'Reg', (65, 73))	('gliomas', 'Disease', (77, 84))	('IDH2', 'Gene', '3418', (50, 54))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('glioma', 'Disease', (130, 136))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('glioma', 'Disease', (77, 83))	('IDH1', 'Gene', (41, 45))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('IDH1', 'Gene', '3417', (41, 45))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
182957	33562094	The point mutations recurrently observed in tumour tissue are accumulated on IDH1 R132 and IDH2 R172.	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('R172', 'Var', (96, 100))	('IDH2', 'Gene', (91, 95))	('tumour', 'Disease', (44, 50))	('IDH1', 'Gene', (77, 81))	('IDH2', 'Gene', '3418', (91, 95))	('R132', 'Var', (82, 86))	('IDH1', 'Gene', '3417', (77, 81))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
182959	33562094	The 2-HG produced by these mutants contributes to DNA methylation by suppressing the enzymatic activity of histone lysine demethylases and causes oncogene activation and tumour suppressor gene inactivation.	('mutants', 'Var', (27, 34))	('2-HG', 'Chemical', 'MESH:C019417', (4, 8))	('tumour', 'Disease', 'MESH:D009369', (170, 176))	('tumour', 'Disease', (170, 176))	('met', 'Gene', '79811', (124, 127))	('lysine', 'Chemical', 'MESH:D008239', (115, 121))	('met', 'Gene', (124, 127))	('suppressing', 'NegReg', (69, 80))	('met', 'Gene', '79811', (54, 57))	('enzymatic activity', 'MPA', (85, 103))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('causes', 'Reg', (139, 145))	('met', 'Gene', (54, 57))	('oncogene', 'Protein', (146, 154))	('activation', 'PosReg', (155, 165))
182960	33562094	IDH1/2 mutations are biomarkers with a good prognosis in brain tumours but are not related to the prognosis in biliary tract cancer.	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (111, 131))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('brain tumours', 'Disease', 'MESH:D001932', (57, 70))	('brain tumours', 'Phenotype', 'HP:0030692', (57, 70))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('brain tumours', 'Disease', (57, 70))	('biliary tract cancer', 'Disease', 'MESH:D001661', (111, 131))	('IDH1/2', 'Gene', (0, 6))	('biliary tract cancer', 'Disease', (111, 131))	('mutations', 'Var', (7, 16))
182961	33562094	Ivosidenib, an inhibitor of IDH1 mutants, and enasidenib, an inhibitor of IDH2 mutants, are reportedly effective against relapsed and refractory acute myeloid leukaemia (AML) with IDH1 and IDH2 mutations, respectively.	('acute myeloid leukaemia', 'Disease', 'MESH:D015470', (145, 168))	('AML', 'Disease', 'MESH:D015470', (170, 173))	('IDH1', 'Gene', '3417', (28, 32))	('AML', 'Phenotype', 'HP:0004808', (170, 173))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (145, 168))	('AML', 'Disease', (170, 173))	('IDH2', 'Gene', (189, 193))	('IDH2', 'Gene', '3418', (189, 193))	('acute myeloid leukaemia', 'Disease', (145, 168))	('IDH1', 'Gene', (180, 184))	('IDH2', 'Gene', (74, 78))	('IDH2', 'Gene', '3418', (74, 78))	('mutants', 'Var', (33, 40))	('enasidenib', 'Chemical', 'MESH:C000605269', (46, 56))	('IDH1', 'Gene', (28, 32))	('IDH1', 'Gene', '3417', (180, 184))	('mutations', 'Var', (194, 203))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (151, 168))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))
182962	33562094	For biliary tract cancer patients with IDH1 mutations, a double-blind phase 3 controlled trial, ClarIDHy, was conducted to evaluate the efficacy of ivosidenib; it was observed that the progression-free survival of the group treated with ivosidenib was significantly prolonged compared to the placebo group (2.7 vs. 1.4 months).	('prolonged', 'PosReg', (266, 275))	('IDH', 'Gene', (100, 103))	('ivosidenib', 'Chemical', 'MESH:C000627630', (237, 247))	('progression-free survival', 'CPA', (185, 210))	('IDH', 'Gene', '3417', (100, 103))	('IDH1', 'Gene', (39, 43))	('biliary tract cancer', 'Disease', 'MESH:D001661', (4, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('IDH1', 'Gene', '3417', (39, 43))	('ivosidenib', 'Chemical', 'MESH:C000627630', (148, 158))	('mutations', 'Var', (44, 53))	('biliary tract cancer', 'Disease', (4, 24))	('IDH', 'Gene', (39, 42))	('ivosidenib', 'Var', (237, 247))	('patients', 'Species', '9606', (25, 33))	('IDH', 'Gene', '3417', (39, 42))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (4, 24))
182964	33562094	Although the difference in progression-free survival (PFS) is relatively small, it implies that a new treatment option exists for patients with IDH1/2 mutations who constitute a certain proportion of biliary tract cancer cases.	('biliary tract cancer', 'Disease', (200, 220))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (200, 220))	('patients', 'Species', '9606', (130, 138))	('IDH1/2', 'Gene', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('biliary tract cancer', 'Disease', 'MESH:D001661', (200, 220))	('mutations', 'Var', (151, 160))	('IDH1/2', 'Gene', '3417;3418', (144, 150))
182968	33562094	BRAF mutations found in tumours are classified into three types.	('tumours', 'Disease', (24, 31))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('tumours', 'Disease', 'MESH:D009369', (24, 31))	('BRAF', 'Gene', (0, 4))
182969	33562094	In contrast, the kinase activity of the Class II mutation exhibits functionality ranging from intermediate to high levels, and the mutation forms a dimer regardless of the RAS-GTP type and results in MEK activation.	('activation', 'PosReg', (204, 214))	('MEK', 'Gene', (200, 203))	('mutation', 'Var', (49, 57))	('GTP', 'Chemical', 'MESH:D006160', (176, 179))	('kinase activity', 'MPA', (17, 32))	('dimer', 'MPA', (148, 153))	('results in', 'Reg', (189, 199))	('MEK', 'Gene', '5609', (200, 203))	('mutation', 'Var', (131, 139))
182970	33562094	The Class III mutation loses kinase activity but binds more tightly than the wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to an increased ERK signalling (paradoxical activation).	('ERK', 'Gene', (195, 198))	('tightly', 'Interaction', (60, 67))	('GTP', 'Chemical', 'MESH:D006160', (99, 102))	('enhanced', 'PosReg', (161, 169))	('binds', 'Interaction', (49, 54))	('kinase activity', 'MPA', (29, 44))	('activation', 'PosReg', (129, 139))	('loses', 'NegReg', (23, 28))	('mutation', 'Var', (14, 22))	('binding', 'Interaction', (114, 121))	('CRAF', 'Gene', (153, 157))	('CRAF', 'Gene', '5894', (153, 157))	('BRAF', 'Gene', (87, 91))	('increased', 'PosReg', (185, 194))	('BRAF', 'Gene', '673', (87, 91))	('ERK', 'Gene', '2048', (195, 198))
182971	33562094	Therefore, Class III BRAF mutations often co-occur with RTK overexpression or RAS-activating mutations.	('mutations', 'Var', (26, 35))	('co-occur', 'Reg', (42, 50))	('BRAF', 'Gene', (21, 25))	('BRAF', 'Gene', '673', (21, 25))
182972	33562094	Since paradoxical activation is also caused by BRAF inhibitors, MEK inhibitors or RTK inhibitors (such as EGFR antibodies) in combination with BRAF inhibitors are useful for solid tumours with such BRAF mutations.	('MEK', 'Gene', (64, 67))	('MEK', 'Gene', '5609', (64, 67))	('BRAF', 'Gene', '673', (198, 202))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('BRAF', 'Gene', (198, 202))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('solid tumours', 'Disease', 'MESH:D009369', (174, 187))	('EGFR', 'Gene', '1956', (106, 110))	('tumours', 'Phenotype', 'HP:0002664', (180, 187))	('solid tumours', 'Disease', (174, 187))	('mutations', 'Var', (203, 212))	('activation', 'PosReg', (18, 28))	('EGFR', 'Gene', (106, 110))
182973	33562094	reported the effect of the combination therapy of the BRAF inhibitor and the MEK inhibitor in biliary tract cancer cases with the BRAF mutation.	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('BRAF', 'Gene', '673', (130, 134))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (94, 114))	('BRAF', 'Gene', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('biliary tract cancer', 'Disease', 'MESH:D001661', (94, 114))	('MEK', 'Gene', '5609', (77, 80))	('MEK', 'Gene', (77, 80))	('mutation', 'Var', (135, 143))	('biliary tract cancer', 'Disease', (94, 114))
182976	33562094	Structural abnormalities, such as fusion, amplification, and mutation, are observed in various cancer types, especially FGFR2 and FGFR3.	('Structural abnormalities', 'Disease', (0, 24))	('fusion', 'Var', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('FGFR3', 'Gene', (130, 135))	('FGFR2', 'Gene', '2263', (120, 125))	('mutation', 'Var', (61, 69))	('cancer', 'Disease', (95, 101))	('observed', 'Reg', (75, 83))	('Structural abnormalities', 'Disease', 'MESH:C566527', (0, 24))	('amplification', 'Var', (42, 55))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('FGFR2', 'Gene', (120, 125))	('FGFR3', 'Gene', '2261', (130, 135))
182977	33562094	FGFR2 mutations are found in biliary tract cancer (approximately 7%, especially intrahepatic cholangiocarcinoma) and endometrial cancer (approximately 5%), and FGFR3 mutations are found in bladder cancer (approximately 25%).	('FGFR3', 'Gene', (160, 165))	('endometrial cancer', 'Phenotype', 'HP:0012114', (117, 135))	('FGFR3', 'Gene', '2261', (160, 165))	('endometrial cancer', 'Disease', (117, 135))	('biliary tract cancer', 'Disease', (29, 49))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('endometrial cancer', 'Disease', 'MESH:D016889', (117, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('bladder cancer', 'Disease', 'MESH:D001749', (189, 203))	('bladder cancer', 'Disease', (189, 203))	('FGFR2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('bladder cancer', 'Phenotype', 'HP:0009725', (189, 203))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (80, 111))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (29, 49))	('intrahepatic cholangiocarcinoma', 'Disease', (80, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('FGFR2', 'Gene', '2263', (0, 5))	('found', 'Reg', (180, 185))	('biliary tract cancer', 'Disease', 'MESH:D001661', (29, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('found', 'Reg', (20, 25))
182978	33562094	Since FGFR structural mutations have been reported recurrently, and in a tumour-agnostic manner, several FGFR inhibitors (antibodies, small molecule compounds) have been developed.	('FGFR', 'Gene', (105, 109))	('tumour', 'Disease', (73, 79))	('FGFR', 'Gene', (6, 10))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (22, 31))	('tumour', 'Disease', 'MESH:D009369', (73, 79))
182979	33562094	Of these, pemigatinib, an oral inhibitor of FGFR1, FGFR2, and FGFR3, was the earliest FDA-approved drug intended to be used in chemotherapy-resistant cholangiocarcinoma patients with the FGFR2 fusion gene or rearrangement.	('patients', 'Species', '9606', (169, 177))	('FGFR1', 'Gene', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('FGFR3', 'Gene', '2261', (62, 67))	('FGFR2', 'Gene', (51, 56))	('FGFR2', 'Gene', '2263', (51, 56))	('fusion gene', 'Var', (193, 204))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (150, 168))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (150, 168))	('FGFR2', 'Gene', (187, 192))	('FGFR1', 'Gene', '2260', (44, 49))	('FGFR2', 'Gene', '2263', (187, 192))	('FGFR3', 'Gene', (62, 67))	('rearrangement', 'Var', (208, 221))	('pemigatinib', 'Chemical', '-', (10, 21))	('cholangiocarcinoma', 'Disease', (150, 168))
182980	33562094	The FIGHT-202 study was a phase 2 study in which patients with biliary tract cancer who were refractory to prior treatment were grouped according to the presence or absence of FGFR abnormality, and the efficacy of pemigatinib in each group was verified.	('biliary tract cancer', 'Phenotype', 'HP:0100574', (63, 83))	('abnormality', 'Var', (181, 192))	('pemigatinib', 'Chemical', '-', (214, 225))	('biliary tract cancer', 'Disease', 'MESH:D001661', (63, 83))	('absence', 'NegReg', (165, 172))	('FGFR', 'Gene', (176, 180))	('biliary tract cancer', 'Disease', (63, 83))	('patients', 'Species', '9606', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
182981	33562094	In this study, the objective response rate was 35.5% in the group with FGFR2 fusion gene or rearrangement, but 0% in the group with other FGF/FGFR2 mutations and no mutations.	('FGFR2', 'Gene', '2263', (142, 147))	('FGFR2', 'Gene', (142, 147))	('fusion gene', 'Var', (77, 88))	('FGFR2', 'Gene', (71, 76))	('FGFR2', 'Gene', '2263', (71, 76))	('rearrangement', 'Var', (92, 105))
182983	33562094	Currently, a phase 3 study for unresectable or metastatic cholangiocarcinoma with FGFR2 rearrangement is being conducted to compare pemigatinib with gemcitabine plus cisplatin chemotherapy (FIGHT-302; , NCT03656536).	('met', 'Gene', (47, 50))	('cholangiocarcinoma', 'Disease', (58, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('gemcitabine', 'Chemical', 'MESH:C056507', (149, 160))	('pemigatinib', 'Chemical', '-', (132, 143))	('FGFR2', 'Gene', (82, 87))	('FGFR2', 'Gene', '2263', (82, 87))	('rearrangement', 'Var', (88, 101))	('met', 'Gene', '79811', (47, 50))
182993	33562094	As there is an accumulation of a substantial amount of data on gene mutation profiles of solid tumours, tumour-agnostic treatment based on gene mutations continues to progress, and the usage of personalised medicine is becoming widespread in intractable pancreatic cancer and biliary tract cancer.	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('biliary tract cancer', 'Disease', 'MESH:D001661', (276, 296))	('pancreatic cancer', 'Disease', (254, 271))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('pancreatic cancer', 'Disease', 'MESH:D010190', (254, 271))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumour', 'Disease', (95, 101))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (276, 296))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('solid tumours', 'Disease', 'MESH:D009369', (89, 102))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (254, 271))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('mutations', 'Var', (144, 153))	('tumour', 'Disease', (104, 110))	('solid tumours', 'Disease', (89, 102))	('biliary tract cancer', 'Disease', (276, 296))
182995	33562094	One of the new treatments for the KRAS mutant is Sotorasib (AMG510), which shows a specifically irreversible selective inhibitory effect on KRAS G12C.	('KRAS', 'Gene', '3845', (34, 38))	('KRAS', 'Gene', '3845', (140, 144))	('Sotorasib', 'Chemical', '-', (49, 58))	('inhibitory', 'NegReg', (119, 129))	('AMG510', 'Chemical', '-', (60, 66))	('G12C', 'SUBSTITUTION', 'None', (145, 149))	('G12C', 'Var', (145, 149))	('KRAS', 'Gene', (34, 38))	('KRAS', 'Gene', (140, 144))
182996	33562094	However, the KRAS G12C mutation rate is reported to be high at 13% in lung cancer, and it is only approximately 1% in pancreatic cancer and biliary tract cancer.	('G12C', 'SUBSTITUTION', 'None', (18, 22))	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('G12C', 'Var', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (118, 135))	('biliary tract cancer', 'Disease', 'MESH:D001661', (140, 160))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('pancreatic cancer', 'Disease', (118, 135))	('biliary tract cancer', 'Disease', (140, 160))	('pancreatic cancer', 'Disease', 'MESH:D010190', (118, 135))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('KRAS', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('KRAS', 'Gene', '3845', (13, 17))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (140, 160))
182997	33562094	A novel approach to developing treatments for KRAS mutant cancers, such as those targeting synthetic lethality and metabolism, is expected in the future.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutant', 'Var', (51, 57))	('KRAS', 'Gene', (46, 50))	('met', 'Gene', '79811', (115, 118))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('KRAS', 'Gene', '3845', (46, 50))	('met', 'Gene', (115, 118))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))
183035	33064672	The carcinoma measured 45x15 mm and was diagnosed as periductal-infiltrating type, stage T1a (microinvasion without hepatic parenchymal invasion) N0M0, stage IA according to the Union for International Cancer Control staging system (Figure 7A-7D).	('carcinoma', 'Disease', (4, 13))	('Cancer', 'Phenotype', 'HP:0002664', (202, 208))	('Cancer', 'Disease', (202, 208))	('carcinoma', 'Disease', 'MESH:D009369', (4, 13))	('Cancer', 'Disease', 'MESH:D009369', (202, 208))	('N0M0', 'Var', (146, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (4, 13))
183058	33064672	The presence of a biloma may cause bile peritonitis or lead to severe complications (e.g., sepsis, abscess, pancreatitis, respiratory failure, gastrointestinal bleeding, necrotizing fasciitis, pulmonary embolism, and myocardial infarction); therefore, prompt treatment is recommended.	('sepsis', 'Disease', (91, 97))	('myocardial infarction', 'Disease', (217, 238))	('fasciitis', 'Phenotype', 'HP:0100537', (182, 191))	('respiratory failure', 'Phenotype', 'HP:0002878', (122, 141))	('myocardial infarction', 'Phenotype', 'HP:0001658', (217, 238))	('pancreatitis', 'Phenotype', 'HP:0001733', (108, 120))	('pulmonary embolism', 'Phenotype', 'HP:0002204', (193, 211))	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (143, 168))	('pulmonary embolism', 'Disease', (193, 211))	('pulmonary embolism', 'Disease', 'MESH:D011655', (193, 211))	('men', 'Species', '9606', (264, 267))	('myocardial infarction', 'Disease', 'MESH:D009203', (217, 238))	('biloma', 'Disease', (18, 24))	('peritonitis', 'Phenotype', 'HP:0002586', (40, 51))	('pancreatitis', 'Disease', 'MESH:D010195', (108, 120))	('necrotizing fasciitis', 'Disease', (170, 191))	('cause', 'Reg', (29, 34))	('respiratory failure', 'Disease', 'MESH:D012131', (122, 141))	('gastrointestinal bleeding', 'Disease', 'MESH:D006471', (143, 168))	('biloma', 'Disease', 'None', (18, 24))	('abscess', 'Disease', (99, 106))	('abscess', 'Phenotype', 'HP:0025615', (99, 106))	('pancreatitis', 'Disease', (108, 120))	('gastrointestinal bleeding', 'Disease', (143, 168))	('presence', 'Var', (4, 12))	('men', 'Species', '9606', (277, 280))	('bile peritonitis', 'Disease', (35, 51))	('respiratory failure', 'Disease', (122, 141))	('sepsis', 'Phenotype', 'HP:0100806', (91, 97))	('bile peritonitis', 'Disease', 'MESH:D010534', (35, 51))	('sepsis', 'Disease', 'MESH:D018805', (91, 97))	('necrotizing fasciitis', 'Disease', 'MESH:D019115', (170, 191))	('lead to', 'Reg', (55, 62))
183075	33064672	Stones anywhere in the biliary tree are generally associated with increased iCCA risk, and the risk increases substantially with intrahepatic cholelithiasis, where it is estimated that 10% of patients develop iCCA.	('intrahepatic cholelithiasis', 'Disease', 'MESH:D002769', (129, 156))	('iCCA', 'Gene', '112476', (76, 80))	('iCCA', 'Gene', (209, 213))	('patients', 'Species', '9606', (192, 200))	('intrahepatic cholelithiasis', 'Disease', (129, 156))	('Stones', 'Var', (0, 6))	('iCCA', 'Gene', '112476', (209, 213))	('iCCA', 'Gene', (76, 80))	('cholelithiasis', 'Phenotype', 'HP:0001081', (142, 156))
183113	31391034	At the point when phosphorylated at tyrosine 705 (Tyr705), STAT3 will be dissociated from the receptor and translocated from cytosol to the nucleus in which it regulates target genes expression correlated with proliferation, cell cycle, apoptosis and carcinogenesis.	('tyrosine', 'Chemical', 'MESH:D014443', (36, 44))	('carcinogenesis', 'Disease', 'MESH:D063646', (251, 265))	('Tyr705', 'Var', (50, 56))	('apoptosis', 'CPA', (237, 246))	('STAT3', 'Gene', '6774', (59, 64))	('carcinogenesis', 'Disease', (251, 265))	('expression', 'MPA', (183, 193))	('cell cycle', 'CPA', (225, 235))	('Tyr705', 'Chemical', '-', (50, 56))	('STAT3', 'Gene', (59, 64))	('regulates', 'Reg', (160, 169))
183167	31391034	The result indicates that the expressions of Mcl-1 and Bcl-2 were obviously down-regulated by combination treatment in Huh28 cells, compared with those in control or single agent groups (Fig.	('expressions', 'MPA', (30, 41))	('Bcl-2', 'Gene', (55, 60))	('Bcl-2', 'Gene', '596', (55, 60))	('Mcl-1', 'Gene', '4170', (45, 50))	('combination', 'Var', (94, 105))	('Huh28', 'CellLine', 'CVCL:0336', (119, 124))	('down-regulated', 'NegReg', (76, 90))	('Mcl-1', 'Gene', (45, 50))
183177	31391034	The result indicates that both numbers of migrating and invasive cells were down-regulated by either single agent, and the combination Huaier with 5-FU had a synergistically inhibition on migratory and invasive abilities of Huh28 cells.	('5-FU', 'Var', (147, 151))	('combination', 'Var', (123, 134))	('down-regulated', 'NegReg', (76, 90))	('5-FU', 'Chemical', '-', (147, 151))	('inhibition', 'NegReg', (174, 184))	('Huh28', 'CellLine', 'CVCL:0336', (224, 229))
183200	31391034	Apoptosis regulatory proteins are classified into anti-apoptotic proteins and pro-apoptotic proteins; the loss of balance between these two types of proteins may lead to the generation of tumor.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('balance', 'MPA', (114, 121))	('loss', 'Var', (106, 110))	('lead to', 'Reg', (162, 169))
183202	31391034	Dysregulation of cell cycle is closely associated with the malignant transformation, and agents may exert anticancer effect through affecting cell cycle.	('malignant transformation', 'CPA', (59, 83))	('cancer', 'Disease', (110, 116))	('cell cycle', 'CPA', (17, 27))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cell cycle', 'CPA', (142, 152))	('associated', 'Reg', (39, 49))	('affecting', 'Reg', (132, 141))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
183204	31391034	In this study, it was found that combination therapy could induce S phase arrest in cholangiocarcinoma cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('induce', 'Reg', (59, 65))	('cholangiocarcinoma', 'Disease', (84, 102))	('S phase arrest', 'CPA', (66, 80))	('combination', 'Var', (33, 44))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
183214	31391034	It was observed that patients of Cholangiocarcinoma with high p-STAT3 expression in tissues had poor prognosis, and aberrant stat3 phosphorylation and IL-6/STAT3 signaling were reported in Cholangiocarcinoma cells.	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (189, 207))	('Cholangiocarcinoma', 'Disease', (189, 207))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (189, 207))	('high', 'Var', (57, 61))	('STAT3', 'Gene', '6774', (156, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('stat3', 'Gene', (125, 130))	('patients', 'Species', '9606', (21, 29))	('STAT3', 'Gene', '6774', (64, 69))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (33, 51))	('STAT3', 'Gene', (156, 161))	('IL-6', 'Gene', (151, 155))	('IL-6', 'Gene', '3569', (151, 155))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (33, 51))	('Cholangiocarcinoma', 'Disease', (33, 51))	('STAT3', 'Gene', (64, 69))	('stat3', 'Gene', '6774', (125, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
183225	30518618	Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals of incident cholangiocarcinoma associated with use of DPP-4 inhibitors and GLP-1 receptor agonists, separately.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (109, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('DPP-4', 'Gene', '1803', (151, 156))	('DPP-4', 'Gene', (151, 156))	('GLP-1 receptor', 'Gene', '2740', (172, 186))	('inhibitors', 'Var', (157, 167))	('GLP-1 receptor', 'Gene', (172, 186))	('cholangiocarcinoma', 'Disease', (109, 127))
183230	30518618	In the pharmacovigilance analysis, the use of DPP-4 inhibitors and GLP-1 receptor agonists were both associated with increased reporting odds ratios for cholangiocarcinoma, compared with use of sulfonylureas or thiazolidinediones (1.63, 1.00 to 2.66, 4.73, 2.95 to 7.58, respectively).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (153, 171))	('thiazolidinediones', 'Chemical', 'MESH:D045162', (211, 229))	('GLP-1 receptor', 'Gene', (67, 81))	('cholangiocarcinoma', 'Disease', (153, 171))	('to 7', 'Species', '1214577', (262, 266))	('DPP-4', 'Gene', '1803', (46, 51))	('DPP-4', 'Gene', (46, 51))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (153, 171))	('inhibitors', 'Var', (52, 62))	('GLP-1 receptor', 'Gene', '2740', (67, 81))	('sulfonylureas', 'Chemical', 'MESH:D013453', (194, 207))
183231	30518618	Compared with use of other second or third line antidiabetic drugs, use of DPP-4 inhibitors, and possibly GLP-1 receptor agonists, might be associated with an increased risk of cholangiocarcinoma in adults with type 2 diabetes.	('GLP-1 receptor', 'Gene', '2740', (106, 120))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (177, 195))	('associated', 'Reg', (140, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (177, 195))	('inhibitors', 'Var', (81, 91))	('increased risk of cholangiocarcinoma', 'Phenotype', 'HP:0001402', (159, 195))	('type 2 diabetes', 'Disease', 'MESH:D003924', (211, 226))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (211, 226))	('GLP-1 receptor', 'Gene', (106, 120))	('cholangiocarcinoma', 'Disease', (177, 195))	('type 2 diabetes', 'Disease', (211, 226))	('DPP-4', 'Gene', '1803', (75, 80))	('DPP-4', 'Gene', (75, 80))
183237	30518618	Activation of the GLP-1 receptor has also been shown to increase the proliferation rate of cholangiocytes both in vitro and in vivo, while lowering the rate of apoptosis.	('increase', 'PosReg', (56, 64))	('GLP-1 receptor', 'Gene', (18, 32))	('lowering', 'NegReg', (139, 147))	('proliferation rate', 'CPA', (69, 87))	('Activation', 'Var', (0, 10))	('GLP-1 receptor', 'Gene', '2740', (18, 32))
183241	30518618	Given the conflicting evidence, we carried out a population based cohort study to determine whether use of DPP-4 inhibitors and GLP-1 receptor agonists is associated with an increased risk of cholangiocarcinoma in adults with type 2 diabetes.	('cholangiocarcinoma', 'Disease', (192, 210))	('GLP-1 receptor', 'Gene', (128, 142))	('type 2 diabetes', 'Disease', (226, 241))	('inhibitors', 'Var', (113, 123))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (192, 210))	('DPP-4', 'Gene', '1803', (107, 112))	('DPP-4', 'Gene', (107, 112))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (192, 210))	('GLP-1 receptor', 'Gene', '2740', (128, 142))	('type 2 diabetes', 'Disease', 'MESH:D003924', (226, 241))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (226, 241))	('increased risk of cholangiocarcinoma', 'Phenotype', 'HP:0001402', (174, 210))
183248	30518618	We used a time varying exposure definition, where we categorised each person day of follow-up into one of four mutually exclusive categories: use of DPP-4 inhibitors (alone or in combination with other antidiabetic drugs, excluding GLP-1 receptor agonists); use of GLP-1 receptor agonists (alone or in combination with other antidiabetic drugs, including previous use of DPP-4 inhibitors, as this is a common treatment strategy); use of other second or third line drugs (defined as initiation of treatment with either thiazolidinediones, prandial glucose regulators, acarbose, sodium-glucose cotransporter-2 inhibitors, insulin, or combination of oral antidiabetic drugs; or switch to or add-on of an antidiabetic drug, including insulin, after failure with metformin or sulfonylurea in monotherapy); and use of first line drugs (defined as use of metformin or sulfonylurea in monotherapy).	('thiazolidinediones', 'Chemical', 'MESH:D045162', (518, 536))	('GLP-1 receptor', 'Gene', (232, 246))	('DPP-4', 'Gene', '1803', (371, 376))	('insulin', 'Gene', '3630', (620, 627))	('insulin', 'Gene', '3630', (730, 737))	('sodium-glucose cotransporter-2', 'Gene', '6524', (577, 607))	('metformin', 'Chemical', 'MESH:D008687', (758, 767))	('add-on', 'PosReg', (688, 694))	('DPP-4', 'Gene', (149, 154))	('glucose', 'Chemical', 'MESH:D005947', (584, 591))	('person', 'Species', '9606', (70, 76))	('DPP-4', 'Gene', (371, 376))	('GLP-1 receptor', 'Gene', (265, 279))	('switch', 'Var', (675, 681))	('insulin', 'Gene', (620, 627))	('insulin', 'Gene', (730, 737))	('acarbose', 'Chemical', 'MESH:D020909', (567, 575))	('GLP-1 receptor', 'Gene', '2740', (265, 279))	('metformin', 'Chemical', 'MESH:D008687', (848, 857))	('DPP-4', 'Gene', '1803', (149, 154))	('sodium-glucose cotransporter-2', 'Gene', (577, 607))	('GLP-1 receptor', 'Gene', '2740', (232, 246))	('glucose', 'Chemical', 'MESH:D005947', (547, 554))
183251	30518618	Time dependent Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals of cholangiocarcinoma associated with the use of DPP-4 inhibitors and GLP-1 receptor agonists, separately, when compared with use of other second or third line drugs.	('DPP-4', 'Gene', '1803', (161, 166))	('DPP-4', 'Gene', (161, 166))	('inhibitors', 'Var', (167, 177))	('GLP-1 receptor', 'Gene', '2740', (182, 196))	('cholangiocarcinoma', 'Disease', (115, 133))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (115, 133))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (115, 133))	('GLP-1 receptor', 'Gene', (182, 196))
183262	30518618	In a first analysis, we estimated the reporting odds ratios among users of DPP-4 inhibitors and GLP-1 receptor agonists, separately, compared with users of sulfonylureas or thiazolidinediones (other second or third line drugs).	('inhibitors', 'Var', (81, 91))	('thiazolidinediones', 'Chemical', 'MESH:D045162', (173, 191))	('GLP-1 receptor', 'Gene', '2740', (96, 110))	('sulfonylureas', 'Chemical', 'MESH:D013453', (156, 169))	('DPP-4', 'Gene', '1803', (75, 80))	('DPP-4', 'Gene', (75, 80))	('GLP-1 receptor', 'Gene', (96, 110))
183276	30518618	Compared with use of other second or third line drugs, use of DPP-4 inhibitors was associated with a 77% increase in the hazards of cholangiocarcinoma (hazard ratio 1.77, 95% confidence interval 1.04 to 3.01).	('DPP-4', 'Gene', '1803', (62, 67))	('DPP-4', 'Gene', (62, 67))	('inhibitors', 'Var', (68, 78))	('cholangiocarcinoma', 'Disease', (132, 150))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (132, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (132, 150))
183277	30518618	When investigating specific DPP-4 inhibitors, those primarily excreted through biliary pathways generated a higher hazard ratio than those excreted through renal pathways (2.25, 95% confidence interval 0.86 to 5.90 and 1.64, 0.92 to 2.90, respectively; supplementary table 3), although both generated wide and overlapping confidence intervals.	('DPP-4', 'Gene', '1803', (28, 33))	('DPP-4', 'Gene', (28, 33))	('hazard', 'MPA', (115, 121))	('inhibitors', 'Var', (34, 44))
183283	30518618	Compared with other second or third line drugs, DPP-4 inhibitors generated a hazard ratio of similar magnitude to the one generated in the primary analysis (1.71, 0.86 to 3.43), but with a wider confidence interval that included the null value owing to the fewer events in the exposed groups (supplementary table 12).	('inhibitors', 'Var', (54, 64))	('DPP-4', 'Gene', '1803', (48, 53))	('DPP-4', 'Gene', (48, 53))
183285	30518618	Compared with use of sulfonylureas or thiazolidinediones, use of DPP-4 inhibitors was associated with an increase in the reporting odds ratio of cholangiocarcinoma (1.63, 95% confidence interval 1.00 to 2.66).	('inhibitors', 'Var', (71, 81))	('DPP-4', 'Gene', '1803', (65, 70))	('DPP-4', 'Gene', (65, 70))	('thiazolidinediones', 'Chemical', 'MESH:D045162', (38, 56))	('sulfonylureas', 'Chemical', 'MESH:D013453', (21, 34))	('cholangiocarcinoma', 'Disease', (145, 163))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (145, 163))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (145, 163))
183288	30518618	In this study, use of dipeptidyl peptidase-4 (DPP-4) inhibitors was associated with a near doubling of the risk for cholangiocarcinoma.	('inhibitors', 'Var', (53, 63))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (116, 134))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (116, 134))	('DPP-4', 'Gene', '1803', (46, 51))	('dipeptidyl peptidase-4', 'Gene', '1803', (22, 44))	('DPP-4', 'Gene', (46, 51))	('dipeptidyl peptidase-4', 'Gene', (22, 44))	('cholangiocarcinoma', 'Disease', (116, 134))
183293	30518618	In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial of liraglutide, 13 events occurred in the liraglutide group compared with eight in the placebo group (hazard ratio 1.62, 95% confidence interval 0.67 to 3.90).	('Diabetes', 'Disease', 'MESH:D003920', (40, 48))	('Diabetes', 'Disease', (40, 48))	('liraglutide', 'Var', (152, 163))
183294	30518618	A post hoc analysis providing a breakdown of hepatic versus biliary cancers reported six events in the liraglutide group and two in the placebo group.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('hepatic versus biliary cancers', 'Disease', (45, 75))	('hepatic versus biliary cancers', 'Disease', 'MESH:D008113', (45, 75))	('liraglutide', 'Var', (103, 114))
183318	30518618	The results of this large population based cohort study indicate that use of DPP-4 inhibitors, and possibly GLP-1 receptor agonists, might be associated with an increased risk of cholangiocarcinoma, although the absolute risk is low.	('GLP-1 receptor', 'Gene', (108, 122))	('DPP-4', 'Gene', '1803', (77, 82))	('increased risk of cholangiocarcinoma', 'Phenotype', 'HP:0001402', (161, 197))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (179, 197))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (179, 197))	('GLP-1 receptor', 'Gene', '2740', (108, 122))	('DPP-4', 'Gene', (77, 82))	('cholangiocarcinoma', 'Disease', (179, 197))	('inhibitors', 'Var', (83, 93))
183344	27835650	The HuCCT1 cell line was purchased from the Health Science Research Resources Bank (Osaka, Japan), whereas other cholangiocarcinoma cell lines (SNU245, SNU308, SNU478, SNU869, SNU1079, and SNU1196) were purchased from the Korean Cell Line Bank (Seoul, Korea).	('cholangiocarcinoma', 'Disease', (113, 131))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (113, 131))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (113, 131))	('SNU1196', 'Var', (189, 196))	('SNU1079', 'Var', (176, 183))	('SNU869', 'Var', (168, 174))	('SNU245', 'Var', (144, 150))	('SNU308', 'Var', (152, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('HuCCT1', 'CellLine', 'CVCL:0324', (4, 10))	('SNU478', 'Var', (160, 166))
183347	27835650	In order to prepare ZHX1 expression vector, the ZHX1 gene (Invitrogen, Dane, WI, USA) was inserted into 3XFlag CMV-10 vector (E4401; Sigma-Aldrich Korea, Seoul, Korea).	('Sigma-Aldrich Korea', 'Disease', 'MESH:D014923', (133, 152))	('Sigma-Aldrich Korea', 'Disease', (133, 152))	('E4401;', 'Var', (126, 132))	('ZHX1', 'Gene', (48, 52))
183366	27835650	Cells (5x104) in 500 mul of media containing 0.1% FBS were plated into invasion chambers 36 hours after SCR or ZHX1 siRNA transfection.	('FBS', 'Disease', (50, 53))	('FBS', 'Disease', 'MESH:D005198', (50, 53))	('transfection', 'Var', (122, 134))
183378	27835650	Cell proliferation assays were performed from 3 to 5 days after SCR or ZHX1 siRNA transfection and after plating Mock or ZHX1-overexpressing HuCCT1 cells.	('HuCCT1', 'CellLine', 'CVCL:0324', (141, 147))	('ZHX1', 'Gene', (71, 75))	('transfection', 'Var', (82, 94))
183381	27835650	To examine effects of ZHX1 on CCA cell migration, we used a Boyden chamber assay two days after SCR or ZHX1 siRNA transfection and after seeding Mock or ZHX1-overexpressing HuCCT1 cells.	('CCA', 'Phenotype', 'HP:0030153', (30, 33))	('ZHX1', 'Gene', (103, 107))	('HuCCT1', 'CellLine', 'CVCL:0324', (173, 179))	('transfection', 'Var', (114, 126))
183390	27835650	Confirmatory real-time PCR showed ZHX1 knockdown decreased EGR1 expression in SNU478 and SNU1196 cells (Fig 5A), whereas ZHX1 overexpression increased EGR1 mRNA levels (Fig 5A).	('expression', 'MPA', (64, 74))	('EGR1', 'Gene', '1958', (59, 63))	('EGR1', 'Gene', '1958', (151, 155))	('knockdown', 'Var', (39, 48))	('mRNA levels', 'MPA', (156, 167))	('decreased', 'NegReg', (49, 58))	('ZHX1', 'Gene', (34, 38))	('EGR1', 'Gene', (59, 63))	('EGR1', 'Gene', (151, 155))
183391	27835650	Subsequently, EGR1 knockdown was found to reduce the proliferations of SNU478, SNU1196 and HuCCT1 cells (Fig 5B).	('knockdown', 'Var', (19, 28))	('EGR1', 'Gene', '1958', (14, 18))	('HuCCT1', 'CellLine', 'CVCL:0324', (91, 97))	('proliferations', 'CPA', (53, 67))	('reduce', 'NegReg', (42, 48))	('EGR1', 'Gene', (14, 18))
183398	27835650	In Hodgkin's lymphoma, ZHX2 expression was diminished and ZHX2 knockdown suppressed genes promoting differentiation and apoptosis.	('ZHX2', 'Gene', '22882', (23, 27))	('ZHX2', 'Gene', (58, 62))	('lymphoma', 'Phenotype', 'HP:0002665', (13, 21))	('apoptosis', 'CPA', (120, 129))	('expression', 'MPA', (28, 38))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (3, 21))	("Hodgkin's lymphoma", 'Disease', (3, 21))	('genes', 'MPA', (84, 89))	('ZHX2', 'Gene', '22882', (58, 62))	('suppressed', 'NegReg', (73, 83))	('ZHX2', 'Gene', (23, 27))	('knockdown', 'Var', (63, 72))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (3, 21))	('diminished', 'NegReg', (43, 53))
183399	27835650	Furthermore, it was recently reported ZHX1 inhibited gastric cancer cell proliferation, and that ectopic ZHX1 expression decreased proliferation of SMMC-7721 cells (a hepatocellular carcinoma cell line).	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('ZHX1', 'Gene', (105, 109))	('inhibited', 'NegReg', (43, 52))	('gastric cancer', 'Disease', (53, 67))	('proliferation', 'CPA', (131, 144))	('gastric cancer', 'Disease', 'MESH:D013274', (53, 67))	('decreased', 'NegReg', (121, 130))	('SMMC-7721', 'CellLine', 'CVCL:0534', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (167, 191))	('gastric cancer', 'Phenotype', 'HP:0012126', (53, 67))	('ZHX1', 'Gene', (38, 42))	('hepatocellular carcinoma', 'Disease', (167, 191))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (167, 191))	('ectopic', 'Var', (97, 104))
183402	27835650	Similarly, in the present study, ZHX1 knockdown reduced and its overexpression increased cell proliferation in cholangiocarcinoma cell lines (Fig 2 and S2 Fig).	('cell proliferation', 'CPA', (89, 107))	('ZHX1', 'Gene', (33, 37))	('cholangiocarcinoma', 'Disease', (111, 129))	('reduced', 'NegReg', (48, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 129))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))	('knockdown', 'Var', (38, 47))	('overexpression increased', 'PosReg', (64, 88))
183405	27835650	Consistent with our results, in non-metastatic human breast cancer cells, ZHX1 expression was reduced by Pea3 knockdown, and this led to decreases in invasiveness and metastasis.	('knockdown', 'Var', (110, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('Pea3', 'Gene', '2118', (105, 109))	('Pea3', 'Gene', (105, 109))	('invasiveness', 'Disease', 'MESH:D009362', (150, 162))	('expression', 'MPA', (79, 89))	('invasiveness', 'Disease', (150, 162))	('reduced', 'NegReg', (94, 101))	('ZHX1', 'Gene', (74, 78))	('decreases', 'NegReg', (137, 146))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('human', 'Species', '9606', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))
183412	27835650	Interestingly, EGF has been shown to promote the migration and invasion of CCA cells, and knockdown of thymosin beta10, which leads to the increase in CCA metastasis, was found to increase EGR1 expression in CCA cells.	('EGF', 'Gene', (15, 18))	('EGR1', 'Gene', (189, 193))	('thymosin beta10', 'Gene', '9168', (103, 118))	('knockdown', 'Var', (90, 99))	('promote', 'PosReg', (37, 44))	('increase', 'PosReg', (180, 188))	('CCA', 'Phenotype', 'HP:0030153', (151, 154))	('migration', 'CPA', (49, 58))	('EGR1', 'Gene', '1958', (189, 193))	('EGF', 'Gene', '1950', (15, 18))	('increase', 'PosReg', (139, 147))	('invasion', 'CPA', (63, 71))	('thymosin beta10', 'Gene', (103, 118))	('expression', 'MPA', (194, 204))	('CCA', 'Phenotype', 'HP:0030153', (208, 211))	('CCA', 'Phenotype', 'HP:0030153', (75, 78))	('CCA', 'Disease', (151, 154))
183413	27835650	Furthermore, the expression of EGR1 was decreased by silencing PRR11, which has oncogenic effects in hilar cholangiocarcinoma.	('EGR1', 'Gene', (31, 35))	('PRR11', 'Gene', (63, 68))	('expression', 'MPA', (17, 27))	('cholangiocarcinoma', 'Disease', (107, 125))	('EGR1', 'Gene', '1958', (31, 35))	('silencing', 'Var', (53, 62))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (107, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (107, 125))	('decreased', 'NegReg', (40, 49))	('PRR11', 'Gene', '55771', (63, 68))
183479	32700810	In a meta-analysis of 32 149 patients with diverse cancers who underwent early phase clinical trials, targeted therapy approaches without specific biomarkers had significantly worse clinical outcomes (ie, objective response rate, PFS and OS) when compared to patients who received targeted therapies based upon biomarkers.	('patients', 'Species', '9606', (29, 37))	('patients', 'Species', '9606', (259, 267))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('worse', 'NegReg', (176, 181))	('objective response', 'Disease', (205, 223))	('targeted therapy', 'Var', (102, 118))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
183504	32700810	The median number of characterized alterations per patient was 2 (range, 0-9), and a total of 147 characterized alterations were observed, including 112 mutations (76%), 32 gene amplifications (22%), 2 gene fusions (1.4%) and 1 indel (0.7%).	('mutations', 'Var', (153, 162))	('gene fusions', 'Var', (202, 214))	('gene amplifications', 'Var', (173, 192))	('patient', 'Species', '9606', (51, 58))
183515	32700810	When comparing according to tissue biopsy site, ctDNA alteration was numerically more concordant with metastatic site DNA than primary tumor DNA in these three genes (overall concordance [Kappa], 78% vs 65% [0.57 vs 0.17] for TP53; 100% vs 74% [1.00 vs 0.41] for KRAS; and 100% vs 87% [1.00 vs 0.45] for PIK3CA).	('PIK3CA', 'Gene', (304, 310))	('alteration', 'Var', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('PIK3CA', 'Gene', '5290', (304, 310))	('tumor', 'Disease', (135, 140))	('KRAS', 'Gene', (263, 267))	('KRAS', 'Gene', '3845', (263, 267))	('TP53', 'Gene', '7157', (226, 230))	('TP53', 'Gene', (226, 230))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
183525	32700810	For instance, 31% of the treated patients (n = 25/80) harbored KRAS alterations in either of the tissue DNA or ctDNA testing or both (n = 14, only in tissue; n = 6, only in ctDNA; and n = 5, in both), and five patients of them (ID#23, #37, #38, #52 and #59) received matched treatment regimens including trametinib, a MEK inhibitor (Table S4).	('KRAS', 'Gene', '3845', (63, 67))	('trametinib', 'Chemical', 'MESH:C560077', (304, 314))	('MEK', 'Gene', '5609', (318, 321))	('patients', 'Species', '9606', (33, 41))	('alterations', 'Var', (68, 79))	('patients', 'Species', '9606', (210, 218))	('harbored', 'Reg', (54, 62))	('eg', 'Gene', '50512', (286, 288))	('MEK', 'Gene', (318, 321))	('KRAS', 'Gene', (63, 67))
183542	32700810	However, CDKN2A/B alterations were detected in only 3% of patients by ctDNA, as compared to 33% by tissue-DNA NGS.	('patients', 'Species', '9606', (58, 66))	('CDKN2A/B', 'Gene', (9, 17))	('alterations', 'Var', (18, 29))	('CDKN2A/B', 'Gene', '1029;1030', (9, 17))
183553	32700810	This finding likely suggests that additional mutations develop in metastatic tumors and that ctDNA may be able to detect DNA shed into bloodstream from the tumors throughout the patient's whole body.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('mutations', 'Var', (45, 54))	('tumors', 'Disease', (156, 162))	('patient', 'Species', '9606', (178, 185))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
183559	32700810	This discrepancy may result from the issue that our study was not performed in prospective exploratory setting such as randomized control trials, but in more pragmatic setting including patients with history of previous aggressive therapy (23%), poor performance status (ECOG-PS 2-3, 26%) or abnormal total bilirubin levels (> the institutional upper limit of normal [1.2 mg/dL], 23%).	('bilirubin', 'Chemical', 'MESH:D001663', (307, 316))	('poor', 'Var', (246, 250))	('patients', 'Species', '9606', (186, 194))	('total bilirubin levels', 'MPA', (301, 323))
183560	32700810	On the other hand, 11 patients were treated with gemcitabine plus platinum regimens in the setting of >=1 characterized alterations in BRCA-associated genes that were considered as the molecularly matched group.	('platinum', 'Chemical', 'MESH:D010984', (66, 74))	('patients', 'Species', '9606', (22, 30))	('gemcitabine', 'Chemical', 'MESH:C056507', (49, 60))	('BRCA', 'Gene', (135, 139))	('alterations', 'Var', (120, 131))	('BRCA', 'Gene', '672;675', (135, 139))	('eg', 'Gene', '50512', (76, 78))
183561	32700810	Previous studies have suggested that similar to ovarian and breast cancers, cholangiocarcinoma harboring BRCA-associated gene alterations are more sensitive to platinum-based therapy.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('BRCA', 'Gene', '672;675', (105, 109))	('cholangiocarcinoma', 'Disease', (76, 94))	('ovarian and breast cancers', 'Disease', 'MESH:D001943', (48, 74))	('platinum', 'Chemical', 'MESH:D010984', (160, 168))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (76, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('breast cancers', 'Phenotype', 'HP:0003002', (60, 74))	('BRCA', 'Gene', (105, 109))	('more', 'PosReg', (142, 146))	('sensitive', 'MPA', (147, 156))	('alterations', 'Var', (126, 137))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (76, 94))
183714	23520144	Moreover, Ca19-9 can be expressed in any obstructive jaundice, and cannot therefore discriminate CCA from pancreatic or gastric malignancy.	('Ca19-9', 'Chemical', 'MESH:C086528', (10, 16))	('CCA', 'Disease', (97, 100))	('gastric malignancy', 'Disease', 'MESH:D013274', (120, 138))	('jaundice', 'Phenotype', 'HP:0000952', (53, 61))	('gastric malignancy', 'Phenotype', 'HP:0006753', (120, 138))	('CCA', 'Phenotype', 'HP:0030153', (97, 100))	('pancreatic', 'Disease', 'MESH:D010195', (106, 116))	('obstructive jaundice', 'Disease', 'MESH:D041781', (41, 61))	('Ca19-9', 'Var', (10, 16))	('obstructive jaundice', 'Disease', (41, 61))	('gastric malignancy', 'Disease', (120, 138))	('pancreatic', 'Disease', (106, 116))
183717	23520144	In PSC strictures, the occurrence of polysomy [detected by fluorescent in-situ hybridisation (FISH)] is 88% specific for CCA, and can precede radiological and pathological changes by up to 2.7 years.	('CCA', 'Disease', (121, 124))	('PSC', 'Gene', '100653366', (3, 6))	('CCA', 'Phenotype', 'HP:0030153', (121, 124))	('PSC', 'Gene', (3, 6))	('polysomy', 'Var', (37, 45))
183760	23520144	Dissection of the underlying molecular mechanisms of CCA has begun to reveal that a background of chronic inflammation - providing a high rate of cell turnover and a rich milieu of cytokines and growth factors - allows the accumulation of mutations (Table 2) and the proliferation of mutated cells.	('rat', 'Species', '10116', (138, 141))	('rat', 'Species', '10116', (274, 277))	('mutations', 'Var', (239, 248))	('CCA', 'Disease', (53, 56))	('proliferation', 'CPA', (267, 280))	('inflammation', 'Disease', 'MESH:D007249', (106, 118))	('inflammation', 'Disease', (106, 118))	('CCA', 'Phenotype', 'HP:0030153', (53, 56))
183761	23520144	CCA can also arise in the absence of chronic inflammation, however, through mutations that alter pathways in a manner similar to chronic inflammation.	('inflammation', 'Disease', (45, 57))	('mutations', 'Var', (76, 85))	('CCA', 'Phenotype', 'HP:0030153', (0, 3))	('alter', 'Reg', (91, 96))	('inflammation', 'Disease', 'MESH:D007249', (137, 149))	('inflammation', 'Disease', (137, 149))	('pathways', 'Pathway', (97, 105))	('CCA', 'Disease', (0, 3))	('inflammation', 'Disease', 'MESH:D007249', (45, 57))	('man', 'Species', '9606', (111, 114))
183784	23520144	NGAL knockdown in RMCCA1 cells (a CCA cell line) showed decreased invasiveness and migration in vitro.	('NGAL', 'Gene', '3934', (0, 4))	('NGAL', 'Gene', (0, 4))	('CCA', 'Phenotype', 'HP:0030153', (34, 37))	('CCA', 'Phenotype', 'HP:0030153', (20, 23))	('knockdown', 'Var', (5, 14))	('decreased', 'NegReg', (56, 65))	('rat', 'Species', '10116', (86, 89))
183792	23520144	Mutations in the tyrosine kinase domain of EGFR have been identified in CCA tissue in 15% of patient samples; these mutations correlate with increased phosphorylation of downstream MAPK or Akt.	('CCA', 'Disease', (72, 75))	('Akt', 'Pathway', (189, 192))	('MAPK', 'Gene', '5595;5594;5595', (181, 185))	('MAPK', 'Gene', (181, 185))	('increased', 'PosReg', (141, 150))	('phosphorylation', 'MPA', (151, 166))	('CCA', 'Phenotype', 'HP:0030153', (72, 75))	('EGFR', 'Gene', '1956', (43, 47))	('mutations', 'Var', (116, 125))	('patient', 'Species', '9606', (93, 100))	('Mutations in', 'Var', (0, 12))	('EGFR', 'Gene', (43, 47))
183812	23520144	In particular, the bile-acid component deoxycholic acid activates EGFR (via TGFalpha) and induces COX-2 expression, activating p42/44 and p38 MAPK, as well as c-jun-N-terminal kinase (JNK); as discussed, activation of these pathways contributes to CCA.	('activates', 'PosReg', (56, 65))	('p42', 'Gene', '23552', (127, 130))	('CCA', 'Phenotype', 'HP:0030153', (248, 251))	('bile-acid', 'Chemical', 'MESH:D001647', (19, 28))	('CCA', 'Disease', (248, 251))	('p38', 'Gene', (138, 141))	('EGFR', 'Gene', (66, 70))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (39, 55))	('deoxycholic acid', 'Var', (39, 55))	('expression', 'MPA', (104, 114))	('MAPK', 'Gene', '5595;5594;5595', (142, 146))	('TGFalpha', 'Gene', (76, 84))	('activating', 'PosReg', (116, 126))	('MAPK', 'Gene', (142, 146))	('COX-2', 'Gene', (98, 103))	('p38', 'Gene', '5594', (138, 141))	('TGFalpha', 'Gene', '7039', (76, 84))	('EGFR', 'Gene', '1956', (66, 70))	('induces', 'PosReg', (90, 97))	('p42', 'Gene', (127, 130))	('c-jun-N-terminal', 'MPA', (159, 175))
183817	23520144	In CCA, this suppression generally involves mutation or dysregulation of proteins such as p53 and the anti-apoptotic protein Bcl-2.	('mutation', 'Var', (44, 52))	('Bcl-2', 'Gene', (125, 130))	('CCA', 'Phenotype', 'HP:0030153', (3, 6))	('Bcl-2', 'Gene', '596', (125, 130))	('dysregulation', 'Var', (56, 69))	('CCA', 'Disease', (3, 6))	('p53', 'Protein', (90, 93))
183819	23520144	p53 mutation is seen in 20-61% of CCA cases, dysregulating cell-cycle arrest, allowing Bcl-2 expression and suppressing the normal apoptotic response.	('p53', 'Gene', (0, 3))	('Bcl-2', 'Gene', (87, 92))	('Bcl-2', 'Gene', '596', (87, 92))	('CCA', 'Phenotype', 'HP:0030153', (34, 37))	('mutation', 'Var', (4, 12))	('cell-cycle arrest', 'CPA', (59, 76))	('expression', 'MPA', (93, 103))	('dysregulating', 'Reg', (45, 58))	('allowing', 'PosReg', (78, 86))	('apoptotic response', 'CPA', (131, 149))	('CCA', 'Disease', (34, 37))	('suppressing', 'NegReg', (108, 119))
183822	23520144	Promoter methylation, which reduces transcription, and loss-of-function mutations in the cell-cycle regulators p14ARF and p16INK4a, and in beta-catenin, occur less frequently in CCA than in other cancers, but when present are thought to promote cell survival.	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('p14ARF', 'Gene', '1029', (111, 117))	('CCA', 'Phenotype', 'HP:0030153', (178, 181))	('reduces', 'NegReg', (28, 35))	('promote', 'PosReg', (237, 244))	('beta-catenin', 'Gene', (139, 151))	('CCA', 'Disease', (178, 181))	('p16INK4a', 'Gene', (122, 130))	('loss-of-function', 'NegReg', (55, 71))	('p14ARF', 'Gene', (111, 117))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('cancers', 'Disease', (196, 203))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('p16INK4a', 'Gene', '1029', (122, 130))	('beta-catenin', 'Gene', '1499', (139, 151))	('transcription', 'MPA', (36, 49))
183824	23520144	High concentrations of inflammatory mediators cause or allow the accumulation of mutations in proto-oncogenes, DNA mismatch-repair genes and tumour suppressor genes, and directly promote cell proliferation.	('rat', 'Species', '10116', (12, 15))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('DNA mismatch-repair genes', 'Gene', (111, 136))	('promote', 'PosReg', (179, 186))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('proto-oncogenes', 'Gene', (94, 109))	('mutations', 'Var', (81, 90))	('tumour', 'Disease', (141, 147))	('rat', 'Species', '10116', (199, 202))	('cell proliferation', 'CPA', (187, 205))
183826	23520144	Aberrant AID expression in biliary cells results in somatic mutations in p53, MYC and p16INK4A, potentiating malignant transformation.	('Aberrant', 'Var', (0, 8))	('p16INK4A', 'Gene', '1029', (86, 94))	('p53', 'Gene', (73, 76))	('MYC', 'Gene', '4609', (78, 81))	('AID', 'Gene', (9, 12))	('AID', 'Gene', '57379', (9, 12))	('malignant transformation', 'CPA', (109, 133))	('potentiating', 'PosReg', (96, 108))	('mutations', 'Var', (60, 69))	('p16INK4A', 'Gene', (86, 94))	('MYC', 'Gene', (78, 81))
183833	23520144	In vitro, demethylation re-establishes SOCS3 expression and decreases IL-6-dependent STAT3 phosphorylation.	('decreases', 'NegReg', (60, 69))	('SOCS3', 'Gene', (39, 44))	('IL-6', 'Gene', (70, 74))	('IL-6', 'Gene', '3569', (70, 74))	('STAT3', 'Gene', '6774', (85, 90))	('expression', 'MPA', (45, 55))	('demethylation', 'Var', (10, 23))	('SOCS3', 'Gene', '9021', (39, 44))	('STAT3', 'Gene', (85, 90))	('re-establishes', 'PosReg', (24, 38))
183844	23520144	Furthermore, recombinant PGRN increased proliferation of the same CCA cell lines through an Akt-dependent pathway.	('PGRN', 'Gene', '2896', (25, 29))	('Akt-dependent pathway', 'Pathway', (92, 113))	('CCA', 'Phenotype', 'HP:0030153', (66, 69))	('recombinant', 'Var', (13, 24))	('PGRN', 'Gene', (25, 29))	('rat', 'Species', '10116', (47, 50))	('increased', 'PosReg', (30, 39))	('proliferation', 'CPA', (40, 53))
183847	23520144	Furthermore, liver-specific disruption of the tumour suppressors SMAD4 (also known as DPC4) and PTEN leads to increased Akt phosphorylation and the development of CCA.	('CCA', 'Disease', (163, 166))	('men', 'Species', '9606', (155, 158))	('SMAD4', 'Gene', '4089', (65, 70))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('increased', 'PosReg', (110, 119))	('tumour', 'Disease', (46, 52))	('disruption', 'Var', (28, 38))	('DPC4', 'Gene', (86, 90))	('CCA', 'Phenotype', 'HP:0030153', (163, 166))	('DPC4', 'Gene', '4089', (86, 90))	('SMAD4', 'Gene', (65, 70))	('tumour', 'Disease', 'MESH:D009369', (46, 52))	('PTEN', 'Gene', (96, 100))	('Akt', 'Pathway', (120, 123))
183861	23520144	Nascent mechanistic understanding suggests that these changes in miRNA expression increase CCA proliferation and survival: for example, miR-141 decreases CLOCK expression, which disinhibits cell proliferation.	('survival', 'CPA', (113, 121))	('decreases', 'NegReg', (144, 153))	('CLOCK', 'Gene', (154, 159))	('changes', 'Var', (54, 61))	('CCA', 'Disease', (91, 94))	('miR-141', 'Gene', (136, 143))	('CLOCK', 'Gene', '9575', (154, 159))	('increase', 'PosReg', (82, 90))	('cell proliferation', 'CPA', (190, 208))	('miR-141', 'Gene', '406933', (136, 143))	('rat', 'Species', '10116', (102, 105))	('CCA', 'Phenotype', 'HP:0030153', (91, 94))	('rat', 'Species', '10116', (202, 205))
183863	23520144	miR-21 transfection decreases expression of PTEN, disinhibiting PI3K signalling and desensitising cells to death signals.	('desensitising', 'Reg', (84, 97))	('expression', 'MPA', (30, 40))	('decreases', 'NegReg', (20, 29))	('miR-21', 'Gene', (0, 6))	('PTEN', 'Protein', (44, 48))	('disinhibiting', 'NegReg', (50, 63))	('transfection', 'Var', (7, 19))	('PI3K signalling', 'Pathway', (64, 79))	('miR-21', 'Gene', '406991', (0, 6))
183867	23520144	Clinical and basic research opportunities To develop animal models with mutations in key genes implicated in cholangiocarcinogenesis.	('mutations', 'Var', (72, 81))	('carcinogenesis', 'Disease', (118, 132))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))
183900	16868542	Silencing of the CEACAM6 gene impairs metastasis and suppresses tumor growth (Duxbury et al, 2004a, 2004b).	('tumor', 'Disease', (64, 69))	('suppresses', 'NegReg', (53, 63))	('impairs', 'NegReg', (30, 37))	('CEACAM6', 'Gene', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('Silencing', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('metastasis', 'CPA', (38, 48))	('CEACAM6', 'Gene', '4680', (17, 24))
183904	16868542	We also examined whether silencing the CEACAM6 gene by siRNA enhanced gemcitabine chemosensitivity.	('silencing', 'Var', (25, 34))	('gemcitabine chemosensitivity', 'MPA', (70, 98))	('enhanced', 'PosReg', (61, 69))	('gemcitabine', 'Chemical', 'MESH:C056507', (70, 81))	('CEACAM6', 'Gene', (39, 46))	('CEACAM6', 'Gene', '4680', (39, 46))
183935	16868542	Cells (5.0 x 104 cells well-1) were placed in the upper chamber, and the lower chamber was filled with 750 mul of RPMI1640 with 10% FBS as a chemoattractant.	('FBS', 'Disease', 'MESH:D005198', (132, 135))	('FBS', 'Disease', (132, 135))	('RPMI1640', 'Var', (114, 122))	('RPMI1640', 'Chemical', '-', (114, 122))
183958	16868542	In the disease-free survival curve, patients in the high expression group had a significantly poorer prognosis than those in the low expression group, as illustrated in Figure 1C (P<0.05; Wilcoxon test, log-rank test).	('high expression', 'Var', (52, 67))	('patients', 'Species', '9606', (36, 44))	('poorer', 'NegReg', (94, 100))
183972	16868542	In the clinicopathological studies, we found a tendency that the incidence of lymphatic invasion was higher in the CEACAM6 high expression group than in the CEACAM6 low expression group (Table 1).	('CEACAM6', 'Gene', '4680', (157, 164))	('higher', 'PosReg', (101, 107))	('CEACAM6', 'Gene', (115, 122))	('high expression', 'Var', (123, 138))	('CEACAM6', 'Gene', '4680', (115, 122))	('CEACAM6', 'Gene', (157, 164))	('lymphatic invasion', 'CPA', (78, 96))
183992	16868542	Overexpression of CEACAM6 is associated with greater resistance to anoikis (Ordonez et al, 2000; Ilantzis et al, 2002), a subset of apoptosis induced by inadequate or inappropriate cell substrate adhesion, and increased Akt and c-Src kinase activities (Duxbury et al, 2004a).	('CEACAM6', 'Gene', (18, 25))	('inadequate', 'NegReg', (153, 163))	('increased', 'PosReg', (210, 219))	('greater', 'PosReg', (45, 52))	('c-Src kinase', 'Gene', '1445', (228, 240))	('CEACAM6', 'Gene', '4680', (18, 25))	('Akt', 'Gene', '207', (220, 223))	('resistance', 'CPA', (53, 63))	('c-Src kinase', 'Gene', (228, 240))	('Akt', 'Gene', (220, 223))	('inappropriate', 'Var', (167, 180))
183995	16868542	c-Src-dependent modulation of MMP9 activity contributes significantly to the increased cellular invasiveness induced by CEACAM6 overexpression (Duxbury et al, 2004d).	('MMP9', 'Gene', (30, 34))	('overexpression', 'PosReg', (128, 142))	('activity', 'MPA', (35, 43))	('c-Src', 'Gene', (0, 5))	('CEACAM6', 'Gene', (120, 127))	('c-Src', 'Gene', '6714', (0, 5))	('modulation', 'Var', (16, 26))	('increased', 'PosReg', (77, 86))	('CEACAM6', 'Gene', '4680', (120, 127))	('cellular invasiveness', 'CPA', (87, 108))	('MMP9', 'Gene', '4318', (30, 34))
183996	16868542	This study demonstrates that the transfectants of the CEACAM6 gene were more proliferative in MTT assay (Figure 4B and C), had greater invasive abilities in matrigel assay (Figure 5A) and were more resistant to anoikis in anoikis assay (Figure 5B) compared to mock-transfected cells, concurring with the reports described above.	('greater', 'PosReg', (127, 134))	('CEACAM6', 'Gene', (54, 61))	('proliferative', 'CPA', (77, 90))	('MTT assay', 'CPA', (94, 103))	('resistant', 'CPA', (198, 207))	('CEACAM6', 'Gene', '4680', (54, 61))	('MTT', 'Chemical', 'MESH:C070243', (94, 97))	('more', 'PosReg', (72, 76))	('transfectants', 'Var', (33, 46))	('invasive abilities', 'CPA', (135, 153))
183998	16868542	Furthermore, CEACAM6 gene silencing reversed the acquired anoikis resistance and inhibited metastatic ability (Duxbury et al, 2004a).	('anoikis', 'MPA', (58, 65))	('reversed', 'PosReg', (36, 44))	('metastatic ability', 'CPA', (91, 109))	('inhibited', 'NegReg', (81, 90))	('gene silencing', 'Var', (21, 35))	('CEACAM6', 'Gene', (13, 20))	('CEACAM6', 'Gene', '4680', (13, 20))
184056	33644756	Similarly, dice in pancreatic and blood vessel segmentation were comparable in both groups with 0.77, 0.813 for the model, and 0.706 and 0.813 for the expert group.	('0.813', 'Var', (102, 107))	('0.813', 'Var', (137, 142))	('0.706', 'Var', (127, 132))	('pancreatic', 'Disease', 'MESH:D010195', (19, 29))	('pancreatic', 'Disease', (19, 29))
184091	33644756	The area under ROC for the diagnostic ability of malignant from benign pancreatic cystic lesion were 0.739 (p = 0.001), 0.719 (p = 0.002), 0.956 (p < 0.001 and 0.966 (p < 0.001) for cytology, CEA, AI using only CEA and AI, respectively.	('pancreatic cystic lesion', 'Phenotype', 'HP:0001737', (71, 95))	('pancreatic', 'Disease', 'MESH:D010195', (71, 81))	('pancreatic', 'Disease', (71, 81))	('0.719', 'Var', (120, 125))	('CEA', 'Gene', (211, 214))	('CEA', 'Gene', '1084', (211, 214))	('CEA', 'Gene', (192, 195))	('0.956', 'Var', (139, 144))	('CEA', 'Gene', '1084', (192, 195))
184129	33490245	Univariate and multivariate Cox regression analyses identified miR-3913-5p as an independent prognostic factor in patients with CCA.	('miR-3913-5p', 'Chemical', '-', (63, 74))	('CCA', 'Phenotype', 'HP:0030153', (128, 131))	('patients', 'Species', '9606', (114, 122))	('CCA', 'Disease', (128, 131))	('miR-3913-5p', 'Var', (63, 74))
184133	33490245	Furthermore, the differential expression of miR-3913-5p in CCA cells and normal bile duct epithelial cells was confirmed through in vitro experiments.	('CCA', 'Disease', (59, 62))	('CCA', 'Phenotype', 'HP:0030153', (59, 62))	('miR-3913-5p', 'Var', (44, 55))	('miR-3913-5p', 'Chemical', '-', (44, 55))
184135	33490245	In addition, functional experiments showed that miR-3913-5p might be an oncogene that affects the proliferation and migration of CCA cells by inhibiting and mimicking miR-3913-5p.	('CCA', 'Phenotype', 'HP:0030153', (129, 132))	('miR-3913-5p', 'Var', (48, 59))	('miR-3913-5p', 'Chemical', '-', (167, 178))	('CCA', 'Disease', (129, 132))	('mimicking', 'NegReg', (157, 166))	('miR-3913-5p', 'Chemical', '-', (48, 59))	('miR-3913-5p', 'Var', (167, 178))	('affects', 'Reg', (86, 93))	('migration', 'CPA', (116, 125))	('proliferation', 'CPA', (98, 111))	('inhibiting', 'NegReg', (142, 152))
184152	33490245	The aim of this study was to develop CCA biomarkers to predict the survival and prognosis of patients with CCA based on miR-3913-5p.	('CCA', 'Disease', (107, 110))	('miR-3913-5p', 'Chemical', '-', (120, 131))	('CCA', 'Phenotype', 'HP:0030153', (107, 110))	('miR-3913-5p', 'Var', (120, 131))	('CCA', 'Phenotype', 'HP:0030153', (37, 40))	('patients', 'Species', '9606', (93, 101))
184156	33490245	Two independent datasets downloaded from the Gene Expression Omnibus (GEO) database were used to verify the miRNA-3913-5p expression in patients with CCA (GSE85589 and GSE53992).	('GSE85589', 'Var', (155, 163))	('CCA', 'Phenotype', 'HP:0030153', (150, 153))	('CCA', 'Disease', (150, 153))	('patients', 'Species', '9606', (136, 144))	('miR', 'Gene', '220972', (108, 111))	('miR', 'Gene', (108, 111))	('GSE53992', 'Var', (168, 176))
184181	33490245	Based on the sequencing results, miRNAs with  logFC   >1 were defined as CCA with differential expression in the control group.	('miR', 'Gene', '220972', (33, 36))	('miR', 'Gene', (33, 36))	('CCA', 'Phenotype', 'HP:0030153', (73, 76))	('logFC   >1', 'Var', (46, 56))	('CCA', 'Disease', (73, 76))
184184	33490245	Through the exploration of TCGA database, miR-3913-5p was highly expressed in the tumor group (Figure 2(a)).	('miR-3913-5p', 'Var', (42, 53))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('miR-3913-5p', 'Chemical', '-', (42, 53))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
184185	33490245	RNAs from a normal bile duct epithelial and two bile duct cancerous cell lines were extracted, and the significantly high expression of miR-3913-5p in tumor cell lines was verified by RT-qPCR (Figure 2(b)).	('expression', 'MPA', (122, 132))	('bile duct cancerous', 'Disease', (48, 67))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('miR-3913-5p', 'Var', (136, 147))	('bile duct cancerous', 'Disease', 'MESH:D001650', (48, 67))	('high', 'PosReg', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('miR-3913-5p', 'Chemical', '-', (136, 147))
184187	33490245	Therefore, miR-3913-5p may be the oncogenic molecule of CCA.	('miR-3913-5p', 'Var', (11, 22))	('CCA', 'Disease', (56, 59))	('CCA', 'Phenotype', 'HP:0030153', (56, 59))	('miR-3913-5p', 'Chemical', '-', (11, 22))
184193	33490245	The results revealed that the OS in the high-expression group of miR-3913-5p was significantly lower than that in the low-expression group (P = 0.0044) (Figure 3(b)) and that the PFS in the high-expression group was lower than that in the low-expression group (P = 0.0071) (Figure 3(c)).	('lower', 'NegReg', (95, 100))	('lower', 'NegReg', (216, 221))	('PFS', 'MPA', (179, 182))	('miR-3913-5p', 'Chemical', '-', (65, 76))	('miR-3913-5p', 'Var', (65, 76))
184201	33490245	According to expression analysis, it was concluded that RNF24 and SIGLEC might be the target genes of miR-3913-5p (Figure 5).	('miR-3913-5p', 'Chemical', '-', (102, 113))	('SIGLEC', 'Gene', (66, 72))	('miR-3913-5p', 'Var', (102, 113))	('RNF24', 'Gene', '11237', (56, 61))	('RNF24', 'Gene', (56, 61))
184203	33490245	In addition, colony forming assays also revealed that cells that overexpressed miR-3913-5p had an enhanced colony forming capacity, while by inhibiting this gene, the colony forming ability decreased in HCCC cells (Figure 6(g)).	('enhanced', 'PosReg', (98, 106))	('overexpressed', 'PosReg', (65, 78))	('miR-3913-5p', 'Chemical', '-', (79, 90))	('miR-3913-5p', 'Var', (79, 90))	('colony forming ability', 'CPA', (167, 189))	('decreased', 'NegReg', (190, 199))	('inhibiting', 'NegReg', (141, 151))	('colony forming capacity', 'CPA', (107, 130))
184204	33490245	Migration assays revealed that overexpression of miR-3913-5p promoted cell migration, whereas the inhibition of this gene reduced cell migration (Figure 6(h)).	('cell migration', 'CPA', (130, 144))	('promoted', 'PosReg', (61, 69))	('cell migration', 'CPA', (70, 84))	('inhibition', 'NegReg', (98, 108))	('miR-3913-5p', 'Chemical', '-', (49, 60))	('reduced', 'NegReg', (122, 129))	('miR-3913-5p', 'Var', (49, 60))
184209	33490245	A recent study has been reported that have reported miRNA-137 suppresses the proliferation, migration, and invasion of cholangiocarcinoma cells by targeting WNT2B.	('cholangiocarcinoma', 'Disease', (119, 137))	('proliferation', 'CPA', (77, 90))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (119, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (119, 137))	('WNT2B', 'Gene', (157, 162))	('migration', 'CPA', (92, 101))	('WNT2B', 'Gene', '7482', (157, 162))	('targeting', 'Reg', (147, 156))	('invasion', 'CPA', (107, 115))	('suppresses', 'NegReg', (62, 72))	('miRNA-137', 'Var', (52, 61))	('miRNA-137', 'Chemical', '-', (52, 61))
184217	33490245	The present study was the first to report the carcinogenic role of miR-3913-5p in tumors, especially in CCA.	('CCA', 'Disease', (104, 107))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('miR-3913-5p', 'Var', (67, 78))	('CCA', 'Phenotype', 'HP:0030153', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('carcinogenic', 'Disease', 'MESH:D063646', (46, 58))	('miR-3913-5p', 'Chemical', '-', (67, 78))	('carcinogenic', 'Disease', (46, 58))
184218	33490245	A diagnostic and prognostic model of miR-3913-5p was constructed for the first time, which improved the diagnostic effectiveness of CCA to a certain extent, and it is beneficial to observe the prognosis of patients with CCA as a biomarker.	('miR-3913-5p', 'Chemical', '-', (37, 48))	('CCA', 'Phenotype', 'HP:0030153', (220, 223))	('CCA', 'Disease', (132, 135))	('miR-3913-5p', 'Var', (37, 48))	('patients', 'Species', '9606', (206, 214))	('CCA', 'Phenotype', 'HP:0030153', (132, 135))	('improved', 'PosReg', (91, 99))
184222	33490245	Our study combined the clinical information of the samples with the screened miR-3913-5p for univariate and multivariate analyses, further identifying this molecule as an independent factor affecting patient survival.	('affecting', 'Reg', (190, 199))	('miR-3913-5p', 'Var', (77, 88))	('patient', 'Species', '9606', (200, 207))	('miR-3913-5p', 'Chemical', '-', (77, 88))
184225	33490245	Since the majority of the target genes were associated with negative regulation of cell metabolism, it was shown that miR-3913-5p might be a potential tumor promotor.	('miR-3913-5p', 'Var', (118, 129))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cell metabolism', 'MPA', (83, 98))	('tumor', 'Disease', (151, 156))	('miR-3913-5p', 'Chemical', '-', (118, 129))	('negative regulation', 'MPA', (60, 79))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
184230	33490245	To verify these predictions, CCK-8, Transwell, and colony forming assays were conducted, and the results showed that overexpression of miR-3913-5p was associated with increased proliferation, clonal formation, and migration of CCA cells.	('CCA', 'Disease', (227, 230))	('miR-3913-5p', 'Var', (135, 146))	('CCA', 'Phenotype', 'HP:0030153', (227, 230))	('clonal formation', 'CPA', (192, 208))	('increased', 'PosReg', (167, 176))	('migration', 'CPA', (214, 223))	('overexpression', 'PosReg', (117, 131))	('proliferation', 'CPA', (177, 190))	('miR-3913-5p', 'Chemical', '-', (135, 146))
184231	33490245	Therefore, the poor prognosis of patients in the high-expression group might be associated with the proliferation and metastasis of tumor cells mediated by miR-3913-5p.	('patients', 'Species', '9606', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('metastasis', 'CPA', (118, 128))	('miR-3913-5p', 'Var', (156, 167))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('proliferation', 'CPA', (100, 113))	('tumor', 'Disease', (132, 137))	('miR-3913-5p', 'Chemical', '-', (156, 167))
184235	33490245	Due to the complexity of the body, in vivo experiments are needed to further confirm the role of miR-3913-5p in the progression of CCA.	('miR-3913-5p', 'Chemical', '-', (97, 108))	('CCA', 'Disease', (131, 134))	('CCA', 'Phenotype', 'HP:0030153', (131, 134))	('miR-3913-5p', 'Var', (97, 108))
184236	33490245	In conclusion, we have demonstrated that miR-3913-5p is upregulated in CCA cell lines, and high expression of this gene is associated with poor prognosis based on TCGA database.	('CCA', 'Disease', (71, 74))	('miR-3913-5p', 'Chemical', '-', (41, 52))	('miR-3913-5p', 'Var', (41, 52))	('CCA', 'Phenotype', 'HP:0030153', (71, 74))	('upregulated', 'PosReg', (56, 67))
184247	31518056	A total of 11 BDBs were diagnosed as malignant (10 with HCC and 1 with cholangiocarcinoma), 2 were diagnosed as atypical, and 1 BDB was diagnosed as negative; approximately two-thirds were found to have polysomy on fluorescence in situ hybridization.	('BDB', 'Gene', (14, 17))	('polysomy', 'Var', (203, 211))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (71, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('BDB', 'Gene', '4920', (128, 131))	('BDB', 'Gene', '4920', (14, 17))	('BDB', 'Gene', (128, 131))	('HCC', 'Phenotype', 'HP:0001402', (56, 59))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (71, 89))	('HCC', 'Gene', (56, 59))	('cholangiocarcinoma', 'Disease', (71, 89))	('HCC', 'Gene', '619501', (56, 59))
184264	31518056	In addition, the presence of malignant-appearing single cells with preserved granular "oncocytoid" or clear/microvesicular cytoplasm, nuclear pleomorphism or anisonucleosis, an increased nuclear/cytoplasmic ratio, papillae, necrosis, multinucleated tumor giant cells, and a 2-cell population of oncocytoid cells with abundant granular cytoplasm and ductal cells (singly dispersed columnar cells or in honeycomb sheets) was noted.	('necrosis', 'Disease', (224, 232))	('multinucleated tumor giant cells', 'Phenotype', 'HP:0031324', (234, 266))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('nuclear pleomorphism', 'CPA', (134, 154))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('necrosis', 'Disease', 'MESH:D009336', (224, 232))	('increased', 'PosReg', (177, 186))	('anisonucleosis', 'Var', (158, 172))	('tumor', 'Disease', (249, 254))	('nuclear/cytoplasmic ratio', 'CPA', (187, 212))	('honeycomb', 'Species', '119431', (401, 410))
184292	31518056	Fluorescence in situ hybridization (FISH) was performed on 3 specimens and was "positive" in 2 cases, both of which demonstrated polysomy (one by Vysis UroVysion FISH demonstrating >5 cells with >=2 chromosomes [chromosomes 3, 7, and 17] and the other by a pancreatobiliary FISH probe kit that demonstrated gains of >=2 loci of 1q21, 7p12, 8q24, and 9p21).	('Vysis UroVysion FISH', 'Disease', 'None', (146, 166))	('Vysis UroVysion FISH', 'Disease', (146, 166))	('polysomy', 'Var', (129, 137))
184390	32824685	IDH1 harbors missense mutations confined predominantly to a single residue (e.g., R132) in the active site of the enzyme.	('a', 'Gene', '351', (6, 7))	('a', 'Gene', '351', (58, 59))	('a', 'Gene', '351', (25, 26))	('a', 'Gene', '351', (49, 50))	('R132', 'Var', (82, 86))	('R132', 'Chemical', '-', (82, 86))	('IDH1', 'Gene', (0, 4))	('a', 'Gene', '351', (95, 96))
184391	32824685	Five mutations have been described (i.e., p.R132H, p.R132C, p.R132G, p.R132S, and p.R132L) in IDH1-mutated cancers, but R132C is the most frequent in iCCA.	('cancers', 'Disease', (107, 114))	('R132C', 'Var', (120, 125))	('R132C', 'Mutation', 'rs121913499', (120, 125))	('a', 'Gene', '351', (8, 9))	('p.R132S', 'Mutation', 'rs121913499', (69, 76))	('a', 'Gene', '351', (102, 103))	('a', 'Gene', '351', (16, 17))	('a', 'Gene', '351', (78, 79))	('p.R132L', 'Var', (82, 89))	('p.R132G', 'Var', (60, 67))	('p.R132C', 'Mutation', 'rs121913499', (51, 58))	('A', 'Gene', '351', (153, 154))	('R132C', 'Mutation', 'rs121913499', (53, 58))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('p.R132L', 'Mutation', 'rs121913500', (82, 89))	('p.R132C', 'Var', (51, 58))	('a', 'Gene', '351', (108, 109))	('p.R132H', 'Mutation', 'rs121913500', (42, 49))	('p.R132S', 'Var', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('p.R132H', 'Var', (42, 49))	('p.R132G', 'Mutation', 'rs121913499', (60, 67))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
184428	32824685	IDH1 acts as a homodimer and each monomer is characterized by three domains: The large domain (residues 1-103 and 286-414) characterized by a Rossmann fold; the small domain (residues 104-136 and 186-285) composed of an alpha/beta sandwich structure; and the claps domain (residues 137-185) with two two-stranded and anti-parallel beta-sheets.	('a', 'Gene', '351', (317, 318))	('a', 'Gene', '351', (192, 193))	('a', 'Gene', '351', (25, 26))	('a', 'Gene', '351', (224, 225))	('a', 'Gene', '351', (49, 50))	('alpha/beta', 'Gene', (220, 230))	('a', 'Gene', '351', (334, 335))	('a', 'Gene', '351', (229, 230))	('residues 104-136', 'Var', (175, 191))	('a', 'Gene', '351', (71, 72))	('a', 'Gene', '351', (325, 326))	('alpha/beta', 'Gene', '351', (220, 230))	('a', 'Gene', '351', (47, 48))	('a', 'Gene', '351', (127, 128))	('a', 'Gene', '351', (268, 269))	('a', 'Gene', '351', (261, 262))	('a', 'Gene', '351', (125, 126))	('a', 'Gene', '351', (323, 324))	('a', 'Gene', '351', (110, 111))	('a', 'Gene', '351', (140, 141))	('a', 'Gene', '351', (30, 31))	('a', 'Gene', '351', (313, 314))	('a', 'Gene', '351', (13, 14))	('a', 'Gene', '351', (220, 221))	('a', 'Gene', '351', (251, 252))	('a', 'Gene', '351', (170, 171))	('a', 'Gene', '351', (307, 308))	('a', 'Gene', '351', (163, 164))	('a', 'Gene', '351', (82, 83))	('a', 'Gene', '351', (5, 6))	('a', 'Gene', '351', (217, 218))	('a', 'Gene', '351', (10, 11))	('a', 'Gene', '351', (147, 148))	('a', 'Gene', '351', (90, 91))	('residues', 'Var', (95, 103))	('a', 'Gene', '351', (232, 233))
184442	32824685	R132G exhibits the highest levels followed by R132C and R132H, while R132S/L catalyze the conversion of alpha-KG to d-2HG at a rate similar to R132C/H.	('a', 'Gene', '351', (137, 138))	('a', 'Gene', '351', (104, 105))	('R132H', 'SUBSTITUTION', 'None', (56, 61))	('a', 'Gene', '351', (80, 81))	('a', 'Gene', '351', (128, 129))	('R132C', 'Mutation', 'rs121913499', (46, 51))	('a', 'Gene', '351', (78, 79))	('a', 'Gene', '351', (125, 126))	('R132C', 'Mutation', 'rs121913499', (143, 148))	('d-2HG', 'Chemical', 'MESH:C019417', (116, 121))	('alpha-KG', 'Chemical', 'MESH:D007656', (104, 112))	('R132S', 'Var', (69, 74))	('a', 'Gene', '351', (52, 53))	('a', 'Gene', '351', (108, 109))	('R132S', 'SUBSTITUTION', 'None', (69, 74))	('a', 'Gene', '351', (122, 123))	('R132H', 'Var', (56, 61))	('R132G', 'Mutation', 'rs121913499', (0, 5))	('R132G', 'Var', (0, 5))
184444	32824685	In nature, it exists as two enantiomers:S-2-HG (or l-2HG) and R-2-HG (or d-2HG):generally produced at low concentrations in healthy mammalian cells through the activity of two FAD-dependent mitochondrial enzymes:d- and l-2-hydroxyglutarate dehydrogenase (D2HGDH and L2HGDH):that convert the corresponding enantiomer into alpha-KG.	('L2HGDH', 'Gene', '79944', (266, 272))	('a', 'Gene', '351', (262, 263))	('alpha-KG', 'Chemical', 'MESH:D007656', (321, 329))	('L2HGDH', 'Gene', (266, 272))	('d-2HG', 'Chemical', 'MESH:C019417', (73, 78))	('l-2-hydroxyglutarate dehydrogenase', 'Gene', '79944', (219, 253))	('a', 'Gene', '351', (325, 326))	('a', 'Gene', '351', (215, 216))	('a', 'Gene', '351', (160, 161))	('a', 'Gene', '351', (126, 127))	('a', 'Gene', '351', (276, 277))	('l-2-hydroxyglutarate dehydrogenase', 'Gene', (219, 253))	('A', 'Gene', '351', (177, 178))	('a', 'Gene', '351', (236, 237))	('a', 'Gene', '351', (85, 86))	('a', 'Gene', '351', (133, 134))	('a', 'Gene', '351', (30, 31))	('a', 'Gene', '351', (234, 235))	('a', 'Gene', '351', (21, 22))	('a', 'Gene', '351', (4, 5))	('D2HGDH', 'Gene', (255, 261))	('a', 'Gene', '351', (307, 308))	('R-2-HG', 'Var', (62, 68))	('2-HG', 'Chemical', 'MESH:C019417', (42, 46))	('mammalian', 'Species', '9606', (132, 141))	('a', 'Gene', '351', (139, 140))	('a', 'Gene', '351', (250, 251))	('a', 'Gene', '351', (321, 322))	('2-HG', 'Chemical', 'MESH:C019417', (64, 68))	('a', 'Gene', '351', (99, 100))	('a', 'Gene', '351', (58, 59))	('D2HGDH', 'Gene', '728294', (255, 261))	('a', 'Gene', '351', (114, 115))	('a', 'Gene', '351', (201, 202))	('a', 'Gene', '351', (136, 137))
184452	32824685	PHDs are involved in hypoxia inducible factors alpha-subunit paralog 1 (HIF-1alpha) destabilization by hydroxylation of conserved proline residues (Pro402 and Pro564), which triggers pVHL-mediated ubiquitination and the consequent proteasomal degradation of HIF-1alpha subunit.	('a', 'Gene', '351', (247, 248))	('a', 'Gene', '351', (192, 193))	('a', 'Gene', '351', (111, 112))	('a', 'Gene', '351', (47, 48))	('a', 'Gene', '351', (40, 41))	('HIF-1alpha', 'Gene', (258, 268))	('proline', 'Chemical', 'MESH:D011392', (130, 137))	('a', 'Gene', '351', (64, 65))	('a', 'Gene', '351', (206, 207))	('a', 'Gene', '351', (62, 63))	('a', 'Gene', '351', (94, 95))	('a', 'Gene', '351', (267, 268))	('PHDs', 'Disease', 'None', (0, 4))	('HIF-1alpha', 'Gene', '3091', (72, 82))	('Pro564', 'Var', (159, 165))	('a', 'Gene', '351', (236, 237))	('a', 'Gene', '351', (77, 78))	('a', 'Gene', '351', (212, 213))	('a', 'Gene', '351', (155, 156))	('Pro402', 'Var', (148, 154))	('triggers', 'Reg', (174, 182))	('hypoxia', 'Disease', (21, 28))	('Pro402', 'Chemical', '-', (148, 154))	('a', 'Gene', '351', (249, 250))	('a', 'Gene', '351', (5, 6))	('a', 'Gene', '351', (240, 241))	('pVHL', 'Gene', '7428', (183, 187))	('HIF-1alpha', 'Gene', (72, 82))	('a', 'Gene', '351', (27, 28))	('PHDs', 'Disease', (0, 4))	('pVHL', 'Gene', (183, 187))	('hypoxia', 'Disease', 'MESH:D000860', (21, 28))	('HIF-1alpha', 'Gene', '3091', (258, 268))	('a', 'Gene', '351', (51, 52))	('a', 'Gene', '351', (263, 264))	('a', 'Gene', '351', (88, 89))	('a', 'Gene', '351', (81, 82))
184456	32824685	Indeed, the DNA repair enzyme alkB homolog (ALKBH) and the DNA damage response proteins lysine-specific demethylase 4A/B (KDM4A/B) require this metabolite to carry out their activity and implement damage response.	('KDM4A/B', 'Gene', (122, 129))	('a', 'Gene', '351', (159, 160))	('a', 'Gene', '351', (183, 184))	('a', 'Gene', '351', (198, 199))	('men', 'Species', '9606', (192, 195))	('A', 'Gene', '351', (44, 45))	('a', 'Gene', '351', (64, 65))	('a', 'Gene', '351', (174, 175))	('4A/B', 'Var', (125, 129))	('a', 'Gene', '351', (30, 31))	('alkB homolog', 'Gene', '8846', (30, 42))	('4A/B', 'Var', (116, 120))	('KDM4A/B', 'Gene', '9682;23030', (122, 129))	('a', 'Gene', '351', (19, 20))	('ALKBH', 'Gene', '8846', (44, 49))	('4A/B', 'SUBSTITUTION', 'None', (125, 129))	('A', 'Gene', '351', (126, 127))	('a', 'Gene', '351', (147, 148))	('4A/B', 'SUBSTITUTION', 'None', (116, 120))	('A', 'Gene', '351', (117, 118))	('ALKBH', 'Gene', (44, 49))	('A', 'Gene', '351', (14, 15))	('a', 'Gene', '351', (66, 67))	('a', 'Gene', '351', (51, 52))	('a', 'Gene', '351', (200, 201))	('alkB homolog', 'Gene', (30, 42))	('A', 'Gene', '351', (61, 62))	('a', 'Gene', '351', (112, 113))
184464	32824685	In the last decade, the attention on hot-spot mutations of IDH1 has escalated because IDH1mut produces d-2HG isomer that, despite being less potent than l-2HG in inhibiting some alpha-KG-dependent dioxygenases, has a notable impact on epigenetic reprogramming of IDH1 mutated cells, due to the competitive block of TETs and JmjC-KDMs activity.	('a', 'Gene', '351', (24, 25))	('a', 'Gene', '351', (271, 272))	('d-2HG', 'Chemical', 'MESH:C019417', (103, 108))	('a', 'Gene', '351', (49, 50))	('a', 'Gene', '351', (334, 335))	('a', 'Gene', '351', (73, 74))	('a', 'Gene', '351', (65, 66))	('a', 'Gene', '351', (15, 16))	('inhibiting', 'NegReg', (162, 172))	('a', 'Gene', '351', (8, 9))	('alpha-KG', 'Chemical', 'MESH:D007656', (178, 186))	('a', 'Gene', '351', (71, 72))	('a', 'Gene', '351', (253, 254))	('a', 'Gene', '351', (215, 216))	('a', 'Gene', '351', (150, 151))	('a', 'Gene', '351', (182, 183))	('d-2HG', 'Var', (103, 108))	('a', 'Gene', '351', (118, 119))	('a', 'Gene', '351', (205, 206))	('a', 'Gene', '351', (228, 229))	('a', 'Gene', '351', (212, 213))	('a', 'Gene', '351', (220, 221))	('IDH1mut', 'Var', (86, 93))	('IDH1', 'Gene', (59, 63))	('competitive block of TETs and JmjC-KDMs', 'Disease', 'MESH:D006327', (294, 333))	('a', 'Gene', '351', (178, 179))	('a', 'Gene', '351', (320, 321))	('a', 'Gene', '351', (81, 82))
184465	32824685	IDH1mut cancers exhibit an hypermethylated phenotype characterized by CpG island hypermethylation and higher global DNA and histone methylation, in particular an increase in marks such as H3K4me3, H3K9me3 and H3K27me3.	('a', 'Gene', '351', (120, 121))	('a', 'Gene', '351', (24, 25))	('a', 'Gene', '351', (159, 160))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('a', 'Gene', '351', (38, 39))	('cancers', 'Disease', (8, 15))	('H3K4me3', 'Var', (188, 195))	('a', 'Gene', '351', (55, 56))	('higher', 'PosReg', (102, 108))	('a', 'Gene', '351', (149, 150))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('a', 'Gene', '351', (205, 206))	('a', 'Gene', '351', (92, 93))	('a', 'Gene', '351', (77, 78))	('a', 'Gene', '351', (138, 139))	('IDH1mut', 'Gene', (0, 7))	('a', 'Gene', '351', (156, 157))	('a', 'Gene', '351', (98, 99))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('H3K9me3', 'Var', (197, 204))	('a', 'Gene', '351', (185, 186))	('a', 'Gene', '351', (9, 10))	('A', 'Gene', '351', (118, 119))	('H3K27me3', 'Var', (209, 217))	('a', 'Gene', '351', (57, 58))	('a', 'Gene', '351', (167, 168))	('a', 'Gene', '351', (113, 114))	('a', 'Gene', '351', (175, 176))
184466	32824685	The biological effect of high DNA methylation and histone modifications of H3K9me3 and H3K27me3, associated with repression of transcription, is the silencing of genes involved in differentiation and immune response.	('a', 'Gene', '351', (196, 197))	('a', 'Gene', '351', (129, 130))	('H3K9me3', 'Var', (75, 82))	('a', 'Gene', '351', (83, 84))	('silencing', 'NegReg', (149, 158))	('a', 'Gene', '351', (103, 104))	('a', 'Gene', '351', (97, 98))	('a', 'Gene', '351', (65, 66))	('a', 'Gene', '351', (190, 191))	('a', 'Gene', '351', (12, 13))	('A', 'Gene', '351', (32, 33))	('a', 'Gene', '351', (46, 47))	('genes', 'Gene', (162, 167))	('H3K27me3', 'Var', (87, 95))	('a', 'Gene', '351', (40, 41))
184472	32824685	d-2HG may also predispose IDH1mut cells to oncogenic transformation by direct inhibition of ALKBH 1 and 2, other alpha-KG-dependent dioxygenases involved in DNA repair pathways, and/or aberrant expression of DNA repair genes.	('a', 'Gene', '351', (190, 191))	('a', 'Gene', '351', (215, 216))	('d-2HG', 'Var', (0, 5))	('a', 'Gene', '351', (117, 118))	('a', 'Gene', '351', (62, 63))	('A', 'Gene', '351', (210, 211))	('a', 'Gene', '351', (7, 8))	('alpha-KG', 'Chemical', 'MESH:D007656', (113, 121))	('a', 'Gene', '351', (55, 56))	('inhibition', 'NegReg', (78, 88))	('a', 'Gene', '351', (173, 174))	('a', 'Gene', '351', (140, 141))	('ALKBH 1 and 2', 'Gene', '8846;121642', (92, 105))	('a', 'Gene', '351', (164, 165))	('a', 'Gene', '351', (100, 101))	('predispose', 'Reg', (15, 25))	('A', 'Gene', '351', (159, 160))	('a', 'Gene', '351', (185, 186))	('a', 'Gene', '351', (10, 11))	('a', 'Gene', '351', (178, 179))	('d-2HG', 'Chemical', 'MESH:C019417', (0, 5))	('a', 'Gene', '351', (169, 170))	('expression', 'MPA', (194, 204))	('A', 'Gene', '351', (92, 93))	('a', 'Gene', '351', (113, 114))
184473	32824685	Although 2-HG produces genetic instability, which may contribute to cancer initiation by favoring mutagenesis, the accumulation of DNA damage could be an advantage for patients harboring IDH1mut because it increases their vulnerability to chemotherapeutics and radiotherapy.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('a', 'Gene', '351', (262, 263))	('a', 'Gene', '351', (80, 81))	('a', 'Gene', '351', (198, 199))	('a', 'Gene', '351', (270, 271))	('a', 'Gene', '351', (157, 158))	('a', 'Gene', '351', (160, 161))	('a', 'Gene', '351', (151, 152))	('a', 'Gene', '351', (101, 102))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('a', 'Gene', '351', (228, 229))	('A', 'Gene', '351', (0, 1))	('a', 'Gene', '351', (138, 139))	('a', 'Gene', '351', (69, 70))	('a', 'Gene', '351', (115, 116))	('2-HG', 'Chemical', 'MESH:C019417', (9, 13))	('a', 'Gene', '351', (211, 212))	('a', 'Gene', '351', (154, 155))	('a', 'Gene', '351', (122, 123))	('a', 'Gene', '351', (178, 179))	('a', 'Gene', '351', (248, 249))	('a', 'Gene', '351', (257, 258))	('a', 'Gene', '351', (90, 91))	('a', 'Gene', '351', (35, 36))	('a', 'Gene', '351', (51, 52))	('a', 'Gene', '351', (169, 170))	('A', 'Gene', '351', (133, 134))	('patients', 'Species', '9606', (168, 176))	('cancer', 'Disease', (68, 74))	('IDH1mut', 'Var', (187, 194))	('a', 'Gene', '351', (136, 137))
184480	32824685	In a reducing environment and at physiologically relevant concentrations of Fe (II/III), the apparent activation of PHD2 by d-2HG is caused by a non-enzymatic conversion of 2-HG to alpha-KG.	('a', 'Gene', '351', (96, 97))	('a', 'Gene', '351', (102, 103))	('a', 'Gene', '351', (134, 135))	('2-HG', 'Chemical', 'MESH:C019417', (173, 177))	('a', 'Gene', '351', (181, 182))	('a', 'Gene', '351', (143, 144))	('a', 'Gene', '351', (93, 94))	('PHD2', 'Gene', (116, 120))	('a', 'Gene', '351', (54, 55))	('a', 'Gene', '351', (30, 31))	('Fe', 'Chemical', 'MESH:D007501', (76, 78))	('a', 'Gene', '351', (107, 108))	('d-2HG', 'Chemical', 'MESH:C019417', (124, 129))	('PHD2', 'Gene', '54583', (116, 120))	('a', 'Gene', '351', (154, 155))	('a', 'Gene', '351', (44, 45))	('a', 'Gene', '351', (3, 4))	('a', 'Gene', '351', (185, 186))	('d-2HG', 'Var', (124, 129))	('a', 'Gene', '351', (66, 67))	('alpha-KG', 'Chemical', 'MESH:D007656', (181, 189))	('a', 'Gene', '351', (26, 27))
184482	32824685	Moreover, it was demonstrated that d-2HG may contribute to enhanced HIF1 signaling directly by the inhibition of FIH and/or indirectly by fault in collagen protein maturation.	('FIH', 'Protein', (113, 116))	('d-2HG', 'Var', (35, 40))	('a', 'Gene', '351', (25, 26))	('a', 'Gene', '351', (42, 43))	('a', 'Gene', '351', (62, 63))	('a', 'Gene', '351', (151, 152))	('a', 'Gene', '351', (14, 15))	('a', 'Gene', '351', (117, 118))	('HIF1', 'Gene', (68, 72))	('d-2HG', 'Chemical', 'MESH:C019417', (35, 40))	('inhibition', 'NegReg', (99, 109))	('a', 'Gene', '351', (169, 170))	('a', 'Gene', '351', (139, 140))	('a', 'Gene', '351', (32, 33))	('a', 'Gene', '351', (77, 78))	('a', 'Gene', '351', (165, 166))	('HIF1', 'Gene', '3091', (68, 72))
184483	32824685	Inhibition of collagen-4-prolyl hydroxylase by d-2HG reduces endostatin production, potentially favoring the induction of the hypoxia pathway.	('a', 'Gene', '351', (18, 19))	('endostatin', 'Gene', '80781', (61, 71))	('endostatin', 'Gene', (61, 71))	('Inhibition', 'NegReg', (0, 10))	('a', 'Gene', '351', (97, 98))	('hypoxia', 'Disease', (126, 133))	('hypoxia', 'Disease', 'MESH:D000860', (126, 133))	('a', 'Gene', '351', (135, 136))	('a', 'Gene', '351', (139, 140))	('d-2HG', 'Var', (47, 52))	('a', 'Gene', '351', (67, 68))	('reduces', 'NegReg', (53, 60))	('a', 'Gene', '351', (132, 133))	('a', 'Gene', '351', (40, 41))	('d-2HG', 'Chemical', 'MESH:C019417', (47, 52))	('a', 'Gene', '351', (91, 92))
184488	32824685	Besides HIF1 signaling, another important pathway regulated by IDH1mut is the mammalian/mechanistic target of rapamycin (mTOR), which is responsive to mitogenic signals and/or the availability of nutrients/cellular energy, and regulates cell growth, proliferation, autophagy, survival, and metabolism on the basis of signal inputs.	('a', 'Gene', '351', (79, 80))	('a', 'Gene', '351', (24, 25))	('a', 'Gene', '351', (309, 310))	('a', 'Gene', '351', (17, 18))	('a', 'Gene', '351', (271, 272))	('a', 'Gene', '351', (223, 224))	('a', 'Gene', '351', (286, 287))	('a', 'Gene', '351', (111, 112))	('a', 'Gene', '351', (47, 48))	('HIF1', 'Gene', '3091', (8, 12))	('a', 'Gene', '351', (165, 166))	('a', 'Gene', '351', (182, 183))	('a', 'Gene', '351', (38, 39))	('mTOR', 'Gene', (121, 125))	('HIF1', 'Gene', (8, 12))	('a', 'Gene', '351', (180, 181))	('a', 'Gene', '351', (55, 56))	('a', 'Gene', '351', (101, 102))	('a', 'Gene', '351', (293, 294))	('mammalian/mechanistic target of rapamycin', 'Gene', '2475', (78, 119))	('a', 'Gene', '351', (92, 93))	('cell growth', 'CPA', (237, 248))	('a', 'Gene', '351', (85, 86))	('a', 'Gene', '351', (212, 213))	('mTOR', 'Gene', '2475', (121, 125))	('a', 'Gene', '351', (258, 259))	('a', 'Gene', '351', (282, 283))	('IDH1mut', 'Var', (63, 70))	('mammalian/mechanistic target of rapamycin', 'Gene', (78, 119))	('a', 'Gene', '351', (43, 44))	('a', 'Gene', '351', (82, 83))	('a', 'Gene', '351', (321, 322))	('a', 'Gene', '351', (185, 186))	('a', 'Gene', '351', (265, 266))	('a', 'Gene', '351', (169, 170))	('a', 'Gene', '351', (232, 233))	('a', 'Gene', '351', (113, 114))
184494	32824685	demonstrated alterations in cellular concentration of several metabolites (e.g., some amino acids, glutathione metabolites, choline derivatives, and TCA cycle intermediates) for which the 2-HG production by IDH1R132H neomorphic activity was not the unique factor responsible, but alpha-KG and NADPH availability became crucial in the rewiring of the metabolic landscape of cells carrying the mutation.	('a', 'Gene', '351', (137, 138))	('a', 'Gene', '351', (168, 169))	('a', 'Gene', '351', (103, 104))	('glutathione', 'Chemical', 'MESH:D005978', (99, 110))	('a', 'Gene', '351', (65, 66))	('a', 'Gene', '351', (238, 239))	('a', 'Gene', '351', (8, 9))	('a', 'Gene', '351', (301, 302))	('a', 'Gene', '351', (380, 381))	('a', 'Gene', '351', (395, 396))	('alpha-KG', 'Chemical', 'MESH:D007656', (280, 288))	('a', 'Gene', '351', (86, 87))	('choline', 'Chemical', 'MESH:D002794', (124, 131))	('a', 'Gene', '351', (324, 325))	('a', 'Gene', '351', (228, 229))	('a', 'Gene', '351', (92, 93))	('a', 'Gene', '351', (284, 285))	('a', 'Gene', '351', (59, 60))	('a', 'Gene', '351', (315, 316))	('2-HG', 'Chemical', 'MESH:C019417', (188, 192))	('a', 'Gene', '351', (13, 14))	('a', 'Gene', '351', (45, 46))	('a', 'Gene', '351', (299, 300))	('a', 'Gene', '351', (361, 362))	('a', 'Gene', '351', (304, 305))	('a', 'Gene', '351', (353, 354))	('IDH1R132H', 'Var', (207, 216))	('a', 'Gene', '351', (34, 35))	('a', 'Gene', '351', (18, 19))	('a', 'Gene', '351', (257, 258))	('a', 'Gene', '351', (145, 146))	('a', 'Gene', '351', (289, 290))	('a', 'Gene', '351', (114, 115))	('TCA', 'Chemical', 'MESH:D014238', (149, 152))	('NADPH', 'Gene', (293, 298))	('a', 'Gene', '351', (366, 367))	('a', 'Gene', '351', (280, 281))	('NADPH', 'Gene', '1666', (293, 298))
184507	32824685	As a matter of fact, glioma tumors and cells harboring IDH1mut are characterized by lower intracellular lactate levels compared to IDH1wt, probably due to hypermethylation of the lactate dehydrogenase A (LDHA) gene promoter driven by 2-HG increase.	('lactate dehydrogenase A', 'Gene', '3939', (179, 202))	('a', 'Gene', '351', (63, 64))	('a', 'Gene', '351', (166, 167))	('a', 'Gene', '351', (183, 184))	('a', 'Gene', '351', (71, 72))	('LDHA', 'Gene', '3939', (204, 208))	('a', 'Gene', '351', (16, 17))	('lactate dehydrogenase A', 'Gene', (179, 202))	('a', 'Gene', '351', (6, 7))	('a', 'Gene', '351', (143, 144))	('a', 'Gene', '351', (244, 245))	('glioma tumors', 'Disease', 'MESH:D005910', (21, 34))	('2-HG', 'Chemical', 'MESH:C019417', (234, 238))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('a', 'Gene', '351', (180, 181))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('a', 'Gene', '351', (101, 102))	('a', 'Gene', '351', (94, 95))	('lower intracellular lactate', 'Phenotype', 'HP:0030086', (84, 111))	('A', 'Gene', '351', (201, 202))	('a', 'Gene', '351', (46, 47))	('a', 'Gene', '351', (197, 198))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('A', 'Gene', '351', (0, 1))	('a', 'Gene', '351', (69, 70))	('LDHA', 'Gene', (204, 208))	('a', 'Gene', '351', (108, 109))	('IDH1mut', 'Var', (55, 62))	('A', 'Gene', '351', (207, 208))	('lactate', 'Chemical', 'MESH:D019344', (179, 186))	('a', 'Gene', '351', (3, 4))	('a', 'Gene', '351', (123, 124))	('a', 'Gene', '351', (35, 36))	('lower', 'NegReg', (84, 89))	('a', 'Gene', '351', (105, 106))	('lactate', 'Chemical', 'MESH:D019344', (104, 111))	('a', 'Gene', '351', (26, 27))	('glioma tumors', 'Disease', (21, 34))
184508	32824685	The tangled mechanisms by which IDH1mut becomes able to interfere with normal cell functions remain unclear, but it is evident that the balance of intracellular levels of many factors, particularly d-2HG, alphaKG and NADPH, is crucial in contributing to cancer development and progression.	('a', 'Gene', '351', (137, 138))	('a', 'Gene', '351', (129, 130))	('a', 'Gene', '351', (255, 256))	('a', 'Gene', '351', (48, 49))	('a', 'Gene', '351', (96, 97))	('cancer', 'Disease', (254, 260))	('d-2HG', 'Chemical', 'MESH:C019417', (198, 203))	('a', 'Gene', '351', (16, 17))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('a', 'Gene', '351', (213, 214))	('a', 'Gene', '351', (158, 159))	('NADPH', 'Gene', (217, 222))	('a', 'Gene', '351', (151, 152))	('d-2HG', 'Var', (198, 203))	('NADPH', 'Gene', '1666', (217, 222))	('contributing', 'Reg', (238, 250))	('a', 'Gene', '351', (205, 206))	('a', 'Gene', '351', (105, 106))	('a', 'Gene', '351', (172, 173))	('progression', 'CPA', (277, 288))	('a', 'Gene', '351', (186, 187))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('a', 'Gene', '351', (139, 140))	('a', 'Gene', '351', (273, 274))	('a', 'Gene', '351', (5, 6))	('a', 'Gene', '351', (75, 76))	('a', 'Gene', '351', (209, 210))	('men', 'Species', '9606', (268, 271))	('a', 'Gene', '351', (232, 233))	('a', 'Gene', '351', (193, 194))	('a', 'Gene', '351', (177, 178))
184510	32824685	Nonetheless, some downstream effects of both neomorphic enzyme activity and d-2HG accumulation may be seen in other cancer types with similar consequences on cellular physiopathology.	('a', 'Gene', '351', (89, 90))	('a', 'Gene', '351', (174, 175))	('a', 'Gene', '351', (63, 64))	('a', 'Gene', '351', (117, 118))	('a', 'Gene', '351', (164, 165))	('a', 'Gene', '351', (96, 97))	('cancer', 'Disease', (116, 122))	('d-2HG', 'Var', (76, 81))	('a', 'Gene', '351', (72, 73))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('a', 'Gene', '351', (139, 140))	('d-2HG', 'Chemical', 'MESH:C019417', (76, 81))	('a', 'Gene', '351', (82, 83))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('a', 'Gene', '351', (26, 27))
184513	32824685	However, one indisputable observation is that iCCA patients with IDH1mut are characterized by significantly higher levels of d-2HG, compared to wild-type tumors, and this may lead to alterations of normal cellular functions.	('a', 'Gene', '351', (79, 80))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('d-2HG', 'MPA', (125, 130))	('a', 'Gene', '351', (73, 74))	('a', 'Gene', '351', (183, 184))	('a', 'Gene', '351', (32, 33))	('a', 'Gene', '351', (102, 103))	('IDH1mut', 'Var', (65, 72))	('d-2HG', 'Chemical', 'MESH:C019417', (125, 130))	('patients', 'Species', '9606', (51, 59))	('higher', 'PosReg', (108, 114))	('a', 'Gene', '351', (188, 189))	('a', 'Gene', '351', (21, 22))	('a', 'Gene', '351', (172, 173))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('levels', 'MPA', (115, 121))	('a', 'Gene', '351', (52, 53))	('A', 'Gene', '351', (49, 50))	('a', 'Gene', '351', (162, 163))	('a', 'Gene', '351', (43, 44))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('a', 'Gene', '351', (211, 212))	('tumors', 'Disease', (154, 160))	('a', 'Gene', '351', (202, 203))	('a', 'Gene', '351', (177, 178))	('a', 'Gene', '351', (81, 82))	('a', 'Gene', '351', (136, 137))
184518	32824685	reported that an increase of 2-HG in hepatoblasts, expressing IDH1R123C form, epigenetically controls the expression of HNF-4alpha, a master regulator of hepatocyte lineage progression.	('a', 'Gene', '351', (129, 130))	('HNF-4alpha', 'Gene', '3172', (120, 130))	('a', 'Gene', '351', (135, 136))	('controls', 'Reg', (93, 101))	('2-HG', 'Chemical', 'MESH:C019417', (29, 33))	('a', 'Gene', '351', (40, 41))	('a', 'Gene', '351', (157, 158))	('a', 'Gene', '351', (14, 15))	('expression', 'MPA', (106, 116))	('a', 'Gene', '351', (125, 126))	('HNF-4alpha', 'Gene', (120, 130))	('a', 'Gene', '351', (22, 23))	('a', 'Gene', '351', (146, 147))	('a', 'Gene', '351', (45, 46))	('IDH1R123C form', 'Var', (62, 76))	('a', 'Gene', '351', (132, 133))	('a', 'Gene', '351', (11, 12))	('a', 'Gene', '351', (169, 170))	('a', 'Gene', '351', (88, 89))
184519	32824685	They demonstrated the involvement of d-2HG in the inhibition of hepatocellular differentiation and uncontrolled proliferation of liver progenitor cells, with cooperative function of activated KRas, establishing that IDH1mut may represent an early event in iCCA carcinogenesis, as observed in glioblastoma and acute myeloid leukemia (AML).	('a', 'Gene', '351', (89, 90))	('a', 'Gene', '351', (120, 121))	('a', 'Gene', '351', (309, 310))	('a', 'Gene', '351', (262, 263))	('KRas', 'Gene', '3845', (192, 196))	('a', 'Gene', '351', (238, 239))	('a', 'Gene', '351', (303, 304))	('glioblastoma', 'Disease', (292, 304))	('a', 'Gene', '351', (95, 96))	('a', 'Gene', '351', (277, 278))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (309, 331))	('glioblastoma', 'Phenotype', 'HP:0012174', (292, 304))	('a', 'Gene', '351', (182, 183))	('a', 'Gene', '351', (213, 214))	('IDH1mut', 'Var', (216, 223))	('AML', 'Disease', 'MESH:D015470', (333, 336))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (309, 331))	('leukemia', 'Phenotype', 'HP:0001909', (323, 331))	('AML', 'Disease', (333, 336))	('d-2HG', 'Chemical', 'MESH:C019417', (37, 42))	('a', 'Gene', '351', (13, 14))	('a', 'Gene', '351', (164, 165))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (315, 331))	('a', 'Gene', '351', (330, 331))	('a', 'Gene', '351', (76, 77))	('a', 'Gene', '351', (194, 195))	('a', 'Gene', '351', (225, 226))	('a', 'Gene', '351', (67, 68))	('a', 'Gene', '351', (187, 188))	('a', 'Gene', '351', (242, 243))	('a', 'Gene', '351', (305, 306))	('a', 'Gene', '351', (298, 299))	('iCCA carcinogenesis', 'Disease', 'MESH:D063646', (256, 275))	('glioblastoma', 'Disease', 'MESH:D005909', (292, 304))	('KRas', 'Gene', (192, 196))	('acute myeloid leukemia', 'Disease', (309, 331))	('men', 'Species', '9606', (29, 32))	('a', 'Gene', '351', (201, 202))	('iCCA carcinogenesis', 'Disease', (256, 275))
184526	32824685	By an integrated analysis of CCA samples extracted by The Cancer Genome Atlas (TCGA), another research group identified a class of IDH mutant-enriched clusters with high expression of mitochondrial genes, including components of the electron transport chain and citric acid cycle, low expression of chromatin modifiers, in particular epigenetic silencing of ARID1A, and relatively high mitochondrial DNA copy numbers.	('a', 'Gene', '351', (120, 121))	('a', 'Gene', '351', (254, 255))	('A', 'Gene', '351', (363, 364))	('a', 'Gene', '351', (17, 18))	('low', 'NegReg', (281, 284))	('A', 'Gene', '351', (402, 403))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('a', 'Gene', '351', (397, 398))	('A', 'Gene', '351', (82, 83))	('IDH', 'Gene', '3417', (131, 134))	('expression', 'MPA', (170, 180))	('citric acid', 'Chemical', 'MESH:D019343', (262, 273))	('a', 'Gene', '351', (244, 245))	('a', 'Gene', '351', (373, 374))	('a', 'Gene', '351', (269, 270))	('a', 'Gene', '351', (86, 87))	('a', 'Gene', '351', (331, 332))	('Cancer', 'Disease', (58, 64))	('a', 'Gene', '351', (324, 325))	('ARID1A', 'Gene', (358, 364))	('a', 'Gene', '351', (195, 196))	('a', 'Gene', '351', (59, 60))	('a', 'Gene', '351', (258, 259))	('a', 'Gene', '351', (138, 139))	('A', 'Gene', '351', (72, 73))	('a', 'Gene', '351', (45, 46))	('a', 'Gene', '351', (124, 125))	('high', 'PosReg', (165, 169))	('a', 'Gene', '351', (19, 20))	('expression', 'MPA', (285, 295))	('a', 'Gene', '351', (304, 305))	('a', 'Gene', '351', (12, 13))	('A', 'Gene', '351', (358, 359))	('Cancer', 'Disease', 'MESH:D009369', (58, 64))	('ARID1A', 'Gene', '8289', (358, 364))	('a', 'Gene', '351', (75, 76))	('a', 'Gene', '351', (98, 99))	('a', 'Gene', '351', (3, 4))	('a', 'Gene', '351', (34, 35))	('A', 'Gene', '351', (31, 32))	('epigenetic silencing', 'Var', (334, 354))	('IDH', 'Gene', (131, 134))	('a', 'Gene', '351', (366, 367))
184535	32824685	Many inhibitors are active against common IDH1 mutations (e.g., R132H, R132C, R132G, R132S, and R132L), but few are specific for the IDH1mut isoform (e.g., R140Q or R132C), and only one compound is a pan-inhibitor capable of blocking both IDH1 and IDH2 mutants.	('R132G', 'Mutation', 'rs121913499', (78, 83))	('R132G', 'Var', (78, 83))	('IDH1', 'Gene', (239, 243))	('a', 'Gene', '351', (198, 199))	('a', 'Gene', '351', (16, 17))	('a', 'Gene', '351', (215, 216))	('R132C', 'Var', (71, 76))	('R132C', 'Mutation', 'rs121913499', (71, 76))	('R132H', 'SUBSTITUTION', 'None', (64, 69))	('a', 'Gene', '351', (244, 245))	('R132C', 'Var', (165, 170))	('R132C', 'Mutation', 'rs121913499', (165, 170))	('R140Q', 'Mutation', 'rs121913502', (156, 161))	('a', 'Gene', '351', (29, 30))	('a', 'Gene', '351', (173, 174))	('a', 'Gene', '351', (92, 93))	('a', 'Gene', '351', (20, 21))	('R132L', 'Var', (96, 101))	('R140Q', 'Var', (156, 161))	('IDH2', 'Gene', (248, 252))	('R132S', 'Var', (85, 90))	('a', 'Gene', '351', (256, 257))	('a', 'Gene', '351', (217, 218))	('a', 'Gene', '351', (27, 28))	('IDH2', 'Gene', '3418', (248, 252))	('R132S', 'Mutation', 'rs121913499', (85, 90))	('R132L', 'Mutation', 'rs121913500', (96, 101))	('a', 'Gene', '351', (1, 2))	('a', 'Gene', '351', (201, 202))	('IDH1', 'Gene', (42, 46))	('a', 'Gene', '351', (50, 51))	('a', 'Gene', '351', (112, 113))	('R132H', 'Var', (64, 69))
184546	32824685	With the substitution of specific functional groups, AG-120 was obtained, a molecule characterized by high polarity and solubility; good stability in human liver microsomes; low human pregnane X receptor (PXR) activation, which regulates genes involved in drug metabolism and efflux; good permeability; and low efflux ratio.	('a', 'Gene', '351', (89, 90))	('human', 'Species', '9606', (178, 183))	('a', 'Gene', '351', (87, 88))	('a', 'Gene', '351', (303, 304))	('pregnane X receptor', 'Gene', '8856', (184, 203))	('a', 'Gene', '351', (215, 216))	('a', 'Gene', '351', (294, 295))	('a', 'Gene', '351', (181, 182))	('PXR', 'Gene', '8856', (205, 208))	('a', 'Gene', '351', (189, 190))	('low', 'NegReg', (174, 177))	('a', 'Gene', '351', (110, 111))	('a', 'Gene', '351', (116, 117))	('a', 'Gene', '351', (61, 62))	('human', 'Species', '9606', (150, 155))	('a', 'Gene', '351', (139, 140))	('a', 'Gene', '351', (67, 68))	('a', 'Gene', '351', (74, 75))	('substitution', 'Var', (9, 21))	('a', 'Gene', '351', (233, 234))	('a', 'Gene', '351', (272, 273))	('a', 'Gene', '351', (264, 265))	('a', 'Gene', '351', (42, 43))	('a', 'Gene', '351', (210, 211))	('pregnane X receptor', 'Gene', (184, 203))	('a', 'Gene', '351', (153, 154))	('AG-120', 'Chemical', 'MESH:C000627630', (53, 59))	('a', 'Gene', '351', (319, 320))	('PXR', 'Gene', (205, 208))
184549	32824685	At present, three clinical trials (NCT02073994, NCT02989857, NCT04088188) investigating AG-120 in CCA are underway.	('A', 'Gene', '351', (0, 1))	('AG-120 in CCA', 'Mutation', 'c.120AG>CCA', (88, 101))	('a', 'Gene', '351', (24, 25))	('A', 'Gene', '351', (100, 101))	('NCT04088188', 'Var', (61, 72))	('a', 'Gene', '351', (82, 83))	('a', 'Gene', '351', (102, 103))	('A', 'Gene', '351', (88, 89))	('NCT02073994', 'Var', (35, 46))	('a', 'Gene', '351', (112, 113))	('a', 'Gene', '351', (30, 31))
184570	32824685	Very few pre-clinical studies are available regarding FT-2102 (olutasidenib), a potent, orally active and brain penetrant inhibitor of IDH1mut (Table 1), the development of which was supported by Forma Therapeutics (Watertown, MA, United States).	('olutasidenib', 'Chemical', '-', (63, 75))	('a', 'Gene', '351', (39, 40))	('a', 'Gene', '351', (102, 103))	('a', 'Gene', '351', (47, 48))	('a', 'Gene', '351', (95, 96))	('a', 'Gene', '351', (78, 79))	('a', 'Gene', '351', (206, 207))	('a', 'Gene', '351', (180, 181))	('a', 'Gene', '351', (118, 119))	('FT-2102', 'Var', (54, 61))	('a', 'Gene', '351', (30, 31))	('FT-2102', 'Chemical', '-', (54, 61))	('a', 'Gene', '351', (108, 109))	('a', 'Gene', '351', (19, 20))	('a', 'Gene', '351', (67, 68))	('a', 'Gene', '351', (36, 37))	('IDH1mut', 'Gene', (135, 142))	('a', 'Gene', '351', (217, 218))	('men', 'Species', '9606', (165, 168))	('a', 'Gene', '351', (240, 241))	('a', 'Gene', '351', (34, 35))	('a', 'Gene', '351', (90, 91))	('a', 'Gene', '351', (145, 146))	('a', 'Gene', '351', (200, 201))	('A', 'Gene', '351', (228, 229))
184613	32824685	; Writing:review and editing, F.C., M.P., V.C., F.M., G.B., A.P., A.S., F.E., M.L.	('G.B.', 'Var', (54, 58))	('a', 'Gene', '351', (17, 18))	('A', 'Gene', '351', (66, 67))	('F.E.', 'Var', (72, 76))	('A', 'Gene', '351', (60, 61))
184662	23686724	Solitary tumors, lack of vascular invasion, R0 resection and no involvement of lymph nodes are all associated with a better prognosis.	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('R0 resection', 'Var', (44, 56))	('men', 'Species', '9606', (71, 74))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
184668	23686724	However, patients with T1b or T2 cancers should be considered for radical re-resection to include the hepatic bed and regional lymph nodes.	('patients', 'Species', '9606', (9, 17))	('T1b', 'Var', (23, 26))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('T2 cancers', 'Disease', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('T2 cancers', 'Disease', 'MESH:C535434', (30, 40))
184710	23686724	Progression free survival was better for patients who received doublet chemotherapy rather than monotherapy, although this did not appear to impact overall survival.	('patients', 'Species', '9606', (41, 49))	('doublet chemotherapy', 'Var', (63, 83))	('better', 'PosReg', (30, 36))	('Progression free survival', 'CPA', (0, 25))
184716	23686724	Furthermore, BRAF gene mutations were detected in 15 out of 69 (22%) biliary cancer specimens in another study, with Raf-1 inhibitors causing a cholangiocarcinoma cell line to be more susceptible to apoptosis.	('cholangiocarcinoma', 'Disease', (144, 162))	('BRAF', 'Gene', '673', (13, 17))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (144, 162))	('Raf-1', 'Gene', '5894', (117, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (144, 162))	('more', 'PosReg', (179, 183))	('inhibitors', 'Var', (123, 133))	('BRAF', 'Gene', (13, 17))	('men', 'Species', '9606', (89, 92))	('mutations', 'Var', (23, 32))	('apoptosis', 'CPA', (199, 208))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('causing', 'Reg', (134, 141))	('biliary cancer', 'Disease', (69, 83))	('Raf-1', 'Gene', (117, 122))	('biliary cancer', 'Disease', 'MESH:D001661', (69, 83))
184731	23686724	Appropriate selection criteria such as wild-type KRAS or EGFR mutations have not been defined for biliary cancers.	('KRAS', 'Gene', '3845', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('biliary cancers', 'Disease', 'MESH:D001661', (98, 113))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('EGFR', 'Gene', '1956', (57, 61))	('biliary cancers', 'Disease', (98, 113))	('EGFR', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('KRAS', 'Gene', (49, 53))
184732	23686724	Combined human epidermal growth factor receptor 2 (HER2) and EGFR blockade has been investigated for the treatment of biliary tract cancers in the context of lapatinib therapy, as preclinical models demonstrated growth inhibition of intrahepatic cholangiocarcinomas.	('human', 'Species', '9606', (9, 14))	('growth', 'MPA', (212, 218))	('HER2', 'Gene', (51, 55))	('biliary tract cancers', 'Disease', (118, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('carcinomas', 'Phenotype', 'HP:0030731', (255, 265))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (118, 138))	('blockade', 'Var', (66, 74))	('epidermal growth factor receptor 2', 'Gene', '2064', (15, 49))	('EGFR', 'Gene', '1956', (61, 65))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (246, 264))	('men', 'Species', '9606', (110, 113))	('intrahepatic cholangiocarcinomas', 'Disease', (233, 265))	('epidermal growth factor receptor 2', 'Gene', (15, 49))	('HER2', 'Gene', '2064', (51, 55))	('biliary tract cancers', 'Disease', 'MESH:D001661', (118, 139))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (233, 265))	('lapatinib', 'Chemical', 'MESH:D000077341', (158, 167))	('EGFR', 'Gene', (61, 65))
184734	23686724	Of note, no EGFR or HER2/neu mutations, and no evidence of HER2 overexpression, were found in these tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('HER2', 'Gene', '2064', (20, 24))	('tumor', 'Disease', (100, 105))	('HER2', 'Gene', '2064', (59, 63))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('EGFR', 'Gene', '1956', (12, 16))	('neu', 'Gene', '2064', (25, 28))	('HER2', 'Gene', (20, 24))	('HER2', 'Gene', (59, 63))	('EGFR', 'Gene', (12, 16))	('neu', 'Gene', (25, 28))
184748	23686724	Thus far, mutations in genes such as PIK3CA, KRAS, NRAS, IDH1, and IDH2, among others, have also been found in biliary cancers.	('NRAS', 'Gene', '4893', (51, 55))	('KRAS', 'Gene', '3845', (45, 49))	('PIK3CA', 'Gene', '5290', (37, 43))	('IDH2', 'Gene', (67, 71))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('IDH1', 'Gene', (57, 61))	('biliary cancers', 'Disease', (111, 126))	('IDH2', 'Gene', '3418', (67, 71))	('found', 'Reg', (102, 107))	('biliary cancers', 'Disease', 'MESH:D001661', (111, 126))	('IDH1', 'Gene', '3417', (57, 61))	('NRAS', 'Gene', (51, 55))	('mutations', 'Var', (10, 19))	('KRAS', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('PIK3CA', 'Gene', (37, 43))
184763	31248836	In addition, patients with triple-positive expression of TCF7, c-Myc, and FOSL1 were demonstrated to have a much worse prognosis than patients with TCF7 overexpression alone.	('c-Myc', 'Gene', (63, 68))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (134, 142))	('TCF7', 'Gene', (57, 61))	('triple-positive expression', 'Var', (27, 53))	('FOSL1', 'Gene', (74, 79))	('c-Myc', 'Gene', '4609', (63, 68))
184802	31248836	In both cohorts, patients with high expression of TCF7 had significantly lower survival rates than patients with low TCF7 expression, suggesting that TCF7 was a prognostic biomarker of PHCC (Fig.	('survival rates', 'CPA', (79, 93))	('PHCC', 'Disease', (185, 189))	('TCF7', 'Gene', (50, 54))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (17, 25))	('high expression', 'Var', (31, 46))	('lower', 'NegReg', (73, 78))
184804	31248836	Patients with high TCF7 expression tended to have poor differentiation, larger tumor size, and positive lymphatic invasion, indicating that TCF7 may be involved in the progression of PHCC.	('larger', 'PosReg', (72, 78))	('tumor', 'Disease', (79, 84))	('poor differentiation', 'CPA', (50, 70))	('expression', 'MPA', (24, 34))	('positive lymphatic invasion', 'CPA', (95, 122))	('TCF7', 'Gene', (19, 23))	('PHCC', 'Disease', (183, 187))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('involved', 'Reg', (152, 160))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
184805	31248836	Univariate analysis demonstrated that high TCF7 expression, positive lymphatic invasion, and advanced TNM stage were both correlated with unfavorable prognosis in cohort 1.	('TNM', 'Gene', '10178', (102, 105))	('positive lymphatic invasion', 'CPA', (60, 87))	('expression', 'MPA', (48, 58))	('TNM', 'Gene', (102, 105))	('TCF7', 'Gene', (43, 47))	('high', 'Var', (38, 42))
184813	31248836	Notably, the volumes and weights of xenograft tumors with TCF7 knockdown were smaller and lower, respectively, than those in the control group (Fig.	('xenograft tumors', 'Disease', (36, 52))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('xenograft tumors', 'Disease', 'MESH:D009369', (36, 52))	('lower', 'NegReg', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('knockdown', 'Var', (63, 72))	('TCF7', 'Gene', (58, 62))	('smaller', 'NegReg', (78, 85))
184815	31248836	To explore the underlying mechanisms of TCF7-induced PHCC progression, we evaluated the changes in the expression of c-Myc, CCND1, and MMP7 after silencing or overexpressing TCF7.	('silencing', 'Var', (146, 155))	('CCND1', 'Gene', (124, 129))	('MMP7', 'Gene', '4316', (135, 139))	('overexpressing', 'PosReg', (159, 173))	('expression', 'MPA', (103, 113))	('c-Myc', 'Gene', (117, 122))	('CCND1', 'Gene', '595', (124, 129))	('TCF7', 'Gene', (174, 178))	('MMP7', 'Gene', (135, 139))	('c-Myc', 'Gene', '4609', (117, 122))
184816	31248836	In QBC939 cells, c-Myc expression was upregulated along with TCF7 overexpression and downregulated when TCF7 was knocked down; in contrast, no significant changes in CCND1 or MMP7 were observed (Fig.	('downregulated', 'NegReg', (85, 98))	('overexpression', 'Var', (66, 80))	('c-Myc', 'Gene', (17, 22))	('QBC939', 'CellLine', 'CVCL:6942', (3, 9))	('MMP7', 'Gene', (175, 179))	('upregulated', 'PosReg', (38, 49))	('CCND1', 'Gene', '595', (166, 171))	('TCF7', 'Gene', (61, 65))	('MMP7', 'Gene', '4316', (175, 179))	('c-Myc', 'Gene', '4609', (17, 22))	('CCND1', 'Gene', (166, 171))	('expression', 'MPA', (23, 33))
184819	31248836	The mRNA levels and IHC staining of c-Myc in xenografts with TCF7 knockdown were markedly lower than those in the control group (Fig.	('mRNA levels', 'MPA', (4, 15))	('lower', 'NegReg', (90, 95))	('TCF7', 'Gene', (61, 65))	('c-Myc', 'Gene', '4609', (36, 41))	('knockdown', 'Var', (66, 75))	('c-Myc', 'Gene', (36, 41))
184826	31248836	After c-Myc knockdown, PHCC cell proliferation was significantly attenuated, although cells with Wnt agonist or TCF7 overexpression still showed higher proliferation rates than the cells with only c-Myc knockdown (Fig.	('c-Myc', 'Gene', (6, 11))	('overexpression', 'Var', (117, 131))	('knockdown', 'Var', (12, 21))	('attenuated', 'NegReg', (65, 75))	('c-Myc', 'Gene', '4609', (197, 202))	('proliferation rates', 'CPA', (152, 171))	('TCF7', 'Gene', (112, 116))	('c-Myc', 'Gene', (197, 202))	('c-Myc', 'Gene', '4609', (6, 11))	('PHCC cell proliferation', 'CPA', (23, 46))	('higher', 'PosReg', (145, 151))
184829	31248836	However, it was interesting to note that c-Myc knockdown almost completely abolished the increases in invasion and migration induced by TCF7 overexpression or Wnt agonist treatment, but the proliferation of TCF7-overexpressing or Wnt-treated cells was still increased after c-Myc knockdown.	('c-Myc', 'Gene', '4609', (41, 46))	('increased', 'PosReg', (258, 267))	('migration', 'CPA', (115, 124))	('c-Myc', 'Gene', (41, 46))	('invasion', 'CPA', (102, 110))	('abolished', 'NegReg', (75, 84))	('knockdown', 'Var', (47, 56))	('TCF7', 'Gene', (136, 140))	('c-Myc', 'Gene', '4609', (274, 279))	('c-Myc', 'Gene', (274, 279))	('increases', 'PosReg', (89, 98))
184838	31248836	As a result, both CCK8 and soft agar assays revealed that FOSL1 overexpression could rescue the reduced proliferation induced by TCF7 knockdown in QBC939 and FRH0201 cells to some extent (Fig.	('FOSL1', 'Gene', (58, 63))	('QBC939', 'CellLine', 'CVCL:6942', (147, 153))	('TCF7', 'Gene', (129, 133))	('overexpression', 'PosReg', (64, 78))	('knockdown', 'Var', (134, 143))	('reduced', 'NegReg', (96, 103))
184857	31248836	Mutations in KRAS lead to constitutive activation of MAPK/ERK, an important upstream activator of FOSL1/AP-1, and FOSL1 has been reported to facilitate the progression of cancers with mutant KRAS.	('KRAS', 'Gene', (191, 195))	('facilitate', 'PosReg', (141, 151))	('activation', 'PosReg', (39, 49))	('mutant', 'Var', (184, 190))	('AP-1', 'Gene', '2353', (104, 108))	('ERK', 'Gene', '5594', (58, 61))	('KRAS', 'Gene', '3845', (191, 195))	('AP-1', 'Gene', (104, 108))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('MAPK', 'Gene', '5594', (53, 57))	('cancers', 'Disease', (171, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('ERK', 'Gene', (58, 61))	('KRAS', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('MAPK', 'Gene', (53, 57))	('KRAS', 'Gene', '3845', (13, 17))
184858	31248836	This correlation between FOSL1 and mutant KRAS is interesting because KRAS mutations are the most frequent mutations and most extensively reported fingerprints of CCA.	('KRAS', 'Gene', (42, 46))	('KRAS', 'Gene', '3845', (42, 46))	('KRAS', 'Gene', (70, 74))	('KRAS', 'Gene', '3845', (70, 74))	('CCA', 'Phenotype', 'HP:0030153', (163, 166))	('mutations', 'Var', (75, 84))
184861	31248836	Patients with triple-positive expression of TCF7, c-Myc, and FOSL1 had significantly worse prognoses than other patients.	('TCF7', 'Gene', (44, 48))	('triple-positive expression', 'Var', (14, 40))	('patients', 'Species', '9606', (112, 120))	('c-Myc', 'Gene', '4609', (50, 55))	('Patients', 'Species', '9606', (0, 8))	('c-Myc', 'Gene', (50, 55))	('FOSL1', 'Gene', (61, 66))
184938	29856900	We hope that more basic research of genetic mutations and subsequent basket trials will advance the treatment of unresectable CHC.	('advance', 'PosReg', (88, 95))	('genetic mutations', 'Var', (36, 53))	('men', 'Species', '9606', (105, 108))	('mutations', 'Var', (44, 53))	('CHC', 'Disease', 'MESH:D019698', (126, 129))	('CHC', 'Phenotype', 'HP:0030153', (126, 129))	('CHC', 'Disease', (126, 129))
184991	23345990	The median survival time and median event-free survival time were also longer in the bare metal stent group than those in the plastic stent group.	('longer', 'PosReg', (71, 77))	('metal', 'Chemical', 'MESH:D008670', (90, 95))	('survival time', 'CPA', (11, 24))	('event-free survival', 'CPA', (36, 55))	('bare metal', 'Var', (85, 95))
184996	23345990	Inserting a single biliary stent into one functional liver lobe for unilateral drainage can provide adequate palliation in the majority portion of patients with hilar tumors.	('Inserting', 'Var', (0, 9))	('hilar tumors', 'Disease', (161, 173))	('patients', 'Species', '9606', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('hilar tumors', 'Disease', 'MESH:D018285', (161, 173))
185047	32190288	One recent study has indeed linked HPC origin to the heterogeneity of generated tumors and suggested that both the differentiation state of the TIC as well as specific genetic alterations could affect the phenotypic diversity of the resulting tumors.	('tumors', 'Disease', (243, 249))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('rat', 'Species', '10116', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('affect', 'Reg', (194, 200))	('TIC', 'Phenotype', 'HP:0100033', (144, 147))	('rat', 'Species', '10116', (74, 77))	('alterations', 'Var', (176, 187))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', (80, 86))	('phenotypic', 'MPA', (205, 215))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
185078	32190288	Spontaneous differentiation was then induced over 7-days by withdrawing growth factors, after which single E-cadherin+ fetal liver cell-derived clones contained either exclusively ALB-positive hepatocytes or CK19-positive cholangiocytes (Fig.	('ALB', 'Gene', (180, 183))	('ALB', 'Gene', '11657', (180, 183))	('E-cadherin', 'Gene', (107, 117))	('E-cadherin', 'Gene', '12550', (107, 117))	('CK19-positive', 'Var', (208, 221))
185102	32190288	CK19-positive neoplastic cells with an increased nucleus:cytoplasm ratio and marked pleomorphism were also observed in regions with hepatocellular differentiation.	('CK19-positive', 'Var', (0, 13))	('increased', 'PosReg', (39, 48))	('rat', 'Species', '10116', (67, 70))	('hepatocellular differentiation', 'Disease', (132, 162))
185124	32190288	By multicolor fluorescence immunostaining, we confirmed that the murine tumor cells within intermediate area shared similar intermediate phenotype with cultured hepatoblasts which simultaneously express biliary marker (e.g., CK19), hepatocellular marker (e.g.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('murine', 'Species', '10090', (65, 71))	('CK19', 'Var', (225, 229))
185129	32190288	Not only in intermediate areas, but also in CC or CLC areas of murine tumor, tumor cells with intermediate phenotype featured by co-expressing CK19 and ALB were found.	('CLC', 'Disease', 'MESH:D002277', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CK19', 'Var', (143, 147))	('tumor', 'Disease', (70, 75))	('CLC', 'Disease', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('CC', 'Phenotype', 'HP:0030153', (44, 46))	('ALB', 'Gene', '11657', (152, 155))	('ALB', 'Gene', (152, 155))	('CLC', 'Phenotype', 'HP:0030153', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('CC', 'Disease', 'MESH:D018281', (44, 46))	('murine', 'Species', '10090', (63, 69))
185204	32181431	At MRI, the tumor was hyperintense and hypointense on T2-weighted and T1-weighted images, respectively.	('hypointense', 'Var', (39, 50))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))
185240	31453370	Research has shown that extrahepatic cholangiocarcinoma is more likely to be associated with ERBB2 (HER2) genetic aberrations.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (37, 55))	('HER2', 'Gene', '2064', (100, 104))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (24, 55))	('ERBB2', 'Gene', (93, 98))	('ERBB2', 'Gene', '2064', (93, 98))	('extrahepatic cholangiocarcinoma', 'Disease', (24, 55))	('HER2', 'Gene', (100, 104))	('genetic aberrations', 'Var', (106, 125))	('associated', 'Reg', (77, 87))
185242	31453370	Here, we show in a metastatic cholangiocarcinoma with ERBB2 amplification identified on liquid biopsy (circulating tumor DNA (ctDNA) testing), a dramatic response to now over 12 months of dual-anti-HER2 therapy.	('ERBB2', 'Gene', '2064', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('amplification', 'Var', (60, 73))	('HER2', 'Gene', (198, 202))	('ERBB2', 'Gene', (54, 59))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (30, 48))	('tumor', 'Disease', (115, 120))	('HER2', 'Gene', '2064', (198, 202))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (30, 48))	('cholangiocarcinoma', 'Disease', (30, 48))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
185248	31453370	Multiple aberrations can be seen, including ERBB2, microsatellite instability high (MSI-H), IDH1, BRAF, FGFR fusion, BRCA/DNA-repair related, MET amplification, NTRK fusion, TP53, KRAS, ARID1A, MCL1, PBRM1, SMAD4, FBXW7, and CDKN2A.	('PBRM1', 'Gene', '55193', (200, 205))	('KRAS', 'Gene', (180, 184))	('ERBB2', 'Gene', '2064', (44, 49))	('TP53', 'Gene', (174, 178))	('SMAD4', 'Gene', (207, 212))	('microsatellite instability', 'MPA', (51, 77))	('MET amplification', 'Var', (142, 159))	('ARID1A', 'Gene', '8289', (186, 192))	('NTRK', 'Gene', (161, 165))	('PBRM1', 'Gene', (200, 205))	('FBXW7', 'Gene', (214, 219))	('MCL1', 'Gene', (194, 198))	('MSI-H', 'Disease', (84, 89))	('NTRK', 'Gene', '4914', (161, 165))	('CDKN2A', 'Gene', (225, 231))	('SMAD4', 'Gene', '4089', (207, 212))	('TP53', 'Gene', '7157', (174, 178))	('MCL1', 'Gene', '4170', (194, 198))	('IDH1', 'Gene', (92, 96))	('MSI-H', 'Disease', 'MESH:D000848', (84, 89))	('CDKN2A', 'Gene', '1029', (225, 231))	('FBXW7', 'Gene', '55294', (214, 219))	('ERBB2', 'Gene', (44, 49))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))	('KRAS', 'Gene', '3845', (180, 184))	('IDH1', 'Gene', '3417', (92, 96))	('ARID1A', 'Gene', (186, 192))
185251	31453370	A number of published cases and open clinical trials with early results have demonstrated activity in IDH1, BRAF-mutant, MET-amplified, ERBB2-amplified, and FGFR- fusion tumors.	('MET-amplified', 'Var', (121, 134))	('ERBB2', 'Gene', '2064', (136, 141))	('activity', 'MPA', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('ERBB2', 'Gene', (136, 141))	('IDH1', 'Gene', (102, 106))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('BRAF', 'Gene', '673', (108, 112))	('IDH1', 'Gene', '3417', (102, 106))	('tumors', 'Disease', (170, 176))	('BRAF', 'Gene', (108, 112))
185253	31453370	Breast, stomach and esophageal cancers have well-established associations with ERBB2 genetic aberrations; and are approved for anti-HER2.	('HER2', 'Gene', '2064', (132, 136))	('esophageal cancers', 'Disease', (20, 38))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('esophageal cancers', 'Disease', 'MESH:D004938', (20, 38))	('stomach', 'Disease', (8, 15))	('ERBB2', 'Gene', (79, 84))	('ERBB2', 'Gene', '2064', (79, 84))	('Breast', 'Disease', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('genetic aberrations', 'Var', (85, 104))	('associations', 'Interaction', (61, 73))	('HER2', 'Gene', (132, 136))
185254	31453370	However, reports have also shown the finding of HER2 aberrations in CCA and urinary bladder cancers.	('HER2', 'Gene', '2064', (48, 52))	('CCA', 'Phenotype', 'HP:0030153', (68, 71))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('urinary bladder cancers', 'Disease', 'MESH:D001749', (76, 99))	('aberrations', 'Var', (53, 64))	('CCA', 'Disease', (68, 71))	('bladder cancers', 'Phenotype', 'HP:0009725', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('HER2', 'Gene', (48, 52))	('urinary bladder cancers', 'Disease', (76, 99))
185267	31453370	However, within 2 months, the patient had rapid progression of disease with rising tumor markers, rising ctDNA levels, derangement in liver function tests and decline in clinical condition.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('rising', 'PosReg', (76, 82))	('patient', 'Species', '9606', (30, 37))	('tumor', 'Disease', (83, 88))	('decline', 'NegReg', (159, 166))	('ctDNA levels', 'MPA', (105, 117))	('derangement', 'Var', (119, 130))	('derangement in liver', 'Phenotype', 'HP:0001392', (119, 139))	('liver function tests', 'MPA', (134, 154))	('clinical condition', 'MPA', (170, 188))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('rising', 'PosReg', (98, 104))
185272	31453370	After just one treatment, the patient's liver function tests improved; most notably, the dominant TP53 mutation reduced from 60.7 to 2.1% (Table 1).	('patient', 'Species', '9606', (30, 37))	('liver function tests', 'MPA', (40, 60))	('TP53', 'Gene', '7157', (98, 102))	('reduced', 'NegReg', (112, 119))	('mutation', 'Var', (103, 111))	('TP53', 'Gene', (98, 102))
185274	31453370	Generally, intrahepatic CCA is associated with IDH1, FGFR fusion and BRCA/DNA-repair gene alterations, while extrahepatic CCA is more frequently associated with ERBB2 genetic aberrations.	('alterations', 'Var', (90, 101))	('CCA', 'Phenotype', 'HP:0030153', (122, 125))	('ERBB2', 'Gene', '2064', (161, 166))	('BRCA/DNA-repair gene', 'Gene', (69, 89))	('CCA', 'Phenotype', 'HP:0030153', (24, 27))	('IDH1', 'Gene', (47, 51))	('ERBB2', 'Gene', (161, 166))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (11, 27))	('associated', 'Reg', (31, 41))	('intrahepatic CCA', 'Disease', (11, 27))	('IDH1', 'Gene', '3417', (47, 51))	('FGFR fusion', 'Gene', (53, 64))
185276	31453370	What is unique about our case is that the HER2 aberration was detected on circulating tumor DNA testing ("liquid biopsy").	('HER2', 'Gene', '2064', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('aberration', 'Var', (47, 57))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('HER2', 'Gene', (42, 46))
185280	31453370	They identified TP53, KRAS, ARID1A, IDH1, MCL1, and PBRM1 mutations in 35%, 24%, 20%, 18%, 16%, and 11% of intrahepatic CCA patients, respectively.	('mutations', 'Var', (58, 67))	('IDH1', 'Gene', (36, 40))	('CCA', 'Phenotype', 'HP:0030153', (120, 123))	('ARID1A', 'Gene', '8289', (28, 34))	('ARID1A', 'Gene', (28, 34))	('PBRM1', 'Gene', (52, 57))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (107, 123))	('MCL1', 'Gene', '4170', (42, 46))	('TP53', 'Gene', '7157', (16, 20))	('KRAS', 'Gene', (22, 26))	('IDH1', 'Gene', '3417', (36, 40))	('intrahepatic CCA', 'Disease', (107, 123))	('MCL1', 'Gene', (42, 46))	('KRAS', 'Gene', '3845', (22, 26))	('PBRM1', 'Gene', '55193', (52, 57))	('TP53', 'Gene', (16, 20))	('patients', 'Species', '9606', (124, 132))
185282	31453370	The finding of a higher proportion of ERBB2 mutations in extrahepatic CCA and gallbladder cancer suggests that these patients are more likely to carry it as opposed to intrahepatic CCA.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (168, 184))	('extrahepatic CCA', 'Disease', (57, 73))	('CCA', 'Phenotype', 'HP:0030153', (181, 184))	('intrahepatic CCA', 'Disease', (168, 184))	('ERBB2', 'Gene', (38, 43))	('ERBB2', 'Gene', '2064', (38, 43))	('CCA', 'Phenotype', 'HP:0030153', (70, 73))	('mutations', 'Var', (44, 53))	('gallbladder cancer', 'Disease', (78, 96))	('gallbladder cancer', 'Disease', 'MESH:D005706', (78, 96))	('patients', 'Species', '9606', (117, 125))
185287	31453370	Summary of the studies showing HER2 aberrations in CCA and treatment outcomes where available are presented in Table 2.	('CCA', 'Disease', (51, 54))	('HER2', 'Gene', '2064', (31, 35))	('CCA', 'Phenotype', 'HP:0030153', (51, 54))	('aberrations', 'Var', (36, 47))	('HER2', 'Gene', (31, 35))
185296	31453370	HER2/neu blockade has shown favorable results in cancers carrying HER2 aberrations.	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('HER2', 'Gene', '2064', (66, 70))	('HER2', 'Gene', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('aberrations', 'Var', (71, 82))	('HER2', 'Gene', (0, 4))	('HER2/neu', 'Gene', '2064', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('HER2', 'Gene', '2064', (0, 4))	('cancers', 'Disease', (49, 56))	('HER2/neu', 'Gene', (0, 8))
185297	31453370	investigated the response of anti-HER2 therapy in 8 patients with HER2 mutated gallbladder cancer and showed an overall improvement in terms of disease stability (n = 3), partial response (n = 4), or complete response (n = 1) in their entire patient cohort.	('gallbladder cancer', 'Disease', (79, 97))	('gallbladder cancer', 'Disease', 'MESH:D005706', (79, 97))	('HER2', 'Gene', '2064', (34, 38))	('HER2', 'Gene', '2064', (66, 70))	('HER2', 'Gene', (66, 70))	('mutated', 'Var', (71, 78))	('HER2', 'Gene', (34, 38))	('improvement', 'PosReg', (120, 131))	('patient', 'Species', '9606', (52, 59))	('patient', 'Species', '9606', (242, 249))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('disease stability', 'CPA', (144, 161))	('patients', 'Species', '9606', (52, 60))	('partial response', 'CPA', (171, 187))
185306	31453370	We believe our case and recent single-arm phase 2 study outcomes warrant consideration toward approval of anti-HER2 agents (trastuzumab/pertuzumab) in patients with CCA with ERBB2 amplification who have very limited options and poor prognosis.	('HER2', 'Gene', (111, 115))	('amplification', 'Var', (180, 193))	('HER2', 'Gene', '2064', (111, 115))	('CCA', 'Phenotype', 'HP:0030153', (165, 168))	('ERBB2', 'Gene', '2064', (174, 179))	('patients', 'Species', '9606', (151, 159))	('ERBB2', 'Gene', (174, 179))	('trastuzumab', 'Chemical', 'MESH:D000068878', (124, 135))	('pertuzumab', 'Chemical', 'MESH:C485206', (136, 146))	('CCA', 'Disease', (165, 168))
185309	31453370	In conclusion, we were able to identify ERBB2 (HER2/neu) amplification on liquid biopsy in a patient with CCA and found anti-HER2 therapy as an effective treatment strategy.	('HER2', 'Gene', (125, 129))	('ERBB2', 'Gene', '2064', (40, 45))	('HER2', 'Gene', '2064', (125, 129))	('CCA', 'Phenotype', 'HP:0030153', (106, 109))	('ERBB2', 'Gene', (40, 45))	('amplification', 'Var', (57, 70))	('HER2', 'Gene', (47, 51))	('CCA', 'Disease', (106, 109))	('HER2/neu', 'Gene', '2064', (47, 55))	('HER2', 'Gene', '2064', (47, 51))	('patient', 'Species', '9606', (93, 100))	('HER2/neu', 'Gene', (47, 55))
185319	31383886	The jaundice and liver function were significantly improved in all patients, especially in PTBS + 125I group.	('patients', 'Species', '9606', (67, 75))	('improved', 'PosReg', (51, 59))	('125I', 'Chemical', 'MESH:C000614960', (98, 102))	('PTBS', 'Chemical', '-', (91, 95))	('jaundice', 'Disease', 'MESH:D007565', (4, 12))	('PTBS + 125I', 'Var', (91, 102))	('jaundice', 'Disease', (4, 12))	('jaundice', 'Phenotype', 'HP:0000952', (4, 12))	('liver function', 'CPA', (17, 31))
185321	31383886	Kaplan Meier analysis showed that patients in PTBS + 125I group had a significantly better OS, both for hilar and distal cholangiocarcinoma.	('hilar', 'Disease', (104, 109))	('PTBS', 'Chemical', '-', (46, 50))	('125I', 'Chemical', 'MESH:C000614960', (53, 57))	('cholangiocarcinoma', 'Disease', (121, 139))	('PTBS + 125I', 'Var', (46, 57))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (121, 139))	('OS', 'Chemical', '-', (91, 93))	('patients', 'Species', '9606', (34, 42))	('better', 'PosReg', (84, 90))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))
185324	31383886	In conclusion, for patients with advanced EHC, PTBS combined with 125I particles implantation is superior to PTBS alone in improving liver function, inhibiting biliary re-obstruction, and prolonging survival time.	('patients', 'Species', '9606', (19, 27))	('PTBS', 'Chemical', '-', (109, 113))	('improving liver function', 'Phenotype', 'HP:0001410', (123, 147))	('survival time', 'CPA', (199, 212))	('PTBS', 'Chemical', '-', (47, 51))	('inhibiting', 'NegReg', (149, 159))	('improving', 'PosReg', (123, 132))	('EHC', 'Disease', (42, 45))	('125I', 'Var', (66, 70))	('biliary', 'Disease', (160, 167))	('125I', 'Chemical', 'MESH:C000614960', (66, 70))	('liver function', 'MPA', (133, 147))	('prolonging', 'PosReg', (188, 198))
185333	31383886	Recent studies have shown that biliary stenting combined with 125I particles implantation is a safe and feasible palliative treatment for advanced EHC.	('125I', 'Chemical', 'MESH:C000614960', (62, 66))	('125I', 'Var', (62, 66))	('EHC', 'Disease', (147, 150))	('biliary stenting', 'Disease', (31, 47))
185357	31383886	The length of hospital stay was slightly longer in the PTBS + 125I group, while the difference was not statistically significant (median: 15 vs. 13 days, p = 0.058).	('PTBS', 'Chemical', '-', (55, 59))	('125I', 'Chemical', 'MESH:C000614960', (62, 66))	('PTBS + 125I', 'Var', (55, 66))	('longer', 'PosReg', (41, 47))
185358	31383886	Moreover, hospital costs were relatively higher in PTBS + 125I group compared with PTBS group (median: 36,631 vs. 28,821 CNY, p < 0.001).	('PTBS + 125I', 'Var', (51, 62))	('hospital costs', 'MPA', (10, 24))	('PTBS', 'Chemical', '-', (51, 55))	('higher', 'PosReg', (41, 47))	('PTBS', 'Chemical', '-', (83, 87))	('125I', 'Chemical', 'MESH:C000614960', (58, 62))
185367	31383886	However, compared with PTBS alone, the addition of 125I particles reduced the risk of biliary re-obstruction (19.5% vs. 35.2%, p = 0.017).	('reduced', 'NegReg', (66, 73))	('PTBS', 'Chemical', '-', (23, 27))	('125I', 'Var', (51, 55))	('biliary re-obstruction', 'Disease', (86, 108))	('125I', 'Chemical', 'MESH:C000614960', (51, 55))
185369	31383886	2, the OS was significantly better in the PTBS + 125I group than that in the PTBS group (median: 13 vs. 8 months, 1-year survival rate: 56.8% vs. 11.3%, p < 0.001).	('OS', 'Chemical', '-', (7, 9))	('PTBS + 125I', 'Var', (42, 53))	('PTBS', 'Chemical', '-', (77, 81))	('better', 'PosReg', (28, 34))	('PTBS', 'Chemical', '-', (42, 46))	('125I', 'Chemical', 'MESH:C000614960', (49, 53))
185372	31383886	Compared with PTBS alone, the addition of 125I particles can significantly improve OS both in HCCA and in DCCA (Fig.	('DCCA', 'Disease', (106, 110))	('OS', 'Chemical', '-', (83, 85))	('PTBS', 'Chemical', '-', (14, 18))	('125I', 'Var', (42, 46))	('125I', 'Chemical', 'MESH:C000614960', (42, 46))	('improve', 'PosReg', (75, 82))	('HCCA', 'Disease', (94, 98))
185375	31383886	Higher preoperative levels of CA19-9 (HR = 1.94, 95% CI: 1.19-3.19, p = 0.009) and TBIL (HR = 1.54, 95% CI: 1.04-2.28, p = 0.031) were identified as independent adverse prognostic factors, and the treatment of PTBS plus 125I implantation was an independent favorable prognostic factor (HR = 0.26, 95% CI: 0.17-0.39, p < 0.001) (Fig.	('TBIL', 'MPA', (83, 87))	('CA19-9', 'Var', (30, 36))	('TBIL', 'Chemical', 'MESH:D001663', (83, 87))	('CA19-9', 'Chemical', 'MESH:C086528', (30, 36))	('125I', 'Chemical', 'MESH:C000614960', (220, 224))	('PTBS', 'Chemical', '-', (210, 214))
185379	31383886	In addition, brachytherapy can significantly reduce radiation-induced complications such as peptic ulcers, hemorrhage, and radiation enteritis.	('peptic ulcers', 'Disease', (92, 105))	('peptic ulcers', 'Phenotype', 'HP:0004398', (92, 105))	('radiation enteritis', 'Disease', 'MESH:D004194', (123, 142))	('peptic ulcers', 'Disease', 'MESH:D010437', (92, 105))	('hemorrhage', 'Disease', (107, 117))	('hemorrhage', 'Disease', 'MESH:D006470', (107, 117))	('radiation enteritis', 'Disease', (123, 142))	('reduce', 'NegReg', (45, 51))	('brachytherapy', 'Var', (13, 26))
185381	31383886	We found that, compared with PTBS alone, the addition of 125I particles significantly reduced the risk of biliary re-obstruction and improved survival, while it did not increase the risk of postoperative complications.	('survival', 'MPA', (142, 150))	('PTBS', 'Chemical', '-', (29, 33))	('reduced', 'NegReg', (86, 93))	('125I', 'Var', (57, 61))	('125I', 'Chemical', 'MESH:C000614960', (57, 61))	('improved', 'PosReg', (133, 141))	('biliary re-obstruction', 'Disease', (106, 128))
185384	31383886	Secondly, the tube contained 125I particles may slide or even remove from the stent due to inappropriate postoperative activity.	('remove', 'NegReg', (62, 68))	('125I', 'Var', (29, 33))	('125I', 'Chemical', 'MESH:C000614960', (29, 33))
185391	31383886	In addition, the concentrations of IgM, IgG, and IgA, and complements C3 and C4 also increased, indicating that 125I particles may stimulate not only cellular immunity but also humoral immunity.	('humoral immunity', 'CPA', (177, 193))	('125I', 'Var', (112, 116))	('125I', 'Chemical', 'MESH:C000614960', (112, 116))	('cellular immunity', 'CPA', (150, 167))	('stimulate', 'PosReg', (131, 140))
185393	31383886	In conclusion, for patients with advanced EHC, PTBS combined with 125I particles implantation is superior to PTBS alone in improving liver function, inhibiting biliary re-obstruction and prolonging survival time.	('patients', 'Species', '9606', (19, 27))	('PTBS', 'Chemical', '-', (109, 113))	('improving liver function', 'Phenotype', 'HP:0001410', (123, 147))	('PTBS', 'Chemical', '-', (47, 51))	('prolonging', 'PosReg', (187, 197))	('inhibiting', 'NegReg', (149, 159))	('improving', 'PosReg', (123, 132))	('EHC', 'Disease', (42, 45))	('125I', 'Var', (66, 70))	('125I', 'Chemical', 'MESH:C000614960', (66, 70))	('liver function', 'MPA', (133, 147))	('survival time', 'CPA', (198, 211))	('biliary', 'Disease', (160, 167))
185398	29113809	We tested the effects of HSP90 inhibitors on cells with disruption of the MIR21 gene, cells incubated with MIR21 inhibitors, and stable cell lines with inducible expression of MIR21.	('MIR21', 'Gene', (74, 79))	('tested', 'Reg', (3, 9))	('HSP90', 'Gene', (25, 30))	('HSP90', 'Gene', '3320', (25, 30))	('disruption', 'Var', (56, 66))
185401	29113809	Cells with IDH1 and PBRM1 mutations had the highest level of sensitivity to histone deacetylase inhibitors.	('sensitivity to histone deacetylase inhibitors', 'MPA', (61, 106))	('IDH1', 'Gene', '3417', (11, 15))	('PBRM1', 'Gene', (20, 25))	('PBRM1', 'Gene', '55193', (20, 25))	('mutations', 'Var', (26, 35))	('IDH1', 'Gene', (11, 15))
185404	29113809	Disruption of MIR21 increased cell sensitivity to HSP90 inhibitors.	('increased', 'PosReg', (20, 29))	('HSP90', 'Gene', (50, 55))	('HSP90', 'Gene', '3320', (50, 55))	('MIR21', 'Gene', (14, 19))	('cell sensitivity to', 'MPA', (30, 49))	('Disruption', 'Var', (0, 10))
185405	29113809	CCA cells that expressed transgenic MIR21 were more resistant to HSP90 inhibitors than cells transfected with control vectors; inactivation of MIR21 in these cells restored sensitivity to these agents.	('MIR21', 'Var', (36, 41))	('resistant', 'MPA', (52, 61))	('inactivation', 'Var', (127, 139))	('restored', 'PosReg', (164, 172))	('HSP90', 'Gene', (65, 70))	('MIR21', 'Gene', (143, 148))	('HSP90', 'Gene', '3320', (65, 70))	('sensitivity', 'MPA', (173, 184))	('transgenic MIR21', 'Var', (25, 41))
185406	29113809	MIR21 was shown to target the DnaJ heat shock protein family (Hsp40) member B5 (DNAJB5).	('MIR21', 'Var', (0, 5))	('DNAJB5', 'Gene', (80, 86))	('Hsp40', 'Gene', (62, 67))	('shock', 'Phenotype', 'HP:0031273', (40, 45))	('Hsp40', 'Gene', '171221', (62, 67))	('DNAJB5', 'Gene', '25822', (80, 86))
185422	29113809	Small molecules have entered clinical practice for the treatment of other forms of solid malignancies, where the dependence of the cancer on specific pathways is understood.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Small', 'Var', (0, 5))	('solid malignancies', 'Disease', 'MESH:D009369', (83, 101))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('solid malignancies', 'Disease', (83, 101))
185423	29113809	Here, we report data from a high-throughput screen (HTS) of a library of small-molecule drugs and chemical tools in human CCA cell lines that have been genetically characterized for the most frequent mutations observed in human CCA, along with validation in ex vivo and in vivo models of promising compounds and relative biomarkers of response.	('mutations', 'Var', (200, 209))	('HTS', 'Disease', 'MESH:C537160', (52, 55))	('human', 'Species', '9606', (222, 227))	('HTS', 'Disease', (52, 55))	('human', 'Species', '9606', (116, 121))
185430	29113809	Dissociated cells were collected in Advanced Dulbecco's modified Eagle medium/F12 (Thermo Fisher Scientific), suspended in growth factor reduced matrigel (Corning Inc, Corning, NY), and seeded.	('suspended', 'Var', (110, 119))	('F12', 'Gene', '2161', (78, 81))	('reduced', 'NegReg', (137, 144))	('F12', 'Gene', (78, 81))
185450	29113809	To explore the activity of small molecules in CCA, we screened a library of 484 molecularly targeted small-molecule compounds (Supplementary Table 1) for their effect on the viability of human CCA cell lines.	('small-molecule', 'Var', (101, 115))	('human', 'Species', '9606', (187, 192))	('CCA', 'Disease', (193, 196))
185457	29113809	Interestingly, there was an enrichment of histone-deacetylase inhibitors among the hits in the SNU-1079 cell line, which harbors mutations in the isocitrate dehydrogenase 1 (IDH1) and polybromo1 (PBRM1) chromatin remodeling genes.	('polybromo1', 'Gene', (184, 194))	('mutations', 'Var', (129, 138))	('SNU-1079', 'CellLine', 'CVCL:5008', (95, 103))	('PBRM1', 'Gene', (196, 201))	('polybromo1', 'Gene', '55193', (184, 194))	('IDH1', 'Gene', (174, 178))	('PBRM1', 'Gene', '55193', (196, 201))	('isocitrate dehydrogenase 1', 'Gene', (146, 172))	('IDH1', 'Gene', '3417', (174, 178))	('isocitrate dehydrogenase 1', 'Gene', '3417', (146, 172))
185459	29113809	A number of EGFR inhibitors had a significant effect on the viability of SW1, SNU-1196, and TFK cell lines.	('viability', 'CPA', (60, 69))	('SW1', 'CellLine', 'CVCL:R777', (73, 76))	('EGFR', 'Gene', '1956', (12, 16))	('inhibitors', 'Var', (17, 27))	('SNU-1196', 'Chemical', '-', (78, 86))	('EGFR', 'Gene', (12, 16))
185461	29113809	To investigate whether selected mutations were associated with sensitivity to specific targeted agents, we ran an analysis for BRCA-associated protein (BAP1) and TP53 mutations because these were present in more than 1 cell line (Supplementary Figure 1A,B).	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('BAP1', 'Gene', '8314', (152, 156))	('mutations', 'Var', (167, 176))	('BAP1', 'Gene', (152, 156))
185462	29113809	Our analysis revealed that BAP1-mutant (MUT) CCA cell lines were more sensitive (P < .05) to a range of small molecules that include compounds with activity on PI3K pathway: SANT-2 (SMO antagonist), ABT-737 (inhibitor of Bcl-(X)L, Bcl-2, and Bcl-W), LY294002 (PI3Kalpha/beta/delta inhibitor), PIK-93 (PI3Kalpha/gamma inhibitor), SB203580 (p38 MAPK inhibitor), and SB590885 (BRAF inhibitor).	('Bcl-(X)L', 'Gene', '598', (221, 229))	('SB590885', 'Var', (364, 372))	('Bcl-W', 'Gene', '599', (242, 247))	('Bcl-(X)L', 'Gene', (221, 229))	('BAP1', 'Gene', (27, 31))	('SB203580', 'Var', (329, 337))	('Bcl-2', 'Gene', (231, 236))	('BAP1', 'Gene', '8314', (27, 31))	('Bcl-2', 'Gene', '596', (231, 236))	('BRAF', 'Gene', (374, 378))	('ABT', 'Chemical', 'MESH:C002502', (199, 202))	('BRAF', 'Gene', '673', (374, 378))	('LY294002', 'Var', (250, 258))	('SMO', 'Gene', '6608', (182, 185))	('SMO', 'Gene', (182, 185))	('PI3Kalpha/beta/delta inhibitor), PIK-93', 'Gene', '5290', (260, 299))	('Bcl-W', 'Gene', (242, 247))
185464	29113809	However, we noticed a significant (P < .05) correlation between mutations in TP53 and resistance to PF-573228 (ATP-competitive inhibitor of FAK), ABT-263 (navitoclax, a potent inhibitor of Bcl-(X)L, Bcl-2, and Bcl-W), and MM-102 (MLLT1 inhibitor).	('MLLT1', 'Gene', (230, 235))	('FAK', 'Gene', (140, 143))	('Bcl-(X)L', 'Gene', (189, 197))	('TP53', 'Gene', (77, 81))	('FAK', 'Gene', '5747', (140, 143))	('mutations', 'Var', (64, 73))	('Bcl-W', 'Gene', (210, 215))	('Bcl-W', 'Gene', '599', (210, 215))	('correlation', 'Interaction', (44, 55))	('MLLT1', 'Gene', '4298', (230, 235))	('ABT', 'Chemical', 'MESH:C002502', (146, 149))	('Bcl-(X)L', 'Gene', '598', (189, 197))	('TP53', 'Gene', '7157', (77, 81))	('Bcl-2', 'Gene', (199, 204))	('navitoclax', 'Chemical', 'MESH:C528561', (155, 165))	('MM-102', 'Chemical', '-', (222, 228))	('ATP', 'Chemical', 'MESH:D000255', (111, 114))	('PF-573228', 'Chemical', 'MESH:C521108', (100, 109))	('resistance', 'MPA', (86, 96))	('Bcl-2', 'Gene', '596', (199, 204))
185466	29113809	However, we acknowledge that our system may not be ideal for the assessment of angiogenesis/stroma-directed drugs and that our cells are not known to carry FGFR2 alterations.	('FGFR2', 'Gene', '2263', (156, 161))	('FGFR2', 'Gene', (156, 161))	('alterations', 'Var', (162, 173))
185469	29113809	HSP90 inhibition is attractive in CCA because HSP90 interacts with and controls a variety of client proteins that play a key role in CCA pathogenesis, such as EGFR, PTEN, PI3K, HER2, HER3, and PRKA.	('HER3', 'Gene', (183, 187))	('HSP90', 'Gene', (0, 5))	('HSP90', 'Gene', '3320', (0, 5))	('HER3', 'Gene', '2065', (183, 187))	('EGFR', 'Gene', '1956', (159, 163))	('HER2', 'Gene', (177, 181))	('CCA', 'Disease', (133, 136))	('HER2', 'Gene', '2064', (177, 181))	('EGFR', 'Gene', (159, 163))	('controls', 'MPA', (71, 79))	('HSP90', 'Gene', (46, 51))	('HSP90', 'Gene', '3320', (46, 51))	('PTEN', 'Gene', '5728', (165, 169))	('inhibition', 'NegReg', (6, 16))	('PTEN', 'Gene', (165, 169))	('interacts', 'Interaction', (52, 61))	('PI3K', 'Var', (171, 175))
185470	29113809	Moreover, recent evidence suggests that HSP90 inhibition is remarkably effective in tumors with FGFR fusions and activation of the IL6/STAT pathway.	('HSP90', 'Gene', (40, 45))	('fusions', 'Var', (101, 108))	('HSP90', 'Gene', '3320', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('FGFR', 'Gene', (96, 100))	('IL6', 'Gene', '3569', (131, 134))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('IL6', 'Gene', (131, 134))
185471	29113809	Our small-molecule compound library included 9 HSP90 inhibitors, including those from different chemical series, and 78% were active across our CCA cell line panel, with the highest activity recorded for AUY922, 17-AAG, 17-DMAG, ganetespib, and BIIB021 (Figure 2A).	('ganetespib', 'Chemical', 'MESH:C533237', (229, 239))	('HSP90', 'Gene', '3320', (47, 52))	('AUY922', 'Var', (204, 210))	('AUY922', 'Chemical', 'MESH:C528044', (204, 210))	('17-DMAG', 'Chemical', 'MESH:C448659', (220, 227))	('HSP90', 'Gene', (47, 52))	('BIIB021', 'Chemical', 'MESH:C521963', (245, 252))	('17-AAG', 'Chemical', 'MESH:C112765', (212, 218))
185472	29113809	Notably, the growth inhibitory (GI)50 of AUY922, a potent HSP90 inhibitor, was in the nanomolar range in all of the CCA cell lines tested (Figure 2B).	('AUY922', 'Var', (41, 47))	('AUY922', 'Chemical', 'MESH:C528044', (41, 47))	('HSP90', 'Gene', (58, 63))	('HSP90', 'Gene', '3320', (58, 63))	('CCA', 'Disease', (116, 119))
185473	29113809	We found no correlation between the most frequent mutations in CCA and the activity of the HSP90 inhibitors in our CCA cell lines.	('HSP90', 'Gene', '3320', (91, 96))	('mutations', 'Var', (50, 59))	('activity', 'MPA', (75, 83))	('CCA', 'Disease', (63, 66))	('HSP90', 'Gene', (91, 96))
185476	29113809	Sensitivity to AUY922 was significantly increased in CCA cells transfected with a locked nucleic acid MIR21 inhibitor compared with those transfected with a negative control locked nucleic acid inhibitor (Figure 2D).	('locked nucleic acid', 'Var', (82, 101))	('Sensitivity', 'MPA', (0, 11))	('MIR21', 'Gene', (102, 107))	('CCA', 'Disease', (53, 56))	('increased', 'PosReg', (40, 49))	('AUY922', 'Chemical', 'MESH:C528044', (15, 21))	('AUY922', 'Gene', (15, 21))
185478	29113809	A number of HSP90 inhibitors produced a larger reduction in cell viability in MIR21KO cells in comparison with WT cells (Supplementary Figure 2A), with AUY922, 17-AAG, 17-DMAG, and ganetespib showing the highest activity.	('cell viability', 'CPA', (60, 74))	('HSP90', 'Gene', '3320', (12, 17))	('ganetespib', 'Chemical', 'MESH:C533237', (181, 191))	('reduction', 'NegReg', (47, 56))	('17-DMAG', 'Chemical', 'MESH:C448659', (168, 175))	('MIR21KO', 'Var', (78, 85))	('AUY922', 'Chemical', 'MESH:C528044', (152, 158))	('17-AAG', 'Chemical', 'MESH:C112765', (160, 166))	('HSP90', 'Gene', (12, 17))
185479	29113809	When treated with HSP90 inhibitors, MIR21KO RKO cells were more sensitive than WT RKO cells (Supplementary Figure 2B).	('RKO', 'CellLine', 'CVCL:0504', (44, 47))	('RKO', 'CellLine', 'CVCL:0504', (82, 85))	('MIR21KO', 'Var', (36, 43))	('sensitive', 'MPA', (64, 73))	('HSP90', 'Gene', (18, 23))	('HSP90', 'Gene', '3320', (18, 23))
185481	29113809	Interestingly, we could detect no difference in the sensitivity to AUY922 in WT and MIR21KO DLD1 cells, which is consistent with the lower baseline level of MIR21 in DLD-1 cells and their likely lower dependence on MIR21 (Supplementary Figure 2D).	('MIR21', 'MPA', (157, 162))	('dependence', 'MPA', (201, 211))	('MIR21KO', 'Var', (84, 91))	('AUY922', 'Var', (67, 73))	('DLD1', 'CellLine', 'CVCL:0248', (92, 96))	('AUY922', 'Chemical', 'MESH:C528044', (67, 73))	('lower', 'NegReg', (133, 138))
185482	29113809	Indeed, DLD-1 WT cells were more sensitive to AUY922 than RKO WT, while silencing of MIR21 in RKO cells restored their sensitivity (Supplementary Figure 2E,F).	('silencing', 'Var', (72, 81))	('MIR21', 'Gene', (85, 90))	('RKO', 'CellLine', 'CVCL:0504', (58, 61))	('AUY922', 'Var', (46, 52))	('RKO', 'CellLine', 'CVCL:0504', (94, 97))	('AUY922', 'Chemical', 'MESH:C528044', (46, 52))	('sensitive', 'MPA', (33, 42))	('sensitivity', 'MPA', (119, 130))
185484	29113809	Enforced expression of MIR21 significantly increased resistance to AUY922 (P < .05), when compared with the effect of infection with an empty CTRL vector (Supplementary Figure 3A and Supplementary Video 1).	('MIR21', 'Gene', (23, 28))	('resistance', 'MPA', (53, 63))	('AUY922', 'Var', (67, 73))	('AUY922', 'Chemical', 'MESH:C528044', (67, 73))	('increased', 'PosReg', (43, 52))	('infection', 'Disease', (118, 127))	('infection', 'Disease', 'MESH:D007239', (118, 127))
185485	29113809	Indeed, in co-culture with non-infected MIR21KO DLD-1 cells, MIR21-induced DLD-1 cells could proliferate in the presence of AUY922 (Supplementary Figure 3B and Supplementary Video 2).	('AUY922', 'Chemical', 'MESH:C528044', (124, 130))	('proliferate', 'CPA', (93, 104))	('MIR21-induced', 'Gene', (61, 74))	('AUY922', 'Var', (124, 130))
185488	29113809	Accordingly, deactivation of the Tet-on system restored sensitivity to AUY922 in CCLP cells (Figure 2F,G, Supplementary Table 4).	('restored', 'PosReg', (47, 55))	('deactivation', 'Var', (13, 25))	('AUY922', 'Var', (71, 77))	('sensitivity', 'MPA', (56, 67))	('Tet', 'Chemical', 'MESH:C010349', (33, 36))	('AUY922', 'Chemical', 'MESH:C528044', (71, 77))
185490	29113809	A multiplex sandwich immunoassay showed a reduction in the level of HSP40 (encoded by DnaJ heat shock protein family (Hsp40) member B5, DNAJB5) in MIR21 vector cells compared with CTRL cells (Figure 3A).	('shock', 'Phenotype', 'HP:0031273', (96, 101))	('HSP40', 'Gene', '171221', (68, 73))	('level', 'MPA', (59, 64))	('HSP40', 'Gene', (68, 73))	('DNAJB5', 'Gene', '25822', (136, 142))	('MIR21 vector', 'Var', (147, 159))	('Hsp40', 'Gene', (118, 123))	('Hsp40', 'Gene', '171221', (118, 123))	('DNAJB5', 'Gene', (136, 142))	('reduction', 'NegReg', (42, 51))
185492	29113809	Western blot analysis confirmed induction of DNAJB5 upon AUY922 treatment and reduction in DNAJB5 expression in MIR21 over-expressing cells (Figure 3C), and a luciferase reporter assay confirmed a direct interaction between MIR21 and the 3'UTR of DNAJB5 (Figure 3D).	('MIR21', 'Gene', (112, 117))	('DNAJB5', 'Gene', '25822', (91, 97))	('reduction', 'NegReg', (78, 87))	('interaction', 'Interaction', (204, 215))	('over-expressing', 'PosReg', (118, 133))	('DNAJB5', 'Gene', '25822', (247, 253))	('AUY922', 'Var', (57, 63))	('DNAJB5', 'Gene', '25822', (45, 51))	('DNAJB5', 'Gene', (91, 97))	('AUY922', 'Chemical', 'MESH:C528044', (57, 63))	('DNAJB5', 'Gene', (247, 253))	('DNAJB5', 'Gene', (45, 51))	('expression', 'MPA', (98, 108))
185495	29113809	To assess the clinical relevance of our findings, we tested AUY922 activity in PDOs established from the liver biopsy of a chemoresistant iCCA patient (Figure 4, Figure 5A).	('tested', 'Reg', (53, 59))	('patient', 'Species', '9606', (143, 150))	('activity', 'MPA', (67, 75))	('AUY922', 'Var', (60, 66))	('AUY922', 'Chemical', 'MESH:C528044', (60, 66))
185498	29113809	CCA PDOs were sensitive to AUY922 (Figure 5F,G), and this sensitivity was significantly enhanced after inducible inhibition of MIR21 (Figure 5H,I).	('AUY922', 'Var', (27, 33))	('AUY922', 'Chemical', 'MESH:C528044', (27, 33))	('MIR21', 'Gene', (127, 132))	('sensitive', 'MPA', (14, 23))	('enhanced', 'PosReg', (88, 96))
185500	29113809	Next, we generated CCA PDO-derived tumor xenografts by inoculating Tet-on MIR21 PDOs in the flank of NOD scid gamma mice.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('mice', 'Species', '10090', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('MIR21 PDOs', 'Var', (74, 84))	('Tet', 'Chemical', 'MESH:C010349', (67, 70))
185501	29113809	Mice were treated with AUY922 or vehicle while changes in their diet were applied to modulate the expression of MIR21.	('modulate', 'Reg', (85, 93))	('MIR21', 'Gene', (112, 117))	('Mice', 'Species', '10090', (0, 4))	('AUY922', 'Var', (23, 29))	('AUY922', 'Chemical', 'MESH:C528044', (23, 29))
185503	29113809	While a non-significant change was observed for vehicle-treated mice, AUY922-treated mice on DOX-OFF diet achieved a significantly better tumor response than animals that remained on a doxycycline diet (Figure 6A-C, Supplementary Table 5).	('mice', 'Species', '10090', (85, 89))	('tumor', 'Disease', (138, 143))	('AUY922', 'Chemical', 'MESH:C528044', (70, 76))	('AUY922-treated', 'Var', (70, 84))	('DOX', 'Chemical', 'MESH:D004318', (93, 96))	('better', 'PosReg', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('doxycycline', 'Chemical', 'MESH:D004318', (185, 196))	('mice', 'Species', '10090', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
185512	29113809	The observation that histone-deacetylase inhibitors were enriched amongst the hits in SNU-1079 cells was in line with previous observations on the effect of IDH mutations on the impairment of histone demethylation.	('SNU-1079', 'CellLine', 'CVCL:5008', (86, 94))	('IDH', 'Gene', '3417', (157, 160))	('IDH', 'Gene', (157, 160))	('mutations', 'Var', (161, 170))	('histone demethylation', 'MPA', (192, 213))
185514	29113809	Shirota et al have recently shown that HSP90 inhibitors have potent in vitro and in vivo anti-proliferative activity in CCA, prompting us to investigate potential biomarkers of sensitivity to HSP90 inhibition in our study.	('HSP90', 'Gene', '3320', (39, 44))	('HSP90', 'Gene', (192, 197))	('HSP90', 'Gene', '3320', (192, 197))	('anti-proliferative activity', 'CPA', (89, 116))	('inhibitors', 'Var', (45, 55))	('CCA', 'Disease', (120, 123))	('HSP90', 'Gene', (39, 44))
185515	29113809	HSP90 inhibitors, including AUY922, have shown an acceptable toxicity profile in humans in phase I clinical trials, and are currently investigated in phase II clinical trials for lung and breast cancers.	('toxicity', 'Disease', 'MESH:D064420', (61, 69))	('AUY922', 'Chemical', 'MESH:C528044', (28, 34))	('toxicity', 'Disease', (61, 69))	('HSP90', 'Gene', (0, 5))	('HSP90', 'Gene', '3320', (0, 5))	('breast cancers', 'Disease', (188, 202))	('breast cancers', 'Disease', 'MESH:D001943', (188, 202))	('humans', 'Species', '9606', (81, 87))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('breast cancers', 'Phenotype', 'HP:0003002', (188, 202))	('AUY922', 'Var', (28, 34))	('lung', 'Disease', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
185516	29113809	To date, no reports are available on the role of AUY922 in biliary tract cancer patients.	('biliary tract cancer', 'Phenotype', 'HP:0100574', (59, 79))	('patients', 'Species', '9606', (80, 88))	('AUY922', 'Var', (49, 55))	('AUY922', 'Chemical', 'MESH:C528044', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('biliary tract cancer', 'Disease', 'MESH:D001661', (59, 79))	('biliary tract cancer', 'Disease', (59, 79))
185517	29113809	More interestingly, growing evidence points to a role of HSP90 inhibitors in facilitating the anti-tumor activity of immune cells.	('tumor', 'Disease', (99, 104))	('HSP90', 'Gene', (57, 62))	('HSP90', 'Gene', '3320', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('inhibitors', 'Var', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
185523	29113809	We observed that MIR21 can drive tumor cell proliferation in the presence of HSP90 inhibitors.	('HSP90', 'Gene', (77, 82))	('HSP90', 'Gene', '3320', (77, 82))	('MIR21', 'Var', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('drive', 'PosReg', (27, 32))	('tumor', 'Disease', (33, 38))
185531	29113809	We speculate that MIR21 can interfere with this balance and thus, with the HSP90-mediated activation of client proteins, by modulating the expression of HSP40.	('HSP90', 'Gene', '3320', (75, 80))	('MIR21', 'Var', (18, 23))	('activation', 'MPA', (90, 100))	('modulating', 'Reg', (124, 134))	('interfere', 'NegReg', (28, 37))	('HSP40', 'Gene', (153, 158))	('expression', 'MPA', (139, 149))	('HSP40', 'Gene', '171221', (153, 158))	('HSP90', 'Gene', (75, 80))
185570	33198671	Briefly, hypertension was managed by initiating antihypertensives if blood pressure was >= 140 mmHg (systolic) or >= 90 mmHg (diastolic), and then by dose interruption and reduction if blood pressure was >= 160 mmHg (systolic) or >= 90 mmHg (diastolic), despite optimal management with antihypertensive medications.	('hypertension', 'Disease', (9, 21))	('hypertension', 'Phenotype', 'HP:0000822', (9, 21))	('hypertension', 'Disease', 'MESH:D006973', (9, 21))	('>= 90', 'Var', (230, 235))	('reduction', 'NegReg', (172, 181))
185572	33198671	Plasma samples were collected from all patients on cycle 1, day 1 (C1D1; postdose), C1D8 (predose), C1D15 (pre/postdose), and C2D1 (predose) to assess the pharmacokinetic profile.	('patients', 'Species', '9606', (39, 47))	('C1D8', 'Var', (84, 88))	('C1D15', 'Var', (100, 105))
185610	33198671	evaluated ivosidenib versus placebo in patients with advanced cholangiocarcinoma (primarily intrahepatic) and an isocitrate dehydrogenase 1 (IDH1) gene mutation.	('IDH1', 'Gene', (141, 145))	('cholangiocarcinoma', 'Disease', (62, 80))	('patients', 'Species', '9606', (39, 47))	('isocitrate dehydrogenase 1', 'Gene', '3417', (113, 139))	('IDH1', 'Gene', '3417', (141, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('isocitrate dehydrogenase 1', 'Gene', (113, 139))	('ivosidenib', 'Chemical', 'MESH:C000627630', (10, 20))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (62, 80))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (62, 80))	('mutation', 'Var', (152, 160))
185620	33198671	Additionally, several phase 2 trials evaluating tyrosine kinase inhibitors, such as apatinib (NCT03521219), infigratinib (NCT02150967), derazantinib (NCT03230318), erdafitinib (NCT02699606), and pemigatinib (NCT04256980), as second-line treatment options in patients with BTC are currently ongoing.	('erdafitinib', 'Chemical', 'MESH:C000604580', (164, 175))	('NCT02150967', 'Var', (122, 133))	('infigratinib', 'Chemical', 'MESH:C568950', (108, 120))	('apatinib', 'Chemical', 'MESH:C553458', (84, 92))	('pemigatinib', 'Chemical', '-', (195, 206))	('derazantinib', 'Chemical', 'MESH:C000621805', (136, 148))	('patients', 'Species', '9606', (258, 266))	('NCT03230318', 'Var', (150, 161))	('BTC', 'Phenotype', 'HP:0100574', (272, 275))	('NCT03521219', 'Var', (94, 105))	('NCT02699606', 'Var', (177, 188))
185625	33198671	This study reported that overall tumor recurrence was significantly higher in patients with high levels of TAMs at the tumor invasive fronts compared with patients with low levels of TAMs (69.2% vs 33.3%; P = 0.015).	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('higher', 'PosReg', (68, 74))	('patients', 'Species', '9606', (78, 86))	('TAMs', 'Chemical', '-', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('TAMs', 'Chemical', '-', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', (33, 38))	('patients', 'Species', '9606', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('high levels', 'Var', (92, 103))
185688	33033306	The study was approved by Khon Kaen University Ethics Committee for Human Research (HE551404 and HE621288).	('HE621288', 'Var', (97, 105))	('Human', 'Species', '9606', (68, 73))	('HE551404', 'Var', (84, 92))
185695	33033306	Twenty-one percent (n = 75,640) of study participants had abnormalities that are associated with CCA.	('abnormalities', 'Var', (58, 71))	('CCA', 'Phenotype', 'HP:0030153', (97, 100))	('participants', 'Species', '9606', (41, 53))	('CCA', 'Disease', (97, 100))
185699	33033306	There was a statistically significant difference between men and women, and age groups for overall abnormalities that cause CCA (Table 4).	('women', 'Species', '9606', (65, 70))	('CCA', 'Disease', (124, 127))	('age', 'Gene', '5973', (76, 79))	('men', 'Species', '9606', (67, 70))	('CCA', 'Phenotype', 'HP:0030153', (124, 127))	('age', 'Gene', (76, 79))	('abnormalities', 'Var', (99, 112))	('men', 'Species', '9606', (57, 60))
185891	32884219	In addition, cisplatin in the membrane was associated with inflammatory reactions in the mucosa and submucosa (Figure 5B, Table 1).	('associated with', 'Reg', (43, 58))	('inflammatory reactions', 'CPA', (59, 81))	('w', 'Chemical', 'MESH:D014414', (39, 40))	('w', 'Chemical', 'MESH:D014414', (54, 55))	('cisplatin', 'Var', (13, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))
186010	30702559	Study from Li et al was the only 1 which demonstrated a "bi-polar" effect in the use of adjuvant TACE for ICC patients (i.e., adjuvant TACE was associated with benefit in overall survival but at the same time leading to an inferior disease-free survival).	('adjuvant TACE', 'Var', (126, 139))	('TACE', 'Chemical', '-', (97, 101))	('ICC', 'Disease', (106, 109))	('benefit', 'PosReg', (160, 167))	('TACE', 'Chemical', '-', (135, 139))	('overall survival', 'CPA', (171, 187))	('patients', 'Species', '9606', (110, 118))
186011	30702559	According to the explanation from Li et al, this was partly related to patient selection (i.e., TACE tends to benefit more in patients with advanced disease), and partly related to the 2 effects associated with TACE; Embolization of the hepatic artery leads to growth factor release from ischemic tissue favours local recurrence while chemotherapeutic agents dissipated in the hepatic parenchyma helps to suppress the growth of any recurrent tumor.	('local recurrence', 'CPA', (312, 328))	('Embolization', 'Var', (217, 229))	('tumor', 'Disease', 'MESH:D009369', (442, 447))	('favours', 'PosReg', (304, 311))	('TACE', 'Chemical', '-', (96, 100))	('patient', 'Species', '9606', (126, 133))	('ischemic', 'Disease', 'MESH:D007511', (288, 296))	('tumor', 'Phenotype', 'HP:0002664', (442, 447))	('growth factor release', 'MPA', (261, 282))	('tumor', 'Disease', (442, 447))	('patients', 'Species', '9606', (126, 134))	('patient', 'Species', '9606', (71, 78))	('TACE', 'Chemical', '-', (211, 215))	('ischemic', 'Disease', (288, 296))
186023	30419854	As far as we know, this is the first case report on the success of the combination of immunotherapy and chemotherapy for advanced cholangiocarcinoma with PD-L1 positivity and a high tumour mutational burden.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (130, 148))	('high tumour', 'Disease', (177, 188))	('high tumour', 'Disease', 'MESH:D009369', (177, 188))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('PD-L1', 'Gene', (154, 159))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (130, 148))	('PD-L1', 'Gene', '29126', (154, 159))	('positivity', 'Var', (160, 170))	('cholangiocarcinoma', 'Disease', (130, 148))
186054	30419854	Genomic testing showed the TP53 R249S, ATRX K1177, and RB1 K80 mutations, but no mutations were detected in the ERBB2 or KRAS genes.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('K80', 'Var', (59, 62))	('KRAS', 'Gene', (121, 125))	('ERBB2', 'Gene', '2064', (112, 117))	('RB1', 'Gene', (55, 58))	('ERBB2', 'Gene', (112, 117))	('R249S', 'Mutation', 'rs28934571', (32, 37))	('KRAS', 'Gene', '3845', (121, 125))	('R249S', 'Var', (32, 37))
186070	30419854	BRAF mutations were shown to occur in approximately 5% of iCCA cases, and previous studies have shown that combination therapy with dabrafenib and trametinib were effective in iCCA patients with the BRAF V600E mutation.	('V600E', 'Mutation', 'rs113488022', (204, 209))	('dabrafenib', 'Chemical', 'MESH:C561627', (132, 142))	('iCCA', 'Disease', (58, 62))	('V600E', 'Var', (204, 209))	('trametinib', 'Chemical', 'MESH:C560077', (147, 157))	('BRAF', 'Gene', '673', (0, 4))	('patients', 'Species', '9606', (181, 189))	('BRAF', 'Gene', (199, 203))	('iCCA', 'Disease', (176, 180))	('BRAF', 'Gene', '673', (199, 203))	('BRAF', 'Gene', (0, 4))
186071	30419854	Approximately 11% of iCCAs were demonstrated to harbour gene fusions of FGFR1/2/3, which is rare in other cholangiocarcinomas.	('FGFR1/2/3', 'Gene', '2260;2263;2261', (72, 81))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (106, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (106, 125))	('gene fusions', 'Var', (56, 68))	('cholangiocarcinomas', 'Disease', (106, 125))	('FGFR1/2/3', 'Gene', (72, 81))
186074	30419854	The Checkmate-026 clinical study has shown that nivolumab, compared with chemotherapy, does not lengthen the progression-free survival (PFS) of patients with NSCLC with positive PD-L1 expression.	('NSCLC', 'Disease', (158, 163))	('clinical', 'Species', '191496', (18, 26))	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('patients', 'Species', '9606', (144, 152))	('nivolumab', 'Chemical', 'MESH:D000077594', (48, 57))	('PD-L1', 'Gene', (178, 183))	('PD-L1', 'Gene', '29126', (178, 183))	('positive', 'Var', (169, 177))
186075	30419854	A retrospective analysis suggested that patients with a high TMB had significantly prolonged PFS when treated with nivolumab.	('TMB', 'Chemical', '-', (61, 64))	('patients', 'Species', '9606', (40, 48))	('prolonged', 'PosReg', (83, 92))	('PFS', 'MPA', (93, 96))	('nivolumab', 'Chemical', 'MESH:D000077594', (115, 124))	('high', 'Var', (56, 60))
186137	26430782	Having similar sizes and numbers of tumors, the MF + PI type of ICC was more frequently associated with portal vein invasion, biliary invasion, or lymph node metastasis compared with the MF type (Table 1).	('MF + PI', 'Var', (48, 55))	('portal vein', 'Disease', (104, 115))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('biliary', 'Disease', (126, 133))	('ICC', 'Disease', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('associated', 'Reg', (88, 98))	('lymph node metastasis', 'CPA', (147, 168))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
186138	26430782	The overall survival of patients who had the MF + PI type was significantly worse than that of patients who had the MF type (median survival time [MST], 43.5 vs 17.6 months; P < .001).	('MF + PI', 'Var', (45, 52))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (95, 103))	('worse', 'NegReg', (76, 81))
186139	26430782	The degree of biliary invasion was more advanced in patients who had the MF + PI type than in those who had the MF type, with a significantly higher rate of major biliary invasion (b3 or b4; 36.5% vs 11.7%, respectively; P < .001).	('MF + PI', 'Var', (73, 80))	('biliary', 'Disease', (14, 21))	('major biliary invasion', 'CPA', (157, 179))	('higher', 'PosReg', (142, 148))	('patients', 'Species', '9606', (52, 60))
186148	26430782	No significant difference in survival was observed between 38 patients who had T4N1M0 disease and 7 patients who had M1 disease (MST, 13.4 vs 4.2 months; P = .57).	('T4N1M0 disease', 'Var', (79, 93))	('M1 disease', 'Disease', 'MESH:D015470', (117, 127))	('patients', 'Species', '9606', (100, 108))	('patients', 'Species', '9606', (62, 70))	('M1 disease', 'Disease', (117, 127))
186149	26430782	Therefore, patients with T1-T3N1M0 and T4N0M0 disease were grouped into stage IVA, whereas those with T4N1M0 and M1 disease were grouped into stage IVB (MST, 17.8 vs 12.3 months; P < .001).	('M1 disease', 'Disease', 'MESH:D015470', (113, 123))	('T1-T3N1M0', 'Var', (25, 34))	('IVA', 'Disease', 'MESH:C538167', (78, 81))	('T4N0M0 disease', 'Var', (39, 53))	('M1 disease', 'Disease', (113, 123))	('patients', 'Species', '9606', (11, 19))	('IVA', 'Disease', (78, 81))
186151	26430782	In the seventh edition of the AJCC classification, patients who had T2b tumors had worse survival than those who had T3 tumors (P = .001) and T4 tumors (P = .053), suggesting worse survival for patients who had multiple ICCs (T2b) compared with those who had perforation (T3) or periductal invasion (T4).	('worse', 'NegReg', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (120, 126))	('patients', 'Species', '9606', (194, 202))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('T3 tumors', 'Disease', 'MESH:C537047', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('patients', 'Species', '9606', (51, 59))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('T2b', 'Var', (68, 71))	('T3 tumors', 'Disease', (117, 126))
186153	26430782	The fifth edition of the LCSGJ system did not discriminate well between stages IVA and IVB (P = .12); however, the new staging system did discriminate well between stages IVA and IVB (P < .001), indicating that stage IVB in the fifth edition of the LCSGJ system can be divided into 2 groups, T1-T3N1M0 (stage IVA in the new staging system) and T4N1M0 or M1 (stage IVB in the new staging system).	('T1-T3N1M0', 'Var', (292, 301))	('IVA', 'Disease', (309, 312))	('IVA', 'Disease', (79, 82))	('IVA', 'Disease', 'MESH:C538167', (171, 174))	('IVA', 'Disease', 'MESH:C538167', (79, 82))	('T4N1M0 or', 'Var', (344, 353))	('IVA', 'Disease', 'MESH:C538167', (309, 312))	('IVA', 'Disease', (171, 174))
186168	26430782	However, there is some controversy regarding whether the prognosis for patients with the MF + PI type of ICC is worse than that for those with the MF type.	('patients', 'Species', '9606', (71, 79))	('MF + PI', 'Var', (89, 96))	('ICC', 'Disease', (105, 108))
186175	26430782	Patients who have ICC with lymph node metastasis may have a dismal prognosis, and surgical indications for patients with lymph node metastasis remain controversial.17, 18 In the current study, no significant difference in survival was observed between patients with T1-T3N1M0 disease and those with T4N0M0 disease (MST, 16.6 vs 22.5 months; P = .95) or between patients with T4N1M0 disease and those with M1 disease (MST, 13.4 vs 4.2 months; P = .57).	('patients', 'Species', '9606', (361, 369))	('M1 disease', 'Disease', 'MESH:D015470', (405, 415))	('patients', 'Species', '9606', (252, 260))	('T1-T3N1M0 disease', 'Disease', (266, 283))	('T4N1M0', 'Var', (375, 381))	('Patients', 'Species', '9606', (0, 8))	('M1 disease', 'Disease', (405, 415))	('T1-T3N1M0 disease', 'Disease', 'MESH:C538397', (266, 283))	('patients', 'Species', '9606', (107, 115))
186183	26430782	Patients with T1-T3N1M0 and T4N0M0 disease were included in stage IVA, whereas those with T4N1M0 and M1 disease were included in stage IVB.	('IVA', 'Disease', (66, 69))	('T1-T3N1M0', 'Var', (14, 23))	('M1 disease', 'Disease', (101, 111))	('Patients', 'Species', '9606', (0, 8))	('IVA', 'Disease', 'MESH:C538167', (66, 69))	('M1 disease', 'Disease', 'MESH:D015470', (101, 111))	('T4N0M0 disease', 'Var', (28, 42))
186211	25446840	Currently, five and possibly up to eight isoforms of Postn have been recognized as a result of alternative splicing in the COOH-terminal domain.	('COOH', 'Chemical', 'MESH:D002255', (123, 127))	('Postn', 'Gene', (53, 58))	('alternative splicing in', 'Var', (95, 118))	('result', 'Reg', (85, 91))
186212	25446840	As proposed by Hoersch and Andrade-Navarro, the sequence variation imparted by alternative splicing within the COOH-terminal domain of Postn could be a key determinant of its biological function, and possibly a likely explanation for how Postn has been observed to function either as a promoter or suppressor of cancer cell invasiveness in different carcinoma types.	('cancer cell invasiveness', 'Disease', 'MESH:D009362', (312, 336))	('cancer cell invasiveness', 'Disease', (312, 336))	('carcinoma', 'Disease', 'MESH:D002277', (350, 359))	('Postn', 'Gene', (135, 140))	('COOH', 'Chemical', 'MESH:D002255', (111, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (350, 359))	('alternative splicing', 'Var', (79, 99))	('carcinoma', 'Disease', (350, 359))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))
186234	25446840	Aberrant interactive signaling mediated in part by TGF-beta family members, angiotensin II, platelet derived growth factors, and chemokines like stromal cell-derived factor-1 are regarded as being important regulators of fibrogenesis, potentially acting to promote the desmoplasia/hypoxia milieu and tumor progression in ICC.	('angiotensin II', 'Gene', '183', (76, 90))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('angiotensin II', 'Gene', (76, 90))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', (300, 305))	('TGF-beta', 'Gene', (51, 59))	('ICC', 'Disease', (321, 324))	('interactive signaling', 'MPA', (9, 30))	('stromal cell-derived factor-1', 'Gene', '6387', (145, 174))	('promote', 'PosReg', (257, 264))	('stromal cell-derived factor-1', 'Gene', (145, 174))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('desmoplasia/hypoxia', 'Disease', (269, 288))	('desmoplasia/hypoxia', 'Disease', 'MESH:D000860', (269, 288))	('TGF-beta', 'Gene', '7040', (51, 59))
186272	25446840	Another novel mechanism by which Postn may be cooperating to mediate tumor invasion is suggested by the recent findings of Wong et al., who demonstrated in an organotypic 3-dimensional culture model of esophageal squamous cell carcinoma (ESCC) invasion that Postn cooperates with mutant p53 to mediate invasion through the induction of the signal transducer and activator of transcription 1 signaling network.	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (202, 236))	('tumor', 'Disease', (69, 74))	('rat', 'Species', '10116', (51, 54))	('signal transducer and activator of transcription 1', 'Gene', '6772', (340, 390))	('p53', 'Gene', '7157', (287, 290))	('mutant', 'Var', (280, 286))	('rat', 'Species', '10116', (269, 272))	('esophageal squamous cell carcinoma', 'Disease', (202, 236))	('rat', 'Species', '10116', (147, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('p53', 'Gene', (287, 290))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('invasion', 'CPA', (302, 310))
186280	25446840	In a xenograft model of 4T1cell implantation into the mammary fat pads of female BALB/c mice, intratumorally injected PNDA-3 at 500microg/kg, three times a week for 16 days was observed to significantly decrease primary tumor volume, as well as to significantly reduce the number of distant nodular and focal metastases formed in lung.	('metastases', 'Disease', 'MESH:D009362', (309, 319))	('tumor', 'Disease', (99, 104))	('rat', 'Species', '10116', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('implantation', 'Var', (32, 44))	('tumor', 'Disease', (220, 225))	('PNDA-3', 'Chemical', '-', (118, 124))	('decrease', 'NegReg', (203, 211))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('metastases', 'Disease', (309, 319))	('nodular', 'Disease', (291, 298))	('nodular', 'Disease', 'MESH:D020518', (291, 298))	('4T1', 'CellLine', 'CVCL:0125', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('reduce', 'NegReg', (262, 268))	('PNDA-3', 'Var', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('mice', 'Species', '10090', (88, 92))
186282	25446840	Interestingly, single intraveneous injection of 500microg/kg Cy3-labeled PDNA-3 to the tumor bearing mice was determined to diffuse throughout the primary tumor stroma within 6 hours after the initial injection, with fluorescent signal still being detected in the tumor until 72 hours.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('Cy3-labeled', 'Var', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (264, 269))	('tumor', 'Disease', (87, 92))	('tumor stroma', 'Disease', 'MESH:D009369', (155, 167))	('tumor', 'Disease', (155, 160))	('Cy3', 'Chemical', '-', (61, 64))	('tumor stroma', 'Disease', (155, 167))	('mice', 'Species', '10090', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('PDNA-3', 'Gene', (73, 79))
186290	25446840	Using this radiogenomic mapping approach, high Postn and low microRNA (miR) -219 were determined to be significantly associated with the mesenchymal GMB subset and malignant cell invasion, both of which are major features of GMB aggressiveness and therapy failure.	('high Postn', 'Var', (42, 52))	('GMB', 'Chemical', 'MESH:C032138', (225, 228))	('associated', 'Reg', (117, 127))	('aggressiveness', 'Phenotype', 'HP:0000718', (229, 243))	('low', 'NegReg', (57, 60))	('GMB aggressiveness', 'Disease', (225, 243))	('mesenchymal GMB subset', 'CPA', (137, 159))	('GMB aggressiveness', 'Disease', 'MESH:D001523', (225, 243))	('malignant cell invasion', 'CPA', (164, 187))	('GMB', 'Chemical', 'MESH:C032138', (149, 152))
186295	25446840	In this regard, a need now exists to conduct rationally designed, mechanism-based preclinical studies in which animal models of ICC that closely mimic the human invasive/metastatic disease are used as preclinical platforms to identify and test novel molecular strategies for anti-metastatic ICC therapy based on selective knockdown of stromal cell Postn expression or inhibition of its pro-invasive signaling activity.	('human', 'Species', '9606', (155, 160))	('knockdown', 'Var', (322, 331))	('anti-metastatic ICC', 'Disease', (275, 294))	('rat', 'Species', '10116', (262, 265))	('rat', 'Species', '10116', (45, 48))
186300	25446840	using a genetically engineered mouse model of PDAC were the first to demonstrate that pharmacological inhibition of Hh signaling inhibited the formation of CAF-enriched desmoplastic stroma, resulting in a transient increase in intratumoral microvascularity and concomitant increased in intratumoral concentration of the chemotherapeutic agent gemcitabine, leading to a transient stabilization of the disease.	('PDAC', 'Phenotype', 'HP:0006725', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('rat', 'Species', '10116', (230, 233))	('gemcitabine', 'Chemical', 'MESH:C056507', (343, 354))	('desmoplastic stroma', 'Disease', 'MESH:D018220', (169, 188))	('inhibited', 'NegReg', (129, 138))	('mouse', 'Species', '10090', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('increased', 'PosReg', (273, 282))	('tumor', 'Disease', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('rat', 'Species', '10116', (306, 309))	('rat', 'Species', '10116', (289, 292))	('rat', 'Species', '10116', (76, 79))	('increase', 'PosReg', (215, 223))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('pharmacological', 'Var', (86, 101))	('PDAC', 'Chemical', '-', (46, 50))	('tumor', 'Disease', (291, 296))	('desmoplastic stroma', 'Disease', (169, 188))
186303	25446840	In sharp contrast, Rhim and Olive and their colleagues recently showed in mouse PDAC that deletion of CAFs from tumor microenvironment, either by genetic or pharmacological targeting of the Hh pathway, actually enhanced malignant aggressiveness by increasing vascularity and cancer cell proliferation, together with promoting a more undifferentiated histopathology.	('deletion', 'Var', (90, 98))	('Olive', 'Species', '4146', (28, 33))	('promoting', 'PosReg', (316, 325))	('rat', 'Species', '10116', (294, 297))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('CAFs', 'Gene', (102, 106))	('aggressiveness', 'Phenotype', 'HP:0000718', (230, 244))	('vascularity', 'CPA', (259, 270))	('malignant aggressiveness', 'Disease', (220, 244))	('tumor', 'Disease', (112, 117))	('malignant aggressiveness', 'Disease', 'MESH:D009369', (220, 244))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('mouse', 'Species', '10090', (74, 79))	('enhanced', 'PosReg', (211, 219))	('cancer', 'Disease', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('PDAC', 'Chemical', '-', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('increasing', 'PosReg', (248, 258))	('PDAC', 'Phenotype', 'HP:0006725', (80, 84))
186312	20562908	Blockade of Hh using pharmacological and genetic tools sensitizes the cells to TRAIL cytotoxicity.	('cytotoxicity', 'Disease', (85, 97))	('Blockade', 'Var', (0, 8))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))	('sensitizes', 'Reg', (55, 65))
186314	20562908	Knockdown of DR4 mimics Hh-mediated resistance to TRAIL cytotoxicity.	('Knockdown', 'Var', (0, 9))	('cytotoxicity', 'Disease', 'MESH:D064420', (56, 68))	('DR4', 'Gene', '8797', (13, 16))	('DR4', 'Gene', (13, 16))	('cytotoxicity', 'Disease', (56, 68))
186317	20562908	Finally, small interfering RNA (siRNA)-targeted knockdown of GLI3, but not GLI1 or GLI2, restores DR4 expression and TRAIL sensitivity, indicating that the Hh effect is exclusively mediated by this transcription factor.	('TRAIL sensitivity', 'CPA', (117, 134))	('expression', 'Species', '29278', (102, 112))	('GLI', 'Gene', (75, 78))	('expression', 'MPA', (102, 112))	('GLI', 'Gene', '2735', (83, 86))	('DR4', 'Gene', '8797', (98, 101))	('DR4', 'Gene', (98, 101))	('GLI', 'Gene', (61, 64))	('restores', 'PosReg', (89, 97))	('GLI', 'Gene', '2735', (75, 78))	('GLI3', 'Gene', '2737', (61, 65))	('GLI', 'Gene', '2735', (61, 64))	('GLI', 'Gene', (83, 86))	('GLI3', 'Gene', (61, 65))	('knockdown', 'Var', (48, 57))
186328	20562908	Mechanistically, we have shown that silencing of DR4 by Hh requires an intact GLI3 activity.	('GLI3', 'Gene', '2737', (78, 82))	('silencing', 'Var', (36, 45))	('DR4', 'Gene', '8797', (49, 52))	('GLI3', 'Gene', (78, 82))	('DR4', 'Gene', (49, 52))
186331	20562908	We first ascertained whether inhibiting Smoothened, the signaling component of the Hh receptor complex, using cyclopamine, sensitizes cholangiocarcinoma cells to TRAIL-induced cytotoxicity.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (134, 152))	('cytotoxicity', 'Disease', 'MESH:D064420', (176, 188))	('Smoothened', 'Protein', (40, 50))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (134, 152))	('cyclopamine', 'Chemical', 'MESH:C000541', (110, 121))	('sensitizes', 'Reg', (123, 133))	('inhibiting', 'Var', (29, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('cytotoxicity', 'Disease', (176, 188))	('cholangiocarcinoma', 'Disease', (134, 152))
186337	20562908	Validation using short hairpin RNA (shRNA)-targeted knockdown of Smoothened also sensitizes KMCH cells to TRAIL cytotoxicity (Figures 1c and e), showing that the relevant effect of cyclopamine is on Smoothened inhibition.	('cytotoxicity', 'Disease', (112, 124))	('sensitizes', 'Reg', (81, 91))	('cyclopamine', 'Chemical', 'MESH:C000541', (181, 192))	('TRAIL', 'CPA', (106, 111))	('Smoothened', 'Gene', (65, 75))	('cytotoxicity', 'Disease', 'MESH:D064420', (112, 124))	('knockdown', 'Var', (52, 61))
186341	20562908	In addition, validation using shRNA-targeted knockdown of Smoothened also upregulated DR4 expression at both mRNA and protein level (Figures 2d and e).	('upregulated', 'PosReg', (74, 85))	('Smoothened', 'Gene', (58, 68))	('expression', 'Species', '29278', (90, 100))	('expression', 'MPA', (90, 100))	('DR4', 'Gene', '8797', (86, 89))	('DR4', 'Gene', (86, 89))	('knockdown', 'Var', (45, 54))
186343	20562908	Increased DR4 mRNA and protein expression on cyclopamine treatment or knockdown of Smoothened suggested that sensitization to TRAIL cytotoxicity could be mediated specifically through DR4.	('knockdown', 'Var', (70, 79))	('DR4', 'Gene', '8797', (184, 187))	('DR4', 'Gene', (184, 187))	('cytotoxicity', 'Disease', 'MESH:D064420', (132, 144))	('expression', 'Species', '29278', (31, 41))	('cyclopamine', 'Chemical', 'MESH:C000541', (45, 56))	('Increased', 'PosReg', (0, 9))	('Smoothened', 'Gene', (83, 93))	('DR4', 'Gene', '8797', (10, 13))	('DR4', 'Gene', (10, 13))	('cytotoxicity', 'Disease', (132, 144))
186357	20562908	GLI1 and Patched1 were downregulated by cyclopamine treatment as well as shRNA targeting the knockdown of Smoothened (Figure 4d).	('knockdown', 'Var', (93, 102))	('downregulated', 'NegReg', (23, 36))	('Smoothened', 'Gene', (106, 116))	('GLI', 'Gene', (0, 3))	('Patched1', 'Gene', (9, 17))	('GLI', 'Gene', '2735', (0, 3))	('cyclopamine', 'Chemical', 'MESH:C000541', (40, 51))
186366	20562908	In contrast, when mutant GLI-binding sites (four tandem copies) were incorporated into the reporter gene construct instead, luciferase activity was not enhanced by cyclopamine treatment.	('luciferase', 'Enzyme', (124, 134))	('rat', 'Species', '10116', (76, 79))	('cyclopamine', 'Chemical', 'MESH:C000541', (164, 175))	('mutant', 'Var', (18, 24))	('activity', 'MPA', (135, 143))	('GLI', 'Gene', (25, 28))	('GLI', 'Gene', '2735', (25, 28))
186367	20562908	Consistent with these data, reporter gene activity was actually enhanced in the DR4-promoter construct containing mutated GLI-enhancer sequences compared with that containing intact GLI-binding sites, presumably because of the release from tonic GLI-mediated suppression (Figure 5b).	('GLI', 'Gene', (246, 249))	('DR4', 'Gene', '8797', (80, 83))	('DR4', 'Gene', (80, 83))	('mutated', 'Var', (114, 121))	('GLI', 'Gene', (182, 185))	('GLI', 'Gene', '2735', (246, 249))	('GLI', 'Gene', (122, 125))	('reporter gene activity', 'MPA', (28, 50))	('GLI', 'Gene', '2735', (182, 185))	('GLI', 'Gene', '2735', (122, 125))	('enhanced', 'PosReg', (64, 72))
186373	20562908	DR4 expression was increased by gene silencing of GLI3, while gene silencing of GLI1 or GLI2 did not alter DR4 expression (Figures 6b and c).	('DR4', 'Gene', (107, 110))	('GLI', 'Gene', (80, 83))	('GLI', 'Gene', (50, 53))	('expression', 'Species', '29278', (4, 14))	('GLI', 'Gene', (88, 91))	('GLI3', 'Gene', '2737', (50, 54))	('expression', 'Species', '29278', (111, 121))	('expression', 'MPA', (4, 14))	('GLI', 'Gene', '2735', (80, 83))	('GLI3', 'Gene', (50, 54))	('increased', 'PosReg', (19, 28))	('DR4', 'Gene', (0, 3))	('DR4', 'Gene', '8797', (0, 3))	('GLI', 'Gene', '2735', (88, 91))	('GLI', 'Gene', '2735', (50, 53))	('DR4', 'Gene', '8797', (107, 110))	('gene silencing', 'Var', (32, 46))
186374	20562908	In contrast, gene silencing of GLI1, GLI2 or GLI3 did not alter the DR5 expression.	('GLI', 'Gene', (45, 48))	('GLI3', 'Gene', (45, 49))	('GLI', 'Gene', '2735', (31, 34))	('GLI', 'Gene', '2735', (45, 48))	('expression', 'Species', '29278', (72, 82))	('gene silencing', 'Var', (13, 27))	('GLI', 'Gene', (37, 40))	('expression', 'MPA', (72, 82))	('GLI', 'Gene', '2735', (37, 40))	('GLI', 'Gene', (31, 34))	('DR5', 'Gene', (68, 71))	('GLI3', 'Gene', '2737', (45, 49))
186376	20562908	If this interpretation is correct, knockdown of GLI3 should sensitize cells to TRAIL cytotoxicity.	('knockdown', 'Var', (35, 44))	('GLI3', 'Gene', '2737', (48, 52))	('GLI3', 'Gene', (48, 52))	('cytotoxicity', 'Disease', (85, 97))	('sensitize', 'Reg', (60, 69))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))
186381	20562908	Consistent with repression by GLI3, DR4-reporter activity was decreased in GLI3 overexpressing cells (Figure 6e), as was the activity of an earlier described GLI-responsive promoter (Supplementary Figure 5).	('overexpressing', 'Var', (80, 94))	('GLI3', 'Gene', (30, 34))	('GLI', 'Gene', (75, 78))	('DR4', 'Gene', (36, 39))	('decreased', 'NegReg', (62, 71))	('DR4', 'Gene', '8797', (36, 39))	('GLI', 'Gene', (30, 33))	('activity', 'MPA', (125, 133))	('GLI', 'Gene', (158, 161))	('GLI', 'Gene', '2735', (75, 78))	('GLI3', 'Gene', '2737', (75, 79))	('GLI', 'Gene', '2735', (30, 33))	('GLI3', 'Gene', '2737', (30, 34))	('GLI', 'Gene', '2735', (158, 161))	('GLI3', 'Gene', (75, 79))
186382	20562908	However, the reporter containing mutant GLI-binding sites did not have increased activity on GLI3 silencing, nor decreased function when GLI3 was overexpressed (Figure 6e).	('GLI', 'Gene', (93, 96))	('GLI3', 'Gene', '2737', (93, 97))	('GLI', 'Gene', (40, 43))	('GLI', 'Gene', '2735', (93, 96))	('GLI3', 'Gene', (93, 97))	('GLI', 'Gene', (137, 140))	('GLI', 'Gene', '2735', (40, 43))	('mutant', 'Var', (33, 39))	('activity', 'MPA', (81, 89))	('GLI', 'Gene', '2735', (137, 140))	('GLI3', 'Gene', '2737', (137, 141))	('GLI3', 'Gene', (137, 141))
186393	20562908	Cyclopamine did, however, result in enhanced DR4 expression.	('Cyclopamine', 'Chemical', 'MESH:C000541', (0, 11))	('expression', 'Species', '29278', (49, 59))	('Cyclopamine', 'Var', (0, 11))	('enhanced', 'PosReg', (36, 44))	('DR4', 'Gene', '8797', (45, 48))	('DR4', 'Gene', (45, 48))
186402	20562908	In this study, we have shown that gene silencing of GLI3 increased the expression of DR4, indicating that GLI3 suppresses DR4 expression.	('expression', 'Species', '29278', (126, 136))	('expression', 'MPA', (71, 81))	('GLI3', 'Gene', '2737', (52, 56))	('expression', 'MPA', (126, 136))	('DR4', 'Gene', '8797', (85, 88))	('GLI3', 'Gene', (52, 56))	('DR4', 'Gene', '8797', (122, 125))	('gene silencing', 'Var', (34, 48))	('DR4', 'Gene', (85, 88))	('DR4', 'Gene', (122, 125))	('increased', 'PosReg', (57, 66))	('GLI3', 'Gene', '2737', (106, 110))	('expression', 'Species', '29278', (71, 81))	('suppresses', 'NegReg', (111, 121))	('GLI3', 'Gene', (106, 110))
186403	20562908	The inhibition of DR4 expression by GLI3 appears to be direct, as multiple GLI-binding elements are present in the promoter, and mutation of these elements increases the activity of the DR4 promoter.	('DR4', 'Gene', '8797', (186, 189))	('GLI', 'Gene', (36, 39))	('GLI', 'Gene', (75, 78))	('DR4', 'Gene', (186, 189))	('mutation', 'Var', (129, 137))	('activity', 'MPA', (170, 178))	('GLI3', 'Gene', '2737', (36, 40))	('GLI3', 'Gene', (36, 40))	('increases', 'PosReg', (156, 165))	('GLI', 'Gene', '2735', (36, 39))	('GLI', 'Gene', '2735', (75, 78))	('expression', 'Species', '29278', (22, 32))	('DR4', 'Gene', '8797', (18, 21))	('DR4', 'Gene', (18, 21))
186407	20562908	As these cancers express TRAIL in vivo, pharmacological inhibition of Hh signaling may promote autocrine and/or paracrine cholangiocarcinoma autonomous cytotoxicity.	('cholangiocarcinoma autonomous', 'Disease', (122, 151))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cholangiocarcinoma autonomous', 'Disease', 'MESH:D018281', (122, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('cancers', 'Disease', (9, 16))	('autocrine', 'Disease', (95, 104))	('cytotoxicity', 'Disease', 'MESH:D064420', (152, 164))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (122, 140))	('pharmacological inhibition', 'Var', (40, 66))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('promote', 'PosReg', (87, 94))	('cytotoxicity', 'Disease', (152, 164))
186441	20562908	As a negative control, double-stranded oligonucleotides with two C-to-G mutations in the DR4 GLI-binding site (Figure 5a) were synthesized and ligated (four tandem copies) at the BamHI site of the pGL3 (-586/+63) vector.	('mutations', 'Var', (72, 81))	('GLI', 'Gene', (93, 96))	('GLI', 'Gene', '2735', (93, 96))	('DR4', 'Gene', '8797', (89, 92))	('DR4', 'Gene', (89, 92))	('stranded oligonucleotides', 'Chemical', '-', (30, 55))
186442	20562908	The mutations were positioned within the consensus-binding region to disrupt GLI-binding.	('mutations', 'Var', (4, 13))	('GLI', 'Gene', (77, 80))	('disrupt', 'NegReg', (69, 76))	('GLI', 'Gene', '2735', (77, 80))
186443	20562908	The vectors containing the correct and mutant inserts were sequenced to confirm that the GLI-binding site was as expected and that the luciferase gene did not contain cloning artifacts.	('GLI', 'Gene', '2735', (89, 92))	('GLI', 'Gene', (89, 92))	('mutant', 'Var', (39, 45))
186467	31431036	Indeed, NGS assays are highly sensitive, able to analyze a large panel of genes, and detect novel mutations, small insertions or deletions (indels), copy number alterations, and select gene fusions and rearrangements from small amounts of sample.	('deletions', 'Var', (129, 138))	('rearrangements', 'Var', (202, 216))	('mutations', 'Var', (98, 107))	('men', 'Species', '9606', (211, 214))	('insertions', 'Var', (115, 125))	('copy number alterations', 'Var', (149, 172))
186468	31431036	A pioneer study used NGS to characterize 54 ICC Opisthorchis viverrini:related cholangiocarcinoma cases and found mutations in TP53 (44.4%), KRAS (16.7%), and SMAD4 (16.7%).	('SMAD4', 'Gene', (159, 164))	('cholangiocarcinoma', 'Disease', (79, 97))	('KRAS', 'Gene', (141, 145))	('Opisthorchis viverrini', 'Species', '6198', (48, 70))	('mutations', 'Var', (114, 123))	('KRAS', 'Gene', '3845', (141, 145))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (79, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (79, 97))	('SMAD4', 'Gene', '4089', (159, 164))	('ICC Opisthorchis', 'Phenotype', 'HP:0002179', (44, 60))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))
186469	31431036	Potentially actionable mutations were found in FGFR2 and IDH1/2, however, these were mostly limited to ICC with a prevalence of 11% and 20%, respectively.	('ICC', 'Disease', (103, 106))	('IDH1/2', 'Gene', (57, 63))	('actionable', 'Reg', (12, 22))	('mutations', 'Var', (23, 32))	('IDH1/2', 'Gene', '3417;3418', (57, 63))	('FGFR2', 'Gene', (47, 52))	('FGFR2', 'Gene', '2263', (47, 52))
186470	31431036	Also, ERBB2 amplification was more frequently observed in GBC (16%) and EHC (11%) versus ICC (3%).	('observed', 'Reg', (46, 54))	('EHC', 'Disease', (72, 75))	('ERBB2', 'Gene', '2064', (6, 11))	('amplification', 'Var', (12, 25))	('ERBB2', 'Gene', (6, 11))	('GBC', 'Disease', (58, 61))
186471	31431036	Similarly, a prospective study analyzed 195 cholangiocarcinomas using the targeted MSK-IMPACT platform and found that FGFR2 fusions and IDH1, BAP1 and TP53 mutations occurred with greater frequency among ICCs, whereas KRAS, SMAD4, and STK11 alterations were more commonly seen in EHCs.	('BAP1', 'Gene', '8314', (142, 146))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (44, 62))	('FGFR2', 'Gene', '2263', (118, 123))	('KRAS', 'Gene', '3845', (218, 222))	('TP53', 'Gene', '7157', (151, 155))	('fusions', 'Var', (124, 131))	('IDH', 'Gene', (136, 139))	('ICCs', 'Disease', (204, 208))	('STK11', 'Gene', '6794', (235, 240))	('SMAD4', 'Gene', '4089', (224, 229))	('KRAS', 'Gene', (218, 222))	('BAP1', 'Gene', (142, 146))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (44, 63))	('IDH', 'Gene', '3417', (136, 139))	('occurred', 'Reg', (166, 174))	('mutations', 'Var', (156, 165))	('cholangiocarcinomas', 'Disease', (44, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('TP53', 'Gene', (151, 155))	('FGFR2', 'Gene', (118, 123))	('EHCs', 'Disease', (280, 284))	('STK11', 'Gene', (235, 240))	('SMAD4', 'Gene', (224, 229))
186474	31431036	This analysis found 4 clusters characterized by different clinical features including proportion of ICC and EHC and genomic alterations: Cluster 1 comprised mostly fluke-associated tumors that also displayed hypermethylation of CpG island-promoters, and enrichment of ARID1A and BRCA1/2 mutations.	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('BRCA1/2', 'Gene', '672;675', (279, 286))	('mutations', 'Var', (287, 296))	('ARID1A', 'Gene', '8289', (268, 274))	('ARID1A', 'Gene', (268, 274))	('hypermethylation', 'Var', (208, 224))	('fluke-associated', 'Disease', (164, 180))	('men', 'Species', '9606', (260, 263))	('BRCA1/2', 'Gene', (279, 286))
186476	31431036	Clusters 1 and 2 were significantly enriched in TP53 mutations and ERBB2 amplifications.	('ERBB2', 'Gene', '2064', (67, 72))	('TP53', 'Gene', '7157', (48, 52))	('ERBB2', 'Gene', (67, 72))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('amplifications', 'Var', (73, 87))
186478	31431036	Cluster 3 displayed the highest level of copy number alterations, including enrichment of amplifications at 2p and 2q; these tumors also exhibited upregulation of immune checkpoint genes such as PD-1 and PD-L2.	('immune checkpoint genes', 'Gene', (163, 186))	('PD-L2', 'Gene', (204, 209))	('PD-1', 'Gene', (195, 199))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('PD-1', 'Gene', '5133', (195, 199))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('amplifications', 'Var', (90, 104))	('upregulation', 'PosReg', (147, 159))	('men', 'Species', '9606', (82, 85))
186479	31431036	Cluster 4 was characterized by upregulation of FGFR family and PI3K pathways signatures along with frequent BAP1 and IDH1/2 mutations.	('mutations', 'Var', (124, 133))	('BAP1', 'Gene', '8314', (108, 112))	('IDH1/2', 'Gene', '3417;3418', (117, 123))	('FGFR family', 'Pathway', (47, 58))	('BAP1', 'Gene', (108, 112))	('PI3K pathways signatures', 'Pathway', (63, 87))	('IDH1/2', 'Gene', (117, 123))	('upregulation', 'PosReg', (31, 43))
186482	31431036	Studies have determined that 10-20% of BTC patients display germline mutations on cancer-prone genes.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('BTC', 'Phenotype', 'HP:0100574', (39, 42))	('patients', 'Species', '9606', (43, 51))	('BTC', 'Disease', (39, 42))	('germline mutations', 'Var', (60, 78))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))
186484	31431036	Germline variants were confirmed by the Sanger method and found a 11% of deleterious mutations in several genes including BRCA1, BRCA2, RAD51D, MLH1, or MSH2.	('RAD51D', 'Gene', (136, 142))	('BRCA1', 'Gene', (122, 127))	('BRCA2', 'Gene', (129, 134))	('MLH1', 'Gene', '4292', (144, 148))	('MLH1', 'Gene', (144, 148))	('mutations', 'Var', (85, 94))	('BRCA2', 'Gene', '675', (129, 134))	('BRCA1', 'Gene', '672', (122, 127))	('MSH2', 'Gene', (153, 157))	('RAD51D', 'Gene', '5892', (136, 142))	('MSH2', 'Gene', '4436', (153, 157))
186489	31431036	Series of BTC patients with germline mutations in mismatch repair (MMR) genes such as MLH1 or MSH2 suggest that this phenomenon is infrequent and represent a small minority of patients with MMR-deficient tumors.	('patients', 'Species', '9606', (176, 184))	('MSH2', 'Gene', '4436', (94, 98))	('MMR-deficient tumors', 'Disease', (190, 210))	('MMR', 'Gene', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('BTC', 'Phenotype', 'HP:0100574', (10, 13))	('MMR-deficient tumors', 'Disease', 'MESH:C536928', (190, 210))	('germline mutations', 'Var', (28, 46))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('MLH1', 'Gene', '4292', (86, 90))	('MSH2', 'Gene', (94, 98))	('MLH1', 'Gene', (86, 90))	('men', 'Species', '9606', (122, 125))	('patients', 'Species', '9606', (14, 22))
186492	31431036	FGFR gene-fusions (particularly FGFR2) are considered a promising target for therapeutic inhibition.	('FGFR', 'Gene', (0, 4))	('gene-fusions', 'Var', (5, 17))	('FGFR2', 'Gene', '2263', (32, 37))	('FGFR2', 'Gene', (32, 37))
186494	31431036	As mentioned, FGFR2 fusions that involve its kinase domain are commonly seen in ICCs ranging from 8% to 14%.	('FGFR2', 'Gene', (14, 19))	('FGFR2', 'Gene', '2263', (14, 19))	('kinase domain', 'MPA', (45, 58))	('seen', 'Reg', (72, 76))	('ICCs', 'Disease', (80, 84))	('fusions', 'Var', (20, 27))	('men', 'Species', '9606', (3, 6))
186497	31431036	In a recent phase II study, infigratinib, a selective FGFR1-3 kinase inhibitor, was studied in cholangiocarcinoma patients who harbored FGFR2 fusions or other FGFR alterations.	('fusions', 'Var', (142, 149))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (95, 113))	('infigratinib', 'Chemical', 'MESH:C568950', (28, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (95, 113))	('FGFR2', 'Gene', '2263', (136, 141))	('FGFR2', 'Gene', (136, 141))	('patients', 'Species', '9606', (114, 122))	('cholangiocarcinoma', 'Disease', (95, 113))
186498	31431036	The response rate among patients with FGFR2 fusions was 19%, however no responses were seen in patients with other genetic FGFR alterations.	('FGFR2', 'Gene', '2263', (38, 43))	('patients', 'Species', '9606', (95, 103))	('fusions', 'Var', (44, 51))	('patients', 'Species', '9606', (24, 32))	('FGFR2', 'Gene', (38, 43))
186502	31431036	A phase III trial evaluating first-line infigratinib versus chemotherapy in ICC patients with FGFR2 fusions has started accrual (NCT03773302).	('fusions', 'Var', (100, 107))	('ICC', 'Disease', (76, 79))	('patients', 'Species', '9606', (80, 88))	('FGFR2', 'Gene', (94, 99))	('FGFR2', 'Gene', '2263', (94, 99))	('infigratinib', 'Chemical', 'MESH:C568950', (40, 52))
186504	31431036	The LUC2001 phase II trial (NCT02699606) evaluated 11 ICC patients with different genetic alterations in FGFR2 or FGFR3.	('ICC', 'Disease', (54, 57))	('FGFR3', 'Gene', '2261', (114, 119))	('genetic alterations', 'Var', (82, 101))	('FGFR2', 'Gene', '2263', (105, 110))	('patients', 'Species', '9606', (58, 66))	('FGFR2', 'Gene', (105, 110))	('FGFR3', 'Gene', (114, 119))
186510	31431036	Interestingly, this drug has been recently approved by American Food and Drug Administration (FDA) for metastatic urothelial carcinoma, with susceptible FGFR3 or FGFR2 genetic alterations based on the results of the BLC2001 trial.	('urothelial carcinoma', 'Disease', (114, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('FGFR2', 'Gene', '2263', (162, 167))	('FGFR2', 'Gene', (162, 167))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (114, 134))	('FGFR3', 'Gene', '2261', (153, 158))	('genetic alterations', 'Var', (168, 187))	('FGFR3', 'Gene', (153, 158))
186515	31431036	TAS-120 is highly selective, irreversible FGFR1-4 inhibitor that was also studied in a phase I trial including BTC patients harboring FGFR alterations.	('BTC', 'Phenotype', 'HP:0100574', (111, 114))	('patients', 'Species', '9606', (115, 123))	('FGFR1-4', 'Gene', (42, 49))	('alterations', 'Var', (139, 150))	('TAS-120', 'Chemical', '-', (0, 7))	('FGFR1-4', 'Gene', '2260;2263;2261;2264', (42, 49))
186516	31431036	The outcomes of the subgroup of patients with FGFR2 gene fusions (n=28) were reported showing an objective response rate of 25%.	('FGFR2', 'Gene', '2263', (46, 51))	('FGFR2', 'Gene', (46, 51))	('gene fusions', 'Var', (52, 64))	('patients', 'Species', '9606', (32, 40))
186517	31431036	This drug has also demonstrated preclinical activity against multiple FGFR2 mutations shown to confer resistance to other FGFR inhibitors such as FGFR2 V565F gatekeeper mutation.	('V565F', 'Var', (152, 157))	('mutations', 'Var', (76, 85))	('FGFR2', 'Gene', (70, 75))	('FGFR2', 'Gene', '2263', (70, 75))	('FGFR2', 'Gene', (146, 151))	('FGFR2', 'Gene', '2263', (146, 151))	('resistance', 'MPA', (102, 112))	('gatekeeper', 'Species', '111938', (158, 168))	('V565F', 'Mutation', 'p.V565F', (152, 157))
186519	31431036	In 3 of these patients FGFR2 mutations associated with resistance to FGFR inhibitors were detected in tissue or circulating tumor DNA before starting TAS-120.	('TAS-120', 'Chemical', '-', (150, 157))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', (124, 129))	('FGFR2', 'Gene', (23, 28))	('associated', 'Reg', (39, 49))	('FGFR2', 'Gene', '2263', (23, 28))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
186521	31431036	The FGFR inhibitor pemigatinib has also shown promising results in a phase II trial that included a cohort with tumors with FGFR2 translocations (mostly ICC).	('pemigatinib', 'Chemical', '-', (19, 30))	('FGFR2', 'Gene', (124, 129))	('FGFR2', 'Gene', '2263', (124, 129))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('translocations', 'Var', (130, 144))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
186522	31431036	These results have provided foundation for a phase III trial assessing the efficacy of this drug versus gemcitabine plus cisplatin chemotherapy in first-line treatment of patients with cholangiocarcinoma with FGFR2 rearrangement (NCT03656536).	('FGFR2', 'Gene', '2263', (209, 214))	('men', 'Species', '9606', (224, 227))	('cholangiocarcinoma', 'Disease', (185, 203))	('men', 'Species', '9606', (163, 166))	('cisplatin', 'Chemical', 'MESH:D002945', (121, 130))	('NCT03656536', 'Var', (230, 241))	('gemcitabine', 'Chemical', 'MESH:C056507', (104, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (185, 203))	('patients', 'Species', '9606', (171, 179))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (185, 203))	('FGFR2', 'Gene', (209, 214))
186523	31431036	Likewise, the FGFR inhibitor derazantinib had an encouraging 21% response rate in patients with advanced ICC with FGFR2 fusion in a phase I/II trial.	('fusion', 'Var', (120, 126))	('derazantinib', 'Chemical', 'MESH:C000621805', (29, 41))	('patients', 'Species', '9606', (82, 90))	('FGFR2', 'Gene', '2263', (114, 119))	('FGFR2', 'Gene', (114, 119))	('ICC', 'Disease', (105, 108))
186526	31431036	Cancer-associated mutations in IDH1/2 result in high levels of (R)-2-hydroxyglutarate, an onco-metabolite that seems to be associated with alterations in several cell processes including redox state and DNA repair mechanisms, also modulating the activity of epigenetic tumor suppressor enzymes.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('associated', 'Reg', (123, 133))	('redox', 'MPA', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('IDH1/2', 'Gene', '3417;3418', (31, 37))	('(R)-2-hydroxyglutarate', 'Chemical', '-', (63, 85))	('alterations', 'Reg', (139, 150))	('tumor', 'Disease', (269, 274))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('DNA repair', 'MPA', (203, 213))	('activity', 'MPA', (246, 254))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('modulating', 'Reg', (231, 241))	('IDH1/2', 'Gene', (31, 37))	('mutations', 'Var', (18, 27))
186527	31431036	In addition to its functional impact on cancer progression IDH1/2 mutations have been implicated in ICC prognosis.	('mutations', 'Var', (66, 75))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('IDH1/2', 'Gene', '3417;3418', (59, 65))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ICC prognosis', 'Disease', (100, 113))	('IDH1/2', 'Gene', (59, 65))	('implicated', 'Reg', (86, 96))
186528	31431036	Some studies have found an association between IDH1/2 mutations and improved clinical outcomes.	('IDH1/2', 'Gene', '3417;3418', (47, 53))	('clinical outcomes', 'CPA', (77, 94))	('mutations', 'Var', (54, 63))	('IDH1/2', 'Gene', (47, 53))	('improved', 'PosReg', (68, 76))
186535	31431036	BAY 1436032 is another oral inhibitor against mutant IDH1, whose safety, tolerability and preliminary anti-tumor activity are under evaluation in a phase I basket trial (NCT02746081) including mutant IDH1 BTC patients.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('BAY 1436032', 'Chemical', 'MESH:C000622445', (0, 11))	('IDH', 'Gene', (200, 203))	('mutant', 'Var', (193, 199))	('mutant', 'Var', (46, 52))	('patients', 'Species', '9606', (209, 217))	('IDH', 'Gene', '3417', (200, 203))	('IDH', 'Gene', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('IDH', 'Gene', '3417', (53, 56))	('BTC', 'Phenotype', 'HP:0100574', (205, 208))
186536	31431036	IDH2 mutations are found less frequently in ICC (3% to 5%) and they also have been described as an acquired resistance mutation to IDH1 inhibition in this disease.	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('ICC', 'Disease', (44, 47))	('mutations', 'Var', (5, 14))	('IDH', 'Gene', (131, 134))	('IDH', 'Gene', '3417', (131, 134))
186538	31431036	Amplification of ERBB2 (also known as HER2) occurs in 3% to 19% of BTCs and is more frequent in GBC and EHC versus ICC.	('BTC', 'Phenotype', 'HP:0100574', (67, 70))	('Amplification', 'Var', (0, 13))	('frequent', 'Reg', (84, 92))	('EHC', 'Disease', (104, 107))	('ERBB2', 'Gene', '2064', (17, 22))	('ERBB2', 'Gene', (17, 22))	('HER2', 'Gene', (38, 42))	('HER2', 'Gene', '2064', (38, 42))	('GBC', 'Disease', (96, 99))
186542	31431036	Currently, a multi-cohort phase II trial in China is set to evaluate the combination of gemcitabine and oxaliplatin with trastuzumab in ERBB2-amplified BTC (NCT02836847).	('gemcitabine', 'Chemical', 'MESH:C056507', (88, 99))	('ERBB2', 'Gene', '2064', (136, 141))	('NCT02836847', 'Var', (157, 168))	('trastuzumab', 'Chemical', 'MESH:D000068878', (121, 132))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (104, 115))	('ERBB2', 'Gene', (136, 141))	('BTC', 'Phenotype', 'HP:0100574', (152, 155))
186543	31431036	A limited number of BTC patients with ERBB2 amplification have been recruited in basket trials demonstrating the efficacy of anti-HER2 therapies.	('amplification', 'Var', (44, 57))	('ERBB2', 'Gene', (38, 43))	('patients', 'Species', '9606', (24, 32))	('HER2', 'Gene', (130, 134))	('ERBB2', 'Gene', '2064', (38, 43))	('BTC', 'Phenotype', 'HP:0100574', (20, 23))	('HER2', 'Gene', '2064', (130, 134))
186552	31431036	The most frequent BRAF mutation is located in the V600 codon.	('V600', 'Var', (50, 54))	('BRAF', 'Gene', (18, 22))	('BRAF', 'Gene', '673', (18, 22))
186553	31431036	In BTC patients BRAF mutations occur in 1% to 4% of ICC patients, while they are extremely infrequent in EHC or GBC.	('ICC', 'Disease', (52, 55))	('patients', 'Species', '9606', (56, 64))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('BTC', 'Phenotype', 'HP:0100574', (3, 6))	('patients', 'Species', '9606', (7, 15))	('mutations', 'Var', (21, 30))
186555	31431036	Subsequently, results of the ROAR Basket Trial demonstrated a 42% of response rate to the RAF inhibitor dabrafenib and MEK inhibitor trametinib in V600E BRAF-mutant BTC.	('MEK', 'Gene', (119, 122))	('MEK', 'Gene', '5609', (119, 122))	('V600E', 'Var', (147, 152))	('BRAF', 'Gene', (153, 157))	('RAF', 'Gene', '673', (154, 157))	('RAF', 'Gene', (90, 93))	('trametinib', 'Chemical', 'MESH:C560077', (133, 143))	('RAF', 'Gene', '673', (90, 93))	('BTC', 'Phenotype', 'HP:0100574', (165, 168))	('V600E', 'Mutation', 'rs113488022', (147, 152))	('RAF', 'Gene', (154, 157))	('BRAF', 'Gene', '673', (153, 157))	('dabrafenib', 'Chemical', 'MESH:C561627', (104, 114))
186556	31431036	Alterations in DNA repair genes are relatively frequent in BTC including MSH6, BAP1, ATM, MLH1, MSH2, BRCA1 and BRCA2.	('DNA repair genes', 'Gene', (15, 31))	('BRCA1', 'Gene', (102, 107))	('BAP1', 'Gene', '8314', (79, 83))	('MSH6', 'Gene', (73, 77))	('ATM', 'Gene', (85, 88))	('Alterations', 'Var', (0, 11))	('MSH2', 'Gene', (96, 100))	('MSH6', 'Gene', '2956', (73, 77))	('BAP1', 'Gene', (79, 83))	('frequent', 'Reg', (47, 55))	('BRCA2', 'Gene', (112, 117))	('MSH2', 'Gene', '4436', (96, 100))	('ATM', 'Gene', '472', (85, 88))	('BTC', 'Phenotype', 'HP:0100574', (59, 62))	('BRCA1', 'Gene', '672', (102, 107))	('BRCA2', 'Gene', '675', (112, 117))	('MLH1', 'Gene', '4292', (90, 94))	('MLH1', 'Gene', (90, 94))
186557	31431036	Indeed, studies demonstrate that up to 16% of ICC and 45% of EHC patients display mutations in these genes.	('patients', 'Species', '9606', (65, 73))	('mutations', 'Var', (82, 91))	('ICC', 'Disease', (46, 49))	('EHC', 'Disease', (61, 64))
186558	31431036	DNA-repair deficient cells (particularly BRCA1 or 2 mutants) can accumulate double-strand DNA breaks that result in genomic instability, leading to an increased sensitivity to DNA damaging therapies such as platinum compounds or poly ADP-ribose polymerase (PARP) inhibitors.	('poly ADP-ribose polymerase', 'Gene', (229, 255))	('increased', 'PosReg', (151, 160))	('BRCA1', 'Gene', '672', (41, 46))	('sensitivity', 'MPA', (161, 172))	('double-strand', 'Var', (76, 89))	('genomic instability', 'MPA', (116, 135))	('platinum', 'Chemical', 'MESH:D010984', (207, 215))	('PARP', 'Gene', (257, 261))	('mutants', 'Var', (52, 59))	('BRCA1', 'Gene', (41, 46))	('result in', 'Reg', (106, 115))	('poly ADP-ribose polymerase', 'Gene', '142', (229, 255))	('DNA damaging', 'MPA', (176, 188))	('PARP', 'Gene', '142', (257, 261))
186559	31431036	Several studies have demonstrated the efficacy of PARP inhibitors in BRCA1/2 mutant breast and ovarian cancer.	('BRCA1/2', 'Gene', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (84, 109))	('PARP', 'Gene', '142', (50, 54))	('BRCA1/2', 'Gene', '672;675', (69, 76))	('mutant', 'Var', (77, 83))	('PARP', 'Gene', (50, 54))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))
186562	31431036	This specific patient had a known pathogenic germline BRCA2 mutation, however, the predictive features of germline versus somatic mutations remains to be elucidated.	('mutation', 'Var', (60, 68))	('BRCA2', 'Gene', (54, 59))	('patient', 'Species', '9606', (14, 21))	('pathogenic', 'Reg', (34, 44))	('BRCA2', 'Gene', '675', (54, 59))
186563	31431036	Anecdotal responses to PARP inhibitors have also been reported in metastatic BRCA1 mutant GBC.	('BRCA1', 'Gene', (77, 82))	('PARP', 'Gene', (23, 27))	('mutant', 'Var', (83, 89))	('PARP', 'Gene', '142', (23, 27))	('BRCA1', 'Gene', '672', (77, 82))
186564	31431036	Interestingly, a recent study demonstrated that the accumulation of 2-Hydroxyglutarate associated with IDH mutations can suppress homologous recombination and thereby induces sensitivity to PARP inhibitors.	('homologous recombination', 'MPA', (130, 154))	('suppress', 'NegReg', (121, 129))	('induces', 'Reg', (167, 174))	('mutations', 'Var', (107, 116))	('IDH', 'Gene', (103, 106))	('PARP', 'Gene', '142', (190, 194))	('2-Hydroxyglutarate', 'Chemical', 'MESH:C019417', (68, 86))	('2-Hydroxyglutarate', 'Protein', (68, 86))	('accumulation', 'PosReg', (52, 64))	('IDH', 'Gene', '3417', (103, 106))	('PARP', 'Gene', (190, 194))
186570	31431036	This phenomenon is known as MSI and can be attributed to germline mutations in one or several MMR genes that render a nonfunctional protein or to somatic hypermethylation of the MLH1 promoter that leads to epigenetic silencing.	('nonfunctional protein', 'MPA', (118, 139))	('men', 'Species', '9606', (10, 13))	('render', 'Reg', (109, 115))	('epigenetic silencing', 'MPA', (206, 226))	('germline mutations', 'Var', (57, 75))	('MLH1', 'Gene', '4292', (178, 182))	('leads to', 'Reg', (197, 205))	('MLH1', 'Gene', (178, 182))	('MMR genes', 'Gene', (94, 103))	('hypermethylation', 'Var', (154, 170))
186578	31431036	In BTCs, CDKN2A is frequently silenced by hypermethylation, by homozygous deletion, or by inactivating mutations.	('hypermethylation', 'Var', (42, 58))	('CDKN2A', 'Gene', '1029', (9, 15))	('inactivating mutations', 'Var', (90, 112))	('BTC', 'Phenotype', 'HP:0100574', (3, 6))	('silenced', 'NegReg', (30, 38))	('CDKN2A', 'Gene', (9, 15))
186579	31431036	Studies demonstrate that CDKN2A alterations are more frequently seen in GBC versus ICC or EHC and have been associated with decreased survival.	('decreased', 'NegReg', (124, 133))	('alterations', 'Var', (32, 43))	('GBC versus ICC', 'Disease', (72, 86))	('GBC versus ICC', 'Disease', 'MESH:C566123', (72, 86))	('CDKN2A', 'Gene', (25, 31))	('EHC', 'Disease', (90, 93))	('seen', 'Reg', (64, 68))	('survival', 'MPA', (134, 142))	('CDKN2A', 'Gene', '1029', (25, 31))
186580	31431036	Although CDKN2A alterations are not considered actionable per se, homozygous CDKN2A loss is usually concomitant with methylthioadenosine phosphorylase (MTAP) gene deletions, which might be targetable.	('MTAP', 'Gene', (152, 156))	('CDKN2A', 'Gene', '1029', (9, 15))	('CDKN2A', 'Gene', (77, 83))	('loss', 'NegReg', (84, 88))	('MTAP', 'Gene', '4507', (152, 156))	('methylthioadenosine phosphorylase', 'Gene', (117, 150))	('CDKN2A', 'Gene', '1029', (77, 83))	('methylthioadenosine phosphorylase', 'Gene', '4507', (117, 150))	('deletions', 'Var', (163, 172))	('CDKN2A', 'Gene', (9, 15))
186585	31431036	Studies have identified NTRK fusions at low frequencies across various tumor types, including BTCs.	('fusions', 'Var', (29, 36))	('BTCs', 'Disease', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('TRK', 'Gene', (25, 28))	('TRK', 'Gene', '4914', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('BTC', 'Phenotype', 'HP:0100574', (94, 97))	('tumor', 'Disease', (71, 76))
186593	31431036	Interestingly, some of the abovementioned targetable genomic alterations such as FGFR2 fusions, IDH1 and BRAF mutations, and ERBB2 amplifications have already been identified in circulating-tumor DNA (ctDNA) from ~20% of BTC patients.	('fusions', 'Var', (87, 94))	('BRAF', 'Gene', '673', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('mutations', 'Var', (110, 119))	('patients', 'Species', '9606', (225, 233))	('IDH', 'Gene', (96, 99))	('IDH', 'Gene', '3417', (96, 99))	('BRAF', 'Gene', (105, 109))	('BTC', 'Phenotype', 'HP:0100574', (221, 224))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('men', 'Species', '9606', (32, 35))	('amplifications', 'Var', (131, 145))	('FGFR2', 'Gene', '2263', (81, 86))	('tumor', 'Disease', (190, 195))	('FGFR2', 'Gene', (81, 86))	('ERBB2', 'Gene', (125, 130))	('ERBB2', 'Gene', '2064', (125, 130))	('identified', 'Reg', (164, 174))
186598	33007962	Dysregulated miRNAs have been shown to participate in almost all CCA hallmarks, including cell proliferation, migration and invasion, apoptosis, and the epithelial-to-mesenchymal transition.	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('migration', 'CPA', (110, 119))	('epithelial-to-mesenchymal transition', 'CPA', (153, 189))	('apoptosis', 'CPA', (134, 143))	('cell proliferation', 'CPA', (90, 108))	('participate', 'Reg', (39, 50))	('CCA', 'Phenotype', 'HP:0030153', (65, 68))	('Dysregulated', 'Var', (0, 12))	('CCA', 'Disease', (65, 68))
186611	33007962	While preliminary studies have not shown promising effects in PD-L1-positive CCA, a subsequent phase II study demonstrated an overall response rate of 40.9%, with an average survival of 24.3 months in previously treated patients with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) advanced CCA.	('microsatellite', 'Var', (234, 248))	('PD-L1', 'Gene', '29126', (62, 67))	('CCA', 'Phenotype', 'HP:0030153', (316, 319))	('patients', 'Species', '9606', (220, 228))	('PD-L1', 'Gene', (62, 67))	('CCA', 'Disease', (316, 319))	('CCA', 'Phenotype', 'HP:0030153', (77, 80))
186612	33007962	Tumors with MSI-H/dMMR carry a high mutational burden and the potential for increased neoantigen load, eliciting a response to anti-PD-1 antibody immunotherapy.	('response', 'MPA', (115, 123))	('eliciting', 'Reg', (103, 112))	('increased', 'PosReg', (76, 85))	('mutational burden', 'MPA', (36, 53))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('neoantigen load', 'MPA', (86, 101))	('MSI-H/dMMR', 'Var', (12, 22))
186617	33007962	Pemigatinib, a selective inhibitor of FGFR, achieved an objective response of 36% and a median PFS of 6.9 months in previously treated patients with intrahepatic CCA who have FGFR2 fusions or rearrangements.	('Pemigatinib', 'Chemical', '-', (0, 11))	('patients', 'Species', '9606', (135, 143))	('rearrangements', 'Var', (192, 206))	('FGFR', 'Gene', (38, 42))	('CCA', 'Phenotype', 'HP:0030153', (162, 165))	('FGFR2', 'Gene', (175, 180))	('fusions', 'Var', (181, 188))	('FGFR2', 'Gene', '2263', (175, 180))
186624	33007962	Increasing evidence suggests that aberrant expression of several miRNAs is involved in modulating the response to chemotherapy or other targeted treatments (Table 1).	('involved', 'Reg', (75, 83))	('aberrant expression', 'Var', (34, 53))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('response to chemotherapy', 'CPA', (102, 126))	('modulating', 'Reg', (87, 97))
186641	33007962	In contrast, inhibition of miR-141 reduced the growth of CCA cell lines.	('miR-141', 'Gene', '406933', (27, 34))	('CCA', 'Phenotype', 'HP:0030153', (57, 60))	('reduced', 'NegReg', (35, 42))	('inhibition', 'Var', (13, 23))	('CCA', 'Disease', (57, 60))	('growth', 'CPA', (47, 53))	('miR-141', 'Gene', (27, 34))
186644	33007962	Moreover, the silencing of miR-141 expression increased CLOCK protein expression in CCA cells.	('silencing', 'Var', (14, 23))	('miR-141', 'Gene', '406933', (27, 34))	('CLOCK', 'Gene', '9575', (56, 61))	('increased', 'PosReg', (46, 55))	('CLOCK', 'Gene', (56, 61))	('expression', 'MPA', (35, 45))	('CCA', 'Phenotype', 'HP:0030153', (84, 87))	('miR-141', 'Gene', (27, 34))
186649	33007962	Inhibition of miR-200b increased the expression of protein tyrosine phosphatase, nonreceptor type 12 (PTPN12), leading to the decreased phosphorylation of Src at tyrosine 182, which is essential to mediate downstream signal transduction for cell proliferation and differentiation.	('tyrosine', 'Chemical', 'MESH:D014443', (59, 67))	('decreased', 'NegReg', (126, 135))	('phosphorylation', 'MPA', (136, 151))	('miR-200b', 'Gene', (14, 22))	('tyrosine', 'Chemical', 'MESH:D014443', (162, 170))	('PTPN12', 'Gene', '5782', (102, 108))	('miR-200b', 'Gene', '406984', (14, 22))	('Src', 'Gene', (155, 158))	('Src', 'Gene', '6714', (155, 158))	('increased', 'PosReg', (23, 32))	('Inhibition', 'Var', (0, 10))	('protein tyrosine phosphatase, nonreceptor type 12', 'Gene', '5782', (51, 100))	('expression', 'MPA', (37, 47))	('PTPN12', 'Gene', (102, 108))
186657	33007962	Aberrant expression of these miRNAs is frequent in various cancers, acting as tumor suppressors or oncogenes in a cellular context-dependent manner.	('Aberrant expression', 'Var', (0, 19))	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('tumor', 'Disease', (78, 83))	('cancers', 'Disease', (59, 66))
186660	33007962	Ectopic expression of miR-29b sensitized KMCH CCA cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through directly suppressing Mcl-1.	('Mcl-1', 'MPA', (152, 157))	('TRAIL', 'Gene', (98, 103))	('suppressing', 'NegReg', (140, 151))	('miR-29b', 'Gene', (22, 29))	('Ectopic expression', 'Var', (0, 18))	('miR-29b', 'Gene', '407024', (22, 29))	('CCA', 'Phenotype', 'HP:0030153', (46, 49))	('TRAIL', 'Gene', '8743', (98, 103))	('sensitized', 'Reg', (30, 40))
186661	33007962	On the other hand, the silencing of miR-29b in normal cholangiocytes increased Mcl-1 protein expression, resulting in reduced TRAIL-mediated apoptosis.	('increased', 'PosReg', (69, 78))	('miR-29b', 'Gene', (36, 43))	('TRAIL', 'Gene', (126, 131))	('reduced', 'NegReg', (118, 125))	('silencing', 'Var', (23, 32))	('miR-29b', 'Gene', '407024', (36, 43))	('increased Mcl', 'Phenotype', 'HP:0005518', (69, 82))	('Mcl-1 protein expression', 'MPA', (79, 103))	('TRAIL', 'Gene', '8743', (126, 131))
186667	33007962	Silencing of PI3KR1 or MMP-2 expression further decreased the viability of HuH28 cells upon gemcitabine treatment.	('MMP-2', 'Gene', '4313', (23, 28))	('viability', 'CPA', (62, 71))	('decreased', 'NegReg', (48, 57))	('PI3KR1', 'Gene', (13, 19))	('MMP-2', 'Gene', (23, 28))	('Silencing', 'Var', (0, 9))	('gemcitabine', 'Chemical', 'MESH:C056507', (92, 103))	('HuH28', 'CellLine', 'CVCL:2955', (75, 80))
186679	33007962	On the other hand, inhibition of miR-211 reduced the migration and invasion of malignant cholangiocytes by modulating the PTEN-dependent beta-catenin/cJun signaling pathway.	('cJun', 'Gene', '3725', (150, 154))	('reduced', 'NegReg', (41, 48))	('beta-catenin', 'Gene', '1499', (137, 149))	('inhibition', 'Var', (19, 29))	('modulating', 'Reg', (107, 117))	('cJun', 'Gene', (150, 154))	('invasion of malignant cholangiocytes', 'CPA', (67, 103))	('miR-211', 'Gene', '406993', (33, 40))	('miR-211', 'Gene', (33, 40))	('beta-catenin', 'Gene', (137, 149))	('PTEN', 'Gene', (122, 126))	('PTEN', 'Gene', '5728', (122, 126))
186694	33007962	Moreover, miR-130a-3p was found to be involved in regulating the cisplatin response in esophageal squamous cell carcinoma and gastric cancer, and gemcitabine resistance in hepatocellular carcinoma.	('cisplatin response', 'MPA', (65, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('gastric cancer', 'Disease', (126, 140))	('gemcitabine', 'Chemical', 'MESH:C056507', (146, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (172, 196))	('gastric cancer', 'Disease', 'MESH:D013274', (126, 140))	('esophageal squamous cell carcinoma', 'Disease', (87, 121))	('miR-130a-3p', 'Chemical', '-', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (172, 196))	('gemcitabine', 'MPA', (146, 157))	('involved', 'Reg', (38, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (87, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('hepatocellular carcinoma', 'Disease', (172, 196))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('miR-130a-3p', 'Var', (10, 21))
186695	33007962	reported that tumors with higher expression of miR-130a-3p were associated with poorer survival in patients with CCA.	('survival', 'MPA', (87, 95))	('higher', 'PosReg', (26, 32))	('miR-130a-3p', 'Chemical', '-', (47, 58))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('CCA', 'Disease', (113, 116))	('poorer', 'NegReg', (80, 86))	('tumors', 'Disease', (14, 20))	('patients', 'Species', '9606', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('miR-130a-3p', 'Var', (47, 58))	('expression', 'MPA', (33, 43))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('CCA', 'Phenotype', 'HP:0030153', (113, 116))
186697	33007962	Ectopic expression of miR-130a-3p in parental CCA cells increased gemcitabine resistance.	('gemcitabine', 'Chemical', 'MESH:C056507', (66, 77))	('increased', 'PosReg', (56, 65))	('gemcitabine resistance', 'MPA', (66, 88))	('miR-130a-3p', 'Var', (22, 33))	('CCA', 'Phenotype', 'HP:0030153', (46, 49))	('miR-130a-3p', 'Chemical', '-', (22, 33))	('Ectopic expression', 'MPA', (0, 18))
186698	33007962	Peroxisome proliferator-activated receptor-gamma (PPARgamma) is the direct target of miR-130a-3p.	('miR-130a-3p', 'Chemical', '-', (85, 96))	('Peroxisome proliferator-activated receptor-gamma', 'Gene', '5468', (0, 48))	('Peroxisome proliferator-activated receptor-gamma', 'Gene', (0, 48))	('PPARgamma', 'Gene', '5468', (50, 59))	('miR-130a-3p', 'Var', (85, 96))	('PPARgamma', 'Gene', (50, 59))
186701	33007962	Aberrant expression of miR-1249 has previously been reported in several cancer types.	('miR-1249', 'Gene', '100302149', (23, 31))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('reported', 'Reg', (52, 60))	('expression', 'MPA', (9, 19))	('miR-1249', 'Gene', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
186704	33007962	Overexpressed miR-1249-3p enhanced tumor growth and invasion of hepatocellular carcinoma.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('enhanced', 'PosReg', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('miR-1249-3p', 'Chemical', '-', (14, 25))	('tumor', 'Disease', (35, 40))	('miR-1249-3p', 'Var', (14, 25))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (64, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('invasion', 'CPA', (52, 60))	('hepatocellular carcinoma', 'Disease', (64, 88))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (64, 88))
186707	33007962	Inhibition of miR-1249 enhanced the sensitivity of doublet chemotherapy, including cisplatin and gemcitabine.	('enhanced', 'PosReg', (23, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('miR-1249', 'Gene', (14, 22))	('Inhibition', 'Var', (0, 10))	('gemcitabine', 'Chemical', 'MESH:C056507', (97, 108))	('cisplatin', 'MPA', (83, 92))	('miR-1249', 'Gene', '100302149', (14, 22))	('sensitivity', 'MPA', (36, 47))
186718	33007962	Furthermore, miR-210 decreased gemcitabine sensitivity by targeting HIF-3alpha, a negative regulator of HIF-1alpha.	('HIF-3alpha', 'Gene', (68, 78))	('miR-210', 'Var', (13, 20))	('HIF-1alpha', 'Gene', (104, 114))	('decreased', 'NegReg', (21, 30))	('gemcitabine', 'Chemical', 'MESH:C056507', (31, 42))	('targeting', 'Reg', (58, 67))	('HIF-3alpha', 'Gene', '64344', (68, 78))	('HIF-1alpha', 'Gene', '3091', (104, 114))	('gemcitabine sensitivity', 'MPA', (31, 54))
186735	33007962	Upregulation of miR-200b/c inhibited migration, invasion, and distant metastasis of CCA cells, while silencing miR-200b/c promoted the metastatic process through modulating Zeb1/2 and the Rho-associated protein kinase 2 (ROCK2) pathway.	('miR-200b', 'Gene', (111, 119))	('Zeb1/2', 'Gene', '6935;9839', (173, 179))	('silencing', 'Var', (101, 110))	('miR-200b', 'Gene', (16, 24))	('migration', 'CPA', (37, 46))	('inhibited', 'NegReg', (27, 36))	('distant metastasis', 'CPA', (62, 80))	('ROCK2', 'Gene', '9475', (221, 226))	('Rho-associated protein kinase 2', 'Gene', (188, 219))	('Rho-associated protein kinase 2', 'Gene', '9475', (188, 219))	('miR-200b', 'Gene', '406984', (111, 119))	('invasion', 'CPA', (48, 56))	('CCA', 'Phenotype', 'HP:0030153', (84, 87))	('miR-200b', 'Gene', '406984', (16, 24))	('Upregulation', 'PosReg', (0, 12))	('metastatic process', 'CPA', (135, 153))	('modulating', 'Reg', (162, 172))	('promoted', 'PosReg', (122, 130))	('ROCK2', 'Gene', (221, 226))	('Zeb1/2', 'Gene', (173, 179))
186753	33007962	Taken together, miR-320 could increase sensitivity to 5-FU by targeting Mcl-1 in CCA.	('miR-320', 'Var', (16, 23))	('CCA', 'Disease', (81, 84))	('sensitivity to 5-FU', 'MPA', (39, 58))	('miR-320', 'Chemical', '-', (16, 23))	('targeting', 'Reg', (62, 71))	('Mcl-1', 'Gene', (72, 77))	('increase', 'PosReg', (30, 38))	('CCA', 'Phenotype', 'HP:0030153', (81, 84))	('5-FU', 'Chemical', 'MESH:D005472', (54, 58))
186754	33007962	A number of emerging targeted drugs have been investigated to treat CCA, such as FGFR2 small molecule kinase inhibitors, mutant IDH inhibitors, Mcl-1 selective inhibitors, and MEK inhibitors.	('CCA', 'Phenotype', 'HP:0030153', (68, 71))	('mutant', 'Var', (121, 127))	('IDH', 'Gene', (128, 131))	('IDH', 'Gene', '3417', (128, 131))	('FGFR2', 'Gene', (81, 86))	('CCA', 'Disease', (68, 71))	('MEK', 'Gene', (176, 179))	('MEK', 'Gene', '5609', (176, 179))	('FGFR2', 'Gene', '2263', (81, 86))
186758	33007962	On the other hand, heat shock protein (Hsp) 90 has been shown to serve as a chaperone of FGFR, providing a biochemical basis for targeting CCA with FGFR aberrations.	('aberrations', 'Var', (153, 164))	('CCA', 'Disease', (139, 142))	('heat shock protein (Hsp) 90', 'Gene', (19, 46))	('CCA', 'Phenotype', 'HP:0030153', (139, 142))	('shock', 'Phenotype', 'HP:0031273', (24, 29))	('heat shock protein (Hsp) 90', 'Gene', '3320', (19, 46))
186763	33007962	SRY-related HMG-box 4 (SOX4) was identified as a target of miR-138.	('SRY-related HMG-box 4', 'Gene', (0, 21))	('miR-138', 'Var', (59, 66))	('SOX4', 'Gene', (23, 27))	('SOX4', 'Gene', '6659', (23, 27))	('miR-138', 'Chemical', '-', (59, 66))	('SRY-related HMG-box 4', 'Gene', '6659', (0, 21))
186772	33007962	Additionally, they found that the hypermethylated promoter region and aberrant splicing of hOCT1 lead to decreased hOCT1 expression and sorafenib response.	('hOCT1', 'Gene', (91, 96))	('hOCT1', 'Gene', '6580', (91, 96))	('expression', 'MPA', (121, 131))	('hOCT1', 'Gene', '6580', (115, 120))	('hypermethylated', 'Var', (34, 49))	('hOCT1', 'Gene', (115, 120))	('aberrant splicing', 'Var', (70, 87))	('sorafenib', 'Chemical', 'MESH:D000077157', (136, 145))	('sorafenib response', 'MPA', (136, 154))	('decreased', 'NegReg', (105, 114))
186773	33007962	Ectopic expression of hOCT1 increased sorafenib uptake in malignant cholangiocytes, enhancing the cytotoxic effect of sorafenib.	('increased', 'PosReg', (28, 37))	('cytotoxic effect', 'CPA', (98, 114))	('Ectopic expression', 'Var', (0, 18))	('sorafenib', 'Chemical', 'MESH:D000077157', (118, 127))	('hOCT1', 'Gene', '6580', (22, 27))	('enhancing', 'PosReg', (84, 93))	('sorafenib', 'Chemical', 'MESH:D000077157', (38, 47))	('hOCT1', 'Gene', (22, 27))
186775	33007962	identified that Hsp 90 inhibitors are effective in CCA cell lines from a high-throughput screening.	('CCA', 'Disease', (51, 54))	('inhibitors', 'Var', (23, 33))	('CCA', 'Phenotype', 'HP:0030153', (51, 54))	('Hsp', 'Gene', (16, 19))	('Hsp', 'Gene', '7190', (16, 19))
186789	33007962	Antagonism of miR-25 increased death receptor 4 (DR4) protein expression, sensitizing malignant cholangiocytes to apoptosis.	('increased', 'PosReg', (21, 30))	('Antagonism', 'Var', (0, 10))	('expression', 'MPA', (62, 72))	('sensitizing', 'Reg', (74, 85))	('death receptor 4', 'Gene', '8797', (31, 47))	('death receptor 4', 'Gene', (31, 47))	('DR4', 'Gene', '8797', (49, 52))	('miR-25', 'Gene', '407014', (14, 20))	('miR-25', 'Gene', (14, 20))	('apoptosis', 'CPA', (114, 123))	('DR4', 'Gene', (49, 52))
186815	33007962	Inhibition of CXCR4 signaling decreases CCA cells migration and invasion.	('decreases', 'NegReg', (30, 39))	('invasion', 'CPA', (64, 72))	('CCA', 'Disease', (40, 43))	('CXCR4', 'Gene', '7852', (14, 19))	('Inhibition', 'Var', (0, 10))	('CCA', 'Phenotype', 'HP:0030153', (40, 43))	('CXCR4', 'Gene', (14, 19))
186832	32722302	Dysregulated signaling pathways and various gene mutations are frequent in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which represent the two most common types of liver tumors.	('liver tumors', 'Disease', 'MESH:D008113', (195, 207))	('mutations', 'Var', (49, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('HCC', 'Phenotype', 'HP:0001402', (101, 104))	('liver tumors', 'Disease', (195, 207))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (110, 141))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (123, 141))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (75, 99))	('liver tumors', 'Phenotype', 'HP:0002896', (195, 207))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('intrahepatic cholangiocarcinoma', 'Disease', (110, 141))	('frequent', 'Reg', (63, 71))	('hepatocellular carcinoma', 'Disease', (75, 99))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (75, 99))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('Dysregulated signaling pathways', 'Pathway', (0, 31))	('liver tumor', 'Phenotype', 'HP:0002896', (195, 206))
186834	32722302	Continuous cell proliferation, e.g., by oncogenic mutations, can cause extensive telomere shortening in the absence of sufficient telomerase activity, leading to dysfunctional telomeres and genome instability by breakage-fusion-bridge cycles, which induce senescence or apoptosis as a tumor suppressor mechanism.	('tumor', 'Disease', 'MESH:D009369', (285, 290))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('mutations', 'Var', (50, 59))	('telomere shortening', 'Phenotype', 'HP:0031413', (81, 100))	('tumor', 'Disease', (285, 290))	('genome instability', 'MPA', (190, 208))	('telomere', 'MPA', (81, 89))	('dysfunctional telomeres', 'Disease', (162, 185))	('shortening', 'NegReg', (90, 100))	('leading to', 'Reg', (151, 161))	('dysfunctional telomeres', 'Disease', 'MESH:C536801', (162, 185))
186851	32722302	The molecular heterogeneity in terms of various gene mutations in liver cancer requires the identification of molecular targets for designing individualized therapies.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('liver cancer', 'Phenotype', 'HP:0002896', (66, 78))	('liver cancer', 'Disease', 'MESH:D006528', (66, 78))	('mutations', 'Var', (53, 62))	('liver cancer', 'Disease', (66, 78))
186856	32722302	Telomere shortening and reactivation of telomerase, two common hallmarks of carcinogenesis, are described in a broad range of human cancers, including liver cancer.	('Telomere shortening', 'Phenotype', 'HP:0031413', (0, 19))	('cancers', 'Disease', (132, 139))	('telomerase', 'Protein', (40, 50))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('hallmarks of carcinogenesis', 'Disease', 'MESH:D063646', (63, 90))	('described', 'Reg', (96, 105))	('human', 'Species', '9606', (126, 131))	('liver cancer', 'Disease', 'MESH:D006528', (151, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('liver cancer', 'Phenotype', 'HP:0002896', (151, 163))	('hallmarks of carcinogenesis', 'Disease', (63, 90))	('Telomere shortening', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('liver cancer', 'Disease', (151, 163))	('reactivation', 'MPA', (24, 36))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
186857	32722302	Telomere shortening and reactivation of telomerase, through TERT promoter mutations, for example, represent genetic risk factors for the development of liver cirrhosis and liver cancer.	('Telomere shortening', 'Phenotype', 'HP:0031413', (0, 19))	('telomerase', 'Protein', (40, 50))	('liver cirrhosis', 'Disease', (152, 167))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('TERT', 'Gene', '7015', (60, 64))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (152, 167))	('mutations', 'Var', (74, 83))	('cirrhosis', 'Phenotype', 'HP:0001394', (158, 167))	('liver cancer', 'Disease', 'MESH:D006528', (172, 184))	('liver cancer', 'Phenotype', 'HP:0002896', (172, 184))	('liver cancer', 'Disease', (172, 184))	('liver cirrhosis', 'Disease', 'MESH:D008103', (152, 167))	('reactivation', 'MPA', (24, 36))	('Telomere', 'Protein', (0, 8))	('TERT', 'Gene', (60, 64))
186858	32722302	Therefore, disruptions in telomere biology could be a useful target for the treatment of liver cancer.	('liver cancer', 'Phenotype', 'HP:0002896', (89, 101))	('liver cancer', 'Disease', 'MESH:D006528', (89, 101))	('liver cancer', 'Disease', (89, 101))	('disruptions', 'Var', (11, 22))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
186863	32722302	A disruption of the p53-signaling pathway overcomes the senescence checkpoint and leads to further cell division of hepatocytes with already-shortened telomeres until the telomeres become critically short.	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('shortened telomeres', 'Phenotype', 'HP:0031413', (141, 160))	('disruption', 'Var', (2, 12))	('cell division', 'CPA', (99, 112))	('overcomes', 'NegReg', (42, 51))	('senescence checkpoint', 'MPA', (56, 77))	('leads to', 'Reg', (82, 90))
186866	32722302	So far, two distinct mechanisms were made responsible for telomere shortening upon increased proliferative signals, either due to oncogene activation (e.g., Ras mutations or c-Myc amplification) or expression of viral oncogenic proteins: (i) in most of the cases, absence of sufficient telomerase reactivation and (ii) in some cases, germline mutations within the coding region of telomerase, which impair the enzymatic activity of telomerase in proliferating hepatocytes (see Section 5).	('c-Myc', 'Gene', (174, 179))	('germline mutations within', 'Var', (334, 359))	('telomere shortening', 'Phenotype', 'HP:0031413', (58, 77))	('telomerase', 'Gene', (381, 391))	('enzymatic activity', 'MPA', (410, 428))	('absence', 'NegReg', (264, 271))	('impair', 'NegReg', (399, 405))	('c-Myc', 'Gene', '4609', (174, 179))
186873	32722302	Consequently, telomere shortening is an important risk factor for tumor initiation in liver carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor initiation in liver carcinogenesis', 'Disease', 'MESH:D063646', (66, 106))	('telomere shortening', 'Var', (14, 33))	('tumor initiation in liver carcinogenesis', 'Disease', (66, 106))	('telomere shortening', 'Phenotype', 'HP:0031413', (14, 33))
186890	32722302	In an experimental model of liver regeneration involving the removal of two-thirds of the liver by partial hepatectomy of G3 Terc-/- and Terc+/+ mice, telomere shortening was observed to be a heterogeneous event at the cellular level, which led to the inhibition of a subpopulation of cells with critically short telomeres to enter the cell cycle and prevent those cells from participating in liver regeneration.	('enter', 'PosReg', (326, 331))	('inhibition', 'NegReg', (252, 262))	('short telomeres', 'Phenotype', 'HP:0031413', (307, 322))	('liver regeneration', 'CPA', (393, 411))	('prevent', 'NegReg', (351, 358))	('mice', 'Species', '10090', (145, 149))	('telomere shortening', 'Phenotype', 'HP:0031413', (151, 170))	('telomere', 'Var', (151, 159))
186901	32722302	Telomerase knockout mice (Terc-/-) with chronic telomere dysfunction as well as a model of transient telomere dysfunction by inducing a dominant-negative variant of the TRF2 (telomeric repeat-binding factor 2) protein exhibited higher levels of chromosomal aberrations.	('telomere dysfunction', 'Disease', (101, 121))	('higher', 'PosReg', (228, 234))	('TRF2', 'Gene', '21750', (169, 173))	('mice', 'Species', '10090', (20, 24))	('chromosomal aberrations', 'MPA', (245, 268))	('inducing', 'Reg', (125, 133))	('telomeric repeat-binding factor 2', 'Gene', (175, 208))	('variant', 'Var', (154, 161))	('telomeric repeat-binding factor 2', 'Gene', '21750', (175, 208))	('TRF2', 'Gene', (169, 173))	('telomere dysfunction', 'Disease', 'MESH:C536801', (48, 68))	('telomere dysfunction', 'Disease', (48, 68))	('telomere dysfunction', 'Disease', 'MESH:C536801', (101, 121))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (245, 268))
186916	32722302	Germline loss-of-function mutations in the telomerase components were found in a variety of human diseases, including dyskeratosis congenita, aplastic anemia, familial idiopathic fibrosis and acute myeloid leukemia.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (198, 214))	('anemia', 'Phenotype', 'HP:0001903', (151, 157))	('leukemia', 'Phenotype', 'HP:0001909', (206, 214))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (192, 214))	('aplastic anemia', 'Phenotype', 'HP:0001915', (142, 157))	('familial idiopathic fibrosis', 'Disease', 'MESH:D054990', (159, 187))	('aplastic anemia', 'Disease', 'MESH:D000741', (142, 157))	('mutations', 'Var', (26, 35))	('acute myeloid leukemia', 'Disease', (192, 214))	('dyskeratosis congenita', 'Disease', (118, 140))	('familial idiopathic fibrosis', 'Disease', (159, 187))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (118, 140))	('loss-of-function', 'NegReg', (9, 25))	('human', 'Species', '9606', (92, 97))	('aplastic anemia', 'Disease', (142, 157))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (192, 214))
186917	32722302	These mutations provoked an impaired tissue regeneration due to telomere dysfunction and stem/progenitor cell exhaustion.	('telomere dysfunction', 'Disease', (64, 84))	('telomere dysfunction', 'Disease', 'MESH:C536801', (64, 84))	('tissue regeneration', 'CPA', (37, 56))	('stem/progenitor cell exhaustion', 'CPA', (89, 120))	('mutations', 'Var', (6, 15))	('impaired', 'NegReg', (28, 36))
186920	32722302	An increased number of telomerase mutations were found in the group with liver cirrhosis.	('telomerase', 'Protein', (23, 33))	('liver cirrhosis', 'Disease', 'MESH:D008103', (73, 88))	('cirrhosis', 'Phenotype', 'HP:0001394', (79, 88))	('liver cirrhosis', 'Disease', (73, 88))	('mutations', 'Var', (34, 43))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (73, 88))
186921	32722302	reported nine patients with a mutation in the TERT gene and one patient with a mutation in the TERC gene among 134 patients with liver cirrhosis.	('TERT', 'Gene', '7015', (46, 50))	('patients', 'Species', '9606', (115, 123))	('patient', 'Species', '9606', (64, 71))	('liver cirrhosis', 'Disease', (129, 144))	('mutation', 'Var', (30, 38))	('liver cirrhosis', 'Disease', 'MESH:D008103', (129, 144))	('patient', 'Species', '9606', (14, 21))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (129, 144))	('TERT', 'Gene', (46, 50))	('patient', 'Species', '9606', (115, 122))	('patients', 'Species', '9606', (14, 22))	('cirrhosis', 'Phenotype', 'HP:0001394', (135, 144))
186922	32722302	reported mutations in the TERT and TERC genes in 16 out of 521 patients.	('mutations', 'Var', (9, 18))	('TERT', 'Gene', (26, 30))	('TERT', 'Gene', '7015', (26, 30))	('patients', 'Species', '9606', (63, 71))
186924	32722302	A similar result was shown by the Hartmann study, which stated an increased incidence of telomerase mutations detected in cirrhosis patients (allele frequency 0.017) compared to non-cirrhotic controls (0.003, p = 0.0007).	('mutations', 'Var', (100, 109))	('cirrhosis', 'Phenotype', 'HP:0001394', (122, 131))	('telomerase', 'Gene', (89, 99))	('cirrhosis', 'Disease', 'MESH:D005355', (122, 131))	('cirrhosis', 'Disease', (122, 131))	('patients', 'Species', '9606', (132, 140))
186925	32722302	Consequently, patients with these mutations showed shorter telomeres in peripheral white blood cells.	('patients', 'Species', '9606', (14, 22))	('shorter', 'NegReg', (51, 58))	('mutations', 'Var', (34, 43))	('telomeres', 'MPA', (59, 68))
186928	32722302	Functional evaluation of these mutations exposed reduced protein synthesis from some of the mutations compared to the TERT wild-type protein.	('TERT', 'Gene', '7015', (118, 122))	('mutations', 'Var', (31, 40))	('reduced', 'NegReg', (49, 56))	('mutations', 'Var', (92, 101))	('protein synthesis', 'MPA', (57, 74))	('TERT', 'Gene', (118, 122))
186929	32722302	It is speculated that these TERT mutations could also impair the DNA-binding function of TERT.	('impair', 'NegReg', (54, 60))	('mutations', 'Var', (33, 42))	('TERT', 'Gene', (89, 93))	('TERT', 'Gene', (28, 32))	('TERT', 'Gene', '7015', (89, 93))	('TERT', 'Gene', '7015', (28, 32))	('DNA-binding', 'Interaction', (65, 76))
186930	32722302	In summary, these results indicate that TERT mutations result in impaired telomerase activity, accelerated telomere shortening and impaired regeneration in chronic liver disease.	('TERT', 'Gene', '7015', (40, 44))	('telomere shortening', 'Phenotype', 'HP:0031413', (107, 126))	('mutations', 'Var', (45, 54))	('impaired regeneration in chronic liver disease', 'Disease', (131, 177))	('accelerated', 'PosReg', (95, 106))	('impaired regeneration in chronic liver disease', 'Disease', 'MESH:D058625', (131, 177))	('telomerase', 'Enzyme', (74, 84))	('impaired', 'NegReg', (65, 73))	('liver disease', 'Phenotype', 'HP:0001392', (164, 177))	('activity', 'MPA', (85, 93))	('telomere shortening', 'CPA', (107, 126))	('TERT', 'Gene', (40, 44))
186933	32722302	Telomerase reactivation is associated with the alteration of transcriptional regulators of the TERT promoter in cancer, TERT promoter mutations or rearrangements and DNA copy number amplifications.	('rearrangements', 'Var', (147, 161))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('TERT', 'Gene', (120, 124))	('TERT', 'Gene', (95, 99))	('TERT', 'Gene', '7015', (95, 99))	('TERT', 'Gene', '7015', (120, 124))	('alteration', 'Reg', (47, 57))	('transcriptional regulators', 'MPA', (61, 87))	('mutations', 'Var', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Telomerase', 'Gene', (0, 10))
186938	32722302	TERT promoter mutations which result in increased TERT expression were first identified in melanoma and were subsequently reported in other cancers like bladder cancer, glioma, thyroid cancer and HCC.	('bladder cancer', 'Disease', 'MESH:D001749', (153, 167))	('bladder cancer', 'Disease', (153, 167))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('bladder cancer', 'Phenotype', 'HP:0009725', (153, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('glioma', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('thyroid cancer', 'Disease', (177, 191))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('TERT', 'Gene', (50, 54))	('mutations', 'Var', (14, 23))	('HCC', 'Phenotype', 'HP:0001402', (196, 199))	('TERT', 'Gene', '7015', (50, 54))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('thyroid cancer', 'Disease', 'MESH:D013964', (177, 191))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('thyroid cancer', 'Phenotype', 'HP:0002890', (177, 191))	('TERT', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('TERT', 'Gene', '7015', (0, 4))	('cancers', 'Disease', (140, 147))	('increased', 'PosReg', (40, 49))
186944	32722302	However, it should be noted that in 80% of cases which lacked TERT promoter, mutations showed an enhanced TERT expression.	('TERT', 'Gene', (106, 110))	('TERT', 'Gene', '7015', (106, 110))	('TERT', 'Gene', (62, 66))	('enhanced', 'PosReg', (97, 105))	('mutations', 'Var', (77, 86))	('TERT', 'Gene', '7015', (62, 66))
186946	32722302	For example, it was shown that the insertion of HBV in the TERT promoter region can activate TERT gene expression and telomerase promoting hepatocarcinogenesis in HBV-related HCC.	('activate', 'PosReg', (84, 92))	('HBV-related', 'Disease', (163, 174))	('telomerase', 'Enzyme', (118, 128))	('TERT', 'Gene', (59, 63))	('HCC', 'Phenotype', 'HP:0001402', (175, 178))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (139, 159))	('HBV', 'Gene', (48, 51))	('HBV', 'Species', '10407', (163, 166))	('TERT', 'Gene', '7015', (59, 63))	('promoting', 'PosReg', (129, 138))	('insertion', 'Var', (35, 44))	('HBV', 'Species', '10407', (48, 51))	('hepatocarcinogenesis', 'Disease', (139, 159))	('TERT', 'Gene', (93, 97))	('TERT', 'Gene', '7015', (93, 97))
186948	32722302	Interestingly, mutations in the TERT promoter were identified to be significantly more common in HCV-related HCC tumors compared with tumors without HCV infection.	('HCC tumors', 'Disease', (109, 119))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('HCV infection', 'Disease', (149, 162))	('HCV', 'Species', '11103', (149, 152))	('tumors', 'Disease', (113, 119))	('common', 'Reg', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Disease', (134, 140))	('HCC tumors', 'Disease', 'MESH:D006528', (109, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('mutations', 'Var', (15, 24))	('HCC', 'Phenotype', 'HP:0001402', (109, 112))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('TERT', 'Gene', (32, 36))	('TERT', 'Gene', '7015', (32, 36))	('HCV', 'Species', '11103', (97, 100))	('HCV infection', 'Disease', 'MESH:D006526', (149, 162))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
186950	32722302	The occurrence of TERT promoter mutations in liver carcinogenesis is identified in premalignant lesions, and the prevalence of mutations gradually increased with the degree of dysplasia, indicating that TERT promoter mutations are highly associated with the stepwise transformation from premalignant dysplastic nodules to malignant HCC.	('dysplastic nodules', 'Disease', 'MESH:D004416', (300, 318))	('TERT', 'Gene', '7015', (203, 207))	('premalignant dysplastic', 'Disease', 'MESH:D004416', (287, 310))	('liver carcinogenesis', 'Disease', 'MESH:D063646', (45, 65))	('TERT', 'Gene', (203, 207))	('malignant HCC', 'Disease', (322, 335))	('mutations', 'Var', (32, 41))	('TERT', 'Gene', (18, 22))	('premalignant dysplastic', 'Disease', (287, 310))	('HCC', 'Phenotype', 'HP:0001402', (332, 335))	('associated with', 'Reg', (238, 253))	('dysplasia', 'Disease', 'MESH:C536170', (176, 185))	('dysplastic nodules', 'Disease', (300, 318))	('TERT', 'Gene', '7015', (18, 22))	('mutations', 'Var', (217, 226))	('liver carcinogenesis', 'Disease', (45, 65))	('dysplasia', 'Disease', (176, 185))
186951	32722302	TERT promoter mutations were identified in 6% of low-grade dysplastic nodules, 19% of high-grade dysplastic nodules and 61% of early HCCs.	('dysplastic nodules', 'Disease', (97, 115))	('HCCs', 'Gene', (133, 137))	('dysplastic nodules', 'Disease', 'MESH:D004416', (59, 77))	('HCCs', 'Gene', '3052', (133, 137))	('TERT', 'Gene', (0, 4))	('HCC', 'Phenotype', 'HP:0001402', (133, 136))	('TERT', 'Gene', '7015', (0, 4))	('dysplastic nodules', 'Disease', 'MESH:D004416', (97, 115))	('dysplastic nodules', 'Disease', (59, 77))	('mutations', 'Var', (14, 23))
186957	32722302	Interestingly, the TERT promoter mutation at the -124 bp hotspot appears more often compared with the TERT promoter mutation at the -146 bp hotspot was shown that the TERT promoter mutations generate a de novo consensus binding site for the E-twenty-six (ETS) transcription factor family, leading to an increase in TERT protein amounts, telomerase activity and telomere length.	('TERT', 'Gene', (19, 23))	('TERT', 'Gene', (167, 171))	('increase', 'PosReg', (303, 311))	('TERT', 'Gene', '7015', (19, 23))	('TERT', 'Gene', (102, 106))	('TERT', 'Gene', '7015', (102, 106))	('TERT', 'Gene', (315, 319))	('TERT', 'Gene', '7015', (167, 171))	('TERT', 'Gene', '7015', (315, 319))	('activity', 'MPA', (348, 356))	('binding', 'Interaction', (220, 227))	('telomere length', 'CPA', (361, 376))	('mutations', 'Var', (181, 190))	('telomerase', 'CPA', (337, 347))
186964	32722302	These studies identified TERT promoter mutations in 31-47% of the HCCs.	('TERT', 'Gene', (25, 29))	('mutations', 'Var', (39, 48))	('HCCs', 'Gene', (66, 70))	('TERT', 'Gene', '7015', (25, 29))	('HCCs', 'Gene', '3052', (66, 70))	('HCC', 'Phenotype', 'HP:0001402', (66, 69))
186969	32722302	They described TERT promoter mutations in 5.12% (4/78) of intrahepatic cholangiocarcinoma and in 53.3% (8/15) of combined hepatocellular cholangiocarcinoma.	('TERT', 'Gene', '7015', (15, 19))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (71, 89))	('intrahepatic cholangiocarcinoma', 'Disease', (58, 89))	('mutations', 'Var', (29, 38))	('hepatocellular cholangiocarcinoma', 'Disease', 'MESH:D018281', (122, 155))	('hepatocellular cholangiocarcinoma', 'Disease', (122, 155))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (137, 155))	('TERT', 'Gene', (15, 19))
186970	32722302	The high percentage of TERT promoter mutations in HCC/iCCA may reflect the presence of the HCC part consisting of the TERT promoter mutation or indicate that both tumor types may arise from the same cell type of origin (Table 3).	('TERT', 'Gene', '7015', (118, 122))	('TERT', 'Gene', (23, 27))	('TERT', 'Gene', '7015', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('HCC', 'Phenotype', 'HP:0001402', (91, 94))	('HCC', 'Phenotype', 'HP:0001402', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('mutations', 'Var', (37, 46))	('HCC/iCCA', 'Disease', (50, 58))	('tumor', 'Disease', (163, 168))	('TERT', 'Gene', (118, 122))
186979	32722302	Structural rearrangements in the TERT gene have been shown in several cancers like neuroblastoma, renal cell carcinoma, sarcoma and prostate carcinoma, and also in liver carcinoma.	('sarcoma and prostate carcinoma', 'Disease', 'MESH:D011471', (120, 150))	('liver carcinoma', 'Phenotype', 'HP:0001402', (164, 179))	('shown', 'Reg', (53, 58))	('liver carcinoma', 'Disease', (164, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (132, 150))	('renal cell carcinoma', 'Disease', (98, 118))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (98, 118))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('liver carcinoma', 'Disease', 'MESH:D008113', (164, 179))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('Structural rearrangements', 'Var', (0, 25))	('neuroblastoma', 'Disease', (83, 96))	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('neuroblastoma', 'Phenotype', 'HP:0003006', (83, 96))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('neuroblastoma', 'Disease', 'MESH:D009447', (83, 96))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (98, 118))
186982	32722302	The high frequency of HBV integration within the TERT promoter region might be a reason for a low rate of TERT promoter mutations in HBV-related HCC, which is known to induce telomerase transcription.	('HBV', 'Species', '10407', (133, 136))	('TERT', 'Gene', (106, 110))	('TERT', 'Gene', '7015', (106, 110))	('induce', 'PosReg', (168, 174))	('TERT', 'Gene', (49, 53))	('TERT', 'Gene', '7015', (49, 53))	('mutations', 'Var', (120, 129))	('HBV-related', 'Gene', (133, 144))	('HBV', 'Species', '10407', (22, 25))	('HCC', 'Phenotype', 'HP:0001402', (145, 148))
186984	32722302	The insertion of AAV2 can take place in the TERT promoter region and thereby lead to overexpression of the TERT gene.	('lead to', 'Reg', (77, 84))	('TERT', 'Gene', (44, 48))	('TERT', 'Gene', '7015', (44, 48))	('AAV2', 'Gene', (17, 21))	('insertion', 'Var', (4, 13))	('overexpression', 'MPA', (85, 99))	('TERT', 'Gene', (107, 111))	('TERT', 'Gene', '7015', (107, 111))	('AAV2', 'Species', '10804', (17, 21))
186993	32722302	Of note, c-MYC amplification correlates with liver cancer progression, mainly HCC, and to a lesser extent, iCCA.	('liver cancer', 'Phenotype', 'HP:0002896', (45, 57))	('amplification', 'Var', (15, 28))	('liver cancer', 'Disease', 'MESH:D006528', (45, 57))	('HCC', 'Disease', (78, 81))	('liver cancer', 'Disease', (45, 57))	('c-MYC', 'Gene', (9, 14))	('iCCA', 'Disease', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('HCC', 'Phenotype', 'HP:0001402', (78, 81))	('c-MYC', 'Gene', '4609', (9, 14))
186994	32722302	In a recent study using a genome-wide shRNA screening strategy in HepG2 cell line, Chr15orf55 (also known as NUTM1) and Chr7orf43, two regulatory factors with currently unknown functions, were found to activate TERT gene expression through SP1 or YAP1, respectively.	('HepG2', 'CellLine', 'CVCL:0027', (66, 71))	('TERT', 'Gene', '7015', (211, 215))	('NUTM1', 'Gene', '256646', (109, 114))	('NUTM1', 'Gene', (109, 114))	('activate', 'PosReg', (202, 210))	('Chr15orf55', 'Var', (83, 93))	('Chr7orf43', 'Var', (120, 129))	('expression', 'MPA', (221, 231))	('TERT', 'Gene', (211, 215))	('YAP1', 'Gene', '10413', (247, 251))	('YAP1', 'Gene', (247, 251))	('SP1', 'Gene', (240, 243))
186999	32722302	The overexpression of DNMTs is thought to be responsible for suppressing the expression of tumor suppressor proteins by methylating the promoters of their genes, which leads to the early switching off of these factors.	('methylating', 'Var', (120, 131))	('suppressing', 'NegReg', (61, 72))	('expression', 'MPA', (77, 87))	('promoters', 'MPA', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
187009	32722302	observed that aberrant methylation of TERT promoter in HCC patients of the Han Chinese population showed a nearly 56-fold increase of TERT expression from the hypermethylated promoter.	('TERT', 'Gene', (134, 138))	('HCC', 'Phenotype', 'HP:0001402', (55, 58))	('TERT', 'Gene', (38, 42))	('aberrant', 'Var', (14, 22))	('TERT', 'Gene', '7015', (134, 138))	('patients', 'Species', '9606', (59, 67))	('TERT', 'Gene', '7015', (38, 42))	('increase', 'PosReg', (122, 130))	('methylation', 'MPA', (23, 34))
187010	32722302	In contrast to that study, an analysis of 106 patient tissues (64 with HCC and 42 without liver disorders) and hepatocarcinoma cell lines revealed that the TERT promoter was methylated in normal liver but was hypomethylated in most of the hepatocellular carcinomas.	('hepatocellular carcinomas', 'Disease', (239, 264))	('patient', 'Species', '9606', (46, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (254, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('hepatocarcinoma', 'Disease', (111, 126))	('hepatocarcinoma', 'Disease', 'None', (111, 126))	('HCC', 'Phenotype', 'HP:0001402', (71, 74))	('liver disorders', 'Disease', 'MESH:D017093', (90, 105))	('liver disorders', 'Disease', (90, 105))	('hypomethylated', 'Var', (209, 223))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (239, 263))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (239, 264))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (239, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('liver disorders', 'Phenotype', 'HP:0001392', (90, 105))	('TERT', 'Gene', (156, 160))	('TERT', 'Gene', '7015', (156, 160))
187017	32722302	Tumors from skin and bone showed low and heterogeneous methylation levels, which indicates the use of other mechanisms of telomere maintenance like TERT promoter mutations or the alternative lengthening of telomeres (ALT).	('mutations', 'Var', (162, 171))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TERT', 'Gene', (148, 152))	('TERT', 'Gene', '7015', (148, 152))	('heterogeneous methylation levels', 'MPA', (41, 73))
187018	32722302	described hypermethylation in the region upstream of the recurrent C228T and C250T promoter mutations in immortalized and cancer cell lines (including hepatocarcinoma cell lines).	('C250T', 'Mutation', 'rs750051656', (77, 82))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('C228T', 'Var', (67, 72))	('C228T', 'Mutation', 'rs749551247', (67, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('hepatocarcinoma', 'Disease', 'None', (151, 166))	('hypermethylation', 'MPA', (10, 26))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('hepatocarcinoma', 'Disease', (151, 166))	('C250T', 'Var', (77, 82))
187019	32722302	Interestingly, the authors could show on an allele level that the hypermethylation of TERT promoter sequences in cancer cells is associated with TERT repression, while the remaining unmethylated allele marked with an open chromatin is largely responsible for the TERT expression in cancer cells.	('associated', 'Reg', (129, 139))	('TERT', 'Gene', '7015', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('hypermethylation', 'Var', (66, 82))	('TERT', 'Gene', '7015', (263, 267))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('TERT', 'Gene', (86, 90))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('cancer', 'Disease', (282, 288))	('TERT', 'Gene', (145, 149))	('TERT', 'Gene', '7015', (86, 90))	('TERT', 'Gene', (263, 267))
187020	32722302	In cancers with TERT promoter mutations, the expressed allele is mutated, while the WT allele is silenced.	('TERT', 'Gene', (16, 20))	('TERT', 'Gene', '7015', (16, 20))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('mutated', 'Var', (65, 72))
187034	32722302	The low frequency of TERT promoter mutations reported in iCCA might be due to a not-detected HCCs part (mixed differentiation) of the analyzed tumors.	('HCC', 'Phenotype', 'HP:0001402', (93, 96))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('TERT', 'Gene', (21, 25))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('TERT', 'Gene', '7015', (21, 25))	('HCCs', 'Gene', (93, 97))	('HCCs', 'Gene', '3052', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('mutations', 'Var', (35, 44))
187035	32722302	This links to the phenomenon that some tumor entities lacking specific mutations in the TERT promoter region and where other mechanisms leading to telomerase activation exist.	('TERT', 'Gene', '7015', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('mutations', 'Var', (71, 80))	('tumor', 'Disease', (39, 44))	('TERT', 'Gene', (88, 92))
187039	32722302	The observation that TERT promoter mutations occur early during liver carcinogenesis highlights the importance of telomerase activity for tumor cell survival.	('tumor', 'Disease', (138, 143))	('TERT', 'Gene', (21, 25))	('TERT', 'Gene', '7015', (21, 25))	('liver carcinogenesis', 'Disease', (64, 84))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('liver carcinogenesis', 'Disease', 'MESH:D063646', (64, 84))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('mutations', 'Var', (35, 44))
187041	32722302	In melanoma, a two-step mechanism was described, which showed that mutations in the TERT promoter region contribute to tumorigenesis.	('tumor', 'Disease', (119, 124))	('TERT', 'Gene', (84, 88))	('TERT', 'Gene', '7015', (84, 88))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
187042	32722302	This study showed that TERT promoter mutations are not sufficient to counteract telomere shortening, but they contribute to tumorigenesis by promoting the immortalization and chromosomal instability in two phases: (1) extend the cellular life span by healing the shortest telomeres without prevention of bulk telomere shortening, and (2) the existence of critically short telomeres conducts to genome instability and thereby, telomerase is further up-regulated to proceed cell proliferation.	('TERT', 'Gene', (23, 27))	('TERT', 'Gene', '7015', (23, 27))	('promoting', 'PosReg', (141, 150))	('tumor', 'Disease', (124, 129))	('telomere shortening', 'Phenotype', 'HP:0031413', (309, 328))	('extend', 'PosReg', (218, 224))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('genome instability', 'MPA', (394, 412))	('conducts', 'Reg', (382, 390))	('chromosomal instability', 'Phenotype', 'HP:0040012', (175, 198))	('short telomeres', 'Phenotype', 'HP:0031413', (366, 381))	('telomerase', 'Enzyme', (426, 436))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mutations', 'Var', (37, 46))	('cellular life span', 'CPA', (229, 247))	('up-regulated', 'PosReg', (448, 460))	('immortalization', 'CPA', (155, 170))	('telomere shortening', 'Phenotype', 'HP:0031413', (80, 99))	('cell proliferation', 'CPA', (472, 490))
187043	32722302	There is strong experimental evidence indicating that oncogenic mutations or mutations which result in genome instability induce cellular senescence by inducing telomere replication stress.	('stress', 'Disease', (182, 188))	('genome', 'MPA', (103, 109))	('cellular senescence', 'CPA', (129, 148))	('stress', 'Disease', 'MESH:D000079225', (182, 188))	('mutations', 'Var', (77, 86))	('inducing', 'Reg', (152, 160))	('mutations', 'Var', (64, 73))	('induce', 'Reg', (122, 128))
187044	32722302	This mechanism functions to limit continuous proliferation of cells carrying detrimental mutations, preventing tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('mutations', 'Var', (89, 98))	('preventing', 'NegReg', (100, 110))
187046	32722302	Whether telomere maintenance or even elongation of telomeres during chronic liver diseases or an inactivation of the telomerase could be beneficial for the treatment of liver carcinoma remains to be elucidated in future studies.	('liver disease', 'Phenotype', 'HP:0001392', (76, 89))	('chronic liver diseases', 'Disease', 'MESH:D058625', (68, 90))	('liver carcinoma', 'Disease', (169, 184))	('liver diseases', 'Phenotype', 'HP:0001392', (76, 90))	('inactivation', 'Var', (97, 109))	('liver carcinoma', 'Disease', 'MESH:D008113', (169, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('telomerase', 'Enzyme', (117, 127))	('chronic liver diseases', 'Disease', (68, 90))	('liver carcinoma', 'Phenotype', 'HP:0001402', (169, 184))
187047	32315352	INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models Alterations in fibroblast growth factor receptor (FGFR) genes have been identified as potential driver oncogenes.	('INCB054828', 'Chemical', '-', (0, 10))	('pemigatinib', 'Chemical', '-', (12, 23))	('rat', 'Species', '10116', (173, 176))	('fibroblast growth factor receptors 1, 2, and 3', 'Gene', '2260;2263;2261', (62, 108))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('Alterations', 'Var', (169, 180))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('FGF', 'Gene', (219, 222))	('tumor', 'Disease', (156, 161))	('FGF', 'Gene', '9965;8074', (219, 222))
187050	32315352	INCB054828 pharmacokinetics and pharmacodynamics were investigated using cell lines and tumor models, and the antitumor effect of oral INCB054828 was investigated using xenograft tumor models with genetic alterations in FGFR1, 2, or 3.	('INCB054828', 'Chemical', '-', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('INCB054828', 'Chemical', '-', (135, 145))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('genetic alterations', 'Var', (197, 216))	('tumor', 'Disease', (114, 119))	('rat', 'Species', '10116', (209, 212))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('FGFR1', 'Gene', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (179, 184))
187051	32315352	Enzymatic assays with recombinant human FGFR kinases showed potent inhibition of FGFR1, 2, and 3 by INCB054828 (half maximal inhibitory concentration [IC50] 0.4, 0.5, and 1.0 nM, respectively) with weaker activity against FGFR4 (IC50 30 nM).	('human', 'Species', '9606', (34, 39))	('inhibition', 'NegReg', (67, 77))	('FGF', 'Gene', (81, 84))	('FGF', 'Gene', (40, 43))	('INCB054828', 'Var', (100, 110))	('FGF', 'Gene', (222, 225))	('FGF', 'Gene', '9965;8074', (81, 84))	('FGF', 'Gene', '9965;8074', (40, 43))	('FGFR4', 'Gene', '2264', (222, 227))	('FGF', 'Gene', '9965;8074', (222, 225))	('FGFR4', 'Gene', (222, 227))	('rat', 'Species', '10116', (143, 146))	('INCB054828', 'Chemical', '-', (100, 110))
187052	32315352	INCB054828 selectively inhibited growth of tumor cell lines with activation of FGFR signaling compared with cell lines lacking FGFR aberrations.	('INCB054828', 'Chemical', '-', (0, 10))	('INCB054828', 'Var', (0, 10))	('FGF', 'Gene', '9965;8074', (79, 82))	('inhibited', 'NegReg', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('FGF', 'Gene', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('growth', 'CPA', (33, 39))	('FGF', 'Gene', (79, 82))	('rat', 'Species', '10116', (136, 139))	('FGF', 'Gene', '9965;8074', (127, 130))	('tumor', 'Disease', (43, 48))	('activation', 'PosReg', (65, 75))
187054	32315352	INCB054828 suppressed the growth of xenografted tumor models with FGFR1, 2, or 3 alterations as monotherapy, and the combination of INCB054828 with cisplatin provided significant benefit over either single agent, with an acceptable tolerability.	('INCB054828', 'Chemical', '-', (0, 10))	('benefit', 'PosReg', (179, 186))	('tumor', 'Disease', (48, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('INCB054828', 'Chemical', '-', (132, 142))	('rat', 'Species', '10116', (85, 88))	('INCB054828', 'Gene', (0, 10))	('suppressed', 'NegReg', (11, 21))	('FGFR1', 'Gene', (66, 71))	('INCB054828', 'Var', (132, 142))	('growth', 'CPA', (26, 32))	('combination', 'Interaction', (117, 128))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
187055	32315352	The preclinical data presented for INCB054828, together with preliminary clinical observations, support continued investigation in patients with FGFR alterations, such as fusions and activating mutations.	('patients', 'Species', '9606', (131, 139))	('activating mutations', 'Var', (183, 203))	('INCB054828', 'Chemical', '-', (35, 45))	('fusions', 'Disease', (171, 178))	('rat', 'Species', '10116', (154, 157))	('FGF', 'Gene', (145, 148))	('FGF', 'Gene', '9965;8074', (145, 148))
187056	32315352	Deregulation of receptor tyrosine kinase (RTK) signaling has the potential to promote the acquisition of several hallmarks of cancer cells notably self-sustaining proliferation, enhanced angiogenesis, evasion of cell death, and increased migration and invasion.	('RTK', 'Gene', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('promote', 'PosReg', (78, 85))	('enhanced', 'PosReg', (178, 186))	('Deregulation', 'Var', (0, 12))	('rat', 'Species', '10116', (241, 244))	('rat', 'Species', '10116', (170, 173))	('invasion', 'CPA', (252, 260))	('cancer', 'Disease', (126, 132))	('RTK', 'Gene', '5979', (42, 45))	('self-sustaining proliferation', 'CPA', (147, 176))	('receptor tyrosine kinase', 'Gene', (16, 40))	('increased', 'PosReg', (228, 237))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('receptor tyrosine kinase', 'Gene', '5979', (16, 40))	('evasion', 'CPA', (201, 208))	('angiogenesis', 'CPA', (187, 199))
187057	32315352	Aberrant activation of RTK signaling can proceed through conserved mechanisms including genomic amplification and protein overexpression, gain-of-function mutations, chromosomal translocations, and autocrine activation.	('chromosomal translocations', 'Var', (166, 192))	('activation', 'PosReg', (9, 19))	('mutations', 'Var', (155, 164))	('overexpression', 'PosReg', (122, 136))	('protein', 'Protein', (114, 121))	('RTK', 'Gene', (23, 26))	('gain-of-function', 'PosReg', (138, 154))	('RTK', 'Gene', '5979', (23, 26))
187058	32315352	Through systematic sequencing of cancer genomes, genetic alterations in many RTKs were identified across numerous tumor types.	('RTK', 'Gene', '5979', (77, 80))	('genetic alterations', 'Var', (49, 68))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('RTK', 'Gene', (77, 80))	('identified', 'Reg', (87, 97))	('rat', 'Species', '10116', (61, 64))	('tumor', 'Disease', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
187059	32315352	The oncogenic activity of deregulated RTKs (e.g.	('oncogenic activity', 'CPA', (4, 22))	('deregulated', 'Var', (26, 37))	('RTK', 'Gene', '5979', (38, 41))	('RTK', 'Gene', (38, 41))
187067	32315352	There is strong genetic and functional evidence that dysregulation of FGFR can lead to the establishment and progression of cancer.	('dysregulation', 'Var', (53, 66))	('progression', 'CPA', (109, 120))	('cancer', 'Disease', (124, 130))	('FGF', 'Gene', '9965;8074', (70, 73))	('establishment', 'CPA', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lead to', 'Reg', (79, 86))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('FGF', 'Gene', (70, 73))
187068	32315352	Genetic alterations in FGFR1, FGFR2, and FGFR3 are reported in many tumor types and include all of the mechanisms described leading to constitutive activation of the receptors or aberrant ligand-dependent signaling through FGFRs.	('tumor', 'Disease', (68, 73))	('Genetic alterations', 'Var', (0, 19))	('rat', 'Species', '10116', (12, 15))	('FGF', 'Gene', (23, 26))	('reported', 'Reg', (51, 59))	('activation', 'PosReg', (148, 158))	('FGF', 'Gene', (223, 226))	('FGF', 'Gene', (30, 33))	('ligand-dependent signaling', 'MPA', (188, 214))	('FGF', 'Gene', (41, 44))	('FGF', 'Gene', '9965;8074', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('FGF', 'Gene', '9965;8074', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('FGFR2', 'Gene', (30, 35))	('FGFR2', 'Gene', '2263', (30, 35))	('FGF', 'Gene', '9965;8074', (41, 44))	('FGF', 'Gene', '9965;8074', (223, 226))
187070	32315352	In a pan-cancer survey of >4,800 solid tumors, 7.1% had alterations in FGFR genes with wide distribution and variable frequency; however, enrichment was observed in several cancers including bladder, breast, and lung, consistent with previous tumor-specific studies .	('cancer', 'Disease', (9, 15))	('FGF', 'Gene', (71, 74))	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (39, 45))	('tumor', 'Disease', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('lung', 'Disease', (212, 216))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('cancers', 'Disease', (173, 180))	('cancer', 'Disease', (173, 179))	('rat', 'Species', '10116', (60, 63))	('breast', 'Disease', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Disease', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('alterations', 'Var', (56, 67))	('bladder', 'Disease', (191, 198))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('FGF', 'Gene', '9965;8074', (71, 74))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
187071	32315352	Among these aberrations, chromosomal translocations that deregulate kinase activity are strong oncogenic drivers, and fusions involving FGFR1, FGFR2, and FGFR3 have been described.	('FGFR2', 'Gene', (143, 148))	('fusions', 'Var', (118, 125))	('FGFR2', 'Gene', '2263', (143, 148))	('FGFR1', 'Gene', (136, 141))	('FGFR3', 'Gene', (154, 159))	('rat', 'Species', '10116', (16, 19))	('deregulate', 'NegReg', (57, 67))	('kinase activity', 'MPA', (68, 83))	('chromosomal translocations', 'Var', (25, 51))
187073	32315352	In intrahepatic cholangiocarcinoma, fusions of FGFR2 with various partners are reported in 10-15% of cases.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 34))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (16, 34))	('intrahepatic cholangiocarcinoma', 'Disease', (3, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('fusions', 'Var', (36, 43))	('FGFR2', 'Gene', (47, 52))	('FGFR2', 'Gene', '2263', (47, 52))
187074	32315352	Similarly, FGFR1 is translocated to multiple chromosomal loci in a rare myeloproliferative neoplasm: myeloid/lymphoid neoplasms with FGFR1 rearrangement.	('neoplasms', 'Phenotype', 'HP:0002664', (118, 127))	('myeloproliferative neoplasm', 'Phenotype', 'HP:0005547', (72, 99))	('myeloproliferative neoplasm', 'Disease', (72, 99))	('FGFR1', 'Gene', (133, 138))	('myeloid/lymphoid neoplasms', 'Phenotype', 'HP:0005531', (101, 127))	('myeloproliferative neoplasm', 'Disease', 'MESH:D009196', (72, 99))	('myeloid/lymphoid neoplasms', 'Disease', (101, 127))	('neoplasm', 'Phenotype', 'HP:0002664', (118, 126))	('myeloid/lymphoid neoplasm', 'Phenotype', 'HP:0005531', (101, 126))	('lymphoid neoplasms', 'Phenotype', 'HP:0002665', (109, 127))	('FGFR1', 'Gene', (11, 16))	('neoplasm', 'Phenotype', 'HP:0002664', (91, 99))	('lymphoid neoplasm', 'Phenotype', 'HP:0002665', (109, 126))	('rearrangement', 'Var', (139, 152))	('myeloid/lymphoid neoplasms', 'Disease', 'MESH:D008223', (101, 127))
187075	32315352	Evidence suggests that the genetically activated FGFR pathway sensitizes FGFR-altered cancer cells to knockdown or inhibition of these receptors.	('inhibition', 'NegReg', (115, 125))	('FGF', 'Gene', '9965;8074', (73, 76))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('knockdown', 'Var', (102, 111))	('FGF', 'Gene', (49, 52))	('FGF', 'Gene', (73, 76))	('sensitizes', 'Reg', (62, 72))	('FGF', 'Gene', '9965;8074', (49, 52))	('cancer', 'Disease', (86, 92))
187076	32315352	Collectively, these data indicate that alterations in FGFR genes can be driver oncogenes in some, though not all, contexts.	('alterations', 'Var', (39, 50))	('rat', 'Species', '10116', (43, 46))	('FGF', 'Gene', '9965;8074', (54, 57))	('FGF', 'Gene', (54, 57))
187079	32315352	INCB054828 differs from earlier kinase inhibitors with FGFR activity with high selectivity for FGFR family members; its potency and drug-like properties have translated to antitumor efficacy at very low doses in preclinical models.	('INCB054828', 'Chemical', '-', (0, 10))	('INCB054828', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('FGF', 'Gene', (95, 98))	('tumor', 'Disease', (176, 181))	('FGF', 'Gene', '9965;8074', (95, 98))	('FGF', 'Gene', (55, 58))	('FGF', 'Gene', '9965;8074', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
187087	32315352	9740, Antibody Registry Identifier AB_11178519), ERK (monoclonal [mouse], 9107, AB_10695739), phospho-p42/44 ERK1/2 (monoclonal [rabbit], 4370, AB_2315112), phospho-STAT5 (Tyr694; monoclonal [rabbit], 4322, AB_10544692), and STAT5 (monoclonal [rabbit], 9358, AB_659905) were from Cell Signaling Technologies (Danvers, MA) and used at 1:1000 dilution; FGFR3 (monoclonal [rabbit], AB133644, AB_2810262) and FRS2 (polyclonal [rabbit], AB10425, AB_2247176) were from Abcam (Cambridge, UK) and used at 1:2000; and phospho-FRS2 (Tyr436; polyclonal [rabbit], AF5126, AB_2106234) was from R&D Systems (Minneapolis, MN) and used at 1 mug/mL.	('MN', 'CellLine', 'CVCL:U508', (607, 609))	('ERK', 'Gene', '26413', (49, 52))	('mouse', 'Species', '10090', (66, 71))	('ERK1/2', 'Gene', '26417;26413', (109, 115))	('ERK1/2', 'Gene', (109, 115))	('ERK', 'Gene', (109, 112))	('Tyr436;', 'Var', (523, 530))	('ERK', 'Gene', '26413', (109, 112))	('ERK', 'Gene', (49, 52))
187125	32315352	Enzymatic assays with recombinant human FGFR kinases showed potent inhibition of FGFR1, FGFR2, and FGFR3 by INCB054828 (half maximal inhibitory concentration [IC50] values of 0.4, 0.5, and 1 nmol/L, respectively) with weaker activity against the related family member FGFR4 (Fig 1B).	('human', 'Species', '9606', (34, 39))	('FGF', 'Gene', (40, 43))	('FGF', 'Gene', (88, 91))	('rat', 'Species', '10116', (151, 154))	('INCB054828', 'Chemical', '-', (108, 118))	('INCB054828', 'Var', (108, 118))	('FGF', 'Gene', '9965;8074', (268, 271))	('FGF', 'Gene', '9965;8074', (99, 102))	('FGFR2', 'Gene', (88, 93))	('FGF', 'Gene', (268, 271))	('inhibition', 'NegReg', (67, 77))	('FGFR4', 'Gene', '2264', (268, 273))	('FGF', 'Gene', (99, 102))	('FGF', 'Gene', '9965;8074', (81, 84))	('FGFR2', 'Gene', '2263', (88, 93))	('FGF', 'Gene', (81, 84))	('FGFR4', 'Gene', (268, 273))	('FGF', 'Gene', '9965;8074', (40, 43))	('FGF', 'Gene', '9965;8074', (88, 91))
187128	32315352	Only vascular endothelial growth factor receptor-2/kinase insert domain containing receptor (VEGFR2/KDR) (IC50, 182 nM) and c-KIT (IC50, 266 nM) showed IC50 values less than 1,000 nM indicating that INCB054828 exhibited high selectivity for the FGFR kinases (Fig 1C, S1 Table).	('KDR', 'Gene', (100, 103))	('FGF', 'Gene', (245, 248))	('FGF', 'Gene', '9965;8074', (245, 248))	('VEGFR2', 'Gene', '3791', (93, 99))	('c-KIT', 'Gene', (124, 129))	('KDR', 'Gene', '3791', (100, 103))	('INCB054828', 'Chemical', '-', (199, 209))	('c-KIT', 'Gene', '3815', (124, 129))	('VEGFR2', 'Gene', (93, 99))	('INCB054828', 'Var', (199, 209))
187130	32315352	Subsequent profiling against a broader panel of 161 kinases (PerkinElmer, Akron, OH) confirmed the selectivity; no additional kinases were significantly inhibited by INCB054828 at a concentration of 100 nM besides the 4 FGFR enzymes and VEGFR2 (S2 Table).	('VEGFR2', 'Gene', '3791', (237, 243))	('INCB054828', 'Chemical', '-', (166, 176))	('FGF', 'Gene', (220, 223))	('VEGFR2', 'Gene', (237, 243))	('INCB054828', 'Var', (166, 176))	('rat', 'Species', '10116', (189, 192))	('inhibited', 'NegReg', (153, 162))	('FGF', 'Gene', '9965;8074', (220, 223))
187140	32315352	Using this method, potent inhibition of FGFR3 by INCB054828 (<10 nM) was confirmed in a second urothelial cell line RT-112 that also harbors the FGFR3-TACC3 fusion (Fig 2C).	('INCB054828', 'Chemical', '-', (49, 59))	('INCB054828', 'Var', (49, 59))	('FGFR3', 'Gene', (40, 45))	('TACC3', 'Gene', '10460', (151, 156))	('inhibition', 'NegReg', (26, 36))	('TACC3', 'Gene', (151, 156))
187141	32315352	INCB054828 selectively inhibits the growth of tumor cell lines with activation of FGFR signaling (Table 1).	('INCB054828', 'Chemical', '-', (0, 10))	('INCB054828', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('FGF', 'Gene', (82, 85))	('activation', 'PosReg', (68, 78))	('FGF', 'Gene', '9965;8074', (82, 85))	('inhibits', 'NegReg', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
187145	32315352	The data reveal a clear separation in sensitivity to INCB054828 between cell lines with genetic alterations in FGFR1, FGFR2, or FGFR3 and cell lines lacking these aberrations.	('INCB054828', 'Chemical', '-', (53, 63))	('FGFR2', 'Gene', '2263', (118, 123))	('FGFR2', 'Gene', (118, 123))	('genetic alterations', 'Var', (88, 107))	('rat', 'Species', '10116', (167, 170))	('FGFR1', 'Gene', (111, 116))	('rat', 'Species', '10116', (100, 103))	('rat', 'Species', '10116', (28, 31))	('FGFR3', 'Gene', (128, 133))
187148	32315352	In vitro, INCB054828 showed moderate to high permeability across Caco-2 cell monolayers, exhibited moderate metabolic stability in human liver microsome, and demonstrated IC50s greater than 25 muM for all of the CYP isoforms tested (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4).	('Caco-2', 'CellLine', 'CVCL:0025', (65, 71))	('rat', 'Species', '10116', (103, 106))	('INCB054828', 'Chemical', '-', (10, 20))	('INCB054828', 'Var', (10, 20))	('rat', 'Species', '10116', (32, 35))	('IC50s', 'MPA', (171, 176))	('human', 'Species', '9606', (131, 136))	('permeability', 'MPA', (45, 57))	('rat', 'Species', '10116', (165, 168))	('metabolic stability', 'MPA', (108, 127))
187150	32315352	In vivo, the systemic clearance of INCB054828 was low in monkeys and dogs (8% and 10% of hepatic blood flow, respectively), but moderate in rats (31% of hepatic blood flow).	('low', 'NegReg', (50, 53))	('INCB054828', 'Chemical', '-', (35, 45))	('INCB054828', 'Var', (35, 45))	('rat', 'Species', '10116', (132, 135))	('rats', 'Species', '10116', (140, 144))	('rat', 'Species', '10116', (140, 143))	('dogs', 'Species', '9615', (69, 73))	('hepatic blood flow', 'MPA', (89, 107))	('systemic clearance', 'MPA', (13, 31))
187159	32315352	Inhibition of FGF23 signaling results in phosphorus reabsorption, and changes can be measured in plasma.	('phosphorus reabsorption', 'MPA', (41, 64))	('FGF23', 'Gene', '8074', (14, 19))	('phosphorus', 'Chemical', 'MESH:D010758', (41, 51))	('results in', 'Reg', (30, 40))	('FGF23', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))
187160	32315352	After a single oral dose of INCB054828, a dose-dependent increase in serum phosphorus was observed in mice (Fig 3C).	('mice', 'Species', '10090', (102, 106))	('INCB054828', 'Var', (28, 38))	('phosphorus', 'Chemical', 'MESH:D010758', (75, 85))	('serum phosphorus', 'MPA', (69, 85))	('increase', 'PosReg', (57, 65))	('INCB054828', 'Chemical', '-', (28, 38))
187161	32315352	The antitumor effect of orally dosed INCB054828 was investigated using xenograft tumor models with genetic alterations in FGFR1 (KG1), FGFR2 (KATO III), and FGFR3 (RT-112).	('rat', 'Species', '10116', (111, 114))	('FGFR3', 'Gene', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('FGFR2', 'Gene', (135, 140))	('alterations', 'Var', (107, 118))	('FGFR2', 'Gene', '2263', (135, 140))	('FGFR1', 'Gene', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('INCB054828', 'Chemical', '-', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
187162	32315352	A full dose-response was evaluated using the KATO III gastric cancer model harboring genetic amplification of FGFR2 (Fig 4A).	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('FGFR2', 'Gene', (110, 115))	('FGFR2', 'Gene', '2263', (110, 115))	('gastric cancer', 'Disease', (54, 68))	('gastric cancer', 'Disease', 'MESH:D013274', (54, 68))	('genetic amplification', 'Var', (85, 106))	('gastric cancer', 'Phenotype', 'HP:0012126', (54, 68))
187164	32315352	The KG1 erythroleukemia AML cell line carries a translocation of FGFR1 (FGFROP2-FGFR1) that has been described in patients with 8p11 myeloproliferative neoplasms.	('FGF', 'Gene', '9965;8074', (65, 68))	('FGF', 'Gene', (80, 83))	('FGF', 'Gene', '9965;8074', (72, 75))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (133, 161))	('translocation', 'Var', (48, 61))	('FGF', 'Gene', '9965;8074', (80, 83))	('neoplasm', 'Phenotype', 'HP:0002664', (152, 160))	('myeloproliferative neoplasms', 'Disease', (133, 161))	('erythroleukemia AML', 'Disease', (8, 27))	('FGF', 'Gene', (65, 68))	('erythroleukemia AML', 'Disease', 'MESH:D015470', (8, 27))	('leukemia', 'Phenotype', 'HP:0001909', (15, 23))	('myeloproliferative neoplasm', 'Phenotype', 'HP:0005547', (133, 160))	('patients', 'Species', '9606', (114, 122))	('neoplasms', 'Phenotype', 'HP:0002664', (152, 161))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (133, 161))	('FGF', 'Gene', (72, 75))
187174	32315352	Deregulation of FGFR signaling is a recurrent event across many cancer types.	('FGF', 'Gene', (16, 19))	('Deregulation', 'Var', (0, 12))	('FGF', 'Gene', '9965;8074', (16, 19))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
187175	32315352	Preclinical modeling has confirmed that many of these FGFR genetic alterations can be drivers, and growth of cell lines and tumor models bearing such lesions can be effectively inhibited by selective blockade of the aberrant FGFR.	('inhibited', 'NegReg', (177, 186))	('FGF', 'Gene', (225, 228))	('aberrant', 'Var', (216, 224))	('rat', 'Species', '10116', (71, 74))	('FGF', 'Gene', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('FGF', 'Gene', '9965;8074', (225, 228))	('tumor', 'Disease', (124, 129))	('FGF', 'Gene', '9965;8074', (54, 57))	('blockade', 'NegReg', (200, 208))	('growth', 'CPA', (99, 105))	('genetic alterations', 'Var', (59, 78))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
187178	32315352	This profile translates into potent activity in xenograft tumor models with translocations in FGFR1 (8p11-translocated myeloid leukemia), FGFR2 (cholangiocarcinoma), and FGFR3 (urothelial carcinoma).	('FGFR2', 'Gene', (138, 143))	('leukemia', 'Phenotype', 'HP:0001909', (127, 135))	('myeloid leukemia', 'Disease', 'MESH:D007951', (119, 135))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (119, 135))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (145, 163))	('tumor', 'Disease', (58, 63))	('FGFR2', 'Gene', '2263', (138, 143))	('cholangiocarcinoma', 'Disease', (145, 163))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('FGFR1', 'Gene', (94, 99))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (145, 163))	('FGFR3', 'Gene', (170, 175))	('activity', 'MPA', (36, 44))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (177, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('myeloid leukemia', 'Disease', (119, 135))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('urothelial carcinoma', 'Disease', (177, 197))	('translocations', 'Var', (76, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))
187180	32315352	Furthermore, in cell-based assays INCB054828 was more than 80-fold selective against VEGFR, reducing the risk of toxicities associated with inhibition of VEGF signaling that have been observed with first-generation multi-kinase FGFR inhibitors.	('reducing', 'NegReg', (92, 100))	('toxicities', 'Disease', 'MESH:D064420', (113, 123))	('VEGF', 'Gene', '7422', (154, 158))	('VEGFR', 'Gene', '3791', (85, 90))	('VEGF', 'Gene', '7422', (85, 89))	('rat', 'Species', '10116', (208, 211))	('FGF', 'Gene', '9965;8074', (228, 231))	('VEGFR', 'Gene', (85, 90))	('toxicities', 'Disease', (113, 123))	('INCB054828', 'Chemical', '-', (34, 44))	('VEGF', 'Gene', (154, 158))	('VEGF', 'Gene', (85, 89))	('INCB054828', 'Var', (34, 44))	('FGF', 'Gene', (228, 231))
187185	32315352	At a dose of 1 mg/kg, the plasma exposure of INCB054828 exceeded this IC50 target for approximately 12-14 hours per day and was associated with significant efficacy in several tumor models driven by FGFR1, 2, or 3 deregulation.	('INCB054828', 'Chemical', '-', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('INCB054828', 'Var', (45, 55))	('tumor', 'Disease', (176, 181))	('efficacy', 'PosReg', (156, 164))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
187187	32315352	As shown previously, inhibition of FGFR signaling antagonizes the phosphaturic function of FGF23, and a dose-dependent increase in plasma phosphorus was observed after a single oral dose of INCB054828.	('FGF', 'Gene', (91, 94))	('FGF', 'Gene', '9965;8074', (35, 38))	('INCB054828', 'Chemical', '-', (190, 200))	('INCB054828', 'Var', (190, 200))	('FGF23', 'Gene', (91, 96))	('FGF', 'Gene', '9965;8074', (91, 94))	('antagonizes', 'NegReg', (50, 61))	('phosphorus', 'Chemical', 'MESH:D010758', (138, 148))	('phosphaturic function', 'MPA', (66, 87))	('increase', 'PosReg', (119, 127))	('FGF', 'Gene', (35, 38))	('plasma phosphorus', 'MPA', (131, 148))	('FGF23', 'Gene', '8074', (91, 96))	('inhibition', 'NegReg', (21, 31))
187191	32315352	INCB054828 has also demonstrated a favorable safety profile with early signs of clinical activity in several patients with tumors harboring gene fusions with FGFRs.	('INCB054828', 'Chemical', '-', (0, 10))	('gene fusions', 'Var', (140, 152))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('patients', 'Species', '9606', (109, 117))	('FGF', 'Gene', (158, 161))	('rat', 'Species', '10116', (27, 30))	('FGF', 'Gene', '9965;8074', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
187192	32315352	A patient who presented with a myeloid/lymphoid neoplasm with an FGFR1 rearrangement that expressed the fusion CEP110-FGFR1 transcript achieved a complete cytogenetic and hematologic remission with complete molecular remission of the CEP110-FGFR1 transcript.	('myeloid/lymphoid neoplasm', 'Phenotype', 'HP:0005531', (31, 56))	('lymphoid neoplasm', 'Disease', (39, 56))	('CEP110', 'Gene', '9738', (111, 117))	('CEP110', 'Gene', '9738', (234, 240))	('lymphoid neoplasm', 'Disease', 'MESH:D008223', (39, 56))	('FGFR1', 'Gene', (65, 70))	('neoplasm', 'Phenotype', 'HP:0002664', (48, 56))	('lymphoid neoplasm', 'Phenotype', 'HP:0002665', (39, 56))	('CEP110', 'Gene', (111, 117))	('CEP110', 'Gene', (234, 240))	('rearrangement', 'Var', (71, 84))	('patient', 'Species', '9606', (2, 9))
187193	32315352	The emerging clinical data for other selective FGFR inhibitors have also demonstrated promising activity in several malignancies with FGFR alterations; specifically, erdafitinib, which has been approved for the treatment of patients with urothelial cancers with FGFR alterations.	('activity', 'MPA', (96, 104))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('rat', 'Species', '10116', (143, 146))	('FGF', 'Gene', '9965;8074', (47, 50))	('FGF', 'Gene', (262, 265))	('FGF', 'Gene', '9965;8074', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('urothelial cancers', 'Disease', 'MESH:D014523', (238, 256))	('rat', 'Species', '10116', (80, 83))	('FGF', 'Gene', (47, 50))	('alterations', 'Var', (139, 150))	('erdafitinib', 'Gene', (166, 177))	('FGF', 'Gene', (134, 137))	('erdafitinib', 'Chemical', 'MESH:C000604580', (166, 177))	('patients', 'Species', '9606', (224, 232))	('urothelial cancers', 'Disease', (238, 256))	('malignancies', 'Disease', 'MESH:D009369', (116, 128))	('malignancies', 'Disease', (116, 128))	('rat', 'Species', '10116', (271, 274))	('FGF', 'Gene', '9965;8074', (262, 265))
187194	32315352	Identifying biomarkers for response remains an important translational question, however, as not all cancers with FGFR alterations have shown equivalent responses.	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('FGF', 'Gene', '9965;8074', (114, 117))	('cancers', 'Disease', (101, 108))	('rat', 'Species', '10116', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('FGF', 'Gene', (114, 117))	('alterations', 'Var', (119, 130))
187195	32315352	These findings suggest that, for example, in lung cancers characterized by FGFR1 gene amplification there is greater tumor complexity or heterogeneity within the amplicon that may modulate the dependency on the FGFR1.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('amplification', 'Var', (86, 99))	('lung cancers', 'Disease', (45, 57))	('modulate', 'Reg', (180, 188))	('FGFR1', 'Gene', (75, 80))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('tumor', 'Disease', (117, 122))	('lung cancers', 'Disease', 'MESH:D008175', (45, 57))	('lung cancers', 'Phenotype', 'HP:0100526', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
187196	32315352	In summary, the preclinical data for INCB054828 together with its preliminary clinical observations suggest that this compound warrants continued investigation in patients selected for FGFR alterations, such as fusions and activating mutations.	('patients', 'Species', '9606', (163, 171))	('fusions', 'Var', (211, 218))	('rat', 'Species', '10116', (194, 197))	('INCB054828', 'Chemical', '-', (37, 47))	('FGF', 'Gene', (185, 188))	('activating', 'Disease', (223, 233))	('FGF', 'Gene', '9965;8074', (185, 188))	('INCB054828', 'Gene', (37, 47))
187197	32315352	As a result, phase 2 studies have been initiated in cholangiocarcinoma with FGFR2 fusions (FIGHT 201, NCT02872714), urothelial cancer with activating mutations or fusions (FIGHT 202, NCT02924376), and myeloid/lymphoid neoplasms with FGFR1 rearrangement (FIGHT 203, NCT03011372).	('myeloid/lymphoid neoplasm', 'Phenotype', 'HP:0005531', (201, 226))	('cholangiocarcinoma', 'Disease', (52, 70))	('FGFR2', 'Gene', (76, 81))	('urothelial cancer', 'Disease', 'MESH:D014523', (116, 133))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (52, 70))	('lymphoid neoplasm', 'Phenotype', 'HP:0002665', (209, 226))	('urothelial cancer', 'Disease', (116, 133))	('neoplasms', 'Phenotype', 'HP:0002664', (218, 227))	('FGFR2', 'Gene', '2263', (76, 81))	('myeloid/lymphoid neoplasms', 'Disease', (201, 227))	('mutations', 'Var', (150, 159))	('neoplasm', 'Phenotype', 'HP:0002664', (218, 226))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('activating', 'PosReg', (139, 149))	('myeloid/lymphoid neoplasms', 'Disease', 'MESH:D008223', (201, 227))	('myeloid/lymphoid neoplasms', 'Phenotype', 'HP:0005531', (201, 227))	('lymphoid neoplasms', 'Phenotype', 'HP:0002665', (209, 227))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (52, 70))
187281	31787106	Growing evidence has indicated that the mutation and dysregulation of lncRNAs play a critical role in the development of many complex human diseases.	('mutation', 'Var', (40, 48))	('dysregulation', 'Var', (53, 66))	('lncRNAs', 'Gene', (70, 77))	('human', 'Species', '9606', (134, 139))
187363	30658608	Furthermore both tumors exhibited the same V-Ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in G12D.	('G12D', 'Var', (115, 119))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('sarcoma', 'Disease', (65, 72))	('G12D', 'Mutation', 'rs121913529', (115, 119))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('rat', 'Species', '10116', (61, 64))	('sarcoma', 'Disease', 'MESH:D012509', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
187378	30658608	Moreover, there was a KRAS mutation in G12D.	('KRAS', 'Disease', (22, 26))	('G12D', 'Mutation', 'rs121913529', (39, 43))	('G12D', 'Var', (39, 43))
187393	30658608	(depth ss, ly2, v1, aw(-), ow(-), n(+) [#201 5/15, #202 1/4, #211 0/2, #213 0/1]; Japanese Classification of Colorectal Carcinoma).	('Colorectal Carcinoma', 'Disease', (109, 129))	('Carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('Colorectal Carcinoma', 'Disease', 'MESH:D015179', (109, 129))	('#202', 'Var', (51, 55))
187420	30518128	The etiology of cholangiopathies includes genetic and hereditary variants (Autosomal Dominant Polycystic Kidney Disease (ADPKD), Autosomal Recessive Polycystic Kidney Disease (ARPKD), Polycystic Liver Disease (PCLD), Chongenital Hepatic Fibrosis (CHF), Caroli's disease (CD), and Alagille Syndrome (AGS)), immune-mediated diseases (Primary Biliary Cholangitis (PBC), Primary Sclerosing Colangitis (PSC), and Autoimmune Hepatitis (AIH)), pathologies associated to ischemia, infections, or toxic agents, such as drugs, alcohol, and herbal remedies, tumors (cholangiocarcinoma), and idiopathic diseases (Table 1).	('CHF', 'Disease', (247, 250))	('ischemia, infections', 'Disease', 'MESH:D007511', (463, 483))	('tumors', 'Phenotype', 'HP:0002664', (547, 553))	('Autosomal Dominant Polycystic Kidney Disease', 'Disease', 'MESH:D007690', (75, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (564, 573))	('idiopathic diseases', 'Disease', 'MESH:D010300', (580, 599))	('Chongenital Hepatic Fibrosis', 'Disease', (217, 245))	('Polycystic Kidney', 'Phenotype', 'HP:0000113', (94, 111))	('PSC', 'Gene', (398, 401))	('AGS', 'Gene', (299, 302))	('Polycystic Kidney', 'Phenotype', 'HP:0000113', (149, 166))	('variants', 'Var', (65, 73))	('PCLD', 'Disease', (210, 214))	('Hepatitis', 'Phenotype', 'HP:0012115', (419, 428))	('tumors', 'Disease', (547, 553))	('Autosomal Recessive Polycystic Kidney Disease', 'Disease', (129, 174))	('ARPKD', 'Gene', (176, 181))	("Caroli's disease", 'Disease', 'MESH:D016767', (253, 269))	('PCLD', 'Disease', 'None', (210, 214))	('Primary Biliary Cholangitis', 'Disease', 'MESH:D008105', (332, 359))	('Primary Sclerosing Colangitis', 'Disease', 'MESH:D012598', (367, 396))	('AGS', 'Gene', '182', (299, 302))	('Hepatic Fibrosis', 'Phenotype', 'HP:0001395', (229, 245))	('Kidney Disease', 'Phenotype', 'HP:0000112', (105, 119))	('CHF', 'Disease', 'MESH:D006333', (247, 250))	('ARPKD', 'Gene', '5314', (176, 181))	('Chongenital Hepatic Fibrosis', 'Disease', 'MESH:D008103', (217, 245))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (555, 573))	('Cholangitis', 'Phenotype', 'HP:0030151', (348, 359))	('Liver Disease', 'Phenotype', 'HP:0001392', (195, 208))	('Alagille Syndrome', 'Disease', (280, 297))	('AIH', 'Disease', (430, 433))	('Autosomal Dominant Polycystic Kidney Disease', 'Disease', (75, 119))	('cholangiopathies', 'Disease', 'None', (16, 32))	('Primary Biliary Cholangitis', 'Disease', (332, 359))	('cholangiocarcinoma', 'Disease', (555, 573))	('Alagille Syndrome', 'Disease', 'MESH:D016738', (280, 297))	('AIH', 'Disease', 'None', (430, 433))	('tumors', 'Disease', 'MESH:D009369', (547, 553))	('Kidney Disease', 'Phenotype', 'HP:0000112', (160, 174))	("Caroli's disease", 'Disease', (253, 269))	('Autosomal Recessive Polycystic Kidney Disease', 'Disease', 'MESH:D007690', (129, 174))	('Polycystic Liver Disease', 'Disease', 'MESH:C536330', (184, 208))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (555, 573))	('Polycystic Liver Disease', 'Disease', (184, 208))	('idiopathic diseases', 'Disease', (580, 599))	('Autoimmune Hepatitis', 'Disease', 'MESH:D019693', (408, 428))	('cholangiopathies', 'Disease', (16, 32))	('Primary Sclerosing Colangitis', 'Disease', (367, 396))	('Autoimmune Hepatitis', 'Disease', (408, 428))	('Polycystic Liver Disease', 'Phenotype', 'HP:0006557', (184, 208))	('tumor', 'Phenotype', 'HP:0002664', (547, 552))	('PSC', 'Gene', '100653366', (398, 401))
187422	30518128	The presence of an extensive portal inflammatory infiltrate coupled with intense peribiliary fibrosis is one of the most significant histopathological features for the most of the cholagiopathies, except for AGS, a genetic pathology due to mutation in Notch2 or Jagged1 genes and characterized by the near absence of biliary tree and sinusoidal fibrosis with scant inflammation.	('fibrosis', 'Disease', 'MESH:D005355', (345, 353))	('Jagged1', 'Gene', (262, 269))	('inflammation', 'Disease', 'MESH:D007249', (365, 377))	('AGS', 'Gene', '182', (208, 211))	('Notch2', 'Gene', '4853', (252, 258))	('inflammation', 'Disease', (365, 377))	('fibrosis', 'Disease', 'MESH:D005355', (93, 101))	('fibrosis', 'Disease', (93, 101))	('biliary fibrosis', 'Disease', (85, 101))	('mutation', 'Var', (240, 248))	('fibrosis', 'Disease', (345, 353))	('biliary fibrosis', 'Disease', 'MESH:D005355', (85, 101))	('Jagged1', 'Gene', '182', (262, 269))	('cholagiopathies', 'Disease', (180, 195))	('AGS', 'Gene', (208, 211))	('rat', 'Species', '10116', (55, 58))	('Notch2', 'Gene', (252, 258))
187482	30518128	Furthermore, fibrotic livers are infiltrated by CD4+ T cells that actively participate to fibrosis progression.	('fibrotic liver', 'Phenotype', 'HP:0001395', (13, 27))	('fibrotic liver', 'Disease', 'MESH:D017093', (13, 27))	('CD4+ T', 'Var', (48, 54))	('fibrotic liver', 'Disease', (13, 27))	('rat', 'Species', '10116', (39, 42))	('fibrosis', 'Disease', 'MESH:D005355', (90, 98))	('fibrosis', 'Disease', (90, 98))
187483	30518128	In particular, Th2 cells increase fibrosis deposition by secreting IL-13 and leading to the hyper-expression of TGF-beta1 by HSCs, ultimately resulting in MMP9 expression and secretion, which, in turn, cleaves more pro-TGF, to further sustain fibrogenesis.	('HSC', 'Gene', (125, 128))	('HSC', 'Gene', '2523', (125, 128))	('fibrosis deposition', 'Disease', 'MESH:D005355', (34, 53))	('fibrosis deposition', 'Disease', (34, 53))	('cleaves', 'Var', (202, 209))	('secretion', 'MPA', (175, 184))	('MMP9', 'Gene', '4318', (155, 159))	('MMP9', 'Gene', (155, 159))	('sustain', 'PosReg', (235, 242))	('pro-TGF', 'Protein', (215, 222))	('IL-13', 'Gene', (67, 72))	('increase', 'PosReg', (25, 33))	('fibrogenesis', 'CPA', (243, 255))	('TGF-beta1', 'Gene', (112, 121))	('IL-13', 'Gene', '3596', (67, 72))	('hyper-expression', 'PosReg', (92, 108))	('TGF-beta1', 'Gene', '7040', (112, 121))
187485	30518128	Another subset of T cells likely actively involved in fibrosis progression are the Th17, that release IL-17, which activates its cognate receptor expressed on HSCs surface, to stimulate the signal transducer and activator of transcription (STAT)3-dependent synthesis of collagen I. Tregs cells are putatively the counterpart of Th17 because this cell type secretes IL-10 that, through the phosphorylation of STAT5, contributes to ameliorate fibrosis in rodent models of BDL and parasitic infestation.	('STAT5', 'Gene', (408, 413))	('BDL', 'Disease', (470, 473))	('IL-10', 'Gene', '3586', (365, 370))	('IL-17', 'Gene', '3605', (102, 107))	('rat', 'Species', '10116', (436, 439))	('IL-17', 'Gene', (102, 107))	('IL-10', 'Gene', (365, 370))	('signal transducer and activator of transcription (STAT)3', 'Gene', '6774', (190, 246))	('phosphorylation', 'Var', (389, 404))	('Th1', 'Gene', (83, 86))	('HSC', 'Gene', (159, 162))	('HSC', 'Gene', '2523', (159, 162))	('fibrosis', 'Disease', 'MESH:D005355', (54, 62))	('Th1', 'Gene', (328, 331))	('fibrosis', 'Disease', (54, 62))	('Th1', 'Gene', '51497', (83, 86))	('Th1', 'Gene', '51497', (328, 331))	('ameliorate', 'PosReg', (430, 440))	('fibrosis', 'Disease', 'MESH:D005355', (441, 449))	('fibrosis', 'Disease', (441, 449))	('STAT5', 'Gene', '6776', (408, 413))
187513	30518128	Furthermore, the activation of this signaling is involved in HSC-MF transdifferentiation and activation, and in BDL mice, the inactivation of this signal pathway using an adenovirus carrying Dickkopf-1, a WNT antagonist, is able to significantly reduce the extent of fibrosis.	('mice', 'Species', '10090', (116, 120))	('reduce', 'NegReg', (246, 252))	('fibrosis', 'Disease', (267, 275))	('Dickkopf-1', 'Gene', (191, 201))	('inactivation', 'Var', (126, 138))	('fibrosis', 'Disease', 'MESH:D005355', (267, 275))	('HSC', 'Gene', (61, 64))	('HSC', 'Gene', '2523', (61, 64))	('Dickkopf-1', 'Gene', '13380', (191, 201))
187514	30518128	Moreover, its aberrant phosphorylation at the Ser675 of beta-catenin in a mouse model of CHF/CD, act as protein stabilizer, impeding its phosphorylation and degradation thus stimulating the secretion of profibrotic and proinflammatory mediators by cystic epithelia.	('cystic epithelia', 'Disease', (248, 264))	('beta-catenin', 'Protein', (56, 68))	('phosphorylation', 'MPA', (23, 38))	('impeding', 'NegReg', (124, 132))	('phosphorylation', 'MPA', (137, 152))	('cystic epithelia', 'Disease', 'MESH:D052177', (248, 264))	('stimulating', 'Reg', (174, 185))	('aberrant', 'Var', (14, 22))	('Ser675', 'Chemical', '-', (46, 52))	('mouse', 'Species', '10090', (74, 79))	('CHF', 'Disease', 'MESH:D006333', (89, 92))	('cystic epithelia', 'Phenotype', 'HP:0200040', (248, 264))	('degradation', 'MPA', (157, 168))	('CHF', 'Disease', (89, 92))
187516	30518128	Notably, mutations of Notch2 or of its ligand Jagged1 are responsible for the development of Alagille syndrome, a recessive genetic disease characterized by a lack of biliary structures that fail to elongate from the hilum and characterized by an accumulation of cells of intermediate hepato-biliary morphology.	('Notch2', 'Gene', (22, 28))	('a recessive genetic disease', 'Disease', 'MESH:D030342', (112, 139))	('a recessive genetic disease', 'Disease', (112, 139))	('mutations', 'Var', (9, 18))	('Alagille syndrome', 'Disease', (93, 110))	('Jagged1', 'Gene', (46, 53))	('Notch2', 'Gene', '4853', (22, 28))	('Alagille syndrome', 'Disease', 'MESH:D016738', (93, 110))	('men', 'Species', '9606', (85, 88))	('responsible', 'Reg', (58, 69))	('Jagged1', 'Gene', '182', (46, 53))
187518	30518128	Moreover, Notch signaling is involved in inflammatory responses, acting concomitantly with TLR4, to stimulate the secretion of IFNgamma, and of chemokines, among which CXCL10 that is able to recruit infiltrating macrophages and to stimulate their M1 polarization.	('stimulate', 'PosReg', (231, 240))	('rat', 'Species', '10116', (205, 208))	('CXCL10', 'Var', (168, 174))	('M1 polarization', 'CPA', (247, 262))	('IFNgamma', 'Gene', (127, 135))	('IFNgamma', 'Gene', '3458', (127, 135))	('stimulate', 'PosReg', (100, 109))	('secretion', 'MPA', (114, 123))
187520	30518128	Hh deregulation could act at a different level in hepatic regenerative mechanisms responsible for fibrosis deposition and inflammation.	('fibrosis deposition', 'Disease', 'MESH:D005355', (98, 117))	('deregulation', 'Var', (3, 15))	('hepatic regenerative mechanisms', 'MPA', (50, 81))	('fibrosis deposition', 'Disease', (98, 117))	('rat', 'Species', '10116', (64, 67))	('inflammation', 'Disease', 'MESH:D007249', (122, 134))	('inflammation', 'Disease', (122, 134))
187522	30518128	Notably, in liver diseases such as PBC, MFs, and RDCs express high levels of Hh that could act in an autocrine/paracrine manner on surrounding cells and MFs itself further stimulating the proliferation of BECs, through the upregulation of PDGF-B signaling in an (Protein Kinase B Alpha) Akt-dependent fashion.	('RDCs', 'Disease', (49, 53))	('MFs', 'Var', (153, 156))	('PBC', 'Disease', (35, 38))	('liver diseases', 'Disease', 'MESH:D008107', (12, 26))	('MFs', 'Disease', (40, 43))	('stimulating', 'PosReg', (172, 183))	('liver disease', 'Phenotype', 'HP:0001392', (12, 25))	('PDGF-B', 'Gene', (239, 245))	('Protein Kinase B Alpha', 'Gene', '207', (263, 285))	('rat', 'Species', '10116', (195, 198))	('liver diseases', 'Phenotype', 'HP:0001392', (12, 26))	('Protein Kinase B Alpha', 'Gene', (263, 285))	('liver diseases', 'Disease', (12, 26))	('proliferation', 'CPA', (188, 201))	('upregulation', 'PosReg', (223, 235))
187536	30518128	It is mainly involved in chemoattraction and proliferation of neutrophils, but several papers demonstrate that its effect is not limited to this inflammatory cell type; CXCL1 could, in fact, stimulate proliferation of HSCs in an autocrine loop, and inhibition of the PI3K/Akt pathway is able to slow cell proliferation and, in vivo, to reduce development of fibrosis in a mouse model of carbon tetrachloride (CCl4) intoxication.	('rat', 'Species', '10116', (208, 211))	('mouse', 'Species', '10090', (372, 377))	('CCl4', 'Gene', (409, 413))	('stimulate', 'PosReg', (191, 200))	('CCl4', 'Gene', '20303', (409, 413))	('PI3K/Akt pathway', 'Pathway', (267, 283))	('inhibition', 'Var', (249, 259))	('fibrosis', 'Disease', 'MESH:D005355', (358, 366))	('fibrosis', 'Disease', (358, 366))	('men', 'Species', '9606', (350, 353))	('rat', 'Species', '10116', (101, 104))	('HSC', 'Gene', (218, 221))	('HSC', 'Gene', '2523', (218, 221))	('slow', 'NegReg', (295, 299))	('proliferation', 'CPA', (201, 214))	('cell proliferation', 'CPA', (300, 318))	('rat', 'Species', '10116', (52, 55))	('carbon tetrachloride', 'Chemical', 'MESH:D002251', (387, 407))	('rat', 'Species', '10116', (312, 315))	('reduce', 'NegReg', (336, 342))
187537	30518128	Moreover, stimulation of TLR4 increases NF-kB-mediated secretion of CXCL1 in a CFLD mouse model, likely responsible for the accumulation of neutrophils in CFTR-related liver diseases.	('stimulation', 'Var', (10, 21))	('TLR4', 'Gene', (25, 29))	('CFTR', 'Gene', '1080', (155, 159))	('liver diseases', 'Disease', 'MESH:D008107', (168, 182))	('CFLD', 'Disease', 'None', (79, 83))	('liver diseases', 'Phenotype', 'HP:0001392', (168, 182))	('liver diseases', 'Disease', (168, 182))	('CFLD', 'Disease', (79, 83))	('NF-kB-mediated secretion of CXCL1', 'MPA', (40, 73))	('mouse', 'Species', '10090', (84, 89))	('CFTR', 'Gene', (155, 159))	('increases', 'PosReg', (30, 39))	('liver disease', 'Phenotype', 'HP:0001392', (168, 181))
187566	30518128	In particular, NO-dependent activation of iNOS may also promote antiapoptotic mechanisms by interfering with Notch signaling.	('iNOS', 'Gene', '4843', (42, 46))	('iNOS', 'Gene', (42, 46))	('Notch signaling', 'MPA', (109, 124))	('interfering', 'NegReg', (92, 103))	('promote', 'PosReg', (56, 63))	('antiapoptotic mechanisms', 'MPA', (64, 88))	('NO-dependent activation', 'Var', (15, 38))
187579	30518128	For example, Mdr2 knockout (Mdr2-/-) mice were obtained by genetically disrupting the Mdr2 (Abcb4) gene, which is a mouse orthologue of human MDR3 (ABCB4), encoding for a canalicular flippase expressed by hepatocytes, mediating the transport of biliary phospholipids into the outer leaflet of the canalicular cell membrane, which enables their subsequent secretion into the bile.	('human', 'Species', '9606', (136, 141))	('ABCB4', 'Gene', (148, 153))	('mouse', 'Species', '10090', (116, 121))	('MDR3', 'Gene', '5244', (142, 146))	('Abcb4', 'Gene', (92, 97))	('phospholipids', 'Chemical', 'MESH:D010743', (253, 266))	('Abcb4', 'Gene', '18670', (92, 97))	('MDR3', 'Gene', (142, 146))	('ABCB4', 'Gene', '5244', (148, 153))	('secretion into the bile', 'MPA', (355, 378))	('disrupting', 'Var', (71, 81))	('mice', 'Species', '10090', (37, 41))
187580	30518128	Inactivation of the Mdr2 gene in mice produces periductular onion-skin type fibrotic lesions and pronounced ductular reaction, liver fibrosis, early-onset severe portal hypertension, and increased transcripts of Col1a1.	('hypertension', 'Disease', (169, 181))	('portal hypertension', 'Phenotype', 'HP:0001409', (162, 181))	('liver fibrosis', 'Phenotype', 'HP:0001395', (127, 141))	('Col1a1', 'Gene', (212, 218))	('hypertension', 'Phenotype', 'HP:0000822', (169, 181))	('liver fibrosis', 'Disease', 'MESH:D008103', (127, 141))	('Mdr2', 'Gene', (20, 24))	('onion-skin type fibrotic lesions', 'Disease', 'MESH:D012871', (60, 92))	('liver fibrosis', 'Disease', (127, 141))	('transcripts', 'MPA', (197, 208))	('increased', 'PosReg', (187, 196))	('mice', 'Species', '10090', (33, 37))	('hypertension', 'Disease', 'MESH:D006973', (169, 181))	('ductular reaction', 'CPA', (108, 125))	('Inactivation', 'Var', (0, 12))	('onion-skin type fibrotic lesions', 'Disease', (60, 92))
187582	30518128	Another genetically induced PSC-like model is the cystic fibrosis transmembrane conductance regulator knockout (Cftr-/-) mouse, which harbors a mutation of exon 10 of the Cftr gene.	('Cftr', 'Gene', (112, 116))	('Cftr-/-)', 'Gene', '1080', (112, 120))	('Cftr', 'Gene', (171, 175))	('PSC', 'Gene', '100653366', (28, 31))	('mouse', 'Species', '10090', (121, 126))	('Cftr', 'Gene', '12638', (112, 116))	('Cftr', 'Gene', '12638', (171, 175))	('PSC', 'Gene', (28, 31))	('mutation of exon', 'Var', (144, 160))	('cystic fibrosis transmembrane conductance regulator', 'Gene', '12638', (50, 101))	('Cftr-/-', 'Gene', (112, 119))
187587	30518128	It was proposed that, in PSC, neoplastic transformation was associated to mutations of the tumor suppressor p53, and of the oncogene KRAS.	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('PSC', 'Gene', '100653366', (25, 28))	('mutations', 'Var', (74, 83))	('PSC', 'Gene', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('KRAS', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('neoplastic transformation', 'CPA', (30, 55))	('KRAS', 'Gene', '3845', (133, 137))	('tumor', 'Disease', (91, 96))	('associated', 'Reg', (60, 70))
187590	30518128	CD is a genetic cholangiopathy caused by mutations in polycystic kidney and hepatic disease 1 (PKHD1), the gene coding for fibrocystin/polyductin (FPC), a large protein with a single transmembrane domain expressed by cilia and centromers of cholangiocytes and renal epithelial cells.	('mutations', 'Var', (41, 50))	('caused', 'Reg', (31, 37))	('PKHD1', 'Gene', (95, 100))	('polyductin', 'Gene', '5314', (135, 145))	('polycystic kidney and hepatic disease 1', 'Gene', '5314', (54, 93))	('hepatic disease', 'Phenotype', 'HP:0001392', (76, 91))	('genetic cholangiopathy', 'Disease', 'MESH:D030342', (8, 30))	('fibrocystin', 'Gene', (123, 134))	('genetic cholangiopathy', 'Disease', (8, 30))	('polycystic kidney', 'Phenotype', 'HP:0000113', (54, 71))	('fibrocystin', 'Gene', '5314', (123, 134))	('PKHD1', 'Gene', '5314', (95, 100))	('polyductin', 'Gene', (135, 145))
187596	30518128	Notably, recent findings suggest that the aberrant activation of beta-catenin in FPC-defective epithelial cells causes a chronic, low-grade inflammatory response named "parainflammation", a process of adaptation to an unresolving cell dysfunction or noxious conditions.	('causes', 'Reg', (112, 118))	('inflammation', 'Disease', 'MESH:D007249', (173, 185))	('inflammation', 'Disease', (173, 185))	('aberrant', 'Var', (42, 50))	('cell dysfunction', 'Disease', 'MESH:C538614', (230, 246))	('cell dysfunction', 'Disease', (230, 246))	('FPC-defective', 'Disease', (81, 94))	('beta-catenin', 'Protein', (65, 77))	('activation', 'PosReg', (51, 61))
187599	30518128	This goal could be achieved by means of the Pkhd1del4/del4 mouse, a well-established model of CD obtained with a targeting construct designed to inactivate Pkhd1 gene by disrupting exon 4 in mice with a C57BL6/129 mixed background.	('exon 4', 'Protein', (181, 187))	('mouse', 'Species', '10090', (59, 64))	('mice', 'Species', '10090', (191, 195))	('Pkhd1', 'Gene', (156, 161))	('Pkhd1', 'Gene', '241035', (156, 161))	('inactivate', 'NegReg', (145, 155))	('disrupting', 'Var', (170, 180))	('Pkhd1', 'Gene', (44, 49))	('Pkhd1', 'Gene', '241035', (44, 49))
187601	30518128	Another important model is the Pkhd1del2/del2 mouse, obtained deleting Exon 2 of the Pkhd1 gene and replacing it with a neomycin resistance cassette flanked by loxP sites, which could be subsequently removed by Cre-lox recombinase.	('Pkhd1', 'Gene', '241035', (85, 90))	('neomycin', 'Chemical', 'MESH:D009355', (120, 128))	('Pkhd1', 'Gene', (31, 36))	('Pkhd1', 'Gene', '241035', (31, 36))	('mouse', 'Species', '10090', (46, 51))	('deleting', 'Var', (62, 70))	('Pkhd1', 'Gene', (85, 90))	('replacing', 'Reg', (100, 109))
187607	30518128	As for others risk factors, the malignant transformation of cholangiocyte in CD conditions arises in a background of chronic inflammation, in which the high amount of cytokines and factors secreted as a result of the aberrant activation of beta-catenin in FPC-defective cholangiocytes, triggers and maintains the process of cholangiocarcinogenesis.	('inflammation', 'Disease', 'MESH:D007249', (125, 137))	('inflammation', 'Disease', (125, 137))	('carcinogenesis', 'Disease', 'MESH:D063646', (333, 347))	('aberrant', 'Var', (217, 225))	('carcinogenesis', 'Disease', (333, 347))	('activation', 'PosReg', (226, 236))	('beta-catenin', 'Protein', (240, 252))
187613	30518128	Thus, the above described rodent models of fibropolycystic liver disease (Pkhd1del2/del2, Pkhd1del4/del4, and PCK,) or PSC (Mdr2-/-, and Cftr-/-), could be successfully employed to evaluate if their mutations enable CCA carcinogenesis after toxic insults, for example following chronic oral administration of TAA.	('PCK', 'Phenotype', 'HP:0000113', (110, 113))	('PSC', 'Gene', (119, 122))	('Cftr-/-)', 'Gene', '1080', (137, 145))	('CCA', 'Phenotype', 'HP:0030153', (216, 219))	('Pkhd1', 'Gene', (90, 95))	('Pkhd1', 'Gene', '241035', (90, 95))	('PSC', 'Gene', '100653366', (119, 122))	('Pkhd1', 'Gene', (74, 79))	('fibropolycystic liver disease', 'Disease', (43, 72))	('enable', 'Reg', (209, 215))	('carcinogenesis', 'Disease', 'MESH:D063646', (220, 234))	('mutations', 'Var', (199, 208))	('fibropolycystic liver disease', 'Disease', 'MESH:D008107', (43, 72))	('carcinogenesis', 'Disease', (220, 234))	('Pkhd1', 'Gene', '241035', (74, 79))	('liver disease', 'Phenotype', 'HP:0001392', (59, 72))	('Cftr-/-', 'Gene', (137, 144))	('rat', 'Species', '10116', (299, 302))
187616	26765459	Double hit BAP1 inactivation has been reported in a range of tumor types, including intrahepatic cholangiocarcinoma (ICC), sometimes in association with germline mutation.	('BAP1', 'Gene', '8314', (11, 15))	('reported', 'Reg', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('inactivation', 'Var', (16, 28))	('BAP1', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('intrahepatic cholangiocarcinoma', 'Disease', (84, 115))	('tumor', 'Disease', (61, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))
187627	26765459	That is, germline BAP1 mutation is associated with a newly recognized autosomal-dominant hereditary cancer syndrome, (OMIM #6143), characterized by uveal melanoma, mesothelioma, cutaneous melanocytic lesions, renal cell carcinoma, basal cell carcinoma, and intrahepatic cholangiocarcinoma (ICC); while biallelic inactivations including somatic mutations or deletions have also been reported in a range of tumors including uveal melanoma, mesothelioma, cutaneous melanocytic neoplasms, and clear cell renal carcinoma.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (209, 229))	('mesothelioma', 'Disease', (164, 176))	('uveal melanoma', 'Disease', 'MESH:C536494', (148, 162))	('autosomal-dominant hereditary cancer syndrome', 'Disease', (70, 115))	('BAP1', 'Gene', (18, 22))	('uveal melanoma', 'Disease', (148, 162))	('basal cell carcinoma', 'Disease', (231, 251))	('mesothelioma', 'Disease', 'MESH:D008654', (164, 176))	('clear cell renal carcinoma', 'Disease', (489, 515))	('germline', 'Var', (9, 17))	('cutaneous melanocytic lesions', 'Disease', 'MESH:D009508', (178, 207))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (462, 483))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (257, 288))	('tumors', 'Disease', 'MESH:D009369', (405, 411))	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('uveal melanoma', 'Phenotype', 'HP:0007716', (148, 162))	('intrahepatic cholangiocarcinoma', 'Disease', (257, 288))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (489, 515))	('melanoma', 'Phenotype', 'HP:0002861', (428, 436))	('cutaneous melanocytic neoplasms', 'Disease', (452, 483))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('mesothelioma', 'Disease', (438, 450))	('renal cell carcinoma', 'Disease', (209, 229))	('uveal melanoma', 'Disease', 'MESH:C536494', (422, 436))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (209, 229))	('uveal melanoma', 'Disease', (422, 436))	('carcinoma', 'Phenotype', 'HP:0030731', (506, 515))	('mesothelioma', 'Disease', 'MESH:D008654', (438, 450))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (270, 288))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (231, 251))	('autosomal-dominant hereditary cancer syndrome', 'Disease', 'MESH:D009386', (70, 115))	('cutaneous melanocytic neoplasms', 'Disease', 'MESH:D009508', (452, 483))	('tumors', 'Phenotype', 'HP:0002664', (405, 411))	('uveal melanoma', 'Phenotype', 'HP:0007716', (422, 436))	('BAP1', 'Gene', '8314', (18, 22))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (489, 515))	('mutation', 'Var', (23, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('associated', 'Reg', (35, 45))	('deletions', 'Var', (357, 366))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('renal carcinoma', 'Phenotype', 'HP:0005584', (500, 515))	('cutaneous melanocytic lesions', 'Disease', (178, 207))	('neoplasms', 'Phenotype', 'HP:0002664', (474, 483))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (231, 251))	('tumor', 'Phenotype', 'HP:0002664', (405, 410))	('tumors', 'Disease', (405, 411))
187634	26765459	It has recently been suggested that germline BAP1 mutations predispose to intrahepatic cholangiocarcinoma and somatic biallelic inactivating BAP1 mutations have been reported in up to 25% of intrahepatic cholangiocarcinomas (ICC).	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (204, 222))	('intrahepatic cholangiocarcinomas', 'Disease', (191, 223))	('mutations', 'Var', (146, 155))	('BAP1', 'Gene', (45, 49))	('BAP1', 'Gene', '8314', (141, 145))	('mutations', 'Var', (50, 59))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (191, 223))	('reported', 'Reg', (166, 174))	('BAP1', 'Gene', (141, 145))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (191, 222))	('predispose', 'Reg', (60, 70))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('biallelic inactivating', 'Var', (118, 140))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (74, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('BAP1', 'Gene', '8314', (45, 49))	('intrahepatic cholangiocarcinoma', 'Disease', (74, 105))
187666	26765459	Although our study was not intended or designed to assess the sensitivity and specificity of BAP1 IHC for BAP1 mutation, our incidence of negative staining for BAP1 is very similar to the rate of inactivating mutations reported by Jiao et al (25%) and Chan-On et al (22.2%), suggesting that loss of IHC staining for BAP1 is likely to correlate strongly with BAP1 mutation in ICC as it has been proven to do in mesothelioma and uveal melanoma.	('BAP1', 'Gene', '8314', (93, 97))	('BAP1', 'Gene', '8314', (358, 362))	('BAP1', 'Gene', (106, 110))	('mutation', 'Var', (363, 371))	('melanoma', 'Phenotype', 'HP:0002861', (433, 441))	('BAP1', 'Gene', '8314', (316, 320))	('BAP1', 'Gene', '8314', (160, 164))	('BAP1', 'Gene', (358, 362))	('uveal melanoma', 'Phenotype', 'HP:0007716', (427, 441))	('BAP1', 'Gene', '8314', (106, 110))	('BAP1', 'Gene', (93, 97))	('BAP1', 'Gene', (316, 320))	('BAP1', 'Gene', (160, 164))	('mesothelioma and uveal melanoma', 'Disease', 'MESH:C536494', (410, 441))
187672	26765459	Presumably this indicates that pathways other than those associated with BAP1 mutation are more lethal in mesothelioma but less lethal that BAP1 associated pathways in uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (168, 182))	('BAP1', 'Gene', '8314', (73, 77))	('mutation', 'Var', (78, 86))	('mesothelioma', 'Disease', (106, 118))	('BAP1', 'Gene', (140, 144))	('BAP1', 'Gene', (73, 77))	('mesothelioma', 'Disease', 'MESH:D008654', (106, 118))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('BAP1', 'Gene', '8314', (140, 144))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('uveal melanoma', 'Disease', (168, 182))
187681	26765459	It has been suggested that ICC may be a component of the hereditary cancer syndrome associated with germline BAP1 mutations.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutations', 'Var', (114, 123))	('BAP1', 'Gene', '8314', (109, 113))	('component of the hereditary cancer syndrome', 'Disease', (40, 83))	('associated', 'Reg', (84, 94))	('BAP1', 'Gene', (109, 113))	('ICC', 'Disease', (27, 30))	('component of the hereditary cancer syndrome', 'Disease', 'MESH:D009386', (40, 83))
187682	26765459	Therefore, it is possible that IHC for BAP1 may play a role in triaging formal genetic testing for germline BAP1 mutation in patients presenting with cholangiocarcinoma.	('patients', 'Species', '9606', (125, 133))	('mutation', 'Var', (113, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('BAP1', 'Gene', '8314', (108, 112))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (150, 168))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (150, 168))	('BAP1', 'Gene', (108, 112))	('BAP1', 'Gene', '8314', (39, 43))	('cholangiocarcinoma', 'Disease', (150, 168))	('BAP1', 'Gene', (39, 43))
187683	26765459	That is, if a tumor shows positive staining for BAP1 then germline BAP1 mutation can be considered unlikely, whereas if a tumor shows negative staining for BAP1 then BAP1 mutation is not excluded and formal counselling and genetic testing may be warranted in patients considered at high risk for hereditary disease for example due to onset at a young age or a family history of BAP1-associated malignancy such as mesothelioma, uveal melanoma, or cholangiocarcinoma.	('BAP1', 'Gene', '8314', (48, 52))	('BAP1', 'Gene', '8314', (166, 170))	('uveal melanoma', 'Phenotype', 'HP:0007716', (427, 441))	('tumor', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('malignancy', 'Disease', 'MESH:D009369', (394, 404))	('patients', 'Species', '9606', (259, 267))	('BAP1', 'Gene', '8314', (156, 160))	('BAP1', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mesothelioma', 'Disease', (413, 425))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (446, 464))	('BAP1', 'Gene', (166, 170))	('mesothelioma', 'Disease', 'MESH:D008654', (413, 425))	('BAP1', 'Gene', '8314', (378, 382))	('malignancy', 'Disease', (394, 404))	('hereditary disease', 'Disease', (296, 314))	('cholangiocarcinoma', 'Disease', (446, 464))	('hereditary disease', 'Disease', 'MESH:D030342', (296, 314))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (446, 464))	('BAP1', 'Gene', '8314', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mutation', 'Var', (72, 80))	('BAP1', 'Gene', (156, 160))	('melanoma', 'Phenotype', 'HP:0002861', (433, 441))	('tumor', 'Disease', (14, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (455, 464))	('BAP1', 'Gene', (378, 382))	('uveal melanoma', 'Disease', 'MESH:C536494', (427, 441))	('uveal melanoma', 'Disease', (427, 441))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('BAP1', 'Gene', (67, 71))
187684	26765459	The incidence of germline BAP1 mutations in cholangiocarcinoma is not currently known; however, the incidence of germline BAP1 mutations in malignancies such as mesothelioma and metastasising uveal melanoma has been estimated at 1 to 2% or less.	('BAP1', 'Gene', (26, 30))	('malignancies', 'Disease', 'MESH:D009369', (140, 152))	('uveal melanoma', 'Disease', (192, 206))	('BAP1', 'Gene', (122, 126))	('mesothelioma', 'Disease', (161, 173))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (44, 62))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (44, 62))	('malignancies', 'Disease', (140, 152))	('mesothelioma', 'Disease', 'MESH:D008654', (161, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('BAP1', 'Gene', '8314', (122, 126))	('BAP1', 'Gene', '8314', (26, 30))	('mutations', 'Var', (127, 136))	('cholangiocarcinoma', 'Disease', (44, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (192, 206))	('uveal melanoma', 'Phenotype', 'HP:0007716', (192, 206))
187685	26765459	It is likely that the rate of germline BAP1 mutations to be lower in cholangiocarcinoma than that found in mesothelioma and uveal melanoma, given that somatic mutations resulting in BAP1 loss occur in approximately half of mesotheliomas and in up to 84% of uveal melanomas, which is higher than the rate of BAP1 loss so far reported in cholangiocarcinoma.	('loss', 'NegReg', (187, 191))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (336, 354))	('melanoma', 'Phenotype', 'HP:0002861', (263, 271))	('cholangiocarcinoma', 'Disease', (69, 87))	('BAP1', 'Gene', '8314', (39, 43))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (69, 87))	('cholangiocarcinoma', 'Disease', (336, 354))	('uveal melanomas', 'Disease', 'MESH:C536494', (257, 272))	('lower', 'NegReg', (60, 65))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (336, 354))	('BAP1', 'Gene', '8314', (182, 186))	('uveal melanoma', 'Phenotype', 'HP:0007716', (124, 138))	('mesothelioma and uveal melanoma', 'Disease', 'MESH:C536494', (107, 138))	('BAP1', 'Gene', '8314', (307, 311))	('mesotheliomas', 'Disease', (223, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('BAP1', 'Gene', (39, 43))	('uveal melanoma', 'Phenotype', 'HP:0007716', (257, 271))	('mesotheliomas', 'Disease', 'MESH:D008654', (223, 236))	('BAP1', 'Gene', (182, 186))	('uveal melanomas', 'Disease', (257, 272))	('uveal melanomas', 'Phenotype', 'HP:0007716', (257, 272))	('BAP1', 'Gene', (307, 311))	('melanomas', 'Phenotype', 'HP:0002861', (263, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (345, 354))	('mutations', 'Var', (44, 53))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (69, 87))
187686	26765459	Given that real rate of germline BAP1 mutations is likely to be less than 1%, it is reasonable that formal genetic testing for BAP1 mutation be reserved for those patients who are considered high-risk based on family and personal history and demonstrate loss of BAP1 expression by IHC.	('loss', 'NegReg', (254, 258))	('BAP1', 'Gene', '8314', (262, 266))	('BAP1', 'Gene', (127, 131))	('patients', 'Species', '9606', (163, 171))	('BAP1', 'Gene', (262, 266))	('BAP1', 'Gene', '8314', (33, 37))	('BAP1', 'Gene', (33, 37))	('BAP1', 'Gene', '8314', (127, 131))	('mutation', 'Var', (132, 140))	('expression', 'MPA', (267, 277))
187746	22510747	While the mechanism of action for this anabolic reaction for selumetinib remains unproven, it seems likely that the observed increase in muscle is related to inhibition of cytokine secretion, as inhibition of MEK1/2 would be expected to actually inhibit muscle growth.	('MEK1/2', 'Gene', (209, 215))	('inhibit', 'NegReg', (246, 253))	('muscle growth', 'CPA', (254, 267))	('MEK1/2', 'Gene', '5604;5605', (209, 215))	('muscle', 'MPA', (137, 143))	('increase', 'PosReg', (125, 133))	('inhibition', 'Var', (195, 205))	('cytokine secretion', 'MPA', (172, 190))	('selumetinib', 'Chemical', 'MESH:C517975', (61, 72))	('inhibition', 'NegReg', (158, 168))
187756	22510747	A potential survival benefit of cachexia therapy was raised by the study of, who showed that blocking muscle wasting by antagonism of the action of myostatin can have significant beneficial effects on survival in an animal model of cachexia.	('cachexia', 'Phenotype', 'HP:0004326', (232, 240))	('cachexia', 'Disease', 'MESH:D002100', (32, 40))	('muscle', 'Disease', (102, 108))	('antagonism', 'Var', (120, 130))	('cachexia', 'Disease', (32, 40))	('muscle wasting', 'Phenotype', 'HP:0003202', (102, 116))	('cachexia', 'Disease', (232, 240))	('cachexia', 'Disease', 'MESH:D002100', (232, 240))	('survival', 'CPA', (201, 209))	('cachexia', 'Phenotype', 'HP:0004326', (32, 40))	('beneficial effects', 'PosReg', (179, 197))
187866	33663535	It is postulated that dysregulated NUP85 functions may lead to tissue homeostasis imbalance.	('imbalance', 'Phenotype', 'HP:0002172', (82, 91))	('NUP85', 'Gene', '79902', (35, 40))	('dysregulated', 'Var', (22, 34))	('NUP85', 'Gene', (35, 40))	('lead to', 'Reg', (55, 62))	('tissue homeostasis imbalance', 'MPA', (63, 91))
187868	33663535	It has been reported that targeting NUP85 in pancreatic cancer cells inhibits their invasiveness and metastasis.	('targeting', 'Var', (26, 35))	('pancreatic cancer', 'Disease', (45, 62))	('pancreatic cancer', 'Disease', 'MESH:D010190', (45, 62))	('NUP85', 'Gene', (36, 41))	('inhibits', 'NegReg', (69, 77))	('NUP85', 'Gene', '79902', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (45, 62))
187870	33663535	Abnormal GDP1 expression may exert adverse effects on human health.	('expression', 'MPA', (14, 24))	('GDP1', 'Gene', (9, 13))	('Abnormal', 'Var', (0, 8))	('human', 'Species', '9606', (54, 59))
187873	33663535	As a central component of lipid metabolism and synthesis, abnormal GDP1 activity can induce multiple digestive system diseases.	('GDP1', 'Gene', (67, 71))	('component of lipid metabolism', 'Disease', (13, 42))	('component of lipid metabolism', 'Disease', 'MESH:D052439', (13, 42))	('abnormal', 'Var', (58, 66))	('activity', 'MPA', (72, 80))	('multiple digestive system diseases', 'Disease', (92, 126))	('digestive system diseases', 'Phenotype', 'HP:0011024', (101, 126))	('induce', 'Reg', (85, 91))
187890	33663535	In recent years, studies have reported that non-coding RNA plays an important role in the initiation and progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (120, 126))	('non-coding RNA', 'Var', (44, 58))
187962	32440145	Histamine deficiency promoted inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+ immature myeloid cells.	('rat', 'Species', '10116', (97, 100))	('accumulation', 'PosReg', (108, 120))	('myeloid maturation', 'CPA', (85, 103))	('CD11b', 'Gene', (124, 129))	('Histamine', 'Chemical', 'MESH:D006632', (0, 9))	('promoted', 'PosReg', (21, 29))	('CD11b', 'Gene', '3684', (124, 129))	('inflammation', 'Disease', 'MESH:D007249', (30, 42))	('reduced', 'NegReg', (77, 84))	('deficiency', 'Var', (10, 20))	('Histamine', 'Gene', (0, 9))	('inflammation', 'Disease', (30, 42))
187967	32440145	Meng et al reported that activation of HRH4 suppressed human cholangiocarcinoma progression by disruption of epithelial mesenchymal transition and tumor metastasis.	('suppressed', 'NegReg', (44, 54))	('HRH4', 'Gene', '59340', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (61, 79))	('tumor metastasis', 'Disease', 'MESH:D009362', (147, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('activation', 'Var', (25, 35))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (61, 79))	('HRH4', 'Gene', (39, 43))	('disruption', 'NegReg', (95, 105))	('tumor metastasis', 'Disease', (147, 163))	('human', 'Species', '9606', (55, 60))	('epithelial mesenchymal transition', 'CPA', (109, 142))	('cholangiocarcinoma', 'Disease', (61, 79))
188006	32440145	Moreover, we analyzed the relationship between the HRH3 expression level and the pathological characteristic of patients with HCC (Table S3) and found that HRH3 expression level in patients with low differentiation HCC was remarkably higher than that in patients with high and medium differentiation HCC (P = 0.008).	('HCC', 'Phenotype', 'HP:0001402', (300, 303))	('HRH3 expression level', 'MPA', (156, 177))	('HCC', 'Phenotype', 'HP:0001402', (215, 218))	('patients', 'Species', '9606', (112, 120))	('patients', 'Species', '9606', (181, 189))	('low', 'Var', (195, 198))	('higher', 'PosReg', (234, 240))	('HCC', 'Phenotype', 'HP:0001402', (126, 129))	('patients', 'Species', '9606', (254, 262))
188007	32440145	Kaplan-Meier survival analysis revealed that HCC patients with high HRH3 expression had significantly shorter overall survival when compared with those in HCC patients with low HRH3 expression (Figure 1D).	('shorter', 'NegReg', (102, 109))	('overall survival', 'MPA', (110, 126))	('HCC', 'Phenotype', 'HP:0001402', (45, 48))	('HRH3', 'Gene', (68, 72))	('high', 'Var', (63, 67))	('patients', 'Species', '9606', (49, 57))	('patients', 'Species', '9606', (159, 167))	('HCC', 'Phenotype', 'HP:0001402', (155, 158))
188009	32440145	MTS assay showed that HRH3 knockdown in HepG2 and PLC/PRF/5 cells significantly reduced cell growth in comparison with the control (Figure 2B).	('knockdown', 'Var', (27, 36))	('reduced', 'NegReg', (80, 87))	('cell growth', 'CPA', (88, 99))	('HepG2', 'CellLine', 'CVCL:0027', (40, 45))	('HRH3', 'Gene', (22, 26))
188010	32440145	As supported, EdU incorporation assay also demonstrated that knockdown of HRH3 in HepG2 and PLC/PRF/5 cells significantly attenuated cell proliferation activity compared to the control (Figure 2C).	('EdU', 'Chemical', '-', (14, 17))	('rat', 'Species', '10116', (50, 53))	('HepG2', 'CellLine', 'CVCL:0027', (82, 87))	('cell proliferation activity', 'CPA', (133, 160))	('knockdown', 'Var', (61, 70))	('rat', 'Species', '10116', (145, 148))	('HRH3', 'Gene', (74, 78))	('rat', 'Species', '10116', (25, 28))	('attenuated', 'NegReg', (122, 132))
188011	32440145	As shown in Figure 2D and supplementary Figure 1B, knockdown of HRH3 in HepG2 and PLC/PRF/5 cells remarkably induced cell apoptosis compared to the control, whereas forced expression of HRH3 in Huh-7 and BEL-7402 cells dramatically promoted cell growth (Figure 2E and F).	('BEL-7402', 'CellLine', 'CVCL:5492', (204, 212))	('Huh-7', 'Gene', (194, 199))	('promoted', 'PosReg', (232, 240))	('Huh-7', 'Gene', '284424', (194, 199))	('induced', 'Reg', (109, 116))	('cell apoptosis', 'CPA', (117, 131))	('HRH3', 'Gene', (64, 68))	('HepG2', 'CellLine', 'CVCL:0027', (72, 77))	('cell growth', 'CPA', (241, 252))	('knockdown', 'Var', (51, 60))
188014	32440145	As shown in Figure 3A, HRH3 knockdown significantly elevated the percentage of HepG2 and PLC/PRF/5 cells in the G1 phase, but reduced the percentage S phase compared with the control.	('S phase', 'CPA', (149, 156))	('HRH3', 'Gene', (23, 27))	('knockdown', 'Var', (28, 37))	('HepG2', 'CellLine', 'CVCL:0027', (79, 84))	('HepG2', 'CPA', (79, 84))	('reduced', 'NegReg', (126, 133))	('elevated', 'PosReg', (52, 60))
188018	32440145	As shown in Figure 4A, HRH3 knockdown in HepG2 and PLC/PRF/5 cells resulted to a significant upregulated of cAMP content in comparison with the control.	('HepG2', 'CellLine', 'CVCL:0027', (41, 46))	('cAMP content', 'MPA', (108, 120))	('HRH3', 'Gene', (23, 27))	('knockdown', 'Var', (28, 37))	('upregulated', 'PosReg', (93, 104))	('cAMP', 'Chemical', 'MESH:D000242', (108, 112))
188020	32440145	To prove this, we treated HepG2 and PLC/PRF/5 cells with 1 mM SQ22536, a highly inhibitor of adenylyl cyclase, which functioned to inhibit the formation of cAMP for 96 h in cell viability assay and for 48 h in EdU incorporation assay.	('SQ22536', 'Chemical', 'MESH:C017759', (62, 69))	('inhibit', 'NegReg', (131, 138))	('rat', 'Species', '10116', (221, 224))	('formation', 'MPA', (143, 152))	('SQ22536', 'Var', (62, 69))	('HepG2', 'CellLine', 'CVCL:0027', (26, 31))	('EdU', 'Chemical', '-', (210, 213))	('cAMP', 'Chemical', 'MESH:D000242', (156, 160))
188021	32440145	Our results showed that the inhibitory effect of HRH3 depletion on cell growth was effectively reversed upon SQ22536 treatment (Figure 4B and supplementary Figure 2A and 2B), as also supported by EdU incorporation assay (Figure 4C).	('HRH3', 'Gene', (49, 53))	('rat', 'Species', '10116', (207, 210))	('cell growth', 'CPA', (67, 78))	('SQ22536 treatment', 'Var', (109, 126))	('SQ22536', 'Chemical', 'MESH:C017759', (109, 116))	('depletion', 'NegReg', (54, 63))	('EdU', 'Chemical', '-', (196, 199))
188024	32440145	To prove this, we used PKA Activity Assay Kit to investigate the effect of HRH3 knockdown on PKA activity in HepG2 and PLC/PRF/5 cells.	('HepG2', 'CellLine', 'CVCL:0027', (109, 114))	('knockdown', 'Var', (80, 89))	('HRH3', 'Gene', (75, 79))
188025	32440145	As shown in Figure 4D, knockdown of HRH3 dramatically enhanced the PKA activity in HepG2 and PLC/PRF/5 cells relative to the control.	('HRH3', 'Gene', (36, 40))	('knockdown', 'Var', (23, 32))	('PKA', 'Enzyme', (67, 70))	('enhanced', 'PosReg', (54, 62))	('HepG2', 'CellLine', 'CVCL:0027', (83, 88))
188035	32440145	On the other hand, HRH3 knockdown in HepG2 cell significantly increased the level of phosphorylated CREB and the protein expression of CDKN1A, while these effects could be effectively reversed by SQ22536 treatment (Figure 5B).	('increased', 'PosReg', (62, 71))	('CDKN1A', 'Gene', '1026', (135, 141))	('protein expression', 'MPA', (113, 131))	('SQ22536', 'Chemical', 'MESH:C017759', (196, 203))	('HepG2', 'CellLine', 'CVCL:0027', (37, 42))	('CREB', 'Gene', (100, 104))	('CREB', 'Gene', '1385', (100, 104))	('CDKN1A', 'Gene', (135, 141))	('knockdown', 'Var', (24, 33))
188036	32440145	Similarly, H89 treatment also reversed the effects of HRH3 knockdown on upregulating the level of phosphorylated CREB and the expression of PKA in PLC/PRG/5 cells (Figure 5D and E).	('CREB', 'Gene', (113, 117))	('CREB', 'Gene', '1385', (113, 117))	('H89', 'Chemical', 'MESH:C063509', (11, 14))	('PKA', 'Gene', (140, 143))	('upregulating', 'PosReg', (72, 84))	('HRH3', 'Gene', (54, 58))	('knockdown', 'Var', (59, 68))
188038	32440145	Moreover, the inhibitory effect of HRH3 knockdown on G1-S phase transition was clearly reversed by the treatment of CDKN1A knockdown (Figure 5G).	('CDKN1A', 'Gene', (116, 122))	('HRH3', 'Gene', (35, 39))	('CDKN1A', 'Gene', '1026', (116, 122))	('knockdown', 'Var', (40, 49))	('G1-S', 'MPA', (53, 57))
188042	32440145	Conversely, the HRH3-knockdown tumors showed a much slower rate and smaller tumor volumes compared to the control, while this inhibitory effect of HRH3 knockdown on tumor growth could be partially reversed by the treatment of siCDKN1A intratumoral injection (Figure 6A and B).	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', (76, 81))	('slower', 'NegReg', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (240, 245))	('tumors', 'Disease', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('HRH3', 'Gene', (147, 151))	('knockdown', 'Var', (152, 161))	('smaller', 'NegReg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('rat', 'Species', '10116', (59, 62))	('CDKN1A', 'Gene', (228, 234))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumor', 'Disease', (165, 170))	('CDKN1A', 'Gene', '1026', (228, 234))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('rat', 'Species', '10116', (238, 241))
188046	32440145	Moreover, the level of phosphorylated CREB and protein expression of CDKN1A were clearly upregulated in HRH3-knockdown tumors compared to the control tumors, and the effect of HRH3 knockdown on upregulating the expression of CDKN1A was effectively reversed by the treatment of CDKN1A knockdown (Figure 6C).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('HRH3-knockdown', 'Gene', (104, 118))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('upregulating', 'PosReg', (194, 206))	('tumors', 'Disease', (150, 156))	('CDKN1A', 'Gene', (225, 231))	('tumors', 'Disease', (119, 125))	('CDKN1A', 'Gene', '1026', (225, 231))	('HRH3-knockdown', 'Var', (104, 118))	('CREB', 'Gene', (38, 42))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('CDKN1A', 'Gene', (277, 283))	('upregulated', 'PosReg', (89, 100))	('CDKN1A', 'Gene', '1026', (277, 283))	('CREB', 'Gene', '1385', (38, 42))	('protein expression', 'MPA', (47, 65))	('level', 'MPA', (14, 19))	('CDKN1A', 'Gene', (69, 75))	('CDKN1A', 'Gene', '1026', (69, 75))
188068	32440145	Furthermore, inhibition of HRH3 suppressed glioblastoma tumor growth, invasion, and epithelial-to-mesenchymal transition.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (43, 61))	('inhibition', 'Var', (13, 23))	('glioblastoma', 'Phenotype', 'HP:0012174', (43, 55))	('epithelial-to-mesenchymal transition', 'CPA', (84, 120))	('glioblastoma tumor', 'Disease', (43, 61))	('HRH3', 'Gene', (27, 31))	('invasion', 'CPA', (70, 78))	('suppressed', 'NegReg', (32, 42))
188073	32440145	In contrast, Francis et al reported that HRH3 inhibited the growth of cholangiocarcinoma in vitro and in vivo.	('growth', 'MPA', (60, 66))	('cholangiocarcinoma', 'Disease', (70, 88))	('HRH3', 'Var', (41, 45))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (70, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('inhibited', 'NegReg', (46, 55))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (70, 88))
188167	31814823	In one study, analysis of microdissected BilIN for the KRAS and GNAS mutations and p53 expression of BilIN and cholangiocarcinoma revealed similarities to pancreatic intraepithelial neoplasia.	('GNAS', 'Gene', (64, 68))	('p53', 'Gene', (83, 86))	('pancreatic intraepithelial neoplasia', 'Disease', (155, 191))	('BilIN', 'Disease', 'MESH:D018290', (101, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('GNAS', 'Gene', '2778', (64, 68))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (166, 191))	('pancreatic intraepithelial neoplasia', 'Disease', 'MESH:D018290', (155, 191))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))	('mutations', 'Var', (69, 78))	('cholangiocarcinoma', 'Disease', (111, 129))	('KRAS', 'Gene', '3845', (55, 59))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 129))	('BilIN', 'Disease', (41, 46))	('KRAS', 'Gene', (55, 59))	('p53', 'Gene', '7157', (83, 86))	('neoplasia', 'Phenotype', 'HP:0002664', (182, 191))	('BilIN', 'Disease', 'MESH:D018290', (41, 46))	('BilIN', 'Disease', (101, 106))
188168	31814823	Existing KRAS mutations were observed in early BilIN-1 lesions (25%), increasing slightly during progression to BilIN-3 (30%).	('BilIN', 'Disease', (112, 117))	('BilIN', 'Disease', 'MESH:D018290', (47, 52))	('BilIN', 'Disease', (47, 52))	('KRAS', 'Gene', (9, 13))	('KRAS', 'Gene', '3845', (9, 13))	('mutations', 'Var', (14, 23))	('BilIN', 'Disease', 'MESH:D018290', (112, 117))
188191	31814823	The progression of dysplasia is accompanied by the accumulation of genetic alterations.	('dysplasia', 'Disease', (19, 28))	('genetic alterations', 'Var', (67, 86))	('dysplasia', 'Disease', 'MESH:D015792', (19, 28))
188193	31814823	Surprisingly, GNAS mutations, which are linked to the molecular pathogenesis of pancreatic IPMN, seem to be much less important.	('IPMN', 'Disease', 'MESH:D002285', (91, 95))	('GNAS', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('IPMN', 'Disease', (91, 95))	('GNAS', 'Gene', '2778', (14, 18))
188299	31348232	The pathogenesis of MPM remains unclear, but several risk factors of the disease have been identified, including hereditary elements, immune deficiency and immune escape of cancer cells, accumulation of genetic mutations and abnormal gene expression, and administration of radiotherapy, chemotherapy, and some drugs.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('immune escape', 'CPA', (156, 169))	('immune deficiency', 'Phenotype', 'HP:0002721', (134, 151))	('immune deficiency', 'Disease', (134, 151))	('immune deficiency', 'Disease', 'MESH:D007153', (134, 151))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('MPM', 'Disease', (20, 23))	('genetic mutations', 'Var', (203, 220))	('MPM', 'Disease', 'MESH:D009378', (20, 23))	('abnormal gene expression', 'Var', (225, 249))
188302	31348232	In addition, precancerous lesions are highly likely to progress to malignancies due to accumulation of genetic changes.	('malignancies', 'Disease', (67, 79))	('precancerous lesions', 'Disease', 'MESH:D011230', (13, 33))	('genetic changes', 'Var', (103, 118))	('progress', 'PosReg', (55, 63))	('precancerous lesions', 'Disease', (13, 33))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('malignancies', 'Disease', 'MESH:D009369', (67, 79))
188337	31360102	Besides, high-expression of ARK5 is also associated with poor prognosis.	('ARK5', 'Gene', (28, 32))	('high-expression', 'Var', (9, 24))	('ARK5', 'Gene', '9891', (28, 32))
188368	31360102	The antibodies used of immunofluorescence: beta-catenin (8480, CST, 1:200), N-cadherin (13116, CST, 1:200), E-cadherin (3195, CST, 1:200).	('E-cadherin', 'Gene', (108, 118))	('E-cadherin', 'Gene', '999', (108, 118))	('CST', 'Gene', '106478911', (63, 66))	('CST', 'Gene', (126, 129))	('CST', 'Gene', (63, 66))	('N-cadherin', 'Gene', (76, 86))	('8480', 'Var', (57, 61))	('CST', 'Gene', '106478911', (95, 98))	('13116', 'Var', (88, 93))	('beta-catenin', 'Gene', (43, 55))	('CST', 'Gene', '106478911', (126, 129))	('N-cadherin', 'Gene', '1000', (76, 86))	('CST', 'Gene', (95, 98))	('beta-catenin', 'Gene', '1499', (43, 55))
188369	31360102	The antibody used for immunohistochemistry: anti-ARK5 (22723-1-AP, Proteintech, 1:200).	('ARK5', 'Gene', '9891', (49, 53))	('22723-1-AP', 'Var', (55, 65))	('ARK5', 'Gene', (49, 53))
188387	31360102	As a result, none of CCLP-1, RBE and HuCCT-1 cell viability was inhibited by miR-424-5p mimics transfecting in CCK-8 assay, compared to the negative-control (Figure 2 G and Supplementary Figure 3).	('HuCCT-1', 'Gene', (37, 44))	('CCLP-1', 'Gene', '8495', (21, 27))	('inhibited', 'NegReg', (64, 73))	('5p', 'Chemical', '-', (85, 87))	('miR-424', 'Gene', (77, 84))	('transfecting', 'Var', (95, 107))	('miR-424', 'Gene', '494336', (77, 84))	('CCLP-1', 'Gene', (21, 27))
188404	31360102	In transwell assays, knockdown ARK5 significantly decreased the motility of HuCCT1 cells and RBE cells comparing with negative control (Figure 5A), while over-expressing ARK5 leads to an opposite result (Figure 5B).	('ARK5', 'Gene', '9891', (31, 35))	('ARK5', 'Gene', '9891', (170, 174))	('ARK5', 'Gene', (31, 35))	('decreased', 'NegReg', (50, 59))	('ARK5', 'Gene', (170, 174))	('knockdown', 'Var', (21, 30))	('HuCCT1', 'CellLine', 'CVCL:0324', (76, 82))
188406	31360102	In cell immunofluorescence assay, knockdown ARK5 deregulated the expression of N-cadherin in HuCCT1 cells and RBE cells, while up-regulating E-cadherin expression (Figure 5D&E).	('E-cadherin', 'Gene', '999', (141, 151))	('deregulated', 'NegReg', (49, 60))	('HuCCT1', 'CellLine', 'CVCL:0324', (93, 99))	('N-cadherin', 'Gene', (79, 89))	('N-cadherin', 'Gene', '1000', (79, 89))	('expression', 'MPA', (65, 75))	('ARK5', 'Gene', '9891', (44, 48))	('knockdown', 'Var', (34, 43))	('up-regulating', 'PosReg', (127, 140))	('expression', 'MPA', (152, 162))	('ARK5', 'Gene', (44, 48))	('E-cadherin', 'Gene', (141, 151))
188407	31360102	What's more, western blot assays show the same results of N-cadherin decreasing and E-cadherin increasing (Figure 5F) in ARK5 knockdown.	('E-cadherin', 'Gene', (84, 94))	('E-cadherin', 'Gene', '999', (84, 94))	('increasing', 'PosReg', (95, 105))	('ARK5', 'Gene', '9891', (121, 125))	('N-cadherin', 'Gene', (58, 68))	('N-cadherin', 'Gene', '1000', (58, 68))	('decreasing', 'NegReg', (69, 79))	('ARK5', 'Gene', (121, 125))	('knockdown', 'Var', (126, 135))
188437	31360102	Besides, it is reported that AMPK inhibits the mTORC1 pathway that controls anabolic cell growth.	('anabolic cell growth', 'MPA', (76, 96))	('inhibits', 'NegReg', (34, 42))	('mTORC1', 'Gene', (47, 53))	('AMPK', 'Var', (29, 33))	('mTORC1', 'Gene', '382056', (47, 53))
188471	28178675	Thus, it is suggested that dysregulation of MRN complex-induced DNA repair contributes to gemcitabine resistance.	('contributes', 'Reg', (75, 86))	('MRN complex-induced', 'Protein', (44, 63))	('gemcitabine', 'Chemical', 'MESH:C056507', (90, 101))	('gemcitabine resistance', 'MPA', (90, 112))	('dysregulation', 'Var', (27, 40))
188474	28178675	It has been demonstrated that knockout of any component of the MRN complex causes early embryonic lethality in mice.	('embryonic lethality', 'Disease', 'MESH:D020964', (88, 107))	('embryonic lethality', 'Disease', (88, 107))	('causes', 'Reg', (75, 81))	('knockout', 'Var', (30, 38))	('mice', 'Species', '10090', (111, 115))
188479	28178675	Our previous studies identified that high KPNA2 expression was correlated with poor prognosis and cancer progression in esophageal squamous cell carcinoma, gastric carcinoma, and colorectal carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (179, 199))	('high', 'Var', (37, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (156, 173))	('esophageal squamous cell carcinoma', 'Disease', (120, 154))	('expression', 'MPA', (48, 58))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('gastric carcinoma', 'Disease', 'MESH:D013274', (156, 173))	('cancer', 'Disease', (98, 104))	('KPNA2', 'Gene', (42, 47))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (120, 154))	('colorectal carcinoma', 'Disease', (179, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('gastric carcinoma', 'Disease', (156, 173))
188491	28178675	There were no significant differences in age, sex, histological type, T factor, tumor size, lymph node metastasis, vascular invasion, perineural invasion, and TNM stage between patients with high and low KPNA2 expression.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('low', 'NegReg', (200, 203))	('KPNA2', 'Gene', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('patients', 'Species', '9606', (177, 185))	('lymph node metastasis', 'CPA', (92, 113))	('tumor', 'Disease', (80, 85))	('high', 'Var', (191, 195))
188492	28178675	Patients with high KPNA2 expression exhibited significantly shorter overall survival than those with low KPNA2 expression (P = 0.001; Figure 2A).	('KPNA2', 'Gene', (19, 24))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (68, 84))	('shorter', 'NegReg', (60, 67))	('expression', 'Var', (25, 35))
188501	28178675	Gemcitabine sensitivity was enhanced in KPNA2 siRNA-treated cells compared with control TFK1 and HuCCT1 cells (Figure 3C).	('Gemcitabine', 'Chemical', 'MESH:C056507', (0, 11))	('HuCCT1', 'CellLine', 'CVCL:0324', (97, 103))	('enhanced', 'PosReg', (28, 36))	('Gemcitabine sensitivity', 'MPA', (0, 23))	('KPNA2 siRNA-treated', 'Var', (40, 59))
188503	28178675	The volume of tumors injected with KPNA2 siRNA significantly decreased compared with that of control tumors (Figure 3D).	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('KPNA2 siRNA', 'Var', (35, 46))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('decreased', 'NegReg', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (101, 107))
188504	28178675	The volume of gemcitabine-treated tumors injected with KPNA2 siRNA significantly decreased, as compared with tumors treated with only gemcitabine (Figure 3D).	('decreased', 'NegReg', (81, 90))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('gemcitabine', 'Chemical', 'MESH:C056507', (14, 25))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('KPNA2 siRNA', 'Var', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('gemcitabine', 'Chemical', 'MESH:C056507', (134, 145))
188507	28178675	On the contrary, tumor growth decreased in mice treated with KPNA2 siRNA.	('mice', 'Species', '10090', (43, 47))	('KPNA2', 'Var', (61, 66))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('decreased', 'NegReg', (30, 39))
188508	28178675	Moreover, tumor growth was further decreased in mice treated with KPNA2 siRNA and gemcitabine compared with that in mice treated with gemcitabine or KPNA2 siRNA only.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mice', 'Species', '10090', (116, 120))	('tumor', 'Disease', (10, 15))	('mice', 'Species', '10090', (48, 52))	('KPNA2 siRNA', 'Var', (66, 77))	('decreased', 'NegReg', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('gemcitabine', 'Chemical', 'MESH:C056507', (134, 145))	('gemcitabine', 'Chemical', 'MESH:C056507', (82, 93))
188512	28178675	In this study, overexpression of nuclear KPNA2 was significantly associated with poor prognosis and chemosensitivity of cholangiocarcinoma.	('overexpression', 'PosReg', (15, 29))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (120, 138))	('nuclear', 'Var', (33, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (120, 138))	('associated', 'Reg', (65, 75))	('KPNA2', 'Gene', (41, 46))	('cholangiocarcinoma', 'Disease', (120, 138))
188517	28178675	Several studies revealed that high KPNA2 expression is associated with cancer progression and poor prognosis, suggesting KPNA2 as a potential prognostic marker.	('KPNA2', 'Gene', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('expression', 'MPA', (41, 51))	('cancer', 'Disease', (71, 77))	('associated', 'Reg', (55, 65))	('high', 'Var', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
188518	28178675	In the current study, nuclear KPNA2 expression exhibited a significant association with poor prognosis in cholangiocarcinoma.	('nuclear', 'Var', (22, 29))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (106, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (106, 124))	('KPNA2', 'Gene', (30, 35))	('cholangiocarcinoma', 'Disease', (106, 124))
188519	28178675	Furthermore, a significant correlation was observed between high KPNA2 expression and shorter overall survival and relapse-free survival in patients with EHCC and IHCC.	('expression', 'MPA', (71, 81))	('overall', 'MPA', (94, 101))	('high', 'Var', (60, 64))	('shorter', 'NegReg', (86, 93))	('IHCC', 'Disease', (163, 167))	('patients', 'Species', '9606', (140, 148))	('KPNA2', 'Gene', (65, 70))	('EHCC', 'Disease', (154, 158))	('relapse-free survival', 'CPA', (115, 136))
188525	28178675	These transcription factors may be involved in the molecular mechanism underlying reduced proliferation upon KPNA2 depletion in cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (128, 146))	('proliferation', 'CPA', (90, 103))	('cholangiocarcinoma', 'Disease', (128, 146))	('KPNA2', 'Gene', (109, 114))	('reduced', 'NegReg', (82, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (128, 146))	('depletion', 'Var', (115, 124))
188530	28178675	dFdCTP is incorporated into DNA and causes stalling of replication forks and DNA DSBs.	('replication forks', 'CPA', (55, 72))	('dFdCTP', 'Var', (0, 6))	('stalling', 'MPA', (43, 51))	('DSBs', 'Chemical', '-', (81, 85))	('dFdCTP', 'Chemical', 'MESH:C000622105', (0, 6))	('causes', 'Reg', (36, 42))
188536	28178675	In conclusion, the results of this study demonstrated that KPNA2 expression was significantly associated with poor prognosis in patients with cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (142, 160))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (142, 160))	('cholangiocarcinoma', 'Disease', (142, 160))	('associated', 'Reg', (94, 104))	('KPNA2', 'Gene', (59, 64))	('patients', 'Species', '9606', (128, 136))	('expression', 'Var', (65, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
188604	28178675	The sections were then washed in TNT buffer three times for 5 min each and the application of secondary detection reagents was performed using similar methods [Cy3-conjugated streptavidin; secondary antibodies: MRE11 (1:800), RAD50 (1:800), and NBS1 (1:800)].	('RAD50', 'Gene', (226, 231))	('RAD50', 'Gene', '10111', (226, 231))	('NBS1', 'Gene', (245, 249))	('Cy3', 'Chemical', '-', (160, 163))	('MRE11', 'Gene', '4361', (211, 216))	('NBS1', 'Gene', '4683', (245, 249))	('TNT', 'Chemical', '-', (33, 36))	('MRE11', 'Gene', (211, 216))	('1:800)]', 'Var', (251, 258))
188615	24131658	Both in vitro and in vivo preliminary experiments indicated that BCH significantly suppressed growth of the tumor and yielded an additive therapeutic efficacy to gemcitabine and 5-FU.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('BCH', 'Var', (65, 68))	('5-FU', 'Chemical', 'MESH:D005472', (178, 182))	('tumor', 'Disease', (108, 113))	('gemcitabine', 'Chemical', 'MESH:C056507', (162, 173))	('suppressed', 'NegReg', (83, 93))
188616	24131658	High expression of LAT1 is a promising pathological marker to predict the outcome in patients with biliary tract adenocarcinoma.	('LAT1', 'Gene', '8140', (19, 23))	('High', 'Var', (0, 4))	('LAT1', 'Gene', (19, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('patients', 'Species', '9606', (85, 93))	('biliary tract adenocarcinoma', 'Disease', (99, 127))	('biliary tract adenocarcinoma', 'Disease', 'MESH:D001661', (99, 127))
188617	24131658	Inhibition of LAT1 may be an effective targeted therapy for this distressing disease.	('LAT1', 'Gene', (14, 18))	('LAT1', 'Gene', '8140', (14, 18))	('Inhibition', 'Var', (0, 10))
188662	24131658	A human cholangiocarcinoma cell lines, HuCCT1 (JCRB0425), OZ (JCRB1032), and HuH28 (JCRB0426) were purchased from the Health Science Research Resources Bank (Osaka, Japan), and routinely maintained in DMEM containing 10% heat-inactivated fetal bovine serum (AusGeneX, Loganholme, QLD, Australia), penicillin (100 units/ml), streptomycin (100 mug/ml) and L-glutamine (2 mM) at 37 C in 5% CO2, 95% air.	('penicillin', 'Chemical', 'MESH:D010406', (297, 307))	('streptomycin', 'Chemical', 'MESH:D013307', (324, 336))	('HuCCT1', 'CellLine', 'CVCL:0324', (39, 45))	('DMEM', 'Chemical', '-', (201, 205))	('100 mug/ml', 'Var', (338, 348))	('bovine', 'Species', '9913', (244, 250))	('cholangiocarcinoma', 'Disease', (8, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('human', 'Species', '9606', (2, 7))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (8, 26))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (8, 26))
188725	24131658	Multivariate analysis confirmed that lymphatic permeation and a high LAT1 expression, lymphatic permeation and Ki-67 were independent prognostic factors for predicting poor OS, and lymphatic permeation and vascular invasion for poor PFS.	('LAT1', 'Gene', '8140', (69, 73))	('high', 'Var', (64, 68))	('poor OS', 'Disease', (168, 175))	('Ki-67', 'Gene', (111, 116))	('LAT1', 'Gene', (69, 73))
188726	24131658	Figure 2 shows the Kaplan-Meier survival curve in patients with high and low for LAT1 expression.	('high', 'Var', (64, 68))	('patients', 'Species', '9606', (50, 58))	('expression', 'MPA', (86, 96))	('LAT1', 'Gene', '8140', (81, 85))	('low', 'NegReg', (73, 76))	('LAT1', 'Gene', (81, 85))
188732	24131658	These results indicate that BCH inhibits amino acid transport through LAT1 in HuCCT1 cells.	('LAT1', 'Gene', '8140', (70, 74))	('LAT1', 'Gene', (70, 74))	('BCH', 'Var', (28, 31))	('amino acid transport', 'MPA', (41, 61))	('HuCCT1', 'CellLine', 'CVCL:0324', (78, 84))	('inhibits', 'NegReg', (32, 40))
188742	24131658	Therefore, a high LAT1 expression may play an important role on the growth of biliary tract cancer.	('LAT1', 'Gene', (18, 22))	('biliary tract cancer', 'Disease', 'MESH:D001661', (78, 98))	('biliary tract cancer', 'Disease', (78, 98))	('high', 'Var', (13, 17))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (78, 98))	('play', 'Reg', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('LAT1', 'Gene', '8140', (18, 22))	('expression', 'MPA', (23, 33))
188764	24131658	reported that BCH could lead to apoptosis by inducing intracellular depletion of amino acids required for the growth of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('apoptosis', 'CPA', (32, 41))	('inducing', 'Reg', (45, 53))	('cancer', 'Disease', (120, 126))	('BCH', 'Var', (14, 17))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('lead to', 'Reg', (24, 31))
188766	24131658	Therefore, the inhibition of LAT1 gives rise to growth inhibition effects of highly proliferative cells that require increased amino acid metabolism.	('rat', 'Species', '10116', (91, 94))	('LAT1', 'Gene', '8140', (29, 33))	('LAT1', 'Gene', (29, 33))	('increased amino acid metabolism', 'Phenotype', 'HP:0004337', (117, 148))	('growth inhibition', 'CPA', (48, 65))	('inhibition', 'Var', (15, 25))
188770	24131658	A recent systemic review has suggested that p53 mutation, cyclins, proliferation indices (Ki-67), mucins, CA19-9, and CEA have potential as prognostic predictors in cholangiocarcinoma, however, there is no targeting therapy for these molecules at present.	('cholangiocarcinoma', 'Disease', (165, 183))	('CEA', 'Gene', (118, 121))	('CEA', 'Gene', '1084', (118, 121))	('rat', 'Species', '10116', (74, 77))	('p53', 'Gene', (44, 47))	('mutation', 'Var', (48, 56))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (165, 183))	('p53', 'Gene', '7157', (44, 47))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (165, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))
188773	24131658	In conclusion, high expression of LAT1 plays an important role in enhancing tumor growth and cell proliferation and is a promising pathological marker for predicting poor prognosis in patients with biliary tract cancer.	('high expression', 'Var', (15, 30))	('biliary tract cancer', 'Disease', (198, 218))	('patients', 'Species', '9606', (184, 192))	('rat', 'Species', '10116', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('cell proliferation', 'CPA', (93, 111))	('enhancing', 'PosReg', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('LAT1', 'Gene', '8140', (34, 38))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (198, 218))	('LAT1', 'Gene', (34, 38))	('biliary tract cancer', 'Disease', 'MESH:D001661', (198, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
188786	33535865	High Gal1GalNAc1 expression was significantly associated with the late stage of cholangiocarcinoma (stages II-IV), lymphatic invasion, and vascular invasion.	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('High', 'Var', (0, 4))	('lymphatic invasion', 'CPA', (115, 133))	('expression', 'MPA', (17, 27))	('vascular invasion', 'CPA', (139, 156))	('cholangiocarcinoma', 'Disease', (80, 98))	('Gal1GalNAc1', 'Chemical', '-', (5, 16))	('Gal1GalNAc1', 'Protein', (5, 16))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (80, 98))	('associated', 'Reg', (46, 56))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (80, 98))
188794	33535865	Sialyl Lewis a expression in patients' tissues is related to a poor prognosis in CCA.	('patients', 'Species', '9606', (29, 37))	('CCA', 'Disease', (81, 84))	('Sialyl', 'Var', (0, 6))	('related to', 'Reg', (50, 60))	('CCA', 'Phenotype', 'HP:0030153', (81, 84))
188795	33535865	A study that used a monoclonal antibody of the glycans for mucin 5ACS from serum of patients with CCA showed that the level of a glycan epitope (S121) was related to prognosis and was specific to CCA.	('CCA', 'Phenotype', 'HP:0030153', (98, 101))	('glycan', 'Chemical', 'MESH:D011134', (47, 53))	('glycan', 'Chemical', 'MESH:D011134', (129, 135))	('patients', 'Species', '9606', (84, 92))	('related to', 'Reg', (155, 165))	('CCA', 'Phenotype', 'HP:0030153', (196, 199))	('mucin', 'Gene', (59, 64))	('S121', 'Var', (145, 149))	('glycans', 'Chemical', 'MESH:D011134', (47, 54))	('CCA', 'Disease', (196, 199))	('mucin', 'Gene', '100508689', (59, 64))
188798	33535865	Another study in serum of patients with CCA by sandwich ELISA showed that the glycan epitope CA-S27 may have immunodiagnostic value for the prognosis or diagnosis of CCA.	('glycan', 'Chemical', 'MESH:D011134', (78, 84))	('CCA', 'Disease', (166, 169))	('patients', 'Species', '9606', (26, 34))	('CA-S27', 'Var', (93, 99))	('CCA', 'Phenotype', 'HP:0030153', (166, 169))	('CCA', 'Phenotype', 'HP:0030153', (40, 43))
188837	33535865	Gal1GalNAc1 and Gal2GlcNAc1GalNAc1 were significantly higher in tissue of patients with CCA compared with adjacent normal tissue (P = 0.003 and P = 0.002, respectively).	('higher', 'PosReg', (54, 60))	('patients', 'Species', '9606', (74, 82))	('Gal', 'Chemical', 'MESH:D005690', (4, 7))	('Gal', 'Chemical', 'MESH:D005690', (16, 19))	('Gal', 'Chemical', 'MESH:D005690', (27, 30))	('CCA', 'Disease', (88, 91))	('Gal2GlcNAc1GalNAc1', 'Var', (16, 34))	('Gal', 'Chemical', 'MESH:D005690', (0, 3))	('CCA', 'Phenotype', 'HP:0030153', (88, 91))	('GalNAc', 'Chemical', '-', (27, 33))	('GalNAc', 'Chemical', '-', (4, 10))	('Gal1GalNAc1', 'Var', (0, 11))	('GlcNAc', 'Chemical', 'MESH:D000117', (20, 26))	('Gal1GalNAc1', 'Chemical', '-', (0, 11))
188852	33535865	Therefore, high Gal1GalNAc1 expression in CCA may be associated with progression and metastasis of tumors.	('metastasis of tumors', 'Disease', 'MESH:D009362', (85, 105))	('Gal1GalNAc1', 'Protein', (16, 27))	('expression', 'MPA', (28, 38))	('metastasis of tumors', 'Disease', (85, 105))	('CCA', 'Phenotype', 'HP:0030153', (42, 45))	('Gal1GalNAc1', 'Chemical', '-', (16, 27))	('associated', 'Reg', (53, 63))	('high', 'Var', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('progression', 'CPA', (69, 80))	('CCA', 'Disease', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
188858	33535865	We observed the isobaric structure NeuAc1Gal1GalNAc1 (structure 2a and 2b) in tissue of patients with CCA.	('NeuAc1Gal1GalNAc1', 'Var', (35, 52))	('CCA', 'Phenotype', 'HP:0030153', (102, 105))	('patients', 'Species', '9606', (88, 96))	('CCA', 'Disease', (102, 105))	('NeuAc', 'Chemical', 'MESH:D019158', (35, 40))	('Gal1GalNAc1', 'Chemical', '-', (41, 52))
188860	33535865	Competition of NeuAc1Gal1GalNAc1 (sialylated core 1) and the core 2 structure, which compete for the core 1 substrate, has been reported in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('Gal1GalNAc1', 'Chemical', '-', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('NeuAc1Gal1GalNAc1', 'Var', (15, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('reported', 'Reg', (128, 136))	('NeuAc', 'Chemical', 'MESH:D019158', (15, 20))
188865	33535865	These findings suggest that O-linked glycan expression, especially that of Gal1GalNAc1 and Gal2GlcNAc1GalNAc1, plays an important role in progression of CCA.	('Gal', 'Chemical', 'MESH:D005690', (75, 78))	('Gal', 'Chemical', 'MESH:D005690', (102, 105))	('O-linked glycan', 'Protein', (28, 43))	('CCA', 'Disease', (153, 156))	('Gal', 'Chemical', 'MESH:D005690', (79, 82))	('Gal1GalNAc1', 'Chemical', '-', (75, 86))	('GalNAc', 'Chemical', '-', (102, 108))	('Gal2GlcNAc1GalNAc1', 'Var', (91, 109))	('GlcNAc', 'Chemical', 'MESH:D000117', (95, 101))	('GalNAc', 'Chemical', '-', (79, 85))	('O-linked glycan', 'Chemical', '-', (28, 43))	('CCA', 'Phenotype', 'HP:0030153', (153, 156))	('Gal', 'Chemical', 'MESH:D005690', (91, 94))
188869	28602220	Inhibition of microRNA-24 increases liver fibrosis by enhanced menin expression in Mdr2-/- mice Liver transplantation remains the primary treatment for primary sclerosing cholangitis (PSC).	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (160, 182))	('PSC', 'Gene', (184, 187))	('menin', 'Gene', (63, 68))	('primary sclerosing cholangitis', 'Disease', (152, 182))	('menin', 'Gene', '17283', (63, 68))	('increases liver fibrosis', 'Disease', (26, 50))	('microRNA-24', 'Gene', (14, 25))	('Mdr2', 'Gene', '18670', (83, 87))	('microRNA-24', 'Gene', '407012', (14, 25))	('cholangitis', 'Phenotype', 'HP:0030151', (171, 182))	('expression', 'MPA', (69, 79))	('Mdr2', 'Gene', (83, 87))	('PSC', 'Gene', '100653366', (184, 187))	('Inhibition', 'Var', (0, 10))	('increases liver fibrosis', 'Disease', 'MESH:D008103', (26, 50))	('liver fibrosis', 'Phenotype', 'HP:0001395', (36, 50))	('enhanced', 'PosReg', (54, 62))	('primary sclerosing cholangitis', 'Disease', 'MESH:D015209', (152, 182))
188873	28602220	Twelve-week-old FVB/NJ wild-type (WT) and Mdr2-/- mice were treated with miR-24 Vivo-Morpholino to knockdown miR-24 expression levels.	('expression levels', 'MPA', (116, 133))	('knockdown', 'Var', (99, 108))	('mice', 'Species', '10090', (50, 54))	('miR-24', 'Gene', (109, 115))
188878	28602220	In vitro, inhibition of miR-24 also significantly increased the expression of fibrosis genes.	('fibrosis', 'Disease', 'MESH:D005355', (78, 86))	('fibrosis', 'Disease', (78, 86))	('expression', 'MPA', (64, 74))	('miR-24', 'Gene', (24, 30))	('increased', 'PosReg', (50, 59))	('inhibition', 'Var', (10, 20))
188879	28602220	Inhibition of miR-24 increases menin and TGF-beta1 expression, subsequently increasing hepatic fibrosis in FVB/NJ WT and Mdr2-/- mice.	('increases', 'PosReg', (21, 30))	('hepatic fibrosis', 'Disease', 'MESH:D008103', (87, 103))	('TGF-beta1', 'Gene', (41, 50))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (87, 103))	('miR-24', 'Gene', (14, 20))	('expression', 'MPA', (51, 61))	('increasing', 'PosReg', (76, 86))	('Inhibition', 'Var', (0, 10))	('menin', 'Protein', (31, 36))	('mice', 'Species', '10090', (129, 133))	('hepatic fibrosis', 'Disease', (87, 103))
188880	28602220	Modulation of the menin/miR-24 axis may provide novel targeted therapies to slow the progression of hepatic fibrosis into cirrhosis in PSC patients by altering TGF-beta1 expression.	('Modulation', 'Var', (0, 10))	('hepatic fibrosis', 'Disease', 'MESH:D008103', (100, 116))	('altering', 'Reg', (151, 159))	('patients', 'Species', '9606', (139, 147))	('cirrhosis', 'Phenotype', 'HP:0001394', (122, 131))	('cirrhosis', 'Disease', 'MESH:D005355', (122, 131))	('TGF-beta1', 'Gene', (160, 169))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (100, 116))	('PSC', 'Gene', '100653366', (135, 138))	('hepatic fibrosis', 'Disease', (100, 116))	('cirrhosis', 'Disease', (122, 131))	('slow', 'NegReg', (76, 80))	('PSC', 'Gene', (135, 138))	('expression', 'MPA', (170, 180))
188889	28602220	Germline mutations in the MEN1 gene cause the MEN1 syndrome, a neuroendocrine tumor syndrome that predisposes patients to neoplasms of the parathyroid glands, pancreas, and the pituitary gland.	('Germline mutations', 'Var', (0, 18))	('neoplasms of the parathyroid glands', 'Disease', 'MESH:C563238', (122, 157))	('MEN1 syndrome', 'Disease', 'MESH:D018761', (46, 59))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (63, 83))	('cause', 'Reg', (36, 41))	('neoplasms of the parathyroid glands', 'Disease', (122, 157))	('neuroendocrine tumor syndrome', 'Disease', 'MESH:D018358', (63, 92))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('neoplasms', 'Phenotype', 'HP:0002664', (122, 131))	('neoplasms of the parathyroid glands', 'Phenotype', 'HP:0100733', (122, 157))	('pancreas', 'Disease', (159, 167))	('pancreas', 'Disease', 'MESH:D010190', (159, 167))	('MEN1 syndrome', 'Disease', (46, 59))	('MEN1', 'Gene', (26, 30))	('patients', 'Species', '9606', (110, 118))	('neuroendocrine tumor syndrome', 'Disease', (63, 92))
188894	28602220	SMAD3 phosphorylation and TGF-beta1 have previously been shown to contribute to hepatic fibrosis; however, the role of menin in this pathway is unknown.	('hepatic fibrosis', 'Disease', (80, 96))	('SMAD3', 'Gene', (0, 5))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (80, 96))	('SMAD3', 'Gene', '17127', (0, 5))	('hepatic fibrosis', 'Disease', 'MESH:D008103', (80, 96))	('contribute', 'Reg', (66, 76))	('phosphorylation', 'Var', (6, 21))	('TGF-beta1', 'Gene', (26, 35))
188924	28602220	MEN1 expression was significantly decreased in the 12-wk-old Mdr2-/- mice compared with the FVB/NJ WT control, but was significantly upregulated in the 66-wk-old Mdr2-/- mice (Fig.	('Mdr2-/-', 'Var', (61, 68))	('expression', 'MPA', (5, 15))	('upregulated', 'PosReg', (133, 144))	('decreased', 'NegReg', (34, 43))	('mice', 'Species', '10090', (69, 73))	('mice', 'Species', '10090', (170, 174))	('MEN1', 'Gene', (0, 4))
188936	28602220	Similar to our in vitro results, inhibition of miR-24 resulted in significantly increased expression of fibrosis-related genes, including TGF-beta1 in both the FVB/NJ WT and Mdr2-/- mice (Fig.	('inhibition', 'Var', (33, 43))	('TGF-beta1', 'Gene', (138, 147))	('increased', 'PosReg', (80, 89))	('mice', 'Species', '10090', (182, 186))	('fibrosis', 'Disease', 'MESH:D005355', (104, 112))	('fibrosis', 'Disease', (104, 112))	('expression', 'MPA', (90, 100))	('miR-24', 'Gene', (47, 53))
188942	28602220	Also, we demonstrated that inhibition of miR-24 signaling in vitro and in vivo increases MEN1 gene expression and subsequently promotes expression of fibrotic genes in cultured cholangiocytes and liver tissues.	('expression', 'MPA', (99, 109))	('expression', 'MPA', (136, 146))	('promotes', 'PosReg', (127, 135))	('increases', 'PosReg', (79, 88))	('rat', 'Species', '10116', (16, 19))	('inhibition', 'Var', (27, 37))	('MEN1 gene', 'Gene', (89, 98))
188943	28602220	We demonstrate increased hepatic fibrosis in Mdr2-/- mice, as well as the nondiseased FVB/NJ control strain, with miR-24 Vivo-Morpholino treatment.	('hepatic fibrosis', 'Disease', 'MESH:D008103', (25, 41))	('Mdr2-/-', 'Var', (45, 52))	('increased', 'PosReg', (15, 24))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (25, 41))	('hepatic fibrosis', 'Disease', (25, 41))	('rat', 'Species', '10116', (10, 13))	('mice', 'Species', '10090', (53, 57))
188952	28602220	Early studies suggested that menin inactivation contributes to parathyroid tumorigenesis through a loss of TGF-beta1 signaling.	('rat', 'Species', '10116', (65, 68))	('inactivation', 'Var', (35, 47))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('TGF-beta1 signaling', 'MPA', (107, 126))	('loss', 'NegReg', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('menin', 'Protein', (29, 34))
188954	28602220	Specifically, inactivation of menin disrupts SMAD3 binding to its cognate DNA element and blocks TGF-beta1 signaling.	('binding', 'Interaction', (51, 58))	('inactivation', 'Var', (14, 26))	('TGF-beta1 signaling', 'MPA', (97, 116))	('blocks', 'NegReg', (90, 96))	('menin', 'Gene', (30, 35))	('SMAD3', 'Gene', (45, 50))	('SMAD3', 'Gene', '17127', (45, 50))	('disrupts', 'NegReg', (36, 44))
188962	28602220	suggested that deletion of MEN1 in hepatocytes induced lipid accumulation and liver steatosis in aging mice.	('liver steatosis', 'Phenotype', 'HP:0001397', (78, 93))	('liver steatosis', 'Disease', 'MESH:D005234', (78, 93))	('MEN1', 'Gene', (27, 31))	('lipid accumulation', 'MPA', (55, 73))	('deletion', 'Var', (15, 23))	('mice', 'Species', '10090', (103, 107))	('lipid', 'Chemical', 'MESH:D008055', (55, 60))	('liver steatosis', 'Disease', (78, 93))
188981	28602220	Furthermore, we have shown that inhibition of miR-24 increases menin expression and drives hepatic fibrosis.	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (91, 107))	('inhibition', 'Var', (32, 42))	('hepatic fibrosis', 'Disease', (91, 107))	('menin', 'Protein', (63, 68))	('expression', 'MPA', (69, 79))	('hepatic fibrosis', 'Disease', 'MESH:D008103', (91, 107))	('increases', 'PosReg', (53, 62))	('miR-24', 'Gene', (46, 52))	('drives', 'PosReg', (84, 90))
189034	25838819	Disorder in any part of the GI tract results in various malfunctions such as diseases of digestive system and cancer.	('malfunctions', 'MPA', (56, 68))	('digestive system', 'Disease', (89, 105))	('results in', 'Reg', (37, 47))	('cancer', 'Disease', (110, 116))	('diseases of digestive system', 'Phenotype', 'HP:0011024', (77, 105))	('diseases', 'Disease', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Disorder', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
189113	25838819	Glutathione (GSH) depletion has been shown to be a major contributing factor in arbitrating 6-shogaol-induced apoptosis of Mahlavu cells.	('Glutathione', 'Chemical', 'MESH:D005978', (0, 11))	('rat', 'Species', '10116', (85, 88))	('depletion', 'Var', (18, 27))	('GSH', 'Chemical', 'MESH:D005978', (13, 16))	('apoptosis', 'CPA', (110, 119))	('6-shogaol', 'Chemical', 'MESH:C040115', (92, 101))
189184	25838819	In another pilot, randomized control trial with 20 patients at increased risk for colorectal cancer, ginger (2 g for 28 days) supplementation was also found to reduce the proliferation of normal-appearing colorectal epithelium and increased apoptosis and differentiation of the crypts.	('colorectal cancer', 'Disease', (82, 99))	('reduce', 'NegReg', (160, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('differentiation of the crypts', 'CPA', (255, 284))	('increased', 'PosReg', (231, 240))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('apoptosis', 'CPA', (241, 250))	('patients', 'Species', '9606', (51, 59))	('supplementation', 'Var', (126, 141))	('ginger', 'Gene', (101, 107))	('rat', 'Species', '10116', (178, 181))	('ginger', 'Species', '94328', (101, 107))	('proliferation', 'CPA', (171, 184))
189187	25838819	It has been observed that ginger significantly lowers COX-1 protein expression in participants at increased risk for colorectal cancer but not in the participants at normal risk.	('colorectal cancer', 'Disease', 'MESH:D015179', (117, 134))	('colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('participants', 'Species', '9606', (82, 94))	('ginger', 'Species', '94328', (26, 32))	('participants', 'Species', '9606', (150, 162))	('colorectal cancer', 'Disease', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ginger', 'Var', (26, 32))	('COX-1', 'Gene', '4512', (54, 59))	('COX-1', 'Gene', (54, 59))	('lowers', 'NegReg', (47, 53))
189228	24422711	Improved median survival has been observed in patients with microscopic residual disease with the addition of adjuvant irradiation after charged-particle therapy, also in comparison to patients treated with conventional radiotherapy.	('patients', 'Species', '9606', (46, 54))	('microscopic', 'Var', (60, 71))	('patients', 'Species', '9606', (185, 193))	('Improved', 'PosReg', (0, 8))	('median survival', 'MPA', (9, 24))
189263	24422711	Univariate analysis indicated better LC in patients to whom a BED10 greater than 70 Gy PBT had been administered compared with those to whom a BED10 less than 70 Gy had been administered (83.1% vs. 22.2%, respectively, at 1 year; p = 0.002) (Figure 2).	('patients', 'Species', '9606', (43, 51))	('BED10 greater than 70 Gy', 'Var', (62, 86))	('better', 'PosReg', (30, 36))
189281	24422711	Although we did observe a better LC in patients administered a BED10 of greater than 70 Gy PBT compared to those receiving a BED10 of less than 70 Gy (89% vs. 36%, respectively, at 1 year), no survival benefit was found with administration of a higher proton dose in the current study.	('patients', 'Species', '9606', (39, 47))	('PBT', 'Var', (91, 94))	('BED10 of greater than 70 Gy PBT', 'Var', (63, 94))
189314	32781500	ICIs, specifically PD-1, PDL-1 and CTLA-4 inhibitors have been approved for the treatment of a variety of solid tumors, initially beginning with melanoma in 2011.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('solid tumors', 'Disease', (106, 118))	('CTLA-4', 'Gene', (35, 41))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PDL-1', 'Gene', '29126', (25, 30))	('inhibitors', 'Var', (42, 52))	('men', 'Species', '9606', (85, 88))	('CTLA-4', 'Gene', '1493', (35, 41))	('solid tumors', 'Disease', 'MESH:D009369', (106, 118))	('PDL-1', 'Gene', (25, 30))	('PD-1', 'Gene', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
189358	32781500	However, a subgroup analysis demonstrated a significant benefit for use of pembrolizumab over a taxane in patients with a deficient mismatch repair (dMMR) GEJ or gastric cancer.	('dMMR', 'Chemical', '-', (149, 153))	('gastric cancer', 'Disease', 'MESH:D013274', (162, 176))	('deficient mismatch', 'Var', (122, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (162, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('pembrolizumab', 'Chemical', 'MESH:C582435', (75, 88))	('mismatch', 'Var', (132, 140))	('patients', 'Species', '9606', (106, 114))	('gastric cancer', 'Disease', (162, 176))	('taxane', 'Chemical', 'MESH:C080625', (96, 102))
189451	32781500	There are currently ongoing ICI combination studies including ICIs with TGF-beta inhibitors, with indoleamine dioxygenase inhibitors, with intra-arterial therapies, with radiation and with angiogenesis inhibitors.	('TGF-beta', 'Gene', '7039', (72, 80))	('indoleamine dioxygenase', 'MPA', (98, 121))	('TGF-beta', 'Gene', (72, 80))	('inhibitors', 'Var', (81, 91))
189452	32781500	Some ongoing Phase III ICIs combination studies include: Nivolumab plus ipilimumab in advanced HCC as first line therapy (NCT03510871, NCT03222076, NCT03203304, NCT01658878, NCT04039607) and durvalumab plus tremelimumab in advanced HCC as second line therapy (NCT03298451).	('Nivolumab', 'Chemical', 'MESH:D000077594', (57, 66))	('durvalumab plus tremelimumab', 'Disease', 'MESH:D007625', (191, 219))	('ipilimumab', 'Chemical', 'MESH:D000074324', (72, 82))	('NCT03510871', 'Var', (122, 133))	('NCT03203304', 'Var', (148, 159))	('durvalumab plus tremelimumab', 'Disease', (191, 219))	('NCT03222076', 'Var', (135, 146))
189453	32781500	Phase III studies involving ICI and angiogenesis inhibitors include: nivolumab plus sorafenib in advanced HCC as first line therapy (NCT02576509, NCT01658878, NCT03439891), pembrolizumab plus lenvatinib in patients with advanced HCC as first line therapy (NCT03713593), atezolizumab plus cabozantinib in advanced HCC as first line therapy (NCT03755791), atezolizumab plus bevacizumab in advanced HCC as first line therapy (NCT03434379), durvalumab plus bevacizumab in localized and locally advanced HCC (NCT03847428, NCT03778957), camrelizumab plus apatinib in advanced HCC as first line therapy (NCT02942329, NCT03764293), tislelizumab plus sorafenib for advanced HCC as first line therapy (NCT03412773) and sintilimab plus IBI305 in advanced HCC as first line therapy (NCT03794440).	('bevacizumab', 'Chemical', 'MESH:D000068258', (372, 383))	('sorafenib', 'Chemical', 'MESH:D000077157', (642, 651))	('tislelizumab plus sorafenib', 'Disease', (624, 651))	('sorafenib', 'Chemical', 'MESH:D000077157', (84, 93))	('atezolizumab', 'Chemical', 'MESH:C000594389', (270, 282))	('NCT03412773', 'Var', (692, 703))	('tislelizumab plus sorafenib', 'Disease', 'MESH:D007625', (624, 651))	('lenvatinib', 'Chemical', 'MESH:C531958', (192, 202))	('atezolizumab plus bevacizumab', 'Disease', (354, 383))	('nivolumab', 'Chemical', 'MESH:D000077594', (69, 78))	('atezolizumab plus bevacizumab', 'Disease', 'MESH:D007625', (354, 383))	('cabozantinib', 'Chemical', 'MESH:C558660', (288, 300))	('pembrolizumab', 'Chemical', 'MESH:C582435', (173, 186))	('atezolizumab', 'Chemical', 'MESH:C000594389', (354, 366))	('bevacizumab', 'Chemical', 'MESH:D000068258', (453, 464))	('durvalumab', 'Chemical', 'MESH:C000613593', (437, 447))	('NCT02942329', 'Var', (597, 608))	('patients', 'Species', '9606', (206, 214))	('NCT03764293', 'CellLine', 'None', (610, 621))
189471	32781500	KEYNOTE-158, was a nonrandomized, open label, multisite phase II study that enrolled patients with histologically or cytologically confirmed MSI-H/dMMR advanced non-colorectal cancer, including biliary adenocarcinoma, who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years until disease progression, unacceptable toxicity or patient withdrawal.	('patient', 'Species', '9606', (85, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (165, 182))	('pembrolizumab', 'Chemical', 'MESH:C582435', (270, 283))	('patient', 'Species', '9606', (374, 381))	('non-colorectal cancer', 'Disease', 'MESH:D015179', (161, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('dMMR', 'Chemical', '-', (147, 151))	('patients', 'Species', '9606', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('toxicity', 'Disease', 'MESH:D064420', (362, 370))	('toxicity', 'Disease', (362, 370))	('biliary adenocarcinoma', 'Disease', 'MESH:D000230', (194, 216))	('MSI-H/dMMR', 'Var', (141, 151))	('non-colorectal cancer', 'Disease', (161, 182))	('biliary adenocarcinoma', 'Disease', (194, 216))
189472	32781500	There are ongoing phase II trials with first line combination nivolumab plus ipilimumab in advanced cholangiocarcinoma (NCT03101566, NCT02834013), second line pembrolizumab monotherapy in advanced cholangiocarcinoma (NCT03110328, NCT02628067), second line nivolumab in advanced cholangiocarcinoma (NCT02829918), first line durvalumab and tremelimumab with chemotherapy in advanced cholangiocarcinoma (NCT03473574, NCT03046862, NCT03704480), first line toripalimab with chemotherapy in advanced cholangiocarcinoma (NCT03796429, NCT03982680, NCT04027764).	('carcinoma', 'Phenotype', 'HP:0030731', (390, 399))	('nivolumab', 'Chemical', 'MESH:D000077594', (256, 265))	('cholangiocarcinoma', 'Disease', (100, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (100, 118))	('durvalumab', 'Chemical', 'MESH:C000613593', (323, 333))	('pembrolizumab', 'Chemical', 'MESH:C582435', (159, 172))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (494, 512))	('NCT02829918', 'Var', (298, 309))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (278, 296))	('NCT04027764', 'Var', (540, 551))	('nivolumab', 'Chemical', 'MESH:D000077594', (62, 71))	('tremelimumab', 'Chemical', 'MESH:C520704', (338, 350))	('NCT03110328', 'Var', (217, 228))	('cholangiocarcinoma', 'Disease', (494, 512))	('NCT03704480', 'Var', (427, 438))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (494, 512))	('cholangiocarcinoma', 'Disease', (278, 296))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (278, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (381, 399))	('ipilimumab', 'Chemical', 'MESH:D000074324', (77, 87))	('NCT03982680', 'Var', (527, 538))	('NCT03473574', 'Var', (401, 412))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (197, 215))	('cholangiocarcinoma', 'Disease', (381, 399))	('carcinoma', 'Phenotype', 'HP:0030731', (503, 512))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (381, 399))	('cholangiocarcinoma', 'Disease', (197, 215))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (197, 215))	('NCT03796429', 'Var', (514, 525))
189473	32781500	There are ongoing phase III trials of first line durvalumab with chemotherapy for advanced cholangiocarcinoma (NCT03875235) and first line pembrolizumab with chemotherapy in advanced cholangiocarcinoma (NCT03260712, NCT03111732, NCT04003636).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('NCT03875235', 'Var', (111, 122))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (183, 201))	('NCT03260712', 'Var', (203, 214))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('pembrolizumab', 'Chemical', 'MESH:C582435', (139, 152))	('NCT03111732', 'Var', (216, 227))	('cholangiocarcinoma', 'Disease', (183, 201))	('NCT04003636', 'Var', (229, 240))	('cholangiocarcinoma', 'Disease', (91, 109))	('durvalumab', 'Chemical', 'MESH:C000613593', (49, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (183, 201))
189507	32781500	Another option is encorafenib along with cetuximab for BRAF mutation positive tumors.	('cetuximab', 'Chemical', 'MESH:D000068818', (41, 50))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutation positive', 'Var', (60, 77))	('BRAF', 'Gene', '673', (55, 59))	('encorafenib', 'Chemical', 'MESH:C000601108', (18, 29))	('BRAF', 'Gene', (55, 59))
189512	32781500	In a follow-up study with a larger cohort, patients with dMMR metastatic colorectal cancer had a 50% objective response rate.	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('dMMR', 'Chemical', '-', (57, 61))	('patients', 'Species', '9606', (43, 51))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', (73, 90))	('dMMR', 'Var', (57, 61))
189627	32318894	3a, b) and distal cholangiocarcinoma with well-differentiated adenocarcinoma (Bp, nodular-infiltrating type, circ, 21 mm, tub1 > tub2, pT2a (SS), int, INFb, ly1, v1(VB), ne2, pN0(0/38), pPM0, pDM0, pEM0, pPV0, pA0, R0) (Japanese rule 6th edition) (Fig.	('pPM0', 'Var', (186, 190))	('ly1', 'Var', (157, 160))	('cholangiocarcinoma', 'Disease', (18, 36))	('adenocarcinoma', 'Disease', (62, 76))	('adenocarcinoma', 'Disease', 'MESH:D000230', (62, 76))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (18, 36))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (18, 36))
189681	24423918	On the basis of evidence of dysregulation of the epidermal growth factor receptor, vascular endothelial growth factor and mitogen-activated protein kinase pathways in biliary cancers, we performed a phase 2 trial of sorafenib and erlotinib in patients with advanced biliary cancers.	('biliary cancers', 'Disease', 'MESH:D001661', (266, 281))	('biliary cancers', 'Disease', (167, 182))	('vascular endothelial growth factor', 'Gene', (83, 117))	('epidermal growth factor receptor', 'Gene', (49, 81))	('patients', 'Species', '9606', (243, 251))	('cancers', 'Phenotype', 'HP:0002664', (274, 281))	('dysregulation', 'Var', (28, 41))	('biliary cancers', 'Disease', 'MESH:D001661', (167, 182))	('vascular endothelial growth factor', 'Gene', '7422', (83, 117))	('advanced biliary cancers', 'Disease', 'MESH:D006223', (257, 281))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('advanced biliary cancers', 'Disease', (257, 281))	('erlotinib', 'Chemical', 'MESH:D000069347', (230, 239))	('epidermal growth factor receptor', 'Gene', '1956', (49, 81))	('sorafenib', 'Chemical', 'MESH:D000077157', (216, 225))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('mitogen-activated protein kinase pathways', 'Pathway', (122, 163))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
189697	24423918	Overexpression of EGFR is associated with poor prognostic features including lymph node metastasis, lymphatic invasion and perineural invasion in EHCC, whereas VEGF overexpression is associated with intrahepatic metastasis in IHCC.	('lymphatic invasion', 'CPA', (100, 118))	('EHCC', 'Disease', (146, 150))	('EGFR', 'Gene', '1956', (18, 22))	('VEGF', 'Gene', (160, 164))	('intrahepatic metastasis', 'Disease', 'MESH:D009362', (199, 222))	('intrahepatic metastasis', 'Disease', (199, 222))	('EGFR', 'Gene', (18, 22))	('lymph node metastasis', 'CPA', (77, 98))	('Overexpression', 'Var', (0, 14))	('perineural invasion', 'CPA', (123, 142))	('VEGF', 'Gene', '7422', (160, 164))
189701	24423918	For instance, one study showed BRAF mutations in 15 out of 69 (22%) patients with cholangiocarcinoma.	('BRAF', 'Gene', (31, 35))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (82, 100))	('mutations', 'Var', (36, 45))	('patients', 'Species', '9606', (68, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (82, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('BRAF', 'Gene', '673', (31, 35))	('cholangiocarcinoma', 'Disease', (82, 100))
189702	24423918	Recently, reported transcriptome analyses of 104 cholangiocarcinoma specimens and identified a poor prognostic subgroup characterised by KRAS mutations, and activation of EGFR and HER2 signalling pathways.	('EGFR', 'Gene', (171, 175))	('mutations', 'Var', (142, 151))	('HER2', 'Gene', (180, 184))	('HER2', 'Gene', '2064', (180, 184))	('cholangiocarcinoma', 'Disease', (49, 67))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (49, 67))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (49, 67))	('KRAS', 'Gene', (137, 141))	('activation', 'PosReg', (157, 167))	('EGFR', 'Gene', '1956', (171, 175))	('KRAS', 'Gene', '3845', (137, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
189716	24423918	Other eligibility criteria included a Zubrod performance status of 0-1; a measured or calculated creatinine clearance >=60 ml min-1; adequate bone marrow function indicated by a leukocyte count >=3000 mcl-1, absolute neutrophil count >=1000 mcl-1 and platelet count >=100 000 mcl-1; adequate hepatic function with a total bilirubin up to 1.5 x the institutional upper limit of normal; serum albumin >=2.5 g dl-1; AST and ALT levels <=2.5 the upper limit of normal or <=5 x upper limit of normal in the presence of liver metastases.	('liver metastases', 'Disease', 'MESH:D009362', (514, 530))	('min-1', 'Gene', (126, 131))	('mcl-1', 'Gene', (241, 246))	('mcl-1', 'Gene', '4170', (241, 246))	('mcl-1', 'Gene', (276, 281))	('mcl-1', 'Gene', '4170', (276, 281))	('min-1', 'Gene', '966', (126, 131))	('AST', 'Gene', (413, 416))	('mcl-1', 'Gene', (201, 206))	('hepatic function', 'MPA', (292, 308))	('bilirubin', 'Chemical', 'MESH:D001663', (322, 331))	('AST', 'Gene', '26503', (413, 416))	('mcl-1', 'Gene', '4170', (201, 206))	('liver metastases', 'Disease', (514, 530))	('>=100 000', 'Var', (266, 275))	('ALT levels', 'MPA', (421, 431))	('serum albumin', 'MPA', (385, 398))
189768	24423918	Activation of EGFR has been shown to result in upregulation of VEGF-A production in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('cancer', 'Disease', (84, 90))	('VEGF-A', 'Gene', '7422', (63, 69))	('VEGF-A', 'Gene', (63, 69))	('upregulation', 'PosReg', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Activation', 'Var', (0, 10))
189769	24423918	Similarly, secretion of proangiogenic factors including VEGF, interleukin 8 and transforming growth factor-beta is inhibited by EGFR blockade.	('VEGF', 'Gene', (56, 60))	('interleukin 8 and transforming growth factor-beta', 'Gene', '3576;7040', (62, 111))	('blockade', 'Var', (133, 141))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('secretion of proangiogenic factors', 'MPA', (11, 45))	('VEGF', 'Gene', '7422', (56, 60))	('inhibited', 'NegReg', (115, 124))
189782	24423918	Furthermore, the likelihood of targeted therapies resulting in improved therapeutic outcomes may be optimised by selecting patients whose tumours harbour specific genetic alterations.	('genetic alterations', 'Var', (163, 182))	('patients', 'Species', '9606', (123, 131))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('tumours', 'Disease', 'MESH:D009369', (138, 145))	('tumours', 'Disease', (138, 145))
189786	24423918	Despite the emergence of data about genetic alterations in biliary cancers, several challenges continue to face targeted drug development in this disease.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('biliary cancers', 'Disease', (59, 74))	('genetic alterations', 'Var', (36, 55))	('biliary cancers', 'Disease', 'MESH:D001661', (59, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
189793	24423918	Another promising target in biliary cancers is the MET oncogene the expression of which has been shown to be an independent predictor of poor survival in patients with cholangiocarcinoma.	('biliary cancers', 'Disease', (28, 43))	('cholangiocarcinoma', 'Disease', (168, 186))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (168, 186))	('patients', 'Species', '9606', (154, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('expression', 'Var', (68, 78))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (168, 186))	('biliary cancers', 'Disease', 'MESH:D001661', (28, 43))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
189794	24423918	Evaluation of MET targeting agents in cholangiocarcinoma would be warranted, especially given the promising activity of MET inhibitors in hepatocellular carcinoma where MET expression appears to be associated with the likelihood of benefit.	('cholangiocarcinoma', 'Disease', (38, 56))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (138, 162))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (138, 162))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (38, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('hepatocellular carcinoma', 'Disease', (138, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('MET expression', 'Var', (169, 183))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (38, 56))
189835	21725997	In addition, analysis of H&E-stained sections of the kidney supported the observation that O. viverrini infection resulted in a higher magnitude of inflammatory response in Mta1+/+ mice when compared to age-matched Mta1-/- mice (Fig.	('that', 'Gene', (86, 90))	('Mta1', 'Gene', '116870', (215, 219))	('mice', 'Species', '10090', (181, 185))	('O. viverrini', 'Species', '6198', (91, 103))	('Mta1', 'Gene', '116870', (173, 177))	('mice', 'Species', '10090', (223, 227))	('of inflammatory', 'MPA', (145, 160))	('Mta1', 'Gene', (215, 219))	('H&E', 'Chemical', '-', (25, 28))	('Mta1', 'Gene', (173, 177))	('infection', 'Disease', (104, 113))	('viverrini', 'Var', (94, 103))	('infection', 'Disease', 'MESH:D007239', (104, 113))
189836	21725997	To determine whether the presence or absence of MTA1 had a significant effect on the pathology associated with infection, levels of critical cellular markers known to be upregulated during O. viverrini infection were evaluated using immunohistochemistry and quantitative RT-PCR.	('MTA1', 'Gene', '116870', (48, 52))	('absence', 'Var', (37, 44))	('infection', 'Disease', (202, 211))	('infection', 'Disease', (111, 120))	('infection', 'Disease', 'MESH:D007239', (202, 211))	('infection', 'Disease', 'MESH:D007239', (111, 120))	('MTA1', 'Gene', (48, 52))	('O. viverrini', 'Species', '6198', (189, 201))	('upregulated', 'PosReg', (170, 181))	('presence', 'Var', (25, 33))
189878	21725997	Over-expression of MTA1 has been associated with a variety of cancers and previous investigations have established a distinct role for MTA1 in mediating inflammatory responses.	('MTA1', 'Gene', (135, 139))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('MTA1', 'Gene', (19, 23))	('MTA1', 'Gene', '116870', (135, 139))	('associated', 'Reg', (33, 43))	('MTA1', 'Gene', '116870', (19, 23))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('Over-expression', 'Var', (0, 15))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
189904	21725997	Loss of MTA1 results in aberrant cytokine expression and we now speculate that, following helminth parasite infection, aberrant cytokine expression is disadvantageous for the establishment of infection and/or a productive parasitism.	('aberrant', 'Var', (119, 127))	('aberrant cytokine expression', 'Phenotype', 'HP:0031407', (119, 147))	('parasitism', 'Disease', (222, 232))	('aberrant cytokine expression', 'Phenotype', 'HP:0031407', (24, 52))	('MTA1', 'Gene', (8, 12))	('infection', 'Disease', (192, 201))	('infection', 'Disease', 'MESH:D007239', (192, 201))	('infection', 'Disease', (108, 117))	('Loss', 'NegReg', (0, 4))	('infection', 'Disease', 'MESH:D007239', (108, 117))	('parasitism', 'Disease', 'MESH:D010272', (222, 232))	('helminth parasite infection', 'Disease', 'MESH:D010272', (90, 117))	('MTA1', 'Gene', '116870', (8, 12))	('helminth parasite infection', 'Disease', (90, 117))	('cytokine expression', 'MPA', (33, 52))
189955	19825989	RAMH inhibited the growth of cholangiocarcinoma cells.	('inhibited', 'NegReg', (5, 14))	('RAMH', 'Var', (0, 4))	('cholangiocarcinoma', 'Disease', (29, 47))	('growth', 'CPA', (19, 25))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (29, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (29, 47))	('RAMH', 'Chemical', 'MESH:C069357', (0, 4))
189956	19825989	RAMH increased IP3 levels and PKCalpha phosphorylation and decreased ERK1/2 phosphorylation.	('decreased', 'NegReg', (59, 68))	('RAMH', 'Var', (0, 4))	('ERK1/2', 'Gene', (69, 75))	('ERK1/2', 'Gene', '5595;5594', (69, 75))	('IP3 levels', 'MPA', (15, 25))	('IP3', 'Chemical', 'MESH:D015544', (15, 18))	('increased', 'PosReg', (5, 14))	('PKCalpha', 'Enzyme', (30, 38))	('increased IP3 levels', 'Phenotype', 'HP:0032297', (5, 25))	('RAMH', 'Chemical', 'MESH:C069357', (0, 4))
189957	19825989	RAMH induced a shift in the localization of PKCalpha expression from the cytosolic domain into the membrane region of Mz-ChA-1 cells.	('Mz-ChA-1', 'Chemical', '-', (118, 126))	('shift', 'Reg', (15, 20))	('localization', 'MPA', (28, 40))	('RAMH', 'Var', (0, 4))	('PKCalpha', 'Enzyme', (44, 52))	('RAMH', 'Chemical', 'MESH:C069357', (0, 4))
189958	19825989	Silencing of PKCalpha prevented RAMH inhibition of Mz-ChA-1 cell growth and ablated RAMH effects on ERK1/2 phosphorylation.	('ERK1/2', 'Gene', (100, 106))	('ERK1/2', 'Gene', '5595;5594', (100, 106))	('RAMH', 'Chemical', 'MESH:C069357', (32, 36))	('PKCalpha', 'Enzyme', (13, 21))	('ablated', 'NegReg', (76, 83))	('RAMH', 'Chemical', 'MESH:C069357', (84, 88))	('Mz-ChA-1', 'Chemical', '-', (51, 59))	('Silencing', 'Var', (0, 9))
189959	19825989	In vivo, RAMH decreased tumor growth and expression of VEGF and its receptors; PKCalpha expression was increased.	('tumor growth', 'Disease', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor growth', 'Disease', 'MESH:D006130', (24, 36))	('decreased', 'NegReg', (14, 23))	('increased', 'PosReg', (103, 112))	('expression', 'MPA', (41, 51))	('VEGF', 'Protein', (55, 59))	('RAMH', 'Chemical', 'MESH:C069357', (9, 13))	('RAMH', 'Var', (9, 13))	('PKCalpha', 'Enzyme', (79, 87))	('expression', 'MPA', (88, 98))
189960	19825989	RAMH inhibits cholangiocarcinoma growth by PKCalpha-dependent ERK1/2 dephosphorylation.	('ERK1/2', 'Gene', (62, 68))	('dephosphorylation', 'MPA', (69, 86))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (14, 39))	('ERK1/2', 'Gene', '5595;5594', (62, 68))	('RAMH', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('RAMH', 'Chemical', 'MESH:C069357', (0, 4))	('inhibits', 'NegReg', (5, 13))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (14, 32))	('cholangiocarcinoma growth', 'Disease', (14, 39))
189961	19825989	Modulation of PKCalpha by histamine receptors may be important in regulating cholangiocarcinoma growth.	('Modulation', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (77, 95))	('PKCalpha', 'Enzyme', (14, 22))	('cholangiocarcinoma growth', 'Disease', (77, 102))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (77, 102))	('histamine', 'Chemical', 'MESH:D006632', (26, 35))
189982	19825989	1,2-Bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, tetraacetoxymethyl ester (BAPTA/AM), Go6976, and U73122 blocked the inhibitory effect of RAMH on Mz-ChA-1 cell growth (Fig.	("1,2-Bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid", 'Chemical', 'MESH:C025603', (0, 58))	('tetraacetoxymethyl ester', 'Chemical', '-', (60, 84))	('Go6976', 'Chemical', 'MESH:C081021', (97, 103))	('U73122', 'Var', (109, 115))	('BAPTA', 'Chemical', 'MESH:C025603', (86, 91))	('RAMH', 'Chemical', 'MESH:C069357', (149, 153))	('U73122', 'Chemical', 'MESH:C060229', (109, 115))	('Mz-ChA-1', 'Chemical', '-', (157, 165))	('Mz-ChA-1 cell growth', 'CPA', (157, 177))	('RAMH', 'Gene', (149, 153))
189984	19825989	Treatment of Mz-ChA-1 cells with the specific agonists for HRH1, HRH2, or HRH4 showed that HRH1 and HRH2 had slight proliferative effects on Mz-ChA-1 growth, whereas the HRH4 agonist decreases growth (data not shown).	('Mz-ChA-1', 'Chemical', '-', (141, 149))	('HRH1', 'Var', (91, 95))	('Mz-ChA-1', 'Chemical', '-', (13, 21))	('decreases growth', 'Phenotype', 'HP:0001510', (183, 199))	('proliferative effects', 'CPA', (116, 137))	('HRH2', 'Gene', (100, 104))
189985	19825989	As RAMH was shown to decrease cholangiocarcinoma growth at varying concentrations, we chose to use a similar dose (10 mumol/L) that we have previously used to inhibit the growth of hyperplastic cholangiocytes.	('RAMH', 'Chemical', 'MESH:C069357', (3, 7))	('growth', 'MPA', (171, 177))	('decrease', 'NegReg', (21, 29))	('RAMH', 'Var', (3, 7))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (30, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('cholangiocarcinoma growth', 'Disease', (30, 55))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (30, 55))	('inhibit', 'NegReg', (159, 166))
189986	19825989	RAMH (10 mumol/L) significantly (P < 0.05) increased intracellular IP3 levels of Mz-ChA-1 cells compared with their corresponding basal levels [0.98 +- 0.026 (basal) versus 1.82 +- 0.002 (RAMH) pmol/1 x 106 cells], but not cAMP levels [144.48 +- 5.6 (basal) versus 153.48 +- 5.7 (RAMH) fmol/1 x 105 cells].	('increased intracellular IP3', 'Phenotype', 'HP:0003575', (43, 70))	('RAMH', 'Var', (0, 4))	('IP3', 'Chemical', 'MESH:D015544', (67, 70))	('RAMH', 'Chemical', 'MESH:C069357', (280, 284))	('intracellular IP3 levels', 'MPA', (53, 77))	('Mz-ChA-1', 'Chemical', '-', (81, 89))	('RAMH', 'Chemical', 'MESH:C069357', (188, 192))	('increased', 'PosReg', (43, 52))	('RAMH', 'Chemical', 'MESH:C069357', (0, 4))
189996	19825989	Figure 3C clearly shows that PKCalpha expression is increased in the membrane fraction after RAMH treatment, compared with the higher basal expression seen in the cytosol fraction.	('increased', 'PosReg', (52, 61))	('RAMH', 'Chemical', 'MESH:C069357', (93, 97))	('expression', 'MPA', (38, 48))	('RAMH treatment', 'Var', (93, 107))	('PKCalpha', 'Protein', (29, 37))
190000	19825989	However, in mock-transfected cells, RAMH (10 mumol/L) decreased the proliferation (similar to levels seen in Fig.	('RAMH', 'Chemical', 'MESH:C069357', (36, 40))	('proliferation', 'CPA', (68, 81))	('decreased', 'NegReg', (54, 63))	('RAMH', 'Var', (36, 40))
190003	19825989	However, RAMH decreased the phosphorylation of the mitogen-activated protein kinase (MAPK), ERK1/2, compared with its basal value (Fig.	('decreased', 'NegReg', (14, 23))	('RAMH', 'Chemical', 'MESH:C069357', (9, 13))	('phosphorylation', 'MPA', (28, 43))	('ERK1/2', 'Gene', (92, 98))	('RAMH', 'Var', (9, 13))	('ERK1/2', 'Gene', '5595;5594', (92, 98))
190012	19825989	Histologically, no changes were seen in fibrosis or inflammation in tumors from either RAMH- or vehicle-treated mice (data not shown); however, necrosis was significantly upregulated in RAMH-treated tumors [20.17 +- 1.84 (vehicle) versus 36.88 +- 4.92 (RAMH)] compared with tumors from vehicle-treated mice.	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('necrosis', 'Disease', 'MESH:D009336', (144, 152))	('necrosis', 'Disease', (144, 152))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('upregulated', 'PosReg', (171, 182))	('RAMH', 'Chemical', 'MESH:C069357', (186, 190))	('RAMH-treated', 'Var', (186, 198))	('fibrosis', 'Disease', 'MESH:D005355', (40, 48))	('fibrosis', 'Disease', (40, 48))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mice', 'Species', '10090', (112, 116))	('tumors', 'Disease', (274, 280))	('inflammation in tumors', 'Disease', 'MESH:D007249', (52, 74))	('tumors', 'Disease', (68, 74))	('RAMH', 'Chemical', 'MESH:C069357', (87, 91))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('inflammation in tumors', 'Disease', (52, 74))	('mice', 'Species', '10090', (302, 306))	('RAMH', 'Chemical', 'MESH:C069357', (253, 257))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
190013	19825989	The number of proliferating cell nuclear antigen (PCNA)-positive cells was decreased in RAMH-treated animals compared with vehicle-treated mice (Fig.	('proliferating cell nuclear antigen', 'Gene', '18538', (14, 48))	('proliferating cell nuclear antigen', 'Gene', (14, 48))	('RAMH', 'Chemical', 'MESH:C069357', (88, 92))	('mice', 'Species', '10090', (139, 143))	('RAMH-treated', 'Var', (88, 100))	('decreased', 'NegReg', (75, 84))
190014	19825989	5B, top), whereas apoptosis (evaluated by caspase-3 protein expression) increased in tumors from RAMH-treated compared with vehicle-treated mice (Fig.	('increased', 'PosReg', (72, 81))	('mice', 'Species', '10090', (140, 144))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('RAMH', 'Chemical', 'MESH:C069357', (97, 101))	('RAMH-treated', 'Var', (97, 109))	('apoptosis', 'CPA', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
190016	19825989	3A), we found that total PKCalpha expression was significantly increased in tumors from RAMH-treated mice compared with vehicle (Fig.	('increased', 'PosReg', (63, 72))	('expression', 'MPA', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('mice', 'Species', '10090', (101, 105))	('RAMH', 'Chemical', 'MESH:C069357', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('RAMH-treated', 'Var', (88, 100))	('PKCalpha', 'Enzyme', (25, 33))
190021	19825989	In vitro, we showed that (a) HRH3 are upregulated in cholangiocarcinoma cells and in human tissue arrays compared with normal cells and tissues; (b) RAMH inhibits the growth of cholangiocarcinoma growth by increased levels of IP3; further, RAMH induces translocation and enhanced phosphorylation of PKCalpha, which leads to a dephosphorylation of ERK1/2; and (c) PKCalpha knockdown prevents RAMH inhibition of cholangiocarcinoma growth and ERK1/2 phosphorylation.	('phosphorylation', 'MPA', (280, 295))	('ERK1/2', 'Gene', (440, 446))	('enhanced', 'PosReg', (271, 279))	('ERK1/2', 'Gene', '5595;5594', (440, 446))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (410, 428))	('RAMH', 'Chemical', 'MESH:C069357', (149, 153))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (177, 202))	('growth', 'CPA', (167, 173))	('PKCalpha', 'Enzyme', (299, 307))	('cholangiocarcinoma', 'Disease', (410, 428))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (177, 195))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (410, 428))	('cholangiocarcinoma growth', 'Disease', (410, 435))	('cholangiocarcinoma', 'Disease', (177, 195))	('RAMH', 'Chemical', 'MESH:C069357', (391, 395))	('dephosphorylation', 'MPA', (326, 343))	('carcinoma', 'Phenotype', 'HP:0030731', (419, 428))	('RAMH', 'Chemical', 'MESH:C069357', (240, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('IP3', 'Chemical', 'MESH:D015544', (226, 229))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (177, 195))	('ERK1/2', 'Gene', (347, 353))	('RAMH', 'Var', (240, 244))	('ERK1/2', 'Gene', '5595;5594', (347, 353))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (410, 435))	('human', 'Species', '9606', (85, 90))	('prevents', 'NegReg', (382, 390))	('knockdown', 'Var', (372, 381))	('translocation', 'MPA', (253, 266))	('inhibits', 'NegReg', (154, 162))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (53, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('phosphorylation', 'MPA', (447, 462))	('cholangiocarcinoma growth', 'Disease', (177, 202))	('cholangiocarcinoma', 'Disease', (53, 71))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (53, 71))
190022	19825989	In vivo, we showed that (a) RAMH inhibits the growth of Mz-ChA-1 cells implanted in nude mice coupled with enhanced apoptosis, and (b) RAMH inhibition of cholangiocarcinoma growth was associated with enhanced expression of PKCalpha and reduced expression of VEGF-A, VEGF-C, VEGFR-2, and VEGFR-3.	('expression', 'MPA', (209, 219))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (154, 172))	('RAMH', 'Var', (135, 139))	('enhanced', 'PosReg', (200, 208))	('Mz-ChA-1', 'Chemical', '-', (56, 64))	('RAMH', 'Chemical', 'MESH:C069357', (28, 32))	('VEGFR-3', 'Gene', (287, 294))	('apoptosis', 'CPA', (116, 125))	('RAMH', 'Var', (28, 32))	('VEGF-C', 'Gene', (266, 272))	('inhibition', 'NegReg', (140, 150))	('VEGFR-2', 'Gene', (274, 281))	('nude mice', 'Species', '10090', (84, 93))	('growth', 'CPA', (46, 52))	('reduced', 'NegReg', (236, 243))	('cholangiocarcinoma growth', 'Disease', (154, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('VEGF-A', 'Gene', (258, 264))	('PKCalpha', 'Protein', (223, 231))	('RAMH', 'Chemical', 'MESH:C069357', (135, 139))	('expression', 'MPA', (244, 254))	('inhibits', 'NegReg', (33, 41))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (154, 179))
190023	19825989	Our present studies correlate with our previous study showing that RAMH decreases the growth of hyperplastic cholangiocytes.	('growth of hyperplastic cholangiocytes', 'CPA', (86, 123))	('RAMH', 'Chemical', 'MESH:C069357', (67, 71))	('RAMH', 'Var', (67, 71))	('decreases', 'NegReg', (72, 81))
190038	19825989	In our study, we have shown that PKCalpha plays a key role in RAMH inhibition of cholangiocarcinoma growth because (a) this HRH3 agonist induces activation of the PLC/Ca2+/IP3/PKCalpha signaling pathway; (b) RAMH inhibitory action is dependent on this signaling pathway; (c) RAMH induces activation and translocation of PKCalpha; and (d) gene silencing of PKCalpha prevents the inhibitory effects induced by RAMH including phosphorylation of ERK1/2.	('RAMH', 'Chemical', 'MESH:C069357', (62, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('phosphorylation', 'MPA', (423, 438))	('PKCalpha', 'Enzyme', (356, 364))	('gene silencing', 'Var', (338, 352))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (81, 106))	('IP3', 'Chemical', 'MESH:D015544', (172, 175))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (81, 99))	('translocation', 'MPA', (303, 316))	('RAMH', 'Chemical', 'MESH:C069357', (408, 412))	('Ca2+', 'Chemical', 'MESH:D000069285', (167, 171))	('RAMH', 'Chemical', 'MESH:C069357', (208, 212))	('ERK1/2', 'Gene', (442, 448))	('ERK1/2', 'Gene', '5595;5594', (442, 448))	('activation', 'MPA', (288, 298))	('PKCalpha', 'Enzyme', (320, 328))	('PLC/Ca2+/IP3/PKCalpha signaling pathway', 'Pathway', (163, 202))	('cholangiocarcinoma growth', 'Disease', (81, 106))	('RAMH', 'Chemical', 'MESH:C069357', (275, 279))
190055	19825989	Further, RAMH increased PKCalpha expression and significantly decreased the expression of VEGF (and its receptors) in vivo.	('increased', 'PosReg', (14, 23))	('VEGF', 'Gene', (90, 94))	('decreased', 'NegReg', (62, 71))	('RAMH', 'Chemical', 'MESH:C069357', (9, 13))	('PKCalpha', 'Protein', (24, 32))	('expression', 'MPA', (76, 86))	('expression', 'MPA', (33, 43))	('RAMH', 'Var', (9, 13))
190072	19825989	To evaluate the intracellular mechanisms by which RAMH regulates cholangiocarcinoma growth, Mz-ChA-1 cells were stimulated with 0.1% BSA (basal) or RAMH (10 mumol/L with 0.1% BSA, 24 h) in the absence or presence of the following inhibitors: BAPTA/AM (an intracellular Ca2+ chelator, 5 mumol/L), Go6976 (a PKCalpha inhibitor, 1 mumol/L), and U73122 (a PLC inhibitor; 1 mumol/L).	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (65, 90))	('U73122', 'Var', (342, 348))	('RAMH', 'Chemical', 'MESH:C069357', (148, 152))	('Go6976', 'Var', (296, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('RAMH', 'Chemical', 'MESH:C069357', (50, 54))	('Mz-ChA-1', 'Chemical', '-', (92, 100))	('Ca2+', 'Chemical', 'MESH:D000069285', (269, 273))	('BAPTA', 'Chemical', 'MESH:C025603', (242, 247))	('U73122', 'Chemical', 'MESH:C060229', (342, 348))	('Go6976', 'Chemical', 'MESH:C081021', (296, 302))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))	('cholangiocarcinoma growth', 'Disease', (65, 90))
190082	19825989	To evaluate the effects of PKCalpha on cholangiocarcinoma growth, we used siRNA to knock down the expression of PKCalpha and evaluated cholangiocarcinoma growth by PCNA protein expression and the phosphorylation of ERK1/2 by immunoblotting analysis.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (39, 57))	('phosphorylation', 'MPA', (196, 211))	('cholangiocarcinoma growth', 'Disease', (135, 160))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (135, 160))	('cholangiocarcinoma growth', 'Disease', (39, 64))	('cholangiocarcinoma growth', 'Disease', 'MESH:D018281', (39, 64))	('knock', 'Var', (83, 88))	('ERK1/2', 'Gene', (215, 221))	('PKCalpha', 'Gene', (112, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('ERK1/2', 'Gene', '5595;5594', (215, 221))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (135, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
190158	30719105	With regards to the Mayo Clinic protocol, the clinical diagnosis of hilar cholangiocarcinoma requires the presence of a malignant-appearing stricture on percutaneous or endoscopic cholangiography, and at least one of the following: Polysomy on fluorescent in situ hybridization-16; CA19.9 level >100 U/ml; malignant cytology or histology on transluminal brushings or biopsy; and identification of a hilar mass on cross-sectional imaging at the site of the malignant-appearing stricture.	('Polysomy', 'Var', (232, 240))	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (68, 92))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (74, 92))	('hilar cholangiocarcinoma', 'Disease', (68, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('Mayo', 'Species', '162683', (20, 24))
190191	28622513	Significant alterations by mutation or down-regulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed.	('hypermethylation', 'Var', (58, 74))	('alterations', 'Reg', (12, 23))	('down-regulation', 'NegReg', (39, 54))	('mutation', 'Var', (27, 35))	('HCC', 'Gene', (104, 107))	('APOB', 'Gene', '338', (138, 142))	('ALB', 'Gene', '213', (133, 136))	('APOB', 'Gene', (138, 142))	('CPS1', 'Gene', '1373', (148, 152))	('CPS1', 'Gene', (148, 152))	('HCC', 'Gene', '619501', (104, 107))	('ALB', 'Gene', (133, 136))
190200	28622513	Genetic and epigenetic alterations that progressively accumulate in a background of increased reactive oxygen species, inflammatory cytokines and fibrosis likely lead to the initiation of HCC.	('HCC', 'Gene', (188, 191))	('epigenetic alterations', 'Var', (12, 34))	('HCC', 'Gene', '619501', (188, 191))	('increased', 'PosReg', (84, 93))	('fibrosis', 'Disease', 'MESH:D005355', (146, 154))	('fibrosis', 'Disease', (146, 154))	('increased reactive oxygen species', 'Phenotype', 'HP:0025464', (84, 117))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (94, 117))	('lead to', 'Reg', (162, 169))
190205	28622513	As part of The Cancer Genome Atlas (TCGA) network we have performed the first large scale multi-platform analysis of HCC, including evaluation of somatic mutations and DNA copy number in 363 patients, and examination of DNA methylation, mRNA expression, microRNA (miRNA) expression and protein expression in 196 patients to understand the molecular landscape of HCCs (Table S1A-C).	('Cancer Genome Atlas', 'Disease', (15, 34))	('patients', 'Species', '9606', (191, 199))	('HCC', 'Gene', '619501', (117, 120))	('Cancer', 'Phenotype', 'HP:0002664', (15, 21))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (15, 34))	('patients', 'Species', '9606', (312, 320))	('HCCs', 'Gene', (362, 366))	('miR', 'Gene', '220972', (264, 267))	('HCC', 'Gene', (117, 120))	('HCC', 'Gene', (362, 365))	('miR', 'Gene', (264, 267))	('mutations', 'Var', (154, 163))	('HCCs', 'Gene', '3052', (362, 366))	('HCC', 'Gene', '619501', (362, 365))	('mRNA', 'MPA', (237, 241))
190210	28622513	These included the tumor suppressor genes TP53 (31%), AXIN1 (8%) and RB1 (4%) that were inactivated by mutation, the WNT pathway oncogene CTNNB1 (27%), and the chromatin remodeling genes ARID1A (7%), ARID2 (5%) and BAP1 (5%) (Figure 1, Table S2A-B).	('ARID2', 'Gene', '196528', (200, 205))	('CTNNB1', 'Gene', (138, 144))	('TP53', 'Gene', '7157', (42, 46))	('CTNNB1', 'Gene', '1499', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('TP53', 'Gene', (42, 46))	('ARID2', 'Gene', (200, 205))	('RB1', 'Gene', '5925', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('BAP1', 'Gene', '8314', (215, 219))	('AXIN1', 'Gene', '8312', (54, 59))	('tumor', 'Disease', (19, 24))	('BAP1', 'Gene', (215, 219))	('mutation', 'Var', (103, 111))	('ARID1A', 'Gene', (187, 193))	('AXIN1', 'Gene', (54, 59))	('ARID1A', 'Gene', '8289', (187, 193))	('RB1', 'Gene', (69, 72))
190211	28622513	NFE2L2 and its interactor KEAP1, important in cellular anti-oxidant defenses, were significantly mutated in 3% and 5% of HCC, respectively.	('HCC', 'Gene', '619501', (121, 124))	('KEAP1', 'Gene', (26, 31))	('mutated', 'Var', (97, 104))	('NFE2L2', 'Gene', '4780', (0, 6))	('HCC', 'Gene', (121, 124))	('NFE2L2', 'Gene', (0, 6))	('KEAP1', 'Gene', '9817', (26, 31))
190212	28622513	Albumin (ALB) and APOB mutations were observed in 13% and 10% of tumors, consistent with previous HCC sequencing studies (Figure 1, Table S2B).	('HCC', 'Gene', (98, 101))	('ALB', 'Gene', '213', (9, 12))	('HCC', 'Gene', '619501', (98, 101))	('Albumin', 'Gene', '213', (0, 7))	('mutations', 'Var', (23, 32))	('tumors', 'Disease', (65, 71))	('ALB', 'Gene', (9, 12))	('APOB', 'Gene', (18, 22))	('Albumin', 'Gene', (0, 7))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('APOB', 'Gene', '338', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('observed', 'Reg', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
190215	28622513	Because ALB expression accounts for 20% of cellular mRNA and APOB consumes large amounts of cellular energy by facilitating VLDL secretion, there may be selection for ALB or APOB inactivating mutations to divert energy into cancer-relevant metabolic pathways.	('facilitating', 'PosReg', (111, 123))	('ALB', 'Gene', '213', (8, 11))	('APOB', 'Gene', '338', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('APOB', 'Gene', (61, 65))	('APOB', 'Gene', '338', (174, 178))	('APOB', 'Gene', (174, 178))	('ALB', 'Gene', (8, 11))	('ALB', 'Gene', '213', (167, 170))	('VLDL secretion', 'MPA', (124, 138))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('divert', 'Reg', (205, 211))	('ALB', 'Gene', (167, 170))	('cancer', 'Disease', (224, 230))	('inactivating mutations', 'Var', (179, 201))
190217	28622513	LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes, was mutated in 10 of 377 HCC (3%).	('HCC', 'Gene', (92, 95))	('CUL3', 'Gene', '8452', (30, 34))	('HCC', 'Gene', '619501', (92, 95))	('mutated', 'Var', (71, 78))	('CUL3', 'Gene', (30, 34))	('LZTR1', 'Gene', '8216', (0, 5))	('LZTR1', 'Gene', (0, 5))
190218	28622513	Eight LZTR1 mutations were inactivating splice site mutations at codon 217, a mutation observed in adrenocortical and pancreatic cancers.	('LZTR1', 'Gene', (6, 11))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('mutations', 'Var', (12, 21))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (118, 136))	('LZTR1', 'Gene', '8216', (6, 11))	('adrenocortical and pancreatic cancers', 'Disease', 'MESH:D000306', (99, 136))
190219	28622513	LZTR1 germline mutations have been associated with inherited segmental schwannomatosis and somatic LTZR1 mutations are identified as driver mutations in glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (153, 165))	('inherited segmental schwannomatosis', 'Disease', (51, 86))	('LTZR1', 'Gene', (99, 104))	('glioblastoma', 'Phenotype', 'HP:0012174', (153, 165))	('associated', 'Reg', (35, 45))	('mutations', 'Var', (105, 114))	('inherited segmental schwannomatosis', 'Disease', 'MESH:C537538', (51, 86))	('LZTR1', 'Gene', '8216', (0, 5))	('glioblastoma', 'Disease', (153, 165))	('LZTR1', 'Gene', (0, 5))
190220	28622513	The translation elongation factor gene EEF1A1 was significantly mutated in 10 tumors and five tumors contained S432I/S mutations, a codon mutation observed in HCC and other cancers.	('tumors', 'Disease', (78, 84))	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('HCC', 'Gene', '619501', (159, 162))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('EEF1A1', 'Gene', (39, 45))	('cancers', 'Disease', (173, 180))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('HCC', 'Gene', (159, 162))	('EEF1A1', 'Gene', '1915', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('S432I', 'Var', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('S432I', 'SUBSTITUTION', 'None', (111, 116))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))
190223	28622513	In addition to algorithmically curated SMGs, we manually curated two genes with MutSigCV q values close to 0.1 as likely driver genes due to recurrent mutations.	('SMG', 'Gene', '23034', (39, 42))	('mutations', 'Var', (151, 160))	('SMG', 'Gene', (39, 42))
190224	28622513	SF3B1, a splicing factor gene, was mutated in 10 patients, with mutations in codons N626 and K666 occurring twice each in our HCC tumor set and 11 and 21 times, respectively, across other tumor studies.	('tumor', 'Disease', (188, 193))	('SF3B1', 'Gene', (0, 5))	('HCC tumor', 'Disease', (126, 135))	('K666', 'Var', (93, 97))	('HCC tumor', 'Disease', 'MESH:D006528', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('SF3B1', 'Gene', '23451', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('patients', 'Species', '9606', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', (130, 135))
190225	28622513	SF3B1 mutations have been reported as likely driver mutations in hematopoietic malignancies.	('SF3B1', 'Gene', (0, 5))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (65, 91))	('SF3B1', 'Gene', '23451', (0, 5))	('hematopoietic malignancies', 'Disease', (65, 91))	('mutations', 'Var', (6, 15))
190226	28622513	SMARCA4, encoding a chromatin modifier of the SWI/SNF family, was mutated in 11 HCC patient tumors.	('SMARCA4', 'Gene', (0, 7))	('mutated', 'Var', (66, 73))	('HCC', 'Gene', '619501', (80, 83))	('SMARCA4', 'Gene', '6597', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('HCC', 'Gene', (80, 83))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('patient', 'Species', '9606', (84, 91))
190228	28622513	Mutations in SMARCA4 have been observed in some cancer types, including 4 of 36 HCC.	('SMARCA4', 'Gene', (13, 20))	('HCC', 'Gene', '619501', (80, 83))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('SMARCA4', 'Gene', '6597', (13, 20))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('observed', 'Reg', (31, 39))	('HCC', 'Gene', (80, 83))
190231	28622513	Further analysis revealed a germline TERT promoter mutation (C228T) in the blood and tumor of an HBV-positive 29-year-old Asian male with no recorded family history of HCC.	('tumor', 'Disease', (85, 90))	('HCC', 'Gene', (168, 171))	('TERT', 'Gene', (37, 41))	('TERT', 'Gene', '7015', (37, 41))	('C228T', 'Mutation', 'c.228C>T', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('HCC', 'Gene', '619501', (168, 171))	('C228T', 'Var', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('HBV', 'Species', '10407', (97, 100))
190232	28622513	Germline TERT mutations (1,295,161 T>G at the transcription start site) were associated with familial melanoma, but germline mutation at position C228T has not been reported.	('familial melanoma', 'Disease', (93, 110))	('161 T>G', 'Mutation', 'c.161T>G', (31, 38))	('1,295,161 T>G', 'Var', (25, 38))	('TERT', 'Gene', '7015', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('C228T', 'Mutation', 'c.228C>T', (146, 151))	('TERT', 'Gene', (9, 13))	('associated', 'Reg', (77, 87))
190233	28622513	Patients with a TERT promoter mutation were older (p=0.0006), predominantly male (p=0.006), more likely to be HCV positive (p=0.04) and less likely to be HBV positive (p=0.02) than patients without the mutation.	('TERT', 'Gene', (16, 20))	('HBV', 'Species', '10407', (154, 157))	('TERT', 'Gene', '7015', (16, 20))	('mutation', 'Var', (30, 38))	('HCV', 'Species', '11103', (110, 113))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (181, 189))
190237	28622513	We performed mutational signature analysis on the core set of 196 HCC applying a Bayesian variant of the non-negative matrix factorization (NMF) algorithm to mutation counts of single nucleotide variants (SNVs) stratified by 96-trinucleotide contexts.	('trinucleotide', 'Chemical', '-', (228, 241))	('single nucleotide variants', 'Var', (177, 203))	('HCC', 'Gene', (66, 69))	('HCC', 'Gene', '619501', (66, 69))
190239	28622513	Nine samples significantly associated with the plant-derived carcinogen aristolochic acid (AA) signature had a predominance of A:T-to-T:A transversions at [C T]AG tri-nucleotide motifs and these samples had a significant enrichment of splice-site mutations (P=10-6 by Wilcoxon rank-sum test) due to overlap of the motif with the canonical splice acceptor site.	('associated', 'Reg', (27, 37))	('aristolochic acid', 'Chemical', 'MESH:C000228', (72, 89))	('splice-site', 'MPA', (235, 246))	('transversions', 'Var', (138, 151))	('tri-', 'Chemical', '-', (163, 167))
190240	28622513	Seven samples were significantly correlated with mutational signature B (Sig B), associated with Aflatoxin B1 exposure, characterized by an excess of G:C-to-T:A transversions.	('Aflatoxin B1', 'Chemical', 'MESH:D016604', (97, 109))	('mutational signature B', 'Var', (49, 71))	('Aflatoxin B1', 'Gene', (97, 109))	('G:C-to-T:A transversions', 'Var', (150, 174))
190241	28622513	Aflatoxin B1 exposure is a risk factor for HCC, associated with hotspot mutation R249S.	('Aflatoxin B1', 'Chemical', 'MESH:D016604', (0, 12))	('R249S', 'Mutation', 'rs28934571', (81, 86))	('HCC', 'Gene', '619501', (43, 46))	('R249S', 'Var', (81, 86))	('HCC', 'Gene', (43, 46))
190245	28622513	GISTIC 2.0 analysis of all tumors identified 28 significantly reoccurring focal amplifications including those containing well characterized driver oncogenes such as CCND1 and FGF19 (11q13.3), MYC (8q24.21), MET (7q31.2), VEGFA (6p21.1), and MCL1 (1q21.3).	('MYC', 'Gene', '4609', (193, 196))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('MCL1', 'Gene', (242, 246))	('VEGFA', 'Gene', '7422', (222, 227))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('CCND1', 'Gene', '595', (166, 171))	('FGF19', 'Gene', (176, 181))	('MYC', 'Gene', (193, 196))	('FGF19', 'Gene', '9965', (176, 181))	('MET (7q31.2', 'Var', (208, 219))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('VEGFA', 'Gene', (222, 227))	('MCL1', 'Gene', '4170', (242, 246))	('CCND1', 'Gene', (166, 171))
190247	28622513	Among 36 deletion events, 13q14.2 (RB1) and 9p21.3 (CDKN2A) were prominent (Figure S2B).	('RB1', 'Gene', (35, 38))	('RB1', 'Gene', '5925', (35, 38))	('13q14.2', 'Var', (26, 33))	('CDKN2A', 'Gene', (52, 58))	('9p21.3', 'Var', (44, 50))	('CDKN2A', 'Gene', '1029', (52, 58))
190252	28622513	Cluster 3 in particular contained all of the tumors with IDH1/2 mutations and exhibited a distinct DNA hypermethylation profile (Figure 2A), consistent with previous data that IDH1/2 mutations are gain of function lesions that increase levels of cellular D-2-hydroxyglutarate that regulate genomic methylation rates.	('increase', 'PosReg', (227, 235))	('IDH1/2', 'Gene', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mutations', 'Var', (183, 192))	('levels of cellular D-2-hydroxyglutarate', 'MPA', (236, 275))	('regulate', 'Reg', (281, 289))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('IDH1/2', 'Gene', '3417;3418', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('mutations', 'Var', (64, 73))	('IDH1/2', 'Gene', '3417;3418', (57, 63))	('IDH1/2', 'Gene', (176, 182))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (255, 275))	('genomic methylation rates', 'MPA', (290, 315))
190253	28622513	Cluster 4 HCC were disproportionately enriched for CDKN2A epigenetic silencing, TERT promoter mutations and CTNNB1 mutations (Figure 2A).	('CDKN2A', 'Gene', '1029', (51, 57))	('mutations', 'Var', (115, 124))	('CTNNB1', 'Gene', '1499', (108, 114))	('epigenetic silencing', 'Var', (58, 78))	('HCC', 'Gene', (10, 13))	('HCC', 'Gene', '619501', (10, 13))	('CDKN2A', 'Gene', (51, 57))	('TERT', 'Gene', (80, 84))	('CTNNB1', 'Gene', (108, 114))	('TERT', 'Gene', '7015', (80, 84))
190255	28622513	Two approaches (see Supplementary Methods) were used to identify those genes with high levels of tumor-specific hypermethylation in conjunction with reduced RNA expression (Table S4A).	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('hypermethylation', 'Var', (112, 128))
190257	28622513	CDKN2A epigenetic silencing was found in 53% (102/191) of samples whereas CDKN2A mutations were observed in 4% of HCC, indicating that DNA methylation is the predominant mechanism for CDKN2A inactivation (Figure 2B, Table S4A) in HCC.	('CDKN2A', 'Gene', '1029', (0, 6))	('CDKN2A', 'Gene', '1029', (184, 190))	('epigenetic silencing', 'Var', (7, 27))	('HCC', 'Gene', (230, 233))	('CDKN2A', 'Gene', (74, 80))	('CDKN2A', 'Gene', '1029', (74, 80))	('HCC', 'Gene', '619501', (114, 117))	('HCC', 'Gene', (114, 117))	('inactivation', 'NegReg', (191, 203))	('HCC', 'Gene', '619501', (230, 233))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', (184, 190))
190260	28622513	Hypermethylation-mediated downregulation of CPS1 (carbamoyl phosphate synthase I), a liver-specific rate-limiting enzyme of the urea cycle reported as a HCC-hypermethylated gene, may favor glutamine usage in HCC by CAD (carbamoyl phosphate synthase II), which initiates the de novo pyrimidine synthesis pathway, thus favoring cell division (Figure 2H, Table S4A).	('urea', 'Chemical', 'MESH:D014508', (128, 132))	('CPS1', 'Gene', (44, 48))	('glutamine', 'Chemical', 'MESH:D005973', (189, 198))	('CPS1', 'Gene', '1373', (44, 48))	('downregulation', 'NegReg', (26, 40))	('favoring', 'PosReg', (317, 325))	('HCC', 'Gene', '619501', (208, 211))	('favor', 'PosReg', (183, 188))	('HCC', 'Gene', '619501', (153, 156))	('cell division', 'CPA', (326, 339))	('Hypermethylation-mediated', 'Var', (0, 25))	('pyrimidine', 'Chemical', 'MESH:C030986', (282, 292))	('HCC', 'Gene', (208, 211))	('HCC', 'Gene', (153, 156))	('glutamine usage', 'MPA', (189, 204))
190262	28622513	Of the 298 genes exhibiting significant HCC-specific hypermethylation, 81 have been reported to be hypermethylated and another 28 have been reported to be downregulated (methylation status unknown) in HCC or other cancers relative to normal tissues (Table S4A).	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('HCC', 'Gene', '619501', (40, 43))	('cancers', 'Disease', (214, 221))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('HCC', 'Gene', (201, 204))	('downregulated', 'NegReg', (155, 168))	('hypermethylation', 'Var', (53, 69))	('HCC', 'Gene', (40, 43))	('HCC', 'Gene', '619501', (201, 204))
190267	28622513	HBV+ HCCs were significantly more likely to be mutated in TP53 and significantly less likely to harbor TERT promoter mutations than HBV- HCCs.	('HCCs', 'Gene', (137, 141))	('HCCs', 'Gene', '3052', (5, 9))	('HCCs', 'Gene', '3052', (137, 141))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('HBV', 'Species', '10407', (0, 3))	('HBV', 'Species', '10407', (132, 135))	('less', 'NegReg', (81, 85))	('TERT', 'Gene', (103, 107))	('mutated', 'Var', (47, 54))	('TERT', 'Gene', '7015', (103, 107))	('HCCs', 'Gene', (5, 9))
190272	28622513	The five tumors with MLL4 insertions and one of the two TERT insertions displayed the highest levels of MLL4 and TERT RNA expression among all HCC, suggesting an HBV cis-activating event (Table S5C).	('insertions', 'Var', (26, 36))	('MLL4', 'MPA', (104, 108))	('TERT', 'Gene', '7015', (113, 117))	('MLL4', 'Gene', (21, 25))	('HCC', 'Gene', (143, 146))	('levels', 'MPA', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('TERT', 'Gene', '7015', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('HCC', 'Gene', '619501', (143, 146))	('TERT', 'Gene', (56, 60))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('HBV', 'Species', '10407', (162, 165))	('TERT', 'Gene', (113, 117))
190279	28622513	Unsupervised clustering of data from five platforms (DNA copy number, DNA methylation, mRNA expression, miRNA expression and RPPA) gave a collection of discordant subgroupings specific to each data platform.	('mRNA expression', 'MPA', (87, 102))	('miR', 'Gene', (104, 107))	('methylation', 'Var', (74, 85))	('miR', 'Gene', '220972', (104, 107))
190282	28622513	Molecular correlations with iClust1 included a low frequency of CDKN2A silencing (32%) as compared to iClust2 and iClust3 (69% and 63%, respectively, low frequency of CTNNB1 mutation (12% in iClust1 vs 38% and 43% in iClust2 and iClust3, respectively), low frequency of TERT promoter mutation and low TERT expression (Figure 3A, Table S6).	('CTNNB1', 'Gene', (167, 173))	('TERT', 'Gene', (301, 305))	('TERT', 'Gene', '7015', (301, 305))	('TERT', 'Gene', '7015', (270, 274))	('mutation', 'Var', (174, 182))	('CDKN2A', 'Gene', (64, 70))	('silencing', 'NegReg', (71, 80))	('CTNNB1', 'Gene', '1499', (167, 173))	('CDKN2A', 'Gene', '1029', (64, 70))	('TERT', 'Gene', (270, 274))
190283	28622513	iClust1 tumors exhibited specific changes in miRNA expression, including high expression of miR-181a (a lipid metabolism regulator) and epigenetic silencing of miR-122 (Figure S3D).	('miR', 'Gene', (160, 163))	('epigenetic silencing', 'Var', (136, 156))	('expression', 'MPA', (78, 88))	('miR', 'Gene', '220972', (92, 95))	('miR', 'Gene', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('miR', 'Gene', '220972', (45, 48))	('changes', 'Reg', (34, 41))	('miR-122', 'Gene', (160, 167))	('miR', 'Gene', (45, 48))	('tumors', 'Disease', (8, 14))	('lipid', 'Chemical', 'MESH:D008055', (104, 109))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('high', 'PosReg', (73, 77))	('miR-122', 'Gene', '406906', (160, 167))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('miR', 'Gene', '220972', (160, 163))
190285	28622513	In contrast, iClust2 (n=55) and iClust3 (n=63) exhibited a high frequency of CDKN2A silencing by DNA hypermethylation, high frequency of TERT promoter mutation, CTNNB1 mutation, and enrichment for HNF1A mutation.	('HNF1A', 'Gene', '6927', (197, 202))	('TERT', 'Gene', (137, 141))	('CDKN2A', 'Gene', (77, 83))	('silencing', 'NegReg', (84, 93))	('hypermethylation', 'Var', (101, 117))	('TERT', 'Gene', '7015', (137, 141))	('CTNNB1', 'Gene', (161, 167))	('CDKN2A', 'Gene', '1029', (77, 83))	('mutation', 'Var', (203, 211))	('HNF1A', 'Gene', (197, 202))	('mutation', 'Var', (168, 176))	('CTNNB1', 'Gene', '1499', (161, 167))
190287	28622513	iClust3 was characterized by a higher degree of chromosomal instability with distinct 17p loss, high frequency of TP53 mutation and hypomethylation of multiple CpG sites.	('mutation', 'Var', (119, 127))	('loss', 'NegReg', (90, 94))	('chromosomal instability', 'Phenotype', 'HP:0040012', (48, 71))	('17p', 'Protein', (86, 89))	('TP53', 'Gene', '7157', (114, 118))	('hypomethylation', 'Var', (132, 147))	('TP53', 'Gene', (114, 118))
190292	28622513	Analysis of the mutation data revealed two mutations in IDH1 (R132C, R132G) and two mutations in IDH2 (R172K, R172S), in four different tumors.	('IDH2', 'Gene', (97, 101))	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('IDH2', 'Gene', '3418', (97, 101))	('R132C', 'Var', (62, 67))	('R132C', 'Mutation', 'rs121913499', (62, 67))	('IDH1', 'Gene', '3417', (56, 60))	('R132G', 'Mutation', 'rs121913499', (69, 74))	('R172K', 'Mutation', 'rs121913503', (103, 108))	('R172S', 'Mutation', 'rs1057519736', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('R172S', 'Var', (110, 115))	('R132G', 'Var', (69, 74))	('R172K', 'Var', (103, 108))	('IDH1', 'Gene', (56, 60))
190293	28622513	These specific IDH1/2 mutations, seen in multiple human cancers, result in a neomorphic isocitrate dehydrogenase that produces an oncometabolite believed to alter cellular epigenetic programs and block normal differentiation.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('block', 'NegReg', (196, 201))	('IDH1/2', 'Gene', (15, 21))	('alter', 'Reg', (157, 162))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (22, 31))	('result in', 'Reg', (65, 74))	('human', 'Species', '9606', (50, 55))	('normal differentiation', 'CPA', (202, 224))	('IDH1/2', 'Gene', '3417;3418', (15, 21))
190294	28622513	IDH1/2 mutations are more frequent in intrahepatic cholangiocarcinomas (CCA) than in HCC, hence the possibility that these tumors actually represented mixed HCC-CCA was considered.	('HCC', 'Gene', (157, 160))	('tumors', 'Disease', (123, 129))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (38, 70))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('intrahepatic cholangiocarcinomas', 'Disease', (38, 70))	('HCC', 'Gene', '619501', (85, 88))	('frequent', 'Reg', (26, 34))	('HCC', 'Gene', '619501', (157, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('IDH1/2', 'Gene', (0, 6))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (51, 69))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('HCC', 'Gene', (85, 88))	('mutations', 'Var', (7, 16))
190298	28622513	These samples were all classified with the poor prognosis iCluster 1 subclass and exhibited similarity to non-differentiated RNA clustering phenotypes (Hoshida C2), cholangiocarcinoma-like (CCL-HCC), silencing of the Hippo pathway (Hippo), and had high Risk Scores based on a gene expression signature of 65 genes (RS65) (Figure 4A), suggesting that HCC with the IDH-like gene expression signature represent a poor prognostic subtype of HCC.	('IDH', 'Gene', '3417', (363, 366))	('cholangiocarcinoma', 'Disease', (165, 183))	('HCC', 'Gene', (350, 353))	('HCC', 'Gene', '619501', (437, 440))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('HCC', 'Gene', '619501', (194, 197))	('IDH', 'Gene', (363, 366))	('Hoshida C2', 'Disease', 'OMIM:217000', (152, 162))	('silencing', 'Var', (200, 209))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (165, 183))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (165, 183))	('HCC', 'Gene', '619501', (350, 353))	('Hoshida C2', 'Disease', (152, 162))	('HCC', 'Gene', (437, 440))	('HCC', 'Gene', (194, 197))
190301	28622513	Intriguingly, miR-122, which is liver-specific and the most abundant miRNA in liver (Figure S4B), was significantly downregulated in some of the IDH-mutant and IDH-like tumors by promoter DNA hypermethylation (Figure S4C).	('miR-122', 'Gene', '406906', (14, 21))	('miR-122', 'Gene', (14, 21))	('downregulated', 'NegReg', (116, 129))	('IDH', 'Gene', (145, 148))	('IDH', 'Gene', '3417', (145, 148))	('promoter DNA hypermethylation', 'Var', (179, 208))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('IDH', 'Gene', (160, 163))	('miR', 'Gene', '220972', (69, 72))	('miR', 'Gene', (69, 72))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('IDH', 'Gene', '3417', (160, 163))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (169, 175))
190302	28622513	miR-122 dysregulation has been observed in HCC studies and has been associated with poor survival.	('dysregulation', 'Var', (8, 21))	('associated', 'Reg', (68, 78))	('HCC', 'Gene', '619501', (43, 46))	('miR-122', 'Gene', '406906', (0, 7))	('miR-122', 'Gene', (0, 7))	('HCC', 'Gene', (43, 46))
190305	28622513	Mutations involving TP53 were found in 31% of patients.	('patients', 'Species', '9606', (46, 54))	('TP53', 'Gene', (20, 24))	('found', 'Reg', (30, 35))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (20, 24))
190309	28622513	While only one HCC with high p53 target expression had a TP53 mutation, 11 out of 48 (23%) samples in the low p53 expression quartile were TP53 wildtype.	('p53', 'Gene', (110, 113))	('HCC', 'Gene', '619501', (15, 18))	('p53', 'Gene', '7157', (110, 113))	('TP53', 'Gene', '7157', (139, 143))	('p53', 'Gene', (29, 32))	('mutation', 'Var', (62, 70))	('p53', 'Gene', '7157', (29, 32))	('TP53', 'Gene', (139, 143))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('HCC', 'Gene', (15, 18))
190314	28622513	Of three external HCC cohorts tested, two showed significantly reduced overall survival of the low p53 signature patients (Figure S5B-D).	('S5B', 'Gene', '5711', (130, 133))	('reduced', 'NegReg', (63, 70))	('low', 'Var', (95, 98))	('patients', 'Species', '9606', (113, 121))	('S5B', 'Gene', (130, 133))	('HCC', 'Gene', (18, 21))	('overall survival', 'MPA', (71, 87))	('p53', 'Gene', '7157', (99, 102))	('p53', 'Gene', (99, 102))	('HCC', 'Gene', '619501', (18, 21))
190320	28622513	The low p53 signature HCC had increased expression of the p53-repressed cell cycle positive regulatory genes CCNB1/2, E2F2/3, and FOXM1.	('expression', 'MPA', (40, 50))	('E2F2/3', 'Gene', '1870;1871', (118, 124))	('CCNB1/2', 'Gene', '891;9133', (109, 116))	('p53', 'Gene', (8, 11))	('HCC', 'Gene', '619501', (22, 25))	('p53', 'Gene', '7157', (8, 11))	('increased', 'PosReg', (30, 39))	('FOXM1', 'Gene', '2305', (130, 135))	('E2F2/3', 'Gene', (118, 124))	('FOXM1', 'Gene', (130, 135))	('CCNB1/2', 'Gene', (109, 116))	('low', 'Var', (4, 7))	('p53', 'Gene', (58, 61))	('HCC', 'Gene', (22, 25))	('p53', 'Gene', '7157', (58, 61))
190321	28622513	We hypothesize that p53 regulates HCC phenotypes in part through the sonic hedgehog pathway via upregulated PTCHD4, the Polycomb repressive complex 2 via downregulated EZH2, and downregulation of S/G2/M promoting cell cycle genes.	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('downregulated', 'NegReg', (154, 167))	('HCC', 'Gene', (34, 37))	('downregulation', 'NegReg', (178, 192))	('EZH2', 'Gene', (168, 172))	('EZH2', 'Gene', '2146', (168, 172))	('PTCHD4', 'Gene', '442213', (108, 114))	('cell', 'CPA', (213, 217))	('regulates', 'Reg', (24, 33))	('PTCHD4', 'Gene', (108, 114))	('upregulated', 'PosReg', (96, 107))	('S/G2', 'Var', (196, 200))	('HCC', 'Gene', '619501', (34, 37))	('sonic hedgehog', 'Gene', (69, 83))	('S/G2', 'SUBSTITUTION', 'None', (196, 200))	('sonic hedgehog', 'Gene', '6469', (69, 83))
190322	28622513	While most gene and pathway alterations were evenly distributed with respect to iCluster classification, some mutations, such as TERT and CTNNB1, were underrepresented in iCluster1 (Figure 6, Figure S6A,B).	('underrepresented', 'NegReg', (151, 167))	('CTNNB1', 'Gene', '1499', (138, 144))	('mutations', 'Var', (110, 119))	('TERT', 'Gene', '7015', (129, 133))	('CTNNB1', 'Gene', (138, 144))	('TERT', 'Gene', (129, 133))
190323	28622513	As described in previous HCC genomics studies, WNT pathway members were frequently mutated or subject to copy number alterations.	('subject', 'Reg', (94, 101))	('HCC', 'Gene', (25, 28))	('HCC', 'Gene', '619501', (25, 28))	('mutated', 'Reg', (83, 90))	('copy number alterations', 'Var', (105, 128))	('WNT pathway', 'Pathway', (47, 58))
190325	28622513	Other key pathways included cell cycle regulatory pathways driven by mutations and copy number changes in RB1, CCND1, CDKN2A and RTK/PI-3 kinase signaling driven by PTEN, PIK3CA, MET, and VEGFA copy number/mutational changes.	('CCND1', 'Gene', (111, 116))	('mutations', 'Var', (69, 78))	('VEGFA', 'Gene', (188, 193))	('CDKN2A', 'Gene', (118, 124))	('RTK', 'Gene', '5979', (129, 132))	('PIK3CA', 'Gene', (171, 177))	('RB1', 'Gene', '5925', (106, 109))	('CDKN2A', 'Gene', '1029', (118, 124))	('PIK3CA', 'Gene', '5290', (171, 177))	('CCND1', 'Gene', '595', (111, 116))	('RTK', 'Gene', (129, 132))	('VEGFA', 'Gene', '7422', (188, 193))	('cell cycle regulatory pathways', 'Pathway', (28, 58))	('copy number/mutational', 'Var', (194, 216))	('RB1', 'Gene', (106, 109))	('PTEN', 'Gene', (165, 169))	('copy number changes', 'Var', (83, 102))	('PTEN', 'Gene', '5728', (165, 169))
190346	28622513	We also noted that a high fraction of HCC exhibited CPS1 hypermethylation accompanied by decreased RNA expression.	('HCC', 'Gene', (38, 41))	('RNA expression', 'MPA', (99, 113))	('CPS1', 'Gene', (52, 56))	('CPS1', 'Gene', '1373', (52, 56))	('hypermethylation', 'Var', (57, 73))	('HCC', 'Gene', '619501', (38, 41))	('decreased', 'NegReg', (89, 98))
190349	28622513	Thus, a key component in the progression of hepatocytes to malignant HCC cells may be metabolic reprogramming through either genetic (ALB, APOB), epigenetic (CPS1) or other mechanisms, converting a cell committed to normal organismal support functions to a cell that supports only its own requirements for growth and division.	('ALB', 'Gene', (134, 137))	('epigenetic', 'Var', (146, 156))	('CPS1', 'Gene', (158, 162))	('HCC', 'Gene', (69, 72))	('CPS1', 'Gene', '1373', (158, 162))	('ALB', 'Gene', '213', (134, 137))	('APOB', 'Gene', '338', (139, 143))	('APOB', 'Gene', (139, 143))	('HCC', 'Gene', '619501', (69, 72))
190354	28622513	The high frequency of TERT promoter mutations suggests that upregulated TERT expression in HCC might be targeted with telomerase inhibitors currently in development.	('TERT', 'Gene', (22, 26))	('upregulated', 'PosReg', (60, 71))	('HCC', 'Gene', '619501', (91, 94))	('TERT', 'Gene', '7015', (22, 26))	('mutations', 'Var', (36, 45))	('TERT', 'Gene', (72, 76))	('TERT', 'Gene', '7015', (72, 76))	('HCC', 'Gene', (91, 94))
190355	28622513	Finally, IDH1/2 mutations were observed in four HCC.	('IDH1/2', 'Gene', (9, 15))	('mutations', 'Var', (16, 25))	('HCC', 'Gene', (48, 51))	('IDH1/2', 'Gene', '3417;3418', (9, 15))	('observed', 'Reg', (31, 39))	('HCC', 'Gene', '619501', (48, 51))
190356	28622513	The recent development of IDH1 small molecule inhibitors suggests these drugs may be useful in that minority of HCC with IDH mutations.	('mutations', 'Var', (125, 134))	('HCC', 'Gene', (112, 115))	('IDH', 'Gene', (121, 124))	('IDH1', 'Gene', (26, 30))	('HCC', 'Gene', '619501', (112, 115))	('IDH', 'Gene', (26, 29))	('IDH', 'Gene', '3417', (121, 124))	('IDH', 'Gene', '3417', (26, 29))	('IDH1', 'Gene', '3417', (26, 30))
190358	28622513	Hence, the presence of IDH1/2 mutation in HCC may be associated with a shift towards a biliary phenotype, molecularly, even when the tumors do not resemble mixed tumors by histopathology.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('IDH1/2', 'Gene', '3417;3418', (23, 29))	('shift', 'Reg', (71, 76))	('presence', 'Var', (11, 19))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('mutation', 'Var', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('HCC', 'Gene', (42, 45))	('IDH1/2', 'Gene', (23, 29))	('biliary', 'Disease', (87, 94))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('HCC', 'Gene', '619501', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('associated with', 'Reg', (53, 68))
190359	28622513	The discovery of an expression signature associated with this mutant, found in varying intensity in approximately 10% of the patients in several independent cohorts, supports this view.	('patients', 'Species', '9606', (125, 133))	('mutant', 'Var', (62, 68))	('expression signature', 'MPA', (20, 40))
190434	28622513	IDH1/2 mutations are frequent in intrahepatic cholangiocarcinomas (CCA) but rare or possibly noexistant in HCC; hence the possibility that these tumors actually represented mixed HCC-CCA or intrahepatic CCAs was considered.	('intrahepatic CCAs', 'Disease', (190, 207))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('intrahepatic cholangiocarcinomas', 'Disease', (33, 65))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('IDH1/2', 'Gene', (0, 6))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (33, 65))	('intrahepatic CCAs', 'Disease', 'MESH:D002780', (190, 207))	('mutations', 'Var', (7, 16))	('carcinomas', 'Phenotype', 'HP:0030731', (55, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('frequent', 'Reg', (21, 29))	('HCC', 'Gene', '619501', (179, 182))	('HCC', 'Gene', '619501', (107, 110))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (46, 64))	('HCC', 'Gene', (179, 182))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('HCC', 'Gene', (107, 110))
190457	28622513	For inactivating SMG analysis the raw MAF file was first filtered using the following filtering strategy; 1) variants were removed if they appeared in a cohort of normal samples, 2) variants were removed if they were observed greater than 2 times in the matched normal sample, had a variant allele fraction less than 0.04, if the gene had greater than 3 variants in the matched sample, or if the base coverage of the normal sample was less than 6.	('SMG', 'Gene', (17, 20))	('variants', 'Var', (182, 190))	('SMG', 'Gene', '23034', (17, 20))
190459	28622513	Two amplicons were attempted for each subject and the subject was considered to harbor a TERT promoter mutation if either amplicon generated a positive SNP call.	('mutation', 'Var', (103, 111))	('TERT', 'Gene', '7015', (89, 93))	('harbor', 'Reg', (80, 86))	('TERT', 'Gene', (89, 93))
190470	28622513	The enrichment analysis of splice site mutations on nine samples with a high activity of aristolochic acid (AA) signature (Supplemental Figure 1b) and aflatoxin B1 (AFB1) mutations in TP53 R249S mutant samples (Supplemental Figure 1c) was accomplished by two-sided Wilcoxon rank-sum tests.	('R249S', 'Var', (189, 194))	('AFB1', 'Chemical', 'MESH:D016604', (165, 169))	('aristolochic acid', 'Chemical', 'MESH:C000228', (89, 106))	('aflatoxin B1', 'Chemical', 'MESH:D016604', (151, 163))	('TP53', 'Gene', '7157', (184, 188))	('TP53', 'Gene', (184, 188))	('R249S', 'Mutation', 'rs28934571', (189, 194))
190514	28622513	Out of the 236 fusions 26 involved a kinase gene, and 27 involved a cancer gene.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('involved', 'Reg', (26, 34))	('fusions', 'Var', (15, 22))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('involved', 'Reg', (57, 65))
190546	28622513	We then performed unsupervised hierarchical clustering based on CpG sites that had hypomethylation in at least 10% of the tumours.	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('hypomethylation', 'Var', (83, 98))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('tumours', 'Disease', (122, 129))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
190548	28622513	We used two different approaches to identify genes epigenetically silenced in HCC, as described below.	('HCC', 'Gene', (78, 81))	('HCC', 'Gene', '619501', (78, 81))	('epigenetically', 'Var', (51, 65))
190555	28622513	We then estimated the frequency of epigenetic silencing for each gene by counting the number of tumors belonging to the methylated group.	('tumors belonging', 'Disease', 'MESH:D009369', (96, 112))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors belonging', 'Disease', (96, 112))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('epigenetic silencing', 'Var', (35, 55))
190556	28622513	CDKN2A epigenetic silencing calls were made using the exon level RNA-seq data.	('CDKN2A', 'Gene', '1029', (0, 6))	('epigenetic silencing', 'Var', (7, 27))	('CDKN2A', 'Gene', (0, 6))
190557	28622513	CDKN2A DNA methylation status was assessed in each sample based on the probe (cg13601799) located in the p16INK4 promoter CpG island.	('p16INK4', 'Gene', '1029', (105, 112))	('CDKN2A', 'Gene', (0, 6))	('p16INK4', 'Gene', (105, 112))	('CDKN2A', 'Gene', '1029', (0, 6))	('cg13601799', 'Var', (78, 88))
190564	28622513	We identified groups of samples with similar abundance profiles using unsupervised non-negative matrix factorization (NMF) consensus clustering of reads-per-million (RPM) data for the ~300 (25%) most-variant 5p or 3p miRBase v16 mature strands.	('most-variant', 'Var', (195, 207))	('miR', 'Gene', '220972', (217, 220))	('miR', 'Gene', (217, 220))
190589	28622513	Four tissues (TCGA-CC-5260, TCGA-DD-A4NA, TCGA-ED-A82E, and TCGA-G3-A25T) had mutations in IDH1 or IDH2 (two mutations in IDH1 (R132C, R132G) and two mutations in IDH2 (R172K, R172S)).	('A25T', 'Mutation', 'c.25A>T', (68, 72))	('R172K', 'Var', (169, 174))	('IDH2', 'Gene', (99, 103))	('A82E', 'Mutation', 'p.A82E', (50, 54))	('R132C', 'Mutation', 'rs121913499', (128, 133))	('IDH2', 'Gene', '3418', (163, 167))	('IDH1', 'Gene', (91, 95))	('IDH1', 'Gene', (122, 126))	('mutations', 'Var', (78, 87))	('R172S', 'Mutation', 'rs1057519736', (176, 181))	('IDH1', 'Gene', '3417', (122, 126))	('IDH1', 'Gene', '3417', (91, 95))	('R132C', 'Var', (128, 133))	('R132G', 'Mutation', 'rs121913499', (135, 140))	('IDH2', 'Gene', '3418', (99, 103))	('R172K', 'Mutation', 'rs121913503', (169, 174))	('IDH2', 'Gene', (163, 167))	('R132G', 'Var', (135, 140))
190590	28622513	Two-sample t-test were carried out to uncover mRNAs differentially expressed between mutant and wildtype HCC tissues and identified 1009 genes (P < 0.0001).	('HCC', 'Gene', (105, 108))	('mutant', 'Var', (85, 91))	('HCC', 'Gene', '619501', (105, 108))
190591	28622513	Interestingly, several tissues without IDH mutations had highly similar mRNA expression patterns (Figure 4A).	('mutations', 'Var', (43, 52))	('IDH', 'Gene', '3417', (39, 42))	('IDH', 'Gene', (39, 42))
190592	28622513	When Bayesian compound covariate predictor (BCCP) algorithm was applied to mRNA expression data to stratify the HCC tissues according to similarity to IDH mutation expression signature, 11 tissues without IDH1/2 mutations were classified into IDH-like subtype (Probability < 2 in range from 0 to 4 in log2 scale).	('HCC', 'Gene', (112, 115))	('IDH1/2', 'Gene', (205, 211))	('IDH', 'Gene', '3417', (151, 154))	('HCC', 'Gene', '619501', (112, 115))	('IDH', 'Gene', (205, 208))	('IDH', 'Gene', '3417', (205, 208))	('mutations', 'Var', (212, 221))	('IDH1/2', 'Gene', '3417;3418', (205, 211))	('IDH', 'Gene', (243, 246))	('IDH', 'Gene', (151, 154))	('IDH', 'Gene', '3417', (243, 246))
190601	28622513	Briefly, a BCCP algorithm was applied to generate probability of IDH mutation signature in each of the human HCC tumors as previously described.	('HCC tumors', 'Disease', (109, 119))	('IDH', 'Gene', (65, 68))	('HCC tumors', 'Disease', 'MESH:D006528', (109, 119))	('human', 'Species', '9606', (103, 108))	('IDH', 'Gene', '3417', (65, 68))	('mutation', 'Var', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
190602	28622513	When the HCC patients were dichotomized according to IDH1/2 mutation signature probability (Figure 4B), patients with IDH1/2 mutation signature (IDH-like) had significantly worse prognosis than those without IDH1/2 mutation signature (WT) (P = 1.0 x 10-4, Figure 4C), strongly indicating that IDH1/2 mutations or their activation in HCC may dictate clinical outcome and is associated with poor prognosis.	('clinical outcome', 'CPA', (349, 365))	('dictate', 'Reg', (341, 348))	('HCC', 'Gene', '619501', (9, 12))	('IDH', 'Gene', '3417', (145, 148))	('patients', 'Species', '9606', (13, 21))	('HCC', 'Gene', '619501', (333, 336))	('IDH', 'Gene', (208, 211))	('IDH1/2', 'Gene', '3417;3418', (293, 299))	('worse', 'NegReg', (173, 178))	('IDH1/2', 'Gene', '3417;3418', (118, 124))	('IDH1/2', 'Gene', '3417;3418', (53, 59))	('HCC', 'Gene', (9, 12))	('HCC', 'Gene', (333, 336))	('IDH1/2', 'Gene', (293, 299))	('IDH1/2', 'Gene', (118, 124))	('IDH1/2', 'Gene', (53, 59))	('IDH', 'Gene', (293, 296))	('IDH', 'Gene', (118, 121))	('activation', 'PosReg', (319, 329))	('IDH', 'Gene', '3417', (208, 211))	('IDH1/2', 'Gene', '3417;3418', (208, 214))	('IDH', 'Gene', '3417', (293, 296))	('IDH', 'Gene', '3417', (118, 121))	('IDH', 'Gene', (53, 56))	('patients', 'Species', '9606', (104, 112))	('mutation signature', 'Var', (125, 143))	('IDH1/2', 'Gene', (208, 214))	('IDH', 'Gene', (145, 148))	('IDH', 'Gene', '3417', (53, 56))
190603	28622513	The significant association of IDH1/2 mutation signature with worse prognosis was further validated in two independent cohorts (National Cancer Institute (NCI) cohort and Fudan University cohort) (Figure 4C).	('IDH1/2', 'Gene', '3417;3418', (31, 37))	('Cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Cancer', 'Disease', (137, 143))	('Cancer', 'Disease', 'MESH:D009369', (137, 143))	('mutation', 'Var', (38, 46))	('IDH1/2', 'Gene', (31, 37))
190613	28622513	All HCC with TP53 non-synonymous missense, frameshift, nonsense, splice sites, and indels (n = 60) were compared to HCC without TP53 mutations (n = 131) for RNA expression of 20,531 analyzed genes.	('TP53', 'Gene', (13, 17))	('HCC', 'Gene', (116, 119))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('HCC', 'Gene', (4, 7))	('frameshift', 'Var', (43, 53))	('HCC', 'Gene', '619501', (116, 119))	('HCC', 'Gene', '619501', (4, 7))	('TP53', 'Gene', '7157', (13, 17))	('non-synonymous missense', 'Var', (18, 41))
190631	28622513	ploidy, HBV status, tumor grade).	('ploidy', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('HBV', 'Species', '10407', (8, 11))	('tumor', 'Disease', (20, 25))
190632	28622513	For all mutations in the HCC cohort, the Evolutionary Action (EA) method1 was applied to predict the functional impact of missense mutations.	('HCC', 'Gene', '619501', (25, 28))	('missense mutations', 'Var', (122, 140))	('mutations', 'Var', (8, 17))	('HCC', 'Gene', (25, 28))
190643	28622513	KEY RESOURCES TABLE          Analysis of hepatocellular carcinomas integrates data of multiple genomic platforms Mutated genes reveal oncogenic processes altering hepatocyte energy balance Multiplex analyses suggest a key role for Sonic hedgehog signaling in HCC IDH mutations point to a HCC subgroup molecularly similar to cholangiocarcinoma	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (41, 66))	('IDH', 'Gene', (263, 266))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (41, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('hepatocellular carcinomas', 'Disease', (41, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('Sonic hedgehog', 'Gene', '6469', (231, 245))	('IDH', 'Gene', '3417', (263, 266))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (41, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (333, 342))	('HCC', 'Gene', '619501', (259, 262))	('Sonic hedgehog', 'Gene', (231, 245))	('mutations', 'Var', (267, 276))	('HCC', 'Gene', (259, 262))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (324, 342))	('HCC', 'Gene', '619501', (288, 291))	('cholangiocarcinoma', 'Disease', (324, 342))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (324, 342))	('HCC', 'Gene', (288, 291))
190716	27552844	Of all 34 patients, 18 (52.9%) had co-expression of Hep Par1, GPC3, and CK7 in both the hepatic and biliary zones, 3 (8.8%) had expression of Hep Par1 (hepatocyte marker), 14 (41.2%) had expression of GPC3 (hepatocyte marker), and 11 (32.4%) had expression of CK7 (cholangiocyte marker).	('CK7', 'Gene', (72, 75))	('GPC3', 'Gene', '2719', (201, 205))	('Hep Par1', 'CellLine', 'CVCL:D695', (52, 60))	('CK7', 'Gene', '3855', (72, 75))	('Hep Par1', 'CellLine', 'CVCL:D695', (142, 150))	('CK7', 'Gene', (260, 263))	('Hep Par1', 'Gene', (52, 60))	('CK7', 'Gene', '3855', (260, 263))	('GPC3', 'Gene', (62, 66))	('patients', 'Species', '9606', (10, 18))	('Hep Par1', 'Var', (142, 150))	('GPC3', 'Gene', (201, 205))	('GPC3', 'Gene', '2719', (62, 66))
190740	27552844	The cellular origin of CHC is a controversial issue, but three main theories have been proposed: (i) collision (double) tumor of HCC and ICC that coincidentally exist in the same liver; (ii) subsequent differentiation of HCC or ICC into the other component; and (iii) derivation from HPCs, which have the potential to differentiate into both HCC and ICC.	('HCC', 'Gene', (129, 132))	('HCC', 'Gene', '619501', (221, 224))	('HCC', 'Phenotype', 'HP:0001402', (221, 224))	('CHC', 'Disease', 'MESH:D019698', (23, 26))	('HCC', 'Gene', '619501', (129, 132))	('HCC', 'Phenotype', 'HP:0001402', (129, 132))	('HPCs', 'Gene', (284, 288))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('derivation', 'Var', (268, 278))	('HCC', 'Gene', '619501', (342, 345))	('CHC', 'Phenotype', 'HP:0030153', (23, 26))	('HCC', 'Phenotype', 'HP:0001402', (342, 345))	('HCC', 'Gene', (221, 224))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('CHC', 'Disease', (23, 26))	('tumor', 'Disease', (120, 125))	('HCC', 'Gene', (342, 345))
190905	23914068	Transgenic mice were noticeably smaller than their age- and sex-matched wildtype (WT) littermates.	('Transgenic mice', 'Species', '10090', (0, 15))	('Transgenic', 'Var', (0, 10))	('smaller', 'NegReg', (32, 39))
190915	23914068	Besides background strain, alterations in genotype can influence the incidence of this lesion, particularly in models of immune dysfunction such as Cyp1a2-/-, p47phox-/- and Gp91phox-/- mice, , , and immunocompromised strains including the Ptpn6mo (motheaten) mouse, , which is deficient in B, T, and natural killer (NK) cells, the athymic nude mouse, which is deficient in functional T cells, and the severe combined immunodeficient mouse (SCID), which is deficient in B and T cells.	('SCID', 'Disease', (441, 445))	('p47phox-/-', 'Gene', '17969', (159, 169))	('SCID', 'Disease', 'MESH:D053632', (441, 445))	('Ptpn6', 'Gene', (240, 245))	('immune dysfunction', 'Disease', (121, 139))	('immunodeficient', 'Disease', (418, 433))	('Gp91phox', 'Gene', (174, 182))	('immunodeficient', 'Disease', 'MESH:D007153', (418, 433))	('Ptpn6', 'Gene', '15170', (240, 245))	('p47phox-/-', 'Gene', (159, 169))	('Cyp1a2', 'Gene', (148, 154))	('Cyp1a2', 'Gene', '13077', (148, 154))	('Gp91phox', 'Gene', '13058', (174, 182))	('immune dysfunction', 'Disease', 'MESH:D007154', (121, 139))	('influence', 'Reg', (55, 64))	('alterations', 'Var', (27, 38))
190921	23914068	Some investigators have demonstrated CHI3L3 in rough endoplasmic reticulum, while a similar membrane-bound material has also been shown to accumulate in degenerating mitochondria as a result of mitochondrial dysfunction and hypoxia,,.	('CHI3L3', 'Var', (37, 43))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (194, 219))	('hypoxia', 'Disease', 'MESH:D000860', (224, 231))	('accumulate', 'PosReg', (139, 149))	('degenerating mitochondria', 'MPA', (153, 178))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (194, 219))	('hypoxia', 'Disease', (224, 231))	('mitochondrial dysfunction', 'Disease', (194, 219))
190922	23914068	It is associated with aberrant expression of CHI3L3 protein, in this case likely a result of macrophage dysfunction due to aberrant expression of the transgene.	('aberrant', 'Var', (22, 30))	('macrophage dysfunction', 'Disease', 'MESH:D055501', (93, 115))	('aberrant', 'Var', (123, 131))	('associated', 'Reg', (6, 16))	('protein', 'Protein', (52, 59))	('expression', 'MPA', (31, 41))	('macrophage dysfunction', 'Disease', (93, 115))	('CHI3L3', 'Gene', (45, 51))
191008	33557655	One patient had suspected hilar cholangiocarcinoma by imaging examination and cancer cells were detected by ERCP cell brushing; the patient was excluded because of lack of tumor markers such as CA19-9 and CEA and loss of in-hospital follow-up.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (32, 50))	('CA19-9', 'Var', (194, 200))	('lack', 'NegReg', (164, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (32, 50))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('cancer', 'Disease', (78, 84))	('CEA', 'Gene', (205, 208))	('patient', 'Species', '9606', (4, 11))	('CA19-9', 'Chemical', 'MESH:C086528', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('CEA', 'Gene', '1084', (205, 208))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cholangiocarcinoma', 'Disease', (32, 50))	('patient', 'Species', '9606', (132, 139))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
191014	33557655	None of age, gender, stricture location, thickness of the bile duct wall in the narrow segment, maximum diameter of the biliary duct above the stenotic segment, number of cell brush smears, CA19-9 or CEA were associated with positive results of cytology brushing (Table 2).	('CEA', 'Gene', '1084', (200, 203))	('CA19-9', 'Chemical', 'MESH:C086528', (190, 196))	('CEA', 'Gene', (200, 203))	('CA19-9', 'Var', (190, 196))
191191	26287849	Efforts by the Cancer Genome Atlas and other initiatives to characterize the genetic landscape of most tumor types have identified BRAF V600 mutations in nonmelanoma cancers, including colorectal cancer, non-small-cell lung cancer, papillary thyroid cancer, diffuse gliomas, cholangiocarcinoma, hairy-cell leukemia, multiple myeloma, Langerhans'-cell histiocytosis, and Erdheim-Chester disease.	('hairy-cell leukemia', 'Disease', (295, 314))	('multiple myeloma', 'Disease', 'MESH:D009101', (316, 332))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cholangiocarcinoma', 'Disease', (275, 293))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('gliomas', 'Disease', (266, 273))	('colorectal cancer', 'Disease', (185, 202))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (275, 293))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (204, 230))	('papillary thyroid cancer', 'Disease', (232, 256))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (15, 34))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('multiple myeloma', 'Disease', (316, 332))	('gliomas', 'Disease', 'MESH:D005910', (266, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('Erdheim-Chester disease', 'Disease', 'MESH:D031249', (370, 393))	('nonmelanoma cancers', 'Disease', (154, 173))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('nonmelanoma cancers', 'Disease', 'MESH:D009369', (154, 173))	('Cancer Genome Atlas', 'Disease', (15, 34))	('histiocytosis', 'Phenotype', 'HP:0100727', (351, 364))	('colorectal cancer', 'Phenotype', 'HP:0003003', (185, 202))	('mutations', 'Var', (141, 150))	('thyroid cancer', 'Phenotype', 'HP:0002890', (242, 256))	('tumor', 'Disease', (103, 108))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (232, 256))	('gliomas', 'Phenotype', 'HP:0009733', (266, 273))	('non-small-cell lung cancer', 'Disease', (204, 230))	("Langerhans'-cell histiocytosis", 'Disease', (334, 364))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (204, 230))	('hairy-cell leukemia', 'Disease', 'MESH:D007943', (295, 314))	('leukemia', 'Phenotype', 'HP:0001909', (306, 314))	('Erdheim-Chester disease', 'Disease', (370, 393))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('BRAF', 'Gene', '673', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('BRAF', 'Gene', (131, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (219, 230))	('multiple myeloma', 'Phenotype', 'HP:0006775', (316, 332))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (232, 256))	('Cancer', 'Phenotype', 'HP:0002664', (15, 21))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (208, 230))	('colorectal cancer', 'Disease', 'MESH:D015179', (185, 202))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (275, 293))
191203	26287849	From April 11, 2012, through June 10, 2014, we enrolled 122 patients with BRAF V600-mutated cancers from 23 centers worldwide.	('V600-mutated', 'Var', (79, 91))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('patients', 'Species', '9606', (60, 68))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
191275	26287849	These data show that BRAF V600-mutated tumor types do not respond uniformly to BRAF-targeted therapy.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('BRAF', 'Gene', '673', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('BRAF', 'Gene', '673', (79, 83))	('BRAF', 'Gene', (21, 25))	('tumor', 'Disease', (39, 44))	('V600-mutated', 'Var', (26, 38))	('BRAF', 'Gene', (79, 83))
191279	26287849	Given the highly aggressive and chemotherapy-resistant nature of BRAF V600-mutated colorectal cancers, strategies using dual EGFR and BRAF inhibition deserve further evaluation.	('colorectal cancer', 'Phenotype', 'HP:0003003', (83, 100))	('colorectal cancers', 'Disease', 'MESH:D015179', (83, 101))	('EGFR', 'Gene', '1956', (125, 129))	('V600-mutated', 'Var', (70, 82))	('BRAF', 'Gene', '673', (134, 138))	('colorectal cancers', 'Disease', (83, 101))	('EGFR', 'Gene', (125, 129))	('BRAF', 'Gene', (134, 138))	('BRAF', 'Gene', '673', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('BRAF', 'Gene', (65, 69))
191346	22024438	One patient developed a chronic cholangitis caused by Pseudomonas aeruginosa, treated by a long-term administration of ertapenem.	('cholangitis', 'Disease', 'MESH:D002761', (32, 43))	('patient', 'Species', '9606', (4, 11))	('caused by', 'Reg', (44, 53))	('ertapenem', 'Chemical', 'MESH:D000077727', (119, 128))	('Pseudomonas aeruginosa', 'Var', (54, 76))	('Pseudomonas aeruginosa', 'Species', '287', (54, 76))	('cholangitis', 'Phenotype', 'HP:0030151', (32, 43))	('cholangitis', 'Disease', (32, 43))
191354	22024438	The second prospective randomised trial included 32 unselected nonresectable patients, especially those with successful biliary drainage, and confirmed the survival advantage in the PDT group (630 vs 210 days, p = 0.019).	('patients', 'Species', '9606', (77, 85))	('advantage', 'PosReg', (165, 174))	('PDT', 'Var', (182, 185))
191392	19774418	found that patients with microscopically positive margin (R1 resection) still had some benefit in survival compared with patients with locally advanced, unresectable disease who were bypassed.	('benefit', 'PosReg', (87, 94))	('survival', 'MPA', (98, 106))	('patients', 'Species', '9606', (11, 19))	('patients', 'Species', '9606', (121, 129))	('microscopically', 'Var', (25, 40))
191453	19774418	Patients who underwent resection, regardless of tumor position or margin status, had median survival of 17 months, compared with unresected patients who had median survival of 11 months (p = 0.03).	('tumor', 'Disease', (48, 53))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (140, 148))	('resection', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
191491	19774418	found that patients who underwent an R0 resection had median disease-specific survival of 65 months, compared with 4 months in unresected patients; but, in addition, patients who underwent an R1/R2 resection still had better disease-specific survival of 16 months compared with unresected patients (p < 0.001).	('patients', 'Species', '9606', (138, 146))	('R1/R2', 'Var', (192, 197))	('patients', 'Species', '9606', (289, 297))	('disease-specific survival', 'CPA', (225, 250))	('patients', 'Species', '9606', (11, 19))	('patients', 'Species', '9606', (166, 174))	('better', 'PosReg', (218, 224))
191527	30895496	Patients who underwent a LLR were less likely to undergo an adequate lymph node evaluation (>= 6 nodes) compared with those who underwent OLR (9%, n = 27 vs. 15%, n = 305, respectively, p<0.001, Fig.	('Patients', 'Species', '9606', (0, 8))	('less', 'NegReg', (34, 38))	('LLR', 'Var', (25, 28))
191539	30895496	However, only 50% of patients who underwent LLR also had a LND compared with 97% of patients in the OLR cohort.	('LLR', 'Var', (44, 47))	('patients', 'Species', '9606', (84, 92))	('patients', 'Species', '9606', (21, 29))	('LND', 'MPA', (59, 62))
191555	32494639	Mutations in isocitrate dehydrogenase (IDH) genes occur in multiple cancer types, lead to global changes in the epigenome, and drive tumorigenesis.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lead to', 'Reg', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('drive', 'Reg', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('isocitrate dehydrogenase', 'Gene', (13, 37))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (133, 138))	('cancer', 'Disease', (68, 74))	('IDH', 'Gene', (39, 42))	('isocitrate dehydrogenase', 'Gene', '3417', (13, 37))	('epigenome', 'MPA', (112, 121))	('changes', 'Reg', (97, 104))
191556	32494639	Yet, effective strategies targeting solid tumors harboring IDH mutations remain elusive.	('mutations', 'Var', (63, 72))	('IDH', 'Gene', (59, 62))	('solid tumors', 'Disease', 'MESH:D009369', (36, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('solid tumors', 'Disease', (36, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
191557	32494639	Here, we demonstrate that IDH-mutant gliomas and cholangiocarcinomas display elevated DNA damage.	('cholangiocarcinomas', 'Disease', (49, 68))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (49, 68))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('elevated', 'PosReg', (77, 85))	('gliomas', 'Disease', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (49, 67))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('DNA damage', 'MPA', (86, 96))	('IDH-mutant', 'Var', (26, 36))
191558	32494639	Using multiple in vitro and preclinical animal models of glioma and cholangiocarcinoma, we developed treatment strategies that use a synthetic lethality approach targeting the reduced DNA damage repair conferred by mutant IDH using poly(adenosine 5'-diphosphate) ribose polymerase inhibitors (PARPis).	('PARP', 'Gene', '142', (293, 297))	('reduced', 'NegReg', (176, 183))	('glioma', 'Disease', (57, 63))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (68, 86))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (68, 86))	('mutant', 'Var', (215, 221))	('PARP', 'Gene', (293, 297))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('DNA damage repair', 'MPA', (184, 201))	('IDH', 'Gene', (222, 225))	('adenosine', 'Chemical', 'MESH:D000241', (237, 246))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('cholangiocarcinoma', 'Disease', (68, 86))
191560	32494639	Neomorphic mutations in the genes encoding isocitrate dehydrogenase 1 and 2 (IDH1/2) have been identified in multiple cancer types, including lower grade glioma (LGG), secondary glioblastoma, intrahepatic cholangiocarcinoma (ICC), acute myeloid leukemia (AML), chondrosarcoma (CS), and others.	('mutations', 'Var', (11, 20))	('C', 'Chemical', 'MESH:D002244', (227, 228))	('acute myeloid leukemia', 'Disease', (231, 253))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (237, 253))	('glioblastoma', 'Disease', 'MESH:D005909', (178, 190))	('glioma', 'Disease', (154, 160))	('AML', 'Disease', 'MESH:D015470', (255, 258))	('leukemia', 'Phenotype', 'HP:0001909', (245, 253))	('AML', 'Disease', (255, 258))	('IDH1/2', 'Gene', '3417;3418', (77, 83))	('AML', 'Phenotype', 'HP:0004808', (255, 258))	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('chondrosarcoma', 'Disease', 'MESH:D002813', (261, 275))	('glioblastoma', 'Disease', (178, 190))	('chondrosarcoma', 'Disease', (261, 275))	('IDH1/2', 'Gene', (77, 83))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (231, 253))	('glioblastoma', 'Phenotype', 'HP:0012174', (178, 190))	('isocitrate dehydrogenase', 'Gene', '3417', (43, 67))	('identified', 'Reg', (95, 105))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (192, 223))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (231, 253))	('cancer', 'Disease', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('intrahepatic cholangiocarcinoma', 'Disease', (192, 223))	('CS', 'Phenotype', 'HP:0006765', (277, 279))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (268, 275))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (261, 275))	('C', 'Chemical', 'MESH:D002244', (277, 278))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (205, 223))	('isocitrate dehydrogenase', 'Gene', (43, 67))	('C', 'Chemical', 'MESH:D002244', (226, 227))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
191561	32494639	The mutant IDH enzyme (IDHmut) converts the Krebs cycle intermediate alpha-ketoglutarate (alphaKG) into 2-hydroxyglutarate (2-HG), which functions as an oncometabolite.	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (69, 88))	('IDH', 'Gene', (11, 14))	('Krebs', 'Chemical', '-', (44, 49))	('mutant', 'Var', (4, 10))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (104, 122))	('2-HG', 'Chemical', 'MESH:C019417', (124, 128))
191562	32494639	2-HG can induce global DNA hypermethylation, inhibition of histone lysine demethylases, and block of cell differentiation.	('inhibition', 'NegReg', (45, 55))	('2-HG', 'Chemical', 'MESH:C019417', (0, 4))	('global DNA hypermethylation', 'MPA', (16, 43))	('lysine', 'Chemical', 'MESH:D008239', (67, 73))	('cell differentiation', 'CPA', (101, 121))	('histone', 'Protein', (59, 66))	('2-HG', 'Var', (0, 4))	('block', 'NegReg', (92, 97))
191563	32494639	One strategy to treat IDHmut tumors is to inhibit the mutant IDH protein and 2-HG production.	('2-HG production', 'MPA', (77, 92))	('IDH protein', 'Protein', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('mutant', 'Var', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('inhibit', 'NegReg', (42, 49))	('tumors', 'Disease', (29, 35))	('2-HG', 'Chemical', 'MESH:C019417', (77, 81))
191565	32494639	Recently, inhibitors of IDH2 (enasidenib) and IDH1 (ivosidenib) have been shown to induce differentiation of cancer cells in patients with recurrent or refractory AML.	('enasidenib', 'Chemical', 'MESH:C000605269', (30, 40))	('differentiation', 'CPA', (90, 105))	('AML', 'Phenotype', 'HP:0004808', (163, 166))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('IDH1', 'Gene', (46, 50))	('AML', 'Disease', (163, 166))	('ivosidenib', 'Chemical', 'MESH:C000627630', (52, 62))	('cancer', 'Disease', (109, 115))	('induce', 'PosReg', (83, 89))	('IDH2', 'Gene', (24, 28))	('inhibitors', 'Var', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('IDH2', 'Gene', '3418', (24, 28))	('AML', 'Disease', 'MESH:D015470', (163, 166))	('patients', 'Species', '9606', (125, 133))
191567	32494639	Paradoxically, exogenous 2-HG can cause toxicity and slow down cell proliferation by inhibiting mammalian target of rapamycin signaling and mRNA m6A modification.	('toxicity', 'Disease', (40, 48))	('inhibiting', 'NegReg', (85, 95))	('2-HG', 'Chemical', 'MESH:C019417', (25, 29))	('exogenous', 'Var', (15, 24))	('2-HG', 'Protein', (25, 29))	('cell proliferation', 'CPA', (63, 81))	('mammalian target of rapamycin', 'Gene', (96, 125))	('mammalian target of rapamycin', 'Gene', '2475', (96, 125))	('toxicity', 'Disease', 'MESH:D064420', (40, 48))	('slow down', 'NegReg', (53, 62))	('mRNA m6A modification', 'MPA', (140, 161))
191568	32494639	Furthermore, 2-HG directly inhibits homologous recombination (HR), thus weakening DNA damage repair (DDR) and potentially improving the outcome from DNA damaging agents in patients receiving standard-of-care cytotoxic therapies.	('DNA damage repair', 'MPA', (82, 99))	('inhibits', 'NegReg', (27, 35))	('weakening', 'NegReg', (72, 81))	('2-HG', 'Var', (13, 17))	('improving', 'PosReg', (122, 131))	('homologous recombination', 'MPA', (36, 60))	('patients', 'Species', '9606', (172, 180))	('2-HG', 'Chemical', 'MESH:C019417', (13, 17))
191569	32494639	IDH mutations are associated with better outcomes from radiation therapy (RT) and chemotherapy in patients with glioma.	('IDH', 'Gene', (0, 3))	('patients', 'Species', '9606', (98, 106))	('glioma', 'Disease', (112, 118))	('mutations', 'Var', (4, 13))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
191574	32494639	Cells with deficient HR, the main compensatory mechanism to manage the increased DSB stress imposed by PARPi, are unable to efficiently repair these DSB and enter mitotic catastrophe and apoptosis.	('PARP', 'Gene', '142', (103, 107))	('apoptosis', 'CPA', (187, 196))	('unable', 'NegReg', (114, 120))	('PARP', 'Gene', (103, 107))	('enter', 'PosReg', (157, 162))	('deficient', 'Var', (11, 20))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('mitotic catastrophe', 'CPA', (163, 182))
191581	32494639	We demonstrate in multiple in vitro contexts that expression of mutant IDH1 sensitizes the cell to radiation and PARPi.	('sensitizes', 'Reg', (76, 86))	('PARP', 'Gene', '142', (113, 117))	('IDH1', 'Gene', (71, 75))	('mutant', 'Var', (64, 70))	('PARP', 'Gene', (113, 117))
191582	32494639	Last, we used two orthotopic LGG and one heterotopic ICC xenograft animal model to show that PARPi sensitizes the tumors to IR and that this sensitization is specifically associated with IDH mutation status.	('PARP', 'Gene', '142', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('IDH', 'Gene', (187, 190))	('sensitizes', 'Reg', (99, 109))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('PARP', 'Gene', (93, 97))	('mutation', 'Var', (191, 199))	('associated', 'Reg', (171, 181))
191584	32494639	Previous studies have suggested that repair of DNA damage by HR is impaired by mutant IDH1 expression in a human colon cancer cell line through the oncometabolite 2-HG.	('colon cancer', 'Phenotype', 'HP:0003003', (113, 125))	('IDH1', 'Gene', (86, 90))	('human', 'Species', '9606', (107, 112))	('repair', 'MPA', (37, 43))	('impaired', 'NegReg', (67, 75))	('mutant', 'Var', (79, 85))	('colon cancer', 'Disease', 'MESH:D015179', (113, 125))	('colon cancer', 'Disease', (113, 125))	('2-HG', 'Chemical', 'MESH:C019417', (163, 167))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
191585	32494639	To ascertain whether this effect is generalizable, we first used an immortalized human astrocyte (IHA) isogenic cell line system, which includes one line that expresses mutant IDH1 R132H (IHA-IDH1mut), and a matching isogenic control, which does not express mutant IDH1 (IHA-EV).	('IHA-EV', 'Chemical', '-', (271, 277))	('R132H', 'Mutation', 'rs121913500', (181, 186))	('IHA', 'Chemical', '-', (98, 101))	('IHA', 'Chemical', '-', (188, 191))	('mutant', 'Var', (169, 175))	('IHA', 'Chemical', '-', (271, 274))	('human', 'Species', '9606', (81, 86))	('R132H', 'Var', (181, 186))	('IDH1', 'Gene', (176, 180))
191586	32494639	Expression of mutant IDH1 induces changes in the DNA methylation and histone landscape, which recapitulates those in IDH1-mutant tumors and blocks differentiation.	('differentiation', 'CPA', (147, 162))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('blocks', 'NegReg', (140, 146))	('mutant', 'Var', (14, 20))	('changes', 'Reg', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('DNA methylation', 'MPA', (49, 64))	('IDH1', 'Gene', (21, 25))	('histone landscape', 'MPA', (69, 86))
191589	32494639	The DSBs marked by gamma-H2AX positivity in IDH1mut cells indicates a higher level of unrepaired DNA damage.	('positivity', 'Var', (30, 40))	('gamma-H2AX', 'Gene', '15270', (19, 29))	('gamma-H2AX', 'Gene', (19, 29))	('DSBs', 'Disease', (4, 8))	('DSBs', 'Chemical', '-', (4, 8))
191591	32494639	IHA-IDH1mut displayed notably higher levels of KAP1 phosphorylation compared to IHA-EV, suggesting increased engagement of the replication stress pathway (Fig.	('IHA-EV', 'Chemical', '-', (80, 86))	('IHA', 'Chemical', '-', (80, 83))	('replication stress pathway', 'Pathway', (127, 153))	('IHA-IDH1mut', 'Var', (0, 11))	('higher', 'PosReg', (30, 36))	('levels', 'MPA', (37, 43))	('KAP1', 'Gene', (47, 51))	('IHA', 'Chemical', '-', (0, 3))	('KAP1', 'Gene', '10155', (47, 51))	('increased engagement', 'PosReg', (99, 119))
191593	32494639	However, consistent with previous reports, these unrepaired DNA damage sites did not induce significant change in cell death, likely due to concurrent inactivation of p53 as a part of immortalization.	('inactivation', 'NegReg', (151, 163))	('sites', 'Var', (71, 76))	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('p53', 'Gene', '7157', (167, 170))	('p53', 'Gene', (167, 170))
191596	32494639	We reasoned that the IDH1mut-induced DDR deficiency can be targeted by PARP inhibition similar to the scenario in BRCA-mutant breast and ovarian cancer and that this synthetic lethality could be augmented by inflicting further DNA damage through radiotherapy.	('inhibition', 'NegReg', (76, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (137, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('DDR deficiency', 'Disease', (37, 51))	('DDR deficiency', 'Disease', 'MESH:D007153', (37, 51))	('PARP', 'Gene', '142', (71, 75))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (126, 151))	('C', 'Chemical', 'MESH:D002244', (116, 117))	('IDH1mut-induced', 'Var', (21, 36))	('PARP', 'Gene', (71, 75))
191598	32494639	Elevated gamma-H2AX positivity was observed in IHA-IDH1mut compared to IHA-EV at baseline (Fig.	('IHA', 'Chemical', '-', (71, 74))	('gamma-H2AX', 'Gene', (9, 19))	('IHA', 'Chemical', '-', (47, 50))	('IHA-EV', 'Chemical', '-', (71, 77))	('Elevated', 'PosReg', (0, 8))	('gamma-H2AX', 'Gene', '15270', (9, 19))	('positivity', 'MPA', (20, 30))	('IHA-IDH1mut', 'Var', (47, 58))
191600	32494639	IDH mutation was associated with a markedly reduced ability to repair DNA damage from IR and PARPi, as measured by the neutral Comet assay (Fig.	('IDH', 'Gene', (0, 3))	('PARP', 'Gene', '142', (93, 97))	('mutation', 'Var', (4, 12))	('C', 'Chemical', 'MESH:D002244', (127, 128))	('reduced', 'NegReg', (44, 51))	('PARP', 'Gene', (93, 97))	('repair DNA damage', 'MPA', (63, 80))
191602	32494639	Moreover, the deficiency in DDR found in IHA-IDH1mut cells leads to a greater extent of cell death when treated with the combination as shown by annexin V flow cytometry (Fig.	('annexin V', 'Gene', '308', (145, 154))	('death', 'Disease', 'MESH:D003643', (93, 98))	('IHA', 'Chemical', '-', (41, 44))	('annexin V', 'Gene', (145, 154))	('DDR', 'Gene', (28, 31))	('deficiency', 'Var', (14, 24))	('death', 'Disease', (93, 98))
191605	32494639	However, treatment with strong PARP-trapping agents, such as olaparib and talazoparib, tends to confer resistance through genetic mutation.	('olaparib', 'Chemical', 'MESH:C531550', (61, 69))	('PARP', 'Gene', '142', (31, 35))	('PARP', 'Gene', (31, 35))	('genetic mutation', 'Var', (122, 138))	('talazoparib', 'Chemical', 'MESH:C586365', (74, 85))	('resistance', 'MPA', (103, 113))
191611	32494639	Under all IR conditions, IHA-EV yielded modest reduction of colonies when simultaneously treated with veliparib, while this reduction was markedly enhanced in IHA-IDH1mut (Fig.	('enhanced', 'PosReg', (147, 155))	('veliparib', 'MPA', (102, 111))	('veliparib', 'Chemical', 'MESH:C521013', (102, 111))	('IHA-IDH1mut', 'Var', (159, 170))	('reduction', 'NegReg', (47, 56))	('IHA', 'Chemical', '-', (25, 28))	('IHA', 'Chemical', '-', (159, 162))	('colonies', 'CPA', (60, 68))	('IHA-EV', 'Chemical', '-', (25, 31))
191614	32494639	TS603 GSC also showed notably amplified synthetic lethality when treated with IR and olaparib (fig.	('amplified', 'PosReg', (30, 39))	('olaparib', 'Chemical', 'MESH:C531550', (85, 93))	('C', 'Chemical', 'MESH:D002244', (8, 9))	('TS603', 'Var', (0, 5))	('synthetic lethality', 'MPA', (40, 59))
191615	32494639	These results indicate that IR + PARPi preferentially inhibits the clonogenic growth of IDH-mutant cells.	('IDH-mutant', 'Gene', (88, 98))	('PARP', 'Gene', (33, 37))	('PARP', 'Gene', '142', (33, 37))	('inhibits', 'NegReg', (54, 62))	('IDH-mutant', 'Var', (88, 98))	('clonogenic growth', 'CPA', (67, 84))
191616	32494639	We tested whether the synthetic lethality conferred by PARPi in the setting of mutant IDH is observed in other tumor types that commonly harbor IDH mutations.	('PARP', 'Gene', '142', (55, 59))	('IDH', 'Gene', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mutant', 'Var', (79, 85))	('tested', 'Reg', (3, 9))	('tumor', 'Disease', (111, 116))	('PARP', 'Gene', (55, 59))
191619	32494639	We tested whether expression of mutant IDH1 sensitizes ICC cancer cells to PARPis.	('PARP', 'Gene', (75, 79))	('IDH1', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tested', 'Reg', (3, 9))	('sensitizes', 'Reg', (44, 54))	('mutant', 'Var', (32, 38))	('PARP', 'Gene', '142', (75, 79))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
191620	32494639	First, we expressed IDH1-R132H in a human cholangiocarcinoma cell line (HUCCT1) that is wild type for IDH.	('cholangiocarcinoma', 'Disease', (42, 60))	('R132H', 'Mutation', 'rs121913500', (25, 30))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (42, 60))	('IDH1-R132H', 'Var', (20, 30))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (42, 60))	('human', 'Species', '9606', (36, 41))
191625	32494639	Clonogenic capacity of HUCCT1 cells was severely decreased by IDH1mut expression, demonstrated by a 100-fold difference in clonogenicity when IDH1mut HUCCT1 cells were exposed to 6-Gy radiation and 4 muM olaparib (Fig.	('Clonogenic capacity', 'CPA', (0, 19))	('olaparib', 'Chemical', 'MESH:C531550', (204, 212))	('IDH1mut expression', 'Var', (62, 80))	('clonogenicity', 'CPA', (123, 136))	('C', 'Chemical', 'MESH:D002244', (153, 154))	('decreased', 'NegReg', (49, 58))	('C', 'Chemical', 'MESH:D002244', (152, 153))	('muM', 'Gene', '56925', (200, 203))	('C', 'Chemical', 'MESH:D002244', (26, 27))	('Gy', 'Species', '214032', (181, 183))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('muM', 'Gene', (200, 203))	('C', 'Chemical', 'MESH:D002244', (25, 26))
191628	32494639	Together, we showed in two different cancers, using both engineered isogenic cells and native IDH-mutant tumor cell lines, that mutant IDH1 expression leads to hypersensitivity to PARPi, and this hypersensitivity is markedly amplified by radiation.	('leads to', 'Reg', (151, 159))	('hypersensitivity', 'Disease', 'MESH:D004342', (196, 212))	('PARP', 'Gene', '142', (180, 184))	('IDH1', 'Gene', (135, 139))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('hypersensitivity', 'Disease', (160, 176))	('cancers', 'Disease', (37, 44))	('mutant', 'Var', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('hypersensitivity', 'Disease', 'MESH:D004342', (160, 176))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('PARP', 'Gene', (180, 184))	('tumor', 'Disease', (105, 110))	('hypersensitivity', 'Disease', (196, 212))
191629	32494639	Having confirmed that expression of mutant IDH1 is associated with increased levels of DNA damage in vitro, we sought to ascertain whether this is true in patient tumors.	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('IDH1', 'Gene', (43, 47))	('patient', 'Species', '9606', (155, 162))	('levels of DNA damage', 'MPA', (77, 97))	('tumors', 'Disease', (163, 169))	('increased', 'PosReg', (67, 76))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('mutant', 'Var', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))
191631	32494639	With assistance from expert clinical pathologists at MSKCC, we determined the IDH mutation status of the tumors and ensured that the IDH-mutant and wild-type tumors were matched for similar disease stage, grade, and pathologic features.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('mutation', 'Var', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('IDH', 'Gene', (78, 81))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
191633	32494639	IDH1mut World Health Organization (WHO) grade III glioma sections showed elevated gamma-H2AX signals compared to their IDHwt controls, regardless of their histopathologic classification as oligodendroglioma or astrocytoma (Fig.	('gamma-H2AX', 'Gene', '15270', (82, 92))	('astrocytoma', 'Phenotype', 'HP:0009592', (210, 221))	('IDH1mut', 'Var', (0, 7))	('gamma-H2AX', 'Gene', (82, 92))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('oligodendroglioma or astrocytoma', 'Disease', (189, 221))	('III glioma', 'Disease', 'MESH:D005910', (46, 56))	('III glioma', 'Disease', (46, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('elevated', 'PosReg', (73, 81))	('oligodendroglioma or astrocytoma', 'Disease', 'MESH:D009837', (189, 221))
191634	32494639	Similarly, ICC tumor pairs collected at similar disease stage (T1, no lymph node or distant metastases, no neoadjuvant therapy, and no intrahepatic therapy before resection) demonstrated that IDH mutations lead to significantly augmented gamma-H2AX staining (Fig.	('gamma-H2AX', 'Gene', (238, 248))	('ICC tumor', 'Disease', 'MESH:C566123', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('metastases', 'Disease', (92, 102))	('ICC tumor', 'Disease', (11, 20))	('metastases', 'Disease', 'MESH:D009362', (92, 102))	('augmented', 'PosReg', (228, 237))	('gamma-H2AX', 'Gene', '15270', (238, 248))	('IDH', 'Gene', (192, 195))	('mutations', 'Var', (196, 205))
191640	32494639	Mice with TS543 (IDHwt) tumors showed similar OS in veliparib and control groups (median OS, 11 days versus 10 days) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('veliparib', 'Chemical', 'MESH:C521013', (52, 61))	('TS543', 'Var', (10, 15))	('Mice', 'Species', '10090', (0, 4))
191642	32494639	However, the IDH1mut tumors (TS603) showed significant improvement of OS in veliparib treated group (11 days) compared to control (8.5 days), as well as in RT + veliparib (21 days) versus RT alone (14 days) (Fig.	('improvement', 'PosReg', (55, 66))	('veliparib', 'Chemical', 'MESH:C521013', (161, 170))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('IDH1mut', 'Var', (13, 20))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('veliparib', 'Chemical', 'MESH:C521013', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
191651	32494639	To rule out the possibility that the observed sensitivity could be due to different genetic backgrounds (i.e., TS543 and TS603), we performed similar trials in a genetically engineered mouse model of glioma with RCAS-TVA (replication competent avian sarcoma-leukosis virus long terminal repeat with a splice acceptor)-mediated gene transfer of mutant IDH in an isogenic setting.	('glioma', 'Disease', (200, 206))	('mouse', 'Species', '10090', (185, 190))	('sarcoma-leukosis virus long terminal repeat', 'Disease', 'MESH:D000647', (250, 293))	('RCAS', 'Chemical', '-', (212, 216))	('IDH', 'Gene', (351, 354))	('sarcoma', 'Phenotype', 'HP:0100242', (250, 257))	('mutant', 'Var', (344, 350))	('sarcoma-leukosis virus long terminal repeat', 'Disease', (250, 293))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('TVA', 'Chemical', '-', (217, 220))
191652	32494639	This is a previously established model where mutant IDH is expressed in endogenously generated gliomas.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('mutant', 'Var', (45, 51))	('IDH', 'Gene', (52, 55))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('gliomas', 'Disease', (95, 102))
191653	32494639	In these animal models, tumors that express the wild-type or mutant IDH1 were generated through intracranial injection of DF1 cells that carry the corresponding expression cassette (Fig.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('IDH1', 'Gene', (68, 72))	('mutant', 'Var', (61, 67))
191657	32494639	On the contrary, IDH1mut gliomas are somewhat sensitive to both RT or veliparib as monotherapy (median OS, 22 days versus 22 days versus 14 days for vehicle control) and the combination of RT and veliparib substantially extended OS (median, 66 days, >4-fold longer OS than vehicle control and 3-fold longer than RT or veliparib alone) (Fig.	('veliparib', 'Chemical', 'MESH:C521013', (318, 327))	('IDH1mut', 'Var', (17, 24))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('extended', 'PosReg', (220, 228))	('veliparib', 'Chemical', 'MESH:C521013', (196, 205))	('veliparib', 'Chemical', 'MESH:C521013', (70, 79))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))
191660	32494639	5D, circled areas) and demonstrate that veliparib limited the tumor growth compared to vehicle-treated tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('veliparib', 'Chemical', 'MESH:C521013', (40, 49))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (62, 67))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('veliparib', 'Var', (40, 49))	('limited', 'NegReg', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
191665	32494639	BGB-290 prolonged the OS of mice with IDH1mut glioma, both as monotherapy (median OS, 28 days) or in combination with RT (median OS, 44 days), with 4 of 13 mice living more than 90 days (Fig.	('mice', 'Species', '10090', (28, 32))	('glioma', 'Disease', (46, 52))	('IDH1mut', 'Var', (38, 45))	('BGB-290', 'Gene', (0, 7))	('prolonged', 'PosReg', (8, 17))	('mice', 'Species', '10090', (156, 160))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
191673	32494639	However, HUCCT1 cells competently form subcutaneous tumors in athymic nude mice regardless of the mutational status of IDH1.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (39, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('mutational', 'Var', (98, 108))	('IDH1', 'Gene', (119, 123))	('nude mice', 'Species', '10090', (70, 79))
191675	32494639	The IDH1mut tumors grew slightly slower than the wild-type tumors (median survival, 31 days versus 21 days; Fig.	('grew', 'CPA', (19, 23))	('tumors', 'Disease', (59, 65))	('IDH1mut', 'Var', (4, 11))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('slower', 'NegReg', (33, 39))
191685	32494639	Together, these in vivo findings support, in ICC cells, that IDH mutations confer vulnerability to PARPi, which can be further exploited by introducing DNA damaging agents, such as radiation.	('PARP', 'Gene', '142', (99, 103))	('IDH', 'Gene', (61, 64))	('PARP', 'Gene', (99, 103))	('mutations', 'Var', (65, 74))
191690	32494639	Although directly targeting the mutant IDH enzyme with small-molecule inhibitors has been shown to have benefits in patients with AML, concerns exist regarding their application to solid tumors, such as systemic availability of the drug, ability to penetrate into tumor, and lack of efficacy.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', (264, 269))	('patients', 'Species', '9606', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('solid tumors', 'Disease', (181, 193))	('tumor', 'Disease', (187, 192))	('mutant', 'Var', (32, 38))	('AML', 'Disease', (130, 133))	('AML', 'Disease', 'MESH:D015470', (130, 133))	('IDH', 'Gene', (39, 42))	('solid tumors', 'Disease', 'MESH:D009369', (181, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('AML', 'Phenotype', 'HP:0004808', (130, 133))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('benefits', 'PosReg', (104, 112))
191692	32494639	Moreover, in solid tumors, mutation of IDH typically portends a better prognosis compared to tumors with wild-type IDH.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('solid tumors', 'Disease', (13, 25))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('portends', 'Reg', (53, 61))	('mutation', 'Var', (27, 35))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('solid tumors', 'Disease', 'MESH:D009369', (13, 25))	('IDH', 'Gene', (39, 42))	('tumors', 'Disease', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
191694	32494639	We examine an approach to treating IDHmut tumors that takes advantage of their unique metabolic, genomic, and epigenetic state through exploitation of impaired HR associated with mutations in IDH1.	('impaired HR', 'Disease', (151, 162))	('impaired HR', 'Disease', 'MESH:D001919', (151, 162))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('IDH1', 'Gene', (192, 196))	('mutations', 'Var', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
191698	32494639	Using these models, we were able to determine that IDH mutation confers sensitivity to DNA damaging agents and PARP inhibitors, and we established preclinical strategies to target these therapeutic vulnerabilities.	('PARP', 'Gene', '142', (111, 115))	('IDH', 'Gene', (51, 54))	('sensitivity', 'MPA', (72, 83))	('PARP', 'Gene', (111, 115))	('mutation', 'Var', (55, 63))
191704	32494639	Ongoing clinical trials have been set up to test this concept (e.g., NCT03212274, NCT03561870, NCT03749187, etc.	('C', 'Chemical', 'MESH:D002244', (96, 97))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('NCT03561870', 'Var', (82, 93))	('NCT03212274', 'Var', (69, 80))	('C', 'Chemical', 'MESH:D002244', (83, 84))	('NCT03749187', 'Var', (95, 106))
191710	32494639	Isogenic cell lines and genetically engineered tumors were produced by introducing mutant IDH1, along with appropriate controls.	('IDH1', 'Gene', (90, 94))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('mutant', 'Var', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
191717	32494639	Parental IHAs (a gift from R. O. Peiper, University of California, San Francisco) were infected with a viral vector carrying expression cassette for IDH1-R132H or the empty vector control.	('Parental IHAs', 'Disease', 'MESH:D063129', (0, 13))	('IDH1-R132H', 'Var', (149, 159))	('C', 'Chemical', 'MESH:D002244', (55, 56))	('infected', 'Disease', 'MESH:D007239', (87, 95))	('Parental IHAs', 'Disease', (0, 13))	('R132H', 'Mutation', 'rs121913500', (154, 159))	('infected', 'Disease', (87, 95))
191722	32494639	To generate HUCCT1 isogenic cells, the parental HUCCT1 cells were infected with pLNCX2 retroviruses expressing IDH1-R132H or the empty vector control.	('C', 'Chemical', 'MESH:D002244', (14, 15))	('R132H', 'Mutation', 'rs121913500', (116, 121))	('IDH1-R132H', 'Var', (111, 121))	('C', 'Chemical', 'MESH:D002244', (15, 16))	('C', 'Chemical', 'MESH:D002244', (51, 52))	('infected', 'Disease', 'MESH:D007239', (66, 74))	('C', 'Chemical', 'MESH:D002244', (50, 51))	('infected', 'Disease', (66, 74))	('C', 'Chemical', 'MESH:D002244', (83, 84))
191735	32494639	Ten glioma (five wild-type and six mutant) and six cholangiocarcinoma (three wild-type and three mutant) samples were included in this study.	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('cholangiocarcinoma', 'Disease', (51, 69))	('mutant', 'Var', (35, 41))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (51, 69))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (51, 69))	('glioma', 'Disease', (4, 10))
191772	32494639	RCAS vectors carrying expression cassette for platelet-derived growth factor A (PDGFA), IDH1wt-shTP53, and IDH1R132H-shTP53 were gifts from E. Holland.	('IDH1R132H-shTP53', 'Var', (107, 123))	('RCAS', 'Chemical', '-', (0, 4))	('platelet-derived growth factor A', 'Gene', (46, 78))	('platelet-derived growth factor A', 'Gene', '18590', (46, 78))
191774	32494639	Cells expressing PDGFA were mixed with cells expressing IDH1wt-shTP53 or IDH1R132H-shTP53 at a ratio of 1:1 (3 x 105 total) and intracranially injected as described above.	('IDH1wt-shTP53', 'Var', (56, 69))	('PDGFA', 'Gene', (17, 22))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('R132H', 'Mutation', 'rs121913500', (77, 82))	('IDH1R132H-shTP53', 'Var', (73, 89))
191803	31545466	For example, KRAS mutations and PRKACB fusion genes have been identified in pCCA and dCCA, and somatic mutations of isocitrate dehydrogenase (IDH) have been identified in iCCA.	('isocitrate dehydrogenase', 'Gene', '3417', (116, 140))	('mutations', 'Var', (103, 112))	('IDH', 'Gene', (142, 145))	('CCA', 'Phenotype', 'HP:0030153', (86, 89))	('CCA', 'Disease', 'MESH:D018281', (86, 89))	('PRKACB', 'Gene', '5567', (32, 38))	('CCA', 'Phenotype', 'HP:0030153', (77, 80))	('CCA', 'Disease', (86, 89))	('CCA', 'Disease', 'MESH:D018281', (77, 80))	('CCA', 'Disease', (77, 80))	('identified', 'Reg', (62, 72))	('CCA', 'Phenotype', 'HP:0030153', (172, 175))	('isocitrate dehydrogenase', 'Gene', (116, 140))	('IDH', 'Gene', '3417', (142, 145))	('CCA', 'Disease', 'MESH:D018281', (172, 175))	('CCA', 'Disease', (172, 175))	('KRAS', 'Gene', '3845', (13, 17))	('identified', 'Reg', (157, 167))	('KRAS', 'Gene', (13, 17))	('PRKACB', 'Gene', (32, 38))
191806	31545466	In particular, understanding of the genetic variations that promote CCA initiation and development are still fragmented.	('CCA', 'Disease', 'MESH:D018281', (68, 71))	('variations', 'Var', (44, 54))	('CCA', 'Phenotype', 'HP:0030153', (68, 71))	('CCA', 'Disease', (68, 71))
191825	31545466	CCA-related transcriptomic datasets were obtained from GEO (GSE76297 and GSE26566) and ArrayExpress (E-GEOD-32879 and E-GEOD-45001).	('E-GEOD-32879', 'Chemical', 'MESH:C052019', (101, 113))	('CCA', 'Phenotype', 'HP:0030153', (0, 3))	('CCA', 'Disease', 'MESH:D018281', (0, 3))	('GSE26566', 'Var', (73, 81))	('CCA', 'Disease', (0, 3))
191843	31545466	For hub genes validated by qRT-PCR, R package 'ggpubr'  was used to visualize gene expression based on the expression profile of DEGs in TCGA and the results of qRT-PCR.	('TCGA', 'Gene', (137, 141))	('hub', 'Gene', (4, 7))	('hub', 'Gene', '1993', (4, 7))	('DEGs', 'Var', (129, 133))
191886	31545466	Aberrant expression of CDK1 is involved in cell cycle arrest in many tumor types such as melanoma, colon cancer and pancreatic cancer.	('colon cancer', 'Disease', 'MESH:D015179', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('colon cancer', 'Disease', (99, 111))	('pancreatic cancer', 'Disease', (116, 133))	('Aberrant expression', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cell cycle arrest', 'CPA', (43, 60))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('colon cancer', 'Phenotype', 'HP:0003003', (99, 111))	('CDK1', 'Gene', (23, 27))	('CDK1', 'Gene', '983', (23, 27))	('tumor', 'Disease', (69, 74))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('involved in', 'Reg', (31, 42))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
191947	30638862	This study suggests plasma PI15 holds significant value for predicting diagnosis for cholangiocarcinoma patients, and the combination of PI15 and carbohydrate antigen 19-9 improves diagnostic performance for cholangiocarcinoma.	('combination', 'Var', (122, 133))	('diagnostic performance', 'MPA', (181, 203))	('PI15', 'Gene', (137, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('PI15', 'Gene', (27, 31))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (85, 103))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (208, 226))	('PI15', 'Gene', '51050', (137, 141))	('improves', 'PosReg', (172, 180))	('cholangiocarcinoma', 'Disease', (208, 226))	('PI15', 'Gene', '51050', (27, 31))	('cholangiocarcinoma', 'Disease', (85, 103))	('patients', 'Species', '9606', (104, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (208, 226))
191990	30638862	We found that the sensitivity and specificity of PI15 expression was superior to those of other tumor markers.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('expression', 'Var', (54, 64))	('PI15', 'Gene', (49, 53))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('PI15', 'Gene', '51050', (49, 53))
192004	30638862	Therefore, the sensitivity and specificity of PI15 expression was higher than those of other tumor markers in CCA.	('CCA', 'Disease', (110, 113))	('PI15', 'Gene', '51050', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('CCA', 'Phenotype', 'HP:0030153', (110, 113))	('higher', 'PosReg', (66, 72))	('PI15', 'Gene', (46, 50))	('expression', 'Var', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
192021	30638862	ROC curve analysis was performed to further illustrate the diagnostic value of plasma PI15 for CCA patients.	('PI15', 'Gene', '51050', (86, 90))	('CCA', 'Disease', (95, 98))	('plasma', 'Var', (79, 85))	('patients', 'Species', '9606', (99, 107))	('PI15', 'Gene', (86, 90))	('CCA', 'Phenotype', 'HP:0030153', (95, 98))
192035	30638862	In the same sample set, CA19-9 had a comparable AUC of 0.849 for iCCA samples compared to HCC controls (Fig.	('HCC', 'Phenotype', 'HP:0001402', (90, 93))	('CCA', 'Phenotype', 'HP:0030153', (66, 69))	('CA19-9', 'Var', (24, 30))	('iCCA', 'Disease', (65, 69))	('HCC', 'Gene', (90, 93))	('HCC', 'Gene', '619501', (90, 93))	('CA19-9', 'Chemical', 'MESH:C086528', (24, 30))
192039	30638862	For healthy individuals, the combination of PI15 and CA19-9 was not able to increase the ability to discriminate between iCCA samples and healthy individuals (Fig.	('CA19-9', 'Var', (53, 59))	('CCA', 'Phenotype', 'HP:0030153', (122, 125))	('PI15', 'Gene', '51050', (44, 48))	('iCCA', 'Disease', (121, 125))	('CA19-9', 'Chemical', 'MESH:C086528', (53, 59))	('PI15', 'Gene', (44, 48))
192044	30638862	As seen in Table 2, plasma PI15 could detect approximately 57.7% of iCCA patients (sensitivity) with 94.4% specificity when the cut off value was set to 13 ng/ml.	('PI15', 'Gene', (27, 31))	('CCA', 'Phenotype', 'HP:0030153', (69, 72))	('PI15', 'Gene', '51050', (27, 31))	('patients', 'Species', '9606', (73, 81))	('iCCA', 'Disease', (68, 72))	('plasma', 'Var', (20, 26))
192059	30638862	The differentially methylated CpG of PI15 was previously found to be a potential novel prognostic marker capable of distinguishing prostate cancer patients with metastatic-lethal tumors from nonrecurrent tumors.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumors', 'Disease', (179, 185))	('PI15', 'Gene', '51050', (37, 41))	('prostate cancer', 'Disease', 'MESH:D011471', (131, 146))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('prostate cancer', 'Phenotype', 'HP:0012125', (131, 146))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('patients', 'Species', '9606', (147, 155))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('PI15', 'Gene', (37, 41))	('differentially methylated', 'Var', (4, 29))	('prostate cancer', 'Disease', (131, 146))
192087	28931489	A recent systematic review and meta-analysis (SRMA) of eight studies involving 828 patients demonstrated that the pooled sensitivity and specificity of FISH polysomy to detect cholangiocarcinoma was 51% and 93%, respectively.	('cholangiocarcinoma', 'Disease', (176, 194))	('SRMA', 'Chemical', '-', (46, 50))	('FISH polysomy', 'Var', (152, 165))	('patients', 'Species', '9606', (83, 91))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (176, 194))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (176, 194))
192094	28931489	In one retrospective study, patients undergoing EUS-FNA prior to liver transplantation for perihilar cholangiocarcinoma were more likely to have peritoneal metastases at the time of staging laparotomy (83% vs. 8%), although the number of patients who underwent EUS-FNA was small (n=16).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('EUS-FNA', 'Var', (48, 55))	('metastases', 'Disease', (156, 166))	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (95, 119))	('hilar cholangiocarcinoma', 'Disease', (95, 119))	('metastases', 'Disease', 'MESH:D009362', (156, 166))	('patients', 'Species', '9606', (28, 36))	('patients', 'Species', '9606', (238, 246))
192118	28931489	The authors concluded that pre-operative biliary drainage is not indicated in patients with a bilirubin <250umol/l.	('<250umol/l', 'Var', (104, 114))	('patients', 'Species', '9606', (78, 86))	('bilirubin', 'Chemical', 'MESH:D001663', (94, 103))	('bilirubin', 'MPA', (94, 103))
192121	28931489	In those patients with a longer interval to surgery, such as those receiving neo-adjuvant chemotherapy, FCSEMS provide longer patency than plastic stents therefore reducing the need for re-intervention and minimising interruptions to chemotherapy.	('patients', 'Species', '9606', (9, 17))	('patency', 'MPA', (126, 133))	('longer', 'PosReg', (119, 125))	('reducing', 'NegReg', (164, 172))	('FCSEMS', 'Var', (104, 110))
192134	28931489	Balloon dilatation alone without subsequent stenting is associated with a high rate of stricture recurrence in anastomotic strictures and chronic pancreatitis.	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (138, 158))	('pancreatitis', 'Phenotype', 'HP:0001733', (146, 158))	('chronic pancreatitis', 'Disease', (138, 158))	('Balloon dilatation', 'Var', (0, 18))	('anastomotic strictures', 'Disease', (111, 133))	('dilatation', 'Phenotype', 'HP:0002617', (8, 18))	('stricture', 'MPA', (87, 96))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (138, 158))
192159	29483830	In other cases, such as skin cancer, loss of SMAD4 plays an important initiating role by disrupting DNA damage response and repair mechanisms and enhance genomic instability, suggesting its distinct roles in different types of tumors.	('genomic instability', 'CPA', (154, 173))	('skin cancer', 'Phenotype', 'HP:0008069', (24, 35))	('disrupting', 'NegReg', (89, 99))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('skin cancer', 'Disease', (24, 35))	('enhance', 'PosReg', (146, 153))	('repair mechanisms', 'MPA', (124, 141))	('loss', 'Var', (37, 41))	('skin cancer', 'Disease', 'MESH:D012878', (24, 35))	('SMAD4', 'Gene', (45, 50))	('DNA damage response', 'MPA', (100, 119))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
192160	29483830	This review lists SMAD4 mutations in various types of cancer and summarizes recent advances on SMAD4 with focuses on the function, signaling pathway, and the possibility of SMAD4 as a prognostic indicator.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('SMAD4', 'Gene', (18, 23))	('mutations', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
192170	29483830	While SMAD2/3 mainly mediate signaling from TGF-beta subfamily members, SMAD1/5/8 transduct signaling from bone morphogenic protein (BMP) subfamily members; (2) the common-mediator SMAD (Co-SMAD) including only SMAD4, which is the central mediator of both TGF-beta and BMP signaling pathway; and (3) the inhibitory SMAD (I-SMAD) including SMAD6 and SMAD7, which mainly function to inhibit receptor mediated R-SMAD phosphorylation, thus preventing the complex formation with Co-SMAD (Figure 1B).	('BMP', 'Gene', (269, 272))	('bone morphogenic protein', 'Gene', (107, 131))	('inhibit', 'NegReg', (381, 388))	('TGF-beta', 'Gene', (44, 52))	('BMP', 'Gene', (133, 136))	('receptor', 'Protein', (389, 397))	('bone morphogenic protein', 'Gene', '649', (107, 131))	('TGF-beta', 'Gene', '7040', (256, 264))	('SMAD6', 'Gene', (339, 344))	('SMAD1/5', 'Gene', '4086;4090', (72, 79))	('complex formation', 'MPA', (451, 468))	('SMAD1/5', 'Gene', (72, 79))	('BMP', 'Gene', '649', (269, 272))	('SMAD2/3', 'Gene', (6, 13))	('TGF-beta', 'Gene', (256, 264))	('SMAD6', 'Gene', '4091', (339, 344))	('TGF-beta', 'Gene', '7040', (44, 52))	('BMP', 'Gene', '649', (133, 136))	('SMAD2/3', 'Gene', '4087;4088', (6, 13))	('SMAD7', 'Var', (349, 354))	('preventing', 'NegReg', (436, 446))
192196	29483830	(2005) identified ERK phosphorylation sites in SMAD3 at Thr178, Ser203, and Ser207 in lung epithelial cells.	('SMAD3', 'Gene', (47, 52))	('ERK', 'Gene', (18, 21))	('Ser203', 'Chemical', '-', (64, 70))	('Ser207', 'Var', (76, 82))	('Ser207', 'Chemical', '-', (76, 82))	('Thr178', 'Chemical', '-', (56, 62))	('ERK', 'Gene', '5594', (18, 21))	('SMAD3', 'Gene', '4088', (47, 52))
192202	29483830	Inversely, JNK is implicated to reduce the secretion of TGF-beta1, as upon JNK inactivation, RAS gains ability to induce TGF-beta1 autocrine.	('secretion', 'MPA', (43, 52))	('reduce', 'NegReg', (32, 38))	('TGF-beta1', 'Gene', '7040', (56, 65))	('JNK', 'Gene', '5599', (11, 14))	('TGF-beta1', 'Gene', (56, 65))	('TGF-beta1', 'Gene', '7040', (121, 130))	('TGF-beta1', 'Gene', (121, 130))	('inactivation', 'Var', (79, 91))	('JNK', 'Gene', (75, 78))	('induce', 'PosReg', (114, 120))	('JNK', 'Gene', '5599', (75, 78))	('JNK', 'Gene', (11, 14))	('ability', 'MPA', (103, 110))
192215	29483830	Inactivating PI3K/AKT pathway by inhibitors affects TGF-beta mediated EMT and cell migration.	('PI3K/AKT', 'Gene', '5290;207', (13, 21))	('TGF-beta', 'Gene', (52, 60))	('PI3K/AKT', 'Gene', (13, 21))	('Inactivating', 'Var', (0, 12))	('inhibitors', 'Var', (33, 43))	('rat', 'Species', '10116', (86, 89))	('TGF-beta', 'Gene', '7040', (52, 60))
192226	29483830	For example, deletion of SMAD4 in the Mullerian duct led to reduced LEF1 signal, suggesting the alleviated WNT/beta-catenin signaling pathway.	('LEF1', 'Gene', '51176', (68, 72))	('beta-catenin', 'Gene', (111, 123))	('LEF1', 'Gene', (68, 72))	('deletion', 'Var', (13, 21))	('reduced', 'NegReg', (60, 67))	('beta-catenin', 'Gene', '1499', (111, 123))	('SMAD4', 'Gene', (25, 30))	('alleviated', 'NegReg', (96, 106))
192230	29483830	Moreover, in the human pancreatic adenocarcinoma cells BxPC3, in which SMAD4 is homozigously deleted, chronic EGF stimulation induces beta-catenin phosphorylation that can be antagonized by SMAD4 restoration, suggesting that SMAD4 homozigous deletion is critical to EGF induced WNT/beta-catenin signaling pathway inhibition.	('beta-catenin', 'Gene', '1499', (134, 146))	('beta-catenin', 'Gene', (282, 294))	('rat', 'Species', '10116', (201, 204))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (23, 48))	('pancreatic adenocarcinoma', 'Disease', (23, 48))	('BxPC3', 'CellLine', 'CVCL:0186', (55, 60))	('human', 'Species', '9606', (17, 22))	('SMAD4', 'Gene', (71, 76))	('deleted', 'Var', (93, 100))	('beta-catenin', 'Gene', '1499', (282, 294))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (23, 48))	('beta-catenin', 'Gene', (134, 146))
192233	29483830	Representative SMAD4 mutations in various cancers are summaried in Figure 3.	('cancers', 'Disease', (42, 49))	('SMAD4', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('mutations', 'Var', (21, 30))
192235	29483830	So many studies have demonstrated that SMAD4 alteration is closely related with pancreatic cancer since its discovery in 1996.	('related', 'Reg', (67, 74))	('SMAD4', 'Gene', (39, 44))	('pancreatic cancer', 'Disease', (80, 97))	('pancreatic cancer', 'Disease', 'MESH:D010190', (80, 97))	('alteration', 'Var', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('rat', 'Species', '10116', (49, 52))	('rat', 'Species', '10116', (28, 31))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (80, 97))
192237	29483830	A further study revealed that SMAD4 mutation was associated with pancreatic pathologic stages.	('pancreatic', 'Disease', (65, 75))	('associated', 'Reg', (49, 59))	('SMAD4', 'Gene', (30, 35))	('pancreatic', 'Disease', 'MESH:D010195', (65, 75))	('mutation', 'Var', (36, 44))
192240	29483830	Although knockout of SMAD4 by pancreatic-specific PDX1-Cre or P48-Cre did not initiate pancreatic cancer in mice, they markedly facilitated tumor progression initiated by KRASG12D activation or PTEN inactivation.	('pancreatic', 'Disease', (87, 97))	('PTEN', 'Protein', (194, 198))	('pancreatic cancer', 'Disease', (87, 104))	('mice', 'Species', '10090', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('pancreatic', 'Disease', (30, 40))	('KRAS', 'Gene', (171, 175))	('PDX1', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('PDX1', 'Gene', '18609', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))	('facilitated', 'PosReg', (128, 139))	('P48-Cre', 'Var', (62, 69))	('pancreatic', 'Disease', 'MESH:D010195', (87, 97))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('inactivation', 'Var', (199, 211))	('pancreatic', 'Disease', 'MESH:D010195', (30, 40))	('KRAS', 'Gene', '3845', (171, 175))	('tumor', 'Disease', (140, 145))
192247	29483830	However, tissue-specific deletion of SMAD4 along in mouse hepatocytes and bile duct epithelial cells did not cause discernable tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('SMAD4', 'Gene', (37, 42))	('mouse', 'Species', '10090', (52, 57))	('deletion', 'Var', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
192251	29483830	Accumulation of evidence has confirmed that the loss of SMAD4 in colorectal cancer occurs at a frequency of about 30%.	('loss', 'Var', (48, 52))	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('colorectal cancer', 'Disease', (65, 82))	('SMAD4', 'Gene', (56, 61))	('colorectal cancer', 'Disease', 'MESH:D015179', (65, 82))
192255	29483830	The rate of SMAD4 loss has a positive correlation with colorectal cancer progression, convincing that inactivation of SMAD4 is a late event in colorectal carcinogenesis.	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (143, 168))	('loss', 'NegReg', (18, 22))	('SMAD4', 'Gene', (118, 123))	('inactivation', 'Var', (102, 114))	('colorectal cancer', 'Disease', 'MESH:D015179', (55, 72))	('SMAD4', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (55, 72))	('colorectal carcinogenesis', 'Disease', (143, 168))	('colorectal cancer', 'Disease', (55, 72))	('rat', 'Species', '10116', (4, 7))
192256	29483830	Although germline loss of SMAD4 in human or heterozygous deletion in mice caused juvenile polyposis (JP), the risk of carcinoma is low and associated with a long latency, suggesting that SMAD4 loss alone may be insufficient for tumor initiation.	('carcinoma', 'Disease', 'MESH:D002277', (118, 127))	('loss', 'Var', (18, 22))	('deletion', 'Var', (57, 65))	('SMAD4', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('human', 'Species', '9606', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('juvenile polyposis', 'Disease', 'MESH:C537702', (81, 99))	('mice', 'Species', '10090', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('juvenile polyposis', 'Disease', (81, 99))	('carcinoma', 'Disease', (118, 127))	('tumor', 'Disease', (228, 233))	('juvenile polyposis', 'Phenotype', 'HP:0004784', (81, 99))	('caused', 'Reg', (74, 80))	('JP', 'Phenotype', 'HP:0004784', (101, 103))	('low', 'NegReg', (131, 134))
192257	29483830	It has been reported that heterozygous deletion of SMAD4 promotes progression of colorectal cancer initiated by germline mutation of APC.	('colorectal cancer', 'Disease', (81, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))	('APC', 'Gene', '324', (133, 136))	('germline mutation', 'Var', (112, 129))	('heterozygous deletion', 'Var', (26, 47))	('progression', 'CPA', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('APC', 'Gene', (133, 136))	('SMAD4', 'Gene', (51, 56))	('promotes', 'PosReg', (57, 65))
192260	29483830	Moreover, deletion of SMAD4 in human colorectal tumor cells reduced the number of S100A8-positive monocytes and attenuated the sensitivity of tumor cells to chemokine S100A8, suggesting the effect of SMAD4 on monocyte infiltrate.	('S100A8', 'Gene', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (48, 53))	('SMAD4', 'Gene', (22, 27))	('S100A8', 'Gene', '6279', (167, 173))	('tumor', 'Disease', (142, 147))	('S100A8', 'Gene', (82, 88))	('human', 'Species', '9606', (31, 36))	('colorectal tumor', 'Disease', (37, 53))	('S100A8', 'Gene', '6279', (82, 88))	('reduced', 'NegReg', (60, 67))	('rat', 'Species', '10116', (224, 227))	('deletion', 'Var', (10, 18))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('colorectal tumor', 'Disease', 'MESH:D015179', (37, 53))	('attenuated', 'NegReg', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
192262	29483830	Similar to pancreatic and intrahepatic cholangiocarcinoma, prostate specific deletion of SMAD4 did not initiate cancer formation, but synergistically promotes tumorigenesis together with PTEN deletion.	('pancreatic and intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (11, 57))	('cancer', 'Disease', (112, 118))	('promotes', 'PosReg', (150, 158))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (39, 57))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('SMAD4', 'Gene', (89, 94))	('deletion', 'Var', (77, 85))	('tumor', 'Disease', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
192263	29483830	SMAD4 mutations are rare in human prostate cancer, but SMAD4 promotor methylation is commonly detected, which may reduce SMAD4 expression.	('expression', 'MPA', (127, 137))	('human prostate cancer', 'Disease', 'MESH:D011471', (28, 49))	('methylation', 'Var', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('human prostate cancer', 'Disease', (28, 49))	('reduce', 'NegReg', (114, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (34, 49))	('SMAD4', 'Gene', (121, 126))	('SMAD4', 'Gene', (55, 60))
192264	29483830	Of note, SMAD4 downregulation was found at an early stage in human HNSCC, and deletion of SMAD4 alone in murine head and neck epithelia results in spontaneous HNSCC that mimics human HNSCC.	('downregulation', 'NegReg', (15, 29))	('SCC', 'Gene', (161, 164))	('SCC', 'Phenotype', 'HP:0002860', (161, 164))	('SCC', 'Gene', (185, 188))	('SCC', 'Phenotype', 'HP:0002860', (185, 188))	('SCC', 'Gene', (69, 72))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('murine', 'Species', '10090', (105, 111))	('deletion', 'Var', (78, 86))	('SCC', 'Gene', '6317', (161, 164))	('neck epithelia', 'Disease', 'MESH:D006258', (121, 135))	('SCC', 'Gene', '6317', (185, 188))	('SCC', 'Gene', '6317', (69, 72))	('neck epithelia', 'Disease', (121, 135))	('human', 'Species', '9606', (177, 182))	('human', 'Species', '9606', (61, 66))	('SMAD4', 'Gene', (90, 95))
192265	29483830	Keratinocyte-specific deletion of SMAD4 results in predominantly well-differentiated skin tumors, revealing that SMAD4 is a tumor initiator.	('skin tumors', 'Disease', 'MESH:D012878', (85, 96))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('rat', 'Species', '10116', (2, 5))	('deletion', 'Var', (22, 30))	('results in', 'Reg', (40, 50))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', (124, 129))	('skin tumors', 'Phenotype', 'HP:0008069', (85, 96))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('skin tumors', 'Disease', (85, 96))	('SMAD4', 'Gene', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
192266	29483830	A very similar phenotype is obtained in the mouse mammary tumor virus (MMTV)-Cre mediated SMAD4 deletion.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('MMTV', 'Species', '11757', (71, 75))	('deletion', 'Var', (96, 104))	('SMAD4', 'Gene', (90, 95))	('mouse mammary tumor virus', 'Species', '11757', (44, 69))
192268	29483830	It was also reported that mice carrying K5-Cre mediated deletion of SMAD4 in keratinocytes developed forestomach squamous cell carcinoma (SCC) at 8 months, while deletion of PTEN only suffered dysplasia.	('deletion', 'Var', (56, 64))	('SCC', 'Gene', (138, 141))	('dysplasia', 'Disease', (193, 202))	('rat', 'Species', '10116', (79, 82))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('SMAD4', 'Gene', (68, 73))	('SCC', 'Gene', '6317', (138, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('forestomach squamous cell carcinoma', 'Disease', (101, 136))	('dysplasia', 'Disease', 'MESH:D004476', (193, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('forestomach squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 136))	('mice', 'Species', '10090', (26, 30))
192269	29483830	However, concurrent deletion of SMAD4 and PTEN led to invasive SCC in 2 months.	('PTEN', 'Gene', (42, 46))	('SCC', 'Gene', (63, 66))	('SCC', 'Phenotype', 'HP:0002860', (63, 66))	('SMAD4', 'Gene', (32, 37))	('SCC', 'Gene', '6317', (63, 66))	('deletion', 'Var', (20, 28))	('led to', 'Reg', (47, 53))
192270	29483830	Moreover, deletion of SMAD4 and PTEN by LGR5-Cre drived gastric LGR5+ stem cells transformation, thus causing invasive intestinal-type gastric cancer.	('gastric cancer', 'Disease', (135, 149))	('causing', 'Reg', (102, 109))	('LGR5', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('gastric cancer', 'Disease', 'MESH:D013274', (135, 149))	('LGR5', 'Gene', (64, 68))	('SMAD4', 'Gene', (22, 27))	('LGR5', 'Gene', '8549', (64, 68))	('PTEN', 'Gene', (32, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (135, 149))	('deletion', 'Var', (10, 18))	('LGR5', 'Gene', '8549', (40, 44))
192271	29483830	In the gastric cancer cell lines MGC-803 and BGC-823, SMAD4 serves as the direct target of miR-324-3p, which promotes gastric cancer progression.	('gastric cancer', 'Phenotype', 'HP:0012126', (7, 21))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('gastric cancer', 'Disease', (118, 132))	('gastric cancer', 'Disease', 'MESH:D013274', (118, 132))	('MGC-803', 'CellLine', 'CVCL:5334', (33, 40))	('324-3p', 'Chemical', '-', (95, 101))	('gastric cancer', 'Disease', (7, 21))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('gastric cancer', 'Disease', 'MESH:D013274', (7, 21))	('miR-324-3p', 'Var', (91, 101))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('promotes', 'PosReg', (109, 117))
192272	29483830	This miR-324-3p induced tumor growth can be rescued by restoration of SMAD4.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('324-3p', 'Chemical', '-', (9, 15))	('tumor', 'Disease', (24, 29))	('restoration', 'Var', (55, 66))	('rat', 'Species', '10116', (60, 63))	('miR-324-3p', 'Var', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('SMAD4', 'Gene', (70, 75))
192277	29483830	When knocking down SMAD4 in mammary gland epithelial cell NMuMG, the TGF-beta induced EMT was potently blocked with the failure of E-cadherin reduction and N-cadherin induction, as well as morphologic transformation.	('E-cadherin', 'Gene', '999', (131, 141))	('TGF-beta', 'Gene', (69, 77))	('NMuMG', 'CellLine', 'CVCL:0075', (58, 63))	('SMAD4', 'Gene', (19, 24))	('knocking down', 'Var', (5, 18))	('N-cadherin', 'Gene', (156, 166))	('TGF-beta', 'Gene', '7040', (69, 77))	('E-cadherin', 'Gene', (131, 141))	('N-cadherin', 'Gene', '1000', (156, 166))	('blocked', 'NegReg', (103, 110))	('EMT', 'CPA', (86, 89))
192278	29483830	Similarly, SMAD4 knockdown in liver significantly reduced liver tumorigenesis through upregulating SNAIL, suggesting that TGF-beta signal promotes EMT in a SMAD4-dependent manner.	('tumor', 'Disease', (64, 69))	('upregulating', 'PosReg', (86, 98))	('promotes', 'PosReg', (138, 146))	('TGF-beta', 'Gene', '7040', (122, 130))	('SNAIL', 'Gene', '6615', (99, 104))	('reduced', 'NegReg', (50, 57))	('knockdown', 'Var', (17, 26))	('SNAIL', 'Gene', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('TGF-beta', 'Gene', (122, 130))	('EMT', 'CPA', (147, 150))
192284	29483830	It has been shown that mice carrying specific disruption of SMAD4 in head and neck epithelia developed head and neck cancer that is associated with increased genomic instability and downregulated expression and function of genes encoding proteins in the Fanconi anemia/BRCA (FANC/BRCA) DNA repair pathway.	('Fanconi anemia', 'Disease', 'MESH:D005199', (254, 268))	('disruption', 'Var', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('SMAD4', 'Gene', (60, 65))	('anemia', 'Phenotype', 'HP:0001903', (262, 268))	('expression', 'MPA', (196, 206))	('downregulated', 'NegReg', (182, 195))	('neck epithelia', 'Disease', (78, 92))	('head and neck cancer', 'Phenotype', 'HP:0012288', (103, 123))	('neck epithelia', 'Disease', 'MESH:D006258', (78, 92))	('Fanconi anemia', 'Disease', (254, 268))	('neck cancer', 'Disease', 'MESH:D006258', (112, 123))	('neck cancer', 'Disease', (112, 123))	('function', 'MPA', (211, 219))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (254, 268))	('mice', 'Species', '10090', (23, 27))
192285	29483830	It was also shown mice carrying K14-Cre mediated disruption of SMAD4 (K14.SMAD4-/-) in keratinocytes suffered increased DNA damage and increased susceptibility to UV induced carcinogenesis.	('K14', 'Gene', '16664', (70, 73))	('K14', 'Gene', (70, 73))	('increased', 'PosReg', (110, 119))	('K14', 'Gene', (32, 35))	('carcinogenesis', 'Disease', 'MESH:D063646', (174, 188))	('K14', 'Gene', '16664', (32, 35))	('mice', 'Species', '10090', (18, 22))	('increased', 'PosReg', (135, 144))	('carcinogenesis', 'Disease', (174, 188))	('DNA damage', 'MPA', (120, 130))	('susceptibility', 'Reg', (145, 159))	('rat', 'Species', '10116', (89, 92))	('disruption', 'Var', (49, 59))
192295	29483830	The transcription of miR-23a~27a~24 was upregulated quickly upon TGF-beta treatment, and attenuated by SMAD4 deletion.	('TGF-beta', 'Gene', (65, 73))	('deletion', 'Var', (109, 117))	('transcription', 'MPA', (4, 17))	('upregulated', 'PosReg', (40, 51))	('miR-23a', 'Gene', '407010', (21, 28))	('miR-23a', 'Gene', (21, 28))	('SMAD4', 'Gene', (103, 108))	('TGF-beta', 'Gene', '7040', (65, 73))	('attenuated', 'NegReg', (89, 99))
192301	29483830	The survival analysis revealed that the patients with positive SMAD4 signal lived longer than those with negative signal, with the median survival of 16.5 months versus 9 months.	('SMAD4', 'Gene', (63, 68))	('positive', 'Var', (54, 62))	('patients', 'Species', '9606', (40, 48))
192302	29483830	Recently, Singh's group focused on an Indian population with pancreatic duct adenocarcinoma for SMAD4 alteration and effect of its loss on patient survival.	('pancreatic duct adenocarcinoma', 'Disease', 'MESH:D010190', (61, 91))	('SMAD4', 'Gene', (96, 101))	('alteration', 'Var', (102, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('pancreatic duct adenocarcinoma', 'Phenotype', 'HP:0006725', (61, 91))	('rat', 'Species', '10116', (106, 109))	('pancreatic duct adenocarcinoma', 'Disease', (61, 91))	('patient', 'Species', '9606', (139, 146))
192303	29483830	The SMAD4 gene was altered by homozygous deletion in 5 patients and intragenic mutation in the MH2 domain in 3 patients, together accounting for 32% of the patients.	('patients', 'Species', '9606', (156, 164))	('homozygous deletion', 'Var', (30, 49))	('SMAD4', 'Gene', (4, 9))	('patients', 'Species', '9606', (55, 63))	('altered', 'Reg', (19, 26))	('mutation in', 'Var', (79, 90))	('patients', 'Species', '9606', (111, 119))
192304	29483830	The follow-up investigation provided a median survival of 5 months in the SMAD4 alteration group while 10 months in the SMAD4 wildtype group.	('alteration', 'Var', (80, 90))	('rat', 'Species', '10116', (84, 87))	('SMAD4', 'Gene', (74, 79))
192306	29483830	SMAD4 expression level has a positive correlation with survival in colon cancer, and the loss of SMAD4 leads to poor prognosis.	('SMAD4', 'Gene', (97, 102))	('loss', 'Var', (89, 93))	('colon cancer', 'Phenotype', 'HP:0003003', (67, 79))	('colon cancer', 'Disease', 'MESH:D015179', (67, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('colon cancer', 'Disease', (67, 79))	('expression level', 'MPA', (6, 22))
192310	29483830	Through evaluating the expression level of SMAD4 and PTEN in patients bearing colorectal cdenocarcinoma, there was a significant difference in the overall survival, showing patients with loss of both SMAD4 and PTEN had worse outcome than cases with SMAD4 or PTEN loss alone.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('patients', 'Species', '9606', (173, 181))	('loss', 'Var', (187, 191))	('patients', 'Species', '9606', (61, 69))	('colorectal cdenocarcinoma', 'Disease', 'MESH:D015179', (78, 103))	('colorectal cdenocarcinoma', 'Disease', (78, 103))	('PTEN', 'Gene', (210, 214))	('SMAD4', 'Gene', (200, 205))
192312	29483830	Numerous studies during passed two decades provide strong evidence that SMAD4 is a tumor suppressor, whose mutations are found in at least 26 types of cancer, with higher frequencies in GI tract cancers, such as Esophagus, Stomach, pancrease and Colorectal cancers (Table 1).	('Colorectal cancers', 'Disease', (246, 264))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('tumor', 'Disease', (83, 88))	('GI tract cancers', 'Disease', 'MESH:D004067', (186, 202))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('found', 'Reg', (121, 126))	('higher frequencies', 'PosReg', (164, 182))	('GI tract cancers', 'Disease', (186, 202))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('Esophagus', 'Disease', (212, 221))	('cancer', 'Disease', (195, 201))	('pancrease', 'Disease', (232, 241))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('mutations', 'Var', (107, 116))	('Colorectal cancers', 'Disease', 'MESH:D015179', (246, 264))	('Stomach', 'Disease', (223, 230))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('SMAD4', 'Gene', (72, 77))	('cancer', 'Disease', (257, 263))
192313	29483830	Additionally, loss of SMAD4 in tumors affects cancer progression and therapy, such as reduced response to adjuvant chemotherapy.	('reduced', 'NegReg', (86, 93))	('loss', 'Var', (14, 18))	('response to adjuvant chemotherapy', 'CPA', (94, 127))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('SMAD4', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('therapy', 'CPA', (69, 76))	('cancer', 'Disease', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('affects', 'Reg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
192316	29483830	Even though the SMAD4 mediated TGF-beta signaling pathway has been elucidated well, how SMAD4 alteration causes tumor formation and progression remains unclear due to the crosstalk with other pathways.	('TGF-beta', 'Gene', (31, 39))	('causes', 'Reg', (105, 111))	('crosstalk', 'Reg', (171, 180))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('SMAD4', 'Gene', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('rat', 'Species', '10116', (98, 101))	('TGF-beta', 'Gene', '7040', (31, 39))	('tumor', 'Disease', (112, 117))	('alteration', 'Var', (94, 104))
192320	29483830	Although limited knowledge is availabale regarding the mechanism, some molecules associated to SMAD4, including UA62001 and UA62784, have been developed as candidates in cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('SMAD4', 'Gene', (95, 100))	('UA62784', 'Var', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('UA62001', 'Var', (112, 119))
192374	20846273	PDT-treated patients had significantly better survival than those who had biliary drainage procedures alone (1-year survival 51% vs. 20%, respectively, p=0.01; T3/T4 stage in 93% vs. 85%, respectively, p=0.18), and there was a trend towards better survival compared to those who received chemo- and/or radiotherapy alone (1-year survival 51% vs. 37%, p=0.07; T3/T4 stage in 93% vs. 89%, respectively, p=0.45).	('PDT-treated', 'Var', (0, 11))	('patients', 'Species', '9606', (12, 20))	('better', 'PosReg', (39, 45))
192390	20846273	In patients who underwent surgery with curative intent, R0 resection was the only independent predictor of improved survival, although well differentiated tumours and negative lymph node status have also been identified by other groups as predicting a better outcome.	('tumours', 'Disease', (155, 162))	('R0 resection', 'Var', (56, 68))	('improved', 'PosReg', (107, 115))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('survival', 'MPA', (116, 124))	('patients', 'Species', '9606', (3, 11))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('tumours', 'Disease', 'MESH:D009369', (155, 162))
192395	20846273	A recent analysis of a German cohort of 184 patients with hilar cholangiocarcinoma has also demonstrated no significant difference in median survival between R1/R2 resection (n=18; 12.2 months) and palliative PDT plus stenting (n=68; 12.0 months).	('R1/R2 resection', 'Var', (158, 173))	('patients', 'Species', '9606', (44, 52))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (58, 82))	('hilar cholangiocarcinoma', 'Disease', (58, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
192397	20846273	In order to select such patients for PDT, improvements in the accuracy of current preoperative staging are needed; for example MRI/MRCP can under-stage the disease in up to 20% of cases.	('under-stage', 'NegReg', (140, 151))	('MRI/MRCP', 'Var', (127, 135))	('patients', 'Species', '9606', (24, 32))
192426	19175944	The hexahistidine tag can be used for one-step affinity purification with immobilized metal affinity chromatography (IMAC), whereas the Myc epitope can be recognized by 9E10 monoclonal antibody for detection.	('hexahistidine', 'Var', (4, 17))	('IMAC', 'Chemical', '-', (117, 121))	('Myc', 'Gene', '4609', (136, 139))	('Myc', 'Gene', (136, 139))	('metal', 'Chemical', 'MESH:D008670', (86, 91))	('hexahistidine', 'Chemical', 'MESH:C471213', (4, 17))
192451	19175944	HB2151, unlike TG-1, is not able to suppress the amber stop codon upstream of the gene III sequence in pMod1 vector, thus resulting in expression of non-fused scFv.	('HB2151', 'CellLine', 'CVCL:K913', (0, 6))	('Mod1', 'Gene', (104, 108))	('resulting in', 'Reg', (122, 134))	('Mod1', 'Gene', '10951', (104, 108))	('amber stop codon', 'MPA', (49, 65))	('expression', 'Species', '29278', (135, 145))	('scFv', 'Gene', '652070', (159, 163))	('scFv', 'Gene', (159, 163))	('expression', 'MPA', (135, 145))	('HB2151', 'Var', (0, 6))
192455	19175944	The variations of the CDR3 length in VH genes (6-19) were higher than that of the VL genes (9-11).	('variations', 'Var', (4, 14))	('CDR3', 'Gene', (22, 26))	('CDR3', 'Gene', '8163', (22, 26))	('higher', 'PosReg', (58, 64))
192474	19175944	In order to create scFv fragment genes as a VH-linker-VL type, the 3' ends of VH genes were made complementary to 5' ends of VL genes through a (Gly4Ser)3 linker peptide, and the VH and VL genes were assembled and amplified by overlap extension followed by pull-through PCR.	('scFv', 'Gene', (19, 23))	('Gly4Ser', 'SUBSTITUTION', 'None', (145, 152))	('scFv', 'Gene', '652070', (19, 23))	('Gly4Ser', 'Var', (145, 152))
192733	24055987	In the absence of acute cholangitis, a CA19-9 greater than 1000 units/mL usually indicates the presence of extrahepatic disease .	('extrahepatic disease', 'Disease', 'MESH:D001651', (107, 127))	('CA19-9', 'Var', (39, 45))	('hepatic disease', 'Phenotype', 'HP:0001392', (112, 127))	('extrahepatic disease', 'Disease', (107, 127))	('cholangitis', 'Phenotype', 'HP:0030151', (24, 35))	('acute cholangitis', 'Disease', 'MESH:D002761', (18, 35))	('acute cholangitis', 'Disease', (18, 35))
192785	24055987	With MRI contrast agents such as gadoxetate disodium (Eovist) or gadobenate dimeglumine (MultiHance) that have both renal and biliary excretion, FNHs show active hepatocyte uptake and look similar to or brighter than the surrounding liver tissue in the hepatocyte phase of imaging (Figure 4).	('active', 'PosReg', (155, 161))	('gadobenate dimeglumine', 'Chemical', 'MESH:C064572', (65, 87))	('Eovist', 'Chemical', 'MESH:C073590', (54, 60))	('brighter', 'PosReg', (203, 211))	('hepatocyte', 'MPA', (162, 172))	('gadoxetate disodium', 'Chemical', 'MESH:C073590', (33, 52))	('gadobenate', 'Var', (65, 75))	('MultiHance', 'Chemical', 'MESH:C064572', (89, 99))
192801	24055987	Based on genetic and immunohistochemical analyses, hepatic adenomas are subclassified into (1) inflammatory hepatic adenomas, 60% of which are characterized by activating in-frame deletions of the IL-6 signal transduction protein gp130 and expression of the inflammation-associated proteins C-reactive protein and serum amyloid A protein; (2) HNF1alpha-inactivated hepatic adenomas, which are steatotic and do not express liver fatty acid binding protein; HNF1alpha gene mutations are also associated with familial maturity-onset diabetes of the young and hepatic adenomatosis; (3) beta-catenin-activated hepatic adenomas, which overexpress glutamine synthetase in the cytoplasm and show aberrant expression of beta-catenin in the nucleus; and (4) an indeterminate subgroup.	('mutations', 'Var', (471, 480))	('hepatic adenomas', 'Phenotype', 'HP:0012028', (108, 124))	('hepatic adenomas', 'Disease', (51, 67))	('fat', 'Gene', '2195', (428, 431))	('IL-6', 'Gene', '3569', (197, 201))	('C-reactive protein', 'Gene', '1401', (291, 309))	('diabetes', 'Disease', 'MESH:D003920', (530, 538))	('glutamine synthetase', 'Gene', (641, 661))	('gp130', 'Gene', (230, 235))	('hepatic adenoma', 'Phenotype', 'HP:0012028', (108, 123))	('inflammation', 'Disease', 'MESH:D007249', (258, 270))	('hepatic adenomas', 'Disease', 'MESH:C564190', (605, 621))	('gp130', 'Gene', '3572', (230, 235))	('hepatic adenomas', 'Phenotype', 'HP:0012028', (51, 67))	('fat', 'Gene', (428, 431))	('IL-6', 'Gene', (197, 201))	('overexpress', 'PosReg', (629, 640))	('hepatic adenoma', 'Phenotype', 'HP:0012028', (605, 620))	('hepatic adenoma', 'Phenotype', 'HP:0012028', (51, 66))	('inflammatory hepatic adenomas', 'Disease', 'MESH:C564190', (95, 124))	('hepatic adenomas', 'Disease', (605, 621))	('serum amyloid A protein', 'Gene', '6288', (314, 337))	('glutamine synthetase', 'Gene', '2752', (641, 661))	('HNF1alpha', 'Gene', (456, 465))	('hepatic adenomas', 'Disease', 'MESH:C564190', (365, 381))	('inflammation', 'Disease', (258, 270))	('hepatic adenomatosis', 'Phenotype', 'HP:0012028', (556, 576))	('associated', 'Reg', (490, 500))	('diabetes', 'Disease', (530, 538))	('HNF1alpha', 'Gene', (343, 352))	('HNF1alpha', 'Gene', '6927', (456, 465))	('hepatic adenomas', 'Phenotype', 'HP:0012028', (605, 621))	('hepatic adenomas', 'Disease', 'MESH:C564190', (108, 124))	('hepatic adenomatosis', 'Disease', (556, 576))	('hepatic adenomas', 'Disease', (365, 381))	('hepatic adenoma', 'Phenotype', 'HP:0012028', (556, 571))	('HNF1alpha', 'Gene', '6927', (343, 352))	('serum amyloid A protein', 'Gene', (314, 337))	('inflammatory hepatic adenomas', 'Disease', (95, 124))	('beta-catenin', 'Gene', (582, 594))	('beta-catenin', 'Gene', (711, 723))	('C-reactive protein', 'Gene', (291, 309))	('maturity-onset diabetes of the young', 'Phenotype', 'HP:0004904', (515, 551))	('beta-catenin', 'Gene', '1499', (711, 723))	('hepatic adenomas', 'Phenotype', 'HP:0012028', (365, 381))	('hepatic adenomas', 'Disease', 'MESH:C564190', (51, 67))	('beta-catenin', 'Gene', '1499', (582, 594))	('hepatic adenomatosis', 'Disease', 'MESH:D056486', (556, 576))	('hepatic adenoma', 'Phenotype', 'HP:0012028', (365, 380))
192804	24055987	Similarly, inflammatory hepatic adenomas may carry beta-catenin mutations and are hence at risk for malignant transformation.	('hepatic adenomas', 'Phenotype', 'HP:0012028', (24, 40))	('inflammatory hepatic adenomas', 'Disease', 'MESH:C564190', (11, 40))	('beta-catenin', 'Gene', '1499', (51, 63))	('carry', 'Reg', (45, 50))	('hepatic adenoma', 'Phenotype', 'HP:0012028', (24, 39))	('inflammatory hepatic adenomas', 'Disease', (11, 40))	('mutations', 'Var', (64, 73))	('beta-catenin', 'Gene', (51, 63))
192854	24055987	HCCs are thought to arise as a consequence of premature hepatocyte senescence caused by repeated cycles of cell injury, regeneration and repair, occurring in an inflammatory environment that leads to genetic and epigenetic aberrations.	('hepatocyte senescence', 'MPA', (56, 77))	('HCCs', 'Gene', (0, 4))	('epigenetic aberrations', 'Var', (212, 234))	('HCCs', 'Gene', '3052', (0, 4))	('leads', 'Reg', (191, 196))	('men', 'Species', '9606', (181, 184))
192855	24055987	HCCs show significant molecular heterogeneity; a substantial percentage of HCCs have mutations in the p53 and CTNNB1 genes, as well as in genes regulating chromatin remodeling.	('HCCs', 'Gene', (75, 79))	('p53', 'Gene', '7157', (102, 105))	('CTNNB1', 'Gene', '1499', (110, 116))	('HCCs', 'Gene', (0, 4))	('HCCs', 'Gene', '3052', (75, 79))	('mutations', 'Var', (85, 94))	('HCCs', 'Gene', '3052', (0, 4))	('p53', 'Gene', (102, 105))	('CTNNB1', 'Gene', (110, 116))
192869	24055987	Hyperintensity on DWI has been proposed as a new imaging criterion for HCC.	('HCC', 'Gene', '619501', (71, 74))	('Hyperintensity', 'Var', (0, 14))	('HCC', 'Gene', (71, 74))
192893	24055987	When cholangiocarcinomas develop in bile duct strictures, the demonstration of chromosomal polysomy in cytologic specimens using fluorescence in situ hybridization has proven more sensitive than cytology, while maintaining high specificity.	('cholangiocarcinomas develop in bile duct strictures', 'Phenotype', 'HP:0030153', (5, 56))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (5, 24))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (5, 23))	('men', 'Species', '9606', (118, 121))	('cholangiocarcinomas', 'Disease', (5, 24))	('bile', 'Disease', (36, 40))	('chromosomal polysomy', 'Var', (79, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
192894	24055987	Molecular analyses of cholangiocarcinomas show mutations in the KRAS, p53, IDH1/2, BRAF, EGFR, MET, and PIK3CA genes.	('PIK3CA', 'Gene', '5290', (104, 110))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (22, 41))	('MET', 'Gene', (95, 98))	('mutations', 'Var', (47, 56))	('cholangiocarcinomas', 'Disease', (22, 41))	('IDH1/2', 'Gene', '3417;3418', (75, 81))	('KRAS', 'Gene', '3845', (64, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('EGFR', 'Gene', (89, 93))	('p53', 'Gene', '7157', (70, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('IDH1/2', 'Gene', (75, 81))	('KRAS', 'Gene', (64, 68))	('PIK3CA', 'Gene', (104, 110))	('BRAF', 'Gene', '673', (83, 87))	('BRAF', 'Gene', (83, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (22, 40))	('p53', 'Gene', (70, 73))	('EGFR', 'Gene', '1956', (89, 93))
192912	24055987	Metastases have variable imaging features, but are typically hypoechoic on ultrasound, hypodense on CT and hypointense on MRI during the portal venous phase, compared to the surrounding liver parenchyma.	('hypodense', 'MPA', (87, 96))	('Metastases', 'Disease', (0, 10))	('hypointense', 'Var', (107, 118))	('liver parenchyma', 'Disease', (186, 202))	('Metastases', 'Disease', 'MESH:D009362', (0, 10))	('liver parenchyma', 'Disease', 'MESH:D010195', (186, 202))
192923	18636547	These effects are inhibited by the cPLA2alpha siRNA and inhibitors as well as by siRNA knockdown of PPARdelta.	('PPARdelta', 'Gene', '5467', (100, 109))	('PPARdelta', 'Gene', (100, 109))	('inhibited', 'NegReg', (18, 27))	('knockdown', 'Var', (87, 96))
192924	18636547	Overexpression of PPARdelta or treatment with the selective PPARdelta ligand, GW501516, also increased beta-catenin binding to TCF/LEF response element and increased its reporter activity.	('GW501516', 'Chemical', 'MESH:C425931', (78, 86))	('binding', 'Interaction', (116, 123))	('reporter activity', 'MPA', (170, 187))	('PPARdelta', 'Gene', (18, 27))	('increased', 'PosReg', (93, 102))	('beta-catenin', 'Gene', (103, 115))	('PPARdelta', 'Gene', '5467', (60, 69))	('increased', 'PosReg', (156, 165))	('TCF/LEF', 'Gene', '3172', (127, 134))	('beta-catenin', 'Gene', '1499', (103, 115))	('TCF/LEF', 'Gene', (127, 134))	('PPARdelta', 'Gene', '5467', (18, 27))	('GW501516', 'Var', (78, 86))	('PPARdelta', 'Gene', (60, 69))
192925	18636547	Addition of AA and GW501516 to nuclear extracts induced a comparable degree of beta-catenin binding to TCF/LEF response element.	('binding', 'Interaction', (92, 99))	('beta-catenin', 'Gene', '1499', (79, 91))	('GW501516', 'Var', (19, 27))	('GW501516', 'Chemical', 'MESH:C425931', (19, 27))	('TCF/LEF', 'Gene', '3172', (103, 110))	('beta-catenin', 'Gene', (79, 91))	('TCF/LEF', 'Gene', (103, 110))
192927	18636547	Thus the close proximity between cPLA2alpha and PPARdelta provides a unique advantage for their efficient functional coupling in the nucleus, where AA produced by cPLA2alpha comes immediately available for PPARdelta binding and subsequent beta-catenin activation.	('binding', 'Interaction', (216, 223))	('functional coupling', 'MPA', (106, 125))	('PPARdelta', 'Gene', (48, 57))	('activation', 'PosReg', (252, 262))	('PPARdelta', 'Gene', (206, 215))	('PPARdelta', 'Gene', '5467', (206, 215))	('PPARdelta', 'Gene', '5467', (48, 57))	('beta-catenin', 'Gene', (239, 251))	('beta-catenin', 'Gene', '1499', (239, 251))	('cPLA2alpha', 'Var', (163, 173))
192928	18636547	These results depict a novel interaction linking cPLA2alpha, PPARdelta and Wnt/beta-catenin signaling pathways and provide insight for further understanding the roles of these key molecules in human cells and diseases.	('interaction', 'Interaction', (29, 40))	('PPARdelta', 'Gene', '5467', (61, 70))	('beta-catenin', 'Gene', '1499', (79, 91))	('cPLA2alpha', 'Var', (49, 59))	('PPARdelta', 'Gene', (61, 70))	('human', 'Species', '9606', (193, 198))	('beta-catenin', 'Gene', (79, 91))
192932	18636547	The free AA cleaved by cPLA2alpha is subsequently converted to prostaglandins (PGs) and leukotrienes (LTs), whereas the lysophospholipid is converted to platelet-activating factor (PAF), lysophosphatidic acid (LPA), and sphingosine-1-phosphate (S1P).	('leukotrienes', 'MPA', (88, 100))	('cPLA2alpha', 'Var', (23, 33))	('leukotrienes', 'Chemical', 'MESH:D015289', (88, 100))	('PGs', 'Chemical', 'MESH:D011453', (79, 82))	('prostaglandins', 'Chemical', 'MESH:D011453', (63, 77))	('LTs', 'Chemical', 'MESH:D015289', (102, 105))	('lysophospholipid', 'Chemical', 'MESH:D008246', (120, 136))	('S1P', 'Chemical', 'MESH:C060506', (245, 248))	('sphingosine-1-phosphate', 'Chemical', 'MESH:C060506', (220, 243))	('lysophosphatidic acid', 'Chemical', 'MESH:C032881', (187, 208))	('converted', 'MPA', (50, 59))	('PAF', 'Chemical', 'MESH:D010972', (181, 184))	('LPA', 'Chemical', 'MESH:C032881', (210, 213))
192937	18636547	Recent studies from our laboratory show that the cPLA2alpha-controlled arachidonic acid metabolism in cell nucleus can activate the PPARdelta, which belongs to one of three subtypes of the PPAR nuclear receptor family.	('PPAR', 'Gene', (132, 136))	('arachidonic acid metabolism in', 'MPA', (71, 101))	('PPAR', 'Gene', '5465', (189, 193))	('arachidonic acid', 'Chemical', 'MESH:D016718', (71, 87))	('cPLA2alpha-controlled', 'Var', (49, 70))	('PPARdelta', 'Gene', (132, 141))	('PPAR', 'Gene', '5465', (132, 136))	('PPARdelta', 'Gene', '5467', (132, 141))	('activate', 'PosReg', (119, 127))	('PPAR', 'Gene', (189, 193))
192956	18636547	The PPARdelta agonist GW501516 was purchased from Cayman Chemical (Ann Arbor, MI).	('PPARdelta', 'Gene', '5467', (4, 13))	('PPARdelta', 'Gene', (4, 13))	('GW501516', 'Var', (22, 30))	('GW501516', 'Chemical', 'MESH:C425931', (22, 30))
192968	18636547	After transfection, the cells were treated with specific reagent such as PPARdelta agonist GW501516 in serum-free medium for 24 hours.	('GW501516', 'Chemical', 'MESH:C425931', (91, 99))	('PPARdelta', 'Gene', '5467', (73, 82))	('GW501516', 'Var', (91, 99))	('PPARdelta', 'Gene', (73, 82))
193000	18636547	Consistent with this, overexpression of cPLA2alpha enhanced the binding of beta-catenin to the TCF/LEF response element, as determined by the combined immunoprecipitation and immunoblotting assay (Figure 2a).	('binding', 'Interaction', (64, 71))	('beta-catenin', 'Gene', '1499', (75, 87))	('overexpression', 'PosReg', (22, 36))	('cPLA2alpha', 'Var', (40, 50))	('TCF/LEF', 'Gene', '3172', (95, 102))	('TCF/LEF', 'Gene', (95, 102))	('enhanced', 'PosReg', (51, 59))	('beta-catenin', 'Gene', (75, 87))
193002	18636547	The involvement of cPLA2alpha in beta-catenin activation is further confirmed by the observations that inhibition of cPLA2alpha by specific siRNA or chemical inhibitors (pyrolidine and AACOCF3) significantly reduced the TCF/LEF reporter activity (Figure 3A and B).	('cPLA2alpha', 'Gene', (117, 127))	('pyrolidine', 'Chemical', '-', (170, 180))	('AACOCF3', 'Chemical', 'MESH:C081565', (185, 192))	('reduced', 'NegReg', (208, 215))	('inhibition', 'Var', (103, 113))	('beta-catenin', 'Gene', (33, 45))	('TCF/LEF', 'Gene', '3172', (220, 227))	('TCF/LEF', 'Gene', (220, 227))	('beta-catenin', 'Gene', '1499', (33, 45))
193003	18636547	Moreover, inactivation of cPLA2alpha by site directed mutagenesis (Ser-228   Alanine) abolished TCF/LEF transcription activity (Figure 3C), suggesting that cPLA2alpha activity is likely required for beta-catenin activation.	('beta-catenin', 'Gene', '1499', (199, 211))	('Ser-228   Alanine', 'Mutation', 'p.S228A', (67, 84))	('activity', 'MPA', (118, 126))	('inactivation', 'Var', (10, 22))	('abolished', 'NegReg', (86, 95))	('TCF/LEF', 'Gene', '3172', (96, 103))	('TCF/LEF', 'Gene', (96, 103))	('beta-catenin', 'Gene', (199, 211))
193008	18636547	We have shown that overexpression of cPLA2alpha or activation of cPLA2alpha by the calcium ionophore, A23187,significantly increases PPARdelta transcription activity and enhances the binding of PPARdelta to its DNA response element, which was blocked by the specific cPLA2 inhibitors, AACOCF3 and pyrrolidine derivative.	('cPLA2', 'Gene', (37, 42))	('enhances', 'PosReg', (170, 178))	('cPLA2', 'Gene', '5321', (65, 70))	('PPARdelta', 'Gene', (133, 142))	('calcium', 'Chemical', 'MESH:D002118', (83, 90))	('overexpression', 'PosReg', (19, 33))	('increases', 'PosReg', (123, 132))	('PPARdelta', 'Gene', '5467', (133, 142))	('cPLA2', 'Gene', (65, 70))	('A23187', 'Chemical', 'MESH:D000001', (102, 108))	('binding', 'Interaction', (183, 190))	('AACOCF3', 'Chemical', 'MESH:C081565', (285, 292))	('pyrrolidine', 'Chemical', 'MESH:C032519', (297, 308))	('PPARdelta', 'Gene', (194, 203))	('cPLA2', 'Gene', '5321', (37, 42))	('A23187', 'Var', (102, 108))	('PPARdelta', 'Gene', '5467', (194, 203))	('cPLA2', 'Gene', '5321', (267, 272))	('cPLA2', 'Gene', (267, 272))
193011	18636547	As shown in Figure 2b, overexpression of cPLA2alpha enhanced the association of PPARdelta with the beta-catenin-TCF/LEF complex, whereas it did not alter PPARdelta protein level.	('PPARdelta', 'Gene', (154, 163))	('overexpression', 'PosReg', (23, 37))	('PPARdelta', 'Gene', '5467', (154, 163))	('TCF/LEF', 'Gene', '3172', (112, 119))	('TCF/LEF', 'Gene', (112, 119))	('association', 'Interaction', (65, 76))	('enhanced', 'PosReg', (52, 60))	('PPARdelta', 'Gene', (80, 89))	('cPLA2alpha', 'Var', (41, 51))	('beta-catenin', 'Gene', (99, 111))	('PPARdelta', 'Gene', '5467', (80, 89))	('beta-catenin', 'Gene', '1499', (99, 111))
193013	18636547	These results suggest a potential role for PPARdelta in cPLA2alpha-mediated beta-catenin activation.	('PPARdelta', 'Gene', '5467', (43, 52))	('cPLA2alpha-mediated', 'Var', (56, 75))	('beta-catenin', 'Gene', (76, 88))	('activation', 'PosReg', (89, 99))	('beta-catenin', 'Gene', '1499', (76, 88))	('PPARdelta', 'Gene', (43, 52))
193018	18636547	In addition, treatment with the selective PPARdelta ligand, GW501516, also increased the TCF/LEF luciferase reporter activity (Figure 5C).	('PPARdelta', 'Gene', (42, 51))	('TCF/LEF', 'Gene', '3172', (89, 96))	('TCF/LEF', 'Gene', (89, 96))	('PPARdelta', 'Gene', '5467', (42, 51))	('GW501516', 'Var', (60, 68))	('increased', 'PosReg', (75, 84))	('GW501516', 'Chemical', 'MESH:C425931', (60, 68))
193019	18636547	Moreover, RNAi knockdown of PPARdelta.	('PPARdelta', 'Gene', '5467', (28, 37))	('PPARdelta', 'Gene', (28, 37))	('knockdown', 'Var', (15, 24))
193021	18636547	The involvement of cPLA2alpha and PPARdelta in beta-catenin activation is further supported by the observation that overexpression of cPLA2alpha and PPARdelta induced the expression of c-myc, a beta-catenin downstream gene (Figure 1 and Figure 5A).	('PPARdelta', 'Gene', (34, 43))	('expression', 'MPA', (171, 181))	('beta-catenin', 'Gene', '1499', (47, 59))	('c-myc', 'Gene', '4609', (185, 190))	('cPLA2alpha', 'Var', (134, 144))	('c-myc', 'Gene', (185, 190))	('PPARdelta', 'Gene', '5467', (34, 43))	('beta-catenin', 'Gene', (194, 206))	('induced', 'PosReg', (159, 166))	('PPARdelta', 'Gene', (149, 158))	('beta-catenin', 'Gene', (47, 59))	('beta-catenin', 'Gene', '1499', (194, 206))	('PPARdelta', 'Gene', '5467', (149, 158))
193022	18636547	After the role of PPARdelta in beta-catenin activation is documented, we performed further experiments to determine whether the PPARdelta ligand, GW501516, and AA might be able to alter the binding of beta-catenin to TCF/LEF response element.	('beta-catenin', 'Gene', (31, 43))	('PPARdelta', 'Gene', (18, 27))	('beta-catenin', 'Gene', (201, 213))	('beta-catenin', 'Gene', '1499', (31, 43))	('GW501516', 'Var', (146, 154))	('PPARdelta', 'Gene', '5467', (18, 27))	('TCF/LEF', 'Gene', '3172', (217, 224))	('PPARdelta', 'Gene', (128, 137))	('TCF/LEF', 'Gene', (217, 224))	('GW501516', 'Chemical', 'MESH:C425931', (146, 154))	('PPARdelta', 'Gene', '5467', (128, 137))	('beta-catenin', 'Gene', '1499', (201, 213))	('alter', 'Reg', (180, 185))	('binding', 'Interaction', (190, 197))
193023	18636547	As shown in Figure 7, both GW501516 and AA induced the binding of beta-catenin to TCF/LEF response element when added to either intact cells or isolated nuclear extracts.	('GW501516', 'Chemical', 'MESH:C425931', (27, 35))	('beta-catenin', 'Gene', (66, 78))	('beta-catenin', 'Gene', '1499', (66, 78))	('TCF/LEF', 'Gene', '3172', (82, 89))	('TCF/LEF', 'Gene', (82, 89))	('binding', 'Interaction', (55, 62))	('GW501516', 'Var', (27, 35))
193032	18636547	Phosphorylation of cPLA2alpha is not required for its association with PPARdelta, given that inhibition of the p42/44 and p38 MAP kinases (key enzymes for cPLA2alpha phosphorylation) by PD98059 and SB203580 did not alter the formation of cPLA2alpha-PPARdelta binding complex (Figure 8A), despite that these inhibitors prevent cytokine/growth factor-induced cPLA2alpha phosphorylation in these cells.	('SB203580', 'Chemical', 'MESH:C093642', (198, 206))	('p42', 'Gene', (111, 114))	('PPARdelta', 'Gene', '5467', (71, 80))	('p38', 'Gene', '1432', (122, 125))	('p42', 'Gene', '23552', (111, 114))	('PPARdelta', 'Gene', (249, 258))	('PPARdelta', 'Gene', (71, 80))	('p38', 'Gene', (122, 125))	('PPARdelta', 'Gene', '5467', (249, 258))	('PD98059', 'Var', (186, 193))	('SB203580', 'Var', (198, 206))	('PD98059', 'Chemical', 'MESH:C093973', (186, 193))
193033	18636547	Similarly, cPLA2alpha enzyme activity is also not required for cPLA2alpha and PPARdelta association, since their binding was not altered by site-directed mutation of cPLA2alpha (S228A mutant) (Figure 8B).	('S228A', 'Mutation', 'p.S228A', (178, 183))	('S228A', 'Var', (178, 183))	('PPARdelta', 'Gene', (78, 87))	('binding', 'Interaction', (113, 120))	('PPARdelta', 'Gene', '5467', (78, 87))
193034	18636547	Therefore, the association between cPLA2alpha and PPARdelta Cis likely mediated through their protein interactions.	('interactions', 'Interaction', (102, 114))	('mediated', 'Reg', (71, 79))	('protein', 'Protein', (94, 101))	('PPARdelta', 'Gene', (50, 59))	('cPLA2alpha', 'Var', (35, 45))	('PPARdelta', 'Gene', '5467', (50, 59))
193039	18636547	In the current study, we provide further evidence for cPLA2alpha-mediated PPARdelta activation in the regulation of beta-catenin signaling pathway.	('PPARdelta', 'Gene', '5467', (74, 83))	('activation', 'PosReg', (84, 94))	('cPLA2alpha-mediated', 'Var', (54, 73))	('PPARdelta', 'Gene', (74, 83))	('regulation', 'MPA', (102, 112))	('beta-catenin', 'Gene', (116, 128))	('beta-catenin', 'Gene', '1499', (116, 128))
193041	18636547	This conclusion is based on the following observations: (1) overexpression of cPLA2alpha increases TCF/LEF reporter activity; (2) overexpression of cPLA2alpha enhanced the binding of beta-catenin to the TCF/LEF response element; (3) inhibition of cPLA2alpha by chemical inhibitors, siRNA and site-direct mutagenesis reduced the TCF/LEF transcription activity; and (4) AA induced the binding of beta-catenin to TCF/LEF response element.	('TCF/LEF', 'Gene', '3172', (410, 417))	('binding', 'Interaction', (172, 179))	('reduced', 'NegReg', (316, 323))	('TCF/LEF', 'Gene', (410, 417))	('beta-catenin', 'Gene', (183, 195))	('TCF/LEF', 'Gene', (99, 106))	('TCF/LEF', 'Gene', (328, 335))	('beta-catenin', 'Gene', '1499', (394, 406))	('enhanced', 'PosReg', (159, 167))	('TCF/LEF', 'Gene', '3172', (99, 106))	('TCF/LEF', 'Gene', '3172', (328, 335))	('binding', 'Interaction', (383, 390))	('beta-catenin', 'Gene', '1499', (183, 195))	('mutagenesis', 'Var', (304, 315))	('TCF/LEF', 'Gene', (203, 210))	('TCF/LEF', 'Gene', '3172', (203, 210))	('increases', 'PosReg', (89, 98))	('beta-catenin', 'Gene', (394, 406))
193045	18636547	This conclusion is based on (1) overexpression of PPARdelta enhanced the formation of beta-catenin-PPARdelta binding complex; (2) overexpression of PPARdelta increased the association of beta-catenin with TCF/LEF response element; (3) overexpression of PPARdelta increased the TCF/LEF reporter activity; (4) activation of PPARdelta by its ligand, GW501516, increased the TCF/LEF luciferase reporter activity; (5) RNAi knockdown of PPARdelta decreased beta-catenin binding to TCF/LEF response element and reduced TCF/LEF reporter activity.	('PPARdelta', 'Gene', '5467', (431, 440))	('TCF/LEF', 'Gene', '3172', (512, 519))	('knockdown', 'Var', (418, 427))	('PPARdelta', 'Gene', (253, 262))	('PPARdelta', 'Gene', '5467', (253, 262))	('TCF/LEF', 'Gene', (512, 519))	('association', 'Interaction', (172, 183))	('binding', 'Interaction', (464, 471))	('PPARdelta', 'Gene', (148, 157))	('beta-catenin', 'Gene', (451, 463))	('PPARdelta', 'Gene', '5467', (148, 157))	('TCF/LEF', 'Gene', '3172', (475, 482))	('beta-catenin', 'Gene', '1499', (451, 463))	('PPARdelta', 'Gene', (322, 331))	('TCF/LEF', 'Gene', '3172', (205, 212))	('PPARdelta', 'Gene', '5467', (322, 331))	('GW501516', 'Var', (347, 355))	('beta-catenin', 'Gene', (86, 98))	('beta-catenin', 'Gene', (187, 199))	('TCF/LEF', 'Gene', '3172', (277, 284))	('beta-catenin', 'Gene', '1499', (86, 98))	('beta-catenin', 'Gene', '1499', (187, 199))	('GW501516', 'Chemical', 'MESH:C425931', (347, 355))	('TCF/LEF', 'Gene', '3172', (371, 378))	('PPARdelta', 'Gene', (50, 59))	('TCF/LEF', 'Gene', (475, 482))	('PPARdelta', 'Gene', '5467', (50, 59))	('PPARdelta', 'Gene', (99, 108))	('TCF/LEF', 'Gene', (205, 212))	('PPARdelta', 'Gene', '5467', (99, 108))	('TCF/LEF', 'Gene', (371, 378))	('TCF/LEF', 'Gene', (277, 284))	('reduced', 'NegReg', (504, 511))	('decreased', 'NegReg', (441, 450))	('PPARdelta', 'Gene', (431, 440))
193048	18636547	Since cPLA2alpha lacks a nuclear localization signal, it is likely that association with PPARdelta may direct the import of cPLA2alpha into the nucleus (this process does not appear to require cPLA2alpha phosphorylation or enzyme activity).	('PPARdelta', 'Gene', '5467', (89, 98))	('association', 'Interaction', (72, 83))	('cPLA2alpha', 'Var', (124, 134))	('direct', 'PosReg', (103, 109))	('import', 'MPA', (114, 120))	('PPARdelta', 'Gene', (89, 98))
193053	18636547	Instead, our data indicate that the cPLA2alpha-dervied AA represents a novel mechanism for activation of beta-catenin and the effect is mediated via PPARdelta and beta-catenin binding and their association with the TCF/LEF response element.	('TCF/LEF', 'Gene', '3172', (215, 222))	('beta-catenin', 'Gene', (163, 175))	('TCF/LEF', 'Gene', (215, 222))	('activation', 'PosReg', (91, 101))	('beta-catenin', 'Gene', (105, 117))	('PPARdelta', 'Gene', (149, 158))	('beta-catenin', 'Gene', '1499', (163, 175))	('binding', 'Interaction', (176, 183))	('beta-catenin', 'Gene', '1499', (105, 117))	('PPARdelta', 'Gene', '5467', (149, 158))	('cPLA2alpha-dervied', 'Var', (36, 54))	('association', 'Interaction', (194, 205))
193054	18636547	Our findings in this study suggest that PPARdelta is a key molecule that mediates beta-catenin activation by cPLA2alpha.	('PPARdelta', 'Gene', '5467', (40, 49))	('cPLA2alpha', 'Var', (109, 119))	('activation', 'PosReg', (95, 105))	('beta-catenin', 'Gene', (82, 94))	('PPARdelta', 'Gene', (40, 49))	('beta-catenin', 'Gene', '1499', (82, 94))
193056	18636547	We show that activation of PPARdelta by cPLA2alpha results in the formation of PPARdelta-beta-catenin complex, thus leading to beta-catenin activation.	('PPARdelta', 'Gene', (79, 88))	('cPLA2alpha', 'Var', (40, 50))	('PPARdelta', 'Gene', (27, 36))	('beta-catenin', 'Gene', '1499', (89, 101))	('PPARdelta', 'Gene', '5467', (79, 88))	('activation', 'PosReg', (140, 150))	('PPARdelta', 'Gene', '5467', (27, 36))	('beta-catenin', 'Gene', (127, 139))	('beta-catenin', 'Gene', (89, 101))	('beta-catenin', 'Gene', '1499', (127, 139))
193058	18636547	The latter is supported by the observation that addition of AA, but not PGE2, into nuclear extracts or recombinant PPARdelta protein enhanced the ability of PPARdelta binding to its DNA response element and that the COX-2 inhibitor, indomethacin, had no apparent influence on A23187-induced PPARdelta DNA binding.	('PPARdelta', 'Gene', '5467', (157, 166))	('PPARdelta', 'Gene', '5467', (291, 300))	('DNA', 'Interaction', (182, 185))	('A23187', 'Chemical', 'MESH:D000001', (276, 282))	('indomethacin', 'Chemical', 'MESH:D007213', (233, 245))	('COX-2', 'Gene', '4513', (216, 221))	('PPARdelta', 'Gene', (115, 124))	('A23187-induced', 'Var', (276, 290))	('PGE2', 'Chemical', 'MESH:D015232', (72, 76))	('PPARdelta', 'Gene', '5467', (115, 124))	('COX-2', 'Gene', (216, 221))	('PPARdelta', 'Gene', (291, 300))	('PPARdelta', 'Gene', (157, 166))	('enhanced', 'PosReg', (133, 141))	('binding', 'Interaction', (167, 174))
193061	18636547	In summary, this study depicts a novel connection linking cPLA2alpha, PPARdelta nd Wnt/beta-catenin signaling pathways in human cholangiocarcinoma cells.	('human', 'Species', '9606', (122, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (128, 146))	('beta-catenin', 'Gene', (87, 99))	('PPARdelta', 'Gene', (70, 79))	('cholangiocarcinoma', 'Disease', (128, 146))	('beta-catenin', 'Gene', '1499', (87, 99))	('cPLA2alpha', 'Var', (58, 68))	('PPARdelta', 'Gene', '5467', (70, 79))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (128, 146))
193062	18636547	Given the documented involvement of these molecules in bile duct inflammation and cancer, it is conceivable that activation of beta-catenin by cPLA2alpha and PPARdelta may represent an important mechanism by which inflammatory process drives carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('PPARdelta', 'Gene', (158, 167))	('carcinogenesis', 'Disease', (242, 256))	('PPARdelta', 'Gene', '5467', (158, 167))	('bile duct inflammation', 'Disease', (55, 77))	('bile duct inflammation', 'Phenotype', 'HP:0030151', (55, 77))	('cPLA2alpha', 'Var', (143, 153))	('cancer', 'Disease', (82, 88))	('activation', 'PosReg', (113, 123))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('bile duct inflammation', 'Disease', 'MESH:D007249', (55, 77))	('carcinogenesis', 'Disease', 'MESH:D063646', (242, 256))	('beta-catenin', 'Gene', (127, 139))	('beta-catenin', 'Gene', '1499', (127, 139))